Combined drug of estrogen receptor degrader and AKT inhibitor and use thereof

Abstract

A combined drug of an estrogen receptor degrader and an AKT inhibitor and use thereof. The present invention pertains to the field of pharmaceuticals. The combined drug comprises an estrogen receptor degrader and an AKT inhibitor of the same specification or different specifications that are administered simultaneously or separately and a pharmaceutically acceptable carrier, can degrade estrogen receptors, inhibit cancer cell growth, exert a synergistic inhibitory effect, and significantly improve the effect of treating estrogen receptor-related diseases, and has good application prospects.

Description

Combination of an estrogen receptor degrader and an AKT inhibitor and uses thereof TECHNICAL FIELD

[0001] The present application belongs to the field of medicine, and particularly relates to a combination of an estrogen receptor degrader and an AKT inhibitor and uses thereof. BACKGROUND

[0002] The estrogen receptor (ER) is a ligand-activated transcriptional regulatory protein that mediates the induction of a variety of biological effects through interaction with endogenous estrogens. Endogenous estrogens include 17beta-estradiol and estrone. Two different configurations of ER have been discovered, i.e. ER-alpha and ER-beta. Estrogens and estrogen receptors are associated with many diseases or conditions, such as bone cancer, breast cancer, colorectal cancer, endometrial cancer, prostate cancer, ovarian cancer, uterine cancer, cervical cancer, lung cancer, and other diseases or conditions. For example, about 70% of patients with breast cancer express ER and / or progesterone receptors. Treatment of these diseases can be carried out by inhibiting ER signaling through various ways, including antagonizing the binding of ligands to ER, antagonizing or down-regulating ERa, blocking estrogen synthesis, etc. Estrogen receptor degraders can compete with estrogen receptors (ER) present in estrogen-responsive tissues for binding. It is expected to treat estrogen receptor related diseases. However, estrogen receptor degraders as single agents can produce adverse reactions such as endometrial hyperplasia, deep vein thrombosis, etc. in clinical application. At the same time, drug resistance is prone to occur.

[0003] The phosphoinositide 3-kinase (PI3K)-protein kinase B (AKT)-mammalian target of rapamycin (mTOR) signaling pathway is abnormally activated in a variety of tumors, which is involved in the regulation of tumor cell proliferation, differentiation and apoptosis, and is also an important pathway for the development of anti-tumor drugs. AKT is located at the core position of the PI3K-AKT-mTOR pathway, and has three subtypes, AKT1, AKT2 and AKT3, which have highly similar structures, and are composed of the amino-terminal PH domain, the central kinase domain (ATP binding domain) and the carboxy-terminal regulatory domain. First, the PH domain specifically binds to PIP2 and PIP3, which enables AKT to be localized on the cell membrane; second, the kinase domain transfers the phosphate group of ATP to the substrate threonine, which phosphorylates AKT and causes it to have partial activity; finally, the phosphorylation of the regulatory domain serine site further improves the activity of AKT and further stabilizes its active structure. AKT can regulate cell function by phosphorylating various enzymes, kinases and transcription factors, such as phosphorylating the TSC1 / TSC2 complex (tuberous sclerosis complex) and activating mTORC (mTOR complex), activating protein translation and promoting cell growth. AKT participates in anti-apoptosis by phosphorylating target proteins through multiple downstream pathways; phosphorylating the Bcl-2 family member BAD prevents it from binding to Bcl-XL and initiating apoptosis. AKT phosphorylates the transcription factor FOXO1, inhibits its nuclear translocation and prevents its transcriptional activation, AKT activation leads to the degradation of the inhibitor of NF-κB, increases the nuclear translocation of the nuclear transcription factor NF-κB, activates its target genes and promotes cell migration and invasion, etc. Mutations or deletions of PTEN, mutations or amplifications of AKT1 / AKT2 / AKT3 / PIK3CA, etc. can cause overactivation of the AKT signaling pathway, which is one of the key pathways driving cancer growth, and the dysregulation of the AKT signaling pathway is more common in recurrent ovarian cancer, breast cancer and prostate cancer, etc. AKT inhibitors can inhibit AKT and be used for the treatment of related diseases, such as anti-tumor. However, AKT inhibitors alone are prone to cause side effects such as hypotension, nausea, anorexia, headache, diarrhea, neutropenia, rash, fatigue, constipation, weakness, vomiting and loss of appetite, etc. In particular, Ipatasertib stopped development in phase I clinical trials due to serious adverse reactions (especially hyperglycemia). In another study, the common adverse reactions of AKT inhibitor Capivasertib were diarrhea and nausea, and the grade 3 or higher adverse events were mainly hyperglycemia. These side effects limit the application of AKT inhibitors.

[0004] How to overcome the current single drug inhibitor treatment problems, is the current treatment of estrogen receptor related diseases need to study the problem. Currently, there is no estrogen receptor degrader and AKT inhibitor combination therapy for estrogen receptor related diseases. SUMMARY

[0005] The purpose of the present application is to provide a combination of an estrogen receptor degrader and an AKT inhibitor and its use.

[0006] The present application provides a pharmaceutical composition for degrading estrogen receptor, which consists of an estrogen receptor degrader and an AKT inhibitor.

[0007] Further, the molar ratio of the estrogen receptor degrader to the AKT inhibitor is 1:0.1-300.

[0008] Further, the molar ratio of the estrogen receptor degrader to the AKT inhibitor is 1:1-300;

[0009] Alternatively, the molar ratio of the estrogen receptor degrader to the AKT inhibitor is 1:0.3-100;

[0010] Preferably,

[0011] The molar ratio of the estrogen receptor degrader to the AKT inhibitor is 1:1.1-268.3;

[0012] Alternatively, the molar ratio of the estrogen receptor degrader to the AKT inhibitor is 1:0.37-90.2;

[0013] More preferably,

[0014] The molar ratio of the estrogen receptor degrader to the AKT inhibitor is 1:1.1, 1:29.7, 1:268.3;

[0015] Alternatively, the molar ratio of the estrogen receptor degrader to the AKT inhibitor is 1:0.37, 1:10, 1:90.2.

[0016] Further, the estrogen receptor degrader is Fulvestrant, Estrogen receptor modulator 10, Estrogen receptor antagonist 3, Estrogen receptor antagonist 4, ER degrader 4, ER degrader 8, Taragarestrant, Taragarestrant meglumine, ER degrader 5, GDC-0927 Racemate, Elacestrant dihydrochloride, Elacestrant, Rintodestrant, Imlunestrant, ERa degrader 5, Imlunestrant tosylate, ERa degrader 8, LX-039, Elacestrant-d10, SNIPER(ER)-110, Elacestrant-d6, Elacestrant-d4, PROTAC ERa Degrader-7, PROTAC ERa Degrader-4, or an optical isomer thereof, or a salt thereof, or a hydrate thereof, or a solvate thereof;

[0017] Alternatively, the estrogen receptor degrader is a compound represented by formula (I), or an optical isomer thereof, or a salt thereof, or a hydrate thereof, or a solvate thereof:

[0018] wherein,

[0019] R 1 is selected from hydrogen, C1-C6 alkyl, hydroxyl, amino, carboxyl, C1-C6 alkoxy, boronic acid group, -OR’;

[0020] R’ is selected from phenyl, benzyl;

[0021] R 2 is a substituent on the benzene ring at any position, and a is the number of substituents R 2 ;

[0022] each R 2 is independently selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3- to 6-membered cycloalkyl, C1-C6 alkoxy;

[0023] a is 0, 1, 2, or 3;

[0024] when the dotted line in the benzene ring is a bond, R 3 , R 4 are independently selected from none;

[0025] R 3 , R 4 are independently selected from hydrogen, C1-C6 alkyl, or R 3 , R 4 form together a 3-6 membered cycloalkyl group;

[0026] R 5 is selected from C1-C6 alkyl, 3-6 membered cycloalkyl, trifluoromethyl, trifluoroethyl, substituted or unsubstituted 6-10 membered aryl, substituted or unsubstituted 5-8 membered heteroaryl; the substituents of said aryl or heteroaryl are selected from halogen, hydroxy, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, C1-C6 alkoxy;

[0027] X is selected from CR 7 R 8 , O, S, SO, SO2, NR 7 ;

[0028] R 7 , R 8 are independently selected from hydrogen, halogen, C1-C6 alkyl, 3-6 membered cycloalkyl;

[0029] n is 0, 1 or 2;

[0030] R 6 is a substituent at any position of the phenyl ring, b is the number of substituents R 6 ;

[0031] each R 6 is independently selected from halogen, hydroxy, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, C1-C6 alkoxy;

[0032] b is 0, 1, 2 or 3;

[0033] Ring A and Ring B are independently selected from 4-12 membered cycloalkyl, 4-12 membered heterocycloalkyl;

[0034] M is selected from none, CR 9 R 10 , O, S, SO, SO2, NR 9 ;

[0035] R 9 , R 10 are independently selected from hydrogen, C1-C6 alkyl;

[0036] E 3 is a substituent at any position of the phenyl ring, c is the number of substituents E 3 ;

[0037] each E 3each independently selected from the group consisting of halogen, hydroxy, amino, cyano, trifluoromethyl, C1-C6alkyl, 3-6 membered cycloalkyl, C1-C6alkoxy; or any two E 3 to form a 3-6 membered cycloalkyl, 6-10 membered aryl, 4-12 membered heterocycloalkyl, 5-8 membered heteroaryl;

[0038] c is 0, 1, 2 or 3;

[0039] when the dotted line between Y and W is absent, W is NH, Y is halogen;

[0040] when the dotted line between Y and W is a bond, W is N, Y is absent, CR Y1 R Y2 , C(O), -CR 11 =CR 12 -, -CR 11 =N-, -N=N-, -OC(O)-;

[0041] R Y1 , R Y2 are each independently selected from the group consisting of hydrogen, C1-C6alkyl;

[0042] R 11 , R 12 are each independently selected from the group consisting of hydrogen, C1-C6alkyl;

[0043] R 21 is selected from the group consisting of hydrogen or deuterium;

[0044] the heteroatom of the heteroaryl is O, N or S; the number of the heteroatom is 1, 2 or 3;

[0045] the heteroatom of the heterocycloalkyl is N; the number of the heteroatom is 1, 2 or 3.

[0046] Further, the compound is shown as formula (II):

[0047] wherein,

[0048] R 1 is selected from the group consisting of hydrogen, C1-C6alkyl, hydroxy, amino, carboxyl, C1-C6alkoxy, boronic acid group, -OR';

[0049] R' is selected from the group consisting of phenyl, benzyl;

[0050] R 2 is a substituent on the phenyl ring, a is the number of substituents R 2 ;

[0051] each R 2Each is independently selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, and C1-C6 alkoxy.

[0052] a can be 0, 1, 2, or 3;

[0053] When the dashed line in the benzene ring represents a bond, R 3 R 4 Each is independently selected from none;

[0054] When the dashed line in the benzene ring is absent, R 3 R 4 Each is independently selected from hydrogen, C1-C6 alkyl, or R 3 R 4 Linkage forms 3- to 6-membered cycloalkyl groups;

[0055] R 5 The aryl or heteroaryl group is selected from C1-C6 alkyl, 3-6 membered cycloalkyl, trifluoromethyl, trifluoroethyl, substituted or unsubstituted 6-10 membered aryl, substituted or unsubstituted 5-8 membered heteroaryl; the substituent of the aryl or heteroaryl group is selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, C1-C6 alkoxy.

[0056] X is selected from CR 7 R 8 O, S, SO, SO2, NR 7 ;

[0057] R 7 R 8 Each is independently selected from hydrogen, halogen, C1-C6 alkyl, and 3-6 membered cycloalkyl;

[0058] n is 0, 1, or 2;

[0059] R 6 b is a substituent at any position on the benzene ring, and r is a substituent R. 6 The number of;

[0060] Each R 6 Each is independently selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, and C1-C6 alkoxy.

[0061] b can be 0, 1, 2, or 3;

[0062] Ring A and ring B are independently selected from 4- to 12-membered cycloalkyl and 4- to 12-membered heterocycloalkyl, respectively;

[0063] M is selected from none, CR 9 R 10 O, S, SO, SO2, NR 9 ;

[0064] R 9 , R 10 are independently selected from hydrogen, C1-C6 alkyl;

[0065] E 3 is a substituent on the benzene ring, and c is the number of substituents E 3 ;

[0066] Each E 3 is independently selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, C1-C6 alkoxy; or any two E 3 are joined to form a 3-6 membered cycloalkyl, 6-10 membered aryl, 4-12 membered heterocycloalkyl, 5-8 membered heteroaryl;

[0067] c is 0, 1, 2, or 3;

[0068] Y is absent, CR Y1 R Y2 , C(O), -CR 11 =CR 12 -, -CR 11 =N-, -N=N-, -OC(O)-;

[0069] R Y1 , R Y2 are independently selected from hydrogen, C1-C6 alkyl;

[0070] R 11 , R 12 are independently selected from hydrogen, C1-C6 alkyl;

[0071] The heteroatoms of the heteroaryl are O, N, or S; and the number of heteroatoms is 1, 2, or 3;

[0072] The heteroatoms of the heterocycloalkyl are N; and the number of heteroatoms is 1, 2, or 3.

[0073] Further, the compound is shown as formula (III):

[0074] wherein,

[0075] R 2 is a substituent on the benzene ring, and a is the number of substituents R 2 ;

[0076] Each R 2 is independently selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, C1-C6 alkoxy;

[0077] a is 0, 1, 2, or 3;

[0078] When the dashed line in the benzene ring represents a bond, R 3 R 4 Each is independently selected from none;

[0079] When the dashed line in the benzene ring is absent, R 3 R 4 Each is independently selected from hydrogen, C1-C6 alkyl, or R 3 R 4 Linkage forms 3- to 6-membered cycloalkyl groups;

[0080] R 5 The aryl or heteroaryl group is selected from C1-C6 alkyl, 3-6 membered cycloalkyl, trifluoromethyl, trifluoroethyl, substituted or unsubstituted 6-10 membered aryl, substituted or unsubstituted 5-8 membered heteroaryl; the substituent of the aryl or heteroaryl group is selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, C1-C6 alkoxy.

[0081] X is selected from CR 7 R 8 O, S, SO, SO2, NR 7 ;

[0082] R 7 R 8 Each is independently selected from hydrogen, halogen, C1-C6 alkyl, and 3-6 membered cycloalkyl;

[0083] n is 0, 1, or 2;

[0084] R 6 b is a substituent at any position on the benzene ring, and r is a substituent R. 6 The number of;

[0085] Each R 6 Each is independently selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, and C1-C6 alkoxy.

[0086] b can be 0, 1, 2, or 3;

[0087] Ring A and ring B are independently selected from 4- to 12-membered cycloalkyl and 4- to 12-membered heterocycloalkyl, respectively;

[0088] M is selected from none, CR 9 R 10 O, S, SO, SO2, NR 9 ;

[0089] R 9 R 10 Each is independently selected from hydrogen and C1-C6 alkyl groups;

[0090] E3 is a substituent on the phenyl ring at any position, c is the number of substituents E 3 is the number of substituents E

[0091] each E is independently selected from the group consisting of halogen, hydroxy, amino, cyano, trifluoromethyl, Ci-C6-alkyl, 3- to 6-membered cycloalkyl, Ci-C6-alkoxy; or any two E 3 are independently selected from the group consisting of halogen, hydroxy, amino, cyano, trifluoromethyl, Ci-C6-alkyl, 3- to 6-membered cycloalkyl, Ci-C6-alkoxy; or any two E 3 are linked to form a 3- to 6-membered cycloalkyl, a 6- to 10-membered aryl, a 4- to 12-membered heterocycloalkyl, a 5- to 8-membered heteroaryl;

[0092] c is 0, 1, 2 or 3;

[0093] Y is none, CR Y1 , C(O), -CR Y2 , -CR 11 =CR 12 , -CR 11 =N-, -N=N-, -OC(O)-;

[0094] R Y1 , R Y2 are independently selected from the group consisting of hydrogen, Ci-C6-alkyl;

[0095] R 11 , R 12 are independently selected from the group consisting of hydrogen, Ci-C6-alkyl;

[0096] the heteroatoms of the heteroaryl are O, N or S; the number of heteroatoms is 1, 2 or 3;

[0097] the heteroatoms of the heterocycloalkyl are N; the number of heteroatoms is 1, 2 or 3;

[0098] Preferably,

[0099] R 5 is selected from the group consisting of Ci-C6-alkyl, 3- to 6-membered cycloalkyl, trifluoromethyl, trifluoroethyl, substituted or unsubstituted phenyl, substituted or unsubstituted thienyl, substituted or unsubstituted furanyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted pyrimidinyl, substituted or unsubstituted pyridazinyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted pyrazinyl; the substituents of the phenyl, thienyl, furanyl, pyrrolyl, pyrimidinyl, pyridazinyl, pyrazolyl or pyrazinyl are selected from the group consisting of halogen, hydroxy, amino, cyano, trifluoromethyl, Ci-C6-alkyl, 3- to 6-membered cycloalkyl, Ci-C6-alkoxy;

[0100] X is selected from CH2, CF2, O, S, SO, SO2, NR 7 ;

[0101] R 7selected from hydrogen, halogen, C1-C6 alkyl, 3-6 membered cycloalkyl;

[0102] Ring A and Ring B are each independently selected from 4-12 membered cycloalkyl, 4-12 membered heterocycloalkyl; when both of said Ring A and Ring B are heterocycloalkyl, one of the rings has one heteroatom N and the other ring has two heteroatoms N.

[0103] Further, said compound is represented by Formula (IV):

[0104] wherein,

[0105] R 2 is a substituent on the benzene ring, and a is the number of substituents R 2 ;

[0106] each R 2 is independently selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, C1-C6 alkoxy;

[0107] a is 0, 1, 2, or 3;

[0108] R 3 , R 4 are each independently selected from hydrogen, C1-C6 alkyl; or R 3 , R 4 are joined to form a 3-6 membered cycloalkyl;

[0109] R 5 is selected from C1-C6 alkyl, 3-6 membered cycloalkyl, trifluoromethyl, trifluoroethyl, substituted or unsubstituted 6-10 membered aryl, substituted or unsubstituted 5-8 membered heteroaryl; the substituents of said aryl or heteroaryl are selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, C1-C6 alkoxy;

[0110] X is selected from CR 7 R 8 , O, S, SO, SO2, NR 7 ;

[0111] R 7 , R 8 are each independently selected from hydrogen, halogen, C1-C6 alkyl, 3-6 membered cycloalkyl;

[0112] n is 0, 1, or 2;

[0113] R 6 is a substituent on the benzene ring, and b is the number of substituents R 6 ;

[0114] each R 6each independently selected from the group consisting of halogen, hydroxy, amino, cyano, trifluoromethyl, C1-C6alkyl, 3-6 membered cycloalkyl, C1-C6alkoxy;

[0115] b is 0, 1, 2 or 3;

[0116] ring A and ring B are each independently selected from the group consisting of 4-12 membered cycloalkyl, 4-12 membered heterocycloalkyl;

[0117] M is selected from the group consisting of nothing, CR 9 R 10 , O, S, SO, SO2, NR 9 ;

[0118] R 9 , R 10 are each independently selected from the group consisting of hydrogen, C1-C6alkyl;

[0119] E 3 is a substituent on a benzene ring at any position, and c is the number of substituents E 3 ;

[0120] each E 3 is independently selected from the group consisting of halogen, hydroxy, amino, cyano, trifluoromethyl, C1-C6alkyl, 3-6 membered cycloalkyl, C1-C6alkoxy; or any two E 3 are linked to form a 3-6 membered cycloalkyl, 6-10 membered aryl, 4-12 membered heterocycloalkyl, 5-8 membered heteroaryl;

[0121] c is 0, 1, 2 or 3;

[0122] Y is nothing, CR Y1 R Y2 , C(O), -CR 11 =CR 12 -, -CR 11 =N-, -N=N-, -OC(O)-;

[0123] R Y1 , R Y2 are each independently selected from the group consisting of hydrogen, C1-C6alkyl;

[0124] R 11 , R 12 are each independently selected from the group consisting of hydrogen, C1-C6alkyl;

[0125] the heteroatom of the heteroaryl is O, N or S; and the number of heteroatoms is 1, 2 or 3;

[0126] the heteroatom of the heterocycloalkyl is N; and the number of heteroatoms is 1, 2 or 3;

[0127] Preferably,

[0128] R 5 selected from the group consisting of C1-C6 alkyl, 3-6 membered cycloalkyl, trifluoromethyl, trifluoroethyl, substituted or unsubstituted phenyl, substituted or unsubstituted thienyl, substituted or unsubstituted furanyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted pyrimidinyl, substituted or unsubstituted pyridazinyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted pyrazinyl; the substituents of the phenyl, thienyl, furanyl, pyrrolyl, pyrimidinyl, pyridazinyl, pyrazolyl or pyrazinyl are selected from the group consisting of halogen, hydroxyl, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, C1-C6 alkoxy;

[0129] X is selected from the group consisting of CH2, CF2, O, S, SO, SO2, NR 7 ;

[0130] R 7 is selected from the group consisting of hydrogen, halogen, C1-C6 alkyl, 3-6 membered cycloalkyl;

[0131] ring A and ring B are each independently selected from the group consisting of 4-12 membered cycloalkyl, 4-12 membered heterocycloalkyl; when both ring A and ring B are heterocycloalkyl, one of the rings has 1 heteroatom N and the other ring has 2 heteroatoms N.

[0132] Further, the compound is shown as formula (V):

[0133] wherein,

[0134] R 2 is a substituent on the phenyl ring, and a is the number of substituents R 2 ;

[0135] each R 2 is independently selected from the group consisting of halogen, hydroxyl, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, C1-C6 alkoxy;

[0136] a is 0, 1, 2 or 3;

[0137] R 3 , R 4 are each independently selected from the group consisting of hydrogen, C1-C6 alkyl, or R 3 , R 4 are linked to form a 3-6 membered cycloalkyl;

[0138] R 5 is selected from the group consisting of C1-C6 alkyl, 3-6 membered cycloalkyl, trifluoromethyl, trifluoroethyl, substituted or unsubstituted 6-10 membered aryl, substituted or unsubstituted 5-8 membered heteroaryl; the substituents of the aryl or heteroaryl are selected from the group consisting of halogen, hydroxyl, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, C1-C6 alkoxy;

[0139] X is selected from CR 7 R 8 , O, S, SO, SO2, NR 7 ;

[0140] R 7 , R 8 are each independently selected from hydrogen, halogen, C1-C6 alkyl, 3-6 membered cycloalkyl;

[0141] n is 0, 1 or 2;

[0142] R 6 is a substituent on the benzene ring, and b is the number of substituents R 6 ;

[0143] Each R 6 is independently selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, C1-C6 alkoxy;

[0144] b is 0, 1, 2 or 3;

[0145] Ring A and Ring B are each independently selected from 4-12 membered cycloalkyl, 4-12 membered heterocycloalkyl;

[0146] M is selected from none, CR 9 R 10 , O, S, SO, SO2, NR 9 ;

[0147] R 9 , R 10 are each independently selected from hydrogen, C1-C6 alkyl;

[0148] E 3 is a substituent on the benzene ring, and c is the number of substituents E 3 ;

[0149] Each E 3 is independently selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, C1-C6 alkoxy; or any two E 3 are joined to form a 3-6 membered cycloalkyl, 6-10 membered aryl, 4-12 membered heterocycloalkyl, 5-8 membered heteroaryl;

[0150] c is 0, 1, 2 or 3;

[0151] Y is selected from none, CR Y1 R Y2 , C(O), -CR 11 =CR 12 -, -CR 11= N-, -N=N-, -OC(O)-;

[0152] R Y1 , R Y2 are each independently selected from the group consisting of hydrogen, C1-C6 alkyl;

[0153] R 11 , R 12 are each independently selected from the group consisting of hydrogen, C1-C6 alkyl;

[0154] the heteroatom of the heteroaryl is O, N or S; the number of heteroatoms is 1, 2 or 3;

[0155] the heteroatom of the heterocycloalkyl is N; the number of heteroatoms is 1, 2 or 3;

[0156] Preferably,

[0157] R 5 is selected from the group consisting of C1-C6 alkyl, 3-6 membered cycloalkyl, trifluoromethyl, trifluoroethyl, substituted or unsubstituted phenyl, substituted or unsubstituted thienyl, substituted or unsubstituted furanyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted pyrimidinyl, substituted or unsubstituted pyridazinyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted pyrazinyl; the substituents of the phenyl, thienyl, furanyl, pyrrolyl, pyrimidinyl, pyridazinyl, pyrazolyl or pyrazinyl are selected from the group consisting of halogen, hydroxyl, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, C1-C6 alkoxy;

[0158] X is selected from the group consisting of CH2, CF2, O, S, SO, SO2, NR 7 ;

[0159] R 7 is selected from the group consisting of hydrogen, halogen, C1-C6 alkyl, 3-6 membered cycloalkyl;

[0160] ring A and ring B are each independently selected from the group consisting of 4-12 membered cycloalkyl, 4-12 membered heterocycloalkyl; when both ring A and ring B are heterocycloalkyl, one of the rings has 1 heteroatom N and the other ring has 2 heteroatoms N.

[0161] Further, the compound is shown as formula (VI):

[0162] wherein,

[0163] R 2 is a substituent on the phenyl ring, and a is the number of substituents R 2 ;

[0164] each R 2Each is independently selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, and C1-C6 alkoxy.

[0165] a can be 0, 1, 2, or 3;

[0166] R 3 R 4 Each is independently selected from hydrogen, C1-C6 alkyl, or R 3 R 4 Linkage forms 3- to 6-membered cycloalkyl groups;

[0167] R 5 The aryl or heteroaryl group is selected from C1-C6 alkyl, 3-6 membered cycloalkyl, trifluoromethyl, trifluoroethyl, substituted or unsubstituted 6-10 membered aryl, substituted or unsubstituted 5-8 membered heteroaryl; the substituent of the aryl or heteroaryl group is selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, C1-C6 alkoxy.

[0168] X is selected from CR 7 R 8 O, S, SO, SO2, NR 7 ;

[0169] R 7 R 8 Each is independently selected from hydrogen, halogen, C1-C6 alkyl, and 3-6 membered cycloalkyl;

[0170] R 6 b is a substituent at any position on the benzene ring, and r is a substituent R. 6 The number of;

[0171] Each R 6 Each is independently selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, and C1-C6 alkoxy.

[0172] b can be 0, 1, 2, or 3;

[0173] Ring A and ring B are independently selected from 4- to 12-membered cycloalkyl and 4- to 12-membered heterocycloalkyl, respectively;

[0174] M is selected from none, CR 9 R 10 O, S, SO, SO2, NR 9 ;

[0175] R 9 R 10 Each is independently selected from hydrogen and C1-C6 alkyl groups;

[0176] E 3 c is a substituent at any position on the benzene ring, and E is a substituent.3 The number of;

[0177] Each E 3 Each of the following groups is independently selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, C1-C6 alkoxy; or any two E groups. 3 They can be linked to form 3-6 membered cycloalkyl groups, 6-10 membered aryl groups, 4-12 membered heterocycloalkyl groups, and 5-8 membered heteroaryl groups;

[0178] c can be 0, 1, 2, or 3;

[0179] Y is none, CR Y1 R Y2 C(O), -CR 11 =CR 12 -、-CR 11 =N-, -N=N-, -OC(O)-;

[0180] R Y1 R Y2 Each is independently selected from hydrogen and C1-C6 alkyl groups;

[0181] R 11 R 12 Each is independently selected from hydrogen and C1-C6 alkyl groups;

[0182] The heteroatom of the heteroaryl group is O, N, or S; the number of heteroatoms is 1, 2, or 3;

[0183] The heterocyclic alkyl group has N heteroatom; the number of heteroatoms is 1, 2 or 3;

[0184] Preferably,

[0185] R 5 The substituent is selected from C1-C6 alkyl, 3-6 membered cycloalkyl, trifluoromethyl, trifluoroethyl, substituted or unsubstituted phenyl, substituted or unsubstituted thiophene, substituted or unsubstituted furanyl, substituted or unsubstituted pyrrole, substituted or unsubstituted pyrimidinyl, substituted or unsubstituted pyridazinyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted pyrazinyl; the substituent of the phenyl, thiophene, furanyl, pyrrole, pyrimidinyl, pyridazinyl, pyrazolyl or pyrazinyl is selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, C1-C6 alkoxy;

[0186] X is selected from CH2, CF2, O, S, SO, SO2, NR 7 ;

[0187] R 7 Selected from hydrogen, halogens, C1-C6 alkyl groups, and 3-6 membered cycloalkyl groups;

[0188] Ring A and ring B are independently selected from 4-12 membered cycloalkyl, 4-12 membered heterocycloalkyl; when both ring A and ring B are heterocycloalkyl, one of the rings has one heteroatom N and the other ring has two heteroatoms N.

[0189] Further, the compound is represented by formula (VII):

[0190] wherein,

[0191] R 3 , R 4 are independently selected from hydrogen, C1-C6 alkyl, or R 3 , R 4 are linked to form a 3-6 membered cycloalkyl group;

[0192] R 5 is selected from C1-C6 alkyl, 3-6 membered cycloalkyl, trifluoromethyl, trifluoroethyl, substituted or unsubstituted 6-10 membered aryl, substituted or unsubstituted 5-8 membered heteroaryl; the substituents of the aryl or heteroaryl are selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, C1-C6 alkoxy;

[0193] X is selected from CR 7 R 8 , O, S, SO, SO2, NR 7 ;

[0194] R 7 , R 8 are independently selected from hydrogen, halogen, C1-C6 alkyl, 3-6 membered cycloalkyl;

[0195] R 6 is a substituent on the benzene ring at any position, and b is the number of substituents R 6 ;

[0196] each R 6 is independently selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, C1-C6 alkoxy;

[0197] b is 0, 1, 2 or 3;

[0198] Ring A and ring B are independently selected from 4-12 membered cycloalkyl, 4-12 membered heterocycloalkyl;

[0199] M is selected from none, CR 9 R 10 , O, S, SO, SO2, NR 9 ;

[0200] R 9 , R 10each independently selected from the group consisting of hydrogen, C1-C6alkyl;

[0201] Y is none, CR Y1 R Y2 , C(O), -CR 11 =CR 12 -, -CR 11 =N-, -N=N-, -OC(O)-;

[0202] R Y1 , R Y2 each independently selected from the group consisting of hydrogen, C1-C6alkyl;

[0203] R 11 , R 12 each independently selected from the group consisting of hydrogen, C1-C6alkyl;

[0204] the heteroatom of the heteroaryl is O, N or S; the number of the heteroatom is 1, 2 or 3;

[0205] the heteroatom of the heterocycloalkyl is N; the number of the heteroatom is 1, 2 or 3;

[0206] Preferably,

[0207] R 5 is selected from the group consisting of C1-C6alkyl, 3-6 membered cycloalkyl, trifluoromethyl, trifluoroethyl, substituted or unsubstituted phenyl, substituted or unsubstituted thienyl, substituted or unsubstituted furanyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted pyrimidinyl, substituted or unsubstituted pyridazinyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted pyrazinyl; the substituents of the phenyl, thienyl, furanyl, pyrrolyl, pyrimidinyl, pyridazinyl, pyrazolyl or pyrazinyl are selected from the group consisting of halogen, hydroxyl, amino, cyano, trifluoromethyl, C1-C6alkyl, 3-6 membered cycloalkyl, C1-C6alkoxy;

[0208] X is selected from the group consisting of CH2, CF2, O, S, SO, SO2, NR 7 ;

[0209] R 7 is selected from the group consisting of hydrogen, halogen, C1-C6alkyl, 3-6 membered cycloalkyl;

[0210] ring A and ring B are each independently selected from the group consisting of 4-12 membered cycloalkyl, 4-12 membered heterocycloalkyl; when both ring A and ring B are heterocycloalkyl, one of the rings has 1 heteroatom N and the other ring has 2 heteroatoms N.

[0211] Further, the compound is shown as formula (VIII):

[0212] wherein,

[0213] R 3 , R 4 are each independently selected from hydrogen, C1-C6alkyl; or R 3 , R 4 are joined to form a 3-6 membered cycloalkyl group;

[0214] R 5 is selected from C1-C6alkyl, 3-6 membered cycloalkyl, trifluoromethyl, trifluoroethyl, substituted or unsubstituted 6-10 membered aryl, substituted or unsubstituted 5-8 membered heteroaryl; the substituents of said aryl or heteroaryl are selected from halogen, hydroxy, amino, cyano, trifluoromethyl, C1-C6alkyl, 3-6 membered cycloalkyl, C1-C6alkoxy;

[0215] X is selected from CR 7 R 8 , O, S, SO, SO2, NR 7 ;

[0216] R 7 , R 8 are each independently selected from hydrogen, halogen, C1-C6alkyl, 3-6 membered cycloalkyl;

[0217] Ring A and Ring B are each independently selected from 4-12 membered cycloalkyl, 4-12 membered heterocycloalkyl;

[0218] M is selected from none, CR 9 R 10 , O, S, SO, SO2, NR 9 ;

[0219] R 9 , R 10 are each independently selected from hydrogen, C1-C6alkyl;

[0220] Y is none, CR Y1 R Y2 , C(O), -CR 11 =CR 12 -, -CR 11 =N-, -N=N-, -OC(O)-;

[0221] R Y1 , R Y2 are each independently selected from hydrogen, C1-C6alkyl;

[0222] R 11 , R 12 are each independently selected from hydrogen, C1-C6alkyl;

[0223] the heteroatoms of said heteroaryl are O, N or S; the number of heteroatoms is 1, 2 or 3;

[0224] The heteroatom of the heterocycloalkyl group is N; the number of heteroatoms is 1, 2 or 3;

[0225] Preferably,

[0226] R 5 is selected from the group consisting of C1-C6 alkyl, 3-6 membered cycloalkyl, trifluoromethyl, substituted or unsubstituted phenyl, substituted or unsubstituted thienyl, substituted or unsubstituted furanyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted pyrimidinyl, substituted or unsubstituted pyridazinyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted pyrazinyl; the substituents of the phenyl, thienyl, furanyl, pyrrolyl, pyrimidinyl, pyridazinyl, pyrazolyl or pyrazinyl are selected from the group consisting of halogen, hydroxyl, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, C1-C6 alkoxy;

[0227] X is selected from the group consisting of CH2, CF2, O, S, SO, SO2, NR 7 ;

[0228] R 7 is selected from the group consisting of hydrogen, halogen, C1-C6 alkyl, 3-6 membered cycloalkyl;

[0229] ring A and ring B are each independently selected from the group consisting of 4-12 membered cycloalkyl, 4-12 membered heterocycloalkyl; when both ring A and ring B are heterocycloalkyl, one of the rings has 1 heteroatom N and the other ring has 2 heteroatoms N.

[0230] Further, the compound is as shown in formula (IX):

[0231] wherein,

[0232] R 3 , R 4 are each independently selected from the group consisting of hydrogen, C1-C6 alkyl, or R 3 , R 4 are linked to form a 3-6 membered cycloalkyl;

[0233] R 5 is selected from the group consisting of C1-C6 alkyl, 3-6 membered cycloalkyl, trifluoromethyl, trifluoroethyl, substituted or unsubstituted 6-10 membered aryl, substituted or unsubstituted 5-8 membered heteroaryl; the substituents of the aryl or heteroaryl are selected from the group consisting of halogen, hydroxyl, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, C1-C6 alkoxy;

[0234] X is selected from the group consisting of CR 7 R 8 , O, S, SO, SO2, NR 7 ;

[0235] R 7 , R8 each independently selected from the group consisting of hydrogen, halogen, C1-C6 alkyl, 3-6 membered cycloalkyl;

[0236] R 6 is a substituent on the phenyl ring, b is the number of substituents R 6 ;

[0237] each R 6 is independently selected from the group consisting of halogen, hydroxy, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, C1-C6 alkoxy;

[0238] b is 0, 1, 2 or 3;

[0239] ring A and ring B are each independently selected from the group consisting of 4-12 membered cycloalkyl, 4-12 membered heterocycloalkyl;

[0240] Y is absent, CR Y1 R Y2 , C(O), -CR 11 =CR 12 -, -CR 11 =N-, -N=N-, -OC(O)-;

[0241] R Y1 , R Y2 are each independently selected from the group consisting of hydrogen, C1-C6 alkyl;

[0242] R 11 , R 12 are each independently selected from the group consisting of hydrogen, C1-C6 alkyl;

[0243] the heteroatoms of said heteroaryl are O, N or S; the number of said heteroatoms is 1, 2 or 3;

[0244] the heteroatoms of said heterocycloalkyl are N; the number of said heteroatoms is 1, 2 or 3;

[0245] Preferably,

[0246] R 5 is selected from the group consisting of C1-C6 alkyl, 3-6 membered cycloalkyl, trifluoromethyl, trifluoroethyl, substituted or unsubstituted phenyl, substituted or unsubstituted thienyl, substituted or unsubstituted furanyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted pyrimidinyl, substituted or unsubstituted pyridazinyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted pyrazinyl; the substituents of said phenyl, thienyl, furanyl, pyrrolyl, pyrimidinyl, pyridazinyl, pyrazolyl or pyrazinyl are selected from the group consisting of halogen, hydroxy, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, C1-C6 alkoxy;

[0247] X is selected from CH2, CF2, O, S, SO, SO2, NR7 ;

[0248] R 7 is selected from hydrogen, halogen, C1-C6 alkyl, 3-6 membered cycloalkyl;

[0249] Ring A and Ring B are each independently selected from 4-12 membered cycloalkyl, 4-12 membered heterocycloalkyl; when both of said Ring A and Ring B are heterocycloalkyl, one of the rings has one heteroatom N and the other ring has two heteroatoms N.

[0250] Further, said compound is represented by Formula (X):

[0251] wherein,

[0252] R 3 , R 4 are each independently selected from hydrogen, C1-C6 alkyl; or R 3 , R 4 are joined to form a 3-6 membered cycloalkyl;

[0253] R 5 is selected from C1-C6 alkyl, 3-6 membered cycloalkyl, trifluoromethyl, trifluoroethyl, substituted or unsubstituted 6-10 membered aryl, substituted or unsubstituted 5-8 membered heteroaryl; the substituents of said aryl or heteroaryl are selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, C1-C6 alkoxy;

[0254] X is selected from CR 7 R 8 , O, S, SO, SO2, NR 7 ;

[0255] R 7 , R 8 are each independently selected from hydrogen, halogen, C1-C6 alkyl, 3-6 membered cycloalkyl;

[0256] Ring A and Ring B are each independently selected from 4-12 membered cycloalkyl, 4-12 membered heterocycloalkyl;

[0257] Y is absent, CR Y1 R Y2 , C(O), -CR 11 =CR 12 -, -CR 11 =N-, -N=N-, -OC(O)-;

[0258] R Y1 , R Y2 are each independently selected from hydrogen, C1-C6 alkyl;

[0259] R 11 , R12 each independently selected from hydrogen, C1-C6alkyl;

[0260] the heteroatoms of said heteroaryl are O, N or S; the number of said heteroatoms is 1, 2 or 3;

[0261] the heteroatoms of said heterocycloalkyl are N; the number of said heteroatoms is 1, 2 or 3;

[0262] Preferably,

[0263] R 5 selected from C1-C6alkyl, 3-6 membered cycloalkyl, trifluoromethyl, trifluoroethyl, substituted or unsubstituted phenyl, substituted or unsubstituted thienyl, substituted or unsubstituted furanyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted pyrimidinyl, substituted or unsubstituted pyridazinyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted pyrazinyl; the substituents of said phenyl, thienyl, furanyl, pyrrolyl, pyrimidinyl, pyridazinyl, pyrazolyl or pyrazinyl are selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C1-C6alkyl, 3-6 membered cycloalkyl, C1-C6alkoxy;

[0264] X is selected from CH2, CF2, O, S, SO, SO2, NR 7 ;

[0265] R 7 selected from hydrogen, halogen, C1-C6alkyl, 3-6 membered cycloalkyl;

[0266] rings A and B are each independently selected from 4-12 membered cycloalkyl, 4-12 membered heterocycloalkyl; when both of said rings A and B are heterocycloalkyl, one of said rings has 1 heteroatom N and the other ring has 2 heteroatoms N.

[0267] Further, said compound is represented by formula (XI):

[0268] wherein,

[0269] R 2 is a substituent on the phenyl ring, a is the number of substituents R 2 ;

[0270] each R 2 is independently selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C1-C6alkyl, 3-6 membered cycloalkyl, C1-C6alkoxy;

[0271] a is 0, 1, 2 or 3;

[0272] R 3 , R 4 are each independently selected from hydrogen, C1-C6alkyl; or R3 R 4 is a substituent on the phenyl ring, d is the number of substituents R 11 ;

[0273] R 11 is a substituent on the phenyl ring, d is the number of substituents R 11 ;

[0274] each R 11 is independently selected from the group consisting of halogen, hydroxy, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3- to 6-membered cycloalkyl, C1-C6 alkoxy;

[0275] d is 0, 1, 2 or 3;

[0276] X is selected from the group consisting of CR 7 R 8 , O, S, SO, SO2, NR 7 ;

[0277] R 7 , R 8 are each independently selected from the group consisting of hydrogen, halogen, C1-C6 alkyl, 3- to 6-membered cycloalkyl;

[0278] R 6 is a substituent on the phenyl ring, b is the number of substituents R 6 ;

[0279] each R 6 is independently selected from the group consisting of halogen, hydroxy, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3- to 6-membered cycloalkyl, C1-C6 alkoxy;

[0280] b is 0, 1, 2 or 3;

[0281] ring A and ring B are each independently selected from the group consisting of 4- to 12-membered cycloalkyl, 4- to 12-membered heterocycloalkyl;

[0282] M is selected from the group consisting of none, CR 9 R 10 , O, S, SO, SO2, NR 9 ;

[0283] R 9 , R 10 are each independently selected from the group consisting of hydrogen, C1-C6 alkyl;

[0284] E 3 is a substituent on the phenyl ring, c is the number of substituents E 3 ;

[0285] each E 3 is independently selected from the group consisting of halogen, hydroxy, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3- to 6-membered cycloalkyl, C1-C6 alkoxy; or any two E3 forming a 3-6 membered cycloalkyl, a 6-10 membered aryl, a 4-12 membered cycloalkyl, a 5-8 membered heteroaryl;

[0286] c is 0, 1, 2 or 3;

[0287] Y is nothing, CR Y1 R Y2 , C(O), -CR 11 =CR 12 -, -CR 11 =N-, -N=N-, -OC(O)-;

[0288] R Y1 , R Y2 are each independently selected from hydrogen, C1-C6 alkyl;

[0289] R 11 , R 12 are each independently selected from hydrogen, C1-C6 alkyl;

[0290] the heteroatom of the heteroaryl is O, N or S; the number of the heteroatom is 1, 2 or 3;

[0291] the heteroatom of the heterocycloalkyl is N; the number of the heteroatom is 1, 2 or 3;

[0292] Preferably,

[0293] X is selected from CH2, CF2, O, S, SO, SO2, NR 7 ;

[0294] R 7 is selected from hydrogen, halogen, C1-C6 alkyl, 3-6 membered cycloalkyl;

[0295] ring A and ring B are each independently selected from 4-12 membered cycloalkyl, 4-12 membered heterocycloalkyl; when both of the ring A and ring B are heterocycloalkyl, one of the rings has 1 heteroatom N and the other ring has 2 heteroatoms N.

[0296] Further, the compound is shown as formula (XII):

[0297] wherein,

[0298] R 2 is a substituent on the benzene ring, and a is the number of the substituent R 2 ;

[0299] each R 2 is independently selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, C1-C6 alkoxy;

[0300] a is 0, 1, 2 or 3;

[0301] R 3 , R 4 are each independently selected from the group consisting of hydrogen, C1-C6 alkyl, or R 3 , R 4 are linked to form a 3- to 6-membered cycloalkyl group;

[0302] R 11 is a substituent on the phenyl ring, and d is the number of substituents R 11 ;

[0303] each R 11 is independently selected from the group consisting of halogen, hydroxy, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3- to 6-membered cycloalkyl, C1-C6 alkoxy;

[0304] d is 0, 1, 2 or 3;

[0305] X is selected from the group consisting of CR 7 R 8 , O, S, SO, SO2, NR 7 ;

[0306] R 7 , R 8 are each independently selected from the group consisting of hydrogen, halogen, C1-C6 alkyl, 3- to 6-membered cycloalkyl;

[0307] R 6 is a substituent on the phenyl ring, and b is the number of substituents R 6 ;

[0308] each R 6 is independently selected from the group consisting of halogen, hydroxy, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3- to 6-membered cycloalkyl, C1-C6 alkoxy;

[0309] b is 0, 1, 2 or 3;

[0310] M is selected from the group consisting of none, CR 9 R 10 , O, S, SO, SO2, NR 9 ;

[0311] R 9 , R 10 are each independently selected from the group consisting of hydrogen, C1-C6 alkyl;

[0312] R 12 is selected from the group consisting of hydrogen, halogen, C1-C6 alkyl, hydroxy;

[0313] m1, m2, m3, m4, m5, m6 are each independently selected from 0, 1, 2 or 3;

[0314] E 3 is a substituent on the phenyl ring, c is the number of substituents E 3 ;

[0315] each E 3 is independently selected from halogen, hydroxy, amino, cyano, trifluoromethyl, Ci-C6-alkyl, 3- to 6-membered cycloalkyl, Ci-C6-alkoxy; or any two E 3 are linked to form a 3- to 6-membered cycloalkyl, a 6- to 10-membered aryl, a 4- to 12-membered heterocycloalkyl, a 5- to 8-membered heteroaryl;

[0316] c is 0, 1, 2 or 3;

[0317] Y is nothing, CR Y1 R Y2 , C(O), -CR 11 =CR 12 -, -CR 11 =N-, -N=N-, -OC(O)-;

[0318] R Y1 , R Y2 are independently selected from hydrogen, Ci-C6-alkyl;

[0319] R 11 , R 12 are independently selected from hydrogen, Ci-C6-alkyl;

[0320] the heteroatoms of the heteroaryl are O, N or S; the number of heteroatoms is 1, 2 or 3;

[0321] the heteroatoms of the heterocycloalkyl are N; the number of heteroatoms is 1, 2 or 3;

[0322] Preferably,

[0323] X is selected from CH2, CF2, O, S, SO, SO2, NR 7 ;

[0324] R 7 is selected from hydrogen, halogen, Ci-C6-alkyl, 3- to 6-membered cycloalkyl;

[0325] Y is nothing, CR Y1 R Y2 , C(O), -CR 11 =CR 12 -, -CR 11 =N-, -N=N-, -OC(O)-;

[0326] R Y1 , R Y2are each independently selected from the group consisting of hydrogen, C1-C6alkyl;

[0327] R 11 , R 12 are each independently selected from the group consisting of hydrogen, C1-C6alkyl.

[0328] Further, the compound is represented by formula (XIII):

[0329] wherein,

[0330] R 2 is a substituent on the benzene ring, and a is the number of substituents R 2 ;

[0331] each R 2 is independently selected from the group consisting of halogen, hydroxy, amino, cyano, trifluoromethyl, C1-C6alkyl, 3- to 6-membered cycloalkyl, C1-C6alkoxy;

[0332] a is 0, 1, 2, or 3;

[0333] R 3 , R 4 are each independently selected from the group consisting of hydrogen, C1-C6alkyl, or R 3 , R 4 are joined to form a 3- to 6-membered cycloalkyl group;

[0334] R 11 is a substituent on the benzene ring, and d is the number of substituents R 11 ;

[0335] each R 11 is independently selected from the group consisting of halogen, hydroxy, amino, cyano, trifluoromethyl, C1-C6alkyl, 3- to 6-membered cycloalkyl, C1-C6alkoxy;

[0336] d is 0, 1, 2, or 3;

[0337] X is selected from the group consisting of CR 7 R 8 , O, S, SO, SO2, NR 7 ;

[0338] R 7 , R 8 are each independently selected from the group consisting of hydrogen, halogen, C1-C6alkyl, 3- to 6-membered cycloalkyl;

[0339] R 6 is a substituent on the benzene ring, and b is the number of substituents R 6 ;

[0340] each R 6each E is independently selected from the group consisting of halogen, hydroxyl, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, C1-C6 alkoxy; or any two E are linked to form a 3-6 membered cycloalkyl, 6-10 membered aryl, 4-12 membered heterocycloalkyl, 5-8 membered heteroaryl;

[0341] b is 0, 1, 2 or 3;

[0342] R 12 is selected from the group consisting of hydrogen, halogen, C1-C6 alkyl, hydroxyl;

[0343] m1, m2, m3, m4, m5, m6 are each independently selected from 0, 1, 2 or 3;

[0344] E 3 is a substituent on the benzene ring, c is the number of substituents E 3 ;

[0345] each E 3 is independently selected from the group consisting of halogen, hydroxyl, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, C1-C6 alkoxy; or any two E are linked to form a 3-6 membered cycloalkyl, 6-10 membered aryl, 4-12 membered heterocycloalkyl, 5-8 membered heteroaryl; 3

[0346] c is 0, 1, 2 or 3;

[0347] Y is absent, CR Y1 R Y2 , C(O), -CR 11 =CR 12 -, -CR 11 =N-, -N=N-, -OC(O)-;

[0348] R Y1 , R Y2 are each independently selected from the group consisting of hydrogen, C1-C6 alkyl;

[0349] R 11 , R 12 are each independently selected from the group consisting of hydrogen, C1-C6 alkyl;

[0350] the heteroatoms of the heteroaryl are O, N or S; the number of heteroatoms is 1, 2 or 3;

[0351] the heteroatoms of the heterocycloalkyl are N; the number of heteroatoms is 1, 2 or 3;

[0352] Preferably,

[0353] X is selected from CH2, CF2, O, S, SO, SO2, NR 7 ;

[0354] R 7 ​selected from the group consisting of hydrogen, halogen, C1-C6 alkyl, 3-6 membered cycloalkyl;

[0355] Y is none, CR Y1 R Y2 , C(O), -CR 11 =CR 12 -, -CR 11 =N-, -N=N-, -OC(O)-;

[0356] R Y1 , R Y2 are each independently selected from the group consisting of hydrogen, C1-C6 alkyl;

[0357] R 11 , R 12 are each independently selected from the group consisting of hydrogen, C1-C6 alkyl.

[0358] Further, the compound is represented by formula (XIV):

[0359] wherein,

[0360] R 2 is a substituent on the benzene ring at any position, and a is the number of substituents R 2 ;

[0361] Each R 2 is independently selected from the group consisting of halogen, hydroxy, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, C1-C6 alkoxy;

[0362] a is 0, 1, 2, or 3;

[0363] R 3 , R 4 are each independently selected from the group consisting of hydrogen, C1-C6 alkyl, or R 3 , R 4 are linked to form a 3-6 membered cycloalkyl group;

[0364] R 11 is a substituent on the benzene ring at any position, and d is the number of substituents R 11 ;

[0365] Each R 11 is independently selected from the group consisting of halogen, hydroxy, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, C1-C6 alkoxy;

[0366] d is 0, 1, 2, or 3;

[0367] X is selected from the group consisting of CR 7 R 8 , O, S, SO, SO2, NR 7 ;

[0368] R 7 , R 8 are each independently selected from the group consisting of hydrogen, halogen, C1-C6 alkyl, 3-6 membered cycloalkyl;

[0369] R 6 is a substituent on the benzene ring, and b is the number of substituents R 6 ;

[0370] each R 6 is independently selected from the group consisting of halogen, hydroxyl, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, C1-C6 alkoxy;

[0371] b is 0, 1, 2, or 3;

[0372] R 12 is selected from the group consisting of hydrogen, halogen, C1-C6 alkyl, hydroxyl;

[0373] m1, m2, m3, m4, m5, m6 are each independently selected from 0, 1, 2, or 3;

[0374] E 3 is a substituent on the benzene ring, and c is the number of substituents E 3 ;

[0375] each E 3 is independently selected from the group consisting of halogen, hydroxyl, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, C1-C6 alkoxy; or any two E 3 are linked to form a 3-6 membered cycloalkyl, 6-10 membered aryl, 4-12 membered heterocycloalkyl, 5-8 membered heteroaryl;

[0376] c is 0, 1, 2, or 3;

[0377] Y is absent, CR Y1 R Y2 , C(O), -CR 11 =CR 12 -, -CR 11 =N-, -N=N-, -OC(O)-;

[0378] R Y1 , R Y2 are each independently selected from the group consisting of hydrogen, C1-C6 alkyl;

[0379] R 11 , R 12 are each independently selected from the group consisting of hydrogen, C1-C6 alkyl;

[0380] the heteroatoms of the heteroaryl are O, N, or S; and the number of heteroatoms is 1, 2, or 3;

[0381] the heteroatom of the heterocycloalkyl group is N; the number of heteroatoms is 1, 2 or 3;

[0382] Preferably,

[0383] X is selected from CH2, CF2, O, S, SO, SO2, NR 7 ;

[0384] R 7 is selected from hydrogen, halogen, C1-C6 alkyl, 3-6 membered cycloalkyl;

[0385] Y is none, CR Y1 R Y2 , C(O), -CR 11 =CR 12 -, -CR 11 =N-, -N=N-, -OC(O)-;

[0386] R Y1 , R Y2 are each independently selected from hydrogen, C1-C6 alkyl;

[0387] R 11 , R 12 are each independently selected from hydrogen, C1-C6 alkyl.

[0388] Further, the compound is represented by formula (XV):

[0389] wherein,

[0390] R 2 is a substituent on the phenyl ring at any position, and a is the number of substituents R 2 ;

[0391] each R 2 is independently selected from halogen, hydroxy, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, C1-C6 alkoxy;

[0392] a is 0, 1, 2 or 3;

[0393] R 3 , R 4 are each independently selected from hydrogen, C1-C6 alkyl, or R 3 , R 4 are linked to form a 3-6 membered cycloalkyl group;

[0394] R 11 is a substituent on the thiophene ring at any position, and d is the number of substituents R 11 ;

[0395] each R 11each independently selected from the group consisting of halogen, hydroxy, amino, cyano, trifluoromethyl, C1-C6alkyl, 3- to 6-membered cycloalkyl, C1-C6alkoxy;

[0396] d is 0, 1, 2, or 3;

[0397] X is selected from CR 7 R 8 , O, S, SO, SO2, NR 7 ;

[0398] R 7 , R 8 are each independently selected from the group consisting of hydrogen, halogen, C1-C6alkyl, 3- to 6-membered cycloalkyl;

[0399] R 6 is a substituent on the phenyl ring, and b is the number of substituents R 6 ;

[0400] each R 6 is independently selected from the group consisting of halogen, hydroxy, amino, cyano, trifluoromethyl, C1-C6alkyl, 3- to 6-membered cycloalkyl, C1-C6alkoxy;

[0401] b is 0, 1, 2, or 3;

[0402] Ring A and Ring B are each independently selected from 4- to 12-membered cycloalkyl, 4- to 12-membered heterocycloalkyl;

[0403] M is selected from none, CR 9 R 10 , O, S, SO, SO2, NR 9 ;

[0404] R 9 , R 10 are each independently selected from the group consisting of hydrogen, C1-C6alkyl;

[0405] E 3 is a substituent on the phenyl ring, and c is the number of substituents E 3 ;

[0406] each E 3 is independently selected from the group consisting of halogen, hydroxy, amino, cyano, trifluoromethyl, C1-C6alkyl, 3- to 6-membered cycloalkyl, C1-C6alkoxy; or any two E 3 are joined to form a 3- to 6-membered cycloalkyl, 6- to 10-membered aryl, 4- to 12-membered heterocycloalkyl, 5- to 8-membered heteroaryl;

[0407] c is 0, 1, 2, or 3;

[0408] Y is selected from none, CR Y1 R Y2 , C(O), -CR11 =CR 12 -、-CR 11 =N-、-N=N-、-OC(O)-;

[0409] R Y1 、R Y2 are each independently selected from the group consisting of hydrogen, C1-C6 alkyl;

[0410] R 11 、R 12 are each independently selected from the group consisting of hydrogen, C1-C6 alkyl;

[0411] the heteroatom of the heteroaryl is O, N or S; and the number of the heteroatom is 1, 2 or 3;

[0412] the heteroatom of the heterocycloalkyl is N; and the number of the heteroatom is 1, 2 or 3;

[0413] Preferably,

[0414] X is selected from the group consisting of CH2, CF2, O, S, SO, SO2, NR 7 ;

[0415] R 7 is selected from the group consisting of hydrogen, halogen, C1-C6 alkyl, 3-6 membered cycloalkyl;

[0416] ring A and ring B are each independently selected from the group consisting of 4-12 membered cycloalkyl, 4-12 membered heterocycloalkyl; when both ring A and ring B are heterocycloalkyl, one of the rings has 1 heteroatom N and the other ring has 2 heteroatoms N.

[0417] Further, the compound is shown as formula (XVI):

[0418] wherein,

[0419] R 2 is a substituent on the benzene ring, and a is the number of substituents R 2 ;

[0420] each R 2 is independently selected from the group consisting of halogen, hydroxyl, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, C1-C6 alkoxy;

[0421] a is 0, 1, 2 or 3;

[0422] R 3 , R 4 are each independently selected from the group consisting of hydrogen, C1-C6 alkyl, or R 3 , R 4 are linked to form a 3-6 membered cycloalkyl;

[0423] R 11 is a substituent on the thiophene ring at any position, and d is the number of substituents R 11 ;

[0424] each R 11 is independently selected from the group consisting of halogen, hydroxy, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3- to 6-membered cycloalkyl, C1-C6 alkoxy;

[0425] d is 0, 1, 2, or 3;

[0426] X is selected from the group consisting of CR 7 R 8 , O, S, SO, SO2, NR 7 ;

[0427] R 7 , R 8 are each independently selected from the group consisting of hydrogen, halogen, C1-C6 alkyl, 3- to 6-membered cycloalkyl;

[0428] R 6 is a substituent on the benzene ring at any position, and b is the number of substituents R 6 ;

[0429] each R 6 is independently selected from the group consisting of halogen, hydroxy, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3- to 6-membered cycloalkyl, C1-C6 alkoxy;

[0430] b is 0, 1, 2, or 3;

[0431] Ring A and Ring B are each independently selected from the group consisting of 4- to 12-membered cycloalkyl, 4- to 12-membered heterocycloalkyl;

[0432] M is selected from the group consisting of none, CR 9 R 10 , O, S, SO, SO2, NR 9 ;

[0433] R 9 , R 10 are each independently selected from the group consisting of hydrogen, C1-C6 alkyl;

[0434] E 3 is a substituent on the benzene ring at any position, and c is the number of substituents E 3 ;

[0435] each E 3 is independently selected from the group consisting of halogen, hydroxy, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3- to 6-membered cycloalkyl, C1-C6 alkoxy; or any two E 3 are joined to form a 3- to 6-membered cycloalkyl, 6- to 10-membered aryl, 4- to 12-membered heterocycloalkyl, 5- to 8-membered heteroaryl;

[0436] c is 0, 1, 2 or 3;

[0437] Y is nothing, CR Y1 R Y2 , C(O), -CR 11 =CR 12 -, -CR 11 =N-, -N=N-, -OC(O)-;

[0438] R Y1 , R Y2 are each independently selected from the group consisting of hydrogen, C1-C6 alkyl;

[0439] R 11 , R 12 are each independently selected from the group consisting of hydrogen, C1-C6 alkyl;

[0440] the heteroatom of the heteroaryl is O, N or S; the number of the heteroatom is 1, 2 or 3;

[0441] the heteroatom of the heterocycloalkyl is N; the number of the heteroatom is 1, 2 or 3;

[0442] Preferably,

[0443] X is selected from the group consisting of CH2, CF2, O, S, SO, SO2, NR 7 ;

[0444] R 7 is selected from the group consisting of hydrogen, halogen, C1-C6 alkyl, 3-6 membered cycloalkyl;

[0445] ring A and ring B are each independently selected from the group consisting of 4-12 membered cycloalkyl, 4-12 membered heterocycloalkyl; when both of ring A and ring B are heterocycloalkyl, one of the rings has 1 heteroatom N and the other ring has 2 heteroatoms N.

[0446] Further, the compound is shown as formula (XVII):

[0447] wherein,

[0448] R 3 , R 4 are each independently selected from the group consisting of hydrogen, C1-C6 alkyl, or R 3 , R 4 are linked to form a 3-6 membered cycloalkyl;

[0449] X is selected from the group consisting of CR 7 R 8 , O, S, SO, SO2, NR 7 ;

[0450] R 7 , R8 Each is independently selected from hydrogen, halogen, C1-C6 alkyl, and 3-6 membered cycloalkyl;

[0451] R 11 d represents a substituent at any position on the benzene ring, where d is the substituent R. 11 The number of R; 6 b is a substituent at any position on the benzene ring, and r is a substituent R. 6 The number of;

[0452] d is 0, 1, 2, or 3; b is 0, 1, 2, or 3; and at least one of d and b is not 0;

[0453] Each R 11 R 6 Each of the following groups is independently selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, and C1-C6 alkoxy groups; and at least one of them is fluorine.

[0454] Ring A and ring B are independently selected from 4- to 12-membered cycloalkyl and 4- to 12-membered heterocycloalkyl, respectively;

[0455] M is selected from none, CR 9 R 10 O, S, SO, SO2, NR 9 ;

[0456] R 9 R 10 Each is independently selected from hydrogen and C1-C6 alkyl groups;

[0457] Y is none, CR Y1 R Y2 C(O), -CR 11 =CR 12 -、-CR 11 =N-, -N=N-, -OC(O)-;

[0458] R Y1 R Y2 Each is independently selected from hydrogen and C1-C6 alkyl groups;

[0459] R 11 R 12 Each is independently selected from hydrogen and C1-C6 alkyl groups;

[0460] The heterocyclic alkyl group has N heteroatom; the number of heteroatoms is 1, 2 or 3;

[0461] Preferably,

[0462] X is selected from CH2, CF2, O, S, SO, SO2, NR 7 ;

[0463] R 7 Selected from hydrogen, halogens, C1-C6 alkyl groups, and 3-6 membered cycloalkyl groups;

[0464] Ring A and ring B are independently selected from 4- to 12-membered cycloalkyl and 4- to 12-membered heterocycloalkyl, respectively; when both ring A and ring B are heterocycloalkyl, one ring has one heteroatom N and the other ring has two heteroatom N.

[0465] Furthermore, the compound is as shown in formula (XVIII):

[0466] in,

[0467] X is selected from CR 7 R 8 O, S, SO, SO2, NR 7 ;

[0468] R 7 R 8 Each is independently selected from hydrogen, halogen, C1-C6 alkyl, and 3-6 membered cycloalkyl;

[0469] R 11 d represents a substituent at any position on the benzene ring, where d is the substituent R. 11 The number of R; 6 b is a substituent at any position on the benzene ring, and r is a substituent R. 6 The number of;

[0470] d is 0, 1, 2, or 3; b is 0, 1, 2, or 3; and at least one of d and b is not 0;

[0471] Each R 11 R 6 Each of the following groups is independently selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, and C1-C6 alkoxy groups; and at least one of them is fluorine.

[0472] Ring A and ring B are independently selected from 4- to 12-membered cycloalkyl and 4- to 12-membered heterocycloalkyl, respectively;

[0473] M is selected from none, CR 9 R 10 ;

[0474] R 9 R 10 Each is independently selected from hydrogen and C1-C6 alkyl groups;

[0475] Y is none, CR Y1 R Y2 C(O), -CR 11 =CR 12 -、-CR 11=O-, =S-, =N-, =N=, -OC(O)-;

[0476] R Y1 , R Y2 are each independently selected from the group consisting of hydrogen, C1-C6 alkyl;

[0477] R 11 , R 12 are each independently selected from the group consisting of hydrogen, C1-C6 alkyl;

[0478] the heteroatom of the heterocycloalkyl is N; the number of heteroatoms is 1, 2 or 3;

[0479] Preferably,

[0480] X is selected from CH2, CF2 or O;

[0481] ring A and ring B are each independently selected from the group consisting of 4-12 membered cycloalkyl, 4-12 membered heterocycloalkyl; when both ring A and ring B are heterocycloalkyl, one of the rings has 1 heteroatom N and the other ring has 2 heteroatoms N.

[0482] Further, the compound is represented by formula (XIX):

[0483] wherein,

[0484] R 1 is selected from the group consisting of hydrogen, C1-C6 alkyl, hydroxyl, amino or C1-C6 alkoxy, boronic acid group;

[0485] R 2 is a substituent on the benzene ring, and a is the number of substituents R 2 ;

[0486] each R 2 is independently selected from the group consisting of halogen, hydroxyl, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, C1-C6 alkoxy;

[0487] a is 0, 1, 2 or 3;

[0488] R 5 is selected from the group consisting of C1-C6 alkyl, 3-6 membered cycloalkyl, trifluoromethyl, trifluoroethyl, substituted or unsubstituted 6-10 membered aryl, substituted or unsubstituted 5-8 membered heteroaryl; the substituents of the aryl or heteroaryl are selected from the group consisting of halogen, hydroxyl, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, C1-C6 alkoxy;

[0489] X is selected from CR 7 R 8 , O, S, SO, SO2, NR 7 ;

[0490] R 7 , R 8 are each independently selected from the group consisting of hydrogen, halogen, C1-C6 alkyl, 3-6 membered cycloalkyl;

[0491] n is 0, 1 or 2;

[0492] R 6 is a substituent on the phenyl ring, and b is the number of substituents R 6 ;

[0493] each R 6 is independently selected from the group consisting of halogen, hydroxy, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, C1-C6 alkoxy;

[0494] b is 0, 1, 2 or 3;

[0495] ring A and ring B are each independently selected from the group consisting of 4-12 membered cycloalkyl, 4-12 membered heterocycloalkyl;

[0496] M is selected from the group consisting of nothing, CR 9 R 10 , O, S, SO, SO2, NR 9 ;

[0497] R 9 , R 10 are each independently selected from the group consisting of hydrogen, C1-C6 alkyl;

[0498] E 3 is a substituent on the phenyl ring, and c is the number of substituents E 3 ;

[0499] each E 3 is independently selected from the group consisting of halogen, hydroxy, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, C1-C6 alkoxy; or any two E 3 are joined to form a 3-6 membered cycloalkyl, 6-10 membered aryl, 4-12 membered heterocycloalkyl, 5-8 membered heteroaryl;

[0500] c is 0, 1, 2 or 3;

[0501] Y is selected from the group consisting of nothing, CR Y1 R Y2 , C(O), -CR 11 =CR 12 -, -CR 11 =N-, -N=N-, -OC(O)-;

[0502] R Y1 , R Y2 are each independently selected from the group consisting of hydrogen, C1-C6 alkyl;

[0503] R 11 , R 12 are independently selected from the group consisting of hydrogen, C1-C6 alkyl;

[0504] the heteroatom of the heteroaryl is O, N or S; the number of heteroatoms is 1, 2 or 3;

[0505] the heteroatom of the heterocycloalkyl is N; the number of heteroatoms is 1, 2 or 3;

[0506] Preferably,

[0507] R 5 is selected from the group consisting of C1-C6 alkyl, 3-6 membered cycloalkyl, trifluoromethyl, trifluoroethyl, substituted or unsubstituted phenyl, substituted or unsubstituted thienyl, substituted or unsubstituted furanyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted pyrimidinyl, substituted or unsubstituted pyridazinyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted pyrazinyl; the substituents of the phenyl, thienyl, furanyl, pyrrolyl, pyrimidinyl, pyridazinyl, pyrazolyl or pyrazinyl are selected from the group consisting of halogen, hydroxyl, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, C1-C6 alkoxy.

[0508] Further, the compound is according to formula (XX):

[0509] wherein,

[0510] R 5 is selected from the group consisting of C1-C6 alkyl, 3-6 membered cycloalkyl, trifluoromethyl, trifluoroethyl, substituted or unsubstituted 6-10 membered aryl, substituted or unsubstituted 5-8 membered heteroaryl; the substituents of the aryl or heteroaryl are selected from the group consisting of halogen, hydroxyl, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, C1-C6 alkoxy;

[0511] X is selected from CR 7 R 8 , O, S, SO, SO2, NR 7 ;

[0512] R 7 , R 8 are independently selected from the group consisting of hydrogen, halogen, C1-C6 alkyl, 3-6 membered cycloalkyl;

[0513] R 6 is a substituent at any position of the phenyl ring, b is the number of substituents R 6 ;

[0514] each R 6each independently selected from the group consisting of halogen, hydroxy, amino, cyano, trifluoromethyl, Ci-C6-alkyl, 3- to 6-membered cycloalkyl, Ci-C6-alkoxy;

[0515] b is 0, 1, 2 or 3;

[0516] ring A and ring B are each independently selected from the group consisting of 4- to 12-membered cycloalkyl, 4- to 12-membered heterocycloalkyl;

[0517] M is selected from the group consisting of nothing, CR 9 R 10 , O, S, SO, SO2, NR 9 ;

[0518] R 9 , R 10 are each independently selected from the group consisting of hydrogen, Ci-C6-alkyl;

[0519] Y is nothing, CR Y1 R Y2 , C(O), -CR 11 =CR 12 -, -CR 11 =N-, -N=N-, -OC(O)-;

[0520] R Y1 , R Y2 are each independently selected from the group consisting of hydrogen, Ci-C6-alkyl;

[0521] R 11 , R 12 are each independently selected from the group consisting of hydrogen, Ci-C6-alkyl;

[0522] the heteroatoms of said heteroaryl are O, N or S; the number of heteroatoms is 1, 2 or 3;

[0523] the heteroatoms of said heterocycloalkyl are N; the number of heteroatoms is 1, 2 or 3;

[0524] Preferably,

[0525] R 5 is selected from the group consisting of Ci-C6-alkyl, 3- to 6-membered cycloalkyl, trifluoromethyl, trifluoroethyl, substituted or unsubstituted phenyl, substituted or unsubstituted thienyl, substituted or unsubstituted furanyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted pyrimidinyl, substituted or unsubstituted pyridazinyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted pyrazinyl; the substituents of said phenyl, thienyl, furanyl, pyrrolyl, pyrimidinyl, pyridazinyl, pyrazolyl or pyrazinyl are selected from the group consisting of halogen, hydroxy, amino, cyano, trifluoromethyl, Ci-C6-alkyl, 3- to 6-membered cycloalkyl, Ci-C6-alkoxy;

[0526] X is selected from the group consisting of CH2, CF2, O, S, SO, SO2, NR7 ;

[0527] R 7 is selected from hydrogen, halogen, C1-C6 alkyl, 3-6 membered cycloalkyl;

[0528] ring A and ring B are each independently selected from 4-12 membered cycloalkyl, 4-12 membered heterocycloalkyl; when both ring A and ring B are heterocycloalkyl, one ring has one heteroatom N and the other ring has two heteroatoms N.

[0529] Further, the compound is shown as formula (XXI):

[0530] wherein,

[0531] R 11 is a substituent on the benzene ring at any position, and d is the number of substituents R 11 ;

[0532] each R 11 is independently selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, C1-C6 alkoxy;

[0533] d is 0, 1, 2, or 3;

[0534] X is selected from CR 7 R 8 , O, S, SO, SO2, NR 7 ;

[0535] R 7 , R 8 are each independently selected from hydrogen, halogen, C1-C6 alkyl, 3-6 membered cycloalkyl;

[0536] R 6 is a substituent on the benzene ring at any position, and b is the number of substituents R 6 ;

[0537] each R 6 is independently selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, C1-C6 alkoxy;

[0538] b is 0, 1, 2, or 3;

[0539] M is selected from none, CR 9 R 10 , O, S, SO, SO2, NR 9 ;

[0540] R 9 , R 10 are each independently selected from hydrogen, C1-C6 alkyl;

[0541] m1, m2, m3, m4, m5, m6 are each independently selected from 0, 1, 2 or 3;

[0542] Y is absent, CR Y1 R Y2 , C(O), -CR 11 =CR 12 -, -CR 11 =N-, -N=N-, -OC(O)-;

[0543] R Y1 , R Y2 are each independently selected from hydrogen, C1-C6 alkyl;

[0544] R 11 , R 12 are each independently selected from hydrogen, C1-C6 alkyl;

[0545] Preferably,

[0546] X is selected from CH2, CF2, O, S, SO, SO2, NR 7 ;

[0547] R 7 is selected from hydrogen, halogen, C1-C6 alkyl, 3-6 membered cycloalkyl.

[0548] Further, the ring A and ring B are each independently selected from the following structures:

[0549] Further, the is selected from the following structures:

[0550] Further, the compound is one of the following compounds:

[0551] Further, the compound is ARV-471 or compound 75 or compound 63 or compound 65;

[0552] The structure of the ARV-471 is The structure of the compound 75 is The structure of the compound 63 is The structure of the compound 65 is

[0553] Further, the salt is a pharmaceutically acceptable salt; the pharmaceutically acceptable salt is a phosphate salt, a d-camphorsulfonic acid salt, a hydrochloride salt, a hydrobromic acid salt, a hydrofluoric acid salt, a sulfuric acid salt, a nitric acid salt, a formic acid salt, an acetic acid salt, a propionic acid salt, an oxalic acid salt, a malonic acid salt, a succinic acid salt, a fumaric acid salt, a maleic acid salt, a lactic acid salt, a malic acid salt, a tartaric acid salt, a citric acid salt, a picric acid salt, a methane sulfonic acid salt, a benzene sulfonic acid salt, a benzenesulfonic acid salt, an aspartic acid salt, or a glutamic acid salt of the compound.

[0554] Further, the AKT inhibitor is MK-2206 2HCl, Perifosine, GSK69069, Ipatasertib, Capivasertib, PF-04691502, AT7867, Triciribine (API-2), CCT128930, A-674563HCl, PHT-427, Miransertib HCl, Akti-1 / 2, Uprosertib, Afuresertib, AT13148, Miltefosine, Honokiol, TIC10 Analogue, Deguelin, TIC10 (ONC201), or an optical isomer thereof, a salt thereof, a hydrate thereof, a solvate thereof.

[0555] Preferably, the AKT inhibitor is Capivasertib or an optical isomer thereof, a salt thereof, a hydrate thereof, a solvate thereof.

[0556] Further, when the estrogen receptor degrader is ARV-471 or an optical isomer thereof, a salt thereof, a hydrate thereof, a solvate thereof, and the AKT inhibitor is Capivasertib or an optical isomer thereof, a salt thereof, a hydrate thereof, a solvate thereof, the molar ratio of the estrogen receptor degrader to the AKT inhibitor is 1:1.1-1:268.3; the molar ratio is preferably 1:1.1, 1:29.7, 1:268.3.

[0557] Further, when the estrogen receptor degrader is Compound 75 or an optical isomer thereof, a salt thereof, a hydrate thereof, a solvate thereof, and the AKT inhibitor is Capivasertib or an optical isomer thereof, a salt thereof, a hydrate thereof, a solvate thereof, the molar ratio of the estrogen receptor degrader to the AKT inhibitor is 1:1.1-1:268.3; the molar ratio is preferably 1:1.1, 1:29.7, 1:268.3.

[0558] Further, when the estrogen receptor degrader is Compound 63 or an optical isomer thereof, a salt thereof, a hydrate thereof, a solvate thereof, and the AKT inhibitor is Capivasertib or an optical isomer thereof, a salt thereof, a hydrate thereof, a solvate thereof, the molar ratio of the estrogen receptor degrader to the AKT inhibitor is 1:0.37-90.2; preferably, the molar ratio is 1:0.37, 1:10, 1:90.2.

[0559] Further, when the estrogen receptor degrader is Compound 65 or an optical isomer thereof, a salt thereof, a hydrate thereof, a solvate thereof, and the AKT inhibitor is Capivasertib or an optical isomer thereof, a salt thereof, a hydrate thereof, a solvate thereof, the molar ratio of the estrogen receptor degrader to the AKT inhibitor is 1:0.37-90.2; preferably, the molar ratio is 1:0.37, 1:10, 1:90.2.

[0560] The present application also provides a preparation method of the aforementioned pharmaceutical composition, which comprises the following steps: taking the estrogen receptor degrader and the AKT inhibitor according to the molar ratio, and mixing.

[0561] The present application also provides the use of the aforementioned pharmaceutical composition in the preparation of a medicine for degrading estrogen receptors and / or treating estrogen receptor-related diseases.

[0562] The present application also provides the use of the aforementioned pharmaceutical composition in the preparation of a medicine for treating and / or preventing cancer.

[0563] Preferably, the cancer is bone cancer, colorectal cancer, endometrial cancer, prostate cancer, ovarian cancer, uterine cancer, cervical cancer, lung cancer, breast cancer.

[0564] The present application also provides a medicine preparation for degrading estrogen receptors, which is a preparation prepared from the aforementioned pharmaceutical composition as an active ingredient, plus pharmaceutically acceptable adjuvants or auxiliary ingredients.

[0565] The present application also provides a combination medicine for degrading estrogen receptors, which contains the estrogen receptor degrader and the AKT inhibitor of the same or different specifications, which are administered simultaneously or separately, and a pharmaceutically acceptable carrier.

[0566] Further, the molar ratio of the estrogen receptor degrader to the AKT inhibitor is 1:0.1-300.

[0567] Further, the molar ratio of the estrogen receptor degrader to the AKT inhibitor is 1:1-300.

[0568] Alternatively, the molar ratio of the estrogen receptor degrader to the AKT inhibitor is 1:0.3-100.

[0569] Preferably,

[0570] the molar ratio of the estrogen receptor degrader to the AKT inhibitor is 1:1.1-268.3;

[0571] or, the molar ratio of the estrogen receptor degrader to the AKT inhibitor is 1:0.37-90.2;

[0572] More preferably,

[0573] the molar ratio of the estrogen receptor degrader to the AKT inhibitor is 1:1.1, 1:29.7, 1:268.3;

[0574] or, the molar ratio of the estrogen receptor degrader to the AKT inhibitor is 1:0.37, 1:10, 1:90.2.

[0575] Further, the estrogen receptor degrader is selected from the aforementioned compounds, or an optical isomer thereof, or a salt thereof, or a hydrate thereof, or a solvate thereof;

[0576] the AKT inhibitor is MK-2206 2HCl, Perifosine, GSK69069, Ipatasertib, Capivasertib, PF-04691502, AT7867, Triciribine (API-2), CCT128930, A-674563HCl, PHT-427, Miransertib HCl, Akti-1 / 2, Uprosertib, Afuresertib, AT13148, Miltefosine, Honokiol, TIC10 Analogue, Deguelin, TIC10 (ONC201), or an optical isomer thereof, a salt thereof, a hydrate thereof, a solvate thereof;

[0577] Preferably, the AKT inhibitor is Capivasertib, or an optical isomer thereof, a salt thereof, a hydrate thereof, a solvate thereof.

[0578] Further, when the estrogen receptor degrader is ARV-471, or an optical isomer thereof, a salt thereof, a hydrate thereof, a solvate thereof, and the AKT inhibitor is Capivasertib, or an optical isomer thereof, a salt thereof, a hydrate thereof, a solvate thereof, the molar ratio of the estrogen receptor degrader to the AKT inhibitor is 1:1.1-1:268.3; preferably, the molar ratio is 1:1.1, 1:29.7, 1:268.3.

[0579] Further, when the estrogen receptor degrader is Compound 75 or an optical isomer thereof, a salt thereof, a hydrate thereof, a solvate thereof, and the AKT inhibitor is Capivasertib or an optical isomer thereof, a salt thereof, a hydrate thereof, a solvate thereof, the molar ratio of the estrogen receptor degrader to the AKT inhibitor is 1:1.1-1:268.3, preferably 1:1.1, 1:29.7, 1:268.3.

[0580] Further, when the estrogen receptor degrader is Compound 63 or an optical isomer thereof, a salt thereof, a hydrate thereof, a solvate thereof, and the AKT inhibitor is Capivasertib or an optical isomer thereof, a salt thereof, a hydrate thereof, a solvate thereof, the molar ratio of the estrogen receptor degrader to the AKT inhibitor is 1:0.37-90.2, preferably 1:0.37, 1:10, 1:90.2.

[0581] Further, when the estrogen receptor degrader is Compound 65 or an optical isomer thereof, a salt thereof, a hydrate thereof, a solvate thereof, and the AKT inhibitor is Capivasertib or an optical isomer thereof, a salt thereof, a hydrate thereof, a solvate thereof, the molar ratio of the estrogen receptor degrader to the AKT inhibitor is 1:0.37-90.2, preferably 1:0.37, 1:10, 1:90.2.

[0582] The present application also provides the use of an estrogen receptor degrader in combination with an AKT inhibitor in the preparation of a medicament for degrading estrogen receptor.

[0583] Further, the molar ratio of the estrogen receptor degrader to the AKT inhibitor is 1:0.1-300.

[0584] Further, the molar ratio of the estrogen receptor degrader to the AKT inhibitor is 1:1-300;

[0585] Alternatively, the molar ratio of the estrogen receptor degrader to the AKT inhibitor is 1:0.3-100;

[0586] Preferably,

[0587] The molar ratio of the estrogen receptor degrader to the AKT inhibitor is 1:1.1-268.3;

[0588] Alternatively, the molar ratio of the estrogen receptor degrader to the AKT inhibitor is 1:0.37-90.2;

[0589] More preferably,

[0590] The molar ratio of the estrogen receptor degrader to the AKT inhibitor is 1:1.1, 1:29.7, 1:268.3;

[0591] Alternatively, the molar ratio of the estrogen receptor degrader to the AKT inhibitor is 1 :0.37, 1 :10, 1 :90.2.

[0592] Further, the estrogen receptor degrader is selected from the aforementioned compounds, or an optical isomer thereof, or a salt thereof, or a hydrate thereof, or a solvate thereof;

[0593] The AKT inhibitor is MK-2206 2HC1, Perifosine, GSK69069, Ipatasertib, Capivasertib, PF-04691502, AT7867, Triciribine (API-2), CCT128930, A-674563 HC1, PHT-427, Miransertib HC1, Akti-1 / 2, Uprosertib, Afuresertib, AT13148, Miltefosine, Honokiol, TIC10 Analogue, Deguelin, TIC10 (ONC201), or an optical isomer thereof, a salt thereof, a hydrate thereof, a solvate thereof;

[0594] Preferably, the AKT inhibitor is Capivasertib, or an optical isomer thereof, a salt thereof, a hydrate thereof, a solvate thereof.

[0595] Further, when the estrogen receptor degrader is ARV-471, or an optical isomer thereof, a salt thereof, a hydrate thereof, a solvate thereof, and the AKT inhibitor is Capivasertib, or an optical isomer thereof, a salt thereof, a hydrate thereof, a solvate thereof, the molar ratio of the estrogen receptor degrader to the AKT inhibitor is 1:1.1-1:268.3; preferably, the molar ratio is 1:1.1, 1:29.7, 1:268.3.

[0596] Further, when the estrogen receptor degrader is Compound 75, or an optical isomer thereof, a salt thereof, a hydrate thereof, a solvate thereof, and the AKT inhibitor is Capivasertib, or an optical isomer thereof, a salt thereof, a hydrate thereof, a solvate thereof, the molar ratio of the estrogen receptor degrader to the AKT inhibitor is 1:1.1-1:268.3; preferably, the molar ratio is 1:1.1, 1:29.7, 1:268.3.

[0597] Further, when the estrogen receptor degrader is Compound 63 or an optical isomer thereof, a salt thereof, a hydrate thereof, a solvate thereof, and the AKT inhibitor is Capivasertib or an optical isomer thereof, a salt thereof, a hydrate thereof, a solvate thereof, the molar ratio of the estrogen receptor degrader to the AKT inhibitor is 1:0.37-90.2; preferably, the molar ratio is 1:0.37, 1:10, 1:90.2.

[0598] Further, when the estrogen receptor degrader is Compound 65 or an optical isomer thereof, a salt thereof, a hydrate thereof, a solvate thereof, and the AKT inhibitor is Capivasertib or an optical isomer thereof, a salt thereof, a hydrate thereof, a solvate thereof, the molar ratio of the estrogen receptor degrader to the AKT inhibitor is 1:0.37-90.2; preferably, the molar ratio is 1:0.37, 1:10, 1:90.2.

[0599] Further, the drug for degrading estrogen receptor is an estrogen receptor degrader and / or a drug for treating an estrogen receptor related disease.

[0600] Further, the drug is for use in treating and / or preventing cancer.

[0601] Preferably, the cancer is bone cancer, colorectal cancer, endometrial cancer, prostate cancer, ovarian cancer, uterine cancer, cervical cancer, lung cancer, breast cancer.

[0602] The compounds and derivatives provided in the present application can be named according to the IUPAC (International Union of Pure and Applied Chemistry) or CAS (Chemical Abstract Service, Columbus, OH) nomenclature system.

[0603] Definitions of terms used in the present application: unless otherwise indicated, the initial definition of a group or term provided herein is intended to apply throughout the description of the specification of that group or term; to the extent a term is not specifically defined herein, it should be given its ordinary meaning to the person of skill in the art in light of the disclosure and context.

[0604] "Substitution" refers to the replacement of a hydrogen atom in a molecule by another different atom or molecule.

[0605] The minimum and maximum number of carbon atoms in a hydrocarbon group is indicated by a prefix, e.g., the prefix C a ~C b Alkyl indicates any alkyl group containing "a" to "b" carbon atoms. Thus, for example, "C1-C8 alkyl" means an alkyl group containing 1 to 8 carbon atoms; "C1-C8 alkoxy" means an alkoxy group containing 1 to 8 carbon atoms.

[0606] "Alkyl" refers to a saturated hydrocarbon chain having the indicated number of carbon atoms. For example, C1-C8alkyl refers to an alkyl group having from 1 to 8 carbon atoms, i.e., 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms. Alkyl groups can be straight or branched. Representative branched alkyl groups have one, two, or three branches. Alkyl includes methyl, ethyl, propyl (n-propyl and i-propyl), butyl (n-butyl, i-butyl, and t-butyl), pentyl (n-pentyl, i-pentyl, and neopentyl), hexyl, and the like.

[0607] "Halogen" is fluorine, chlorine, bromine, or iodine.

[0608] In the present application, cycloalkyl refers to a saturated or partially saturated non-aromatic cyclic group having a single ring or multiple rings (including fused, bridged, and spiro ring systems) of carbon atoms and no ring heteroatoms. Heterocycloalkyl refers to a saturated or partially saturated non-aromatic cyclic group containing at least one heteroatom; including a single ring or multiple rings (including fused, bridged, and spiro ring systems); wherein the heteroatom refers to a nitrogen atom, an oxygen atom, a sulfur atom. Examples of heterocyclyl groups include, for example, piperidinyl, piperazinyl, morpholinyl.

[0609] In the present application, aryl refers to an aromatic unsaturated group having a single ring or multiple rings (including fused, bridged, and spiro ring systems) of no ring heteroatoms, such as phenyl, anthryl, naphthyl. Heteroaryl refers to an aromatic unsaturated ring containing at least one heteroatom; including a single ring or multiple rings (including fused, bridged, and spiro ring systems); wherein the heteroatom refers to a nitrogen atom, an oxygen atom, a sulfur atom. Such as pyridyl, pyrazinyl, pyridazinyl, pyrazolyl, furanyl, thienyl, oxazolyl, and the like.

[0610] In the present application, the structure of OBn is

[0611] In the present application, in the compound of formula (I), when the dotted line in the benzene ring is a bond, the structure of the compound is when the dotted line in the benzene ring is nothing, the structure of the compound is

[0612] In the present application, in the compound of formula (I), when the dotted line between Y and W is nothing, the structure of the compound is

[0613] R ab when the dotted line between Y and W is a bond, the structure of the compound is

[0614] The AKT inhibitors are: MK-2206 2HC1, Perifosine, GSK69069, Ipatasertib, Capivasertib, PF-04691502, AT7867, Triciribine (API-2), CCT128930, A-674563 HC1, PHT-427, Miransertib HC1, Akti-1 / 2, Uprosertib, Afuresertib, AT13148, Miltefosine, Honokiol, TIC10 Analogue, Deguelin, TIC10 (ONC201); their structures are as follows, respectively:

[0615] MK-2206 2HC1, Perifosine, GSK69069, Ipatasertib, Capivasertib, PF-04691502, AT7867, Triciribine (API-2), CCT128930, A-674563 HC1, PHT-427, Miransertib HC1, Akti-1 / 2, Uprosertib, Afuresertib, AT13148, Miltefosine, Honokiol, TIC10 Analogue, Deguelin, TIC10 (ONC201),

[0616] The estrogen receptor degraders (ER degraders) are: Fulvestrant, Estrogen receptor modulator 10, Estrogen receptor antagonist 3, Estrogen receptor antagonist 4, ER degrader 4, ER degrader 8, Taragarestrant, Taragarestrant meglumine, ER degrader 5, GDC-0927 Racemate, Elacestrant dihydrochloride, Elacestrant, Rintodestrant, Imlunestrant, ERa degrader 5, Imlunestrant tosylate, ERa degrader 8, LX-039, Elacestrant-d10, SNIPER(ER)-110, Elacestrant-d6, Elacestrant-d4, PROTAC ERa Degrader-7, PROTAC ERa Degrader-4; their structures are as follows, respectively:

[0617] Fulvestrant, Estrogen receptor modulator 10, Estrogen receptor antagonist 3, Estrogen receptor antagonist 4, ER degrader 4, ER degrader 8, Taragarestrant, Taragarestrant meglumine, ER degrader 5, GDC-0927 Racemate, Elacestrant dihydrochloride, Elacestrant, Rintodestrant, Imlunestrant, ERa degrader 5, Imlunestrant tosylate, ERa degrader 8, LX-039, Elacestrant-d10, SNIPER(ER)-110, Elacestrant-d6, Elacestrant-d4, PROTAC ERa Degrader-7, PROTAC ERa Degrader-4,

[0618] The estrogen receptor degrader is combined with the AKT inhibitor to degrade the estrogen receptor, inhibit the growth of cancer cells, can exert synergistic inhibitory effect, significantly improve the effect of treating diseases related to estrogen receptor, such as breast cancer, and has good application prospect.

[0619] Obviously, according to the above content of the present application, according to the ordinary technical knowledge and usual means in the art, other various forms of modification, replacement or change can be made without departing from the above basic technical idea of the present application.

[0620] The above content of the present application will be further described in detail through the specific embodiments in the form of examples. However, this should not be understood as the scope of the above subject matter of the present application being limited to the following examples. Any technology realized based on the above content of the present application belongs to the scope of the present application. BRIEF DESCRIPTION OF DRAWINGS

[0621] Figure 1 is a result graph of the inhibitory effect of compound 75 and Capivasertib on the growth of MCF-7 cells.

[0622] Figure 2 is a result graph of the inhibitory effect of ARV-471 and Capivasertib on the growth of MCF-7 cells.

[0623] Figure 3 is a result graph of the inhibitory effect of compound 63 and Capivasertib on the growth of MCF-7 cells.

[0624] Figure 4 is a result graph of the inhibitory effect of compound 65 and Capivasertib on the growth of MCF-7 cells. DETAILED DESCRIPTION

[0625] The raw materials and equipment used in the specific embodiments of the present application are known products, which are obtained by purchasing commercially available products.

[0626] Example 1, combination of an estrogen receptor degrader and AKT inhibitor Capivasertib

[0627] AKT inhibitor: Capivasertib, structure

[0628] Estrogen receptor degrader: ARV-471, structure

[0629] The molar ratio of ARV-471 and Capivasertib is 1:268.3~1:1.1 (such as 1:268.3, 1:29.7 or 1:1.1).

[0630] The above estrogen receptor degrader ARV-471 can be replaced by compound 75, structure

[0631] Example 2, combination of an estrogen receptor degrader and AKT inhibitor Capivasertib

[0632] AKT inhibitor: Capivasertib, structure

[0633] Estrogen receptor degrader: compound 63, structure

[0634] The molar ratio of compound 63 and Capivasertib is 1:90.2~1:0.37 (such as 1:90.2, 1:10 or 1:0.37).

[0635] The above estrogen receptor degrader compound 63 can be replaced by compound 65, structure

[0636] The beneficial effects of the present application are demonstrated below through specific test examples.

[0637] Test Example 1

[0638] Inhibition of breast cancer cells MCF-7 by combination of ER Protac compound 75, ARV-471, compound 63, compound 65 and AKT inhibitor Capivasertib

[0639] 1. Experimental method

[0640] (1) Combination of compound 75 and Capivasertib

[0641] Take breast cancer cells MCF-7 in the logarithmic growth phase, 2x10 3The cells were seeded at a density of 1.5×103cells / well in 96-well plates in 100 μL of medium. The cells were incubated at 37 °C in a 5% CO2saturated humidified incubator for 24 hours. After 24 hours, compound 75 and ARV-471 were added to the 96-well plates. The negative control wells were added with the same volume of cell culture medium containing 10% fetal bovine serum as the drugs.

[0642] The concentration range of compound 75 was: 0 nM, 0.15 nM, 0.46 nM, 1.4 nM, 4.1 nM, 12 nM, 37 nM, 111 nM, 333 nM, 1000 nM.

[0643] The concentration range of ARV-471 was: 0 nM, 0.15 nM, 0.46 nM, 1.4 nM, 4.1 nM, 12 nM, 37 nM, 111 nM, 333 nM, 1000 nM.

[0644] After 6 days of co-incubation with the drugs, 10 μL of CCK-8 was added to each well, and the incubation was continued for 3 hours. The absorbance (OD) value of each well was measured at 450 nm on an enzyme-linked instrument. The cell survival rate was calculated according to formula (I):

[0645] Survival rate (%) = OD value of drug-added well / OD value of control well x 100% Formula (I)

[0646] The dose-effect curve of the drug was plotted according to the cell survival rate, the combination index (CI) of the drug was calculated by the Chou-Talalay method, and the CI value was determined according to the CI value. The CI value determination standard is shown in Table 1.

[0647] The calculation method of the combination index (CI) of the drug is as follows:

[0648] Wherein, C A,x and C B,x are the concentrations of drugs A and B when they reach x% inhibition rate when used in combination;

[0649] IC x,A and IC x,B are the concentrations of drugs A and B when they reach x% inhibition rate when used alone.

[0650] Table 1. CI value determination standard

[0651] (2) ARV-471 and Capivasertib combination

[0652] Take the breast cancer cells MCF-7 in the logarithmic growth phase, seed 2×10 3The cells were seeded in 96-well plates at a density of 2 x 10

[0653] ARV-471 concentration range: 0 nM, 0.15 nM, 0.46 nM, 1.4 nM, 4.1 nM, 12 nM, 37 nM, 111 nM, 333 nM, 1000 nM.

[0654] Capivasertib concentration range: 0 nM, 123 nM, 370 nM, 1111 nM, 3333 nM, 10000 nM.

[0655] After 6 days of co-incubation with drugs, 10 μL CCK-8 was added to each well, and incubation was continued for 3 hours. The absorbance (OD) value of each well was measured at 450 nm on an enzyme-linked instrument. Cell survival rate was calculated according to the formula: survival rate (%) = OD value of drug-added well / OD value of control well x 100%. The CI value was calculated according to the method described in "(1) Compound 75 and Capivasertib combination" and was determined according to the CI value. The CI value determination criteria are shown in Table 1.

[0656] (3) Compound 63 and Capivasertib combination

[0657] The breast cancer cells MCF-7 in the logarithmic growth phase were seeded in 96-well plates at a density of 2 x 10 3 The cells were seeded in 96-well plates at a density of 2 x 10

[0658] Compound 63 concentration range: 0 nM, 0.15 nM, 0.46 nM, 1.4 nM, 4.1 nM, 12 nM, 37 nM, 111 nM, 333 nM, 1000 nM.

[0659] Capivasertib concentration range: 0 nM, 123 nM, 370 nM, 1111 nM, 3333 nM, 10000 nM.

[0660] After 6 days of co-incubation with drugs, 100 μL CTG detection reagent was added to each well, and shaken at 400 rpm for 10 minutes. Luminescence-Endpoint detection was performed using a FLUOstar Omega multifunctional microplate reader, and the detection results were exported in an Excel table. Cell survival rate was calculated according to the formula: Survival rate (%) = OD value of drug-added well / OD value of control well x 100%. The CI value was calculated according to the method described in "(1) Compound 75 and Capivasertib combination drug", and then judged according to the CI value. The CI value judgment standard is shown in Table 1.

[0661] (4) Compound 65 and Capivasertib combination drug

[0662] The breast cancer cells MCF-7 in the logarithmic growth phase were inoculated in a 96-well culture plate at a concentration of 2 x 10 3 cells / well, and 80 μL was inoculated in each well. After 24 hours of incubation at 37°C, 5% CO2concentration and saturated humidity in an incubator, Compound 65 and Capivasertib were added to the 96-well plate in turn. The negative control well was added with the same volume of cell culture medium containing 10% fetal bovine serum as the drug.

[0663] The concentration range of Compound 65 was: 0 nM, 0.15 nM, 0.46 nM, 1.4 nM, 4.1 nM, 12 nM, 37 nM, 111 nM, 333 nM, 1000 nM.

[0664] The concentration range of Capivasertib was: 0 nM, 123 nM, 370 nM, 1111 nM, 3333 nM, 10000 nM.

[0665] After 6 days of co-incubation with drugs, 100 μL CTG detection reagent was added to each well, and shaken at 400 rpm for 10 minutes. Luminescence-Endpoint detection was performed using a FLUOstar Omega multifunctional microplate reader, and the detection results were exported in an Excel table. Cell survival rate was calculated according to the formula: Survival rate (%) = OD value of drug-added well / OD value of control well x 100%. The CI value was calculated according to the method described in "(1) Compound 75 and Capivasertib combination drug", and then judged according to the CI value. The CI value judgment standard is shown in Table 1.

[0666] 2、Experimental results

[0667] (1) Compound 75 and Capivasertib combination drug

[0668] The combination result of Compound 75 and Capivasertib is shown in Figure 1. It can be known from the figure that when the molar ratio of Compound 75 and Capivasertib is 1:268.3 or 1:29.7 or 1:1.1, the CI value of drug combination is 0.16, 0.12, 0.27 respectively, and the combination of Compound 75 and Capivasertib has synergistic effect on inhibiting the growth of MCF-7 cells under the above three drug molar ratios.

[0669] (2) Combination of ARV-471 and Capivasertib

[0670] The combination result of ARV-471 and Capivasertib is shown in Figure 2. It can be known from the figure that when the molar ratio of ARV-471 and Capivasertib is 1:268.3 or 1:29.7 or 1:1.1, the CI value of drug combination is 0.20, 0.12, 0.44 respectively, and the combination of ARV-471 and Capivasertib has synergistic effect on inhibiting the growth of MCF-7 cells under the above three drug molar ratios.

[0671] (3) Combination of Compound 63 and Capivasertib

[0672] The combination result of Compound 63 and Capivasertib is shown in Figure 3. It can be known from the figure that when the molar ratio of Compound 63 and Capivasertib is 1:90.2 or 1:10 or 1:0.37, the CI value of drug combination is 0.36, 0.15, 0.11 respectively, and the combination of Compound 63 and Capivasertib has synergistic effect on inhibiting the growth of MCF-7 cells under the above three drug molar ratios.

[0673] (4) Combination of Compound 65 and Capivasertib

[0674] The combination result of Compound 65 and Capivasertib is shown in Figure 4. It can be known from the figure that when the molar ratio of Compound 65 and Capivasertib is 1:90.2 or 1:10 or 1:0.37, the CI value of drug combination is 0.35, 0.11, 0.11 respectively, and the combination of Compound 65 and Capivasertib has synergistic effect on inhibiting the growth of MCF-7 cells under the above three drug molar ratios.

[0675] In conclusion, the estrogen receptor degrading agent is combined with the AKT inhibitor to degrade the estrogen receptor and inhibit the growth of cancer cells, can exert synergistic inhibitory effect, significantly improve the effect of treating diseases related to estrogen receptor, such as breast cancer, and has good application prospect.

Claims

1. A pharmaceutical composition for degrading an estrogen receptor, characterized by: It consists of an estrogen receptor degrader and an AKT inhibitor.

2. The pharmaceutical composition of claim 1, wherein: The molar ratio of the estrogen receptor degrader to the AKT inhibitor is 1:0.1-300.

3. The pharmaceutical composition of claim 1, wherein: The molar ratio of the estrogen receptor degrader to the AKT inhibitor is 1:1-300; Alternatively, the molar ratio of the estrogen receptor degrader to the AKT inhibitor is 1:0.3-100; Preferably, The molar ratio of the estrogen receptor degrader to the AKT inhibitor is 1:1.1-268.3; Alternatively, the molar ratio of the estrogen receptor degrader to the AKT inhibitor is 1:0.37-90.2; More preferably, The molar ratio of the estrogen receptor degrader to the AKT inhibitor is 1:1.1, 1:29.7, 1:268.3; Alternatively, the molar ratio of the estrogen receptor degrader to the AKT inhibitor is 1:0.37, 1:10, 1:90.

2.

4. The pharmaceutical composition according to any one of claims 1 to 3, characterized in that: The estrogen receptor degrader is Fulvestrant, Estrogen receptor modulator 10, Estrogen receptor antagonist 3, Estrogen receptor antagonist 4, ER degrader 4, ER degrader 8, Taragarestrant, Taragarestrant meglumine, ER degrader 5, GDC-0927 Racemate, Elacestrant dihydrochloride, Elacestrant, Rintodestrant, Imlunestrant, ERa degrader 5, Imlunestrant tosylate, ERa degrader 8, LX-039, Elacestrant-d10, SNIPER(ER)-110, Elacestrant-d6, Elacestrant-d4, PROTAC ERa Degrader-7, PROTAC ERa Degrader-4, or an optical isomer thereof, or a salt thereof, or a hydrate thereof, or a solvate thereof; Alternatively, the estrogen receptor degrader is a compound represented by Formula (I), or an optical isomer thereof, or a salt thereof, or a hydrate thereof, or a solvate thereof: wherein, R 1 selected from the group consisting of hydrogen, C1-C6alkyl, hydroxyl, amino, carboxyl, C1-C6alkoxy, boronic acid group, -OR'; R' is selected from phenyl, benzyl; R 2 R is a substituent on the phenyl ring at any position, a is the number of substituents R 2 ​ Each R 2 Each is independently selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, and C1-C6 alkoxy. a is 0, 1, 2, or 3; R 3 , R 4 are each independently selected from the group consisting of nothing; R 3 , R 4 are each independently selected from the group consisting of hydrogen, C1-C6alkyl, or R 3 , R 4 are joined to form a 3- to 6-membered cycloalkyl group; R 5 selected from the group consisting of C1-C6alkyl, 3-6 membered cycloalkyl, trifluoromethyl, trifluoroethyl, substituted or unsubstituted 6-10 membered aryl, substituted or unsubstituted 5-8 membered heteroaryl; the substituents of the aryl or heteroaryl are selected from the group consisting of halogen, hydroxy, amino, cyano, trifluoromethyl, C1-C6alkyl, 3-6 membered cycloalkyl, C1-C6alkoxy; X is selected from CR 7 R 8 , O, S, SO, SO2, NR 7 ; R 7 , R 8 are each independently selected from hydrogen, halogen, Ci-C6alkyl, 3- to 6-membered cycloalkyl; n is 0, 1, or 2; R 6 R is a substituent on the phenyl ring at any position, b is the number of substituents R 6 R is a substituent on the phenyl ring at any position, b is the number of substituents R Each R 6 Each is independently selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, and C1-C6 alkoxy. b is 0, 1, 2, or 3; Ring A and Ring B are each independently selected from 4-12 membered cycloalkyl, 4-12 membered heterocycloalkyl; M is selected from none, CR 9 R 10 , O, S, SO, SO2, NR 9 ; R 9 , R 10 are each independently selected from the group consisting of hydrogen, C1-C6alkyl; E 3 for a substituent on the phenyl ring at any position, c is the number of substituents E 3 ​ Each E 3 Each of the following groups is independently selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, C1-C6 alkoxy; or any two E groups. 3 They can be linked to form 3-6 membered cycloalkyl groups, 6-10 membered aryl groups, 4-12 membered heterocycloalkyl groups, and 5-8 membered heteroaryl groups; c is 0, 1, 2, or 3; When the dotted line between Y and W is absent, W is NH, and Y is halogen; when the dotted line between Y and W is a bond, W is N, Y is none, CR Y1 R Y2 , C(O), -CR 11 =CR 12 -, -CR 11 =N-, -N=N-, -OC(O)-; R Y1 , R Y2 are each independently selected from the group consisting of hydrogen, C1-C6alkyl; R 11 , R 12 are each independently selected from the group consisting of hydrogen, C1-C6alkyl; R 21 selected from hydrogen or deuterium; The heteroatom of the heteroaryl is O, N, or S; the number of heteroatoms is 1, 2, or 3; The heteroatom of the heterocycloalkyl is N; the number of heteroatoms is 1, 2, or 3.

5. The pharmaceutical composition of claim 4, wherein: The compound is as shown in formula (II): wherein, R 1 selected from the group consisting of hydrogen, C1-C6alkyl, hydroxyl, amino, carboxyl, C1-C6alkoxy, boronic acid group, -OR'; R' is selected from phenyl, benzyl; R 2 R is a substituent on the phenyl ring at any position, a is the number of substituents R 2 ​ Each R 2 Each is independently selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, and C1-C6 alkoxy. a is 0, 1, 2, or 3; R 3 , R 4 are each independently selected from the group consisting of nothing; R 3 , R 4 are each independently selected from the group consisting of hydrogen, C1-C6alkyl, or R 3 , R 4 are joined to form a 3- to 6-membered cycloalkyl group; R 5 selected from the group consisting of C1-C6alkyl, 3-6 membered cycloalkyl, trifluoromethyl, trifluoroethyl, substituted or unsubstituted 6-10 membered aryl, substituted or unsubstituted 5-8 membered heteroaryl; the substituents of the aryl or heteroaryl are selected from the group consisting of halogen, hydroxy, amino, cyano, trifluoromethyl, C1-C6alkyl, 3-6 membered cycloalkyl, C1-C6alkoxy; X is selected from CR 7 R 8 , O, S, SO, SO2, NR 7 ; R 7 , R 8 are each independently selected from the group consisting of hydrogen, halogen, Ci-C6-alkyl, 3- to 6-membered cycloalkyl; n is 0, 1, or 2; R 6 R is a substituent on the phenyl ring at any position, b is the number of substituents R 6 R is a substituent on the phenyl ring at any position, b is the number of substituents R Each R 6 Each is independently selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, and C1-C6 alkoxy. b is 0, 1, 2, or 3; Ring A and Ring B are each independently selected from 4-12 membered cycloalkyl, 4-12 membered heterocycloalkyl; M is selected from none, CR 9 R 10 , O, S, SO, SO2, NR 9 ; R 9 , R 10 are each independently selected from the group consisting of hydrogen, C1-C6alkyl; E 3 for a substituent on the phenyl ring at any position, c is the number of substituents E 3 ​ Each E 3 Each of the following groups is independently selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, C1-C6 alkoxy; or any two E groups. 3 They can be linked to form 3-6 membered cycloalkyl groups, 6-10 membered aryl groups, 4-12 membered heterocycloalkyl groups, and 5-8 membered heteroaryl groups; c is 0, 1, 2, or 3; Y is none, CR Y1 R Y2 , C(O), -CR 11 =CR 12 -, -CR 11 =N-, -N=N-, -OC(O)-; R Y1 , R Y2 are each independently selected from the group consisting of hydrogen, C1-C6alkyl; R 11 , R 12 are each independently selected from the group consisting of hydrogen, C1-C6alkyl; the heteroatom of the heteroaryl is O, N or S; the number of heteroatoms is 1, 2 or 3; the heteroatom of the heterocycloalkyl is N; the number of heteroatoms is 1, 2 or 3.

6. The pharmaceutical composition of claim 5, wherein: The compound is as shown in formula (III): wherein, R 2 R is a substituent on the phenyl ring at any position, a is the number of substituents R 2 ​ Each R 2 Each is independently selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, and C1-C6 alkoxy. a is 0, 1, 2 or 3; R 3 , R 4 are each independently selected from the group consisting of nothing; R 3 , R 4 are each independently selected from the group consisting of hydrogen, C1-C6alkyl, or R 3 , R 4 are joined to form a 3- to 6-membered cycloalkyl group; R 5 selected from the group consisting of C1-C6alkyl, 3-6 membered cycloalkyl, trifluoromethyl, trifluoroethyl, substituted or unsubstituted 6-10 membered aryl, substituted or unsubstituted 5-8 membered heteroaryl; the substituents of the aryl or heteroaryl are selected from the group consisting of halogen, hydroxy, amino, cyano, trifluoromethyl, C1-C6alkyl, 3-6 membered cycloalkyl, C1-C6alkoxy; X is selected from CR 7 R 8 , O, S, SO, SO2, NR 7 ; R 7 , R 8 are each independently selected from hydrogen, halogen, Ci-C6alkyl, 3- to 6-membered cycloalkyl; n is 0, 1 or 2; R 6 R is a substituent on the phenyl ring at any position, b is the number of substituents R 6 R is a substituent on the phenyl ring at any position, b is the number of substituents R Each R 6 Each is independently selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, and C1-C6 alkoxy. b is 0, 1, 2 or 3; ring A and ring B are each independently selected from 4-12 membered cycloalkyl, 4-12 membered heterocycloalkyl; M is selected from none, CR 9 R 10 , O, S, SO, SO2, NR 9 ; R 9 , R 10 are each independently selected from the group consisting of hydrogen, C1-C6alkyl; E 3 for a substituent on the phenyl ring at any position, c is the number of substituents E 3 ​ Each E 3 Each of the following groups is independently selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, C1-C6 alkoxy; or any two E groups. 3 They can be linked to form 3-6 membered cycloalkyl groups, 6-10 membered aryl groups, 4-12 membered heterocycloalkyl groups, and 5-8 membered heteroaryl groups; c is 0, 1, 2 or 3; Y is none, CR Y1 R Y2 , C(O), -CR 11 =CR 12 -, -CR 11 =N-, -N=N-, -OC(O)-; R Y1 , R Y2 are each independently selected from the group consisting of hydrogen, C1-C6alkyl; R 11 , R 12 are each independently selected from hydrogen, C1-C6alkyl; the heteroatom of the heteroaryl is O, N or S; the number of heteroatoms is 1, 2 or 3; the heteroatom of the heterocycloalkyl is N; the number of heteroatoms is 1, 2 or 3. Preferably, R 5 selected from the group consisting of C1-C6alkyl, 3- to 6-membered cycloalkyl, trifluoromethyl, trifluoroethyl, substituted or unsubstituted phenyl, substituted or unsubstituted thienyl, substituted or unsubstituted furanyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted pyrimidinyl, substituted or unsubstituted pyridazinyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted pyrazinyl; the substituents of the phenyl, thienyl, furanyl, pyrrolyl, pyrimidinyl, pyridazinyl, pyrazolyl or pyrazinyl are selected from the group consisting of halogen, hydroxyl, amino, cyano, trifluoromethyl, C1-C6alkyl, 3- to 6-membered cycloalkyl, C1-C6alkoxy; X is selected from CH2, CF2, O, S, SO, SO2, NR 7 ; R 7 selected from hydrogen, halogen, Ci-C6alkyl, 3- to 6-membered cycloalkyl; ring A and ring B are each independently selected from 4-12 membered cycloalkyl, 4-12 membered heterocycloalkyl; when both ring A and ring B are heterocycloalkyl, one of the rings has 1 heteroatom N and the other ring has 2 heteroatoms N.

7. The pharmaceutical composition of claim 6, wherein: The compound is as shown in formula (IV): wherein, R 2 R is a substituent on the phenyl ring at any position, a is the number of substituents R 2 the number of R Each R 2 Each is independently selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, and C1-C6 alkoxy. a is 0, 1, 2 or 3; R 3 , R 4 are each independently selected from the group consisting of hydrogen, C1-C6alkyl; or R 3 , R 4 are joined to form a 3- to 6-membered cycloalkyl group; R 5 selected from the group consisting of C1-C6alkyl, 3-6 membered cycloalkyl, trifluoromethyl, trifluoroethyl, substituted or unsubstituted 6-10 membered aryl, substituted or unsubstituted 5-8 membered heteroaryl; the substituents of the aryl or heteroaryl are selected from the group consisting of halogen, hydroxy, amino, cyano, trifluoromethyl, C1-C6alkyl, 3-6 membered cycloalkyl, C1-C6alkoxy; X is selected from CR 7 R 8 , O, S, SO, SO2, NR 7 ; R 7 , R 8 are each independently selected from hydrogen, halogen, Ci-C6alkyl, 3- to 6-membered cycloalkyl; n is 0, 1 or 2; R 6 R is a substituent on the phenyl ring at any position, b is the number of substituents R 6 R is a substituent on the phenyl ring at any position, b is the number of substituents R Each R 6 Each is independently selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, and C1-C6 alkoxy. b is 0, 1, 2 or 3; ring A and ring B are each independently selected from 4-12 membered cycloalkyl, 4-12 membered heterocycloalkyl; M is selected from none, CR 9 R 10 , O, S, SO, SO2, NR 9 ; R 9 , R 10 are each independently selected from the group consisting of hydrogen, C1-C6alkyl; E 3 for a substituent on the phenyl ring at any position, c is the number of substituents E 3 ​ Each E 3 Each of the following groups is independently selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, C1-C6 alkoxy; or any two E groups. 3 They can be linked to form 3-6 membered cycloalkyl groups, 6-10 membered aryl groups, 4-12 membered heterocycloalkyl groups, and 5-8 membered heteroaryl groups; c is 0, 1, 2 or 3; Y is none, CR Y1 R Y2 , C(O), -CR 11 =CR 12 -, -CR 11 =N-, -N=N-, -OC(O)-; R Y1 , R Y2 are each independently selected from the group consisting of hydrogen, C1-C6alkyl; R 11 , R 12 are each independently selected from the group consisting of hydrogen, C1-C6alkyl; the heteroatom of the heteroaryl is O, N or S; the number of heteroatoms is 1, 2 or 3; the heteroatom of the heterocycloalkyl is N; the number of heteroatoms is 1, 2 or 3. Preferably, R 5 selected from the group consisting of Ci-C6alkyl, 3- to 6-membered cycloalkyl, trifluoromethyl, trifluoroethyl, substituted or unsubstituted phenyl, substituted or unsubstituted thienyl, substituted or unsubstituted furanyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted pyrimidinyl, substituted or unsubstituted pyridazinyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted pyrazinyl; the substituents of the phenyl, thienyl, furanyl, pyrrolyl, pyrimidinyl, pyridazinyl, pyrazolyl or pyrazinyl are selected from the group consisting of halogen, hydroxyl, amino, cyano, trifluoromethyl, Ci-C6alkyl, 3- to 6-membered cycloalkyl, Ci-C6alkoxy; X is selected from CH2, CF2, O, S, SO, SO2, NR 7 ; R 7 selected from hydrogen, halogen, Ci-C6alkyl, 3- to 6-membered cycloalkyl; ring A and ring B are each independently selected from 4-12 membered cycloalkyl, 4-12 membered heterocycloalkyl; when both ring A and ring B are heterocycloalkyl, one of the rings has 1 heteroatom N and the other ring has 2 heteroatoms N.

8. The pharmaceutical composition of claim 7, wherein: The compound is as shown in formula (V): wherein, R 2 R is a substituent on the phenyl ring at any position, a is the number of substituents R 2 ​ Each R 2 Each is independently selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, and C1-C6 alkoxy. a is 0, 1, 2 or 3; R 3 R 4 Each is independently selected from hydrogen, C1-C6 alkyl, or R 3 R 4 Linkage forms 3- to 6-membered cycloalkyl groups; R 5 selected from the group consisting of C1-C6alkyl, 3-6 membered cycloalkyl, trifluoromethyl, trifluoroethyl, substituted or unsubstituted 6-10 membered aryl, substituted or unsubstituted 5-8 membered heteroaryl; the substituents of the aryl or heteroaryl are selected from the group consisting of halogen, hydroxy, amino, cyano, trifluoromethyl, C1-C6alkyl, 3-6 membered cycloalkyl, C1-C6alkoxy; X is selected from CR 7 R 8 , O, S, SO, SO2, NR 7 ; R 7 , R 8 are each independently selected from hydrogen, halogen, Ci-C6alkyl, 3- to 6-membered cycloalkyl; n is 0, 1 or 2; R 6 R is a substituent on the phenyl ring at any position, b is the number of substituents R 6 R is a substituent on the phenyl ring at any position, b is the number of substituents R Each R 6 Each is independently selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, and C1-C6 alkoxy. b is 0, 1, 2 or 3; ring A and ring B are each independently selected from 4-12 membered cycloalkyl, 4-12 membered heterocycloalkyl; M is selected from none, CR 9 R 10 , O, S, SO, SO2, NR 9 ; R 9 , R 10 are each independently selected from the group consisting of hydrogen, C1-C6alkyl; E 3 for a substituent on the phenyl ring at any position, c is the number of substituents E 3 ​ Each E 3 Each of the following groups is independently selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, C1-C6 alkoxy; or any two E groups. 3 They can be linked to form 3-6 membered cycloalkyl groups, 6-10 membered aryl groups, 4-12 membered heterocycloalkyl groups, and 5-8 membered heteroaryl groups; c is 0, 1, 2 or 3; Y is none, CR Y1 R Y2 , C(O), -CR 11 =CR 12 -, -CR 11 =N-, -N=N-, -OC(O)-; R Y1 , R Y2 are each independently selected from the group consisting of hydrogen, C1-C6alkyl; R 11 , R 12 are each independently selected from the group consisting of hydrogen, C1-C6alkyl; the heteroatom of the heteroaryl is O, N or S; the number of heteroatoms is 1, 2 or 3; the heteroatom of the heterocycloalkyl is N; the number of heteroatoms is 1, 2 or 3. Preferably, R 5 selected from the group consisting of Ci-C6alkyl, 3- to 6-membered cycloalkyl, trifluoromethyl, trifluoroethyl, substituted or unsubstituted phenyl, substituted or unsubstituted thienyl, substituted or unsubstituted furanyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted pyrimidinyl, substituted or unsubstituted pyridazinyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted pyrazinyl; the substituents of the phenyl, thienyl, furanyl, pyrrolyl, pyrimidinyl, pyridazinyl, pyrazolyl or pyrazinyl are selected from the group consisting of halogen, hydroxyl, amino, cyano, trifluoromethyl, Ci-C6alkyl, 3- to 6-membered cycloalkyl, Ci-C6alkoxy; X is selected from CH2, CF2, O, S, SO, SO2, NR 7 ; R 7 selected from hydrogen, halogen, Ci-C6alkyl, 3- to 6-membered cycloalkyl; ring A and ring B are each independently selected from 4-12 membered cycloalkyl, 4-12 membered heterocycloalkyl; when both ring A and ring B are heterocycloalkyl, one of the rings has 1 heteroatom N and the other ring has 2 heteroatoms N.

9. The pharmaceutical composition of claim 8, wherein: The compound is as shown in formula (VI): wherein, R 2 R is a substituent on the phenyl ring at any position, a is the number of substituents R 2 R is a substituent on the phenyl ring at any position, a is the number of substituents R Each R 2 Each is independently selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, and C1-C6 alkoxy. b is 0, 1, 2 or 3; R 3 R 4 Each is independently selected from hydrogen, C1-C6 alkyl, or R 3 R 4 Linkage forms 3- to 6-membered cycloalkyl groups; R 5 selected from the group consisting of C1-C6alkyl, 3-6 membered cycloalkyl, trifluoromethyl, trifluoroethyl, substituted or unsubstituted 6-10 membered aryl, substituted or unsubstituted 5-8 membered heteroaryl; the substituents of the aryl or heteroaryl are selected from the group consisting of halogen, hydroxy, amino, cyano, trifluoromethyl, C1-C6alkyl, 3-6 membered cycloalkyl, C1-C6alkoxy; X is selected from CR 7 R 8 , O, S, SO, SO2, NR 7 ; R 7 , R 8 are each independently selected from hydrogen, halogen, Ci-C6alkyl, 3- to 6-membered cycloalkyl; R 6 R is a substituent on the phenyl ring at any position, b is the number of substituents R 6 R is a substituent on the phenyl ring at any position, b is the number of substituents R Each R 6 Each is independently selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, and C1-C6 alkoxy. ring A and ring B are each independently selected from 4-12 membered cycloalkyl, 4-12 membered heterocycloalkyl; the heteroatom of the heteroaryl is O, N or S; the number of heteroatoms is 1, 2 or 3; M is selected from none, CR 9 R 10 , O, S, SO, SO2, NR 9 ; R 9 , R 10 are each independently selected from the group consisting of hydrogen, C1-C6alkyl; E 3 for a substituent on the phenyl ring at any position, c is the number of substituents E 3 ​ Each E 3 Each of the following groups is independently selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, C1-C6 alkoxy; or any two E groups. 3 They can be linked to form 3-6 membered cycloalkyl groups, 6-10 membered aryl groups, 4-12 membered heterocycloalkyl groups, and 5-8 membered heteroaryl groups; the heteroatom of the heterocycloalkyl is N; the number of heteroatoms is 1, 2 or 3. Y is none, CR Y1 R Y2 , C(O), -CR 11 =CR 12 -, -CR 11 =N-, -N=N-, -OC(O)-; R Y1 , R Y2 are each independently selected from the group consisting of hydrogen, C1-C6alkyl; R 11 , R 12 are each independently selected from hydrogen, C1-C6alkyl; Preferably, ring A and ring B are each independently selected from 4-12 membered cycloalkyl, 4-12 membered heterocycloalkyl; when both ring A and ring B are heterocycloalkyl, one of the rings has 1 heteroatom N and the other ring has 2 heteroatoms N. ​ R 5 selected from the group consisting of C1-C6alkyl, 3- to 6-membered cycloalkyl, trifluoromethyl, trifluoroethyl, substituted or unsubstituted phenyl, substituted or unsubstituted thienyl, substituted or unsubstituted furanyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted pyrimidinyl, substituted or unsubstituted pyridazinyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted pyrazinyl; the substituents of the phenyl, thienyl, furanyl, pyrrolyl, pyrimidinyl, pyridazinyl, pyrazolyl or pyrazinyl are selected from the group consisting of halogen, hydroxyl, amino, cyano, trifluoromethyl, C1-C6alkyl, 3- to 6-membered cycloalkyl, C1-C6alkoxy; X is selected from CH2, CF2, O, S, SO, SO2, NR 7 ; R 7 selected from hydrogen, halogen, Ci-C6alkyl, 3- to 6-membered cycloalkyl; ​ 10. The pharmaceutical composition of claim 9, wherein: The compound is as shown in formula (VII): ​ R 3 R 4 Each is independently selected from hydrogen, C1-C6 alkyl, or R 3 R 4 Linkage forms 3- to 6-membered cycloalkyl groups; R 5 selected from the group consisting of C1-C6alkyl, 3-6 membered cycloalkyl, trifluoromethyl, trifluoroethyl, substituted or unsubstituted 6-10 membered aryl, substituted or unsubstituted 5-8 membered heteroaryl; the substituents of the aryl or heteroaryl are selected from the group consisting of halogen, hydroxy, amino, cyano, trifluoromethyl, C1-C6alkyl, 3-6 membered cycloalkyl, C1-C6alkoxy; X is selected from CR 7 R 8 , O, S, SO, SO2, NR 7 ; R 7 , R 8 are each independently selected from hydrogen, halogen, Ci-C6alkyl, 3- to 6-membered cycloalkyl; R 6 is a substituent on any position of the phenyl ring, b is the number of substituents R 6 . Each R 6 Each is independently selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, and C1-C6 alkoxy. ​ ​ M is selected from none, CR 9 R 10 , O, S, SO, SO2, NR 9 ; R 9 , R 10 are each independently selected from the group consisting of hydrogen, C1-C6alkyl; Y is none, CR Y1 R Y2 , C(O), -CR 11 =CR 12 -, -CR 11 =N-, -N=N-, -OC(O)-; R Y1 , R Y2 are each independently selected from the group consisting of hydrogen, C1-C6alkyl; R 11 , R 12 are each independently selected from the group consisting of hydrogen, C1-C6alkyl; ​ ​ ​ R 5 selected from the group consisting of C1-C6alkyl, 3- to 6-membered cycloalkyl, trifluoromethyl, trifluoroethyl, substituted or unsubstituted phenyl, substituted or unsubstituted thienyl, substituted or unsubstituted furanyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted pyrimidinyl, substituted or unsubstituted pyridazinyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted pyrazinyl; the substituents of the phenyl, thienyl, furanyl, pyrrolyl, pyrimidinyl, pyridazinyl, pyrazolyl or pyrazinyl are selected from the group consisting of halogen, hydroxyl, amino, cyano, trifluoromethyl, C1-C6alkyl, 3- to 6-membered cycloalkyl, C1-C6alkoxy; X is selected from CH2, CF2, O, S, SO, SO2, NR 7 ; R 7 selected from hydrogen, halogen, Ci-C6alkyl, 3- to 6-membered cycloalkyl; A and B are independently selected from 4-12 membered cycloalkyl, 4-12 membered heterocycloalkyl; 11. The pharmaceutical composition of claim 10, wherein: The compound is as shown in formula (VIII): wherein, R 3 , R 4 are each independently selected from the group consisting of hydrogen, C1-C6alkyl; or R 3 , R 4 are joined to form a 3- to 6-membered cycloalkyl group; R 5 selected from the group consisting of C1-C6alkyl, 3-6 membered cycloalkyl, trifluoromethyl, trifluoroethyl, substituted or unsubstituted 6-10 membered aryl, substituted or unsubstituted 5-8 membered heteroaryl; the substituents of the aryl or heteroaryl are selected from the group consisting of halogen, hydroxy, amino, cyano, trifluoromethyl, C1-C6alkyl, 3-6 membered cycloalkyl, C1-C6alkoxy; X is selected from CR 7 R 8 , O, S, SO, SO2, NR 7 ; R 7 , R 8 are each independently selected from hydrogen, halogen, Ci-C6alkyl, 3- to 6-membered cycloalkyl; A and B are independently selected from 4-12 membered cycloalkyl, 4-12 membered heterocycloalkyl; M is selected from none, CR 9 R 10 , O, S, SO, SO2, NR 9 ; R 9 , R 10 are each independently selected from the group consisting of hydrogen, C1-C6alkyl; Y is none, CR Y1 R Y2 , C(O), -CR 11 =CR 12 -, -CR 11 =N-, -N=N-, -OC(O)-; R Y1 , R Y2 are each independently selected from hydrogen, C1-C6alkyl; R 11 , R 12 are each independently selected from the group consisting of hydrogen, C1-C6alkyl; the heteroatom of the heteroaryl is O, N or S; the number of the heteroatoms is 1, 2 or 3; the heteroatom of the heterocycloalkyl is N; the number of the heteroatoms is 1, 2 or 3; Preferably, R 5 selected from the group consisting of C1-C6alkyl, 3- to 6-membered cycloalkyl, trifluoromethyl, substituted or unsubstituted phenyl, substituted or unsubstituted thienyl, substituted or unsubstituted furanyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted pyrimidinyl, substituted or unsubstituted pyridazinyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted pyrazinyl; the substituents of the phenyl, thienyl, furanyl, pyrrolyl, pyrimidinyl, pyridazinyl, pyrazolyl or pyrazinyl are selected from the group consisting of halogen, hydroxyl, amino, cyano, trifluoromethyl, C1-C6alkyl, 3- to 6-membered cycloalkyl, C1-C6alkoxy; X is selected from CH2, CF2, O, S, SO, SO2, NR 7 ; R 7 selected from hydrogen, halogen, Ci-C6alkyl, 3- to 6-membered cycloalkyl; A and B are independently selected from 4-12 membered cycloalkyl, 4-12 membered heterocycloalkyl; when both A and B are heterocycloalkyl, one of the rings has 1 heteroatom N and the other has 2 heteroatoms N.

12. The pharmaceutical composition of claim 10, wherein: The compound is as shown in formula (IX): wherein, R 3 , R 4 are each independently selected from hydrogen, C1-C6alkyl, or R 3 , R 4 are joined to form a 3- to 6-membered cycloalkyl group; R 5 selected from the group consisting of C1-C6alkyl, 3-6 membered cycloalkyl, trifluoromethyl, trifluoroethyl, substituted or unsubstituted 6-10 membered aryl, substituted or unsubstituted 5-8 membered heteroaryl; the substituents of the aryl or heteroaryl are selected from the group consisting of halogen, hydroxy, amino, cyano, trifluoromethyl, C1-C6alkyl, 3-6 membered cycloalkyl, C1-C6alkoxy; X is selected from CR 7 R 8 , O, S, SO, SO2, NR 7 ; R 7 , R 8 are each independently selected from hydrogen, halogen, Ci-C6alkyl, 3- to 6-membered cycloalkyl; R 6 R is a substituent on the phenyl ring at any position, b is the number of substituents R 6 R is a substituent on the phenyl ring at any position, b is the number of substituents R Each R 6 Each is independently selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, and C1-C6 alkoxy. b is 0, 1, 2 or 3; A and B are independently selected from 4-12 membered cycloalkyl, 4-12 membered heterocycloalkyl; Y is none, CR Y1 R Y2 , C(O), -CR 11 =CR 12 -, -CR 11 =N-, -N=N-, -OC(O)-; R Y1 , R Y2 are each independently selected from the group consisting of hydrogen, C1-C6alkyl; R 11 , R 12 are each independently selected from the group consisting of hydrogen, C1-C6alkyl; the heteroatom of the heteroaryl is O, N or S; the number of the heteroatoms is 1, 2 or 3; the heteroatom of the heterocycloalkyl is N; the number of the heteroatoms is 1, 2 or 3; Preferably, R 5 selected from the group consisting of C1-C6alkyl, 3- to 6-membered cycloalkyl, trifluoromethyl, trifluoroethyl, substituted or unsubstituted phenyl, substituted or unsubstituted thienyl, substituted or unsubstituted furanyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted pyrimidinyl, substituted or unsubstituted pyridazinyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted pyrazinyl; the substituents of the phenyl, thienyl, furanyl, pyrrolyl, pyrimidinyl, pyridazinyl, pyrazolyl or pyrazinyl are selected from the group consisting of halogen, hydroxyl, amino, cyano, trifluoromethyl, C1-C6alkyl, 3- to 6-membered cycloalkyl, C1-C6alkoxy; X is selected from CH2, CF2, O, S, SO, SO2, NR 7 ; R 7 selected from hydrogen, halogen, Ci-C6alkyl, 3- to 6-membered cycloalkyl; A and B are independently selected from 4-12 membered cycloalkyl, 4-12 membered heterocycloalkyl; when both A and B are heterocycloalkyl, one of the rings has 1 heteroatom N and the other has 2 heteroatoms N.

13. The pharmaceutical composition of claim 12, wherein: The compound is as shown in formula (X): wherein, R 3 , R 4 are each independently selected from the group consisting of hydrogen, C1-C6alkyl; or R 3 , R 4 are joined to form a 3- to 6-membered cycloalkyl group; R 5 selected from the group consisting of C1-C6alkyl, 3-6 membered cycloalkyl, trifluoromethyl, trifluoroethyl, substituted or unsubstituted 6-10 membered aryl, substituted or unsubstituted 5-8 membered heteroaryl; the substituents of the aryl or heteroaryl are selected from the group consisting of halogen, hydroxy, amino, cyano, trifluoromethyl, C1-C6alkyl, 3-6 membered cycloalkyl, C1-C6alkoxy; X is selected from CR 7 R 8 , O, S, SO, SO2, NR 7 ; R 7 , R 8 are each independently selected from hydrogen, halogen, Ci-C6alkyl, 3- to 6-membered cycloalkyl; A and B are independently selected from 4-12 membered cycloalkyl, 4-12 membered heterocycloalkyl; Y is none, CR Y1 R Y2 , C(O), -CR 11 =CR 12 -, -CR 11 =N-, -N=N-, -OC(O)-; R Y1 , R Y2 are each independently selected from the group consisting of hydrogen, C1-C6alkyl; R 11 , R 12 are each independently selected from hydrogen, C1-C6alkyl; the heteroatom of the heteroaryl is O, N or S; the number of the heteroatoms is 1, 2 or 3; the heteroatom of the heterocycloalkyl is N; the number of the heteroatoms is 1, 2 or 3; Preferably, R 5 selected from the group consisting of C1-C6alkyl, 3- to 6-membered cycloalkyl, trifluoromethyl, trifluoroethyl, substituted or unsubstituted phenyl, substituted or unsubstituted thienyl, substituted or unsubstituted furanyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted pyrimidinyl, substituted or unsubstituted pyridazinyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted pyrazinyl; the substituents of the phenyl, thienyl, furanyl, pyrrolyl, pyrimidinyl, pyridazinyl, pyrazolyl or pyrazinyl are selected from the group consisting of halogen, hydroxyl, amino, cyano, trifluoromethyl, C1-C6alkyl, 3- to 6-membered cycloalkyl, C1-C6alkoxy; X is selected from CH2, CF2, O, S, SO, SO2, NR 7 ; R 7 selected from hydrogen, halogen, Ci-C6alkyl, 3- to 6-membered cycloalkyl; A and B are independently selected from 4-12 membered cycloalkyl, 4-12 membered heterocycloalkyl; when both A and B are heterocycloalkyl, one of the rings has 1 heteroatom N and the other has 2 heteroatoms N.

14. The pharmaceutical composition of claim 9, wherein: The compound is as shown in formula (XI): wherein, R 2 R is a substituent on the phenyl ring at any position, a is the number of substituents R 2 ​ Each R 2 Each is independently selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, and C1-C6 alkoxy. a is 0, 1, 2 or 3; R 3 , R 4 are each independently selected from the group consisting of hydrogen, C1-C6alkyl; or R 3 , R 4 are joined to form a 3- to 6-membered cycloalkyl group; R 11 is a substituent on any position of the phenyl ring, d is the number of substituents R 11 . Each R 11 Each is independently selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, and C1-C6 alkoxy. d is 0, 1, 2 or 3; X is selected from CR 7 R 8 , O, S, SO, SO2, NR 7 ; R 7 , R 8 are each independently selected from hydrogen, halogen, Ci-C6alkyl, 3- to 6-membered cycloalkyl; R 6 R is a substituent on the phenyl ring at any position, b is the number of substituents R 6 R is a substituent on the phenyl ring at any position, b is the number of substituents R Each R 6 Each is independently selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, and C1-C6 alkoxy. b is 0, 1, 2 or 3; A and B are independently selected from 4-12 membered cycloalkyl, 4-12 membered heterocycloalkyl; M is selected from none, CR 9 R 10 , O, S, SO, SO2, NR 9 ; R 9 , R 10 are each independently selected from the group consisting of hydrogen, C1-C6alkyl; E 3 for a substituent on the phenyl ring at any position, c is the number of substituents E 3 ​ Each E 3 Each of the following groups is independently selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, C1-C6 alkoxy; or any two E groups. 3 They can be linked to form 3-6 membered cycloalkyl groups, 6-10 membered aryl groups, 4-12 membered heterocycloalkyl groups, and 5-8 membered heteroaryl groups; c is 0, 1, 2 or 3; Y is none, CR Y1 R Y2 , C(O), -CR 11 =CR 12 -, -CR 11 =N-, -N=N-, -OC(O)-; R Y1 , R Y2 are each independently selected from the group consisting of hydrogen, C1-C6alkyl; R 11 , R 12 are each independently selected from hydrogen, C1-C6alkyl; the heteroatom of the heteroaryl is O, N or S; the number of the heteroatoms is 1, 2 or 3; the heteroatom of the heterocycloalkyl is N; the number of the heteroatoms is 1, 2 or 3; Preferably, X is selected from CH2, CF2, O, S, SO, SO2, NR 7 ; R 7 selected from hydrogen, halogen, Ci-C6alkyl, 3- to 6-membered cycloalkyl; A and B are independently selected from 4-12 membered cycloalkyl, 4-12 membered heterocycloalkyl; when both A and B are heterocycloalkyl, one of the rings has 1 heteroatom N and the other has 2 heteroatoms N.

15. The pharmaceutical composition of claim 14, wherein: The compound is as shown in formula (XII): wherein, R 2 R is a substituent on the phenyl ring at any position, a is the number of substituents R 2 ​ Each R 2 Each is independently selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, and C1-C6 alkoxy. a is 0, 1, 2 or 3; R 3 R 4 Each is independently selected from hydrogen, C1-C6 alkyl, or R 3 R 4 Linkage forms 3- to 6-membered cycloalkyl groups; R 11 is a substituent on the phenyl ring at any position, d is the number of substituents R 11 . Each R 11 Each is independently selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, and C1-C6 alkoxy. d is 0, 1, 2 or 3; X is selected from CR 7 R 8 , O, S, SO, SO2, NR 7 ; R 7 , R 8 are each independently selected from hydrogen, halogen, Ci-C6alkyl, 3- to 6-membered cycloalkyl; R 6 R is a substituent on the phenyl ring at any position, b is the number of substituents R 6 R is a substituent on the phenyl ring at any position, b is the number of substituents R Each R 6 Each is independently selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, and C1-C6 alkoxy. b is 0, 1, 2 or 3; M is selected from none, CR 9 R 10 , O, S, SO, SO2, NR 9 ; R 9 , R 10 are each independently selected from the group consisting of hydrogen, C1-C6alkyl; R 12 selected from hydrogen, halogen, Ci-C6alkyl, hydroxyl; m1, m2, m3, m4, m5, m6 are independently selected from 0, 1, 2 or 3; E 3 for a substituent on the phenyl ring at any position, c is the number of substituents E 3 ​ Each E 3 Each of the following groups is independently selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, C1-C6 alkoxy; or any two E groups. 3 They can be linked to form 3-6 membered cycloalkyl groups, 6-10 membered aryl groups, 4-12 membered heterocycloalkyl groups, and 5-8 membered heteroaryl groups; c is 0, 1, 2 or 3; Y is none, CR Y1 R Y2 , C(O), -CR 11 =CR 12 -, -CR 11 =N-, -N=N-, -OC(O)-; R Y1 , R Y2 are each independently selected from the group consisting of hydrogen, C1-C6alkyl; R 11 , R 12 are each independently selected from the group consisting of hydrogen, C1-C6alkyl; the heteroatom of the heteroaryl is O, N or S; the number of the heteroatoms is 1, 2 or 3; the heteroatom of the heterocycloalkyl is N; the number of the heteroatoms is 1, 2 or 3; Preferably, X is selected from CH2, CF2, O, S, SO, SO2, NR 7 ; R 7 selected from hydrogen, halogen, Ci-C6alkyl, 3- to 6-membered cycloalkyl; Y is none, CR Y1 R Y2 , C(O), -CR 11 =CR 12 -, -CR 11 =N-, -N=N-, -OC(O)-; R Y1 , R Y2 are each independently selected from the group consisting of hydrogen, C1-C6alkyl; R 11 , R 12 are each independently selected from hydrogen, C1-C6alkyl.

16. The pharmaceutical composition of claim 15, wherein: The compound is as shown in formula (XIII): wherein, R 2 R is a substituent on the phenyl ring at any position, a is the number of substituents R 2 ​ Each R 2 Each is independently selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, and C1-C6 alkoxy. a is 0, 1, 2 or 3; R 3 R 4 Each is independently selected from hydrogen, C1-C6 alkyl, or R 3 R 4 Linkage forms 3- to 6-membered cycloalkyl groups; R 11 is a substituent on the phenyl ring at any position, d is the number of substituents R 11 . Each R 11 Each is independently selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, and C1-C6 alkoxy. d is 0, 1, 2 or 3; X is selected from CR 7 R 8 , O, S, SO, SO2, NR 7 ; R 7 , R 8 are each independently selected from hydrogen, halogen, Ci-C6alkyl, 3- to 6-membered cycloalkyl; R 6 R is a substituent on the phenyl ring at any position, b is the number of substituents R 6 R is a substituent on the phenyl ring at any position, b is the number of substituents R Each R 6 Each is independently selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, and C1-C6 alkoxy. b is 0, 1, 2 or 3; R 12 selected from hydrogen, halogen, Ci-C6alkyl, hydroxyl; m1, m2, m3, m4, m5, m6 are independently selected from 0, 1, 2 or 3; E 3 for a substituent on the phenyl ring at any position, c is the number of substituents E 3 ​ Each E 3 Each of the following groups is independently selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, C1-C6 alkoxy; or any two E groups. 3 They can be linked to form 3-6 membered cycloalkyl groups, 6-10 membered aryl groups, 4-12 membered heterocycloalkyl groups, and 5-8 membered heteroaryl groups; c is 0, 1, 2 or 3; Y is none, CR Y1 R Y2 , C(O), -CR 11 =CR 12 -, -CR 11 =N-, -N=N-, -OC(O)-; R Y1 , R Y2 are each independently selected from the group consisting of hydrogen, C1-C6alkyl; R 11 , R 12 are each independently selected from the group consisting of hydrogen, C1-C6alkyl; the heteroatom of the heteroaryl is O, N or S; the number of the heteroatoms is 1, 2 or 3; the heteroatom of the heterocycloalkyl is N; the number of the heteroatoms is 1, 2 or 3; Preferably, X is selected from CH2, CF2, O, S, SO, SO2, NR 7 ; R 7 selected from hydrogen, halogen, Ci-C6alkyl, 3- to 6-membered cycloalkyl; Y is none, CR Y1 R Y2 , C(O), -CR 11 =CR 12 -, -CR 11 =N-, -N=N-, -OC(O)-; R Y1 , R Y2 are each independently selected from hydrogen, C1-C6alkyl; R 11 , R 12 are each independently selected from hydrogen, C1-C6alkyl.

17. The pharmaceutical composition of claim 15, wherein: The compound is as shown in formula (XIV): wherein, R 2 R is a substituent on the phenyl ring at any position, a is the number of substituents R 2 ​ Each R 2 Each is independently selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, and C1-C6 alkoxy. a is 0, 1, 2 or 3; R 3 R 4 Each is independently selected from hydrogen, C1-C6 alkyl, or R 3 R 4 Linkage forms 3- to 6-membered cycloalkyl groups; R 11 is a substituent on any position of the phenyl ring, d is the number of substituents R 11 . Each R 11 Each is independently selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, and C1-C6 alkoxy. d is 0, 1, 2 or 3; X is selected from CR 7 R 8 , O, S, SO, SO2, NR 7 ; R 7 , R 8 are each independently selected from hydrogen, halogen, Ci-C6alkyl, 3- to 6-membered cycloalkyl; R 6 is a substituent on the phenyl ring at any position, b is the number of substituents R 6 ​ Each R 6 Each is independently selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, and C1-C6 alkoxy. b is 0, 1, 2 or 3; R 12 selected from hydrogen, halogen, Ci-C6alkyl, hydroxyl; m1, m2, m3, m4, m5, m6 are independently selected from 0, 1, 2 or 3; E 3 for a substituent on the phenyl ring at any position, c is the number of substituents E 3 ​ Each E 3 Each of the following groups is independently selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, C1-C6 alkoxy; or any two E groups. 3 They can be linked to form 3-6 membered cycloalkyl groups, 6-10 membered aryl groups, 4-12 membered heterocycloalkyl groups, and 5-8 membered heteroaryl groups; c is 0, 1, 2 or 3; Y is none, CR Y1 R Y2 , C(O), -CR 11 =CR 12 -, -CR 11 =N-, -N=N-, -OC(O)-; R Y1 , R Y2 are each independently selected from the group consisting of hydrogen, C1-C6alkyl; R 11 , R 12 are each independently selected from the group consisting of hydrogen, C1-C6alkyl; the heteroatom of the heteroaryl is O, N or S; the number of the heteroatoms is 1, 2 or 3; the heteroatom of the heterocycloalkyl is N; the number of the heteroatoms is 1, 2 or 3; Preferably, X is selected from CH2, CF2, O, S, SO, SO2, NR 7 ; R 7 selected from hydrogen, halogen, Ci-C6alkyl, 3- to 6-membered cycloalkyl; Y is none, CR Y1 R Y2 , C(O), -CR 11 =CR 12 -, -CR 11 =N-, -N=N-, -OC(O)-; R Y1 , R Y2 are each independently selected from the group consisting of hydrogen, C1-C6alkyl; R 11 , R 12 are each independently selected from the group consisting of hydrogen, C1-C6alkyl.

18. The pharmaceutical composition of claim 9, wherein: The compound is as shown in formula (XV): wherein, R 2 R is a substituent on the phenyl ring at any position, a is the number of substituents R 2 ​ Each R 2 Each is independently selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, and C1-C6 alkoxy. a is 0, 1, 2 or 3; R 3 R 4 Each is independently selected from hydrogen, C1-C6 alkyl, or R 3 R 4 Linkage forms 3- to 6-membered cycloalkyl groups; R 11 R is a substituent on the thiophene ring at any position, d is the number of substituents R 11 ​ Each R 11 Each is independently selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, and C1-C6 alkoxy. d is 0, 1, 2 or 3; X is selected from CR 7 R 8 , O, S, SO, SO2, NR 7 ; R 7 , R 8 are each independently selected from hydrogen, halogen, Ci-C6alkyl, 3- to 6-membered cycloalkyl; R 6 R is a substituent on the phenyl ring at any position, b is the number of substituents R 6 R is a substituent on the phenyl ring at any position, b is the number of substituents R Each R 6 Each is independently selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, and C1-C6 alkoxy. b is 0, 1, 2 or 3; ring A and ring B are independently selected from 4-12 membered cycloalkyl, 4-12 membered heterocycloalkyl; M is selected from none, CR 9 R 10 , O, S, SO, SO2, NR 9 ; R 9 , R 10 are each independently selected from the group consisting of hydrogen, C1-C6alkyl; E 3 for a substituent on the phenyl ring at any position, c is the number of substituents E 3 ​ Each E 3 Each of the following groups is independently selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, C1-C6 alkoxy; or any two E groups. 3 They can be linked to form 3-6 membered cycloalkyl groups, 6-10 membered aryl groups, 4-12 membered heterocycloalkyl groups, and 5-8 membered heteroaryl groups; c is 0, 1, 2 or 3; Y is none, CR Y1 R Y2 , C(O), -CR 11 =CR 12 -, -CR 11 =N-, -N=N-, -OC(O)-; R Y1 , R Y2 are each independently selected from the group consisting of hydrogen, C1-C6alkyl; R 11 , R 12 are each independently selected from the group consisting of hydrogen, C1-C6alkyl; the heteroatom of the heteroaryl is O, N or S; the number of the heteroatoms is 1, 2 or 3; the heteroatom of the heterocycloalkyl is N; the number of the heteroatoms is 1, 2 or 3; Preferably, X is selected from CH2, CF2, O, S, SO, SO2, NR 7 ; R 7 selected from hydrogen, halogen, Ci-C6alkyl, 3- to 6-membered cycloalkyl; ring A and ring B are independently selected from 4-12 membered cycloalkyl, 4-12 membered heterocycloalkyl; when both ring A and ring B are heterocycloalkyl, one of the rings has 1 heteroatom N and the other ring has 2 heteroatoms N.

19. The pharmaceutical composition of claim 9, wherein: The compound is as shown in formula (XVI): wherein, R 2 R is a substituent on the phenyl ring at any position, a is the number of substituents R 2 ​ Each R 2 Each is independently selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, and C1-C6 alkoxy. a is 0, 1, 2 or 3; R 3 R 4 Each is independently selected from hydrogen, C1-C6 alkyl, or R 3 R 4 Linkage forms 3- to 6-membered cycloalkyl groups; R 11 is a substituent on the thiophene ring at any position, d is the number of substituents R 11 . Each R 11 Each is independently selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, and C1-C6 alkoxy. d is 0, 1, 2 or 3; X is selected from CR 7 R 8 , O, S, SO, SO2, NR 7 ; R 7 , R 8 are each independently selected from hydrogen, halogen, Ci-C6alkyl, 3- to 6-membered cycloalkyl; R 6 R is a substituent on the phenyl ring at any position, b is the number of substituents R 6 R is a substituent on the phenyl ring at any position, b is the number of substituents R Each R 6 Each is independently selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, and C1-C6 alkoxy. b is 0, 1, 2 or 3; ring A and ring B are independently selected from 4-12 membered cycloalkyl, 4-12 membered heterocycloalkyl; M is selected from none, CR 9 R 10 , O, S, SO, SO2, NR 9 ; R 9 , R 10 are each independently selected from the group consisting of hydrogen, C1-C6alkyl; E 3 for a substituent on the phenyl ring at any position, c is the number of substituents E 3 ​ Each E 3 Each of the following groups is independently selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, C1-C6 alkoxy; or any two E groups. 3 They can be linked to form 3-6 membered cycloalkyl groups, 6-10 membered aryl groups, 4-12 membered heterocycloalkyl groups, and 5-8 membered heteroaryl groups; c is 0, 1, 2 or 3; Y is none, CR Y1 R Y2 , C(O), -CR 11 =CR 12 -, -CR 11 =N-, -N=N-, -OC(O)-; R Y1 , R Y2 are each independently selected from the group consisting of hydrogen, C1-C6alkyl; R 11 , R 12 are each independently selected from the group consisting of hydrogen, C1-C6alkyl; the heteroatom of the heteroaryl is O, N or S; the number of the heteroatoms is 1, 2 or 3; the heteroatom of the heterocycloalkyl is N; the number of the heteroatoms is 1, 2 or 3; Preferably, X is selected from CH2, CF2, O, S, SO, SO2, NR 7 ; R 7 selected from hydrogen, halogen, Ci-C6alkyl, 3- to 6-membered cycloalkyl; ring A and ring B are independently selected from 4-12 membered cycloalkyl, 4-12 membered heterocycloalkyl; when both ring A and ring B are heterocycloalkyl, one of the rings has 1 heteroatom N and the other ring has 2 heteroatoms N.

20. The pharmaceutical composition of claim 5, wherein: The compound is as shown in formula (XVII): wherein, R 3 R 4 Each is independently selected from hydrogen, C1-C6 alkyl, or R 3 R 4 Linkage forms 3- to 6-membered cycloalkyl groups; X is selected from CR 7 R 8 , O, S, SO, SO2, NR 7 ; R 7 , R 8 are each independently selected from hydrogen, halogen, Ci-C6alkyl, 3- to 6-membered cycloalkyl; R 11 is a substituent on the phenyl ring at any position, d is the number of substituents R 11 ; R 6 is a substituent on the phenyl ring at any position, b is the number of substituents R 6 ; R d is 0, 1, 2 or 3; b is 0, 1, 2 or 3; and at least one of d and b is not 0; each R 11 , R 6 is independently selected from the group consisting of halogen, hydroxy, amino, cyano, trifluoromethyl, Ci-C6-alkyl, 3- to 6-membered cycloalkyl, Ci-C6-alkoxy; and at least one is fluorine; ring A and ring B are independently selected from 4-12 membered cycloalkyl, 4-12 membered heterocycloalkyl; M is selected from none, CR 9 R 10 , O, S, SO, SO2, NR 9 ; R 9 , R 10 are each independently selected from the group consisting of hydrogen, C1-C6alkyl; Y is none, CR Y1 R Y2 , C(O), -CR 11 =CR 12 -, -CR 11 =N-, -N=N-, -OC(O)-; R Y1 , R Y2 are each independently selected from the group consisting of hydrogen, C1-C6alkyl; R 11 , R 12 are each independently selected from the group consisting of hydrogen, C1-C6alkyl; the heteroatom of the heterocycloalkyl is N; the number of the heteroatoms is 1, 2 or 3; Preferably, X is selected from CH2, CF2, O, S, SO, SO2, NR 7 ; R 7 selected from hydrogen, halogen, Ci-C6alkyl, 3- to 6-membered cycloalkyl; ring A and ring B are independently selected from 4-12 membered cycloalkyl, 4-12 membered heterocycloalkyl; when both ring A and ring B are heterocycloalkyl, one of the rings has 1 heteroatom N and the other ring has 2 heteroatoms N.

21. The pharmaceutical composition of claim 20, wherein: The compound is as shown in formula (XVIII): wherein, X is selected from CR 7 R 8 , O, S, SO, SO2, NR 7 ; R 7 , R 8 are each independently selected from hydrogen, halogen, Ci-C6alkyl, 3- to 6-membered cycloalkyl; R 11 is a substituent on any position of the benzene ring, d is the number of substituents R 11 ; R 6 is a substituent on any position of the benzene ring, b is the number of substituents R 6 ; d is 0, 1, 2 or 3; b is 0, 1, 2 or 3; and at least one of d and b is not 0; each R 11 , R 6 is independently selected from the group consisting of halogen, hydroxy, amino, cyano, trifluoromethyl, Ci-C6-alkyl, 3- to 6-membered cycloalkyl, Ci-C6-alkoxy; and at least one is fluorine; ring A and ring B are independently selected from 4-12 membered cycloalkyl, 4-12 membered heterocycloalkyl; M is selected from none, CR 9 R 10 ; R 9 , R 10 are each independently selected from the group consisting of hydrogen, C1-C6alkyl; Y is none, CR Y1 R Y2 , C(O), -CR 11 =CR 12 -, -CR 11 =N-, -N=N-, -OC(O)-; R Y1 , R Y2 are each independently selected from the group consisting of hydrogen, C1-C6alkyl; R 11 , R 12 are each independently selected from the group consisting of hydrogen, C1-C6alkyl; the heteroatom of the heterocycloalkyl is N; the number of the heteroatoms is 1, 2 or 3; Preferably, X is selected from CH2, CF2 or O; ring A and ring B are independently selected from 4-12 membered cycloalkyl, 4-12 membered heterocycloalkyl; when both ring A and ring B are heterocycloalkyl, one of the rings has 1 heteroatom N and the other ring has 2 heteroatoms N.

22. The pharmaceutical composition of claim 5, wherein: The compound is as shown in formula (XIX): wherein, R 1 selected from hydrogen, C1-C6alkyl, hydroxy, amino, or C1-C6alkoxy, boronic acid group; R 2 R is a substituent on the phenyl ring at any position, a is the number of substituents R 2 ​ Each R 2 Each is independently selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, and C1-C6 alkoxy. a is 0, 1, 2 or 3; R 5 selected from the group consisting of C1-C6alkyl, 3-6 membered cycloalkyl, trifluoromethyl, trifluoroethyl, substituted or unsubstituted 6-10 membered aryl, substituted or unsubstituted 5-8 membered heteroaryl; the substituents of the aryl or heteroaryl are selected from the group consisting of halogen, hydroxy, amino, cyano, trifluoromethyl, C1-C6alkyl, 3-6 membered cycloalkyl, C1-C6alkoxy; X is selected from CR 7 R 8 , O, S, SO, SO2, NR 7 ; R 7 , R 8 are each independently selected from hydrogen, halogen, Ci-C6alkyl, 3- to 6-membered cycloalkyl; n is 0, 1 or 2; R 6 R is a substituent on the phenyl ring at any position, b is the number of substituents R 6 R is a substituent on the phenyl ring at any position, b is the number of substituents R Each R 6 Each is independently selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, and C1-C6 alkoxy. b is 0, 1, 2 or 3; ring A and ring B are each independently selected from 4-12 membered cycloalkyl, 4-12 membered heterocycloalkyl; M is selected from none, CR 9 R 10 , O, S, SO, SO2, NR 9 ; R 9 , R 10 are each independently selected from the group consisting of hydrogen, C1-C6alkyl; E 3 for a substituent on the phenyl ring at any position, c is the number of substituents E 3 ​ Each E 3 Each of the following groups is independently selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, C1-C6 alkoxy; or any two E groups. 3 They can be linked to form 3-6 membered cycloalkyl groups, 6-10 membered aryl groups, 4-12 membered heterocycloalkyl groups, and 5-8 membered heteroaryl groups; c is 0, 1, 2 or 3; Y is none, CR Y1 R Y2 , C(O), -CR 11 =CR 12 -, -CR 11 =N-, -N=N-, -OC(O)-; R Y1 , R Y2 are each independently selected from hydrogen, C1-C6alkyl; R 11 , R 12 are each independently selected from the group consisting of hydrogen, C1-C6alkyl; the heteroatom of the heteroaryl is O, N or S; the number of the heteroatom is 1, 2 or 3; the heteroatom of the heterocycloalkyl is N; the number of the heteroatom is 1, 2 or 3; Preferably, R 5 selected from the group consisting of C1-C6alkyl, 3- to 6-membered cycloalkyl, trifluoromethyl, trifluoroethyl, substituted or unsubstituted phenyl, substituted or unsubstituted thienyl, substituted or unsubstituted furanyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted pyrimidinyl, substituted or unsubstituted pyridazinyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted pyrazinyl; the substituents of the phenyl, thienyl, furanyl, pyrrolyl, pyrimidinyl, pyridazinyl, pyrazolyl or pyrazinyl are selected from the group consisting of halogen, hydroxyl, amino, cyano, trifluoromethyl, C1-C6alkyl, 3- to 6-membered cycloalkyl, C1-C6alkoxy.

23. The pharmaceutical composition of claim 22, wherein: The compound is as shown in formula (XX): wherein, R 5 selected from the group consisting of C1-C6alkyl, 3-6 membered cycloalkyl, trifluoromethyl, trifluoroethyl, substituted or unsubstituted 6-10 membered aryl, substituted or unsubstituted 5-8 membered heteroaryl; the substituents of the aryl or heteroaryl are selected from the group consisting of halogen, hydroxy, amino, cyano, trifluoromethyl, C1-C6alkyl, 3-6 membered cycloalkyl, C1-C6alkoxy; X is selected from CR 7 R 8 , O, S, SO, SO2, NR 7 ; R 7 , R 8 are each independently selected from hydrogen, halogen, Ci-C6alkyl, 3- to 6-membered cycloalkyl; R 6 R is a substituent on the phenyl ring at any position, b is the number of substituents R 6 R is a substituent on the phenyl ring at any position, b is the number of substituents R Each R 6 Each is independently selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, and C1-C6 alkoxy. b is 0, 1, 2 or 3; ring A and ring B are each independently selected from 4-12 membered cycloalkyl, 4-12 membered heterocycloalkyl; M is selected from none, CR 9 R 10 , O, S, SO, SO2, NR 9 ; R 9 , R 10 are each independently selected from the group consisting of hydrogen, C1-C6alkyl; Y is none, CR Y1 R Y2 , C(O), -CR 11 =CR 12 -, -CR 11 =N-, -N=N-, -OC(O)-; R Y1 , R Y2 are each independently selected from the group consisting of hydrogen, C1-C6alkyl; R 11 , R 12 are each independently selected from the group consisting of hydrogen, C1-C6alkyl; the heteroatom of the heteroaryl is O, N or S; the number of the heteroatom is 1, 2 or 3; the heteroatom of the heterocycloalkyl is N; the number of the heteroatom is 1, 2 or 3; Preferably, R 5 selected from the group consisting of C1-C6alkyl, 3- to 6-membered cycloalkyl, trifluoromethyl, trifluoroethyl, substituted or unsubstituted phenyl, substituted or unsubstituted thienyl, substituted or unsubstituted furanyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted pyrimidinyl, substituted or unsubstituted pyridazinyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted pyrazinyl; the substituents of the phenyl, thienyl, furanyl, pyrrolyl, pyrimidinyl, pyridazinyl, pyrazolyl or pyrazinyl are selected from the group consisting of halogen, hydroxyl, amino, cyano, trifluoromethyl, C1-C6alkyl, 3- to 6-membered cycloalkyl, C1-C6alkoxy; X is selected from CH2, CF2, O, S, SO, SO2, NR 7 ; R 7 selected from hydrogen, halogen, Ci-C6alkyl, 3- to 6-membered cycloalkyl; ring A and ring B are each independently selected from 4-12 membered cycloalkyl, 4-12 membered heterocycloalkyl; when both ring A and ring B are heterocycloalkyl, one of the rings has 1 heteroatom N and the other ring has 2 heteroatoms N.

24. The pharmaceutical composition of claim 23, wherein: The compound is as shown in formula (XXI): wherein, R 11 is a substituent on the phenyl ring at any position, d is the number of substituents R 11 . Each R 11 Each is independently selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, and C1-C6 alkoxy. d is 0, 1, 2 or 3; X is selected from CR 7 R 8 , O, S, SO, SO2, NR 7 ; R 7 , R 8 are each independently selected from hydrogen, halogen, Ci-C6alkyl, 3- to 6-membered cycloalkyl; R 6 R is a substituent on the phenyl ring at any position, b is the number of substituents R 6 R is a substituent on the phenyl ring at any position, b is the number of substituents R Each R 6 Each is independently selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, and C1-C6 alkoxy. b is 0, 1, 2 or 3; M is selected from none, CR 9 R 10 , O, S, SO, SO2, NR 9 ; R 9 , R 10 are each independently selected from the group consisting of hydrogen, C1-C6alkyl; m1, m2, m3, m4, m5, m6 are each independently selected from 0, 1, 2 or 3; Y is none, CR Y1 R Y2 , C(O), -CR 11 =CR 12 -, -CR 11 =N-, -N=N-, -OC(O)-; R Y1 , R Y2 are each independently selected from the group consisting of hydrogen, C1-C6alkyl; R 11 , R 12 are each independently selected from the group consisting of hydrogen, C1-C6alkyl; Preferably, X is selected from CH2, CF2, O, S, SO, SO2, NR 7 ; R 7 selected from hydrogen, halogen, Ci-C6alkyl, 3- to 6-membered cycloalkyl.

25. The pharmaceutical composition according to any one of claims 4 to 24, wherein: said rings A and B are each independently selected from the following structures:

26. The pharmaceutical composition of any one of claims 4-24, wherein: The selected from the group consisting of:

27. The pharmaceutical composition of any one of claims 4-24, wherein: The compound is one of the following compounds:

28. The pharmaceutical composition of any one of claims 4-24, wherein: the compound is ARV-471 or compound 75 or compound 63 or compound 65; The structure of the ARV-471 is The structure of the compound 75 is The structure of the compound 63 is The structure of the compound 65 is 29. The pharmaceutical composition of any one of claims 4-24, wherein: the salt is a pharmaceutically acceptable salt; the pharmaceutically acceptable salt is a phosphate salt, a d-camphorsulfonic acid salt, a hydrochloride salt, a hydrobromide salt, a hydrofluoride salt, a sulfate salt, a nitrate salt, a formate salt, an acetate salt, a propionate salt, an oxalate salt, a malonate salt, a succinate salt, a fumarate salt, a maleate salt, a lactate salt, a malate salt, a tartrate salt, a citrate salt, a picrate salt, a mesylate salt, a tosylate salt, a benzenesulfonate salt, an aspartate salt or a glutamate salt of the compound.

30. The pharmaceutical composition of any one of claims 1-3, wherein: the AKT inhibitor is MK-2206 2HCl, Perifosine, GSK69069, Ipatasertib, Capivasertib, PF-04691502, AT7867, Triciribine (API-2), CCT128930, A-674563HCl, PHT-427, Miransertib HCl, Akti-1 / 2, Uprosertib, Afuresertib, AT13148, Miltefosine, Honokiol, TIC10 Analogue, Deguelin, TIC10 (ONC201) or an optical isomer thereof, a salt thereof, a hydrate thereof, a solvate thereof; Preferably, the AKT inhibitor is Capivasertib or an optical isomer thereof, a salt thereof, a hydrate thereof, a solvate thereof.

31. The pharmaceutical composition of any one of claims 1-3, wherein: When the estrogen receptor degrader is ARV-471 or an optical isomer thereof, a salt thereof, a hydrate thereof, a solvate thereof, and the AKT inhibitor is Capivasertib or an optical isomer thereof, a salt thereof, a hydrate thereof, a solvate thereof, the molar ratio of the estrogen receptor degrader to the AKT inhibitor is 1:1.1-1:268.3; preferably, the molar ratio is 1:1.1, 1:29.7, 1:268.

3.

32. The pharmaceutical composition of any one of claims 1-3, wherein: When the estrogen receptor degrader is Compound 75 or an optical isomer thereof, a salt thereof, a hydrate thereof, a solvate thereof, and the AKT inhibitor is Capivasertib or an optical isomer thereof, a salt thereof, a hydrate thereof, a solvate thereof, the molar ratio of the estrogen receptor degrader to the AKT inhibitor is 1:1.1-1:268.3; preferably, the molar ratio is 1:1.1, 1:29.7, 1:268.

3.

33. The pharmaceutical composition of any one of claims 1-3, wherein: When the estrogen receptor degrader is Compound 63 or an optical isomer thereof, a salt thereof, a hydrate thereof, a solvate thereof, and the AKT inhibitor is Capivasertib or an optical isomer thereof, a salt thereof, a hydrate thereof, a solvate thereof, the molar ratio of the estrogen receptor degrader to the AKT inhibitor is 1:0.37-90.2; preferably, the molar ratio is 1:0.37, 1:10, 1:90.

2.

34. The pharmaceutical composition of any one of claims 1-3, wherein: When the estrogen receptor degrader is Compound 65 or an optical isomer thereof, a salt thereof, a hydrate thereof, a solvate thereof, and the AKT inhibitor is Capivasertib or an optical isomer thereof, a salt thereof, a hydrate thereof, a solvate thereof, the molar ratio of the estrogen receptor degrader to the AKT inhibitor is 1:0.37-90.2; preferably, the molar ratio is 1:0.37, 1:10, 1:90.

2.

35. A method of preparing a pharmaceutical composition according to any one of claims 1 to 34, characterized by: It comprises the following steps: taking the estrogen receptor degrader and the AKT inhibitor in a molar ratio, and mixing.

36. Use of the pharmaceutical composition of any one of claims 1-34 in the preparation of a medicament for degrading estrogen receptor and / or treating estrogen receptor related diseases.

37. Use of the pharmaceutical composition of any one of claims 1-34 in the preparation of a medicament for treating and / or preventing cancer. Preferably, the cancer is bone cancer, colorectal cancer, endometrial cancer, prostate cancer, ovarian cancer, uterine cancer, cervical cancer, lung cancer, breast cancer.

38. A pharmaceutical preparation that degrades an estrogen receptor, characterized by: It is a preparation prepared from the pharmaceutical composition of any one of claims 1-34 as an active ingredient, plus pharmaceutically acceptable adjuvants or auxiliary ingredients.

39. A combination drug for degrading estrogen receptors, characterized in that: It contains the estrogen receptor degrader and the AKT inhibitor of the same or different specifications, which are administered simultaneously or separately, and a pharmaceutically acceptable carrier.

40. The combination of claim 39, wherein: The molar ratio of the estrogen receptor degrader to the AKT inhibitor is 1:0.1-300.

41. The combination of claim 40, wherein: The molar ratio of the estrogen receptor degrader to the AKT inhibitor is 1:1-300. Alternatively, the molar ratio of the estrogen receptor degrader to the AKT inhibitor is 1:0.3-100. Preferably, The molar ratio of the estrogen receptor degrader to the AKT inhibitor is 1:1.1-268.

3. The molar ratio of the estrogen receptor degrader to the AKT inhibitor is 1:1-300. or the molar ratio of the estrogen receptor degrader to the AKT inhibitor is 1:0.37-90.2; More preferably, the molar ratio of the estrogen receptor degrader to the AKT inhibitor is 1:1.1, 1:29.7, 1:268.3; or the molar ratio of the estrogen receptor degrader to the AKT inhibitor is 1:0.37, 1:10, 1:90.

2.

42. The combination of any one of claims 39 to 41, wherein: the estrogen receptor degrader is selected from the compound of any one of claims 4-29, or an optical isomer thereof, or a salt thereof, or a hydrate thereof, or a solvate thereof; the AKT inhibitor is MK-2206 2HCl, Perifosine, GSK69069, Ipatasertib, Capivasertib, PF-04691502, AT7867, Triciribine (API-2), CCT128930, A-674563 HCl, PHT-427, Miransertib HCl, Akti-1 / 2, Uprosertib, Afuresertib, AT13148, Miltefosine, Honokiol, TIC10 Analogue, Deguelin, TIC10 (ONC201), or an optical isomer thereof, a salt thereof, a hydrate thereof, a solvate thereof; Preferably, the AKT inhibitor is Capivasertib, or an optical isomer thereof, a salt thereof, a hydrate thereof, a solvate thereof.

43. The combination of claim 42, wherein: when the estrogen receptor degrader is ARV-471, or an optical isomer thereof, a salt thereof, a hydrate thereof, a solvate thereof, and the AKT inhibitor is Capivasertib, or an optical isomer thereof, a salt thereof, a hydrate thereof, a solvate thereof, the molar ratio of the estrogen receptor degrader to the AKT inhibitor is 1:1.1-1:268.3; preferably, the molar ratio is 1:1.1, 1:29.7, 1:268.

3.

44. The combination of claim 42, wherein: when the estrogen receptor degrader is compound 75, or an optical isomer thereof, a salt thereof, a hydrate thereof, a solvate thereof, and the AKT inhibitor is Capivasertib, or an optical isomer thereof, a salt thereof, a hydrate thereof, a solvate thereof, the molar ratio of the estrogen receptor degrader to the AKT inhibitor is 1:1.1-1:268.3; preferably, the molar ratio is 1:1.1, 1:29.7, 1:268.

3.

45. The combination of claim 42, wherein: ###00017### when the estrogen receptor degrader is compound 63, or an optical isomer thereof, a salt thereof, a hydrate thereof, a solvate thereof, and the AKT inhibitor is Capivasertib, or an optical isomer thereof, a salt thereof, a hydrate thereof, a solvate thereof, the molar ratio of the estrogen receptor degrader to the AKT inhibitor is 1:0.37-90.2; preferably, the molar ratio is 1:0.37, 1:10, 1:90.

2.

46. The combination of claim 42, wherein: when the estrogen receptor degrader is Compound 65 or an optical isomer thereof, a salt thereof, a hydrate thereof, a solvate thereof, and the AKT inhibitor is Capivasertib or an optical isomer thereof, a salt thereof, a hydrate thereof, a solvate thereof, the molar ratio of the estrogen receptor degrader to the AKT inhibitor is 1:0.37-90.2; preferably, the molar ratio is 1:0.37, 1:10, 1:90.

2.

47. Use of an estrogen receptor degrader in combination with an AKT inhibitor for the manufacture of a medicament for degrading estrogen receptor.

48. The use according to claim 47, characterized in that: The molar ratio of the estrogen receptor degrader to the AKT inhibitor is 1:0.1-300.

49. The use according to claim 48, characterized in that: The molar ratio of the estrogen receptor degrader to the AKT inhibitor is 1:1-300; Alternatively, the molar ratio of the estrogen receptor degrader to the AKT inhibitor is 1:0.3-100; Preferably, The molar ratio of the estrogen receptor degrader to the AKT inhibitor is 1:1.1-268.

3. Alternatively, the molar ratio of the estrogen receptor degrader to the AKT inhibitor is 1:0.37-90.

2. More preferably, The molar ratio of the estrogen receptor degrader to the AKT inhibitor is 1:1.1, 1:29.7, 1:268.

3. Alternatively, the molar ratio of the estrogen receptor degrader to the AKT inhibitor is 1:0.37, 1:10, 1:90.

2.

50. Use according to any one of claims 47 to 49, characterized in that: The estrogen receptor degrader is selected from the compound of any one of claims 4-29, or an optical isomer thereof, or a salt thereof, or a hydrate thereof, or a solvate thereof; The AKT inhibitor is MK-2206 2HCl, Perifosine, GSK69069, Ipatasertib, Capivasertib, PF-04691502, AT7867, Triciribine (API-2), CCT128930, A-674563 HCl, PHT-427, Miransertib HCl, Akti-1 / 2, Uprosertib, Afuresertib, AT13148, Miltefosine, Honokiol, TIC10 Analogue, Deguelin, TIC10 (ONC201), or an optical isomer thereof, or a salt thereof, or a hydrate thereof, or a solvate thereof; Preferably, the AKT inhibitor is Capivasertib or an optical isomer thereof, or a salt thereof, or a hydrate thereof, or a solvate thereof.

51. The use according to claim 50, characterized in that: when the estrogen receptor degrader is ARV-471 or an optical isomer thereof, a salt thereof, a hydrate thereof, a solvate thereof, and the AKT inhibitor is Capivasertib or an optical isomer thereof, a salt thereof, a hydrate thereof, a solvate thereof, the molar ratio of the estrogen receptor degrader to the AKT inhibitor is 1:1.1-1:268.3; preferably, the molar ratio is 1:1.1, 1:29.7, 1:268.

3.

52. The use of claim 50, wherein: When the estrogen receptor degrader is Compound 75 or an optical isomer thereof, a salt thereof, a hydrate thereof, a solvate thereof, and the AKT inhibitor is Capivasertib or an optical isomer thereof, a salt thereof, a hydrate thereof, a solvate thereof, the molar ratio of the estrogen receptor degrader to the AKT inhibitor is 1:1.1-1:268.3; preferably, the molar ratio is 1:1.1, 1:29.7, 1:268.

3.

53. The use of claim 50, wherein: When the estrogen receptor degrader is Compound 63 or an optical isomer thereof, a salt thereof, a hydrate thereof, a solvate thereof, and the AKT inhibitor is Capivasertib or an optical isomer thereof, a salt thereof, a hydrate thereof, a solvate thereof, the molar ratio of the estrogen receptor degrader to the AKT inhibitor is 1:0.37-90.2; preferably, the molar ratio is 1:0.37, 1:10, 1:90.

2.

54. The use of claim 50, wherein: When the estrogen receptor degrader is Compound 65 or an optical isomer thereof, a salt thereof, a hydrate thereof, a solvate thereof, and the AKT inhibitor is Capivasertib or an optical isomer thereof, a salt thereof, a hydrate thereof, a solvate thereof, the molar ratio of the estrogen receptor degrader to the AKT inhibitor is 1:0.37-90.2; preferably, the molar ratio is 1:0.37, 1:10, 1:90.

2.

55. Use according to any one of claims 47 to 49, characterized in that: The drug for degrading estrogen receptor is an estrogen receptor degrader and / or a drug for treating an estrogen receptor related disease.

56. The use according to claim 55, characterized in that: The drug is for use in a drug for treating and / or preventing cancer; Preferably, the cancer is bone cancer, colorectal cancer, endometrial cancer, prostate cancer, ovarian cancer, uterine cancer, cervical cancer, lung cancer, breast cancer.

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