Combined drug of estrogen protein targeted degrader and use thereof

Abstract

Provided are a combined drug of an estrogen protein targeted degrader and the use thereof, belonging to the field of medicines. The combined drug contains an estrogen receptor targeted degrader and an mTOR inhibitor which have same or different specifications and which are simultaneously or separately administrated, and a pharmaceutically acceptable carrier. Using the estrogen receptor degrader and the mTOR inhibitor in combination can degrade estrogen receptors, inhibit the growth of cancer cells and exert the synergistic inhibition effect, thus remarkably improving the effect of treating diseases related to estrogen receptors. Therefore, the present invention achieves good application prospects.

Description

A combined drug of estrogen protein targeted degradation agent and its use Technical Field

[0001] The present invention belongs to the field of medicine, and in particular relates to a combined drug of an estrogen protein targeted degrader and uses thereof. Background Art

[0002] The estrogen receptor (ER) is a ligand-activated transcriptional regulatory protein that mediates the induction of various biological effects through interaction with endogenous estrogens. Endogenous estrogens include 17β-estradiol and estrone. ER has been found to have two distinct conformations: ER-α and ER-β. Estrogen and estrogen receptors are associated with numerous diseases and conditions, such as bone cancer, breast cancer, colorectal cancer, endometrial cancer, prostate cancer, ovarian cancer, uterine cancer, cervical cancer, lung cancer, and other diseases and conditions. For example, approximately 70% of patients with breast cancer express ER and / or progesterone receptors. Treatment of these diseases can be achieved by inhibiting ER signaling through various approaches, including antagonizing ligand binding to ER, antagonizing or downregulating ERα, and blocking estrogen synthesis. Estrogen receptor degraders can compete for binding to estrogen receptors (ER) present in estrogen-responsive tissues and hold promise for treating ER-related diseases. However, single-agent ER degraders can cause adverse reactions in clinical use, such as endometrial hyperplasia and deep vein thrombosis. They are also prone to developing drug resistance.

[0003] mTOR (mammalian target of rapamycin) is a protein encoded by the mTOR gene. mTOR is a serine / threonine protein kinase that is downstream of the PI3K / Akt pathway. The mTOR signaling pathway is primarily involved in regulating cell growth and differentiation, controlling these processes at the translational level. Its downstream signaling pathways primarily include two signaling molecules: ribosomal p70 S6 (S6K1) and eukaryotic translation initiation factor 4E binding protein (4E-BP1). Both proteins activate translation processes related to ribosome biogenesis and translation, including protein synthesis essential for cell cycle progression. In addition to influencing protein translation through S6K1 and 4E-BP1, mTOR can also phosphorylate a variety of downstream effector molecules and transcription factors. Research has shown that abnormal mTOR expression is associated with a variety of diseases, such as diabetes, obesity, depression, and cancer. mTOR inhibitors can inhibit mTOR and are used to treat related diseases. mTOR inhibitors have shown promising results in the treatment of estrogen receptor-positive breast cancer. However, the monotherapy of mROR inhibitors can cause side effects such as stomatitis, infection, diarrhea, and liver damage, and can also lead to drug resistance.

[0004] How to overcome the problems of current single-drug inhibitor therapy is a problem that needs to be studied in the treatment of estrogen receptor-related diseases. Currently, there is no evidence of combining estrogen receptor degraders with mTOR inhibitors to treat estrogen receptor-related diseases.

[0005] Summary of the Invention

[0006] The purpose of the present invention is to provide a combined drug of an estrogen protein targeted degrader and its use.

[0007] The present invention provides a pharmaceutical composition for degrading estrogen receptors, which consists of an estrogen receptor targeted degrader and an mTOR inhibitor.

[0008] Furthermore, the molar ratio of the estrogen receptor targeted degrader to the mTOR inhibitor is 1:0011 to 1:8;

[0009] Preferably, the molar ratio of the estrogen receptor targeted degrader to the mTOR inhibitor is 1:0.011 to 1:2.7 or 1:0.033 to 1:8;

[0010] More preferably, the molar ratio of the estrogen receptor targeted degrader to the mTOR inhibitor is 1:0.011, 1:0.033, 1:0.3, 1:0.89, 1:2.7 or 1:8.

[0011] Furthermore, the estrogen receptor targeted 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, ERαdegrader 5, Imlunestrant tosylate, ERαdegrader 8, LX-039, Elacestrant-d10, SNIPER (ER) -110, Elacestrant-d6, Elacestrant-d4, PROTAC ERαDegrader-7, PROTAC ERαDegrader-4 or an optical isomer thereof, or a salt thereof, or a hydrate thereof, or a solvate thereof:

[0012] Alternatively, the estrogen receptor targeted degradation agent is a compound represented by formula (I), or an optical isomer thereof, or a salt thereof, or a hydrate thereof, or a solvate thereof:

[0013] in,

[0014] R 1 Selected from hydrogen, C1-C6 alkyl, hydroxy, amino, carboxyl, C1-C6 alkoxy, boric acid, -OR';

[0015] R' is selected from phenyl, benzyl;

[0016] R 2 is a substituent at any position on the benzene ring, a is a substituent R 2 The number of

[0017] Each R 2 Each of the following groups is independently selected from halogen, hydroxy, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, and C1-C6 alkoxy;

[0018] a is 0, 1, 2, or 3;

[0019] When the dotted line in the benzene ring is a bond, R 3 、R 4 are independently selected from none;

[0020] When there is no dotted line in the benzene ring, R 3 、R 4 are independently selected from hydrogen, C1-C6 alkyl, or R 3 、R 4 Connected to form a 3- to 6-membered cycloalkyl group;

[0021] 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 substituent of the aryl or heteroaryl is selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, C1-C6 alkoxy;

[0022] X is selected from CR 7 R 8 、O、S、SO、SO2、NR 7 ;

[0023] R 7 、R 8 are independently selected from hydrogen, halogen, C1-C6 alkyl, 3-6 membered cycloalkyl;

[0024] n is 0, 1, or 2;

[0025] R 6 is a substituent at any position on the benzene ring, and b is a substituent R 6 The number of

[0026] Each R 6 Each of the following groups is independently selected from halogen, hydroxy, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, and C1-C6 alkoxy;

[0027] b is 0, 1, 2, or 3;

[0028] Ring A and Ring B are independently selected from 4- to 12-membered cycloalkyl and 4- to 12-membered heterocycloalkyl;

[0029] M is selected from None, CR 9 R 10 、O、S、SO、SO2、NR 9 ;

[0030] R 9 、R 10 are independently selected from hydrogen, C1-C6 alkyl;

[0031] E 3 is a substituent at any position on the benzene ring, and c is a substituent E 3 The number of

[0032] Each E 3 are independently selected from halogen, hydroxy, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, C1-C6 alkoxy; or any two E 3 Connect to form 3-6 membered cycloalkyl, 6-10 membered aryl, 4-12 membered heterocycloalkyl, 5-8 membered heteroaryl;

[0033] c is 0, 1, 2, or 3;

[0034] When there is no dashed line between Y and W, W is NH and Y is halogen;

[0035] When the dashed 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)-;

[0036] R Y1 、R Y2 are independently selected from hydrogen, C1-C6 alkyl;

[0037] R 11 、R 12 are independently selected from hydrogen, C1-C6 alkyl;

[0038] R 21 selected from hydrogen or deuterium;

[0039] The heteroatom of the heteroaryl group is O, N or S; the number of heteroatoms is 1, 2 or 3;

[0040] The heteroatom of the heterocycloalkyl group is N; the number of the heteroatoms is 1, 2 or 3.

[0041] Furthermore, the compound is represented by formula (II):

[0042] in,

[0043] R 1 Selected from hydrogen, C1-C6 alkyl, hydroxy, amino, carboxyl, C1-C6 alkoxy, boric acid, -OR';

[0044] R' is selected from phenyl, benzyl;

[0045] R 2 is a substituent at any position on the benzene ring, a is a substituent R 2 The number of

[0046] Each R 2 Each of the following groups is independently selected from halogen, hydroxy, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, and C1-C6 alkoxy;

[0047] a is 0, 1, 2, or 3;

[0048] When the dotted line in the benzene ring is a bond, R 3 、R 4 are independently selected from none;

[0049] When there is no dotted line in the benzene ring, R 3 、R 4 are independently selected from hydrogen, C1-C6 alkyl, or R 3 、R 4 Connected to form a 3- to 6-membered cycloalkyl group;

[0050] 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 substituent of the aryl or heteroaryl is selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, C1-C6 alkoxy;

[0051] X is selected from CR 7 R 8 、O、S、SO、SO2、NR7 ;

[0052] R 7 、R 8 are independently selected from hydrogen, halogen, C1-C6 alkyl, 3-6 membered cycloalkyl;

[0053] n is 0, 1, or 2;

[0054] R 6 is a substituent at any position on the benzene ring, and b is a substituent R 6 The number of

[0055] Each R 6 Each of the following groups is independently selected from halogen, hydroxy, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, and C1-C6 alkoxy;

[0056] b is 0, 1, 2, or 3;

[0057] Ring A and Ring B are independently selected from 4- to 12-membered cycloalkyl and 4- to 12-membered heterocycloalkyl;

[0058] M is selected from None, CR 9 R 10 、O、S、SO、SO2、NR 9 ;

[0059] R 9 、R 10 are independently selected from hydrogen, C1-C6 alkyl;

[0060] E 3 is a substituent at any position on the benzene ring, and c is a substituent E 3 The number of

[0061] Each E 3 are independently selected from halogen, hydroxy, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, C1-C6 alkoxy; or any two E 3 Connect to form 3-6 membered cycloalkyl, 6-10 membered aryl, 4-12 membered heterocycloalkyl, 5-8 membered heteroaryl;

[0062] c is 0, 1, 2, or 3;

[0063] Y is none, CR Y1 R Y2 、C(O)、-CR 11 =CR 12 -、-CR 11 =N-, -N=N-, -OC(O)-;

[0064] R Y1 、R Y2are independently selected from hydrogen, C1-C6 alkyl;

[0065] R 11 、R 12 are independently selected from hydrogen, C1-C6 alkyl;

[0066] The heteroatom of the heteroaryl group is O, N or S; the number of heteroatoms is 1, 2 or 3;

[0067] The heteroatom of the heterocycloalkyl group is N; the number of the heteroatoms is 1, 2 or 3.

[0068] Furthermore, the compound is represented by formula (III):

[0069] in,

[0070] R 2 is a substituent at any position on the benzene ring, a is a substituent R 2 The number of

[0071] Each R 2 Each of the following groups is independently selected from halogen, hydroxy, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, and C1-C6 alkoxy;

[0072] a is 0, 1, 2, or 3;

[0073] When the dotted line in the benzene ring is a bond, R 3 、R 4 Each independently selected from none;

[0074] When there is no dotted line in the benzene ring, R 3 、R 4 are independently selected from hydrogen, C1-C6 alkyl, or R 3 、R 4 Connected to form a 3- to 6-membered cycloalkyl group;

[0075] 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 substituent of the aryl or heteroaryl is selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, C1-C6 alkoxy;

[0076] X is selected from CR 7 R 8 、O、S、SO、SO2、NR 7 ;

[0077] R 7 、R 8are independently selected from hydrogen, halogen, C1-C6 alkyl, 3-6 membered cycloalkyl;

[0078] n is 0, 1, or 2;

[0079] R 6 is a substituent at any position on the benzene ring, and b is a substituent R 6 The number of

[0080] Each R 6 Each of the following groups is independently selected from halogen, hydroxy, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, and C1-C6 alkoxy;

[0081] b is 0, 1, 2, or 3;

[0082] Ring A and Ring B are independently selected from 4- to 12-membered cycloalkyl and 4- to 12-membered heterocycloalkyl;

[0083] M is selected from None, CR 9 R 10 、O、S、SO、SO2、NR 9 ;

[0084] R 9 、R 10 are independently selected from hydrogen, C1-C6 alkyl;

[0085] E 3 is a substituent at any position on the benzene ring, and c is a substituent E 3 The number of

[0086] Each E 3 are independently selected from halogen, hydroxy, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, C1-C6 alkoxy; or any two E 3 Connected to form 3-6 membered cycloalkyl, 6-10 membered aryl, 4-12 membered heterocycloalkyl, 5-8 membered heteroaryl;

[0087] c is 0, 1, 2, or 3;

[0088] Y is none, CR Y1 R Y2 、C(O)、-CR 11 =CR 12 -、-CR 11 =N-, -N=N-, -OC(O)-;

[0089] R Y1 、R Y2 are independently selected from hydrogen, C1-C6 alkyl;

[0090] R 11 、R 12are independently selected from hydrogen, C1-C6 alkyl;

[0091] The heteroatom of the heteroaryl group is O, N or S; the number of heteroatoms is 1, 2 or 3;

[0092] The heteroatom of the heterocycloalkyl group is N; the number of heteroatoms is 1, 2 or 3;

[0093] Preferably,

[0094] R 5 is selected from C1-C6 alkyl, 3-6 membered cycloalkyl, trifluoromethyl, trifluoroethyl, substituted or unsubstituted phenyl, substituted or unsubstituted thienyl, substituted or unsubstituted furyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted pyrimidinyl, substituted or unsubstituted pyridazinyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted pyrazinyl; the substituent of the phenyl, thienyl, furyl, pyrrolyl, pyrimidinyl, pyridazinyl, pyrazolyl or pyrazinyl is selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, C1-C6 alkoxy;

[0095] X is selected from CH2, CF2, O, S, SO, SO2, NR 7 ;

[0096] R 7 Selected from hydrogen, halogen, C1-C6 alkyl, 3-6 membered cycloalkyl;

[0097] Ring A and ring B are independently selected from 4-12 membered cycloalkyl and 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.

[0098] Furthermore, the compound is represented by formula (IV):

[0099] in,

[0100] R 2 is a substituent at any position on the benzene ring, a is a substituent R 2 The number of

[0101] Each R 2 Each of the following groups is independently selected from halogen, hydroxy, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, and C1-C6 alkoxy;

[0102] a is 0, 1, 2, or 3;

[0103] R 3 、R 4 are independently selected from hydrogen, C1-C6 alkyl; or R 3 、R4 Connected to form a 3- to 6-membered cycloalkyl group;

[0104] 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 substituent of the aryl or heteroaryl is selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, C1-C6 alkoxy;

[0105] X is selected from CR 7 R 8 、O、S、SO、SO2、NR 7 ;

[0106] R 7 、R 8 are independently selected from hydrogen, halogen, C1-C6 alkyl, 3-6 membered cycloalkyl;

[0107] n is 0, 1, or 2;

[0108] R 6 is a substituent at any position on the benzene ring, and b is a substituent R 6 The number of

[0109] Each R 6 Each of the following groups is independently selected from halogen, hydroxy, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, and C1-C6 alkoxy;

[0110] b is 0, 1, 2, or 3;

[0111] Ring A and Ring B are independently selected from 4- to 12-membered cycloalkyl and 4- to 12-membered heterocycloalkyl;

[0112] M is selected from None, CR 9 R 10 、O、S、SO、SO2、NR 9 ;

[0113] R 9 、R 10 are independently selected from hydrogen, C1-C6 alkyl;

[0114] E 3 is a substituent at any position on the benzene ring, and c is a substituent E 3 The number of

[0115] Each E 3 are independently selected from halogen, hydroxy, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, C1-C6 alkoxy; or any two E 3Connect to form 3-6 membered cycloalkyl, 6-10 membered aryl, 4-12 membered heterocycloalkyl, 5-8 membered heteroaryl;

[0116] c is 0, 1, 2, or 3;

[0117] Y is none, CR Y1 R Y2 、C(O)、-CR 11 =CR 12 -、-CR 11 =N-, -N=N-, -OC(O)-;

[0118] R Y1 、R Y2 are independently selected from hydrogen, C1-C6 alkyl;

[0119] R 11 、R 12 are independently selected from hydrogen, C1-C6 alkyl;

[0120] The heteroatom of the heteroaryl group is O, N or S; the number of heteroatoms is 1, 2 or 3;

[0121] The heteroatom of the heterocycloalkyl group is N; the number of heteroatoms is 1, 2 or 3;

[0122] Preferably,

[0123] R 5 is selected from C1-C6 alkyl, 3-6 membered cycloalkyl, trifluoromethyl, trifluoroethyl, substituted or unsubstituted phenyl, substituted or unsubstituted thienyl, substituted or unsubstituted furyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted pyrimidinyl, substituted or unsubstituted pyridazinyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted pyrazinyl; the substituent of the phenyl, thienyl, furyl, pyrrolyl, pyrimidinyl, pyridazinyl, pyrazolyl or pyrazinyl is selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, C1-C6 alkoxy;

[0124] X is selected from CH2, CF2, O, S, SO, SO2, NR 7 ;

[0125] R 7 Selected from hydrogen, halogen, C1-C6 alkyl, 3-6 membered cycloalkyl;

[0126] Ring A and ring B are independently selected from 4-12 membered cycloalkyl and 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.

[0127] Furthermore, the compound is represented by formula (V):

[0128] in,

[0129] R 2 is a substituent at any position on the benzene ring, a is a substituent R 2 The number of

[0130] Each R 2 Each of the following groups is independently selected from halogen, hydroxy, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, and C1-C6 alkoxy;

[0131] a is 0, 1, 2, or 3;

[0132] R 3 、R 4 are independently selected from hydrogen, C1-C6 alkyl, or R 3 、R 4 Connected to form a 3- to 6-membered cycloalkyl group;

[0133] 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 substituent of the aryl or heteroaryl is selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, C1-C6 alkoxy;

[0134] X is selected from CR 7 R 8 、O、S、SO、SO2、NR 7 ;

[0135] R 7 、R 8 are independently selected from hydrogen, halogen, C1-C6 alkyl, 3-6 membered cycloalkyl;

[0136] n is 0, 1, or 2;

[0137] R 6 is a substituent at any position on the benzene ring, and b is a substituent R 6 The number of

[0138] Each R 6 Each of the following groups is independently selected from halogen, hydroxy, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, and C1-C6 alkoxy;

[0139] b is 0, 1, 2, or 3;

[0140] Ring A and Ring B are independently selected from 4- to 12-membered cycloalkyl and 4- to 12-membered heterocycloalkyl;

[0141] M is selected from None, CR 9 R 10 、O、S、SO、SO2、NR 9 ;

[0142] R 9 、R 10 are independently selected from hydrogen, C1-C6 alkyl;

[0143] E 3 is a substituent at any position on the benzene ring, and c is a substituent E 3 The number of

[0144] Each E 3 are independently selected from halogen, hydroxy, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, C1-C6 alkoxy; or any two E 3 Connect to form 3-6 membered cycloalkyl, 6-10 membered aryl, 4-12 membered heterocycloalkyl, 5-8 membered heteroaryl;

[0145] c is 0, 1, 2, or 3;

[0146] Y is none, CR Y1 R Y2 、C(O)、-CR 11 =CR 12 -、-CR 11 =N-, -N=N-, -OC(O)-;

[0147] R Y1 、R Y2 are independently selected from hydrogen, C1-C6 alkyl;

[0148] R 11 、R 12 are independently selected from hydrogen, C1-C6 alkyl;

[0149] The heteroatom of the heteroaryl group is O, N or S; the number of heteroatoms is 1, 2 or 3;

[0150] The heteroatom of the heterocycloalkyl group is N; the number of heteroatoms is 1, 2 or 3;

[0151] Preferably,

[0152] R 5is selected from C1-C6 alkyl, 3-6 membered cycloalkyl, trifluoromethyl, trifluoroethyl, substituted or unsubstituted phenyl, substituted or unsubstituted thienyl, substituted or unsubstituted furyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted pyrimidinyl, substituted or unsubstituted pyridazinyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted pyrazinyl; the substituent of the phenyl, thienyl, furyl, pyrrolyl, pyrimidinyl, pyridazinyl, pyrazolyl or pyrazinyl is selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, C1-C6 alkoxy;

[0153] X is selected from CH2, CF2, O, S, SO, SO2, NR 7 ;

[0154] R 7 Selected from hydrogen, halogen, C1-C6 alkyl, 3-6 membered cycloalkyl;

[0155] Ring A and ring B are independently selected from 4-12 membered cycloalkyl and 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.

[0156] Furthermore, the compound is represented by formula (VI):

[0157] in,

[0158] R 2 is a substituent at any position on the benzene ring, a is a substituent R 2 The number of

[0159] Each R 2 Each of the following groups is independently selected from halogen, hydroxy, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, and C1-C6 alkoxy;

[0160] a is 0, 1, 2, or 3;

[0161] R 3 、R 4 are independently selected from hydrogen, C1-C6 alkyl, or R 3 、R 4 Connected to form a 3- to 6-membered cycloalkyl group;

[0162] 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 substituent of the aryl or heteroaryl is selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, C1-C6 alkoxy;

[0163] X is selected from CR 7 R 8 、O、S、SO、SO2、NR 7 ;

[0164] R 7 、R 8 are independently selected from hydrogen, halogen, C1-C6 alkyl, 3-6 membered cycloalkyl;

[0165] R 6 is a substituent at any position on the benzene ring, and b is a substituent R 6 The number of

[0166] Each R 6 Each of the following groups is independently selected from halogen, hydroxy, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, and C1-C6 alkoxy;

[0167] b is 0, 1, 2, or 3;

[0168] Ring A and Ring B are independently selected from 4- to 12-membered cycloalkyl and 4- to 12-membered heterocycloalkyl;

[0169] M is selected from None, CR 9 R 10 、O、S、SO、SO2、NR 9 ;

[0170] R 9 、R 10 are independently selected from hydrogen, C1-C6 alkyl;

[0171] E 3 is a substituent at any position on the benzene ring, and c is a substituent E 3 The number of

[0172] Each E 3 are independently selected from halogen, hydroxy, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, C1-C6 alkoxy; or any two E 3 Connected to form 3-6 membered cycloalkyl, 6-10 membered aryl, 4-12 membered heterocycloalkyl, 5-8 membered heteroaryl;

[0173] c is 0, 1, 2, or 3;

[0174] Y is none, CR Y1 R Y2 、C(O)、-CR 11 =CR 12 -、-CR 11 =N-, -N=N-, -OC(O)-;

[0175] R Y1、R Y2 are independently selected from hydrogen, C1-C6 alkyl;

[0176] R 11 、R 12 are independently selected from hydrogen, C1-C6 alkyl;

[0177] The heteroatom of the heteroaryl group is O, N or S; the number of heteroatoms is 1, 2 or 3;

[0178] The heteroatom of the heterocycloalkyl group is N; the number of heteroatoms is 1, 2 or 3;

[0179] Preferably,

[0180] R 5 is selected from C1-C6 alkyl, 3-6 membered cycloalkyl, trifluoromethyl, trifluoroethyl, substituted or unsubstituted phenyl, substituted or unsubstituted thienyl, substituted or unsubstituted furyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted pyrimidinyl, substituted or unsubstituted pyridazinyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted pyrazinyl; the substituent of the phenyl, thienyl, furyl, pyrrolyl, pyrimidinyl, pyridazinyl, pyrazolyl or pyrazinyl is selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, C1-C6 alkoxy;

[0181] X is selected from CH2, CF2, O, S, SO, SO2, NR 7 ;

[0182] R 7 Selected from hydrogen, halogen, C1-C6 alkyl, 3-6 membered cycloalkyl;

[0183] Ring A and ring B are independently selected from 4-12 membered cycloalkyl and 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.

[0184] Furthermore, the compound is represented by formula (VII):

[0185] in,

[0186] R 3 、R 4 are independently selected from hydrogen, C1-C6 alkyl, or R 3 、R 4 Connected to form a 3- to 6-membered cycloalkyl group;

[0187] R 5is 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 is selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, C1-C6 alkoxy;

[0188] X is selected from CR 7 R 8 、O、S、SO、SO2、NR 7 ;

[0189] R 7 、R 8 are independently selected from hydrogen, halogen, C1-C6 alkyl, 3-6 membered cycloalkyl;

[0190] R 6 is a substituent at any position on the benzene ring, and b is a substituent R 6 The number of

[0191] Each R 6 Each of the following groups is independently selected from halogen, hydroxy, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, and C1-C6 alkoxy;

[0192] b is 0, 1, 2, or 3;

[0193] Ring A and Ring B are independently selected from 4- to 12-membered cycloalkyl and 4- to 12-membered heterocycloalkyl;

[0194] M is selected from None, CR 9 R 10 、O、S、SO、SO2、NR 9 ;

[0195] R 9 、R 10 are independently selected from hydrogen, C1-C6 alkyl;

[0196] Y is none, CR Y1 R Y2 、C(O)、-CR 11 =CR 12 -、-CR 11 =N-, -N=N-, -OC(O)-;

[0197] R Y1 、R Y2 are independently selected from hydrogen, C1-C6 alkyl;

[0198] R 11 、R 12 are independently selected from hydrogen, C1-C6 alkyl;

[0199] The heteroatom of the heteroaryl group is O, N or S; the number of heteroatoms is 1, 2 or 3;

[0200] The heteroatom of the heterocycloalkyl group is N; the number of heteroatoms is 1, 2 or 3;

[0201] Preferably,

[0202] R 5 is selected from C1-C6 alkyl, 3-6 membered cycloalkyl, trifluoromethyl, trifluoroethyl, substituted or unsubstituted phenyl, substituted or unsubstituted thienyl, substituted or unsubstituted furyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted pyrimidinyl, substituted or unsubstituted pyridazinyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted pyrazinyl; the substituent of the phenyl, thienyl, furyl, pyrrolyl, pyrimidinyl, pyridazinyl, pyrazolyl or pyrazinyl is selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, C1-C6 alkoxy;

[0203] X is selected from CH2, CF2, O, S, SO, SO2, NR 7 ;

[0204] R 7 Selected from hydrogen, halogen, C1-C6 alkyl, 3-6 membered cycloalkyl;

[0205] Ring A and ring B are independently selected from 4-12 membered cycloalkyl and 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.

[0206] Furthermore, the compound is represented by formula (VIII):

[0207] in,

[0208] R 3 、R 4 are independently selected from hydrogen, C1-C6 alkyl; or R 3 、R 4 Connected to form a 3- to 6-membered cycloalkyl group;

[0209] 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 substituent of the aryl or heteroaryl is selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, C1-C6 alkoxy;

[0210] X is selected from CR 7 R 8、O、S、SO、SO2、NR 7 ;

[0211] R 7 、R 8 are independently selected from hydrogen, halogen, C1-C6 alkyl, 3-6 membered cycloalkyl;

[0212] Ring A and Ring B are independently selected from 4- to 12-membered cycloalkyl and 4- to 12-membered heterocycloalkyl;

[0213] M is selected from None, CR 9 R 10 、O、S、SO、SO2、NR 9 ;

[0214] R 9 、R 10 are independently selected from hydrogen, C1-C6 alkyl;

[0215] Y is none, CR Y1 R Y2 、C(O)、-CR 11 =CR 12 -、-CR 11 =N-, -N=N-, -OC(O)-;

[0216] R Y1 、R Y2 are independently selected from hydrogen, C1-C6 alkyl;

[0217] R 11 、R 12 are independently selected from hydrogen, C1-C6 alkyl;

[0218] The heteroatom of the heteroaryl group is O, N or S; the number of heteroatoms is 1, 2 or 3;

[0219] The heteroatom of the heterocycloalkyl group is N; the number of heteroatoms is 1, 2 or 3;

[0220] Preferably,

[0221] R 5 is selected from C1-C6 alkyl, 3-6 membered cycloalkyl, trifluoromethyl, substituted or unsubstituted phenyl, substituted or unsubstituted thienyl, substituted or unsubstituted furyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted pyrimidinyl, substituted or unsubstituted pyridazinyl, substituted or unsubstituted pyrazolyl, and substituted or unsubstituted pyrazinyl; the substituent of the phenyl, thienyl, furyl, pyrrolyl, pyrimidinyl, pyridazinyl, pyrazolyl, or pyrazinyl group is selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, and C1-C6 alkoxy;

[0222] X is selected from CH2, CF2, O, S, SO, SO2, NR 7 ;

[0223] R 7 Selected from hydrogen, halogen, C1-C6 alkyl, 3-6 membered cycloalkyl;

[0224] Ring A and ring B are independently selected from 4-12 membered cycloalkyl and 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.

[0225] Furthermore, the compound is represented by formula (IX):

[0226] in,

[0227] R 3 、R 4 are independently selected from hydrogen, C1-C6 alkyl, or R 3 、R 4 Connected to form a 3- to 6-membered cycloalkyl group;

[0228] 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 substituent of the aryl or heteroaryl is selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, C1-C6 alkoxy;

[0229] X is selected from CR 7 R 8 、O、S、SO、SO2、NR 7 ;

[0230] R 7 、R 8 are independently selected from hydrogen, halogen, C1-C6 alkyl, 3-6 membered cycloalkyl;

[0231] R 6 is a substituent at any position on the benzene ring, and b is a substituent R 6 The number of

[0232] Each R 6 Each of the following groups is independently selected from halogen, hydroxy, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, and C1-C6 alkoxy;

[0233] b is 0, 1, 2, or 3;

[0234] Ring A and Ring B are independently selected from 4- to 12-membered cycloalkyl and 4- to 12-membered heterocycloalkyl;

[0235] Y is none, CR Y1 R Y2 、C(O)、-CR 11 =CR 12 -、-CR 11 =N-, -N=N-, -OC(O)-;

[0236] R Y1 、R Y2 are independently selected from hydrogen, C1-C6 alkyl;

[0237] R 11 、R 12 are independently selected from hydrogen, C1-C6 alkyl;

[0238] The heteroatom of the heteroaryl group is O, N or S; the number of heteroatoms is 1, 2 or 3;

[0239] The heteroatom of the heterocycloalkyl group is N; the number of heteroatoms is 1, 2 or 3;

[0240] Preferably,

[0241] R 5 is selected from C1-C6 alkyl, 3-6 membered cycloalkyl, trifluoromethyl, trifluoroethyl, substituted or unsubstituted phenyl, substituted or unsubstituted thienyl, substituted or unsubstituted furyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted pyrimidinyl, substituted or unsubstituted pyridazinyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted pyrazinyl; the substituent of the phenyl, thienyl, furyl, pyrrolyl, pyrimidinyl, pyridazinyl, pyrazolyl or pyrazinyl is selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, C1-C6 alkoxy;

[0242] X is selected from CH2, CF2, O, S, SO, SO2, NR 7 ;

[0243] R 7 Selected from hydrogen, halogen, C1-C6 alkyl, 3-6 membered cycloalkyl;

[0244] Ring A and ring B are independently selected from 4-12 membered cycloalkyl and 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.

[0245] Furthermore, the compound is represented by formula (X):

[0246] in,

[0247] R 3 、R 4are independently selected from hydrogen, C1-C6 alkyl; or R 3 、R 4 Connected to form a 3- to 6-membered cycloalkyl group;

[0248] 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 substituent of the aryl or heteroaryl is selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, C1-C6 alkoxy;

[0249] X is selected from CR 7 R 8 、O、S、SO、SO2、NR 7 ;

[0250] R 7 、R 8 are independently selected from hydrogen, halogen, C1-C6 alkyl, 3-6 membered cycloalkyl;

[0251] Ring A and Ring B are independently selected from 4- to 12-membered cycloalkyl and 4- to 12-membered heterocycloalkyl;

[0252] Y is none, CR Y1 R Y2 、C(O)、-CR 11 =CR 12 -、-CR 11 =N-, -N=N-, -OC(O)-;

[0253] R Y1 、R Y2 are independently selected from hydrogen, C1-C6 alkyl;

[0254] R 11 、R 12 are independently selected from hydrogen, C1-C6 alkyl;

[0255] The heteroatom of the heteroaryl group is O, N or S; the number of heteroatoms is 1, 2 or 3;

[0256] The heteroatom of the heterocycloalkyl group is N; the number of heteroatoms is 1, 2 or 3;

[0257] Preferably,

[0258] R 5is selected from C1-C6 alkyl, 3-6 membered cycloalkyl, trifluoromethyl, trifluoroethyl, substituted or unsubstituted phenyl, substituted or unsubstituted thienyl, substituted or unsubstituted furyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted pyrimidinyl, substituted or unsubstituted pyridazinyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted pyrazinyl; the substituent of the phenyl, thienyl, furyl, pyrrolyl, pyrimidinyl, pyridazinyl, pyrazolyl or pyrazinyl is selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, C1-C6 alkoxy;

[0259] X is selected from CH2, CF2, O, S, SO, SO2, NR 7 ;

[0260] R 7 Selected from hydrogen, halogen, C1-C6 alkyl, 3-6 membered cycloalkyl;

[0261] Ring A and ring B are independently selected from 4-12 membered cycloalkyl and 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.

[0262] Furthermore, the compound is represented by formula (XI):

[0263] in,

[0264] R 2 is a substituent at any position on the benzene ring, a is a substituent R 2 The number of

[0265] Each R 2 Each of the following groups is independently selected from halogen, hydroxy, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, and C1-C6 alkoxy;

[0266] a is 0, 1, 2, or 3;

[0267] R 3 、R 4 are independently selected from hydrogen, C1-C6 alkyl; or R 3 、R 4 Connected to form a 3- to 6-membered cycloalkyl group;

[0268] R 11 is a substituent at any position on the benzene ring, and d is a substituent R 11 The number of

[0269] Each R 11 Each of the following groups is independently selected from halogen, hydroxy, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, and C1-C6 alkoxy;

[0270] d is 0, 1, 2, or 3;

[0271] X is selected from CR 7 R 8 、O、S、SO、SO2、NR 7 ;

[0272] R 7 、R 8 are independently selected from hydrogen, halogen, C1-C6 alkyl, 3-6 membered cycloalkyl;

[0273] R 6 is a substituent at any position on the benzene ring, and b is a substituent R 6 The number of

[0274] Each R 6 Each of the following groups is independently selected from halogen, hydroxy, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, and C1-C6 alkoxy;

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

[0276] Ring A and Ring B are independently selected from 4- to 12-membered cycloalkyl and 4- to 12-membered heterocycloalkyl;

[0277] M is selected from None, CR 9 R 10 、O、S、SO、SO2、NR 9 ;

[0278] R 9 、R 10 are independently selected from hydrogen, C1-C6 alkyl;

[0279] E 3 is a substituent at any position on the benzene ring, and c is a substituent E 3 The number of

[0280] Each E 3 are independently selected from halogen, hydroxy, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, C1-C6 alkoxy; or any two E 3 Connect to form 3-6 membered cycloalkyl, 6-10 membered aryl, 4-12 membered heterocycloalkyl, 5-8 membered heteroaryl;

[0281] c is 0, 1, 2, or 3;

[0282] Y is none, CR Y1 R Y2 、C(O)、-CR 11 =CR 12 -、-CR 11=N-, -N=N-, -OC(O)-;

[0283] R Y1 、R Y2 are independently selected from hydrogen, C1-C6 alkyl;

[0284] R 11 、R 12 are independently selected from hydrogen, C1-C6 alkyl;

[0285] The heteroatom of the heteroaryl group is O, N or S; the number of heteroatoms is 1, 2 or 3;

[0286] The heteroatom of the heterocycloalkyl group is N; the number of heteroatoms is 1, 2 or 3;

[0287] Preferably,

[0288] X is selected from CH2, CF2, O, S, SO, SO2, NR 7 ;

[0289] R 7 Selected from hydrogen, halogen, C1-C6 alkyl, 3-6 membered cycloalkyl;

[0290] Ring A and ring B are independently selected from 4-12 membered cycloalkyl and 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.

[0291] Furthermore, the compound is represented by formula (XII):

[0292] in,

[0293] R 2 is a substituent at any position on the benzene ring, a is a substituent R 2 The number of

[0294] Each R 2 Each of the following groups is independently selected from halogen, hydroxy, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, and C1-C6 alkoxy;

[0295] a is 0, 1, 2, or 3;

[0296] R 3 、R 4 are independently selected from hydrogen, C1-C6 alkyl, or R 3 、R 4 Connected to form a 3- to 6-membered cycloalkyl group;

[0297] R 11 is a substituent at any position on the benzene ring, and d is a substituent R 11The number of

[0298] Each R 11 Each of the following groups is independently selected from halogen, hydroxy, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, and C1-C6 alkoxy;

[0299] d is 0, 1, 2, or 3;

[0300] X is selected from CR 7 R 8 、O、S、SO、SO2、NR 7 ;

[0301] R 7 、R 8 are independently selected from hydrogen, halogen, C1-C6 alkyl, 3-6 membered cycloalkyl;

[0302] R 6 is a substituent at any position on the benzene ring, and b is a substituent R 6 The number of

[0303] Each R 6 Each of the following groups is independently selected from halogen, hydroxy, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, and C1-C6 alkoxy;

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

[0305] M is selected from None, CR 9 R 10 、O、S、SO、SO2、NR 9 ;

[0306] R 9 、R 10 are independently selected from hydrogen, C1-C6 alkyl;

[0307] R 12 is selected from hydrogen, halogen, C1-C6 alkyl, and hydroxyl;

[0308] m1, m2, m3, m4, m5, and m6 are independently selected from 0, 1, 2, or 3;

[0309] E 3 is a substituent at any position on the benzene ring, and c is a substituent E 3 The number of

[0310] Each E 3 are independently selected from halogen, hydroxy, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, C1-C6 alkoxy; or any two E 3 Connected to form 3-6 membered cycloalkyl, 6-10 membered aryl, 4-12 membered heterocycloalkyl, 5-8 membered heteroaryl;

[0311] c is 0, 1, 2, or 3;

[0312] Y is none, CR Y1 R Y2 、C(O)、-CR 11 =CR 12 -、-CR 11 =N-, -N=N-, -OC(O)-;

[0313] R Y1 、R Y2 are independently selected from hydrogen, C1-C6 alkyl;

[0314] R 11 、R 12 are independently selected from hydrogen, C1-C6 alkyl;

[0315] The heteroatom of the heteroaryl group is O, N or S; the number of heteroatoms is 1, 2 or 3;

[0316] The heteroatom of the heterocycloalkyl group is N; the number of heteroatoms is 1, 2 or 3;

[0317] Preferably,

[0318] X is selected from CH2, CF2, O, S, SO, SO2, NR 7 ;

[0319] R 7 Selected from hydrogen, halogen, C1-C6 alkyl, 3-6 membered cycloalkyl;

[0320] Y is none, CR Y1 R Y2 、C(O)、-CR 11 =CR 12 -、-CR 11 =N-, -N=N-, -OC(O)-;

[0321] R Y1 、R Y2 are independently selected from hydrogen, C1-C6 alkyl;

[0322] R 11 、R 12 Each is independently selected from hydrogen and C1-C6 alkyl.

[0323] Furthermore, the compound is represented by formula (XIII):

[0324] in,

[0325] R 2 is a substituent at any position on the benzene ring, a is a substituent R2 The number of

[0326] Each R 2 Each of the following groups is independently selected from halogen, hydroxy, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, and C1-C6 alkoxy;

[0327] a is 0, 1, 2, or 3;

[0328] R 3 、R 4 are independently selected from hydrogen, C1-C6 alkyl, or R 3 、R 4 Connected to form a 3- to 6-membered cycloalkyl group;

[0329] R 11 is a substituent at any position on the benzene ring, and d is a substituent R 11 The number of

[0330] Each R 11 Each of the following groups is independently selected from halogen, hydroxy, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, and C1-C6 alkoxy;

[0331] d is 0, 1, 2, or 3;

[0332] X is selected from CR 7 R 8 、O、S、SO、SO2、NR 7 ;

[0333] R 7 、R 8 are independently selected from hydrogen, halogen, C1-C6 alkyl, 3-6 membered cycloalkyl;

[0334] R 6 is a substituent at any position on the benzene ring, and b is a substituent R 6 The number of

[0335] Each R 6 Each of the following groups is independently selected from halogen, hydroxy, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, and C1-C6 alkoxy;

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

[0337] R 12 is selected from hydrogen, halogen, C1-C6 alkyl, and hydroxyl;

[0338] m1, m2, m3, m4, m5, and m6 are independently selected from 0, 1, 2, or 3;

[0339] E 3 is a substituent at any position on the benzene ring, and c is a substituent E3 The number of

[0340] Each E 3 are independently selected from halogen, hydroxy, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, C1-C6 alkoxy; or any two E 3 Connected to form 3-6 membered cycloalkyl, 6-10 membered aryl, 4-12 membered heterocycloalkyl, 5-8 membered heteroaryl;

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

[0342] Y is none, CR Y1 R Y2 、C(O)、-CR 11 =CR 12 -、-CR 11 =N-, -N=N-, -OC(O)-;

[0343] R Y1 、R Y2 are independently selected from hydrogen, C1-C6 alkyl;

[0344] R 11 、R 12 are independently selected from hydrogen, C1-C6 alkyl;

[0345] The heteroatom of the heteroaryl group is O, N or S; the number of heteroatoms is 1, 2 or 3;

[0346] The heteroatom of the heterocycloalkyl group is N; the number of heteroatoms is 1, 2 or 3;

[0347] Preferably,

[0348] X is selected from CH2, CF2, O, S, SO, SO2, NR 7 ;

[0349] R 7 Selected from hydrogen, halogen, C1-C6 alkyl, 3-6 membered cycloalkyl;

[0350] Y is none, CR Y1 R Y2 、C(O)、-CR 11 =CR 12 -、-CR 11 =N-, -N=N-, -OC(O)-;

[0351] R Y1 、R Y2 are independently selected from hydrogen, C1-C6 alkyl;

[0352] R 11 、R 12Each is independently selected from hydrogen and C1-C6 alkyl.

[0353] Furthermore, the compound is represented by formula (XIV):

[0354] in,

[0355] R 2 is a substituent at any position on the benzene ring, a is a substituent R 2 The number of

[0356] Each R 2 Each of the following groups is independently selected from halogen, hydroxy, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, and C1-C6 alkoxy;

[0357] a is 0, 1, 2, or 3;

[0358] R 3 、R 4 are independently selected from hydrogen, C1-C6 alkyl, or R 3 、R 4 Connected to form a 3- to 6-membered cycloalkyl group;

[0359] R 11 is a substituent at any position on the benzene ring, and d is a substituent R 11 The number of

[0360] Each R 11 Each of the following groups is independently selected from halogen, hydroxy, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, and C1-C6 alkoxy;

[0361] d is 0, 1, 2, or 3;

[0362] X is selected from CR 7 R 8 、O、S、SO、SO2、NR 7 ;

[0363] R 7 、R 8 are independently selected from hydrogen, halogen, C1-C6 alkyl, 3-6 membered cycloalkyl;

[0364] R 6 is a substituent at any position on the benzene ring, and b is a substituent R 6 The number of

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

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

[0367] R 12 is selected from hydrogen, halogen, C1-C6 alkyl, and hydroxyl;

[0368] m1, m2, m3, m4, m5, and m6 are independently selected from 0, 1, 2, or 3;

[0369] E 3 is a substituent at any position on the benzene ring, and c is a substituent E 3 The number of

[0370] Each E 3 are independently selected from halogen, hydroxy, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, C1-C6 alkoxy; or any two E 3 Connected to form 3-6 membered cycloalkyl, 6-10 membered aryl, 4-12 membered heterocycloalkyl, 5-8 membered heteroaryl;

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

[0372] Y is none, CR Y1 R Y2 、C(O)、-CR 11 =CR 12 -、-CR 11 =N-, -N=N-, -OC(O)-;

[0373] R Y1 、R Y2 are independently selected from hydrogen, C1-C6 alkyl;

[0374] R 11 、R 12 are independently selected from hydrogen, C1-C6 alkyl;

[0375] The heteroatom of the heteroaryl group is O, N or S; the number of heteroatoms is 1, 2 or 3;

[0376] The heteroatom of the heterocycloalkyl group is N; the number of heteroatoms is 1, 2 or 3;

[0377] Preferably,

[0378] X is selected from CH2, CF2, O, S, SO, SO2, NR 7 ;

[0379] R 7 Selected from hydrogen, halogen, C1-C6 alkyl, 3-6 membered cycloalkyl;

[0380] Y is none, CR Y1 R Y2 、C(O)、-CR 11 =CR12 -、-CR 11 =N-, -N=N-, -OC(O)-;

[0381] R Y1 、R Y2 are independently selected from hydrogen, C1-C6 alkyl;

[0382] R 11 、R 12 Each is independently selected from hydrogen and C1-C6 alkyl.

[0383] Furthermore, the compound is represented by formula (XV):

[0384] in,

[0385] R 2 is a substituent at any position on the benzene ring, a is a substituent R 2 The number of

[0386] Each R 2 Each of the following groups is independently selected from halogen, hydroxy, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, and C1-C6 alkoxy;

[0387] a is 0, 1, 2, or 3;

[0388] R 3 、R 4 are independently selected from hydrogen, C1-C6 alkyl, or R 3 、R 4 Connected to form a 3- to 6-membered cycloalkyl group;

[0389] R 11 is a substituent at any position on the thiophene ring, and d is a substituent R 11 The number of

[0390] Each R 11 Each of the following groups is independently selected from halogen, hydroxy, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, and C1-C6 alkoxy;

[0391] d is 0, 1, 2, or 3;

[0392] X is selected from CR 7 R 8 、O、S、SO、SO2、NR 7 ;

[0393] R 7 、R 8 are independently selected from hydrogen, halogen, C1-C6 alkyl, 3-6 membered cycloalkyl;

[0394] R6 is a substituent at any position on the benzene ring, and b is a substituent R 6 The number of

[0395] Each R 6 Each of the following groups is independently selected from halogen, hydroxy, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, and C1-C6 alkoxy;

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

[0397] Ring A and Ring B are independently selected from 4- to 12-membered cycloalkyl and 4- to 12-membered heterocycloalkyl;

[0398] M is selected from None, CR 9 R 10 、O、S、SO、SO2、NR 9 ;

[0399] R 9 、R 10 are independently selected from hydrogen, C1-C6 alkyl;

[0400] E 3 is a substituent at any position on the benzene ring, and c is a substituent E 3 The number of

[0401] Each E 3 are independently selected from halogen, hydroxy, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, C1-C6 alkoxy; or any two E 3 Connected to form 3-6 membered cycloalkyl, 6-10 membered aryl, 4-12 membered heterocycloalkyl, 5-8 membered heteroaryl;

[0402] c is 0, 1, 2, or 3;

[0403] Y is none, CR Y1 R Y2 、C(O)、-CR 11 =CR 12 -、-CR 11 =N-, -N=N-, -OC(O)-;

[0404] R Y1 、R Y2 are independently selected from hydrogen, C1-C6 alkyl;

[0405] R 11 、R 12 are independently selected from hydrogen, C1-C6 alkyl;

[0406] The heteroatom of the heteroaryl group is O, N or S; the number of heteroatoms is 1, 2 or 3;

[0407] The heteroatom of the heterocycloalkyl group is N; the number of heteroatoms is 1, 2 or 3;

[0408] Preferably,

[0409] X is selected from CH2, CF2, O, S, SO, SO2, NR 7 ;

[0410] R 7 Selected from hydrogen, halogen, C1-C6 alkyl, 3-6 membered cycloalkyl;

[0411] Ring A and ring B are independently selected from 4-12 membered cycloalkyl and 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.

[0412] Furthermore, the compound is represented by formula (XVI):

[0413] in,

[0414] R 2 is a substituent at any position on the benzene ring, a is a substituent R 2 The number of

[0415] Each R 2 Each of the following groups is independently selected from halogen, hydroxy, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, and C1-C6 alkoxy;

[0416] a is 0, 1, 2, or 3;

[0417] R 3 、R 4 are independently selected from hydrogen, C1-C6 alkyl, or R 3 、R 4 Connected to form a 3- to 6-membered cycloalkyl group;

[0418] R 11 is a substituent at any position on the thiophene ring, and d is a substituent R 11 The number of

[0419] Each R 11 Each of the following groups is independently selected from halogen, hydroxy, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, and C1-C6 alkoxy;

[0420] d is 0, 1, 2, or 3;

[0421] X is selected from CR 7 R 8 、O、S、SO、SO2、NR 7 ;

[0422] R 7 、R 8 are independently selected from hydrogen, halogen, C1-C6 alkyl, 3-6 membered cycloalkyl;

[0423] R 6 is a substituent at any position on the benzene ring, and b is a substituent R 6 The number of

[0424] Each R 6 Each of the following groups is independently selected from halogen, hydroxy, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, and C1-C6 alkoxy;

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

[0426] Ring A and Ring B are independently selected from 4- to 12-membered cycloalkyl and 4- to 12-membered heterocycloalkyl;

[0427] M is selected from None, CR 9 R 10 、O、S、SO、SO2、NR 9 ;

[0428] R 9 、R 10 are independently selected from hydrogen, C1-C6 alkyl;

[0429] E 3 is a substituent at any position on the benzene ring, and c is a substituent E 3 The number of

[0430] Each E 3 are independently selected from halogen, hydroxy, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, C1-C6 alkoxy; or any two E 3 Connect to form 3-6 membered cycloalkyl, 6-10 membered aryl, 4-12 membered heterocycloalkyl, 5-8 membered heteroaryl;

[0431] c is 0, 1, 2, or 3;

[0432] Y is none, CR Y1 R Y2 、C(O)、-CR 11 =CR 12 -、-CR 11 =N-, -N=N-, -OC(O)-;

[0433] R Y1 、R Y2 are independently selected from hydrogen, C1-C6 alkyl;

[0434] R 11 、R 12are independently selected from hydrogen, C1-C6 alkyl;

[0435] The heteroatom of the heteroaryl group is O, N or S; the number of heteroatoms is 1, 2 or 3;

[0436] The heteroatom of the heterocycloalkyl group is N; the number of heteroatoms is 1, 2 or 3;

[0437] Preferably,

[0438] X is selected from CH2, CF2, O, S, SO, SO2, NR 7 ;

[0439] R 7 Selected from hydrogen, halogen, C1-C6 alkyl, 3-6 membered cycloalkyl;

[0440] Ring A and ring B are independently selected from 4-12 membered cycloalkyl and 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.

[0441] Furthermore, the compound is represented by formula (XVII):

[0442] in,

[0443] R 3 、R 4 are independently selected from hydrogen, C1-C6 alkyl, or R 3 、R 4 Connected to form a 3- to 6-membered cycloalkyl group;

[0444] X is selected from CR 7 R 8 、O、S、SO、SO2、NR 7 ;

[0445] R 7 、R 8 are independently selected from hydrogen, halogen, C1-C6 alkyl, 3-6 membered cycloalkyl;

[0446] R 11 is a substituent at any position on the benzene ring, and d is a substituent R 11 The number of R 6 is a substituent at any position on the benzene ring, and b is a substituent R 6 The number of

[0447] 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;

[0448] Each R 11 、R 6Each of the following groups is independently selected from halogen, hydroxy, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, and C1-C6 alkoxy; and at least one of the groups is fluorine;

[0449] Ring A and Ring B are independently selected from 4- to 12-membered cycloalkyl and 4- to 12-membered heterocycloalkyl;

[0450] M is selected from None, CR 9 R 10 、O、S、SO、SO2、NR 9 ;

[0451] R 9 、R 10 are independently selected from hydrogen, C1-C6 alkyl;

[0452] Y is none, CR Y1 R Y2 、C(O)、-CR 11 =CR 12 -、-CR 11 =N-, -N=N-, -OC(O)-;

[0453] R Y1 、R Y2 are independently selected from hydrogen, C1-C6 alkyl;

[0454] R 11 、R 12 are independently selected from hydrogen, C1-C6 alkyl;

[0455] The heteroatom of the heterocycloalkyl group is N; the number of heteroatoms is 1, 2 or 3;

[0456] Preferably,

[0457] X is selected from CH2, CF2, O, S, SO, SO2, NR 7 ;

[0458] R 7 Selected from hydrogen, halogen, C1-C6 alkyl, 3-6 membered cycloalkyl;

[0459] Ring A and ring B are independently selected from 4-12 membered cycloalkyl and 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.

[0460] Furthermore, the compound is represented by formula (XVIII):

[0461] in,

[0462] X is selected from CR 7 R8 、O、S、SO、SO2、NR 7 ;

[0463] R 7 、R 8 are independently selected from hydrogen, halogen, C1-C6 alkyl, 3-6 membered cycloalkyl;

[0464] R 11 is a substituent at any position on the benzene ring, and d is a substituent R 11 The number of R 6 is a substituent at any position on the benzene ring, and b is a substituent R 6 The number of

[0465] 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;

[0466] Each R 11 、R 6 Each of the following groups is independently selected from halogen, hydroxy, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, and C1-C6 alkoxy; and at least one of the groups is fluorine;

[0467] Ring A and Ring B are independently selected from 4- to 12-membered cycloalkyl and 4- to 12-membered heterocycloalkyl;

[0468] M is selected from None, CR 9 R 10 ;

[0469] R 9 、R 10 are independently selected from hydrogen, C1-C6 alkyl;

[0470] Y is none, CR Y1 R Y2 、C(O)、-CR 11 =CR 12 -、-CR 11 =N-, -N=N-, -OC(O)-;

[0471] R Y1 、R Y2 are independently selected from hydrogen, C1-C6 alkyl;

[0472] R 11 、R 12 are independently selected from hydrogen, C1-C6 alkyl;

[0473] The heteroatom of the heterocycloalkyl group is N; the number of heteroatoms is 1, 2 or 3;

[0474] Preferably,

[0475] X is selected from CH2, CF2 or O;

[0476] Ring A and ring B are independently selected from 4-12 membered cycloalkyl and 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.

[0477] Furthermore, the compound is represented by formula (XIX):

[0478] in,

[0479] R 1 Selected from hydrogen, C1-C6 alkyl, hydroxy, amino or C1-C6 alkoxy, boric acid group;

[0480] R 2 is a substituent at any position on the benzene ring, a is a substituent R 2 The number of

[0481] Each R 2 Each of the following groups is independently selected from halogen, hydroxy, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, and C1-C6 alkoxy;

[0482] a is 0, 1, 2, or 3;

[0483] 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 substituent of the aryl or heteroaryl is selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, C1-C6 alkoxy;

[0484] X is selected from CR 7 R 8 、O、S、SO、SO2、NR 7 ;

[0485] R 7 、R 8 are independently selected from hydrogen, halogen, C1-C6 alkyl, 3-6 membered cycloalkyl;

[0486] n is 0, 1, or 2;

[0487] R 6 is a substituent at any position on the benzene ring, and b is a substituent R 6 The number of

[0488] Each R 6 Each of the following groups is independently selected from halogen, hydroxy, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, and C1-C6 alkoxy;

[0489] b is 0, 1, 2, or 3;

[0490] Ring A and Ring B are independently selected from 4- to 12-membered cycloalkyl and 4- to 12-membered heterocycloalkyl;

[0491] M is selected from None, CR 9 R 10 、O、S、SO、SO2、NR 9 ;

[0492] R 9 、R 10 are independently selected from hydrogen, C1-C6 alkyl;

[0493] E 3 is a substituent at any position on the benzene ring, and c is a substituent E 3 The number of

[0494] Each E 3 are independently selected from halogen, hydroxy, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, C1-C6 alkoxy; or any two E 3 Connect to form 3-6 membered cycloalkyl, 6-10 membered aryl, 4-12 membered heterocycloalkyl, 5-8 membered heteroaryl;

[0495] c is 0, 1, 2, or 3;

[0496] Y is none, CR Y1 R Y2 、C(O)、-CR 11 =CR 12 -、-CR 11 =N-, -N=N-, -OC(O)-;

[0497] R Y1 、R Y2 are independently selected from hydrogen, C1-C6 alkyl;

[0498] R 11 、R 12 are independently selected from hydrogen, C1-C6 alkyl;

[0499] The heteroatom of the heteroaryl group is O, N or S; the number of heteroatoms is 1, 2 or 3;

[0500] The heteroatom of the heterocycloalkyl group is N; the number of heteroatoms is 1, 2 or 3;

[0501] Preferably,

[0502] R 5is selected from C1-C6 alkyl, 3-6 membered cycloalkyl, trifluoromethyl, trifluoroethyl, substituted or unsubstituted phenyl, substituted or unsubstituted thienyl, substituted or unsubstituted furyl, 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, furyl, pyrrolyl, pyrimidinyl, pyridazinyl, pyrazolyl or pyrazinyl are selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl and C1-C6 alkoxy.

[0503] Furthermore, the compound is represented by formula (XX):

[0504] in,

[0505] 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 substituent of the aryl or heteroaryl is selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, C1-C6 alkoxy;

[0506] X is selected from CR 7 R 8 、O、S、SO、SO2、NR 7 ;

[0507] R 7 、R 8 are independently selected from hydrogen, halogen, C1-C6 alkyl, 3-6 membered cycloalkyl;

[0508] R 6 is a substituent at any position on the benzene ring, and b is a substituent R 6 The number of

[0509] Each R 6 Each of the following groups is independently selected from halogen, hydroxy, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, and C1-C6 alkoxy;

[0510] b is 0, 1, 2, or 3;

[0511] Ring A and Ring B are independently selected from 4- to 12-membered cycloalkyl and 4- to 12-membered heterocycloalkyl;

[0512] M is selected from None, CR 9 R 10 、O、S、SO、SO2、NR 9 ;

[0513] R 9 、R10 are independently selected from hydrogen, C1-C6 alkyl;

[0514] Y is none, CR Y1 R Y2 、C(O)、-CR 11 =CR 12 -、-CR 11 =N-, -N=N-, -OC(O)-;

[0515] R Y1 、R Y2 are independently selected from hydrogen, C1-C6 alkyl;

[0516] R 11 、R 12 are independently selected from hydrogen, C1-C6 alkyl;

[0517] The heteroatom of the heteroaryl group is O, N or S; the number of heteroatoms is 1, 2 or 3;

[0518] The heteroatom of the heterocycloalkyl group is N; the number of heteroatoms is 1, 2 or 3;

[0519] Preferably,

[0520] R 5 is selected from C1-C6 alkyl, 3-6 membered cycloalkyl, trifluoromethyl, trifluoroethyl, substituted or unsubstituted phenyl, substituted or unsubstituted thienyl, substituted or unsubstituted furyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted pyrimidinyl, substituted or unsubstituted pyridazinyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted pyrazinyl; the substituent of the phenyl, thienyl, furyl, pyrrolyl, pyrimidinyl, pyridazinyl, pyrazolyl or pyrazinyl is selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, C1-C6 alkoxy;

[0521] X is selected from CH2, CF2, O, S, SO, SO2, NR 7 ;

[0522] R 7 Selected from hydrogen, halogen, C1-C6 alkyl, 3-6 membered cycloalkyl;

[0523] Ring A and ring B are independently selected from 4-12 membered cycloalkyl and 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.

[0524] Furthermore, the compound is represented by formula (XXI):

[0525] in,

[0526] R 11 is a substituent at any position on the benzene ring, and d is a substituent R 11 The number of

[0527] Each R 11 Each of the following groups is independently selected from halogen, hydroxy, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, and C1-C6 alkoxy;

[0528] d is 0, 1, 2, or 3;

[0529] X is selected from CR 7 R 8 、O、S、SO、SO2、NR 7 ;

[0530] R 7 、R 8 are independently selected from hydrogen, halogen, C1-C6 alkyl, 3-6 membered cycloalkyl;

[0531] R 6 is a substituent at any position on the benzene ring, and b is a substituent R 6 The number of

[0532] Each R 6 Each of the following groups is independently selected from halogen, hydroxy, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, and C1-C6 alkoxy;

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

[0534] M is selected from None, CR 9 R 10 、O、S、SO、SO2、NR 9 ;

[0535] R 9 、R 10 are independently selected from hydrogen, C1-C6 alkyl;

[0536] m1, m2, m3, m4, m5, and m6 are independently selected from 0, 1, 2, or 3;

[0537] Y is none, CR Y1 R Y2 、C(O)、-CR 11 =CR 12 -、-CR 11 =N-, -N=N-, -OC(O)-;

[0538] R Y1 、R Y2 are independently selected from hydrogen, C1-C6 alkyl;

[0539] R 11 、R 12 are independently selected from hydrogen, C1-C6 alkyl;

[0540] Preferably,

[0541] X is selected from CH2, CF2, O, S, SO, SO2, NR 7 ;

[0542] R 7 Selected from hydrogen, halogen, C1-C6 alkyl, 3-6 membered cycloalkyl.

[0543] Furthermore, the ring A and ring B are independently selected from the following structures:

[0544] Furthermore, the Selected from the following structures:

[0545] Furthermore, the compound is one of the following compounds:

[0546] Further, the compound is ARV-471, compound 63, compound 65 or compound 75;

[0547] The structure of ARV-471 is The structure of compound 63 is The structure of compound 65 is The structure of compound 75 is

[0548] Furthermore, the salt is a pharmaceutically acceptable salt; the pharmaceutically acceptable salt is a phosphate, dextrorotatory camphorsulfonate, hydrochloride, hydrobromide, hydrofluoride, sulfate, nitrate, formate, acetate, propionate, oxalate, malonate, succinate, fumarate, maleate, lactate, malate, tartrate, citrate, picrate, methanesulfonate, toluenesulfonate, benzenesulfonate, aspartate or glutamate of the compound.

[0549] Furthermore, the mTOR inhibitor is Rapamycin, Everolimus, Dactolisib, AZD8055, Temsirolimus, PI-103, NU7441, Torin 2, KU-0063794, Torkinib, Ridaforolimus, Sapanisertib, Voxtalisib (XL765) Analogue, Torin 1, Omipalisib, OSI-027, PF-04691502, Apitolisib, GSK1059615, Gedatolisib, WYE-354, Vistusertib, WYE-125132, PP121, WYE-687, WAY-600, ETP-46464, GDC-0349, XL388, PI3K / mTOR Inhibitor-2, MTI-31, PQR620, Compound 401, GNE-477, Bimiralisib, SF2523, CZ415, Paxalisib, CC-115, Onatasertib, Voxtalisib, Zotarolimus, BGT226, Palomid 529, Nitazoxanide, 4EGI-1, MHY-1685, COH-SR4, JR-AB2-011, ABTL-0812, mTOR inhibitor-1, Astragaloside IV, Samotolisib, Chrysophanic Acid or its optical isomers, salts, hydrates or solvates;

[0550] Preferably, the mTOR inhibitor is Rapamycin, Everolimus or an optical isomer, salt, hydrate or solvate thereof.

[0551] Furthermore, when the estrogen receptor degrader is ARV-471 or an optical isomer, salt, hydrate or solvate thereof, and the mTOR inhibitor is Rapamycin or an optical isomer, salt, hydrate or solvate thereof, the molar ratio of the estrogen receptor degrader to the mTOR inhibitor is 1:0.011 to 1:2.7; preferably, the molar ratio is 1:0.011, 1:0.3 or 1:2.7;

[0552] Alternatively, when the estrogen receptor degrader is ARV-471 or an optical isomer, a salt, a hydrate, or a solvate thereof, and the mTOR inhibitor is Everolimus or an optical isomer, a salt, a hydrate, or a solvate thereof, the molar ratio of the estrogen receptor degrader to the mTOR inhibitor is 1:0.033 to 1:8; the molar ratio is preferably 1:0.033, 1:0.89, or 1:8.

[0553] Furthermore, when the estrogen receptor degrader is compound 75 or its optical isomer, salt, hydrate or solvate, and the mTOR inhibitor is rapamycin or its optical isomer, salt, hydrate or solvate, the molar ratio of the estrogen receptor degrader to the mTOR inhibitor is 1:0.011 to 1:2.7; preferably, the molar ratio is 1:0.011, 1:0.3 or 1:2.7;

[0554] Alternatively, when the estrogen receptor degrader is compound 75 or an optical isomer, a salt, a hydrate, or a solvate thereof, and the mTOR inhibitor is everolimus or an optical isomer, a salt, a hydrate, or a solvate thereof, the molar ratio of the estrogen receptor degrader to the mTOR inhibitor is 1:0.033 to 1:8; the molar ratio is preferably 1:0.033, 1:0.89, or 1:8.

[0555] Furthermore, when the estrogen receptor degrader is compound 65 or its optical isomer, salt, hydrate or solvate, and the mTOR inhibitor is rapamycin or its optical isomer, salt, hydrate or solvate, the molar ratio of the estrogen receptor degrader to the mTOR inhibitor is 1:0.011 to 1:2.7; preferably, the molar ratio is 1:0.011, 1:0.3 or 1:2.7;

[0556] Alternatively, when the estrogen receptor degrader is compound 65 or an optical isomer, a salt, a hydrate, or a solvate thereof, and the mTOR inhibitor is everolimus or an optical isomer, a salt, a hydrate, or a solvate thereof, the molar ratio of the estrogen receptor degrader to the mTOR inhibitor is 1:0.033 to 1:8; the molar ratio is preferably 1:0.033, 1:0.89, or 1:8.

[0557] Furthermore, when the estrogen receptor degrader is compound 63 or its optical isomer, salt, hydrate or solvate, and the mTOR inhibitor is rapamycin or its optical isomer, salt, hydrate or solvate, the molar ratio of the estrogen receptor degrader to the mTOR inhibitor is 1:0.011 to 1:2.7; preferably, the molar ratio is 1:0.011, 1:0.3 or 1:2.7;

[0558] Alternatively, when the estrogen receptor degrader is compound 63 or its optical isomer, salt, hydrate or solvate, and the mTOR inhibitor is everolimus or its optical isomer, salt, hydrate or solvate, the molar ratio of the estrogen receptor degrader to the mTOR inhibitor is 1:0.033 to 1:8; the molar ratio is preferably 1:0.033, 1:0.89 or 1:8.

[0559] The present invention also provides a method for preparing the aforementioned pharmaceutical composition, which comprises the following steps: taking an estrogen receptor targeted degrader and an mTOR inhibitor according to a molar ratio and mixing them.

[0560] The present invention also provides use of the aforementioned pharmaceutical composition in preparing an estrogen receptor degrader and / or a drug for treating estrogen receptor-related diseases.

[0561] The present invention also provides the use of the aforementioned pharmaceutical composition in preparing a drug for treating and / or preventing cancer;

[0562] Preferably, the cancer is bone cancer, colorectal cancer, endometrial cancer, prostate cancer, ovarian cancer, uterine cancer, cervical cancer, lung cancer, or breast cancer.

[0563] The present invention also provides a pharmaceutical preparation for degrading estrogen receptors, which is a preparation prepared by taking the aforementioned pharmaceutical composition as an active ingredient and adding pharmaceutically acceptable excipients or auxiliary ingredients.

[0564] The present invention also provides a combined drug for degrading estrogen receptors, which contains an estrogen receptor targeted degrader and an mTOR inhibitor of the same or different specifications, which are administered simultaneously or separately, and a pharmaceutically acceptable carrier.

[0565] Furthermore, the molar ratio of the estrogen receptor targeted degrader to the mTOR inhibitor is 1:0011 to 1:8;

[0566] Preferably, the molar ratio of the estrogen receptor targeted degrader to the mTOR inhibitor is 1:0.011 to 1:2.7 or 1:0.033 to 1:8;

[0567] More preferably, the molar ratio of the estrogen receptor targeted degrader to the mTOR inhibitor is 1:0.011, 1:0.033, 1:0.3, 1:0.89, 1:2.7 or 1:8.

[0568] Furthermore, the estrogen receptor targeted degradation agent is selected from the aforementioned compound, or an optical isomer thereof, or a salt thereof, or a hydrate thereof, or a solvate thereof;

[0569] The mTOR inhibitors are Rapamycin, Everolimus, Dactolisib, AZD8055, Temsirolimus, PI-103, NU7441, Torin 2, KU-0063794, Torkinib, Ridaforolimus, Sapanisertib, Voxtalisib (XL765) Analogue, Torin 1. Omipalisib, OSI-027, PF-04691502, Apitolisib, GSK1059615, Gedatolisib, WYE-354, Vi stusertib, WYE-125132, PP121, WYE-687, WAY-600, ETP-46464, GDC-0349, XL388, PI3K / mTOR Inhibitor-2, MTI-31, PQR620, Compound 401, GNE-477, Bimiralisib, SF2523, CZ415, Paxalisib, CC-115, Onatasertib, Voxtalisib, Zotarolimus, BGT226, Palomid 529, Nitazoxanide, 4EGI-1, MHY-1685, COH-SR4, JR-AB2-011, ABTL-0812, mTOR inhibitor-1, Astragaloside IV, Samotolisib, Chrysophanic Acid or its optical isomers, salts, hydrates or solvates;

[0570] Preferably, the mTOR inhibitor is Rapamycin, Everolimus or an optical isomer, salt, hydrate or solvate thereof.

[0571] Furthermore, when the estrogen receptor degrader is ARV-471 or an optical isomer, salt, hydrate or solvate thereof, and the mTOR inhibitor is Rapamycin or an optical isomer, salt, hydrate or solvate thereof, the molar ratio of the estrogen receptor degrader to the mTOR inhibitor is 1:0.011 to 1:2.7; preferably, the molar ratio is 1:0.011, 1:0.3 or 1:2.7;

[0572] Alternatively, when the estrogen receptor degrader is ARV-471 or an optical isomer, a salt, a hydrate, or a solvate thereof, and the mTOR inhibitor is Everolimus or an optical isomer, a salt, a hydrate, or a solvate thereof, the molar ratio of the estrogen receptor degrader to the mTOR inhibitor is 1:0.033 to 1:8; the molar ratio is preferably 1:0.033, 1:0.89, or 1:8.

[0573] Furthermore, when the estrogen receptor degrader is compound 75 or its optical isomer, salt, hydrate or solvate, and the mTOR inhibitor is rapamycin or its optical isomer, salt, hydrate or solvate, the molar ratio of the estrogen receptor degrader to the mTOR inhibitor is 1:0.011 to 1:2.7; preferably, the molar ratio is 1:0.011, 1:0.3 or 1:2.7;

[0574] Alternatively, when the estrogen receptor degrader is compound 75 or an optical isomer, a salt, a hydrate, or a solvate thereof, and the mTOR inhibitor is everolimus or an optical isomer, a salt, a hydrate, or a solvate thereof, the molar ratio of the estrogen receptor degrader to the mTOR inhibitor is 1:0.033 to 1:8; the molar ratio is preferably 1:0.033, 1:0.89, or 1:8.

[0575] Furthermore, when the estrogen receptor degrader is compound 65 or its optical isomer, salt, hydrate or solvate, and the mTOR inhibitor is rapamycin or its optical isomer, salt, hydrate or solvate, the molar ratio of the estrogen receptor degrader to the mTOR inhibitor is 1:0.011 to 1:2.7; preferably, the molar ratio is 1:0.011, 1:0.3 or 1:2.7;

[0576] Alternatively, when the estrogen receptor degrader is compound 65 or an optical isomer, a salt, a hydrate, or a solvate thereof, and the mTOR inhibitor is everolimus or an optical isomer, a salt, a hydrate, or a solvate thereof, the molar ratio of the estrogen receptor degrader to the mTOR inhibitor is 1:0.033 to 1:8; the molar ratio is preferably 1:0.033, 1:0.89, or 1:8.

[0577] Furthermore, when the estrogen receptor degrader is compound 63 or its optical isomer, salt, hydrate or solvate, and the mTOR inhibitor is rapamycin or its optical isomer, salt, hydrate or solvate, the molar ratio of the estrogen receptor degrader to the mTOR inhibitor is 1:0.011 to 1:2.7; preferably, the molar ratio is 1:0.011, 1:0.3 or 1:2.7;

[0578] Alternatively, when the estrogen receptor degrader is compound 63 or its optical isomer, salt, hydrate or solvate, and the mTOR inhibitor is everolimus or its optical isomer, salt, hydrate or solvate, the molar ratio of the estrogen receptor degrader to the mTOR inhibitor is 1:0.033 to 1:8; the molar ratio is preferably 1:0.033, 1:0.89 or 1:8.

[0579] The present invention also provides the use of an estrogen receptor targeted degrader in combination with an mTOR inhibitor in the preparation of a drug for degrading estrogen receptors.

[0580] Furthermore, the molar ratio of the estrogen receptor targeted degrader to the mTOR inhibitor is 1:0011 to 1:8;

[0581] Preferably, the molar ratio of the estrogen receptor targeted degrader to the mTOR inhibitor is 1:0.011 to 1:2.7 or 1:0.033 to 1:8;

[0582] More preferably, the molar ratio of the estrogen receptor targeted degrader to the mTOR inhibitor is 1:0.011, 1:0.033, 1:0.3, 1:0.89, 1:2.7 or 1:8.

[0583] Furthermore, the estrogen receptor targeted degradation agent is selected from the aforementioned compound, or an optical isomer thereof, or a salt thereof, or a hydrate thereof, or a solvate thereof;

[0584] The mTOR inhibitors are Rapamycin, Everolimus, Dactolisib, AZD8055, Temsirolimus, PI-103, NU7441, Torin 2, KU-0063794, Torkinib, Ridaforolimus, Sapanisertib, Voxtalisib (XL765) Analogue, Torin 1. Omipalisib, OSI-027, PF-04691502, Apitolisib, GSK1059615, Gedatolisib, WYE-354, Vi stusertib, WYE-125132, PP121, WYE-687, WAY-600, ETP-46464, GDC-0349, XL388, PI3K / mTOR Inhibitor-2, MTI-31, PQR620, Compound 401, GNE-477, Bimiralisib, SF2523, CZ415, Paxalisib, CC-115, Onatasertib, Voxtalisib, Zotarolimus, BGT226, Palomid 529, Nitazoxanide, 4EGI-1, MHY-1685, COH-SR4, JR-AB2-011, ABTL-0812, mTOR inhibitor-1, Astragaloside IV, Samotolisib, Chrysophanic Acid or its optical isomers, salts, hydrates or solvates;

[0585] Preferably, the mTOR inhibitor is Rapamycin, Everolimus or an optical isomer, salt, hydrate or solvate thereof.

[0586] Furthermore, when the estrogen receptor degrader is ARV-471 or an optical isomer, salt, hydrate or solvate thereof, and the mTOR inhibitor is Rapamycin or an optical isomer, salt, hydrate or solvate thereof, the molar ratio of the estrogen receptor degrader to the mTOR inhibitor is 1:0.011 to 1:2.7; preferably, the molar ratio is 1:0.011, 1:0.3 or 1:2.7;

[0587] Alternatively, when the estrogen receptor degrader is ARV-471 or an optical isomer, a salt, a hydrate, or a solvate thereof, and the mTOR inhibitor is Everolimus or an optical isomer, a salt, a hydrate, or a solvate thereof, the molar ratio of the estrogen receptor degrader to the mTOR inhibitor is 1:0.033 to 1:8; the molar ratio is preferably 1:0.033, 1:0.89, or 1:8.

[0588] Furthermore, when the estrogen receptor degrader is compound 75 or its optical isomer, salt, hydrate or solvate, and the mTOR inhibitor is rapamycin or its optical isomer, salt, hydrate or solvate, the molar ratio of the estrogen receptor degrader to the mTOR inhibitor is 1:0.011 to 1:2.7; preferably, the molar ratio is 1:0.011, 1:0.3 or 1:2.7;

[0589] Alternatively, when the estrogen receptor degrader is compound 75 or an optical isomer, a salt, a hydrate, or a solvate thereof, and the mTOR inhibitor is everolimus or an optical isomer, a salt, a hydrate, or a solvate thereof, the molar ratio of the estrogen receptor degrader to the mTOR inhibitor is 1:0.033 to 1:8; the molar ratio is preferably 1:0.033, 1:0.89, or 1:8.

[0590] Furthermore, when the estrogen receptor degrader is compound 65 or its optical isomer, salt, hydrate or solvate, and the mTOR inhibitor is rapamycin or its optical isomer, salt, hydrate or solvate, the molar ratio of the estrogen receptor degrader to the mTOR inhibitor is 1:0.011 to 1:2.7; preferably, the molar ratio is 1:0.011, 1:0.3 or 1:2.7;

[0591] Alternatively, when the estrogen receptor degrader is compound 65 or an optical isomer, a salt, a hydrate, or a solvate thereof, and the mTOR inhibitor is everolimus or an optical isomer, a salt, a hydrate, or a solvate thereof, the molar ratio of the estrogen receptor degrader to the mTOR inhibitor is 1:0.033 to 1:8; the molar ratio is preferably 1:0.033, 1:0.89, or 1:8.

[0592] Furthermore, when the estrogen receptor degrader is compound 63 or its optical isomer, salt, hydrate or solvate, and the mTOR inhibitor is rapamycin or its optical isomer, salt, hydrate or solvate, the molar ratio of the estrogen receptor degrader to the mTOR inhibitor is 1:0.011 to 1:2.7; preferably, the molar ratio is 1:0.011, 1:0.3 or 1:2.7;

[0593] Alternatively, when the estrogen receptor degrader is compound 63 or its optical isomer, salt, hydrate or solvate, and the mTOR inhibitor is everolimus or its optical isomer, salt, hydrate or solvate, the molar ratio of the estrogen receptor degrader to the mTOR inhibitor is 1:0.033 to 1:8; the molar ratio is preferably 1:0.033, 1:0.89 or 1:8.

[0594] Furthermore, the drug for degrading estrogen receptors is an estrogen receptor degrader and / or a drug for treating estrogen receptor-related diseases.

[0595] Furthermore, the drug is used in a drug for treating and / or preventing cancer;

[0596] Preferably, the cancer is bone cancer, colorectal cancer, endometrial cancer, prostate cancer, ovarian cancer, uterine cancer, cervical cancer, lung cancer, or breast cancer.

[0597] The compounds and derivatives provided herein can be named according to the IUPAC (International Union of Pure and Applied Chemistry) or CAS (Chemical Abstracts Service, Columbus, OH) nomenclature system.

[0598] Definitions of terms used in the present invention: Unless otherwise stated, the initial definitions provided for groups or terms in this document apply to the groups or terms throughout the specification; for terms that are not specifically defined herein, they should be given the meaning that a person skilled in the art would give them based on the disclosure and context.

[0599] "Substitution" refers to the replacement of a hydrogen atom in a molecule by another different atom or molecule.

[0600] The minimum and maximum carbon atom content in a hydrocarbon group is indicated by a prefix, for example, the prefix C a ~C b Alkyl refers to any alkyl group containing from "a" to "b" carbon atoms. Thus, for example, "C1-C8 alkyl" refers to an alkyl group containing from 1 to 8 carbon atoms; and "C1-C8 alkoxy" refers to an alkoxy group containing from 1 to 8 carbon atoms.

[0601] "Alkyl" refers to a saturated hydrocarbon chain having a specified number of carbon atoms. For example, C1-C8 alkyl 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 groups include methyl, ethyl, propyl (n-propyl and isopropyl), butyl (n-butyl, isobutyl, and tert-butyl), pentyl (n-pentyl, isopentyl, and neopentyl), and hexyl, among others.

[0602] "Halogen" is fluorine, chlorine, bromine or iodine.

[0603] In the present invention, cycloalkyl refers to a saturated or partially saturated non-aromatic cyclic group composed of carbon atoms and no ring heteroatoms, and having a single ring or multiple rings (including fused, bridged, and spiro ring systems). 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, or a sulfur atom. Examples of heterocyclyl groups include, for example, piperidinyl, piperazinyl, and morpholinyl.

[0604] In the present invention, an aryl group refers to an aromatic unsaturated group with no ring heteroatoms and a single ring or multiple rings (including fused, bridged, and spiro ring systems), such as phenyl, anthracenyl, and naphthyl. A heteroaryl group refers to an aromatic unsaturated ring containing at least one heteroatom; it includes a single ring or multiple rings (including fused, bridged, and spiro ring systems); wherein the heteroatom refers to a nitrogen atom, an oxygen atom, or a sulfur atom. Examples include pyridyl, pyrazinyl, pyridazinyl, pyrazolyl, furanyl, thienyl, and oxazolyl.

[0605] In the present invention, the structure of OBn is

[0606] In the present invention, in the compound of formula (I), when the dotted line in the benzene ring is a bond, the compound structure is When there is no dotted line in the benzene ring, the compound structure is

[0607] In the present invention, in the compound of formula (I), when the dotted line between Y and W is absent, the compound structure is

[0608] R ab When the dotted line between Y and W is a bond, the compound structure is

[0609] The mTOR inhibitors are Rapamycin, Everolimus, Dactolisib, AZD8055, Temsirolimus, PI-103, NU7441, Torin 2, KU-0063794, Torkinib, Ridaforolimus, Sapanisertib, Voxtalisib (XL765) Analogue, Torin 1. Omipalisib, OSI-027, PF-04691502, Apitolisib, GSK1059615, Gedatolisib, WYE-354, Vi stusertib, WYE-125132, PP121, WYE-687, WAY-600, ETP-46464, GDC-0349, XL388, PI3K / mTOR Inhibitor-2, MTI-31, PQR620, Compound 401, GNE-477, Bimiralisib, SF2523, CZ415, Paxalisib, CC-115, Onatasertib, Voxtalisib, Zotarolimus, BGT226, Palomid 529, Nitazoxanide, 4EGI-1, MHY-1685, COH-SR4, JR-AB2-011, ABTL-0812, mTOR inhibitor-1, Astragaloside IV, Samotolisib, Chrysophanic Acid; their structures are as follows:

[0610] Rapamycin, Everolimus,

[0611] Dactolisib, AZD8055,

[0612] Temsirolimus, PI-103,

[0613] NU7441, Torin 2,

[0614] KU-0063794, Torkinib,

[0615] Ridaforolimus, Sapanisertib,

[0616] Voxtalisib(XL765)Analogue,

[0617] Torin 1, Omipalisib,

[0618] OSI-027, PF-04691502,

[0619] Apitolisib, GSK1059615,

[0620] Gedatolisib, WYE-354,

[0621] Vistusertib, WYE-125132,

[0622] PP121, WYE-687,

[0623] WAY-600, ETP-46464,

[0624] GDC-0349, XL388,

[0625] PI3K / mTOR Inhibitor-2, MTI-31,

[0626] PQR620, Compound 401,

[0627] GNE-477, Bimiralisib,

[0628] SF2523, CZ415, <h2 style=";text-align:left;direction:ltr">

[0629] <h2 style=";text-align:left;direction:ltr"> Paxalisib<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> CC-115<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr">

[0630] <h2 style=";text-align:left;direction:ltr"> Onatasertib<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> Voxtalisib<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr">

[0631] <h2 style=";text-align:left;direction:ltr"> Zotarolimus<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> BGT226,<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr">

[0632] <h2 style=";text-align:left;direction:ltr"> Palomid 529,<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> Nitazoxanide<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr">

[0633] <h2 style=";text-align:left;direction:ltr"> 4EGI-1,<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> MHY-1685<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr">

[0634] <h2 style=";text-align:left;direction:ltr"> COH-SR4,<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> JR-AB2-011,<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr">

[0635] <h2 style=";text-align:left;direction:ltr"> ABTL-0812,<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> mTOR inhibitor-1<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr">

[0636] <h2 style=";text-align:left;direction:ltr"> Astragaloside IV<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> Samotilib<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> Chrysophanic Acid<h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr"> <h2 style=";text-align:left;direction:ltr">

[0637] The estrogen receptor degraders (ER degraders) are: Fulvestrant, Estrogen receptor modulator 10, Estrogen receptor antagonist 3, Estrogen receptor antagonist 4, ER degrader4, ER degrader 8, Taragarestrant, Taragarestrant meglumine, ER degrader 5, GDC-0927 Racemate, Elacestrant dihydrochloride, Elacestrant, Rintodestrant, Imlunestrant, ERαdegrader 5, Imlunestrant tosylate, ERαdegrader 8, LX-039, Elacestrant-d10, SNIPER(ER)-110, Elacestrant-d6, Elacestrant-d4, PROTAC ERαDegrader-7, PROTAC ERαDegrader-4; their structures are as follows:

[0638] Fulvestrant,

[0639] Estrogen receptor modulator 10,

[0640] Estrogen receptor antagonist 3,

[0641] Estrogen receptor antagonist 4,

[0642] ER degrader 4, ER degrader 8,

[0643] Taragarestrant, Taragarestrant meglumine,

[0644] ER degrader 5, GDC-0927 Racemate,

[0645] Elacestrant dihydrochloride,

[0646] Elacestrant, Rintodestrant,

[0647] Imlunestrant, ERαdegrader 5,

[0648] Imlunestrant tosylate

[0649] ERαdegrader 8, LX-039,

[0650] Elacestrant-d10,

[0651] SNIPER(ER)-110,

[0652] Elacestrant-d6, Elacestrant-d4,

[0653] PROTAC ERαDegrader-7,

[0654] PROTAC ERαDegrader-4,

[0655] The present invention combines an estrogen receptor degrader with an mTOR inhibitor to degrade estrogen receptors and inhibit cancer cell growth, which can exert a synergistic inhibitory effect and significantly improve the effect of treating diseases related to estrogen receptors, such as breast cancer, and has good application prospects.

[0656] Obviously, based on the above contents of the present invention, according to common technical knowledge and customary means in this field, without departing from the above basic technical ideas of the present invention, other various forms of modifications, replacements or changes can be made.

[0657] The following further describes the above content of the present invention in detail through specific embodiments in the form of examples. However, this should not be construed as limiting the scope of the above subject matter of the present invention to the following examples. All technologies implemented based on the above content of the present invention fall within the scope of the present invention. BRIEF DESCRIPTION OF THE DRAWINGS

[0658] Figure 1 shows the inhibitory effects of compound 63 and Everolimus on the growth of MCF-7 cells.

[0659] FIG2 shows the inhibitory effects of compound 65 and Everolimus on the growth of MCF-7 cells.

[0660] FIG3 shows the inhibitory effects of compound 75 and Everolimus on the growth of MCF-7 cells.

[0661] FIG4 shows the inhibitory effects of ARV-471 and Everolimus on the growth of MCF-7 cells.

[0662] FIG5 shows the inhibitory effects of compound 63 and rapamycin on the growth of MCF-7 cells.

[0663] FIG6 shows the inhibitory effects of compound 65 and rapamycin on the growth of MCF-7 cells.

[0664] FIG7 shows the inhibitory effects of compound 75 and rapamycin on the growth of MCF-7 cells.

[0665] FIG8 shows the inhibitory effects of ARV-471 and Rapamycin on the growth of MCF-7 cells. DETAILED DESCRIPTION

[0666] The raw materials and equipment used in the specific embodiments of the present invention are all known products and are obtained by purchasing commercial products.

[0667] Example 1: Combination of estrogen receptor targeted degrader and mTOR inhibitor

[0668] mTOR inhibitor: Everolimus, the structure is

[0669] Estrogen receptor degrader: ARV-471, the structure is

[0670] The molar ratio of ARV-471 to Everolimus is 1:0.033 to 1:8 (eg, 1:0.033, 1:0.89, or 1:8).

[0671] The above-mentioned estrogen receptor degrader ARV-471 can be replaced by compound 63, the structure of which is

[0672] The above-mentioned estrogen receptor degrader ARV-471 can be replaced by compound 65, the structure of which is

[0673] The above-mentioned estrogen receptor degrader ARV-471 can be replaced by compound 75, the structure of which is

[0674] Example 2: Combination of estrogen receptor targeted degraders and mTOR inhibitors

[0675] mTOR inhibitor: Rapamycin, the structure is

[0676] Estrogen receptor degrader: ARV-471, the structure is

[0677] The molar ratio of ARV-471 to Rapamycin is 1:0.011 to 1:2.7 (eg, 1:0.011, 1:0.3, or 1:2.7).

[0678] The above-mentioned estrogen receptor degrader ARV-471 can be replaced by compound 63, compound 65, and compound 75.

[0679] The beneficial effects of the present invention are demonstrated below through specific test examples.

[0680] Test Example 1

[0681] Inhibitory effects of four ER Protac compounds 63, 65, 75, and ARV-471 in combination with the mTOR inhibitor Everolimus on breast cancer MCF-7 cells

[0682] (1) Combination of Compound 63 and Everolimus

[0683] 1. Experimental methods

[0684] Breast cancer cells MCF-7 in the logarithmic growth phase were cultured at 2×10 3 Cells were seeded at a concentration of 100 μL / well in a 96-well culture plate, with 80 μL per well. The cells were incubated for 24 hours in a 37°C incubator with 5% CO2 and saturated humidity. After 24 hours, compound 63 and everolimus were added to the 96-well plate. Negative control wells were treated with the same volume of cell culture medium supplemented with 10% fetal bovine serum as the drug.

[0685] The concentration range of compound 63 is: 0nM, 0.15nM, 0.46nM, 1.4nM, 4.1nM, 12nM, 37nM, 111nM, 333nM, 1000nM.

[0686] The concentration range of Everolimus is: 0nM, 1.2nM, 3.7nM, 11nM, 33nM, 100nM.

[0687] After 6 days of drug incubation, the 96-well plate was equilibrated to room temperature. 100 μL of room-temperature CTG reagent was added to each well and the plate was shaken at 400 rpm for 10 minutes. Luminescence endpoint analysis was performed using a FLUOstar Omega multi-function microplate reader. Cell viability was calculated using the formula: Viability (%) = Signal value in drug-treated wells / Signal value in control wells × 100%. Combination index (CI) was then used for evaluation. The CI value criteria are shown in Table 1.

[0688] (2) Combination of Compound 65 and Everolimus

[0689] 1. Experimental methods

[0690] Breast cancer cells MCF-7 in the logarithmic growth phase were cultured at 2×10 3 Cells were seeded at a concentration of 100 μL / well in a 96-well culture plate, with 80 μL per well. The cells were incubated for 24 hours in a 37°C incubator with 5% CO2 and saturated humidity. After 24 hours, compound 65 and everolimus were added to the 96-well plate. Negative control wells were treated with the same volume of cell culture medium supplemented with 10% fetal bovine serum as the drug.

[0691] The concentration range of compound 65 is: 0nM, 0.15nM, 0.46nM, 1.4nM, 4.1nM, 12nM, 37nM, 111nM, 333nM, 1000nM.

[0692] The concentration range of Everolimus is: 0nM, 1.2nM, 3.7nM, 11nM, 33nM, 100nM.

[0693] After 6 days of drug incubation, the 96-well plate was equilibrated to room temperature. 100 μL of room-temperature CTG reagent was added to each well and the plate was shaken at 400 rpm for 10 minutes. Luminescence endpoint analysis was performed using a FLUOstar Omega multi-function microplate reader. Cell viability was calculated using the formula: Viability (%) = Signal value in drug-treated wells / Signal value in control wells × 100%. Combination index (CI) was then used for evaluation. The CI value criteria are shown in Table 1.

[0694] (3) Combination of Compound 75 and Everolimus

[0695] 1. Experimental methods

[0696] Breast cancer cells MCF-7 in the logarithmic growth phase were cultured at 2×10 3 Cells were seeded into 96-well plates at a concentration of 100 μL per well. The plates were incubated for 24 hours in a 37°C incubator with 5% CO2 and saturated humidity. After 24 hours, compound 75 and everolimus were added to the 96-well plates. Negative control wells were treated with the same volume of cell culture medium supplemented with 10% fetal bovine serum as the drug.

[0697] The concentration range of compound 75 is: 0nM, 0.15nM, 0.46nM, 1.4nM, 4.1nM, 12nM, 37nM, 111nM, 333nM, 1000nM.

[0698] The concentration range of Everolimus is: 0nM, 1.2nM, 3.7nM, 11nM, 33nM, 100nM.

[0699] After adding the drug and incubating for 6 days, add 10 μL of CCK-8 to each well and continue incubation for another 3 hours. Measure the absorbance (OD) of each well at 450 nm using an enzyme-linked immunosorbent assay (ELISA). Calculate cell viability using the formula: Viability (%) = OD value of drug-treated well / OD value of control well × 100%. The combination index (CI) was then used to determine the drug combination. The CI determination criteria are shown in Table 1.

[0700] (4) Combination therapy of ARV-471 and Everolimus

[0701] 1. Experimental methods

[0702] Breast cancer cells MCF-7 in the logarithmic growth phase were cultured at 2×10 3 Cells were seeded into 96-well plates at a concentration of 100 μL per well. The plates were incubated for 24 hours in a 37°C incubator with 5% CO2 and saturated humidity. After 24 hours, ARV-471 and everolimus were added to the 96-well plates. Negative control wells were treated with the same volume of cell culture medium supplemented with 10% fetal bovine serum as the drug.

[0703] The ARV-471 concentration range is: 0nM, 0.15nM, 0.46nM, 1.4nM, 4.1nM, 12nM, 37nM, 111nM, 333nM, 1000nM.

[0704] The concentration range of Everolimus is: 0nM, 1.2nM, 3.7nM, 11nM, 33nM, 100nM.

[0705] After adding the drug and incubating for 6 days, add 10 μL of CCK-8 to each well and continue incubation for another 3 hours. Measure the absorbance (OD) of each well at 450 nm using an enzyme-linked immunosorbent assay (ELISA). Calculate cell viability using the formula: Viability (%) = OD value of drug-treated well / OD value of control well × 100%. The combination index (CI) was then used to determine the drug combination. The CI determination criteria are shown in Table 1.

[0706] Table 1. CI value judgment criteria

[0707] 2. Experimental results

[0708] (1) Combination of Compound 63 and Everolimus

[0709] The results of the combination of compound 63 and everolimus are shown in Figure 1. As shown in Figure 1, when the molar ratio of compound 63 to everolimus is 1:8, 1:0.89, or 1:0.033, the CI values ​​of the drug combination are 0.14, 0.05, and 0.48, respectively. At these three drug molar ratios, the combination of compound 63 and everolimus has a synergistic effect in inhibiting the growth of MCF-7 cells.

[0710] (2) Combination of Compound 65 and Everolimus

[0711] The results of the combination of compound 65 and everolimus are shown in Figure 2. As shown in Figure 2, when the molar ratio of compound 65 to everolimus is 1:8, 1:0.89, or 1:0.033, the CI values ​​of the drug combination are 0.23, 0.08, and 0.40, respectively. At these three drug molar ratios, the combination of compound 65 and everolimus has a synergistic effect in inhibiting the growth of MCF-7 cells.

[0712] (3) Combination of Compound 75 and Everolimus

[0713] The results of the combination of Compound 75 and Everolimus are shown in Figure 3. As shown in Figure 3, when the molar ratio of Compound 75 to Everolimus is 1:8, 1:0.89, or 1:0.033, the CI values ​​of the drug combination are 0.36, 0.40, and 0.42, respectively. At these three drug molar ratios, the combination of Compound 75 and Everolimus has a synergistic effect in inhibiting the growth of MCF-7 cells.

[0714] (4) Combination therapy of ARV-471 and Everolimus

[0715] The results of the combination of ARV-471 and Everolimus are shown in Figure 4. As shown in Figure 4, when the molar ratio of ARV-471 to Everolimus is 1:8, 1:0.89, or 1:0.033, the CI values ​​of the drug combination are 0.40, 0.22, and 0.74, respectively. At these three drug molar ratios, the combination of Compound 75 and Everolimus has a synergistic effect in inhibiting the growth of MCF-7 cells.

[0716] The above experimental results show that the combination of four ER Protacids (Compound 63, Compound 65, Compound 75, ARV-471) and Everolimus has a synergistic effect, which can significantly inhibit the growth and proliferation of MCF-7 cells, and its anti-cancer effect is significantly better than that of ER Protac and Everolimus used alone.

[0717] Test Example 2

[0718] Inhibitory effects of four ER Protac compounds 63, 65, 75, and ARV-471 in combination with the mTOR inhibitor Rapamycin on breast cancer cells MCF-7

[0719] (1) Combination of Compound 63 and Rapamycin

[0720] 1. Experimental methods

[0721] Breast cancer cells MCF-7 in the logarithmic growth phase were cultured at 2×10 3 Cells were seeded at a concentration of 100 μL / well in a 96-well culture plate, with 80 μL per well. The cells were incubated for 24 hours in a 37°C incubator with 5% CO2 and saturated humidity. After 24 hours, compound 63 and rapamycin were added to the 96-well plate. Negative control wells were treated with the same volume of cell culture medium supplemented with 10% fetal bovine serum as the drug.

[0722] The concentration range of compound 63 is: 0nM, 0.15nM, 0.46nM, 1.4nM, 4.1nM, 12nM, 37nM, 111nM, 333nM, 1000nM.

[0723] The concentration range of rapamycin is: 0nM, 1.2nM, 3.7nM, 11nM, 33nM, 100nM.

[0724] After 6 days of drug incubation, the 96-well plate was equilibrated to room temperature. 100 μL of room-temperature CTG reagent was added to each well and the plate was shaken at 400 rpm for 10 minutes. Luminescence endpoint analysis was performed using a FLUOstar Omega multi-function microplate reader. Cell viability was calculated using the formula: Viability (%) = Signal value in drug-treated wells / Signal value in control wells × 100%. Combination index (CI) was then used for evaluation. The CI value criteria are shown in Table 1.

[0725] (2) Combination of Compound 65 and Rapamycin

[0726] 1. Experimental methods

[0727] Breast cancer cells MCF-7 in the logarithmic growth phase were cultured at 2×10 3 Cells were seeded at a concentration of 100 μL / well in a 96-well culture plate, with 80 μL per well. The cells were incubated for 24 hours in a 37°C incubator with 5% CO2 and saturated humidity. After 24 hours, compound 65 and rapamycin were added to the 96-well plate. Negative control wells were treated with the same volume of cell culture medium supplemented with 10% fetal bovine serum as the drug.

[0728] The concentration range of compound 65 is: 0nM, 0.15nM, 0.46nM, 1.4nM, 4.1nM, 12nM, 37nM, 111nM, 333nM, 1000nM.

[0729] The concentration range of rapamycin is: 0nM, 1.2nM, 3.7nM, 11nM, 33nM, 100nM.

[0730] After 6 days of drug incubation, the 96-well plate was equilibrated to room temperature. 100 μL of room-temperature CTG reagent was added to each well and the plate was shaken at 400 rpm for 10 minutes. Luminescence endpoint analysis was performed using a FLUOstar Omega multi-function microplate reader. Cell viability was calculated using the formula: Viability (%) = Signal value in drug-treated wells / Signal value in control wells × 100%. Combination index (CI) was then used for evaluation. The CI value criteria are shown in Table 1.

[0731] (3) Combination of Compound 75 and Rapamycin

[0732] 1. Experimental methods

[0733] Breast cancer cells MCF-7 in the logarithmic growth phase were cultured at 2×10 3Cells were seeded into 96-well plates at a concentration of 100 μL per well. The plates were incubated for 24 hours in a 37°C incubator with 5% CO2 and saturated humidity. After 24 hours, compound 75 and rapamycin were added to the 96-well plates. Negative control wells were treated with the same volume of cell culture medium supplemented with 10% fetal bovine serum as the drug.

[0734] The concentration range of compound 75 is: 0nM, 0.15nM, 0.46nM, 1.4nM, 4.1nM, 12nM, 37nM, 111nM, 333nM, 1000nM.

[0735] The concentration range of rapamycin is: 0nM, 1.2nM, 3.7nM, 11nM, 33nM, 100nM.

[0736] After adding the drug and incubating for 6 days, add 10 μL of CCK-8 to each well and continue incubation for another 3 hours. Measure the absorbance (OD) of each well at 450 nm using an enzyme-linked immunosorbent assay (ELISA). Calculate cell viability using the formula: Viability (%) = OD value of drug-treated well / OD value of control well × 100%. The combination index (CI) was then used to determine the drug combination. The CI determination criteria are shown in Table 1.

[0737] (4) Combination of ARV-471 and Rapamycin

[0738] 1. Experimental methods

[0739] Breast cancer cells MCF-7 in the logarithmic growth phase were cultured at 2×10 3 Cells were seeded into 96-well plates at a concentration of 100 μL per well. The plates were incubated for 24 hours in a 37°C incubator with 5% CO2 and saturated humidity. After 24 hours, ARV-471 and rapamycin were added to the 96-well plates. Negative control wells were treated with the same volume of cell culture medium supplemented with 10% fetal bovine serum as the drug.

[0740] The ARV-471 concentration range is: 0nM, 0.15nM, 0.46nM, 1.4nM, 4.1nM, 12nM, 37nM, 111nM, 333nM, 1000nM.

[0741] The concentration range of rapamycin is: 0nM, 1.2nM, 3.7nM, 11nM, 33nM, 100nM.

[0742] After adding the drug and incubating for 6 days, add 10 μL of CCK-8 to each well and continue incubation for another 3 hours. Measure the absorbance (OD) of each well at 450 nm using an enzyme-linked immunosorbent assay (ELISA). Calculate cell viability using the formula: Viability (%) = OD value of drug-treated well / OD value of control well × 100%. The combination index (CI) was then used to determine the drug combination. The CI determination criteria are shown in Table 1.

[0743] 2. Experimental results

[0744] (1) Combination of Compound 63 and Rapamycin

[0745] The results of the combination of compound 63 and rapamycin are shown in Figure 5. As shown in Figure 5, when the molar ratio of compound 63 to rapamycin is 1:2.7, 1:0.3, or 1:0.011, the CI values ​​of the drug combination are 0.11, 0.04, and 0.41, respectively. At these three drug molar ratios, the combination of compound 63 and rapamycin has a synergistic effect in inhibiting the growth of MCF-7 cells.

[0746] (2) Combination of Compound 65 and Rapamycin

[0747] The results of the combination of compound 65 and rapamycin are shown in Figure 6. As shown in Figure 6, when the molar ratio of compound 65 to rapamycin is 1:2.7, 1:0.3, or 1:0.011, the CI values ​​of the drug combination are 0.24, 0.06, and 0.51, respectively. At these three drug molar ratios, the combination of compound 65 and rapamycin has a synergistic effect in inhibiting the growth of MCF-7 cells.

[0748] (3) Combination of Compound 75 and Rapamycin

[0749] The results of the combination of Compound 75 and Rapamycin are shown in Figure 7. As shown in Figure 7, when the molar ratio of Compound 75 to Rapamycin is 1:2.7, 1:0.3, or 1:0.011, the CI values ​​of the drug combination are 0.33, 0.11, and 0.76, respectively. At these three drug molar ratios, the combination of Compound 75 and Rapamycin has a synergistic effect in inhibiting the growth of MCF-7 cells.

[0750] (4) Combination of ARV-471 and Rapamycin

[0751] The results of the combination of ARV-471 and rapamycin are shown in Figure 8. As shown in Figure 8, when the molar ratio of ARV-471 to rapamycin is 1:2.7, 1:0.3, or 1:0.011, the CI values ​​of the drug combination are 0.31, 0.20, and 0.34, respectively. At these three drug molar ratios, the combination of compound 75 and ARV-471 has a synergistic effect in inhibiting the growth of MCF-7 cells.

[0752] The above experimental results show that the combination of four ER Protacids (Compound 63, Compound 65, Compound 75, ARV-471) and Rapamycin has a synergistic effect and can significantly inhibit the growth and proliferation of MCF-7 cells. Its anticancer effect is significantly better than that of ER Protacid and Rapamycin used alone.

[0753] In summary, the present invention combines an estrogen receptor degrader with an mTOR inhibitor to degrade estrogen receptors and inhibit cancer cell growth, which can exert a synergistic inhibitory effect and significantly improve the treatment of estrogen receptor-related diseases, such as breast cancer, and has good application prospects.

Claims

1. A pharmaceutical composition for degrading estrogen receptors, characterized in that: It consists of an estrogen receptor targeted degrader and an mTOR inhibitor.

2. The pharmaceutical composition according to claim 1, characterized in that: The molar ratio of the estrogen receptor targeted degradation agent to the mTOR inhibitor is 1:0011 to 1:8; Preferably, the molar ratio of the estrogen receptor targeted degrader to the mTOR inhibitor is 1:0.011 to 1:2.7 or 1:0.033 to 1:8; More preferably, the molar ratio of the estrogen receptor targeted degrader to the mTOR inhibitor is 1:0.011, 1:0.033, 1:0.3, 1:0.89, 1:2.7 or 1:

8.

3. The pharmaceutical composition according to claim 1 or 2, characterized in that: The estrogen receptor targeted 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, ERαdegrader 5, Imlunestrant tosylate, ERαdegrader 8, LX-039, Elacestrant-d10, SNIPER(ER)-110, Elacestrant-d6, Elacestrant-d4, PROTAC ERαDegrader-7, PROTAC ERαDegrader-4 or an optical isomer thereof, or a salt thereof, or a hydrate thereof, or a solvate thereof: Alternatively, the estrogen receptor targeted degradation agent is a compound represented by formula (I), or an optical isomer thereof, or a salt thereof, or a hydrate thereof, or a solvate thereof: in, R 1 is selected from hydrogen, C1-C6 alkyl, hydroxy, amino, carboxyl, C1-C6 alkoxy, boric acid, -OR'; R' is selected from phenyl, benzyl; R 2 is a substituent at any position on the benzene ring, a is a substituent R 2 The number of Each R 2 Each of the following is independently selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, C1-C6 alkoxy; a is 0, 1, 2 or 3; When the dotted line in the benzene ring is a bond, R 3 , R 4 Each independently selected from none; When there is no dotted line in the benzene ring, R 3 , R 4 are independently selected from hydrogen, C1-C6 alkyl, or R 3 , R 4 Connect to form a 3- to 6-membered cycloalkyl group; 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 substituent of the aryl or heteroaryl is selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, C1-C6 alkoxy; X is selected from CR 7 R 8 、O、S、SO、SO2、NR 7 ; R 7 , R 8 Each of them is independently selected from hydrogen, halogen, C1-C6 alkyl, 3-6 membered cycloalkyl; n is 0, 1 or 2; R 6 is a substituent at any position on the benzene ring, and b is a substituent R 6 The number of Each R 6 Each of the following is independently selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, C1-C6 alkoxy; b is 0, 1, 2, or 3; Ring A and Ring B are independently selected from 4- to 12-membered cycloalkyl and 4- to 12-membered heterocycloalkyl; M is selected from None, CR 9 R 10 、O、S、SO、SO2、NR 9 ; R 9 , R 10 are independently selected from hydrogen, C1-C6 alkyl; E 3 is a substituent at any position on the benzene ring, and c is a substituent E 3 The number of Each E 3 are independently selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6-membered cycloalkyl, C1-C6 alkoxy; or any two E 3 Connect to form 3-6 membered cycloalkyl, 6-10 membered aryl, 4-12 membered heterocycloalkyl, 5-8 membered heteroaryl; c is 0, 1, 2, or 3; When there is no dashed line between Y and W, W is NH and Y is halogen; When the dashed 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 independently selected from hydrogen, C1-C6 alkyl; R 11 , R 12 are independently selected from hydrogen, C1-C6 alkyl; R 21 is selected from hydrogen or deuterium; The heteroatom of the heteroaryl group is O, N or S; the number of the heteroatoms is 1, 2 or 3; The heteroatom of the heterocycloalkyl group is N; the number of the heteroatoms is 1, 2 or 3.

4. The pharmaceutical composition according to claim 3, characterized in that: The compound is shown in formula (II): in, R 1 is selected from hydrogen, C1-C6 alkyl, hydroxy, amino, carboxyl, C1-C6 alkoxy, boric acid, -OR'; R' is selected from phenyl, benzyl; R 2 is a substituent at any position on the benzene ring, a is a substituent R 2 The number of Each R 2 Each of the following is independently selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, C1-C6 alkoxy; a is 0, 1, 2 or 3; When the dotted line in the benzene ring is a bond, R 3 , R 4 Each independently selected from none; When there is no dotted line in the benzene ring, R 3 , R 4 are independently selected from hydrogen, C1-C6 alkyl, or R 3 , R 4 Connect to form a 3- to 6-membered cycloalkyl group; 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 substituent of the aryl or heteroaryl is selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, C1-C6 alkoxy; X is selected from CR 7 R 8 、O、S、SO、SO2、NR 7 ; R 7 , R 8 Each of them is independently selected from hydrogen, halogen, C1-C6 alkyl, 3-6 membered cycloalkyl; n is 0, 1 or 2; R 6 is a substituent at any position on the benzene ring, and b is a substituent R 6 The number of Each R 6 Each of the following is independently selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, C1-C6 alkoxy; b is 0, 1, 2, or 3; Ring A and Ring B are independently selected from 4- to 12-membered cycloalkyl and 4- to 12-membered heterocycloalkyl; M is selected from None, CR 9 R 10 、O、S、SO、SO2、NR 9 ; R 9 , R 10 are independently selected from hydrogen, C1-C6 alkyl; E 3 is a substituent at any position on the benzene ring, and c is a substituent E 3 The number of Each E 3 are independently selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6-membered cycloalkyl, C1-C6 alkoxy; or any two E 3 Connect to form 3-6 membered cycloalkyl, 6-10 membered aryl, 4-12 membered heterocycloalkyl, 5-8 membered heteroaryl; c is 0, 1, 2, or 3; Y is absent, CR Y1 R Y2 , C(O), -CR 11 =CR 12 -, -CR 11 =N-, -N=N-, -OC(O)-; R Y1 , R Y2 are independently selected from hydrogen, C1-C6 alkyl; R 11 , R 12 are independently selected from hydrogen, C1-C6 alkyl; The heteroatom of the heteroaryl group is O, N or S; the number of the heteroatoms is 1, 2 or 3; The heteroatom of the heterocycloalkyl group is N; the number of the heteroatoms is 1, 2 or 3.

5. The pharmaceutical composition according to claim 4, characterized in that: The compound is shown in formula (III): in, R 2 is a substituent at any position on the benzene ring, a is a substituent R 2 The number of Each R 2 Each of the following is independently selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, C1-C6 alkoxy; a is 0, 1, 2 or 3; When the dotted line in the benzene ring is a bond, R 3 , R 4 Each independently selected from none; When there is no dotted line in the benzene ring, R 3 , R 4 are independently selected from hydrogen, C1-C6 alkyl, or R 3 , R 4 Connect to form a 3- to 6-membered cycloalkyl group; 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 substituent of the aryl or heteroaryl is selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, C1-C6 alkoxy; X is selected from CR 7 R 8 、O、S、SO、SO2、NR 7 ; R 7 , R 8 Each of them is independently selected from hydrogen, halogen, C1-C6 alkyl, 3-6 membered cycloalkyl; n is 0, 1 or 2; R 6 is a substituent at any position on the benzene ring, and b is a substituent R 6 The number of Each R 6 Each of the following is independently selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, C1-C6 alkoxy; b is 0, 1, 2, or 3; Ring A and Ring B are independently selected from 4- to 12-membered cycloalkyl and 4- to 12-membered heterocycloalkyl; M is selected from None, CR 9 R 10 、O、S、SO、SO2、NR 9 ; R 9 , R 10 are independently selected from hydrogen, C1-C6 alkyl; E 3 is a substituent at any position on the benzene ring, and c is a substituent E 3 The number of Each E 3 are independently selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6-membered cycloalkyl, C1-C6 alkoxy; or any two E 3 Connect to form 3-6 membered cycloalkyl, 6-10 membered aryl, 4-12 membered heterocycloalkyl, 5-8 membered heteroaryl; c is 0, 1, 2, or 3; Y is absent, CR Y1 R Y2 , C(O), -CR 11 =CR 12 -, -CR 11 =N-, -N=N-, -OC(O)-; R Y1 , R Y2 are independently selected from hydrogen, C1-C6 alkyl; R 11 , R 12 are independently selected from hydrogen, C1-C6 alkyl; The heteroatom of the heteroaryl group is O, N or S; the number of the heteroatoms is 1, 2 or 3; The heteroatom of the heterocycloalkyl group is N; the number of heteroatoms is 1, 2 or 3; Preferably, R 5 is selected from 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 substituent of the phenyl, thienyl, furanyl, pyrrolyl, pyrimidinyl, pyridazinyl, pyrazolyl or pyrazinyl is selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, C1-C6 alkoxy; X is selected from CH2, CF2, O, S, SO, SO2, NR 7 ; R 7 Selected from hydrogen, halogen, C1-C6 alkyl, 3-6 membered cycloalkyl; Ring A and ring B are independently selected from 4-12 membered cycloalkyl and 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 heteroatom N.

6. The pharmaceutical composition according to claim 5, characterized in that: The compound is shown in formula (IV): in, R 2 is a substituent at any position on the benzene ring, a is a substituent R 2 The number of Each R 2 Each of the following is independently selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, C1-C6 alkoxy; a is 0, 1, 2 or 3; R 3 , R 4 are independently selected from hydrogen, C1-C6 alkyl; or R 3 , R 4 Connect to form a 3- to 6-membered cycloalkyl group; 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 substituent of the aryl or heteroaryl is selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, C1-C6 alkoxy; X is selected from CR 7 R 8 、O、S、SO、SO2、NR 7 ; R 7 , R 8 Each of them is independently selected from hydrogen, halogen, C1-C6 alkyl, 3-6 membered cycloalkyl; n is 0, 1 or 2; R 6 is a substituent at any position on the benzene ring, and b is a substituent R 6 The number of Each R 6 Each of the following is independently selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, C1-C6 alkoxy; b is 0, 1, 2, or 3; Ring A and Ring B are independently selected from 4- to 12-membered cycloalkyl and 4- to 12-membered heterocycloalkyl; M is selected from None, CR 9 R 10 、O、S、SO、SO2、NR 9 ; R 9 , R 10 are independently selected from hydrogen, C1-C6 alkyl; E 3 is a substituent at any position on the benzene ring, and c is a substituent E 3 The number of Each E 3 are independently selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6-membered cycloalkyl, C1-C6 alkoxy; or any two E 3 Connect to form 3-6 membered cycloalkyl, 6-10 membered aryl, 4-12 membered heterocycloalkyl, 5-8 membered heteroaryl; c is 0, 1, 2, or 3; Y is absent, CR Y1 R Y2 , C(O), -CR 11 =CR 12 -, -CR 11 =N-, -N=N-, -OC(O)-; R Y1 , R Y2 are independently selected from hydrogen, C1-C6 alkyl; R 11 , R 12 are independently selected from hydrogen, C1-C6 alkyl; The heteroatom of the heteroaryl group is O, N or S; the number of the heteroatoms is 1, 2 or 3; The heteroatom of the heterocycloalkyl group is N; the number of heteroatoms is 1, 2 or 3; Preferably, R 5 is selected from 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 substituent of the phenyl, thienyl, furanyl, pyrrolyl, pyrimidinyl, pyridazinyl, pyrazolyl or pyrazinyl is selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, C1-C6 alkoxy; X is selected from CH2, CF2, O, S, SO, SO2, NR 7 ; R 7 Selected from hydrogen, halogen, C1-C6 alkyl, 3-6 membered cycloalkyl; Ring A and ring B are independently selected from 4-12 membered cycloalkyl and 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 heteroatom N.

7. The pharmaceutical composition according to claim 6, characterized in that: The compound is shown in formula (V): in, R 2 is a substituent at any position on the benzene ring, a is a substituent R 2 The number of Each R 2 Each of them is independently selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, C1-C6 alkoxy; a is 0, 1, 2 or 3; R 3 , R 4 are independently selected from hydrogen, C1-C6 alkyl, or R 3 , R 4 Connect to form a 3- to 6-membered cycloalkyl group; 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 substituent of the aryl or heteroaryl is selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, C1-C6 alkoxy; X is selected from CR 7 R 8 、O、S、SO、SO2、NR 7 ; R 7 , R 8 Each of them is independently selected from hydrogen, halogen, C1-C6 alkyl, 3-6 membered cycloalkyl; n is 0, 1 or 2; R 6 is a substituent at any position on the benzene ring, and b is a substituent R 6 The number of Each R 6 Each of them is independently selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, C1-C6 alkoxy; b is 0, 1, 2, or 3; Ring A and Ring B are independently selected from 4- to 12-membered cycloalkyl and 4- to 12-membered heterocycloalkyl; M is selected from None, CR 9 R 10 、O、S、SO、SO2、NR 9 ; R 9 , R 10 are independently selected from hydrogen, C1-C6 alkyl; E 3 is a substituent at any position on the benzene ring, and c is a substituent E 3 The number of Each E 3 are independently selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6-membered cycloalkyl, C1-C6 alkoxy; or any two E 3 Connect to form 3-6 membered cycloalkyl, 6-10 4- to 12-membered heterocycloalkyl, 5- to 8-membered heteroaryl; c is 0, 1, 2, or 3; Y is absent, CR Y1 R Y2 , C(O), -CR 11 =CR 12 -, -CR 11 =N-, -N=N-, -OC(O)-; R Y1 , R Y2 are independently selected from hydrogen, C1-C6 alkyl; R 11 , R 12 are independently selected from hydrogen, C1-C6 alkyl; The heteroatom of the heteroaryl group is O, N or S; the number of the heteroatoms is 1, 2 or 3; The heteroatom of the heterocycloalkyl group is N; the number of heteroatoms is 1, 2 or 3; Preferably, R 5 is selected from 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 substituent of the phenyl, thienyl, furanyl, pyrrolyl, pyrimidinyl, pyridazinyl, pyrazolyl or pyrazinyl is selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, C1-C6 alkoxy; X is selected from CH2, CF2, O, S, SO, SO2, NR 7 ; R 7 Selected from hydrogen, halogen, C1-C6 alkyl, 3-6 membered cycloalkyl; Ring A and ring B are independently selected from 4-12 membered cycloalkyl and 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 heteroatom N.

8. The pharmaceutical composition according to claim 7, characterized in that: The compound is shown in formula (VI): in, R 2 is a substituent at any position on the benzene ring, a is a substituent R 2 The number of Each R 2 Each of them is independently selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, C1-C6 alkoxy; a is 0, 1, 2 or 3; R 3 , R 4 are independently selected from hydrogen, C1-C6 alkyl, or R 3 , R 4 Connect to form a 3- to 6-membered cycloalkyl group; R 5 Selected from C1-C6 alkyl, 3-6 membered cycloalkyl, trifluoromethyl, trifluoroethyl, substituted or unsubstituted substituted 6-10 membered aryl, substituted or unsubstituted 5-8 membered heteroaryl; the substituent of the aryl or heteroaryl is selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, C1-C6 alkoxy; X is selected from CR 7 R 8 、O、S、SO、SO2、NR 7 ; R 7 , R 8 Each of them is independently selected from hydrogen, halogen, C1-C6 alkyl, 3-6 membered cycloalkyl; R 6 is a substituent at any position on the benzene ring, and b is a substituent R 6 The number of Each R 6 Each of them is independently selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, C1-C6 alkoxy; b is 0, 1, 2, or 3; Ring A and Ring B are independently selected from 4- to 12-membered cycloalkyl and 4- to 12-membered heterocycloalkyl; M is selected from None, CR 9 R 10 、O、S、SO、SO2、NR 9 ; R 9 , R 10 are independently selected from hydrogen, C1-C6 alkyl; E 3 is a substituent at any position on the benzene ring, and c is a substituent E 3 The number of Each E 3 are independently selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6-membered cycloalkyl, C1-C6 alkoxy; or any two E 3 Connect to form 3-6 membered cycloalkyl, 6-10 membered aryl, 4-12 membered heterocycloalkyl, 5-8 membered heteroaryl; c is 0, 1, 2, or 3; Y is absent, CR Y1 R Y2 , C(O), -CR 11 =CR 12 -, -CR 11 =N-, -N=N-, -OC(O)-; R Y1 , R Y2 are independently selected from hydrogen, C1-C6 alkyl; R 11 , R 12 are independently selected from hydrogen, C1-C6 alkyl; The heteroatom of the heteroaryl group is O, N or S; the number of the heteroatoms is 1, 2 or 3; The heteroatom of the heterocycloalkyl group is N; the number of heteroatoms is 1, 2 or 3; Preferably, R 5 is selected from 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 substituent of the phenyl, thienyl, furanyl, pyrrolyl, pyrimidinyl, pyridazinyl, pyrazolyl or pyrazinyl is selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, C1-C6 alkoxy; X is selected from CH2, CF2, O, S, SO, SO2, NR 7 ; R 7 Selected from hydrogen, halogen, C1-C6 alkyl, 3-6 membered cycloalkyl; Ring A and ring B are independently selected from 4-12 membered cycloalkyl and 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 heteroatom N.

9. The pharmaceutical composition according to claim 8, characterized in that: The compound is shown in formula (VII): in, R 3 , R 4 are independently selected from hydrogen, C1-C6 alkyl, or R 3 , R 4 Connect to form a 3- to 6-membered cycloalkyl group; 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 substituent of the aryl or heteroaryl is selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, C1-C6 alkoxy; X is selected from CR 7 R 8 、O、S、SO、SO2、NR 7 ; R 7 , R 8 Each of them is independently selected from hydrogen, halogen, C1-C6 alkyl, 3-6 membered cycloalkyl; R 6 is a substituent at any position on the benzene ring, and b is a substituent R 6 The number of Each R 6 Each of them is independently selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, C1-C6 alkoxy; b is 0, 1, 2, or 3; Ring A and Ring B are independently selected from 4- to 12-membered cycloalkyl and 4- to 12-membered heterocycloalkyl; M is selected from None, CR 9 R 10 、O、S、SO、SO2、NR 9 ; R 9 , R 10 are independently selected from hydrogen, C1-C6 alkyl; Y is absent, CR Y1 R Y2 , C(O), -CR 11 =CR 12 -, -CR 11 =N-, -N=N-, -OC(O)-; R Y1 , R Y2 are independently selected from hydrogen, C1-C6 alkyl; R 11 , R 12 are independently selected from hydrogen, C1-C6 alkyl; The heteroatom of the heteroaryl group is O, N or S; the number of the heteroatoms is 1, 2 or 3; The heteroatom of the heterocycloalkyl group is N; the number of heteroatoms is 1, 2 or 3; Preferably, R 5 is selected from 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 substituent of the phenyl, thienyl, furanyl, pyrrolyl, pyrimidinyl, pyridazinyl, pyrazolyl or pyrazinyl is selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, C1-C6 alkoxy; X is selected from CH2, CF2, O, S, SO, SO2, NR 7 ; R 7 Selected from hydrogen, halogen, C1-C6 alkyl, 3-6 membered cycloalkyl; Ring A and ring B are independently selected from 4-12 membered cycloalkyl and 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 heteroatom N.

10. The pharmaceutical composition according to claim 9, characterized in that: The compound is shown in formula (VIII): in, R 3 , R 4 are independently selected from hydrogen, C1-C6 alkyl; or R 3 , R 4 Connect to form a 3- to 6-membered cycloalkyl group; 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 substituent of the aryl or heteroaryl is selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, C1-C6 alkoxy; X is selected from CR 7 R 8 、O、S、SO、SO2、NR 7 ; R 7 , R 8 Each of them is independently selected from hydrogen, halogen, C1-C6 alkyl, 3-6 membered cycloalkyl; Ring A and Ring B are independently selected from 4- to 12-membered cycloalkyl and 4- to 12-membered heterocycloalkyl; M is selected from None, CR 9 R 10 、O、S、SO、SO2、NR 9 ; R 9 , R 10 are independently selected from hydrogen, C1-C6 alkyl; Y is absent, CR Y1 R Y2 , C(O), -CR 11 =CR 12 -, -CR 11 =N-, -N=N-, -OC(O)-; R Y1 , R Y2 are independently selected from hydrogen, C1-C6 alkyl; R 11 , R 12 are independently selected from hydrogen, C1-C6 alkyl; The heteroatom of the heteroaryl group is O, N or S; the number of the heteroatoms is 1, 2 or 3; The heteroatom of the heterocycloalkyl group is N; the number of heteroatoms is 1, 2 or 3; Preferably, R 5 is selected from 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 phenyl, thienyl, furanyl, pyrrolyl, pyrimidinyl, pyridazinyl The substituent of the oxazinyl, pyrazolyl or pyrazinyl group is selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, C1-C6 alkoxy; X is selected from CH2, CF2, O, S, SO, SO2, NR 7 ; R 7 Selected from hydrogen, halogen, C1-C6 alkyl, 3-6 membered cycloalkyl; Ring A and ring B are independently selected from 4-12 membered cycloalkyl and 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 heteroatom N.

11. The pharmaceutical composition according to claim 9, characterized in that: The compound is shown in formula (IX): in, R 3 , R 4 are independently selected from hydrogen, C1-C6 alkyl, or R 3 , R 4 Connect to form a 3- to 6-membered cycloalkyl group; 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 substituent of the aryl or heteroaryl is selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, C1-C6 alkoxy; X is selected from CR 7 R 8 、O、S、SO、SO2、NR 7 ; R 7 , R 8 Each of them is independently selected from hydrogen, halogen, C1-C6 alkyl, 3-6 membered cycloalkyl; R 6 is a substituent at any position on the benzene ring, and b is a substituent R 6 The number of Each R 6 Each of them is independently selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, C1-C6 alkoxy; b is 0, 1, 2, or 3; Ring A and Ring B are independently selected from 4- to 12-membered cycloalkyl and 4- to 12-membered heterocycloalkyl; Y is absent, CR Y1 R Y2 , C(O), -CR 11 =CR 12 -, -CR 11 =N-, -N=N-, -OC(O)-; R Y1 , R Y2 are independently selected from hydrogen, C1-C6 alkyl; R 11 , R 12 are independently selected from hydrogen, C1-C6 alkyl; The heteroatom of the heteroaryl group is O, N or S; the number of the heteroatoms is 1, 2 or 3; The heteroatom of the heterocycloalkyl group is N; the number of heteroatoms is 1, 2 or 3; Preferably, R 5 is selected from 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 substituent of the phenyl, thienyl, furanyl, pyrrolyl, pyrimidinyl, pyridazinyl, pyrazolyl or pyrazinyl is selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, C1-C6 alkoxy; X is selected from CH2, CF2, O, S, SO, SO2, NR 7 ; R 7 Selected from hydrogen, halogen, C1-C6 alkyl, 3-6 membered cycloalkyl; Ring A and ring B are independently selected from 4-12 membered cycloalkyl and 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 heteroatom N.

12. The pharmaceutical composition according to claim 11, characterized in that: The compound is shown in formula (X): in, R 3 , R 4 are independently selected from hydrogen, C1-C6 alkyl; or R 3 , R 4 Connect to form a 3- to 6-membered cycloalkyl group; 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 substituent of the aryl or heteroaryl is selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, C1-C6 alkoxy; X is selected from CR 7 R 8 、O、S、SO、SO2、NR 7 ; R 7 , R 8 Each of them is independently selected from hydrogen, halogen, C1-C6 alkyl, 3-6 membered cycloalkyl; Ring A and Ring B are independently selected from 4- to 12-membered cycloalkyl and 4- to 12-membered heterocycloalkyl; Y is absent, CR Y1 R Y2 , C(O), -CR 11 =CR 12 -, -CR 11 =N-, -N=N-, -OC(O)-; R Y1 , R Y2 are independently selected from hydrogen, C1-C6 alkyl; R 11 , R 12 are independently selected from hydrogen, C1-C6 alkyl; The heteroatom of the heteroaryl group is O, N or S; the number of the heteroatoms is 1, 2 or 3; The heteroatom of the heterocycloalkyl group is N; the number of heteroatoms is 1, 2 or 3; Preferably, R 5 Selected from C1-C6 alkyl, 3-6 membered cycloalkyl, trifluoromethyl, trifluoroethyl, substituted or unsubstituted substituted 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 substituent of the phenyl, thienyl, furanyl, pyrrolyl, pyrimidinyl, pyridazinyl, pyrazolyl or pyrazinyl is selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, C1-C6 alkoxy; X is selected from CH2, CF2, O, S, SO, SO2, NR 7 ; R 7 Selected from hydrogen, halogen, C1-C6 alkyl, 3-6 membered cycloalkyl; Ring A and ring B are independently selected from 4-12 membered cycloalkyl and 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 heteroatom N.

13. The pharmaceutical composition according to claim 8, characterized in that: The compound is shown in formula (XI): in, R 2 is a substituent at any position on the benzene ring, a is a substituent R 2 The number of Each R 2 Each of them is independently selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, C1-C6 alkoxy; a is 0, 1, 2 or 3; R 3 , R 4 are independently selected from hydrogen, C1-C6 alkyl; or R 3 , R 4 Connect to form a 3- to 6-membered cycloalkyl group; R 11 is a substituent at any position on the benzene ring, and d is a substituent R 11 The number of Each R 11 Each of them is independently selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, 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 Each of them is independently selected from hydrogen, halogen, C1-C6 alkyl, 3-6 membered cycloalkyl; R 6 is a substituent at any position on the benzene ring, and b is a substituent R 6 The number of Each R 6 Each of them is independently selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, C1-C6 alkoxy; b is 0, 1, 2, or 3; Ring A and Ring B are independently selected from 4- to 12-membered cycloalkyl and 4- to 12-membered heterocycloalkyl; M is selected from None, CR 9 R 10 、O、S、SO、SO2、NR 9 ; R 9 , R 10 are independently selected from hydrogen, C1-C6 alkyl; E 3 is a substituent at any position on the benzene ring, and c is a substituent E 3 The number of Each E 3 are independently selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6-membered cycloalkyl, C1-C6 alkoxy; or any two E 3 Connect to form 3-6 membered cycloalkyl, 6-10 membered aryl, 4-12 membered heterocycloalkyl, 5-8 membered heteroaryl; c is 0, 1, 2, or 3; Y is absent, CR Y1 R Y2 , C(O), -CR 11 =CR 12 -, -CR 11 =N-, -N=N-, -OC(O)-; R Y1 , R Y2 are independently selected from hydrogen, C1-C6 alkyl; R 11 , R 12 are independently selected from hydrogen, C1-C6 alkyl; The heteroatom of the heteroaryl group is O, N or S; the number of the heteroatoms is 1, 2 or 3; The heteroatom of the heterocycloalkyl group is N; the number of 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, C1-C6 alkyl, 3-6 membered cycloalkyl; Ring A and ring B are independently selected from 4-12 membered cycloalkyl and 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 heteroatom N.

14. The pharmaceutical composition according to claim 13, characterized in that: The compound is shown in formula (XII): in, R 2 is a substituent at any position on the benzene ring, a is a substituent R 2 The number of Each R 2 Each of the following is independently selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, C1-C6 alkoxy; a is 0, 1, 2 or 3; R 3 , R 4 are independently selected from hydrogen, C1-C6 alkyl, or R 3 , R 4 Connect to form a 3- to 6-membered cycloalkyl group; R 11 is a substituent at any position on the benzene ring, and d is a substituent R 11 The number of Each R 11 Each of them is independently selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, 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 Each of them is independently selected from hydrogen, halogen, C1-C6 alkyl, 3-6 membered cycloalkyl; R 6 is a substituent at any position on the benzene ring, and b is a substituent R 6 The number of Each R 6 Each of them is independently selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, 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 independently selected from hydrogen, C1-C6 alkyl; R 12 Selected from hydrogen, halogen, C1-C6 alkyl, hydroxyl; m1, m2, m3, m4, m5, m6 are independently selected from 0, 1, 2 or 3; E 3 is a substituent at any position on the benzene ring, and c is a substituent E 3 The number of Each E 3 are independently selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6-membered cycloalkyl, C1-C6 alkoxy; or any two E 3 Connect to form 3-6 membered cycloalkyl, 6-10 membered aryl, 4-12 membered heterocycloalkyl, 5-8 membered heteroaryl; c is 0, 1, 2, or 3; Y is absent, CR Y1 R Y2 , C(O), -CR 11 =CR 12 -, -CR 11 =N-, -N=N-, -OC(O)-; R Y1 , R Y2 are independently selected from hydrogen, C1-C6 alkyl; R 11 , R 12 are independently selected from hydrogen, C1-C6 alkyl; The heteroatom of the heteroaryl group is O, N or S; the number of the heteroatoms is 1, 2 or 3; The heteroatom of the heterocycloalkyl group is N; the number of 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, C1-C6 alkyl, 3-6 membered cycloalkyl; Y is absent, CR Y1 R Y2 , C(O), -CR 11 =CR 12 -, -CR 11 =N-, -N=N-, -OC(O)-; R Y1 , R Y2 are independently selected from hydrogen, C1-C6 alkyl; R 11 , R 12 Each is independently selected from hydrogen and C1-C6 alkyl.

15. The pharmaceutical composition according to claim 14, characterized in that: The compound is shown in formula (XIII): in, R 2 is a substituent at any position on the benzene ring, a is a substituent R 2 The number of Each R 2 Each of the following is independently selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, C1-C6 alkoxy; a is 0, 1, 2 or 3; R 3 , R 4 are independently selected from hydrogen, C1-C6 alkyl, or R 3 , R 4 Connect to form a 3- to 6-membered cycloalkyl group; R 11 is a substituent at any position on the benzene ring, and d is a substituent R 11 The number of Each R 11 Each of them is independently selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, 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 Each of them is independently selected from hydrogen, halogen, C1-C6 alkyl, 3-6 membered cycloalkyl; R 6 is a substituent at any position on the benzene ring, and b is a substituent R 6 The number of Each R 6 Each of the following is independently selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, C1-C6 alkoxy; b is 0, 1, 2, or 3; R 12 Selected from hydrogen, halogen, C1-C6 alkyl, hydroxyl; m1, m2, m3, m4, m5, m6 are independently selected from 0, 1, 2 or 3; E 3 is a substituent at any position on the benzene ring, and c is a substituent E 3 The number of Each E 3 are independently selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6-membered cycloalkyl, C1-C6 alkoxy; or any two E 3 Connect to form 3-6 membered cycloalkyl, 6-10 membered aryl, 4-12 membered heterocycloalkyl, 5-8 membered heteroaryl; 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 independently selected from hydrogen, C1-C6 alkyl; R 11 , R 12 are independently selected from hydrogen, C1-C6 alkyl; The heteroatom of the heteroaryl group is O, N or S; the number of the heteroatoms is 1, 2 or 3; The heteroatom of the heterocycloalkyl group is N; the number of 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, C1-C6 alkyl, 3-6 membered cycloalkyl; Y is absent, CR Y1 R Y2 , C(O), -CR 11 =CR 12 -, -CR 11 =N-, -N=N-, -OC(O)-; R Y1 , R Y2 are independently selected from hydrogen, C1-C6 alkyl; R 11 , R 12 Each is independently selected from hydrogen and C1-C6 alkyl.

16. The pharmaceutical composition according to claim 14, characterized in that: The compound is shown in formula (XIV): in, R 2 is a substituent at any position on the benzene ring, a is a substituent R 2 The number of Each R 2 Each of the following is independently selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, C1-C6 alkoxy; a is 0, 1, 2 or 3; R 3 , R 4 are independently selected from hydrogen, C1-C6 alkyl, or R 3 , R 4 Connect to form a 3- to 6-membered cycloalkyl group; R 11 is a substituent at any position on the benzene ring, and d is a substituent R 11 The number of Each R 11 Each of the following is independently selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, 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 Each of them is independently selected from hydrogen, halogen, C1-C6 alkyl, 3-6 membered cycloalkyl; R 6 is a substituent at any position on the benzene ring, and b is a substituent R 6 The number of Each R 6 Each of the following is independently selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, C1-C6 alkoxy; b is 0, 1, 2, or 3; R 12 Selected from hydrogen, halogen, C1-C6 alkyl, hydroxyl; m1, m2, m3, m4, m5, m6 are independently selected from 0, 1, 2 or 3; E 3 is a substituent at any position on the benzene ring, and c is a substituent E 3 The number of Each E 3 are independently selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6-membered cycloalkyl, C1-C6 alkoxy; or any two E 3 Connect to form 3-6 membered cycloalkyl, 6-10 membered aryl, 4-12 membered heterocycloalkyl, 5-8 membered heteroaryl; c is 0, 1, 2, or 3; Y is absent, CR Y1 R Y2 , C(O), -CR 11 =CR 12 -, -CR 11 =N-, -N=N-, -OC(O)-; R Y1 , R Y2 are independently selected from hydrogen, C1-C6 alkyl; R 11 , R 12 are independently selected from hydrogen, C1-C6 alkyl; The heteroatom of the heteroaryl group is O, N or S; the number of the heteroatoms is 1, 2 or 3; The heteroatom of the heterocycloalkyl group is N; the number of 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, C1-C6 alkyl, 3-6 membered cycloalkyl; Y is absent, CR Y1 R Y2 , C(O), -CR 11 =CR 12 -, -CR 11 =N-, -N=N-, -OC(O)-; R Y1 , R Y2 are independently selected from hydrogen, C1-C6 alkyl; R 11 , R 12 Each is independently selected from hydrogen and C1-C6 alkyl.

17. The pharmaceutical composition according to claim 8, characterized in that: The compound is shown in formula (XV): in, R 2 is a substituent at any position on the benzene ring, a is a substituent R 2 The number of Each R 2 Each of them is independently selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, C1-C6 alkoxy; a is 0, 1, 2 or 3; R 3 , R 4 are independently selected from hydrogen, C1-C6 alkyl, or R 3 , R 4 Connect to form a 3- to 6-membered cycloalkyl group; R 11 is a substituent at any position on the thiophene ring, and d is a substituent R 11 The number of Each R 11 Each of them is independently selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, 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 Each of them is independently selected from hydrogen, halogen, C1-C6 alkyl, 3-6 membered cycloalkyl; R 6 is a substituent at any position on the benzene ring, and b is a substituent R 6 The number of Each R 6 Each of them is independently selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, C1-C6 alkoxy; b is 0, 1, 2, or 3; Ring A and Ring B are independently selected from 4- to 12-membered cycloalkyl and 4- to 12-membered heterocycloalkyl; M is selected from None, CR 9 R 10 、O、S、SO、SO2、NR 9 ; R 9 , R 10 are independently selected from hydrogen, C1-C6 alkyl; E 3 is a substituent at any position on the benzene ring, and c is a substituent E 3 The number of Each E 3 are independently selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6-membered cycloalkyl, C1-C6 alkoxy; or any two E 3 Connect to form 3-6 membered cycloalkyl, 6-10 membered aryl, 4-12 membered heterocycloalkyl, 5-8 membered heteroaryl; c is 0, 1, 2, or 3; Y is absent, CR Y1 R Y2 , C(O), -CR 11 =CR 12 -, -CR 11 =N-, -N=N-, -OC(O)-; R Y1 , R Y2 are independently selected from hydrogen, C1-C6 alkyl; R 11 , R 12 are independently selected from hydrogen, C1-C6 alkyl; The heteroatom of the heteroaryl group is O, N or S; the number of the heteroatoms is 1, 2 or 3; The heteroatom of the heterocycloalkyl group is N; the number of 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, C1-C6 alkyl, 3-6 membered cycloalkyl; Ring A and ring B are independently selected from 4-12 membered cycloalkyl and 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 heteroatom N.

18. The pharmaceutical composition according to claim 8, characterized in that: The compound is shown in formula (XVI): in, R 2 is a substituent at any position on the benzene ring, a is a substituent R 2 The number of Each R 2 Each of the following is independently selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, C1-C6 alkoxy; a is 0, 1, 2 or 3; R 3 , R 4 are independently selected from hydrogen, C1-C6 alkyl, or R 3 , R 4 Connect to form a 3- to 6-membered cycloalkyl group; R 11 is a substituent at any position on the thiophene ring, and d is a substituent R 11 The number of Each R 11 Each of the following is independently selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, 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 Each of them is independently selected from hydrogen, halogen, C1-C6 alkyl, 3-6 membered cycloalkyl; R 6 is a substituent at any position on the benzene ring, and b is a substituent R 6 The number of Each R 6 Each of them is independently selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, C1-C6 alkoxy; b is 0, 1, 2, or 3; Ring A and Ring B are independently selected from 4- to 12-membered cycloalkyl and 4- to 12-membered heterocycloalkyl; M is selected from None, CR 9 R 10 、O、S、SO、SO2、NR 9 ; R 9 , R 10 are independently selected from hydrogen, C1-C6 alkyl; E 3 is a substituent at any position on the benzene ring, and c is a substituent E 3 The number of Each E 3 are independently selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6-membered cycloalkyl, C1-C6 alkoxy; or any two E 3 Connect to form 3-6 membered cycloalkyl, 6-10 membered aryl, 4-12 membered heterocycloalkyl, 5-8 membered heteroaryl; c is 0, 1, 2, or 3; Y is absent, CR Y1 R Y2 , C(O), -CR 11 =CR 12 -, -CR 11 =N-, -N=N-, -OC(O)-; R Y1 , R Y2 are independently selected from hydrogen, C1-C6 alkyl; R 11 , R 12 are independently selected from hydrogen, C1-C6 alkyl; The heteroatom of the heteroaryl group is O, N or S; the number of the heteroatoms is 1, 2 or 3; The heteroatom of the heterocycloalkyl group is N; the number of 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, C1-C6 alkyl, 3-6 membered cycloalkyl; Ring A and ring B are independently selected from 4-12 membered cycloalkyl and 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 heteroatom N.

19. The pharmaceutical composition according to claim 4, characterized in that: The compound is represented by formula (XVII): in, R 3 , R 4 are independently selected from hydrogen, C1-C6 alkyl, or R 3 , R 4 Connect to form a 3- to 6-membered cycloalkyl group; X is selected from CR 7 R 8 、O、S、SO、SO2、NR 7 ; R 7 , R 8 Each of them is independently selected from hydrogen, halogen, C1-C6 alkyl, 3-6 membered cycloalkyl; R 11 is a substituent at any position on the benzene ring, and d is a substituent R 11 The number of 6 is a substituent at any position on the benzene ring, and b is a substituent R 6 The number of 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 Each of them is independently selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, C1-C6 alkoxy; and at least one of them is fluorine; Ring A and Ring B are independently selected from 4- to 12-membered cycloalkyl and 4- to 12-membered heterocycloalkyl; M is selected from None, CR 9 R 10 、O、S、SO、SO2、NR 9 ; R 9 , R 10 are independently selected from hydrogen, C1-C6 alkyl; Y is absent, CR Y1 R Y2 , C(O), -CR 11 =CR 12 -, -CR 11 =N-, -N=N-, -OC(O)-; R Y1 , R Y2 are independently selected from hydrogen, C1-C6 alkyl; R 11 , R 12 are independently selected from hydrogen, C1-C6 alkyl; The heteroatom of the heterocycloalkyl group is N; the number of 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, C1-C6 alkyl, 3-6 membered cycloalkyl; Ring A and ring B are independently selected from 4-12 membered cycloalkyl and 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 heteroatom N.

20. The pharmaceutical composition according to claim 19, characterized in that: The compound is shown in formula (XVIII): in, X is selected from CR 7 R 8 、O、S、SO、SO2、NR 7 ; R 7 , R 8 Each of them is independently selected from hydrogen, halogen, C1-C6 alkyl, 3-6 membered cycloalkyl; R 11 is a substituent at any position on the benzene ring, and d is a substituent R 11 The number of 6 is a substituent at any position on the benzene ring, and b is a substituent R 6 The number of 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 Each of them is independently selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, C1-C6 alkoxy; and at least one of them is fluorine; Ring A and Ring B are independently selected from 4- to 12-membered cycloalkyl and 4- to 12-membered heterocycloalkyl; M is selected from None, CR 9 R 10 ; R 9 , R 10 are independently selected from hydrogen, C1-C6 alkyl; Y is absent, CR Y1 R Y2 , C(O), -CR 11 =CR 12 -, -CR 11 =N-, -N=N-, -OC(O)-; R Y1 , R Y2 are independently selected from hydrogen, C1-C6 alkyl; R 11 , R 12 are independently selected from hydrogen, C1-C6 alkyl; The heteroatom of the heterocycloalkyl group is N; the number of 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 and 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 heteroatom N.

21. The pharmaceutical composition according to claim 4, characterized in that: The compound is represented by formula (XIX): in, R 1 Selected from hydrogen, C1-C6 alkyl, hydroxyl, amino or C1-C6 alkoxy, boric acid; R 2 is a substituent at any position on the benzene ring, a is a substituent R 2 The number of Each R 2 Each of the following is independently selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, C1-C6 alkoxy; a is 0, 1, 2 or 3; 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 substituent of the aryl or heteroaryl is selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, C1-C6 alkoxy; X is selected from CR 7 R 8 、O、S、SO、SO2、NR 7 ; R 7 , R 8 Each of them is independently selected from hydrogen, halogen, C1-C6 alkyl, 3-6 membered cycloalkyl; n is 0, 1 or 2; R 6 is a substituent at any position on the benzene ring, and b is a substituent R 6 The number of Each R 6 Each of the following is independently selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, C1-C6 alkoxy; b is 0, 1, 2, or 3; Ring A and Ring B are independently selected from 4- to 12-membered cycloalkyl and 4- to 12-membered heterocycloalkyl; M is selected from None, CR 9 R 10 、O、S、SO、SO2、NR 9 ; R 9 , R 10 are independently selected from hydrogen, C1-C6 alkyl; E 3 is a substituent at any position on the benzene ring, and c is a substituent E 3 The number of Each E 3 are independently selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6-membered cycloalkyl, C1-C6 alkoxy; or any two E 3 Connect to form 3-6 membered cycloalkyl, 6-10 membered aryl, 4-12 membered heterocycloalkyl, 5-8 membered heteroaryl; c is 0, 1, 2, or 3; Y is absent, CR Y1 R Y2 , C(O), -CR 11 =CR 12 -, -CR 11 =N-, -N=N-, -OC(O)-; R Y1 , R Y2 are independently selected from hydrogen, C1-C6 alkyl; R 11 , R 12 are independently selected from hydrogen, C1-C6 alkyl; The heteroatom of the heteroaryl group is O, N or S; the number of the heteroatoms is 1, 2 or 3; The heteroatom of the heterocycloalkyl group is N; the number of heteroatoms is 1, 2 or 3; Preferably, R 5 is selected from 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 substituent of phenyl, thienyl, furanyl, pyrrolyl, pyrimidinyl, pyridazinyl, pyrazolyl or pyrazinyl is selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, C1-C6 alkoxy.

22. The pharmaceutical composition according to claim 21, characterized in that: The compound is shown in formula (XX): in, 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 substituent of the aryl or heteroaryl is selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, C1-C6 alkoxy; X is selected from CR 7 R 8 、O、S、SO、SO2、NR 7 ; R 7 , R 8 Each of them is independently selected from hydrogen, halogen, C1-C6 alkyl, 3-6 membered cycloalkyl; R 6 is a substituent at any position on the benzene ring, and b is a substituent R 6 The number of Each R 6 Each of the following is independently selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, C1-C6 alkoxy; b is 0, 1, 2, or 3; Ring A and Ring B are independently selected from 4- to 12-membered cycloalkyl and 4- to 12-membered heterocycloalkyl; M is selected from None, CR 9 R 10 、O、S、SO、SO2、NR 9 ; R 9 , R 10 are independently selected from hydrogen, C1-C6 alkyl; Y is absent, CR Y1 R Y2 , C(O), -CR 11 =CR 12 -, -CR 11 =N-, -N=N-, -OC(O)-; R Y1 , R Y2 are independently selected from hydrogen, C1-C6 alkyl; R 11 , R 12 are independently selected from hydrogen, C1-C6 alkyl; The heteroatom of the heteroaryl group is O, N or S; the number of the heteroatoms is 1, 2 or 3; The heteroatom of the heterocycloalkyl group is N; the number of heteroatoms is 1, 2 or 3; Preferably, R 5 is selected from 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 substituent of the phenyl, thienyl, furanyl, pyrrolyl, pyrimidinyl, pyridazinyl, pyrazolyl or pyrazinyl is selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, C1-C6 alkoxy; X is selected from CH2, CF2, O, S, SO, SO2, NR 7 ; R 7 Selected from hydrogen, halogen, C1-C6 alkyl, 3-6 membered cycloalkyl; Ring A and ring B are independently selected from 4-12 membered cycloalkyl and 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 heteroatom N.

23. The pharmaceutical composition according to claim 22, characterized in that: The compound is shown in formula (XXI): in, R 11 is a substituent at any position on the benzene ring, and d is a substituent R 11 The number of Each R 11 Each of the following is independently selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, 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 Each of them is independently selected from hydrogen, halogen, C1-C6 alkyl, 3-6 membered cycloalkyl; R 6 is a substituent at any position on the benzene ring, and b is a substituent R 6 The number of Each R 6 Each of the following is independently selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, 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 independently selected from hydrogen, C1-C6 alkyl; m1, m2, m3, m4, m5, m6 are independently selected from 0, 1, 2 or 3; Y is absent, CR Y1 R Y2 , C(O), -CR 11 =CR 12 -, -CR 11 =N-, -N=N-, -OC(O)-; R Y1 , R Y2 are independently selected from hydrogen, C1-C6 alkyl; R 11 , R 12 are independently selected from hydrogen, C1-C6 alkyl; Preferably, X is selected from CH2, CF2, O, S, SO, SO2, NR 7 ; R 7 Selected from hydrogen, halogen, C1-C6 alkyl, 3-6 membered cycloalkyl.

24. The pharmaceutical composition according to any one of claims 3 to 23, characterized in that: The ring A and ring B are independently selected from the following structures:

25. The pharmaceutical composition according to any one of claims 3 to 23, characterized in that: Said Selected from the following structures:

26. The pharmaceutical composition according to any one of claims 3 to 23, characterized in that: The compound is one of the following compounds:

27. The pharmaceutical composition according to any one of claims 3 to 23, characterized in that: The compound is ARV-471, compound 63, compound 65 or compound 75; The structure of ARV-471 is The structure of compound 63 is The structure of compound 65 is The structure of compound 75 is 28. The pharmaceutical composition according to any one of claims 3 to 23, characterized in that: The salt is a pharmaceutically acceptable salt; the pharmaceutically acceptable salt is a phosphate, dextrorotatory camphorsulfonate, hydrochloride, hydrobromide, hydrofluoride, sulfate, nitrate, format, acetate, propionate, oxalate, malonate, succinate, fumarate, maleate, lactate, malate, tartrate, citrate, picrate, methanesulfonate, toluenesulfonate, benzenesulfonate, aspartate or glutamate of the compound.

29. The pharmaceutical composition according to claim 1 or 2, characterized in that: The mTOR inhibitors are Rapamycin, Everolimus, Dactolisib, AZD8055, Temsirolimus, PI-103, NU7441, Torin 2, KU-0063794, Torkinib, Ridaforolimus, Sapanisertib, Voxtalisib (XL765) Analogue, Torin 1. Omipalisib, OSI-027, PF-04691502, Apitolisib, GSK1059615, Gedatolisib, WYE-354, Vi stusertib, WYE-125132, PP121, WYE-687, WAY-600, ETP-46464, GDC-0349, XL388, PI3K / mTOR Inhibitor-2, MTI-31, PQR620, Compound 401, GNE-477, Bimiralisib, SF2523, CZ415, Paxalisib, CC-115, Onatasertib, Voxtalisib, Zotarolimus, BGT226, Palomid 529, Nitazoxanide, 4EGI-1, MHY-1685, COH-SR4, JR-AB2-011, ABTL-0812, mTOR inhibitor-1, Astragaloside IV, Samotolisib, Chrysophanic Acid or its optical isomers, salts, hydrates or solvates thereof; Preferably, the mTOR inhibitor is Rapamycin, Everolimus or an optical isomer thereof, a salt thereof, a hydrate thereof, or a solvate thereof.

30. The pharmaceutical composition according to claim 1 or 2, characterized in that: When the estrogen receptor degrader is ARV-471 or its optical isomers, salts, hydrates or solvates, and the mTOR inhibitor is Rapamycin or its optical isomers, salts, hydrates or solvates, the molar ratio of the estrogen receptor degrader to the mTOR inhibitor is 1:0.011 to 1:2.7; preferably, the molar ratio is 1:0.011, 1:0.3 or 1:2.7; Alternatively, the estrogen receptor degrader is ARV-471 or its optical isomers, salts, hydrates or solvates, and the mTOR inhibitor is Everolimus or its optical isomers, salts, hydrates or solvates. In the case of hydrates and solvates thereof, the molar ratio of the estrogen receptor degrader to the mTOR inhibitor is 1:0.033 to 1:8; the molar ratio is preferably 1:0.033, 1:0.89, or 1:

8.

31. The pharmaceutical composition according to claim 1 or 2, characterized in that: When the estrogen receptor degrader is compound 75 or its optical isomer, salt, hydrate or solvate, and the mTOR inhibitor is rapamycin or its optical isomer, salt, hydrate or solvate, the molar ratio of the estrogen receptor degrader to the mTOR inhibitor is 1:0.011 to 1:2.7; preferably, the molar ratio is 1:0.011, 1:0.3 or 1:2.7; Alternatively, when the estrogen receptor degrader is compound 75 or its optical isomer, salt, hydrate or solvate, and the mTOR inhibitor is Everolimus or its optical isomer, salt, hydrate or solvate, the molar ratio of the estrogen receptor degrader to the mTOR inhibitor is 1:0.033 to 1:8; the molar ratio is preferably 1:0.033, 1:0.89 or 1:

8.

32. The pharmaceutical composition according to claim 1 or 2, characterized in that: When the estrogen receptor degrader is compound 65 or its optical isomer, salt, hydrate or solvate, and the mTOR inhibitor is rapamycin or its optical isomer, salt, hydrate or solvate, the molar ratio of the estrogen receptor degrader to the mTOR inhibitor is 1:0.011 to 1:2.7; preferably, the molar ratio is 1:0.011, 1:0.3 or 1:2.7; Alternatively, when the estrogen receptor degrader is compound 65 or its optical isomer, salt, hydrate or solvate, and the mTOR inhibitor is Everolimus or its optical isomer, salt, hydrate or solvate, the molar ratio of the estrogen receptor degrader to the mTOR inhibitor is 1:0.033 to 1:8; the molar ratio is preferably 1:0.033, 1:0.89 or 1:

8.

33. The pharmaceutical composition according to claim 1 or 2, characterized in that: When the estrogen receptor degrader is compound 63 or its optical isomer, salt, hydrate or solvate, and the mTOR inhibitor is rapamycin or its optical isomer, salt, hydrate or solvate, the molar ratio of the estrogen receptor degrader to the mTOR inhibitor is 1:0.011 to 1:2.7; preferably, the molar ratio is 1:0.011, 1:0.3 or 1:2.7; Alternatively, when the estrogen receptor degrader is compound 63 or its optical isomer, salt, hydrate or solvate, and the mTOR inhibitor is Everolimus or its optical isomer, salt, hydrate or solvate, the molar ratio of the estrogen receptor degrader to the mTOR inhibitor is 1:0.033 to 1:8; the molar ratio is preferably 1:0.033, 1:0.89 or 1:

8.

34. A method for preparing the pharmaceutical composition according to any one of claims 1 to 33, characterized in that: The method comprises the following steps: taking an estrogen receptor targeted degradation agent and an mTOR inhibitor according to a molar ratio and mixing them.

35. Use of the pharmaceutical composition according to any one of claims 1 to 33 in the preparation of an estrogen receptor degrader and / or a drug for treating estrogen receptor-related diseases.

36. Use of the pharmaceutical composition according to any one of claims 1 to 33 in the preparation of 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.

37. A pharmaceutical preparation for degrading estrogen receptors, characterized in that: The invention is a preparation prepared by taking the pharmaceutical composition according to any one of claims 1 to 33 as an active ingredient and adding pharmaceutically acceptable excipients or auxiliary ingredients.

38. A combined drug for degrading estrogen receptors, characterized in that: It contains an estrogen receptor targeted degradation agent and an mTOR inhibitor of the same or different specifications, which are administered simultaneously or separately, and a pharmaceutically acceptable carrier.

39. The combined drug according to claim 38, characterized in that: The molar ratio of the estrogen receptor targeted degradation agent to the mTOR inhibitor is 1:0011 to 1:8; Preferably, the molar ratio of the estrogen receptor targeted degrader to the mTOR inhibitor is 1:0.011 to 1:2.7 or 1:0.033 to 1:8; More preferably, the molar ratio of the estrogen receptor targeted degrader to the mTOR inhibitor is 1:0.011, 1:0.033, 1:0.3, 1:0.89, 1:2.7 or 1:

8.

40. The combined drug according to claim 38 or 39, characterized in that: The estrogen receptor targeted degradation agent is selected from the compound described in any one of claims 3 to 28, or an optical isomer thereof, or a salt thereof, or a hydrate thereof, or a solvate thereof; The mTOR inhibitors are Rapamycin, Everolimus, Dactolisib, AZD8055, Temsirolimus, PI-103, NU7441, Torin 2, KU-0063794, Torkinib, Ridaforolimus, Sapanisertib, Voxtalisib (XL765) Analogue, Torin 1. Omipalisib, OSI-027, PF-04691502, Apitolisib, GSK1059615, Gedatolisib, WYE-354, Vi stusertib, WYE-125132, PP121, WYE-687, WAY-600, ETP-46464, GDC-0349, XL388, PI3K / mTOR Inhibitor-2, MTI-31, PQR620, Compound 401, GNE-477, Bimiralisib, SF2523, CZ415, Paxalisib, CC-115, Onatasertib, Voxtalisib, Zotarolimus, BGT226, Palomid 529, Nitazoxanide, 4EGI-1, MHY-1685, COH-SR4, JR-AB2-011, ABTL-0812, mTOR inhibitor-1, Astragaloside IV, Samotolisib, Chrysophanic Acid or its optical isomers, salts, hydrates or solvates thereof; Preferably, the mTOR inhibitor is Rapamycin, Everolimus or an optical isomer thereof, a salt thereof, a hydrate thereof, or a solvate thereof.

41. The combined drug according to claim 40, characterized in that: When the estrogen receptor degrader is ARV-471 or its optical isomers, salts, hydrates or solvates, and the mTOR inhibitor is Rapamycin or its optical isomers, salts, hydrates or solvates, the molar ratio of the estrogen receptor degrader to the mTOR inhibitor is 1:0.011 to 1:2.7; preferably, the molar ratio is 1:0.011, 1:0.3 or 1:2.7; Alternatively, when the estrogen receptor degrader is ARV-471 or an optical isomer, a salt, a hydrate or a solvate thereof, and the mTOR inhibitor is Everolimus or an optical isomer, a salt, a hydrate or a solvate thereof, the molar ratio of the estrogen receptor degrader to the mTOR inhibitor is 1:0.033~1:8; The molar ratio is preferably 1:0.033, 1:0.89, 1:

8.

42. The combination drug according to claim 40, characterized in that: When the estrogen receptor degrader is compound 75 or its optical isomer, salt, hydrate or solvate, and the mTOR inhibitor is rapamycin or its optical isomer, salt, hydrate or solvate, the molar ratio of the estrogen receptor degrader to the mTOR inhibitor is 1:0.011 to 1:2.7; preferably, the molar ratio is 1:0.011, 1:0.3 or 1:2.7; Alternatively, when the estrogen receptor degrader is compound 75 or its optical isomer, salt, hydrate or solvate, and the mTOR inhibitor is Everolimus or its optical isomer, salt, hydrate or solvate, the molar ratio of the estrogen receptor degrader to the mTOR inhibitor is 1:0.033 to 1:8; the molar ratio is preferably 1:0.033, 1:0.89 or 1:

8.

43. The combination drug according to claim 40, characterized in that: When the estrogen receptor degrader is compound 65 or its optical isomer, salt, hydrate or solvate, and the mTOR inhibitor is rapamycin or its optical isomer, salt, hydrate or solvate, the molar ratio of the estrogen receptor degrader to the mTOR inhibitor is 1:0.011 to 1:2.7; preferably, the molar ratio is 1:0.011, 1:0.3 or 1:2.7; Alternatively, when the estrogen receptor degrader is compound 65 or its optical isomer, salt, hydrate or solvate, and the mTOR inhibitor is Everolimus or its optical isomer, salt, hydrate or solvate, the molar ratio of the estrogen receptor degrader to the mTOR inhibitor is 1:0.033 to 1:8; the molar ratio is preferably 1:0.033, 1:0.89 or 1:

8.

44. The combination drug according to claim 40, characterized in that: When the estrogen receptor degrader is compound 63 or its optical isomer, salt, hydrate or solvate, and the mTOR inhibitor is rapamycin or its optical isomer, salt, hydrate or solvate, the molar ratio of the estrogen receptor degrader to the mTOR inhibitor is 1:0.011 to 1:2.7; preferably, the molar ratio is 1:0.011, 1:0.3 or 1:2.7; Alternatively, when the estrogen receptor degrader is compound 63 or its optical isomer, salt, hydrate or solvate, and the mTOR inhibitor is Everolimus or its optical isomer, salt, hydrate or solvate, the molar ratio of the estrogen receptor degrader to the mTOR inhibitor is 1:0.033 to 1:8; the molar ratio is preferably 1:0.033, 1:0.89 or 1:

8.

45. Use of an estrogen receptor targeted degrader in combination with an mTOR inhibitor in the preparation of a drug for degrading estrogen receptors.

46. ​​The use according to claim 41, characterized in that: The molar ratio of the estrogen receptor targeted degradation agent to the mTOR inhibitor is 1:0011 to 1:8; Preferably, the molar ratio of the estrogen receptor targeted degrader to the mTOR inhibitor is 1:0.011 to 1:2.7 or 1:0.033 to 1:8; More preferably, the molar ratio of the estrogen receptor targeted degrader to the mTOR inhibitor is 1:0.011, 1:0.033, 1:0.3, 1:0.89, 1:2.7 or 1:

8.

47. The use according to claim 45 or 46, characterized in that: The estrogen receptor targeted degradation agent is selected from the compound described in any one of claims 3 to 28, or an optical isomer thereof, or a salt thereof, or a hydrate thereof, or a solvate thereof; The mTOR inhibitors are Rapamycin, Everolimus, Dactolisib, AZD8055, Temsirolimus, PI-103, NU7441, Torin 2, KU-0063794, Torkinib, Ridaforolimus, Sapanisertib, Voxtalisib (XL765) Analogue, Torin 1. Omipalisib, OSI-027, PF-04691502, Apitolisib, GSK1059615, Gedatolisib, WYE-354, Vi stusertib, WYE-125132, PP121, WYE-687, WAY-600, ETP-46464, GDC-0349, XL388, PI3K / mTOR Inhibitor-2, MTI-31, PQR620, Compound 401, GNE-477, Bimiralisib, SF2523, CZ415, Paxalisib, CC-115, Onatasertib, Voxtalisib, Zotarolimus, BGT226, Palomid 529, Nitazoxanide, 4EGI-1, MHY-1685, COH-SR4, JR-AB2-011, ABTL-0812, mTOR inhibitor-1, Astragaloside IV, Samotolisib, Chrysophanic Acid or its optical isomers, salts, hydrates or solvates thereof; Preferably, the mTOR inhibitor is Rapamycin, Everolimus or an optical isomer thereof, a salt thereof, a hydrate thereof, or a solvate thereof.

48. The use according to claim 47, characterized in that: When the estrogen receptor degrader is ARV-471 or its optical isomers, salts, hydrates or solvates, and the mTOR inhibitor is Rapamycin or its optical isomers, salts, hydrates or solvates, the molar ratio of the estrogen receptor degrader to the mTOR inhibitor is 1:0.011 to 1:2.7; preferably, the molar ratio is 1:0.011, 1:0.3 or 1:2.7; Alternatively, when the estrogen receptor degrader is ARV-471 or an optical isomer thereof, a salt thereof, a hydrate thereof, or a solvate thereof, and the mTOR inhibitor is Everolimus or an optical isomer thereof, a salt thereof, a hydrate thereof, or a solvate thereof, the molar ratio of the estrogen receptor degrader to the mTOR inhibitor is 1:0.033 to 1:8; the molar ratio is preferably 1:0.033, 1:0.89, or 1:

8.

49. The use according to claim 47, characterized in that: When the estrogen receptor degrader is compound 75 or its optical isomer, salt, hydrate or solvate, and the mTOR inhibitor is rapamycin or its optical isomer, salt, hydrate or solvate, the molar ratio of the estrogen receptor degrader to the mTOR inhibitor is 1:0.011 to 1:2.7; preferably, the molar ratio is 1:0.011, 1:0.3 or 1:2.7; Alternatively, when the estrogen receptor degrader is compound 75 or its optical isomer, salt, hydrate or solvate, and the mTOR inhibitor is Everolimus or its optical isomer, salt, hydrate or solvate, the molar ratio of the estrogen receptor degrader to the mTOR inhibitor is 1:0.033 to 1:8; the molar ratio is preferably 1:0.033, 1:0.89 or 1:

8.

50. The use according to claim 47, characterized in that: When the estrogen receptor degrader is compound 65 or its optical isomer, salt, hydrate or solvate, and the mTOR inhibitor is rapamycin or its optical isomer, salt, hydrate or solvate, the molar ratio of the estrogen receptor degrader to the mTOR inhibitor is 1:0.011 to 1:2.7; preferably, the molar ratio is 1:0.011, 1:0.3 or 1:2.7; Alternatively, the estrogen receptor degrader is compound 65 or its optical isomers, salts thereof, water thereof When the mTOR inhibitor is Everolimus or its optical isomers, salts, hydrates or solvates thereof, the molar ratio of the estrogen receptor degrader to the mTOR inhibitor is 1:0.033 to 1:8; the molar ratio is preferably 1:0.033, 1:0.89 or 1:

8.

51. The use according to claim 47, characterized in that: When the estrogen receptor degrader is compound 63 or its optical isomer, salt, hydrate or solvate, and the mTOR inhibitor is rapamycin or its optical isomer, salt, hydrate or solvate, the molar ratio of the estrogen receptor degrader to the mTOR inhibitor is 1:0.011 to 1:2.7; preferably, the molar ratio is 1:0.011, 1:0.3 or 1:2.7; Alternatively, when the estrogen receptor degrader is compound 63 or its optical isomer, salt, hydrate or solvate, and the mTOR inhibitor is Everolimus or its optical isomer, salt, hydrate or solvate, the molar ratio of the estrogen receptor degrader to the mTOR inhibitor is 1:0.033 to 1:8; the molar ratio is preferably 1:0.033, 1:0.89 or 1:

8.

52. The use according to claim 45 or 46, characterized in that: The drug for degrading estrogen receptors is an estrogen receptor degrader and / or a drug for treating estrogen receptor-related diseases.

53. The use according to claim 52, characterized in that: The drug is used 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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