CN111662232B

CN111662232B - Small molecule compound with 2H-indazole structure and synthesis and application thereof

Info

Publication number: CN111662232B
Application number: CN202010135402.8A
Authority: CN
Inventors: 赵玉军; 王欢; 陈德恒; 周飞龙; 严子琴; 吕细林
Original assignee: Shanghai Institute of Materia Medica of CAS
Current assignee: Shanghai Institute of Materia Medica of CAS
Priority date: 2019-03-06
Filing date: 2020-03-02
Publication date: 2022-08-02
Anticipated expiration: 2040-03-02
Also published as: CN111662232A

Abstract

The invention relates to a small molecule compound with a 2H-indazole structure, and synthesis and application thereof. Specifically, the invention discloses a compound shown in formula (I), an enantiomer, a diastereoisomer, a racemate or a mixture thereof, or a pharmaceutically acceptable salt, a hydrate or a solvate thereof, a preparation method thereof, and application thereof in preparing a small molecule inhibitor of kRAS, or medicines for preventing and/or treating diseases related to the kRAS, especially tumor diseasesWherein the substituents are as defined in the description and claims.

Description

Small molecule compound with 2H-indazole structure and synthesis and application thereof

Technical Field

The invention belongs to the field of medicines, relates to a small molecule inhibitor of kRAS, and particularly relates to a small molecule compound with a 2H-indazole structure, a preparation method thereof and application thereof in preparing a small molecule inhibitor of kRAS or medicines for preventing and/or treating diseases related to the kRAS, especially tumor diseases.

Background

RAS proteins are a member of the GTP (guanosine triphosphate) hydrolase family and have three subtypes, k-RAS, N-RAS, and H-RAS. In cells, RAS has a function of conducting biological signals from cell membrane receptors downstream, and plays an important role in regulating cell growth, proliferation and stress. Mutations in the RAS are common in all human tumor cells, with a proportion of up to 20-30%. Among these, kRAS mutation is the most prominent of the three subtypes, with a proportion of up to 86%. In the tumor tissues of patients with pancreatic cancer, intestinal cancer, multiple myeloma and lung cancer, the mutation of the kRAS is quite common, the mutation rate is 97.7%, 44.7%, 22.8% and 30.9%, and the abnormal increase of the activity of the kRAS mutant is closely related to the generation and development of tumors. Inhibition of aberrant enhancement of kRAS mutant activity is currently considered as a potential therapeutic strategy for the treatment of cancer associated with kRAS mutations.

The kRAS mutant shows amino acid residue mutation of the amino acid sequence, wherein the amino acid residue mutation which is closely related to tumor occurrence and development and is relatively common is of various subtypes such as G12C, G12D, G12A, G12S, G12R, G12F and the like. In the non-small cell lung cancer tumor cells, the mutation rate of G12C is 45-50%, and in the pancreatic cancer tumor cells, the mutation rate of G12C is 1-4%. Since the cysteine residue of G12C can be covalently bound with electrophilic chemical substances, the literature reports that some small-molecule compounds can act with the kRAS G12C mutant, induce the kRAS mutant to degrade, promote the tumor cell death and have the medicinal potential for treating related cancers. The research on drug development in this field is receiving a certain degree of attention.

Disclosure of Invention

The invention aims to provide a small molecule inhibitor of the kRAS with a novel structure.

The invention provides a compound shown in a formula (I), an enantiomer, a diastereoisomer, a racemate or a mixture thereof, or a pharmaceutically acceptable salt, a hydrate and a solvate thereof,

wherein M is ₁ And M ₂ One of them is Ar and the other is R ₃ Wherein Ar is C6-C10 aryl or 4-12 membered heteroaryl;

R ₃ 、R ₄ 、R ₅ Each independently hydrogen, deuterium, halogen, C1-C6 alkoxy, C1-C6 alkyl, cyano, hydroxyl;

R ₁ is hydrogen, halogen, cyano, (C1-C6) alkyl, (C3-C8) cycloalkyl, - (C1-C6 alkylene) - (C3-C8 cycloalkyl), - (NH- (C6-C10 aryl), - (C1-C6 alkylene) (C)6-C10 aryl), -NH- (C1-C6 alkyl), -NH- (C3-C8 cycloalkyl), -NH- (C1-C6 alkylene) - (C3-C8 cycloalkyl), -NH- (3-to 10-membered saturated heterocyclic ring and partially saturated heterocyclic ring containing 1 to 2 nitrogen atoms), -NH- (C1-C6 alkylene) - (3-to 10-membered saturated heterocyclic ring and partially saturated heterocyclic ring containing 1 to 2 nitrogen atoms), 3-to 10-membered saturated heterocyclic ring and partially saturated heterocyclic ring containing 1 to 2 nitrogen atoms, or 5-to 12-membered heteroaryl containing at least one nitrogen;

R ₂ is hydrogen, (C1-C6) alkyl, (C3-C8) cycloalkyl, - (C1-C6 alkylene) - (C3-C8 cycloalkyl), (C6-C10 aryl), (C1-C6 alkylene) (C6-C10 aryl), - (C1-C6 alkylene) - (3-10 membered saturated heterocyclic and partially saturated heterocyclic rings containing 1-2 nitrogen atoms), 3-10 membered saturated heterocyclic and partially saturated heterocyclic rings containing 1-2 nitrogen atoms, 5-12 membered heteroaryl containing at least one nitrogen, or- (C1-C6 alkylene) - (5-12 membered heteroaryl containing at least one nitrogen);

wherein each of the foregoing groups, as valency permits, is optionally substituted with 1 to 3 of the following groups: -NH-Z, -NZ- (C1-C6 alkyl), -O-Z, - (C1-C6 alkylene) -NH-Z, - (C1-C6 alkylene) -NZ- (C1-C6 alkyl), -C1-C6 alkylene) -O-Z, -halogen, C1-C6 haloalkyl, cyano, hydroxy, amino, (C1-C6) alkoxy, (C1-C6) alkyl, N- (C1-C6 alkyl) amino, N-di (C1-C6 alkyl) amino, N- (C1-C6) alkylaminocarbonyl, N-di (C1-C6) alkylaminocarbonyl, N- (C1-C6) alkylaminocarbonylamino, N-di (C1-C6) alkylaminocarbonylamino, Aminocarbonylamino, guanidino, (C1-C6) alkylguanidino, (C1-C8) nitrogen-containing heterocyclylaminocarbonyl, (C1-C6 alkoxy) carbonylamino, (C1-C6) alkylsulfide, (C1-C6) alkylsulfonyl, sulfonylamino, aminosulfonyl, carboxyl, phosphonic acid, nitrogen-containing 5-to 12-membered heteroaromatic rings; wherein one nitrogen atom of the saturated heterocyclic ring and partially saturated heterocyclic ring containing 1 to 2 nitrogen atoms may be substituted by Z, or by (C1-C6) alkyl, (C1-C6) acyl;

Z represents a reactive group that can covalently bind to a cysteine thiol group, including the following groups:

wherein R is ₆ 、R ₇ 、R ₈ Each independent representation represents: hydrogen, deuterium, (C1-C6) alkyl, (C1-C6) haloalkyl, (C1-C6) alkoxy, hydroxy (C1-C6) alkyl, or R ₆ And R ₇ And the carbon atom to which it is attached forms a 3-10 membered alicyclic ring or a 3-10 membered nitrogen-containing heterocyclic ring, or R ₇ And R ₈ And the carbon atoms to which they are attached form a 3-10 membered alicyclic ring or a 3-10 membered nitrogen-containing heterocyclic ring;

wherein R is ₉ 、R ₁₀ Each independently represents: hydrogen, (C1-C6) alkyl, (C1-C6) haloalkyl, (C1-C6) alkoxy, hydroxy (C1-C6) alkyl, or R ₉ And R ₁₀ And the nitrogen atom to which it is attached form a 3-10 membered nitrogen containing heterocyclic ring;

n represents 1, 2 or 3.

The invention provides a compound shown in formula (I), enantiomer, diastereoisomer, racemate or mixture thereof, or pharmaceutically acceptable salt, hydrate and solvate thereof,

R ₃ 、R ₄ 、R ₅ each independently hydrogen, deuterium, halogen, C1-C6 alkoxy, C1-C6 alkyl, cyano, hydroxy;

R ₁ are hydrogen, halogen, cyano, (C1-C6) alkyl, (C2-C6) alkenyl, (C3-C8) cycloalkyl, - (C1-C6 alkylene) - (C3-C8 cycloalkyl), -NH- (C6-C10 aryl), -NH- (C1-C6 alkylene) (C6-C10 aryl), -NH- (C1-C6 alkyl), -NH- (C3-C8 cycloalkyl), -NH- (4-12 membered heteroaryl), -NH- (C1-C6 alkylene) - (4-12 membered heteroaryl), -NH- (C1-C6 alkylene) - (C3-C8 cycloalkyl), -NH- (3-10 membered saturated heterocyclic ring and partially saturated heterocyclic ring containing 1-2 nitrogen atoms), -NH- (C1-C6 alkylene) - (3-to 10-membered saturated heterocyclic ring and partially saturated heterocyclic ring containing 1 to 2 nitrogen atoms), 3-to 10-membered saturated heterocyclic ring and moiety containing 1 to 2 nitrogen atoms A saturated heterocycle, a methylenephenyl group, a C6-C10 aryl group, a methylphenyl group, or a 4-12 membered heteroaryl group containing at least one nitrogen (preferably a 5-12 membered heteroaryl group);

R ₂ is hydrogen, (C1-C6) alkyl, (C3-C8) cycloalkyl, - (C1-C6 alkylene) - (C3-C8 cycloalkyl), (C6-C10 aryl), (C1-C6 alkylene) (C6-C10 aryl), - (C1-C6 alkylene) - (3-to 10-membered saturated and partially saturated heterocyclic rings containing 1 to 2 nitrogen atoms), 3-to 10-membered saturated and partially saturated heterocyclic rings containing 1 to 2 nitrogen atoms, 5-to 12-membered heteroaryl containing at least one nitrogen, C6-C10 aryl, - (C1-C6 alkylene) -NH- (4-to 12-membered heteroaryl) or- (C1-C6 alkylene) - (5-to 12-membered heteroaryl containing at least one nitrogen);

wherein each of the above groups, under valency permitting conditions, is optionally substituted with 1 to 3 of the following groups: -NH-Z, -NZ- (C1-C6 alkyl), -O-Z, - (C1-C6 alkylene) -NH-Z, - (C1-C6 alkylene) -NZ- (C1-C6 alkyl), -C1-C6 alkylene) -O-Z, -halogen, C1-C6 haloalkyl, cyano, hydroxy, amino, (C1-C6) alkoxy, (C1-C6) alkyl, N- (C1-C6 alkyl) amino, N-di (C1-C6 alkyl) amino, N- (C1-C6) alkylaminocarbonyl, N-di (C1-C6) alkylaminocarbonyl, N- (C1-C6) alkylaminocarbonylamino, N-di (C1-C6) alkylaminocarbonylamino, Aminocarbonylamino, aminocarbonyl, guanidino, (C1-C6) alkylguanidino, (C1-C8) nitrogen-containing heterocyclylaminocarbonyl, (C1-C8) nitrogen-containing heterocyclylcarbonyl, (C1-C6 alkoxy) carbonylamino, (C1-C6) alkylsulfide, (C1-C6) alkylsulfone, sulfonylamino, aminosulfonyl, carboxyl, phospho, nitrogen-containing 5-12 membered heteroaromatic ring; wherein one nitrogen atom of the saturated heterocyclic ring and partially saturated heterocyclic ring containing 1 to 2 nitrogen atoms may be substituted by Z, or by (C1-C6) alkyl, (C1-C6) alkylacyl;

n represents 1, 2 or 3.

In another preferred embodiment, M ₁ 、M ₂ 、R ₁ 、R ₂ 、R ₄ 、R ₅ Each independently is a group as shown in compounds numbered 1-247.

In another preferred embodiment, R ₆ 、R ₇ 、R ₈ Each independently represents hydrogen, deuterium, (C1-C6) alkyl, trifluoromethyl, methoxy (C1-C6) alkyl, hydroxy (C1-C6) alkyl, or R ₆ And R ₇ And the carbon atom to which it is attached forms a 3-10 membered alicyclic ring or a 3-10 membered nitrogen-containing heterocyclic ring, or R ₇ And R ₈ And the carbon atoms to which they are attached form a 3-10 membered alicyclic ring or a 3-10 membered nitrogen-containing heterocyclic ring.

In another preferred embodiment, R ₉ 、R ₁₀ Each independently represents: hydrogen, (C1-C6) alkyl, trifluoromethyl, methoxy (C1-C6) alkyl, hydroxy (C1-C6) alkyl, or R ₉ And R ₁₀ And the nitrogen atom to which it is attached form a 3-to 10-membered nitrogen-containing heterocyclic ring.

In another preferred embodiment, R ₁ Is halogen, trifluoromethyl, cyano, hydroxy, 3-10 membered heterocyclyl, NRaRb, hydrogen, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C3-C8 cycloalkyl, C6-C10 aryl or 4-12 membered heteroaryl. In another preferred embodiment, R ₂ Is- (C1-C6 alkylene)- (C1-C6 alkylene) -C (O) -NRaRb, C6-C10 aryl, C3-C8 cycloalkyl, - (C1-C6 alkylene) - (C6-C10 aryl), - (C1-C6 alkylene) - (C3-C8 cycloalkyl), - (C1-C6 alkylene) - (3-10 membered heterocyclic), - (C1-C6 alkylene) - (4-12 membered heteroaryl), C1-C6 alkyl, cyano, 3-10 membered heterocyclic or 4-12 membered heteroaryl. In another preferred embodiment, each Ra, each Rb, when present, is independently selected from the group consisting of: hydrogen, deuterium, C3-C8 cycloalkyl, 3-10 membered heterocyclyl, C6-C10 aryl, 4-12 membered heteroaryl, C1-C6 alkyl, - (C1-C6 alkylene) - (C6-C10 aryl), - (C1-C6 alkylene) - (C3-C8 cycloalkyl), - (C1-C6 alkylene) - (3-10 membered heterocyclyl), or Ra, Rb together with the linking N form a 3-10 membered heterocyclyl. In another preferred embodiment, M ₁ And M ₂ One of them is Ar and the other is R ₃ Wherein Ar is a C6-C10 aryl or a 4-12 membered heteroaryl. In another preferred embodiment, R ₃ 、R ₄ 、R ₅ Each independently hydrogen, deuterium, halogen, C1-C6 alkoxy, C1-C6 alkyl, cyano, hydroxyl. Wherein each of the above 3-to 10-membered heterocyclic group, C3-C8 cycloalkyl, C1-C6 alkyl, C1-C6 alkylene, C6-C10 aryl, and 4-to 12-membered heteroaryl is optionally substituted with 1 to 3 substituents selected from the group consisting of: deuterium, guanidino, C1-C6 alkyl, C3-C8 cycloalkyl, C6-C10 aryl, 4-12 membered heteroaryl, -C (O) - (C2-C6 alkenyl), -C (O) - (C1-C6 alkyl), -C (O) NH ₂ C (O) (3-10 membered heterocyclyl), -OC (O) (C2-C6 alkenyl), -C (O) -NH (C1-C4 alkyl), -C (O) -N (C1-C4 alkyl) (C1-C4 alkyl), -NH-C (O) (C2-C6 alkenyl), -C1-C6 alkylene) -NH-C (O) - (C2-C6 alkenyl), -NH-C (O) - (C2-C6 alkynyl), -NH-SO-SO (3-10 membered heterocyclyl), -OC (O) - (C2-C6 alkenyl), -NH-C (O) - (C2-C6 alkynyl) ₂ - (C2-C6 alkenyl), -N (C1-C6 alkyl) (C1-C6 alkyl), -SO- (C1-C6 alkyl), -SO ₂ - (C1-C6 alkyl), -SO ₂ -N (C1-C4 alkyl) (C1-C4 alkyl), -SO ₂ -NH ₂ 、-SO ₂ -NH (C1-C4 alkyl), C1-C6 alkoxy, halogen, C1-C6 haloalkyl, cyano, hydroxy, carboxy, nitro, amino, -N (C1-C4 alkyl) (C1-C4 alkyl) -C (O) -N (C1-C4 alkyl) (C1-C4 alkyl), phosphoric acid, -NH-C (O) -NH ₂ Wherein, C2-C6 alkenyl, C2-C6 alkynyl are optionally substituted with 1-3 substituents selected from the group consisting of: halogen, trifluoromethyl, cyano, hydroxy, amino, -N (C1-C4 alkyl) (C1-C4 alkyl), 3-10 membered heterocyclyl.

In another preferred embodiment, the heterocyclic group is a saturated or partially saturated heterocyclic group containing 1 or 2 nitrogen atoms.

In another preferred embodiment, the heteroaryl group contains at least one N atom.

In another preferred embodiment, R ₁ Is halogen, trifluoromethyl, cyano, hydroxy, 3-8 membered heterocyclyl, NRaRb, hydrogen, deuterium, C1-C4 alkyl, C2-C4 alkenyl, C3-C8 cycloalkyl, phenyl or 4-8 membered heteroaryl;

wherein each Ra, each Rb, when present, is independently selected from the group consisting of: hydrogen, deuterium, C3-C8 cycloalkyl, 3-8 membered heterocyclyl, phenyl, 4-8 membered heteroaryl, C1-C4 alkyl, - (C1-C4 alkylene) -phenyl, - (C1-C4 alkylene) - (C3-C8 cycloalkyl), - (C1-C4 alkylene) - (3-8 membered heterocyclyl);

wherein each of the above 3-8 membered heterocyclic groups, each of the C3-C8 cycloalkyl groups, each of the C1-C4 alkyl groups, each of the phenyl groups, each of the 4-8 membered heteroaryl groups is optionally substituted with 1-3 substituents selected from the group consisting of: deuterium, guanidino, C1-C4 alkyl, C3-C8 cycloalkyl, phenyl, 4-8 membered heteroaryl, -C (O) (C1-C4 alkyl), -C (O) - (C2-C4 alkenyl), -C (O) NH ₂ C (O) (3-8 membered heterocyclyl), -OC (O) (C2-C4 alkenyl), -NH-C (O) (C2-C4 alkenyl), - (C1-C4 alkylene) -NH-C (O) (C2-C4 alkenyl), -NH-C (O) (C2-C4 alkynyl), -NH-SO ₂ - (C2-C4 alkenyl), -N (C1-C4 alkyl) (C1-C4 alkyl), -C (O) -N (C1-C4 alkyl) (C1-C4 alkyl), -SO- (C1-C4 alkyl), -SO ₂ - (C1-C4 alkyl), -SO ₂ -N (C1-C4 alkyl) (C1-C4 alkyl), C1-C4 alkoxy, halogen, C1-C4 haloalkyl, cyano, hydroxy, carboxy, nitro, amino, -N (C1-C4 alkyl) (C1-C4 alkyl) -C (O) -N (C1-C4 alkyl) (C1-C4 alkyl), -NH-C (O) -NH ₂ Wherein, C2-C4 alkenyl, C2-C4 alkynyl are optionally substituted with 1-3 substituents selected from the group consisting of: halogen, trifluoromethyl, cyano, hydroxy, amino, -N (C1-C4 alkyl) (C1-C4 alkyl), 3-6 membered heterocyclyl.

In another preferred embodiment, R ₂ Are- (C1-C4 alkylene) -NRaRb, - (C1-C4 alkylene) -C (O) -NRaRb, phenyl, C3-C8 cycloalkyl, - (C1-C4 alkylene) - (phenyl), - (C1-C4 alkylene) - (C3-C8 cycloalkyl), - (C1-C4 alkylene) - (3-8 membered heterocyclyl)1-C4 alkylene) - (4-12 membered heteroaryl), C1-C4 alkyl;

wherein each Ra, each Rb, when present, is independently selected from the group consisting of: hydrogen, 4-12 membered heteroaryl, deuterium, C3-C8 cycloalkyl, 3-8 membered heterocyclyl, phenyl, C1-C4 alkyl, - (C1-C4 alkylene) -phenyl, - (C1-C4 alkylene) - (C3-C8 cycloalkyl), - (C1-C4 alkylene) - (3-8 membered heterocyclyl), or Ra, Rb taken together with the linking N form a 3-8 membered heterocyclyl;

Wherein each of the above 3-8 membered heterocyclic group, C3-C8 cycloalkyl, C1-C4 alkyl, phenyl, 4-12 membered heteroaryl is optionally substituted with 1-3 substituents selected from the group consisting of: deuterium, guanidino, C1-C4 alkyl, C3-C8 cycloalkyl, phenyl, -C (O) - (C2-C4 alkenyl), -C (O) - (C1-C4 alkyl), -C (O) NH ₂ C (O) - (C1-C4 alkyl) (C1-C4 alkyl), -C (O) - (C1-C4 alkyl), -C (O) (3-8 membered heterocyclic group), -OC (O) - (C2-C4 alkenyl), -NH-C (O) - (C2-C4 alkenyl), -C1-C4 alkylene) -NH-C (O) - (C2-C4 alkenyl), -NH-C (O) - (C2-C4 alkynyl), -NH-SO-C4 alkyl ₂ - (C2-C4 alkenyl), -SO- (C1-C4 alkyl), -SO ₂ - (C1-C4 alkyl), -SO ₂ -NH ₂ 、-SO ₂ -N (C1-C4 alkyl) (C1-C4 alkyl), C1-C4 alkoxy, halogen, C1-C4 haloalkyl, cyano, hydroxy, carboxy, nitro, amino, -N (C1-C4 alkyl) (C1-C4 alkyl) -C (O) -N (C1-C4 alkyl) (C1-C4 alkyl), phosphate, -NH-C (O) -NH ₂ Wherein, C2-C4 alkenyl, C2-C4 alkynyl are optionally substituted with 1-3 substituents selected from the group consisting of: fluoro, chloro, bromo, trifluoromethyl, cyano, hydroxy, amino, -N (C1-C4 alkyl) (C1-C4 alkyl), 3-8 membered heterocyclyl.

In another preferred embodiment, Ar is C6-C10 aryl or 5-12 membered heteroaryl, optionally substituted with 1-3 substituents selected from the group consisting of: fluorine, chlorine, bromine, C1-C4 haloalkyl, hydroxyl, C1-C4 alkyl, C1-C4 alkoxy; and/or

R ₃ 、R ₄ 、R ₅ Each independently hydrogen, deuterium, fluorine, chlorine, bromine, C1-C4 alkoxy, C1-C4 alkyl, cyano, hydroxyl.

In another preferred embodiment, the compound has a structure represented by one of the following formulae:

wherein R is ₁ 、R ₂ 、R ₃ 、R ₄ 、R ₅ Ar and Z are as defined above;

L ₁ represents a substituted or unsubstituted group: (C1-C6) alkylene, - (C1-C6 alkylene) -NH-, - (C1-C6 alkylene) -N (C1-C4 alkyl) -, - (C1-C6 alkylene) -N (C1-C5 acyl) -, - (C1-C6 alkylene) -O-, -O- (C1-C6 alkylene);

L ₃ represents a substituted or unsubstituted group: (C1-C6) alkylene, -NH-, -N (C1-C4 alkyl) -, -N (C1-C5 acyl) -, -NH- (C1-C6 alkylene) -, -N (C1-C4 alkyl) - (C1-C6 alkylene) -, -N (C1-C5 acyl) - (C1-C6 alkylene) -, - (C1-C6 alkylene) -NH-, - (C1-C6 alkylene) -N (C1-C4 alkyl) -, - (C1-C6 alkylene) -N (C1-C5 acyl) -, - (C1-C6 alkylene) -O-, -O- (C1-C6 alkylene), -O-.

In another preferred embodiment, the compound has a structure represented by one of the following formulas:

L ₂ 、L ₃ 、L ₄ Each independently represents a substituted or unsubstituted group: (C1-C6) alkylene, -NH-, -N (C1-C4 alkyl) -, -N (C1-C5 acyl) -, -NH- (C1-C6 alkylene) -, -N (C1-C4 alkyl) - (C1-C6 alkylene) -, -N (C1-C5 acyl) - (C1-C6 alkylene) -, - (C1-C6 alkylene) -NH-, - (C1-C6 alkylene) -N (C1-C4 alkyl) -, - (C1-C6 alkylene) -N (C1-C5 acyl) -, - (C1-C6 alkylene) -O-, -O- (C1-C6 alkyl) -, - (C4-C4 alkylene) -O-, -C1-C6Alkylene), -O-;

each independently represents a substituted or unsubstituted benzene ring and naphthalene ring, a substituted or unsubstituted 5-to 12-membered heteroaromatic ring containing a nitrogen atom, a C3-C8 saturated or partially saturated aliphatic ring, or a 3-to 10-membered saturated or partially saturated heterocyclic ring containing a nitrogen atom.

L ₂ 、L ₃ 、L ₄ each independently represents a substituted or unsubstituted group: (C1-C6) alkylene, -NH-, -N (C1-C4 alkyl) -, -N (C1-C5 acyl) -, -NH- (C1-C6 alkylene) -, -N (C1-C4 alkyl) - (C1-C6 alkylene) -, -N (C1-C5 acyl) - (C1-C6 alkylene) -, - (C1-C6 alkylene) -NH-, - (C1-C6 alkylene) -N (C1-C4 alkyl) -, - (C1-C6 alkylene) -N (C1-C5 acyl) -, - (C1-C6 alkylene) -O-, -O- (C1-C6 alkylene), -O-;

In another preferred embodiment, each of L is ₁ Represents a substituted or unsubstituted group: (C1-C4) alkylene, - (C1-C4 alkylene) -NH-, - (C1-C4 alkylene) -N (C1-C4 alkyl) -, - (C1-C4 alkylene) -N (C1-C4 acyl) -, - (C1-C4 alkylene) -O-, -O- (C1-C4 alkylene).

In another preferred embodiment, each of L is ₂ 、L ₃ 、L ₄ Each independently represents a substituted or unsubstituted group: (C1-C4) alkylene, -NH-, -N (C1-C4 alkyl) -, -N (C1-C4 acyl) -, -NH- (C1-C4 alkylene) -, -N (C1-C4 alkyl) - (C1-C4 alkylene) -, -N (C1-C4 acyl) - (C1-C4 alkylene) -, - (C1-C4 alkylene) -NH-, - (C1-C4 alkylene) -N (C1-C4 alkyl) -, - (C1-C4 alkylene) -N (C1-C4 acyl) -, - (C1-C4 alkylene) -O-, -O- (C1-C4 alkylene), -O-.

In another preferred embodiment, each of the above

Each one of

Each independently represents a substituted or unsubstituted benzene ring and naphthalene ring, a substituted or unsubstituted 5-to 8-membered heteroaromatic ring containing a nitrogen atom, a C3-C6 saturated or partially saturated aliphatic ring, or a 3-to 8-membered saturated or partially saturated heterocyclic ring containing a nitrogen atom.

In another preferred embodiment, the compound is any one of the compounds numbered 1-247 in table 1.

In a second aspect of the present invention, there is provided a pharmaceutical composition comprising a compound of the first aspect, its enantiomers, diastereomers, racemates or mixtures thereof, or pharmaceutically acceptable salts, hydrates and solvates thereof; and a pharmaceutically acceptable carrier.

In a third aspect of the invention, there is provided a use of a compound of the first aspect, its enantiomers, diastereomers, racemates or mixtures thereof, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or of a pharmaceutical composition of the second aspect, (a) as a kRAS small molecule inhibitor; (b) used for preparing a small molecule inhibitor of kRAS; (c) is used for preparing a medicament for preventing and/or treating diseases related to the kRAS.

In another preferred embodiment, the kRAS-associated disease is a tumor.

In another preferred embodiment, the tumor is selected from the group consisting of: lung cancer, pancreatic cancer, and intestinal cancer.

In a fourth aspect of the invention, there is provided a method of treating a tumor or inhibiting kRAS by administering a compound of the first aspect, its enantiomers, diastereomers, racemates or mixtures thereof, or pharmaceutically acceptable salts, hydrates and solvates thereof, or a pharmaceutical composition of the second aspect, to a subject in need thereof.

It is to be understood that within the scope of the present invention, the above-described features of the present invention and those specifically described below (e.g., in the examples) may be combined with each other to form new or preferred embodiments. Each feature disclosed in this specification may be replaced by an alternative feature serving the same, equivalent, or similar purpose. For reasons of space, they will not be described in detail.

Drawings

Figure 1 is the effect of compounds on the stability of kRAS protein and their effect on ERK phosphorylation of kRAS downstream proteins.

Detailed Description

The inventor finds a compound which has a novel structure and can be used as a kRAS inhibitor through extensive and intensive research. The compound has good kRAS inhibitory activity, shows good cell activity on tumor cells with a kRAS G12C mutant, can induce intracellular kRAS, inhibit the phosphorylation level of ERK kinase downstream of the kRAS, has obvious influence on the biological signal pathway downstream of the kRAS, and has the potential of treating cancers related to kRAS G12C mutation. On the basis of this, the present invention has been completed.

Term(s) for

Herein, unless otherwise specified, the term "substituted" means that one or more hydrogen atoms on a group are replaced.

C1-C6 means 1-6 carbon atoms, C6-C10 means 6-10 carbon atoms, and so on. For example, the term "C6-C10 aryl" refers to aryl groups having 6-10 carbon atoms, such as phenyl, naphthyl, and the like, which may be substituted or unsubstituted. The term "C1-C6 alkyl" refers to a straight or branched chain saturated aliphatic hydrocarbon group having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, or the like. (C1-C6) haloalkyl means one or more halogen-substituted C1-C6 alkyl groups.

4-12 ring atoms, 3-10 ring atoms, and so on. For example, a 4-12 membered heteroaryl is a heteroaryl group containing 4-12 ring atoms, containing 1, 2, 3, 4, or 5 heteroatoms selected from O, N and S, including but not limited to furyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl, and the like. The terms 3-10 membered saturated heterocyclic ring and partially saturated heterocyclic ring refer to saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituents containing 3 to 10 ring atoms, wherein one or more ring atoms are selected from heteroatoms of nitrogen, oxygen or S, and the remaining ring atoms are carbon.

The term "alkoxy" refers to an-O-alkyl group such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, or the like. The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, e.g., "C3-C8 cycloalkyl" refers to a cycloalkyl group including 3 to 8 carbon atoms, including but not limited to cyclopropyl, cyclobutyl, cyclopentyl, or the like. The term "halogen" refers to F, Cl, Br and I.

The term "alkylene" refers to a hydrocarbon group of an alkane molecule lacking two hydrogen atoms, e.g., -CH ₂ CH ₂ -、-CH ₂ CH ₂ CH ₂ CH ₂ -、-CH ₂ -、-CH ₂ CH(CH ₃ )CH ₂ -、-CH ₂ CH ₂ CH ₂ -, or the like.

The term "C1-C6 acyl" denotes substituents of the structure, such as straight-chain or branched alkyl/cycloalkyl/heteroaryl-carbonyl having 0-5 carbon atoms, such as formyl, acetyl, propionyl, cyclopropylacyl, 3-pyrazoloyl or the like.

In the present invention, the term "pharmaceutically acceptable" ingredient refers to a substance that is suitable for use in humans and/or animals without undue adverse side effects (such as toxicity, irritation, and allergic response), i.e., at a reasonable benefit/risk ratio.

In the present invention, the term "effective amount" refers to an amount of a therapeutic agent that treats, alleviates, or prevents a target disease or condition, or an amount that exhibits a detectable therapeutic or prophylactic effect. The precise effective amount for a subject will depend upon the size and health of the subject, the nature and extent of the disorder, and the therapeutic agent and/or combination of therapeutic agents selected for administration. Therefore, it is not useful to specify an exact effective amount in advance. However, for a given condition, the effective amount can be determined by routine experimentation and can be determined by a clinician.

Unless otherwise specified, all occurrences of a compound in the present invention are intended to include all possible optical isomers, such as a single chiral compound, or a mixture of various chiral compounds (i.e., a racemate). In all compounds of the present invention, each chiral carbon atom may optionally be in the R configuration or the S configuration, or a mixture of the R configuration and the S configuration.

As used herein, the term "compounds of the invention" refers to compounds of formula I. The term also includes various crystalline forms, pharmaceutically acceptable salts, hydrates or solvates of the compounds of formula I.

As used herein, the term "pharmaceutically acceptable salt" refers to a salt formed by a compound of the present invention and an acid or base, which is suitable for use as a pharmaceutical. Pharmaceutically acceptable salts include inorganic and organic salts. One preferred class of salts is that formed by reacting a compound of the present invention with an acid. Suitable acids for forming the salts include, but are not limited to: inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid, etc., organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, phenylmethanesulfonic acid, benzenesulfonic acid, etc.; and acidic amino acids such as aspartic acid and glutamic acid. Suitable bases for salt formation include, but are not limited to: lithium hydroxide, sodium hydroxide, potassium hydroxide, magnesium hydroxide, calcium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, magnesium carbonate, calcium carbonate, lithium hydrogencarbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, magnesium hydrogencarbonate, calcium hydrogencarbonate, and the like.

Preparation method

The general synthetic scheme for compounds (II-VII) is shown in the following synthetic scheme:

x represents a halogen; r' represents hydrogen, halogen, cyano, (C1-C6) alkyl, (C3-C8) cycloalkyl, - (C1-C6 alkylene) - (C3-C8 cycloalkyl), -NH- (C6-C10 aryl), -NH- (C1-C6 alkylene) (C6-C10 aryl), -NH- (C1-C6 alkyl), -NH- (C3-C8 cycloalkyl), -NH- (C1-C6 alkylene) - (C3-C8 cycloalkyl), -NH- (3-10 membered saturated heterocyclic ring and partially saturated heterocyclic ring containing 1-2 nitrogen atoms), -NH- (C1-C6 alkylene) - (3-10 membered saturated heterocyclic ring and partially saturated heterocyclic ring containing 1-2 nitrogen atoms), 3-10 membered saturated and partially saturated heterocyclic rings containing 1-2 nitrogen atoms, or 5-12 membered heteroaryl containing at least one nitrogen; r' represents hydrogen, (C1-C6) alkyl, (C3-C8) cycloalkyl, - (C1-C6 alkylene) - (C3-C8 cycloalkyl), (C6-C10 aryl), (C1-C6 alkylene) (C6-C10 aryl), - (C1-C6 alkylene) - (3-to 10-membered saturated heterocyclic and partially saturated heterocyclic rings containing 1 to 2 nitrogen atoms), 3-to 10-membered saturated heterocyclic and partially saturated heterocyclic rings containing 1 to 2 nitrogen atoms, 5-to 12-membered heteroaryl containing at least one nitrogen, or- (C1-C6 alkylene) - (5-to 12-membered heteroaryl containing at least one nitrogen);

wherein R 'and R' are optionally substituted with 1-3 of the following groups: -NHR _P 、-NR _P - (C1-C6 alkyl), -OR _P - (C1-C6 alkylene) -NHR _P - (C1-C6 alkylene) -NR _P - (C1-C6 alkyl), - (C1-C6 alkylene) -OR _P Halogen, C1-C6 haloalkyl, cyano, hydroxy, amino, (C1-C6) alkoxy, (C1-C6) alkyl, N- (C1-C6 alkyl) amino, N-di (C1-C6 alkyl) amino, N- (C1-C6) alkylaminocarbonyl, N-di (C1-C6) alkylaminocarbonyl, N- (C1-C6) alkylaminocarbonylaminocarbonylaminoA group, N-di (C1-C6) alkylaminocarbonylamino, aminocarbonylamino, guanidino, (C1-C6) alkylguanidino, (C1-C8) nitrogen-containing heterocyclylaminocarbonyl, (C1-C6 alkoxy) carbonylamino, (C1-C6) alkylsulfide, (C1-C6) alkylsulfide, aminosulfone, carboxyl, phosphoric acid, nitrogen-containing 5-12 membered heteroaromatic ring; wherein the nitrogen atom of the saturated heterocyclic and partially saturated heterocyclic ring containing 1-2 nitrogen atoms may be replaced by R _P Substituted or substituted by (C1-C6) alkyl, (C1-C6) acyl;

r is as defined above _P Commonly used protecting Groups for nitrogen or oxygen atoms [ Protective Groups in Organic Synthesis (Peter G.M. Wuts, ISBN:978-1-118-]For example-Boc, -Cbz, Fmoc, phthalimidyl, triphenylmethyl, benzyl, C1-C4 acyl, benzoyl, methoxymethyl, 2-tetrahydropyranyl, triisopropylsilyl, diphenyl tert-butylsilyl, dimethyl tert-butylsilyl, p-methoxybenzyl, methyl, ethyl and the like;

Step 1: heating o-nitrobenzaldehyde S1 and amino compound S2 under the action of organic phosphorus (such as tributyl phosphorus) to obtain an intermediate S3 containing a parent nucleus structure of a 2H-indazole structure;

step 2: s3 undergoes a Suzuki coupling reaction with Ar-substituted boronic acid, Ar-substituted boronic ester, or other Ar-substituted boronic acid derivatives to form an intermediate S4;

and 3, step 3: reaction of intermediate S4 with a brominating reagent (e.g., NBS, NCS) to give halogen substituted intermediate S5;

and 4, step 4: intermediate S5 is C-N coupled, C-O coupled, Suzuki coupled or other C-C coupled with R '-H, R' substituted boronic acid, R 'substituted boronic ester, or other R' substituted boronic acid derivative to provide intermediate S6;

and 5: the intermediate S6 reacts with Z acylation reagents such as Z-Cl, Z-OSu, Z activated ester and the like to directly generate a target compound II-VII;

step 6: the R' group of intermediate S6 is synthesized into a structure required by R1 based on the methods reported in the prior literature, for example, the methods described in comparative Organic Transformations (Richard C. Larock, Print ISBN:9781119166306) and Protective Groups in Organic Synthesis (Peter G. M. Wuts, ISBN:978-1-118-05748-3) are referred to, the corresponding chemical functional Groups are protected and deprotected, and the corresponding functional Groups are transformed to synthesize a structure required by R1, and finally obtain intermediate S7;

And 7: the intermediate S7 can react with Z-Cl to directly generate a target compound II-VII;

and 8: the R' group of intermediate S6 can be synthesized into a structure required by R2 based on the methods reported in the prior literature, for example, the methods described in comparative Organic Transformations (Richard C. Larock, Print ISBN:9781119166306) and Protective Groups in Organic Synthesis (Peter G. M. Wuts, ISBN:978-1-118-05748-3) are referred to, and the structures required by R2 can be synthesized to finally obtain intermediate S8;

and step 9: the intermediate S8 reacts with Z acylation reagents such as Z-Cl, Z-OSu, Z activated ester and the like to directly generate target compounds II-VII;

the general synthetic scheme for compounds (VIII-XIII) is shown in the following synthetic scheme:

wherein X, R' are as defined above;

step 1: heating o-nitrobenzaldehyde S11 and amino compound S12 under the action of organic phosphorus (such as tributyl phosphorus) to obtain an intermediate S13 containing a parent nucleus structure of a 2H-indazole structure;

step 2: (ii) Suzuki coupling of S13 with Ar-substituted boronic acid, Ar-substituted boronic ester, or other Ar-substituted boronic acid derivative to yield intermediate S14;

And step 3: reaction of intermediate S14 with a brominating reagent (e.g., NBS, NCS) to give halogen substituted intermediate S15;

and 4, step 4: intermediate S15 is C-N coupled, C-O coupled, Suzuki coupled or other C-C coupled with R '-H, R' substituted boronic acid, R 'substituted boronic ester, or other R' substituted boronic acid derivative to provide intermediate S16;

and 5: the intermediate S16 can react with Z acylating reagent such as Z-Cl, Z-OSu, Z activated ester and the like to directly generate target compounds VIII-XIII;

step 6: the R' group of intermediate S16 is synthesized into a structure required by R1 based on the methods reported in the prior literature, for example, the methods described in comparative Organic Transformations (Richard C. Larock, Print ISBN:9781119166306) and Protective Groups in Organic Synthesis (Peter G. M. Wuts, ISBN:978-1-118-05748-3) are referred to, the corresponding chemical functional Groups are protected and deprotected, and the corresponding functional Groups are transformed to synthesize a structure required by R1, and finally obtain intermediate S17;

and 7: the intermediate S17 can react with Z-Cl to directly generate target compounds VIII-XIII;

and 8: the R' group of intermediate S16 can be synthesized into a structure required by R2 based on the methods reported in the prior literature, for example, the methods described in comparative Organic Transformations (Richard C. Larock, Print ISBN:9781119166306) and Protective Groups in Organic Synthesis (Peter G. M. Wuts, ISBN:978-1-118-05748-3) are referred to, and the structures required by R2 can be synthesized to finally obtain intermediate S18;

And step 9: the intermediate S18 reacts with Z acylating reagent such as Z-Cl, Z-OSu, Z activated ester and the like to directly generate target compounds VIII-XIII;

compared with the prior art, the invention has the main advantages that:

(1) the preparation method has the advantages of mild reaction conditions, abundant and easily-obtained raw materials, simple operation and post-treatment, good corresponding selectivity and the like. The compound has good cell activity in a kRAS mutant cell strain, can induce kRAS in cells, inhibits the phosphorylation level of ERK kinase downstream of the kRAS, and has obvious influence on biological signal pathways downstream of the kRAS.

(2) Provides a kRAS inhibitor which shows strong cell growth inhibition activity in a kRAS mutant cell strain and promotes the degradation of intracellular kRAS, and is a potential drug for treating tumor diseases.

The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. Experimental procedures without specific conditions noted in the following examples, generally according to conventional conditions, or according to conditions recommended by the manufacturer. Unless otherwise specified, percentages and parts are percentages by mass and fractions by mass.

The test materials and reagents used in the following examples are commercially available without specific reference.

Experimental example 1: synthesis of Compounds

Synthesizing an intermediate:

the method comprises the following steps: synthesis of 3- (6-bromo-2H-indazol-2-butyl) -1-ol (ZA156)

4-bromo-2-nitro-benzaldehyde (1.1447g, 5.0mmol) and 3-amino-1-butanol (490.3mg, 5.5mmol) were added to an eggplant-type bottle, and then 25ml of isopropanol was added, followed by heating and stirring at 80 ℃ for 4 hours. After the reaction was completed, the reaction solution was cooled to room temperature and then added ⁿ Bu ₃ P (3.03g, 15mmol) was reacted at 80 ℃ for 16 hours with heating. After the reaction is finished, the reaction product is cooled to room temperature, and after the solvent is dried in a spinning mode, the reaction product is separated and purified through a chromatographic column, so that 1.25g of the target compound is obtained. ¹ H NMR(400MHz,Chloroform-d)δ7.99(d,J＝1.0Hz,1H),7.90(p,J＝0.9Hz,1H),7.55(d,J＝8.8Hz,1H),7.18(dd,J＝1.6,8.8Hz,1H),4.92(h,J＝6.9Hz,1H),3.64(dd,J＝5.2,11.0Hz,1H),3.34(dt,J＝5.8,11.4Hz,1H),2.17(td,J＝5.0,6.8Hz,2H),1.72(d,J＝7.0Hz,3H).

Step two: synthesis of 3- (6- (2- (trifluoromethyl) phenyl) -2H-indazol-2-butyl) -1-ol (ZA158)

ZA156(670mg, 2.5mmol), 2-trifluoromethylphenylboronic acid (1.01g, 6.25mmol) were dissolved in DME (20ml) and Na ₂ CO ₃ (2M aq，10ml) removing oxygen in the system, charging nitrogen, and adding Pd (dppf) Cl ₂ ·CH ₂ Cl ₂ And then the reaction is carried out overnight at 95 ℃ after oxygen and nitrogen are removed again. After the reaction is finished, cooling to room temperature, adding water and ethyl acetate for extraction, combining organic phases, drying by using anhydrous sodium sulfate, and separating and purifying by using a chromatographic column after spin drying. The target product was obtained at 698 mg. ¹ H NMR(400MHz,Chloroform-d)δ8.04(d,J＝0.9Hz,1H),7.79(d,J＝7.8Hz,1H),7.70-7.63(m,3H),7.58(q,J＝8.0,8.7Hz,1H),7.51(q,J＝6.7,7.6Hz,1H),7.42(d,J＝7.6Hz,1H),7.09(d,J＝8.6Hz,1H),4.96(q,J＝6.9Hz,1H),3.67(dt,J＝5.4,10.6Hz,1H),3.42(dq,J＝6.2,11.6Hz,1H),2.55(t,J＝5.6Hz,1H),2.21(td,J＝4.9,6.7Hz,2H),1.75(d,J＝6.9Hz,3H).

3- (6- (2- (methyl) phenyl) -2H-indazol-2-butyl) -1-ol (ZB086) can be synthesized by following the procedures and procedures described above for the synthesis of ZA158, using the corresponding amine and boronic ester in sequence as starting materials for the two successive steps of the reaction. ¹ H NMR(400MHz,Chloroform-d)δ8.03(d,J＝0.9Hz,1H),7.69(dd,J＝0.9,8.6Hz,1H),7.64(q,J＝1.1Hz,1H),7.31(dt,J＝2.6,6.7Hz,3H),7.28(s,1H),7.10(dd,J＝1.4,8.6Hz,1H),4.96(h,J＝6.9Hz,1H),3.68(dd,J＝5.0,11.2Hz,1H),3.42(d,J＝6.2Hz,1H),2.75(s,1H),2.34(s,3H),2.25-2.16(m,2H),1.75(d,J＝6.8Hz,3H).

3- (6- (2- (trifluoromethyl) phenyl) -2H-indazol-2-yl) propan-1-ol can be synthesized by following the procedures and procedures described above for the synthesis of ZA158, using the corresponding amine and borate in sequence as starting materials in two consecutive steps (see ZB139 for the synthesis): 1H NMR (400MHz, Chloroform-d) δ 7.99(d, J ═ 1.0Hz,1H),7.76(d, J ═ 7.9Hz,1H),7.66(dd, J ═ 1.0,8.7Hz,1H),7.63(s,1H),7.57(t, J ═ 7.6Hz,1H),7.48(t, J ═ 7.6Hz,1H),7.40(d, J ═ 7.5Hz,1H),7.07(d, J ═ 8.6Hz,1H),4.62(t, t ═ 7J ═ 6.4Hz,2H),3.70(t, J ═ 5.6Hz,2H),2.78(s,1H),2.29-2.12(m,2H) ₁₇ H ₁₅ F ₃ N ₂ O[M+H]321.11; the experiment shows that: 32107

Referring to the above-described methods and procedures for the synthesis of ZA156, 3- (6-bromo-2H-indazol-2-yl) cyclohex-1-amine (ZC028) can be synthesized using 4-bromo-2-nitro-benzaldehyde and 1, 3-cyclohexanediamine as starting materials. ¹ H NMR(500MHz,Chloroform-d)δ7.88(d,J＝1.0Hz,1H),7.85(d,J＝1.0Hz,1H),7.81(tt,J＝0.8,1.7Hz,2H),7.46(dd,J＝0.7,3.5Hz,1H),7.44(dd,J＝0.7,3.5Hz,1H),7.08(dd,J＝1.6,4.3Hz,1H),7.06(dd,J＝1.6,4.4Hz,1H),4.82(tt,J＝4.0,10.3Hz,1H),4.37(tt,J＝3.8,12.1Hz,2H),3.46(q,J＝4.1Hz,1H),2.88(ddt,J＝3.8,7.6,11.3Hz,1H),2.37(dtd,J＝1.8,3.6,11.5Hz,2H),2.26-2.21(m,1H),2.20-2.14(m,1H),2.09(dd,J＝4.3,12.8Hz,1H),2.03-1.96(m,1H),1.91(dtt,J＝3.7,7.6,14.3Hz,3H),1.77-1.71(m,2H),1.55(dd,J＝4.6,9.3Hz,1H),1.45(tdd,J＝3.6,10.0,13.3Hz,1H).

Synthesis of the final product 1: 1- (4- (2- (3- (dimethylamino) propyl) -6- (2-fluorophenyl) -2H-indazol-3-yl) piperidin-1-yl) -2-propen-1-one (WHD100)

Step 1: synthesis of 3- (6-bromo-2H-indazol-2-yl) -N, N-dimethylpropan-1-amine (WHD111)

In a 150mL round-bottom flask, the starting materials 4-bromo-2-nitro-benzaldehyde (3.06g, 13.3mmol), 3-N, N-dimethylaminopropylamine (2.36g, 23.1mmol) and isopropanol (30mL) were added in this order, and the mixture was heated and stirred at 80 ℃ for 4 hours. The reaction solution was cooled to room temperature, followed by addition of (n-Bu) ₃ P (5.904g,29.2mmol), and heating at 80 ℃ was continued for 16 hours. Cooling to room temperature after the reaction is finished, removing most of solvent by a rotary evaporator, and performing column chromatography (mobile phase is 1:1 ethyl acetate and methanol) to obtain a target product WHD111(2.50g)。 ¹ H NMR(CDCl ₃ ,400MHz):7.92(s,1H),7.88(s,1H),7.52(d,J＝8.8Hz,1H),7.15(dd,J＝8.8,1.6Hz,1H),4.46(t,J＝6.8Hz,2H),2.23(t,J＝9.0Hz,2H),2.21(s,6H),2.17-2.11(m,2H).

Step 2: synthesis of 3- (6- (2-fluorophenyl) -2H-indazol-2-yl) -N, N-dimethylpropan-1-amine (WHD91)

Into a 50mL round-bottom flask were added WHD111(0.25g, 0.89mmol), 2-fluorobenzeneboronic acid (0.2577g,1.84mmol), Pd (dppf) Cl in that order ₂ DCM (0.0754g, 0.09mmol) and then DME (6mL), Na ₂ CO ₃ Aqueous solution (2M, 2mL), purge twice, N ₂ The reaction system was heated at 95 ℃ for 12 hours with protection. After the reaction is finished, the reaction product is cooled to room temperature, the solvent is removed, and column chromatography is carried out (mobile phase is 1:1 ethyl acetate methanol and 10% ammonia water), so that the target compound WHD91(0.32) is obtained. ¹ H NMR(CDCl ₃ ,400MHz):7.97(s,1H),7.86(s,1H),7.71(d,J＝8.6Hz,1H),7.52(td,J＝7.76 and 1.8Hz,1H),7.34-7.28(m,2H),7.25-7.15(m,2H),4.51(t,J＝6.7Hz,2H),2.28-2.25(m,2H),2.23(s,6H),2.22-2.16(m,2H).

And step 3: synthesis of 3- (3-bromo-6- (2-fluorophenyl) -2H-indazol-2-yl) -N, N-dimethylpropan-1-amine (WHD93)

The starting material WHD91(0.292g,0.98mmol) was dissolved in HOAc and NBS (0.1735g,0.98mmol) was added and stirred at room temperature for 18 h. After the reaction is finished, water is added for quenching, the solvent is removed, and NaHCO is used ₃ The solution neutralizes acidity. By CH ₂ Cl ₂ Extracting with ethyl acetate for three times, mixing organic phases, and adding Na ₂ SO ₄ Dried (anhydrous) and concentrated to give crude WHD93(0.37g) which was used directly in the next reaction. ¹ H NMR(CDCl ₃ ,400MHz):7.82(s,1H),7.57(d,J＝8.68Hz,1H),7.51(td,J＝7.8,1.72Hz,1H),7.37-7.32(m,2H),7.26-7.15(m,2H),4.57(t,J＝7.0Hz,2H),2.54(t,J＝7.5Hz,2H),2.36(s,6H),2.30-2.23(m,2H).

And 4, step 4: synthesis of 4- (2- (3- (dimethylamino) propyl) -6- (2-fluorophenyl) -2H-indazol-3-yl) -3, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester (WHD94)

A50 mL round-bottom flask was charged with the starting material WHD93(0.33g,0.88mmol) obtained in the previous step and N-Boc-1 in this order2,5, 6-tetrahydropyridine-4-boronic acid pinacol ester (0.3806g,1.23mmol), Pd (dppf) Cl ₂ DCM (0.0657g, 0.08mmol) and then DME (6mL), Na ₂ CO ₃ Aqueous solution (2M, 2mL), purge twice, N ₂ The reaction system was heated at 95 ℃ for 12 hours with protection. After the reaction is finished, the solvent is removed, and column chromatography is carried out (mobile phase is 1:1 ethyl acetate methanol and methanol), so as to obtain a product WHD94(0.4155 g). ¹ H NMR(CDCl ₃ ,400MHz):7.82(s,1H),7.57(d,J＝8.7Hz,1H),7.51(td,J＝7.8,1.7Hz,1H),7.37-7.32(m,2H),7.26-7.15(m,2H),4.57(t,J＝7.0Hz,2H),2.54(t,J＝7.5Hz,2H),2.36(s,6H),2.30-2.23(m,2H).

And 5: synthesis of tert-butyl 4- (2- (3- (dimethylamino) propyl) -6- (2-fluorophenyl) -2H-indazol-3-yl) piperidine-1-carboxylate (WHD95)

Dissolving raw material WHD94(0.4155g) in methanol, degassing, and adding N ₂ Pd/C (0.0415g) was added under protection, pumped down and then replaced with H ₂ Stirring for 24 hours at room temperature under the atmosphere, filtering the palladium catalyst, and concentrating to obtain a target product WHD95 which is directly used for the next reaction.

Step 6: synthesis of 1- (4- (2- (3- (dimethylamino) propyl) -6- (2-fluorophenyl) -2H-indazol-3-yl) piperidin-1-yl) -2-propen-1-one (WHD100)

Starting material WHD95(25mg,0.05mmol) dissolved in CH ₂ Cl ₂ (2mL), TFA (1mL) was added, the mixture was stirred at room temperature for 30min, the solvent was removed, and a small amount of toluene was added, followed by removal. Dissolved in THF (8mL) and Et added ₃ N (0.5mL), followed by addition of acryloyl chloride (6mg,0.06mmol) was stirred at room temperature for 1 hour. After removal of the solvent, HPLC purification gave 7.6mg of trifluoroacetate salt of WHD100 as a final product (condition: 20% CH) ₃ CN start, retention time 11.6 min). ¹ H NMR(400MHz,Methanol-d ₄ )δ7.84(d,J＝8.8Hz,1H),7.71(s,1H),7.52(td,J＝7.8,1.7Hz,1H),7.41-7.35(m,1H),7.26(td,J＝7.5,1.0Hz,1H),7.24-7.17(m,2H),6.88(dd,J＝16.8,10.7Hz,1H),6.28(dd,J＝16.8,2.0Hz,1H),5.80(dd,J＝10.6,2.0Hz,1H),4.82(d,J＝13.2Hz,1H),4.65(t,J＝6.6Hz,2H),4.35(d,J＝13.7Hz,1H),3.57(tt,J＝12.2,3.9Hz,1H),3.38(t,J＝12.2Hz,1H),3.24(t,J＝7.9Hz,2H),2.97-2.91(m,1H),2.92(s,6H),2.41(p,J＝6.7Hz,2H),2.27-2.11(m,2H),2.07(s,2H).ESI-Theoretical calculation of MS value C ₂₆ H ₃₂ FN ₄ O[M+H] ⁺ 435.25; the experiment shows that: 435.95.

synthesis of the final product 2: 1- (4- (2- (3- (dimethylamino) propyl) -6- (4-quinolyl) -2H-indazol-3-yl) piperidin-1-yl) -2-propen-1-one (WHD137)

Step 1: synthesis of 3- (6- (4-quinolyl) -2H-indazol-2-yl) -N, N-dimethylpropan-1-amine (WHD124)

Into a 50mL round-bottom flask were added WHD111(0.2952g, 1.05mmol), quinoline-4-boronic acid (0.2405g,1.39mmol), Pd (dppf) Cl in that order ₂ DCM (0.0814g, 0.1mmol) and then DME (6mL), Na ₂ CO ₃ Aqueous solution (2M, 2mL), purge twice, N ₂ The reaction system was heated at 95 ℃ for 12 hours with protection. After the reaction is finished, the reaction product is cooled to room temperature, the solvent is removed, and column chromatography is carried out (mobile phase is 1:1 ethyl acetate methanol and 10% ammonia water), so that the target compound WHD124(0.38) is obtained. ¹ H NMR(400MHz,Methanol-d ₄ )δ8.88(s,1H),8.37(s,1H),8.12(d,J＝8.4Hz,1H),7.97(s,1H),7.87(s,1H),7.79(s,1H),7.76(s,1H),7.57(s,1H),7.52(s,1H),7.22(s,1H),4.56(t,J＝6.2Hz,2H),2.35(t,J＝7.1Hz,2H),2.24(s,6H),2.23-2.20(m,2H).

Step 2: synthesis of 3- (3-bromo-6- (4-quinolyl) -2H-indazol-2-yl) -N, N-dimethylpropan-1-amine (WHD129)

The starting material WHD124(0.37g,1.12mmol) was dissolved in HOAc, NBS (0.2039g,1.15mmol) was added, and the mixture was stirred at room temperature for 18 hours. After the reaction is finished, water is added for quenching, the solvent is removed, and NaHCO is used ₃ The solution neutralizes acidity. By CH ₂ Cl ₂ Extracting with ethyl acetate for three times, mixing organic phases, and adding Na ₂ SO ₄ Dried (anhydrous) and concentrated to give the crude WHD129(0.45g) which was used directly in the next reaction.

And step 3: synthesis of 4- (2- (3- (dimethylamino) propyl) -6- (4-quinolyl) -2H-indazol-3-yl) -3, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester (WHD130)

A50 mL round-bottom flask was charged with the starting material WHD129(0.24g,0.59mmol) obtained in the previous step, N-Boc-1,2,5, 6-tetrahydropyridine-4-boronic acid pinacol ester (0.2752g,0.89mmol), Pd (dppf) Cl ₂ DCM (0.0519g, 0.06mmol) was added followed by DME (6mL), Na ₂ CO ₃ Aqueous solution (2M, 2mL), purge twice, N ₂ The reaction system was heated at 95 ℃ for 12 hours with protection. After the reaction is finished, the solvent is removed, and column chromatography is carried out (mobile phase is 1:1 ethyl acetate methanol and methanol), so as to obtain a product WHD130(0.2843 g). ¹ H NMR(400MHz,Chloroform-d)δ8.96(d,J＝4.4Hz,1H),8.19(d,J＝8.3Hz,1H),8.01(d,J＝8.0Hz,1H),7.81(s,1H),7.73(t,J＝7.2Hz,1H),7.69(d,J＝8.6Hz,1H),7.49(t,J＝8.1Hz,1H),7.42(d,J＝4.4Hz,1H),7.20(dd,J＝8.6,1.2Hz,1H),6.07(s,1H),4.47(t,J＝7.2Hz,2H),4.21(d,J＝1.9Hz,2H),3.76(t,J＝5.4Hz,2H),2.61(s,2H),2.37(t,J＝6.9Hz,2H),2.24(s,6H),2.26-2.17(m,2H),1.54(s,9H).

And 4, step 4: synthesis of tert-butyl 4- (2- (3- (dimethylamino) propyl) -6- (4-quinolyl) -2H-indazol-3-yl) piperidine-1-carboxylate (WHD133)

Dissolving raw material WHD130(0.2g) in methanol, degassing, and adding N ₂ Adding Pd (OH) under protection ₂ (0.1075g) in H after evacuation ₂ The reaction mixture was stirred at room temperature for 24 hours under an atmosphere, and the palladium catalyst was filtered and concentrated to obtain a target product WHD133(0.13g) which was used directly in the next reaction.

And 5: synthesis of 1- (4- (2- (3- (dimethylamino) propyl) -6- (4-quinolyl) -2H-indazol-3-yl) piperidin-1-yl) -2-propen-1-one (WHD137)

Raw material WHD133(0.13g,0.25mmol) was dissolved in CH ₂ Cl ₂ (2mL), TFA (1mL) was added, the mixture was stirred at room temperature for 30min, the solvent was removed, and a small amount of toluene was added, followed by removal. Dissolved in THF (8mL) and Et added ₃ N (1mL), followed by addition of acryloyl chloride (27mg,0.3mmol) and stirring at room temperature for 1 hour. After removal of the solvent, HPLC purification gave 8.3mg of the trifluoroacetate salt of WHD137 as the final product (purification conditions: 5% CH) ₃ CN start, retention time 27 min). ¹ H NMR(400MHz,Methanol-d ₄ )δ9.22(d,J＝5.7Hz,1H),8.35(d,J＝5.7Hz,2H),8.31(d,J＝8.5Hz,1H),8.21(td,J＝8.4,1.1Hz,1H),8.10(d,J＝2.6Hz,2H),8.08(s,1H),7.987.96(m,1H),7.94(s,1H),7.31(dd, J ═ 8.8,1.5Hz,1H),6.89(dd, J ═ 16.8,10.7Hz,1H),6.28(dd, J ═ 16.8,2.0Hz,1H),5.81(dd, J ═ 10.7,2.0Hz,1H),4.85(d, J ═ 12.6Hz,1H),4.73(t, J ═ 6.8Hz,2H),4.38(d, J ═ 12.9Hz,1H),3.67(tt, J ═ 12.1,3.8Hz,1H),3.42(t, J ═ 12.4Hz,1H),3.33-3.29(m,2H),3.01 (s,2H), 2.47 (m,2H), 2.47.6H, 2H, 13.6H, 2H, 13H, 2H, 13.3.3.3.3.3.3, 3.42 (m ═ 2H), 2H, 13H, 2H, 13H, 2H, 13H, 2H, 1H, 2H, 1H, 13H, 1H, 2H, 1H, 2H, etc., 1H, 15H, etc ₂₉ H ₃₄ N ₅ O[M+H] ⁺ 468.27; the experiment shows that: 468.54.

synthesis of the final product 3: 1- (4- (2- (3- (dimethylamino) propyl) -6-naphthyl-2H-indazol-3-yl) piperidin-1-yl) -2-propen-1-one (WHD157)

Step 1: synthesis of 3- (6-naphthyl-2H-indazol-2-yl) -N, N-dimethylpropan-1-amine (WHD138)

Into a 50mL round-bottom flask were added WHD111(0.2120g, 0.75mmol), 1-naphthalene boronic acid (0.1888g,1.10mmol), Pd (dppf) Cl in that order ₂ DCM (0.0557g, 0.07mmol) and then DME (6mL), Na ₂ CO ₃ Aqueous solution (2M, 2mL), purging twice, N ₂ The reaction system was heated at 95 ℃ for 12 hours with protection. After the reaction is finished, the reaction product is cooled to room temperature, the solvent is removed, and column chromatography is carried out (mobile phase is 1:1 ethyl acetate methanol and 10% ammonia water), so that the target compound WHD138(0.1961) is obtained. ¹ H NMR(400MHz,Methanol-d ₄ )δ8.30(s,1H),7.92-7.84(m,3H),7.79-7.78(m,1H),7.65(s,1H),7.53-7.40(m,4H),7.20-7.19(m,1H),4.53(s,2H),2.34(s,2H),2.24-2.20(m,8H).

Step 2: synthesis of 3- (3-bromo-6-naphthyl-2H-indazol-2-yl) -N, N-dimethylpropan-1-amine (WHD145)

The starting material WHD138(0.1961g,0.596mmol) was dissolved in HOAc, NBS (0.1184g,0.67mmol) was added, and the mixture was stirred at room temperature for 18 hours. After the reaction is finished, water is added for quenching, the solvent is removed, and NaHCO is used ₃ The solution neutralizes acidity. By CH ₂ Cl ₂ Extracting with ethyl acetate for three times, mixing organic phases, and adding Na ₂ SO ₄ (Anhydrous) drying and concentratingCrude WHD145(0.24g) was obtained and used directly in the next reaction.

And step 3: synthesis of 4- (2- (3- (dimethylamino) propyl) -6-naphthyl-2H-indazol-3-yl) -3, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester (WHD148)

A50 mL round-bottom flask was charged with the starting material WHD145(0.12g,0.29mmol) obtained in the previous step, N-Boc-1,2,5, 6-tetrahydropyridine-4-boronic acid pinacol ester (0.1324g,0.43mmol), Pd (dppf) Cl ₂ DCM (0.0278g, 0.03mmol) and then DME (6mL), Na ₂ CO ₃ Aqueous solution (2M, 2mL), purge twice, N ₂ The reaction system was heated at 95 ℃ for 12 hours with protection. After the reaction, the solvent was removed and column chromatography was carried out (mobile phase 1:1 ethyl acetate methanol, methanol) to obtain the product WHD148(0.1479 g). ¹ H NMR(400MHz,Methanol-d ₄ )δ7.93(d,J＝8.1Hz,1H),7.89(d,J＝8.2Hz,1H),7.83(d,J＝8.4Hz,1H),7.71(d,J＝8.4Hz,1H),7.62(s,1H),7.54(t,J＝8.7Hz,1H),7.49(t,J＝8.1Hz,1H),7.45(d,J＝7.0Hz,1H),7.40(t,J＝8.0Hz,1H),7.18(d,J＝8.6Hz,1H),6.15(s,1H),4.53(t,J＝6.8Hz,2H),4.22(s,2H),3.77(s,2H),2.84(d,J＝5.3Hz,2H),2.63(s,2H),2.59(s,6H),2.32(p,J＝7.2Hz,2H),1.53(s,9H).

And 4, step 4: synthesis of tert-butyl 4- (2- (3- (dimethylamino) propyl) -6-naphthyl-2H-indazol-3-yl) piperidine-1-carboxylate (WHD152)

The raw material WHD148(0.1479g) was dissolved in methanol and degassed N ₂ Adding Pd (OH) under protection ₂ (0.0506g) after evacuation in H ₂ The reaction mixture was stirred at room temperature for 24 hours under an atmosphere, and the palladium catalyst was filtered and concentrated to obtain the aimed product WHD152(0.079g) which was used directly in the next reaction.

And 5: synthesis of 1- (4- (2- (3- (dimethylamino) propyl) -6-naphthyl-2H-indazol-3-yl) piperidin-1-yl) -2-propen-1-one (WHD157)

Starting material WHD152(0.079g,0.15mmol) was dissolved in CH ₂ Cl ₂ (2mL), TFA (1mL) was added, the mixture was stirred at room temperature for 30min, the solvent was removed, and a small amount of toluene was added, followed by removal. Dissolved in THF (8mL) and Et added ₃ N (1mL), followed by addition of acryloyl chloride (15mg,0.16mmol) and stirring at room temperature for 1 hour. After removing the solvent, HPLC purification gives the final product WHD157 as the trifluoroacetate salt16mg (purification conditions: 10% CH) ₃ CN start, retention time 26 min). ¹ H NMR(400MHz,Methanol-d ₄ ) δ 7.94(d, J ═ 8.1Hz,1H),7.90(d, J ═ 5.2Hz,1H),7.88(d, J ═ 5.4Hz,1H),7.82(d, J ═ 8.5Hz,1H),7.62(s,1H),7.54(t, J ═ 8.1Hz,1H),7.49(td, J ═ 6.9,1.0Hz,1H),7.45-7.39(m,2H),7.16(dd, J ═ 8.7,1.3Hz,1H),6.88(dd, J ═ 16.8,10.6Hz,1H),6.28(dd, J ═ 16.8,2.0Hz,1H),5.80(dd, J ═ 10.8, 8, 2.8, 2H, 1H), 2.8, 1H, 8, 2.8, 2H, 1H, 2H, 1H, 6.8, 2H, 1H, 2H, 1H, 2H, 1H, 2H, 1H, 2H, 1H, 2H, 1H, 2H, 1H, 2H, 1H, 2H, 1H, 2H, 1H, 2H, 1H, 2H, 1H, 2H, 1H, 2H, 1H, 2H, 1H, 2H, 6H) 2.43(p, J ═ 6.8Hz,2H),2.30-2.19(m,2H),2.09(d, J ═ 12.7Hz,2H) ₃₀ H ₃₅ N ₄ O[M+H] ⁺ 467.27; the experiment shows that: 467.56.

synthesis of the final product 4: 1- (4- (2- (3- (dimethylamino) propyl) -6- (2-tolyl) -2H-indazol-3-yl) piperidin-1-yl) -2-propen-1-one (WHE05)

Step 1: synthesis of 3- (6- (2-tolyl) -2H-indazol-2-yl) -N, N-dimethylpropan-1-amine (WHD144)

Into a 50mL round-bottom flask were added WHD111(0.2117g, 0.75mmol), 2-tolylboronic acid (0.1477g,1.08mmol), Pd (dppf) Cl in that order ₂ DCM (0.0580g, 0.07mmol) and then DME (6mL), Na ₂ CO ₃ Aqueous solution (2M, 2mL), purge twice, N ₂ The reaction system was heated at 95 ℃ for 12 hours with protection. After the reaction is finished, the reaction product is cooled to room temperature, the solvent is removed, and column chromatography is carried out (mobile phase is 1:1 ethyl acetate methanol and 10% ammonia water), so that the target compound WHD144(0.2037) is obtained. ¹ H NMR(400MHz,Methanol-d ₄ )δ8.26(d,J＝0.9Hz,1H),7.73(d,J＝8.6Hz,1H),7.46(s,1H),7.27-7.23(m,4H),7.04(dd,J＝8.6,1.2Hz,1H),4.51(t,J＝6.8Hz,2H),2.34(dd,J＝9.0,6.0Hz,2H),2.26(s,3H),2.25(s,6H),2.20(t,J＝7.6Hz,2H).

Step 2: synthesis of 3- (3-bromo-6- (2-tolyl) -2H-indazol-2-yl) -N, N-dimethylpropan-1-amine (WHD155)

The starting material WHD144(0.2037g,0.7mmol) was dissolved in HOAc and NBS (0.1330g,0.75mmol) was added and stirred at room temperature for 18 h. After the reaction is finished, water is added for quenching, the solvent is removed, and NaHCO is used ₃ The solution neutralizes acidity. By CH ₂ Cl ₂ Extracting with ethyl acetate for three times, mixing organic phases, and adding Na ₂ SO ₄ Dried (anhydrous) and concentrated to give crude WHD155(0.24g) which was used directly in the next reaction.

And step 3: synthesis of 4- (2- (3- (dimethylamino) propyl) -6- (2-tolyl) -2H-indazol-3-yl) -3, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester (WHD156)

A50 mL round-bottomed flask was charged with the starting material WHD155(0.12g,0.32mmol) obtained in the previous step, N-Boc-1,2,5, 6-tetrahydropyridine-4-boronic acid pinacol ester (0.1527g,0.49mmol), Pd (dppf) Cl ₂ DCM (0.0274g, 0.033mmol) was added followed by DME (6mL), Na ₂ CO ₃ Aqueous solution (2M, 2mL), purge twice, N ₂ The reaction system was heated at 95 ℃ for 12 hours with protection. After the reaction, the solvent was removed and column chromatography was carried out (mobile phase 1:1 ethyl acetate methanol, methanol) to obtain the product WHD156(0.15 g). ¹ H NMR(400MHz,Methanol-d ₄ )δ7.66(dd,J＝8.6,0.6Hz,1H),7.44(s,1H),7.29-7.22(m,3H),7.05(dd,J＝8.6,1.3Hz,1H),6.14(s,1H),4.55(t,J＝6.6Hz,2H),4.22(s,2H),3.77(s,2H),3.12((t,J＝7.6Hz,2H),2.81(s,6H),2.62(s,2H),2.39(p,J＝6.7Hz,2H),2.25(s,3H),1.52(s,9H).

And 4, step 4: synthesis of tert-butyl 4- (2- (3- (dimethylamino) propyl) -6- (2-tolyl) -2H-indazol-3-yl) piperidine-1-carboxylate (WHE01)

The raw material WHD156(0.15g) was dissolved in methanol and degassed N ₂ Adding Pd (OH) under protection ₂ (0.0296g) in H after evacuation ₂ Stirring for 24 hours at room temperature under the atmosphere, filtering the palladium catalyst, and concentrating to obtain a target product WHE01 which is directly used for the next reaction. ¹ H NMR(400MHz,Methanol-d ₄ )δ7.80(d,J＝8.7Hz,1H),7.42(s,1H),7.27-7.21(m,4H),7.00(dd,J＝8.8,1.2Hz,1H),4.62(t,J＝6.4Hz,2H),4.30(d,J＝13.4Hz,2H),3.51-3.45(m,1H),3.14-3.03(m,4H),2.80(s,6H),2.36(p,J＝7.0Hz,2H),2.25(s,3H),2.20-2.10(m,2H),1.97(d,J＝9.2Hz,2H),1.51(s,9H).

And 5: synthesis of 1- (4- (2- (3- (dimethylamino) propyl) -6- (2-tolyl) -2H-indazol-3-yl) piperidin-1-yl) -2-propen-1-one (WHE05)

The starting material WHE01(50mg,0.105mmol) was dissolved in CH ₂ Cl ₂ (2mL), TFA (1mL) was added, the mixture was stirred at room temperature for 30min, the solvent was removed, and a small amount of toluene was added, followed by removal. Dissolved in THF (8mL) and Et added ₃ N (1mL), followed by addition of acryloyl chloride (9.73mg,0.108mmol) and stirring at room temperature for 1 hour. After removal of the solvent, HPLC purification was carried out to obtain 20mg of the trifluoroacetate salt of WHE05 as a final product (purification conditions: 15% CH) ₃ CN start, retention time 17.6 min). ¹ H NMR(400MHz,Methanol-d ₄ ): δ 7.81(d, J ═ 8.4Hz,1H),7.44(s,1H),7.28-7.20(m,4H),7.01(dd, J ═ 8.7,1.4Hz,1H),6.87(dd, J ═ 16.8,10.6Hz,1H),6.27(dd, J ═ 16.8,2.0Hz,1H),5.80(dd, J ═ 10.6,2.0Hz,1H),4.82(d, J ═ 13.0Hz,1H),4.66(t, J ═ 6.72Hz,2H),4.35(d, J ═ 13.6Hz,1H),3.58(tt, J ═ 12.2,3.52, 1H),3.40(d, J ═ 0, 13.92, 3.2H), 2.8 (d, 2.6H, 2H), 2.8H, 2H, 23.8H, 2H, 23.6H, 2H, 23.7.8H, 2H, 23H, 2H, 17H, 2H, 18H, 2H, 18H, 2H, 18H, 2H, 18H, 2H, 18H, 1H, 2H, 1H, 2H, 1H, 2H, 18H, 1H, 2H, 1H, 18, 1H, 2H, 1H, 18H, and so on the like ₂₇ H ₃₅ N ₄ O[M+H] ⁺ 431.27; the experiment shows that: 431.38.

synthesis of the final product 5: 1- (4- (2- (3- (dimethylamino) propyl) -6- (3-methylphenyl) -2H-indazol-3-yl) piperidin-1-yl) -2-propen-1-one (WHE09)

Step 1: synthesis of 3- (6- (3-methylphenyl) -2H-indazol-2-yl) -N, N-dimethylpropan-1-amine (WHD160)

Into a 50mL round-bottomed flask, WHD111(0.2035g, 0.72mmol), 3-methylphenylboronic acid (0.1448g,1.06mmol), Pd (dppf) Cl were added in this order ₂ DCM (0.0592g, 0.072mmol) and then DME (6mL), Na ₂ CO ₃ Aqueous solution (2M, 2mL), purge twice, N ₂ The reaction system was heated at 95 ℃ for 12 hours with protection. After the reaction is finished, cooling to room temperature, removing the solvent, and obtaining a column layerThe mixture was separated (mobile phase 1:1 ethyl acetate methanol and 10% ammonia) to obtain the aimed compound WHD160(0.1510 g). ¹ H NMR(400MHz,Methanol-d ₄ )δ8.16(s,1H),7.78(s,1H),7.71(d,J＝8.5Hz,1H),7.46(s,1H),7.43(d,J＝7.0Hz,1H),7.35-7.28(m,2H),7.13(s,1H),4.44(s,2H),2.38(s,3H),2.28(s,2H),2.20(s,6H),2.19-2.15(m,2H).

Step 2: synthesis of 3- (3-bromo-6- (3-methylphenyl) -2H-indazol-2-yl) -N, N-dimethylpropan-1-amine (WHE02)

The starting material WHD160(0.1510g,0.52mmol) was dissolved in HOAc and NBS (0.1120g,0.63mmol) was added and stirred at room temperature for 18 h. After the reaction is finished, water is added for quenching, the solvent is removed, and NaHCO is used ₃ The solution neutralizes acidity. By CH ₂ Cl ₂ Extracting with ethyl acetate for three times, mixing organic phases, and adding Na ₂ SO ₄ Dried (anhydrous) and concentrated to give crude WHE02(0.19g) which was used directly in the next reaction.

And 3, step 3: synthesis of 4- (2- (3- (dimethylamino) propyl) -6- (3-tolyl) -2H-indazol-3-yl) -3, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester (WHE04)

A50 mL round-bottom flask was charged with the starting material WHE02(0.10g,0.27mmol) obtained in the previous step, N-Boc-1,2,5, 6-tetrahydropyridine-4-boronic acid pinacol ester (0.1287g,0.416mmol), Pd (dppf) Cl ₂ DCM (0.0293g, 0.036mmol) and then DME (6mL), Na ₂ CO ₃ Aqueous solution (2M, 2mL), purge twice, N ₂ The reaction system was heated at 95 ℃ for 12 hours with protection. After the reaction, the solvent was removed and column chromatography was carried out (mobile phase 1:1 ethyl acetate methanol, methanol) to obtain WHE04(0.13 g). ¹ H NMR(400MHz,Methanol-d ₄ )δ7.73(s,1H),7.69(d,J＝8.8Hz,1H),7.49(s,1H),7.45(d,J＝8.1Hz,1H),7.38(dd,J＝8.8,1.4Hz,1H),7.33(t,J＝7.6Hz,1H),7.18(d,J＝7.4Hz,1H),6.12(s,1H),4.51(t,J＝6.6Hz,2H),4.21(s,2H),3.77(s,2H),2.91-2.84(m,2H),2.63(s,6H),2.51-2.42(m,2H),2.34-2.27(m,2H),1.94(s,3H),1.52(s,9H).

And 4, step 4: synthesis of tert-butyl 4- (2- (3- (dimethylamino) propyl) -6- (3-methylphenyl) -2H-indazol-3-yl) piperidine-1-carboxylate (WHE07)

Mixing raw material WHE04 (0.13)g) Dissolved in methanol, degassed N ₂ Adding Pd (OH) under protection ₂ (0.0302g) after evacuation in H ₂ The reaction mixture was stirred at room temperature for 24 hours under an atmosphere, and the palladium catalyst was filtered and concentrated to obtain the desired product WHE07(0.13g) which was used directly in the next reaction. ¹ H NMR(400MHz,Methanol-d ₄ )δ7.82(d,J＝8.7Hz,1H),7.72(s,1H),7.48(s,1H),7.44(d,J＝7.9Hz,1H),7.34-7.30(m,2H),7.17(d,J＝7.4Hz,1H),4.60(t,J＝6.6Hz,2H),4.29(d,J＝12.7Hz,2H),3.49-3.43(m,1H),3.11-3.01(m,4H),2.78(s,6H),2.51-2.47(m,2H),2.41(s,3H),2.39-2.35(m,2H),2.18-2.09(m,2H),1.52(s,9H).

And 5: synthesis of 1- (4- (2- (3- (dimethylamino) propyl) -6- (3-methylphenyl) -2H-indazol-3-yl) piperidin-1-yl) -2-propen-1-one (WHE09)

The starting material WHE07(0.065g,0.136mmol) was dissolved in CH ₂ Cl ₂ (2mL), TFA (1mL) was added, the mixture was stirred at room temperature for 30min, the solvent was removed, and a small amount of toluene was added, followed by removal. Dissolved in THF (8mL) and Et added ₃ N (2mL), followed by addition of acryloyl chloride (12.2mg,0.136mmol) and stirring at room temperature for 1 hour. After removal of the solvent, HPLC purification gave 21.2mg of the trifluoroacetate salt of WHE09 as a final product (purification conditions: 15% CH) ₃ CN start, retention time 17.8 min). ¹ H NMR(400MHz,Methanol-d ₄ ) δ 7.83(d, J ═ 8.9Hz,1H),7.74(s,1H),7.48(s,1H),7.44(d, J ═ 7.8Hz,1H),7.34-7.31(m,2H),7.18-7.17(m,1H),6.87(dd, J ═ 16.8,10.7Hz,1H),6.28(dd, J ═ 16.8,2.0Hz,1H),5.80(dd, J ═ 10.6,2.0Hz,1H),4.82(d, J ═ 12.8Hz,1H),4.64(t, J ═ 6.6Hz, 2H),4.35(d, J ═ 13.0Hz,1H),3.55 (ett, J ═ 12.2, 3.92, 3.7H, 3.7, 7(t, 2H), 2H, 15.7.7 (15, 7.7H), 15.7.7H, 7H, 7.4.7H, 7H, 15 (dd, 15H), 15H, 15, 2H, 15, 2H, 15, 2H, 15, 2H, 2H, 2, 15, 2H, 15, 2H, 2, etc ₂₇ H ₃₅ N ₄ O[M+H] ⁺ 431.27; the experiment shows that: 431.35.

synthesis of final product 6: 1- (4- (2- (3- (dimethylamino) propyl) -6- (2-hydroxyphenyl) -2H-indazol-3-yl) piperidin-1-yl) -2-propen-1-one (WHE11)

Step 1: synthesis of 3- (6- (2-hydroxyphenyl) -2H-indazol-2-yl) -N, N-dimethylpropan-1-amine (WHD141)

Into a 50mL round-bottomed flask, WHD111(0.2099g, 0.74mmol), 2-hydroxyphenylboronic acid (0.1611g,1.16mmol), Pd (dppf) Cl were added in this order ₂ DCM (0.0594g, 0.073mmol) and then DME (6mL), Na ₂ CO ₃ Aqueous solution (2M, 2mL), purge twice, N ₂ The reaction system was heated at 95 ℃ for 12 hours with protection. After the reaction was completed, it was cooled to room temperature, the solvent was removed, and column chromatography (mobile phase 1:1 ethyl acetate methanol, and 10% ammonia water) was performed to obtain the aimed compound WHD141(0.2007 g). ¹ H NMR(400MHz,Methanol-d ₄ )δ8.19(s,1H),7.73(s,1H),7.67(d,J＝8.7Hz,1H),7.33-7.31(m,1H),7.30(t,J＝1.3Hz,2H),7.21-7.14(m,1H),6.92(d,J＝4.4Hz,1H),6.90(d,J＝7.0Hz,1H),4.48(t,J＝6.8Hz,2H),2.31(t,J＝6.7Hz,2H),2.21(s,6H),2.23-2.16(m,2H).

Step 2: synthesis of 3- (3-bromo-6- (2-hydroxyphenyl) -2H-indazol-2-yl) -N, N-dimethylpropan-1-amine (WHD149)

The starting material WHD141(0.2g,0.68mmol) was dissolved in HOAc, NBS (0.1239g,0.75mmol) was added, and the mixture was stirred at room temperature for 18 hours. After the reaction is finished, water is added for quenching, the solvent is removed, and NaHCO is used ₃ The solution neutralizes acidity. By CH ₂ Cl ₂ Extracting with ethyl acetate for three times, mixing organic phases, and adding Na ₂ SO ₄ Dried (anhydrous) and concentrated to give the crude WHD154(0.24g) which was used directly in the next reaction.

And step 3: synthesis of 4- (2- (3- (dimethylamino) propyl) -6- (2-hydroxyphenyl) -2H-indazol-3-yl) -3, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester (WHD154)

A50 mL round-bottom flask was charged with the starting material WHD149(0.13g,0.33mmol) obtained in the previous step, N-Boc-1,2,5, 6-tetrahydropyridine-4-boronic acid pinacol ester (0.1761g,0.57mmol), Pd (dppf) Cl ₂ DCM (0.0298g,0.036mmol) and then DME (6mL), Na ₂ CO ₃ Aqueous solution (2M, 2mL), purge twice, N ₂ The reaction system was heated at 95 ℃ for 12 hours with protection. After the reaction is finished, removing the solvent, and performing column chromatography (mobile phase is 1:1 ethyl acetate methanol and methyl acetate)Alcohol) to give a product WHD154(0.1 g). ¹ H NMR(400MHz,Methanol-d ₄ )δ8.23(d,J＝11.7Hz,1H),7.74-7.67(m,2H),7.36-7.15(m,3H),6.94-6.87(m,1H),6.00(s,0.5H),5.80(s,0.5H),4.52(s,2H),4.04(s,2H),3.63(s,2H),2.58-2.49(m,1),2.49(s,6H),2.43(s,2H),2.27(s,2H),1.49(s,4H),1.48(s,5H).

And 4, step 4: synthesis of tert-butyl 4- (2- (3- (dimethylamino) propyl) -6- (2-hydroxyphenyl) -2H-indazol-3-yl) piperidine-1-carboxylate (WHE08)

The raw material WHD154(0.1g) was dissolved in methanol and degassed N ₂ Adding Pd (OH) under protection ₂ (0.0272g) in H after evacuation ₂ Stirring for 24 hours at room temperature under the atmosphere, filtering the palladium catalyst, and concentrating to obtain a target product WHE08 which is directly used for the next reaction. ¹ H NMR(400MHz,Methanol-d ₄ )δ8.36(s,1H),7.76(d,J＝8.8Hz,2H),7.38(dd,J＝8.7,5.3Hz,1H),7.20(d,J＝25.7Hz,1H),7.11(dd,J＝20.9,8.4Hz,1H),6.92(dd,J＝14.1,8.2Hz,1H),4.65(t,J＝6.5Hz,2H),4.20(d,J＝12.8Hz,1H),3.51(d,J＝12.0Hz,1H),3.24-3.06(m,3H),2.89(s,6H),2.88-2.83(m,1H),2.71-2.67(m,1H),2.47(s,2H),2.10(d,J＝13.0Hz,1H),1.95(t,J＝11.3Hz,1H),1.89(d,J＝12.7Hz,1H),1.63-1.53(m,1H),1.47(s,9H).

And 5: synthesis of 1- (4- (2- (3- (dimethylamino) propyl) -6- (2-hydroxyphenyl) -2H-indazol-3-yl) piperidin-1-yl) -2-propen-1-one (WHE11)

The starting material WHE08(18.8mg,0.0393mmol) was dissolved in CH ₂ Cl ₂ (1mL), TFA (0.5mL) was added, the mixture was stirred at room temperature for 30min, and the solvent was removed, followed by addition of a small amount of toluene. Dissolved in THF (8mL) and Et added ₃ N (0.9mL), followed by addition of acryloyl chloride (3.54mg,0.0393mmol) was stirred at room temperature for 1 hour. After removal of the solvent, HPLC purification gave 4mg of the trifluoroacetate salt of WHE11 as a final product (purification conditions: 15% CH) ₃ CN start, retention time 12 min). ¹ H NMR(400MHz,Methanol-d ₄ )δ8.26(d,J＝0.9Hz,1H),7.75(s,1H),7.70(dd,J＝8.7,0.6Hz,1H),7.34(dd,J＝8.7,1.3Hz,1H),7.17(d,J＝2.2Hz,1H),7.06(dd,J＝8.3,2.2Hz,1H),6.85(d,J＝8.2Hz,1H),6.80(dd,J＝16.8,10.7Hz,1H),6.19(dd,J＝16.8,2.0Hz,1H),5.74(dd,J＝10.7,2.0Hz,1H),4.70(d,J＝13.0Hz,1H),4.61(t,J＝6.4Hz2H),4.22(d, J ═ 13.3Hz,1H),3.25(d, J ═ 13.2Hz,1H),3.17(d, J ═ 8.0Hz,2H),2.88(s,6H),2.85-2.77(m,2H),2.49-2.37(p, J ═ 6.9Hz,2H),1.93(s,2H),1.67-1.58(m,2H), ESI-MS theoretical calculation C ₂₆ H ₃₃ N ₄ O ₂ [M+H] ⁺ 433.25; the experiment shows that: 433.23.

synthesis of final product 7: 1- (4- (2- (3- (dimethylamino) propyl) -6- (3-hydroxyphenyl) -2H-indazol-3-yl) piperidin-1-yl) -2-propen-1-one (WHE19)

Step 1: synthesis of 3- (6- (3-hydroxyphenyl) -2H-indazol-2-yl) -N, N-dimethylpropan-1-amine (WHD142)

A50 mL round-bottomed flask was charged with WHD111(0.2155g, 0.76mmol), 3-hydroxyphenylboronic acid (0.1712g,1.24mmol), Pd (dppf) Cl in that order ₂ DCM (0.0591g, 0.072mmol) and then DME (6mL), Na ₂ CO ₃ Aqueous solution (2M, 2mL), purge twice, N ₂ The reaction system was heated at 95 ℃ for 12 hours with protection. After the reaction was completed, it was cooled to room temperature, the solvent was removed, and column chromatography (mobile phase 1:1 ethyl acetate methanol, and 10% aqueous ammonia) was performed to obtain the aimed compound WHD142(0.2254 g). ¹ H NMR(400MHz,Methanol-d ₄ )δ8.24(s,1H),7.76-7.74(m,2H),7.36(dd,J＝9.0,1.4Hz,1H),7.27(t,J＝7.8Hz,1H),7.18-7.07(m,2H),6.79(dd,J＝8.0,2.2Hz,1H),4.51(t,J＝6.8Hz,2H),2.36(d,J＝6.8Hz,2H),2.26(s,6H),2.24-2.18(m,2H).

Step 2: synthesis of 3- (3-bromo-6- (3-hydroxyphenyl) -2H-indazol-2-yl) -N, N-dimethylpropan-1-amine (WHD150)

The starting material WHD142(0.2200g,0.75mmol) was dissolved in HOAc and NBS (0.1334g,0.75mmol) was added and stirred at room temperature for 18 h. After the reaction is finished, water is added for quenching, the solvent is removed, and NaHCO is used ₃ The solution neutralizes acidity. By CH ₂ Cl ₂ Extracting with ethyl acetate for three times, mixing organic phases, and adding Na ₂ SO ₄ Dried (anhydrous) and concentrated to give the crude WHD150(0.28g) which was used directly in the next reaction.

And step 3: synthesis of 4- (2- (3- (dimethylamino) propyl) -6- (3-hydroxyphenyl) -2H-indazol-3-yl) -3, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester (WHD153)

A50 mL round-bottom flask was charged with the starting material WHD150(0.14g,0.37mmol) obtained in the previous step, N-Boc-1,2,5, 6-tetrahydropyridine-4-boronic acid pinacol ester (0.1833g,0.59mmol), Pd (dppf) Cl ₂ DCM (0.0301g, 0.037mmol) and then DME (6mL), Na ₂ CO ₃ Aqueous solution (2M, 2mL), purge twice, N ₂ The reaction system was heated at 95 ℃ for 12 hours with protection. After the reaction is finished, the solvent is removed, and column chromatography is carried out (mobile phase is 1:1 ethyl acetate methanol and methanol), so as to obtain a product WHD153(0.1777 g). ¹ H NMR(400MHz,Methanol-d ₄ )δ8.31-8.25(m,1H),7.76-7.59(m,2H),7.42-7.39(m,2H),7.03-6.80(m,2H),5.58(s,1H),4.60(td,J＝6.6,2.2Hz,2H),3.78(s,2H),3.22(q,J＝7.7Hz,2H),3.14-3.11(m,2H),2.90(s,6H),2.46-2.41(m,2H),1.85-1.71(m,2H),1.35(d,J＝13.4Hz,9H).

And 4, step 4: synthesis of tert-butyl 4- (2- (3- (dimethylamino) propyl) -6- (3-hydroxyphenyl) -2H-indazol-3-yl) piperidine-1-carboxylate (WHE12)

The raw material WHD153(0.1777g) was dissolved in methanol and degassed N ₂ Adding Pd (OH) under protection ₂ (0.0450g) in H after evacuation ₂ The reaction mixture was stirred at room temperature for 24 hours under an atmosphere, and the palladium catalyst was filtered and concentrated to obtain the desired product WHE12(0.13g) which was used directly in the next reaction.

And 5: synthesis of 1- (4- (2- (3- (dimethylamino) propyl) -6- (3-hydroxyphenyl) -2H-indazol-3-yl) piperidin-1-yl) -2-propen-1-one (WHE19)

The starting material WHE12(0.0252g,0.053mmol) was dissolved in CH ₂ Cl ₂ (2mL), TFA (1mL) was added, the mixture was stirred at room temperature for 30min, the solvent was removed, and a small amount of toluene was added, followed by removal. Dissolved in THF (8mL) and Et added ₃ N (1mL), followed by addition of acryloyl chloride (4.74mg,0.053mmol) and stirring at room temperature for 1 hour. After removal of the solvent, HPLC purification gave 14.5mg of the trifluoroacetate salt of the final product WHE19 (purification conditions: 15% CH) ₃ CN start, retention time 12.4 min). ¹ H NMR(400MHz,Methanol-d ₄ )δ7.82(d,J＝8.9Hz,1H),7.72(s,1H),7.31(dt, J8.8, 1.5Hz,1H),7.26(t, J7.9 Hz,1H),7.12(d, J7.8 Hz,1H),7.08(t, J1.8 Hz,1H),6.87(dd, J16.8, 10.7Hz,1H),6.79(dd, J8.0, 2.3,0.7Hz,1H),6.28(dd, J16.8, 2.0Hz,1H),5.80(dd, J10.6, 2.0Hz,1H),4.81(d, J12.3 Hz,1H),4.63(td, J6.6, 1.2, 2H),4.35(d, J5, t, 3.6, 7.6H, 7.6, 7.8, 7H, 5H, 6.6, 7.6H, 7H, 7.6H, 5H, 7.6H, 7H, 5H, 6.6H, 6H, 5H, 7.6H, 5H, 6H, 3H, 5H, 6H, 5H, 7H, 5H, 6H, 5H, 7H, 5H, 6H, 3H, 5H, 6H, 7H, 5H, 6H, 3H, 7H, 3H, 5H, 6H, 5H, 3H, 7H, 3H, 5H, 6H, 3H, 6H, 5H, 6H, 5H, 6H, 3H, 5H, 6H, 3H, 5H, etc., 1.5H),2.18(p, J ═ 9.5Hz,2H),2.05(s,2H) ESI-MS theoretically calculated value C ₂₆ H ₃₃ N ₄ O ₂ [M+H] ⁺ 433.25; the experiment shows that: 433.29.

synthesis of the final product 8: 1- (4- (2- (3- (dimethylamino) propyl) -6- (2-trifluoromethylphenyl) -2H-indazol-3-yl) piperidin-1-yl) -2-propen-1-one (WHE23)

Step 1: synthesis of 3- (6- (2-trifluoromethylphenyl) -2H-indazol-2-yl) -N, N-dimethylpropan-1-amine (WHE15)

Into a 50mL round-bottom flask, WHD111(0.15g, 0.53mmol), 2-trifluoromethylphenylboronic acid (0.1540g,0.8mmol), Pd (dppf) Cl were added in this order ₂ DCM (0.0428g, 0.052mmol) and then DME (6mL), Na ₂ CO ₃ Aqueous solution (2M, 2mL), purge twice, N ₂ The reaction system was heated at 95 ℃ for 12 hours with protection. After the reaction was completed, it was cooled to room temperature, the solvent was removed, and column chromatography (mobile phase 1:1 ethyl acetate methanol, and 10% ammonia water) was performed to obtain the objective compound WHE15(0.1463 g). ¹ H NMR(400MHz,Methanol-d ₄ )δ8.29(s,1H),7.79(d,J＝8.0Hz,1H),7.72(d,J＝8.6Hz,1H),7.65(t,J＝7.6Hz,1H),7.55(t,J＝7.7Hz,1H),7.50(s,1H),7.42(d,J＝7.5Hz,1H),7.03(d,J＝8.6Hz,1H),4.52(t,J＝6.8Hz,2H),2.38(t,J＝8.0Hz,2H),2.27(s,6H),2.23(p,J＝7.1Hz,2H).

Step 2: synthesis of 3- (3-bromo-6- (2-trifluoromethylphenyl) -2H-indazol-2-yl) -N, N-dimethylpropan-1-amine (WHE17)

The raw material WHE15(0.14g,0.40mmol)Dissolve in HOAc, add NBS (0.0783g,0.44mmol) and stir at room temperature for 18 h. After the reaction is finished, water is added for quenching, the solvent is removed, and NaHCO is used ₃ The solution neutralizes acidity. By CH ₂ Cl ₂ Extracting with ethyl acetate for three times, mixing organic phases, and adding Na ₂ SO ₄ Dried (anhydrous) and concentrated to give crude WHE17(0.17g) which was used directly in the next reaction.

And step 3: synthesis of 4- (2- (3- (dimethylamino) propyl) -6- (2-trifluoromethylphenyl) -2H-indazol-3-yl) -3, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester (WHE18)

A50 mL round-bottom flask was charged with the starting material WHE17(0.10g,0.23mmol) obtained in the previous step, N-Boc-1,2,5, 6-tetrahydropyridine-4-boronic acid pinacol ester (0.1188g,0.38mmol), Pd (dppf) Cl ₂ DCM (0.0245g, 0.03mmol) and then DME (6mL), Na ₂ CO ₃ Aqueous solution (2M, 2mL), purge twice, N ₂ The reaction system was heated at 95 ℃ for 12 hours with protection. After the reaction, the solvent was removed and column chromatography was carried out (mobile phase 1:1 ethyl acetate methanol, methanol) to obtain WHE18(0.2 g). ¹ H NMR(400MHz,Methanol-d ₄ )δ7.80(d,J＝7.7Hz,1H),7.68-7.64(m,2H),7.57(t,J＝7.5Hz,1H),7.48(s,1H),7.41(d,J＝7.6Hz,1H),7.03(d,J＝8.7Hz,1H),6.15(s,1H),4.54(t,J＝6.8Hz,2H),4.22(s,2H),3.78-3.76(m,2H),2.99(t,J＝8.0Hz,2H),2.71(s,6H),2.62(s,2H),2.35(p,J＝6.9Hz,2H),1.52(s,9H).

And 4, step 4: synthesis of tert-butyl 4- (2- (3- (dimethylamino) propyl) -6- (2-trifluoromethylphenyl) -2H-indazol-3-yl) piperidine-1-carboxylate (WHE20)

The raw material WHE18(0.2g) was dissolved in methanol, degassed N ₂ Adding Pd (OH) under protection ₂ (0.0789g) after evacuation in H ₂ The reaction mixture was stirred at room temperature for 24 hours under an atmosphere, and the palladium catalyst was filtered and concentrated to obtain a target product WHE20(0.1833g) which was used directly in the next reaction. ¹ H NMR(400MHz,Methanol-d ₄ )δ7.80(d,J＝4.0Hz,1H),7.78(d,J＝3.1Hz,1H),7.65(t,J＝7.5Hz,1H),7.56(t,J＝7.5Hz,1H),7.46(s,1H),7.40(d,J＝7.6Hz,1H),6.98(d,J＝8.7Hz,1H),4.63(t,J＝6.8Hz,2H),4.30(d,J＝13.1Hz,2H),3.53-3.47(m,1H),3.10-3.01(m,4H),2.76(s,6H),2.38(p,J＝6.9Hz,2H),2.14(qd,J＝12.6,4.2Hz,2H),1.99-1.94(m,2H),1.51(s,9H).

And 5: synthesis of 1- (4- (2- (3- (dimethylamino) propyl) -6- (2-trifluoromethylphenyl) -2H-indazol-3-yl) piperidin-1-yl) -2-propen-1-one (WHE23)

The starting material WHE20(0.107g,0.2mmol) was dissolved in CH ₂ Cl ₂ (2mL), TFA (1mL) was added, the mixture was stirred at room temperature for 30min, the solvent was removed, and a small amount of toluene was added, followed by removal. Dissolved in THF (8mL) and Et added ₃ N (2mL), followed by addition of acryloyl chloride (18.2mg,0.2mmol) and stirring at room temperature for 1 hour. After removal of the solvent, HPLC purification gave 54.5mg of the trifluoroacetate salt of WHE23 as a final product (purification conditions: 15% CH) ₃ CN start, retention time 18.2 min). ¹ H NMR(400MHz,Methanol-d ₄ ) δ 7.80(t, J ═ 7.4Hz,2H),7.65(t, J ═ 7.5Hz,1H),7.56(t, J ═ 7.6Hz,1H),7.48(s,1H),7.39(d, J ═ 7.6Hz,1H),6.99(d, J ═ 8.8Hz,1H),6.87(dd, J ═ 16.8,10.7Hz,1H),6.27(dd, J ═ 16.8,2.0Hz,1H),5.80(dd, J ═ 10.7,2.0Hz,1H),4.82(d, J ═ 13.0Hz,1H),4.66(t, J ═ 6.6Hz,2H),4.35(d, J ═ 13.4, 3.59, 3, 3.2H, 3, 3.7H, 3, 2,3, 2,3, 2,3, 2,3, 2,3, 2,3, 2,3, 2,3, 2, etc. H. ₂₇ H ₃₂ F ₃ N ₄ O[M+H] ⁺ 485.24; the experiment shows that: 485.48.

synthesis of end product 9: 1- (4- (2- (3- (dimethylamino) propyl) -6- (3-methoxyphenyl) -2H-indazol-3-yl) piperidin-1-yl) -2-propen-1-one (WHE53)

Step 1: synthesis of 3- (6- (3-methoxyphenyl) -2H-indazol-2-yl) -N, N-dimethylpropan-1-amine (WHE31)

Into a 50mL round bottom flask were added WHD111(0.2122g, 0.75mmol), 3-methoxyphenylboronic acid (0.1612g,1.06mmol), Pd (dppf) Cl in that order ₂ DCM (0.0590g, 0.072mmol) and then DME (6mL), Na ₂ CO ₃ Aqueous solution (2M, 2mL), purge twice, N ₂ Reaction under protectionThe system was heated at 95 ℃ for 12 hours. After the reaction was completed, it was cooled to room temperature, and the solvent was removed, followed by column chromatography (mobile phase 1:1 ethyl acetate methanol and 10% ammonia water) to obtain the objective compound WHE31(0.093 g). ¹ H NMR(400MHz,Methanol-d ₄ )δ8.25(s,1H),7.77(s,1.5H),7.75(s,0.5H),7.39–7.35(m,2H),7.24(d,J＝7.7Hz,1H),7.20(t,J＝2.0Hz,1H),6.92(dd,J＝8.0,2.1Hz,1H),4.52(t,J＝6.8Hz,2H),3.86(s,3H),2.52-2.42(m,2H),2.34(s,6H),2.23(p,J＝7.0Hz,2H).

Step 2: synthesis of 3- (3-bromo-6- (3-methoxyphenyl) -2H-indazol-2-yl) -N, N-dimethylpropan-1-amine (WHE39)

The starting material WHE31(0.093g,0.3mmol) was dissolved in HOAc, NBS (0.0546g,0.3mmol) was added, and the mixture was stirred at room temperature for 18 hours. After the reaction is finished, water is added for quenching, the solvent is removed, and NaHCO is used ₃ The solution neutralizes acidity. By CH ₂ Cl ₂ Extracting with ethyl acetate for three times, mixing organic phases, and adding Na ₂ SO ₄ Dried (anhydrous) and concentrated to give crude WHE39(0.116g) which was used directly in the next reaction.

And step 3: synthesis of 4- (2- (3- (dimethylamino) propyl) -6- (3-methoxyphenyl) -2H-indazol-3-yl) -3, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester (WHE43)

A50 mL round-bottom flask was charged with WHE39(0.116g,0.3mmol), N-Boc-1,2,5, 6-tetrahydropyridine-4-boronic acid pinacol ester (0.1366g,0.44mmol), Pd (dppf) Cl ₂ DCM (0.0245g, 0.03mmol) and then DME (6mL), Na ₂ CO ₃ Aqueous solution (2M, 2mL), purging twice, N ₂ The reaction system was heated at 95 ℃ for 12 hours with protection. After the reaction, the solvent was removed and column chromatography was carried out (mobile phase 1:1 ethyl acetate methanol, methanol) to obtain WHE43(0.17 g). ¹ H NMR(400MHz,Methanol-d ₄ )δ7.74(s,0.6H),7.67(dd,J＝8.6,3.4Hz,0.6H),7.61(dd,J＝8.6,3.4Hz,0.3H),7.56(s,0.3H),7.38–7.34(m,1.5H),7.24-7.10(m,2H),6.94-6.89(m,1.5H),6.11(s,1H),4.50(t,J＝6.5Hz,2H),4.21(s,2H),3.86(s,1.9H),3.82(s,1.1H),3.76(s,2H),2.79(s,2H),2.52-2.47(m,6H),2.28(s,2H),1.52(s,9H).

And 4, step 4: synthesis of tert-butyl 4- (2- (3- (dimethylamino) propyl) -6- (3-methoxyphenyl) -2H-indazol-3-yl) piperidine-1-carboxylate (WHE47)

The raw material WHE43(0.17g) was dissolved in methanol, degassed N ₂ Adding Pd (OH) under protection ₂ (0.0634g) in H after evacuation ₂ The reaction mixture was stirred at room temperature for 24 hours under an atmosphere, and the palladium catalyst was filtered and concentrated to obtain the desired product WHE47(0.112g) which was used directly in the next reaction.

And 5: synthesis of 1- (4- (2- (3- (dimethylamino) propyl) -6- (3-methoxyphenyl) -2H-indazol-3-yl) piperidin-1-yl) -2-propen-1-one (WHE53)

The starting material WHE47(0.1g,0.2mmol) was dissolved in CH ₂ Cl ₂ (2mL), TFA (1mL) was added, the mixture was stirred at room temperature for 30min, the solvent was removed, and a small amount of toluene was added, followed by removal. Dissolved in THF (8mL) and Et added ₃ N (2mL), followed by addition of acryloyl chloride (14.9mg,0.17mmol) and stirring at room temperature for 1 hour. After removal of the solvent, HPLC purification gave 3.2mg of the trifluoroacetate salt of WHE53 as a final product (purification conditions: 15% CH) ₃ CN start, retention time 17.2 min). ¹ H NMR(400MHz,Methanol-d ₄ ) δ 7.85-7.75(m,2H),7.56(s,1H),7.38-7.33(m,1H),7.27-7.16(m,2H),6.94-6.81(m,2H),6.27(dd, J ═ 16.8,2.0Hz,1H),5.80(dd, J ═ 10.6,2.0Hz,1H),4.82(d, J ═ 12.6Hz,1H),4.66-4.61(m,2H),4.35(d, J ═ 12.8Hz,1H),3.97-3.82(m,3H), 3.59-3.53 (m,1H),3.49-3.46(m,1H),3.40-3.35(m,1H),3.25(t, J ═ 2H), 7.92 (t, 2H), 2.03, 2H), 2H, 15.4.6H, 2H, 15H), theoretical calculated values (m,2H), 2H, 15, 2H, 15H, 2H, 15, 2H, 15, 2H, or similar to 5H, 15H, 6H, 15H, 6, 2H, 15H, 15H, 15, or similar to 4, 15H, 2, 15H, 2H, 15H, 2H, 2, 15, 2, 6,2, 15, 2, 15, 2, 4, or similar to 4, 2, 4, 2, 6,2, 4, 2, or similar to 4 ₂₇ H ₃₅ N ₄ O ₂ [M+H] ⁺ 447.27; the experiment shows that: 447.26.

synthesis of the final product 10: 1- (4- (2- (3- (dimethylamino) propyl) -6- (2-methoxyphenyl) -2H-indazol-3-yl) piperidin-1-yl) -2-propen-1-one (WHE54)

Step 1: synthesis of 3- (6- (2-methoxyphenyl) -2H-indazol-2-yl) -N, N-dimethylpropan-1-amine (WHE30)

Into a 50mL round bottom flask, WHD111(0.2121g, 0) was added sequentially75mmol), 2-methoxyphenylboronic acid (0.1615g,1.06mmol), Pd (dppf) Cl ₂ DCM (0.0582g, 0.07mmol) was added followed by DME (6mL), Na ₂ CO ₃ Aqueous solution (2M, 2mL), purge twice, N ₂ The reaction system was heated at 95 ℃ for 12 hours with protection. After the reaction was completed, it was cooled to room temperature, and the solvent was removed, followed by column chromatography (mobile phase 1:1 ethyl acetate methanol and 10% ammonia water) to obtain the objective compound WHE30(0.073 g). ¹ H NMR(400MHz,Methanol-d ₄ )δ8.22(s,1H),7.67(d,J＝9.2Hz,1H),7.64(s,1H),7.35-7.31(m,2H),7.23(dd,J＝8.7,1.3Hz,1H),7.08(d,J＝8.4Hz,1H),7.03(td,J＝7.5,1.1Hz,1H),4.50(t,J＝6.8Hz,2H),3.80(s,3H),2.36(dd,J＝8.9,6.1Hz,2H),2.27(s,6H),2.19(p,J＝7.1Hz,2H).

Step 2: synthesis of 3- (3-bromo-6- (2-methoxyphenyl) -2H-indazol-2-yl) -N, N-dimethylpropan-1-amine (WHE38)

The starting material WHE30(0.073g,0.24mmol) was dissolved in HOAc, NBS (0.0423g,0.24mmol) was added, and the mixture was stirred at room temperature for 18 hours. After the reaction is finished, water is added for quenching, the solvent is removed, and NaHCO is used ₃ The solution neutralizes acidity. By CH ₂ Cl ₂ Extracting with ethyl acetate for three times, mixing organic phases, and adding Na ₂ SO ₄ Dried (anhydrous) and concentrated to give crude WHE38(0.09g) which was used directly in the next reaction.

And step 3: synthesis of 4- (2- (3- (dimethylamino) propyl) -6- (2-methoxyphenyl) -2H-indazol-3-yl) -3, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester (WHE42)

A50 mL round-bottom flask was charged with WHE38(0.09g,0.23mmol), N-Boc-1,2,5, 6-tetrahydropyridine-4-boronic acid pinacol ester (0.107g,0.35mmol), Pd (dppf) Cl ₂ DCM (0.0243g, 0.03mmol) and then DME (6mL), Na ₂ CO ₃ Aqueous solution (2M, 2mL), purge twice, N ₂ The reaction system was heated at 95 ℃ for 12 hours with protection. After the reaction, the solvent was removed and column chromatography was carried out (mobile phase 1:1 ethyl acetate methanol, methanol) to obtain WHE42(0.10 g). ¹ H NMR(400MHz,Methanol-d ₄ )δ7.60(s,1H),7.56(s,1H),7.39-7.32(m,2H),7.21(d,J＝8.6Hz,1H),7.08(d,J＝8.5Hz,1H),7.02(t,J＝7.4Hz,1H),6.10(s,1H),4.45(t,J＝6.9Hz,2H),4.20(s,2H),3.79(s,3H),3.75(s,2H),2.59(s,2H),2.40(t,J＝7.5Hz,2H),2.27(s,6H),2.17(p,J＝7.2Hz,2H),1.52(s,9H).

And 4, step 4: synthesis of tert-butyl 4- (2- (3- (dimethylamino) propyl) -6- (2-methoxyphenyl) -2H-indazol-3-yl) piperidine-1-carboxylate (WHE46)

The raw material WHE42(0.17g) was dissolved in methanol, degassed N ₂ Adding Pd (OH) under protection ₂ (0.0603g) after evacuation in H ₂ The reaction mixture was stirred at room temperature for 24 hours under an atmosphere, and the palladium catalyst was filtered and concentrated to obtain the desired product WHE46(0.16g) which was used directly in the next reaction. ¹ H NMR(400MHz,Methanol-d ₄ )δ7.72(d,J＝8.8Hz,1H),7.58(s,1H),7.34-7.31(m,2H),7.17(d,J＝8.8Hz,1H),7.07(d,J＝8.4Hz,1H),7.02(t,J＝7.5Hz,1H),4.54(t,J＝6.9Hz,2H),4.29(d,J＝12.6Hz,2H),3.79(s,3H),3.46-3.40(m,2H),3.00(s,2H),2.65(s,2H),2.46(s,.6H),2.22-2.20(m,2H),2.15-2.09(m,2H),1.52(s,9H).

And 5: synthesis of 1- (4- (2- (3- (dimethylamino) propyl) -6- (2-methoxyphenyl) -2H-indazol-3-yl) piperidin-1-yl) -2-propen-1-one (WHE54)

The starting material WHE46(0.08g,0.16mmol) was dissolved in CH ₂ Cl ₂ (2mL), TFA (1mL) was added, the mixture was stirred at room temperature for 30min, the solvent was removed, and a small amount of toluene was added, followed by removal. Dissolved in THF (8mL) and Et added ₃ N (2mL), followed by addition of acryloyl chloride (14.6mg,0.16mmol) and stirring at room temperature for 1 hour. After removal of the solvent, HPLC purification gave 13.1mg of the trifluoroacetate salt of WHE54 as a final product (purification conditions: 15% CH) ₃ CN start, retention time 11.8 min). ¹ H NMR(400MHz,Methanol-d ₄ ) δ 7.74(d, J ═ 8.8Hz,1H),7.61(s,1H),7.42-7.31(m,2H),7.19(d, J ═ 8.7Hz,1H),7.08(d, J ═ 8.0Hz,1H),7.09(t, J ═ 7.3Hz,1H),6.87(dd, J ═ 16.8,10.6Hz,1H),6.27(d, J ═ 16.8Hz,1H),5.80(d, J ═ 10.6Hz,1H),4.82(d, J ═ 13.5Hz,1H),4.63(s,2H),4.35(d, J ═ 13.2Hz,1H),3.79(s,3H),3.73-3.62(m, 3.2H), 3.91 (m ═ 2H), 3.8 (s,2H), 3.49 (s, 3.06H), 3.3.3H, 3.8 (s,3H), 3.6H), 3.8H, 1H), 3.6H, 1H, 23, 8H, 1H, 6H, 1H, etc., C, etc., C, etc., C ₂₇ H ₃₅ N ₄ O ₂ [M+H] ⁺ 447.27; the experiment shows that: 447.36

Synthesis of the final product 11: 1- (4- (2- (3- (dimethylamino) propyl) -6- (3-trifluoromethylphenyl) -2H-indazol-3-yl) piperidin-1-yl) -2-propen-1-one (WHE58)

Step 1: synthesis of 3- (6- (3-trifluoromethylphenyl) -2H-indazol-2-yl) -N, N-dimethylpropan-1-amine (WHE32)

Into a 50mL round-bottom flask were added WHD111(0.2175g, 0.77mmol), 3-trifluoromethylphenylboronic acid (0.2029g,1.07mmol), Pd (dppf) Cl in that order ₂ DCM (0.0591g, 0.072mmol) and then DME (6mL), Na ₂ CO ₃ Aqueous solution (2M, 2mL), purge twice, N ₂ The reaction system was heated at 95 ℃ for 12 hours with protection. After the reaction is finished, the reaction product is cooled to room temperature, the solvent is removed, and column chromatography is carried out (mobile phase is 1:1 ethyl acetate methanol and 10% ammonia water), so that the target compound WHE32(0.011) is obtained. ¹ H NMR(400MHz,Methanol-d ₄ )δ8.30(d,J＝4.2Hz,1H),7.96-7.93(m,2H),7.84-7.82(m,2H),7.67-7.66(m,2H),7.42-7.39(m,1H),4.59(t,J＝6.7Hz,0.8H),4.53(t,J＝6.9Hz,1.2H),2.40-2.36(m,2H),2.27(s,6H),2.25-2.20(m,2H).

Step 2: synthesis of 3- (3-bromo-6- (3-trifluoromethylphenyl) -2H-indazol-2-yl) -N, N-dimethylpropan-1-amine (WHE40)

The starting material WHE32(0.11g,0.32mmol) was dissolved in HOAc and NBS (0.0638g,0.36mmol) was added and stirred at room temperature for 18 h. After the reaction is finished, water is added for quenching, the solvent is removed, and NaHCO is used ₃ The solution neutralizes acidity. By CH ₂ Cl ₂ Extracting with ethyl acetate for three times, mixing organic phases, and adding Na ₂ SO ₄ Dried (anhydrous) and concentrated to give crude WHE40(0.13g) which was used directly in the next reaction.

And step 3: synthesis of 4- (2- (3- (dimethylamino) propyl) -6- (3-trifluoromethylphenyl) -2H-indazol-3-yl) -3, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester (WHE44)

A50 mL round-bottom flask was charged with WHE40(0.13g,0.3mmol), N-Boc-1,2,5,6, which was the starting material obtained in the previous step, in that order-tetrahydropyridine-4-boronic acid pinacol ester (0.1436g,0.46mmol), Pd (dppf) Cl ₂ DCM (0.0274g, 0.03mmol) and then DME (6mL), Na ₂ CO ₃ Aqueous solution (2M, 2mL), purge twice, N ₂ The reaction system was heated at 95 ℃ for 12 hours with protection. After the reaction is finished, the solvent is removed, and column chromatography is carried out (mobile phase is 1:1 ethyl acetate methanol and methanol), so as to obtain a product WHE44(0.075 g). ¹ H NMR(400MHz,Methanol-d ₄ )δ7.96(d,J＝4.2Hz,1H),7.93(s,1H),7.82(s,1H),7.75(d,J＝8.6Hz,1H),7.68-7.66(m,2H),7.40(d,J＝8.8Hz,1H),6.13(s,1H),4.52(t,J＝6.6Hz,2H),4.22(s,2H),3.77(s,2H),2.80(s,2H),2.61-2.58(m,8H),2.30(s,2H),1.52(s,9H).

And 4, step 4: synthesis of tert-butyl 4- (2- (3- (dimethylamino) propyl) -6- (3-trifluoromethylphenyl) -2H-indazol-3-yl) piperidine-1-carboxylate (WHE48)

The raw material WHE44(0.075g) was dissolved in methanol and degassed N ₂ Adding Pd (OH) under protection ₂ (0.0354g) in H after evacuation ₂ The reaction mixture was stirred at room temperature for 24 hours under an atmosphere, and the palladium catalyst was filtered and concentrated to obtain a target product WHE48(0.0905g) which was used directly in the next reaction.

And 5: synthesis of 1- (4- (2- (3- (dimethylamino) propyl) -6- (3-trifluoromethylphenyl) -2H-indazol-3-yl) piperidin-1-yl) -2-propen-1-one (WHE58)

The starting material WHE48(0.09g,0.17mmol) was dissolved in CH ₂ Cl ₂ (2mL), TFA (1mL) was added, the mixture was stirred at room temperature for 30min, the solvent was removed, and a small amount of toluene was added, followed by removal. Dissolved in THF (8mL) and Et added ₃ N (2mL), followed by addition of acryloyl chloride (15.4mg,0.17mmol) and stirring at room temperature for 1 hour. After removal of the solvent, HPLC purification gave 22.5mg of the trifluoroacetate salt of WHE58 as a final product (purification conditions: 15% CH) ₃ CN start, retention time 29 min). ¹ H NMR(400MHz,Methanol-d ₄ )δ7.95-7.90(m,3H),7.83(s,1H),7.67(d,J＝1.1Hz,2H),7.66(s,2H),7.37(dd,J＝8.9,1.5Hz,1H),6.88(dd,J＝16.8,10.6Hz,1H),6.28(dd,J＝16.8,2.0Hz,1H),5.81(dd,J＝10.6,2.0Hz,1H),4.83(d,J＝12.6Hz,1H),4.67(t,J＝6.7Hz,2H),4.36(d,J＝13.8Hz,1H),3.58(tt,J＝12.2,3.3Hz,1H),3.38((t,J＝12.7Hz,1H),3.26(t,J＝7.9Hz,2H),2.93(s,6H),2.97-2.89(m,1H),2.42(p, J ═ 6.6Hz,2H),2.28-2.11(m,2H),2.07(s,2H) ESI-MS theoretically calculated value C ₂₇ H ₃₂ F ₃ N ₄ O[M+H] ⁺ 485.24; the experiment shows that: 485.30.

synthesis of the end product 12: 1- (4- (2- (3- (dimethylamino) propyl) -6- (pyridin-2-yl) -2H-indazol-3-yl) piperidin-1-yl) -2-propen-1-one (WHE71)

Step 1: synthesis of 3- (6- (pyridin-2-yl) -2H-indazol-2-yl) -N, N-dimethylpropan-1-amine (WHE52)

Into a 50mL round-bottomed flask, WHD111(0.2006g, 0.71mmol), pyridine-2-boronic acid (0.1365g,1.11mmol), Pd (dppf) Cl were added in this order ₂ DCM (0.0589g, 0.072mmol) and then DME (6mL), Na ₂ CO ₃ Aqueous solution (2M, 2mL), purge twice, N ₂ The reaction system was heated at 95 ℃ for 12 hours with protection. After the reaction is finished, the reaction product is cooled to room temperature, the solvent is removed, and column chromatography is carried out (mobile phase is 1:1 ethyl acetate methanol and 10% ammonia water), so that the target compound WHE52(0.1972) is obtained. ¹ H NMR(400MHz,Methanol-d ₄ )δ8.29-8.15(m,2H),7.92-7.75(m,3H),7.71-7.57(m,2H),7.16(d,J＝8.9Hz,1H),4.48(t,J＝6.5Hz,1H),2.39(t,J＝8.5Hz,2H),2.32(s,2H),2.29(s,4H),2.25-2.18(m,2H).

And 2, step: synthesis of 3- (3-bromo-6- (pyridin-2-yl) -2H-indazol-2-yl) -N, N-dimethylpropan-1-amine (WHE55)

The starting material WHE52(0.1972g,0.7mmol) was dissolved in HOAc, NBS (0.1486g,0.84mmol) was added, and the mixture was stirred at room temperature for 18 hours. After the reaction is finished, water is added for quenching, the solvent is removed, and NaHCO is used ₃ The solution neutralizes acidity. By CH ₂ Cl ₂ Extracting with ethyl acetate for three times, mixing organic phases, and adding Na ₂ SO ₄ Dried (anhydrous) and concentrated to give crude WHE55(0.25g) which was used directly in the next reaction.

And step 3: synthesis of 4- (2- (3- (dimethylamino) propyl) -6- (pyridin-2-yl) -2H-indazol-3-yl) -3, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester (WHE57)

A50 mL round-bottom flask was charged with WHE55(0.25g,0.70mmol), N-Boc-1,2,5, 6-tetrahydropyridine-4-boronic acid pinacol ester (0.3250g,1.05mmol), Pd (dppf) Cl ₂ DCM (0.0619g, 0.07mmol) and then DME (6mL), Na ₂ CO ₃ Aqueous solution (2M, 2mL), purge twice, N ₂ The reaction system was heated at 95 ℃ for 12 hours with protection. After the reaction, the solvent was removed and column chromatography was carried out (mobile phase 1:1 ethyl acetate methanol, methanol) to obtain WHE57(0.109 g). ¹ H NMR(400MHz,Methanol-d ₄ )δ8.63(d,J＝4.8Hz,1H),8.13(s,1H),7.95-7.90(m,2H),7.77-7.65(m,2H),7.38(q,J＝4.6Hz,1H),6.13(s,1H),4.48(t,J＝7.2Hz,2H),4.21(s,2H),3.76(s,2H),2.61(s,2H),2.45(s,6H),2.35(t,J＝7.4Hz,2H),2.20-2.14(m,2H),1.52(s,9H).

And 4, step 4: synthesis of tert-butyl 4- (2- (3- (dimethylamino) propyl) -6- (pyridin-2-yl) -2H-indazol-3-yl) piperidine-1-carboxylate (WHE63)

The raw material WHE57(0.109g) was dissolved in methanol, degassed N ₂ Adding Pd (OH) under protection ₂ (0.0436g) in H after evacuation ₂ The reaction mixture was stirred at room temperature for 24 hours under an atmosphere, and the palladium catalyst was filtered and concentrated to obtain the desired product WHE63(0.1g) which was used directly in the next reaction.

And 5: synthesis of 1- (4- (2- (3- (dimethylamino) propyl) -6- (pyridin-2-yl) -2H-indazol-3-yl) piperidin-1-yl) -2-propen-1-one (WHE71)

The starting material WHE63(0.1g,0.21mmol) was dissolved in CH ₂ Cl ₂ (2mL), TFA (1mL) was added, the mixture was stirred at room temperature for 30min, the solvent was removed, and a small amount of toluene was added, followed by removal. Dissolved in THF (8mL) and Et added ₃ N (2mL), followed by addition of acryloyl chloride (19mg,0.21mmol) and stirring at room temperature for 1 hour. After removal of the solvent, HPLC purification gave 3.1mg of the trifluoroacetate salt of WHE71 as a final product (purification conditions: 5% CH) ₃ CN start, retention time 18.2 min). ¹ H NMR(400MHz,Methanol-d ₄ )δ8.80(dd,J＝5.6,0.8Hz,1H),8.50(td,J＝7.8,1.6Hz,1H),8.32(d,J＝8.1Hz,1H),8.24(s,1H),8.06(d,J＝8.9Hz,1H),7.88(ddd,J＝7.4,5.8,1.2Hz,1H),7.55(dd,J＝8.9,1.6Hz,1H),6.91-6.83(m,1H),6.31-6.25(m,1H),5.82-5.78(m,1H),4.83(d, J ═ 11.4Hz,1H),4.70(t, J ═ 6.6Hz,1.5H),4.65(t, J ═ 6.7Hz,0.5H),4.36(d, J ═ 11.6Hz,1H),3.68-3.54(m,2H),3.39(t, J ═ 12.5Hz,1H),3.28-3.23(m,2H),2.93(s,4.5H),2.91(s,1.5H),2.48-2.38(m,2H),2.20-2.16(m,2H),2.09-2.01(m,2H), ESI-MS theoretical calculated value C, 1H), 2.09 ₂₅ H ₃₂ N ₅ O[M+H] ⁺ 418.25; the test shows that: 418.27

Synthesis of the final product 13: 1- (4- ((2- (3- (dimethylamino) propyl) -6- (2-fluorophenyl) -2H-indazol-3-yl) amino) piperidin-1-yl) prop-2-en-1-one (WHE87)

Step 1: preparation of 4- (2- (3- (dimethylamino) propyl) -6- (2-fluorophenyl) -2H-indazol-3-yl) amino) piperidine-1-carboxylic acid tert-butyl ester (WHE85)

(a) In a 50mL dry two-necked flask, Pd was added sequentially ₂ (dba) ₃ (0.0498g,0.054mmol), BINAP (0.0990g,0.159mmol) and 4mL of toluene, suction gas, N ₂ The mixture was heated (80 ℃ C.) for about 10min under protection. And cooling for later use. (b) Additionally, a dry double-neck bottle was taken and sequentially added with WHD93(0.2023g,0.539mmol), 4-amino-1- (N-Boc) piperidine (0.2346g, 1.17mmol), ^t Buona (0.2000g, 2.08mmol) and 5mL of toluene, twice with suction of gas, N ₂ The catalyst prepared in the first step was transferred with a syringe with a long needle under protection and then heated with stirring (100 ℃ C.) for 14 hours. After the reaction is finished, after filtration by a filter membrane, HPLC purification conditions are as follows: 30% CH ₃ CN was started and the retention time was 12min to obtain the trifluoroacetate salt of WHE85 (28 mg). ¹ H NMR(400MHz,Methanol-d ₄ )δ8.12(d,J＝8.8Hz,1H),7.64(s,1H),7.58(tt,J＝7.8,2.3Hz,1H),7.55-7.43(m,2H),7.33(td,J＝7.6,1.2Hz,1H),7.27(ddd,J＝11.1,8.2,1.3Hz,1H),4.47-4.41(m,2H),4.39-4.31(m,1H),4.20(d,J＝13.8Hz,2H),3.28-3.26(m,2H),3.09-3.06(m,2H),2.92(s,6H),2.39-2.31(m,2H),2.17(d,J＝10.8Hz,,2H),1.75-1.68(m,2H),1.48(s,9H).

Step 2: synthesis of 1- (4- ((2- (3- (dimethylamino) propyl) -6- (2-fluorophenyl) -2H-indazol-3-yl) amino) piperidin-1-yl) prop-2-en-1-one (WHE87)

The product of the previous step WHE85(20mg,0.04mmol) was dissolved in CH ₂ Cl ₂ (2mL), TFA (1mL) was added, the mixture was stirred at room temperature for 30min, the solvent was removed, and a small amount of toluene was added, followed by removal. Dissolved in THF, Et is added ₃ N (1.0mL), followed by addition of acryloyl chloride (4.2mg,0.047mmol) was stirred at room temperature for 1 hour. After removal of the solvent, HPLC purification gave 10.8mg of the trifluoroacetate salt of the final product WHE 87. (HPLC condition: 25% CH) ₃ CN start, retention time 11.4 min). ¹ H NMR(400MHz,Methanol-d ₄ ) δ 8.10(dd, J ═ 8.8,3.6Hz,1H),7.63(s,1H),7.58(td, J ═ 7.8,1.6Hz,1H),7.50-7.44(m,2H),7.32(t, J ═ 7.5Hz,1H),7.26(dd, J ═ 11.0,8.4Hz,1H),6.82(dd, J ═ 16.8,10.7Hz,1H),6.23(dd, J ═ 16.8,2.0Hz,1H),5.78(dd, J ═ 10.6,2.0Hz,1H),4.65(d, J ═ 13.7Hz,1H),4.43(t, J ═ 7.0, 2H), 4.25.25, 2.0Hz,1H), 3.5.31H, 3.5H, 3.6H, 3.7H, 3.8, 3.5H, 3.6H, 3.7H, 1H, 3H, 1H, 3H, 5H, 1H, 3H, 5H, 3H, 5H, 3H, 5H, 3H, 5H, 3H, 5H, 3H, 5, theoretical calculation of C2.25 (s,2H),1.77-1.66(m,2H). ESI-MS ₂₆ H ₃₃ FN ₅ O[M+H] ⁺ 450.26; the experiment shows that: 450.20.

synthesis of end products 14 and 15: cis-N- (4- ((2- (3- (dimethylamino) propyl) -6- (2-fluorophenyl) -2H-indazol-3-yl) amino) cyclohexyl) acrylamide (WHE94) and trans-N- (4- ((2- (3- (dimethylamino) propyl) -6- (2-fluorophenyl) -2H-indazol-3-yl) amino) cyclohexyl) acrylamide (WHE95)

Step 1: synthesis of cis-N- (4- ((2- (3- (dimethylamino) propyl) -6- (2-fluorophenyl) -2H-indazol-3-yl) amino) cyclohexylamine (WHE89-2) and trans-N- (4- ((2- (3- (dimethylamino) propyl) -6- (2-fluorophenyl) -2H-indazol-3-yl) amino) cyclohexylamine (WHE89-3)

(a) Pd was added sequentially in a 50mL dry two-necked flask ₂ (dba) ₃ (0.0752g,0.08mmol), BINAP (0.1562g,0.25mmol) and 4mL of toluene, suction gas, N ₂ The mixture was heated (80 ℃ C.) for about 10min under protection. Cooling downAnd (5) standby. (b) Additionally, a dry double-neck bottle is taken, and raw materials WHD93(0.3542g,0.94mmol), 1, 4-diamino-cyclohexane (0.2908g, 2.55mmol) and, ^t Buona (0.3102g, 3.23mmol) and 5mL of toluene, twice with suction of gas, N ₂ The catalyst prepared in the first step was transferred with a syringe with a long needle under protection and then heated with stirring (100 ℃ C.) for 14 hours. After the reaction was completed, the mixture was filtered through a filter and purified by HPLC (10% CH) ₃ CN was started, resulting in retention times of 7.5min (WHE89-2,45mg) and 9min (WHE89-3,18mg), respectively. WHE 89-2: ¹ H NMR(400MHz,Methanol-d4)δ8.05(d,J＝8.8Hz,1H),7.65(s,1H),7.59(td,J＝7.8,1.7Hz,1H),7.52(d,J＝8.9Hz,1H),7.49-7.45(m,1H),7.33(td,J＝7.6,1.2Hz,1H),7.27(ddd,J＝11.1,8.2,1.1Hz,1H),4.44(t,J＝7.2Hz,2H),4.19-7.16(m,1H),3.29-3.26(m,2H),3.22-3.19(m,1H),2.92(s,6H),2.40-2.32(m,4H),2.22-2.19(m,2H),1.81-1.67(m,4H).WHE89-3： ¹ H NMR(400MHz,Methanol-d4)δ8.06(d,J＝8.8Hz,1H),7.64(s,1H),7.58(td,J＝7.8,1.8Hz,1H),7.50-7.44(m,2H),7.33(td,J＝7.6,1.2Hz,1H),7.26(ddd,J＝11.1,8.2,1.1Hz,1H),4.51(t,J＝7.2Hz,2H),4.43(d,J＝3.1Hz,1H),3.42(d,J＝5.1Hz,1H),3.33-3.29(m,2H),2.92(s,6H),2.42-2.38(m,2H),2.12-2.02(m,8H).

step 2: synthesis of cis-N- (4- ((2- (3- (dimethylamino) propyl) -6- (2-fluorophenyl) -2H-indazol-3-yl) amino) cyclohexyl) acrylamide (WHE94) and trans-N- (4- ((2- (3- (dimethylamino) propyl) -6- (2-fluorophenyl) -2H-indazol-3-yl) amino) cyclohexyl) acrylamide (WHE95)

(a) The starting material WHE89-1(45mg,0.11mmol) was dissolved in THF (8mL) and Et was added ₃ N (1.0mL), followed by addition of acryloyl chloride (9.9mg,0.11mmol) was stirred at room temperature for 1 hour. After removal of the solvent, HPLC purification gave 26.5mg of the trifluoroacetate salt of WHE94 as a final product (purification conditions: 15% CH) ₃ CN start, retention time 15.8 min). (b) The starting material WHE89-2(18mg,0.044mmol) was dissolved in THF (8mL) and Et was added ₃ N (1.0mL), followed by addition of acryloyl chloride (3.96mg,0.044mmol) was stirred at room temperature for 1 hour. After removal of the solvent, HPLC purification gave 16.8mg of the trifluoroacetate salt of the final product WHE95 (purification conditions: 15% CH) ₃ CN start, retention time 16 min). WHE94 and WHE95 are cis-trans isomers of each other. WHE 94: ¹ h NMR (400MHz, Methanol-d4) δ 8.06(d, J ═ 8.8Hz,1H),7.63(s,1H),7.61(td, J ═ 7.8,1.7Hz,1H),7.52-7.47(m,2H),7.35(td, J ═ 7.6,1.0Hz,1H),7.26(dd, J ═ 11.0,8.3Hz,1H),6.27(d, J ═ 2.8, 1H),6.26(s,1H),5.68(dd, J ═ 7.4,4.6Hz,1H),4.44(t, J ═ 7.1Hz,2H),4.14(tt, J ═ 11.3,3.9, 1H, 3.84, tt ═ 3.84, 3.7, 3, 13, 3, 13, 3, 13, 3, 13, 3, 12, 3, 2, 3, 13, 2, 3, 12, 2, 3, 2, 3, 2, 3, 12, 3, 2, 12, 2, etc. H, 13, etc. H, 13, etc. H, 13, C, H, d, H, d, H, C, d, H, C, d, C, d, H, d, H, d, C, H, d, H, C, H, C, H, C, H, C, d, C, H, C, d, C, H, C. ₂₇ H ₃₅ FN ₅ O[M+H] ⁺ 464.27; the experiment shows that: 464.42.WHE 95: ¹ h NMR (400MHz, Methanol-d4) δ 8.06(d, J ═ 8.8Hz,1H),7.63(s,1H),7.58(td, J ═ 7.8,1.7Hz,1H),7.50-7.44(m,2H),7.34(dd, J ═ 7.6,1.0Hz,1H),7.31-7.23(m,1H),6.39(dd, J ═ 17.1,10.2Hz,1H),6.24(dd, J ═ 17.1,1.8Hz,1H),5.66(dd, J ═ 10.2,1.9Hz,1H),4.47(t, J ═ 7.1Hz,2H),4.27-4.24(m,1H),4.04(s, 3.92H), 3.84H, 3.4.84H, 2H, 4.47(t, J ═ 7.1H, 2H),4.27-4.24(m, ESI), 2H, 3.8H, 2H, 18H, 4.8H, 18, 4.84, 18H, 18, 2H, 18H, 2H, 18, MS (m, 18H, 2H, 18, 2H, C, d, C ₂₇ H ₃₅ FN ₅ O[M+H] ⁺ 464.27; the test shows that: 464.30.

synthesis of the final product 16: 1- (3- ((2- (3- (dimethylamino) propyl) -6- (2-fluorophenyl) -2H-indazol-3-yl) amino) azetidin-1-yl) prop-2-en-1-one (WHE96)

Step 1: synthesis of tert-butyl 3- ((2- (3- (dimethylamino) propyl) -6- (2-fluorophenyl) -2H-indazol-3-yl) amino) azetidine-1-carboxylate (WHE92)

(a) Pd was added sequentially to a 50mL dry double-necked flask ₂ (dba) ₃ (0.0480g,0.05mmol), BINAP (0.0990g,0.16mmol) and 4mL of toluene, suction gas, N ₂ The mixture was heated (80 ℃ C.) for about 10min under protection. And cooling for later use. (b) In addition, a dry double-neck bottle is taken, and raw materials WHD93(0.2099g,0.56mmol), 3-amino azetidine-1-carboxylic acid tert-butyl ester (0.2172g, 1.26mmol) and, ^t Buona (0.2015g, 2.10mmol) and 5mL of toluene, twice with suction of gas, N ₂ Under the protection, the catalyst prepared in the first step is catalyzedThe preparation was transferred using a syringe with a long needle and then heated with stirring (100 ℃ C.) for 14 hours. After completion of the reaction, the reaction mixture was filtered through a filter and purified by HPLC (purification conditions: 30% CH) ₃ CN start, retention time 10.2min) to yield the trifluoroacetate salt of WHE92 (56 mg). ¹ H NMR(400MHz,Methanol-d ₄ )δ8.00(d,J＝8.9Hz,1H),7.65(s,1H),7.57(td,J＝7.8,1.6Hz,1H),7.50-7.44(m,2H),7.32(td,J＝7.6,1.2Hz,1H),7.25(dd,J＝11.1,8.2Hz,1H),5.09-5.05(m,1H),4.51-4.47(m,4H),4.14-4.09(m,2H),3.32-3.28(m,2H),2.93(s,6H),2.44-2.36(m,2H),1.47(s,9H).

Step 2: synthesis of 1- (3- ((2- (3- (dimethylamino) propyl) -6- (2-fluorophenyl) -2H-indazol-3-yl) amino) azetidin-1-yl) prop-2-en-1-one (WHE96)

The starting material WHE92(43mg,0.092mmol) was dissolved in CH ₂ Cl ₂ (2mL), TFA (1mL) was added, the mixture was stirred at room temperature for 30min, the solvent was removed, and a small amount of toluene was added, followed by removal. Dissolved in THF (8mL) and Et added ₃ N (1.0mL), followed by addition of acryloyl chloride (8.29mg,0.092mmol) was stirred at room temperature for 1 hour. After removal of the solvent, HPLC purification gave 22.7mg of the trifluoroacetate salt of WHE96 as a final product (purification conditions: 15% CH) ₃ CN start, retention time 16.8 min). ¹ H NMR(400MHz,Methanol-d ₄ ) δ 8.00(d, J ═ 8.8Hz,1H),7.65(s,1H),7.57(td, J ═ 7.8,1.7Hz,1H),7.48-7.44(m,2H),7.32(td, J ═ 7.6,1.0Hz,1H),7.25(ddd, J ═ 11.0,8.3,0.7Hz,1H),6.40(dd, J ═ 17.0,10.1Hz,1H),6.29(dd, J ═ 17.0,2.1Hz,1H),5.79(dd, J ═ 10.1,2.1Hz,1H),5.19-5.13(m,1H),4.87(t, J ═ 8.3, 1H),4.62(dd, 4.1, 2.1H), 4.19 (m,1H),4.87(t, J ═ 8.3, 1H),4.62(dd, 4.8, 7.8H), 7.7.44, 2H), 7.7.7H, 7.6H, 7H, 7.6.6 (dd, 2.6H), 5.6.6 (dd, 2.6.6, 2.1H), 5.6.6.6, 15 (dd, 15H), 5H), 4.7, 2.7, 2.6.6.6, 2.6, 1H), 15 (dd, 15, 18H), 4.2.2.2.2H), 4.2.2.2.2.2.2, 1H), etc ₂₄ H ₂₉ FN ₅ O[M+H] ⁺ 422.23; the experiment shows that: 422.76.

synthesis of the end product 17: n- (1- (2- (3- (dimethylamino) propyl) -6- (2-fluorophenyl) -2H-indazol-3-yl) azetidin-3-yl) acrylamide (WHE97)

Step 1: (1- (2- (3- (dimethylamino) propyl) -6- (2-fluorophenyl) -2H-indazol-3-yl) azetidin-3-yl) carbamic acid tert-butyl ester (WHE93)

(a) Pd was added sequentially to a 50mL dry double-necked flask ₂ (dba) ₃ (0.0480g,0.05mmol), BINAP (0.0990g,0.16mmol) and 4mL of toluene, suction gas, N ₂ The mixture was heated (80 ℃ C.) for about 10min under protection. And cooling for later use. (b) Additionally, a dry double-neck bottle is taken, and raw materials WHD93(0.1950g,0.52mmol), azetidin-3-yl tert-butyl carbamate (0.3458g, 1.66mmol) and, ^t Buona (0.2184g, 2.28mmol) and 5mL of toluene, twice with suction of gas, N ₂ The catalyst prepared in the first step was transferred with a syringe with a long needle under protection and then heated with stirring (100 ℃ C.) for 14 hours. After the reaction was completed, the reaction mixture was filtered through a filter and purified by HPLC to obtain a trifluoroacetate salt of WHE93 (97.2 mg). (purification conditions: 30% CH) ₃ CN start, retention time 8.5 min). ¹ H NMR(400MHz,Methanol-d ₄ )δ7.97(d,J＝8.7Hz,1H),7.61(s,1H),7.56(t,J＝7.8Hz,1H),7.48-7.44(m,2H),7.32(t,J＝7.5Hz,1H),7.25(t,J＝8.5Hz,1H),5.19-5.08(m,1H),4.76-4.70(m,3H),4.37(t,J＝7.1Hz,2H),3.30-3.27(m,2H),2.93(s,6H),2.46-2.36(m,2H),1.47(s,9H).

Step 2: synthesis of N- (1- (2- (3- (dimethylamino) propyl) -6- (2-fluorophenyl) -2H-indazol-3-yl) azetidin-3-yl) acrylamide (WHE97)

The starting material WHE93(92mg,0.197mmol) was dissolved in CH ₂ Cl ₂ (2mL), TFA (1mL) was added, the mixture was stirred at room temperature for 30min, the solvent was removed, and a small amount of toluene was added, followed by removal. Dissolved in THF (8mL) and Et added ₃ N (2mL), followed by addition of acryloyl chloride (17.73mg,0.197mmol) and stirring at room temperature for 1 hour. After removal of the solvent, HPLC purification gave 12.4mg of the trifluoroacetate salt of WHE97 as a final product (purification conditions: 15% CH) ₃ CN start, retention time 15.1 min). ¹ H NMR(400MHz,Methanol-d ₄ )δ7.98(d,J＝8.7Hz,1H),7.62(s,1H),7.56(td,J＝7.8,1.7Hz,1H),7.49-7.44(m,2H),7.32(td,J＝7.6,1.0Hz,1H),7.26(dd,J＝11.0,8.3Hz,1H),6.31(d,J＝3.7Hz,1H),6.30(s,1H),5.75(dd,J＝7.6,4.3Hz,1H),5.09(t,J＝8.2Hz,2H),4.98-4.95(m,1H),4.76(dd,J＝8.4,5.4Hz,2H),4.38(t,J＝7.0Hz,2H),3.29-3.26(m,2H),2.92(s,6H),2.44-2.36(m,2H). ESI-MS theoretical calculation C ₂₄ H ₂₉ FN ₅ O[M+H] ⁺ 422.23; the experiment shows that: 422.73.

synthesis of the end product 18: 1- (4- (2- (3- (dimethylamino) propyl) -6- (3-hydroxynaphthyl) -2H-indazol-3-yl) piperidin-1-yl) -2-propen-1-one (WHE100)

Step 1: synthesis of 3- (6- (3-benzyloxynaphthyl) -2H-indazol-2-yl) -N, N-dimethylpropan-1-amine (WHE76)

A50 mL round-bottomed flask was charged with WHD111(0.6125g, 2.17mmol), 3-benzyloxynaphthaleneboronic acid pinacol ester (0.9751g,2.71mmol), Pd (dppf) Cl ₂ DCM (0.1723g, 0.21mmol) and then DME (6mL), Na ₂ CO ₃ Aqueous solution (2M, 2mL), purge twice, N ₂ The reaction system was heated at 95 ℃ for 12 hours with protection. After the reaction is finished, the reaction product is cooled to room temperature, the solvent is removed, and column chromatography is carried out (mobile phase is 1:1 ethyl acetate methanol and 10% ammonia water), so that the target compound WHE76(0.7184) is obtained. ¹ H NMR(400MHz,Methanol-d ₄ )δ8.39(s,1H),7.84(s,1H),7.81(s,1H),7.72(d,J＝8.4Hz,1H),7.67(s,1H),7.52-7.51(m,2H),7.45-7.38(m,4H),7.34-7.28(m,1H),7.28-7.23(m,1H),7.22-7.18(m,1H),5.25(s,2H),4.65(t,J＝6.5Hz,2H),3.17-3.14(m,2H),2.86(s,6H),2.45(p,J＝6.6Hz,2H).

Step 2: synthesis of 3- (3-bromo-6- (3-benzyloxynaphthyl) -2H-indazol-2-yl) -N, N-dimethylpropan-1-amine (WHE79)

The starting material WHE76(0.72g,1.66mmol) was dissolved in HOAc, NBS (0.3242g,1.83mmol) was added, and the mixture was stirred at room temperature for 18 hours. After the reaction is finished, water is added for quenching, the solvent is removed, and NaHCO is used ₃ The solution neutralizes acidity. By CH ₂ Cl ₂ Extracting with ethyl acetate for three times, mixing organic phases, and adding Na ₂ SO ₄ Dried (anhydrous) and concentrated to give crude WHE79(0.076g) which was used directly in the next reaction.

And step 3: synthesis of 4- (2- (3- (dimethylamino) propyl) -6- (3-benzyloxynaphthyl) -2H-indazol-3-yl) -3, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester (WHE83)

A50 mL round-bottomed flask was charged with WHE79(0.076g,0.15mmol) as a starting material obtained in the previous step, N-Boc-1,2,5, 6-tetrahydropyridine-4-boronic acid pinacol ester (0.0964g,0.31mmol), Pd (dppf) Cl ₂ DCM (0.0256g, 0.03mmol) and then DME (6mL), Na ₂ CO ₃ Aqueous solution (2M, 2mL), purge twice, N ₂ The reaction system was heated at 95 ℃ for 12 hours with protection. After the reaction is finished, the solvent is removed, and column chromatography is carried out (mobile phase is 1:1 ethyl acetate methanol and methanol), so as to obtain a product WHE83(0.026 g). ¹ H NMR(400MHz,Methanol-d ₄ )δ8.37(s,1H),7.92(d,J＝8.4Hz,1H),7.83(d,J＝8.6Hz,1H),7.75(d,J＝8.4Hz,1H),7.66(s,1H),7.46-7.43(m,3H),7.38-7.34(m,3H),7.31-7.25(m,2H),7.21(d,J＝8.6Hz,1H),5.65(s,1H),5.23(s,2H),4.66(t,J＝6.2Hz,2H),4.23-4.09(q,J＝19.3Hz,2H),3.75-3.68(m,2H),3.22(t,J＝6.2Hz,2H),2.91(s,6H),2.60-2.56(m,1H),2.50-2.40(m,2H),2.32-2.27(m,1H),1.53(s,9H).

And 4, step 4: synthesis of tert-butyl 4- (2- (3- (dimethylamino) propyl) -6- (3-hydroxynaphthyl) -2H-indazol-3-yl) piperidine-1-carboxylate (WHE91)

Dissolving raw material WHE83(0.026g) in methanol, degassing, and adding N ₂ Adding Pd (OH) under protection ₂ (0.0216g) after evacuation in H ₂ The reaction mixture was stirred at room temperature for 24 hours under an atmosphere, and the palladium catalyst was filtered and concentrated to obtain the desired product WHE91(0.010g) which was used directly in the next reaction.

And 5: synthesis of 1- (4- (2- (3- (dimethylamino) propyl) -6- (3-hydroxynaphthyl) -2H-indazol-3-yl) piperidin-1-yl) -2-propen-1-one (WHE100)

The starting material WHE91(0.01g,0.19mmol) was dissolved in CH ₂ Cl ₂ (2mL), TFA (1mL) was added, the mixture was stirred at room temperature for 30min, the solvent was removed, and a small amount of toluene was added, followed by removal. Dissolved in THF (8mL) and Et added ₃ N (2mL), followed by addition of acryloyl chloride (1.7mg,0.019mmol) and stirring at room temperature for 1 hour. After removal of the solvent, HPLC purification gave 2.3mg of the trifluoroacetate salt of the final product WHE100 (purification conditions: 25% CH) ₃ CN start, retention time 15 min). ¹ H NMR(400MHz,Methanol-d ₄ ) δ 8.36(s,1H),8.23(d, J ═ 8.7Hz,1H),7.81(d, J ═ 8.6,0.9Hz,1H),7.73-7.70(m,1H),7.63(s, J ═ 1.1Hz,1H),7.45(t, J ═ 8.0Hz,1H),7.21-7.17(m,2H),7.07(s,1H),6.87(dd, J ═ 16.8,10.7Hz,1H),6.25(dd, J ═ 16.8,2.0Hz,1H),5.77(dd, J ═ 10.7,2.0Hz,1H),4.78(d, J ═ 13.0Hz,1H),4.64(q, 2.6, 2, 3.86, 3.6H, 3H, 3.6.6.6H, 3H, 3.6H, 3H, 6H, 3H, 6H, 3H, 6H, 3H, etc., 2.72-2.63(m,2H),2.60-2.52(m,1.5H),2.49-2.42(m,0.5H),1.75(t, J ═ 11.8Hz,2H) ₃₀ H ₃₅ N ₄ O ₂ [M+H] ⁺ 483.27; the experiment shows that: 483.45.

Synthesis of the end product 19: n- (3- ((2- (3- (dimethylamino) propyl) -6- (2-fluorophenyl) -2H-indazol-3-yl) amino) propyl) acrylamide (WHE103)

Step 1: synthesis of 3- ((2- (3- (dimethylamino) propyl) -6- (2-fluorophenyl) -2H-indazol-3-yl) amino) propylamine (WHE99)

(a) Pd was added sequentially to a 50mL dry double-necked flask ₂ (dba) ₃ (0.0480g,0.05mmol), BINAP (0.0990g,0.16mmol) and 4mL of toluene, suction gas, N ₂ Heat (80 ℃) for about 10min under protection. And cooling for later use. (b) In addition, a dry double-neck bottle is taken, and raw materials WHD93(0.2129g,0.57mmol), 1, 3-propane diamine (0.1425g, 1.93mmol) and, ^t Buona (0.2106g, 2.19mmol) and 5mL of toluene, twice with suction of gas, N ₂ The catalyst prepared in the first step was transferred with a syringe with a long needle under protection and then heated with stirring (100 ℃ C.) for 14 hours. After the reaction, the reaction mixture was filtered through a filter and purified by HPLC to obtain 36mg of WHE99 trifluoroacetate salt. (purification Condition: 15% CH) ₃ CN start, retention time 10.8 min).

Step 2: synthesis of N- (3- ((2- (3- (dimethylamino) propyl) -6- (2-fluorophenyl) -2H-indazol-3-yl) amino) propyl) acrylamide (WHE103)

The starting material WHE99(36mg,0.10mmol) was dissolved in THF (8mL) and addedEt ₃ N (1.0mL), followed by addition of acryloyl chloride (10mg,0.11mmol) was stirred at room temperature for 1 hour. After removal of the solvent, purification by HPLC afforded the final product WHE103 as 0.8mg of trifluoroacetate salt. (purification Condition: 15% CH) ₃ CN Start, Retention time 5min) ¹ H NMR(400MHz,Methanol-d ₄ ) δ 8.06(d, J ═ 8.8Hz,1H),7.58(s,1H),7.55(td, J ═ 7.7,1.6Hz,1H),7.48-7.42(m,1H),7.35(d, J ═ 8.8Hz,1H),7.31(td, J ═ 7.6,1.0Hz,1H),7.25(ddd, J ═ 11.1,8.2,1.2Hz,1H),6.23(d, J ═ 9.3Hz,1H),6.20(d, J ═ 2.6Hz,1 ddh), 5.67(d, J ═ 9.3,2.6Hz,1H),4.40(t, J ═ 6.8, 2H),3.83(t, 6.6, J ═ 2H),3.47(t, 2.2H), 3H, 2H, 26(m ═ 3H, 26H), 2H, 26 (C, 26H, 18H, C, 2H, C ₂₄ H ₃₀ FN ₅ O[M] ⁺ 423.24; the experiment shows that: 423.49.

synthesis of the final product 20: n- (3- ((2- (3- (dimethylamino) propyl) -6- (2-fluorophenyl) -2H-indazol-3-yl) amino) ethyl) acrylamide (WHE104)

Step 1: synthesis of 3- ((2- (3- (dimethylamino) propyl) -6- (2-fluorophenyl) -2H-indazol-3-yl) amino) ethylamine (WHE98)

(a) Pd was added sequentially to a 50mL dry double-necked flask ₂ (dba) ₃ (0.0480g,0.05mmol), BINAP (0.0990g,0.16mmol) and 4mL of toluene, suction gas, N ₂ The mixture was heated (80 ℃ C.) for about 10min under protection. And cooling for later use. (b) In addition, a dry double-neck bottle is taken, and raw materials WHD93(0.2023g,0.54mmol), 1, 2-ethylenediamine (0.1855g, 3.09mmol) and, ^t Buona (0.2021g, 2.10mmol) and 5mL of toluene, twice with suction of gas, N ₂ The catalyst prepared in the first step was transferred with a syringe with a long needle under protection and then heated with stirring (100 ℃ C.) for 14 hours. After the reaction, the reaction mixture was filtered through a filter and purified by HPLC to obtain 34mg of a trifluoroacetate salt of WHE 98. (purification Condition: 15% CH) ₃ CN start, retention time 10 min).

Step 2: synthesis of N- (3- ((2- (3- (dimethylamino) propyl) -6- (2-fluorophenyl) -2H-indazol-3-yl) amino) ethyl) acrylamide (WHE104)

The starting material WHE98(34mg,0.10mmol) was dissolved in THF (8mL) and Et was added ₃ N (1.0mL), followed by addition of acryloyl chloride (10mg,0.11mmol) was stirred at room temperature for 1 hour. After removal of the solvent, purification by HPLC afforded the final product WHE104 as 1.6mg of trifluoroacetate salt. (purification Condition: 15% CH) ₃ CN start, retention time 5 min). ¹ H NMR(400MHz,Methanol-d ₄ ) δ 8.15(d, J ═ 8.8Hz,1H),7.57(s,1H),7.56(dd, J ═ 7.8,1.7Hz,1H),7.47-7.42(m,1H),7.37(d, J ═ 8.8Hz,1H),7.31(td, J ═ 7.5,1.2Hz,1H),7.24(dd, J ═ 11.0,8.2Hz,1H),6.21-6.18(m,2H),5.66(dd, J ═ 7.5,4.4Hz,1H),4.33(q, J ═ 6.6Hz,2H),3.94-3.91(m,2H),3.70-3.64(q, J ═ 6.4,5.3, 3.92, 3.5H, 3.51 (m,2H), 3.5-3.5 (q, 5.5, 2H), 3.5.5.47-2H), 3.5 (m, 5.5.5, 5.2H), 3.5 (m,2H), 3.47-2H), 3.5 (m,2H), 5.47 (m,2H), 5.5.8.8, 1H), 1H), 5.6.6.6, 2H), 2H, 1H, 2H, 1H, 2H, 1H, 2H, 1H, 2H, 1H, 2H, 1H, 2, 1H, 2H, 2H, 1H, 2, 1, 2H, 2, 1, 2H, 2H, 1, 2, 1, 2H, 1, 2, 1, 2, 1, 2, 1, 2, 1, 2, 1, 2, 1, 2, 1, 2, 1, 2, 1, 2 ₂₃ H ₂₉ FN ₅ O[M+H] ⁺ 410.23; the experiment shows that: 410.26.

synthesis of the end product 21: n- (3- ((2- (3- (dimethylamino) propyl) -6- (2-fluorophenyl) -2H-indazol-3-yl) amino) cyclobutyl) acrylamide (WHE106)

Step 1: tert-butyl (3- ((2- (3- (dimethylamino) propyl) -6- (2-fluorophenyl) -2H-indazol-3-yl) amino) cyclobutyl) carbamate (WHE101)

(a) Pd was added sequentially in a 50mL dry two-necked flask ₂ (dba) ₃ (0.0752g,0.08mmol), BINAP (0.1562g,0.25mmol) and 4mL of toluene, suction gas, N ₂ The mixture was heated (80 ℃ C.) for about 10min under protection. And cooling for later use. (b) Additionally, a dry double-neck bottle is taken, and raw materials WHD93(0.2012g,0.54mmol), (3-aminocyclobutylalkyl) carbamic acid tert-butyl ester (0.1407g, 0.76mmol) and, ^t Buona (0.2226g, 2.32mmol) and 5mL of toluene, twice with suction of gas, N ₂ The catalyst prepared in the first step was transferred with a syringe with a long needle under protection and then heated with stirring (100 ℃ C.) for 14 hours. After the reaction, the reaction mixture was filtered through a filter and purified by HPLC to obtain 20mg of the trifluoroacetate salt of WHE 101. (purification conditions: 30% CH) ₃ CN Start, Retention time 5min)。

Step 2: synthesis of N- (3- ((2- (3- (dimethylamino) propyl) -6- (2-fluorophenyl) -2H-indazol-3-yl) amino) cyclobutyl) acrylamide (WHE106)

The starting material WHE101(20mg,0.04mmol) was dissolved in THF (8mL) and Et was added ₃ N (1.0mL), followed by addition of acryloyl chloride (3.7mg,0.04mmol) was stirred at room temperature for 1 hour. After removal of the solvent, HPLC purification gave 4.4mg of the trifluoroacetate salt of WHE106 as the final product (purification conditions: 15% CH) ₃ CN start, retention time 13.2 min). ¹ H NMR(400MHz,Methanol-d ₄ ) δ 8.17(d, J ═ 8.7Hz,0.5H),7.98(d, J ═ 8.7Hz,0.5H),7.62(s,1H),7.57(tdd, J ═ 7.8,3.1,1.7Hz,1H),7.49-7.44(m,2H),7.32(tt, J ═ 7.6,1.3Hz,1H),7.28-7.24(m,1H),6.27-6.24(m,2H),5.71-5.67(m,1H),4.82-4.76(m,0.5H),4.67-4.60(m,0.5H),4.54-4.41(m,2.5H),4.25-4.16(m,0.5H),3.28-3.25 (m), 2.5H), 3.25-2H, 3.93 (m,2H), 2.92H), 2.93-2H, 2.5H, 2H, 9(m,2H), 2.5H), 2H, 5H, theoretical calculated values (m, 2.93, 2H), 2H, 5H, 15H, 5H, 2H, 15H, 2H, 5H, 2H, 15H, 2H, 5H, 2H, etc. (m, 15H), 2H, 15H, etc. (m, 15H), 2H, 15H), 2H, 15H, etc. (m, 15H), 2H, etc. (m, 15H), 2H, etc. (m, 15H), calculated values ₂₅ H ₃₁ FN ₅ O[M+H] ⁺ 436.24; the experiment shows that: 436.79.

synthesis of end product 22: 1- (4- (2- (4- (dimethylamino) but-2-yl) -6- (o-tolyl) -2H-indazol-3-yl) piperidin-1-yl) prop-2-en-1-one (ZB45)

The method comprises the following steps: 3- (3-bromo-6- (o-tolyl) -2H-indazol-2-yl) butan-1-ol (ZB090)

ZB086(1.0g, 3.574mmol) was dissolved in AcOH (10ml) and N-bromosuccinimide (631.8mg, 3.57mmol) was added and stirred at room temperature overnight. After the reaction is finished, water and ethyl acetate are added for extraction, organic phases are combined and dried by anhydrous sodium sulfate, and the solvent is separated and purified by a chromatographic column. 728mg of target product are obtained. ¹ H NMR(400MHz,Chloroform-d)δ7.61(t,J＝1.1Hz,1H),7.57(dd,J＝0.9,8.6Hz,1H),7.31(td,J＝2.6,3.8Hz,4H),7.14(dd,J＝1.3,8.6Hz,1H),5.29-5.17(m,1H),3.74-3.63(m,1H),3.60-3.47(m,1H),2.58-2.42(m,1H),2.33(s,3H),2.26-2.14(m,1H),1.68(d,J＝6.8Hz,3H).

Step two: 4- (2- (4-hydroxybut-2-yl) -6- (o-tolyl) -2H-indazol-3-yl) -3, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester (ZB092)

ZB090(1.572g, 5.08mmol) was dissolved in DME (16ml) and Na ₂ CO ₃ (2M aqueous solution, 8ml) was added to the mixed solution, oxygen was removed from the system and nitrogen was purged, followed by addition of Pd (dppf) Cl ₂ ·CH ₂ Cl ₂ (82mg,0.1mmol), again after purging with oxygen and nitrogen, the reaction was carried out at 95 ℃ overnight. After the reaction is finished, cooling to room temperature, adding water and ethyl acetate for extraction, combining organic phases, drying by using anhydrous sodium sulfate, and separating and purifying by using a chromatographic column after spin drying. 1.06g of the target product was obtained. ¹ H NMR(400MHz,Chloroform-d)δ7.61(d,J＝1.2Hz,1H),7.58(dd,J＝0.9,8.7Hz,1H),7.34-7.29(m,3H),7.27(d,J＝3.3Hz,1H),7.06(dd,J＝1.4,8.6Hz,1H),6.03(s,1H),4.96(ddd,J＝4.4,6.7,8.9Hz,1H),4.21(s,2H),3.83-3.69(m,2H),3.64(dd,J＝5.3,10.8Hz,1H),3.50(d,J＝10.4Hz,1H),2.59(s,2H),2.45(ddt,J＝4.5,9.0,13.8Hz,1H),2.34(s,3H),2.15(ddt,J＝4.4,9.0,13.8Hz,1H),1.66(d,J＝6.7Hz,3H),1.55(s,9H).

Step three: 4- (2- (4-hydroxybut-2-yl) -6- (o-tolyl) -2H-indazol-3-yl) piperidine-1-carboxylic acid tert-butyl ester (ZB093)

ZB092(1.06g) was dissolved in methanol, oxygen was removed from the system and nitrogen was purged, followed by addition of Pd (OH) ₂ (200mg, 20%) and was again deoxygenated and hydrogen-charged and reacted overnight at room temperature. The target product is obtained in 960 mg. ¹ H NMR(400MHz,Chloroform-d)δ7.79-7.73(m,1H),7.61(t,J＝1.1Hz,1H),7.30(dd,J＝2.1,4.2Hz,3H),7.26(dd,J＝2.9,6.3Hz,1H),7.02(dd,J＝1.4,8.7Hz,1H),5.03(q,J＝7.2,8.3Hz,1H),4.36(s,3H),3.70(dt,J＝4.6,9.9Hz,1H),3.47-3.28(m,1H),2.89(s,3H),2.48(ddd,J＝4.7,8.9,13.9Hz,1H),2.35(s,3H),2.28-2.12(m,2H),1.99(d,J＝13.4Hz,1H),1.91(d,J＝13.1Hz,1H),1.68(d,J＝6.7Hz,3H),1.54(s,9H).

Step four: 4- (2- (4-Oxobutan-2-yl) -6- (o-tolyl) -2H-indazol-3-yl) piperidine-1-carboxylic acid tert-butyl ester (ZB038)

Dissolving ZB093(82mg, 0.18mmol) in DMSO (3ml), adding IBX (148mg, 0.53mmol), stirring at room temperature, monitoring reaction with UPLC, adding water and ethyl acetate, and extractingThe organic phases were taken, combined and dried over anhydrous sodium sulfate, and the solvent was dried by rotation to obtain 80mg of a crude product containing the objective compound. ¹ H NMR(400MHz,Chloroform-d)δ9.70(s,1H),7.72(d,J＝8.7Hz,1H),7.53(t,J＝1.1Hz,1H),7.28-7.21(m,4H),6.97(dd,J＝1.4,8.8Hz,1H),5.34-5.22(m,1H),4.35(s,2H),3.74(dd,J＝8.4,18.4Hz,1H),3.36(ddd,J＝3.7,8.5,12.2Hz,1H),3.03(dd,J＝4.6,18.5Hz,1H),2.96-2.83(m,3H),2.31(s,3H),2.19(t,J＝13.0Hz,1H),1.88(d,J＝13.2Hz,1H),1.61(d,J＝6.7Hz,3H),1.51(s,9H).

Step five: n, N-dimethyl-3- (3- (piperidin-4-yl) -6- (o-tolyl) -2H-indazol-2-yl) but-1-amine (ZB041)

ZB038(80mg, 0.17mmol), dimethylamine (23.4mg, 0.52mmol) were dissolved in DCE (5ml), sodium triacetoxyborohydride (184mg, 0.88mmol) was added, AcOH (0.2ml) was added and the reaction was allowed to proceed overnight at room temperature. After the reaction is finished, water and dichloromethane are added for extraction, organic phases are combined and dried by anhydrous sodium sulfate, and the solvent is dried by spinning. The obtained crude product was dissolved in a mixed solution of dichloromethane and trifluoroacetic acid (3:1), stirred at room temperature for 2 hours, and then the solvent was spin-dried, to obtain 18.7mg of the target product after purification. Theoretical calculation of ESI-MS C ₂₅ H ₃₄ N ₄ [M+H] ⁺ 391.58, the experiment found: 391.85.

step six: 1- (4- (2- (4- (dimethylamino) but-2-yl) -6- (o-tolyl) -2H-indazol-3-yl) piperidin-1-yl) prop-2-en-1-one (ZB45)

ZB041(18.7mg, 0.048mmol) was dissolved in dry dichloromethane (5ml), triethylamine (0.03ml, 0.144mmol) was added, a solution of acryloyl chloride (5.0mg, 0.053mmol) in dichloromethane was added dropwise, the reaction was carried out at room temperature for 1 hour, and the solvent was dried by rotary evaporation and purified by HPLC. 4.8mg of the target product is obtained. HPLC purification conditions: initial acetonitrile proportion 30%, retention time 10 minutes. ¹ H NMR(400MHz,Methanol-d ₄ ) δ 7.85(dd, J ═ 3.6,8.4Hz,1H),7.45(s,1H),7.34-7.25(m,5H),7.13(ddd, J ═ 1.2,2.4,8.2Hz,1H),6.86(ddd, J ═ 3.3,10.6,16.8Hz,1H),6.25(ddd, J ═ 2.0,3.3,16.9Hz,1H),5.79(dt, J ═ 2.3,10.6Hz,1H),4.68(d, J ═ 12.7Hz,1H),4.29(s,2H),3.64(t, J ═ 7.8Hz,2H),3.57-3.38(m,1H),2.85(d, J ═ 8.1H), theoretical calculated values of C-C, 3.4.6 Hz,1H, and theoretical values ₂₈ H ₃₆ N ₄ O[M+H] ⁺ 445.62; the experiment shows that: 445.18.

synthesis of the final product 23: 1- (4- (2- (4- (dimethylamino) but-2-yl) -6- (2- (trifluoromethyl) phenyl) -2H-indazol-3-yl) piperidin-1-yl) prop-2-en-1-one (ZB85)

The method comprises the following steps: 3- (3-bromo-6- (2- (trifluoromethyl) phenyl) -2H-indazol-2-butyl) -1-ol (ZB036)

ZA158(450mg, 1.34mmol) was dissolved in AcOH and N-bromosuccinimide (245mg, 1.34mmol) was added and stirred at room temperature overnight. After the reaction is finished, water and ethyl acetate are added for extraction, organic phases are combined and dried by anhydrous sodium sulfate, and the solvent is separated and purified by a chromatographic column. 570mg of the target product are obtained. ¹ H NMR(400MHz,Chloroform-d)δ7.82-7.76(m,1H),7.64(s,1H),7.60(t,J＝7.9Hz,1H),7.56(dd,J＝0.9,8.7Hz,1H),7.51(t,J＝7.7Hz,1H),7.39(d,J＝7.6Hz,1H),7.13(d,J＝8.6Hz,1H),5.28-5.17(m,1H),3.68(dt,J＝5.2,10.7Hz,1H),3.54(ddd,J＝4.3,8.7,11.1Hz,1H),2.48(ddt,J＝4.8,9.3,14.0Hz,1H),2.30-2.16(m,1H),1.68(d,J＝6.8Hz,3H).

Step two: 4- (2- (4-hydroxybut-2-yl) -6- (2- (trifluoromethyl) phenyl) -2H-indazol-3-yl) -3, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester (ZB039)

ZB036(570mg, 1.38mmol), tert-butyl 4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -3, 6-dihydropyridine-1- (2H) carboxylate (1.07g, 3.45mmol) were dissolved in DME (10ml) and Na ₂ CO ₃ (2M aq, 5ml) was added to the mixed solution, the oxygen in the system was removed and nitrogen was purged, followed by addition of Pd (dppf) Cl ₂ ·CH ₂ Cl ₂ (56mg, 0.07mmol), again after purging with oxygen and nitrogen, the reaction was carried out at 95 ℃ overnight. After the reaction is finished, cooling to room temperature, adding water and ethyl acetate for extraction, combining organic phases, drying by using anhydrous sodium sulfate, and separating and purifying by using a chromatographic column after spin drying. The target product was obtained (577 mg). ¹ H NMR(400MHz,Chloroform-d)δ7.81-7.75(m,1H),7.62(s,1H),7.61-7.53(m,2H),7.49(t,J＝7.6Hz,1H),7.40(d,J＝7.6Hz,1H),7.04(d,J＝8.6Hz,1H),6.03(s,1H),5.03-4.90(m,1H),4.20(d,J＝3.2Hz,2H),3.82-3.69(m,2H),3.62(s,1H),3.48(d,J＝10.2Hz,1H),2.59(s,2H),2.50-2.33(m,1H),2.14(ddt,J＝4.6,9.1,13.9Hz,1H),1.75(d,J＝3.6Hz,2H),1.65(d,J＝6.7Hz,3H),1.55(s,9H).

Step three: synthesis of tert-butyl 4- (2- (4-hydroxybut-2-yl) -6- (2- (trifluoromethyl) phenyl) -2H-indazol-3-yl) piperidine-1-carboxylate (ZB040)

ZB039(577mg) was dissolved in methanol, oxygen was removed from the system and nitrogen was purged, followed by addition of Pd (OH) ₂ (100mg, 20%) and was again purged with oxygen and hydrogen and reacted at room temperature overnight. Obtain 496mg of target product. ¹ H NMR(400MHz,Chloroform-d)δ7.78(d,J＝8.1Hz,1H),7.75(d,J＝8.8Hz,1H),7.62(s,1H),7.58(t,J＝7.5Hz,1H),7.49(t,J＝7.6Hz,1H),7.40(d,J＝7.5Hz,1H),7.00(d,J＝8.8Hz,1H),5.03(s,1H),4.37(s,2H),3.81-3.61(m,1H),3.51-3.25(m,2H),2.89(s,2H),2.48(s,1H),2.24(d,J＝31.2Hz,3H),1.95(dd,J＝13.2,32.6Hz,2H),1.69(d,J＝6.5Hz,3H),1.54(s,9H).

Step four: synthesis of tert-butyl 4- (2- (4-oxobutan-2-yl) -6- (2- (trifluoromethyl) phenyl) -2H-indazol-3-yl) piperidine-1-carboxylate (ZB049)

And dissolving ZB040 in DMSO, adding IBX, stirring at room temperature, monitoring the reaction by UPLC, adding water and ethyl acetate after the reaction is finished, extracting, combining organic phases, drying by using anhydrous sodium sulfate, and spin-drying the solvent to obtain a crude product containing the target compound of 340 mg. ¹ H NMR(400MHz,Chloroform-d)δ9.75(s,1H),7.78(d,J＝7.8Hz,1H),7.75-7.70(m,1H),7.57(d,J＝8.1Hz,2H),7.49(t,J＝7.7Hz,1H),7.39(d,J＝7.6Hz,1H),6.98(d,J＝8.6Hz,1H),5.31(q,J＝6.6Hz,1H),4.39(s,2H),3.77(dd,J＝8.3,18.5Hz,1H),3.39(t,J＝12.3Hz,1H),3.14-2.99(m,1H),2.94(s,2H),2.20(d,J＝12.4Hz,1H),2.07(s,2H),1.92(d,J＝12.8Hz,1H),1.65(d,J＝6.7Hz,3H),1.54(s,9H).

Step five: synthesis of N, N-dimethyl-3- (3- (piperidin-4-yl) -6- (2- (trifluoromethyl) phenyl) -2H-indazol-2-yl) butan-1-amine (ZB060)

ZB049(40mg, 0.08mmol), dimethylamine (0.12ml, 0.23mmol) were dissolved in DCE, sodium triacetoxyborohydride (82.2mg, 0.39mmol) was added, AcOH (0.1ml) was added, and the mixture was warmed to room temperatureThe reaction was allowed to proceed overnight. After the reaction is finished, water and dichloromethane are added for extraction, organic phases are combined and dried by anhydrous sodium sulfate, and the solvent is dried by spinning. The obtained crude product was dissolved in a mixed solution of dichloromethane and trifluoroacetic acid (3:1), stirred at room temperature for 2 hours, and then the solvent was spin-dried, to obtain 35mg of the target product after purification. Theoretical calculation of ESI-MS C ₂₅ H ₃₁ F ₃ N ₄ [M+H] ⁺ 445.25, experimentally determined: 445.29.

step six: synthesis of 1- (4- (2- (4- (dimethylamino) but-2-yl) -6- (2- (trifluoromethyl) phenyl) -2H-indazol-3-yl) piperidin-1-yl) prop-2-en-1-one (ZB85)

ZB060(35mg, 0.08mmol) was dissolved in dry dichloromethane, triethylamine (0.33ml, 0.24mmol) was added, a solution of acryloyl chloride (8.0mg, 0.09mmol) in dichloromethane was added dropwise, the reaction was carried out at room temperature for 1 hour, the solvent was dried, and HPLC purification was carried out. 2.3mg of the target product is obtained. HPLC purification conditions: the initial acetonitrile proportion was 25%, the retention time was 11 minutes. ¹ H NMR(400MHz,Methanol-d ₄ ) δ 7.85-7.82(m,1H),7.82-7.79(m,1H),7.67(t, J-7.5 Hz,1H),7.58(t, J-7.7 Hz,1H),7.50(s,1H),7.41(d, J-7.6 Hz,1H),7.00(d, J-8.7 Hz,1H),6.90(dd, J-10.7, 16.8Hz,1H),6.29(dd, J-2.0, 16.8Hz,1H),5.82(dd, J-2.0, 10.6Hz,1H),5.06(q, J-4.8, 7.1Hz,1H),4.85(d, J-13.7, 1H),4.38 (H), 3.38 (d, 3.6H), 3.6H, 3.0, 3.6H, 13H, 3.6H, 3H, j ═ 5.5,12.5,17.2Hz,1H),2.24(q, J ═ 13.6,15.3Hz,2H),2.08(s,2H),1.67(d, J ═ 6.5Hz,3H), ESI-MS theoretically calculated value C ₂₈ H ₃₃ F ₃ N ₄ O[M+H] ⁺ 499.59, the experiment found: 499.37.

synthesis of the final product 24: 1- (4- (2- (4-Morpholinobutan-2-yl) -6- (2- (trifluoromethyl) phenyl) -2H-indazol-3-yl) piperidin-1-yl) prop-2-en-1-one (ZB54)

The method comprises the following steps: synthesis of 4- (3- (3- (piperidin-4-yl) -6- (2- (trifluoromethyl) phenyl) -2H-indazol-2-yl) butyl) morpholine (ZB052)

ZB049(60mg,0.12mmol), morpholine (30.4mg, 0.35mmol) were dissolved in DCE, sodium triacetoxyborohydride (123.4mg, 0.60mmol) was added, AcOH (0.15ml) was added and the reaction was allowed to proceed overnight at room temperature. After the reaction is finished, water and dichloromethane are added for extraction, organic phases are combined and dried by anhydrous sodium sulfate, and the solvent is dried by spinning. The obtained crude product was dissolved in a mixed solution of dichloromethane and trifluoroacetic acid (3:1), stirred at room temperature for 2 hours, and then the solvent was spin-dried, purified to obtain 49mg of a crude product containing the target product, and the obtained crude product was directly used for the next reaction. ESI-MS theoretical calculation C ₂₅ H ₃₁ F ₃ N ₄ [M+H] ⁺ 486.26, the experiment found: 486.33.

step two: synthesis of 1- (4- (2- (4-morpholinobutane-2-yl) -6- (2- (trifluoromethyl) phenyl) -2H-indazol-3-yl) piperidin-1-yl) prop-2-en-1-one (ZB54)

ZB052(49mg) was dissolved in dry dichloromethane, triethylamine (3.0eq.) was added, and then a dichloromethane solution of acryloyl chloride (1.1eq.) was added dropwise and reacted at room temperature for 1 hour. After the reaction, the solvent was dried by spinning and purified by HPLC. 7.1mg of the target product was obtained. HPLC purification conditions: the initial acetonitrile proportion was 25%, the retention time was 16 minutes. ¹ H NMR(400MHz,Methanol-d ₄ ) δ 7.84(dd, J-5.5, 8.2Hz,2H),7.70(t, J-7.5 Hz,1H),7.61(t, J-7.7 Hz,1H),7.50(s,1H),7.46(d, J-7.5 Hz,1H),7.13(d, J-8.3 Hz,1H),6.87(dd, J-10.6, 16.8Hz,1H),6.26(dd, J-2.0, 16.8Hz,1H),5.80(dd, J-2.0, 10.7Hz,1H),4.88-4.79(m,0H),4.68(d, J-13.3 Hz,1H),4.29(d, J-13.8, 1H), 4.13H, 13.3Hz,1H),4.29(d, J-13.7 Hz,1H), 4.9-4.7H), 13.7 (m,0H), 13.68 (t, 3.3H, 13H, 13.3H, 13H, 3H, 13H, 3H, 13H, 3H, 1H, 13H, 3H, 1H, 13H, 3H, 1H, 13H, 3H, 1H, 3H, 13H, 1H, 13H, etc., j ═ 4.6,12.5Hz,1H),2.18(d, J ═ 12.1Hz,2H),2.07-1.89(m,2H),1.56(d, J ═ 6.6Hz,3H), ESI-MS theoretical calculated value C ₂₅ H ₃₁ F ₃ N ₄ [M+H] ⁺ 541.27, the experiment found: 541.12.

Synthesis of the final product 25: 1- (4- (2- (4- (4-methylpiperazin-1-yl) but-2-yl) -6- (2- (trifluoromethyl) phenyl) -2H-indazol-3-yl) piperidin-1-yl) prop-2-en-1-one (ZB61)

The method comprises the following steps: synthesis of 2- (4- (4-methylpiperazin-1-yl) but-2-yl) -3- (piperidin-4-yl) -6- (2- (trifluoromethyl) phenyl) -2H-indazole (ZB055)

ZB049(60mg,0.116mmol) and 1-methylpiperazine (35mg, 0.35mmol) were dissolved in DCE, and after addition of sodium triacetoxyborohydride (123.4mg, 0.58mmol), AcOH (0.15ml) was added and the reaction was allowed to proceed at room temperature overnight. After the reaction is finished, water and dichloromethane are added for extraction, organic phases are combined and dried by anhydrous sodium sulfate, and the solvent is dried by spinning. The obtained crude product was dissolved in a mixed solution of dichloromethane and trifluoroacetic acid (3:1), stirred at room temperature for 2 hours, and then the solvent was spin-dried, to obtain 45.3mg of the target product after purification. Theoretical calculation of ESI-MS C ₂₈ H ₃₆ F ₃ N ₅ [M+H] ⁺ 500.29, the experiment found: 500.56.

step two: synthesis of 1- (4- (2- (4- (4-methylpiperazin-1-yl) but-2-yl) -6- (2- (trifluoromethyl) phenyl) -2H-indazol-3-yl) piperidin-1-yl) prop-2-en-1-one (ZB61)

ZB055(45.3mg) was dissolved in dry dichloromethane, triethylamine (3.0eq) was added, and then a solution of acryloyl chloride (1.1eq) in dichloromethane was added dropwise and the reaction was carried out at room temperature for 1 hour. After the reaction, the solvent was dried by spinning and purified by HPLC. 11.8mg of the target product is obtained. HPLC purification conditions: the initial acetonitrile proportion was 25%, the retention time was 14 minutes. ¹ H NMR(400MHz,Methanol-d ₄ ) δ 7.83(dd, J ═ 3.0,8.0Hz,2H),7.70(t, J ═ 7.5Hz,1H),7.61(t, J ═ 7.6Hz,1H),7.51-7.43(m,2H),7.10(d, J ═ 8.3Hz,1H),6.87(dd, J ═ 10.7,16.8Hz,1H),6.26(dd, J ═ 2.0,16.8Hz,1H),5.79(dd, J ═ 2.0,10.6Hz,1H),4.65(s,1H),4.28(d, J ═ 14.0Hz,1H),3.63-3.38(m,2H),3.12(d, J ═ 22.3, 3H), 3.76 (d, J ═ 14.0Hz,1H), 3.19H, 19H, 2H, 19J ═ 2H, d, 2H, 1H, d, 1H, and J ═ 2H). Theoretical calculation of ESI-MS C ₃₁ H ₃₈ F ₃ N ₅ O[M+H] ⁺ 554.3, the experiment found: 554.11.

synthesis of the end product 26: 1- (4- (2- (4- ((1, 3-dimethyl-1H-pyrazol-5-yl) amino) but-2-yl) -6- (2- (trifluoromethyl) phenyl) -2H-indazol-3-yl) piperidin-1-yl) prop-2-en-1-one (ZB62)

The method comprises the following steps: synthesis of 1, 3-dimethyl-N- (3- (3- (piperidin-4-yl) -6- (2- (trifluoromethyl) phenyl) -2H-indazol-2-yl) butyl) -1H-pyrazol-5-amine (ZB053)

ZB049(60mg, 0.116mmol), 1, 3-dimethyl-4, 5-dihydro-1H-pyrazol-5-amine (38.8mg, 0.35mmol) were dissolved in DCE, and after addition of sodium triacetoxyborohydride (123.4mg, 0.58mmol), AcOH (0.15ml) was added thereto to react at room temperature overnight. After the reaction is finished, water and dichloromethane are added for extraction, organic phases are combined and dried by anhydrous sodium sulfate, and the solvent is dried by spinning. The obtained crude product was dissolved in a mixed solution of dichloromethane and trifluoroacetic acid (3:1), stirred at room temperature for 2 hours, and then the solvent was spin-dried, purified to obtain 48.1mg of crude product containing the objective product, which was used directly in the next step.

Step two: synthesis of 1- (4- (2- (4- ((1, 3-dimethyl-1H-pyrazol-5-yl) amino) but-2-yl) -6- (2- (trifluoromethyl) phenyl) -2H-indazol-3-yl) piperidin-1-yl) prop-2-en-1-one (ZB62)

ZB53(48.1mg) was dissolved in dry dichloromethane, triethylamine (3.0eq.) was added, and then a solution of acryloyl chloride (1.1eq.) in dichloromethane was added dropwise and reacted at room temperature for 1 hour. After the reaction, the solvent was dried by spinning and purified by HPLC. 3.7mg of the target product is obtained. HPLC purification conditions: the initial acetonitrile proportion was 25%, the retention time was 12 minutes. ¹ H NMR(400MHz,Methanol-d ₄ ) δ 7.83(dd, J ═ 8.3,10.9Hz,2H),7.68(t, J ═ 7.5Hz,1H),7.59(t, J ═ 7.7Hz,1H),7.52(s,1H),7.44(d, J ═ 7.7Hz,1H),7.02(d, J ═ 8.6Hz,1H),6.90(dd, J ═ 10.7,16.8Hz,1H),6.30(dd, J ═ 2.0,16.8Hz,1H),5.83(dd, J ═ 2.0,10.6Hz,1H),4.40(d, J ═ 14.0Hz,1H),3.64(s,3H),3.39(d, J ═ 14.0, 1H), 2.96H (s,1H),2.54 (s,3H), 3.77H), theoretical m — (m-1H), calculated values (C, m-1H), 3.6H, 15.7 (15.7H, 1H, 15H, 24.6H, 1H, 15H, 18H, 15, 18H, 1H, 15H, 18H, 15H, 18H, 15H, 18H, 1H, 18H, 1H, 18H, C, 1H, 18H, C, 18H, 1H, 18H, C, calculated values (d, 18H, m ₃₁ H ₃₅ F ₃ N ₆ O[M+H] ⁺ 565.28, the experiment found: 565.10.

synthesis of the final product 27: 1- (4- (2- (4-hydroxybut-2-yl) -6- (2- (trifluoromethyl) phenyl) -2H-indazol-3-yl) piperidin-1-yl) prop-2-en-1-one (ZB73)

Synthesis of 1- (4- (2- (4-hydroxybut-2-yl) -6- (2- (trifluoromethyl) phenyl) -2H-indazol-3-yl) piperidin-1-yl) prop-2-en-1-one (ZB73)

ZB040(50mg) was dissolved in a mixed solution of dichloromethane and trifluoroacetic acid (3:1), reacted at room temperature for 1 hour, then water was added, dichloromethane was added, and the solvent was extracted and spin-dried. The obtained product was dissolved in dry dichloromethane, triethylamine (3.0eq) was added, and then a dichloromethane solution of acryloyl chloride (0.9eq.) was added dropwise and reacted at room temperature for 1 hour. After the reaction, the solvent was dried by spinning and purified by HPLC. 5.6mg of the target product is obtained. HPLC purification conditions: the initial acetonitrile proportion was 25%, the retention time was 20 minutes. ¹ H NMR(400MHz,Methanol-d ₄ ) δ 7.84(dd, J-0.9, 8.8Hz,1H),7.81(d, J-8.1 Hz,1H),7.67(t, J-7.5 Hz,1H),7.58(t, J-7.7 Hz,1H),7.49(s,1H),7.43(d, J-7.6 Hz,1H),7.02(d, J-8.7 Hz,1H),6.89(dd, J-10.7, 16.8Hz,1H),6.28(dd, J-2.0, 16.8Hz, ddh), 5.81(dd, J-2.0, 10.6Hz,1H),5.19(dt, J-6.5, 9.7, 1H),4.84(d, 4.84, 13.13H), 13.13H, 3.13H, 13H, 3.13H, 3H, 13H, 3H, 13H, 3.7H, 13H, 3H, 13H, 3H, 13H, 1H, 13H, 1H, 13H, 3H, 1H, 3H, 13H, 1H, 3H, 1H, 13H, 1H, 7H, 1H, 7H, 1H, 7H, 1H, 7H, 1H, 7H, 13H, 7H, 1H, etc., 2.31-2.10(m,4H),2.10-2.00(m,1H),1.67(d, J ═ 6.6Hz,3H). ESI-MS theoretical calculation C ₂₆ H ₂₈ F ₃ N ₃ O ₂ [M+H] ⁺ 472.21, the experiment found: 472.96.

synthesis of the end product 28: 1- (4- (2- (4- (piperidin-1-yl) but-2-yl) -6- (2- (trifluoromethyl) phenyl) -2H-indazol-3-yl) piperidin-1-yl) prop-2-en-1-one (ZB75)

The method comprises the following steps: synthesis of 2- (4- (piperidin-1-yl) but-2-yl) -3- (piperidin-4-yl) -6- (2- (trifluoromethyl) phenyl) -2H-indazole (ZB069)

ZB049(60mg, 0.116mmol), 1, 3-dimethyl-4, 5-dihydro-1H-pyrazol-5-amine (30mg, 0.35mmol) were dissolved in DCE, and after addition of sodium triacetoxyborohydride (123.4mg, 0.58mmol), AcOH (0.15ml) was added thereto and the reaction was allowed to proceed at room temperature overnight. After the reaction is finished, water and dichloromethane are added for extraction, organic phases are combined and dried by anhydrous sodium sulfate, and the solvent is dried by spinning. The obtained crude product was dissolved in a mixed solution of dichloromethane and trifluoroacetic acid (3:1), stirred at room temperature for 2 hours, and then the solvent was spin-dried, and after purification, 40.8mg of the crude product containing the objective product was obtained and used directly in the next step. Theoretical calculation of ESI-MS C ₂₈ H ₃₅ F ₃ N ₄ [M+H] ⁺ 485.28; the experiment shows that: 485.23.

step two: synthesis of 1- (4- (2- (4- (piperidin-1-yl) but-2-yl) -6- (2- (trifluoromethyl) phenyl) -2H-indazol-3-yl) piperidin-1-yl) prop-2-en-1-one (ZB75)

ZB069(40.8mg, 0.08mmol) was dissolved in dry dichloromethane (5ml), triethylamine (0.02ml, 0.25mmol) was added, and then a solution of acryloyl chloride (8.3mg,0.09mmol) in dichloromethane was added dropwise and reacted at room temperature for 1 hour. After the reaction, the solvent was dried by spinning and purified by HPLC. 4.3mg of the target product is obtained. ¹ H NMR(400MHz,Methanol-d ₄ ) δ 7.83(t, J ═ 8.0Hz,2H),7.68(t, J ═ 7.5Hz,1H),7.59(t, J ═ 7.7Hz,1H),7.50(s,1H),7.41(d, J ═ 7.6Hz,1H),7.01(d, J ═ 8.8Hz,1H),6.90(dd, J ═ 10.7,16.8Hz,1H),6.29(dd, J ═ 2.0,16.8Hz,1H),5.82(dd, J ═ 2.0,10.6Hz,1H),5.07(s,1H),4.39(d, J ═ 14.0Hz,1H),3.70-3.53(m,2H),3.49(d, J ═ 2.12, 3.12 (s,1H),4.39(d, J ═ 14.0Hz,1H),3.70-3.53(m,2H),3.49(d, J ═ 2, 3.8H), 3.8H, 1H), 3.8H, 7 (t, 3.8H), 3.8H, 7, 7.8H, 1H, 7.8H), 3.8H, 7 (t, 3.8H), 3.8H, 7.8H, 7, 7.8H), 3.8H), 7.8H, 7H), 7.8H), theoretical calculation C of ESI-MS 2.07(d, J ═ 10.8Hz,2H),2.02-1.70(m,4H),1.67(d, J ═ 6.6Hz,3H),1.57-1.45(m,1H) ₃₁ H ₃₇ F ₃ N ₄ O[M+H] ⁺ 539.29; the experiment shows that: 539.24.

synthesis of the end product 29: 3- (3- (1-Acrylopiperidin-4-yl) -6- (2- (trifluoromethyl) phenyl) -2H-indazol-2-yl) acrylic acid butyl ester (ZB89)

ZB73(50mg) was dissolved in a mixed solution of dichloromethane and trifluoroacetic acid (3:1) and reacted at room temperature for 1 hour, followed by addition of water, extraction with dichloromethane and spin-drying of the solvent. The obtained product was dissolved in dry dichloromethane, triethylamine (3.0eq) was added, and then a dichloromethane solution of acryloyl chloride (2.0eq) was added dropwise and reacted at room temperature for 1 hour. After the reaction, the solvent was dried by spinning and purified by HPLC. 3.7mg of the target product is obtained. HPLC purification conditions: the initial acetonitrile proportion was 45%, the retention time was 13 minutes. ¹ H NMR(400MHz,Methanol-d ₄ ) δ 7.84-7.81(m,1H),7.80(t, J ═ 1.4Hz,1H),7.67(t, J ═ 7.5Hz,1H),7.57(t, J ═ 7.7Hz,1H),7.50(s,1H),7.42(d, J ═ 7.6Hz,1H),7.01(dd, J ═ 1.4,8.8Hz,1H),6.95-6.81(m,1H),6.30(d, J ═ 1.9Hz,1H),6.26(d, J ═ 1.8Hz,1H),6.00(dd, J ═ 10.4,17.3Hz,1H),5.15(dd, J ═ 4.3,6.8,10.6, 1H),4.82(d, J ═ 10.4,17.3Hz,1H),5.15(dd, J ═ 4.3,6.8,10.6, 1H),4, 13.82 (d, J ═ 4.3, 13.2H, 13.12H, 13.8, 13.6, 13, 2, 13.6, 2, 13, 5.6, 13, 2, 5, 2, 3, 2, 3, 1H, 5, 2, 5, 2, 1H, 2, 1H, 2, 1H, 2, 3, 1H, 2H, 3, 1H, 2H, 2, 1H, 2H, 1H, 2H, 1H, 2H, 1H, 2H, 1H, 2, 1H, 2H, 1H, 2H, 1H, 3, 1H, 2H, 1H, 2H, 1H, 2H, etc., 1H) 2.41-2.08(m,3H),2.09-1.92(m,2H),1.68(d, J ═ 6.6Hz,3H) ESI-MS theoretical calculation C ₂₉ H ₃₀ F ₃ N ₃ O ₃ [M+H] ⁺ 526.22, the experiment found: 526.00.

synthesis of the final product 30: 3- (6- (2- (trifluoromethyl) phenyl) -2H-indazol-2-yl) acrylic acid butyl ester (ZB91)

ZA158(40mg, 0.12mmol) was dissolved in a dry dichloromethane solution, triethylamine (0.05ml, 0.36mmol) was added and a solution of acryloyl chloride (12mg, 0.13mmol) in dichloromethane was added dropwise. Reacting at room temperature for 1 hour, spin-drying the solvent after the reaction is finished, and purifying by HPLC. HPLC purification conditions: the initial acetonitrile proportion was 50%, the retention time was 13 minutes. The target compound (9.7 mg) was obtained. ¹ H NMR(400MHz,Methanol-d ₄ ) δ 8.38(d, J ═ 1.0Hz,1H),7.81(dd, J ═ 1.3,7.9Hz,1H),7.75(dd, J ═ 1.0,8.7Hz,1H),7.67(td, J ═ 1.3,7.7Hz,1H),7.62-7.56(m,1H),7.54(s,1H),7.44(d, J ═ 7.6Hz,1H),7.11-7.02(m,1H),6.24(dd, J ═ 1.5,17.3Hz,1H),5.96(dd, J ═ 10.5,17.3Hz,1H),5.77(dd, J ═ 1.5,10.4, 1H),4.92-4.85 (dd, J ═ 10.5,17.3Hz,1H),5.77(dd, J ═ 1.5, 10.5, 10.4, 1H),4.92-4.85 (dd, 1.5, 5, 5.5, 5H), 5(dd, 5.5, 5, 5.5, 5H), 5H), 5H, etc. ₂₁ H ₁₉ F ₃ N ₂ O ₂ [M+H] ⁺ 389.14, the experiment found: 389.09.

using the corresponding amines and acryloyl chloride as starting materials, the following products, ZB37-11, ZB37-13, ZB88, ZB102 and ZB140, were synthesized using the procedure for the synthesis of ZB73/ZB85/ZB 89.

Synthesis of the final product 31: 1- (4- (2- (4-hydroxybut-2-yl) -6- (o-tolyl) -2H-indazol-3-yl) piperidin-1-yl) prop-2-en-1-one (ZB37-11)

ZB093(41mg, 0.088mmol) was used as a starting material to synthesize ZB37-11(3.9 mg). HPLC purification conditions: the initial acetonitrile proportion was 35%, the retention time was 11 minutes. ¹ H NMR(400MHz,Methanol-d ₄ ) δ 7.89(dd, J ═ 0.9,8.7Hz,1H),7.47(t, J ═ 1.1Hz,1H),7.33-7.26(m,2H),7.27-7.21(m,2H),7.09(dd, J ═ 1.4,8.7Hz,1H),6.89(dd, J ═ 10.6,16.8Hz,1H),6.29(dd, J ═ 2.0,16.8Hz,1H),5.81(dd, J ═ 2.0,10.6Hz,1H),5.23(dt, J ═ 6.4,9.6Hz,1H),4.84(d, J ═ 14.6Hz,1H),4.37(d, J ═ 14.0, 1H),3.60 (J ═ 3.4, 9.6Hz,1H),4.84(d, J ═ 14.6Hz,1H),4.37(d, J ═ 14.0, 10.0, 3.5.7H, 3.5.5.7H, 3.6H, 1H, 3.9.6H, 1H, 5.9.6H, 1H, 13H, 1H, 13H, 1H, 13H, 1H, d, 2H, 1H, d, 17H, 1H, 2H, 1H, d, 2H, 1H, 2H, 1H, 2H, 1H, d, 2H, 3, 2H, 3, 1H, 2H, 1H, 3, 2H, 3, 1H, 2H, 1H, 2H, 1H, 2H, 1H, 2H, 1H. ₂₆ H ₃₁ N ₃ O ₂ [M+H] ⁺ 418.24; the experiment shows that: 418.50.

synthesis of the final product 32: 1- (4- (2- (4-hydroxybut-2-yl) -6- (o-tolyl) -2H-indazol-3-yl) piperidin-1-yl) prop-2-en-1-one (ZB37-13)

ZB093(41mg, 0.088mmol) was used as a starting material to synthesize ZB37-13(4.3 mg). ¹ H NMR(400MHz,Methanol-d ₄ ) δ 7.84(dd, J-0.9, 8.7Hz,1H),7.46(t, J-1.1 Hz,1H),7.33-7.27(m,2H),7.25(dd, J-2.0, 4.9Hz,2H),7.05(dd, J-1.4, 8.8Hz,1H),6.89(dd, J-10.7, 16.9Hz,1H),6.31(dd, J-1.7, 4.5Hz,1H),6.27(dd, J-1.7, 4.0Hz, dd1H), 6.02(dd, J-10.4, 17.3Hz,1H),5.83(td, J-1.7, 10.7, 2H), 17.02 (dd, J-10.4, 17.3Hz,1H),5.83(td, J-1.7, 10.7, 2H), 17.17, 17.8H, 6.9H, 1H, 13H, 1H, 13H, 3H, 5.83 (dd, 1.7,10.7, 8H, 1H, 4H, 1H, 6.9H, 1H, 6.9H, 1H, 13H, 1H, 7, 13H, 7H, 6.9H, 7, 13H, 7H, 1H, 4H, 7H, 1H, 4H, 7, 4H, 1H, 7H, 4H, 7, 4H, 1H, 7H, 2H, 7H, 1H, 2H, 1H, 7H, 6.9H, 2H, 1H, 7H, 2H, 6.9H, 1H, 2H, 1H, 2H, 1H, 2H, 1H, 2H, 7H, 2H, 1H, 2H, 1H, 2H, 1H, 2H, 1H, 2H, 1H, 2H, 14H, 1H, 2H, 1H, 2H, 1H, 2H, 14H, 2H, 14H, 1H, 2H, 1H) 2.35(ddd, J ═ 4.4,8.7,19.2Hz,1H),2.28(s,3H),2.26-2.08(m,1H),2.04(d, J ═ 13.2Hz,2H),1.69(d, J ═ 6.6Hz,3H), ESI-MS theoretical calculation C ₂₉ H ₃₃ N ₃ O ₃ [M+H] ⁺ 472.25; the experiment shows that: 472.73.

synthesis of the final product 33: 3- (6- (o-tolyl) -2H-indazol-2-yl) acrylic acid butyl ester (ZB88)

ZB88(3.7mg) was synthesized using 3- (6- (o-tolyl) -2H-indazol-2-yl) butan-1-ol (ZB086, 50mg) as the starting material, and HPLC purification conditions: the initial acetonitrile proportion was 50%, the retention time was 13 minutes. ¹ H NMR(400MHz,Methanol-d ₄ ) δ 8.32(d, J ═ 1.0Hz,1H),7.73(dd, J ═ 1.0,8.7Hz,1H),7.49(q, J ═ 1.1Hz,1H),7.31-7.22(m,4H),7.06(dd, J ═ 1.3,8.6Hz,1H),6.26(dd, J ═ 1.5,17.3Hz,1H),5.99(dd, J ═ 10.4,17.3, 1H),5.79(dd, J ═ 1.5,10.4Hz,1H),4.90-4.82(m,1H),4.14(dd, J ═ 5.3,6.2,11.5Hz,1H),3.96(dd, J ═ 4.9,7.8,11.5, 6.5 Hz,1H), 3.6.6.2, 11.5Hz,1H),3.96(dd, J ═ 4.9,7, 6.8, 6.5, 6.6.5, 6.5, 9, 6.5H), 5, 9, 6.6.6.6.6.6, 9, 5, 9, 5H, 9, 1H, 9, 1H, 9, 1H, 9, 1H, 9, 1H, 9, 1H, etc.), calculated values of (dd, 15H, 15, etc., 1H, 15, etc., 1H, 15, etc., 1H, d, 1H, d, 1H, d, 1H, d ₂₁ H ₂₂ N ₂ O ₂ [M+H] ⁺ 335.17; the experiment shows that: 335.94.

synthesis of the final product 34: butyl 3- (3- (1-acetylpiperidin-4-yl) -6- (o-tolyl) -2H-indazol-2-yl) acrylate (ZB102):

ZB099(30mg, 0.074mmol) was dissolved in a dry dichloromethane solution, triethylamine (0.03ml, 0.22mmol) was added, and a solution of acryloyl chloride (7.3mg, 0.081mmol) in dichloromethane was added dropwise. Reacting at room temperature for 1 hour, spin-drying the solvent after the reaction is finished, and purifying by HPLC. HPLC purification conditions: the initial acetonitrile proportion was 45%, the retention time was 12 minutes. 26.2mg of the objective compound was obtained. ¹ H NMR(400MHz,Methanol-d ₄ ) δ 7.89-7.81(m,1H),7.45(t, J ═ 1.1Hz,1H),7.34-7.22(m,4H),7.03(dd, J ═ 1.5,8.8Hz,1H),6.31(dt, J ═ 1.3,17.3Hz,1H),6.04(ddd, J ═ 1.3,10.5,17.3Hz,1H),5.85(dt, J ═ 1.7,10.5Hz,1H),5.14(ddd, J ═ 4.4,6.8,10.6Hz,1H),4.77(d, J ═ 13.5Hz,1H),4.16 (tdd, J ═ 5.4,11.2Hz,2H),3.82(ddt, J ═ 4, 3.8, J ═ 13.5Hz,1H), 3.16 (tdd, J ═ 5.4,11.2H, 2H), 2H, 3.82 (1H), 3.9, 3.7, 3.8, 3.7H, 1H, 7 (ddd, 3.7H), 3.7H, 3H, 3.7H, 3H, 3.9H, 3H, 1H, 3H), 3H, 1H, 3H, 3.7H, 3H, 1H, 3H, 1H, 7H, 1H, 3.7H, 3H, 7H, 3H, 3.7H, 3H, 1H, 3H, 7H, 3H, 1H, 3H, 1H, 3H, 1H, 7H, 1H, 3H, 1H, 3H, 1H, 3H, 1H, 7H, 1H, 3H, 1H, 5H, 1H, 5H, 1H, 3H, 1H, 5H, 1, 2.18-2.04(m,1H),1.98(q, J ═ 14.4Hz,2H),1.68(d, J ═ 6.6Hz,3H) ₂₈ H ₃₃ N ₃ O ₃ [M+H] ⁺ 460.25; the experiment shows that: 460.48.

Synthesis of the final product 35: propyl 3- (6- (2- (trifluoromethyl) phenyl) -2H-indazol-2-yl) acrylate (ZB140)

Starting with ZB139(50mg, 0.156mmol), synthesis of ZB 140: ¹ H NMR(400MHz,Methanol-d ₄ )δ8.36(d,J＝0.9Hz,1H),7.82(d,J＝7.7Hz,1H),7.76(dd,J＝0.9,8.6Hz,1H),7.68(t,J＝7.5Hz,1H),7.59(t,J＝7.7Hz,1H),7.53(s,1H),7.45(d,J＝7.6Hz,1H),7.07(d,j ═ 8.4Hz,1H),6.32(dd, J ═ 1.5,17.3Hz,1H),6.07(dd, J ═ 10.5,17.3Hz,1H),5.84(dd, J ═ 1.5,10.5Hz,1H),4.64(t, J ═ 6.8Hz,2H),4.23(t, J ═ 6.0Hz,2H),2.43(p, J ═ 6.5Hz,2H), ESI-MS theoretical calculation C ₂₀ H ₁₇ F ₃ N ₂ O ₂ [M+H] ⁺ 374.12; the experiment shows that: 374.95.

synthesis of the final product 36: n- (3- (6- (2- (trifluoromethyl) phenyl) -2H-indazol-2-yl) butyl) acrylamide (ZB143)

The method comprises the following steps: 3- (6- (2- (trifluoromethyl) phenyl) -2H-indazol-2-yl) butanal (ZB122)

ZA158(144mg, 0.43mmol) was dissolved in DMSO (5ml) and IBX (362mg, 1.29mmol) was added and reacted at room temperature overnight. After the reaction is finished, water and ethyl acetate are added for extraction, organic phases are combined and washed by saturated sodium chloride solution, and the solvent is dried by anhydrous sodium sulfate and then is dried to obtain the target product of 106.9 mg. ¹ H NMR(400MHz,Chloroform-d)δ9.79(s,1H),8.07(d,J＝1.0Hz,1H),7.78(d,J＝7.8Hz,1H),7.71-7.63(m,2H),7.59(t,J＝7.2Hz,1H),7.50(t,J＝7.7Hz,1H),7.41(d,J＝7.6Hz,1H),7.07(d,J＝8.6Hz,1H),5.24(h,J＝6.9Hz,1H),3.48(ddd,J＝1.1,7.4,18.1Hz,1H),3.11-2.98(m,1H),1.76(d,J＝6.8Hz,3H).

Step two: n-benzyl-3- (6- (2- (trifluoromethyl) phenyl) -2H-indazol-2-yl) butan-1-amine (ZB126)

ZB122(53.4mg, 0.16mmol) and benzylamine (51.7mg, 0.48mmol) were dissolved in a mixed solution of tetrahydrofuran and methanol (1:1), stirred at room temperature for 2 hours, and then added with sodium borohydride (30mg, 0.80mmol) to react at room temperature overnight. After the reaction is finished, the solvent is dried by spinning, and separated and purified by a chromatographic column. The target compound (36 mg) was obtained. ¹ H NMR(400MHz,Chloroform-d)δ7.95(s,1H),7.79(d,J＝7.8Hz,1H),7.71-7.64(m,2H),7.59(t,J＝7.5Hz,1H),7.50(t,J＝7.7Hz,1H),7.43(d,J＝7.6Hz,1H),7.34-7.27(m,5H),7.08(d,J＝8.6Hz,1H),4.94-4.77(m,1H),2.60(ddd,J＝5.4,7.2,12.4Hz,1H),2.51(dt,J＝7.2,11.9Hz,1H),2.31(ddt,J＝6.0,8.8,14.4Hz,1H),2.11(ddd,J＝5.1,7.2,13.9Hz,1H),2.04(d,J＝9.2Hz,2H),1.69(d,J＝6.8Hz,3H).

Step three: n- (3- (6- (2- (trifluoromethyl) phenyl) -2H-indazol-2-yl) butyl) acrylamide (ZB143)

ZB126(36mg, 0.085mmol) was dissolved in methanol, purged with oxygen and nitrogen, Pd/C (10mg) was added, purged again with oxygen and nitrogen, purged with nitrogen and hydrogen again, and stirred at room temperature overnight. After the reaction was complete, Pd/C was filtered off and the solvent was dried by spinning to give 25.8mg of intermediate. The crude product (25.8mg, 0.08mmol) obtained above was dissolved in a solution of dried dichloromethane, triethylamine (0.04ml, 0.23mmol) was added, and then a solution of acryloyl chloride (7.7mg, 0.085mmol) in dichloromethane was added and reacted at room temperature for 1 hour. After the reaction, the solvent was dried by spinning and purified by HPLC. The target compound (22.8 mg) was obtained. ¹ H NMR(400MHz,Methanol-d ₄ ) δ 8.40(d, J ═ 1.0Hz,1H),7.82(d, J ═ 7.9Hz,1H),7.77(dd, J ═ 0.9,8.7Hz,1H),7.68(t, J ═ 7.5Hz,1H),7.59(t, J ═ 7.7Hz,1H),7.54(s,1H),7.45(d, J ═ 7.6Hz,1H),7.08(d, J ═ 8.6Hz,1H),5.63(dd, J ═ 3.9,8.1Hz,1H),4.86-4.73(m,1H),3.25-3.09(m,2H),2.36(ddt, J ═ 6,9.4,13.4, 1H),2.19 (m,1H), 3.19, 5.70 Hz, 14.6, 14H), theoretical calculated values of J ═ 6.6,9.4,13.4, 1H, 5, 7.6, 5, 1H, 7.6, 14, 1H, 15, 1H, 4, 15, 1H, theoretical calculated values of d, 1H, C, d, 1H, 1, C, 1, C ₂₁ H ₂₀ F ₃ N ₃ O ₁ [M+H] ⁺ 388.16; the experiment shows that: 386.10.

synthesis of end product 37: n- (3- (6- (2- (trifluoromethyl) phenyl) -2H-indazol-2-yl) butyl) acrylamide (ZB152)

The method comprises the following steps: synthesis of 3- (6- (2- (trifluoromethyl) phenyl) -2H-indazol-2-yl) propanal (ZB141)

ZB139(200mg, 0.63mmol) was dissolved in DMSO (5ml), IBX (525mg, 1.88mmol) was added and stirred at room temperature, the reaction was monitored by UPLC, water was added after the reaction was completed, ethyl acetate was extracted, the organic phases were combined and dried over anhydrous sodium sulfate, and the solvent was dried by spinning to obtain 179mg of the objective compound. ¹ H NMR(400MHz,Chloroform-d)δ9.86(s,1H),8.06(s,1H),7.78(d,J＝7.9Hz,1H),7.70-7.61(m,2H),7.59(t,J＝7.5Hz,1H),7.50(t,J＝7.6Hz,1H),7.40(d,J＝7.6Hz,1H),7.07(d,J＝8.6Hz,1H),4.79(t,J＝6.3Hz,2H),3.29(t,J＝6.3Hz,2H).

Step two: synthesis of N-benzyl-3- (6- (2- (trifluoromethyl) phenyl) -2H-indazol-2-yl) propan-1-amine (ZB144)

ZB141(89.5mg, 0.28mmol) and benzylamine (90.5mg, 0.84mmol) were dissolved in a mixed solution (6ml) of THF and methanol (1:1), followed by addition of sodium borohydride (53.4mg, 1.41mmol) and reaction at room temperature overnight. After the reaction is finished, water and dichloromethane are added for extraction, organic phases are combined and dried by anhydrous sodium sulfate, and the solvent is dried by spinning. Used directly in the next step.

Step three: n- (3- (6- (2- (trifluoromethyl) phenyl) -2H-indazol-2-yl) butyl) acrylamide (ZB152)

The resulting crude ZB144 was dissolved in a mixed solution of dichloromethane and trifluoroacetic acid (3:1), stirred at room temperature for 2 hours, added with water, extracted with dichloromethane, the combined organic phases washed with saturated sodium chloride, dried over anhydrous sodium sulfate and the solvent dried, and then the resulting product was dissolved in an anhydrous dichloromethane solution, triethylamine (0.12ml) was added, and a dichloromethane solution of acryloyl chloride (15mg) was added dropwise. The reaction was carried out at room temperature for 1 hour. And (4) after the reaction is finished, spin-drying the solvent. And (5) HPLC purification. To obtain the target compound 2.3 mg. ¹ H NMR(400MHz,Methanol-d ₄ ) δ 8.34(d, J ═ 1.0Hz,1H),8.25(s,1H),7.81(d, J ═ 7.9Hz,1H),7.75(dd, J ═ 1.0,8.6Hz,1H),7.68(t, J ═ 7.5Hz,1H),7.58(t, J ═ 7.7Hz,1H),7.52(s,1H),7.45(d, J ═ 7.6Hz,1H),7.05(d, J ═ 8.6Hz,1H),6.22(d, J ═ 5.9Hz,2H),5.66(t, J ═ 6.0Hz,1H),4.55(t, J ═ 6.8Hz,2H),2.27(p, J ═ 6.8, 2H), theoretical ESI-C-calculated values (t, J ═ 6.8Hz,2H),2.27(p, J ═ 6.8, 2H), theoretical ESI ═ C-ESI-C-1H), and C ₂₀ H ₁₈ F ₃ N ₃ O[M+H] ⁺ 374.14; the experiment shows that: 374.95.

synthesis of the end product 38: n- (3- (3- (1-acetylpiperidin-4-yl) -6- (o-tolyl) -2H-indazol-2-yl) butyl) acrylamide (ZC004)

The method comprises the following steps: 1- (4- (2- (4-hydroxybut-2-yl) -6- (o-tolyl) -2H-indazol-3-yl) piperidin-1-yl) ethan-1-one (ZB099)

ZB093(260mg) was dissolved in a mixed solution of dichloromethane and trifluoroacetic acid (3:1) and reacted at room temperature for 2 hours. After the reaction, water and dichloromethane were added for extraction, the organic phases were combined and washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate and the solvent was dried to obtain 241mg of an intermediate. The resulting intermediate (241mg) was then dissolved in a dry dichloromethane solution, triethylamine (0.28ml, 1.99mmol) was added, acetyl chloride (115mg, 1.46mmol) was finally added, and the solvent was allowed to react at room temperature for 1 hour, with spin-drying. And purified by HPLC. 120mg of the objective compound was obtained. HPLC purification conditions: the initial acetonitrile proportion was 40%, the retention time was 10 minutes. ¹ H NMR(400MHz,Methanol-d ₄ )δ7.91(dd,J＝2.4,8.7Hz,1H),7.46(s,1H),7.30(d,J＝3.1Hz,2H),7.28-7.23(m,2H),7.07(dd,J＝1.4,8.7Hz,1H),5.29-5.15(m,1H),4.80(d,J＝13.3Hz,1H),4.17(d,J＝13.7Hz,1H),3.67(t,J＝12.2Hz,1H),3.59(dt,J＝5.0,10.4Hz,1H),3.43-3.35(m,1H),3.24-3.11(m,1H),2.85(q,J＝12.2Hz,1H),2.35(ddt,J＝4.4,9.5,13.6Hz,2H),2.29(s,3H),2.22(d,J＝2.3Hz,3H),2.20(t,J＝4.6Hz,1H),2.17(d,J＝5.1Hz,1H),2.12(s,1H),2.02(t,J＝13.8Hz,1H),1.68(d,J＝6.7Hz,3H).

Step two: 3- (3- (1-acetylpiperidin-4-yl) -6- (o-tolyl) -2H-indazol-2-yl) butanal (ZB120)

ZB099(90mg, 0.222mmol) was dissolved in DMSO (5ml), and IBX (186mg, 0.666mmol) was added thereto to react at room temperature for 9 hours. After the reaction, water and ethyl acetate were added to extract, the combined organic phases were washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and the solvent was dried to obtain 43.8mg of the objective compound, which was used directly in the next step. ¹ H NMR(400MHz,Chloroform-d)δ9.63(s,1H),7.62(dd,J＝0.9,8.8Hz,1H),7.45(d,J＝1.1Hz,1H),7.21-7.16(m,4H),6.90(dd,J＝1.5,8.8Hz,1H),5.23(d,J＝9.9Hz,2H),4.83(d,J＝13.8Hz,2H),3.97(s,1H),3.70(ddd,J＝8.7,18.6,21.6Hz,1H),3.49-3.36(m,1H),3.32-3.16(m,1H),3.01-2.92(m,1H),2.23(s,3H),2.13(d,J＝2.0Hz,3H),2.10-2.02(m,2H),1.94(s,2H),1.88(d,J＝12.8Hz,1H),1.55(dd,J＝2.9,6.7Hz,3H).

Step three: 1- (4- (2- (4- (benzylamino) but-2-yl) -6- (o-tolyl) -2H-indazol-3-yl) piperidin-1-yl) ethan-1-one (ZB156)

ZB120(90mg, 0.223mmol) and benzylamine (71.7mg, 0.67mmol) were dissolved in a mixed solution of tetrahydrofuran and methanol (1:1), and after stirring at room temperature for 2 hours, sodium borohydride (42.4mg, 1.12mmol) was added to react at room temperature overnight. After the reaction is finished, the solvent is dried by spinning, and separated and purified by a chromatographic column. The target compound (42.7mg) was obtained. ¹ H NMR(400MHz,Chloroform-d)δ7.72(d,J＝8.7Hz,1H),7.62(d,J＝1.3Hz,1H),7.38-7.34(m,2H),7.34-7.29(m,5H),7.26(d,J＝6.4Hz,2H),7.02(dt,J＝1.2,8.6Hz,1H),5.07-4.94(m,1H),4.89(t,J＝13.0Hz,1H),4.02(d,J＝13.7Hz,1H),3.94(d,J＝14.7Hz,1H),3.73(qd,J＝4.2,13.2Hz,1H),3.52-3.40(m,1H),3.25(t,J＝13.0Hz,1H),3.10(t,J＝12.7Hz,1H),2.66(dtd,J＝6.9,12.9,13.7,25.0Hz,2H),2.57-2.47(m,1H),2.47-2.38(m,1H),2.36(s,3H),2.19(d,J＝2.0Hz,2H),2.16-2.07(m,2H),1.98(s,2H),1.64(d,J＝6.6Hz,3H).

Step four: n- (3- (3- (1-acetylpiperidin-4-yl) -6- (o-tolyl) -2H-indazol-2-yl) butyl) acrylamide (ZC004)

Dissolving ZB156(42.7mg) in methanol, purging with nitrogen and oxygen, adding Pd (OH) ₂ (10mg), the mixture was again purged with oxygen and then purged with nitrogen, and then purged with hydrogen and stirred at room temperature overnight. After the reaction was complete, Pd (OH) was filtered off ₂ The solvent was dried by evaporation to give 23.7mg of intermediate. The crude product (23.7mg, 0.06mmol) obtained above was dissolved in a solution of dried dichloromethane, triethylamine (0.04ml, 0.18mmol) was added, and then a solution of acryloyl chloride (6.0mg, 0.066mmol) in dichloromethane was added and reacted at room temperature for 1 hour. After the reaction, the solvent was dried by spinning and purified by HPLC. 14.4mg of the objective compound was obtained. ¹ H NMR(400MHz,Methanol-d ₄ ) δ 7.95-7.80(m,1H),7.47(t, J ═ 1.1Hz,1H),7.29(dq, J ═ 3.6,9.0Hz,2H),7.26-7.22(m,2H),7.05(dd, J ═ 1.4,8.7Hz,1H),6.26-6.12(m,2H),5.66(dd, J ═ 5.4,6.5Hz,1H),5.02(dt, J ═ 6.2,9.1Hz,1H),4.78(d, J ═ 13.3Hz,1H),4.15(d, J ═ 14.0Hz,1H),3.53(t, J ═ 12.2, 1H),3.30-3.19(m,1H), 3.81 (d, J ═ 14.0Hz,1H), 3.7.7.7.7 (t, J ═ 1.6.4.2, 6.2 Hz,1H), 15(d, J ═ 6.2, 13.0 Hz,1H), 3.7H, 15 (q ═ 6.2, 6.2H), 3.7H, 15 (15, 13.7H), 3.7H, 15(d, 15, 1H), 15H, 15H), 3.7H, 15H), 15H, 15H, 15H), 3.7H, 15, 3, 15, 3, 15, 3, 15, 3, 6, 15, 3, 15, 6, 15. ₂₈ H ₃₄ N ₄ O ₂ [M+H] ⁺ 459.27; the experiment shows that: 459.09.

synthesis of end product 39: n- (3- (6- (2- (trifluoromethyl) phenyl) -2H-indazol-2-yl) propyl) acrylamide (ZC09)

The method comprises the following steps: synthesis of 3- (6- (2- (trifluoromethyl) phenyl) -2H-indazol-2-yl) butanal (ZC003)

ZB086(150mg, 0.54mmol) was dissolved in DMSO (5ml) and IBX (450mg, 1.61mmol) was added. The reaction was at room temperature and monitored by UPLC. After the reaction, water and ethyl acetate were added for extraction, washed with saturated NaCl solution, and spin-dried to obtain a crude product of 91 mg. ¹ H NMR(400MHz,Chloroform-d)δ9.77(d,J＝0.9Hz,1H),8.06(d,J＝1.0Hz,1H),7.69(dd,J＝0.9,8.6Hz,1H),7.64(q,J＝1.1Hz,1H),7.35-7.29(m,4H),7.09(dd,J＝1.4,8.6Hz,1H),5.23(td,J＝5.9,7.2Hz,1H),3.48(ddd,J＝1.1,7.5,18.1Hz,1H),3.04(ddd,J＝0.9,5.7,18.1Hz,1H),2.34(s,3H),1.75(d,J＝6.8Hz,3H).

Step two: synthesis of N-benzyl-3- (6- (2- (trifluoromethyl) phenyl) -2H-indazol-2-yl) propan-1-amine (ZC005)

ZC003(91mg, 0.33mmol) and benzylamine (105mg, 0.98mmol) were dissolved in a mixed solution of tetrahydrofuran and methanol (1:1), stirred at room temperature for 2 hours, and then added with sodium borohydride (62.3mg, 1.64mmol) to react at room temperature overnight. After the reaction is finished, the solvent is dried by spinning, and separated and purified by a chromatographic column. ¹ H NMR(400MHz,Chloroform-d)δ7.96(d,J＝1.0Hz,1H),7.72-7.65(m,2H),7.42-7.33(m,2H),7.33-7.29(m,7H),7.10(dd,J＝1.4,8.5Hz,1H),4.85(dtd,J＝1.6,5.3,9.5Hz,1H),3.77(q,J＝13.2Hz,2H),2.69-2.47(m,2H),2.36(s,3H),2.35-2.27(m,1H),2.13(dtd,J＝4.9,7.4,14.4Hz,1H),1.69(d,J＝6.8Hz,3H).

Step three: synthesis of N- (3- (6- (2- (trifluoromethyl) phenyl) -2H-indazol-2-yl) propyl) acrylamide (ZC09)

Dissolving ZC005 in methanol, deoxidizing, charging nitrogen gas, adding Pd (OH) ₂ (20mg), the oxygen and nitrogen were again purged, and then the nitrogen was purgedThe mixture was purged with hydrogen and stirred at room temperature overnight. After the reaction was complete, Pd (OH) was filtered off ₂ The solvent was dried by vortexing to give intermediate 55.4 mg. The crude product (27.7mg, 0.1mmol) was dissolved in a dried dichloromethane solution, triethylamine (0.05ml, 0.3mmol) was added, a dichloromethane solution of acryloyl chloride (10mg, 0.11mmol) was added, and the reaction was carried out at room temperature for 1 hour. After the reaction was completed, the solvent was dried by spinning, and purified by HPLC, whereby 4.2mg of the objective compound was obtained. ¹ H NMR(400MHz,Methanol-d ₄ ) δ 8.37(d, J ═ 1.0Hz,1H),7.76(dd, J ═ 0.9,8.6Hz,1H),7.50(q, J ═ 1.1Hz,1H),7.32-7.26(m,2H),7.24(dd, J ═ 1.3,3.5Hz,2H),7.09(dd, J ═ 1.3,8.6Hz,1H),6.23-6.11(m,2H),5.63(dd, J ═ 4.5,7.5Hz,1H),4.79(dqd, J ═ 5.0,6.7,9.4Hz,1H),3.25-3.08(m,2H),2.35 (ESI, J ═ 6.6,9.4,13.3, 13.7, 9.4Hz,1H), 2.35 (ESI, 9.6, 13.3, 3, 3.3, 2H), theoretical calculated values (15, 3, 3.3, 2H),2.35 (ESI, J ═ 6.6, 9.6, 9, 3, 3.6, 3, 2, 3, 2,1, d, 1, H), and so on ₂₁ H ₂₃ N ₃ O[M+H] ⁺ 334.18, the experiment found: 334.18.

synthesis of final product 40: n- (4- ((2- (4-hydroxybut-2-yl) -6- (2- (trifluoromethyl) phenyl) -2H-indazol-3-yl) amino) phenyl) acrylamide (ZC19)

The method comprises the following steps: 3-bromo-2- (4- ((tert-butyldiphenyl) oxy) but-2-yl) -6- (2- (trifluoromethyl) phenyl) -2H-indazole (ZB154)

ZB036(ZB036, 650mg, 1.57mmol) and imidazole (214.1mg, 3.15mmol) were dissolved in dry DMF (6ml) and TBDPSCl (562mg, 2.04mmol) was added dropwise and the mixture was stirred at 50 ℃ overnight. After the reaction is finished, water and ethyl acetate are added for extraction, organic phases are combined and dried by anhydrous sodium sulfate, and the solvent is separated and purified by a chromatographic column. 1.04g of the target product was obtained. ¹ H NMR(400MHz,Chloroform-d)δ7.83-7.76(m,1H),7.79-7.71(m,3H),7.71-7.63(m,2H),7.62(s,1H),7.62-7.57(m,1H),7.57(q,J＝1.3,2.2Hz,2H),7.55(d,J＝1.5Hz,1H),7.51(t,J＝7.6Hz,1H),7.44(d,J＝2.7Hz,1H),7.36(q,J＝1.5Hz,1H),7.33-7.26(m,2H),7.13(d,J＝8.6Hz,1H),3.71(dt,J＝5.2,10.7Hz,1H),3.57(ddd,J＝4.2,7.9,10.7Hz,1H),2.56-2.42(m,1H),2.26-2.09(m,2H),1.62(d,J＝6.7Hz,3H),1.08(s,9H).

Step two: n is a radical of ¹ - (2- (4- ((tert-butyldiphenylsilyl) oxy) but-2-yl) -6- (2- (trifluoromethyl) phenyl) -2H-indazol-3-yl) benzene-1, 4-diamine (ZC015)

(1) Taking a dry reaction bottle and adding Pd ₂ (dba) ₃ (157mg, 0.17mmol) and BINAP (213.4mg, 0.34mmol), toluene (5ml) was added, oxygen and nitrogen were purged, heated at 80 ℃ for 5min and cooled to room temperature for further use. (2) Another dry two-necked flask with a condenser was sequentially charged with ZB154(372.6mg, 0.57mmol), 1, 4-phenylenediamine (185.5mg, 1.72mmol), and t-BuONa (219.6mg, 2.29mmol), and finally toluene (6ml), and after purging with oxygen and nitrogen, the solution in (1) was transferred to (2) with a syringe, purged again with oxygen and nitrogen, and heated at 80 ℃ for 16 hours. After the reaction is finished, water and ethyl acetate are added for extraction, the combined organic phase is dried by anhydrous sodium sulfate, and then the solvent is dried by spinning and is separated and purified by a chromatographic column. 100.8mg of the objective compound was obtained. ¹ H NMR(400MHz,Chloroform-d)δ7.80-7.75(m,1H),7.66-7.60(m,4H),7.56(d,J＝6.9Hz,2H),7.52-7.40(m,3H),7.36(ddd,J＝6.6,7.9,13.1Hz,5H),7.22(dd,J＝0.9,8.7Hz,1H),6.86(d,J＝8.6Hz,1H),6.62-6.54(m,2H),6.53-6.46(m,2H),5.80(s,1H),5.17(ddd,J＝4.5,6.8,10.6Hz,1H),3.75(dt,J＝4.4,11.1Hz,1H),3.32(td,J＝3.3,10.6Hz,1H),2.29-2.16(m,1H),1.66(d,J＝6.7Hz,3H),1.12(s,9H).

Step three: n- (4- ((2- (4- ((tert-butyldiphenyl) oxy) but-2-yl) -6- (2- (trifluoromethyl) phenyl) -2H-indazol-3-yl) amino) phenyl) acrylamide (ZC017)

ZC015(100mg, 0.147mmol) was dissolved in dry dichloromethane (6ml), triethylamine (0.06ml, 0.44mmol) was added, a solution of acryloyl chloride (13.3mg, 0.147mmol) in dichloromethane was added dropwise, the reaction was carried out at room temperature for 1 hour, and the solvent was dried by evaporation. The target product 41.4mg is obtained after separation and purification by a chromatographic column. ¹ H NMR(400MHz,Chloroform-d)δ7.78(d,J＝7.9Hz,1H),7.66-7.55(m,6H),7.53-7.45(m,3H),7.43(d,J＝6.7Hz,2H),7.41-7.36(m,5H),7.36-7.29(m,3H),6.94(d,J＝8.6Hz,1H),6.49(d,J＝8.5Hz,2H),6.24(dd,J＝10.1,16.8Hz,1H),5.72(dd,J＝1.4,10.2Hz,1H),5.17(td,J＝4.6,8.5,10.7Hz,1H),3.77(dt,J＝4.2,11.2Hz,1H),3.28(td,J＝3.1,10.6Hz,1H),2.26(dt,J＝11.7,14.0Hz,1H),2.11(dt,J＝4.4,9.4Hz,1H),1.65(d,J＝6.7Hz,3H),1.12(s,9H).

Step four: n- (4- ((2- (4-hydroxybut-2-yl) -6- (2- (trifluoromethyl) phenyl) -2H-indazol-3-yl) amino) phenyl) acrylamide (ZC19)

ZC017(41.4mg, 0.059mmol) was dissolved in DMSO (3ml), CsF (17.2mg, 0.113mmol) was added and reacted overnight at room temperature, and after the reaction was completed, 1.5ml of water was added and purified by HPLC. 4.2mg of the target product is obtained. ¹ H NMR(400MHz,Methanol-d ₄ ) δ 7.83(d, J ═ 7.8Hz,1H),7.72-7.65(m,3H),7.65-7.55(m,1H),7.45(q, J ═ 6.7,7.6Hz,2H),7.20-7.12(m,3H),7.00(dd, J ═ 1.3,8.6Hz,1H),6.52-6.33(m,2H),5.79(dd, J ═ 2.3,9.7Hz,1H),5.20-5.03(m,1H),3.67(dt, J ═ 5.4,10.9Hz,1H),3.45-3.36(m,1H),2.68(s,1H),2.29 (ESI, J ═ 5.1,9.8,14.4, 2.17H), theoretical calculated values (m,1H), 2.8, 17, 17.13H, 17, 3.13H), theoretical calculated values ₂₇ H ₂₅ F ₃ N ₄ O ₂ [M+H] ⁺ 494.19, the experiment found: 494.72.

synthesis of end products 41 and 42: n- (cis-3- (6- (2- (trifluoromethyl) phenyl) -2H-indazol-2-yl) cyclohexyl) acrylamide (ZC37-18) and N- (trans-3- (6- (2- (trifluoromethyl) phenyl) -2H-indazol-2-yl) cyclohexyl) acrylamide (ZC37-19)

The method comprises the following steps: synthesis of tert-butyl (3- (6- (2- (trifluoromethyl) phenyl) -2H-indazol-2-yl) cyclohexyl) carbamate (ZC035)

ZC028(278.3mg, 0.95mmol) and DMAP (11.6mg, 0.095mmol) were dissolved in a dry tetrahydrofuran solution, and di-tert-butyl dicarbonate (829.2mg, 3.8mmol) was added to the solution to react at room temperature overnight. And after the reaction is finished, the solvent is dried by spinning, washed by water and extracted by dichloromethane, organic phases are combined and dried by anhydrous sodium sulfate, and the crude product 178mg of the reaction product is obtained after primary purification. The crude reaction product obtained, 2-trifluoromethylphenylboronic acid (205mg, 1.08mmol) were charged to an eggplant type bottle and dissolved with DME (8ml) and 2M sodium carbonate solution (4ml) exceptIntroducing nitrogen into the oxygen, adding Pd (dppf) Cl ₂ ·CH ₂ Cl ₂ (30mg), the reaction was again heated at 95 ℃ overnight after purging oxygen and nitrogen again. After the reaction is finished, water and ethyl acetate are added for extraction, organic phases are combined and dried by anhydrous sodium sulfate, and a chromatographic column is used for separation and purification after a solvent is evaporated. 162mg of the objective compound (as a mixture of cis-trans isomers) was obtained.

Step two: n- (cis-3- (6- (2- (trifluoromethyl) phenyl) -2H-indazol-2-yl) cyclohexyl) acrylamide (ZC37-18) and N- (trans-3- (6- (2- (trifluoromethyl) phenyl) -2H-indazol-2-yl) cyclohexyl) acrylamide (ZC37-19)

ZC035(162mg) was dissolved in a mixed solution of dichloromethane and trifluoroacetic acid (3:1), reacted at room temperature for 2 hours, then the solvent was spin-dried, washed with water, extracted with dichloromethane, the organic phases were combined and dried over anhydrous sodium sulfate, and the solvent was spin-dried to give crude 83.4mg of the reaction product. The crude reaction product was dissolved in dry dichloromethane, triethylamine (0.09ml, 0.64mmol) was added, followed by addition of acryloyl chloride (21mg, 0.23mmol) in dichloromethane and reaction at room temperature for 1 hour. After the reaction, the solvent was dried by spinning and purified by HPLC. ZC 37-18: ¹ H NMR(400MHz,Methanol-d ₄ ) δ 8.38(d, J ═ 1.0Hz,1H),7.83-7.78(m,1H),7.75(dd, J ═ 0.9,8.7Hz,1H),7.67(dd, J ═ 7.1,8.4Hz,1H),7.61-7.54(m,1H),7.53(s,1H),7.44(d, J ═ 7.6Hz,1H),7.11-7.00(m,1H),6.30-6.20(m,2H),5.67(dd, J ═ 5.6,6.5Hz,1H),4.68(tt, J ═ 3.8,12.1Hz,1H),4.04(ddt, J ═ 3.8,7.5,11.8, 1H),2.47 (tt, J ═ 3.8,12.1Hz, 12.1H), theoretical calculated values (15.31H, 11.11H, 11.47, 12.6H), 15.11H, 11H, 11.6H, 11H, 11.8 (H), 11H, 11.47 ═ 3.8, 12H, 15, 1, 15, 1, 15, 1, 15, 1, 15, 1, 2,1, 2,1, 15, 1, 15, 2,1, 15, 1, 2, 15, 2, d, 1, C, 1, C, H, C, d, H, d, H, C, 1, H, 1, H, 1, H, 1, H, d, H, 1, C, 1, C, 1, C, d, C ₂₃ H ₂₂ F ₃ N ₃ O[M+H] ⁺ 414.17; the experiment shows that: 414.39. ZC 37-19: ¹ H NMR(400MHz,Methanol-d ₄ ) δ 8.43(d, J ═ 1.0Hz,1H),7.83-7.73(m,2H),7.70-7.63(m,1H),7.60-7.54(m,1H),7.53(s,1H),7.43(d, J ═ 7.6Hz,1H),7.07(dd, J ═ 1.3,8.7Hz,1H),6.42(dd, J ═ 10.2,17.0Hz,1H),6.28(dd, J ═ 1.9,17.0Hz,1H),5.70(dd, J ═ 1.9,10.2Hz,1H),4.83(tt, J ═ 4.3,9.6Hz,1H),4.39(t, J ═ 4.3, 1H), 2.29.48H, 29.29H, 29.82H), theoretical calculated values of C, 1H, 15.6H, 4.39(t, J ═ 4.3, 1H), 2H, 29.29.6H, 15, 18H, 15, 18H, 18, m, 18, m, C, 1H, C ₂₃ H ₂₂ F ₃ N ₃ O[M+H] ⁺ 414.17; the experiment shows that: 414.38.

synthesis of the end product 43: n- (3- ((2- (3-hydroxypropyl) -6- (2- (trifluoromethyl) phenyl) -2H-indazol-3-yl) amino) phenyl) acrylamide (ZC50)

The method comprises the following steps: 3- (3-bromo-6- (2- (trifluoromethyl) phenyl) -2H-indazol-2-yl) propan-1-ol (ZC039)

ZB139(1.08g, 3.375mmol) was dissolved in AcOH (10ml) and N-bromosuccinimide (600.7mg, 3.375mmol) was added and stirred at room temperature overnight. After the reaction is finished, water and ethyl acetate are added for extraction, organic phases are combined and dried by anhydrous sodium sulfate, and the solvent is separated and purified by a chromatographic column. 716mg of the target product is obtained. ¹ H NMR(400MHz,Chloroform-d)δ7.79(d,J＝8.0Hz,1H),7.62(s,1H),7.58(d,J＝6.5Hz,1H),7.55(d,J＝3.0Hz,1H),7.51(d,J＝8.0Hz,1H),7.40(d,J＝7.6Hz,1H),7.15(d,J＝8.8Hz,1H),4.73(q,J＝6.6Hz,2H),3.71(t,J＝5.7Hz,2H),2.23(p,J＝6.2Hz,2H).

Step two: 3-bromo-2- (3- ((tert-butyldiphenyl) oxy) propyl) -6- (2- (trifluoromethyl) phenyl) -2H-indazole (ZC040)

ZC039(716mg, 1.8mmol) and imidazole (246mg, 3.6mmol) were dissolved in anhydrous DMF (5ml), TBDPSCl (646mg, 2.35mmol) was added dropwise, and the mixture was stirred at 50 ℃ overnight. After the reaction is finished, water and ethyl acetate are added for extraction, organic phases are combined and dried by anhydrous sodium sulfate, and the solvent is separated and purified by a chromatographic column. 1.24g of the target product was obtained.

Step three: synthesis of N ¹ - (2- (3- ((tert-butyldiphenylsilyl) oxy) propyl) -6- (2- (trifluoromethyl) phenyl) -2H-indazol-3-yl) benzene-1, 3-diamine (ZC044)

(1) Taking a dry reaction bottle and adding Pd ₂ (dba) ₃ (86mg, 0.094mmol) and BINAP (117.3mg, 0.188mmol), toluene (5ml) was added, oxygen and nitrogen were removed, the mixture was heated at 80 ℃ for 5min and then cooled to room temperature for further use. (2) Taking another dry two-mouth bottle with a condenser tube, sequentially adding ZC040(200mg, 0.31mmol) and 1,3-phenylenediamine (102mg, 0.94mmol), t-BuONa (121mg, 1.26mmol) and finally toluene (6ml) were added, the solution from (1) was transferred to (2) with a syringe after purging with oxygen and nitrogen, again purged with oxygen and nitrogen and heated at 80 ℃ for 16 hours. After the reaction is finished, water and ethyl acetate are added for extraction, the combined organic phase is dried by anhydrous sodium sulfate, and then the solvent is dried by spinning and is separated and purified by a chromatographic column. 97mg of the objective compound was obtained. ¹ H NMR(400MHz,Chloroform-d)δ7.82-7.76(m,1H),7.67-7.63(m,4H),7.58(d,J＝7.6Hz,2H),7.53-7.47(m,1H),7.47-7.41(m,3H),7.41-7.35(m,5H),7.01-6.93(m,2H),6.24(ddd,J＝0.8,2.2,7.9Hz,1H),6.15-6.06(m,1H),5.94(s,1H),5.83(t,J＝2.2Hz,1H),4.57(t,J＝6.6Hz,2H),3.70(t,J＝5.6Hz,2H),2.21(p,J＝6.2Hz,2H),1.29(t,J＝7.2Hz,2H),1.11(s,9H).

Step four: synthesis of N- (3- ((2- (3-hydroxypropyl) -6- (2- (trifluoromethyl) phenyl) -2H-indazol-3-yl) amino) phenyl) acrylamide (ZC50)

ZC044(97mg, 0.147mmol) is dissolved in dried dichloromethane, triethylamine (0.06ml, 0.44mmol) is added, finally a solution of acryloyl chloride (13.3mg, 0.162mmol) in dichloromethane is added dropwise and reacted at room temperature for 1 hour, after the reaction is finished, water and dichloromethane are added for extraction, organic phases are combined and dried by anhydrous sodium sulfate, and the solvent is dried. The crude product obtained (108mg, 0.147mmol) was then dissolved in DMSO, cesium fluoride (44.8mg, 0.29mmol) was added and stirred at room temperature overnight. After the reaction was completed, purification was performed by HPLC. The target compound ZC 506.4 mg is obtained: ¹ H NMR(400MHz,Methanol-d ₄ ) δ 7.88-7.78(m,1H),7.69(t, J ═ 7.7Hz,1H),7.62(d, J ═ 7.7Hz,1H),7.59(t, J ═ 1.6Hz,1H),7.47(s,1H),7.43(d, J ═ 7.6Hz,1H),7.34(dd, J ═ 1.3,5.0Hz,2H),7.31(dd, J ═ 0.9,8.7Hz,1H),7.03(d, J ═ 8.7Hz,1H),6.90(ddd, J ═ 2.3,3.5,5.9Hz,1H),6.49-6.29(m,2H),5.77(dd, J ═ 2.3,9.6, t ═ 2.3,3, 5.9Hz,1H), theoretical calculated values of J ═ 2.6, 5.29 (m,2H),5.77(dd, J ═ 2.3,9, t ═ 2.6, 6, t ═ 2.6, 6, 5.6, 5, 5.6, 6, 5.6, and theoretical calculated values of (C, 15H), and theoretical calculated values of C, 15H), and theoretical values of C (d, 15H), and C, 1H), and theoretical values of C, 1H, and theoretical values of the theoretical values of C, 1H, and the theoretical values of C, 1H, and theoretical values of C, and theoretical values of the like ₂₆ H ₂₃ F ₃ N ₄ O ₂ [M+H] ⁺ 481.18, the experiment found: 481.70.

synthesis of end product 97: n- (3- (6- (2- (trifluoromethyl) phenyl) -2H-indazol-2-yl) phenyl) acrylamide (ZC72)

Step one, 3- (6-bromo-2H-indazol-2-yl) aniline (ZC64)

4-bromo-2-nitro-benzaldehyde (500mg, 2.18mmol) and 1, 3-phenylenediamine (260g, 2.40mmol) were added to an eggplant type flask, followed by addition of 15ml of isopropanol and stirring with heating at 80 ℃ for 4 hours. After the reaction was completed, the reaction solution was cooled to room temperature and then added ⁿ Bu ₃ P (1.32g, 6.55mmol) was reacted by heating at 80 ℃ for 16 hours. After the reaction, the reaction mixture was cooled to room temperature, and the solvent was dried by evaporation, and then purified by column chromatography to obtain 727.9mg of the objective compound. ¹ H NMR(400MHz,Chloroform-d)δ8.28(d,J＝0.9Hz,1H),7.97(s,1H),7.69–7.63(m,2H),7.59(d,J＝8.8Hz,1H),7.20(dd,J＝1.6,8.8Hz,1H),6.84–6.77(m,2H),3.88(s,2H).

Step two: (3- (6- (2- (trifluoromethyl) phenyl) -2H-indazol-2-yl) phenyl) carbamic acid tert-butyl ester (ZC70)

ZC64(727.9mg, 1.8mmol) and DMAP (22.4mg, 0.18mmol) were dissolved in THF, followed by the addition of Boc ₂ O (1.6g, 7.2mmol) was reacted at room temperature overnight. After the reaction was completed, water was added to quench and extracted with dichloromethane, dried over anhydrous sodium sulfate and the solvent was dried under reduced pressure to obtain 502mg of a crude korean target compound. Then the phase reaction flask was charged with 2-trifluoromethylphenylboronic acid (548mg, 2.87mmol) and DME (12ml) and Na ₂ CO ₃ (2M aq, 6ml) was dissolved, oxygen was removed from the system and nitrogen was purged, followed by addition of Pd (dppf) Cl ₂ ·CH ₂ Cl ₂ (80mg), the reaction was carried out overnight at 95 ℃ after purging oxygen and nitrogen again. After the reaction is finished, cooling to room temperature, adding water and ethyl acetate for extraction, combining organic phases, drying by using anhydrous sodium sulfate, and separating and purifying by using a chromatographic column after spin drying. 484.6mg of the target product are obtained.

Step three: n- (3- (6- (2- (trifluoromethyl) phenyl) -2H-indazol-2-yl) phenyl) acrylamide (ZC72)

ZC70(27.8mg) is dissolved in the mixed solution of dichloromethane and trifluoroacetic acid (3:1), reacted at room temperature for 2 hours, then solvent is spin-dried, washed by water and dichloro-washedExtraction with methane, combination of the organic phases and drying over anhydrous sodium sulfate, and spin-drying of the solvent gave 22mg of the desired product. The obtained product was dissolved in dry dichloromethane, triethylamine (18mg, 0.18mmol) was added, and then a solution of acryloyl chloride (8mg, 0.07mmol) in dichloromethane was added, and the reaction was carried out at room temperature for 1 hour. After the reaction, the solvent was dried by spinning and purified by HPLC. The objective compound (4.3 mg) was obtained. ¹ H NMR(400MHz,Methanol-d ₄ ) δ 8.84(d, J ═ 1.0Hz,1H),8.45(t, J ═ 2.1Hz,1H), 7.87-7.80 (m,2H),7.76(ddd, J ═ 1.0,2.2,8.1Hz,1H), 7.73-7.67 (m,2H),7.61(d, J ═ 7.3Hz,2H),7.58(d, J ═ 8.1Hz,1H),7.49(d, J ═ 7.6Hz,1H),7.11(d, J ═ 8.7Hz,1H),6.48(d, J ═ 9.3Hz,1H),6.46(d, J ═ 2.6Hz,1H),5.84(dd, J ═ 2.6,9.3, 1H), theoretical calculated values of C-C ═ C —, calculated values ₂₃ H ₁₆ F ₃ N ₃ O[M+H] ⁺ 408.12; the test result is 408.11.

Synthesis of final product 98: n- (4- (6- (2- (trifluoromethyl) phenyl) -2H-indazol-2-yl) phenyl) acrylamide (ZC75)

Step one, 4- (6-bromo-2H-indazol-2-yl) aniline (ZC63)

4-bromo-2-nitro-benzaldehyde (500mg, 2.18mmol) and 1, 3-phenylenediamine (260g, 2.40mmol) were added to an eggplant type flask, followed by addition of 15ml of isopropanol and stirring with heating at 80 ℃ for 4 hours. After the reaction was completed, the reaction solution was cooled to room temperature and then added ⁿ Bu ₃ P (1.32g, 6.55mmol) was reacted by heating at 80 ℃ for 16 hours. After the reaction is finished, the reaction product is cooled to room temperature, and the solvent is dried in a spinning mode and then is separated and purified through a chromatographic column, so that 524.8mg of the target compound is obtained. ZC63: ¹ H NMR(400MHz,Chloroform-d)δ8.28(d,J＝0.9Hz,1H),7.97(s,1H),7.69–7.62(m,2H),7.59(d,J＝8.8Hz,1H),7.20(dd,J＝1.6,8.8Hz,1H),6.86–6.77(m,2H).

step two: (4- (6-bromo-2H-indazol-2-yl) phenyl) carbamic acid tert-butyl ester (ZC67)

ZC63(524.8mg, 1.83mmol) and DMAP (22.4mg, 0.18mmol) were dissolved in THF (15ml) and Boc was added ₂ O(1.6g，7.2mmol) reaction at room temperature overnight. After the reaction was completed, water was added to quench and extracted with dichloromethane, dried over anhydrous sodium sulfate and the solvent was dried under reduced pressure to obtain crude product 581mg of the Korean target compound. ZC67: ¹ H NMR(400MHz,Chloroform-d)δ8.41(d,J＝1.0Hz,1H),7.97(dt,J＝0.8,1.6Hz,1H),7.94(d,J＝2.0Hz,1H),7.92(d,J＝2.2Hz,1H),7.59(dd,J＝0.8,8.9Hz,1H),7.54–7.47(m,2H),7.20(dd,J＝1.6,8.9Hz,1H),1.48(s,9H).

Step three: (4- (6- (2- (trifluoromethyl) phenyl) -2H-indazol-2-yl) phenyl) carbamic acid tert-butyl ester (ZC69)

ZC67(581mg, 1.3mmol) was charged to a reaction flask, 2-trifluoromethylphenylboronic acid (631mg, 3.3mmol) was added and DME (12mL) was added with Na ₂ CO ₃ (2M aq, 6ml) was dissolved, oxygen was removed from the system and nitrogen was purged, followed by addition of Pd (dppf) Cl ₂ ·CH ₂ Cl ₂ (50mg), the reaction was carried out overnight at 95 ℃ after purging oxygen and nitrogen again. After the reaction is finished, cooling to room temperature, adding water and ethyl acetate for extraction, combining organic phases, drying by using anhydrous sodium sulfate, and separating and purifying by using a chromatographic column after spin drying. 484.6mg of the target product are obtained. ¹ H NMR(400MHz,Chloroform-d)δ8.49(t,J＝1.1Hz,1H),8.02–7.93(m,2H),7.83–7.78(m,1H),7.78–7.72(m,2H),7.62(t,J＝7.5Hz,1H),7.53–7.49(m,2H),7.45(d,J＝7.5Hz,1H),7.38–7.31(m,1H),7.13(d,J＝8.8Hz,1H),1.50(s,9H).

Step four: n- (4- (6- (2- (trifluoromethyl) phenyl) -2H-indazol-2-yl) phenyl) acrylamide (ZC75)

ZC69(92mg) is dissolved in a mixed solution of dichloromethane and trifluoroacetic acid (3:1) and reacted for 2 hours at room temperature, then the solvent is dried by spinning, washed and extracted by dichloromethane, organic phases are combined and dried by anhydrous sodium sulfate, and the solvent is dried by spinning to obtain a crude product containing the target product. The crude product was then dissolved in dry dichloromethane, triethylamine (57.1mg, 0.56mmol) was added, followed by addition of acryloyl chloride (18.7mg, 0.21mmol) in dichloromethane and reaction at room temperature for 1 hour. After the reaction, the solvent was dried by spinning and purified by HPLC. The objective compound (4.3 mg) was obtained. ¹ H NMR(400MHz,Methanol-d ₄ )δ8.83(d,J＝1.0Hz,1H),8.02–7.96(m,2H),7.94–7.88(m,2H),7.86–7.79(m,2H) 7.70(t, J ═ 7.5Hz,1H),7.61(d, J ═ 6.1Hz,2H),7.49(d, J ═ 7.6Hz,1H),7.10(d, J ═ 8.7Hz,1H), 6.52-6.38 (m,2H),5.83(dd, J ═ 2.4,9.4Hz,1H), ESI-MS theoretical calculation C ₂₃ H ₁₆ F ₃ N ₃ O[M+H] ⁺ 408.12; the test result is 409.05.

Synthesis of end products 99 and 143: trans-N- (4- (6- (2- (trifluoromethyl) phenyl) -2H-indazol-2-yl) cyclohexyl) acrylamide (99, ZC71-30) and cis-N- (4- (6- (2- (trifluoromethyl) phenyl) -2H-indazol-2-yl) cyclohexyl) acrylamide (143, ZC71-31)

Step one, (4- (6-bromo-2H-indazol-2-yl) cyclohexyl) carbamic acid tert-butyl ester (ZC57)

4-bromo-2-nitro-benzaldehyde (450mg, 2.0mmol) and tert-butyl (4-aminocyclohexyl) carbamate (468mg, 2.19mmol) were added to an eggplant-shaped flask, followed by addition of 15ml of isopropanol, and stirring was carried out at 80 ℃ for 4 hours. After the reaction was completed, the reaction solution was cooled to room temperature and then added ⁿ Bu ₃ P (1.2g, 5.97mmol) was reacted at 80 ℃ for 16 hours with heating. After the reaction is finished, the reaction product is cooled to room temperature, and the solvent is dried by spinning and then separated and purified by a chromatographic column to obtain 310mg of the target compound. ¹ H NMR(400MHz,Chloroform-d)δ8.01(d,J＝1.0Hz,1H),7.94–7.91(m,1H),7.57(d,J＝8.8Hz,1H),7.20(dd,J＝1.6,8.8Hz,1H),4.59(s,1H),2.52(d,J＝7.6Hz,2H),2.30(t,J＝10.4Hz,2H),1.68(d,J＝10.7Hz,2H),1.57(dd,J＝7.2,16.1Hz,2H),1.46(s,9H),1.28(s,1H),1.23(d,J＝6.1Hz,1H).

Step two: synthesis of tert-butyl (4- (6- (2- (trifluoromethyl) phenyl) -2H-indazol-2-yl) cyclohexyl) carbamate (ZC66)

ZC57(310mg, 0.9mmol), 2-trifluoromethylphenylboronic acid (470mg, 2.5mmol) were dissolved in DME (8ml) and Na ₂ CO ₃ (2M aq, 4ml) was added to the mixed solution, the oxygen in the system was removed and nitrogen was purged, followed by addition of Pd (dppf) Cl ₂ ·CH ₂ Cl ₂ (60mg), the reaction was carried out overnight at 95 ℃ after purging oxygen and nitrogen again. After the reaction is finished, cooling to the chamberExtracting with water and ethyl acetate, mixing the organic phases, drying with anhydrous sodium sulfate, spin drying, and separating and purifying with chromatographic column. 456.2mg of the target product are obtained.

Step three: trans-N- (4- (6- (2- (trifluoromethyl) phenyl) -2H-indazol-2-yl) cyclohexyl) acrylamide (ZC71-30) and cis-N- (4- (6- (2- (trifluoromethyl) phenyl) -2H-indazol-2-yl) cyclohexyl) acrylamide (ZC71-31)

ZC66(152mg) is dissolved in a mixed solution of dichloromethane and trifluoroacetic acid (3:1), the mixture is reacted for 2 hours at room temperature, then the solvent is dried by spinning, washed by water and extracted by dichloromethane, organic phases are combined and dried by anhydrous sodium sulfate, and the solvent is dried by spinning to obtain 132mg of a target product. The resulting product was dissolved in dry dichloromethane, triethylamine (0.14ml, 0.37mmol) was added, and then a solution of acryloyl chloride (33mg, 0.37mmol) in dichloromethane was added and reacted at room temperature for 1 hour. After the reaction, the solvent was dried by spinning and purified by HPLC. Obtaining a target compound ZC 71-30: 5.2 mg. ¹ H NMR(400MHz,Methanol-d ₄ ) δ 8.41(d, J ═ 1.0Hz,1H),7.82(d, J ═ 7.9Hz,1H),7.77(dd, J ═ 1.0,8.6Hz,1H),7.68(t, J ═ 7.5Hz,1H),7.58(t, J ═ 7.7Hz,1H),7.53(s,1H),7.45(d, J ═ 7.6Hz,1H),7.07(d, J ═ 8.6Hz,1H),6.27(d, J ═ 2.1Hz,1H),6.26(s,1 ddh), 5.68 (J ═ 5.0,7.0Hz,1H), 4.64-4.50 (m,1H), 4.01-3.87 (m,1H),2.35 (m, 2.35, 10.10H), theoretical calculated values of J ═ 2.13H, 10H, 10.13H, 10H, 1H, and theoretical values of calculated for d, 1H ₂₈ H ₃₆ N ₄ O[M+H] ⁺ 445.62; the theoretical calculation value C of the ESI-MS of 445.18 is measured by experiments ₂₈ H ₂₂ F ₃ N ₃ O[M+H] ⁺ 414.17; the test result is 414.1. Obtaining a target compound ZC 71-31: 3.2 mg. ¹ H NMR(400MHz,Methanol-d ₄ ) δ 8.42(d, J ═ 1.0Hz,1H),7.82(d, J ═ 7.9Hz,1H),7.77(dd, J ═ 0.9,8.6Hz,1H),7.68(t, J ═ 7.5Hz,1H),7.58(t, J ═ 7.7Hz,1H),7.54(s,1H),7.45(d, J ═ 7.6Hz,1H),7.07(d, J ═ 8.6Hz,1H),6.40(dd, J ═ 10.1,17.1Hz,1H),6.27(dd, J ═ 1.9,17.0Hz,1H),5.69(dd, J ═ 2.0,10.1, 1H),4.64 (dd, J ═ 1.0, 17.0Hz,1H),5.69(dd, J ═ 2.0,10.1, 1H),4.64 (ESI, J ═ 0, 1.5, 2.5, 2.0, 14H, 2.5, 2.0, 2.5, 1H, 2H, 1H, 2H, 1H, 2H, 1H, 2H, 1H, 2H, 1H, 2H, 1H, 2H, 1H, 2H, 1H, 2H ₂₈ H ₂₂ F ₃ N ₃ O[M+H] ⁺ 414.17; the experiment found that 414.2.

Synthesis of the final product 101: n- (3- (6- (2- (trifluoromethyl) phenyl) -2H-indazol-2-yl) benzyl) acrylamide (ZC87)

Step one, (3- (6-bromo-2H-indazol-2-yl) benzyl) carbamic acid tert-butyl ester (ZC77)

4-bromo-2-nitro-benzaldehyde (229mg, 1.0mmol), (3-aminobenzyl) carbamic acid tert-butyl ester (244.5mg, 1.1mmol in THF) was added to an eggplant type flask, followed by addition of 10ml isopropanol, and stirring with heating at 80 ℃ for 4 hours. After the reaction was completed, the reaction solution was cooled to room temperature and then added ⁿ Bu ₃ P (606mg, 3.0mmol) was reacted by heating at 80 ℃ for 16 hours. After the reaction is finished, the reaction product is cooled to room temperature, and after the solvent is dried in a spinning mode, the reaction product is separated and purified through a chromatographic column, so that 384.8g of the target compound is obtained. ¹ H NMR(400MHz,Chloroform-d)δ8.42(d,J＝1.0Hz,1H),7.99(dt,J＝0.8,1.7Hz,1H),7.86(d,J＝1.9Hz,1H),7.78(dt,J＝1.5,8.2Hz,1H),7.62(dd,J＝0.8,8.9Hz,1H),7.51(t,J＝7.8Hz,1H),7.38(d,J＝7.7Hz,1H),7.22(dd,J＝1.6,8.9Hz,1H),4.45(d,J＝6.1Hz,2H),1.50(s,9H).

Step two: (3- (6- (2- (trifluoromethyl) phenyl) -2H-indazol-2-yl) benzyl) carbamic acid tert-butyl ester (ZC82)

ZC77(150mg, 0.37mmol), 2-trifluoromethylphenylboronic acid (177.6mg, 0.94mmol) were dissolved in DME (8ml) and Na ₂ CO ₃ (2M aq, 4ml) was added to the mixed solution, the oxygen in the system was removed and nitrogen was purged, followed by addition of Pd (dppf) Cl ₂ ·CH ₂ Cl ₂ (40mg, 0.03mmol), again after purging with oxygen and nitrogen, the reaction was carried out at 95 ℃ overnight. After the reaction is finished, cooling to room temperature, adding water and ethyl acetate for extraction, combining organic phases, drying by using anhydrous sodium sulfate, and separating and purifying by using a chromatographic column after spin drying. 176mg of the target product was obtained.

Step three: n- (3- (6- (2- (trifluoromethyl) phenyl) -2H-indazol-2-yl) benzyl) acrylamide (ZC87)

ZC82(116mg) was dissolved in dichloroThe mixture of methane and trifluoroacetic acid (3:1) was reacted at room temperature for 2 hours, followed by spin-drying of the solvent, washing with water, extraction with dichloromethane, and drying of the combined organic phases with anhydrous sodium sulfate to obtain 77mg of the desired product. The resulting product was dissolved in dry dichloromethane, triethylamine (0.89ml, 0.63mmol) was added, and then a solution of acryloyl chloride (21mg, 0.23mmol) in dichloromethane was added and reacted at room temperature for 1 hour. After the reaction, the solvent was dried by spinning and purified by HPLC. 28.6mg of the objective compound was obtained. ¹ H NMR(400MHz,Methanol-d ₄ ) δ 8.81(s,1H),7.96(s,1H),7.85(d, J ═ 30.7Hz,3H),7.61(t, J ═ 23.5Hz,4H), 7.50-7.35 (m,2H),7.08(d, J ═ 8.4Hz,1H), 6.49-6.14 (m,2H),5.72(s,1H),4.59(s,2H), ESI-MS theoretical calculation C ₂₈ H ₃₆ N ₄ O[M+H] ⁺ 422.14; the test result is 422.19.

Synthesis of the final product 102: n- (4- (6- (2- (trifluoromethyl) phenyl) -2H-indazol-2-yl) benzyl) acrylamide (ZC85)

Step one, (4- (6-bromo-2H-indazol-2-yl) benzyl) carbamic acid tert-butyl ester (ZC74)

4-bromo-2-nitro-benzaldehyde (140mg, 0.61mmol), (4-aminobenzyl) carbamic acid tert-butyl ester (150mg, 0.68mmol in THF) was added to an eggplant type flask, followed by addition of 10ml isopropanol, and stirring with heating at 80 ℃ for 4 hours. After the reaction was completed, the reaction solution was cooled to room temperature and then added ⁿ Bu ₃ P (372mg, 1.83mmol) was heated at 80 ℃ for 16 hours. After the reaction is finished, the reaction product is cooled to room temperature, and the solvent is dried by spinning and then separated and purified by a chromatographic column, so that 311.8mg of the target compound is obtained. ZC074: ¹ H NMR(400MHz,Chloroform-d)δ8.39(d,J＝1.0Hz,1H),7.98(dt,J＝0.9,1.7Hz,1H),7.91–7.81(m,2H),7.60(dd,J＝0.7,8.9Hz,1H),7.46(d,J＝8.3Hz,2H),7.21(dd,J＝1.6,8.9Hz,1H),4.96(d,J＝23.6Hz,1H),4.40(d,J＝6.1Hz,2H),1.49(s,9H).

step two: (4- (6- (2- (trifluoromethyl) phenyl) -2H-indazol-2-yl) benzyl) carbamic acid tert-butyl ester (ZC81)

ZC74(135mg, 0.34mmol), 2-trifluoromethylphenylboronic acid (160mg, 0.84mmol) were dissolved in DME (8ml) and Na ₂ CO ₃ (2M aq, 4ml) was added to the mixed solution, the oxygen in the system was removed and nitrogen was purged, followed by addition of Pd (dppf) Cl ₂ ·CH ₂ Cl ₂ (50mg), the reaction was carried out overnight at 95 ℃ after purging oxygen and nitrogen again. After the reaction is finished, cooling to room temperature, adding water and ethyl acetate for extraction, combining organic phases, drying by using anhydrous sodium sulfate, and separating and purifying by using a chromatographic column after spin drying. 156.1mg of the target product is obtained. ¹ H NMR(400MHz,Chloroform-d)δ8.46(s,1H),7.91(d,J＝8.4Hz,2H),7.80(d,J＝8.0Hz,1H),7.74(dd,J＝1.6,7.1Hz,2H),7.61(t,J＝7.7Hz,1H),7.53(d,J＝7.8Hz,1H),7.49(d,J＝6.2Hz,1H),7.45(d,J＝9.3Hz,2H),7.12(d,J＝8.8Hz,1H),4.49–4.32(m,2H),1.50(s,9H).

Step three: n- (4- (6- (2- (trifluoromethyl) phenyl) -2H-indazol-2-yl) benzyl) acrylamide (ZC85)

ZC81(156.1mg) is dissolved in a mixed solution of dichloromethane and trifluoroacetic acid (3:1) and reacted for 2 hours at room temperature, then the solvent is dried by spinning, washed by water, extracted by dichloromethane, the organic phases are combined and dried by anhydrous sodium sulfate, and the solvent is dried by spinning to obtain 140mg of a target product. 56mg of the obtained product was dissolved in dry dichloromethane, triethylamine (0.06ml, 0.39mmol) was added thereto, and a solution of acryloyl chloride (12.9mg, 0.14mmol) in dichloromethane was added thereto, followed by reaction at room temperature for 1 hour. After the reaction, the solvent was dried by spinning and purified by HPLC. 18.3mg of the objective compound was obtained. ¹ H NMR(400MHz,Methanol-d ₄ ) δ 8.82(d, J ═ 1.0Hz,1H), 8.02-7.92 (m,2H), 7.87-7.77 (m,2H), 7.72-7.64 (m,1H),7.60(s,1H),7.57(d, J ═ 7.7Hz,1H), 7.56-7.51 (m,2H),7.47(d, J ═ 7.6Hz,1H),7.09(d, J ═ 8.6Hz,1H), 6.35-6.29 (m,2H),5.73(dd, J ═ 3.4,8.6Hz,1H),4.55(s,2H), ESI-MS theoretical calculation value C ₂₈ H ₃₆ N ₄ O[M+H] ⁺ 422.14; the test result is 422.94.

Synthesis of the end product 139 Synthesis of N- (3- ((5-chloro-6- (2-fluorophenyl) -2- (3-guanidinopropyl) -2H-indazol-3-yl) amino) phenyl) acrylamide (WHE144)

Step 1: synthesis of (3- (6-bromo-5-chloro-2H-indazol-2-yl) propyl) carbamic acid tert-butyl ester (WHE121)

In a 150mL round-bottom flask, the starting materials 4-bromo-5-chloro-2-nitro-benzaldehyde (2.34g, 8.86mmol), tert-butyl 3-aminopropylcarbamate (2.54g, 14.6mmol), and isopropanol (30mL) were added in this order, and the mixture was heated and stirred at 80 ℃ for 4 hours. The reaction solution was cooled to room temperature, followed by addition of (n-Bu) ₃ P (4.46g,22.1mmol), and heating at 80 ℃ was continued for 16 hours. After the reaction is finished, the reaction product is cooled to room temperature, most of solvent is removed by a rotary evaporator, and the target product WHE121(2g) is obtained by column chromatography. ¹ H NMR(400MHz,Methanol-d ₄ )δ8.27(s,1H),7.98(s,1H),7.91(s,1H),4.47(t,J＝6.9Hz,2H),3.06(t,J＝6.6Hz,2H),2.14(p,J＝6.8Hz,2H),1.42(s,9H).

Step 2: synthesis of (3- (5-chloro-6- (2-fluorophenyl) -2H-indazol-2-yl) propyl) carbamic acid tert-butyl ester (WHE126)

Into a 50mL round-bottom flask were added WHD121(1.5369g, 3.96mmol), 2-fluorobenzeneboronic acid (0.9146g,6.53mmol), Pd (dppf) Cl in that order ₂ ·CH ₂ Cl ₂ (0.2943g,0.36mmol) followed by 1, 2-dimethylglycol (6mL), Na ₂ CO ₃ Aqueous solution (2M, 10mL), purge twice, N ₂ The reaction system was heated at 95 ℃ for 10 hours with protection. After the reaction was completed, the reaction mixture was cooled to room temperature, and the solvent was removed by column chromatography to obtain the objective compound WHE126(1.35g). ¹ H NMR(400MHz,Chloroform-d)δ7.99(s,1H),7.79(s,1H),7.66(s,1H),7.43-7.37(m,1H),7.35(td,J＝7.4,1.6Hz,1H),7.22(t,J＝7.8Hz,1H),7.16(t,J＝9.0Hz,1H),4.50(t,J＝6.6Hz,2H),3.16(d,J＝6.6Hz,2H),2.19(p,J＝6.6Hz,2H),1.44(s,9H).

And step 3: synthesis of (3- (3-bromo-5-chloro-6- (2-fluorophenyl) -2H-indazol-2-yl) propyl) carbamic acid tert-butyl ester (WHE128)

The raw material WHE126(1.35g,3.35mmol) was dissolved in HOAc (1mL)/Ac ₂ NBS (0.6022g,3.4mmol) was added to O (5mL), and the mixture was stirred at room temperature for 18 hours. After the reaction is finished, water is added for quenching, the solvent is removed, and NaHCO is used ₃ Neutralization of the solutionAnd (4) acidity. By CH ₂ Cl ₂ Extracting with ethyl acetate for three times, mixing organic phases, and adding Na ₂ SO ₄ Dried (anhydrous) and concentrated to give crude WHE128(0.51g) which was used directly in the next reaction. ¹ H NMR(400MHz,Chloroform-d)δ7.66(s,1H),7.63(s,1H),7.44-7.38(m,1H),7.32(td,J＝7.5,1.9Hz,1H),7.21(t,J＝7.5Hz,1H),7.17(t,J＝8.7Hz,1H),4.56(t,J＝6.8Hz,3H),3.16(d,J＝7.2Hz,3H),2.17(p,J＝6.7Hz,2H),1.43(s,9H).

And 4, step 4: synthesis of N1- (2- (3-aminopropyl) -5-chloro-6- (2-fluorophenyl) -2H-indazol-3-yl) benzene-1, 3-diamine (WHE129)

(a) Pd was added sequentially to a 50mL dry double-necked flask ₂ (dba) ₃ (0.0914g,0.1mmol), BINAP (0.1992g,0.32mmol) and toluene (4mL), suction gas, N ₂ The mixture was heated (80 ℃ C.) for about 10min under protection. And cooling for later use. (b) In addition, a dry double-neck bottle is taken, and raw materials WHE128(0.5025g,1.04mmol), 1, 3-phenylenediamine (0.3382g, 3.13mmol) and, ^t Buona (0.3997g, 4.16mmol) and toluene (5mL), purge twice, N ₂ The catalyst prepared in step (a) is transferred by a syringe with a long needle under protection, and then heated (100 ℃) for 14 hours under stirring. After the reaction, the reaction mixture was cooled, washed with a dilute hydrochloric acid solution (1M), the aqueous phases were combined, and then concentrated by HPLC to separate and purify the product, trifluoroacetate WHE129(27mg) (purification conditions: 10% CH) ₃ CN Start, Retention time 16min) ¹ H NMR(400MHz,Methanol-d ₄ )δ7.74-7.08(m,7H),6.91-6.86(m,2H),6.67(s,1H),4.51(t,J＝6.4Hz,2H),3.03(t,J＝7.7Hz,2H),2.60-2.19(m,2H).

And 5: synthesis of N ¹ ,N ² -bis-tert-butoxycarbonyl-1- (3- (3- ((3-aminophenyl) amino) -5-chloro-6- (2-fluorophenyl) -2H-indazol-2-yl) propyl) guanidine (WHE137)

The raw material WHE129(27mg,0.066mmol) was dissolved in acetonitrile (5mL), ethyl acetate (0.5mL) was added, and N, N' -di-Boc-1H-1-guanidinopyrazole (0.0227g,0.07mmol) was added and reacted at room temperature overnight. After the reaction was completed, the solvent was removed, and the final product, trifluoroacetic acid salt WHE137(6mg), was isolated and purified by HPLC. ¹ H NMR(400MHz,Methanol-d ₄ )δ7.61(s,1H),7.46(s,2H),7.40-7.25(m,3H),7.20(t,J＝9.1Hz,1H),6.90(d,J＝8.1Hz,1H),6.83(d,J＝7.8Hz,1H),6.64(t,J＝9.1Hz,2.1H),4.50(t,J＝6.2Hz,2H),3.64(t,J＝5.8Hz,2H),2.27(t,J＝5.8Hz,2H),1.52(s,9H),1.49(s,9H).

Step 6: synthesis of N- (3- ((5-chloro-6- (2-fluorophenyl) -2- (3-guanidinopropyl) -2H-indazol-3-yl) amino) phenyl) acrylamide (WHE144)

The starting material WHE137(15mg,0.024mmol) was dissolved in THF (8mL) and Et was added ₃ N (0.5mL), acryloyl chloride (2.13mg,0.024mmol), stirred for 1 h. After the reaction was completed, the solvent was removed. Redissolved in CH ₂ Cl ₂ (2mL), trifluoroacetic acid (1mL) was added and the mixture was stirred at room temperature for 30 minutes. The solvent was removed and the final product obtained was purified by HPLC separation to obtain the trifluoroacetate salt WHE144(3mg) (purification conditions: 15% CH) ₃ CN start, retention time: 32min) ¹ H NMR(400MHz,Methanol-d ₄ ) δ 7.53(s,1H),7.51(s,1H),7.48-7.42(m,1H),7.34(td, J ═ 7.5,1.9Hz,1H),7.26(t, J ═ 7.5Hz,1H),7.23-7.14(m,3H),7.02(d, J ═ 8.0Hz,1H),6.55(dd, J ═ 8.0,1.5Hz,1H),6.42-6.28(m,2H),5.73(dd, J ═ 9.8,2.1Hz,1H),4.45(t, J ═ 6.7Hz,2H),3.24(t, J ═ 6.8Hz,2H),2.23(p, J ═ 6.7, ESI, 2H), theoretical calculated values (MS, 29H, C-1H), calculated values ₂₆ H ₂₆ ClFN ₇ O[M+H] ⁺ 506.18; the test result is 506.32.

Synthesis of end product 144: n- (3- ((2- (3- (dimethylamino) propyl) -6- (2-fluorophenyl) -2H-indazol-3-yl) amino) phenyl) acrylamide (WHE123)

Step 1: N ¹ - (2- (3- (dimethylamino) propyl) -6- (2-fluorophenyl) -2H-indazol-3-yl) benzene-1, 3-diamine (WHE117)

(a) Pd was added sequentially in a 50mL dry two-necked flask ₂ (dba) ₃ (0.0489g,0.05mmol), BINAP (0.099g,0.16mmol) and 4mL of toluene, suction gas, N ₂ The mixture was heated (80 ℃ C.) for about 10min under protection. And cooling for later use. (b) Additionally, a dry double-neck bottle is taken, and raw materials WHD93(0.2014g,0.54mmol), 1, 3-phenylenediamine (0.1775g, 1.64mmol) and, ^t Buona (0.2012g, 2.10mmol) andtoluene 5mL, purging twice, N ₂ The catalyst prepared in the first step was transferred with a syringe with a long needle under protection and then heated with stirring (100 ℃ C.) for 14 hours. After the reaction, the reaction mixture was filtered through a filter and purified by HPLC to obtain 50mg of the trifluoroacetate salt of WHE 117. (purification Condition: 15% CH) ₃ CN start, retention time 15.5 min). ¹ H NMR(400MHz,Methanol-d ₄ ) δ 7.74(s,1H),7.53(td, J ═ 7.8,1.8Hz,1H),7.46-7.35(m,3H),7.27(td, J ═ 7.5,1.0Hz,1H),7.23-7.19(m,2H),6.95-6.86(m,2H),6.74(s,1H),4.53(t, J ═ 6.6Hz,2H),3.25-3.21(m,2H),2.88(s,6H),2.46-2.38(m,2H), ESI-MS theoretical calculated value C ₂₄ H ₂₇ FN ₅ [M+H] ⁺ 404.22; the experiment shows that: 404.14.

step 2N- (3- ((2- (3- (dimethylamino) propyl) -6- (2-fluorophenyl) -2H-indazol-3-yl) amino) phenyl) acrylamide (WHE123)

The starting material WHE117(50mg,0.124mmol) was dissolved in THF (8mL) and Et was added ₃ N (1.0mL), followed by addition of acryloyl chloride (11mg,0.122mmol) was stirred at room temperature for 1 hour. After removal of the solvent, HPLC purification gave 4.4mg of the trifluoroacetate salt of the final product WHE123 (purification conditions: 20% CH) ₃ CN start, retention time 18.4 min). ¹ H NMR(400MHz,Methanol-d ₄ ) δ 7.71(s,1H),7.53(td, J ═ 7.8,1.7Hz,1H),7.46(d, J ═ 8.7Hz,1H), 7.42-7.36 (m,1H),7.30-7.27(m,2H),7.25-7.18(m,3H),6.99-6.93(m,1H),6.64(dd, J ═ 8.0,2.0Hz,1H),6.40-6.24(m,2H),5.71(dd, J ═ 9.9,2.0Hz,1H),4.54-4.50(m,2H),3.20-3.18(m,1.5H),3.05(s,1.5H),2.86(s,4.5H),2.84-2.80(m, 2.84, 2.5H), theoretical calculated values (MS, 5H), 2.47-5H, 2.47, 5H), 2.47-2.47 (m, 5H), theoretical calculated values (m, 5H), 2.47-3.5H, 2.5H, 2.47, 2.5H, 2.47, 2.5H, 2, 2.5H, 2H, C ₂₇ H ₂₉ FN ₅ O[M+H] ⁺ 458.23; the experiment shows that: 458.01.

synthesis of the final product 145N- (3- (((2- (3- (dimethylamino) propyl) -6- (2-fluorophenyl) -2H-indazol-3-yl) amino) methyl) phenyl) acrylamide (WHE125)

Step 1 (3- (((2- (3- (dimethylamino) propyl) -6- (2-fluorophenyl) -2H-indazol-3-yl) amino) methyl) phenyl) carbamic acid tert-butyl ester (WHE119)

(a) Pd was added sequentially in a 50mL dry two-necked flask ₂ (dba) ₃ (0.0489g,0.05mmol), BINAP (0.099g,0.16mmol) and 4mL of toluene, suction gas, N ₂ The mixture was heated (80 ℃ C.) for about 10min under protection. And cooling for later use. (b) In addition, a dry double-neck bottle is taken, and raw materials WHD93(0.2032g,0.54mmol), (3- (aminomethyl) phenyl) carbamic acid tert-butyl ester (0.2335g, 1.05mmol) and, ^t Buona (0.2036g, 2.12mmol) and 5mL of toluene, twice with suction of gas, N ₂ The catalyst prepared in the first step was transferred with a syringe with a long needle under protection and then heated with stirring (100 ℃ C.) for 14 hours. After the reaction, the reaction mixture was filtered through a filter and purified by HPLC to obtain 10mg of the trifluoroacetate salt of WHE 119. (purification conditions: 30% CH) ₃ CN start, retention time 10 min). ¹ H NMR(400MHz,Methanol-d ₄ ) δ 7.91(d, J ═ 8.8Hz,1H),7.67(s,1H),7.59(s,1H),7.53(M,1H),7.48-7.38(M,2H),7.31-7.20(M,2H),7.23-7.20(M,2H),7.10(d, J ═ 7.5Hz,1H),4.98(s,2H),4.44(t, J ═ 7.0Hz,2H),3.28-3.24(M,2H),2.91(s,6H),2.40-2.35(M,2H),1.49(s,9H), ESI-MS theoretically calculated value C30H37FN5O2[ M + H, 6H ], 2.] ⁺ 518.29; the experiment shows that: 518.24.

step 2N- (3- (((2- (3- (dimethylamino) propyl) -6- (2-fluorophenyl) -2H-indazol-3-yl) amino) methyl) phenyl) acrylamide (WHE125)

The starting material WHE119(10mg,0.019mmol) was dissolved in CH ₂ Cl ₂ (2mL), TFA (1mL) was added, the mixture was stirred at room temperature for 30min, the solvent was removed, and a small amount of toluene was added, followed by removal. Redissolved in THF (8mL) and Et added ₃ N (1.0mL), followed by addition of acryloyl chloride (1.7mg,0.019mmol) was stirred at room temperature for 1 hour. After removal of the solvent, HPLC purification gave 0.8mg of trifluoroacetate salt of the final product WHE125 (purification conditions: 20% CH) ₃ CN start, retention time 13.8 min). ¹ H NMR(400MHz,Methanol-d ₄ ) δ 8.11(s,1H),7.86(d, J ═ 8.8Hz,1H),7.55(s,1H),7.52(td, J ═ 7.6,1.6Hz,2H),7.44-7.39(m,1H),7.37(t, J ═ 7.8Hz,2H),7.27(t, J ═ 7.6Hz,2H),7.25-7.19(m,2H),6.44-6.29(m,2H),5.75(dd, J ═ 9.9,2.0Hz,1H),4.98(s,2H),4.42(t, J ═ 7.0Hz,2H),3.49-3.44(m,2H),3.14(s,6H),2.50-2.45 (MS, 2H), theoretical work (ESI ), theoretical workCalculation of C ₂₈ H ₃₁ FN ₅ O[M+H] ⁺ 472.24; the experiment shows that: 472.85.

synthesis of the end product 146: n- (1- (2- (3- (dimethylamino) propyl) -6- (3-hydroxynaphthalen-1-yl) -2H-indazol-3-yl) azetidin-3-yl) acrylamide (WHE127)

Step 1: 4- (2- (3- (dimethylamino) propyl) -2H-indazol-6-yl) naphthalen-2-ylpivalate (WHE113)

Into a 50mL round-bottom flask were added WHD111(0.7538g, 2.67mmol), 3-pivalate-1-naphthaleneboronic acid pinacol ester (0.98g,2.77mmol), Pd (dppf) Cl ₂ DCM (0.1728g, 0.21mmol) was added followed by DME (6mL), Na ₂ CO ₃ Aqueous solution (2M, 2mL), purge twice, N ₂ The reaction system was heated at 95 ℃ for 12 hours with protection. After the reaction was completed, it was cooled to room temperature, the solvent was removed, and column chromatography (mobile phase 1:1 ethyl acetate methanol, and 10% aqueous ammonia) was performed to obtain the objective compound WHE113(1.0367 g). ¹ H NMR(400MHz,Methanol-d ₄ )δ8.32-8.09(m,1H),7.92-7.77(m,3H),7.72-7.64(m,1H),7.58(s,1H),7.50-7.33(m,2H),7.19-7.17(m,1H),4.55-4.47(m,2H),2.45-2.38(m,2H),2.31(s,6H),2.29(s,4H),2.27–2.17(m,2H),1.40(m,5H).

Step 2: 4- (3-bromo-2- (3- (dimethylamino) propyl) -2H-indazol-6-yl) naphthalen-2-ylpivalate (WHE115)

The starting material WHE113(1g,2.33mmol) was dissolved in HOAc, NBS (0.4163g,2.35mmol) was added, and the mixture was stirred at room temperature for 18 hours. After the reaction is finished, water is added for quenching, the solvent is removed, and NaHCO is used ₃ The solution neutralizes acidity. By CH ₂ Cl ₂ Extracting with ethyl acetate for three times, mixing organic phases, and adding Na ₂ SO ₄ Drying (anhydrous), concentrating, and performing column chromatography to obtain a crude product. HPLC purification gave 0.43g of WHE115 as trifluoroacetate. (purification conditions: 40% CH) ₃ CN start, retention time 9.8 min). ¹ H NMR(400MHz,Methanol-d ₄ )δ7.94(d,J＝8.1Hz,1H),7.81(d,J＝8.5Hz,1H),7.71(s,1H),7.68(d, J ═ 8.6Hz,1H),7.62(d, J ═ 2.1Hz,1H),7.54(t, J ═ 8.2Hz,1H),7.44(t, J ═ 8.3Hz,1H),7.30(dd, J ═ 8.7,1.3Hz,1H),7.19(d, J ═ 2.3Hz,1H),4.71(t, J ═ 6.5Hz,2H),3.29-3.21(m,2H),2.91(s,6H),2.46(p, J ═ 6.6Hz,2H),1.41(s,9H), ESI-MS theoretically calculated value C ₂₇ H ₃₁ BrN ₃ O ₂ [M+H] ⁺ 508.15; the experiment shows that: 508.13.

step 3 (3- (((2- (3- (dimethylamino) propyl) -6- (2-fluorophenyl) -2H-indazol-3-yl) amino) methyl) phenyl) carbamic acid tert-butyl ester (WHE124)

(a) Pd was added sequentially in a 50mL dry two-necked flask ₂ (dba) ₃ (0.0828g,0.09mmol), BINAP (0.166g,0.27mmol) and 4mL of toluene, air purge, N ₂ The mixture was heated (80 ℃ C.) for about 10min under protection. And cooling for later use. (b) In addition, a dry double-neck bottle is taken, and raw materials WHE115(0.43g,0.85mmol), azetidin-3-yl tert-butyl carbamate (0.3457g, 1.66mmol) and, ^t Buona (0.3468g, 3.61mmol) and 5mL of toluene, twice with suction of gas, N ₂ The catalyst prepared in the first step was transferred with a syringe with a long needle under protection and then heated with stirring (100 ℃ C.) for 14 hours. After the reaction, the reaction mixture was filtered through a filter and purified by HPLC to obtain 60mg of the trifluoroacetate salt of WHE 124. (purification conditions: 20% CH) ₃ CN start, retention time 16.6 min). ¹ H NMR(400MHz,Methanol-d ₄ ) δ 7.96(s,1H),7.81-7.72(m,2H),7.62(d, J ═ 8.8Hz,1H),7.53-7.36(m,2H),7.41(t, J ═ 7.5Hz,1H),7.32(d, J ═ 8.5Hz,1H),7.05(s,1H),5.13-4.93(m,4H),4.72(t, J ═ 17.2Hz,3H),4.37(t, J ═ 7.3Hz,2H),3.25-3.23(m,1H),2.92(s,6H),2.40(p, J ═ 7.5Hz,2H),1.48(s,9H), ESI-MS theoretical calculation C ₃₀ H ₃₈ N ₅ O ₃ [M+H] ⁺ 516.29; the experiment shows that: 516.61.

step 4N- (1- (2- (3- (dimethylamino) propyl) -6- (3-hydroxynaphthalen-1-yl) -2H-indazol-3-yl) azetidin-3-yl) acrylamide (WHE127)

The starting material WHE124(60mg,0.116mmol) was dissolved in CH ₂ Cl ₂ (2mL), TFA (1mL) was added, the mixture was stirred at room temperature for 30min, the solvent was removed, and a small amount of toluene was added, followed by removal. Redissolved in THF (8mL) and Et added ₃ N(2.0mL)，Acryloyl chloride (10.48mg,0.116mmol) was then added and the mixture was stirred at room temperature for 1 hour. After removal of the solvent, HPLC purification gave 15mg of trifluoroacetate salt of WHE127 as a final product (purification conditions: 20% CH) ₃ CN start, retention time 12.6 min). ¹ H NMR(400MHz,Methanol-d ₄ ) δ 7.96(d, J ═ 8.6Hz,1H),7.73(d, J ═ 8.2Hz,1H),7.62(d, J ═ 8.5Hz,1H),7.49(s,1H),7.40(t, J ═ 7.2Hz,1H),7.29(dd, J ═ 8.6,1.4Hz,1H),7.23-7.19(m,2H),7.05(d, J ═ 2.4Hz,1H),6.37-6.28(m,2H),5.76(dd, J ═ 7.7,4.3Hz,1H),5.03(t, J ═ 7.5Hz,2H),4.99-4.96(m,2H),4.72 (ESI, J ═ 8.1,5, 1H), 4.03 (t, J ═ 7.5Hz,2H), theoretical calculated values (m,2H), 7.15, 2H, 15H, 15.96 (m,2H), 4.6.6.6H), 15 (ESI, 15H), 7.6.6.6.6.6H), 15 (H), 7, 15 (H), 7.6.6.6.6.6.6.6, 2H),7, 15 (H), 7, 15, 2H),7, 15 (H), 7, 15, 2H),7, 2H), 8, 2H), 8.6, 2H), 8, 2H),7, 15 (H), 8.2H), 2H),7, 15 (H), 8, 15, 2H), 8.2H), 2H), 8, 2H), 2H),7, 2H), 8, 15 (m,2H),7, 2H), 2H, 15 (m,2H), 15 (m, 15 (theoretical m, 15, 2H), etc., C, 15, 2H), etc., C, 15, 2H), etc., C, 15, 2H), etc., C, 2H), etc ₂₈ H ₃₂ N ₅ O ₂ [M+H] ⁺ 470.25; the experiment shows that: 470.48.

synthesis of the final product 147N- (3- ((2- (3- (dimethylamino) propyl) -6- (2-fluorophenyl) -2H-indazol-3-yl) amino) cyclohexyl) acrylamide (WHE133)

Step 1: synthesis of N ¹ - (2- (3- (dimethylamino) propyl) -6- (2-fluorophenyl) -2H-indazol-3-yl) cyclohexane-1, 3-diamine (WHE130)

(a) Pd was added sequentially to a 50mL dry double-necked flask ₂ (dba) ₃ (0.0486g,0.05mmol), BINAP (0.1009g,0.16mmol) and toluene (4mL), suction gas, N ₂ Heating (80 deg.C) for about 10min under protection, and cooling for use. (b) Additionally, a dry double-neck bottle is taken, and raw materials WHD93(0.2025g,0.54mmol), 1, 3-cyclohexanediamine (0.1902g, 1.67mmol) and, ^t Buona (0.2133g, 2.22mmol) and toluene (5mL), purging twice with nitrogen, N ₂ The catalyst prepared in step (a) is transferred by a syringe with a long needle under protection, and then heated (100 ℃) for 14 hours under stirring. After the reaction, the reaction mixture was cooled, diluted hydrochloric acid (1M) was added to wash the reaction mixture, the aqueous phases were combined, concentrated, and separated and purified by HPLC to obtain the trifluoroacetate salt WHE130(0.1g) of the objective compound (purification conditions: 10% CH) ₃ CN start, retention time 16 min). ¹ H NMR(400MHz,Methanol-d ₄ )δ8.08(t,J＝7.6Hz,1H),7.65(s,1H),7.58(tt,J＝7.8,2.0Hz,1H),7.52-7.45(m,2H),7.33(tt,J＝7.6,1.5Hz,1H),7.26(td,J＝9.4,1.0Hz,1H),4.66-4.61(s,0.3H),4.53-4.39(m,2H),4.26(tt,J＝11.4,3.8Hz,0.7H),3.77-3.71(m,0.3H),3.44(tt,J＝11.4,3.8Hz,0.7H),3.29-3.27(m,2H),2.92(s,6H),2.55(d,J＝12.0Hz,1H),2.40-2.32(m,2H),2.29-2.21(m,1H),2.13-2.11(m,1H),2.06-2.01(m,1H),1.90-1.87(m,1H),1.78-1.53(m,2H),1.43(qd,J＝12.3,3.9Hz,1H).

Step 2: synthesis of N- (3- ((2- (3- (dimethylamino) propyl) -6- (2-fluorophenyl) -2H-indazol-3-yl) amino) cyclohexyl) acrylamide (WHE133)

The starting material WHE130 was dissolved in THF (8mL) and Et was added ₃ N (2.5mL), followed by addition of acryloyl chloride (22mg,0.24mmol) was stirred at room temperature for 1 hour. After removal of the solvent, HPLC purification gave 79mg of trifluoroacetate salt as a final product (purification conditions: 15% CH) ₃ CN start, retention time 13.8 min). ¹ H NMR(400MHz,Methanol-d ₄ ) δ 8.11(d, J ═ 8.8Hz,0.7H),7.99(d, J ═ 8.8Hz,0.3H),7.64(s,1H),7.59(td, J ═ 7.7,1.6Hz,1H),7.55(d, J ═ 7.7,1.6Hz,1H),7.55-7.44(m,1H),7.33(td, J ═ 7.6,1.0Hz,2H),7.26(td, J ═ 9.0,1.8Hz,2H),6.44-6.37(m,0.2H),6.29-6.20(m,1.7H),5.71(dd, J ═ 10.2,1.8Hz,0.2H),5.65(dd, 8, 4.7H), 4.42H (d, 4.7H), 4.7H, 3.7H, 5.7H (dd, 3.2, 4.2, 3.8H, 3.7H, 3, 3.7H, 3, 2H, 3, 2, 3, 2H, 2H) theoretical calculation values C of ESI-MS, 1.90-1.79(m,1H),1.70-1.65(m,1H),1.62-1.50(m,2H),1.39-1.28(m,1H) ₂₇ H ₃₅ FN ₅ O[M+H] ⁺ 464.27; the test result is 464.02.

Synthesis of the final product 148 (3- (5- (2-fluorophenyl) -2H-indazol-2-yl) piperidin-1-yl) prop-2-en-1-one (WHF03)

Step 1: synthesis of tert-butyl 3- (5-bromo-2H-indazol-2-yl) piperidine-1-carboxylate (WHE159)

In a 150mL round bottom flask, the starting material 5-bromo-2-nitro-benzaldehyde (5g, 2) was added sequentially1.7mmol), 1-N-Boc-3-aminopiperidine (0.65g, 3.25mmol) and isopropanol (30mL) were heated and stirred at 80 ℃ for 4 hours. The reaction solution was cooled to room temperature, followed by addition of (n-Bu) ₃ P (10.66g,52.7mmol), and heating at 80 ℃ was continued for 16 hours. After the reaction, the reaction mixture was cooled to room temperature, most of the solvent was removed by a rotary evaporator, and column chromatography was carried out to obtain the desired product WHE159(8.0 g). ¹ H NMR(400MHz,Chloroform-d)δ7.99(s,1H),7.82(d,J＝1.2Hz,1H),7.60(d,J＝9.1Hz,1H),7.35(dd,J＝9.1,1.8Hz,1H),4.51-4.44(m,1H),4.30(d,J＝12.2Hz,1H),3.97(d,J＝9.6Hz,1H),3.49-3.39(m,1H),3.02(t,J＝11.0Hz,1H),2.28(s,2H),1.89-1.83(m,1H),1.72-1.62(m,1H),1.47(s,9H).

Step 2: synthesis of tert-butyl 3- (5- (2-fluorophenyl) -2H-indazol-2-yl) piperidine-1-carboxylate (WHF01)

Into a 50mL round-bottomed flask, WHE159(0.492g, 1.30mmol), 2-fluorophenylboronic acid (0.274g,1.97mmol), Pd (dppf) Cl were added in this order ₂ ·CH ₂ Cl ₂ (0.101g,0.12mmol), followed by the addition of 1, 2-ethanediol dimethyl ether (6mL), Na ₂ CO ₃ Aqueous solution (2M, 10mL), purge twice, N ₂ The reaction system was heated at 95 ℃ for 10 hours with protection. After the reaction is finished, the reaction product is cooled to room temperature, the solvent is removed, and column chromatography is carried out to obtain a target compound WHF01(0.437g) ¹ H NMR(400MHz,Chloroform-d)δ8.06(s,1H),7.82(s,1H),7.78(d,J＝9.0Hz,1H),7.50-7.46(m,2H),7.34-7.28(m,1H),7.24-7.14(m,2H),4.54-4.47(m,1H),4.35(d,J＝13.1Hz,1H),4.03-4.02(m,1H),3.54-3.48(m,1H),3.05-2.97(m,1H),2.31(s,2H),1.86-1.82(m,1H),1.69-1.65(m,1H),1.47(s,9H).

And step 3: synthesis of (3- (5- (2-fluorophenyl) -2H-indazol-2-yl) piperidin-1-yl) prop-2-en-1-one (WHF03)

Starting material WHF01(45mg,0.11mmol) dissolved in CH ₂ Cl ₂ (2mL), trifluoroacetic acid (1mL) was added, the mixture was stirred at room temperature for 30min, the solvent was removed, and a small amount of toluene (5mL) was added, followed by removal. Dissolved in THF (8mL) and Et added ₃ N (1mL), followed by addition of acryloyl chloride (10mg,0.11mmol) and stirring at room temperature for 1 hour. After removal of the solvent, HPLC purification gave the trifluoroacetate salt (30mg) of WHF03 as a final product (purification conditions: 50% CH) ₃ CN start, retention time: 12 min). ¹ H NMR(400MHz,Methanol-d ₄ ) δ 8.39(s,1H),7.86(s,1H),7.68(d, J ═ 9.0Hz,1H),7.56-7.49(m,2H),7.38-7.32(m,1H),7.25(td, J ═ 7.5,1.0Hz,1H),7.19(dd, J ═ 8.2,1.0Hz,1H),6.86-6.77(m,1H),6.26-6.17(m,1H),5.78(d, J ═ 10.8Hz,0.6H),5.72(d, J ═ 10.8Hz,0.4H),4.79(d, J ═ 11.3Hz,0.5H),4.65-4.62(m,1H),4.42(d, J ═ 13.0, 1H), 4.79(d, J ═ 11.3Hz,0.5H),4.65-4.62(m,1H),4.42(d, J ═ 13.13, 0.13.13, 1H), 3H, 3H, 3H, 3H, 1H, 3H, 1H, 3H, 1H, 3H, 1H, 3H, 1H, 3H, 1H, 3, theoretical calculation value C of ESI-MS of 1.78-1.70(m,1H) ₂₁ H ₂₁ FN ₃ O[M+H] ⁺ 350.16; the experimental result shows that 350.18

Synthesis of the final product 149:1- (3- (5- (3-hydroxynaphthalen-1-yl) -2H-indazol-2-yl) piperidin-1-yl) prop-2-en-1-one (WHF19)

Step 1: synthesis of tert-butyl 3- (5- (3- ((4-methoxybenzyl) oxy) naphthol-1-yl) -2H-indazol-2-yl) piperidine-1-carboxylate (WHF02)

Into a 100mL round-bottomed flask, WHE159(0.4256g,1.12mmol), Naphthoronic acid pinacol ester (0.5514g, 1.41mmol), Pd (dppf) Cl were added in this order ₂ ·CH ₂ Cl ₂ (0.0882g,0.11mmol) followed by the addition of 1, 2-ethanediol dimethyl ether (6mL), Na ₂ CO ₃ Aqueous solution (2M, 4mL), purge twice, N ₂ The reaction system was heated at 95 ℃ for 10 hours with protection. After the reaction was completed, the reaction mixture was cooled to room temperature, and the solvent was removed by column chromatography to obtain the objective compound WHF02(0.34 g).

Step 2: synthesis of tert-butyl 3- (5- (3-hydroxynaphthalen-1-yl) -2H-indazol-2-yl) piperidine-1-carboxylate (WHF14)

WHF02(93mg,0.17mmol) was dissolved in MeOH (10mL) and after one purge, N ₂ Adding Pd (OH) under protection ₂ C (60 mg). After re-pumping, at H ₂ The mixture was stirred at room temperature for 24 hours. After the reaction was completed, the catalyst was removed by filtration, and the reaction mixture was concentrated to obtain a crude compound WHF14(73mg,0.16mmol) which was directly used in the next reaction.

And step 3: synthesis of 1- (3- (5- (3-hydroxynaphthalen-1-yl) -2H-indazol-2-yl) piperidin-1-yl) prop-2-en-1-one (WHF19)

Raw material WHF14(73mg,0.16mmol) was dissolved in CH ₂ Cl ₂ (2mL), trifluoroacetic acid (1mL) was added and the mixture was stirred at room temperature for 30 min. After the reaction was complete, the solvent was removed, toluene (5mL) azeotropically removed TFA, dissolved again in THF (8mL), and Et was added ₃ N (1.5mL) and acryloyl chloride (15mg) were stirred at room temperature for 1 hour. After the reaction was completed, the solvent was removed, and the product was purified by HPLC to obtain trifluoroacetate WHF19(3mg,0.007mmol) (purification conditions: 40% CH) ₃ CN start, retention time: 16 min). ¹ H NMR(400MHz,Methanol-d ₄ ) δ 8.41(s,1H),7.76-7.69(m,4H),7.42(dd, J-8.9, 1.2Hz,1H),7.37(td, J-8.0, 0.9Hz,1H),7.19(t, J-7.8 Hz,1H),7.13(d, J-2.4 Hz,1H),7.06(d, J-2.0 Hz,1H),6.84(dd, J-17.2, 10.9Hz,1H),6.23(t, J-17.8 Hz,1H),5.79(d, J-10.6 Hz,0.6H),5.74(d, J-10.6 Hz,0.4H),4.84-4.80(m,0.5H), 4.60-7.69 (m,4H), 3.42-5.47 (m-3.47H), 3.42 (t, 3.8H, 5H), 5.47-2H, 5.6H, 5.47 (m-2H), 3.6H, 3.47H, 3.8H, 3-2H, 5.47 (m-2H), 3.6H, 3.47H, 3.8H, 3H, 3.6H, 5-2H, 3H, 3.47H, 3-2H, 2H) ESI-MS theoretical calculation value C ₂₅ H ₂₄ N ₃ O ₂ [M+H] ⁺ 398.18; the experimental result shows that 398.05

Synthesis of the final product 150:1- (3- (6- (2-fluorophenyl) -2H-indazol-2-yl) piperidin-1-yl) prop-2-en-1-one (WHF46)

Step 1: synthesis of tert-butyl 3- (6-bromo-2H-indazol-2-yl) piperidine-1-carboxylate (WHF37)

In a 150mL round-bottom flask, the starting materials 4-bromo-2-nitro-benzaldehyde (2.3168g, 10.0mmol), 1-N-Boc-3-aminopiperidine (3.1059g, 15.5mmol) and isopropanol (30mL) were added in this order, and the mixture was heated and stirred at 80 ℃ for 4 hours. The reaction solution was cooled to room temperature, followed by addition of (n-Bu) ₃ P (5.05g,25mmol), and heating at 80 ℃ was continued for 16 hours. Cooling to room temperature after the reaction is finished, removing most of solvent by a rotary evaporator, and carrying out column chromatography The target product WHF37(3g) was obtained. ¹ H NMR(400MHz,Chloroform-d)δ7.99(s,1H),7.89(s,1H),7.53(d,J＝8.8Hz,1H),7.16(dd,J＝8.8,1.4Hz,1H),4.50-4.43(m,1H),4.30(d,J＝12.0Hz,1H),4.10-3.96(m,1H),3.50-3.45(m,1H),3.01(s,1H),2.28(s,2H),1.81-1.76(m,2H),1.47(m,9H).

Step 2: synthesis of tert-butyl 3- (6- (2-fluorophenyl) -2H-indazol-2-yl) piperidine-1-carboxylate (WHF39)

Into a 50mL round-bottomed flask were added WHF37(0.1901g, 0.5mmol), 2-fluorobenzeneboronic acid (0.1143g,0.82mmol), Pd (dppf) Cl ₂ ·CH ₂ Cl ₂ (0.0461g,0.056mmol) followed by the addition of 1, 2-ethanediol dimethyl ether (6mL), Na ₂ CO ₃ Aqueous solution (2M, 2mL), purge twice, N ₂ The reaction system was heated at 95 ℃ for 10 hours with protection. After the reaction was completed, the reaction mixture was cooled to room temperature, and the solvent was removed by column chromatography to obtain the objective compound WHF39(0.172 g). ¹ H NMR(400MHz,Chloroform-d)δ8.03(s,1H),7.87(s,1H),7.71(d,J＝8.7Hz,1H),7.51(t,J＝8.7Hz,1H),7.35-7.24(m,2H),7.24-7.14(m,2H),4.54-4.45(m,1H),4.37-4.30(m,1H),4.02-3.94(m,1H),3.54-3.44(m,1H),3.00(s,1H),2.31(s,2H),1.88-1.84(m,1H),1.77-1.59(m,1H),1.47(s,9H).

And step 3: synthesis of 1- (3- (6- (2-fluorophenyl) -2H-indazol-2-yl) piperidin-1-yl) prop-2-en-1-one (WHF46)

Starting material WHF39(86mg,0.22mmol) was dissolved in CH ₂ Cl ₂ (2mL), trifluoroacetic acid (1mL) was added, the mixture was stirred at room temperature for 30min, the solvent was removed, and a small amount of toluene (5mL) was added to remove TFA azeotropically. Redissolved in THF (8mL) and Et added ₃ N (1mL), followed by addition of acryloyl chloride (19mg,0.21mmol) and stirring at room temperature for 1 hour. After removal of the solvent, HPLC purification gave the final product as trifluoroacetate WHF46(50mg) (purification conditions: 45% CH) ₃ CN start, retention time: 15.6 min). ¹ H NMR(400MHz,Methanol-d ₄ )δ8.37(s,1H),7.77(d,J＝9.1Hz,1H),7.75(s,1H),7.54(td,J＝7.8,1.8Hz,1H),7.41-7.35(m,1H),7.29-7.18(m,3H),6.86-6.77(m,1H),6.26-6.17(m,1H),5.78(d,J＝10.6Hz,0.6H),5.72(d,J＝10.6Hz,0.4H),4.78(d,J＝12.6Hz,0.5H),4.65-4.61(m,1H),4.43(d,J＝13.3Hz,1H),4.11(d,J＝13.6Hz,0.5H),3.85–3.69(m,0.4H),3.52-3.44(m,0.6H),3.37-3.35(m,0.6H),3.05(t, J ═ 12.4Hz,0.4H),2.41-2.35(m,2H),2.03-1.95(m,1H),1.78-1.68(m,1H), ESI-MS theoretical calculation C ₂₁ H ₂₁ FN ₃ O[M+H] ⁺ 350.16; the test result is 350.15.

Synthesis of the final product 151- (2- ((2- (1-acryloylpiperidin-3-yl) -5- (2-fluorophenyl) -2H-indazol-3-yl) amino) ethyl) guanidine (WHF50)

Step 1: synthesis of tert-butyl 3- (3-bromo-5- (2-fluorophenyl) -2H-indazol-2-yl) piperidine-1-carboxylate (WHF04)

The starting material WHF01(0.1g,0.25mmol) was dissolved in HOAc (1mL)/Ac ₂ NBS (0.0489g,0.27mmol) was added to O (5mL), and the mixture was stirred at room temperature for 18 hours. After the reaction is finished, water is added for quenching, the solvent is removed, and NaHCO is used ₃ The solution neutralizes acidity. By CH ₂ Cl ₂ Extracting with ethyl acetate for three times, mixing organic phases, and adding Na ₂ SO ₄ Dried (anhydrous) and concentrated to give crude WHF04(0.12g) which was used directly in the next reaction.

Step 2: synthesis of N ¹ - (5- (2-fluorophenyl) -2- (piperidin-3-yl) -2H-indazol-3-yl) ethane-1, 2-diamine (WHF10)

(a) Pd was added sequentially to a 50mL dry double-necked flask ₂ (dba) ₃ (0.023g,0.025mmol), BINAP (0.047g,0.075mmol) and toluene (4mL), suction gas, N ₂ Heating (80 deg.C) for about 10min under protection, and cooling for use. (b) Additionally, a dry double-neck bottle is taken, and raw materials WHF04(0.12g,0.25mmol), 1, 2-ethylenediamine (0.0982g, 1.64mmol) and, ^t Buona (0.1115g, 1.16mmol) and toluene (5mL), purge twice, N ₂ The catalyst prepared in step (a) was transferred with a syringe with a long needle under protection, and then heated with stirring (100 ℃ C.) for 14 hours. After the reaction, the reaction mixture was cooled, diluted hydrochloric acid (1M) was added to wash the reaction mixture, the aqueous phases were combined, and then concentrated by HPLC for separation and purification to obtain the objective compound WHF10(47mg) (purification conditions: 15% CH) ₃ CN start, retention time: 13 min). ¹ H NMR(400MHz,Methanol-d ₄ )δ7.94(s,1H),7.57-7.48(m,3H),7.37-7.14(m,3H),5.10(q,J＝5.5Hz,1H),3.94(t,J＝5.8Hz,2H),3.79-3.64(m,3H),3.55-3.48(m,1H),3.38-3.35(m,2H),2.33-2.20(m,2H),2.14-2.08(m,1H),1.99-1.91(m,1H).

And step 3: synthesis of N ¹ ,N ² -bis-tert-butoxycarbonyl-1- (2- ((5- (2-fluorobenzene) -2- (piperidin-3-yl) -2H-indazol-3-yl) amino) ethyl) guanidine (WHF27)

Raw material WHF10(47mg,0.13mmol) was dissolved in acetonitrile (5mL) and Et was added ₃ N (1mL) and N, N' -di-Boc-1H-1-guanidinopyrazole (42mg,0.13mmol) were stirred at room temperature overnight. After completion of the reaction, the desired compound WHF27(30mg) was directly charged into the next step after removal of the solvent.

And 4, step 4: synthesis of 1- (2- ((2- (1-acryloylpiperidin-3-yl) -5- (2-fluorophenyl) -2H-indazol-3-yl) amino) ethyl) guanidine (WHF50)

Starting material WHF27(30mg,0.042mmol), dissolved in THF (6mL) and Et added ₃ N (2mL) and acryloyl chloride (3.8mg,0.042mmol) were stirred at room temperature for 1 hour. After the reaction is completed, the reaction solvent is removed and then dissolved in CH again ₂ Cl ₂ (2mL), trifluoroacetic acid (1mL) was added. Removal of CH after completion of the reaction ₂ Cl ₂ Then separated and purified by HPLC to obtain the final product WHF50 trifluoroacetate 10mg (purification conditions: 15% CH) ₃ CN start, retention time: 18.8min) ¹ H NMR(400MHz,Methanol-d ₄ ) δ 8.07(s,1H),7.76(d, J ═ 9.0Hz,1H),7.57-7.53(m,2H),7.43-7.37(m,1H),7.29(td, J ═ 7.5,1.2Hz,1H),7.22(dd, J ═ 11.1,8.2Hz,1H),6.85(dd, J ═ 16.7,10.6Hz,1H),6.28(d, J ═ 16.9Hz,1H),5.83(d, J ═ 10.5Hz,1H),4.75(d, J ═ 12.7Hz,1H),4.61-4.57(m,1H),4.22(d, J ═ 13.8Hz,1H),4.05-3.91(m, 3.59(t, 3.59H), 3.3.7H), 3.7 (m, 3.9H), 5.7H, 1H), 5.9H, 1H, 25.9H, 1H, 15H, 25, 15H, 15H, 25, 15, 2H, 1H, 15, 2H, 1H, 15, 1H, etc ₂₄ H ₂₉ FN ₇ O[M+H] ⁺ 450.23; the experimental result shows that 450.31

Synthesis of the final product 152:1- (3- (5- (2-fluoro-6-methoxyphenyl) -2H-indazol-2-yl) piperidin-1-yl) prop-2-en-1-one (WHF55)

Step 1: synthesis of tert-butyl 3- (5- (2-fluoro-6-methoxyphenyl) -2H-indazol-2-yl) piperidine-1-carboxylate (WHF41)

Into a 50mL round-bottomed flask, WHE159(1.025g, 2.70mmol), 2-methoxy-3-fluorobenzeneboronic acid (0.677g,3.99mmol), Pd (dppf) Cl were added in this order ₂ ·CH ₂ Cl ₂ (0.200g,0.25mmol), followed by the addition of 1, 2-ethanediol dimethyl ether (20mL), Na ₂ CO ₃ Aqueous solution (2M, 10mL), purge twice, N ₂ The reaction system was heated at 95 ℃ for 10 hours with protection. After the reaction was completed, the reaction mixture was cooled to room temperature, and the solvent was removed by column chromatography to obtain 0.85g of the objective compound. ¹ H NMR(400MHz,Chloroform-d)δ8.02(s,1H),7.75(d,J＝9.0Hz,1H),7.68(s,1H),7.31(d,J＝8.8Hz,1H),7.29-7.24(m,1H),6.83-6.78(m,2H),4.48(d,J＝6.5Hz,1H),4.52-4.45(m,1H),4.34(d,J＝13.3Hz,1H),4.11-4.03(m,1H),3.78(s,3H),3.50-3.45(m,1H),2.98(s,1H),2.29(s,2H),1.84(s,1H),1.47(s,9H).

Step 2: synthesis of 1- (3- (5- (2-fluoro-6-methoxyphenyl) -2H-indazol-2-yl) piperidin-1-yl) prop-2-en-1-one (WHF55)

The starting material (0.18g, 0.42mmol) was dissolved in CH ₂ Cl ₂ (4mL), trifluoroacetic acid (2mL) was added, the mixture was stirred at room temperature for 30min, and the solvent was removed and then taken up with toluene once. Then dissolved in THF, Et is added ₃ N (3.5mL), acryloyl chloride (39mg,0.43mmol), stir at room temperature for 1 h. After the reaction was completed, the solvent was removed, and the final product, i.e., a trifluoroacetate salt, WHF55(0.11mg, separation conditions: 45% CH), was obtained by HPLC separation and purification ₃ CN start, retention time: 13.6min) ¹ H NMR(400MHz,Methanol-d ₄ )δ8.33(s,1H),7.65(s,1H),7.62(d,J＝8.8Hz,1H),7.34-7.27(m,2H),6.89(d,J＝8.4Hz,1H),6.85-6.78(m,2H),6.22(t,J＝18.5Hz,1H),5.78(d,J＝10.8Hz,0.6H),5.72(d,J＝10.8Hz,0.4H),4.79-4.76(m,0.5H),4.62-4.59(m,1H),4.42(t,J＝10.1Hz,1H),4.09(d,J＝13.7Hz,0.5H),3.75(s,3H),3.73-3.69(m,0.4H),3.34-3.28(m,0.6H),3.45(t,J＝12.3Hz,0.6H),3.02(t,J＝12.3Hz,0.4H),2.37-2.32(m,2H),1.97-1.93(m,1H),1.75-1.68(m,1H).

Synthesis of the final product 153:1- (3- (6- (2-fluoro-6-methoxyphenyl) -2H-indazol-2-yl) piperidin-1-yl) prop-2-en-1-one (WHF58)

Step 1: synthesis of tert-butyl 3- (6- (2-fluoro-6-methoxyphenyl) -2H-indazol-2-yl) piperidine-1-carboxylate (WHF42)

Into a 50mL round-bottomed flask were added WHF37(0.545g, 1.43mmol), 2-methoxy-3-fluorobenzeneboronic acid (0.350g,2.06mmol), Pd (dppf) Cl ₂ ·CH ₂ Cl ₂ (0.105g,0.13mmol), followed by the addition of 1, 2-ethanediol dimethyl ether (12mL), Na ₂ CO ₃ Aqueous solution (2M, 10mL), purge twice, N ₂ The reaction system was heated at 95 ℃ for 10 hours with protection. After the reaction was completed, the reaction mixture was cooled to room temperature, and the solvent was removed by column chromatography to obtain the objective compound WHF42(0.43 g). ¹ H NMR(400MHz,Chloroform-d)δ8.02(s,1H),7.76(s,1H),7.69(d,J＝8.7Hz,1H),7.31-7.27(m,1H),7.11(d,J＝8.6Hz,1H),6.84-6.78(m,2H),4.52-4.46(m,1H),4.36-4.32(m,1H),4.07-3.98(m,1H),3.78(s,3H),3.55-3.46(m,1H),2.98(s,1H),2.27(s,2H),1.84(s,1H),1.68(s,1H),1.47(s,9H).

Step 2: synthesis of 1- (3- (6- (2-fluoro-6-methoxyphenyl) -2H-indazol-2-yl) piperidin-1-yl) prop-2-en-1-one (WHF58)

Raw material WHF42(49.7mg,0.12mmol) was dissolved in CH ₂ Cl ₂ (2mL), trifluoroacetic acid (1mL) was added, the mixture was stirred at room temperature for 30min, the solvent was removed, and a small amount of toluene (5mL) was added to remove TFA azeotropically. Redissolved in THF (8mL) and Et added ₃ N (1mL), followed by addition of acryloyl chloride (10.5mg,0.12mmol) and stirring at room temperature for 1 hour. After removal of the solvent, HPLC purification gave the final product as trifluoroacetate WHF58(40mg, purification conditions: 45% CH) ₃ CN start, retention time: 14 min). ¹ H NMR(400MHz,Methanol-d ₄ )δ8.31(s,1H),7.69(d,J＝8.7Hz,1H),7.57(s,1H),7.32(q,J＝8.4Hz,1H),7.06(d,J＝8.7Hz,1H),6.90(d,J＝8.4Hz,1H),6.86-6.69(m,2H),6.26-6.16(m,1H),5.77(d,J＝10.6Hz,0.6H),5.70(d,J＝10.6Hz,0.4H),4.76(d,J＝12.1Hz,0.5H),4.67-4.49(m,1H),4.41(t,J＝13.9Hz,1H),4.07(d,J＝13.7Hz,05H),3.75(s,3H),3.70(t, J ═ 12.7Hz,0.4H),3.43(d, J ═ 12.7Hz,0.6H),3.29 to 3.26(m,0.6H),2.99(t, J ═ 12.2Hz,0.4H),2.36 to 2.30(m,2H),2.01 to 1.91(m,1H),1.73 to 1.68(m,1H), ESI-MS theoretical calculation C ₂₂ H ₂₃ FN ₃ O ₂ [M+H] ⁺ 380.17; the experimental result shows that 380.95

Synthesis of the final product 154 1- (3- ((2-ethyl-5- (2-fluoro-6-methoxyphenyl) -2H-indazol-3-yl) amino) piperidin-1-yl) prop-2-en-1-one (WHF59)

Step 1: synthesis of 6-bromo-2-ethyl-2H-indazole (WHF44)

In a 150mL round bottom flask, the starting materials 4-bromo-2-nitro-benzaldehyde (2.2728g, 9.88mmol), ethylamine (3.2066g, 30% -35% in EtOH,21.4mmol), isopropanol (10mL) were added in that order and heated at 80 ℃ with stirring for 4 hours. The reaction solution was cooled to room temperature, followed by addition of (n-Bu) ₃ P (4.92g,24.3mmol), and heating at 80 ℃ was continued for 16 hours. After the reaction is finished, the reaction product is cooled to room temperature, most of solvent is removed by a rotary evaporator, and column chromatography is carried out to obtain a target product WHF44(2.23 g). ¹ H NMR(400MHz,Chloroform-d)δ7.91(s,1H),.88(s,1H),7.52(d,J＝8.8Hz,1H),7.15(dd,J＝8.9,1.6Hz,1H),4.46(q,J＝7.3Hz,2H),1.63(t,J＝7.3Hz,3H).

Step 2: synthesis of 2-ethyl-6- (2-fluoro-6-methoxyphenyl) -2H-indazole (WHF48)

Into a 50mL round-bottomed flask were added WHF44(0.74g,3.29mmol), 2-methoxy-3-fluorobenzeneboronic acid (0.8302g,4.88mmol), Pd (dppf) Cl ₂ ·CH ₂ Cl ₂ (0.1002g,0.12mmol) followed by the addition of 1, 2-ethanediol dimethyl ether (6mL), Na ₂ CO ₃ Aqueous solution (2M, 6mL), purge twice, N ₂ The reaction system was heated at 90 ℃ for 12 hours with protection. After the reaction was completed, the reaction mixture was cooled to room temperature, and the solvent was removed by column chromatography to obtain the objective compound WHF48(0.76 g). ¹ H NMR(400MHz,Chloroform-d)δ7.94(s,1H),7.76(s,1H),7.68(d,J＝8.6Hz,1H),7.30-7.25(m,1H),7.11(d,J＝8.6Hz,1H),6.83-6.78(m,2H),4.50(q,J＝7.4Hz,2H),1.64(t,J＝7.4Hz,3H).

And step 3: synthesis of 3-bromo-2-ethyl-6- (2-fluoro-6-methoxyphenyl) -2H-indazole (WHF53)

Raw material WHF48(0.4134g,1.53mmol) was dissolved in HOAc (1mL)/Ac ₂ NBS (0.275g,1.56mmol) was added to O (5mL), and the mixture was stirred at room temperature for 18 hours. After the reaction is finished, water is added for quenching, the solvent is removed, and NaHCO is used ₃ The solution neutralizes acidity. By CH ₂ Cl ₂ Extracting with ethyl acetate for three times, mixing organic phases, and adding Na ₂ SO ₄ Dried (anhydrous) and concentrated to give crude WHF53(0.56g) which was used directly in the next reaction. ¹ H NMR(400MHz,Chloroform-d)δ7.71(s,1H),7.54(d,J＝8.7Hz,1H),7.31-7.27(m,1H),7.15(d,J＝8.7Hz,1H),6.83-6.78(m,2H),4.54(q,J＝7.3Hz,2H),1.57(t,J＝7.2Hz,3H).

And 4, step 4: synthesis of tert-butyl tert-3- ((2-ethyl-5- (2-fluoro-6-methoxyphenyl) -2H-indazol-3-yl) amino) piperidine-1-carboxylate (WHF54)

(a) Pd is added into a 50mL dry double-necked bottle in sequence ₂ (dba) ₃ (0.1434g,0.16mmol), BINAP (0.2971g,0.49mmol) and toluene (10mL), suction gas, N ₂ Heating (80 deg.C) for about 10min under protection, and cooling for use. (b) In addition, a dry double-neck bottle is taken, and raw materials of WHF53(0.5576g,1.60mmol), 3-amino-1-Boc-piperidine (0.9817g, 4.91mmol) and, ^t Buona (0.6169g, 6.43mmol) and toluene (10mL), purging twice, N ₂ The catalyst prepared in step (a) was transferred with a syringe with a long needle under protection, and then heated with stirring (100 ℃ C.) for 14 hours. After the reaction, the reaction mixture was cooled, the solvent was removed, and column chromatography was carried out to obtain a crude WHF54(1.09g) which was directly subjected to the next reaction.

And 5: synthesis of 1- (3- ((2-ethyl-5- (2-fluoro-6-methoxyphenyl) -2H-indazol-3-yl) amino) piperidin-1-yl) prop-2-en-1-one (WHF59)

Raw material WHF54(0.25g, 0.52mmol) was dissolved in CH ₂ Cl ₂ (4mL), trifluoroacetic acid (2mL) was added, the mixture was stirred at room temperature for 30min, and the solvent was removed and then taken up with toluene once. Then dissolved in THF, Et is added ₃ N (3.5mL), acryloyl chloride (47mg,0.52mmol), stir at room temperature for 1 h. After the reaction is finished, removingThe solvent was removed and column chromatography was carried out to give 0.3g of the objective compound. HPLC separation purification (purification conditions: 30% CH) ₃ CN start, retention time: 11min) to obtain trifluoroacetate WHF59 of the target compound, and the characterization data are as follows ¹ H NMR(400MHz,Methanol-d ₄ ) δ 8.21(d, J-8.8 Hz,0.7H),7.99(d, J-8.8 Hz,0.3H),7.46-7.38(m,2H),7.33(d, J-8.7 Hz,0.7H),7.28(d, J-8.7 Hz,0.3H),6.97(d, J-8.4 Hz,1H),6.88-6.80(m,1.7H),6.71(d, J-16.7, 10.6Hz,0.3H),6.28-6.21(m,1H),5.80(dd, J-10.5, 1.9Hz,0.7H),5.69(d, J-10.6 Hz,0.3H),4.78(d, J-8.7H), 1.7 (J-10.7H), 1.7H (d, J-3H), 1.7H, 3H), 1.7H, 1H, 3H, 1H, 1.7H, 1H, 7H, 1H, 1.7H, 7H, 1H, 7H, 1H, 7H, 1.7H, 7H, 1H, 7H, 1.7H, 7H, 1H, 7H, 1.7H, 7H, 1H, 7H, 1H, 7H, 1H, 7H, 1H, 7H, 1.7H, 7H, 1H, 7H, 1.7H, 7H, 1.7H, 1H, 7H, 1.7H, 7H, 1H) theoretical calculation of ESI-MS C, 1.51(t, J ═ 7.2Hz,3H) ₂₄ H ₂₈ FN ₄ O ₂ [M+H] ⁺ 423.21; the experimental result shows that 423.40

Synthesis of the final product 155:1- (3- (5- (2-fluoro-6-hydroxyphenyl) -2H-indazol-2-yl) piperidin-1-yl) prop-2-en-1-one (WHF60)

Raw material WHF57(75mg,0.20mmol) was dissolved in CH ₂ Cl ₂ (6mL), BBr was added under cooling at 78 deg.C ₃ (1M in CH ₂ Cl ₂ 2mL) and then stirred at room temperature for 3 h. After the reaction is finished, NaHCO is cooled at-30 DEG C ₃ Quenching the reaction with saturated solution, adding water and CH ₂ Cl ₂ And ethyl acetate, respectively, and mixing the organic phases, concentrating, and purifying by HPLC to obtain 50mg of trifluoroacetate salt of WHF60 (purification conditions: 40% CH) ₃ CN start, retention time: 11.8 min). ¹ H NMR(400MHz,Methanol-d ₄ )δ8.31(s,1H),7.71(s,1H),7.63(d,J＝9.0Hz,1H),7.36(d,J＝9.0Hz,1H),7.14(q,J＝8.2Hz,1H),6.80(d,J＝16.9,10.9Hz,1H),6.67(d,J＝8.2Hz,1H),6.66(t,J＝8.9Hz,1H),6.21(t,J＝17.8Hz,1H),5.77(d,J＝10.7Hz,0.55H),5.72(d,J＝10.7Hz,0.45H),4.77(d,J＝13.1,4.0Hz,0.5H),4.58(s,1H),4.40(t,J＝10.2Hz,1H),4.08(dd,J＝11.7,6.0Hz,0.5H),3.29-3.26(m,0.6H) 3.70(t, J ═ 12.1Hz,0.4H),3.42(t, J ═ 12.7Hz,0.6H),3.00(t, J ═ 12.3Hz,0.4H),2.32(s,2H),1.94-1.91(m,1H),1.73-1.68(m,1H), ESI-MS theoretical calculation C ₂₁ H ₂₁ FN ₃ O ₂ [M+H] ⁺ 366.15; the experimental result shows that 366.52

Synthesis of the final product 156:1- (3- (6- (2-fluoro-6-hydroxyphenyl) -2H-indazol-2-yl) piperidin-1-yl) prop-2-en-1-one (WHF61)

The starting material WHF65(30mg,0.08mmol) was dissolved in CH ₂ Cl ₂ (6mL), BBr was added under cooling at 78 deg.C ₃ (1M in CH ₂ Cl ₂ 4.5mL), then stirred at room temperature for 3 h. After the reaction is finished, NaHCO is cooled at-30 DEG C ₃ Quenching the reaction with saturated solution, adding water and CH ₂ Cl ₂ And ethyl acetate, respectively, and the organic phases were combined, concentrated, and purified by HPLC to give the final product, trifluoroacetate WHF61(18mg, purification conditions: 40% CH) ₃ CN start, retention time: 12 min). ¹ H NMR(400MHz,Methanol-d ₄ ) δ 8.30(d, J ═ 5.1Hz,1H),7.70(d, J ═ 8.7Hz,1H),7.64(s,1H),7.19-7.13(m,2H),6.83-6.73(m,2H),6.67(t, J ═ 9.4Hz,1H),6.25-6.16(m,1H),5.77(d, J ═ 10.7Hz,0.6H),5.71(d, J ═ 10.7Hz,0.4H),4.76(dd, J ═ 12.7,4.1Hz,0.5H),4.60-4.56(m,1H),4.41(t, J ═ 13.2Hz,1H),4.06(d, J ═ 13.7, 0.5H),3.68(t, 3.70H), 3.6 (m,1H), 3.6H, 3, 3.6H, 15H, 3.6H, 26H, 3H, 18H, 1H, 18H, 1H, 18H, and the calculated values of t, 1H. ₂₁ H ₂₁ FN ₃ O ₂ [M+H] ⁺ 366.15; the experimental result shows that 366.96

Synthesis of the final product 157:1- (3- ((2-ethyl-5- (2-fluoro-6-hydroxyphenyl) -2H-indazol-3-yl) amino) piperidin-1-yl) prop-2-en-1-one (WHF62)

The starting material WHF59(0.10g,0.23mmol) was dissolved in CH ₂ Cl ₂ (6mL), BBr was added under cooling at 78 deg.C ₃ (1M in CH ₂ Cl ₂ 2.5mL), then stirred at room temperature for 3 h. After the reaction is finished, NaHCO is cooled at-30 DEG C ₃ Quenching the reaction with saturated solution, adding water and CH ₂ Cl ₂ And ethyl acetate, respectively, and the organic phases were combined, concentrated, and purified by HPLC to give the final product, WHF62, as the trifluoroacetate salt (35mg, purification conditions: 20% CH) ₃ CN start, retention time: 11.4min) ¹ H NMR(400MHz,Methanol-d ₄ ) δ 8.20(d, J ═ 8.8Hz,0.7H),7.99(d, J ═ 8.8Hz,0.3H),7.51(s,1H),7.41(d, J ═ 8.7Hz,0.7H),7.39(d, J ═ 8.7Hz,0.3H),7.23(q, J ═ 8.2Hz,1H),6.87-6.67(m,3H),6.28-6.21(m,1H),5.80(d, J ═ 10.7Hz,0.7H),5.69(d, J ═ 10.8Hz,0.3H),4.77(d, J ═ 12.9Hz,1H),4.33(q, J ═ 7.1, 2H),4.24-4.21(m, 4.3H), 4.77(d, J ═ 12.9Hz,1H),4.33(q, J ═ 7.1, 2H), 4.24-4.3H), 3H, 1.7H, 1H, 3H, 1H. ₂₃ H ₂₆ FN ₄ O ₂ [M+H] ⁺ 409.20; the experimental result shows that 409.6

Synthesis of the final product 158 1- (3- (5- (2-fluoro-6-methoxyphenyl) -3- ((pyridin-3-ylmethyl) amino) -2H-indazol-2-yl) piperidin-1-yl) prop-2-en-1-one (WHF63)

Step 1: synthesis of tert-butyl 3- (3-bromo-5- (2-fluoro-6-methoxyphenyl) -2H-indazol-2-yl) piperidine-1-carboxylate (WHF47)

Raw material WHF41(0.7469g,1.76mmol) was dissolved in HOAc (2mL)/Ac ₂ NBS (0.3111g,1.76mmol) was added to O (6mL), and the mixture was stirred at room temperature for 18 hours. After the reaction is finished, water is added for quenching, the solvent is removed, and NaHCO is used ₃ The solution neutralizes acidity. By CH ₂ Cl ₂ Extracting with ethyl acetate for three times, mixing organic phases, and adding Na ₂ SO ₄ Dried (anhydrous) and concentrated to give crude WHF47(0.89g) which was used directly in the next reaction. ¹ H NMR(400MHz,Methanol-d ₄ )δ7.62(d,J＝8.9Hz,1H),7.47(s,1H),7.34-7.27(m,2H),6.89(d,J＝8.4Hz,1H),6.80(t,J＝8.8Hz,1H),4.72(s,1H),4.46-3.91(m,2H),3.76(s,3H),3.53-3.31(m,1H),2.95(s,1H),2.35-2.32(m,1H),2.10-1.89(m,2H),1.67(d,J＝12.8Hz,1H),1.41(s,9H).

Step 2: synthesis of tert-butyl 3- (5- (2-fluoro-6-methoxyphenyl) -3- ((pyridin-3-ylmethyl) amino) -2H-indazol-2-yl) piperidine-1-carboxylate (WHF49)

(a) Pd was added sequentially to a 50mL dry double-necked flask ₂ (dba) ₃ (0.149g,0.16mmol), BINAP (0.3037g,0.49mmol) and toluene (10mL), suction gas, N ₂ Heating (80 deg.C) for about 10min under protection, and cooling for use. (b) Additionally, a dry double-neck bottle is taken, and raw materials WHF47(0.8857g,1.76mmol), 3-aminomethyl pyridine (0.5912g, 5.47mmol) and, ^t Buona (0.6737g, 7.02mmol) and toluene (10mL), purging twice with air, N ₂ The catalyst prepared in step (a) was transferred with a syringe with a long needle under protection, and then heated with stirring (100 ℃ C.) for 14 hours. After the reaction was completed, the reaction mixture was cooled, the solvent was removed, and column chromatography was performed to obtain WHF49(0.35 g). A small amount of HPLC purification was performed, and the mass spectrum found the Boc-free molecular weight of the target compound: theoretical calculation of ESI-MS C ₃₀ H ₃₅ FN ₅ O ₃ [M+H] ⁺ 532.26; the test result is 432.32.

And step 3: synthesis of 1- (3- (5- (2-fluoro-6-methoxyphenyl) -3- ((pyridin-3-ylmethyl) amino) -2H-indazol-2-yl) piperidin-1-yl) prop-2-en-1-one (WHF63)

Raw material WHF49(0.35g, 0.66mmol) was dissolved in CH ₂ Cl ₂ (4mL), trifluoroacetic acid (2mL) was added, the mixture was stirred at room temperature for 30min, and the solvent was removed and then taken up with toluene once. Then dissolved in THF, Et is added ₃ N (3.5mL), acryloyl chloride (39mg,0.43mmol), stir at room temperature for 1 h. After the reaction, the solvent was removed, and column chromatography (mobile phase 10:1 ethyl acetate methanol) was performed on 0.3 g. A portion of the HPLC separation purification (separation conditions: 25% CH) ₃ CN start, retention time: 9min) ¹ H NMR(400MHz,Methanol-d ₄ )δ9.01(s,0.7H),8.96(s,0.3H),8.82(d,J＝5.6Hz,1H),8.68(d,J＝5.6Hz,0.7H),8.60(s,0.3H),8.06(t,J＝7.1Hz,1H),7.76(s,0.7H),7.70(s,0.3H),7.59(d,J＝8.9Hz,1H),7.52(d, J ═ 8.9Hz,1H),7.34(q, J ═ 7.9Hz,1H),6.90(d, J ═ 8.4Hz,1H),6.85-6.77(m,2H),6.27(d, J ═ 16.6Hz,1H),5.82(d, J ═ 10.6Hz,1H),5.21(q, J ═ 16.6Hz,2H),4.81(d, J ═ 12.7Hz,1H),4.67-4.62(m,1H),4.22(d, J ═ 14.0Hz,1H),3.71(s,3H),3.28-3.23(m,1H),2.36-2.29(m,2H),2.09(d, J ═ 14.5, 1H), theoretical calculated values (MS, 1H),1, 79 (theoretical calculated values of C, 1H),1.79 (theoretical calculated values of C, 1H), and calculated values of C, 1H, and C, and their values ₂₈ H ₂₉ FN ₅ O ₂ [M+H] ⁺ 486.22; the experimental result shows that 486.27

Synthesis of the final product 159:1- (3- (5- (2-fluoro-6-hydroxyphenyl) -3- ((pyridin-3-ylmethyl) amino) -2H-indazol-2-yl) piperidin-1-yl) prop-2-en-1-one (WHF64)

Raw material WHF63(0.15g,0.31mmol) was dissolved in CH ₂ Cl ₂ (10mL), BBr was added under cooling at 78 deg.C ₃ (1M in CH ₂ Cl ₂ 4mL) and then stirred at room temperature for 3 h. After the reaction is finished, NaHCO is cooled at-30 DEG C ₃ Quenching the reaction with saturated solution, adding water and CH ₂ Cl ₂ And ethyl acetate, respectively, and the organic phases are combined, concentrated and purified by HPLC to obtain the final product, namely trifluoroacetate WHF64(26mg) purification conditions: 20% CH ₃ CN start, retention time: 11.4 min). ¹ H NMR(400MHz,Methanol-d ₄ ) δ 9.03(s,1H),8.82(d, J ═ 5.6Hz,1H),8.72(d, J ═ 7.8Hz,1H),8.08(t, J ═ 7.0Hz,1H),7.83(s,1H),7.70(d, J ═ 9.0Hz,1H),7.54(d, J ═ 8.8Hz,1H),7.15(q,1H),6.84(dd, J ═ 16.7,10.6Hz,1H),6.72(d, J ═ 8.2Hz,1H),6.65(t, J ═ 9.1Hz,1H),6.27(d, J ═ 16.9Hz,1H),5.82(d, J ═ 10.8, 1H), 5.25.25 (q,1H), 1H), 4.17.1H, 4.9H, 1H, 3.9H, 1H, 3.9H, 1H, 5.9H, 3.9H, 1H, 3.9, 1H, 3.9, 3, 2, 3, 2, 3, 2, 1, 3, 2, 1, 3, 2, 1, 3, 1, 2, 3, 1, 3, 2, 3, 1, 2, 1, 3, 1, 2, 3, 1, 3, 2, 3, 2, 3, 2, 1, 3, 2, 1, 2, 1, 2, 1, 3, 2, 1, 2, 1, 3, 1, 3, 1, 2, 1, 3, 2, 1, 2, 1, 2, 1, 2, 1, 2, 1H) ESI-MS theoretical calculation value C ₂₇ H ₂₇ FN ₅ O ₂ [M+H] ⁺ 472.21; the experimental measurement is 472.6

Synthesis of the final product 160 1- (4- (5- (2-fluorophenyl) -2H-indazol-2-yl) piperidin-1-yl) prop-2-en-1-one (WHF74)

Step 1: synthesis of 4- (5-bromo-2H-indazol-2-yl) piperidine-1-carboxylic acid tert-butyl ester (WHF67)

In a 150mL round-bottom flask, the starting materials 5-bromo-2-nitro-benzaldehyde (2.0106g, 8.74mmol), 1-N-Boc-4-aminopiperidine (2.6132g, 13.1mmol) and isopropanol (10mL) were sequentially added, and the mixture was heated and stirred at 80 ℃ for 4 hours. The reaction solution was cooled to room temperature, followed by addition of (n-Bu) ₃ P (4.35g,21.5mmol), and heating at 80 ℃ was continued for 16 hours. After the reaction is finished, the reaction product is cooled to room temperature, most of solvent is removed by a rotary evaporator, and the target product WHF67(3.0g) is obtained by column chromatography. ¹ H NMR(400MHz,Chloroform-d)δ7.90(s,1H),7.81(s,1H),7.58(d,J＝9.1Hz,1H),7.34(dd,J＝9.2,1.8Hz,1H),4.54(tt,J＝11.7,4.1Hz,1H),4.32(s,2H),2.94(s,2H),2.23(d,J＝12.5Hz,2H),2.10(td,J＝12.3,4.5Hz,2H),1.49(s,9H).

Step 2: synthesis of 4- (5- (2-fluorophenyl) -2H-indazol-2-yl) piperidine-1-carboxylic acid tert-butyl ester (WHF70)

Into a 50mL round-bottomed flask were added WHF67(0.74g, 3.29mmol), 2-methoxy-3-fluorobenzeneboronic acid (0.8302g,4.88mmol), Pd (dppf) Cl ₂ ·CH ₂ Cl ₂ (0.1002g, 0.12mmol) followed by the addition of 1, 2-ethanediol dimethyl ether (6mL), Na ₂ CO ₃ Aqueous solution (2M, 6mL), purge twice, N ₂ The reaction system was heated at 90 ℃ for 12 hours with protection. After the reaction was completed, the reaction mixture was cooled to room temperature, and the solvent was removed by column chromatography to obtain the objective compound WHF70(75 mg). ¹ H NMR(400MHz,Chloroform-d)δ8.01(s,1H),7.83(s,1H),7.77(d,J＝9.0Hz,1H),7.50-7.46(m,2H),7.34-7.28(m,1H),7.22(td,J＝7.5,1.1Hz,1H),7.20-7.14(m,1H),4.59(tt,J＝11.7,3.8Hz,1H),4.34(s,2H),2.95(s,2H),2.26(d,J＝12.6Hz,2H),2.17-2.10(qd,J＝12.0,3.9Hz,2H),1.49(s,9H).

And step 3: synthesis of 1- (4- (5- (2-fluorophenyl) -2H-indazol-2-yl) piperidin-1-yl) prop-2-en-1-one (WHF74)

Raw material WHF70(75mg, 0.18mmol) was dissolved in CH ₂ Cl ₂ (4mL), add trifluoroAcetic acid (2mL) was stirred at room temperature for 30min, and the solvent was removed and taken up with toluene once. Then dissolved in THF, Et is added ₃ N (3mL), acryloyl chloride (17mg,0.19mmol), stir at room temperature for 1 h. After the reaction, the solvent was removed, and HPLC separation and purification were carried out to obtain 53mg of the trifluoroacetate salt of the objective compound (separation conditions: 45% CH) ₃ CN start, retention time: 13.4 min). ¹ H NMR(400MHz,Methanol-d ₄ ) δ 8.39(s,1H),7.86(s,1H),7.67(d, J ═ 9.0Hz,1H),7.53-7.49(m,2H),7.38-7.32(m,1H),7.25(td, J ═ 7.5,1.3Hz,1H),7.18(dd, J ═ 11.1,1.2Hz,1H),6.84(dd, J ═ 16.8,10.6Hz,1H),6.24(dd, J ═ 16.8,2.0Hz,1H),5.78(dd, J ═ 10.7,2.0Hz,1H),4.86-4.75(m,2H),4.32(d, J ═ 13.9, 1H),3.38(t ═ 2, 2.0Hz,1H),4.86-4.75(m,2H), 13.32 (d, J ═ 13.9, 1H),3.38(t ═ 13.2, 2, 1H), 2.13.2H, 13.12 (15, 15.12H), 15 (C, 13.12H), 13.9, 1H), 13.8 (d, 1H), 1H), 15, 1H, 15, 1H, 15, 1H), 15, 1H, 15, 1H, and so on the calculated values of the balance of the like ₂₁ H ₂₁ FN ₃ O[M+H] ⁺ 350.16; the experimental result shows that 350.35

Synthesis of the final product 161 1- (4- (6- (2-fluorophenyl) -2H-indazol-2-yl) piperidin-1-yl) prop-2-en-1-one (WHF75)

Step 1: synthesis of 4- (6-bromo-2H-indazol-2-yl) piperidine-1-carboxylic acid tert-butyl ester (WHF68)

In a 150mL round-bottom flask, the starting materials 4-bromo-2-nitro-benzaldehyde (2.0078g, 8.73mmol), 1-N-Boc-4-aminopiperidine (2.6285g, 13.1mmol) and isopropanol (50mL) were sequentially added, and the mixture was heated and stirred at 80 ℃ for 4 hours. The reaction solution was cooled to room temperature, followed by addition of (n-Bu) ₃ P (4.35g,21.5mmol), and heating at 80 ℃ was continued for 16 hours. After the reaction is finished, the reaction product is cooled to room temperature, a rotary evaporator is used for removing most of the solvent, and column chromatography is carried out to obtain a target product WHF68(3.2g) ¹ H NMR(400MHz,Chloroform-d)δ7.93(s,1H),7.88(s,1H),7.53(d,J＝8.8Hz,1H),7.16(dd,J＝8.8,1.5Hz,1H),4.54(tt,J＝11.7,3.8Hz,1H),4.33(s,2H),2.94(s,2H),2.24(d,J＝12.3Hz,2H),2.08(qd,J＝13.1,4.9Hz,2H),1.49(s,9H).

Step 2: synthesis of 4- (6- (2-fluorophenyl) -2H-indazol-2-yl) piperidine-1-carboxylic acid tert-butyl ester (WHF71)

Into a 50mL round-bottom flask were added WHF68(0.1034g, 0.27mmol), 2-fluorobenzeneboronic acid (0.0694g,0.5mmol), Pd (dppf) Cl in that order ₂ ·CH ₂ Cl ₂ (0.0229g, 0.03mmol) followed by 1, 2-dimethylglycol (6mL), Na ₂ CO ₃ Aqueous solution (2M, 1mL), purge twice, N ₂ The reaction system was heated at 90 ℃ for 10 hours with protection. After the reaction was completed, the reaction mixture was cooled to room temperature, and the solvent was removed by column chromatography to obtain the objective compound WHF71(0.109 g). ¹ H NMR(400MHz,Chloroform-d)δ7.98(s,1H),7.86(s,1H),7.72(d,J＝9.0Hz,1H),7.53–7.49(m,1H),7.36-7.29(m,1H),7.23-7.15(m,1H),4.62-4.56(m,1H),4.35(s,2H),2.95(s,2H),2.28(d,J＝10.2Hz,2H),2.16-2.08(m,2H),1.49(s,9H).

And step 3: synthesis of 1- (4- (6- (2-fluorophenyl) -2H-indazol-2-yl) piperidin-1-yl) prop-2-en-1-one (WHF75)

The starting material WHF71(0.1g, 0.25mmol) was dissolved in CH ₂ Cl ₂ (4mL), trifluoroacetic acid (2mL) was added, the mixture was stirred at room temperature for 30min, and the solvent was removed and then taken up with toluene once. Then dissolved in THF (8mL) and Et added ₃ N (3mL), acryloyl chloride (23mg,0.25mmol), stir at room temperature for 1 h. After the reaction was completed, the solvent was removed, and the product was separated and purified by HPLC to obtain trifluoroacetate WHF75(25mg, separation conditions: 40% CH) ₃ CN start, retention time: 16.4min) ¹ H NMR(400MHz,Methanol-d ₄ ) δ 8.32(s,1H),7.77-7.74(m,2H),7.51(td, J ═ 7.8,1.8Hz,1H),7.39-7.34(m,1H),7.28-7.17(m,3H),6.81(dd, J ═ 16.8,10.6Hz,1H),6.24(dd, J ═ 16.8,2.0Hz,1H),5.77(dd, J ═ 10.6,2.0Hz,1H),4.82-4.74(m,2H),4.30(d, J ═ 13.7Hz,1H), 3.37-3.33 (m,1H),2.94(t, J ═ 12.1Hz,1H),2.26(d, J ═ 11.9, 2H),2.15 (m,2H), theoretical calculated values (MS-15H), 2.09-C, 2H), 2.8 (d, J ═ 16.8, 1H), 1H, ESI, 2.9, 15H, theoretical calculation values of calculated values ₂₁ H ₂₁ FN ₃ O[M+H] ⁺ 350.16; the test result is 350.26.

Synthesis of the final product 162:1- (4- (6- (2-fluoro-6-methoxyphenyl) -2H-indazol-2-yl) piperidin-1-yl) prop-2-en-1-one (WHF76)

Step 1: synthesis of 4- (6- (2-fluoro-6-methoxyphenyl) -2H-indazol-2-yl) piperidine-1-carboxylic acid tert-butyl ester (WHF73)

Into a 50mL round-bottomed flask were added WHF68(0.2102g, 0.55mmol), 2-methoxy-3-fluorobenzeneboronic acid (0.1341g,0.79mmol), Pd (dppf) Cl ₂ ·CH ₂ Cl ₂ (0.049g, 0.06mmol) followed by the addition of 1, 2-ethylene glycol dimethyl ether (6mL), Na ₂ CO ₃ Aqueous solution (2M, 2mL), purge twice, N ₂ The reaction system was heated at 90 ℃ for 10 hours with protection. After the reaction, the reaction mixture was cooled to room temperature, and the solvent was removed and column chromatography was carried out to obtain 0.17g of the aimed compound WHF 73. ¹ H NMR(400MHz,Chloroform-d)δ7.96(s,1H),7.76(s,1H),7.69(d,J＝8.6Hz,1H),7.31 7.25(m,1H),7.12(d,J＝8.6Hz,1H),6.84-6.78(m,2H),4.62-4.56(m,1H),4.33(s,2H),3.78(s,3H),2.94(s,2H),2.24(d,J＝10.6Hz,2H),2.14-2.09(m,2H),1.49(s,9H).

Step 2: synthesis of 1- (4- (6- (2-fluoro-6-methoxyphenyl) -2H-indazol-2-yl) piperidin-1-yl) prop-2-en-1-one (WHF76)

Raw material WHF73(0.17g, 0.4mmol) was dissolved in CH ₂ Cl ₂ (3mL), trifluoroacetic acid (1.5mL) was added, the mixture was stirred at room temperature for 30min, the solvent was removed, and then TFA was removed azeotropically with toluene (5 mL). Then dissolved in THF (10mL) and Et added ₃ N (3mL), acryloyl chloride (36mg,0.4mmol), stir at room temperature for 1 h. After the completion of the reaction, the solvent was removed, and the compound was isolated and purified by HPLC as WHF76 trifluoroacetate (109mg, isolation conditions: 45% CH) ₃ CN start, retention time: 12 min). ¹ H NMR(400MHz,Methanol-d ₄ ) δ 8.33(s,1H),7.70(dd, J ═ 8.7,0.9Hz,1H),7.55(s,1H),7.33(dt, J ═ 8.4,6.6Hz,1H),7.06(d, J ═ 8.6Hz,1H),6.91(d, J ═ 8.3Hz,1H),6.87-6.79(m,2H),6.24(dd, J ═ 16.8,2.0Hz,1H),5.77(dd, J ═ 10.6,2.0Hz,1H),4.82-4.74(m,2H),4.30(d, J ═ 13.6Hz,1H),3.76(s,3H),3.39-3.32(m,1H),2.96(t, 12.12H), theoretical calculated values (MS, 17H), 2.17H, 11H, 17H, 2H, and C ₂₂ H ₂₃ FN ₃ O ₂ [M+H] ⁺ 380.17; the experimental result shows that 380.23

Synthesis of the final product 163:1- (4- (5- (2-fluoro-6-methoxyphenyl) -2H-indazol-2-yl) piperidin-1-yl) prop-2-en-1-one (WHF77)

Step 1: synthesis of 4- (5- (2-fluoro-6-methoxyphenyl) -2H-indazol-2-yl) piperidine-1-carboxylic acid tert-butyl ester (WHF72)

Into a 50mL round-bottomed flask were added WHF67(0.80g, 2.1mmol), 2-methoxy-3-fluorobenzeneboronic acid (0.8302g,4.88mmol), Pd (dppf) Cl ₂ ·CH ₂ Cl ₂ (0.1g, 0.12mmol), followed by the addition of 1, 2-ethanediol dimethyl ether (6mL), Na ₂ CO ₃ Aqueous solution (2M, 8mL), purge twice, N ₂ The reaction system was heated at 90 ℃ for 10 hours with protection. After the reaction was completed, the reaction mixture was cooled to room temperature, and the solvent was removed by column chromatography to obtain the objective compound WHF72(0.76 g). ¹ H NMR(400MHz,Chloroform-d)δ7.97(s,1H),7.74(d,J＝8.9Hz,1H),7.69(s,1H),7.32-7.26(m,2H),6.83-6.78(m,2H),4.59-4.54(m,1H),4.33(s,2H),3.78(s,3H),2.94(s,2H),2.23(d,J＝12.7Hz,2H),2.11(td,J＝12.2,6.4Hz,2H),1.49(s,9H).

Step 2: synthesis of 1- (4- (5- (2-fluoro-6-methoxyphenyl) -2H-indazol-2-yl) piperidin-1-yl) prop-2-en-1-one (WHF77)

Raw material WHF72(0.11g, 0.26mmol) was dissolved in CH ₂ Cl ₂ (3mL), trifluoroacetic acid (1.5mL) was added, the mixture was stirred at room temperature for 30min, the solvent was removed, and then TFA was removed azeotropically with toluene (5 mL). Then dissolved in THF (10mL) and Et added ₃ N (3mL), acryloyl chloride (23mg,0.25mmol), stir at room temperature for 1 h. After the reaction was completed, the solvent was removed, and the product was purified by HPLC separation to obtain a trifluoroacetate salt WHF77(0.097 g). (separation conditions: 45% CH) ₃ CN start, retention time: 12min) ¹ H NMR(400MHz,Methanol-d ₄ ) δ 8.32(s,1H),7.65(s,1H),7.60(d, J ═ 8.9Hz,1H),7.34-7.26(m,2H),6.89(d, J ═ 8.4Hz,1H),6.88-6.78(m,2H),6.24(dd, J ═ 16.8,2.0Hz,1H),5.78(dd, J ═ 10.6,2.0Hz,1H),4.83-4.75(m,2H),4.32(d, J ═ 14.0Hz,1H),3.76(s,3H),3.41-3.34(m,1H),3.03-2.95(m,1H),2.29(d, J ═ 12.8, 2H),2.18-2.11(m, 11H), theoretical calculated values of C-C, 2H, and ESI (d, J ═ 14.8 Hz,1H) ₂₂ H ₂₃ FN ₃ O ₂ [M+H] ⁺ 380.17; the experimental result shows that 380.20

Synthesis of the final product 164:1- (4- (5- (2-fluoro-6-hydroxyphenyl) -2H-indazol-2-yl) piperidin-1-yl) prop-2-en-1-one (WHF78)

The starting material WHF77(0.077g,0.20mmol) was dissolved in CH ₂ Cl ₂ (10mL), BBr was added under cooling at 78 deg.C ₃ (1M in CH ₂ Cl ₂ 2mL) and then stirred at room temperature for 3 h. After the reaction is finished, NaHCO is cooled at-30 DEG C ₃ Quenching the reaction with saturated solution, adding water and CH ₂ Cl ₂ And ethyl acetate, respectively, and mixing the organic phases, concentrating, and purifying by HPLC to obtain 50mg of trifluoroacetate salt of WHF78 (purification conditions: 40% CH) ₃ CN start, retention time: 10 min). ¹ H NMR(400MHz,Methanol-d ₄ ) Δ 8.13(s,1H),7.60(s,1H),7.52-7.50(m,1H),7.24-7.21(m,1H),7.01-6.97(m,1H),6.70-6.52(m,3H),6.14-6.10(m,1H),5.67-5.64(m,1H),4.40-4.38(m,2H),4.17(s,1H),2.89-2.83(s,2H),2.18(s,2H),2.072.05(m,2H), ESI-MS theoretical calculation C ₂₁ H ₂₁ FN ₃ O ₂ [M+H] ⁺ 366.15; the experimental result shows that 366.47

Synthesis of the final product 165:1- (4- (6- (2-fluoro-6-hydroxyphenyl) -2H-indazol-2-yl) piperidin-1-yl) prop-2-en-1-one (WHF79)

The starting material WHF76(0.089g,0.23mmol) was dissolved in CH ₂ Cl ₂ (10mL), BBr was added under cooling at 78 deg.C ₃ (1M in CH ₂ Cl ₂ 2mL) and then stirred at room temperature for 3 h. After the reaction is finished, NaHCO is cooled at-30 DEG C ₃ Quenching the reaction with saturated solution, adding water and CH ₂ Cl ₂ And ethyl acetate, respectively, and combining the organic phases, concentrating, and purifying by HPLC to obtain 76mg (pure WHF79 as trifluoroacetate salt) of the final productThe chemical conditions are as follows: 40% CH ₃ CN start, retention time: 10 min). ¹ H NMR(400MHz,Methanol-d ₄ ) δ 8.30(s,1H),7.72(dd, J ═ 8.6,0.6Hz,1H),7.63(s,1H),7.19-7.13(m,2H),6.80(dd, J ═ 16.8,10.7Hz,1H),6.74(d, J ═ 8.2Hz,1H),6.67(td, J ═ 9.4,0.8Hz,1H),6.22(dd, J ═ 16.8,2.0, 1H),5.76(dd, J ═ 10.6,2.0Hz,1H),4.79-4.72(tt, J ═ 11.6,4.0Hz,2H),4.27(d, J ═ 13.8, 1H),3.36-3.30(m, 1.93, 2.93(t, 2.93, 2.7H), theoretical calculated values (d, J ═ 13.06, 1H), 3.06, 3.7, 3.3, 3, 12, 15, 2, 3, 2, 3, 2, H, 2, etc., H, 3, d, H, 2, H, C, etc., C ₂₁ H ₂₁ FN ₃ O ₂ [M+H] ⁺ 366.15; the experimental result shows that 366.13

Synthesis of the final product 166 1- (3- (5- (2-fluoro-6-methoxyphenyl) -3- ((pyridin-2-ylmethyl) amino) -2H-indazol-2-yl) piperidin-1-yl) prop-2-en-1-one (WHF83)

Step 1: synthesis of tert-butyl 3- (5- (2-fluoro-6-methoxyphenyl) -3- ((pyridin-2-ylmethyl) amino) -2H-indazole 2-yl) piperidine-1-carboxylate (WHF81-3)

The reaction steps are as follows: (a) pd was added sequentially to a 50mL dry double-necked flask ₂ (dba) ₃ (0.0915g,0.1mmol), BINAP (0.1874g,0.3mmol) and toluene (10mL), suction gas, N ₂ Heating (80 deg.C) for about 10min under protection, and cooling for use. (b) In addition, a dry double-neck bottle is taken, and raw materials WHF69(0.5g,1.00mmol), 2-aminomethyl pyridine (0.3722g, 3.45mmol) and, ^t Buona (0.3886g, 4.05mmol) and toluene (10mL), purge twice, N ₂ The catalyst prepared in step (a) was transferred with a syringe with a long needle under protection, and then heated with stirring (100 ℃ C.) for 14 hours. After the reaction is finished, cooling, removing the solvent, and carrying out column chromatography to obtain a WHF81-3(0.262g) crude product which is directly used for the next reaction.

Step 2: synthesis of 1- (3- (5- (2-fluoro-6-methoxyphenyl) -3- ((pyridin-2-ylmethyl) amino) -2H-indazol-2-yl) piperidin-1-yl) prop-2-en-1-one (WHF83)

The raw material WHF81-3(0.262g, 0.49mmol) was dissolved in CH ₂ Cl ₂ (3mL), add trifluoroAcetic acid (1.5mL) was stirred at room temperature for 30min, and the solvent was removed and taken up with toluene once. Then dissolved in THF (8mL) and Et added ₃ N (3mL), acryloyl chloride (44.5mg,0.49mmol), stir at room temperature for 1 h. After the reaction was completed, column chromatography was carried out to obtain WHF83(0.10 g). Purification by HPLC (separation conditions: 25% CH) ₃ CN start, retention time: 12 min). ¹ H NMR(400MHz,Methanol-d ₄ ) δ 8.64(d, J-4.3 Hz,0.7H),8.62-8.60(m,0.3H),8.12(t, J-7.7 Hz,0.7H),8.07-8.02(m,0.3),7.79(d, J-8.1 Hz,0.7H),7.71(d, J-7.6 Hz,0.3H),7.67(s,1H),7.57(d, J-8.7 Hz,2H),7.50(d, J-8.8 Hz,1H),7.33(dt, J-8.4, 6.6Hz,1H),6.89-6.79(m,2H),6.78(t, J-8.5 Hz,1H),6.27(d, J-8.5, 1H), 1H, 6.8, 1H, 6.82 (d, J-6.5H), 1H, 6.6.6.6.6H, 6.7H, 6.6H, 6H, 6.9 (d, 8, 1H), 6.6.6.6H, 6.6H), 6.6H, 6H, 6.6H, 6.6.6H, 6H, 6.6H, 6H, 6.6H, 6H, 1H, 6H, 6.6.6H, 6H, 6.6H, 6.6.6H, 6H, 1H, 6H, t, 6H, 1H, 6H, 1H, 6H, 1H, 6.6H, 6H, 1H, 6H, 1H, 6H, 1H, 6H, 1H, 6H, 6.6.6H, 6H, 6.6.6H, 6H, 1H, 6H, 6.6.6H, 6H, 2.29-2.26(m,1H),2.09(d, J ═ 12.0Hz,1H),1.80-1.70(d, J ═ 13.6Hz,1H) ₂₈ H ₂₉ FN ₅ O ₂ [M+H] ⁺ 486.22; the experimental result shows that 486.11

Synthesis of the final product 167:1- (3- (5- (2-fluoro-6-hydroxyphenyl) -3- ((pyridin-2-ylmethyl) amino) -2H-indazol-2-yl) piperidin-1-yl) prop-2-en-1-one (WHF87)

The starting material WHF83(89.7mg,0.19mmol) was dissolved in CH ₂ Cl ₂ (10mL), BBr was added under cooling at 78 deg.C ₃ (1M in CH ₂ Cl ₂ 1.9mL), then stirred at room temperature for 3 h. After the reaction is finished, NaHCO is cooled at-30 DEG C ₃ Quenching the reaction with saturated solution, adding water and CH ₂ Cl ₂ And ethyl acetate, respectively, and the organic phases were combined, concentrated, and purified by HPLC to obtain 73mg of trifluoroacetate salt of WHF87 as a final product (separation conditions: 20% CH 87) ₃ CN start, retention time: 13min) ¹ H NMR(400MHz,Methanol-d ₄ )δ8.75(d,J＝5.0Hz,1H),8.31(m,1H),7.98(d,J＝7.9Hz,1H),7.75(s,2H),7.68(d,J＝8.9Hz,1H),7.52(d,J＝8.9Hz,1H),7.14(dt,J＝8.1,6.6Hz,1H),6.83(dd,J＝16.710.5Hz,1H),6.72(d, J ═ 8.3Hz,1H),6.63(t, J ═ 9.0Hz,1H),6.25(d, J ═ 16.7Hz,1H),5.81(d, J ═ 16.7Hz,0.7H),5.74(d, J ═ 10.4Hz,0.3H),5.29(s,2H),4.85(d, J ═ 12.0Hz,1H),4.73-4.55(m,2H),4.21(d, J ═ 13.2Hz,1H),3.28-3.25(m,1H),2.40(d, J ═ 10.5Hz,1H),2.33-2.25(m,1H),2.08(d, J ═ 13.4, 1H), theoretical calculated values of C, 1H, and theoretical calculated values of d, J ═ 12.7 Hz,1H ₂₇ H ₂₇ FN ₅ O ₂ [M+H] ⁺ 472.21; the experimental result shows that 472.33

Synthesis of the final product 168:1- (4- (5- (2-fluoro-6-methoxyphenyl) -3- ((pyridin-3-yl) amino) -2H-indazol-2-yl) piperidin-1-yl) prop-2-en-1-one (WHF92)

Step 1: synthesis of tert-butyl 4- (3-bromo-5- (2-fluoro-6-methoxyphenyl) -2H-indazol-2-yl) piperidine-1-carboxylate (WHF80)

The starting material WHF72(0.67g,1.58mmol) was dissolved in HOAc (1mL)/Ac ₂ NBS (0.2825g,1.59mmol) was added to O (5mL), and the mixture was stirred at room temperature for 18 hours. After the reaction is finished, water is added for quenching, the solvent is removed, and NaHCO is used ₃ The solution neutralizes acidity. By CH ₂ Cl ₂ Extracting with ethyl acetate for three times, mixing organic phases, and adding Na ₂ SO ₄ Dried (anhydrous) and concentrated to give crude WHF80(0.79g) which was used directly in the next reaction. ¹ H NMR(400MHz,Chloroform-d)δ7.71(d,J＝8.9Hz,1H),7.55(s,1H),7.32(d,J＝8.9Hz,1H),7.27(d,J＝6.8Hz,1H),6.84-6.78(m,2H),4.77(tt,J＝11.4,4.1Hz,1H),4.36(s,2H),3.79(s,3H),2.95(s,2H),2.30(q,J＝15.4,14.1Hz,2H),2.02(d,J＝13.0Hz,2H),1.49(s,9H).

Step 2: synthesis of 5- (2-fluoro-6-methoxyphenyl) -2- (piperidin-4-yl) -N- (pyridin-3-ylmethyl) -2H-indazol-3-amine (WHF91)

(a) Pd was added sequentially to a 50mL dry double-necked flask ₂ (dba) ₃ (0.143g,0.16mmol), BINAP (0.293g,0.47mmol) and toluene (6mL), suction gas, N ₂ The mixture was heated (80 ℃ C.) for about 10min under protection. And cooling for later use. (b) Separately, a dry double-neck bottle is taken, and the raw material WHD80 (0.79g) is added in turn1.56mmol), 3-aminomethylpyridine (0.5281g, 4.89mmol), ^t Buona (0.6021g, 6.27mmol) and toluene (5mL), purge twice, N ₂ The catalyst prepared in step (a) is transferred by a syringe with a long needle under protection, and then heated (100 ℃) for 14 hours under stirring. After the reaction is finished, column chromatography is carried out for coarse separation, and the obtained crude product of the compound is dissolved in CH ₂ Cl ₂ Then, trifluoroacetic acid was added thereto, and stirred for 30 min. Purification by HPLC to give the product as trifluoroacetate, WHF91(30mg) (purification conditions: 20% CH) ₃ CN start, retention time: 7.8 min). Theoretical calculation of ESI-MS C ₂₅ H ₂₇ FN ₅ O[M+H] ⁺ 432.21; the experiment result shows that 432.6

And step 3: synthesis of 1- (4- (5- (2-fluoro-6-methoxyphenyl) -3- ((pyridin-3-yl) amino) -2H-indazol-2-yl) piperidin-1-yl) prop-2-en-1-one (WHF92)

WHF91(30mg,0.07mmol) was dissolved in THF, Et was added ₃ N (1mL) and acryloyl chloride (6mg,0.07mmol) were stirred at room temperature for 1 hour. After the reaction was completed, the solvent was removed, and HPLC purification was carried out to obtain trifluoroacetate WHF92(3mg, purification conditions: 20% CH) as a final product ₃ CN start, retention time: 13min) ¹ H NMR(400MHz,Methanol-d ₄ ) δ 8.92(s,1H),8.77(d, J ═ 5.5Hz,1H),8.52(d, J ═ 8.1Hz,1H),7.94(dd, J ═ 8.1,5.5Hz,1H),7.72(s,1H),7.61(d, J ═ 8.9Hz,1H),7.49(d, J ═ 8.9Hz,1H),7.33(td, J ═ 8.4,6.7Hz,1H),6.89(d, J ═ 8.4Hz,1H),6.86(dd, J ═ 16.7,10.6Hz,1H),6.78(t, J ═ 8.6Hz,1H),6.27(dd, J, 16.8, 1.9H), 1.82 (d, 10.6H, 1H),6.78(t, J ═ 8.6H, 1H),6.27(dd, 1H, 1.8, 1.82H), 6.2H, 3.6.6.8, 3.6H, 3.8, 3.6H, 3H, 3.6H, 3H, etc., 2H) ESI-MS theoretical calculation value C ₂₈ H ₂₉ FN ₅ O ₂ [M+H] ⁺ 486.22; the experimental result shows that 486.02

Synthesis of the final product 169 1- (4- (5- (2-fluoro-6-hydroxyphenyl) -3- ((pyridin-3-yl) amino) -2H-indazol-2-yl) piperidin-1-yl) prop-2-en-1-one (WHF94)

The starting material WHF92(0.24g,0.49mmol) was dissolved in CH ₂ Cl ₂ (10mL) BBr was added at-78 deg.C ₃ (1M in CH ₂ Cl ₂ 4mL) and then stirred at room temperature for 3 h. After the reaction is finished, NaHCO is cooled at-30 DEG C ₃ Quenching the reaction with saturated solution, adding water and CH ₂ Cl ₂ And ethyl acetate, respectively, and mixing the organic phases, concentrating, and purifying by HPLC to obtain the final product, trifluoroacetate WHF94(0.2g) (purification conditions: 20% CH) ₃ CN start, retention time: 10.8min) ¹ H NMR(400MHz,Methanol-d ₄ ) δ 8.85(d, J ═ 1.5Hz,1H),8.69(d, J ═ 4.4Hz,1H),8.41(d, J ═ 8.1Hz,1H),7.83(dd, J ═ 8.0,5.5Hz,1H),7.77(s,1H),7.64(d, J ═ 8.9Hz,1H),7.48(d, J ═ 8.8Hz,1H),7.14(td, J ═ 8.3,6.6Hz,1H),6.86(dd, J ═ 16.8,10.7Hz,1H),6.70(d, J ═ 8.1Hz,1H),6.64(td, J ═ 9.6,1.1, 1H),6.27 (J ═ 8, 8.8, 2H), 2.81 (d, J ═ 2.2H, 2H), 2.4.4.4H, 2H, 3.6.6H, 2H, 2.6H, 2H, 3H, 2H, 3H, 2H, 3H, 2H, 4H, 2H, 1H, 2H, 4H, 1H, 4H, 1H, 4H, 2H, 4H, 2H, 1H, 4H, 1H, 2H, 1H, 2H, 1H, 2H, 1H, 2H, 1H, 2H, 1H, 2H, 4H, 1H, 2H, 1H, 2H, 1H, 4H, 1H, 2H, 1H, 2H, 1H, 2H, 1H, 2H, 1H, 2H, 1H, 2H, 1H, 2H, 1H, 4, 2H) ESI-MS theoretical calculation value C ₂₇ H ₂₇ FN ₅ O ₂ [M+H] ⁺ 472.21; the test result is 472.57.

Synthesis of the final product 170 1- (3- (5- (2-fluoro-6-methoxyphenyl) -3- ((pyridin-4-ylmethyl) amino) -2H-indazol-2-yl) piperidin-1-yl) prop-2-en-1-one (WHF107)

Step 1 Synthesis of tert-butyl 3- (5- (2-fluoro-6-methoxyphenyl) -3- ((pyridin-4-ylmethyl) amino) -2H-indazol-2-yl) piperidine-1-carboxylate (WHF100)

The reaction steps are as follows: (a) pd was added sequentially to a 50mL dry double-necked flask ₂ (dba) ₃ (0.037g,0.04mmol), BINAP (0.075g,0.12mmol) and toluene (10mL), suction gas, N ₂ Heating (80 deg.C) for about 10min under protection, and cooling for use. (b) In addition, a dry double-neck bottle is taken, and raw materials WHF47(0.2107g,0.42mmol), 4-aminomethyl pyridine (0.1732g,1.6mmol) and, ^t Buona (0.1559g, 1.62mmol) and toluene (10 m)L), two times of ventilation, N ₂ The catalyst prepared in step (a) was transferred with a syringe with a long needle under protection, and then heated with stirring (100 ℃ C.) for 14 hours. After the reaction is finished, cooling, removing the solvent, carrying out column chromatography to obtain a WHF100 crude product, and directly carrying out the next reaction.

Step 2 Synthesis of 5- (2-fluoro-6-methoxyphenyl) -2- (piperidin-3-yl) -N- (pyridin-4-ylmethyl) -2H-indazol-3-amine (WHF100B)

The starting material WHF100 was dissolved in dichloromethane (2mL), trifluoroacetic acid (1mL) was added thereto, and the mixture was stirred at room temperature for 30min, after completion of the reaction, the solvent was removed and the product was purified by HPLC to obtain trifluoroacetate WHF100B (30mg) (purification conditions: 20% CH) ₃ CN start, retention time: 10.4 min). ¹ H NMR(400MHz,Methanol-d ₄ ) δ 8.82(d, J ═ 6.7Hz,2H),8.17(d, J ═ 6.6Hz,2H),7.45(dd, J ═ 9.0,0.6Hz,1H),7.32-7.24(m,3H),6.85(d, J ═ 8.4Hz,1H),6.74(t, J ═ 8.5Hz,1H),5.15(d, J ═ 4.1Hz,2H),5.10(p, J ═ 4.9Hz,1H),3.6-3.74(m,2H),3.69(s,3H),3.39-3.35(m,2H),2.29(q, J ═ 6.0Hz,2H),2.14-2.08(m,1H),2.00-1.92 (MS, 1H), theoretical calculated values (theoretical calculation C, 1H), 2H), and the like ₂₅ H ₂₇ FN ₅ O[M+H] ⁺ 432.21; the experimental result shows that 432.65

Step 3 Synthesis of 1- (3- (5- (2-fluoro-6-methoxyphenyl) -3- ((pyridin-4-ylmethyl) amino) -2H-indazol-2-yl) piperidin-1-yl) prop-2-en-1-one (WHF107)

WHF100B (30mg,0.07mmol) was dissolved in THF (6mL) and Et was added ₃ N (2mL) and acryloyl chloride (6mg,0.07mmol) were stirred at room temperature for 1 hour. After the reaction was completed, the solvent was removed, and HPLC purification was carried out to obtain trifluoroacetate salt WHF107(13mg, purification conditions: 15% CH) as a final product ₃ CN start, retention time: 14min). ¹ H NMR(400MHz,Methanol-d ₄ ) δ 8.84(d, J ═ 6.4Hz,2H),8.19(dd, J ═ 15.8,6.3Hz,2H),7.54-7.44(m,3H),7.32(q, J ═ 7.9Hz,1H),6.89-6.82(m,2H),6.76(t, J ═ 8.9Hz,1H),6.28(d, J ═ 16.8Hz,1H),5.83(d, J ═ 10.6Hz,1H),5.26(q, J ═ 18.7Hz,2H),4.83(d, J ═ 13.3Hz,1H),4.68-4.65(m,1H),4.23(d, J ═ 13.9Hz,1H),3.69(s,3.2H), 3.35-3.24.3H, 1H), theoretical calculated values (m, 1.23, 1.9H, 1H), 2.31.31.8-2H), 1.3.3.3H, 1.3.3, 1H, 1.84 (m-2H), theoretical calculated values (m, 1-1H), 1.75(m, 2H), 1H, 2H), 2H, 1.6, 1H, 2H, 1H, 2H, 1H, 2H, 1H, 2H, 1H, and m,2H, 1H, and m,1H, and m,2H ₂₈ H ₂₉ FN ₅ O ₂ [M+H] ⁺ 486.22; the experimental result shows that 486.43

Synthesis of the final product 171, 1- (3- (5- (2-fluoro-6-methoxyphenyl) -3- (pyridin-4-ylamino) -2H-indazol-2-yl) piperidin-1-yl) prop-2-en-1-one (WHF108)

Step 1: synthesis of tert-butyl 1- (3- (5- (2-fluoro-6-methoxyphenyl) -3- (pyridin-4-ylamino) -2H-indazol-2-yl) piperidin-1-yl) carboxylate (WHF98)

The reaction steps are as follows: (a) pd was added sequentially to a 50mL dry double-necked flask ₂ (dba) ₃ (0.0725g,0.08mmol), BINAP (0.1512g,0.24mmol) and toluene (10mL), suction gas, N ₂ Heating (80 deg.C) for about 10min under protection, and cooling for use. (b) In addition, a dry double-neck bottle is taken, and raw materials WHF47(0.4116g,0.82mmol), 4-aminopyridine (0.2521g, 2.68mmol) and, ^t Buona (0.303g, 3.15mmol) and toluene (10mL), purging twice, N ₂ The catalyst prepared in step (a) was transferred with a syringe with a long needle under protection, and then heated with stirring (100 ℃ C.) for 14 hours. After the reaction is finished, cooling, removing the solvent, performing column chromatography to obtain a WHF98 crude product, and directly performing the next reaction.

Step 2: synthesis of 5- (2-fluoro-6-methoxyphenyl) -2- (piperidin-3-yl) -N- (pyridin-4-yl) -2H-indazol-3-amine (WHF98B)

The starting material WHF98 was dissolved in DCM (2mL), TFA (1mL) was added, and the mixture was stirred at room temperature for 30min, after completion of the reaction, the solvent was removed and the product was purified by HPLC to give trifluoroacetate salt WHF98B (60mg) (purification conditions: 20% CH) ₃ CN start, retention time: 12 min). ¹ H NMR(400MHz,Methanol-d ₄ ) δ 8.33(s,2H),7.75(dd, J ═ 8.5,1.4Hz,1H),7.38 to 7.28(m,4H),6.89(d, J ═ 8.4Hz,1H),6.78(t, J ═ 9.2Hz,1H),5.11(p, J ═ 5.9Hz,1H),3.84 to 3.79(m,1H),3.75(s,3H),3.69(d, J ═ 4.0Hz,0.6H),3.66(d, J ═ 4.0Hz,0.4H),3.36(d, J ═ 6.1Hz,2H),2.26(d, J ═ 5.6Hz,2H),2.18 to 2.11(m,1H),1.96 to 1.91 (MS, 1H), theoretical calculated values of C to ESI, 1H, and their values ₂₄ H ₂₅ FN ₅ O[M+H] ⁺ 418.20; the test result is 418.84.

And step 3: synthesis of 1- (3- (5- (2-fluoro-6-methoxyphenyl) -3- (pyridin-4-ylamino) -2H-indazol-2-yl) piperidin-1-yl) prop-2-en-1-one (WHF108)

WHF98B (56mg,0.13mmol) was dissolved in THF (6mL) and Et was added ₃ N (2mL) and acryloyl chloride (12mg,0.13mmol) were stirred at room temperature for 1 hour. After the reaction was completed, the solvent was removed, and HPLC purification was carried out to obtain trifluoroacetate WHF108(35mg, purification conditions: 20% CH) as a final product ₃ CN start, retention time: 12.8min) ¹ H NMR(400MHz,Methanol-d ₄ ) δ 8.31(s,2H),7.70(d, J ═ 8.9Hz,1H),7.36-7.28(m,4H),6.89(d, J ═ 8.4Hz,1H),6.84-6.62(m,3H),6.18(d, J ═ 17.0Hz,0.7H),6.13(d, J ═ 17.0Hz,0.3H),5.77(d, J ═ 11.1Hz,0.7H),5.61-5.59(m,0.3H),4.68-4.50(m,2H),4.27(d, J ═ 14.6Hz,0.3H),4.17(d, J ═ 14.3Hz,0.7H),3.88-3.82(m,0.3H),3.75(s,3H), 3H, 3.1.3H, 3H, 33.3H, 3H, 31 (m,3H), 3H, 31 (m,3H), 3H, 15H, 1H, 15.1H, 2H, 1H, 2H, 15H, 1H, 2H, 15H, 1H, 2H, 15H, 2H, 3H, 15, 1H, 2H, 15H, 15H, etc. ₂₇ H ₂₇ FN ₅ O ₂ [M+H] ⁺ 472.21; the test result is 472.59.

Synthesis of the final product 172:1- (3- (5- (2-fluoro-6-hydroxyphenyl) -3- (pyridin-4-ylamino) -2H-indazol-2-yl) piperidin-1-yl) prop-2-en-1-one (WHF114)

The starting material WHF108(30mg,0.06mmol) was dissolved in CH ₂ Cl ₂ (5mL) BBr was added at-78 deg.C ₃ (1M in CH ₂ Cl ₂ 0.6mL) and then stirred at room temperature for 3 h. After the reaction is finished, NaHCO is cooled at-30 DEG C ₃ Quenching the reaction with saturated solution, adding water and CH ₂ Cl ₂ And ethyl acetate, respectively, and then the organic phases are combined, concentrated and purified by HPLC to obtain trifluoroacetate WHF114(16mg) of a final product (purification condition: 20% CH) ₃ CN start, retention time: 16min). ¹ H NMR(400MHz,Methanol-d ₄ )δ8.30(s,2H),7.70(d,J＝9.8Hz,1H),7.42(d,J＝8.2Hz,2H),7.16-7.11(m,1H),6.80(dd,J＝16.7,10.6Hz,1H),6.71(d, J ═ 8.2Hz,1H),6.64(d, J ═ 9.4Hz,1H),6.19(d, J ═ 16.7Hz,0.7H),6.13(d, J ═ 16.7Hz,0.3H),5.78(d, J ═ 10.7Hz,0.7H),5.61-5.59(m,0.3H),4.69-4.50(m,2H),4.28(d, J ═ 12.3Hz,0.3H),4.16(d, J ═ 13.6Hz,0.7H),3.85(t, J ═ 11.2Hz,0.3H),3.38(t, J ═ 11.6Hz,0.7H), 3.33.3, 0.7H),3.85(t, J ═ 11.2Hz,0.3H),3.38(t, J ═ 11.6, 0.7H), 3.27 (t, 3.7H), 1.7H, 1H), 1.1H, 1H, 5H, 1H ₂₆ H ₂₅ FN ₅ O ₂ [M+H] ⁺ 458.19; the experimental result shows that 458.93

Synthesis of end product 173 1- (3- (5- (2-fluoro-6-hydroxyphenyl) -3- ((pyridin-4-ylmethyl) amino) -2H-indazol-2-yl) piperidin-1-yl) prop-2-en-1-one (WHF115)

Raw material WHF107(10mg,0.02mmol) was dissolved in CH ₂ Cl ₂ (5mL), BBr was added under cooling at 78 deg.C ₃ (1M in CH ₂ Cl ₂ 0.2mL) and then stirred at room temperature for 3 h. After the reaction is finished, NaHCO is cooled at-30 DEG C ₃ Quenching the reaction with saturated solution, adding water and CH ₂ Cl ₂ And ethyl acetate, respectively, and the organic phases were combined, concentrated, and purified by HPLC to give final product, trifluoroacetate salt WHF115(11 mg). WHF115 ¹ H NMR(400MHz,Methanol-d ₄ ) δ 8.82(d, J ═ 6.4Hz,2H),8.17(d, J ═ 5.7Hz,2H),7.61(d, J ═ 6Hz,2H),7.50(d, J ═ 9.3Hz,1H),7.13(q, J ═ 7.0Hz,1H),6.85(dd, J ═ 16.8,10.7Hz,1H),6.70(d, J ═ 8.2Hz,1H),6.62(t, J ═ 9.0Hz,1H),6.27(d, J ═ 16.7Hz,1H),5.83(d, J ═ 10.7Hz,1H),5.28(q, J ═ 18.8Hz,2H),4.83(d, J ═ 13.7H, 4.68, 4.3H, 3.3H, 3H, 1H, 3H, 1H, 3H, 1H, 3H, 1H, 3H, 1H, 13H, 1H, etc. H, 13H, etc. 3H, 13H, etc. 3H, 13H, etc. H, 13H, etc. 2H, etc. 1H, etc. H, 13H, etc. 2H, 13H, etc. 3H, etc. ₂₇ H ₂₇ FN ₅ O ₂ [M+H] ⁺ 472.21; the experimental result shows that 472.58

Synthesis of the final product 174:4- (2- (1-acryloylpiperidin-3-yl) -2H-indazol-6-yl) benzonitrile (WHF122)

Step 1: synthesis of tert-butyl 3- (6- (4-cyanophenyl) -2H-indazol-2-yl) piperidine-1-carboxylate (WHF113)

Into a 50mL round-bottom flask were added WHF37(0.1992g, 0.52mmol), 4-cyanophenylboronic acid (0.1187g,0.81mmol), Pd (dppf) Cl in that order ₂ ·CH ₂ Cl ₂ (0.047g, 0.058mmol) followed by the addition of 1, 2-ethylene glycol dimethyl ether (6mL), Na ₂ CO ₃ Aqueous solution (2M, 2mL), purge twice, N ₂ The reaction system was heated at 90 ℃ for 10 hours with protection. After the reaction is finished, cooling to room temperature, removing the solvent, and carrying out column chromatography to obtain 50mg of a target compound WHF113 crude product which is directly used for the next reaction.

Step 2: synthesis of 4- (2- (1-acryloylpiperidin-3-yl) -2H-indazol-6-yl) benzonitrile (WHF122)

The starting material WHF113(50mg, 0.12mmol) was dissolved in CH ₂ Cl ₂ (2mL), trifluoroacetic acid (1mL) was added, the mixture was stirred at room temperature for 30min, the solvent was removed, and then TFA was removed by azeotroping with toluene (5 mL). Then dissolved in THF (10mL) and Et added ₃ N (2mL), acryloyl chloride (11mg,0.12mmol), stir at room temperature for 1 h. After the reaction was completed, the solvent was removed, and the compound was separated and purified by HPLC to obtain trifluoroacetate salt WHF122(12mg, separation conditions: 45% CH) ₃ CN start, retention time: 13 min). ¹ H NMR(400MHz,Methanol-d ₄ ) δ 8.38(s,1H),7.90(s,1H),7.89-7.80(m,5H),7.42(dd, J ═ 8.7,1.4Hz,1H),6.86-6.76(m,1H),6.24(d, J ═ 16.7Hz,0.6H),6.18(d, J ═ 16.9Hz,0.4H),5.79(d, J ═ 10.6Hz,0.6H),5.71(d, J ═ 10.6Hz,0.4H),4.80-4.77(m,1H),4.67-4.60(s,1H),4.41(d, J ═ 13.4Hz,0.6H),4.12(d, J ═ 13.6Hz,0.4H), 3.90 (t, t ═ 3.9H), 3.9 (t, 1H), 3.9H, 3, 3.6H), 3.9 (m, 3.6H), 3.6H, 3H, 3.6H, 3, 6, 3, 9, 6, 3, 6, 9, 3, 6, 3, 9, 6, 3, H, 9, H, 3, 6, 1H, 3, 9, H, 1H, 9, 1H, 6H, 9, 1H, 5, 1H, 5, 1H, d, 1H, 5, 1H, d, 1H, 1H, d, etc. H, 15H, d, H, 15H, etc. H, 15H. ₂₂ H ₂₁ N ₄ O[M+H] ⁺ 357.16; the test result is 357.96.

Synthesis of the final product 175 1- (3- (6- (4-fluorophenyl) -2H-indazol-2-yl) piperidin-1-yl) prop-2-en-1-one (WHF124)

Step 1: synthesis of tert-butyl 3- (6- (4-fluorophenyl) -2H-indazol-2-yl) piperidine-1-carboxylate (WHF104)

Into a 50mL round-bottom flask were added WHF37(0.2260g, 0.59mmol), 4-fluorobenzeneboronic acid (0.1187g,0.85mmol), Pd (dppf) Cl in that order ₂ ·CH ₂ Cl ₂ (0.0454g, 0.055mmol), then 1, 2-ethylene glycol dimethyl ether (6mL), Na was added ₂ CO ₃ Aqueous solution (2M, 2mL), purge twice, N ₂ The reaction system was heated at 90 ℃ for 10 hours with protection. After the reaction is finished, cooling to room temperature, removing the solvent, and carrying out column chromatography to obtain 0.22g of a target compound WHF104 ¹ H NMR(400MHz,Chloroform-d)δ8.01(s,1H),7.85(s,1H),7.70(d,J＝8.6Hz,1H),7.62-7.59(m,2H),7.30(d,J＝8.6Hz,1H),7.15-7.11(m,2H),4.52-4.45(m,1H),4.35(d,J＝11.2Hz,1H),4.09-4.01(m,1H),3.49(td,J＝11.0,9.8,2.5Hz,1H),2.99(s,1H),2.30(s,2H),1.83(s,1H),1.65(s,1H),1.47(s,9H).

Step 2: synthesis of 1- (3- (6- (4-fluorophenyl) -2H-indazol-2-yl) piperidin-1-yl) prop-2-en-1-one (WHF124)

Raw material WHF104(50mg, 0.127mmol) was dissolved in CH ₂ Cl ₂ (2mL), trifluoroacetic acid (1mL) was added, the mixture was stirred at room temperature for 30min, the solvent was removed, and then TFA was azeotropically removed with toluene (5 mL). Then dissolved in THF (10mL) and Et added ₃ N (2mL), acryloyl chloride (11mg,0.12mmol), stir at room temperature for 1 h. After the completion of the reaction, the solvent was removed, and the compound was separated and purified by HPLC to obtain trifluoroacetate salt WHF124(20mg, separation conditions: 45% CH) ₃ CN start, retention time: 16.2 min). ¹ H NMR(400MHz,Methanol-d ₄ )δ8.33(s,1H),7.78-7.76(m,2H),7.70-7.65(m,2H),7.36(dd,J＝8.9,1.3Hz,1H),7.23-7.15(m,2H),6.85-6.75(m,1H),6.24(d,J＝17.1Hz,0.6H),6.18(d,J＝17.1Hz,0.4H),5.78(d,J＝10.7Hz,0.6H),5.71(d,J＝10.7Hz,0.4H),4.78(d,J＝12.8Hz,0.5H),4.60-4.59(m,1H),4.43-4.39(m,1H),4.10(d,J＝13.8Hz,0.5H),3.74(t,J＝10.7Hz,0.4H) 3.45(t, J ═ 10.7 Hz,0.6H),3.35-3.29(m,0.6H),3.04(t, J ═ 11.1Hz,0.4H),2.41-2.31(m,2H),1.96-1.94(m,1H),1.77-1.65(m,1H), ESI-MS theoretical calculation C ₂₁ H ₂₁ FN ₃ O[M+H] ⁺ 350.16; the test result is 350.55.

Synthesis of the final product 176, 1- (3- (6- (3-chlorophenyl) -2H-indazol-2-yl) piperidin-1-yl) prop-2-en-1-one (WHF125)

Step 1: synthesis of tert-butyl 3- (6- (3-chlorophenyl) -2H-indazol-2-yl) piperidine-1-carboxylate (WHF110)

Into a 50mL round bottom flask were added WHF37(0.2271g, 0.60mmol), 3-chlorobenzeneboronic acid (0.1283g,0.82mmol), Pd (dppf) Cl in that order ₂ ·CH ₂ Cl ₂ (0.0468g, 0.057mmol) and then 1, 2-ethylene glycol dimethyl ether (6mL), Na was added ₂ CO ₃ Aqueous solution (2M, 2mL), purge twice, N ₂ The reaction system was heated at 90 ℃ for 10 hours with protection. After the reaction, the reaction mixture was cooled to room temperature, and the solvent was removed and column chromatography was carried out to obtain 0.2532g of the aimed compound WHF 110. ¹ H NMR(400MHz,Chloroform-d)δ8.03(s,1H),7.88(s,1H),7.72(d,J＝8.7Hz,1H),7.64(s,1H),7.54(d,J＝7.6Hz,1H),7.40-7.31(m,3H),4.54-4.47(m,1H),4.35(d,J＝12.9Hz,1H),4.10-4.02(m,1H),3.50(dd,J＝13.1,9.7Hz,1H),3.01(s,1H),2.31(s,2H),1.84(s,1H),1.68(s,1H),1.48(s,9H).

Step 2: synthesis of 1- (3- (6- (3-chlorophenyl) -2H-indazol-2-yl) piperidin-1-yl) prop-2-en-1-one (WHF125)

Raw material WHF110(50mg, 0.12mmol) was dissolved in CH ₂ Cl ₂ (2mL), trifluoroacetic acid (1mL) was added, the mixture was stirred at room temperature for 30min, the solvent was removed, and then TFA was azeotropically removed with toluene (5 mL). Then dissolved in THF (10mL) and Et added ₃ N (2mL), acryloyl chloride (11mg,0.12mmol), stir at room temperature for 1 h. After the reaction was completed, the solvent was removed, and the compound was separated and purified by HPLC to obtain trifluoroacetate salt WHF125(32mg, separation conditions: 50% CH) ₃ CN start, retention time: 17 min). ¹ H NMR(400MHz,Methanol-d ₄ ) δ 8.33(s,1H),7.79(s,1H),7.78(d, J ═ 8.8Hz,1H),7.66(t, J ═ 1.9Hz,1H),7.59(ddd, J ═ 7.7,1.8,1.1Hz,1H),7.42(t, J ═ 7.8Hz,1H),7.38-7.25(m,2H),6.84-6.75(m,1H),6.34(d, J ═ 16.9Hz,0.6H),6.18(d, J ═ 17.0Hz,0.4H),5.78(d, J ═ 10.6Hz,0.6H),5.71(d, J ═ 10.7Hz,0.4H),4.78(d, J ═ 12.0, 5.9H), 4.9 (t, J ═ 3.9H, 3.9H), 3.9H, 3H, 3.9H, 3H, 3.9H, 3H, 3.9H, 3H, etc., 2H) theoretical calculation of C for ESI-MS, 2.01-1.93(m,1H),1.76-1.66(m,1H) ₂₁ H ₂₁ ³⁵ ClN ₃ O and C ₂₁ H ₂₁ ³⁷ ClN ₃ O[M+H] ⁺ 366.13,368.13; the test result is 366.86,368.52.

Synthesis of the final product 177:1- (3- (6- (4-chlorophenyl) -2H-indazol-2-yl) piperidin-1-yl) prop-2-en-1-one (WHF126)

Step 1: synthesis of tert-butyl 3- (6- (4-chlorophenyl) -2H-indazol-2-yl) piperidine-1-carboxylate (WHF111)

Into a 50mL round-bottom flask were added WHF37(0.2399g, 0.63mmol), 4-chlorobenzeneboronic acid (0.1379g,0.88mmol), Pd (dppf) Cl in that order ₂ ·CH ₂ Cl ₂ (0.0462g, 0.057mmol) and then 1, 2-ethylene glycol dimethyl ether (6mL), Na was added ₂ CO ₃ Aqueous solution (2M, 2mL), purge twice, N ₂ The reaction system was heated at 90 ℃ for 10 hours with protection. After the reaction, the reaction mixture was cooled to room temperature, and the solvent was removed and column chromatography was carried out to obtain 0.1939g of the aimed compound WHF 111. ¹ H NMR(400MHz,Chloroform-d)δ8.02(s,1H),7.86(s,1H),7.71(d,J＝8.7Hz,1H),7.58(d,J＝8.5Hz,2H),7.41(d,J＝8.5Hz,2H),7.31(d,J＝8.7Hz,1H),4.53-4.46(m,1H),4.35(m,d,J＝11.9Hz,1H),4.14-4.02(m,1H),3.51-3.46(m,1H),3.00(s,1H),2.30(s,2H),1.83(s,1H),1.65(s,1H),1.47(s,9H).

Step 2: synthesis of 1- (3- (6- (4-chlorophenyl) -2H-indazol-2-yl) piperidin-1-yl) prop-2-en-1-one (WHF126)

Mixing raw material WHF111(50mg, 0.12mmol) was dissolved in CH ₂ Cl ₂ (2mL), trifluoroacetic acid (1mL) was added, the mixture was stirred at room temperature for 30min, the solvent was removed, and then TFA was azeotropically removed with toluene (5 mL). Then dissolved in THF (10mL) and Et added ₃ N (2mL), acryloyl chloride (11mg,0.12mmol), stir at room temperature for 1 h. After the reaction was completed, the solvent was removed, and the compound was separated and purified by HPLC to obtain trifluoroacetate salt WHF126(50mg, separation conditions: 50% CH) ₃ CN start, retention time: 17 min). ¹ H NMR(400MHz,Methanol-d ₄ ) δ 8.31(s,1H),7.77(s,1H),7.74(d, J ═ 8.8Hz,1H),7.62(s,1H),7.60(s,1H),7.41(s,1H),7.39(s,1H),7.33(dd, J ═ 8.7,1.4Hz,1H),6.82-6.73(m,1H),6.24(d, J ═ 16.9Hz,0.6H),6.18(d, J ═ 16.7Hz,0.4H),5.77(d, J ═ 10.6Hz,0.6H),5.70(d, J ═ 10.6Hz,1H),4.77(d, J ═ 12.6Hz,0.5H),4.56(s,1H),4.39(t, 39(s,1H),7 (t, 3.6H), 3.6H, 3H, 6H, 3.6H, 6H, 3, 3.6H, 3H, 6H, 3.6H, 3H, 6H, 3H, 6H, 3H, 6H, 3H, 6H, 3H, 6H, 3H, etc., 1H) theoretical calculation of ESI-MS C from 1.73 to 1.62(m,1H) ₂₁ H ₂₁ ³⁵ ClN ₃ O and C ₂₁ H ₂₁ ³⁷ ClN ₃ O[M+H] ⁺ 366.13,368.13; the experimental result shows that 366.32,368.32

Synthesis of the final product 178:1- (3- (6- (2-chlorophenyl) -2H-indazol-2-yl) piperidin-1-yl) prop-2-en-1-one (WHF127)

Step 1: synthesis of tert-butyl 3- (6- (2-chlorophenyl) -2H-indazol-2-yl) piperidine-1-carboxylate (WHF109)

Into a 50mL round bottom flask were added WHF37(0.2101g, 0.55mmol), 2-chlorobenzeneboronic acid (0.1352g,0.87mmol), Pd (dppf) Cl in that order ₂ ·CH ₂ Cl ₂ (0.0472g, 0.058mmol) followed by the addition of 1, 2-ethanediol dimethyl ether (6mL), Na ₂ CO ₃ Aqueous solution (2M, 2mL), purge twice, N ₂ The reaction system was heated at 90 ℃ for 10 hours with protection. After the reaction, the reaction mixture was cooled to room temperature, and the solvent was removed and column chromatography was carried out to obtain 0.23g of the aimed compound WHF 109. ¹ H NMR(400MHz,Chloroform-d)δ8.04(s,1H),7.75(s,1H),7.69(d,J＝8.7Hz,1H),7.49(dd,J＝7.5,1.8Hz,1H),7.42(dd,J＝7.3,2.1Hz,1H),7.35-7.28(m,2H),7.19(d,J＝8.6Hz,1H),4.54-4.47(m,1H),4.35(d,J＝13.3Hz,1H),4.03(s,1H),3.50(dd,J＝13.1,9.8Hz,1H),3.00(s,1H),2.31(s,2H),1.85(s,1H),1.67(s,1H),1.47(s,9H).

Step 2: synthesis of 1- (3- (6- (2-chlorophenyl) -2H-indazol-2-yl) piperidin-1-yl) prop-2-en-1-one (WHF127)

Raw material WHF109(53.5mg, 0.13mmol) was dissolved in CH ₂ Cl ₂ (2mL), trifluoroacetic acid (1mL) was added, the mixture was stirred at room temperature for 30min, the solvent was removed, and then TFA was azeotropically removed with toluene (5 mL). Then dissolved in THF (10mL) and Et added ₃ N (2mL), acryloyl chloride (12mg,0.12mmol), stir at room temperature for 1 h. After the reaction was completed, the solvent was removed, and HPLC separation and purification were carried out to obtain 44mg of a trifluoroacetate salt of the compound WHF 127. (separation conditions: 50% CH) ₃ CN start, retention time: 14.6 min). ¹ H NMR(400MHz,Methanol-d ₄ ) δ 8.35(s,1H),7.74(d, J ═ 8.6Hz,1H),7.61(s,1H),7.53-7.46(m,1H),7.42-7.31(m,3H),7.14(d, J ═ 8.7Hz,1H),6.84-6.75(m,1H),6.24(d, J ═ 16.9Hz,0.6H),6.18(d, J ═ 16.9Hz,0.4H),5.78(d, J ═ 10.5Hz,0.6H),5.70(d, J ═ 10.5Hz,0.4H),4.78(d, J ═ 12.0Hz,0.5H),4.63-4.57(m,1H),4.40(d, J ═ 11.92, 1H, 4.02 (t, 3.2H), 3.3.3H, 3.3H, 3.8 (m,3H), 3.7H, 3.6H), 3.8H, 3.5H, 3H, 3.6H, 3H, 3.9H, 3H, 3.4H, 3H, theoretical calculation value C of ESI-MS of 1.75-1.65(m,1H) ₂₁ H ₂₁ ³⁵ ClN ₃ O and C ₂₁ H ₂₁ ³⁷ ClN ₃ O[M+H] ⁺ 366.13,368.13; experimental determination of 366.67,368.65 Synthesis of end product 179:2- (2- (1-acryloylpiperidin-3-yl) -2H-indazol-6-yl) benzonitrile (WHF128)

Step 1: synthesis of tert-butyl 3- (6- (2-cyanophenyl) -2H-indazol-2-yl) piperidine-1-carboxylate (WHF105)

To a 50mL round bottom flask, WHF37(0.2002g,0.53mmol), 2-cyanophenylboronic acid (0.1193g,0.81mmol), Pd (dppf) Cl ₂ .CH ₂ Cl ₂ (0.0454g, 0.056mmol) and then 1, 2-ethylene glycol dimethyl ether (6mL), Na ₂ CO ₃ Aqueous solution (2M, 2mL), purge twice, N ₂ The reaction system was heated at 90 ℃ for 10 hours with protection. After the reaction, the reaction mixture was cooled to room temperature, and the solvent was removed and column chromatography was performed to obtain 41mg of the target compound WHF 105. ¹ H NMR(400MHz,Chloroform-d)δ8.07(s,1H),7.86(s,1H),7.79-7.76(m,2H),7.66(t,J＝7.5Hz,1H),7.58(d,J＝7.6Hz,1H),7.45(t,J＝7.6Hz,1H),7.29(d,J＝8.7Hz,1H),4.55-4.48(m,1H),4.35(d,J＝12.3Hz,1H),4.03(s,1H),3.50(dd,J＝13.1,9.8Hz,1H),3.01(s,1H),2.31(s,2H),1.82(s,1H),1.66(s,1H),1.48(s,9H).

Step 2: synthesis of 2- (2- (1-acryloylpiperidin-3-yl) -2H-indazol-6-yl) benzonitrile (WHF128)

Raw material WHF105(40mg, 0.1mmol) was dissolved in CH ₂ Cl ₂ (2mL), trifluoroacetic acid (1mL) was added, the mixture was stirred at room temperature for 30min, the solvent was removed, and then TFA was azeotropically removed with toluene (5 mL). Then dissolved in THF (10mL) and Et added ₃ N (2mL), acryloyl chloride (9mg,0.1mmol), stir at room temperature for 1 h. After the reaction, the solvent was removed, and the resulting mixture was separated and purified by HPLC to obtain 17mg of a compound, trifluoroacetate salt WHF128 (separation conditions: 45% CH) ₃ CN start, retention time: 12 min). ¹ H NMR(400MHz,Methanol-d ₄ ) δ 8.29(s,1H),7.74-7.69(m,3H),7.63(td, J-7.7, 1.4Hz,1H),7.53(d, J-8.0 Hz,1H),7.43(td, J-7.6, 1.2Hz,1H),7.15(d, J-8.6 Hz,1H),6.74-6.65(m,1H),6.13(d, J-16.9 Hz,0.6H),6.07(d, J-16.9 Hz,0.4H),5.67(d, J-10.6 Hz,0.6H),5.60(d, J-10.6 Hz,0.4H),4.68(d, J-13.0, 0.5H), 4.54.4H, 3.3.3H, 3.3H, 3H, 6H, 3H, 6H, 3H, 6H, 3H, 6, 1H) theoretical calculation of C1.66-1.56 (m,1H). ESI-MS ₂₂ H ₂₁ N ₄ O[M+H] ⁺ 357.16; the test result is 357.57.

Synthesis of the final product 180:1- (3- (6- (3-fluorophenyl) -2H-indazol-2-yl) piperidin-1-yl) prop-2-en-1-one (WHF129)

Step 1: synthesis of tert-butyl 3- (6- (3-fluorophenyl) -2H-indazol-2-yl) piperidine-1-carboxylate (WHF112)

Into a 50mL round-bottom flask were added WHF37(0.2072g, 0.55mmol), 3-fluorobenzeneboronic acid (0.1145g,0.82mmol), Pd (dppf) Cl in that order ₂ .CH ₂ Cl ₂ (0.0455g, 0.056mmol) and then 1, 2-ethylene glycol dimethyl ether (6mL), Na ₂ CO ₃ Aqueous solution (2M, 2mL), purge twice, N ₂ The reaction system was heated at 90 ℃ for 10 hours with protection. After the reaction, the reaction mixture was cooled to room temperature, and the solvent was removed and column chromatography was carried out to obtain 0.174g of the aimed compound WHF 112. ¹ H NMR(400MHz,Chloroform-d)δ8.03(s,1H),7.89(s,1H),7.72(d,J＝8.6Hz,1H),7.45-7.40(m,2H),7.34(t,J＝8.9Hz,2H),7.04(t,J＝8.7Hz,1H),4.54-4.47(m,1H),4.35(d,J＝12.3Hz,1H),4.02(s,1H),3.50(dd,J＝13.1,9.7Hz,1H),3.01(s,1H),2.31(s,2H),1.84(s,1H),1.66(s,1H),1.47(s,9H).

Step 2: synthesis of 1- (3- (6- (3-fluorophenyl) -2H-indazol-2-yl) piperidin-1-yl) prop-2-en-1-one (WHF129)

Raw material WHF112(50mg, 0.13mmol) was dissolved in CH ₂ Cl ₂ (2mL), trifluoroacetic acid (1mL) was added, the mixture was stirred at room temperature for 30min, the solvent was removed, and then TFA was azeotropically removed with toluene (5 mL). Then dissolved in THF (10mL) and Et added ₃ N (2mL), acryloyl chloride (12mg,0.13mmol), stir at room temperature for 1 h. After the reaction, the solvent was removed, and the resulting product was separated and purified by HPLC to obtain 26mg of a compound, trifluoroacetate salt WHF129 (separation conditions: 50% CH) ₃ CN start, retention time: 13.4 min). ¹ H NMR(400MHz,Methanol-d ₄ )δ8.33(s,1H),7.82(s,1H),7.78(d,J＝8.7Hz,1H),7.50-7.36(m,4H),7.08(t,J＝8.7Hz,1H),6.84-6.75(m,1H),6.25(d,J＝17.0Hz,0.6H),6.19(d,J＝17.0Hz,0.4H),5.78(d,J＝10.6Hz,0.6H),5.71(d,J＝10.6Hz,0.4H),4.78(d,J＝11.2Hz,0.5H),4.59(s,1H),4.40(d,J＝13.3Hz,1H),4.09(d,J＝13.1Hz,0.5H),3.73(t,J＝11.7Hz,0.4H),3.44(t,J＝11.4Hz,0.6H),3.36-3.28(m,0.6H),3.03(t,J＝12.2Hz,0.4H),2.35(d,J＝8.7Hz,2H),2.01-1.88(m,1H) Theoretical calculation of ESI-MS value C of 1.72(m,1H) ₂₁ H ₂₁ FN ₃ O[M+H] ⁺ 350.16; the experimental result shows that 350.26

Synthesis of the final product 181:1- (3- (5- (pyridin-2-yl) -2H-indazol-2-yl) piperidin-1-yl) prop-2-en-1-one (WHF130)

Step 1: synthesis of 3- (5- (pyridin-2-yl) -2H-indazol-2-yl) piperidine-1-carboxylic acid tert-butyl ester (WHF117)

Into a 50mL round-bottomed flask were added WHF37(0.233g, 0.61mmol), pyridine-2-boronic acid (0.1085g,0.88mmol), Pd (dppf) Cl in that order ₂ ·CH ₂ Cl ₂ (0.0479g, 0.059mmol) followed by the addition of 1, 2-ethanediol dimethyl ether (6mL), Na ₂ CO ₃ Aqueous solution (2M, 2mL), purge twice, N ₂ The reaction system was heated at 90 ℃ for 10 hours with protection. After the reaction was completed, the reaction mixture was cooled to room temperature, and the solvent was removed, followed by column chromatography to obtain 43mg of the objective compound WHF 117. ¹ H NMR(400MHz,Chloroform-d)δ8.72(s,1H),8.37(s,1H),8.12-7.96(m,1H),7.86-7.79(m,2H),7.63(d,J＝21.2Hz,1H),7.37-7.25(m,2H),4.51(s,1H),4.38(d,J＝11.7Hz,1H),4.03(s,1H),3.51(t,J＝12.2Hz,1H),3.02(s,1H),2.33(s,2H),1.91(s,1H),1.74(s,1H),1.55(s,9H).

Step 2: synthesis of 1- (3- (5- (pyridin-2-yl) -2H-indazol-2-yl) piperidin-1-yl) prop-2-en-1-one (WHF130)

Raw material WHF117(43mg, 0.11mmol) was dissolved in CH ₂ Cl ₂ (2mL), trifluoroacetic acid (1mL) was added, the mixture was stirred at room temperature for 30min, the solvent was removed, and then TFA was azeotropically removed with toluene (5 mL). Then dissolved in THF (10mL) and Et added ₃ N (2mL), acryloyl chloride (12mg,0.13mmol), stir at room temperature for 1 h. After the reaction, the solvent was removed, and the compound was separated and purified by HPLC to obtain 18mg of a trifluoroacetate salt WHF 130. (separation conditions: 15% CH) ₃ CN start, retention time: 15min) ¹ H NMR(400MHz,Methanol-d ₄ )δ8.78(dd,J＝5.9,0.8Hz,1H),8.64(s,1H),8.60(t,J＝8.0Hz,1H),8.45(d,J＝0.9Hz,1H),8.40(d,J＝8.2Hz,1H),7.95(t,J＝6.8Hz,1H),7.90(d, J ═ 9.1Hz,1H),7.81(dd, J ═ 9.1,1.8Hz,1H),6.87 to 6.75(m,1H),6.25(d, J ═ 16.6Hz,0.6H),6.17(d, J ═ 16.7Hz,0.4H),5.80(d, J ═ 10.9Hz,0.6H),5.70(d, J ═ 10.4Hz,0.4H),4.77 to 4.67(m,1.6H),4.40(d, J ═ 12.2Hz,0.4H),4.34(d, J ═ 13.6Hz,0.4H),4.11(d, J ═ 13.7Hz,0.6H),3.89(dd, J ═ 9.1H, 3.6H), 3.7, 7, 3.6H, 3.7, 3, 7, 3, 3.6H), 3, 3.6H, 3, 6H, 1H, 6H, 1, 6H, 1H, 6H, 1H, 6H, 1H, 6H, 4H, 6H, 4H, 1H, 6H, 1H, 4H, 6H, 1H, 6H, 1H, 4H, 1H, 6H, 1H, 6H, 4H, 1H, 4H, 1H, 4H, 1H, 4H, 6H, 1H, 4H, 1H, etc., 1H, 4H, etc., 1H, 4H, etc., 1H, 4H, etc., 4H ₂₀ H ₂₁ N ₄ O[M+H] ⁺ 333.16; the experimental result shows that 333.10

Synthesis of the final product 182:3- (2- (1-acryloylpiperidin-3-yl) -2H-indazol-6-yl) benzonitrile (WHF132)

Step 1: synthesis of tert-butyl 3- (6- (3-cyanophenyl) -2H-indazol-2-yl) piperidine-1-carboxylate (WHF106)

Into a 50mL round-bottom flask were added WHF37(0.2084g, 0.55mmol), 3-cyanophenylboronic acid (0.1203g,0.82mmol), Pd (dppf) Cl in that order ₂ ·CH ₂ Cl ₂ (0.0452g, 0.055mmol), then 1, 2-ethylene glycol dimethyl ether (6mL), Na was added ₂ CO ₃ Aqueous solution (2M, 2mL), purge twice, N ₂ The reaction system was heated at 90 ℃ for 10 hours with protection. After the reaction, the reaction mixture was cooled to room temperature, and the solvent was removed and subjected to column chromatography to obtain 0.26g of the aimed compound WHF 106. ¹ H NMR(400MHz,Chloroform-d)δ8.06(s,1H),7.95-7.91(m,1H),7.93-7.85(m,2H),7.76(d,J＝8.8Hz,1H),7.65-7.61(m,1H),7.58-7.54(m,1H),7.30(d,J＝8.6Hz,1H),4.55-4.48(m,1H),4.35(d,J＝13.2Hz,1H),4.09-4.01(m,1H),3.50(dd,J＝13.4,9.7Hz,1H),3.02(s,1H),2.32(s,2H),1.85(s,1H),1.67(s,1H),1.48(s,9H).

Step 2: synthesis of 3- (2- (1-acryloylpiperidin-3-yl) -2H-indazol-6-yl) benzonitrile (WHF132)

The starting material WHF106(42mg, 0.1mmol) was dissolved in CH ₂ Cl ₂ (2mL), trifluoroacetic acid (1mL) was added, the mixture was stirred at room temperature for 30min, the solvent was removed, and then TFA was azeotropically removed with toluene (5 mL).Then dissolved in THF (10mL) and Et added ₃ N (2mL), acryloyl chloride (9.4mg,0.1mmol), stir at room temperature for 1 h. After the reaction was completed, the solvent was removed, and separated and purified by HPLC to obtain 34mg of a compound, i.e., a trifluoroacetate salt WHF 132. (separation conditions: 45% CH) ₃ CN start, retention time: 13min) ¹ H NMR(400MHz,Methanol-d ₄ ) δ 8.35(s,1H),8.03-7.99(m,1H),7.98-7.95(m,1H),7.84(s,1H),7.80(dd, J ═ 8.7,0.9Hz,1H),7.69(d, J ═ 7.7Hz,1H),7.62(t, J ═ 7.8Hz,1H),7.36(dd, J ═ 8.7,1.6Hz,1H),6.85-6.75(m,1H),6.25(d, J ═ 17.0Hz,0.6H),6.19(d, J ═ 17.0Hz,0.4H),5.79(d, J ═ 10.6Hz,0.6H),5.72(d, J ═ 10.6, 0.4H), 4.4H, 3.7.7 (t, 3.7, 3.9H, 3.7H), 3.7.9H, 1H, 3.7H, 3.9H, 3.7 (d, 1H), 3.7H, 1H, 3.7H, 1H, 3H, 1H, 6H, 3.7H, 6H, 3H, 4H, 3H, 4H, 3H, 4H, 3H, 4H, 1H, 3H, 1H, 4H, 3H, 4H, 1H, 3H, 4H, 3H, 1H, 4H, 1H, 3H, 1H, 3H, 1H, 7H, 3H, 4H, 7H, 4H, 3H, 1H, 7H, 1H, 4H, 1H, 4H, 1H, 4H, 1H, 7H, 1H, 3H, 1H, 4H, 7H, 3H, 7H, 3H, 4H, 3H, 4H, 3H, 1H, 3H, 4H, 1H, 3H, 1H, 4H, 1H, 4H, 1H, 4H, 7H, 3H, 1H, 4H, 7H, 4H, 1H, 3H, 4H, 3H, 1H, 4H, 7H, 4H, 1H, 0.4H),2.42-2.34(m,2H),2.02-1.95(m,1H),1.77-1.63(m,1H). ESI-MS theoretical calculation values C ₂₂ H ₂₁ N ₄ O[M+H] ⁺ 357.16; the experimental result shows that 357.92

Synthesis of the final product 183 1- (3- (5- (pyridin-3-yl) -2H-indazol-2-yl) piperidin-1-yl) prop-2-en-1-one (WHF133) (WHF145,31mg)

Step 1: synthesis of tert-butyl tert-3- (5- (pyridin-3-yl) -2H-indazol-2-yl) piperidine-1-carboxylate (WHF120)

Into a 50mL round-bottomed flask, WHE159(0.2098g, 0.55mmol), pyridine-3-boronic acid (0.1171g,0.95mmol), Pd (dppf) Cl were added in this order ₂ ·CH ₂ Cl ₂ (0.0519g, 0.06mmol) followed by the addition of 1, 2-ethanediol dimethyl ether (6mL), Na ₂ CO ₃ Aqueous solution (2M, 2mL), purge twice, N ₂ The reaction system was heated at 90 ℃ for 10 hours with protection. After the reaction, the reaction mixture was cooled to room temperature, and the solvent was removed and column chromatography was carried out to obtain 0.26g of the aimed compound WHF 120. ¹ H NMR(400MHz,Chloroform-d)δ8.96(s,1H),8.65(s,1H),8.13-8.11(m,1H),7.92-7.81(m,3H),7.57-7.40(m,2H),4.53(s,1H),4.36(d,J＝7.8Hz,1H),4.11-4.02(m,1H),3.58-3.40(m,1H),3.02(s,1H),2.32(s,2H),1.85(s,1H),1.69(s,1H),1.49(s,9H).

Step 2: synthesis of 1- (3- (5- (pyridin-3-yl) -2H-indazol-2-yl) piperidin-1-yl) prop-2-en-1-one (WHF133)

Raw material WHF120(50mg, 0.13mmol) was dissolved in CH ₂ Cl ₂ (2mL), trifluoroacetic acid (1mL) was added, the mixture was stirred at room temperature for 30min, the solvent was removed, and then TFA was azeotropically removed with toluene (5 mL). Then dissolved in THF (10mL) and Et added ₃ N (2mL), acryloyl chloride (12mg,0.13mmol), stir at room temperature for 1 h. After the reaction, the solvent was removed, and the mixture was separated and purified by HPLC to obtain 32mg of a compound, i.e., trifluoroacetate salt WHF133 (separation condition: 15% CH) ₃ CN start, retention time: 11.4 min). Theoretical calculation of ESI-MS C ₂₀ H ₂₁ N ₄ O[M+H] ⁺ 333.16; the experimental result shows that 333.65

Synthesis of the final product 184 1- (3- (6- (pyridin-3-yl) -2H-indazol-2-yl) piperidin-1-yl) prop-2-en-1-one (WHF134) (WHF146)

Step 1: 3- (6- (pyridin-3-yl) -2H-indazol-2-yl) piperidine-1-carboxylic acid tert-butyl ester (WHF121)

Into a 50mL round-bottom flask were added WHF37(0.2005g, 0.53mmol), pyridine-3-boronic acid (0.1053g,0.85mmol), Pd (dppf) Cl in that order ₂ ·CH ₂ Cl ₂ (0.0453g, 0.056mmol) followed by the addition of 1, 2-ethanediol dimethyl ether (6mL), Na ₂ CO ₃ Aqueous solution (2M, 2mL), purge twice, N ₂ The reaction system was heated at 90 ℃ for 10 hours with protection. After the reaction, the reaction mixture was cooled to room temperature, and the solvent was removed and column chromatography was carried out to obtain 0.19g of the aimed compound WHF 121. ¹ H NMR(400MHz,Chloroform-d)δ8.93(d,J＝1.9Hz,1H),8.59(dd,J＝4.8,1.4Hz,1H),8.06(s,1H),7.95(dt,J＝6.1,1.8Hz,1H),7.92(s,1H),7.77(d,J＝8.7Hz,1H),7.38(dd,J＝7.8,4.8Hz,1H),7.33(dd,J＝8.7,1.1Hz,1H),4.55-4.48(m,1H),4.36(d,J＝12.9Hz,1H),4.09-4.02(m,1H),3.50(dd,J＝13.1,9.7Hz,1H),3.01(s,1H),2.31(s,2H),1.84(s,1H),1.66(s,1H),1.48(s,9H).

Step 2: synthesis of 1- (3- (6- (pyridin-3-yl) -2H-indazol-2-yl) piperidin-1-yl) prop-2-en-1-one (WHF134)

The starting material WHF121(50mg, 0.13mmol) was dissolved in CH ₂ Cl ₂ (2mL), trifluoroacetic acid (1mL) was added, the mixture was stirred at room temperature for 30min, the solvent was removed, and then TFA was azeotropically removed with toluene (5 mL). Then dissolved in THF (10mL) and Et added ₃ N (2mL), acryloyl chloride (12mg,0.13mmol), stir at room temperature for 1 h. After the reaction, the solvent was removed, and 53mg of the compound, i.e., the trifluoroacetate salt WHF134, was obtained by HPLC separation and purification (separation conditions: 15% CH) ₃ CN start, retention time: 11.8 min). Theoretical calculation of ESI-MS C ₂₀ H ₂₁ N ₄ O[M+H] ⁺ 333.16; the experimental result shows that 333.36

Synthesis of the final product 185:1- (3- (6- (2-methoxyphenyl) -2H-indazol-2-yl) piperidin-1-yl) prop-2-en-1-one (WHF135)

Step 1: synthesis of tert-butyl 3- (6- (2-methoxyphenyl) -2H-indazol-2-yl) piperidine-1-carboxylate (WHF101)

Into a 50mL round-bottomed flask were added WHF37(0.2320g, 0.61mmol), 2-methoxyphenylboronic acid (0.1275g,0.84mmol), Pd (dppf) Cl ₂ ·CH ₂ Cl ₂ (0.0496g, 0.056mmol) and then 1, 2-ethylene glycol dimethyl ether (6mL), Na was added ₂ CO ₃ Aqueous solution (2M, 2mL), purge twice, N ₂ The reaction system was heated at 90 ℃ for 10 hours with protection. After the reaction, the reaction mixture was cooled to room temperature, and the solvent was removed and column chromatography was carried out to obtain 0.2158g of the aimed compound WHF 101. ¹ H NMR(400MHz,Chloroform-d)δ8.00(s,1H),7.84(s,1H),7.66(d,J＝8.7Hz,1H),7.40(dd,J＝7.4,1.6Hz,1H),7.34(td,J＝8.0,1.7Hz,1H),7.29(d,J＝8.6Hz,1H),7.05(t,J＝7.4Hz,1H),7.01(d,J＝8.2Hz,1H),4.52-4.45(m,1H),4.35(d,J＝13.1Hz,1H),4.09-4.00(m,1H),3.82(s,3H),3.48(dd,J＝13.0,9.9Hz,1H),2.99(s,1H),2.30(s,2H),1.83(s,1H),1.67(s,1H),1.48(s,9H).

Step 2: synthesis of 1- (3- (6- (2-methoxyphenyl) -2H-indazol-2-yl) piperidin-1-yl) prop-2-en-1-one (WHF135)

Raw material WHF101(0.22g, 0.54mmol) was dissolved in CH ₂ Cl ₂ (4mL), trifluoroacetic acid (2mL) was added, the mixture was stirred at room temperature for 30min, the solvent was removed, and then TFA was azeotropically removed with toluene (5 mL). Then dissolved in THF (10mL) and Et added ₃ N (2mL), acryloyl chloride (48.6mg,0.54mmol), stir at room temperature for 1 h. After the reaction, the solvent was removed and column chromatography was carried out to obtain 72mg of the objective compound. 16mg of the compound was separated and purified by HPLC to obtain trifluoroacetate WHF 135. (separation conditions: 45% CH) ₃ CN start, retention time: 15min) ¹ H NMR(400MHz,Methanol-d ₄ ) δ 8.34(d, J ═ 9.3Hz,1H),7.69(d, J ═ 8.5Hz,2H),7.35-7.26(m,2H),7.29-7.21(m,1H),7.08(dd, J ═ 8.7,1.1Hz,1H),7.03(td, J ═ 7.5,1.1Hz,1H),6.84-6.76(m,1H),6.25(d, J ═ 17.1Hz,0.6H),6.18(d, J ═ 17.1Hz,0.4H),5.78(d, J ═ 10.7Hz,1H),5.72(d, J ═ 10.7Hz,0.4H),4.76(d, J ═ 12.9, 0.5H), 4.5.5 (t ═ 4H), 3.3.7H, 3.7H, 3.6H, 3H, 3.7H, 3.6H, 3H, etc., 2H) theoretical calculation of C for ESI-MS, 2.01-1.93(m,1H),1.76-1.65(m,1H) ₂₂ H ₂₄ N ₃ O ₂ [M+H] ⁺ 362.18; the test result is 362.20.

Synthesis of the final product 186:1- (3- (6- (3-methoxyphenyl) -2H-indazol-2-yl) piperidin-1-yl) prop-2-en-1-one (WHF136)

Step 1: synthesis of tert-butyl 3- (6- (3-methoxyphenyl) -2H-indazol-2-yl) piperidine-1-carboxylate (WHF102)

Into a 50mL round-bottom flask were added WHF37(0.2323g, 0.61mmol), 3-methoxyphenylboronic acid (0.1272g,0.84mmol), Pd (dppf) Cl in that order ₂ ·CH ₂ Cl ₂ (0.0490g, 0.056mmol) followed by the addition of 1, 2-ethylene glycol dimethyl ether (6mL), Na ₂ CO ₃ Aqueous solution (2M, 2mL), purge twice, N ₂ The reaction system was heated at 90 ℃ for 10 hours with protection. After the reaction is finished, cooling to room temperature, removing the solvent, And performing column chromatography to obtain 0.24g of a target compound WHF 102. ¹ H NMR(400MHz,Chloroform-d)δ8.01(s,1H),7.91(s,1H),7.70(d,J＝8.7Hz,1H),7.39-7.35(m,2H),7.27-7.25(m,1H),7.20(t,J＝2.1Hz,1H),6.90(dd,J＝8.2,2.5Hz,1H),4.53-4.45(m,1H),4.35(d,J＝13.5Hz,1H),4.04-3.98(m,1H),3.86(s,3H),3.79-3.73(m,1H),3.55-3.39(m,1H),2.99(s,1H),2.30(s,2H),1.83(s,1H),1.65(s,1H),1.47(s,9H).

Step 2: synthesis of 1- (3- (6- (3-methoxyphenyl) -2H-indazol-2-yl) piperidin-1-yl) prop-2-en-1-one (WHF136)

Raw material WHF101(0.24g, 0.59mmol) was dissolved in CH ₂ Cl ₂ (4mL), trifluoroacetic acid (2mL) was added, the mixture was stirred at room temperature for 30min, the solvent was removed, and then TFA was azeotropically removed with toluene (5 mL). Then dissolved in THF (10mL) and Et added ₃ N (2mL), acryloyl chloride (53mg,0.59mmol), stir at room temperature for 1 h. After the reaction, the solvent was removed, and column chromatography was performed to obtain 0.14g of the objective compound. 30mg of the compound was separated and purified by HPLC to obtain trifluoroacetate salt WHF136 (purification conditions: 45% CH) ₃ CN start, retention time: 15.2 min). WHF136 ¹ H NMR(400MHz,Methanol-d ₄ ) δ 8.31(s,1H),7.78(s,1H),7.75(d, J ═ 8.7Hz,1H),7.39-7.33(m,2H),7.23(d, J ═ 7.7Hz,1H),7.19(t, J ═ 2.1Hz,1H),6.92(dd, J ═ 8.2,2.6Hz,1H),6.81-6.74(m,1H),6.24(d, J ═ 16.8Hz,0.6H),6.18(d, J ═ 16.8Hz,0.4H),5.78(d, J ═ 10.6Hz,0.6H),5.71(d, J ═ 10.7Hz,0.4H),4.77(d, J ═ 13.4, 0.5 (t, J ═ 10.7H), 0.4H),4.7 (d, 3.7H), 3.3.7H, 3.3.3.3H, 3.3.3 (t, 3.3.3H), 3.7H, 3H, 3.7H, 3.6H, 3H, 3.7H, 3.6H, 3H, 3.7H, 3H, 2H) theoretical calculation of C2.00-1.92 (m,1H),1.75-1.64(m,1H). ESI-MS ₂₂ H ₂₄ N ₃ O ₂ [M+H] ⁺ 362.18; the test result is 362.17.

Synthesis of the final product 187 1- (3- (6- (4-methoxyphenyl) -2H-indazol-2-yl) piperidin-1-yl) prop-2-en-1-one (WHF137)

Step 1: 3- (6- (4-methoxyphenyl) -2H-indazol-2-yl) piperidine-1-carboxylic acid tert-butyl ester (WHF103)

Into a 50mL round-bottomed flask were added WHF37(0.2315g, 0.61mmol), 3-methoxyphenylboronic acid (0.1271g,0.84mmol), Pd (dppf) Cl ₂ ·CH ₂ Cl ₂ (0.0436g, 0.05mmol) followed by the addition of 1, 2-ethylene glycol dimethyl ether (6mL), Na ₂ CO ₃ Aqueous solution (2M, 2mL), purge twice, N ₂ The reaction system was heated at 90 ℃ for 10 hours with protection. After the reaction, the reaction mixture was cooled to room temperature, and the solvent was removed and column chromatography was carried out to obtain 0.23g of the aimed compound WHF 103. ¹ H NMR(400MHz,Chloroform-d)δ7.99(s,1H),7.85(s,1H),7.69(d,J＝8.7Hz,1H),7.62-7.59(m,2H),7.34(dd,J＝8.7,1.5Hz,1H),6.99(d,J＝8.7Hz,2H),4.52-4.45(m,1H),4.35(d,J＝13.1Hz,1H),4.03(s,2H),3.86(s,3H),3.48(dd,J＝13.1,9.8Hz,1H),2.99(s,1H),2.30(s,2H),1.84(s,1H),1.65(s,1H),1.47(s,9H).

Step 2: synthesis of 1- (3- (6- (4-methoxyphenyl) -2H-indazol-2-yl) piperidin-1-yl) prop-2-en-1-one (WHF137)

The starting material WHF103(0.21g, 0.52mmol) was dissolved in CH ₂ Cl ₂ (4mL), trifluoroacetic acid (2mL) was added, the mixture was stirred at room temperature for 30min, the solvent was removed, and then TFA was azeotropically removed with toluene (5 mL). Then dissolved in THF (10mL) and Et added ₃ N (2mL), acryloyl chloride (46.8mg,0.52mmol), stir at room temperature for 1 h. After the reaction, the solvent was removed, and column chromatography was performed to obtain 0.14g of the objective compound. 30mg of the compound is separated and purified by HPLC to obtain trifluoroacetate WHF137 of the compound. (purification Condition: 45% CH) ₃ CN start, retention time: 14.2 min). ¹ H NMR(400MHz,Methanol-d ₄ ) δ 8.26(s,1H),7.72(s,1H),7.60(d, J ═ 8.8Hz,1H),7.57(d, J ═ 8.8Hz,2H),7.35(d, J ═ 8.8Hz,1H),6.97(d, J ═ 8.7Hz,2H),6.80-6.72(m,1H),6.24(d, J ═ 17.0Hz,0.6H),6.18(d, J ═ 17.1Hz,0.4H),5.76(d, J ═ 10.7Hz,0.6H),5.69(d, J ═ 10.7Hz,0.4H), 4.4-4.74 (m,0.5H),4.54-4.52(m,1H),4.38(t, J ═ 10.7Hz, 0.95H), 3.3H, 3.95H, 3.3H, 3, 3.6H, 3H, 3.6H, 3, 3.6H, 3H, 6H, 3.6H, 6H, 3H, 6H, 4H, 6H, 5H, 6H, 4H, 6H, 4H, 6H, 3H, 4H, 4.74H, 6H, 3.74H, 3H, 5H, 3.5H, 6H, 3H, 3.74H, 3H, etc., 1H) theoretical calculation value C of ESI-MS of 1.70-1.60(m,1H) ₂₂ H ₂₄ N ₃ O ₂ [M+H] ⁺ ＝362.18; the experimental result shows that 362.19

Synthesis of the final product 188:1- (3- (6- (2-hydroxyphenyl) -2H-indazol-2-yl) piperidin-1-yl) prop-2-en-1-one (WHF138)

Raw material WHF135(54mg,0.15mmol) was dissolved in CH ₂ Cl ₂ (5mL), BBr was added under cooling at 78 deg.C ₃ (1M in CH ₂ Cl ₂ 1.5mL) and then stirred at room temperature for 3 h. After the reaction is finished, NaHCO is cooled at-30 DEG C ₃ Quenching the reaction with saturated solution, adding water and CH ₂ Cl ₂ And ethyl acetate, respectively, and then the organic phases are combined, concentrated and purified by HPLC to obtain trifluoroacetate WHF138(47mg) of the final product (purification condition: 40% CH) ₃ CN start, retention time: 11.2 min). ¹ H NMR(400MHz,Methanol-d ₄ ) δ 8.27(d, J-12.3 Hz,1H),7.77(s,1H),7.67(d, J-8.7 Hz,1H),7.37-7.29(m,2H),7.20-7.15(m,1H),6.93-6.89(m,2H),6.76(dd, J-16.8, 10.7Hz,1H),6.23(d, J-16.8 Hz,0.6H),6.15(d, J-16.8 Hz,0.4H),5.76(d, J-10.7 Hz,0.6H),5.70(d, J-10.7 Hz,0.4H),4.73(d, J-12.8 Hz,0.5H),4.55-4.53(m, 1.3H, 1.8H, 1H, 3.8H, 1H, 3.8H, 3H, 6H, 3H, 1H, 6H, 3H, 1H, 3.8H, 1H, 6H, 3H, 1H, 6H, 1H, 6H, 1H, 6H, 3H, 1H, 3H, 1H, 3, 1H, 6H, 1H, 6H, 1H, 6H, 1, 6H, 1, 6H, 3, 1H, 1H, 3, 1H, 6H, 1, 3, 1H, 6H, etc., 1H) theoretical calculation of C1.71-1.59 (m,1H). ESI-MS ₂₁ H ₂₂ N ₃ O ₂ [M+H] ⁺ 348.16; the test result is 348.26.

Synthesis of the final product 189:1- (3- (6- (2-hydroxyphenyl) -2H-indazol-2-yl) piperidin-1-yl) prop-2-en-1-one (WHF139)

Raw material WHF136(0.11g,0.3mmol) was dissolved in CH ₂ Cl ₂ (5mL) BBr was added at-78 deg.C ₃ (1M in CH ₂ Cl ₂ 3mL), then stirred at room temperature for 3 h.After the reaction is finished, NaHCO is cooled at-30 DEG C ₃ Quenching the reaction with saturated solution, adding water and CH ₂ Cl ₂ And ethyl acetate, respectively, and then the organic phases are combined, concentrated and purified by HPLC to obtain trifluoroacetate WHF139(99.2mg) of the final product (purification condition: 40% CH) ₃ CN start, retention time: 10.4 min). ¹ H NMR(400MHz,Methanol-d ₄ ) δ 8.14(d, J ═ 9.7Hz,1H),7.64(s,1H),7.59(d, J ═ 8.7Hz,1H),7.23(d, J ═ 8.8Hz,1H),7.14(t, J ═ 8.1Hz,1H),7.01-7.00(m,2H),6.71-6.68(m,1H),6.63(dd, J ═ 16.9,10.7Hz,1H),6.11(d, J ═ 17.2Hz,0.6H),6.05(d, J ═ 17.2Hz,0.4H),5.65(d, J ═ 10.6Hz,0.6H),5.58(d, J ═ 10.7, 0.4H),4.63(d, J ═ 0.13.8H), 5.5.58 (d, J ═ 10.7, 0.4H), 4.8 (d, 13.8, 8, 6H), 3.8, 6H, 3.8 (t, 3.6H), 3.6H, 1H, 11H, 1H, 6H, 1H, 6H, 1H, 6H, 8(t ═ 6H), theoretical calculation values C of 2.17-2.15(m,2H),1.90-1.75(m,1H),1.58-1.47(m,1H). ESI-MS ₂₁ H ₂₂ N ₃ O ₂ [M+H] ⁺ 348.16; the test result is 348.25.

Synthesis of the final product 190:1- (3- (6- (4-hydroxyphenyl) -2H-indazol-2-yl) piperidin-1-yl) prop-2-en-1-one (WHF140)

The starting material WHF137(0.11g,0.3mmol) was dissolved in CH ₂ Cl ₂ (5mL), BBr was added under cooling at 78 deg.C ₃ (1M in CH ₂ Cl ₂ 2.8mL), then stirred at room temperature for 3 h. After the reaction is finished, NaHCO is cooled at-30 DEG C ₃ Quenching the reaction with saturated solution, adding water and CH ₂ Cl ₂ And ethyl acetate, respectively, and the organic phases were combined, concentrated, and purified by HPLC to give final product, trifluoroacetate salt WHF140(25 mg). (purification conditions: 40% CH) ₃ CN start, retention time: 9.2 min). ¹ H NMR(400MHz,Methanol-d ₄ )δ8.19(d,J＝12.2Hz,1H),7.60(d,J＝8.6Hz,2H),7.41(s,1H),7.39(s,1H),7.26(d,J＝8.2Hz,1H),6.80-6.76(m,2H),6.70-6.63(m,1H),6.15-6.05(m,1H),5.66(d,J＝10.6Hz,0.6H),5.60(d,J＝10.7Hz,0.4H) 4.64(d, J ═ 12.6Hz,0.5H),4.55 to 4.40(m,1H),4.32 to 4.26(m,1H),3.94(d, J ═ 13.3Hz,0.5H),3.56(t, J ═ 10.8Hz,0.4H),3.31(t, J ═ 10.7Hz,0.6H),3.18(t, J ═ 11.7Hz,0.6H),2.88(t, J ═ 11.4Hz,0H),2.22 to 2.18(m,2H),1.87 to 1.79(m,1H),1.62 to 1.54(m,1H), ESI-MS theoretically calculated values C ₂₁ H ₂₂ N ₃ O ₂ [M+H] ⁺ 348.16; the test result is 348.34.

Synthesis of the final product 191:1- (3- (6- (pyridin-4-yl) -2H-indazol-2-yl) piperidin-1-yl) prop-2-en-1-one (WHF141)

Step 1: synthesis of 3- (6- (pyridin-4-yl) -2H-indazol-2-yl) piperidine-1-carboxylic acid tert-butyl ester (WHF118)

Into a 50mL round bottom flask were added WHF37(0.2005g, 0.53mmol), pyridine-4-boronic acid (0.1311g,1.06mmol), Pd (dppf) Cl in that order ₂ ·CH ₂ Cl ₂ (0.0498g, 0.06mmol) followed by the addition of 1, 2-ethanediol dimethyl ether (6mL), Na ₂ CO ₃ Aqueous solution (2M, 2mL), purge twice, N ₂ The reaction system was heated at 90 ℃ for 10 hours with protection. After the reaction, the reaction mixture was cooled to room temperature, and the solvent was removed and column chromatography was carried out to obtain 0.19g of the aimed compound WHF 118. ¹ H NMR(400MHz,Chloroform-d)δ8.69(s,2H),8.07(s,1H),8.00(s,1H),7.77(d,J＝8.7Hz,1H),7.60(d,J＝5.0Hz,2H),7.37(dd,J＝8.7,1.5Hz,1H),4.55-4.48(m,1H),4.36(d,J＝13.0Hz,1H),3.99(s,1H),3.53-3.48(m,1H),3.02(s,1H),2.32(s,2H),1.85(m,1H),1.66(s,1H),1.48(s,9H)。

Step 2: synthesis of 1- (3- (6- (pyridin-4-yl) -2H-indazol-2-yl) piperidin-1-yl) prop-2-en-1-one (WHF141)

Raw material WHF118(50mg, 0.13mmol) was dissolved in CH ₂ Cl ₂ (4mL), trifluoroacetic acid (2mL) was added, the mixture was stirred at room temperature for 30min, the solvent was removed, and then TFA was azeotropically removed with toluene (5 mL). Then dissolved in THF (10mL) and Et added ₃ N (2mL), acryloyl chloride (11.5mg,0.13mmol), stir at room temperature for 1 h. After the reaction is finished, the solvent is removed, and HPLC separation and purification are carried out to obtain the trifluoroacetate of the compoundWHF141(22.4 mg). (purification conditions: 20% CH) ₃ CN start, retention time: 7.6min). ¹ H NMR(400MHz,Methanol-d ₄ ) δ 8.86-8.81(m,2H),8.50-8.45(m,3H),8.33(s,1H),7.97(d, J ═ 8.8Hz,1H),7.63(dd, J ═ 8.8,1.6Hz,1H),6.87-6.75(m,1H),6.25(d, J ═ 16.8Hz,0.6H),6.17(d, J ═ 16.7Hz,0.4H),5.80(d, J ═ 10.6Hz,0.6H),5.70(d, J ═ 10.6Hz,0.4H),4.80-4.77(m,1H),4.71-4.68(m,0.7H),4.42-4.38(m,0.3H),4.36-4.33(m, 3.7H), 3.3.9-4.3H, 3.9 (m,3H), 3.6H), 3.9-4.6H, 3.6H, 3H, 3.9 (m-3H), 3.6H, 3.9, 3.6H), 3.9 (m-4.6H), 3.6H), 3H), 3.6H), 3.9-4.6H, 3.9 (m-4.6H), 3H), 3.6H), theoretical calculation value C of ESI-MS of 1.80-1.70(m,1H) ₂₀ H ₂₁ N ₄ O[M+H] ⁺ 333.16; the test result is 333.27.

Synthesis of the final product 192:1- (3- (5- (pyridin-4-yl) -2H-indazol-2-yl) piperidin-1-yl) prop-2-en-1-one (WHF144)

Step 1: synthesis of 3- (5- (pyridin-4-yl) -2H-indazol-2-yl) piperidine-1-carboxylic acid tert-butyl ester (WHF143)

Into a 50mL round-bottomed flask, WHE159(0.4193g, 1.1mmol), pyridine-4-boronic acid (0.2165g,1.76mmol), Pd (dppf) Cl were added in this order ₂ ·CH ₂ Cl ₂ (0.0884g, 0.11mmol) followed by the addition of 1, 2-ethanediol dimethyl ether (6mL), Na ₂ CO ₃ Aqueous solution (2M, 2mL), purge twice, N ₂ The reaction system was heated at 90 ℃ for 10 hours with protection. After the reaction, the reaction mixture was cooled to room temperature, and the solvent was removed and column chromatography was carried out to obtain 0.36g of the aimed compound WHF 143. ¹ H NMR(400MHz,Chloroform-d)δ8.66(dd,J＝4.6,1.6Hz,2H),8.12(s,1H),7.95(dd,J＝1.8,0.9Hz,1H),7.82(d,J＝9.2Hz,1H),7.59(dd,J＝9.0,1.6Hz,1H),7.55(dd,J＝4.6,1.6Hz,2H),4.55-4.48(m,1H),4.35(d,J＝13.6Hz,1H),4.01(s,1H),3.52(dd,J＝13.1,9.7Hz,1H),3.03(s,1H),2.32(s,2H),1.87(s,1H),1.68(s,1H),1.48(s,9H)。

Step 2: synthesis of 1- (3- (5- (pyridin-4-yl) -2H-indazol-2-yl) piperidin-1-yl) prop-2-en-1-one (WHF144)

The starting material WHF143(50mg, 0.13mmol) was dissolved in CH ₂ Cl ₂ (4mL), trifluoroacetic acid (2mL) was added, the mixture was stirred at room temperature for 30min, the solvent was removed, and then TFA was azeotropically removed with toluene (5 mL). Then dissolved in THF (10mL) and Et added ₃ N (2mL), acryloyl chloride (12mg,0.13mmol), stir at room temperature for 1 h. After the reaction, the solvent was removed, and HPLC separation and purification was carried out to obtain trifluoroacetate salt WHF144(55mg, purification conditions: 20% CH) ₃ CN start, retention time: 7.4 min). ¹ H NMR(400MHz,Methanol-d ₄ ) δ 8.82(d, J ═ 4.0Hz,2H),8.61(s,1H),8.52(s,1H),8.42(d, J ═ 4.0Hz,2H),7.89-7.83(m,2H),6.84-6.76(m,1H),6.25(d, J ═ 16.8Hz,0.6H),6.18(d, J ═ 16.8Hz,0.4H),5.80(d, J ═ 10.6Hz,0.6H),5.71(d, J ═ 10.6Hz,0.4H),4.77-4.65(m,1.5H),4.43-4.34(m,1H),4.11(d, J ═ 14.2Hz,0.6H),3.85(dd, J ═ 13.65 (m,1.5H),4.43-4.34(m,1H),4.11(d, J ═ 14.2Hz,0.6H),3.85(dd, J ═ 13.7, 7.7.7, 7.7, 7, 7.6H), 15, 7, 15, 7, 15, 7, 15, 1H, 15, etc. H, 15, etc. H. ₂₀ H ₂₁ N ₄ O[M+H] ⁺ 333.16; the test result is 333.75.

Synthesis of end product 193: 1- (3- (6- (2-fluoro-6-methoxyphenyl) -2H-indazol-2-yl) azetidin-1-yl) propan-2-en-1-one (CDM146)

Step 1: synthesis of tert-butyl 3- (6-bromo-2H-indazol-2-yl) azetidine-1-carboxylate (CDM142).

To a round bottom flask were added 4-bromo-2-nitro-benzaldehyde (1.00g,4.35mmol), 3-aminoazetidine-1-carboxylic acid tert-butyl ester (1.12g,6.52mmol) and isopropanol (15mL) in that order, and the mixture was heated and stirred at 80 ℃ for 4 hours. The reaction solution was cooled to room temperature, followed by addition of tributylphosphine (2.20g,10.80mmol) and heating at 80 ℃ continued for 16 hours. After the reaction, the reaction mixture was cooled to room temperature, most of the solvent was removed by a rotary evaporator, and column chromatography was performed to obtain the objective product CDM142(1.56 g). ¹ H NMR(400MHz,Chloroform-d):8.08-8.00(m,1H),7.94-7.86(m,1H),7.51(d,J＝8.81Hz,1H),7.16(dd,J＝8.81,1.63Hz,1H),5.33-5.24(m,1H),4.54-4.39(m,4H),1.47(s,9H).

Step 2: synthesis of tert-butyl 3- (6- (2-fluoro-6-methoxyphenyl) -2H-indazol-2-yl) azetidine-1-carboxylate (CDM144) to a round bottom flask were added CDM142(430mg,1.22mmol), 2-fluoro-6-methoxyphenylboronic acid (311mg,1.83mmol), ethylene glycol dimethyl ether (10mL) and 2M Na in that order ₂ CO ₃ Aqueous solution (5mL), deoxygenated, Pd (dppf) Cl was added ₂ ·CH ₂ Cl ₂ (99mg,0.12mmol) and then oxygen was removed again. The reaction was heated at 95 ℃ for 10 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, and the solvent was removed to carry out column chromatography, thereby obtaining the objective compound CDM144(377 mg). ¹ H NMR(400MHz,Chloroform-d):8.04(d,J＝1.01Hz,1H),7.87-7.77(m,1H),7.68(d,J＝8.68Hz,1H),7.36-7.22(m,1H),7.15(d,J＝8.72Hz,1H),6.90-6.71(m,2H),5.36-5.24(m,1H),4.58-4.41(m,4H),3.79(s,3H),1.49(s,9H).

And step 3: synthesis of 1- (3- (6- (2-fluoro-6-methoxyphenyl) -2H-indazol-2-yl) azetidin-1-yl) prop-2-en-1-one (CDM146).

CDM144(125mg,0.31mmol) in CH ₂ Cl ₂ (6mL), trifluoroacetic acid (2mL) was added, the mixture was stirred at room temperature for 30min, and the volatile components were removed on a rotary evaporator. The resulting oil was dissolved in THF (8mL), triethylamine (0.1mL) was added, and acryloyl chloride (70mg,0.77mmol) was added dropwise and stirred at room temperature for 1 hour. After removal of the solvent, HPLC purification gave 80mg of the trifluoroacetate salt of the final product CDM146 (purification conditions: starting with 45% acetonitrile, retention time: 11.0 min). ¹ H NMR(400MHz,MeOD-d ₄ ) 8.32(s,1H),7.68(dd, J ═ 8.70,1.00Hz,1H),7.60(s,1H),7.37-7.28(m,1H),7.05(d, J ═ 8.68Hz,1H),6.90(d, J ═ 8.40Hz,1H),6.81(t, J ═ 8.83Hz,1H),6.40(dd, J ═ 17.02,10.04Hz,1H),6.30(dd, J ═ 17.02,2.11Hz,1H),5.78(dd, J ═ 10.04,2.11Hz,1H),5.63-5.50(m,1H),4.87-4.81(m,1H),4.81-4.74(m,1H), 4.66H, 4.59-4.59 (m, 3.58H), theoretical calculation values (MS, 1H), 3-5.51H), theoretical calculation values (MS, 1H), and calculation values (m,1H), and calculation values of C, 1H ₂₀ H ₁₉ FN ₃ O ₂ [M+H] ⁺ 352.13; the experiment shows that: 352.20.

synthesis of end product 194: 1- (3- (5- (2-fluoro-6-methoxyphenyl) -2H-indazol-2-yl) azetidin-1-yl) propan-2-en-1-one (CDM149)

Step 1: synthesis of tert-butyl 3- (5-bromo-2H-indazol-2-yl) azetidine-1-carboxylate (CDM145).

Starting with 5-bromo-2-nitro-benzaldehyde (1.00g,4.35mmol) and tert-butyl 3-aminoazetidine-1-carboxylate (1.12g,6.52mmol), the title compound, CDM145(1.30g), was synthesized according to the experimental procedure for CDM 142. ¹ H NMR(400MHz,Chloroform-d):8.06-7.98(m,1H),7.85-7.77(m,1H),7.63(d,J＝9.19,0.89Hz,1H),7.37(dd,J＝9.17,1.86Hz,1H),5.36-5.26(m,1H),4.57-4.42(m,4H),1.49(s,9H).

Step 2: synthesis of tert-butyl 3- (5- (2-fluoro-6-methoxyphenyl) -2H-indazol-2-yl) azetidine-1-carboxylate (CDM147).

CDM145(411mg,1.16mmol) and 2-fluoro-6-methoxyphenylboronic acid (298mg,1.75mmol) were used as starting materials, and CDM144 was used as an experimental method to synthesize the objective compound CDM147(363 mg). ¹ H NMR(400MHz,Chloroform-d):8.11-7.99(m,1H),7.79(d,J＝8.88Hz,1H),7.74-7.65(m,1H),7.36(d,J＝8.97Hz,1H),7.32-7.22(m,1H),6.88-6.75(m,2H),5.39-5.22(m,1H),4.57-4.40(m,4H),3.79(s,3H),1.50(s,9H).

And step 3: synthesis of 1- (3- (5- (2-fluoro-6-methoxyphenyl) -2H-indazol-2-yl) azetidin-1-yl) prop-2-en-1-one (CDM149).

Starting from CDM147(121mg), the title compound was synthesized according to the experimental procedure of CDM146 and purified by HPLC to give 98mg of trifluoroacetate salt of the final product CDM149 (purification conditions: starting with 45% acetonitrile, retention time: 11.0 min). ¹ H NMR(400MHz,MeOD-d ₄ ) 8.31(s,1H),7.72-7.56(m,2H),7.37-7.22(m,2H),6.88(d, J ═ 8.56Hz,1H),6.80(t, J ═ 8.38Hz,1H),6.40(dd, J ═ 16.99,10.00Hz,1H),6.31(dd, J ═ 16.99,2.32Hz,1H),5.78(dd, J ═ 10.00,2.32Hz,1H),5.61-5.51(m,1H),4.88-4.80(m,1H),4.80-4.73(m,1H),4.66-4.58(m,1H),4.58-4.50(m,1H),3.75(s,3H), theoretical calculated values of C-ESI ₂₀ H ₁₉ FN ₃ O ₂ [M+H] ⁺ 352.13; is measured by experiments：352.06。

Synthesis of the final product 195: 1- (3- (5- (2-fluoro-6-hydroxyphenyl) -2H-indazol-2-yl) azetidin-1-yl) propan-2-en-1-one (CDM151).

Starting material CDM149(25mg,0.07mmol) was dissolved in CH ₂ Cl ₂ (10mL), BBr was added under cooling at 78 deg.C ₃ (1M in CH ₂ Cl ₂ 0.21mL), and then stirred at room temperature for 3 h. After the reaction is finished, NaHCO is cooled at-30 DEG C ₃ Quenching the reaction with saturated solution, adding water and CH ₂ Cl ₂ And ethyl acetate were extracted three times, respectively, and the organic phases were combined, dried, concentrated, and purified by HPLC to give 5mg of trifluoroacetate salt of the final product CDM151 (purification conditions: 40% CH) ₃ CN start, retention time: 9.5 min). ¹ H NMR(400MHz,MeOD-d ₄ ) 8.37(s,1H),7.71(s,1H),7.67(d, J ═ 9.06Hz,1H),7.36(d, J ═ 9.05,1H),7.20-7.08(m,1H),6.73(d, J ═ 8.31Hz,1H),6.66(t, J ═ 9.44Hz,1H),6.44(dd, J ═ 16.99,10.15Hz,1H),6.32(dd, J ═ 16.99,2.09Hz,1H),5.81(dd, J ═ 10.15,2.09Hz,1H),5.67-5.57(m,1H),4.95-4.90(m,1H),4.86-4.78 (ESI, 1H),4.71-4.61(m, 61H), 4.53-4.53 (m,1H), theoretical calculated values (MS, 53-C), calculated values ₁₉ H ₁₇ FN ₃ O ₂ [M+H] ⁺ 338.12; the experiment shows that: 338.08.

synthesis of end product 196: 1- (3- (5- (2-fluoro-6-methoxy) -3- (pyridin-3-yl) -2H-indazol-2-yl) piperidin-1-yl) prop-2-en-1-one (CDM155).

Step 1: synthesis of tert-butyl 3- (5- (2-fluoro-6-methoxyphenyl) -3- (pyridin-3-yl) -2H-indazol-2-yl) piperidine-1-carboxylate (CDM152).

The target compound CDM152(192mg) was synthesized by an experimental method with reference to CDM144, starting from WHF47(200mg,0.40mmol) and 3-pyridineboronic acid (98mg,0.80 mmol). ¹ H NMR(400MHz,Chloroform-d):8.82(d,J＝2.30Hz,1H),8.77-8.69(m,1H),7.97-7.83(m,1H),7.79(d,J＝8.93Hz,1H),7.56(d,J＝1.47Hz,1H),7.51(dd,J＝7.91,4.89Hz,1H),7.36(d,J＝9.01Hz,1H),7.29-7.21(m,1H),6.83-6.71(m,2H),4.48-4.36(m,1H),4.34-4.12(m,2H),3.76(s,3H),3.56-3.43(m,1H),2.94-2.71(m,1H),2.61-2.42(m,1H),2.21-2.08(m,1H),1.90-1.80(m,1H),1.66-1.50(m,1H),1.42(s,9H).

Step 2: synthesis of 1- (3- (5- (2-fluoro-6-methoxy) -3- (pyridin-3-yl) -2H-indazol-2-yl) piperidin-1-yl) prop-2-en-1-one (CDM155).

Starting from CDM152(121mg,0.38mmol), the title compound was synthesized according to the experimental procedure of CDM146 and purified by HPLC to give 27mg of the trifluoroacetate salt of the final product CDM155 (purification conditions: 40% acetonitrile start, retention time: 8.5 min). ¹ H NMR(400MHz,MeOD-d ₄ ) 8.86-8.77 (m,1H),8.73(dd, J ═ 5.10,1.60Hz,1H),8.21(d, J ═ 7.95Hz,0.6H),8.11(d, J ═ 7.95Hz,0.4H),7.81-7.66(m,2H),7.52-7.41(m,1H),7.40-7.22(m,2H),6.88(d, J ═ 8.37Hz,1H),6.84-6.71(m,1.6H),6.70-6.56(m,0.4H),6.20(d, J ═ 16.69Hz,0.6H),6.10(d, J ═ 16.69, 0.4H),5.76(d, J ═ 10.44, 0.65 (d, J ═ 16.69, 0.4H),3.7 (m, 3.7H), 3.7H, 3.7 (m, 3.7H), 6H, 3.7H, 6H, 3.7H, 6H, 3.7H, 3, 3.7H, 6H, 3, 3.7H, 3, 6H, 3, 3.7H, 3, 3.7H, 3H, 3.7H, 3H, 3.7H, 3H, 3.7H, 3, 6H, 3.7H, 6H, 3H, 6H, 3.7H, 3H, 6H, 3.7H, 6H, 3H, 0.6H), 3.00-2.83 (m,0.4H),2.65-2.40(m,1H),2.38-2.17(m,1H),2.08-1.87(m,1H),1.70-1.51(m,1H) ESI-MS theoretical calculation C ₂₇ H ₂₆ FN ₄ O ₂ [M+H] ⁺ 457.19; the experiment shows that: 457.16.

synthesis of end product 197: 1- (3- (6- (2-fluoro-6-methoxyphenyl) -2H-indazol-2-yl) pyrrol-1-yl) prop-2-en-1-one (CDM159).

Step 1: synthesis of tert-butyl 3- (6-bromo-2H-indazol-2-yl) pyrrole-1-carboxylate (CDM154).

Starting with 4-bromo-2-nitro-benzaldehyde (1.00g,4.35mmol) and tert-butyl 3-aminopyrrole-1-carboxylate (1.20g,6.52mmol)The target compound CDM154(1.70g) was synthesized according to the experimental method of CDM 142. ¹ H NMR(400MHz,Chloroform-d):7.93(s,1H),7.89-7.85(m,1H),7.51(d,J＝8.81Hz,1H),7.15(dd,J＝8.81,1.62Hz,1H),5.20-5.10(m,1H),4.02-3.77(m,2H),3.75-3.50(m,2H),2.61-2.39(m,2H),1.44(s,9H).

Step 2: synthesis of tert-butyl 3- (6- (2-fluoro-6-methoxyphenyl) -2H-indazol-2-yl) pyrrole-1-carboxylate (CDM157).

CDM157(1.54g) was synthesized from CDM154(1.70g,4.64mmol) and 2-fluoro-6-methoxyphenylboronic acid (1.18g,6.97mmol) by the experimental procedure according to CDM 144. ¹ H NMR(400MHz,Chloroform-d)δ7.95(d,J＝0.98Hz,1H),7.78-7.71(m,1H),7.67(d,J＝8.59Hz,1H),7.33-7.22(m,1H),7.11(dt,J＝8.59,1.44Hz,1H),6.86-6.74(m,2H),5.24-5.10(m,1H),4.04-3.80(m,2H),3.77(s,3H),3.74-3.46(m,2H),2.64-2.43(m,2H),1.48(s,9H).

And step 3: synthesis of 1- (3- (6- (2-fluoro-6-methoxyphenyl) -2H-indazol-2-yl) pyrrol-1-yl) prop-2-en-1-one (CDM159).

Starting from CDM157(140mg), the title compound was synthesized according to the experimental procedure of CDM146 and purified by HPLC to give 125mg of trifluoroacetate salt of the final product CDM159 (purification conditions: starting with 45% acetonitrile, retention time: 11.0 min). ¹ H NMR(400MHz,MeOD-d ₄ ) 8.32-8.20(m,1H),7.68(d, J ═ 8.67Hz,1H),7.56(s,1H),7.39-7.23(m,1H),7.04(d, J ═ 8.89Hz,1H),6.89(d, J ═ 8.44Hz,1H),6.80(t, J ═ 8.69Hz,1H),6.70-6.52(m,1H),6.30(dd, J ═ 16.83,6.55Hz,1H),5.75(dd, J ═ 16.83,10.44Hz,1H),5.44-5.24(m,1H),4.27-4.18(m,0.4H),4.16-4.09(m,0.6H),4.10-4.02(m,1H), 3.91.91.91-5.24 (m,1H), 3.27-4.18 (m,0.4H), 3.79(m, 3.74H), 3.3.79-3.3H), 3.79(m, 3.74H), 3.9-4H, 3.9H, 5(m, 5.75 (m,1H), 5.9H), 5(m, 5.9H), 4.9H), 4H, 15H), 4H, 15H, 5H, 15H, 5H, 15H), 4H, 15H, 5H), 4H, 5H, 15H, 5H, 2H, 5H, 2H), 4H, 2H, 15H, etc ₂₁ H ₂₁ FN ₃ O ₂ [M+H] ⁺ 366.15; the experiment shows that: 366.17.

synthesis of end product 198: 1- (3- (5- (2-fluoro-6-hydroxyphenyl) -3- (pyridin-3-yl) -2H-indazol-2-yl) piperidin-1-yl) prop-2-en-1-one (CDM160).

The title compound was synthesized from CDM155(20mg) by the experimental procedure of CDM151 and purified by HPLC to give 11mg of trifluoroacetate salt of the final product CDM160 (purification conditions: 30% acetonitrile start, retention time: 11.0 min). ¹ H NMR(400MHz,MeOD-d ₄ ) 9.04(s,0.7H),8.93(s,0.3H),8.89-8.74(m,1H),8.55(d, J-8.05 Hz,0.7H),8.36(d, J-8.05 Hz,0.3H),8.06-7.96(m,0.7H),7.93-7.85(m,0.3H),7.82-7.67(m,1H),7.59(s,0.7H),7.54(s,0.3H),7.47-7.37(m,1H),7.19-7.08(m,1H),6.85-6.58(m,3H),6.21(d, J-16.73 Hz,0.7H),6.11(d, J-16.73H, 0.7H),6.11(d, J-3.73H), 0.5 (s, 3.3H), 4.3H), 3H, 3.3H, 3H, 3.7H, 3H, 3.3.3H, 3H, 3.3H, 3H, 3.3H, 3.3.73H, 3H, 3.6.6.6.6.6.3H, 3H, 0.7H),3.30-3.21(m,0.7H),3.06-2.84(m,0.3H),2.70-2.38(m,1H),2.40-2.16(m,1H),2.10-1.85(m,1H),1.75-1.44(m,1H) ESI-MS theoretical calculation C ₂₆ H ₂₄ FN ₄ O ₂ [M+H] ⁺ 443.18; the experiment shows that: 443.25.

synthesis of end product 199: 1- (3- (5- (2-fluoro-6-methoxy) -3- (pyridin-2-yl) -2H-indazol-2-yl) piperidin-1-yl) prop-2-en-1-one (CDN02).

Step 1: synthesis of tert-butyl 3- (5- (2-fluoro-6-methoxyphenyl) -3- (pyridin-2-yl) -2H-indazol-2-yl) piperidine-1-carboxylate (CDM156).

The objective compound CDM156(20mg) was synthesized by the experimental method with reference to CDM144, starting with WHF47(120mg,0.24mmol) and 2-pyridineboronic acid (59mg,0.48 mmol). ¹ H NMR(400MHz,Chloroform-d)δ8.80(d,J＝4.26Hz,1H),7.93-7.69(m,4H),7.42-7.25(m,3H),6.89-6.75(m,2H),5.34-5.21(m,1H),4.55-4.36(m,1H),4.32-4.11(m,1H),3.79(s,3H),3.56-3.40(m,1H),2.90-2.77(m,1H),2.54-2.28(m,2H),1.98-1.82(m,1H),1.74-1.64(m,1H),1.41(s,9H).

And 2, step: synthesis of 1- (3- (5- (2-fluoro-6-methoxy) -3- (pyridin-2-yl) -2H-indazol-2-yl) piperidin-1-yl) prop-2-en-1-one (CDN02).

Starting from CDM156(20mg), the title compound was synthesized according to the experimental procedure of CDM146 and purified by HPLC to give 13mg of trifluoroacetate salt of CDN02 as the final product (purification conditions: 50% acetonitrile start, retention time: 15.0 min). ¹ H NMR(400MHz,MeOD-d ₄ ) 8.81(d, J ═ 4.96Hz,0.4H),8.75(d, J ═ 4.96Hz,0.6H),8.12(t, J ═ 7.81Hz,0.4H),8.02(t, J ═ 7.81Hz,0.6H),7.91(d, J ═ 7.89Hz,0.4H),7.84(d, J ═ 7.89Hz,0.6H),7.77-7.68(m,1H),7.67(s,1H),7.55(t, J ═ 6.38Hz,0.4H),7.47(t, J ═ 6.38Hz,0.6H),7.39-7.23(m,2H),6.98-6.85(m,1.6H),6.84-6.72 (t, J ═ 6.38Hz,0.6H), 3.39-7.23 (m,2H),6.98-6.85(m,1.6H), 6.84-6H), 6.72(m, 3.5-5.5H), 3.5-5 (m, 3.08H, 3.5-5H, 3.5-7.5 (m, 3.5H), 0.4H),3.28-3.17(m,0.4H),2.98-2.82(m,0.6H),2.68-2.41(m,1H),2.42-2.18(m,1H),2.08-1.93(m,1H),1.73-1.51(m,1H) ESI-MS theoretical calculation C ₂₇ H ₂₆ FN ₄ O ₂ [M+H] ⁺ 457.20; the test shows that: 457.22.

synthesis of the end product 200: 1- (3- (6- (2-fluoro-6-hydroxyphenyl) -2H-indazol-2-yl) pyrrol-1-yl) prop-2-en-1-one (CDN03).

Starting from CDM159(30mg), the title compound was synthesized according to the experimental procedure of CDM151 and purified by HPLC to give 21mg of trifluoroacetate salt of CDN03 as the final product (purification conditions: starting with 35% acetonitrile, retention time: 12.0 min). ¹ H NMR(400MHz,MeOD-d ₄ ) 8.26(s,1H),7.69(d, J ═ 8.69Hz,1H),7.63(s,1H),7.21-7.08(m,2H),6.77-6.53(m,3H),6.32(dd, J ═ 6.10,1.98Hz,0.6H),6.27(dd, J ═ 6.10,1.98Hz,0.4H),5.77(dd, J ═ 10.42,1.98Hz,0.6H),5.74(dd, J ═ 10.42,1.98Hz,0.4H),5.42-5.25(m,1H),4.26-4.17(m,0.4H),4.16-4.09(m,0.6H),4.09-4.03(m,1H), 3.91-6H), 3.7 (m, 3.79-7H), 3.79(m, 3.7H), 3.7-4.7 (m, 7H), 3.7 (mm, 3.7H), 3.7 (mm, 7H), 7 (mm, 7H), 3.7 (mm, 7H), 4 (mm, 7, 2, 7, 2, 7, 2, 7, 4, 7, 2, 4, 7, 4, 7, 2, 4, 2, 4, 2, 4, 2, 4, 2, 4, 2, 4, 3, 2, 4, 2, etc. and the calculated values of which are included in terms of the same ₂₀ H ₁₉ FN ₃ O ₂ [M+H] ⁺ 352.14; the experiment shows that: 352.03.

synthesis of end product 201: 1- (3- (6- (2-fluoro-6-hydroxyphenyl) -2H-indazol-2-yl) azetidin-1-yl) propan-2-en-1-one (CDN06).

Starting from CDM146(34mg), the title compound was synthesized according to the experimental procedure of CDM151 and purified by HPLC to give 19mg of the trifluoroacetate salt of CDN06 as the final product (purification conditions: starting with 35% acetonitrile, retention time: 12.0 min). ¹ H NMR(400MHz,MeOD-d ₄ ) 8.32(s,1H),7.75-7.63(m,2H),7.21-7.07(m,2H),6.74(dd, J ═ 8.26,1.17Hz,1H),6.71-6.60(m,1H),6.46-6.27(m,2H),5.79(dd, J ═ 9.82,2.44Hz,1H),5.67-5.52(m,1H),4.96-4.85(m,2H),4.70-4.53(m,2H), ESI-MS theoretical calculation C ₁₉ H ₁₇ FN ₃ O ₂ [M+H] ⁺ 338.12; the experiment shows that: 338.20.

synthesis of the final product 202: 1- (3- (5- (2-fluoro-6-methoxyphenyl) -2H-indazol-2-yl) pyrrol-1-yl) prop-2-en-1-one (CDN08).

Step 1: synthesis of tert-butyl 3- (5-bromo-2H-indazol-2-yl) pyrrole-1-carboxylate (CDN01).

Starting with 5-bromo-2-nitro-benzaldehyde (1.00g,4.35mmol) and tert-butyl 3-aminopyrrole-1-carboxylate (1.20g,6.52mmol), the title compound CDN01(1.30g) was synthesized according to the experimental procedure for CDM 142. ¹ H NMR(400MHz,Chloroform-d):7.89(s,1H),7.79(d,J＝1.84Hz,1H),7.57(d,J＝9.15Hz,1H),7.33(dd,J＝9.15,1.84Hz,1H),5.22-5.07(m,1H),4.04-3.77(m,2H),3.77-3.50(m,2H),2.59-2.45(m,2H),1.47(s,9H).

Step 2: synthesis of tert-butyl 3- (5- (2-fluoro-6-methoxyphenyl) -2H-indazol-2-yl) pyrrole-1-carboxylate (CDN05).

Starting with CDN01(552mg,1.51mmol) and 2-fluoro-6-methoxyphenylboronic acid (385mg,2.26mmol), with reference to CDM144 to obtain the target compound CDN05(562 mg). ¹ H NMR(400MHz,Chloroform-d):7.96(s,1H),7.76(d,J＝8.97Hz,1H),7.69(s,1H),7.37-7.23(m,2H),6.87-6.75(m,2H),5.21-5.09(m,1H),4.04-3.82(m,2H),3.78(s,3H),3.74-3.50(m,2H),2.60-2.43(m,2H),1.50(s,9H).

Starting from CDN05(140mg), the target compound was synthesized according to the experimental method of CDM146, and purified by HPLC to give 110mg of trifluoroacetate salt of CDN08 as a final product (purification conditions: 35% acetonitrile start, retention time: 17.0 min). ¹ H NMR(400MHz,MeOD-d ₄ ) 8.33-8.18(m,1H),7.69-7.54(m,2H),7.38-7.17(m,2H),6.88(d, J ═ 8.42Hz,1H),6.80(t, J ═ 8.71Hz,1H),6.70-6.54(m,1H),6.33(dd, J ═ 6.06,1.98Hz,0.6H),6.29(dd, J ═ 6.06,1.98Hz,0.4H),5.78(dd, J ═ 10.61,1.98Hz,0.6H),5.74(dd, J ═ 10.61,1.98Hz,0.4H),5.41-5.28(m,1H),4.27-4.18(m,0.4H), 4.17-4.92 (m, 4.91H), 3.79(m, 3.79H), 3.9-5.9 (m, 3.9H), 3.9-3.79 (m, 3.9H), 3.9 (m-3.9H), 3.9 (m-9H), 3.9H, 3.9 (m,1H), 3.9, 1H, 3.9, 1H, 3.9, 3, 3.9, 1H, 3.9, 3, 3.9, etc ₂₁ H ₂₁ FN ₃ O ₂ [M+H] ⁺ 366.15; the experiment shows that: 366.08.

synthesis of end product 203: 1- (3- (5- (2-fluoro-6-hydroxyphenyl) -2H-indazol-2-yl) pyrrol-1-yl) prop-2-en-1-one (CDN09).

Starting from CDN08(23mg), the target compound was synthesized according to the experimental method of CDM151, and purified by HPLC to give 18mg of trifluoroacetate salt of CDN09 as a final product (purification conditions: 35% acetonitrile start, retention time: 12.0 min). ¹ H NMR(400MHz,MeOD-d ₄ ) 8.09-7.93(m,1H),7.72-7.51(m,2H),7.42-7.23(m,1H),7.16-6.95(m,1H),6.73-6.64(m,1H),6.64-6.53(m,1H),6.52-6.35(m,1H),6.34-6.21(m,1H),5.83-5.55(m,1H),5.35-5.08(m,1H),4.19-3.96(m,2H),3.96-3.59(m,2H),2.67-2.39(m,2H), ESI-MS theoretical calculation value C ₂₀ H ₁₉ FN ₃ O ₂ [M+H] ⁺ 352.14; the experiment shows that: 352.08.

synthesis of the final product 204: 1- (3- (5- (2-fluoro-6-methoxyphenyl) -3- (pyridin-3-ylamino) -2H-indazol-2-yl) piperidin-1-yl) prop-2-en-1-one (CDN13).

Step 1: synthesis of tert-butyl 3- (5- (2-fluoro-6-methoxyphenyl) -3- (pyridin-3-ylamino) -2H-indazol-2-yl) piperidine-1-carboxylate (CDN07).

Starting from WHF47(200mg,0.40mmol) and 3-aminopyridine (112mg,1.20mmol), a mixture (56mg) containing the target compound CDN07 was synthesized according to the experimental procedure of WHF49 and subjected to preliminary purification on a silica gel column to be used in the next step.

Step 2: synthesis of 1- (3- (5- (2-fluoro-6-methoxyphenyl) -3- (pyridin-3-ylamino) -2H-indazol-2-yl) piperidin-1-yl) prop-2-en-1-one (CDN13).

Starting from a mixture containing CDN07 (56mg), the target compound was synthesized according to the experimental method of CDM146, and purified by HPLC to give 25mg of trifluoroacetate salt of CDN13 as an end product (purification conditions: 35% acetonitrile start, retention time: 8.0 min). ¹ H NMR(400MHz,MeOD-d ₄ ) 8.31-8.10(m,2H),7.93-7.73(m,2H),7.68(d, J-8.76 Hz,1H),7.41-7.18(m,3H),6.88(d, J-8.43 Hz,1H),6.84-6.71(m,1.7H),6.70-6.56(m,0.3H),6.19(d, J-16.75 Hz,0.7H),6.12(d, J-16.75 Hz,0.3H),5.77(d, J-10.56 Hz,0.7H),5.60(d, J-10.56 Hz,0.3H),4.78-4.57(m,1.7H),4.57-4.45(m,0.3H), 4.38-4.38 (m, 3.3H), 3.3-3.78-4.57 (m,3H), 3.3.3H), 3-3.9 (m, 3.9-3.9H), 3.3.7H), 3.9 (m, 3.9-3H), 3.3.9 (m,3H), 3.9-4.9 (m-4.9, 3H), 3.9 (m-3H), 3.9-3.9 (m-3H), 3.9.9, 3.9 (m-3.9, 3H), 3.9 (m-3H), 3.9, 3H), 3.9 (m-4.9H), 3.3.9, 3.9, 3H), 3.9, 3H), 3.9 (m-4.9, 3.9, 3.3.3.3.3.3.9, 3H), 3.9, 3H), 3.9 (m-3H), 3.9 (m-3H), 3.9, 3H), 3.9 (m-3.9, 3H), 3.9, 3H), 3.9, 3H), 3.9, 3H, 3.9, 3.9.9, 3.9 (m-3H), 3.9, 3H), 3H, 3.9, 3H), 3H), 3H, 3.9, 3H, 3.9, 3H, 3., 1H) theoretical calculation of C for ESI-MS, 2.14-1.92(m,1H),1.77-1.54(m,1H) ₂₇ H ₂₇ FN ₅ O ₂ [M+H] ⁺ 472.20; the experiment shows that: 472.15.

synthesis of the final product 205: 1- (3- (5- (2-fluoro-6-methoxyphenyl) -3-phenyl-2H-indazol-2-yl) piperidin-1-yl) prop-2-en-1-one (CDN16).

Step 1: synthesis of tert-butyl 3- (5- (2-fluoro-6-methoxyphenyl) -3-phenyl-2H-indazol-2-yl) piperidine-1-carboxylate (CDN14).

CDN14(60mg) as a target compound was synthesized by an experimental method with reference to CDM144, starting from WHF47(68mg,0.13mmol) and phenylboronic acid (33mg,0.27 mmol). ¹ H NMR(400MHz,Chloroform-d)δ7.81(d,J＝8.93Hz,1H),7.68-7.47(m,6H),7.43-7.34(m,1H),7.32-7.21(m,1H),6.86-6.74(m,2H),4.62-4.49(m,1H),4.33-4.02(m,2H),3.79(s,3H),3.60-3.48(m,1H),2.95-2.75(m,1H),2.65-2.44(m,1H),2.23-2.09(m,1H),1.95-1.77(m,2H),1.45(s,9H).

Step 2: synthesis of 1- (3- (5- (2-fluoro-6-methoxyphenyl) -3-phenyl-2H-indazol-2-yl) piperidin-1-yl) prop-2-en-1-one (CDN16).

Starting from CDN14(60mg), the target compound was synthesized according to the experimental method of CDM146, and purified by HPLC to give 39mg of trifluoroacetate salt of CDN16 as the final product (purification conditions: 50% acetonitrile start, retention time: 22.0 min). ¹ H NMR(400MHz,MeOD-d ₄ ) 7.66(s,0.4H),7.64(s,0.6H),7.61-7.47(m,5H),7.46-7.36(m,1H),7.35-7.22(m,2H),6.86(d, J ═ 8.41Hz,1H),6.82-6.68(m,1.6H),6.60-6.45(m,0.4H),6.19(d, J ═ 16.73Hz,0.6H),6.06(d, J ═ 16.73Hz,0.4H),5.74(d, J ═ 10.26Hz,0.6H),5.62(d, J ═ 10.26Hz,0.4H),4.87-4.78(m,0.6H),4.62-4.43(m, 1.92H), 4.34 (d, J ═ 4.26 Hz,0.4H), 3.19 (m, 3.19H), 3.3.19 (m, 3.3.19H), 3.3.3.19 (m, 3H), 3.3.7H, 3.7H), 3.7H, 3.19 (m, 3.7H), theoretical calculation values C of 2.29-2.11(m,1H),2.01-1.87(m,1H),1.62-1.42(m,1H). ESI-MS ₂₈ H ₂₇ FN ₃ O ₂ [M+H] ⁺ 456.20; the experiment shows that: 456.18.

synthesis of the final product 206: 1- (3- (5- (2-fluoro-6-hydroxyphenyl) -3-phenyl-2H-indazol-2-yl) piperidin-1-yl) prop-2-en-1-one (CDN21).

Starting from CDN16(38mg), the target compound was synthesized according to the experimental method of CDM151, and purified by HPLC to give 17mg of trifluoroacetate salt of CDN21 as a final product (purification conditions: 50% acetonitrile start, retention time: 13.0 min). ¹ H NMR(400MHz,MeOD-d ₄ ) 7.70(s,0.4H),7.67(s,0.6H),7.65-7.47(m,6H),7.45-7.37(m,1H),7.18-7.08(m,1H),6.84-6.70(m,1.6H),6.66(t, J-8.75 Hz,1H),6.61-6.48(m,0.4H),6.21(d, J-16.86, Hz,0.6H),6.08(d, J-16.86 Hz,0.4H),5.76(d, J-10.49 Hz,0.6H),5.64(d, J-10.49 Hz,0.4H),4.86-4.76(m,0.6H),4.68-4.45(m, 4.45H), 4.67 (m, 4.7H), 3.7-7 (m, 3.7H), 3.7-7.7H), 3.4H, 3.7 (m-3.7H), 3.7.7H), 3.4H, 3.7 (m-3.7H), 3.7H, 3.4H, 3.7 (m-3.7H), 1H) theoretical calculation of C2.05-1.87 (m,1H),1.68-1.44(m,1H). ESI-MS ₂₇ H ₂₅ FN ₃ O ₂ [M+H] ⁺ 442.19; the experiment shows that: 442.15.

synthesis of final product 207: 1- (3- (5- (2-fluoro-6-methoxyphenyl) -3- (phenylamino) -2H-indazol-2-yl) piperidin-1-yl) prop-2-en-1-one (CDN32).

Step 1: synthesis of tert-butyl 3- (5- (2-fluoro-6-methoxyphenyl) -3- (phenylamino) -2H-indazol-2-yl) piperidine-1-carboxylate (CDN23).

Starting from WHF47(300mg,0.60mmol) and aniline (168mg,1.80mmol), the synthesis was carried out according to the experimental procedure of WHF49, and a mixture (260mg) containing the target compound CDN23 was obtained by preliminary purification on silica gel column and used in the next step.

Step 2: synthesis of 1- (3- (5- (2-fluoro-6-methoxyphenyl) -3- (phenylamino) -2H-indazol-2-yl) piperidin-1-yl) prop-2-en-1-one (CDN32).

The target compound was synthesized from a mixture (260mg) containing CDN23 by the experimental method with reference to CDM146, and purified by HPLC to give 120mg of trifluoroacetate salt of CDN32 as an end product (purification conditions: 50% acetonitrile starting material)Beginning, retention time: 14.0 min). ¹ H NMR(400MHz,MeOD-d ₄ ) 7.64-7.37(m,2H),7.37-7.22(m,3H),7.22-6.89(m,4H),6.89-6.66(m,2.6H),6.58-6.40(m,0.4H),6.23(d, J ═ 16.62Hz,0.6H),6.12(d, J ═ 16.62Hz,0.4H),5.78(d, J ═ 10.61Hz,0.6H),5.59(d, J ═ 10.61Hz,0.4H),4.90-4.77(m,0.6H),4.75-4.62(m,1H),4.62-4.51(m,0.4H),4.38-4.26(m,0.4H),4.24-4.12(m, 3.70H), 3.35-4.35H, 3.35-6H, 3.3.3H, 3.3.6H), 3.3.3.5-4H, 3.6 m-4H, 3.6 m, 3.6H, 3, 3.6H, 3.6H, 3, 3.4H, 3, 3.6H, 3, 3.4, 3, 6, 3, 6, 3, 6, 3, 6, 3, 6, 3, 6, 3, 6, 3, 5, 3, 5, 3, 6, 2, 6, 2, 6, 3, 6, 3, 6, 5, 2, 6, 5, 6, 2, 5, 2, 1H) ESI-MS theoretical calculation value C ₂₅ H ₂₆ FN ₄ O[M+H] ⁺ 417.20; the experiment shows that: 417.23.

synthesis of the final product 208: 1- (4- (2-ethyl-6- (2-fluoro-6-methoxyphenyl) -2H-indazol-3-yl) piperazin-1-yl) prop-2-en-1-one (CDN35).

Step 1: synthesis of 6-bromo-2-ethyl-2H-indazole (CDN26).

Starting with 4-bromo-2-nitro-benzaldehyde (2.00g,8.70mmol) and ethylamine in tetrahydrofuran (2M,5.20mL,10.40mmol), the title compound CDN26(2.44g) was synthesized according to the experimental procedure for CDM 142. ¹ H NMR(400MHz,Chloroform-d)δ7.87(s,1H),7.85-7.81(m,1H),7.48(d,J＝8.81Hz,1H),7.10(dd,J＝8.81,1.61Hz,1H),4.41(q,J＝7.33Hz,2H),1.59(t,J＝7.33Hz,3H).

And 2, step: synthesis of 2-ethyl-6- (2-fluoro-6-methoxyphenyl) -2H-indazole (CDN28).

CDN28(730mg) as a target compound was synthesized from CDN26(1.41g,6.26mmol) and 2-fluoro-6-methoxyphenylboronic acid (1.60g,9.40mmol) by the experimental method with reference to CDM 144. ¹ H NMR(400MHz,Chloroform-d):7.90-7.82(m,2H),7.70(d,J＝8.63Hz,1H),7.34-7.23(m,1H),7.17(d,J＝8.51,Hz,1H),6.85(t,J＝8.78Hz,1H),6.79(d,J＝8.37Hz,1H),4.42(q,J＝7.34Hz,2H),3.76(s,3H),1.60(t,J＝7.34Hz,3H).

And step 3: synthesis of 3-bromo-2-ethyl-6- (2-fluoro-6-methoxyphenyl) -2H-indazole (CDN30).

CDN28(687mg,2.54mmol) was dissolved in acetic anhydride (7.5mL) and acetic acid (1.5mL), N-bromosuccinimide (452mg,2.54mmol) was added, and the mixture was stirred at room temperature for 12 hours. After completion of the reaction, most of the solvent was removed by a rotary evaporator, and the reaction mixture was purified by a silica gel column to obtain CDN30(850 mg). ¹ H NMR(400MHz,Chloroform-d):7.78-7.73(m,1H),7.58(d,J＝8.67Hz,1H),7.35-7.27(m,1H),7.19(d,J＝8.55Hz,1H),6.88-6.78(m,2H),4.58(q,J＝7.21Hz,2H),3.80(s,3H),1.60(t,J＝7.21Hz,3H).

And 4, step 4: synthesis of tert-butyl 4- (2-ethyl-6- (2-fluoro-6-methoxyphenyl) -2H-indazol-3-yl) piperazine-1-carboxylate (CDN31).

The target compound CDN31(232mg) was synthesized using CDN30(300mg,0.86mmol) and piperazine-1-carboxylic acid tert-butyl ester (480mg,2.58mmol) as raw materials according to the experimental method of WHF 49. ¹ H NMR(400MHz,Chloroform-d):7.76(d,J＝8.70Hz,1H),7.71-7.67(m,1H),7.31-7.25(m,1H),7.04(d,J＝8.67,Hz,1H),6.88-6.77(m,2H),4.45(q,J＝7.28Hz,2H),3.80(s,3H),3.72-3.59(m,4H),3.31-3.21(m,4H),1.57(t,J＝7.28Hz,3H),1.54(s,9H).

And 5: synthesis of 1- (4- (2-ethyl-6- (2-fluoro-6-methoxyphenyl) -2H-indazol-3-yl) piperazin-1-yl) prop-2-en-1-one (CDN35).

Starting from CDN31(195mg), the target compound was synthesized according to the experimental method of CDM146, and purified by HPLC to give 33mg of trifluoroacetate salt of CDN35 as the final product (purification conditions: 40% acetonitrile start, retention time: 13.0 min). ¹ H NMR(400MHz,MeOD-d ₄ ) 7.89(dd, J ═ 8.73,0.90Hz,1H),7.54-7.44(m,1H),7.40-7.31(m,1H),7.09(t, J ═ 8.87Hz,1H),6.96-6.78(m,3H),6.28(dd, J ═ 16.79,1.96Hz,1H),5.81(dd, J ═ 10.63,1.96Hz,1H),4.49(q, J ═ 7.29Hz,2H),3.97-3.86(m,4H),3.49-3.39(m,4H),1.58(t, J ═ 7.29Hz,3H), ESI-MS theoretical calculation value C ₂₃ H ₂₆ FN ₄ O ₂ [M+H] ⁺ 409.19; the experiment shows that: 409.15.

synthesis of end product 209: 1- (3- (5- (2-fluoro-6-hydroxyphenyl) -3- (phenylamino) -2H-indazol-2-yl) piperidin-1-yl) prop-2-en-1-one (CDN39).

Starting from CDN32(98mg), the target compound was synthesized according to the experimental method of CDM151, and purified by HPLC to give 69mg of trifluoroacetate salt of CDN39 as a final product (purification conditions: 45% acetonitrile start, retention time: 12.0 min). ¹ H NMR(400MHz,MeOD-d ₄ ) 7.62-7.44(m,2H),7.39-7.15(m,3H),7.15-6.87(m,4H),6.85-6.74(m,0.6H),6.68(d, J ═ 8.28Hz,1H),6.60(t, J ═ 9.03Hz,1H),6.55-6.42(m,0.4H),6.23(d, J ═ 16.68Hz,0.6H),6.11(d, J ═ 16.68Hz,0.4H),5.78(d, J ═ 10.36Hz,0.6H),5.58(d, J ═ 10.36Hz,0.4H),4.88-4.78(m,0.6H),4.74-4.62(m,1H),4.63-4.53(m, 4.53, 4.3H), 4.3-3H, 3.3H, 3m, 3H, 3.3H, 3H, 3.7 (m,3H), 3.7-6H, 3.7H, 3H, 3.7H, 3H, 7H, 3H, 7H, 3H, 7H, 3H, 7H, 3H, 7H, 3H, 7H, 6H, 7H, 6H, 7H, 6H, theoretical calculation value C of ESI-MS of 2.10-1.92(m,1H),1.77-1.54(m,1H) ₂₇ H ₂₆ FN ₄ O ₂ [M+H] ⁺ 457.20; the experiment shows that: 457.15.

synthesis of the final product 210: 1- (4- (2-ethyl-6- (2-fluoro-6-hydroxyphenyl) -2H-indazol-3-yl) piperazin-1-yl) prop-2-en-1-one (CDN40).

Starting from CDN35(43mg), the target compound was synthesized according to the experimental method of CDM151, and purified by HPLC to give 9mg of trifluoroacetate salt of CDN40 as a final product (purification conditions: 35% acetonitrile start, retention time: 11.0 min). ¹ H NMR(400MHz,MeOD-d ₄ ) 7.86(d, J ═ 8.82Hz,1H),7.55(s,1H),7.23-7.14(m,1H),7.12(d, J ═ 8.77Hz,1H),6.94-6.82(m,1H),6.75(d, J ═ 8.26Hz,1H),6.69(t, J ═ 8.94Hz,1H),6.30(dd, J ═ 16.76,1.96Hz,1H),5.83(dd, J ═ 10.61,1.96Hz,1H),4.51(q, J ═ 7.27Hz,2H), 4.02-3.85 (m,4H),3.53-3.37(m,4H),1.59(t, J ═ 7.25, 3H), theoretical calculated values of C-C ₂₂ H ₂₄ FN ₄ O ₂ [M+H] ⁺ 395.18; the experiment shows that: 395.25.

synthesis of the final product 211: 1- (4- (2-ethyl-6- (4-fluorophenyl) -2H-indazol-3-yl) piperazin-1-yl) prop-2-en-1-one (CDN53).

Step 1: synthesis of 2-ethyl-6- (4-fluorophenyl) -2H-indazole (CDN45).

Starting with CDN26(300mg,1.33mmol) and 4-fluorobenzeneboronic acid (373mg,2.66mmol), the title compound CDN45(126mg) was synthesized according to the CDM144 protocol. ¹ H NMR(400MHz,Chloroform-d):7.95-7.90(m,1H),7.87-7.83(m,1H),7.70(d,J＝8.68Hz,1H),7.65-7.58(m,2H),7.30(dd,J＝8.67,1.48Hz,1H),7.18-7.10(m,2H),4.48(q,J＝7.35Hz,2H),1.65(t,J＝7.34Hz,3H).

Step 2: synthesis of 3-bromo-2-ethyl-6- (4-fluorophenyl) -2H-indazole (CDN48).

The target compound CDN49(164mg) was synthesized using CDN45(148mg,0.61mmol) as a starting material according to the experimental method for CDN 30. ¹ H NMR(400MHz,Chloroform-d):7.83-7.77(m,1H),7.64-7.57(m,2H),7.55(d,J＝8.76Hz,1H),7.33(dd,J＝8.78,1.46Hz,1H),7.18-7.09(m,2H),4.54(q,J＝7.27Hz,2H),1.58(t,J＝7.27Hz,3H).

And step 3: synthesis of tert-butyl 4- (2-ethyl-6- (4-fluorophenyl) -2H-indazol-3-yl) piperazine-1-carboxylate (CDN51).

The target compound CDN51(93mg) was synthesized using CDN48(164mg,0.51mmol) and piperazine-1-carboxylic acid tert-butyl ester (287mg,1.54mmol) as starting materials according to the experimental method of WHF 49. ¹ H NMR(400MHz,Chloroform-d):7.79-7.72(m,2H),7.62-7.54(m,2H),7.22-7.16(m,1H),7.15-7.06(m,2H),4.41(q,J＝7.27Hz,2H),3.71-3.57(m,4H),3.31-3.14(m,4H),1.55(t,J＝7.28Hz,3H),1.51(s,9H).

And 4, step 4: synthesis of 1- (4- (2-ethyl-6- (4-fluorophenyl) -2H-indazol-3-yl) piperazin-1-yl) prop-2-en-1-one (CDN53).

Starting from CDN51(93mg,0.22mmol), the title compound was synthesized according to the experimental procedure of CDM146 and purified by HPLC to give 45mg of the trifluoroacetate salt of the end product CDN53 (purification conditions: 40% acetonitrile start, retention time: 14.0 min). ¹ H NMR(400MHz,MeOD-d ₄ ) 7.95(dd, J ═ 8.88,0.88Hz,1H),7.77-7.62(m,3H),7.40(dd, J ═ 8.84,1.53Hz,1H),7.25-7.11(m,2H),6.84(dd, J ═ 16.76,10.64Hz,1H),6.29(dd, J ═ 16.76,1.98Hz,1H),5.82(dd, J ═ 10.64,1.98, 1H),4.48(q, J ═ 7.28Hz,2H), 4.00-3.83 (m,4H), 3.55-3.34 (m,4H),1.59(t, J ═ 7.28Hz,3H), ESI-MS theoretical calculation value C ₂₂ H ₂₄ FN ₄ O[M+H] ⁺ 379.19; the experiment shows that: 379.22.

synthesis of end product 212: 1- (4- (2-ethyl-6- (2-fluorophenyl) -2H-indazol-3-yl) piperazin-1-yl) prop-2-en-1-one (CDN54).

Step 1: synthesis of 2-ethyl-6- (2-fluorophenyl) -2H-indazole (CDN47).

Starting with CDN26(300mg,1.33mmol) and 2-fluorobenzeneboronic acid (373mg,2.66mmol), the title compound CDN47(126mg) was synthesized according to the CDM144 protocol. ¹ H NMR(400MHz,Chloroform-d):7.99-7.93(m,1H),7.93-7.88(m,1H),7.73(d,J＝8.69Hz,1H),7.55(td,J＝7.74,1.85Hz,1H),7.39-7.29(m,2H),7.29-7.15(m,2H),4.51(q,J＝7.34Hz,2H),1.67(t,J＝7.34Hz,3H).

Step 2: synthesis of 3-bromo-2-ethyl-6- (2-fluorophenyl) -2H-indazole (CDN49).

The target compound CDN49(150mg) was synthesized using CDN47(126mg,0.52mmol) as a starting material according to the experimental method for CDN 30. ¹ H NMR(400MHz,Chloroform-d):7.9-7.83(m,1H),7.59(d,J＝8.70Hz,1H),7.53(td,J＝7.72,1.85Hz,1H),7.40-7.31(m,2H),7.29-7.15(m,2H),4.57(q,J＝7.27Hz,2H),1.61(t,J＝7.27Hz,4H).

And step 3: synthesis of 4- (2-ethyl-6- (2-fluorophenyl) -2H-indazol-3-yl) piperazine-1-carboxylic acid tert-butyl ester (CDN52).

The target compound CDN52(80mg) was synthesized using CDN49(150mg,0.47mmol) and piperazine-1-carboxylic acid tert-butyl ester (262mg,1.41mmol) as raw materials according to the experimental method of WHF 49. ¹ H NMR(400MHz,Chloroform-d):7.79-7.73(m,2H),7.48(td,J＝7.72,1.84Hz,1H),7.34-7.27(m,1H),7.24-7.11(m,3H),4.42(q,J＝7.21Hz,2H),3.74-3.54(m,4H),3.31-3.04(m,4H),1.54(t,J＝7.23Hz,3H),1.51(s,9H).

And 4, step 4: synthesis of 1- (4- (2-ethyl-6- (2-fluorophenyl) -2H-indazol-3-yl) piperazin-1-yl) prop-2-en-1-one (CDN54).

Starting from CDN52(80mg,0.19mmol), the title compound was synthesized according to the experimental procedure of CDM146 and purified by HPLC to yield 43mg of the trifluoroacetate salt of the end product CDN54 (purification conditions: 40% acetonitrile start, retention time: 13.5 min). ¹ H NMR(400MHz,MeOD-d ₄ ) 7.94(d, J-8.78 Hz,1H),7.76-7.61(m,1H),7.53(td, J-7.80, 1.75Hz,1H),7.40(td, J-7.27, 4.98Hz,1H),7.33-7.25(m,2H),7.24-7.17(m,1H),6.84(dd, J-16.77, 10.62Hz,1H),6.28(dd, J-16.77, 1.97Hz,1H),5.81(dd, J-10.63, 1.99Hz,1H),4.49(q, J-7.28 Hz,2H),4.02-3.78(m,5H),3.51-3.35(m,5H), 7.58 (theory, 27H), theoretical calculation of MS-27, 27H, 15H, 1H, 5H, and MS-7.58H ₂₂ H ₂₄ FN ₄ O[M+H] ⁺ 379.19; the experiment shows that: 379.13.

synthesis of the end product 213: 1- (4- (2-ethyl-6- (3-fluorophenyl) -2H-indazol-3-yl) piperazin-1-yl) prop-2-en-1-one (CDN57).

Step 1: synthesis of 2-ethyl-6- (3-fluorophenyl) -2H-indazole (CDN46) starting from CDN26(300mg,1.33mmol) and 3-fluorobenzeneboronic acid (373mg,2.66mmol), the title compound CDN46(109mg) was synthesized according to the experimental procedure for CDM 144. ¹ H NMR(400MHz,Chloroform-d):7.97-7.87(m,2H),7.72(d,J＝8.69Hz,1H),7.48-7.34(m,3H),7.32(dd,J＝8.68,1.53Hz,1H),7.11-6.99(m,1H),4.49(q,J＝7.33Hz,2H),1.65(t,J＝7.35Hz,3H).

Step 2: synthesis of 3-bromo-2-ethyl-6- (3-fluorophenyl) -2H-indazole (CDN50) starting from CDN46(109mg,0.45mmol), the title compound CDN50(136mg) was synthesized according to the experimental procedure for CDN 30. ¹ H NMR(400MHz,Chloroform-d):7.87-7.81(m,1H),7.56(d,J＝8.71Hz,1H),7.46-7.38(m,2H),7.38-7.31(m,2H),7.09-7.01(m,1H),4.54(q,J＝7.25Hz,2H),1.58(t,J＝7.27Hz,3H).

Step 3. Synthesis of tert-butyl 4- (2-ethyl-6- (3-fluorophenyl) -2H-indazol-3-yl) piperazine-1-carboxylate (CDN55). The objective compound CDN55(80mg) was obtained using CDN50(136mg,0.43mmol) and tert-butyl piperazine-1-carboxylate (262mg,1.4mmol) as starting materials, according to the experimental procedure of WHF 49. ¹ H NMR(400MHz,CDCl ₃ ):7.86-7.76(m,2H),7.48-7.31(m,3H),7.24(dd,J＝8.71,1.57Hz,1H),7.08-7.01(m,1H),4.44(q,J＝7.30Hz,2H),3.73-3.58(m,4H),3.33-3.18(m,4H),1.58(t,J＝7.24Hz,3H),1.54(s,9H).

And 4, step 4: 1- (4- (2-ethyl-6- (3-fluorophenyl) -2H-indazol-3-yl) piperazin-1-yl) prop-2-en-1-one (CDN57) was synthesized starting from CDN50(66mg,0.16mmol) according to the experimental procedure for CDM146 to give the title compound, which was purified by HPLC to give 38mg of the trifluoroacetate salt of the final product CDN57 (purification conditions: 40% acetonitrile start, retention time: 15.0 min). ¹ H NMR(400MHz,MeOD-d ₄ ) 7.95(dd, J ═ 8.89,0.89Hz,1H),7.81-7.65(m,1H),7.54-7.35(m,4H),7.20-7.01(m,1H),6.84(dd, J ═ 16.77,10.62Hz,1H),6.28(dd, J ═ 16.77,1.98Hz,1H),5.81(dd, J ═ 10.62,1.98Hz,1H),4.48(q, J ═ 7.30Hz,2H),4.04-3.76(m,4H),3.49-3.37(m,4H),1.58(t, J ═ 7.30Hz,3H), ESI-MS theoretical calculated value C ₂₂ H ₂₄ FN ₄ O[M+H] ⁺ 379.19; the experiment shows that: 379.21.

synthesis of end product 214: 1- (4- (2-ethyl-6- (4-methoxyphenyl) -2H-indazol-3-yl) piperazin-1-yl) prop-2-en-1-one (CDN68).

Step 1: synthesis of 2-ethyl-6- (4-methoxyphenyl) -2H-indazole (CDN44).

CDN44(350mg) as a target compound was synthesized by an experimental method with reference to CDM144, starting with CDN26(300mg,1.33mmol) and 4-methoxyphenylboronic acid (304mg,2.09 mmol). ¹ H NMR(400MHz,Chloroform-d):7.93-7.89(m,1H),7.88-7.84(m,1H),7.69(d,J＝8.71Hz,1H),7.65-7.59(m,2H),7.34(dd,J＝8.71,1.53Hz,1H),7.03-6.98(m,2H),4.47(q,J＝7.34Hz,2H),3.86(s,3H),1.64(t,J＝7.33Hz,3H).

Step 2: synthesis of 3-bromo-2-ethyl-6- (4-methoxyphenyl) -2H-indazole (CDN60).

The target compound CDN60(109mg) was synthesized using CDN44(350mg,1.39mmol) as a starting material according to the experimental method for CDN 30. ¹ H NMR(400MHz,Chloroform-d):8.08-8.02(m,1H),7.60(d,J＝8.47Hz,1H),7.48-7.40(m,2H),7.06(d,J＝8.47Hz,1H),7.02-6.97(m,2H),4.55(q,J＝7.34Hz,2H),3.87(s,3H),1.66(t,J＝7.36Hz,3H).

And step 3: synthesis of tert-butyl 4- (2-ethyl-6- (4-methoxyphenyl) -2H-indazol-3-yl) piperazine-1-carboxylate (CDN64).

The target compound CDN60(84mg) was synthesized using CDN60(109mg,0.33mmol) and piperazine-1-carboxylic acid tert-butyl ester (185mg,0.99mmol) as starting materials according to the experimental method of WHF 49. ¹ H NMR(400MHz,Chloroform-d):7.89(s,1H),7.48-7.40(m,2H),7.35(d,J＝8.53Hz,1H),7.04-6.91(m,3H),4.45(q,J＝7.32Hz,2H),3.87(s,3H),3.49-3.34(m,4H),3.32-3.11(m,4H),1.63(t,J＝7.31Hz,3H),1.47(s,9H).

And 4, step 4: synthesis of 1- (4- (2-ethyl-6- (4-methoxyphenyl) -2H-indazol-3-yl) piperazin-1-yl) prop-2-en-1-one (CDN68).

Starting from CDN64(84mg,0.19mmol), the title compound was synthesized according to the experimental procedure of CDM146 and purified by HPLC to give 54mg of the trifluoroacetate salt of the end product CDN68 (purification conditions: 40% acetonitrile start, retention time: 15.0 min). ¹ H NMR(400MHz,MeOD-d ₄ ) 8.22(s,1H),7.46(d, J ═ 8.55Hz,1H),7.38(d, J ═ 8.73Hz,2H),7.07-6.87(m,3H),6.74(dd, J ═ 16.77,10.63Hz,1H),6.21(dd, J ═ 16.77,2.03Hz,1H),5.74(dd, J ═ 10.63,2.03Hz,1H),4.49(q, J ═ 7.30Hz,2H),3.74-3.54(m,4H),3.40-3.26(m,4H),1.60(t, J ═ 7.30Hz,3H), ESI-MS theoretical calculation value C ₂₃ H ₂₇ N ₄ O ₂ [M+H] ⁺ 391.21; the experiment shows that: 391.27.

synthesis of final product 215: 1- (4- (2-ethyl-6- (3-methoxyphenyl) -2H-indazol-3-yl) piperazin-1-yl) prop-2-en-1-one (CDN69).

Step 1: synthesis of 2-ethyl-6- (3-methoxyphenyl) -2H-indazole (CDN43).

CDN43(320mg) as a target compound was synthesized by an experimental method with reference to CDM144, starting with CDN26(300mg,1.33mmol) and 3-methoxyphenylboronic acid (304mg,2.09 mmol). ¹ H NMR(400MHz,Chloroform-d):7.97-7.92(m,2H),7.73(d,J＝8.67Hz,1H),7.45-7.35(m,2H),7.34-7.28(m,1H),7.25(t,J＝2.11Hz,1H),6.98-6.90(m,1H),4.51(q,J＝7.34Hz,2H),3.90(s,3H),1.67(t,J＝7.34Hz,3H).

Step 2: synthesis of 3-bromo-2-ethyl-6- (3-methoxyphenyl) -2H-indazole (CDN59).

The target compound CDN59(356mg) was synthesized from CDN43(320mg,1.27mmol) as a starting material by an experimental method with reference to CDN 30. ¹ H NMR(400MHz,Chloroform-d):7.93-7.86(m,1H),7.61-7.54(m,1H),7.45-7.36(m,2H),7.31-7.25(m,1H),7.23(dd,J＝2.61,1.67Hz,1H),6.94(dd,J＝8.21,2.63Hz,1H),4.56(q,J＝7.30Hz,2H),3.89(s,3H),1.61(t,J＝7.31Hz,4H).

And step 3: synthesis of tert-butyl 4- (2-ethyl-6- (3-methoxyphenyl) -2H-indazol-3-yl) piperazine-1-carboxylate (CDN63).

The target compound CDN63(174mg) was synthesized using CDN59(356mg,1.08mmol) and piperazine-1-carboxylic acid tert-butyl ester (600mg,3.23mmol) as raw materials according to the experimental method of WHF 49. ¹ H NMR(400MHz,Chloroform-d):7.85-7.81(m,1H),7.77(d,J＝8.79Hz,1H),7.37(t,J＝7.90Hz,1H),7.30-7.23(m,2H),7.20(t,J＝2.10Hz,1H),6.91(dd,J＝8.21,2.57Hz,1H),4.44(q,J＝7.26Hz,2H),3.87(s,3H),3.71-3.58(m,4H),3.32-3.18(m,4H),1.57(t,J＝7.24Hz,3H),1.53(s,9H).

And 4, step 4: synthesis of 1- (4- (2-ethyl-6- (3-methoxyphenyl) -2H-indazol-3-yl) piperazin-1-yl) prop-2-en-1-one (CDN69).

Starting from CDN63(174mg,0.40mmol), the title compound was synthesized according to the experimental procedure of CDM146 and purified by HPLC to give 80mg of the trifluoroacetate salt of the end product CDN69 (purification conditions: 50% acetonitrile start, retention time: 8.5 min). ¹ H NMR(400MHz,MeOD-d ₄ ):7.91(dd,J＝8.82,0.87Hz,1H),7.71-7.63(m,1H),7.42-7.32(m,2H),7.26-7.20(m,1H),7.20-7.17(m,1H),6.98-6.90(m,1H),6.84(dd, J ═ 16.77,10.61Hz,1H),6.28(dd, J ═ 16.77,2.01Hz,1H),5.81(dd, J ═ 10.61,2.01Hz,1H),4.47(q, J ═ 7.28Hz,2H), 3.94-3.86 (m,4H),3.85(s,3H), 3.47-3.36 (m,4H),1.57(t, J ═ 7.28Hz,3H), ESI-MS theoretical calculation C ₂₃ H ₂₇ N ₄ O ₂ [M+H] ⁺ 391.21; the experiment shows that: 391.23.

synthesis of end product 216: 1- (4- (6- (2-fluoro-6-methoxyphenyl) -2-methyl-2H-indazol-3-yl) piperazin-1-yl) prop-2-en-1-one (CDN71).

Step 1: synthesis of 6-bromo-2-methyl-2H-indazole (CDN58).

Starting with 4-bromo-2-nitro-benzaldehyde (300mg,1.30mmol) and an alcoholic methylamine solution (30%, 230mg,1.96mmol), CDN58(305mg) was synthesized according to the experimental procedure of CDM 142. ¹ H NMR(400MHz,Chloroform-d):7.88–7.83(m,1H),7.79(s,1H),7.46(d,J＝8.89Hz,1H),7.11(dd,J＝8.81,1.66Hz,1H),4.12(s,3H).

Step 2: synthesis of 2-methyl-6- (2-fluoro-6-methoxyphenyl) -2H-indazole (CDN61).

CDN61(269mg) as a target compound was synthesized from CDN58(305mg,1.44mmol) and 2-fluoro-6-methoxyphenylboronic acid (490mg,2.88mmol) by the experimental method with reference to CDM 144. ¹ H NMR(400MHz,Chloroform-d):7.93-7.89(m,1H),7.79-7.75(m,1H),7.69(d,J＝8.60Hz,1H),7.34-7.26(m,1H),7.14(dt,J＝8.63,1.42Hz,1H),6.88-6.79(m,2H),4.25(s,3H),3.80(s,3H).

And step 3: synthesis of 3-bromo-2-methyl-6- (2-fluoro-6-methoxyphenyl) -2H-indazole (CDN65).

CDN61(269mg,1.05mmol) was dissolved in acetic anhydride (7.5mL) and acetic acid (1.5mL), N-bromosuccinimide (187mg,1.05mmol) was added, and the mixture was stirred at room temperature for 12 hours. After completion of the reaction, most of the solvent was removed by a rotary evaporator, and the reaction mixture was purified by a silica gel column to obtain CDN65(322 mg). ¹ H NMR(400MHz,Chloroform-d):7.79-7.74(m,1H),7.57(d,J＝8.68Hz,1H),7.34-7.26(m,1H),7.21(dt,J＝8.71,1.33Hz,1H),6.89-6.76(m,2H),4.20(s,3H),3.79(s,3H).

And 4, step 4: synthesis of tert-butyl 4- (2-methyl-6- (2-fluoro-6-methoxyphenyl) -2H-indazol-3-yl) piperazine-1-carboxylate (CDN67).

The target compound CDN 67-containing mixture 204mg was synthesized by taking CDN65(291mg,0.87mmol) and piperazine-1-carboxylic acid tert-butyl ester (485mg,2.61mmol) as raw materials according to the experimental method of WHF49 and subjected to preliminary purification by silica gel column and used for the next reaction.

And 5: synthesis of 1- (4- (6- (2-fluoro-6-methoxyphenyl) -2-methyl-2H-indazol-3-yl) piperazin-1-yl) prop-2-en-1-one (CDN71).

Starting from a mixture (200mg) containing CDN67, the target compound was synthesized according to the experimental method of CDM146, and purified by HPLC to give 21mg of trifluoroacetate salt of CDN71 as an end product (purification conditions: 40% acetonitrile start, retention time: 10.0 min). ¹ H NMR(400MHz,MeOD-d ₄ ) 7.93(d, J ═ 8.76Hz,1H),7.55-7.42(m,1H),7.42-7.29(m,1H),7.19-7.02(m,1H),6.93(d, J ═ 8.43Hz,1H),6.90-6.78(m,2H),6.28(dd, J ═ 16.75,1.95Hz,1H),5.82(dd, J ═ 10.63,1.95Hz,1H),4.11(s,3H),4.00-3.83(m,4H),3.77(s,3H),3.62-3.42(m,4H), ESI-MS theoretical calculated value C ₂₂ H ₂₄ FN ₄ O ₂ [M+H] ⁺ 395.18; the experiment shows that: 395.21.

synthesis of the final product 217: 1- (4- (2-ethyl-6- (2-methoxyphenyl) -2H-indazol-3-yl) piperazin-1-yl) prop-2-en-1-one (CDN72).

Step 1: synthesis of 2-ethyl-6- (2-methoxyphenyl) -2H-indazole (CDN42).

CDN42(388mg) as a target compound was synthesized by an experimental method with reference to CDM144, starting with CDN26(300mg,1.33mmol) and 2-methoxyphenylboronic acid (304mg,2.09 mmol). ¹ H NMR(400MHz,Chloroform-d):7.96-7.92(m,1H),7.88-7.85(m,1H),7.68(d,J＝8.68Hz,1H),7.43(dd,J＝7.43,1.76Hz,1H),7.39-7.33(m,1H),7.31(dd,J＝8.69,1.39Hz,1H),7.08(t,J＝7.41Hz,1H),7.03(d,J＝8.11Hz,1H),4.51(q,J＝7.32Hz,2H),3.84(s,3H),1.66(t,J＝7.33Hz,3H).

Step 2: synthesis of 3-bromo-2-ethyl-6- (2-methoxyphenyl) -2H-indazole (CDN62).

The target compound CDN62(383mg) was synthesized from CDN42(388mg,1.54mmol) by an experimental method with reference to CDN 30. ¹ H NMR(400MHz,Chloroform-d):7.83-7.81(m,1H),7.55(d,J＝8.76Hz,1H),7.42(dd,J＝7.47,1.74Hz,1H),7.37(dt,J＝8.67,1.18Hz,2H),7.08(t,J＝7.25Hz,1H),7.04(d,J＝8.28Hz,1H),4.58(q,J＝7.29Hz,2H),3.85(s,3H),1.60(t,J＝7.26Hz,3H).

And 3, step 3: synthesis of tert-butyl 4- (2-ethyl-6- (2-methoxyphenyl) -2H-indazol-3-yl) piperazine-1-carboxylate (CDN66).

The target compound CDN66(140mg) was synthesized using CDN62(380mg,1.14mmol) and piperazine-1-carboxylic acid tert-butyl ester (640mg,3.44mmol) as raw materials according to the experimental method of WHF 49. ¹ H NMR(400MHz,Chloroform-d):7.77-7.73(m,1H),7.71(d,J＝8.81Hz,1H),7.38(dd,J＝7.43,1.74Hz,1H),7.35-7.31(m,1H),7.19(dd,J＝8.72,1.40Hz,1H),7.03(td,J＝7.48,1.10Hz,1H),6.99(dd,J＝8.22,1.02Hz,1H),4.42(q,J＝7.27Hz,2H),3.81(s,3H),3.70-3.57(m,4H),3.29-3.15(m,4H),1.55(t,J＝7.24Hz,3H),1.52(s,9H).

And 4, step 4: synthesis of 1- (4- (2-ethyl-6- (2-methoxyphenyl) -2H-indazol-3-yl) piperazin-1-yl) prop-2-en-1-one (CDN72).

Starting from CDN66(140mg,0.32mmol), the title compound was synthesized according to the experimental procedure of CDM146 and purified by HPLC to give 72mg of the trifluoroacetate salt of the end product CDN72 (purification conditions: 45% acetonitrile start, retention time: 9.0 min). ¹ H NMR(400MHz,MeOD-d ₄ ) 7.90(dd, J ═ 8.82,0.88Hz,1H),7.67-7.56(m,1H),7.44-7.27(m,3H),7.10(dd, J ═ 8.34,1.05Hz,1H),7.07-7.00(m,1H),6.84(dd, J ═ 16.78,10.59Hz,1H),6.28(dd, J ═ 16.78,1.96Hz,1H),5.82(dd, J ═ 10.59,1.96Hz,1H),4.48(q, J ═ 7.29Hz,2H),4.06-3.85(m,4H),3.80(s,3H),3.58-3.38(m,4H),1.59(t, 7.29H), theoretical calculated values of C-29 Hz,1H), 3.58-3.38(m,4H),1.59(t ═ 7.29H), theoretical calculated values of C-29 Hz,1H), and C ₂₃ H ₂₇ N ₄ O ₂ [M+H] ⁺ 391.21; the experiment shows that: 391.24.

synthesis of the end product 218: 1- (4- (6- (2-fluoro-6-hydroxyphenyl) -2-methyl-2H-indazol-3-yl) piperazin-1-yl) prop-2-en-1-one (CDN74).

Starting from CDN71(20mg,0.05mmol), the title compound was synthesized according to the experimental procedure of CDM151 and purified by HPLC to give the final product CDN74 as trifluoroacetate salt at 7mg (purification conditions: 30% acetonitrile start, retention time: 10.5 min). ¹ H NMR(400MHz,MeOD-d ₄ ) 7.94(d, J ═ 8.82Hz,1H),7.54(s,1H),7.31-7.11(m,2H),6.84(dd, J ═ 16.81,10.61Hz,1H),6.75(d, J ═ 8.26Hz,1H),6.72-6.65(m,1H),6.28(dd, J ═ 16.75,1.96Hz,1H),5.81(dd, J ═ 10.62,1.96Hz,1H),4.09(s,3H),4.00-3.83(m,4H), 3.61-3.44 (m,4H), ESI-MS theoretical calculation value C ₂₁ H ₂₂ FN ₄ O ₂ [M+H] ⁺ 381.16; the experiment shows that: 381.09.

synthesis of end product 219: n- (4- (6- (2-fluoro-6-methoxyphenyl) -2-methyl-2H-indazol-3-yl) phenyl) acrylamide (CDN81).

Step 1: synthesis of tert-butyl (4- (6- (2-fluoro-6-methoxyphenyl) -2-methyl-2H-indazol-3-yl) phenyl) carbamate (CDN76).

Starting from CDN65(100mg,0.30mmol) and (4- ((tert-butoxycarbonyl) amino) phenyl) boronic acid (142mg,0.60mmol), the product was synthesized according to the experimental procedure of CDM144 and purified by silica gel column to give CDN76(146 mg). ¹ H NMR(400MHz,Chloroform-d):7.80-7.74(m,1H),7.66-7.56(m,3H),7.51-7.44(m,2H),7.33-7.24(m,1H),7.20(s,1H),7.13(d,J＝8.63-Hz,1H),6.88-6.77(m,2H),4.18(s,3H),3.79(s,3H),1.56(s,9H).

Step 2: synthesis of N- (4- (6- (2-fluoro-6-methoxyphenyl) -2-methyl-2H-indazol-3-yl) phenyl) acrylamide (CDN81).

Starting from CDN76(146mg,0.33mmol), the title compound was synthesized according to the experimental procedure of CDM146 and purified by HPLC to give the final product CDN81 as trifluoroacetate 70mg (purification conditions: 50% acetonitrile start, retention time: 13.0 min). ¹ H NMR(400MHz,MeOD-d ₄ ) 8.01-7.86(m,2H),7.68-7.59(m,3H),7.56(s,1H),7.40-7.28(m,1H),7.11(d, J ═ 8.82Hz,1H),6.92(dd, J ═ 8.49,1.12Hz,1H),6.82(t, J ═ 8.86Hz,1H),6.49(dd, J ═ 16.93,9.57Hz,1H),6.42(dd, J ═ 16.93,2.30Hz,1H),5.82(dd, J ═ 9.57,2.30Hz,1H),4.19(s,3H),3.77(s,3H), ESI-MS theoretical calculated value C ₂₄ H ₂₁ FN ₃ O ₂ [M+H] ⁺ 402.15; the experiment shows that: 402.21.

synthesis of the final product 220: n- (3- (6- (2-fluoro-6-methoxyphenyl) -2-methyl-2H-indazol-3-yl) phenyl) acrylamide (CDN82).

Step 1: synthesis of tert-butyl (3- (6- (2-fluoro-6-methoxyphenyl) -2-methyl-2H-indazol-3-yl) phenyl) carbamate (CDN80).

Starting from CDN65(100mg,0.30mmol) and (3- ((tert-butoxycarbonyl) amino) phenyl) boronic acid (142mg,0.60mmol), the product was synthesized according to the experimental procedure of CDM144 and purified by silica gel column to give CDN80(126 mg). ¹ H NMR(400MHz,Chloroform-d):7.80-7.75(m,1H),7.65(d,J＝8.69Hz,1H),7.62-7.58(m,1H),7.54-7.44(m,2H),7.34-7.25(m,1H),7.21(d,J＝7.09Hz,1H),7.13(d,J＝8.68Hz,1H),7.02(s,1H),6.87-6.78(m,2H),4.20(s,3H),3.79(s,3H),1.54(s,9H).

Step 2: synthesis of N- (4- (6- (2-fluoro-6-methoxyphenyl) -2-methyl-2H-indazol-3-yl) phenyl) acrylamide (CDN82).

Starting from CDN80(126mg,0.28mmol), the title compound was synthesized according to the experimental procedure of CDM146 and purified by HPLC to yield 105mg of trifluoroacetic acid as the final product CDN82 (purification conditions: 50% acetonitrile start, retention time: 14.0 min). ¹ H NMR(400MHz,MeOD-d ₄ ):8.08(s,1H),778-7.69(m,1H),7.65(d, J ═ 8.68Hz,1H),7.61-7.51(m,2H),7.43-7.27(m,2H),7.10(d, J ═ 8.66Hz,1H),6.91(dd, J ═ 8.45,1.07Hz,1H),6.81(t, J ═ 8.38Hz,1H),6.56-6.33(m,2H),5.80(dd, J ═ 9.55,2.26Hz,1H),4.20(s,3H),3.76(s,3H). ESI-MS theoretically calculated value C, 5.80(dd, J ═ 9.55,2.26Hz,1H),4.20(s,3H),3.76(s,3H) ₂₄ H ₂₁ FN ₃ O ₂ [M+H] ⁺ 402.15; the experiment shows that: 402.19.

synthesis of the final product 221: n- (3- (6- (2-fluoro-6-hydroxyphenyl) -2-methyl-2H-indazol-3-yl) phenyl) acrylamide (CDN83).

Starting from CDN82(70mg,0.17mmol), the title compound was synthesized according to the experimental procedure of CDM151 and purified by HPLC to give 51mg of the trifluoroacetate salt of the final product CDN83 (purification conditions: 50% acetonitrile start, retention time: 10.0 min). ¹ H NMR(400MHz,MeOD-d ₄ ) 8.06(s,1H),7.74-7.61(m,3H),7.48-7.24(m,2H),7.25-7.11(m,2H),6.75(d, J ═ 8.31Hz,1H),6.67(t, J ═ 9.48Hz,1H),6.45(dd, J ═ 16.97,9.54Hz,1H),6.38(dd, J ═ 16.97,2.34Hz,1H),5.79(dd, J ═ 9.54,2.34Hz,1H),4.17(s,3H), ESI-MS theoretical calculated value C ₂₃ H ₁₉ FN ₃ O ₂ [M+H] ⁺ 388.14; the test shows that: 388.17.

synthesis of the final product 222: n- (4- (6- (2-fluoro-6-hydroxyphenyl) -2-methyl-2H-indazol-3-yl) phenyl) acrylamide (CDN84).

Starting from CDN81(87mg,0.22mmol), the title compound was synthesized according to the experimental procedure of CDM151 and purified by HPLC to give 35mg of the trifluoroacetate salt of the end product CDN84 (purification conditions: 50% acetonitrile start, retention time: 9.0 min). ¹ H NMR(400MHz,MeOD-d ₄ ):7.98-7.87(m,2H),7.67-7.56(m,4H),7.22-7.12(m,2H),6.75(d,J＝8.32,0.94Hz,1H),6.68(t,J＝9.49,8.27,1.03Hz,1H),6.49(dd,J＝16.98,9.54Hz,1H),6.Theoretical calculation of C41 (dd, J ═ 16.98,2.32Hz,1H),5.82(dd, J ═ 9.54,2.32Hz,1H),4.17(s,3H) ₂₃ H ₁₉ FN ₃ O ₂ [M+H] ⁺ 388.14; the experiment shows that: 388.21.

synthesis of final product 223: 1- (5- (6- (2-fluoro-6-methoxyphenyl) -2-methyl-2H-indazol-3-yl) -3, 6-dihydropiperidin-1 (2H) -yl) prop-2-en-1-one (CDN86).

Step 1: synthesis of 5- (6- (2-fluoro-6-methoxyphenyl) -2-methyl-2H-indazol-3-yl) -3, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester (CDN77).

Starting from CDN65(150mg,0.45mmol) and tert-butyl 5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -3, 6-dihydropyridine-1 (2H) -carboxylate (208mg,0.67mmol), the title compound CDN77(212mg) was synthesized according to the experimental procedure for CDM144 and purified by a silica gel column. ¹ H NMR(400MHz,Chloroform-d):7.77-7.69(m,1H),7.65(d,J＝8.64Hz,1H),7.34-7.25(m,1H),7.12(d,J＝8.79Hz,1H),6.89-6.76(m,2H),6.19-6.07(m,1H),4.26(s,2H),4.17(s,3H),3.68(t,J＝5.77Hz,2H),2.53-2.37(m,2H),1.52(s,9H).

And 2, step: synthesis of 1- (5- (6- (2-fluoro-6-methoxyphenyl) -2-methyl-2H-indazol-3-yl) -3, 6-dihydropiperidin-1 (2H) -yl) prop-2-en-1-one (CDN86).

Starting from CDN77(70mg,0.16mmol), the title compound was synthesized according to the experimental procedure of CDM146 and purified by HPLC to give the final product CDN86 as trifluoroacetate 42mg (purification conditions: 45% acetonitrile start, retention time: 13.0 min). ¹ H NMR(400MHz,MeOD-d ₄ ) 7.76-7.59(m,1H),7.53(s,1H),7.40-7.29(m,1H),7.16-7.05(m,1H),6.97-6.72(m,3H),6.39-6.19(m,2H),5.92-5.70(m,1H),4.58-4.45(m,2H),4.22-4.12(m,3H),3.98-3.87(m,2H),3.77(s,3H),2.64-2.43(m,2H), ESI-MS theoretical calculation of C ₂₃ H ₂₃ FN ₃ O ₂ [M+H] ⁺ 392.17; the experiment shows that: 392.18.

synthesis of the final product 224: 1- (3- (6- (2-fluoro-6-methoxyphenyl) -2-methyl-2H-indazol-3-yl) piperidin-1-yl) prop-2-en-1-one (CDN87).

Step 1: synthesis of tert-butyl 3- (6- (2-fluoro-6-methoxyphenyl) -2-methyl-2H-indazol-3-yl) piperidine-1-carboxylate (CDN79).

CDN77(140mg,0.32mmol) was dissolved in 10mL of methanol, the air in the system was removed and nitrogen was purged, then palladium hydroxide (30mg) was added, and after purging again, hydrogen was purged and reacted overnight at room temperature. After removal of the solvent using a rotary evaporator, the mixture containing CDN79 as the objective compound (116mg) was primarily purified by silica gel column and used for the next reaction.

And 2, step: synthesis of 1- (3- (6- (2-fluoro-6-methoxyphenyl) -2-methyl-2H-indazol-3-yl) piperidin-1-yl) prop-2-en-1-one (CDN87).

Starting from a mixture containing CDN79 (116mg), the target compound was synthesized according to the experimental method of CDM146, and purified by HPLC to give 63mg of trifluoroacetate salt of CDN87 as an end product (purification conditions: 45% acetonitrile start, retention time: 12.0 min). ¹ H NMR(400MHz,MeOD-d ₄ ) 7.93(d, J ═ 8.90Hz,1H),7.52(s,1H),7.40-7.27(m,1H),7.08(d, J ═ 9.02Hz,1H),6.95-6.73(m,3H),6.32-6.17(m,1H),5.84-5.67(m,1H),4.80-4.64(m,1H),4.37-4.13(m,4H),3.76(s,3H),3.73-3.63(m,0.4H),3.47-3.27(m,1.6H),3.27-3.15(m,0.6H),2.95-2.82(m,0.4H),2.40-2.10(m,2H),2.03-1.89(m,1H),1.80 (m,1H), theoretical calculation values (m,1H), 1H), calculated values ₂₃ H ₂₅ FN ₃ O ₂ [M+H] ⁺ 394.19; the test shows that: 394.22.

synthesis of end product 225: 1- (5- (6- (2-fluoro-6-hydroxyphenyl) -2-methyl-2H-indazol-3-yl) -3, 6-dihydropiperidin-1 (2H) -yl) prop-2-en-1-one (CDN88).

CDN86(33mg,0.88mmol) as starting material, refExperimental method for CDM151 the title compound was synthesized and purified by HPLC to give 9mg of trifluoroacetate salt of the final product CDN88 (purification conditions: 40% acetonitrile start, retention time: 11.0 min). ¹ H NMR(400MHz,MeOD-d ₄ ) 7.79-7.61(m,1H),7.59(s,1H),7.24-7.11(m,2H),6.96-6.78(m,1H),6.78-6.62(m,2H),6.42-6.21(m,2H),5.89-5.74(m,1H),4.61-4.44(m,2H),4.26-4.12(m,3H),3.99-3.88(m,2H),2.66-2.47(m,2H), ESI-MS theoretical calculation value C ₂₂ H ₂₁ FN ₃ O ₂ [M+H] ⁺ 378.15; the experiment shows that: 378.20.

synthesis of the final product 226: 1- (3- (6- (2-fluoro-6-methoxyphenyl) -2-methyl-2H-indazol-3-yl) -2, 5-dihydro-1H-pyrrol-1-yl) prop-2-en-1-one (CDN90).

Step 1: synthesis of 3- (6- (2-fluoro-6-methoxyphenyl) -2-methyl-2H-indazol-3-yl) -2, 5-dihydro-1H-pyrrole-1-carboxylic acid tert-butyl ester (CDN78).

Starting from CDN65(150mg,0.45mmol) and 3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -2, 5-dihydro-1H-pyrrole-1-carboxylic acid tert-butyl ester (198mg,0.67mmol), the title compound CDN78(208mg) was synthesized according to the experimental procedure for CDM144 and purified by a silica gel column. ¹ H NMR(400MHz,Chloroform-d):7.76-7.72(m,1H),7.72-7.63(m,1H),7.35-7.23(m,1H),7.20-7.11(m,1H),6.88-6.76(m,2H),6.18-6.08(m,1H),4.82-4.63(m,2H),4.50-4.34(m,2H),4.23(s,3H),3.78(s,3H),1.54(s,9H).

Step 2: synthesis of 1- (3- (6- (2-fluoro-6-methoxyphenyl) -2-methyl-2H-indazol-3-yl) -2, 5-dihydro-1H-pyrrol-1-yl) prop-2-en-1-one (CDN90).

Starting from CDN78(70mg,0.16mmol), the title compound was synthesized according to the experimental procedure of CDM146 and purified by HPLC to give the final product CDN90 as trifluoroacetate salt at 18mg (purification conditions: 40% acetonitrile start, retention time: 16.0 min). ¹ H NMR(400MHz,MeOD-d ₄ ):7.83-7.71(m,1H),7.59-7.47(m,1H),7.41-7.29(m,1H),7.11(dd,J＝8.74,1.26Hz,1H),6.93(d,J8.40Hz,1H),6.87-6.78(m,1H),6.78-6.64(m,1H),6.47-6.35(m,2H),5.90-5.79(m,1H),5.05-5.10(m,1H),4.95-4.91(m,1H),4.78-4.69(m,1H),4.61-4.55(m,1H),4.27(s,3H),3.78(s,3H), ESI-MS theoretical calculation C ₂₂ H ₂₁ FN ₃ O ₂ [M+H] ⁺ 378.15; the experiment shows that: 378.22.

synthesis of the end product 227: 1- (3- (6- (2-fluoro-6-methoxyphenyl) -2-methyl-2H-indazol-3-yl) pyrrolidin-1-yl) prop-2-en-1-one (CDN91).

Step 1: synthesis of tert-butyl 3- (6- (2-fluoro-6-methoxyphenyl) -2-methyl-2H-indazol-3-yl) pyrrolidine-1-carboxylate (CDN85).

CDN78(140mg,0.33mmol) was dissolved in 10mL of methanol, the air in the system was removed and nitrogen was purged, palladium hydroxide (60mg) was added, followed by purging again and hydrogen purging, and the reaction was allowed to proceed overnight at room temperature. After removal of the solvent using a rotary evaporator, purification by silica gel column gave the target compound CDN85(88 mg). ¹ HNMR(400MHz,Chloroform-d):7.74-7.69(m,1H),7.66(d,J＝8.80Hz,1H),7.33-7.24(m,1H),7.07(d,J＝8.75Hz,1H),6.87-6.76(m,2H),4.18(s,3H),3.97-3.82(m,3H),3.79(s,3H),3.73-3.59(m,1H),3.58-3.45(m,1H),2.48-2.28(m,2H),1.52(s,9H).

And 2, step: synthesis of 1- (3- (6- (2-fluoro-6-methoxyphenyl) -2-methyl-2H-indazol-3-yl) pyrrolidin-1-yl) prop-2-en-1-one (CDN91).

Starting from CDN85(88mg,0.21mmol), the title compound was synthesized according to the experimental procedure of CDM146 and purified by HPLC to give 17mg of the trifluoroacetate salt of the end product CDN91 (purification conditions: 35% acetonitrile start, retention time: 15.5 min). ¹ H NMR(400MHz,MeOD-d ₄ ) 7.77-7.65(m,1H),7.54(s,1H),7.35(td, J is 8.41,6.58Hz,1H),7.06(dd, J is 8.80,1.44Hz,1H),6.93(d, J is 8.47Hz,1H),6.83(t, J is 8.72Hz,1H),6.75-6.61(m,1H),6.41-6.32(m,1H),5.85-5.76(m,1H),4.23(s,3H),4.21-3.97(m,3H),3.97-3.63(m,2H),3.78(s,3H),2.66-2.40(m,2H), ESI-MS theoretical calculation of C ₂₂ H ₂₃ FN ₃ O ₂ [M+H] ⁺ 380.17; the experiment shows that: 380.22.

synthesis of end product 228: 1- (3- (6- (2-fluoro-6-hydroxyphenyl) -2-methyl-2H-indazol-3-yl) -2, 5-dihydro-1H-pyrrol-1-yl) prop-2-en-1-one (CDN92).

Starting from CDN90(20mg,0.05mmol), the title compound was synthesized according to the experimental procedure of CDM151 and purified by HPLC to give 3mg of the trifluoroacetate salt of the end product CDN92 (purification conditions: 40% acetonitrile start, retention time: 10.0 min). ¹ H NMR(400MHz,DMSO-d ₆ ) 9.90(br,1H),7.93-7.67(m,1H),7.59-7.48(m,1H),7.28-7.13(m,1H),7.13-7.00(m,1H),6.86-6.62(m,3H),6.55-6.43(m,1H),6.25(dt, J ═ 16.74,2.29Hz,1H),5.80-5.74(m,1H),5.15-5.00(m,1H),4.89-4.77(m,1H),4.74-4.62(m,1H),4.53-4.39(m,1H),4.26(s,3H), ESI-MS theoretical calculation value C ₂₁ H ₁₉ FN ₃ O ₂ [M+H] ⁺ 364.14; the test shows that: 364.08.

synthesis of end product 229: 1- (3- (6- (2-fluoro-6-hydroxyphenyl) -2-methyl-2H-indazol-3-yl) pyrrolidin-1-yl) prop-2-en-1-one (CDN93).

Starting from CDN91(45mg,0.12mmol), the title compound was synthesized according to the experimental procedure of CDM151 and purified by HPLC to give 24mg of the trifluoroacetate salt of the end product CDN93 (purification conditions: 40% acetonitrile start, retention time: 10.0 min). ¹ H NMR(400MHz,MeOD-d ₄ ) 7.83-7.74(m,1H),7.65-7.60(m,1H),7.26-7.15(m,2H),6.81-6.64(m,3H),6.37(dd, J ═ 16.86,1.96Hz,1H),5.83(dd, J ═ 10.40,1.96Hz,1H),4.27(s,3H),4.25-3.64(m,4H),2.65-2.47(m,2H), ESI-MS theoretical calculation C ₂₁ H ₂₁ FN ₃ O ₂ [M+H] ⁺ 366.15; the experiment shows that: 366.09.

synthesis of final product 230: 1- (4- (2-ethyl-6- (4-hydroxyphenyl) -2H-indazol-3-yl) piperazin-1-yl) prop-2-en-1-one (CDN95).

Starting from CDN68(43mg,0.11mmol), the title compound was synthesized according to the experimental procedure of CDM151 and purified by HPLC to give 16mg of the trifluoroacetate salt of the end product CDN95 (purification conditions: 35% acetonitrile start, retention time: 12.0 min). ¹ H NMR(400MHz,MeOD-d ₄ ) 8.35(s,1H),7.58(d, J ═ 8.53Hz,1H),7.31(d, J ═ 8.58Hz,2H),7.00(d, J ═ 8.55Hz,1H),6.91(d, J ═ 8.58Hz,2H),6.79(dd, J ═ 16.82,10.62Hz,1H),6.26(dd, J ═ 16.82,1.97Hz,1H),5.79(dd, J ═ 10.62,1.97Hz,1H),4.54(q, J ═ 7.28Hz,2H),3.87-3.67(m,4H),3.64-3.44(m,4H),1.64(t, J ═ 7.28Hz,3H), theoretical calculated values of C-ESI (t, J ═ 7.28Hz,3H), and theoretical calculated values of C-C ₂₂ H ₂₅ N ₄ O ₂ [M+H] ⁺ 377.19; the test shows that: 377.25.

synthesis of end product 231: 1- (4- (2-ethyl-6- (3-hydroxyphenyl) -2H-indazol-3-yl) piperazin-1-yl) prop-2-en-1-one (CDN96).

Starting from CDN69(68mg,0.17mmol), the title compound was synthesized according to the experimental procedure of CDM151 and purified by HPLC to give the final product CDN96 as trifluoroacetate salt at 37mg (purification conditions: 30% acetonitrile start, retention time: 13.0 min). ¹ H NMR(400MHz,MeOD-d ₄ ) 7.86(d, J ═ 8.83Hz,1H),7.64(s,1H),7.33(d, J ═ 8.81Hz,1H),7.26(t, J ═ 7.87Hz,1H),7.13-7.08(m,1H),7.06(t, J ═ 2.07Hz,1H),6.87-6.76(m,2H),6.28(dd, J ═ 16.80,1.99Hz,1H),5.80(dd, J ═ 10.63,1.99Hz,1H),4.44(q, J ═ 7.25Hz,2H),3.94-3.77(m,4H),3.41-3.35(m,4H),1.56(t, J ═ 7.27, 3H), theoretical calculated values of C-C ₂₂ H ₂₅ N ₄ O ₂ [M+H] ⁺ 377.19; the experiment shows that: 377.22.

synthesis of end product 232: 1- (4- (2-ethyl-6- (2-hydroxyphenyl) -2H-indazol-3-yl) piperazin-1-yl) prop-2-en-1-one (CDN98).

Starting from CDN72(55mg, 0.14mmol), the title compound was synthesized according to the experimental procedure of CDM151 and purified by HPLC to give 19mg of the trifluoroacetate salt of the end product CDN98 (purification conditions: 30% acetonitrile start, retention time: 13.0 min). ¹ H NMR(400MHz,MeOD-d ₄ ) 7.89(d, J-8.85 Hz,1H),7.71(s,1H),7.42(dd, J-8.81, 1.36Hz,1H),7.32(dd, J-7.85, 1.71Hz,1H),7.20(td, J-7.71, 1.70Hz,1H),6.97-6.88(m,2H),6.83(dd, J-16.76, 10.61Hz,1H),6.28(dd, J-16.76, 1.96Hz,1H),5.81(dd, J-10.61, 1.96Hz,1H),4.47(q, J-7.28 Hz,2H),3.94-3.84(m,4H),3.51-3.40(m, 7.58H), theoretical calculation (MS, 26-26H), theoretical calculation values (C, 26H), and calculated values ₂₂ H ₂₅ N ₄ O ₂ [M+H] ⁺ 377.19; the test shows that: 377.23.

synthesis of the final product 233: n- (4- (6- (3-fluorophenyl) -2-methyl-2H-indazol-3-yl) phenyl) acrylamide (CDN102).

Step 1: synthesis of 2-methyl-6- (3-fluorophenyl) -2H-indazole (CDN97).

CDN58(2.10g,9.95mmol) and 3-fluorobenzeneboronic acid (2.10g,14.93mmol) were used as raw materials to synthesize the target compound CDN97(1.77g) according to the experimental method of CDM 144. ¹ H NMR(400MHz,Chloroform-d):8.05-8.00(m,1H),7.92-7.88(m,1H),7.71(d,J＝8.78Hz,1H),7.44-7.31(m,4H),7.09-7.01(m,1H),4.25(s,3H).

Step 2: synthesis of 3-bromo-2-methyl-6- (3-fluorophenyl) -2H-indazole (CDN99).

CDN97(1.77g,7.83mmol) was dissolved in acetic anhydride (7.5mL) and acetic acid (1.5mL), N-bromosuccinimide (1.40g,7.83mmol) was added, and the mixture was stirred at room temperature for 12 hours. After the reaction is finished, the reaction is carried outMost of the solvent was removed by rotary evaporator and purified by silica gel column to obtain CDN99(1.30g) as a target compound. ¹ H NMR(400MHz,Chloroform-d):7.85-7.82(m,1H),7.55(dd,J＝8.79Hz,1H),7.46-7.33(m,4H),7.10-7.03(m,1H),4.21(s,3H).

And step 3: synthesis of tert-butyl (4- (6- (3-fluorophenyl) -2-methyl-2H-indazol-3-yl) phenyl) carbamate (CDN100).

Starting from CDN99(80mg,0.26mmol) and (4- ((tert-butoxycarbonyl) amino) phenyl) boronic acid (125mg,0.53mmol), the reaction was synthesized according to the experimental procedure of CDM144 and was primarily purified by silica gel column to give a mixture (110mg) containing CDN100, which was used directly in the next reaction.

And 4, step 4: synthesis of N- (4- (6- (3-fluorophenyl) -2-methyl-2H-indazol-3-yl) phenyl) acrylamide (CDN102).

Starting from a mixture containing CDN100 (110mg), the target compound was synthesized according to the experimental method of CDM146, and purified by HPLC to obtain 30mg of trifluoroacetate salt of CDN102 as a final product (purification conditions: 50% acetonitrile start, retention time: 16.0 min). ¹ H NMR(400MHz,MeOD-d ₄ ) 7.91(d, J ═ 8.77Hz,2H),7.81-7.74(m,1H),7.64(d, J ═ 8.77Hz,1H),7.58(d, J ═ 8.77Hz,2H),7.50-7.34(m,4H),7.13-7.04(m,1H),6.49(dd, J ═ 16.97,9.48Hz,1H),6.41(dd, J ═ 16.97,2.34Hz,1H),5.82(dd, J ═ 9.48,2.34Hz,1H),4.16(s,3H), ESI-MS theoretical calculation value C ₂₃ H ₁₉ FN ₃ O[M+H] ⁺ 372.14; the test shows that: 372.16.

synthesis of the end product 234: n- (3- (6- (3-fluorophenyl) -2-methyl-2H-indazol-3-yl) phenyl) acrylamide (CDN103).

Step 1: synthesis of tert-butyl (3- (6- (3-fluorophenyl) -2-methyl-2H-indazol-3-yl) phenyl) carbamate (CDN101).

Starting from CDN99(80mg,0.26mmol) and (3- ((tert-butoxycarbonyl) amino) phenyl) boronic acid (125mg,0.53mmol), the reaction was synthesized according to the experimental procedure of CDM144 and was primarily purified by silica gel column to give a mixture (100mg) containing CDN101, which was used directly in the next reaction.

Step 2: synthesis of N- (3- (6- (3-fluorophenyl) -2-methyl-2H-indazol-3-yl) phenyl) acrylamide (CDN103).

Starting from a mixture containing CDN101 (100mg), the title compound was synthesized according to the experimental procedure of CDM146 and purified by HPLC to give 36mg of trifluoroacetate salt of CDN103 as the final product (purification conditions: 55% acetonitrile start, retention time: 14.0 min). ¹ H NMR(400MHz,MeOD-d ₄ ) 8.11-8.03(m,1H),7.83-7.75(m,1H),7.74-7.65(m,2H),7.56(t, J ═ 7.91Hz,1H),7.51-7.33(m,5H),7.12-7.04(m,1H),6.47(dd, J ═ 16.98,9.52Hz,1H),6.42(dd, J ═ 16.98,2.32Hz,1H),5.81(dd, J ═ 9.52,2.32Hz,1H),4.19(s,3H), ESI-MS theoretical calculated value C ₂₃ H ₁₉ FN ₃ O[M+H] ⁺ 372.14; the experiment shows that: 372.19.

synthesis of end product 235: 1- (5- (6- (3-fluorophenyl) -2-methyl-2H-indazol-3-yl) -3, 6-dihydropiperidin-1 (2H) -yl) prop-2-en-1-one (CDN106).

Step 1: synthesis of 5- (6- (3-fluorophenyl) -2-methyl-2H-indazol-3-yl) -3, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester (CDN104).

Starting from CDN99(200mg,0.60mmol) and tert-butyl 5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -3, 6-dihydropyridine-1 (2H) -carboxylate (275mg,0.90mmol), the mixture containing CDN104 (189mg) was synthesized according to the experimental procedure for CDM144 and was initially purified by silica gel column and used directly in the next reaction.

Step 2: synthesis of 1- (5- (6- (3-fluorophenyl) -2-methyl-2H-indazol-3-yl) -3, 6-dihydropiperidin-1 (2H) -yl) prop-2-en-1-one (CDN106).

Starting from a mixture containing CDN104 (40mg), the target compound was synthesized according to the experimental method of CDM146, and purified by HPLC to give 22mg of trifluoroacetate salt of CDN106 as an end product (purification conditions: 50% acetonitrile start, retention time: 13.0 min). ¹ H NMR(400MHz,MeOD-d ₄ ) 7.83-7.62(M,2H),7.52-7.31(M,4H),7.14-7.02(M,1H),6.82(M,1H),6.38-6.16(M,2H),5.81(dd, J ═ 10.65,1.62Hz,1H),4.58-4.40(M,2H),4.15(s,3H),3.90(t, J ═ 5.82Hz,2H),2.60-2.42(M,2H), ESI-MS theoretical calculation value C ₂₂ H ₂₁ FN ₃ O[M+H] ⁺ 362.16; the experiment shows that: 362.09.

synthesis of end product 236: 1- (4- (6- (3-fluorophenyl) -2-methyl-2H-indazol-3-yl) piperazin-1-yl) prop-2-en-1-one (CDN108).

Step 1: synthesis of 4- (6- (3-fluorophenyl) -2-methyl-2H-indazol-3-yl) piperazine-1-carboxylic acid tert-butyl ester (CDN105).

CDN99(150mg,0.45mmol) and piperazine-1-carboxylic acid tert-butyl ester (250mg,1.34mmol) were synthesized according to the experimental method of WHF49, and purified by a silica gel column to obtain CDN105(67mg) as a target compound. ¹ H NMR(400MHz,Chloroform-d):7.82-7.76(m,2H),7.46-7.33(m,3H),7.23(dd,J＝8.70,1.59Hz,1H),7.08-7.02(m,1H),4.08(s,3H),3.67(t,J＝4.97Hz,4H),3.27(t,J＝4.98Hz,4H),1.54(s,9H).

Step 2: synthesis of 1- (4- (6- (3-fluorophenyl) -2-methyl-2H-indazol-3-yl) piperazin-1-yl) prop-2-en-1-one (CDN108).

The target compound was synthesized starting from CDN105(40mg, 0.10mmol) according to the experimental method of CDM146, and purified by HPLC to give 20mg of trifluoroacetate salt of the final product CDN108 (purification conditions: 35% acetonitrile start, retention time: 15.0 min). ¹ H NMR(400MHz,MeOD-d ₄ ) 7.95(d, J ═ 8.81Hz,1H),7.72-7.68(m,1H),7.54-7.35(m,4H),7.16-7.05(m,1H),6.84(dd, J ═ 16.76,10.63Hz,1H),6.28(dd, J ═ 16.76,1.96Hz,1H),5.82(dd, J ═ 10.63,1.96Hz,1H),4.09(s,3H),3.95-3.85(m,4H),3.48-3.39(m,4H), ESI-MS theoretical calculated value C ₂₁ H ₂₂ FN ₄ O[M+H] ⁺ 365.17; the experiment shows that: 365.21.

synthesis of end product 237: 1- (3- (6- (3-fluorophenyl) -2-methyl-2H-indazol-3-yl) piperidin-1-yl) prop-2-en-1-one (CDN110).

Step 1: synthesis of tert-butyl 3- (6- (3-fluorophenyl) -2-methyl-2H-indazol-3-yl) piperidine-1-carboxylate (CDN107).

The mixture (120mg) containing CDN104 was dissolved in 10mL of methanol, air in the system was removed and nitrogen gas was purged, then palladium hydroxide (50mg) was added, purging was performed again, hydrogen gas was purged, and the reaction was performed overnight at room temperature. After removal of the solvent using a rotary evaporator, initial purification by silica gel column gave CDN 107-containing mixture (112mg) for next reaction.

Step 2: synthesis of 1- (3- (6- (3-fluorophenyl) -2-methyl-2H-indazol-3-yl) piperidin-1-yl) prop-2-en-1-one (CDN110).

Starting from a mixture containing CDN107 (110mg), the target compound was synthesized according to the experimental method of CDM146, and purified by HPLC to obtain 33mg of trifluoroacetate salt of the final product CDN110 (purification conditions: 45% acetonitrile start, retention time: 13.5 min). ¹ H NMR(400MHz,MeOD-d ₄ ) 7.97(d, J ═ 8.90Hz,1H),7.75(s,1H),7.50-7.32(m,4H),7.15-7.03(m,1H),6.9-6.73(m,1H),6.31-6.17(m,1H),5.76(dd, J ═ 10.48,1.50Hz,1H),4.77-4.66(m,1H),4.35-4.21(m,1H),4.19(s,3H),3.43-3.35(m,2H),3.17(t, J ═ 12.24Hz,1H),2.36-2.09(m,2H),2.03-1.85(m,1H),1.78-1.59(m,1H), ESI-theoretical calculation of C ₂₂ H ₂₃ FN ₃ O[M+H] ⁺ 364.17; the experiment shows that: 364.08.

synthesis of end product 238: 1- (3- (6- (3-fluorophenyl) -2-methyl-2H-indazol-3-yl) -2, 5-dihydro-1H-pyrrol-1-yl) prop-2-en-1-one (CDN112).

Step 1: synthesis of 3- (6- (3-fluorophenyl) -2-methyl-2H-indazol-3-yl) -2, 5-dihydro-1H-pyrrole-1-carboxylic acid tert-butyl ester (CDN109).

Starting from CDN99(200mg,0.66mmol) and 3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -2, 5-dihydro-1H-pyrrole-1-carboxylic acid tert-butyl ester (291mg,0.99mmol), the synthesis was carried out according to the experimental procedure for CDM144 and preliminary purification by silica gel column gave a mixture (230mg) containing CDN109 for the next reaction.

Step 2: synthesis of 1- (3- (6- (3-fluorophenyl) -2-methyl-2H-indazol-3-yl) -2, 5-dihydro-1H-pyrrol-1-yl) prop-2-en-1-one (CDN112).

Starting from a mixture containing CDN109 (53mg), the title compound was synthesized according to the experimental procedure of CDM146 and purified by HPLC to give 17mg of the trifluoroacetate salt of the final product CDN112 (purification conditions: 40% acetonitrile start, retention time: 17.5 min). ¹ H NMR(400MHz,MeOD-d ₄ ) 7.79-7.65(m,2H),7.50-7.31(m,4H),7.13-7.01(m,1H),6.59(dd, J ═ 16.80,10.36Hz,1H),6.40-6.27(m,2H),5.81(dt, J ═ 10.36,1.88Hz,1H),4.98-4.90(m,1H),4.82-4.71(m,1H),4.67-4.55(m,1H),4.53-4.44(m,1H),4.19(s,3H), ESI-MS theoretical calculation C ₂₁ H ₁₉ FN ₃ O[M+H] ⁺ 348.14; the experiment shows that: 348.06.

synthesis of the final product 239: 1- (3- (6- (3-fluorophenyl) -2-methyl-2H-indazol-3-yl) pyrrolidin-1-yl) prop-2-en-1-one (CDN115).

Step 1: synthesis of tert-butyl 3- (6- (3-fluorophenyl) -2-methyl-2H-indazol-3-yl) pyrrolidine-1-carboxylate (CDN111) A mixture (150mg) containing CDN109 was dissolved in 10mL of methanol, and the air in the system was removed and nitrogen gas was purged, followed by addition of palladium hydroxide (50mg), purging again, and hydrogen gas was purged, and the reaction was allowed to proceed at room temperature overnight. After removal of the solvent using a rotary evaporator, it was primarily purified by silica gel column to obtain a mixture (100mg) containing CDN111 for the next reaction.

Step 2: synthesis of 1- (3- (6- (3-fluorophenyl) -2-methyl-2H-indazol-3-yl) pyrrolidin-1-yl) prop-2-en-1-one (CDN115).

Starting with a mixture containing CDN111 (80mg), see example CDM146The target compound was synthesized by an empirical method and purified by HPLC to give 35mg of trifluoroacetate salt of the final product CDN115 (purification conditions: 40% acetonitrile start, retention time: 14.0 min). ¹ H NMR(400MHz,MeOD-d ₄ ) Calculated values of 7.81-7.67(m,2H),7.50-7.28(m,4H),7.11-7.02(m,1H),6.74-6.58(m,1H),6.37(dd, J ═ 6.50,2.00Hz,0.6H),6.33(dd, J ═ 6.50,2.00Hz,0.4H),5.81(dd, J ═ 10.42,2.00Hz,0.6H),5.77(dd, J ═ 10.42,2.00Hz,0.4H),4.21(s,1.8H),4.20(s,1.2H),4.18-3.75(m,4.6H),3.69-3.57(m,0.4H),2.59-2.37(m,2H), theoretical ESI, C-theoretical ₂₁ H ₂₁ FN ₃ O[M+H] ⁺ 350.16; the test shows that: 350.20.

synthesis of the end product 240: 1- (3- ((6- (3-fluorophenyl) -2-methyl-2H-indazol-3-yl) amino) azetidin-1-yl) prop-2-en-1-one (CDN116).

Step 1: synthesis of tert-butyl 3- ((6- (3-fluorophenyl) -2-methyl-2H-indazol-3-yl) amino) azetidine-1-carboxylate (CDN113).

The reaction was carried out using CDN99(150mg,0.49mmol) and tert-butyl 3-aminoazetidine-1-carboxylate (255mg,1.48mmol) as starting materials, according to the experimental procedure of WHF49, and was initially purified by silica gel column to give a mixture (55mg) containing CDN113, which was used for the next reaction.

Step 2: synthesis of 1- (3- ((6- (3-fluorophenyl) -2-methyl-2H-indazol-3-yl) amino) azetidin-1-yl) prop-2-en-1-one (CDN116).

Starting from a mixture containing CDN113 (55mg), the title compound was synthesized according to the experimental procedure of CDM146 and purified by HPLC to give the final product CDN116 as trifluoroacetate salt in an amount of 4mg (purification conditions: 40% acetonitrile start, retention time: 16.0 min). ¹ H NMR(400MHz,MeOD-d ₄ ):8.08(s,1H),7.58-7.43(m,1H),7.40-7.25(m,1H),7.24-7.18(m,1H),7.16(d,J＝8.54Hz,1H),7.13-7.04(m,1H),6.83(d,J＝8.52Hz,1H),6.27(dd,J＝17.00,9.92Hz,1H),6.23-6.13(m,1H),5.75-5.62(m,1H),4.78-4.67(m,1H),4.37-4.31(m,1H),4.21(s,3H),4.15-4.07(m,1H),4.06-398(m,1H),3.81-3.72(m,1H). ESI-MS theoretical calculation C ₂₀ H ₂₀ FN ₄ O[M+H] ⁺ 351.15; the experiment shows that: 351.20.

synthesis of end product 241: 1- (4- (6- (3-methoxyphenyl) -2-methyl-2H-indazol-3-yl) piperazin-1-yl) prop-2-en-1-one (CDN127).

Step 1: synthesis of 2-methyl-6- (3-methoxyphenyl) -2H-indazole (CDN120).

CDN120(243mg) as a target compound was synthesized by an experimental method with reference to CDM144, using CDN58(200mg,0.95mmol) and 3-methoxyphenylboronic acid (216mg,1.42mmol) as starting materials. ¹ H NMR(400MHz,Chloroform-d):8.00-7.95(m,1H),7.86(s,1H),7.72(d,J＝8.68Hz,1H),7.44-7.38(m,2H),7.33-7.28(m,1H),7.27-7.24(m,1H),6.95(dd,J＝8.17,2.62Hz,1H),4.21(s,3H),3.89(s,3H).

And 2, step: synthesis of 3-bromo-2-methyl-6- (3-methoxyphenyl) -2H-indazole (CDN121).

CDN120(230mg,0.97mmol) was dissolved in acetic anhydride (7.5mL) and acetic acid (1.5mL), N-bromosuccinimide (172mg,0.97mmol) was added, and the mixture was stirred at room temperature for 12 hours. After completion of the reaction, most of the solvent was removed by a rotary evaporator, and the reaction mixture was purified by a silica gel column to obtain CDN121(231mg) as a target compound. ¹ H NMR(400MHz,Chloroform-d):7.91-7.86(m,1H),7.55(d,J＝8.73Hz,1H),7.44-7.37(m,2H),7.28(d,J＝7.68,Hz,1H),7.25-7.22(m,1H),6.93(dd,J＝8.22,2.64Hz,1H),4.19(s,3H),3.89(s,3H).

And 3, step 3: synthesis of tert-butyl 4- (2-methyl-6- (3-methoxyphenyl) -2H-indazol-3-yl) piperazine-1-carboxylate (CDN122).

CDN122(131mg) was synthesized by an experimental method with reference to WHF49 using CDN121(200mg,0.63mmol) and piperazine-1-carboxylic acid tert-butyl ester (352mg,1.89mmol) as starting materials, and was purified by a silica gel column. ¹ H NMR(400MHz,Chloroform-d):7.84-7.77(m,2H),7.39(t,J＝7.93Hz,1H),7.31(dd,J＝8.73,1.54Hz,1H),7.28-7.23(m,1H),7.20(t,J＝2.10Hz,1H),6.93(dd,J＝8.26,2.61Hz,1H),4.11(s,3H),3.89(s,3H),3.68(t,J＝4.94Hz,4H),3.30(t,J＝4.96Hz,4H),1.54(s,9H).

And 4, step 4: synthesis of 1- (4- (6- (3-methoxyphenyl) -2-methyl-2H-indazol-3-yl) piperazin-1-yl) prop-2-en-1-one (CDN127).

Starting from CDN122(90mg,0.21mmol), the title compound was synthesized according to the experimental procedure of CDM146 and purified by HPLC to give 30mg of the trifluoroacetate salt of the end product CDN127 (purification conditions: 50% acetonitrile start, retention time: 6.0 min). ¹ H NMR(400MHz,MeOD-d ₄ ) δ 7.96(d, J ═ 8.83,0.86Hz,1H),7.70-7.64(m,1H),7.42(dd, J ═ 8.87,1.50Hz,1H),7.38(t, J ═ 7.97Hz,1H),7.28-7.22(m,1H),7.21-7.16(m,1H),7.01-6.92(m,1H),6.85(dd, J ═ 16.77,10.64Hz,1H),6.29(dd, J ═ 16.77,1.95Hz,1H),5.82(dd, J ═ 10.64,1.95Hz,1H),4.09(s,3H),3.95-3.88(m,4H),3.86(s,3H),3.54 (m, 3H), 3.54-3.54 (m,4H), theoretical ESI, 3.54, 4H), 3.70 (m,4H), 3.54, 4H), 4C, 1H, and calculated values ₂₂ H ₂₅ N ₄ O ₂ [M+H] ⁺ 377.19; the test shows that: 377.21.

synthesis of the end product 242: 1- (4- (6- (3-hydroxyphenyl) -2-methyl-2H-indazol-3-yl) piperazin-1-yl) prop-2-en-1-one (CDN129).

Starting from CDN127(30mg,0.08mmol), the title compound was synthesized according to the experimental procedure of CDM151 and purified by HPLC to give 16mg of the trifluoroacetate salt of the end product CDN129 (purification conditions: 30% acetonitrile start, retention time: 10.0 min). ¹ H NMR(400MHz,MeOD-d ₄ ) δ 7.91(d, J ═ 8.80Hz,1H),7.62(s,1H),7.37(d, J ═ 8.82Hz,1H),7.27(t, J ═ 7.86Hz,1H),7.16-7.09(m,1H),7.09-7.02(m,1H),6.89-6.76(m,2H),6.28(dd, J ═ 16.77,1.98Hz,1H),5.82(dd, J ═ 10.63,1.98Hz,1H),4.07(s,3H),3.95-3.82(m,4H),3.51-3.39(m,4H), ESI-MS theoretical calculation value C ₂₁ H ₂₃ N ₄ O ₂ [M+H] ⁺ 363.17; the experiment shows that: 363.20

Synthesis of end product 243: n- (4- (6- (3-fluorophenyl) -2-methyl-2H-indazol-3-yl) benzyl) acrylamide (CDN134).

Step 1: synthesis of tert-butyl (4- (6- (3-fluorophenyl) -2-methyl-2H-indazol-3-yl) benzyl) carbamate (CDN130).

Starting from CDN99(200mg,0.05mmol) and tert-butyl (4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzyl) carboxylate (98mg,0.80mmol), CDN130(80mg) was synthesized according to the experimental method for CDM144 and purified by a silica gel column. ¹ H NMR(400MHz,Chloroform-d):7.91-7.87(m,1H),7.64(d,J＝8.75Hz,1H),7.57-7.36(m,7H),7.34(dd,J＝8.73,1.52Hz,1H),7.10-7.03(m,1H),4.53-4.39(m,2H),4.21(s,3H),1.52(s,9H).

Step 2: synthesis of N- (4- (6- (3-fluorophenyl) -2-methyl-2H-indazol-3-yl) benzyl) acrylamide (CDN134).

Starting from CDN130(40mg,0.09mmol), the title compound was synthesized according to the experimental procedure of CDM146 and purified by HPLC to yield 17mg of the trifluoroacetate salt of the final product CDN134 (purification conditions: 50% acetonitrile start, retention time: 13.0 min). ¹ H NMR(400MHz,MeOD-d ₄ ) δ 7.89-7.78(m,1H),7.71-7.55(m,5H),7.55-7.39(m,4H),7.19-7.04(m,1H),6.44-6.26(m,2H),5.74(dd, J ═ 8.94,3.06Hz,1H),4.60(s,2H),4.19(s,3H). ESI-MS theoretical calculation C ₂₄ H ₂₁ FN ₃ O[M+H] ⁺ 386.16; the experiment shows that: 386.09.

synthesis of the end product 244: n- (3- (6- (3-fluorophenyl) -2-methyl-2H-indazol-3-yl) benzyl) acrylamide (CDN136).

Step 1: synthesis of tert-butyl (3- (6- (3-fluorophenyl) -2-methyl-2H-indazol-3-yl) benzyl) carbamate (CDN135).

CDN99(50mg,0.16mmol) and tert-butyl (3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzyl) formate (82mg,0.25mmol) as starting materials were added Synthesized according to the experimental procedure of CDM144 and purified by silica gel column to give CDN135(88 mg). ¹ H NMR(400MHz,Chloroform-d):7.91-7.88(m,1H),7.65(d,J＝8.72Hz,1H),7.59-7.53(m,1H),7.53-7.41(m,5H),7.39(d,J＝10.27Hz,1H),7.33(dd,J＝8.75,1.52Hz,1H),7.07(t,J＝8.35Hz,1H),4.51-4.40(m,2H),4.21(s,3H),1.49(s,9H).

Step 2: synthesis of N- (3- (6- (3-fluorophenyl) -2-methyl-2H-indazol-3-yl) benzyl) acrylamide (CDN136).

Starting from CDN135(40mg,0.09mmol), the title compound was synthesized according to the experimental procedure of CDM146 and purified by HPLC to give 22mg of the trifluoroacetate salt of the final product CDN136 (purification conditions: 40% acetonitrile start, retention time: 21.0 min). ¹ H NMR(400MHz,MeOD-d ₄ ) Theoretical calculated values of C, δ 7.86-7.77(m,1H),7.67(d, J ═ 8.73Hz,1H),7.64-7.56(m,2H),7.56-7.37(m,7H),7.15-7.06(m,1H),6.40-6.24(m,2H),5.71(dd, J ═ 8.90,3.04Hz,1H),4.58(s,2H),4.18(s,3H), ESI-MS ₂₄ H ₂₁ FN ₃ O[M+H] ⁺ 386.16; the experiment shows that: 386.24.

synthesis of end product 245: n- (1- (6- (3-fluorophenyl) -2-methyl-2H-indazol-3-yl) piperidin-4-yl) acrylamide (CDN137).

Step 1: tert-butyl (1- (6- (3-fluorophenyl) -2-methyl-2H-indazol-3-yl) piperidin-4-yl) carbamate (CDN123) was synthesized.

The reaction was carried out using CDN99(100mg,0.33mmol) and tert-butyl piperidin-4-ylcarbamate (198mg,0.99mmol) as starting materials, according to the experimental procedure of WHF49, and was primarily purified by silica gel column to obtain a mixture (33mg) containing CDN123, which was used for the next reaction.

Step 2: synthesis of N- (1- (6- (3-fluorophenyl) -2-methyl-2H-indazol-3-yl) piperidin-4-yl) acrylamide (CDN137).

The target compound was synthesized from a mixture (33mg) containing CDN123 according to the experimental method of CDM146, and purified by HPLC to obtain 14mg (pure trifluoroacetate salt of CDN137 as a final product)The chemical conditions are as follows: 40% acetonitrile start, retention time: 9.0 min). ¹ H NMR(400MHz,MeOD-d ₄ ) δ 8.00(d, J ═ 8.84Hz,1H),7.73-7.64(m,1H),7.53-7.34(m,4H),7.17-7.03(m,1H),6.36-6.18(m,2H),5.69(dd, J ═ 8.10,3.95Hz,1H),4.21-3.89(m,4H),3.61-3.38(m,4H),2.25-2.00(m,2H),1.90-1.68(m,2H), ESI-MS theoretical calculation C ₂₂ H ₂₄ FN ₄ O[M+H] ⁺ 379.19; the experiment shows that: 379.27.

synthesis of end product 246: n- (1- (6- (3-fluorophenyl) -2-methyl-2H-indazol-3-yl) azetidin-3-yl) acrylamide (CDN138).

Step 1: synthesis of tert-butyl (1- (6- (3-fluorophenyl) -2-methyl-2H-indazol-3-yl) azetidin-3-yl) carbamate (CDN118).

Using CDN99(150mg,0.49mmol) and azetidin-3-ylcarbamic acid tert-butyl ester (170mg,0.99mmol) as raw materials, synthesizing according to the experimental method of WHF49, and performing primary purification by silica gel column to obtain a mixture (35mg) containing CDN118, which is used for the next reaction.

Step 2: synthesis of N- (1- (6- (3-fluorophenyl) -2-methyl-2H-indazol-3-yl) azetidin-3-yl) acrylamide (CDN138).

Starting from a mixture containing CDN118 (35mg), the title compound was synthesized according to the experimental procedure of CDM146 and purified by HPLC to give the final product CDN138 trifluoroacetate salt 13mg (purification conditions: 30% acetonitrile start, retention time: 9.5 min). ¹ H NMR(400MHz,MeOD-d ₄ ) δ 7.94(d, J ═ 8.71Hz,1H),7.62(s,1H),7.56-7.39(m,4H),7.24-7.11(m,1H),6.36-6.24(m,2H),5.75(t, J ═ 5.98Hz,1H),5.06-4.98(m,2H),4.98-4.92(m,1H),4.70-4.57(m,2H),3.96(s,3H) ESI-MS theoretically calculated values C ₂₀ H ₂₀ FN ₄ O[M+H] ⁺ 351.15; the experiment shows that: 351.20.

synthesis of end product 247: n- (1- (6- (3-fluorophenyl) -2-methyl-2H-indazol-3-yl) piperidin-3-yl) acrylamide (CDN139).

Step 1: tert-butyl (1- (6- (3-fluorophenyl) -2-methyl-2H-indazol-3-yl) piperidin-3-yl) carbamate (CDN133) was synthesized.

The reaction was carried out using CDN99(100mg,0.33mmol) and tert-butyl piperidin-3-ylcarbamate (198mg,0.99mmol) as starting materials, according to the experimental procedure of WHF49, and was primarily purified by silica gel column to obtain a mixture (34mg) containing CDN133, which was used for the next reaction.

Step 2: n- (1- (6- (3-fluorophenyl) -2-methyl-2H-indazol-3-yl) piperidin-3-yl) acrylamide (CDN139).

Starting from a mixture containing CDN133 (34mg), the target compound was synthesized according to the experimental procedure of CDM146 and purified by HPLC to give 10mg of the trifluoroacetate salt of the final product CDN139 (purification conditions: 35% acetonitrile start, retention time: 13.0 min). ¹ H NMR(400MHz,MeOD-d ₄ ) Calculated values of δ 8.10(d, J ═ 8.84Hz,1H),7.69(s,1H),7.55-7.39(m,4H),7.21-7.07(m,1H),6.38-6.19(m,2H),5.69(dd, J ═ 8.92,3.07Hz,1H),4.21-4.10(m,1H),4.06(s,3H),3.86-3.75(m,1H),3.64-3.53(m,1H),3.48-3.38(m,1H),3.25-3.13(m,1H),2.15-2.06(m,1H),2.04-1.97(m,1H),1.98-1.80(m,1H),1.77-1.58(m,1H), theoretical calculated values of C-1H, and theoretical values of C ₂₂ H ₂₄ FN ₄ O[M+H] ⁺ 379.19; the experiment shows that: 379.06.

by selecting the corresponding raw materials, the compounds shown in the following table 1 can be synthesized.

TABLE 1

Experimental example 2: cellular activity assay for compounds

NCI-H358 and Calu-1 are lung cancer cell lines, and the genes of both have the characteristic of the mutation of kraS G12C. One feature of these two cell lines is the relative sensitivity to kRAS inhibitors.

Compound WHB75 served here as a positive control compound. The structure of WHB75 is similar to that of the kRAS inhibitor reported in the literature (2017, Cell Chemical Biology,24, 1-12; 2018, ACS Medicinal Chemistry Letters,2018,9, 1230-1234; WO 2017/087528A 1), and is shown below.

A20 mM compound stock solution was prepared by dissolving a sample to be tested in 100% dimethyl sulfoxide. Compounds were diluted with 100% dimethylsulfoxide to the highest concentration required for the experiment (2.5mM or 10 mM).

First, 145. mu.L of complete cell culture medium was added to wells B1-G1 and 100. mu.L of complete cell culture medium was added to wells B2-G12, respectively, of a 96-well flat-bottom clear cell culture plate. Then, 5. mu.L of 2.5mM or 10mM compound solution was added to each of the wells B1-D1 and E1-G1, and the mixture was sequentially diluted to B12-D12 and E12-G12 in a 3-fold gradient. Finally, 50 μ L of the cell solution to be tested was added to each well, the number of cells per well was about 8000, and the total volume per well was 150 μ L. In the experiment, two control groups were set up in addition to the compound tested: 1) cells and medium were added, but no compound control; 2) only complete medium was added, cell-free and compound-free. After incubating the 96-well plate in a 37 ℃ cell incubator containing 5% carbon dioxide for 4 days, 15uL of CCK-8 reagent was added to each well, followed by incubation at 37 ℃ for 2-3 hours. The absorbance at 450nm was read with a TECAN microplate reader.

The effect of different concentrations of compound on cell activity was calculated using the following formula: [ experimental group absorbance-complete medium only (cell-free compound-free group) absorbance ]/[ cell-free compound-complete medium only (cell-free compound-free group) absorbance ] × 100%. The data were processed using GraphPad Prism 6 software, and the IC50 value was taken as the concentration of compound corresponding to 50% inhibition of cell growth.

Wherein represents the IC of the compound inhibiting cell growth ₅₀ >50uM, IC representing inhibition of cell growth by the compound ₅₀ <50uM and>10uM, IC representing inhibition of cell growth by the compound ₅₀ <10uM and>1.0uM, IC indicating that the compound inhibits cell growth ₅₀ <1.0uM。

Experimental example 3: modification of intracellular kRAS mutants with compounds

The H358 cells are evenly paved on a 6-hole plate after being digested by pancreatin, the 6-hole plate is placed in a 37 ℃ cell culture box containing 5% carbon dioxide for culture for 24 hours, the original culture medium is removed after the cells are completely attached to the wall, then fresh culture mediums containing compounds with different concentrations are respectively added into each hole of the 6-hole plate, and the 6-hole plate is placed in the 37 ℃ cell culture box for culture for 6 hours by taking a DMSO group as a blank control. After the incubation was completed, the 6-well plate was removed, and after removing the compound-containing medium, 1mL of ice-incubated 1 XPBS was added to each well and washed once. 100 μ of LRIPA cell lysate was added to each well, cells were lysed on ice for 30 minutes, and cell lysis supernatant was collected after centrifugation at 14000 rpm for 30 minutes at 4 ℃. The concentration of each protein sample was determined using the BCA protein concentration detection kit. 20 μ g of protein per well was subjected to SDS-PAGE, and then transferred to nitrocellulose. The nitrocellulose membrane was blocked with a 5% skim milk 1 XTSST (20mM Tris, 150mM NaCl, pH 7.6, 0.1% Tween-20) solution at room temperature for 2 hours and washed with 1 XTSST for 5 XTSST. Subsequently, the primary antibody to the corresponding protein (K-Ras, pERK, GAPDH) was added and incubated overnight at 4 ℃. After removing the primary antibody the next day, the membrane was washed with 1 × TBST for 5 × 5 min, the corresponding secondary antibody was added, and after incubation for 2 h at room temperature, the membrane was washed with 1 × TBST for 5 × 5 min. Finally, the band of the corresponding protein was analyzed by ECL luminescence kit (Thermo Scientific). And processing the read picture by photoshop and power point to obtain corresponding picture data.

As shown in figure 1, in accordance with WHB75, the synthesized highly active compounds, such as WHE23, ZB88, ZB89, have the ability to inhibit ERK phosphorylation in H358 cells. Compound ZB89 can promote a gradual decrease in kRAS protein concentration as drug concentration increases. These results demonstrate that the compounds have the ability to modulate intracellular kRAS protein stability, affect the level of ERK phosphorylation of proteins downstream of kRAS, and demonstrate that the compounds have the ability to modulate intracellular kRAS-ERK signaling pathways.

All documents referred to herein are incorporated by reference into this application as if each were individually incorporated by reference. Furthermore, it should be understood that various changes and modifications of the present invention can be made by those skilled in the art after reading the above teachings of the present invention, and these equivalents also fall within the scope of the present invention as defined by the appended claims.

Claims

1. A compound or a pharmaceutically acceptable salt thereof, wherein the compound has a structure according to one of the following formulae:

wherein, the first and the second end of the pipe are connected with each other,

ar is C6-C10 aryl or 4-12 membered heteroaryl; optionally substituted, with valency permitting conditions, with 1 to 3 groups selected from: -halogen, C1-C6 haloalkyl, cyano, hydroxy, C1-C6 alkoxy, C1-C6 alkyl;

R ₃ 、R ₄ 、R ₅ Each independently hydrogen, deuterium, halogen, C1-C6 alkoxy, C1-C6 alkyl, cyano or hydroxy;

L ₃ 、L ₄ each independently is-NH-, -NH (C1-C6 alkylene) -or- (C1-C6 alkylene) -NH-;

selected from: a benzene ring, a C3-C8 saturated aliphatic ring, a 3-10 membered saturated or partially saturated heterocyclic ring containing a nitrogen atom;

R ₂ is C1-C6 alkyl, - (C1-C6 alkylene) - (containing3-10 membered saturated heterocyclic and partially saturated heterocyclic of 1-2 nitrogen atoms) or- (C1-C6 alkylene) -NH- (4-12 membered heteroaryl); under the condition of bond permission, R ₂ Optionally substituted with 1-3 groups selected from: hydroxyl, C1-C6 alkyl, N-di (C1-C6 alkyl) amino, N- (C1-C6 alkyl) aminocarbonyl, N-di (C1-C6 alkyl) aminocarbonyl, aminocarbonylamino, aminocarbonyl, guanidino, C1-C8 nitrogen-containing heterocyclylcarbonyl, aminosulfonyl, carboxyl, phosphate;

z represents a reactive group capable of covalent bonding with a cysteine thiol group, selected from the following groups:

wherein R is ₆ 、R ₇ 、R ₈ Each independently hydrogen, deuterium, or C1-C6 alkyl;

wherein R is ₉ 、R ₁₀ Each independently hydrogen or C1-C6 alkyl; or R ₉ And R ₁₀ And the nitrogen atom to which it is attached form a 3-10 membered nitrogen containing heterocyclic ring;

n represents 1, 2 or 3.

2. The compound of claim 1, wherein L is ₃ 、L ₄ Each independently-NH-, -NH- (C1-C4 alkylene) -or- (C1-C4 alkylene) -NH-.

3. The compound of claim 1,

selected from the group consisting of: a benzene ring, a C3-C6 saturated aliphatic ring, a 3-8 membered saturated or partially saturated heterocyclic ring containing a nitrogen atom.

4. A compound or a pharmaceutically acceptable salt thereof, wherein the compound is any one compound selected from the group consisting of:

。

5. a pharmaceutical composition, comprising:

a compound of any one of claims 1-4 or a pharmaceutically acceptable salt thereof; and

a pharmaceutically acceptable carrier.

6. Use of a compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 5, for (a) use in the preparation of a kRAS small molecule inhibitor; or (b) for use in the manufacture of a medicament for the treatment of a disease associated with kRAS.

7. The use of claim 6, wherein the kRAS-associated disease is a tumor selected from the group consisting of: lung cancer, pancreatic cancer, and intestinal cancer.