Aromatic compounds, a method for producing the same, and use in the production of estrogen receptor degrading agents

Abstract

The present invention provides an aromatic compound, a method for producing the same, and use in the production of an estrogen receptor degrader, and belongs to the technical field of chemical drugs. The aromatic compound is a compound represented by formula (I), or an optical isomer thereof, or a salt thereof, or a hydrate thereof, or a solvate thereof. The compounds of the present invention can be used in the production of estrogen receptor degraders and in the production of drugs for the treatment of diseases related to estrogen receptors, such as drugs for the treatment and / or prevention of cancer, such as breast cancer. TIFF2025523440000258.tif47170

Description

Technical Field

[0001] The present invention belongs to the technical field of chemical drugs, and specifically relates to aromatic compounds and their manufacturing methods, as well as their use in the manufacture of estrogen receptor degraders.

Background Art

[0002] Estrogen receptor (ER) is a transcription regulatory protein activated by a ligand, and mediates the induction of various biological effects through interaction with endogenous estrogen. Endogenous estrogens include 17β-estradiol and estrone. ER is known to have two different steric structures, namely ER-α and ER-β. Estrogen and estrogen receptor are involved in many diseases and disorders, such as bone cancer, breast cancer, colorectal cancer, endometrial cancer, prostate cancer, ovarian cancer, uterine cancer, cervical cancer, lung cancer, and other diseases or disorders. For example, in about 70% of breast cancer patients, ER and / or progesterone receptor are expressed. The treatment of these diseases can be achieved by inhibiting the transmission of ER signals by various methods, including antagonizing the binding of ligand to ER, antagonizing or downregulating ERα, blocking estrogen synthesis, and the like.

[0003] Estrogen receptor degrading agents can competitively bind to estrogen receptors (ERs) present in estrogen-responsive tissues, thereby offering the potential for treating diseases associated with estrogen receptors. For example, conventional non-steroidal estrogen receptor degrading agents such as tamoxifen can effectively compete and bind to ERs. However, these degrading agents sometimes exhibit partial agonist activity, which often limits their effectiveness, reduces their efficacy, and fails to completely block estrogen-mediated activities. In the treatment of estrogen-dependent diseases, specific or "pure" anti-estrogens that have high affinity for ERs and no agonist effects may have advantages over conventional non-steroidal anti-estrogens. Therefore, it is of great significance to study estrogen receptor degrading agents that reduce ER expression at the transcript or protein level.

Summary of the Invention

[0004] The object of the present invention is to provide an aromatic compound, a method for producing the same, and use in the production of an estrogen receptor degrading agent.

[0005] The present invention provides a compound represented by formula (I), or an optical isomer thereof, or a salt thereof, or a hydrate thereof, or a solvate thereof. TIFF2025523440000002.tif45170

[0006] However, R 1 is selected from hydrogen, a C1-C6 alkyl group, a hydroxy group, an amino group, a carboxy group, a C1-C6 alkoxy group, a boronic acid group, -OR', R' is selected from a phenyl group and a benzyl group, R 2 is a substituent at any position on the benzene ring, and a is the number of substituents R 2 and each R 2Each is independently selected from a halogen, a hydroxy group, an amino group, a cyano group, a trifluoromethyl group, a C1-C6 alkyl group, a 3-6 membered cycloalkyl group, and a C1-C6 alkoxy group, a is 0, 1, 2, or 3, When the dashed line in the benzene ring is a bond, R 3 , R 4 are each independently selected from none, When there is no dashed line in the benzene ring, R 3 , R 4 are each independently selected from hydrogen and a C1-C6 alkyl group, or R 3 , R 4 are linked to form a 3-6 membered cycloalkyl group, R 5 is selected from a C1-C6 alkyl group, a 3-6 membered cycloalkyl group, a trifluoromethyl group, a trifluoroethyl group, a substituted or unsubstituted 6-10 membered aryl group, and a substituted or unsubstituted 5-8 membered heteroaryl group, and the substituents of the aryl group or heteroaryl group are selected from a halogen, a hydroxy group, an amino group, a cyano group, a trifluoromethyl group, a C1-C6 alkyl group, a 3-6 membered cycloalkyl group, and a C1-C6 alkoxy group, X is selected from CR 7 R 8 , O, S, SO, SO2, NR 7 and, R 7 , R 8 are each independently selected from hydrogen, a halogen, a C1-C6 alkyl group, and a 3-6 membered cycloalkyl group, n is 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 a halogen, a hydroxy group, an amino group, a cyano group, a trifluoromethyl group, a C1-C6 alkyl group, a 3-6 membered cycloalkyl group, and a C1-C6 alkoxy group, b is 0, 1, 2, or 3, Ring A and ring B are each independently selected from a 4- to 12-membered cycloalkyl group and a 4- to 12-membered heterocycloalkyl group. M is absent, CR 9 R 10 , O, S, SO, SO2, NR 9 and is selected from R 9 , R 10 are each independently selected from hydrogen and a C1-C6 alkyl group. 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, hydroxy group, amino group, cyano group, trifluoromethyl group, C1-C6 alkyl group, 3- to 6-membered cycloalkyl group, C1-C6 alkoxy group, or any two E 3 are linked to form a 3- to 6-membered cycloalkyl group, 6- to 10-membered aryl group, 4- to 12-membered heterocycloalkyl group, 5- to 8-membered heteroaryl group. 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 and 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 each independently selected from hydrogen and a C1-C6 alkyl group. R 11 , R 12 are each independently selected from hydrogen and a C1-C6 alkyl group. R 21 is selected from hydrogen and deuterium. The heteroatom of the heteroaryl group is O, N, or S, and the number of heteroatoms is 1, 2, or 3. The heteroatom of the heterocycloalkyl group is N, and the number of the heteroatoms is 1, 2 or 3.

[0007] Furthermore, the compound is represented by formula (II). TIFF2025523440000003.tif45170

[0008] However, R 1 is selected from hydrogen, a C1-C6 alkyl group, a hydroxy group, an amino group, a carboxy group, a C1-C6 alkoxy group, a boronic acid group, and -OR', R' is selected from a phenyl group and a benzyl group, R 2 is a substituent at any position on the benzene ring, and a is the number of substituents R 2 and each R 2 is independently selected from a halogen, a hydroxy group, an amino group, a cyano group, a trifluoromethyl group, a C1-C6 alkyl group, a 3- to 6-membered cycloalkyl group, and a C1-C6 alkoxy group, a is 0, 1, 2 or 3, when the dashed line in the benzene ring is a bond, R 3 , R 4 are each independently selected from none, when the dashed line in the benzene ring is absent, R 3 , R 4 are each independently selected from hydrogen and a C1-C6 alkyl group, or R 3 , R 4 are linked to form a 3- to 6-membered cycloalkyl group, R 5 is selected from a C1-C6 alkyl group, a 3- to 6-membered cycloalkyl group, a trifluoromethyl group, a trifluoroethyl group, a substituted or unsubstituted 6- to 10-membered aryl group, and a substituted or unsubstituted 5- to 8-membered heteroaryl group, and the substituents of the aryl group or heteroaryl group are selected from a halogen, a hydroxy group, an amino group, a cyano group, a trifluoromethyl group, a C1-C6 alkyl group, a 3- to 6-membered cycloalkyl group, and a C1-C6 alkoxy group, X is CR 7 R 8 、O, S, SO, SO2, NR 7 selected from, R 7 、R 8 each is independently selected from hydrogen, halogen, a C1-C6 alkyl group, and a 3-6 membered cycloalkyl group, n is 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, hydroxy group, amino group, cyano group, trifluoromethyl group, a C1-C6 alkyl group, a 3-6 membered cycloalkyl group, and a C1-C6 alkoxy group, b is 0, 1, 2 or 3, ring A and ring B are each independently selected from a 4-12 membered cycloalkyl group and a 4-12 membered heterocycloalkyl group, M is none, CR 9 R 10 、O, S, SO, SO2, NR 9 selected from, R 9 、R 10 each is independently selected from hydrogen and a C1-C6 alkyl group, 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, hydroxy group, amino group, cyano group, trifluoromethyl group, a C1-C6 alkyl group, a 3-6 membered cycloalkyl group, a C1-C6 alkoxy group, or any two E 3 are linked to form a 3-6 membered cycloalkyl group, a 6-10 membered aryl group, a 4-12 membered heterocycloalkyl group, or a 5-8 membered heteroaryl group, c is 0, 1, 2 or 3, Y is none, CR Y1 R Y2 、C(O), -CR 11=CR 12 -, -CR 11 =N-, -N=N-, -OC(O)-, R Y1 、R Y2 are each independently selected from hydrogen and C1-C6 alkyl groups, R 11 、R 12 are each independently selected from hydrogen and C1-C6 alkyl groups, The heteroatom of the heteroaryl group is O, N or S, and the number of the heteroatoms is 1, 2 or 3, The heteroatom of the heterocycloalkyl group is N, and the number of the heteroatoms is 1, 2 or 3.

[0009] Furthermore, the compound is as shown in formula (III). TIFF2025523440000004.tif45170

[0010] However, R 2 is a substituent at any position on the benzene ring, a is the number of substituents R 2 and each R 2 is independently selected from halogen, hydroxy group, amino group, cyano group, trifluoromethyl group, C1-C6 alkyl group, 3-6 membered cycloalkyl group, C1-C6 alkoxy group, a is 0, 1, 2 or 3, When the dashed line in the benzene ring is a bond, R 3 、R 4 are each independently selected from none, When the dashed line in the benzene ring is absent, R 3 、R 4 are each independently selected from hydrogen and C1-C6 alkyl groups, or R 3 、R 4 are linked to form a 3-6 membered cycloalkyl group, R 5is selected from a C1-C6 alkyl group, a 3-6 membered cycloalkyl group, a trifluoromethyl group, a trifluoroethyl group, a substituted or unsubstituted 6-10 membered aryl group, and a substituted or unsubstituted 5-8 membered heteroaryl group, and the substituent of the aryl group or heteroaryl group is selected from a halogen, a hydroxy group, an amino group, a cyano group, a trifluoromethyl group, a C1-C6 alkyl group, a 3-6 membered cycloalkyl group, and a C1-C6 alkoxy group, X is CR 7 R 8 , O, S, SO, SO2, NR 7 is selected from R 7 , R 8 is independently selected from hydrogen, a halogen, a C1-C6 alkyl group, and a 3-6 membered cycloalkyl group, n is 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 a halogen, a hydroxy group, an amino group, a cyano group, a trifluoromethyl group, a C1-C6 alkyl group, a 3-6 membered cycloalkyl group, and a C1-C6 alkoxy group, b is 0, 1, 2 or 3, Ring A and ring B are independently selected from a 4-12 membered cycloalkyl group and a 4-12 membered heterocycloalkyl group, M is none, CR 9 R 10 , O, S, SO, SO2, NR 9 is selected from R 9 , R 10 is independently selected from hydrogen and a C1-C6 alkyl group, E 3 is a substituent at any position on the benzene ring, and c is the number of substituents E 3 , each E 3are each independently selected from halogen, hydroxy group, amino group, cyano group, trifluoromethyl group, C1-C6 alkyl group, 3-6 membered cycloalkyl group, C1-C6 alkoxy group, or any two of E 3 are linked to form a 3-6 membered cycloalkyl group, 6-10 membered aryl group, 4-12 membered heterocycloalkyl group, 5-8 membered heteroaryl group, 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 each independently selected from hydrogen, C1-C6 alkyl group, R 11 , R 12 are each independently selected from hydrogen, C1-C6 alkyl group, the heteroatoms of the heteroaryl group are O, N or S, and the number of the heteroatoms is 1, 2 or 3, the heteroatom of the heterocycloalkyl group is N, and the number of the heteroatoms is 1, 2 or 3, Preferably, R 5 is selected from C1-C6 alkyl group, 3-6 membered cycloalkyl group, trifluoromethyl group, trifluoroethyl group, substituted or unsubstituted phenyl group, substituted or unsubstituted thienyl group, substituted or unsubstituted furyl group, substituted or unsubstituted pyrrolyl group, substituted or unsubstituted pyrimidinyl group, substituted or unsubstituted pyridazinyl group, substituted or unsubstituted pyrazolyl group, substituted or unsubstituted pyrazinyl group, and the substituents of the phenyl group, thienyl group, furyl group, pyrrolyl group, pyrimidinyl group, pyridazinyl group, pyrazolyl group or pyrazinyl group are selected from halogen, hydroxy group, amino group, cyano group, trifluoromethyl group, C1-C6 alkyl group, 3-6 membered cycloalkyl group, C1-C6 alkoxy group, X is CH2, CF2, O, S, SO, SO2, NR7 selected from R 7 is selected from hydrogen, halogen, a C1-C6 alkyl group, and a 3-6 membered cycloalkyl group, ring A and ring B are each independently selected from a 4-12 membered cycloalkyl group and a 4-12 membered heterocycloalkyl group, and when both ring A and ring B are heterocycloalkyl groups, one ring has one heteroatom N and the other ring has two heteroatoms N.

[0011] Furthermore, the compound is represented by formula (IV). TIFF2025523440000005.tif38170

[0012] However, R 2 is a substituent at any position on the benzene ring, and a is the number of substituents R 2 and each R 2 is independently selected from halogen, hydroxy group, amino group, cyano group, trifluoromethyl group, a C1-C6 alkyl group, a 3-6 membered cycloalkyl group, and a C1-C6 alkoxy group, a is 0, 1, 2 or 3, R 3 and R 4 are each independently selected from hydrogen and a C1-C6 alkyl group, or R 3 and R 4 are linked to form a 3-6 membered cycloalkyl group, R 5 is selected from a C1-C6 alkyl group, a 3-6 membered cycloalkyl group, trifluoromethyl group, trifluoroethyl group, a substituted or unsubstituted 6-10 membered aryl group, and a substituted or unsubstituted 5-8 membered heteroaryl group, and the substituents of the aryl group or heteroaryl group are selected from halogen, hydroxy group, amino group, cyano group, trifluoromethyl group, a C1-C6 alkyl group, a 3-6 membered cycloalkyl group, and a C1-C6 alkoxy group, X is CR 7 R 8 O, S, SO, SO2, NR7 selected from R 7 , R 8 is independently selected from hydrogen, halogen, a C1-C6 alkyl group, and a 3-6 membered cycloalkyl group, n is 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, hydroxy group, amino group, cyano group, trifluoromethyl group, C1-C6 alkyl group, 3-6 membered cycloalkyl group, and C1-C6 alkoxy group, b is 0, 1, 2 or 3, Ring A and ring B are independently selected from a 4-12 membered cycloalkyl group and a 4-12 membered heterocycloalkyl group, M is none, CR 9 R 10 , O, S, SO, SO2, NR 9 selected from R 9 , R 10 is independently selected from hydrogen and a C1-C6 alkyl group, 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, hydroxy group, amino group, cyano group, trifluoromethyl group, C1-C6 alkyl group, 3-6 membered cycloalkyl group, C1-C6 alkoxy group, or any two E 3 are linked to form a 3-6 membered cycloalkyl group, a 6-10 membered aryl group, a 4-12 membered heterocycloalkyl group, or a 5-8 membered heteroaryl group, 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 is independently selected from hydrogen and C1-C6 alkyl groups, R 11 、R 12 is independently selected from hydrogen and C1-C6 alkyl groups, The heteroatom of the heteroaryl group is O, N or S, and the number of the heteroatoms is 1, 2 or 3, The heteroatom of the heterocycloalkyl group is N, and the number of the heteroatoms is 1, 2 or 3, Preferably, R 5 is selected from C1-C6 alkyl groups, 3-6 membered cycloalkyl groups, trifluoromethyl groups, trifluoroethyl groups, substituted or unsubstituted phenyl groups, substituted or unsubstituted thienyl groups, substituted or unsubstituted furyl groups, substituted or unsubstituted pyrrolyl groups, substituted or unsubstituted pyrimidinyl groups, substituted or unsubstituted pyridazinyl groups, substituted or unsubstituted pyrazolyl groups, substituted or unsubstituted pyrazinyl groups, and the substituents of the phenyl group, thienyl group, furyl group, pyrrolyl group, pyrimidinyl group, pyridazinyl group, pyrazolyl group or pyrazinyl group are selected from halogens, hydroxy groups, amino groups, cyano groups, trifluoromethyl groups, C1-C6 alkyl groups, 3-6 membered cycloalkyl groups, C1-C6 alkoxy groups, X is selected from CH2, CF2, O, S, SO, SO2, NR 7 selected from, R 7 is selected from hydrogen, halogens, C1-C6 alkyl groups, 3-6 membered cycloalkyl groups, Ring A and ring B are each independently selected from 4-12 membered cycloalkyl groups and 4-12 membered heterocycloalkyl groups. When both ring A and ring B are heterocycloalkyl groups, one ring has 1 heteroatom N and the other ring has 2 heteroatoms N.

[0013] Furthermore, the compound is the one shown in formula (V). TIFF2025523440000006.tif38170

[0014] However, R 2 is a substituent at any position on the benzene ring, and a is the number of substituents R 2 and each R 2 is independently selected from halogen, hydroxy group, amino group, cyano group, trifluoromethyl group, C1-C6 alkyl group, 3-6 membered cycloalkyl group, C1-C6 alkoxy group, a is 0, 1, 2 or 3, R 3 and R 4 are each independently selected from hydrogen, C1-C6 alkyl group, or R 3 and R 4 are linked to form a 3-6 membered cycloalkyl group, R 5 is selected from C1-C6 alkyl group, 3-6 membered cycloalkyl group, trifluoromethyl group, trifluoroethyl group, substituted or unsubstituted 6-10 membered aryl group, substituted or unsubstituted 5-8 membered heteroaryl group, and the substituents of the aryl group or heteroaryl group are selected from halogen, hydroxy group, amino group, cyano group, trifluoromethyl group, C1-C6 alkyl group, 3-6 membered cycloalkyl group, C1-C6 alkoxy group, X is selected from CR 7 R 8 O, S, SO, SO2, NR 7 and R 7 and R 8 are each independently selected from hydrogen, halogen, C1-C6 alkyl group, 3-6 membered cycloalkyl group, n is 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 and each R 6is independently selected from a halogen, a hydroxy group, an amino group, a cyano group, a trifluoromethyl group, a C1-C6 alkyl group, a 3-6 membered cycloalkyl group, and a C1-C6 alkoxy group; b is 0, 1, 2, or 3; Ring A and Ring B are independently selected from a 4-12 membered cycloalkyl group and a 4-12 membered heterocycloalkyl group; M is absent, CR 9 R 10 , O, S, SO, SO2, NR 9 and is selected from; R 9 , R 10 is independently selected from hydrogen and a C1-C6 alkyl group; 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 a halogen, a hydroxy group, an amino group, a cyano group, a trifluoromethyl group, a C1-C6 alkyl group, a 3-6 membered cycloalkyl group, and a C1-C6 alkoxy group, or any two E 3 are linked to form a 3-6 membered cycloalkyl group, a 6-10 membered aryl group, a 4-12 membered heterocycloalkyl group, or a 5-8 membered heteroaryl group; 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 is independently selected from hydrogen and a C1-C6 alkyl group; R 11 , R 12 is independently selected from hydrogen and a C1-C6 alkyl group; The heteroatom of the heteroaryl group is O, N, or S, and the number of heteroatoms is 1, 2, or 3; The heteroatom of the heterocycloalkyl group is N, and the number of the heteroatoms is 1, 2 or 3. Preferably, R 5 is selected from a C1-C6 alkyl group, a 3-6 membered cycloalkyl group, a trifluoromethyl group, a trifluoroethyl group, a substituted or unsubstituted phenyl group, a substituted or unsubstituted thienyl group, a substituted or unsubstituted furyl group, a substituted or unsubstituted pyrrolyl group, a substituted or unsubstituted pyrimidinyl group, a substituted or unsubstituted pyridazinyl group, a substituted or unsubstituted pyrazolyl group, a substituted or unsubstituted pyrazinyl group, and the substituents of the phenyl group, thienyl group, furyl group, pyrrolyl group, pyrimidinyl group, pyridazinyl group, pyrazolyl group or pyrazinyl group are selected from halogen, hydroxy group, amino group, cyano group, trifluoromethyl group, C1-C6 alkyl group, 3-6 membered cycloalkyl group, C1-C6 alkoxy group. X is selected from CH2, CF2, O, S, SO, SO2, NR 7 and R 7 is selected from hydrogen, halogen, C1-C6 alkyl group, 3-6 membered cycloalkyl group. Ring A and ring B are each independently selected from a 4-12 membered cycloalkyl group, a 4-12 membered heterocycloalkyl group. When both ring A and ring B are heterocycloalkyl groups, one ring has one heteroatom N and the other ring has two heteroatoms N.

[0015] Furthermore, the compound is the one shown in formula (VI). TIFF2025523440000007.tif43170

[0016] However, R 2 is a substituent at any position on the benzene ring, a is the number of the substituents R 2 and each R 2Each independently is selected from a halogen, a hydroxy group, an amino group, a cyano group, a trifluoromethyl group, a C1-C6 alkyl group, a 3-6 membered cycloalkyl group, and a C1-C6 alkoxy group, a is 0, 1, 2 or 3, R 3 、R 4 are each independently selected from hydrogen and a C1-C6 alkyl group, or R 3 、R 4 are linked to form a 3-6 membered cycloalkyl group, R 5 is selected from a C1-C6 alkyl group, a 3-6 membered cycloalkyl group, a trifluoromethyl group, a trifluoroethyl group, a substituted or unsubstituted 6-10 membered aryl group, and a substituted or unsubstituted 5-8 membered heteroaryl group, and the substituent of the aryl group or heteroaryl group is selected from a halogen, a hydroxy group, an amino group, a cyano group, a trifluoromethyl group, a C1-C6 alkyl group, a 3-6 membered cycloalkyl group, and a C1-C6 alkoxy group, X is selected from CR 7 R 8 、O、S、SO、SO2、NR 7 and is selected from R 7 、R 8 are each independently selected from hydrogen, a halogen, a C1-C6 alkyl group, and a 3-6 membered cycloalkyl group, R 6 is a substituent at any position on the benzene ring, and b is the number of substituents R 6 and is Each R 6 is each independently selected from a halogen, a hydroxy group, an amino group, a cyano group, a trifluoromethyl group, a C1-C6 alkyl group, a 3-6 membered cycloalkyl group, and a C1-C6 alkoxy group, b is 0, 1, 2 or 3, Ring A and ring B are each independently selected from a 4-12 membered cycloalkyl group and a 4-12 membered heterocycloalkyl group, M is absent, CR 9 R 10 、O、S、SO、SO2、NR 9selected from R 9 and R 10 are each independently selected from hydrogen and C1-C6 alkyl groups, E 3 is a substituent at any position on the benzene ring, and c is the number of substituents E 3 and each E 3 is independently selected from halogen, hydroxy group, amino group, cyano group, trifluoromethyl group, C1-C6 alkyl group, 3-6 membered cycloalkyl group, C1-C6 alkoxy group, or any two Es 3 are linked to form a 3-6 membered cycloalkyl group, 6-10 membered aryl group, 4-12 membered heterocycloalkyl group, or 5-8 membered heteroaryl group, 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 and R Y2 are each independently selected from hydrogen and C1-C6 alkyl groups, R 11 and R 12 are each independently selected from hydrogen and C1-C6 alkyl groups, the heteroatoms of the heteroaryl group are O, N or S, and the number of heteroatoms is 1, 2 or 3, the heteroatom of the heterocycloalkyl group is N, and the number of heteroatoms is 1, 2 or 3, Preferably, R 5is selected from a C1-C6 alkyl group, a 3-6 membered cycloalkyl group, a trifluoromethyl group, a trifluoroethyl group, a substituted or unsubstituted phenyl group, a substituted or unsubstituted thienyl group, a substituted or unsubstituted furyl group, a substituted or unsubstituted pyrrolyl group, a substituted or unsubstituted pyrimidinyl group, a substituted or unsubstituted pyridazinyl group, a substituted or unsubstituted pyrazolyl group, a substituted or unsubstituted pyrazinyl group, and substituents of the phenyl group, thienyl group, furyl group, pyrrolyl group, pyrimidinyl group, pyridazinyl group, pyrazolyl group or pyrazinyl group are selected from halogen, hydroxy group, amino group, cyano group, trifluoromethyl group, C1-C6 alkyl group, 3-6 membered cycloalkyl group, C1-C6 alkoxy group, X is CH2, CF2, O, S, SO, SO2, NR 7 is selected from R 7 is selected from hydrogen, halogen, C1-C6 alkyl group, 3-6 membered cycloalkyl group, Ring A and ring B are each independently selected from a 4-12 membered cycloalkyl group, a 4-12 membered heterocycloalkyl group. When both ring A and ring B are heterocycloalkyl groups, one ring has one heteroatom N and the other ring has two heteroatoms N.

[0017] Furthermore, the compound is the one shown in formula (VII). TIFF2025523440000008.tif43170

[0018] However, R 3 and R 4 are each independently selected from hydrogen and C1-C6 alkyl group, or R 3 and R 4 are linked to form a 3-6 membered cycloalkyl group, R 5is selected from a C1-C6 alkyl group, a 3-6 membered cycloalkyl group, a trifluoromethyl group, a trifluoroethyl group, a substituted or unsubstituted 6-10 membered aryl group, and a substituted or unsubstituted 5-8 membered heteroaryl group, and the substituent of the aryl group or heteroaryl group is selected from a halogen, a hydroxy group, an amino group, a cyano group, a trifluoromethyl group, a C1-C6 alkyl group, a 3-6 membered cycloalkyl group, and a C1-C6 alkoxy group. X is CR 7 R 8 is selected from O, S, SO, SO2, NR 7 and R 7 and R 8 are each independently selected from hydrogen, a halogen, a C1-C6 alkyl group, and a 3-6 membered cycloalkyl group. R 6 is a substituent at any position on the benzene ring, and b is the number of substituents R 6 and each R 6 is independently selected from a halogen, a hydroxy group, an amino group, a cyano group, a trifluoromethyl group, a C1-C6 alkyl group, a 3-6 membered cycloalkyl group, and a C1-C6 alkoxy group. b is 0, 1, 2, or 3. Ring A and ring B are each independently selected from a 4-12 membered cycloalkyl group and a 4-12 membered heterocycloalkyl group. M is selected from none, CR 9 R 10 is selected from O, S, SO, SO2, NR 9 and R 9 and R 10 are each independently selected from hydrogen and a C1-C6 alkyl group. Y is selected from none, CR Y1 R Y2 is selected from C(O), -CR 11 =CR 12 -, -CR 11 =N-, -N=N-, -OC(O)-. R Y1 and R Y2Each is independently selected from hydrogen and C1-C6 alkyl groups, R 11 and R 12 Each is independently selected from hydrogen and C1-C6 alkyl groups, The heteroatom of the heteroaryl group is O, N or S, and the number of the heteroatoms is 1, 2 or 3, The heteroatom of the heterocycloalkyl group is N, and the number of the heteroatoms is 1, 2 or 3, Preferably, R 5 is selected from C1-C6 alkyl groups, 3-6 membered cycloalkyl groups, trifluoromethyl group, trifluoroethyl group, substituted or unsubstituted phenyl groups, substituted or unsubstituted thienyl groups, substituted or unsubstituted furyl groups, substituted or unsubstituted pyrrolyl groups, substituted or unsubstituted pyrimidinyl groups, substituted or unsubstituted pyridazinyl groups, substituted or unsubstituted pyrazolyl groups, substituted or unsubstituted pyrazinyl groups, and the substituents of the phenyl group, thienyl group, furyl group, pyrrolyl group, pyrimidinyl group, pyridazinyl group, pyrazolyl group or pyrazinyl group are selected from halogen, hydroxy group, amino group, cyano group, trifluoromethyl group, C1-C6 alkyl groups, 3-6 membered cycloalkyl groups, C1-C6 alkoxy groups, X is selected from CH2, CF2, O, S, SO, SO2, NR 7 selected from, R 7 is selected from hydrogen, halogen, C1-C6 alkyl groups, 3-6 membered cycloalkyl groups, Ring A and ring B are each independently selected from 4-12 membered cycloalkyl groups, 4-12 membered heterocycloalkyl groups. When both ring A and ring B are heterocycloalkyl groups, one ring has one heteroatom N and the other ring has two heteroatoms N.

[0019] Furthermore, the compound is the one shown in formula (VIII). TIFF2025523440000009.tif38170

[0020] However, R 3 、R 4 are each independently selected from hydrogen and C1-C6 alkyl groups, or R 3 、R 4 are linked to form a 3- to 6-membered cycloalkyl group, R 5 is selected from a C1-C6 alkyl group, a 3- to 6-membered cycloalkyl group, a trifluoromethyl group, a trifluoroethyl group, a substituted or unsubstituted 6- to 10-membered aryl group, and a substituted or unsubstituted 5- to 8-membered heteroaryl group, and the substituents of the aryl group or heteroaryl group are selected from halogen, hydroxy group, amino group, cyano group, trifluoromethyl group, C1-C6 alkyl group, 3- to 6-membered cycloalkyl group, and C1-C6 alkoxy group, X is selected from CR 7 R 8 、O、S、SO、SO2、NR 7 、 R 7 、R 8 are each independently selected from hydrogen, halogen, C1-C6 alkyl group, and 3- to 6-membered cycloalkyl group, Ring A and ring B are each independently selected from a 4- to 12-membered cycloalkyl group and a 4- to 12-membered heterocycloalkyl group, M is selected from none, CR 9 R 10 、O、S、SO、SO2、NR 9 、 R 9 、R 10 are each independently selected from hydrogen and C1-C6 alkyl group, Y is selected from none, CR Y1 R Y2 、C(O)、-CR 11 =CR 12 -、-CR 11 =N-、-N=N-、-OC(O)-, R Y1 、R Y2 are each independently selected from hydrogen and C1-C6 alkyl group, R 11 、R 12are each independently selected from hydrogen and C1-C6 alkyl groups, the heteroatom of the heteroaryl group is O, N or S, and the number of the heteroatoms is 1, 2 or 3, the heteroatom of the heterocycloalkyl group is N, and the number of the heteroatoms is 1, 2 or 3, preferably, R 5 is selected from C1-C6 alkyl groups, 3-6 membered cycloalkyl groups, trifluoromethyl groups, substituted or unsubstituted phenyl groups, substituted or unsubstituted thienyl groups, substituted or unsubstituted furyl groups, substituted or unsubstituted pyrrolyl groups, substituted or unsubstituted pyrimidinyl groups, substituted or unsubstituted pyridazinyl groups, substituted or unsubstituted pyrazolyl groups, substituted or unsubstituted pyrazinyl groups, and the substituents of the phenyl group, thienyl group, furyl group, pyrrolyl group, pyrimidinyl group, pyridazinyl group, pyrazolyl group or pyrazinyl group are selected from halogens, hydroxy groups, amino groups, cyano groups, trifluoromethyl groups, C1-C6 alkyl groups, 3-6 membered cycloalkyl groups, C1-C6 alkoxy groups, X is selected from CH2, CF2, O, S, SO, SO2, NR 7 and, R 7 is selected from hydrogen, halogens, C1-C6 alkyl groups, 3-6 membered cycloalkyl groups, ring A and ring B are each independently selected from 4-12 membered cycloalkyl groups and 4-12 membered heterocycloalkyl groups, and when both ring A and ring B are heterocycloalkyl groups, one ring has 1 heteroatom N and the other ring has 2 heteroatoms N.

[0021] Furthermore, the compound is as shown in formula (IX). TIFF2025523440000010.tif38170

[0022] However, R 3 and R 4 are each independently selected from hydrogen and C1-C6 alkyl groups, or R3 and R 4 are linked to form a 3- to 6-membered cycloalkyl group, R 5 is selected from a C1-C6 alkyl group, a 3- to 6-membered cycloalkyl group, a trifluoromethyl group, a trifluoroethyl group, a substituted or unsubstituted 6- to 10-membered aryl group, and a substituted or unsubstituted 5- to 8-membered heteroaryl group, and the substituents of the aryl group or heteroaryl group are selected from halogen, a hydroxy group, an amino group, a cyano group, a trifluoromethyl group, a C1-C6 alkyl group, a 3- to 6-membered cycloalkyl group, and a C1-C6 alkoxy group, X is CR 7 R 8 O, S, SO, SO2, NR 7 selected from, R 7 and R 8 are each independently selected from hydrogen, halogen, a C1-C6 alkyl group, and a 3- to 6-membered cycloalkyl group, R 6 is a substituent at any position on the benzene ring, and b is the number of substituents R 6 and, each R 6 is each independently selected from halogen, a hydroxy group, an amino group, a cyano group, a trifluoromethyl group, a C1-C6 alkyl group, a 3- to 6-membered cycloalkyl group, and a C1-C6 alkoxy group, b is 0, 1, 2, or 3, Ring A and ring B are each independently selected from a 4- to 12-membered cycloalkyl group and a 4- to 12-membered heterocycloalkyl group, Y is absent, CR Y1 R Y2 C(O), -CR 11 =CR 12 -, -CR 11 =N-, -N=N-, -OC(O)-, R Y1 and R Y2 are each independently selected from hydrogen and a C1-C6 alkyl group, R 11 and R 12 are each independently selected from hydrogen and a C1-C6 alkyl group, The heteroatom of the heteroaryl group is O, N or S, and the number of the heteroatoms is 1, 2 or 3. The heteroatom of the heterocycloalkyl group is N, and the number of the heteroatoms is 1, 2 or 3. Preferably, R 5 is selected from a C1-C6 alkyl group, a 3-6 membered cycloalkyl group, a trifluoromethyl group, a trifluoroethyl group, a substituted or unsubstituted phenyl group, a substituted or unsubstituted thienyl group, a substituted or unsubstituted furyl group, a substituted or unsubstituted pyrrolyl group, a substituted or unsubstituted pyrimidinyl group, a substituted or unsubstituted pyridazinyl group, a substituted or unsubstituted pyrazolyl group, a substituted or unsubstituted pyrazinyl group, and the substituents of the phenyl group, thienyl group, furyl group, pyrrolyl group, pyrimidinyl group, pyridazinyl group, pyrazolyl group or pyrazinyl group are selected from halogen, hydroxy group, amino group, cyano group, trifluoromethyl group, C1-C6 alkyl group, 3-6 membered cycloalkyl group, C1-C6 alkoxy group. X is selected from CH2, CF2, O, S, SO, SO2, NR 7 and R 7 is selected from hydrogen, halogen, C1-C6 alkyl group, 3-6 membered cycloalkyl group. Ring A and ring B are each independently selected from a 4-12 membered cycloalkyl group, a 4-12 membered heterocycloalkyl group. When both ring A and ring B are heterocycloalkyl groups, one ring has one heteroatom N and the other ring has two heteroatoms N.

[0023] Furthermore, the compound is the one shown in formula (X). TIFF2025523440000011.tif38170

[0024] However, R 3 and R 4 are each independently selected from hydrogen, C1-C6 alkyl group, or R 3 and R 4are linked to form a 3- to 6-membered cycloalkyl group, R 5 is selected from a C1-C6 alkyl group, a 3- to 6-membered cycloalkyl group, a trifluoromethyl group, a trifluoroethyl group, a substituted or unsubstituted 6- to 10-membered aryl group, and a substituted or unsubstituted 5- to 8-membered heteroaryl group, and the substituents of the aryl group or heteroaryl group are selected from halogen, a hydroxy group, an amino group, a cyano group, a trifluoromethyl group, a C1-C6 alkyl group, a 3- to 6-membered cycloalkyl group, and a C1-C6 alkoxy group, X is CR 7 R 8 O, S, SO, SO2, NR 7 is selected from, R 7 R 8 are each independently selected from hydrogen, halogen, a C1-C6 alkyl group, and a 3- to 6-membered cycloalkyl group, Ring A and ring B are each independently selected from a 4- to 12-membered cycloalkyl group and a 4- to 12-membered heterocycloalkyl group, 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 each independently selected from hydrogen and a C1-C6 alkyl group, R 11 R 12 are each independently selected from hydrogen and a C1-C6 alkyl group, The heteroatom of the heteroaryl group is O, N, or S, and the number of heteroatoms is 1, 2, or 3, The heteroatom of the heterocycloalkyl group is N, and the number of heteroatoms is 1, 2, or 3, Preferably, R 5is selected from a C1-C6 alkyl group, a 3-6 membered cycloalkyl group, a trifluoromethyl group, a trifluoroethyl group, a substituted or unsubstituted phenyl group, a substituted or unsubstituted thienyl group, a substituted or unsubstituted furyl group, a substituted or unsubstituted pyrrolyl group, a substituted or unsubstituted pyrimidinyl group, a substituted or unsubstituted pyridazinyl group, a substituted or unsubstituted pyrazolyl group, a substituted or unsubstituted pyrazinyl group, and substituents of the phenyl group, thienyl group, furyl group, pyrrolyl group, pyrimidinyl group, pyridazinyl group, pyrazolyl group or pyrazinyl group are selected from halogen, hydroxy group, amino group, cyano group, trifluoromethyl group, C1-C6 alkyl group, 3-6 membered cycloalkyl group, C1-C6 alkoxy group, X is CH2, CF2, O, S, SO, SO2, NR 7 selected from R 7 is selected from hydrogen, halogen, C1-C6 alkyl group, 3-6 membered cycloalkyl group, Ring A and Ring B are each independently selected from a 4-12 membered cycloalkyl group, a 4-12 membered heterocycloalkyl group, and when both Ring A and Ring B are heterocycloalkyl groups, one ring has one heteroatom N and the other ring has two heteroatoms N.

[0025] Furthermore, the compound is as shown in formula (XI). TIFF2025523440000012.tif45170

[0026] However, R 2 is a substituent at any position on the benzene ring, a is the number of substituents R 2 and each R 2 is independently selected from halogen, hydroxy group, amino group, cyano group, trifluoromethyl group, C1-C6 alkyl group, 3-6 membered cycloalkyl group, C1-C6 alkoxy group, a is 0, 1, 2 or 3, R 3 R 4is independently selected from hydrogen and C1-C6 alkyl groups, or R 3 and R 4 are linked to form a 3- to 6-membered cycloalkyl group, 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, hydroxy group, amino group, cyano group, trifluoromethyl group, C1-C6 alkyl group, 3- to 6-membered cycloalkyl group, and C1-C6 alkoxy group, d is 0, 1, 2, or 3, X is selected from CR 7 R 8 , O, S, SO, SO2, NR 7 ; R 7 and R 8 are independently selected from hydrogen, halogen, C1-C6 alkyl group, and 3- to 6-membered cycloalkyl group, 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, hydroxy group, amino group, cyano group, trifluoromethyl group, C1-C6 alkyl group, 3- to 6-membered cycloalkyl group, and C1-C6 alkoxy group, b is 0, 1, 2, or 3, Ring A and ring B are independently selected from 4- to 12-membered cycloalkyl groups and 4- to 12-membered heterocycloalkyl groups, M is selected from none, CR 9 R 10 , O, S, SO, SO2, NR 9 ; R 9 and R 10 are independently selected from hydrogen and C1-C6 alkyl groups, 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 a halogen, a hydroxy group, an amino group, a cyano group, a trifluoromethyl group, a C1-C6 alkyl group, a 3-6 membered cycloalkyl group, a C1-C6 alkoxy group, or any two Es 3 are linked to form a 3-6 membered cycloalkyl group, a 6-10 membered aryl group, a 4-12 membered heterocycloalkyl group, or a 5-8 membered heteroaryl group, 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 each independently selected from hydrogen and a C1-C6 alkyl group, R 11 , R 12 are each independently selected from hydrogen and a C1-C6 alkyl group, The heteroatom of the heteroaryl group is O, N, or S, and the number of heteroatoms is 1, 2, or 3, The heteroatom of the heterocycloalkyl group is N, and the number of heteroatoms is 1, 2, or 3, Preferably, X is selected from CH2, CF2, O, S, SO, SO2, NR 7 and R 7 is selected from hydrogen, a halogen, a C1-C6 alkyl group, and a 3-6 membered cycloalkyl group, Ring A and ring B are each independently selected from a 4-12 membered cycloalkyl group and a 4-12 membered heterocycloalkyl group. When both ring A and ring B are heterocycloalkyl groups, one ring has one heteroatom N and the other ring has two heteroatoms N.

[0027] Furthermore, the compound is the one shown in formula (XII). TIFF2025523440000013.tif52170

[0028] However, R 2 is a substituent at any position on the benzene ring, a is the number of substituents R 2 and each R 2 is independently selected from halogen, hydroxy group, amino group, cyano group, trifluoromethyl group, C1-C6 alkyl group, 3-6 membered cycloalkyl group, C1-C6 alkoxy group, a is 0, 1, 2 or 3, R 3 and R 4 are each independently selected from hydrogen, C1-C6 alkyl group, or R 3 and R 4 are linked to form a 3-6 membered cycloalkyl group, R 11 is a substituent at any position on the benzene ring, d is the number of substituents R 11 and each R 11 is independently selected from halogen, hydroxy group, amino group, cyano group, trifluoromethyl group, C1-C6 alkyl group, 3-6 membered cycloalkyl group, C1-C6 alkoxy group, d is 0, 1, 2 or 3, X is selected from CR 7 R 8 , O, S, SO, SO2, NR 7 and R 7 and R 8 are each independently selected from hydrogen, halogen, C1-C6 alkyl group, 3-6 membered cycloalkyl group, R 6 is a substituent at any position on the benzene ring, b is the number of substituents R 6 and each R 6 is independently selected from halogen, hydroxy group, amino group, cyano group, trifluoromethyl group, C1-C6 alkyl group, 3-6 membered cycloalkyl group, C1-C6 alkoxy group, b is 0, 1, 2 or 3, M is none, CR 9 R 10 , O, S, SO, SO2, NR 9 is selected from, R 9 , R 10 is each independently selected from hydrogen and C1-C6 alkyl groups, R 12 is selected from hydrogen, halogen, C1-C6 alkyl groups, and hydroxy groups, m1, m2, m3, m4, m5, m6 are each independently selected from 0, 1, 2, or 3, 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 each independently selected from halogen, hydroxy groups, amino groups, cyano groups, trifluoromethyl groups, C1-C6 alkyl groups, 3-6 membered cycloalkyl groups, C1-C6 alkoxy groups, or any two Es 3 are linked to form a 3-6 membered cycloalkyl group, a 6-10 membered aryl group, a 4-12 membered heterocycloalkyl group, or a 5-8 membered heteroaryl group, 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 is each independently selected from hydrogen and C1-C6 alkyl groups, R 11 , R 12 is each independently selected from hydrogen and C1-C6 alkyl groups, The heteroatoms of the heteroaryl group are O, N, or S, and the number of heteroatoms is 1, 2, or 3, The heteroatom of the heterocycloalkyl group is N, and the number of heteroatoms is 1, 2, or 3, Preferably, X is selected from CH2, CF2, O, S, SO, SO2, NR 7 and is selected from R 7 is selected from hydrogen, halogen, a C1-C6 alkyl group, and a 3-6 membered cycloalkyl group, 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 each independently selected from hydrogen and a C1-C6 alkyl group, R 11 , R 12 are each independently selected from hydrogen and a C1-C6 alkyl group.

[0029] Furthermore, the compound is the one shown in formula (XIII). TIFF2025523440000014.tif52170

[0030] However, 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, a hydroxy group, an amino group, a cyano group, a trifluoromethyl group, a C1-C6 alkyl group, a 3-6 membered cycloalkyl group, and a C1-C6 alkoxy group, a is 0, 1, 2, or 3, R 3 , R 4 are each independently selected from hydrogen and a C1-C6 alkyl group, or R 3 , R 4 are linked to form a 3-6 membered cycloalkyl group, R 11 is a substituent at any position on the benzene ring, and d is the number of substituents R 11 , each R 11is independently selected from halogen, hydroxy group, amino group, cyano group, trifluoromethyl group, C1-C6 alkyl group, 3-6 membered cycloalkyl group, and C1-C6 alkoxy group, d is 0, 1, 2 or 3, X is CR 7 R 8 , O, S, SO, SO2, NR 7 is selected from, R 7 , R 8 is independently selected from hydrogen, halogen, C1-C6 alkyl group, and 3-6 membered cycloalkyl group, 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, hydroxy group, amino group, cyano group, trifluoromethyl group, C1-C6 alkyl group, 3-6 membered cycloalkyl group, and C1-C6 alkoxy group, b is 0, 1, 2 or 3, R 12 is selected from hydrogen, halogen, C1-C6 alkyl group, and hydroxy group, 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 the number of substituents E 3 , Each E 3 is independently selected from halogen, hydroxy group, amino group, cyano group, trifluoromethyl group, C1-C6 alkyl group, 3-6 membered cycloalkyl group, and C1-C6 alkoxy group, or any two Es 3 are linked to form a 3-6 membered cycloalkyl group, 6-10 membered aryl group, 4-12 membered heterocycloalkyl group, or 5-8 membered heteroaryl group, c is 0, 1, 2 or 3, Y is none, CR Y1 R Y2 , C(O), -CR 11 =CR12 -, -CR 11 =N-, -N=N-, -OC(O)-, R Y1 、R Y2 each independently is selected from hydrogen and C1-C6 alkyl groups, R 11 、R 12 each independently is selected from hydrogen and C1-C6 alkyl groups, the heteroatom of the heteroaryl group is O, N or S, and the number of the heteroatoms is 1, 2 or 3, the heteroatom of the heterocycloalkyl group is N, and the number of the heteroatoms is 1, 2 or 3, Preferably, X is selected from CH2, CF2, O, S, SO, SO2, NR 7 selected from, R 7 is selected from hydrogen, halogen, C1-C6 alkyl groups, and 3-6 membered cycloalkyl groups, Y is absent, CR Y1 R Y2 、C(O), -CR 11 =CR 12 -, -CR 11 =N-, -N=N-, -OC(O)-, R Y1 、R Y2 each independently is selected from hydrogen and C1-C6 alkyl groups, R 11 、R 12 each independently is selected from hydrogen and C1-C6 alkyl groups.

[0031] Furthermore, the compound is the one shown in formula (XIV). TIFF2025523440000015.tif52170

[0032] However, R 2 is a substituent at any position on the benzene ring, a is the number of substituents R 2 , each R 2Each is independently selected from a halogen, a hydroxy group, an amino group, a cyano group, a trifluoromethyl group, a C1-C6 alkyl group, a 3-6 membered cycloalkyl group, and a C1-C6 alkoxy group, a is 0, 1, 2 or 3, R 3 and R 4 are each independently selected from hydrogen and a C1-C6 alkyl group, or R 3 and R 4 are linked to form a 3-6 membered cycloalkyl group, 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 a halogen, a hydroxy group, an amino group, a cyano group, a trifluoromethyl group, a C1-C6 alkyl group, a 3-6 membered cycloalkyl group, and a C1-C6 alkoxy group, d is 0, 1, 2 or 3, X is selected from CR 7 R 8 , O, S, SO, SO2, NR 7 ; R 7 and R 8 are each independently selected from hydrogen, a halogen, a C1-C6 alkyl group, and a 3-6 membered cycloalkyl group, 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 a halogen, a hydroxy group, an amino group, a cyano group, a trifluoromethyl group, a C1-C6 alkyl group, a 3-6 membered cycloalkyl group, and a C1-C6 alkoxy group, b is 0, 1, 2 or 3, R 12 is selected from hydrogen, a halogen, a C1-C6 alkyl group, and a hydroxy group, m1, m2, m3, m4, m5, m6 are each independently selected from 0, 1, 2 or 3, E 3is a substituent at any position on the benzene ring, and c is the number of substituents E 3 and each E 3 is independently selected from halogen, hydroxy group, amino group, cyano group, trifluoromethyl group, C1-C6 alkyl group, 3-6 membered cycloalkyl group, C1-C6 alkoxy group, or any two Es 3 are linked to form a 3-6 membered cycloalkyl group, 6-10 membered aryl group, 4-12 membered heterocycloalkyl group, 5-8 membered heteroaryl group, 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 is independently selected from hydrogen and C1-C6 alkyl group, R 11 R 12 is independently selected from hydrogen and C1-C6 alkyl group, the heteroatom of the heteroaryl group is O, N or S, and the number of the heteroatoms is 1, 2 or 3, the heteroatom of the heterocycloalkyl group is N, and the number of the heteroatoms is 1, 2 or 3, preferably, X is selected from CH2, CF2, O, S, SO, SO2, NR 7 and R 7 is selected from hydrogen, halogen, C1-C6 alkyl group, 3-6 membered cycloalkyl group, Y is absent, CR Y1 R Y2 , C(O), -CR 11 =CR 12 -, -CR 11 =N-, -N=N-, -OC(O)-, R Y1 R Y2each independently selected from hydrogen and C1-C6 alkyl groups R 11 and R 12 each independently selected from hydrogen and C1-C6 alkyl groups.

[0033] Furthermore, the compound is represented by formula (XV). TIFF2025523440000016.tif45170

[0034] However 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, hydroxy group, amino group, cyano group, trifluoromethyl group, C1-C6 alkyl group, 3-6 membered cycloalkyl group, and C1-C6 alkoxy group a is 0, 1, 2 or 3 R 3 and R 4 are each independently selected from hydrogen and C1-C6 alkyl groups, or R 3 and R 4 are linked to form a 3-6 membered cycloalkyl group 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, hydroxy group, amino group, cyano group, trifluoromethyl group, C1-C6 alkyl group, 3-6 membered cycloalkyl group, and C1-C6 alkoxy group d is 0, 1, 2 or 3 X is selected from CR 7 R 8 , O, S, SO, SO2, NR 7 . R 7 and R 8 are each independently selected from hydrogen, halogen, C1-C6 alkyl group, and 3-6 membered cycloalkyl group R 6 is a substituent at any position on the benzene ring, and b is the number of substituents R 6 and each R 6 is independently selected from halogen, hydroxy group, amino group, cyano group, trifluoromethyl group, C1-C6 alkyl group, 3-6 membered cycloalkyl group, C1-C6 alkoxy group, b is 0, 1, 2 or 3, ring A and ring B are independently selected from 4-12 membered cycloalkyl group, 4-12 membered heterocycloalkyl group, M is none, CR 9 R 10 、O, S, SO, SO2, NR 9 selected from, R 9 、R 10 is independently selected from hydrogen, C1-C6 alkyl group, E 3 is a substituent at any position on the benzene ring, and c is the number of substituents E 3 and each E 3 is independently selected from halogen, hydroxy group, amino group, cyano group, trifluoromethyl group, C1-C6 alkyl group, 3-6 membered cycloalkyl group, C1-C6 alkoxy group, or any two E 3 are linked to form a 3-6 membered cycloalkyl group, 6-10 membered aryl group, 4-12 membered heterocycloalkyl group, 5-8 membered heteroaryl group, 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 is independently selected from hydrogen, C1-C6 alkyl group, R 11 、R 12Each is independently selected from hydrogen and C1-C6 alkyl groups. The heteroatom of the heteroaryl group is O, N or S, and the number of the heteroatoms is 1, 2 or 3. The heteroatom of the heterocycloalkyl group is N, and the number of the heteroatoms is 1, 2 or 3. Preferably, X is selected from CH2, CF2, O, S, SO, SO2, NR 7 and R 7 is selected from hydrogen, halogen, C1-C6 alkyl groups, and 3-6 membered cycloalkyl groups. Ring A and ring B are each independently selected from 4-12 membered cycloalkyl groups and 4-12 membered heterocycloalkyl groups. When both ring A and ring B are heterocycloalkyl groups, one ring has 1 heteroatom N and the other ring has 2 heteroatoms N.

[0035] Furthermore, the compound is as shown in formula (XVI). TIFF2025523440000017.tif52170

[0036] However, 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, hydroxy group, amino group, cyano group, trifluoromethyl group, C1-C6 alkyl groups, 3-6 membered cycloalkyl groups, and C1-C6 alkoxy groups. a is 0, 1, 2 or 3. R 3 and R 4 are each independently selected from hydrogen and C1-C6 alkyl groups, or R 3 and R 4 are linked to form a 3-6 membered cycloalkyl group. R 11 is a substituent at any position on the thiophene ring, and d is the number of substituents R 11is the number of Each R 11 is independently selected from halogen, hydroxy group, amino group, cyano group, trifluoromethyl group, C1-C6 alkyl group, 3-6 membered cycloalkyl group, and C1-C6 alkoxy group; d is 0, 1, 2 or 3; X is CR 7 R 8 is selected from O, S, SO, SO2, NR 7 ; R 7 and R 8 are independently selected from hydrogen, halogen, C1-C6 alkyl group, and 3-6 membered cycloalkyl group; 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, hydroxy group, amino group, cyano group, trifluoromethyl group, C1-C6 alkyl group, 3-6 membered cycloalkyl group, and C1-C6 alkoxy group; b is 0, 1, 2 or 3; Ring A and ring B are independently selected from 4-12 membered cycloalkyl group and 4-12 membered heterocycloalkyl group; M is selected from none, CR 9 R 10 is selected from O, S, SO, SO2, NR 9 ; R 9 and R 10 are independently selected from hydrogen and C1-C6 alkyl group; 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, hydroxy group, amino group, cyano group, trifluoromethyl group, C1-C6 alkyl group, 3-6 membered cycloalkyl group, and C1-C6 alkoxy group, or any two E 3are linked to form a 3- to 6-membered cycloalkyl group, a 6- to 10-membered aryl group, a 4- to 12-membered heterocycloalkyl group, or a 5- to 8-membered heteroaryl group, 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 each independently selected from hydrogen and C1-C6 alkyl groups, R 11 、R 12 are each independently selected from hydrogen and C1-C6 alkyl groups, the heteroatoms of the heteroaryl group are O, N, or S, and the number of heteroatoms is 1, 2, or 3, the heteroatom of the heterocycloalkyl group is N, and the number of heteroatoms is 1, 2, or 3, Preferably, X is selected from CH2, CF2, O, S, SO, SO2, NR 7 , R 7 is selected from hydrogen, halogen, C1-C6 alkyl groups, and 3- to 6-membered cycloalkyl groups, ring A and ring B are each independently selected from 4- to 12-membered cycloalkyl groups and 4- to 12-membered heterocycloalkyl groups. When both ring A and ring B are heterocycloalkyl groups, one ring has one heteroatom N and the other ring has two heteroatoms N.

[0037] Furthermore, the compound is the one shown in formula (XVII). TIFF2025523440000018.tif45170

[0038] However, R 3 、R 4 are each independently selected from hydrogen and C1-C6 alkyl groups, or R3 and R 4 are linked to form a 3- to 6-membered cycloalkyl group, X is CR 7 R 8 , O, S, SO, SO2, NR 7 selected from, R 7 , R 8 are each independently selected from hydrogen, halogen, C1-C6 alkyl group, 3- to 6-membered cycloalkyl group, R 11 is a substituent at any position on the benzene ring, d is the number of substituents R 11 , R 6 is a substituent at any position on the benzene ring, b is the number of substituents R 6 , d is 0, 1, 2, or 3, b is 0, 1, 2, or 3, and at least one of d and b is not 0, each R 11 , R 6 are each independently selected from halogen, hydroxy group, amino group, cyano group, trifluoromethyl group, C1-C6 alkyl group, 3- to 6-membered cycloalkyl group, C1-C6 alkoxy group, and at least one is fluorine, Ring A and ring B are each independently selected from 4- to 12-membered cycloalkyl group, 4- to 12-membered heterocycloalkyl group, M is none, CR 9 R 10 , O, S, SO, SO2, NR 9 selected from, R 9 , R 10 are each independently selected from hydrogen, C1-C6 alkyl group, Y is none, CR Y1 R Y2 , C(O), -CR 11 =CR 12 -, -CR 11 =N-, -N=N-, -OC(O)-, R Y1 , R Y2 are each independently selected from hydrogen, C1-C6 alkyl group, R 11 and R 12 are each independently selected from hydrogen and C1-C6 alkyl groups, the heteroatom of the heterocycloalkyl group is N, and the number of the heteroatoms is 1, 2 or 3, preferably, X is selected from CH2, CF2, O, S, SO, SO2, NR 7 and, R 7 is selected from hydrogen, halogen, C1-C6 alkyl groups and 3-6 membered cycloalkyl groups, ring A and ring B are each independently selected from 4-12 membered cycloalkyl groups and 4-12 membered heterocycloalkyl groups. When both ring A and ring B are heterocycloalkyl groups, one ring has 1 heteroatom N and the other ring has 2 heteroatoms N.

[0039] Furthermore, the compound is as shown in formula (XVIII). TIFF2025523440000019.tif45170

[0040] However, X is CR 7 R 8 O, S, SO, SO2, NR 7 and, R 7 and R 8 are each independently selected from hydrogen, halogen, C1-C6 alkyl groups and 3-6 membered cycloalkyl groups, R 11 is a substituent at any position on the benzene ring, d is the number of substituents R 11 and R 6 is a substituent at any position on the benzene ring, b is the number of substituents R 6 and, 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 and R 6Each is independently selected from a halogen, a hydroxy group, an amino group, a cyano group, a trifluoromethyl group, a C1-C6 alkyl group, a 3-6 membered cycloalkyl group, and a C1-C6 alkoxy group, and at least one is fluorine. Ring A and Ring B are each independently selected from a 4-12 membered cycloalkyl group and a 4-12 membered heterocycloalkyl group. M is none, CR 9 R 10 selected from R 9 R 10 are each independently selected from hydrogen and a C1-C6 alkyl group. Y is none, CR Y1 R Y2 C(O), -CR 11 =CR 12 -, -CR 11 =N-, -N=N-, -OC(O)-. R Y1 R Y2 are each independently selected from hydrogen and a C1-C6 alkyl group. R 11 R 12 are each independently selected from hydrogen and a C1-C6 alkyl group. The heteroatom of the heterocycloalkyl group is N, and the number of heteroatoms is 1, 2, or 3. Preferably, X is selected from CH2, CF2, or O. Ring A and Ring B are each independently selected from a 4-12 membered cycloalkyl group and a 4-12 membered heterocycloalkyl group. When both Ring A and Ring B are heterocycloalkyl groups, one ring has one heteroatom N and the other ring has two heteroatoms N.

[0041] Furthermore, the compound is the one shown in formula (XIX). TIFF2025523440000020.tif45170

[0042] However, R 1is selected from hydrogen, a C1-C6 alkyl group, a hydroxy group, an amino group, a C1-C6 alkoxy group, and a boronic acid group, R 2 is a substituent at any position on the benzene ring, and a is the number of substituents R 2 and each R 2 is independently selected from halogen, a hydroxy group, an amino group, a cyano group, a trifluoromethyl group, a C1-C6 alkyl group, a 3-6 membered cycloalkyl group, and a C1-C6 alkoxy group, a is 0, 1, 2, or 3, R 5 is selected from a C1-C6 alkyl group, a 3-6 membered cycloalkyl group, a trifluoromethyl group, a trifluoroethyl group, a substituted or unsubstituted 6-10 membered aryl group, and a substituted or unsubstituted 5-8 membered heteroaryl group, and the substituents of the aryl group or heteroaryl group are selected from halogen, a hydroxy group, an amino group, a cyano group, a trifluoromethyl group, a C1-C6 alkyl group, a 3-6 membered cycloalkyl group, and a C1-C6 alkoxy group, X is selected from CR 7 R 8 O, S, SO, SO2, NR 7 and R 7 R 8 is independently selected from hydrogen, halogen, a C1-C6 alkyl group, and a 3-6 membered cycloalkyl group, n is 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 and each R 6 is independently selected from halogen, a hydroxy group, an amino group, a cyano group, a trifluoromethyl group, a C1-C6 alkyl group, a 3-6 membered cycloalkyl group, and a C1-C6 alkoxy group, b is 0, 1, 2, or 3, Ring A and ring B are independently selected from a 4-12 membered cycloalkyl group and a 4-12 membered heterocycloalkyl group, M is none, CR9 R 10 、O, S, SO, SO2, NR 9 selected from, R 9 、R 10 is each independently selected from hydrogen and C1-C6 alkyl groups, E 3 is a substituent at any position on the benzene ring, and c is the number of substituents E 3 of, each E 3 is each independently selected from halogen, hydroxy group, amino group, cyano group, trifluoromethyl group, C1-C6 alkyl group, 3-6 membered cycloalkyl group, C1-C6 alkoxy group, or any two Es 3 are linked to form a 3-6 membered cycloalkyl group, 6-10 membered aryl group, 4-12 membered heterocycloalkyl group, 5-8 membered heteroaryl group, 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 is each independently selected from hydrogen and C1-C6 alkyl groups, R 11 、R 12 is each independently selected from hydrogen and C1-C6 alkyl groups, The heteroatom of the heteroaryl group is O, N or S, and the number of heteroatoms is 1, 2 or 3, The heteroatom of the heterocycloalkyl group is N, and the number of heteroatoms is 1, 2 or 3, Preferably, R 5is selected from a C1-C6 alkyl group, a 3-6 membered cycloalkyl group, a trifluoromethyl group, a trifluoroethyl group, a substituted or unsubstituted phenyl group, a substituted or unsubstituted thienyl group, a substituted or unsubstituted furyl group, a substituted or unsubstituted pyrrolyl group, a substituted or unsubstituted pyrimidinyl group, a substituted or unsubstituted pyridazinyl group, a substituted or unsubstituted pyrazolyl group, and a substituted or unsubstituted pyrazinyl group, and the substituents of the phenyl group, thienyl group, furyl group, pyrrolyl group, pyrimidinyl group, pyridazinyl group, pyrazolyl group or pyrazinyl group are selected from halogen, a hydroxy group, an amino group, a cyano group, a trifluoromethyl group, a C1-C6 alkyl group, a 3-6 membered cycloalkyl group, and a C1-C6 alkoxy group.

[0043] Furthermore, the compound is as shown in formula (XX). TIFF2025523440000021.tif38170

[0044] However, R 5 is selected from a C1-C6 alkyl group, a 3-6 membered cycloalkyl group, a trifluoromethyl group, a trifluoroethyl group, a substituted or unsubstituted 6-10 membered aryl group, and a substituted or unsubstituted 5-8 membered heteroaryl group, and the substituents of the aryl group or heteroaryl group are selected from halogen, a hydroxy group, an amino group, a cyano group, a trifluoromethyl group, a C1-C6 alkyl group, a 3-6 membered cycloalkyl group, and a C1-C6 alkoxy group, X is CR 7 R 8 O, S, SO, SO2, NR 7 selected from, R 7 R 8 are each independently selected from hydrogen, halogen, a C1-C6 alkyl group, and a 3-6 membered cycloalkyl group, R 6 is a substituent at any position on the benzene ring, b is the number of substituents R 6 and each R 6are each independently selected from a halogen, a hydroxy group, an amino group, a cyano group, a trifluoromethyl group, a C1-C6 alkyl group, a 3- to 6-membered cycloalkyl group, and a C1-C6 alkoxy group, b is 0, 1, 2, or 3, Ring A and Ring B are each independently selected from a 4- to 12-membered cycloalkyl group and a 4- to 12-membered heterocycloalkyl group, M is none, CR 9 R 10 O, S, SO, SO2, NR 9 and is selected from R 9 R 10 are each independently selected from hydrogen and a C1-C6 alkyl group, Y is none, CR Y1 R Y2 C(O), -CR 11 =CR 12 -, -CR 11 =N-, -N=N-, -OC(O)-, R Y1 R Y2 are each independently selected from hydrogen and a C1-C6 alkyl group, R 11 R 12 are each independently selected from hydrogen and a C1-C6 alkyl group, The heteroatom of the heteroaryl group is O, N, or S, and the number of the heteroatoms is 1, 2, or 3, The heteroatom of the heterocycloalkyl group is N, and the number of the heteroatoms is 1, 2, or 3, Preferably, R 5is selected from a C1-C6 alkyl group, a 3-6 membered cycloalkyl group, a trifluoromethyl group, a trifluoroethyl group, a substituted or unsubstituted phenyl group, a substituted or unsubstituted thienyl group, a substituted or unsubstituted furyl group, a substituted or unsubstituted pyrrolyl group, a substituted or unsubstituted pyrimidinyl group, a substituted or unsubstituted pyridazinyl group, a substituted or unsubstituted pyrazolyl group, a substituted or unsubstituted pyrazinyl group, and the substituents of the phenyl group, thienyl group, furyl group, pyrrolyl group, pyrimidinyl group, pyridazinyl group, pyrazolyl group or pyrazinyl group are selected from halogen, hydroxy group, amino group, cyano group, trifluoromethyl group, C1-C6 alkyl group, 3-6 membered cycloalkyl group, C1-C6 alkoxy group, X is CH2, CF2, O, S, SO, SO2, NR 7 is selected from R 7 is selected from hydrogen, halogen, C1-C6 alkyl group, 3-6 membered cycloalkyl group, Ring A and ring B are each independently selected from a 4-12 membered cycloalkyl group, a 4-12 membered heterocycloalkyl group, and when both ring A and ring B are heterocycloalkyl groups, one ring has one heteroatom N and the other ring has two heteroatoms N.

[0045] Furthermore, the compound is as shown in formula (XXI). TIFF2025523440000022.tif52170

[0046] However, R 11 is a substituent at any position on the benzene ring, d is the number of substituents R 11 and each R 11 is independently selected from halogen, hydroxy group, amino group, cyano group, trifluoromethyl group, C1-C6 alkyl group, 3-6 membered cycloalkyl group, C1-C6 alkoxy group, d is 0, 1, 2 or 3, X is CR 7 R 8, O, S, SO, SO2, NR 7 selected from R 7 , R 8 is independently selected from hydrogen, halogen, a C1-C6 alkyl group, and a 3- to 6-membered cycloalkyl group, R 6 is a substituent at any position on the benzene ring, and b is the number of substituents R 6 and each R 6 is independently selected from halogen, a hydroxy group, an amino group, a cyano group, a trifluoromethyl group, a C1-C6 alkyl group, a 3- to 6-membered cycloalkyl group, and a C1-C6 alkoxy group, b is 0, 1, 2, or 3, M is none, CR 9 R 10 , O, S, SO, SO2, NR 9 selected from R 9 , R 10 is independently selected from hydrogen and a C1-C6 alkyl group, m1, m2, m3, m4, m5, m6 are independently selected from 0, 1, 2, or 3, Y is none, CR Y1 R Y2 , C(O), -CR 11 =CR 12 -, -CR 11 =N-, -N=N-, -OC(O)-, R Y1 , R Y2 is independently selected from hydrogen and a C1-C6 alkyl group, R 11 , R 12 is independently selected from hydrogen and a C1-C6 alkyl group, Preferably, X is selected from CH2, CF2, O, S, SO, SO2, NR 7 selected from R 7 is selected from hydrogen, halogen, a C1-C6 alkyl group, and a 3- to 6-membered cycloalkyl group.

[0047] Furthermore, the ring A and the ring B are each independently selected from the following structures. TIFF2025523440000023.tif70170TIFF2025523440000024.tif39170

[0048] Furthermore, the TIFF2025523440000025.tif22170 is selected from the following structures. TIFF2025523440000026.tif36170TIFF2025523440000027.tif37170TIFF2025523440000028.tif36170TIFF2025523440000029.tif37170

[0049] Furthermore, the compound is one of the following compounds. TIFF2025523440000030.tif28170TIFF2025523440000031.tif28170TIFF2025523440000032.tif28170TIFF2025523440000033.tif23170TIFF2025523440000034.tif28170TIFF2025523440000035.tif39170TIFF2025523440000036.tif87170TIFF2025523440000037.tif27170TIFF2025523440000038.tif91170TIFF2025523440000039.tif24170TIFF2025523440000040.tif28170TIFF2025523440000041.tif28170TIFF2025523440000042.tif30170TIFF2025523440000043.tif28170TIFF2025523440000044.tif30170TIFF2025523440000045.tif28170TIFF2025523440000046.tif29170TIFF2025523440000047.tif28170TIFF2025523440000048.tif55170TIFF2025523440000049.tif24170TIFF2025523440000050.tif28170TIFF2025523440000051.tif49170TIFF2025523440000052.tif24170TIFF2025523440000053.tif29170TIFF2025523440000054.tif24170TIFF2025523440000055.tif30170TIFF2025523440000056.tif24170TIFF2025523440000057.tif29170TIFF2025523440000058.tif36170TIFF2025523440000059.tif29170TIFF2025523440000060.tif30170TIFF2025523440000061.tif28170TIFF2025523440000062.tif28170TIFF2025523440000063.tif28170TIFF2025523440000064.tif28170TIFF2025523440000065.tif22170TIFF2025523440000066.tif24170TIFF2025523440000067.tif28170TIFF2025523440000068.tif38170TIFF2025523440000069.tif40170TIFF2025523440000070.tif28170TIFF2025523440000071.tif24170TIFF2025523440000072.tif24170TIFF2025523440000073.tif57170TIFF2025523440000074.tif55170TIFF2025523440000075.tif54170.

[0050] Furthermore, the salt is a pharmaceutically acceptable salt, and the pharmaceutically acceptable salt is a phosphate, d-camphorsulfonate, hydrochloride, hydrobromide, hydrofluoric acid salt, sulfate, nitrate, carboxylate, acetate, propionate, oxalate, malonate, succinate, fumarate, maleate, lactate, malate, tartrate, citrate, picrate, methanesulfonate, benzenemethanesulfonate, benzenesulfonate, aspartate or glutamate of the compound.

[0051] The present invention also provides the use of the above compound, or its optical isomer, or its salt, or its hydrate, or its solvate, in the manufacture of an estrogen receptor degrader.

[0052] The present invention also provides the use of the above compound, or its optical isomer, or its salt, or its hydrate, or its solvate, in the manufacture of a drug for treating a disease related to estrogen receptor.

[0053] The present invention also provides the use of the above compound, or its optical isomer, or its salt, or its hydrate, or its solvate, in the manufacture of a drug for the treatment and / or prevention of cancer.

[0054] The present invention also provides the use of the above-mentioned compound, or its optical isomer, or its salt, or its hydrate, or its solvate, in the manufacture of a drug for the treatment and / or prevention of bone cancer, colon cancer, endometrial cancer, prostate cancer, ovarian cancer, uterine cancer, cervical cancer, lung cancer, breast cancer.

[0055] The present invention also provides a drug for treating cancer, which is a preparation manufactured by using the above-mentioned compound, or its optical isomer, or its salt, or its hydrate, or its solvate as an active ingredient and further adding a pharmaceutically acceptable auxiliary material.

[0056] The compounds and derivatives provided by 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.

[0057] The definitions of the terms used in the present invention are as follows. Unless otherwise specified, the first definition provided by a group or a term in the text applies to the said group or term throughout the specification, and for terms not specifically defined in the text, they shall represent the meanings that can be conceived by those skilled in the art based on the disclosure content and context.

[0058] "Substitution" means that a hydrogen atom in a molecule is replaced by another different atom or molecule.

[0059] The minimum and maximum values of the carbon atom content in a hydrocarbon group are represented by a prefix. For example, the prefix C a~ C b The alkyl group represents any alkyl group containing "a" to "b" carbon atoms. Therefore, for example, "C1-C8 alkyl group" refers to an alkyl group containing 1 to 8 carbon atoms, and "C1-C8 alkoxy group" refers to an alkoxy group containing 1 to 8 carbon atoms.

[0060] The "alkyl group" refers to a saturated hydrocarbon chain having a specified number of carbon atoms. For example, the C1-C8 alkyl group refers to an alkyl group having 1 to 8 carbon atoms, that is, 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms. The alkyl group may be linear or branched. Representative branched alkyl groups have one, two, or three branches. The alkyl group includes a methyl group, an ethyl group, a propyl group (n-propyl group and isopropyl group), a butyl group (n-butyl group, isobutyl group, and tert-butyl group), a pentyl group (n-pentyl group, isopentyl group, and neopentyl group), a hexyl group, and the like.

[0061] "Halogen" is fluorine, chlorine, bromine, or iodine.

[0062] In the present invention, the cycloalkyl group refers to a saturated or partially saturated non-aromatic cyclic group composed of carbon atoms, having no ring heteroatoms, and having a monocyclic or polycyclic (including fused, bridged, and spiro ring systems). The heterocycloalkyl group refers to a saturated or partially saturated non-aromatic cyclic group containing at least one heteroatom, including a monocyclic or polycyclic (including fused, bridged, and spiro ring systems), where the heteroatom refers to a nitrogen atom, an oxygen atom, or a sulfur atom. Examples of the heterocyclyl group include, for example, a piperidyl group, a piperazinyl group, and a morpholinyl group.

[0063] In the present invention, the aryl group refers to a group containing aromatic unsaturation having no ring heteroatoms and having a monocyclic or polycyclic (including fused, bridged, and spiro ring systems), such as a phenyl group, an anthracenyl group, and a naphthyl group. The heteroaryl group refers to an aromatic unsaturated ring containing at least one heteroatom, including a monocyclic or polycyclic (including fused, bridged, and spiro ring systems), and the heteroatom refers to a nitrogen atom, an oxygen atom, or a sulfur atom. For example, a pyridyl group, a pyrazinyl group, a pyridazinyl group, a pyrazolyl group, a furyl group, a thienyl group, an oxazolyl group, and the like.

[0064] In the present invention, the structure of OBn is It is TIFF2025523440000076.tif20170.

[0065] In the compound of formula (I) of the present invention, when the dashed line in the benzene ring is a bond, the structure of the compound is It is TIFF2025523440000077.tif29170, and when there is no dashed line in the benzene ring, the structure of the compound is It is TIFF2025523440000078.tif29170.

[0066] In the compound of formula (I) of the present invention, when there is no dashed line between Y and W, the structure of the compound is It is TIFF2025523440000079.tif29170, and R ab is a halogen, and when the dashed line between Y and W is a bond, the structure of the compound is It is TIFF2025523440000080.tif29170.

[0067] The present invention provides an aromatic compound that can be used for the production of an estrogen receptor degrader and for the production of a drug for the treatment of diseases related to estrogen receptors, such as a drug for the treatment and / or prevention of cancer, which may be breast cancer.

[0068] Of course, based on the above content of the present invention, various other forms of modification, substitution, or change can be made on the premise of not departing from the above basic technical idea of the present invention in light of the general technical knowledge and customary means in the art.

[0069] Hereinafter, the above content of the present invention will be further described in more detail by means of "modes for carrying out the invention" in the form of examples. However, it should not be understood that the scope of the above subject matter of the present invention is limited to the following examples. Any technology realized based on the above content of the present invention belongs to the scope of the present invention.

Brief Description of the Drawings

[0070]

Figure 1

Figure 2

Mode for Carrying Out the Invention

[0071] All the raw materials and equipment used in the "Mode for Carrying Out the Invention" of the present invention are existing products, and are those purchased as commercially available products.

[0072] Example 1. 2-(2,6-Dioxopiperidin-3-yl)-5-(4-(2-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)-2,7-diazaspiro[3.5]non-7-yl)methyl)piperidin-1-yl)isoindoline-1,3-dione TIFF2025523440000081.tif63170

[0073] Raw material A-1 was prepared by the method of the literature (WO2018102725).

[0074] First Step: Synthesis of 4-((1R,2S)-6-(tert-butoxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl 1,1,2,2,3,4,4-monofluorobutane-1-sulfonate 4-((1R,2S)-6-(tert-butoxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenol (1.5 g, 4.0 mmol) was dissolved in a mixed solvent of THF (10 mL) and MeCN (10 mL), K2CO3 (837 mg, 6.0 mmol) and perfluorobutanesulfonyl fluoride (1.22 g, 4.0 mmol) were added, and the reaction was carried out overnight at room temperature, and monitored by TLC until the raw materials were completely reacted. The reaction solution was concentrated and subjected to column chromatography to obtain 2.27 g of the product. Yield: 87%.

[0075] Step 2: Synthesis of tert-Butyl 2-(4-((1R,2S)-6-(tert-Butoxy)-2-Phenyl-1,2,3,4-Tetrahydronaphthalen-1-Yl)phenyl)-2,7-Diazaspiro[3.5]Nonane-7-Carboxylate 4-((1R,2S)-6-(tert-Butoxy)-2-Phenyl-1,2,3,4-Tetrahydronaphthalen-1-Yl)phenyl 1,1,2,2,3,4,4-Monofluorobutane-1-Sulfonate (200 mg, 0.33 mmol), tert-Butyl 2,7-Diazaspiro[3.5]Nonane-7-Carboxylate (112 mg, 0.49 mmol) were dissolved in toluene (10 mL), Pd(OAc)2 (11 mg, 0.05 mmol), X-Phos (32 mg, 0.07 mmol) and sodium tert-butoxide (95 mg, 0.99 mmol) were added, the reaction mixture was purged with Ar gas three times, and the reaction was carried out at 90 °C overnight. After complete reaction, it was cooled to room temperature, filtered through celite, water was added, extracted with ethyl acetate, washed with saturated sodium chloride, dried and concentrated, and then subjected to column chromatography to obtain 145 mg of the product. Yield: 82%. It was identified as the target compound by LC-MS.

[0076] Step 3: Synthesis of (5R,6S)-5-(4-(2,7-Diazaspiro[3.5]Non-2-Yl)phenyl)-6-Phenyl-5,6,7,8-Tetrahydronaphthalen-2-Ol tert-Butyl 2-(4-((1R,2S)-6-(tert-Butoxy)-2-Phenyl-1,2,3,4-Tetrahydronaphthalen-1-Yl)phenyl)-2,7-Diazaspiro[3.5]Nonane-7-Carboxylate (145 mg, 0.25 mmol) was dissolved in DCM (6 mL), TFA (3 mL) was added under an ice bath, and the reaction was carried out at room temperature for 1 h. The reaction was monitored by TLC until the raw material was completely reacted, adjusted to neutral with saturated NaHCO3 under an ice bath, extracted with DCM, washed with saturated sodium chloride, dried and concentrated, and then subjected to column chromatography to obtain 97 mg. Yield: 92%. It was used directly in the next step. LC / MS (ESI+) calcd for C 29 H32 N2O([M+H] + ) m / z 425.3; found 425.3。

[0077] Step 4: Synthesis of 2-(2,6-dioxopiperidin-3-yl)-5-(4-(2-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)-2,7-diazaspiro[3.5]non-7-yl)methyl)piperidin-1-yl)isoindoline-1,3-dione (5R,6S)-5-(4-(2,7-diazaspiro[3.5]non-2-yl)phenyl)-6-phenyl-5,6,7,8-tetrahydronaphthalen-2-ol (47 mg, 0.11 mmol) was dissolved in dichloromethane / methanol (2 mL, 10:1), 1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidine-4-carboxaldehyde (37 mg, 0.1 mmol) was added, glacial acetic acid (18 mg, 0.3 mmol) was added, and the mixture was stirred at 35 °C for 0.5 h, cooled to room temperature, sodium triacetoxyborohydride (42 mg, 0.2 mmol) was added, and the reaction was carried out overnight. The reaction was monitored by TLC until the raw materials were completely reacted, and saturated sodium bicarbonate solution was added to quench the reaction. The mixture was extracted with dichloromethane, dried and concentrated, and separated and purified by prep-TLC to obtain 39 mg of the product. Yield: 50%. 11H NMR (400 MHz, DMSO-d6) δ 11.08 (s, 1H), 9.11 (s, 1H), 7.64 (d, J = 8.5 Hz, 1H), 7.29 (d, J = 2.3 Hz, 1H), 7.21 (dd, J = 8.8, 2.3 Hz, 1H), 7.12 (dd, J = 10.0, 6.9 Hz, 3H), 6.82 (d, J = 7.1 Hz, 2H), 6.67 - 6.54 (m, 2H), 6.47 (dd, J = 8.3, 2.6 Hz, 1H), 6.15 (d, J = 8.0 Hz, 2H), 6.02 (d, J = 8.2 Hz, 2H), 5.06 (dd, J = 12.9, 5.4 Hz, 1H), 4.10 (d, J = 4.9 Hz, 1H), 4.03 (d, J = 12.9 Hz, 2H), 3.37 (s, 4H), 3.30 - 3.19 (m, 2H), 3.06 - 2.79 (m, 5H), 2.66 - 2.51 (m, 2H), 2.26 (s, 3H), 2.08 (d, J = 6.9 Hz, 3H), 2.04 - 1.92 (m, 2H), 1.76 (d, J = 12.5 Hz, 2H), 1.68 (q, J = 6.9, 5.5 Hz, 4H), 1.17 - 1.05 (m, 2H). LC / MS (ESI+) calcd for C 48 H 51 N5O5([M+H] + ) m / z 778.4; found 778.4。

[0078] Example 2. 3-(5-(7-((1-(4-((1R,2S)-6-Hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperidin-4-yl)methyl)-2,7-diazaspiro[4.4]non-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione TIFF2025523440000082.tif70170

[0079] Step 1: Synthesis of 1-(4-((1R,2S)-6-(tert-butoxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)-4-(dimethoxymethyl)piperidine 4-((1R,2S)-6-(tert-butoxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl 1,1,2,2,3,4,4-monofluorobutane-1-sulfonate (1.2 g, 1.83 mmol), 4-(dimethoxymethyl)piperidine (407 mg, 2.75 mmol) were dissolved in toluene (30 mL), Pd(OAc)2 (62 mg, 0.28 mmol), X-Phos (175 mg, 0.37 mmol) and sodium tert-butoxide (529 mg, 5.50 mmol) were added, the reaction mixture was purged with Ar gas three times, and the reaction was carried out at 90 °C overnight. After complete reaction, it was cooled to room temperature, filtered through celite, water was added, extracted with ethyl acetate, washed with saturated sodium chloride, dried and concentrated, and then subjected to column chromatography to obtain 798 mg of the product. Yield: 85%. It was identified as the target compound by LC-MS.

[0080] Step 2: Synthesis of 1-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperidine-4-carboxaldehyde 1-(4-((1R,2S)-6-(tert-butoxy)-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)-4-(dimethoxymethyl)piperidine (760 mg, 1.48 mmol) was dissolved in THF (40 mL), sulfuric acid (30 mL, 2 M) was added, and the reaction was carried out at 70 °C for half an hour. The reaction was monitored by TLC until the raw material was completely reacted. After cooling to room temperature, the pH was adjusted to about 8 with saturated sodium bicarbonate, extracted with ethyl acetate, washed with saturated sodium chloride, dried and concentrated, and then subjected to column chromatography to obtain 547 mg of the crude product, which was used directly in the next step.

[0081] Step 3: Synthesis of 3-(5-(7-((1-(4-((1R,2S)-6-Hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperidin-4-yl)methyl)-2,7-diazaspiro[4.4]nona-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione 3-(1-Oxo-5-(2,7-diazaspiro[4.4]nona-2-yl)isoindol-2-yl)piperidine-2,6-dione hydrochloride (20 mg, 0.05 mmol) was dissolved in dichloromethane / methanol (3 mL, 10:1), DIPEA (20 mg, 0.15 mmol) was added, and the mixture was stirred at room temperature for 5 min. 1-(4-((1R,2S)-6-Hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperidine-4-carboxaldehyde (20 mg, 0.05 mmol) was added, glacial acetic acid (19 mg, 0.14 mmol) was added, and the mixture was stirred at 35 °C for 0.5 h, cooled to room temperature, sodium triacetoxyborohydride (30 mg, 0.14 mmol) was added, and the reaction was carried out overnight. The reaction was monitored by TLC until the raw materials were completely reacted, and saturated sodium bicarbonate solution was added to quench the reaction. The mixture was extracted with dichloromethane, dried and concentrated, and subjected to column chromatography to obtain 20 mg of the product. Yield: 51%. 11H NMR (400 MHz, DMSO-d6) δ 10.94 (s, 1H), 9.12 (s, 1H), 7.47 (d, J = 8.4 Hz, 1H), 7.19 - 7.04 (m, 3H), 6.85 - 6.78 (m, 2H), 6.65 - 6.56 (m, 4H), 6.54 - 6.43 (m, 3H), 6.18 (d, J = 8.5 Hz, 2H), 5.03 (dd, J = 13.3, 5.1 Hz, 1H), 4.28 (d, J = 16.7 Hz, 1H), 4.16 (dd, J = 16.8, 2.4 Hz, 1H), 4.11 (d, J = 4.9 Hz, 1H), 3.60 - 3.45 (m, 3H), 3.32 - 3.12 (m, 6H), 2.93 (dd, J = 16.1, 9.7 Hz, 3H), 2.69 - 2.51 (m, 3H), 2.45 - 2.38 (m, 2H), 2.33 (s, 1H), 2.26 (d, J = 7.1 Hz, 2H), 2.10 (dt, J = 12.4, 6.1 Hz, 1H), 1.95 (dt, J = 13.9, 6.2 Hz, 3H), 1.75 (q, J = 10.5, 8.8 Hz, 5H), 1.49 (td, J = 7.5, 3.5 Hz, 1H), 1.13 (tt, J = 12.1, 6.8 Hz, 2H). LC / MS (ESI+) calcd for C 48 H 53 N5O4([M+H] + ) m / z: 764.4; found 764.5。

[0082] Example 3. 2-(2,6-Dioxopiperidin-3-yl)-5-(6-((1-(4-((1R,2S)-6-Hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperidin-4-yl)methyl)-2,6-diazaspiro[3.3]heptan-2-yl)isoindoline-1,3-dione TIFF2025523440000083.tif29170

[0083] The target compound was prepared in a method similar to Example 2. 1 H NMR (400 MHz, DMSO-d6) δ 11.08 (s, 1H), 9.12 (s, 1H), 7.64 (d, J = 8.3 Hz, 1H), 7.13 (q, J = 7.9, 7.1 Hz, 3H), 6.85 - 6.73 (m, 3H), 6.67 - 6.58 (m, 3H), 6.55 - 6.43 (m, 3H), 6.19 (d, J = 8.3 Hz, 2H), 5.05 (dd, J = 12.9, 5.4 Hz, 1H), 4.09 (s, 4H), 3.47 (d, J = 10.7 Hz, 2H), 3.29 (s, 4H), 3.01 - 2.79 (m, 4H), 2.63 - 2.54 (m, 1H), 2.49 - 2.37 (m, 3H), 2.28 (s, 2H), 2.10 (dd, J = 11.6, 5.5 Hz, 1H), 2.05 - 1.93 (m, 2H), 1.67 (d, J = 12.3 Hz, 3H), 1.14 (tt, J = 12.7, 6.6 Hz, 3H). LC / MS (ESI+) calcd for C 46 H 47 N5O5( [M+H] + ) m / z: 750.4; found 750.4。

[0084] Example 4. 3-(5-(4-(2-(4-((1R,2S)-6-Hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)-2,7-diazaspiro[3.5]non-7-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione TIFF2025523440000084.tif32170

[0085] The target compound was prepared in a method similar to Example 1. 11H NMR (400 MHz, DMSO-d6) δ 10.96 (s, 1H), 9.12 (d, J = 30.4 Hz, 1H), 7.53 - 7.34 (m, 2H), 7.15 - 7.10 (m, 2H), 7.02 (d, J = 8.3 Hz, 2H), 6.82 (d, J = 7.2 Hz, 2H), 6.67 - 6.57 (m, 2H), 6.52 - 6.42 (m, 1H), 6.15 (d, J = 8.2 Hz, 2H), 6.02 (d, J = 8.1 Hz, 2H), 5.03 (dd, J = 13.3, 5.1 Hz, 1H), 4.30 (d, J = 16.7 Hz, 1H), 4.18 (d, J = 16.9 Hz, 1H), 4.10 (d, J = 4.9 Hz, 1H), 3.85 (d, J = 12.3 Hz, 2H), 3.37 (s, 7H), 2.89 (ddd, J = 18.2, 11.2, 5.4 Hz, 3H), 2.79 (t, J = 12.2 Hz, 2H), 2.60 - 2.54 (m, 1H), 2.31 (dtd, J = 31.3, 18.9, 16.1, 9.1 Hz, 4H), 2.09 (dd, J = 16.7, 6.5 Hz, 3H), 1.95 (dd, J = 12.0, 6.1 Hz, 1H), 1.75 (d, J = 11.2 Hz, 3H), 1.71 - 1.65 (m, 4H), 1.19 - 1.12 (m, 2H). LC / MS (ESI+) calcd for C 48 H 53 N5O4([M+H] + ) m / z: 764.4; found 764.4。

[0086] Example 5. 3-(5-(7-((1-(4-(cis-3-(2-Fluorophenyl)-7-hydroxypyran-4-yl)phenyl)azetidin-3-yl)methyl)-2,7-diazaspiro[3.5]non-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione TIFF2025523440000085.tif113170

[0087] Step 1: Synthesis of (1-(4-bromophenyl)azetidin-3-yl)methanol Azetidin-3-ylmethanol hydrochloride (3.00 g, 24.3 mmol), p-bromoiodobenzene (5.72 g, 20.0 mmol), cuprous iodide (571 mg, 3.0 mmol), L-proline (392 mg, 3.0 mmol), K3PO4 (8.49 g, 40 mmol) were added to DMSO (80 mL), the system was purged with nitrogen gas, and reacted at 90 °C overnight. Cooled to room temperature, filtered through celite, water was added, extracted with ethyl acetate, washed with saturated sodium chloride, dried and concentrated, and subjected to column chromatography to obtain 1.93 g of the product. Yield: 40%. LC / MS (ESI+) calcd for C 10 H 12 BrNO ([M+H] + ) m / z: 242.0; found 242.1。

[0088] Step 2: Synthesis of 1-(4-bromophenyl)azetidine-3-carboxaldehyde Under the protection of Ar, oxalyl chloride (388 mg, 3.05 mmol) and dry DCM (5 mL) were added to a dry three-necked flask, and a solution of DMSO (477 mg, 6.11 mmol) in DCM (2 mL) was added to the system at -78 °C. After reacting at low temperature for 30 mins, a solution of (1-(4-bromophenyl)azetidin-3-yl)methanol (320 mg, 1.33 mmol) in DCM (3 mL) was added dropwise at -78 °C. After keeping warm and reacting for 30 mins, triethylamine (698 mg, 6.92 mmol) was continuously added dropwise. After the dropping was completed, the temperature was slowly raised to room temperature and the reaction was continued for 2 h. The reaction was monitored by TLC until the raw materials were completely reacted, quenched by adding water, extracted with DCM, concentrated, and subjected to column chromatography to obtain 300 mg of the product. Yield 94%. LC / MS (ESI+) calcd for C 10 H 10 BrNO ([M+19] + ) m / z: 257.9; found 257.9。

[0089] Step 3: Synthesis of 1-(4-bromophenyl)-3-(dimethoxymethyl)azetidine 1-(4-Bromophenyl)azetidine-3-carboxaldehyde (300 mg, 1.25 mmol) was dissolved in MeOH (10 mL), trimethyl orthoformate (399 mg, 3.76 mmol) and p-toluenesulfonic acid (22 mg, 0.12 mmol) were added, and the reaction was carried out overnight at room temperature. The reaction was monitored by TLC until the raw materials were completely reacted, quenched by adding water, extracted with ethyl acetate, washed with saturated sodium chloride, dried and concentrated, and then subjected to column chromatography to obtain 193 mg of the product. Yield: 64%. LC / MS (ESI+) calcd for C 12 H 16 BrNO2([M+H] + ) m / z: 286.0; found 285.9。

[0090] Step 4: Synthesis of 7-(benzyloxy)-4-(4-(3-(dimethoxymethyl)azetidin-1-yl)phenyl)pyran-4-ol Under a nitrogen gas atmosphere, 1-(4-bromophenyl)-3-(dimethoxymethyl)azetidine (1.25 g, 4.38 mmol) was dissolved in dry THF (15 mL), the temperature was lowered to -70 °C or below, and n-butyllithium (2.6 mL, 2.5 M, 6.57 mmol) was slowly added while maintaining the temperature of the reaction system at -70 °C or below throughout the dropping process. After the addition was complete, the reaction was carried out for 1 hour while maintaining the temperature, and 7-(benzyloxy)pyran-4-one (1.01 g, 3.98 mmol) dissolved in dry THF (10 mL) was slowly added dropwise to the system while maintaining the temperature of the reaction system at -70 °C or below throughout the dropping process. The reaction was carried out for 1 hour while maintaining the temperature, the reaction system was gradually warmed up to about -40 °C, and TLC was used to monitor until the raw material 7-(benzyloxy)pyran-4-one completely reacted. Saturated ammonium chloride was added to quench the reaction, extracted with ethyl acetate, washed with saturated sodium chloride, dried and concentrated, and then subjected to column chromatography to obtain 1.4 g of the product. Yield: 69%. LC / MS (ESI+) calcd for C 28 H 31 NO5( [M+H] + ) m / z: 462.2; found 462.1。

[0091] Step 5: Synthesis of 1-(4-(7-(benzyloxy)-2H-chromen-4-yl)phenyl)-3-(dimethoxymethyl)azetidine 7-(Benzyloxy)-4-(4-(3-(dimethoxymethyl)azetidin-1-yl)phenyl)pyran-4-ol (1.4 g, 3.04 mmol) was dissolved in dichloromethane (15 mL), triethylamine (921 mg, 9.12 mmol) was added, methanesulfonyl chloride (692 mg, 6.07 mmol) was added under an ice bath, and after the addition, the temperature was raised to room temperature and the reaction was carried out for 2 hours. TLC was used to monitor until the raw material completely reacted, water was added to quench the reaction, extracted with dichloromethane, dried and concentrated, and then subjected to column chromatography to obtain 875 mg of the product. Yield: 65%. LC / MS (ESI+) calcd for C 28 H 29 NO4( [M+H]+ ) m / z: 444.2; found 444.1。

[0092] Step 6: Synthesis of 1-(4-(7-(Benzyloxy)-3-bromo-2H-chromen-4-yl)phenyl)-3-(dimethoxymethyl)azetidine 1-(4-(7-(Benzyloxy)-2H-chromen-4-yl)phenyl)-3-(dimethoxymethyl)azetidine (760 mg, 1.72 mmol) was dissolved in DMF (10 mL), DIPEA (666 mg, 5.16 mmol) was added, and pyridinium tribromide (604 mg, 1.89 mmol) was added portionwise under an ice bath. After addition, the temperature was raised to room temperature and stirred overnight. The reaction was monitored by TLC until the raw material was completely reacted. Water was added to quench the reaction, and the mixture was extracted with ethyl acetate, dried and concentrated, and separated by column chromatography to obtain 800 mg of the product. Yield: 90%. LC / MS (ESI+) calcd for C 28 H 28 BrNO4( [M+H] + ) m / z: 522.1; found 522.1。

[0093] Step 7: Synthesis of 1-(4-(7-(Benzyloxy)-3-(2-fluorophenyl)-2H-chromen-4-yl)phenyl)-3-(dimethoxymethyl)azetidine To the reaction flask were added 1-(4-(7-(Benzyloxy)-3-bromo-2H-chromen-4-yl)phenyl)-3-(dimethoxymethyl)azetidine (300 mg, 0.57 mmol), 2-fluorophenylboronic acid (89 mg, 0.63 mmol), Pd(dppf)Cl2 (42 mg, 0.06 mmol), potassium carbonate (157 mg, 1.14 mmol), and dioxane / H2O (12 mL / 3 mL). The system was purged with nitrogen gas and reacted at 90 °C overnight. The reaction was monitored by TLC until the raw material was completely reacted. After cooling to room temperature, it was filtered through celite, concentrated, and subjected to column chromatography to obtain 290 mg of the product. Yield: 95%. LC / MS (ESI+) calcd for C 34 H 32FNO4([M+H] + ) m / z: 538.2; found 538.2。

[0094] Step 8: Synthesis of cis-4-(4-(3-(dimethoxymethyl)azetidin-1-yl)phenyl)-3-(2-fluorophenyl)pyran-7-ol 1-(4-(7-(Benzyloxy)-3-(2-fluorophenyl)-2H-chromen-4-yl)phenyl)-3-(dimethoxymethyl)azetidine (290 mg, 0.54 mmol) was dissolved in THF (10 mL), methanol (20 mL) was added, 10% palladium on carbon (30 mg, 10%) was added, the system was purged with hydrogen gas atmosphere, reacted overnight at room temperature, and monitored by TLC until the raw material was completely reacted. It was filtered through celite to remove palladium on carbon, concentrated and subjected to column chromatography to obtain 200 mg of the product. Yield: 83%. LC / MS (ESI+) calcd for C 27 H 28 FNO4([M+H] + ) m / z: 450.2; found 450.1。

[0095] Step 9: Synthesis of 1-(4-(cis-3-(2-fluorophenyl)-7-hydroxychroman-4-yl)phenyl)azetidine-3-carboxaldehyde cis-4-(4-(3-(dimethoxymethyl)azetidin-1-yl)phenyl)-3-(2-fluorophenyl)pyran-7-ol (165 mg, 0.37 mmol) was dissolved in THF (10 mL), sulfuric acid (3 mL, 2 M) was added, reacted at 70 °C for half an hour, monitored by TLC until the raw material was completely reacted, cooled to room temperature, adjusted the pH to about 8 with saturated sodium bicarbonate, extracted with ethyl acetate, washed with saturated sodium chloride, dried and concentrated, and subjected to column chromatography to obtain 150 mg of the crude product, which was used directly in the next step. LC / MS (ESI+) calcd for C 25 H 22 FNO3([M+H] + ) m / z: 404.2; found 404.1。

[0096] Step 10: Synthesis of 3-(5-(7-((1-(4-(cis-3-(2-fluorophenyl)-7-hydroxypyran-4-yl)phenyl)azetidin-3-yl)methyl)-2,7-diazaspiro[3.5]nona-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione 2-(2,6-dioxopiperidin-3-yl)-5-(2,7-diazaspiro[3.5]nona-2-yl)isoindoline-1,3-dione trifluoroacetate (47 mg, 0.13 mmol) was dissolved in dichloromethane / methanol (5 mL, 10:1), DIPEA (40 mg, 0.3 mmol) was added, and the mixture was stirred at room temperature for 5 min. 1-(4-(cis-3-(2-fluorophenyl)-7-hydroxycoumaran-4-yl)phenyl)azetidine-3-carboxaldehyde (52 mg, 0.13 mmol) was added, glacial acetic acid (23 mg, 0.39 mmol) was added, and the mixture was stirred at 35 °C for 0.5 h, cooled to room temperature, sodium triacetoxyborohydride (82 mg, 0.39 mmol) was added, and the reaction was carried out overnight. The reaction was monitored by TLC until the raw materials were completely reacted, and saturated sodium bicarbonate solution was added to quench the reaction. The mixture was extracted with dichloromethane, dried and concentrated, and subjected to column chromatography to obtain 30 mg of the product. Yield: 31%. 11H NMR (400 MHz, DMSO-d6) δ 10.94 (s, 1H), 9.32 (s, 1H), 7.47 (d, J = 8.3 Hz, 1H), 7.26 - 7.19 (m, 1H), 7.16 - 7.10 (m, 1H), 6.92 - 6.86 (m, 1H), 6.65 (d, J = 8.2 Hz, 1H), 6.51 - 6.39 (m, 3H), 6.36 (d, J = 8.1 Hz, 2H), 6.32 - 6.26 (m, 2H), 6.09 (d, J = 8.1 Hz, 2H), 5.03 (dd, J = 13.3, 5.1 Hz, 1H), 4.39 - 4.26 (m, 2H), 4.23 - 4.11 (m, 3H), 3.78 (td, J = 7.4, 4.8 Hz, 2H), 3.70 (dd, J = 10.9, 4.5 Hz, 1H), 3.61 (s, 4H), 3.30 (s, 2H), 2.88 (ddt, J = 20.6, 14.8, 6.2 Hz, 2H), 2.62 - 2.54 (m, 1H), 2.40 - 2.18 (m, 5H), 1.96 (dd, J = 12.9, 7.1 Hz, 1H), 1.72 (t, J = 5.4 Hz, 4H), 1.23 (d, J = 3.7 Hz, 2H). LC / MS (ESI+) calcd for C 45 H 46 FN5O5([M+H] + ) m / z: 756.3; found 756.2。

[0097] Example 6. 3-(5-(2-((1-(4-((3R,4S)-7-Hydroxy-3-phenyltryptophan-4-yl)phenyl)piperidin-4-yl)methyl)-2,7-diazaspiro[3.5]non-7-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione TIFF2025523440000086.tif29170

[0098] The target compound was prepared in a manner similar to Example 5. 11H NMR (400 MHz, DMSO-d6) δ 10.96 (s, 1H), 9.34 (s, 1H), 7.50 (d, J = 8.4 Hz, 1H), 7.14 (p, J = 3.7 Hz, 3H), 7.11 - 7.01 (m, 2H), 6.76 (dd, J = 6.6, 3.0 Hz, 2H), 6.63 (dd, J = 14.0, 8.4 Hz, 3H), 6.38 (d, J = 8.4 Hz, 2H), 6.34 - 6.22 (m, 2H), 5.04 (dd, J = 13.3, 5.1 Hz, 1H), 4.38 - 4.31 (m, 1H), 4.29 (s, 1H), 4.20 (s, 1H), 4.17 (d, J = 4.7 Hz, 2H), 3.56 (t, J = 10.8 Hz, 6H), 3.29 (s, 4H), 3.16 - 3.01 (m, 3H), 2.63 - 2.55 (m, 1H), 2.52 (s, 2H), 2.47 (s, 1H), 2.42 - 2.31 (m, 1H), 2.01 (d, J = 7.4 Hz, 1H), 1.97 - 1.90 (m, 2H), 1.85 (s, 2H), 1.76 (d, J = 12.3 Hz, 3H), 1.23 (s, 2H). LC / MS (ESI+) calcd for C 47 H 51 N5O5([M+H] + ) m / z: 766.4; found 766.4。

[0099] Example 7. 3-(5-(7-((1-(4-((3R,4S)-7-Hydroxy-3-phenyltryptophan-4-yl)phenyl)piperidin-4-yl)methyl)-2,7-diazaspiro[4.4]non-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione TIFF2025523440000087.tif32170

[0100] Starting material 7-1 was prepared according to the method in the literature (US10800770). The target compound was prepared by a method similar to that of Example 5. 11H NMR (400 MHz, DMSO-d6) δ 10.94 (s, 1H), 9.30 (s, 1H), 7.50 - 7.43 (m, 1H), 7.15 - 7.11 (m, 3H), 6.78 - 6.73 (m, 2H), 6.65 (d, J = 8.3 Hz, 1H), 6.59 (d, J = 9.2 Hz, 4H), 6.36 (d, J = 8.2 Hz, 2H), 6.31 - 6.23 (m, 2H), 5.03 (dd, J = 13.3, 5.1 Hz, 1H), 4.34 - 4.25 (m, 2H), 4.22 - 4.13 (m, 3H), 3.51 (dt, J = 11.5, 6.5 Hz, 5H), 3.22 (d, J = 9.4 Hz, 3H), 2.89 (td, J = 13.1, 12.0, 6.2 Hz, 2H), 2.71 - 2.58 (m, 2H), 2.54 (d, J = 7.9 Hz, 2H), 2.48 - 2.40 (m, 2H), 2.31 (dd, J = 17.9, 5.6 Hz, 3H), 1.96 (dq, J = 9.8, 5.5 Hz, 3H), 1.76 (q, J = 8.0, 7.5 Hz, 4H), 1.23 (d, J = 3.6 Hz, 2H). LC / MS (ESI+) calcd for C 47 H 51 N5O5([M+H] + ) m / z: 766.4; found 766.4。

[0101] Example 8. 3-(5-(7-((1-(4-((3S,4R)-7-Hydroxy-3-phenyltryptophan-4-yl)phenyl)piperidin-4-yl)methyl)-2,7-diazaspiro[4.4]non-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione TIFF2025523440000088.tif36170

[0102] Starting material 8-1 was prepared using the method in the literature. The target compound was prepared by a method similar to that of Example 5. 11H NMR (400 MHz, DMSO-d6) δ 11.13 - 10.66 (m, 1H), 9.31 (s, 1H), 7.48 (t, J = 8.4 Hz, 1H), 7.17 - 7.11 (m, 3H), 6.77 - 6.72 (m, 2H), 6.65 (d, J = 8.3 Hz, 1H), 6.59 (d, J = 9.3 Hz, 4H), 6.36 (d, J = 8.2 Hz, 2H), 6.31 - 6.24 (m, 2H), 5.03 (dd, J = 13.3, 5.1 Hz, 1H), 4.36 - 4.25 (m, 2H), 4.21 - 4.11 (m, 3H), 3.51 (dt, J = 11.8, 6.6 Hz, 5H), 3.22 (d, J = 9.5 Hz, 3H), 2.98 - 2.78 (m, 2H), 2.59 (td, J = 16.3, 6.0 Hz, 4H), 2.47 - 2.38 (m, 2H), 2.34 (dd, J = 13.2, 4.4 Hz, 1H), 2.26 (d, J = 7.2 Hz, 2H), 2.00 - 1.92 (m, 3H), 1.75 (q, J = 6.6 Hz, 4H), 1.23 (d, J = 3.6 Hz, 2H). LC / MS (ESI+) calcd for C 47 H 51 N5O5([M+H] + ) m / z: 766.4; found 766.4。

[0103] Example 9. 3-(5-(7-((1-(4-(cis-3-(4-Fluorophenyl)-7-hydroxytryptophan-4-yl)phenyl)piperidin-4-yl)methyl)-2,7-diazaspiro[3.5]non-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione TIFF2025523440000089.tif62170

[0104] The target compound was prepared in a similar manner to Example 5. 11H NMR (400 MHz, DMSO-d6) δ 10.95 (s, 1H), 9.32 (s, 1H), 7.50 (d, J = 8.3 Hz, 1H), 6.98 (t, J = 8.8 Hz, 2H), 6.79 (dd, J = 8.5, 5.6 Hz, 2H), 6.65 (d, J = 8.3 Hz, 3H), 6.53 - 6.45 (m, 2H), 6.39 (d, J = 8.2 Hz, 2H), 6.34 - 6.21 (m, 2H), 5.03 (dd, J = 13.3, 5.1 Hz, 1H), 4.35 - 4.25 (m, 2H), 4.22 - 4.12 (m, 3H), 3.70 (d, J = 13.5 Hz, 4H), 3.64 - 3.52 (m, 4H), 3.17 - 3.10 (m, 1H), 3.05 - 2.84 (m, 4H), 2.58 (d, J = 16.0 Hz, 3H), 2.41 - 2.27 (m, 2H), 1.98 (td, J = 15.0, 6.7 Hz, 5H), 1.78 (s, 3H), 1.25 - 1.24 (m, 2H). LC / MS (ESI+) calcd for C 47 H 50 FN5O5([M+H] + ) m / z: 784.4; found 784.4。

[0105] Example 10. 3-(5-(7-((1-(4-(cis-7-Hydroxy-3-(pyrazin-2-yl)pyran-4-yl)phenyl)piperidin-4-yl)methyl)-2,7-diazaspiro[3.5]non-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione TIFF2025523440000090.tif57170

[0106] Step 1: Synthesis of 4-(dimethoxymethyl)-1-(4-(7-((tetrahydro-2H-pyran-2-yl)oxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-toluene-4-yl)phenyl)piperidine 1-(4-(3-bromo-7-((tetrahydro-2H-pyran-2-yl)oxy)-2H-methylene-4-yl)phenyl)-4-(dimethoxymethyl)piperidine (543 mg, 1.00 mmol), bis(pinacolato)diboron (381 mg, 1.50 mmol), PdCl2(dppf) (73 mg, 0.1 mmol), potassium acetate (294 mg, 3.00 mmol) were added to 1,4-dioxane (15 mL), the system was purged with nitrogen gas, and reacted at 90 °C for 3 h. After cooling to room temperature, water was added to quench the reaction, and the mixture was extracted with ethyl acetate, washed with saturated sodium chloride, dried and concentrated, and then subjected to column chromatography to obtain 508 mg of the product. Yield: 86%. LC / MS (ESI+) calcd for C 34 H 46 BNO7( [M+H] + ) m / z: 592.3; found 592.4。

[0107] Step 2: Synthesis of 2-(4-(4-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)-7-((tetrahydro-2H-pyran-2-yl)oxy)-2H-amino-3-yl)pyrazine 4-(dimethoxymethyl)-1-(4-(7-((tetrahydro-2H-pyran-2-yl)oxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-toluen-4-yl)phenyl)piperidine (300 mg, 0.51 mmol), 2-bromopyrazine (105 mg, 0.66 mmol), PdCl2(dppf) (37 mg, 0.05 mmol), K2CO3 (211 mg, 1.53 mmol) were added to a mixed solvent of 1,4-dioxane / H2O (15 mL / 4 mL), the system was purged with nitrogen gas, and reacted at 90 °C overnight. After cooling to room temperature, water was added to quench the reaction, and the mixture was extracted with ethyl acetate, washed with saturated sodium chloride, dried and concentrated, and then subjected to column chromatography to obtain 147 mg of the product. Yield: 53%. LC / MS (ESI+) calcd for C 32 H 37 N3O5( [M+H] + ) m / z: 544.3; found 544.2。

[0108] Step 3: Synthesis of 2-(cis-4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)-7-((tetrahydro-2H-pyran-2-yl)oxy)pyran-3-yl)pyrazine 2-(4-(4-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)-7-((tetrahydro-2H-pyran-2-yl)oxy)-2H-amino-3-yl)pyrazine (147 g, 0.27 mmol) was dissolved in a mixed solvent of THF (10 mL) and MeOH (10 mL), Pd / C (20 mg) was added, replaced three times under H2 atmosphere, stirred overnight at room temperature, monitored by LCMS until the raw material completely reacted, filtered through celite to remove palladium carbon, concentrated, and then separated by column chromatography to obtain 125 mg of the product. Yield: 85%.

[0109] Step 4: Synthesis of 1-(4-(cis-7-hydroxy-3-(pyrazin-2-yl)pyran-4-yl)phenyl)piperidine-4-carboxaldehyde 2-(cis-4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)-7-((tetrahydro-2H-pyran-2-yl)oxy)pyran-3-yl)pyrazine (125 mg, 0.23 mmol) was dissolved in THF (15 mL), 2M H2SO4 (5 mL) was added, the temperature was raised to 50 °C and reacted for 20 mins, monitored by TLC until the raw material completely reacted, adjusted to alkaline with saturated sodium bicarbonate under ice bath, extracted with ethyl acetate, dried and concentrated to obtain 88 mg of the product. Yield: 93%.

[0110] Step 5: Synthesis of 3-(5-(7-((1-(4-(cis-7-hydroxy-3-(pyrazin-2-yl)pyran-4-yl)phenyl)piperidin-4-yl)methyl)-2,7-diazaspiro[3.5]non-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione 3-(1-Oxo-5-(2,7-diazaspiro[3.5]non-2-yl)isoindolin-2-yl)piperidine-2,6-dione trifluoroacetate (38 mg, 0.08 mmol) was dissolved in dichloromethane / methanol (5 mL, 10:1), DIPEA (37 mg, 0.29 mmol) was added, and after stirring for 10 mins, 1-(4-(cis-7-hydroxy-3-(pyrazin-2-yl)pyran-4-yl)phenyl)piperidine-4-carboxaldehyde (30 mg, 0.07 mmol) and glacial acetic acid (18 mg, 0.3 mmol) were added. The mixture was stirred at 35 °C for 0.5 h, cooled to room temperature, sodium triacetoxyborohydride (46 mg, 0.2 mmol) was added, and the reaction was allowed to proceed overnight. The reaction was monitored by TLC until the raw materials were completely reacted, and saturated sodium bicarbonate solution was added to quench the reaction. The mixture was extracted with dichloromethane, dried and concentrated, and then subjected to column chromatography to obtain 28 mg of the product, which was identified as the target compound by LC-MS. Yield: 51%. 11H NMR (400 MHz, DMSO-d6) δ 10.94 (s, 1H), 9.33 (s, 1H), 8.47 (d, J = 1.5 Hz, 1H), 8.40 (d, J = 2.5 Hz, 1H), 8.36 (t, J = 2.1 Hz, 1H), 7.47 (d, J = 8.3 Hz, 1H), 6.69 (d, J = 8.3 Hz, 1H), 6.57 (d, J = 8.5 Hz, 2H), 6.53 - 6.43 (m, 2H), 6.39 - 6.26 (m, 4H), 5.03 (dd, J = 13.3, 5.1 Hz, 1H), 4.47 - 4.34 (m, 3H), 4.33 - 4.14 (m, 2H), 3.80 (dt, J = 10.4, 4.7 Hz, 1H), 3.62 (s, 4H), 3.55 - 3.47 (m, 2H), 2.94 - 2.83 (m, 1H), 2.57 (dd, J = 17.5, 4.3 Hz, 1H), 2.48 - 2.43 (m, 1H), 2.41 - 2.22 (m, 4H), 2.15 (d, J = 24.0 Hz, 2H), 2.03 - 1.90 (m, 2H), 1.83 - 1.65 (m, 6H), 1.59 (s, 1H), 1.22 (s, 1H), 1.15 - 1.05 (m, 2H). LC / MS (ESI+) calcd for C 45 H 49 N7O5([M+H] + ) m / z: 768.4; found 768.3。

[0111] Example 11. 3-(5-(4-(7-(4-(cis-6-Hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)-2,7-diazaspiro[3.5]non-2-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione TIFF2025523440000091.tif28170

[0112] Step 1: Synthesis of 1-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperidine-4-carboxaldehyde 3-(5-(4-(Hydroxymethyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (150 mg, 0.42 mmol) was dissolved in DCM (40 mL), Dess-Martin (356 mg, 0.84 mmol) was added at 0 °C, and the reaction was carried out at room temperature for 2 h. The reaction was monitored by TLC until the raw materials were completely reacted. The reaction system was cooled to room temperature, quenched by adding water, extracted with ethyl acetate, dried and concentrated, and purified by prep-TLC to obtain 60 mg of the product, which was identified as the target compound by LC-MS. The yield was 40%. LC / MS (ESI+) calcd for C 19 H 21 N3O4([M + H] + ) m / z: 356.2; found 356.1。

[0113] Step 2: Synthesis of 3-(5-(4-(7-(4-(cis-6-Hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)-2,7-diazaspiro[3.5]nonan-2-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione cis-5-(4-(2,7-Diazaspiro[3.5]non-7-yl)phenyl)-6-phenyl-5,6,7,8-tetrahydronaphthalen-2-ol trifluoroacetate (30 mg, 0.07 mmol) was dissolved in DCM / MeOH (5 mL / 1 mL), DIPEA (27 mg, 0.2 mmol) was added, and after stirring for 5 min, 1-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindol-5-yl)piperidine-4-carboxaldehyde (25 mg, 0.07 mmol) and AcOH (27 mg, 0.2 mmol) were added. After reacting at room temperature for 30 min, NaBH(OAc)3 (45 mg, 0.2 mmol) was added and reacted overnight. The reaction was monitored by TLC until the raw materials were completely reacted, extracted with dichloromethane, dried and concentrated, and then subjected to column chromatography to obtain 13 mg of the product, which was identified as the target compound by LC-MS. Yield: 25%. 11H NMR (400 MHz, DMSO-d6) δ 10.95 (s, 1H), 9.11 (s, 1H), 7.49 (d, J = 8.5 Hz, 1H), 7.18 - 7.07 (m, 3H), 7.02 (d, J = 8.6 Hz, 2H), 6.86 - 6.78 (m, 2H), 6.73 - 6.58 (m, 3H), 6.53 (d, J = 8.6 Hz, 2H), 6.47 (dd, J = 8.3, 2.6 Hz, 1H), 6.19 (d, J = 8.4 Hz, 1H), 5.04 (dd, J = 13.3, 5.1 Hz, 1H), 4.30 (d, J = 16.9 Hz, 1H), 4.18 (d, J = 16.8 Hz, 1H), 4.12 (d, J = 5.0 Hz, 1H), 3.84 (d, J = 12.7 Hz, 2H), 3.27 (s, 2H), 2.92 (s, 8H), 2.77 (t, J = 12.2 Hz, 2H), 2.60 (s, 2H), 2.33 (t, J = 1.9 Hz, 2H), 2.09 (dd, J = 12.2, 6.3 Hz, 1H), 1.97 (dd, J = 16.6, 9.9 Hz, 3H), 1.70 (s, 6H), 1.50 - 1.41 (m, 2H), 1.22 (s, 2H). LC / MS (ESI+) calcd for C 48 H 53 N5O4([M+H] + ) m / z: 764.4; found 764.3。

[0114] Example 12. 3-(5-(4-(4-(cis-6-Hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)-2,7-diazaspiro[3.5]non-2-yl)piperidin-1-yl)-1-oxoisoindolin-2-yl)pyridine-2,6-dione TIFF2025523440000092.tif55170

[0115] Step 1: Synthesis of Methyl 2-(1,3-dioxolan-2-yl)-4-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)benzoate To a reaction flask were added methyl 4-bromo-2-(1,3-dioxolan-2-yl)benzoate (1.0 g, 3.5 mmol), 1,4-dioxo-8-azaspiro[4.5]decane (553 mg, 3.86 mmol), Pd2(dba)3 (320 mg, 0.35 mmol), X-Phos (333 mg, 0.70 mmol), cesium carbonate (2.29 g, 7.02 mmol) and dioxane (30 mL). The system was purged with nitrogen gas and reacted at 100 °C overnight. The reaction was monitored by TLC until the raw materials were completely reacted. After cooling to room temperature, it was filtered through celite, and the filtrate was concentrated and subjected to column chromatography to obtain 1.04 g of the product. Yield: 85%. SC / MS (ESI+) calcd for C 18 H 23 NO6( [M+H] + ) m / z: 350.2; found 350.1。

[0116] Step 2: Synthesis of Methyl 2-formyl-4-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)benzoate Methyl 2-(1,3-dioxolan-2-yl)-4-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)benzoate (1 g, 2.87 mmol) was dissolved in acetone (15 mL), and p-toluenesulfonic acid monohydrate (654 mg, 3.44 mmol) was added under an ice bath. The reaction was carried out at room temperature for 1.5 h and monitored by TLC until the raw materials were completely reacted. Water was added to quench the reaction, and the mixture was extracted with ethyl acetate, concentrated and subjected to column chromatography to obtain 656 mg of the product. Yield 75%. LC / MS (ESI+) calcd for C 16 H 19 NO5( [M+H] + ) m / z: 306.1; found 306.0。

[0117] Step 3: Synthesis of 3-(1-oxo-5-(1,4-dioxo-8-azaspiro[4.5]decan-8-yl)isoindolin-2-yl)piperidine-2,6-dione 3-Aminopiperidine-2,6-dione (388 mg, 2.36 mmol) was added to a one-neck flask, DCM (20 mL) was added, DIPEA (507 mg, 3.92 mmol) was added dropwise, and after stirring for 10 minutes, methyl 2-formyl-4-(1,4-dioxo-8-azaspiro[4.5]decan-8-yl)benzoate (600 mg, 1.96 mmol) and AcOH (1.18 g, 19.6 mmol) were added, and the reaction was carried out at 35 °C for 6 h. After cooling to room temperature, NaBH(OAc)3 (2.49 g, 11.76 mmol) was added and the reaction was carried out overnight. After the reaction was complete, water was added to quench, extracted with DCM, washed with saturated sodium chloride, dried and concentrated, and then subjected to column chromatography to obtain 377 mg. Yield 50%. LC / MS (ESI+) calcd for C 20 H 23 N3O5([M+H] + ) m / z: 386.2; found 386.1。

[0118] Step 4: Synthesis of 3-(1-oxo-5-(4-oxopiperidin-1-yl)isoindolin-2-yl)piperidine-2,6-dione 3-(1-Oxo-5-(1,4-dioxo-8-azaspiro[4.5]decan-8-yl)isoindol-2-yl)piperidine-2,6-dione (150 mg, 0.39 mmol) was dissolved in THF (10 mL), 2M H2SO4 (3 mL) was added, the temperature was raised to 50 °C and the reaction was carried out for 20 mins, monitored by TLC until the raw materials were completely reacted, adjusted to alkaline with saturated sodium bicarbonate under an ice bath, extracted with ethyl acetate, dried and concentrated, and separated and purified by prep-TLC to obtain 73 mg of the product. Yield: 55%, Yield 55%. LC / MS (ESI+) calcd for C 18 H 19 N3O4([M+H] + ) m / z: 342.1; found 342.0。

[0119] Step 5: Synthesis of 3-(5-(4-(4-(cis-6-Hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)-2,7-diazaspiro[3.5]non-2-yl)piperidin-1-yl)-1-oxoisoindolin-2-yl)pyridine-2,6-dione Dissolve cis-5-(4-(2,7-diazaspiro[3.5]non-7-yl)phenyl)-6-phenyl-5,6,7,8-tetrahydronaphthalen-2-ol trifluoroacetate (30 mg, 0.07 mmol) in dichloromethane / methanol (2 mL, 10:1), add DIPEA (27 mg, 0.2 mmol), stir for 5 mins, then add 3-(1-oxo-5-(4-oxopiperidin-1-yl)isoindolin-2-yl)piperidine-2,6-dione (24 mg, 0.07 mmol) and AcOH (27 mg, 0.2 mmol), react at room temperature for 30 mins, then add NaBH(OAc)3 (45 mg, 0.2 mmol) and react overnight. Monitor by TLC until the raw materials are completely reacted, extract with dichloromethane, dry and concentrate, and subject to column chromatography to obtain 34 mg of the product, which was identified as the target compound by LC-MS. Yield: 65%. 11H NMR (400 MHz, DMSO-d6) δ 10.95 (s, 1H), 9.11 (s, 1H), 7.49 (d, J = 8.3 Hz, 1H), 7.18 - 7.07 (m, 3H), 7.03 (d, J = 9.6 Hz, 2H), 6.89 - 6.78 (m, 2H), 6.67 - 6.59 (m, 2H), 6.57 - 6.42 (m, 3H), 6.19 (d, J = 8.3 Hz, 2H), 5.04 (dd, J = 13.2, 5.1 Hz, 1H), 4.33 - 4.10 (m, 3H), 3.74 (s, 2H), 3.26 (s, 1H), 2.92 (s, 10H), 2.75 - 2.55 (m, 2H), 2.42 - 2.31 (m, 2H), 2.19 - 1.86 (m, 5H), 1.69 (s, 6H), 1.22 (s, 2H). LC / MS (ESI+) calcd for C 47 H 51 N5O4([M+H] + ) m / z: 750.4; found 750.3。

[0120] Example 13. 3-(5-(4-(7-(4-(cis-7-Hydroxy-3-phenyltryptophan-4-yl)phenyl)-2,7-diazaspiro[3.5]non-2-yl)piperidin-1-yl)-1-oxoisoindolin-2-yl)pyridine-2,6-dione TIFF2025523440000093.tif90170

[0121] The target compound was prepared in a similar manner to Example 5. 11H NMR (400 MHz, DMSO-d6) δ 10.95 (s, 1H), 9.31 (s, 1H), 7.49 (d, J = 8.4 Hz, 1H), 7.14 (p, J = 3.6 Hz, 3H), 7.03 (d, J = 8.4 Hz, 2H), 6.75 (dd, J = 6.6, 3.0 Hz, 2H), 6.65 (d, J = 8.3 Hz, 1H), 6.60 (d, J = 8.4 Hz, 2H), 6.37 (d, J = 8.4 Hz, 2H), 6.32 - 6.24 (m, 2H), 5.04 (dd, J = 13.3, 5.1 Hz, 1H), 4.38 - 4.26 (m, 2H), 4.23 - 4.12 (m, 3H), 3.76 - 3.69 (m, 2H), 3.53 - 3.48 (m, 2H), 2.98 - 2.85 (m, 10H), 2.58 (ddd, J = 17.1, 4.2, 2.3 Hz, 1H), 2.37 (dd, J = 13.2, 8.6 Hz, 1H), 2.24 (dd, J = 8.8, 4.5 Hz, 1H), 1.98 - 1.93 (m, 1H), 1.70 (q, J = 5.9, 5.1 Hz, 6H), 1.22 (s, 2H). LC / MS (ESI+) calcd for C 46 H 49 N5O5([M+H] + ) m / z: 752.4; found 752.3。

[0122] Example 14. 3-(5-(4-(7-(4-((3S,4R)-3-(2-Fluorophenyl)-7-hydroxycoumarin-4-yl)phenyl)-2,7-diazaspiro[3.5]non-2-yl)piperidin-1-yl)-1-oxoisoindolin-2-yl)pyridine-2,6-dione TIFF2025523440000094.tif47170

[0123] The target compound was prepared in a manner similar to Example 5. 11H NMR (400 MHz, DMSO-d6) δ 10.95 (s, 1H), 9.36 (s, 1H), 7.49 (d, J = 8.4 Hz, 1H), 7.22 (tdd, J = 7.4, 5.4, 1.7 Hz, 1H), 7.13 (ddd, J = 9.9, 8.1, 1.3 Hz, 1H), 7.03 (d, J = 8.3 Hz, 2H), 6.88 (td, J = 7.5, 1.3 Hz, 1H), 6.66 (d, J = 8.3 Hz, 1H), 6.60 (d, J = 8.5 Hz, 2H), 6.46 - 6.34 (m, 3H), 6.34 - 6.24 (m, 2H), 5.04 (dd, J = 13.3, 5.1 Hz, 1H), 4.40 - 4.27 (m, 2H), 4.24 - 4.13 (m, 3H), 3.71 (td, J = 8.7, 8.2, 5.0 Hz, 4H), 3.00 - 2.86 (m, 10H), 2.62 - 2.54 (m, 1H), 2.37 (td, J = 13.3, 4.6 Hz, 1H), 2.25 (d, J = 8.6 Hz, 1H), 2.01 - 1.93 (m, 1H), 1.69 (q, J = 7.3, 4.9 Hz, 6H), 1.21 (d, J = 8.1 Hz, 2H). LC / MS (ESI+) calcd for C 46 H 48 FN5O5([M+H] + ) m / z: 770.4; found 770.2。

[0124] Example 15. 3-(5-(4-(7-(4-((3R,4S)-3-(2-Fluorophenyl)-7-hydroxypyran-4-yl)phenyl)-2,7-diazaspiro[3.5]non-2-yl)piperidin-1-yl)-1-oxoisoindolin-2-yl)pyridine-2,6-dione TIFF2025523440000095.tif45170

[0125] The target compound was prepared in a similar manner to Example 5. 11H NMR (400 MHz, DMSO-d6) δ 10.95 (s, 1H), 9.33 (s, 1H), 7.49 (d, J = 8.4 Hz, 1H), 7.25 - 7.19 (m, 1H), 7.17 - 7.11 (m, 1H), 7.03 (d, J = 8.5 Hz, 2H), 6.90 - 6.86 (m, 1H), 6.66 (d, J = 8.3 Hz, 1H), 6.61 (d, J = 8.5 Hz, 2H), 6.41 (td, J = 8.5, 8.0, 6.1 Hz, 3H), 6.32 - 6.27 (m, 2H), 5.04 (dd, J = 13.3, 5.1 Hz, 1H), 4.38 - 4.28 (m, 2H), 4.23 - 4.16 (m, 3H), 3.90 - 3.57 (m, 4H), 2.98 - 2.89 (m, 10H), 2.61 - 2.55 (m, 1H), 2.37 (td, J = 13.0, 4.3 Hz, 1H), 2.30 - 2.23 (m, 1H), 1.99 - 1.93 (m, 1H), 1.69 (dd, J = 7.3, 3.9 Hz, 6H), 1.21 (d, J = 7.5 Hz, 2H). LC / MS (ESI+) calcd for C 46 H 48 FN5O5([M+H] + ) m / z: 770.4; found 770.2。

[0126] Example 16. 3-(5-(7-((1-(4-((3S,4R)-3-(2,3-difluorophenyl)-7-hydroxycoumarin-4-yl)-2-fluorophenyl)piperidin-4-yl)methyl)-2,7-diazaspiro[3.5]non-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione TIFF2025523440000096.tif32170

[0127] In the same manner as in Example 5, racemic cis-3-(2,3-difluorophenyl)-4-(4-(4-(dimethoxymethyl)piperidin-1-yl)-3-fluorophenyl)chroman-7-ol was prepared and then resolved by chiral SFC to recover the second component, obtaining 252 mg of the product (3S,4R)-3-(2,3-difluorophenyl)-4-(4-(4-(dimethoxymethyl)piperidin-1-yl)-3-fluorophenyl)chroman-7-ol. Yield 47%. The chiral column was CHIRALPAK AY (30*250 mm 10 μm) (Daicel), the mobile phase was A = CO2, Co-Solvent B = EtOH (25%). The target compound was prepared in a manner similar to Example 5. 1 H NMR (400 MHz, DMSO-d6) δ 10.94 (s, 1H), 9.40 (s, 1H), 7.47 (d, J = 8.3 Hz, 1H), 7.27 (dtd, J = 9.7, 8.1, 1.5 Hz, 1H), 6.95 (dtt, J = 9.7, 5.4, 2.1 Hz, 1H), 6.75 (t, J = 8.8 Hz, 1H), 6.68 (d, J = 8.2 Hz, 1H), 6.53 - 6.44 (m, 2H), 6.40 - 6.22 (m, 5H), 5.03 (dd, J = 13.2, 5.1 Hz, 1H), 4.30 (ddt, J = 26.5, 12.7, 7.1 Hz, 4H), 4.16 (d, J = 16.9 Hz, 1H), 3.78 (ddd, J = 11.0, 5.5, 3.4 Hz, 1H), 3.61 (s, 4H), 3.21 (d, J = 10.9 Hz, 2H), 2.96 - 2.83 (m, 1H), 2.61 - 2.51 (m, 3H), 2.43 - 2.17 (m, 5H), 2.12 (d, J = 7.0 Hz, 2H), 1.97 - 1.90 (m, 1H), 1.79 - 1.68 (m, 6H), 1.59 (t, J = 10.4 Hz, 1H), 1.22 - 1.14 (m, 2H). LC / MS (ESI+) calcd for C 47 H 48F3N5O5([M+H] + ) m / z: 820.4; found 820.2。

[0128] Example 17. 3-(5-(7-((1-(2,6-difluoro-4-(cis-7-hydroxy-3-isobutylchroman-4-yl)phenyl)piperidin-4-yl)methyl)-2,7-diazaspiro[3.5]non-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione TIFF2025523440000097.tif63170

[0129] The target compound was prepared in a similar manner to Example 5. 1 H NMR (400 MHz, DMSO-d6) δ 10.95 (s, 1H), 9.31 (s, 1H), 7.47 (d, J = 8.3 Hz, 1H), 6.70 - 6.58 (m, 3H), 6.52 - 6.43 (m, 2H), 6.24 (d, J = 7.5 Hz, 2H), 5.03 (dd, J = 13.3, 5.1 Hz, 1H), 4.33 - 4.13 (m, 2H), 4.03 - 3.95 (m, 2H), 3.74 (t, J = 11.3 Hz, 1H), 3.62 (s, 4H), 3.12 (d, J = 11.2 Hz, 2H), 3.02 - 2.86 (m, 3H), 2.57 (dd, J = 17.8, 4.3 Hz, 1H), 2.42 - 2.26 (m, 4H), 2.14 (tt, J = 11.9, 7.8 Hz, 4H), 1.97 - 1.90 (m, 1H), 1.77 - 1.59 (m, 8H), 1.22 (d, J = 3.2 Hz, 2H), 1.17 (dd, J = 9.1, 5.2 Hz, 2H), 0.83 (dd, J = 6.5, 3.9 Hz, 6H). LC / MS (ESI+) calcd for C 45 H 53 F2N5O5([M+H] + ) m / z: 782.4; found 782.2。

[0130] Example 18. 3-(5-(7-((1-(4-(3-(2,6-difluorophenyl)-7-hydroxy-2H-chromen-4-yl)phenyl)piperidin-4-yl)methyl)-2,7-diazaspiro[3.5]non-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione TIFF2025523440000098.tif30170

[0131] The target compound was prepared in a similar manner to Example 5. 1 H NMR (400 MHz, DMSO-d6) δ 10.95 (s, 1H), 9.82 (s, 1H), 7.48 (d, J = 8.2 Hz, 1H), 7.28 (tt, J = 8.3, 6.6 Hz, 1H), 6.97 (q, J = 8.0, 6.7 Hz, 2H), 6.88 - 6.72 (m, 4H), 6.64 (d, J = 8.3 Hz, 1H), 6.53 - 6.43 (m, 2H), 6.38 - 6.29 (m, 2H), 5.03 (dd, J = 13.3, 5.1 Hz, 1H), 4.79 (s, 2H), 4.33 - 4.14 (m, 2H), 3.65 (d, J = 11.1 Hz, 7H), 2.94 - 2.85 (m, 1H), 2.66 - 2.53 (m, 3H), 2.40 - 2.23 (m, 4H), 2.15 (d, J = 6.8 Hz, 2H), 1.97 - 1.92 (m, 1H), 1.85 - 1.54 (m, 7H), 1.21 (d, J = 4.4 Hz, 2H). LC / MS (ESI+) calcd for C 47 H 47 F2N5O5( [M+H] + ) m / z: 800.3; found 799.9。

[0132] Example 19. 3-(5-(4-(7-(4-(cis-2-(2-Fluorophenyl)-6-hydroxy-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)-2,7-diazaspiro[3.5]non-2-yl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione TIFF2025523440000099.tif81170

[0133] Step 1: Synthesis of tert-Butyl 7-(4-(1-hydroxy-6-((tetrahydro-2H-pyran-2-yl)oxy)-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)-2,7-diazaspiro[3.5]nonane-2-carboxylate Under a nitrogen gas atmosphere, tert-Butyl 7-(4-bromophenyl)-2,7-diazaspiro[3.5]nonane-2-carboxylate (2 g, 5.4 mmol) was dissolved in dry THF (40 mL), the temperature was lowered to -70 °C or below, and n-butyllithium (4.8 mL, 2.5 M, 12.3 mmol) was slowly added while maintaining the temperature of the reaction system at -70 °C or below throughout the dropping process. After the addition was complete, the reaction was carried out for 1 hour while maintaining the temperature, and 6-((tetrahydro-2H-pyran-2-yl)oxy)-3,4-dihydronaphthalen-1(2H)-one (1.2 g, 4.9 mmol) dissolved in dry THF (40 mL) was slowly added dropwise to the system while maintaining the temperature of the reaction system at -70 °C or below throughout the dropping process. The reaction was carried out for 1 hour while maintaining the temperature, and the reaction system was gradually warmed up to about -40 °C and monitored by TLC until the starting material 6-((tetrahydro-2H-pyran-2-yl)oxy)-3,4-dihydronaphthalen-1(2H)-one was completely reacted. Saturated ammonium chloride was added to quench the reaction, extracted with ethyl acetate, washed with saturated sodium chloride, dried and concentrated, and subjected to column chromatography to obtain 713 g of the product. LC / MS (ESI+) calcd for C 33 H 44 N2O5( [M+H] + ) m / z: 549.3; found 549.2. Yield: 27%.

[0134] Step 2: Synthesis of tert-butyl 7-(4-(6-((tetrahydro-2H-pyran-2-yl)oxy)-3,4-dihydronaphthalen-1-yl)phenyl)-2,7-diazaspiro[3.5]nonane-2-carboxylate tert-Butyl 7-(4-(1-hydroxy-6-((tetrahydro-2H-pyran-2-yl)oxy)-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)-2,7-diazaspiro[3.5]nonane-2-carboxylate (713 mg, 1.3 mmol) was dissolved in dichloromethane (15 mL), triethylamine (394 mg, 3.9 mmol) was added, methanesulfonyl chloride (0.2 mL, 2.6 mmol) was added under an ice bath, and after addition, the temperature was raised to room temperature and reacted for 2 hours. The reaction was monitored by TLC until the raw materials were completely reacted, water was added to quench the reaction, extracted with dichloromethane, dried and concentrated, and subjected to column chromatography to obtain 539 mg of the product. LC / MS (ESI+) calcd for C 33 H 42 N2O4([M+H] + ) m / z: 531.3; found 531.2. Yield: 78%.

[0135] Step 3: Synthesis of tert-butyl 7-(4-(2-bromo-6-((tetrahydro-2H-pyran-2-yl)oxy)-3,4-tetrahydronaphthalen-1-yl)phenyl)-2,7-diazaspiro[3.5]nonane-2-carboxylate tert-Butyl 7-(4-(6-((tetrahydro-2H-pyran-2-yl)oxy)-3,4-dihydronaphthalen-1-yl)phenyl)-2,7-diazaspiro[3.5]nonane-2-carboxylate (539 mg, 1.0 mmol) was dissolved in DMF (10 mL), DIPEA (0.33 mL, 2 mmol) was added, and pyridinium tribromide (384 mg, 1.2 mmol) was added portionwise under an ice bath. After addition, the mixture was warmed to room temperature and stirred overnight. The reaction was monitored by TLC until the raw materials were completely reacted. Water was added to quench the reaction, and the mixture was extracted with ethyl acetate, dried, and concentrated. The residue was subjected to column chromatography on petroleum ether / ethyl acetate (3:1) to obtain 598 mg of the product. Yield: 97%.

[0136] Step 4: Synthesis of tert-Butyl 7-(4-(2-(2-Fluorophenyl)-6-((tetrahydro-2H-pyran-2-yl)oxy)-3,4-tetrahydronaphthalen-1-yl)phenyl)-2,7-diazaspiro[3.5]nonane-2-carboxylate To a reaction flask were added tert-butyl 7-(4-(2-bromo-6-((tetrahydro-2H-pyran-2-yl)oxy)-3,4-tetrahydronaphthalen-1-yl)phenyl)-2,7-diazaspiro[3.5]nonane-2-carboxylate (598 mg, 0.98 mmol), 2-fluorophenylboronic acid (165 mg, 1.26 mmol), Pd(dppf)Cl2 (72 mg, 0.098 mmol), potassium carbonate (270 mg, 1.96 mmol), and dioxane / water (20 mL / 5 mL) as the solvent. The system was purged with nitrogen gas and reacted at 90 °C overnight. The reaction was monitored by TLC until the raw materials were completely reacted. After cooling to room temperature, the mixture was filtered through celite, concentrated, and subjected to column chromatography to obtain 498 mg of the product. LC / MS (ESI+) calcd for C 39 H 45 FN2O4 ([M+H] + ) m / z: 625.3; found 625.3. Yield: 81%.

[0137] Step 5: Synthesis of tert-Butyl 7-(4-(cis-2-(2-Fluorophenyl)-6-((tetrahydro-2H-pyran-2-yl)oxy)-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)-2,7-diazaspiro[3.5]nonane-2-carboxylate tert-Butyl 7-(4-(2-(2-Fluorophenyl)-6-((tetrahydro-2H-pyran-2-yl)oxy)-3,4-tetrahydronaphthalen-1-yl)phenyl)-2,7-diazaspiro[3.5]nonane-2-carboxylate (498 mg, 0.8 mmol) was dissolved in THF (15 mL), methanol (15 mL) and 10% palladium on carbon (50 mg, 10% wt) were added, the system was purged with hydrogen gas, reacted overnight at room temperature, and monitored by TLC until the raw materials were completely reacted. It was filtered through celite to remove palladium on carbon, concentrated and subjected to column chromatography to obtain 429 mg of the product. Yield: 86%.

[0138] Step 6: Synthesis of tert-Butyl 7-(4-(cis-2-(2-Fluorophenyl)-6-hydroxy-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)-2,7-diazaspiro[3.5]nonane-2-carboxylate tert-Butyl 7-(4-(cis-2-(2-Fluorophenyl)-6-((tetrahydro-2H-pyran-2-yl)oxy)-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)-2,7-diazaspiro[3.5]nonane-2-carboxylate was dissolved in acetone (20 mL), p-toluenesulfonic acid monohydrate (156 mg, 0.82 mmol) was added, and after addition, it was stirred at room temperature for 0.5 h - 1.5 h and monitored by TLC until the raw materials were completely reacted. Water was added to quench the reaction, extracted with ethyl acetate, dried and concentrated, and subjected to column chromatography with petroleum ether / ethyl acetate (5:1) to obtain 320 mg of the product. LC / MS (ESI+) calcd for C 34 H 39 FN2O3([M+H] + ) m / z: 543.3; found 543.2. Yield: 86%.

[0139] Step 7: Synthesis of cis-5-(4-(2,7-diazaspiro[3.5]nonan-7-yl)phenyl)-6-(2-fluorophenyl)-5,6,7,8-tetrahydronaphthalen-2-ol Dissolve tert-butyl 7-(4-(cis-2-(2-fluorophenyl)-6-hydroxy-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)-2,7-diazaspiro[3.5]nonane-2-carboxylate (55 mg, 0.1 mmol) in dichloromethane (4 mL), add trifluoroacetic acid (1 mL) under an ice bath, react at room temperature for about 1 h, and monitor by TLC until the raw materials are completely reacted. Under an ice bath, adjust the pH of the reaction system to about 8 with saturated sodium bicarbonate, extract with dichloromethane / methanol (10:1), and concentrate to obtain 50 mg of the crude product. LC / MS (ESI+) calcd for C 29 H 31 FN2O ([M+H] + ) m / z: 443.2; found 443.1. Yield: 100%.

[0140] Step 8: Synthesis of 3-(5-(4-(7-(4-(cis-2-(2-fluorophenyl)-6-hydroxy-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)-2,7-diazaspiro[3.5]non-2-yl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione The crude product cis-5-(4-(2,7-diazaspiro[3.5]nonan-7-yl)phenyl)-6-(2-fluorophenyl)-5,6,7,8-tetrahydronaphthalen-2-ol (50 mg, 0.1 mmol) and 3-(1-oxo-5-(4-oxopiperidin-1-yl)isoindolin-2-yl)piperidine-2,6-dione (45 mg, 0.1 mmol) were dissolved in dichloromethane / methanol (5 mL, 4:1), glacial acetic acid (20 mg, 0.3 mmol) was added, and the mixture was stirred at 35 °C for 0.5 h, cooled to room temperature, sodium triacetoxyborohydride (70 mg, 0.3 mmol) was added, and the reaction was allowed to proceed overnight. The reaction was monitored by TLC until the raw materials were completely reacted, and saturated sodium bicarbonate solution was added to quench the reaction. The mixture was extracted with dichloromethane, dried and concentrated, and then subjected to column chromatography to obtain 39 mg of the product. The total yield of the two steps: 45%. 11H NMR (400 MHz, DMSO-d6) δ 10.95 (s, 1H), 9.15 (s, 1H), 7.49 (d, J = 8.4 Hz, 1H), 7.21 - 7.11 (m, 2H), 7.03 (d, J = 8.5 Hz, 2H), 6.87 (td, J = 7.4, 1.5 Hz, 1H), 6.64 (d, J = 8.4 Hz, 1H), 6.60 (d, J = 2.5 Hz, 1H), 6.54 (d, J = 8.5 Hz, 2H), 6.48 (dd, J = 8.3, 2.5 Hz, 1H), 6.41 (td, J = 7.8, 1.7 Hz, 1H), 6.23 (d, J = 8.4 Hz, 2H), 5.04 (dd, J = 13.3, 5.1 Hz, 1H), 4.31 (d, J = 16.8 Hz, 1H), 4.23 - 4.13 (m, 2H), 3.72 (d, J = 12.5 Hz, 2H), 3.55 - 3.51 (m, 1H), 2.93 (d, J = 6.6 Hz, 12H), 2.63 - 2.54 (m, 1H), 2.43 - 2.30 (m, 1H), 2.23 (t, J = 6.9 Hz, 1H), 2.11 (tt, J = 14.6, 7.2 Hz, 1H), 2.04 - 1.91 (m, 2H), 1.68 (s, 7H), 1.23 (s, 2H). LC / MS (ESI+) calcd for C 47 H 50 FN5O4( [M+H] + ) m / z: 768.4; found 768.3。

[0141] Example 20. 3-(5-(4-(7-(4-(cis-3-(2-Fluorophenyl)-7-hydroxycoumarin-4-yl)phenyl)-2,7-diazaspiro[3.5]non-2-yl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione TIFF2025523440000100.tif30170

[0142] The target compound was prepared in a method similar to Example 19. 1 H NMR (400 MHz, DMSO-d6) δ 10.95 (s, 1H), 9.33 (s, 1H), 7.49 (d, J = 8.5 Hz, 1H), 7.21 (t, J = 6.9 Hz, 1H), 7.14 (s, 1H), 7.03 (d, J = 9.7 Hz, 2H), 6.89 (t, J = 7.5 Hz, 1H), 6.67 (d, J = 8.3 Hz, 1H), 6.61 (d, J = 8.3 Hz, 2H), 6.40 (t, J = 7.4 Hz, 3H), 6.32 - 6.27 (m, 2H), 5.04 (dd, J = 13.2, 5.1 Hz, 1H), 4.38 - 4.28 (m, 2H), 4.20 (q, J = 12.0, 10.5 Hz, 3H), 3.72 (s, 4H), 2.95 (d, J = 6.7 Hz, 10H), 2.60 (s, 1H), 2.34 (d, J = 4.8 Hz, 2H), 1.98 (d, J = 10.1 Hz, 1H), 1.68 (d, J = 6.5 Hz, 6H), 1.24 - 1.22 (m, 2H). LC / MS (ESI+) calcd for C 46 H 48 FN5O5( [M+H] + ) m / z: 770.3; found 770.2。

[0143] Example 21. 3-(5-(4-(7-(4-((1S,2R)-2-(2-Fluorophenyl)-6-hydroxy-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)-2,7-diazaspiro[3.5]nonan-2-yl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione TIFF2025523440000101.tif54170

[0144] Step 1: Synthesis of tert-butyl 7-(4-((1S,2R)-2-(2-fluorophenyl)-6-hydroxy-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)-2,7-diazaspiro[3.5]nonane-2-carboxylate The racemic tert-butyl 7-(4-(cis-2-(2-fluorophenyl)-6-hydroxy-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)-2,7-diazaspiro[3.5]nonane-2-carboxylate (276 mg, 0.51 mmol) was resolved by chiral SFC to obtain two components. Here, the first component was tert-butyl 7-(4-((1S,2R)-2-(2-fluorophenyl)-6-hydroxy-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)-2,7-diazaspiro[3.5]nonane-2-carboxylate (129 mg, 0.24 mmol) with a yield of 47%, and the second component was tert-butyl 7-(4-((1R,2S)-2-(2-fluorophenyl)-6-hydroxy-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)-2,7-diazaspiro[3.5]nonane-2-carboxylate (137 mg, 0.25 mmol) with a yield of 50%. The column was CHIRALPAK AD (30 * 250 mm 5 μm) (Daicel), the mobile phase was A = CO2, and the co-solvent B = MeOH / ACN = 1 / 1 = 40%. The following reaction was carried out using the first component, tert-butyl 7-(4-((1S,2R)-2-(2-fluorophenyl)-6-hydroxy-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)-2,7-diazaspiro[3.5]nonane-2-carboxylate.

[0145] Step 2: Synthesis of (5S,6R)-5-(4-(2,7-diazaspiro[3.5]nonan-7-yl)phenyl)-6-(2-fluorophenyl)-5,6,7,8-tetrahydronaphthalen-2-ol tert-Butyl 7-(4-((1S,2R)-2-(2-fluorophenyl)-6-hydroxy-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)-2,7-diazaspiro[3.5]nonane-2-carboxylate (129 mg, 0.29 mmol) was dissolved in DCM (6 mL), trifluoroacetic acid (1.5 mL) was added under an ice bath, and the reaction was carried out at room temperature for about 1 h and monitored by TLC until the raw materials were completely reacted. Under an ice bath, the pH of the reaction system was adjusted to about 8 with saturated sodium bicarbonate, extracted with dichloromethane / methanol (10:1), and concentrated to obtain 105 mg of the crude product. LC / MS (ESI+) calcd for C 29 H 31 FN2O([M+H] + ) m / z: 443.2; found 443.1. Yield: 97%.

[0146] Step 3: Synthesis of 3-(5-(4-(7-(4-((1S,2R)-2-(2-fluorophenyl)-6-hydroxy-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)-2,7-diazaspiro[3.5]nonan-2-yl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione The crude product (5S,6R)-5-(4-(2,7-diazaspiro[3.5]nonan-7-yl)phenyl)-6-(2-fluorophenyl)-5,6,7,8-tetrahydronaphthalen-2-ol (31 mg, 0.07 mmol) and 3-(1-oxo-5-(4-oxopiperidin-1-yl)isoindolin-2-yl)piperidine-2,6-dione (29 mg, 0.08 mmol) were dissolved in dichloromethane / methanol (5 mL, 4:1), glacial acetic acid (20 mg, 0.3 mmol) was added, stirred at 35 °C for 0.5 h, cooled to room temperature, sodium triacetoxyborohydride (70 mg, 0.3 mmol) was added, and the reaction was carried out overnight. The reaction was monitored by TLC until the raw materials were completely reacted, and a saturated sodium bicarbonate solution was added to quench the reaction. Extracted with dichloromethane, dried and concentrated, and subjected to column chromatography to obtain 26 mg of the product. Yield: 45%. 11H NMR (400 MHz, DMSO-d6) δ 10.95 (s, 1H), 9.14 (s, 1H), 7.49 (d, J = 8.5 Hz, 1H), 7.26 - 7.09 (m, 2H), 7.03 (d, J = 8.7 Hz, 2H), 6.86 (td, J = 7.3, 1.5 Hz, 1H), 6.64 (d, J = 8.4 Hz, 1H), 6.60 (d, J = 2.5 Hz, 1H), 6.54 (d, J = 8.5 Hz, 2H), 6.48 (dd, J = 8.3, 2.6 Hz, 1H), 6.44 - 6.38 (m, 1H), 6.23 (d, J = 8.3 Hz, 2H), 5.04 (dd, J = 13.3, 5.1 Hz, 1H), 4.31 (d, J = 16.9 Hz, 1H), 4.24 - 4.13 (m, 2H), 3.73 (d, J = 12.3 Hz, 2H), 3.53 (dd, J = 12.8, 4.4 Hz, 1H), 2.92 (d, J = 10.8 Hz, 12H), 2.63 - 2.54 (m, 1H), 2.43 - 2.32 (m, 1H), 2.32 - 2.21 (m, 1H), 2.20 - 2.05 (m, 1H), 1.97 (ddd, J = 20.9, 15.4, 8.5 Hz, 2H), 1.71 - 1.66 (m, 7H), 1.23 (s, 2H). LC / MS (ESI+) calcd for C 47 H 50 FN5O4([M+H] + ) m / z: 768.3; found 768.3。

[0147] Example 22. 3-(5-(4-(7-(4-((1R,2S)-2-(2-Fluorophenyl)-6-hydroxy-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)-2,7-diazaspiro[3.5]nonan-2-yl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione TIFF2025523440000102.tif31170

[0148] In a method similar to Example 21, the reaction was carried out using 7-(4-((1R,2S)-2-(2-fluorophenyl)-6-hydroxy-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester as the second component to prepare the target compound. 1 H NMR (400 MHz, DMSO-d6) δ 10.95 (s, 1H), 9.14 (s, 1H), 7.49 (d, J = 8.5 Hz, 1H), 7.24 - 7.10 (m, 2H), 7.03 (d, J = 8.7 Hz, 2H), 6.86 (td, J = 7.4, 1.5 Hz, 1H), 6.64 (d, J = 8.4 Hz, 1H), 6.60 (d, J = 2.6 Hz, 1H), 6.54 (d, J = 8.5 Hz, 2H), 6.48 (dd, J = 8.3, 2.6 Hz, 1H), 6.41 (td, J = 7.7, 1.7 Hz, 1H), 6.23 (d, J = 8.3 Hz, 2H), 5.04 (dd, J = 13.3, 5.1 Hz, 1H), 4.31 (d, J = 17.0 Hz, 1H), 4.23 - 4.12 (m, 2H), 3.72 (t, J = 8.5 Hz, 2H), 3.52 (dt, J = 13.1, 3.7 Hz, 1H), 2.93 (t, J = 9.7 Hz, 12H), 2.70 - 2.54 (m, 1H), 2.43 - 2.33 (m, 1H), 2.32 - 2.20 (m, 1H), 2.19 - 2.05 (m, 1H), 2.03 - 1.89 (m, 2H), 1.68 (s, 7H), 1.23 (d, J = 3.5 Hz, 2H). LC / MS (ESI+) calcd for C 47 H 50 FN5O4( [M+H] + ) m / z: 768.3; found 768.3。

[0149] Example 23. 3-(5-(4-(7-(4-(cis-3-(2-Fluorophenyl)-7-hydroxychroman-4-yl)phenyl)-2,7-diazaspiro[3.5]non-2-yl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione TIFF2025523440000103.tif31170

[0150] The target compound was prepared in a manner similar to Example 19. 1 H NMR (400 MHz, DMSO-d6) δ 10.96 (s, 1H), 9.37 (s, 1H), 7.49 (d, J = 8.4 Hz, 1H), 7.20 - 7.15 (m, 3H), 7.03 (d, J = 8.6 Hz, 2H), 6.78 (dd, J = 6.6, 3.1 Hz, 2H), 6.69 (dd, J = 13.0, 8.6 Hz, 2H), 6.34 - 6.26 (m, 3H), 6.14 (dd, J = 14.2, 2.0 Hz, 1H), 5.04 (dd, J = 13.3, 5.1 Hz, 1H), 4.37 - 4.27 (m, 2H), 4.27 - 4.16 (m, 3H), 3.72 (dd, J = 10.9, 6.8 Hz, 2H), 3.55 (dt, J = 11.4, 4.6 Hz, 2H), 2.93 (d, J = 15.5 Hz, 6H), 2.79 (s, 4H), 2.64 - 2.55 (m, 1H), 2.43 - 2.32 (m, 1H), 2.26 (s, 1H), 2.00 - 1.91 (m, 1H), 1.74 (t, J = 5.6 Hz, 6H), 1.23 (d, J = 3.5 Hz, 2H). LC / MS (ESI+) calcd for C 46 H 48 FN5O5( [M+H] + ) m / z: 770.3; found 770.2。

[0151] Example 24. 3-(5-(7-((1-(4-((3R,4S)-3-(2,3-Difluorophenyl)-7-hydroxychroman-4-yl)-2-fluorophenyl)piperidin-4-yl)methyl)-2,7-diazaspiro[3.5]non-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione TIFF2025523440000104.tif84170

[0152] Step 1: Synthesis of 7-(Benzyloxy)-4-(4-(4-(dimethoxymethyl)piperidin-1-yl)-3-fluorophenyl)chroman-4-ol Under a nitrogen gas atmosphere, 4-(dimethoxymethyl)-1-(2-fluoro-4-iodophenyl)piperidine (15 g, 39.6 mmol) was dissolved in dry THF (90 mL), the temperature was lowered to -70 °C or below, and n-butyllithium (18.7 mL, 2.5 M, 46.77 mmol) was slowly added while maintaining the temperature of the reaction system at -70 °C or below throughout the dropping process. After the addition was complete, the reaction was carried out for 1 hour while maintaining the temperature, and 7-(benzyloxy)chroman-4-one (9.14 g, 35.98 mmol) dissolved in dry THF (50 mL) was slowly added dropwise to the system while maintaining the temperature of the reaction system at -70 °C or below throughout the dropping process. The reaction was carried out for 1 hour while maintaining the temperature, and the reaction system was gradually warmed to about -40 °C and monitored by TLC until the starting material 7-(benzyloxy)chroman-4-one was completely reacted. Saturated ammonium chloride was added to quench the reaction, extracted with ethyl acetate, washed with saturated sodium chloride, dried and concentrated, and then subjected to column chromatography to obtain 13 g of the product. LC / MS (ESI+) calcd for C 30 H 34 FNO5([M+H] + ) m / z: 508.2; found 508.2. Yield 65%.

[0153] Step 2: Synthesis of 1-(4-(7-(Benzyloxy)-2H-chromen-4-yl)-2-fluorophenyl)-4-(dimethoxymethyl)piperidine 7-(Benzyloxy)-4-(4-(4-(dimethoxymethyl)piperidin-1-yl)-3-fluorophenyl)chroman-4-ol (13 g, 25.56 mmol) was dissolved in dichloromethane (100 mL), triethylamine (7.77 g, 76.9 mmol) was added, methanesulfonyl chloride (5.85 g, 51.3 mmol) was added under an ice bath, and after addition, the temperature was raised to room temperature and reacted for 2 hours. The reaction was monitored by TLC until the raw materials were completely reacted, water was added to quench the reaction, extracted with dichloromethane, dried and concentrated, and then subjected to column chromatography to obtain 8 g of the product. LC / MS (ESI+) calcd for C 30 H 32 FNO4([M+H] + ) m / z: 490.2; found 490.2. Yield 64%.

[0154] Step 3: Synthesis of 1-(4-(7-(benzyloxy)-3-bromo-2H-chromen-4-yl)-2-fluorophenyl)-4-(dimethoxymethyl)piperidine 1-(4-(7-(Benzyloxy)-2H-chromen-4-yl)-2-fluorophenyl)-4-(dimethoxymethyl)piperidine (8 g, 16.35 mmol) was dissolved in DMF (40 mL), DIPEA (6.33 g, 49.08 mmol) was added, pyridinium tribromide (5.76 g, 17.99 mmol) was added in several portions under an ice bath, and after addition, the temperature was raised to room temperature and stirred overnight. The reaction was monitored by TLC until the raw materials were completely reacted, water was added to quench the reaction, extracted with ethyl acetate, dried and concentrated, and slurried with petroleum ether / ethyl acetate (6:1) to obtain 7 g of the product. Yield 75%.

[0155] Step 4: Synthesis of 1-(4-(7-(benzyloxy)-3-(2,3-difluorophenyl)-2H-chromen-4-yl)-2-fluorophenyl)-4-(dimethoxymethyl)piperidine 1-(4-(7-(Benzyloxy)-3-bromo-2H-chromen-4-yl)-2-fluorophenyl)-4-(dimethoxymethyl)piperidine (1.0 g, 1.76 mmol), 2,3-difluorophenylboronic acid (335 mg, 2.12 mmol), Pd(dppf)Cl2 (130 mg, 0.18 mmol), potassium carbonate (488 mg, 3.54 mmol) and dioxane (30 mL) were added to a reaction flask. The system was purged with nitrogen gas and reacted at 80 °C overnight. The reaction was monitored by TLC until the raw materials were completely reacted. After cooling to room temperature, it was filtered through celite, concentrated and subjected to column chromatography to obtain 715 mg of the product. LC / MS (ESI+) calcd for C 36 H 34 F3NO4([M+H] + ) m / z: 602.2; found 602.2. Yield: 68%.

[0156] Step 5: Synthesis of cis-3-(2,3-difluorophenyl)-4-(4-(4-(dimethoxymethyl)piperidin-1-yl)-3-fluorophenyl)chroman-7-ol 1-(4-(7-(Benzyloxy)-3-(2,3-difluorophenyl)-2H-chromen-4-yl)-2-fluorophenyl)-4-(dimethoxymethyl)piperidine (700 mg, 1.2 mmol) was dissolved in THF (2 mL), methanol (20 mL) was added, 10% palladium on carbon (70 mg, 10%) was added, the system was purged with hydrogen gas and reacted at room temperature overnight. The reaction was monitored by TLC until the raw materials were completely reacted. It was filtered through celite to remove palladium on carbon, concentrated and subjected to column chromatography to obtain 480 mg of the product. LC / MS (ESI+) calcd for C 29 H 30 F3NO4([M+H] + ) m / z: 514.2; found 514.1. Yield: 80%.

[0157] Step 6: Synthesis of (3R,4S)-3-(2,3-difluorophenyl)-4-(4-(4-(dimethoxymethyl)piperidin-1-yl)-3-fluorophenyl)chroman-7-ol The racemic cis 3-(2,3-difluorophenyl)-4-(4-(4-(dimethoxymethyl)piperidin-1-yl)-3-fluorophenyl)chroman-7-ol (491 mg, 0.96 mmol) was resolved by chiral SFC to obtain two components. Here, the first component was (3R,4S)-3-(2,3-difluorophenyl)-4-(4-(4-(dimethoxymethyl)piperidin-1-yl)-3-fluorophenyl)chroman-7-ol (239 mg, 0.47 mmol), the yield was 49%, the second component was (3S,4R)-3-(2,3-difluorophenyl)-4-(4-(4-(dimethoxymethyl)piperidin-1-yl)-3-fluorophenyl)chroman-7-ol (252 mg, 0.49 mmol), and the yield was 51%. The column was CHIRALPAK AY (30*250 mm 10 μm) (Daicel), the mobile phase was A = CO2, the co-solvent B = EtOH = 25%, and the following reaction was carried out using the first component (3R,4S)-3-(2,3-difluorophenyl)-4-(4-(4-(dimethoxymethyl)piperidin-1-yl)-3-fluorophenyl)chroman-7-ol.

[0158] Step 7: Synthesis of 1-(4-((3R,4S)-3-(2,3-difluorophenyl)-7-hydroxychroman-4-yl)-2-fluorophenyl)piperidine-4-carboxaldehyde (3R,4S)-3-(2,3-Difluorophenyl)-4-(4-(4-(dimethoxymethyl)piperidin-1-yl)-3-fluorophenyl)chroman-7-ol (100 mg, 0.19 mmol) was dissolved in THF (9 mL), sulfuric acid (3 mL, 2 M) was added, and the mixture was reacted at 70 °C for half an hour. The reaction was monitored by TLC until the raw material was completely reacted. After cooling to room temperature, the pH was adjusted to about 8 with saturated sodium bicarbonate, extracted with ethyl acetate, washed with saturated sodium chloride, dried and concentrated, and then subjected to column chromatography to obtain 98 mg of a crude product. LC / MS (ESI+) calcd for C 27 H 24 F3NO3([M+H] + ) m / z: 468.1; found 468.1. It was used directly in the next step.

[0159] Step 8: Synthesis of 3-(5-(7-((1-(4-((3R,4S)-3-(2,3-difluorophenyl)-7-hydroxychroman-4-yl)-2-fluorophenyl)piperidin-4-yl)methyl)-2,7-diazaspiro[3.5]non-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione 3-(1-Oxo-5-(piperazin-1-yl)isoindolin-2-yl)piperidine-2,6-dione hydrochloride (89 mg, 0.24 mmol) was dissolved in dichloromethane / methanol (12 mL, 5:1), DIPEA (84 mg, 0.65 mmol) was added, and the mixture was stirred at room temperature for 5 min. 1-(4-((3R,4S)-3-(2,3-Difluorophenyl)-7-hydroxychroman-4-yl)-2-fluorophenyl)piperidine-4-carboxaldehyde (98 mg, 0.22 mmol) was added, glacial acetic acid (40 mg, 0.66 mmol) was added, and the mixture was stirred at 35 °C for 0.5 h. After cooling to room temperature, sodium triacetoxyborohydride (140 mg, 0.66 mmol) was added and reacted overnight. The reaction was monitored by TLC until the raw material was completely reacted, and the reaction was quenched by adding saturated sodium bicarbonate solution. It was extracted with dichloromethane, dried and concentrated, and then subjected to column chromatography to obtain 20 mg of the product. Yield: 12%.1 1H NMR (400 MHz, DMSO-d6) δ 10.94 (s, 1H), 9.40 (s, 1H), 7.48 (d, J = 8.3 Hz, 1H), 7.27 (q, J = 8.8 Hz, 1H), 6.95 (q, J = 7.7 Hz, 1H), 6.75 (t, J = 8.8 Hz, 1H), 6.68 (d, J = 8.2 Hz, 1H), 6.51 (s, 1H), 6.47 (dd, J = 8.3, 2.0 Hz, 1H), 6.38 (td, J = 8.7, 8.2, 4.0 Hz, 2H), 6.35 - 6.29 (m, 2H), 6.26 (dd, J = 14.1, 2.0 Hz, 1H), 5.03 (dd, J = 13.3, 5.1 Hz, 1H), 4.37 (t, J = 10.8 Hz, 1H), 4.33 - 4.22 (m, 3H), 4.16 (d, J = 16.9 Hz, 1H), 3.83 - 3.74 (m, 1H), 3.62 (s, 4H), 3.21 (d, J = 11.0 Hz, 2H), 2.90 (ddd, J = 17.9, 13.4, 5.4 Hz, 1H), 2.69 - 2.52 (m, 3H), 2.46 - 2.19 (m, 5H), 2.13 (d, J = 7.1 Hz, 2H), 1.96 - 1.88 (m, 1H), 1.74 (t, J = 6.1 Hz, 6H), 1.59 (s, 1H), 1.23 (s, 2H). LC / MS (ESI+) calcd for C 47 H 48 F3N5O5( [M+H] + ) m / z: 820.3; found 820.3。

[0160] Example 25: 2-(2,6-Dioxopiperidin-3-yl)-5-(5-((1-(4-((1R,2S)-6-Hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperidin-4-yl)methyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)isoindoline-1,3-dione TIFF2025523440000105.tif61170

[0161] Step 1: Synthesis of tert-Butyl 5-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate Compound 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (552 mg, 2.00 mmol) and tert-butyl hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (530 mg, 2.50 mmol) were added to 8 mL of DMSO, and further DIPEA (516 mg, 4.00 mmol) was added. The mixture was stirred at 90 °C overnight. After cooling to room temperature, a small amount of water was added to the reaction solution, and the mixture was extracted 3 times with EA. The organic phases were combined, washed 3 times with saturated NaCl solution, dried over anhydrous sodium sulfate, rotary evaporated, and purified by column chromatography to obtain the target compound (608 mg, 1.30 mmol). Yield: 65%. LC / MS (ESI+) calcd for C 24 H 28 N4O6(M + H + ) m / z, 469.2; found, 469.2。

[0162] Step 2: Synthesis of 2-(2,6-dioxopiperidin-3-yl)-5-(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)isoindoline-1,3-dione Compound tert-Butyl 5-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (50 mg, 0.10 mmol) was added to 4 mL of DCM and 1 mL of MeOH, and further 2 mL of 4M hydrogen chloride-dioxane solution was added. The mixture was stirred at room temperature for 1 h. It was concentrated to obtain the target compound (32 mg, 0.08 mmol). Yield: 85%. LC / MS (ESI+) calcd for C 19 H 20 N4O4(M + H +) m / z, 369.1; found, 369.1。

[0163] Step 3: Synthesis of 2-(2,6-dioxopiperidin-3-yl)-5-(5-((1-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperidin-4-yl)methyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)isoindoline-1,3-dione Compound 2-(2,6-dioxopiperidin-3-yl)-5-(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)isoindoline-1,3-dione (30 mg, 0.08 mmol), 1-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperidine-4-carboxaldehyde (32 mg, 0.08 mmol) were added to 6 mL of DCM and 2 mL of MeOH, and DIEA (13 mg, 0.10 mmol), AcOH (13 mg, 0.20 mmol) were added in sequence. The mixture was stirred at room temperature for 1 h, NaBH(OAc)3 (65 mg, 0.30 mmol) was added, and the reaction was carried out overnight at room temperature. Water was added, and the mixture was extracted twice with DCM. The organic phases were combined, washed with saturated NaCl solution, dried over anhydrous sodium sulfate, rotary evaporated, and purified by column chromatography to obtain the target compound (27 mg, 0.03 mmol). Yield: 45%. LC / MS (ESI+) calcd for C 47 H 49 N5O5(M + H + ) m / z, 764.3; found, 764.3. 11H NMR (400 MHz, DMSO-d6) δ 11.08 (s, 1H), 9.10 (s, 1H), 7.64 (d, J = 8.5 Hz, 1H), 7.17 - 7.06 (m, 3H), 6.95 (d, J = 2.2 Hz, 1H), 6.88 - 6.77 (m, 3H), 6.67 - 6.55 (m, 2H), 6.48 (dd, J = 12.2, 7.3 Hz, 3H), 6.17 (d, J = 8.3 Hz, 2H), 5.06 (dd, J = 12.8, 5.4 Hz, 1H), 4.11 (d, J = 4.9 Hz, 1H), 3.67 (s, 2H), 3.47 (d, J = 11.8 Hz, 2H), 3.25 (d, J = 9.6 Hz, 3H), 2.99 - 2.80 (m, 5H), 2.56 (t, J = 8.9 Hz, 3H), 2.46 (d, J = 11.4 Hz, 4H), 2.23 (d, J = 7.2 Hz, 2H), 2.13 -1.95 (m, 3H), 1.69 (s, 3H), 1.48 (s, 2H).

[0164] Example 26: 3-(5-(5-((1-(4-((1R,2S)-6-Hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperidin-4-yl)methyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione TIFF2025523440000106.tif30170

[0165] The target compound was prepared in a similar manner to Example 25. LC / MS (ESI+) calcd for C 47 H 51 N5O4(M + H + ) m / z, 750.4; found, 750.4. 11H NMR (400 MHz, DMSO-d6) δ 10.94 (s, 1H), 9.11 (s, 1H), 7.47 (dd, J = 12.7, 8.7 Hz, 1H), 7.12 (q, J = 8.4, 7.3 Hz, 3H), 6.86 - 6.77 (m, 2H), 6.70 (d, J = 7.3 Hz, 2H), 6.65 - 6.56 (m, 2H), 6.54 - 6.42 (m, 3H), 6.17 (d, J = 8.3 Hz, 2H), 5.03 (dd, J = 13.3, 5.2 Hz, 1H), 4.31 (d, J = 16.9 Hz, 1H), 4.22 - 4.06 (m, 2H), 3.62 - 3.42 (m, 5H), 3.12 (d, J = 10.6 Hz, 2H), 2.92 (m, 5H), 2.63 - 2.52 (m, 3H), 2.46 - 2.30 (m, 4H), 2.25 (m, 2H), 2.13 (m, 4H), 1.70 (m, 3H), 1.50 (s, 2H).

[0166] Example 27: 3-(5-(2-((1-(4-((1R,2S)-6-Hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperidin-4-yl)methyl)-2,7-diazaspiro[3.5]non-7-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione TIFF2025523440000107.tif57170

[0167] Step 1: Synthesis of tert-Butyl 7-(3-(1,3-dioxolan-2-yl)-4-(methoxycarbonyl)phenyl)-2,7-diazaspiro[3.5]nonane-2-carboxylate tert-Butyl 2,7-diazaspiro[3.5]nonane-2-carboxylate (700 mg, 3.10 mmol), methyl 4-bromo-2-(1,3-dioxolan-2-yl)benzoate (850 mg, 3.00 mmol), Pd2(dba)3 (274 mg, 0.30 mmol), X-Phos (285 mg, 0.60 mmol), and Cs2CO3 (1950 mg, 6.00 mmol) were dissolved in 15 mL of 1,4-dioxane and stirred at 100 °C overnight under N2 protection. Water was added to the reaction mixture, and the mixture was extracted twice with EA. The organic phases were combined, washed with saturated NaCl solution, dried over anhydrous sodium sulfate, rotary evaporated, and purified by column chromatography and dried to obtain the target compound (712 mg, 1.65 mmol). Yield: 55%. LC / MS (ESI+) calcd for C 23 H 32 N2O6(M + H + ) m / z, 433.2; found, 433.2。

[0168] Step 2: Synthesis of tert-butyl 7-(3-formyl-4-(methoxycarbonyl)phenyl)-2,7-diazaspiro[3.5]nonane-2-carboxylate tert-Butyl 7-(3-(1,3-dioxolan-2-yl)-4-(methoxycarbonyl)phenyl)-2,7-diazaspiro[3.5]nonane-2-carboxylate (712 mg, 1.65 mmol) and TsOH·H2O (380 mg, 2.00 mmol) were dissolved in 10 mL of THF and stirred at room temperature for 1 h. Water was added to the reaction mixture, and the mixture was extracted twice with EA. The organic phases were combined, washed successively with saturated NaHCO3 solution and NaCl solution, dried over anhydrous sodium sulfate, rotary evaporated, and purified by column chromatography and dried to obtain the target compound (499 mg, 1.28 mmol). Yield: 78%. LC / MS (ESI+) calcd for C 21 H 28 N2O5(M + H + ) m / z, 389.2; found, 389.2。

[0169] Step 3: Synthesis of tert-butyl 7-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylate Compound tert-butyl 7-(3-formyl-4-(methoxycarbonyl)phenyl)-2,7-diazaspiro[3.5]nonane-2-carboxylate (499 mg, 1.28 mmol) and 3-aminopiperidine-2,6-dione (249 mg, 1.53 mmol) were dissolved in 20 mL of DCM. DIEA (496 mg, 3.84 mmol) and AcOH (768 mg, 12.80 mmol) were added, and the mixture was stirred at 35 °C for 4 h. After cooling to room temperature, NaBH(OAc)3 (815 mg, 3.84 mmol) was added to the reaction solution, and the mixture was stirred at room temperature overnight. An NH4Cl solution was added, and the mixture was extracted three times with EA. The organic phases were combined, washed with an NaCl solution, dried over anhydrous sodium sulfate, rotary evaporated, and purified by column chromatography and dried to obtain the target compound (329 mg, 0.70 mmol). Yield: 55%. LC / MS (ESI+) calcd for C 25 H 32 N4O5(M + H + ) m / z, 469.2; found, 469.2。

[0170] Step 4: Synthesis of 3-(1-oxo-5-(2,7-diazaspiro[3.5]non-7-yl)isoindolin-2-yl)piperidine-2,6-dione The target compound was prepared in a similar manner to Example 11. LC / MS (ESI+) calcd for C 20 H 24 N4O3(M + H + ) m / z, 369.2; found, 369.2。

[0171] Step 5: Synthesis of 3-(5-(2-((1-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperidin-4-yl)methyl)-2,7-diazaspiro[3.5]non-7-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione The target compound was prepared in a similar manner to Example 11. LC / MS (ESI+) calcd for C 48 H 53 N5O4(M + H + ) m / z, 764.4; found, 764.4. 1 H NMR (400 MHz, DMSO-d6) δ 10.95 (s, 1H), 9.15 (s, 1H), 7.49 (d, J = 8.4 Hz, 1H), 7.19 - 6.98 (m, 5H), 6.88 - 6.76 (m, 2H), 6.65 - 6.57 (m, 2H), 6.56 - 6.44 (m, 3H), 6.19 (d, J = 8.3 Hz, 2H), 5.03 (dd, J = 13.3, 5.1 Hz, 1H), 4.31 (d, J = 16.9 Hz, 1H), 4.22 - 4.05 (m, 2H), 3.69 - 3.48 (m, 7H), 3.04 (d, J = 6.9 Hz, 3H), 2.90 (ddd, J = 18.8, 15.1, 5.9 Hz, 4H), 2.78 (s, 2H), 2.63 - 2.54 (m, 1H), 2.47 - 2.29 (m, 2H), 2.17 - 1.92 (m, 3H), 1.83 (t, J = 5.3 Hz, 3H), 1.72 (d, J = 11.7 Hz, 3H), 1.56 (s, 1H).

[0172] Example 28: 3-(5-(4-((2-(4-((3,4-cis)-7-hydroxy-3-phenylchroman-4-yl)phenyl)-2,7-diazaspiro[3.5]non-7-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione TIFF2025523440000108.tif79170

[0173] Step 1: Synthesis of tert-Butyl 2-(4-(3-bromo-7-((tetrahydro-2H-pyran-2-yl)oxy)-2H-chromen-4-yl)phenyl)-2,7-diazaspiro[3.5]nonane-7-carboxylate Compound tert-Butyl 2-(4-(7-((tetrahydro-2H-pyran-2-yl)oxy)-2H-chromen-4-yl)phenyl)-2,7-diazaspiro[3.5]nonane-7-carboxylate (266 mg, 0.50 mmol) and DIEA (200 mg, 1.50 mmol) were dissolved in 4 mL of DMF. Pyridinium tribromide (239 mg, 0.75 mmol) was added under an ice bath, and the mixture was stirred for 1.5 h under the ice bath. Water was added, and the mixture was extracted 3 times with EA. The organic phases were combined, washed 3 times with an NaCl solution, dried over anhydrous sodium sulfate, rotary evaporated, purified by column chromatography, and dried to obtain the target compound (137 mg, 0.22 mmol). Yield: 45%. LC / MS (ESI+) calcd for C 32 H 39 BrN2O5(M + H + ) m / z, 611.2; found, 611.2。

[0174] Step 2: Synthesis of tert-Butyl 2-(4-(3-phenyl-7-((tetrahydro-2H-pyran-2-yl)oxy)-2H-chromen-4-yl)phenyl)-2,7-diazaspiro[3.5]nonane-7-carboxylate tert-Butyl 2-(4-(3-bromo-7-((tetrahydro-2H-pyran-2-yl)oxy)-2H-chromen-4-yl)phenyl)-2,7-diazaspiro[3.5]nonane-7-carboxylate (136 mg, 0.22 mmol), phenylboronic acid (41 mg, 0.33 mmol), Pd(dppf)Cl2 (15 mg, 0.02 mmol), and K2CO3 (82 mg, 0.60 mmol) were dissolved in 8 mL of 1,4-dioxane and 3 mL of H2O and stirred at 95 °C overnight. The mixture was cooled to room temperature, water was added, and the mixture was extracted three times with EA. The combined organic phases were washed with an NaCl solution, dried over anhydrous sodium sulfate, rotary evaporated, purified by column chromatography, and dried to obtain the target compound (80 mg, 0.13 mmol). Yield: 60%. LC / MS (ESI+) calcd for C 38 H 44 N2O5 (M + H + ) m / z, 609.3; found, 609.3。

[0175] Step 3: Synthesis of tert-Butyl 2-(4-((3S,4R)-3-phenyl-7-((tetrahydro-2H-pyran-2-yl)oxy)chroman-4-yl)phenyl)-2,7-diazaspiro[3.5]nonane-7-carboxylate tert-Butyl 2-(4-(3-phenyl-7-((tetrahydro-2H-pyran-2-yl)oxy)-2H-chromen-4-yl)phenyl)-2,7-diazaspiro[3.5]nonane-7-carboxylate (80 mg, 0.13 mmol) was dissolved in 10 mL of THF and 10 mL of MeOH. Under Ar protection, 20 mg of Pd / C was added, and the reaction was carried out at room temperature overnight in a hydrogen gas atmosphere. The mixture was filtered through celite and rotary evaporated to obtain the target compound (67 mg, 0.11 mmol). Yield: 85%. LC / MS (ESI+) calcd for C 38 H 46 N2O5 (M + H + ) m / z, 611.3; found, 611.3。

[0176] Step 4: Synthesis of tert-Butyl 2-(4-((3S,4R)-7-Hydroxy-3-phenylchroman-4-yl)phenyl)-2,7-diazaspiro[3.5]nonane-7-carboxylate Compound tert-Butyl 2-(4-((3S,4R)-3-Phenyl-7-((tetrahydro-2H-pyran-2-yl)oxy)chroman-4-yl)phenyl)-2,7-diazaspiro[3.5]nonane-7-carboxylate (67 mg, 0.11 mmol) was dissolved in 5 mL of THF, TsOH·H2O (30 mg, 0.16 mmol) was added, and the reaction was carried out at room temperature for 1 h. The reaction solution was diluted with EA, washed once with NaHCO3 solution and once with NaCl solution respectively, dried over anhydrous sodium sulfate, and rotary evaporated to obtain the target compound (43 mg, 0.08 mmol). Yield: 75%. LC / MS (ESI+) calcd for C 33 H 38 N2O4(M + H + ) m / z, 527.3; found, 527.3。

[0177] Step 5: Synthesis of (3S,4R)-4-(4-(2,7-Diazaspiro[3.5]non-2-yl)phenyl)-3-phenylchroman-7-ol Compound tert-Butyl 2-(4-((3S,4R)-7-Hydroxy-3-phenylchroman-4-yl)phenyl)-2,7-diazaspiro[3.5]nonane-7-carboxylate (43 mg, 0.08 mmol) was dissolved in 8 mL of DCM, 2 mL of TFA was added under an ice bath, the ice bath was removed, and the reaction was carried out at room temperature for 30 min. It was concentrated, the residue was dissolved in DCM, adjusted to alkaline with NaHCO3 solution, extracted 3 times with DCM, the organic phases were combined, washed once with NaCl solution, dried over anhydrous sodium sulfate, and rotary evaporated to obtain the target compound (26 mg, 0.06 mmol). Yield: 78%. LC / MS (ESI+) calcd for C 28 H 30 N2O2(M + H + ) m / z, 427.2; found, 427.2。

[0178] Step 6: Synthesis of 3-(5-(4-((2-(4-((3,4-cis)-7-hydroxy-3-phenylchroman-4-yl)phenyl)-2,7-diazaspiro[3.5]non-7-yl)methyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione The target compound was prepared in a similar manner to Example 25. LC / MS (ESI+) calcd for C 47 H 51 N5O5(M + H + ) m / z, 766.4; found, 766.4. 1 H NMR (400 MHz, DMSO-d6) δ 10.94 (s, 1H), 9.21 (s, 1H), 7.48 (d, J = 8.7 Hz, 1H), 7.41 - 7.25 (m, 6H), 7.01 (d, J = 7.9 Hz, 2H), 6.92 (dd, J = 8.4, 2.1 Hz, 1H), 6.76 (d, J = 2.1 Hz, 1H), 6.55 (dd, J = 19.9, 8.3 Hz, 2H), 6.24 - 6.15 (m, 2H), 5.03 (dd, J = 13.3, 5.1 Hz, 1H), 4.22 - 3.95 (m, 5H), 3.83 (d, J = 12.3 Hz, 2H), 3.11 (s, 5H), 2.96 - 2.69 (m, 5H), 2.62 - 2.53 (m, 1H), 2.35 (qd, J = 13.1, 4.5 Hz, 2H), 1.98 - 1.92 (m, 2H), 1.71 (d, J = 12.6 Hz, 4H), 1.55 (d, J = 5.7 Hz, 5H), 1.22 (s, 2H).

[0179] Example 29: 3-(5-(7-((1-(4-((3,4-cis)-7-hydroxy-3-(1-methyl-1H-pyrazol-4-yl)chroman-4-yl)phenyl)piperidin-4-yl)methyl)-2,7-diazaspiro[3.5]non-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione TIFF2025523440000109.tif36170

[0180] The target compound was prepared in a manner similar to Example 10. LC / MS (ESI+) calcd for C 45 H 51 N7O5(M + H + ) m / z, 770.4; found, 770.4. 1 H NMR (400 MHz, DMSO-d6) δ 10.94 (s, 1H), 9.26 (s, 1H), 7.71 - 7.31 (m, 1H), 7.02 (s, 1H), 6.75 - 6.66 (m, 3H), 6.59 (dd, J = 17.6, 8.3 Hz, 3H), 6.52 - 6.44 (m, 2H), 6.29 - 6.20 (m, 2H), 5.03 (dd, J = 13.2, 5.1 Hz, 1H), 4.29 (d, J = 17.0 Hz, 1H), 4.20 - 4.00 (m, 4H), 3.67 (s, 3H), 3.64 - 3.53 (m, 6H), 3.38 (d, J = 5.9 Hz, 2H), 2.97 - 2.77 (m, 1H), 2.57 (d, J = 15.0 Hz, 2H), 2.41 - 2.20 (m, 5H), 2.12 (d, J = 6.7 Hz, 2H), 1.95 (s, 2H), 1.75 (d, J = 8.8 Hz, 6H), 1.62 (s, 2H), 1.45 (s,1H).

[0181] Example 30: 3-(5-(7-((1-(4-((3,4-cis)-3-(2-fluorophenyl)-7-hydroxycoumarin-4-yl)phenyl)piperidin-4-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione TIFF2025523440000110.tif36170

[0182] The target compound was prepared in a manner similar to Example 10. LC / MS (ESI+) calcd for C47 H 50 FN5O5(M + H + ) m / z, 784.4; found, 784.4. 1 1H NMR (400 MHz, DMSO-d6) δ 10.94 (s, 1H), 9.34 (s, 1H), 7.47 (d, J = 8.3 Hz, 1H), 7.22 (q, J = 7.1 Hz, 1H), 7.14 (dd, J = 10.7, 8.1 Hz, 1H), 6.89 (t, J = 7.5 Hz, 1H), 6.67 (d, J = 8.3 Hz, 1H), 6.60 (d, J = 8.4 Hz, 2H), 6.53 - 6.36 (m, 5H), 6.34 - 6.24 (m, 2H), 5.03 (dd, J = 13.3, 5.1 Hz, 1H), 4.43 - 4.07 (m, 5H), 3.70 (dt, J = 11.5, 4.2 Hz, 1H), 3.61 (s, 4H), 3.57 - 3.48 (m, 2H), 2.89 (td, J = 13.2, 6.7 Hz, 1H), 2.62 - 2.54 (m, 1H), 2.47 (s, 1H), 2.41 - 2.16 (m, 5H), 2.10 (d, J = 7.3 Hz, 2H), 1.90 (s, 3H), 1.73 (t, J = 5.3 Hz, 6H), 1.59 (s, 1H).

[0183] Example 31: 3-(5-(6-((1-(4-((1,2-cis)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperidin-4-yl)methyl)-2,6-diazaspiro[3.4]octa-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-one TIFF2025523440000111.tif29170

[0184] The target compound was prepared in a similar manner to Example 10. LC / MS (ESI+) calcd for C 47 H 51 N5O4(M + H+ ) m / z, 750.4; found, 750.4. 1 1H NMR (400 MHz, DMSO-d6) δ 10.96 (s, 1H), 9.15 (s, 1H), 7.50 (d, J = 8.3 Hz, 1H), 7.20 - 7.05 (m, 3H), 6.87 - 6.77 (m, 2H), 6.66 - 6.58 (m, 2H), 6.57 - 6.45 (m, 5H), 6.20 (d, J = 8.4 Hz, 2H), 5.04 (dd, J = 13.3, 5.1 Hz, 1H), 4.30 (d, J = 17.0 Hz, 1H), 4.24 - 4.08 (m, 2H), 3.89 (d, J = 22.9 Hz, 4H), 3.60 (t, J = 6.5 Hz, 1H), 3.56 - 3.46 (m, 2H), 3.32 - 3.21 (m, 3H), 3.12 (d, J = 7.5 Hz, 2H), 3.03 - 2.78 (m, 5H), 2.65 - 2.52 (m, 2H), 2.35 (dd, J = 13.3, 4.5 Hz, 1H), 2.20 - 2.03 (m, 2H), 2.02 - 1.92 (m, 2H), 1.80 (d, J = 12.1 Hz, 2H), 1.70 (d, J = 9.8 Hz, 2H).

[0185] Example 32: 3-(5-(7-((1-(2,6-difluoro-4-((3,4-cis)-3-(2-fluorophenyl)-7-hydroxycoumarin-4-yl)phenyl)piperidin-4-yl)methyl)-2,7-diazaspiro[3.5]non-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione TIFF2025523440000112.tif30170

[0186] The target compound was prepared in a similar manner to Example 10. LC / MS (ESI+) calcd for C 47 H 48 F3N5O5(M + H +) m / z, 820.3; found, 820.3. 1 1H NMR (400 MHz, DMSO-d6) δ 10.95 (s, 1H), 9.45 (s, 1H), 7.48 (d, J = 8.3 Hz, 1H), 7.32 - 7.22 (m, 1H), 7.21 - 7.10 (m, 1H), 6.97 (td, J = 7.5, 1.3 Hz, 1H), 6.70 (d, J = 8.0 Hz, 1H), 6.60 (d, J = 1.7 Hz, 1H), 6.53 - 6.43 (m, 2H), 6.33 (d, J = 7.7 Hz, 2H), 6.13 (d, J = 10.7 Hz, 2H), 5.03 (dd, J = 13.3, 5.1 Hz, 1H), 4.38 - 4.28 (m, 2H), 4.27 (s, 1H), 4.18 (s, 1H), 3.76 (dd, J = 8.7, 3.9 Hz, 1H), 3.62 (s, 4H), 3.02 (d, J = 11.1 Hz, 3H), 2.96 - 2.80 (m, 1H), 2.44 - 2.23 (m, 4H), 2.12 (s, 2H), 1.91 (s, 2H), 1.74 (s, 6H), 1.59 (s, 1H), 1.22 (s, 2H).

[0187] Example 33: 3-(5-(7-((1-(2,6-difluoro-4-((3,4-cis)-3-(2-fluorophenyl)-7-hydroxycoumarin-4-yl)phenyl)piperidin-4-yl)methyl)-2,7-diazaspiro[3.5]non-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione TIFF2025523440000113.tif29170

[0188] The target compound was prepared in a similar manner to Example 10. LC / MS (ESI+) calcd for C 47 H 48 F3N5O5(M + H + ) m / z 820.3; found 820.3. 11H NMR (400 MHz, DMSO-d6) δ 10.95 (s, 1H), 9.42 (s, 1H), 7.48 (d, J = 8.3 Hz, 1H), 7.19 (p, J = 3.7 Hz, 3H), 6.84 (dd, J = 6.7, 2.9 Hz, 2H), 6.69 (d, J = 8.0 Hz, 1H), 6.56 - 6.42 (m, 2H), 6.35 - 6.25 (m, 2H), 6.08 (d, J = 10.7 Hz, 2H), 5.03 (dd, J = 13.3, 5.1 Hz, 1H), 4.35 - 4.26 (m, 3H), 4.16 (d, J = 17.0 Hz, 1H), 3.67 - 3.52 (m, 5H), 3.02 (d, J = 11.2 Hz, 2H), 2.91 (dt, J = 17.3, 9.1 Hz, 3H), 2.63 - 2.53 (m, 1H), 2.41 - 2.23 (m, 4H), 2.13 (s, 2H), 1.98 (dd, J = 14.6, 6.7 Hz, 1H), 1.81 - 1.64 (m, 6H), 1.60 (s, 1H), 1.23 (d, J = 3.4 Hz, 2H).

[0189] Example 34: 3-(5-(7-((1-(4-((3R,4S)-3-(2-Fluorophenyl)-7-hydroxycoumaran-4-yl)phenyl)piperidin-4-yl)methyl)-2,7-diazaspiro[3.5]non-2-yl)-1-oxoisoindol-2-yl)piperidine-2,6-dione TIFF2025523440000114.tif29170

[0190] 1-(4-((3R,4S)-3-(2-Fluorophenyl)-7-hydroxycoumaran-4-yl)phenyl)piperidine-4-carboxaldehyde was prepared in a similar manner to Example 10 using it as a raw material. LC / MS (ESI+) calcd for C 47 H 50 FN5O5(M + H + ) m / z, 784.3; found, 784.3.1 1H NMR (400 MHz, DMSO-d6) δ 10.95 (s, 1H), 9.34 (s, 1H), 7.47 (d, J = 8.3 Hz, 1H), 7.27 - 7.19 (m, 1H), 7.17 - 7.10 (m, 1H), 6.92 - 6.86 (m, 1H), 6.67 (dd, J = 8.3, 2.2 Hz, 1H), 6.60 (d, J = 8.5 Hz, 2H), 6.52 - 6.36 (m, 5H), 6.33 - 6.25 (m, 2H), 5.03 (dd, J = 13.3, 5.1 Hz, 1H), 4.41 - 4.11 (m, 5H), 3.71 (dt, J = 11.2, 4.5 Hz, 1H), 3.62 (s, 4H), 3.53 (d, J = 11.9 Hz, 2H), 2.96 - 2.79 (m, 1H), 2.63 - 2.52 (m, 2H), 2.42 - 2.19 (m, 5H), 2.11 (d, J = 7.3 Hz, 2H), 2.03 - 1.90 (m, 2H), 1.79 - 1.54 (m, 7H), 1.23 (d, J = 3.4 Hz, 2H).

[0191] Example 35: 3-(5-(7-((1-(4-(cis-7-Hydroxy-3-(o-tolyl)chroman-4-yl)phenyl)piperidin-4-yl)methyl)-2,7-diazaspiro[3.5]non-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione TIFF2025523440000115.tif29170

[0192] The target compound was prepared in a similar manner to Example 10. LC / MS (ESI+) calcd for C 48 H 53 N5O5(M + H + ) m / z, 780.4; found, 780.4. 11H NMR (400 MHz, DMSO-d6) δ 10.94 (s, 1H), 9.31 (s, 1H), 7.47 (d, J = 8.3 Hz, 1H), 7.25 - 7.14 (m, 1H), 7.03 (t, J = 7.2 Hz, 1H), 6.78 (t, J = 7.6 Hz, 1H), 6.67 (d, J = 8.2 Hz, 1H), 6.58 (d, J = 8.5 Hz, 2H), 6.52 - 6.43 (m, 2H), 6.37 - 6.21 (m, 4H), 5.99 (d, J = 7.7 Hz, 1H), 5.03 (dd, J = 13.2, 5.1 Hz, 1H), 4.41 - 4.16 (m, 4H), 4.15 - 4.05 (m, 1H), 3.56 (d, J = 44.5 Hz, 6H), 2.96 - 2.79 (m, 1H), 2.62 - 2.53 (m, 1H), 2.40 (s, 3H), 2.37 - 2.20 (m, 4H), 2.10 (d, J = 7.1 Hz, 2H), 1.96 (ddd, J = 18.8, 14.1, 7.8 Hz, 3H), 1.73 (s, 6H), 1.59 (s, 1H), 1.22 (s, 2H).

[0193] Example 36: 3-(5-(7-((1-(4-(cis-3-(2,3-difluorophenyl)-7-hydroxycoumarin-4-yl)phenyl)piperidin-4-yl)methyl)-2,7-diazaspiro[3.5]non-2-yl)-1-oxoisoindol-2-yl)piperidine-2,6-dione TIFF2025523440000116.tif36170

[0194] The target compound was prepared in a similar manner to Example 10. LC / MS (ESI+) calcd for C 47 HF2N5O5(M + H + ) m / z, 802.3; found, 802.3. 11H NMR (400 MHz, DMSO-d6) δ 10.95 (s, 1H), 9.36 (s, 1H), 7.48 (d, J = 8.3 Hz, 1H), 7.25 (dt, J = 11.2, 7.8 Hz, 1H), 6.96 - 6.88 (m, 1H), 6.70 - 6.61 (m, 3H), 6.53 - 6.39 (m, 4H), 6.35 - 6.27 (m, 3H), 5.03 (dd, J = 13.3, 5.1 Hz, 1H), 4.45 - 4.08 (m, 6H), 3.79 - 3.71 (m, 1H), 3.62 (s, 3H), 3.59 - 3.50 (m, 2H), 2.90 (s, 1H), 2.69 - 2.53 (m, 2H), 2.41 - 2.19 (m, 5H), 2.12 (s, 2H), 1.97 (ddt, J = 18.0, 12.4, 7.2 Hz, 3H), 1.72 (d, J = 15.9 Hz, 7H), 1.17 (s, 2H).

[0195] Example 37: 3-(5-(7-((1-(4-(cis-3-(2,6-difluorophenyl)-7-hydroxychroman-4-yl)-2,6-difluorophenyl)(piperidin-4-yl)methyl)-2,7-diazaspiro[3.5]non-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione TIFF2025523440000117.tif30170

[0196] The target compound was prepared in a similar manner to Example 10. LC / MS (ESI+) calcd for C47H47F4N5O5 (M + H+) m / z, 838.3; found, 838.3. 11H NMR (400 MHz, DMSO-d6) δ 10.94 (s, 1H), 9.47 (s, 1H), 7.47 (d, J = 8.3 Hz, 1H), 7.36 (tt, J = 8.3, 6.4 Hz, 1H), 6.99 (t, J = 9.2 Hz, 2H), 6.71 (d, J = 8.3 Hz, 1H), 6.52 - 6.44 (m, 2H), 6.34 (d, J = 7.5 Hz, 2H), 6.18 (d, J = 10.8 Hz, 2H), 5.03 (dd, J = 13.3, 5.1 Hz, 1H), 4.45 (d, J = 11.6 Hz, 1H), 4.34 - 4.23 (m, 2H), 4.22 - 4.12 (m, 2H), 3.83 (ddd, J = 11.9, 5.3, 3.0 Hz, 1H), 3.62 (s, 4H), 3.04 (d, J = 11.1 Hz, 2H), 2.91 (d, J = 13.4 Hz, 3H), 2.62 - 2.53 (m, 1H), 2.41 - 2.23 (m, 4H), 2.12 (d, J = 6.5 Hz, 2H), 1.97 (d, J = 12.8 Hz, 2H), 1.79 - 1.67 (m, 6H), 1.60 (s, 1H), 1.22 (d, J = 3.4 Hz, 2H).

[0197] Example 38: 3-(5-(7-((1-(2,6-Difluoro-4-((3R,4S)-3-(2-fluorophenyl)-7-hydroxycoumarin-4-yl)phenyl)piperidin-4-yl)methyl)-2,7-diazaspiro[3.5]non-2-yl)-1-oxoisoindol-2-yl)piperidine-2,6-dione TIFF2025523440000118.tif29170

[0198] The target compound was prepared in a similar manner to Example 34. LC / MS (ESI+) calcd for C 47 H 48 F3N5O5(M + H + ) m / z 820.3; found 820.3.1 1H NMR (400 MHz, DMSO-d6) δ 10.95 (s, 1H), 9.45 (s, 1H), 7.48 (d, J = 8.2 Hz, 1H), 7.33 - 7.23 (m, 1H), 7.17 (ddd, J = 9.8, 8.4, 1.3 Hz, 1H), 6.97 (td, J = 7.6, 1.3 Hz, 1H), 6.70 (d, J = 8.0 Hz, 1H), 6.60 (td, J = 7.8, 1.7 Hz, 1H), 6.53 - 6.42 (m, 2H), 6.33 (d, J = 7.8 Hz, 2H), 6.13 (d, J = 10.6 Hz, 2H), 5.03 (dd, J = 13.2, 5.1 Hz, 1H), 4.42 - 4.22 (m, 4H), 4.17 (d, J = 16.9 Hz, 1H), 3.76 (dt, J = 10.2, 4.4 Hz, 1H), 3.63 (s, 4H), 3.03 (d, J = 11.1 Hz, 2H), 2.90 (q, J = 12.1, 9.8 Hz, 3H), 2.63 - 2.53 (m, 1H), 2.42 - 2.18 (m, 4H), 2.13 (d, J = 14.2 Hz, 2H), 1.98 - 1.92 (m, 1H), 1.70 (d, J = 19.0 Hz, 7H), 1.18 (d, J = 7.1 Hz, 2H).

[0199] Example 39: 3-(5-(7-((1-(4-((3R,4S)-3-(2,3-difluorophenyl)-7-hydroxycoumarin-4-yl)-2,6-difluorobenzene)piperidin-4-yl)methyl)-2,7-diazaspiro[3.5]non-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-one TIFF2025523440000119.tif30170

[0200] The target compound was prepared in a similar manner to Example 34. LC / MS (ESI+) calcd for C 47 H 47F4N5O5(M + H + ) m / z 838.3; found 838.3. 1 1H NMR (400 MHz, DMSO-d6) δ 10.94 (s, 1H), 9.46 (s, 1H), 7.47 (d, J = 8.3 Hz, 1H), 7.29 (dt, J = 8.2, 1.6 Hz, 1H), 7.04 - 6.90 (m, 1H), 6.75 - 6.62 (m, 1H), 6.57 - 6.41 (m, 3H), 6.33 (d, J = 7.4 Hz, 2H), 6.20 (d, J = 10.7 Hz, 2H), 5.03 (dd, J = 13.3, 5.1 Hz, 1H), 4.42 - 4.29 (m, 2H), 4.25 (d, J = 10.7 Hz, 1H), 4.16 (d, J = 17.0 Hz, 1H), 3.86 - 3.72 (m, 1H), 3.62 (s, 4H), 3.09 - 2.81 (m, 6H), 2.59 (d, J = 3.5 Hz, 1H), 2.44 - 2.20 (m, 4H), 2.10 (d, J = 27.1 Hz, 2H), 1.99 (s, 1H), 1.83 - 1.48 (m, 7H), 1.24 (d, J = 5.6 Hz, 2H).

[0201] Example 40: 3-(5-(7-((1-(4-((3S,4R)-3-(2,6-difluorophenyl)-7-hydroxycoumarin-4-yl)-2,6-difluorophenyl)(piperidin-4-yl)methyl)-2,7-diazaspiro[3.5]non-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-one TIFF2025523440000120.tif29170

[0202] The target compound was prepared in a similar manner to Example 16. LC / MS (ESI+) calcd for C 47 H 47 F4N5O5(M + H + ) m / z 838.3; found 838.3. 11H NMR (400 MHz, DMSO-d6) δ 10.95 (s, 1H), 9.51 (s, 1H), 7.48 (d, J = 8.3 Hz, 1H), 7.41 - 7.29 (m, 1H), 6.99 (t, J = 9.2 Hz, 2H), 6.75 - 6.67 (m, 1H), 6.52 - 6.44 (m, 2H), 6.35 (d, J = 7.1 Hz, 2H), 6.18 (d, J = 10.7 Hz, 2H), 5.03 (dd, J = 13.3, 5.1 Hz, 1H), 4.46 (s, 1H), 4.34 - 4.11 (m, 4H), 3.83 (dq, J = 8.7, 2.7 Hz, 1H), 3.61 (d, J = 26.4 Hz, 6H), 3.14 - 2.84 (m, 8H), 2.62 - 2.53 (m, 1H), 2.34 (dd, J = 13.2, 4.6 Hz, 2H), 1.98 - 1.92 (m, 1H), 1.78 (d, J = 43.9 Hz, 7H), 1.22 - 1.10 (m, 2H).

[0203] Example 41: 3-(5-(7-((1-(4-((3R,4S)-3-(2,6-difluorophenyl)-7-hydroxycoumarin-4-yl)-2,6-difluorophenyl)(piperidin-4-yl)methyl)-2,7-diazaspiro[3.5]non-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-one TIFF2025523440000121.tif29170

[0204] The target compound was prepared in a similar manner to Example 34. LC / MS (ESI+) calcd for C 47 H 47 F4N5O5(M + H + ) m / z 838.3; found 838.3. 11H NMR (400 MHz, DMSO-d6) δ 10.94 (s, 1H), 9.47 (s, 1H), 7.47 (d, J = 8.3 Hz, 1H), 7.36 (tt, J = 8.3, 6.4 Hz, 1H), 6.99 (t, J = 9.2 Hz, 2H), 6.71 (d, J = 8.3 Hz, 1H), 6.52 - 6.44 (m, 2H), 6.34 (d, J = 7.5 Hz, 2H), 6.18 (d, J = 10.8 Hz, 2H), 5.03 (dd, J = 13.3, 5.1 Hz, 1H), 4.45 (d, J = 11.6 Hz, 1H), 4.34 - 4.23 (m, 2H), 4.22 - 4.12 (m, 2H), 3.83 (ddd, J = 11.9, 5.3, 3.0 Hz, 1H), 3.62 (s, 4H), 3.04 (d, J = 11.1 Hz, 2H), 2.91 (d, J = 13.4 Hz, 3H), 2.62 - 2.53 (m, 1H), 2.41 - 2.23 (m, 4H), 2.12 (d, J = 6.5 Hz, 2H), 1.97 (d, J = 12.8 Hz, 2H), 1.79 - 1.67 (m, 6H), 1.60 (s, 1H), 1.22 (d, J = 3.4 Hz, 2H).

[0205] Example 42: 3-(5-(7-((1-(4-(3-(2,6-difluorophenyl)-7-hydroxy-2H-chromen-4-yl)-2,6-difluorophenyl)(piperidin-4-yl)methyl)-2,7-diazaspiro[3.5]non-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione TIFF2025523440000122.tif80170

[0206] Step 1: Synthesis of 3-(2,6-difluorophenyl)-4-(4-(4-dimethoxymethyl)piperidin-1-yl)-3,5-difluorophenyl)-2H-chromen-7-ol Compound 1-(4-(7-(benzyloxy)-3-(2,6-difluorophenyl)-2h-chromen-4-yl)-2,6-difluorophenyl]-4-(dimethoxymethyl)piperidine (200 mg, 0.32 mmol) was dissolved in 10 mL of EA and 10 mL of MeOH, Pd / C (50 mg, 10%) was added, and the reaction was carried out for 2 h under a hydrogen gas atmosphere. It was filtered through celite, the filter cake was washed with DCM / MeOH = 10:1, and the filtrate was concentrated to obtain the target compound (138 mg, 0.26 mmol). Yield: 82%. LC / MS (ESI+) calcd for C 29 H 27 F4NO4(M + H + ) m / z, 530.2; found, 530.2。

[0207] Step 2: Synthesis of 1-(4-(3-(2,6-difluorophenyl)-7-hydroxy-2H-chromen-4-yl)-2,6-difluorophenyl)piperidine-4-carboxaldehyde The target compound was prepared in a similar manner to Example 23. LC / MS (ESI+) calcd for C 27 H 21 F4NO3(M + H + ) m / z, 484.1; found, 484.1。

[0208] Step 3: Synthesis of 3-(5-(7-((1-(4-(3-(2,6-difluorophenyl)-7-hydroxy-2H-chromen-4-yl)-2,6-difluorophenyl(piperidin-4-yl)methyl)-2,7-diazaspiro[3.5]non-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione The target compound was prepared in a similar manner to Example 23. LC / MS (ESI+) calcd for C 47 H 45 F4N5O5(M + H + ) m / z 836.3; found 836.3. 11H NMR (400 MHz, DMSO-d6) δ 10.95 (s, 1H), 9.93 (s, 1H), 7.50 (d, J = 8.2 Hz, 1H), 7.39 - 7.29 (m, 1H), 7.04 (t, J = 7.9 Hz, 2H), 6.69 - 6.58 (m, 3H), 6.54 - 6.44 (m, 2H), 6.40 - 6.34 (m, 2H), 5.04 (dd, J = 13.2, 5.1 Hz, 1H), 4.82 (s, 2H), 4.31 (d, J = 17.0 Hz, 1H), 4.18 (d, J = 16.9 Hz, 1H), 3.85 - 3.52 (m, 6H), 3.13 (q, J = 9.8, 7.2 Hz, 4H), 3.05 - 2.84 (m, 5H), 2.60 (d, J = 3.6 Hz, 2H), 2.43 - 2.27 (m, 2H), 2.04 - 1.92 (m, 4H), 1.78 (d, J = 12.6 Hz, 2H), 1.24 - 1.19 (m, 2H).

[0209] Example 43: 3-(5-(7-((1-(4-(7-(Benzyloxy)-3-(2,6-difluorophenyl)-2H-chromen-4-yl)-2,6-difluorophenyl)(piperidin-4-yl)methyl)-2,7-diazaspiro[3.5]non-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione TIFF2025523440000123.tif32170

[0210] The target compound was prepared in a manner similar to Example 42. LC / MS (ESI+) calcd for C 54 H 51 F4N5O5(M + H + ) m / z 926.3; found 926.3. 11H NMR (400 MHz, DMSO-d6) δ 10.95 (s, 1H), 7.47 - 7.30 (m, 7H), 7.05 (t, J = 8.0 Hz, 2H), 6.72 (d, J = 8.5 Hz, 1H), 6.63 (ddd, J = 19.7, 7.3, 3.0 Hz, 4H), 6.54 - 6.44 (m, 2H), 5.12 (s, 2H), 5.04 (dd, J = 13.2, 5.1 Hz, 1H), 4.30 (d, J = 17.0 Hz, 1H), 4.17 (d, J = 17.0 Hz, 1H), 3.82 - 3.55 (m, 7H), 3.13 (q, J = 7.9, 7.4 Hz, 5H), 3.04 - 2.84 (m, 5H), 2.63 - 2.54 (m, 1H), 2.35 (tt, J = 14.0, 6.9 Hz, 2H), 1.97 (td, J = 14.3, 11.7, 6.7 Hz, 4H), 1.75 (d, J = 12.4 Hz, 3H), 1.22 (s, 2H).

[0211] Example 44: (R)-3-(5-(7-((1-(4-((3S,4R)-3-(2,6-difluorophenyl)-7-hydroxychroman-4-yl)-2,6-difluorophenyl)(piperidin-4-yl)methyl)-2,7-diazaspiro[3.5]non-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione Example 45: (S)-3-(5-(7-((1-(4-((3S,4R)-3-(2,6-difluorophenyl)-7-hydroxychroman-4-yl)-2,6-difluorophenyl)(piperidin-4-yl)methyl)-2,7-diazaspiro[3.5]non-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione TIFF2025523440000124.tif46170

[0212] Compound 40 of the example was resolved by chiral SFC to obtain the target product. The chiral column was CHIRALPAK AS (30*250mm 5μm) (Daicel), and the mobile phase was A = CO2, Co-Solvent B = IPA / ACN = 1 / 1 (0.1% 7M NH3In MeOH).

[0213] The first component is Example 44. LC / MS (ESI+) calcd for C 47 H 47 F4N5O5(M + H + ) m / z 838.3; found 838.3. 1 H NMR (400 MHz, DMSO-d6) δ 10.95 (s, 1H), 9.47 (s, 1H), 7.47 (d, J = 8.3 Hz, 1H), 7.41 - 7.27 (m, 1H), 6.99 (t, J = 9.2 Hz, 2H), 6.71 (d, J = 8.2 Hz, 1H), 6.53 - 6.42 (m, 2H), 6.34 (d, J = 7.6 Hz, 2H), 6.18 (d, J = 10.8 Hz, 2H), 5.03 (dd, J = 13.3, 5.1 Hz, 1H), 4.46 (s, 1H), 4.34 - 4.24 (m, 2H), 4.22 - 4.10 (m, 2H), 3.89 - 3.77 (m, 1H), 3.62 (s, 4H), 3.09 - 2.82 (m, 5H), 2.54 (s, 1H), 2.41 - 2.20 (m, 4H), 2.12 (d, J = 6.8 Hz, 2H), 1.93 (dd, J = 12.0, 6.3 Hz, 1H), 1.71 (d, J = 20.5 Hz, 7H), 1.23 (s, 2H).

[0214] The second component is Example 45. LC / MS (ESI+) calcd for C 47 H 47 F4N5O5(M + H + ) m / z 838.3; found 838.3. 11H NMR (400 MHz, DMSO-d6) δ 10.95 (s, 1H), 9.47 (s, 1H), 7.47 (d, J = 8.3 Hz, 1H), 7.41 - 7.27 (m, 1H), 6.99 (t, J = 9.2 Hz, 2H), 6.71 (d, J = 8.2 Hz, 1H), 6.53 - 6.42 (m, 2H), 6.34 (d, J = 7.6 Hz, 2H), 6.18 (d, J = 10.8 Hz, 2H), 5.03 (dd, J = 13.3, 5.1 Hz, 1H), 4.46 (s, 1H), 4.34 - 4.24 (m, 2H), 4.22 - 4.10 (m, 2H), 3.89 - 3.77 (m, 1H), 3.62 (s, 4H), 3.09 - 2.82 (m, 5H), 2.54 (s, 1H), 2.41 - 2.20 (m, 4H), 2.12 (d, J = 6.8 Hz, 2H), 1.93 (dd, J = 12.0, 6.3 Hz, 1H), 1.71 (d, J = 20.5 Hz, 7H), 1.23 (s, 2H).

[0215] Example 46: 3-(5-(7-((1-(4-(cis-3-(2,4-difluorophenyl)-7-hydroxychroman-4-yl)phenyl)piperidin-4-yl)methyl)-2,7-diazaspiro[3.5]non-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione TIFF2025523440000125.tif62170

[0216] Step 1: Synthesis of 1-(4-(3-(2,4-difluorophenyl)-7-((tetrahydro-2H-pyran-2-yl)oxy)-2H-chromen-4-yl)phenyl)-4-(dimethoxymethyl)piperidine To the reaction flask, 1-(4-(3-bromo-7-((tetrahydro-2H-pyran-2-yl)oxy)-2H-chromen-4-yl)phenyl)-4-(dimethoxymethyl)piperidine (120 mg, 0.22 mmol), 2,4-difluorophenylboronic acid (70 mg, 0.44 mmol), Pd(dppf)Cl2 (16 mg, 0.02 mmol), potassium carbonate (76 mg, 0.66 mmol) and dioxane (8 mL) were added. The system was purged with nitrogen gas and reacted at 95 °C overnight. The reaction was monitored by TLC until the raw materials were completely reacted. After cooling to room temperature, it was filtered through celite, concentrated and subjected to column chromatography to obtain 100 mg of the product, which was identified as the target compound by LC-MS. Yield: 78%. LC / MS (ESI + ) calcd for C 34 H 37 F2NO5(M+H + ) m / z, 578.2; found, 578.2。

[0217] Step 2: Synthesis of 1-(4-(cis-3-(2,4-difluorophenyl)-7-((tetrahydro-2H-pyran-2-yl)oxy)chroman-4-yl)phenyl)-4-(dimethoxymethyl)piperidine 1-(4-(3-(2,4-Difluorophenyl)-7-((tetrahydro-2H-pyran-2-yl)oxy)-2H-chromen-4-yl)phenyl)-4-(dimethoxymethyl)piperidine (100 mg, 0.17 mmol) was dissolved in THF (25 mL), methanol (25 mL) was added, 10% palladium on carbon (20 mg, 20%) was added, the system was purged with hydrogen gas and reacted at room temperature overnight. The reaction was monitored by TLC until the raw materials were completely reacted. It was filtered through celite to remove palladium on carbon, concentrated and subjected to column chromatography to obtain 80 mg of the product, which was identified as the target compound by LC-MS. Yield 81%. LC / MS (ESI+) calcd for C 34 H 39 F2NO5(M + H + ) m / z, 580.2; found, 580.2。

[0218] Step 3: Synthesis of 1-(4-(cis-3-(2,4-difluorophenyl)-7-hydroxychroman-4-yl)phenyl)piperidine-4-carboxaldehyde Dissolve 1-(4-(cis-3-(2,4-difluorophenyl)-7-((tetrahydro-2H-pyran-2-yl)oxy)chroman-4-yl)phenyl)-4-(dimethoxymethyl)piperidine (80 mg, 0.14 mmol) in THF (4 mL), add sulfuric acid (1 mL, 2 M), react at 60 °C for half an hour, and continue until MS indicates that the raw materials have completely reacted. After cooling to room temperature, adjust the pH to about 8 with saturated sodium bicarbonate, extract with ethyl acetate, wash with saturated sodium chloride, dry and concentrate, and subject to column chromatography to obtain 42 mg of the crude product, which was used directly in the next step. Yield 54%. LC / MS (ESI+) calcd for C 27 H 25 F2NO3(M + H + ) m / z, 450.5; found, 450.5。

[0219] Step 4: Synthesis of 3-(5-(7-((1-(4-(cis-3-(2,4-difluorophenyl)-7-hydroxychroman-4-yl)phenyl)piperidine-4-yl)methyl)-2,7-diazaspiro[3.5]non-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione 3-(1-Oxo-5-(2,7-diazaspiro[3.5]non-2-yl)isoindolin-2-yl)piperidine-2,6-dione trifluoroacetate (50 mg, 0.1 mmol) was dissolved in dichloromethane / methanol (2 mL, 10:1), DIPEA (40 mg, 0.3 mmol) was added, and the mixture was stirred at room temperature for 5 min. 1-(4-(cis-3-(2,4-Difluorophenyl)-7-hydroxycoumarin-4-yl)phenyl)piperidine-4-carboxaldehyde (40 mg, 0.09 mmol) was added, glacial acetic acid (22 mg, 0.3 mmol) was added, the mixture was stirred at room temperature for 0.5 h, sodium triacetoxyborohydride (42 mg, 0.2 mmol) was added, and the reaction was allowed to proceed overnight. The reaction was monitored by TLC until the raw materials were completely reacted, and saturated sodium bicarbonate solution was added to quench the reaction. The mixture was extracted with dichloromethane, dried and concentrated, and subjected to column chromatography to obtain 2 mg of the product, which was identified as the target compound by LC-MS. The yield was 3%. LC / MS (ESI+) calcd for C 47 H 49 F2N5O5(M + H + ) m / z, 802.3; found, 802.3。

[0220] Example 47: 3-(5-(7-((1-(4-(cis-3-(2,5-Difluorophenyl)-7-hydroxycoumarin-4-yl)phenyl)piperidine-4-yl)methyl)-2,7-diazaspiro[3.5]non-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione TIFF2025523440000126.tif55170

[0221] Step 1: Synthesis of 1-(4-(3-(2,5-Difluorophenyl)-7-((tetrahydro-2H-pyran-2-yl)oxy)-2H-chromen-4-yl)-2-fluorophenyl)-4-(dimethoxymethyl)piperidine The target compound was prepared in a similar manner to Example 10. LC / MS (ESI+) calcd for C 34 H 37 F2NO5(M + H+ ) m / z, 578.2; found, 578.2。

[0222] Step 2: Synthesis of 1-(4-(3-(2,5-difluorophenyl)-7-((tetrahydro-2H-pyran-2-yl)oxy)chroman-4-yl)phenyl)-4-(dimethoxymethyl)piperidine The target compound was prepared in a similar manner to Example 10. LC / MS (ESI+) calcd for C 34 H 39 F2NO5(M + H + ) m / z, 580.2; found, 580.2。

[0223] Step 3: Synthesis of 1-(4-(3-(2,5-difluorophenyl)-7-hydroxychroman-4-yl)phenyl)piperidine-4-carboxaldehyde The target compound was prepared in a similar manner to Example 10. LC / MS (ESI+) calcd for C 27 H 25 F2NO3(M + H + ) m / z, 450.5; found, 450.5。

[0224] Step 4: Synthesis of 3-(5-(7-((1-(4-(cis-3-(2,5-difluorophenyl)-7-hydroxychroman-4-yl)phenyl)piperidine-4-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione The target compound was prepared in a similar manner to Example 10. LC / MS (ESI+) calcd for C 47 H 49 F2N5O5(M + H + ) m / z, 802.3; found, 802.3。

[0225] Example 48: 3-(5-(7-((1-(2,6-difluoro-4-(cis-3-(2,3-difluorophenyl)-7-hydroxychroman-4-yl)phenyl)piperidin-4-yl)methyl)-2,7-diazaspiro[3.5]non-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione TIFF2025523440000127.tif32170

[0226] The target compound was prepared in a manner similar to Example 10. LC / MS (ESI+) calcd for C 47 H 47 F4N5O5(M + H + ) m / z, 838.3; found, 838.3。 1 H NMR (400 MHz, DMSO-d6) δ 10.94 (s, 1H), 9.46 (s, 1H), 7.47 (d, J = 8.3 Hz, 1H), 7.35-7.24 (m, 1H), 7.03-6.93 (m, 1H), 6.73-6.66 (m, 1H), 6.53-6.42 (m, 3H), 6.33 (d, J = 7.3 Hz, 2H), 6.20 (d, J = 10.7 Hz, 2H), 5.03 (dd, J = 13.3, 5.1 Hz, 1H), 4.42-4.20 (m, 4H), 4.16 (d, J = 16.9 Hz, 1H), 3.80 (ddd, J = 9.7, 5.6, 3.4 Hz, 1H), 3.62 (s, 4H), 3.03 (d, J = 11.3 Hz, 2H), 2.89 (td, J = 13.4, 5.5 Hz, 3H), 2.62-2.53 (m, 1H), 2.38-2.28 (m, 3H), 2.13 (d, J = 6.7 Hz, 2H), 1.97 (d, J = 13.4 Hz, 1H), 1.77-1.65 (m, 6H), 1.60 (s, 1H), 1.22 (s, 2H).

[0227] Example 49: 3-(5-(7-((1-(4-((3S,4R)-3-(2,3-difluorophenyl)-7-hydroxy-4-chromanyl)-2,6-difluorobenzene)piperidin-4-yl)methyl)-2,7-diazaspiro[3.5]non-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione TIFF2025523440000128.tif32170

[0228] The target compound was prepared in a similar manner to Example 16. LC / MS (ESI+) calcd for C 47 H 47 F4N5O5(M + H + ) m / z, 838.3; found, 838.3。 1 H NMR (400 MHz, DMSO-d6) δ 10.94 (s, 1H), 9.46 (s, 1H), 7.47 (d, J = 8.3 Hz, 1H), 7.35-7.24 (m, 1H), 7.03-6.93 (m, 1H), 6.73-6.66 (m, 1H), 6.53-6.42 (m, 3H), 6.33 (d, J = 7.3 Hz, 2H), 6.20 (d, J = 10.7 Hz, 2H), 5.03 (dd, J = 13.3, 5.1 Hz, 1H), 4.42-4.20 (m, 4H), 4.16 (d, J = 16.9 Hz, 1H), 3.80 (ddd, J = 9.7, 5.6, 3.4 Hz, 1H), 3.62 (s, 4H), 3.03 (d, J = 11.3 Hz, 2H), 2.89 (td, J = 13.4, 5.5 Hz, 3H), 2.62-2.53 (m, 1H), 2.38-2.28 (m, 3H), 2.13 (d, J = 6.7 Hz, 2H), 1.97 (d, J = 13.4 Hz, 1H), 1.77-1.65 (m, 6H), 1.60 (s, 1H), 1.22 (s, 2H).

[0229] Example 50: 3-(5-(7-((1-(4-((3S,4R)-3-(2-Fluorophenyl)-7-hydroxycoumaran-4-yl)-2,6-difluorobenzene)piperidin-4-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-one TIFF2025523440000129.tif29170

[0230] The target compound was prepared in a manner similar to Example 16. LC / MS (ESI+) calcd for C 47 H 48 F3N5O5(M + H + ) m / z, 820.3.; found, 820.3。 11H NMR (400 MHz, DMSO-d6) δ 10.95 (s, 1H), 9.45 (s, 1H), 7.48 (d, J = 8.2 Hz, 1H), 7.33 - 7.23 (m, 1H), 7.17 (ddd, J = 9.8, 8.4, 1.3 Hz, 1H), 6.97 (td, J = 7.6, 1.3 Hz, 1H), 6.70 (d, J = 8.0 Hz, 1H), 6.60 (td, J = 7.8, 1.7 Hz, 1H), 6.53 - 6.42 (m, 2H), 6.33 (d, J = 7.8 Hz, 2H), 6.13 (d, J = 10.6 Hz, 2H), 5.03 (dd, J = 13.2, 5.1 Hz, 1H), 4.42 - 4.22 (m, 4H), 4.17 (d, J = 16.9 Hz, 1H), 3.76 (dt, J = 10.2, 4.4 Hz, 1H), 3.63 (s, 4H), 3.03 (d, J = 11.1 Hz, 2H), 2.90 (q, J = 12.1, 9.8 Hz, 3H), 2.63 - 2.53 (m, 1H), 2.42 - 2.18 (m, 4H), 2.13 (d, J = 14.2 Hz, 2H), 1.98 - 1.92 (m, 1H), 1.70 (d, J = 19.0 Hz, 7H), 1.18 (d, J = 7.1 Hz, 2H).

[0231] Example 51: 3-(5-(7-((1-(4-(cis-7-(Benzyloxy)-3-(2-fluorophenyl)chroman-4-yl)-2,6-difluorophenyl)piperidin-4-yl)methyl)-2,7-diazaspiro[3.5]non-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-one TIFF2025523440000130.tif29170

[0232] The target compound was prepared in a manner similar to Example 10. LC / MS (ESI+) calcd for C 54 H 54 F3N5O5(M + H +) m / z, 910.4; found, 910.4。 1 1H NMR (400 MHz, DMSO-d6) δ 10.95 (s, 1H), 7.51 - 7.41 (m, 4H), 7.41 - 7.31 (m, 3H), 7.27 (dtd, J = 7.3, 5.9, 5.0, 1.7 Hz, 1H), 7.22 - 7.14 (m, 1H), 7.14 - 7.02 (m, 1H), 6.71 - 6.65 (m, 1H), 6.65 - 6.59 (m, 2H), 6.59 - 6.54 (m, 1H), 6.52 - 6.43 (m, 2H), 5.10 (d, J = 8.4 Hz, 2H), 5.03 (dd, J = 13.2, 5.1 Hz, 1H), 4.46 - 4.21 (m, 4H), 4.16 (d, J = 16.9 Hz, 1H), 3.78 (dt, J = 10.6, 4.6 Hz, 1H), 3.63 (s, 4H), 3.02 (d, J = 11.4 Hz, 2H), 2.94 (d, J = 5.4 Hz, 3H), 2.92 - 2.84 (m, 2H), 2.62 - 2.53 (m, 1H), 2.34 (dd, J = 18.2, 9.5 Hz, 3H), 2.12 (s, 2H), 2.03 - 1.92 (m, 2H), 1.72 (d, J = 13.5 Hz, 6H), 1.60 (s, 1H) 1.33 (s, 2H) 。

[0233] Example 52: 3-(5-(7-((1-(4-(cis-7-(Benzyloxy)-3-(2-fluorophenyl)chroman-4-yl)-2,6-difluorophenyl)piperidin-4-yl)methyl)-2,7-diazaspiro[3.5]non-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-one TIFF2025523440000131.tif32170

[0234] The target compound was prepared in a similar manner to Example 42. LC / MS (ESI+) calcd for C 54 H 52 F3N5O5(M + H+ ) m / z, 908.3; found, 908.3。 1 1H NMR (400 MHz, DMSO-d6) δ 10.95 (s, 1H), 7.50 - 7.41 (m, 4H), 7.40 - 7.32 (m, 3H), 7.28 (dddd, J = 12.5, 7.9, 5.5, 3.0 Hz, 1H), 7.20 - 7.11 (m, 1H), 7.08 (td, J = 7.3, 5.0 Hz, 2H), 6.69 (d, J = 9.0 Hz, 3H), 6.63 (d, J = 2.5 Hz, 1H), 6.59 (dd, J = 8.6, 2.5 Hz, 1H), 6.53 - 6.43 (m, 2H), 5.11 (s, 2H), 5.03 (dd, J = 13.3, 5.1 Hz, 1H), 4.29 (d, J = 17.0 Hz, 1H), 4.16 (d, J = 16.9 Hz, 1H), 3.62 (s, 4H), 3.14 (d, J = 11.3 Hz, 2H), 3.03 - 2.83 (m, 3H), 2.63 - 2.53 (m, 1H), 2.35 - 2.24 (m, 3H), 2.16 (d, J = 15.0 Hz, 2H), 2.02 - 1.91 (m, 2H), 1.72 (d, J = 17.4 Hz, 6H), 1.64 (s, 1H), 1.22 (s, 2H).

[0235] Example 53. 2-(2,6-Dioxopiperidin-3-yl)-5-(7-((1-(4-((1R,2S)-6-Hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperidin-4-yl)methyl)-2,7-diazaspiro[4.4]nona-2-yl)isoindoline-1,3-dione TIFF2025523440000132.tif28170

[0236] Dissolve 2-(2,6-dioxopiperidin-3-yl)-5-(2,7-diazaspiro[4.4]non-2-yl)isoindoline-1,3-dione hydrochloride (36 mg, 0.075 mmol) in a 5 mL mixed solution of dichloromethane / methanol = 5:1, add N,N-diisopropylethylamine (13 mg, 0.1 mmol), stir at room temperature for 10 minutes, add 1-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperidine-4-carboxaldehyde (20 mg, 0.05 mmol) and glacial acetic acid (6 mg, 0.1 mmol), stir at room temperature for 10 minutes, add sodium triacetoxyborohydride (21 mg, 0.1 mmol), stir at room temperature for 3 hours, wash with water, extract with dichloromethane, dry, concentrate to dryness under reduced pressure, and separate and purify by thin layer chromatography to obtain 15 mg of the product 2-(2,6-dioxopiperidin-3-yl)-5-(7-((1-(4-((1R,2S)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperidine-4-yl)methyl)-2,7-diazaspiro[4.4]non-2-yl)isoindoline-1,3-dione. Yield: 39%. LC / MS (ESI+) calcd for C 48 H 51 N5O5([M+H] + ) m / e 778.4, found 778.4; 11H NMR (400 MHz, DMSO-d6) δ 7.63 (d, J = 8.4 Hz, 1H), 7.13 (qd, J = 7.4, 6.1, 2.9 Hz, 3H), 6.88 (d, J = 2.2 Hz, 1H), 6.81 (ddd, J = 12.5, 8.3, 2.1 Hz, 3H), 6.63 (d, J = 8.4 Hz, 1H), 6.59 (d, J = 2.6 Hz, 1H), 6.51 (d, J = 8.8 Hz, 2H), 6.47 (dd, J = 8.2, 2.6 Hz, 1H), 6.18 (d, J = 8.4 Hz, 2H), 5.05 (dd, J = 12.9, 5.4 Hz, 1H), 4.11 (d, J = 5.0 Hz, 1H), 3.26 (s, 2H), 3.01 - 2.84 (m, 4H), 2.65 - 2.56 (m, 2H), 2.56 - 2.51 (m, 2H), 2.47 - 2.38 (m, 3H), 2.28 - 2.21 (m, 2H), 2.15 - 2.07 (m, 1H), 2.06 - 1.88 (m, 4H), 1.79 - 1.67 (m, 5H), 1.49 (s, 1H), 1.23 (d, J = 3.5 Hz, 1H), 1.13 (d, J = 12.2 Hz, 2H).

[0237] Example 54. 2-(2,6-Dioxopiperidin-3-yl)-5-(6-((1-(4-((1R,2S)-6-Hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperidin-4-yl)methyl)-2,6-diazaspiro[3.3]heptan-2-yl)isoindoline-1,3-dione TIFF2025523440000133.tif29170

[0238] Prepared in a similar manner to Example 1. LC / MS (ESI+) calcd for C 48 H 51 N5O5([M+H] + ) m / e 750.4, found 750.4, 11H NMR (400 MHz, DMSO-d6) δ 10.94 (s, 1H), 9.12 (s, 1H), 7.48 (d, J = 8.3 Hz, 1H), 7.17 - 7.08 (m, 3H), 6.86 - 6.79 (m, 2H), 6.64 (d, J = 8.4 Hz, 1H), 6.59 (d, J = 2.5 Hz, 1H), 6.55 - 6.49 (m, 3H), 6.47 (ddd, J = 7.4, 4.8, 2.3 Hz, 2H), 6.19 (d, J = 8.3 Hz, 2H), 5.02 (dd, J = 13.3, 5.1 Hz, 1H), 4.29 (d, J = 17.0 Hz, 1H), 4.16 (d, J = 17.0 Hz, 1H), 4.12 (d, J = 5.0 Hz, 1H), 3.95 (d, J = 4.7 Hz, 4H), 3.50 - 3.45 (m, 2H), 3.28 (s, 4H), 3.01 - 2.83 (m, 3H), 2.62 - 2.53 (m, 1H), 2.48 - 2.38 (m, 2H), 2.34 (dd, J = 13.2, 4.5 Hz, 1H), 2.24 (d, J = 6.7 Hz, 2H), 2.14 - 2.06 (m, 1H), 1.99 - 1.90 (m, 1H), 1.67 (d, J = 12.1 Hz, 3H), 1.32 (d, J = 9.5 Hz, 1H).

[0239] Example 55. 2-(2,6-Dioxopiperidin-3-yl)-5-(3-(4-(4-((1R,2S)-6-Hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)azetidin-1-yl)isoindoline-1,3-dione TIFF2025523440000134.tif30170

[0240] Prepared in a manner similar to Example 1. LC / MS (ESI+) calcd for C 42 H 41 N5O5([M+H] +) m / e 696.3, found 696.3; 1 1H NMR (400 MHz, DMSO-d6) δ 11.03 (s, 1H), 9.12 (s, 1H), 7.64 (d, J = 8.3 Hz, 1H), 7.19 - 7.08 (m, 3H), 6.88 - 6.81 (m, 2H), 6.79 (d, J = 2.1 Hz, 1H), 6.68 - 6.61 (m, 2H), 6.60 (d, J = 2.5 Hz, 1H), 6.55 (d, J = 8.6 Hz, 2H), 6.47 (dd, J = 8.3, 2.6 Hz, 1H), 6.21 (d, J = 8.5 Hz, 2H), 5.05 (dd, J = 12.9, 5.4 Hz, 1H), 4.18 - 4.05 (m, 3H), 3.87 (dd, J = 8.9, 4.9 Hz, 2H), 3.31 - 3.23 (m, 2H), 3.01 (t, J = 4.9 Hz, 4H), 2.98 - 2.81 (m, 3H), 2.62 - 2.55 (m, 1H), 2.54 (d, J = 3.0 Hz, 1H), 2.46 (d, J = 4.9 Hz, 4H), 2.18 - 2.05 (m, 1H), 2.05 - 1.96 (m, 1H), 1.70 (s, 1H).

[0241] Example 56. 3-(5-(6-((1-(4-((3R,4S)-7-Hydroxy-3-phenyl-chroman-4-yl)phenyl)piperidin-4-yl)methyl)-2,6-diazaspiro[3.3]hept-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-one TIFF2025523440000135.tif29170

[0242] The target compound was prepared in a similar manner to Example 24. LC / MS (ESI+) calcd for C 45 H 47 N5O5([M+H] + ) m / e 738.4, found 738.4. 11H NMR (400 MHz, DMSO-d6) δ 10.94 (s, 1H), 9.32 (s, 1H), 7.48 (d, J = 8.3 Hz, 1H), 7.14 (p, J = 3.7 Hz, 3H), 6.75 (dd, J = 6.6, 3.0 Hz, 2H), 6.65 (d, J = 8.3 Hz, 1H), 6.59 (d, J = 8.5 Hz, 2H), 6.51 (d, J = 1.9 Hz, 1H), 6.47 (dd, J = 8.3, 2.0 Hz, 1H), 6.37 (d, J = 8.4 Hz, 2H), 6.30 (d, J = 2.5 Hz, 1H), 6.27 (dd, J = 8.2, 2.4 Hz, 1H), 5.02 (dd, J = 13.3, 5.1 Hz, 1H), 4.36 - 4.25 (m, 2H), 4.16 (dd, J = 11.0, 6.1 Hz, 3H), 3.98 (s, 4H), 3.54 - 3.49 (m, 6H), 3.03 (s, 1H), 2.96 - 2.85 (m, 2H), 2.57 (d, J = 23.6 Hz, 2H), 2.45 (s, 2H), 2.40 - 2.28 (m, 2H), 2.00 - 1.92 (m, 1H), 1.68 (d, J = 12.5 Hz, 2H), 1.39 (s, 1H), 1.22 (m, J = 3.2 Hz, 2H).

[0243] Example 57. 3-(5-(6-((1-(4-((3S,4R)-7-Hydroxy-3-phenyl-chroman-4-yl)phenyl)piperidin-4-yl)methyl)-2,6-diazaspiro[3.3]heptan-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-one TIFF2025523440000136.tif30170

[0244] The target compound was prepared in a manner similar to Example 16. LC / MS (ESI+) calcd for C 45 H 47 N5O5([M+H] +) m / e 738.4, found 738.4. 1 1H NMR (400 MHz, DMSO-d6) δ 10.94 (s, 1H), 9.29 (s, 1H), 7.48 (d, J = 8.3 Hz, 1H), 7.14 (p, J = 3.5 Hz, 3H), 6.75 (dd, J = 6.6, 3.0 Hz, 2H), 6.66 (d, J = 8.3 Hz, 1H), 6.59 (d, J = 8.7 Hz, 2H), 6.51 (d, J = 1.9 Hz, 1H), 6.46 (dd, J = 8.3, 2.0 Hz, 1H), 6.37 (d, J = 8.5 Hz, 2H), 6.30 (d, J = 2.4 Hz, 1H), 6.27 (dd, J = 8.2, 2.4 Hz, 1H), 5.03 (dd, J = 13.3, 5.1 Hz, 1H), 4.39 - 4.25 (m, 2H), 4.16 (dd, J = 11.1, 6.1 Hz, 3H), 3.96 (s, 4H), 3.57 - 3.46 (m, 3H), 3.28 (s, 4H), 2.89 (ddd, J = 17.5, 13.7, 5.7 Hz, 1H), 2.64 - 2.54 (m, 1H), 2.46 (d, J = 11.3 Hz, 1H), 2.34 (dd, J = 13.1, 4.5 Hz, 1H), 2.25 (d, J = 6.7 Hz, 2H), 1.99 - 1.90 (m, 1H), 1.69 (d, J = 12.4 Hz, 2H), 1.34 (s, 1H), 1.23 (s, 1H), 1.20 - 1.08 (m, 2H).

[0245] Example 58. 3-(5-(2-((1-(4-((3S,4R)-7-Hydroxy-3-phenyl-chroman-4-yl)phenyl)piperidin-4-yl)methyl)-2,7-diazaspiro[3.5]non-7-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione TIFF2025523440000137.tif 29170

[0246] The target compound was prepared in a method similar to Example 16. LC / MS (ESI+) calcd for C 47 H 51 N5O5([M+H] + ) m / e 766.4, found 766.4. 1 H NMR (400 MHz, DMSO-d6) δ 10.96 (s, 1H), 9.31 (s, 1H), 7.49 (d, J = 8.4 Hz, 1H), 7.18 - 7.10 (m, 3H), 7.04 (d, J = 9.0 Hz, 2H), 6.75 (dd, J = 6.6, 3.0 Hz, 2H), 6.65 (d, J = 8.3 Hz, 1H), 6.59 (d, J = 8.8 Hz, 2H), 6.36 (d, J = 8.5 Hz, 2H), 6.30 (d, J = 2.4 Hz, 1H), 6.27 (dd, J = 8.2, 2.4 Hz, 1H), 5.03 (dd, J = 13.3, 5.1 Hz, 1H), 4.37 - 4.26 (m, 2H), 4.23 - 4.12 (m, 3H), 3.52 (d, J = 3.8 Hz, 2H), 3.28 - 3.24 (m, 4H), 2.94 (s, 4H), 2.91 - 2.84 (m, 1H), 2.62 - 2.53 (m, 1H), 2.45 (d, J = 12.2 Hz, 1H), 2.39 - 2.32 (m, 1H), 2.28 (d, J = 6.8 Hz, 2H), 1.99 - 1.91 (m, 1H), 1.78 - 1.62 (m, 6H), 1.33 (s, 1H), 1.23 (d, J = 3.7 Hz, 2H), 1.20 - 1.08 (m, 2H).

[0247] Example 59. 3-(5-(3-(4-(4-((1R,2S)-6-Hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperazin-1-yl)azetidin-1-yl)-1-oxoisoindol-2-yl)piperidine-2,6-dione TIFF2025523440000138.tif36170

[0248] The target compound was prepared in a manner similar to Example 19. LC / MS (ESI+) calcd for C 42 H 43 N5O4([M+H] + ) m / e 682.3, found 682.3. 1 H NMR (400 MHz, DMSO-d6) δ 10.94 (s, 1H), 9.12 (s, 1H), 7.49 (d, J = 8.3 Hz, 1H), 7.18 - 7.09 (m, 3H), 6.87 - 6.81 (m, 2H), 6.63 (d, J = 8.4 Hz, 1H), 6.60 (d, J = 2.5 Hz, 1H), 6.58 - 6.51 (m, 3H), 6.48 (ddd, J = 8.3, 4.5, 2.3 Hz, 2H), 6.21 (d, J = 8.5 Hz, 2H), 5.03 (dd, J = 13.3, 5.1 Hz, 1H), 4.30 (d, J = 16.9 Hz, 1H), 4.17 (d, J = 16.9 Hz, 1H), 4.13 (d, J = 4.9 Hz, 1H), 4.01 (t, J = 7.4 Hz, 2H), 3.73 (d, J = 6.8 Hz, 2H), 3.27 (s, 2H), 3.00 (s, 4H), 2.98 - 2.82 (m, 3H), 2.58 (d, J = 14.3 Hz, 1H), 2.43 (d, J = 9.6 Hz, 4H), 2.34 (dd, J = 13.7, 4.3 Hz, 1H), 2.09 (dd, J = 12.4, 6.3 Hz, 1H), 2.00 - 1.93 (m, 1H), 1.70 (d, J = 12.1 Hz, 1H).

[0249] Example 60. 3-(5-(7-((1-(4-((3,4-cis)-3-(3-fluorophenyl)-7-hydroxy-chroman-4-yl)phenyl)piperidin-4-yl)methyl)-2,7-diazaspiro[3.5]non-2-yl)-1-oxoisoindol-2-yl)piperidine-2,6-dione TIFF2025523440000139.tif80170

[0250] Step 1: Synthesis of 7-Hydroxychroman-4-one Resorcinol (80 g, 0.73 mmol), 3-chloropropionic acid (86.7 g, 0.80 mmol) were added to a round-bottom flask, 68 mL of trifluoromethanesulfonic acid was added, stirred at 80 °C for 1 hour, cooled to room temperature, poured into 200 mL of ice water, 300 mL of dichloromethane was added for extraction, the aqueous layer was further extracted 3 times with dichloromethane, the organic layers were combined, concentrated to dryness under reduced pressure. While cooling in an ice-water bath, 800 mL of 25% aqueous NaOH solution was slowly added, after addition, kept warm for 1 hour for reaction, adjusted the pH to about 4 with 6N hydrochloric acid solution, 600 mL of ethyl acetate was added for extraction, the aqueous phase was further extracted 2 times with ethyl acetate, the organic layers were combined, dried over anhydrous sodium sulfate, concentrated to dryness under reduced pressure to obtain 90 g of the product 7-hydroxychroman-4-one, which was directly used in the next reaction.

[0251] Step 2: Synthesis of 7-((Tetrahydro-2H-pyran-2-yl)oxy)chroman-4-one The crude product 7-hydroxychroman-4-one (90 g, 0.55 mol) obtained in the previous step was dissolved in 700 mL of dichloromethane, DHP (134 g, 1.59 mol), PPTS (20 g, 0.08 mol) were added, stirred at room temperature overnight, solid potassium carbonate (13.8 g, 0.1 mol) was added, stirred at room temperature for half an hour, filtered, the filtrate was concentrated to dryness under reduced pressure, and separated and purified by column chromatography to obtain 90 g of the product 7-((tetrahydro-2H-pyran-2-yl)oxy)chroman-4-one. Yield: 66%.

[0252] Step 3: Synthesis of 4-(Dimethoxymethyl)-1-(4-(7-((tetrahydro-2H-pyran-2-yl)oxy)-2H-chromen-4-yl)phenyl)piperidine 1-(4-Bromophenyl)-4-(dimethoxymethyl)piperidine (8.0 g, 25.5 mmol) was dissolved in 80 mL of anhydrous tetrahydrofuran. Under the protection of argon gas, the temperature was lowered to -78 °C in a dry ice-acetone bath, and 21 mL of 1.6 N n-butyllithium solution was slowly added dropwise. After the addition was complete, the mixture was kept warm for 1.5 hours. 7-((Tetrahydro-2H-pyran-2-yl)oxy)chroman-4-one (6.34 g, 25.5 mmol) was dissolved in anhydrous tetrahydrofuran and added dropwise to the reaction system. After the addition was complete, the mixture was kept warm for 2 hours and then slowly warmed to about 0 °C. Water was added to quench the reaction. 200 mL of ethyl acetate was added for extraction, and the aqueous layer was back-extracted once with 150 mL. The organic layers were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, concentrated to dryness under reduced pressure, and separated and purified by column chromatography to obtain 6.48 g of the product. It was dissolved in 100 mL of dichloromethane, triethylamine (4.0 g, 39.7 mmol) was added, and methanesulfonyl chloride (1.82 g, 15.9 mmol) was added while cooling in an ice-water bath. The ice-water bath was removed, and the reaction was carried out at room temperature for 1 hour. The reaction was monitored by TLC until the raw materials were completely reacted, washed with water, dried over anhydrous sodium sulfate, concentrated to dryness under reduced pressure, and separated and purified by column chromatography to obtain 4.87 g of the product 4-(dimethoxymethyl)-1-(4-(7-((tetrahydro-2H-pyran-2-yl)oxy)-2H-chromen-4-yl)phenyl)piperidine. Yield: 41%. LC / MS (ESI+) calcd for C 28 H 35 NO5([M+H] + ) m / e 466.2, found 466.2。

[0253] Step 4: Synthesis of 1-(4-(3-Bromo-7-((tetrahydro-2H-pyran-2-yl)oxy)-2H-chromen-4-yl)phenyl)-4-(dimethoxymethyl)piperidine 4-(Dimethoxymethyl)-1-(4-(7-((tetrahydro-2H-pyran-2-yl)oxy)-2H-toluen-4-yl)phenyl)piperidine (2.33 g, 5.0 mmol) was dissolved in 15 mL of DMF, N,N-diisopropylethylamine (1.29 g, 10.0 mmol) was added, tribromopyridine (1.76 g, 5.5 mmol) was added under an ice-water bath, and the mixture was kept warm for 20 minutes for reaction. Then 35 mL of water was added, and the mixture was extracted with 50 mL of ethyl acetate. The aqueous layer was further back-extracted once with 40 mL of ethyl acetate, and the organic layers were combined. The combined organic layer was washed once with saturated brine, dried over anhydrous sodium sulfate, concentrated to dryness under reduced pressure, and separated and purified by column chromatography to obtain 2.36 g of the product 1-(4-(3-bromo-7-((tetrahydro-2H-pyran-2-yl)oxy)-2H-chromen-4-yl)phenyl)-4-(dimethoxymethyl)piperidine. Yield: 87%.

[0254] Step 5: Synthesis of 4-(dimethoxymethyl)-1-(4-(3-(3-fluorophenyl)-7-((tetrahydro-2H-pyran-2-yl)oxy)-2H-chromen-4-yl)phenyl)piperidine 1-(4-(3-Bromo-7-((tetrahydro-2H-pyran-2-yl)oxy)-2H-chromen-4-yl)phenyl)-4-(dimethoxymethyl)piperidine (200 mg, 0.37 mmol), m-fluorophenylboronic acid (77 mg, 0.55 mmol) were added to a 50 mL round-bottom flask, 6 mL of 1,4-dioxane was added and dissolved, 2 mL of water, potassium carbonate (128 mg, 1.0 mmol), PdpaloCl2 (29 mg, 0.04 mmol) were added, and the reaction was carried out overnight at 95 °C under the protection of argon gas. 35 mL of water was added, and the mixture was extracted with 50 mL of ethyl acetate. The aqueous layer was further back-extracted once with 40 mL of ethyl acetate, and the organic layers were combined. The organic layer was washed once with saturated brine, dried over anhydrous sodium sulfate, concentrated to dryness under reduced pressure, and separated and purified by thin-layer chromatography to obtain 160 mg of the product 4-(dimethoxymethyl)-1-(4-(3-(3-fluorophenyl)-7-((tetrahydro-2H-pyran-2-yl)oxy)-2H-chromen-4-yl)phenyl)piperidine. Yield: 76%. LC / MS (ESI+) calcd for C 34 H 38 FNO5([M+H] + ) m / e 560.3, found 560.3。

[0255] Step 6: Synthesis of 4-(dimethoxymethyl)-1-(4-(3-(3-fluorophenyl)-7-((tetrahydro-2H-pyran-2-yl)oxy)chroman-4-yl)phenyl)piperidine 4-(Dimethoxymethyl)-1-(4-(3-(3-fluorophenyl)-7-((tetrahydro-2H-pyran-2-yl)oxy)-2H-chromen-4-yl)phenyl)piperidine (160 mg, 0.28 mmol) was dissolved in a 20 mL mixed solution of tetrahydrofuran / methanol = 1:1. 20 mg of palladium carbon was added, the mixture was purged with hydrogen gas three times, and reacted overnight. It was filtered, the filtrate was concentrated to dryness under reduced pressure, and separated and purified by thin layer chromatography to obtain 90 mg of the product 4-(dimethoxymethyl)-1-(4-(3-(3-fluorophenyl)-7-((tetrahydro-2H-pyran-2-yl)oxy)chroman-4-yl)phenyl)piperidine. LC / MS (ESI+) calcd for C 34 H 40 FNO5([M+H] + ) m / e 562.3, found 562.3。

[0256] Step 7: Synthesis of 1-(4-(3-(3-fluorophenyl)-7-hydroxy-chroman-4-yl)phenyl)piperidine-4-carboxaldehyde 4-(Dimethoxymethyl)-1-(4-(3-(3-fluorophenyl)-7-((tetrahydro-2H-pyran-2-yl)oxy)chroman-4-yl)phenyl)piperidine (90 mg, 0.16 mmol) was dissolved in 5 mL of tetrahydrofuran. 2 mL of 2N H2SO4 was added, and the mixture was reacted at 60 °C for 1 hour. While cooling in an ice-water bath, the pH was adjusted to neutral with a saturated aqueous sodium bicarbonate solution. 15 mL of ethyl acetate was added for extraction, and the aqueous layer was further extracted once with 10 mL of ethyl acetate. It was dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure to obtain 60 mg of the product 1-(4-(3-(3-fluorophenyl)-7-hydroxy-chroman-4-yl)phenyl)piperidine-4-carboxaldehyde. Yield: 90%.

[0257] Step 8: Synthesis of 3-(5-(7-((1-(4-((3,4-cis)-3-(3-fluorophenyl)-7-hydroxy-chroman-4-yl)phenyl)piperidin-4-yl)methyl)-2,7-diazaspiro[3.5]nona-2-yl)-1-oxoisoindol-2-yl)piperidine-2,6-dione 3-(1-Oxo-5-(2,7-diazaspiro[3.5]nona-2-yl)isoindol-2-yl)piperidine-2,6-dione trifluoroacetate (42 mg, 0.087 mmol) was dissolved in a 10 mL mixed solution of dichloromethane / methanol 5:1, N,N-diisopropylethylamine (34 mg, 0.26 mmol) was added, and the mixture was stirred at room temperature for 10 minutes. 1-(4-(3-(3-Fluorophenyl)-7-hydroxy-chroman-4-yl)phenyl)piperidine-4-carboxaldehyde (30 mg, 0.069 mmol) was added, glacial acetic acid (20 mg, 0.34 mmol) was added, and after stirring at room temperature for 10 minutes, sodium triacetoxyborohydride (55 mg, 0.26 mmol) was added, and the mixture was stirred at room temperature for 3 hours. It was washed with water, extracted with dichloromethane, concentrated to dryness under reduced pressure, and separated and purified by thin layer chromatography to obtain 25 mg of the product 3-(5-(7-((1-(4-(3-(3-fluorophenyl)-7-hydroxy-chroman-4-yl)phenyl)piperidin-4-yl)methyl)-2,7-diazaspiro[3.5]nona-2-yl)-1-oxoisoindol-2-yl)piperidine-2,6-dione. Yield: 46%. LC / MS (ESI+) calcd for C 47 H 50 FN5O5([M+H] + ) m / e 784.3, found 784.4; 11H NMR (400 MHz, DMSO-d6) δ 10.94 (s, 1H), 9.30 (s, 1H), 7.47 (d, J = 8.3 Hz, 1H), 7.19 (td, J = 7.9, 6.3 Hz, 1H), 7.01 - 6.94 (m, 1H), 6.70 - 6.59 (m, 4H), 6.57 - 6.44 (m, 3H), 6.40 (d, J = 8.4 Hz, 2H), 6.33 - 6.25 (m, 2H), 5.03 (dd, J = 13.2, 5.1 Hz, 1H), 4.30 (dd, J = 13.7, 10.8 Hz, 2H), 4.19 (d, J = 5.3 Hz, 2H), 4.14 (s, 1H), 3.62 (s, 4H), 3.55 (d, J = 11.4 Hz, 3H), 2.96 - 2.83 (m, 1H), 2.57 (d, J = 18.2 Hz, 2H), 2.38 - 2.21 (m, 4H), 2.10 (d, J = 7.1 Hz, 2H), 1.98 - 1.91 (m, 1H), 1.74 (s, 6H), 1.60 (s, 1H), 1.23 (d, J = 3.8 Hz, 2H), 1.16 - 1.07 (m, 2H).

[0258] Example 61. 3-(5-(7-((1-(4-(7-Hydroxy-(3,4-cis)-3-(thiophen-3-yl)-chroman-4-yl)phenyl)piperidin-4-yl)methyl)-2,7-diazaspiro[3.5]non-2-yl)-1-oxoisoindol-2-yl)piperidine-2,6-dione TIFF2025523440000140.tif28170

[0259] The target compound was prepared in a similar manner to Example 60. LC / MS (ESI+) calcd for C 45 H 49 N5O5S([M+H] + ) m / e 772.3, found 772.3. 11H NMR (400 MHz, DMSO-d6) δ 10.94 (s, 1H), 9.28 (s, 1H), 7.47 (d, J = 8.3 Hz, 1H), 7.36 (dd, J = 4.9, 2.9 Hz, 1H), 6.75 (d, J = 2.9 Hz, 1H), 6.71 (dd, J = 5.0, 1.2 Hz, 1H), 6.64 (dd, J = 8.5, 4.7 Hz, 3H), 6.47 (dd, J = 19.1, 9.1 Hz, 4H), 6.29 (d, J = 2.4 Hz, 1H), 6.26 (dd, J = 8.2, 2.4 Hz, 1H), 5.03 (dd, J = 13.2, 5.1 Hz, 1H), 4.35 - 4.22 (m, 2H), 4.23 - 4.12 (m, 3H), 3.62 (s, 4H), 3.57 (dd, J = 15.0, 9.0 Hz, 3H), 2.97 - 2.83 (m, 1H), 2.62 - 2.52 (m, 2H), 2.38 - 2.25 (m, 4H), 2.11 (d, J = 7.2 Hz, 2H), 1.94 (d, J = 13.7 Hz, 1H), 1.74 (s, 6H), 1.60 (s, 1H), 1.23 (d, J = 3.8 Hz, 2H), 1.14 (m, J = 11.8 Hz, 2H).

[0260] Example 62. 3-(5-(7-(1-(4-(7-Hydroxy-3-(6-methylpyridazin-4-yl)-chroman-4-yl)phenyl)piperidin-4-yl)methyl)-2,7-diazaspiro[3.5]non-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione TIFF2025523440000141.tif29170

[0261] The target compound was prepared in a manner similar to Example 60. LC / MS (ESI+) calcd for C 46 H 51 N7O5([M+H] + ) m / e 782.4, found 782.4;1 1H NMR (400 MHz, DMSO-d6) δ 10.94 (s, 1H), 9.37 (s, 1H), 8.55 (d, J = 2.1 Hz, 1H), 7.47 (d, J = 8.2 Hz, 1H), 6.77 (d, J = 2.1 Hz, 1H), 6.67 (dd, J = 8.5, 4.5 Hz, 3H), 6.51 (s, 1H), 6.47 (dd, J = 8.3, 2.0 Hz, 1H), 6.44 (d, J = 8.4 Hz, 2H), 6.33 (d, J = 2.4 Hz, 1H), 6.30 (dd, J = 8.2, 2.5 Hz, 1H), 5.03 (dd, J = 13.3, 5.1 Hz, 1H), 4.39 - 4.21 (m, 4H), 4.16 (d, J = 16.9 Hz, 1H), 3.62 (s, 4H), 3.59 - 3.52 (m, 3H), 2.95 - 2.85 (m, 1H), 2.56 (d, J = 17.7 Hz, 2H), 2.42 (s, 3H), 2.34 (dd, J = 13.3, 4.4 Hz, 4H), 2.12 (s, 2H), 1.94 (d, J = 11.0 Hz, 1H), 1.75 (s, 6H), 1.63 (s, 1H), 1.23 (d, J = 3.6 Hz, 2H), 1.17 - 1.09 (m, 2H).

[0262] Example 63. 3-(5-(7-((1-(4-(3-(2,6-Difluorophenyl)-7-hydroxy-chroman-4-yl)phenyl)piperidin-4-yl)methyl)-2,7-diazaspiro[3.5]non-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione TIFF2025523440000142.tif30170

[0263] The target compound was prepared in a manner similar to Example 60. LC / MS (ESI+) calcd for C 47 H 49 F2N5O5([M+H] +) m / e 802.4, found 802.4; 1 1H NMR (400 MHz, DMSO-d6) δ 10.94 (s, 1H), 9.36 (s, 1H), 7.51 (d, J = 7.8 Hz, 1H), 7.31 (t, J = 7.0 Hz, 1H), 6.94 (t, J = 9.4 Hz, 2H), 6.66 (d, J = 9.2 Hz, 3H), 6.57 - 6.38 (m, 4H), 6.31 (d, J = 7.0 Hz, 2H), 5.03 (dd, J = 13.3, 5.1 Hz, 1H), 4.53 (s, 1H), 4.31 (d, J = 16.6 Hz, 2H), 4.17 (d, J = 16.8 Hz, 1H), 4.10 (d, J = 5.0 Hz, 1H), 3.73 (d, J = 29.7 Hz, 3H), 3.67 - 3.52 (m, 4H), 3.45 (s, 1H), 3.31 (dd, J = 7.4, 4.3 Hz, 1H), 3.14 (dd, J = 7.4, 4.3 Hz, 1H), 2.92 (dd, J = 31.7, 18.6 Hz, 4H), 2.58 (d, J = 16.4 Hz, 2H), 2.34 (d, J = 11.3 Hz, 2H), 2.17 - 1.86 (m, 6H), 1.77 (s, 2H), 1.28 (m, 2H).

[0264] Example 64. 3-(5-(2-(1-(4-((1,2-cis)-6-Hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperidin-4-yl)-2,7-diazaspiro[3.5]non-7-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione TIFF2025523440000143.tif30170

[0265] The target compound was prepared in a similar manner to Example 19. LC / MS (ESI+) calcd for C 47 H 51 N5O4 ([M+H] +) m / e 750.4, found 750.4; 1 1H NMR (400 MHz, DMSO-d6) δ 10.95 (s, 1H), 9.11 (s, 1H), 7.49 (d, J = 8.4 Hz, 1H), 7.13 (dq, J = 6.7, 5.7, 5.0 Hz, 3H), 7.04 (d, J = 10.5 Hz, 2H), 6.86 - 6.80 (m, 2H), 6.63 (d, J = 8.4 Hz, 1H), 6.60 (d, J = 2.5 Hz, 1H), 6.53 (d, J = 8.5 Hz, 2H), 6.47 (dd, J = 8.1, 2.6 Hz, 1H), 6.19 (d, J = 8.4 Hz, 2H), 5.04 (dd, J = 13.3, 5.1 Hz, 1H), 4.31 (d, J = 17.0 Hz, 1H), 4.18 (d, J = 16.9 Hz, 1H), 4.12 (d, J = 5.0 Hz, 1H), 3.43 (s, 2H), 3.28 (s, 6H), 2.93 (dq, J = 26.6, 14.0 Hz, 6H), 2.58 (d, J = 13.8 Hz, 3H), 2.42 - 2.29 (m, 2H), 2.14 - 2.06 (m, 1H), 2.01 - 1.91 (m, 2H), 1.74 (s, 8H).

[0266] Example 65. 3-(5-(7-((1-(4-(3-(2,6-Difluorophenyl)-7-hydroxy-chroman-4-yl)-2-fluorophenyl)piperidin-4-yl)methyl)-2,7-diazaspiro[3.5]non-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione TIFF2025523440000144.tif30170

[0267] The target compound was prepared in a similar manner to Example 60. LC / MS (ESI+) calcd for C 47 H 48 F3N5O5([M+H] +) m / e 820.2, found 820.2; 1 1H NMR (400 MHz, DMSO-d6) δ 10.95 (s, 1H), 9.46 (d, J = 1.5 Hz, 1H), 7.51 (d, J = 8.3 Hz, 1H), 7.34 (p, J = 7.4 Hz, 1H), 6.96 (t, J = 9.4 Hz, 2H), 6.78 (t, J = 8.8 Hz, 1H), 6.72 - 6.66 (m, 1H), 6.51 (s, 1H), 6.48 (d, J = 8.3 Hz, 1H), 6.37 (d, J = 8.4 Hz, 1H), 6.35 - 6.30 (m, 2H), 6.25 (d, J = 14.0 Hz, 1H), 5.03 (dd, J = 13.2, 5.2 Hz, 1H), 4.50 (d, J = 11.9 Hz, 1H), 4.36 - 4.25 (m, 2H), 4.18 (d, J = 17.6 Hz, 2H), 3.81 (d, J = 11.1 Hz, 1H), 3.72 (d, J = 27.4 Hz, 4H), 3.65 - 3.53 (m, 4H), 3.43 (s, 2H), 3.23 (s, 2H), 3.14 (d, J = 7.4 Hz, 1H), 3.00 (s, 2H), 2.92 (d, J = 18.3 Hz, 2H), 2.58 (d, J = 13.7 Hz, 2H), 2.39 - 2.30 (m, 1H), 2.14 (s, 1H), 1.99 - 1.83 (m, 4H), 1.30 (m, 2H).

[0268] Example 66. 3-(5-(7-(1-(4-(6-Hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)piperidin-4-yl)-2,7-diazaspiro[4.4]nona-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione TIFF2025523440000145.tif32170

[0269] The target compound was prepared in a similar manner to Example 19. LC / MS (ESI+) calcd for C 47 H 51 N5O4([M+H] + ) m / e 750.4, found 750.4; 1 H NMR (400 MHz, DMSO-d6) δ 10.95 (s, 1H), 9.16 (s, 1H), 7.50 (d, J = 8.8 Hz, 1H), 7.13 (dd, J = 12.0, 7.1 Hz, 3H), 6.86 - 6.80 (m, 2H), 6.68 - 6.52 (m, 6H), 6.48 (dd, J = 8.3, 2.5 Hz, 1H), 6.21 (d, J = 8.4 Hz, 2H), 5.03 (dd, J = 13.2, 5.1 Hz, 1H), 4.31 (d, J = 16.9 Hz, 1H), 4.18 (d, J = 16.9 Hz, 1H), 4.12 (t, J = 5.3 Hz, 2H), 3.60 (d, J = 6.8 Hz, 5H), 3.33 - 3.25 (m, 4H), 3.16 (d, J = 5.2 Hz, 2H), 3.12 (d, J = 7.6 Hz, 2H), 3.03 - 2.83 (m, 4H), 2.58 (d, J = 17.6 Hz, 2H), 2.35 (dd, J = 13.0, 4.3 Hz, 1H), 2.15 - 1.89 (m, 8H), 1.71 (s, 2H).

[0270] Example 67. 3-(5-(4-(7-(2-Fluoro-4-((1,2-cis)-2-(2-fluorophenyl)-6-hydroxy-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)-2,7-diazaspiro[3.5]non-2-yl)piperidin-1-yl)-1-oxoisoindolin-2-yl)pyridine-2,6-dione TIFF2025523440000146.tif46170

[0271] The target compound was prepared in a similar manner to Example 19. LC / MS (ESI+) calcd for C47 H 49 F2N5O4([M+H] + ) m / e 786.4, found 786.4; 1 1H NMR (400 MHz, DMSO-d6) δ 10.95 (s, 1H), 9.21 (s, 1H), 7.49 (d, J = 8.5 Hz, 1H), 7.25 - 7.12 (m, 2H), 7.03 (d, J = 8.6 Hz, 2H), 6.89 (td, J = 7.4, 1.5 Hz, 1H), 6.71 - 6.59 (m, 3H), 6.53 - 6.41 (m, 2H), 6.11 (dd, J = 8.3, 2.0 Hz, 1H), 6.02 (dd, J = 14.2, 2.0 Hz, 1H), 5.04 (dd, J = 13.3, 5.1 Hz, 1H), 4.30 (d, J = 16.9 Hz, 1H), 4.24 - 4.14 (m, 2H), 3.72 (d, J = 12.2 Hz, 2H), 3.61 - 3.51 (m, 1H), 3.01 - 2.84 (m, 8H), 2.75 (d, J = 6.3 Hz, 4H), 2.62 - 2.53 (m, 1H), 2.37 (td, J = 13.2, 4.6 Hz, 1H), 2.27 (d, J = 18.5 Hz, 1H), 2.09 (dd, J = 12.7, 6.3 Hz, 1H), 2.00 - 1.88 (m, 2H), 1.71 (d, J = 5.6 Hz, 7H), 1.23 (m, 2H).

[0272] Example 68. 3-(5-(4-(7-(2-Fluoro-4-((3,4-cis)-3-(2-fluorophenyl)-7-hydroxy-chroman-4-yl)phenyl)-2,7-diazaspiro[3.5]nonan-2-yl)piperidin-1-yl)-1-oxoisoindolin-2-yl)pyridine-2,6-dione TIFF2025523440000147.tif45170

[0273] The target compound was prepared in a method similar to Example 19. LC / MS (ESI+) calcd for C 46 H 47 F2N5O5([M+H] + ) m / e 788.3, found 788.3 1 H NMR (400 MHz, DMSO-d6) δ 10.96 (s, 1H), 9.47 (s, 1H), 7.52 (d, J = 8.4 Hz, 1H), 7.24 (q, J = 7.3 Hz, 1H), 7.20 - 7.13 (m, 1H), 7.13 - 7.04 (m, 2H), 6.92 (t, J = 7.5 Hz, 1H), 6.74 (t, J = 8.8 Hz, 1H), 6.68 (d, J = 8.3 Hz, 1H), 6.50 (t, J = 7.3 Hz, 1H), 6.40 - 6.27 (m, 3H), 6.20 (dd, J = 14.0, 2.0 Hz, 1H), 5.04 (dd, J = 13.2, 5.1 Hz, 1H), 4.27 (ddd, J = 34.2, 23.5, 13.3 Hz, 5H), 3.99 (d, J = 12.4 Hz, 2H), 3.83 (s, 2H), 3.74 (dd, J = 10.3, 5.1 Hz, 1H), 3.58 (p, J = 6.7 Hz, 4H), 3.10 (q, J = 7.4 Hz, 4H), 2.83 (dd, J = 25.8, 8.9 Hz, 5H), 2.58 (d, J = 16.5 Hz, 1H), 2.44 - 2.30 (m, 1H), 1.97 (d, J = 12.4 Hz, 4H), 1.83 (s, 1H), 1.56 (d, J = 11.9 Hz, 1H).

[0274] Example 69. 3-(5-(4-(7-(2-Fluoro-4-((1,2-cis)-6-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenyl)-2,7-diazaspiro[3.5]non-2-yl)piperidin-1-yl)-1-oxoisoindolin-2-yl)pyridine-2,6-dione TIFF2025523440000148.tif46170

[0275] The target compound was prepared in a manner similar to Example 19. LC / MS (ESI+) calcd for C 47 H 50 FN5O4([M+H] + ) m / e 768.4, found 768.4. 1 H NMR (400 MHz, DMSO-d6) δ 10.96 (s, 1H), 9.21 (s, 1H), 7.51 (d, J = 8.5 Hz, 1H), 7.16 (qd, J = 7.5, 6.4, 3.7 Hz, 3H), 7.07 (d, J = 11.1 Hz, 2H), 6.90 - 6.82 (m, 2H), 6.70 - 6.59 (m, 3H), 6.50 (dd, J = 8.3, 2.6 Hz, 1H), 6.09 (dd, J = 8.4, 1.9 Hz, 1H), 5.97 (dd, J = 14.3, 1.9 Hz, 1H), 5.04 (dd, J = 13.3, 5.1 Hz, 1H), 4.32 (d, J = 16.9 Hz, 1H), 4.24 - 4.14 (m, 2H), 3.91 (s, 2H), 3.57 (s, 2H), 3.09 (s, 2H), 3.03 - 2.66 (m, 10H), 2.63 - 2.54 (m, 1H), 2.37 (tt, J = 13.2, 6.5 Hz, 1H), 2.04 (dt, J = 13.0, 6.2 Hz, 1H), 1.95 (dd, J = 9.2, 4.1 Hz, 1H), 1.87 (d, J = 27.8 Hz, 6H), 1.78 - 1.63 (m, 2H), 1.42 (s, 2H).

[0276] Example 70. 3-(5-(7-((1-(4-((3S,4R)-3-(2,6-difluorophenyl)-7-hydroxychroman-4-yl)-2-fluorophenyl)piperidin-4-yl)methyl)-2,7-diazaspiro[3.5]nona-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione TIFF2025523440000149.tif30170

[0277] The target compound was prepared in a similar manner to Example 60. LC / MS (ESI+) calcd for C 47 H 48 F3N5O5([M+H] + ) m / e 820.2, found 820.2. 11H NMR (400 MHz, DMSO-d6) δ 10.95 (s, 1H), 9.47 (s, 1H), 7.48 (d, J = 8.2 Hz, 1H), 7.33 (tt, J = 8.3, 6.4 Hz, 1H), 6.96 (t, J = 9.2 Hz, 2H), 6.75 (t, J = 8.8 Hz, 1H), 6.71 - 6.66 (m, 1H), 6.50 (d, J = 1.9 Hz, 1H), 6.46 (dd, J = 8.4, 1.9 Hz, 1H), 6.38 - 6.30 (m, 3H), 6.24 (dd, J = 14.1, 2.0 Hz, 1H), 5.03 (dd, J = 13.2, 5.1 Hz, 1H), 4.55 - 4.44 (m, 1H), 4.30 (d, J = 6.8 Hz, 1H), 4.27 (s, 1H), 4.19 - 4.14 (m, 2H), 3.81 (ddd, J = 11.7, 5.2, 3.1 Hz, 1H), 3.64 (s, 4H), 3.58 (q, J = 6.6 Hz, 1H), 3.35 (d, J = 12.3 Hz, 1H), 3.27 - 3.19 (m, 2H), 3.10 (q, J = 7.3 Hz, 1H), 2.95 - 2.84 (m, 1H), 2.56 (dd, J = 22.3, 7.2 Hz, 3H), 2.50 (p, J = 1.8 Hz, 2H), 2.34 (qd, J = 13.0, 4.5 Hz, 2H), 1.98 - 1.92 (m, 1H), 1.91 (s, 1H), 1.76 (d, J = 11.4 Hz, 6H), 1.24 - 1.22 (m, 2H).

[0278] Example 71. 3-(5-(7-((1-(4-((3R,4S)-3-(2,6-difluorophenyl)-7-hydroxycoumarin-4-yl)-2-fluorophenyl)piperidin-4-yl)methyl)-2,7-diazaspiro[3.5]non-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione TIFF2025523440000150.tif29170

[0279] The target compound was prepared in a manner similar to Example 60. LC / MS (ESI+) calcd for C 47 H 48 F3N5O5([M+H] + ) m / e 820.2, found 820.2. 1 H NMR (400 MHz, DMSO-d6) δ 10.95 (s, 1H), 9.41 (s, 1H), 7.48 (d, J = 8.3 Hz, 1H), 7.38 - 7.29 (m, 1H), 6.97 (t, J = 9.3 Hz, 2H), 6.76 (t, J = 8.8 Hz, 1H), 6.70 (d, J = 9.0 Hz, 1H), 6.51 (s, 1H), 6.47 (dd, J = 8.3, 2.0 Hz, 1H), 6.35 (d, J = 9.0 Hz, 1H), 6.32 (dt, J = 4.7, 2.2 Hz, 2H), 6.27 - 6.20 (m, 1H), 5.03 (dd, J = 13.2, 5.1 Hz, 1H), 4.49 (t, J = 10.7 Hz, 1H), 4.29 (d, J = 16.6 Hz, 2H), 4.22 - 4.11 (m, 2H), 3.81 (dt, J = 11.6, 4.6 Hz, 1H), 3.61 (d, J = 9.4 Hz, 4H), 3.32 (s, 1H), 3.22 (d, J = 10.8 Hz, 2H), 2.96 - 2.84 (m, 1H), 2.57 (d, J = 22.1 Hz, 2H), 2.43 - 2.19 (m, 5H), 2.15 (d, J = 20.2 Hz, 2H), 1.95 (dd, J = 16.3, 9.4 Hz, 1H), 1.75 (t, J = 3.3 Hz, 6H), 1.60 (s, 1H), 1.23 (m, J = 3.9 Hz, 2H).

[0280] Example 72. 3-(5-(7-((1-(4-((3R,4S)-3-(2,6-difluorophenyl)-7-hydroxychroman-4-yl)phenyl)piperidin-4-yl)methyl)-2,7-diazaspiro[3.5]nona-2-yl)-1-oxoisoindol-2-yl)piperidine-2,6-dione TIFF2025523440000151.tif30170

[0281] The target compound was prepared in a similar manner to Example 60. LC / MS (ESI+) calcd for C 47 H 49 F2N5O5([M+H] + ) m / e 802.3, found 802.3. 11H NMR (400 MHz, DMSO-d6) δ 10.95 (s, 1H), 9.36 (s, 1H), 7.48 (d, J = 8.3 Hz, 1H), 7.31 (tt, J = 8.3, 6.4 Hz, 1H), 6.94 (t, J = 9.3 Hz, 2H), 6.69 - 6.60 (m, 3H), 6.51 (d, J = 1.9 Hz, 1H), 6.47 (dd, J = 8.3, 2.0 Hz, 1H), 6.43 (d, J = 8.4 Hz, 2H), 6.31 (s, 1H), 6.31 - 6.28 (m, 1H), 5.03 (dd, J = 13.2, 5.1 Hz, 1H), 4.59 - 4.48 (m, 1H), 4.29 (d, J = 17.2 Hz, 2H), 4.16 (d, J = 16.9 Hz, 1H), 4.10 (s, 1H), 3.78 (ddd, J = 11.8, 5.2, 3.1 Hz, 1H), 3.63 (s, 4H), 3.55 (d, J = 11.6 Hz, 2H), 3.17 (d, J = 4.7 Hz, 1H), 2.90 (ddd, J = 17.9, 13.5, 5.4 Hz, 1H), 2.63 - 2.52 (m, 2H), 2.49 (s, 1H), 2.41 - 2.21 (m, 4H), 2.12 (s, 2H), 1.99 - 1.91 (m, 1H), 1.73 (d, J = 15.5 Hz, 6H), 1.62 (s, 1H), 1.20 - 1.08 (m, 2H).

[0282] Example 73. 3-(5-(7-((1-(4-((3S,4R)-3-(2,6-difluorophenyl)-7-hydroxycoumarin-4-yl)phenyl)piperidin-4-yl)methyl)-2,7-diazaspiro[3.5]non-2-yl)-1-oxoisoindol-2-yl)piperidine-2,6-dione TIFF2025523440000152.tif30170

[0283] The target compound was prepared in a similar manner to Example 60. LC / MS (ESI+) calcd for C 47 H 49 F2N5O5([M+H] + ) m / e 802.3, found 802.3. 1 H NMR (400 MHz, DMSO-d6) δ 10.95 (s, 1H), 9.36 (s, 1H), 7.47 (d, J = 8.2 Hz, 1H), 7.31 (s, 1H), 6.94 (s, 2H), 6.65 (dd, J = 16.7, 8.4 Hz, 3H), 6.51 (s, 1H), 6.47 (d, J = 8.4 Hz, 1H), 6.42 (d, J = 8.2 Hz, 2H), 6.30 (d, J = 6.0 Hz, 2H), 5.03 (d, J = 13.4 Hz, 1H), 4.53 (s, 1H), 4.27 (s, 2H), 4.22 - 4.07 (m, 2H), 3.78 (s, 1H), 3.62 (s, 4H), 3.56 (s, 2H), 2.88 (d, J = 15.6 Hz, 1H), 2.59 (s, 2H), 2.32 (s, 4H), 2.11 (s, 2H), 1.96 (s, 2H), 1.74 (s, 6H), 1.61 (s, 1H), 1.46 (s, 1H), 1.13 (m, J = 9.6 Hz, 2H).

[0284] Example 74. (R)-3-(5-(7-((1-(4-((3S,4R)-3-(2,6-difluorophenyl)-7-hydroxycoumarin-4-yl)-2-fluorophenyl)piperidin-4-yl)methyl)-2,7-diazaspiro[3.5]non-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione TIFF2025523440000153.tif36170

[0285] Using Intermediate 74-1 as the starting material, the target compound was prepared in a similar manner to Example 78. LC / MS (ESI+) calcd for C 47 H 48F3N5O5([M+H] + ) m / e 820.2, found 820.2. 1 1H NMR (400 MHz, DMSO-d6) δ 10.95 (s, 1H), 9.60 (s, 1H), 7.47 (d, J = 8.3 Hz, 1H), 7.33 (tt, J = 8.4, 6.5 Hz, 1H), 7.03 - 6.92 (m, 2H), 6.79 - 6.72 (m, 1H), 6.69 (d, J = 9.0 Hz, 1H), 6.50 (d, J = 1.9 Hz, 1H), 6.47 (dd, J = 8.4, 2.0 Hz, 1H), 6.35 (d, J = 7.7 Hz, 1H), 6.34 - 6.30 (m, 2H), 6.23 (dd, J = 14.0, 2.0 Hz, 1H), 5.03 (dd, J = 13.3, 5.1 Hz, 1H), 4.54 - 4.44 (m, 1H), 4.35 - 4.24 (m, 2H), 4.21 - 4.11 (m, 2H), 3.81 (ddd, J = 11.7, 5.3, 3.0 Hz, 1H), 3.62 (s, 4H), 3.22 (d, J = 9.4 Hz, 2H), 2.89 (ddd, J = 17.2, 13.5, 5.4 Hz, 1H), 2.64 - 2.52 (m, 2H), 2.41 - 2.23 (m, 4H), 2.12 (d, J = 7.0 Hz, 2H), 1.98 - 1.91 (m, 1H), 1.89 (s, 2H), 1.81 - 1.68 (m, 6H), 1.59 (s, 1H), 1.26 - 1.18 (m, 2H).

[0286] Example 75. (S)-3-(5-(7-((1-(4-((3S,4R)-3-(2,6-difluorophenyl)-7-hydroxycoumarin-4-yl)-2-fluorophenyl)piperidin-4-yl)methyl)-2,7-diazaspiro[3.5]non-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione TIFF2025523440000154.tif36170

[0287] Using intermediate 75-1 as a raw material, the target compound was prepared in a similar manner to Example 78. LC / MS (ESI+) calcd for C 47 H 48 F3N5O5([M+H] + ) m / e 820.2, found 820.2. 1 H NMR (400 MHz, DMSO-d6) δ 10.95 (s, 1H), 7.47 (d, J = 8.3 Hz, 1H), 7.33 (tt, J = 8.3, 6.5 Hz, 1H), 6.97 (q, J = 9.2, 7.5 Hz, 2H), 6.76 (t, J = 8.7 Hz, 1H), 6.72 - 6.66 (m, 1H), 6.50 (d, J = 2.0 Hz, 1H), 6.47 (dd, J = 8.3, 2.0 Hz, 1H), 6.38 - 6.34 (m, 1H), 6.34 - 6.30 (m, 2H), 6.23 (dd, J = 14.2, 2.0 Hz, 1H), 5.03 (dd, J = 13.3, 5.1 Hz, 1H), 4.48 (d, J = 11.8 Hz, 1H), 4.35 - 4.25 (m, 2H), 4.21 - 4.11 (m, 2H), 3.81 (dd, J = 10.7, 4.7 Hz, 1H), 3.62 (s, 4H), 3.23 (s, 2H), 2.94 - 2.85 (m, 1H), 2.62 - 2.52 (m, 2H), 2.41 - 2.24 (m, 4H), 2.12 (d, J = 7.1 Hz, 2H), 1.99 - 1.91 (m, 1H), 1.85 (s, 3H), 1.78 - 1.69 (m, 5H), 1.59 (s, 1H), 1.18 (m, 2H).

[0288] Example 76. 3-(5-(7-((1-(4-(3-(2,6-difluorophenyl)-7-hydroxy-2H-chromen-4-yl)-2-fluorophenyl)piperidin-4-yl)methyl)-2,7-diazaspiro[3.5]non-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione TIFF2025523440000155.tif32170

[0289] The target compound was prepared in a similar manner to Example 42. LC / MS (ESI+) calcd for C 47 H 46 F3N5O5([M+H] + ) m / e 817.3, found 817.3. 1 H NMR (400 MHz, DMSO-d6) δ 10.95 (s, 1H), 9.84 (s, 1H), 7.47 (d, J = 8.3 Hz, 1H), 7.31 (tt, J = 8.4, 6.6 Hz, 1H), 7.00 (t, J = 8.1 Hz, 2H), 6.89 (t, J = 8.8 Hz, 1H), 6.76 - 6.66 (m, 2H), 6.60 (dt, J = 8.7, 1.3 Hz, 1H), 6.51 (d, J = 1.8 Hz, 1H), 6.47 (dd, J = 8.4, 2.0 Hz, 1H), 6.39 - 6.32 (m, 2H), 5.03 (dd, J = 13.3, 5.1 Hz, 1H), 4.81 (s, 2H), 4.29 (d, J = 17.0 Hz, 1H), 4.16 (d, J = 16.9 Hz, 1H), 3.62 (s, 4H), 3.30 (s, 2H), 2.95 - 2.83 (m, 1H), 2.65 - 2.54 (m, 3H), 2.34 (td, J = 13.3, 8.6 Hz, 4H), 2.13 (d, J = 7.2 Hz, 2H), 1.99 - 1.91 (m, 1H), 1.74 (s, 6H), 1.62 (s, 1H), 1.27 - 1.15 (m, 3H).

[0290] Example 77. 3-(5-(7-((1-(4-((3S,4R)-3-(2,6-difluorophenyl)-7-hydroxychroman-4-yl)phenyl)piperidin-4-yl)methyl)-2,7-diazaspiro[3.5]non-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione TIFF2025523440000156.tif29170

[0291] Prepared in a manner similar to Example 60. LC / MS: calcd for C 47 H 49 F2N5O5([M+H] + ) m / z 802.37, found 802; 1 H NMR (400 MHz, DMSO-d6) δ 10.95 (s, 1H), 9.37 (s, 1H), 7.48 (d, J = 8.2 Hz, 1H), 7.31 (tt, J = 8.4, 6.4 Hz, 1H), 6.94 (t, J = 9.3 Hz, 2H), 6.70 - 6.59 (m, 3H), 6.50 (d, J = 2.0 Hz, 1H), 6.47 (dd, J = 8.3, 2.0 Hz, 1H), 6.42 (d, J = 8.3 Hz, 2H), 6.32 (s, 1H), 6.31 - 6.29 (m, 1H), 5.03 (dd, J = 13.3, 5.1 Hz, 1H), 4.59 - 4.47 (m, 1H), 4.30 (d, J = 9.6 Hz, 1H), 4.27 (s, 1H), 4.16 (d, J = 16.9 Hz, 1H), 4.09 (d, J = 5.1 Hz, 1H), 3.78 (ddd, J = 11.7, 5.2, 3.1 Hz, 1H), 3.63 (s, 4H), 3.55 (d, J = 12.0 Hz, 3H), 3.11 (s, 1H), 2.95 - 2.84 (m, 1H), 2.61 - 2.52 (m, 2H), 2.34 (qd, J = 13.9, 13.5, 4.8 Hz, 4H), 2.09 (d, J = 17.1 Hz, 2H), 1.98 - 1.91 (m, 1H), 1.74 (s, 6H), 1.62 (s, 1H), 1.15 (h, J = 6.8 Hz, 2H).

[0292] Example 78. (S)-3-(6-(7-((1-(4-((3S,4R)-3-(2,6-difluorophenyl)-7-hydroxychroman-4-yl)phenyl)piperidin-4-yl)methyl)-2,7-diazaspiro[3.5]non-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione TIFF2025523440000157.tif98170

[0293] Step 1: Synthesis of tert-butyl 2-(3-(1,3-dioxolan-2-yl)-4-(methoxycarbonyl)phenyl)-2,7-diazaspiro[3.5]nonane-7-carboxylate Methyl 4-bromo-2-(1,3-dioxolan-2-yl)benzoate (10 g, 17 mmol), tert-butyl 2,7-diazaspiro[3.5]nonane-7-carboxylate (4.35 g, 19.2 mmol) were dissolved in dioxane (100 ml), cesium carbonate (11.3 g, 35 mmol), X-phos (0.83 g, 1.75 mmol), Pd2(dba)3 (0.8 g, 0.847 mmol) were added, the mixture was purged with nitrogen gas and then protected with nitrogen, reacted at 90 °C overnight, monitored by TLC until the reaction was complete, filtered through celite, washed with water, extracted with ethyl acetate, washed with saturated brine, and the system was purified with petroleum ether / ethyl acetate, identified as the target product by LCMS, and 13 g of the product was obtained. Yield: 86%. Chemical formula: C 23 H 32 N2O6. LC / MS: calcd for 432.23 ([M+H] + ) m / z 433.23, found 423.

[0294] Step 2: Synthesis of tert-butyl 2-(3-formyl-4-(methoxycarbonyl)phenyl)-2,7-diazaspiro[3.5]nonane-7-carboxylate tert-Butyl 2-(3-(1,3-dioxolan-2-yl)-4-(methoxycarbonyl)phenyl)-2,7-diazaspiro[3.5]nonane-7-carboxylate (13 g, 30 mmol) was dissolved in acetone (130 ml), TSOH·H2O (7.44 g, 39 mmol) was added, and the reaction was carried out at room temperature. After monitoring by TLC for complete reaction, it was adjusted to alkaline with saturated aqueous sodium hydrogen carbonate solution, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated to obtain 11.5 g of the product. Yield: 94%.

[0295] Step 3: Synthesis of (S)-2-(2-(1-amino-5-(tert-butoxy)-1,5-dioxopentan-2-yl)-1-oxoisoindolin-5-yl)-2,7-diazaspiro[3.5]nonene-7-carboxylic acid tert-butyl ester tert-Butyl 2-(3-formyl-4-(methoxycarbonyl)phenyl)-2,7-diazaspiro[3.5]nonane-7-carboxylate (3.55 g, 9.14 mmol) and tert-butyl (S)-4,5-diamino-5-oxopentanoate (1.85 g, 9.14 mmol) were dissolved in dichloroethane (50 ml), acetic acid (548 mg, 9.14 mmol) was added, and the mixture was stirred at room temperature for 50 min. Then, sodium cyanoborohydride (1.14 g, 18.3 mmol) was added, and the mixture was stirred at room temperature for 50 min. After that, the temperature was raised to 50 °C and the reaction was carried out overnight. The complete reaction of the raw materials and the target product were monitored by LCMS. Water was added to quench the reaction, and the mixture was extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated. It was purified by dichloromethane / methanol system and identified as the target product by LCMS to obtain 4.5 g of the product. Yield: 95%. Chemical formula: C 29 H 42 N4O6. LC / MS: calcd for 542.31 ([M+H] + ) m / z 543.32, found 543.

[0296] Step 4: Synthesis of (S)-3-(1-oxo-5-(2,7-diazaspiro[3.5]non-2-yl)isoindol-2-yl)piperidine-2,6-dione-4-methylbenzenesulfonate (S)-2-(2-(1-Amino-5-(tert-butoxy)-1,5-dioxopentan-2-yl)-1-oxoisoindol-5-yl)-2,7-diazaspiro[3.5]nonen-7-carboxylic acid tert-butyl ester (5.00 g, 9.22 mmol) was dissolved in acetonitrile (50 ml), TSOH·H2O (4.39 g, 23 mmol) was added, and the mixture was reacted at 80 °C overnight. The target product was monitored by LCMS, and the reaction system was concentrated as it was, slurried with ethyl acetate at 70 °C overnight, and filtered to obtain 3.5 g of the product. Chemical formula: C 27 H 32 N4O6S. LC / MS: calcd for 368.18 ([M+H] + ) m / z 369.18, found 369。

[0297] Step 5: Synthesis of (S)-3-(6-(7-((1-(4-((3S,4R)-3-(2,6-difluorophenyl)-7-hydroxycoumarin-4-yl)phenyl)piperidin-4-yl)methyl)-2,7-diazaspiro[3.5]non-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (S)-3-(1-Oxo-5-(2,7-diazaspiro[3.5]non-2-yl)isoindol-2-yl)piperidine-2,6-dione-4-methylbenzenesulfonate (100 mg, 0.29 mmol) was dissolved in dichloromethane / methanol (10 mL, 10:1), NaOAc (63 mg, 0.67 mmol) was added, and the mixture was stirred at room temperature for 5 min. 1-(4-((3S,4R)-3-(2,6-difluorophenyl)-7-hydroxytryptophan-4-yl)phenyl)piperidine-4-carboxaldehyde (100 mg, 0.22 mmol) was added, glacial acetic acid (40 mg, 0.67 mmol) was added, and the mixture was stirred at room temperature for 0.5 h. Sodium triacetoxyborohydride (42 mg, 0.67 mmol) was added, and the reaction was carried out overnight. The reaction was monitored by TLC until the raw materials were completely reacted, and saturated sodium bicarbonate solution was added to quench the reaction. The mixture was extracted with dichloromethane, dried and concentrated, and subjected to prep-TLC in dichloromethane / methanol system to obtain 65 mg of the target compound. Yield: 43%. Chemical formula: C 47 H 49 F2N5O5.LC / MS: calcd for C 47 H 49 F2N5O5([M+H] + ) m / z 802.38, found 802; 11H NMR (400 MHz, DMSO-d6) δ 10.95 (s, 1H), 9.35 (s, 1H), 7.47 (d, J = 8.4 Hz, 1H), 7.31 (s, 1H), 6.94 (s, 2H), 6.65 (dd, J = 16.3, 8.3 Hz, 3H), 6.58 - 6.38 (m, 4H), 6.31 (s, 2H), 5.03 (d, J = 13.3 Hz, 1H), 4.53 (s, 1H), 4.29 (s, 1H), 4.27 (s, 1H), 4.16 (d, J = 16.8 Hz, 1H), 4.09 (s, 1H), 3.78 (s, 1H), 3.62 (s, 4H), 3.55 (s, 2H), 2.89 (s, 1H), 2.62 (d, J = 35.4 Hz, 3H), 2.32 (s, 4H), 2.10 (s, 2H), 1.96 (s, 2H), 1.74 (s, 5H), 1.61 (s, 2H), 1.13 (d, J = 12.7 Hz, 2H).

[0298] Example 79. 3-(5-(7-((1-(4-((3S,4R)-7-Hydroxy-3-phenylchroman-4-yl)phenyl)piperidin-4-yl)methyl)-2,7-diazaspiro[3.5]non-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione TIFF2025523440000158.tif28170

[0299] Prepared in a similar manner to Example 60. 11H NMR (400 MHz, DMSO-d6) δ 10.98 (s, 1H), 9.28 (s, 1H), 7.54 (d, J = 8.3 Hz, 1H), 7.14 (p, J = 3.2, 2.7 Hz, 3H), 6.81 - 6.71 (m, 3H), 6.67 (dd, J = 8.2, 5.1 Hz, 2H), 6.51 - 6.49 (m, 2H), 6.35 (d, J = 8.6 Hz, 2H), 6.31 (d, J = 2.4 Hz, 1H), 6.27 (dd, J = 8.2, 2.5 Hz, 1H), 5.04 (dd, J = 12.9, 5.4 Hz, 1H), 4.33 (t, J = 11.1 Hz, 1H), 4.17 (t, J = 6.9 Hz, 2H), 4.15 - 4.13 (m, 2H),3.74 (s, 4H), 3.63 - 3.45 (m, 5H), 2.98 - 2.74 (m, 1H), 2.65 - 2.53 (m, 2H), 2.48 - 2.46 (m, 1H), 2.30 - 2.28 (m, 4H), 2.10 (d, J = 7.1 Hz, 2H), 2.02 - 1.99 (m, 1H), 1.78 - 1.73 (m, 7H), 1.28 - 1.23 (m, 2H). LC / MS (ESI+) calcd for C 47 H 51 N5O5([M+H] + ) m / z: 766.4; found 766.4。

[0300] Example 80. 2-(2,6-Dioxopiperidin-3-yl)-5-(7-((1-(4-((3R,4S)-7-Hydroxy-3-phenylchroman-4-yl)phenyl)piperidin-4-yl)methyl)-2,7-diazaspiro[3.5]non-2-yl)isoindoline-1,3-dione TIFF2025523440000159.tif29170

[0301] Prepared in a manner similar to Example 60. 11H NMR (400 MHz, DMSO-d6) δ 11.12 (s, 1H), 9.31 (s, 1H), 7.63 (d, J = 8.3 Hz, 1H), 7.14 (p, J = 3.2, 2.7 Hz, 3H), 6.81 - 6.71 (m, 3H), 6.65 (dd, J = 8.2, 5.1 Hz, 2H), 6.62 - 6.56 (m, 2H), 6.37 (d, J = 8.6 Hz, 2H), 6.30 (d, J = 2.4 Hz, 1H), 6.27 (dd, J = 8.2, 2.5 Hz, 1H), 5.05 (dd, J = 12.9, 5.4 Hz, 1H), 4.33 (t, J = 11.1 Hz, 1H), 4.17 (t, J = 6.9 Hz, 2H), 3.73 (s, 4H), 3.63 - 3.45 (m, 4H), 2.98 - 2.74 (m, 2H), 2.65 - 2.53 (m, 3H), 2.48 - 2.46 (m, 1H), 2.30 - 2.28 (m, 3H), 2.10 (d, J = 7.1 Hz, 2H), 2.00 (dq, J = 11.0, 5.6, 4.5 Hz, 1H), 1.78 - 1.73 (m, 6H), 1.28 - 1.23 (m, 2H). LC / MS (ESI+) calcd for C 47 H 49 N5O6([M+H] + ) m / z: 780.4; found 780.4。

[0302] Example 81. 2-(2,6-Dioxopiperidin-3-yl)-5-(7-((1-(4-((3S,4R)-7-Hydroxy-3-phenylchroman-4-yl)phenyl)piperidin-4-yl)methyl)-2,7-diazaspiro[3.5]non-2-yl)isoindoline-1,3-dione TIFF2025523440000160.tif31170

[0303] The target compound was prepared in a similar manner to Example 1. 11H NMR (400 MHz, DMSO-d6) δ 11.07 (s, 1H), 9.32 (s, 1H), 7.68 - 7.57 (m, 1H), 7.14 (p, J = 3.4, 3.0 Hz, 3H), 6.80 - 6.71 (m, 3H), 6.67 - 6.62 (m, 2H), 6.60 (d, J = 8.5 Hz, 2H), 6.37 (d, J = 8.6 Hz, 2H), 6.31 (d, J = 2.4 Hz, 1H), 6.27 (dd, J = 8.2, 2.4 Hz, 1H), 5.05 (dd, J = 12.9, 5.4 Hz, 1H), 4.32 (t, J = 11.1 Hz, 1H), 4.18 (dd, J = 11.5, 4.2 Hz, 2H), 3.73 (s, 4H), 3.60 - 3.49 (m, 4H), 2.96 - 2.78 (m, 2H), 2.63 - 2.57 (m, 1H), 2.54 (d, J = 8.3 Hz, 2H), 2.47 (d, J = 2.9 Hz, 1H), 2.42 - 2.20 (m, 3H), 2.11 (d, J = 7.1 Hz, 2H), 2.04 - 1.93 (m, 1H), 1.80 - 1.64 (m, 6H), 1.27 - 1.22 (m, 2H). LC / MS (ESI+) calcd for C 47 H 49 N5O6( [M+H] + ) m / z: 780.4; found 780.4。

[0304] Example 82. 3-(5-(5-((1-(4-((3R,4S)-7-Hydroxy-3-phenylchroman-4-yl)phenyl)piperidin-4-yl)methyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione TIFF2025523440000161.tif30170

[0305] The target compound was prepared in a similar manner to Example 60. 11H NMR (400 MHz, DMSO-d6) δ 10.89 (s, 1H), 9.32 (s, 1H), 7.48 (dd, J = 10.2, 3.4 Hz, 1H), 7.13 (p, J = 3.4, 3.0 Hz, 3H), 6.74 (dd, J = 6.6, 3.0 Hz, 2H), 6.70 (d, J = 7.4 Hz, 2H), 6.64 (d, J = 8.3 Hz, 1H), 6.58 (d, J = 8.8 Hz, 2H), 6.35 (d, J = 8.4 Hz, 2H), 6.30 (d, J = 2.4 Hz, 1H), 6.26 (dd, J = 8.2, 2.4 Hz, 1H), 5.03 (dd, J = 13.3, 5.1 Hz, 1H), 4.37 - 4.24 (m, 2H), 4.17 (dd, J = 17.0, 5.8 Hz, 3H), 3.62 - 3.45 (m, 4H), 3.16 - 3.04 (m, 3H), 2.93 - 2.89 (m, 3H), 2.80 (q, J = 7.2 Hz, 1H), 2.60 - 2.55 (m, 2H), 2.45 - 2.43 (m, 2H), 2.39 - 2.32 (m, 1H), 2.23 (d, J = 7.2 Hz, 2H), 2.07 -1.89 (m, 3H), 1.71 (d, J = 12.6 Hz, 2H), 1.23 (d, J = 3.7 Hz, 3H). LC / MS (ESI+) calcd for C 46 H 49 N5O5([M+H] + ) m / z: 752.4; found 752.4。

[0306] Example 83. 3-(5-(5-((1-(4-((3S,4R)-7-Hydroxy-3-phenylchroman-4-yl)phenyl)piperidin-4-yl)methyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione TIFF2025523440000162.tif30170

[0307] The target compound was prepared in a manner similar to Example 78. 1 H NMR (400 MHz, DMSO-d6) δ 10.93 (s, 1H), 9.31 (s, 1H), 7.48 (dd, J = 10.2, 3.4 Hz, 1H), 7.13 (p, J = 3.4, 3.0 Hz, 3H), 6.74 (dd, J = 6.6, 3.0 Hz, 2H), 6.70 (d, J = 7.4 Hz, 2H), 6.65 (d, J = 8.3 Hz, 1H), 6.58 (d, J = 8.8 Hz, 2H), 6.35 (d, J = 8.4 Hz, 2H), 6.30 (d, J = 2.4 Hz, 1H), 6.27 - 6.24 (m, 1H), 5.03 (dd, J = 13.3, 5.1 Hz, 1H), 4.39 - 4.24 (m, 2H), 4.17 (dd, J = 17.0, 5.8 Hz, 3H), 3.62 - 3.45 (m, 4H), 3.13 - 3.09 (m, 3H), 2.93 - 2.89 (m, 3H), 2.80 (q, J = 7.2 Hz, 1H), 2.65 - 2.52 (m, 2H), 2.45 - 2.43 (m, 2H), 2.39 - 2.32 (m, 1H), 2.23 (d, J = 7.2 Hz, 2H), 2.10 - 2.08 (m, 1H), 2.03 - 1.90 (m, 2H), 1.71 (d, J = 12.6 Hz, 2H), 1.23 (d, J = 3.7 Hz, 3H). LC / MS (ESI+) calcd for C 46 H 49 N5O5([M+H] + ) m / z: 752.4; found 752.4。

[0308] Example 84. 3-(5-(7-((1-(4-(cis-7-Hydroxy-3-(pyrimidin-5-yl)chroman-4-yl)phenyl)piperidin-4-yl)methyl)-2,7-diazaspiro[3.5]non-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione TIFF2025523440000163.tif29170

[0309] It was prepared in a similar manner to Example 60. 1 H NMR (400 MHz, DMSO-d6) δ 10.89 (s, 1H), 9.37 (s, 1H), 8.95 (s, 1H), 8.13 (s, 2H), 7.47 (d, J = 8.3 Hz, 1H), 6.67 (dd, J = 8.4, 4.0 Hz, 3H), 6.47 (dd, J = 15.3, 8.7 Hz, 4H), 6.35 - 6.26 (m, 2H), 5.03 (dd, J = 13.3, 5.1 Hz, 1H), 4.38 (t, J = 10.9 Hz, 1H), 4.34 - 4.12 (m, 4H), 3.62 - 3.57 (m, 7H),2.91 - 2.87 (m, 2H), 2.75 (q, J = 7.2 Hz, 1H), 2.64 - 2.53 (m, 3H), 2.44 - 2.21 (m, 6H), 2.11 (d, J = 7.2 Hz, 3H), 1.96 - 1.92 (m, 2H), 1.79 - 1.67 (m, 2H), 1.27 - 1.23 (m, 2H). LC / MS (ESI+) calcd for C 45 H 49 N7O5([M+H] + ) m / z: 768.4; found 768.4.

[0310] Example 85. 2-(2,6-Dioxopiperidin-3-yl)-5-(3-(4-(4-(cis-7-Hydroxy-3-phenylchroman-4-yl)phenyl)piperazin-1-yl)azetidin-1-yl)isoindoline-1,3-dione TIFF2025523440000164.tif40170

[0311] It was prepared in a similar manner to Example 19. 11H NMR (400 MHz, DMSO-d6) δ 11.06 (s, 1H), 9.29 (s, 1H), 7.65 (d, J = 8.3 Hz, 1H), 7.14 (dp, J = 5.7, 2.1 Hz, 3H), 6.85 - 6.71 (m, 3H), 6.64 (dd, J = 11.0, 8.5 Hz, 4H), 6.39 (d, J = 8.4 Hz, 2H), 6.35 - 6.20 (m, 2H), 5.06 (dd, J = 12.9, 5.4 Hz, 1H), 4.33 (t, J = 11.2 Hz, 1H), 4.24 - 4.14 (m, 2H), 4.15 - 4.07 (m, 2H), 3.88 (dd, J = 8.9, 4.9 Hz, 2H), 3.51 (dt, J = 11.7, 4.3 Hz, 1H), 3.17 - 2.95 (m, 4H), 2.87 (ddd, J = 17.4, 13.9, 5.5 Hz, 1H), 2.63 - 2.52 (m, 2H), 2.46 (t, J = 4.7 Hz, 4H), 2.04 - 1.96 (m, 1H), 1.29 - 1.20 (m, 1H). LC / MS (ESI+) calcd for C 41 H 39 N5O6([M+H] + ) m / z: 698.3; found 698.3。

[0312] Example 86. 3-(5-(3-(4-(4-(cis-7-Hydroxy-3-phenylchroman-4-yl)phenyl)piperazin-1-yl)azetidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione TIFF2025523440000165.tif37170

[0313] 2-(2,6-Dioxopiperidin-3-yl)-5-(3-(4-(4-(cis-7-Hydroxy-3-phenylchroman-4-yl)phenyl)piperazin-1-yl)azetidin-1-yl)isoindoline-1,3-dione (70 mg, 0.05 mmol) was dissolved in 5 mL of glacial acetic acid, zinc powder (64 mg, 1 mmol) was added, and the mixture was reacted at 60 °C for 2 hours. The consumption of the starting material was monitored by TLC. The reaction mixture was cooled to room temperature, filtered through celite, and concentrated hydrochloric acid in glacial acetic acid. Saturated sodium bicarbonate was added to make the reaction mixture weakly alkaline, and 5 mL of ethyl acetate was added multiple times for extraction. The organic phases were combined, washed with saturated brine, dried, and concentrated. The resulting residue was dissolved in 1 mL of dichloromethane, 0.2 mL of trifluoroacetic acid was added, triethylsilane (12 mg, 0.1 mmol) was added, and the mixture was stirred overnight at room temperature. The consumption of the hydroxy compound was monitored by LC-MS, and the reaction was stopped. Most of the dichloromethane and trifluoroacetic acid were directly concentrated and removed. Saturated sodium bicarbonate was added to make the system weakly alkaline, and 5 mL of ethyl acetate was added multiple times for extraction. The organic phases were dried and combined, concentrated, and 7 mg of the target compound was separated and purified by a chromatographic column. Yield: 21%. 11H NMR (400 MHz, DMSO-d6) δ 10.94 (s, 1H), 9.30 (s, 1H), 7.49 (d, J = 8.2 Hz, 1H), 7.23 - 7.09 (m, 3H), 6.76 (d, J = 6.0 Hz, 2H), 6.64 (dd, J = 11.7, 8.3 Hz, 3H), 6.53 (s, 1H), 6.49 (d, J = 8.4 Hz, 1H), 6.39 (d, J = 8.3 Hz, 2H), 6.34 - 6.21 (m, 2H), 5.03 (dd, J = 13.3, 5.1 Hz, 1H), 4.35 - 4.25 (m, 2H), 4.19 (q, J = 9.3, 8.5 Hz, 3H), 4.01 (t, J = 7.5 Hz, 2H), 3.74 - 3.71 (m, 2H), 3.04 - 3.03 (m, 4H), 2.94 - 2.85 (m, 1H), 2.67 - 2.60 (m, 2H), 2.46 - 2.45 (m, 3H), 2.01 - 1.89 (m, 1H). LC / MS (ESI+) calcd for C 41 H 41 N5O5( [M+H] + ) m / z: 684.3; found 684.3。

[0314] Example 87. 3-(5-(7-((1-(2-Fluoro-4-(cis-3-(2-fluorophenyl)-7-hydroxybenzopyran-4-yl)phenyl)piperidin-4-yl)methyl)-2,7-diazaspiro[3.5]non-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione TIFF2025523440000166.tif45170TIFF2025523440000167.tif88170

[0315] Step 1: Synthesis of (1-(2-Fluoro-4-nitrophenyl)piperidin-4-yl)methanol 3,4-Difluoronitrobenzene (16 g, 100 mmol) and piperidinomethanol (12.1 g, 105 mmol) were dissolved in acetonitrile (200 mL), potassium carbonate (27.6 g, 200 mmol) was added, and the mixture was heated at 80 °C overnight. The reaction was monitored by TLC until the starting 3,4-difluoronitrobenzene was completely reacted. The reaction system was cooled to room temperature, poured into water, and a solid was precipitated. The solid was filtered and dried to obtain 21.3 g of the product, which was identified as the target compound by LC-MS. The yield was 90%.

[0316] Step 2: Synthesis of (1-(4-amino-2-fluorophenyl)piperidin-4-yl)methanol (1-(2-Fluoro-4-nitrophenyl)piperidin-4-yl)methanol (21.3 g, 95 mmol) was dissolved in methanol (260 mL), 10% palladium on carbon (1.1 g, 5%) was added, the system was purged with hydrogen gas, and the reaction was carried out overnight at room temperature. The reaction was monitored by TLC until the starting material was completely reacted. The reaction mixture was filtered through celite to remove palladium on carbon, concentrated, and 20.2 g of the product was obtained, which was identified as the target compound by LC-MS and used directly in the next step. The yield was 95%.

[0317] Step 3: Synthesis of (1-(2-fluoro-4-iodophenyl)piperidin-4-yl)methanol (1-(4-Amino-2-fluorophenyl)piperidin-4-yl)methanol (20.2 g, 90 mmol) was dissolved in acetonitrile (100 mL). After cooling the reaction mixture to 0 °C, concentrated hydrochloric acid (12 M, 22.5 mL) was added, and then a solution of sodium nitrite (7.5 g, 108 mmol) in water (10 mL) was slowly added dropwise at 0 °C. After the addition was complete, the mixture was stirred for half an hour while maintaining the low temperature. Then, a solution of potassium iodide (15 g, 90 mmol) in water (25 mL) was added at 0 °C. The reaction mixture was warmed to 15 °C and stirred overnight until the starting materials had completely reacted. The reaction was quenched with saturated sodium bisulfite solution, extracted with ethyl acetate, washed with saturated sodium chloride, dried and concentrated, and then subjected to column chromatography to obtain 19 g of the product, which was identified as the target compound by LC-MS. The yield was 63%.

[0318] Step 4: Synthesis of 1-(2-Fluoro-4-iodophenyl)piperidine-4-carboxaldehyde (1-(2-Fluoro-4-iodophenyl)piperidin-4-yl)methanol (19 g, 56.7 mmol) was dissolved in dichloromethane (300 mL). Sodium hydrogen carbonate (9.5 g, 113.5 mmol) was added, and after cooling to 0 °C, Dess-Martin periodinane (48 g, 113.5 mmol) was slowly added in several portions. After the addition was complete, the mixture was reacted for 1 hour, and the complete reaction of the starting materials was monitored by TLC. The mixture was filtered through Celite, concentrated, and subjected to column chromatography to obtain 15.5 g of the product, which was identified as the target compound by LC-MS. The yield was 82%.

[0319] Step 5: Synthesis of 4-(Dimethoxymethyl)-1-(2-fluoro-4-iodophenyl)piperidine 1-(2-Fluoro-4-iodophenyl)piperidine-4-carboxaldehyde (15.5 g, 46.6 mmol) was dissolved in methanol (100 mL), trimethyl orthoformate (7.4 g, 70 mmol) was added, p-toluenesulfonic acid (1.2 g, 7 mmol) was added, and the reaction was carried out at 65 °C overnight. TLC was used to monitor until the raw materials were completely reacted. After cooling to room temperature, the pH was adjusted to 9 with saturated sodium bicarbonate solution, then the organic solvent in the system was concentrated and removed, extracted with ethyl acetate, washed with saturated sodium chloride, concentrated and dried, and then subjected to column chromatography to obtain 15 grams of the product, which was identified as the target compound by LC-MS. The yield was 85%.

[0320] Step 6: Synthesis of 3-chloro-1-(2,4-dihydroxyphenyl)propan-1-one Resorcinol (11 g, 100 mmol) and 1-chloropropionic acid (11.9 g, 110 mmol) were dissolved in trifluoromethanesulfonic acid (52.5 g, 350 mmol), and the reaction was carried out at 80 °C for 2 hours. TLC was used to monitor until the raw material resorcinol was completely reacted. After cooling to room temperature, water was added, and the mixture was extracted with dichloromethane / methanol (10 / 1), concentrated to obtain 23 g of the crude product, which was directly used in the next step.

[0321] Step 7: Synthesis of 7-hydroxycoumarin-4-one The crude product obtained in the previous step was placed in an ice bath and cooled to 0 °C. An aqueous solution (80 mL) of sodium hydroxide (28 g, 700 mmol) was added, and the reaction temperature was maintained at 0 °C and stirred for half an hour. TLC was used to monitor until the raw materials were completely reacted. The pH of the system was adjusted to about 5 with 6N hydrochloric acid, extracted with ethyl acetate, dried and concentrated to obtain 10.8 g of the crude product, which was directly used in the next step.

[0322] Step 8: Synthesis of 7-(benzyloxy)coumarin-4-one The crude product obtained in the previous step was dissolved in DMF (60 mL), potassium carbonate (27.6 g, 200 mmol) was added, benzyl bromide (17.1 g, 100 mmol) was added, and the mixture was reacted at 40 °C overnight. TLC was used to monitor until the raw materials were completely reacted. Water was added to quench the reaction, and the mixture was extracted with ethyl acetate, washed with saturated sodium chloride, dried and concentrated, and then subjected to column chromatography to obtain 8.2 g of the product, which was identified as the target compound by LC-MS. The total yield of the previous three steps was 32.6%.

[0323] Step 9: Synthesis of 7-(benzyloxy)-4-(4-(4-(dimethoxymethyl)piperidin-1-yl)-3-fluorophenyl)chroman-4-ol Under a nitrogen gas atmosphere, 4-(dimethoxymethyl)-1-(2-fluoro-4-iodophenyl)piperidine (12.5 g, 33 mmol) was dissolved in dry THF (180 mL), the temperature was lowered to -70 °C or below, and n-butyllithium (14.4 mL, 2.5 M, 36 mmol) was slowly added, maintaining the temperature of the reaction system at -70 °C or below throughout the dropping process. After the addition was complete, the reaction was carried out for 1 hour while maintaining the temperature, and 7-(benzyloxy)chroman-4-one (7.6 g, 30 mmol) dissolved in dry THF (40 mL) was slowly added dropwise to the system, maintaining the temperature of the reaction system at -70 °C or below throughout the dropping process. The reaction was carried out for 1 hour while maintaining the temperature, and the reaction system was gradually heated to about -40 °C. TLC was used to monitor until the raw material 7-(benzyloxy)chroman-4-one was completely reacted. Saturated ammonium chloride was added to quench the reaction, and the mixture was extracted with ethyl acetate, washed with saturated sodium chloride, dried and concentrated, and then subjected to column chromatography to obtain 9.9 g of the product, which was identified as the target compound by LC-MS. The yield was 65%.

[0324] Step 10: Synthesis of 1-(4-(7-(benzyloxy)-2H-chromen-4-yl)-2-fluorophenyl)-4-(dimethoxymethyl)piperidine 7-(Benzyloxy)-4-(4-(4-(dimethoxymethyl)piperidin-1-yl)-3-fluorophenyl)chroman-4-ol (9.9 g, 19.5 mmol) was dissolved in dichloromethane (100 mL), triethylamine (8 g, 80 mmol) was added, methanesulfonyl chloride (4.5 g, 40 mmol) was added under an ice bath, and after addition, the temperature was raised to room temperature and reacted for 2 hours. The reaction was monitored by TLC until the raw materials were completely reacted, water was added to quench the reaction, extracted with dichloromethane, dried and concentrated, and then subjected to column chromatography to obtain 5.6 g of the product, which was identified as the target compound by LC-MS. The yield was 60%.

[0325] Step 11: Synthesis of 1-(4-(7-(benzyloxy)-3-bromo-2H-chromen-4-yl)-2-fluorophenyl)-4-(dimethoxymethyl)piperidine 1-(4-(7-(Benzyloxy)-2H-chromen-4-yl)-2-fluorophenyl)-4-(dimethoxymethyl)piperidine (5.6 g, 11.7 mmol) was dissolved in DMF (40 mL), DIPEA (4.6 g, 35 mmol) was added, pyridinium tribromide (5.6 g, 17.5 mmol) was added in several portions under an ice bath, and after addition, the temperature was raised to room temperature and stirred overnight. The reaction was monitored by TLC until the raw materials were completely reacted, water was added to quench the reaction, extracted with ethyl acetate, dried and concentrated, and slurried with petroleum ether / ethyl acetate (6:1) to obtain 5.6 g of the product, which was identified as the target compound by LC-MS. The yield was 86%.

[0326] Step 12: Synthesis of 1-(4-(7-(benzyloxy)-3-(2-fluorophenyl)-2H-chromen-4-yl)-2-fluorophenyl)-4-(dimethoxymethyl)piperidine 1-(4-(7-(Benzyloxy)-3-bromo-2H-chromen-4-yl)-2-fluorophenyl)-4-(dimethoxymethyl)piperidine (5.6 g, 10 mmol), 2-fluorophenylboronic acid (3.2 g, 20 mmol), Pd(dppf)Cl2 (0.85 g, 1 mmol), potassium carbonate (15 g, 70 mmol) and dioxane (50 mL) were added to a reaction flask. The system was purged with nitrogen gas and reacted at 80 °C overnight. The reaction was monitored by TLC until the raw materials were completely reacted. After cooling to room temperature, it was filtered through celite, concentrated and subjected to column chromatography to obtain 4.3 mg of the product, which was identified as the target compound by LC-MS. Yield: 91%.

[0327] Step 13: Synthesis of cis-4-(4-(4-(dimethoxymethyl)piperidin-1-yl)-3-fluorophenyl)-3-(2-fluorophenyl)chroman-7-ol 1-(4-(7-(Benzyloxy)-3-(2-fluorophenyl)-2H-chromen-4-yl)-2-fluorophenyl)-4-(dimethoxymethyl)piperidine (4.3 g, 7.2 mmol) was dissolved in THF (25 mL), methanol (250 mL) was added, 10% palladium on carbon (800 mg, 20%) was added, the system was purged with hydrogen gas and reacted at room temperature overnight. The reaction was monitored by TLC until the raw materials were completely reacted. It was filtered through celite to remove palladium on carbon, concentrated and subjected to column chromatography to obtain 3 g of the product, which was identified as the target compound by LC-MS. Yield 82%.

[0328] Step 14: Synthesis of 1-(2-fluoro-4-(cis-3-(2-fluorophenyl)-7-hydroxychromen-4-yl)phenyl)piperidine-4-carboxaldehyde cis-4-(4-(4-(Dimethoxymethyl)piperidin-1-yl)-3-fluorophenyl)-3-(2-fluorophenyl)chroman-7-ol (51 mg, 0.1 mmol) was dissolved in THF (2 mL), sulfuric acid (1 mL, 2 M) was added, and the mixture was reacted at 70 °C for half an hour. TLC was used to monitor until the raw materials were completely reacted. After cooling to room temperature, the pH was adjusted to about 8 with saturated sodium bicarbonate, extracted with ethyl acetate, washed with saturated sodium chloride, dried and concentrated, and then subjected to column chromatography to obtain 56 mg of a crude product, which was used directly in the next step.

[0329] Step 15: Synthesis of 3-(5-(7-((1-(2-Fluoro-4-(cis-3-(2-fluorophenyl)-7-hydroxybenzopyran-4-yl)phenyl)piperidin-4-yl)methyl)-2,7-diazaspiro[3.5]non-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione 3-(1-Oxo-5-(2,7-diazaspiro[3.5]non-2-yl)isoindolin-2-yl)piperidine-2,6-dione trifluoroacetate (56 mg, 1.1 mmol) was dissolved in dichloromethane / methanol (2 mL, 10:1), DIPEA (40 mg, 0.3 mmol) was added, and the mixture was stirred at room temperature for 5 min. 1-(2-Fluoro-4-(cis-3-(2-fluorophenyl)-7-hydroxycoumen-4-yl)phenyl)piperidine-4-carboxaldehyde (51 mg, 0.11 mmol) was added, glacial acetic acid (18 mg, 0.3 mmol) was added, and the mixture was stirred at 35 °C for 0.5 h. After cooling to room temperature, sodium triacetoxyborohydride (42 mg, 0.2 mmol) was added and reacted overnight. TLC was used to monitor until the raw materials were completely reacted, and a saturated sodium bicarbonate solution was added to quench the reaction. Extracted with dichloromethane, dried and concentrated, and then subjected to column chromatography to obtain 67 mg of a product, which was identified as the target compound by LC-MS. The yield was 77%. 11H NMR (400 MHz, DMSO-d6) δ 10.94 (s, 1H), 9.41 (s, 1H), 7.47 (d, J = 8.3 Hz, 1H), 7.32 - 7.13 (m, 4H), 6.92 (t, J = 7.6 Hz, 1H), 6.78 - 6.65 (m, 2H), 6.49 (q, J = 8.5, 7.8 Hz, 2H), 6.35 - 6.28 (m, 2H), 6.19 (d, J = 14.0 Hz, 1H), 5.03 (dd, J = 13.2, 5.0 Hz, 1H), 4.48 - 4.06 (m, 5H), 3.76 - 3.73 (m, 1H), 3.63 (s, 4H), 3.50 - 3.42 (m, 6H), 3.20 (d, J = 11.1 Hz, 2H), 2.88 (d, J = 13.2 Hz, 1H), 2.57 (d, J = 19.3 Hz, 2H), 2.29 - 2.25 (m, 6H), 2.07 - 1.88 (m, 2H), 1.75 - 1.69 (m, 2H), 1.24 - 1.22 (m, 2H). LC / MS (ESI+) calcd for C 47 H 49 F2N5O5([M+H] + ) m / z: 802.4; found 802.4。

[0330] Example 88. 3-(5-(7-((1-(2-Fluoro-4-(cis-7-hydroxy-3-phenylchroman-4-yl)phenyl)piperidin-4-yl)methyl)-2,7-diazaspiro[3.5]non-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione TIFF2025523440000168.tif24170

[0331] The target compound was prepared in a similar manner to Example 60. 11H NMR (400 MHz, DMSO-d6) δ 10.94 (s, 1H), 9.37 (s, 1H), 7.48 (d, J = 8.3 Hz, 1H), 7.26 - 7.06 (m, 3H), 6.79 (dd, J = 6.6, 3.0 Hz, 2H), 6.73 (t, J = 8.8 Hz, 1H), 6.67 (d, J = 8.2 Hz, 1H), 6.50 (s, 1H), 6.47 (dd, J = 8.3, 2.0 Hz, 1H), 6.38 - 6.23 (m, 3H), 6.14 (dd, J = 14.2, 2.0 Hz, 1H), 5.03 (dd, J = 13.3, 5.1 Hz, 1H), 4.43 - 4.10 (m, 5H), 3.84 - 3.51 (m, 7H), 3.25 - 3.00 (m, 6H), 2.89 (td, J = 13.4, 6.9 Hz, 1H), 2.67 - 2.54 (m, 2H), 2.34 (td, J = 13.6, 9.1 Hz, 3H), 1.95 (d, J = 6.1 Hz, 1H), 1.77 - 1.75 (m, 6H), 1.29 - 1.22 (m, 2H). LC / MS (ESI+) calcd for C 47 H 50 FN5O5( [M+H] + ) m / z: 784.4; found 784.4。

[0332] Example 89. 3-(5-(7-((1-(4-((3S,4R)-3-(2-Fluorophenyl)-7-hydroxycoumarin-4-yl)phenyl)piperidin-4-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione TIFF2025523440000169.tif29170

[0333] The target compound was prepared in a similar manner to Example 78. 11H NMR (400 MHz, DMSO-d6) δ 10.95 (s, 1H), 9.36 (s, 1H), 7.48 (d, J = 8.3 Hz, 1H), 7.26 - 7.18 (m, 1H), 7.14 (ddd, J = 9.7, 8.2, 1.3 Hz, 1H), 6.89 (td, J = 7.5, 1.3 Hz, 1H), 6.67 (d, J = 8.3 Hz, 1H), 6.60 (d, J = 8.4 Hz, 2H), 6.50 (d, J = 1.9 Hz, 1H), 6.47 (dd, J = 8.3, 2.0 Hz, 1H), 6.41 (td, J = 8.4, 8.0, 6.1 Hz, 3H), 6.32 (d, J = 2.4 Hz, 1H), 6.29 (dd, J = 8.3, 2.4 Hz, 1H), 5.03 (dd, J = 13.3, 5.1 Hz, 1H), 4.36 (t, J = 11.0 Hz, 1H), 4.29 (d, J = 16.9 Hz, 1H), 4.25 - 4.13 (m, 3H), 3.74 - 3.68 (m, 1H), 3.63 (s, 4H), 3.55 - 3.52 (m, 3H), 3.36 - 3.34 (m, 1H), 2.90 (ddd, J = 17.5, 13.3, 5.3 Hz, 1H), 2.63 - 2.52 (m, 2H), 2.48 - 2.46 (m, 2H), 2.34 (qd, J = 13.2, 4.5 Hz, 4H), 2.12 - 2.10 (m, 1H), 2.00 - 1.98 (m, 1H), 1.75 - 1.72 (m, 6H), 1.27 - 1.22 (m, 2H). LC / MS (ESI+) calcd for C 47 H 50 FN5O5([M+H] + ) m / z: 784.4; found 784.4。

[0334] Example 90. (R)-3-(5-(7-((1-(4-((3S,4R)-3-(2-Fluorophenyl)-7-hydroxychroman-4-yl)phenyl)piperidin-4-yl)methyl)-2,7-diazaspiro[3.5]non-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione TIFF2025523440000170.tif22170

[0335] Compound 89 was resolved by chiral SFC to obtain the target product. The column was CHIRALPAK AS (30 * 250 mm 5 μm) (Daicel), the mobile phase was A = CO2, Co-Solvent B = IPA / ACN = 1 / 1 (0.1% 7M NH3 in MeOH), and the first component, i.e., the desired product, was recovered. 11H NMR (400 MHz, DMSO-d6) δ 10.94 (s, 1H), 9.33 (s, 1H), 7.46 (dd, J = 12.5, 8.3 Hz, 1H), 7.32 - 7.18 (m, 1H), 7.14 (ddd, J = 9.6, 8.3, 1.4 Hz, 1H), 6.89 (td, J = 7.5, 1.3 Hz, 1H), 6.67 (d, J = 8.3 Hz, 1H), 6.60 (d, J = 8.5 Hz, 2H), 6.53 - 6.49 (m, 1H), 6.47 (dd, J = 8.4, 2.0 Hz, 1H), 6.45 - 6.41 (m, 1H), 6.39 (d, J = 8.5 Hz, 2H), 6.31 (d, J = 2.3 Hz, 1H), 6.28 (dd, J = 8.2, 2.4 Hz, 1H), 5.03 (dd, J = 13.3, 5.1 Hz, 1H), 4.36 (t, J = 11.0 Hz, 1H), 4.29 (d, J = 16.9 Hz, 1H), 4.25 - 4.11 (m, 3H), 3.70 (dt, J = 11.4, 4.4 Hz, 1H), 3.61 (s, 4H), 3.52 (d, J = 15.7 Hz, 3H), 3.32 - 3.25 (m, 1H), 2.96 - 2.84 (m, 1H), 2.70 - 2.52 (m, 2H), 2.46 - 2.48 (m, 2H), 2.39 - 2.18 (m, 2H), 2.12 - 2.09 (m, 3H), 1.97 - 1.90 (m, 1H), 1.71 - 1.73 (m, 6H), 1.27 - 1.22 (m, 2H). LC / MS (ESI+) calcd for C 47 H 50 FN5O5([M+H] + ) m / z: 784.4; found 784.4。

[0336] (S)-3-(5-(7-((1-(4-((3S,4R)-3-(2-Fluorophenyl)-7-hydroxycoumarin-4-yl)phenyl)piperidin-4-yl)methyl)-2,7-diazaspiro[3.5]non-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione TIFF2025523440000171.tif22170

[0337] Compound 89 was resolved by chiral SFC to obtain the target product. The column was CHIRALPAK AS (30*250mm 5μm) (Daicel), the mobile phase was A = CO2, Co-Solvent B = IPA / ACN = 1 / 1 (0.1% 7M NH3In MeOH), and the second component, i.e., the desired product, was recovered. 11H NMR (400 MHz, DMSO-d6) δ 10.94 (s, 1H), 9.33 (s, 1H), 7.46 (dd, J = 12.5, 8.3 Hz, 1H), 7.32 - 7.18 (m, 1H), 7.14 (ddd, J = 9.6, 8.3, 1.4 Hz, 1H), 6.89 (td, J = 7.5, 1.3 Hz, 1H), 6.67 (d, J = 8.3 Hz, 1H), 6.60 (d, J = 8.5 Hz, 2H), 6.53 - 6.49 (m, 1H), 6.47 (dd, J = 8.4, 2.0 Hz, 1H), 6.45 - 6.41 (m, 1H), 6.39 (d, J = 8.5 Hz, 2H), 6.31 (d, J = 2.3 Hz, 1H), 6.28 (dd, J = 8.2, 2.4 Hz, 1H), 5.03 (dd, J = 13.3, 5.1 Hz, 1H), 4.36 (t, J = 11.0 Hz, 1H), 4.29 (d, J = 16.9 Hz, 1H), 4.25 - 4.11 (m, 3H), 3.70 (dt, J = 11.4, 4.4 Hz, 1H), 3.61 (s, 4H), 3.52 (d, J = 15.7 Hz, 3H), 3.32 - 3.25 (m, 1H), 2.96 - 2.84 (m, 1H), 2.70 - 2.52 (m, 2H), 2.46 - 2.48 (m, 1H), 2.39 - 2.18 (m, 3H), 2.10 (d, J = 7.0 Hz, 3H), 1.97 - 1.90 (m, 1H), 1.71 - 1.73 (m, 6H), 1.27 - 1.22 (m, 2H). LC / MS (ESI+) calcd for C 47 H 50 FN5O5( [M+H] + ) m / z: 784.4; found 784.4。

[0338] Example 92. 3-(5-(7-((1-(4-(cis-7-Hydroxy-3-(2,2,2-trifluoroethyl)chroman-4-yl)phenyl)piperidin-4-yl)methyl)-2,7-diazaspiro[3.5]non-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione TIFF2025523440000172.tif47170

[0339] Step 1: Synthesis of 4-(Dimethoxymethyl)-1-(4-(7-((tetrahydro-2H-pyran-2-yl)oxy)-3-(2,2,2-trifluoroethyl)-2H-chromen-4-yl)phenyl)piperidine To a high-pressure sealed tube were added 4-(dimethoxymethyl)-1-(4-(7-((tetrahydro-2H-pyran-2-yl)oxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-chromen-4-yl)phenyl)piperidine (591 mg, 1 mmol), nickel(II) bromide ethylene glycol dimethyl ether complex (31 mg, 0.1 mmol), bipyridine (31 mg, 0.2 mmol), potassium phosphate (640 mg, 3 mmol) and dimethyl sulfoxide (5 mL). The system was purged with nitrogen gas, and 2-iodo-1,1,1-trifluoroethane (630 mg, 3 mmol) was added under a nitrogen gas atmosphere. The reaction was carried out at 80 °C overnight in a sealed state. The reaction was monitored by TLC until the raw materials were completely reacted. After cooling to room temperature, it was filtered through celite, concentrated and subjected to column chromatography to obtain 180 mg of the product, which was identified as the target compound by LC-MS. Yield: 33%.

[0340] Step 2: Synthesis of 4-(Dimethoxymethyl)-1-(4-(cis-7-((tetrahydro-2H-pyran-2-yl)oxy)-3-(2,2,2-trifluoroethyl)chroman-4-yl)phenyl)piperidine 4-(Dimethoxymethyl)-1-(4-(7-((tetrahydro-2H-pyran-2-yl)oxy)-3-(2,2,2-trifluoroethyl)-2H-chromen-4-yl)phenyl)piperidine (180 mg, 0.33 mmol) was dissolved in THF (2 mL), methanol (25 mL) was added, 10% palladium on carbon (20 mg, 10%) was added, the system was purged with hydrogen gas, reacted overnight at room temperature, and monitored by TLC until the raw material completely reacted. It was filtered through celite to remove palladium on carbon, concentrated, and subjected to column chromatography to obtain 130 mg of the product, which was identified as the target compound by LC-MS. Yield 73%.

[0341] Step 3: Synthesis of 1-(4-(cis-7-hydroxy-3-(2,2,2-trifluoroethyl)chroman-4-yl)phenyl)piperidine-4-carboxaldehyde 4-(Dimethoxymethyl)-1-(4-(cis-7-((tetrahydro-2H-pyran-2-yl)oxy)-3-(2,2,2-trifluoroethyl)chroman-4-yl)phenyl)piperidine (130 mg, 0.23 mmol) was dissolved in THF (2 mL), sulfuric acid (1 mL, 2 M) was added, reacted at 70 °C for half an hour, monitored by TLC until the raw material completely reacted, cooled to room temperature, adjusted the pH to about 8 with saturated sodium bicarbonate, extracted with ethyl acetate, washed with saturated sodium chloride, dried and concentrated, and subjected to column chromatography to obtain 130 mg of the crude product, which was used directly in the next step.

[0342] Step 4: Synthesis of 3-(5-(7-((1-(4-(cis-7-hydroxy-3-(2,2,2-trifluoroethyl)chroman-4-yl)phenyl)piperidine-4-yl)methyl)-2,7-diazaspiro[3.5]non-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione The crude product 3-(1-oxo-5-(2,7-diazaspiro[3.5]nonan-2-yl)isoindolin-2-yl)piperidine-2,6-dione trifluoroacetate (51 mg, 0.11 mmol) was dissolved in dichloromethane / methanol (2 mL, 10:1), DIPEA (40 mg, 0.3 mmol) was added, and the mixture was stirred at room temperature for 5 min. 1-(4-(cis-7-hydroxy-3-(2,2,2-trifluoroethyl)chroman-4-yl)phenyl)piperidine-4-carboxaldehyde (42 mg, 0.1 mmol) was added, glacial acetic acid (18 mg, 0.3 mmol) was added, and the mixture was stirred at 35 °C for 0.5 h, cooled to room temperature, sodium triacetoxyborohydride (42 mg, 0.2 mmol) was added, and the reaction was carried out overnight. The reaction was monitored by TLC until the raw materials were completely reacted, and a saturated sodium bicarbonate solution was added to quench the reaction. The mixture was extracted with dichloromethane, dried and concentrated, and subjected to column chromatography to obtain 37 mg of the product, which was identified as the target compound by LC-MS. The total yield of the two steps was 48%. 11H NMR (400 MHz, DMSO-d6) δ 10.94 (s, 1H), 9.30 (s, 1H), 7.47 (d, J = 8.3 Hz, 1H), 6.88 (q, J = 8.7 Hz, 3H), 6.82 - 6.72 (m, 1H), 6.64 (dd, J = 9.1, 5.8 Hz, 1H), 6.55 - 6.42 (m, 2H), 6.31 - 6.18 (m, 2H), 5.03 (dd, J = 13.3, 5.1 Hz, 1H), 4.29 (d, J = 16.9 Hz, 1H), 4.16 (d, J = 17.0 Hz, 1H), 4.08 (dd, J = 18.1, 8.0 Hz, 2H), 3.89 (t, J = 10.9 Hz, 1H), 3.61 - 3.63 (m, 5H), 3.29 - 3.22 (m, 1H), 3.05 - 2.76 (m, 2H), 2.69 - 2.51 (m, 4H), 2.33 (d, J = 17.3 Hz, 6H), 2.13 (d, J = 7.2 Hz, 2H), 2.04 - 1.88 (m, 2H), 1.73 - 1.75 (m, 6H), 1.29 - 1.22 (m, 2H). LC / MS (ESI+) calcd for C 43 H 48 F3N5O5( [M+H] + ) m / z: 772.4; found 772.4。

[0343] Example 93: 3-Dideuterio-3-(5-(7-((1-(4-((3S,4R)-3-(2,6-difluorophenyl)-7-hydroxycoumarin-4-yl)-2-fluorophenyl)piperidin-4-yl)methyl)-2,7-diazaspiro[3.5]non-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione TIFF2025523440000173.tif24170

[0344] Compound 75 (100 mg, 0.12 mmol) was dissolved in a mixed solvent of 2 mL of deuterium oxide and 4 mL of acetonitrile. 4 drops of DIEA were added to the reaction solution, and the mixture was stirred at room temperature for 72 h. DCM was added to dilute the reaction solution. The organic phase was washed with water and saturated NaCl solution respectively, dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography to obtain the target compound (55 mg, 0.06 mmol) with a deuteration rate of 84%. Yield: 50%. LC / MS (ESI+) calcd for C 47 H 47 DF3N5O5(M + H + ) m / z, 821.3; found 821.3. 1 H NMR (400 MHz, DMSO-d6) δ 10.94 (s, 1H), 9.41 (s, 1H), 7.47 (d, J = 8.3 Hz, 1H), 7.38 - 7.29 (m, 1H), 6.96 (t, J = 9.3 Hz, 2H), 6.76 (t, J = 8.8 Hz, 1H), 6.69 (d, J = 9.1 Hz, 1H), 6.52 - 6.44 (m, 2H), 6.33 (ddt, J = 9.0, 5.0, 2.2 Hz, 3H), 6.23 (dd, J = 14.2, 2.0 Hz, 1H), 4.48 (d, J = 11.5 Hz, 1H), 4.29 (d, J = 16.5 Hz, 2H), 4.20 - 4.12 (m, 2H), 3.81 (dt, J = 11.6, 4.8 Hz, 1H), 3.62 (s, 4H), 3.22 (d, J = 8.7 Hz, 2H), 2.88 (d, J = 13.0 Hz, 1H), 2.57 (d, J = 18.7 Hz, 2H), 2.40 - 2.23 (m, 4H), 2.12 (d, J = 6.8 Hz, 2H), 1.97 - 1.87 (m, 1H), 1.74 (s, 6H), 1.59 (s, 1H), 1.22 (d, J = 7.7 Hz, 2H).

[0345] In Examples 94 to 100, Compounds 94 to 100 could be obtained by a method similar to that of Example 93.

[0346] Example 101. (cis-4-(4-(4-((2-(2-(2,6-Dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-2,7-diazaspiro[3.5]non-7-yl)methyl)piperidin-1-yl)phenyl)-3-(2-fluorophenyl)pyran-7-yl)boronic acid TIFF2025523440000174.tif54170

[0347] In a manner similar to Example 102, (cis)-4-(4-(4-((2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-2,7-diazaspiro[3.5]non-7-yl)methyl)piperidin-1-yl)phenyl)-3-(2-fluorophenyl)chroman-7-yl trifluoromethanesulfonate was prepared. (cis)-4-(4-(4-((2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-2,7-diazaspiro[3.5]non-7-yl)methyl)piperidin-1-yl)phenyl)-3-(2-fluorophenyl)chroman-7-yl trifluoromethanesulfonate (50 mg, 0.05 mmol), bis(pinacolato)diboron (28 mg, 0.11 mmol) were dissolved in 1,4-dioxane (5 mL), PdCl2(dppf) (4 mg, 0.005 mmol) and KOAc (20 mg, 0.11 mmol) were added, replaced with Ar gas three times, and reacted at 90 °C overnight. After complete reaction, it was cooled to room temperature, quenched by adding water, extracted with ethyl acetate, rotary dried, and the crude product was separated and purified by prep-TLC to obtain 10 mg of the target product. Yield: 22%. LC / MS (ESI+) calcd for C 47 H 51 BFN5O6( [M+H] + ) m / z 811.4; found 812.3。

[0348] 11H NMR (400 MHz, DMSO-d6) δ 10.94 (s, 1H), 8.01 (s, 2H), 7.47 (d, J = 8.3 Hz, 1H), 7.36 (d, J = 1.3 Hz, 1H), 7.28 - 7.20 (m, 2H), 7.14 (dd, J = 8.0, 2.6 Hz, 1H), 6.93 - 6.82 (m, 2H), 6.61 (d, J = 8.4 Hz, 2H), 6.52 - 6.35 (m, 5H), 5.03 (dd, J = 13.2, 5.0 Hz, 1H), 4.43 (t, J = 11.1 Hz, 1H), 4.35 - 4.14 (m, 4H), 3.76 (dd, J = 10.3, 5.6 Hz, 1H), 3.62 (s, 4H), 3.53 (d, J = 11.5 Hz, 2H), 2.93 - 2.84 (m, 1H), 2.57 (d, J = 22.2 Hz, 3H), 2.38 - 2.23 (m, 4H), 2.10 (s, 2H), 1.96 (dd, J = 12.6, 6.3 Hz, 2H), 1.74 (s, 5H), 1.60 (s, 1H), 1.46 (d, J = 7.6 Hz, 1H), 1.11 (d, J = 12.3 Hz, 2H).

[0349] Example 102. cis-4-(4-(4-((2-(2-(2,6-Dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-2,7-diazaspiro[3.5]non-7-yl)methyl)piperidin-1-yl)phenyl)-3-(2-fluorophenyl)chroman-7-carboxylic acid TIFF2025523440000175.tif47170

[0350] Step 1: Synthesis of cis-4-(4-(4-((2-(2-(2,6-Dioxopiperidin-3-yl)-1-oxoisoindol-5-yl)-2,7-diazaspiro[3.5]non-7-yl)methyl)piperidin-1-yl)phenyl)-3-(2-fluorophenyl)chroman-7-yl trifluoromethanesulfonate 3-(5-(7-((1-(4-(cis-3-(2-Fluorophenyl)-7-hydroxychroman-4-yl)phenyl)piperidin-4-yl)methyl)-2,7-diazaspiro[3.5]non-2-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (783 mg, 1 mmol) was dissolved in dichloromethane (15 mL), triethylamine (505 mg, 5 mmol) was added, and trifluoromethanesulfonic anhydride (846 mg, 3 mmol) was slowly added under an ice bath. The reaction was allowed to proceed overnight at room temperature. The cessation of the reaction was monitored by TLC. Water was added to quench the reaction, and the mixture was extracted with dichloromethane, washed with saturated sodium chloride, concentrated, dried, and subjected to column chromatography to obtain 360 mg of the product, which was identified as the target compound by LC-MS. Yield: 39%.

[0351] Step 2: cis-4-(4-(4-((2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-2,7-diazaspiro[3.5]non-7-yl)methyl)piperidin-1-yl)phenyl)-3-(2-fluorophenyl)chromane-7-carboxylic acid Palladium acetate (7 mg, 0.03 mmol) and Xantphos (17.3 mg, 0.03 mmol) were added to a sealed tube, and the reaction system was purged with nitrogen gas. Subsequently, a solution of cis-4-(4-(4-((2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindol-5-yl)-2,7-diazaspiro[3.5]non-7-yl)methyl)piperidin-1-yl)phenyl)-3-(2-fluorophenyl)chroman-7-yl trifluoromethanesulfonate (305 mg, 0.3 mmol) and carboxylic acid (86 mg, 1.5 mmol) dissolved in DMF (2 mL) was added to the sealed tube under a nitrogen gas atmosphere. Then, triethylamine (90 mg, 0.9 mmol) and DCC (7 mg, 0.03 mmol) were further added. The sealed tube was sealed and reacted at 100 °C overnight. The completion of the reaction was detected by TLC. The reaction system was cooled to room temperature, filtered through celite, concentrated, and subjected to column chromatography to obtain 12 mg of the target product. Yield: 5%.1 1H NMR (400 MHz, DMSO-d6) δ 10.94 (s, 1H), 7.48 - 7.46 (m, 2H), 7.40 (dd, J = 8.0, 1.6 Hz, 1H), 7.27 - 7.22 (m, 1H), 7.15 (td, J = 10.4, 2.8 Hz, 1H), 7.03 (d, J = 8.0 Hz, 1H), 6.92 (td, J = 7.6, 1.2 Hz, 1H), 6.68 - 6.61 (m, 2H), 6.50 - 6.45 (m, 3H), 6.41 (d, J = 8.4 Hz, 2H), 5.02 (dd, J = 13.2, 4.8 Hz, 1H), 4.48 (t, J = 11.2 Hz, 1H), 4.40 - 4.35 (m, 2H), 4.29 (d, J = 17.2 Hz, 1H), 4.16 (d, J = 16.8 Hz, 1H), 3.81 - 3.76 (m, 1H), 3.62 (s, 4H), 3.57 - 3.48 (m, 3H), 3.36 - 3.34 (m, 1H), 2.94 - 2.85 (m, 1H), 2.60 - 2.51 (m, 2H), 2.48 - 2.46 (m, 2H), 2.39 - 2.30 (m, 4H), 2.11 (d, J = 7.2 Hz, 2H), 1.96 - 1.91 (m, 1H), 1.75 - 1.72 (m, 5H), 1.23 - 1.22 (m, 2H). LC / MS (ESI+) calcd for C 48 H 50 FN5O6( [M+H] + ) m / z: 812.4; found 812.4。

[0352] Example 103. N-(2,6-Dioxopiperidin-3-yl)-2-fluoro-4-(7-((1-(4-(cis-3-(2-fluorophenyl)-7-hydroxycoumarin-4-yl)phenyl)piperidin-4-yl)methyl)-2,7-diazaspiro[3.5]non-2-yl)benzamide TIFF2025523440000176.tif32170

[0353] Step 1: Synthesis of 1-(4-(cis-3-(2-fluorophenyl)-7-hydroxy chroman-4-yl)phenyl)piperidine-4-carboxaldehyde Dissolve cis-4-(4-(4-(dimethoxymethyl)piperidin-1-yl)phenyl)-3-(2-fluorophenyl)pyran-7-ol (100 mg, 0.23 mmol) in dry THF (3 mL), add H2SO4 (2N, 1 mL), replace the system with an argon gas atmosphere, and react at 65 °C for 30 min. Monitor by TLC until the raw materials are completely reacted. After cooling to room temperature, adjust the pH to 7 - 8 with saturated NaHCO3, extract with ethyl acetate, wash with saturated sodium chloride, dry and concentrate to obtain 90 mg of a pink oily crude product. LC / MS (ESI+) calcd for C 27 H 26 FNO3 ([M + H] + ) m / z: 432.2; found 450.2. Yield: 99%.

[0354] Step 2: N-(2,6-dioxopiperidin-3-yl)-2-fluoro-4-(7-((1-(4-(cis-3-(2-fluorophenyl)-7-hydroxy chroman-4-yl)phenyl)piperidin-4-yl)methyl)-2,7-diazaspiro[3.5]non-2-yl)benzamide The crude product N-(2,6-dioxopiperidin-3-yl)-2-fluoro-4-(2,7-diazaspiro[3.5]non-2-yl)benzamide trifluoroacetate (79 mg, 0.21 mmol) and 1-(4-(cis-3-(2-fluorophenyl)-7-hydroxychroman-4-yl)phenyl)piperidine-4-carboxaldehyde (90 mg, 0.21 mmol) were dissolved in dichloromethane / methanol (4 mL, 4:1), glacial acetic acid (38 mg, 0.63 mmol) was added, stirred at room temperature for 1 hour, sodium triacetoxyborohydride (134 mg, 0.63 mmol) was added, and reacted overnight. The reaction was monitored by TLC until the raw materials were completely reacted, and saturated sodium bicarbonate solution was added to quench the reaction. Extracted with dichloromethane, dried and concentrated, and subjected to column chromatography to obtain 6 mg of a white solid. Total yield of two steps: 3%.

[0355] 11H NMR (400 MHz, DMSO-d6) δ 10.84 (s, 1H), 9.32 (s, 1H), 7.97 (d, J = 7.1 Hz, 1H), 7.59 (d, J = 8.9 Hz, 1H), 7.22 (s, 1H), 7.17 - 7.11 (m, 1H), 6.99 (d, J = 10.7 Hz, 1H), 6.89 (t, J = 7.5 Hz, 1H), 6.67 (d, J = 8.4 Hz, 1H), 6.60 (d, J = 8.5 Hz, 2H), 6.54 (s, 1H), 6.41 (t, J = 9.2 Hz, 2H), 6.32 - 6.26 (m, 2H), 6.22 (d, J = 13.3 Hz, 1H), 4.74 - 4.68 (m, 1H), 4.35 (d, J = 10.9 Hz, 1H), 4.22 (d, J = 10.2 Hz, 1H), 4.03 (d, J = 7.2 Hz, 1H), 3.70 (s, 1H), 3.61 (s, 4H), 3.53 (d, J = 12.4 Hz, 3H), 2.69 - 2.66 (m, 1H), 2.35 - 2.31 (m, 1H), 2.28 (s, 3H), 2.16 - 2.04 (m, 3H), 2.00 (d, J = 7.5 Hz, 2H), 1.90 (s, 1H), 1.73 (s, 6H), 1.61 - 1.56 (m, 1H), 1.17 (t, J = 7.1 Hz, 2H). LC / MS (ESI+) calcd for C 46 H 49 F2N5O5( [M+H] + ) m / z: 790.4; found 790.4。

[0356] Hereinafter, the beneficial effects of the present invention will be described by test examples.

[0357] Experimental Example 1. Degradation activity of the compound of the present invention against ER (Elisa enzyme-linked immunosorbent assay) After subculturing T47D breast cancer cells in cell culture medium, cells in good growth condition were inoculated into a 96-well plate, with 80 μL in each well and the number of cells in each well set to 25,000, and cultured in a cell incubator at 37 °C and 5% CO2 for 3 days. The drug was prepared as a 10 mM stock solution in dimethyl sulfoxide (DMSO). Before use, the cells were further diluted with cell culture medium and finally adjusted to six concentrations (100, 25, 6.25, 1.56, 0.39, 0.98 nM), and gently shaken to mix uniformly. Also, negative control wells (added with only the culture medium) and positive control wells (added with only cells and DMSO) were set up. After culturing the cells in the incubator for 24 hours, the cells were washed once with ice-cold 1×PBS. The PBS was discarded, and 60 μl of ice-cold 1× cell lysis buffer was added to each well of the cell culture plate, and the plate was placed on ice and incubated for 10 minutes. 50 μl of the diluted sample was pipetted into an ELISA plate, and after sealing the ELISA plate with plastic adhesive film, it was placed in an incubator at 37 °C and incubated for 2 hours. The adhesive film was removed, 200 μl of 1× wash buffer was added to each well, shaken for 5 minutes, discarded, and gently tapped to dry. The washing was performed 4 times. 100 μl of freshly prepared detection antibody (green) was added to each well of the ELISA plate. After sealing with plastic adhesive film, it was placed in an incubator at 37 °C and incubated for 1 hour. The adhesive film was removed, the detection antibody was discarded, gently tapped to dry, 200 μl of 1× wash buffer was added to each well, shaken for 5 minutes, discarded, and gently tapped to dry. The washing was performed 4 times. 100 μl of freshly prepared HRP-labeled secondary antibody (red) was added to each well of the ELISA plate. After sealing with plastic adhesive film, it was placed in an incubator at 37 °C and incubated for 30 minutes. The adhesive film was removed, the secondary antibody was discarded, gently tapped to dry, 200 μl of 1× wash buffer was added to each well, shaken for 5 minutes, discarded, and gently tapped to dry. The washing was performed 4 times. 100 μl of TMB substrate was added to each well of the ELISA plate and incubated in an incubator at 37 °C for 5 minutes. 100 μl of stop solution was added to each well of the ELISA plate and gently shaken for a few seconds.The bottom of each well was wiped with lint-free cloth. Absorbance was read at 450 nm within 30 minutes after the addition of the stop solution. Using the formula: Residual ERα% = 100 * (OD value of the detection well - OD value of the blank control well) / (OD value of the positive control well - OD value of the blank control well), the data was analyzed with the dose-response equation of the software GraphPad Prism8 to obtain the DC 50 value and D max value. The DC 50 and D max values are important indicators for measuring the degradation activity of the compound against the target protein. The DC 50 value is the compound concentration required to degrade 50% of the target protein. The D max value is the maximum percentage at which the compound can degrade the target protein. The DC 50 value and D max values of each compound are shown in Table 1. Taking Example 22 as an example, the experimental curve is shown in Figure 1.

[0358]

Table 1

[0359] Note: DC 50 : A: <10 nM, B: 10 - 50 nM, C: 50 - 100 nM, D: >100 nM. Dmax: A: >75%, B: 75 - 50%, C: <50%.

[0360] The results in Table 1 indicate that the compounds of the present invention have good degradation activity against ER. Among them, Compounds 12 - 13, 18 - 20, 22, 45, 67 - 69, 75 - 76, 78, and 91 showed better effects.

[0361] Experimental Example 2. Degradation Activity of the Compounds of the Present Invention against ER (Western Blotting) After subculturing T47D breast cancer cells in cell culture medium, cells with good growth status were inoculated into 6-well plates at 2 ml per well and 250,000 cells per well, and cultured overnight in a cell incubator at 37°C and 5% CO2. The drug was prepared as a 10 mM stock solution with dimethyl sulfoxide (DMSO). Before use, it was further diluted 3-fold with DMSO, and 2 μl of the diluted compound was taken and added to the cell culture wells (this resulted in a DMSO concentration of 0.1% in the culture system). Two wells were made in duplicate for each concentration, gently shaken, and uniformly mixed. Also, negative control wells (added with an equal amount of DMSO) and positive control wells were set up. After culturing for 24 hours, the cells were lysed with RIPA cell lysate, proteins were extracted, and the protein concentration was measured with a BCA kit. 5x concentrated protein loading buffer was added, heated at 100°C for 5 minutes, and then the samples were stored at -20°C. The protein amount per well was loaded onto a polyacrylamide gel at 30 μg and electrophoresis was performed. After transferring the proteins from the polyacrylamide gel to a PVDF membrane, 5% skim milk was added, sealed at room temperature for 1 hour, and incubated overnight at 4°C with the primary antibodies, anti-ERα rabbit mAb (CST, Cat#: 8644S) and anti-GAPDH rabbit mAb (CST, Cat#: 2118L). Then, the membrane was washed 3 times with TBST solution for 10 minutes each time, incubated with the secondary antibody (horseradish peroxidase-labeled goat anti-rabbit IgG) at room temperature for 2 hours, and washed 3 times with TBST solution for 10 minutes each time. Finally, ECL developing solution was added for color development, a photo was taken with an automatic chemiluminescence device, the image was collected, and analysis was performed. The results showed that the compound of the present invention had good degradation activity against ER.

[0362] Taking Example 81 as an example, Western blotting showed ER degradation results as shown in Figure 2, indicating that the compound had good ER degradation activity. Table 2 shows the degradation activity of the compound of the present invention against ER measured by protein blotting.

[0363]

Table 2

[0364] The results in Table 2 indicate that the compounds of the present invention have good degradation activity against ER.

[0365] Experimental Example 3. Anti-proliferation inhibitory activity of the compounds of the present invention against breast cancer cells After autoclaving 1.6% and 0.7% agarose, it was cooled to about 50 °C and placed in a water bath at 42 °C for use. MCF-7 breast cancer cells were subcultured in complete cell culture medium, and cells with good growth status were taken, digested, and counted for use. A gel prepared by mixing 50 μl of 1.6% agarose and 2× medium at a ratio of 1:1 was spread on the bottom of a 96-well plate and prepared for cooling and solidification. After uniformly mixing 0.7% agarose and the diluted cell suspension at a ratio of 1:1, 50 μl of the mixed solution of gel and cells was added to each well, with the number of cells in each well being 2000, and it was left to cool and solidify at room temperature. 50 μl of medium was added to the culture plate containing cells, and it was placed in an incubator at 37 °C and 5% CO2 for 24-hour culture. The drug was prepared as a 10 mM stock solution in dimethyl sulfoxide (DMSO). The stock solution was serially diluted 3-fold to obtain nine concentration gradients, and then each concentration of the compound was further diluted 250-fold with the culture medium (so that the DMSO concentration in the culture system became 0.1%), and two wells were duplicated for each concentration. 50 μL of the diluted compound was taken and added to the cell culture wells (the final concentrations were 10 μM, 3.3 μM, 1.1 μM, 0.37 μM…), and it was gently shaken to mix uniformly. In addition, three negative control wells with only cells added and three blank control wells with only the culture medium added (50 μL of DMSO diluted 250-fold with the culture medium was added to each of the 6 wells) were set up. After culturing for 15 days, the cell plate and CellTiter-Glo 3D Cell Viability were taken out and pre-equilibrated to room temperature. 80 μl of the medium was pipetted out and discarded from the cell plate, 120 μL of the CellTiter-Glo 3D Cell Viability solution was added to each well, shaken at 1200 rpm / min for 5 min, left in the dark for 25 min, and the fluorescence value was measured with a multimicroplate reader. The data was analyzed with the dose-response-inhibition equation of the software GraphPad Prism8 to obtain the IC 50 value shown in Table 3.

[0366]

Table 3

[0367] A: IC 50 <10 nM, B: IC 50 = 11 - 50 nM, C: IC 50 > 50 nM The results in Table 3 indicate that the compounds of the present invention have good anti - proliferation inhibitory activity against MCF - 7 breast cancer cells.

[0368] Experimental Example 4. Pharmacokinetics of the Compounds of the Present Invention Pharmacokinetics experimental procedure: An appropriate amount of the administered compound was weighed, and after calculating the final volume to be added, a drug solution at the corresponding concentration was prepared using a solvent (DMSO / HS - 15 / Tween 80 / D5W (5:5:2:88, v / v / v / v)). For 9 animals (female ICR mice, provided by Chengdu Dasi Experimental Animal Co., Ltd.), intravenous administration was performed at a dose of 1 mg / kg (administration volume 10 mL / kg, administration concentration 0.1 mg / mL). After administration, at the time points of 5 min, 15 min, 30 min, 1 h, 2 h, 4 h, 8 h, 12 h, and 24 h, sampling was performed alternately in groups of 3 animals each. For 9 animals (female ICR mice), forced oral administration was performed at a dose of 3 mg / kg (administration volume 10 mL / kg, administration concentration 0.3 mg / mL). After administration, at the time points of 15 min, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h, 12 h, and 24 h, sampling was performed alternately in groups of 3 animals each. The samples were anticoagulated with EDTA - K2 and centrifuged at 4°C for 5 min to separate the plasma. The plasma samples were mixed uniformly by vortexing. An appropriate amount of the internal standard solution was added to a 96 - well plate containing the standard curve sample, quality control sample, or sample to be measured, and an appropriate amount of methanol was added to the blank sample, followed by uniform mixing by vortexing. Then, after centrifugation for 15 min, the supernatant was taken and the sample was injected into LC - MS / MS for analysis. For the plasma drug concentration data at each time point, the main pharmacokinetic parameters were calculated using the Winnolin 8.3 non - compartmental model. TIFF2025523440000181.tif28170

[0369] Compound X (reference WO2018102725) and Y (reference US10800770) are each publicly available ER Protac compounds. The compounds of the present invention have better pharmacokinetics compared to these compounds. The exposure (AUC) and half-life (T 1 / 2 ) experimental results when orally administered at 3 mg / kg are shown in Table 4.

[0370]

Table 4

[0371] Note: AUC inf : A: >2.5 μg*h / mL, B: 1.4 - 2.5 μg*h / mL, T 1 / 2 : A: >3.5 h, B: 2.5 - 3.5 h.

[0372] Experimental Example 5. Efficacy experiment of the compounds of the present invention in a human-derived breast cancer mouse tumor model MCF-7 breast cancer cells were cultured in MEM culture medium containing 10% FBS, 0.01 mM NEAA, and 10 μg / ml insulin. MCF-7 cells in the exponential growth phase were collected and resuspended in PBS to a concentration suitable for subcutaneous inoculation in mice. The experimental animals were NOD / SCID female mice (purchased from Jiangsu Jicui Extract Biotechnology Co., Ltd.). Before tumor cell inoculation, a sustained-release estrogen tablet (17β-estradiol, Innovative Research of America, Sarasota, Florida, USA) at 0.36 mg / 60 days was subcutaneously implanted on the right back of the experimental animals. The day after the estrogen tablet was inoculated, 2×10 7 MCF-7 cells were inoculated into the right mammary pad of the experimental mice, and the cells were resuspended in PBS and Matrigel (1:1) (0.2 ml / mouse), and the growth status of the tumors was observed regularly.

[0373] When the tumors of the tumor-bearing mice reached an average volume of about 245.56 mm 3After growing until, they were randomly grouped based on the tumor size and administered. The grouping was performed using StudyDirector(TM) (version 3.1.399.19, supplier Studylog System, Inc., San Francisco, California, USA). The day of grouping was designated as day0, and administration was started according to the experimental plan. The experiment was conducted by forced oral administration once a day, and included a solvent group, a control group (Compound X, dose 10 mg / kg), and a compound administration group of the present invention (Compound 40 and 70 of the examples were administered at 3 mg / kg for the low-dose group, 10 mg / kg for the medium-dose group, and 30 mg / kg for the high-dose group, respectively, and Compound 89 and 73 of the examples were administered at 10 mg / kg for the medium-dose group and 30 mg / kg for the high-dose group, respectively). TIFF2025523440000183.tif28170

[0374] The administered compounds were prepared into a 0.3 mg / mL solution (3 mg / kg dose), a 1 mg / mL solution (10 mg / kg dose), or a 3 mg / mL solution (30 mg / kg dose) according to the administered dose using a solvent [DMSO + HS-15 + Tween 80 + D5W (5:5:2:88, v / v / v / v)] and administered by forced oral administration. The solvent group was administered by forced oral administration of a solvent added to DMSO.

[0375] After the start of administration, the body weight and tumor size of the mice were measured twice a week. Tumor volume calculation formula: Tumor volume (mm 3 ) = 1 / 2 × (a × b 2 ) (where a represents the major axis and b represents the minor axis). In the experiment, data was collected using software called StudyDirectorTM (version 3.1.399.19, supplier Studylog System, Inc.), and the raw data measured with a scale and calipers was imported into the software as it was. All processes of administration, tumor measurement, and body weight measurement were performed in a biosafety cabinet or a clean bench. The experiment was conducted for a total of 4 weeks and ended on day28. Tumor growth inhibition rate TGI calculation formula: TGI% = (1 - tumor volume of the administration group / tumor volume of the solvent control group) * 100%.

[0376] At the end of the experiment, the average tumor volume of the solvent control group was 513 mm 3 and the average tumor volume of the positive control group (Compound X, dose 10 mg / kg) was 362 mm 3 resulting in a corresponding TGI of 29%. The low-dose groups (3 mg / kg) of Compounds 40 and 70 of the examples both had a TGI of 29% - 30%, and the drug efficacy was equivalent to that of the 10 mg / kg dose group of Compound X. The medium- and high-dose groups (10 mg / kg, 30 mg / kg) of the compound administration groups of the present invention had a TGI of 40% - 72%. A higher TGI indicates better drug efficacy in suppressing tumors. The results show that the drug efficacy of the compounds of the present invention is significantly superior to that of Compound X in the control group. The solvent group, the control group, and each administration group all showed no significant change in body weight and no obvious toxic side effects, indicating that they have the characteristics of a good formulation drug.

[0377] As described above, the present invention provides an aromatic compound that can be used for the production of an estrogen receptor degrader and for the production of a drug for the treatment of diseases related to estrogen receptors, such as a drug for the treatment and / or prevention of cancer that may be breast cancer.

Claims

1. A compound represented by formula (I), or an optical isomer thereof, or a salt thereof, or a hydrate thereof, or a solvate thereof (provided that R １ is selected from hydrogen, C １ ~C ６ alkyl group, hydroxy group, amino group, carboxy group, C １ ~C ６ alkoxy group, boronic acid group, -OR', R' is selected from a phenyl group and a benzyl group, R ２ is a substituent at any position on the benzene ring, and a is the number of substituents R ２ and Each R ２ is independently selected from a halogen, a hydroxy group, an amino group, a cyano group, a trifluoromethyl group, a C １ -C ６ alkyl group, a 3- to 6-membered cycloalkyl group, a C １ -C ６ alkoxy group, a is 0, 1, 2 or 3, When the dashed line in the benzene ring is a bond, R ３ , R ４ is each independently selected from none, When there is no dashed line in the benzene ring, R ３ , R ４ are each independently selected from hydrogen, C １ to C ６ alkyl groups, or R ３ , R ４ are linked to form a 3- to 6-membered cycloalkyl group, R ５ is selected from C １ to C ６ alkyl group, 3- to 6-membered cycloalkyl group, trifluoromethyl group, trifluoroethyl group, substituted or unsubstituted 6- to 10-membered aryl group, substituted or unsubstituted 5- to 8-membered heteroaryl group, and the substituent of the aryl group or heteroaryl group is halogen, hydroxy group, amino group, cyano group, trifluoromethyl group, C １ to C ６ alkyl group, 3- to 6-membered cycloalkyl group, C １ to C ６ alkoxy group, and X is CR ７ R ８ , O, S, SO, SO ２ , NR ７ selected from R ７ 、R ８ each independently represents hydrogen, halogen, C １ -C ６ alkyl group, or a 3- to 6-membered cycloalkyl group, and is selected from them n is 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 and Each R ６ is independently selected from a halogen, a hydroxy group, an amino group, a cyano group, a trifluoromethyl group, C １ to C ６ alkyl group, a 3- to 6-membered cycloalkyl group, C １ to C ６ alkoxy group, b is 0, 1, 2 or 3, ring A and ring B are each independently selected from a 4- to 12-membered cycloalkyl group and a 4- to 12-membered heterocycloalkyl group, M is none, CR ９ R １０ , O, S, SO, SO ２ , NR ９ is selected from R ９ 、R １０ each independently represents hydrogen, C １ to C ６ alkyl group, and is selected from E ３ is a substituent at any position on the benzene ring, and c is the number of substituents E ３ and Each E ３ is independently selected from a halogen, a hydroxy group, an amino group, a cyano group, a trifluoromethyl group, a C １ to C ６ alkyl group, a 3- to 6-membered cycloalkyl group, a C １ to C ６ alkoxy group, or any two E ３ are linked to form a 3- to 6-membered cycloalkyl group, a 6- to 10-membered aryl group, a 4- to 12-membered heterocycloalkyl group, or a 5- to 8-membered heteroaryl group, c is 0, 1, 2 or 3, when there is no dashed line between Y and W, W is NH and Y is a halogen, When the dashed line between Y and W is a bond, W is N, Y is absent, and CR Ｙ１ R Ｙ２ , C(O), -CR １１ =CR １２ -, -CR １１ =N-, -N=N-, -OC(O)-, R Ｙ１ 、R Ｙ２ each independently represents hydrogen, C １ -C ６ alkyl group, and is selected from R １１ and R １２ are each independently selected from hydrogen, C １ to C ６ alkyl groups, R ２１ is selected from hydrogen or deuterium, the heteroatom of the heteroaryl group is O, N or S, and the number of the heteroatoms is 1, 2 or 3, the heteroatom of the heterocycloalkyl group is N, and the number of the heteroatoms is 1, 2 or 3.).

2. The compound according to claim 1, or an optical isomer thereof, or a salt thereof, or a hydrate thereof, or a solvate thereof, wherein the compound is represented by formula (II) (provided that R １ is selected from hydrogen, C １ to C ６ alkyl group, hydroxy group, amino group, carboxy group, C １ to C ６ alkoxy group, boronic acid group, -OR', R' is selected from a phenyl group and a benzyl group, R ２ is a substituent at any position on the benzene ring, and a is the number of substituents R ２ and Each R ２ is independently selected from a halogen, a hydroxy group, an amino group, a cyano group, a trifluoromethyl group, a C １ to C ６ alkyl group, a 3- to 6-membered cycloalkyl group, a C １ to C ６ alkoxy group, a is 0, 1, 2 or 3, When the dashed line in the benzene ring is a bond, R ３ , R ４ is each independently selected from none, When there is no dashed line in the benzene ring, R ３ , R ４ are each independently hydrogen, C １ to C ６ alkyl group, or R ３ , R ４ are linked to form a 3- to 6-membered cycloalkyl group, R ５ is selected from a C １ -C ６ alkyl group, a 3- to 6-membered cycloalkyl group, a trifluoromethyl group, a trifluoroethyl group, a substituted or unsubstituted 6- to 10-membered aryl group, and a substituted or unsubstituted 5- to 8-membered heteroaryl group, and the substituent of the aryl group or heteroaryl group is halogen, a hydroxy group, an amino group, a cyano group, a trifluoromethyl group, a C １ -C ６ alkyl group, a 3- to 6-membered cycloalkyl group, a C １ -C ６ alkoxy group, and X is CR ７ R ８ , O, S, SO, SO ２ , NR ７ selected from R ７ 、R ８ are each independently selected from hydrogen, halogen, C １ - C ６ alkyl group, and 3- to 6-membered cycloalkyl group, n is 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 and is Each R ６ is independently selected from a halogen, a hydroxy group, an amino group, a cyano group, a trifluoromethyl group, C １ to C ６ alkyl group, a 3- to 6-membered cycloalkyl group, C １ to C ６ alkoxy group, b is 0, 1, 2 or 3, ring A and ring B are each independently selected from a 4- to 12-membered cycloalkyl group and a 4- to 12-membered heterocycloalkyl group, M is none, CR ９ R １０ , O, S, SO, SO ２ , NR ９ is selected from R ９ and R １０ are each independently selected from hydrogen, C １ to C ６ alkyl groups, E ３ is a substituent at any position on the benzene ring, and c is the number of substituents E ３ and Each E ３ is independently selected from a halogen, a hydroxy group, an amino group, a cyano group, a trifluoromethyl group, a C １ to C ６ alkyl group, a 3- to 6-membered cycloalkyl group, a C １ to C ６ alkoxy group, or any two E ３ are linked to form a 3- to 6-membered cycloalkyl group, a 6- to 10-membered aryl group, a 4- to 12-membered heterocycloalkyl group, or a 5- to 8-membered heteroaryl group, 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 each independently represents hydrogen, C １ -C ６ alkyl group selected from, R １１ 、R １２ are each independently selected from hydrogen, C １ to C ６ alkyl groups, the heteroatom of the heteroaryl group is O, N or S, and the number of the heteroatoms is 1, 2 or 3, the heteroatom of the heterocycloalkyl group is N, and the number of the heteroatoms is 1, 2 or 3.).

3. The compound according to claim 2, or an optical isomer thereof, or a salt thereof, or a hydrate thereof, or a solvate thereof, wherein the compound is represented by formula (III) (provided that R ２ is a substituent at any position on the benzene ring, and a is the number of substituents R ２ and Each R ２ is independently selected from a halogen, a hydroxy group, an amino group, a cyano group, a trifluoromethyl group, C １ to C ６ alkyl group, a 3- to 6-membered cycloalkyl group, C １ to C ６ alkoxy group, a is 0, 1, 2 or 3, When the dashed line in the benzene ring is a bond, R ３ , R ４ is each independently selected from nothing, When there is no dashed line in the benzene ring, R ３ , R ４ are each independently hydrogen, C １ to C ６ alkyl group, or R ３ , R ４ are linked to form a 3- to 6-membered cycloalkyl group, R ５ is selected from a C １ -C ６ alkyl group, a 3- to 6-membered cycloalkyl group, a trifluoromethyl group, a trifluoroethyl group, a substituted or unsubstituted 6- to 10-membered aryl group, and a substituted or unsubstituted 5- to 8-membered heteroaryl group, and the substituent of the aryl group or heteroaryl group is halogen, a hydroxy group, an amino group, a cyano group, a trifluoromethyl group, C １ -C ６ alkyl group, a 3- to 6-membered cycloalkyl group, C １ -C ６ alkoxy group, and X is CR ７ R ８ , O, S, SO, SO ２ , NR ７ selected from R ７ 、 R ８ are each independently selected from hydrogen, halogen, C １ -C ６ alkyl group, and 3- to 6-membered cycloalkyl group n is 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 and Each R ６ is independently selected from a halogen, a hydroxy group, an amino group, a cyano group, a trifluoromethyl group, a C １ -C ６ alkyl group, a 3- to 6-membered cycloalkyl group, a C １ -C ６ alkoxy group, b is 0, 1, 2 or 3, ring A and ring B are each independently selected from a 4- to 12-membered cycloalkyl group and a 4- to 12-membered heterocycloalkyl group, M is none, CR ９ R １０ , O, S, SO, SO ２ , NR ９ is selected from R ９ 、 R １０ are each independently selected from hydrogen, C １ -C ６ alkyl groups, E ３ is a substituent at any position on the benzene ring, and c is the number of substituents E ３ and Each E ３ is independently selected from a halogen, a hydroxy group, an amino group, a cyano group, a trifluoromethyl group, a C １ to C ６ alkyl group, a 3- to 6-membered cycloalkyl group, a C １ to C ６ alkoxy group, or any two E ３ are linked to form a 3- to 6-membered cycloalkyl group, a 6- to 10-membered aryl group, a 4- to 12-membered heterocycloalkyl group, or a 5- to 8-membered heteroaryl group, c is 0, 1, 2 or 3, Y is none, CR Ｙ１ R Ｙ２ , C(O), -CR １１ =CR １２ -, -CR １１ =N-, -N=N-, -OC(O)-, R Ｙ１ 、R Ｙ２ are each independently selected from hydrogen, C １ -C ６ alkyl groups, R １１ 、R １２ each independently represents hydrogen, C １ to C ６ alkyl group, and is selected from them the heteroatom of the heteroaryl group is O, N or S, and the number of the heteroatoms is 1, 2 or 3, the heteroatom of the heterocycloalkyl group is N, and the number of the heteroatoms is 1, 2 or 3, Preferably, R ５ is selected from C １ to C ６ alkyl group, 3- to 6-membered cycloalkyl group, trifluoromethyl group, trifluoroethyl group, substituted or unsubstituted phenyl group, substituted or unsubstituted thienyl group, substituted or unsubstituted furyl group, substituted or unsubstituted pyrrolyl group, substituted or unsubstituted pyrimidinyl group, substituted or unsubstituted pyridazinyl group, substituted or unsubstituted pyrazolyl group, substituted or unsubstituted pyrazinyl group, and the substituents of the phenyl group, thienyl group, furyl group, pyrrolyl group, pyrimidinyl group, pyridazinyl group, pyrazolyl group or pyrazinyl group are halogen, hydroxy group, amino group, cyano group, trifluoromethyl group, C １ to C ６ alkyl group, 3- to 6-membered cycloalkyl group, C １ to C ６ alkoxy group, and is selected from X is CH ２ , CF ２ , O, S, SO, SO ２ , NR ７ selected from R ７ is selected from hydrogen, halogen, C １ to C ６ alkyl group, 3- to 6-membered cycloalkyl group, Ring A and ring B are each independently selected from a 4- to 12-membered cycloalkyl group and a 4- to 12-membered heterocycloalkyl group. When both ring A and ring B are heterocycloalkyl groups, one ring has one heteroatom N and the other ring has two heteroatoms N.).

4. The compound according to claim 3, or an optical isomer thereof, or a salt thereof, or a hydrate thereof, or a solvate thereof, wherein the compound is represented by formula (IV) (However,[[]]END]] R ２ is a substituent at any position on the benzene ring, and a is the number of substituents R ２ and Each R ２ is independently selected from a halogen, a hydroxy group, an amino group, a cyano group, a trifluoromethyl group, C １ to C ６ alkyl group, a 3- to 6-membered cycloalkyl group, C １ to C ６ alkoxy group, a is 0, 1, 2 or 3, R ３ and R ４ are each independently selected from hydrogen, C １ to C ６ alkyl groups, or R ３ and R ４ are linked to form a 3- to 6-membered cycloalkyl group, R ５ is selected from C １ -C ６ alkyl group, 3- to 6-membered cycloalkyl group, trifluoromethyl group, trifluoroethyl group, substituted or unsubstituted 6- to 10-membered aryl group, substituted or unsubstituted 5- to 8-membered heteroaryl group, and a substituent of the aryl group or heteroaryl group is halogen, hydroxy group, amino group, cyano group, trifluoromethyl group, C １ -C ６ alkyl group, 3- to 6-membered cycloalkyl group, C １ -C ６ alkoxy group, and X is CR ７ R ８ , O, S, SO, SO ２ , NR ７ selected from R ７ 、 R ８ each independently represents hydrogen, halogen, C １ -C ６ alkyl group, or a 3- to 6-membered cycloalkyl group, and is selected from the group consisting of: n is 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 and Each R ６ is independently selected from a halogen, a hydroxy group, an amino group, a cyano group, a trifluoromethyl group, C １ to C ６ alkyl group, a 3- to 6-membered cycloalkyl group, C １ to C ６ alkoxy group, b is 0, 1, 2 or 3, Ring A and ring B are each independently selected from a 4- to 12-membered cycloalkyl group and a 4- to 12-membered heterocycloalkyl group, M is none, CR ９ R １０ , O, S, SO, SO ２ , NR ９ is selected from R ９ 、R １０ are each independently selected from hydrogen, C １ -C ６ alkyl groups, E ３ is a substituent at any position on the benzene ring, and c is the number of substituents E ３ and Each E ３ is independently selected from a halogen, a hydroxy group, an amino group, a cyano group, a trifluoromethyl group, a C １ to C ６ alkyl group, a 3- to 6-membered cycloalkyl group, a C １ to C ６ alkoxy group, or any two E ３ are linked to form a 3- to 6-membered cycloalkyl group, a 6- to 10-membered aryl group, a 4- to 12-membered heterocycloalkyl group, or a 5- to 8-membered heteroaryl group, 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 each independently represents hydrogen, C １ -C ６ alkyl group, and is selected from R １１ and R １２ are each independently selected from hydrogen, C １ to C ６ alkyl groups, The heteroatom of the heteroaryl group is O, N or S, and the number of the heteroatoms is 1, 2 or 3, The heteroatom of the heterocycloalkyl group is N, and the number of the heteroatoms is 1, 2 or 3, Preferably,[[]]END]] R ５ is C １ to C ６ an alkyl group, a 3- to 6-membered cycloalkyl group, a trifluoromethyl group, a trifluoroethyl group, a substituted or unsubstituted phenyl group, a substituted or unsubstituted thienyl group, a substituted or unsubstituted furyl group, a substituted or unsubstituted pyrrolyl group, a substituted or unsubstituted pyrimidinyl group, a substituted or unsubstituted pyridazinyl group, a substituted or unsubstituted pyrazolyl group, a substituted or unsubstituted pyrazinyl group, and the substituents of the phenyl group, thienyl group, furyl group, pyrrolyl group, pyrimidinyl group, pyridazinyl group, pyrazolyl group or pyrazinyl group are halogen, a hydroxy group, an amino group, a cyano group, a trifluoromethyl group, C １ to C ６ an alkyl group, a 3- to 6-membered cycloalkyl group, C １ to C ６ an alkoxy group, and is selected from X is CH ２ , CF ２ , O, S, SO, SO ２ , NR ７ selected from R ７ is selected from hydrogen, halogen, C １ to C ６ alkyl group, and 3- to 6-membered cycloalkyl group, Ring A and ring B are each independently selected from a 4- to 12-membered cycloalkyl group and a 4- to 12-membered heterocycloalkyl group. When both ring A and ring B are heterocycloalkyl groups, one ring has one heteroatom N and the other ring has two heteroatoms N.).

5. The compound according to claim 4, or an optical isomer thereof, or a salt thereof, or a hydrate thereof, or a solvate thereof, wherein the compound is represented by formula (V) (However,[[]]END]] R ２ is a substituent at any position on the benzene ring, and a is the number of substituents R ２ and Each R ２ is independently selected from a halogen, a hydroxy group, an amino group, a cyano group, a trifluoromethyl group, C １ to C ６ alkyl group, a 3- to 6-membered cycloalkyl group, C １ to C ６ alkoxy group, a is 0, 1, 2 or 3, R ３ and R ４ are each independently selected from hydrogen, C １ to C ６ alkyl groups, or R ３ and R ４ are linked to form a 3- to 6-membered cycloalkyl group, R ５ is selected from C １ to C ６ alkyl group, 3- to 6-membered cycloalkyl group, trifluoromethyl group, trifluoroethyl group, substituted or unsubstituted 6- to 10-membered aryl group, substituted or unsubstituted 5- to 8-membered heteroaryl group, and the substituent of the aryl group or heteroaryl group is halogen, hydroxy group, amino group, cyano group, trifluoromethyl group, C １ to C ６ alkyl group, 3- to 6-membered cycloalkyl group, C １ to C ６ alkoxy group, and X is CR ７ R ８ , O, S, SO, SO ２ , NR ７ selected from, R ７ 、 R ８ each independently represents hydrogen, halogen, C １ ~C ６ alkyl group, or a 3- to 6-membered cycloalkyl group, and is selected from the group consisting of: n is 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 and Each R ６ is independently selected from a halogen, a hydroxy group, an amino group, a cyano group, a trifluoromethyl group, C １ to C ６ alkyl group, a 3- to 6-membered cycloalkyl group, C １ to C ６ alkoxy group, b is 0, 1, 2 or 3, Ring A and ring B are each independently selected from a 4- to 12-membered cycloalkyl group and a 4- to 12-membered heterocycloalkyl group, M is none, CR ９ R １０ , O, S, SO, SO ２ , NR ９ is selected from R ９ 、 R １０ are each independently selected from hydrogen, C １ to C ６ alkyl groups, E ３ is a substituent at any position on the benzene ring, and c is the number of substituents E ３ and Each E ３ is independently selected from a halogen, a hydroxy group, an amino group, a cyano group, a trifluoromethyl group, a C １ to C ６ alkyl group, a 3- to 6-membered cycloalkyl group, a C １ to C ６ alkoxy group, or any two E ３ are linked to form a 3- to 6-membered cycloalkyl group, a 6- to 10-membered aryl group, a 4- to 12-membered heterocycloalkyl group, or a 5- to 8-membered heteroaryl group, 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)-, and R Ｙ１ 、R Ｙ２ each independently represents hydrogen, C １ to C ６ and is selected from alkyl groups, R １１ 、R １２ are each independently selected from hydrogen, C １ -C ６ alkyl groups, The heteroatom of the heteroaryl group is O, N or S, and the number of the heteroatoms is 1, 2 or 3, The heteroatom of the heterocycloalkyl group is N, and the number of the heteroatoms is 1, 2 or 3, Preferably,[[]]END]] R ５ is selected from C １ -C ６ alkyl group, 3-6 membered cycloalkyl group, trifluoromethyl group, trifluoroethyl group, substituted or unsubstituted phenyl group, substituted or unsubstituted thienyl group, substituted or unsubstituted furyl group, substituted or unsubstituted pyrrolyl group, substituted or unsubstituted pyrimidinyl group, substituted or unsubstituted pyridazinyl group, substituted or unsubstituted pyrazolyl group, substituted or unsubstituted pyrazinyl group, and the substituents of the phenyl group, thienyl group, furyl group, pyrrolyl group, pyrimidinyl group, pyridazinyl group, pyrazolyl group or pyrazinyl group are halogen, hydroxy group, amino group, cyano group, trifluoromethyl group, C １ -C ６ alkyl group, 3-6 membered cycloalkyl group, C １ -C ６ alkoxy group, X is CH ２ , CF ２ , O, S, SO, SO ２ , NR ７ selected from R ７ is selected from hydrogen, halogen, C １ to C ６ alkyl group, 3- to 6-membered cycloalkyl group, Ring A and ring B are each independently selected from a 4- to 12-membered cycloalkyl group and a 4- to 12-membered heterocycloalkyl group. When both ring A and ring B are heterocycloalkyl groups, one ring has one heteroatom N and the other ring has two heteroatoms N.).

6. The compound according to claim 5, or an optical isomer thereof, or a salt thereof, or a hydrate thereof, or a solvate thereof, wherein the compound is represented by formula (VI) (wherein R ２ is a substituent at any position on the benzene ring, and a is the number of substituents R ２ and Each R ２ is independently selected from a halogen, a hydroxy group, an amino group, a cyano group, a trifluoromethyl group, C １ to C ６ alkyl group, a 3- to 6-membered cycloalkyl group, C １ to C ６ alkoxy group, a is 0, 1, 2 or 3; R ３ and R ４ are each independently selected from hydrogen, C １ to C ６ alkyl groups, or R ３ and R ４ are linked to form a 3- to 6-membered cycloalkyl group, R ５ is selected from a C １ -C ６ alkyl group, a 3- to 6-membered cycloalkyl group, a trifluoromethyl group, a trifluoroethyl group, a substituted or unsubstituted 6- to 10-membered aryl group, and a substituted or unsubstituted 5- to 8-membered heteroaryl group, and the substituent of the aryl group or heteroaryl group is halogen, a hydroxy group, an amino group, a cyano group, a trifluoromethyl group, a C １ -C ６ alkyl group, a 3- to 6-membered cycloalkyl group, a C １ -C ６ alkoxy group, X is CR ７ R ８ , O, S, SO, SO ２ , NR ７ selected from R ７ 、R ８ are each independently selected from hydrogen, halogen, C １ -C ６ alkyl group, and 3- to 6-membered cycloalkyl group R ６ is a substituent at any position on the benzene ring, and b is the number of substituents R ６ and Each R ６ is independently selected from a halogen, a hydroxy group, an amino group, a cyano group, a trifluoromethyl group, C １ to C ６ alkyl group, a 3- to 6-membered cycloalkyl group, C １ to C ６ alkoxy group, b is 0, 1, 2 or 3; Ring A and ring B are each independently selected from a 4- to 12-membered cycloalkyl group and a 4- to 12-membered heterocycloalkyl group; M is none, CR ９ R １０ , O, S, SO, SO ２ , NR ９ selected from R ９ 、R １０ each independently represents hydrogen, C １ -C ６ alkyl group, and is selected from E ３ is a substituent at any position on the benzene ring, and c is the number of substituents E ３ and Each E ３ is independently selected from halogen, hydroxy group, amino group, cyano group, trifluoromethyl group, C １ to C ６ alkyl group, 3- to 6-membered cycloalkyl group, C １ to C ６ alkoxy group, or any two E ３ are linked to form a 3- to 6-membered cycloalkyl group, 6- to 10-membered aryl group, 4- to 12-membered heterocycloalkyl group, 5- to 8-membered heteroaryl group, c is 0, 1, 2 or 3; Y is none, CR Ｙ１ R Ｙ２ , C(O), -CR １１ =CR １２ -, -CR １１ =N-, -N=N-, -OC(O)-, R Ｙ１ 、 R Ｙ２ are each independently selected from hydrogen, C １ - C ６ alkyl groups, R １１ 、 R １２ are each independently selected from hydrogen, C １ -C ６ alkyl groups, the heteroatom of the heteroaryl group is O, N or S, and the number of the heteroatoms is 1, 2 or 3; the heteroatom of the heterocycloalkyl group is N, and the number of the heteroatoms is 1, 2 or 3; preferably R ５ is selected from C １ -C ６ alkyl group, 3-6 membered cycloalkyl group, trifluoromethyl group, trifluoroethyl group, substituted or unsubstituted phenyl group, substituted or unsubstituted thienyl group, substituted or unsubstituted furyl group, substituted or unsubstituted pyrrolyl group, substituted or unsubstituted pyrimidinyl group, substituted or unsubstituted pyridazinyl group, substituted or unsubstituted pyrazolyl group, substituted or unsubstituted pyrazinyl group, and the substituents of the phenyl group, thienyl group, furyl group, pyrrolyl group, pyrimidinyl group, pyridazinyl group, pyrazolyl group or pyrazinyl group are halogen, hydroxy group, amino group, cyano group, trifluoromethyl group, C １ -C ６ alkyl group, 3-6 membered cycloalkyl group, C １ -C ６ alkoxy group, and is selected from X is CH ２ , CF ２ , O, S, SO, SO ２ , NR ７ selected from R ７ is selected from hydrogen, halogen, C １ to C ６ alkyl group, 3- to 6-membered cycloalkyl group, ring A and ring B are each independently selected from a 4- to 12-membered cycloalkyl group and a 4- to 12-membered heterocycloalkyl group, and when both ring A and ring B are heterocycloalkyl groups, one ring has one heteroatom N and the other ring has two heteroatoms N.).

7. The compound according to claim 6, or an optical isomer thereof, or a salt thereof, or a hydrate thereof, or a solvate thereof, wherein the compound is represented by formula (VII) (wherein R ３ and R ４ are each independently selected from hydrogen, C １ to C ６ alkyl groups, or R ３ and R ４ are linked to form a 3- to 6-membered cycloalkyl group, R ５ is selected from a C １ -C ６ alkyl group, a 3- to 6-membered cycloalkyl group, a trifluoromethyl group, a trifluoroethyl group, a substituted or unsubstituted 6- to 10-membered aryl group, a substituted or unsubstituted 5- to 8-membered heteroaryl group, and a substituent of the aryl group or heteroaryl group is halogen, a hydroxy group, an amino group, a cyano group, a trifluoromethyl group, a C １ -C ６ alkyl group, a 3- to 6-membered cycloalkyl group, a C １ -C ６ alkoxy group, X is CR ７ R ８ , O, S, SO, SO ２ , NR ７ selected from R ７ 、R ８ each independently represents hydrogen, halogen, C １ -C ６ alkyl group, or 3- to 6-membered cycloalkyl group, and is selected from among them R ６ is a substituent at any position on the benzene ring, and b is the number of substituents R ６ and Each R ６ is independently selected from a halogen, a hydroxy group, an amino group, a cyano group, a trifluoromethyl group, C １ to C ６ alkyl group, a 3- to 6-membered cycloalkyl group, C １ to C ６ alkoxy group, b is 0, 1, 2 or 3; Ring A and ring B are each independently selected from a 4- to 12-membered cycloalkyl group and a 4- to 12-membered heterocycloalkyl group; M is none, CR ９ R １０ , O, S, SO, SO ２ , NR ９ is selected from R ９ 、R １０ are each independently selected from hydrogen, C １ -C ６ alkyl groups, Y is none, CR Ｙ１ R Ｙ２ , C(O), -CR １１ =CR １２ -, -CR １１ =N-, -N=N-, -OC(O)-, and R Ｙ１ and R Ｙ２ are each independently selected from hydrogen, C １ to C ６ alkyl groups, R １１ 、 R １２ are each independently selected from hydrogen, C １ -C ６ alkyl groups, the heteroatom of the heteroaryl group is O, N or S, and the number of the heteroatoms is 1, 2 or 3; the heteroatom of the heterocycloalkyl group is N, and the number of the heteroatoms is 1, 2 or 3; preferably R ５ is selected from C １ to C ６ alkyl group, 3-6 membered cycloalkyl group, trifluoromethyl group, trifluoroethyl group, substituted or unsubstituted phenyl group, substituted or unsubstituted thienyl group, substituted or unsubstituted furyl group, substituted or unsubstituted pyrrolyl group, substituted or unsubstituted pyrimidinyl group, substituted or unsubstituted pyridazinyl group, substituted or unsubstituted pyrazolyl group, substituted or unsubstituted pyrazinyl group, and the substituents of the phenyl group, thienyl group, furyl group, pyrrolyl group, pyrimidinyl group, pyridazinyl group, pyrazolyl group or pyrazinyl group are halogen, hydroxy group, amino group, cyano group, trifluoromethyl group, C １ to C ６ alkyl group, 3-6 membered cycloalkyl group, C １ to C ６ alkoxy group, X is CH ２ , CF ２ , O, S, SO, SO ２ , NR ７ selected from, R ７ is selected from hydrogen, halogen, C １ to C ６ alkyl group, 3- to 6-membered cycloalkyl group, ring A and ring B are each independently selected from a 4- to 12-membered cycloalkyl group and a 4- to 12-membered heterocycloalkyl group, and when both ring A and ring B are heterocycloalkyl groups, one ring has one heteroatom N and the other ring has two heteroatoms N.).

8. The compound according to claim 7, or an optical isomer thereof, or a salt thereof, or a hydrate thereof, or a solvate thereof, wherein the compound is represented by formula (VIII) (wherein R ３ and R ４ are each independently selected from hydrogen, C １ to C ６ alkyl groups, or R ３ and R ４ are linked to form a 3- to 6-membered cycloalkyl group, R ５ is selected from C １ -C ６ alkyl group, 3-6 membered cycloalkyl group, trifluoromethyl group, trifluoroethyl group, substituted or unsubstituted 6-10 membered aryl group, substituted or unsubstituted 5-8 membered heteroaryl group, and the substituent of the aryl group or heteroaryl group is halogen, hydroxy group, amino group, cyano group, trifluoromethyl group, C １ -C ６ alkyl group, 3-6 membered cycloalkyl group, C １ -C ６ alkoxy group, and X is CR ７ R ８ , O, S, SO, SO ２ , NR ７ selected from R ７ 、 R ８ each independently represents hydrogen, halogen, C １ ~C ６ alkyl group, or a 3- to 6-membered cycloalkyl group, and is selected from among them Ring A and ring B are each independently selected from a 4- to 12-membered cycloalkyl group and a 4- to 12-membered heterocycloalkyl group; M is none, CR ９ R １０ , O, S, SO, SO ２ , NR ９ selected from R ９ 、 R １０ are each independently selected from hydrogen, C １ to C ６ alkyl groups, Y is none, CR Ｙ１ R Ｙ２ , C(O), -CR １１ =CR １２ -, -CR １１ =N-, -N=N-, -OC(O)-, R Ｙ１ and R Ｙ２ are each independently selected from hydrogen, C １ to C ６ alkyl groups, R １１ 、R １２ are each independently selected from hydrogen, C １ -C ６ alkyl groups, The heteroatom of the heteroaryl group is O, N or S, and the number of the heteroatoms is 1, 2 or 3. The heteroatom of the heterocycloalkyl group is N, and the number of the heteroatoms is 1, 2 or 3. Preferably, R ５ is C １ to C ６ an alkyl group, a 3- to 6-membered cycloalkyl group, a trifluoromethyl group, a substituted or unsubstituted phenyl group, a substituted or unsubstituted thienyl group, a substituted or unsubstituted furyl group, a substituted or unsubstituted pyrrolyl group, a substituted or unsubstituted pyrimidinyl group, a substituted or unsubstituted pyridazinyl group, a substituted or unsubstituted pyrazolyl group, or a substituted or unsubstituted pyrazinyl group, and the substituent of the phenyl group, thienyl group, furyl group, pyrrolyl group, pyrimidinyl group, pyridazinyl group, pyrazolyl group, or pyrazinyl group is halogen, a hydroxy group, an amino group, a cyano group, a trifluoromethyl group, C １ to C ６ an alkyl group, a 3- to 6-membered cycloalkyl group, C １ to C ６ an alkoxy group, and is selected from: X is CH ２ , CF ２ , O, S, SO, SO ２ , NR ７ selected from R ７ is selected from hydrogen, halogen, C １ to C ６ alkyl group, and 3- to 6-membered cycloalkyl group, ring A and ring B are each independently selected from a 4- to 12-membered cycloalkyl group and a 4- to 12-membered heterocycloalkyl group, and when both ring A and ring B are heterocycloalkyl groups, one ring has 1 heteroatom N and the other ring has 2 heteroatoms N.).

9. The compound according to claim 7, or an optical isomer thereof, or a salt thereof, or a hydrate thereof, or a solvate thereof, wherein the compound is the one represented by formula (IX) However, R ３ and R ４ are each independently selected from hydrogen, C １ to C ６ alkyl groups, or R ３ and R ４ are linked to form a 3- to 6-membered cycloalkyl group, R ５ is selected from a C １ -C ６ alkyl group, a 3- to 6-membered cycloalkyl group, a trifluoromethyl group, a trifluoroethyl group, a substituted or unsubstituted 6- to 10-membered aryl group, and a substituted or unsubstituted 5- to 8-membered heteroaryl group, and the substituent of the aryl group or heteroaryl group is halogen, a hydroxy group, an amino group, a cyano group, a trifluoromethyl group, a C １ -C ６ alkyl group, a 3- to 6-membered cycloalkyl group, a C １ -C ６ alkoxy group, X is CR ７ R ８ , O, S, SO, SO ２ , NR ７ selected from R ７ 、 R ８ each independently represents hydrogen, halogen, C １ -C ６ alkyl group, or a 3- to 6-membered cycloalkyl group, and is selected from them R ６ is a substituent at any position on the benzene ring, and b is the number of substituents R ６ and Each R ６ is independently selected from a halogen, a hydroxy group, an amino group, a cyano group, a trifluoromethyl group, a C １ -C ６ alkyl group, a 3- to 6-membered cycloalkyl group, a C １ -C ６ alkoxy group, b is 0, 1, 2 or 3, ring A and ring B are each independently selected from a 4- to 12-membered cycloalkyl group and a 4- to 12-membered heterocycloalkyl group, Y is none, CR Ｙ１ R Ｙ２ , C(O), -CR １１ =CR １２ -, -CR １１ =N-, -N=N-, -OC(O)-, and R Ｙ１ and R Ｙ２ are each independently selected from hydrogen, C １ to C ６ alkyl groups, R １１ and R １２ are each independently selected from hydrogen, C １ to C ６ alkyl groups, The heteroatom of the heteroaryl group is O, N or S, and the number of the heteroatoms is 1, 2 or 3. The heteroatom of the heterocycloalkyl group is N, and the number of the heteroatoms is 1, 2 or 3. Preferably, R ５ is selected from C １ to C ６ alkyl group, 3- to 6-membered cycloalkyl group, trifluoromethyl group, trifluoroethyl group, substituted or unsubstituted phenyl group, substituted or unsubstituted thienyl group, substituted or unsubstituted furyl group, substituted or unsubstituted pyrrolyl group, substituted or unsubstituted pyrimidinyl group, substituted or unsubstituted pyridazinyl group, substituted or unsubstituted pyrazolyl group, substituted or unsubstituted pyrazinyl group, and the substituents of the phenyl group, thienyl group, furyl group, pyrrolyl group, pyrimidinyl group, pyridazinyl group, pyrazolyl group or pyrazinyl group are halogen, hydroxy group, amino group, cyano group, trifluoromethyl group, C １ to C ６ alkyl group, 3- to 6-membered cycloalkyl group, C １ to C ６ alkoxy group, X is CH ２ , CF ２ , O, S, SO, SO ２ , NR ７ selected from R ７ is selected from hydrogen, halogen, C １ to C ６ alkyl group, and 3- to 6-membered cycloalkyl group, ring A and ring B are each independently selected from a 4- to 12-membered cycloalkyl group and a 4- to 12-membered heterocycloalkyl group, and when both ring A and ring B are heterocycloalkyl groups, one ring has 1 heteroatom N and the other ring has 2 heteroatoms N.).

10. The compound according to claim 9, or an optical isomer thereof, or a salt thereof, or a hydrate thereof, or a solvate thereof, wherein the compound is the one represented by formula (X) However, R ３ and R ４ are each independently selected from hydrogen, C １ to C ６ alkyl groups, or R ３ and R ４ are linked to form a 3- to 6-membered cycloalkyl group, R ５ is selected from a C １ -C ６ alkyl group, a 3- to 6-membered cycloalkyl group, a trifluoromethyl group, a trifluoroethyl group, a substituted or unsubstituted 6- to 10-membered aryl group, and a substituted or unsubstituted 5- to 8-membered heteroaryl group, and the substituent of the aryl group or heteroaryl group is halogen, a hydroxy group, an amino group, a cyano group, a trifluoromethyl group, a C １ -C ６ alkyl group, a 3- to 6-membered cycloalkyl group, a C １ -C ６ alkoxy group, X is CR ７ R ８ , O, S, SO, SO ２ , NR ７ selected from R ７ 、 R ８ are each independently selected from hydrogen, halogen, C １ -C ６ alkyl group, 3- to 6-membered cycloalkyl group, ring A and ring B are each independently selected from a 4- to 12-membered cycloalkyl group and a 4- to 12-membered heterocycloalkyl group, Y is none, CR Ｙ１ R Ｙ２ , C(O), -CR １１ =CR １２ -, -CR １１ =N-, -N=N-, -OC(O)-, and R Ｙ１ 、R Ｙ２ are each independently selected from hydrogen, C １ to C ６ alkyl groups, R １１ 、 R １２ are each independently selected from hydrogen, C １ to C ６ alkyl groups, The heteroatom of the heteroaryl group is O, N or S, and the number of the heteroatoms is 1, 2 or 3. The heteroatom of the heterocycloalkyl group is N, and the number of the heteroatoms is 1, 2 or 3. Preferably, R ５ is selected from C １ -C ６ alkyl group, 3- to 6-membered cycloalkyl group, trifluoromethyl group, trifluoroethyl group, substituted or unsubstituted phenyl group, substituted or unsubstituted thienyl group, substituted or unsubstituted furyl group, substituted or unsubstituted pyrrolyl group, substituted or unsubstituted pyrimidinyl group, substituted or unsubstituted pyridazinyl group, substituted or unsubstituted pyrazolyl group, substituted or unsubstituted pyrazinyl group, and the substituents of the phenyl group, thienyl group, furyl group, pyrrolyl group, pyrimidinyl group, pyridazinyl group, pyrazolyl group or pyrazinyl group are halogen, hydroxy group, amino group, cyano group, trifluoromethyl group, C １ -C ６ alkyl group, 3- to 6-membered cycloalkyl group, C １ -C ６ alkoxy group, and is selected from X is CH ２ , CF ２ , O, S, SO, SO ２ , NR ７ selected from R ７ is selected from hydrogen, halogen, C １ to C ６ alkyl group, 3- to 6-membered cycloalkyl group, ring A and ring B are each independently selected from a 4- to 12-membered cycloalkyl group and a 4- to 12-membered heterocycloalkyl group, and when both ring A and ring B are heterocycloalkyl groups, one ring has 1 heteroatom N and the other ring has 2 heteroatoms N.).

11. The compound according to claim 6, or an optical isomer thereof, or a salt thereof, or a hydrate thereof, or a solvate thereof, wherein the compound is represented by formula (XI) (wherein R ２ is a substituent at any position on the benzene ring, and a is the number of substituents R ２ and Each R ２ is independently selected from a halogen, a hydroxy group, an amino group, a cyano group, a trifluoromethyl group, C １ to C ６ alkyl group, a 3- to 6-membered cycloalkyl group, C １ to C ６ alkoxy group, a is 0, 1, 2 or 3; R ３ and R ４ are each independently selected from hydrogen, C １ to C ６ alkyl groups, or R ３ and R ４ are linked to form a 3- to 6-membered cycloalkyl group, R １１ is a substituent at any position on the benzene ring, and d is the number of substituents R １１ and Each R １１ is independently selected from a halogen, a hydroxy group, an amino group, a cyano group, a trifluoromethyl group, C １ to C ６ alkyl group, a 3- to 6-membered cycloalkyl group, C １ to C ６ alkoxy group, d is 0, 1, 2 or 3; X is CR ７ R ８ , O, S, SO, SO ２ , NR ７ selected from R ７ 、R ８ are each independently selected from hydrogen, halogen, C １ to C ６ alkyl group, and 3- to 6-membered cycloalkyl group R ６ is a substituent at any position on the benzene ring, and b is the number of substituents R ６ and Each R ６ is independently selected from a halogen, a hydroxy group, an amino group, a cyano group, a trifluoromethyl group, C １ to C ６ alkyl group, a 3- to 6-membered cycloalkyl group, C １ to C ６ alkoxy group, b is 0, 1, 2 or 3; ring A and ring B are each independently selected from a 4- to 12-membered cycloalkyl group and a 4- to 12-membered heterocycloalkyl group; M is none, CR ９ R １０ , O, S, SO, SO ２ , NR ９ is selected from R ９ and R １０ are each independently selected from hydrogen, C １ to C ６ alkyl groups, E ３ is a substituent at any position on the benzene ring, and c is the number of substituents E ３ and Each E ３ is independently selected from halogen, a hydroxy group, an amino group, a cyano group, a trifluoromethyl group, a C １ to C ６ alkyl group, a 3- to 6-membered cycloalkyl group, a C １ to C ６ alkoxy group, or any two E ３ are linked to form a 3- to 6-membered cycloalkyl group, a 6- to 10-membered aryl group, a 4- to 12-membered heterocycloalkyl group, or a 5- to 8-membered heteroaryl group, 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)-, and R Ｙ１ 、R Ｙ２ are each independently selected from hydrogen, C １ -C ６ alkyl groups, R １１ and R １２ are each independently selected from hydrogen, C １ to C ６ alkyl groups, the heteroatom of the heteroaryl group is O, N or S, and the number of the heteroatoms is 1, 2 or 3; the heteroatom of the heterocycloalkyl group is N, and the number of the heteroatoms is 1, 2 or 3; preferably, X is CH ２ , CF ２ , O, S, SO, SO ２ , NR ７ selected from, R ７ is selected from hydrogen, halogen, C １ to C ６ alkyl group, 3- to 6-membered cycloalkyl group, ring A and ring B are each independently selected from a 4- to 12-membered cycloalkyl group and a 4- to 12-membered heterocycloalkyl group, and when both ring A and ring B are heterocycloalkyl groups, one ring has one heteroatom N and the other ring has two heteroatoms N.).

12. The compound according to claim 11, or an optical isomer thereof, or a salt thereof, or a hydrate thereof, or a solvate thereof, wherein the compound is represented by formula (XII) (wherein R ２ is a substituent at any position on the benzene ring, and a is the number of substituents R ２ and Each R ２ is independently selected from a halogen, a hydroxy group, an amino group, a cyano group, a trifluoromethyl group, a C １ to C ６ alkyl group, a 3- to 6-membered cycloalkyl group, a C １ to C ６ alkoxy group, a is 0, 1, 2 or 3; R ３ and R ４ are each independently selected from hydrogen, C １ to C ６ alkyl groups, or R ３ and R ４ are linked to form a 3- to 6-membered cycloalkyl group, R １１ is a substituent at any position on the benzene ring, and d is the number of substituents R １１ and Each R １１ is independently selected from a halogen, a hydroxy group, an amino group, a cyano group, a trifluoromethyl group, a C １ to C ６ alkyl group, a 3- to 6-membered cycloalkyl group, a C １ to C ６ alkoxy group, d is 0, 1, 2 or 3; X is CR ７ R ８ , O, S, SO, SO ２ , NR ７ selected from R ７ 、 R ８ each independently represents hydrogen, halogen, C １ -C ６ alkyl group, or 3- to 6-membered cycloalkyl group, and is selected from among them R ６ is a substituent at any position on the benzene ring, and b is the number of substituents R ６ and Each R ６ is independently selected from a halogen, a hydroxy group, an amino group, a cyano group, a trifluoromethyl group, C １ to C ６ alkyl group, a 3- to 6-membered cycloalkyl group, C １ to C ６ alkoxy group, b is 0, 1, 2 or 3; M is none, CR ９ R １０ , O, S, SO, SO ２ , NR ９ selected from R ９ and R １０ are each independently selected from hydrogen, C １ to C ６ alkyl groups, R １２ is selected from hydrogen, halogen, C １ to C ６ alkyl group, and hydroxy group, m1, m2, m3, m4, m5, m6 are each independently selected from 0, 1, 2 or 3; E ３ is a substituent at any position on the benzene ring, and c is the number of substituents E ３ and Each E ３ is independently selected from a halogen, a hydroxy group, an amino group, a cyano group, a trifluoromethyl group, a C １ to C ６ alkyl group, a 3- to 6-membered cycloalkyl group, a C １ to C ６ alkoxy group, or any two E ３ are linked to form a 3- to 6-membered cycloalkyl group, a 6- to 10-membered aryl group, a 4- to 12-membered heterocycloalkyl group, or a 5- to 8-membered heteroaryl group, 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)-, and R Ｙ１ and R Ｙ２ are each independently selected from hydrogen, C １ to C ６ alkyl groups, R １１ 、R １２ each independently represents hydrogen, C １ -C ６ alkyl group, and is selected from the heteroatom of the heteroaryl group is O, N or S, and the number of the heteroatoms is 1, 2 or 3; the heteroatom of the heterocycloalkyl group is N, and the number of the heteroatoms is 1, 2 or 3; preferably, X is CH ２ , CF ２ , O, S, SO, SO ２ , NR ７ and is selected from R ７ is selected from hydrogen, halogen, C １ to C ６ alkyl group, 3- to 6-membered cycloalkyl group, Y is absent, CR Ｙ１ R Ｙ２ , C(O), -CR １１ =CR １２ -, -CR １１ =N-, -N=N-, -OC(O)-, and R Ｙ１ , R Ｙ２ is, independently, hydrogen, C １ -C ６ selected from alkyl groups, R １１ 、 R １２ are each independently selected from hydrogen, C １ -C ６ alkyl groups.).

13. The compound according to claim 12, or an optical isomer thereof, or a salt thereof, or a hydrate thereof, or a solvate thereof, wherein the compound is represented by formula (XIII) (wherein R ２ is a substituent at any position on the benzene ring, and a is the number of substituents R ２ and Each R ２ is independently selected from a halogen, a hydroxy group, an amino group, a cyano group, a trifluoromethyl group, a C １ to C ６ alkyl group, a 3- to 6-membered cycloalkyl group, a C １ to C ６ alkoxy group, a is 0, 1, 2 or 3; R ３ 、R ４ are each independently selected from hydrogen, C １ -C ６ alkyl groups, or R ３ 、R ４ are linked to form a 3- to 6-membered cycloalkyl group, R １１ is a substituent at any position on the benzene ring, and d is the number of substituents R １１ and Each R １１ is independently selected from a halogen, a hydroxy group, an amino group, a cyano group, a trifluoromethyl group, C １ to C ６ alkyl group, a 3- to 6-membered cycloalkyl group, C １ to C ６ alkoxy group, d is 0, 1, 2 or 3; X is CR ７ R ８ , O, S, SO, SO ２ , NR ７ selected from R ７ 、R ８ each independently represents hydrogen, halogen, C １ -C ６ alkyl group, or 3- to 6-membered cycloalkyl group, and is selected from them R ６ is a substituent at any position on the benzene ring, and b is the number of substituents R ６ and Each R ６ is independently selected from a halogen, a hydroxy group, an amino group, a cyano group, a trifluoromethyl group, C １ to C ６ alkyl group, a 3- to 6-membered cycloalkyl group, C １ to C ６ alkoxy group, b is 0, 1, 2 or 3; R １２ is selected from hydrogen, halogen, C １ to C ６ alkyl group, and hydroxy group, m1, m2, m3, m4, m5, m6 are each independently selected from 0, 1, 2 or 3; E ３ is a substituent at any position on the benzene ring, and c is the number of substituents E ３ and Each E ３ is independently selected from a halogen, a hydroxy group, an amino group, a cyano group, a trifluoromethyl group, a C １ to C ６ alkyl group, a 3- to 6-membered cycloalkyl group, a C １ to C ６ alkoxy group, or any two E ３ are linked to form a 3- to 6-membered cycloalkyl group, a 6- to 10-membered aryl group, a 4- to 12-membered heterocycloalkyl group, or a 5- to 8-membered heteroaryl group, 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)-, and R Ｙ１ 、R Ｙ２ are each independently selected from hydrogen, C １ -C ６ alkyl groups, R １１ 、 R １２ are each independently selected from hydrogen, C １ -C ６ alkyl groups, the heteroatom of the heteroaryl group is O, N or S, and the number of the heteroatoms is 1, 2 or 3; The heteroatom of the heterocycloalkyl group is N, and the number of the heteroatoms is 1, 2 or 3. Preferably, X is CH ２ , CF ２ , O, S, SO, SO ２ , NR ７ is selected from, R ７ is selected from hydrogen, halogen, C １ to C ６ alkyl group, 3- to 6-membered cycloalkyl group, Y is none, CR Ｙ１ R Ｙ２ , C(O), -CR １１ =CR １２ -, -CR １１ =N-, -N=N-, -OC(O)-, and R Ｙ１ 、R Ｙ２ are each independently selected from hydrogen, C １ -C ６ alkyl groups, R １１ 、 R １２ are each independently selected from hydrogen, C １ -C ６ alkyl groups.).

14. The compound according to claim 12, or an optical isomer thereof, or a salt thereof, or a hydrate thereof, or a solvate thereof, wherein the compound is represented by the formula (XIV) provided that R ２ is a substituent at any position on the benzene ring, and a is the number of substituents R ２ and Each R ２ is independently selected from a halogen, a hydroxy group, an amino group, a cyano group, a trifluoromethyl group, C １ to C ６ alkyl group, a 3- to 6-membered cycloalkyl group, C １ to C ６ alkoxy group, a is 0, 1, 2 or 3; R ３ and R ４ are each independently selected from hydrogen, C １ to C ６ alkyl groups, or R ３ and R ４ are linked to form a 3- to 6-membered cycloalkyl group, R １１ is a substituent at any position on the benzene ring, and d is the number of substituents R １１ and is Each R １１ is independently selected from a halogen, a hydroxy group, an amino group, a cyano group, a trifluoromethyl group, a C １ to C ６ alkyl group, a 3- to 6-membered cycloalkyl group, a C １ to C ６ alkoxy group, d is 0, 1, 2 or 3; X is CR ７ R ８ , O, S, SO, SO ２ , NR ７ selected from R ７ 、 R ８ are each independently selected from hydrogen, halogen, C １ -C ６ alkyl group, and 3- to 6-membered cycloalkyl group R ６ is a substituent at any position on the benzene ring, and b is the number of substituents R ６ and Each R ６ is independently selected from a halogen, a hydroxy group, an amino group, a cyano group, a trifluoromethyl group, C １ to C ６ alkyl group, a 3- to 6-membered cycloalkyl group, C １ to C ６ alkoxy group, b is 0, 1, 2 or 3; R １２ is selected from hydrogen, halogen, C １ to C ６ alkyl group, and hydroxy group, m1, m2, m3, m4, m5, m6 are each independently selected from 0, 1, 2 or 3; E ３ is a substituent at any position on the benzene ring, and c is the number of substituents E ３ and Each E ３ is independently selected from a halogen, a hydroxy group, an amino group, a cyano group, a trifluoromethyl group, a C １ to C ６ alkyl group, a 3- to 6-membered cycloalkyl group, a C １ to C ６ alkoxy group, or any two E ３ are linked to form a 3- to 6-membered cycloalkyl group, a 6- to 10-membered aryl group, a 4- to 12-membered heterocycloalkyl group, or a 5- to 8-membered heteroaryl group, 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 each independently represents hydrogen, C １ to C ６ alkyl group, and is selected from them R １１ 、R １２ are each independently selected from hydrogen, C １ -C ６ alkyl groups, the heteroatom of the heteroaryl group is O, N or S, and the number of the heteroatoms is 1, 2 or 3; the heteroatom of the heterocycloalkyl group is N, and the number of the heteroatoms is 1, 2 or 3. Preferably, X is CH ２ , CF ２ , O, S, SO, SO ２ , NR ７ and is selected from R ７ is selected from hydrogen, halogen, C １ to C ６ alkyl group, 3- to 6-membered cycloalkyl group, Y is none, CR Ｙ１ R Ｙ２ , C(O), -CR １１ =CR １２ -, -CR １１ =N-, -N=N-, -OC(O)-, and R Ｙ１ 、 R Ｙ２ are each independently selected from hydrogen, C １ -C ６ alkyl groups, R １１ , R １２ are each independently selected from hydrogen, C １ -C ６ alkyl groups.).

15. The compound according to claim 6, or an optical isomer thereof, or a salt thereof, or a hydrate thereof, or a solvate thereof, wherein the compound is represented by the formula (XV) provided that R ２ is a substituent at any position on the benzene ring, and a is the number of substituents R ２ and Each R ２ is independently selected from a halogen, a hydroxy group, an amino group, a cyano group, a trifluoromethyl group, C １ to C ６ alkyl group, a 3- to 6-membered cycloalkyl group, C １ to C ６ alkoxy group, a is 0, 1, 2 or 3; R ３ and R ４ are each independently selected from hydrogen, C １ to C ６ alkyl groups, or R ３ and R ４ are linked to form a 3- to 6-membered cycloalkyl group, R １１ is a substituent at any position on the thiophene ring, and d is the number of substituents R １１ and is Each R １１ is independently selected from a halogen, a hydroxy group, an amino group, a cyano group, a trifluoromethyl group, C １ to C ６ alkyl group, a 3- to 6-membered cycloalkyl group, C １ to C ６ alkoxy group, d is 0, 1, 2 or 3; X is CR ７ R ８ , O, S, SO, SO ２ , NR ７ selected from R ７ 、R ８ each independently represents hydrogen, halogen, C １ to C ６ alkyl group, or a 3- to 6-membered cycloalkyl group, and is selected from R ６ is a substituent at any position on the benzene ring, and b is the number of substituents R ６ and Each R ６ is independently selected from a halogen, a hydroxy group, an amino group, a cyano group, a trifluoromethyl group, C １ to C ６ alkyl group, a 3- to 6-membered cycloalkyl group, C １ to C ６ alkoxy group, b is 0, 1, 2 or 3; ring A and ring B are each independently selected from a 4- to 12-membered cycloalkyl group and a 4- to 12-membered heterocycloalkyl group; M is none, CR ９ R １０ , O, S, SO, SO ２ , NR ９ is selected from R ９ 、 R １０ are each independently selected from hydrogen, C １ to C ６ alkyl groups, E ３ is a substituent at any position on the benzene ring, and c is the number of substituents E ３ and Each E ３ is independently selected from a halogen, a hydroxy group, an amino group, a cyano group, a trifluoromethyl group, a C １ to C ６ alkyl group, a 3- to 6-membered cycloalkyl group, a C １ to C ６ alkoxy group, or any two E ３ are linked to form a 3- to 6-membered cycloalkyl group, a 6- to 10-membered aryl group, a 4- to 12-membered heterocycloalkyl group, or a 5- to 8-membered heteroaryl group, c is 0, 1, 2 or 3; Y is none, CR Ｙ１ R Ｙ２ , C(O), -CR １１ =CR １２ -, -CR １１ =N-, -N=N-, -OC(O)-, R Ｙ１ 、R Ｙ２ are each independently selected from hydrogen, C １ - C ６ alkyl groups, R １１ 、R １２ each independently represents hydrogen, C １ -C ６ selected from alkyl groups, the heteroatom of the heteroaryl group is O, N or S, and the number of the heteroatoms is 1, 2 or 3; the heteroatom of the heterocycloalkyl group is N, and the number of the heteroatoms is 1, 2 or 3. Preferably, X is CH ２ , CF ２ , O, S, SO, SO ２ , NR ７ selected from R ７ is selected from hydrogen, halogen, C １ to C ６ alkyl group, 3- to 6-membered cycloalkyl group, ring A and ring B are each independently selected from a 4- to 12-membered cycloalkyl group and a 4- to 12-membered heterocycloalkyl group. When both ring A and ring B are heterocycloalkyl groups, one ring has one heteroatom N and the other ring has two heteroatoms N.

16. The compound according to claim 6, or an optical isomer thereof, or a salt thereof, or a hydrate thereof, or a solvate thereof, wherein the compound is represented by the formula (XVI) provided that R ２ is a substituent at any position on the benzene ring, and a is the number of substituents R ２ and Each R ２ is independently selected from a halogen, a hydroxy group, an amino group, a cyano group, a trifluoromethyl group, C １ to C ６ alkyl group, a 3- to 6-membered cycloalkyl group, C １ to C ６ alkoxy group, a is 0, 1, 2 or 3; R ３ and R ４ are each independently selected from hydrogen, C １ to C ６ alkyl groups, or R ３ and R ４ are linked to form a 3- to 6-membered cycloalkyl group, R １１ is a substituent at any position on the thiophene ring, and d is the number of substituents R １１ and is Each R １１ is independently selected from a halogen, a hydroxy group, an amino group, a cyano group, a trifluoromethyl group, C １ to C ６ alkyl group, a 3- to 6-membered cycloalkyl group, C １ to C ６ alkoxy group, d is 0, 1, 2 or 3; X is CR ７ R ８ , O, S, SO, SO ２ , NR ７ selected from R ７ 、 R ８ each independently represents hydrogen, halogen, C １ -C ６ alkyl group, or a 3- to 6-membered cycloalkyl group, and is selected from R ６ is a substituent at any position on the benzene ring, and b is the number of substituents R ６ and Each R ６ is independently selected from a halogen, a hydroxy group, an amino group, a cyano group, a trifluoromethyl group, C １ to C ６ alkyl group, a 3- to 6-membered cycloalkyl group, C １ to C ６ alkoxy group, b is 0, 1, 2 or 3; ring A and ring B are each independently selected from a 4- to 12-membered cycloalkyl group and a 4- to 12-membered heterocycloalkyl group. M is none, CR ９ R １０ , O, S, SO, SO ２ , NR ９ is selected from R ９ 、R １０ each independently represents hydrogen, C １ to C ６ alkyl group, and is selected from E ３ is a substituent at any position on the benzene ring, and c is the number of substituents E ３ and Each E ３ is independently selected from a halogen, a hydroxy group, an amino group, a cyano group, a trifluoromethyl group, a C １ to C ６ alkyl group, a 3- to 6-membered cycloalkyl group, a C １ to C ６ alkoxy group, or any two E ３ are linked to form a 3- to 6-membered cycloalkyl group, a 6- to 10-membered aryl group, a 4- to 12-membered heterocycloalkyl group, or a 5- to 8-membered heteroaryl group, 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)-, and R Ｙ１ 、 R Ｙ２ are each independently selected from hydrogen, C １ -C ６ alkyl groups, R １１ 、 R １２ are each independently selected from hydrogen, C １ to C ６ alkyl groups, the heteroatom of the heteroaryl group is O, N or S, and the number of the heteroatoms is 1, 2 or 3, the heteroatom of the heterocycloalkyl group is N, and the number of the heteroatoms is 1, 2 or 3, preferably, X is CH ２ , CF ２ , O, S, SO, SO ２ , NR ７ selected from R ７ is selected from hydrogen, halogen, C １ to C ６ alkyl group, 3- to 6-membered cycloalkyl group, ring A and ring B are each independently selected from a 4- to 12-membered cycloalkyl group and a 4- to 12-membered heterocycloalkyl group. When both ring A and ring B are heterocycloalkyl groups, one ring has one heteroatom N and the other ring has two heteroatoms N.).

17. The compound according to claim 2, or an optical isomer thereof, or a salt thereof, or a hydrate thereof, or a solvate thereof, wherein the compound is represented by formula (XVII) provided that R ３ and R ４ are each independently selected from hydrogen, C １ to C ６ alkyl groups, or R ３ and R ４ are linked to form a 3- to 6-membered cycloalkyl group, X is CR ７ R ８ , O, S, SO, SO ２ , NR ７ selected from R ７ 、 R ８ each independently represents hydrogen, halogen, C １ to C ６ alkyl group, or 3- to 6-membered cycloalkyl group, and is selected from the group consisting of: R １１ is a substituent at any position on the benzene ring, and d is the number of substituents R １１ where R ６ is a substituent at any position on the benzene ring, and b is the number of substituents R ６ where d is 0, 1, 2, or 3, b is 0, 1, 2, or 3, and at least one of d and b is not 0, Each R １１ , R ６ is independently selected from a halogen, a hydroxy group, an amino group, a cyano group, a trifluoromethyl group, a C １ to C ６ alkyl group, a 3- to 6-membered cycloalkyl group, a C １ to C ６ alkoxy group, and at least one is fluorine, ring A and ring B are each independently selected from a 4- to 12-membered cycloalkyl group and a 4- to 12-membered heterocycloalkyl group, M is none, CR ９ R １０ , O, S, SO, SO ２ , NR ９ is selected from R ９ 、R １０ each independently represents hydrogen, C １ -C ６ alkyl group, and is selected from Y is none, CR Ｙ１ R Ｙ２ , C(O), -CR １１ =CR １２ -, -CR １１ =N-, -N=N-, -OC(O)-, and R Ｙ１ 、R Ｙ２ are each independently selected from hydrogen, C １ to C ６ alkyl groups, R １１ 、R １２ each independently represents hydrogen, C １ ~C ６ selected from alkyl groups, the heteroatom of the heterocycloalkyl group is N, and the number of the heteroatoms is 1, 2 or 3, preferably, X is CH ２ , CF ２ , O, S, SO, SO ２ , NR ７ selected from R ７ is selected from hydrogen, halogen, C １ to C ６ alkyl group, 3- to 6-membered cycloalkyl group, ring A and ring B are each independently selected from a 4- to 12-membered cycloalkyl group and a 4- to 12-membered heterocycloalkyl group. When both ring A and ring B are heterocycloalkyl groups, one ring has one heteroatom N and the other ring has two heteroatoms N.).

18. The compound according to claim 17, or an optical isomer thereof, or a salt thereof, or a hydrate thereof, or a solvate thereof, wherein the compound is represented by formula (XVIII) provided that X is CR ７ R ８ , O, S, SO, SO ２ , NR ７ selected from R ７ 、R ８ each independently represents hydrogen, halogen, C １ -C ６ alkyl group, or 3- to 6-membered cycloalkyl group, and is selected from among them R １１ is a substituent at any position on the benzene ring, and d is the number of substituents R １１ where R ６ is a substituent at any position on the benzene ring, and b is the number of substituents R ６ where d is 0, 1, 2, or 3, b is 0, 1, 2, or 3, and at least one of d and b is not 0, Each R １１ , R ６ is independently selected from a halogen, a hydroxy group, an amino group, a cyano group, a trifluoromethyl group, a C １ -C ６ alkyl group, a 3- to 6-membered cycloalkyl group, a C １ -C ６ alkoxy group, and at least one is fluorine, ring A and ring B are each independently selected from a 4- to 12-membered cycloalkyl group and a 4- to 12-membered heterocycloalkyl group, M is none, CR ９ R １０ is selected from R ９ and R １０ are each independently selected from hydrogen, C １ to C ６ alkyl groups, Y is none, CR Ｙ１ R Ｙ２ , C(O), -CR １１ =CR １２ -, -CR １１ =N-, -N=N-, -OC(O)-, and R Ｙ１ and R Ｙ２ are each independently selected from hydrogen, C １ to C ６ alkyl groups, R １１ 、 R １２ are each independently selected from hydrogen, C １ -C ６ alkyl groups, the heteroatom of the heterocycloalkyl group is N, and the number of the heteroatoms is 1, 2 or 3, preferably, X is CH ２ , CF ２ or O, and is selected from Ring A and ring B are each independently selected from a 4- to 12-membered cycloalkyl group and a 4- to 12-membered heterocycloalkyl group, and when both ring A and ring B are heterocycloalkyl groups, one ring has one heteroatom N and the other ring has two heteroatoms N.).

19. The compound according to claim 2, or an optical isomer thereof, or a salt thereof, or a hydrate thereof, or a solvate thereof, wherein the compound is represented by formula (XIX) (However, R １ is hydrogen, C １ to C ６ alkyl group, hydroxy group, amino group or C １ to C ６ alkoxy group, boronic acid group, and is selected from R ２ is a substituent at any position on the benzene ring, and a is the number of substituents R ２ and Each R ２ is independently selected from a halogen, a hydroxy group, an amino group, a cyano group, a trifluoromethyl group, C １ to C ６ alkyl group, a 3- to 6-membered cycloalkyl group, C １ to C ６ alkoxy group, a is 0, 1, 2 or 3, R ５ is selected from C １ to C ６ alkyl group, 3- to 6-membered cycloalkyl group, trifluoromethyl group, trifluoroethyl group, substituted or unsubstituted 6- to 10-membered aryl group, substituted or unsubstituted 5- to 8-membered heteroaryl group, and the substituent of the aryl group or heteroaryl group is halogen, hydroxy group, amino group, cyano group, trifluoromethyl group, C １ to C ６ alkyl group, 3- to 6-membered cycloalkyl group, C １ to C ６ alkoxy group, and is selected from X is CR ７ R ８ , O, S, SO, SO ２ , NR ７ selected from R ７ 、 R ８ each independently represents hydrogen, halogen, C １ -C ６ alkyl group, or 3- to 6-membered cycloalkyl group, and is selected from them n is 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 and is Each R ６ is independently selected from a halogen, a hydroxy group, an amino group, a cyano group, a trifluoromethyl group, C １ to C ６ alkyl group, a 3- to 6-membered cycloalkyl group, C １ to C ６ alkoxy group, b is 0, 1, 2 or 3, Ring A and ring B are each independently selected from a 4- to 12-membered cycloalkyl group and a 4- to 12-membered heterocycloalkyl group, M is none, CR ９ R １０ , O, S, SO, SO ２ , NR ９ is selected from R ９ and R １０ are each independently selected from hydrogen, C １ to C ６ alkyl groups, E ３ is a substituent at any position on the benzene ring, and c is the number of substituents E ３ and Each E ３ is independently selected from a halogen, a hydroxy group, an amino group, a cyano group, a trifluoromethyl group, a C １ to C ６ alkyl group, a 3- to 6-membered cycloalkyl group, a C １ to C ６ alkoxy group, or any two E ３ are linked to form a 3- to 6-membered cycloalkyl group, a 6- to 10-membered aryl group, a 4- to 12-membered heterocycloalkyl group, or a 5- to 8-membered heteroaryl group, c is 0, 1, 2 or 3, Y is none, CR Ｙ１ R Ｙ２ , C(O), -CR １１ =CR １２ -, -CR １１ =N-, -N=N-, -OC(O)-, R Ｙ１ 、 R Ｙ２ are each independently selected from hydrogen, C １ to C ６ alkyl groups, R １１ and R １２ are each independently selected from hydrogen, C １ to C ６ alkyl groups, the heteroatom of the heteroaryl group is O, N or S, and the number of the heteroatoms is 1, 2 or 3, the heteroatom of the heterocycloalkyl group is N, and the number of the heteroatoms is 1, 2 or 3, Preferably, R ５ is C １ to C ６ alkyl group, 3- to 6-membered cycloalkyl group, trifluoromethyl group, trifluoroethyl group, substituted or unsubstituted phenyl group, substituted or unsubstituted thienyl group, substituted or unsubstituted furyl group, substituted or unsubstituted pyrrolyl group, substituted or unsubstituted pyrimidinyl group, substituted or unsubstituted pyridazinyl group, substituted or unsubstituted pyrazolyl group, substituted or unsubstituted pyrazinyl group, and the substituent of the phenyl group, thienyl group, furyl group, pyrrolyl group, pyrimidinyl group, pyridazinyl group, pyrazolyl group or pyrazinyl group is halogen, hydroxy group, amino group, cyano group, trifluoromethyl group, C １ to C ６ alkyl group, 3- to 6-membered cycloalkyl group, C １ to C ６ alkoxy group. ).

20. The compound according to claim 19, or an optical isomer thereof, or a salt thereof, or a hydrate thereof, or a solvate thereof, wherein the compound is represented by formula (XX) (However, R ５ is selected from C １ -C ６ alkyl group, 3- to 6-membered cycloalkyl group, trifluoromethyl group, trifluoroethyl group, substituted or unsubstituted 6- to 10-membered aryl group, substituted or unsubstituted 5- to 8-membered heteroaryl group, and a substituent of the aryl group or heteroaryl group is halogen, hydroxy group, amino group, cyano group, trifluoromethyl group, C １ -C ６ alkyl group, 3- to 6-membered cycloalkyl group, C １ -C ６ alkoxy group, and is selected from X is CR ７ R ８ , O, S, SO, SO ２ , NR ７ selected from, R ７ and R ８ are each independently selected from hydrogen, halogen, C １ to C ６ alkyl group, 3- to 6-membered cycloalkyl group R ６ is a substituent at any position on the benzene ring, and b is the number of substituents R ６ and Each R ６ is independently selected from a halogen, a hydroxy group, an amino group, a cyano group, a trifluoromethyl group, C １ to C ６ alkyl group, a 3- to 6-membered cycloalkyl group, C １ to C ６ alkoxy group, b is 0, 1, 2 or 3, Ring A and ring B are each independently selected from a 4- to 12-membered cycloalkyl group and a 4- to 12-membered heterocycloalkyl group, M is none, CR ９ R １０ , O, S, SO, SO ２ , NR ９ selected from R ９ 、R １０ each independently represents hydrogen, C １ -C ６ alkyl group selected from, Y is none, CR Ｙ１ R Ｙ２ , C(O), -CR １１ =CR １２ -, -CR １１ =N-, -N=N-, -OC(O)-, R Ｙ１ 、R Ｙ２ are each independently selected from hydrogen, C １ to C ６ alkyl groups, R １１ 、 R １２ each independently represents hydrogen, C １ to C ６ and is selected from alkyl groups, the heteroatom of the heteroaryl group is O, N or S, and the number of the heteroatoms is 1, 2 or 3, the heteroatom of the heterocycloalkyl group is N, and the number of the heteroatoms is 1, 2 or 3, Preferably, R ５ is C １ -C ６ alkyl group, 3- to 6-membered cycloalkyl group, trifluoromethyl group, trifluoroethyl group, substituted or unsubstituted phenyl group, substituted or unsubstituted thienyl group, substituted or unsubstituted furyl group, substituted or unsubstituted pyrrolyl group, substituted or unsubstituted pyrimidinyl group, substituted or unsubstituted pyridazinyl group, substituted or unsubstituted pyrazolyl group, substituted or unsubstituted pyrazinyl group, and the substituents of the phenyl group, thienyl group, furyl group, pyrrolyl group, pyrimidinyl group, pyridazinyl group, pyrazolyl group or pyrazinyl group are halogen, hydroxy group, amino group, cyano group, trifluoromethyl group, C １ -C ６ alkyl group, 3- to 6-membered cycloalkyl group, C １ -C ６ alkoxy group, and is selected from: X is CH ２ , CF ２ , O, S, SO, SO ２ , NR ７ selected from R ７ is selected from hydrogen, halogen, C １ to C ６ alkyl group, 3- to 6-membered cycloalkyl group, Ring A and ring B are each independently selected from a 4- to 12-membered cycloalkyl group and a 4- to 12-membered heterocycloalkyl group, and when both ring A and ring B are heterocycloalkyl groups, one ring has one heteroatom N and the other ring has two heteroatoms N.).

21. The compound according to claim 20, or an optical isomer thereof, or a salt thereof, or a hydrate thereof, or a solvate thereof, wherein the compound is represented by formula (XXI) (However, R １１ is a substituent at any position on the benzene ring, and d is the number of substituents R １１ and Each R １１ is independently selected from a halogen, a hydroxy group, an amino group, a cyano group, a trifluoromethyl group, C １ to C ６ alkyl group, a 3- to 6-membered cycloalkyl group, C １ to C ６ alkoxy group, d is 0, 1, 2 or 3, X is CR ７ R ８ , O, S, SO, SO ２ , NR ７ and is selected from R ７ 、 R ８ each independently represents hydrogen, halogen, C １ -C ６ alkyl group, or 3- to 6-membered cycloalkyl group R ６ is a substituent at any position on the benzene ring, and b is the number of substituents R ６ and is Each R ６ is independently selected from a halogen, a hydroxy group, an amino group, a cyano group, a trifluoromethyl group, C １ to C ６ alkyl group, a 3- to 6-membered cycloalkyl group, C １ to C ６ alkoxy group, b is 0, 1, 2 or 3, M is none, CR ９ R １０ , O, S, SO, SO ２ , NR ９ is selected from R ９ 、 R １０ are each independently selected from hydrogen, C １ to C ６ alkyl groups, m1, m2, m3, m4, m5, m6 are each independently selected from 0, 1, 2 or 3, Y is none, CR Ｙ１ R Ｙ２ , C(O), -CR １１ =CR １２ -, -CR １１ =N-, -N=N-, -OC(O)-, and R Ｙ１ 、R Ｙ２ are each independently selected from hydrogen, C １ -C ６ alkyl groups, R １１ 、R １２ are each independently selected from hydrogen, C １ to C ６ alkyl groups, Preferably, X is CH ２ , CF ２ , O, S, SO, SO ２ , NR ７ and is selected from R ７ is selected from hydrogen, halogen, C １ to C ６ alkyl group, 3- to 6-membered cycloalkyl group.).

22. The compound according to any one of claims 1 to 11 or 15 to 20, or an optical isomer thereof, or a salt thereof, or a hydrate thereof, or a solvate thereof, wherein the ring A and the ring B are each independently selected from the following structures.

23. The is selected from the following structures, and the compound according to any one of claims 1 to 21, or an optical isomer thereof, or a salt thereof, or a hydrate thereof, or a solvate thereof.

24. The compound according to any one of claims 1 to 21, or an optical isomer thereof, or a salt thereof, or a hydrate thereof, or a solvate thereof, wherein the compound is one of the following compounds.

25. The salt is a pharmaceutically acceptable salt, and the pharmaceutically acceptable salt is a phosphate, d-camphorsulfonate, hydrochloride, hydrobromide, hydrofluoride, sulfate, nitrate, carboxylate, acetate, propionate, oxalate, malonate, succinate, fumarate, maleate, lactate, malate, tartrate, citrate, picrate, methanesulfonate, benzenemethanesulfonate, benzenesulfonate, aspartate or glutamate of the compound, and the compound according to any one of claims 1 to 21, or an optical isomer thereof, or a salt thereof, or a hydrate thereof, or a solvate thereof.

26. Use of the compound according to any one of claims 1 to 25, or an optical isomer thereof, or a salt thereof, or a hydrate thereof, or a solvate thereof, in the manufacture of an estrogen receptor degrader.

27. Use of the compound according to any one of claims 1 to 25, or an optical isomer thereof, or a salt thereof, or a hydrate thereof, or a solvate thereof, in the manufacture of a drug for treating a disease related to an estrogen receptor.

28. Use of the compound according to any one of claims 1 to 25, or an optical isomer thereof, or a salt thereof, or a hydrate thereof, or a solvate thereof, in the manufacture of a drug for treating and / or preventing cancer.

29. Use of the compound according to any one of claims 1 to 25, or its optical isomer, or its salt, or its hydrate, or its solvate, in the manufacture of a medicament for the treatment and / or prevention of bone cancer, colorectal cancer, endometrial cancer, prostate cancer, ovarian cancer, uterine cancer, cervical cancer, lung cancer, breast cancer.

30. A medicament for treating cancer, characterized in that it is a preparation manufactured by using the compound according to any one of claims 1 to 25, or its optical isomer, or its salt, or its hydrate, or its solvate as an active ingredient and further adding a pharmaceutically acceptable auxiliary material.

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