Estrogen receptor modulator and use thereof

Abstract

The present invention relates to the technical field of medicine. Provided are an estrogen receptor modulator and a use thereof, particularly a compound as represented by general formula (i) or an isomer or pharmaceutically acceptable salt thereof and a use thereof, particularly a use thereof as an estrogen receptor degrading agent, a use thereof in the preparation of a medicament for treating and / or preventing an estrogen receptor-mediated or dependent disease or condition, and a use thereof in the preparation of a medicament for treating and / or preventing a disease or condition by degrading a target protein.

Description

Estrogen receptor modulators and uses thereof

[0001] The present invention claims:

[0002] Priority to the prior application, patent application number 202311681737.X, filed with the State Intellectual Property Office of China on December 8, 2023, entitled “Estrogen Receptor Modulators and Uses Thereof”;

[0003] Priority to the prior application, patent application number 202311700571.1, filed with the State Intellectual Property Office of China on December 12, 2023, entitled “Estrogen Receptor Modulators and Uses Thereof”;

[0004] Priority to the prior application, patent application number 202311711928.6, filed with the State Intellectual Property Office of China on December 13, 2023, entitled “Estrogen Receptor Modulators and Uses Thereof”;

[0005] Priority to the prior application, patent application number 202311808960.6, filed with the State Intellectual Property Office of China on December 26, 2023, entitled “Estrogen Receptor Modulators and Uses Thereof”;

[0006] Priority to the prior application, patent application number 202410106933.2, filed with the State Intellectual Property Office of China on January 25, 2024, entitled “Estrogen Receptor Modulators and Uses Thereof”;

[0007] Priority to the prior application, patent application number 202410214069.8, filed with the State Intellectual Property Office of China on February 27, 2024, entitled “Estrogen Receptor Modulators and Uses Thereof”;

[0008] Priority to the prior application, patent application number 202410863924.8, filed with the State Intellectual Property Office of China on June 29, 2024, entitled “Estrogen Receptor Modulators and Uses Thereof”;

[0009] The entire contents of said prior application are incorporated herein by reference. Technical Field

[0010] The present invention belongs to the field of medical technology and relates to an estrogen receptor modulator represented by formula (I), its isomers or pharmaceutically acceptable salts thereof and uses thereof. Background Art

[0011] Anti-estrogen (hormone) therapy is the first choice for treating estrogen-positive breast cancer. Anti-estrogen therapy is divided into three main categories: aromatase inhibitors (such as letrozole and anastrozole); estrogen antagonists (such as tamoxifen and raloxifene); and selective estrogen receptor degraders (such as fulvestrant). These types of anti-estrogen therapy work through different mechanisms, blocking estrogen production and inhibiting tumor growth.

[0012] Targeted protein degradation chimera (PROTAC) is a new therapeutic technology that blocks signaling pathways by degrading target proteins, thereby exerting a therapeutic effect. PROTAC molecules are generally composed of three parts: a target protein binding ligand, an E3 ubiquitin ligase ligand, and a linker. PROTAC molecules tightly bind to the target protein through one end of the chimera and bind to the E3 ubiquitin ligase at the other end to form a target protein-PROTAC-E3 ubiquitin ligase ternary complex. Ubiquitination is mediated by the E3 ubiquitin ligase, so that the target protein is ubiquitinated "tagged"; the ubiquitinated "tagged" target protein is then transported to the proteasome and then degraded by the proteasome.

[0013] Compared with traditional small molecule inhibitors, PROTAC technology has the following advantages: 1. A smaller dosage may be required. The target protein degradation process is similar to a catalytic reaction. PROTAC molecules can be reused, and only a catalytic amount of drug is needed to inhibit the target protein. 2. Feedback upregulation of target protein expression due to target protein inhibition can be avoided. 3. Expanding the scope of drug targeting. PROTAC technology makes proteins such as transcription factors, regulatory proteins, and other non-enzyme proteins that traditional small molecule inhibitors cannot directly act on become regulatable proteins, turning the target from "non-druggable" to "druggable."

[0014] ER-PROTAC drugs that target the degradation of estrogen receptors have preliminarily demonstrated efficacy and excellent safety in clinical studies and are expected to become a new type of hormone therapy, an important supplement to traditional therapies that are resistant, intolerant, and ineffective. Summary of the Invention

[0015] One object of the invention is to provide a class of ER-PROTAC compounds, isomers thereof or pharmaceutically acceptable salts thereof that target the degradation of estrogen receptors.

[0016] The technical solutions of the present invention are as follows:

[0017] The compound represented by formula (i), its isomer or pharmaceutically acceptable salt thereof:

[0018] ABC

[0019] (i)

[0020] in,

[0021] A is

[0022] X is selected from N or CH;

[0023] Cy1 is selected from (For example ), described (For example ), are unsubstituted, or are each independently substituted with 1-3 R a1 Substituted; G is selected from unsubstituted or optionally substituted by one, two or more R a1 Substituted with the following groups: C 6-10 Aryl or 5-10 membered heteroaryl, such as phenyl, pyridyl, pyrimidinyl;

[0024] Each R a1 are independently selected from hydrogen, deuterium, halogen, hydroxyl, carboxyl, amino, cyano, nitro, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, hydroxy C 1-6 Alkyl, C 1-6 Alkylamino, (C 1-6 Alkyl)2amino, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-6 Alkylcarbonyl, aminocarbonyl, C 1-6 Alkylaminocarbonyl, (C 1-6 alkyl)2-aminocarbonyl;

[0025] B is -L2-Cy2-L3-Cy3-L4-Cy4-L5-; A is connected to L2; C is connected to L5;

[0026] L1, L2, L3, L4, L5, L6 are independently selected from a bond, -(CH2) n -(NH) m -、-O-、-S-、-NR2、-CR 31 R 32 -, -C(O)-, -C(O)O-, -C(O)NR4-, -NR5-C(O)-, -S(O)-, -S(O)2-, -P(O)(R6)-, C 2-8 Alkenyl and C 2-8 Alkynyl;

[0027] n and m are each independently any integer from zero to six; for example, 0, 1, 2, 3, 4, 5 or 6;

[0028] R2, R 31 、R 32 , R4 and R5 and R6 are independently selected from hydrogen, deuterium, halogen, hydroxyl, carboxyl, amino, cyano, nitro, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, hydroxy C 1-6 Alkyl, C 1-6 Alkylamino, (C 1-6 Alkyl)2amino, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-6 Alkylcarbonyl, aminocarbonyl, C 1-6 Alkylaminocarbonyl, (C 1-6 alkyl)2aminocarbonyl, wherein the C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, hydroxy C 1-6 Alkyl, C 1-6 Alkylamino, (C 1-6 Alkyl)2amino, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-6 Alkylcarbonyl, aminocarbonyl, C 1-6 Alkylaminocarbonyl, (C 1-6 Alkyl) 2 aminocarbonyl is unsubstituted or optionally substituted by one or more independently selected from hydroxy, amino, carboxyl, cyano, nitro, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkoxy C 1-6 Alkoxy, C 1-6 Alkylamino, (C 1-6 Alkyl)2amino, C 1-6 Alkylcarbonylamino, C 1-6 Alkylsulfonylamino, C 1-6 Alkylcarbonyloxy, C 3-6 Cycloalkyl, C 3-6 Cycloalkylcarbonyloxy, C 2-8 Alkynyl, halo C 1-6 Alkyl, C 2-8 Alkenyl, halogenated C 1-6 Alkoxy group substitution;

[0029] Cy2 is selected from 3-13 membered cycloalkyl, 3-13 membered heterocyclic group, 3-13 membered cycloalkenyl, 1-3 R a2Substituted 3-13 membered cycloalkyl, 1-3 R a2 substituted 3-13 membered heterocyclic group, substituted by 1-3 R a2 Substituted 3-13 membered cycloalkenyl, Cy21-Cy22, wherein the heteroatom of the 3-13 membered heterocyclic group is selected from O, N or S; Cy21 and Cy22 are the same or different and are independently selected from 3-13 membered cycloalkyl, 3-13 membered heterocyclic group, 3-13 membered cycloalkenyl;

[0030] Cy3 is selected from 3-13 membered cycloalkyl, 3-13 membered heterocyclic group, 6-13 membered bicyclic condensed ring group or 8-21 membered polycyclic condensed ring group, wherein the 3-13 membered cycloalkyl, 3-13 membered heterocyclic group, 6-13 membered bicyclic condensed ring group or 8-21 membered polycyclic condensed ring group is unsubstituted or each of them is independently substituted with 1-5 R a3 Substitution, the heteroatom of the 5-6 membered heterocyclic group is N, O, S, or Si;

[0031] Cy4 is selected from 3-8 membered cycloalkyl, 3-8 membered heterocyclic group, 3-8 membered cycloalkenyl, 6-13 membered bicyclic condensed ring cycloalkyl, 6-13 membered bicyclic condensed ring alkenyl, 6-13 membered bicyclic condensed ring heterocyclic group, 1-3 R a4 Substituted 3-8 membered cycloalkyl, 1-3 R a4 substituted 3-8 membered heterocyclic group, substituted by 1-3 R a4 Substituted 3-8 membered cycloalkenyl, 1-3 R a4 Substituted 6-13 bicyclic condensed ring cycloalkyl, 1-3 R a4 Substituted 6-13 membered bicyclic fused cycloalkenyl, 1-3 R a4 a substituted 6-13 membered bicyclic fused ring heterocyclic group, wherein the heteroatom of the 3-8 membered heterocyclic group or the 6-13 membered bicyclic fused ring heterocyclic group is selected from O, N or S;

[0032] Each R a2 、R a3 and R a4 When present, each is independently selected from hydrogen, deuterium, halogen, hydroxyl, mercapto, silanol, selenohydroxyl, carboxyl, amino, cyano, nitro, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Alkyl-C(O)O-, C 1-6 Alkylthio, C 1-6 Alkyl selenyl, hydroxyl C 1-6 Alkyl, C 1-6 Alkyl-C(O)NH-, C 1-6 Alkylamino, (C 1-6 Alkyl)2amino, C 2-8 Alkenyl, C2-8 Alkynyl, C 1-6 Alkylcarbonyl, aminocarbonyl, C 1-6 Alkylaminocarbonyl, (C 1-6 alkyl) 2-aminocarbonyl, 3-8-membered cycloalkyl, 3-8-membered heterocyclic group, 3-8-membered cycloalkenyl, wherein the C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, hydroxy C 1-6 Alkyl, C 1-6 Alkylamino, (C 1-6 Alkyl)2amino, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-6 Alkylcarbonyl, aminocarbonyl, C 1-6 Alkylaminocarbonyl, (C 1-6 alkyl) 2-aminocarbonyl, 3-8-membered cycloalkyl, 3-8-membered heterocyclyl, 3-8-membered cycloalkenyl are unsubstituted or optionally substituted with one or more hydroxyl, amino, carboxyl, cyano, nitro, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkoxy C 1-6 Alkoxy, C 1-6 Alkylamino, (C 1-6 Alkyl)2amino, C 1-6 Alkylcarbonylamino, C 1-6 Alkylsulfonylamino, C 1-6 Alkylcarbonyloxy, C 3-6 Cycloalkyl, C 3-6 Cycloalkylcarbonyloxy, C 2-8 Alkynyl, halo C 1-6 Alkyl, C 2-8 Alkenyl, halogenated C 1-6 Alkoxy, 3-8 membered cycloalkyl, 3-8 membered heterocyclyl, 3-8 membered cycloalkenyl group substitution;

[0033] C is

[0034] X1 is N or CR b1 ;

[0035] X2 is N or CR b2 ;

[0036] X3 is N or CR b3 ;

[0037] X4 is N or CR b4 ;

[0038] X5 is N or CR b5 ;

[0039] R b1 、R b2 、R b3 、R b4 and R b5 are independently selected from hydrogen, deuterium, halogen, hydroxyl, carboxyl, amino, cyano, nitro, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, hydroxy C 1-6 Alkyl, C 1-6 Alkylamino, (C 1-6 Alkyl)2amino, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-6 Alkylcarbonyl, aminocarbonyl, C 1-6 Alkylaminocarbonyl, (C 1-6 alkyl)2-aminocarbonyl;

[0040] Cy5 is selected from 6-13 membered bicyclic condensed ring group and 8-21 membered polycyclic condensed ring group; the 6-13 membered bicyclic condensed ring group or 8-21 membered polycyclic condensed ring group is unsubstituted or replaced by 1-3 R a5 replace;

[0041] Each R a5 are independently selected from hydrogen, deuterium, hydroxyl, amino, carboxyl, cyano, nitro, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, (C 1-6 Alkyl) 2-amino, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-6 Alkylsulfonyl, C 1-6 Alkylthio, C 3-6 Cycloalkyl, 4-6 membered heterocyclic group, 5-6 membered heteroaryl, aryl, C 1-6 Alkylcarbonyl, aminocarbonyl, C 1-6 Alkylaminocarbonyl, (C 1-6 alkyl) 2-aminocarbonyl, 4-6-membered heterocyclylcarbonyl and 5-6-membered heteroaryl-oxy, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, (C 1-6 Alkyl) 2-amino, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-6Alkylsulfonyl, C 1-6 Alkylthio, C 3-6 Cycloalkyl, 4-6 membered heterocyclic group, 5-6 membered heteroaryl, aryl, C 1-6 Alkylcarbonyl, aminocarbonyl, C 1-6 Alkylaminocarbonyl, (C 1-6 alkyl) 2-aminocarbonyl, 4-6-membered heterocyclylcarbonyl and 5-6-membered heteroaryl-oxy are unsubstituted or optionally substituted by one or more independently selected from hydroxy, amino, carboxyl, cyano, nitro, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkoxy C 1-6 Alkoxy, C 1-6 Alkylamino, (C 1-6 Alkyl)2amino, C 1-6 Alkylcarbonylamino, C 1-6 Alkylsulfonylamino, C 1-6 Alkylcarbonyloxy, C 3-6 Cycloalkyl, C 3-6 Cycloalkylcarbonyloxy, C 2-8 Alkynyl, halo C 1-6 Alkyl, C 2-8 Alkenyl, halogenated C 1-6 Alkoxy group substitution;

[0042] The condition is that when Cy3 is hour, Not for

[0043] In one embodiment, the compound represented by formula (i), its isomer or pharmaceutically acceptable salt thereof:

[0044] in,

[0045] A is

[0046] X is selected from N or CH;

[0047] Cy1 is selected from and phenyl, the and phenyl are unsubstituted, or are each independently substituted with 1-3 R a1 replace;

[0048] Each R a1 are independently selected from hydrogen, halogen, hydroxy, carboxyl, amino, cyano, nitro, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, hydroxy C 1-6 Alkyl, C1-6 Alkylamino, (C 1-6 Alkyl)2amino, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-6 Alkylcarbonyl, aminocarbonyl, C 1-6 Alkylaminocarbonyl, (C 1-6 alkyl)2-aminocarbonyl;

[0049] B is -L2-Cy2-L3-Cy3-L4-Cy4-L5-;

[0050] L1, L2, L3, L4, L5, L6 are independently selected from a bond, -(CH2) n -(NH) m -、-O-、-S-、-NR2、-CR 31 R 32 -, -C(O)-, -C(O)O-, -C(O)NR4-, -NR5-C(O)-, -CH2NR4-, -NR5-CH2-, C 2-8 Alkenyl and C 2-8 Alkynyl;

[0051] n and m are each independently any integer from zero to six;

[0052] R2, R 31 、R 32 , R4 and R5 are independently selected from hydrogen, halogen, hydroxy, carboxyl, amino, cyano, nitro, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, hydroxy C 1-6 Alkyl, C 1-6 Alkylamino, (C 1-6 Alkyl)2amino, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-6 Alkylcarbonyl, aminocarbonyl, C 1-6 Alkylaminocarbonyl, (C 1-6 alkyl)2aminocarbonyl, wherein the C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, hydroxy C 1-6 Alkyl, C 1-6 Alkylamino, (C 1-6 Alkyl)2amino, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-6 Alkylcarbonyl, aminocarbonyl, C 1-6 Alkylaminocarbonyl, (C1-6 Alkyl) 2 aminocarbonyl is unsubstituted or optionally substituted by one or more independently selected from hydroxy, amino, carboxyl, cyano, nitro, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkoxy C 1-6 Alkoxy, C 1-6 Alkylamino, (C 1-6 Alkyl)2amino, C 1-6 Alkylcarbonylamino, C 1-6 Alkylsulfonylamino, C 1-6 Alkylcarbonyloxy, C 3-6 Cycloalkyl, C 3-6 Cycloalkylcarbonyloxy, C 2-8 Alkynyl, halo C 1-6 Alkyl, C 2-8 Alkenyl, halogenated C 1-6 Alkoxy group substitution;

[0053] Cy2 is selected from 4-6 membered cycloalkyl, 4-6 membered heterocyclic group, 4-6 membered cycloalkenyl, 1-3 R a2 Substituted 4-6 membered cycloalkyl, 1-3 R a2 substituted 4-6 membered heterocyclic group, 1-3 R a2 a substituted 4-6 membered cycloalkenyl group, wherein the heteroatom of the 4-6 membered heterocyclic group is selected from O, N or S;

[0054] Cy3 is selected from 5-6 membered cycloalkyl or 5-6 membered heterocyclic group, wherein the 5-6 membered cycloalkyl or 5-6 membered heterocyclic group is unsubstituted or each of them is independently substituted with 1-3 R a3 Substitution, the heteroatom of the 5-6 membered heterocyclic group is N;

[0055] Cy4 is selected from 3-8 membered cycloalkyl, 3-8 membered heterocyclic group, 3-8 membered cycloalkenyl, 6-13 membered bicyclic condensed ring cycloalkyl, 6-13 membered bicyclic condensed ring alkenyl, 6-13 membered bicyclic condensed ring heterocyclic group, 1-3 R a4 Substituted 3-8 membered cycloalkyl, 1-3 R a4 substituted 3-8 membered heterocyclic group, substituted by 1-3 R a4 Substituted 3-8 membered cycloalkenyl, 1-3 R a4 Substituted 6-13 bicyclic condensed ring cycloalkyl, 1-3 R a4 Substituted 6-13 membered bicyclic fused cycloalkenyl, 1-3 R a4 a substituted 6-13 membered bicyclic fused ring heterocyclic group, wherein the heteroatom of the 3-8 membered heterocyclic group or the 6-13 membered bicyclic fused ring heterocyclic group is selected from O, N or S;

[0056] Each R a2 、R a3 and Ra4 When present, each is independently selected from hydrogen, halogen, hydroxy, carboxyl, amino, cyano, nitro, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, hydroxy C 1-6 Alkyl, C 1-6 Alkylamino, (C 1-6 Alkyl)2amino, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-6 Alkylcarbonyl, aminocarbonyl, C 1-6 Alkylaminocarbonyl, (C 1-6 alkyl) 2-aminocarbonyl, 3-8-membered cycloalkyl, 3-8-membered heterocyclic group, 3-8-membered cycloalkenyl, wherein the C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, hydroxy C 1-6 Alkyl, C 1-6 Alkylamino, (C 1-6 Alkyl)2amino, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-6 Alkylcarbonyl, aminocarbonyl, C 1-6 Alkylaminocarbonyl, (C 1-6 alkyl) 2-aminocarbonyl, 3-8-membered cycloalkyl, 3-8-membered heterocyclyl, 3-8-membered cycloalkenyl are unsubstituted or optionally substituted with one or more hydroxyl, amino, carboxyl, cyano, nitro, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkoxy C 1-6 Alkoxy, C 1-6 Alkylamino, (C 1-6 Alkyl)2amino, C 1-6 Alkylcarbonylamino, C 1-6 Alkylsulfonylamino, C 1-6 Alkylcarbonyloxy, C 3-6 Cycloalkyl, C 3-6 Cycloalkylcarbonyloxy, C 2-8 Alkynyl, halo C 1-6 Alkyl, C 2-8 Alkenyl, halogenated C 1-6 Alkoxy, 3-8 membered cycloalkyl, 3-8 membered heterocyclyl, 3-8 membered cycloalkenyl group substitution;

[0057] C is

[0058] X1 is N or CR b1 ;

[0059] X2 is N or CR b2 ;

[0060] X3 is N or CR b3 ;

[0061] X4 is N or CR b4 ;

[0062] X5 is N or CR b5 ;

[0063] R b1 、R b2 、R b3 、R b4 and R b5 are independently selected from hydrogen, halogen, hydroxy, carboxyl, amino, cyano, nitro, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, hydroxy C 1-6 Alkyl, C 1-6 Alkylamino, (C 1-6 Alkyl)2amino, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-6 Alkylcarbonyl, aminocarbonyl, C 1-6 Alkylaminocarbonyl, (C 1-6 alkyl)2-aminocarbonyl;

[0064] Cy5 is selected from 6-13 membered bicyclic condensed ring group and 8-21 membered polycyclic condensed ring group; the 6-13 membered bicyclic condensed ring group or 8-21 membered polycyclic condensed ring group is unsubstituted or replaced by 1-3 R a5 replace;

[0065] Each R a5 are independently selected from hydroxy, amino, carboxyl, cyano, nitro, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, (C 1-6 Alkyl) 2-amino, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-6 Alkylsulfonyl, C 1-6 Alkylthio, C 3-6 Cycloalkyl, 4-6 membered heterocyclic group, 5-6 membered heteroaryl, aryl, C 1-6 Alkylcarbonyl, aminocarbonyl, C 1-6 Alkylaminocarbonyl, (C 1-6alkyl) 2-aminocarbonyl, 4-6-membered heterocyclylcarbonyl and 5-6-membered heteroaryl-oxy, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, (C 1-6 Alkyl) 2-amino, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-6 Alkylsulfonyl, C 1-6 Alkylthio, C 3-6 Cycloalkyl, 4-6 membered heterocyclic group, 5-6 membered heteroaryl, aryl, C 1-6 Alkylcarbonyl, aminocarbonyl, C 1-6 Alkylaminocarbonyl, (C 1-6 alkyl) 2-aminocarbonyl, 4-6-membered heterocyclylcarbonyl and 5-6-membered heteroaryl-oxy are unsubstituted or optionally substituted by one or more independently selected from hydroxy, amino, carboxyl, cyano, nitro, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkoxy C 1-6 Alkoxy, C 1-6 Alkylamino, (C 1-6 Alkyl)2amino, C 1-6 Alkylcarbonylamino, C 1-6 Alkylsulfonylamino, C 1-6 Alkylcarbonyloxy, C 3-6 Cycloalkyl, C 3-6 Cycloalkylcarbonyloxy, C 2-8 Alkynyl, halo C 1-6 Alkyl, C 2-8 Alkenyl, halogenated C 1-6 Alkoxy group substitution;

[0066] The condition is that when Cy3 is hour, Not for

[0067] Another embodiment of the present invention relates to a compound represented by formula (i), an isomer thereof or a pharmaceutically acceptable salt thereof,

[0068] in,

[0069] A is

[0070] X is selected from N or CH;

[0071] Cy1 is selected from and phenyl, the and phenyl are unsubstituted, or are each independently substituted with 1-3 R a1 replace;

[0072] Each R a1 are independently selected from hydrogen, halogen, hydroxy, carboxyl, amino, cyano, nitro, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, hydroxy C 1-6 Alkyl, C 1-6 Alkylamino, (C 1-6 Alkyl)2amino, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-6 Alkylcarbonyl, aminocarbonyl, C 1-6 Alkylaminocarbonyl, (C 1-6 alkyl)2-aminocarbonyl;

[0073] B is -L2-Cy2-L3-Cy3-L4-Cy4-L5-;

[0074] L1, L2, L3, L4, L5, L6 are independently selected from a bond, -(CH2) n -(NH) m -、-O-、-S-、-NR2、-CR 31 R 32 -, -C(O)-, -C(O)O-, -C(O)NR4-, -NR5-C(O)-, C 2-8 Alkenyl and C 2-8 Alkynyl;

[0075] n and m are each independently any integer from zero to six;

[0076] R2, R 31 、R 32 , R4 and R5 are independently selected from hydrogen, halogen, hydroxy, carboxyl, amino, cyano, nitro, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, hydroxy C 1-6 Alkyl, C 1-6 Alkylamino, (C 1-6 Alkyl)2amino, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-6 Alkylcarbonyl, aminocarbonyl, C 1-6 Alkylaminocarbonyl, (C 1-6 alkyl)2aminocarbonyl, wherein the C 1-6 Alkyl, halogenated C1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, hydroxy C 1-6 Alkyl, C 1-6 Alkylamino, (C 1-6 Alkyl)2amino, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-6 Alkylcarbonyl, aminocarbonyl, C 1-6 Alkylaminocarbonyl, (C 1-6 Alkyl) 2 aminocarbonyl is unsubstituted or optionally substituted by one or more independently selected from hydroxy, amino, carboxyl, cyano, nitro, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkoxy C 1-6 Alkoxy, C 1-6 Alkylamino, (C 1-6 Alkyl)2amino, C 1-6 Alkylcarbonylamino, C 1-6 Alkylsulfonylamino, C 1-6 Alkylcarbonyloxy, C 3-6 Cycloalkyl, C 3-6 Cycloalkylcarbonyloxy, C 2-8 Alkynyl, halo C 1-6 Alkyl, C 2-8 Alkenyl, halogenated C 1-6 Alkoxy group substitution;

[0077] Cy2 is selected from 4-6 membered cycloalkyl, 4-6 membered heterocyclic group, 4-6 membered cycloalkenyl, 1-3 R a2 Substituted 4-6 membered cycloalkyl, 1-3 R a2 substituted 4-6 membered heterocyclic group, 1-3 R a2 a substituted 4-6 membered cycloalkenyl group, wherein the heteroatom of the 4-6 membered heterocyclic group is selected from O, N or S;

[0078] Cy3 is selected from 5-6 membered cycloalkyl or 5-6 membered heterocyclic group, wherein the 5-6 membered cycloalkyl or 5-6 membered heterocyclic group is unsubstituted or each of them is independently substituted with 1-3 R a3 Substitution, the heteroatom of the 5-6 membered heterocyclic group is N;

[0079] Cy4 is selected from 3-8 membered cycloalkyl, 3-8 membered heterocyclic group, 3-8 membered cycloalkenyl, 6-13 membered bicyclic condensed ring cycloalkyl, 6-13 membered bicyclic condensed ring alkenyl, 6-13 membered bicyclic condensed ring heterocyclic group, 1-3 R a4 Substituted 3-8 membered cycloalkyl, 1-3 R a4 substituted 3-8 membered heterocyclic group, substituted by 1-3 R a4 Substituted 3-8 membered cycloalkenyl, 1-3 Ra4 Substituted 6-13 bicyclic condensed ring cycloalkyl, 1-3 R a4 Substituted 6-13 membered bicyclic fused cycloalkenyl, 1-3 R a4 a substituted 6-13 membered bicyclic fused ring heterocyclic group, wherein the heteroatom of the 3-8 membered heterocyclic group or the 6-13 membered bicyclic fused ring heterocyclic group is selected from O, N or S;

[0080] Each R a2 、R a3 and R a4 When present, each is independently selected from hydrogen, halogen, hydroxy, carboxyl, amino, cyano, nitro, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, hydroxy C 1-6 Alkyl, C 1-6 Alkylamino, (C 1-6 Alkyl)2amino, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-6 Alkylcarbonyl, aminocarbonyl, C 1-6 Alkylaminocarbonyl, (C 1-6 alkyl)2-aminocarbonyl, 3-8-membered cycloalkyl, 3-8-membered heterocyclic group, 3 - 8-membered cycloalkenyl, wherein the C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, hydroxy C 1-6 Alkyl, C 1-6 Alkylamino, (C 1-6 Alkyl)2amino, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-6 Alkylcarbonyl, aminocarbonyl, C 1-6 Alkylaminocarbonyl, (C 1-6 alkyl) 2-aminocarbonyl, 3-8-membered cycloalkyl, 3-8-membered heterocyclyl, 3-8-membered cycloalkenyl are unsubstituted or optionally substituted with one or more hydroxyl, amino, carboxyl, cyano, nitro, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkoxy C 1-6 Alkoxy, C 1-6 Alkylamino, (C 1-6 Alkyl)2amino, C 1-6 Alkylcarbonylamino, C 1-6 Alkylsulfonylamino, C 1-6 Alkylcarbonyloxy, C 3-6 Cycloalkyl, C 3-6Cycloalkylcarbonyloxy, C 2-8 Alkynyl, halo C 1-6 Alkyl, C 2-8 Alkenyl, halogenated C 1-6 Alkoxy, 3-8 membered cycloalkyl, 3-8 membered heterocyclyl, 3-8 membered cycloalkenyl group substitution;

[0081] C is

[0082] X1 is N or CR b1 ;

[0083] X2 is N or CR b2 ;

[0084] X3 is N or CR b3 ;

[0085] X4 is N or CR b4 ;

[0086] X5 is N or CR b5 ;

[0087] R b1 、R b2 、R b3 、R b4 and R b5 are independently selected from hydrogen, halogen, hydroxy, carboxyl, amino, cyano, nitro, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, hydroxy C 1-6 Alkyl, C 1-6 Alkylamino, (C 1-6 Alkyl)2amino, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-6 Alkylcarbonyl, aminocarbonyl, C 1-6 Alkylaminocarbonyl, (C 1-6 alkyl)2-aminocarbonyl;

[0088] Cy5 is selected from 6-13 membered bicyclic condensed ring group and 8-21 membered polycyclic condensed ring group; the 6-13 membered bicyclic condensed ring group or 8-21 membered polycyclic condensed ring group is unsubstituted or replaced by 1-3 R a5 replace;

[0089] Each R a5 are independently selected from hydroxy, amino, carboxyl, cyano, nitro, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, (C 1-6 Alkyl) 2-amino, halogenated C1-6 Alkyl, halogenated C 1-6 Alkoxy, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-6 Alkylsulfonyl, C 1-6 Alkylthio, C 3-6 Cycloalkyl, 4-6 membered heterocyclic group, 5-6 membered heteroaryl, aryl, C 1-6 Alkylcarbonyl, aminocarbonyl, C 1-6 Alkylaminocarbonyl, (C 1-6 alkyl) 2-aminocarbonyl, 4-6-membered heterocyclylcarbonyl and 5-6-membered heteroaryl-oxy, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, (C 1-6 Alkyl) 2-amino, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-6 Alkylsulfonyl, C 1-6 Alkylthio, C 3-6 Cycloalkyl, 4-6 membered heterocyclic group, 5-6 membered heteroaryl, aryl, C 1-6 Alkylcarbonyl, aminocarbonyl, C 1-6 Alkylaminocarbonyl, (C 1-6 alkyl) 2-aminocarbonyl, 4-6-membered heterocyclylcarbonyl and 5-6-membered heteroaryl-oxy are unsubstituted or optionally substituted by one or more independently selected from hydroxy, amino, carboxyl, cyano, nitro, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkoxy C 1-6 Alkoxy, C 1-6 Alkylamino, (C 1-6 Alkyl)2amino, C 1-6 Alkylcarbonylamino, C 1-6 Alkylsulfonylamino, C 1-6 Alkylcarbonyloxy, C 3-6 Cycloalkyl, C 3-6 Cycloalkylcarbonyloxy, C 2-8 Alkynyl, halo C 1-6 Alkyl, C 2-8 Alkenyl, halogenated C 1-6 Alkoxy group substitution;

[0090] The condition is that when Cy3 is hour, Not for

[0091] Another embodiment of the present invention relates to a compound represented by formula (i), an isomer thereof or a pharmaceutically acceptable salt thereof,

[0092] in,

[0093] A is

[0094] X is selected from N or CH;

[0095] Cy1 is selected from and phenyl, the and phenyl are unsubstituted, or are each independently substituted with 1-3 R a1 replace;

[0096] Each R a1 are independently selected from hydrogen, halogen, hydroxy, carboxyl, amino, cyano, nitro, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, hydroxy C 1-6 Alkyl, C 1-6 Alkylamino, (C 1-6 Alkyl)2amino, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-6 Alkylcarbonyl, aminocarbonyl, C 1-6 Alkylaminocarbonyl, (C 1-6 alkyl)2-aminocarbonyl;

[0097] B is -L2-Cy2-L3-Cy3-L4-Cy4-L5-;

[0098] L1, L2, L3, L4, L5, L6 are independently selected from a bond, -(CH2) n -(NH) m -、-O-、-S-、-NR2、-CR 31 R 32 -, -C(O)-, -C(O)O-, -C(O)NR4-, -NR5-C(O)-, C 2-8 Alkenyl and C 2-8 Alkynyl;

[0099] n and m are each independently any integer from zero to six;

[0100] R2, R 31 、R 32 , R4 and R5 are independently selected from hydrogen, halogen, hydroxy, carboxyl, amino, cyano, nitro, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C1-6 Alkoxy, halogenated C 1-6 Alkoxy, hydroxy C 1-6 Alkyl, C 1-6 Alkylamino, (C 1-6 Alkyl)2amino, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-6 Alkylcarbonyl, aminocarbonyl, C 1-6 Alkylaminocarbonyl, (C 1-6 alkyl)2aminocarbonyl, wherein the C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, hydroxy C 1-6 Alkyl, C 1-6 Alkylamino, (C 1-6 Alkyl)2amino, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-6 Alkylcarbonyl, aminocarbonyl, C 1-6 Alkylaminocarbonyl, (C 1-6 Alkyl) 2 aminocarbonyl is unsubstituted or optionally substituted by one or more independently selected from hydroxy, amino, carboxyl, cyano, nitro, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkoxy C 1-6 Alkoxy, C 1-6 Alkylamino, (C 1-6 Alkyl)2amino, C 1-6 Alkylcarbonylamino, C 1-6 Alkylsulfonylamino, C 1-6 Alkylcarbonyloxy, C 3-6 Cycloalkyl, C 3-6 Cycloalkylcarbonyloxy, C 2-8 Alkynyl, halo C 1-6 Alkyl, C 2-8 Alkenyl, halogenated C 1-6 Alkoxy group substitution;

[0101] Cy2 is selected from 4-6 membered cycloalkyl, 4-6 membered heterocyclic group, 4-6 membered cycloalkenyl, 1-3 R a2 Substituted 4-6 membered cycloalkyl, 1-3 R a2 substituted 4-6 membered heterocyclic group, 1-3 R a2 a substituted 4-6 membered cycloalkenyl group, wherein the heteroatom of the 4-6 membered heterocyclic group is selected from O, N or S;

[0102] Cy3 is selected from described are unsubstituted or are each independently substituted with 1-3 Ra3 replace;

[0103] Cy4 is selected from 3-8 membered cycloalkyl, 3-8 membered heterocyclic group, 3-8 membered cycloalkenyl, 6-13 membered bicyclic condensed ring cycloalkyl, 6-13 membered bicyclic condensed ring alkenyl, 6-13 membered bicyclic condensed ring heterocyclic group, 1-3 R a4 Substituted 3-8 membered cycloalkyl, 1-3 R a4 substituted 3-8 membered heterocyclic group, substituted by 1-3 R a4 Substituted 3-8 membered cycloalkenyl, 1-3 R a4 Substituted 6-13 bicyclic condensed ring cycloalkyl, 1-3 R a4 Substituted 6-13 membered bicyclic fused cycloalkenyl, 1-3 R a4 a substituted 6-13 membered bicyclic fused ring heterocyclic group, wherein the heteroatom of the 3-8 membered heterocyclic group or the 6-13 membered bicyclic fused ring heterocyclic group is selected from O, N or S;

[0104] Each R a2 、R a3 and R a4 When present, each is independently selected from hydrogen, halogen, hydroxy, carboxyl, amino, cyano, nitro, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, hydroxy C 1-6 Alkyl, C 1-6 Alkylamino, (C 1-6 Alkyl)2amino, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-6 Alkylcarbonyl, aminocarbonyl, C 1-6 Alkylaminocarbonyl, (C 1-6 alkyl) 2-aminocarbonyl, 3-8-membered cycloalkyl, 3-8-membered heterocyclic group, 3-8-membered cycloalkenyl, wherein the C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, hydroxy C 1-6 Alkyl, C 1-6 Alkylamino, (C 1-6 Alkyl)2amino, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-6 Alkylcarbonyl, aminocarbonyl, C 1-6 Alkylaminocarbonyl, (C 1-6 alkyl) 2-aminocarbonyl, 3-8-membered cycloalkyl, 3-8-membered heterocyclyl, 3-8-membered cycloalkenyl are unsubstituted or optionally substituted with one or more hydroxyl, amino, carboxyl, cyano, nitro, halogen, C 1-6Alkyl, C 1-6 Alkoxy, C 1-6 Alkoxy C 1-6 Alkoxy, C 1-6 Alkylamino, (C 1-6 Alkyl)2amino, C 1-6 Alkylcarbonylamino, C 1-6 Alkylsulfonylamino, C 1-6 Alkylcarbonyloxy, C 3-6 Cycloalkyl, C 3-6 Cycloalkylcarbonyloxy, C 2-8 Alkynyl, halo C 1-6 Alkyl, C 2-8 Alkenyl, halogenated C 1-6 Alkoxy, 3-8 membered cycloalkyl, 3-8 membered heterocyclyl, 3-8 membered cycloalkenyl group substitution;

[0105] C is

[0106] X1 is N or CR b1 ;

[0107] X2 is N or CR b2 ;

[0108] X3 is N or CR b3 ;

[0109] X4 is N or CR b4 ;

[0110] X5 is N or CR b5 ;

[0111] R b1 、R b2 、R b3 、R b4 and R b5 are independently selected from hydrogen, halogen, hydroxy, carboxyl, amino, cyano, nitro, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, hydroxy C 1-6 Alkyl, C 1-6 Alkylamino, (C 1-6 Alkyl)2amino, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-6 Alkylcarbonyl, aminocarbonyl, C 1-6 Alkylaminocarbonyl, (C 1-6 alkyl)2-aminocarbonyl;

[0112] Cy5 is selected from 6-13 membered bicyclic condensed ring groups and 8-21 membered polycyclic condensed ring groups; the 6-13 membered bicyclic condensed ring groups and 8-21 membered polycyclic condensed ring groups are unsubstituted or optionally substituted with 1-3 R a5 replace;

[0113] Each R a5 are independently selected from hydroxy, amino, carboxyl, cyano, nitro, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, (C 1-6 Alkyl) 2-amino, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-6 Alkylsulfonyl, C 1-6 Alkylthio, C 3-6 Cycloalkyl, 4-6 membered heterocyclic group, 5-6 membered heteroaryl, aryl, C 1-6 Alkylcarbonyl, aminocarbonyl, C 1-6 Alkylaminocarbonyl, (C 1-6 alkyl) 2-aminocarbonyl, 4-6-membered heterocyclylcarbonyl and 5-6-membered heteroaryl-oxy, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, (C 1-6 Alkyl) 2-amino, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-6 Alkylsulfonyl, C 1-6 Alkylthio, C 3-6 Cycloalkyl, 4-6 membered heterocyclic group, 5-6 membered heteroaryl, aryl, C 1-6 Alkylcarbonyl, aminocarbonyl, C 1-6 Alkylaminocarbonyl, (C 1-6 alkyl) 2-aminocarbonyl, 4-6-membered heterocyclylcarbonyl and 5-6-membered heteroaryl-oxy are unsubstituted or optionally substituted by one or more independently selected from hydroxy, amino, carboxyl, cyano, nitro, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkoxy C 1-6 Alkoxy, C 1-6 Alkylamino, (C 1-6 Alkyl)2amino, C 1-6 Alkylcarbonylamino, C 1-6 Alkylsulfonylamino, C 1-6 Alkylcarbonyloxy, C 3-6 Cycloalkyl, C3-6 Cycloalkylcarbonyloxy, C 2-8 Alkynyl, halo C 1-6 Alkyl, C 2-8 Alkenyl, halogenated C 1-6 Alkoxy group substitution;

[0114] The condition is that when Cy3 is hour, Not for

[0115] Another embodiment of the present invention relates to a compound represented by formula (i), an isomer thereof or a pharmaceutically acceptable salt thereof,

[0116] A is

[0117] X is selected from N or CH;

[0118] Cy1 is selected from and phenyl, the and phenyl are unsubstituted, or are each independently substituted with 1-3 R a1 replace;

[0119] Each R a1 are independently selected from hydrogen, halogen, hydroxy, amino, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, hydroxy C 1-6 alkyl;

[0120] B is -L2-Cy2-L3-Cy3-L4-Cy4-L5-;

[0121] L1, L2, L3, L4, L5, L6 are independently selected from a bond, -(CH2) n -(NH) m -, -O-, -C(O)-;

[0122] n and m are each independently 0, 1 or 2;

[0123] Cy2 is selected from 4-6 membered cycloalkyl, 4-6 membered heterocyclic group, 4-6 membered cycloalkenyl, 1-3 R a2 Substituted 4-6 membered cycloalkyl, 1-3 R a2 substituted 4-6 membered heterocyclic group, 1-3 R a2 a substituted 4-6 membered cycloalkenyl group, wherein the heteroatom of the 4-6 membered heterocyclic group is selected from O, N or S;

[0124] Cy3 is selected from described are unsubstituted or are each independently substituted with 1-3 R a3 replace;

[0125] Cy4 is selected from 3-8 membered cycloalkyl, 3-8 membered heterocyclic group, 3-8 membered cycloalkenyl, 6-13 membered bicyclic condensed ring cycloalkyl, 6-13 membered bicyclic condensed ring alkenyl, 6-13 membered bicyclic condensed ring heterocyclic group, 1-3 R a4 Substituted 3-8 membered cycloalkyl, 1-3 R a4 substituted 3-8 membered heterocyclic group, substituted by 1-3 R a4 Substituted 3-8 membered cycloalkenyl, 1-3 R a4 Substituted 6-13 bicyclic condensed ring cycloalkyl, 1-3 R a4 Substituted 6-13 membered bicyclic fused cycloalkenyl, 1-3 R a4 a substituted 6-13 membered bicyclic fused ring heterocyclic group, wherein the heteroatom of the 3-8 membered heterocyclic group or the 6-13 membered bicyclic fused ring heterocyclic group is selected from O, N or S;

[0126] Each R a2 、R a3 and R a4 When present, each is independently selected from hydrogen, halogen, hydroxy, carboxyl, amino, cyano, nitro, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, hydroxy C 1-6 Alkyl, C 1-6 Alkylamino, (C 1-6 alkyl) 2-amino, 3-8-membered cycloalkyl, 3-8-membered heterocyclic group, 3-8-membered cycloalkenyl group, wherein the C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, hydroxy C 1-6 Alkyl, C 1-6 Alkylamino, (C 1-6 alkyl) 2 amino, 3-8 membered cycloalkyl, 3-8 membered heterocyclyl, 3-8 membered cycloalkenyl are unsubstituted or optionally substituted with one or more selected from hydroxy, amino, carboxyl, cyano, nitro, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkoxy C 1-6 Alkoxy, C 1-6 Alkylamino, (C 1-6 Alkyl) 2-amino, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, 3-8 membered cycloalkyl, 3-8 membered heterocyclyl, 3-8 membered cycloalkenyl group substitution;

[0127] C is

[0128] X1 is N or CR b1 ;

[0129] X2 is N or CR b2 ;

[0130] X4 is N or CR b4 ;

[0131] X5 is N or CR b5 ;

[0132] R b1 、R b2 、R b3 、R b4 and R b5 are independently selected from hydrogen, halogen, hydroxyl, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, hydroxy C 1-6 Alkyl, C 1-6 Alkylamino, (C 1-6 Alkyl)2amino;

[0133] Cy5 is selected from 6-13 membered bicyclic alkenyl, 6-13 membered bicyclic heterocyclyl, 6-13 membered bicyclic heteroaryl, 8-21 membered polycyclic heterocyclyl, 8-21 membered polycyclic heteroaryl; the 6-13 membered bicyclic alkenyl, 6-13 membered bicyclic heterocyclyl, 6-13 membered bicyclic heteroaryl, 8-21 membered polycyclic heterocyclyl, 8-21 membered polycyclic heteroaryl are unsubstituted or optionally substituted with 1-3 R a5 replace;

[0134] Each R a5 are independently selected from hydroxy, amino, carboxyl, cyano, nitro, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, (C 1-6 Alkyl) 2-amino, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, C 2-8 Alkenyl, C 2-8 Alkynyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclyl, 5-6 membered heteroaryl, aryl, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, (C 1-6 Alkyl) 2-amino, halogenated C1-6 Alkyl, halogenated C 1-6 Alkoxy, C 2-8 Alkenyl, C 2-8 Alkynyl, C 3-6 Cycloalkyl, 4-6 membered heterocyclyl, 5-6 membered heteroaryl, aryl are unsubstituted or optionally substituted by one or more independently selected from hydroxy, amino, carboxyl, cyano, nitro, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkoxy C 1-6 Alkoxy, C 1-6 Alkylamino, (C 1-6 Alkyl)2amino, C 3-6 Cycloalkyl, C 3-6 Cycloalkylcarbonyloxy, C 2-8 Alkynyl, halo C 1-6 Alkyl, C 2-8 Alkenyl, halogenated C 1-6 Alkoxy groups are substituted.

[0135] Another embodiment of the present invention relates to a compound represented by formula (i), an isomer thereof or a pharmaceutically acceptable salt thereof, having a structure represented by formula (ii),

[0136] X is selected from N or CH;

[0137] Ring Cy1 is selected from and phenyl, the and phenyl are unsubstituted, or are each independently substituted with 1-3 R a1 replace;

[0138] Each R a1 are independently selected from hydrogen, C 1-6 Alkyl, C 1-6 alkoxy;

[0139] L1, L2, L3, L4, L5, L6 are independently selected from a bond, -(CH2) n -(NH) m -, -O-, -C(O)-;

[0140] n and m are each independently 0, 1 or 2;

[0141] Cy2 is selected from 4-6 membered nitrogen-containing heterocyclic groups or 1-3 R a2 a substituted 4-6 membered nitrogen-containing heterocyclic group;

[0142] Cy4 is selected from a 3-8 membered heterocyclic group, a4 substituted 3-8 membered heterocyclic group, 6-13 membered bicyclic spiro heterocyclic group or 1-3 Ra4 a substituted 6-13 membered bicyclic spiro heterocyclic group, wherein the heteroatom of the 3-8 membered heterocyclic group or the 6-13 membered bicyclic spiro heterocyclic group is selected from O, N or S;

[0143] Each R a2 and R a4 When present, each independently selected from hydrogen, C 1-6 Alkyl, 3-8 membered heterocyclic group, the C 1-6 The alkyl group or the 3-8 membered heterocyclic group is unsubstituted or substituted by one or more C 1-6 Alkyl or 3-8 membered heterocyclic group substitution;

[0144] X1 is N or CR b1 ;

[0145] X2 is N or CR b2 ;

[0146] X4 is N or CR b4 ;

[0147] X5 is N or CR b5 ;

[0148] R b1 、R b2 、R b3 、R b4 and R b5 are independently selected from hydrogen and halogen;

[0149] Cy5 is selected from 6-13 membered bicyclic alkenyl, 6-13 membered bicyclic heteroaryl, 8-21 membered polycyclic heterocyclyl, wherein the 6-13 membered bicyclic alkenyl, 6-13 membered bicyclic heteroaryl, 8-21 membered polycyclic heterocyclyl is unsubstituted or optionally substituted with 1-3 R a5 replace;

[0150] Each R a5 are independently selected from hydrogen, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, phenyl, the phenyl is unsubstituted or substituted by one or more halogen, halogenated C 1-6 Alkyl, C 1-6 Alkoxy substitution.

[0151] Another embodiment of the present invention relates to a compound represented by formula (ii), an isomer thereof or a pharmaceutically acceptable salt thereof,

[0152] X is selected from N or CH;

[0153] Cy1 is selected from and phenyl, the and phenyl are unsubstituted, or are each independently substituted with 1-3 R a1 replace;

[0154] Each R a1 are independently selected from hydrogen, methoxy, methyl, and ethyl;

[0155] L1 is selected from a bond, -NH-;

[0156] L2 is selected from a bond, -NH-;

[0157] Cy2 is selected from

[0158] L3 is selected from -CH2-, -C(O)-, -NH-CH2-;

[0159] Cy3 is selected from

[0160] L4 is selected from -CH2-, -NH-CH2-, -C(O)-;

[0161] Cy4 is selected from

[0162] L5 is selected from a bond;

[0163] Selected from

[0164] L6 is selected from a bond, -O-;

[0165] Cy5 is selected from described unsubstituted or optionally substituted with 1-3 R a5 replace;

[0166] Each R a5 are independently selected from hydroxy, methyl, methoxy, phenyl, The phenyl group is unsubstituted or substituted by one or more fluorine, methoxy, trifluoromethyl, replace.

[0167] In another embodiment of the present invention, Cy1 is selected from *Terminal is connected to L1.

[0168] In another embodiment of the present invention, the are unsubstituted, or are each independently substituted with 1-3 R a1 More preferably, each of the Ra1 Each independently selected from hydrogen, halogen, hydroxy, carboxyl, amino, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, hydroxy C 1-6 Alkyl, C 1-6 Alkylamino, (C 1-6 Alkyl)2amino, C 1-6 Alkylcarbonyl, aminocarbonyl, C 1-6 Alkylaminocarbonyl, (C 1-6 Alkyl) 2 aminocarbonyl; Still more preferably, each R a1 Each independently substituted with 1-3 halogens (such as F) or C 1-6 Alkyl (such as methyl) substitution.

[0169] In another embodiment of the present invention, Cy1 is selected from *Terminal is connected to L1.

[0170] In another embodiment of the present invention, L1, L2, L3, L4, L5, L6 are the same or different and are independently selected from a bond, -O-, -NH-, C 1-6 Alkylene, -NHC(O)-, NH(C 1-6 alkylene), -C(O)-.

[0171] In another embodiment of the present invention, L1 is selected from a bond, -NHC(O)-; preferably, when L1 is -NHC(O)-, the C(O) end is connected to Cy1.

[0172] In another embodiment of the present invention, L2 is selected from a bond, NH or NH(C 1-3 alkylene).

[0173] In another embodiment of the present invention, L2 is selected from a bond, -NH- or -NHCH 2- ; preferably a bond.

[0174] In another embodiment of the present invention, L3 is selected from C 1-3 Alkylene, -C(O), -CH2NR4-, -NR5-CH2-- or NHC 1-3 Alkylene, R4, R5 are independently selected from C3-6 cycloalkyl.

[0175] In another embodiment of the present invention, L3 is selected from methylene, -C(O)- or NHCH 2- ; preferably methylene.

[0176] In another embodiment of the present invention, L4 is selected from a bond, C1-3 Alkylene or -C(O)-.

[0177] In another embodiment of the present invention, L4 is selected from a bond, methylene or -C(O)-; preferably methylene.

[0178] In another embodiment of the present invention, L5 is selected from a bond or C 1-3 Alkylene.

[0179] In another embodiment of the present invention, L5 is selected from a bond or a methylene group; preferably a bond.

[0180] In another embodiment of the present invention, L6 is selected from a bond or -O-; preferably a bond.

[0181] In another embodiment of the present invention, Cy2 is selected from 4-10 membered cycloalkyl, 4-10 membered heterocyclyl, 4-10 membered cycloalkenyl, 4-10 membered cycloalkyl substituted by 1-3 Ra2, 4-10 membered heterocyclyl substituted by 1-3 Ra2, 4-10 membered cycloalkenyl substituted by 1-3 Ra2, Cy21-Cy22, wherein the heteroatom of the 4-10 membered heterocyclyl is selected from O, N or S; Cy21 and Cy22 are the same or different and are independently selected from 4-6 membered cycloalkyl, 4-6 membered heterocyclyl, 4-6 membered cycloalkenyl.

[0182] In another embodiment of the present invention, Cy2 is selected from 4-6 membered cycloalkyl, 4-6 membered heterocyclyl, 4-6 membered cycloalkenyl, 1-3 R a2 Substituted 4-6 membered cycloalkyl, 1-3 R a2 substituted 4-6 membered heterocyclic group, 1-3 R a2 a substituted 4- to 6-membered cycloalkenyl group, wherein the heteroatom of the 4- to 6-membered heterocyclic group is selected from O, N or S.

[0183] In another embodiment of the present invention, Cy2 is selected from unsubstituted or substituted with 1-3 R a2 Substituted 6-9 membered heterocyclic group, Cy21-Cy22; Cy21 and Cy22 are the same or different and are independently selected from cyclohexyl, piperazinyl, and piperidinyl.

[0184] In another embodiment of the present invention, Cy2 is selected from piperazinyl and piperidinyl which are unsubstituted or substituted with 1-3 H or F groups.

[0185] In another embodiment of the present invention, Cy2 is selected from unsubstituted or substituted with 1-3 R a2 Substituted piperazinyl, piperidinyl,

[0186] In another embodiment of the present invention, Cy2 is selected from (For example ), (For example ), (For example ), *end is connected to Cy1.

[0187] In another embodiment of the present invention, Cy3 is selected from 5-10 membered cycloalkyl, 5-10 membered heterocyclyl, 6-13 membered bicyclic fused cycloalkyl, 6-13 membered bicyclic fused cycloalkenyl, 6-13 membered bicyclic fused heterocyclyl, 8-13 membered bicyclic fused heteroaryl, 8-13 membered bicyclic fused aryl, 8-21 membered polycyclic fused cycloalkyl, 8-21 membered polycyclic fused cycloalkenyl, 8-21 membered polycyclic fused heterocyclyl, 8-21 membered polycyclic fused heteroaryl, 8-21 membered polycyclic fused aryl.

[0188] In another embodiment of the present invention, Cy3 is selected from a 5-6 membered cycloalkyl group or a 5-6 membered heterocyclyl group, wherein the 5-6 membered cycloalkyl group or the 5-6 membered heterocyclyl group is unsubstituted or each is independently substituted with 1-3 Ra3, and the heteroatom of the 5-6 membered heterocyclyl group is N, O, S, or Si.

[0189] In another embodiment of the present invention, Cy3 is selected from 5-6 membered cycloalkyl or 5-6 membered heterocyclic group; said 5-6 membered cycloalkyl or 5-6 membered heterocyclic group is unsubstituted or each is independently substituted with 1-3 R a3 replace.

[0190] In another embodiment of the present invention, Cy3 is selected from cyclohexyl, piperidinyl, tetrahydropyranyl, dioxanyl, tetrahydropyrrolyl; the cyclohexyl, piperidinyl, tetrahydropyranyl, dioxanyl, tetrahydropyrrolyl are unsubstituted or are each independently substituted with 1-3 R a3 Substituted; preferably cyclohexyl.

[0191] In another embodiment of the present invention, Cy3 is selected from described are unsubstituted or are each independently substituted with 1-3 R a3 replace.

[0192] In another embodiment of the present invention, Cy4 is selected from the group consisting of unsubstituted or optionally substituted with one, two or more C 1-6 Alkyl or C 1-6 Alkoxy-substituted 5- to 6-membered heterocyclic group.

[0193] In another embodiment of the present invention, Cy4 is selected from piperazinyl, For example *End is connected to L5.

[0194] In another embodiment of the present invention, Cy5 is selected from the group consisting of unsubstituted or substituted with 1-3 R a5 Substituted groups include: 6-13 membered bicyclic alkenyl, 6-13 membered bicyclic heteroaryl, and 8-21 membered polycyclic heterocyclyl.

[0195] In another embodiment of the present invention, Cy5 is selected from the group consisting of unsubstituted or substituted with 1-3 OH or phenyl groups. For example

[0196] In another embodiment of the present invention, Cy5 is For example

[0197] In another embodiment of the present invention, R a1 Selected from halogen, C 1-6 Alkyl, C 1-6 Alkoxy.

[0198] In another embodiment of the present invention, R a1 Selected from F, methyl, ethyl, methoxy.

[0199] In another embodiment of the present invention, each R a2 、R a3 and R a4 The same or different are independently selected from H, OH, amino, thiol, silanol, selenohydroxyl, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl-NH-, C 3-6 Cycloalkyl, C 1-6 Alkyl-C(O)NH-, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, hydroxy C 1-6 alkyl.

[0200] In another embodiment of the present invention, R a2 Selected from H, OH, amino, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl-NH-, C 3-6 Cycloalkyl, C 1-6 Alkyl-C(O)NH-.

[0201] In another embodiment of the present invention, R a2 Selected from H, F, OH, amino, methylamino, acetamido, methyl, methoxy, cyclopropyl.

[0202] In another embodiment of the present invention, R a3 and Ra4 are the same or different and are independently selected from H, halogen.

[0203] In another embodiment of the present invention, R a3 and R a4 are the same or different and are independently selected from H and F.

[0204] In another embodiment of the present invention, R a5 Selected from hydroxyl or C 6-10 Aryl.

[0205] In another embodiment of the present invention, R a5 Selected from hydroxyl or phenyl.

[0206] In another embodiment of the present invention, R a 5 is selected from hydroxyl, C6-10 aryl, and halogen-substituted C6-10 aryl.

[0207] In another embodiment of the present invention, Selected from unsubstituted or optionally substituted by R b1 、R b2 、R b3 、R b4 、R b5 The following groups substituted by 1 to 4 substituents: phenyl, 6-membered heteroaryl containing 1 or 2 heteroatoms, for example

[0208] Another embodiment of the present invention relates to a compound represented by formula (i), an isomer thereof, or a pharmaceutically acceptable salt thereof, having a structure represented by formula (iii):

[0209] X is selected from N or CH;

[0210] R a1 Selected from hydrogen, C 1-6 Alkyl, C 1-6 alkoxy;

[0211] L2, L3, L4, L5, L6 are independently selected from a bond, -(CH2) n -(NH) m -, -O-, -C(O)-;

[0212] n and m are each independently 0, 1 or 2;

[0213] Cy2 is selected from 4-6 membered nitrogen-containing heterocyclic groups or 1-3 R a2 a substituted 4-6 membered nitrogen-containing heterocyclic group;

[0214] Cy4 is selected from a 3-8 membered heterocyclic group, a4substituted 3-8 membered heterocyclic group, 6-13 membered bicyclic spiro heterocyclic group or 1-3 R a4 a substituted 6-13 membered bicyclic spiro heterocyclic group, wherein the heteroatom of the 3-8 membered heterocyclic group or the 6-13 membered bicyclic spiro heterocyclic group is selected from O, N or S;

[0215] Each R a2 and R a4 When present, each independently selected from hydrogen, C 1-6 Alkyl, 3-8 membered heterocyclic group, the C 1-6 The alkyl group or the 3-8 membered heterocyclic group is unsubstituted or substituted by one or more C 1-6 Alkyl or 3-8 membered heterocyclic group substitution;

[0216] X1 is N or CR b1 ;

[0217] X2 is N or CR b2 ;

[0218] X4 is N or CR b4 ;

[0219] X5 is N or CR b5 ;

[0220] R b1 、R b2 、R b3 、R b4 and R b5 are independently selected from hydrogen and halogen;

[0221] Cy5 is selected from 6-13 membered bicyclic alkenyl, 6-13 membered bicyclic heteroaryl, 8-21 membered polycyclic heterocyclyl, wherein the 6-13 membered bicyclic alkenyl, 6-13 membered bicyclic heteroaryl, 8-21 membered polycyclic heterocyclyl is unsubstituted or optionally substituted with 1-3 R a5 replace;

[0222] Each R a5 are independently selected from hydrogen, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, phenyl, the phenyl is unsubstituted or substituted by one or more halogen, halogenated C 1-6 Alkyl, C 1-6 Alkoxy substitution.

[0223] Another embodiment of the present invention relates to a compound represented by formula (i), an isomer thereof, or a pharmaceutically acceptable salt thereof, having a structure represented by formula (iv):

[0224] X is selected from N or CH;

[0225] Each Ra1 are independently selected from hydrogen, halogen, hydroxy, carboxyl, amino, cyano, nitro, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, hydroxy C 1-6 Alkyl, C 1-6 Alkylamino, (C 1-6 Alkyl)2amino, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-6 Alkylcarbonyl, aminocarbonyl, C 1-6 Alkylaminocarbonyl, (C 1-6 alkyl)2-aminocarbonyl;

[0226] L2, L3, L4, L5, L6 are independently selected from a bond, -(CH2) n -(NH) m -, -O-, -C(O)-;

[0227] n and m are each independently 0, 1 or 2;

[0228] Cy2 is selected from 4-6 membered nitrogen-containing heterocyclic groups or 1-3 R a2 a substituted 4-6 membered nitrogen-containing heterocyclic group;

[0229] Cy4 is selected from a 3-8 membered heterocyclic group, a4 substituted 3-8 membered heterocyclic group, 6-13 membered bicyclic spiro heterocyclic group or 1-3 R a4 a substituted 6-13 membered bicyclic spiro heterocyclic group, wherein the heteroatom of the 3-8 membered heterocyclic group or the 6-13 membered bicyclic spiro heterocyclic group is selected from O, N or S;

[0230] Each R a2 and R a4 When present, each independently selected from hydrogen, C 1-6 Alkyl, 3-8 membered heterocyclic group, the C 1-6 The alkyl group or the 3-8 membered heterocyclic group is unsubstituted or substituted by one or more C 1-6 Alkyl or 3-8 membered heterocyclic group substitution;

[0231] X1 is N or CR b1 ;

[0232] X2 is N or CR b2 ;

[0233] X4 is N or CR b4 ;

[0234] X5 is N or CR b5 ;

[0235] R b1 、R b2 、R b3 、R b4 and R b5 are independently selected from hydrogen and halogen;

[0236] Cy5 is selected from 6-13 membered bicyclic alkenyl, 6-13 membered bicyclic heteroaryl, 8-21 membered polycyclic heterocyclyl, wherein the 6-13 membered bicyclic alkenyl, 6-13 membered bicyclic heteroaryl, 8-21 membered polycyclic heterocyclyl is unsubstituted or optionally substituted with 1-3 R a5 replace;

[0237] Each R a5 are independently selected from hydrogen, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkyl, phenyl, the phenyl is unsubstituted or substituted by one or more halogen, halogenated C 1-6 Alkyl, C 1-6 Alkoxy substitution.

[0238] Another embodiment of the present invention relates to a compound represented by formula (i), an isomer thereof, or a pharmaceutically acceptable salt thereof, having a structure represented by formula (v):

[0239] A is

[0240] X is selected from N or CH;

[0241] Cy1 is selected from and phenyl, the and phenyl are unsubstituted, or are each independently substituted with 1-3 R a1 replace;

[0242] Each R a1 are independently selected from hydrogen, halogen, hydroxy, carboxyl, amino, cyano, nitro, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, hydroxy C 1-6 Alkyl, C 1-6 Alkylamino, (C 1-6 Alkyl)2amino, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-6 Alkylcarbonyl, aminocarbonyl, C 1-6 Alkylaminocarbonyl, (C 1-6 alkyl)2-aminocarbonyl;

[0243] L1, L2, L3, L4, L5, L6 are independently selected from a bond, -(CH2) n -(NH) m -、-O-、-S-、-NR2、-CR 31 R 32 -, -C(O)-, -C(O)O-, -C(O)NR4-, -NR5-C(O)-, C 2-8 Alkenyl and C 2-8 Alkynyl;

[0244] n and m are each independently any integer from zero to six;

[0245] R2, R 31 、R 32 , R4 and R5 are independently selected from hydrogen, halogen, hydroxy, carboxyl, amino, cyano, nitro, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, hydroxy C 1-6 Alkyl, C 1-6 Alkylamino, (C 1-6 Alkyl)2amino, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-6 Alkylcarbonyl, aminocarbonyl, C 1-6 Alkylaminocarbonyl, (C 1-6 alkyl)2aminocarbonyl, wherein the C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, hydroxy C 1-6 Alkyl, C 1-6 Alkylamino, (C 1-6 Alkyl)2amino, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-6 Alkylcarbonyl, aminocarbonyl, C 1-6 Alkylaminocarbonyl, (C 1-6 Alkyl) 2 aminocarbonyl is unsubstituted or optionally substituted by one or more independently selected from hydroxy, amino, carboxyl, cyano, nitro, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkoxy C 1-6 Alkoxy, C 1-6 Alkylamino, (C 1-6 Alkyl)2amino, C 1-6 Alkylcarbonylamino, C 1-6 Alkylsulfonylamino, C 1-6 Alkylcarbonyloxy, C 3-6Cycloalkyl, C 3-6 Cycloalkylcarbonyloxy, C 2-8 Alkynyl, halo C 1-6 Alkyl, C 2-8 Alkenyl, halogenated C 1-6 Alkoxy group substitution;

[0246] Cy2 is selected from 4-6 membered cycloalkyl, 4-6 membered heterocyclic group, 4-6 membered cycloalkenyl, 1-3 R a2 Substituted 4-6 membered cycloalkyl, 1-3 R a2 substituted 4-6 membered heterocyclic group, 1-3 R a2 a substituted 4-6 membered cycloalkenyl group, wherein the heteroatom of the 4-6 membered heterocyclic group is selected from O, N or S;

[0247] Cy4 is selected from 3-8 membered cycloalkyl, 3-8 membered heterocyclic group, 3-8 membered cycloalkenyl, 6-13 membered bicyclic condensed ring cycloalkyl, 6-13 membered bicyclic condensed ring alkenyl, 6-13 membered bicyclic condensed ring heterocyclic group, 1-3 R a4 Substituted 3-8 membered cycloalkyl, 1-3 R a4 substituted 3-8 membered heterocyclic group, substituted by 1-3 R a4 Substituted 3-8 membered cycloalkenyl, 1-3 R a4 Substituted 6-13 bicyclic condensed ring cycloalkyl, 1-3 R a4 Substituted 6-13 membered bicyclic fused cycloalkenyl, 1-3 R a4 a substituted 6-13 membered bicyclic fused ring heterocyclic group, wherein the heteroatom of the 3-8 membered heterocyclic group or the 6-13 membered bicyclic fused ring heterocyclic group is selected from O, N or S;

[0248] Each R a2 and R a4 When present, each is independently selected from hydrogen, halogen, hydroxy, carboxyl, amino, cyano, nitro, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, hydroxy C 1-6 Alkyl, C 1-6 Alkylamino, (C 1-6 Alkyl)2amino, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-6 Alkylcarbonyl, aminocarbonyl, C 1-6 Alkylaminocarbonyl, (C 1-6 alkyl) 2-aminocarbonyl, 3-8-membered cycloalkyl, 3-8-membered heterocyclic group, 3-8-membered cycloalkenyl, wherein the C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C1-6 Alkoxy, hydroxy C 1-6 Alkyl, C 1-6 Alkylamino, (C 1-6 Alkyl)2amino, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-6 Alkylcarbonyl, aminocarbonyl, C 1-6 Alkylaminocarbonyl, (C 1-6 alkyl) 2-aminocarbonyl, 3-8-membered cycloalkyl, 3-8-membered heterocyclyl, 3-8-membered cycloalkenyl are unsubstituted or optionally substituted with one or more hydroxyl, amino, carboxyl, cyano, nitro, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkoxy C 1-6 Alkoxy, C 1-6 Alkylamino, (C 1-6 Alkyl)2amino, C 1-6 Alkylcarbonylamino, C 1-6 Alkylsulfonylamino, C 1-6 Alkylcarbonyloxy, C 3-6 Cycloalkyl, C 3-6 Cycloalkylcarbonyloxy, C 2-8 Alkynyl, halo C 1-6 Alkyl, C 2-8 Alkenyl, halogenated C 1-6 Alkoxy, 3-8 membered cycloalkyl, 3-8 membered heterocyclyl, 3-8 membered cycloalkenyl group substitution;

[0249] X1 is N or CR b1 ;

[0250] X2 is N or CR b2 ;

[0251] X4 is N or CR b4 ;

[0252] X5 is N or CR b5 ;

[0253] R b1 、R b2 、R b3 、R b4 and R b5 are independently selected from hydrogen, halogen, hydroxy, carboxyl, amino, cyano, nitro, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, hydroxy C 1-6 Alkyl, C 116 Alkylamino, (C 1-6 Alkyl)2amino, C2-8 Alkenyl, C 2-8 Alkynyl, C 1-6 Alkylcarbonyl, aminocarbonyl, C 1-6 Alkylaminocarbonyl, (C 1-6 alkyl)2-aminocarbonyl;

[0254] Cy5 is selected from 6-13 membered bicyclic condensed ring group and 8-21 membered polycyclic condensed ring group; the 6-13 membered bicyclic condensed ring group or 8-21 membered polycyclic condensed ring group is unsubstituted or replaced by 1-3 R a5 replace;

[0255] Each R a5 are independently selected from hydroxy, amino, carboxyl, cyano, nitro, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, (C 1-6 Alkyl) 2-amino, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-6 Alkylsulfonyl, C 1-6 Alkylthio, C 3-6 Cycloalkyl, 4-6 membered heterocyclic group, 5-6 membered heteroaryl, aryl, C 1-6 Alkylcarbonyl, aminocarbonyl, C 1-6 Alkylaminocarbonyl, (C 1-6 alkyl) 2-aminocarbonyl, 4-6-membered heterocyclylcarbonyl and 5-6-membered heteroaryl-oxy, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, (C 1-6 Alkyl) 2-amino, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-6 Alkylsulfonyl, C 1-6 Alkylthio, C 3-6 Cycloalkyl, 4-6 membered heterocyclic group, 5-6 membered heteroaryl, aryl, C 1-6 Alkylcarbonyl, aminocarbonyl, C 1-6 Alkylaminocarbonyl, (C 1-6 alkyl) 2-aminocarbonyl, 4-6-membered heterocyclylcarbonyl and 5-6-membered heteroaryl-oxy are unsubstituted or optionally substituted by one or more independently selected from hydroxy, amino, carboxyl, cyano, nitro, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkoxy C 1-6 Alkoxy, C1-6 Alkylamino, (C 1-6 Alkyl)2amino, C 1-6 Alkylcarbonylamino, C 1-6 Alkylsulfonylamino, C 1-6 Alkylcarbonyloxy, C 3-6 Cycloalkyl, C 3-6 Cycloalkylcarbonyloxy, C 2-8 Alkynyl, halo C 1-6 Alkyl, C 2-8 Alkenyl, halogenated C 1-6 Alkoxy groups are substituted.

[0256] The compound according to any embodiment, its isomer or pharmaceutically acceptable salt thereof,

[0257] Cy1 is selected from and phenyl, the and phenyl are unsubstituted, or are each independently substituted with 1-3 R a1 replace.

[0258] The compound according to any embodiment, its isomer or pharmaceutically acceptable salt thereof,

[0259] Cy1 is unsubstituted or replaced by 1-3 R a1 Replaced

[0260] The compound according to any embodiment, its isomer or pharmaceutically acceptable salt thereof,

[0261] Cy1 is unsubstituted or replaced by 1-3 R a1 Replaced

[0262] The compound according to any embodiment, its isomer or pharmaceutically acceptable salt thereof,

[0263] Cy1 is unsubstituted or replaced by 1-3 R a1 Replaced

[0264] The compound according to any embodiment, its isomer or pharmaceutically acceptable salt thereof,

[0265] Cy1 is unsubstituted or replaced by 1-3 R a1 Replaced

[0266] The compound according to any embodiment, its isomer or pharmaceutically acceptable salt thereof,

[0267] Cy1 is unsubstituted or replaced by 1-3 R a1 Replaced

[0268] In another embodiment of the present invention, the compound represented by formula (i) has the structure shown below:

[0269] Wherein, Y is selected from N or CR a2 ;X, L1, Cy1, R a2 Has the definition given above.

[0270] In another embodiment of the present invention, the compound represented by formula (i-1) has the structure shown below:

[0271] Wherein, Y is selected from N or CR a2 ;X, L1, Cy1, R a2 Has the definition given above.

[0272] In another embodiment of the present invention, the compound represented by formula (i) has the structure shown below:

[0273] Wherein, Z1 and Z2 are the same or different and are independently selected from C(R a3 )(R a3 )、O、N(R a3 )、S、Si(R a3 )(R a3 ); X, G, L2, L3, L4, L5, Cy2, Cy4, Cy5, R a1 、R a33 , X1, X2, X4, X5 have the definitions described above.

[0274] In another embodiment of the present invention, the compound represented by formula (i-2) has the structure shown below:

[0275] Wherein, Z3 is selected from N, C or CR a4 ; Indicates a single bond or a double bond; G, Y, Z1, Z2, R b1 、R b2 、R b4 、R b5 、R a1 、R a5 Has the definition given above.

[0276] In some embodiments of the present invention, the compound of the aforementioned formula (i), its isomers or pharmaceutically acceptable salts thereof are shown in the following table:

[0277] Table 1

[0278] Table 2

[0279] Table 3

[0280] Table 4

[0281] Table 5

[0282] Table 6

[0283] Table 7

[0284] The present invention also provides a pharmaceutical composition comprising the compound of formula (i), its isomers or pharmaceutically acceptable salts thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

[0285] The present invention also provides use of the compound of formula (i), its isomer or pharmaceutically acceptable salt thereof, or the pharmaceutical composition in the preparation of a drug for treating and / or preventing a disease or condition by degrading a target protein.

[0286] According to an embodiment of the present invention, the disease or disorder is selected from abnormal cell proliferation, tumors, immune diseases, diabetes, cardiovascular diseases, infectious diseases and inflammatory diseases; preferably tumors and infectious diseases.

[0287] According to an embodiment of the present invention, the tumor is cancer; preferably selected from breast cancer, endometrial cancer, testicular cancer, cervical cancer, prostate cancer, ovarian cancer, fallopian tube tumor, leukemia, skin cancer, squamous cell carcinoma, basal cell carcinoma, bladder cancer, colorectal cancer, esophageal cancer, head and neck cancer, kidney cancer, liver cancer, lung cancer, pancreatic cancer, gastric cancer, lymphoma, melanoma, sarcoma, peripheral neuroepithelial tumor, glioma, astrocytoma, ependymoma, glioblastoma, neuroblastoma, gangliocytoma, medulloblastoma, pineal cell tumor, meningioma, neurofibroma, neurilemoma, thyroid cancer, Wilms' tumor and teratoma; more preferably selected from breast cancer, endometrial cancer, testicular cancer, cervical cancer, prostate cancer, ovarian cancer and fallopian tube tumor.

[0288] According to an embodiment of the present invention, the infectious disease is selected from viral pneumonia, influenza, avian influenza, meningitis, gonorrhea, or infection with HIV, HBV, HCV, HSV, HPV, RSV, CMV, Ebola virus, flavivirus, rotavirus, coronavirus, EBV, drug-resistant virus, RNA virus, DNA virus, adenovirus, poxvirus, picornavirus, togavirus, orthomyxovirus, retrovirus, hepadnavirus, Gram-negative bacteria, Gram-positive bacteria, atypical bacteria, Staphylococcus, Streptococcus, Escherichia coli, Salmonella, Helicobacter pylori, Chlamydiaceae, Mycoplasmaceae, fungi, protozoa, intestinal worms, worms, prions or parasites.

[0289] The present invention also provides the use of a compound of formula (i), an isomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the preparation of a medicament for treating and / or preventing estrogen receptor-mediated or dependent diseases or conditions, wherein the estrogen receptor-mediated or dependent disease or condition is a tumor, preferably cancer, more preferably selected from breast cancer, endometrial cancer, testicular cancer, cervical cancer, prostate cancer, ovarian cancer, and fallopian tube tumors, and most preferably breast cancer.

[0290] The present invention also provides a method for treating and / or preventing a disease or condition by degrading a target protein, comprising administering to a patient a therapeutically effective amount of a compound of formula (i), an isomer thereof, or a pharmaceutically acceptable salt thereof.

[0291] The present invention also provides a method for treating and / or preventing estrogen receptor-mediated or dependent diseases or conditions, comprising administering to a patient a therapeutically effective amount of a compound of formula (i), an isomer thereof, or a pharmaceutically acceptable salt thereof. Beneficial effects

[0292] The present invention provides a compound represented by formula (i), an isomer thereof or a pharmaceutically acceptable salt thereof, which can be used as an estrogen receptor degrader for preparing a drug for treating and / or preventing estrogen receptor-mediated or dependent diseases or conditions. BRIEF DESCRIPTION OF THE DRAWINGS

[0293] Figure 1 shows the effect of compound IV-9 on ER protein degradation in MCF-7 cells;

[0294] FIG2 shows the effect of compound VI-20 on ER protein degradation in MCF-7 cells;

[0295] FIG3 shows the effect of compound VI-23 on ER protein degradation in MCF-7 cells;

[0296] Figure 4 shows the effect of compound VI-24 on ER protein degradation in MCF-7 cells;

[0297] FIG5 shows the effect of compound VI-29 on ER protein degradation in MCF-7 cells;

[0298] FIG6 shows the ER protein degradation effect of compound VI-28 on MCF-7 cells.

[0299] Definitions and Explanations of Terms

[0300] Unless otherwise indicated, the definitions of groups and terms in this specification and claims, including definitions used as examples, exemplary definitions, preferred definitions, definitions in tables, and definitions of specific compounds in the Examples, may be arbitrarily combined and coupled with one another. The group definitions and compound structures resulting from such combinations and couplings should be understood to be within the scope of this specification and / or claims.

[0301] The "halogen" described in the present invention refers to fluorine, chlorine, bromine, iodine, etc., preferably fluorine and chlorine.

[0302] The term "halo" as used herein means that any hydrogen atom in a substituent group may be replaced by one or more halogen atoms, which may be the same or different. "Halogen" is as defined above.

[0303] The "C 1-6The term "alkyl" refers to a straight or branched chain alkyl derived from a hydrocarbon moiety containing 1 to 6 carbon atoms by removing a hydrogen atom, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, n-hexyl, isohexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 2-ethylbutyl and 1-methyl-2-methylpropyl. The "C 1-6 "Alkyl" is preferably C 1-4 Alkyl, C 1-3 alkyl.

[0304] The "C 2-8 The term "alkenyl" refers to a straight chain, branched chain or cyclic olefin group derived from an olefin moiety of 2 to 8 carbon atoms containing a carbon-carbon double bond by removing one hydrogen atom, such as ethenyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 1,3-butadienyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 1,3-pentadienyl, 1,4-pentadienyl, 1-hexenyl and 1,4-hexadienyl.

[0305] The "C 2-8 "Alkynyl" refers to a straight-chain or branched alkyne group derived from an alkyne portion of 2 to 8 carbon atoms containing a carbon-carbon triple bond by removing a hydrogen atom, such as ethynyl, propynyl, 2-butynyl, 2-pentynyl, 3-pentynyl, 4-methyl-2-pentynyl, 2-hexynyl, 3-hexynyl, etc. The "C 2-8 "Alkynyl" is preferably C 2-4 Alkynyl, C 2-3 Alkynyl.

[0306] The "C 1-6 "Alkoxy" refers to the "C 1-6 Alkyl" is a group connected to the parent molecule through an oxygen atom, that is, "C 1-6 Alkyl-O-" groups, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, n-pentoxy, neopentoxy and n-hexoxy, etc. The "C 1-6 "Alkoxy" is preferably C 1-4 Alkoxy, C 1-3 Alkoxy.

[0307] The "C 1-6 Alkylamino", "(C 1-6 Alkyl)2amino", "C 1-6 Alkylcarbonylamino", "C 1-6 Alkylsulfonylamino", "C1-6 Alkylaminocarbonyl", "(C 1-6 Alkyl)2amino-carbonyl", "C 1-6 Alkoxy-carbonyl", "C 1-6 Alkylsulfonyl", "C 1-6 Alkylthio", "C 1-6 Alkylcarbonyl", "aminocarbonyl", "hydroxyl C 1-6 "Alkyl" refers to C 1-6 Alkyl-NH-, (C 1-6 Alkyl)(C 1-6 Alkyl) N-, C 1-6 Alkyl-C(O)-NH-, C 1-6 Alkyl-S(O)2-NH2-, C 1-6 Alkyl-NH-C(O)-, (C 1-6 Alkyl)(C 1-6 Alkyl)NC(O)-, C 1-6 Alkyl-OC(O)-, C 1-6 Alkyl-S(O)2-, C 1-6 Alkyl-S-, C 1-6 Alkyl-C(O)-, NH 2- C(O)-、OH-C 1-6 Alkyl-; the "C 1-6 "Alkyl" is as defined above, preferably "C 1-4 Alkyl, C 1-3 alkyl".

[0308] The "condensed ring" described in the present invention refers to a polycyclic structure formed by two or more cyclic structures in the form of parallel, spiro or bridged connections. Each cyclic structure refers to any monocyclic alkyl, monoheterocyclic, monocycloalkenyl, phenyl or monoheteroaryl. The parallel ring refers to a condensed ring structure formed by two or more cyclic structures sharing two adjacent ring atoms (i.e., sharing a bond). The bridged ring refers to a condensed ring structure formed by two or more cyclic structures sharing two non-adjacent ring atoms. The spiro ring refers to a condensed ring structure formed by two or more cyclic structures sharing one ring atom. Multiple cyclic structures are optionally connected in parallel, spiro or bridged modes.

[0309] A bicyclic fused ring group is one in which two ring structures are connected in a parallel, spiro, or bridged manner, such as a 6-13 membered bicyclic fused ring group. The 6-13 membered bicyclic fused ring group further includes a 6-13 membered bicyclic fused cycloalkyl group, a 6-13 membered bicyclic fused cycloalkenyl group, a 6-13 membered bicyclic fused heterocyclic group, an 8-13 membered bicyclic fused heteroaryl group, and an 8-13 membered bicyclic fused aryl group.

[0310] A polycyclic fused ring group is one in which two or more cyclic structures are connected by a parallel, spiro, or bridge connection. For example, a monocyclic ring structure is connected by a parallel, spiro, or bridge connection to a 6-13 membered bicyclic fused ring group, such as an 8-21 membered polycyclic fused ring group. The 8-21 membered polycyclic fused ring group further includes an 8-21 membered polycyclic fused cycloalkyl group, an 8-21 membered polycyclic fused cycloalkenyl group, an 8-21 membered polycyclic fused heterocyclic group, an 8-21 membered polycyclic fused heteroaryl group, and an 8-21 membered polycyclic fused aryl group.

[0311] The 8-21 membered polycyclic fused heterocyclic group includes an 8-21 membered polycyclic bridged heterocyclic group, an 8-21 membered polycyclic fused heterocyclic group and an 8-21 membered polycyclic spiro heterocyclic group.

[0312] Examples of 8-21 membered polycyclic heterocyclic groups include, but are not limited to

[0313] The 3-8 membered monocyclic group of the present invention includes monocyclic alkyl, monoheterocyclic, monocyclic alkenyl, monoheteroaryl and phenyl.

[0314] Monocycloalkyl groups are cyclic hydrocarbon groups containing 3 to 13 carbon atoms, including 3 to 13-membered cycloalkyl groups, 3 to 8-membered cycloalkyl groups, 4 to 7-membered cycloalkyl groups, 4 to 6-membered cycloalkyl groups, and 5 to 6-membered cycloalkyl groups. Examples of 3 to 8-membered cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl groups.

[0315] A monoheterocyclic group refers to a non-aromatic cyclic group in which at least one ring carbon atom is replaced by a heteroatom selected from O, S, and N, preferably 1-3 heteroatoms. The monoheterocyclic group may be saturated or partially saturated, and includes 3-13 membered heterocyclic groups, 3-8 membered heterocyclic groups, 3-6 membered heterocyclic groups, 4-6 membered heterocyclic groups, 4-7 membered heterocyclic groups, 5-7 membered heterocyclic groups, 5-6 membered heterocyclic groups, 4-6 membered nitrogen-containing heterocyclic groups, 5-6 membered oxygen-containing heterocyclic groups, 3-8 membered nitrogen-containing heterocyclic groups, 5-6 membered nitrogen-containing heterocyclic groups, and 5-6 membered saturated heterocyclic groups. “3-8 membered saturated heterocyclic group”, examples of which include but are not limited to aziridine, oxirane, thiirane, azetidinyl, oxetanyl, thietanyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydrothiophenyl, imidazolidinyl, pyrazolidinyl, 1,2-oxazolidinyl, 1,3-oxazolidinyl, 1,2-thiazolidinyl, 1,3-thiazolidinyl, tetrahydro-2H-pyranyl, tetrahydro-2H-thiopyranyl, piperidinyl, piperazinyl, morpholinyl, 1,4-dioxanyl, 1,4-oxathianyl; “3-8 membered partially saturated heterocyclic group”, examples of which include but are not limited to 4,5-dioxanyl, oxazolyl, 2,3-dihydro-1H-imidazolyl, 4,5-dihydro-1H-imidazolyl, 4,5-dihydro-1H-pyrazolyl, 4,5-dihydro-3H-pyrazolyl, 4,5-dihydrothiazolyl, 2,5-dihydrothiazolyl, 2H-pyranyl, 4H-pyranyl, 2H-thiopyranyl, 4H-thiopyranyl, 2,3,4,5-tetrahydropyridinyl, 1,2-isoxazinyl, 1,4-isoxazinyl or 6H-1,3-oxazinyl, etc.

[0316] Monocycloalkenyl refers to a partially saturated carbocyclic group, including 3-13 membered cycloalkenyl, 3-8 membered cycloalkenyl, 4-7 membered cycloalkenyl, and 5-6 membered cycloalkenyl.

[0317] The heteroaryl group described in the present invention refers to an aromatic cyclic group in which at least one ring carbon atom is replaced by a heteroatom selected from O, S, and N. The monoheteroaryl group may be a 5-7 membered heteroaryl group or a 5-6 membered heteroaryl group, and examples thereof include but are not limited to furyl, imidazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, oxazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyrrolyl, tetrazolyl, thiadiazolyl, thienyl, triazolyl, and triazinyl.

[0318] 6-13 bicyclic condensed cycloalkyl includes cycloalkyl, bridged cycloalkyl, spirocycloalkyl. It can be saturated, partially saturated or unsaturated, but not aromatic. Cycloalkyl can be 6-11 membered cycloalkyl, 7-10 membered cycloalkyl, and its representative examples include but are not limited to bicyclo [3.1.1] heptane, bicyclo [2.2.1] heptane, bicyclo [2.2.2] octane, bicyclo [3.2.2] nonane, bicyclo [3.3.1] nonane and bicyclo [4.2.1] nonane. The spirocyclyl can be 7-12 membered spirocyclyl, 7-11 membered spirocyclyl, 10-11 membered spirocyclyl, and its examples include but are not limited to: The bridged ring group may be a 6-11 membered bridged ring group or a 7-10 membered bridged ring group, and examples thereof include but are not limited to:

[0319] 6-13 membered bicyclic fused cycloalkenyl groups include cycloalkenyl, bridged cycloalkenyl, and spirocycloalkenyl. Representative examples of 6-13 membered bicyclic cycloalkenyl groups include, but are not limited to

[0320] 6-13 membered bicyclic fused heterocyclic groups include heterocyclic groups, spiro heterocyclic groups, and bridged heterocyclic groups, which may be saturated, partially saturated, or unsaturated, but not aromatic. A fused heterocyclic group is a 5-6 membered monocyclic heterocyclic group fused to a benzene ring, a 5-6 membered monocyclic cycloalkyl group, a 5-6 membered monocyclic cycloalkenyl group, a 5-6 membered monocyclic heterocyclic group, or a 5-6 membered monocyclic heteroaryl group. The heterocyclic group may be a 6-12 membered heterocyclic group, a 7-10 membered heterocyclic group, a 6-10 membered heterocyclic group, an 8-10 membered bicyclic heterocyclic group, or a 6-12 membered saturated heterocyclic group. Representative examples include, but are not limited to, 3-azabicyclo[3.1.0]hexane, 3,6-diazabicyclo[3.2.0]heptane, 3,8-diazabicyclo[4.2.0]octanyl, 3,7-diazabicyclo[4.2.0]octanyl, octahydropyrrolo[ 3,4-c]pyrrolyl, octahydropyrrolo[3,4-b]pyrrolyl, octahydropyrrolo[3,4-b][1,4]oxazinyl, octahydro-1H-pyrrolo[3,4-c]pyridinyl, 2,3-dihydrobenzofuran-2-yl, 2,3-dihydrobenzofuran-3-yl, dihydroindole-1-yl, dihydroindole-2-yl, dihydroindole-3-yl, 2,3-dihydrobenzothiophen-2-yl, octahydro-1H-indole, octahydrobenzofuranyl. The spiroheterocyclyl may be a 6-12 membered spiroheterocyclyl, a 7-11 membered spiroheterocyclyl, a 6-12 membered saturated spiroheterocyclyl, or a 10-11 membered bicyclic spiroheterocyclyl, examples of which include but are not limited to:

[0321] The bridged heterocyclic group may be a 6-12 membered bridged heterocyclic group, a 7-11 membered bridged heterocyclic group, or a 6-12 membered saturated bridged heterocyclic group, examples of which include but are not limited to:

[0322] An 8-13 membered bicyclic fused heteroaryl group refers to a group formed by a monocyclic heteroaryl ring fused to a phenyl group or a monoheteroaryl group. The fused heteroaryl group may be an 8-13 membered heteroaryl group, a 9-10 membered heteroaryl group, or an 8-10 membered bicyclic heteroaryl group. Examples thereof include but are not limited to

[0323] The 8-13 membered bicyclic fused aryl group refers to a group formed by condensing a single aromatic ring to a single aromatic group, including naphthalene, phenanthrene and the like.

[0324] The term "pharmaceutically acceptable salt" as used herein refers to pharmaceutically acceptable acid and base addition salts or solvates thereof. Such pharmaceutically acceptable salts include salts of acids such as hydrochloric acid, phosphoric acid, hydrobromic acid, sulfuric acid, sulfurous acid, formic acid, toluenesulfonic acid, methanesulfonic acid, nitric acid, benzoic acid, citric acid, tartaric acid, maleic acid, hydroiodic acid, and alkanoic acids such as acetic acid and HOOC-(CH2)n-COOH (wherein n is 0 to 4). Salts of bases such as sodium, potassium, calcium, and ammonium salts are known to those skilled in the art. Numerous non-toxic, pharmaceutically acceptable addition salts are known to those skilled in the art.

[0325] The "isomers" mentioned in the present invention refer to stereoisomers and tautomers.

[0326] Stereoisomers refer to enantiomers produced when asymmetric atoms exist in a compound; cis-trans isomers are produced when a double bond or a cyclic structure exists in a compound; all enantiomers, diastereomers, racemates, cis-trans isomers, geometric isomers, epimers and mixtures thereof of the compounds of formula (I) are included in the scope of the present invention.

[0327] "Tautomers" refer to functional group isomers produced by the rapid movement of an atom in a molecule between two positions. Tautomers are a special type of functional group isomers. For example, the tautomerism of carbonyl compounds containing α-H is more specific. Such as other proton migration tautomerism, specifically phenol-keto tautomerism, nitroso-oxime tautomerism, imine-enamine tautomerism.

[0328] T, T1, and T2 are each independently any group that conforms to the bonding rules of the compound.

[0329] The R of the present invention a2 and R a4 , and can be optionally connected to L2, L3, L4 or L5 when it complies with the bonding rules. DETAILED DESCRIPTION

[0330] The technical solutions of the present disclosure will be further described in detail below with reference to specific embodiments. It should be understood that the following embodiments are merely illustrative and explanations of the present disclosure and should not be construed as limiting the scope of protection of the present disclosure. All technologies implemented based on the above content of the present disclosure are included within the scope of protection intended by the present disclosure.

[0331] Unless otherwise specified, the raw materials and reagents used in the following examples are commercially available or can be prepared by known methods.

[0332] Abbreviations of some reagents

[0333] BnBr, benzyl bromide

[0334] TIPT, tetraisopropyl titanate

[0335] STAB, sodium triacetoxyborohydride

[0336] TBAF, tetrabutylammonium fluoride

[0337] NMO, N-methylmorpholine oxide

[0338] TPAP, tetra-n-propylammonium perruthenate

[0339] Pd-PEPPSI IHept-Cl, (SP-4-1)-[1,3-bis[2,6-bis(1-propylbutyl)phenyl]-4,5-dichloro-1,3-dihydro-2H-imidazol-2-ylidene]dichloro(3-chloropyridine-KN)palladium

[0340] Xphos-Pd-G2, chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)

[0341] Pd(dppf)Cl2, 1,1′-bis(diphenylphosphino)ferrocenepalladium(II) dichloride

[0342] Mn(TMHD)3, tris(2,2,6,6-tetramethyl-3,5-heptenoate)manganese

[0343] PhSiH3, phenylsilane

[0344] PMBCl, methoxybenzyl chloride

[0345] The structures of the individual specific compounds contained in the compound of formula (i) of the present invention are similar, and their synthesis methods or mechanisms are similar. For the convenience of those skilled in the art, for example, their general synthesis methods are as follows:

[0346] Step 1: Using the aldehyde compound int-1 and the amino compound int-2 as starting materials, the intermediate int-3 is obtained through reductive amination.

[0347] Step 2: The intermediate int-3 is further hydrogenated and reduced to obtain the final product compound.

[0348] In the above general formula, X is selected from N or CH;

[0349] Y1, Y2 and Y3 are selected from N, NR a1 , CR a1 、C(R a1 )2 or C(O);

[0350] M is selected from N or CR a2 ;

[0351] Refers to single bonds or double bonds that conform to the bonding rules.

[0352] The above general formulas int-1, int-2, int-3 and compound may be further substituted by substituents, and the scope of the substituents is the same as any embodiment described in the specification.

[0353] Example 1: Synthesis of 1-(5-fluoro-6-(4-((1R,2R)-2-((4-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)piperazin-1-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (Compound IV-5)

[0354] Step 1: Synthesis of 6-methoxy-2-phenyl-3,4-dihydronaphthalen-1(2-hydro)-one

[0355] Toluene (750 ml), potassium tert-butoxide (75.60 g, 673.73 mmol), palladium acetate (7.8 g, 34.74 mmol), and 1,1′-binaphthyl-2,2′-bisdiphenylphosphine (25.8 g, 41.43 mmol) were added sequentially to a single-necked flask at room temperature and stirred thoroughly. 6-Methoxy-1-naphthyl ketone (60 g, 340.5 mmol) and bromobenzene (53.4 g, 340.5 mmol) were then added, and the mixture was heated to 100°C for 3 h. The mixture was cooled to room temperature, quenched with saturated ammonium chloride solution (500 mL), and extracted with methyl tert-butyl ether (500 mL x 3). The organic phases were combined and washed sequentially with saturated brine and water. The mixture was dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (eluent: ethyl acetate / petroleum ether = 0-15%) to obtain 51 g of a white solid in a 59.3% yield. 1 H NMR (400MHz, DMSO-d6) δ7.92-7.85 (m, 1H), 7.32 (t, J=7.6Hz, 2H), 7.28-7.22 (m, 1H), 7.21-7.15 (m, 2H), 6.93 (d, J=7.2Hz, 2H), 3.85 (s, 4H ), 3.11 (ddd, J=16.0, 10.8, 4.6Hz, 1H), 2.96 (dt, J=16.8, 4.4Hz, 1H), 2.31 (dddt, J=35.2, 17.7, 9.3, 4.4Hz, 2H). MS (ESI) m / z: 253.4[M+H] + .

[0356] Step 2: Synthesis of 4-bromo-7-methoxy-3-phenyl-1,2-dihydronaphthalene

[0357] To a 500 mL flask, add 6-methoxy-2-phenyl-3,4-dihydronaphthalen-1(2-hydro)-one (51 g, 202.2 mmol) and toluene (800 mL) and stir until completely dissolved. Slowly add a solution of phosphorus tribromide (108 g, 398.9 mmol) in toluene (400 mL), heat to reflux, and react for 24 hours before evaporating most of the toluene. After cooling, add 1000 mL of dichloromethane and wash once with 500 mL of saturated sodium bisulfite and once with water. Dry over anhydrous sodium sulfate, concentrate, and purify by column chromatography (eluent: dichloromethane / petroleum ether = 0-30%) to obtain 42 g of a white solid in a 66% yield.

[0358] Step 3: Synthesis of 4-(6-methoxy-2-phenyl-3,4-dihydronaphthalen-1-yl)phenol

[0359] The compound 4-bromo-7-methoxy-3-phenyl-1,2-dihydronaphthalene (42 g, 133.2 mmol), 4-hydroxyphenylboronic acid (23.85 g, 172.9 mmol), tetrakistriphenylphosphine palladium (5.13 g, 4.4 mmol), and tetrahydrofuran (600 ml) were added to a 2L three-necked flask. A solution of sodium carbonate (42.34 g, 399.4 mmol) in water (200 mL) was added, stirred, and the mixture was heated to reflux for 18 hours. After cooling, the mixture was adjusted with dilute hydrochloric acid until distinct layers formed. The layers were separated, and the aqueous layer was extracted with ethyl acetate (500 mL x 2). The organic phases were combined, washed sequentially with saturated sodium carbonate solution and saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (eluent: dichloromethane / petroleum ether = 0-30%) to obtain 30.4 g of a white solid in a yield of 69%. 1 H NMR (400MHz, DMSO-d6) δ9.31 (s, 1H), 7.12 (t, J=7.5Hz, 2H), 7.06-6.99 (m, 3H), 6.84 (d, J=2.6Hz, 1H), 6.8 0-6.75 (m, 2H), 6.67-6.57 (m, 4H), 3.75 (s, 3H), 2.89 (dd, J=9.2, 6.5Hz, 2H), 2.68 (dd, J=9.2, 6.4Hz, 2H).

[0360] Step 4: Synthesis of 4-(6-methoxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenol

[0361] At room temperature, methanol (250 ml), tetrahydrofuran (250 ml), 20% palladium hydroxide / carbon (13 g), and 4-(6-methoxy-2-phenyl-3,4-dihydronaphthalen-1-yl)phenol (26.94 g, 82.03 mmol) were added sequentially to a 1 L autoclave. The autoclave was sealed. The atmosphere was replaced with nitrogen once and hydrogen three times, with the final hydrogen pressure maintained at 3 MPa. The mixture was stirred at room temperature for 48 h. The reaction mixture was filtered through celite, and the filtrate was concentrated to afford 18.9 g of an off-white solid (100% yield). 1H NMR (400MHz, DMSO-d6) δ9.00 (s, 1H), 7.19-7.11 (m, 3H), 6.86-6.81 (m, 2H), 6.8 1-6.75 (m, 2H), 6.66 (dd, J=8.5, 2.6Hz, 1H), 6.37 (d, J=8.1Hz, 2H), 6.17 (d, J=8. 3Hz, 2H), 4.18 (d, J=5.0Hz, 1H), 3.74 (s, 3H), 3.30 (ddd, J=13.1, 5.2, 2.1Hz, 1H) , 3.12-2.91 (m, 2H), 2.12 (qd, J=12.6, 6.1Hz, 1H), 1.73 (dd, J=13.0, 6.1Hz, 1H).

[0362] Step 5: Preparation of 4-((1R,2S)-6-methoxy-2-phenyl-1,2,3,4-tetrahydronaphthyl-1-yl)phenol

[0363] 4-(6-methoxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenol (0.14 g, 0.25 mmol) was subjected to chiral column separation to obtain the product with absolute configuration B peak as a white solid (0.05 g) with a yield of 35%.

[0364] Separation and preparation method:

[0365] Instrument: WATERS SFC-350

[0366] Chromatographic column: CHIRALPAK IA 5cm×25cm, 5um

[0367] Mobile phase: A is CO2, B is IPA

[0368] Wavelength: 220nm

[0369] Flow rate: 200ml / min

[0370] Solvent: MeOH, DCM

[0371] Gradient conditions: B: 50%

[0372] Cycle time: 11 minutes

[0373] Column temperature: 35°C

[0374] Separation and detection method:

[0375] Instrument: Waters ACQUITY UPC2

[0376] Column: Lux 3u-Cellulose-3 4.6×50mm, 3um

[0377] Mobile phase: A is CO2, B is MeOH (0.1% DEA)

[0378] Wavelength: 220nm

[0379] Column temperature: 35°C

[0380] Flow rate: 4ml / min

[0381] Injection volume: 1uL

[0382] Injection concentration: 1 mg / ml

[0383] Solvent: MeOH

[0384] Gradient conditions: B: 10% to 50% in 2 min, hold 1 min at 50%

[0385] Run time: 3 minutes

[0386] Retention time: 0.972min, 1.095min

[0387] Step 6: Synthesis of 4-((1R,2S)-6-methoxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl 1,1,2,2,3,3,4,4,4-perfluorobutyl-1-sulfonate

[0388] At room temperature, 4-((1R,2S)-6-methoxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenol (22.00 g, 66.58 mmol), perfluorobutylsulfonyl fluoride (26.14 g, 86.55 mmol), K2CO3 (18.40 g, 133.16 mmol), CH3CN (120 mL), and THF (120 mL) were added sequentially to a single-necked flask. The reaction was terminated at room temperature for 20 h under nitrogen protection. The reaction mixture was filtered, the filter cake washed, and the mother liquor collected, concentrated, and purified by column chromatography (EA / PE system) to obtain 27.14 g of a white solid, with a yield of 67%.

[0389] Step 7: Synthesis of tert-butyl 4-(4-((1R,2S)-6-methoxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazine-1-carboxylate

[0390] At room temperature, 4-((1R,2S)-6-methoxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl 1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonate (7.4 g, 12.1 mmol), N-Boc piperazine (6.7 g, 36.2 mmol), palladium acetate (542 mg, 2.42 mmol), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (1.7 g, 3.63 mmol), and sodium tert-butoxide (4.6 g, 48.4 mmol) were placed in toluene (200 mL) and reacted at 95°C under nitrogen for 4 hours. The reaction was completed by TLC. The mixture was cooled to room temperature, poured into ice water, and extracted with EA. The organic phase was concentrated, sanded, and then chromatographed with PE / EA (0-8%) to obtain 4.7 g of a brown oil in a 78% yield.

[0391] Step 8: Synthesis of (5R,6S)-6-phenyl-5-(4-(piperazin-1-yl)phenyl)-5,6,7,8-tetrahydronaphthalen-2-ol

[0392] At room temperature, tert-butyl 4-(4-((1R,2S)-6-methoxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazine-1-carboxylate (3.0 g, 6.0 mmol) was dissolved in 100 mL of dichloromethane. 30 mL of a 1.0 N boron tribromide solution in n-heptane was added dropwise at -60°C. After addition, the mixture was allowed to warm naturally overnight. The mixture was cooled and quenched dropwise with methanol. The mixture was concentrated and purified by silica gel column chromatography to afford 1.7 g of a yellow solid in a 73% yield. MS (ESI) m / z: 385.2 [M+H] + .

[0393] Step 9: Synthesis of tert-butyl 4-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazine-1-carboxylate

[0394] At room temperature, (5R,6S)-6-phenyl-5-(4-(piperazin-1-yl)phenyl)-5,6,7,8-tetrahydronaphthalen-2-ol (0.38 g, 1.0 mmol) was dissolved in methanol (10 mL), and Boc anhydride (0.26 g, 1.2 mmol) was added at 10°C. The reaction was stirred for 2 hours. The reaction solution was then spin-dried to dryness, and an EA / NaHCO3 aqueous solution was added to adjust the pH to 8. The layers were separated, and the organic phase was concentrated to afford 0.36 g of a white solid in a 75% yield. MS (ESI) m / z: 485.2 [M+H] + .

[0395] Step 10: Synthesis of tert-butyl 4-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazine-1-carboxylate

[0396] At room temperature, tert-butyl 4-(4-((1R, 2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazine-1-carboxylate (220.00 g, 0.45 mol), potassium carbonate (94.11 g, 0.68 mol), 18 crown 6 (2.2 g, 1% w / w), acetonitrile (2 L) were added sequentially to the reaction flask, and BnBr (89.28 g, 0.52 mol) was added dropwise. The reaction was carried out at 60 ° C. for 18 h, and the mixture was cooled to room temperature. The reaction solution was added to water, crystallized and filtered, and the filter cake was slurried with methanol and filtered to obtain 247.90 g of the product with a yield of 95%.

[0397] Step 11: Synthesis of 1-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazine hydrochloride

[0398] To the reaction flask, 1 L of HCl in ethyl acetate and tert-butyl 4-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazine-1-carboxylate (265.00 g, 0.46 mol) were added sequentially at room temperature. The mixture was allowed to react for 2 h. After completion of the reaction, the mixture was filtered to obtain 235.65 g of the product in a 100% yield.

[0399] Step 12: Synthesis of 1-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)-4-(((1R,2R)-2-(((tert-butyldiphenylsilyl)oxy)methyl)cyclohexyl)methyl)piperazine

[0400] At room temperature, 1-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazine hydrochloride (50.00 g, 97.83 mmol), (1R,2R)-2-(((tert-butyldiphenylsilyl)oxy)methyl)cyclohexane-1-carbaldehyde (48.40 g, 127.17 mmol), and dichloromethane (500 mL) were added to the reaction flask in sequence. TIPT (50 mL) was then added, and the mixture was stirred at room temperature for 16 hours. STAB (31.00 g, 146.74 mmol) was then added, and the reaction was stirred at room temperature for 2 hours. After completion of the reaction, dichloromethane was added to dilute the mixture, and diatomaceous earth was added. After stirring, water was added to quench the reaction. After stirring for 20 minutes, the mixture was filtered and the filter cake was slurried twice with dichloromethane. The organic phases were combined, desolventized, and slurried with methanol to obtain 74.00 g of the product with a yield of 90%.

[0401] Step 13: Synthesis of ((1R,2R)-2-((4-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methanol

[0402] At room temperature, 1-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)-4-(((1R,2R)-2-(((tert-butyldiphenylsilyl)oxy)methyl)cyclohexyl)methyl)piperazine (74.00 g, 88.17 mmol), TBAF (23.00 g, 88.17 mmol) and tetrahydrofuran (300 mL) were added to the reaction flask in sequence, and the mixture was stirred at 50°C for 4 h. After completion of the reaction, the mixture was spin-dried, and dichloromethane and water were added to separate the mixture. The organic phase was dried and spin-dried, and methanol was added to slurry to obtain 45.00 g of the product in a yield of 85%.

[0403] Step 14: Synthesis of (1R,2R)-2-((4-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexane-1-carbaldehyde

[0404] At room temperature, ((1R,2R)-2-((4-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methanol (45.00 g, 74.89 mmol) were added to the reaction flask in sequence, Molecular sieves (45 g, 100% w / w), NMO (13.16 g, 112.34 mmol), and DCM (450 mL) were added with TPAP (2.63 g, 7.49 mmol) and allowed to react at room temperature for 12 h. After completion, the reaction was filtered, separated by water, and the organic phase was dried and spin-dried. Column chromatography (MeOH / DCM) afforded 40.00 g of the product in an 89% yield.

[0405] Step 15: Synthesis of tert-butyl 4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-5-fluoro-1-methyl-1H-indazol-6-yl)piperazine-1-carboxylate

[0406] At room temperature, 1-(6-bromo-5-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (0.25 g, 0.73 mmol), 1-Boc-piperazine (0.14 g, 0.73 mmol), Pd-PEPPSI IHept-Cl (0.07 g, 0.07 mmol), cesium carbonate (0.72 g, 2.20 mmol), 4A molecular sieves (0.70 g), and 1,4-dioxane (15 ml) were added to the reaction flask in sequence. The nitrogen atmosphere was replaced 3-4 times, and the temperature was raised to 100° C. for 15 h. After completion of the reaction, the temperature was lowered to room temperature, ethyl acetate and water were added, the layers were separated, and the organic phase was dried and purified by PE / EA column chromatography to obtain 0.14 g of the product in a yield of 44%.

[0407] Step 16: Synthesis of 1-(5-fluoro-1-methyl-6-(piperazin-1-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

[0408] At room temperature, tert-butyl 4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-5-fluoro-1-methyl-1H-indazol-6-yl)piperazine-1-carboxylate (0.14 g, 0.32 mmol) and dichloromethane (10 ml) were added to a reaction flask. After the solution was dissolved, hydrochloric acid / dioxane (4 ml) was added and the mixture was stirred at room temperature for 3 h. After completion of the reaction, the solvent was removed to obtain 0.11 g of crude product, which was directly used in the next step.

[0409] Step 17: Synthesis of 1-(6-(4-(((1R,2R)-2-((4-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)piperazin-1-yl)-5-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

[0410] At room temperature, 1-(5-fluoro-1-methyl-6-(piperazin-1-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (0.11 g, 0.34 mmol), (1R,2R)-2-((4-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexane-1-carbaldehyde (0.19 g, 0.31 mmol), and dichloromethane (10 ml) were added to the reaction flask in sequence. TIPT (0.5 ml) was then added, and the mixture was stirred at room temperature for 16 hours. STAB (0.13 g, 0.62 mmol) was then added, and the reaction was stirred at room temperature for 2 hours. After completion of the reaction, dichloromethane was added to dilute the mixture, and celite was added. After stirring for a long time, water was added to quench the reaction. After stirring for 20 minutes, the mixture was filtered. The filter cake was slurried twice with dichloromethane. The organic phases were combined, desolventized, and subjected to column chromatography using a DCM / MeOH system to obtain 0.20 g of the product with a yield of 63%.

[0411] Step 18: 1-(5-Fluoro-6-(4-(((1R,2R)-2-((4-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)piperazin-1-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

[0412] At room temperature, 1-(6-(4-(((1R, 2R)-2-((4-((1R, 2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)piperazin-1-yl)-5-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (0.20 g, 0.22 mmol), 10% palladium on carbon (0.02 g) and tetrahydrofuran (10 ml) were added to the reaction flask in sequence, and hydrogen was added 3-4 times to replace the mixture. The reaction was stirred at room temperature for 24 hours. After completion of the reaction, the mixture was filtered through celite, the filter cake was washed with tetrahydrofuran and the filtrate was desolvated. The product was purified by column chromatography using a DCM / MeOH system to obtain 0.07 g of the product in a yield of 39%.

[0413] 1H NMR (400MHz, DMSO-d6) δ10.55 (s, 1H), 9.13 (s, 1H), 7.36 (d, J = 12.8Hz, 1H), 7.19-7.04 (m, 4H), 6.83 (d, J = 7.2Hz, 2H), 6.67-6.59 (m, 2H), 6.54 (d, J=8.3Hz, 2H), 6.48 (dd, J=8.3, 2.5Hz, 1H), 6.21 (d, J=8.2Hz, 2H), 4.14 (d, J=4.9Hz, 1H), 3.95-3.90 (m, 3H), 3.90-3.86 ( m, 2H), 3.31-3.21 (m, 2H), 3.12-3.04 (m, 4H), 3.02-2.88 (m, 5H), 2.74 (t, J=6.7Hz, 2H), 2.68-2.51 (m, 4H), 2.29-2.00 (m, 8H), 1.88-1 .81 (m, 2H), 1.74-1.66 (m, 2H), 1.62-1.55 (m, 2H), 1.52-1.39 (m, 2H), 1.30-1.12 (m, 2H), 1.07-0.89 (m, 2H).MS (ESI) m / z: 839.5[M+H] + .

[0414] Example 2: Synthesis of 3-(4-(4-(((1R,2R)-2-((4-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)piperazin-1-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (Compound VII-1)

[0415] The synthesis method of (1R,2R)-2-((4-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexane-1-carbaldehyde is as described in Example 1.

[0416] Step 1: Synthesis of 1-(4-methoxybenzyl)-2,6-dioxopiperidin-3-yl trifluoromethanesulfonate

[0417] At room temperature, 3-hydroxy-1-(4-methoxybenzyl)piperidine-2,6-dione (4.00 g, 16.05 mmol) and dichloromethane (50 ml) were added to the reaction flask in sequence. After dissolving, the temperature was lowered to -10°C. Trifluoromethanesulfonic anhydride (6.80 g, 24.07 mmol) was slowly added while maintaining the temperature. After the addition, the temperature was maintained at 0°C for 2 hours. After the reaction was completed, the solvent was directly removed and chromatographed using a PE / EA system to obtain 4.41 g of the product in a yield of 72%.

[0418] Step 2: Synthesis of 3-(4-bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)-1-(4-methoxybenzyl)piperidine-2,6-dione

[0419] At room temperature, 7-bromo-1-methyl-1,3-dihydro-2H-benzimidazol-2-one (1.00 g, 3.61 mmol), potassium tert-butoxide (0.49 g, 4.33 mmol), and tetrahydrofuran (20 ml) were added to the reaction flask in sequence. The temperature was lowered to 0°C and stirred for 30 minutes. 1-(4-methoxybenzyl)-2,6-dioxopiperidin-3-yl trifluoromethanesulfonate (1.38 g, 3.61 mmol) was then added. After the addition was complete, the reaction was allowed to return to room temperature and allowed to react for 3 hours. After completion of the reaction, ethyl acetate and water were added, the layers separated, and the organic phase was dried and purified by PE / EA column chromatography to obtain 1.48 g of the product in a 90% yield.

[0420] Step 3: Synthesis of tert-butyl 4-(1-(1-(4-methoxybenzyl)-2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)piperazine-1-carboxylate

[0421] At room temperature, 3-(4-bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)-1-(4-methoxybenzyl)piperidine-2,6-one (0.74 g, 1.62 mmol), 1-Boc-piperazine (0.30 g, 1.62 mmol), Pd-PEPPSI IHept-Cl (0.16 g, 0.16 mmol), cesium carbonate (1.58 g, 4.85 mmol), 4A molecular sieves (0.16 g), and 1,4-dioxane (9 ml) were added to the reaction flask in sequence. The nitrogen atmosphere was replaced 3-4 times, and the temperature was raised to 100° C. for 15 h. After completion of the reaction, the temperature was cooled to room temperature, ethyl acetate and water were added, the layers were separated, and the organic phase was dried and purified by PE / EA column chromatography to obtain 0.41 g of the product in a yield of 45%.

[0422] Step 4: Synthesis of 3-(3-methyl-2-oxo-4-(piperazin-1-yl)-2,3-dihydro-1H-benzimidazol-1-yl)piperidine-2,6-dione

[0423] At room temperature, tert-butyl 4-(1-(1-(4-methoxybenzyl)-2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)piperazine-1-carboxylate (0.41 g, 0.73 mmol), trifluoroacetic acid (3 ml), and TfOH (0.5 ml) were added to the reaction flask in sequence. The temperature was raised to 65°C and stirred for 2 h. After completion of the reaction, the solvent was removed and the product was purified by reverse phase column chromatography (acetonitrile / water) to obtain 0.10 g of a crude product, which was directly used in the next step.

[0424] Step 5: Synthesis of 3-(4-(4-(((1R,2R)-2-((4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)piperazin-1-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione

[0425] At room temperature, 3-(3-methyl-2-oxo-4-(piperazin-1-yl)-2,3-dihydro-1H-benzimidazol-1-yl)piperidine-2,6-dione (0.10 g, 0.21 mmol), (1R,2R)-2-((4-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexane-1-carbaldehyde (0.13 g, 0.21 mmol), and dichloromethane (10 ml) were added to the reaction flask in sequence. TIPT (0.5 ml) was then added, and the mixture was stirred at room temperature for 16 hours. STAB (0.09 g, 0.42 mmol) was then added, and the reaction was stirred at room temperature for 2 hours. After completion of the reaction, dichloromethane was added to dilute the mixture, and celite was added. After stirring for a long time, water was added to quench the reaction. After stirring for 20 minutes, the mixture was filtered and the filter cake was slurried twice with dichloromethane. The organic phases were combined, desolventized, and subjected to column chromatography using a DCM / MeOH system to obtain 0.11 g of the product with a yield of 58%.

[0426] Step 6: Synthesis of 3-(4-(4-(((1R,2R)-2-((4-(4-(1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)piperazin-1-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione

[0427] At room temperature, 3-(4-(4-(((1R,2R)-2-((4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)piperazin-1-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (0.11 g, 0.12 mmol), 10% palladium on carbon (0.01 g) and tetrahydrofuran (10 ml) were added to the reaction flask in sequence, and hydrogen was replaced 3-4 times. The reaction was stirred at 30°C for 16 h. After the reaction was completed, the mixture was filtered through a pad of celite, the filter cake was washed with tetrahydrofuran and the filtrate was desolvated, and column chromatography using a DCM / MeOH system was performed to obtain 0.030 g of the product (0.026 g in storage), with a yield of 29%.

[0428] 1 H NMR (400MHz, DMSO-d6) δ11.10 (s, 1H), 9.12 (s, 1H), 7.12 (d, J=8.9Hz, 3H), 7.05-6.87 (m, 3H), 6.83 (d, J=7.1Hz, 2H), 6.69-6.54 (m, 3H), 6.48 (d, J=8.3Hz, 1H), 6.24 (s, 2H), 5.60-4.99 (m, 1H), 4.15 (d, J=4. 7Hz, 1H), 3.61 (s, 3H), 3.43-3.20 (m, 10H), 3.12-2.82 (m, 10H), 2.81-2.54 (m, 4H), 2.20-1.98 (m, 4H), 1.83-1.59(m, 5H), 1.49-1.39(m, 2H), 1.29-1.17(m, 3H), 1.07-0.92(m, 2H).MS(ESI)m / z: 836.5[M+H] + .

[0429] Example 3: Synthesis of 1-(5-fluoro-6-(1-(((1R,2R)-2-((4-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (Compound IV-9)

[0430] The synthesis method of (1R,2R)-2-((4-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexane-1-carbaldehyde is as described in Example 1.

[0431] Step 1: Synthesis of tert-butyl 4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-5-fluoro-1-methyl-1H-indazol-6-yl)-3,6-dihydropyridine-1(2H)-carboxylate

[0432] At room temperature, 1-(6-bromo-5-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (0.25 g, 0.73 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (0.34 g, 1.10 mmol), Xphos-Pd-G2 (0.06 g, 0.07 mmol), potassium phosphate (0.31 g, 1.47 mmol), water (3 ml) and 1,4-dioxane (10 ml) were added to the reaction flask in sequence. The nitrogen was replaced 3-4 times, and the temperature was raised to 80°C for 4 h. After the reaction was completed, the temperature was lowered to room temperature, the solvent was removed, ethyl acetate was added to dilute, and the mixture was filtered through a pad of celite. The filtrate was dried, the solvent was removed, and PE / EA system column chromatography was used to obtain 0.25 g of the product with a yield of 78%.

[0433] Step 2: Synthesis of tert-butyl 4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-5-fluoro-1-methyl-1H-indazol-6-yl)piperidine-1-carboxylate

[0434] At room temperature, tert-butyl 4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-5-fluoro-1-methyl-1H-indazol-6-yl)-3,6-dihydropyridine-1(2H)-carboxylate (0.25 g, 0.57 mmol) and tetrahydrofuran (15 ml) were added to a reaction flask. 10% palladium on carbon (0.03 g) was added, and the hydrogen atmosphere was replaced 3-4 times. The reaction was stirred at room temperature for 16 h. After completion of the reaction, the mixture was filtered through a pad of celite and desolvated to obtain 0.25 g of the product, which was directly used in the next step.

[0435] Step 3: Synthesis of 1-(5-fluoro-1-methyl-6-(piperidin-4-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

[0436] At room temperature, tert-butyl 4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-5-fluoro-1-methyl-1H-indazol-6-yl)piperidine-1-carboxylate (0.25 g, 0.56 mmol) and dichloromethane (10 ml) were added to a reaction flask. After the solution was dissolved, hydrochloric acid / dioxane (9 ml) was added and the mixture was stirred at room temperature for 3 h. After completion of the reaction, the solvent was removed to obtain 0.19 g of crude product, which was directly used in the next step.

[0437] Step 4: Synthesis of 1-(6-(1-(((1R,2R)-2-((4-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)piperidin-4-yl)-5-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

[0438] At room temperature, 1-(5-fluoro-1-methyl-6-(piperidin-4-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (0.19 g, 0.50 mmol), (1R,2R)-2-((4-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexane-1-carbaldehyde (0.27 g, 0.45 mmol), and dichloromethane (10 ml) were added to the reaction flask in sequence. TIPT (0.5 ml) was then added, and the mixture was stirred at room temperature for 16 hours. STAB (0.19 g, 0.91 mmol) was then added, and the reaction was stirred at room temperature for 2 hours. After completion of the reaction, dichloromethane was added to dilute the mixture, and celite was added. After stirring for a long time, water was added to quench the reaction. After stirring for 20 minutes, the mixture was filtered. The filter cake was slurried twice with dichloromethane. The organic phases were combined, desolventized, and subjected to column chromatography using a DCM / MeOH system to obtain 0.27 g of the product with a yield of 58%.

[0439] Step 5: Synthesis of 1-(5-fluoro-6-(1-(((1R,2R)-2-((4-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

[0440] At room temperature, 1-(6-(1-(((1R, 2R)-2-((4-((1R, 2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)piperidin-4-yl)-5-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (0.27 g, 0.29 mmol), 10% palladium on carbon (0.03 g) and tetrahydrofuran (10 ml) were added to the reaction flask in sequence, and hydrogen was added to replace it 3-4 times. The reaction was stirred at room temperature for 24 hours. After completion of the reaction, the mixture was filtered through celite, the filter cake was washed with tetrahydrofuran and the filtrate was desolvated. The product was purified by column chromatography using a DCM / MeOH system to obtain 0.135 g of the product (0.130 g in storage), with a yield of 54%.

[0441] 1 H NMR (400MHz, DMSO-d6) δ10.57 (s, 1H), 9.15 (s, 1H), 7.58 (d, J = 6.0Hz, 1H), 7.36 (d, J = 10.8Hz, 1H), 7.13 (dd, J = 10.3, 6.9Hz , 3H), 6.83 (d, J=7.2Hz, 2H), 6.69-6.31 (m, 5H), 6.21 (d, J=8.2Hz, 2H), 4.13 (d, J=4.9Hz, 1H), 3.99 (s, 3H), 3.90 (t, J=6.7Hz , 2H), 3.10-2.81 (m, 9H), 2.75 (t, J=6.7Hz, 2H), 2.48-2.24 (m, 6H), 2.19-2.03 (m, 3H), 1.96-1.86 (m, 4H), 1.83-1.75 (m, 4H ), 1.73-1.64(m, 2H), 1.60-1.50(m, 2H), 1.46-1.31(m, 2H), 1.27-1.12(m, 2H), 1.03-0.85(m, 2H).MS(ESI)m / z: 838.5[M+H] + .

[0442] Example 4: Synthesis of N-(2,6-dioxopiperidin-3-yl)-2-fluoro-4-(4-(((1R,2R)-2-((4-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenylpiperazin-1-yl)methyl)cyclohexyl)methyl)piperazin-1-yl)benzamide (Compound I-69)

[0443] The synthesis method of (1R,2R)-2-((4-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexane-1-carbaldehyde is as described in Example 1.

[0444] Step 1: Synthesis of tert-butyl 4-(3-fluoro-4-(methoxycarbonyl)phenyl)piperazine-1-carboxylate

[0445] At room temperature, methyl 4-bromo-2-fluorobenzoate (2.00 g, 9.26 mmol), N-Boc-piperazine (3.45 g, 18.52 mmol), Pd(OAc)2 (0.10 g, 0.46 mmol), BINAP (0.58 g, 0.93 mmol), Cs2CO3 (9.05 g, 27.77 mmol), and Toluene (20 ml) were added to the reaction flask in sequence. The nitrogen atmosphere was replaced 3-4 times, and the temperature was raised to 100°C for 16 h. After completion of the reaction, the temperature was cooled to room temperature, filtered, and the filtrate was concentrated and purified by PE / EA column chromatography to obtain 2.50 g of the product as a brown oil in an 83% yield.

[0446] Step 2: Synthesis of 4-(4-(tert-Butyloxycarbonyl)piperazin-1-yl)-2-fluorobenzoic acid

[0447] To a reaction flask at room temperature were added tert-butyl 4-(3-fluoro-4-(methoxycarbonyl)phenyl)piperazine-1-carboxylate (2.50 g, 7.78 mmol), NaOH (1.24 g, 31.11 mmol), MeOH (30 ml), and H₂O (10 ml), in that order. The temperature was raised to 50°C and the reaction was allowed to proceed for 4 h. After completion of the reaction, the solvent was removed and the mixture was acidified by adding aqueous HCl. The product precipitated and was filtered to obtain 2.20 g of a white solid in a 92% yield.

[0448] Step 3: Synthesis of tert-butyl 4-(4-((2,6-dioxopiperidin-3-yl)carbamoyl)-3-fluorophenyl)piperazine-1-carboxylate

[0449] At room temperature, 4-(4-(tert-Butyloxycarbonyl)piperazin-1-yl)-2-fluorobenzoic acid (0.20 g, 0.65 mmol), 3-aminopiperidine-2,6-dione hydrochloride (0.13 g, 0.78 mmol), HATU (0.37 g, 0.98 mmol), DIEA (0.25 g, 1.95 mmol), and DMF (3 ml) were added to a reaction flask in this order. The mixture was stirred at room temperature for 2 h. After completion of the reaction, water (3 mL) and saturated brine (3 mL) were added to the reaction solution to precipitate a large amount of solid. The solid was filtered, and the filter cake was dissolved in DCM, dried over anhydrous magnesium sulfate, and then directly proceeded to the next step.

[0450] Step 4: Synthesis of N-(2,6-dioxopiperidin-3-yl)-2-fluoro-4-(piperazin-1-yl)benzamide

[0451] At room temperature, tert-butyl 4-(4-((2,6-dioxopiperidin-3-yl)carbamoyl)-3-fluorophenyl)piperazine-1-carboxylate (0.27 g, 0.65 mmol) and dichloromethane (2 mL) were added to a reaction flask. After the solution was dissolved, hydrochloric acid / dioxane (2 mL) was added and the mixture was stirred at room temperature for 3 h. After completion of the reaction, the solvent was removed to obtain 0.26 g of crude product, which was directly carried out to the next step.

[0452] Step 5: Synthesis of 4-(4-(((1R,2R)-2-((4-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)piperazin-1-yl)-N-(2,6-dioxopiperidin-3-yl)-2-fluorobenzamide

[0453] At room temperature, N-(2,6-dioxopiperidin-3-yl)-2-fluoro-4-(piperazin-1-yl)benzamide (0.15 g, 0.47 mmol), (1R,2R)-2-((4-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexane-1-carbaldehyde (0.28 g, 0.47 mmol), and dichloromethane (5 mL) were added to the reaction flask in sequence. TIPT (0.5 mL) was then added, and the mixture was stirred at room temperature for 16 hours. STAB (0.15 g, 0.71 mmol) was then added, and the reaction was stirred at room temperature for 2 hours. After completion of the reaction, dichloromethane was added to dilute the mixture, and celite was added. After stirring for a long time, water was added to quench the reaction. After stirring for 20 minutes, the mixture was filtered. The filter cake was slurried twice with dichloromethane. The organic phases were combined, desolventized, and subjected to column chromatography using a DCM / MeOH system to obtain 0.21 g of the product. The three-step yield was 62%.

[0454] Step 6: Synthesis of N-(2,6-dioxopiperidin-3-yl)-2-fluoro-4-(4-(((1R,2R)-2-((4-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenylpiperazin-1-yl)methyl)cyclohexyl)methyl)piperazin-1-yl)benzamide

[0455] At room temperature, 4-(4-(((1R,2R)-2-((4-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)piperazin-1-yl)-N-(2,6-dioxopiperidin-3-yl)-2-fluorobenzamide (0.21 g, 0.23 mmol), 10% palladium on carbon (0.10 g) and THF (3 mL) were added to the reaction flask in sequence. The hydrogen was replaced 3-4 times, and the reaction was stirred at room temperature for 24 h. After completion of the reaction, the mixture was filtered through celite, the filter cake was rinsed with THF, the filtrate was desolvated, and column chromatography using a DCM / MeOH system was performed to obtain 0.07 g of the product in a yield of 37%.

[0456] 1 H NMR (400MHz, DMSO-d6) δ10.86 (s, 1H), 9.12 (s, 1H), 8.05 (t, J=7.2Hz, 1H), 7.62 (t, J=9.0Hz, 1H), 7.17-7.10 (m, 3H), 6.85-6.7 4 (m, 4H), 6.66-6.59 (m, 2H), 6.55-6.46 (m, 3H), 6.21 (d, J = 8.3Hz, 2H), 4.73 (dt, J = 12.9, 6.8Hz, 1H), 4.14 (d, J = 4.9Hz, 1H), 3.2 9-3.20(m, 6H), 3.00-2.93(m, 5H), 2.83-2.68(m, 1H), 2.48-2.29(m, 10H), 2.16-1.99(m, 5H), 1.90-1.81(m, 2H), 1.73-1.68(m , 1H), 1.60-1.52(m, 2H), 1.45-1.40(m, 2H), 1.23-1.15(m, 2H), 1.02-0.93(m, 2H), 0.87-0.81(m, 1H).MS (ESI) m / z: 827.4[M+H] + .

[0457] Example 5: Synthesis of 3-(6-(4-(((1R,2R)-2-((4-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)piperazin-1-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione (Compound IV-3)

[0458] The synthesis method of (1R,2R)-2-((4-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexane-1-carbaldehyde is as described in Example 1.

[0459] Step 1: Synthesis of 3-(2,6-bis(benzyloxy)pyridin-3-yl)-6-bromo-1-methyl-1H-indazole

[0460] At room temperature, 6-bromo-3-iodo-1-methyl-1H-indazole (1.00 g, 2.97 mmol), 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxolan-2-yl)pyridine (1.24 g, 2.97 mmol), sodium carbonate (0.94 g, 8.90 mmol), tetrakistriphenylphosphine palladium (0.34 g, 0.30 mmol), water (1 mL), and dioxane (10 ml) were added to the reaction flask in sequence. The mixture was reacted at 90° C. under a nitrogen atmosphere for 5 h. After completion of the reaction, the mixture was cooled to room temperature, ethyl acetate and water were added, the layers were separated, and the organic phase was dried and purified by PE / EA column chromatography to obtain 1.20 g of the product in an 81% yield.

[0461] Step 2: Synthesis of tert-butyl 4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)-1-methyl-1H-indazol-6-yl)piperazine-1-carboxylate

[0462] At room temperature, a reaction flask was added with 3-(2,6-bis(benzyloxy)pyridin-3-yl)-6-bromo-1-methyl-1H-indazole (0.25 g, 0.50 mmol), 1-Boc-piperazine (0.28 g, 1.50 mmol), Pd2(dba)3 (0.05 g, 0.05 mmol), 10% tri-tert-butylphosphine in toluene solution (200 mg, 0.10 mmol), sodium tert-butoxide (0.10 g, 1.00 mmol), and toluene (10 ml). The reaction was allowed to proceed at 100°C under a nitrogen atmosphere for 5 h. After completion of the reaction, the mixture was cooled to room temperature, ethyl acetate and water were added, and the layers were separated. The organic phase was dried and purified by PE / EA column chromatography to obtain 0.20 g of the product in a 66% yield.

[0463] Step 3: Synthesis of tert-butyl 4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-6-yl)piperazine-1-carboxylate

[0464] To a reaction flask at room temperature was added tert-butyl 4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)-1-methyl-1H-indazol-6-yl)piperazine-1-carboxylate (0.20 g, 0.33 mmol), 10% Pd / C (0.02 g), tetrahydrofuran (5 mL), and ethanol (5 mL). The mixture was reacted at room temperature for 24 h. After completion of the reaction, the mixture was filtered and dried to give 0.13 g of a crude product, which was used directly in the next step.

[0465] Step 4: Synthesis of 3-(1-methyl-6-(piperazin-1-yl)-1H-indazol-3-yl)piperazine-2,6-dione

[0466] To the reaction flask, tert-butyl 4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-6-yl)piperazine-1-carboxylate (0.13 g, 0.30 mmol) and HCl in dioxane (5 ml) were added sequentially at room temperature for 2 h. After completion, the reaction was spin-dried to give 0.11 g of crude product, which was used directly in the next step.

[0467] Step 5: Synthesis of 3-(6-(4-(((1R,2R)-2-((4-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)piperazin-1-yl)-1-methyl-1H-indazol-3-yl)piperazine-2,6-dione

[0468] At room temperature, 3-(1-methyl-6-(piperazin-1-yl)-1H-indazol-3-yl)piperazine-2,6-dione (0.06 g, 0.18 mmol), (1R,2R)-2-((4-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexane-1-carbaldehyde (0.11 g, 0.18 mmol), and dichloromethane (10 ml) were added to the reaction flask in sequence. TIPT (0.5 ml) was then added, and the mixture was stirred at room temperature for 16 hours. STAB (0.08 g, 0.36 mmol) was then added, and the reaction was stirred at room temperature for 2 hours. After completion of the reaction, dichloromethane was added to dilute the mixture, and celite was added. After stirring for a long time, water was added to quench the reaction. After stirring for 20 minutes, the mixture was filtered. The filter cake was slurried twice with dichloromethane. The organic phases were combined, desolventized, and subjected to column chromatography using a DCM / MeOH system to obtain 0.03 g of the product with a yield of 27%.

[0469] Step 6: Synthesis of 3-(6-(4-(((1R,2R)-2-((4-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)piperazin-1-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione

[0470] At room temperature, 3-(6-(4-(((1R, 2R)-2-((4-(4-((1R, 2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)piperazin-1-yl)-1-methyl-1H-indazol-3-yl)piperazine-2,6-dione (0.03 g, 0.03 mmol), 10% palladium on carbon (0.01 g) and tetrahydrofuran (5 ml) were added to the reaction flask in sequence, and hydrogen was added for replacement 3-4 times. The reaction was stirred at 30° C. for 16 h. After completion of the reaction, the mixture was filtered through celite, the filter cake was washed with tetrahydrofuran and the filtrate was desolvated. The product was purified by column chromatography using a DCM / MeOH system to obtain 0.01 g of the product in a yield of 37%.

[0471] 1H NMR (400MHz, DMSO-d6) δ10.87 (s, 1H), 9.15 (s, 1H), 7.51 (d, J=9.0Hz, 1H), 7.11 (dt, J=11.5, 7.1Hz, 3H), 6.93 (d , J=9.1Hz, 1H), 6.82 (d, J=8.5Hz, 3H), 6.65-6.60 (m, 2H), 6.55 (d, J=8.3Hz, 2H), 6.48 (dd, J=8.2, 2.6Hz, 1H), 6.2 2 (d, J=8.2Hz, 2H), 4.27 (dd, J=9.3, 5.1Hz, 1H), 4.14 (d, J=5.0Hz, 1H), 3.85 (s, 3H), 3.14-2.86 (m, 10H), 2.72-2. 55 (m, 6H), 2.35-1.97 (m, 7H), 1.83-1.46 (m, 9H), 1.03-0.96 (m, 2H), 0.87-0.81 (m, 1H). MS (ESI) m / z: 820.8[M+H] + .

[0472] Example 6: Synthesis of 3-(5-(4-(((1R,2R)-2-((4-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenylpiperazin-1-yl)methyl)cyclohexyl)methyl)piperazin-1-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (Compound VII-2)

[0473] The synthesis method of (1R,2R)-2-((4-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexane-1-carbaldehyde is as described in Example 1.

[0474] Step 1: Synthesis of tert-butyl 4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)piperazine-1-carboxylate

[0475] At room temperature, 3-(5-bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzo[D]imidazol-1-yl)piperidine-2,6-dione (0.50 g, 1.48 mmol), N-Boc-piperazine (0.55 g, 2.96 mmol), RuPhos-Pd-G3 (0.25 g, 0.30 mmol), RuPhos (0.14 g, 0.30 mmol), 1M LiHMDS (6 mL), 4AMS, and Toluene (5 ml) were added to the reaction flask in sequence. The atmosphere was purged with nitrogen 3-4 times, and the temperature was raised to 100° C. for 5 h. After completion of the reaction, the mixture was cooled to room temperature, concentrated, and purified by PE / EA column chromatography to obtain 0.45 g of a brown oil with a yield of 68%.

[0476] Step 2: Synthesis of 3-(3-methyl-2-oxo-5-piperazin-1-yl-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperazine-2,6-dione

[0477] To a reaction flask at room temperature, tert-butyl 4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)piperazine-1-carboxylate (0.45 mg, 1.01 mmol) and dichloromethane (2 ml) were added sequentially. After the solution was dissolved, hydrochloric acid / dioxane (2 ml) was added and the mixture was stirred at room temperature for 3 h. After completion of the reaction, the solvent was removed to obtain 0.30 g of crude product, which was directly carried out to the next step.

[0478] Step 3: Synthesis of 3-(5-(4-(((1R,2R)-2-((4-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenylpiperazin-1-yl)methyl)cyclohexyl)methyl)piperazin-1-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperazine-2,6-dione

[0479] At room temperature, 3-(3-methyl-2-oxo-5-piperazin-1-yl-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperazine-2,6-dione (0.15 g, 0.44 mmol), (1R,2R)-2-((4-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexane-1-carbaldehyde (0.26 g, 0.44 mmol), and dichloromethane (5 ml) were added to the reaction flask in sequence. TIPT (0.45 ml) was then added, and the mixture was stirred at room temperature for 16 hours. STAB (0.14 g, 0.66 mmol) was then added, and the reaction was stirred at room temperature for 2 hours. After completion of the reaction, dichloromethane was added to dilute the mixture, and celite was added. After stirring until uniform, water was added to quench the reaction. After stirring for 20 minutes, the mixture was filtered. The filter cake was slurried twice with dichloromethane. The organic phases were combined, desolventized, and subjected to column chromatography using a DCM / MeOH system to obtain 0.11 g of the product. The two-step yield was 23%.

[0480] Step 4: Synthesis of 3-(5-(4-(((1R,2R)-2-((4-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenylpiperazin-1-yl)methyl)cyclohexyl)methyl)piperazin-1-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione

[0481] At room temperature, 3-(5-(4-(((1R, 2R)-2-((4-(4-((1R, 2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenylpiperazin-1-yl)methyl)cyclohexyl)methyl)piperazin-1-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (0.11 g, 0.12 mmol), 10% palladium on carbon (0.10 g) and THF (3 ml) were added to the reaction bottle in sequence. The hydrogen was replaced 3-4 times and the reaction was stirred at 25° C. for 24 h. After completion of the reaction, the mixture was filtered through celite, the filter cake was rinsed with THF, the filtrate was desolvated, and column chromatography using a DCM / MeOH system was used to obtain 0.01 g of the product in a yield of 11%.

[0482] 1H NMR (400MHz, DMSO-d6) δ11.08 (s, 1H), 9.16 (s, 1H), 7.11 (dd, J=11.4, 6.9Hz, 3H), 6.95 (d, J=8.6Hz, 1H), 6.82 (d, J=8. 6Hz, 3H), 6.63-6.48 (m, 6H), 6.22 (d, J=8.0Hz, 2H), 5.76 (s, 3H), 5.30 (dd, J=12.7, 5.5Hz, 1H), 4.14 (d, J=5.0Hz, 1H), 3 .14 ​​(s, 2H), 3.04 (s, 2H), 2.94 (dd, J=17.2, 9.0Hz, 5H), 2.76-2.56 (m, 10H), 2.30 (d, J=26.0Hz, 2H), 2.09 (dd, J=12.9, 6.7Hz, 2H), 1.98 (d, J=10.8Hz, 2H), 1.87-1.40 (m, 10H), 1.21 (s, 2H), 0.99 (d, J=13.1Hz, 2H). MS (ESI) m / z: 837.0 [M+H] + .

[0483] Example 7: Synthesis of N-(2,6-dioxopiperidin-3-yl)-5-(4-(((1R,2R)-2-((4-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)piperazin-1-yl)picolinamide (Compound III-1)

[0484] The synthesis method of (1R,2R)-2-((4-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexane-1-carbaldehyde is as described in Example 1.

[0485] Step 1: Synthesis of methyl tert-butyl 4-(6-(methoxycarbonyl)pyridin-3-yl)piperazine-1-carboxylate

[0486] At room temperature, methyl 5-bromopyridine-2-carboxylate (2.00 g, 9.26 mmol), N-Boc-piperazine (3.45 g, 18.52 mmol), Pd(OAc)2 (0.10 g, 0.46 mmol), BINAP (0.58 g, 0.93 mmol), Cs2CO3 (9.05 g, 27.77 mmol) and Toluene (20 ml) were added to the reaction flask in sequence. The nitrogen atmosphere was replaced 3-4 times, and the temperature was raised to 100°C for 16 h. After completion of the reaction, the temperature was cooled to room temperature, filtered, and the filtrate was concentrated and purified by PE / EA column chromatography to obtain 2.50 g of the product as a brown oil with a yield of 83%.

[0487] Step 2: Synthesis of 5-(4-(tert-Butyloxycarbonyl)piperazin-1-yl)picolinic acid

[0488] To a reaction flask at room temperature were added methyl tert-butyl 4-(6-(methoxycarbonyl)pyridin-3-yl)piperazine-1-carboxylate (2.50 g, 7.78 mmol), NaOH (1.24 g, 31.11 mmol), MeOH (30 ml), and H₂O (10 ml), in that order. The temperature was raised to 50°C and the reaction was allowed to proceed for 4 h. After completion of the reaction, the solvent was removed, the mixture was acidified by adding aqueous HCl, and extracted three times with DCM to yield 2.20 g of a yellow solid in a 92% yield.

[0489] Step 3: Synthesis of tert-butyl 4-(6-((2,6-dioxopiperidin-3-yl)carbamoyl)pyridin-3-yl)piperazine-1-carboxylate

[0490] To a reaction flask at room temperature were added 5-(4-(tert-Butyloxycarbonyl)piperazin-1-yl)picolinic acid (0.20 g, 0.65 mmol), 3-aminopiperidine-2,6-dione hydrochloride (0.13 g, 0.78 mmol), HATU (0.37 g, 0.98 mmol), DIEA (0.25 g, 1.95 mmol), and DMF (3 ml) in this order. The mixture was stirred at room temperature for 2 h. After completion of the reaction, water (3 mL) and saturated brine (3 mL) were added to the reaction mixture to precipitate a large amount of solid. The solid was filtered, and the filter cake was dissolved in DCM, dried over anhydrous magnesium sulfate, and then directly proceeded to the next step.

[0491] Step 4: Synthesis of N-(2,6-dioxopiperidin-3-yl)-5-(piperazin-1-yl)pyridine-3-carboxamide

[0492] At room temperature, tert-butyl 4-(6-((2,6-dioxopiperidin-3-yl)carbamoyl)pyridin-3-yl)piperazine-1-carboxylate (0.27 mg, 0.65 mmol) and dichloromethane (2 ml) were added to a reaction flask. After the solution was dissolved, hydrochloric acid / dioxane (2 ml) was added and the mixture was stirred at room temperature for 3 hours. After completion of the reaction, the solvent was removed to obtain 0.26 g of crude product, which was directly carried out to the next step.

[0493] Step 5: Synthesis of 5-(4-(((1R,2R)-2-((4-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenylpiperazin-1-yl)methyl)cyclohexyl)methyl)piperazin-1-yl)-N-(2,6-dioxopiperidin-3-yl)pyridine-3-carboxamide

[0494] At room temperature, N-(2,6-dioxopiperidin-3-yl)-5-(piperazin-1-yl)pyridine-3-carboxamide (0.15 g, 0.47 mmol), (1R,2R)-2-((4-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexane-1-carbaldehyde (0.28 g, 0.47 mmol), and dichloromethane (5 ml) were added to the reaction flask in sequence. TIPT (0.45 ml) was then added, and the mixture was stirred at room temperature for 16 hours. STAB (0.15 g, 0.71 mmol) was then added, and the reaction was stirred at room temperature for 2 hours. After completion of the reaction, dichloromethane was added to dilute the mixture, and celite was added. After stirring for a long time, water was added to quench the reaction. After stirring for 20 minutes, the mixture was filtered. The filter cake was slurried twice with dichloromethane. The organic phases were combined, desolventized, and subjected to column chromatography using a DCM / MeOH system to obtain 0.21 g of the product. The three-step yield was 62%.

[0495] Step 6: Synthesis of N-(2,6-dioxopiperidin-3-yl)-5-(4-(((1R,2R)-2-((4-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenylpiperazin-1-yl)methyl)cyclohexyl)methyl)piperazin-1-yl)picolinamide

[0496] At room temperature, 5-(4-(((1R,2R)-2-((4-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenylpiperazin-1-yl)methyl)cyclohexyl)methyl)piperazin-1-yl)-N-(2,6-dioxopiperidin-3-yl)pyridine-3-carboxamide (0.21 g, 0.23 mmol), 10% palladium on carbon (0.10 g) and THF (3 ml) were added to the reaction flask in sequence, the hydrogen was replaced 3-4 times, and the reaction was stirred at room temperature for 24 h. After completion of the reaction, the mixture was filtered through celite, the filter cake was rinsed with THF, the filtrate was desolvated, and column chromatography using a DCM / MeOH system was used to obtain 0.04 g of the product in a yield of 21%.

[0497] 1 H NMR (400MHz, DMSO-d6) δ10.86 (s, 1H), 9.12 (s, 1H), 8.73 (d, J = 8.3Hz, 1H), 8.31 (d, J = 2.8Hz, 1H), 7.86 (d, J = 8.8Hz, 1H), 7.41 (dd, J = 8.9, 2 .8Hz, 1H), 7.13 (dd, J=10.3, 6.8Hz, 3H), 6.86-6.82 (m, 2H), 6.66-6.60 (m, 2H), 6.54-6.46 (m, 3H), 6.21 (d, J=8.3Hz, 2H), 4.75 (ddd, J=13.0 . 86 (s, 1H), 1.70 (dd, J=13.2, 5.8Hz, 1H), 1.57 (d, J=8.9Hz, 2H), 1.44 (s, 2H), 1.22 (d, J=12.7Hz, 2H), 0.98 (s, 2H). MS (ESI) m / z: 810.4[M+H] + .

[0498] Example 8: Synthesis of 3-(4-(1-(((1R,2R)-2-((4-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenylpiperazin-1-yl)methyl)cyclohexyl)methyl)piperidin-4-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (Compound VII-3)

[0499] The synthesis method of (1R,2R)-2-((4-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexane-1-carbaldehyde is as described in Example 1.

[0500] Step 1: Synthesis of tert-butyl 4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)-3,6-dihydropyridine-1(2H)-carboxylate

[0501] At room temperature, 3-(4-bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzo[D]imidazol-1-yl)piperidine-2,6-dione (0.25 g, 0.74 mmol), N-Boc-1,2,5,6-tetrahydropyridine-4-boronic acid pinacol ester (0.34 g, 1.11 mmol), Xphos-Pd-G2 (0.06 g, 0.07 mmol), K3PO4 (0.31 g, 1.48 mmol), Do (5 mL), and H2O (1 ml) were added to the reaction flask in sequence. The nitrogen atmosphere was replaced 3-4 times, and the temperature was raised to 80°C for 3 h. After completion of the reaction, the mixture was cooled to room temperature, concentrated, and purified by PE / EA column chromatography to obtain 0.22 g of a white solid with a yield of 67%.

[0502] Step 2: Synthesis of tert-butyl 4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)piperidine-1-carboxylate

[0503] At room temperature, tert-butyl 4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)-3,6-dihydropyridine-1(2H)-carboxylate (0.22 g, 0.50 mmol), 10% palladium on carbon (0.10 g), and THF (3 ml) were added to the reaction flask in this order. The hydrogen atmosphere was replaced 3-4 times, and the reaction was stirred at room temperature for 8 h. After completion of the reaction, the mixture was filtered through a pad of celite, the filter cake was rinsed with THF, and the filtrate was desolvated to obtain 0.20 g of crude product, which was directly used in the next step.

[0504] Step 3: Synthesis of 3-(3-methyl-2-oxo-4-(piperidin-4-yl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione

[0505] At room temperature, tert-butyl 4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)piperidine-1-carboxylate (0.20 mg, 0.45 mmol) and dichloromethane (2 ml) were added to a reaction flask. After the solution was dissolved, hydrochloric acid / dioxane (2 ml) was added and the mixture was stirred at room temperature for 3 hours. After completion of the reaction, the solvent was removed to obtain 0.11 g of crude product, which was directly carried out to the next step.

[0506] Step 4: Synthesis of 3-(4-(1-(((1R,2R)-2-((4-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenylpiperazin-1-yl)methyl)cyclohexyl)methyl)piperidin-4-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione

[0507] At room temperature, 3-(3-methyl-2-oxo-4-(piperidin-4-yl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (0.11 g, 0.32 mmol), (1R,2R)-2-((4-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexane-1-carbaldehyde (0.19 g, 0.32 mmol), and dichloromethane (5 ml) were added to the reaction flask in sequence. TIPT (0.3 ml) was then added, and the mixture was stirred at room temperature for 16 hours. STAB (0.10 g, 0.48 mmol) was then added, and the reaction was stirred at room temperature for 2 hours. After completion of the reaction, dichloromethane was added to dilute the mixture, and celite was added. After stirring until uniform, water was added to quench the reaction. After stirring for 20 minutes, the mixture was filtered. The filter cake was slurried twice with dichloromethane. The organic phases were combined, desolventized, and subjected to column chromatography using a DCM / MeOH system to obtain 0.06 g of the product. The three-step yield was 13%.

[0508] Step 5: Synthesis of 3-(4-(1-(((1R,2R)-2-((4-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenylpiperazin-1-yl)methyl)cyclohexyl)methyl)piperidin-4-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione

[0509] At room temperature, 3-(4-(1-(((1R,2R)-2-((4-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenylpiperazin-1-yl)methyl)cyclohexyl)methyl)piperidin-4-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (0.06 g, 0.06 mmol), 10% palladium on carbon (0.05 g) and THF (3 ml) were added to the reaction flask in sequence. The hydrogen was replaced 3-4 times, and the reaction was stirred at 25°C for 24 h. After completion of the reaction, the mixture was filtered through celite, the filter cake was rinsed with THF, the filtrate was desolvated, and column chromatography using a DCM / MeOH system was used to obtain 0.008 g of the product in a yield of 14%.

[0510] 1 H NMR (400MHz, DMSO-d6) δ11.11 (s, 1H), 9.15 (s, 1H), 7.12 (q, J=5.9, 4.5Hz, 3H), 7.02-6.95 (m, 3H), 6.83 (d, J=7.3Hz, 2H ), 6.59 (dd, J=15.9, 6.0Hz, 4H), 6.48 (d, J=8.5Hz, 1H), 6.23 (d, J=8.1Hz, 2H), 5.40-5.33 (m, 1H), 4.14 (d, J=5.0Hz, 1H), 3.59 (s, 3H), 3.07 (s, 3H), 2.97-2.86 (m, 4H), 2.64 (dd, J=17.3, 12.2Hz, 8H), 2.20-2.08 (m, 2H), 1.98-1.90 (m, 4H), 1.68 (d, J=30.7Hz, 4H), 1.53-1.44 (m, 2H), 1.24 (s, 10H), 1.05-0.97 (m, 2H), 0.86 (t, J=6.5Hz, 1H). MS (ESI) m / z: 836.0 [M+H] + .

[0511] Example 9: Synthesis of 3-(5-(4-(((1R,2R)-2-((4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)piperazin-1-yl)-1H-indazol-1-yl)piperidine-2,6-dione (Compound VI-6)

[0512] The synthesis method of (1R,2R)-2-((4-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexane-1-carbaldehyde is as described in Example 1.

[0513] Step 1: Synthesis of tert-butyl 4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-5-fluoro-1-methyl-1H-indazol-6-yl)piperazine-1-carboxylate

[0514] At room temperature, 5-bromoindazole (0.50 g, 2.54 mmol), potassium tert-butoxide (0.34 g, 3.05 mmol), and tetrahydrofuran (15 ml) were added to the reaction flask in sequence. The temperature was lowered to 0°C and stirred for 30 minutes. 1-(4-methoxybenzyl)-2,6-dioxopiperidin-3-yl trifluoromethanesulfonate (0.97 g, 2.54 mmol) was then added. After the addition was complete, the reaction was allowed to return to room temperature and react for 3 hours. After completion of the reaction, ethyl acetate and water were added, the layers separated, and the organic phase was dried and purified by PE / EA column chromatography to obtain 0.47 g of the product in a 43% yield.

[0515] Step 2: Synthesis of tert-butyl 4-(1-(1-(4-methoxybenzyl)-2,6-dioxopiperidin-3-yl)-1H-indazol-5-yl)piperazine-1-carboxylate

[0516] At room temperature, tert-butyl 4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-5-fluoro-1-methyl-1H-indazol-6-yl)piperazine-1-carboxylate (0.47 g, 1.09 mmol), 1-Boc-piperazine (0.20 g, 1.09 mmol), PEPPSI IHept-Cl (0.11 g, 0.11 mmol), cesium carbonate (1.07 g, 3.28 mmol), 4A molecular sieves (0.11 g) and 1,4-dioxane (15 ml) were added to the reaction flask in sequence. The nitrogen atmosphere was replaced 3-4 times, and the temperature was raised to 100° C. for 15 h. After completion of the reaction, the temperature was lowered to room temperature, ethyl acetate and water were added, the liquids were separated, and the organic phase was dried and purified by PE / EA column chromatography to obtain 0.13 g of the product in a yield of 21%.

[0517] Step 3: Synthesis of 3-(5-(piperazin-1-yl)-1H-indazol-1-yl)piperidine-2,6-dione

[0518] At room temperature, tert-butyl 4-(1-(1-(4-methoxybenzyl)-2,6-dioxopiperidin-3-yl)-1H-indazol-5-yl)piperazine-1-carboxylate (0.13 g, 0.23 mmol), trifluoroacetic acid (3 ml), and TfOH (0.5 ml) were added to the reaction flask in sequence. The temperature was raised to 65°C and stirred for 2 h. After completion of the reaction, the solvent was removed and the product was purified by reverse-phase column chromatography (acetonitrile / water) to obtain 0.06 g of a crude product, which was directly used in the next step.

[0519] Step 4: Synthesis of 3-(5-(4-(((1R,2R)-2-((4-(4-(1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)yl)cyclohexyl)methyl)piperazin-1-yl)-1H-indazol-1-yl)piperidine-2,6-dione

[0520] At room temperature, 3-(5-(piperazin-1-yl)-1H-indazol-1-yl)piperidine-2,6-dione (0.06 g, 0.18 mmol), (1R,2R)-2-((4-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexane-1-carbaldehyde (0.11 g, 0.18 mmol), and dichloromethane (10 ml) were added to the reaction flask in sequence. TIPT (0.5 ml) was then added, and the mixture was stirred at room temperature for 16 hours. STAB (0.08 g, 0.36 mmol) was then added, and the reaction was stirred at room temperature for 2 hours. After completion of the reaction, dichloromethane was added to dilute the mixture, and celite was added. After stirring for a long time, water was added to quench the reaction. After stirring for 20 minutes, the mixture was filtered. The filter cake was slurried twice with dichloromethane. The organic phases were combined, desolventized, and subjected to column chromatography using a DCM / MeOH system to obtain 0.03 g of the product with a yield of 27%.

[0521] Step 5: Synthesis of 3-(5-(4-(((1R,2R)-2-((4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)piperazin-1-yl)-1H-indazol-1-yl)piperidine-2,6-dione

[0522] At room temperature, 3-(5-(4-(((1R,2R)-2-((4-(4-(2R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)yl)cyclohexyl)methyl)piperazin-1-yl)-1H-indazol-1-yl)piperidine-2,6-dione (0.03 g, 0.04 mmol), 10% palladium on carbon (0.01 g) and tetrahydrofuran (10 ml) were added to the reaction flask in sequence, and hydrogen was added to replace it 3-4 times. The reaction was stirred at 30°C for 16 hours. After the reaction was completed, the mixture was filtered through celite, the filter cake was washed with tetrahydrofuran and the filtrate was desolvated. The product was purified by column chromatography using a DCM / MeOH system to obtain 0.008 g of the product (0.004 g in storage), with a yield of 29%.

[0523] 1H NMR (400MHz, DMSO-d6) δ11.08 (s, 1H), 9.25 (s, 1H), 7.93 (s, 1H), 7.53 (d, J = 9.0Hz, 1H), 7.26 (d, J = 9.4Hz, 1H), 7.12 (d, .J = 10.0Hz, 3H), 6 .82 (d, J=7.2Hz, 2H), 6.63 (d, J=5.9Hz, 2H), 6.52 (dd, J=21.0, 8.2Hz, 3H), 6.22 (d, J=8.1Hz, 2H), 5.89-5.77 (m, 1H), 4.66-4.39 (m, 1H), 4. 13(d, J=5.0Hz, 1H), 3.24-3.02(m, 8H), 2.98-2.66(m, 9H), 2.40-2.31(m, 2H), 2.29-2.16(m, 2H), 2.13-2.01(m, 2H), 1.87-1.76(m, 2H), 1. 72-1.63(m, 2H), 1.65-1.56(m, 2H), 1.46-1.37(m, 2H), 1.31-1.13(m, 4H), 1.12-0.95(m, 2H), 0.87-0.79(m, 2H).MS(ESI)m / z:806.6[M+H] + .

[0524] Example 10: Synthesis of N-(2,6-dioxopiperidin-3-yl)-2-fluoro-4-(1-(((1R,2R)-2-((4-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)piperidin-4-yl)benzamide (Compound I-67)

[0525] The synthesis method of (1R,2R)-2-((4-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexane-1-carbaldehyde is as described in Example 1.

[0526] Step 1: Synthesis of tert-butyl 4-(3-fluoro-4-(methoxycarbonyl)phenyl)-3,6-dihydropyridine-1(2H)-carboxylate

[0527] At room temperature, methyl 4-bromo-2-fluorobenzoate (2.00 g, 8.58 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (2.78 g, 9.01 mmol), dppfPdCl2 (0.31 g, 0.43 mmol), cesium carbonate (7.00 g, 21.46 mmol), water (5 mL), and dioxane (20 ml) were added to the reaction flask in sequence. The reaction was allowed to proceed at 90°C under a nitrogen atmosphere for 5 h. After completion of the reaction, the mixture was cooled to room temperature, ethyl acetate and water were added, and the layers were separated. After drying the organic phase, PE / EA column chromatography was used to obtain 2.50 g of the product as a brown oil in an 83% yield.

[0528] Step 2: Synthesis of 4-(1-(tert-Butyloxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl)-2-fluorobenzoic acid

[0529] To a reaction flask at room temperature were added tert-butyl 4-(3-fluoro-4-(methoxycarbonyl)phenyl)-3,6-dihydropyridine-1(2H)-carboxylate (2.50 g, 7.78 mmol), NaOH (1.24 g, 31.11 mmol), MeOH (30 ml), and H₂O (10 ml), in that order. The temperature was raised to 50°C and the reaction was allowed to proceed for 4 h. After completion of the reaction, the solvent was removed and the mixture was acidified by adding aqueous HCl. The product precipitated and was filtered to obtain 2.20 g of a white solid in a 92% yield.

[0530] Step 3: Synthesis of tert-butyl 4-(4-((2,6-dioxopiperidin-3-yl)carbamoyl)-3-fluorophenyl)-3,6-dihydropyridine-1(2H)-carboxylate

[0531] At room temperature, 4-(1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl)-2-fluorobenzoic acid (0.20 g, 0.65 mmol), 3-aminopiperidine-2,6-dione hydrochloride (0.13 g, 0.78 mmol), HATU (0.37 g, 0.98 mmol), DIEA (0.25 g, 1.95 mmol), and DMF (3 ml) were added to a reaction flask in this order. The mixture was stirred at room temperature for 2 h. After completion of the reaction, water (3 mL) and saturated brine (3 mL) were added to the reaction mixture to precipitate a large amount of solid. The solid was filtered, and the filter cake was dissolved in DCM, dried over anhydrous magnesium sulfate, and then directly proceeded to the next step.

[0532] Step 4: Synthesis of N-(2,6-dioxopiperidin-3-yl)-2-fluoro-4-(1,2,3,6-tetrahydropyridin-4-yl)benzamide

[0533] At room temperature, tert-butyl 4-(4-((2,6-dioxopiperidin-3-yl)carbamoyl)-3-fluorophenyl)-3,6-dihydropyridine-1(2H)-carboxylate (0.27 g, 0.65 mmol) and dichloromethane (2 mL) were added to the reaction flask. After the solution was dissolved, hydrochloric acid / dioxane (2 mL) was added and the mixture was stirred at room temperature for 3 h. After completion of the reaction, the solvent was removed to obtain 0.26 g of crude product, which was directly carried out to the next step.

[0534] Step 5: Synthesis of 4-(1-(((1R,2R)-2-((4-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)-1,2,3,6-tetrahydropyridin-4-yl)-N-(2,6-dioxopiperidin-3-yl)-2-fluorobenzamide

[0535] At room temperature, N-(2,6-dioxopiperidin-3-yl)-2-fluoro-4-(1,2,3,6-tetrahydropyridin-4-yl)benzamide (0.15 g, 0.47 mmol), (1R,2R)-2-((4-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexane-1-carbaldehyde (0.28 g, 0.47 mmol), and dichloromethane (5 mL) were added to the reaction flask in sequence. TIPT (0.5 mL) was then added, and the mixture was stirred at room temperature for 16 hours. STAB (0.15 g, 0.71 mmol) was then added, and the reaction was stirred at room temperature for 2 hours. After completion of the reaction, dichloromethane was added to dilute the mixture, and celite was added. After stirring for a long time, water was added to quench the reaction. After stirring for 20 minutes, the mixture was filtered. The filter cake was slurried twice with dichloromethane. The organic phases were combined, desolventized, and subjected to column chromatography using a DCM / MeOH system to obtain 0.21 g of the product. The three-step yield was 62%.

[0536] Step 6: Synthesis of N-(2,6-dioxopiperidin-3-yl)-2-fluoro-4-(1-(((1R,2R)-2-((4-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)piperidin-4-yl)benzamide

[0537] At room temperature, 4-(1-(((1R,2R)-2-((4-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)-1,2,3,6-tetrahydropyridin-4-yl)-N-(2,6-dioxopiperidin-3-yl)-2-fluorobenzamide (0.21 g, 0.23 mmol), 10% palladium on carbon (0.10 g) and THF (3 mL) were added to the reaction flask in sequence. The hydrogen was replaced 3-4 times, and the reaction was stirred at room temperature for 24 h. After completion of the reaction, the mixture was filtered through celite, the filter cake was rinsed with THF, the filtrate was desolvated, and column chromatography using a DCM / MeOH system was performed to obtain 0.01 g of the product in a yield of 5%.

[0538] 1 H NMR (400MHz, DMSO-d6) δ10.88 (s, 1H), 9.13 (s, 1H), 8.49 (dd, J=8.3, 3.8Hz, 1H), 7.64 (dd, J=11.1, 4.9Hz, 1H), 7.23-7.09 (m, 5H), 6.83 (d, J=7.1Hz, 2H), 6.65-6.46 (m, 5H), 6.23 (d, J=8.2Hz, 2H), 4.85-4.66(m, 1H), 4.15(d, J=4.9Hz, 1H), 3.09-2.62(m, 15H), 2.28-2.07(m ,5H),1.86-1.43(m,15H),1.03-0.94(m,3H),0.87-0.82(m,2H).MS(ESI)m / z:826.6[M+H] + .

[0539] Example 11: Synthesis of 3-(5-fluoro-6-(4-(((1R,2R)-2-((4-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)piperazin-1-yl)-1-methyl-1H-indazol-3-yl)piperazine-2,6-dione (Compound IV-1)

[0540] The synthesis method of (1R,2R)-2-((4-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexane-1-carbaldehyde is as described in Example 1.

[0541] Step 1: Synthesis of 3-(2,6-bis(benzyloxy)pyridin-3-yl)-6-bromo-5-fluoro-1-methyl-1H-indazole

[0542] At room temperature, 6-bromo-5-fluoro-3-iodo-1-methyl-1H-indazole (1.00 g, 2.97 mmol), 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxolan-2-yl)pyridine (1.24 g, 2.97 mmol), sodium carbonate (0.94 g, 8.90 mmol), tetrakistriphenylphosphine palladium (0.34 g, 0.30 mmol), water (1 mL), and dioxane (10 ml) were added to the reaction flask in sequence. The mixture was reacted at 90° C. under a nitrogen atmosphere for 5 h. After completion of the reaction, the mixture was cooled to room temperature, ethyl acetate and water were added, the layers were separated, and the organic phase was dried and purified by PE / EA column chromatography to obtain 1.20 g of the product in an 81% yield.

[0543] Step 2: Synthesis of tert-butyl 4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)-5-fluoro-1-methyl-1H-indazol-6-yl)piperazine-1-carboxylate

[0544] At room temperature, a reaction flask was added with 3-(2,6-bis(benzyloxy)pyridin-3-yl)-6-bromo-5-fluoro-1-methyl-1H-indazole (0.25 g, 0.50 mmol), 1-Boc-piperazine (0.28 g, 1.50 mmol), Pd2(dba)3 (0.05 g, 0.05 mmol), 10% tri-tert-butylphosphine in toluene (200 mg, 0.10 mmol), sodium tert-butoxide (0.10 g, 1.00 mmol), and toluene (10 ml). The reaction was continued at 100°C under a nitrogen atmosphere for 5 h. After completion of the reaction, the mixture was cooled to room temperature, ethyl acetate and water were added, and the layers were separated. The organic phase was dried and purified by PE / EA column chromatography to obtain 0.20 g of the product in a 66% yield.

[0545] Step 3: Synthesis of tert-butyl 4-(3-(2,6-dioxopiperidin-3-yl)-5-fluoro-1-methyl-1H-indazol-6-yl)piperazine-1-carboxylate

[0546] To a reaction flask at room temperature was added tert-butyl 4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)-5-fluoro-1-methyl-1H-indazol-6-yl)piperazine-1-carboxylate (0.20 g, 0.33 mmol), 10% Pd / C (0.02 g), tetrahydrofuran (5 mL), and ethanol (5 mL). The mixture was reacted at room temperature for 24 h. After completion of the reaction, the mixture was filtered and dried to afford 0.13 g of a crude product, which was used directly in the next step.

[0547] Step 4: Synthesis of 3-(5-fluoro-1-methyl-6-(piperazin-1-yl)-1H-indazol-3-yl)piperazine-2,6-dione

[0548] To the reaction flask, tert-butyl 4-(3-(2,6-dioxopiperidin-3-yl)-5-fluoro-1-methyl-1H-indazol-6-yl)piperazine-1-carboxylate (0.13 g, 0.30 mmol) and HCl in dioxane (5 ml) were added sequentially at room temperature for 2 h. After completion of the reaction, the mixture was spin-dried to give 0.11 g of crude product, which was used directly in the next step.

[0549] Step 5: Synthesis of 3-(6-(4-(((1R,2R)-2-((4-(4-(1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)piperazin-1-yl)-5-fluoro-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione

[0550] At room temperature, 3-(5-fluoro-1-methyl-6-(piperazin-1-yl)-1H-indazol-3-yl)piperazine-2,6-dione (0.15 g, 0.47 mmol), (1R,2R)-2-((4-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexane-1-carbaldehyde (0.28 g, 0.47 mmol), and dichloromethane (5 mL) were added to the reaction flask in sequence. TIPT (0.5 mL) was then added, and the mixture was stirred at room temperature for 16 hours. STAB (0.15 g, 0.71 mmol) was then added, and the reaction was stirred at room temperature for 2 hours. After completion of the reaction, dichloromethane was added to dilute the mixture, and celite was added. After stirring for a long time, water was added to quench the reaction. After stirring for 20 minutes, the mixture was filtered. The filter cake was slurried twice with dichloromethane. The organic phases were combined, desolventized, and subjected to column chromatography using a DCM / MeOH system to obtain 0.21 g of the product. The three-step yield was 62%.

[0551] Step 6: Synthesis of 3-(5-fluoro-6-(4-(((1R,2R)-2-((4-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)piperazin-1-yl)-1-methyl-1H-indazol-3-yl)piperazine-2,6-dione

[0552] At room temperature, 3-(6-(4-(((1R, 2R)-2-((4-(4-(1R, 2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)piperazin-1-yl)-5-fluoro-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione (0.21 g, 0.23 mmol), 10% palladium on carbon (0.10 g) and THF (3 mL) were added to the reaction flask in sequence. The hydrogen was replaced 3-4 times, and the reaction was stirred at room temperature for 24 h. After completion of the reaction, the mixture was filtered through celite, the filter cake was rinsed with THF, the filtrate was desolvated, and column chromatography using a DCM / MeOH system was performed to obtain 0.07 g of the product in a yield of 37%.

[0553] 1 H NMR (400MHz, DMSO-d6) δ10.88 (s, 1H), 9.15 (d, J = 4.4Hz, 1H), 7.48 (d, J = 12.6Hz, 1H), 7.11 (dt, J = 15.7, 7.3Hz, 4H), 6.83 (d, J=7.2Hz, 2H), 6.67-6.54 (m, 4H), 6.48 (dd, J=8.3, 2.5Hz, 1H), 6.23 (d, J=8.1Hz, 2H), 4.28 (dd, J=9 .8, 5.1Hz, 1H), 4.14 (d, J=5.0Hz, 1H), 3.91 (d, J=17.0Hz, 3H), 3.24-2.84 (m, 15H), 2.77-2.53 (m, 7H), 2.41-2.2 9(m, 2H), 2.26-1.98(m, 3H), 1.88-1.40(m, 7H), 1.28-1.15(m, 3H), 1.07-0.93(m, 2H).MS(ESI)m / z:838.6[M+H] + .

[0554] Example 12: Synthesis of 3-(6-fluoro-5-(4-(((1R,2R)-2-((4-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)piperazin-1-yl)-1-methyl-1H-indazol-3-yl)piperazine-2,6-dione (Compound VI-5)

[0555] The synthesis method of (1R,2R)-2-((4-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexane-1-carbaldehyde is as described in Example 1.

[0556] Step 1: Synthesis of 3-(5-bromo-6-fluoro-1H-indazol-1-yl)-1-(4-methoxyphenylmethyl)piperazine-2,6-dione

[0557] At room temperature, 5-bromo-6-fluoro-1H-indazole (0.50 g, 2.54 mmol), potassium tert-butoxide (0.34 g, 3.05 mmol), and tetrahydrofuran (15 ml) were added to the reaction flask in sequence. The temperature was lowered to 0°C and stirred for 30 minutes. 1-(4-methoxybenzyl)-2,6-dioxopiperidin-3-yl trifluoromethanesulfonate (0.97 g, 2.54 mmol) was then added. After the addition was complete, the mixture was allowed to react at room temperature for 3 hours. After the reaction was complete, ethyl acetate and water were added, the layers were separated, and the organic phase was dried and purified by PE / EA column chromatography to obtain 0.47 g of the product in a 43% yield. Step 2: Synthesis of tert-butyl 4-(6-fluoro-1-(1-(4-methoxybenzyl)-2,6-dioxopiperidin-3-yl)-1H-indazol-5-yl)piperazine-1-carboxylate

[0558] At room temperature, 3-(5-bromo-6-fluoro-1H-indazol-1-yl)-1-(4-methoxyphenylmethyl)piperazine-2,6-dione (0.47 g, 1.09 mmol), 1-Boc-piperazine (0.20 g, 1.09 mmol), PEPPSI IHept-Cl (0.11 g, 0.11 mmol), cesium carbonate (1.07 g, 3.28 mmol), 4A molecular sieves (0.11 g) and 1,4-dioxane (15 ml) were added to the reaction flask in sequence. The nitrogen atmosphere was replaced 3-4 times, and the temperature was raised to 100° C. for 16 h. After completion of the reaction, the temperature was lowered to room temperature, ethyl acetate and water were added, the layers were separated, and the organic phase was dried and purified by PE / EA column chromatography to obtain 0.13 g of the product in a yield of 21%.

[0559] Step 3: Synthesis of 3-(6-fluoro-5-(piperazin-1-yl)-1H-indazol-1-yl)piperazine-2,6-dione

[0560] At room temperature, tert-butyl 4-(6-fluoro-1-(1-(4-methoxybenzyl)-2,6-dioxopiperidin-3-yl)-1H-indazol-5-yl)piperazine-1-carboxylate (0.13 g, 0.23 mmol), trifluoroacetic acid (3 ml), and TfOH (0.5 ml) were added to the reaction flask in sequence. The temperature was raised to 65°C and stirred for 2 h. After completion of the reaction, the solvent was removed and the product was purified by reverse-phase column chromatography (acetonitrile / water) to obtain 0.07 g of a crude product, which was directly used in the next step.

[0561] Step 5: Synthesis of 3-(5-(4-(((1R,2R)-2-((4-(4-(1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)piperazin-1-yl)-6-fluoro-1H-indazol-1-yl)piperidine-2,6-dione

[0562] At room temperature, 3-(6-fluoro-5-(piperazin-1-yl)-1H-indazol-1-yl)piperazine-2,6-dione (0.15 g, 0.47 mmol), (1R,2R)-2-((4-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexane-1-carbaldehyde (0.28 g, 0.47 mmol), and dichloromethane (5 mL) were added to the reaction flask in sequence. TIPT (0.5 mL) was then added, and the mixture was stirred at room temperature for 16 hours. STAB (0.15 g, 0.71 mmol) was then added, and the reaction was stirred at room temperature for 2 hours. After completion of the reaction, dichloromethane was added to dilute the mixture, and celite was added. After stirring for a long time, water was added to quench the reaction. After stirring for 20 minutes, the mixture was filtered. The filter cake was slurried twice with dichloromethane. The organic phases were combined, desolventized, and subjected to column chromatography using a DCM / MeOH system to obtain 0.21 g of the product. The three-step yield was 62%.

[0563] Step 6: Synthesis of 3-(6-fluoro-5-(4-(((1R,2R)-2-((4-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)piperazin-1-yl)-1-methyl-1H-indazol-3-yl)piperazine-2,6-dione

[0564] At room temperature, 3-(5-(4-(((1R, 2R)-2-((4-(4-(1R, 2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)piperazin-1-yl)-6-fluoro-1H-indazol-1-yl)piperidine-2,6-dione (0.21 g, 0.23 mmol), 10% palladium on carbon (0.10 g) and THF (3 mL) were added to the reaction flask in sequence. The hydrogen was replaced 3-4 times and the reaction was stirred at room temperature for 24 h. After completion of the reaction, the mixture was filtered through celite, the filter cake was rinsed with THF, the filtrate was desolvated, and column chromatography using a DCM / MeOH system was performed to obtain 0.07 g of the product in a yield of 37%.

[0565] 1H NMR (400MHz, DMSO-d6) δ11.11 (s, 1H), 9.14 (s, 1H), 8.00 (s, 1H), 7.55 (d, J = 12.4Hz, 1H), 7.37 (d, J = 8.2Hz, 1H) , 7.10 (d, J=9.5Hz, 2H), 6.81 (dd, J=7.5, 3.7Hz, 2H), 6.65-6.56 (m, 4H), 6.48 (dd, J=8.3, 2.5Hz, 1H), 6.26-6.21 (m, 2H), 5.76 (dd, J=11.5, 5.1Hz, 1H), 4.15 (d, J=5.0Hz, 1H), 3.17-2.89 (m, 17H), 2.85-2.55 (m, 8H), 2.26-2.2 1(m, 1H), 2.11-2.05(m, 1H), 1.81-1.43(m, 8H), 1.26-1.16(m, 3H), 1.06-0.95(m, 2H).MS(ESI)m / z:824.5[M+H] + .

[0566] Example 13: Synthesis of N-(2,6-dioxopiperidin-3-yl)-5-(1-(((1R,2R)-2-((4-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)piperidin-4-yl)picolinamide (Compound III-3)

[0567] The synthesis method of (1R,2R)-2-((4-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexane-1-carbaldehyde is as described in Example 1.

[0568] Step 1: Synthesis of 1′-(tert-butyl)6-methyl 3′,6′-dihydro-[3,4′-bipyridine]-1′,6(2′H)-dicarboxylate

[0569] At room temperature, methyl 5-bromopyridine-2-carboxylate (1.00 g, 4.63 mmol), N-Boc-1,2,5,6-tetrahydropyridine-4-boronic acid pinacol ester (2.15 g, 6.94 mmol), Pd(dppf)Cl2 (0.34 g, 0.46 mmol), Cs2CO3 (3.00 g, 9.26 mmol), Do (10 ml), and H2O (2 ml) were added to the reaction flask in sequence. The nitrogen atmosphere was replaced 3-4 times, and the temperature was raised to 100°C for 3 h. After completion of the reaction, the temperature was cooled to room temperature, filtered, and the filtrate was concentrated and chromatographed on a PE / EA column to obtain 1.25 g of the product as a brown oil in an 83% yield.

[0570] Step 2: Synthesis of 1′-(tert-butyloxycarbonyl)-1′,2′,3′,6′-tetrahydro-[3,4′-bipyridine]-6-carboxylic acid

[0571] To a reaction flask at room temperature were added methyl tert-butyl 4-(6-(methoxycarbonyl)pyridin-3-yl)piperazine-1-carboxylate (1.25 g, 3.93 mmol), NaOH (0.63 g, 15.72 mmol), MeOH (15 ml), and H₂O (5 ml), in that order. The temperature was raised to 50°C and the reaction was allowed to proceed for 4 h. After completion of the reaction, the solvent was removed, the mixture was acidified by adding aqueous HCl, and extracted three times with DCM to afford 1.10 g of a yellow solid in a 92% yield.

[0572] Step 3: Synthesis of tert-butyl 6-((2,6-dioxopiperidin-3-yl)carbamoyl)-3′,6′-dihydro-[3,4′-bipyridine]-1′(2′H)-carboxylate

[0573] At room temperature, 1′-(tert-butyloxycarbonyl)-1′,2′,3′,6′-tetrahydro-[3,4′-bipyridine]-6-carboxylic acid (0.20 g, 0.65 mmol), 3-aminopiperidine-2,6-dione hydrochloride (0.13 g, 0.78 mmol), HATU (0.37 g, 0.98 mmol), DIEA (0.25 g, 1.95 mmol), and DMF (3 ml) were added to a reaction flask in this order. The mixture was stirred at room temperature for 2 h. After completion of the reaction, water (3 mL) and saturated brine (3 mL) were added to the reaction mixture to precipitate a large amount of solid. The solid was filtered, and the filter cake was dissolved in DCM, dried over anhydrous magnesium sulfate, and then directly processed into the next step.

[0574] Step 4: Synthesis of N-(2,6-dioxopiperidin-3-yl)-1′,2′,3′,6′-tetrahydro-[3,4′-bipyridine]-6-carboxamide

[0575] At room temperature, tert-butyl 6-((2,6-dioxopiperidin-3-yl)carbamoyl)-3′,6′-dihydro-[3,4′-bipyridine]-1′(2′H)-carboxylate (0.27 mg, 0.65 mmol) and dichloromethane (2 ml) were added to the reaction flask. After the solution was dissolved, hydrochloric acid / dioxane (2 ml) was added and the mixture was stirred at room temperature for 3 h. After completion of the reaction, the solvent was removed to obtain 0.26 g of crude product, which was directly carried out to the next step.

[0576] Step 5: Synthesis of 1′-(((1R,2R)-2-((4-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)-N-(2,6-dioxopiperidin-3-yl)-1′,2′,3′,6′-tetrahydro-[3,4′-bipyridine]-6-carboxamide

[0577] At room temperature, N-(2,6-dioxopiperidin-3-yl)-1′,2′,3′,6′-tetrahydro-[3,4′-bipyridine]-6-carboxamide (0.15 g, 0.47 mmol), (1R,2R)-2-((4-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexane-1-carbaldehyde (0.28 g, 0.47 mmol), and dichloromethane (5 ml) were added to the reaction flask in sequence. TIPT (0.45 ml) was then added, and the mixture was stirred at room temperature for 16 hours. STAB (0.15 g, 0.71 mmol) was then added, and the reaction was stirred at room temperature for 2 hours. After completion of the reaction, dichloromethane was added to dilute the mixture, and celite was added. After stirring for a long time, water was added to quench the reaction. After stirring for 20 minutes, the mixture was filtered. The filter cake was slurried twice with dichloromethane. The organic phases were combined, desolventized, and subjected to column chromatography using a DCM / MeOH system to obtain 0.21 g of the product. The three-step yield was 62%.

[0578] Step 6: Synthesis of N-(2,6-dioxopiperidin-3-yl)-5-(1-(((1R,2R)-2-((4-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)piperidin-4-yl)pyridine-2-carboxamide

[0579] At room temperature, 1′-(((1R,2R)-2-((4-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)-N-(2,6-dioxopiperidin-3-yl)-1′,2′,3′,6′-tetrahydro-[3,4′-bipyridine]-6-carboxamide (0.16 g, 0.18 mmol), 10% palladium on carbon (0.05 g) and THF (3 ml) were added to the reaction flask in sequence. The hydrogen was replaced 3-4 times and the reaction was stirred at room temperature for 24 h. After completion of the reaction, the mixture was filtered through celite, the filter cake was rinsed with THF, the filtrate was desolvated, and column chromatography using a DCM / MeOH system was performed to obtain 0.033 g of the product, 0.028 g of which was stored, with a yield of 22.9%.

[0580] 1 H NMR (400MHz, DMSO-d6) δ10.88 (s, 1H), 9.15 (s, 1H), 9.03 (d, J=8.5Hz, 1H), 8.58 (s, 1H), 8.01 (d, J = 8.2Hz, 1H), 7.88 (d, J = 8.4Hz, 1H), 7.11 (q, J = 10.0, 8.6Hz, 3 H), 6.82 (d, J=7.3Hz, 2H), 6.64-6.60 (m, 2H), 6.55 (d, J=8.5Hz, 2H), 6.48 (d, J= 8.5Hz, 1H), 6.22 (d, J=8.2Hz, 2H), 4.79 (t, J=6.8Hz, 1H), 4.14 (d, J=5.1Hz, 1H), 3.17 (s, 1H), 3.03-2.96 (m, 4H), 2.82-2.75 (m, 2H), 2.54 (s, 2H), 2.22 (dd, J=12 .6, 4.2Hz, 3H), 2.12-1.96 (m, 4H), 1.87 (d, J=37.5Hz, 8H), 1.72-1.66 (m, 2H), 1 .62 (s, 2H), 1.50 (dd, J=12.5, 7.1Hz, 2H), 1.40 (s, 1H), 1.22 (d, J=11.7Hz, 4H), 1.00 (p, J=9.6, 8.5Hz, 3H), 0.85 (q, J=8.7, 7.9Hz, 2H).MS (ESI) m / z: 809.6[M+H] + .

[0581] Example 14: Synthesis of 3-(5-(1-(((1R,2R)-2-((4-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenylpiperazin-1-yl)methyl)cyclohexyl)methyl)piperidin-4-yl)-3-methyl-1H-indazol-1-yl)piperidine-2,6-dione (Compound VI-8)

[0582] The synthesis method of (1R,2R)-2-((4-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexane-1-carbaldehyde is as described in Example 1.

[0583] Step 1: Synthesis of 5-(4-(((1S,2S)-2-((4-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenylpiperazin-1-yl)methyl)cyclohexyl)methyl)piperazin-1-yl)-N-(2,6-dioxopiperidin-3-yl)pyridine-3-carboxamide

[0584] At room temperature, a reaction flask was added with 3-(5-bromo-3-methyl-1H-indazol-1-yl)-1-(4-methoxybenzyl)piperidine-2,6-dione (0.40 g, 0.90 mmol), N-Boc-1,2,5,6-tetrahydropyridine-4-boronic acid pinacol ester (0.28 g, 0.90 mmol), Xphos-Pd-G2 (0.07 g, 0.09 mmol), K3PO4 (0.38 g, 1.81 mmol), Do (5 mL), and H2O (1 ml). The atmosphere was purged with nitrogen 3-4 times and the temperature was raised to 80°C for 2 h. After completion of the reaction, the mixture was cooled to room temperature, concentrated, and purified by PE / EA column chromatography to obtain 0.30 g of a white solid in a 61% yield.

[0585] Step 2: Synthesis of 3-(3-methyl-5-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indazol-1-yl)piperidine-2,6-dione

[0586] At room temperature, 5-(4-(((1S,2S)-2-((4-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenylpiperazin-1-yl)methyl)cyclohexyl)methyl)piperazin-1-yl)-N-(2,6-dioxopiperidin-3-yl)pyridine-3-carboxamide (0.27 g, 0.50 mmol) was dissolved in TFA (6 mL), TfOH (1 mL) was added, and the reaction was carried out at 65 ° C. for 5 h. After completion of the reaction, the reaction solution was concentrated and purified by reverse phase column chromatography (H2O / ACN) to give 0.12 g of a yellow solid with a yield of 74.6%.

[0587] Step 3: Synthesis of 3-(5-(1-(((1R,2R)-2-((4-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenylpiperazin-1-yl)methyl)cyclohexyl)methyl)-1,2,3,6-tetrahydropyridin-4-yl)-3-methyl-1H-indazol-1-yl)piperidine-2,6-dione

[0588] At room temperature, 3-(3-methyl-5-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indazol-1-yl)piperidine-2,6-dione (0.12 g, 0.37 mmol), (1S,2S)-2-((4-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexane-1-carbaldehyde (0.22 g, 0.37 mmol), and dichloromethane (5 ml) were added to the reaction flask in sequence. TIPT (0.4 ml) was then added, and the mixture was stirred at room temperature for 16 hours. STAB (0.12 g, 0.55 mmol) was then added, and the reaction was stirred at room temperature for 2 hours. After completion of the reaction, dichloromethane was added to dilute the mixture, and celite was added. After stirring for a long time, water was added to quench the reaction. After stirring for 20 minutes, the mixture was filtered. The filter cake was slurried twice with dichloromethane. The organic phases were combined, desolventized, and subjected to column chromatography using a DCM / MeOH system to obtain 0.06 g of a white solid with a yield of 16.4%.

[0589] Step 4: Synthesis of 3-(5-(1-(((1R,2R)-2-((4-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenylpiperazin-1-yl)methyl)cyclohexyl)methyl)piperidin-4-yl)-3-methyl-1H-indazol-1-yl)piperidine-2,6-dione

[0590] At room temperature, 3-(5-(1-(((1R,2R)-2-((4-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenylpiperazin-1-yl)methyl)cyclohexyl)methyl)-1,2,3,6-tetrahydropyridin-4-yl)-3-methyl-1H-indazol-1-yl)piperidine-2,6-dione (0.10 g, 0.11 mmol), 10% palladium on carbon (0.05 g) and THF (3 ml) were added to the reaction flask in sequence, the hydrogen was replaced 3-4 times, and the reaction was stirred at 30°C for 24 h. After the reaction was completed, the mixture was filtered on celite, the filter cake was rinsed with THF, the filtrate was desolvated, and column chromatography using a DCM / MeOH system was used to obtain 0.006 g of the product, 0.002 g of which was put into storage, with a yield of 6.7%.

[0591] 1 H NMR (400MHz, DMSO-d6) δ11.07 (s, 1H), 9.15 (d, J=7.1Hz, 1H), 7.51-7.43 (m, 2H), 7.31 (d, J=8.6Hz, 1H), 7.08 (d, J=7.3Hz, 2H), 6. 81 (d, J=7.8Hz, 2H), 6.64-6.57 (m, 4H), 6.48 (dd, J=8.2, 2.6Hz, 1H), 6.24 (d, J=8.2Hz, 2H), 5.73 (dd, J=11.8, 5.2Hz, 1H), 4.39 (t, J=5.2Hz, 1H), 4.15 (d, J=5.1Hz, 1H), 2.98-2.85 (m, 7H), 2.72 (qd, J=13.9, 11.0, 4.5Hz, 5H), 2.37-2.29 (m, 3H), 2.21 (q, J=8.3, 7 .4Hz, 2H), 2.14-1.88(m, 6H), 1.78-1.65(m, 6H), 1.43(h, J=3.1Hz, 2H), 1.30(s, 8H), 1.10-0.77(m, 4H).MS(ESI)m / z:819.7[M+H] + .

[0592] Example 15: Synthesis of 3-(6-fluoro-5-(1-(((1R,2R)-2-((4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)piperidin-4-yl)-3-methyl-1H-indazol-1-yl)piperidine-2,6-dione (Compound VI-9)

[0593] The synthesis method of (1R,2R)-2-((4-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexane-1-carbaldehyde is as described in Example 1.

[0594] Step 1: Synthesis of 3-(5-bromo-6-fluoro-3-methyl-1h-indazol-1-yl)-1-(4-methoxybenzyl)piperidine-2,6-dione

[0595] At room temperature, 5-bromo-6-fluoro-3-methylindazole (0.50 g, 2.18 mmol), potassium tert-butoxide (0.29 g, 2.62 mmol), and tetrahydrofuran (15 ml) were added to the reaction flask in sequence. The temperature was lowered to 0°C and stirred for 30 minutes. 1-(4-methoxybenzyl)-2,6-dioxopiperidin-3-yl trifluoromethanesulfonate (0.83 g, 2.18 mmol) was then added. After the addition was complete, the reaction was allowed to return to room temperature and allowed to react for 3 hours. After completion of the reaction, ethyl acetate and water were added, the layers separated, and the organic phase was dried and purified by PE / EA column chromatography to obtain 0.88 g of the product in a 44% yield.

[0596] Step 2: Synthesis of tert-butyl 4-(6-fluoro-1-(1-(4-methoxybenzyl)-2,6-dioxopiperidin-3-yl)-3-methyl-1H-indazol-5-yl)-3,6-dihydropyridine-1(2H)-carboxylate

[0597] At room temperature, 3-(5-bromo-6-fluoro-3-methyl-1H-indazol-1-yl)-1-(4-methoxybenzyl)piperidine-2,6-dione (0.88 g, 1.91 mmol), N-Boc-1,2,5,6-tetrahydropyridine-4-boronic acid pinacol ester (0.59 g, 1.91 mmol), Xphos-Pd-G2 (0.16 g, 0.20 mmol), potassium phosphate (0.81 g, 3.82 mmol), water (3 ml), and 1,4-dioxane (10 ml) were added to the reaction flask in sequence. The nitrogen atmosphere was replaced 3-4 times, and the temperature was raised to 80°C for 4 hours. After completion of the reaction, the temperature was cooled to room temperature, the solvent was removed, ethyl acetate was added to dilute, and the mixture was filtered through a pad of celite. The filtrate was dried, the solvent was removed, and PE / EA system column chromatography was used to obtain 0.80 g of the product with a yield of 80%.

[0598] Step 3: Synthesis of tert-butyl 4-(6-fluoro-1-(1-(4-methoxybenzyl)-2,6-dioxopiperidin-3-yl)-3-methyl-1H-indazol-5-yl)piperidine-1-carboxylate

[0599] At room temperature, tert-butyl 4-(6-fluoro-1-(1-(4-methoxybenzyl)-2,6-dioxopiperidin-3-yl)-3-methyl-1H-indazol-5-yl)-3,6-dihydropyridine-1(2H)-carboxylate (0.80 g, 1.42 mmol) and tetrahydrofuran (15 ml) were added to the reaction flask. 10% palladium on carbon (0.08 g) was added, and the hydrogen atmosphere was replaced 3-4 times. The reaction was stirred at room temperature for 16 h. After completion of the reaction, the mixture was filtered through a pad of celite and desolvated to obtain 0.50 g of the product, which was directly used in the next step.

[0600] Step 4: Synthesis of 3-(6-fluoro-3-methyl-5-(piperidin-4-yl)-1h-indazol-1-yl)piperidine-2,6-dione

[0601] At room temperature, tert-butyl 4-(6-fluoro-1-(1-(4-methoxybenzyl)-2,6-dioxopiperidin-3-yl)-3-methyl-1H-indazol-5-yl)piperidine-1-carboxylate (0.50 g, 0.89 mmol), trifluoroacetic acid (3 ml), and TfOH (0.5 ml) were added to the reaction flask in sequence. The temperature was raised to 65°C and stirred for 2 h. After completion of the reaction, the solvent was removed and the product was purified by reverse-phase column chromatography (acetonitrile / water) to obtain 0.20 g of a crude product, which was directly used in the next step.

[0602] Step 5: Synthesis of 3-(5-(1-(((1R,2R)-2-((4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)piperidin-4-yl)-6-fluoro-3-methyl-1H-indazol-1-yl)piperidine-2,6-dione

[0603] At room temperature, 3-(6-fluoro-3-methyl-5-(piperidin-4-yl)-1H-indazol-1-yl)piperidine-2,6-dione (0.20 g, 0.58 mmol), (1R,2R)-2-((4-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexane-1-carbaldehyde (0.35 g, 0.58 mmol), and dichloromethane (10 ml) were added to the reaction flask in sequence. TIPT (0.5 ml) was then added, and the mixture was stirred at room temperature for 16 hours. STAB (0.25 g, 0.1.16 mmol) was then added, and the reaction was stirred at room temperature for 2 hours. After completion of the reaction, dichloromethane was added to dilute the mixture, and celite was added. After stirring for a long time, water was added to quench the reaction. After stirring for 20 minutes, the mixture was filtered. The filter cake was slurried twice with dichloromethane. The organic phases were combined, desolventized, and subjected to column chromatography using a DCM / MeOH system to obtain 0.15 g of the product with a yield of 28%.

[0604] Step 6: Synthesis of 3-(6-fluoro-5-(1-(((1R,2R)-2-((4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)piperidin-4-yl)-3-methyl-1H-indazol-1-yl)piperidine-2,6-dione

[0605] At room temperature, 3-(5-(1-(((1R,2R)-2-((4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)piperidin-4-yl)-6-fluoro-3-methyl-1H-indazol-1-yl)piperidine-2,6-dione (0.15 g, 0.16 mmol), 10% palladium on carbon (0.02 g) and tetrahydrofuran (10 ml) were added to the reaction flask in sequence, and hydrogen was added to replace it 3-4 times. The reaction was stirred at room temperature for 24 hours. After completion of the reaction, the mixture was filtered through celite, the filter cake was washed with tetrahydrofuran and the filtrate was desolvated. The product was purified by column chromatography using a DCM / MeOH system to obtain 0.05 g of the product in a yield of 37%.

[0606] 1 H NMR (400MHz, DMSO-d6) δ11.09 (s, 1H), 9.15 (s, 1H), 7.55-7.38 (m, 2H), 7.09 (q, J=6.7Hz, 2H), 7.01 (d, J=7.2Hz, 1H ), 6.81 (d, J = 7.5Hz, 2H), 6.67-6.58 (m, 4H), 6.48 (d, J = 8.2Hz, 1H), 6.25 (d, J = 8.2Hz, 2H), 5.74-5.61 (m, 1H), 4.16 (d, J=4.9Hz, 1H), 3.79-3.47(m, 6H), 3.25-3.11(m, 5H), 3.04-2.85(m, 6H), 2.81-2.65(m, 6H), 2.29(s, 3H), 2.25- 2.19(m, 1H), 2.12-1.95(m, 4H), 1.76-1.51(m, 7H), 1.35-1.13(m, 3H), 1.09-0.94(m, 2H).MS(ESI)m / z:837.5[M+H] + .

[0607] Example 16: Synthesis of 3-(5-fluoro-6-(1-(((1R,2R)-2-((4-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione (Compound IV-9)

[0608] The synthesis method of (1R,2R)-2-((4-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexane-1-carbaldehyde is as described in Example 1.

[0609] Step 1: Synthesis of 3-(2,6-bis(benzyloxy)pyridin-3-yl)-6-bromo-5-fluoro-1-methyl-1H-indazole

[0610] At room temperature, 6-bromo-5-fluoro-3-iodo-1-methyl-1H-indazole (1.00 g, 2.97 mmol), 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxolan-2-yl)pyridine (1.24 g, 2.97 mmol), sodium carbonate (0.94 g, 8.90 mmol), tetrakistriphenylphosphine palladium (0.34 g, 0.30 mmol), water (1 mL), and dioxane (10 ml) were added to the reaction flask in sequence. The mixture was reacted at 90° C. under a nitrogen atmosphere for 5 h. After completion of the reaction, the mixture was cooled to room temperature, ethyl acetate and water were added, the layers were separated, and the organic phase was dried and purified by PE / EA column chromatography to obtain 1.20 g of the product in an 81% yield.

[0611] Step 2: Synthesis of tert-butyl 4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)-5-fluoro-1-methyl-1H-indazol-6-yl)-3,6-dihydropyridine-1(2H)-carboxylate

[0612] At room temperature, a reaction flask was added with 3-(2,6-bis(benzyloxy)pyridin-3-yl)-6-bromo-5-fluoro-1-methyl-1H-indazole (0.60 g, 1.16 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (0.40 g, 1.27 mmol), dppfPdCl2 (0.09 g, 0.12 mmol), potassium carbonate (0.48 g, 3.47 mmol), water (1 mL), and dioxane (10 mL). The reaction was allowed to proceed at 90°C under a nitrogen atmosphere for 5 h. After completion of the reaction, the mixture was cooled to room temperature, ethyl acetate and water were added, and the layers were separated. The organic phase was dried and then purified by PE / EA column chromatography to obtain 0.47 g of the product in a 66% yield.

[0613] Step 3: Synthesis of tert-butyl 4-(3-(2,6-dioxopiperidin-3-yl)-5-fluoro-1-methyl-1H-indol-6-yl)piperidine-1-carboxylate

[0614] To a reaction flask at room temperature was added tert-butyl 4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)-5-fluoro-1-methyl-1H-indazol-6-yl)-3,6-dihydropyridine-1(2H)-carboxylate (0.40 g, 0.66 mmol), 10% Pd / C (0.04 g), tetrahydrofuran (5 mL), and ethanol (5 mL). The mixture was reacted at room temperature for 24 h. After completion of the reaction, the mixture was filtered and dried to give 0.26 g of a crude product, which was used directly in the next step.

[0615] Step 4: Synthesis of 3-(5-fluoro-1-methyl-6-(piperidin-4-yl)-1H-indol-3-yl)piperidine-2,6-dione

[0616] To the reaction flask, tert-butyl 4-(3-(2,6-dioxopiperidin-3-yl)-5-fluoro-1-methyl-1H-indol-6-yl)piperidine-1-carboxylate (0.26 g, 0.60 mmol) and a solution of HCl in dioxane (5 ml) were added sequentially at room temperature for 2 h. After completion of the reaction, the mixture was spin-dried to give 0.22 g of crude product, which was used directly in the next step.

[0617] Step 5: Synthesis of 3-(6-(1-(((1R,2R)-2-((4-(4-(((2R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)piperidin-4-yl)-5-fluoro-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione

[0618] At room temperature, 3-(5-fluoro-1-methyl-6-(piperidin-4-yl)-1H-indol-3-yl)piperidine-2,6-dione (0.15 g, 0.47 mmol), (1R,2R)-2-((4-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexane-1-carbaldehyde (0.28 g, 0.47 mmol), and dichloromethane (5 mL) were added to the reaction flask in sequence. TIPT (0.5 mL) was then added, and the mixture was stirred at room temperature for 16 hours. STAB (0.15 g, 0.71 mmol) was then added, and the reaction was stirred at room temperature for 2 hours. After completion of the reaction, dichloromethane was added to dilute the mixture, and celite was added. After stirring, water was added to quench the reaction. After stirring for 20 minutes, the mixture was filtered. The filter cake was slurried twice with dichloromethane. The organic phases were combined, desolventized, and subjected to column chromatography using a DCM / MeOH system to obtain 0.21 g of the product. The three-step yield was 62%.

[0619] Step 6: Synthesis of 3-(5-fluoro-6-(1-(((1R,2R)-2-((4-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione

[0620] At room temperature, 3-(6-(1-(((1R, 2R)-2-((4-(4-(((2R, 2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)piperidin-4-yl)-5-fluoro-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione (0.21 g, 0.23 mmol), 10% palladium on carbon (0.10 g) and THF (3 mL) were added to the reaction flask in sequence, the hydrogen was replaced 3-4 times, and the reaction was stirred at room temperature for 24 h. After completion of the reaction, the mixture was filtered through celite, the filter cake was rinsed with THF, the filtrate was desolvated, and column chromatography using a DCM / MeOH system was used to obtain 0.11 g of the product in a yield of 58%.

[0621] 1H NMR (400MHz, DMSO-d6) δ10.90 (s, 1H), 9.15 (s, 1H), 7.46 (d, J = 53.3Hz, 2H), 7.04 (d, J = 39.6Hz, 3H), 6. 82 (d, J=7.5Hz, 2H), 6.63 (t, J=6.3Hz, 4H), 6.49 (dd, J=8.2, 2.7Hz, 1H), 6.23 (d, J=8.1Hz, 2H), 4.34 (dd , J=10.5, 5.0Hz, 1H), 4.15 (d, J=5.0Hz, 1H), 3.90 (d, J=46.4Hz, 3H), 3.63 (s, 1H), 3.22-2.86 (m, 12H), 2.75-2.57(m, 4H), 2.42-2.26(m, 3H), 2.17-1.41(m, 17H), 1.08-0.78(m, 3H).MS(ESI)m / z:837.7[M+H] + .

[0622] Example 17: Synthesis of N-(2,6-dioxopiperidin-3-yl)-5-(4-(((1S,2S)-2-((4-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)piperazin-1-yl)picolinamide (Compound III-2)

[0623] The synthesis method of (1S,2S)-2-((4-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexane-1-carbaldehyde is as described in Example 1.

[0624] Step 1: Synthesis of 5-(4-(((1S,2S)-2-((4-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenylpiperazin-1-yl)methyl)cyclohexyl)methyl)piperazin-1-yl)-N-(2,6-dioxopiperidin-3-yl)pyridine-3-carboxamide

[0625] At room temperature, N-(2,6-dioxopiperidin-3-yl)-5-(piperazin-1-yl)pyridine-3-carboxamide (0.09 g, 0.28 mmol), (1S,2S)-2-((4-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexane-1-carbaldehyde (0.17 g, 0.28 mmol), and dichloromethane (5 ml) were added to the reaction flask in sequence. TIPT (0.3 ml) was then added, and the mixture was stirred at room temperature for 16 hours. STAB (0.09 g, 0.42 mmol) was then added, and the reaction was stirred at room temperature for 2 hours. After completion of the reaction, dichloromethane was added to dilute the mixture, and celite was added. After stirring for a long time, water was added to quench the reaction. After stirring for 20 minutes, the mixture was filtered. The filter cake was slurried twice with dichloromethane. The organic phases were combined, desolventized, and subjected to column chromatography using a DCM / MeOH system to obtain 0.09 g of the product with a yield of 35%.

[0626] Step 2: Synthesis of N-(2,6-dioxopiperidin-3-yl)-5-(4-(((1S,2S)-2-((4-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenylpiperazin-1-yl)methyl)cyclohexyl)methyl)piperazin-1-yl)picolinamide

[0627] At room temperature, 5-(4-(((1R, 2R)-2-((4-(4-((1R, 2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenylpiperazin-1-yl)methyl)cyclohexyl)methyl)piperazin-1-yl)-N-(2,6-dioxopiperidin-3-yl)pyridine-3-carboxamide (0.09 g, 0.10 mmol), 10% palladium on carbon (0.05 g) and THF (3 ml) were added to the reaction flask in sequence, the hydrogen was replaced 3-4 times, and the reaction was stirred at room temperature for 24 h. After completion of the reaction, the mixture was filtered through celite, the filter cake was rinsed with THF, the filtrate was desolvated, and column chromatography using a DCM / MeOH system was used to obtain 0.03 g of the product in a yield of 37%.

[0628] 1H NMR (400MHz, DMSO-d6) δ10.87 (s, 1H), 9.13 (s, 1H), 8.74 (d, J = 8.3Hz, 1H), 8.31 (d, J = 2.8Hz, 1H), 7.86 (d, J = 8.8Hz, 1H), 7.41 (dd, J = 9.0, 2.9Hz , 1H), 7.13 (dd, J=9.7, 6.7Hz, 3H), 6.84 (d, J=7.1Hz, 2H), 6.65-6.59 (m, 2H), 6.53 (d, J=8.3Hz, 2H), 6.48 (dd, J=8.3, 2.5Hz, 1H), 6.21 (d, J=8.3 Hz, 2H), 4.74 (td, J=8.0, 4.1Hz, 1H), 4.14 (d, J=5.0Hz, 1H), 3.22 (d, J=42.3Hz, 4H), 3.08-2.62 (m, 10H), 2.53 (s, 5H), 2.31 (t, J=7.4Hz, 2H), 2. 23-1.95 (m, 6H), 1.93-1.64 (m, 4H), 1.57 (s, 2H), 1.44 (d, J=8.7Hz, 2H), 1.22 (d, J=12.2Hz, 2H), 0.98 (h, J=7.2Hz, 2H). MS (ESI) m / z: 810.7[M+H] + .

[0629] Example 18: Synthesis of 3-(6-(4-(((1S,2S)-2-((4-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)piperazin-1-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione (Compound IV-4)

[0630] The synthesis method of (1S,2S)-2-((4-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexane-1-carbaldehyde is as described in Example 1.

[0631] Step 1: Synthesis of 3-(2,6-bis(benzyloxy)pyridin-3-yl)-6-bromo-1-methyl-1H-indazole

[0632] At room temperature, 6-bromo-3-iodo-1-methyl-1H-indazole (1.00 g, 2.97 mmol), 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxolan-2-yl)pyridine (1.24 g, 2.97 mmol), sodium carbonate (0.94 g, 8.90 mmol), tetrakistriphenylphosphine palladium (0.34 g, 0.30 mmol), water (1 mL), and dioxane (10 ml) were added to the reaction flask in sequence. The mixture was reacted at 90° C. under a nitrogen atmosphere for 5 h. After completion of the reaction, the mixture was cooled to room temperature, ethyl acetate and water were added, the layers were separated, and the organic phase was dried and purified by PE / EA column chromatography to obtain 1.20 g of the product in an 81% yield.

[0633] Step 2: Synthesis of tert-butyl 4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)-1-methyl-1H-indazol-6-yl)piperazine-1-carboxylate

[0634] At room temperature, a reaction flask was added with 3-(2,6-bis(benzyloxy)pyridin-3-yl)-6-bromo-1-methyl-1H-indazole (0.25 g, 0.50 mmol), 1-Boc-piperazine (0.28 g, 1.50 mmol), Pd2(dba)3 (0.05 g, 0.05 mmol), 10% tri-tert-butylphosphine in toluene solution (200 mg, 0.10 mmol), sodium tert-butoxide (0.10 g, 1.00 mmol), and toluene (10 ml). The reaction was allowed to proceed at 100°C under a nitrogen atmosphere for 5 h. After completion of the reaction, the mixture was cooled to room temperature, ethyl acetate and water were added, and the layers were separated. The organic phase was dried and purified by PE / EA column chromatography to obtain 0.20 g of the product in a 66% yield.

[0635] Step 3: Synthesis of tert-butyl 4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-6-yl)piperazine-1-carboxylate

[0636] To a reaction flask at room temperature was added tert-butyl 4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)-1-methyl-1H-indazol-6-yl)piperazine-1-carboxylate (0.20 g, 0.33 mmol), 10% Pd / C (0.02 g), tetrahydrofuran (5 mL), and ethanol (5 mL). The mixture was reacted at room temperature for 24 h. After completion of the reaction, the mixture was filtered and dried to give 0.13 g of a crude product, which was used directly in the next step.

[0637] Step 4: Synthesis of 3-(1-methyl-6-(piperazin-1-yl)-1H-indazol-3-yl)piperazine-2,6-dione

[0638] To the reaction flask, tert-butyl 4-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-6-yl)piperazine-1-carboxylate (0.13 g, 0.30 mmol) and HCl in dioxane (5 ml) were added sequentially at room temperature for 2 h. After completion, the reaction was spin-dried to give 0.11 g of crude product, which was used directly in the next step.

[0639] Step 5: Synthesis of 3-(6-(4-(((1S,2S)-2-((4-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)piperazin-1-yl)-1-methyl-1H-indazol-3-yl)piperazine-2,6-dione

[0640] At room temperature, 3-(1-methyl-6-(piperazin-1-yl)-1H-indazol-3-yl)piperazine-2,6-dione (0.06 g, 0.18 mmol), (1S,2S)-2-((4-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexane-1-carbaldehyde (0.11 g, 0.18 mmol), and dichloromethane (10 ml) were added to the reaction flask in sequence. TIPT (0.5 ml) was then added, and the mixture was stirred at room temperature for 16 hours. STAB (0.08 g, 0.36 mmol) was then added, and the reaction was stirred at room temperature for 2 hours. After completion of the reaction, dichloromethane was added to dilute the mixture, and celite was added. After stirring for a long time, water was added to quench the reaction. After stirring for 20 minutes, the mixture was filtered. The filter cake was slurried twice with dichloromethane. The organic phases were combined, desolventized, and subjected to column chromatography using a DCM / MeOH system to obtain 0.03 g of the product with a yield of 27%.

[0641] Step 6: Synthesis of 3-(6-(4-(((1S,2S)-2-((4-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)piperazin-1-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione

[0642] At room temperature, 3-(6-(4-(((1S,2S)-2-((4-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)piperazin-1-yl)-1-methyl-1H-indazol-3-yl)piperazine-2,6-dione (0.03 g, 0.03 mmol), 10% palladium on carbon (0.01 g) and tetrahydrofuran (5 ml) were added to the reaction flask in sequence, and hydrogen was added for replacement 3-4 times. The reaction was stirred at 30°C for 16 h. After completion of the reaction, the mixture was filtered through celite, the filter cake was washed with tetrahydrofuran and the filtrate was desolvated. The product was purified by column chromatography using a DCM / MeOH system to obtain 0.01 g of the product in a yield of 37%.

[0643] 1 H NMR (400MHz, DMSO-d6) δ10.87 (s, 1H), 9.12 (s, 1H), 7.50 (d, J=8.9Hz, 1H), 7.17-7.10 (m, 3H), 6.91 (dd, J=9.0, 1.9Hz, 1H), 6.8 6-6.81 (m, 3H), 6.66-6.60 (m, 2H), 6.55-6.46 (m, 3H), 6.21 (d, J=8.3Hz, 2H), 4.26 (dd, J=9.2, 5.1Hz, 1H), 4.14 (d, J=5.0Hz, 1H ), 3.88(s, 3H), 3.30-3.15(m, 6H), 3.01-2.88(m, 6H), 2.69-2.56(m, 3H), 2.47-2.24(m, 8H), 2.19-2.04(m, 4H), 1.92-1.81(m, 2H), 1.73-1.68(m, 1H), 1.61-1.53(m, 2H), 1.49-1.39(m, 2H), 1.23-1.15(m, 2H), 1.08-0.68(m, 3H).MS(ESI)m / z:821.0[M+H] + .

[0644] Example 19: Synthesis of 3-(6-fluoro-5-(4-(((1R,2R)-2-((4-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenylpiperazin-1-yl)methyl)cyclohexyl)methyl)piperazin-1-yl)-1H-benzimidazol-1-yl)piperidine-2,6-dione (Compound V-2)

[0645] The synthesis method of (1R,2R)-2-((4-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexane-1-carbaldehyde is as described in Example 1.

[0646] Step 1: Synthesis of 2,6-bis(benzyloxy)-3-nitropyridine

[0647] At room temperature, BnOH (7.57 g, 69.95 mmol) was dissolved in THF (25 mL), cooled to -15°C, and potassium tert-butoxide (7.00 g, 62.18 mmol) was added. The mixture was stirred at room temperature for 30 min. The reaction solution was then added dropwise to 2,6-dichloro-3-nitropyridine (5.00 g, 25.91 mmol) in THF (15 mL) at -15°C. After addition, the mixture was allowed to react at room temperature for 16 h. After completion of the reaction, the reaction solution was poured into ice water, stirred for 30 min, filtered, and the filter cake was slurried with tertiary methyl ether to obtain 6.50 g of a white solid (74.6% yield).

[0648] Step 2: Synthesis of 2,6-bis(benzyloxy)pyridin-3-amine

[0649] At room temperature, 2,6-bis(benzyloxy)-3-nitropyridine (6.50 g, 19.32 mmol) was dissolved in THF (10 mL) and MeOH (10 mL). NiCl2·6H2O (0.45 g, 1.93 mmol) was added, and the mixture was cooled to 0°C. NaBH4 (1.82 g, 48.31 mmol) was slowly added, and the mixture was allowed to react in an ice bath for 1 h. After completion of the reaction, ice water (1 mL) was added to quench the reaction mixture, and the residue was concentrated by column chromatography (EA / PE) to afford 4.41 g of a colorless oil (74.5% yield).

[0650] Step 3: Synthesis of 2,6-bis(benzyloxy)N-(4-bromo-5-fluoro-2-nitrophenyl)pyridin-3-amine

[0651] At room temperature, 2,4-difluoro-5-bromonitrobenzene (4.41 g, 13.06 mmol), 2,6-bis(benzyloxy)pyridin-3-amine (4.00 g, 13.06 mmol), KF (0.90 g, 15.67 mmol), and DMF (20 ml) were added to the reaction flask in sequence. The temperature was raised to 118°C and the reaction mixture was reacted for 8 h. After completion of the reaction, the temperature was lowered to room temperature, and water (20 mL) was added to the reaction solution to precipitate a solid. The solid was filtered, and the filter cake was slurried with tertiary methyl ether to obtain 3.5 g of a yellow solid, with a yield of 35.9%.

[0652] Step 4: N 1Synthesis of -(2,6-bis(benzyloxy)pyridin-3-yl)-4-bromo-5-fluorobenzene-1,2-diamine

[0653] At room temperature, 2,6-bis(benzyloxy)N-(4-bromo-5-fluoro-2-nitrophenyl)pyridin-3-amine (3.50 g, 6.67 mmol) was dissolved in THF (20 mL) and MeOH (20 mL). NiCl2.6H2O (0.16 g, 1.67 mmol) was added, and the mixture was cooled to 0°C. NaBH4 (0.63 g, 16.69 mmol) was slowly added, and the mixture was reacted in an ice bath for 1 h. After completion of the reaction, ice water (1 mL) was added to quench the reaction mixture, and the residue was concentrated by column chromatography (EA / PE) to afford 3.25 g of a brown oil in a 98.8% yield.

[0654] Step 5: Synthesis of 1-(2,6-bisbenzyloxy)pyridin-3-yl)-5-bromo-6-fluoro-1H-benzimidazole

[0655] At room temperature, N 1 4-(2,6-bis(benzyloxy)pyridin-3-yl)-4-bromo-5-fluorobenzene-1,2-diamine (3.25 g, 6.57 mmol) was dissolved in toluene (30 mL), and trimethyl orthoformate (1.74 g, 16.44 mmol) and TsOH (0.23 g, 1.31 mmol) were added. The mixture was reacted at 120°C for 1 h. After completion of the reaction, the reaction solution was cooled to room temperature and concentrated by column chromatography (EA / PE) to obtain 3.00 g of a brown oil with a yield of 90.5%.

[0656] Step 6: Synthesis of tert-butyl 4-(1-(2,6-bisbenzyloxy)pyridin-3-yl)-6-fluoro-1H-benzimidazol-5-yl)piperazine-1-carboxylate

[0657] At room temperature, 1-(2,6-bisbenzyloxy)pyridin-3-yl)-5-bromo-6-fluoro-1H-benzimidazole (0.60 g, 1.19 mmol), N-Boc-piperazine (0.44 g, 2.38 mmol), Pd-PEPPSI IHept-Cl (0.12 g, 0.12 mmol), Cs2CO3 (1.16 g, 3.57 mmol) were added to the reaction bottle in sequence. MS (0.60 g) and Do (5 ml) were added, nitrogen was replaced 3-4 times, and the temperature was raised to 100°C for 8 h. After completion of the reaction, the temperature was cooled to room temperature, filtered, and the filtrate was concentrated and purified by column chromatography using a DCM / MeOH system. Ethanol was then used to slurry the mixture to obtain 0.60 g of a white solid (82.8% yield).

[0658] Step 7: Synthesis of tert-butyl 4-(1-(2,6-dioxapiperidin-3-yl)-6-fluoro-1H-benzimidazol-5-yl)piperazine-1-carboxylate

[0659] At room temperature, tert-butyl 4-(1-(2,6-bisbenzyloxy)pyridin-3-yl)-6-fluoro-1H-benzimidazol-5-yl)piperazine-1-carboxylate (0.60 g, 0.98 mmol), DMF (15 mL), AcOH (2 mL), and Pd / C (200 mg) were added to the reaction flask in sequence. The hydrogen was replaced 3-4 times, and the temperature was raised to 35°C for 8 h. After completion of the reaction, the reaction was filtered, and the filtrate was added with water to precipitate a solid. The crude product (0.60 g) was filtered and directly carried out to the next step.

[0660] Step 8: Synthesis of 3-(6-fluoro-5-(piperazin-1-yl)-1H-benzimidazol-1-yl)piperidine-2,6-dione

[0661] To the reaction flask, tert-butyl 4-(1-(2,6-dioxapiperidin-3-yl)-6-fluoro-1H-benzimidazol-5-yl)piperazine-1-carboxylate (0.30 g, 0.70 mmol), DCM (3 mL), and HCl in D0 (5 mL) were added sequentially at room temperature. The temperature was raised to 35°C and the reaction was allowed to react for 30 min. After completion of the reaction, the mixture was concentrated to afford 0.25 g of crude product, which was directly carried out to the next step.

[0662] Step 9: Synthesis of 3-(5-(4-(((1R,2R)-2-((4-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenylpiperazin-1-yl)methyl)cyclohexyl)methyl)piperazin-1-yl)-6-fluoro-1H-benzimidazol-1-yl)piperidine-2,6-dione

[0663] At room temperature, 3-(6-fluoro-5-(piperazin-1-yl)-1H-benzimidazol-1-yl)piperidine-2,6-dione (0.10 g, 0.30 mmol), (1R,2R)-2-((4-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexane-1-carbaldehyde (0.15 g, 0.24 mmol), and dichloromethane (5 ml) were added to the reaction flask in sequence. TIPT (0.3 mL) was then added, and the mixture was stirred at room temperature for 8 hours. STAB (0.10 g, 0.45 mmol) was then added, and the reaction was stirred at room temperature for 2 hours. After completion of the reaction, dichloromethane was added to dilute the mixture, and celite was added. After stirring evenly, water was added to quench the reaction. After stirring for 20 minutes, the mixture was filtered. The filter cake was slurried twice with dichloromethane. The organic phases were combined, desolventized, and subjected to column chromatography using a DCM / MeOH system to obtain 0.125 g of a brown solid with a yield of 45.3%.

[0664] Step 4: Synthesis of 3-(6-fluoro-5-(4-(((1R,2R)-2-((4-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenylpiperazin-1-yl)methyl)cyclohexyl)methyl)piperazin-1-yl)-1H-benzimidazol-1-yl)piperidine-2,6-dione

[0665] At room temperature, 3-(5-(4-(((1R, 2R)-2-((4-(4-((1R, 2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenylpiperazin-1-yl)methyl)cyclohexyl)methyl)piperazin-1-yl)-6-fluoro-1H-benzimidazol-1-yl)piperidine-2,6-dione (0.13 g, 0.14 mmol), 10% palladium on carbon (0.05 g) and THF (5 ml) were added to the reaction flask in sequence, the hydrogen was replaced 3-4 times, and the reaction was stirred at room temperature for 8 h. After the reaction was completed, the mixture was filtered on celite, the filter cake was rinsed with THF, the filtrate was desolvated, and column chromatography using a DCM / MeOH system was used to obtain 0.017 g of the product, of which 0.012 g was stored.

[0666] 1H NMR (400MHz, DMSO-d6) δ11.19 (s, 1H), 9.14 (s, 1H), 8.20 (s, 1H), 7.47 (d, J=13.1Hz, 1H), 7.32 (d, J=8.1Hz, 1H), 7.13-7.08 (m, 2H), 6.83 (d, J=7.3Hz, 2H), 6.62-6.46 (m, 5H), 6.22 (d, J=8.1H z, 2H), 5.63 (dd, J=13.0, 5.1Hz, 1H), 4.14 (d, J=5.1Hz, 2H), 3.07-2.68 (m, 19H), 2.23-2.05 (m, 4H), 1.65 (dd, J=91.4, 44.9Hz, 10H), 1.27-1.15 (m, 4H), 0.99 (s, 2H). MS (ESI) m / z: 824.4[M+H] + .

[0667] Example 20: Synthesis of 3-(6-fluoro-5-(1-(((1R,2R)-2-((4-(4-(((2R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)piperidin-4-yl)-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (Compound V-5)

[0668] The synthesis method of (1R,2R)-2-((4-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexane-1-carbaldehyde is as described in Example 1.

[0669] Step 1: Synthesis of 2,6-bis(benzyloxy)-3-nitropyridine

[0670] At room temperature, BnOH (7.57 g, 69.95 mmol) was dissolved in THF (25 mL), cooled to -15°C, and potassium tert-butoxide (7.00 g, 62.18 mmol) was added. The mixture was stirred at room temperature for 30 min. The reaction solution was then added dropwise to 2,6-dichloro-3-nitropyridine (5.00 g, 25.91 mmol) in THF (15 mL) at -15°C. After addition, the mixture was allowed to react at room temperature for 16 h. After completion of the reaction, the reaction solution was poured into ice water, stirred for 30 min, filtered, and the filter cake was slurried with tertiary methyl ether to obtain 6.50 g of a white solid (74.6% yield).

[0671] Step 2: Synthesis of 2,6-bis(benzyloxy)pyridin-3-amine

[0672] At room temperature, 2,6-bis(benzyloxy)-3-nitropyridine (6.50 g, 19.32 mmol) was dissolved in THF (10 mL) and MeOH (10 mL). NiCl2·6H2O (0.45 g, 1.93 mmol) was added, and the mixture was cooled to 0°C. NaBH4 (1.82 g, 48.31 mmol) was slowly added, and the mixture was allowed to react in an ice bath for 1 h. After completion of the reaction, ice water (1 mL) was added to quench the reaction mixture, and the residue was concentrated by column chromatography (EA / PE) to afford 4.41 g of a colorless oil (74.5% yield).

[0673] Step 3: Synthesis of 2,6-bis(benzyloxy)N-(4-bromo-5-fluoro-2-nitrophenyl)pyridin-3-amine

[0674] At room temperature, 2,4-difluoro-5-bromonitrobenzene (4.41 g, 13.06 mmol), 2,6-bis(benzyloxy)pyridin-3-amine (4.00 g, 13.06 mmol), KF (0.90 g, 15.67 mmol), and DMF (20 ml) were added to the reaction flask in sequence. The temperature was raised to 118°C and the reaction mixture was reacted for 8 h. After completion of the reaction, the temperature was lowered to room temperature, and water (20 mL) was added to the reaction solution to precipitate a solid. The solid was filtered, and the filter cake was slurried with tertiary methyl ether to obtain 3.5 g of a yellow solid, with a yield of 35.9%.

[0675] Step 4: N 1 Synthesis of -(2,6-bis(benzyloxy)pyridin-3-yl)-4-bromo-5-fluorobenzene-1,2-diamine

[0676] At room temperature, 2,6-bis(benzyloxy)N-(4-bromo-5-fluoro-2-nitrophenyl)pyridin-3-amine (3.50 g, 6.67 mmol) was dissolved in THF (20 mL) and MeOH (20 mL). NiCl2·6H2O (0.16 g, 1.67 mmol) was added. The temperature was lowered to 0°C, and NaBH4 (0.63 g, 16.69 mmol) was slowly added. The mixture was reacted in an ice bath for 1 h. After completion of the reaction, ice water (1 mL) was added to quench the reaction mixture, and the residue was concentrated by column chromatography (EA / PE) to afford 3.25 g of a brown oil (98.8% yield).

[0677] Step 5: Synthesis of 1-(2,6-bisbenzyloxy)pyridin-3-yl)-5-bromo-6-fluoro-1H-benzimidazole

[0678] At room temperature, N 14-(2,6-bis(benzyloxy)pyridin-3-yl)-4-bromo-5-fluorobenzene-1,2-diamine (3.25 g, 6.57 mmol) was dissolved in toluene (30 mL), and trimethyl orthoformate (1.74 g, 16.44 mmol) and TsOH (0.23 g, 1.31 mmol) were added. The mixture was reacted at 120°C for 1 h. After completion of the reaction, the reaction solution was cooled to room temperature and concentrated by column chromatography (EA / PE) to obtain 3.00 g of a brown oil with a yield of 90.5%.

[0679] Step 6: Synthesis of tert-butyl 4-(1-(2,6-di(benzyloxy)pyridin-3-yl)-6-fluoro-1H-benzo[d]imidazol-5-yl)-3,6-dihydropyridine-1(2H)-carboxylate

[0680] At room temperature, 1-(2,6-bisbenzyloxy)pyridin-3-yl)-5-bromo-6-fluoro-1H-benzimidazole (1.20 g, 2.38 mmol), 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxolan-2-yl)pyridine (1.24 g, 2.97 mmol), potassium carbonate (1.23 g, 8.90 mmol), dppfPdCl2 (0.22 g, 0.30 mmol), water (1 mL), and dioxane (10 ml) were added to the reaction flask in sequence. The mixture was reacted at 90°C under a nitrogen atmosphere for 5 h. After completion of the reaction, the mixture was cooled to room temperature, ethyl acetate and water were added, the layers were separated, and the organic phase was dried and purified by PE / EA column chromatography to obtain 1.20 g of the product in an 81% yield.

[0681] Step 7: Synthesis of tert-butyl 4-(1-(2,6-dioxopiperidin-3-yl)-6-fluoro-1H-benzo[d]imidazol-5-yl)piperidine-1-carboxylate

[0682] At room temperature, tert-butyl 4-(1-(2,6-di(benzyloxy)pyridin-3-yl)-6-fluoro-1H-benzo[d]imidazol-5-yl)-3,6-dihydropyridine-1(2H)-carboxylate (0.60 g, 0.98 mmol), DMF (15 mL), AcOH (2 mL), and Pd / C (200 mg) were added to the reaction flask in sequence. The hydrogen was replaced 3-4 times, and the temperature was raised to 35°C for 8 h. After the reaction was completed, the reaction was filtered, and the filtrate was added with water to precipitate a solid. The crude product (0.60 g) was filtered and directly carried out to the next step.

[0683] Step 8: Synthesis of 3-(6-fluoro-5-(piperidin-4-yl)-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione

[0684] To a reaction flask at room temperature was added tert-butyl 4-(1-(2,6-dioxopiperidin-3-yl)-6-fluoro-1H-benzo[d]imidazol-5-yl)piperidine-1-carboxylate (0.30 g, 0.70 mmol), DCM (3 mL), and HCl in D0 (5 mL). The temperature was raised to 35°C and the reaction was allowed to react for 30 min. After completion of the reaction, the mixture was concentrated to afford 0.25 g of crude product, which was directly carried out to the next step.

[0685] Step 9: Synthesis of 3-(5-(1-(((1R,2R)-2-((4-(4-(((2R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)piperidin-4-yl)-6-fluoro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione

[0686] At room temperature, 3-(6-fluoro-5-(piperidin-4-yl)-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (0.10 g, 0.30 mmol), (1R,2R)-2-((4-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexane-1-carbaldehyde (0.15 g, 0.24 mmol), and dichloromethane (5 ml) were added to the reaction flask in sequence. TIPT (0.3 mL) was then added, and the mixture was stirred at room temperature for 8 hours. STAB (0.10 g, 0.45 mmol) was then added, and the reaction was stirred at room temperature for 2 hours. After completion of the reaction, dichloromethane was added to dilute the mixture, and celite was added. After stirring until uniform, water was added to quench the reaction. After stirring for 20 minutes, the mixture was filtered. The filter cake was slurried twice with dichloromethane. The organic phases were combined, desolventized, and subjected to column chromatography using a DCM / MeOH system to obtain 0.13 g of a brown solid. The yield was 46%.

[0687] Step 10: 3-(6-Fluoro-5-(1-(((1R,2R)-2-((4-(4-(((2R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)piperidin-4-yl)-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione

[0688] At room temperature, 3-(5-(1-(((1R, 2R)-2-((4-(4-(((2R, 2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)piperidin-4-yl)-6-fluoro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (0.08 g, 0.14 mmol), 10% palladium on carbon (0.05 g) and THF (5 ml) were added to the reaction flask in sequence, the hydrogen was replaced 3-4 times, and the reaction was stirred at room temperature for 8 h. After completion of the reaction, the mixture was filtered through celite, the filter cake was rinsed with THF, the filtrate was desolvated, and column chromatography using a DCM / MeOH system was used to obtain 0.02 g of the product in a yield of 27%.

[0689] 1 H NMR (400MHz, DMSO-d6) δ11.21 (s, 1H), 9.15 (s, 1H), 8.26 (s, 1H), 7.47 (d, J=10.3Hz, 1H), 7.11 (d , J=7.5Hz, 3H), 6.82 (d, J=7.4Hz, 2H), 6.65-6.54 (m, 4H), 6.48 (dd, J=8.2, 2.5Hz, 1H), 6.22 (d, J =8.3Hz, 2H), 5.73-5.60(m, 1H), 4.15-4.11(m, 1H), 3.54-3.50(m, 1H), 3.15-2.66(m, 18H), 2.28 -1.94(m, 8H), 1.80-1.52(m, 9H), 1.09-0.94(m, 3H), 0.92-0.77(m, 2H).MS(ESI)m / z: 821.4[MH] - .

[0690] Example 21: Synthesis of 3-(5-(1-(((1R,2R)-2-((4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)piperidin-4-yl)-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (Compound V-7)

[0691] The synthesis method of (1R,2R)-2-((4-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexane-1-carbaldehyde is as described in Example 1.

[0692] Step 1: Synthesis of 2,6-bis(benzyloxy)pyridin-3-amine

[0693] At room temperature, 2,6-dichloro-3-aminopyridine (9.00 g, 55.21 mmol), potassium tert-butoxide (18.58 g, 165.64 mmol), benzyl alcohol (17.92 g, 165.64 mmol), and tetrahydrofuran (200 ml) were added to the reaction flask in sequence. The temperature was raised to 70°C and stirred for 20 hours. After completion of the reaction, the temperature was lowered, ethyl acetate and water were added, and the layers were separated. The organic phase was dried and purified by PE / EA column chromatography to obtain 4.08 g of the product in a 48% yield.

[0694] Step 2: Synthesis of 2,6-bis(benzyloxy)-N-(4-bromo-2-nitrophenyl)pyridin-3-amine

[0695] To a reaction flask were added 2,6-bis(benzyloxy)pyridin-3-amine (3.58 g, 11.70 mmol), 4-bromo-1-fluoro-2-nitrobenzene (3.09 g, 14.03 mmol), potassium fluoride (0.82 g, 14.03 mmol), and DMF (20 ml) in sequence. The mixture was stirred at 130°C for 18 hours. After completion of the reaction, the temperature was lowered, and ethyl acetate and water were added. The layers were separated, and the organic phase was dried and purified by PE / EA column chromatography to obtain 5.90 g of the product in a 99% yield.

[0696] Step 3: Synthesis of N1-(2,6-bis(benzyloxy)pyridin-3-yl)-4-bromobenzene-1,2-diamine

[0697] Methanol (80 ml), tetrahydrofuran (80 ml), 2,6-bis(benzyloxy)-N-(4-bromo-2-nitrophenyl)pyridin-3-amine (5.90 g, 11.65 mmol), and nickel chloride hexahydrate (0.28 g, 1.17 mmol) were added to the reaction flask in sequence. The temperature was lowered to 0°C, and sodium borohydride (1.10 g, 29.01 mmol) was added in portions with temperature control. After the addition, the mixture was reacted in an ice bath for 1 hour. After completion, the reaction was quenched with water, stirred for 10 minutes, and then desolvated. The crude product was purified by PE / EA column chromatography to obtain 3.30 g of the product, with a yield of 59%.

[0698] Step 4: Synthesis of 1-(2,6-bis(benzyloxy)pyridin-3-yl)-5-bromo-1H-benzo[d]imidazole

[0699] Toluene (15 ml), N1-(2,6-bis(benzyloxy)pyridin-3-yl)-4-bromobenzene-1,2-diamine (2.00 g, 4.20 mmol), trimethyl orthoformate (1.11 g, 10.50 mmol), and PTSA (0.14 g, 0.84 mmol) were added to the reaction flask in sequence. The temperature was raised to 120°C and the reaction was allowed to react for 2 hours. After the reaction was complete, the temperature was lowered to room temperature, the toluene was removed, and the mixture was stripped once with dichloromethane. The crude product was purified by PE / EA column chromatography to obtain 1.21 g of the product in a 59% yield.

[0700] Step 5: Synthesis of tert-butyl 4-(1-(2,6-bis(benzyloxy)pyridin-3-yl)-1H-benzo[d]imidazol-5-yl)-3,6-dihydropyridine-1(2H)-carboxylate

[0701] At room temperature, 1-(2,6-bis(benzyloxy)pyridin-3-yl)-5-bromo-1H-benzo[d]imidazole (0.60 g, 1.23 mmol), N-Boc-1,2,5,6-tetrahydropyridine-4-boronic acid pinacol ester (0.57 g, 1.85 mmol), Xphos-Pd-G2 (0.10 g, 0.12 mmol), potassium phosphate (0.52 g, 2.47 mmol), water (3 ml), and 1,4-dioxane (10 ml) were added to the reaction flask in sequence. The nitrogen atmosphere was replaced 3-4 times, and the temperature was raised to 80°C for 4 h. After completion of the reaction, the temperature was cooled to room temperature, the solvent was removed, and the mixture was diluted with ethyl acetate. The mixture was filtered through a pad of celite. The filtrate was dried, the solvent was removed, and chromatography on a PE / EA column system was performed to obtain 0.51 g of the product in a yield of 71%.

[0702] Step 6: Synthesis of tert-butyl 4-(1-(2,6-dioxopiperidin-3-yl)-1H-benzo[d]imidazol-5-yl)piperidine-1-carboxylate

[0703] At room temperature, tert-butyl 4-(1-(2,6-bis(benzyloxy)pyridin-3-yl)-1H-benzo[d]imidazol-5-yl)-3,6-dihydropyridine-1(2H)-carboxylate (0.51 g, 0.87 mmol) and tetrahydrofuran (15 ml) were added to a reaction flask. 10% palladium on carbon (0.08 g) was added, and the hydrogen atmosphere was replaced 3-4 times. The reaction was stirred at room temperature for 16 hours. After completion of the reaction, the mixture was filtered through a pad of celite and desolvated to obtain 0.15 g of the product in a 41% yield.

[0704] Step 7: Synthesis of 3-(5-(piperidin-4-yl)-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione

[0705] At room temperature, 3-(5-(piperidin-4-yl)-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (0.15 g, 0.35 mmol), a hydrochloric acid / dioxane solution (3 ml), and dichloromethane (3 ml) were added to the reaction flask in that order. The mixture was stirred at room temperature for 2 hours. After completion of the reaction, the solvent was removed to obtain 0.16 g of crude product, which was directly used in the next step (the theoretical yield of 0.11 g was calculated).

[0706] Step 8: Synthesis of 3-(5-(1-(((1R,2R)-2-((4-(((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)piperidin-4-yl)-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione

[0707] At room temperature, 3-(5-(piperidin-4-yl)-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (0.11 g, 0.35 mmol), (1R,2R)-2-((4-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexane-1-carbaldehyde (0.21 g, 0.35 mmol), and dichloromethane (10 ml) were added to the reaction flask in sequence. TIPT (0.5 ml) was then added, and the mixture was stirred at room temperature for 16 hours. STAB (0.15 g, 0.70 mmol) was then added, and the reaction was stirred at room temperature for 2 hours. After completion of the reaction, dichloromethane was added to dilute the mixture, and celite was added. After stirring until uniform, water was added to quench the reaction. After stirring for 20 minutes, the mixture was filtered. The filter cake was slurried twice with dichloromethane. The organic phases were combined, desolventized, and subjected to column chromatography using a DCM / MeOH system to obtain 0.26 g of the product with a yield of 83%.

[0708] Step 9: Synthesis of 3-(5-(1-(((1R,2R)-2-((4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)piperidin-4-yl)-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione

[0709] At room temperature, 3-(5-(1-(((1R,2R)-2-((4-(((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)piperidin-4-yl)-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (0.26 g, 0.29 mmol), 10% palladium on carbon (0.02 g) and tetrahydrofuran (10 ml) were added to the reaction flask in sequence, and hydrogen was added to replace it 3-4 times. The reaction was stirred at room temperature for 90 hours. After completion of the reaction, the mixture was filtered through celite, the filter cake was washed with tetrahydrofuran and the filtrate was desolvated. The product was purified by column chromatography using a DCM / MeOH system to obtain 0.006 g of the product with a yield of 5%, and 0.003 g was stored.

[0710] 1 H NMR (400MHz, DMSO-d6) δ11.21 (s, 1H), 9.15 (s, 1H), 8.25 (s, 1H), 7.55 (s, 1H), 7.47 (d, J=8.4Hz, 1H), 7.21-7.07 (m, 4H) , 6.82 (d, J=7.7Hz, 2H), 6.67-6.54 (m, 3H), 6.47 (dd, J=8.4, 2.5Hz, 1H), 6.23 (d, J=7.9Hz, 2H), 5.69 (dd, J=12.8, 5.0Hz, 1H), 4.47 (s, 1H), 4.14 (d, J=5.0Hz, 1H), 3.18-3.05 (m, 4H), 3.00-2.85 (m, 6H), 2.82-2.67 (m, 4H), 2.30-2.14 (m, 2H), 2. 12-1.91(m, 4H), 1.77-1.60(m, 6H), 1.39-1.18(m, 10H), 1.08-0.97(m, 2H), 0.90-0.79(m, 2H).MS(ESI)m / z: 805.2[M+H] + .

[0711] Example 22: Synthesis of 3-(5-(4-(((1R,2R)-2-((4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)piperazin-1-yl)-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (Compound V-3)

[0712] The synthesis method of (1R,2R)-2-((4-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexane-1-carbaldehyde is as described in Example 1.

[0713] Step 1: Synthesis of tert-butyl 4-(1-(2,6-bis(benzyloxy)pyridin-3-yl)-1H-benzo[d]imidazol-5-yl)piperazine-1-carboxylate

[0714] At room temperature, 1-(2,6-bis(benzyloxy)pyridin-3-yl)-5-bromo-1H-benzo[d]imidazole (0.42 g, 0.84 mmol), 1-Boc-piperazine (0.63 g, 3.37 mmol), Pd2(dba)3 (0.08 g, 0.08 mmol), sodium tert-butoxide (0.16 g, 1.69 mmol), 10% tri-tert-butylphosphine solution (0.30 g, 0.17 mmol) and toluene (10 ml) were added to the reaction flask in sequence. The nitrogen atmosphere was replaced 3-4 times, and the temperature was raised to 100°C for 16 hours. After completion of the reaction, the temperature was cooled to room temperature, the solvent was removed, ethyl acetate was added to dilute, and the mixture was filtered through a pad of celite. After the filtrate was dried, the solvent was removed, and PE / EA system column chromatography was used to obtain 0.30 g of the product in a yield of 59%.

[0715] Step 2: Synthesis of tert-butyl 4-(1-(2,6-dioxopiperidin-3-yl)-1H-benzo[d]imidazol-5-yl)piperazine-1-carboxylate

[0716] At room temperature, tert-butyl 4-(1-(2,6-bis(benzyloxy)pyridin-3-yl)-1H-benzo[d]imidazol-5-yl)piperazine-1-carboxylate (0.30 g, 0.50 mmol) and tetrahydrofuran (15 ml) were added to the reaction flask in sequence, and 10% palladium on carbon (0.03 g) was added to replace the hydrogen 3-4 times. The reaction was stirred at room temperature for 16 hours. After the reaction was completed, the mixture was filtered through celite and desolvated to obtain 0.08 g of the product in a yield of 35%. Step 3: Synthesis of 3-(5-(piperazin-1-yl)-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione

[0717] To the reaction flask, tert-butyl 4-(1-(2,6-dioxopiperidin-3-yl)-1H-benzo[d]imidazol-5-yl)piperazine-1-carboxylate (0.08 g, 0.18 mmol), a hydrochloric acid / dioxane solution (3 ml), and dichloromethane (3 ml) were added sequentially at room temperature. The mixture was stirred at room temperature for 2 hours. After completion of the reaction, the solvent was removed to obtain 0.09 g of crude product, which was directly used in the next step.

[0718] Step 4: Synthesis of 3-(5-(4-(((1R,2R)-2-((4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)piperazin-1-yl)-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione

[0719] At room temperature, 3-(5-(piperazin-1-yl)-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (0.07 g, 0.23 mmol), (1R,2R)-2-((4-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexane-1-carbaldehyde (0.11 g, 0.19 mmol), and dichloromethane (10 ml) were added to the reaction flask in sequence. TIPT (0.5 ml) was then added, and the mixture was stirred at room temperature for 16 hours. STAB (0.10 g, 0.47 mmol) was then added, and the reaction was stirred at room temperature for 2 hours. After completion of the reaction, dichloromethane was added to dilute the mixture, and celite was added. After stirring until uniform, water was added to quench the reaction. After stirring for 20 minutes, the mixture was filtered. The filter cake was slurried twice with dichloromethane. The organic phases were combined, desolventized, and subjected to column chromatography using a DCM / MeOH system to obtain 0.10 g of the product with a yield of 62%.

[0720] Step 5: 3-(5-(4-(((1R,2R)-2-((4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)piperazin-1-yl)-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione

[0721] At room temperature, 3-(5-(4-(((1R,2R)-2-((4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)piperazin-1-yl)-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (0.10 g, 0.12 mmol), 10% palladium on carbon (0.01 g) and tetrahydrofuran (10 ml) were added to the reaction flask in sequence, and hydrogen was added 3-4 times to replace the mixture. The mixture was stirred at room temperature for 48 hours. After the reaction was completed, the mixture was filtered through celite, the filter cake was washed with tetrahydrofuran and the filtrate was desolvated. The product was purified by column chromatography using a DCM / MeOH system to obtain 0.006 g of the product with a yield of 5%, and 0.002 g was stored.

[0722] 1H NMR (400MHz, DMSO-d6) δ 11.18 (s, 1H), 8.22 (s, 1H), 8.14 (s, 1H), 7.37 (d, J = 9.0Hz, 1H), 7.14 (d, J = 9.1Hz, 4H), 7.00 (d, J=8.9Hz, 1H), 6.83 (d, J=7.3Hz, 2H), 6.69-6.58 (m, 2H), 6.50 (dd, J=19.9, 8.6Hz, 3H), 6.21 (d, J=8.0Hz, 1H), 5.61 (dd, J =13.0, 4.9Hz, 1H), 4.13 (d, J = 4.8Hz, 1H), 3.11-3.02 (m, 5H), 3.02-2.84 (m, 6H), 2.81-2.60 (m, 3H), 2.42-2.31 (m, 4H), 2 .29-2.16(m, 2H), 2.14-2.03(m, 4H), 1.95-1.78(m, 3H), 1.75-1.36(m, 7H), 1.25-0.92(m, 6H).MS(ESI)m / z: 806.4[M+H] + .

[0723] Example 23: Synthesis of 3-(5-(4-(((1R,2R)-2-((4-(4-(1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)piperazin-1-yl)-2-methyl-1H-benzimidazol-1-yl)piperidine-2,6-dione (Compound V-1)

[0724] The synthesis method of (1R,2R)-2-((4-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexane-1-carbaldehyde is as described in Example 1.

[0725] Step 1: Synthesis of 1-(2,6-bis(benzyloxy)pyridin-3-yl)-5-bromo-2-methyl-1H-benzo[d]imidazole

[0726] Acetic acid (10 ml), N1-(2,6-bis(benzyloxy)pyridin-3-yl)-4-bromobenzene-1,2-diamine (0.84 g, 1.77 mmol), and triethyl orthoformate (0.32 g, 2.65 mmol) were added to the reaction flask in sequence, and the temperature was raised to 120°C for 3 hours. After the reaction was completed, the temperature was lowered to room temperature, and the solvent was removed until no obvious droplets were present. Sand was prepared and chromatographed using a PE / EA system column to obtain 0.92 g of the product (a small amount of acetic acid remained, which did not affect the next step).

[0727] Step 2: Synthesis of tert-butyl 4-(1-(2,6-bis(benzyloxy)pyridin-3-yl)-2-methyl-1H-benzo[d]imidazol-5-yl)piperazine-1-carboxylate

[0728] At room temperature, 1-(2,6-bis(benzyloxy)pyridin-3-yl)-5-bromo-2-methyl-1H-benzo[d]imidazole (0.92 g, 1.84 mmol), 1-Boc-piperazine (1.37 g, 7.36 mmol), Pd2(dba)3 (0.17 g, 0.18 mmol), sodium tert-butoxide (0.35 g, 3.68 mmol), 10% tri-tert-butylphosphine solution (0.74 g, 0.37 mmol) and toluene (10 ml) were added to the reaction flask in sequence. The nitrogen atmosphere was replaced 3-4 times and the temperature was raised to 100° C. for 16 h. After completion of the reaction, the temperature was cooled to room temperature, the solvent was removed, ethyl acetate was added to dilute, and the mixture was filtered through a pad of celite. After the filtrate was dried, the solvent was removed, and PE / EA system column chromatography was used to obtain 0.46 g of the product with a yield of 42%. Step 3: Synthesis of tert-butyl 4-(1-(2,6-dioxopiperidin-3-yl)-2-methyl-1H-benzo[d]imidazol-5-yl)piperazine-1-carboxylate

[0729] At room temperature, tert-butyl 4-(1-(2,6-bis(benzyloxy)pyridin-3-yl)-2-methyl-1H-benzo[d]imidazol-5-yl)piperazine-1-carboxylate (0.46 g, 0.76 mmol) and tetrahydrofuran (15 ml) were added to a reaction flask. 10% palladium on carbon (0.03 g) was added, and the hydrogen atmosphere was replaced 3-4 times. The reaction was stirred at room temperature for 16 hours. After completion, the reaction was filtered through a pad of celite and desolventized to obtain 0.18 g of the product in a 57% yield.

[0730] Step 4: Synthesis of 3-(2-methyl-5-(piperazin-1-yl)-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione

[0731] At room temperature, tert-butyl 4-(1-(2,6-dioxopiperidin-3-yl)-2-methyl-1H-benzo[d]imidazol-5-yl)piperazine-1-carboxylate (0.18 g, 0.41 mmol), a hydrochloric acid / dioxane solution (3 ml), and dichloromethane (3 ml) were added to the reaction flask in that order. The mixture was stirred at room temperature for 2 hours. After completion of the reaction, the solvent was removed to obtain the crude product, which was directly used in the next step. The theoretical yield was 0.13 g. Step 5: Synthesis of 3-(5-(4-(((1R,2R)-2-((4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)piperazin-1-yl)-2-methyl-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione

[0732] At room temperature, 3-(2-methyl-5-(piperazin-1-yl)-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (0.13 g, 0.23 mmol), (1R,2R)-2-((4-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexane-1-carbaldehyde (0.20 g, 0.33 mmol), and dichloromethane (10 ml) were added to the reaction flask in sequence. TIPT (0.5 ml) was then added, and the mixture was stirred at room temperature for 16 hours. STAB (0.13 g, 0.61 mmol) was then added, and the reaction was stirred at room temperature for 2 hours. After completion of the reaction, dichloromethane was added to dilute the mixture, and celite was added. After stirring until uniform, water was added to quench the reaction. After stirring for 20 minutes, the mixture was filtered. The filter cake was slurried twice with dichloromethane. The organic phases were combined, desolventized, and subjected to column chromatography using a DCM / MeOH system to obtain 0.04 g of the product. The two-step yield was 15%.

[0733] Step 6: Synthesis of 3-(5-(4-(((1R,2R)-2-((4-(4-(1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)piperazin-1-yl)-2-methyl-1H-benzimidazol-1-yl)piperidine-2,6-dione

[0734] At room temperature, 3-(5-(4-(((1R,2R)-2-((4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)piperazin-1-yl)-2-methyl-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (0.04 g, 0.04 mmol), 10% palladium on carbon (0.01 g), and tetrahydrofuran (10 ml) were added to the reaction flask in sequence. Hydrogen was then added for replacement 3-4 times, and the reaction was stirred at room temperature for 6 h. After completion of the reaction, the mixture was filtered through celite, the filter cake was washed with tetrahydrofuran, and the filtrate was desolvated. Column chromatography using a DCM / MeOH system gave 0.002 g of the product in a yield of 6%. MS (ESI) m / z: 821.09 [M+H] + .

[0735] Example 24: Synthesis of 3-(5-fluoro-6-(1-(((1S,2S)-2-((4-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione (Compound IV-10)

[0736] The synthesis method of (1S,2S)-2-((4-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexane-1-carbaldehyde is as described in Example 1.

[0737] Step 1: Synthesis of 3-(2,6-bis(benzyloxy)pyridin-3-yl)-6-bromo-5-fluoro-1-methyl-1H-indazole

[0738] At room temperature, 6-bromo-5-fluoro-3-iodo-1-methyl-1H-indazole (1.00 g, 2.97 mmol), 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxolan-2-yl)pyridine (1.24 g, 2.97 mmol), sodium carbonate (0.94 g, 8.90 mmol), tetrakistriphenylphosphine palladium (0.34 g, 0.30 mmol), water (1 mL), and dioxane (10 ml) were added to the reaction flask in sequence. The mixture was reacted at 90° C. under a nitrogen atmosphere for 5 h. After completion of the reaction, the mixture was cooled to room temperature, ethyl acetate and water were added, the layers were separated, and the organic phase was dried and purified by PE / EA column chromatography to obtain 1.20 g of the product in an 81% yield.

[0739] Step 2: Synthesis of tert-butyl 4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)-5-fluoro-1-methyl-1H-indazol-6-yl)-3,6-dihydropyridine-1(2H)-carboxylate

[0740] At room temperature, a reaction flask was added with 3-(2,6-bis(benzyloxy)pyridin-3-yl)-6-bromo-5-fluoro-1-methyl-1H-indazole (0.60 g, 1.16 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (0.40 g, 1.27 mmol), dppfPdCl2 (0.09 g, 0.12 mmol), potassium carbonate (0.48 g, 3.47 mmol), water (1 mL), and dioxane (10 mL). The reaction was allowed to proceed at 90°C under a nitrogen atmosphere for 5 h. After completion of the reaction, the mixture was cooled to room temperature, ethyl acetate and water were added, and the layers were separated. The organic phase was dried and then purified by PE / EA column chromatography to obtain 0.47 g of the product in a 66% yield.

[0741] Step 3: Synthesis of tert-butyl 4-(3-(2,6-dioxopiperidin-3-yl)-5-fluoro-1-methyl-1H-indol-6-yl)piperidine-1-carboxylate

[0742] To a reaction flask at room temperature was added tert-butyl 4-(3-(2,6-bis(benzyloxy)pyridin-3-yl)-5-fluoro-1-methyl-1H-indazol-6-yl)-3,6-dihydropyridine-1(2H)-carboxylate (0.40 g, 0.66 mmol), 10% Pd / C (0.04 g), tetrahydrofuran (5 mL), and ethanol (5 mL). The mixture was reacted at room temperature for 24 h. After completion of the reaction, the mixture was filtered and dried to give 0.26 g of a crude product, which was used directly in the next step.

[0743] Step 4: Synthesis of 3-(5-fluoro-1-methyl-6-(piperidin-4-yl)-1H-indol-3-yl)piperidine-2,6-dione

[0744] To the reaction flask, tert-butyl 4-(3-(2,6-dioxopiperidin-3-yl)-5-fluoro-1-methyl-1H-indol-6-yl)piperidine-1-carboxylate (0.26 g, 0.60 mmol) and a solution of HCl in dioxane (5 ml) were added sequentially at room temperature for 2 h. After completion of the reaction, the mixture was spin-dried to give 0.22 g of crude product, which was used directly in the next step.

[0745] Step 5: Synthesis of 3-(6-(1-(((1S,2S)-2-((4-(4-(((2R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)piperidin-4-yl)-5-fluoro-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione

[0746] At room temperature, 3-(5-fluoro-1-methyl-6-(piperidin-4-yl)-1H-indol-3-yl)piperidine-2,6-dione (0.15 g, 0.47 mmol), (1S,2S)-2-((4-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexane-1-carbaldehyde (0.28 g, 0.47 mmol), and dichloromethane (5 mL) were added to the reaction flask in sequence. TIPT (0.5 mL) was then added, and the mixture was stirred at room temperature for 16 hours. STAB (0.15 g, 0.71 mmol) was then added, and the reaction was stirred at room temperature for 2 hours. After completion of the reaction, dichloromethane was added to dilute the mixture, and celite was added. After stirring for a long time, water was added to quench the reaction. After stirring for 20 minutes, the mixture was filtered. The filter cake was slurried twice with dichloromethane. The organic phases were combined, desolventized, and subjected to column chromatography using a DCM / MeOH system to obtain 0.21 g of the product. The three-step yield was 62%.

[0747] Step 6: Synthesis of 3-(5-fluoro-6-(1-(((1S,2S)-2-((4-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione

[0748] At room temperature, 3-(6-(1-(((1S,2S)-2-((4-(4-(((2R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)piperidin-4-yl)-5-fluoro-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione (0.21 g, 0.23 mmol), 10% palladium on carbon (0.10 g) and THF (3 mL) were added to the reaction flask in sequence, the hydrogen was replaced 3-4 times, and the reaction was stirred at room temperature for 24 h. After completion of the reaction, the mixture was filtered through celite, the filter cake was rinsed with THF, the filtrate was desolvated, and column chromatography using a DCM / MeOH system was used to obtain 0.11 g of the product in a yield of 58%.

[0749] 1H NMR (400MHz, DMSO-d6) δ10.91 (s, 1H), 9.16 (s, 1H), 7.59-7.40 (m, 2H), 7.16-7.05 (m, 3H), 6.78 (s, 2H), 6.65-6.54 (m, 4H), 6.47 (dd, J=8.2, 2.6Hz, 1H), 6.22 (d, J=8.1Hz, 2H), 4.32 (dd, J=10.1 , 5.0Hz, 1H), 4.14 (d, J=5.0Hz, 1H), 3.95 (s, 3H), 3.64-3.60 (m, 1H), 3.20-2.88 (m, 12H), 2.72-2 .59(m, 4H), 2.43-2.19(m, 3H), 2.17-1.44(m, 17H), 1.06-0.83(m, 3H).MS(ESI)m / z: 837.7[M+H] + .

[0750] Example 25: Synthesis of 1-(5-fluoro-6-(8-(((1R,2R)-2-((4-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenylpiperazin-1-yl)methyl)cyclohexyl)methyl)-8-azabicyclo[3.2.1]octan-3-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (Compound VI-17)

[0751] The synthesis method of (1R,2R)-2-((4-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexane-1-carbaldehyde is as described in Example 1.

[0752] Step 1: Synthesis of tert-butyl 3-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-5-fluoro-1-methyl-1H-indazol-6-yl)-8-azabicyclo-4-oct-2-ene-8-carboxylate

[0753] At room temperature, 1-(6-bromo-5-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (0.10 g, 0.29 mmol), 8-tert-butoxycarbonyl-8-azabicyclo[3.2.1]oct-2-ene-3-boronic acid pinacol ester (0.11 g, 0.32 mmol), Pd(dppf)Cl2 (0.02 g, 0.03 mmol), Cs2CO3 (0.29 g, 0.88 mmol), Do (5 ml), and H2O (1 ml) were added to the reaction flask in sequence. The nitrogen atmosphere was replaced 3-4 times, and the temperature was raised to 80°C for 2 h. After completion of the reaction, the temperature was cooled to room temperature, filtered, and the filtrate was concentrated and purified by column chromatography using a DCM / MeOH system. The mixture was then slurried with EA to give 0.10 g of a white solid in a yield of 72.9%.

[0754] Step 2: Synthesis of 1-(6-(8-azabicyclo[3.2.1]oct-2-en-3-yl)-5-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

[0755] At room temperature, tert-butyl 3-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-5-fluoro-1-methyl-1H-indol-6-yl)-8-azabicyclo-4-oct-2-ene-8-carboxylate (0.10 mg, 0.21 mmol) and dichloromethane (2 ml) were added to the reaction flask. After dissolving, hydrochloric acid / dioxane (5 ml) was added and the mixture was stirred at room temperature for 2 h. After completion of the reaction, the solvent was removed to obtain 0.10 g of a crude white solid, which was directly used in the next step.

[0756] Step 3: Synthesis of 1-(6-(8-(((1R,2R)-2-((4-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenylpiperazin-1-yl)methyl)cyclohexyl)methyl)-8-azabicyclo[3.2.1]oct-2-en-3-yl)-5-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

[0757] At room temperature, 1-(6-(8-azabicyclo[3.2.1]oct-2-en-3-yl)-5-fluoro-1-methyl-1H-indol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (0.10 g, 0.27 mmol), (1R,2R)-2-((4-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexane-1-carbaldehyde (0.11 g, 0.19 mmol) and dichloromethane (5 ml) were added to the reaction flask in sequence, and TIPT (0.30 mL) was added. The mixture was stirred at room temperature for 8 hours. STAB (0.086 g, 0.41 mmol) was then added and the reaction was stirred at room temperature for 2 hours. After the reaction was complete, dichloromethane was added for dilution, diatomaceous earth was added, and the mixture was stirred until uniform. Water was then added to quench the reaction. After stirring for 20 minutes, the mixture was filtered and the filter cake was slurried twice with dichloromethane. The organic phases were combined, desolventized, and purified by column chromatography using a DCM / MeOH system to obtain 0.15 g of the product, with a three-step yield of 53.9%.

[0758] Step 4: Synthesis of 1-(5-fluoro-6-(8-(((1R,2R)-2-((4-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenylpiperazin-1-yl)methyl)cyclohexyl)methyl)-8-azabicyclo[3.2.1]octan-3-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

[0759] At room temperature, 1-(6-(8-(((1R,2R)-2-((4-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenylpiperazin-1-yl)methyl)cyclohexyl)methyl)-8-azabicyclo[3.2.1]oct-2-en-3-yl)-5-fluoro-1-methyl-1H-indol-3-yl)dihydropyrimidine Pyridine-2,4(1H,3H)-dione (0.15 g, 0.16 mmol), 10% palladium on carbon (0.05 g) and THF (3 ml) were replaced with hydrogen 3-4 times and stirred at room temperature for 8 h. After completion of the reaction, the mixture was filtered through a pad of celite, the filter cake was rinsed with THF, and the filtrate was desolvated and purified by column chromatography using a DCM / MeOH system to obtain 0.015 g of the product, 0.010 g of which was stored, for a yield of 11.0%.

[0760] 1H NMR (400MHz, DMSO-d6) δ10.58 (d, J=2.5Hz, 1H), 9.15 (s, 1H), 7.72 (s, 1H), 7.41 (d, J=10.7Hz, 1H), 7.13 (dd, J=7.4, 4.6 Hz, 3H), 6.83 (d, J=4.2Hz, 2H), 6.62-6.60 (m, 2H), 6.54 (d, J=7.4Hz, 2H), 6.49 (d, J=2.9Hz, 1H), 6.21 (d, J=8.2Hz, 2H), 4 .13 (d, J=4.9Hz, 1H), 4.01 (s, 3H), 3.95 (s, 2H), 3.90 (t, J=6.7Hz, 4H), 3.51 (s, 1H), 3.27 (s, 2H), 2.98 (d, J=20.0Hz, 9H) , 2.75 (d, J=2.1Hz, 2H), 2.15-1.92 (m, 8H), 1.72-1.51 (m, 8H), 1.24 (s, 4H), 1.13-1.01 (m, 2H).MS (ESI) m / z: 864.7[M+H] + .

[0761] Example 26: Synthesis of 1-(5-fluoro-6-(4-((1R,2R)-2-((4-(4-(1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)-4-azaspiro[2.5]octan-7-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (Compound VI-18)

[0762] The synthesis method of (1R,2R)-2-((4-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexane-1-carbaldehyde is as described in Example 1.

[0763] Step 1: Synthesis of tert-butyl 7-(((trifluoromethyl)sulfonyl)oxy)-4-azaspiro[2.5]oct-6-ene-4-carboxylate

[0764] At room temperature, tert-butyl 7-oxo-4-azaspiro[2.5]octane-4-carboxylate (1 g, 4.44 mmol) and N-phenylbis(trifluoromethanesulfonyl)imide (2.38 g, 6.66 mmol) were dissolved in THF (20 mL), cooled to -78°C, and LiHMDS (7 mL, 7.00 mmol) was added. After addition, the mixture was allowed to react at room temperature for 8 h. After completion of the reaction, water (3 mL) was added to the reaction solution, which was then directly concentrated by column chromatography (EA / PE) to afford 1.2 g of a yellow solid (75% yield).

[0765] Step 2: Synthesis of tert-butyl 7-(3-(2,4-dioxytetrahydropyrimidin-1(2H)-yl)-5-fluoro-1-methyl-1H-indazol-6-yl)-4-azaspiro[2.5]oct-6-ene-4-carboxylate

[0766] At room temperature, tert-butyl 7-(((trifluoromethyl)sulfonyl)oxy)-4-azaspiro[2.5]oct-6-ene-4-carboxylate (0.18 g, 0.77 mmol), 1-(5-fluoro-1-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (0.20 g, 0.52 mmol), Pd(dppf)Cl2 (0.04 g, 0.05 mmol), Na2CO3 (0.11 g, 1.03 mmol), Do (10 ml) and H2O (2 ml) were added to the reaction bottle in sequence. The nitrogen was replaced 3-4 times, and the temperature was raised to 80°C for 2 h. After the reaction was completed, the temperature was lowered to room temperature, filtered, and the filtrate was concentrated. The product was purified by column chromatography using a DCM / MeOH system to obtain 0.20 g of a brown solid with a yield of 81.3%.

[0767] Step 3: Synthesis of 1-(5-fluoro-1-methyl-6-(4-azaspiro[2.5]oct-6-en-7-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

[0768] At room temperature, tert-butyl 4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-5-fluoro-1-methyl-1H-indol-6-yl)-3,3-difluoro-3,6-dihydropyridine-1(2H)-carboxylate (0.20 mg, 0.42 mmol) and dichloromethane (2 ml) were added to the reaction flask. After the solution was dissolved, hydrochloric acid / dioxane (3 ml) was added and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, the solvent was removed to obtain 0.20 g of a crude white solid, which was directly used in the next step.

[0769] Step 4: Synthesis of 1-(6-(4-(((1R,2R)-2-((4-(4-(2R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)-4-azaspiro[2.5]oct-6-en-7-yl)-5-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

[0770] At room temperature, 1-(5-fluoro-1-methyl-6-(4-azaspiro[2.5]oct-6-en-7-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (0.10 g, 0.26 mmol), (1R,2R)-2-((4-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexane-1-carbaldehyde (0.11 g, 0.18 mmol) and dichloromethane (5 ml) were added to the reaction flask in sequence, and TIPT (0.30 mL) was added. The mixture was stirred at room temperature for 8 hours. STAB (0.084 g, 0.40 mmol) was then added and the reaction was stirred at room temperature for 2 hours. After the reaction was complete, dichloromethane was added for dilution, diatomaceous earth was added, and the mixture was stirred until uniform. Water was then added to quench the reaction. After stirring for 20 minutes, the mixture was filtered and the filter cake was slurried twice with dichloromethane. The organic phases were combined, desolventized, and purified by column chromatography using a DCM / MeOH system to obtain 0.06 g of the product, with a two-step yield of 30%.

[0771] Step 5: Synthesis of 1-(5-fluoro-6-(4-((1R,2R)-2-((4-(4-(1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)-4-azaspiro[2.5]octan-7-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

[0772] At room temperature, 1-(6-(4-(((1R,2R)-2-((4-(4-(2R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)-4-azaspiro[2.5]oct-6-en-7-yl)-5-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (0.060 g, 0.06 mmol), 10% palladium on carbon (0.05 g) and THF (5 ml) were added to the reaction flask in sequence, the hydrogen was replaced 3-4 times, and the reaction was stirred at room temperature for 8 h. After the reaction was completed, the mixture was filtered through a pad of celite, the filter cake was rinsed with THF, the filtrate was desolvated, and column chromatography using a DCM / MeOH system was performed to obtain 0.012 g of the product with a yield of 22.0%.

[0773] 1 H NMR (400MHz, DMSO-d6) δ10.59 (s, 1H), 9.18 (s, 1H), 7.41 (d, J=11.1Hz, 1H), 7.11 (q, J=6.6, 6 .0Hz, 3H), 6.83 (d, J=7.0Hz, 2H), 6.69-6.54 (m, 4H), 6.53-6.41 (m, 2H), 6.21 (t, J=9.8Hz, 2H ), 4.16-4.12(m, 1H), 4.01-3.93(m, 3H), 3.93-3.78(m, 4H), 3.06-2.88(m, 7H), 2.75(t, J=6. 8Hz, 5H), 2.20-1.86(m, 10H), 1.75-1.57(m, 7H), 1.08-0.87(m, 6H).MS(ESI)m / z: 866.4[M+H] + .

[0774] Example 27: Synthesis of 1-(6-(3,3-difluoro-1-(((1R,2R)-2-((4-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenylpiperazin-1-yl)methyl)cyclohexyl)methyl)piperidin-4-yl)-5-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (Compound IV-12)

[0775] The synthesis method of (1R,2R)-2-((4-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexane-1-carbaldehyde is as described in Example 1.

[0776] Step 1: Synthesis of tert-butyl 3,3-difluoro-4-(((trifluoromethyl)sulfonyloxy)-3,6-dihydropyridine-1(2H)-carboxylate

[0777] At room temperature, tert-butyl 3,3-difluoro-4-oxopiperidine-1-carboxylate (5 g, 21.26 mmol) was dissolved in DCM (50 mL), cooled to -15°C, and TEA (6.45 g, 63.77 mmol) was added. Trifluoromethanesulfonic anhydride (9.00 g, 31.88 mmol) was slowly added dropwise. After addition, the mixture was allowed to react at room temperature for 8 h. After completion of the reaction, saturated aqueous sodium bicarbonate (30 mL) was added to the reaction solution, extracted with DCM, and the organic phase was concentrated and column chromatography (EA / PE) was performed to obtain 3.2 g of a yellow solid, with a yield of 41.0%.

[0778] Step 2: Synthesis of tert-butyl 4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-5-fluoro-1-methyl-1H-indazol-6-yl)-3,3-difluoro-3,6-dihydropyridine-1(2H)-carboxylate

[0779] At room temperature, tert-butyl 3,3-difluoro-4-(((trifluoromethyl)sulfonyloxy)-3,6-dihydropyridine-1(2H)-carboxylate (0.18 g, 0.77 mmol), 1-(5-fluoro-1-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (0.20 g) were added to the reaction flask in sequence. , 0.52 mmol), Pd(dppf)Cl2 (0.04 g, 0.05 mmol), Na2CO3 (0.11 g, 1.03 mmol), Do (10 ml), and H2O (2 ml) were added. The nitrogen atmosphere was replaced 3-4 times, and the temperature was raised to 80°C for 2 h. After completion of the reaction, the temperature was cooled to room temperature, filtered, and the filtrate was concentrated and purified by column chromatography using a DCM / MeOH system to obtain 0.20 g of a brown solid with a yield of 81.3%.

[0780] Step 3: Synthesis of 1-(6-(3,3-difluoro-1,2,3,6-tetrahydropyridin-4-yl)-5-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

[0781] At room temperature, tert-butyl 4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-5-fluoro-1-methyl-1H-indol-6-yl)-3,3-difluoro-3,6-dihydropyridine-1(2H)-carboxylate (0.20 mg, 0.42 mmol) and dichloromethane (2 ml) were added to the reaction flask. After the solution was dissolved, hydrochloric acid / dioxane (3 ml) was added and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, the solvent was removed to obtain 0.20 g of a crude white solid, which was directly used in the next step.

[0782] Step 4: Synthesis of 1-(6-(1-(((1R,2R)-2-((4-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenylpiperazin-1-yl)methyl)cyclohexyl)methyl)-3,3-difluoro-1,2,3,6-tetrahydropyridin-4-yl)-5-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

[0783] At room temperature, 1-(6-(3,3-difluoro-1,2,3,6-tetrahydropyridin-4-yl)-5-fluoro-1-methyl-1H-indol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (0.10 g, 0.26 mmol), (1R,2R)-2-((4-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexane-1-carbaldehyde (0.11 g, 0.18 mmol) and dichloromethane (5 ml) were added to the reaction bottle in sequence, and TIPT (0.30 mL) was added. The mixture was stirred at room temperature for 8 hours. STAB (0.084 g, 0.40 mmol) was then added and the reaction was stirred at room temperature for 2 hours. After the reaction was complete, dichloromethane was added for dilution, diatomaceous earth was added, and the mixture was stirred until uniform. Water was then added to quench the reaction. After stirring for 20 minutes, the mixture was filtered and the filter cake was slurried twice with dichloromethane. The organic phases were combined, desolventized, and purified by column chromatography using a DCM / MeOH system to obtain 0.060 g of the product, with a two-step yield of 29.9%.

[0784] Step 5: Synthesis of 1-(6-(3,3-difluoro-1-(((1R,2R)-2-((4-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenylpiperazin-1-yl)methyl)cyclohexyl)methyl)piperidin-4-yl)-5-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

[0785] At room temperature, 1-(6-(1-(((1R,2R)-2-((4-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenylpiperazin-1-yl)methyl)cyclohexyl)methyl)-3,3-difluoro-1,2,3,6-tetrahydropyridin-4-yl)-5-fluoro-1-methyl-1H-indol-3-yl)dihydropyrimidine Pyridine-2,4(1H,3H)-dione (0.060 g, 0.06 mmol), 10% palladium on carbon (0.05 g) and THF (5 ml) were replaced with hydrogen 3-4 times and stirred at room temperature for 8 h. After completion of the reaction, the mixture was filtered through a pad of celite, the filter cake was rinsed with THF, and the filtrate was desolvated and purified by column chromatography using a DCM / MeOH system to obtain 0.012 g of the product, 0.007 g of which was stored, for a yield of 22.0%.

[0786] 1 H NMR (400MHz, DMSO-d6) δ10.59 (s, 1H), 9.13 (d, J=1.6Hz, 1H), 7.74 (d, J=5.5Hz, 1H), 7.43-7.41 (m, 1H), 7.13 (dt, J=8. 8, 4.2Hz, 3H), 6.85-6.81 (m, 2H), 6.65-6.59 (m, 2H), 6.55-6.46 (m, 3H), 6.21 (dd, J=8.6, 3.7Hz, 2H), 4.13 (t, J=4.5Hz, 1H), 4.02 (d, J=3.6Hz, 3H), 3.92 (t, J=6.7Hz, 3H), 3.17 (s, 1H), 3.06-2.91 (m, 8H), 2.76 (t, J=6.7Hz, 4H), 2.36 (d, J=1 0.4Hz, 4H), 2.11 (d, J=6.5Hz, 2H), 1.84 (s, 2H), 1.71-1.38 (m, 8H), 1.24 (s, 4H), 0.99 (s, 2H). MS (ESI) m / z: 874.8[M+H] + .

[0787] Example 28: Synthesis of 1-(5-fluoro-6-(1′-((1R,2R)-2-((4-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)-[1,4′-dipiperidinyl]-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (Compound VI-19)

[0788] The synthesis method of (1R,2R)-2-((4-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexane-1-carbaldehyde is as described in Example 1.

[0789] Step 1: Synthesis of tert-butyl 4-(3-(2,4-dioxytetrahydropyrimidin-1(2H)-yl)-5-fluoro-1-methyl-1H-indazol-6-yl)-[1,4′-dipiperidine]-1′-carboxylate

[0790] At room temperature, 1-(5-fluoro-1-methyl-6-(piperidin-4-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 6-bromo-3-iodo-1-methyl-1H-indazole (0.50 g, 1.45 mmol), N-tert-butyloxycarbonyl-4-piperidone (0.58 g, 2.90 mmol), and dichloromethane (10 mL) were added to a reaction flask. TIPT (0.5 mL) was then added and stirred at room temperature for 16 hours. STAB (0.61 g, 2.90 mmol) was then added and the reaction was stirred at room temperature for 2 hours. After completion of the reaction, dichloromethane was added to dilute the mixture, celite was added, stirred until uniform, and water was added to quench the reaction. After stirring for 20 minutes, the mixture was filtered. The filter cake was slurried twice with dichloromethane. The organic phases were combined, desolventized, and subjected to column chromatography using a DCM / MeOH system to obtain 0.50 g of the product with a yield of 65%.

[0791] Step 2: Synthesis of 1-(6-([1,4′-dipiperidinyl]-4-yl)-5-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

[0792] At room temperature, tert-butyl 4-(3-(2,4-dioxytetrahydropyrimidin-1(2H)-yl)-5-fluoro-1-methyl-1H-indazol-6-yl)-[1,4′-dipiperidine]-1′-carboxylate (0.50 g, 0.95 mmol) and HCl in dioxane (10 ml) were added to the reaction flask in sequence. The mixture was reacted for 2 h. After completion of the reaction, the mixture was spin-dried to give 0.40 g of crude product, which was used directly in the next step.

[0793] Step 3: Synthesis of 1-(6-(1′-(((1R,2R)-2-((4-(4-(((3R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)-[1,4′-bipiperidinyl]-4-yl)-5-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

[0794] At room temperature, 1-(6-([1,4′-dipiperidinyl]-4-yl)-5-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (0.08 g, 0.18 mmol), (1S,2S)-2-((4-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexane-1-carbaldehyde (0.11 g, 0.18 mmol), and dichloromethane (10 ml) were added to the reaction flask in sequence. TIPT (0.5 ml) was then added, and the mixture was stirred at room temperature for 16 hours. STAB (0.08 g, 0.36 mmol) was then added, and the reaction was stirred at room temperature for 2 hours. After completion of the reaction, dichloromethane was added to dilute the mixture, and celite was added. After stirring for a long time, water was added to quench the reaction. After stirring for 20 minutes, the mixture was filtered. The filter cake was slurried twice with dichloromethane. The organic phases were combined, desolventized, and subjected to column chromatography using a DCM / MeOH system to obtain 0.08 g of the product with a yield of 72%.

[0795] Step 4: 1-(5-Fluoro-6-(1′-((1R,2R)-2-((4-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)-[1,4′-dipiperidinyl]-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

[0796] At room temperature, 1-(6-(1′-(((1R,2R)-2-((4-(4-(((3R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)-[1,4′-bipiperidinyl]-4-yl)-5-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidine Pyridine-2,4(1H,3H)-dione (0.08 g, 0.08 mmol), 10% palladium on carbon (0.01 g), and tetrahydrofuran (5 ml) were added, and hydrogen was replaced 3-4 times. The reaction was stirred at 30°C for 16 h. After completion of the reaction, the mixture was filtered through celite, and the filter cake was washed with tetrahydrofuran and the filtrate was desolvated. Column chromatography using a DCM / MeOH system gave 0.06 g of the product in an 82% yield.

[0797] 1H NMR (400MHz, DMSO-d6) δ10.58 (s, 1H), 9.17 (s, 1H), 7.40 (d, J=10.8Hz, 1H), 7.13 (q , J=6.0, 5.6Hz, 4H), 6.83 (d, J=7.1Hz, 2H), 6.64-6.56 (m, 5H), 6.50-6.47 (m, 1H), 6 .23 (d, J=8.1Hz, 2H), 4.14 (d, J=4.8Hz, 1H), 4.00 (s, 3H), 3.91 (t, J=6.7Hz, 2H), 3. 14-2.67(m, 24H), 2.05-1.58(m, 19H), 1.18-0.94(m, 4H).MS(ESI)m / z: 921.8[M+H] + .

[0798] Example 29: Synthesis of 1-(5-fluoro-6-((2R)-1-(((1R,2R)-2-((4-(4-(((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)-2-methylpiperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (Compound VI-20)

[0799] The synthesis method of (1R,2R)-2-((4-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexane-1-carbaldehyde is as described in Example 1.

[0800] Step 1: Synthesis of tert-butyl (R)-2-methyl-4-(((trifluoromethyl)sulfonyl)oxy)-3,6-dihydropyridine-1(2H)-carboxylate.

[0801] To a single-necked flask, (R)-tert-butyl 2-methyl-4-oxopiperidine-1-carboxylate (2.00 g, 9.38 mmol), PhNTf2 (3.68 g, 10.92 mmol), THF (20 mL), and LiHMDS (10.50 g, 10.32 mmol) were added sequentially at -78°C. The reaction was allowed to warm to room temperature under a nitrogen atmosphere and allowed to react for 16 h. The mixture was diluted with saturated aqueous ammonium chloride and extracted with EA. The organic phase was dried over anhydrous Na2SO4, filtered, concentrated, and purified by column chromatography (EA / PE system) to afford 3.00 g of a yellow oil.

[0802] Step 2: Synthesis of (R)-tert-butyl 4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-5-fluoro-1-methyl-1H-indazol-6-yl)-2-methyl-3,6-dihydropyridine-1(2H)-carboxylate.

[0803] To a single-necked flask at room temperature were added tert-butyl (R)-2-methyl-4-(((trifluoromethyl)sulfonyl)oxy)-3,6-dihydropyridine-1(2H)-carboxylate (0.21 g, 0.62 mmol), 1-(5-fluoro-1-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (0.20 g, 0.51 mmol), sodium carbonate (0.11 g, 1.02 mmol), Pd(dppf)Cl2 (0.04 g, 0.05 mmol), 1.4-dioxane (20 mL), and H2O (1 mL). The reaction was terminated by heating to 85°C under nitrogen protection for 8 h. The mixture was cooled to room temperature, diluted with water, extracted with EA, and the organic phase was dried over anhydrous Na2SO4, filtered, concentrated, and purified by column chromatography (EA / PE system) to obtain 0.20 g of a yellow solid.

[0804] Step 3: Synthesis of (R)-1-(5-fluoro-1-methyl-6-(2-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione.

[0805] To a single-necked flask at room temperature was added tert-butyl (R)-4-(3-(2,4-dioxytetrahydropyrimidin-1(2H)-yl)-5-fluoro-1-methyl-1H-indazol-6-yl)-2-methyl-3,6-dihydropyridine-1(2H)-carboxylate (0.20 g, 0.44 mmol), DCM (10 mL), and a dioxane hydrochloride solution (10 mL). The reaction was terminated at room temperature for 3 h. The solution was concentrated to afford 0.20 g of a crude yellow solid.

[0806] Step 4: Synthesis of 1-(6-((R)-1-(((1R,2R)-2-((4-(4-(((3R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)-2-methyl-1,2,3,6-tetrahydropyridin-4-yl)-5-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione.

[0807] At room temperature, to a single-necked flask were added (R)-1-(5-fluoro-1-methyl-6-(2-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (0.16 g, 0.44 mmol), (1R,2R)-2-((4-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexane-1-carbaldehyde (0.16 g, 0.44 mmol), and DCM (20 mL), and the mixture was reacted at room temperature for 16 h. Sodium triacetoxyborohydride (0.18 g, 0.87 mmol) was added and the reaction was continued for 1 h. Water (1 mL) was added, stirred for 5 min, and filtered through a pad of celite. The filtrate was concentrated and subjected to column chromatography (MeOH / DCM system) to obtain 0.14 g of a yellow solid.

[0808] Step 5: Synthesis of 1-(5-fluoro-6-((2R)-1-(((1R,2R)-2-((4-(4-(((3R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)-2-methylpiperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione.

[0809] At room temperature, 1-(6-((R)-1-(((1R,2R)-2-((4-(4-(((3R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)-2-methyl-1,2,3,6-tetrahydropyridin-4-yl)-5-fluoro-1-methyl-1H-indole A mixture of oxazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (0.14 g, 0.15 mmol), Pd / C (0.20 g, 10%), and MeOH (20 mL) was reacted at room temperature under a hydrogen balloon for 16 h. The mixture was then filtered through a pad of Celite. The filtrate was concentrated and subjected to column chromatography (MeOH / DCM) to afford 0.50 g of a white solid. MS (ESI) m / z: 852.9 [M+H] + .

[0810] Example 30: Synthesis of 1-(5-fluoro-6-((2S)-1-(((1R,2R)-2-((4-(4-(((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)-2-methylpiperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (Compound VI-21)

[0811] The synthesis method of (1R,2R)-2-((4-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexane-1-carbaldehyde is as described in Example 1.

[0812] Step 1: Synthesis of (S)-tert-butyl 2-methyl-4-(((trifluoromethyl)sulfonyl)oxy)-3,6-dihydropyridine-1(2H)-carboxylate.

[0813] To a single-necked flask, (S)-tert-butyl 2-methyl-4-oxopiperidine-1-carboxylate (2.00 g, 9.38 mmol), PhNTf2 (3.68 g, 10.92 mmol), THF (20 mL), and LiHMDS (10.50 g, 10.32 mmol) were added sequentially at -78°C. The reaction was allowed to warm to room temperature under a nitrogen atmosphere and allowed to react for 16 h. The mixture was diluted with saturated aqueous ammonium chloride and extracted with EA. The organic phase was dried over anhydrous Na2SO4, filtered, concentrated, and purified by column chromatography (EA / PE system) to afford 3.00 g of a yellow oil.

[0814] Step 2: Synthesis of (S)-tert-butyl 4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-5-fluoro-1-methyl-1H-indazol-6-yl)-2-methyl-3,6-dihydropyridine-1(2H)-carboxylate.

[0815] To a single-necked flask at room temperature were added tert-butyl (S)-2-methyl-4-(((trifluoromethyl)sulfonyl)oxy)-3,6-dihydropyridine-1(2H)-carboxylate (0.21 g, 0.62 mmol), 1-(5-fluoro-1-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (0.20 g, 0.51 mmol), sodium carbonate (0.11 g, 1.02 mmol), Pd(dppf)Cl2 (0.04 g, 0.05 mmol), 1.4-dioxane (20 mL), and H2O (1 mL). The reaction was terminated by heating to 85°C under nitrogen protection for 8 h. The mixture was cooled to room temperature, diluted with water, extracted with EA, and the organic phase was dried over anhydrous Na2SO4, filtered, concentrated, and purified by column chromatography (EA / PE system) to obtain 0.20 g of a yellow solid.

[0816] Step 3: Synthesis of (S)-1-(5-fluoro-1-methyl-6-(2-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione.

[0817] To a single-necked flask at room temperature was added tert-butyl (S)-4-(3-(2,4-dioxytetrahydropyrimidin-1(2H)-yl)-5-fluoro-1-methyl-1H-indazol-6-yl)-2-methyl-3,6-dihydropyridine-1(2H)-carboxylate (0.20 g, 0.44 mmol), DCM (10 mL), and a dioxane hydrochloride solution (10 mL). The reaction was terminated at room temperature for 3 h. The solution was concentrated to afford 0.20 g of a crude yellow solid.

[0818] Step 4: Synthesis of 1-(6-((S)-1-(((1R,2R)-2-((4-(4-(((3R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)-2-methyl-1,2,3,6-tetrahydropyridin-4-yl)-5-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione.

[0819] At room temperature, to a single-necked flask were added (S)-1-(5-fluoro-1-methyl-6-(2-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (0.16 g, 0.44 mmol), (1R,2R)-2-((4-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexane-1-carbaldehyde (0.16 g, 0.44 mmol), and DCM (20 mL). The mixture was reacted at room temperature for 16 h. Sodium triacetoxyborohydride (0.18 g, 0.87 mmol) was added and the reaction was continued for 1 h. Water (1 mL) was added, stirred for 5 min, and filtered through a pad of celite. The filtrate was concentrated and subjected to column chromatography (MeOH / DCM system) to obtain 0.14 g of a yellow solid.

[0820] Step 5: Synthesis of 1-(5-fluoro-6-((2S)-1-(((1R,2R)-2-((4-(4-(((3R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)-2-methylpiperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione.

[0821] At room temperature, 1-(6-((S)-1-(((1R,2R)-2-((4-(4-(((3R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)-2-methyl-1,2,3,6-tetrahydropyridin-4-yl)-5-fluoro-1-methyl-1H-indole was added to the single-necked bottle in sequence. A mixture of oxazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (0.14 g, 0.15 mmol), Pd / C (0.20 g, 10%), and MeOH (20 mL) was reacted at room temperature under a hydrogen balloon for 16 h. The mixture was then filtered through a pad of Celite. The filtrate was concentrated and subjected to column chromatography (MeOH / DCM) to afford 0.50 g of a white solid. MS (ESI) m / z: 852.9 [M+H] + .

[0822] Example 31: Synthesis of 1-(5-fluoro-6-((2S,6R)-1-(((1R,2R)-2-((4-(4-(((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)-2,6-dimethylpiperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (Compound VI-22)

[0823] The synthesis method of (1R,2R)-2-((4-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexane-1-carbaldehyde is as described in Example 1.

[0824] Step 1: Synthesis of (2S,6R)-1-(4-methoxybenzyl)-2,6-dimethylpiperidin-4-one.

[0825] To a solution of acetone dicarboxylic acid (4.00 g, 27.40 mmol) in water (20 mL) was added 40% acetaldehyde (6.00 g, 54.80 mmol) at room temperature. 4-Methoxyphenylmethylamine (3.75 g, 27.40 mmol) was then added in small portions over 10 minutes. The mixture was stirred at room temperature for 24 hours. The reaction mixture was extracted with dichloromethane. The combined extracts were washed with brine and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated by column chromatography (DCM / EA) to yield 4.00 g of a light yellow oil.

[0826] Step 2: Synthesis of (2S,6R)-2,6-dimethylpiperidin-4-one.

[0827] At room temperature, cis-1-(4-methoxybenzyl)-2,6-dimethylpiperidin-4-one (4.00 g, 16.20 mmol) was dissolved in ethanol (20 mL) and a catalyst (0.40 g, 10% Pd-C) was added. The mixture was stirred under a hydrogen atmosphere for 16 h. The mixture was filtered and the filtrate was concentrated to afford 1.80 g of a crude yellow oil.

[0828] Step 3: Synthesis of tert-butyl (2S,6R)-2,6-dimethyl-4-oxopiperidine-1-carboxylate.

[0829] Di-tert-butyl dicarbonate (3.14 g, 14.40 mmol) and DIEA (3.10 g, 24.0 mmol) were added to a solution of cis-1-(4-methoxybenzyl)-2,6-dimethylpiperidin-4-one (1.54 g, 12.0 mmol) in dichloromethane (30 mL) at room temperature, and the mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated and subjected to column chromatography (EA / PE) to obtain 2.0 g of a white solid.

[0830] Step 4: Synthesis of tert-butyl (2S,6R)-2,6-dimethyl-4-(((trifluoromethyl)sulfonyl)oxy)-3,6-dihydropyridine-1(2H)-carboxylate.

[0831] To a single-necked flask, tert-butyl (2S,6R)-2,6-dimethyl-4-oxopiperidine-1-carboxylate (2.00 g, 8.80 mmol), PhNTf2 (3.68 g, 10.92 mmol), THF (20 mL), and LiHMDS (10.50 mL, 10.50 mmol) were added sequentially at -78°C. The reaction was allowed to warm to room temperature under a nitrogen atmosphere and allowed to react for 16 h. The mixture was diluted with saturated aqueous ammonium chloride and extracted with EA. The organic phase was dried over anhydrous Na2SO4, filtered, concentrated, and purified by column chromatography (EA / PE system) to afford 3.00 g of a yellow oil.

[0832] Step 5: Synthesis of tert-butyl (2S,6R)-4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-5-fluoro-1-methyl-1H-indazol-6-yl)-2,6-dimethyl-3,6-dihydropyridine-1(2H)-carboxylate.

[0833] To a single-necked flask at room temperature were added tert-butyl (2S,6R)-2,6-dimethyl-4-(((trifluoromethyl)sulfonyl)oxy)-3,6-dihydropyridine-1(2H)-carboxylate (0.21 g, 0.58 mmol), 1-(5-fluoro-1-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (0.20 g, 0.51 mmol), sodium carbonate (0.11 g, 1.02 mmol), Pd(dppf)Cl2 (0.04 g, 0.05 mmol), 1.4-dioxane (20 mL), and H2O (1 mL). The reaction was terminated by heating to 85°C under nitrogen protection for 8 h. The mixture was cooled to room temperature, diluted with water, extracted with EA, and the organic phase was dried over anhydrous Na2SO4, filtered, concentrated, and purified by column chromatography (EA / PE system) to obtain 0.20 g of a yellow solid.

[0834] Step 6: Synthesis of 1-(6-((2S,6R)-2,6-dimethyl-1,2,3,6-tetrahydropyridin-4-yl)-5-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione.

[0835] To a single-necked flask at room temperature was added tert-butyl (2S,6R)-4-(3-(2,4-dioxytetrahydropyrimidin-1(2H)-yl)-5-fluoro-1-methyl-1H-indazol-6-yl)-2,6-dimethyl-3,6-dihydropyridine-1(2H)-carboxylate (0.20 g, 0.42 mmol), DCM (10 mL), and a dioxane hydrochloride solution (10 mL). The reaction was terminated at room temperature for 3 h. The solution was concentrated to afford 0.20 g of a crude yellow solid.

[0836] Step 7: Synthesis of 1-(6-((2S,6R)-1-(((1R,2R)-2-((4-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)-2,6-dimethyl-1,2,3,6-tetrahydropyridin-4-yl)-5-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione.

[0837] At room temperature, 1-(6-((2S,6R)-2,6-dimethyl-1,2,3,6-tetrahydropyridin-4-yl)-5-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (0.16 g, 0.40 mmol), (1R,2R)-2-((4-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexane-1-carbaldehyde (0.16 g, 0.44 mmol) and DCM (20 mL) were added to a single-necked bottle in sequence. The mixture was reacted at room temperature for 16 h. Sodium triacetoxyborohydride (0.18 g, 0.87 mmol) was added and the reaction was carried out for 1 h. Water (1 mL) was added, stirred for 5 min, and filtered through a pad of celite. The filtrate was concentrated and subjected to column chromatography (MeOH / DCM system) to obtain 0.14 g of a yellow solid.

[0838] Step 8: Synthesis of 1-(5-fluoro-6-((2S,6R)-1-(((1R,2R)-2-((4-(4-(((3R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)-2,6-dimethylpiperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione.

[0839] At room temperature, to a single-necked flask were added 1-(6-((2S,6R)-1-(((1R,2R)-2-((4-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)-2,6-dimethyl-1,2,3,6-tetrahydropyridin-4-yl)-5-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 0.14 g, 0.14 mmol), Pd / C (0.20 g, 10%), and MeOH (20 mL). The reaction was carried out at room temperature for 16 h under a hydrogen balloon atmosphere, and the mixture was filtered through a celite pad. The filtrate was concentrated and subjected to column chromatography (MeOH / DCM system) to obtain 0.01 g of a white solid. MS (ESI) m / z: 866.9 [M+H] + .

[0840] Example 32: Synthesis of 1-(5-fluoro-6-(4-hydroxy-1-(((1R,2R)-2-((4-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (Compound VI-23)

[0841] The synthesis method of (1R,2R)-2-((4-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexane-1-carbaldehyde is as described in Example 1.

[0842] Step 1: tert-Butyl 4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-5-fluoro-1-methyl-1H-indazol-6-yl)-3,6-dihydropyridine-1(2H)-carboxylate

[0843]

[0844] 1-(6-bromo-5-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (10 g, 29.3 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (10.9 g, 35.2 mmol) and Pd(dppf)Cl2 (1.1 g, 1.5 mmol) were placed in 200 mL of 1,4-dioxane, 80 mL of Na2CO3 (6.2 g, 58.6 mmol) aqueous solution was added, nitrogen was replaced, and the reaction was carried out at 90 ° C. for 6 hours. The reaction was completed by TLC and LC-MS detection; the reaction solution was concentrated, water was added, EA was extracted, the organic phase was dried, concentrated, sanded, and column chromatography (DCM / MeOH) was used to obtain a crude product, which was slurried with ethyl acetate to obtain 9.5 g of an off-white solid product.

[0845] Step 2: tert-Butyl 4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-5-fluoro-1-methyl-1H-indazol-6-yl)-4-hydroxypiperidine-1-carboxylate

[0846] 4-(3-(2,4-dioxytetrahydropyrimidin-1(2H)-yl)-5-fluoro-1-methyl-1H-indazol-6-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (9.5 g, 21.4 mmol) was dissolved in 300 mL of dichloromethane and 100 mL of isopropanol, and Mn(TMHD)3 (1.3 g, 2.1 mmol) was added at room temperature. PhSiH3 (3.5 g, 32.1 mmol) was added under ice-water bath conditions. After the addition was complete, the mixture was reacted under an oxygen balloon atmosphere for 2 hours. TLC and LC-MS detected the completion of the reaction. The reaction solution was concentrated, water was added, and the mixture was extracted with ethyl acetate. The organic phase was concentrated, sanded, and column chromatography (PE / EA / DCM / MeOH) was performed to obtain a crude product. Ethyl acetate was used for slurrying to obtain 3.6 g of an off-white solid product.

[0847] Step 3: 1-(5-Fluoro-6-(4-hydroxypiperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione hydrochloride

[0848] Tert-butyl 4-(3-(2,4-dioxytetrahydropyrimidin-1(2H)-yl)-5-fluoro-1-methyl-1H-indazol-6-yl)-4-hydroxypiperidine-1-carboxylate (3.6 g, 7.8 mmol) was placed in 40 mL of 1,4-dioxane hydrochloride and allowed to react at room temperature for 2 hours. LC-MS confirmed the reaction was complete. The reaction mixture was filtered, and the filter cake was air-dried to yield 3.1 g of an off-white solid product.

[0849] Step 4: 1-(6-(1-(((1R,2R)-2-((4-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)-4-hydroxypiperidin-4-yl)-5-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

[0850] 1-(5-Fluoro-6-(4-hydroxypiperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione hydrochloride (2.6 g, 7.2 mmol) and (1R,2R)-2-((4-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexane-1-aldehyde (4.3 g, 7.2 mmol) were placed in 150 mL of dichloromethane, 10 mL of tetraisopropyl titanate was added, the reaction was carried out at 20° C. for 16 hours, sodium triacetoxyborohydride (2.3 g, 10.8 mmol) was added, and the reaction was continued for 1 hour. The reaction was completed by TLC and LC-MS. 3 mL of water was added to quench the reaction, and then 3 mL of aqueous ammonia was added, stirred for 20 min, filtered, and the filtrate was concentrated to make sand. Column chromatography (DCM / MeOH) was performed to obtain 2.6 g of an off-white solid product.

[0851] Step 5: 1-(5-Fluoro-6-(4-hydroxy-1-(((1R,2R)-2-((4-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

[0852] 1-(6-(1-(((1R,2R)-2-((4-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)-4-hydroxypiperidin-4-yl)-5-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (2.6 g, 2.75 mmol) was placed in 50 mL of tetrahydrofuran, 3.0 g of 5% by mass Pd / C was added, hydrogen was replaced, and the reaction was carried out at 20° C. for 16 hours. The reaction was completed by TLC and LC-MS detection; the reaction solution was filtered, the filtrate was concentrated to prepare sand, and column chromatography (DCM / MeOH) was performed to obtain 1.3 g of an off-white solid product. 1 H NMR (400MHz, DMSO-d6) δ10.58 (s, 1H), 9.15 (s, 1H), 7.77 (d, J = 6.3Hz, 1H), 7.38 (d, J = 12.7Hz, 1H), 7.13 (dt, J = 11.2, 6.7Hz, 3H), 6.83 (d, J=7.3Hz, 2H), 6.73-6.42 (m, 5H), 6.22 (d, J=8.2Hz, 2H), 5.25 (br, 1H), 4.14 (d, J=5. 1Hz, 1H), 4.08-3.78(m, 5H), 3.34-3.24(m, 6H), 3.07-2.90(m, 6H), 2.78-2.73(m, 2H), 2.58-2.50(m, 6H), 2.37 -2.28(m, 2H), 2.17-2.05(m, 2H), 1.84-1.44(m, 8H), 1.28-1.14(m, 3H), 0.99(s, 2H).MS(ESI)m / z: 854.8[M+H] + .

[0853] Example 33: Synthesis of 1-(5-fluoro-6-(4-(4-(((1R,2R)-2-((4-(-4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)piperazin-1-yl)cyclohexyl-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (Compound VI-24)

[0854] The synthesis method of (1R,2R)-2-((4-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexane-1-carbaldehyde is as described in Example 1.

[0855] Step 1: Synthesis of 1-(5-fluoro-1-methyl-6-(1,4-dioxaspirino[4.5]dec-7-en-8-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione.

[0856] At room temperature, 4,4,5,5-tetramethyl-2-(1,4-dioxaspirino[4.5]dec-7-en-8-yl)-1,3,2-dioxaborolane (0.96 g, 1.23 mmol), 1-(6-bromo-5-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (1.02 g, 3.00 mmol), sodium carbonate (0.64 g, 6.00 mmol), Pd(dppf)Cl2 (0.22 g, 0.30 mmol), 1.4-dioxane (20 mL), and H2O (1 mL) were added to a single-necked bottle in sequence. The reaction was terminated by heating to 85°C under nitrogen protection for 8 h. The mixture was cooled to room temperature, diluted with water, extracted with EA, and the organic phase was dried over anhydrous Na2SO4, filtered, concentrated, and purified by column chromatography (EA / PE system) to obtain 1.0 g of a yellow solid.

[0857] Step 2: Synthesis of 1-(5-fluoro-1-methyl-6-(1,4-dioxaspirino[4.5]dec-8-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione.

[0858] 1-(5-Fluoro-1-methyl-6-(1,4-dioxaspirino[4.5]dec-7-en-8-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (1.00 g, 2.70 mmol) was dissolved in ethanol (20 mL) at room temperature, and a catalyst (0.40 g, 10% Pd-C) was added. The mixture was stirred under a hydrogen atmosphere for 16 h. The mixture was filtered, and the filtrate was concentrated to afford 1.0 g of a crude yellow oil.

[0859] Step 3: Synthesis of 1-(5-fluoro-1-methyl-6-(4-oxocyclohexyl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione.

[0860] To a single-necked flask at room temperature was added 1-(5-fluoro-1-methyl-6-(1,4-dioxaspirino[4.5]dec-8-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (1.0 g, 2.70 mmol), DCM (10 mL), and TFA (2 mL). The mixture was stirred at room temperature for 6 h. The reaction mixture was concentrated to obtain 0.80 g of a crude yellow solid.

[0861] Step 4: Synthesis of tert-butyl 4-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-5-fluoro-1-methyl-1H-indazol-6-yl)cyclohexyl)piperazine-1-carboxylate.

[0862] At room temperature, 1-(5-fluoro-1-methyl-6-(4-oxocyclohexyl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (0.80 g, 2.23 mmol), tert-butyl piperazine-1-carboxylate (0.62 g, 3.35 mmol), DCM (20 mL), and STAB (0.95 g, 4.46 mmol) were added sequentially to a single-necked flask. The reaction was allowed to proceed for 16 h at room temperature. The mixture was diluted with saturated aqueous sodium carbonate solution and extracted with DCM. The organic phase was dried over anhydrous NaSO, filtered, concentrated, and purified by column chromatography (MeOH / DCM system) to afford 1.05 g of a yellow solid.

[0863] Step 5: Synthesis of 1-(5-fluoro-1-methyl-6-(4-(piperazin-1-yl)cyclohexyl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione.

[0864] To a single-necked flask at room temperature was added tert-butyl 4-(4-(3-(2,4-dioxytetrahydropyrimidin-1(2H)-yl)-5-fluoro-1-methyl-1H-indazol-6-yl)cyclohexyl)piperazine-1-carboxylate (1.05 g, 2.00 mmol), DCM (10 mL), and a dioxane hydrochloride solution (10 mL). The reaction was terminated at room temperature for 3 h. The mixture was concentrated to afford 1.00 g of a crude yellow solid.

[0865] Step 6: Synthesis of 1-(6-(4-(4-(((1R,2R)-2-)(4-(-4-(((3R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)piperazin-1-yl)cyclohexyl)-5-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione.

[0866] At room temperature, 1-(5-fluoro-1-methyl-6-(4-(piperazin-1-yl)cyclohexyl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (0.10 g, 0.23 mmol), (1R,2R)-2-((4-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexane-1-carbaldehyde (0.14 g, 0.23 mmol), DCM (20 mL), and TIPT (1 mL) were added sequentially into a single-necked flask. The mixture was reacted at room temperature for 16 h. Sodium triacetoxyborohydride (0.07 g, 0.35 mmol) was added and the reaction was continued for 1 h. Water (1 mL) was added, stirred for 5 min, and filtered through a pad of celite. The filtrate was concentrated and subjected to column chromatography (MeOH / DCM system) to obtain 0.10 g of a yellow solid.

[0867] Step 7: Synthesis of 1-(5-fluoro-6-(4-(4-((1R,2R)-2-((4-(-4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)piperazin-1-yl)cyclohexyl-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione.

[0868] At room temperature, 1-(6-(4-(4-(((1R,2R)-2-)(4-(-4-(((3R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)piperazin-1-yl)cyclohexyl)-5-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (0.10 g, 0.10 mmol), Pd / C (0.20 g, 10%), and MeOH (20 mL) were added to a single-necked bottle in sequence. The mixture was reacted at room temperature for 16 h under a hydrogen balloon atmosphere, filtered through a celite pad, and the filtrate was concentrated and subjected to column chromatography (MeOH / DCM system) to obtain 0.02 g of a white solid. NMR (400MHz, DMSO-d6) δ10.56 (s, 1H), 9.14 (s, 1H), 7.42 (d, J=6.0Hz, 1H), 7.35 (d, J=10.9Hz, 1H), 7.19-7.08 (m, 3H ), 6.83 (d, J = 7.1Hz, 2H), 6.67-6.58 (m, 2H), 6.56-6.44 (m, 3H), 6.21 (d, J = 8.3Hz, 2H), 4.13 (d, J = 5.0Hz, 1H), 3.99 ( s, 3H), 3.90 (t, J=6.7Hz, 2H), 3.04-2.89 (m, 8H), 2.75 (t, J=6.7Hz, 2H), 2.48-2.29 (m, 8H), 2.22-2.17 (m, 1H), 2.11 -2.02(m, 4H), 1.88-1.67(m, 5H), 1.62-1.37(m, 9H), 1.33-1.12(m, 8H), 1.03-0.90(m, 2H).MS(ESI)m / z: 921.9[M+H] + .

[0869] Example 34: Synthesis of 1-(6-(4-(cyclopropyl(((1R,2R)-2-((4-(4-(((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)amino)cyclohexyl)-5-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (Compound VI-25)

[0870] The synthesis method of (1R,2R)-2-((4-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexane-1-carbaldehyde is as described in Example 1.

[0871] Step 1: Synthesis of 1-(6-(4-(cyclopropylamino)cyclohexyl)-5-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione.

[0872] At room temperature, 1-(5-fluoro-1-methyl-6-(4-oxocyclohexyl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (0.10 g, 0.28 mmol), cyclopropylamine (0.06 g, 1.12 mmol), DCM (20 mL), and STAB (0.12 g, 0.56 mmol) were added sequentially to a single-necked flask. The reaction was allowed to proceed for 16 h at room temperature. The mixture was diluted with saturated aqueous sodium carbonate solution and extracted with DCM. The organic phase was dried over anhydrous NaSO, filtered, concentrated, and purified by column chromatography (MeOH / DCM) to afford 0.09 g of a yellow solid.

[0873] Step 2: Synthesis of 1-(6-(4-((((1R,2R)-2-((4-(4-(2R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)(cyclopropyl)amino)cyclohexyl)-5-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione.

[0874] At room temperature, 1-(6-(4-(cyclopropylamino)cyclohexyl)-5-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (0.09 g, 0.23 mmol), (1R,2R)-2-((4-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexane-1-carbaldehyde (0.14 g, 0.23 mmol), DCM (20 mL), and TIPT (1 mL) were added to a single-necked bottle in sequence. The mixture was reacted at room temperature for 16 h. Sodium triacetoxyborohydride (0.07 g, 0.35 mmol) was added and the reaction was continued for 1 h. Water (1 mL) was added, stirred for 5 min, and filtered through a pad of celite. The filtrate was concentrated and subjected to column chromatography (MeOH / DCM system) to obtain 0.08 g of a yellow solid.

[0875] Step 3: 1-(6-(4-(cyclopropyl(((1R,2R)-2-((4-(4-(((3R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)amino)cyclohexyl)-5-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione.

[0876] At room temperature, 1-(6-(4-((((1R,2R)-2-((4-(4-(2R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)(cyclopropyl)amino)cyclohexyl)-5-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (0.08 g, 0.08 mmol), Pd / C (0.20 g, 10%), and MeOH (20 mL) were added sequentially to a single-necked bottle. The reaction was allowed to proceed at room temperature for 16 h under a hydrogen balloon atmosphere. The mixture was filtered through a celite pad, and the filtrate was concentrated and subjected to column chromatography (MeOH / DCM system) to obtain 0.01 g of a white solid. MS (ESI) m / z: 893.1 [M+H]+

[0877] Example 35: Synthesis of 1-(5-fluoro-6-(6-(((1R,2R)-2-((4-(4-(((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)-2,6-diazaspiro[3.3]heptane-2-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (Compound VI-26)

[0878] The synthesis method of (1R,2R)-2-((4-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexane-1-carbaldehyde is as described in Example 1.

[0879] Step 1: Synthesis of tert-butyl 6-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-5-fluoro-1-methyl-1H-indazol-6-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate.

[0880] At room temperature, 1-(6-bromo-5-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (1.00 g, 2.93 mmol), tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate (1.16 g, 5.86 mmol), cesium carbonate (1.91 g, 5.86 mmol), Ruphos (0.27 g, 0.58 mmol), RuphosPdG2 (0.24 g, 0.29 mmol), and DMF (100 mL) were added sequentially to a single-necked flask. The reaction was terminated at 120°C under a nitrogen atmosphere for 16 h. The mixture was cooled to room temperature, diluted with water, and extracted three times with EA. The organic phases were combined, washed with water, washed with brine, dried over anhydrous Na2SO4, filtered, concentrated, and purified by column chromatography (MeOH / DCM system) to obtain 0.80 g of a yellow solid.

[0881] Step 2: Synthesis of 1-(5-fluoro-1-methyl-6-(2,6-diazaspiro[3.3]heptan-2-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione.

[0882] At room temperature, tert-butyl 6-(3-(2,4-dioxytetrahydropyrimidin-1(2H)-yl)-5-fluoro-1-methyl-1H-indazol-6-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (0.80 g, 1.75 mmol), TFA (2 mL), and DCM (10 mL) were added sequentially to a single-necked flask. The reaction was allowed to proceed at room temperature for 3 h. The product was concentrated to afford 0.70 g of a crude yellow solid.

[0883] Step 3: Synthesis of 1-(6-(6-(((1R,2R)-2-((4-(4-(((3R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)-2,6-diazaspiro[3.3]heptan-2-yl)-5-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione.

[0884] At room temperature, 1-(5-fluoro-1-methyl-6-(2,6-diazaspiro[3.3]heptane-2-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (0.20 g, 0.56 mmol), (1R,2R)-2-((4-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexane-1-carbaldehyde (0.33 g, 0.56 mmol), DCM (20 mL), and TIPT (1 mL) were added sequentially into a single-necked bottle and reacted at room temperature for 16 h. Sodium triacetoxyborohydride (0.18 g, 0.84 mmol) was added and reacted for 1 h. Water (1 mL) was added, stirred for 5 min, and filtered through a pad of celite. The filtrate was concentrated and subjected to column chromatography (MeOH / DCM system) to obtain 0.20 g of a white solid.

[0885] Step 4: Synthesis of 1-(5-fluoro-6-(6-(((1R,2R)-2-((4-(4-(((3R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)-2,6-diazaspiro[3.3]heptan-2-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione.

[0886] At room temperature, 1-(6-(6-(((1R,2R)-2-((4-(4-(((3R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)-2,6-diazaspiro[3.3]heptane-2-yl)-5-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (0.20 g, 0.21 mmol), Pd / C (0.20 g, 10%), and MeOH (20 mL) were added sequentially to a single-necked bottle. The reaction was allowed to proceed at room temperature under a hydrogen balloon atmosphere for 16 h. The mixture was then filtered through a celite pad. The filtrate was concentrated and subjected to column chromatography (MeOH / DCM system) to obtain 0.08 g of a white solid. MS (ESI) m / z: 851.8 [M+H] + .

[0887] Example 36: Synthesis of 1-(5-fluoro-6-(7-(((1R,2R)-2-((4-(4-(((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (Compound VI-27)

[0888] The synthesis method of (1R,2R)-2-((4-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexane-1-carbaldehyde is as described in Example 1.

[0889] Step 1: Synthesis of tert-butyl 2-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-5-fluoro-1-methyl-1H-indazol-6-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylate.

[0890] At room temperature, 1-(6-bromo-5-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (1.00 g, 2.93 mmol), tert-butyl 2,7-diazaspiro[3.5]nonane-7-carboxylate (1.20 g, 5.86 mmol), cesium carbonate (1.91 g, 5.86 mmol), Ruphos (0.27 g, 0.58 mmol), RuphosPdG2 (0.24 g, 0.29 mmol), and DMF (100 mL) were added sequentially to a single-necked flask. The reaction was terminated at 120°C under a nitrogen atmosphere for 16 h. The mixture was cooled to room temperature, diluted with water, and extracted three times with EA. The organic phases were combined, washed with water, washed with brine, dried over anhydrous Na2SO4, filtered, concentrated, and purified by column chromatography (MeOH / DCM system) to obtain 0.80 g of a yellow solid.

[0891] Step 2: Synthesis of 1-(5-fluoro-1-methyl-6-(2,7-diazaspiro[3.5]nonan-2-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione.

[0892] At room temperature, tert-butyl 2-(3-(2,4-dioxytetrahydropyrimidin-1(2H)-yl)-5-fluoro-1-methyl-1H-indazol-6-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylate (0.80 g, 1.74 mmol), TFA (2 mL), and DCM (10 mL) were added sequentially to a single-necked flask. The reaction was allowed to proceed at room temperature for 3 h. The product was concentrated to afford 0.70 g of a crude yellow solid.

[0893] Step 3: Synthesis of 1-(6-(7-(((1R,2R)-2-((4-(4-(((3R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)-5-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione.

[0894] At room temperature, 1-(5-fluoro-1-methyl-6-(2,7-diazaspiro[3.5]nonan-2-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (0.20 g, 0.52 mmol), (1R,2R)-2-((4-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexane-1-carbaldehyde (0.31 g, 0.52 mmol), DCM (20 mL), and TIPT (1 mL) were added to a single-necked bottle in sequence. The mixture was reacted at room temperature for 16 h. Sodium triacetoxyborohydride (0.16 g, 0.78 mmol) was added and the reaction was continued for 1 h. Water (1 mL) was added, stirred for 5 min, and filtered through a pad of celite. The filtrate was concentrated and subjected to column chromatography (MeOH / DCM system) to obtain 0.20 g of a white solid.

[0895] Step 4: Synthesis of 1-(5-fluoro-6-(7-(((1R,2R)-2-((4-(4-(((3R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione.

[0896] To a single-necked flask at room temperature was added 1-(6-(7-(((1R,2R)-2-((4-(4-(((3R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)-5-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (0.20 g, 0.20 mmol), Pd / C (0.20 g, 10%), and MeOH (20 mL). The reaction was carried out at room temperature for 16 h under a hydrogen balloon atmosphere. The mixture was filtered through a celite pad, and the filtrate was concentrated and subjected to column chromatography (MeOH / DCM system) to obtain 0.06 g of a white solid. 1H NMR (400MHz, DMSO-d6) δ10.52 (s, 1H), 9.15 (s, 1H), 7.28 (d, J=12.8Hz, 1H), 7.18-7.08 (m, 3H), 6.91-6.78 (m, 2H), 6.67-6.53 (m, 4H), 6.52-6.46 (m, 2H), 6.27-6.18 (m, 2H), 4.18-4.12 (m, 1H), 3.92-3.84 (m, 4H), 3. 81-3.72 (m, 4H), 3.14-2.89 (m, 8H), 2.73 (t, J=6.7Hz, 3H), 2.29-2.20 (m, 1H), 2.15-1.91 (m, 5H), 1.78-1. 59 (m, 6H), 1.36 (s, 3H), 1.30-1.16 (m, 6H), 1.07-0.93 (m, 1H), 0.89-0.80 (m, 2H). MS (ESI) m / z: 879.8 [M+H] + .

[0897] Example 37: Synthesis of 1-(5-fluoro-6-(1-(((1R,2R)-2-((4-(4-(((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)-4-methoxypiperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (Compound VI-28)

[0898] The synthesis method of (1R,2R)-2-((4-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl...

Claims

1. A compound represented by formula (i), an isomer thereof or a pharmaceutically acceptable salt thereof: ABC (i) in, A is X is selected from N or CH; Cy1 is selected from (For example )and Said (For example )and are unsubstituted, or are each independently substituted with 1 to 3 R a1 substituted; G is selected from unsubstituted or optionally substituted with one, two or more R a1 Substituted with the following groups: C 6-10 Aryl or 5-10 membered heteroaryl, such as phenyl, pyridyl, pyrimidinyl; Each R a1 are independently selected from hydrogen, deuterium, halogen, hydroxyl, carboxyl, amino, cyano, nitro, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, hydroxyl C 1-6 Alkyl, C 1-6 Alkylamino, (C 1-6 Alkyl)2amino, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-6 Alkylcarbonyl, aminocarbonyl, C 1-6 Alkylaminocarbonyl, (C 1-6 Alkyl)2-aminocarbonyl; B is -L2-Cy2-L3-Cy3-L4-Cy4-L5-; L1, L2, L3, L4, L5, L6 are independently selected from a bond, -(CH2) n -(NH) m -, -O-, -S-, -NR2, -CR 31 R 32 -, -C(O)-, -C(O)O-, -C(O)NR4-, -NR5-C(O)-, -S(O)-, -S(O)2-, -P(O)(R6)-, C 2-8 Alkenyl and C 2-8 Alkynyl; n and m are each independently any integer from zero to six; R2, R 31 , R 32 R4, R5 and R6 are independently selected from hydrogen, deuterium, halogen, hydroxyl, carboxyl, amino, cyano, nitro, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, hydroxyl C 1-6 Alkyl, C 1-6 Alkylamino, (C 1-6 Alkyl)2amino, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-6 Alkylcarbonyl, aminocarbonyl, C 1-6 Alkylaminocarbonyl, (C 1-6 alkyl)2aminocarbonyl, wherein the C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, hydroxyl C 1-6 Alkyl, C 1-6 Alkylamino, (C 1-6 Alkyl)2amino, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-6 Alkylcarbonyl, aminocarbonyl, C 1-6 Alkylaminocarbonyl, (C 1-6 The aminocarbonyl group is unsubstituted or optionally substituted by one or more groups independently selected from hydroxy, amino, carboxyl, cyano, nitro, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkoxy C 1-6 Alkoxy, C 1-6 Alkylamino, (C 1-6 Alkyl)2amino, C 1-6 Alkylcarbonylamino, C 1-6 Alkylsulfonylamino, C 1-6 Alkylcarbonyloxy, C 3-6 Cycloalkyl, C 3-6 Cycloalkylcarbonyloxy, C 2-8 Alkynyl, halo C 1-6 Alkyl, C 2-8 Alkenyl, halogenated C 1-6 Alkoxy group substitution; Cy2 is selected from 3-13 membered cycloalkyl, 3-13 membered heterocyclic group, 3-13 membered cycloalkenyl, 1-3 R a2 Substituted 3-13-membered cycloalkyl, 1-3 R a2 substituted 3-13 membered heterocyclic group, 1-3 R a2 Substituted 3-13 membered cycloalkenyl, Cy21-Cy22, wherein the heteroatom of the 3-13 membered heterocyclic group is selected from O, N or S; Cy21 and Cy22 are the same or different and are independently selected from 3-13 membered cycloalkyl, 3-13 membered heterocyclic group, 3-13 membered cycloalkenyl; Cy3 is selected from 3-13 membered cycloalkyl, 3-13 membered heterocyclic group, 6-13 membered bicyclic condensed ring group or 8-21 membered polycyclic condensed ring group, wherein the 3-13 membered cycloalkyl, 3-13 membered heterocyclic group, 6-13 membered bicyclic condensed ring group or 8-21 membered polycyclic condensed ring group is unsubstituted or each of them is independently substituted with 1-5 R a3 Substitution, preferably 5-6 membered heterocyclic group, wherein the heteroatom of the 5-6 membered heterocyclic group is N, O, S, Si; Cy4 is selected from 3-8 membered cycloalkyl, 3-8 membered heterocyclic group, 3-8 membered cycloalkenyl, 6-13 membered bicyclic condensed ring cycloalkyl, 6-13 membered bicyclic condensed ring alkenyl, 6-13 membered bicyclic condensed ring heterocyclic group, 1-3 R a4 Substituted 3-8 membered cycloalkyl, 1-3 R a4 substituted 3-8 membered heterocyclic group, 1-3 R a4 Substituted 3-8 membered cycloalkenyl, 1-3 R a4 Substituted 6-13 bicyclic condensed ring cycloalkyl, 1-3 R a4 Substituted 6-13 membered bicyclic condensed cycloalkenyl, 1-3 R a4 A substituted 6-13 membered bicyclic fused ring heterocyclic group, wherein the heteroatom of the 3-8 membered heterocyclic group or the 6-13 membered bicyclic fused ring heterocyclic group is selected from O, N or S; Each R a2 , R a3 and R a4 When present, each is independently selected from hydrogen, deuterium, halogen, hydroxyl, thiol, silanol, selenohydroxyl, carboxyl, amino, cyano, nitro, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Alkyl-C(O)O-, C 1-6 Alkylthio, C 1-6 Alkyl selenyl, hydroxyl C 1-6 Alkyl, C 1-6 Alkyl-C(O)NH-, C 1-6 Alkylamino, (C 1-6 Alkyl)2amino, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-6 Alkylcarbonyl, aminocarbonyl, C 1-6 Alkylaminocarbonyl, (C 1-6 alkyl)2-aminocarbonyl, 3-8-membered cycloalkyl, 3-8-membered heterocyclic group, 3-8-membered cycloalkenyl, wherein the C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, hydroxyl C 1-6 Alkyl, C 1-6 Alkylamino, (C 1-6 Alkyl)2amino, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-6 Alkylcarbonyl, aminocarbonyl, C 1-6 Alkylaminocarbonyl, (C 1-6 alkyl)2-aminocarbonyl, 3-8-membered cycloalkyl, 3-8-membered heterocyclyl, 3-8-membered cycloalkenyl, unsubstituted or optionally substituted with one or more selected from hydroxy, amino, carboxyl, cyano, nitro, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkoxy C 1-6 Alkoxy, C 1-6 Alkylamino, (C 1-6 Alkyl)2amino, C 1-6 Alkylcarbonylamino, C 1-6 Alkylsulfonylamino, C 1-6 Alkylcarbonyloxy, C 3-6 Cycloalkyl, C 3-6 Cycloalkylcarbonyloxy, C 2-8 Alkynyl, halo C 1-6 Alkyl, C 2-8 Alkenyl, halogenated C 1-6 Alkoxy, 3-8 membered cycloalkyl, 3-8 membered heterocyclyl, 3-8 membered cycloalkenyl; C is X1 is N or CR b1 ; X2 is N or CR b2 ; X3 is N or CR b3 ; X4 is N or CR b4 ; X5 is N or CR b5 ; R b1 , R b2 , R b3 , R b4 and R b5 are independently selected from hydrogen, deuterium, halogen, hydroxyl, carboxyl, amino, cyano, nitro, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, hydroxyl C 1-6 Alkyl, C 1-6 Alkylamino, (C 1-6 Alkyl)2amino, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-6 Alkylcarbonyl, aminocarbonyl, C 1-6 Alkylaminocarbonyl, (C 1-6 Alkyl)2-aminocarbonyl; Cy5 is selected from a 6-13 membered bicyclic fused ring group and an 8-21 membered polycyclic fused ring group; the 6-13 membered bicyclic fused ring group or the 8-21 membered polycyclic fused ring group is unsubstituted or replaced by 1-3 R a5 replace; Each R a5 are independently selected from hydrogen, deuterium, hydroxyl, amino, carboxyl, cyano, nitro, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, (C 1-6 Alkyl)2amino, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-6 Alkylsulfonyl, C 1-6 Alkylthio, C 3-6 Cycloalkyl, 4-6 membered heterocyclyl, 5-6 membered heteroaryl, aryl, C 1-6 Alkylcarbonyl, aminocarbonyl, C 1-6 Alkylaminocarbonyl, (C 1-6 alkyl)2aminocarbonyl, 4-6 membered heterocyclylcarbonyl and 5-6 membered heteroaryl-oxy, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, (C 1-6 Alkyl)2amino, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, C 2-8 Alkenyl, C 2-8 Alkynyl, C 1-6 Alkylsulfonyl, C 1-6 Alkylthio, C 3-6 Cycloalkyl, 4-6 membered heterocyclyl, 5-6 membered heteroaryl, aryl, C 1-6 Alkylcarbonyl, aminocarbonyl, C 1-6 Alkylaminocarbonyl, (C 1-6 alkyl)2-aminocarbonyl, 4-6-membered heterocyclylcarbonyl and 5-6-membered heteroaryl-oxy are unsubstituted or optionally substituted by one or more independently selected from hydroxy, amino, carboxyl, cyano, nitro, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkoxy C 1-6 Alkoxy, C 1-6 Alkylamino, (C 1-6 Alkyl)2amino, C 1-6 Alkylcarbonylamino, C 1-6 Alkylsulfonylamino, C 1-6 Alkylcarbonyloxy, C 3-6 Cycloalkyl, C 3-6 Cycloalkylcarbonyloxy, C 2-8 Alkynyl, halo C 1-6 Alkyl, C 2-8 Alkenyl, halogenated C 1-6 Alkoxy group substitution; The condition is that when Cy3 is hour, Not for 2. The compound of formula (i) according to claim 1, its isomer or a pharmaceutically acceptable salt thereof, wherein: Cy1 is selected from * terminal is connected to L1; Preferably, the are unsubstituted, or are each independently substituted with 1 to 3 R a1 More preferably, each R a1 Each is independently selected from hydrogen, halogen, hydroxyl, carboxyl, amino, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, hydroxyl C 1-6 Alkyl, C 1-6 Alkylamino, (C 1-6 Alkyl)2amino, C 1-6 Alkylcarbonyl, aminocarbonyl, C 1-6 Alkylaminocarbonyl, (C 1-6 More preferably, each R a1 Each is independently substituted by 1-3 halogens (such as F) or C 1-6 Alkyl (such as methyl) substitution; Preferably, Cy1 is selected from *Terminal is connected to L1.

3. The compound of formula (i) according to claim 1 or 2, its isomer or a pharmaceutically acceptable salt thereof, wherein: L1, L2, L3, L4, L5, L6 are the same or different and are independently selected from a bond, O, NH, C 1-6 Alkylene, -NHC(O)-, NH(C 1-6 Alkylene), -C(O)-; Preferably, L1 is selected from a bond, -NHC(O)-; preferably, when L1 is -NHC(O)-, the C(O) terminus is connected to Cy1; Preferably, L2 is selected from a bond, NH or NH(C 1-3 Alkylene); Preferably, L2 is selected from a bond, NH or NHCH2; preferably a bond; Preferably, L3 is selected from C 1-3 Alkylene, -C(O)-, -CH2NR4-, -NR5-CH2- or NH(C 1-3 R4, R5 are independently selected from C 3-6 Cycloalkyl; Preferably, L3 is selected from methylene, -C(O)- or NHCH2; preferably methylene; Preferably, L4 is selected from a bond, C 1-3 Alkylene or -C(O)-; Preferably, L4 is selected from a bond, a methylene group or -C(O)-; preferably a methylene group; Preferably, L5 is selected from a bond or C 1-3 Alkylene; Preferably, L5 is selected from a bond or a methylene group; preferably a bond; Preferably, L6 is selected from a bond or -O-; preferably a bond.

4. The compound of formula (i) according to any one of claims 1 to 3, its isomer or a pharmaceutically acceptable salt thereof, wherein: Cy2 is selected from 4-10 membered cycloalkyl, 4-10 membered heterocyclic group, 4-10 membered cycloalkenyl, 1-3 R a2 Substituted 4-10 membered cycloalkyl, 1-3 R a2 substituted 4-10 membered heterocyclic group, 1-3 R a2 Substituted 4-10 membered cycloalkenyl, Cy21-Cy22, wherein the heteroatom of the 4-10 membered heterocyclic group is selected from O, N or S; Cy21 and Cy22 are the same or different and are independently selected from 4-6 membered cycloalkyl, 4-6 membered heterocyclic group, 4-6 membered cycloalkenyl; Preferably, Cy2 is selected from 4-6 membered cycloalkyl, 4-6 membered heterocyclyl, 4-6 membered cycloalkenyl, a2 Substituted 4-6 membered cycloalkyl, 1-3 R a2 substituted 4-6 membered heterocyclic group, 1-3 R a2 A substituted 4-6 membered cycloalkenyl group, wherein the heteroatom of the 4-6 membered heterocyclic group is selected from O, N or S; Preferably, Cy2 is selected from unsubstituted or substituted with 1-3 R a2 Substituted 6-9 membered heterocyclic group, Cy21-Cy22; Cy21 and Cy22 are the same or different and are independently selected from cyclohexyl, piperazinyl, piperidinyl; Preferably, Cy2 is selected from unsubstituted or substituted with 1-3 R a2 Substituted piperazinyl, piperidinyl, Preferably, Cy2 is selected from (For example )、 (For example )、 (For example )、 * end connected to Cy1; Preferably, Cy3 is selected from 5-10 membered cycloalkyl, 5-10 membered heterocyclyl, 6-13 membered bicyclic condensed cycloalkyl, 6-13 membered bicyclic condensed cycloalkenyl, 6-13 membered bicyclic condensed heterocyclyl, 8-13 membered bicyclic condensed heteroaryl, 8-13 membered bicyclic condensed aryl, 8-21 membered polycyclic condensed cycloalkyl, 8-21 membered polycyclic condensed cycloalkenyl, 8-21 membered polycyclic condensed heterocyclyl, 8-21 membered polycyclic condensed heteroaryl, 8-21 membered polycyclic condensed aryl; Preferably, Cy3 is selected from 5-6 membered cycloalkyl or 5-6 membered heterocyclic group; the 5-6 membered cycloalkyl or 5-6 membered heterocyclic group is unsubstituted or each is independently substituted with 1-3 R a3 replace; Preferably, Cy3 is selected from cyclohexyl, piperidinyl, tetrahydropyranyl, dioxanyl, tetrahydropyrrolyl; the cyclohexyl, piperidinyl, tetrahydropyranyl, dioxanyl, tetrahydropyrrolyl are unsubstituted or are each independently substituted with 1-3 R a3 Substituted; preferably cyclohexyl; Preferably, Cy3 is selected from Said are unsubstituted or are each independently substituted with 1 to 3 R a3 replace; Preferably, Cy4 is selected from unsubstituted or optionally substituted with one, two or more C 1-6 Alkyl or C 1-6 Alkoxy-substituted 5-6-membered heterocyclic group; Preferably, Cy4 is selected from piperazinyl, such as * end is connected to L5; Preferably, Cy5 is selected from unsubstituted or substituted with 1-3 R a5 Substituted groups: 6-13 membered bicyclic cycloalkenyl, 6-13 membered bicyclic heteroaryl, 8-21 membered polycyclic heterocyclic group; Preferably, Cy5 is selected from unsubstituted or substituted with 1-3 OH or phenyl groups. For example Preferably, Cy5 is For example 5. The compound of formula (i) according to any one of claims 1 to 4, its isomer or a pharmaceutically acceptable salt thereof, wherein: R a1 Selected from halogen, C 1-6 Alkyl, C 1-6 Alkoxy; Preferably, R a1 Selected from F, methyl, ethyl, methoxy; Preferably, R a2 , R a3 and R a4 are the same or different and are independently selected from H, OH, amino, thiol, silanol, selenohydroxyl, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl-NH-, C 3-6 Cycloalkyl, C 1-6 Alkyl-C(O)NH-, halo-C 1-6 Alkyl, halogenated C 1-6 Alkoxy, hydroxyl C 1-6 alkyl; Preferably, R a2 Selected from H, OH, amino, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl-NH-, C 3-6 Cycloalkyl, C 1-6 Alkyl-C(O)NH-; Preferably, R a2 is selected from H, F, OH, amino, methylamino, acetamido, methyl, methoxy, and cyclopropyl; Preferably, R a3 and R a4 are the same or different and are independently selected from H, halogen; Preferably, R a3 and R a4 The same or different, independently selected from H, F; Preferably, R a5 Selected from hydroxyl or C 6-10 Aryl; Preferably, R a5 Selected from hydroxyl or phenyl; Preferably, R a5 Selected from hydroxyl or C 6-10 Aryl, halogen substituted C 6-10 Aryl; Preferably, Selected from unsubstituted or optionally substituted by R b1 , R b2 , R b3 , R b4 , R b5 The following groups substituted by 1 to 4 substituents in: phenyl, 6-membered heteroaryl containing 1 or 2 heteroatoms, for example 6. The compound of formula (i) according to any one of claims 1 to 5, its isomer or a pharmaceutically acceptable salt thereof, wherein: Has the following structure: Wherein, Y is selected from N or CR a2 ; X, L1, Cy1, R a2 It has the definition as described in any one of claims 1 to 5.

7. The compound represented by formula (i-1) according to claim 6, its isomer or a pharmaceutically acceptable salt thereof, wherein: Has the following structure: Wherein, Y is selected from N or CR a2 ; X, L1, Cy1, R a2 It has the definition as described in any one of claims 1 to 5.

8. The compound of formula (i) according to any one of claims 1 to 5, its isomer or a pharmaceutically acceptable salt thereof, wherein: Has the following structure: Wherein, Z1 and Z2 are the same or different and are independently selected from C(R a3 )(R a3 )、O、N(R a3 )、S、Si(R a3 )(R a3 ); X, G, L2, L3, L4, L5, L6, Cy2, Cy4, Cy5, R a1 , R a3 , X1, X2, X4, X5 have the definitions as described in any one of claims 1-5.

9. The compound represented by formula (i-2) according to claim 8, its isomer or a pharmaceutically acceptable salt thereof, wherein: Has the following structure: Wherein, Z3 is selected from N, C or CR a4 ; Indicates a single bond or a double bond; G, Y, Z1, Z2, R b1 , R b2 , R b4 , R b5 , R a1 , R a5 It has the definition as described in any one of claims 1 to 5.

10. The compound according to any one of claims 1 to 9, its isomer or a pharmaceutically acceptable salt thereof, which is selected from the compounds shown below:

11. A pharmaceutical composition comprising the compound according to any one of claims 1 to 10, its isomer or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

12. Use of the compound according to any one of claims 1 to 10, its isomer or pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 11 in the preparation of a drug for treating and / or preventing a disease or condition by degrading a target protein; Preferably, the disease or disorder is selected from abnormal cell proliferation, tumors, immune diseases, diabetes, cardiovascular diseases, infectious diseases and inflammatory diseases; preferably tumors and infectious diseases; Preferably, the tumor is cancer; preferably selected from breast cancer, endometrial cancer, testicular cancer, cervical cancer, prostate cancer, ovarian cancer, fallopian tube tumor, leukemia, skin cancer, squamous cell carcinoma, basal cell carcinoma, bladder cancer, colorectal cancer, esophageal cancer, head and neck cancer, kidney cancer, liver cancer, lung cancer, pancreatic cancer, gastric cancer, lymphoma, melanoma, sarcoma, peripheral neuroepithelioma, glioma, astrocytoma, ependymoma, glioblastoma, neuroblastoma, gangliocytoma, medulloblastoma, pineal cell tumor, meningioma, neurofibroma, neurilemoma, thyroid cancer, Wilms' tumor and teratoma; more preferably selected from breast cancer, endometrial cancer, testicular cancer, cervical cancer, prostate cancer, ovarian cancer and fallopian tube tumor; Preferably, the infectious disease is selected from viral pneumonia, influenza, avian influenza, meningitis, gonorrhea or infection with HIV, HBV, HCV, HSV, HPV, RSV, CMV, Ebola virus, flavivirus, rotavirus, coronavirus, EBV, drug-resistant virus, RNA virus, DNA virus, adenovirus, poxvirus, picornavirus, togavirus, orthomyxovirus, retrovirus, hepadnavirus, Gram-negative bacteria, Gram-positive bacteria, atypical bacteria, Staphylococcus, Streptococcus, Escherichia coli, Salmonella, Helicobacter pylori, Chlamydiaceae, Mycoplasmaceae, fungi, protozoa, intestinal worms, worms, prions or parasites.

13. Use of the compound according to any one of claims 1 to 10, its isomer or pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 11 in the preparation of a medicament for treating and / or preventing an estrogen receptor-mediated or dependent disease or condition, wherein the estrogen receptor-mediated or dependent disease or condition is a tumor, preferably cancer, more preferably breast cancer, endometrial cancer, testicular cancer, cervical cancer, prostate cancer, ovarian cancer and fallopian tube tumor, and most preferably breast cancer.

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