Er-protac compound for targeted degradation of estrogen receptor and use thereof

Abstract

The present invention belongs to the technical field of medicine, and relates to an ER-PROTAC compound for targeted degradation of an estrogen receptor, specifically a compound represented by general formula (I), an isomer thereof or a pharmaceutically acceptable salt thereof, and the use thereof, especially the use thereof as an estrogen receptor degradation agent, the use thereof in the preparation of a drug for treating and / or preventing an estrogen receptor-mediated or estrogen receptor-dependent disease or condition, and the use thereof in the preparation of a drug for treating and / or preventing a disease or condition by degrading a target protein.

Description

ER-PROTAC compounds targeting estrogen receptor degradation and their uses

[0001] This invention claims priority to the earlier application filed on March 25, 2025, with China National Intellectual Property Administration, patent application number 202510359950.1, entitled "ER-PROTAC Compounds Targeting Estrogen Receptors and Their Uses Thereof". The entire contents of the aforementioned earlier application are incorporated herein by reference. Technical Field

[0002] This invention belongs to the field of pharmaceutical technology and relates to ER-PROTAC compounds of formula (I) that target the degradation of estrogen receptors, their isomers or pharmaceutically acceptable salts thereof, and their uses. Background Technology

[0003] Estrogen receptor (ER) is a crucial marker for molecular subtyping of breast cancer, and its expression in breast cancer tissue largely determines a patient's response to endocrine therapy and prognosis. Currently, anti-estrogenic (hormone) therapy is the first-line treatment for estrogen-positive breast cancer. Anti-estrogenic therapies are mainly divided into three categories: aromatase inhibitors (such as letrozole and anastrozole); estrogen antagonists (such as tamoxifen and raloxifene); and selective estrogen receptor degraders (such as fulvestrant). These categories of anti-estrogenic therapies exert their effects through different mechanisms of action, blocking estrogen and inhibiting tumor growth.

[0004] Protein-targeting chimeras (PROTACs) are a novel therapeutic technique that blocks signaling pathways by degrading target proteins, thereby exerting a therapeutic effect. PROTAC molecules typically consist of three parts: a target protein-binding ligand, an E3 ubiquitin ligase ligand, and a linker. The PROTAC molecule binds tightly to the target protein at one end of the chimera and to the E3 ubiquitin ligase at the other, forming a target protein-PROTAC-E3 ubiquitin ligase ternary complex. Ubiquitination, mediated by the E3 ubiquitin ligase, results in the ubiquitinated target protein being "labeled." Subsequently, the ubiquitinated target protein is transported to the proteasome and degraded thereafter.

[0005] Compared to traditional small molecule inhibitors, PROTAC technology has the following advantages: 1. It may require a smaller dosage. The degradation process of target proteins is similar to a catalytic reaction, and PROTAC molecules can be reused, requiring only a catalytic amount of drug to inhibit the target protein. 2. It can avoid the feedback upregulation of target protein expression caused by inhibiting the target protein. 3. It expands the drug targeting range. PROTAC technology enables proteins that traditional small molecule inhibitors cannot directly target, such as transcription factors, regulatory proteins, and other non-enzymatic proteins, to become regulated proteins, transforming the target from "undruggable" to "drugable."

[0006] ER-PROTAC drugs that target and degrade estrogen receptors have demonstrated efficacy and excellent safety in clinical studies and are expected to become a new type of hormone therapy, serving as an important supplement to traditional therapies that are resistant, intolerant, or have poor efficacy. Summary of the Invention

[0007] One object of the invention is to provide a class of compounds that target and degrade estrogen receptors ER-PROTAC, their isomers or pharmaceutically acceptable salts thereof.

[0008] The technical solution of the present invention is as follows:

[0009] The compound represented by formula (I), its isomers, or pharmaceutically acceptable salts thereof:

[0010] in,

[0011] X is selected from N or CH;

[0012] G is selected from unsubstituted or optionally by one, two or more Rs. a1 The following groups are substituted: C 6-10 Aryl or 5-10 membered heteroaryl, including but not limited to phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, etc.;

[0013] Each R a1 Each group is independently selected from hydrogen, deuterium, halogen, hydroxyl, carboxyl, amino, cyano, nitro, and 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, C 2-8 alkenyl, C 2-8 alkynyl group, C 1-6 Alkyl carbonyl, amino carbonyl, C 1-6 Alkylamine carbonyl, (C 1-6 alkyl)2-aminocarbonyl;

[0014] Cy1 is selected from 3-13 membered cycloalkyl, 3-13 membered heterocyclic, 3-13 membered cycloalkenyl, and surrounded by 1-3 R groups. a2 Substituted 3-13 membered cycloalkyl groups, with 1-3 R groups a2 Substituted 3-13 membered heterocyclic groups, replaced by 1-3 R groups a2 Substituted 3-13 membered cycloalkenyl, Cy 11 -Cy 12 The heteroatom of the 3-13 membered heterocyclic group is selected from O, N, or S; Cy 11 and Cy 12 They may be the same or different, and are independently selected from 3-13 membered cycloalkyl, 3-13 membered heterocyclic, and 3-13 membered cycloalkenyl groups;

[0015] Each R a2 Each group is independently selected from hydrogen, halogen, hydroxyl, mercapto, silanol, selenol, carboxyl, amino, cyano, nitro, and 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, C 2-8 alkenyl, C 2-8 alkynyl group, C 1-6 Alkyl carbonyl, amino carbonyl, C 1-6 Alkylamine carbonyl, (C 1-6 Alkyl)2-aminocarbonyl, 3-8-membered cycloalkyl, 3-8-membered heterocyclic, 3-8-membered cycloalkenyl, wherein 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, C 2-8 alkenyl, C 2-8 alkynyl group, C 1-6 Alkyl carbonyl, amino carbonyl, C 1-6 Alkylamine carbonyl, (C 1-6 Alkyl) 2-aminocarbonyl, 3-8 membered cycloalkyl, 3-8 membered heterocyclic, 3-8 membered cycloalkenyl are unsubstituted or optionally substituted by one or more groups selected from 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 1-6alkyl)2-amino, C 1-6 Alkyl carbonyl amino, C 1-6 Alkylsulfonamide, C 1-6 Alkylcarbonyl group, C 3-6 cycloalkyl, C 3-6 Cycloalkylcarbonyloxy, C 2-8 alkynyl, halogenated C 1-6 Alkyl, C 2-8 alkenyl, halogenated C 1-6 Substitution of alkoxy, 3-8 membered cycloalkyl, 3-8 membered heterocyclic, and 3-8 membered cycloalkenyl groups;

[0016] Z1 and Z2 may be the same or different, and are independently selected from C(R). a3 (R) a3 ), O, N (R) a3 ), S, Si(R) a3 (R) a3 );

[0017] Cy2 is selected from 3-8 membered cycloalkyl, 3-8 membered heterocyclic, 3-8 membered cycloalkenyl, 6-13 bicyclic fused-ring cycloalkyl, 6-13 membered bicyclic fused-ring alkenyl, 6-13 membered bicyclic fused-ring heterocyclic, and is surrounded by 1-3 R groups. a4 Substituted 3-8 membered cycloalkyl groups, with 1-3 R groups a4 The substituted 3-8 membered heterocyclic group is replaced by 1-3 R a4 Substituted 3-8 membered cycloalkenyl groups, with 1-3 R groups a4 Substituted 6-13 bicyclic fused-ring alkyl groups, with 1-3 R a4 The substituted 6-13 membered bicyclic fused-ring alkenyl group, with 1-3 R groups a4 The 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;

[0018] Each R a3 R a4 Each group is independently selected from hydrogen, deuterium, halogen, hydroxyl, mercapto, silanol, selenol, carboxyl, amino, cyano, nitro, and 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)2-amino, C 2-8 alkenyl, C2-8 alkynyl group, C 1-6 Alkyl carbonyl, amino carbonyl, C 1-6 Alkylamine carbonyl, (C 1-6 Alkyl)2-aminocarbonyl, 3-8-membered cycloalkyl, 3-8-membered heterocyclic, 3-8-membered cycloalkenyl, wherein 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, C 2-8 alkenyl, C 2-8 alkynyl group, C 1-6 Alkyl carbonyl, amino carbonyl, C 1-6 Alkylamine carbonyl, (C 1-6 Alkyl) 2-aminocarbonyl, 3-8 membered cycloalkyl, 3-8 membered heterocyclic, 3-8 membered cycloalkenyl are unsubstituted or optionally substituted by one or more groups selected from 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)2-amino, C 1-6 Alkyl carbonyl amino, C 1-6 Alkylsulfonamide, C 1-6 Alkylcarbonyl group, C 3-6 cycloalkyl, C 3-6 Cycloalkylcarbonyloxy, C 2-8 alkynyl, halogenated C 1-6 Alkyl, C 2-8 alkenyl, halogenated C 1-6 Substitution of alkoxy, 3-8 membered cycloalkyl, 3-8 membered heterocyclic, and 3-8 membered cycloalkenyl groups;

[0019] X1 is N or CR b1 ;

[0020] X2 is N or CR b2 ;

[0021] X3 is N or CR b3 ;

[0022] X4 is N or CR b4 ;

[0023] R b1 R b2 R b3 and R b4Each group is independently selected from hydrogen, halogen, hydroxyl, carboxyl, amino, cyano, nitro, and 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, C 2-8 alkenyl, C 2-8 alkynyl group, C 1-6 Alkyl carbonyl, amino carbonyl, C 1-6 Alkylamine carbonyl, (C 1-6 alkyl)2-aminocarbonyl;

[0024] Z4 consists of C(Rc)(Rc), O, and S;

[0025] Each Rc is 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)2-amino, C 2-8 alkenyl, C 2-8 alkynyl group, C 1-6 Alkyl carbonyl, amino carbonyl, C 1-6 Alkylamine carbonyl, (C 1-6 alkyl)2-aminocarbonyl;

[0026] R is selected from hydrogen, 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)2-amino, C 2-8 alkenyl, C 2-8 alkynyl group, C 1-6 Alkyl carbonyl, amino carbonyl, C 1-6 Alkylamine carbonyl, (C 1-6 Alkyl) 2-aminocarbonyl, 3-8 membered cycloalkyl, 3-8 membered heterocyclic, 3-8 membered cycloalkenyl, C 6-10 Aryl or 5-10 heteroaryl, wherein the C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6Alkoxy, hydroxy C 1-6 Alkyl, C 1-6 Alkylamino, (C 1-6 alkyl)2-amino, C 2-8 alkenyl, C 2-8 alkynyl group, C 1-6 Alkyl carbonyl, amino carbonyl, C 1-6 Alkylamine carbonyl, (C 1-6 Alkyl) 2-aminocarbonyl, 3-8 membered cycloalkyl, 3-8 membered heterocyclic, 3-8 membered cycloalkenyl, C 6-10 The aryl group or 5-10 heteroaryl group is unsubstituted or optionally substituted with one or more groups selected from 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)2-amino, C 1-6 Alkyl carbonyl amino, C 1-6 Alkylsulfonamide, C 1-6 Alkylcarbonyl group, C 3-6 cycloalkyl, C 3-6 Cycloalkylcarbonyloxy, C 2-8 alkynyl, halogenated C 1-6 Alkyl, C 2-8 alkenyl, halogenated C 1-6 Substitution of alkoxy, 3-8 membered cycloalkyl, 3-8 membered heterocyclic, and 3-8 membered cycloalkenyl groups;

[0027] The condition is that when Z4 is CH2, R is not phenyl.

[0028] In one embodiment, the compound of formula (I), its isomers, or pharmaceutically acceptable salts thereof, wherein X is selected from N or CH; G is selected from Among them, the Not replaced, or each independently replaced by 1-3 Rs a1 Replacement; preferably, each R a1 Each group is independently selected from hydrogen, halogen, hydroxyl, carboxyl, amino, and 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, C 1-6 Alkyl carbonyl, amino carbonyl, C 1-6 Alkylamine carbonyl, (C 1-6Alkyl)2-aminocarbonyl; more preferably, each R a1 Each is independently selected from halogens and C. 1-6 Alkyl or C 1-6 Alkyl substitution; most preferably, each R... a1 Each is independently selected from F, methyl, ethyl, and methoxy.

[0029] Cy1 is selected from 3-13 membered cycloalkyl, 3-13 membered heterocyclic, 3-13 membered cycloalkenyl, and surrounded by 1-3 R groups. a2 Substituted 3-13 membered cycloalkyl groups, with 1-3 R groups a2 Substituted 3-13 membered heterocyclic groups, replaced by 1-3 R groups a2 Substituted 3-13 membered cycloalkenyl, Cy 11 -Cy 12 Wherein, the heteroatom of the 3-13 membered heterocyclic group is selected from O, N, or S; Cy 11 and Cy 12 Whether the groups are the same or different, they are each independently selected from 3-13 membered cycloalkyl, 3-13 membered heterocyclic, and 3-13 membered cycloalkenyl groups;

[0030] Each R a2 Each group is independently selected from hydrogen, halogen, hydroxyl, mercapto, silanol, selenol, carboxyl, amino, cyano, nitro, and 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, C 2-8 alkenyl, C 2-8 alkynyl group, C 1-6 Alkyl carbonyl, amino carbonyl, C 1-6 Alkylamine carbonyl, (C 1-6 Alkyl)2-aminocarbonyl, 3-8 membered cycloalkyl, 3-8 membered heterocyclic, 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)2-amino, C 2-8 alkenyl, C 2-8 alkynyl group, C 1-6 Alkyl carbonyl, amino carbonyl, C 1-6 Alkylamine carbonyl, (C 1-6Alkyl) 2-aminocarbonyl, 3-8 membered cycloalkyl, 3-8 membered heterocyclic, 3-8 membered cycloalkenyl are unsubstituted or optionally substituted by one or more groups selected from 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)2-amino, C 1-6 Alkyl carbonyl amino, C 1-6 Alkylsulfonamide, C 1-6 Alkylcarbonyl group, C 3-6 cycloalkyl, C 3-6 Cycloalkylcarbonyloxy, C 2-8 alkynyl, halogenated C 1-6 Alkyl, C 2-8 alkenyl, halogenated C 1-6 Substitution of alkoxy, 3-8 membered cycloalkyl, 3-8 membered heterocyclic, and 3-8 membered cycloalkenyl groups;

[0031] Z1 and Z2 may be the same or different, and are independently selected from C(R). a3 (R) a3 ), O, N (R) a3 ), S, Si(R) a3 (R) a3 );

[0032] Cy2 is selected from 3-8 membered cycloalkyl, 3-8 membered heterocyclic, 3-8 membered cycloalkenyl, 6-13 bicyclic fused-ring cycloalkyl, 6-13 membered bicyclic fused-ring alkenyl, 6-13 membered bicyclic fused-ring heterocyclic, and is surrounded by 1-3 R groups. a4 Substituted 3-8 membered cycloalkyl groups, with 1-3 R groups a4 The substituted 3-8 membered heterocyclic group is replaced by 1-3 R a4 Substituted 3-8 membered cycloalkenyl groups, with 1-3 R groups a4 Substituted 6-13 bicyclic fused-ring alkyl groups, with 1-3 R a4 The substituted 6-13 membered bicyclic fused-ring alkenyl group, with 1-3 R groups a4 The 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;

[0033] Each R a3 R a4 Each group is independently selected from hydrogen, deuterium, halogen, hydroxyl, mercapto, silanol, selenol, carboxyl, amino, cyano, nitro, and C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C1-6 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)2-amino, C 2-8 alkenyl, C 2-8 alkynyl group, C 1-6 Alkyl carbonyl, amino carbonyl, C 1-6 Alkylamine carbonyl, (C 1-6 Alkyl)2-aminocarbonyl, 3-8 membered cycloalkyl, 3-8 membered heterocyclic, 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)2-amino, C 2-8 alkenyl, C 2-8 alkynyl group, C 1-6 Alkyl carbonyl, amino carbonyl, C 1-6 Alkylamine carbonyl, (C 1-6 Alkyl) 2-aminocarbonyl, 3-8 membered cycloalkyl, 3-8 membered heterocyclic, 3-8 membered cycloalkenyl are unsubstituted or optionally substituted by one or more groups selected from 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)2-amino, C 1-6 Alkyl carbonyl amino, C 1-6 Alkylsulfonamide, C 1-6 Alkylcarbonyl group, C 3-6 cycloalkyl, C 3-6 Cycloalkylcarbonyloxy, C 2-8 alkynyl, halogenated C 1-6 Alkyl, C 2-8 alkenyl, halogenated C 1-6 Substitution of alkoxy, 3-8 membered cycloalkyl, 3-8 membered heterocyclic, and 3-8 membered cycloalkenyl groups;

[0034] X1 is N or CR b1 ;

[0035] X2 is N or CR b2 ;

[0036] X3 is N or CRb3 ;

[0037] X4 is N or CR b4 ;

[0038] R b1 R b2 R b3 and R b4 Each group is independently selected from hydrogen, halogen, hydroxyl, carboxyl, amino, cyano, nitro, and 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, C 2-8 alkenyl, C 2-8 alkynyl group, C 1-6 Alkyl carbonyl, amino carbonyl, C 1-6 Alkylamine carbonyl, (C 1-6 alkyl)2-aminocarbonyl;

[0039] Z4 consists of C(Rc)(Rc), O, and S;

[0040] Each Rc is 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)2-amino, C 2-8 alkenyl, C 2-8 alkynyl group, C 1-6 Alkyl carbonyl, amino carbonyl, C 1-6 Alkylamine carbonyl, (C 1-6 alkyl)2-aminocarbonyl;

[0041] R is selected from hydrogen, 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)2-amino, C 2-8 alkenyl, C 2-8 alkynyl group, C 1-6 Alkyl carbonyl, amino carbonyl, C 1-6 Alkylamine carbonyl, (C1-6 Alkyl) 2-aminocarbonyl, 3-8 membered cycloalkyl, 3-8 membered heterocyclic, 3-8 membered cycloalkenyl, C 6-10 Aryl or 5-10 heteroaryl, 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, C 2-8 alkenyl, C 2-8 alkynyl group, C 1-6 Alkyl carbonyl, amino carbonyl, C 1-6 Alkylamine carbonyl, (C 1-6 Alkyl) 2-aminocarbonyl, 3-8 membered cycloalkyl, 3-8 membered heterocyclic, 3-8 membered cycloalkenyl, C 6-10 The aryl group or 5-10 heteroaryl group is unsubstituted or optionally substituted with one or more groups selected from 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)2-amino, C 1-6 Alkyl carbonyl amino, C 1-6 Alkylsulfonamide, C 1-6 Alkylcarbonyl group, C 3-6 cycloalkyl, C 3-6 Cycloalkylcarbonyloxy, C 2-8 alkynyl, halogenated C 1-6 Alkyl, C 2-8 alkenyl, halogenated C 1-6 Substitution of alkoxy, 3-8 membered cycloalkyl, 3-8 membered heterocyclic, and 3-8 membered cycloalkenyl groups;

[0042] The condition is that when Z4 is CH2, R is not phenyl.

[0043] Another embodiment of the invention relates to a compound of formula (I), its isomers, or a pharmaceutically acceptable salt thereof, wherein X is selected from N or CH; G is selected from unsubstituted or optionally substituted with one, two, or more R atoms. a1 The following groups are substituted: C 6-10 Aryl or 5-10-membered heteroaryl groups, including but not limited to phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, etc.; each R a1 Each group is independently selected from hydrogen, deuterium, halogen, hydroxyl, carboxyl, amino, cyano, nitro, and 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)2-amino, C 2-8 alkenyl, C 2-8 alkynyl group, C 1-6 Alkyl carbonyl, amino carbonyl, C 1-6 Alkylamine carbonyl, (C 1-6 Alkyl)2-aminocarbonyl.

[0044] Cy1 is selected from 4-6 membered cycloalkyl, 4-6 membered heterocyclic, 4-6 membered cycloalkenyl, and surrounded by 1-3 R groups. a2 Substituted 4-6 membered cycloalkyl groups, with 1-3 R groups a2 The substituted 4-6 membered heterocyclic group is replaced by 1-3 R a2 The substituted 4-6 membered cycloalkenyl group, wherein the heteroatom of the 4-6 membered heterocyclic group is selected from O, N, or S; preferably, Cy1 is selected from 4-6 membered nitrogen-containing heterocyclic groups or those substituted with 1-3 R atoms. a2 Substituted 4-6 membered nitrogen-containing heterocyclic groups; more preferably, Cy1 is selected from unsubstituted or substituted groups with 1-3 R groups. a2 Replacement Among them, each R a2 Each is independently selected from hydrogen, hydroxyl, amino, mercapto, silanol, selenol, halogen, and 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; more preferably, each R a2 Each element is independently selected from hydrogen, hydroxyl, amino, halogen, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl-NH-, C 3-6 cycloalkyl, C 1-6 Alkyl-C(O)NH-; Most preferably, each R a2 Each group is independently selected from hydrogen, fluorine, hydroxyl, amino, methylamino, acetamido, methyl, methoxy, and cyclopropyl.

[0045] Z1 and Z2 may be the same or different, and are independently selected from C(R). a3 (R) a3 ), O, N (R) a3 ), S, Si(R) a3 (R) a3 );

[0046] Cy2 is selected from 3-8 membered cycloalkyl, 3-8 membered heterocyclic, 3-8 membered cycloalkenyl, 6-13 bicyclic fused-ring cycloalkyl, 6-13 membered bicyclic fused-ring alkenyl, 6-13 membered bicyclic fused-ring heterocyclic, and is surrounded by 1-3 R groups. a4 Substituted 3-8 membered cycloalkyl groups, with 1-3 R groups a4 The substituted 3-8 membered heterocyclic group is replaced by 1-3 R a4 Substituted 3-8 membered cycloalkenyl groups, with 1-3 R groups a4 Substituted 6-13 bicyclic fused-ring alkyl groups, with 1-3 R a4 The substituted 6-13 membered bicyclic fused-ring alkenyl group, with 1-3 R groups a4 The 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;

[0047] Each R a3 R a4 Each group is independently selected from hydrogen, deuterium, halogen, hydroxyl, mercapto, silanol, selenol, carboxyl, amino, cyano, nitro, and 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)2-amino, C 2-8 alkenyl, C 2-8 alkynyl group, C 1-6 Alkyl carbonyl, amino carbonyl, C 1-6 Alkylamine carbonyl, (C 1-6 Alkyl)2-aminocarbonyl, 3-8 membered cycloalkyl, 3-8 membered heterocyclic, 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)2-amino, C 2-8 alkenyl, C 2-8 alkynyl group, C 1-6 Alkyl carbonyl, amino carbonyl, C 1-6 Alkylamine carbonyl, (C 1-6Alkyl) 2-aminocarbonyl, 3-8 membered cycloalkyl, 3-8 membered heterocyclic, 3-8 membered cycloalkenyl are unsubstituted or optionally substituted by one or more groups selected from 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)2-amino, C 1-6 Alkyl carbonyl amino, C 1-6 Alkylsulfonamide, C 1-6 Alkylcarbonyl group, C 3-6 cycloalkyl, C 3-6 Cycloalkylcarbonyloxy, C 2-8 alkynyl, halogenated C 1-6 Alkyl, C 2-8 alkenyl, halogenated C 1-6 Substitution of alkoxy, 3-8 membered cycloalkyl, 3-8 membered heterocyclic, and 3-8 membered cycloalkenyl groups;

[0048] X1 is N or CR b1 ;

[0049] X2 is N or CR b2 ;

[0050] X3 is N or CR b3 ;

[0051] X4 is N or CR b4 ;

[0052] R b1 R b2 R b3 and R b4 Each group is independently selected from hydrogen, halogen, hydroxyl, carboxyl, amino, cyano, nitro, and 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, C 2-8 alkenyl, C 2-8 alkynyl group, C 1-6 Alkyl carbonyl, amino carbonyl, C 1-6 Alkylamine carbonyl, (C 1-6 alkyl)2-aminocarbonyl;

[0053] Z4 consists of C(Rc)(Rc), O, and S;

[0054] Each Rc is 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)2-amino, C 2-8 alkenyl, C 2-8 alkynyl group, C 1-6 Alkyl carbonyl, amino carbonyl, C 1-6 Alkylamine carbonyl, (C 1-6 alkyl)2-aminocarbonyl;

[0055] R is selected from hydrogen, 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)2-amino, C 2-8 alkenyl, C 2-8 alkynyl group, C 1-6 Alkyl carbonyl, amino carbonyl, C 1-6 Alkylamine carbonyl, (C 1-6 Alkyl) 2-aminocarbonyl, 3-8 membered cycloalkyl, 3-8 membered heterocyclic, 3-8 membered cycloalkenyl, C 6-10 Aryl or 5-10 heteroaryl, 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, C 2-8 alkenyl, C 2-8 alkynyl group, C 1-6 Alkyl carbonyl, amino carbonyl, C 1-6 Alkylamine carbonyl, (C 1-6 Alkyl) 2-aminocarbonyl, 3-8 membered cycloalkyl, 3-8 membered heterocyclic, 3-8 membered cycloalkenyl, C 6-10 The aryl group or 5-10 heteroaryl group is unsubstituted or optionally substituted with one or more groups selected from hydroxyl, amino, carboxyl, cyano, nitro, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkoxy C 1-6 Alkoxy, C 1-6Alkylamino, (C 1-6 alkyl)2-amino, C 1-6 Alkyl carbonyl amino, C 1-6 Alkylsulfonamide, C 1-6 Alkylcarbonyl group, C 3-6 cycloalkyl, C 3-6 Cycloalkylcarbonyloxy, C 2-8 alkynyl, halogenated C 1-6 Alkyl, C 2-8 alkenyl, halogenated C 1-6 Substitution of alkoxy, 3-8 membered cycloalkyl, 3-8 membered heterocyclic, and 3-8 membered cycloalkenyl groups;

[0056] The condition is that when Z4 is CH2, R is not phenyl.

[0057] Another embodiment of the present invention relates to a compound of formula (I), an isomer thereof or a pharmaceutically acceptable salt thereof, wherein X is selected from N or CH;

[0058] G is selected from unsubstituted or optionally by one, two or more Rs. a1 The following groups are substituted: C 6-10 Aryl or 5-10 membered heteroaryl, including but not limited to phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, etc.;

[0059] Each R a1 Each group is independently selected from hydrogen, deuterium, halogen, hydroxyl, carboxyl, amino, cyano, nitro, and 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, C 2-8 alkenyl, C 2-8 alkynyl group, C 1-6 Alkyl carbonyl, amino carbonyl, C 1-6 Alkylamine carbonyl, (C 1-6 alkyl)2-aminocarbonyl;

[0060] Cy1 is selected from 3-13 membered cycloalkyl, 3-13 membered heterocyclic, 3-13 membered cycloalkenyl, and surrounded by 1-3 R groups. a2 Substituted 3-13 membered cycloalkyl groups, with 1-3 R groups a2 Substituted 3-13 membered heterocyclic groups, replaced by 1-3 R groups a2 Substituted 3-13 membered cycloalkenyl, Cy 11 -Cy 12 The heteroatom of the 3-13 membered heterocyclic group is selected from O, N, or S; Cy 11 and Cy12 They may be the same or different, and are independently selected from 3-13 membered cycloalkyl, 3-13 membered heterocyclic, and 3-13 membered cycloalkenyl groups;

[0061] Each R a2 Each group is independently selected from hydrogen, halogen, hydroxyl, mercapto, silanol, selenol, carboxyl, amino, cyano, nitro, and 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, C 2-8 alkenyl, C 2-8 alkynyl group, C 1-6 Alkyl carbonyl, amino carbonyl, C 1-6 Alkylamine carbonyl, (C 1-6 Alkyl)2-aminocarbonyl, 3-8 membered cycloalkyl, 3-8 membered heterocyclic, 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)2-amino, C 2-8 alkenyl, C 2-8 alkynyl group, C 1-6 Alkyl carbonyl, amino carbonyl, C 1-6 Alkylamine carbonyl, (C 1-6 Alkyl) 2-aminocarbonyl, 3-8 membered cycloalkyl, 3-8 membered heterocyclic, 3-8 membered cycloalkenyl are unsubstituted or optionally substituted by one or more groups selected from 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)2-amino, C 1-6 Alkyl carbonyl amino, C 1-6 Alkylsulfonamide, C 1-6 Alkylcarbonyl group, C 3-6 cycloalkyl, C 3-6 Cycloalkylcarbonyloxy, C 2-8 alkynyl, halogenated C 1-6 Alkyl, C 2-8 alkenyl, halogenated C 1-6 Substitution of alkoxy, 3-8 membered cycloalkyl, 3-8 membered heterocyclic, and 3-8 membered cycloalkenyl groups;

[0062] Both Z1 and Z2 are CH(R) a3 ), where R a3 Selected from hydrogen, deuterium, halogen, hydroxyl, mercapto, silanol, selenol, 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)2-amino, C 2-8 alkenyl, C 2-8 alkynyl group, C 1-6 Alkyl carbonyl, amino carbonyl, C 1-6 Alkylamine carbonyl, (C 1-6 Alkyl)2-aminocarbonyl, 3-8-membered cycloalkyl, 3-8-membered heterocyclic, 3-8-membered cycloalkenyl, wherein 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, C 2-8 alkenyl, C 2-8 alkynyl group, C 1-6 Alkyl carbonyl, amino carbonyl, C 1-6 Alkylamine carbonyl, (C 1-6 Alkyl) 2-aminocarbonyl, 3-8 membered cycloalkyl, 3-8 membered heterocyclic, 3-8 membered cycloalkenyl are unsubstituted or optionally substituted by one or more groups selected from 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)2-amino, C 1-6 Alkyl carbonyl amino, C 1-6 Alkylsulfonamide, C 1-6 Alkylcarbonyl group, C 3-6 cycloalkyl, C 3-6 Cycloalkylcarbonyloxy, C 2-8 alkynyl, halogenated C 1-6 Alkyl, C 2-8alkenyl, halogenated C 1-6 Substitution with alkoxy, 3-8 membered cycloalkyl, 3-8 membered heterocyclic, or 3-8 membered cycloalkenyl groups; preferably, R a3 Selected from hydrogen, hydroxyl, amino, mercapto, silanol, selenol, 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; more preferably, R a3 Selected from hydrogen, deuterium, halogen, hydroxyl, mercapto, silanol, selenol, carboxyl, amino, cyano, nitro, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkyloxy; more preferably, R a3 Selected from hydrogen and halogens; most preferably, R a3 Selected from hydrogen and fluorine.

[0063] Cy2 is selected from 3-8 membered cycloalkyl, 3-8 membered heterocyclic, 3-8 membered cycloalkenyl, 6-13 bicyclic fused-ring cycloalkyl, 6-13 membered bicyclic fused-ring alkenyl, 6-13 membered bicyclic fused-ring heterocyclic, and is surrounded by 1-3 R groups. a4 Substituted 3-8 membered cycloalkyl groups, with 1-3 R groups a4 The substituted 3-8 membered heterocyclic group is replaced by 1-3 R a4 Substituted 3-8 membered cycloalkenyl groups, with 1-3 R groups a4 Substituted 6-13 bicyclic fused-ring alkyl groups, with 1-3 R a4 The substituted 6-13 membered bicyclic fused-ring alkenyl group, with 1-3 R groups a4 The 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;

[0064] Each R a4 Each group is independently selected from hydrogen, deuterium, halogen, hydroxyl, mercapto, silanol, selenol, carboxyl, amino, cyano, nitro, and 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-, C1-6 Alkylamino, (C 1-6 alkyl)2-amino, C 2-8 alkenyl, C 2-8 alkynyl group, C 1-6 Alkyl carbonyl, amino carbonyl, C 1-6 Alkylamine carbonyl, (C 1-6 Alkyl)2-aminocarbonyl, 3-8-membered cycloalkyl, 3-8-membered heterocyclic, 3-8-membered cycloalkenyl, wherein 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, C 2-8 alkenyl, C 2-8 alkynyl group, C 1-6 Alkyl carbonyl, amino carbonyl, C 1-6 Alkylamine carbonyl, (C 1-6 Alkyl) 2-aminocarbonyl, 3-8 membered cycloalkyl, 3-8 membered heterocyclic, 3-8 membered cycloalkenyl are unsubstituted or optionally substituted by one or more groups selected from 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)2-amino, C 1-6 Alkyl carbonyl amino, C 1-6 Alkylsulfonamide, C 1-6 Alkylcarbonyl group, C 3-6 cycloalkyl, C 3-6 Cycloalkylcarbonyloxy, C 2-8 alkynyl, halogenated C 1-6 Alkyl, C 2-8 alkenyl, halogenated C 1-6 Substitution of alkoxy, 3-8 membered cycloalkyl, 3-8 membered heterocyclic, and 3-8 membered cycloalkenyl groups;

[0065] X1 is N or CR b1 ;

[0066] X2 is N or CR b2 ;

[0067] X3 is N or CR b3 ;

[0068] X4 is N or CR b4 ;

[0069] R b1 Rb2 R b3 and R b4 Each group is independently selected from hydrogen, halogen, hydroxyl, carboxyl, amino, cyano, nitro, and 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, C 2-8 alkenyl, C 2-8 alkynyl group, C 1-6 Alkyl carbonyl, amino carbonyl, C 1-6 Alkylamine carbonyl, (C 1-6 alkyl)2-aminocarbonyl;

[0070] Z4 consists of C(Rc)(Rc), O, and S;

[0071] Each Rc is 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)2-amino, C 2-8 alkenyl, C 2-8 alkynyl group, C 1-6 Alkyl carbonyl, amino carbonyl, C 1-6 Alkylamine carbonyl, (C 1-6 alkyl)2-aminocarbonyl;

[0072] R is selected from hydrogen, 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)2-amino, C 2-8 alkenyl, C 2-8 alkynyl group, C 1-6 Alkyl carbonyl, amino carbonyl, C 1-6 Alkylamine carbonyl, (C 1-6 Alkyl) 2-aminocarbonyl, 3-8 membered cycloalkyl, 3-8 membered heterocyclic, 3-8 membered cycloalkenyl, C 6-10 Aryl or 5-10 heteroaryl, wherein the C 1-6 Alkyl, Halogenated C 1-6Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, hydroxy C 1-6 Alkyl, C 1-6 Alkylamino, (C 1-6 alkyl)2-amino, C 2-8 alkenyl, C 2-8 alkynyl group, C 1-6 Alkyl carbonyl, amino carbonyl, C 1-6 Alkylamine carbonyl, (C 1-6 Alkyl) 2-aminocarbonyl, 3-8 membered cycloalkyl, 3-8 membered heterocyclic, 3-8 membered cycloalkenyl, C 6-10 The aryl group or 5-10 heteroaryl group is unsubstituted or optionally substituted with one or more groups selected from 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)2-amino, C 1-6 Alkyl carbonyl amino, C 1-6 Alkylsulfonamide, C 1-6 Alkylcarbonyl group, C 3-6 cycloalkyl, C 3-6 Cycloalkylcarbonyloxy, C 2-8 alkynyl, halogenated C 1-6 Alkyl, C 2-8 alkenyl, halogenated C 1-6 Substitution of alkoxy, 3-8 membered cycloalkyl, 3-8 membered heterocyclic, and 3-8 membered cycloalkenyl groups;

[0073] The condition is that when Z4 is CH2, R is not phenyl.

[0074] Another embodiment of the present invention relates to a compound of formula (I), an isomer thereof or a pharmaceutically acceptable salt thereof, wherein X is selected from N or CH;

[0075] G is selected from unsubstituted or optionally by one, two or more Rs. a1 The following groups are substituted: C 6-10 Aryl or 5-10 membered heteroaryl, including but not limited to phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, etc.;

[0076] Each R a1 Each group is independently selected from hydrogen, deuterium, halogen, hydroxyl, carboxyl, amino, cyano, nitro, and 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)2-amino, C 2-8 alkenyl, C 2-8 alkynyl group, C 1-6 Alkyl carbonyl, amino carbonyl, C 1-6 Alkylamine carbonyl, (C 1-6 alkyl)2-aminocarbonyl;

[0077] Cy1 is selected from 3-13 membered cycloalkyl, 3-13 membered heterocyclic, 3-13 membered cycloalkenyl, and surrounded by 1-3 R groups. a2 Substituted 3-13 membered cycloalkyl groups, with 1-3 R groups a2 Substituted 3-13 membered heterocyclic groups, replaced by 1-3 R groups a2 Substituted 3-13 membered cycloalkenyl, Cy 11 -Cy 12 The heteroatom of the 3-13 membered heterocyclic group is selected from O, N, or S; Cy 11 and Cy 12 They may be the same or different, and are independently selected from 3-13 membered cycloalkyl, 3-13 membered heterocyclic, and 3-13 membered cycloalkenyl groups;

[0078] Each R a2 Each group is independently selected from hydrogen, halogen, hydroxyl, mercapto, silanol, selenol, carboxyl, amino, cyano, nitro, and 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, C 2-8 alkenyl, C 2-8 alkynyl group, C 1-6 Alkyl carbonyl, amino carbonyl, C 1-6 Alkylamine carbonyl, (C 1-6 Alkyl)2-aminocarbonyl, 3-8 membered cycloalkyl, 3-8 membered heterocyclic, 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)2-amino, C 2-8 alkenyl, C 2-8 alkynyl group, C 1-6 Alkyl carbonyl, amino carbonyl, C 1-6 Alkylamine carbonyl, (C 1-6Alkyl) 2-aminocarbonyl, 3-8 membered cycloalkyl, 3-8 membered heterocyclic, 3-8 membered cycloalkenyl are unsubstituted or optionally substituted by one or more groups selected from 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)2-amino, C 1-6 Alkyl carbonyl amino, C 1-6 Alkylsulfonamide, C 1-6 Alkylcarbonyl group, C 3-6 cycloalkyl, C 3-6 Cycloalkylcarbonyloxy, C 2-8 alkynyl, halogenated C 1-6 Alkyl, C 2-8 alkenyl, halogenated C 1-6 Substitution of alkoxy, 3-8 membered cycloalkyl, 3-8 membered heterocyclic, and 3-8 membered cycloalkenyl groups;

[0079] Z1 and Z2 may be the same or different, and are independently selected from C(R). a3 (R) a3 ), O, N (R) a3 ), S, Si(R) a3 (R) a3 );

[0080] Each R a3 Each group is independently selected from hydrogen, deuterium, halogen, hydroxyl, mercapto, silanol, selenol, carboxyl, amino, cyano, nitro, and 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)2-amino, C 2-8 alkenyl, C 2-8 alkynyl group, C 1-6 Alkyl carbonyl, amino carbonyl, C 1-6 Alkylamine carbonyl, (C 1-6 Alkyl)2-aminocarbonyl, 3-8-membered cycloalkyl, 3-8-membered heterocyclic, 3-8-membered cycloalkenyl, wherein 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)2-amino, C 2-8 alkenyl, C 2-8 alkynyl group, C 1-6 Alkyl carbonyl, amino carbonyl, C 1-6 Alkylamine carbonyl, (C 1-6 Alkyl) 2-aminocarbonyl, 3-8 membered cycloalkyl, 3-8 membered heterocyclic, 3-8 membered cycloalkenyl are unsubstituted or optionally substituted by one or more groups selected from 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)2-amino, C 1-6 Alkyl carbonyl amino, C 1-6 Alkylsulfonamide, C 1-6 Alkylcarbonyl group, C 3-6 cycloalkyl, C 3-6 Cycloalkylcarbonyloxy, C 2-8 alkynyl, halogenated C 1-6 Alkyl, C 2-8 alkenyl, halogenated C 1-6 Substitution of alkoxy, 3-8 membered cycloalkyl, 3-8 membered heterocyclic, and 3-8 membered cycloalkenyl groups;

[0081] The Cy2 is selected from 3-8 membered heterocyclic groups, surrounded by 1-3 R groups. a4 The substituted 3-8 membered heterocyclic group, 6-13 membered bicyclic spirocyclic group, or grouped by 1-3 R a4 The substituted 6-13 membered bicyclic spirocyclic heterocyclic group, wherein the heteroatom of the 3-8 membered heterocyclic group or the 6-13 membered bicyclic spirocyclic heterocyclic group is selected from O, N or S; preferably, the Cy2 is selected from unsubstituted or substituted with 1-3 R atoms. a4 Replacement Among them, each R a4 Each is independently selected from hydrogen, hydroxyl, amino, mercapto, silanol, selenol, halogen, and 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 or hydroxy C 1-6 Alkyl; more preferably, each R a4 Each R is independently selected from hydrogen and halogen; most preferably, each Ra4 They are selected independently from hydrogen and fluorine, respectively.

[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] R b1 R b2 R b3 and R b4 Each group is independently selected from hydrogen, halogen, hydroxyl, carboxyl, amino, cyano, nitro, and 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, C 2-8 alkenyl, C 2-8 alkynyl group, C 1-6 Alkyl carbonyl, amino carbonyl, C 1-6 Alkylamine carbonyl, (C 1-6 alkyl)2-aminocarbonyl;

[0087] Z4 consists of C(Rc)(Rc), O, and S;

[0088] Each Rc is 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)2-amino, C 2-8 alkenyl, C 2-8 alkynyl group, C 1-6 Alkyl carbonyl, amino carbonyl, C 1-6 Alkylamine carbonyl, (C 1-6 alkyl)2-aminocarbonyl;

[0089] R is selected from hydrogen, halogen, hydroxyl, carboxyl, amino, cyano, nitro, 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)2-amino, C 2-8 alkenyl, C 2-8 alkynyl group, C 1-6 Alkyl carbonyl, amino carbonyl, C 1-6 Alkylamine carbonyl, (C 1-6 Alkyl) 2-aminocarbonyl, 3-8 membered cycloalkyl, 3-8 membered heterocyclic, 3-8 membered cycloalkenyl, C 6-10 Aryl or 5-10 heteroaryl, 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, C 2-8 alkenyl, C 2-8 alkynyl group, C 1-6 Alkyl carbonyl, amino carbonyl, C 1-6 Alkylamine carbonyl, (C 1-6 Alkyl) 2-aminocarbonyl, 3-8 membered cycloalkyl, 3-8 membered heterocyclic, 3-8 membered cycloalkenyl, C 6-10 The aryl group or 5-10 heteroaryl group is unsubstituted or optionally substituted with one or more groups selected from 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)2-amino, C 1-6 Alkyl carbonyl amino, C 1-6 Alkylsulfonamide, C 1-6 Alkylcarbonyl group, C 3-6 cycloalkyl, C 3-6 Cycloalkylcarbonyloxy, C 2-8 alkynyl, halogenated C 1-6 Alkyl, C 2-8 alkenyl, halogenated C 1-6 Substitution of alkoxy, 3-8 membered cycloalkyl, 3-8 membered heterocyclic, and 3-8 membered cycloalkenyl groups;

[0090] The condition is that when Z4 is CH2, R is not phenyl.

[0091] Another embodiment of the invention relates to a compound of formula (I), its isomers, or a pharmaceutically acceptable salt thereof, wherein X is selected from N or CH; G is selected from unsubstituted or optionally substituted with one, two, or more R atoms.a1 The following groups are substituted: C 6-10 Aryl or 5-10 membered heteroaryl, including but not limited to phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, etc.;

[0092] Each R a1 Each group is independently selected from hydrogen, deuterium, halogen, hydroxyl, carboxyl, amino, cyano, nitro, and 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, C 2-8 alkenyl, C 2-8 alkynyl group, C 1-6 Alkyl carbonyl, amino carbonyl, C 1-6 Alkylamine carbonyl, (C 1-6 alkyl)2-aminocarbonyl;

[0093] Cy1 is selected from 3-13 membered cycloalkyl, 3-13 membered heterocyclic, 3-13 membered cycloalkenyl, and surrounded by 1-3 R groups. a2 Substituted 3-13 membered cycloalkyl groups, with 1-3 R groups a2 Substituted 3-13 membered heterocyclic groups, replaced by 1-3 R groups a2 Substituted 3-13 membered cycloalkenyl, Cy 11 -Cy 12 The heteroatom of the 3-13 membered heterocyclic group is selected from O, N, or S; Cy 11 and Cy 12 They may be the same or different, and are independently selected from 3-13 membered cycloalkyl, 3-13 membered heterocyclic, and 3-13 membered cycloalkenyl groups;

[0094] Each R a2 Each group is independently selected from hydrogen, halogen, hydroxyl, mercapto, silanol, selenol, carboxyl, amino, cyano, nitro, and 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, C 2-8 alkenyl, C 2-8 alkynyl group, C 1-6 Alkyl carbonyl, amino carbonyl, C 1-6 Alkylamine carbonyl, (C 1-6 Alkyl)2-aminocarbonyl, 3-8-membered cycloalkyl, 3-8-membered heterocyclic, 3-8-membered cycloalkenyl, wherein C1-6 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, C 2-8 alkenyl, C 2-8 alkynyl group, C 1-6 Alkyl carbonyl, amino carbonyl, C 1-6 Alkylamine carbonyl, (C 1-6 Alkyl) 2-aminocarbonyl, 3-8 membered cycloalkyl, 3-8 membered heterocyclic, 3-8 membered cycloalkenyl are unsubstituted or optionally substituted by one or more groups selected from 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)2-amino, C 1-6 Alkyl carbonyl amino, C 1-6 Alkylsulfonamide, C 1-6 Alkylcarbonyl group, C 3-6 cycloalkyl, C 3-6 Cycloalkylcarbonyloxy, C 2-8 alkynyl, halogenated C 1-6 Alkyl, C 2-8 alkenyl, halogenated C 1-6 Substitution of alkoxy, 3-8 membered cycloalkyl, 3-8 membered heterocyclic, and 3-8 membered cycloalkenyl groups;

[0095] Z1 and Z2 may be the same or different, and are independently selected from C(R). a3 (R) a3 ), O, N (R) a3 ), S, Si(R) a3 (R) a3 );

[0096] Cy2 is selected from 3-8 membered cycloalkyl, 3-8 membered heterocyclic, 3-8 membered cycloalkenyl, 6-13 bicyclic fused-ring cycloalkyl, 6-13 membered bicyclic fused-ring alkenyl, 6-13 membered bicyclic fused-ring heterocyclic, and is surrounded by 1-3 R groups. a4 Substituted 3-8 membered cycloalkyl groups, with 1-3 R groups a4 The substituted 3-8 membered heterocyclic group is replaced by 1-3 R a4 Substituted 3-8 membered cycloalkenyl groups, with 1-3 R groups a4 Substituted 6-13 bicyclic fused-ring alkyl groups, with 1-3 R a4 The substituted 6-13 membered bicyclic fused-ring alkenyl group, with 1-3 R groups a4The 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;

[0097] Each R a3 R a4 Each group is independently selected from hydrogen, deuterium, halogen, hydroxyl, mercapto, silanol, selenol, carboxyl, amino, cyano, nitro, and 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)2-amino, C 2-8 alkenyl, C 2-8 alkynyl group, C 1-6 Alkyl carbonyl, amino carbonyl, C 1-6 Alkylamine carbonyl, (C 1-6 Alkyl)2-aminocarbonyl, 3-8-membered cycloalkyl, 3-8-membered heterocyclic, 3-8-membered cycloalkenyl, wherein 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, C 2-8 alkenyl, C 2-8 alkynyl group, C 1-6 Alkyl carbonyl, amino carbonyl, C 1-6 Alkylamine carbonyl, (C 1-6 Alkyl) 2-aminocarbonyl, 3-8 membered cycloalkyl, 3-8 membered heterocyclic, 3-8 membered cycloalkenyl are unsubstituted or optionally substituted by one or more groups selected from 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)2-amino, C 1-6 Alkyl carbonyl amino, C 1-6 Alkylsulfonamide, C 1-6 Alkylcarbonyl group, C 3-6 cycloalkyl, C 3-6 Cycloalkylcarbonyloxy, C2-8 alkynyl, halogenated C 1-6 Alkyl, C 2-8 alkenyl, halogenated C 1-6 Substitution of alkoxy, 3-8 membered cycloalkyl, 3-8 membered heterocyclic, and 3-8 membered cycloalkenyl groups;

[0098] The Selected from phenyl or a 6-membered heteroaryl group containing 1-2 heteroatoms, wherein the phenyl or the 6-membered heteroaryl group containing 1-2 heteroatoms is not substituted or is R-substituted. b1 R b2 R b3 and R b4 Replace, where R b1 R b2 R b3 and R b4 Each group is independently selected from hydrogen, halogen, hydroxyl, carboxyl, amino, cyano, nitro, and 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, C 2-8 alkenyl, C 2-8 alkynyl group, C 1-6 Alkyl carbonyl, amino carbonyl, C 1-6 Alkylamine carbonyl, (C 1-6 Alkyl)2-aminocarbonyl; preferably, Selected from phenyl, pyridyl; more preferably, for

[0099] Z4 consists of C(Rc)(Rc), O, and S;

[0100] Each Rc is 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)2-amino, C 2-8 alkenyl, C 2-8 alkynyl group, C 1-6 Alkyl carbonyl, amino carbonyl, C 1-6 Alkylamine carbonyl, (C 1-6 alkyl)2-aminocarbonyl;

[0101] R is selected from hydrogen, 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)2-amino, C 2-8 alkenyl, C 2-8 alkynyl group, C 1-6 Alkyl carbonyl, amino carbonyl, C 1-6 Alkylamine carbonyl, (C 1-6 Alkyl) 2-aminocarbonyl, 3-8 membered cycloalkyl, 3-8 membered heterocyclic, 3-8 membered cycloalkenyl, C 6-10 Aryl or 5-10 heteroaryl, 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, C 2-8 alkenyl, C 2-8 alkynyl group, C 1-6 Alkyl carbonyl, amino carbonyl, C 1-6 Alkylamine carbonyl, (C 1-6 Alkyl) 2-aminocarbonyl, 3-8 membered cycloalkyl, 3-8 membered heterocyclic, 3-8 membered cycloalkenyl, C 6-10 The aryl group or 5-10 heteroaryl group is unsubstituted or optionally substituted with one or more groups selected from 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)2-amino, C 1-6 Alkyl carbonyl amino, C 1-6 Alkylsulfonamide, C 1-6 Alkylcarbonyl group, C 3-6 cycloalkyl, C 3-6 Cycloalkylcarbonyloxy, C 2-8 alkynyl, halogenated C 1-6 Alkyl, C 2-8 alkenyl, halogenated C 1-6 Substitution of alkoxy, 3-8 membered cycloalkyl, 3-8 membered heterocyclic, and 3-8 membered cycloalkenyl groups;

[0102] The condition is that when Z4 is CH2, R is not phenyl.

[0103] Another embodiment of the invention relates to a compound of formula (I), its isomers, or a pharmaceutically acceptable salt thereof, wherein X is selected from N or CH; G is selected from unsubstituted or optionally substituted with one, two, or more R atoms. a1 The following groups are substituted: C 6-10 Aryl or 5-10 membered heteroaryl, including but not limited to phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, etc.;

[0104] Each R a1 Each group is independently selected from hydrogen, deuterium, halogen, hydroxyl, carboxyl, amino, cyano, nitro, and 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, C 2-8 alkenyl, C 2-8 alkynyl group, C 1-6 Alkyl carbonyl, amino carbonyl, C 1-6 Alkylamine carbonyl, (C 1-6 alkyl)2-aminocarbonyl;

[0105] Cy1 is selected from 3-13 membered cycloalkyl, 3-13 membered heterocyclic, 3-13 membered cycloalkenyl, and surrounded by 1-3 R groups. a2 Substituted 3-13 membered cycloalkyl groups, with 1-3 R groups a2 Substituted 3-13 membered heterocyclic groups, replaced by 1-3 R groups a2 Substituted 3-13 membered cycloalkenyl, Cy 11 -Cy 12 The heteroatom of the 3-13 membered heterocyclic group is selected from O, N, or S; Cy 11 and Cy 12 They may be the same or different, and are independently selected from 3-13 membered cycloalkyl, 3-13 membered heterocyclic, and 3-13 membered cycloalkenyl groups;

[0106] Each R a2 Each group is independently selected from hydrogen, halogen, hydroxyl, mercapto, silanol, selenol, carboxyl, amino, cyano, nitro, and 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, C 2-8 alkenyl, C 2-8 alkynyl group, C 1-6Alkyl carbonyl, amino carbonyl, C 1-6 Alkylamine carbonyl, (C 1-6 Alkyl)2-aminocarbonyl, 3-8-membered cycloalkyl, 3-8-membered heterocyclic, 3-8-membered cycloalkenyl, wherein 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, C 2-8 alkenyl, C 2-8 alkynyl group, C 1-6 Alkyl carbonyl, amino carbonyl, C 1-6 Alkylamine carbonyl, (C 1-6 Alkyl) 2-aminocarbonyl, 3-8 membered cycloalkyl, 3-8 membered heterocyclic, 3-8 membered cycloalkenyl are unsubstituted or optionally substituted by one or more groups selected from 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)2-amino, C 1-6 Alkyl carbonyl amino, C 1-6 Alkylsulfonamide, C 1-6 Alkylcarbonyl group, C 3-6 cycloalkyl, C 3-6 Cycloalkylcarbonyloxy, C 2-8 alkynyl, halogenated C 1-6 Alkyl, C 2-8 alkenyl, halogenated C 1-6 Substitution of alkoxy, 3-8 membered cycloalkyl, 3-8 membered heterocyclic, and 3-8 membered cycloalkenyl groups;

[0107] Z1 and Z2 may be the same or different, and are independently selected from C(R). a3 (R) a3 ), O, N (R) a3 ), S, Si(R) a3 (R) a3 );

[0108] Cy2 is selected from 3-8 membered cycloalkyl, 3-8 membered heterocyclic, 3-8 membered cycloalkenyl, 6-13 bicyclic fused-ring cycloalkyl, 6-13 membered bicyclic fused-ring alkenyl, 6-13 membered bicyclic fused-ring heterocyclic, and is surrounded by 1-3 R groups. a4 Substituted 3-8 membered cycloalkyl groups, with 1-3 R groups a4 The substituted 3-8 membered heterocyclic group is replaced by 1-3 R a4Substituted 3-8 membered cycloalkenyl groups, with 1-3 R groups a4 Substituted 6-13 bicyclic fused-ring alkyl groups, with 1-3 R a4 The substituted 6-13 membered bicyclic fused-ring alkenyl group, with 1-3 R groups a4 The 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;

[0109] Each R a3 R a4 Each group is independently selected from hydrogen, deuterium, halogen, hydroxyl, mercapto, silanol, selenol, carboxyl, amino, cyano, nitro, and 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)2-amino, C 2-8 alkenyl, C 2-8 alkynyl group, C 1-6 Alkyl carbonyl, amino carbonyl, C 1-6 Alkylamine carbonyl, (C 1-6 Alkyl)2-aminocarbonyl, 3-8-membered cycloalkyl, 3-8-membered heterocyclic, 3-8-membered cycloalkenyl, wherein 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, C 2-8 alkenyl, C 2-8 alkynyl group, C 1-6 Alkyl carbonyl, amino carbonyl, C 1-6 Alkylamine carbonyl, (C 1-6 Alkyl) 2-aminocarbonyl, 3-8 membered cycloalkyl, 3-8 membered heterocyclic, 3-8 membered cycloalkenyl are unsubstituted or optionally substituted by one or more groups selected from 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)2-amino, C 1-6Alkyl carbonyl amino, C 1-6 Alkylsulfonamide, C 1-6 Alkylcarbonyl group, C 3-6 cycloalkyl, C 3-6 Cycloalkylcarbonyloxy, C 2-8 alkynyl, halogenated C 1-6 Alkyl, C 2-8 alkenyl, halogenated C 1-6 Substitution of alkoxy, 3-8 membered cycloalkyl, 3-8 membered heterocyclic, and 3-8 membered cycloalkenyl groups;

[0110] X1 is N or CR b1 ;

[0111] X2 is N or CR b2 ;

[0112] X3 is N or CR b3 ;

[0113] X4 is N or CR b4 ;

[0114] R b1 R b2 R b3 and R b4 Each group is independently selected from hydrogen, halogen, hydroxyl, carboxyl, amino, cyano, nitro, and 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, C 2-8 alkenyl, C 2-8 alkynyl group, C 1-6 Alkyl carbonyl, amino carbonyl, C 1-6 Alkylamine carbonyl, (C 1-6 alkyl)2-aminocarbonyl;

[0115] Z4 is CH(Rc) or O, where Rc is 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)2-amino, C 2-8 alkenyl, C 2-8 alkynyl group, C 1-6 Alkyl carbonyl, amino carbonyl, C 1-6 Alkylamine carbonyl, (C1-6 Alkyl)2-aminocarbonyl; preferably, Rc is selected from hydrogen, deuterium, halogen, hydroxyl, carboxyl, amino, cyano, nitro, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy;

[0116] R is selected from hydrogen, 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)2-amino, C 2-8 alkenyl, C 2-8 alkynyl group, C 1-6 Alkyl carbonyl, amino carbonyl, C 1-6 Alkylamine carbonyl, (C 1-6 Alkyl) 2-aminocarbonyl, 3-8 membered cycloalkyl, 3-8 membered heterocyclic, 3-8 membered cycloalkenyl, C 6-10 Aryl or 5-10 heteroaryl, 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, C 2-8 alkenyl, C 2-8 alkynyl group, C 1-6 Alkyl carbonyl, amino carbonyl, C 1-6 Alkylamine carbonyl, (C 1-6 Alkyl) 2-aminocarbonyl, 3-8 membered cycloalkyl, 3-8 membered heterocyclic, 3-8 membered cycloalkenyl, C 6-10 The aryl group or 5-10 heteroaryl group is unsubstituted or optionally substituted with one or more groups selected from 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)2-amino, C 1-6 Alkyl carbonyl amino, C 1-6 Alkylsulfonamide, C 1-6 Alkylcarbonyl group, C 3-6 cycloalkyl, C 3-6 Cycloalkylcarbonyloxy, C 2-8 alkynyl, halogenated C 1-6 Alkyl, C2-8 alkenyl, halogenated C 1-6 Substitution of alkoxy, 3-8 membered cycloalkyl, 3-8 membered heterocyclic, and 3-8 membered cycloalkenyl groups;

[0117] The condition is that when Z4 is CH2, R is not phenyl.

[0118] Another embodiment of the invention relates to a compound of formula (I), its isomers, or a pharmaceutically acceptable salt thereof, wherein X is selected from N or CH; G is selected from unsubstituted or optionally substituted with one, two, or more R atoms. a1 The following groups are substituted: C 6-10 Aryl or 5-10 membered heteroaryl, including but not limited to phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, etc.;

[0119] Each R a1 Each group is independently selected from hydrogen, deuterium, halogen, hydroxyl, carboxyl, amino, cyano, nitro, and 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, C 2-8 alkenyl, C 2-8 alkynyl group, C 1-6 Alkyl carbonyl, amino carbonyl, C 1-6 Alkylamine carbonyl, (C 1-6 alkyl)2-aminocarbonyl;

[0120] Cy1 is selected from 3-13 membered cycloalkyl, 3-13 membered heterocyclic, 3-13 membered cycloalkenyl, and surrounded by 1-3 R groups. a2 Substituted 3-13 membered cycloalkyl groups, with 1-3 R groups a2 Substituted 3-13 membered heterocyclic groups, replaced by 1-3 R groups a2 Substituted 3-13 membered cycloalkenyl, Cy 11 -Cy 12 The heteroatom of the 3-13 membered heterocyclic group is selected from O, N, or S; Cy 11 and Cy 12 They may be the same or different, and are independently selected from 3-13 membered cycloalkyl, 3-13 membered heterocyclic, and 3-13 membered cycloalkenyl groups;

[0121] Each R a2 Each group is independently selected from hydrogen, halogen, hydroxyl, mercapto, silanol, selenol, carboxyl, amino, cyano, nitro, and 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)2-amino, C 2-8 alkenyl, C 2-8 alkynyl group, C 1-6 Alkyl carbonyl, amino carbonyl, C 1-6 Alkylamine carbonyl, (C 1-6 Alkyl)2-aminocarbonyl, 3-8-membered cycloalkyl, 3-8-membered heterocyclic, 3-8-membered cycloalkenyl, wherein 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, C 2-8 alkenyl, C 2-8 alkynyl group, C 1-6 Alkyl carbonyl, amino carbonyl, C 1-6 Alkylamine carbonyl, (C 1-6 Alkyl) 2-aminocarbonyl, 3-8 membered cycloalkyl, 3-8 membered heterocyclic, 3-8 membered cycloalkenyl are unsubstituted or optionally substituted by one or more groups selected from 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)2-amino, C 1-6 Alkyl carbonyl amino, C 1-6 Alkylsulfonamide, C 1-6 Alkylcarbonyl group, C 3-6 cycloalkyl, C 3-6 Cycloalkylcarbonyloxy, C 2-8 alkynyl, halogenated C 1-6 Alkyl, C 2-8 alkenyl, halogenated C 1-6 Substitution of alkoxy, 3-8 membered cycloalkyl, 3-8 membered heterocyclic, and 3-8 membered cycloalkenyl groups;

[0122] Z1 and Z2 may be the same or different, and are independently selected from C(R). a3 (R) a3 ), O, N (R) a3 ), S, Si(R) a3 (R) a3 );

[0123] Cy2 is selected from 3-8 membered cycloalkyl, 3-8 membered heterocyclic, 3-8 membered cycloalkenyl, 6-13 bicyclic fused-ring cycloalkyl, 6-13 membered bicyclic fused-ring alkenyl, 6-13 membered bicyclic fused-ring heterocyclic, and is surrounded by 1-3 R groups. a4 Substituted 3-8 membered cycloalkyl groups, with 1-3 R groups a4 The substituted 3-8 membered heterocyclic group is replaced by 1-3 R a4 Substituted 3-8 membered cycloalkenyl groups, with 1-3 R groups a4 Substituted 6-13 bicyclic fused-ring alkyl groups, with 1-3 R a4 The substituted 6-13 membered bicyclic fused-ring alkenyl group, with 1-3 R groups a4 The 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;

[0124] Each R a3 R a4 Each group is independently selected from hydrogen, deuterium, halogen, hydroxyl, mercapto, silanol, selenol, carboxyl, amino, cyano, nitro, and 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)2-amino, C 2-8 alkenyl, C 2-8 alkynyl group, C 1-6 Alkyl carbonyl, amino carbonyl, C 1-6 Alkylamine carbonyl, (C 1-6 Alkyl)2-aminocarbonyl, 3-8-membered cycloalkyl, 3-8-membered heterocyclic, 3-8-membered cycloalkenyl, wherein 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, C 2-8 alkenyl, C 2-8 alkynyl group, C 1-6 Alkyl carbonyl, amino carbonyl, C 1-6 Alkylamine carbonyl, (C 1-6Alkyl) 2-aminocarbonyl, 3-8 membered cycloalkyl, 3-8 membered heterocyclic, 3-8 membered cycloalkenyl are unsubstituted or optionally substituted by one or more groups selected from 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)2-amino, C 1-6 Alkyl carbonyl amino, C 1-6 Alkylsulfonamide, C 1-6 Alkylcarbonyl group, C 3-6 cycloalkyl, C 3-6 Cycloalkylcarbonyloxy, C 2-8 alkynyl, halogenated C 1-6 Alkyl, C 2-8 alkenyl, halogenated C 1-6 Substitution of alkoxy, 3-8 membered cycloalkyl, 3-8 membered heterocyclic, and 3-8 membered cycloalkenyl groups;

[0125] X1 is N or CR b1 ;

[0126] X2 is N or CR b2 ;

[0127] X3 is N or CR b3 ;

[0128] X4 is N or CR b4 ;

[0129] R b1 R b2 R b3 and R b4 Each group is independently selected from hydrogen, halogen, hydroxyl, carboxyl, amino, cyano, nitro, and 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, C 2-8 alkenyl, C 2-8 alkynyl group, C 1-6 Alkyl carbonyl, amino carbonyl, C 1-6 Alkylamine carbonyl, (C 1-6 alkyl)2-aminocarbonyl;

[0130] Z4 consists of C(Rc)(Rc), O, and S;

[0131] Each Rc is 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)2-amino, C 2-8 alkenyl, C 2-8 alkynyl group, C 1-6 Alkyl carbonyl, amino carbonyl, C 1-6 Alkylamine carbonyl, (C 1-6 alkyl)2-aminocarbonyl;

[0132] R is selected from hydrogen, 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)2-amino, C 2-8 alkenyl, C 2-8 alkynyl group, C 1-6 Alkyl carbonyl, amino carbonyl, C 1-6 Alkylamine carbonyl, (C 1-6 Alkyl) 2-aminocarbonyl, 3-8 membered cycloalkyl, 3-8 membered heterocyclic, 3-8 membered cycloalkenyl, C 6-10 aryl or 5-10 heteroaryl; preferably, R is selected from hydrogen, C 1-6 Alkyl, C 6-10 Aryl or 5-10 heteroaryl; more preferably, R is selected from hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, phenyl, pyridyl.

[0133] Another embodiment of the present invention relates to a compound of formula (I), an isomer thereof, or a pharmaceutically acceptable salt thereof, having the structure shown in formula (I-1):

[0134] Where X is selected from N or CH; R a1 Selected from halogens, C 1-6 Alkyl, C 1-6 Alkoxy;

[0135] Preferably, R a1 Selected from F, methyl, ethyl, and methoxy;

[0136] Preferably, R a2 Selected from H, OH, amino, mercapto, silanol, selenol, halogen, C1-6 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; more 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-; most preferably, R a2 Selected from H, F, OH, amino, methylamino, acetamido, methyl, methoxy, and cyclopropyl;

[0137] Z3 is selected from CH or N;

[0138] Z4 is selected from CH2 or O;

[0139] R is selected from hydrogen, halogen, hydroxyl, carboxyl, amino, cyano, nitro, C 1-6 Alkyl, C 6-10 Aryl or 5-10 heteroaryl; more preferably, R is selected from hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, phenyl, pyridyl;

[0140] The condition is that when Z4 is selected from CH2, R is not a phenyl group.

[0141] In some embodiments of the present invention, the compounds of formula (I) described above, their isomers or pharmaceutically acceptable salts thereof are selected from the compounds shown in the table below:

[0142] The present invention also provides a pharmaceutical composition comprising a compound of formula (I), an isomer thereof or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

[0143] The present invention also provides the use of the compound of formula (I), its isomers or pharmaceutically acceptable salts thereof, or the pharmaceutical composition thereof in the preparation of a medicament for treating and / or preventing a disease or condition by degrading a target protein.

[0144] According to an embodiment of the present invention, the disease or symptom is selected from abnormal cell proliferation, tumors, immune diseases, diabetes, cardiovascular diseases, infectious diseases, and inflammatory diseases; preferably tumors and infectious diseases.

[0145] According to embodiments 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 tumors, 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, ductoblastoma, pineal cell tumor, meningioma, neurofibroma, schwannoma, 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 tumors.

[0146] According to embodiments of the present invention, the infectious disease is selected from viral pneumonia, influenza, avian influenza, meningitis, gonorrhea, or diseases caused by HIV, HBV, HCV, HSV, HPV, RSV, CMV, Ebola virus, flavivirus, stoma virus, rotavirus, coronavirus, EBV, drug-resistant virus, RNA virus, DNA virus, adenovirus, poxvirus, microRNA virus, capsular virus, orthomyxovirus, retrovirus, hepatotropic DNA virus, Gram-negative bacteria, Gram-positive bacteria, atypical bacteria, Staphylococcus, Streptococcus, Escherichia coli, Salmonella, Helicobacter pylori, Chlamydia, Mycoplasma, fungi, protozoa, intestinal worms, worms, prions, or parasites.

[0147] The present invention also provides the use of the compound of formula (I), its isomers or pharmaceutically acceptable salts thereof, or the 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 diseases or conditions are tumors, preferably cancers, 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.

[0148] The present invention also provides a method for treating and / or preventing diseases or conditions by degrading target proteins, comprising administering to a patient a therapeutically effective amount of the compound of formula (I), its isomers, or a pharmaceutically acceptable salt thereof.

[0149] 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 the compound of formula (I), its isomers, or a pharmaceutically acceptable salt thereof. Beneficial effects

[0150] The present invention provides a compound of formula (I), an isomer thereof or a pharmaceutically acceptable salt thereof, which can be used as an estrogen receptor degrader for the preparation of a medicament for the treatment and / or prevention of estrogen receptor-mediated or dependent diseases or conditions. Attached Figure Description

[0151] Figure 1 shows the degradation effect of compound 13 on ER protein in MCF-7 cells.

[0152] Figure 2 shows the degradation effect of compound 14 on ER protein in MCF-7 cells.

[0153] Terminology Definitions and Explanations

[0154] Unless otherwise stated, the definitions of groups and terms recorded in this application specification and claims, including definitions as examples, exemplary definitions, preferred definitions, definitions recorded in tables, and definitions of specific compounds in the examples, can be arbitrarily combined and combined with each other. Such combinations and combinations of group definitions and compound structures should be understood as being within the scope of this application specification and / or claims.

[0155] The "halogen" mentioned in this invention refers to fluorine, chlorine, bromine, iodine, etc., with fluorine and chlorine being preferred.

[0156] In this invention, "halogenation" refers to the substitution of any hydrogen atom in a substituent by one or more identical or different halogen atoms. "Halogen" is as defined above.

[0157] The "C" described in this invention 1-6 "Alkyl" refers to a straight-chain or branched alkyl group derived from a hydrocarbon moiety containing 1-6 carbon atoms by removing one 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, etc. 1-6 "alkyl" is preferably C 1-4 Alkyl, C 1-3 alkyl.

[0158] The "C" described in this invention 2-8"Alkenyl" refers to a straight-chain, branched, or cyclic olefinic group derived from the removal of one hydrogen atom from an olefinic moiety containing 2 to 8 carbon atoms with a carbon-carbon double bond, such as vinyl, 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.

[0159] The "C" described in this invention 2-8 "Alkyne" refers to a straight-chain or branched alkyne group derived from the removal of a hydrogen atom from a carbon-carbon triple bond (2-8 carbon atoms), such as ethynyl, propynyl, 2-butynyl, 2-pentynyl, 3-pentynyl, 4-methyl-2-pentynyl, 2-hexynyl, 3-hexynyl, etc. The "C" in the original text is missing. 2-8 "Alkyne group" is preferably C 2-4 alkynyl group, C 2-3 Alkyne group.

[0160] The "C" described in this invention 1-6 "Alkoxy" refers to the "C" defined above. 1-6 An alkyl group is a group that is attached to the parent molecule by an oxygen atom, i.e., a C18 group. 1-6 Alkyl-O- groups, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, n-pentoxy, neopentoxy, and n-hexyloxy. The "C" group... 1-6 "Alkoxy" is preferably C 1-4 Alkoxy, C 1-3 Alkyl group.

[0161] The "C" described in this invention 1-6 Alkylamino, (C 1-6 Alkyl)2-amino", C 1-6 Alkyl carbonyl amino, C 1-6 Alkylsulfonamide, C 1-6 Alkylaminocarbonyl", (C 1-6 Alkyl)2-amino-carbonyl", C 1-6 "alkoxy-carbonyl", "C" 1-6 alkylsulfonyl, C 1-6 Alkyl thioyl", C 1-6 Alkyl carbonyl, amino carbonyl, 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 1-6Alkyl)(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" as defined above, preferably "C" 1-4 Alkyl, C 1-3 alkyl".

[0162] The aryl group described in this invention refers to a group derived from an aromatic monocyclic or aromatic polycyclic hydrocarbon ring system by removing a hydrogen atom from a ring carbon atom. An aromatic monocyclic or aromatic polycyclic hydrocarbon ring system contains only hydrogen and carbon, and consists of five to eighteen carbon atoms, wherein at least one ring in the ring system is aromatic, i.e., it contains a cyclic delocalized (4n+2)π electron system conforming to Hückel's theory. Ring systems derived from aryl groups include, but are not limited to, groups such as benzene, fluorene, indene, tetrahydronaphthalene, and naphthalene. The aryl group may optionally be substituted with one or more substituents such as those described herein.

[0163] The heteroaryl group described in this 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. Monoheteroaryl groups can be 5-7 membered heteroaryl groups or 5-6 membered heteroaryl groups, examples of which include, but are not limited to, furanyl, imidazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, oxazolyl, pyridinyl, pyrazinyl, pyrazinyl, pyrrolyl, tetrazolyl, thiadiazolyl, thiophenyl, triazolyl, and triazinyl.

[0164] The cycloalkyl group described in this invention refers to a non-aromatic cyclic hydrocarbon moiety that optionally contains one or more alkenyl groups as part of a ring structure. The cycloalkyl group can comprise a monocyclic or polycyclic (e.g., having 2, 3, or 4 fused, spiro, or bridged rings) ring system. The definition of cycloalkyl also includes a moiety having one or more aromatic rings fused to a cycloalkyl ring (i.e., sharing a bond with the cycloalkyl ring), such as benzo[a] derivatives of cyclopentane, cyclopentene, cyclohexane, etc. One or more cyclic carbon atoms of the cycloalkyl group can be oxidized to form a carbonyl bond. In some embodiments, the cycloalkyl group is a 3-7 membered cycloalkyl group, which is monocyclic or bicyclic. In some embodiments, the cycloalkyl group is a 3-6 or 3-7 membered monocyclic cycloalkyl group. Exemplary cycloalkyl groups include 1,2,3,4-tetrahydro-naphthalene, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cyclohepttrienyl, norbornyl, norpineyl, norcareyl, adamantyl, etc. In some embodiments, the cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0165] The cycloalkenyl group described in this invention refers to a stable, unsaturated, non-aromatic monocyclic or polycyclic hydrocarbon group consisting only of carbon and hydrogen atoms, such as cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl.

[0166] The heterocyclic group described in this invention refers to a non-aromatic ring system that optionally contains one or more alkenyl or alkyneyl groups as part of a ring structure, and has at least one heteroatom ring member independently selected from nitrogen, sulfur, and oxygen. When a heterocyclic alkyl group contains more than one heteroatom, the heteroatoms may be the same or different. Heterocyclic alkyl groups may include monocyclic or polycyclic (e.g., having 2, 3, or 4 fused, spirocyclic, or bridged rings) ring systems. The definition of heterocyclic alkyl groups also includes portions having one or more aromatic rings fused with non-aromatic rings (i.e., sharing a bond with a non-aromatic ring), such as 1,2,3,4-tetrahydro-quinoline, etc. The carbon atoms or heteroatoms in one or more rings of a heterocyclic alkyl group may be oxidized to form a carbonyl or sulfonyl group (or other oxidized bond), or the nitrogen atom may be quaternized. In some embodiments, a heterocyclic alkyl group is a monocyclic 4-7 membered heterocyclic alkyl group containing 2-6 carbon atoms and 1, 2, 3, or 4 heteroatom ring members independently selected from nitrogen, sulfur, and oxygen. Examples of heterocyclic alkyl groups include aziridine, aziridine, pyrrolidine, piperidine, morpholine, thiomorpholine, pyran, and 2-oxo-1,3-oxazolidine ring.

[0167] The bicyclic fused alkyl group described in this invention includes fused cycloalkyl, bridged cycloalkyl, and spirocycloalkyl groups. It may be saturated, partially saturated, or unsaturated, but not aromatic. Representative examples of fused cycloalkyl groups 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. Examples of spirocyclic groups include, but are not limited to: The bridge ring base examples include, but are not limited to:

[0168] The bicyclic fused-ring alkenyl groups described in this invention include fused-ring alkenyl, bridged-ring alkenyl, and spirocyclic alkenyl groups, with representative examples including but not limited to...

[0169] The bicyclic fused heterocyclic group described in this invention includes fused heterocyclic groups, spirocyclic groups, and bridged heterocyclic groups, which can be saturated, partially saturated, or unsaturated, but are not aromatic. The fused heterocyclic group is a 5-6 member monocyclic heterocyclic group fused to a benzene ring, a 5-6 member monocyclic cycloalkyl group, a 5-6 member monocyclic cycloalkenyl group, a 5-6 member monocyclic heterocyclic group, or a 5-6 member monocyclic heteroaryl group. The fused heterocyclic group can be a 6-12 member fused cycloyl group, a 7-10 member fused cycloyl group, a 6-10 member fused cycloyl group, an 8-10 member bicyclic fused heterocyclic group, or a 6-12 member saturated fused cycloyl group. Representative examples include, but are not limited to: 3-azabicyclo[3.1.0]hexyl, 3,6-diazabicyclo[3.2.0]heptyl, 3,8-diazabicyclo[4.2.0]octyl, 3,7-diazabicyclo[4.2.0]octyl, octahydropyrrolo[...]. [3,4-c]pyrroloyl, octahydropyrrolo[3,4-b]pyrroloyl, octahydropyrrolo[3,4-b][1,4]oxazinyl, octahydro-1H-pyrrolo[3,4-c]pyridyl, 2,3-dihydrobenzofuran-2-yl, 2,3-dihydrobenzofuran-3-yl, dihydroindol-1-yl, dihydroindol-2-yl, dihydroindol-3-yl, 2,3-dihydrobenzothiophene-2-yl, octahydro-1H-indolyl, octahydrobenzofuranyl. The spiroheterocyclic group can be a 6-12 membered spiroheterocyclic group, a 7-11 membered spiroheterocyclic group, a 6-12 membered saturated spirocyclic group, or a 10-11 membered bicyclic spiroheterocyclic group, examples of which include, but are not limited to:

[0170] The bridged heterocyclic group described in this invention can be a 6-12 member bridged heterocyclic group, a 7-11 member bridged heterocyclic group, or a 6-12 member saturated bridged heterocyclic group, examples of which include, but are not limited to:

[0171] The "pharmaceutically acceptable salt" described in this invention refers to pharmaceutically acceptable addition salts of acids and bases or their solvates. Those skilled in the art are familiar with a variety of non-toxic, pharmaceutically acceptable addition salts.

[0172] The term "isomer" in this invention refers to stereoisomers and tautomers.

[0173] Stereoisomers refer to the enantiomers produced when a compound has asymmetric atoms; cis-trans isomers produced when a compound has double bonds or cyclic structures; enantiomers, diastereomers, racemic isomers, cis-trans isomers, geometric isomers, epimers and mixtures thereof of all compounds of formula (I) are included in the scope of this invention.

[0174] "Tautomerism" refers to functional group isomers that occur when an atom in a molecule rapidly moves between two positions. Tautomerism is a special type of functional group isomer. Examples include the tautomerism of carbonyl compounds containing α-H groups. Other proton migration tautomers include phenol-ketone tautomers, nitroso-oxime tautomers, and imine-enamine tautomers.

[0175] T, T1, and T2 are each an independent group that conforms to the bonding rules of compounds.

[0176] The term "pharmaceuticalally acceptable excipient" or "pharmaceuticalally acceptable carrier" as used in this invention refers to pharmaceutically acceptable materials, compositions, or media, such as liquid or solid fillers, diluents, excipients, solvents, or encapsulating materials. Each carrier must be "acceptable" in the sense that it is compatible with other components of the formulation and is harmless to the patient. Detailed Implementation

[0177] The technical solutions of this 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 explanatory of this disclosure and should not be construed as limiting the scope of protection of this disclosure. All technologies implemented based on the above content of this disclosure are covered within the scope of protection intended by this disclosure.

[0178] Unless otherwise stated, the raw materials and reagents used in the following examples are commercially available products or can be prepared by known methods.

[0179] The individual compounds contained in formula (I) of this invention have similar structures, and their synthetic methods or mechanisms are similar. For ease of understanding by those skilled in the art, taking compound (I-1) as an example, its general synthetic method is as follows:

[0180] Step 1: Using aldehyde compound int-1 and amino compound int-2 as starting materials, the intermediate int-3 is obtained by reductive amination.

[0181] Step 2: The intermediate int-3 is then hydrogenated and reduced to obtain the final product I-1.

[0182] Compound int-1 can be prepared using the following example method:

[0183] Wherein, P1 is a hydroxyl protecting group, such as benzyl; P2 is an amino protecting group, such as Boc group, Fmoc group, etc.; Hal is a halogen.

[0184] Compound int-2 can be purchased directly or prepared using existing techniques such as those disclosed in WO2023250029A1.

[0185] Example 1: Synthesis of 1-(5-fluoro-6-(4-hydroxy-1-((1R,2R)-2-((4-(4-(7-hydroxy-3-benzodihydropyran-4-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (Compound 13)

[0186] Step 1: Synthesis of (Z)-N'-(7-(benzyloxy)benzodihydropyran-4-ylidene)-4-methylbenzenesulfonylhydrazine

[0187] At room temperature, methanol (0.7 L), 6-benzyloxy-1-naphthone (70.00 g) and p-toluenesulfonyl hydrazine (51.70 g) were added sequentially to a 20 L reactor. The mixture was stirred overnight at room temperature and filtered to obtain 110 g of white product, with a yield of 94%.

[0188] Step 2: Synthesis of tert-butyl 4-(4-(7-(benzyloxy)-2H-benzopyran-4-yl)phenyl)piperazine-1-carboxylate

[0189] At room temperature, dioxane, (Z)-N'-(7-(benzyloxy)benzopyran-4-ylidene)-4-methylbenzenesulfonylhydrazine (100 g), 4-(4-bromophenyl)piperazine-1-carboxylic acid tert-butyl ester (85 g), Pd2(dba)3 (2.30 g), X-Phos (1.20 g), and lithium tert-butoxide (59.80 g) were added sequentially to the reactor. After purging with nitrogen three times, the reaction was terminated at 100°C for 12 h under a nitrogen atmosphere. The mixture was cooled to room temperature, and water (1 L) and EA (1 L) were added. The mixture was separated, and the aqueous phase was extracted once with EA. The organic phases were combined, washed once with sodium chloride aqueous solution, and the organic phase was evaporated to dryness. The crude product was directly used for the next step.

[0190] Step 3: Synthesis of tert-butyl 4-(4-(7-(benzyloxy)-3-bromo-2H-benzopyran-4-yl)phenyl)piperazine-1-carboxylate

[0191] At room temperature, 11.81 g of tert-butyl 4-(4-(7-(benzyloxy)-2H-benzopyran-4-yl)phenyl)piperazine-1-carboxylate, 3.61 g of triethylamine, and 0.1 L of DCM obtained in step 2 were added sequentially to a reaction vessel. Pyridinium tribromide (8.37 g) was added in portions at 0 °C. After the addition was complete, the reaction was terminated at room temperature for 2 h. A 10% sodium bisulfite solution (1 L) was added to the reaction solution to quench the reaction. The mixture was separated, and the aqueous phase was extracted once with DCM. The combined organic phases were washed once with water, dissolved, and then distilled with methanol. The mixture was filtered to obtain 12.0 g of a pale yellow solid product, with a two-step yield of 88%.

[0192] Step 4: Synthesis of tert-butyl 4-(4-(7-(benzyloxy)-3-phenyl-2H-benzopyran-4-yl)phenyl)piperazine-1-carboxylate

[0193] At room temperature, dioxane (0.1 L), water (10 mL), tert-butyl 4-(4-(7-(benzyloxy)-3-bromo-2H-benzopyran-4-yl)phenyl)piperazine-1-carboxylate (12.00 g), phenylboronic acid (2.67 g), Pd(dppf)Cl2 (1.50 g), and Na2CO3 (6.63 g) were added sequentially to a 20 L reactor. The reaction was terminated at 100 °C for 8 h under nitrogen protection. EA (1 L) and water (1 L) were added to the system, and the mixture was separated. The aqueous phase was extracted once with EA (1 L), and the organic phases were combined, washed once with water, and dissolved. Methanol was added and evaporated, and the mixture was filtered to obtain 10.50 g of a pale yellow solid, with a yield of 88%.

[0194] Step 5: Synthesis of tert-butyl 4-(4-(7-hydroxy-3-benzodihydropyran-4-yl)phenyl)piperazine-1-carboxylate

[0195] At room temperature, 10.50 g of 4-(4-(7-(benzyloxy)-3-phenyl-2H-benzopyran-4-yl)phenyl)piperazine-1-carboxylic acid tert-butyl ester, 200 mL of MeOH, 200 mL of THF, and 1.05 g of Pd(OH)₂ / C were added sequentially to a 1 L autoclave. The hydrogen pressure was maintained above 3.0 MPa, and the reaction was terminated at 40 °C for 2 days. The Pd(OH)₂ / C was filtered and concentrated to give 8.0 g of a white solid, with a yield of 90%.

[0196] Step 6: Synthesis of tert-butyl 4-(4-(7-(benzyloxy)-3-benzodihydropyran-4-yl)phenyl)piperazine-1-carboxylate

[0197] At room temperature, tert-butyl 4-(4-(7-hydroxy-3-benzopyran-4-yl)phenyl)piperazine-1-carboxylate (8.00 g), potassium carbonate (3.42 g), and acetonitrile (100 mL) were added sequentially to a reaction flask, followed by the dropwise addition of BnBr (3.25 g). The reaction was carried out at 60 °C for 18 h. After cooling to room temperature, the reaction solution was added to water, crystallized, and filtered. The filter cake was slurried with methanol and filtered to obtain 9.01 g of product, with a yield of 95%.

[0198] Step 7: Synthesis of 1-(4-(7-(benzyloxy)-3-benzodihydropyran-4-yl)phenyl)piperazine hydrochloride

[0199] At room temperature, 1 L of HCl ethyl acetate solution and 9.0 g of 4-(4-(7-(benzyloxy)-3-benzopyran-4-yl)phenyl)piperazine-1-carboxylic acid tert-butyl ester were added sequentially to a reaction flask, and the reaction was carried out at room temperature for 2 h. After the reaction was completed, the mixture was filtered to give 8.0 g of the product, with a yield of 100%.

[0200] Step 8: Synthesis of 1-(4-(7-(benzyloxy)-3-phenylbenzodihydropyran-4-yl)phenyl)-4-(((1R,2R)-2-(((tert-butyldiphenylsilyl)oxy)methyl)cyclohexyl)methyl)piperazine

[0201] At room temperature, 1-(4-(7-(benzyloxy)-3-benzopyran-4-yl)phenyl)piperazine hydrochloride (8.00 g), (1R,2R)-2-(((tert-butyldiphenylsilyl)oxy)methyl)cyclohexane-1-carboxaldehyde (7.74 g), and dichloromethane (200 mL) were added sequentially to a reaction flask. Tetraisopropyl titanate (TIPT) (5 mL) was added, and the mixture was stirred at room temperature for 16 hours. Then, sodium triacetoxyborohydride (4.96 g) was added, and the reaction was stirred at room temperature for 2 hours. After the reaction was complete, dichloromethane was added for dilution, followed by the addition of diatomaceous earth. After thorough mixing, 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, dissolved, and slurried with methanol to obtain 11.84 g of the product, with a yield of 90%.

[0202] Step 9: Synthesis of ((1R,2R)-2-((4-(4-(7-(benzyloxy)-3-benzodihydropyran-4-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methanol

[0203] At room temperature, 1-(4-(7-(benzyloxy)-3-phenylbenzopyran-4-yl)phenyl)-4-(((1R,2R)-2-(((tert-butyldiphenylsilyl)oxy)methyl)cyclohexyl)methyl)piperazine (8.22 g), TBAF (2.55 g), and tetrahydrofuran (100 mL) were added sequentially to a reaction flask, and the mixture was stirred at 50 °C for 4 h. After the reaction was complete, the mixture was evaporated to dryness, and dichloromethane and water were added to form a lye. The organic phase was dried and evaporated to dryness, and methanol was added to form a slurry to give 5.00 g of the product, with a yield of 85%.

[0204] Step 10: Synthesis of (1R,2R)-2-((4-(4-(7-(benzyloxy)-3-benzodihydropyran-4-yl)phenyl)piperazin-1-yl)methyl)cyclohexane-1-carboxaldehyde

[0205] At room temperature, ((1R,2R)-2-((4-(4-(7-(benzyloxy)-3-benzopyran-4-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methanol (5.00 g) was added sequentially to the reaction flask. Molecular sieve (5 g, 100% w / w), N-methylmorpholine oxide (NMO) (1.46 g), and DCM (50 mL) were added, followed by tetrapropylammonium perruthenate (TPAP) (0.29 g). The mixture was reacted at room temperature for 12 h. After the reaction was complete, the mixture was filtered, diluted with water, dried to dryness, and subjected to column chromatography (MeOH / DCM system) to give 4.44 g of the product, with a yield of 89%.

[0206] Step 11: 1-(6-(1-(((1R,2R)-2-((4-(4-(7-(benzyloxy)-3-benzodihydropyran-4-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

[0207] 1-(5-fluoro-6-(4-hydroxypiperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione hydrochloride (2.60 g) and (1R,2R)-2-((4-(4-(7-(benzyloxy)-3-benzopyran-4-yl)phenyl)piperazin-1-yl)methyl)cyclohexane-1-carboxaldehyde (4.30 g) were placed in 150 mL of dichloromethane, and 10 mL of tetraisopropyl titanate (TIPT) was added. The reaction was carried out at room temperature for 16 hours, and sodium triacetoxyborohydride (STAB) (2.30 g) was added to continue the reaction for 1 hour. The reaction was stopped by TLC and LC-MS. The reaction was quenched with 3 mL of water, and then 3 mL of ammonia was added. The mixture was stirred for 20 min, filtered, and the filtrate was concentrated to prepare slurry. Column chromatography (DCM / MeOH) yielded 2.60 g of a white solid product.

[0208] Step 12: 1-(5-fluoro-6-(4-hydroxy-1-((1R,2R)-2-((4-(4-(7-hydroxy-3-benzodihydropyran-4-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)piperidin-4-yl)-1-methyl-1H-indazole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (Compound 13)

[0209] 0.26 g of 1-(6-(1-(((1R,2R)-2-((4-(4-(7-(benzyloxy)-3-benzopyran-4-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 was placed in 30 mL of tetrahydrofuran, and 1.0 g of 5% Pd / C was added. The mixture was purged with hydrogen and reacted at room temperature for 16 hours. The reaction was detected by TLC and LC-MS to indicate the end of the reaction. The reaction solution was filtered, the filtrate was concentrated and prepared into sand, and column chromatography (DCM / MeOH) was performed to obtain 0.15 g of the final product.

[0210] 1 H NMR (400MHz, DMSO-d6) δ10.58(s,1H),9.35(d,J=3.9Hz,1H),7.78(dd,J=6.4,3.2Hz,1H),7.43(d,J=12.7Hz,1H),7.12(dd, J=6.6,3.1Hz,3H),6.81–6.69(m,2H),6.65(dd,J=8.1,3.5Hz,3H),6.42(d,J=8.0Hz,2H),6.35–6.24(m,2H),5.95(s,1H),4. 32(t,J=11.4Hz,1H),4.20(d,J=6.1Hz,2H),3.99(d,J=6.4Hz,3H),3.92(t,J=6.7Hz,2H),3.20–3.05(m,7H),2.98–2.57(m,9 H),2.29–2.17(m,1H),1.91–1.54(m,9H),1.33–1.16(m,4H),1.11–0.96(m,2H),0.92–0.80(m,1H).MS(ESI)m / z:856.9[M+H] + .

[0211] Example 2: Synthesis of 1-(5-fluoro-6-(4-hydroxy-1-(((1R,2R)-2-((4-(4-(6-hydroxy-2-isobutyl-1,2,3,4-tetrahydronaphthyl-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 14)

[0212] Step 1: 4-(4-(6-benzyloxy)-2-(2-methylprop-1-en-1-yl)-3,4-dihydronaphth-1-yl)phenyl)piperazine-1-carboxylic acid tert-butyl ester

[0213] At room temperature, tert-butyl 4-(4-(6-(benzyloxy)-2-bromo-3,4-dihydronaphthyl)phenyl)piperazine-1-carboxylic acid tert-butyl ester (1.50 g), 4,4,5,5-tetramethyl-2-(2-methylprop-1-en-1-yl)-1,3,2-dioxoborane (0.52 g), potassium carbonate (1.08 g), dioxane / H2O (0.015 L / 1.5 mL), and Pd(dppf)Cl2 (0.019 g) were added sequentially to a reaction flask. The reaction was carried out at 100 °C for 5 h under nitrogen protection, and the reaction was confirmed to be complete by LC-MS. Water and 10 mL of EA were added, and the organic phase was desolvated. Column chromatography (PE / EA system) was performed to obtain 1.25 g of a yellow oil.

[0214] Step 2: 4-(4-(6-hydroxy-2-isobutyl-1,2,3,4-tetrahydronaphthyl-1-yl)phenyl)piperazine-1-carboxylic acid tert-butyl ester

[0215] At room temperature, 0.50 g of 4-(4-(6-benzyloxy)-2-(2-methylprop-1-en-1-yl)-3,4-dihydronaphthyl-1-yl)phenyl)piperazine-1-carboxylic acid tert-butyl ester, 1 g of Pd / C, and 3 mL / 3 mL of THF / MeOH were added sequentially to an autoclave. The reaction was carried out at 55 °C under a hydrogen atmosphere for 48 h. LC-MS analysis confirmed that the reaction was complete. The mixture was filtered through a diatomaceous earth liner, and the filtrate was evaporated to dryness to obtain 0.45 g of the product.

[0216] Step 3: 4-(4-(6-(benzyloxy)-2-isobutyl-1,2,3,4-tetrahydronaphthyl-1-yl)phenyl)piperazine-1-carboxylic acid tert-butyl ester

[0217] At room temperature, 0.45 g of 4-(4-(6-hydroxy-2-isobutyl-1,2,3,4-tetrahydronaphthyl-1-yl)phenyl)piperazine-1-carboxylic acid tert-butyl ester, 0.21 g of potassium carbonate, and 5 mL of acetonitrile were added sequentially to a reaction flask, followed by the dropwise addition of BnBr (0.205 g). The reaction was carried out at 60 °C for 18 h. LC-MS analysis confirmed that the reaction was complete. The mixture was cooled to room temperature, and 5 mL of water and 5 mL of EA were added. The mixture was separated, and the organic phase was desolvated to obtain 0.469 g of a yellow oily product.

[0218] Step 4: Synthesis of 1-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphth-1-yl)phenyl)piperazine hydrochloride

[0219] At room temperature, 2 mL of HCl dioxane solution, 2 mL of DCM, and 0.469 g of 4-(4-(6-(benzyloxy)-2-isobutyl-1,2,3,4-tetrahydronaphthyl-1-yl)phenyl)piperazine-1-carboxylic acid tert-butyl ester were added sequentially to a reaction flask, and the reaction was carried out at room temperature for 2 h. LC-MS analysis showed that the reaction was complete, and the product was obtained after solvent removal, yielding 0.42 g of product.

[0220] Step 5: 1-(4-(6-(benzyloxy)-2-isobutyl-1,2,3,4-tetrahydronaphth-1-yl)phenyl)-4-(((1R,2R)-2-(((tert-butyl-diphenylsilyl)oxy)methyl)cyclohexyl)methyl)piperazine

[0221] At room temperature, 1-(4-((1R,2S)-6-(benzyloxy)-2-phenyl-1,2,3,4-tetrahydronaphth-1-yl)phenyl)piperazine hydrochloride (0.42 g), (1R,2R)-2-(((tert-butyldiphenylsilyl)oxy)methyl)cyclohexane-1-carboxaldehyde (0.761 g), and dichloromethane (5 mL) were added sequentially to a reaction flask. The mixture was stirred at room temperature for 2 hours, followed by the addition of sodium triacetoxyborohydride (0.34 g), and the reaction was allowed to proceed for 17 hours at room temperature. LC-MS analysis confirmed the reaction was complete. The reaction was quenched by adding 2 mL of saturated sodium carbonate solution, stirred for 10 minutes, and separated. The aqueous phase was extracted once with dichloromethane. The organic phases were combined, dissolved, and subjected to column chromatography (PE / EA system) to obtain 0.52 g of a yellow oily product.

[0222] Step 6: ((1R,2R)-2-((4-(4-(6-(benzyloxy)-2-isobutyl-1,2,3,4-tetrahydronaphthyl-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methanol

[0223] At room temperature, 1-(4-(6-(benzyloxy)-2-isobutyl-1,2,3,4-tetrahydronaphth-1-yl)phenyl)-4-(((1R,2R)-2-(((tert-butyl-diphenylsilyl)oxy)methyl)cyclohexyl)methyl)piperazine (0.52 g), tetrabutylammonium fluoride (TBAF) (0.31 g), and tetrahydrofuran (6 mL) were added sequentially to a reaction flask, and the reaction was carried out at 50 °C for 6 h. LC-MS was used to confirm the complete reaction of the starting materials. After solvent removal, column chromatography (PE / EA system) was performed to give 0.30 g of the product, a yellow oily substance.

[0224] Step 7: (1R, 2R)-2-((4-(4-(6-(benzyloxy)-2-isobutyl-1,2,3,4-tetrahydronaphthyl-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexane-1-aminocarboxaldehyde

[0225] At room temperature, ((1R,2R)-2-((4-(4-(6-(benzyloxy)-2-isobutyl-1,2,3,4-tetrahydronaphthyl-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methanol (0.30 g) was added sequentially to the reaction flask. Molecular sieve (0.3 g, 100% w / w), N-methylmorpholine oxide (NMO) (0.094 g) and DCM (3 mL) were added, followed by tetrapropylammonium perruthenate (TPAP) (0.034 g). The reaction was carried out at room temperature for 2 h. The reaction was confirmed to be complete by LC-MS. The mixture was filtered, the filtrate was desolventized, and column chromatography (PE / EA system) was performed to obtain 0.27 g of a yellow oily product.

[0226] Step 8: 1-(6-(1-(((1R,2R)-2-((4-(4-(6-(benzyloxy)-2-isobutyl-1,2,3,4-tetrahydronaphthyl-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

[0227] At room temperature, (1R,2R)-2-((4-(4-(6-(benzyloxy)-2-isobutyl-1,2,3,4-tetrahydronaphthyl-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexane-1-aminocarboxaldehyde (0.27 g), 1-(5-fluoro-6-(4-hydroxypiperidin-4-yl)-1-methyl-1H-indoleazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione-methane (1 / 1) hydrochloride (0.20 g) and DCM (9 mL) were added sequentially to the reaction flask, followed by tetraisopropyl titanate (TIPT) (1.35 mL), and the reaction was carried out at room temperature for 17 h. The next day, sodium triacetoxyborohydride (0.197 g) was added, and the reaction was carried out at room temperature for 1 h. The reaction of the raw materials was detected by LC-MS and the reaction was complete. 1 mL of water was added to quench the reaction, and a large amount of solid precipitated out. The mixture was filtered through diatomaceous earth, the filtrate was desolventized, and column chromatography (DCM / MeOH system) was performed to obtain 0.295 g of brown solid product.

[0228] Step 9: 1-(5-fluoro-6-(4-hydroxy-1-(((1R,2R)-2-((4-(4-(6-hydroxy-2-isobutyl-1,2,3,4-tetrahydronaphthyl-1-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)piperidin-4-yl)-1-methyl-1H-indazole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (Compound 14)

[0229] At room temperature, 0.295 g of 1-(6-(1-(((1R,2R)-2-((4-(4-(6-(benzyloxy)-2-isobutyl-1,2,3,4-tetrahydronaphthyl-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, 0.06 g of Pd / C (20% w / w), 5 mL of THF, and 0.5 mL of ethanol were added to an autoclave. The reaction was carried out at room temperature for 16 h under a hydrogen atmosphere. The reaction was confirmed to be complete by LC-MS. The mixture was filtered, the filtrate was desolventized, and column chromatography (DCM / MeOH system) was performed to give 0.145 g of the final product. 1H NMR (400MHz, DMSO-d6) δ10.57(s,1H),8.22(s,2H),7.77(d,J=6.4Hz,1H),7. 38(d,J=12.6Hz,1H),6.77(s,4H),6.60(d,J=8.3Hz,1H),6.52(d,J=2.5Hz,1H ),6.42(dd,J=8.3,2.4Hz,1H),3.91(m,6H),3.08(m,4H),2.87–2.67(m,7H), 2.38–2.10(m,6H),1.97–1.40(m,14H),1.27–0.93(m,6H),0.86–0.50(m,9H). MS(ESI) m / z: 834.7 [M+H] + .

[0230] Example 3: Synthesis of 1-(6-(1-((1R,2R)-2-((4-(3-(2,6-difluorophenyl)-7-hydroxy-2H-chromen-4-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)-4-hydroxypiperidin-4-yl)-5-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (Compound 35)

[0231] Step 1: Synthesis of tert-butyl 4-(4-(7-(benzyloxy)-3-(2,6-difluorophenyl)-2H-benzopyran-4-yl)phenyl)piperazine-1-carboxylate

[0232] At room temperature, tert-butyl 4-(4-(7-(benzyloxy)-3-bromo-2H-benzopyran-4-yl)phenyl)piperazine-1-carboxylate (0.50 g, 0.87 mmol), (2,6-difluorophenyl)boronic acid (0.41 g, 2.60 mmol), potassium carbonate (0.24 g, 1.74 mmol), dioxane / H2O (8 mL / 2 mL), and Pd(dppf)Cl2 (0.06 g, 0.09 mmol) were added sequentially to a reaction flask. The reaction was carried out at 100 °C for 16 h under nitrogen protection, and the reaction proceeds were confirmed to be complete by LC-MS. The reaction solution was filtered through diatomaceous earth, the filtrate was concentrated, and the residue was subjected to column chromatography (PE / EA system) to obtain 0.70 g of a yellow oily substance.

[0233] Step 2: Synthesis of tert-butyl 4-(4-(3-(2,6-difluorophenyl)-7-hydroxy-2H-benzopyran-4-yl)phenyl)piperazine-1-carboxylate

[0234] At room temperature, tert-butyl 4-(4-(7-(benzyloxy)-3-(2,6-difluorophenyl)-2H-benzopyran-4-yl)phenyl)piperazine-1-carboxylate (0.70 g, 1.15 mmol), Pd / C (1.00 g), and THF / MeOH (40 mL / 40 mL) were added sequentially to an autoclave, and the reaction was carried out at 55 °C under a hydrogen atmosphere for 48 h. LC-MS analysis confirmed that the reaction proceeds were complete. The mixture was filtered through a diatomaceous earth liner, and the filtrate was evaporated to dryness to obtain 350 mg of a white solid.

[0235] Step 3: Synthesis of tert-butyl 4-(4-(7-(benzyloxy)-3-(2,6-difluorophenyl)-2H-benzopyran-4-yl)phenyl)piperazine-1-carboxylate

[0236] At room temperature, tert-butyl 4-(4-(3-(2,6-difluorophenyl)-7-hydroxy-2H-benzopyran-4-yl)phenyl)piperazine-1-carboxylic acid ester (0.35 g, 0.67 mmol), potassium carbonate (0.19 g, 1.34 mmol), DMF (10 mL) were added sequentially to the reaction flask, followed by the dropwise addition of BnBr (0.17 g, 1.00 mmol). The reaction was carried out at room temperature for 16 h. The reaction was confirmed to be complete by LC-MS. The reaction solution was added to water (100 mL), followed by the addition of dichloromethane (50 mL) for extraction and separation. The organic phase was concentrated, and the residue was subjected to column chromatography (PE / EA system) to obtain 0.40 g of a yellow oil.

[0237] Step 4: Synthesis of 1-(4-(7-(benzyloxy)-3-(2,6-difluorophenyl)-2H-benzopyran-4-yl)phenyl)piperazine

[0238] At room temperature, 5 mL of HCl dioxane solution and 0.40 g (0.65 mmol) of tert-butyl 4-(4-(7-(benzyloxy)-3-(2,6-difluorophenyl)-2H-benzopyran-4-yl)phenyl)piperazine-1-carboxylate were added sequentially to a reaction flask, and the mixture was reacted at room temperature for 2 h. LC-MS was used to confirm the complete reaction of the starting materials. The reaction solution was evaporated to dryness, and the residue was dissolved in 5 mL of methanol, followed by the addition of 1 mL of ammonia. The solution was then concentrated under vacuum to obtain 0.29 g of a yellow solid.

[0239] Step 5: Synthesis of 1-(4-(7-(benzyloxy)-3-(2,6-difluorophenyl)-2H-benzopyran-4-yl)phenyl)-4-(((1R,2R)-2-((tert-butyldiphenylsiloxy)methyl)cyclohexyl)methyl)piperazine

[0240] At room temperature, 1-(4-(7-(benzyloxy)-3-(2,6-difluorophenyl)-2H-benzopyran-4-yl)phenyl)piperazine (0.29 g, 0.57 mmol), (1R,2R)-2-(((tert-butyldiphenylsilyl)oxy)methyl)cyclohexane-1-carboxaldehyde (0.43 g, 1.13 mmol), and dichloromethane (5 mL) were added sequentially to a reaction flask. The reaction was allowed to proceed at room temperature for 2 h, followed by the addition of STAB (0.24 g, 1.13 mmol), and the reaction was allowed to proceed at room temperature for 16 h. LC-MS was used to confirm the complete reaction of the starting materials. The reaction was quenched by adding saturated sodium carbonate solution (10 mL), stirred for 10 min, and then extracted with dichloromethane. The aqueous phase was extracted once with dichloromethane. The organic phases were combined, dissolved, and subjected to column chromatography (PE / EA system) to obtain 0.25 g of a yellow oil.

[0241] Step 6: Synthesis of ((1R,2R)-2-((4-(4-(7-(benzyloxy)-3-(2,6-difluorophenyl)-2H-benzopyran-4-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methanol

[0242] At room temperature, 1-(4-(7-(benzyloxy)-3-(2,6-difluorophenyl)-2H-benzopyran-4-yl)phenyl)-4-(((1R,2R)-2-((tert-butyldiphenylsiloxy)methyl)cyclohexyl)methyl)piperazine (0.25 g, 0.29 mmol), TBAF (0.13 g, 0.43 mmol), and tetrahydrofuran (5 mL) were added sequentially to a reaction flask, and the reaction was carried out at 50 °C for 16 h. LC-MS was used to confirm the complete reaction of the starting material. After solvent removal, column chromatography (PE / EA system) was performed to give 0.12 g of a white solid.

[0243] Step 7: Synthesis of (1R,2R)-2-((4-(4-(7-(benzyloxy)-3-(2,6-difluorophenyl)-2H-benzopyran-4-yl)phenyl)piperazin-1-yl)methyl)cyclohexane-1-carboxaldehyde

[0244] At room temperature, ((1R,2R)-2-((4-(4-(7-(benzyloxy)-3-(2,6-difluorophenyl)-2H-benzopyran-4-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methanol (0.12 g, 0.19 mmol)) was added sequentially to the reaction flask. Molecular sieve (0.12 g, 100% w / w), NMO (0.03 g, 0.28 mmol), and DCM (5 mL) were added, followed by TPAP (0.01 g, 0.02 mmol). The reaction was carried out at room temperature for 16 h. The reaction was confirmed to be complete by LC-MS. The mixture was filtered, the filtrate was desolventized, and column chromatography (PE / EA system) was performed to obtain 0.08 g of white solid.

[0245] Step 8: Synthesis of 1-(6-(1-(((1R,2R)-2-((4-(4-(7-(benzyloxy)-3-(2,6-difluorophenyl)-2H-benzopyran-4-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

[0246] At room temperature, (1R,2R)-2-((4-(4-(7-(benzyloxy)-3-(2,6-difluorophenyl)-2H-benzopyran-4-yl)phenyl)piperazin-1-yl)methyl)cyclohexane-1-carboxaldehyde (0.08 g, 0.12 mmol), 1-(5-fluoro-6-(4-hydroxypiperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (0.04 g, 0.12 mmol) and DCM (5 mL) were added sequentially to the reaction flask, followed by TIPT (0.5 mL). The reaction was carried out at room temperature for 16 h. The next day, STAB (0.05 g, 0.25 mmol) was added, and the reaction was carried out at room temperature for 1 h. The reaction of the starting material was detected by LC-MS and the reaction was completed. Water (1 mL) was added to quench the reaction, and a large amount of solid precipitated out. Ammonia (0.2 mL) was added, followed by methanol (3 mL). The mixture was filtered through diatomaceous earth, and the filtrate was desolventized and subjected to column chromatography (PE / EA system) to obtain 0.05 g of white solid.

[0247] Step 9: Synthesis of 1-(6-(1-((1R,2R)-2-((4-(3-(2,6-difluorophenyl)-7-hydroxy-2H-chromen-4-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)-4-hydroxypiperidin-4-yl)-5-fluoro-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

[0248] At room temperature, 1-(6-(1-(((1R,2R)-2-((4-(4-(7-(benzyloxy)-3-(2,6-difluorophenyl)-2H-benzopyran-4-yl)phenyl)piperazin-1-yl)methyl)cyclohexyl)methyl)-4-hydroxypiperidin-4-yl)-5-fluoro-1-methyl-1H-indazole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (0.05 g, 0.05 mmol), Pd / C (0.05 g, 10% w / w), and THF (5 mL) were added to a single-necked flask. The reaction was carried out at room temperature for 16 h under a hydrogen atmosphere. LC-MS was used to confirm the complete reaction of the starting material. The mixture was filtered, the filtrate was desolvated, and column chromatography (DCM / MeOH system) was performed to give 0.01 g of the final product. MS (ESI) m / z: 890.6 [M+H] + .

[0249] The compounds listed in the table below can be prepared using the methods described above:

[0250] Experimental Example 1: Cell Viability Test

[0251] (1) MCF7 cell viability test

[0252] Cell Culture: MCF7 cells (culture conditions: MEM medium + 20% FBS + 1% essential amino acids + 1 mg / 100 mL insulin, 37℃, 5% CO2). Plating: Collect cells from passages in logarithmic growth phase and transfer to centrifuge tubes, centrifuge at 800 rpm for 5 min. Resuspend in complete medium and count cells. Dilute and adjust the final cell concentration to 30,000 cells / mL. Then seed cells into 96-well plates, 100 μL per well, and incubate overnight. Drug Administration: Add each drug solution to 96-well plates, 100 μL per well, with n = 3 for each drug concentration. Also, set up negative wells (n = 6) and blank wells (n = 3). Continue incubating the 96-well plates for 6 days. Add CCK8 reagent to each well, 20 μL, and incubate for another 4 h. Measure the absorbance of the solution at 450 nm using a microplate reader. The proliferation inhibition rate was calculated, and the half-maximal inhibitory concentration (IC50) was calculated using GraphpadPrism 6.0 software. 50 value.

[0253] (2) T47D cell viability test

[0254] Cell Culture: T47D cells (culture conditions: RPMI 1640 medium + 10% FBS, 37℃, 5% CO2). Plating: Collect cells from passaged cells in logarithmic growth phase and transfer to centrifuge tubes, centrifuge at 800 rpm for 5 min. Resuspend in complete culture medium and count cells. Dilute and adjust the final cell concentration to 30,000 cells / mL. Then seed cells into 96-well plates, 100 μL per well, and incubate overnight. Drug Administration: Add each drug solution to 96-well plates, 100 μL per well, with n = 3 for each drug concentration. Also, set up negative wells (n = 6) and blank wells (n = 3). Continue incubating the 96-well plates for 6 days. Add CCK8 reagent to each well, 20 μL, and incubate for another 4 h. Measure the absorbance of the solution at 450 nm using a microplate reader. Calculate the proliferation inhibition rate and IC50. 50 The cell viability test results are shown in the table below.

[0255] Experimental Example 2: ER Protein Degradation Activity Test

[0256] Cell culture: MCF7 cells (culture conditions: RPMI 1640 medium + 10% carbon-adsorbed FBS, 37℃, 5% CO2), T47D cells (culture conditions: RPMI 1640 medium + 10% FBS, 37℃, 5% CO2). Cells passaged to the logarithmic growth phase were collected and transferred to centrifuge tubes, centrifuged at 800 rpm for 5 min. Cells were resuspended in complete culture medium, counted, and adjusted to a cell count of 5 × 10⁶ cells / year. 5Cells / mL. Then, evenly seed the cells into 6-well plates, 1 mL per well, and incubate overnight. Drug treatment: Add the diluted drug solution to the 6-well plates, 1 mL per well. Two negative control wells are also included, each containing 1 mL of empty culture medium with an equal volume of DMSO. Incubate the 6-well plates for 48 h. Cell protein extraction: Prepare protein lysis buffer containing the inhibitor in advance. Remove the culture medium from the adherent cell culture flask and wash the adherent cells twice with pre-chilled PBS. Add 100 μL of pre-chilled protein lysis buffer containing the inhibitor to the 6-well plate and gently shake for 5 minutes. Scrape the adherent cells from the wells with a cell scraper, transfer the cell suspension to centrifuge tubes, and lyse on ice for 30 minutes, shaking every 5-10 minutes. Centrifuge the lysis buffer at 12000 rpm for 10 minutes in a pre-chilled 4°C centrifuge. Discard the precipitate, and immediately transfer the supernatant to a new centrifuge tube for later use. Protein concentration detection: Following the BCA kit instructions, the OD value of each well was measured using a microplate reader. The protein concentration in the sample was calculated based on the standard curve, and the protein concentration of each sample was balanced by adjusting the lysis buffer volume. Protein denaturation: Protein loading buffer (5x) was added at a ratio of 1:4 and mixed thoroughly with the sample protein supernatant. After mixing, the mixture was heated at 100℃ for 10 min, and then stored at -80℃. Sample loading and electrophoresis: The pre-prepared SDS-PAGE gel was fixed in the electrophoresis chamber, electrophoresis buffer was added, and the comb was slowly and gently removed to begin sample loading. The electrophoresis voltage was set to 150V until completion. Wet transfer: After electrophoresis, the target protein molecular weight region was determined according to the marker, and the membrane was cut using a comb. Simultaneously, similarly sized PVDF membranes were cut and soaked in methanol for 15 s before use. Transfer buffer was poured into a tray, and sponge pads and filter paper were placed in the prescribed order. The transfer current was set to 200mA, and the transfer time was 1 hour. Blocking: Cut a small opening at the lower right corner of the PVDF membrane to record the front and back sides in contact with the gel. Immerse the membrane in 5% BSA solution and incubate at low speed on a horizontal shaker at room temperature for 1 hour. Antibody Incubation: After blocking, wash the membrane three times in TBST solution for 10 minutes each time. Place the PVDF membrane directly into the primary antibody incubation solution and the secondary antibody incubation solution sequentially. The primary antibody incubation solution requires incubation at 4°C on a horizontal shaker for at least 12 hours, while the secondary antibody incubation solution requires incubation at room temperature on a horizontal shaker for 1 hour. After each incubation, wash the membrane three times in TBST solution for 10 minutes each time. Development: Mix the A and B solutions of the developing solution at a 1:1 ratio, prepare fresh, and develop using the developing instrument according to the program. The results are shown in Figures 1 and 2.

[0257] Conclusion: The compounds of this invention have strong ER protein degradation activity and have potential for tumor treatment.

[0258] Experimental Example 3: In vivo tumor suppression activity test

[0259] MCF-7 cell culture (culture conditions: MEM medium + 20% FBS + 1% essential amino acids + 1 mg / 100 ml insulin, 37℃, 5% CO2), cells passaged to the logarithmic growth phase were collected and transferred to centrifuge tubes, centrifuged at 800 rpm for 5 min. On the day of inoculation, the cell density was adjusted to 3*102 7 cells / mL.

[0260] For estradiol injection, all experimental animals were subcutaneously injected with 8 μg / 100 μL estradiol solution (solvent: 30% propylene glycol + 70% glucose injection) one day before vaccination. From the day of vaccination until the end of the experiment, each animal was subcutaneously injected with 4 μg / 50 μL of estradiol.

[0261] Cell seeding: The seeding site was selected at the right scapula of the experimental animal, with a seeding density of 3*102. 6 cells / 100μL / each.

[0262] Grouped administration: When the average tumor volume reaches 80-150 mm 3 Mice were randomly assigned to groups based on tumor volume, with the coefficient of variation (CV) not exceeding one-third of the mean volume. The day of grouping was defined as day D0, and drug administration began on that day. Mice body weight was measured before administration, and drug delivery was based on that day's body weight.

[0263] Experimental observation and data collection: After cell inoculation, the effect of tumors on the normal behavior of animals was routinely monitored weekly. Specific monitoring included the activity level of the experimental animals, food and water intake, weight gain or loss, and any abnormalities in the eyes, coat, or other areas. After the start of drug administration, mice were weighed and administered the drug daily, and tumor volume was measured twice weekly. Tumor volume was calculated as: tumor volume (mm²) 3 = 0.52 × tumor long diameter (mm) × tumor short diameter (mm) 2 At the end of the experiment, the following indicators were analyzed: tumor growth curve, mouse body weight curve, tumor weight, and the dissected tumors were photographed uniformly after being arranged according to the groups. The tumor volume inhibition rate (TGI) was then calculated.

[0264] TGI TV Formula for calculating (relative tumor volume inhibition rate):

[0265] V nt : Tumor volume of mouse number n on day t;

[0266] V n0 : Tumor volume of mouse number n on day 0;

[0267] RTV n : The relative tumor volume of mouse number n on day t;

[0268] meanRTV treat : Mean RTV of the treatment group;

[0269] meanRTV vehicle : Average RTV of the Vehicle group;

[0270] Tumor volume, mouse body weight, and other experimental results for each group of animals are expressed as mean ± standard error (Mean ± SEM). All data were analyzed using GraphPad Prism 6.0. P < 0.05 was considered statistically significant.

[0271] Conclusion: The compounds of this invention have significant inhibitory effects on tumor growth in vivo.

[0272] Experiment 4: In vivo PK test in mice

[0273] Female BALB / c mice were weighed and drug-treated. Approximately 50 μL of whole blood was collected via the orbital venous plexus at 5 min (IV group), 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h, and 24 h post-drug administration, and anticoagulated with EDTA-K2. Blood samples were centrifuged at 4000 rpm for 10 min at 4°C. 20 μL of the supernatant plasma sample was transferred to an EP tube and immediately stored at -80°C for analysis. 10 μL of plasma sample was transferred to a 96-well plate and 250 μL of acetonitrile (containing internal standard) was added to precipitate proteins. The plate was centrifuged at 4000 rpm for 20 min at 4°C. 180 μL of the supernatant was transferred to a new 96-well plate and 180 μL of 0.1% formic acid solution was added and thoroughly mixed. Drug concentration was detected by LC MS / MS. A standard curve was established using the internal standard method. Sample concentrations were calculated from the standard curve. Pharmacokinetic parameters were calculated.

[0274] Conclusion: The compounds of this invention have good oral bioavailability, good in vivo half-life, and good exposure levels.

[0275] Experimental Example 5: In vivo brain and plasma distribution test

[0276] Mice were administered the drug orally multiple times (>7 days). Brain tissue and whole blood were collected from the animals 3 hours and 6 hours after the last administration. Whole blood was anticoagulated with EDTA-K2 and centrifuged at 4000 rpm for 10 min at 4°C. 20 μL of the supernatant plasma sample was transferred to an EP tube and immediately stored at -80°C for analysis. Brain tissue was flash-frozen at -80°C for analysis. 10 μL of plasma sample was transferred to a 96-well plate and 250 μL of acetonitrile (containing internal standard) was added to precipitate proteins. The plate was centrifuged at 4000 rpm for 20 min at 4°C. 180 μL of the supernatant was transferred to a new 96-well plate and 180 μL of 0.1% formic acid solution was added and mixed thoroughly. 10 μL of the sample was analyzed by LC MS / MS for drug concentration. Brain samples were weighed and homogenized with 4 times (w / v = 1 / 4) ice-cold PBS. Transfer 20 μL of brain homogenate sample to a 96-well plate and add 250 μL of acetonitrile (containing internal standard) to precipitate proteins. Centrifuge at 4000 rpm / min for 20 minutes at 4°C. Transfer 180 μL of supernatant to a new 96-well plate and add 180 μL of 0.1% formic acid solution, mixing thoroughly. Determine drug concentration using LC MS / MS with 10 μL of the sample. Establish a standard curve using the internal standard method. Calculate the sample concentration using the standard curve.

[0277] Conclusion: The compounds of this invention have better distribution in the brain.

[0278] The above description provides an exemplary account of the implementation methods of the technical solution disclosed herein. It should be understood that the scope of protection of this disclosure is not limited to the above-described embodiments. Any modifications, equivalent substitutions, or improvements made by those skilled in the art within the spirit and principles of this disclosure should be included within the scope of protection of the claims of this application.

Claims

1. The compound represented by formula (I), its isomers, or pharmaceutically acceptable salts thereof: in, X is selected from N or CH; G is selected from unsubstituted or optionally by one, two or more Rs. a1 The following groups are substituted: C 6-10 Aryl or 5-10 heteroaryl groups; Each R a1 Each group is independently selected from hydrogen, deuterium, halogen, hydroxyl, carboxyl, amino, cyano, nitro, and 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, C 2-8 alkenyl, C 2-8 alkynyl group, C 1-6 Alkyl carbonyl, amino carbonyl, C 1-6 Alkylamine carbonyl, (C 1-6 alkyl)2-aminocarbonyl; Cy1 is selected from 3-13 membered cycloalkyl, 3-13 membered heterocyclic, 3-13 membered cycloalkenyl, and surrounded by 1-3 R groups. a2 Substituted 3-13 membered cycloalkyl groups, with 1-3 R groups a2 Substituted 3-13 membered heterocyclic groups, replaced by 1-3 R groups a2 Substituted 3-13 membered cycloalkenyl, Cy 11 -Cy 12 The heteroatom of the 3-13 membered heterocyclic group is selected from O, N, or S; Cy 11 and Cy 12 They may be the same or different, and are independently selected from 3-13 membered cycloalkyl, 3-13 membered heterocyclic, and 3-13 membered cycloalkenyl groups; Each R a2 Each group is independently selected from hydrogen, halogen, hydroxyl, mercapto, silanol, selenol, carboxyl, amino, cyano, nitro, and 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, C 2-8 alkenyl, C 2-8 alkynyl group, C 1-6 Alkyl carbonyl, amino carbonyl, C 1-6 Alkylamine carbonyl, (C 1-6 Alkyl)2-aminocarbonyl, 3-8-membered cycloalkyl, 3-8-membered heterocyclic, 3-8-membered cycloalkenyl, wherein 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, C 2-8 alkenyl, C 2-8 alkynyl group, C 1-6 Alkyl carbonyl, amino carbonyl, C 1-6 Alkylamine carbonyl, (C 1-6 Alkyl) 2-aminocarbonyl, 3-8 membered cycloalkyl, 3-8 membered heterocyclic, 3-8 membered cycloalkenyl are unsubstituted or optionally substituted by one or more groups selected from 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)2-amino, C 1-6 Alkyl carbonyl amino, C 1-6 Alkylsulfonamide, C 1-6 Alkylcarbonyl group, C 3-6 cycloalkyl, C 3-6 Cycloalkylcarbonyloxy, C 2-8 alkynyl, halogenated C 1-6 Alkyl, C 2-8 alkenyl, halogenated C 1-6 Substitution of alkoxy, 3-8 membered cycloalkyl, 3-8 membered heterocyclic, and 3-8 membered cycloalkenyl groups; Z1 and Z2 may be the same or different, and are independently selected from C(R). a3 (R) a3 ), O, N (R) a3 ), S, Si(R) a3 (R) a3 ); Cy2 is selected from 3-8 membered cycloalkyl, 3-8 membered heterocyclic, 3-8 membered cycloalkenyl, 6-13 bicyclic fused-ring cycloalkyl, 6-13 membered bicyclic fused-ring alkenyl, 6-13 membered bicyclic fused-ring heterocyclic, and is surrounded by 1-3 R groups. a4 Substituted 3-8 membered cycloalkyl groups, with 1-3 R groups a4 The substituted 3-8 membered heterocyclic group is replaced by 1-3 R a4 Substituted 3-8 membered cycloalkenyl groups, with 1-3 R groups a4 Substituted 6-13 bicyclic fused-ring alkyl groups, with 1-3 R a4 The substituted 6-13 membered bicyclic fused-ring alkenyl group, with 1-3 R groups a4 The 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 a3 R a4 Each group is independently selected from hydrogen, deuterium, halogen, hydroxyl, mercapto, silanol, selenol, carboxyl, amino, cyano, nitro, and 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)2-amino, C 2-8 alkenyl, C 2-8 alkynyl group, C 1-6 Alkyl carbonyl, amino carbonyl, C 1-6 Alkylamine carbonyl, (C 1-6 Alkyl)2-aminocarbonyl, 3-8-membered cycloalkyl, 3-8-membered heterocyclic, 3-8-membered cycloalkenyl, wherein 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, C 2-8 alkenyl, C 2-8 alkynyl group, C 1-6 Alkyl carbonyl, amino carbonyl, C 1-6 Alkylamine carbonyl, (C 1-6 Alkyl) 2-aminocarbonyl, 3-8 membered cycloalkyl, 3-8 membered heterocyclic, 3-8 membered cycloalkenyl are unsubstituted or optionally substituted by one or more groups selected from 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)2-amino, C 1-6 Alkyl carbonyl amino, C 1-6 Alkylsulfonamide, C 1-6 Alkylcarbonyl group, C 3-6 cycloalkyl, C 3-6 Cycloalkylcarbonyloxy, C 2-8 alkynyl, halogenated C 1-6 Alkyl, C 2-8 alkenyl, halogenated C 1-6 Substitution of alkoxy, 3-8 membered cycloalkyl, 3-8 membered heterocyclic, and 3-8 membered cycloalkenyl groups; X1 is N or CR b1 ; X2 is N or CR b2 ; X3 is N or CR b3 ; X4 is N or CR b4 ; R b1 R b2 R b3 and R b4 Each group is independently selected from hydrogen, halogen, hydroxyl, carboxyl, amino, cyano, nitro, and 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, C 2-8 alkenyl, C 2-8 alkynyl group, C 1-6 Alkyl carbonyl, amino carbonyl, C 1-6 Alkylamine carbonyl, (C 1-6 alkyl)2-aminocarbonyl; Z4 consists of C(Rc)(Rc), O, and S; Each Rc is 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)2-amino, C 2-8 alkenyl, C 2-8 alkynyl group, C 1-6 Alkyl carbonyl, amino carbonyl, C 1-6 Alkylamine carbonyl, (C 1-6 alkyl)2-aminocarbonyl; R is selected from hydrogen, 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)2-amino, C 2-8 alkenyl, C 2-8 alkynyl group, C 1-6 Alkyl carbonyl, amino carbonyl, C 1-6 Alkylamine carbonyl, (C 1-6 Alkyl) 2-aminocarbonyl, 3-8 membered cycloalkyl, 3-8 membered heterocyclic, 3-8 membered cycloalkenyl, C 6-10 Aryl or 5-10 heteroaryl, 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, C 2-8 alkenyl, C 2-8 alkynyl group, C 1-6 Alkyl carbonyl, amino carbonyl, C 1-6 Alkylamine carbonyl, (C 1-6 Alkyl) 2-aminocarbonyl, 3-8 membered cycloalkyl, 3-8 membered heterocyclic, 3-8 membered cycloalkenyl, C 6-10 The aryl group or 5-10 heteroaryl group is unsubstituted or optionally substituted with one or more groups selected from 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)2-amino, C 1-6 Alkyl carbonyl amino, C 1-6 Alkylsulfonamide, C 1-6 Alkylcarbonyl group, C 3-6 cycloalkyl, C 3-6 Cycloalkylcarbonyloxy, C 2-8 alkynyl, halogenated C 1-6 Alkyl, C 2-8 alkenyl, halogenated C 1-6 Substitution of alkoxy, 3-8 membered cycloalkyl, 3-8 membered heterocyclic, and 3-8 membered cycloalkenyl groups; The condition is that when Z4 is CH2, R is not phenyl.

2. The compound of formula (I) according to claim 1, its isomers or pharmaceutically acceptable salts thereof, wherein, G is selected from Among them, the Not replaced, or each independently replaced by 1-3 Rs a1 Replacement; preferably, each R a1 Each group is independently selected from hydrogen, halogen, hydroxyl, carboxyl, amino, and 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, C 1-6 Alkyl carbonyl, amino carbonyl, C 1-6 Alkylamine carbonyl, (C 1-6 alkyl)2-aminocarbonyl; more preferably, each R a1 Selected independently from halogens and C 1-6 Alkyl or C 1-6 Alkyl groups; most preferably, each R a1 Each is independently selected from F, methyl, ethyl, and methoxy.

3. The compound of formula (I) according to any one of claims 1-2, its isomers or pharmaceutically acceptable salts thereof, wherein, Cy1 is selected from 4-6 membered cycloalkyl, 4-6 membered heterocyclic, 4-6 membered cycloalkenyl, and surrounded by 1-3 R groups. a2 Substituted 4-6 membered cycloalkyl groups, with 1-3 R groups a2 The substituted 4-6 membered heterocyclic group is replaced by 1-3 R a2 The substituted 4-6 membered cycloalkenyl group, wherein the heteroatom of the 4-6 membered heterocyclic group is selected from O, N, or S; preferably, Cy1 is selected from 4-6 membered nitrogen-containing heterocyclic groups or those substituted with 1-3 R atoms. a2 Substituted 4-6 membered nitrogen-containing heterocyclic groups; more preferably, Cy1 is selected from unsubstituted or substituted groups with 1-3 R groups. a2 Replacement Among them, each R a2 Each is independently selected from hydrogen, hydroxyl, amino, mercapto, silanol, selenol, halogen, and 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; more preferably, each R a2 Each element is independently selected from hydrogen, hydroxyl, amino, halogen, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl-NH-, C 3-6 cycloalkyl, C 1-6 Alkyl-C(O)NH-; Most preferably, each R a2 Each group is independently selected from hydrogen, fluorine, hydroxyl, amino, methylamino, acetamido, methyl, methoxy, and cyclopropyl.

4. The compound of formula (I) according to any one of claims 1-3, its isomers or pharmaceutically acceptable salts thereof, wherein, Both Z1 and Z2 are CH(R) a3 ), where R a3 Selected from hydrogen, deuterium, halogen, hydroxyl, mercapto, silanol, selenol, 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)2-amino, C 2-8 alkenyl, C 2-8 alkynyl group, C 1-6 Alkyl carbonyl, amino carbonyl, C 1-6 Alkylamine carbonyl, (C 1-6 Alkyl)2-aminocarbonyl, 3-8 membered cycloalkyl, 3-8 membered heterocyclic, 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)2-amino, C 2-8 alkenyl, C 2-8 alkynyl group, C 1-6 Alkyl carbonyl, amino carbonyl, C 1-6 Alkylamine carbonyl, (C 1-6 Alkyl) 2-aminocarbonyl, 3-8 membered cycloalkyl, 3-8 membered heterocyclic, 3-8 membered cycloalkenyl are unsubstituted or optionally substituted by one or more groups selected from 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)2-amino, C 1-6 Alkyl carbonyl amino, C 1-6 Alkylsulfonamide, C 1-6 Alkylcarbonyl group, C 3-6 cycloalkyl, C 3-6 Cycloalkylcarbonyloxy, C 2-8 alkynyl, halogenated C 1-6 Alkyl, C 2-8 alkenyl, halogenated C 1-6 Substitution with alkoxy, 3-8 membered cycloalkyl, 3-8 membered heterocyclic, or 3-8 membered cycloalkenyl groups; preferably, R a3 Selected from hydrogen, hydroxyl, amino, mercapto, silanol, selenol, 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; more preferably, R a3 Selected from hydrogen, deuterium, halogen, hydroxyl, mercapto, silanol, selenol, carboxyl, amino, cyano, nitro, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkyloxy; more preferably, R a3 Selected from hydrogen and halogens; most preferably, R a3 Selected from hydrogen and fluorine.

5. The compound of formula (I) according to any one of claims 1-4, its isomers or pharmaceutically acceptable salts thereof, wherein, The Cy2 is selected from 3-8 membered cycloalkyl, 3-8 membered heterocyclic, 3-8 membered cycloalkenyl, 6-13 bicyclic fused-ring cycloalkyl, 6-13 membered bicyclic fused-ring alkenyl, 6-13 membered bicyclic fused-ring heterocyclic, and those with 1-3 R groups. a4 Substituted 3-8 membered cycloalkyl groups, with 1-3 R groups a4 The substituted 3-8 membered heterocyclic group is replaced by 1-3 R a4 Substituted 3-8 membered cycloalkenyl groups, with 1-3 R groups a4 Substituted 6-13 bicyclic fused-ring alkyl groups, with 1-3 R a4 The substituted 6-13 membered bicyclic fused-ring alkenyl group, with 1-3 R groups a4 The 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; preferably, the Cy2 is selected from a 3-8 membered heterocyclic group and surrounded by 1-3 R atoms. a4 The substituted 3-8 membered heterocyclic group, 6-13 membered bicyclic spirocyclic group, or grouped by 1-3 R a4 The substituted 6-13 membered bicyclic spiroheterocyclic group, wherein the heteroatom of the 3-8 membered heterocyclic group or the 6-13 membered bicyclic spiroheterocyclic group is selected from O, N or S; more preferably, the Cy2 is selected from unsubstituted or substituted with 1-3 R atoms. a4 Replacement Among them, each R a4 Each is independently selected from hydrogen, hydroxyl, amino, mercapto, silanol, selenol, halogen, and 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 or hydroxy C 1-6 Alkyl; more preferably, each R a4 Each R is independently selected from hydrogen and halogen; most preferably, each R a4 They are selected independently from hydrogen and fluorine, respectively.

6. The compound of formula (I) according to any one of claims 1-5, its isomers or pharmaceutically acceptable salts thereof, wherein, Selected from phenyl or a 6-membered heteroaryl group containing 1-2 heteroatoms, wherein the phenyl or the 6-membered heteroaryl group containing 1-2 heteroatoms is not substituted or is R-substituted. b1 R b2 R b3 and R b4 Replace, where R b1 R b2 R b3 and R b4 Each group is independently selected from hydrogen, halogen, hydroxyl, carboxyl, amino, cyano, nitro, and 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, C 2-8 alkenyl, C 2-8 alkynyl group, C 1-6 Alkyl carbonyl, amino carbonyl, C 1-6 Alkylamine carbonyl, (C 1-6 Alkyl)2-aminocarbonyl; preferably, Selected from phenyl, pyridyl; more preferably, for 7. The compound of formula (I) according to any one of claims 1-6, its isomers or pharmaceutically acceptable salts thereof, wherein, Z4 is CH(Rc) or O, where Rc is 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)2-amino, C 2-8 alkenyl, C 2-8 alkynyl group, C 1-6 Alkyl carbonyl, amino carbonyl, C 1-6 Alkylamine carbonyl, (C 1-6 Alkyl)2-aminocarbonyl; preferably, Rc is selected from hydrogen, deuterium, halogen, hydroxyl, carboxyl, amino, cyano, nitro, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkyl group.

8. The compound of formula (I) according to any one of claims 1-7, its isomers or pharmaceutically acceptable salts thereof, wherein, R is selected from hydrogen, 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)2-amino, C 2-8 alkenyl, C 2-8 alkynyl group, C 1-6 Alkyl carbonyl, amino carbonyl, C 1-6 Alkylamine carbonyl, (C 1-6 Alkyl) 2-aminocarbonyl, 3-8 membered cycloalkyl, 3-8 membered heterocyclic, 3-8 membered cycloalkenyl, C 6-10 aryl or 5-10 heteroaryl; preferably, R is selected from hydrogen, C 1-6 Alkyl, C 6-10 Aryl or 5-10 heteroaryl; more preferably, R is selected from hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, phenyl, pyridyl.

9. The compound of formula (I) according to any one of claims 1-8, its isomers or pharmaceutically acceptable salts thereof, wherein, It has the structure shown in equation (I-1): Where X is selected from N or CH; R a1 Selected from halogens, C 1-6 Alkyl, C 1-6 Alkoxy; Preferably, R a1 Selected from F, methyl, ethyl, and methoxy; R a2 Selected from H, OH, amino, mercapto, silanol, selenol, 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; more 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-; most preferably, R a2 Selected from H, F, OH, amino, methylamino, acetamido, methyl, methoxy, and cyclopropyl; Z3 is selected from CH or N; Z4 is selected from CH2 or O; R is selected from hydrogen, halogen, hydroxyl, carboxyl, amino, cyano, nitro, C 1-6 Alkyl, C 6-10 Aryl or 5-10 heteroaryl; more preferably, R is selected from hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, phenyl, pyridyl; The condition is that when Z4 is selected from CH2, R is not a phenyl group.

10. The compound, its isomer, or a pharmaceutically acceptable salt thereof according to any one of claims 1-9, wherein the compound is selected from the following:

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

12. Use of the compound, its isomer, or a pharmaceutically acceptable salt thereof according to any one of claims 1-10, or the pharmaceutical composition of claim 11, in the preparation of a medicament for treating and / or preventing a disease or condition by degrading a target protein; Preferably, the disease or symptom is selected from abnormal cell proliferation, tumors, immune diseases, diabetes, cardiovascular diseases, infectious diseases, and inflammatory diseases; more preferably, tumors and infectious diseases; Preferably, the tumor is cancer; more preferably selected from breast cancer, endometrial cancer, testicular cancer, cervical cancer, prostate cancer, ovarian cancer, fallopian tube tumors, 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, ductoblastoma, pineal cell tumor, meningioma, neurofibroma, schwannoma, 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 tumors; Preferably, the infectious disease is selected from viral pneumonia, influenza, avian influenza, meningitis, gonorrhea, or diseases caused by HIV, HBV, HCV, HSV, HPV, RSV, CMV, Ebola virus, flavivirus, stoma virus, rotavirus, coronavirus, EBV, drug-resistant virus, RNA virus, DNA virus, adenovirus, poxvirus, microRNA virus, capsid virus, orthomyxovirus, retrovirus, hepatotropic DNA virus, Gram-negative bacteria, Gram-positive bacteria, atypical bacteria, Staphylococcus, Streptococcus, Escherichia coli, Salmonella, Helicobacter pylori, Chlamydia, Mycoplasma, fungi, protozoa, intestinal worms, worms, prions, or parasites.

13. Use of the compound, its isomer, or a pharmaceutically acceptable salt thereof according to any one of claims 1-10, or the pharmaceutical composition of claim 11, 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 diseases or conditions are tumors, preferably cancers, more preferably breast cancer, endometrial cancer, testicular cancer, cervical cancer, prostate cancer, ovarian cancer, and fallopian tube tumors, and most preferably breast cancer.

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