Combined medicine for degrading estrogen receptor and application thereof

Abstract

The invention provides a combined medicine for degrading an estrogen receptor and application of the combined medicine, and belongs to the field of medicines. The combined medicine contains the estrogen receptor degradation agent and the CDK4 / 6 inhibitor which have the same or different specifications and are administered simultaneously or respectively, and a pharmaceutically acceptable carrier. The estrogen receptor degradation agent and the CDK4 / 6 inhibitor are combined to degrade the estrogen receptor, the synergistic interaction effect can be achieved, the effect of treating diseases related to the estrogen receptor is remarkably improved, and the application prospect is good.

Description

Technical Field

[0001] The invention belongs to the field of medicine, and in particular relates to a combined drug for degrading estrogen receptors and a use thereof. Background Art

[0002] Estrogen receptor (ER) is a ligand-activated transcriptional regulatory protein that mediates the induction of a variety of biological effects through interaction with endogenous estrogens. Endogenous estrogens include 17β-estradiol and estrone. It has been found that ER has two different configurations, namely ER-α and ER-β. Estrogen and estrogen receptors are associated with many diseases or conditions, such as bone cancer, breast cancer, colorectal cancer, endometrial cancer, prostate cancer, ovarian cancer, uterine cancer, cervical cancer, lung cancer and other diseases or conditions. For example, about 70% of patients with breast cancer express ER and / or progesterone receptors. The treatment of these diseases can be carried out by inhibiting ER signaling in a variety of ways, including antagonizing the binding of ligands to ER, antagonizing or downregulating ERα, blocking estrogen synthesis, etc. Estrogen receptor degraders can compete with estrogen receptors (ER) present in estrogen-responsive tissues for binding. It is expected to treat estrogen receptor-related diseases. However, estrogen receptor degraders alone can produce adverse reactions such as endometrial hyperplasia and deep vein thrombosis in clinical applications. At the same time, drug resistance is easily produced.

[0003] Cyclin dependent kinases (CDKs) play an important role in the initiation of the cell cycle and the regulation of the transition between various phases. CDK4 / 6 and cyclin D can phosphorylate the retinoblastoma gene (Rb) and then release the transcription factor E2F, which promotes the transcription of cell cycle-related genes and allows cells to enter the S phase. CDK4 / 6 inhibitors effectively block the progression of tumor cells from the G1 phase to the S phase. In estrogen receptor-positive (ER+) breast cancer, overactivity of CDK4 / 6 is very frequent. Preclinical data show that dual inhibition of CDK4 / 6 and ER signaling has a synergistic effect and can inhibit the growth of G1 phase ER+ breast cancer cells. Therefore, CDK4 / 6 inhibitors are expected to be used to treat cancer. However, in the clinical application of CDK4 / 6 inhibitors alone, due to factors such as CDK overexpression and cyclin E1 overexpression, patients will develop acquired resistance to CDK4 / 6 inhibitors.

[0004] Currently, there is no evidence of the combined use of estrogen receptor degraders and CDK4 / 6 inhibitors to treat estrogen receptor-related diseases. Summary of the invention

[0005] The purpose of the present invention is to provide a combined drug for degrading estrogen receptors and its use.

[0006] The present invention provides a pharmaceutical composition for degrading estrogen receptors, characterized in that the pharmaceutical composition consists of an estrogen receptor degrader and a CDK4 / 6 inhibitor.

[0007] Furthermore, the molar ratio of the estrogen receptor degrader to the CDK4 / 6 inhibitor is 1:0.01 to 1:666.7.

[0008] Furthermore, the estrogen receptor degrading 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:

[0009]

[0010] in,

[0011] R 1 is selected from hydrogen, C1-C6 alkyl, hydroxy, amino, carboxyl, C1-C6 alkoxy, boric acid, -OR';

[0012] R' is selected from phenyl, benzyl;

[0013] R 2 is a substituent at any position on the benzene ring, a is a substituent R 2 The number of

[0014] 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;

[0015] a is 0, 1, 2 or 3;

[0016] When the dotted line in the benzene ring is a bond, R 3 , R 4 Each independently selected from none;

[0017] 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;

[0018] 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;

[0019] X is selected from CR 7 R 8、O、S、SO、SO2、NR 7 ;

[0020] R 7 , R 8 Each of them is independently selected from hydrogen, halogen, C1-C6 alkyl, 3-6 membered cycloalkyl;

[0021] n is 0, 1 or 2;

[0022] R 6 is a substituent at any position on the benzene ring, and b is a substituent R 6 The number of

[0023] 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;

[0024] b is 0, 1, 2, or 3;

[0025] Ring A and Ring B are independently selected from 4- to 12-membered cycloalkyl and 4- to 12-membered heterocycloalkyl;

[0026] M is selected from None, CR 9 R 10 、O、S、SO、SO2、NR 9 ;

[0027] R 9 , R 10 are independently selected from hydrogen, C1-C6 alkyl;

[0028] E 3 is a substituent at any position on the benzene ring, and c is a substituent E 3 The number of

[0029] 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;

[0030] c is 0, 1, 2, or 3;

[0031] When there is no dashed line between Y and W, W is NH and Y is halogen;

[0032] 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)-;

[0033] R Y1 , R Y2 are independently selected from hydrogen, C1-C6 alkyl;

[0034] R 11 , R 12 are independently selected from hydrogen, C1-C6 alkyl;

[0035] R 21 is selected from hydrogen or deuterium;

[0036] The heteroatom of the heteroaryl group is O, N or S; the number of the heteroatoms is 1, 2 or 3;

[0037] The heteroatom of the heterocycloalkyl group is N; the number of the heteroatoms is 1, 2 or 3.

[0038] Furthermore, the compound is as shown in formula (II):

[0039]

[0040] in,

[0041] R 1 is selected from hydrogen, C1-C6 alkyl, hydroxy, amino, carboxyl, C1-C6 alkoxy, boric acid, -OR';

[0042] R' is selected from phenyl, benzyl;

[0043] R 2 is a substituent at any position on the benzene ring, a is a substituent R 2 The number of

[0044] 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;

[0045] a is 0, 1, 2 or 3;

[0046] When the dotted line in the benzene ring is a bond, R 3 , R 4 Each independently selected from none;

[0047] 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;

[0048] 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;

[0049] X is selected from CR 7 R 8 、O、S、SO、SO2、NR 7 ;

[0050] R 7 , R 8 Each of them is independently selected from hydrogen, halogen, C1-C6 alkyl, 3-6 membered cycloalkyl;

[0051] n is 0, 1 or 2;

[0052] R 6 is a substituent at any position on the benzene ring, and b is a substituent R 6 The number of

[0053] 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;

[0054] b is 0, 1, 2, or 3;

[0055] Ring A and Ring B are independently selected from 4- to 12-membered cycloalkyl and 4- to 12-membered heterocycloalkyl;

[0056] M is selected from None, CR 9 R 10 、O、S、SO、SO2、NR 9 ;

[0057] R 9 , R 10 are independently selected from hydrogen, C1-C6 alkyl;

[0058] E 3 is a substituent at any position on the benzene ring, and c is a substituent E 3 The number of

[0059] 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;

[0060] c is 0, 1, 2, or 3;

[0061] Y is none, CR Y1 R Y2 、C(O)、-CR 11 =CR 12 -、-CR 11 =N-, -N=N-, -OC(O)-;

[0062] R Y1 , R Y2 are independently selected from hydrogen, C1-C6 alkyl;

[0063] R 11 , R 12 are independently selected from hydrogen, C1-C6 alkyl;

[0064] The heteroatom of the heteroaryl group is O, N or S; the number of the heteroatoms is 1, 2 or 3;

[0065] The heteroatom of the heterocycloalkyl group is N; the number of the heteroatoms is 1, 2 or 3.

[0066] Furthermore, the compound is represented by formula (III):

[0067]

[0068] in,

[0069] R 2 is a substituent at any position on the benzene ring, a is a substituent R 2 The number of

[0070] 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;

[0071] a is 0, 1, 2 or 3;

[0072] When the dotted line in the benzene ring is a bond, R 3 , R 4 Each independently selected from none;

[0073] 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;

[0074] 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;

[0075] X is selected from CR 7 R 8 、O、S、SO、SO2、NR 7 ;

[0076] R 7 , R 8 Each of them is independently selected from hydrogen, halogen, C1-C6 alkyl, 3-6 membered cycloalkyl;

[0077] n is 0, 1 or 2;

[0078] R 6 is a substituent at any position on the benzene ring, and b is a substituent R 6 The number of

[0079] 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;

[0080] b is 0, 1, 2, or 3;

[0081] Ring A and Ring B are independently selected from 4- to 12-membered cycloalkyl and 4- to 12-membered heterocycloalkyl;

[0082] M is selected from None, CR 9 R 10 、O、S、SO、SO2、NR 9 ;

[0083] R 9 , R 10 are independently selected from hydrogen, C1-C6 alkyl;

[0084] E 3 is a substituent at any position on the benzene ring, and c is a substituent E 3 The number of

[0085] 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;

[0086] c is 0, 1, 2, or 3;

[0087] Y is none, CR Y1 R Y2 、C(O)、-CR 11 =CR 12 -、-CR 11 =N-, -N=N-, -OC(O)-;

[0088] R Y1 , R Y2 are independently selected from hydrogen, C1-C6 alkyl;

[0089] R 11 , R 12 are independently selected from hydrogen, C1-C6 alkyl;

[0090] The heteroatom of the heteroaryl group is O, N or S; the number of the heteroatoms is 1, 2 or 3;

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

[0092] Preferably,

[0093] 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;

[0094] X is selected from CH2, CF2, O, S, SO, SO2, NR 7 ;

[0095] R 7 Selected from hydrogen, halogen, C1-C6 alkyl, 3-6 membered cycloalkyl;

[0096] 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.

[0097] Furthermore, the compound is represented by formula (IV):

[0098]

[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 is independently selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, 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 , R 4 Connect 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 Each of them is 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 is independently selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, 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, 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;

[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 the heteroatoms is 1, 2 or 3;

[0121] The heteroatom of the heterocycloalkyl group is N; the number of the 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 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;

[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 1 heteroatom N and the other ring has 2 heteroatom N.

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

[0128]

[0129] in,

[0130] R 2 is a substituent at any position on the benzene ring, a is a substituent R 2 The number of

[0131] 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;

[0132] a is 0, 1, 2 or 3;

[0133] 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;

[0134] 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;

[0135] X is selected from CR 7 R 8 、O、S、SO、SO2、NR 7 ;

[0136] R 7 , R 8 Each of them is independently selected from hydrogen, halogen, C1-C6 alkyl, 3-6 membered cycloalkyl;

[0137] n is 0, 1 or 2;

[0138] R 6 is a substituent at any position on the benzene ring, and b is a substituent R 6 The number of

[0139] 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;

[0140] b is 0, 1, 2, or 3;

[0141] Ring A and Ring B are independently selected from 4- to 12-membered cycloalkyl and 4- to 12-membered heterocycloalkyl;

[0142] M is selected from None, CR 9 R 10 、O、S、SO、SO2、NR 9 ;

[0143] R 9 , R 10 are independently selected from hydrogen, C1-C6 alkyl;

[0144] E 3 is a substituent at any position on the benzene ring, and c is a substituent E 3 The number of

[0145] 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;

[0146] c is 0, 1, 2, or 3;

[0147] Y is none, CR Y1 R Y2 、C(O)、-CR 11 =CR 12 -、-CR 11 =N-, -N=N-, -OC(O)-;

[0148] R Y1 , R Y2 are independently selected from hydrogen, C1-C6 alkyl;

[0149] R 11 , R 12 are independently selected from hydrogen, C1-C6 alkyl;

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

[0151] The heteroatom of the heterocycloalkyl group is N; the number of the heteroatoms is 1, 2 or 3;

[0152] Preferably,

[0153] 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;

[0154] X is selected from CH2, CF2, O, S, SO, SO2, NR 7 ;

[0155] R 7 Selected from hydrogen, halogen, C1-C6 alkyl, 3-6 membered cycloalkyl;

[0156] 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.

[0157] Furthermore, the compound is as shown in formula (VI):

[0158]

[0159]

[0160] in,

[0161] R 2 is a substituent at any position on the benzene ring, a is a substituent R 2 The number of

[0162] 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;

[0163] a is 0, 1, 2 or 3;

[0164] R 3 , R 4are independently selected from hydrogen, C1-C6 alkyl, or R 3 , R 4 Connect to form a 3- to 6-membered cycloalkyl group;

[0165] 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;

[0166] X is selected from CR 7 R 8 、O、S、SO、SO2、NR 7 ;

[0167] R 7 , R 8 Each of them is independently selected from hydrogen, halogen, C1-C6 alkyl, 3-6 membered cycloalkyl;

[0168] R 6 is a substituent at any position on the benzene ring, and b is a substituent R 6 The number of

[0169] 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;

[0170] b is 0, 1, 2, or 3;

[0171] Ring A and Ring B are independently selected from 4- to 12-membered cycloalkyl and 4- to 12-membered heterocycloalkyl;

[0172] M is selected from None, CR 9 R 10 、O、S、SO、SO2、NR 9 ;

[0173] R 9 , R 10 are independently selected from hydrogen, C1-C6 alkyl;

[0174] E 3 is a substituent at any position on the benzene ring, and c is a substituent E 3 The number of

[0175] 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 3Connect to form 3-6 membered cycloalkyl, 6-10 membered aryl, 4-12 membered heterocycloalkyl, 5-8 membered heteroaryl;

[0176] c is 0, 1, 2, or 3;

[0177] Y is none, CR Y1 R Y2 、C(O)、-CR 11 =CR 12 -、-CR 11 =N-, -N=N-, -OC(O)-;

[0178] R Y1 , R Y2 are independently selected from hydrogen, C1-C6 alkyl;

[0179] R 11 , R 12 are independently selected from hydrogen, C1-C6 alkyl;

[0180] The heteroatom of the heteroaryl group is O, N or S; the number of the heteroatoms is 1, 2 or 3;

[0181] The heteroatom of the heterocycloalkyl group is N; the number of heteroatoms is 1, 2 or 3;

[0182] Preferably,

[0183] 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;

[0184] X is selected from CH2, CF2, O, S, SO, SO2, NR 7 ;

[0185] R 7 Selected from hydrogen, halogen, C1-C6 alkyl, 3-6 membered cycloalkyl;

[0186] 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.

[0187] Furthermore, the compound is represented by formula (VII):

[0188]

[0189] in,

[0190] 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;

[0191] 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;

[0192] X is selected from CR 7 R 8 、O、S、SO、SO2、NR 7 ;

[0193] R 7 , R 8 Each of them is independently selected from hydrogen, halogen, C1-C6 alkyl, 3-6 membered cycloalkyl;

[0194] R 6 is a substituent at any position on the benzene ring, and b is a substituent R 6 The number of

[0195] 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;

[0196] b is 0, 1, 2, or 3;

[0197] Ring A and Ring B are independently selected from 4- to 12-membered cycloalkyl and 4- to 12-membered heterocycloalkyl;

[0198] M is selected from None, CR 9 R 10 、O、S、SO、SO2、NR 9 ;

[0199] R 9 , R 10 are independently selected from hydrogen, C1-C6 alkyl;

[0200] Y is none, CR Y1 R Y2 、C(O)、-CR 11=CR 12 -、-CR 11 =N-, -N=N-, -OC(O)-;

[0201] R Y1 , R Y2 are independently selected from hydrogen, C1-C6 alkyl;

[0202] R 11 , R 12 are independently selected from hydrogen, C1-C6 alkyl;

[0203] The heteroatom of the heteroaryl group is O, N or S; the number of the heteroatoms is 1, 2 or 3;

[0204] The heteroatom of the heterocycloalkyl group is N; the number of heteroatoms is 1, 2 or 3;

[0205] Preferably,

[0206] 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;

[0207] X is selected from CH2, CF2, O, S, SO, SO2, NR 7 ;

[0208] R 7 Selected from hydrogen, halogen, C1-C6 alkyl, 3-6 membered cycloalkyl;

[0209] 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.

[0210] Furthermore, the compound is represented by formula (VIII):

[0211]

[0212] in,

[0213] R 3 , R 4 are independently selected from hydrogen, C1-C6 alkyl; or R 3 , R4 Connect to form a 3- to 6-membered cycloalkyl group;

[0214] 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;

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

[0216] R 7 , R 8 Each of them is independently selected from hydrogen, halogen, C1-C6 alkyl, 3-6 membered cycloalkyl;

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

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

[0219] R 9 , R 10 are independently selected from hydrogen, C1-C6 alkyl;

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

[0221] R Y1 , R Y2 are independently selected from hydrogen, C1-C6 alkyl;

[0222] R 11 , R 12 are independently selected from hydrogen, C1-C6 alkyl;

[0223] The heteroatom of the heteroaryl group is O, N or S; the number of the heteroatoms is 1, 2 or 3;

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

[0225] Preferably,

[0226] R 5 is selected from 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 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;

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

[0228] R 7 Selected from hydrogen, halogen, C1-C6 alkyl, 3-6 membered cycloalkyl;

[0229] 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.

[0230] Furthermore, the compound is represented by formula (IX):

[0231]

[0232] in,

[0233] 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;

[0234] 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;

[0235] X is selected from CR 7 R 8 、O、S、SO、SO2、NR 7 ;

[0236] R 7 , R 8 Each of them is independently selected from hydrogen, halogen, C1-C6 alkyl, 3-6 membered cycloalkyl;

[0237] R 6 is a substituent at any position on the benzene ring, and b is a substituent R 6 The number of

[0238] 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;

[0239] b is 0, 1, 2, or 3;

[0240] Ring A and Ring B are independently selected from 4- to 12-membered cycloalkyl and 4- to 12-membered heterocycloalkyl;

[0241] Y is none, CR Y1 R Y2 、C(O)、-CR 11 =CR 12 -、-CR 11 =N-, -N=N-, -OC(O)-;

[0242] R Y1 , R Y2 are independently selected from hydrogen, C1-C6 alkyl;

[0243] R 11 , R 12 are independently selected from hydrogen, C1-C6 alkyl;

[0244] The heteroatom of the heteroaryl group is O, N or S; the number of the heteroatoms is 1, 2 or 3;

[0245] The heteroatom of the heterocycloalkyl group is N; the number of the heteroatoms is 1, 2 or 3;

[0246] Preferably,

[0247] 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;

[0248] X is selected from CH2, CF2, O, S, SO, SO2, NR 7 ;

[0249] R 7Selected from hydrogen, halogen, C1-C6 alkyl, 3-6 membered cycloalkyl;

[0250] 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.

[0251] Furthermore, the compound is as shown in formula (X):

[0252]

[0253] in,

[0254] 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;

[0255] 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;

[0256] X is selected from CR 7 R 8 、O、S、SO、SO2、NR 7 ;

[0257] R 7 , R 8 Each of them is independently selected from hydrogen, halogen, C1-C6 alkyl, 3-6 membered cycloalkyl;

[0258] Ring A and Ring B are independently selected from 4- to 12-membered cycloalkyl and 4- to 12-membered heterocycloalkyl;

[0259] Y is none, CR Y1 R Y2 、C(O)、-CR 11 =CR 12 -、-CR 11 =N-, -N=N-, -OC(O)-;

[0260] R Y1 , R Y2 are independently selected from hydrogen, C1-C6 alkyl;

[0261] R 11 , R 12 are independently selected from hydrogen, C1-C6 alkyl;

[0262] The heteroatom of the heteroaryl group is O, N or S; the number of the heteroatoms is 1, 2 or 3;

[0263] The heteroatom of the heterocycloalkyl group is N; the number of heteroatoms is 1, 2 or 3;

[0264] Preferably,

[0265] 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;

[0266] X is selected from CH2, CF2, O, S, SO, SO2, NR 7 ;

[0267] R 7 Selected from hydrogen, halogen, C1-C6 alkyl, 3-6 membered cycloalkyl;

[0268] 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.

[0269] Furthermore, the compound is as shown in formula (XI):

[0270]

[0271] in,

[0272] R 2 is a substituent at any position on the benzene ring, a is a substituent R 2 The number of

[0273] 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;

[0274] a is 0, 1, 2 or 3;

[0275] 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;

[0276] R 11 is a substituent at any position on the benzene ring, and d is a substituent R 11 The number of

[0277] 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;

[0278] d is 0, 1, 2 or 3;

[0279] X is selected from CR 7 R 8 、O、S、SO、SO2、NR 7 ;

[0280] R 7 , R 8 Each of them is independently selected from hydrogen, halogen, C1-C6 alkyl, 3-6 membered cycloalkyl;

[0281] R 6 is a substituent at any position on the benzene ring, and b is a substituent R 6 The number of

[0282] 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;

[0283] b is 0, 1, 2, or 3;

[0284] Ring A and Ring B are independently selected from 4- to 12-membered cycloalkyl and 4- to 12-membered heterocycloalkyl;

[0285] M is selected from None, CR 9 R 10 、O、S、SO、SO2、NR 9 ;

[0286] R 9 , R 10 are independently selected from hydrogen, C1-C6 alkyl;

[0287] E 3 is a substituent at any position on the benzene ring, and c is a substituent E 3 The number of

[0288] 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 3Connect to form 3-6 membered cycloalkyl, 6-10 membered aryl, 4-12 membered heterocycloalkyl, 5-8 membered heteroaryl;

[0289] c is 0, 1, 2, or 3;

[0290] Y is none, CR Y1 R Y2 、C(O)、-CR 11 =CR 12 -、-CR 11 =N-, -N=N-, -OC(O)-;

[0291] R Y1 , R Y2 are independently selected from hydrogen, C1-C6 alkyl;

[0292] R 11 , R 12 are independently selected from hydrogen, C1-C6 alkyl;

[0293] The heteroatom of the heteroaryl group is O, N or S; the number of the heteroatoms is 1, 2 or 3;

[0294] The heteroatom of the heterocycloalkyl group is N; the number of heteroatoms is 1, 2 or 3;

[0295] Preferably,

[0296] X is selected from CH2, CF2, O, S, SO, SO2, NR 7 ;

[0297] R 7 Selected from hydrogen, halogen, C1-C6 alkyl, 3-6 membered cycloalkyl;

[0298] 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.

[0299] Furthermore, the compound is represented by formula (XII):

[0300]

[0301] in,

[0302] R 2 is a substituent at any position on the benzene ring, a is a substituent R 2 The number of

[0303] 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;

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

[0305] 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;

[0306] R 11 is a substituent at any position on the benzene ring, and d is a substituent R 11 The number of

[0307] 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;

[0308] d is 0, 1, 2 or 3;

[0309] X is selected from CR 7 R 8 、O、S、SO、SO2、NR 7 ;

[0310] R 7 , R 8 Each of them is independently selected from hydrogen, halogen, C1-C6 alkyl, 3-6 membered cycloalkyl;

[0311] R 6 is a substituent at any position on the benzene ring, and b is a substituent R 6 The number of

[0312] 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;

[0313] b is 0, 1, 2, or 3;

[0314] M is selected from None, CR 9 R 10 、O、S、SO、SO2、NR 9 ;

[0315] R 9 , R 10 are independently selected from hydrogen, C1-C6 alkyl;

[0316] R 12 Selected from hydrogen, halogen, C1-C6 alkyl, hydroxyl;

[0317] m1, m2, m3, m4, m5, m6 are independently selected from 0, 1, 2 or 3;

[0318] E 3 is a substituent at any position on the benzene ring, and c is a substituent E 3 The number of

[0319] 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;

[0320] c is 0, 1, 2, or 3;

[0321] Y is none, CR Y1 R Y2 、C(O)、-CR 11 =CR 12 -、-CR 11 =N-, -N=N-, -OC(O)-;

[0322] R Y1 , R Y2 are independently selected from hydrogen, C1-C6 alkyl;

[0323] R 11 , R 12 are independently selected from hydrogen, C1-C6 alkyl;

[0324] The heteroatom of the heteroaryl group is O, N or S; the number of the heteroatoms is 1, 2 or 3;

[0325] The heteroatom of the heterocycloalkyl group is N; the number of the heteroatoms is 1, 2 or 3;

[0326] Preferably,

[0327] X is selected from CH2, CF2, O, S, SO, SO2, NR 7 ;

[0328] R 7 Selected from hydrogen, halogen, C1-C6 alkyl, 3-6 membered cycloalkyl;

[0329] Y is none, CR Y1 R Y2 、C(O)、-CR 11 =CR 12 -、-CR 11 =N-, -N=N-, -OC(O)-;

[0330] R Y1 , R Y2are independently selected from hydrogen, C1-C6 alkyl;

[0331] R 11 , R 12 Each is independently selected from hydrogen and C1-C6 alkyl.

[0332] Furthermore, the compound is represented by formula (XIII):

[0333]

[0334] in,

[0335] R 2 is a substituent at any position on the benzene ring, a is a substituent R 2 The number of

[0336] 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;

[0337] a is 0, 1, 2 or 3;

[0338] 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;

[0339] R 11 is a substituent at any position on the benzene ring, and d is a substituent R 11 The number of

[0340] 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;

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

[0342] X is selected from CR 7 R 8 、O、S、SO、SO2、NR 7 ;

[0343] R 7 , R 8 Each of them is independently selected from hydrogen, halogen, C1-C6 alkyl, 3-6 membered cycloalkyl;

[0344] R 6 is a substituent at any position on the benzene ring, and b is a substituent R 6 The number of

[0345] Each R6 Each of the following is independently selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, C1-C6 alkoxy;

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

[0347] R 12 Selected from hydrogen, halogen, C1-C6 alkyl, hydroxyl;

[0348] m1, m2, m3, m4, m5, m6 are independently selected from 0, 1, 2 or 3;

[0349] E 3 is a substituent at any position on the benzene ring, and c is a substituent E 3 The number of

[0350] 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;

[0351] c is 0, 1, 2, or 3;

[0352] Y is none, CR Y1 R Y2 、C(O)、-CR 11 =CR 12 -、-CR 11 =N-, -N=N-, -OC(O)-;

[0353] R Y1 , R Y2 are independently selected from hydrogen, C1-C6 alkyl;

[0354] R 11 , R 12 are independently selected from hydrogen, C1-C6 alkyl;

[0355] The heteroatom of the heteroaryl group is O, N or S; the number of the heteroatoms is 1, 2 or 3;

[0356] The heteroatom of the heterocycloalkyl group is N; the number of heteroatoms is 1, 2 or 3;

[0357] Preferably,

[0358] X is selected from CH2, CF2, O, S, SO, SO2, NR 7 ;

[0359] R 7Selected from hydrogen, halogen, C1-C6 alkyl, 3-6 membered cycloalkyl;

[0360] Y is none, CR Y1 R Y2 、C(O)、-CR 11 =CR 12 -、-CR 11 =N-, -N=N-, -OC(O)-;

[0361] R Y1 , R Y2 are independently selected from hydrogen, C1-C6 alkyl;

[0362] R 11 , R 12 Each is independently selected from hydrogen and C1-C6 alkyl.

[0363] Furthermore, the compound is represented by formula (XIV):

[0364]

[0365] in,

[0366] R 2 is a substituent at any position on the benzene ring, a is a substituent R 2 The number of

[0367] 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;

[0368] a is 0, 1, 2 or 3;

[0369] 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;

[0370] R 11 is a substituent at any position on the benzene ring, and d is a substituent R 11 The number of

[0371] 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;

[0372] d is 0, 1, 2 or 3;

[0373] X is selected from CR 7 R 8、O、S、SO、SO2、NR 7 ;

[0374] R 7 , R 8 Each of them is independently selected from hydrogen, halogen, C1-C6 alkyl, 3-6 membered cycloalkyl;

[0375] R 6 is a substituent at any position on the benzene ring, and b is a substituent R 6 The number of

[0376] 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;

[0377] b is 0, 1, 2, or 3;

[0378] R 12 Selected from hydrogen, halogen, C1-C6 alkyl, hydroxyl;

[0379] m1, m2, m3, m4, m5, m6 are independently selected from 0, 1, 2 or 3;

[0380] E 3 is a substituent at any position on the benzene ring, and c is a substituent E 3 The number of

[0381] 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;

[0382] c is 0, 1, 2, or 3;

[0383] Y is none, CR Y1 R Y2 、C(O)、-CR 11 =CR 12 -、-CR 11 =N-, -N=N-, -OC(O)-;

[0384] R Y1 , R Y2 are independently selected from hydrogen, C1-C6 alkyl;

[0385] R 11 , R 12 are independently selected from hydrogen, C1-C6 alkyl;

[0386] The heteroatom of the heteroaryl group is O, N or S; the number of the heteroatoms is 1, 2 or 3;

[0387] The heteroatom of the heterocycloalkyl group is N; the number of the heteroatoms is 1, 2 or 3;

[0388] Preferably,

[0389] X is selected from CH2, CF2, O, S, SO, SO2, NR 7 ;

[0390] R 7 Selected from hydrogen, halogen, C1-C6 alkyl, 3-6 membered cycloalkyl;

[0391] Y is none, CR Y1 R Y2 、C(O)、-CR 11 =CR 12 -、-CR 11 =N-, -N=N-, -OC(O)-;

[0392] R Y1 , R Y2 are independently selected from hydrogen, C1-C6 alkyl;

[0393] R 11 , R 12 Each is independently selected from hydrogen and C1-C6 alkyl.

[0394] Furthermore, the compound is represented by formula (XV):

[0395]

[0396] in,

[0397] R 2 is a substituent at any position on the benzene ring, a is a substituent R 2 The number of

[0398] 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;

[0399] a is 0, 1, 2 or 3;

[0400] 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;

[0401] R 11is a substituent at any position on the thiophene ring, and d is a substituent R 11 The number of

[0402] 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;

[0403] d is 0, 1, 2 or 3;

[0404] X is selected from CR 7 R 8 、O、S、SO、SO2、NR 7 ;

[0405] R 7 , R 8 Each of them is independently selected from hydrogen, halogen, C1-C6 alkyl, 3-6 membered cycloalkyl;

[0406] R 6 is a substituent at any position on the benzene ring, and b is a substituent R 6 The number of

[0407] 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;

[0408] b is 0, 1, 2, or 3;

[0409] Ring A and Ring B are independently selected from 4- to 12-membered cycloalkyl and 4- to 12-membered heterocycloalkyl;

[0410] M is selected from None, CR 9 R 10 、O、S、SO、SO2、NR 9 ;

[0411] R 9 , R 10 are independently selected from hydrogen, C1-C6 alkyl;

[0412] E 3 is a substituent at any position on the benzene ring, and c is a substituent E 3 The number of

[0413] 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;

[0414] c is 0, 1, 2, or 3;

[0415] Y is none, CR Y1 R Y2 、C(O)、-CR 11 =CR 12 -、-CR 11 =N-, -N=N-, -OC(O)-;

[0416] R Y1 , R Y2 are independently selected from hydrogen, C1-C6 alkyl;

[0417] R 11 , R 12 are independently selected from hydrogen, C1-C6 alkyl;

[0418] The heteroatom of the heteroaryl group is O, N or S; the number of the heteroatoms is 1, 2 or 3;

[0419] The heteroatom of the heterocycloalkyl group is N; the number of the heteroatoms is 1, 2 or 3;

[0420] Preferably,

[0421] X is selected from CH2, CF2, O, S, SO, SO2, NR 7 ;

[0422] R 7 Selected from hydrogen, halogen, C1-C6 alkyl, 3-6 membered cycloalkyl;

[0423] 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.

[0424] Furthermore, the compound is represented by formula (XVI):

[0425]

[0426] in,

[0427] R 2 is a substituent at any position on the benzene ring, a is a substituent R 2 The number of

[0428] 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;

[0429] a is 0, 1, 2 or 3;

[0430] R3 , 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;

[0431] R 11 is a substituent at any position on the thiophene ring, and d is a substituent R 11 The number of

[0432] 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;

[0433] d is 0, 1, 2 or 3;

[0434] X is selected from CR 7 R 8 、O、S、SO、SO2、NR 7 ;

[0435] R 7 , R 8 Each of them is independently selected from hydrogen, halogen, C1-C6 alkyl, 3-6 membered cycloalkyl;

[0436] R 6 is a substituent at any position on the benzene ring, and b is a substituent R 6 The number of

[0437] 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;

[0438] b is 0, 1, 2, or 3;

[0439] Ring A and Ring B are independently selected from 4- to 12-membered cycloalkyl and 4- to 12-membered heterocycloalkyl;

[0440] M is selected from None, CR 9 R 10 、O、S、SO、SO2、NR 9 ;

[0441] R 9 , R 10 are independently selected from hydrogen, C1-C6 alkyl;

[0442] E 3 is a substituent at any position on the benzene ring, and c is a substituent E 3 The number of

[0443] Each E 3are 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;

[0444] c is 0, 1, 2, or 3;

[0445] Y is none, CR Y1 R Y2 、C(O)、-CR 11 =CR 12 -、-CR 11 =N-, -N=N-, -OC(O)-;

[0446] R Y1 , R Y2 are independently selected from hydrogen, C1-C6 alkyl;

[0447] R 11 , R 12 are independently selected from hydrogen, C1-C6 alkyl;

[0448] The heteroatom of the heteroaryl group is O, N or S; the number of the heteroatoms is 1, 2 or 3;

[0449] The heteroatom of the heterocycloalkyl group is N; the number of heteroatoms is 1, 2 or 3;

[0450] Preferably,

[0451] X is selected from CH2, CF2, O, S, SO, SO2, NR 7 ;

[0452] R 7 Selected from hydrogen, halogen, C1-C6 alkyl, 3-6 membered cycloalkyl;

[0453] 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.

[0454] Furthermore, the compound is represented by formula (XVII):

[0455]

[0456] in,

[0457] R 3 , R 4 are independently selected from hydrogen, C1-C6 alkyl, or R 3 , R 4Connect to form a 3- to 6-membered cycloalkyl group;

[0458] X is selected from CR 7 R 8 、O、S、SO、SO2、NR 7 ;

[0459] R 7 , R 8 Each of them is independently selected from hydrogen, halogen, C1-C6 alkyl, 3-6 membered cycloalkyl;

[0460] 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

[0461] 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;

[0462] 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;

[0463] Ring A and Ring B are independently selected from 4- to 12-membered cycloalkyl and 4- to 12-membered heterocycloalkyl;

[0464] M is selected from None, CR 9 R 10 、O、S、SO、SO2、NR 9 ;

[0465] R 9 , R 10 are independently selected from hydrogen, C1-C6 alkyl;

[0466] Y is none, CR Y1 R Y2 、C(O)、-CR 11 =CR 12 -、-CR 11 =N-, -N=N-, -OC(O)-;

[0467] R Y1 , R Y2 are independently selected from hydrogen, C1-C6 alkyl;

[0468] R 11 , R 12 are independently selected from hydrogen, C1-C6 alkyl;

[0469] The heteroatom of the heterocycloalkyl group is N; the number of the heteroatoms is 1, 2 or 3;

[0470] Preferably,

[0471] X is selected from CH2, CF2, O, S, SO, SO2, NR 7 ;

[0472] R 7 Selected from hydrogen, halogen, C1-C6 alkyl, 3-6 membered cycloalkyl;

[0473] 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.

[0474] Furthermore, the compound is represented by formula (XVIII):

[0475]

[0476]

[0477] in,

[0478] X is selected from CR 7 R 8 、O、S、SO、SO2、NR 7 ;

[0479] R 7 , R 8 Each of them is independently selected from hydrogen, halogen, C1-C6 alkyl, 3-6 membered cycloalkyl;

[0480] 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

[0481] 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;

[0482] 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;

[0483] Ring A and Ring B are independently selected from 4- to 12-membered cycloalkyl and 4- to 12-membered heterocycloalkyl;

[0484] M is selected from None, CR9 R 10 ;

[0485] R 9 , R 10 are independently selected from hydrogen, C1-C6 alkyl;

[0486] Y is none, CR Y1 R Y2 、C(O)、-CR 11 =CR 12 -、-CR 11 =N-, -N=N-, -OC(O)-;

[0487] R Y1 , R Y2 are independently selected from hydrogen, C1-C6 alkyl;

[0488] R 11 , R 12 are independently selected from hydrogen, C1-C6 alkyl;

[0489] The heteroatom of the heterocycloalkyl group is N; the number of heteroatoms is 1, 2 or 3;

[0490] Preferably,

[0491] X is selected from CH2, CF2 or O;

[0492] 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.

[0493] Furthermore, the compound is represented by formula (XIX):

[0494]

[0495] in,

[0496] R 1 Selected from hydrogen, C1-C6 alkyl, hydroxyl, amino or C1-C6 alkoxy, boric acid;

[0497] R 2 is a substituent at any position on the benzene ring, a is a substituent R 2 The number of

[0498] 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;

[0499] a is 0, 1, 2 or 3;

[0500] 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;

[0501] X is selected from CR 7 R 8 、O、S、SO、SO2、NR 7 ;

[0502] R 7 , R 8 Each of them is independently selected from hydrogen, halogen, C1-C6 alkyl, 3-6 membered cycloalkyl;

[0503] n is 0, 1 or 2;

[0504] R 6 is a substituent at any position on the benzene ring, and b is a substituent R 6 The number of

[0505] 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;

[0506] b is 0, 1, 2, or 3;

[0507] Ring A and Ring B are independently selected from 4- to 12-membered cycloalkyl and 4- to 12-membered heterocycloalkyl;

[0508] M is selected from None, CR 9 R 10 、O、S、SO、SO2、NR 9 ;

[0509] R 9 , R 10 are independently selected from hydrogen, C1-C6 alkyl;

[0510] E 3 is a substituent at any position on the benzene ring, and c is a substituent E 3 The number of

[0511] 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;

[0512] c is 0, 1, 2, or 3;

[0513] Y is none, CR Y1 R Y2 、C(O)、-CR 11 =CR 12 -、-CR 11 =N-, -N=N-, -OC(O)-;

[0514] R Y1 , R Y2 are independently selected from hydrogen, C1-C6 alkyl;

[0515] R 11 , R 12 are independently selected from hydrogen, C1-C6 alkyl;

[0516] The heteroatom of the heteroaryl group is O, N or S; the number of the heteroatoms is 1, 2 or 3;

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

[0518] Preferably,

[0519] 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; and the substituents of the phenyl, thienyl, furanyl, pyrrolyl, pyrimidinyl, pyridazinyl, pyrazolyl or pyrazinyl are selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C1-C6 alkyl, 3-6 membered cycloalkyl, C1-C6 alkoxy.

[0520] Furthermore, the compound is as shown in formula (XX):

[0521]

[0522]

[0523] in,

[0524] 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;

[0525] X is selected from CR 7 R 8 、O、S、SO、SO2、NR 7 ;

[0526] R 7 , R 8 Each of them is independently selected from hydrogen, halogen, C1-C6 alkyl, 3-6 membered cycloalkyl;

[0527] R 6 is a substituent at any position on the benzene ring, and b is a substituent R 6 The number of

[0528] 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;

[0529] b is 0, 1, 2, or 3;

[0530] Ring A and Ring B are independently selected from 4- to 12-membered cycloalkyl and 4- to 12-membered heterocycloalkyl;

[0531] M is selected from None, CR 9 R 10 、O、S、SO、SO2、NR 9 ;

[0532] R 9 , R 10 are independently selected from hydrogen, C1-C6 alkyl;

[0533] Y is none, CR Y1 R Y2 、C(O)、-CR 11 =CR 12 -、-CR 11 =N-, -N=N-, -OC(O)-;

[0534] R Y1 , R Y2 are independently selected from hydrogen, C1-C6 alkyl;

[0535] R 11 , R 12 are independently selected from hydrogen, C1-C6 alkyl;

[0536] The heteroatom of the heteroaryl group is O, N or S; the number of the heteroatoms is 1, 2 or 3;

[0537] The heteroatom of the heterocycloalkyl group is N; the number of heteroatoms is 1, 2 or 3;

[0538] Preferably,

[0539] 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;

[0540] X is selected from CH2, CF2, O, S, SO, SO2, NR 7 ;

[0541] R 7 Selected from hydrogen, halogen, C1-C6 alkyl, 3-6 membered cycloalkyl;

[0542] 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.

[0543] Furthermore, the compound is represented by formula (XXI):

[0544]

[0545] in,

[0546] R 11 is a substituent at any position on the benzene ring, and d is a substituent R 11 The number of

[0547] 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;

[0548] d is 0, 1, 2 or 3;

[0549] X is selected from CR 7 R 8 、O、S、SO、SO2、NR 7 ;

[0550] R 7 , R 8 Each of them is independently selected from hydrogen, halogen, C1-C6 alkyl, 3-6 membered cycloalkyl;

[0551] R 6 is a substituent at any position on the benzene ring, and b is a substituent R 6The number of

[0552] 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;

[0553] b is 0, 1, 2, or 3;

[0554] M is selected from None, CR 9 R 10 、O、S、SO、SO2、NR 9 ;

[0555] R 9 , R 10 are independently selected from hydrogen, C1-C6 alkyl;

[0556] m1, m2, m3, m4, m5, m6 are independently selected from 0, 1, 2 or 3;

[0557] Y is none, CR Y1 R Y2 、C(O)、-CR 11 =CR 12 -、-CR 11 =N-, -N=N-, -OC(O)-;

[0558] R Y1 , R Y2 are independently selected from hydrogen, C1-C6 alkyl;

[0559] R 11 , R 12 are independently selected from hydrogen, C1-C6 alkyl;

[0560] Preferably,

[0561] X is selected from CH2, CF2, O, S, SO, SO2, NR 7 ;

[0562] R 7 Selected from hydrogen, halogen, C1-C6 alkyl, 3-6 membered cycloalkyl.

[0563] Furthermore, the ring A and ring B are independently selected from the following structures:

[0564]

[0565] Furthermore, the Selected from the following structures:

[0566]

[0567]

[0568] Furthermore, the compound is one of the following compounds:

[0569]

[0570]

[0571]

[0572]

[0573]

[0574]

[0575]

[0576]

[0577] Further, the compound is ARV-471, compound 63, compound 65 or compound 75;

[0578] The structure of ARV-471 is The structure of compound 63 is The structure of compound 65 is The structure of compound 75 is

[0579] Further, 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.

[0580] Further, the CDK4 / 6 inhibitor is Palbociclib, Abemaciclib, Ribociclib, Trilaciclib, Dalpiciclib, Lerociclib, AT7519M, Dinaciclib, BSJ-03-204, Narazaciclib, XY028-140, BSJ-04-132, PF-07220060, Nimbolide, XY028-133, Cimpuciclib, CDK4 / 6-IN-2, CDK4 / 6-IN-12, CDK4 / 6-IN-7, CDK-IN-12, CDK4 / 6-IN-8, CDK4 / 6-IN-10 or its optical isomers, salts, hydrates or solvates;

[0581] Preferably, the CDK4 / 6 inhibitor is Palbociclib, Abemaciclib, Ribociclib, Dalpiciclib or an optical isomer thereof, a salt thereof, a hydrate thereof, or a solvate thereof.

[0582] Further, 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 CDK4 / 6 inhibitor is Palbociclib 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 CDK4 / 6 inhibitor is 1:0.3 to 1:666.7; the molar ratio is preferably 1:0.3 to 1:24.4; the molar ratio is more preferably 1:0.3, 1:2.7, or 1:24.4;

[0583] And / or, when the estrogen receptor degrader is ARV-471 or an optical isomer, a salt, a hydrate or a solvate thereof, and the CDK4 / 6 inhibitor is Abemaciclib or an optical isomer, a salt, a hydrate or a solvate thereof, the molar ratio of the estrogen receptor degrader to the CDK4 / 6 inhibitor is 1:0.3 to 1:2.7; preferably, the molar ratio is 1:0.3, 1:0.9 or 1:2.7;

[0584] And / or, 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 CDK4 / 6 inhibitor is Ribociclib 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 CDK4 / 6 inhibitor is 1:0.1 to 1:8.3; the molar ratio is preferably 1:0.1, 1:0.9, or 1:8.3.

[0585] Further, when the estrogen receptor degrader is compound 75 or its optical isomer, salt, hydrate or solvate, and the CDK4 / 6 inhibitor is Palbociclib or its optical isomer, salt, hydrate or solvate, the molar ratio of the estrogen receptor degrader to the CDK4 / 6 inhibitor is 1:0.1 to 1:666.7; the molar ratio is preferably 1:0.9 to 1:71.4; the molar ratio is more preferably 1:0.9, 1:8.3 or 1:71.4;

[0586] And / or, when the estrogen receptor degrader is compound 75 or its optical isomer, salt, hydrate or solvate, and the CDK4 / 6 inhibitor is Abemaciclib or its optical isomer, salt, hydrate or solvate, the molar ratio of the estrogen receptor degrader to the CDK4 / 6 inhibitor is 1:0.011 to 1:24.4; the molar ratio is preferably 1:0.03 to 1:0.9; the molar ratio is more preferably 1:0.03, 1:0.3 or 1:0.9;

[0587] And / or, when the estrogen receptor degrader is compound 75 or its optical isomer, salt, hydrate or solvate, and the CDK4 / 6 inhibitor is Ribociclib or its optical isomer, salt, hydrate or solvate, the molar ratio of the estrogen receptor degrader to the CDK4 / 6 inhibitor is 1:0.1 to 1:71.4; the molar ratio is preferably 1:0.3 to 1:71.4; the molar ratio is more preferably 1:0.3, 1:8.3, or 1:71.4.

[0588] Further, when the estrogen receptor degrader is compound 65 or its optical isomer, salt, hydrate or solvate, and the CDK4 / 6 inhibitor is Palbociclib or its optical isomer, salt, hydrate or solvate, the molar ratio of the estrogen receptor degrader to the CDK4 / 6 inhibitor is 1:0.1 to 1:8.3; the molar ratio is preferably 1:0.1, 1:0.9 or 1:8.3;

[0589] And / or, when the estrogen receptor degrader is compound 65 or its optical isomer, salt, hydrate or solvate, and the CDK4 / 6 inhibitor is Abemaciclib or its optical isomer, salt, hydrate or solvate, the molar ratio of the estrogen receptor degrader to the CDK4 / 6 inhibitor is 1:0.03 to 1:0.3; preferably, the molar ratio is 1:0.03 or 1:0.3;

[0590] And / or, when the estrogen receptor degrader is compound 65 or its optical isomer, salt, hydrate or solvate, and the CDK4 / 6 inhibitor is Ribociclib or its optical isomer, salt, hydrate or solvate, the molar ratio of the estrogen receptor degrader to the CDK4 / 6 inhibitor is 1:0.1 to 1:8.3; the molar ratio is preferably 1:0.1, 1:0.9 or 1:8.3.

[0591] Further, when the estrogen receptor degrader is compound 63 or its optical isomer, salt, hydrate or solvate, and the CDK4 / 6 inhibitor is Palbociclib or its optical isomer, salt, hydrate or solvate, the molar ratio of the estrogen receptor degrader to the CDK4 / 6 inhibitor is 1:0.3 to 1:8.3; the molar ratio is preferably 1:0.3, 1:0.9 or 1:8.3;

[0592] And / or, when the estrogen receptor degrader is compound 63 or its optical isomer, salt, hydrate or solvate, and the CDK4 / 6 inhibitor is Abemaciclib or its optical isomer, salt, hydrate or solvate, the molar ratio of the estrogen receptor degrader to the CDK4 / 6 inhibitor is 1:0.03 to 1:0.9; preferably, the molar ratio is 1:0.03, 1:0.3 or 1:0.9;

[0593] And / or, when the estrogen receptor degrader is compound 63 or its optical isomer, salt, hydrate or solvate, and the CDK4 / 6 inhibitor is Ribociclib or its optical isomer, salt, hydrate or solvate, the molar ratio of the estrogen receptor degrader to the CDK4 / 6 inhibitor is 1:0.3 to 1:24.4; the molar ratio is preferably 1:0.3, 1:2.7, or 1:24.4.

[0594] The present invention also provides a method for preparing the aforementioned pharmaceutical composition, which comprises the following steps: taking an estrogen receptor degrader and a CDK4 / 6 inhibitor according to a molar ratio or a mass ratio, and mixing them.

[0595] The present invention also provides the use of the aforementioned pharmaceutical composition in preparing an estrogen receptor degrader and / or a drug for treating estrogen receptor-related diseases.

[0596] The present invention also provides the use of the aforementioned pharmaceutical composition in preparing a drug for treating and / or preventing cancer;

[0597] Preferably, the cancer is breast cancer, ovarian cancer, or lung cancer.

[0598] 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.

[0599] The present invention also provides a combined drug for degrading estrogen receptors, which contains an estrogen receptor degrader and a CDK4 / 6 inhibitor of the same or different specifications, which are administered simultaneously or separately, and a pharmaceutically acceptable carrier.

[0600] Furthermore, the molar ratio of the estrogen receptor degrader to the CDK4 / 6 inhibitor is 1:0.01 to 1:666.7.

[0601] Furthermore, the estrogen receptor degrading agent is selected from the aforementioned compounds, or optical isomers thereof, or salts thereof, or hydrates thereof, or solvates thereof;

[0602] The CDK4 / 6 inhibitor is Palbociclib, Abemaciclib, Ribociclib, Trilaciclib, Dalpiciclib, Lerociclib, AT7519M, Dinaciclib, BSJ-03-204, Narazaciclib, XY028-140, BSJ-04-132, PF-07220060, Nimbolide, XY028-133, Cimpuciclib, CDK4 / 6-IN-2, CDK4 / 6-IN-12, CDK4 / 6-IN-7, CDK-IN-12, CDK4 / 6-IN-8, CDK4 / 6-IN-10 or its optical isomers, salts, hydrates or solvates;

[0603] Preferably, the CDK4 / 6 inhibitor is Palbociclib, Abemaciclib, Ribociclib, Dalpiciclib or an optical isomer thereof, a salt thereof, a hydrate thereof, or a solvate thereof.

[0604] Further, 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 CDK4 / 6 inhibitor is Palbociclib 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 CDK4 / 6 inhibitor is 1:0.3 to 1:666.7; the molar ratio is preferably 1:0.3 to 1:24.4; the molar ratio is more preferably 1:0.3, 1:2.7, or 1:24.4;

[0605] And / or, when the estrogen receptor degrader is ARV-471 or an optical isomer, a salt, a hydrate or a solvate thereof, and the CDK4 / 6 inhibitor is Abemaciclib or an optical isomer, a salt, a hydrate or a solvate thereof, the molar ratio of the estrogen receptor degrader to the CDK4 / 6 inhibitor is 1:0.3 to 1:2.7; preferably, the molar ratio is 1:0.3, 1:0.9 or 1:2.7;

[0606] And / or, 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 CDK4 / 6 inhibitor is Ribociclib 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 CDK4 / 6 inhibitor is 1:0.1 to 1:8.3; the molar ratio is preferably 1:0.1, 1:0.9, or 1:8.3.

[0607] Further, when the estrogen receptor degrader is compound 75 or its optical isomer, salt, hydrate or solvate, and the CDK4 / 6 inhibitor is Palbociclib or its optical isomer, salt, hydrate or solvate, the molar ratio of the estrogen receptor degrader to the CDK4 / 6 inhibitor is 1:0.1 to 1:666.7; the molar ratio is preferably 1:0.9 to 1:71.4; the molar ratio is more preferably 1:0.9, 1:8.3 or 1:71.4;

[0608] And / or, when the estrogen receptor degrader is compound 75 or its optical isomer, salt, hydrate or solvate, and the CDK4 / 6 inhibitor is Abemaciclib or its optical isomer, salt, hydrate or solvate, the molar ratio of the estrogen receptor degrader to the CDK4 / 6 inhibitor is 1:0.011 to 24.4; the molar ratio is preferably 1:0.03 to 1:0.9; the molar ratio is more preferably 1:0.03, 1:0.3 or 1:0.9;

[0609] And / or, when the estrogen receptor degrader is compound 75 or its optical isomer, salt, hydrate or solvate, and the CDK4 / 6 inhibitor is Ribociclib or its optical isomer, salt, hydrate or solvate, the molar ratio of the estrogen receptor degrader to the CDK4 / 6 inhibitor is 1:0.1 to 1:71.4; the molar ratio is preferably 1:0.3 to 1:71.4; the molar ratio is more preferably 1:0.3, 1:8.3, or 1:71.4.

[0610] Further, when the estrogen receptor degrader is compound 65 or its optical isomer, salt, hydrate or solvate, and the CDK4 / 6 inhibitor is Palbociclib or its optical isomer, salt, hydrate or solvate, the molar ratio of the estrogen receptor degrader to the CDK4 / 6 inhibitor is 1:0.1 to 1:8.3; the molar ratio is preferably 1:0.1, 1:0.9 or 1:8.3;

[0611] And / or, when the estrogen receptor degrader is compound 65 or its optical isomer, salt, hydrate or solvate, and the CDK4 / 6 inhibitor is Abemaciclib or its optical isomer, salt, hydrate or solvate, the molar ratio of the estrogen receptor degrader to the CDK4 / 6 inhibitor is 1:0.03 to 1:0.3; preferably, the molar ratio is 1:0.03 or 1:0.3;

[0612] And / or, when the estrogen receptor degrader is compound 65 or its optical isomer, salt, hydrate or solvate, and the CDK4 / 6 inhibitor is Ribociclib or its optical isomer, salt, hydrate or solvate, the molar ratio of the estrogen receptor degrader to the CDK4 / 6 inhibitor is 1:0.1 to 1:8.3; the molar ratio is preferably 1:0.1, 1:0.9 or 1:8.3.

[0613] Further, when the estrogen receptor degrader is compound 63 or its optical isomer, salt, hydrate or solvate, and the CDK4 / 6 inhibitor is Palbociclib or its optical isomer, salt, hydrate or solvate, the molar ratio of the estrogen receptor degrader to the CDK4 / 6 inhibitor is 1:0.3 to 1:8.3; the molar ratio is preferably 1:0.3, 1:0.9 or 1:8.3;

[0614] And / or, when the estrogen receptor degrader is compound 63 or its optical isomer, salt, hydrate or solvate, and the CDK4 / 6 inhibitor is Abemaciclib or its optical isomer, salt, hydrate or solvate, the molar ratio of the estrogen receptor degrader to the CDK4 / 6 inhibitor is 1:0.03 to 1:0.9; preferably, the molar ratio is 1:0.03, 1:0.3 or 1:0.9;

[0615] And / or, when the estrogen receptor degrader is compound 63 or its optical isomer, salt, hydrate or solvate, and the CDK4 / 6 inhibitor is Ribociclib or its optical isomer, salt, hydrate or solvate, the molar ratio of the estrogen receptor degrader to the CDK4 / 6 inhibitor is 1:0.3 to 1:24.4; the molar ratio is preferably 1:0.3, 1:2.7, or 1:24.4.

[0616] The present invention also provides the use of an estrogen receptor degrader in combination with a CDK4 / 6 inhibitor in the preparation of a drug for degrading estrogen receptors.

[0617] Furthermore, the molar ratio of the estrogen receptor degrader to the CDK4 / 6 inhibitor is 1:0.01 to 1:666.7.

[0618] Furthermore, the estrogen receptor degrading agent is selected from the aforementioned compounds, or optical isomers thereof, or salts thereof, or hydrates thereof, or solvates thereof;

[0619] The CDK4 / 6 inhibitor is Palbociclib, Abemaciclib, Ribociclib, Trilaciclib, Dalpiciclib, Lerociclib, AT7519M, Dinaciclib, BSJ-03-204, Narazaciclib, XY028-140, BSJ-04-132, PF-07220060, Nimbolide, XY028-133, Cimpuciclib, CDK4 / 6-IN-2, CDK4 / 6-IN-12, CDK4 / 6-IN-7, CDK-IN-12, CDK4 / 6-IN-8, CDK4 / 6-IN-10 or its optical isomers, salts, hydrates or solvates;

[0620] Preferably, the CDK4 / 6 inhibitor is Palbociclib, Abemaciclib, Ribociclib, Dalpiciclib or an optical isomer thereof, a salt thereof, a hydrate thereof, or a solvate thereof.

[0621] Further, 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 CDK4 / 6 inhibitor is Palbociclib 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 CDK4 / 6 inhibitor is 1:0.3 to 1:666.7; the molar ratio is preferably 1:0.3 to 1:24.4; the molar ratio is more preferably 1:0.3, 1:2.7, or 1:24.4;

[0622] And / or, when the estrogen receptor degrader is ARV-471 or an optical isomer, a salt, a hydrate or a solvate thereof, and the CDK4 / 6 inhibitor is Abemaciclib or an optical isomer, a salt, a hydrate or a solvate thereof, the molar ratio of the estrogen receptor degrader to the CDK4 / 6 inhibitor is 1:0.3 to 1:2.7; preferably, the molar ratio is 1:0.3, 1:0.9 or 1:2.7;

[0623] And / or, 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 CDK4 / 6 inhibitor is Ribociclib 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 CDK4 / 6 inhibitor is 1:0.1 to 1:8.3; the molar ratio is preferably 1:0.1, 1:0.9, or 1:8.3.

[0624] Further, when the estrogen receptor degrader is compound 75 or its optical isomer, salt, hydrate or solvate, and the CDK4 / 6 inhibitor is Palbociclib or its optical isomer, salt, hydrate or solvate, the molar ratio of the estrogen receptor degrader to the CDK4 / 6 inhibitor is 1:0.1 to 1:666.7; the molar ratio is preferably 1:0.9 to 1:71.4; the molar ratio is more preferably 1:0.9, 1:8.3 or 1:71.4;

[0625] And / or, when the estrogen receptor degrader is compound 75 or its optical isomer, salt, hydrate or solvate, and the CDK4 / 6 inhibitor is Abemaciclib or its optical isomer, salt, hydrate or solvate, the molar ratio of the estrogen receptor degrader to the CDK4 / 6 inhibitor is 1:0.011 to 24.4; the molar ratio is preferably 1:0.03 to 1:0.9; the molar ratio is more preferably 1:0.03, 1:0.3 or 1:0.9;

[0626] And / or, when the estrogen receptor degrader is compound 75 or its optical isomer, salt, hydrate or solvate, and the CDK4 / 6 inhibitor is Ribociclib or its optical isomer, salt, hydrate or solvate, the molar ratio of the estrogen receptor degrader to the CDK4 / 6 inhibitor is 1:0.1 to 1:71.4; the molar ratio is preferably 1:0.3 to 1:71.4; the molar ratio is more preferably 1:0.3, 1:8.3, or 1:71.4.

[0627] Further, when the estrogen receptor degrader is compound 65 or its optical isomer, salt, hydrate or solvate, and the CDK4 / 6 inhibitor is Palbociclib or its optical isomer, salt, hydrate or solvate, the molar ratio of the estrogen receptor degrader to the CDK4 / 6 inhibitor is 1:0.1 to 1:8.3; the molar ratio is preferably 1:0.1, 1:0.9 or 1:8.3;

[0628] And / or, when the estrogen receptor degrader is compound 65 or its optical isomer, salt, hydrate or solvate, and the CDK4 / 6 inhibitor is Abemaciclib or its optical isomer, salt, hydrate or solvate, the molar ratio of the estrogen receptor degrader to the CDK4 / 6 inhibitor is 1:0.03 to 1:0.3; preferably, the molar ratio is 1:0.03 or 1:0.3;

[0629] And / or, when the estrogen receptor degrader is compound 65 or its optical isomer, salt, hydrate or solvate, and the CDK4 / 6 inhibitor is Ribociclib or its optical isomer, salt, hydrate or solvate, the molar ratio of the estrogen receptor degrader to the CDK4 / 6 inhibitor is 1:0.1 to 1:8.3; the molar ratio is preferably 1:0.1, 1:0.9 or 1:8.3.

[0630] Further, when the estrogen receptor degrader is compound 63 or its optical isomer, salt, hydrate or solvate, and the CDK4 / 6 inhibitor is Palbociclib or its optical isomer, salt, hydrate or solvate, the molar ratio of the estrogen receptor degrader to the CDK4 / 6 inhibitor is 1:0.3 to 1:8.3; the molar ratio is preferably 1:0.3, 1:0.9 or 1:8.3;

[0631] And / or, when the estrogen receptor degrader is compound 63 or its optical isomer, salt, hydrate or solvate, and the CDK4 / 6 inhibitor is Abemaciclib or its optical isomer, salt, hydrate or solvate, the molar ratio of the estrogen receptor degrader to the CDK4 / 6 inhibitor is 1:0.03 to 1:0.9; preferably, the molar ratio is 1:0.03, 1:0.3 or 1:0.9;

[0632] And / or, when the estrogen receptor degrader is compound 63 or its optical isomer, salt, hydrate or solvate, and the CDK4 / 6 inhibitor is Ribociclib or its optical isomer, salt, hydrate or solvate, the molar ratio of the estrogen receptor degrader to the CDK4 / 6 inhibitor is 1:0.3 to 1:24.4; the molar ratio is preferably 1:0.3, 1:2.7, or 1:24.4.

[0633] Furthermore, the drug for degrading estrogen receptors is an estrogen receptor degrader or a drug for treating estrogen receptor-related diseases.

[0634] Furthermore, the drug is used in a drug for treating and / or preventing cancer;

[0635] Preferably, the cancer is breast cancer, ovarian cancer, or lung cancer.

[0636] The compounds and derivatives provided in the present invention can be named according to the IUPAC (International Union of Pure and Applied Chemistry) or CAS (Chemical Abstracts Service, Columbus, OH) nomenclature system.

[0637] 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 in this document, the meaning that a person skilled in the art can give them should be given based on the disclosure and context.

[0638] "Substitution" refers to the replacement of a hydrogen atom in a molecule by another different atom or molecule.

[0639] 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 1 to 8 carbon atoms; "C1-C8 alkoxy" refers to an alkoxy group containing 1 to 8 carbon atoms.

[0640] "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 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, etc.

[0641] "Halogen" is fluorine, chlorine, bromine or iodine.

[0642] In the present invention, cycloalkyl refers to a saturated or partially saturated non-aromatic cyclic group consisting 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, a sulfur atom. Examples of heterocyclyl groups include, for example, piperidinyl, piperazinyl, morpholinyl.

[0643] In the present invention, aryl refers to an aromatic unsaturated group without ring heteroatoms and having a single ring or multiple rings (including fused, bridged and spiro ring systems), such as phenyl, anthracenyl, naphthyl. Heteroaryl refers to an aromatic unsaturated ring containing at least one heteroatom; including a single ring or multiple rings (including fused, bridged and spiro ring systems); wherein the heteroatom refers to a nitrogen atom, an oxygen atom, a sulfur atom. Such as pyridyl, pyrazinyl, pyridazinyl, pyrazolyl, furanyl, thienyl, oxazolyl, etc.

[0644] In the present invention, the structure of OBn is

[0645] 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

[0646] In the present invention, in the compound of formula (I), when there is no dotted line between Y and W, the compound structure is

[0647] R ab is a halogen; when the dotted line between Y and W is a bond, the compound structure is

[0648]

[0649] Palbociclib, Abemaciclib, Ribociclib, Trilaciclib, Dalpiciclib, Lerociclib, AT7519M, Dinaciclib, BSJ-03-204, Narazaciclib, XY028-140, BS J-04-132, PF-07220060, Nimbolide, XY028-133, Cimpuciclib, CDK4 / 6-IN-2, CDK4 / 6-IN-12, CDK4 / 6-IN-7, CDK-IN-12, CDK4 / 6-IN-8, CDK4 / 6-IN-10. palbociclib, Abemaciclib, Ribociclib, Trilaciclib, Dalpiciclib, Lerociclib, AT7519M, Dinaciclib, BSJ-03-204, Narazaciclib. XY028-140, BSJ-04-132, PF-07220060, Nimbolide, XY028-133, Cimpuciclib, CDK4 / 6-IN-2, CDK4 / 6-IN-12, CDK4 / 6-IN-7, CDK-IN-12, CDK4 / 6-IN-8, CDK4 / 6-IN-10,

[0650] The present invention combines an estrogen receptor degrader with a CDK4 / 6 inhibitor to degrade estrogen receptors and inhibit cancer cell growth, which can play a synergistic role, significantly improve the effect of treating diseases related to estrogen receptors, and has good application prospects.

[0651] Obviously, according to the above contents of the present invention, in accordance with common technical knowledge and customary means in the art, without departing from the above basic technical ideas of the present invention, other various forms of modification, replacement or change may be made.

[0652] The above contents of the present invention are further described in detail below through specific implementation methods in the form of embodiments. However, this should not be understood as the scope of the above subject matter of the present invention being limited to the following examples. All technologies realized based on the above contents of the present invention belong to the scope of the present invention. BRIEF DESCRIPTION OF THE DRAWINGS

[0653] Figure 1 The inhibitory effect of compound 63 and Palbociclib on the growth of MCF-7 cells.

[0654] Figure 2 The inhibitory effect of compound 65 and Palbociclib on the growth of MCF-7 cells.

[0655] Figure 3The inhibitory effect of compound 75 and Palbociclib on the growth of MCF-7 cells.

[0656] Figure 4 The inhibitory effects of ARV-471 and Palbociclib on the growth of MCF-7 cells.

[0657] Figure 5 The inhibitory effect of compound 63 and Abemaciclib on the growth of MCF-7 cells.

[0658] Figure 6 The inhibitory effect of compound 65 and Abemaciclib on the growth of MCF-7 cells.

[0659] Figure 7 The inhibitory effect of compound 75 and Abemaciclib on the growth of MCF-7 cells.

[0660] Figure 8 The inhibitory effects of ARV-471 and Abemaciclib on the growth of MCF-7 cells.

[0661] Fig. 9 The inhibitory effect of compound 63 and Ribociclib on the growth of MCF-7 cells.

[0662] Fig.10 The inhibitory effect of compound 65 and Ribociclib on the growth of MCF-7 cells.

[0663] Fig.11 The inhibitory effect of compound 75 and Ribociclib on the growth of MCF-7 cells.

[0664] Fig.12 The inhibitory effects of ARV-471 and Ribociclib on the growth of MCF-7 cells. DETAILED DESCRIPTION

[0665] The CDK4 / 6 inhibitors and devices used in the specific embodiments of the present invention are all known products and are obtained by purchasing commercially available products.

[0666] Example 1: Combination of an estrogen receptor degrader and a CDK4 / 6 inhibitor, Palbociclib

[0667] CDK4 / 6 inhibitor: Palbociclib, with a structure of

[0668] Estrogen receptor degrader: ARV-471, the structure is

[0669] The molar ratio of ARV-471 to Palbociclib is 1:0.3 to 1:24.4 (eg, 1:0.3, 1:2.7 or 1:24.4).

[0670] The above-mentioned estrogen receptor degrader ARV-471 can be replaced by compound 63, the structure of which is

[0671]

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

[0673]

[0674] The above-mentioned estrogen receptor degrader ARV-471 can be replaced by compound 75, the structure of which is

[0675]

[0676] Example 2: Combination of estrogen receptor degrader and CDK4 / 6 inhibitor Abemaciclib

[0677] CDK4 / 6 inhibitor: Abemaciclib, with the structure

[0678] Estrogen receptor degrader: ARV-471.

[0679] The molar ratio of ARV-471 and Abemaciclib is 1:0.3 to 1:2.7 (such as 1:0.3, 1:0.9 or 1:2.7).

[0680] The above-mentioned estrogen receptor degrader ARV-471 can be replaced by compound 63, compound 65, and compound 75.

[0681] Example 3: Combination of estrogen receptor degraders and CDK4 / 6 inhibitor Ribociclib

[0682] CDK4 / 6 inhibitor: Ribociclib, with the structure

[0683] Estrogen receptor degrader: ARV-471.

[0684] The molar ratio of ARV-471 and Ribociclib is 1:0.1 to 1:8.3 (eg, 1:0.1, 1:0.9 or 1:8.3).

[0685] The above-mentioned estrogen receptor degrader ARV-471 can be replaced by compound 63, compound 65, and compound 75.

[0686] The beneficial effects of the present invention are demonstrated below through specific test examples.

[0687] Test Example 1

[0688] Inhibitory effects of four ER Protac compounds 63, 65, 75, and ARV-471 in combination with the CDK4 / 6 inhibitor Palbociclib on breast cancer cells MCF-7

[0689] (1) Combination therapy of compound 63 and Palbociclib

[0690] 1. Experimental methods

[0691] Breast cancer MCF-7 cells in the logarithmic growth phase were cultured at 2×10 3 The cells were inoculated into a 96-well culture plate at a concentration of 100 μL per well. The cells were incubated in an incubator at 37°C, 5% CO2 concentration and saturated humidity for 24 hours. After 24 hours, compound 63 and Palbociclib were added to the 96-well plate. The negative control wells were added with the same volume of cell culture medium containing 10% fetal bovine serum as the drug.

[0692] The concentration range of compound 63 is: 0nM, 0.15nM, 0.46nM, 1.4nM, 4.1nM, 12nM, 37nM, 111nM, 333nM, 1000nM.

[0693] The concentration range of Palbociclib is: 0nM, 1.2nM, 3.7nM, 11nM, 33nM, 100nM.

[0694] After adding drugs and incubating for 5 days, add 10 μL CCK-8 to each well and continue to culture for 3 hours. Measure the absorbance (OD) value of each well at a wavelength of 450nm on an enzyme-linked analyzer. Calculate the cell survival rate according to the formula. Survival rate (%) = OD value of drug-added well / OD value of control well × 100%. Then judge according to the combination index (CI). The CI value judgment standard is shown in Table 1.

[0695] (2) Combination therapy of compound 65 and Palbociclib

[0696] 1. Experimental methods

[0697] Breast cancer cells MCF-7 in the logarithmic growth phase were cultured at 2×10 3The cells were inoculated into a 96-well culture plate at a concentration of 100 μL per well. The cells were incubated in an incubator at 37°C, 5% CO2 concentration and saturated humidity for 24 hours. After 24 hours, compound 65 and Palbociclib were added to the 96-well plate. The negative control wells were added with the same volume of cell culture medium containing 10% fetal bovine serum as the drug.

[0698] The concentration range of compound 65 is: 0nM, 0.15nM, 0.46nM, 1.4nM, 4.1nM, 12nM, 37nM, 111nM, 333nM, 1000nM.

[0699] The concentration range of Palbociclib is: 0nM, 1.2nM, 3.7nM, 11nM, 33nM, 100nM.

[0700] After adding drugs and incubating for 5 days, add 10 μL CCK-8 to each well and continue to culture for 3 hours. Measure the absorbance (OD) value of each well at a wavelength of 450nm on an enzyme-linked analyzer. Calculate the cell survival rate according to the formula. Survival rate (%) = OD value of drug-added well / OD value of control well × 100%. Then judge according to the combination index (CI). The CI value judgment standard is shown in Table 1.

[0701] (3) Combination therapy of compound 75 and Palbociclib

[0702] 1. Experimental methods

[0703] Breast cancer cells MCF-7 in the logarithmic growth phase were cultured at 2×10 3 The cells were inoculated into a 96-well culture plate at a concentration of 100 μL per well. The cells were incubated in an incubator at 37°C, 5% CO2 concentration and saturated humidity for 24 hours. After 24 hours, compound 75 and Palbociclib were added to the 96-well plate. The negative control wells were added with the same volume of cell culture medium containing 10% fetal bovine serum as the drug.

[0704] The concentration range of compound 75 is: 0nM, 0.15nM, 0.46nM, 1.4nM, 4.1nM, 12nM, 37nM, 111nM, 333nM, 1000nM.

[0705] The concentration range of Palbociclib is: 0nM, 1.2nM, 3.7nM, 11nM, 33nM, 100nM.

[0706] After adding drugs and incubating for 5 days, add 10 μL CCK-8 to each well and continue to culture for 3 hours. Measure the absorbance (OD) value of each well at a wavelength of 450nm on an enzyme-linked analyzer. Calculate the cell survival rate according to the formula. Survival rate (%) = OD value of drug-added well / OD value of control well × 100%. Then judge according to the combination index (CI). The CI value judgment standard is shown in Table 1.

[0707] (4) Combination therapy of ARV-471 and Palbociclib

[0708] 1. Experimental methods

[0709] Breast cancer cells MCF-7 in the logarithmic growth phase were cultured at 2×10 3 The cells were inoculated into a 96-well culture plate at a concentration of 100 μL per well. The cells were incubated in an incubator at 37°C, 5% CO2 concentration and saturated humidity for 24 hours. After 24 hours, ARV-471 and Palbociclib were added to the 96-well plate. The negative control wells were added with the same volume of cell culture medium containing 10% fetal bovine serum as the drug.

[0710] The concentration range of ARV-471 is: 0nM, 0.15nM, 0.46nM, 1.4nM, 4.1nM, 12nM, 37nM, 111nM, 333nM, 1000nM.

[0711] The concentration range of Palbociclib is: 0nM, 1.2nM, 3.7nM, 11nM, 33nM, 100nM.

[0712] After adding drugs and incubating for 5 days, add 10 μL CCK-8 to each well and continue to culture for 3 hours. Measure the absorbance (OD) value of each well at a wavelength of 450nm on an enzyme-linked analyzer. Calculate the cell survival rate according to the formula. Survival rate (%) = OD value of drug-added well / OD value of control well × 100%. Then judge according to the combination index (CI). The CI value judgment standard is shown in Table 1.

[0713] Table 1. CI value judgment criteria

[0714]

[0715] 2. Experimental results

[0716] (1) Combination therapy of compound 63 and Palbociclib

[0717] The results of the combination of compound 63 and Palbociclib are as follows Figure 1As shown in the figure, when the molar ratio of compound 63 to Palbociclib is 1:8.3, 1:0.9 or 1:0.3, the CI values ​​of the drug combination are 0.46, 0.48 and 0.70, respectively. Under the above three drug molar ratios, the combination of compound 63 and Palbociclib has a synergistic effect in inhibiting the growth of MCF-7 cells.

[0718] (2) Combination therapy of compound 65 and Palbociclib

[0719] The results of the combination of compound 65 and Palbociclib are as follows Figure 2 As shown in the figure, when the molar ratio of compound 65 to Palbociclib is 1:8.3, 1:0.9 or 1:0.1, the CI values ​​of the drug combination are 0.44, 0.44 and 0.55, respectively. Under the above three drug molar ratios, the combination of compound 65 and Palbociclib has a synergistic effect in inhibiting the growth of MCF-7 cells.

[0720] (3) Combination therapy of compound 75 and Palbociclib

[0721] The results of the combination of compound 75 and Palbociclib are as follows Figure 3 As shown in the figure, when the molar ratio of compound 75 to Palbociclib is 1:71.4, 1:8.3 or 1:0.9, the CI values ​​of the drug combination are 0.17, 0.11 and 0.23, respectively. Under the above three drug molar ratios, the combination of compound 75 and Palbociclib has a synergistic effect in inhibiting the growth of MCF-7 cells.

[0722] (4) Combination therapy of ARV-471 and Palbociclib

[0723] Results of the ARV-471 and Palbociclib combination therapy Figure 4 As shown in the figure, when the molar ratio of ARV-471 to Palbociclib is 1:24.4, 1:2.7 or 1:0.3, the CI values ​​of the drug combination are 0.24, 0.22 and 0.54, respectively. Under the above three drug molar ratios, the combination of ARV-471 and Palbociclib has a synergistic effect in inhibiting the growth of MCF-7 cells.

[0724] The above experimental results show that the combination of four ER Protaks (Compound 63, Compound 65, Compound 75, ARV-471) and Palbociclib has a synergistic effect and can significantly inhibit the growth and proliferation of MCF-7 cells. Its anti-cancer effect is significantly better than that of ER Protac or Palbociclib used alone.

[0725] Test Example 2

[0726] Inhibitory effects of four ER Protac compounds 63, 65, 75, and ARV-471 in combination with the CDK4 / 6 inhibitor Abemaciclib on breast cancer cells MCF-7

[0727] (1) Combination therapy of compound 63 and Abemaciclib

[0728] 1. Experimental methods

[0729] Breast cancer cells MCF-7 in the logarithmic growth phase were cultured at 2×10 3 The cells were inoculated into a 96-well culture plate at a concentration of 100 μL per well. The cells were incubated in an incubator at 37°C, 5% CO2 concentration and saturated humidity for 24 hours. After 24 hours, compound 63 and Abemaciclib were added to the 96-well plate. The negative control wells were added with the same volume of cell culture medium containing 10% fetal bovine serum as the drug.

[0730] The concentration range of compound 63 is: 0nM, 0.15nM, 0.46nM, 1.4nM, 4.1nM, 12nM, 37nM, 111nM, 333nM, 1000nM.

[0731] Abemaciclib concentration range is: 0nM, 1.2nM, 3.7nM, 11nM, 33nM, 100nM.

[0732] After adding drugs and incubating for 5 days, add 10 μL CCK-8 to each well and continue to culture for 3 hours. Measure the absorbance (OD) value of each well at a wavelength of 450nm on an enzyme-linked analyzer. Calculate the cell survival rate according to the formula. Survival rate (%) = OD value of drug-added well / OD value of control well × 100%. Then judge according to the combination index (CI). The CI value judgment standard is shown in Table 1.

[0733] (2) Combination therapy of compound 65 and Abemaciclib

[0734] 1. Experimental methods

[0735] Breast cancer cells MCF-7 in the logarithmic growth phase were cultured at 2×10 3 The cells were inoculated into a 96-well culture plate at a concentration of 100 μL per well. The cells were incubated in an incubator at 37°C, 5% CO2 concentration and saturated humidity for 24 hours. After 24 hours, compound 65 and Abemaciclib were added to the 96-well plate. The negative control wells were added with the same volume of cell culture medium containing 10% fetal bovine serum as the drug.

[0736] The concentration range of compound 65 is: 0nM, 0.15nM, 0.46nM, 1.4nM, 4.1nM, 12nM, 37nM, 111nM, 333nM, 1000nM.

[0737] Abemaciclib concentration range is: 0nM, 1.2nM, 3.7nM, 11nM, 33nM, 100nM.

[0738] After adding drugs and incubating for 5 days, add 10 μL CCK-8 to each well and continue to culture for 3 hours. Measure the absorbance (OD) value of each well at a wavelength of 450nm on an enzyme-linked analyzer. Calculate the cell survival rate according to the formula. Survival rate (%) = OD value of drug-added well / OD value of control well × 100%. Then judge according to the combination index (CI). The CI value judgment standard is shown in Table 1.

[0739] (3) Combination therapy of compound 75 and Abemaciclib

[0740] 1. Experimental methods

[0741] Breast cancer cells MCF-7 in the logarithmic growth phase were cultured at 2×10 3 The cells were inoculated into a 96-well culture plate at a concentration of 100 μL per well. The cells were incubated in an incubator at 37°C, 5% CO2 concentration and saturated humidity for 24 hours. After 24 hours, compound 75 and Abemaciclib were added to the 96-well plate. The negative control wells were added with the same volume of cell culture medium containing 10% fetal bovine serum as the drug.

[0742] The concentration range of compound 75 is: 0nM, 0.15nM, 0.46nM, 1.4nM, 4.1nM, 12nM, 37nM, 111nM, 333nM, 1000nM.

[0743] Abemaciclib concentration range is: 0nM, 1.2nM, 3.7nM, 11nM, 33nM, 100nM.

[0744] After adding drugs and incubating for 5 days, add 10 μL CCK-8 to each well and continue to culture for 3 hours. Measure the absorbance (OD) value of each well at a wavelength of 450nm on an enzyme-linked analyzer. Calculate the cell survival rate according to the formula. Survival rate (%) = OD value of drug-added well / OD value of control well × 100%. Then judge according to the combination index (CI). The CI value judgment standard is shown in Table 1.

[0745] (4) Combination therapy of ARV-471 and Abemaciclib

[0746] 1. Experimental methods

[0747] Breast cancer cells MCF-7 in the logarithmic growth phase were cultured at 2×10 3 The cells were inoculated into a 96-well culture plate at a concentration of 100 μL per well. The cells were incubated in an incubator at 37°C, 5% CO2 concentration and saturated humidity for 24 hours. After 24 hours, ARV-471 and Abemaciclib were added to the 96-well plate. The negative control wells were added with the same volume of cell culture medium containing 10% fetal bovine serum as the drug.

[0748] The concentration range of ARV-471 is: 0nM, 0.15nM, 0.46nM, 1.4nM, 4.1nM, 12nM, 37nM, 111nM, 333nM, 1000nM.

[0749] Abemaciclib concentration range is: 0nM, 1.2nM, 3.7nM, 11nM, 33nM, 100nM.

[0750] After adding drugs and incubating for 5 days, add 10 μL CCK-8 to each well and continue to culture for 3 hours. Measure the absorbance (OD) value of each well at a wavelength of 450nm on an enzyme-linked analyzer. Calculate the cell survival rate according to the formula. Survival rate (%) = OD value of drug-added well / OD value of control well × 100%. Then judge according to the combination index (CI). The CI value judgment standard is shown in Table 1.

[0751] 2. Experimental results

[0752] (1) Combination therapy of compound 63 and Abemaciclib

[0753] The results of the combination of compound 63 and Abemaciclib are as follows Figure 5As shown in the figure, when the molar ratio of compound 63 to Abemaciclib is 1:0.9, 1:0.3 or 1:0.03, the CI values ​​of the drug combination are 0.52, 0.75 and 0.84, respectively. Under the above three drug molar ratios, the combination of compound 63 and Abemaciclib has a synergistic effect in inhibiting the growth of MCF-7 cells.

[0754] (2) Combination therapy of compound 65 and Abemaciclib

[0755] The results of the combination of compound 65 and Abemaciclib are as follows Figure 6 As shown in the figure, when the molar ratio of compound 65 to Abemaciclib is 1:0.3 or 1:0.3 or 1:0.03, the CI values ​​of the drug combination are 0.32, 0.50, and 0.44, respectively. Under the above three drug molar ratios, the combination of compound 65 and Abemaciclib has a synergistic effect in inhibiting the growth of MCF-7 cells.

[0756] (3) Combination therapy of compound 75 and Abemaciclib

[0757] The results of the combination of compound 75 and Abemaciclib are as follows Figure 7 As shown in the figure, when the molar ratio of compound 75 to Abemaciclib is 1:0.9, 1:0.3 or 1:0.03, the CI values ​​of the drug combination are 0.35, 0.38 and 0.61, respectively. Under the above three drug molar ratios, the combination of compound 75 and Abemaciclib has a synergistic effect in inhibiting the growth of MCF-7 cells.

[0758] (4) Combination therapy of ARV-471 and Abemaciclib

[0759] The results of the combination of ARV-471 and Abemaciclib are as follows Figure 8 As shown in the figure, when the molar ratio of ARV-471 to Abemaciclib is 1:2.7, 1:0.9 or 1:0.3, the CI values ​​of the drug combination are 0.51, 0.33 and 0.34, respectively. Under the above three drug molar ratios, the combination of compound 75 and Abemaciclib has a synergistic effect in inhibiting the growth of MCF-7 cells.

[0760] The above experimental results show that the combination of four ER ProtaCs (Compound 63, Compound 65, Compound 75, ARV-471) and Abemaciclib has a synergistic effect and can significantly inhibit the growth and proliferation of MCF-7 cells. Its anti-cancer effect is significantly better than that of ER ProtaC or Abemaciclib used alone.

[0761] Test Example 3

[0762] Inhibitory effects of four ER Protac compounds 63, 65, 75, and ARV-471 in combination with the CDK4 / 6 inhibitor Ribociclib on breast cancer cells MCF-7

[0763] (1) Combination therapy of compound 63 and Ribociclib

[0764] 1. Experimental methods

[0765] Breast cancer cells MCF-7 in the logarithmic growth phase were cultured at 2×10 3 The cells were inoculated into a 96-well culture plate at a concentration of 100 μL per well. The cells were incubated in an incubator at 37°C, 5% CO2 concentration and saturated humidity for 24 hours. After 24 hours, compound 63 and Ribociclib were added to the 96-well plate. The negative control wells were added with the same volume of cell culture medium containing 10% fetal bovine serum as the drug.

[0766] The concentration range of compound 63 is: 0nM, 0.15nM, 0.46nM, 1.4nM, 4.1nM, 12nM, 37nM, 111nM, 333nM, 1000nM.

[0767] The concentration range of Ribociclib is: 0nM, 1.2nM, 3.7nM, 11nM, 33nM, 100nM.

[0768] After adding drugs and incubating for 5 days, add 10 μL CCK-8 to each well and continue to culture for 3 hours. Measure the absorbance (OD) value of each well at a wavelength of 450nm on an enzyme-linked analyzer. Calculate the cell survival rate according to the formula. Survival rate (%) = OD value of drug-added well / OD value of control well × 100%. Then judge according to the combination index (CI). The CI value judgment standard is shown in Table 1.

[0769] (2) Combination therapy of compound 65 and Ribociclib

[0770] 1. Experimental methods

[0771] Breast cancer cells MCF-7 in the logarithmic growth phase were cultured at 2×103 The cells were inoculated into a 96-well culture plate at a concentration of 100 μL per well. The cells were incubated in an incubator at 37°C, 5% CO2 concentration and saturated humidity for 24 hours. After 24 hours, compound 65 and Ribociclib were added to the 96-well plate. The negative control wells were added with the same volume of cell culture medium containing 10% fetal bovine serum as the drug.

[0772] The concentration range of compound 65 is: 0nM, 0.15nM, 0.46nM, 1.4nM, 4.1nM, 12nM, 37nM, 111nM, 333nM, 1000nM.

[0773] The concentration range of Ribociclib is: 0nM, 1.2nM, 3.7nM, 11nM, 33nM, 100nM.

[0774] After adding drugs and incubating for 5 days, add 10 μL CCK-8 to each well and continue to culture for 3 hours. Measure the absorbance (OD) value of each well at a wavelength of 450nm on an enzyme-linked analyzer. Calculate the cell survival rate according to the formula. Survival rate (%) = OD value of drug-added well / OD value of control well × 100%. Then judge according to the combination index (CI). The CI value judgment standard is shown in Table 1.

[0775] (3) Combination therapy of compound 75 and Ribociclib

[0776] 1. Experimental methods

[0777] Breast cancer cells MCF-7 in the logarithmic growth phase were cultured at 2×10 3 The cells were inoculated into a 96-well culture plate at a concentration of 100 μL per well. The cells were incubated in an incubator at 37°C, 5% CO2 concentration and saturated humidity for 24 hours. After 24 hours, compound 75 and Ribociclib were added to the 96-well plate. The negative control wells were added with the same volume of cell culture medium containing 10% fetal bovine serum as the drug.

[0778] The concentration range of compound 75 is: 0nM, 0.15nM, 0.46nM, 1.4nM, 4.1nM, 12nM, 37nM, 111nM, 333nM, 1000nM.

[0779] The concentration range of Ribociclib is: 0nM, 1.2nM, 3.7nM, 11nM, 33nM, 100nM.

[0780] After adding drugs and incubating for 5 days, add 10 μL CCK-8 to each well and continue to culture for 3 hours. Measure the absorbance (OD) value of each well at a wavelength of 450nm on an enzyme-linked analyzer. Calculate the cell survival rate according to the formula. Survival rate (%) = OD value of drug-added well / OD value of control well × 100%. Then judge according to the combination index (CI). The CI value judgment standard is shown in Table 1.

[0781] (4) Combination therapy of ARV-471 and Ribociclib

[0782] 1. Experimental methods

[0783] Breast cancer cells MCF-7 in the logarithmic growth phase were cultured at 2×10 3 The cells were inoculated into a 96-well culture plate at a concentration of 100 μL per well. The cells were incubated in an incubator at 37°C, 5% CO2 concentration and saturated humidity for 24 hours. After 24 hours, ARV-471 and Ribociclib were added to the 96-well plate. The negative control wells were added with the same volume of cell culture medium containing 10% fetal bovine serum as the drug.

[0784] The concentration range of ARV-471 is: 0nM, 0.15nM, 0.46nM, 1.4nM, 4.1nM, 12nM, 37nM, 111nM, 333nM, 1000nM.

[0785] The concentration range of Ribociclib is: 0nM, 1.2nM, 3.7nM, 11nM, 33nM, 100nM.

[0786] After adding drugs and incubating for 5 days, add 10 μL CCK-8 to each well and continue to culture for 3 hours. Measure the absorbance (OD) value of each well at a wavelength of 450nm on an enzyme-linked analyzer. Calculate the cell survival rate according to the formula. Survival rate (%) = OD value of drug-added well / OD value of control well × 100%. Then judge according to the combination index (CI). The CI value judgment standard is shown in Table 1.

[0787] 2. Experimental results

[0788] (1) Combination therapy of compound 63 and Ribociclib

[0789] The results of the combination of compound 63 and Ribociclib are as follows Fig. 9As shown in the figure, when the molar ratio of compound 63 to Ribociclib is 1:24.4, 1:2.7 or 1:0.3, the CI values ​​of the drug combination are 0.52, 0.34 and 0.70, respectively. Under the above three drug molar ratios, the combination of compound 63 and Ribociclib has a synergistic effect in inhibiting the growth of MCF-7 cells.

[0790] (2) Combination therapy of compound 65 and Ribociclib

[0791] The results of the combination of compound 65 and Ribociclib are as follows Fig.10 As shown in the figure, when the molar ratio of compound 65 to Ribociclib is 1:8.3, 1:0.9 or 1:0.1, the CI values ​​of the drug combination are 0.29, 0.32 and 0.89, respectively. Under the above three drug molar ratios, the combination of compound 65 and Ribociclib has a synergistic effect in inhibiting the growth of MCF-7 cells.

[0792] (3) Combination therapy of compound 75 and Ribociclib

[0793] The results of the combination of compound 75 and Ribociclib are as follows Fig.11 As shown in the figure, when the molar ratio of compound 75 to Ribociclib is 1:71.4, 1:8.3 or 1:0.3, the CI values ​​of the drug combination are 0.06, 0.05 and 0.26, respectively. Under the above three drug molar ratios, the combination of compound 75 and Ribociclib has a synergistic effect in inhibiting the growth of MCF-7 cells.

[0794] (4) Combination therapy of ARV-471 and Ribociclib

[0795] The results of the combination of ARV-471 and Ribociclib are as follows Fig.12 As shown in the figure, when the molar ratio of ARV-471 to Ribociclib is 1:8.3, 1:0.9 or 1:0.1, the CI values ​​of the drug combination are 0.09, 0.14 and 0.61, respectively. Under the above three drug molar ratios, the combination of ARV-471 and Ribociclib has a synergistic effect in inhibiting the growth of MCF-7 cells.

[0796] The above experimental results show that the combination of four ER ProtaCs (Compound 63, Compound 65, Compound 75, ARV-471) and Ribociclib has a synergistic effect and can significantly inhibit the growth and proliferation of MCF-7 cells. Its anti-cancer effect is significantly better than that of ER ProtaC or Ribociclib used alone.

[0797] Test Example 4

[0798] In vivo inhibitory effect of ER Protac compound 75 and CDK4 / 6 inhibitor Palbociclib on MCF-7 human tumor cell line xenograft model

[0799] 1. Experimental methods

[0800] 0.36mg / 60-day sustained-release estrogen tablets were implanted subcutaneously on the right back of NOD / SCID mice. The next day, MCF-7 cells were inoculated in the right breast pad of the experimental mice to establish an orthotopic xenograft tumor model of human breast cancer. The experimental groups were vehicle control group (G01), compound 75 10mg / kg group (G02), Palbociclib 60mg / kg group (G03), and compound 75 10mg / kg and Palbociclib 60mg / kg co-administration group (G04). There were 10 mice in each group, and the mice were orally gavaged every day for 4 consecutive weeks. The day of group administration was defined as Day 0. The efficacy was evaluated according to the tumor inhibition rate (TGI).

[0801] 2. Analysis methods

[0802] To compare the tumor volumes on a certain day in different treatment groups, the assumption of homogeneity of variance among all groups was first verified using the Bartlett test. When the p-value of the Bartlett test was not less than 0.05, one-way ANOVA was used to test whether the means of all groups were equal. If the p-value of the one-way ANOVA was less than 0.05, the Tukey HSD test was used for pairwise comparisons between all groups or the Dunnett's t-test was used for pairwise comparisons between each treatment group and the control group. When the p-value of the Bartlett test was less than 0.05, the Kruskal Wallis test was used to test whether the medians of all groups were equal. If the p-value of the KruskalWallis test was less than 0.05, the Conover test was used for pairwise comparisons between all groups or between each treatment group and the control group, and the p-value was corrected accordingly according to the number of groups for multiple testing.

[0803] In addition, for the purpose of exploratory data analysis, pairwise comparisons between all groups at any time point were performed. Because this comparison only used the tumor volume data of the two groups to be compared at a specific time point, no multiple testing correction was required. The Shapiro Wilk test was first used to verify the assumption of homogeneity of variance between the two groups. When the p value of the Shapiro Wilk test was not less than 0.05, the Welch's t test was used to compare whether the means of the two groups were equal; when the p value of the Shapiro Wilk test was less than 0.05, the MannWhitney U test was used to compare whether the medians of the two groups were equal.

[0804] All statistical analyses and graphics were performed in R (version 3.3.1). Unless otherwise specified, all tests were two-tailed, and p values ​​less than 0.05 were considered statistically significant.

[0805] Survival analysis was performed using the Kaplan-Meier model and the Log-rank method.

[0806] 3. Experimental results

[0807] The experimental results are shown in Table 2. The compound 7510 mg / kg treatment group had a significant tumor inhibition effect. The average tumor volume on Day 28 was 161.11 mm 3 The TGI was 59.43%, which was significantly different from the control group (p<0.001). The Palbociclib 60mg / kg treatment group had a significant tumor inhibition effect, with an average tumor volume of 143.46mm on Day 28. 3 The TGI was 63.87%, which was significantly different from the control group (p<0.001). The compound 75 10 mg / kg and Palbociclib 60 mg / kg co-administered group had a significant tumor inhibition effect, with an average tumor volume of 53.02 mm on Day 28. 3 The TGI was 86.65%, which was significantly different from that of the control group (p<0.001), the group treated with compound 7510 mg / kg alone (p<0.05), and the group treated with Palbociclib 60 mg / kg alone (p<0.001).

[0808] Table 2. Efficacy results on Day 28 of the experiment

[0809]

[0810] Note: Because the Bartlett test value was <0.05 and the Kruskal-Wallis test value was <0.05, the Conover test was used for pairwise comparisons between all groups and the control group; the p value was calculated from the absolute tumor volume, and p < 0.05 indicated a significant difference between the two groups.

[0811] The above results indicate that the combined use of compound 75 and Palbociclib has a significant in vivo tumor inhibitory effect on the MCF-7 human tumor cell line xenograft model, and the tumor inhibitory effect is significantly better than the use of compound 75 and Palbociclib alone, with significant differences.

[0812] In summary, the present invention combines the estrogen receptor degrader with the CDK4 / 6 inhibitor, which can exert a synergistic effect, significantly improve the effect of treating diseases related to the estrogen receptor, and has good application prospects.

Claims

1. A pharmaceutical composition for degrading estrogen receptors, characterized in that: It consists of an estrogen receptor degrader and a CDK4 / 6 inhibitor.

2. The pharmaceutical composition according to claim 1, characterized in that: The molar ratio of the estrogen receptor degrader to the CDK4 / 6 inhibitor is 1:0.01 to 1:666.

7.

3. The pharmaceutical composition according to claim 1 or 2, characterized in that: The estrogen receptor degrading 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 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.

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 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; 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.

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 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 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, 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 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.

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 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; 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 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.

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 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; 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 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; 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.

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 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.

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 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; 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 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 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, 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; and the substituents of the phenyl, thienyl, furanyl, pyrrolyl, pyrimidinyl, pyridazinyl, pyrazolyl or pyrazinyl are 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 CDK4 / 6 inhibitor is Palbociclib, Abemaciclib, Ribociclib, Trilaciclib, Dalpiciclib, Lerociclib, AT7519M, Dinaciclib, BSJ-03-204, Narazaciclib, XY028-140, BSJ-04-132, PF-07220060, Nimbolide, XY028-133, Cimpuciclib, CDK4 / 6-IN-2, CDK4 / 6-IN-12, CDK4 / 6-IN-7, CDK-IN-12, CDK4 / 6-IN-8, CDK4 / 6-IN-10 or its optical isomers, salts, hydrates or solvates; Preferably, the CDK4 / 6 inhibitor is Palbociclib, Abemaciclib, Ribociclib, Dalpiciclib 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 an optical isomer, a salt, a hydrate or a solvate thereof, and the CDK4 / 6 inhibitor is Palbociclib or an optical isomer, a salt, a hydrate or a solvate thereof, the molar ratio of the estrogen receptor degrader to the CDK4 / 6 inhibitor is 1:0.3 to 1:666.7; the molar ratio is preferably 1:0.3 to 1:24.4; the molar ratio is more preferably 1:0.3, 1:2.7, 1:24.4; And / or, when the estrogen receptor degrader is ARV-471 or an optical isomer, a salt, a hydrate or a solvate thereof, and the CDK4 / 6 inhibitor is Abemaciclib or an optical isomer, a salt, a hydrate or a solvate thereof, the molar ratio of the estrogen receptor degrader to the CDK4 / 6 inhibitor is 1:0.3 to 1:2.7; preferably, the molar ratio is 1:0.3, 1:0.9 or 1:2.7; And / or, 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 CDK4 / 6 inhibitor is Ribociclib 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 CDK4 / 6 inhibitor is 1:0.1 to 1:8.3; the molar ratio is preferably 1:0.1, 1:0.9, or 1:8.

3.

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 CDK4 / 6 inhibitor is Palbociclib or its optical isomer, salt, hydrate or solvate, the molar ratio of the estrogen receptor degrader to the CDK4 / 6 inhibitor is 1:0.1 to 1:666.7; the molar ratio is preferably 1:0.9 to 1:71.4; the molar ratio is more preferably 1:0.9, 1:8.3 or 1:71.4; And / or, when the estrogen receptor degrader is compound 75 or its optical isomer, salt, hydrate or solvate, and the CDK4 / 6 inhibitor is Abemaciclib or its optical isomer, salt, hydrate or solvate, the molar ratio of the estrogen receptor degrader to the CDK4 / 6 inhibitor is 1:0.011 to 1:24.4; the molar ratio is preferably 1:0.03 to 1:0.9; the molar ratio is more preferably 1:0.03, 1:0.3 or 1:0.9; And / or, when the estrogen receptor degrader is compound 75 or its optical isomer, salt, hydrate or solvate, and the CDK4 / 6 inhibitor is Ribociclib or its optical isomer, salt, hydrate or solvate, the molar ratio of the estrogen receptor degrader to the CDK4 / 6 inhibitor is 1:0.1 to 1:71.4; the molar ratio is preferably 1:0.3 to 1:71.4; the molar ratio is more preferably 1:0.3, 1:8.3, or 1:71.

4.

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 CDK4 / 6 inhibitor is Palbociclib or its optical isomer, salt, hydrate or solvate, the molar ratio of the estrogen receptor degrader to the CDK4 / 6 inhibitor is 1:0.1 to 1:8.3; preferably, the molar ratio is 1:0.1, 1:0.9 or 1:8.3; And / or, when the estrogen receptor degrader is compound 65 or its optical isomer, salt, hydrate or solvate, and the CDK4 / 6 inhibitor is Abemaciclib or its optical isomer, salt, hydrate or solvate, the molar ratio of the estrogen receptor degrader to the CDK4 / 6 inhibitor is 1:0.03 to 1:0.3; preferably, the molar ratio is 1:0.03 or 1:0.3; And / or, when the estrogen receptor degrader is compound 65 or its optical isomer, salt, hydrate or solvate, and the CDK4 / 6 inhibitor is Ribociclib or its optical isomer, salt, hydrate or solvate, the molar ratio of the estrogen receptor degrader to the CDK4 / 6 inhibitor is 1:0.1 to 1:8.3; the molar ratio is preferably 1:0.1, 1:0.9 or 1:8.

3.

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 CDK4 / 6 inhibitor is Palbociclib or its optical isomer, salt, hydrate or solvate, the molar ratio of the estrogen receptor degrader to the CDK4 / 6 inhibitor is 1:0.3 to 1:8.3; preferably, the molar ratio is 1:0.3, 1:0.9 or 1:8.3; And / or, when the estrogen receptor degrader is compound 63 or its optical isomer, salt, hydrate or solvate, and the CDK4 / 6 inhibitor is Abemaciclib or its optical isomer, salt, hydrate or solvate, the molar ratio of the estrogen receptor degrader to the CDK4 / 6 inhibitor is 1:0.03 to 1:0.9; preferably, the molar ratio is 1:0.03, 1:0.3 or 1:0.9; And / or, when the estrogen receptor degrader is compound 63 or its optical isomer, salt, hydrate or solvate, and the CDK4 / 6 inhibitor is Ribociclib or its optical isomer, salt, hydrate or solvate, the molar ratio of the estrogen receptor degrader to the CDK4 / 6 inhibitor is 1:0.3 to 1:24.4; the molar ratio is preferably 1:0.3, 1:2.7, or 1:24.

4.

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 degrader and a CDK4 / 6 inhibitor according to a molar ratio or a mass 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 breast cancer, ovarian cancer, or lung 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 degrader and a CDK4 / 6 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 degrader to the CDK4 / 6 inhibitor is 1:0.01 to 1:666.

7.

40. The combined drug according to claim 38 or 39, characterized in that: The estrogen receptor degrading agent is selected from the compounds described in claims 3 to 28, or optical isomers thereof, or salts thereof, or hydrates thereof, or solvates thereof; The CDK4 / 6 inhibitor is Palbociclib, Abemaciclib, Ribociclib, Trilaciclib, Dalpiciclib, Lerociclib, AT7519M, Dinaciclib, BSJ-03-204, Narazaciclib, XY028-140, BSJ-04-132, PF-07220060, Nimbolide, XY028-133, Cimpuciclib, CDK4 / 6-IN-2, CDK4 / 6-IN-12, CDK4 / 6-IN-7, CDK-IN-12, CDK4 / 6-IN-8, CDK4 / 6-IN-10 or its optical isomers, salts, hydrates or solvates; Preferably, the CDK4 / 6 inhibitor is Palbociclib, Abemaciclib, Ribociclib, Dalpiciclib or an optical isomer thereof, a salt thereof, a hydrate thereof, or a solvate thereof.

41. The combined drug according to claim 38 or 39, characterized in that: When the estrogen receptor degrader is ARV-471 or an optical isomer, a salt, a hydrate or a solvate thereof, and the CDK4 / 6 inhibitor is Palbociclib or an optical isomer, a salt, a hydrate or a solvate thereof, the molar ratio of the estrogen receptor degrader to the CDK4 / 6 inhibitor is 1:0.3 to 1:666.7; the molar ratio is preferably 1:0.3 to 1:24.4; the molar ratio is more preferably 1:0.3, 1:2.7, 1:24.4; And / or, when the estrogen receptor degrader is ARV-471 or an optical isomer, a salt, a hydrate or a solvate thereof, and the CDK4 / 6 inhibitor is Abemaciclib or an optical isomer, a salt, a hydrate or a solvate thereof, the molar ratio of the estrogen receptor degrader to the CDK4 / 6 inhibitor is 1:0.3 to 1:2.7; preferably, the molar ratio is 1:0.3, 1:0.9 or 1:2.7; And / or, 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 CDK4 / 6 inhibitor is Ribociclib 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 CDK4 / 6 inhibitor is 1:0.1 to 1:8.3; the molar ratio is preferably 1:0.1, 1:0.9, or 1:8.

3.

42. The combined drug according to claim 38 or 39, characterized in that: When the estrogen receptor degrader is compound 75 or its optical isomer, salt, hydrate or solvate, and the CDK4 / 6 inhibitor is Palbociclib or its optical isomer, salt, hydrate or solvate, the molar ratio of the estrogen receptor degrader to the CDK4 / 6 inhibitor is 1:0.1 to 1:666.7; the molar ratio is preferably 1:0.9 to 1:71.4; the molar ratio is more preferably 1:0.9, 1:8.3 or 1:71.4; And / or, when the estrogen receptor degrader is compound 75 or its optical isomer, salt, hydrate or solvate, and the CDK4 / 6 inhibitor is Abemaciclib or its optical isomer, salt, hydrate or solvate, the molar ratio of the estrogen receptor degrader to the CDK4 / 6 inhibitor is 1:0.011 to 24.4; the molar ratio is preferably 1:0.03 to 1:0.9; the molar ratio is more preferably 1:0.03, 1:0.3 or 1:0.9; And / or, when the estrogen receptor degrader is compound 75 or its optical isomer, salt, hydrate or solvate, and the CDK4 / 6 inhibitor is Ribociclib or its optical isomer, salt, hydrate or solvate, the molar ratio of the estrogen receptor degrader to the CDK4 / 6 inhibitor is 1:0.1 to 1:71.4; the molar ratio is preferably 1:0.3 to 1:71.4; the molar ratio is more preferably 1:0.3, 1:8.3, or 1:71.

4.

43. The combined drug according to claim 38 or 39, characterized in that: When the estrogen receptor degrader is compound 65 or its optical isomer, salt, hydrate or solvate, and the CDK4 / 6 inhibitor is Palbociclib or its optical isomer, salt, hydrate or solvate, the molar ratio of the estrogen receptor degrader to the CDK4 / 6 inhibitor is 1:0.1 to 1:8.3; preferably, the molar ratio is 1:0.1, 1:0.9 or 1:8.3; And / or, when the estrogen receptor degrader is compound 65 or its optical isomer, salt, hydrate or solvate, and the CDK4 / 6 inhibitor is Abemaciclib or its optical isomer, salt, hydrate or solvate, the molar ratio of the estrogen receptor degrader to the CDK4 / 6 inhibitor is 1:0.03 to 1:0.3; preferably, the molar ratio is 1:0.03 or 1:0.3; And / or, when the estrogen receptor degrader is compound 65 or its optical isomer, salt, hydrate or solvate, and the CDK4 / 6 inhibitor is Ribociclib or its optical isomer, salt, hydrate or solvate, the molar ratio of the estrogen receptor degrader to the CDK4 / 6 inhibitor is 1:0.1 to 1:8.3; the molar ratio is preferably 1:0.1, 1:0.9 or 1:8.

3.

44. The combined drug according to claim 38 or 39, characterized in that: When the estrogen receptor degrader is compound 63 or its optical isomer, salt, hydrate or solvate, and the CDK4 / 6 inhibitor is Palbociclib or its optical isomer, salt, hydrate or solvate, the molar ratio of the estrogen receptor degrader to the CDK4 / 6 inhibitor is 1:0.3 to 1:8.3; preferably, the molar ratio is 1:0.3, 1:0.9 or 1:8.3; And / or, when the estrogen receptor degrader is compound 63 or its optical isomer, salt, hydrate or solvate, and the CDK4 / 6 inhibitor is Abemaciclib or its optical isomer, salt, hydrate or solvate, the molar ratio of the estrogen receptor degrader to the CDK4 / 6 inhibitor is 1:0.03 to 1:0.9; preferably, the molar ratio is 1:0.03, 1:0.3 or 1:0.9; And / or, when the estrogen receptor degrader is compound 63 or its optical isomer, salt, hydrate or solvate, and the CDK4 / 6 inhibitor is Ribociclib or its optical isomer, salt, hydrate or solvate, the molar ratio of the estrogen receptor degrader to the CDK4 / 6 inhibitor is 1:0.3 to 1:24.4; the molar ratio is preferably 1:0.3, 1:2.7, or 1:24.

4.

45. Use of an estrogen receptor degrader in combination with a CDK4 / 6 inhibitor in the preparation of a drug for degrading estrogen receptors.

46. ​​The use according to claim 45, characterized in that: The molar ratio of the estrogen receptor degrader to the CDK4 / 6 inhibitor is 1:0.01 to 1:666.

7.

47. The use according to claim 45 or 46, characterized in that: The estrogen receptor degrading agent is selected from the compounds described in claims 3 to 28, or optical isomers thereof, or salts thereof, or hydrates thereof, or solvates thereof; The CDK4 / 6 inhibitor is Palbociclib, Abemaciclib, Ribociclib, Trilaciclib, Dalpiciclib, Lerociclib, AT7519M, Dinaciclib, BSJ-03-204, Narazaciclib, XY028-140, BSJ-04-132, PF-07220060, Nimbolide, XY028-133, Cimpuciclib, CDK4 / 6-IN-2, CDK4 / 6-IN-12, CDK4 / 6-IN-7, CDK-IN-12, CDK4 / 6-IN-8, CDK4 / 6-IN-10 or its optical isomers, salts, hydrates or solvates; Preferably, the CDK4 / 6 inhibitor is Palbociclib, Abemaciclib, Ribociclib, Dalpiciclib or an optical isomer thereof, a salt thereof, a hydrate thereof, or a solvate thereof.

48. The use according to claim 45 or 46, characterized in that: When the estrogen receptor degrader is ARV-471 or an optical isomer, a salt, a hydrate or a solvate thereof, and the CDK4 / 6 inhibitor is Palbociclib or an optical isomer, a salt, a hydrate or a solvate thereof, the molar ratio of the estrogen receptor degrader to the CDK4 / 6 inhibitor is 1:0.3 to 1:666.7; the molar ratio is preferably 1:0.3 to 1:24.4; the molar ratio is more preferably 1:0.3, 1:2.7, 1:24.4; And / or, when the estrogen receptor degrader is ARV-471 or an optical isomer, a salt, a hydrate or a solvate thereof, and the CDK4 / 6 inhibitor is Abemaciclib or an optical isomer, a salt, a hydrate or a solvate thereof, the molar ratio of the estrogen receptor degrader to the CDK4 / 6 inhibitor is 1:0.3 to 1:2.7; preferably, the molar ratio is 1:0.3, 1:0.9 or 1:2.7; And / or, 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 CDK4 / 6 inhibitor is Ribociclib 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 CDK4 / 6 inhibitor is 1:0.1 to 1:8.3; the molar ratio is preferably 1:0.1, 1:0.9, or 1:8.

3.

49. The use according to claim 45 or 46, characterized in that: When the estrogen receptor degrader is compound 75 or its optical isomer, salt, hydrate or solvate, and the CDK4 / 6 inhibitor is Palbociclib or its optical isomer, salt, hydrate or solvate, the molar ratio of the estrogen receptor degrader to the CDK4 / 6 inhibitor is 1:0.1 to 1:666.7; the molar ratio is preferably 1:0.9 to 1:71.4; the molar ratio is more preferably 1:0.9, 1:8.3 or 1:71.4; And / or, when the estrogen receptor degrader is compound 75 or its optical isomer, salt, hydrate or solvate, and the CDK4 / 6 inhibitor is Abemaciclib or its optical isomer, salt, hydrate or solvate, the molar ratio of the estrogen receptor degrader to the CDK4 / 6 inhibitor is 1:0.011 to 24.4; the molar ratio is preferably 1:0.03 to 1:0.9; the molar ratio is more preferably 1:0.03, 1:0.3 or 1:0.9; And / or, when the estrogen receptor degrader is compound 75 or its optical isomer, salt, hydrate or solvate, and the CDK4 / 6 inhibitor is Ribociclib or its optical isomer, salt, hydrate or solvate, the molar ratio of the estrogen receptor degrader to the CDK4 / 6 inhibitor is 1:0.1 to 1:71.4; the molar ratio is preferably 1:0.3 to 1:71.4; the molar ratio is more preferably 1:0.3, 1:8.3, or 1:71.

4.

50. The use according to claim 45 or 46, characterized in that: When the estrogen receptor degrader is compound 65 or its optical isomer, salt, hydrate or solvate, and the CDK4 / 6 inhibitor is Palbociclib or its optical isomer, salt, hydrate or solvate, the molar ratio of the estrogen receptor degrader to the CDK4 / 6 inhibitor is 1:0.1 to 1:8.3; preferably, the molar ratio is 1:0.1, 1:0.9 or 1:8.3; And / or, when the estrogen receptor degrader is compound 65 or its optical isomer, salt, hydrate or solvate, and the CDK4 / 6 inhibitor is Abemaciclib or its optical isomer, salt, hydrate or solvate, the molar ratio of the estrogen receptor degrader to the CDK4 / 6 inhibitor is 1:0.03 to 1:0.3; preferably, the molar ratio is 1:0.03 or 1:0.3; And / or, when the estrogen receptor degrader is compound 65 or its optical isomer, salt, hydrate or solvate, and the CDK4 / 6 inhibitor is Ribociclib or its optical isomer, salt, hydrate or solvate, the molar ratio of the estrogen receptor degrader to the CDK4 / 6 inhibitor is 1:0.1 to 1:8.3; the molar ratio is preferably 1:0.1, 1:0.9 or 1:8.

3.

51. The use according to claim 45 or 46, characterized in that: When the estrogen receptor degrader is compound 63 or its optical isomer, salt, hydrate or solvate, and the CDK4 / 6 inhibitor is Palbociclib or its optical isomer, salt, hydrate or solvate, the molar ratio of the estrogen receptor degrader to the CDK4 / 6 inhibitor is 1:0.3 to 1:8.3; preferably, the molar ratio is 1:0.3, 1:0.9 or 1:8.3; And / or, when the estrogen receptor degrader is compound 63 or its optical isomer, salt, hydrate or solvate, and the CDK4 / 6 inhibitor is Abemaciclib or its optical isomer, salt, hydrate or solvate, the molar ratio of the estrogen receptor degrader to the CDK4 / 6 inhibitor is 1:0.03 to 1:0.9; preferably, the molar ratio is 1:0.03, 1:0.3 or 1:0.9; And / or, when the estrogen receptor degrader is compound 63 or its optical isomer, salt, hydrate or solvate, and the CDK4 / 6 inhibitor is Ribociclib or its optical isomer, salt, hydrate or solvate, the molar ratio of the estrogen receptor degrader to the CDK4 / 6 inhibitor is 1:0.3 to 1:24.4; the molar ratio is preferably 1:0.3, 1:2.7, or 1:24.

4.

52. The use according to claim 45 or 46, characterized in that: The drug for degrading estrogen receptors is an estrogen receptor degrader 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 breast cancer, ovarian cancer, or lung cancer.

Images