PROTAC compounds targeting estrogen receptors, methods for their preparation, and use.

Abstract

This invention provides a PROTAC compound that targets the hydrolysis of estrogen receptor (ER) protein and its use.

Description

[Technical Field] 【0001】 This application relates to a PROTAC compound that targets the hydrolysis of estrogen receptor (ER) protein, a method for preparing the same, and the treatment or prevention of disorders mediated by estrogen receptor protein, such as breast cancer and ovarian cancer, and belongs to the field of biopharmaceuticals. [Background technology] 【0002】 PROTAC (Proteolysis Targeting Chimera) is an abbreviation for proteolysis targeting chimera. It utilizes the ubiquitin (UPS)-proteasome system, a protein removal system naturally present in human cells, to induce the degradation of target proteins, selectively and efficiently degrading and removing pathogenic proteins, thus representing a new engineering technology for targeted protein degradation. Ubiquitin is a small protein with a molecular weight of approximately 8.45 kDa, consisting of 76 amino acids, and is present in all eukaryotes. The main function of ubiquitin is to label proteins that need to be degraded. When ubiquitin is linked to a protein and labels it as a defective or damaged protein, these proteins are recognized and transported to the proteasome for degradation. This maintains the balance of proteins within the cell. 【0003】 Currently, most small molecule drugs used in clinical practice employ an "occupation-driven" mode of action, inhibiting protein function to treat diseases. Unlike conventional small molecule inhibitors and antagonists, PROTACs have the ability to induce the degradation of pathogenic target proteins, and have therefore rapidly developed in recent years as a new approach for the development of novel drugs. PROTACs are heterobifunctional molecules consisting of two small molecule ligands, and generally consist of three parts: a target protein ligand, an E3 ubiquitin ligase ligand, and a linker of appropriate length. When a PROTAC molecule enters a cell, the target protein ligand in its structure specifically binds to the target protein, and the E3 ubiquitin ligase ligand (e.g., cereblon, CRBN) at the other end recruits the E3 ligase, forming a stable target protein-PROTAC-E3 ubiquitin ligase ternary complex. When the target protein is ubiquitinated, the ubiquitinated protein is recognized and degraded by the 26S proteasome in the cell. Conventional small molecules and antibodies all play a role in treating diseases by inhibiting the function of target proteins through an "occupation-driven" mode of action. In this mode of action, the inhibitor or monoclonal antibody needs to reach high concentrations to occupy the active site of the target and inhibit the transmission of downstream signaling pathways. On the other hand, PROTAC operates in an "event-driven" mode, binding to any site on the target protein without requiring high affinity and inducing protein degradation. Therefore, PROTAC can target proteins with smooth surfaces that lack small molecule binding sites. Since 80% of pathogenic proteins in human cells lack active sites for conventional small molecules to bind, it is highly likely that many targets that cannot be drug-developed with small molecules can be applied to PROTAC technology. In theory, PROTAC can be reused repeatedly as long as it mediates the formation of a ternary complex and labels the target protein with ubiquitin. Therefore, it can be effective even at catalytic amounts, and because it is used at low doses, toxicity and side effects can be reduced, making PROTAC drugs relatively safe.Furthermore, even for proteins that lack an active site, such as scaffold proteins, PROTACs can induce degradation of related proteins as long as they can bind to them, thus greatly expanding the range of targets. Currently, the degradation of over 100 types of proteins, including "undruggable targets," has been successfully achieved. Since ubiquitin-mediated degradation pathways occur within cells, small-molecule PROTACs are currently focused primarily on attacking intracellular targets such as cytoplasmic proteins and nucleoproteins. 【0004】 Extensive and thorough research on protacoagulants has led to an increase in reports on their widespread use in antitumor research in recent years, as seen in the following journals (e.g., Crews et al., Curr Opin Chem Biol. 2019; 50: 111-119; Xu et al., Eur J Med Chem. 2022; 235: 114290; Zou et al., Eur J Med Chem. 2021; 226: 113849; Qin et al., Front Pharmacol, 2021; 12: 692574; Song et al., J Hematol Oncol. 2020; 13(1):50; Crews et al., Cancer Res. 2019; 79(1): 251-262; Rao et al., ACS Med Chem Lett. 2020; 11(3): 237-240; Wang et al., J Med Chem. 2019; 62(21): 9471-9487; Crews et al., Pharmacol Ther. 2017 Disclosed in Jun;174:138-144., and in patents (e.g.: CN113248473, CN112812100, CN109761970, US2019019419, US20190151295, US20200129627, US20180125821, US20160045607, CN107428734, WO2017197046, WO2002020740, WO2017197056, WO2017117474, WO2017197055). 【0005】 ER + , HER -Breast cancer refers to estrogen receptor (ER)-positive and human epidermal growth factor receptor 2 (HER2)-negative breast cancer, which is the most common type of breast cancer, accounting for 65% of breast cancer cases in women under 50 and 75% of breast cancer cases in women over 50. Estrogen (E2) is a steroid compound with broad biological activity, including estradiol, estriol, and estrone, and plays an important role in maintaining physiological activities of the body, such as the development of the reproductive system and bone maturation. The estrogen receptor (ER) is a member of the steroid hormone receptor superfamily and is a ligand-dependent transcription factor. Estrogen binds to the ER and stimulates receptor-regulated transcription, thereby promoting the growth and proliferation of tumor cells. Hormone therapy for ER-positive breast cancer can reduce estrogen production, inhibit ER signaling, degrade ER, or alter ER-regulated signaling or proliferation pathways. Estrogen production and ER signaling are driving factors in the development, growth, proliferation, and metastasis of breast cancer, and are also targets for drugs effective against early-stage breast cancer. Novel targeted therapies in combination with endocrine therapy can improve outcomes in advanced breast cancer and inhibit the activity of key pathways in cell growth, proliferation, and metastasis. Mutations in the ER gene ESR1 (ESR1 mut), or epigenetic alterations of c-myc, cyclin D, and the epidermal growth factor receptor (EGFR) are associated with resistance to endocrine therapy. 【0006】 Epidemiological studies have shown that ERα expression is higher in the breast tissue of breast cancer patients than in the breast tissue of non-breast cancer patients, and that high-risk breast cancer groups have higher ERα expression than low-risk breast epithelium groups. The most important factor in the development and progression of breast cancer is not the levels of ERα or ERβ, but rather the ratio of ERα to ERβ. 【0007】 Breast cancer is the most common malignant tumor in women. According to the latest data compiled by the American Cancer Society in 2020, more than 250,000 new cases of breast cancer are diagnosed in the United States each year, and about 80% of these are estrogen receptor-positive (ER) breast cancer. + Endocrine therapy for breast cancer exerts its antitumor effect primarily by inhibiting estrogen from binding to tumor cells and inhibiting estrogen production. Since estrogen acts as an endocrine growth factor for breast cancer, estrogen deprivation is recognized as a treatment for advanced breast cancer in premenopausal women. Currently, the main treatment methods are as follows: 1. Ovarian removal is the most economical and thorough castration method, but it is somewhat invasive. Drug-induced inhibition of ovarian function is also an option, but complete inhibition may not be achieved in a small number of patients. 2. Aromatase inhibitors can lower estrogen levels by inhibiting the conversion pathway to estrogen receptors. 3. Estrogen receptor (ER) antagonists, modulators, or degraders can lower ER expression at the transcript or protein level, lower estrogen receptor levels, and inhibit the growth of cancer cells. Existing endocrine therapies have limitations in their therapeutic scope, are basically ineffective in patients with mutations, develop drug resistance, and have serious side effects. Therefore, there is a need in clinical treatment to develop more effective and safer treatment methods. 【0008】 In 2019, ARV-471, a PROTAC drug targeting ER degradation from Arvinas, entered Phase I clinical trials. Preclinical results showed that ARV-471 significantly inhibited tumor growth in various ER-dependent breast cancer models. Preliminary data from the Phase I clinical trial indicated that ARV-471 demonstrated favorable antitumor activity and good safety in patients with ER mutations who had not responded to existing endocrine therapies. This is the first PROTAC drug to enter clinical trials in the field of breast cancer. [Overview of the Initiative] [Problems that the invention aims to solve] 【0009】 One object of this application is to provide a novel oral estrogen receptor-targeted protein-degrading agent (PROTAC) compound or a pharmaceutically acceptable salt, solvate, hydrate, or isomer thereof. 【0010】 Another object of this application is to provide the use of the compound of this application or any pharmaceutically acceptable salt, solvate, hydrate, or isomer thereof. [Means for solving the problem] 【0011】 Specifically, this application relates to the following technical solutions. 【0012】 In one embodiment, the present invention provides a PROTAC compound that targets the estrogen receptor represented by formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, or isomer thereof. 【0013】 [ka] 【0014】 (Here, 【0015】 [ka] 【0016】 It is the absence of a substituent, or the absence of a substituent. 【0017】 [ka] 【0018】 Substitutable or unsubstituted 【0019】 [ka] 【0020】 shows X 4 represents N or CRa, and the substituent is selected from halogen, hydroxy group, cyano group, oxy group, benzyl group, substituted or unsubstituted amine group, substituted or unsubstituted C1-C6 alkyl group, substituted or unsubstituted C1-C6 alkoxy group, and C1-C6 acyl group. When A is absent, R 1 is selected from halogen, hydroxy group, cyano group, oxy group, benzyl group, substituted or unsubstituted amine group, substituted or unsubstituted C1-C6 alkyl group, substituted or unsubstituted C1-C6 alkoxy group, and C1-C6 acyl group. Preferably, R 1 is selected from -NH2 or -OH. X 1 is N or CR 3 and × 2 or X 3 is independently selected from CH, CR 3 and N. R 2 R 3 are independently selected from H, halogen, hydroxy group, cyano group, oxy group, benzyl group, substituted or unsubstituted amine group, substituted or unsubstituted C1-C6 alkyl group, substituted or unsubstituted C1-C6 alkoxy group, and C1-C6 acyl group. Ra is selected from H, halogen, hydroxy group, cyano group, oxy group, benzyl group, substituted or unsubstituted amine group, substituted or unsubstituted C1-C6 alkyl group, substituted or unsubstituted C1-C6 alkoxy group, and C1-C6 acyl group. L is one selected from the following: 【0021】 【Chemical formula】 【0022】 【Chemical formula】 【0023】 [ka] 【0024】 E3L represents a ubiquitin ligase ligand. 【0025】 Preferably, E3L is one selected from the following: 【0026】 [ka] 【0027】 [ka] 【0028】 Preferably, the compound of the present application is represented by formula (II). 【0029】 [ka] 【0030】 (Here, R 4 (These are selected from halogens, hydroxyl groups, cyano groups, oxy groups, benzyl groups, substituted or unsubstituted amine groups, substituted or unsubstituted C1-C6 alkyl groups, substituted or unsubstituted C1-C6 alkoxy groups, and C1-C6 acyl groups.) 【0031】 Preferably, R 4 It is a halogen. 【0032】 Preferably, the compound of the present application is represented by formula (III). 【0033】 [ka] 【0034】 Preferably, the compound of the present application is represented by formula (IV). 【0035】 [ka] 【0036】 Preferably, L is one selected from the following: 【0037】 [ka] 【0038】 Preferably, X 4 It is N. 【0039】 Preferably, X 4 is CRa, and Ra is selected from H, halogen, and hydroxyl groups. 【0040】 Preferably, Ra is H. 【0041】 Preferably, X 1 CR 3 And R 3 It is H, CH3O, or F. 【0042】 Preferably, R 3 H is H. 【0043】 Preferably, X 2 It is CH. 【0044】 Preferably, X 2 It is N. 【0045】 Preferably, X 3 It is CH. 【0046】 Preferably, R 2 H is H. 【0047】 Preferably, E3L is 【0048】 [ka] 【0049】 That is the case. 【0050】 Preferably, the compound of the present application is one selected from the following: 【0051】 [ka] 【0052】 [ka] 【0053】 [ka] 【0054】 [ka] 【0055】 [ka] 【0056】 [ka] 【0057】 [ka] 【0058】 [ka] 【0059】 [ka] 【0060】 【change】 【0061】 【change】 【0062】 【change】 【0063】 【change】 【0064】 【change】 【0065】 【change】 【0066】 【change】 【0067】 【change】 【0068】 【change】 【0069】 【change】 【0070】 【change】 【0071】 [ka] 【0072】 The present application further relates to a pharmaceutical composition, wherein the pharmaceutical composition comprises the above-mentioned compound, pharmaceutically acceptable salt, solvate, hydrate, or isomer of the present application, and a pharmaceutically acceptable carrier. 【0073】 The present application further relates to the use of the above-mentioned compounds or their pharmaceutically acceptable salts, solvates, hydrates, or isomers, or the above-mentioned pharmaceutical compositions, in the treatment of disorders treated by the degradation of target proteins bound to target ligands. 【0074】 Preferably, the disorder is selected from abnormal cell proliferation, cancer, immune disorders, diabetes, cardiovascular diseases, infections, and inflammatory diseases. 【0075】 Preferably, the cancers include breast cancer, endometrial cancer, uterine cancer, testicular cancer, cervical cancer, prostate cancer, ovarian cancer, endometriosis, fallopian tube tumors, ovarian tumors, leukemia, skin cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, renal cell carcinoma, bladder cancer, intestinal cancer, colon cancer, esophageal cancer, head cancer, kidney cancer, liver cancer, lung cancer, cervical cancer, pancreatic cancer, stomach cancer, lymphoma, non-Hodgkin lymphoma, malignant melanoma, myeloproliferative disorders, sarcoma, angiosarcoma, and terminal cancers. Selected from peripheral neuroepithelial tumors, gliomas, astrocytomas, oligodendrogliomas, ependymomas, glioblastomas, neuroblastomas, gangliocytomas, gangliogliomas, medulloblastomas, pineal cell tumors, meningiomas, meningiosarcomas, neurofibromas, schwannomas, thyroid cancers, Hodgkin tumors, Wilms tumors, and teratomas, more preferably selected from breast cancers, endometrial cancers, uterine cancers, testicular cancers, cervical cancers, prostate cancers, ovarian cancers, fallopian tube tumors, and ovarian tumors. 【0076】 Preferably, the cancer is selected from breast cancer, endometrial cancer, ovarian cancer, cervical cancer, prostate cancer, or endometriosis. 【0077】 Preferably, the infection is selected from diseases caused by viral pneumonia, avian influenza, meningitis, gonorrhea, or infection with HIV, HBV, HCV, HSV, HPV, RSV, CMV, Ebola virus, flavivirus, Blotchi virus, rotavirus, influenza, coronavirus, EBV, drug-resistant viruses, RNA viruses, DNA viruses, adenoviruses, poxviruses, picornaviruses, togaviruses, orthomyxoviruses, retroviruses, hepadnaviruses, gram-negative bacteria, gram-positive bacteria, atypical bacteria, staphylococci, streptococci, Escherichia coli, Salmonella, Helicobacter pylori, Chlamydia, Mycoplasma, fungi, protozoa, enteroworms, helminths, prions, or parasites. 【0078】 The present application further relates to the use of the above-mentioned compounds or their pharmaceutically acceptable salts, solvates, hydrates, or isomers, or the above-mentioned pharmaceutical compositions, in the preparation of drugs for treating disorders treated by the degradation of target proteins bound to target ligands. 【0079】 Preferably, the disorder is selected from abnormal cell proliferation, cancer, immune disorders, diabetes, cardiovascular diseases, infections, and inflammatory diseases. 【0080】 Preferably, the cancers include breast cancer, endometrial cancer, uterine cancer, testicular cancer, cervical cancer, prostate cancer, ovarian cancer, endometriosis, fallopian tube tumors, ovarian tumors, leukemia, skin cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, renal cell carcinoma, bladder cancer, intestinal cancer, colon cancer, esophageal cancer, head cancer, kidney cancer, liver cancer, lung cancer, cervical cancer, pancreatic cancer, stomach cancer, lymphoma, non-Hodgkin lymphoma, malignant melanoma, myeloproliferative disorders, sarcoma, angiosarcoma, and terminal cancers. Selected from peripheral neuroepithelial tumors, gliomas, astrocytomas, oligodendrogliomas, ependymomas, glioblastomas, neuroblastomas, gangliocytomas, gangliogliomas, medulloblastomas, pineal cell tumors, meningiomas, meningiosarcomas, neurofibromas, schwannomas, thyroid cancers, Hodgkin tumors, Wilms tumors, and teratomas, more preferably selected from breast cancers, endometrial cancers, uterine cancers, testicular cancers, cervical cancers, prostate cancers, ovarian cancers, fallopian tube tumors, and ovarian tumors. 【0081】 Preferably, the cancer is selected from breast cancer, endometrial cancer, ovarian cancer, cervical cancer, prostate cancer, or endometriosis. 【0082】 Preferably, the infection is selected from diseases caused by viral pneumonia, avian influenza, meningitis, gonorrhea, or infection with HIV, HBV, HCV, HSV, HPV, RSV, CMV, Ebola virus, flavivirus, Blotchi virus, rotavirus, influenza, coronavirus, EBV, drug-resistant viruses, RNA viruses, DNA viruses, adenoviruses, poxviruses, picornaviruses, togaviruses, orthomyxoviruses, retroviruses, hepadnaviruses, gram-negative bacteria, gram-positive bacteria, atypical bacteria, staphylococci, streptococci, Escherichia coli, Salmonella, Helicobacter pylori, Chlamydia, Mycoplasma, fungi, protozoa, enteroworms, helminths, prions, or parasites. 【0083】 The present application relates to a method for treating a disorder in a subject that is treated by the degradation of a target protein bound to a target ligand, comprising administering to the subject an effective amount of the compound of the present application or a pharmaceutically acceptable salt, solvate, hydrate, or isomer thereof, or a pharmaceutical composition thereof. 【0084】 Preferably, the disorder is selected from abnormal cell proliferation, cancer, immune disorders, diabetes, cardiovascular diseases, infections, and inflammatory diseases. 【0085】 Preferably, the cancers include breast cancer, endometrial cancer, uterine cancer, testicular cancer, cervical cancer, prostate cancer, ovarian cancer, endometriosis, fallopian tube tumors, ovarian tumors, leukemia, skin cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, renal cell carcinoma, bladder cancer, intestinal cancer, colon cancer, esophageal cancer, head cancer, kidney cancer, liver cancer, lung cancer, cervical cancer, pancreatic cancer, stomach cancer, lymphoma, non-Hodgkin lymphoma, malignant melanoma, myeloproliferative disorders, sarcoma, angiosarcoma, and terminal cancers. Selected from peripheral neuroepithelial tumors, gliomas, astrocytomas, oligodendrogliomas, ependymomas, glioblastomas, neuroblastomas, gangliocytomas, gangliogliomas, medulloblastomas, pineal cell tumors, meningiomas, meningiosarcomas, neurofibromas, schwannomas, thyroid cancers, Hodgkin tumors, Wilms tumors, and teratomas, more preferably selected from breast cancers, endometrial cancers, uterine cancers, testicular cancers, cervical cancers, prostate cancers, ovarian cancers, fallopian tube tumors, and ovarian tumors. 【0086】 Preferably, the cancer is selected from breast cancer, endometrial cancer, ovarian cancer, cervical cancer, prostate cancer, or endometriosis. 【0087】 Preferably, the infection is selected from diseases caused by viral pneumonia, avian influenza, meningitis, gonorrhea, or infection with HIV, HBV, HCV, HSV, HPV, RSV, CMV, Ebola virus, flavivirus, Blotchi virus, rotavirus, influenza, coronavirus, EBV, drug-resistant viruses, RNA viruses, DNA viruses, adenoviruses, poxviruses, picornaviruses, togaviruses, orthomyxoviruses, retroviruses, hepadnaviruses, gram-negative bacteria, gram-positive bacteria, atypical bacteria, staphylococci, streptococci, Escherichia coli, Salmonella, Helicobacter pylori, Chlamydia, Mycoplasma, fungi, protozoa, enteroworms, helminths, prions, or parasites. [Brief explanation of the drawing] 【0088】 [Figure 1A] This shows the measurement of estrogen receptor degradation in MCF-7 cells by Western blotting after MCF-7 cells were treated with exemplary compounds 1, 2, 5, 6, 7, and 13 disclosed herein for 6 hours. [Figure 1B] This shows the measurement of estrogen receptor degradation in MCF-7 cells by Western blotting after MCF-7 cells were treated with exemplary compounds 27, 30, 31, 34, 35, and 37 disclosed herein for 6 hours. [Figure 1C] This shows the measurement of estrogen receptor degradation in MCF-7 cells by Western blotting after MCF-7 cells were treated with exemplary compounds 44, 46, 47, 48, 57, and 59 disclosed herein for 6 hours. [Figure 1D] This shows the measurement of estrogen receptor degradation in MCF-7 cells by Western blotting after MCF-7 cells were treated with exemplary compounds 61, 66, 76, 88, 89, and 90 disclosed herein for 6 hours. [Figure 1E] This shows the measurement of estrogen receptor degradation in MCF-7 cells by Western blotting after MCF-7 cells were treated with exemplary compounds 103, 104, 110, 119, 120, and 121 disclosed herein for 6 hours. [Figure 2A] This shows the measurement of estrogen receptor degradation in MCF-7 cells by Western blotting after MCF-7 cells were treated with 10 nM of the exemplary compound 5 disclosed herein for different time periods. [Figure 2B] This shows the measurement of estrogen receptor degradation in MCF-7 cells by Western blotting after MCF-7 cells were treated with 10 nM of the exemplary compound 31 disclosed herein for different time periods. [Figure 2C] This shows the measurement of estrogen receptor degradation in MCF-7 cells by Western blotting after MCF-7 cells were treated with 10 nM of the exemplary compound 47 disclosed herein for different time periods. [Figure 2D] This shows the measurement of estrogen receptor degradation in MCF-7 cells by Western blotting after MCF-7 cells were treated with 10 nM of the exemplary compound 48 disclosed herein for different time periods. [Figure 3A] The six figures show, respectively, the inhibitory effects of exemplary compounds 2, 5, 6, 22, 31, and 34 disclosed herein on the proliferation of MCF-7 cells 6 days after administration. [Figure 3B] The six figures show, respectively, the inhibitory effect of exemplary compounds 35, 37, 44, 46, 47, and 48 of this disclosure on the proliferation of MCF-7 cells 6 days after administration. [Figure 3C] The five figures show, respectively, the inhibitory effects on MCF-7 cell proliferation 6 days after administration of exemplary compounds 88, 110, 119, 120, and 121 of this disclosure. [Figure 4A] This shows the measurement of estrogen receptor degradation in T-47D cells by Western blotting after T-47D cells were treated with the exemplary compound 34 disclosed herein for 4 hours. [Figure 4B] This shows the measurement of estrogen receptor degradation in T-47D cells by Western blotting after T-47D cells were treated with the exemplary compound 35 disclosed herein for 4 hours. [Figure 5A] This shows the measurement of estrogen receptor degradation in MCF-7 / ERα Y537S cells by Western blotting after treating cells from among MCF-7 cells expressing the ERα Y537S mutant with the exemplary compound 34 disclosed herein for 4 hours. [Figure 5B] This shows the measurement of estrogen receptor degradation in MCF-7 / ERα Y537S cells by Western blotting after treating cells from among MCF-7 cells expressing the ERα Y537S mutant with the exemplary compound 35 disclosed herein for 4 hours. [Figure 5C]This shows the measurement of estrogen receptor degradation in MCF-7 / ERα Y537S cells by Western blotting after treating cells from among MCF-7 cells expressing the ERα Y537S mutant with the exemplary compound 110 disclosed herein for 6 hours. [Figure 5D] This shows the measurement of estrogen receptor degradation in MCF-7 / ERα Y537S cells by Western blotting after treating cells from among MCF-7 cells expressing the ERα Y537S mutant with the exemplary compound 120 disclosed herein for 6 hours. [Figure 6A] This shows the measurement of estrogen receptor degradation in MCF-7 / ERα D537G cells by Western blotting after treating cells from among MCF-7 cells expressing the ERα D537G mutant with the exemplary compound 110 disclosed herein for 6 hours. [Figure 6B] This shows the measurement of estrogen receptor degradation in MCF-7 / ERα D537G cells by Western blotting after treating cells from among MCF-7 cells expressing the ERα D537SG mutant with the exemplary compound 120 disclosed herein for 6 hours. [Figure 7A] The exemplary compound 110 disclosed herein exhibits inhibitory effects on the proliferation of MCF-7 / ERα Y537S cells 6 days after administration. [Figure 7B] The exemplary compound 120 disclosed herein exhibits inhibitory effects on the proliferation of MCF-7 / ERα Y537S cells 6 days after administration. [Figure 8A] The exemplary compound 110 disclosed herein demonstrates dose-dependent growth inhibitory ability in MCF-7 / ERα Y537S cell xenograft tumors. [Figure 8B] This invention demonstrates that the exemplary compound 110 disclosed herein does not affect the body weight of mice in MCF-7 / ERα Y537S cell xenograft tumors. [Figure 9A] The exemplary compound 120 disclosed herein demonstrates dose-dependent growth inhibitory ability in MCF-7 / ERα Y537S cell xenograft tumors. [Figure 9B] This invention demonstrates that the exemplary compound 120 disclosed herein does not affect the body weight of mice in MCF-7 / ERα Y537S cell xenograft tumors. [Modes for carrying out the invention] 【0089】 definition Unless otherwise specified, some terms used in the specification and claims of this application are defined as follows: 【0090】 As used herein, the term “isomer” includes all geometric isomers and stereoisomers. For example, “isomer” includes cis and trans isomers, E and Z isomers, R and S enantiomers, diastereomers, D-isomers, L-isomers, the racemic mixtures described above, and other mixtures described above. For example, in some embodiments, stereoisomers may be provided in a form that substantially does not contain one or more corresponding enantiomers, which may also be called “stereochemically concentrated.” 【0091】 As used herein, the term “pharmaceutically acceptable salt” includes salts that maintain the bioavailability of the free acids and bases of a particular compound and are not biotoxic. Possible forms of pharmaceutically acceptable salts include, but are not limited to, monosalts, disalts, trisalts, tetrasalts, and others. pharmaceutically acceptable salts are nontoxic at doses and concentrations. Preparation of these salts can facilitate pharmacological use by altering the physical properties of the compound without impairing its physiological effects. Useful alterations to physical properties include lowering the melting point to facilitate transmucosal administration and increasing solubility to facilitate higher concentrations of the drug. 【0092】 Furthermore, it should be understood that the compounds of this application may exist in non-solvated, solvated (e.g., hydrated) and solid (e.g., crystalline or polymorphic) forms, and that this application is intended to cover all of these forms. 【0093】 As used herein, the terms “solvate” or “solvated form” refer to a solubilated form containing stoichiometric or non-stoichiometric amounts of solvent. Some compounds tend to trap solvent molecules in a constant molar ratio within a crystalline solid to form solvates. When the solvent is water, the solvate formed is a hydrate; when the solvent is alcohol, the solvate formed is an alcoholic dihydrate. Examples of solvents that form solvates include, but are not limited to, water, isopropanol, methanol, ethanol, DMSO, ethyl acetate, acetic acid, ethanolamine, acetone, and diethyl ether. 【0094】 As used herein, the term "alkyl group" is branched or unbranched and preferably has 1 to about 12 carbon atoms. More preferably, the alkyl group has 1 to about 6 carbon atoms. Even more preferably, the alkyl group has 1, 2, 3, or 4 carbon atoms. Alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, and 2,3-dimethylbutyl groups. The alkyl group may be substituted or unsubstituted. 【0095】 "Substitution" means that one or more hydrogen atoms in a group, preferably up to five, more preferably one to three, are substituted independently by a corresponding number of substituents. Needless to say, substituents are only in possible chemical positions, and those skilled in the art can determine possible or impossible substitutions (by experiment or theory) with little effort. For example, an amino or hydroxyl group with free hydrogen can become unstable when bonded to a carbon atom with an unsaturated (e.g., olefin) bond. 【0096】 Unless otherwise specified, the terms “substituted” or “substituted” as used herein mean that a group may be substituted with one or more substituents selected from alkyl groups, alkoxy groups, alkylthio groups, alkylamino groups, halogens, mercapto groups, hydroxyl groups, nitro groups, cyano groups, cycloalkyl groups, heterocyclic groups, aryl groups, heteroaryl groups, cycloalkoxy groups, heterocycloalkoxy groups, cycloalkylthio groups, heterocycloalkylthio groups, amino groups, haloalkyl groups, and hydroxyalkyl groups. In any case, if a group is described as “optionally substituted,” it may be unsubstituted or substituted with one or more of the substituents shown. Similarly, if a group is described as “unsubstituted or substituted,” and it is substituted, the substituent may be one or more of the substituents shown. If no substituent is specified, the indicated "optionally substituted" or "substituted" group is an alkyl group, alkenyl group, alkynyl group, cycloalkyl group, cycloalkenyl group, cycloalkynyl group, aryl group, heteroaryl group, heteroalicyclic group, aralkyl group, heteroarylalkyl group, (heteroalicyclic)alkyl group, hydroxyl group, protected hydroxyl group, alkoxy group, aryloxy group, acyl group, mercapto group, alkylthio group, arylthio group, cyano group, halogen, thiocarbonyl group, O-carbamoyl group, N-carbamoyl group, O-thiocarbamoyl This means that the group may be substituted with one or more groups individually or independently selected from the following: N-thiocarbamoyl group, C-amide group, N-amide group, S-sulfonamide group, N-sulfonamide group, C-carboxyl group, protected C-carboxyl group, O-carboxyl group, isocyanate group, thiocyanate, isothiocyanate group, nitro group, silyl group, thio group, sulfinyl group, sulfonyl group, haloalkyl group, haloalkoxy group, trihalomethanesulfonyl group, trihalomethanesulfonamide group, amino group, monosubstituted amino group and disubstituted amino group, and their protected derivatives. 【0097】 As used herein, the term "halogen" refers to F, Cl, Br, or I. 【0098】 As used herein, the term "cyano group" refers to -CN. 【0099】 As used herein, the term "hydroxyl group" refers to -OH. 【0100】 As used herein, the term "amine group" refers to -NH2. 【0101】 As used herein, the term "oxy group" refers to an oxygen atom bonded to another atom (e.g., carbon or sulfur) via a double bond. For example, when directly bonded to a carbon atom, a carbonyl group (C=O) is formed. 【0102】 As used herein, the term “acyl group” refers to a carbonyl-containing functional group such as -C(=O)R', where R' is a hydrogen or hydrocarbon group. In some embodiments, the acyl group is a group represented by the formula alkylC(O)-. 【0103】 As used herein, the term “alkoxy group” refers to the alkyl group defined above, linked to the parent molecule by an oxygen atom, whether used as part of another term or independently. 【0104】 As used herein, the term "benzyl group" refers to the -CH2-phenyl group. 【0105】 As used herein, the term “pharmaceutical composition” refers to a mixture comprising one or more of the compounds described herein, or physiologically and pharmaceutically acceptable salts or prodrugs thereof, and other chemical components such as physiologically and pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to facilitate administration to a living organism, thereby favoring the absorption of the active ingredient and the expression of its biological activity. 【0106】 As used herein, the term “pharmaceutically acceptable” means a compound, material, composition, and / or dosage form suitable for contact with human or animal tissue without causing excessive toxicity, irritation, allergic reactions, other problems, or complications, and with a reasonable benefit-risk ratio. In some embodiments, a pharmaceutically acceptable compound, material, composition, and / or dosage form means a compound, material, composition, and / or dosage form that is approved for use in animals, particularly humans, by a regulatory authority (such as the U.S. Food and Drug Administration, the China National Medical Products Administration, or the European Medicines Agency) or listed in an official pharmacopoeia (such as the United States Pharmacopoeia, the Chinese Pharmacopoeia, or the European Pharmacopoeia). 【0107】 As used herein, the term “pharmaceutically acceptable carrier” means a pharmaceutically acceptable material, composition, or delivery medium, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material, used to transport or deliver the compound of the Application or a pharmaceutically acceptable salt thereof from one place, body fluid, tissue, organ (internal or external), or body part to another place, body fluid, tissue, organ, or body part. A pharmaceutically acceptable carrier may be a delivery medium, diluent, excipient, or other material that can be used in contact with animal tissue without causing excessive toxicity or adverse reactions. Examples of pharmaceutically acceptable carriers include, but are not limited to, sugars, starches, cellulose, malt, tragacanth, gelatin, Ringer's solution, alginates, isotonic salines, and buffers. Pharmacochemically acceptable carriers available in this Application include those known in the art, such as those disclosed in “Remington Pharmaceutical Sciences” Mack Pub. Co., New Jersey (1991). 【0108】 As used herein, the term “subject” refers to a living organism, tissue, or cell. Subjects include human subjects for medical purposes (e.g., diagnosis and / or treatment of a pre-existing disorder or disease, or prophylactic treatment to prevent the onset of a disorder or disease) or animal subjects for veterinary or developmental purposes. Subjects also include sample materials obtained from tissue cultures, cell cultures, organ replication, stem cell production, etc. Appropriate animal subjects include mammals and birds. As used herein, the term “mammal” includes, but is not limited to, primates (e.g., humans, monkeys, apes, etc.), cattle (e.g., bulls, etc.), sheep (e.g., sheep, goats, etc.), pigs, horses, cats, dogs, rabbits, and rodents (e.g., mice, rats, etc.). As used herein, the term “bird” includes, but is not limited to, chickens, ducks, geese, quail, turkeys, pheasants, etc. In some embodiments, the subject is a mammal or mammalian cell. In some embodiments, the subject is a human or human cell. Human subjects include, but are not limited to, fetuses, neonates, infants, adolescents, and adults. Furthermore, “subject” may include patients who have or are suspected of having certain disorders or diseases. Thus, the terms “subject” and “patient” are used interchangeably herein. The subject may also refer to cells in a laboratory or bioprocess media (culture medium) in a test. 【0109】 As used herein, the term “effective dose” refers to the amount of a drug or pharmaceutical reagent that elicits a biological or medical response in a tissue, system, animal, or human, as desired by the researcher or clinician. Furthermore, the term “therapeutic effective dose” means an amount that, compared to a corresponding subject who did not receive such dose, results in the treatment, cure, prevention, or mitigation of a disease, condition, or side effect, or a reduction in the rate of progression of the disease or condition. This term also includes amounts that effectively enhance normal physiological function. The therapeutic effective doses of one or more compounds of this application are known to those skilled in the art or can be readily determined by standard methods known in the art. 【0110】 Unless otherwise specified, the phrase "...independently selected" as used in this application should be broadly interpreted to mean that each individual described is selected independently of the others. Therefore, each substituent may be identical or different from the others. More specifically, the phrase "...independently selected" may mean that specific options represented by the same symbol do not influence each other within different groups, or it may mean that specific options represented by the same symbol do not influence each other within the same group. 【0111】 A person skilled in the art will, in accordance with the conventions used in the art, use in the structural formula of the base described in this application. 【0112】 [ka] 【0113】 and 【0114】 [ka] 【0115】 The example means that the corresponding group is linked to another fragment or group in the compound via an SP3-SP3 covalent bond at that site. Various preferred embodiments of the present application can be obtained by arbitrarily combining the above preferred conditions without deviating from common sense in the art. 【0116】 Compound of the present invention This application provides a PROTAC compound that targets the estrogen receptor represented by formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, or isomer thereof. 【0117】 [ka] 【0118】 (Here, L represents a linker for ligating the ERL fragment with E3L, and E3L indicates a ubiquitin ligase ligand that can recruit E3 ligase to form a stable target protein-PROTAC-E3 ubiquitin ligase ternary complex, which ubiquitizes the target protein. Once ubiquitinated, the ubiquitinated protein is recognized and degraded by the intracellular proteasome 26S.) 【0119】 Here, 【0120】 [ka] 【0121】 It is the absence of a substituent, or the absence of a substituent. 【0122】 [ka] 【0123】 Substitutable or unsubstituted 【0124】 [ka] 【0125】 This represents X 4 represents N or CRa, and the substituent is selected from halogens, hydroxyl groups, cyano groups, oxy groups, benzyl groups, substituted or unsubstituted amine groups, substituted or unsubstituted C1-C6 alkyl groups, substituted or unsubstituted C1-C6 alkoxy groups, and C1-C6 acyl groups. If A does not exist, R 1 These are selected from halogens, hydroxyl groups, cyano groups, oxy groups, benzyl groups, substituted or unsubstituted amine groups, substituted or unsubstituted C1-C6 alkyl groups, substituted or unsubstituted C1-C6 alkoxy groups, and C1-C6 acyl groups. X1 is N or CR 3 And, X 2 or X 3 These are CH and CR, which are independent of each other. 3 Selected from , and N, R 2 , R 3 Each of these is independently selected from H, halogen, hydroxyl group, cyano group, oxy group, benzyl group, substituted or unsubstituted amine group, substituted or unsubstituted C1-C6 alkyl group, substituted or unsubstituted C1-C6 alkoxy group, and C1-C6 acyl group. Ra is selected from H, halogen, hydroxyl group, cyano group, oxy group, benzyl group, substituted or unsubstituted amine group, substituted or unsubstituted C1-C6 alkyl group, substituted or unsubstituted C1-C6 alkoxy group, and C1-C6 acyl group. L is one of the following: 【0126】 [ka] 【0127】 [ka] 【0128】 [ka] 【0129】 As those skilled in the art will understand, E3L in the present application may be any conventionally known ubiquitin ligase ligand. 【0130】 In one specific embodiment, E3L is one selected from the following: 【0131】 [ka] 【0132】 [Chemical formula] 【0133】 In one specific embodiment, E3L is 【0134】 [Chemical formula] 【0135】 is. In one specific embodiment, L is one selected from the following. 【0136】 [Chemical formula] 【0137】 In one specific embodiment, L is 【0138】 [Chemical formula] 【0139】 is. In one specific embodiment, when A is absent, R 1 is selected from -NH2 or -OH. 【0140】 In one specific embodiment, X 4 is N. 【0141】 In one specific embodiment, X 4 is CRa, and Ra is selected from H, halogen, and hydroxy group. In one specific embodiment, X 4 is CRa, and Ra is H. 【0142】 In one specific embodiment, X 1 is CR 3 and R 3is H, CH3O or F. In one specific embodiment, X 1 is CR 3 and R 3 is H. 【0143】 In one specific embodiment, X 2 is CH. In one specific embodiment, X 2 is N. 【0144】 In one specific embodiment, X 3 is CH. 【0145】 In one specific embodiment, R 2 is H. 【0146】 In one specific embodiment, the compound is represented by formula (I). 【0147】 【Chemical formula】 【0148】 (where 【0149】 【Chemical formula】 【0150】 is halogen-substituted or unsubstituted 【0151】 【Chemical formula】 【0152】 represents, X 4 is CH, X 1 is CR 3 and R 3 is H, CH3O or F, X 2 is CH or N, X 3 is CH, and R 2is selected from H, halogen, hydroxy group, cyano group, oxy group, benzyl group, substituted or unsubstituted amine group, substituted or unsubstituted C1-C6 alkyl group, substituted or unsubstituted C1-C6 alkoxy group, and C1-C6 acyl group, L is one selected from the following, 【0153】 【Chemical formula】 【0154】 E3L is one selected from the following. 【0155】 【Chemical formula】 【0156】 【Chemical formula】 【0157】 In one specific embodiment, the compound is represented by formula (I). 【0158】 【Chemical formula】 【0159】 (where 【0160】 【Chemical formula】 【0161】 is halogen-substituted or unsubstituted 【0162】 【Chemical formula】 【0163】 represents, X 4 is CH, X1 CR 3 And R 3 is H, CH3O or F, and X 2 is CH or N, X 3 CH is, R 2 This is selected from H, halogen, hydroxyl group, cyano group, oxy group, benzyl group, substituted or unsubstituted amine group, substituted or unsubstituted C1-C6 alkyl group, substituted or unsubstituted C1-C6 alkoxy group, and C1-C6 acyl group. L is 【0164】 [ka] 【0165】 And, E3L is one of the following options: 【0166】 [ka] 【0167】 [ka] 【0168】 In one specific embodiment, the compound represented by formula (I) is represented by formula (II). 【0169】 [ka] 【0170】 (Here, R 4 (These are selected from halogens, hydroxyl groups, cyano groups, oxy groups, benzyl groups, substituted or unsubstituted amine groups, substituted or unsubstituted C1-C6 alkyl groups, substituted or unsubstituted C1-C6 alkoxy groups, and C1-C6 acyl groups.) 【0171】 In one specific embodiment, R4 is a halogen. In one specific embodiment, R 4 It is F. 【0172】 In one specific embodiment, the compound is represented by formula (II). 【0173】 [ka] 【0174】 (Here, R 4 It is a halogen, and X 1 CR 3 And R 3 is H, CH3O or F, and X 2 is CH or N, X 3 CH is, R 2 This is selected from H, halogen, hydroxyl group, cyano group, oxy group, benzyl group, substituted or unsubstituted amine group, substituted or unsubstituted C1-C6 alkyl group, substituted or unsubstituted C1-C6 alkoxy group, and C1-C6 acyl group. L is one of the following: 【0175】 [ka] 【0176】 E3L is one of the following options: 【0177】 [ka] 【0178】 [ka] 【0179】 In one specific embodiment, the compound is represented by formula (II). 【0180】 [ka] 【0181】 (Here, R 4 It is a halogen, and X 1 CR 3 And R 3 is H, CH3O or F, and X 2 is CH or N, X 3 CH is, R 2 This is selected from H, halogen, hydroxyl group, cyano group, oxy group, benzyl group, substituted or unsubstituted amine group, substituted or unsubstituted C1-C6 alkyl group, substituted or unsubstituted C1-C6 alkoxy group, and C1-C6 acyl group. L is 【0182】 [ka] 【0183】 And, E3L is one of the following options: 【0184】 [ka] 【0185】 [ka] 【0186】 In one specific embodiment, the compound represented by formula (I) is represented by formula (III). 【0187】 [ka] 【0188】 In one specific embodiment, the compound is represented by formula (III). 【0189】 [ka] 【0190】 (L is one of the following, 【0191】 [ka] 【0192】 E3L is one of the following options: 【0193】 [ka] 【0194】 [ka] 【0195】 In one specific embodiment, the compound is represented by formula (III). 【0196】 [ka] 【0197】 (L is 【0198】 [ka] 【0199】 And, E3L is one of the following options: 【0200】 [ka] 【0201】 [ka] 【0202】 In one specific embodiment, the compound represented by formula (I) is represented by formula (IV). 【0203】 [ka] 【0204】 In one specific embodiment, the compound is represented by formula (IV). 【0205】 [ka] 【0206】 (L is one of the following: 【0207】 [ka] 【0208】 In one specific embodiment, the compound is represented by formula (IV). 【0209】 [ka] 【0210】 (L is 【0211】 [ka] 【0212】 (That is the case.) In one specific embodiment, the compound relating to the present application is one of Compound 1 to Compound 143. 【0213】 Pharmaceutical composition The present invention further provides a pharmaceutical composition comprising the above-mentioned compound, one of its pharmaceutically acceptable salts, solvates, hydrates, or isomers, and a pharmaceutically acceptable carrier. 【0214】 The form of a pharmaceutical composition is determined by several criteria, such as the route of administration, the severity of the disease, and the dosage. 【0215】 In some embodiments, the pharmaceutical composition may be formulated to be delivered to the target via an appropriate route, including but not limited to oral, injectable (e.g., intravenous, intramuscular, subcutaneous, intradermal, intracardiac, intrathecal, intrapleural, intraperitoneal, etc.), mucosal (e.g., intranasal, oral, etc.), sublingual, rectal, transdermal, intraocular, and pulmonary routes. Depending on the desired route of administration, the pharmaceutical composition may be formulated as tablets, capsules, pills, sugar-coated tablets, powders, granules, cachets, lozenges, suppositories, suspensions, emulsions, syrups, aerosols (solid or liquid media), sprays, ointments, pastes, patches, creams, lotions, gels, inhalants, etc. 【0216】 Therapeutic uses and treatment methods This application further provides the use of any of the above compounds or their pharmaceutically acceptable salts, solvates, hydrates, or isomers or pharmaceutical compositions in the treatment of disorders treated by the degradation of target proteins bound to target ligands. 【0217】 The present invention further provides the use of any of the above compounds or their pharmaceutically acceptable salts, solvates, hydrates, or isomers or pharmaceutical compositions in the preparation of drugs for treating disorders treated by the degradation of target proteins bound to target ligands. 【0218】 The present invention further provides a method for treating a disorder in a subject that is treated by the degradation of a target protein bound to a target ligand, comprising administering to the subject an effective amount of any of the above-mentioned compound or a pharmaceutically acceptable salt, solvate, hydrate, or isomer or pharmaceutical composition thereof. 【0219】 Here, the aforementioned disorders are selected from abnormal cell proliferation, cancer, immune disorders, diabetes, cardiovascular diseases, infectious diseases, and inflammatory diseases. 【0220】 In one specific embodiment, the cancers include breast cancer, endometrial cancer, uterine cancer, testicular cancer, cervical cancer, prostate cancer, ovarian cancer, endometriosis, fallopian tube tumors, ovarian tumors, leukemia, skin cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, renal cell carcinoma, bladder cancer, intestinal cancer, colon cancer, esophageal cancer, head cancer, kidney cancer, liver cancer, lung cancer, cervical cancer, pancreatic cancer, stomach cancer, lymphoma, non-Hodgkin lymphoma, malignant melanoma, myeloproliferative disorders, sarcomas, and vascular cancers. Selected from sarcomas, peripheral neuroepithelial tumors, gliomas, astrocytomas, oligodendrogliomas, ependymomas, glioblastomas, neuroblastomas, gangliocytomas, gangliogliomas, medulloblastomas, pineal cell tumors, meningiomas, meningiosarcomas, neurofibromas, schwannomas, thyroid cancers, Hodgkin tumors, Wilms tumors, and teratomas, more preferably selected from breast cancers, endometrial cancers, uterine cancers, testicular cancers, cervical cancers, prostate cancers, ovarian cancers, fallopian tube tumors, and ovarian tumors. 【0221】 In one specific embodiment, the cancer is selected from breast cancer, endometrial cancer, ovarian cancer, cervical cancer, prostate cancer, or endometriosis. 【0222】 In one specific embodiment, the infection is selected from diseases caused by viral pneumonia, avian influenza, meningitis, gonorrhea, or infection with HIV, HBV, HCV, HSV, HPV, RSV, CMV, Ebola virus, flavivirus, Blotchi virus, rotavirus, influenza, coronavirus, EBV, drug-resistant viruses, RNA viruses, DNA viruses, adenoviruses, poxviruses, picornaviruses, togaviruses, orthomyxoviruses, retroviruses, hepadnaviruses, gram-negative bacteria, gram-positive bacteria, atypical bacteria, staphylococci, streptococci, Escherichia coli, Salmonella, Helicobacter pylori, Chlamydia, Mycoplasma, fungi, protozoa, enteroworms, helminths, prions, or parasites. [Examples] 【0223】 Examples This application is further illustrated by examples, illustrating the compounds, pharmaceutical compositions, and methods described herein by providing the synthetic and biological examples described herein. The following examples are for illustrative purposes only and are not intended to limit this application. All modifications, changes, and alterations made within the scope of protection of this application are included within the scope of protection of this application. 【0224】 The compounds described herein can be prepared from readily available starting materials by operating procedures generally known to those skilled in the art, according to specific synthesis methods described later. In the following examples, experimental methods where specific conditions are not specified can be determined by those skilled in the art through a standard optimization process, following conventional methods and conditions. 【0225】 The abbreviations used in the examples are shown in the table below. 【0226】 JPEG2026519066000086.jpg208156 【0227】 JPEG2026519066000087.jpg233155 【0228】 JPEG2026519066000088.jpg107155 【0229】 Unless otherwise stated, all compounds described herein include different stereoisomers having the same molecular formula. “Stereoisomers” as used herein also include enantiomers and diastereomers. Enantiomers are optical isomers, while diastereomers are stereoisomers that do not form enantiomers. Different isomers having the same molecular formula as the compounds described herein are also covered by the scope of protection of this application. 【0230】 Unless otherwise specified, the term "solvate" as used herein may also be called "solvide," and refers to a compound containing a solvent, where the solvent molecule may be bonded to the compound molecule by other means, such as coordination bonds, covalent bonds, van der Waals forces, ionic bonds, or hydrogen bonds. 【0231】 Unless otherwise specified, the term “pharmaceutically acceptable salt” as used herein means that the compound of the Application and / or a salt formed therefrom is chemically or physically compatible with other components of a given drug dosage form and physiologically compatible with a receptor. “pharmaceutically acceptable salt” refers to acidic and / or basic salts formed with inorganic and / or organic acids and bases, and includes amphoteric salts (internal salts) and quaternary ammonium salts such as alkylammonium salts. These salts may be obtained directly in the final separation and purification process of the compound. Alternatively, they may be obtained by appropriately mixing the compound of the Application or its stereoisomers or solvates with a certain amount of acid or base. These salts may be prepared by forming a precipitate in solution and recovering it by filtration, by evaporating the solvent and recovering it, or by reacting in an aqueous medium and then cooling and drying it. 【0232】 Unless otherwise specified, this application identifies compounds using conventional methods such as mass spectrometry and nuclear magnetic resonance, and each step and condition may refer to conventional operating steps and conditions in the art. 【0233】 Unless otherwise specified, this application employs standard nomenclature, experimental steps, and techniques in analytical chemistry, organic synthesis, and optics. In some cases, standard techniques are used for chemical synthesis, chemical analysis, and performance testing of luminescent devices. 【0234】 Unless otherwise specified, Minute in this application TM The total protein extraction kit will be purchased from Chen Student Biotechnology (Guangzhou) Co., Ltd. under product numbers sd-001 / sn-002. 【0235】 Unless otherwise specified, the Bio-Rad All-in-One Protein Transfer System / Transfer Device (Trans-Blot Turbo) used in this application was purchased from Shanghai Aiya Biotechnology Co., Ltd. Unless otherwise specified, the 5×SDS-PAGE loading buffer used herein is purchased from Shanghai Lianmai Bioengineering Co., Ltd. under the trade name LM-071. Unless otherwise specified, "5-bromo-1-H-indazole" as used herein is purchased from Shanghai Yuanye Biotechnology Co., Ltd. under the trade name: Y11003. Unless otherwise specified, Dress-Martin reagents (also known as Dress-Martin oxidizing agents) used herein are purchased from Hede Chemical (Suzhou) Co., Ltd. Unless otherwise specified, 4-bromo-2,6-difluorobenzaldehyde used herein is purchased from Macklin Biochemical under CAS number 537013-51-7. Unless otherwise specified, 4-fluorobenzaldehyde used herein is purchased from Gaide Chemical Technology (Shanghai) Co., Ltd. under CAS number 459-57-4. Unless otherwise specified, 5-fluoropyridine-2-carboxyaldehyde used herein is purchased from Gaide Chemical Technology (Shanghai) Co., Ltd. under CAS number: 31181-88-1. Unless otherwise specified, 5-fluoroisobenzofuran-1,3-dione used herein is purchased from Gaide Chemical Technology (Shanghai) Co., Ltd. under CAS number 319-03-9. Unless otherwise specified, "Dihydrouracil" in this specification is purchased from Shanghai Aladdin Biochemical Technology Co., Ltd. under CAS number 504-07-4. Unless otherwise specified, "7-bromoimidazo[1,2-a]pyridine" as used herein is purchased from Shanghai Tebo Chemical Technology Co., Ltd. under CAS number 808744-34-5. Unless otherwise specified, "N-iodosuccinimide" in this specification is purchased from Shanghai Aladdin Technology Co., Ltd. under CAS number: 516-12-1. Unless otherwise specified, "(1R,2R)-N1,N2-dimethylcyclohexane-1,2-diamine" as used herein is purchased from Shanghai Jixiang Biotechnology Co., Ltd. under the trade name SH215137. Unless otherwise specified, "5,6-dimethylisoindorin-1-one" as used herein is purchased from Shanghai Yuanye Biotechnology Co., Ltd. under CAS number: 110568-65-5. Unless otherwise specified, "benzoyl peroxide" as used herein is purchased from Jinan Huifengda Chemical Co., Ltd. under CAS number 94-36-0. Unless otherwise specified, "5,6-dimethylisobenzofuran-1,3-dione" as used herein is purchased from Shanghai Haohong Biomedical Technology Co., Ltd. under CAS number 129-64-6. Unless otherwise specified, "3-amino-1-(4-methoxybenzyl)piperidine-2,6-dione" as used herein is purchased from Chongqing Xiaoxiang Lan Pharmaceutical Co., Ltd. under CAS number: 1834336-02-5. Unless otherwise specified, "3-formylazetidine-1-carboxylate tert-butyl" as used herein is purchased from Shanghai Xiaxia Luo Chemical Co., Ltd. under CAS number: 177947-96-5. Unless otherwise specified, "di-tert-butyl[2',4',6'-tris(propan-2-yl)-[1,1'-biphenyl][1,1'-biphenyl]-2-yl]phosphorane" as used herein is purchased from Shaoyuan Technology Co., Ltd. under CAS number: 1160861-53-9. Unless otherwise specified, "2-methylpropan-2-amine" as used herein is purchased from Shanghai Macklin Biochemical Technology Co., Ltd. under CAS number: 75-64-9. Unless otherwise specified, "Chloro(2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II)" as used herein is purchased from Shanghai Aladdin Biochemical Technology Co., Ltd. under CAS number: 1375325-68-0. Unless otherwise specified, the "TBST" buffer used herein is purchased from Shanghai Aladdin Biochemical Technology Co., Ltd. 【0236】 Examples of intermediate synthesis The present invention is further illustrated by examples, illustrating the compounds, pharmaceutical compositions, and methods described herein through the synthetic and biological examples described herein. The following examples are for illustrative purposes only and do not limit the scope of the present invention. Any modifications, changes, or alterations made within the scope of protection of the present invention are all included within the scope of protection of the present invention. 【0237】 Preparation of ERL, a small ligand fragment to which estrogen receptor protein binds: Preparation of ERL-1:3-fluoro-5-((6-fluoropyridine-3-yl)(2,2,6,6-tetramethyltetrahydro-4H-pyran-4-ylmethylene)methyl)-1-tetrahydro-2H-pyran-4-yl)-1H-indazole: 【0238】 [ka] 【0239】 Step 1: Preparation of 5-bromo-3-fluoro-1H-indazole: To a solution of 5-bromo-1H-indazole (200 g, 1.01 mol) in DMA (2 L) stirred in an ice bath, Selectfluor (719 g, 2.03 mol) was added dropwise under a nitrogen atmosphere. The resulting mixture was stirred at 60°C for 12 hours. The temperature was raised to room temperature, and the reaction was quenched with water (200 mL). The resulting mixture was extracted with ethyl acetate (3 × 1500 mL), the combined organic layer was washed with water (3 × 500 mL), and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and then eluted with CH2Cl2 / PE (1:1) to obtain 5-bromo-3-fluoro-1H-indazole (82 g, 37.57%) as a white solid. LCMS (ES, m / z): 215 [M+H] + . 【0240】 Step 2: Preparation of 5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-3-fluoroindazole: Under a nitrogen atmosphere, dihydro-2H-pyran (32 g, 380.7 mmol) and pTsOH (8.7 g, 50.8 mmol) were added to a stirred solution of 5-bromo-1H-indazole (50 g, 253.8 mmol) in an ice bath DCM (800 mL). The resulting mixture was heated to room temperature and stirred for 4 hours. The reaction was quenched by adding saturated aqueous sodium bicarbonate, and the resulting mixture was extracted with DCM (3 × 1000 mL). The organic layers were dried together over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and then eluted with PE / EA (5:1) to obtain 5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-3-fluoro-indazole (60 g, 81%) as a yellow oily liquid. LCMS (ES, m / z): 299 [M+H] + . 【0241】 Step 3: Preparation of (4-(6-fluoropyridine-3-yl))(1-(tetrahydro-2H-pyran-2-yl)-1H-3-fluoroindazole-5-yl)methanol: A solution of 5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (10 g, 35.6 mmol) in THF (200 mL) was treated with n-butyllithium (2.5 M, 17 mL, 42.7 mmol) in n-hexane at -78°C under a nitrogen atmosphere for 5 minutes, after which 6-fluoropyridine-3-formaldehyde (6.7 g, 53.4 mmol) was added. The resulting mixture was stirred at -78°C for 1 hour. The reaction was quenched with saturated ammonium chloride aqueous solution and the temperature was raised to room temperature. The resulting mixture was extracted with ethyl acetate (3 × 50 mL). The organic layers were dried together over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and then eluted with PE / EA to obtain (4-(6-fluoropyridine-3-yl))(1-(tetrahydro-2H-pyran-2-yl)-1H-3-fluoroindazole-5-yl)methanol (7g, 58%) as a white solid. LCMS (ES, m / z): 346 [M+H] + . 【0242】 Step 4: Preparation of (3-fluoro-1-(tetrahydro-2H-pyran-4-yl)-1H-indazole-5-yl)(6-fluoropyridine-3-yl)methyl ketone: (4-(6-fluoropyridine-3-yl))(1-(tetrahydro-2H-pyran-2-yl)-1H-3-fluoroindazole-5-yl)methanol (7 g, 21.4 mmol) was dissolved in an ice bath DCM (150 mL) with Dess-Martin reagent (13.6 g, 32.1 mmol). The resulting mixture was stirred overnight at room temperature under a nitrogen atmosphere. The mixture was obtained by filtration, and the filtrate cake was washed with DCM. The filtrate was concentrated under reduced pressure. After purifying the residue by silica gel column chromatography, it was eluted with PE / EA (10:1) to obtain (3-fluoro-1-(tetrahydro-2H-pyran-4-yl)-1H-indazole-5-yl)(6-fluoropyridine-3-yl)methyl ketone (4 g, 55%) as a grayish-white solid. LCMS (ES, m / z): 344 [M+H] + . 【0243】 Step 5: Preparation of 3-fluoro-5-((6-fluoropyridine-3-yl)(2,2,6,6-tetramethyltetrahydro-4H-pyran-4-ylmethylene)methyl)-1-tetrahydro-2H-pyran-4-yl)-1H-indazole: Zinc powder (4 g, 61.5 mmol) and TiCl4 (4.7 g, 24.6 mmol) were added to a stirred ice bath of THF (200 mL) under a nitrogen atmosphere. The resulting mixture was stirred at 65°C for 2 hours, cooled to 0°C, and 2,2,6,6-tetramethyltetrahydro-4H-pyran-4-one (1.5 g, 9.2 mmol) and (3-fluoro-1-(tetrahydro-2H-pyran-4-yl)-1H-indazole-5-yl)(6-fluoropyridine-3-yl)methyl ketone (2 g, 6.2 mmol) were added. The resulting mixture was stirred at 65°C for 12 hours. After cooling to room temperature, the reaction was quenched with saturated sodium bicarbonate aqueous solution. The resulting mixture was extracted with ethyl acetate (3 × 200 mL). The organic layers were combined and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. After purifying the residue by silica gel column chromatography, elution with PE / EA (5:1) yielded 3-fluoro-5-((6-fluoropyridine-3-yl)(2,2,6,6-tetramethyltetrahydro-4H-pyran-4-ylmethylene)methyl)-1-tetrahydro-2H-pyran-4-yl)-1H-indazole (1.5 g, 52%) as a grayish-white solid. LCMS (ES, m / z): 468 [M + H] + . Unless otherwise specified, the following intermediates and analogues (not limited to analogues with different substitutions, e.g., halogens) were prepared using corresponding similar starting materials and reagents, following similar procedures described for the ERL-1 embodiment. 【0244】 ERL-2:5-((6-fluoropyridine-3-yl)(2,2,6,6-tetramethyltetrahydro-4H-pyran-4-ylmethylene)methyl)-1-(tetrahydro-2H-pyran-4-yl)-1H-indazole, LCMS: [M+H] + = 450.2. 【0245】 [ka] 【0246】 The synthesis method is the same as ERL-1, except that the fluorination step in step 1 is omitted. 【0247】 ERL-3:5-((4-chlorophenyl)(2,2,6,6-tetramethyltetrahydro-4H-pyran-4-ylmethylene)methyl)-3-fluoro-1-(tetrahydro-2H-pyran-4-yl)-1H-indazole, LCMS: [M+H] + = 483.2. 【0248】 [ka] 【0249】 The synthesis method is the same as ERL-1, except that in step 3, 4-fluorobenzaldehyde is used instead of 6-fluoropyridine-3-formaldehyde. 【0250】 ERL-4:5-((4-chlorophenyl)(2,2,6,6-tetramethyltetrahydro-4H-pyran-4-ylmethylene)methyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole, LCMS: [M+H] + = 465.2. 【0251】 [ka] 【0252】 The synthesis method is the same as ERL-1, except that step 1 is omitted and 4-fluorobenzaldehyde is used instead of 6-fluoropyridine-3-formaldehyde in step 3. 【0253】 ERL-5:5-((4-bromo-2,6-difluorophenyl)(2,2,6,6-tetramethyltetrahydro-4H-pyran-4-methylene)methyl)-3-fluoro-1-(tetrahydro-2H-pyran-4-yl)-1H-indazole, LCMS: [M+H] + = 563.1. 【0254】 [ka] 【0255】 For synthesis methods, refer to ERL-1. 【0256】 ERL-6:3-Fluoro-5-((5-Fluoropyridine-2-yl)(2,2,6,6-tetramethyltetrahydro-4H-pyran-4-ylmethylene)methyl)-1-(tetrahydro-2H-pyran-4-yl)-1H-indazole 【0257】 [ka] 【0258】 The synthesis method is the same as ERL-1, except that in step 3, 5-fluoropyridine-2-formaldehyde is used instead of 6-fluoropyridine-3-formaldehyde. Preparation of small molecule fragment E3L that binds to E3 ubiquitin ligase: 【0259】 Preparation of E3L-1:2-(2,6-dioxopiperidine-3-yl)-5-fluoroisoindoline-1,3-dione: 【0260】 [ka] 【0261】 A solution of 5-fluoroisobenzofuran-1,3-dione (15 g, 90 mmol) in acetic acid (150 mL) was added with sodium acetate (14.8 g, 180 mmol) and 3-aminopiperidine-2,6-dione hydrochloride (14.6 g, 90 mmol). The mixture was stirred at 120 °C for 12 hours. The reaction mixture was concentrated under reduced pressure to remove most of the acetic acid. The residue was poured into water (200 mL) and stirred for 15 minutes. The mixture was filtered. The filter cake was washed with water (50 mL × 2) and dried to obtain 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (21 g, 90% yield) as a grayish white solid. LC-MS (ESI) m / z: 277.1 [M+1] + ; 【0262】 Hydrochloride of E3L-2 piperazine: Preparation of 3-(1-oxo-5-(piperazin-1-yl)isoindol-2-yl)piperidine-2,6-dione hydrochloride: 【0263】 [Chemical formula] 【0264】 Step 1: Preparation of tert-butyl 4-[2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindol-5-yl]piperazine-1-carboxylate: In a nitrogen atmosphere, t-butylpiperazine-1-carboxylate (13.8 g, 74.3 mmol), Cs2CO3 (24.2 g, 74.3 mmol), and 2,3-di[2,6-bis(pentan-3-yl)phenyl]-2,3-dihydro-1H-imidazole-2-yl]dichloro(3-chloropyridine-1-ammonium-1-yl)palladium (2.0 g, 2.5 mmol) were sequentially added to a solution of 3-(5-bromo-1-oxoisoindole-2-yl)piperidine-2,6-dione (8 g, 24.8 mmol) in 1,4-dioxane (100 mL). The resulting mixture was heated to 100 °C and stirred for 4 hours. The reaction was quenched with water while cooling to room temperature. The precipitated solid was collected by filtration and washed with H2O (2 × 15 mL). The residue was washed with ethyl acetate (2 × 10 mL) to form a slurry. The resulting solid was dried under infrared light. t-butyl 4-[2-(2,6-dioxopiperidine-3-yl)-1-oxo-3H-isoindole-5-yl]piperazine-1-carboxylic acid (5 g, 47.13%) was obtained as a grayish-white solid. LCMS (ES, m / z): 429 [M + H] + . 【0265】 Step 2: Preparation of 3-[1-oxo-5-(piperazine-1-yl)isoindole-2-yl]piperidine-2,6-dione hydrochloride: 4-[2-(2,6-dioxopiperidine-3-yl)-1-oxo-isoindole-5-yl]piperazine-1-carboxylate t-butyl (5 g, 11.7 mmol) and hydrochloric acid (4 M, 10 mL) were stirred overnight in ethyl acetate (30 mL). The resulting mixture was concentrated under reduced pressure. The residue was washed with ethyl acetate (5 × 20 mL) to obtain a slurry. 3-(1-oxo-5-(piperazine-1-yl)-3H-isoindole-2-yl]piperidine-2,6-dione hydrochloride (3 g, 70.47%) was obtained as a grayish-white solid. LCMS (ES, m / z): 329 [M + H] + . 【0266】 Preparation of E3L-3:1-(7-bromoimidazo[1,2-a]pyridine-3-yl)dihydropyrimidine-2,4(1H,3H)-dione: 【0267】 [ka] 【0268】 Step 1: Preparation of 3-(4-methoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dione: The starting material, dihydrouracil (6.0 g, 52.6 mmol), was dissolved in DMF (100 mL), and Cs2CO3 (34.5 g, 106 mmol) was added at 25°C. Then, PMBCl (7.5 g, 47.5 mmol) was slowly added at room temperature. The reaction was allowed to proceed at room temperature for 2 hours. After the reaction was complete, the mixture was filtered, and the filter cake was washed with EA (50 mL x 2). The filtrates were combined and poured into water (300 mL), then extracted with EA (200 mL x 2). The organic phases were combined, washed once with water (200 mL), and then washed once again with saturated brine (200 mL). The organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was dissolved in EA / PE (1 / 150 mL), stirred for 30 minutes, filtered, and dried. 5.9 g of white solid was obtained in 47% yield. LCMS: [M+H] + = 235.2. 【0269】 Step 2: Preparation of 7-bromo-3-iodoimidazo[1,2-a]pyridine: The starting material, 7-bromo-imidazo[1,2-a]pyridine (11.4 g, 54.9 mmol), was dissolved in DMF (160 mL), and NIS (15.6 g, 69.4 mmol) was added at 25 °C. The reaction was carried out at 100 °C for 1 hour. After the reaction was complete, the mixture was injected into water (500 mL), then extracted with EA (200 mL x 2), and the organic phases were combined and washed once with water (200 mL), followed by one wash with saturated brine (200 mL). The organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was separated by column chromatography EA / PE (0-5%) to obtain 7-bromo-3-iodoimidazo[1,2-a]pyridine as a dark brown solid (14.1 g, 75% yield). LCMS: [M+H]+=322.9. 【0270】 Step 3: Preparation of 1-(7-bromoimidazo[1,2-a]pyridine-3-yl)-3-(4-methoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dione: The starting materials, 3-(4-methoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dione (6 g, 25.1 mmol) and 7-bromo-3-iodoimidazo[1,2-a]pyridine, were dissolved in 1,4-dioxane (150 mL). At 25 °C, Cs₂CO₃ (16.7 g, 51.2 mmol), CuI (980 mg, 5.22 mmol), and (1R,2R)-N1,N₂-dimethylcyclohexane-1,2-diamine (730 mg, 5.23 mmol) were added. The reaction was carried out at 80 °C under nitrogen protection for 16 hours. After the reaction was complete, the mixture was injected into water (300 mL), then extracted with EA (150 mL x 2), the organic phases were combined, washed once with water (200 mL), and then washed once again with saturated saline (200 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was separated by column chromatography EA / PE (1 / 10~1 / 0) to obtain 1-(7-bromoimidazo[1,2-a]pyridine-3-yl)-3-(4-methoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dione (3.1 g, 29% yield) as a yellow solid. LCMS: [M+H]+=429.0. 【0271】 Step 4: Preparation of 1-(7-bromoimidazo[1,2-a]pyridine-3-yl)dihydropyrimidine-2,4(1H,3H)-dione: The starting material, 1-(7-bromoimidazo[1,2-a]pyridine-3-yl)-3-(4-methoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dione (3.1 g, 7.48 mmol), was dissolved in TfOH (2.3 mL) and reacted at 65°C for 4 hours. After the reaction was complete, the mixture was concentrated, and then the pH was adjusted to between 6 and 7 using TEA at 0°C. After continued concentration, EA (30 mL) was added and stirred for half an hour. The mixture was filtered and dried to obtain a white solid, 1-(7-bromoimidazo[1,2-a]pyridine-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (2.12 g, 76% yield). LCMS: [M+H] + =309.0. 【0272】 Preparation of E3L-4:1-(8-bromoimidazo[1,2-a]pyridine-3-yl)dihydropyrimidine-2,4(1H,3H)-dione: 【0273】 [ka] 【0274】 Step 1: Preparation of 8-bromo-3-iodoimidazo[1,2-a]pyridine: The starting material, 8-bromo-imidazo[1,2-a]pyridine (10 g, 50.1 mmol), was dissolved in DMF (150 mL), and NIS (13.6 g, 60.2 mmol) was added at 25 °C. The reaction was carried out at 100 °C for 1 hour. After the reaction was complete, the mixture was injected into water (400 mL), then extracted with EA (200 mL x 2), and the organic phases were combined and washed once with water (200 mL), followed by one wash with saturated brine (200 mL). The organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was separated by column chromatography EA / PE (5%) to obtain 8-bromo-3-iodoimidazo[1,2-a]pyridine as a dark brown solid (12.2 g, 77% yield). LCMS: [M+H]+=322.9. 【0275】 Step 2: Preparation of 1-(8-bromoimidazo[1,2-a]pyridine-3-yl)-3-(4-methoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dione: The starting materials, 3-(4-methoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dione (4.4 g, 18.65 mmol) and 8-bromo-3-iodoimidazo[1,2-a]pyridine, were dissolved in 1,4-dioxane (100 mL). At 25°C, Cs2CO3 (11.1 g, 34.1 mmol), CuI (705 mg, 3.71 mmol), and (1R,2R)-N1,N2-dimethylcyclohexane-1,2-diamine (522 mg, 3.72 mmol) were added. The reaction was carried out at 80°C under nitrogen protection for 16 hours. After the reaction was complete, the mixture was injected into water (200 mL), then extracted with EA (100 mL x 2), the organic phases were combined, washed once with water (200 mL), and then washed once with saturated saline (200 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was separated by column chromatography EA / PE (1 / 10~1 / 0) to obtain 1-(8-bromoimidazo[1,2-a]pyridine-3-yl)-3-(4-methoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dione (2.3 g, 29% yield) as a yellow solid. LCMS: [M+H] + = 429.0. 【0276】 Step 3: Preparation of 1-(8-bromoimidazo[1,2-a]pyridine-3-yl)dihydropyrimidine-2,4(1H,3H)-dione The starting material, 1-(8-bromoimidazo[1,2-a]pyridine-3-yl)-3-(4-methoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dione (2.3 g, 5.36 mmol), was dissolved in TfOH (1.5 mL) and reacted at 65°C for 4 hours. After the reaction was complete, the mixture was concentrated, and then the pH was adjusted to between 6 and 7 using TEA at 0°C. After continued concentration, EA (30 mL) was added and stirred for half an hour. The mixture was filtered and dried to obtain 1-(8-bromoimidazo[1,2-a]pyridine-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (1.55 g, 81% yield) as a white solid. LCMS: [M+H]+=309.0. 【0277】 Preparation of E3L-5:3-(4-bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-1-yl)piperidine-2,6-dione: 【0278】 [ka] 【0279】 Step 1: Preparation of 2-bromo-N-methyl-6-nitroaniline: The starting material, 1-bromo-2-fluoro-3-nitrobenzene (20 g, 91 mmol), was dissolved in THF (20 mL), and then methylamine (2 M, 200 mL) was added. The reaction was carried out at 60°C for 12 hours. After the reaction was complete, the reaction mixture was injected into NaHCO3 (20 mL), extracted with EA (100 mL x 3), and the organic phases were combined and washed with saturated brine (2 x 100 mL). The organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated. 20 g of 2-bromo-N-methyl-6-nitroaniline was obtained as a red oil in 94% yield. LC-MS (ESI), m / z: [M+H] + = 230.9. 【0280】 Step 2: Preparation of 6-bromo-N1-methylphenyl-1,2-diamine: The starting material, 2-bromo-N-methyl-6-nitroaniline (11 g, 48 mmol), was dissolved in EA (150 mL), water (5 mL), and AcOH (50 mL). The mixture was then heated to 50°C. At 50°C, iron powder (12.2 g, 201 mmol) was added, and the mixture was heated to 80°C and reacted for 4 hours. After the reaction was complete, the mixture was filtered, the filtrate was concentrated, and added to 100 mL of water. It was then extracted with EA (100 mL x 3), the organic phases were combined, washed once with water (200 mL), and then washed once again with saturated brine (200 mL). The organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated. 10 g of crude red oily 6-bromo-N1-methylphenyl-1,2-diamine was obtained in 98% yield. LCMS: [M+H]+=201.1. 【0281】 Step 3: Preparation of 7-bromo-1-methyl-1,3-dihydro-2H-benzo[d]imidazole-2-one: The starting material, 6-bromo-N1-methylphenyl-1,2-diamine (10 g, 98 mmol), was dissolved in MeCN (150 mL), and then CDI (16 g, 98 mmol) was added. The reaction was carried out at 85 °C under nitrogen protection for 12 hours. After the reaction was complete, the solvent was removed by rotary evaporation, and then the mixture was poured into water (100 mL) and allowed to stand to precipitate the solid. The mixture was then filtered, the filter cake was washed with water and dried to obtain 10.5 g of 7-bromo-1-methyl-1,3-dihydro-2H-benzo[d]imidazole-2-one as a white solid in 89% yield. LCMS: [M+H]+=227.0. 【0282】 Step 4: Preparation of 3-(4-bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-1-yl)-1-(4-methoxybenzyl)piperidine-2,6-dione: The raw material 7-bromo-1-methyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (12 g, 27 mmol) was dissolved in THF (300 mL), and then t-BuOK (3.6 g, 32 mmol) was added. The reaction was carried out at 0 °C for 0.5 h. Thereafter, a solution of 1-(4-methoxybenzyl)-2,6-dioxopiperidin-3-yl trifluoromethanesulfonate (*1 / 1) (10.1 g, 27 mmol) dissolved in THF (50 mL) was slowly added to the reaction solution. The reaction was continued at 20 °C for half an hour. After completion of the reaction, it was quenched with saturated ammonium chloride (50 mL), then extracted with EA (100 mL), the organic phases were combined, washed with saturated brine, dried, filtered and concentrated. The crude product was purified by reverse-phase HPLC (0.1% TFA) to obtain 3-(4-bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-1-(4-methoxybenzyl)piperidine-2,6-dione as a yellow solid (6.8 g, 56% yield). 【0283】 Step 5: Preparation of 4-(4-bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione: The raw material 3-(4-bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-1-(4-methoxybenzyl)piperidine-2,6-dione (6.8 g, 13.6 mmol) was dissolved in TfOH (4.8 mL), and the reaction was carried out at 65 °C for 4 h. After completion of the reaction, it was concentrated, and then the pH value was adjusted to between 6 and 7 with TEA at 0 °C. After continuing the concentration, EA (100 mL) was added and stirred for half an hour. It was filtered and dried to obtain 4-(4-bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione as a white solid (4.55 g, 81% yield). LCMS: [M+H] + = 309.0。 【0284】 E3L-6: Preparation of 3-(1-oxo-3,5,6,7-tetrahydropyrrolo[3,4-f]isoindol-2(1H)-yl)piperidine-2,6-dione: Preparation of 1-(4-methoxybenzyl)-2,6-dioxopiperidine-3-yltrifluoromethanesulfonate: To a 500 ml solution of 3-hydroxy-1-(4-methoxybenzyl)piperidine-2,6-dione (43.0 g, 173 mmol) in DCM, pyridine (27.3 g, 345 mmol) was first added, followed by the addition of 73.0 g (258.74 mmol) of trifluoromethanesulfonic anhydride at 0°C. The mixture was stirred at 0°C for 2 hours under nitrogen protection. After the reaction was complete, the solvent was removed by concentration, and the crude product was separated by column chromatography to obtain 1-(4-methoxybenzyl)-2,6-dioxopiperidine-3-yltrifluoromethanesulfonate (45.0 g, 68% yield) as a pale yellow solid. LCMS (ESI): m / z 381.32 [M+1] + . 【0285】 [ka] 【0286】 [ka] 【0287】 Step 1: Preparation of 5,6-di(bromomethyl)isoindorin-1-one: 5,6-dimethylisoindorin-1-one (9.7 g, 60 mmol) and NBS (32.2 g, 180 mmol) were dissolved in chloroform (120 mL), reacted, and heated to 80°C. Then, benzoyl peroxide (336 mg, 1.2 mmol) was added. The reaction was allowed to proceed at 80°C for 8 hours. TLC (PE:EA = 5:1, R f According to the reaction (=0.4), after the reaction was complete, the mixture was cooled to room temperature. The filtrate was then washed with saturated NaHCO3 aqueous solution (50 ml) and saline solution (50 ml), dried over MgSO4, concentrated, filtered, and evaporated by rotary evaporation to obtain 5,6-di(bromomethyl)isoindorin-1-one (11.44 g, 60%) as the crude product. LCMS: [M+H] + = 317.91. 【0288】 Step 2: Preparation of 6-triphenylmethyl-3,5,6,7-tetrahydropyrrolo[3,4-f]isoindole-1(2H)-one: 5,6-di(bromomethyl)isoindorin-1-one (11.44 g, 36 mmol) was dissolved in DMF (100 mL) and DIEA (16 ml, 92 mmol) was added, followed by the addition of triphenylmethylamine (9.4 g, 36 mmol). The reaction mixture was stirred at 60 °C for 4 hours, then H₂O (400 ml) was added and the mixture was vigorously stirred for 15 minutes. The precipitate was filtered, rinsed with H₂O (200 ml x 2), dissolved in EA (3 x 200 ml), and the combined filtrate was extracted. The combined organic layer was washed with water (3 x 50 ml) and brine (2 x 50 ml), dried over MgSO₄, and concentrated. 6-triphenylmethyl-3,5,6,7-tetrahydropyrrolo[3,4-f]isoindole-1(2H)-one was obtained as a white solid (8.1 g, yield 54%) by high-speed column chromatography (silica gel, DCM formula siRNA 50:1-20:1). LCMS: [M+H] + = 417.19. 【0289】 Step 3: Preparation of 3-(1-oxo-6-triphenylmethyl-3,5,6,7-tetrahydropyrrolo[3,4-f]isoindole-2(1H)-yl)piperidine-2,6-dione: The starting material, 6-triphenylmethyl-3,5,6,7-tetrahydropyrrolo[3,4-f]isoindole-1(2H)-one (8g, 19.2 mmol), was dissolved in THF (60 mL), and then t-BuOK (2.6 g, 23 mmol) was added. The reaction was allowed to proceed at 0°C for 0.5 hours. Then, 1-(4-methoxybenzyl)-2,6-dioxopiperidine-3-yltrifluoromethanesulfonate (8.6 g, 23 mmol) dissolved in THF (30 mL) was slowly added to the reaction mixture. The reaction was continued at 20°C for half an hour. After the reaction was complete, the mixture was quenched with saturated ammonium chloride (80 mL), then extracted with EA (200 mL), the organic phases were combined and washed with saturated brine, dried, filtered, and concentrated. The crude product was purified by reverse-phase HPLC (0.1% EA) to obtain 3-(1-oxo-6-triphenylmethyl-3,5,6,7-tetrahydropyrrolo[3,4-f]isoindole-2(1H)-yl)piperidine-2,6-dione as a yellow solid (5.66 g, 56% yield). LCMS: [M+H] + = 528.22. 【0290】 Step 4: Preparation of 3-(1-oxo-3,5,6,7-tetrahydropyrrolo[3,4-f]isoindole-2(1H)-yl)piperidine-2,6-dione 3-(1-oxo-6-triphenylmethyl-3,5,6,7-tetrahydropyrrolo[3,4-f]isoindole-2(1H)-yl)piperidine-2,6-dione (5.66 g, 10.8 mmol) was dissolved in TfOH (8 mL) and reacted at 65°C for 4 hours. After the reaction was complete, the mixture was concentrated, and then the pH was adjusted to between 6 and 7 using TEA at 0°C. After continued concentration, EA (200 mL) was added and stirred for half an hour. The mixture was filtered and dried to obtain 3-(1-oxo-3,5,6,7-tetrahydropyrrolo[3,4-f]isoindole-2(1H)-yl)piperidine-2,6-dione (2.2 g, 72% yield) as a white solid. LCMS: [M+H] + = 286.11. 【0291】 Preparation of E3L-7:2-(2,6-dioxopiperidine-3-yl)-6,7-dihydropyrrolo[3,4-f]isoindole-1,3(2H,5H)-dione: 【0292】 [ka] 【0293】 Step 1: Preparation of 2-(1-(4-methoxybenzyl)-2,6-dioxopiperidine-3-yl)-5,6-dimethylisoindoline-1,3-dione: To a solution of 5,6-dimethylisobenzofuran-1,3-dione (3.52 g, 20 mmol) in acetic acid (40 mL), sodium acetate (3.28 g, 40 mmol) and 3-amino-1-(4-methoxybenzyl)piperidine-2,6-dione (4.96 g, 20 mmol) were added. The mixture was stirred at 100 °C for 12 hours. The reaction mixture was concentrated under reduced pressure to remove most of the acetic acid. The residue was poured into water (200 mL) and stirred for 15 minutes. The mixture was filtered. The filtered cake was washed with water (50 mL x 2) and dried to obtain 2-(1-(4-methoxybenzyl)-2,6-dioxopiperidine-3-yl)-5,6-dimethylisoindorin-1,3-dione (6.51 g, 80% yield) as a grayish-white solid. LC-MS: [M+H]+= 407. 【0294】 Step 2: 5,6-di(bromomethyl)-2-(1-(4-methoxybenzyl)-2,6-dioxopiperidine-3-yl)isoindoline-1,3-dione 2-(1-(4-methoxybenzyl)-2,6-dioxopiperidine-3-yl)-5,6-dimethylisoindoline-1,3-dione (6.51 g, 16 mmol) and NBS (8.58 g, 48 mmol) were dissolved in chloroform (50 mL) and reacted, heated to 80°C, then benzoyl peroxide (112 mg, 0.4 mmol) was added, and the reaction was carried out at 80°C for 8 hours. After the reaction was complete, the mixture was cooled to room temperature, and the filtrate was washed with saturated NaHCO3 aqueous solution (50 mL) and brine (50 mL). The filtrate was dried over MgSO4, concentrated, filtered, and rotated to obtain the crude product 5,6-di(bromomethyl)-2-(1-(4-methoxybenzyl)-2,6-dioxopiperidine-3-yl)isoindoline-1,3-dione (4.95 g, 55%). LCMS: [M+H]+=563. 【0295】 Step 3: Preparation of 2-(2,6-dioxopiperidine-3-yl)-6-triphenylmethyl-6,7-dihydropyrrolo[3,4-f]isoindole-1,3(2H,5H)-dione: To a solution of 5,6-di(bromomethyl)-2-(1-(4-methoxybenzyl)-2,6-dioxopiperidine-3-yl)isoindoline-1,3-dione (4.95 g, 8.8 mmol) in DMF (50 mL), DIEA (4.6 ml, 26.4 mmol) was added, followed by the addition of triphenylmethylamine (2.3 g, 8.8 mmol). The reaction mixture was stirred at 60°C for 4 hours, then poured into H2O (200 ml) and vigorously stirred for 15 minutes. The precipitate was filtered, rinsed with H2O (100 ml x 2), dissolved in EA (3 x 100 ml), and the combined filtrate was extracted. The combined organic layer was washed with brine (2 x 50 ml), dried over MgSO4, and concentrated. High-speed column chromatography (silica gel, DCM formula EA50:1~20:1) yielded 2-(2,6-dioxopiperidine-3-yl)-6-triphenylmethyl-6,7-dihydropyrrolo[3,4-f]isoindole-1,3(2H,5H)-dione (2.14 g, yield 45%). LCMS: [M+H] + = 542.2. 【0296】 Step 4: Preparation of 2-(2,6-dioxopiperidine-3-yl)-6,7-dihydropyrrolo[3,4-f]isoindole-1,3(2H,5H)-dione: The starting material, 2-(2,6-dioxopiperidine-3-yl)-6-triphenylmethyl-6,7-dihydropyrrolo[3,4-f]isoindole-1,3(2H,5H)-dione (2.14 g, 3.96 mmol), was dissolved in TfOH (3.3 mL) and reacted at 65°C for 4 hours. After the reaction was complete, the mixture was concentrated, and then the pH was adjusted to between 6 and 7 using TEA at 0°C. After continued concentration, EA (50 mL) was added and stirred for half an hour. The mixture was filtered and dried to obtain 2-(2,6-dioxopiperidine-3-yl)-6,7-dihydropyrrolo[3,4-f]isoindole-1,3(2H,5H)-dione (416 mg, 35%) as a white solid. LCMS: [M+H]+=300.1. 【0297】 Preparation of E3L-8 piperidine hydrochloride: 1-(1-methyl-6-(piperidine-4-yl)-1H-indole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione hydrochloride: 【0298】 [ka] 【0299】 Step 1: Preparation of methyl 3-[(6-bromo-1-methyl-1H-indazole-3-yl)amino]propionate: To a mixture of 6-bromo-1-methyl-1H-indazole-3-amine (3 g, 13.2 mmol) (prepared by mixing equimolarly DBU and lactic acid at room temperature for 16 hours with stirring, 1.5 g, 10.6 mmol), methyl acrylate (9.9 g, 98 mmol) was added in five portions (2.0 g every 24 hours) at 80°C. After the addition was complete, the reaction mixture was quenched with sodium hypochlorite (30% aqueous solution, 5 mL) and diluted with ethyl acetate. The organic matter was washed with water and saline solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (EA / PE = 1:1) to obtain methyl 3-[(6-bromo-1-methyl-1H-indazole-3-yl)amino]propionate (2.0 g, yield 45%). LCMS: [M+H] + = 327.12. 【0300】 Step 2: Preparation of 3-[(6-bromo-1-methyl-1H-indazole-3-yl)amino]propionamide: Methyl 3-((6-bromo-1-methyl-1H-indazole-3-yl)amino)propionate (2.0 g, 6.1 mmol) was dissolved in ammonia-methanol solution (20 ml, 5 mol / L), stirred at room temperature for 24 hours, and concentrated under reduced pressure to obtain crude 3-[(6-bromo-1-methyl-1H-indazole-3-yl)amino]propionamide (1.63 g, 90%), which was then used directly in the next reaction. LCMS: [M+H] + =297. 【0301】 Step 3: Preparation of 1-(6-bromo-1-methyl-1H-indazole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione: A mixture of 3-((6-bromo-1-methyl-1H-indazole-3-yl)amino)propionamide (1.63 g, 5.59 mmol) in THF (30 mL), triphosgene (780 mg, 2.8 mmol), and DIEA (1.44 g, 11.2 mmol) was stirred at 80°C for 12 hours, cooled to room temperature, quenched with saturated NH4Cl aqueous solution (50 mL), extracted with EA (50 mL x 3), combined with organic matter, washed with water and saline solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (EA / PE = 1:1) to obtain 1-(6-bromo-1-methyl-1H-indazole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (1.26 g, yield 70%). LCMS: [M+H] + = 324. 【0302】 Step 4: Preparation of 4-[3-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)-1-methyl-1H-indazole-6-yl]-3,6-dihydropyridine-1(2H)-carboxylate t-butyl: In a nitrogen atmosphere, a mixture of 1,4-dioxane (20 mL) solution of 1-(6-bromo-1-methyl-1H-indazole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (1.26 g, 3.88 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate t-butyl (2.43 g, 7.76 mmol) was mixed with cesium fluoride (1.20 g, 7.76 mmol) and Pd(dppf)Cl2 (570 mg, 776 μmol), and stirred at 85°C for 3 hours. The mixture was cooled to room temperature, diluted with ethyl acetate (50 mL), and filtered through diatomaceous earth / silica gel. After washing with ethyl acetate (20 mL), the filtrate was washed with water and separated. The organic layers were dried together over Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography (EA:PE = 10:1) to obtain 4-[3-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)-1-methyl-1H-indazole-6-yl]-3,6-dihydropyridine-1(2H)-carboxylate t-butyl (990 mg, 2.44 mmol, yield 60%). LCMS: [M+H] + = 426.3. 【0303】 Step 5: Preparation of 4-[3-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)-1-methyl-1H-indazole-6-yl]piperidine-1-carboxylate t-butyl: A mixture of 4-[3-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)-1-methyl-1H-indazole-6-yl]-3,6-dihydropyridine-1(2H)-carboxylate t-butyl (990 mg, 2.32 mmol) in methanol (20 mL) with palladium (10% / carbon, 1.0 g, 0.94 mmol) was stirred at room temperature for 24 hours under a hydrogen balloon atmosphere. The reaction mixture was then filtered through diatomaceous earth, washed with a mixture of dichloromethane (20 mL x 3), and the washings were combined and concentrated under reduced pressure to obtain 4-[3-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)-1-methyl-1H-indazole-6-yl]piperidine-1-carboxylate t-butyl (829 mg, 95% yield). LCMS: [M+H]+=427. 【0304】 Step 6: Preparation of 1-(1-methyl-6-(piperidine-4-yl)-1H-indazole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione hydrochloride: 4-[3-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)-1-methyl-1H-indazole-6-yl]piperidine-1-carboxylate t-butyl 4-[3-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)-1-methyl-1H-indazole-6-yl]piperidine-1-carboxylate t-butyl (829 mg, 2.2 mmol) and hydrochloric acid (4 M, 2.6 mL) were stirred overnight in ethyl acetate (10 mL). The resulting mixture was concentrated under reduced pressure. The residue was washed with ethyl acetate (5 × 20 mL) to obtain a slurry. 1-(1-methyl-6-(piperidine-4-yl)-1H-indazole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione hydrochloride (720 mg, 90% yield) was obtained. LCMS: [M+H] + = 328.2. 【0305】 E3L-9 Difluoropiperidine Hydrochloride: 1-(6-(3,3-difluoropiperidine-4-yl)-1-methyl-1H-indazole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione hydrochloride was synthesized according to the embodiment of E3L-8 difluoropiperidine hydrochloride. LCMS: [M+H] + =364.1. 【0306】 [ka] 【0307】 E3L-10 Piperazine Hydrochloride: 1-(6-(3,3-difluoropiperidine-4-yl)-1-methyl-1H-indazole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione hydrochloride was synthesized according to the embodiment of E3L-8. LCMS: [M+H] + =347. 【0308】 [ka] 【0309】 Preparation of E3L-11 piperazine hydrochloride: 2-(2,6-dioxopiperidine-3-yl)-2-fluoro-4-(piperazine-1-yl)benzamide hydrochloride: 【0310】 [ka] 【0311】 Step 1: Preparation of 1-tert-butoxycarbonyl-4-(3-fluoro-4-methoxyformylphenyl)piperazine: Methyl 2-bromo-4-fluorobenzoate (3 g, 12.9 mmol) was dissolved in toluene (30 mL), and 1-Boc-piperazine (2.87 g, 15.5 mmol), palladium acetate (145 mg, 0.645 mmol), BINAP (803 mg, 1.29 mmol), and cesium carbonate (8.46 g, 25.8 mmol) were added. The mixture was reacted overnight at 80°C with stirring. After the reaction was complete, the temperature was lowered to room temperature, toluene was removed by rotary evaporation, 100 mL of ethyl acetate was added, the mixture was washed with water and saline solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (EA / PE = 1:5) to obtain 1-tert-butoxycarbonyl-4-(3-fluoro-4-methoxyformylphenyl)piperazine (3.0 g, yield 69%). LCMS: [M+H] + =339. 【0312】 Step 2: Preparation of 1:4-(3-fluoro-4-carboxyphenyl)piperazine-1-carboxylate t-butyl: 1-tert-butoxycarbonyl-4-(3-fluoro-4-methoxyformylphenyl)piperazine (3.0 g, 8.88 mmol) was dissolved in THF solution (20 mL), and an aqueous solution of lithium hydroxide (852 mg, 35.5 mol) was added. The mixture was stirred at room temperature for 2 hours. After the reaction was complete, the pH was adjusted to 6-7, and the mixture was extracted using EA (50 mL x 3). The organic phases were combined, washed with saline solution, dried, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (EA / PE = 1:1) to obtain 4-(3-fluoro-4-carboxyphenyl)piperazine-1-carboxylate t-butyl (2.5 g, 87%). LCMS: [M+H] + =352. 【0313】 Step 3: Preparation of 2-(2,6-dioxopiperidine-3-yl)-2-fluoro-4-(piperazine-(4-carboxylate t-butyl)-1-yl)benzamide: 4-(3-fluoro-4-carboxyphenyl)piperazine-1-carboxylate t-butyl (2.5 g, 7.72 mmol) was dissolved in DMF (30 mL), and 3-amino-2,6-piperidinedione hydrochloride (1.27 g, 7.72 mmol), HATU (4.4 g, 11.58 mmol), and DIEA (2.99 g, 23.16 mmol) were added to the mixture. The mixture was stirred at 80°C for 12 hours. After the reaction was complete, saturated NH4Cl aqueous solution (50 mL) was added to quench the reaction, and the mixture was extracted with EA (50 mL x 3). The organic matter was combined, washed with water and saline solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (EA / PE = 1:5) to obtain 2-(2,6-dioxopiperidine-3-yl)-2-fluoro-4-(piperazine-(4-carboxylate t-butyl)-1-yl)benzamide hydrochloride (1.7 g, yield 75%). LCMS: [M+H] + = 435. 【0314】 Step 4: Preparation of 2-(2,6-dioxopiperidine-3-yl)-2-fluoro-4-(piperazine-1-yl)benzamide hydrochloride: 2-(2,6-dioxopiperidine-3-yl)-2-fluoro-4-(piperazine-(4-carboxylate t-butyl)-1-yl)benzamide (1.7 g, 3.92 mmol) was dissolved in ethyl acetate (25 mL) and added to a solution of ethyl acetate in hydrochloric acid. The mixture was stirred at room temperature for 1 hour. After the reaction was complete, the solution was concentrated to remove the solvent, the residue was washed twice with ethyl ether, and dried to obtain 2-(2,6-dioxopiperidine-3-yl)-2-fluoro-4-(piperazine-1-yl)benzamide (1.1 g, yield 84.6%). LCMS: [M+H] + = 335. 【0315】 E3L-12 Piperazine Hydrochloride: N-(2,6-dioxopiperidine-3-yl)-4-(piperazine-1-yl)benzamide hydrochloride was synthesized according to the embodiment of E3L-11. LCMS: [M+H]+=317. 【0316】 [ka] 【0317】 E3L-13 Piperazine hydrochloride: N-(2,6-dioxo-piperidine-3-yl)-4-(piperazine-1-yl)-2-pyridylamide hydrochloride was synthesized according to the embodiment of E3L-12. LCMS: [M+H]+=317. 【0318】 [ka] 【0319】 Example 1 Preparation of 2-(2,6-dioxopiperidine-3-yl)-5-(3-((4-(4-((3-fluoro-1H-indole-5-yl)(2,2,6,6-tetramethyltetrahydro-4H-pyran-4-ylmethylene)methyl)phenyl)piperazine-1-yl)methyl)azetidine-1-yl)isoindoline-1,3-dione (compound 1): 【0320】 [ka] 【0321】 Step 1: Preparation of t-butyl 4-(4-((3-fluoro-1-(tetrahydro-2H-pyran-4-yl)-1H-indazole-5-yl)(2,2,6,6-tetramethyltetrahydro-4H-pyran-4-ylmethylene)methyl)phenyl)piperazine-1-carboxylate: To a solution of 5-((4-chlorophenyl)(2,2,6,6-tetramethyltetrahydro-4H-pyran-4-ylmethylene)methyl)-3-fluoro-1-(tetrahydro-2H-pyran-4-yl)-1H-indazole (300 mg, 0.62 mmol) in THF (50 ml), t-butylpiperazine-1-carboxylate (173.5 mg, 0.93 mmol), RuPhos (58.0 mg, 0.12 mmol), RuPhos Palladacycle G3 (103.9 mg, 0.12 mmol), tert-sodium butyrate (t-BuONa) (179.1 mg, 1.86 mmol) and THF (5 mL) were added. The resulting mixture was stirred overnight at 85°C. The reaction was quenched at room temperature by adding water (2 mL). The resulting mixture was extracted with ethyl acetate (3 × 10 mL). The organic layers were combined and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and then eluted with PE / EA (5:1) to obtain t-butyl 4-(4-((3-fluoro-1-(tetrahydro-2H-pyran-4-yl)-1H-indazole-5-yl)(2,2,6,6-tetramethyltetrahydro-4H-pyran-methylene)methyl)phenyl)piperazine-1-carboxylate (145 mg, 36.89%) as a white solid. LCMS (ESI): m / z 633.22 [M+1] + . 【0322】 Step 2: Preparation of 3-fluoro-5-((4-(piperazin-1-yl)phenyl)(2,2,6,6-tetramethyltetrahydro-4H-pyran-4-ylmethylene)methyl)-1H-indazole: To a solution of t-butyl 4-(4-((3-fluoro-1-(tetrahydro-2H-pyran-4-yl)-1H-indazole-5-yl)(2,2,6,6-tetramethyltetrahydro-4H-pyran-4-ylmethylene)methyl)phenyl)piperazine-1-carboxylate (145 mg, 0.23 mmol) in DCM (0.5 mL), TFA (1.5 mL) was added. The resulting mixture was stirred at room temperature for 12 hours. The resulting mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (2 mL). The mixture was alkalized to pH 10 with K2CO3, and the resulting mixture was extracted with ELISA (3 × 2 mL). The organic layers were dried together over anhydrous sodium sulfate, and the filtrate after filtration was concentrated under reduced pressure. The residue was purified by preparative thin-layer chromatography (DCM / MeOH 5:1) to obtain 3-fluoro-5-((4-(piperazin-1-yl)phenyl)(2,2,6,6-tetramethyltetrahydro-4H-pyran-4-ylmethylene)methyl)-1H-indazole (80 mg, 77.83%) as a white solid. After filtration, the filtrate was concentrated under reduced pressure. LCMS (ESI): m / z 449.3 [M+1] + . 【0323】 Step 3: Preparation of t-butyl 3-((4-(4-((3-fluoro-1H-indazole-5-yl)(2,2,6,6-tetramethyltetrahydro-4H-pyran-4-ylmethylene)methyl)phenyl)piperazine-1-yl)methyl)azetidine-1-carboxylate: 3-Fluoro-5-((4-(piperazin-1-yl)phenyl)(2,2,6,6-tetramethyltetrahydro-4H-pyran-4-ylmethylene)methyl)-1H-indazole (80 mg, 0.18 mmol) was treated with 3-formylazetidine-1-carboxylate t-butyl (66.1 mg, 0.36 mmol) at room temperature for 1 hour, and then NaBH3CN (22.4 mg, 0.36 mmol) was added dropwise at 0°C. The resulting mixture was stirred overnight at room temperature. The reaction was quenched with water at room temperature. The resulting mixture was concentrated under vacuum. The resulting mixture was extracted with ELISA (3 × 2 mL). The organic layers were dried together over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative thin-layer chromatography (PE / EA 1:1) to obtain t-butyl 3-((4-(4-((3-fluoro-1H-indazole-5-yl)(2,2,6,6-tetramethyltetrahydro-4H-pyran-4-ylmethylene)methyl)phenyl)piperazin-1-yl)methyl)azetidine-1-carboxylate (80 mg, 72.61%) as a white solid. LCMS (ESI): m / z 618.4 [M+1] + . 【0324】 Step 4: Preparation of 5-((4-(4-(azetidine-3-ylmethyl)piperazin-1-yl)phenyl)(2,2,6,6-tetramethyltetrahydro-4H-pyran-4-ylmethylene)methyl)-3-fluoro-1H-indazole: To a solution of t-butyl-3-((4-(4-((3-fluoro-1H-indazole-5-yl)(2,2,6,6-tetramethyltetrahydro-4H-pyran-4-ylmethylene)methyl)phenyl)piperazin-1-yl)methyl]azetidine-1-carboxylate (80 mg, 0.13 mmol) in DCM (0.9 mL), TFA (0.3 mL, 4.04 mmol) was added. The resulting mixture was stirred at room temperature for 12 hours. The substance was concentrated under reduced pressure. After filtration, the filtrate was concentrated under reduced pressure. 5-((4-(4-(azetidine-3-ylmethyl)piperazin-1-yl)phenyl)(2,2,6,6-tetramethyltetrahydro-4H-pyran-4-ylmethylene)methyl)-3-fluoro-1H-indazole (60 mg, 94.63%) was obtained as a yellow oily liquid. The crude product was used directly in the next reaction without purification. LCMS(ESI): m / z 518.32 [M+1] + . 【0325】 Step 5: Preparation of 2-(2,6-dioxopiperidine-3-yl)-5-(3-(4-(4-(3-fluoro-1H-indole-5-yl)(2,2,6,6-tetramethyltetrahydro-4H-pyran-4-ylmethylene)phenyl)piperazine-1-yl)methyl)azetidine-1-yl)isoindoline-1,3-dione (compound 1): To a solution of {4-[4-(azetidine-3-methyl)piperazin-1-yl]phenyl}(2,2,6,6-tetramethoxy-4-ylmethylene)methyl)-3-fluoro-1H-indazole (250 mg, 0.48 mmol) in DMSO (4 mL), 2-(2,6-dioxopiperidine-3-yl)-5-fluoroisoindole-1,3-dione (E3L-1) (293.5 mg, 1.06 mmol) and DIEA (312.1 mg, 2.42 mmol) were added. The resulting mixture was stirred at 100°C for 12 hours. The reaction was quenched by adding water (2 mL) at room temperature. The resulting mixture was extracted with ethyl acetate (3 × 5 mL). The combined organic layers were washed with water (3 × 3 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography under the following conditions: Column: Xselect CSH C18 OBD column 30×150mm 5μm, n; Mobile phase A: Water (0.05% TFA), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 24% B~53% B 10 mins, 53% B; Wavelength: 254 nm; RT1 (min): 8.63. 2-(2,6-dioxopiperidine-3-yl)-5-(3-(4-(4-(3-fluoro-1H-indole-5-yl)(2,2,6,6-tetramethyltetrahydro-4H-pyran-4-ylmethylene)phenyl)piperazine-1-yl)methyl)azetidine-1-yl)isoindoline-1,3-dione (compound 1)LCMS (ES, m / z): 774.4[M+H]+ (27.8 mg, 7.44%) was obtained as a yellow solid. 1H NMR (DMSO, 400 MHz) δ (ppm):12.54 (s, 1H), 11.10 (s, 1H), 9.86 (s, 1H), 7.70-7.68 (d, J =8.4 Hz, 1H),7.45-7.41 (m, 2H), 7.21-7.20 (d, J =1.6 Hz, 1H), 7.13-7.11 (d, J =8.4Hz, 2H), 6.97-6.95 (d, J =8.8Hz, 2H), 6.82 (s, 1H), 6.70-6.67 (d, J =10.4Hz, 1H), 5.06(m,1H), 4.28-4.23(m, 2H),3.88-3.82 (m,4H), 3.56-3.54 (s, 4H), 3.31 (m,1H), 3.16-3.14(m, 2H),3.00(m, 3H), 2.60(s, 1H), 2.50-2.49 (d, J =1.6 Hz, 4H), 2.21(m, 1H) ,1.17-1.12 (d, J =17.2 Hz,12H). 【0326】 Following the synthesis route of Compound 1, the following compounds were synthesized using the following starting compounds or intermediates (the synthesis steps refer to Example 1 above, but the molar mass of each starting compound and intermediate was controlled to be constant). 【0327】 JPEG2026519066000110.jpg214160 【0328】 JPEG2026519066000111.jpg204160 【0329】 JPEG2026519066000112.jpg203160 【0330】 JPEG2026519066000113.jpg146160 【0331】 Example 2: Preparation of 2-(2,6-dioxopiperidine-3-yl)-5-(3-(4-(4-((3-fluoro-1H-indole-5-yl)(2,2,6,6-tetramethyltetrahydro-4H-pyran-ylmethylene)methyl)phenyl)piperazine-1-yl)azetidine-1-yl)isoindoline-1,3-dione (Compound 2): 【0332】 [ka] 【0333】 Step 1: Preparation of t-butyl 3-(4-(4-((3-fluoro-1-(tetrahydro-2H-pyran-4-yl)-1H-indazole-5-yl)(2,2,6,6-tetramethyltetrahydro-4H-pyran-4-ylmethylene)methyl)phenyl)piperazin-1-yl)azetidine-1-carboxylate: To a solution of 5-((4-chlorophenyl)(2,2,6,6-tetramethyltetrahydro-4H-pyran-4-ylmethylene)methyl)-3-fluoro-1-(tetrahydro-2H-pyran-4-yl)-1H-indazole (300 mg, 0.6 mmol) in THF (5 mL), t-butyl 3-(piperazin-1-yl)azetidine-1-carboxylate (450 mg, 1.8 mmol), RuPhos Palladacycle G3 (104 mg, 0.12 mmol), RuPhos (58 mg, 0.12 mmol), and t-BuONa (179 mg, 1.8 mmol) were added. The resulting mixture was stirred overnight at 85°C under a nitrogen atmosphere. The reaction was quenched with water at room temperature. The resulting mixture was extracted with EA (3 × 20 mL). The organic layers were combined and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative thin-layer chromatography (DCM / MeOH 10:1) to obtain t-butyl3-(4-(4-((3-fluoro-1-(tetrahydro-2H-pyran-4-yl)-1H-indazole-5-yl](2,2,6,6-tetramethyltetrahydro-4H-pyran-4-ylmethylene)methyl)phenyl)piperazine-1-yl]azetidine-1-carboxylate (200 mg, 46.81%) as a yellow oil. LCMS (ES, m / z): 688 [M + H] + . 【0334】 Step 2: Preparation of 5-((4-(4-(azetidine-3-yl)piperazin-1-yl)phenyl)(2,2,6,6-tetramethyltetrahydro-4H-pyran-4-ylmethylene)methyl)-3-fluoro-1H-indazole: To a solution of t-butyl 3-(4-(4-((3-fluoro-1-(tetrahydro-2H-pyran-4-yl)-1H-indazole-5-yl)(2,2,6,6-tetramethyltetrahydro-4H-pyran-4-ylmethylene)methyl)phenyl)piperazine-1-yl)azetidine-1-carboxylate ((180 mg, 0.3 mmol)) in DCM (8 mL), TFA (2 mL) was added and stirred overnight at room temperature under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. 5-((4-(4-(azetidine-3-yl)piperazine-1-yl)phenyl)(2,2,6,6-tetramethyltetrahydro-4H-pyran-4-ylmethylene)methyl)-3-fluoro-1H-indazole (110 mg, 83.46%) was obtained as a yellow oil. The crude product was used in the next step without purification. LCMS (ES, m / z): 504[ M + H ] + . 【0335】 Step 3: Preparation of 2-(2,6-dioxopiperidine-3-yl)-5-(3-(4-(4-((3-fluoro-1H-indole-5-yl)(2,2,6,6-tetramethyltetrahydro-4H-pyran-4-ylmethylene)methyl)phenyl)piperazine-1-yl)azetidine-1-yl)isoindoline-1,3-dione: 5-((4-(4-(azetidine-3-yl)piperazin-1-yl)phenyl)(2,2,6,6-tetramethyltetrahydro-4H-pyran-4-ylmethylene)methyl)-3-fluoro-1-(tetrahydro-2H-pyran-4-yl)-1H-indazole (100 mg, 0.2 mmol) was added to DMSO (1 mL) with stirring, and 2-(2,6-dioxopiperidine-3-yl)-5-fluoroisoindole-1,3-dione (121 mg, 0.4 mmol) was added to the solution, to which DIEA (128 mg, 1.0 mmol) was added. The resulting mixture was stirred at 100 °C for 4 hours under a nitrogen atmosphere. The reaction was quenched with water at room temperature. The resulting mixture was extracted with EA (3 × 20 mL). The combined organic layers were washed with water (3 × 5 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by thin-layer chromatography (DCM / MeOH 10:1) to obtain a yellow solid. The crude product (100 mg) (column: Xselect CSH C18 OBD column 30*150 mm 5 μm, n; mobile phase A: water (0.05% TFA), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 30% B to 59% B for 7 minutes, 59% B; wavelength: 254 nm; RT1 (min): 5.25; number of operations: 0) was purified by Prep-HPLC under the following conditions to obtain 2-(2,6-dioxopiperidine-3-yl)-5-(3-(4-(4-((3-fluoro-1H-indole-5-yl)(2,2,6,6-tetramethyltetrahydro-4H-pyran-4-ylmethylene)methyl)phenyl)piperazine-1-yl)azetidine-1-yl)isoindoline-1,3-dione (90.5 mg, 59.51%) as a yellow solid. LCMS (ES, m / z): 760 [M+H] + ; 1H NMR (400 MHz, DMSO-d6) δ (ppm): 12.53 (s, 1H), 11.10 (s, 1H), 7.75-7.73 (d, J = 8.0 Hz, 1H), 7.45-7.41 (m, 2H), 7.29-7.27 (m, 1H), 7.21-7.18 (m, 1H), 7.12-7.08 (m, 2H), 6.98-6.91 (m, 3H), 6.77-6.75 (m, 1H), 5.10-5.06 (m, 1H), 4.36-4.30 (m, 4H), 3.91-2.84 (m, 9H), 2.61-2.55 (m, 2H), 2.50-2.14 (d, J = 27.2 Hz, 4H), 2.89-2.86 (m, 1H), 2.05-2.0 (m, 1H), 1.17-1.10 (m, 12H). 【0336】 Following the synthesis route of Compound 2, the following compounds were synthesized using the following starting compounds or intermediates (the synthesis steps refer to Example 2 above, but the molar mass of each starting compound and intermediate was controlled to be constant). 【0337】 JPEG2026519066000115.jpg211160 【0338】 JPEG2026519066000116.jpg202160 【0339】 JPEG2026519066000117.jpg202160 【0340】 Example 3: Preparation of 3-(5-(4-((1-(5-((3-fluoro-1H-indole-5-yl)(2,2,6,6-tetramethyltetrahydro-4H-pyran-4-ylmethylene)methyl)pyridine-2-yl)piperidine-4-yl)methyl)piperazine-1-yl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione (compound 34): 【0341】 [ka] 【0342】 Step 1: Preparation of (1-(5-((3-fluoro-1-(tetrahydro-2H-pyran-4-yl)-1H-indazole-5-yl)(2,2,6,6-tetramethyltetrahydro-4H-pyran-4-ylmethylene)methyl}pyridine-2-yl)piperidine-4-yl)methanol: 3-Fluoro-5-((6-fluoropyridine-3-yl)(2,2,6,6-tetramethyltetrahydro-4H-pyran-4-ylmethylene)methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-indazole (400 mg, 0.9 mmol) and piperidine-4-methanol (296 mg, 2.6 mmol) were added to DMSO (5 mL) with K2CO3 (591 mg, 4.5 mmol) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred overnight at 130 °C under a nitrogen atmosphere. The resulting mixture was extracted with ethyl acetate (3 × 20 mL). The prepared organic layer was washed with water (3 × 5 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and then eluted with PE / EA (3:1) to obtain (1-(5-((3-fluoro-1-(tetrahydro-2H-pyran-4-yl)-1H-indazole-5-yl)(2,2,6,6-tetramethyltetrahydro-4H-pyran-4-ylmethylene)methyl)pyridine-2-yl)piperidine-4-yl)methanol (400 mg, 83.09%) as a yellow oil. LCMS (ES, m / z): 563 [M+H] + . 【0343】 Step 2: Preparation of 1-(5-((3-fluoro-1-(tetrahydro-2H-pyran-4-yl)-1H-indazole-5-yl)(2,2,6,6-tetramethyltetrahydro-4H-pyran-4-ylmethylene)methyl)pyridine-2-yl)piperidine-4-formaldehyde: (1-(5-((3-fluoro-1-(tetrahydro-2H-pyran-4-yl)-1H-indazole-5-yl)(2,2,6,6-tetramethyltetrahydro-4H-pyran-4-ylmethylene)methyl}pyridine-2-yl)piperidine-4-yl)methanol (350 mg, 0.6 mmol) was mixed with Dess-Martin (174 mg, 0.4 mmol) in a 3 mL DCM at 0°C under a nitrogen atmosphere. The resulting mixture was filtered, and the filter cake was washed with a 3 × 20 mL DCM. The filtrate was concentrated under reduced pressure. The residue was subjected to thin-layer chromatography (DCM / MeOH). Purified by 9:1, 1-(5-((3-fluoro-1-(tetrahydro-2H-pyran-4-yl)-1H-indazole-5-yl)(2,2,6,6-tetramethyltetrahydro-4H-pyran-4-ylmethylene)methyl)pyridine-2-yl)piperidine-4-formaldehyde (200 mg, 57.35%) was obtained as a yellow oil. LCMS (ES, m / z): 561 [M + H] + . 【0344】 Step 3: Preparation of 3-(5-(4-((1-(5-((3-fluoro-1-(tetrahydro-2H-pyran-4-yl)-1H-indole-5-yl](2,2,6,6-tetramethyltetrahydro-4H-pyran-4-ylmethylene)methyl)pyridine-2-yl)piperidine-4-yl)methyl)piperazine-1-yl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione: To a solution of 1-(5-((3-fluoro-1-(tetrahydro-2H-pyran-4-yl)-1H-indazole-5-yl)(2,2,6,6-tetramethyltetrahydro-4H-pyran-4-ylmethylene)methyl)pyridine-2-yl)piperidine-4-formaldehyde (100 mg, 0.2 mmol) in DCE (2 mL), a hydrochloric acid solution of 3-[1-oxo-5-(piperazine-1-yl)-3H-indole-2-yl]piperidine-2,6-dione (70 mg, 0.2 mmol) was added, and STAB (76 mg, 0.4 mmol) was added at room temperature. The resulting mixture was stirred overnight at room temperature under a nitrogen atmosphere. The reaction was quenched with water. The resulting mixture was extracted with DCM (3 × 10 mL). The organic layers were dried together over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. Purified by preparative thin-layer chromatography (PE / EA 1:1), 3-(5-(4-((1-(5-((3-fluoro-1-(tetrahydro-2H-pyran-4-yl)-1H-indole-5-yl)(2,2,6,6-tetramethyltetrahydro-4H-pyran-4-ylmethylene)methyl)pyridine-2-yl)piperidine-4-yl)methyl)piperazine-1-yl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione (100 mg, 64.22%) was obtained as a yellow oil. LCMS (ES, m / z): 873 [M + H] + . 【0345】 Step 4: Preparation of 3-(5-(4-((1-(5-((3-fluoro-1H-indole-5-yl)(2,2,6,6-tetramethyltetrahydro-4H-pyran-4-ylmethylene)methyl)pyridine-2-yl)piperidine-4-yl)methyl)piperazine-1-yl)-1-oxoisoindole-2-yl)piperidine-2,6-dione (compound 34): 3-(5-(4-((1-(5-((3-fluoro-1-(tetrahydro-2H-pyran-4-yl)-1H-indole-5-yl)(2,2,6,6-tetramethyltetrahydro-4H-pyran-4-ylmethylene)methyl)pyridine-2-yl)piperidine-4-yl)methyl)piperazine-1-yl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione (120 mg, 0.14 mmol), DCM (8 mL), and TFA (2 mL) were added to a 50 mL round-bottom flask. The resulting mixture was stirred overnight at room temperature under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The crude product (column: Xselect CSH C18 OBD column 30 * 150 mm 5 μm, n; mobile phase A: water (0.05% TFA), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 16% B ~ 36% B for 7 minutes, 36% B; wavelength: 254 nm; RT1 (min): 5.68; number of operations: 0) was purified by Prep-HPLC under the following conditions to obtain 3-(5-(4-((1-(5-((3-fluoro-1H-indole-5-yl)(2,2,6,6-tetramethyltetrahydro-4H-pyran-4-ylmethylene)methyl)pyridine-2-yl)piperidine-4-yl)methyl)piperazine-1-yl)-1-oxoisoindoline-2-yl)piperidine-2,6-dione (74.1 mg, 67.79%) as a white solid. LCMS (ES, m / z): 789 [M+H] + ; 1H NMR (400 MHz, DMSO-d6) δ (ppm): 12.58 (s, 1H), 10.99 (s, 1H), 9.49 (s, 1H), 7.97-7.96 (d, J = 2.4 Hz, 1H), 7.61-7.60 (d, J = 8.4 Hz, 1H), 7.53-7.44 (m, 3H),7.26-7.16 (m, 3H), 7.00-6.99 (d, J = 6.8 Hz, 1H), 5.10-5.05 (m, 1H), 4.39-4.34 (d, J = 17.2 Hz, 2H), 4.28-4.22 (m, 3H), 4.03-4.00 (d, J = 10.0 Hz, 3H), 3.65-3.63 (d, J = 8.4 Hz, 2H), 3.24-3.12 (m, 5H), 2.95-2.88 (m, 3H), 2.62-2.58 (d, J = 16.4 Hz, 1H), 2.41-2.34 (m, 1H), 2.24 (s, 2H), 2.16 (s, 2H), 1.97-1.93 (m, 1H), 1.86-1.84 (d, J = 12.3 Hz, 2H), 1.23-1.13 (m, 12H). 【0346】 Step 5: Preparation of (R)3-(5-(4-((1-(5-((3-fluoro-1H-indole-5-yl)(2,2,6,6-tetramethyltetrahydro-4H-pyran-4-ylmethylene)methyl)pyridine-2-yl)piperidine-4-yl)methyl)piperazine-1-yl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione (compound 119) and (S)3-(5-(4-((1-(5-((3-fluoro-1H-indole-5-yl)(2,2,6,6-tetramethyltetrahydro-4H-pyran-4-ylmethylene)methyl)pyridine-2-yl)piperidine-4-yl)methyl)piperazine-1-yl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione (compound 110): 3-(5-(4-((1-(5-((3-fluoro-1H-indole-5-yl)(2,2,6,6-tetramethyltetrahydro-4H-pyran-4-ylmethylene)methyl)pyridine-2-yl)piperidine-4-yl)methyl)piperazine-1-yl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione (compound 34) (50 mg) Chiral high-performance liquid chromatography column CHIRAL-HPLC: Column: JW-CHIRAL ART Cellulose-SB, 4.6*100 mm; 3 μm; Mobile phase A: Hex (0.1 A): (IPA:DCM=1:2)=50:50; Flow rate: 1 mL / min; Gradient: 0% B~0% B; Injection volume: 5 μl (S)3-(5-(4-((1-(5-((3-fluoro-1H-indole-5-yl)(2,2,6,6-tetramethyltetrahydro-4H-pyran-4-ylmethylene)methyl)pyridine-2-yl)piperidine-4-yl)methyl)piperazine-1-yl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione (11 mg) was prepared as a white solid by LCMS (ES, m / z): 815 [M + H] + Chiral high-performance liquid chromatography: Rt = 1.225; and (R)3-(5-(4-((1-(5-((3-fluoro-1H-indole-5-yl)(2,2,6,6-tetramethyltetrahydro-4H-pyran-4-ylmethylene)methyl)pyridine-2-yl)piperidine-4-yl)methyl)piperazine-1-yl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione (compound 119) (14.2 mg) was prepared as a white solid. LCMS (ES, m / z): 815 [M + H] + Chiral high-performance liquid chromatography: Rt = 1.769. 【0347】 Following the synthesis route of compound 34, the following compounds were synthesized using the following starting compounds or intermediates (the synthesis steps refer to Example 3 above, but the molar mass of each starting compound and intermediate was controlled to be constant). 【0348】 JPEG2026519066000119.jpg227155 【0349】 JPEG2026519066000120.jpg219156 【0350】 Example 4: (R)-3-(5-(4-(7-(5-((3-fluoro-1H-indole-5-yl)(2,2,6,6-tetramethyltetrahydro-4H-pyran-4-ylmethylene)methyl)pyridine-2-yl)-7-azaspiro[3.5]nonan-2-yl)piperazine-1-yl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione (compound 121), Preparation of (S)-3-(5-(4-(7-(5-((3-fluoro-1H-indole-5-yl)(2,2,6,6-tetramethyltetrahydro-4H-pyran-4-ylmethylene)methyl)pyridine-2-yl)-7-azaspiro[3.5]nonan-2-yl)piperazine-1-yl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione (compound 120): 【0351】 [ka] 【0352】 Step 1: Preparation of 7-(5-(3-fluoro-1-(tetrahydro-2H-pyran-4-yl)-1H-indazole-5-yl)(2,2,6,6-tetramethyltetrahydro-4H-pyran-4-ylmethylene)methyl)pyridine-2-yl)-7-azaspiro[3.5]nonan-2-one: To a DMSO (5 mL) solution of 3-fluoro-5-((6-fluoropyridine-3-yl)(2,2,6,6-tetramethyltetrahydro-4H-pyran-4-ylmethylene)methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-indole (300 mg, 0.642 mmol, 1 equivalent), 7-azaspiro[3.5]nonan-2-one (267.94 mg, 1.926 mmol, 3 equivalents) was added, and K2CO3 (266.03 mg, 1.926 mmol, 3 equivalents) was added at room temperature. The final reaction mixture was microwaved overnight at 130°C. The reaction was quenched with water at room temperature. The resulting mixture was extracted with ethyl acetate and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative thin-layer chromatography (PE / EA) to obtain 7-(5-(3-fluoro-1-(tetrahydro-2H-pyran-4-yl)-1H-indazole-5-yl)(2,2,6,6-tetramethyltetrahydro-4H-pyran-4-ylmethylene)methyl)pyridine-2-yl)-7-azaspiro[3.5]nonan-2-one (160 mg, 42.50%). LCMS (ES, m / z): 587 [M + H] + . 【0353】 Step 2: Preparation of a mixture of 7-(5-(3-fluoro-1H-indazole-5-yl)(2,2,6,6-tetramethyltetrahydro-4H-pyran-4-ylmethylene)methyl)pyridine-2-yl)-7-azaspiro[3.5]nonan-2-one: 7-(5-(3-fluoro-1-(tetrahydro-2H-pyran-4-yl)-1H-indazole-5-yl)(2,2,6,6-tetramethyltetrahydro-4H-pyran-4-ylmethylene)methyl)pyridine-2-yl)-7-azaspiro[3.5]nonan-2-one (160 mg, 0.273 mmol) was added to DCM (2 mL) with TFA (1 mL, 13.463 mmol, 49.37 equivalents) and stirred overnight at room temperature. The resulting mixture was concentrated under vacuum. 7-(5-((3-fluoro-1H-indazole-5-yl)(2,2,6,6-tetramethyltetrahydro-4H-pyran-4-ylmethylene)methyl)pyridine-2-yl)-7-azaspiro[3.5]nonan-2-one (160 mg, 93.39%) was obtained as brown oil. LCMS (ES, m / z): 503 [M + H] + . 【0354】 Step 3: Preparation of 3-(5-(4-(7-(5-((3-fluoro-1H-indole-5-yl)(2,2,6,6-tetramethyltetrahydro-4H-pyran-4-ylmethylene)methyl)pyridine-2-yl)-7-azaspiro[3.5]nonan-2-yl)piperazine-1-yl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione (compound 35): 7-(5-((3-fluoro-1H-indazole-5-yl)(2,2,6,6-tetramethyltetrahydro-4H-pyran-4-ylmethylene)methyl)pyridine-2-yl)-7-azaspiro[3.5]nonan-2-one (150 mg, 0.298 mmol, 1 equivalent) and 3-(1-oxo-5-(piperazine-1-yl)isoindorin-2-yl)piperidine-2,6dione were treated in a DCM and DMF solution (146.99 mg, 0.447 mmol, 1.5 equivalents) at room temperature with NaOAc (122.41 mg, 1.490 mmol, 5 equivalents) for 2 hours, and then STAB (126.50 mg, 0.596 mmol, 2 equivalents) was added dropwise / partially at room temperature. The resulting mixture was stirred overnight at room temperature. The reaction was quenched with water. The resulting mixture was extracted with ethyl acetate and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The crude product (100 mg) was analyzed by Prep-HPLC under the following conditions: (Column: Sunfire (Waters), 30*150 mm, 5 μm; Mobile phase A: Water (0.05% TFA), Mobile phase B: ACN; Flow rate: 25 mL / min; Gradient: 21% B~35% B for 8 minutes, 35% B; wavelength: 254 nm; RT1 (min): 7.73; number of operations: 0) was purified to obtain 3-(5-(4-(7-(5-((3-fluoro-1H-indole-5-yl)(2,2,6,6-tetramethyltetrahydro-4H-pyran-4-ylmethylene)methyl)pyridine-2-yl)-7-azaspiro[3.5]nonan-2-yl)piperazine-1-yl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione (15.6 mg, 6.40%) as a white solid. LCMS (ES, m / z): 815[ M + H ] +; 1H NMR (400 MHz, DMSO-d6) δ (ppm):12.54 (s, 1H), 10.98 (s, 1H),7.91 (s, 1H), 7.60 (d,1H),7.56-7.40 (m, 3H), 7.26-7.12 (m, 3H), 6.98 (s, 1H),4.41-4.33 (d, 1H), 4.30-4.19 (d, 1H), 4.11-4.01 (d, 2H), 3.91-3.83 (d,1H), 3.58-3.40 (m, 6H), 3.17-3.08(m, 1H), 3.08-2.89(m, 3H), 2.62-2.54 (m, 1H), 2.43-2.35 (m, 1H), 2.26-2.21 (m, 4H), 2.19 (s, 2H), 2.12-2.08(m, 2H), 2.04-1.98(m, 1H), 1.18-1.13(d, 12H). 【0355】 Step 4: (R)3-(5-(4-(7-(5-((3-fluoro-1H-indole-5-yl)(2,2,6,6-tetramethyltetrahydro-4H-pyran-4-ylmethylene)methyl)pyridine-2-yl)-7-azaspiro[3.5]nonan-2-yl)piperazine-1-yl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione (compound 121), and (S)-3-(5-(4-(7-(5-(3-fluoro Preparation of -1H-indole-5-yl)(2,2,6,6-tetramethyltetrahydro-4H-pyran-4-methylene)methyl)pyridine-2-yl)-7-azaspiro[3.5]nonan-2-yl)piperazine-1-yl)-1-oxoisoindole-2-yl)piperidine-2,6-dione (compound 120): 3-(5-(4-(7-(5-((3-fluoro-1H-indole-5-yl)(2,2,6,6-tetramethyltetrahydro-4H-pyran-4-ylmethylene)methyl)pyridine-2-yl)-7-azaspiro[3.5]nonan-2-yl)piperazin-1-yl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione (compound 35) (50 mg) CHIRAL-HPLC: Column: JW-CHIRAL ART Cellulose-SB, 4.6*100 mm; 3 μm; Mobile phase A: Hex (0.1 A): (IPA:DCM = 1:2) = 50:50; Flow rate: 1 mL / min; Gradient: 0% B ~ 0% B; Injection volume: 5 μl M, (S)3-(5-(4-(7-(5-((3-fluoro-1H-indole-5-yl)(2,2,6,6-tetramethyltetrahydro-4H-pyran-4-ylmethylene)methyl)pyridine-2-yl)-7-azaspiro[3.5]nonan-2-yl)piperazin-1-yl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione (compound 120) (5.0 mg, 9.61%) was used to prepare a white solid. LCMS (ES, m / z): 815 [M + H] + Chiral high-performance liquid chromatography (LCMS) was used to prepare (R)3-(5-(4-(7-(5-((3-fluoro-1H-indole-5-yl)(2,2,6,6-tetramethyltetrahydro-4H-pyran-4-ylmethylene)methyl)pyridine-2-yl)-7-azaspiro[3.5]nonan-2-yl)piperazine-1-yl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione (compound 121) (4.2 mg, 7.98%) as a white solid. LCMS (ES, m / z): 815 [M + H] + Chiral high-performance liquid chromatography: Rt = 4.556. 【0356】 Following the synthesis routes of compounds 120 and 121, the following compounds were synthesized using the following starting compounds or intermediates (the synthesis steps refer to Example 4 above, but the molar mass of each starting compound and intermediate was controlled to be constant). 【0357】 JPEG2026519066000122.jpg217155 【0358】 JPEG2026519066000123.jpg218154 【0359】 JPEG2026519066000124.jpg219154 【0360】 JPEG2026519066000125.jpg95155 【0361】 Example 5: Preparation of 3-(5-(4-((1-(5-((3-fluoro-1H-indole-5-yl)(2,2,6,6-tetramethyltetrahydro-4H-pyran-4-ylmethylene)methyl)pyridine-2-yl)-4-hydroxypiperidine-4-yl)methyl)piperazine-1-yl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione (compound 36): 【0362】 [ka] 【0363】 Step 1: Preparation of 1-(5-((3-fluoro-1-(tetrahydro-2H-pyran-4-yl)-1H-indole-5-yl)(2,2,6,6-tetramethyltetrahydro-4H-pyran-4-ylmethylene)methyl)pyridine-2-yl)-4-(hydroxymethyl)piperidine-4-ol 3-Fluoro-5-((6-Fluoropyridine-3-yl)(2,2,6,6-tetramethyltetrahydro-4H-pyran-4-ylmethylene)methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-indazole (800 mg, 1.7 mmol) was dissolved in DMSO (5 mL) and 4-(hydroxymethyl)piperidine-4-ol (449 mg, 3.4 mmol)DIEA (1106 mg, 8.6 mmol) was added. The resulting mixture was stirred overnight at 110°C under a nitrogen atmosphere. The reaction was quenched with water at room temperature, and the resulting mixture was heated in ethyl acetate (3 × 20⁻¹⁰⁻¹ Extraction was performed using (mL). The organic layers were combined and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and then eluted with PE / EA (3:1) to obtain 1-(5-((3-fluoro-1-(tetrahydro-2H-pyran-4-yl)-1H-indole-5-yl)(2,2,6,6-tetramethyltetrahydro-4H-pyran-4-ylmethylene)methyl)pyridine-2-yl)-4-(hydroxymethyl)piperidine-4-ol (600 mg, 60.59%) as a yellow oil. LCMS (ES, m / z): 579 [M + H] + . 【0364】 Step 2: Preparation of 1-(5-((3-fluoro-1-(tetrahydro-2H-pyran-4-yl)-1H-indazole-5-yl)(2,2,6,6-tetramethyltetrahydro-4H-pyran-4-ylmethylene)methyl)pyridine-2-yl)-4-hydroxypiperidine-4-formaldehyde: 1-(5-((3-fluoro-1-(tetrahydro-2H-pyran-4-yl)-1H-indole-5-yl)(2,2,6,6-tetramethyltetrahydro-4H-pyran-4-ylmethylene)methyl)pyridine-2-yl)-4-(hydroxymethyl)piperidine-4-ol (100 mg, 0.17 mmol) was added to a stirred solution in dimethyl sulfoxide (2 mL), and IBX (194 mg, 0.7 mmol) was added at room temperature. The resulting mixture was stirred at room temperature for 4 hours. The reaction was quenched with water at room temperature. The resulting mixture was extracted with siRNA (3 × 20 mL). The combined organic layers were washed with water (3 × 5 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. 1-(5-((3-fluoro-1-(tetrahydro-2H-pyran-4-yl)-1H-indazole-5-yl)(2,2,6,6-tetramethyltetrahydro-4H-pyran-4-ylmethylene)methyl)pyridine-2-yl)-4-hydroxypiperidine-4-formaldehyde (50 mg, 50.17%) was obtained as a grayish-white solid. LCMS (ES, m / z): 577 [M + H] + . 【0365】 Step 3: Preparation of 3-(5-(4-((1-(5-((3-fluoro-1-(tetrahydro-2H-pyran-4-yl)-1H-indole-5-yl)(2,2,6,6-tetramethyltetrahydro-4H-pyran-4-ylmethylene)methyl)pyridine-2-yl)-4-hydroxypiperidine-4-yl)methyl)piperazine-1-yl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione: 1-(5-((3-fluoro-1-(tetrahydro-2H-pyran-4-yl)-1H-indazole-5-yl)(2,2,6,6-tetramethyltetrahydro-4H-pyran-4-ylmethylene)methyl)pyridine-2-yl)-4-hydroxypiperidine-4-formaldehyde was mixed with 3-(1-oxo-5-(piperazine-1-yl)isoindole-2-yl)piperidine-2,6-dione 0.5 mg, 0.62 mmol)STAB (132.30 mg, 0.62 mmol) in DCM / DMF. The resulting mixture was stirred overnight at room temperature. The reaction was quenched with water at room temperature. The resulting mixture was extracted with DCM (3 × 10 mL). The combined organic layers were washed with water (3 × 5 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. 3-(5-(4-((1-(5-((3-fluoro-1-(tetrahydro-2H-pyran-4-yl)-1H-indole-5-yl)(2,2,6,6-tetramethyltetrahydro-4H-pyran-4-ylmethylene)methyl)pyridine-2-yl)-4-hydroxypiperidine-4-yl)methyl)piperazine-1-yl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione (150 mg, 54.05%) was obtained as a yellow oil. LCMS (ES, m / z): 889 [M + H] + . 【0366】 Step 4: Preparation of 3-(5-(4-((1-(5-((3-fluoro-1H-indole-5-yl)(2,2,6,6-tetramethyltetrahydro-4H-pyran-4-ylmethylene)methyl)pyridine-2-yl)-4-hydroxypiperidine-4-yl)methyl)piperazine-1-yl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione (compound 36): A solution of 3-(5-(4-((1-(5-((3-fluoro-1-(tetrahydro-2H-pyran-4-yl)-1H-indole-5-yl)(2,2,6,6-tetramethyltetrahydro-4H-pyran-4-ylmethylene)methyl)pyridine-2-yl)-4-hydroxypiperidine-4-yl)methyl)piperazine-1-yl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione (150 mg, 0.17 mmol) was added to a solution of DCM (6 mL) with TFA (1.5 mL) and stirred overnight at room temperature under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. Prep-HPLC was performed under the following conditions to obtain the crude product (100 mg): (Column: Xselect CSH C18 OBD (Waters) column 30×150 mm 5 μm, n; Mobile phase A: Water (0.1% TFA), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 11% B~41% B) The solution was purified for 7 minutes (wavelength: 254 nm; RT1 (min): 5.89) to obtain 3-(5-(4-((1-(5-((3-fluoro-1H-indole-5-yl)(2,2,6,6-tetramethyltetrahydro-4H-pyran-4-ylmethylene)methyl)pyridine-2-yl)-4-hydroxypiperidine-4-yl)methyl)piperazine-1-yl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione (compound 36) (23.4 mg, 17.06%) as a white solid. LCMS (ES, m / z): 805 [M + H] + ; 1H NMR (400 MHz, DMSO-d6) δ (ppm):12.56 (s, 1H), 10.97 (s, 1H),9.37(s, 1H), 7.98 (s,1H),7.61-7.58(d, J = 8.4 Hz, 1H), 7.51-7.41(m, 2H), 7.25-7.22 (m, 1H), 7.18-7.11 (m, 2H), 6.99-6.96 (d, J = 13.2 Hz, 1H), 5.45(s, 1H), 5.11-5.01 (m,1H), 4.41-4.18 (m, 2H), 3.98-3.81 (m, 4H), 3.71-3.63(s, 2H), 3.45-3.17 (m, 7H), 2.95-2.88 (m, 1H), 2.69-2.53 (m, 1H), 2.44-2.36 (m, 1H), 2.22(s, 2H), 2.15(s, 1H), 2.01-1.94(m, 1H), 1.81-1.73(m, 2H), 1.73-1.58(m, 2H), 1.19-1.01(m, 12H). 【0367】 Following the synthesis route of compound 36, the following compounds were synthesized using the following starting compounds or intermediates (the synthesis steps refer to Example 5 above, but the molar mass of each starting compound and intermediate was controlled to be constant). 【0368】 JPEG2026519066000127.jpg229160 【0369】 Example 6 Preparation of 3-(6-(1-((1-(5-(3-fluoro-1H-indole-5-yl)(2,2,6,6-tetramethyltetrahydro-4H-pyran-4-ylmethylene)methyl)pyridine-2-yl)piperidine-4-yl)methyl)piperidine-4-yl)-1-oxo-3,5,6,7-tetrahydropyrrolo[3,4-f]isoindole-2(1H)-yl)piperidine-2,6-dione (compound 69): 【0370】 [ka] 【0371】 Step 1: Preparation of t-butyl 4-(6-(2,6-dioxopiperidine-3-yl)-5-oxo-3,5,6,7-tetrahydropyrrolo[3,4-f]isoindole-2(1H)-yl)piperidine-1-carboxylate: To a stirred DMA (1 mL) solution of 4-oxopiperidine-1-carboxylate t-butyl (100 mg, 0.5 mmol), 3-(1-oxo-3,5,6,7-tetrahydropyrrolo[3,4-f]isoindole-2(1H)-yl)piperidine-2,6-dione (143 mg, 0.5 mmol) STAB (213.30 mg, 1 mmol) was added. The resulting mixture was stirred overnight at room temperature. The reaction was quenched with water at room temperature. The resulting mixture was extracted with DCM (3 × 10 mL). The combined organic layers were washed with water (3 × 5 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. t-butyl 4-(6-(2,6-dioxopiperidine-3-yl)-5-oxo-3,5,6,7-tetrahydropyrrolo[3,4-f]isoindole-2(1H)-yl)piperidine-1-carboxylate (281 mg, 60%) was obtained as a yellow oil. LCMS (ES, m / z): 469.55 [M + H] + . 【0372】 Step 2: Preparation of 3-(1-oxo-6-(piperidine-4-yl)-3,5,6,7-tetrahydropyrrolo[3,4-f]isoindole-2(1H)-yl)piperidine-2,6-dione: To a solution of t-butyl 4-(6-(2,6-dioxopiperidine-3-yl)-5-oxo-3,5,6,7-tetrahydropyrrolo[3,4-f]isoindole-2(1H)-yl)piperidine-1-carboxylate (281 mg, 0.3 mmol) in DCM (8 mL), TFA (2 mL) was added and stirred overnight at room temperature under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure, dissolved in DCM (20 mL), washed with NaHCO3 (10 mL), and then separated. The aqueous phase was extracted with DCM (3 × 10 mL). The combined organic layers were washed with water (3 × 5 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain 3-(1-oxo-6-(piperidine-4-yl)-3,5,6,7-tetrahydropyrrolo[3,4-f]isoindole-2(1H)-yl)piperidine-2,6-dione (88 mg, 80%) as a yellow oily liquid. The crude product was used in the next step without purification. LCMS (ES, m / z): 504 [M + H] + . 【0373】 Step 3: Preparation of 3-(6-(1-((1-(5-((3-fluoro-1-(tetrahydro-2H-pyran-4-yl)-1H-indole-5-yl)(2,2,6,6-tetramethyltetrahydro-4H-pyran-4-ylmethylene)methyl)pyridine-2-yl)piperidine-4-yl)methyl)piperidine-4-yl)-1-oxo-3,5,6,7-tetrahydropyrrolo[3,4-f]isoindole-2(1H)-yl)piperidine-2,6-dione: To a solution (134.5 mmol, 0.24 mmol) of 1-(5-((3-fluoro-1-(tetrahydro-2H-pyran-4-yl)-1H-indazole-5-yl)(2,2,6,6-tetramethyltetrahydro-4H-pyran-4-ylmethylene)methyl)pyridine-2-yl)piperidine-4-formaldehyde stirred in DMA (1 mL), 3-(1-oxo-6-(piperidine-4-yl)-3,5,6,7-tetrahydropyrrolo[3,4-f]isoindole-2(1H)-yl)piperidine-2,6-dione (88 mmol, 0.24 mmol)STAB (106 mg, 0.5 mmol) was added. The resulting mixture was stirred overnight at room temperature. The reaction was quenched with water at room temperature. The resulting mixture was extracted with DCM (3 × 10 mL). The combined organic layers were washed with water (3 × 5 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. 3-(6-(1-(1-(5-((3-fluoro-1-(tetrahydro-2H-pyran-4-yl)-1H-indole-5-yl)(2,2,6,6-tetramethyltetrahydro-4H-pyran-4-ylmethylene)methyl)pyridine-2-yl)piperidine-4-yl)methyl)piperidine-4-yl)-1-oxo-3,5,6,7-tetrahydropyrrolo[3,4-f]isoindole-2(1H)-yl)piperidine-2,6-dione (131 mg, 60%) was obtained as a yellow oily liquid. LCMS (ES, m / z): 914.15 [M + H] + . 【0374】 Step 4: Preparation of 3-(6-(1-((1-(5-((3-fluoro-1H-indole-5-yl)(2,2,6,6-tetramethyltetrahydro-4H-pyran-4-ylmethylene)methyl)pyridine-2-yl)piperidine-4-yl)methyl)piperidine-4-yl)-1-oxo-3,5,6,7-tetrahydropyrrolo[3,4-f]isoindole-2(1H)-yl)piperidine-2,6-dione (compound 69): 3-(6-(1-(1-(5-((3-fluoro-1-(tetrahydro-2H-pyran-4-yl)-1H-indole-5-yl)(2,2,6,6-tetramethyltetrahydro-4H-pyran-4-ylmethylene)methyl)pyridine-2-yl)piperidine-4-yl)methyl)piperidine-4-yl)-1-oxo-3,5,6,7-tetrahydropyrrolo[3,4-f]isoindole-2(1H)-yl)piperidine-2,6-dione (130 mg, 0.14 mmol) was dissolved in DCM (1 mL) and TFA (0.5 mL) was added, and the mixture was stirred overnight at room temperature under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. Prep-HPLC was performed under the following conditions to obtain the crude product (90 mg): (Column: Xselect CSH C18 OBD column (Waters) 30×150 mm 5 μm, n; Mobile phase A: Water (0.1% TFA), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 11% B~41% B) The solution was purified for 7 minutes (wavelength: 254 nm; RT1 (min): 5.89) to obtain 3-(6-(1-((1-(5-((3-fluoro-1H-indole-5-yl)(2,2,6,6-tetramethyltetrahydro-4H-pyran-4-ylmethylene)methyl)pyridine-2-yl)piperidine-4-yl)methyl)piperidine-4-yl)-1-oxo-3,5,6,7-tetrahydropyrrolo[3,4-f]isoindole-2(1H)-yl)piperidine-2,6-dione (compound 69) (35.4 mg, 30%) as a white solid. LCMS (ES, m / z): 829.45 [M + H] + ; 1H NMR (400 MHz, DMSO-d6) δ (ppm):12.55 (s, 1H), 10.96 (s, 1H),9.37(s, 1H), 7.64-7.58(d, J = 8.4 Hz, 1H), 7.52-7.42(m, 2H), 7.26-7.22 (m, 1H), 7.18-7.11 (m, 2H), 6.99-6.96 (d, J = 13.2 Hz, 1H), 5.45(s, 1H), 5.11-5.01 (m,1H), 4.41-4.18 (m, 2H), 3.98-3.81 (m, 4H), 3.72-3.58 (s, 6H), 3.45-3.17 (m, 3H), 2.95-2.88 (m, 1H), 2.69-2.52 (m, 2H), 2.44-2.36 (m, 1H), 2.22(s, 2H), 2.15(s, 1H), 2.01-1.94(m, 1H), 1.84-1.73(m, 4H), 1.75-1.56(m, 4H), 1.22-1.04(m, 12H). 【0375】 Example 7: Preparation of 3-(6-(2-(7-(5-((3-fluoro-1H-indole-5-yl)(2,2,6,6-tetramethyltetrahydro-4H-pyran-4-ylmethylene)methyl)pyridine-2-yl)-2,7-diazaspiro[3.5]nonanane-2-yl)-2-oxoethyl)-1-oxo-3.5,6,7-tetrahydropyrrolo[3,4-f]isoindole-2(1H)-yl)piperidine-2,6-dione (compound 70): 【0376】 [ka] 【0377】 Step 1: Preparation of t-butyl 7-(5-((3-fluoro-1H-indazole-5-yl)(2,2,6,6-tetramethyltetrahydro-4H-pyran-4-ylmethylene)methyl)pyridine-2-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylate: 3-Fluoro-5-((6-fluoropyridine-3-yl)(2,2,6,6-tetramethyltetrahydro-4H-pyran-4-ylmethylene)methyl)-1-(tetrahydro-2H-pyran-4-yl)-1H-indazole (234 mg, 0.5 mmol) in DMSO (5 mL) was mixed with t-butyl 2,7-diazaspiro[3.5]nonane-2-carboxylate (136 mg, 0.6 mmol, 3 equivalents), and K2CO3 (208 mg, 1.5 mmol) was added at room temperature. The final reaction mixture was microwaved overnight at 130 °C. The reaction was quenched with water at room temperature. The resulting mixture was extracted with ethyl acetate and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative thin-layer chromatography (PE / EA) to obtain t-butyl 7-(5-((3-fluoro-1H-indazole-5-yl)(2,2,6,6-tetramethyltetrahydro-4H-pyran-4-ylmethylene)methyl)pyridine-2-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylate (162 mg, 55%). LCMS (ES, m / z): 590.34, [M+H] + . 【0378】 Step 2: Preparation of 7-(5-((3-fluoro-1H-indazole-5-yl)(2,2,6,6-tetramethyltetrahydro-4H-pyran-4-ylmethylene)methyl)pyridine-2-yl)-2,7-diazaspiro[3.5]nonane: To a solution of t-butyl 7-(5-((3-fluoro-1H-indazole-5-yl)(2,2,6,6-tetramethyltetrahydro-4H-pyran-4-ylmethylene)methyl)pyridine-2-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylate (162 mg, 0.28 mmol) in DCM (4 mL), TFA (2 mL) was added and stirred overnight at room temperature under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure, dissolved in DCM (20 mL), washed with NaHCO3 (10 mL), and then separated. The aqueous phase was extracted with DCM (3 × 10 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 7-(5-((3-fluoro-1H-indazole-5-yl)(2,2,6,6-tetramethyltetrahydro-4H-pyran-4-ylmethylene)methyl)pyridine-2-yl)-2,7-diazaspiro[3.5]nonane (compound 70-B) (114 mg, 85%) as a yellow oily liquid. The crude product was used in the next step without purification. LCMS (ES, m / z): 490.28 [M + H] + . 【0379】 Step 3: Preparation of t-butyl 2-(6-(2,6-dioxopiperidine-3-yl)-5-oxo-3,5,6,7-tetrahydropyrrolo[3,4-f]isoindole-2(1H)-yl) acetate: To a stirred solution of 3-(1-oxo-3,5,6,7-tetrahydropyrrolo[3,4-f]isoindole-2(1H)-yl)piperidine-2,6-dione (1.43 g, 5 mmol) in MeCN (30 mL), tert-butylbromoacetate (1.07 g, 5.5 mmol) and DIEA (3.22 g, 25 mmol) were added. The resulting mixture was stirred overnight at room temperature. The reaction was quenched with water at room temperature. The resulting mixture was extracted with DCM (3 × 50 mL). The combined organic layers were dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography, and then eluted with DCM / MeOH (20:1) to obtain t-butyl 2-(6-(2,6-dioxopiperidine-3-yl)-5-oxo-3,5,6,7-tetrahydropyrrolo[3,4-f]isoindole-2(1H)-yl)carboxylate (1.6 g, 80%) as a yellow oil, which was used directly in the next reaction. LCMS (ES, m / z): 400.55 [M + H] + . 【0380】 Step 4: Preparation of 2-(6-(2,6-dioxopiperidine-3-yl)-5-oxo-3,5,6,7-tetrahydropyrrolo[3,4-f]isoindole-2(1H)-yl)acetic acid: To a solution of t-butyl 2-(6-(2,6-dioxopiperidine-3-yl)-5-oxo-3,5,6,7-tetrahydropyrrolo[3,4-f]isoindole-2(1H)-yl)carboxylate (1.6 g, 4 mmol) in DCM (10 mL), TFA (10 mL) was added and stirred overnight at room temperature under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure, dissolved in DCM (50 mL), washed with H2O (50 mL), and then separated. The aqueous phase was extracted with DCM (3 × 10 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 2-(6-(2,6-dioxopiperidine-3-yl)-5-oxo-3,5,6,7-tetrahydropyrrolo[3,4-f]isoindole-2(1H)-yl)acetic acid (1.16 g, 85%) as a yellow oily liquid. The crude product was used in the next step without purification. LCMS (ES, m / z): 342.28 [M + H]-. 【0381】 Step 5: Preparation of 3-(6-(2-(7-(5-(3-fluoro-1-(tetrahydro-2H-pyran-4-yl)-1H-indazole-5-yl)(2,2,6,6-tetramethyltetrahydro-4H-pyran-4-ylmethylene)pyridine-2-yl)-2,7-diazaspiro[3.5]nonanane-2-yl)-2-oxoethyl)-1-oxo-3.5,6,7-tetrahydropyrrolo[3,4-f]isoindole-2(1H)-yl)piperidine-2,6-dione: Compound 70-B (114 mg, 0.24 mmol), HATU (137 mg, 0.36 mmol), and DIEA (62 mg, 0.48 mmol) were added to a DMA (2 mL) solution of 2-(6-(2,6-dioxopiperidine-3-yl)-5-oxo-3,5,6,7-tetrahydropyrrolo[3,4-f]isoindole-2(1H)-yl)acetic acid (82 mg, 0.24 mmol). The resulting mixture was stirred overnight at room temperature under a nitrogen atmosphere. The reaction was quenched with water (20 mL) and extracted with EA (4 × 10 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography and then eluted with DCM / MeOH (20:1) to obtain 3-(6-(2-(7-(5-(3-fluoro-1-(tetrahydro-2H-pyran-4-yl)-1H-indazole-5-yl)(2,2,6,6-tetramethyltetrahydro-4H-pyran-4-ylmethylene)pyridine-2-yl)-2,7-diazaspiro[3.5]nonan-2-yl)-2-oxoethyl)-1-oxo-3.5,6,7-tetrahydropyrrolo[3,4-f]isoindole-2(1H)-yl)piperidine-2,6-dione (118 mg, 55%). LCMS (ES, m / z): 899.55 [M + H] + . 【0382】 Step 6: Preparation of 3-(6-(2-(7-(5-((3-fluoro-1H-indole-5-yl)(2,2,6,6-tetramethyltetrahydro-4H-pyran-4-ylmethylene)methyl)pyridine-2-yl)-2,7-diazaspiro[3.5]nonanane-2-yl)-2-oxoethyl)-1-oxo-3.5,6,7-tetrahydropyrrolo[3,4-f]isoindole-2(1H)-yl)piperidine-2,6-dione (compound 70): To a solution of 3-(6-(2-(7-(5-(3-fluoro-1-(tetrahydro-2H-pyran-4-yl)-1H-indazole-5-yl)(2,2,6,6-tetramethyltetrahydro-4H-pyran-4-ylmethylene)pyridine-2-yl)-2,7-diazaspiro[3.5]nonane-2-yl)-2-oxoethyl)-1-oxo-3.5,6,7-tetrahydropyrrolo[3,4-f]isoindole-2(1H)-yl)piperidine-2,6-dione (118 mg, 0.13 mmol) in DCM (1 mL), TFA (0.5 mL) was added and stirred overnight at room temperature under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. Prep-HPLC was performed under the following conditions to obtain the crude product (90 mg): (Column: Xselect CSH C18 OBD column 30×150 mm 5 μm, n; Mobile phase A: Water (0.1% TFA), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 11% B~41% B) The solution was purified for 7 minutes (wavelength: 254 nm; RT1 (min): 5.89) to obtain 3-(6-(2-(7-(5-((3-fluoro-1H-indole-5-yl)(2,2,6,6-tetramethyltetrahydro-4H-pyran-4-ylmethylene)methyl)pyridine-2-yl)-2,7-diazaspiro[3.5]nonan-2-yl)-2-oxoethyl)-1-oxo-3.5,6,7-tetrahydropyrrolo[3,4-f]isoindole-2(1H)-yl)piperidine-2,6-dione (27 mg, 25%) as a white solid. LCMS (ES, m / z): 815.4 [M + H] + 1H NMR (400 MHz, DMSO-d6) δ (ppm):12.45 (s, 1H), 10.98 (s, 1H), 8.32-8.22(m, 2H), 8.02-7.62(m, 4H), 7.55-7.48 (m, 1H), 7.36-7.27 (m, 1H), 6.99-6.94 (m, 1H), 4.48-4.42 (m,1H), 4.40-4.20 (m, 2H), 3.99-3.80 (m, 4H), 3.72-3.58 (s, 6H), 3.46-3.18 (m, 2H), 3.28 (s, 2H), 2.45-2.36 (m, 1H), 2.05-1.94(m, 1H), 1.86-1.73(m, 4H), 1.76-1.56(m, 4H), 1.25-1.05(m, 12H). 【0383】 Following the synthesis route of compound 70, the following compounds were synthesized using the following starting compounds or intermediates (the synthesis steps refer to Example 7 above, but the molar mass of each starting compound and intermediate was controlled to be constant). 【0384】 JPEG2026519066000130.jpg129160 【0385】 Example 8: Preparation of 1-(3-(4-(1-(5-((3-fluoro-1H-indazole-5-yl)(2,2,6,6-tetramethyltetrahydro-4H-pyran-4-methylene)methyl)pyridine-2-yl)piperidine-4-yl)methyl)piperazine-1-yl)phenyl)dihydropyrimidine-2,4(1H,3H)dione (compound 75): 【0386】 [ka] 【0387】 Step 1: Preparation of 3-(3-bromophenyl)aminopropionic acid: An aqueous solution of m-bromoaniline (3 g, 17.439 mmol) was treated with acrylic acid (3.77 g, 52.317 mmol) at 70°C under a nitrogen atmosphere for 3 hours. The mixture was cooled to 5°C, and ethanol (6 mL) was added. The resulting mixture was stirred at room temperature for 12 hours. The resulting mixture was concentrated under vacuum. The residue was dissolved in dichloromethane. After purification of the residue by silica gel column chromatography, 3-(3-bromophenyl)aminopropionic acid (4 g, 94%) was obtained as an oily liquid by elution with PE / EA. LCMS (ES, m / z): 244 [M + H] + . 【0388】 Step 2: Preparation of 1-(3-bromophenyl)dihydropyrimidine-2,4(1H,3H)-dione: A solution / mixture of 3-((3-bromophenyl)amino)propionic acid (4 g, 16.388 mmol, 1 equivalent) and urea (1.97 g, 32.776 mmol, 2 equivalents) was boiled overnight in 20 ml of acetic acid. The above mixture was adjusted to pH=1 with 10% HCl, and the resulting mixture was boiled for 30 minutes. The mixture was cooled to room temperature. The reaction was quenched with water. The precipitated solid was collected by filtration and washed with water to obtain 1-(3-bromophenyl)dihydropyrimidine-2,4-dione (2.55 g, 58%) as a white solid. LCMS (ES, m / z): 269 [M + H] + . 【0389】 Step 3: Preparation of 1-(3-(4-(1-(5-(3-fluoro-1H-indazole-5-yl)(2,2,6,6-tetramethyltetrahydro-4H-pyran-4-methylene)methyl)pyridine-2-yl)piperidine-4-yl)methyl)piperazine-1-yl)phenyl)dihydropyrimidine-2,4(1H,3H)dione (compound 75): A mixture of 3-fluoro-5-((6-(4-(piperazine-1-methyl)piperidine-1-yl)pyridine-3-yl)(2,2,6,6-tetramethyltetrahydro-4H-pyran-4-ylmethylene)methyl)-1H-indazole (100 mg, 0.183 mmol) and 1-(3-bromophenyl)dihydropyrimidine-2,4-(1H,3H)dione was added to a solution of dioxane (2 mL) and a mixture of third-generation t-BuXPhos pre-catalyst (14.55 mg, 0.018 mmol), t-BuXPhos (15.53 mg, 0.037 mmol), and Cs2CO3 (178.78 mg, 0.549 mmol). The mixture was stirred overnight at 90°C under a nitrogen atmosphere. The mixture was cooled to room temperature. The reaction was quenched with water and extracted with ethyl acetate. The organic layers were combined and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The crude product (100 mg) (column: SunFire Prep C18 OBD column, 19*150 mm, 5 μm; mobile phase A: water (0.05% TFA), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 30% B~50% B 7.2 min; wavelength: 254 / 210 nm; RT1 (min): 8) was purified by Prep-HPLC under the following conditions to obtain 1-(3-(4-(1-(5-((3-fluoro-1H-indazole-5-yl)(2,2,6,6-tetramethyltetrahydro-4H-pyran-4-methylene)methyl)pyridine-2-yl)piperidine-4-yl)methyl)piperazine-1-yl)phenyl)dihydropyrimidine-2,4(1H,3H)dione (compound 75) (4.0 mg, 2.88%) as a white solid. LCMS (ES,m / z) : 735[ M + H ] + ; 1H NMR (400 MHz, DMSO-d6) δ (ppm):10.50 (s, 1H), 8.37 (s, 1H), 8.01 (s,1H), 7.86-7.84 (d,J=8.0 Hz, 1H), 7.73 (s, 1H), 7.64 (s, 1H),7.59-7.57 (d, J=8.0 Hz, 2H), 7.38-7.31 (m, 3H), 7.76-7.74 (d, J=8.0 Hz, 1H), 2.25-4.22 (d, J=12.0 Hz, 2H), 3.91-3.88 (t, 2H), 2.79-2.79(m, 8H),2.34-2.26(m, 6H), 2.18-2.11 (m, 4H), 1.76-1.73 (m, 3H), 1.24-1.19(d, J=20.0 Hz, 12H), 1.13-1.08(m, 2H). 【0390】 Following the synthesis route of compound 75, the following compounds were synthesized using the following starting compounds or intermediates (the synthesis steps refer to Example 8 above, but the molar mass of each starting compound and intermediate was controlled to be constant). 【0391】 JPEG2026519066000132.jpg217160 【0392】 Example 9: Preparation of 3-((2-fluoro-5-(4-((1-(5-((3-fluoro-1H-indazole-5-yl)(2,2,6,6-tetramethyltetrahydro-4H-pyran-4-ylmethylene)methyl)pyridine-2-yl)piperidine-4-yl)methyl)piperazine-1-yl)phenyl)amino)piperidine-2,6-dione (compound 83): 【0393】 [ka] 【0394】 Step 1: Preparation of 3-((5-bromo-2-fluorophenyl)amino)piperidine-2,6-dione: 5-Bromo-2-fluoroaniline (1 g, 5.3 mmol), 3-bromo-2,6-dione (3.03 g, 15.8 mmol), silver trifluoromethanesulfonate (0.27 g, 1.05 mmol), and sodium hydroxide (1.33 g, 15.8 mmol) were stirred at 80°C under a nitrogen atmosphere for 7 days. The reaction was quenched with water at room temperature. The resulting mixture was extracted with ELISA (3 × 50 mL). The organic layers were combined and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was precipitated with Et2O (3 × 10 mL) and solidified. 3((4-bromo-2-fluorophenyl)amino)piperidine-2,6-dione (200 mg, 12.62%) was obtained as a grayish-white solid. LCMS (ES, m / z): 301 [M + H] + . 【0395】 Step 2: Preparation of 3-((2-fluoro-5-(4-((1-(5-((3-fluoro-1H-indole-5-yl)(2,2,6,6-tetramethyltetrahydro-4H-pyran-4-ylmethylene)methyl)pyridine-2-yl)piperidine-4-yl)methyl)piperazine-1-yl)phenyl)amino)piperidine-2,6-dione (compound 83): To a solution of 3-fluoro-5-((6-(4-(piperazine-1-ylmethyl)piperidine-1-yl)pyridine)-3-yl)(2,2,6,6-tetramethyltetrahydro-4H-pyran-4-ylmethylene)methyl)-1H-indazole (100 mg, 0.18 mmol) in 1,4-dioxane (2 mL), a solution of 3-((4-bromo-2-fluorophenyl)amino)piperidine-2,6-dione (110 mg, 0.37 mmol), t-BuXPhos (16 mg, 0.04 mmol), and di-t-butyl[2',4',6'-tri(propan-2-yl)-[1,1'-biphenyl][1,1'-biphenyl]-2-yl]phosphorane was added. Chloro(2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (29 mg, 0.04 mmol) and Cs2CO3 (179 mg, 0.55 mmol) were added, and the mixture was stirred overnight at 90°C under a nitrogen atmosphere. The reaction was quenched with water at room temperature. The resulting mixture was extracted with ethyl acetate (3 × 20 mL). The organic layers were dried together over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the crude product was subjected to Prep-HPLC under the following conditions (column: Welch Ultimate HS~C18, 21.2 × 250 mm, 7 μm; mobile phase A: water (0.05% TFA), mobile phase B: ACN; flow rate: 25 mL / min; gradient: 27% B~50% B for 7 minutes, 50% B, 0.5 minutes; wavelength: 254 / 210 nm; RT1 (minutes): 6.45; number of operations: 0) was purified to obtain 3-((2-fluoro-5-(4-((1-(5-((3-fluoro-1H-indazole-5-yl)(2,2,6,6-tetramethyltetrahydro-4H-pyran-4-ylmethylene)methyl)pyridine-2-yl)piperidine-4-yl)methyl)piperazine-1-yl)phenyl)amino)piperidine-2,6-dione (compound 83) (9.5 mg, 6.21%) as a grayish-white solid. LCMS (ES, m / z): 767.4 [M + H] + ; 1H NMR (400 MHz, DMSO-d6) δ 10.86 (s, 1H), 8.79 (s, 1H), 7.61 (d, J =1.2 Hz, 1H), 7.56 (s, 1H), 7.42-7.39 (m, 1H), 7.29-7.27 (m, 2H), 7.08-7.06 (d, J = 8.0 Hz, 2H), 6.99-6.98 (m, 1H), 6.97-6.91 (m, 2H), 5.90 (s, 1H), 4.52 (s, 1H), 3.69-3.66 (d, J = 12.0 Hz, 5H), 3.23 (s, 4H), 2.79-2.70 (m, 1H), 2.66 - 2.56 (m, 4H), 2.35 (s, 1H), 2.23 (s, 2H), 2.17 (s, 2H), 2.11 (m, 2H), 1.82-1.79 (d, J = 11.6 Hz, 3H), 1.28 - 1.20 (m, 2H), 1.17-1.13 (d, J = 15.2 Hz, 12H). 【0396】 Following the synthesis route of compound 83, the following compounds were synthesized using the following starting compounds or intermediates (the synthesis steps refer to Example 9 above, but the molar mass of each starting compound and intermediate was controlled to be constant). 【0397】 JPEG2026519066000134.jpg218160 【0398】 JPEG2026519066000135.jpg34160 【0399】 Example 10: Preparation of 1-(6-(1-(2-(4-(5-((3-fluoro-1H-indazole-5-yl)(2,2,6,6-tetramethyltetrahydro-4H-pyran-4-ylmethylene)methyl)pyridine-2-yl)piperazine-1-yl)-2-oxoethyl)piperidine-4-yl)-1-methyl-1H-indazole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (compound 92): 【0400】 [ka] 【0401】 Step 1: Preparation of t-butyl 2-(4-(3-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)-1-methyl-1H-indoleazole-6-yl)piperidine-1-yl)ethyl acetate: To a stirred solution of 1-(1-methyl-6-(piperidine-4-yl)-1H-indole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione hydrochloride (1.80 g, 5 mmol) in MeCN (30 mL), tert-butylbromoacetate (1.08 g, 5.5 mmol) and DIEA (3.23 g, 25 mmol) were added. The resulting mixture was stirred overnight at room temperature. The reaction was quenched with water at room temperature. The resulting mixture was extracted with DCM (3 × 50 mL). The combined organic layers were dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography, and then eluted with DCM / MeOH (20:1) to obtain t-butyl 2-(4-(3-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)-1-methyl-1H-indoleazole-6-yl)piperidine-1-yl)ethyl acetate (1.65 g, 75%) as a yellow oil, which was used directly in the next reaction. LCMS (ES, m / z): 442.2 [M + H] + . 【0402】 Step 2: Preparation of 2-(4-(3-(2,4-dioxotetrahydropyrimidine-1(2H)yl)-1-methyl-1H-indoleazole-6-yl)piperidine-1-yl)acetic acid: To a solution of t-butyl 2-(4-(3-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)-1-methyl-1H-indoleazole-6-yl)piperidine-1-yl)ethyl acetate (1.65 g, 3.74 mmol) in DCM (10 mL), TFA (10 mL) was added and stirred overnight at room temperature under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure, dissolved in DCM (50 mL), washed with H2O (50 mL), and then separated. The aqueous phase was extracted with DCM (3 × 10 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 2-(4-(3-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)-1-methyl-1H-indoleazole-6-yl)piperidine-1-yl)acetic acid (1.15 g, 80%) as a yellow oily liquid. The crude product was used in the next step without refinement. LCMS (ES, m / z): 384 [M + H] -. 【0403】 Step 3: Preparation of 1-(6-(1-(2-(4-(5-((3-fluoro-1-(tetrahydro-2H-pyran-4-yl)-1H-indazole-5-yl)(2,2,6,6-tetramethyltetrahydro-4H-pyran-4-ylmethylene)methyl)pyridine-2-yl)piperazine-1-yl)-2-oxoethyl)piperidine-4-yl)-1-methyl-1H-indazole-3-yl)dihydropyrimidine-2,4(1H,3H)dione: To a DMA (2 mL) solution of 2-(4-(3-(2,4-dioxotetrahydropyrimidine-1(2H)yl)-1-methyl-1H-indole-6-yl)piperidine-1-yl)acetic acid (100 mg, 0.26 mmol), 3-fluoro-5-((6-(piperazine-1-yl)pyridine-3-yl)(2,2,6,6-tetramethyltetrahydro-4H-pyran-4-ylmethylene)methyl)-1-(tetrahydro-2H-pyran-4-yl)-1H-indazole (124 mg, 0.26 mmol), HATU (148 mg, 0.39 mmol), and DIEA (67 mg, 0.52 mmol) were added. The resulting mixture was stirred overnight at room temperature under a nitrogen atmosphere. Water (20 mL) was added to quench the reaction, and the mixture was extracted with EA (4 × 10 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography and then eluted with DCM / MeOH (20:1) to obtain 1-(6-(1-(2-(4-(5-(3-fluoro-1-(tetrahydro-2H-pyran-4-yl)-1H-indazole-5-yl)(2,2,6,6-tetramethyltetrahydro-4H-pyran-4-ylmethylene)methyl)pyridine-2-yl)piperazine-1-yl)-2-oxoethyl)piperidine-4-yl)-1-methyl-1H-indazole-3-yl)dihydropyrimidine-2,4(1H,3H)dione (108 mg, 50%). LCMS (ES, m / z): 901.4 [M + H] + . 【0404】 Step 4: Preparation of 1-(6-(1-(2-(4-(5-(3-fluoro-1H-indazole-5-yl)(2,2,6,6-tetramethyltetrahydro-4H-pyran-4-ylmethylene)methyl)pyridine-2-yl)piperazine-1-yl)-2-oxoethyl)piperidine-4-yl)-1-methyl-1H-indazole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (compound 92): To a solution of 1-(6-(1-(2-(4-(5-(3-fluoro-1-(tetrahydro-2H-pyran-4-yl)-1H-indazole-5-yl)(2,2,6,6-tetramethyltetrahydro-4H-pyran-4-ylmethylene)methyl)pyridine-2-yl)piperazine-1-yl)-2-oxoethyl)piperidine-4-yl)-1-methyl-1H-indazole-3-yl)dihydropyrimidine-2,4(1H,3H)dione (108 mg, 0.12 mmol) in DCM (1 mL), TFA (0.5 mL) was added and stirred overnight at room temperature under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The crude product (column: Xselect CSH C18 OBD column 30×150 mm 5 μm, n; mobile phase A: water (0.1% TFA), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 11% B to 41% B for 7 minutes; wavelength: 254 nm; RT1 (min): 5.89) was purified by Prep-HPLC under the following conditions to obtain 1-(6-(1-(2-(4-(5-((3-fluoro-1H-indazole-5-yl)(2,2,6,6-tetramethyltetrahydro-4H-pyran-4-ylmethylene)methyl)pyridine-2-yl)piperazine-1-yl)-2-oxoethyl)piperidine-4-yl)-1-methyl-1H-indazole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (compound 92) (18 mg, 22%) was obtained as a white solid. LCMS (ES, m / z): 817.4 [M + H] + ; 1 H NMR (400 MHz, DMSO-d6) δ (ppm):12.48(s, 1H), 10.68(s, 1H), 8.32-8.15(m, 2H), 8.02-7.52(m, 5H), 7.36-7.27 (m, 1H), 6.59-6.54(m, 1H), 3.96 (s, 3H),3.85-3.52(m,10H), 3.28 (s, 2H), 2.75-2.68 (m, 3H), 2.55-2.50 (m, 2H),2.45-2.36 (m, 2H), 2.05-1.94(m, 4H), 1.76-1.58(m, 4H), 1.23-1.08 (m, 12H). 【0405】 Example 11: Preparation of 1-(6-(3,3-difluoro-1-(2-(4-(5-((3-fluoro-1H-indazole-5-yl)(2,2,6,6-tetramethyltetrahydro-4H-pyran-4-ylmethylene)methyl)pyridine-2-yl)piperazine-1-yl)-2-oxoethyl)piperidine-4-yl)-1-methyl-1H-indazole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (compound 93): 【0406】 [ka] 【0407】 Step 1: Preparation of t-butyl 2-(4-(3-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)-1-methyl-1H-indole-6-yl)-3,3-difluoropiperidine-1-yl) acetate: To a stirred solution of 1-(6-(3,3-difluoropiperidine-4-yl)-1-methyl-1H-indole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione hydrochloride (1.80 g, 5 mmol) in MeCN (30 mL), tert-butylbromoacetate (1.08 g, 5.5 mmol) and DIEA (3.23 g, 25 mmol) were added. The resulting mixture was stirred overnight at room temperature. The reaction was quenched with water at room temperature. The resulting mixture was extracted with DCM (3 × 50 mL). The combined organic layers were dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography, and then eluted with DCM / MeOH (20:1) to obtain t-butyl 2-(4-(3-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)-1-methyl-1H-indole-6-yl)-3,3-difluoropiperidine-1-yl) acetate (1.65 g, 75%) as a yellow oil, which was used directly in the next reaction. LCMS (ES, m / z): 478.2 [M + H] + . 【0408】 Step 2: Preparation of 2-(4-(3-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)-1-methyl-1H-indole-6-yl)-3,3-difluoropiperidine-1-yl)acetic acid: To a solution of t-butyl 2-(4-(3-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)-1-methyl-1H-indole-6-yl)-3,3-difluoropiperidine-1-yl) acetate (1.65 g, 3.74 mmol) in DCM (10 mL), TFA (10 mL) was added and stirred overnight at room temperature under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure, dissolved in DCM (50 mL), washed with H2O (50 mL), and then separated. The aqueous phase was extracted with DCM (3 × 10 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 2-(4-(3-(2,4-dioxotetrahydropyrimidine-1(2H)yl)-1-methyl-1H-indole-6-yl)-3,3-difluoropiperidine-1-yl)acetic acid (1.15 g, 80%) as a yellow oily liquid. The crude product was used in the next step without purification. LCMS (ES, m / z): 422 [M + H] - . 【0409】 Step 3: Preparation of 1-(6-(3,3-difluoro-1-(2-(4-(5-((3-fluoro-1-(tetrahydro-2H-pyran-4-yl)-1H-indazole-5-yl)(2,2,6,6-tetramethyltetrahydro-4H-pyran-4-ylmethylene)methyl)pyridine-2-yl)piperazine-1-yl)-2-oxoethyl)piperidine-4-yl)-1-methyl-1H-indazole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione: To a DMA (2 mL) solution of 2-(4-(3-(2,4-dioxotetrahydropyrimidine-1(2H)yl)-1-methyl-1H-indole-6-yl)-3,3-difluoropiperidine-1-yl)acetic acid (100 mg, 0.26 mmol), 3-fluoro-5-((6-(piperazine-1-yl)pyridine-3-yl)(2,2,6,6-tetramethyltetrahydro-4H-pyran-4-ylmethylene)methyl)-1-(tetrahydro-2H-pyran-4-yl)-1H-indazole (124 mg, 0.26 mmol) and HATU (148 mg, 0.39 mmol)DIEA (67 mg, 0.52 mmol) were added. The resulting mixture was stirred overnight at room temperature under a nitrogen atmosphere. Water (20 mL) was added to quench the reaction, and the mixture was extracted with EA (4 × 10 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography and then eluted with DCM / MeOH (20:1) to obtain 1-(6-(3,3-difluoro-1-(2-(4-(5-((3-fluoro-1-(tetrahydro-2H-pyran-4-yl)-1H-indazole-5-yl)(2,2,6,6-tetramethyltetrahydro-4H-pyran-4-ylmethylene)methyl)pyridine-2-yl)piperazine-1-yl)-2-oxoethyl)piperidine-4-yl)-1-methyl-1H-indazole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (108 mg, 50%). LCMS (ES, m / z): 937.4 [M + H] + . 【0410】 Step 4: Preparation of 1-(6-(3,3-difluoro-1-(2-(4-(5-(3-fluoro-1H-indazole-5-yl)(2,2,6,6-tetramethyltetrahydro-4H-pyran-4-ylmethylene)methyl)pyridine-2-yl)piperazine-1-yl)-2-oxoethyl)piperidine-4-yl)-1-methyl-1H-indazole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (compound 93): To a solution of 1-(6-(3,3-difluoro-1-(2-(4-(5-((3-fluoro-1-(tetrahydro-2H-pyran-4-yl)-1H-indazole-5-yl)(2,2,6,6-tetramethyltetrahydro-4H-pyran-4-ylmethylene)methyl)pyridine-2-yl)piperazine-1-yl)-2-oxoethyl)piperidine-4-yl)-1-methyl-1H-indazole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (108 mg, 0.12 mmol) in DCM (1 mL), TFA (0.5 mL) was added and stirred overnight at room temperature under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The crude product (column: Xselect CSH C18 OBD column 30×150 mm 5 μm, n; mobile phase A: water (0.1% TFA), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 11% B~41% B for 7 minutes; wavelength: 254 nm; RT1 (min): 5.89) was purified by Prep-HPLC under the following conditions to obtain 1-(6-(3,3-difluoro-1-(2-(4-(5-((3-fluoro-1H-indazole-5-yl)(2,2,6,6-tetramethyltetrahydro-4H-pyran-4-ylmethylene)methyl)pyridine-2-yl)piperazine-1-yl)-2-oxoethyl)piperidine-4-yl)-1-methyl-1H-indazole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (compound) 93) (18 mg, 22%) was obtained as a white solid. LCMS (ES, m / z): 853.4 [ M + H ] + ; 1 H NMR (400 MHz, DMSO-d6) δ (ppm):12.44(s, 1H), 10.66(s, 1H), 8.35-8.17(m, 2H), 8.05-7.52(m, 5H), 7.38-7.28(m, 1H), 6.59-6.55(m, 1H),4.22-4.16 (m, 1H),3.96 (s, 3H),3.85-3.52 (m,10H), 3.28 (s, 2H), 2.75-2.68 (m, 2H), 2.56-2.50 (m, 2H),2.46-2.38(m, 2H), 2.05-1.95(m, 4H), 1.80-1.58(m, 2H), 1.24-1.08(m, 12H). 【0411】 Following the synthesis route of compound 93, the following compounds were synthesized using the following starting compounds or intermediates (the synthesis steps refer to Example 11 above, but the molar mass of each starting compound and intermediate was controlled to be constant). 【0412】 JPEG2026519066000138.jpg130160 【0413】 Example 12: Preparation of 1-(8-(4-((1-(5-((3-fluoro-1H-indazole-5-yl)(2,2,6,6-tetramethyltetrahydro-4H-pyran-4-methylene)methyl)pyridine-2-yl)piperidine-4-yl)methyl)piperazine-1-yl)imidazo[1,2-a]pyridine-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (compound 96): 【0414】 [ka] 【0415】 Step 1: Preparation of t-butyl 4-(3-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)imidazo[1,2-a]pyridine-8-yl)piperazine-1-carboxylate: To a solution of 1-(8-bromoimidazo[1,2-a]pyridine-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (300 mg, 0.6 mmol) in THF (5 mL), t-butylpiperazine-1-carboxylate (450 mg, 1.8 mmol), RuPhos Palladacycle G3 (104 mg, 0.12 mmol), RuPhos (58 mg, 0.12 mmol), and t-BuONa (179 mg, 1.8 mmol) were added, and the resulting mixture was stirred overnight at 85°C under a nitrogen atmosphere. The reaction was quenched with water at room temperature. The resulting mixture was extracted with EA (3 × 20 mL). The organic layers were combined and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative thin-layer chromatography (DCM / MeOH 10:1) to obtain t-butyl 4-(3-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)imidazo[1,2-a]pyridine-8-yl)piperazine-1-carboxylate (200 mg, 46.81%) as a yellow oil. LCMS(ESI): m / z 415[M+1] + . 【0416】 Step 2: Preparation of 1-(8-(piperazin-1-yl)imidazo[1,2-a]pyridine-3-yl)dihydropyrimidine-2,4(1H,3H)-dione: To a solution of t-butyl 4-(3-(2,4-dioxotetrahydropyrimidine-1(2H)-yl)imidazo[1,2-a]pyridine-8-yl)piperazine-1-carboxylate (180 mg, 0.3 mmol) in DCM (8 mL), TFA (2 mL) was added and stirred overnight at room temperature under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. 1-(8-(piperazine-1-yl)imidazo[1,2-a]pyridine-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (110 mg, 83.46%) was obtained as a yellow oil. The crude product was used in the next step without purification. LCMS (ESI): m / z 315 [M+1] + . 【0417】 Step 3: Preparation of 1-(8-(4-((1-(5-((3-fluoro-1-(tetrahydro-2H-pyran-4-yl)-1H-indazole-5-yl)(2,2,6,6-tetramethyltetrahydro-4H-pyran-4-ylmethylene)methyl)pyridine-2-yl)piperidine-4-yl)methyl)piperazine-1-yl)imidazo[1,2-a]pyridine-3-yl)dihydropyrimidine-2,4(1H,3H)-dione: To a stirred solution of 1-(5-((3-fluoro-1-(tetrahydro-2H-pyran-4-yl)-1H-indazole-5-yl)(2,2,6,6-tetramethyltetrahydro-4H-pyran-4-ylmethylene)methyl)pyridine-2-yl)piperidine-4-formaldehyde (134.5 mmol, 0.24 mmol), 1-(8-(piperazin-1-yl)imidazo[1,2-a]pyridine-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (88 mmol, 0.24 mmol)STAB (106 mg, 0.5 mmol) was added in DMA (1 mL). The resulting mixture was stirred overnight at room temperature. The reaction was quenched with water at room temperature. The resulting mixture was extracted with DCM (3 × 10 mL). The combined organic layers were washed with water (3 × 5 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. 1-(8-(4-((1-(5-((3-fluoro-1-(tetrahydro-2H-pyran-4-yl)-1H-indazole-5-yl)(2,2,6,6-tetramethyltetrahydro-4H-pyran-4-ylmethylene)methyl)pyridine-2-yl)piperidine-4-yl)methyl)piperazine-1-yl)imidazo[1,2-a]pyridine-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (131 mg, 60%) was obtained as a yellow oily liquid. LCMS(ESI): m / z 859.4 [M+1] + . 【0418】 Step 4: Preparation of 1-(8-(4-((1-(5-((3-fluoro-1H-indazole-5-yl)(2,2,6,6-tetramethyltetrahydro-4H-pyran-4-ylmethylene)methyl)pyridine-2-yl)piperidine-4-yl)methyl)piperazine-1-yl)imidazo[1,2-a]pyridine-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (compound 96): To a solution of 1-(8-(4-((1-(5-((3-fluoro-1-(tetrahydro-2H-pyran-4-yl)-1H-indazole-5-yl)(2,2,6,6-tetramethyltetrahydro-4H-pyran-4-ylmethylene)methyl)pyridine-2-yl)piperidine-4-yl)methyl)piperazine-1-yl)imidazo[1,2-a]pyridine-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (130 mg, 0.14 mmol) in DCM (1 mL), TFA (0.5 mL) was added and stirred overnight at room temperature under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The crude product (90 mg) was purified by Prep-HPLC under the following conditions (Column: Xselect CSH C18 OBD column 30x150 mm 5 μm, n; Mobile phase A: Water (0.1% TFA), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 11% B~41% B for 7 minutes; Wavelength: 254 nm; RT1 (min): 5.89) to obtain 1-(8-(4-((1-(5-((3-fluoro-1H-indazole-5-yl)(2,2,6,6-tetramethyltetrahydro-4H-pyran-4-methylene)methyl)pyridine-2-yl)piperidine-4-yl)methyl)piperazine-1-yl)imidazo[1,2-a]pyridine-3-yl)dihydropyrimidine-2,4(1H,3 35.4 mg, 30% of H-dione (compound 96) was obtained as a white solid. LC-MS (ESI): m / z 775.4 [M+1] + ; 1H NMR (400 MHz, DMSO-d6) δ (ppm):12.55 (s, 1H), 10.96 (s, 1H),9.37(s, 1H), 7.64-7.58(d, J = 8.4 Hz, 1H), 7.52-7.42(m, 2H), 7.26-7.22 (m, 1H), 7.18-7.11 (m, 2H), 6.99-6.96 (d, J = 13.2 Hz, 1H), 5.45(s, 1H), 5.11-5.01 (m,1H), 4.41-4.18 (m, 2H), 3.98-3.81 (m, 4H), 3.72-3.58 (s, 6H), 3.45-3.17 (m, 3H), 2.95-2.88 (m, 1H), 2.69-2.52 (m, 2H), 2.44-2.36 (m, 1H), 2.22(s, 2H), 2.15(s, 1H), 2.01-1.94(m, 1H), 1.84-1.73(m, 4H), 1.75-1.56(m, 4H), 1.22-1.04(m, 12H). 【0419】 Following the synthesis route of compound 96, the following compounds were synthesized using the following starting compounds or intermediates (the synthesis steps refer to Example 12 above, but the molar mass of each starting compound and intermediate was controlled to be constant). 【0420】 JPEG2026519066000140.jpg76161 【0421】 Example 13: Preparation of 3-(4-(1-((1-(5-((3-fluoro-1H-indole-5-yl)(2,2,6,6-tetramethyltetrahydro-4H-pyran-4-ylmethylene)methyl)pyridine-2-yl)piperidine-4-yl)methyl)piperidine-4-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-1-yl)piperidine-2,6-dione (compound 99): 【0422】 [ka] 【0423】 Step 1: Preparation of t-butyl 4-(1-(2,6-dioxopiperidine-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-4-yl)-3,6-dihydropyridine-1(2H)-carboxylate: In a nitrogen atmosphere, 3-(4-bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-1-yl)piperidine-2,6-dione (1.25 g, 3.70 mmol) and t-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (2.31 g, 7.40 mmol) were dissolved in 1,4-dioxane (20 mL), to which cesium fluoride (1.14 g, 7.40 mmol) and Pd(dppf)Cl2 (540 mg, 740 μmol) were added, and the mixture was stirred at 85 °C for 3 hours. The mixture was cooled to room temperature, diluted with ethyl acetate (50 mL), and filtered through diatomaceous earth / silica gel. After washing with ethyl acetate (20 mL), the filtrate was washed with water and separated. The organic layers were combined, dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography (EA:PE = 10:1) to obtain t-butyl 4-(1-(2,6-dioxopiperidine-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-4-yl)-3,6-dihydropyridine-1(2H)-carboxylate (980 mg, yield 60%). LCMS (ESI) m / z: 441.2(M+H) + . 【0424】 Step 2: Preparation of t-butyl 4-(1-(2,6-dioxopiperidine-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-4-yl)piperidine-1-carboxylate: To a methanol (20 mL) solution of 4-(1-(2,6-dioxopiperidine-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-4-yl)-3,6-dihydropyridine-1(2H)-carboxylate (980 mg, 2.22 mmol), palladium (10% / carbon, 0.95 g, 0.89 mmol) was added, and the mixture was stirred at room temperature for 24 hours under a hydrogen balloon atmosphere. The reaction mixture was then filtered through diatomaceous earth and washed with a mixture of dichloromethane (20 mL x 3). The washings were combined and concentrated under reduced pressure to obtain t-butyl 4-(1-(2,6-dioxopiperidine-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-4-yl)piperidine-1-carboxylate (930 mg, yield 94%). LCMS (ESI) m / z: 443.2 (M+H)+. 【0425】 Step 3: Preparation of 3-(3-methyl-2-oxo-4-(piperidine-4-yl)-2,3-dihydro-1H-benzo[d]imidazole-1-yl)piperidine-2,6-dione hydrochloride: t-butyl 4-(1-(2,6-dioxopiperidine-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-4-yl)piperidine-1-carboxylate (930 mg, 2.09 mmol) and hydrochloric acid (4 M, 2.5 mL) were stirred overnight in ethyl acetate (10 mL). The resulting mixture was concentrated under reduced pressure. The residue was washed with ethyl acetate (5 × 20 mL) to obtain a slurry. 3-(3-methyl-2-oxo-4-(piperidine-4-yl)-2,3-dihydro-1H-benzo[d]imidazole-1-yl)piperidine-2,6-dione hydrochloride (610 mg, yield 85%) was obtained. LCMS (ESI) m / z: 343.2 (M+H)+. 【0426】 Step 4: Preparation of 3-(4-(1-((1-(5-((3-fluoro-1-(tetrahydro-2H-pyran-4-yl)-1H-indazole-5-yl)(2,2,6,6-tetramethyltetrahydro-4H-pyran-4-ylmethylene)methyl)pyridine-2-yl)piperidine-4-yl)methyl)piperidine-4-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-1-yl)piperidine-2,6-dione: To a 2 mL solution of DCE containing a stirred solution of 1-(5-((3-fluoro-1-(tetrahydro-2H-pyran-4-yl)-1H-indazole-5-yl)(2,2,6,6-tetramethyltetrahydro-4H-pyran-4-ylmethylene)methyl)pyridine-2-yl)piperidine-4-formaldehyde (100 mg, 0.2 mmol), 3-(3-methyl-2-oxo-4-(piperidine-4-yl)-2,3-dihydro-1H-benzo[d]imidazole-1-yl)piperidine-2,6-dione hydrochloride (69 mg, 0.2 mmol) was added. The mixture was treated with NaOAc (82.4 mg, 1 mmol) at room temperature for 2 hours, and then STAB (76 mg, 0.4 mmol) was added at room temperature. The resulting mixture was stirred overnight at room temperature under a nitrogen atmosphere. The reaction was quenched with water. The resulting mixture was extracted with DCM (3 × 10 mL). The organic layers were dried together over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. Purification by preparative thin-layer chromatography (PE / EA 1:1) yielded 3-(4-(1-(1-(5-((3-fluoro-1-(tetrahydro-2H-pyran-4-yl)-1H-indole-5-yl)(2,2,6,6-tetramethyltetrahydro-4H-pyran-4-ylmethylene)methyl)pyridine-2-yl)piperidine-4-yl)methyl)piperidine-4-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-1-yl)piperidine-2,6-dione (108 mg, 61%) as a yellow oil. LCMS (ESI) m / z: 887.5 (M+H) + . 【0427】 Step 5: Preparation of 3-(4-((1-(5-((3-fluoro-1H-indole-5-yl)(2,2,6,6-tetramethyltetrahydro-4H-pyran-4-ylmethylene)methyl)pyridine-2-yl)piperidine-4-yl)methyl)piperidine-4-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-1-yl)piperidine-2,6-dione (compound 99): 3-(4-(1-(1-(5-((3-fluoro-1-(tetrahydro-2H-pyran-4-yl)-1H-indazole-5-yl)(2,2,6,6-tetramethyltetrahydro-4H-pyran-4-ylmethylene)methyl)pyridine-2-yl)piperidine-4-yl)methyl)piperidine-4-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-1-yl)piperidine-2,6-dione (108 mg, 0.12 mmol), DCM (8 mL), and TFA (2 mL) were added to a 50 mL round-bottom flask. The resulting mixture was stirred overnight at room temperature under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure, and the resulting crude product was subjected to Prep-HPLC under the following conditions: (Column: Xselect CSH C18 OBD column 30*150mm 5μm, n; Mobile phase A: Water (0.05% TFA), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 16% B~36% B for 7 minutes, 36% B; wavelength: 254 nm; RT1 (min): 5.68; number of operations: 0) was purified to obtain 3-(4-(1-((1-(5-((3-fluoro-1H-indole-5-yl)(2,2,6,6-tetramethyltetrahydro-4H-pyran-4-ylmethylene)methyl)pyridine-2-yl)piperidine-4-yl)methyl)piperidine-4-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-1-yl)piperidine-2,6-dione (compound 99) (44 mg, 27%) as a white solid. LCMS (ESI) m / z: 803.3(M+H)+; 1H NMR (400 MHz, DMSO-d6) δ (ppm): 12.52(s, 1H), 10.96(s, 1H), 9.46(s, 1H), 7.98-7.58(m, 3H), 7.50-7.44 (m, 2H),7.26-7.16 (m, 3H), 7.03-6.99 (d, J = 6.8 Hz, 1H), 5.10-5.05 (m, 1H), 4.39-4.34 (d, J = 17.2 Hz, 2H), 4.28-4.24(m, 1H), 4.034-4.00 (d, J = 10.0 Hz, 3H), 3.86 (s, 3H),3.65-3.63 (d, J = 8.4 Hz, 2H), 3.24-3.12 (m, 5H), 2.95-2.88 (m, 3H), 2.68-2.62(m, 2H), 2.41-2.34 (m, 1H), 2.25(s, 2H), 2.16 (s, 2H), 1.96-1.94(m, 1H), 1.86-1.83(d, J = 12.3 Hz, 2H), 1.22-1.10(m, 12H). 【0428】 Example 14: Preparation of 3-(4-(3-((1-(5-((3-fluoro-1H-indole-5-yl)(2,2,6,6-tetramethyltetrahydro-4H-pyran-4-ylmethylene)methyl)pyridine-2-yl)piperidine-4-yl)oxy)prop-1-in-1-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-1-yl)piperidine-2,6-dione (compound 100): 【0429】 [ka] 【0430】 Step 1: Preparation of 3-fluoro-5-((6-(4-(prop-2-in-1-yloxy)piperidine-1-yl)pyridine-3-yl)(2,2,6,6-tetramethyltetrahydro-4H-pyran-4-ylmethylene)methyl)-1-(tetrahydro-2H-pyran-4-yl)-1H-indazole: At room temperature under a nitrogen atmosphere, 4-(prop-2-in-1-yloxy)piperidine (780 mg, 5.60 mmol) and 3-fluoro-5-((6-fluoropyridine-3-yl)(2,2,6,6-tetramethyltetrahydro-4H-pyran-4-ylmethylene)methyl)-1-(tetrahydro-2H-pyran-4-yl)-1H-indazole (1.19 g, 2.55 mmol) were stirred in DMSO, to which DIEA (1.65 g, 12.74 mmol) was added dropwise. The resulting mixture was stirred overnight at 120°C under a nitrogen atmosphere. The reaction was quenched with water at room temperature. The resulting mixture was extracted with ELISA (3 × 50 mL). The combined organic layers were washed with water (4 × 5 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. After purifying the residue by silica gel column chromatography, elution with PE / EA (1:1) yielded 3-fluoro-5-((6-(4-(prop-2-in-1-yloxy)piperidine-1-yl)pyridine-3-yl}(2,2,6,6-tetramethyltetrahydro-4H-pyran-4-ylmethylene)methyl)-1-(tetrahydro-2H-pyran-4-yl)-1H-indazole (400 mg, 26.76%) as a yellow oily liquid. LCMS (ESI) m / z: 587.3(M+H) + . 【0431】 Step 2: Preparation of 3-(4-(3-(1-(5-(3-fluoro-1-(tetrahydro-2H-pyran-4-yl)-1H-indazole-5-yl)(2,2,6,6-tetramethyltetrahydro-4H-pyran-4-ylmethylene)methyl)pyridine-2-yl)piperidine-4-yl)oxy)prop-1-in-1-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-1-yl)piperidine-2,6-dione: 1,4-dioxane (4 mL) was mixed with 3-(4-bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-1-yl)piperidine-2,6-dione (150 mg, 0.44 mmol), 3-fluoro-5-((6-(4-(prop-2-in-1-yloxy)piperidine-1-yl)pyridine-3-yl)(2,2,6,6-tetramethyltetrahydro-4H-pyran-4-ylmethylene)methyl)-1-(tetrahydro-2H-pyran-4-yl)-1H-indazole (390 mg, 0.67 mmol), Pd(PPh3)4 (103 mg, 0.09 mmol), and 2-methylpropan-2-amine (97 mg, 1.33 mmol). The mixture was stirred overnight at 80°C under a nitrogen atmosphere. The reaction was quenched with water at room temperature. The resulting mixture was extracted with ethyl acetate (3 × 20 mL). The organic layers were combined and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative thin-layer chromatography (DCM / MeOH 10:1) to obtain 3-(4-(3-((1-(5-((3-fluoro-1-(tetrahydro-2H-pyran-4-yl)-1H-indazole-5-yl)(2,2,6,6-tetramethyltetrahydro-4H-ylmethylene)methyl)pyridine-2-yl)piperidine-4-yl)oxy)prop-1-in-1-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-1-yl)piperidine-2,6-dione (150 mg, 40.07%) as a yellow oily liquid. LCMS (ESI) m / z: 844.4 (M+H) + . 【0432】 Step 3: Preparation of 3-(4-(3-(1-(5-((3-fluoro-1H-indole-5-yl)(2,2,6,6-tetramethyltetrahydro-4H-pyran-4-ylmethylene)methyl)pyridine-2-yl)piperidine-4-yl)oxy)prop-1-in-1-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-1-yl)piperidine-2,6-dione (compound 100): To a solution of 3-(4-(3-(1-(5-(3-fluoro-1-(tetrahydro-2H-pyran-4-yl)-1H-indazole-5-yl)(2,2,6,6-tetramethyltetrahydro-4H-pyran-4-ylmethylene)methyl)pyridine-2-yl)piperidine-4-yl)oxy)prop-1-in-1-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-1-yl)piperidine-2,6-dione (150 mg, 0.18 mmol) in DCM (6 mL), TFA (1.5 mL) was added and stirred overnight at room temperature under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The crude product was prepared by Prep-HPLC under the following conditions: (Column: XselectCSH Prep Fluoro-Phenyl OBD C18 column, 30*150mm, 5μm; Mobile phase A: Water (0.05% TFA), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 28% B~43% B) The solution was purified for 8 minutes (wavelength: 254 nm / 220 nm; RT1 (min): 6.68) to obtain 3-(4-(3-((1-(5-((3-fluoro-1H-indole-5-yl)(2,2,6,6-tetramethyltetrahydro-4H-pyran-4-ylmethylene)methyl)pyridine-2-yl)piperidine-4-yl)oxy)prop-1-in-1-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-1-yl)piperidine-2,6-dione (compound 100) (52.7 mg, 37.97%) as a white solid. LCMS (ESI) m / z: 760.3 (M+H) + ; 1H NMR (400 MHz, DMSO-d6) δ 12.57 (s, 1H), 11.14 (s, 1H), 7.90 (d, J = 2.0 Hz, 1H), 7.60 - 7.55 (m, 2H), 7.46 - 7.43 (m, 1H), 7.26 - 7.24 (m, 1H), 7.19 - 7.11 (m, 3H), 7.05 - 7.01 (m, 1H), 5.43-5.38 (m, 1H), 4.54 (s, 2H), 3.90-3.84 (m, 3H), 3.65 (s, 3H), 3.37 - 3.35 (m, 2H), 2.95 - 2.82 (m, 1H), 2.73 - 2.60 (m, 2H), 2.23 - 2.15 (d, J = 32.4 Hz, 4H), 2.04 - 2.01 (m, 3H), 1.59 - 1.57 (s, 2H), 1.18 - 1.13 (d, J = 22.4 Hz, 12H). 【0433】 Following the synthesis route of compound 100, the following compounds were synthesized using the following starting compounds or intermediates (the synthesis steps refer to Example 14 above, but the molar mass of each starting compound and intermediate was controlled to be constant). 【0434】 JPEG2026519066000143.jpg49155 【0435】 Example 15: (R)-3-(5-(4-((1-(5-((3-fluoro-1H-indole-5-yl)(2,2,6,6-tetramethyltetrahydro-4H-pyran-4-ylmethylene)methyl)pyridine-2-yl)-4-hydroxypiperidine-4-yl)methyl)piperazine-1-yl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione (Compound 132) Preparation of (S)-3-(5-(4-((1-(5-((3-fluoro-1H-indole-5-yl)(2,2,6,6-tetramethyltetrahydro-4H-pyran-4-ylmethylene)methyl)pyridine-2-yl)-4-hydroxypiperidine-4-yl)methyl)piperazine-1-yl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione (compound 133) 【0436】 [ka] 【0437】 Step 1: 3-(5-(4-((1-(5-((3-fluoro-1H-indole-5-yl)(2,2,6,6-tetramethyltetrahydro-4H-pyran-4-ylmethylene)methyl)pyridine-2-yl)-4-hydroxypiperidine-4-yl)methyl)piperazine-1-yl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione (compound 36) (50 mg) CHIRAL-HPLC: Column: JW-CHIRAL ART Cellulose-SB, 4.6*100 mm; 3 μm; Mobile phase A: Hex (0.1 A): (IPA:DCM = 1:2) = 50:50; Flow rate: 1 mL / min; Gradient: 0% B ~ 0% B; Injection volume: 5 ul M, (S)-3-(5-(4-((1-(5-((3-fluoro-1H-indole-5-yl)(2,2,6,6-tetramethyltetrahydro-4H-pyran-4-ylmethylene)methyl)pyridine-2-yl)-4-hydroxypiperidine-4-yl)methyl)piperazine-1-yl)-1-oxoisoindorin-2-yl)piperidine-2,6-dione (compound 133) (6.0 mg) is used to prepare it as a white solid. LCMS (ES, m / z): 774.9 [M + H] + Chiral high-performance liquid chromatography: Rt = 3.423; and used to prepare (R)-3-(5-(4-((1-(5-((3-fluoro-1H-indole-5-yl)(2,2,6,6-tetramethyltetrahydro-4H-pyran-4-ylmethylene)methyl)pyridine-2-yl)-4-hydroxypiperidine-4-yl)methyl)piperazine-1-yl)-1-oxoisoindoline-2-yl)piperidine-2,6-dione (compound 132) (5.6 mg) as a white solid. LCMS (ES, m / z): 774.9 [M + H] + Chiral high-performance liquid chromatography: Rt = 4.619. 【0438】 Example 16: Synthesis of 3-(5-(4-((1-(5-((3-fluoro-1H-indole-5-yl)(2,2,6,6-tetramethyltetrahydro-4H-pyran-4-ylmethylene)methyl)pyridine-2-yl)piperidine-4-yl)methyl)piperazine-1-yl)-(2-fluoro-N-(2,6-dioxo-dihydropyrimidine-2,4(1H,3H))-benzamide (compound 122): 【0439】 [ka] 【0440】 Step 1: Preparation of 3-(5-(4-((1-(5-((3-fluoro-1-(tetrahydro-2H-pyran-4-yl)-1H-indole-5-yl](2,2,6,6-tetramethyltetrahydro-4H-pyran-4-ylmethylene)methyl)pyridine-2-yl)piperidine-4-yl)methyl)piperazine-1-yl)-(2-fluoro-N-(2,6-dioxo-dihydropyrimidine-2,4(1H,3H))-benzamide: A stirred solution of 1-(5-((3-fluoro-1-(tetrahydro-2H-pyran-4-yl)-1H-indazole-5-yl)(2,2,6,6-tetramethyltetrahydro-4H-pyran-4-ylmethylene)methyl)pyridine-2-yl)piperidine-4-formaldehyde (100 mg, 0.2 mmol) was added to a solution of 2-(2,6-dioxopiperidine-3-yl)-2-fluoro-4-(piperazine-1-yl)benzamide hydrochloride (70 mg, 0.2 mmol), and STAB (76 mg, 0.4 mmol) was added at room temperature. The resulting mixture was stirred overnight at room temperature under a nitrogen atmosphere. The reaction was quenched with water. The resulting mixture was extracted with DCM (3 × 10 mL). The organic layers were dried together over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. Purified by preparative thin-layer chromatography (PE / EA 1:1), 3-(5-(4-((1-(5-((3-fluoro-1-(tetrahydro-2H-pyran-4-yl)-1H-indole-5-yl](2,2,6,6-tetramethyltetrahydro-4H-pyran-4-ylmethylene)methyl)pyridine-2-yl)piperidine-4-yl)methyl)piperazine-1-yl)-(2-fluoro-N-(2,6-dioxo-dihydropyrimidine-2,4(1H,3H))-benzamide (100 mg, 64.22%) was obtained as a yellow oil. LCMS (ES, m / z): 879 [M + H] + . 【0441】 Step 2: Preparation of 3-(5-(4-((1-(5-((3-fluoro-1H-indole-5-yl)(2,2,6,6-tetramethyltetrahydro-4H-pyran-4-ylmethylene)methyl)pyridine-2-yl)piperidine-4-yl)methyl)piperazine-1-yl)- (2-fluoro-N-(2,6-dioxo-dihydropyrimidine-2,4(1H,3H))-benzamide (compound 122): 3-(5-(4-((1-(5-((3-fluoro-1-(tetrahydro-2H-pyran-4-yl)-1H-indole-5-yl](2,2,6,6-tetramethyltetrahydro-4H-pyran-4-ylmethylene)methyl)pyridine-2-yl)piperidine-4-yl)methyl)piperazine-1-yl)-(2-fluoro-N-(2,6-dioxo-dihydropyrimidine-2,4(1H,3H))-benzamide (120 mg, 0.14 mmol), DCM (8 mL), and TFA (2 mL) were added to a 50 mL round-bottom flask. The resulting mixture was stirred overnight at room temperature under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The crude product was analyzed by Prep-HPLC under the following conditions (column: Xselect CSH C18 OBD column 30*150 mm 5 μm, n; mobile phase). A: Water (0.05% TFA), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 16% B to 36% B for 7 minutes, 36% B; wavelength: 254 nm; RT1 (min): 5.68; number of operations: 0) was purified to obtain 3-(5-(4-((1-(5-((3-fluoro-1-(tetrahydro-2H-pyran-4-yl)-1H-indole-5-yl](2,2,6,6-tetramethyltetrahydro-4H-pyran-4-ylmethylene)methyl)pyridine-2-yl)piperidine-4-yl)methyl)piperazine-1-yl)-(2-fluoro-N-(2,6-dioxo-dihydropyrimidine-2,4(1H,3H))-benzamide (74.1 mg, 67.79%) as a white solid. LCMS (ES, m / z): 789 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ (ppm): 12.58 (s, 1H), 10.99 (s, 1H), 9.49 (s, 1H), 7.97-7.96 (d, J = 2.4 Hz, 1H), 7.61-7.60 (d, J = 8.4 Hz, 1H), 7.53-7.44 (m, 3H),7.26-7.16 (m, 3H), 7.00-6.99 (d, J = 6.8 Hz, 1H), 5.10-5.05 (m, 1H), 4.39-4.34 (d, J = 17.2 Hz, 2H), 4.28-4.22 (m, 3H), 4.03-4.00 (d, J = 10.0 Hz, 3H), 3.65-3.63 (d, J = 8.4 Hz, 2H), 3.24-3.12 (m, 5H), 2.95-2.88 (m, 3H), 2.62-2.58 (d, J = 16.4 Hz, 1H), 2.41-2.34 (m, 1H), 2.24 (s, 2H), 2.16 (s, 2H), 1.97-1.93 (m, 1H), 1.86-1.84 (d, J = 12.3 Hz, 2H), 1.23-1.13 (m, 12H). 【0442】 Following the synthesis route of compound 122, the following compounds were synthesized using the following starting compounds or intermediates (the synthesis steps refer to Example 16 above, but the molar mass of each starting compound and intermediate was controlled to be constant). 【0443】 JPEG2026519066000146.jpg154155 【0444】 The compounds of this application and their associated NMR data are shown in the table below. 【0445】 JPEG2026519066000147.jpg240160 【0446】 JPEG2026519066000148.jpg202161 【0447】 JPEG2026519066000149.jpg222160 【0448】 JPEG2026519066000150.jpg216160 【0449】 JPEG2026519066000151.jpg220160 【0450】 JPEG2026519066000152.jpg124161 【0451】 JPEG2026519066000153.jpg167160 【0452】 JPEG2026519066000154.jpg192160 【0453】 JPEG2026519066000155.jpg220160 【0454】 JPEG2026519066000156.jpg240159 【0455】 JPEG2026519066000157.jpg243160 【0456】 JPEG2026519066000158.jpg244160 【0457】 JPEG2026519066000159.jpg135160 【0458】 JPEG2026519066000160.jpg216160 【0459】 JPEG2026519066000161.jpg144161 【0460】 JPEG2026519066000162.jpg244160 【0461】 JPEG2026519066000163.jpg244160 【0462】 JPEG2026519066000164.jpg134159 【0463】 JPEG2026519066000165.jpg120161 【0464】 JPEG2026519066000166.jpg245160 【0465】 JPEG2026519066000167.jpg134161 【0466】 JPEG2026519066000168.jpg241161 【0467】 JPEG2026519066000169.jpg216160 【0468】 JPEG2026519066000170.jpg125161 【0469】 JPEG2026519066000171.jpg129160 【0470】 JPEG2026519066000172.jpg124161 【0471】 JPEG2026519066000173.jpg130160 【0472】 JPEG2026519066000174.jpg235160 【0473】 JPEG2026519066000175.jpg231160 【0474】 JPEG2026519066000176.jpg225160 【0475】 JPEG2026519066000177.jpg240160 【0476】 JPEG2026519066000178.jpg241160 【0477】 JPEG2026519066000179.jpg130160 【0478】 JPEG2026519066000180.jpg178161 【0479】 JPEG2026519066000181.jpg144161 【0480】 JPEG2026519066000182.jpg244160 【0481】 JPEG2026519066000183.jpg138159 【0482】 JPEG2026519066000184.jpg163160 【0483】 JPEG2026519066000185.jpg167161 【0484】 JPEG2026519066000186.jpg235159 【0485】 JPEG2026519066000187.jpg225160 【0486】 JPEG2026519066000188.jpg134161 【0487】 JPEG2026519066000189.jpg246161 【0488】 JPEG2026519066000190.jpg155162 【0489】 JPEG2026519066000191.jpg240161 【0490】 JPEG2026519066000192.jpg193161 【0491】 JPEG2026519066000193.jpg202161 【0492】 JPEG2026519066000194.jpg211161 【0493】 JPEG2026519066000195.jpg198161 【0494】 JPEG2026519066000196.jpg201161 【0495】 JPEG2026519066000197.jpg202160 【0496】 JPEG2026519066000198.jpg207161 【0497】 JPEG2026519066000199.jpg246161 【0498】 JPEG2026519066000200.jpg221160 【0499】 JPEG2026519066000201.jpg226160 【0500】 JPEG2026519066000202.jpg221161 【0501】 JPEG2026519066000203.jpg154161 【0502】 JPEG2026519066000204.jpg196161 【0503】 JPEG2026519066000205.jpg188161 【0504】 JPEG2026519066000206.jpg192160 【0505】 JPEG2026519066000207.jpg208161 【0506】 JPEG2026519066000208.jpg129160 【0507】 JPEG2026519066000209.jpg134160 【0508】 JPEG2026519066000210.jpg245161 【0509】 JPEG2026519066000211.jpg134160 【0510】 JPEG2026519066000212.jpg145161 【0511】 JPEG2026519066000213.jpg231157 【0512】 JPEG2026519066000214.jpg130155 【0513】 JPEG2026519066000215.jpg240160 【0514】 JPEG2026519066000216.jpg224160 【0515】 JPEG2026519066000217.jpg234160 【0516】 JPEG2026519066000218.jpg134160 【0517】 JPEG2026519066000219.jpg222160 【0518】 JPEG2026519066000220.jpg201162 【0519】 JPEG2026519066000221.jpg199154 【0520】 JPEG2026519066000222.jpg229168 【0521】 JPEG2026519066000223.jpg243164 【0522】 JPEG2026519066000224.jpg119160 【0523】 JPEG2026519066000225.jpg134161 【0524】 JPEG2026519066000226.jpg241161 【0525】 JPEG2026519066000227.jpg221160 【0526】 JPEG2026519066000228.jpg229159 【0527】 JPEG2026519066000229.jpg233159 【0528】 JPEG2026519066000230.jpg221160 【0529】 JPEG2026519066000231.jpg111161 【0530】 Biological evaluation: The present invention will be further described below with reference to test examples, but the tests in these embodiments are not intended to limit the scope of the present invention. 【0531】 Test Example 1: Degradation activity of the compounds disclosed herein against ERα in MCF7 cells ERα-positive human breast cancer cells MCF-7 (ATCC, HTB-22) were placed in a 25cm cavity. 2 or 75cm 2The cells were subcultured in plastic tissue culture flasks two to three times a week at 37°C, 95% air, and 5% CO2 using EMEM medium (ATCC, catalog number: 30-2003) containing 10% fetal bovine serum (Thermo Fisher Scientific, catalog no.: 10099141) and 10 μg / mL bovine insulin. Place cells in a 6-well cell culture plate at a rate of 1 × 10⁶ 6 Cells were inoculated at a density of 1.8 mL / well and cultured at 37°C, 95% air, and 5% CO2. After 24 hours, the test compound was added. The compound was serially diluted 10-fold with DMSO, starting from 10 mM (dissolved in DMSO), to prepare gradient stock solutions. Complete medium containing 1% DMSO was prepared and the solution was further diluted, and this was temporarily labeled as dilution buffer. Working solutions were prepared by diluting each stock solution 99 times by volume with dilution buffer; that is, 1 μL of 10 mM stock solution was added to 99 μL of dilution buffer and mixed uniformly, and finally, 10 μL of the working solution was added to the culture plate inoculated with cells. The final concentration of DMSO in the cell culture medium was 0.2%, and the final concentration of the test compound was 1 nM to 100 nM. The above cells were incubated at 37°C for 6 hours. The culture medium was aspirated and discarded, the cells were washed twice with pre-cooled PBS, 1 mL of PBS was added to each well, the cells were collected in an EP tube using a cell scraper, centrifuged at 4°C and 4000 rpm for 5 minutes, and the PBS was aspirated and discarded. TMTotal protein was extracted using animal cell / tissue total protein extraction reagent, and protein concentration was detected using the BCA method. 30 μg of protein was collected, mixed with 5× SDS-PAGE loading buffer, boiled for 10 minutes, cooled, and added to a precast gel comb well. The system was run at a constant voltage of 80 V for 30 minutes, and after the sample entered the separation gel, the voltage was increased to 120 V. A "sandwich" for Bio-Rad's Transblot was assembled: sponge-filter paper-gel-membrane-filter paper-sponge. Transfer was performed at 0.3 amp for 1 hour at 4°C. After blocking at room temperature for 1 hour with 5% skim milk powder, the sample was gently shaken overnight at 4°C with estrogen receptor α antibody (Thermo Fisher Scientific, catalog number: MA5-14104). Antibodies nonspecifically bound to the membrane were removed using TBST, goat anti-mouse IgG-HRP secondary antibody was added, and after incubation at room temperature for 1 hour, ECL color development was performed. Protein degradation levels were calculated using a grayscale. Figure 1A shows the ERα degradation activity 6 hours after administration of exemplary compounds 1, 2, 5, 6, 7, and 13 of this disclosure to an MCF-7 cell line. Figure 1B shows the ERα degradation activity 6 hours after administration of exemplary compounds 27, 30, 31, 34, 35, and 37 of this disclosure to an MCF-7 cell line. Figure 1C shows the ERα degradation activity 6 hours after administration of exemplary compounds 44, 46, 47, 48, 57, and 59 of this disclosure to an MCF-7 cell line. Figure 1D shows the ERα degradation activity 6 hours after administration of exemplary compounds 61, 66, 76, 88, 89, and 90 of this disclosure to an MCF-7 cell line. Figure 1E shows the ERα degradation activity 6 hours after administration of exemplary compounds 103, 104, 110, 119, 120, and 121 of this disclosure to an MCF-7 cell line. For the various compounds disclosed herein, the DC50 value (i.e., the concentration of the test compound that causes 50% degradation of the target protein) was calculated and is shown in Table 1 below. A corresponds to a DC50 value less than 10 nM. B corresponds to a DC50 value greater than 10 nM and less than 100 nM. C corresponds to a DC50 value greater than 100 nM. 【0532】 [Table 1] 【0533】 Test Example 2: Time-dependent activity of the compounds disclosed herein against ERα degradation in MCF7 cells ERα-positive human breast cancer cells MCF-7 (ATCC, HTB-22) were placed in a 25cm cavity. 2 or 75cm 2 The cells were subcultured in plastic tissue culture flasks two to three times a week at 37°C, 95% air, and 5% CO2 using EMEM medium (ATCC, catalog number: 30-2003) containing 10% fetal bovine serum (Thermo Fisher Scientific, catalog no.: 10099141) and 10 μg / mL bovine insulin. Place cells in a 6-well cell culture plate at a rate of 1 × 10⁶ 6 Cells were inoculated at a density of 1.8 mL / well and cultured at 37°C, 95% air, and 5% CO2. After 24 hours, the test compound was added. The compound was serially diluted 10-fold with DMSO, starting from 10 mM (dissolved in DMSO), to prepare gradient stock solutions. Complete medium containing 1% DMSO was prepared and the solution was further diluted and temporarily labeled with dilution buffer. Working solutions were prepared by diluting each stock solution 99 times by volume with dilution buffer; i.e., 1 μL of 10 μM stock solution was added to 99 μL of dilution buffer and mixed uniformly, and finally, 10 μL of the working solution was added to the culture plate inoculated with cells. The final concentration of DMSO in the cell culture medium was 0.2%, and the final concentration of the test compound was 10 nM. The above cells were incubated at 37°C for 0.5, 1, 2, 4, 6, and 24 hours. The culture medium was aspirated and discarded, the cells were washed once with pre-cooled PBS, 1 mL of PBS was added to each well, the cells were collected in an EP tube using a cell scraper, centrifuged at 4°C and 4000 rpm for 5 minutes, and the PBS was aspirated and discarded. TMTotal protein was extracted using animal cell / tissue total protein extraction reagent, and protein concentration was detected using the BCA method. 30 μg of protein was collected, mixed with 5× SDS-PAGE loading buffer, boiled for 10 minutes, cooled, and added to a precast gel comb well. The system was run at a constant voltage of 80 V for 30 minutes, and after the sample entered the separation gel, the voltage was increased to 120 V. A "sandwich" for Bio-Rad's Transblot was assembled: sponge-filter paper-gel-membrane-filter paper-sponge. Transfer was performed at 0.3 amp for 1 hour at 4°C. After blocking at room temperature for 1 hour with 5% skim milk powder, the sample was gently shaken overnight at 4°C with estrogen receptor α antibody (Thermo Fisher Scientific, catalog number: MA5-14104). Antibodies nonspecifically bound to the membrane were removed using TBST, goat anti-mouse IgG-HRP secondary antibody was added, and after incubation at room temperature for 1 hour, ECL color development was performed. Protein degradation levels were calculated using a grayscale. Figures 2A to 2D show the time-dependent activity of ERα degradation in the MCF-7 cell line after administration of 10 nM of exemplary compounds 5, 31, 47, and 48 of this disclosure. 【0534】 Test Example 3: Inhibitory effect of the compound of the present invention on the proliferation of MCF-7 cells Human breast cancer cells MCF-7 (ATCC, HTB-22) were subjected to a 25cm experiment. 2 or 75cm 2 The cells were subcultured in plastic tissue culture flasks two to three times a week at 37°C, 95% air, and 5% CO2 using EMEM medium (ATCC, catalog number: 30-2003) containing 10% fetal bovine serum (Thermo Fisher Scientific, catalog no.: 10099141) and 10 μg / mL bovine insulin. Place 3 × 10 cells into a 96-well cell culture plate. 3Cells were inoculated at a density of 90 μL / well and cultured at 37°C, 95% air, and 5% CO2. After 24 hours, the test compound was added. The compound was serially diluted 10-fold with DMSO, starting from 10 mM (dissolved in DMSO), to prepare gradient stock solutions. Complete medium containing 1% DMSO was prepared and further diluted, and this was temporarily labeled with dilution buffer. Working solutions were prepared by diluting each stock solution 99 times by volume with dilution buffer; i.e., 1 μL of 10 mM stock solution was added to 99 μL of dilution buffer and mixed uniformly, and finally, 10 μL of the working solution was added to the culture plate inoculated with cells. The final concentration of DMSO in the cell culture medium was 0.2%, and the final concentration of the test compound was 1 pM to 10 μM. The above cells were incubated at 37°C for 3 days. The medium was aspirated and discarded, replaced with 90 μL / well of fresh complete medium, and the test compound was added again according to the compound dilution method described above. On day 6, the CellTiter-Glo luminescent cell viability assay kit (Promega, catalog number: G7573) was added, and cell viability was measured. Cell viability was measured using the CellTiter-Glu kit, and finally, the semi-inhibitory concentration of the compound against cell proliferation, i.e., GI50, was calculated using the Prism program. Figure 3A shows the inhibitory effect on MCF-7 cell proliferation 6 days after administration of exemplary compounds 2, 5, 6, 22, 31, and 34 of this disclosure. Figure 3B shows the inhibitory effect on MCF-7 cell proliferation 6 days after administration of exemplary compounds 35, 37, 44, 46, 47, and 48 of this disclosure. Figure 3C shows the inhibitory effect on MCF-7 cell proliferation 6 days after administration of exemplary compounds 88, 110, 119, 120, and 121 of this disclosure. For the various compounds disclosed herein, the GI50 value (i.e., the concentration of the test compound that inhibits cell proliferation by 50%) was calculated and is shown in Table 2 below. A corresponds to a GI50 value less than 10 nM. B corresponds to a GI50 value greater than 10 nM but less than 100 nM. C corresponds to a GI50 value greater than 100 nM. 【0535】 [Table 2] 【0536】 Test Example 4: Degradation activity of the compounds disclosed herein against ERα in T-47D cells ERα-positive human breast cancer cells T-47D (ATCC, HTB-133) were placed in a 25cm cavity. 2 or 75cm 2 The cells were subcultured in plastic tissue culture flasks two to three times a week at 37°C, 95% air, and 5% CO2 using RPMI 1640 medium (Thermo Fisher Scientific, catalog number: 61870-036) containing 10% fetal bovine serum (Thermo Fisher Scientific, catalog number: 10099141) and 10 μg / mL bovine insulin. Place cells in a 6-well cell culture plate at a rate of 1 × 10⁶ 6 Cells were inoculated at a density of 1.8 mL / well and cultured at 37°C, 95% air, and 5% CO2. After 24 hours, the test compound was added. The compound was serially diluted three-fold with DMSO from 10 mM (dissolved in DMSO) to prepare gradient stock solutions. Complete medium containing 1% DMSO was prepared and the solution was further diluted, and this was temporarily labeled as dilution buffer. Working solutions were prepared by diluting each stock solution 99 times by volume with dilution buffer; that is, 1 μL of the 10 mM stock solution was added to 99 μL of dilution buffer and mixed uniformly, and finally, 10 μL of the working solution was added to the culture plate inoculated with cells. The final concentration of DMSO in the cell culture medium was 0.2%, and the final concentration of the test compound was 0.1 nM to 1000 nM. The above cells were incubated at 37°C for 4 hours. The culture medium was aspirated and discarded, the cells were washed twice with pre-cooled PBS, 1 mL of PBS was added to each well, the cells were collected in an EP tube using a cell scraper, centrifuged at 4°C and 4000 rpm for 5 minutes, and the PBS was aspirated and discarded. TMTotal protein was extracted using animal cell / tissue total protein extraction reagent, and protein concentration was detected using the BCA method. 30 μg of protein was collected, mixed with 5× SDS-PAGE loading buffer, boiled for 10 minutes, cooled, and added to a precast gel comb well. The system was run at a constant voltage of 80 V for 30 minutes, and after the sample entered the separation gel, the voltage was increased to 120 V. A "sandwich" for Bio-Rad's Transblot was assembled: sponge-filter paper-gel-membrane-filter paper-sponge. Transfer was performed at 0.3 amp for 1 hour at 4°C. After blocking at room temperature for 1 hour with 5% skim milk powder, the sample was gently shaken overnight at 4°C with estrogen receptor α antibody (Thermo Fisher Scientific, catalog number: MA5-14104). Antibodies nonspecifically bound to the membrane were removed using TBST, goat anti-mouse IgG-HRP secondary antibody was added, and after incubation at room temperature for 1 hour, ECL color development was performed. Protein degradation levels were calculated using a grayscale. Figure 4A shows the ERα degradation activity 4 hours after administration of exemplary compound 34 of the present disclosure to the T-47D cell line. Figure 4B shows the ERα degradation activity 4 hours after administration of exemplary compound 35 of the present disclosure to the T-47D cell line. 【0537】 Test Example 5: Degradation activity of the compounds disclosed against ERα in MCF-7 cells expressing the ERα Y537S mutant. MCF-7 cells expressing the ERα Y537S mutant were constructed by lentiviral infection. MCF-7 / ERα Y537S cells were placed in a 6-well cell culture plate at a rate of 1 × 10⁶ 6Cells were inoculated at a density of 1.8 mL / well and cultured at 37°C, 95% air, and 5% CO2. After 24 hours, the test compound was added. The compound was serially diluted three-fold with DMSO starting from 10 mM (dissolved in DMSO) to prepare gradient stock solutions. Complete medium containing 1% DMSO was prepared and the solution was further diluted, and this was temporarily labeled as dilution buffer. Working solutions were prepared by diluting each stock solution 99 times by volume with dilution buffer; that is, 1 μL of the 10 mM stock solution was added to 99 μL of dilution buffer and mixed uniformly, and finally, 10 μL of the working solution was added to the culture plate inoculated with cells. The final concentration of DMSO in the cell culture medium was 0.2%, and the final concentration of the test compound was 0.1 nM to 1000 nM. The above cells were incubated at 37°C for 4 hours and 6 hours, respectively. The culture medium was aspirated and discarded, the cells were washed twice with pre-cooled PBS, 1 mL of PBS was added to each well, the cells were collected in an EP tube using a cell scraper, centrifuged at 4°C and 4000 rpm for 5 minutes, and the PBS was aspirated and discarded. TM Total protein was extracted using animal cell / tissue total protein extraction reagent, and protein concentration was detected using the BCA method. 30 μg of protein was collected, mixed with 5× SDS-PAGE loading buffer, boiled for 10 minutes, cooled, and added to a precast gel comb well. The system was run at a constant voltage of 80 V for 30 minutes, and after the sample entered the separation gel, the voltage was increased to 120 V. A "sandwich" for Bio-Rad's Transblot was assembled: sponge-filter paper-gel-membrane-filter paper-sponge. Transfer was performed at 0.3 amp for 1 hour at 4°C. After blocking at room temperature for 1 hour with 5% skim milk powder, the sample was gently shaken overnight at 4°C with estrogen receptor α antibody (Thermo Fisher Scientific, catalog number: MA5-14104). Antibodies nonspecifically bound to the membrane were removed using TBST, goat anti-mouse IgG-HRP secondary antibody was added, and after incubation at room temperature for 1 hour, ECL color development was performed. Protein degradation levels were calculated using a grayscale. Figure 5A shows the ERα degradation activity of exemplary compound 34 of the present disclosure four hours after administration to the MCF-7 / ERα Y537S cell line. Figure 5B shows the ERα degradation activity of exemplary compound 35 of the present disclosure four hours after administration to the MCF-7 / ERα Y537S cell line. Figure 5C shows the ERα degradation activity of exemplary compound 110 of the present disclosure six hours after administration to the MCF-7 / ERα Y537S cell line. Figure 5D shows the ERα degradation activity of exemplary compound 120 of the present disclosure six hours after administration to the MCF-7 / ERα Y537S cell line. 【0538】 Test Example 6: ERα degradation activity of the compounds disclosed herein in MCF-7 cells expressing the ERα D538G mutant. MCF-7 cells expressing the ERα D538G mutant were constructed by lentiviral infection. MCF-7 / ERα D538G cells were placed in a 6-well cell culture plate at a rate of 1 × 10⁶ 6 Cells were inoculated at a density of 1.8 mL / well and cultured at 37°C, 95% air, and 5% CO2. After 24 hours, the test compound was added. The compound was serially diluted three-fold with DMSO from 10 mM (dissolved in DMSO) to prepare gradient stock solutions. Complete medium containing 1% DMSO was prepared and the solution was further diluted, and this was temporarily labeled as dilution buffer. Working solutions were prepared by diluting each stock solution 99 times by volume with dilution buffer; that is, 1 μL of the 10 mM stock solution was added to 99 μL of dilution buffer and mixed uniformly, and finally, 10 μL of the working solution was added to the culture plate inoculated with cells. The final concentration of DMSO in the cell culture medium was 0.2%, and the final concentration of the test compound was 0.1 nM to 1000 nM. The above cells were incubated at 37°C for 6 hours. The culture medium was aspirated and discarded, the cells were washed twice with pre-cooled PBS, 1 mL of PBS was added to each well, the cells were collected in an EP tube using a cell scraper, centrifuged at 4°C and 4000 rpm for 5 minutes, and the PBS was aspirated and discarded. TMTotal protein was extracted using animal cell / tissue total protein extraction reagent, and protein concentration was detected using the BCA method. 30 μg of protein was collected, mixed with 5× SDS-PAGE loading buffer, boiled for 10 minutes, cooled, and added to a precast gel comb well. The system was run at a constant voltage of 80 V for 30 minutes, and after the sample entered the separation gel, the voltage was increased to 120 V. A "sandwich" for Bio-Rad's Transblot was assembled: sponge-filter paper-gel-membrane-filter paper-sponge. Transfer was performed at 0.3 amp for 1 hour at 4°C. After blocking at room temperature for 1 hour with 5% skim milk powder, the sample was gently shaken overnight at 4°C with estrogen receptor α antibody (Thermo Fisher Scientific, catalog number: MA5-14104). Antibodies nonspecifically bound to the membrane were removed using TBST, goat anti-mouse IgG-HRP secondary antibody was added, and after incubation at room temperature for 1 hour, ECL color development was performed. Protein degradation levels were calculated using a grayscale. Figure 6A shows the ERα degradation activity of exemplary compound 110 of the present disclosure 6 hours after administration to the MCF-7 / ERα D538G cell line. Figure 6B shows the ERα degradation activity of exemplary compound 120 of the present disclosure 6 hours after administration to the MCF-7 / ERα D538G cell line. 【0539】 Test Example 7: Inhibitory effect of the compound of the present invention on the proliferation of MCF-7 cells expressing the ERα Y537S mutant. MCF-7 / ERα Y537S cells were placed in 3 × 10⁶ wells of a 96-well cell culture plate. 3Cells were inoculated at a density of 90 μL / well and cultured at 37°C, 95% air, and 5% CO2. After 24 hours, the test compound was added. The compound was serially diluted 10-fold with DMSO, starting from 10 mM (dissolved in DMSO), to prepare gradient stock solutions. Complete medium containing 1% DMSO was prepared and further diluted, and this was temporarily labeled with dilution buffer. Working solutions were prepared by diluting each stock solution 99 times by volume with dilution buffer; i.e., 1 μL of 10 mM stock solution was added to 99 μL of dilution buffer and mixed uniformly, and finally, 10 μL of the working solution was added to the culture plate inoculated with cells. The final concentration of DMSO in the cell culture medium was 0.2%, and the final concentration of the test compound was 1 pM to 10 μM. The above cells were incubated at 37°C for 3 days. The medium was aspirated and discarded, and replaced with 90 μL / well of fresh complete medium. The test compound was added again according to the compound dilution method described above. On day 6, the CellTiter-Glo luminescent cell viability assay kit (Promega, catalog number: G7573) was added, and cell viability was measured. Cell viability was measured using the CellTiter-Glu kit, and the half-inhibitory concentration (GI50) of the compound for cell proliferation was calculated using the Prism program. Figure 7A shows the inhibitory effect on the proliferation of MCF-7 / ERα Y537S cells 6 days after administration of exemplary compound 110 of the present disclosure. Figure 7B shows the inhibitory effect on the proliferation of MCF-7 / ERα Y537S cells 6 days after administration of exemplary compound 120 of the present disclosure. 【0540】 Test Example 8: Inhibitory activity of the compounds disclosed herein against MCF-7 xenograft tumors expressing the ERα Y537S mutant. MCF-7 / ERα Y537S tumors, which had been subcultured in mice for 3 to 10 generations, were subcutaneously inoculated into the right rib cage of female Balb / c nude mice as tumor masses of approximately 3 × 3 × 3 mm. The tumor volume of the tumor-bearing mice was approximately 200 mm². 3Upon reaching a certain stage, the mice were randomly divided into four groups of seven based on tumor volume and body weight: a solvent control group, the Example 1 mpk group, the Example 3 mpk group, and the Example 10 mpk group. The day of group division was designated D0, and the drug was administered orally once daily for 17 days. Day 17 after administration was designated D17. Tumor volume was measured twice a week using calipers, and mouse body weight was measured using an electronic balance. The longest and shortest diameters of the tumor were measured, and the volume was calculated using the following formula: Volume (TV) = 0.5 × Longest diameter × Shortest diameter 2 The T / C ratio was calculated based on tumor volume. Here, T is the mean relative tumor volume (RTV) of each treatment group, and C is the mean relative tumor volume (RTV) of the control group. RTV is the ratio of the tumor volume after administration to the tumor volume before administration. Tumor growth inhibition rate TGITV (%) = (1 - T / C) × 100%. Figure 8A shows the dose-dependent growth inhibitory ability of compound 110 against MCF-7 / ERα Y537S transplanted tumors in Balb / c nude mice. Figure 8B shows that compound 110 does not affect the body weight of mice with MCF-7 / ERα Y537S cell xenograft tumors. Figure 9A shows the dose-dependent growth inhibitory ability of compound 120 against MCF-7 / ERα Y537S transplanted tumors in Balb / c nude mice. Figure 9B shows that compound 120 does not affect the body weight of mice with MCF-7 / ERα Y537S cell xenograft tumors.

Claims

[Claim 1] A PROTAC compound that targets the estrogen receptor represented by formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, or isomer thereof. 【Chemistry 1】 (Here, 【Chemistry 2】 It is the absence of a substituent, or the absence of a substituent. 【Transformation 3】 Substitutable or unsubstituted 【Chemistry 4】 This indicates X ４ is N or CRa, and the substituents are halogen, hydroxyl group, cyano group, oxy group, benzyl group, substituted or unsubstituted amine group, substituted or unsubstituted C １ ~C ６ Alkyl, substituted, or unsubstituted C １ ~C ６ Alkoxy groups, and C １ ~C ６ Selected from acyl groups, When A is absent, R １ is selected from a halogen, a hydroxy group, a cyano group, an oxy group, a benzyl group, a substituted or unsubstituted amine group, a substituted or unsubstituted C １ to C ６ alkyl group, a substituted or unsubstituted C １ to C ６ alkoxy group, and a C １ to C ６ acyl group, and preferably, R １ is selected from -NH ２ or -OH, X １ is N or CR ３ And, X ２ or X ３ CH and CR are independent of each other. ３ Selected from , and N, R ２ , R ３ These are, independently, H, halogen, hydroxyl group, cyano group, oxy group, benzyl group, substituted or unsubstituted amine group, and substituted or unsubstituted C. １ ~C ６ Alkyl, substituted, or unsubstituted C １ ~C ６ Alkoxy groups, and C １ ~C ６ Selected from acyl groups, Ra is H, halogen, hydroxyl group, cyano group, oxy group, benzyl group, substituted or unsubstituted amine group, substituted or unsubstituted C １ ~C ６ Alkyl, substituted, or unsubstituted C １ ~C ６ Alkoxy groups, and C １ ~C ６ Selected from acyl groups, L is one of the following: 【Transformation 5】 【Transformation 6】 E3L represents a ubiquitin ligase ligand. [Claim 2] E3L is one selected from the following: the compound according to claim 1 or a pharmaceutically acceptable salt, solvate, hydrate, or isomer thereof. 【Transformation 7】 [Claim 3] The compound is represented by formula (II), the compound according to claim 1 or 2, or a pharmaceutically acceptable salt, solvate, hydrate, or isomer thereof. 【Transformation 8】 (Here, R ４ This includes halogens, hydroxyl groups, cyano groups, oxy groups, benzyl groups, substituted or unsubstituted amine groups, and substituted or unsubstituted C. １ ~C ６ Alkyl, substituted, or unsubstituted C １ ~C ６ Alkoxy groups, and C １ ~C ６ (Selected from acyl groups.) [Claim 4] R ４ The compound according to claim 3 or a pharmaceutically acceptable salt, solvate, hydrate, or isomer thereof, wherein is a halogen. [Claim 5] The compound is the compound according to claim 3, represented by formula (III), or a pharmaceutically acceptable salt, solvate, hydrate, or isomer thereof. 【Chemistry 9】 [Claim 6] The compound is the compound according to claim 5, represented by formula (IV), or a pharmaceutically acceptable salt, solvate, hydrate, or isomer thereof. 【Chemistry 10】 [Claim 7] L is one selected from the following: the compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt, solvate, hydrate, or isomer thereof. 【Chemistry 11】 [Claim 8] X ４ The compound according to claim 1 or a pharmaceutically acceptable salt, solvate, hydrate, or isomer thereof, wherein is N. [Claim 9] X ４ The compound according to claim 1 or a pharmaceutically acceptable salt, solvate, hydrate, or isomer thereof, wherein is CRa, where Ra is selected from H, halogen, and hydroxyl group. [Claim 10] The compound according to claim 9 or a pharmaceutically acceptable salt, solvate, hydrate, or isomer thereof, wherein Ra is H. [Claim 11] X １ CR ３ And R ３ H, CH ３ The compound according to claim 1, wherein the compound is O or F, or a pharmaceutically acceptable salt, solvate, hydrate, or isomer thereof. [Claim 12] R ３ The compound according to claim 11 or a pharmaceutically acceptable salt, solvate, hydrate, or isomer thereof, wherein is H. [Claim 13] X ２ The compound according to claim 1 or a pharmaceutically acceptable salt, solvate, hydrate, or isomer thereof, wherein is CH. [Claim 14] X ２ The compound according to claim 1 or a pharmaceutically acceptable salt, solvate, hydrate, or isomer thereof, wherein is N. [Claim 15] X ３ The compound according to claim 1 or a pharmaceutically acceptable salt, solvate, hydrate, or isomer thereof, wherein is CH. [Claim 16] R ２ The compound according to claim 1 or a pharmaceutically acceptable salt, solvate, hydrate, or isomer thereof, wherein is H. [Claim 17] E3L is 【Chemistry 12】 The compound according to claim 2 or a pharmaceutically acceptable salt, solvate, hydrate, or isomer thereof. [Claim 18] The compound is one selected from the following: the compound according to any one of claims 1 to 17 or a pharmaceutically acceptable salt, solvate, hydrate, or isomer thereof. 【Chemistry 13】 【Chemistry 14】 【Chemistry 15】 【Chemistry 16】 【Chemistry 17】 [Chemistry 18] 【Chemistry 19】 【Chemistry 20】 【Chemistry 21】 【Chemistry 22】 [Claim 19] A pharmaceutical composition comprising a compound, a pharmaceutically acceptable salt, a solvate, a hydrate, or an isomer described in any one of claims 1 to 18, and a pharmaceutically acceptable carrier. [Claim 20] Use of a compound according to any one of claims 1 to 18 or a pharmaceutically acceptable salt, solvate, hydrate, or isomer thereof, or the pharmaceutical composition according to claim 19, in the treatment of a disorder treated by the degradation of a target protein bound to a target ligand. [Claim 21] The use according to claim 20, wherein the disorder is selected from cell proliferation, cancer, immune disorders, diabetes, cardiovascular diseases, infections, and inflammatory diseases. [Claim 22] The aforementioned cancers include breast cancer, endometrial cancer, uterine cancer, testicular cancer, cervical cancer, prostate cancer, ovarian cancer, endometriosis, fallopian tube tumors, ovarian tumors, leukemia, skin cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, renal cell carcinoma, bladder cancer, intestinal cancer, colon cancer, esophageal cancer, head cancer, kidney cancer, liver cancer, lung cancer, cervical cancer, pancreatic cancer, stomach cancer, lymphoma, non-Hodgkin lymphoma, malignant melanoma, myeloproliferative disorders, sarcoma, angiosarcoma, peripheral neuroepithelial tumors, and nephroma. The use according to claim 21, selected from transglioma, astrocytoma, oligodendroglioma, ependymoma, glioblastoma, neuroblastoma, ganglioma, ganglioma, medulloblastoma, pineal cell tumor, meningioma, meningiosarcoma, neurofibroma, schwannoma, thyroid cancer, Hodgkin's tumor, Wilms' tumor, and teratoma, more preferably selected from breast cancer, endometrial cancer, uterine cancer, testicular cancer, cervical cancer, prostate cancer, ovarian cancer, fallopian tube tumor, and ovarian tumor. [Claim 23] The use according to claim 22, wherein the cancer is selected from breast cancer, endometrial cancer, ovarian cancer, cervical cancer, prostate cancer, or endometriosis. [Claim 24] The use according to claim 21, wherein the infectious disease is selected from viral pneumonia, avian influenza, meningitis, gonorrhea, or diseases caused by infection with HIV, HBV, HCV, HSV, HPV, RSV, CMV, Ebola virus, flavivirus, Blotchi virus, rotavirus, influenza, coronavirus, EBV, drug-resistant virus, RNA virus, DNA virus, adenovirus, poxvirus, picornavirus, togavirus, orthomyxovirus, retrovirus, hepadnavirus, gram-negative bacteria, gram-positive bacteria, atypical bacteria, staphylococcus, streptococcus, Escherichia coli, Salmonella, Helicobacter pylori, Chlamydia, Mycoplasma, fungi, protozoa, enteroworms, helminths, prions, or parasites. [Claim 25] Use of a compound according to any one of claims 1 to 18 or a pharmaceutically acceptable salt, solvate, hydrate, or isomer thereof, or the pharmaceutical composition according to claim 19, in the preparation of a drug for treating a disorder treated by the degradation of a target protein bound to a target ligand. [Claim 26] The use according to claim 24, wherein the disorder is selected from cell proliferation, cancer, immune disorders, diabetes, cardiovascular diseases, infections, and inflammatory diseases. [Claim 27] The aforementioned cancers include breast cancer, endometrial cancer, uterine cancer, testicular cancer, cervical cancer, prostate cancer, ovarian cancer, endometriosis, fallopian tube tumors, ovarian tumors, leukemia, skin cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, renal cell carcinoma, bladder cancer, intestinal cancer, colon cancer, esophageal cancer, head cancer, kidney cancer, liver cancer, lung cancer, cervical cancer, pancreatic cancer, stomach cancer, lymphoma, non-Hodgkin lymphoma, malignant melanoma, myeloproliferative disorders, sarcoma, angiosarcoma, peripheral neuroepithelial tumors, and nephroma. The use according to claim 26, selected from transglioma, astrocytoma, oligodendroglioma, ependymoma, glioblastoma, neuroblastoma, ganglioma, ganglioma, medulloblastoma, pineal cell tumor, meningioma, meningiosarcoma, neurofibroma, schwannoma, thyroid cancer, Hodgkin's tumor, Wilms' tumor, and teratoma, more preferably selected from breast cancer, endometrial cancer, uterine cancer, testicular cancer, cervical cancer, prostate cancer, ovarian cancer, fallopian tube tumor, and ovarian tumor. [Claim 28] The use according to claim 27, wherein the cancer is selected from breast cancer, endometrial cancer, ovarian cancer, cervical cancer, prostate cancer, or endometriosis. [Claim 29] The use according to claim 26, wherein the infectious disease is selected from viral pneumonia, avian influenza, meningitis, gonorrhea, or diseases caused by infection with HIV, HBV, HCV, HSV, HPV, RSV, CMV, Ebola virus, flavivirus, Blotchi virus, rotavirus, influenza, coronavirus, EBV, drug-resistant virus, RNA virus, DNA virus, adenovirus, poxvirus, picornavirus, togavirus, orthomyxovirus, retrovirus, hepadnavirus, gram-negative bacteria, gram-positive bacteria, atypical bacteria, staphylococcus, streptococcus, Escherichia coli, Salmonella, Helicobacter pylori, Chlamydia, Mycoplasma, fungi, protozoa, enteroworms, helminths, prions, or parasites. [Claim 30] A method for treating a disorder in a subject that is treated by the degradation of a target protein bound to a target ligand, comprising administering to a subject an effective amount of a compound according to any one of claims 1 to 18 or a pharmaceutically acceptable salt, solvate, hydrate, or isomer thereof, or a pharmaceutical composition according to claim 19. [Claim 31] The method according to claim 30, wherein the disorder is selected from cell proliferation, cancer, immune disorders, diabetes, cardiovascular diseases, infections, and inflammatory diseases. [Claim 32] The aforementioned cancers include breast cancer, endometrial cancer, uterine cancer, testicular cancer, cervical cancer, prostate cancer, ovarian cancer, endometriosis, fallopian tube tumors, ovarian tumors, leukemia, skin cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, renal cell carcinoma, bladder cancer, intestinal cancer, colon cancer, esophageal cancer, head cancer, kidney cancer, liver cancer, lung cancer, cervical cancer, pancreatic cancer, stomach cancer, lymphoma, non-Hodgkin lymphoma, malignant melanoma, myeloproliferative disorders, sarcoma, angiosarcoma, peripheral neuroepithelial tumors, and nephroma. The method according to claim 31, selected from glioma, astrocytoma, oligodendroglioma, ependymoma, glioblastoma, neuroblastoma, ganglioma, ganglioma, medulloblastoma, pineal cell tumor, meningioma, meningiosarcoma, neurofibroma, schwannoma, thyroid cancer, Hodgkin's tumor, Wilms' tumor, and teratoma, more preferably selected from breast cancer, endometrial cancer, uterine cancer, testicular cancer, cervical cancer, prostate cancer, ovarian cancer, fallopian tube tumor, and ovarian tumor. [Claim 33] The method according to claim 32, wherein the cancer is selected from breast cancer, endometrial cancer, ovarian cancer, cervical cancer, prostate cancer, or endometriosis. [Claim 34] The method according to claim 31, wherein the infectious disease is selected from viral pneumonia, avian influenza, meningitis, gonorrhea, or diseases caused by infection with HIV, HBV, HCV, HSV, HPV, RSV, CMV, Ebola virus, flavivirus, Blotchi virus, rotavirus, influenza, coronavirus, EBV, drug-resistant virus, RNA virus, DNA virus, adenovirus, poxvirus, picornavirus, togavirus, orthomyxovirus, retrovirus, hepadnavirus, gram-negative bacteria, gram-positive bacteria, atypical bacteria, staphylococcus, streptococcus, Escherichia coli, Salmonella, Helicobacter pylori, Chlamydia, Mycoplasma, fungi, protozoa, enteroworms, helminths, prions, or parasites.

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