Estrogen receptor protein targeted degradation chimera derivative based on estratriene structure as well as preparation method and application of estrogen receptor protein targeted degradation chimera derivative

Abstract

The invention discloses an estrogen receptor protein targeted degradation chimera derivative based on an estratriene structure as well as a preparation method and application of the estrogen receptor protein targeted degradation chimera derivative, and belongs to the technical field of drug synthesis and application. The estrogen receptor protein targeted degradation chimera derivative based on the estratriene structure not only has a good inhibition effect on estrogen-induced signal transduction, but also has a good degradation effect on ERalpha. The compound has good pharmacokinetics, bioavailability and in-vivo efficacy, and can be developed into a novel estrogen receptor degradation agent drug.

Description

Technical Field

[0001] The present application relates to an estrogen receptor protein targeted degradation chimera derivative based on estratriene structure and a preparation method and application thereof, belonging to the technical field of drug synthesis and application. Background Art

[0002] Breast cancer is the most common malignant disease in women worldwide, and most breast cancer tumors are estrogen receptor alpha (ER) positive at diagnosis, about 60%. Estrogen receptors play an important role in the development of the disease. For example, compared with normal tissue, ER protein levels are increased in the early stages of breast malignancy and in malignant lesions. + Tumor growth is significantly correlated with anti-estrogen therapy, which can block the binding sites of estrogen receptors, thereby inhibiting the growth of cancer cells. According to the National Cancer Institute (NCI), approximately 250,000 women were diagnosed with breast cancer in 2017, and more than 40,000 patients died from it. + / HER2 - Breast cancer accounts for about 70% of breast cancer patients. Such patients can be treated with endocrine blockade therapy in the early stages, but as the disease progresses, the tumor will become resistant to this therapy and will also accumulate many mutations, making treatment difficult.

[0003] In recent years, the incidence of breast cancer has been on the rise, and now ranks first among female malignant tumors. Among breast cancer patients, about 70% present with estrogen receptor ER-positive breast cancer. Therefore, ER is an important target in breast cancer drug research. To date, the primary intervention for the treatment of ER-positive breast cancer is still endocrine therapy that inhibits estrogen levels associated with breast cancer, mainly including selective estrogen receptor modulators (such as tamoxifen, raloxifene) and aromatase inhibitors (such as letrozole, exemestane) and selective ER downregulators. Although endocrine therapy has achieved great results in the treatment of breast cancer patients, it has problems such as toxic side effects, long treatment time and drug resistance.

[0004] The protein hydrolysis targeted chimera PROTAC technology was proposed by Professor Craig M. Crews' team. It is currently a cutting-edge targeted therapy strategy. PROTACs is a hybrid bifunctional molecule with a ligand that can bind to the E3 ligase at one end and a ligand that binds to the target protein (protein of interest, POI) at the other end, with a linker in the middle. The mechanism of action is to recruit the target protein to the vicinity of the E3 ligase through PROTACs molecules, so that the target protein is ubiquitinated and then degraded through the ubiquitin-proteasome pathway, ultimately achieving the purpose of treating the disease. It can effectively overcome drug resistance by degrading ER in breast cancer cells to exert its therapeutic effect, and is a promising anti-breast cancer drug.

[0005] There are also relatively few types of estrogen receptor protein targeted degradation chimera derivatives at present. The development of a variety of new estrogen receptor protein targeted degradation chimeras to meet the application has always been a research focus, especially the preparation of estrogen receptor protein targeted degradation chimeras with higher activity and stronger specificity. In addition, the current marketed drug Fulvestrant can only degrade 50% of estrogen receptors, which has a low degradation upper limit, limiting the use of this type of compound. Summary of the invention

[0006] In order to solve the above problems, an estrogen receptor protein targeted degradation chimeric derivative based on estratriene structure is provided, having a compound of general formula (I), which can solve the problems existing in the prior art.

[0007] According to the first aspect of the present application, there is provided an estrogen receptor protein targeted degradation chimeric derivative based on estratriene structure, which has a structure of general formula (I): ABC formula (I); Wherein A is an E3 ligase ligand selected from one of the general formula (II-1), general formula (II-2) or general formula (II-3): Formula (II-1); Formula (II-2); Formula (II-3); * represents the connection site, n = 0 or 1, m = 0 or 1, in formula (II-1), general formula (II-2) and general formula (II-3), R1, R2 and R3 are each independently one of: H, OH, F, Cl, Br, NH2, CH3 or OCH3, and R4 is hydrogen or methyl; B is at least one of a rigid linking group, a flexible linking group, and a bridging group; C has the structure of general formula (III):

[0008] Formula (III).

[0009] The estrogen receptor protein targeted degradation chimeric derivative based on the estratriene structure of the general formula (I) is a bifunctional degrader, which retains the halogenated long-chain part of the degradation mechanism of Fulvestrant and combines the degradation mechanism after the E3 ligase ligand to act as a PROTAC and an estradiol analog to achieve a bifunctional stimulant receptor degrader.

[0010] Compared with fulvestrant, the estrogen receptor protein targeted degradation chimeric derivative based on estratriene structure of general formula (I) has a higher degradation effect on the estrogen receptor of MCF-7 cells, and is expected to solve the defect that fulvestrant can only degrade 50% of the estrogen receptor, degrade the estrogen receptor more effectively, achieve a higher degradation upper limit, and have better efficacy.

[0011] Optionally, the estrogen receptor protein targeted degradation chimeric derivative based on estratriene structure comprises its cis-trans isomers and racemic isomers.

[0012] Preferably, the E3 ligase ligand is selected from lenalidomide, thalidomide, 4-hydroxy-thalidomide, 5-hydroxy-thalidomide, pomalidomide, 3-(1-oxoisoindolin-2-yl)piperidine-2,6-dione, 4-amino-4-oxo-2-(1-oxoisoindol-2-yl)butyric acid or 2-(1-methyl-2,6-dioxopiperidin-3-yl)isoindole-1,3-dione or their derivatives and isomers thereof.

[0013] Preferably, the E3 ligase ligand in formula (I) is lenalidomide (IIa): (IIa).

[0014] The site (*) where lenalidomide (IIa) is connected to the Linker is one of the following: (IIa-1), (IIa-2), (IIa-3), or (IIa-4) (Wherein * indicates the connection site. Same below).

[0015] The *NH- group in formula (IIa-1) may also be a part of the linker group or a terminal group (-NH-), the same below. That is, as shown in the following formula: (IIa-1), wherein -L'-NH- is -Linker- (as a divalent linking group) or -L-. The same shall apply hereinafter.

[0016] Or, in formula (I), the E3 ligase ligand is thalidomide (IIb): (IIb).

[0017] The site (*) where thalidomide (IIb) is connected to the linker is one of the following: (IIb-1), or (IIb-2).

[0018] Or, in formula (I), the E3 ligase ligand is 4-hydroxy-thalidomide (IIc-1) or 5-hydroxy-thalidomide (IIc-2): (IIc-1), or (IIc-2).

[0019] The site where the 4-hydroxy-thalidomide (IIc-1) is connected to the linker is one of the following: (IIc-1a), (IIc-1b), (IIc-1c), or (IIc-1d).

[0020] The site (*) where the 5-hydroxy-thalidomide (IIc-2) is connected to the linker is one of the following: (IIc-2a), (IIc-2b), (IIc-2c), or (IIc-2d).

[0021] The *O- group may also be part of a linker group or a terminal group (-O-), the same below. That is, as shown in the following formula: , wherein -L'-O- is -Linker- or -L- (as a divalent linking group). The same applies below.

[0022] Or, in formula (I), the E3 ligase ligand is pomalidomide (IId): (IId-1), or (IId-2).

[0023] The site where pomalidomide (IId-1) is connected to the linker is one of the following: (IId-1a), (IId-1b), (IId-1c), or (IId-1d).

[0024] The *NH- group may also be part of a linker group or a terminal group (-NH-), the same below. That is, as shown in the following formula: (IId-1), wherein -L'-NH- is -Linker- (as a divalent linking group) or -L-. The same shall apply hereinafter.

[0025] The site where pomalidomide (IId-2) is connected to the linker is one of the following: (IId-2a), (IId-2b), (IId-2c), or (IId-2d).

[0026] The *NH- group may also be part of a linker group or a terminal group (-NH-), the same below. That is, as shown in the following formula: (IId-2), wherein -L'-NH- is -Linker- (as a divalent linking group) or -L-. The same shall apply hereinafter.

[0027] Or, in formula (I), the E3 ligase ligand is 3-(1-oxoisoindolin-2-yl)piperidine-2,6-dione (IIe): (IIe).

[0028] The site (*) or method of connection of the 3-(1-oxoisoindolin-2-yl)piperidine-2,6-dione (IIe) to the linker is, or, the E3 ligase ligand in formula (I) is, for example, one of the following: (IIe-1), (IIe-2), (IIe-3), or (IIe-4).

[0029] Or, in formula (I), the E3 ligase ligand is 4-amino-4-oxo-2-(1-oxoisoindol-2-yl)butyric acid (IIf): (IIf).

[0030] The site (*) at which the 4-amino-4-oxo-2-(1-oxoisoindol-2-yl)butyric acid (IIf) is connected to the linker is one of the following: (IIf-1), (IIf-2), (IIf-3), or (IIf-4).

[0031] Or, the E3 ligase ligand of formula (I) is 2-(1-methyl-2,6-dioxopiperidin-3-yl)isoindole-1,3-dione (IIg): (IIg).

[0032] The site (*) at which the 2-(1-methyl-2,6-dioxopiperidin-3-yl)isoindole-1,3-dione (IIg) is connected to the linker is one of the following: (IIg-1), or (IIg-2).

[0033] is at least one of a rigid linking group, a flexible linking group, and a bridging group. When it is a rigid linking group, it is selected from one of the following formulae: The connection site.

[0034] When it is a flexible linking group, it is selected from one of the following formulae:

[0035] When it is a combination of a flexible linking group and a rigid linking group, it is selected from one of the following formulae:

[0036]

[0037]

[0038]

[0039] In the present application, n=0-5 means n=0, 1, 2, 3, 4 or 5. Similarly, n=2-10 means n=2, 3, 4, 5, 6, 7, 8, 9 or 10.

[0040] Optionally, the estrogen receptor protein targeted degradation chimeric derivative based on the estratriene structure has one of the following structural formulas: ; ; ; ; ; ; ; ; ; ; .

[0041] According to the second aspect of the present application, there is provided a method for preparing an estrogen receptor protein targeted degradation chimera derivative based on an estratriene structure as described in any one of the above, comprising the following steps: (1) placing fulvestrant in a solvent, adding an acid-binding agent and cooling the temperature to 1-5°C, then adding a monomer containing a halogen atom and an acyl halide group to react, thereby obtaining compound 2; (2) reacting compound 2 with a rigid linker and an E3 ligase ligand A with a flexible linker in sequence to obtain an estrogen receptor protein targeted degradation chimeric derivative based on an estratriene structure of general formula (I), wherein the E3 ligase ligand A with a flexible linker has a carboxyl group or a ketocarbonyl group at its end; or Compound 2 is reacted with E3 ligase ligand B with a flexible linker to obtain an estrogen receptor protein targeted degradation chimera derivative based on estratriene structure of general formula (I), wherein the E3 ligase ligand B with a flexible linker has an amino group at the end.

[0042] In the above step (1), the hydroxyl group of Fulvestrant and the acyl halide group of the monomer containing halogen atoms and acyl halide groups react under the action of an acid binding agent, so that the terminal of compound 2 carries a halogen atom.

[0043] In the two reactions of step (2), the first reaction is a condensation reaction between the halogen atom of compound 2 and the amino group or nitrogen of the rigid linker, and then a condensation reaction with the carboxyl group or keto carbonyl group of the E3 ligase ligand A with a flexible linker to obtain a compound of general formula (I); the second reaction is a condensation reaction between the halogen atom of compound 2 and the amino group of the E3 ligase ligand B with a flexible linker to obtain an estrogen receptor protein targeted degradation chimeric derivative based on an estratriene structure of general formula (I).

[0044] Optionally, the molar ratio of compound 2 to E3 ligase ligand B with a flexible linker is 1:1-1.2.

[0045] Optionally, the acid-binding agent in step (1) is a base, and the base is selected from at least one of pyridine, triethylamine, diisopropylethylamine, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide and diisopropylethylamine.

[0046] Optionally, the monomer containing a halogen atom and an acyl halide group in step (1) is selected from at least one of bromoacetyl chloride, chloroacetyl chloride, iodoacetic chloride, bromopropionyl chloride, chloropropionyl chloride, iodopropionyl chloride, bromoacetyl bromide and chloroacetyl bromide.

[0047] Optionally, in step (1), the molar ratio of fulvestrant to the monomer containing a halogen atom and an acyl halide group is 1:1-1.3, and the molar ratio of the acid-binding agent to fulvestrant is 1:2-3.

[0048] Optionally, the monomer having an amino group and a tert-butyloxycarbonyl group is selected from at least one of tert-butyl [4,4'-bipiperidine]-1-carboxylate, tert-butyl 3,9-diazaspiro[5.5]undecane-3-carboxylate, tert-butyl 2,8-diazaspiro[4.5]decane-8-carboxylate, tert-butyl 4-(piperazin-1-ylmethyl)piperazine-1-carboxylate and tert-butyl piperazine-1-carboxylate.

[0049] Optionally, the E3 ligase ligand A with a flexible linker is selected from 2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl)oxy)acetic acid, 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione.

[0050] Optionally, the E3 ligase ligand B with a flexible linker is selected from N-(2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)ethyl)-2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetamide.

[0051] Optionally, in step (2), compound 2 is reacted with a monomer having an amino group and a tert-butyloxycarbonyl group and an E3 ligase ligand A having a flexible linker in sequence to obtain an estrogen receptor protein targeted degradation chimeric derivative based on an estratriene structure of general formula (I), specifically: (2-1): Compound 2 is subjected to a condensation reaction with a monomer having an amino group and a tert-butyloxycarbonyl group to obtain an intermediate A; (2-2): The intermediate A is deprotected under an acidic environment to obtain the intermediate B with an amino group; (2-3): Intermediate B undergoes a condensation reaction with E3 ligase ligand A having a flexible linker to obtain an estrogen receptor protein targeted degradation chimeric derivative based on an estratriene structure of general formula (I).

[0052] In step (2-1), the halogen atom of compound 2 and the amino group of the monomer with amino and tert-butyloxycarbonyl groups undergo condensation reaction to obtain intermediate A. In view of the structure of the monomer with amino and tert-butyloxycarbonyl groups listed above, after reacting with compound 2, the terminal contains a protecting group. Therefore, in step (2-2), intermediate A is deprotected under an acidic environment to obtain intermediate B with amino group. In step (2-3), the amino group of intermediate B undergoes condensation reaction with the carboxyl or ketocarbonyl group of E3 ligase ligand A with a flexible linker to obtain the estrogen receptor protein targeted degradation chimeric derivative based on estradiol structure of general formula (I).

[0053] A condensing agent and a base are added to the condensation reaction of the above steps (2-1) and (2-3), wherein the condensing agent is selected from at least one of 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride, N, N'-diisopropylcarbodiimide, and dicyclohexylcarbodiimide; and the base is selected from at least one of triethylamine, potassium carbonate, sodium carbonate, and diisopropylethylamine.

[0054] The acidic environment of step (2-2) is provided by HCl or TFA, and the pH of the acidic environment is 3-5.

[0055] Optionally, in step (2-1), the molar ratio of compound 2 to the monomer having an amino group and a tert-butyloxycarbonyl group is 1:1-1.2, and in step (2-3), the molar ratio of intermediate B to the E3 ligase ligand A having a flexible linker is 1:1-1.2.

[0056] According to the third aspect of the present application, there is provided another method for preparing the estrogen receptor protein targeted degradation chimera derivative based on the estratriene structure as described in any one of the above, comprising the following steps: S1: stirring fulvestrant and a monomer having a carboxyl group and a tert-butyloxycarbonyl group in the presence of a condensation agent and a base to obtain an intermediate containing a tert-butyloxycarbonyl group; S2: The intermediate containing tert-butyloxycarbonyl protection obtained in S1 is placed in an acidic environment to remove the protecting group to obtain an intermediate containing amino group; S3: The intermediate with amino group obtained in S2 is reacted with E3 ligase ligand A with flexible linker, and extracted and purified to obtain estrogen receptor protein targeted degradation chimeric derivative based on estradiol structure of general formula (I), wherein the terminal of E3 ligase ligand A with flexible linker has carboxyl group or keto carbonyl group.

[0057] In step S1, the molar ratio of fulvestrant to the monomer having carboxyl and tert-butyloxycarbonyl groups and the condensation agent is 1:(1.1-1.2):(1.1-1.2).

[0058] In the above step S1, the monomer having carboxyl and tert-butyloxycarbonyl groups is selected from at least one of 1-(tert-butyloxycarbonyl)piperidine-4-carboxylic acid and 1'-(tert-butyloxycarbonyl)-[1,4'-bipiperidine]-4-carboxylic acid.

[0059] In the above step S3, the E3 ligase ligand A with a flexible linker is selected from at least one of lenalidomide, thalidomide, 4-hydroxy-thalidomide, 5-hydroxy-thalidomide, pomalidomide, 3-(1-oxoisoindolin-2-yl)piperidine-2,6-dione, 4-amino-4-oxo-2-(1-oxoisoindol-2-yl)butyric acid or 2-(1-methyl-2,6-dioxopiperidine-3-yl)isoindole-1,3-dione or a derivative thereof, and a condensing agent is added to the reaction in step S3 and the reaction is carried out at room temperature.

[0060] The condensing agent in the above steps S1 and S3 is selected from at least one of 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride, N, N'-diisopropylcarbodiimide, and dicyclohexylcarbodiimide; the base is selected from at least one of triethylamine, potassium carbonate, sodium carbonate, and diisopropylethylamine.

[0061] The acidic environment in the above step S2 is provided by HCl or TFA, and the pH of the acidic environment is 3-5.

[0062] According to the fourth aspect of the present application, there is provided a method for preparing a chimeric derivative of an estrogen receptor protein targeted for degradation based on an estratriene structure as described in any one of the above, comprising the following steps: D1: Fulvestrant and dihaloalkane are dissolved in a solvent, and an acid-binding agent is added and stirred to obtain FWSQ-C5; D2: Dissolve the compound containing the amino group and the E3 ligase ligand end and FWSQ-C5 in an organic solvent, add N,N-diisopropylethylamine and sodium iodide, stir the reaction, extract and purify, and obtain the estrogen receptor protein targeted degradation chimeric derivative based on the estradiol structure of the general formula (I).

[0063] Optionally, the dihaloalkane in step D1 is selected from at least one of bromoiodomethane, bromochloromethane, bromochloroethane, bromoiodoethane, bromoiodopropane, bromochloropropane, bromoiodobutane and bromochlorobutane; and the acid binding agent is selected from at least one of triethylamine, diisopropylethylamine, potassium carbonate, cesium carbonate and sodium hydroxide.

[0064] Optionally, in the compound containing an amino group and an E3 ligase ligand end in step D2, the E3 ligase ligand end is selected from at least one of lenalidomide, thalidomide, 4-hydroxy-thalidomide, 5-hydroxy-thalidomide, pomalidomide, 3-(1-oxoisoindolin-2-yl)piperidine-2,6-dione, 4-amino-4-oxo-2-(1-oxoisoindol-2-yl)butyric acid or 2-(1-methyl-2,6-dioxopiperidine-3-yl)isoindole-1,3-dione or its derivatives.

[0065] Optionally, the compound containing an amino group and an E3 ligase ligand end in step D2 is obtained by reacting 2-(2,6-dioxyhexahydropyridin-3-yl)-5-fluoroisoindole-1,3-dione with a Linker containing an amino group, and removing the amino protecting group. The specific preparation method is: Mixing a linker monomer containing an amino group and a Boc-protected amino group and 2-(2,6-dioxypyridin-3-yl)-5-fluoroisoindole-1,3-dione, adding an acid-binding agent for reaction, and separating to obtain a Boc-protected CRBN and linker assembly; Then, the Boc-protected CRBN and Linker assembly is placed in an acidic environment (HCl, TFA) at pH 3-5 to remove the amino protecting group to obtain a compound containing an amino group and an E3 ligase ligand end.

[0066] Optionally, the reaction temperature in step D2 is at room temperature, preferably 10-35°C.

[0067] According to the fifth aspect of the present application, a pharmaceutical composition is provided, which contains: a therapeutically effective amount of any of the above-mentioned estrogen receptor protein targeted degradation chimera derivatives based on estratriene structure or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[0068] According to the sixth aspect of the present application, provided is the use of any of the above-mentioned estrogen receptor protein targeted degradation chimera derivatives based on estratriene structure or the above-mentioned pharmaceutical compositions in the preparation of drugs for the prevention and treatment of breast cancer.

[0069] According to the seventh aspect of the present application, provided is the use of any of the above-mentioned estrogen receptor protein targeted degradation chimera derivatives based on estratriene structure or the above-mentioned pharmaceutical compositions in the preparation of drugs for treating diseases related to estrogen receptor protein targeted degradation chimeras.

[0070] Optionally, the estrogen receptor protein degradation targeting chimera-related disease is selected from tumors or cancers.

[0071] Preferably, the disease associated with the estrogen receptor protein degradation targeting chimera is selected from breast cancer, endometrial cancer, ovarian cancer, uterine cancer, prostate cancer, endometriosis, lung cancer and esophageal cancer.

[0072] More preferably, the estrogen receptor protein degradation targeting chimera-related disease is selected from breast cancer.

[0073] The beneficial effects of this application include but are not limited to: 1. The estrogen receptor protein targeted degradation chimeric derivative based on the estratriene structure of the present application not only has a good inhibitory effect on estrogen-induced signal transduction, but also has a good degradation effect on ERα.

[0074] 2. The estrogen receptor protein targeted degradation chimeric derivative based on the estratriene structure of the present application has good properties such as pharmacokinetics, bioavailability and in vivo efficacy, and can be developed into a new type of estrogen receptor degrader drug.

[0075] 3. The estrogen receptor protein targeted degradation chimeric derivative based on the estradiol structure of the present application has high protein degradation ability and a relatively low dosage, which can improve the safety window of drug treatment.

[0076] 4. The estrogen receptor protein targeted degradation chimeric derivative based on the estradiol structure of the present application can be administered orally and by injection, thereby achieving greater convenience in administration. BRIEF DESCRIPTION OF THE DRAWINGS

[0077] The drawings described herein are used to provide a further understanding of the present application and constitute a part of the present application. The illustrative embodiments of the present application and their descriptions are used to explain the present application and do not constitute an improper limitation on the present application. In the drawings: Figure 1 Schematic diagram of Western Blot experimental image showing that QDE-FWSQ-12 involved in the embodiment of the present application inhibits the ER protein level in MCF-7 cells.

[0078] Figure 2 Schematic diagram of Western Blot experimental image showing that QDE-FWSQ-4 involved in the embodiment of the present application inhibits the ER protein level in MCF-7 cells.

[0079] Figure 3 This is a schematic diagram of Western Blot experimental images of QDE-FWSQ-5, QDE-FWSQ-6, QDE-FWSQ-11, QDE-FWSQ-12, QDE-FWSQ-13, and QDE-FWSQ-21 involved in the examples of the present application inhibiting the ER protein level in MCF-7 cells.

[0080] Figure 4 This is a quantitative graph of protein concentration in WB experiment of ER protein degradation. DETAILED DESCRIPTION

[0081] The present application is described in detail below with reference to embodiments, but the present application is not limited to these embodiments.

[0082] Unless otherwise specified, the raw materials in the examples and comparative examples of the present application were purchased through commercial channels.

[0083] Unless otherwise specified, the methods used in the examples and comparative examples of the present application are conventional methods in the prior art.

[0084] Related definitions Unless otherwise specified, the following terms and phrases used herein are intended to have the following meanings. A particular term or phrase should not be considered to be uncertain or unclear in the absence of a special definition, but should be understood according to its ordinary meaning. When a trade name appears in this article, it is intended to refer to its corresponding commercial product or its active ingredient.

[0085] The term "pharmaceutically acceptable" as used herein refers to those compounds, materials, compositions and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reaction, or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0086] The term "pharmaceutically acceptable salt" refers to a salt of a compound of the present application, prepared from a compound with a specific substituent found in the present application and a relatively non-toxic acid or base. When the compound of the present application contains a relatively acidic functional group, a base addition salt can be obtained by contacting such a compound with a sufficient amount of a base in a pure solution or a suitable inert solvent. When the compound of the present application contains a relatively basic functional group, an acid addition salt can be obtained by contacting such a compound with a sufficient amount of an acid in a pure solution or a suitable inert solvent. Certain specific compounds of the present application contain basic and acidic functional groups, and can thus be converted into either a base or acid addition salt.

[0087] The pharmaceutically acceptable salts of the present application can be synthesized by conventional chemical methods from parent compounds containing acid radicals or bases. Generally, the preparation method of such salts is: in water or an organic solvent or a mixture of the two, these compounds in free acid or base form are reacted with a stoichiometric amount of an appropriate base or acid to prepare.

[0088] The compounds of the present application may exist in specific geometric or stereoisomeric forms. The present application contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (Z)-isomers, and racemic mixtures and other mixtures thereof, such as mixtures enriched in enantiomers or diastereomers, all of which are within the scope of the present application. Additional asymmetric carbon atoms may be present in substituents such as alkyl. All of these isomers and their mixtures are included within the scope of the present application.

[0089] The compounds and intermediates of the present application can also exist in different tautomeric forms, and all such forms are included in the scope of the present application. The term "tautomer" or "tautomeric form" refers to structural isomers of different energies that can be interconverted via low energy barriers. For example, proton tautomers (also referred to as proton transfer tautomers) include interconversions via proton migration, such as keto-enol and imine-enamine isomerization. The specific example of proton tautomers is the imidazole moiety, in which the proton can migrate between two ring nitrogens. Valence tautomers include interconversions through the reorganization of some bonding electrons. The compounds of the present application can include atomic isotopes of non-natural proportions on one or more atoms constituting the compound. For example, radioactive isotope labeled compounds can be used, such as tritium (2H), iodine-125 (125I) or C-14 (14C). For another example, deuterium can be used to replace hydrogen to form deuterated drugs. The bond between deuterium and carbon is stronger than the bond between ordinary hydrogen and carbon. Compared with undeuterated drugs, deuterated drugs have the advantages of reducing toxic side effects, increasing drug stability, enhancing efficacy, and extending the biological half-life of drugs. All isotopic composition changes of the compounds of the present application, whether radioactive or not, are included in the scope of the present application.

[0090] The terms "optional" or "optionally" mean that the subsequently described event or circumstance may but need not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.

[0091] The term "targeting chimera" refers to a bifunctional molecule comprising two small molecule ligands, one with high affinity for a target protein of interest, and a second for recruiting an E3 ligase that ubiquitinates and targets the protein for proteolysis by the proteasome.

[0092] The compounds of the present application can be prepared by a variety of synthesis methods known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthesis methods, and equivalent substitution methods known to those skilled in the art. Preferred embodiments include but are not limited to the examples of the present application.

[0093] The solvents used in this application can be obtained from commercial sources. The compounds are named according to the conventional nomenclature in the art, and commercially available compounds are named according to the supplier's catalogue name.

[0094] Example 1 This embodiment relates to a method for preparing a chimeric derivative of an estrogen receptor protein targeted degradation based on an estratriene structure of general formula (I), comprising the following steps: (1) placing fulvestrant in a solvent, adding an acid-binding agent and cooling the temperature to 1-5°C, then adding a monomer containing a halogen atom and an acyl halide group to react, thereby obtaining compound 2; (2) reacting compound 2 with a rigid linker and an E3 ligase ligand A with a flexible linker in sequence to obtain an estrogen receptor protein targeted degradation chimeric derivative based on an estratriene structure of general formula (I), wherein the E3 ligase ligand A with a flexible linker has a carboxyl group or a ketocarbonyl group at its end; or Compound 2 is reacted with E3 ligase ligand B with a flexible linker to obtain an estrogen receptor protein targeted degradation chimera derivative based on estratriene structure of general formula (I), wherein the E3 ligase ligand B with a flexible linker has an amino group at the end.

[0095] Preferably, in step (2), compound 2 is reacted with a monomer having an amino group and a tert-butyloxycarbonyl group and an E3 ligase ligand A having a flexible linker in sequence to obtain an estrogen receptor protein targeted degradation chimeric derivative based on an estratriene structure of general formula (I): (2-1): Compound 2 is subjected to a condensation reaction with a rigid linker to obtain intermediate A; (2-2): The intermediate A is deprotected under an acidic environment to obtain the intermediate B with an amino group; (2-3): Intermediate B undergoes a condensation reaction with E3 ligase ligand A having a flexible linker to obtain an estrogen receptor protein targeted degradation chimeric derivative based on an estratriene structure of general formula (I).

[0096] According to the above preparation method, the following estrogen receptor protein targeted degradation chimeric derivative based on estratriene structure is prepared, specifically as follows: Compound QDE-FWSQ-1 The specific steps and reaction equations are as follows:

[0097] (1) 121.4 g of fulvestrant (0.2 mmol) was dissolved in dichloromethane (5 ml), 40.4 mg of triethylamine (0.4 mmol) was added, the temperature was lowered to 3°C, 31.5 mg of bromoacetyl chloride (0.2 mmol) was added dropwise, nitrogen was ventilated three times, the reaction was carried out at 3°C ​​for 4 hours, and the reaction progress was monitored by TLC. After the reaction was completed, a saturated aqueous ammonium chloride solution was added to quench the reaction, dichloromethane was added for extraction three times, and dichloromethane was separated with a separatory funnel. The methane layer was evaporated to dryness in vacuo and purified by column chromatography to obtain 112.4 mg (7R, 8S, 9S, 12R, 14S, 17S)-17-hydroxy-12-methyl-7-(9-((4,4,5,5,5-pentafluoropentyl)sulfinyl)nonyl)-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthrene-3-yl-2-bromoacetate, with a yield of 77.2%, i.e., compound 2. The mass of this compound was accumulated by multiple reactions.

[0098] (2-1) 112.4 mg of compound 2 (0.154 mmol) and 45.4 mg of [4,4'-bipiperidine]-1-carboxylic acid tert-butyl ester (0.169 mmol) were dissolved in 3 ml of dichloromethane, and 46.75 mg of potassium carbonate (0.338 mmol) was added. The mixture was reacted at 40°C for 6 h. The reaction progress was monitored by TLC. After the reaction was completed, water / dichloromethane was added for extraction. The dichloromethane phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified on a silica gel preparative plate to obtain 100.3 mg 1'-(2-(((7R,8S,9S,12R,14S,17S)-17-hydroxy-12-methyl-7-(9-(4,4,5,5-pentafluoropentyl)sulfinyl)nonyl)-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthrene-3-yl)oxy)-2-oxoethyl)-[4,4'-bipiperidine]-1-carboxylic acid tert-butyl ester, yield 71.3%, i.e., compound FWSQ1-1.

[0099] (2-2) 110.3 mg FWSQ1-1 (0.116 mmol) was dissolved in 5 ml dichloromethane, and the mixture was cooled to 0°C in an ice bath. 0.5 ml trifluoroacetic acid was slowly added dropwise to the reaction system. After the addition was complete, the ice bath was removed and the mixture was reacted at room temperature for 3 h. After quenching with sodium bicarbonate solution, the mixture was extracted three times with dichloromethane and water. The dichloromethane layer was separated with a separatory funnel and distilled under reduced pressure at 30°C. The mixture was purified by column chromatography to obtain (7R, 8S, 9S , 12R, 14S, 17S)-17-hydroxy-12-methyl-7-(9-((4,4,5,5,5-pentafluoropentyl)sulfinyl)nonyl)-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthrene-3-yl-2-([4,4'-bipiperidinyl]-1-yl)acetate 87.1 mg, yield 91.5%, i.e. compound FWSQ1-2.

[0100] (2-3) 35.5 mg of 2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindole-4-yl)oxy)acetic acid (0.107 mmol) was added to a 10 ml single-necked bottle, 2 ml of DCM was added for suspension, 40.7 mg (0.107 mmol) of HATU (2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate) and 27.6 mg (0.214 mmol) of diisopropylethylamine were added, and the mixture was stirred for activation for 30 min. 87.1 mg of compound FWSQ-1-2 (0.107 mmol) was added. The reaction was carried out at room temperature for 3 h, and the progress of the reaction was monitored by TLC. After the reaction was completed, ethyl acetate and water were used for extraction. After extraction three times, ethyl acetate was separated with a separatory funnel, and the mixture was distilled under reduced pressure. The mixture was purified by column chromatography to obtain 53.3 mg of (7R, 8S, 8S, 9S, 12R, 14S, 17S)-17-hydroxy-12-methyl-7 (5,4,4,5,5,5,5-5-pentafluorocarbonyl 9,9,11,11,12,13,14,15,16,16,17, 17-decahydro-6H-cyclopentene, 4'-bipiperidinyl]-1-yl) acetate with a yield of 44.2%, i.e., compound QDE-FWSQ-1.

[0101] The structure of QDE-FWSQ-1 was confirmed by mass spectrometry (HR-ESI-MS) and nuclear magnetic resonance hydrogen spectrum (1H-NMR): ESI-MS (positive mode) m / z: 1158.5 [M+H] + (calculated for C 60 H 80 F5N5O 10S, 1157.5). 1H-NMR (600Hz, CDCl3): 11.033 (NH, 1H), 8.012 (Ph-CH, 1H), 7.677 (Ph-H, 2H), 6.795-6.933 (Ph-H, 3H), 5.53 (O-CH2, 2H), 4.56 (N-CH2, 2H), 4.769 ( C=O-CH2,2H), 4.428 ( N-CH, 1H), 4.134 ( -OH, 1H), 3.416-3.553(CH2, 7H), 2.349-2.909(CH2, CH, 11H), 1.266-2.243(CH2, CH, 43H). 0.893(CH3, 3H).

[0102] Compound QDE-FWSQ-5 The specific steps and reaction equations are as follows:

[0103] (1) Same as compound QDE-FWSQ-1.

[0104] (2-1) 112.4 mg of compound 2 (0.154 mmol) and 42.9 mg of tert-butyl 3,9-diazaspiro[5.5]undecane-3-carboxylate (0.169 mmol) were dissolved in 3 ml of dichloromethane, and 46.75 mg of potassium carbonate (0.338 mmol) was added. The mixture was reacted at 40°C for 6 h. The reaction progress was monitored by TLC. After the reaction was completed, water / dichloromethane was added for extraction. The dichloromethane phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified on a silica gel preparative plate to obtain 115.5 mg 9-(2-(((7R,8R,9R,13S,14S,17S)-17-hydroxy-8,9,13,14-tetramethyl-7-(9-(4,4,5,5-pentafluoropentyl)sulfinyl)nonyl)-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthrene-3-yl)oxy)-2-oxoethyl)-3,9-diazaspiro[5.5]undecane-3-carboxylic acid tert-butyl ester, yield 79.6%, i.e., compound 5-1.

[0105] (2-2) 115.5 mg of compound 5-1 (0.122 mmol) was dissolved in 5 ml of dichloromethane, and the mixture was cooled to 0°C in an ice bath. 0.5 ml of trifluoroacetic acid was slowly added dropwise to the reaction system. After the addition was complete, the ice bath was removed and the mixture was reacted at room temperature for 3 h. After quenching with sodium bicarbonate solution, the mixture was extracted three times with dichloromethane and water. The dichloromethane layer was separated with a separatory funnel and distilled under reduced pressure at 30°C. 93.5 mg (7R, 8R, 9R, 13S, 14S) was obtained by column chromatography. , 17S)-17-hydroxy-8,9,13,14-tetramethyl-7-(9-(4,4,4,5,5-pentafluoropentyl)sulfinyl)nonyl)-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthrene-3-yl-2-(3,9-diazaspiro[5.5]undecane-3-yl)acetate, yield 90.6%, i.e., compound 5-2.

[0106] (2-3) 36.5 mg of 2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindole-4-yl)oxy)acetic acid (same as in Example 1) (0.110 mmol) was added to a 10 ml single-necked bottle, 2 ml of DCM was added for suspension, 41.8 mg (0.110 mmol) of HATU (same as in Example 1) and 28.3 mg (0.220 mmol) of diisopropylethylamine (same as in Example 1) were added and stirred for activation for 30 min, 93.5 mg of compound 5-2 (0.110 mol) was added and reacted at room temperature for 3 h. The reaction progress was monitored by TLC. After the reaction was completed, the mixture was filtered. The mixture was extracted with ethyl acetate and water for three times. After extraction, the ethyl acetate was separated with a separatory funnel, and the mixture was distilled under reduced pressure. The mixture was purified by column chromatography to obtain 52.5 mg of (7R, 8R, 9R, 13S, 14S, 17S)-17-hydroxy-8,9,13,14-tetramethyl-7-(9-(4,4,4,5,5-pentafluoropentyl)sulfinyl)nonyl)-7,8,9,11,12, 13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthrene-3-yl-2-(9-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxindol-4-yl)oxy)acetyl)-3,9-diazaspiro[5.5]undecane-3-yl)acetate with a yield of 41.3%, i.e., compound QDE-FWSQ-5.

[0107] The structure of QDE-FWS-5 was confirmed by mass spectrometry (HR-ESI-MS) and nuclear magnetic resonance hydrogen spectrum (1H-NMR): ESI-MS (positive mode) m / z: 1115.5 [M+H] + (calculated for C 58 H 75 F5N4O 10S, 1114.5594). 1H-NMR (600Hz, CDCl3): 11.323(NH, 1H), 7.9137 (Ph-CH, 1H), 7.594 (Ph-H 2H), 6.764-6.964 (Ph-H, 3H), 4.994 (C=O-CH2, 2H), 4.754 (-OH, 1H), 4.483 (N-CH,1H), 3.782 (N-CH2, 4H), 3.572 (N-CH2, 2H), 3.4134 (OH-CH, 1H), 2.832-2.922(Ph-CH2, 2H), 2.433 - 2.594 (CH2, CH, 10H), 1.902-2.233(CH2,4H), 1.254-1.889(CH2,38H), 0.855(CH3, 3H).

[0108] Compound QDE-FWSQ-6 The specific preparation steps, i.e. the reaction equation, are as follows:

[0109] (1) Same as compound QDE-FWSQ-1.

[0110] (2-1) 112.4 mg of compound 2 (0.154 mmol) and 40.59 mg of tert-butyl 2,8-diazaspiro[4.5]decane-8-carboxylate (0.169 mmol) were dissolved in 3 ml of dichloromethane, and 46.75 mg of potassium carbonate (0.338 mmol) was added. The mixture was reacted at 40°C for 6 h. The reaction progress was monitored by TLC. After the reaction was completed, water / dichloromethane was added for extraction. The dichloromethane phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified on a silica gel preparative plate to obtain 100.2 mg of tert-butyl 2-(2-(((7R,8R,9R,13S,14S,17S)-17-hydroxy-8,9,13,14-tetramethyl-7-(9-((4,4,5,5,5-pentafluoropentyl)sulfinyl)nonyl)-7,8,9,11,12,13, 14,15,16,17-decahydro-6H-cyclopenta[a]phenanthro[3,2-c]azepin-3-yl)oxy)-2-oxoethyl)-2,8-dithioheterocyclo[4.5]octane-8-carboxylate, yield 70.1%, namely compound 6-1 (2-2) 100.2 mg of compound 6-1 (0.108 mmol) was dissolved in 5 ml of dichloromethane, and the mixture was cooled to 0°C in an ice bath. 0.5 ml of trifluoroacetic acid was slowly added dropwise to the reaction system. After the addition was complete, the ice bath was removed and the mixture was reacted at room temperature for 3 h. After quenching with sodium bicarbonate solution, the mixture was extracted three times with dichloromethane and water. The dichloromethane layer was separated with a separatory funnel and distilled under reduced pressure at 30°C. The mixture was purified by column chromatography to obtain 79.0 mg (7R, 8R, 9 R, 13S, 14S, 17S)-17-hydroxy-8,9,13,14-tetramethyl-7-(9-(4,4,4,5,5-pentafluoropentyl)sulfinyl)nonyl)-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthrene-3-yl-2-(3,9-diazaspiro[5.5]undecane-3-yl)acetate, yield 88.3%, i.e., compound 6-2.

[0111] (2-3) 31.6 mg of 2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindole-4-yl)oxy)acetic acid (0.095 mmol) was added to a 10 ml single-necked bottle, and 2 ml of DCM was added to suspend the mixture. 36.1 mg (0.095 mmol) of HATU and 24.5 mg (0.19 mmol) of diisopropylethylamine were added and stirred for activation for 30 min. 79.0 mg of compound 6-2 (0.095 mol) was added and reacted at room temperature for 3 h. The reaction progress was monitored by TLC. After the reaction was completed, the mixture was filtered. The mixture was extracted with ethyl acetate and water for three times. After extraction, the ethyl acetate was separated with a separatory funnel, distilled under reduced pressure, and purified by column chromatography to obtain 42.6 mg of (7R, 8R, 9R, 13S, 14S, 17S)-17-hydroxy-8,9,13,14-tetramethyl-7-(9-((4,4,5,5,5-pentafluoropentyl)sulfinyl)nonyl)-7,8,9,11,12,13, 14,15,16, 17-decahydro-6H-cyclopenta[a]phenanthrene-3-yl 2-(8-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolyl-4-yl)oxy)acetyl)-2,8-diazaspiro[4.5]decane-2-yl)acetate with a yield of 39.3%, i.e., compound QDE-FWSQ-6.

[0112] The structure of QDE-FWS-6 was confirmed by mass spectrometry (HR-ESI-MS) and nuclear magnetic resonance hydrogen spectrum (1H-NMR): ESI-MS (positive mode) m / z: 1111.5 [M+H] + (calculated for C 57 H 73 F5N4O 10S, 1110.4968). 1H-NMR (600Hz, CDCl3): 11.323(NH, 1H), 7.9137 (Ph-CH, 1H), 7.594 (Ph-H 2H), 6.764-6.964 (Ph-H, 3H), 4.994 (C=O-CH2, 2H), 4.754 (-OH, 1H), 4.483 (N-CH,1H), 3.782 (N-CH2, 4H), 3.572 (N-CH2, 2H), 3.4134 (OH-CH, 1H), 2.832-2.922(Ph-CH2, 2H), 2.433-2.594(CH2, 9H), 1.764-1.944(CH2, 6H), 1.902-2.233(CH2CH,5H) 1.254-1.794(CH2, 30H), 0.855(CH3, 3H).

[0113] Compound QDE-FWSQ-11 The specific preparation steps and reaction equations are as follows:

[0114] (1) Same as compound QDE-FWSQ-1.

[0115] (2-1) 112.4 mg of compound 2 (0.154 mmol) and 48.0 mg of tert-butyl 4-(piperazin-1-ylmethyl)piperazine-1-carboxylate (0.169 mmol) were dissolved in 3 ml of dichloromethane, and 46.75 mg of potassium carbonate (0.338 mmol) was added. The mixture was reacted at 40°C for 6 h. The reaction progress was monitored by TLC. After the reaction was completed, water / dichloromethane was added for extraction. The dichloromethane phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified on a silica gel preparative plate to obtain 133.7 mg 4-(4-(2-(((7R,8R,9R,13S,14S,17S)-17-hydroxy-8,9,13,14-tetramethyl-7-(9-(4,4,4,5,5-pentafluoropentyl)sulfinyl)nonyl)-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthrene-3-yl)oxy)-2-oxoethyl)piperazin-1-yl)methyl)piperazine-1-carboxylate, yield 81.4%, i.e., compound 11-1.

[0116] (2-2) 133.7 mg of compound 11-1 (0.137 mmol) was dissolved in 5 ml of dichloromethane, cooled to 0°C in an ice bath, and 0.5 ml of trifluoroacetic acid was slowly dripped into the reaction system. After the addition was complete, the ice bath was removed and the reaction was carried out at room temperature for 3 h. After sodium bicarbonate solution was added to quench, dichloromethane and water were extracted three times. The dichloromethane layer was separated with a separatory funnel and distilled under reduced pressure at 30°C. 101.9 mg was obtained by column chromatography. (7R, 8R, 9R, 13S, 14S, 17S)-17-hydroxy-8,9,13,14-tetramethyl-7-(9-(4,4,4,5,5-pentafluoropentyl)sulfinyl)nonyl)-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthrene-3-yl-2-(4-(piperazin-1-ylmethyl)piperazin-1-yl)acetate, yield 91.4%, i.e., compound 11-2.

[0117] (2-3) 41.5 mg of 2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindole-4-yl)oxy)acetic acid (0.125 mmol) was added to a 10 ml single-necked bottle, and 2 ml of DCM was added to suspend the mixture. 47.6 mg (0.125 mmol) of HATU and 32.3 mg (0.25 mmol) of diisopropylethylamine were added and stirred for activation for 30 min. 101.9 mg of compound 11-2 (0.125 mol) was added and reacted at room temperature for 3 h. The reaction progress was monitored by TLC. After the reaction was completed, the mixture was filtered. The mixture was extracted with ethyl acetate and water for three times. After extraction, the ethyl acetate was separated with a separatory funnel, and the mixture was distilled under reduced pressure. The mixture was purified by column chromatography to obtain 65.6 mg of (7R, 8R, 9R, 13S, 14S, 17S)-17-hydroxy-8,9,13,14-tetramethyl-7-(9-(4,4,4,5,5-pentafluoropentyl)sulfinyl)nonyl)-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthrene-3-yl-2-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl)oxy)acetyl)piperazin-1-yl)methyl)piperazin-1-alkyl)acetate with a yield of 44.2%, i.e., compound QDE-FWSQ-11.

[0118] The structure of QDE-FWS-11 was confirmed by mass spectrometry (HR-ESI-MS) and nuclear magnetic resonance hydrogen spectrum (1H-NMR): ESI-MS (positive mode) m / z: 1145.5 [M+H] + (calculated for C 58 H 77 F5N6O 10S, 1144.5437). 1HNMR: δ 7.86 (Ph-H, 1H), 7.24 (Ph-H, 1H), 7.00 (Ph-H, 1H), 6.91 (Ph -H, 1H), 6.89 (Ph -H, 1H), 6.82 (Ph -H, 1H), 5.53 (Ph -H, 1H), 5.37 (Ph -H ,1H), 5.07(Ph, 1H), 4.36 (CO-CH2, 2H), 4.24 (CO-CH 2, 2H), 3.65 (OH, 1H), 3.48 (N-CH2,2H), 3.37 (N-CH2, 4H), 3.30 (N-CH2, 4H), 3.09 (OH-CH, 1H), 3.01 (CH2, 8H),2.84 (CH2, 2H), 2.57 (CH2, 4H), 2.24 (CH2, 2H), 1.76-1.78 (CH2, 6H), 1.64-1.67(CH2, 4H), 1.25-1.55 (CH2 / CH, 22H), 0.91 (CH, 1H), 0.80 (CH3, 3H). Compound QDE-FWSQ-12 The specific preparation steps and reaction equations are as follows:

[0119] (1) Same as compound QDE-FWSQ-1.

[0120] (2-1) 112.4 mg of compound 2 (0.154 mmol) and 31.4 mg of tert-butyl piperazine-1-carboxylate (0.169 mmol) were dissolved in 3 ml of dichloromethane, and 46.75 mg of potassium carbonate (0.338 mmol) was added. The mixture was reacted at 40°C for 6 h. The reaction progress was monitored by TLC. After the reaction was completed, water / dichloromethane was added for extraction. The dichloromethane phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified on a silica gel preparative plate to obtain 98.8 mg 4-(2-(((7R,8R,9R,13S,14S,17S)-17-hydroxy-8,9,13,14-tetramethyl-7-(9-(4,4,5,5,5-pentafluoropentyl)sulfinyl)nonyl)-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthrene-3-yl)oxy)-2-oxoethyl)piperazine-1-carboxylic acid tert-butyl ester, yield 73.4%, i.e., compound 12-1.

[0121] (2-2) 98.8 mg of compound 12-1 (0.113 mmol) was dissolved in 5 ml of dichloromethane, and the mixture was cooled to 0°C in an ice bath. 0.5 ml of trifluoroacetic acid was slowly added dropwise to the reaction system. After the addition was complete, the ice bath was removed and the mixture was reacted at room temperature for 3 h. After quenching with sodium bicarbonate solution, the mixture was extracted three times with dichloromethane and water. The dichloromethane layer was separated with a separatory funnel and distilled under reduced pressure at 30°C. The mixture was purified by column chromatography to obtain 80.7 mg (7R, 8R, 9R, 13S, 14S, 17S)-17-hydroxy-8,9,13,14-tetramethyl-7-(9-(4,4,4,5,5-pentafluoropentyl)sulfinyl)nonyl)-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthrene-3-yl-2-(3,9-diazaspiro[5.5]undecane-3-yl)acetate, yield 92.3%, i.e., compound 12-2.

[0122] (2-3) 34.5 mg of 2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindole-4-yl)oxy)acetic acid (0.104 mmol) was added to a 10 ml single-necked bottle, and 2 ml of DCM was added for suspension. 39.5 mg (0.104 mmol) of HATU and 26.8 mg (0.208 mmol) of diisopropylethylamine were added and stirred for activation for 30 min. 80.7 mg of compound 12-2 (0.104 mol) was added and reacted at room temperature for 3 h. The reaction progress was monitored by TLC. After the reaction was completed, the mixture was filtered. The product was extracted with ethyl acetate and water for three times. The ethyl acetate was separated with a separatory funnel, and the product was distilled under reduced pressure. The product was purified by column chromatography to obtain 42.6 mg of (7R, 8S, 9S, 12R, 14S, 17S)-17-hydroxy-12-methyl-7-(9-((4,4,5,5,5-pentafluoropentyl)sulfinyl)nonyl)-7,8,9,11,12,13,14, 15,16,17-decahydro-6H-cyclopenta[a]phenanthrene-3-yl-2-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl)oxy)acetyl)piperazin-1-yl)acetate with a yield of 39.2%, i.e., compound QDE-FWS-12.

[0123] The structure of QDE-FWS-12 was confirmed by mass spectrometry (HR-ESI-MS) and nuclear magnetic resonance hydrogen spectrum (1H-NMR): ESI-MS (positive mode) m / z: 1047.4 [M+H] + (calculated for C 53 H 67 F5N4O 10S, 1046.4498). 1H-NMR (600Hz, CDCl3): 11.323(NH, 1H), 7.9137 (Ph-CH, 1H), 7.594 (Ph-H 2H), 6.764-6.964 (Ph-H, 3H), 4.994 (C=O-CH2, 2H), 4.754 (-OH, 1H), 4.483 (N-CH,1H), 3.782 (N-CH2, 4H), 3.572 (N-CH2, 2H), 3.4134 (OH-CH, 1H), 2.690-2.922(CH2,CH, 11H), 2.433-2.594(CH2, 4H), 2.093-2.233(CH2, 4H) 1.254-1.994(CH2,26H), 0.855(CH3,CH, 4H).

[0124] Compound QDE-FWSQ-13 The specific preparation steps and reaction equations are as follows:

[0125] (1) Same as compound QDE-FWSQ-1.

[0126] (2-1) 112.4 mg of compound 2 (0.154 mmol) and 42.9 mg of tert-butyl 3,9-diazaspiro[5.5]undecane-3-carboxylate (0.169 mmol) were dissolved in 3 ml of dichloromethane, and 46.75 mg of potassium carbonate (0.338 mmol) was added. The mixture was reacted at 40°C for 6 h. The reaction progress was monitored by TLC. After the reaction was completed, water / dichloromethane was added for extraction. The dichloromethane phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified on a silica gel preparation plate to obtain 115.5 mg 9-(2-(((7R,8R,9R,13S,14S,17S)-17-hydroxy-8,9,13,14-tetramethyl-7-(9-(4,4,5,5-pentafluoropentyl)sulfinyl)nonyl)-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthrene-3-yl)oxy)-2-oxoethyl)-3,9-diazaspiro[5.5]undecane-3-carboxylic acid tert-butyl ester, yield 79.6%, i.e., compound 13-1.

[0127] (2-2) 115.5 mg of compound 13-1 (0.122 mmol) was dissolved in 5 ml of dichloromethane, and the mixture was cooled to 0°C in an ice bath. 0.5 ml of trifluoroacetic acid was slowly added dropwise to the reaction system. After the addition was complete, the ice bath was removed and the mixture was reacted at room temperature for 3 h. After quenching with sodium bicarbonate solution, the mixture was extracted three times with dichloromethane and water. The dichloromethane layer was separated with a separatory funnel and distilled under reduced pressure at 30°C. After purification by column chromatography, 93.5 mg (7R, 8R, 9R, 13S, 14S, 17S)-17-hydroxy-8,9,13,14-tetramethyl-7-(9-(4,4,4,5,5-pentafluoropentyl)sulfinyl)nonyl)-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthrene-3-yl-2-(3,9-diazaspiro[5.5]undecane-3-yl)acetate, yield 90.6%, i.e., compound 13-2.

[0128] (2-3) 93.5 mg of compound 13-2 (0.110 mol) was added to a 10 ml single-necked bottle, 2 ml of DMF was added to dissolve, 28.3 mg (0.220 mmol) of diisopropylethylamine was stirred for 5 min, 30.4 mg of 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (0.110 mmol) was added and reacted at 70 °C for 12 h. The reaction progress was monitored by TLC. After the reaction was completed, the mixture was filtered. The mixture was extracted with ethyl acetate and water for three times. After extraction, the ethyl acetate was separated with a separatory funnel, and the mixture was distilled under reduced pressure. The mixture was purified by column chromatography and the (7R, 8R, 9S, 13S, 14S, 17S)-17-hydroxy-13-methyl-7-(9-((4,4,5,5,5-pentafluoropentyl)sulfinyl)nonyl)-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthrene-3-yl-2-(9-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxindol-5-yl)-3,9-diazaspiro[5.5]undecane-3-yl) acetate was 80.5 mg with a yield of 69.3%, i.e., compound QDE-FWSQ-13.

[0129] The structure of QDE-FWS-13 was confirmed by mass spectrometry (HR-ESI-MS) and nuclear magnetic resonance hydrogen spectrum (1H-NMR): ESI-MS (positive mode) m / z: 1057.5 [M+H] + (calculated for C 56 H 73F5N4O8S, 1056.5069). 1H-NMR (600Hz, CDCl3): 11.323(NH, 1H), 7.9137 (Ph-CH, 1H), 7.594 (Ph-H 2H), 6.964 (Ph-H, 2H) , 6.764 (Ph-H, 1H) , 4.754 (-OH, 1H), 4.483 (N-CH, 1H), 3.782 (N-CH2, 4H), 3.572 (N-CH2, 2H), 3.4134 (OH-CH, 1H), 2.832-2.922(Ph-CH2, 2H), 2.433 - 2.594 (CH2, CH, 9H), 1.902-2.233(CH2,4H), 1.254-1.889(CH2,39H), 0.855(CH3,3H).

[0130] Compound QDE-FWSQ-21 The specific preparation steps and reaction equations are as follows:

[0131] (1) Same as compound QDE-FWSQ-1.

[0132] (2) 112.4 mg of compound 2 (0.154 mmol) and 85.5 mg of N-(2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)ethyl)-2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetamide (0.169 mmol) were dissolved in 3 ml of acetonitrile, and 46.75 mg of potassium carbonate (0.338 mmol) was added. The mixture was reacted at 40°C for 6 h. The reaction progress was monitored by TLC. After the reaction was completed, water / dichloromethane was added for extraction. The dichloromethane phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified on a silica gel preparative plate to obtain 111.1 mg (7R, 8R, 9R, 13S, 14S, 17S)-17-hydroxy-8,9,13,14-tetramethyl-7-(9-(4,4,4,5,5-pentafluoropentyl)sulfinyl)nonyl)-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthrene-3-yl(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindole-4-yl)oxy)-2-oxo-6,9,12-trioxa-3-azatetradecane-14-yl)glycine ester, yield 60.4%, i.e., compound QDE-FWS-21.

[0133] The structure of QDE-FWS-21 was confirmed by mass spectrometry (HR-ESI-MS) and nuclear magnetic resonance hydrogen spectrum (1H-NMR): ESI-MS (positive mode) m / z: 1153.5 [M+H] + (calculated for C 57 H 77 F5N4O 13 S, 1152.5128). 1H-NMR (600Hz, CDCl3): 10.933(NH, 1H), 8.021 (Ph-CH, 1H), 7.502 (Ph-H 2H), 6.839-6.902 (Ph -H, 3H), 5.426 (NH-H, 1H), 4.994 (C=O-CH2, 2H), 4.701 (-OH,1H), 4.483 (N-CH, O-CH23H), 3.782 (NH-CH2, 2H), 3.782 (O-CH2, 2H), 3.572 (O-CH2, 10H), 3.402 (OH-CH, 1H), 3.245 (NH-CH2, 2H), 2.6334-2.722(Ph-CH2,NH-CH,3H), 2.433- 2.594 (S=O -CH2, 4H), 1.764-2.292(CH2,CH, 5H), 1.254-1.794(CH2,CH,31H), 0.855(CH3, 3H).

[0134] Example 2 This embodiment relates to a method for preparing a chimeric derivative of an estrogen receptor protein targeted degradation based on an estratriene structure of general formula (I), comprising the following steps: S1: stirring fulvestrant with a monomer having a carboxyl group and a tert-butyloxycarbonyl group in the presence of a condensation agent and a base to obtain an intermediate containing a tert-butyloxycarbonyl protection; S2: The intermediate containing tert-butyloxycarbonyl protection obtained in S1 is placed in an acidic environment to remove the protecting group to obtain an intermediate containing amino group; S3: The intermediate with amino group obtained in S2 is reacted with E3 ligase ligand A with flexible linker, and extracted and purified to obtain estrogen receptor protein targeted degradation chimeric derivative based on estradiol structure of general formula (I), wherein the terminal of E3 ligase ligand A with flexible linker has carboxyl group or keto carbonyl group.

[0135] In step S1, the molar ratio of fulvestrant to the monomer having carboxyl and tert-butyloxycarbonyl groups and the condensation agent is 1:(1.1-1.2):(1.1-1.2).

[0136] In the above step S1, the monomer having carboxyl and tert-butyloxycarbonyl groups is selected from at least one of 1-(tert-butyloxycarbonyl)piperidine-4-carboxylic acid and 1'-(tert-butyloxycarbonyl)-[1,4'-bipiperidine]-4-carboxylic acid.

[0137] The E3 ligase ligand A with a flexible linker in step S3 is selected from at least one of lenalidomide, thalidomide, 4-hydroxy-thalidomide, 5-hydroxy-thalidomide, pomalidomide, 3-(1-oxoisoindolin-2-yl)piperidine-2,6-dione, 4-amino-4-oxo-2-(1-oxoisoindol-2-yl)butyric acid or 2-(1-methyl-2,6-dioxopiperidin-3-yl)isoindole-1,3-dione or its derivatives. A condensing agent is added to the reaction in step S3 and the reaction is carried out at room temperature.

[0138] The condensing agent in the above steps S1 and S3 is selected from at least one of 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride, N, N'-diisopropylcarbodiimide, and dicyclohexylcarbodiimide; the base is selected from at least one of triethylamine, potassium carbonate, sodium carbonate, and diisopropylethylamine.

[0139] The acidic environment in the above step S2 is provided by HCl or TFA, and the pH of the acidic environment is 3-5.

[0140] According to the above preparation method, the following estrogen receptor protein targeted degradation chimeric derivative based on estratriene structure is prepared, specifically as follows: Compound QDE-FWSQ-3 The specific steps and reaction equations are as follows:

[0141] S1: 121.4 g of fulvestrine (0.2 mmol) was dissolved in dichloromethane (5 ml), and 50.38 mg of 1-(tert-butyloxycarbonyl)piperidine-4-carboxylic acid (0.22 mmol), 40.4 mg of triethylamine (0.4 mmol), and 45.4 mg of dicyclohexylcarbodiimide (0.22 mmol) were added in sequence. The mixture was stirred at room temperature for 24 h. The reaction progress was monitored by TLC. After the reaction was completed, a saturated aqueous solution of ammonium chloride was added to quench the reaction. Dichloromethane was added to extract three times. The dichloromethane layer was separated with a separatory funnel, evaporated to dryness in vacuo, and purified by column chromatography to obtain 78.4 mg 1-(tert-Butyl) 4-((7R, 8S, 9S, 12R, 14S, 17S)-17-hydroxy-12-methyl-7-(9-(4,4,5,5,5-pentafluoropentyl)sulfinyl)nonyl)-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthrene-3-yl)piperidine-1,4-dicarboxylate, i.e., compound 3-1 (0.096 mmol), with a yield of 48.1%.

[0142] S2: Dissolve 78.4 mg of compound 3-1 (0.096 mmol) in 5 ml of dichloromethane, cool to 0°C in an ice bath, slowly drip 0.5 ml of trifluoroacetic acid into the reaction system, remove the ice bath after the addition is complete, react at room temperature for 3 h, monitor the reaction progress by TLC, and after the reaction is complete, add sodium bicarbonate solution to quench, extract three times with dichloromethane and water, separate the dichloromethane layer with a separatory funnel, distill under reduced pressure at 30°C, and purify by column chromatography to obtain 62.7mg (7R, 8S, 9S, 12R, 14S, 17S)-17-hydroxy-12-methyl-7-(9-((4,4,5,5,5-pentafluoropentyl)sulfinyl)nonyl)-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthrene-3-ylpiperidine-4-carboxylate (0.087mmol), yield 91.1%, i.e., compound 3-2.

[0143] S3: Add 28.8 mg of 2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindole-4-yl)oxy)acetic acid (0.087 mmol) to a 10 ml single-necked bottle, add 2 ml of DCM to suspend, add 33.1 mg (0.087 mmol) of HATU, 22.4 mg (0.174 mmol) of diisopropylethylamine, stir and activate for 30 min, add 62.7 mg of compound 3-2 (0.087 mmol) The reaction was carried out at room temperature for 3 hours, and the progress of the reaction was monitored by TLC. After the reaction was completed, ethyl acetate and water were used for extraction. After extraction three times, ethyl acetate was separated with a separatory funnel, and the mixture was distilled under reduced pressure. The mixture was purified by column chromatography to obtain 27.9 mg of (7R, 8S, 9S, 12R, 14S, 17S)-17-hydroxy-12-methyl-7-(9-((4,4,5,5,5-pentafluoropentyl)sulfinyl)nonyl)-7,8,9,11,12,13,14,15, 16,17-decahydro-6H-cyclopenta[a]phenanthrene-3-yl-1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl)oxy)acetyl)piperidine-4-carboxylate with a yield of 31.2%, i.e., compound QDE-FWSQ-3.

[0144] The structure of QDE-FWS-3 was confirmed by mass spectrometry (HR-ESI-MS) and nuclear magnetic resonance hydrogen spectrum (1H-NMR): ESI-MS (positive mode) m / z: 1032.4 [M+H]+ (calculated for C 53 H 66 F5N3O 10 ( C=O-CH2, 2H), 4.354 (N-CH, 1H),4.022 (-OH, 1H), 3.416-3.553(N-CH2,OH-H, 5H), 2.549-2.909(CH2, CH, 7H),1.266-2.243(CH2, CH, 40H),0.893(CH3, 3H).

[0145] Compound QDE-FWSQ-4 The specific steps and reaction equations are as follows:

[0146] S1: 121.4 g of fulvestrine (0.2 mmol) was dissolved in dichloromethane (5 ml), and 68.64 mg of 1'-(tert-butyloxycarbonyl)-[1,4'-bipiperidine]-4-carboxylic acid (0.22 mmol), 40.4 mg of triethylamine (0.4 mmol), and 45.4 mg of dicyclohexylcarbodiimide (0.22 mmol) were added in sequence. The mixture was stirred at room temperature for 24 h. The progress of the reaction was monitored by TLC. After the reaction was completed, a saturated aqueous solution of ammonium chloride was added to quench the reaction. Dichloromethane was added to extract three times. The dichloromethane layer was separated with a separatory funnel, evaporated to dryness in vacuo, and purified by column chromatography to obtain 108.9 mg. 1'-(tert-Butyl) 4-((7R, 8S, 9S, 12R, 14S, 17S)-17-hydroxy-12-methyl-7-(9-(4,4,5,5,5-pentafluoropentyl)sulfinyl)nonyl)-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthrene-3-yl)[1,4'-bipiperidinyl]-1',4-dicarboxylate (0.121 mmol), i.e., compound 4-1, yield 60.5%.

[0147] S2: 108.9 mg of compound 4-1 (0.121 mmol) was dissolved in 5 ml of dichloromethane, cooled to 0°C in an ice bath, and 0.5 ml of trifluoroacetic acid was slowly added to the reaction system. After the addition was complete, the ice bath was removed and the reaction was carried out at room temperature for 3 h. The reaction progress was monitored by TLC. After the reaction was completed, sodium bicarbonate solution was added to quench the reaction, and dichloromethane and water were extracted three times. The dichloromethane layer was separated with a separatory funnel, and the mixture was distilled under reduced pressure at 30°C. Purification by column chromatography gave 86 .4mg (7R, 8S, 9S, 12R, 14S, 17S)-17-hydroxy-12-methyl-7-(9-((4,4,5,5,5-pentafluoropentyl)sulfinyl)nonyl)-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthrene-3-yl[1,4'-bipiperidine]-4-carboxylate (0.108mmol), yield 89.9%, i.e. compound 4-2.

[0148] S3: 34.7 mg of 2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindole-4-yl)oxy)acetic acid (0.108 mmol) was added to a 10 ml single-necked bottle, 2 ml of DCM was added for suspension, 41.2 mg (0.108 mmol) of HATU and 27.9 mg (0.216 mmol) of diisopropylethylamine were added, and the mixture was stirred for activation for 30 min, and 86.4 mg of compound 4-2 (0.108 mmol) was added. The reaction was carried out at room temperature for 3 h, and the progress of the reaction was monitored by TLC. After the reaction was completed, ethyl acetate and water were used for extraction. After extraction three times, ethyl acetate was separated by a separatory funnel, and the mixture was distilled under reduced pressure. The mixture was purified by column chromatography to obtain 43.8 mg of (7R, 8S, 9S, 12R, 14S, 17S)-17-hydroxy-12-methyl-7-(9-((4,4,5,5,5-pentafluoropentyl)sulfinyl)nonyl)-7,8,9,11,12,13,14,15, 16, 17-decahydro-6H-cyclopenta[a]phenanthrene-3-yl 1'-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl)oxy)acetyl)-[1,4'-bipiperidine]-4-carboxylate with a yield of 36.4%, i.e., compound QDE-FWSQ-4.

[0149] The structure of QDE-FWS-4 was confirmed by mass spectrometry (HR-ESI-MS) and nuclear magnetic resonance hydrogen spectrum (1H-NMR): ESI-MS (positive mode) m / z: 1115.5 [M+H]+ (calculated for C 58 H 75 F5N4O 10 ( C=O-CH2, 2H), 4.354 (N-CH, 1H), 4.022 (-OH, 1H), 3.416-3.553(N-CH2,OH-H, 5H), 2.549-2.909(CH2, CH, 7H), 1.266-2.243(CH2, CH, 49H). 0.893(CH3, 3H).

[0150] Example 3 This embodiment relates to a method for preparing a chimeric derivative of an estrogen receptor protein targeted degradation based on an estratriene structure of general formula (I), comprising the following steps: (1): Fulvestrant and dihaloalkane are dissolved in a solvent, and an acid binding agent is added and stirred to obtain FWSQ-C5.

[0151] (2) Dissolving the compound containing the amino group and the E3 ligase ligand end and FWSQ-C5 in an organic solvent, adding N,N-diisopropylethylamine and sodium iodide, stirring at 10-35° C. after the reaction is completed, extracting and purifying to obtain an estrogen receptor protein targeted degradation chimeric derivative based on the estradiol structure of the general formula (I).

[0152] Compound QDE-FWSQ-17

[0153] S1: 242.6 mg of the compound Fulvestrant (0.4 mmol) and 123.9 mg of 1-bromo-3-iodopropane (0.5 mmol) were added to 3 ml of DMF for dissolution, and 138 mg of potassium carbonate (1.0 mmol) was added. The mixture was reacted at 25°C for 12 h. The reaction progress was monitored by TLC. After the reaction was completed, water / dichloromethane was added for extraction. The dichloromethane phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (DCM:MeOH 40:1-20:1) to obtain 198.4 mg of FWS-C5 with a yield of 68.3%.

[0154] S2: 82.1 mg of 2-(2,6-dioxoylidenehexahydropyridin-3-yl)-5-(3,9-diazaspiro[5.5]undecane-3-yl)isoindole-1,3-dione (0.2 mmol) was dissolved in DMF, 51.6 mg of DIPEA (0.4 mmol) was added, and the mixture was stirred for 5 min. Then 145 mg of 2-(2,6-dioxoylidenehexahydropyridin-3-yl)-5-(3,9-diazaspiro[5.5]undecane-3-yl)isoindole-1,3-dione (0.2 mmol) and 30 mg of NaI (0.2 mmol) were added. The mixture was reacted at 40 °C for 12 h. After the reaction was completed by TLC monitoring, DMF was removed by rotary evaporation, DCM was added for filtration, and the filtrate was concentrated. Purification was performed on a silica gel preparation plate (DCM:MeOH 15:1) to obtain 89.9 mg of QDE-FWSQ-17 with a yield of 42.1%.

[0155] The structure of QDE-FWSQ-17 was confirmed by mass spectrometry (HR-ESI-MS) and nuclear magnetic resonance hydrogen spectrum (1H-NMR): ESI-MS (positive mode) m / z: [M+H]+1057.5 (calculated for C 57 H 77F5N4O7S, 1056.5433).1H NMR: δ 8.15 (Ph-H, 1H), 8.08 (Ph-H, 1H), 7.00 (Ph-H, 1H), 6.91 (Ph-H, 1H), 6.82 (Ph-H, 1H), 6.67 (Ph-H, 1H), 5.53 (N-CH, 1H), 5.07 (OH, 1H), 3.98 (O-CH2, 2H), 3.65 (OH-CH, 1H), 3.33 (N-CH2, 10H), 3.09 (CH, 1H), 2.84 (CH2, 2H),2.44-2.57 (CH2, 12H), 2.24 (CH2, 2H), 1.76-1.90 (CH2, 8H), 1.64-1.67 (CH2,4H), 1.44-1.55 (CH2, 10H), 1.25-1.31 CH2, (12H), 0.91 (CH, 1H), 0.80 (CH3,3H).

[0156] Compound QDE-FWSQ-19

[0157] S1: Take a 10 ml single-mouth bottle, add 96.4 mg tert-butyl 3-(piperazine-1-yl)azetidine-1-carboxylate (0.4 mol), add 2 ml DMSO to dissolve, add 103.2 mg (0.8 mmol) diisopropylethylamine and stir for 5 min, add 110.4 mg 2-(2,6-dioxypyridin-3-yl)-5-fluoroisoindole-1,3-dione (0.4 mmol) and react at 80 ° C for 12 h. Monitor the reaction progress by TLC. After the reaction is completed, filter. The mixture was extracted with ethyl acetate and water for three times. The ethyl acetate was separated with a separatory funnel, and then distilled under reduced pressure. The mixture was purified by column chromatography (DCM: MeOH 30:1-10:1) to obtain 167.7 mg of tert-butyl 3-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindole-5-yl)piperazine-1-yl)azetidine-1-carboxylate, i.e., the yield of CRBN-19 was 84.4%. S2: Take a 10ml single-mouth bottle, add 167.7mg (0.337mmol) tert-butyl 3-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindole-5-yl)piperazine-1-yl)azetidine-1-carboxylate, add 5ml dichloromethane to dissolve, cool to 0℃ in an ice bath, slowly drip 0.5ml trifluoroacetic acid into the reaction system, remove the ice bath after the addition is complete, react at room temperature for 3h, add sodium bicarbonate solution to quench, extract with dichloromethane and water three times, separate the dichloromethane layer with a separatory funnel, distill under reduced pressure at 30℃, and purify by column chromatography (DCM: MeOH 10:1) to give 123.4 mg of compound 5-(4-(azetidin-3-yl)piperazine-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione, with a yield of 92.1%.

[0158] S3: Dissolve 79.4 mg of 5-(4-(azetidin-3-yl)piperazine-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione (0.2 mmol) in DMF, add 51.6 mg of DIPEA (0.4 mmol), stir for 5 min, then add 145 mg of FWSQ-C5 (0.2 mmol), 30 mg of NaI (0.2 mmol), react at 40 °C for 12 h, after the reaction is completed as monitored by TLC, remove DMF by rotary evaporation, add DCM for filtration, and concentrate the filtrate. Purification on silica gel prep plate (DCM:MeOH 15:1) afforded 81.5 mg of 2-(2,6-dioxopiperidin-3-yl)-5-(4-(1-(3-(((7R,8S,9R,13R,14R,17R)-17-hydroxy-13-methyl-7-(9-(4,4,5,5-pentafluoropentyl)sulfinyl)nonyl)-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthrene-3-yl)oxy)propyl)azetidin-3-yl)piperazin-1-yl)isoindole-1,3-dione, i.e., QDE-FWSQ-19, in a 39.1% yield.

[0159] The structure of QDE-FWSQ-17 was confirmed by mass spectrometry (HR-ESI-MS) and nuclear magnetic resonance hydrogen spectrum (1H-NMR): ESI-MS (positive mode) m / z: [M+H]+1044.5 (calculated for C 55 H 74F5N5O7S, 1043.5229).1H NMR: δ 8.15 (Ph-H, 1H), 8.08 (Ph-H,1H), 7.00 (Ph-H,1H), 6.91 (Ph-H,1H), 6.82 (Ph-H,1H), 6.67 (Ph-H,1H), 5.53 (NH, 1H), 5.37 (NH, 1H), 5.07 (OH,1H), 3.98 (N-CH2, 2H), 3.65 (OH-CH, 1H), 3.33 (CH2 / CH, 10H), 3.09 (CH, 1H),2.84 (CH2, 2H), 2.57 (CH2, 4H), 2.44 (CH2, 8H), 2.24 (CH2, 2H), 1.76-1.90 (CH2,8H), 1.64-1.67 (CH2, 4H), 1.44-1.55 (CH2, 10H), 1.25-1.31 (CH2, 12H), 0.91(CH, 1H), 0.80 (CH3, 3H).

[0160] Compound QDE-CEC-4

[0161] S1: Take a 25ml single-mouth bottle, add 54.4mg estradiol (0.2mmol), add dichloromethane (5ml) to dissolve, add 68.64mg 1'-(tert-butyloxycarbonyl)-[1,4'-bipiperidine]-4-carboxylic acid (0.22mmol), 40.4mg triethylamine (0.4mmol), 45.4mg dicyclohexylcarbodiimide (0.22mmol) in sequence, stir at room temperature for 24h, monitor the reaction progress by TLC, after the reaction is completed, add saturated ammonium chloride aqueous solution to quench the reaction, add dichloromethane to extract three times, separate the dichloromethane layer with a separatory funnel, evaporate to dryness in vacuo, and purify by silica gel column chromatography ((DCM :MeOH 40:1-10:1) to obtain 46.6mg 4-[4-({[(1S,3aS,3bR,9bS,11aS)-1-hydroxy-11a-methyl-2,3,3a,3b,4,5,9b,10,11,11a-decahydro-1H-cyclopenta[1,2-a]phenanthrene-7-yl]oxy}carbonyl)piperidin-1-yl]piperidin-1-carboxylic acid-2-methylpropan-2-yl ester, i.e., CEC-4-1, with a yield of 41.2%.

[0162] S2: Take a 25 ml single-mouth bottle and add 46.6 mg of the compound 4-[4-({[(1S,3aS,3bR,9bS,11aS)-1-hydroxy-11a-methyl-2,3,3a,3b,4,5,9b,10,11,11a-decahydro-1H-cyclopenta[1,2-a]phenanthrene-7-yl]oxy}carbonyl)piperidin-1-yl]piperidin-1-carboxylic acid-2-methylpropane-2 -yl ester (0.082mmol), add 5ml of dichloromethane to dissolve, cool to 0℃ in an ice bath, slowly drop 0.5ml of trifluoroacetic acid into the reaction system, remove the ice bath after the addition is complete, react at room temperature for 3h, monitor the reaction progress by TLC, after the reaction is complete, add sodium bicarbonate solution to quench, extract three times with dichloromethane and water, separate the dichloromethane layer with a separatory funnel, distill under reduced pressure at 30℃, and purify by column chromatography (DCM: MeOH 10:1) to give 34.6 mg of 1-(piperidin-4-yl)piperidin-4-carboxylic acid-(1S,3aS,3bR,9bS,11aS)-1-hydroxy-11a-methyl-2,3,3a,3b,4,5,9b,10,11,11a-decahydro-1H-cyclopenta[1,2-i]phenanthrene-7-yl ester, namely CEC-4-2, with a yield of 90.3%.

[0163] S3: Take a 10ml single-mouth bottle, add 24.6mg 2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindole-4-yl)oxy)acetic acid (0.074mmol), add to the 10ml single-mouth bottle, add 2ml DCM to suspend, add 28.1mg (0.074mmol) HATU, 19mg (0.148mmol) diisopropylethylamine, stir and activate for 30min, add 34.6mg CEC-4-2 (0.074mmol) and react at room temperature for 3h. Monitor the reaction progress by TLC. After the reaction is completed, extract with ethyl acetate and water. After extraction three times, separate the ethyl acetate with a separatory funnel, distill under reduced pressure, and purify by column chromatography (DCM: MeOH The reaction mixture was stirred for 30:1-10:1 to obtain 19.2 mg of the compound 1-[1-(2-{[2-(2,6-dioxypyridin-3-yl)-1,3-dioxypyridin-2,3-dihydro-1H-isoindol-4-yl]oxy}acetyl)pyridin-4-yl]pyridin-4-carboxylic acid-(1S,3aS,3bR,9bS,11aS)-1-hydroxy-11a-methyl-2,3,3a,3b,4,5,9b,10,11,11a-decahydro-1H-cyclopenta[1,2-i]phenanthrene-7-yl ester, with a QDE-CEC-4 yield of 33.2%.

[0164] The structure of QDE-CEC-4 was confirmed by mass spectrometry (HR-ESI-MS) and nuclear magnetic resonance hydrogen spectrum (1H-NMR): ESI-MS (positive mode) m / z: [M+H]+ =781.3 (calculated for C 44 H 52 N4O9, 780.3734). 1HNMR: δ 7.86 (Ph-H, 1H), 7.24 (Ph-H, 1H), 7.00 (Ph-H, 1H), 6.91 (Ph-H, 1H), 6.89 (Ph-H, 1H), 6.82 (Ph-H, 1H), 5.53 (N-CH, H), 5.37 (N-CH, 1H), 5.07 (N-CH, 1H), 4.36 (CO-CH2, 2H), 3.65-3.76 (O-CH2, 2H), 3.33 (N-CH2, 8H), 3.09 (OH,1H), 3.00 (CH2, 4H), 2.83 (CH2, 2H), 2.34 (CH , 1H), 2.24 (CH2, 2H), 1.97 (CH2,2H), 1.77-1.78 (CH2, 4H), 1.65 (CH2, 4H), 1.47-1.56 (CH2 / CH, 8H), 0.80 (CH3,3H).

[0165] Test Example 1 Determination of estrogen receptor proteolytic activity The estrogen receptor protein targeted degradation chimeric derivative based on the estratriene structure prepared in the above example was tested for estrogen receptor protein hydrolysis activity, and QDE-003-C in the CN118027003A patent was used as a control. The experimental process is as follows: 1. Take MCF-7 cells in the logarithmic growth phase, plate them into 6-well plates at 1.5×106 / well, and culture them overnight; 2. Add the positive drug and test substance groups with a final concentration of 1 μM (DMSO ratio of 0.1%) and incubate in the incubator for 24 hours; 3. Collect cells from each group and wash once with PBS; add cell lysis buffer containing 1×Protease Inhibitor cocktail and 1×Phosphatase Inhibitor Cocktail II, lyse thoroughly on ice, centrifuge at 4°C, 14,000 rpm for 10 min, and collect the supernatant.

[0166] 4. After the protein concentration was determined by BCA kit, the Estrogen Receptor alpha protein level was detected by Western blot.

[0167] The test results are shown in Table 1. The Western Blot experimental image diagram of the inhibition of ER protein level in MCF-7 cells by the estrogen receptor protein targeted degradation chimeric derivative based on the estradiol structure is shown in Figure 1-3 , the quantitative graph of protein concentration in WB experiment of ER protein degradation is shown in Figure 4 , Figure 1-3 "17: Fulvestrant 0.1μM" is the control of Fulvestrant. It can be seen that at the same dosage concentration (0.1μM), the ratio of the IntDen value of the estrogen receptor protein (ER) to the internal reference (GAPDH) of the four compounds QDE-FWSQ-3, QDE-FWSQ-4, QDE-FWSQ-12, and QDE-FWSQ-21 is lower than that of the positive control drug Fulvestrant. This proves that its ability to degrade the estrogen receptor in MCF-7 breast cancer cells is higher than that of the positive control drug Fulvestrant.

[0168] Table 1 Results of estrogen receptor proteolytic activity assay

[0169] The above is only the embodiment of the present application, and the protection scope of the present application is not limited by these specific embodiments, but is determined by the claims of the present application. For those skilled in the art, the present application can have various changes and variations. Any modification, equivalent replacement, improvement, etc. made within the technical ideas and principles of the present application should be included in the protection scope of the present application.

Claims

1. An estrogen receptor protein targeted degradation chimeric derivative based on estratriene structure, characterized in that: It has the structure of general formula (I): ABC formula (I); Wherein A is an E3 ligase ligand selected from one of the general formula (II-1), general formula (II-2) or general formula (II-3): Formula (II-1); Formula (II-2); Formula (II-3); * represents the connection site, n = 0 or 1, m = 0 or 1, in formula (II-1), general formula (II-2) and general formula (II-3), R1, R2 and R3 are each independently one of: H, OH, F, Cl, Br, NH2, CH3 or OCH3, and R4 is hydrogen or methyl; B is at least one of a rigid linking group, a flexible linking group, and a bridging group; C has the structure of general formula (III): Formula (III).

2. The estrogen receptor protein targeted degradation chimeric derivative based on estratriene structure according to claim 1, characterized in that: The estrogen receptor protein targeted degradation chimeric derivative based on the estratriene structure comprises its cis-trans isomers and racemic isomers.

3. The estrogen receptor protein targeted degradation chimeric derivative based on estratriene structure according to claim 1, characterized in that: Has one of the following structural formulas: ； ； ； ； ； ； ； ； ; ； 。 4. The method for preparing the chimeric derivative of the estrogen receptor protein targeted degradation based on the estratriene structure according to any one of claims 1 to 3, characterized in that: The steps include: (1) placing fulvestrant in a solvent, adding an acid-binding agent and cooling the temperature to 1-5°C, then adding a monomer containing a halogen atom and an acyl halide group to react, thereby obtaining compound 2; (2) reacting compound 2 with a monomer having an amino group and a tert-butyloxycarbonyl group and an E3 ligase ligand A having a flexible linker in sequence to obtain an estrogen receptor protein targeted degradation chimeric derivative based on an estratriene structure of general formula (I), wherein the E3 ligase ligand A having a flexible linker has a carboxyl group or a ketocarbonyl group at its end; or Compound 2 is reacted with E3 ligase ligand B with a flexible linker to obtain an estrogen receptor protein targeted degradation chimera derivative based on estratriene structure of general formula (I), wherein the E3 ligase ligand B with a flexible linker has an amino group at the end.

5. The preparation method according to claim 4, characterized in that: Step (2) Compound 2 is reacted with a monomer having an amino group and a tert-butyloxycarbonyl group and an E3 ligase ligand A having a flexible linker in sequence to obtain an estrogen receptor protein targeted degradation chimeric derivative based on an estratriene structure of general formula (I): (2-1): Compound 2 is subjected to a condensation reaction with a monomer having an amino group and a tert-butyloxycarbonyl group to obtain an intermediate A; (2-2): The intermediate A is deprotected under an acidic environment to obtain an intermediate B with an amino group; (2-3): Intermediate B undergoes a condensation reaction with E3 ligase ligand A having a flexible linker to obtain an estrogen receptor protein targeted degradation chimeric derivative based on an estratriene structure of general formula (I).

6. The method for preparing the chimeric derivative of the estrogen receptor protein targeted degradation based on the estratriene structure according to any one of claims 1 to 3, characterized in that: The steps include: S1: stirring fulvestrant with a monomer having a carboxyl group and a tert-butyloxycarbonyl group in the presence of a condensation agent and a base to obtain an intermediate containing a tert-butyloxycarbonyl protection; S2: The intermediate containing tert-butyloxycarbonyl protection obtained in S1 is placed in an acidic environment to remove the protecting group to obtain an intermediate containing amino group; S3: The intermediate with amino group obtained in S2 is reacted with E3 ligase ligand A with carboxyl group, and extracted and purified to obtain the estrogen receptor protein targeted degradation chimeric derivative based on estradiol structure of general formula (I), wherein the E3 ligase ligand A with flexible linker has a carboxyl group or a keto carbonyl group at the end.

7. The method for preparing the chimeric derivative of the estrogen receptor protein targeted degradation based on the estratriene structure according to any one of claims 1 to 3, characterized in that: The steps include: D1: Fulvestrant and dihaloalkane are dissolved in a solvent, and an acid-binding agent is added and stirred to obtain FWSQ-C5; D2: Dissolve the compound containing the amino group and the E3 ligase ligand end and FWSQ-C5 in an organic solvent, add N,N-diisopropylethylamine and sodium iodide, stir the reaction, extract and purify, and obtain the estrogen receptor protein targeted degradation chimeric derivative based on the estradiol structure of the general formula (I).

8. A pharmaceutical composition, characterized in that The composition contains: a therapeutically effective amount of the estrogen receptor protein targeted degradation chimera derivative based on the estratriene structure according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

9. Use of the estrogen receptor protein targeted degradation chimera derivative based on estratriene structure according to any one of claims 1 to 3 or the pharmaceutical composition according to claim 8 in the preparation of drugs for preventing and treating breast cancer.

10. Use of the estrogen receptor protein targeted degradation chimera derivative based on estratriene structure according to any one of claims 1 to 3 or the pharmaceutical composition according to claim 8 in the preparation of drugs for treating diseases related to the estrogen receptor protein targeted degradation chimera.

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