WO2025007920A1 - Médicament combiné pour dégrader le récepteur des œstrogènes et son utilisation - Google Patents

Médicament combiné pour dégrader le récepteur des œstrogènes et son utilisation Download PDF

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WO2025007920A1
WO2025007920A1 PCT/CN2024/103622 CN2024103622W WO2025007920A1 WO 2025007920 A1 WO2025007920 A1 WO 2025007920A1 CN 2024103622 W CN2024103622 W CN 2024103622W WO 2025007920 A1 WO2025007920 A1 WO 2025007920A1
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alkyl
independently selected
membered cycloalkyl
hydrogen
ring
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Chinese (zh)
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涂志林
李景
杜武
陈坷帆
李兴海
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Hinova Pharmaceuticals Inc
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Hinova Pharmaceuticals Inc
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4965—Non-condensed pyrazines
    • A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/14—Drugs for genital or sexual disorders; Contraceptives for lactation disorders, e.g. galactorrhoea
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
    • A61P5/30—Oestrogens
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D273/00—Heterocyclic compounds containing rings having nitrogen and oxygen atoms as the only ring hetero atoms, not provided for by groups C07D261/00 - C07D271/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/10—Spiro-condensed systems

Definitions

  • the invention belongs to the field of medicine, and in particular relates to a combined drug for degrading estrogen receptors and a use thereof.
  • Estrogen receptor 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 17 ⁇ -estradiol and estrone. It has been found that ER has two different configurations, namely ER- ⁇ and ER- ⁇ . 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.
  • 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.
  • Cyclin dependent kinases play an important role in the initiation of the cell cycle and the regulation of the transitions between various phases.
  • CDK4/6 and cyclin D can phosphorylate the retinoblastoma gene (Rb) and then release the transcription factor E2F, promoting the transcription of cell cycle-related genes and allowing cells to enter the S phase.
  • CDK4/6 inhibitors effectively block the progression of tumor cells from the G1 phase to the S phase.
  • ER+ estrogen receptor-positive breast cancer
  • 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.
  • CDK4/6 inhibitors are expected to be used in the treatment of cancer.
  • CDK4/6 inhibitors due to factors such as CDK overexpression and cyclin E1 overexpression, patients will develop acquired resistance to CDK4/6 inhibitors.
  • the purpose of the present invention is to provide a combined drug for degrading estrogen receptors and its use.
  • 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.
  • the molar ratio of the estrogen receptor degrader to the CDK4/6 inhibitor is 1:0.01 ⁇ 1:666.7.
  • 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:
  • R 1 is selected from hydrogen, C 1 ⁇ C 6 alkyl, hydroxyl, amino, carboxyl, C 1 ⁇ C 6 alkoxy, boric acid, -OR';
  • R' is selected from phenyl and benzyl
  • R 2 is a substituent at any position on the benzene ring, and a is the number of substituents R 2 ;
  • Each R 2 is independently selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C 1 ⁇ C 6 alkyl, 3 ⁇ 6 membered cycloalkyl, C 1 ⁇ C 6 alkoxy;
  • a 0, 1, 2 or 3;
  • R 3 and R 4 are independently selected from none;
  • R 3 and R 4 are independently selected from hydrogen, C 1 to C 6 alkyl, or R 3 and R 4 are connected to form a 3-6 membered cycloalkyl;
  • R5 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, SO 2 , NR 7 ;
  • R 7 and R 8 are independently selected from hydrogen, halogen, C 1 -C 6 alkyl, 3-6 membered cycloalkyl;
  • n 0, 1 or 2;
  • R 6 is a substituent at any position on the benzene ring, and b is the number of substituents R 6 ;
  • Each R 6 is independently selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C 1 ⁇ C 6 alkyl, 3 ⁇ 6 membered cycloalkyl, C 1 ⁇ C 6 alkoxy;
  • b 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, SO 2 , NR 9 ;
  • R 9 and R 10 are independently selected from hydrogen and C 1 -C 6 alkyl
  • E 3 is a substituent at any position on the benzene ring, and c is the number of substituents E 3 ;
  • Each E 3 is independently selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C 1 ⁇ C 6 alkyl, 3 ⁇ 6-membered cycloalkyl, C 1 ⁇ C 6 alkoxy; or any two E 3 are linked to form a 3 ⁇ 6-membered cycloalkyl, 6 ⁇ 10-membered aryl, 4 ⁇ 12-membered heterocycloalkyl, 5 ⁇ 8-membered heteroaryl;
  • c 0, 1, 2, or 3;
  • R Y1 and R Y2 are independently selected from hydrogen and C 1 -C 6 alkyl
  • R 11 and R 12 are independently selected from hydrogen and C 1 -C 6 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.
  • R 1 is selected from hydrogen, C 1 ⁇ C 6 alkyl, hydroxyl, amino, carboxyl, C 1 ⁇ C 6 alkoxy, boric acid, -OR';
  • R' is selected from phenyl and benzyl
  • R 2 is a substituent at any position on the benzene ring, and a is the number of substituents R 2 ;
  • Each R 2 is independently selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C 1 ⁇ C 6 alkyl, 3 ⁇ 6 membered cycloalkyl, C 1 ⁇ C 6 alkoxy;
  • a 0, 1, 2 or 3;
  • R 3 and R 4 are independently selected from none;
  • R 3 and R 4 are independently selected from hydrogen, C 1 to C 6 alkyl, or R 3 and R 4 are connected to form a 3-6 membered cycloalkyl;
  • R5 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, SO 2 , NR 7 ;
  • R 7 and R 8 are independently selected from hydrogen, halogen, C 1 -C 6 alkyl, 3-6 membered cycloalkyl;
  • n 0, 1 or 2;
  • R 6 is a substituent at any position on the benzene ring, and b is the number of substituents R 6 ;
  • Each R 6 is independently selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C 1 ⁇ C 6 alkyl, 3 ⁇ 6 membered cycloalkyl, C 1 ⁇ C 6 alkoxy;
  • b 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, SO 2 , NR 9 ;
  • R 9 and R 10 are independently selected from hydrogen and C 1 -C 6 alkyl
  • E 3 is a substituent at any position on the benzene ring, and c is the number of substituents E 3 ;
  • Each E 3 is independently selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C 1 ⁇ C 6 alkyl, 3 ⁇ 6-membered cycloalkyl, C 1 ⁇ C 6 alkoxy; or any two E 3 are linked to form a 3 ⁇ 6-membered cycloalkyl, 6 ⁇ 10-membered aryl, 4 ⁇ 12-membered heterocycloalkyl, 5 ⁇ 8-membered heteroaryl;
  • c 0, 1, 2, or 3;
  • R Y1 and R Y2 are independently selected from hydrogen and C 1 -C 6 alkyl
  • R 11 and R 12 are independently selected from hydrogen and C 1 -C 6 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.
  • R 2 is a substituent at any position on the benzene ring, and a is the number of substituents R 2 ;
  • Each R 2 is independently selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C 1 ⁇ C 6 alkyl, 3 ⁇ 6 membered cycloalkyl, C 1 ⁇ C 6 alkoxy;
  • a 0, 1, 2 or 3;
  • R 3 and R 4 are independently selected from none;
  • R 3 and R 4 are independently selected from hydrogen, C 1 to C 6 alkyl, or R 3 and R 4 are connected to form a 3-6 membered cycloalkyl;
  • R5 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 aryl or heteroaryl is selected from The substituent is selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C 1 -C 6 alkyl, 3-6 membered cycloalkyl, C 1 -C 6 alkoxy;
  • X is selected from CR 7 R 8 , O, S, SO, SO 2 , NR 7 ;
  • R 7 and R 8 are independently selected from hydrogen, halogen, C 1 -C 6 alkyl, 3-6 membered cycloalkyl;
  • n 0, 1 or 2;
  • R 6 is a substituent at any position on the benzene ring, and b is the number of substituents R 6 ;
  • Each R 6 is independently selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C 1 ⁇ C 6 alkyl, 3 ⁇ 6 membered cycloalkyl, C 1 ⁇ C 6 alkoxy;
  • b 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, SO 2 , NR 9 ;
  • R 9 and R 10 are independently selected from hydrogen and C 1 -C 6 alkyl
  • E 3 is a substituent at any position on the benzene ring, and c is the number of substituents E 3 ;
  • Each E 3 is independently selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C 1 ⁇ C 6 alkyl, 3 ⁇ 6-membered cycloalkyl, C 1 ⁇ C 6 alkoxy; or any two E 3 are linked to form a 3 ⁇ 6-membered cycloalkyl, 6 ⁇ 10-membered aryl, 4 ⁇ 12-membered heterocycloalkyl, 5 ⁇ 8-membered heteroaryl;
  • c 0, 1, 2, or 3;
  • R Y1 and R Y2 are independently selected from hydrogen and C 1 -C 6 alkyl
  • R 11 and R 12 are independently selected from hydrogen and C 1 -C 6 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;
  • R5 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
  • X is selected from CH 2 , CF 2 , O, S, SO, SO 2 , NR 7 ;
  • R7 is 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.
  • R 2 is a substituent at any position on the benzene ring, and a is the number of substituents R 2 ;
  • Each R 2 is independently selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C 1 ⁇ C 6 alkyl, 3 ⁇ 6 membered cycloalkyl, C 1 ⁇ C 6 alkoxy;
  • a 0, 1, 2 or 3;
  • R 3 and R 4 are independently selected from hydrogen and C 1 to C 6 alkyl; or R 3 and R 4 are connected to form a 3-6 membered cycloalkyl;
  • R5 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, SO 2 , NR 7 ;
  • R 7 and R 8 are independently selected from hydrogen, halogen, C 1 -C 6 alkyl, 3-6 membered cycloalkyl;
  • n 0, 1 or 2;
  • R 6 is a substituent at any position on the benzene ring, and b is the number of substituents R 6 ;
  • Each R 6 is independently selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C 1 ⁇ C 6 alkyl, 3 ⁇ 6 membered cycloalkyl, C 1 ⁇ C 6 alkoxy;
  • b 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, SO 2 , NR 9 ;
  • R 9 and R 10 are independently selected from hydrogen and C 1 -C 6 alkyl
  • E 3 is a substituent at any position on the benzene ring, and c is the number of substituents E 3 ;
  • Each E 3 is independently selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C 1 ⁇ C 6 alkyl, 3 ⁇ 6-membered cycloalkyl, C 1 ⁇ C 6 alkoxy; or any two E 3 are linked to form a 3 ⁇ 6-membered cycloalkyl, 6 ⁇ 10-membered aryl, 4 ⁇ 12-membered heterocycloalkyl, 5 ⁇ 8-membered heteroaryl;
  • c 0, 1, 2, or 3;
  • R Y1 and R Y2 are independently selected from hydrogen and C 1 -C 6 alkyl
  • R 11 and R 12 are independently selected from hydrogen and C 1 -C 6 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;
  • R5 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
  • X is selected from CH 2 , CF 2 , O, S, SO, SO 2 , NR 7 ;
  • R7 is 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.
  • R 2 is a substituent at any position on the benzene ring, and a is the number of substituents R 2 ;
  • Each R 2 is independently selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C 1 ⁇ C 6 alkyl, 3 ⁇ 6 membered cycloalkyl, C 1 ⁇ C 6 alkoxy;
  • a 0, 1, 2 or 3;
  • R 3 and R 4 are independently selected from hydrogen, C 1 to C 6 alkyl, or R 3 and R 4 are connected to form a 3-6 membered cycloalkyl;
  • R5 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, SO 2 , NR 7 ;
  • R 7 and R 8 are independently selected from hydrogen, halogen, C 1 -C 6 alkyl, 3-6 membered cycloalkyl;
  • n 0, 1 or 2;
  • R 6 is a substituent at any position on the benzene ring, and b is the number of substituents R 6 ;
  • Each R 6 is independently selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C 1 ⁇ C 6 alkyl, 3 ⁇ 6 membered cycloalkyl, C 1 ⁇ C 6 alkoxy;
  • b 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, SO 2 , NR 9 ;
  • R 9 and R 10 are independently selected from hydrogen and C 1 -C 6 alkyl
  • E 3 is a substituent at any position on the benzene ring, and c is the number of substituents E 3 ;
  • Each E 3 is independently selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C 1 ⁇ C 6 alkyl, 3 ⁇ 6-membered cycloalkyl, C 1 ⁇ C 6 alkoxy; or any two E 3 are linked to form a 3 ⁇ 6-membered cycloalkyl, 6 ⁇ 10-membered aryl, 4 ⁇ 12-membered heterocycloalkyl, 5 ⁇ 8-membered heteroaryl;
  • c 0, 1, 2, or 3;
  • R Y1 and R Y2 are independently selected from hydrogen and C 1 -C 6 alkyl
  • R 11 and R 12 are independently selected from hydrogen and C 1 -C 6 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;
  • R5 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
  • X is selected from CH 2 , CF 2 , O, S, SO, SO 2 , NR 7 ;
  • R7 is 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.
  • R 2 is a substituent at any position on the benzene ring, and a is the number of substituents R 2 ;
  • Each R 2 is independently selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C 1 ⁇ C 6 alkyl, 3 ⁇ 6 membered cycloalkyl, C 1 ⁇ C 6 alkoxy;
  • a 0, 1, 2 or 3;
  • R 3 and R 4 are independently selected from hydrogen, C 1 to C 6 alkyl, or R 3 and R 4 are connected to form a 3-6 membered cycloalkyl;
  • R5 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, SO 2 , NR 7 ;
  • R 7 and R 8 are independently selected from hydrogen, halogen, C 1 -C 6 alkyl, 3-6 membered cycloalkyl;
  • R 6 is a substituent at any position on the benzene ring, and b is the number of substituents R 6 ;
  • Each R 6 is independently selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C 1 ⁇ C 6 alkyl, 3 ⁇ 6 membered cycloalkyl, C 1 ⁇ C 6 alkoxy;
  • b 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, SO 2 , NR 9 ;
  • R 9 and R 10 are independently selected from hydrogen and C 1 -C 6 alkyl
  • E 3 is a substituent at any position on the benzene ring, and c is the number of substituents E 3 ;
  • Each E 3 is independently selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C 1 ⁇ C 6 alkyl, 3 ⁇ 6-membered cycloalkyl, C 1 ⁇ C 6 alkoxy; or any two E 3 are linked to form a 3 ⁇ 6-membered cycloalkyl, 6 ⁇ 10-membered aryl, 4 ⁇ 12-membered heterocycloalkyl, 5 ⁇ 8-membered heteroaryl;
  • c 0, 1, 2, or 3;
  • R Y1 and R Y2 are independently selected from hydrogen and C 1 -C 6 alkyl
  • R 11 and R 12 are independently selected from hydrogen and C 1 -C 6 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;
  • R5 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 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, C 1 ⁇ C 6 alkyl, 3 ⁇ 6 membered cyclo
  • X is selected from CH 2 , CF 2 , O, S, SO, SO 2 , NR 7 ;
  • R7 is 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.
  • R 3 and R 4 are independently selected from hydrogen, C 1 to C 6 alkyl, or R 3 and R 4 are connected to form a 3-6 membered cycloalkyl;
  • R5 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, SO 2 , NR 7 ;
  • R 7 and R 8 are independently selected from hydrogen, halogen, C 1 -C 6 alkyl, 3-6 membered cycloalkyl;
  • R 6 is a substituent at any position on the benzene ring, and b is the number of substituents R 6 ;
  • Each R 6 is independently selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C 1 ⁇ C 6 alkyl, 3 ⁇ 6 membered cycloalkyl, C 1 ⁇ C 6 alkoxy;
  • b 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, SO 2 , NR 9 ;
  • R 9 and R 10 are independently selected from hydrogen and C 1 -C 6 alkyl
  • R Y1 and R Y2 are independently selected from hydrogen and C 1 -C 6 alkyl
  • R 11 and R 12 are independently selected from hydrogen and C 1 -C 6 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;
  • R5 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
  • X is selected from CH 2 , CF 2 , O, S, SO, SO 2 , NR 7 ;
  • R7 is 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.
  • R 3 and R 4 are independently selected from hydrogen and C 1 to C 6 alkyl; or R 3 and R 4 are connected to form a 3-6 membered cycloalkyl;
  • R5 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, SO 2 , NR 7 ;
  • R 7 and R 8 are independently selected from hydrogen, halogen, C 1 -C 6 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, SO 2 , NR 9 ;
  • R 9 and R 10 are independently selected from hydrogen and C 1 -C 6 alkyl
  • R Y1 and R Y2 are independently selected from hydrogen and C 1 -C 6 alkyl
  • R 11 and R 12 are independently selected from hydrogen and C 1 -C 6 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;
  • R5 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,
  • X is selected from CH 2 , CF 2 , O, S, SO, SO 2 , NR 7 ;
  • R7 is 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.
  • R 3 and R 4 are independently selected from hydrogen, C 1 to C 6 alkyl, or R 3 and R 4 are connected to form a 3-6 membered cycloalkyl;
  • R5 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, SO 2 , NR 7 ;
  • R 7 and R 8 are independently selected from hydrogen, halogen, C 1 -C 6 alkyl, 3-6 membered cycloalkyl;
  • R 6 is a substituent at any position on the benzene ring, and b is the number of substituents R 6 ;
  • Each R 6 is independently selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C 1 ⁇ C 6 alkyl, 3 ⁇ 6 membered cycloalkyl, C 1 ⁇ C 6 alkoxy;
  • b 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;
  • R Y1 and R Y2 are independently selected from hydrogen and C 1 -C 6 alkyl
  • R 11 and R 12 are independently selected from hydrogen and C 1 -C 6 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;
  • R5 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
  • X is selected from CH 2 , CF 2 , O, S, SO, SO 2 , NR 7 ;
  • R7 is 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.
  • R 3 and R 4 are independently selected from hydrogen and C 1 to C 6 alkyl; or R 3 and R 4 are connected to form a 3-6 membered cycloalkyl;
  • R5 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, SO 2 , NR 7 ;
  • R 7 and R 8 are independently selected from hydrogen, halogen, C 1 -C 6 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;
  • R Y1 and R Y2 are independently selected from hydrogen and C 1 -C 6 alkyl
  • R 11 and R 12 are independently selected from hydrogen and C 1 -C 6 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;
  • R5 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
  • X is selected from CH 2 , CF 2 , O, S, SO, SO 2 , NR 7 ;
  • R7 is 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.
  • R 2 is a substituent at any position on the benzene ring, and a is the number of substituents R 2 ;
  • Each R 2 is independently selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C 1 ⁇ C 6 alkyl, 3 ⁇ 6 membered cycloalkyl, C 1 ⁇ C 6 alkoxy;
  • a 0, 1, 2 or 3;
  • R 3 and R 4 are independently selected from hydrogen and C 1 to C 6 alkyl; or R 3 and R 4 are connected to form a 3-6 membered cycloalkyl;
  • R 11 is a substituent at any position on the benzene ring, and d is the number of substituents R 11 ;
  • Each R 11 is independently selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C 1 -C 6 alkyl, 3-6 membered cycloalkyl, C 1 -C 6 alkoxy;
  • d 0, 1, 2 or 3;
  • X is selected from CR 7 R 8 , O, S, SO, SO 2 , NR 7 ;
  • R 7 and R 8 are independently selected from hydrogen, halogen, C 1 -C 6 alkyl, 3-6 membered cycloalkyl;
  • R 6 is a substituent at any position on the benzene ring, and b is the number of substituents R 6 ;
  • Each R 6 is independently selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C 1 ⁇ C 6 alkyl, 3 ⁇ 6 membered cycloalkyl, C 1 ⁇ C 6 alkoxy;
  • b 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, SO 2 , NR 9 ;
  • R 9 and R 10 are independently selected from hydrogen and C 1 -C 6 alkyl
  • E 3 is a substituent at any position on the benzene ring, and c is the number of substituents E 3 ;
  • Each E 3 is independently selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C 1 ⁇ C 6 alkyl, 3 ⁇ 6-membered cycloalkyl, C 1 ⁇ C 6 alkoxy; or any two E 3 are linked to form a 3 ⁇ 6-membered cycloalkyl, 6 ⁇ 10-membered aryl, 4 ⁇ 12-membered heterocycloalkyl, 5 ⁇ 8-membered heteroaryl;
  • c 0, 1, 2, or 3;
  • R Y1 and R Y2 are independently selected from hydrogen and C 1 -C 6 alkyl
  • R 11 and R 12 are independently selected from hydrogen and C 1 -C 6 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;
  • X is selected from CH 2 , CF 2 , O, S, SO, SO 2 , NR 7 ;
  • R7 is 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.
  • R 2 is a substituent at any position on the benzene ring, and a is the number of substituents R 2 ;
  • Each R 2 is independently selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C 1 ⁇ C 6 alkyl, 3 ⁇ 6 membered cycloalkyl, C 1 ⁇ C 6 alkoxy;
  • a 0, 1, 2 or 3;
  • R 3 and R 4 are independently selected from hydrogen, C 1 to C 6 alkyl, or R 3 and R 4 are connected to form a 3-6 membered cycloalkyl;
  • R 11 is a substituent at any position on the benzene ring, and d is the number of substituents R 11 ;
  • Each R 11 is independently selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C 1 -C 6 alkyl, 3-6 membered cycloalkyl, C 1 -C 6 alkoxy;
  • d 0, 1, 2 or 3;
  • X is selected from CR 7 R 8 , O, S, SO, SO 2 , NR 7 ;
  • R 7 and R 8 are independently selected from hydrogen, halogen, C 1 -C 6 alkyl, 3-6 membered cycloalkyl;
  • R 6 is a substituent at any position on the benzene ring, and b is the number of substituents R 6 ;
  • Each R 6 is independently selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C 1 ⁇ C 6 alkyl, 3 ⁇ 6 membered cycloalkyl, C 1 ⁇ C 6 alkoxy;
  • b 0, 1, 2, or 3;
  • M is selected from none, CR 9 R 10 , O, S, SO, SO 2 , NR 9 ;
  • R 9 and R 10 are independently selected from hydrogen and C 1 -C 6 alkyl
  • R 12 is selected from hydrogen, halogen, C 1 -C 6 alkyl, hydroxyl
  • n 1;
  • E 3 is a substituent at any position on the benzene ring, and c is the number of substituents E 3 ;
  • Each E 3 is independently selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C 1 ⁇ C 6 alkyl, 3 ⁇ 6-membered cycloalkyl, C 1 ⁇ C 6 alkoxy; or any two E 3 are linked to form a 3 ⁇ 6-membered cycloalkyl, 6 ⁇ 10-membered aryl, 4 ⁇ 12-membered heterocycloalkyl, 5 ⁇ 8-membered heteroaryl;
  • c 0, 1, 2, or 3;
  • R Y1 and R Y2 are independently selected from hydrogen and C 1 -C 6 alkyl
  • R 11 and R 12 are independently selected from hydrogen and C 1 -C 6 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;
  • X is selected from CH 2 , CF 2 , O, S, SO, SO 2 , NR 7 ;
  • R7 is selected from hydrogen, halogen, C1 - C6 alkyl, 3-6 membered cycloalkyl;
  • R Y1 and R Y2 are independently selected from hydrogen and C 1 -C 6 alkyl
  • R 11 and R 12 are each independently selected from hydrogen and C 1 -C 6 alkyl.
  • R 2 is a substituent at any position on the benzene ring, and a is the number of substituents R 2 ;
  • Each R 2 is independently selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C 1 ⁇ C 6 alkyl, 3 ⁇ 6 membered cycloalkyl, C 1 ⁇ C 6 alkoxy;
  • a 0, 1, 2 or 3;
  • R 3 and R 4 are independently selected from hydrogen, C 1 to C 6 alkyl, or R 3 and R 4 are connected to form a 3-6 membered cycloalkyl;
  • R 11 is a substituent at any position on the benzene ring, and d is the number of substituents R 11 ;
  • Each R 11 is independently selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C 1 -C 6 alkyl, 3-6 membered cycloalkyl, C 1 -C 6 alkoxy;
  • d 0, 1, 2 or 3;
  • X is selected from CR 7 R 8 , O, S, SO, SO 2 , NR 7 ;
  • R 7 and R 8 are independently selected from hydrogen, halogen, C 1 -C 6 alkyl, 3-6 membered cycloalkyl;
  • R 6 is a substituent at any position on the benzene ring, and b is the number of substituents R 6 ;
  • Each R 6 is independently selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C 1 ⁇ C 6 alkyl, 3 ⁇ 6 membered cycloalkyl, C 1 ⁇ C 6 alkoxy;
  • b 0, 1, 2, or 3;
  • R 12 is selected from hydrogen, halogen, C 1 -C 6 alkyl, hydroxyl
  • n 1;
  • E 3 is a substituent at any position on the benzene ring, and c is the number of substituents E 3 ;
  • Each E 3 is independently selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C 1 ⁇ C 6 alkyl, 3 ⁇ 6-membered cycloalkyl, C 1 ⁇ C 6 alkoxy; or any two E 3 are linked to form a 3 ⁇ 6-membered cycloalkyl, 6 ⁇ 10-membered aryl, 4 ⁇ 12-membered heterocycloalkyl, 5 ⁇ 8-membered heteroaryl;
  • c 0, 1, 2, or 3;
  • R Y1 and R Y2 are independently selected from hydrogen and C 1 -C 6 alkyl
  • R 11 and R 12 are independently selected from hydrogen and C 1 -C 6 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;
  • X is selected from CH 2 , CF 2 , O, S, SO, SO 2 , NR 7 ;
  • R7 is selected from hydrogen, halogen, C1 - C6 alkyl, 3-6 membered cycloalkyl;
  • R Y1 and R Y2 are independently selected from hydrogen and C 1 -C 6 alkyl
  • R 11 and R 12 are each independently selected from hydrogen and C 1 -C 6 alkyl.
  • R 2 is a substituent at any position on the benzene ring, and a is the number of substituents R 2 ;
  • Each R 2 is independently selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C 1 ⁇ C 6 alkyl, 3 ⁇ 6 membered cycloalkyl, C 1 ⁇ C 6 alkoxy;
  • a 0, 1, 2 or 3;
  • R 3 and R 4 are independently selected from hydrogen, C 1 to C 6 alkyl, or R 3 and R 4 are connected to form a 3-6 membered cycloalkyl;
  • R 11 is a substituent at any position on the benzene ring, and d is the number of substituents R 11 ;
  • Each R 11 is independently selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C 1 -C 6 alkyl, 3-6 membered cycloalkyl, C 1 -C 6 alkoxy;
  • d 0, 1, 2 or 3;
  • X is selected from CR 7 R 8 , O, S, SO, SO 2 , NR 7 ;
  • R 7 and R 8 are independently selected from hydrogen, halogen, C 1 -C 6 alkyl, 3-6 membered cycloalkyl;
  • R 6 is a substituent at any position on the benzene ring, and b is the number of substituents R 6 ;
  • Each R 6 is independently selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C 1 ⁇ C 6 alkyl, 3 ⁇ 6 membered cycloalkyl, C 1 ⁇ C 6 alkoxy;
  • b 0, 1, 2, or 3;
  • R 12 is selected from hydrogen, halogen, C 1 -C 6 alkyl, hydroxyl
  • n 1;
  • E 3 is a substituent at any position on the benzene ring, and c is the number of substituents E 3 ;
  • Each E 3 is independently selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C 1 ⁇ C 6 alkyl, 3 ⁇ 6-membered cycloalkyl, C 1 ⁇ C 6 alkoxy; or any two E 3 are linked to form a 3 ⁇ 6-membered cycloalkyl, 6 ⁇ 10-membered aryl, 4 ⁇ 12-membered heterocycloalkyl, 5 ⁇ 8-membered heteroaryl;
  • c 0, 1, 2, or 3;
  • R Y1 and R Y2 are independently selected from hydrogen and C 1 -C 6 alkyl
  • R 11 and R 12 are independently selected from hydrogen and C 1 -C 6 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;
  • X is selected from CH 2 , CF 2 , O, S, SO, SO 2 , NR 7 ;
  • R7 is selected from hydrogen, halogen, C1 - C6 alkyl, 3-6 membered cycloalkyl;
  • R Y1 and R Y2 are independently selected from hydrogen and C 1 -C 6 alkyl
  • R 11 and R 12 are each independently selected from hydrogen and C 1 -C 6 alkyl.
  • R 2 is a substituent at any position on the benzene ring, and a is the number of substituents R 2 ;
  • Each R 2 is independently selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C 1 ⁇ C 6 alkyl, 3 ⁇ 6 membered cycloalkyl, C 1 ⁇ C 6 alkoxy;
  • a 0, 1, 2 or 3;
  • R 3 and R 4 are independently selected from hydrogen, C 1 to C 6 alkyl, or R 3 and R 4 are connected to form a 3-6 membered cycloalkyl;
  • R 11 is a substituent at any position on the thiophene ring, and d is the number of substituents R 11 ;
  • Each R 11 is independently selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C 1 -C 6 alkyl, 3-6 membered cycloalkyl, C 1 -C 6 alkoxy;
  • d 0, 1, 2 or 3;
  • X is selected from CR 7 R 8 , O, S, SO, SO 2 , NR 7 ;
  • R 7 and R 8 are independently selected from hydrogen, halogen, C 1 -C 6 alkyl, 3-6 membered cycloalkyl;
  • R 6 is a substituent at any position on the benzene ring, and b is the number of substituents R 6 ;
  • Each R 6 is independently selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C 1 ⁇ C 6 alkyl, 3 ⁇ 6 membered cycloalkyl, C 1 ⁇ C 6 alkoxy;
  • b 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, SO 2 , NR 9 ;
  • R 9 and R 10 are independently selected from hydrogen and C 1 -C 6 alkyl
  • E 3 is a substituent at any position on the benzene ring, and c is the number of substituents E 3 ;
  • Each E 3 is independently selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C 1 ⁇ C 6 alkyl, 3 ⁇ 6-membered cycloalkyl, C 1 ⁇ C 6 alkoxy; or any two E 3 are linked to form a 3 ⁇ 6-membered cycloalkyl, 6 ⁇ 10-membered aryl, 4 ⁇ 12-membered heterocycloalkyl, 5 ⁇ 8-membered heteroaryl;
  • c 0, 1, 2, or 3;
  • R Y1 and R Y2 are independently selected from hydrogen and C 1 -C 6 alkyl
  • R 11 and R 12 are independently selected from hydrogen and C 1 -C 6 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;
  • X is selected from CH 2 , CF 2 , O, S, SO, SO 2 , NR 7 ;
  • R7 is 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.
  • R 2 is a substituent at any position on the benzene ring, and a is the number of substituents R 2 ;
  • Each R 2 is independently selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C 1 ⁇ C 6 alkyl, 3 ⁇ 6 membered cycloalkyl, C 1 ⁇ C 6 alkoxy;
  • a 0, 1, 2 or 3;
  • R 3 and R 4 are independently selected from hydrogen, C 1 to C 6 alkyl, or R 3 and R 4 are connected to form a 3-6 membered cycloalkyl;
  • R 11 is a substituent at any position on the thiophene ring, and d is the number of substituents R 11 ;
  • Each R 11 is independently selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C 1 -C 6 alkyl, 3-6 membered cycloalkyl, C 1 -C 6 alkoxy;
  • d 0, 1, 2 or 3;
  • X is selected from CR 7 R 8 , O, S, SO, SO 2 , NR 7 ;
  • R 7 and R 8 are independently selected from hydrogen, halogen, C 1 -C 6 alkyl, 3-6 membered cycloalkyl;
  • R 6 is a substituent at any position on the benzene ring, and b is the number of substituents R 6 ;
  • Each R 6 is independently selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C 1 ⁇ C 6 alkyl, 3 ⁇ 6 membered cycloalkyl, C 1 ⁇ C 6 alkoxy;
  • b 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, SO 2 , NR 9 ;
  • R 9 and R 10 are independently selected from hydrogen and C 1 -C 6 alkyl
  • E 3 is a substituent at any position on the benzene ring, and c is the number of substituents E 3 ;
  • Each E 3 is independently selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C 1 ⁇ C 6 alkyl, 3 ⁇ 6-membered cycloalkyl, C 1 ⁇ C 6 alkoxy; or any two E 3 are linked to form a 3 ⁇ 6-membered cycloalkyl, 6 ⁇ 10-membered aryl, 4 ⁇ 12-membered heterocycloalkyl, 5 ⁇ 8-membered heteroaryl;
  • c 0, 1, 2, or 3;
  • R Y1 and R Y2 are independently selected from hydrogen and C 1 -C 6 alkyl
  • R 11 and R 12 are independently selected from hydrogen and C 1 -C 6 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;
  • X is selected from CH 2 , CF 2 , O, S, SO, SO 2 , NR 7 ;
  • R7 is 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.
  • R 3 and R 4 are independently selected from hydrogen, C 1 to C 6 alkyl, or R 3 and R 4 are connected to form a 3-6 membered cycloalkyl;
  • X is selected from CR 7 R 8 , O, S, SO, SO 2 , NR 7 ;
  • R 7 and R 8 are independently selected from hydrogen, halogen, C 1 -C 6 alkyl, 3-6 membered cycloalkyl;
  • R 11 is a substituent at any position on the benzene ring, and d is the number of substituents R 11 ;
  • R 6 is a substituent at any position on the benzene ring, and b is the number of substituents R 6 ;
  • Each R 11 and R 6 is independently selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C 1 -C 6 alkyl, 3-6 membered cycloalkyl, C 1 -C 6 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, SO 2 , NR 9 ;
  • R 9 and R 10 are independently selected from hydrogen and C 1 -C 6 alkyl
  • R Y1 and R Y2 are independently selected from hydrogen and C 1 -C 6 alkyl
  • R 11 and R 12 are independently selected from hydrogen and C 1 -C 6 alkyl
  • the heteroatom of the heterocycloalkyl group is N; the number of heteroatoms is 1, 2 or 3;
  • X is selected from CH 2 , CF 2 , O, S, SO, SO 2 , NR 7 ;
  • R7 is 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.
  • X is selected from CR 7 R 8 , O, S, SO, SO 2 , NR 7 ;
  • R 7 and R 8 are independently selected from hydrogen, halogen, C 1 -C 6 alkyl, 3-6 membered cycloalkyl;
  • R 11 is a substituent at any position on the benzene ring, and d is the number of substituents R 11 ;
  • R 6 is a substituent at any position on the benzene ring, and b is the number of substituents R 6 ;
  • Each R 11 and R 6 is independently selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C 1 -C 6 alkyl, 3-6 membered cycloalkyl, C 1 -C 6 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 and R 10 are independently selected from hydrogen and C 1 -C 6 alkyl
  • R Y1 and R Y2 are independently selected from hydrogen and C 1 -C 6 alkyl
  • R 11 and R 12 are independently selected from hydrogen and C 1 -C 6 alkyl
  • the heteroatom of the heterocycloalkyl group is N; the number of heteroatoms is 1, 2 or 3;
  • X is selected from CH 2 , CF 2 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.
  • R 1 is selected from hydrogen, C 1 ⁇ C 6 alkyl, hydroxyl, amino or C 1 ⁇ C 6 alkoxy, boric acid;
  • R 2 is a substituent at any position on the benzene ring, and a is the number of substituents R 2 ;
  • Each R 2 is independently selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C 1 ⁇ C 6 alkyl, 3 ⁇ 6 membered cycloalkyl, C 1 ⁇ C 6 alkoxy;
  • a 0, 1, 2 or 3;
  • R5 is selected from C1 - C6 alkyl, 3-6 membered cycloalkyl, trifluoromethyl, trifluoroethyl, substituted or unsubstituted substituted 6-10 membered aryl, substituted or unsubstituted 5-8 membered heteroaryl; the substituent of the aryl or heteroaryl is selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C 1 -C 6 alkyl, 3-6 membered cycloalkyl, C 1 -C 6 alkoxy;
  • X is selected from CR 7 R 8 , O, S, SO, SO 2 , NR 7 ;
  • R 7 and R 8 are independently selected from hydrogen, halogen, C 1 -C 6 alkyl, 3-6 membered cycloalkyl;
  • n 0, 1 or 2;
  • R 6 is a substituent at any position on the benzene ring, and b is the number of substituents R 6 ;
  • Each R 6 is independently selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C 1 ⁇ C 6 alkyl, 3 ⁇ 6 membered cycloalkyl, C 1 ⁇ C 6 alkoxy;
  • b 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, SO 2 , NR 9 ;
  • R 9 and R 10 are independently selected from hydrogen and C 1 -C 6 alkyl
  • E 3 is a substituent at any position on the benzene ring, and c is the number of substituents E 3 ;
  • Each E 3 is independently selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C 1 ⁇ C 6 alkyl, 3 ⁇ 6-membered cycloalkyl, C 1 ⁇ C 6 alkoxy; or any two E 3 are linked to form a 3 ⁇ 6-membered cycloalkyl, 6 ⁇ 10-membered aryl, 4 ⁇ 12-membered heterocycloalkyl, 5 ⁇ 8-membered heteroaryl;
  • c 0, 1, 2, or 3;
  • R Y1 and R Y2 are independently selected from hydrogen and C 1 -C 6 alkyl
  • R 11 and R 12 are independently selected from hydrogen and C 1 -C 6 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;
  • R5 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
  • R5 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, SO 2 , NR 7 ;
  • R 7 and R 8 are independently selected from hydrogen, halogen, C 1 -C 6 alkyl, 3-6 membered cycloalkyl;
  • R 6 is a substituent at any position on the benzene ring, and b is the number of substituents R 6 ;
  • Each R 6 is independently selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C 1 ⁇ C 6 alkyl, 3 ⁇ 6 membered cycloalkyl, C 1 ⁇ C 6 alkoxy;
  • b 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, SO 2 , NR 9 ;
  • R 9 and R 10 are independently selected from hydrogen and C 1 -C 6 alkyl
  • R Y1 and R Y2 are independently selected from hydrogen and C 1 -C 6 alkyl
  • R 11 and R 12 are independently selected from hydrogen and C 1 -C 6 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;
  • R5 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
  • X is selected from CH 2 , CF 2 , O, S, SO, SO 2 , NR 7 ;
  • R7 is 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.
  • R 11 is a substituent at any position on the benzene ring, and d is the number of substituents R 11 ;
  • Each R 11 is independently selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C 1 -C 6 alkyl, 3-6 membered cycloalkyl, C 1 -C 6 alkoxy;
  • d 0, 1, 2 or 3;
  • X is selected from CR 7 R 8 , O, S, SO, SO 2 , NR 7 ;
  • R 7 and R 8 are independently selected from hydrogen, halogen, C 1 -C 6 alkyl, 3-6 membered cycloalkyl;
  • R 6 is a substituent at any position on the benzene ring, and b is the number of substituents R 6 ;
  • Each R 6 is independently selected from halogen, hydroxyl, amino, cyano, trifluoromethyl, C 1 ⁇ C 6 alkyl, 3 ⁇ 6 membered cycloalkyl, C 1 ⁇ C 6 alkoxy;
  • b 0, 1, 2, or 3;
  • M is selected from none, CR 9 R 10 , O, S, SO, SO 2 , NR 9 ;
  • R 9 and R 10 are independently selected from hydrogen and C 1 -C 6 alkyl
  • n 1;
  • R Y1 and R Y2 are independently selected from hydrogen and C 1 -C 6 alkyl
  • R 11 and R 12 are independently selected from hydrogen and C 1 -C 6 alkyl
  • X is selected from CH 2 , CF 2 , O, S, SO, SO 2 , NR 7 ;
  • R7 is selected from hydrogen, halogen, C1 - C6 alkyl, 3-6 membered cycloalkyl.
  • ring A and ring B are independently selected from the following structures:
  • the compound is one of the following compounds:
  • the compound is ARV-471, compound 63, compound 65 or compound 75;
  • ARV-471 is The structure of compound 63 is The structure of compound 65 is The structure of compound 75 is
  • 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.
  • 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;
  • the CDK4/6 inhibitor is Palbociclib, Abemaciclib, Ribociclib, Dalpiciclib 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;
  • 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;
  • 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.
  • the estrogen receptor degrader is compound 75 or its optical isomers, salts thereof, Its hydrate, its solvate, when the CDK4/6 inhibitor is Palbociclib or its optical isomer, its salt, its hydrate, its 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, 1:71.4;
  • 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;
  • 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.
  • 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;
  • 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;
  • 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.
  • 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;
  • 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;
  • the estrogen receptor degrader is compound 63 or its optical isomer, salt, hydrate or solvate
  • the CDK4/6 inhibitor is Ribociclib or its optical isomer, salt 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.
  • 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.
  • 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.
  • the present invention also provides the use of the aforementioned pharmaceutical composition in preparing a drug for treating and/or preventing cancer;
  • the cancer is breast cancer, ovarian cancer, or lung cancer.
  • 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.
  • 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.
  • the molar ratio of the estrogen receptor degrader to the CDK4/6 inhibitor is 1:0.01 to 1:666.7.
  • the estrogen receptor degrading agent is selected from the aforementioned compounds, 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;
  • the CDK4/6 inhibitor is Palbociclib, Abemaciclib, Ribociclib, Dalpiciclib 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;
  • 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;
  • the estrogen receptor degrading agent is ARV-471 or its optical isomers, salts thereof, Hydrates, or solvates thereof; when 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.
  • 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;
  • 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;
  • 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.
  • 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;
  • 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;
  • 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.
  • 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;
  • the molar ratio of the estrogen receptor degrader to the CDK4/6 inhibitor is 1:0.03 to 1:0.9; the molar ratio is preferably 1:0.03, 1:0.3, 1:0.9;
  • 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.
  • 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.
  • the molar ratio of the estrogen receptor degrader to the CDK4/6 inhibitor is 1:0.01 to 1:666.7.
  • the estrogen receptor degrading agent is selected from the aforementioned compounds, 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;
  • the CDK4/6 inhibitor is Palbociclib, Abemaciclib, Ribociclib, Dalpiciclib 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;
  • 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;
  • 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.
  • 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, 1:71.4;
  • 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;
  • 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.
  • 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;
  • 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;
  • 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.
  • 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;
  • 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;
  • 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.
  • the drug for degrading estrogen receptors is an estrogen receptor degrader or a drug for treating estrogen receptor-related diseases.
  • the drug is used in a drug for treating and/or preventing cancer
  • the cancer is breast cancer, ovarian cancer, or lung cancer.
  • 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.
  • substitution refers to the replacement of a hydrogen atom in a molecule by another different atom or molecule.
  • the minimum and maximum carbon atom content of the hydrocarbon group is indicated by a prefix, for example, the prefix Ca - Cb alkyl indicates any alkyl group containing "a" to "b" carbon atoms.
  • 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.
  • Alkyl refers to a saturated hydrocarbon chain having a specified number of carbon atoms.
  • 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.
  • Halogen is fluorine, chlorine, bromine or iodine.
  • 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.
  • heterocyclyl groups include, for example, piperidinyl, piperazinyl, morpholinyl.
  • 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.
  • the compound structure 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
  • the compound structure when there is no dotted line between Y and W, the compound structure is When Rab is a halogen and the dotted line between Y and W is a bond, the compound structure is
  • 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.
  • 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.
  • FIG1 shows the inhibitory effects of compound 63 and Palbociclib on the growth of MCF-7 cells.
  • FIG2 shows the inhibitory effects of compound 65 and Palbociclib on the growth of MCF-7 cells.
  • FIG3 shows the inhibitory effects of compound 75 and Palbociclib on the growth of MCF-7 cells.
  • FIG. 4 shows the inhibitory effects of ARV-471 and Palbociclib on the growth of MCF-7 cells.
  • FIG5 shows the inhibitory effects of compound 63 and Abemaciclib on the growth of MCF-7 cells.
  • FIG6 shows the inhibitory effects of compound 65 and Abemaciclib on the growth of MCF-7 cells.
  • FIG7 shows the inhibitory effects of compound 75 and Abemaciclib on the growth of MCF-7 cells.
  • FIG8 shows the inhibitory effects of ARV-471 and Abemaciclib on the growth of MCF-7 cells.
  • FIG9 shows the inhibitory effects of compound 63 and Ribociclib on the growth of MCF-7 cells.
  • FIG10 shows the inhibitory effects of compound 65 and Ribociclib on the growth of MCF-7 cells.
  • FIG11 shows the inhibitory effects of compound 75 and Ribociclib on the growth of MCF-7 cells.
  • FIG. 12 shows the inhibitory effects of ARV-471 and Ribociclib on the growth of MCF-7 cells.
  • 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.
  • Example 1 Combination of an estrogen receptor degrader and a CDK4/6 inhibitor, Palbociclib
  • CDK4/6 inhibitor Palbociclib, with a structure of
  • Estrogen receptor degrader ARV-471, the structure is
  • 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).
  • the above-mentioned estrogen receptor degrader ARV-471 can be replaced by compound 63, the structure of which is
  • estrogen receptor degrader ARV-471 can be replaced by compound 65, the structure of which is
  • estrogen receptor degrader ARV-471 can be replaced by compound 75, the structure of which is
  • CDK4/6 inhibitor Abemaciclib, with the structure
  • Estrogen receptor degrader ARV-471.
  • 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).
  • the above-mentioned estrogen receptor degrader ARV-471 can be replaced by compound 63, compound 65, and compound 75.
  • CDK4/6 inhibitor Ribociclib, with the structure
  • Estrogen receptor degrader ARV-471.
  • 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).
  • the above-mentioned estrogen receptor degrader ARV-471 can be replaced by compound 63, compound 65, and compound 75.
  • MCF-7 breast cancer cells in the logarithmic growth phase were inoculated in a 96-well culture plate at a concentration of 2 ⁇ 10 3 cells/well, with 100 ⁇ L in each well. The cells were incubated in an incubator at 37°C, 5% CO 2 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.
  • the concentration range of compound 63 is: 0nM, 0.15nM, 0.46nM, 1.4nM, 4.1nM, 12nM, 37nM, 111nM, 333nM, 1000nM.
  • the concentration range of Palbociclib is: 0nM, 1.2nM, 3.7nM, 11nM, 33nM, 100nM.
  • the concentration range of compound 65 is: 0nM, 0.15nM, 0.46nM, 1.4nM, 4.1nM, 12nM, 37nM, 111nM, 333nM, 1000nM.
  • the concentration range of Palbociclib is: 0nM, 1.2nM, 3.7nM, 11nM, 33nM, 100nM.
  • MCF-7 breast cancer cells in the logarithmic growth phase were inoculated in a 96-well culture plate at a concentration of 2 ⁇ 10 3 cells/well, with 100 ⁇ L in each well. The cells were incubated in an incubator at 37°C, 5% CO 2 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.
  • the concentration range of compound 75 is: 0nM, 0.15nM, 0.46nM, 1.4nM, 4.1nM, 12nM, 37nM, 111nM, 333nM, 1000nM.
  • the concentration range of Palbociclib is: 0nM, 1.2nM, 3.7nM, 11nM, 33nM, 100nM.
  • MCF-7 breast cancer cells in the logarithmic growth phase were inoculated in a 96-well culture plate at a concentration of 2 ⁇ 10 3 cells/well, with 100 ⁇ L in each well. The cells were incubated in an incubator at 37°C, 5% CO 2 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.
  • the concentration range of ARV-471 is: 0nM, 0.15nM, 0.46nM, 1.4nM, 4.1nM, 12nM, 37nM, 111nM, 333nM, 1000nM.
  • the concentration range of Palbociclib is: 0nM, 1.2nM, 3.7nM, 11nM, 33nM, 100nM.
  • MCF-7 breast cancer cells in the logarithmic growth phase were inoculated in a 96-well culture plate at a concentration of 2 ⁇ 10 3 cells/well, with 100 ⁇ L inoculated in each well.
  • the cells were incubated in an incubator at 37°C, 5% CO 2 concentration and saturated humidity for 24 hours. After 24 hours, compound 63 and Abemaciclib were added to the 96-well plate successively.
  • the negative control wells were added with the same volume of cell culture medium containing 10% fetal bovine serum as the drug.
  • the concentration range of compound 63 is: 0nM, 0.15nM, 0.46nM, 1.4nM, 4.1nM, 12nM, 37nM, 111nM, 333nM, 1000nM.
  • Abemaciclib concentration range is: 0nM, 1.2nM, 3.7nM, 11nM, 33nM, 100nM.
  • the concentration range of compound 65 is: 0nM, 0.15nM, 0.46nM, 1.4nM, 4.1nM, 12nM, 37nM, 111nM, 333nM, 1000nM.
  • Abemaciclib concentration range is: 0nM, 1.2nM, 3.7nM, 11nM, 33nM, 100nM.
  • MCF-7 breast cancer cells in the logarithmic growth phase were inoculated in a 96-well culture plate at a concentration of 2 ⁇ 10 3 cells/well, with 100 ⁇ L inoculated in each well.
  • the cells were incubated in an incubator at 37°C, 5% CO 2 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.
  • the concentration range of compound 75 is: 0nM, 0.15nM, 0.46nM, 1.4nM, 4.1nM, 12nM, 37nM, 111nM, 333nM, 1000nM.
  • Abemaciclib concentration range is: 0nM, 1.2nM, 3.7nM, 11nM, 33nM, 100nM.
  • MCF-7 breast cancer cells in the logarithmic growth phase were inoculated in a 96-well culture plate at a concentration of 2 ⁇ 10 3 cells/well, with 100 ⁇ L inoculated in each well.
  • the cells were incubated in an incubator at 37°C, 5% CO 2 concentration and saturated humidity for 24 hours. After 24 hours, ARV-471 and Abemaciclib were added to the 96-well plate successively.
  • the negative control wells were added with the same volume of cell culture medium containing 10% fetal bovine serum as the drug.
  • the concentration range of ARV-471 is: 0nM, 0.15nM, 0.46nM, 1.4nM, 4.1nM, 12nM, 37nM, 111nM, 333nM, 1000nM.
  • Abemaciclib concentration range is: 0nM, 1.2nM, 3.7nM, 11nM, 33nM, 100nM.
  • the concentration range of compound 63 is: 0nM, 0.15nM, 0.46nM, 1.4nM, 4.1nM, 12nM, 37nM, 111nM, 333nM, 1000nM.
  • the concentration range of Ribociclib is: 0nM, 1.2nM, 3.7nM, 11nM, 33nM, 100nM.
  • the concentration range of compound 65 is: 0nM, 0.15nM, 0.46nM, 1.4nM, 4.1nM, 12nM, 37nM, 111nM, 333nM, 1000nM.
  • the concentration range of Ribociclib is: 0nM, 1.2nM, 3.7nM, 11nM, 33nM, 100nM.
  • Breast cancer MCF-7 cells in the logarithmic growth phase were inoculated in a 96-well culture plate at a concentration of 2 ⁇ 10 3 cells/well, with 100 ⁇ L inoculated in each well.
  • the cells were incubated in an incubator at 37°C, 5% CO 2 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.
  • the concentration range of compound 75 was: 0nM, 0.15nM, 0.46nM, 1.4nM, 4.1nM, 12nM, 37nM,111nM,333nM,1000nM.
  • the concentration range of Ribociclib is: 0nM, 1.2nM, 3.7nM, 11nM, 33nM, 100nM.
  • MCF-7 breast cancer cells in the logarithmic growth phase were inoculated in a 96-well culture plate at a concentration of 2 ⁇ 10 3 cells/well, with 100 ⁇ L in each well. The cells were incubated in an incubator at 37°C, 5% CO 2 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.
  • the concentration range of ARV-471 is: 0nM, 0.15nM, 0.46nM, 1.4nM, 4.1nM, 12nM, 37nM, 111nM, 333nM, 1000nM.
  • the concentration range of Ribociclib is: 0nM, 1.2nM, 3.7nM, 11nM, 33nM, 100nM.
  • the assumption of homogeneity of variance among all groups was first verified using the Bartlett test.
  • 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.
  • the Kruskal Wallis test was used to test whether the medians of all groups were equal. If the p-value of the Kruskal Wallis 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.
  • the experimental results are shown in Table 2.
  • the compound 75 10 mg/kg treatment group had a significant tumor inhibition effect.
  • the average tumor volume on Day 28 was 161.11 mm 3 and its TGI was 59.43%, which was significantly different from the control group (p ⁇ 0.001).
  • the Palbociclib 60 mg/kg treatment group had a significant tumor inhibition effect.
  • the average tumor volume on Day 28 was 143.46 mm 3 and its TGI was 63.87%, which was significantly different from the control group (p ⁇ 0.001).
  • Compound 75 10 mg/kg and Palbociclib 60 mg/kg co-administration group It has a significant tumor inhibition effect.
  • the average tumor volume was 53.02 mm 3 and the TGI was 86.65%, which was significantly different from the control group (p ⁇ 0.001), the compound 7510 mg/kg single-administration group (p ⁇ 0.05), and the Palbociclib 60 mg/kg single-administration group (p ⁇ 0.001).
  • 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.

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Abstract

L'invention concerne un médicament combiné pour dégrader un récepteur des œstrogènes et son utilisation. Le médicament combiné contient un agent de dégradation du récepteur des œstrogènes et un inhibiteur de CDK4/6, qui sont administrés simultanément ou séparément dans des spécifications identiques ou différentes, et un support pharmaceutiquement acceptable. Le médicament combiné a un effet synergique, améliore significativement l'effet de traitement de maladies liées au récepteur des œstrogènes, et présente de bonnes perspectives d'application.
PCT/CN2024/103622 2023-07-06 2024-07-04 Médicament combiné pour dégrader le récepteur des œstrogènes et son utilisation Ceased WO2025007920A1 (fr)

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