Adamantane derivatives, ER-targeted PROTAC degraders, preparation methods, and applications thereof

Abstract

The present application provides a compound, which is an adamantane derivative, comprising a ligand R1 that specifically binds to a target protein (i.e., an estrogen receptor), a ligand R2 that recruits an E3 ubiquitin ligase, and a chemical chain Linker connecting the two parts. Linker is an alkyl chain of varying lengths, wherein the number of carbon atoms in the alkyl chain is n, where 1≤n≤20, and n is an integer; or Linker is a polyethylene glycol chain of varying lengths, wherein the number of oxygen atoms in the polyethylene glycol chain is m, where 1≤m≤5, and m is an integer. The compound provided herein exhibits significant anti-tumor activity through the PROTAC mechanism; in the breast cancer MCF-7 cell line, the proliferation of tumor cells is inhibited by degrading Erα protein, providing a new strategy for the treatment of breast cancer.

Description

Technical Field

[0001] The present invention relates to the field of anti-tumor drugs, and in particular to an adamantane derivative, an ER-targeting PROTAC degrader, a preparation method and applications thereof. Background Art

[0002] Breast cancer is one of the most common malignant tumors in women worldwide, with high morbidity and mortality rates. According to the World Health Organization (WHO), approximately 1.8 million new cases of breast cancer are diagnosed each year, and approximately 660,000 women die from breast cancer each year. Breast cancer is treated with a variety of methods, including surgery, radiotherapy, chemotherapy, hormone therapy, and targeted therapy. However, treatment success is affected by numerous factors, including the tumor's molecular subtype, patient age, hormone receptor status, and timely treatment. Among molecular subtypes of breast cancer, estrogen receptor (ER)-positive breast cancer is the most common subtype, accounting for approximately 70% of all breast cancer cases. Treatment of ER-positive breast cancer typically relies on hormonal therapy, which involves blocking the effects of estrogen with anti-estrogen drugs such as tamoxifen or anastrozole, thereby inhibiting tumor growth. However, hormonal therapy is not effective for all patients, and long-term treatment can lead to drug resistance, limiting its clinical application. Summary of the Invention

[0003] The present invention provides a method for preparing an adamantane derivative and a PROTAC (targeted protein degradation chimera) degrader targeting ER and its application to solve the above-mentioned technical problems.

[0004] In order to solve the above technical problems, the present invention provides a compound, which is an adamantane derivative, and has the structural formula (I):

[0005]

[0006] Linker is an alkyl chain of different lengths, the number of carbon atoms in the alkyl chain is n, where 1≤n≤20, and n is an integer;

[0007] Or the linker is a polyethylene glycol chain of different lengths, the number of oxygen atoms in the polyethylene glycol chain is m, 1≤m≤5, and m is an integer.

[0008] Furthermore, the alkyl chain includes a branched alkyl chain and an alkyl chain.

[0009] Furthermore, the Linker is selected from any one of the following structures:

[0010]

[0011] Furthermore, the compounds include but are not limited to compounds having the following structural formula:

[0012] Structural formula 1-1

[0013]

[0014] N-(4-(4-(((1r,3r,5R,7S)-adamantan-2-ylidene)(4-hydroxyphenyl)methyl)phenoxy)butyl)-4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)butanamide;

[0015]

[0016] N-(4-(4-(((1r,3r,5R,7S)-adamantan-2-ylidene)(4-hydroxyphenyl)methyl)phenoxy)butyl)-5-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)pentanamide;

[0017]

[0018] N-(4-(4-(((1r,3r,5R,7S)-adamantan-2-ylidene)(4-hydroxyphenyl)methyl)phenoxy)butyl)-6-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)hexanamide;

[0019]

[0020] N-(4-(4-(((1r,3r,5R,7S)-adamantan-2-ylidene)(4-hydroxyphenyl)methyl)phenoxy)butyl)-7-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)heptylamide;

[0021]

[0022] N-(4-(4-(((1r,3r,5R,7S)-adamantan-2-ylidene)(4-hydroxyphenyl)methyl)phenoxy)butyl)-8-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)octanamide;

[0023]

[0024] N-(4-(4-(((1r,3r,5R,7S)-adamantan-2-ylidene)(4-hydroxyphenyl)methyl)phenoxy)butyl)-9-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)nonanamide;

[0025]

[0026] N-(4-(4-(((1r,3r,5R,7S)-adamantan-2-ylidene)(4-hydroxyphenyl)methyl)phenoxy)butyl)-10-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)decanamide;

[0027]

[0028] N-(4-(4-(((1r,3r,5R,7S)-adamantan-2-ylidene)(4-hydroxyphenyl)methyl)phenoxy)butyl)-11-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)undecanoamide;

[0029]

[0030] N-(4-(4-(((1r,3r,5R,7S)-adamantan-2-ylidene)(4-hydroxyphenyl)methyl)phenoxy)butyl)-12-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)dodecanoamide;

[0031]

[0032] N-(4-(4-(((1r,3r,5R,7S)-adamantan-2-ylidene)(4-hydroxyphenyl)methyl)phenoxy)butyl)-13-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)tridecamide;

[0033]

[0034] N-(4-(4-(((1r,3r,5R,7S)-adamantan-2-ylidene)(4-hydroxyphenyl)methyl)phenoxy)butyl)-14-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)tetradecanoic acid amide;

[0035]

[0036] N-(4-(4-(((1r,3r,5R,7S)-adamantan-2-ylidene)(4-hydroxyphenyl)methyl)phenoxy)butyl)-15-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)pentadecanamide;

[0037]

[0038] N-(4-(4-(((1r,3r,5R,7S)-adamantan-2-ylidene)(4-hydroxyphenyl)methyl)phenoxy)butyl)-16-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)hexadecanoamide;

[0039]

[0040] N-(4-(4-(((1r,3r,5R,7S)-adamantan-2-methylene)(4-hydroxyphenyl)methyl)phenoxy)butyl)-3-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)ethoxy)propanamide;

[0041]

[0042] N-(4-(4-(((1r,3r,5R,7S)-adamantan-2-ylidene)(4-hydroxyphenyl)methyl)phenoxy)butyl)-3-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)ethoxy)ethoxy)propanamide;

[0043]

[0044] N-(4-(4-(((1r,3r,5R,7S)-adamantan-2-ylidene)(4-hydroxyphenyl)methyl)phenoxy)butyl)-3-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)ethoxy)ethoxy)ethoxy)propanamide;

[0045]

[0046] N-(4-(4-(((1r,3r,5R,7S)-adamantan-2-ylidene)(4-hydroxyphenyl)methyl)phenoxy)butyl)-1-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)-3,6,9,12-tetraoxopentadecane-15-amide;

[0047]

[0048] N-[4-[4-(1R,3R,5R,7S)-adamantane-2-methylenemethyl]phenoxy]butyl]-1-[(2-[(2,6-dioxopiperidin-3-yl)-1-oxoisoindol-4-yl]amino)-3,6,9,12,15-pentaoxooctane-18-carboxamide].

[0049] To solve the above technical problems, the present invention also provides a method for preparing the above compound, comprising:

[0050] Synthetic intermediate 4-[[4-(4-aminobutyloxy)phenyl]tricyclo[3.3.1.13,7]dec-2-methylene]phenol;

[0051] Then, 3-(4-amino-1-oxoisoindol-2-yl)piperidine-2,6-dione was connected to the intermediate via a linker to obtain the target compound.

[0052] To solve the above technical problems, the present invention also provides a PROTAC degrader targeting ER, wherein the PROTAC degrader targeting ER comprises the above compound, wherein R1 is a ligand that specifically binds to the estrogen receptor, and R2 is a ligand that recruits E3 ubiquitin ligase;

[0053] R1 is

[0054]

[0055] R2 is

[0056]

[0057] To solve the above technical problems, the present invention also provides the use of the above-mentioned compound and the above-mentioned ER-targeting PROTAC degrader in the prevention and treatment of breast tumors.

[0058] To solve the above technical problems, the present invention also provides an anti-tumor drug, comprising a pharmaceutically active ingredient and a pharmaceutical excipient, characterized in that the pharmaceutically active ingredient comprises the above-mentioned compound or the above-mentioned ER-targeting PROTAC degrader.

[0059] To solve the above technical problems, the present invention also provides a method for treating tumors, wherein the above-mentioned compound or the above-mentioned ER-targeting PROTAC degrader is applied to the breast area.

[0060] Compared with the prior art, the compound provided in this application includes a ligand R1 that specifically binds to the target protein (ie, estrogen receptor), a ligand R2 that recruits the E3 ubiquitin ligase, and a chemical chain Linker that connects the two parts. The compound can bring the estrogen receptor closer to the E3 ubiquitin ligase, mark the estrogen receptor through the ubiquitination process, and then degrade it through the 26S proteasome pathway, thereby reducing the concentration of the estrogen receptor in the cell and regulating the biological processes related to it. The compound provided in this application exhibits significant anti-tumor activity through the PROTAC mechanism; it inhibits the proliferation of tumor cells by degrading Erα protein in the breast cancer MCF-7 cell line, providing a new strategy for the treatment of breast cancer.

[0061] Compared to traditional inhibitors, the ER-targeted PROTAC degraders provided in this application do not need to bind to the active site of the target protein, thus overcoming drug resistance caused by mutations. They also present a lower risk to cardiac safety and have a very good safety profile.

[0062] In addition, the metabolic process of the compound of the present application involves more metabolic enzymes and more metabolic pathways, which makes it difficult for potential drug-drug interactions to occur, reduces treatment deviations between patients, and has good safety and high reliability. BRIEF DESCRIPTION OF THE DRAWINGS

[0063] Figure 1 is a graph showing the relationship between the percentage of the estrogen receptor α subtype level of the compound of Example 1 and the concentration of the compound of Example 1;

[0064] Figure 2 is a graph showing the relationship between the percentage of the estrogen receptor α subtype level of the compound of Example 2 and the concentration of the compound of Example 1;

[0065] Figure 3 is a graph showing the relationship between the percentage of the estrogen receptor α subtype level of the compound of Example 3 and the concentration of the compound of Example 1;

[0066] Figure 4 is a graph showing the relationship between the percentage of the estrogen receptor α subtype level of the compound of Example 4 and the concentration of the compound of Example 1;

[0067] Figure 5 is a graph showing the relationship between the percentage of the estrogen receptor α subtype level of the compound of Example 5 and the concentration of the compound of Example 1;

[0068] Figure 6 is a graph showing the relationship between the percentage of the estrogen receptor α subtype level of the compound of Example 6 and the concentration of the compound of Example 1;

[0069] Figure 7is a graph showing the relationship between the percentage of the estrogen receptor α subtype level of the compound of Comparative Example 1 and the concentration of the compound of Example 1;

[0070] Figure 8 is a graph showing the relationship between the inhibition rate and the compound concentration of the compound of Example 1;

[0071] Figure 9 The relationship between the inhibition rate of the compound of Example 4 and the concentration of the compound;

[0072] Figure 10 The relationship between the inhibition rate of the compound of Example 5 and the concentration of the compound;

[0073] Figure 11 The relationship between the inhibition rate of the compound of Example 6 and the concentration of the compound;

[0074] Figure 12 The relationship between the inhibition rate of the compound in Comparative Example 1 and the compound concentration. DETAILED DESCRIPTION

[0075] In order to further illustrate the technical means and effects adopted by the present invention to achieve the predetermined purpose, the specific implementation methods, methods, steps, structures, characteristics and effects of the positive electrode material proposed in accordance with the present invention are described in detail below in conjunction with the accompanying drawings and preferred embodiments.

[0076] The aforementioned and other technical contents, features, and effects of the present invention will be clearly presented in the following detailed description of the preferred embodiments with reference to the accompanying drawings. Through the description of the specific embodiments, a deeper and more detailed understanding of the technical means and effects adopted by the present invention to achieve the intended objectives can be obtained. However, the accompanying drawings are provided for reference and illustration purposes only and are not intended to limit the present invention.

[0077] The present invention includes the following compounds:

[0078]

[0079] N-(4-(4-(((1r,3r,5R,7S)-adamantan-2-ylidene)(4-hydroxyphenyl)methyl)phenoxy)butyl)-4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)butanamide;

[0080]

[0081] N-(4-(4-(((1r,3r,5R,7S)-adamantan-2-ylidene)(4-hydroxyphenyl)methyl)phenoxy)butyl)-5-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)pentanamide;

[0082]

[0083] N-(4-(4-(((1r,3r,5R,7S)-adamantan-2-ylidene)(4-hydroxyphenyl)methyl)phenoxy)butyl)-6-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)hexanamide;

[0084]

[0085] N-(4-(4-(((1r,3r,5R,7S)-adamantan-2-ylidene)(4-hydroxyphenyl)methyl)phenoxy)butyl)-7-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)heptylamide;

[0086]

[0087] N-(4-(4-(((1r,3r,5R,7S)-adamantan-2-ylidene)(4-hydroxyphenyl)methyl)phenoxy)butyl)-8-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)octanamide;

[0088]

[0089] N-(4-(4-(((1r,3r,5R,7S)-adamantan-2-ylidene)(4-hydroxyphenyl)methyl)phenoxy)butyl)-9-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)nonanamide;

[0090]

[0091] N-(4-(4-(((1r,3r,5R,7S)-adamantan-2-ylidene)(4-hydroxyphenyl)methyl)phenoxy)butyl)-10-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)decanamide;

[0092]

[0093] N-(4-(4-(((1r,3r,5R,7S)-adamantan-2-ylidene)(4-hydroxyphenyl)methyl)phenoxy)butyl)-11-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)undecanoamide;

[0094]

[0095] N-(4-(4-(((1r,3r,5R,7S)-adamantan-2-ylidene)(4-hydroxyphenyl)methyl)phenoxy)butyl)-12-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)dodecanoamide;

[0096]

[0097] N-(4-(4-(((1r,3r,5R,7S)-adamantan-2-ylidene)(4-hydroxyphenyl)methyl)phenoxy)butyl)-13-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)tridecamide;

[0098]

[0099] N-(4-(4-(((1r,3r,5R,7S)-adamantan-2-ylidene)(4-hydroxyphenyl)methyl)phenoxy)butyl)-14-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)tetradecanoic acid amide;

[0100]

[0101] N-(4-(4-(((1r,3r,5R,7S)-adamantan-2-ylidene)(4-hydroxyphenyl)methyl)phenoxy)butyl)-15-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)pentadecanamide;

[0102]

[0103] N-(4-(4-(((1r,3r,5R,7S)-adamantan-2-ylidene)(4-hydroxyphenyl)methyl)phenoxy)butyl)-16-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)hexadecanoamide;

[0104]

[0105] N-(4-(4-(((1r,3r,5R,7S)-adamantan-2-methylene)(4-hydroxyphenyl)methyl)phenoxy)butyl)-3-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)ethoxy)propanamide

[0106]

[0107] N-(4-(4-(((1r,3r,5R,7S)-adamantan-2-ylidene)(4-hydroxyphenyl)methyl)phenoxy)butyl)-3-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)ethoxy)ethoxy)propanamide;

[0108]

[0109] N-(4-(4-(((1r,3r,5R,7S)-adamantan-2-ylidene)(4-hydroxyphenyl)methyl)phenoxy)butyl)-3-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)ethoxy)ethoxy)ethoxy)propanamide;

[0110]

[0111] N-(4-(4-(((1r,3r,5R,7S)-adamantan-2-ylidene)(4-hydroxyphenyl)methyl)phenoxy)butyl)-1-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)-3,6,9,12-tetraoxopentadecane-15-amide;

[0112]

[0113] N-[4-[4-(1R,3R,5R,7S)-adamantane-2-methylenemethyl]phenoxy]butyl]-1-[(2-[(2,6-dioxopiperidin-3-yl)-1-oxoisoindol-4-yl]amino)-3,6,9,12,15-pentaoxooctane-18-carboxamide].

[0114] Among them, the synthesis routes of Structural Formula 1-1 to Structural Formula 1-13 are similar, and the only difference is that different linker raw materials are used. The required linker raw materials for synthesizing Structural Formula 1-1 to Structural Formula 1-13 are shown in Table 1 below. The linker raw materials can all be purchased commercially. The specific synthesis routes can refer to the specific synthesis route in Example 1 below.

[0115] The synthetic routes of Structural Formula 2-1 to Structural Formula 2-5 differ only in the use of different linker raw materials. The linker raw materials required for synthesizing Structural Formula 2-1 to Structural Formula 2-5 are shown in Table 1 below. The linker raw materials can all be purchased commercially. For specific synthetic routes, please refer to the specific synthetic route in Example 4 below.

[0116] The synthesis methods of the intermediates involved in the synthesis of the above-mentioned structures 1-1 to 1-13 and structures 2-1 to 2-5, i.e., the compound numbered A-7 in the synthesis route of Example 1-6 below, can also be referred to: ACS Medicinal Chemistry Letters 2018 9(8), 803-808 DOI: 10.1021 / acsmedchemlett.8b00106

[0117] Table 1 Linker raw materials, synthesis methods, and synthesis routes required for synthesizing Structural Formulas 1-1 to 1-13 and Structural Formulas 2-1 to 2-5.

[0118]

[0119]

[0120] Example 1 This Example 1 provides a compound: (Structural Formula 1-4): N-(4-(4-(((1r,3r,5R,7S)-adamantan-2-ylidene)(4-hydroxyphenyl)methyl)phenoxy)butyl)-7-((2-(2,6-dioxopiperidine)-3-yl)-1-oxoisoindolin-4-yl)amino)heptylamide (i.e. Figure 1 The synthetic route of the compound of Example 1 is as follows:

[0121]

[0122] Synthesis route 1: Synthesis route of the compound of Example 1

[0123] Step 1.1 Synthesis of 4-((tert-butoxycarbonyl)amino)butyl methanesulfonate, i.e., the compound labeled A-2 in Synthesis Scheme 1

[0124] Referring to Synthesis Route 1, a dichloromethane solution (20 mL) of A-1 (5 g, 26.3 mmol) and N,N-diisopropylethylamine (6.8 g, 52.6 mmol) was slowly added to a mixture at 0°C (37°F). Methanesulfonic anhydride (6.87 g, 39.5 mol) was stirred at 25°C for 16 hours. After completion of the reaction, the reaction system was diluted with 100 mL of water and extracted three times with 100 mL of dichloromethane. The combined organic phases were dried, concentrated, and separated on a silica gel column (dichloromethane / methanol 95 / 5) to afford A-2 (5.5 g) as a yellow oil in a 74% yield. MS (ESI, m / z): 290.1 ​​[M+Na] +

[0125] Step 1.2 Synthesis of 4,4'-(((1r,3r,5r,7r)-adamantan-2-ylmethylene)methylene)diphenol, i.e., the compound labeled A-5 in Synthesis Scheme 1

[0126] Referring to Synthesis Scheme 1, titanium tetrachloride (22.11 g, 0.117 mol) was added dropwise to a suspension of zinc powder (15.25 g, 0.233 mol) in tetrahydrofuran (THF) (250 mL) at -20°C. After the addition was complete, the reaction mixture was refluxed at 75°C for 3 hours. After the reaction was complete and the solution was cooled to room temperature, the mixture was added to a mixture of A-3 (5 g, 0.033 mol) and A-4 (7.13 g, 0.033 mol) in tetrahydrofuran (50 mL) and heated again at 75°C for 4 hours. Heating was stopped and the reaction mixture was cooled. A 10% aqueous potassium carbonate solution (200 mL) was then added to the reaction mixture and stirred overnight.

[0127] After the reaction was complete, the residue was filtered, washed with water, and extracted with 200 mL of ethyl acetate. The extracted organic phase was concentrated in vacuo and filtered through 200 mL of dichloromethane to obtain a yellow solid A-5 (10 g) in an 81% yield. MS (ESI, m / z): 333.2 [M+H] + .

[0128] Step 1.3: Synthesis of tert-butyl (4-(4-(adamantan-2-ylidene(4-hydroxyphenyl)methyl)phenoxy)butyl)carbamate, i.e., the compound labeled A-6 in Synthesis Scheme 1;

[0129] Referring to Synthesis Route 1, a mixture of A-5 (6 g, 18 mmol), A-2 (4.83 g, 18 mmol), and cesium carbonate (11.73 g, 36 mmol) in N,N-dimethylformamide (20 mL) was stirred at 60°C for 4 hours. After completion of the reaction, the reaction solution was diluted with 100 mL of water, extracted three times with 100 mL of ethyl acetate, and the organic phase was concentrated in vacuo. Separation on a silica gel column (petroleum ether / dichloromethane 70 / 30) afforded A-6 (1.8 g) as a white solid in a 20% yield. MS (ESI, m / z) 448.1 [M-55] + .

[0130] Step 1.4: Synthesis of 4-[[4-(4-aminobutyloxy)phenyl]tricyclo[3.3.1.13,7]dec-2-methylene]phenol, i.e., the compound labeled A-7 in Synthesis Scheme 1;

[0131] Refer to Synthesis Scheme 1. To a solution of A-6 (1.7 g, 3.4 mmol) in dichloromethane (9 mL), add 4N hydrochloric acid in 1,4-dioxane (3 mL) and stir the solution at 25°C for 2 h. After completion of the reaction, concentrate under reduced pressure to afford A-7 (1.25 g) as a white solid in a 91% yield. MS (ESI, m / z) 404.1 [M+H] + .

[0132] Step 1.5: Synthesis of tert-butyl 7-((2-(2,6-dioxypiperidin-3-yl)-1-oxoindole-4-yl)amino)heptanoate, i.e., the compound labeled A-10 in Synthesis Scheme 1;

[0133] Please refer to synthetic route 1, dissolve A-8 (260 mg, 1.00 mmol) in N-methylpyrrolidone (5 mL), add tert-butyl 7-bromoheptanoate (A-9) (531 mg, 2.00 mmol) and N,N-diisopropylethylamine (388 mg, 3.00 mmol), and stir the mixture at 110 ° C for 12 h.

[0134] After the reaction was complete, water (20 mL) was added, and the mixture was extracted with ethyl acetate (20 mL x 3). The mixture was dried over anhydrous sodium sulfate and concentrated to remove the solvent. The crude product was separated and purified on a silica gel column (dichloromethane / methanol 98 / 2) to obtain a yellow oil A-10 (150 mg) in a 30% yield. MS (ESI, m / z): 466.1 [M+Na] + .

[0135] Step 1.6: Synthesis of 7-((2-(2,6-dioxypiperidin-3-yl)-1-oxoindole-4-yl)amino)heptanoic acid, i.e., the compound labeled A-11 in Synthesis Scheme 1;

[0136] Refer to Synthesis Route 1. Dissolve A-10 (150 mg, 0.33 mmol) in dichloromethane (1 mL), add trifluoroacetic acid (1 mL), and react at room temperature for 1 hour. After completion of the reaction, concentrate the reaction solution to obtain A-11 (120 mg) as a yellow solid in an 82% yield. MS (ESI, m / z): 388.1 [M+H] + .

[0137] Step 1.7 Synthesis of N-(4-(4-(((1r,3r,5R,7S)-adamantan-2-ylidene)(4-hydroxyphenyl)methyl)phenoxy)butyl)-7-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)heptylamide, compound numbered A-12 in Scheme 1

[0138] Please refer to synthetic route 1, dissolve A-11 (120 mg, 0.30 mmol) in N,N-dimethylformamide (5 mL), add A-7 (187 mg, 0.46 mmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (176 mg, 0.46 mmol), N,N-diisopropylethylamine (120 mg, 0.92 mmol), and the mixture is reacted at room temperature for 2 h.

[0139] After the reaction was completed, water (20 mL) was added, extracted with ethyl acetate (20 mL*3), dried over anhydrous sodium sulfate, and concentrated to remove the solvent. The crude product was separated on a silica gel column (dichloromethane / methanol 94 / 6) to obtain a yellow solid A-12 (25 mg) with a yield of 10%.

[0140] 1 H NMR (400MHz, DMSO-d6) δ11.00(s,1H),9.25(s,1H),7.76(s,1H),7.27–7.25(m,1H),6.93(t,J=8.3Hz,3H),6.83(dd,J=12.9,8.5 Hz,4H),6.72(d,J=8.0Hz,1H),6.66(d,J=8.3Hz,2H),5.54–5.53(m,1H),5.11(dd,J=13.0,4.8Hz,1H),4.25–4.10(m,2H),3.91(t ,J=6.0Hz,1H),3.64–3.62(m,1H),3.14–3.07(m,4H),3.01–2.82(m,1H),2.70–2.58(m,3H),2.30–2.28(m,1H),2.01–1.99(m,2H) ,1.95(s,2H),1.79(s,8H),1.67–1.65(m,2H),1.63–1.40(m,5H),1.37–1.35(m,2H),1.27–1.22(m,6H).MS(ESI,m / z)773.2[M+H] + .

[0141] Example 2

[0142] Example 2 provides a compound: (Structural Formula 1-7): N-(4-(4-(((1r,3r,5R,7S)-adamantan-2-ylidene)(4-hydroxyphenyl)methyl)phenoxy)butyl)-10-((2-(2,6-dioxopiperidine)-3-yl)-1-oxoisoindolin-4-yl)amino)decylamide,

[0143]

[0144] The synthetic route of the compound provided in Example 2 is as follows:

[0145]

[0146] Synthetic route 2 Synthetic route of the compound of Example 2

[0147] Step 2.1: Synthesis of tert-butyl 10-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)decanoate, i.e., the compound labeled B-2 in Synthesis Scheme 2;

[0148] Please refer to synthetic route 2, 3-(4-amino-1-oxoisoindol-2-yl)piperidine-2,6-dione A-8 (260 mg, 1.00 mmol) was dissolved in N-methylpyrrolidone (5 mL), tert-butyl 10-bromodecanoate B-1 (615 mg, 2.00 mmol) and N,N-diisopropylethylamine (388 mg, 3.00 mmol) were added, and the mixture was stirred at 110 ° C for 12 h.

[0149] After the reaction was complete, water (20 mL) was added, and the mixture was extracted with ethyl acetate (20 mL x 3). The mixture was dried over anhydrous sodium sulfate and concentrated to remove the solvent. The crude product was purified on a silica gel column (dichloromethane / methanol 98 / 2) to afford a yellow oil B-2 (203 mg) in a 37% yield. MS (ESI, m / z): 486.63 [M+H].

[0150] Step 2.2: Synthesize 10-((2-(2,6-diketopiperidin-3-yl)-1-oxoisoindol-4-yl)amino)decanoic acid, i.e., the compound labeled B-3 in Synthesis Scheme 2;

[0151] Refer to Synthesis Route 2. Dissolve B-2 (203 mg, 0.42 mmol) in dichloromethane (1 mL) and add trifluoroacetic acid (1 mL). Allow to react at room temperature for 1 hour. After completion, concentrate the reaction mixture to obtain a yellow solid, B-3 (136 mg), in an 84% yield. MS (ESI, m / z): 430.52 [M+H].

[0152] Step 2.3: Synthesis of 10-((2-(2,6-diketopiperidin-3-yl)-1-oxoisoindol-4-yl)amino)decanoic acid, ie, B-4 in Synthesis Scheme 2.

[0153] Referring to Synthesis Route 2, B-3 (136 mg, 0.32 mmol) was dissolved in N,N-dimethylformamide (5 mL), and A-7 (187 mg, 0.46 mmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (176 mg, 0.46 mmol), and N,N-diisopropylethylamine (120 mg, 0.92 mmol) were added. The mixture was reacted at room temperature for 2 h. After completion of the reaction, water (20 mL) was added, and the mixture was extracted with ethyl acetate (20 mL x 3). The mixture was dried over anhydrous sodium sulfate and concentrated to remove the solvent. The crude product was separated on a silica gel column (dichloromethane / methanol 94 / 6) to afford B-4 (34 mg) as a yellow solid in a 13% yield.

[0154] 1 H NMR (400MHz, DMSO-d6) δ11.02(s,1H),9.28(s,1H),7.78(s,1H),7.27(t,J=7.8Hz,1H),6.98–6.89(m,3H),6.82(dd,J=1 0.9,8.3Hz,4H),6.72(d,J=8.0Hz,1H),6.66(d,J=8.1Hz,2H),5.55(s,1H),5.11(dd,J=13.4,5.2Hz,1H),4.25–4.07(m, 2H),3.91(t,J=6.3Hz,2H),3.12–3.05(m,4H),2.92(t,J=13.2Hz,1H),2.66(t,J=13.3Hz,3H),2.34–2.24(m,1H),2.02( t,J=7.5Hz,3H),1.95(s,2H),1.79(s,9H),1.66(d,J=7.5Hz,2H),1.56–1.46(m,5H),1.28(dd,J=29.1,12.3Hz,12H).1H NMR(400MHz,DMSO-d6)δH-NMR.MS(ESI,m / z)816.1[M+H]+.

[0155] Example 3 (Structural Formula 1-10):

[0156] N-(4-(4-(((1r,3r,5R,7S)-adamantan-2-ylidene)(4-hydroxyphenyl)methyl)phenoxy)butyl)-13-((2-(2,6-dioxopiperidine)-3-yl)-1-oxoisoindolin-4-yl)amino)tridecanamide. The synthetic route of the compound provided in Example 3 is shown in Synthetic Route 3.

[0157]

[0158] Synthesis route 3: Synthesis route of the compound provided in Example 3

[0159] Step 3.1 Synthesis of tert-butyl 7-((2-(2,6-dioxypiperidin-3-yl)-1-oxoindole-4-yl)amino)heptanoate C-2 in Synthesis Scheme 3

[0160] Referring to Synthesis Scheme 3, 3-(4-amino-1-oxoisoindol-2-yl)piperidine-2,6-dione (260 mg, 1.00 mmol) was dissolved in N-methylpyrrolidone (5 mL). Tert-butyl 13-bromotridecanoate (699 mg, 2.00 mmol) and N,N-diisopropylethylamine (388 mg, 3.00 mmol) were added, and the mixture was stirred at 110°C for 12 h. After completion of the reaction, water (20 mL) was added, and the mixture was extracted with ethyl acetate (20 mL x 3). The mixture was dried over anhydrous sodium sulfate and concentrated to remove the solvent. The crude product was purified by silica gel column chromatography (dichloromethane / methanol 98 / 2) to afford C-2 (231 mg) as a yellow oil in a 38% yield. MS (ESI, m / z): 528.71 [M+H]+.

[0161] Step 3.2 Synthesis of 13-((2-(2,6-diketopiperidin-3-yl)-1-oxoisoindol-4-yl)amino)tridecanoic acid, C-3

[0162] Refer to Synthesis Route 3. Dissolve C-2 (231 mg, 0.44 mmol) in dichloromethane (1 mL) and add trifluoroacetic acid (1 mL). Allow to react at room temperature for 1 h. After completion, concentrate the reaction mixture to obtain C-3 (107 mg) as a yellow solid in a 73% yield. MS (ESI, m / z): 472.6 [M+H].

[0163] Step 3.3 Synthesis of N-(4-(4-(adamantan-2-ylmethylene(4-hydroxyphenyl)methyl)phenoxy)butyl)-13-((2-(2,6-diketopiperidin-3-yl)-1-oxoisoindol-4-yl)amino)tridecamide, C-4

[0164] Referring to Synthesis Route 3, C-3 (107 mg, 0.23 mmol) was dissolved in N,N-dimethylformamide (5 mL), and 1-7 (187 mg, 0.46 mmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (176 mg, 0.46 mmol), and N,N-diisopropylethylamine (120 mg, 0.92 mmol) were added. The mixture was allowed to react at room temperature for 2 h. After completion of the reaction, water (20 mL) was added, and the mixture was extracted with ethyl acetate (20 mL x 3). The mixture was dried over anhydrous sodium sulfate and concentrated to remove the solvent. The crude product was separated on a silica gel column (dichloromethane / methanol 94 / 6) to afford C-4 (42 mg) as a yellow solid in a 15% yield.

[0165] 1 H NMR (400MHz, DMSO-d6) δ11.02(s,1H),9.30(s,1H),7.78(t,J=5.8Hz,1H),7.27(t,J=7.7Hz,1H),6.92(d,J=7.3Hz ,3H),6.83(dd,J=11.3,8.6Hz,5H),6.73(d,J=8.0Hz,1H),6.67–6.65(m,2H),5.56(t,J=5.6Hz,1H),5.13–5.08(m, 1H),4.17(d,J=24.5Hz,2H),3.91(t,J=6.4Hz,2H),3.07(d,J=7.9Hz,3H),2.91(d,J=12.8Hz,1H),2.67(s,2H),2.3 3(s,1H),2.03(t,J=7.3Hz,3H),1.79(s,9H),1.66(d,J=8.2Hz,2H),1.53(dt,J=15.4,7.4Hz,5H),1.23(s,20H).1H NMR(400MHz,DMSO-d6)δH-NMR.MS(ESI,m / z)858.2[M+H]+.

[0166] Example 4 (Structural Formula 2-2):

[0167] Example 4 provides a compound: N-(4-(4-(((1r,3r,5R,7S)-adamantan-2-ylidene)(4-hydroxyphenyl)methyl)phenoxy)butyl)-3-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)ethoxy)ethoxy)propanamide, the structure of which is as follows:

[0168]

[0169] The synthetic route of the compound provided in Example 4 is as follows:

[0170]

[0171] Synthesis route 4: Synthesis route of the compound provided in Example 4

[0172] Step 4.1: Synthesis of tert-butyl 3-(2-(2-oxoethoxy)ethoxy)propionate.

[0173] Referring to Synthesis Scheme 4, Dess-Martin periodinane (5.45 g, 0.01 mol) and pyridine (2.03 g, 0.03 mol) were added to a solution of D-1 (2.5 g, 0.01 mol) in dichloromethane (20 mL) at 0°C, and the mixture was stirred at 25°C for 16 h. After completion of the reaction, water (30 mL) was added, and the mixture was extracted with dichloromethane (30 mL x 3). The mixture was dried over anhydrous sodium sulfate, concentrated to remove the solvent, and the crude product was purified on a silica gel column (petroleum ether / ethyl acetate 55 / 45) to afford D-2 (1.3 g) as a white solid in a 49% yield. 1H NMR (400 MHz, CDCl3) δ 9.73 (s, 1H), 4.15 (s, 2H), 3.78–3.59 (m, 6H), 2.51 (t, J = 6.4 Hz, 2H), 1.45 (s, 9H).

[0174] Step 4.2 Synthesis of tert-butyl 3-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)ethoxy)ethoxy)propanoate, D-3

[0175] Referring to Synthesis Scheme 4, to a solution of A-8 (400 mg, 1.54 mmol) in methanol (5 mL) were added D-2 (537 mg, 2.31 mmol) and acetic acid (9 mg, 0.15 mmol), and the mixture was stirred at 25°C for 0.5 hours. Sodium cyanoborohydride (194 mg, 3.09 mmol) was then added to the reaction mixture at 0°C, and stirred at 25°C for 16 hours. After completion of the reaction, sodium bicarbonate (30 mL) was added, and the mixture was extracted with EA (30 mL x 3), dried over anhydrous sodium sulfate, and concentrated to remove the solvent. The crude product was purified on a silica gel column (PE:EA = 9:1) to afford D-3 (600 mg) as a yellow solid in a 74% yield. MS (ESI, m / z): 476.2 [M+H] + .

[0176] Step 4.3 Synthesis of 3-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)ethoxy)ethoxy)propanoic acid, D-4

[0177] Refer to Synthesis Route 4. Dissolve D-3 (300 mg, 0.63 mmol) in dichloromethane (3 mL), add trifluoroacetic acid (1 mL), and react at room temperature for 2 h. After completion of the reaction, concentrate the reaction solution to obtain D-4 (300 mg) as a yellow oil in a 96% yield. MS (ESI, m / z): 420.1 [M+H] + .

[0178] Step 4.4 Synthesis of N-(4-(4-(((1r,3r,5R,7S)-adamantan-2-ylidene)(4-hydroxyphenyl)methyl)phenoxy)butyl)-3-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)ethoxy)ethoxy)propanamide, D-5 (LK-023590)

[0179] Please refer to synthetic route 4. D-4 (300 mg, 0.72 mmol) was dissolved in N,N-dimethylformamide (5 mL). A-7 (346 mg, 0.86 mmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (353 mg, 0.93 mmol), and N,N-diisopropylethylamine (277 mg, 2.14 mmol) were added. The mixture was reacted at room temperature for 2 h.

[0180] After the reaction was completed, water (20 mL) was added, extracted with ethyl acetate (20 mL * 3), dried over anhydrous sodium sulfate, and concentrated to remove the solvent. The residue was separated by Prep-HPLC (column model: Gemini-C18 150 x 21.2 mm, 5 μm, mobile phase: ACN-H2O (0.1% FA), gradient 60%-95%, flow rate: 20 mL / min) to obtain a white solid D-5 (LK-023590) (30.11 mg) with a yield of 5%. 1H NMR (400MHz, DMSO) δ10.99(s,1H),9.29(s,1H),7.83(s,1H),7.27(t,J=7.7Hz,1H),6.94(d,J=8.6Hz,3H),6.88 –6.76(m,5H),6.66(d,J=8.2Hz,2H),5.56(d,J=5.3Hz,1H),5.11(dd,J=13.2,4.8Hz,1H),4.18(dd,J=42.2,17. 1Hz,2H),3.91(t,J=6.1Hz,2H),3.68–3.44(m,9H),3.12–3.03(m,2H),3.00–2.79(m,1H),2.73–2.61(m,3H),2. 39–2.22(m,4H),2.05–1.91(m,4H),1.79(s,9H),1.74–1.56(m,2H),1.58–1.41(m,2H).MS(ESI,m / z)804.8[M+H] + .

[0181] Example 5 (Structural Formula 2-3):

[0182] Example 5 provides a compound: N-(4-(4-(((1r,3r,5R,7S)-adamantan-2-ylidene)(4-hydroxyphenyl)methyl)phenoxy)butyl)-3-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)ethoxy)ethoxy)ethoxy)propanamide, the structure of which is as follows:

[0183]

[0184] The synthetic route of this compound is shown in Synthetic Route 5:

[0185]

[0186] Synthesis route 5: Synthesis route of the compound provided in Example 5

[0187] Step 5.1 Synthesis of tert-butyl 3-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)ethoxy)ethoxy)ethoxy)propanoate,

[0188] Referring to Synthesis Route 5, E-1 (300 mg, 0.69 mmol) was dissolved in N-methylpyrrolidone (5 mL), and A-8 (234 mg, 0.90 mmol), N,N-diisopropylethylamine (269 mg, 2.08 mmol), and sodium iodide (104 mg, 0.69 mmol) were added. The mixture was reacted at 110°C for 12 h. After completion of the reaction, water (40 mL) was added, and the mixture was extracted with ethyl acetate (30 mL x 3). The mixture was dried over anhydrous sodium sulfate and concentrated to remove the solvent. The crude product was separated on a silica gel column (petroleum ether / ethyl acetate 90 / 10) to afford E-2 (200 mg) as a yellow solid in a 52% yield. MS (ESI, m / z): 520.1 [M+H]. + .

[0189] Step 5.2 Synthesis of 3-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)ethoxy)ethoxy)ethoxy)propionic acid, preparation method of E-3

[0190] Refer to Synthesis Route 5. Dissolve E-2 (200 mg, 0.38 mmol) in dichloromethane (3 mL), add trifluoroacetic acid (1 mL), and react at room temperature for 2 h. After completion of the reaction, concentrate the reaction solution to obtain E-3 (200 mg) as a yellow oil in a 95% yield. MS (ESI, m / z): 464.1 [M+H] + .

[0191] Step 5.3 Synthesis of N-(4-(4-(((1r,3r,5R,7S)-adamantan-2-ylidene)(4-hydroxyphenyl)methyl)phenoxy)butyl)-3-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)ethoxy)ethoxy)ethoxy)propanamide, E-4.

[0192] Please refer to synthetic route 5, dissolve E-3 (200 mg, 0.431 mmol) in N,N-dimethylformamide (4 mL), add A-7 (226 mg, 0.56 mmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (246 mg, 0.65 mmol), N,N-diisopropylethylamine (167 mg, 1.29 mmol), and the mixture is reacted at room temperature for 3 h.

[0193] After the reaction was completed, water (20 mL) was added, and the mixture was extracted with ethyl acetate (20 mL*3). The mixture was dried over anhydrous sodium sulfate and concentrated to remove the solvent. The residue was purified by reverse phase column (water / acetonitrile 45 / 55) to obtain white solid E-4 (26.03 mg) in a yield of 7%. 1HNMR (400MHz, DMSO) δ10.99(s,1H),9.27(s,1H),7.82(t,J=5.3Hz,1H),7.28(t,J=7.7Hz,1H),6.94(d,J=8.5Hz,3H),6.82( dt,J=16.4,8.1Hz,5H),6.66(d,J=8.3Hz,2H),5.57(t,J=5.4Hz,1H),5.11(dd,J=13.1,5.0Hz,1H),4.17(dd,J=42.5,17.1H z,2H),3.91(t,J=6.2Hz,2H),3.68–3.39(m,12H),3.08(dd,J=12.5,6.4Hz,2H),3.00–2.81(m,1H),2.78–2.61(m,3H),2.29 (dd,J=13.9,7.6Hz,4H),2.13–1.87(m,4H),1.79(s,10H),1.74–1.60(m,2H),1.58–1.34(m,2H)..MS(ESI,m / z)848.8[M+H] + .

[0194] Example 6 (Structural Formula 2-4):

[0195] Example 6 provides a compound: N-(4-(4-(((1r,3r,5R,7S)-adamantan-2-ylidene)(4-hydroxyphenyl)methyl)phenoxy)butyl)-1-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)-3,6,9,12-tetraoxopentadecane-15-carboxamide, the structure of which is as follows:

[0196]

[0197] The synthetic route of the compound provided in Example 6 is as follows:

[0198]

[0199] Synthesis route 6: Synthesis route of the compound provided in Example 6

[0200] Step 6.1 Synthesis of tert-butyl 1-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)-3,6,9,12-tetraoxopentadecane-15-ol, F-2

[0201] Referring to Synthesis Route 6, A-8 (424 mg, 1.63 mmol) was dissolved in N-methylpyrrolidone (15 mL), and F-1 (1559 mg, 3.27 mmol), N,N-diisopropylethylamine (634.54 mg, 4.90 mmol), and potassium iodide (24.15 mg, 0.16 mmol) were added. The mixture was reacted at 110°C for 12 h. After completion of the reaction, water (40 mL) was added, and the mixture was extracted with ethyl acetate (30 mL x 3). The mixture was dried over anhydrous sodium sulfate and concentrated to remove the solvent. The crude product was separated on a silica gel column (dichloromethane / methanol 95 / 5) to afford F-2 (130 mg) as a yellow oil in a 12% yield. MS (ESI, m / z): 564.3 [M+H] + .

[0202] Step 6.2 Synthesis of 1-((2-(2,6-dioxypiperidin-3-yl)-1-oxoisoindol-4-yl)amino)-3,6,9,12-tetraoxopentadecane-15-oic acid, F-3

[0203] Please refer to synthetic route 6, dissolve F-2 (130 mg, 0.23 mmol) in dichloromethane (1 mL), add trifluoroacetic acid (1 mL), and react at room temperature for 1 h.

[0204] After the reaction was completed, the reaction solution was concentrated to obtain a yellow solid F-3 (100 mg) with a yield of 77%. MS (ESI, m / z): 508.2 [M+H] + .

[0205] Step 6.3 Synthesis of N-(4-(4-(1R,3R,5R,7S)-adamantane-2-methylene)(4-hydroxyphenyl)methyl)phenoxy)butyl)-1-((2-(2,6-dioxypiperidin-3-yl)-1-oxoindole-4-yl)amino)-3,6,9,12-tetraoxopentadecane-15-amide, Preparation Method of F-4

[0206] Please refer to synthetic route 6, dissolve F-3 (100 mg, 0.19 mmol) in N,N-dimethylformamide (5 mL), add A-7 (119 mg, 0.29 mmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (112 mg, 0.29 mmol), N,N-diisopropylethylamine (76 mg, 0.59 mmol), and the mixture is reacted at room temperature for 2 h.

[0207] After the reaction was completed, water (20 mL) was added, and the mixture was extracted with ethyl acetate (20 mL*3). The mixture was dried over anhydrous sodium sulfate and concentrated to remove the solvent. The crude product was separated on a silica gel column (dichloromethane / methanol 94 / 6) to obtain a yellow solid F-4 (LK-023592) (25 mg) in a yield of 14%.1 H NMR (400MHz, DMSO-d6) δ11.00(s,1H),9.25(s,1H),7.82(s,1H),7.28–7.26(m,1H),6.94(d,J=8.4Hz,3H),6 .82(dt,J=15.6,7.7Hz,5H),6.66(d,J=8.3Hz,2H).5.57–5.55(m,1H),5.12–5.08(m,1H),4.25–4.10(m,2H) ,3.91(t,J=6.0Hz,2H),3.52–3.46(m,14H),3.09–3.07(m,2H),3.01–2.92(m,1H),2.70–2.58(m,3H),2.30– 2.28(m,4H),2.01–1.95(m,4H),1.79(s,9H),1.67–1.51(m,4H),1.25–1.23(m,3H).MS(ESI,m / z)893.4[M+H] + .

[0208] Comparative Example 1 ARV-471 has the following structure:

[0209]

[0210] Comparative Example 1 Chemical structure of ARV-47

[0211] ARV-471 is a novel oral estrogen receptor (ER)-targeted proteolysis-targeted chimeric (PROTAC) protein degrader, jointly developed by Pfizer and Arvinas for the treatment of patients with estrogen receptor-positive / human epidermal growth factor receptor 2-negative (ER+ / HER2-) breast cancer. ARV-471 is an orally bioavailable Protein degrader that specifically targets and degrades estrogen receptor (ER).

[0212] Example 7 The compounds of Examples 1-6 and Comparative Example 1 were used to perform an experiment on inhibiting the proliferation of human breast cancer cells MCF-7.

[0213] MCF-7 cells were plated in 384-well cell culture plates (6000 cells per well, 40 μl of charcoal-adsorbed serum-free phenol red medium) and incubated overnight at 37° C. in a 5% CO 2 atmosphere in a humidified incubator.

[0214] 0.2 μl of the compounds of Examples 1-6 and Comparative Example 1 (at a 200X concentration) was added to the wells of a cell culture plate (maximum final concentration was 10 μM, with a 3-fold serial dilution, "9+0" concentration, where "0" is DMSO solvent). MCF-7 cells were then incubated in the above environment for a further 24 hours.

[0215] MCF-7 cells were fixed with 40 μl / well of 8% paraformaldehyde (PFA: final concentration 4%) for 20 minutes at room temperature. The plates were then washed twice with PSB and permeabilized with pre-chilled methanol for 10 minutes. MCF-7 cells were then blocked with Odessery blocking buffer for 1 hour.

[0216] A cocktail of primary antibodies for the detection of ERα (rabbit monoclonal, 1:1000, Cell Signaling Technology catalog #8644) and the housekeeping protein GAPDH (mouse monoclonal, 1:2000, Cell Signaling Technology catalog #97166S) was added and MCF-7 cells were incubated overnight at 4°C.

[0217] Then, MCF-7 cells were washed three times with TBST at room temperature and then incubated with anti-rabbit and anti-mouse fluorescently labeled secondary antibodies (LI-COR) in LI-COR blocking buffer for one hour at room temperature. After washing three times with TBST, the buffer was removed and The plate was read at 700 nm and 800 nm on an infrared imaging system (LI-COR). Using commercial software (ImageStudio™; LI-COR, Lincoln, NE), the staining intensity of ERα and housekeeping proteins in each well was quantified and exported for analysis. For each data point, ERα intensity was normalized to housekeeping protein intensity, and for each ER-targeting PROTAC degrader, all normalized intensity values ​​were normalized to vehicle control.

[0218] Table 2: Reagents, consumables, and instruments required for the experiment of inhibiting the proliferation of human breast cancer cells MCF-7 in Example 7

[0219] Material supplier Product Number DMEM medium Gibco 11995065 FBS Gibco 10099141C DMEM, without phenol red Gibco 21063029 Charcoal stripped FBS BIOSUN BS-0004-500 <![CDATA[TrypLE TM Express Enzyme (1X), Phenol Red Free]]> Gibco 12604-021 Penicillin-Streptomycin Gibco 15140-122 IRDye 800CW goat anti-rabbit IgG (H+L) (0.5 mg) LI-COR 926-32211 IRDye 680RD goat anti-mouse IgG (H+L) (0.5 mg) LI-COR 926-68070 Estrogen Receptor α (D8H8) Rabbit Monoclonal Antibody CST 8644S GAPDH (D4C6R) mouse monoclonal antibody CST 97166S Phosphate-buffered saline (PBS) Solarbio P1010 8% paraformaldehyde Solarbio P1112 Tween-20 Solarbio T8220 Methanol (HPLC grade) Concord Technology 67-56-1 <![CDATA[Intercept TM (PBS) Blocking Solution]]> LI-COR 927-70001 T75 culture flask Corning 430641 384-well microplate Corning 3657 384-well transparent flat bottom Labcyte PP-0200 384-well black wall transparent bottom plate Corning BD356663 DMSO Solarbio D8371

[0220] Table 3 Experimental instruments required for the experiment of inhibiting proliferation of human breast cancer cells MCF-7 in Example 7

[0221]

[0222]

[0223] Experimental steps of Example 7:

[0224] 1) MCF-7 cells (human breast cancer cells) were seeded into 384-well cell culture plates (Coring #356663) at a density of 6000 cells / well / 40 μL using phenol red-free DMEM complete medium (phenol red-free DMEM + 10% Charcoal-FBS + 1% P / S) and incubated at 37°C, 5% CO2 to adhere overnight.

[0225] 2) Use DMSO solvent to dilute the compound in a 3-fold gradient; a total of "9+0" concentrations.

[0226] 3) Use Echo 550 to dispense 200 nL of the compound diluted in step 2) into the cell culture plate (final DMSO concentration: 0.5%) and place the plate in a 37° C., 5% CO 2 incubator for further culturing for 24 hours.

[0227] 4) Add 40 uL / well of 8% paraformaldehyde and incubate at room temperature for 20 minutes.

[0228] 5) After removing the paraformaldehyde, wash the plate twice with PBS, add 40 uL / well of cold methanol (HPLC grade) and incubate at room temperature for 10 minutes.

[0229] 6) Methanol was removed, and the plate was washed once with PBS. 20 μL / well of Odessey blocking buffer was added, and the plate was incubated at room temperature for 1 hour.

[0230] 7) Remove Odessery blocking buffer and add 20uL / well primary (estrogen receptor α

[0231] A mixture of rabbit monoclonal antibody (D8H8) and mouse monoclonal antibody (GAPDH) (D4C6R) was added and incubated at 4°C overnight.

[0232] 8) Remove the primary antibody, wash three times with PBS + 0.05% Tween-20, add 20 uL / well of secondary antibody mixture (goat anti-rabbit 800CW antibody and goat anti-mouse 680RD antibody), and incubate at room temperature in the dark for 1 hour.

[0233] 9) Remove the secondary antibody, wash three times with PBS + 0.05% Tween-20, and finally centrifuge the cell culture plate upside down at 1000 rpm for 1 minute. Then, read the fluorescence signal using Odyssey CLx (infrared fluorescence scanning imaging system).

[0234] The calculation formula is: ERαlevel=100-(High-sample)(High-Low)*100. The relationship between the level percentage of the estrogen receptor α subtype of the compounds of Examples 1-6 and Comparative Example 1 and the concentration of the compounds is plotted. Please refer to Figure 1 、 Figure 2 、 Figure 3 、 Figure 4 、 Figure 5 、 Figure 6 、 Figure 7 ;

[0235] Wherein, High = average of multiple DMSO wells (800 / 700 ratio); Low = average of multiple 100 nM Fulvestrant wells (800 / 700 ratio); and the ratio of 800 / 700 is Relative Signal = Signal Value (total channel 800) / Signal Value (total channel 700).

[0236] DC50 was then calculated by fitting the logarithm of inhibition rate and compound concentration to a nonlinear regression (dose response - slope of variable) using XLFIT, see Table 4.

[0237] Table 4: Experimental data on the inhibition of proliferation of human breast cancer cells MCF-7 by the compounds of Examples 1-6 and Comparative Example 1

[0238] Example DC50(nM) Dmax(%) Example 1 2.55 88.48 Example 2 8.21 92.51 Example 3 30.87 89.21 Example 4 1.79 82.98 Example 5 2.06 82.42 Example 6 2.55 95.47 Comparative Example 1 0.80 93.23

[0239] Please refer to Figure 1 、 Figure 2 、 Figure 3 、 Figure 4 、 Figure 5 、 Figure 6 、 Figure 7 As shown in Table 4, most of the DC50 values ​​of the compounds in Examples 1-6 are below 10 nM, and the Dmax values ​​are all above 80%, indicating that the compounds of the present application, as PROTAC degraders targeting ER, show good degradation efficiency and anti-tumor activity in the ER-positive breast cancer cell line MCF-7, and can be used for the prevention and treatment of ER-positive breast cancer.

[0240] Example 8 Cytochrome P450 inhibition study

[0241] The compounds of Example 1, Example 4, Example 5, Example 6 and Comparative Example 1 were subjected to drug metabolizing enzyme phenotype identification (CYP inhibition test).

[0242] Drug-metabolizing enzyme phenotyping (CYP inhibition testing) tests compounds for their inhibitory effects on cytochrome P450 (CYP450) enzymes. CYP450 is a class of enzymes found in the liver (and other parts of the body) that metabolizes and breaks down many drugs and xenobiotics. The CYP450 enzymes involved in drug metabolism primarily belong to the CYP1, CYP2, and CYP3 families. CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4 / 5 are the primary drug-metabolizing enzymes. Drug-metabolizing enzyme phenotyping primarily investigates the type, number, and relative contribution of metabolizing enzymes involved in drug clearance. If a drug is a strong inhibitor or inducer of a CYP enzyme, it may interact with other drugs metabolized by the same CYP enzyme, resulting in reduced efficacy or an increased risk of adverse reactions. Therefore, during the drug design stage, chemists usually modify the structure of drug molecules to reduce interactions with CYP enzymes, thereby reducing the risk of drug interactions.

[0243] This study used an in vitro assay system to evaluate the effects of test compounds on the activities of seven cytochrome P450 (CYP) isoenzymes (CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4) in human liver microsomes. Specific probe substrates for each CYP450 isoenzyme were incubated with human liver microsomes and various concentrations of the test compound (10 μM, 3.33 μM, 1.11 μM, 0.37 μM, 0.123 μM, 0.041 μM, 0.0137 μM, and 0 μM). The reaction was initiated by the addition of reduced nicotinamide adenine dinucleotide phosphate (NADPH). Following the reaction, samples were processed and metabolites generated from the probe substrates were quantified using liquid chromatography-tandem mass spectrometry (LC-MS / MS).

[0244] Table 5 Reagents and consumables required for cytochrome P450 inhibition study in Example 8

[0245] Reagents & Materials supplier Product Number Acetaminophen-d4 TRC 64315-36-2 Hydroxybupropion-d6 TRC 1216893-18-3 N-Desethylamodiaquine-d5 TRC 1173023-19-2 4′-Hydroxydiclofenac-d4 TRC 254762-27-1 4-Hydroxymephenytoin-D3 TRC 1173022-56-4 Dextrorphan-d3 tartrate TRC 1426174-16-4 Tolbutamide Sigma 64-77-7 Human liver microsomes Bio IVT X008067 1A2 positive control inhibitor α-naphthoflavone Sigma 604-59-1 2B6 positive control inhibitor thiotepa Sigma 52-24-4 2C8 positive control inhibitor montelukast TCI 151767-02-1 2C9 positive control inhibitor sulfaphenazole Sigma 526-08-9 2C19 positive control inhibitor ticlopidine Sigma 53885-35-1 2D6 positive control inhibitor quinidine Damas-beta 56-54-2 3A4 positive control inhibitor ketoconazole TCI 65277-42-1 1A2 substrate phenacetin Sigma Phenacetin 2B6 substrate bupropion Macklin 36177-93-7 2C8 substrate amodiaquine TCI 6398-98-7 2C9 substrate diclofenac Sigma 15307-79-6 2C19 substrate S-mephenytoin MCE 70989-04-7 2D6 substrate dextromethorphan 6700-34-1 Aladdin 3A4 substrate midazolam China Inspection and Quarantine Agency 59467-70-8 3A4 substrate testosterone LGC (lgcstandards) 58-22-0 NADPH MCE 2646-71-1 Acetonitrile Honneywell 01380515 Methanol Honneywell 01380516 Formic acid Adamas 73553B DMSO Saiguo Biotechnology 196055

[0246] Table 6 Instruments and equipment required for cytochrome P450 inhibition study in Example 8

[0247]

[0248] Example 8 Experimental steps:

[0249] Step (1) preparing a mixed solution of the compound and human liver microsomes (the concentrations of the compound and human liver microsomes are both twice the final concentration).

[0250] Step (2) 0.2 mg / mL human liver microsome (HLM) solution: Take 200 μL of 20 mg / mL human liver microsome stock solution and add it to 19.8 mL of buffer.

[0251] Step (3) Dissolve 16 μL of 10 mM test compound or positive inhibitor stock solution in 24 μL of organic solvent, and then dilute it in a 1:2 gradient (the concentration is 400 times the final concentration): 4 mM, 1.33 mM, 0.444 mM, 0.148 mM, 0.0494 mM, 0.0165 mM, 0.00549 mM, 0 mM.

[0252] Step (4) Mixed solution with human liver microsomes: 199 μL of 0.2 mg / mL HLM was added to the wells of a 96-well plate, and 1 μL of a 400-fold solution of the test compound or positive inhibitor was added.

[0253] Table 7: Concentration of the mixed solution of positive control inhibitor and human liver microsomes

[0254]

[0255] Step (5) prepare substrate solution (the prepared concentration is 4 times the final concentration).

[0256] Table 8: Substrate solution preparation

[0257]

[0258]

[0259] Step (6) The substrate solution prepared in step (5) is then dispensed into a 96-well reaction plate: 30 μL of the mixed solution of the compound and human liver microsomes is dispensed into a 96-well plate, and then 15 μL of the substrate solution is added.

[0260] Step (7): Preheat the solution obtained in step (6) and 8 mM NADPH solution at 37°C for 10 minutes.

[0261] Step (8): Add 15 μL of preheated NADPH solution to the reaction plate obtained in step (6), mix well, and start the reaction.

[0262] Step (9): Incubate the reaction plate at 37°C for 5 minutes for CYP3A4; 10 minutes for CYP1A2, 2B6, 2C8, 2C9, and 2D6; and 20 minutes for CYP2C19. At the end of the reaction, add 120 μL of acetonitrile containing the internal standard to terminate the reaction.

[0263] Table 9: Experimental data of drug metabolizing enzyme phenotype identification (CYP inhibition experiment) of Example 1, Example 4, Example 5, Example 6 and Comparative Example 1

[0264] As can be seen from Table 9 above, the compounds provided in Example 1 of the present application have an effect on all CYP450 enzymes.

[0265]

[0266] IC50>10μM; Examples 4, 5, and 6 showed IC50>10μM for most CYP450 enzymes, indicating that the compounds of Examples 1, 4, 5, and 6 have essentially no inhibitory effect on CYP450 enzymes. Therefore, the metabolic processes of the compounds of the present application involve a large number of metabolic enzymes and metabolic pathways, making potential drug-drug interactions less likely to occur, reducing treatment deviations between patients, and demonstrating good safety and reliability.

[0267] Example 9 The above-mentioned Example 1, Example 4, Example 5, Example 6 and Comparative Example 1 were subjected to hERG safety assessment test. The results are shown in Table 10.

[0268] The hERG safety assessment test is a specific safety assessment experiment. It is used to detect the potential effects of drugs on the potassium channel encoded by the human Ether-a-go-go-Related Gene (hERG). The protein encoded by the hERG gene is a channel for the cardiac rapid delayed rectifier potassium current (IKr) and is crucial for the electrophysiological function of the heart. If a drug blocks the hERG channel, it may cause QT interval prolongation, which may in turn cause serious arrhythmias such as torsade de pointes (TdP) or even sudden death. The IC50 in hERG represents the concentration of the drug required to inhibit the hERG channel by 50%. It can predict the cardiac safety risks that may be caused by the drug.

[0269] In safety assessments during drug development, a higher IC50 value indicates that the drug poses less risk to cardiac safety.

[0270] Example 9 Experimental steps

[0271] 9.1 Preparation before the experiment

[0272] 1) Run the Home All Axes method on the SyncroPatch 384i / 384 automated patch clamp system.

[0273] 2) Run the LH_Startup routine and flush the module and tubing with water.

[0274] 3) Place tube 1 into the bottle containing the internal solution in position 1. Prefill with internal solution.

[0275] 4) Place external solution, seal enhancer solvent, and mix in the panel.

[0276] 9.2 Cell Harvest

[0277] 1) Discard the old culture medium from two T75 cell flasks.

[0278] 2) Rinse the cells twice with 6 mL of DPBS-2 mM EDTA at room temperature and discard the solution with a 10 ml plastic pipette.

[0279] 3) Add 2 mL of TrypLE TM Express, gently shake the container to completely cover the cell layer.

[0280] 4) Remove half of the solution, leaving only a thin film covering the cells.

[0281] 5) Incubate at 37°C for 5-7 minutes. Carefully check when the cells begin to float.

[0282] 6) Prepare 10 ml of external standard solution in a centrifuge tube and incubate the culture flask in a refrigerator (4-8°C) for 5 minutes.

[0283] 7) Pipette the cells up and down 3-5 times to separate the cells and collect all the cells in a 5 ml plastic pipette. in a culture dish.

[0284] 8) Count the cells and dilute in cold external solution to a final concentration of 0.5-0.7*106 cells / mL.

[0285] 9) Transfer the cell suspension to a 10 cm ultra-low binding dish and incubate at 4-10°C for 10 minutes.

[0286] 10) Agitate the cells by gentle pipetting and transfer the suspension to a Teflon reservoir in a cell hotel set to 15°C with orbital shaking.

[0287] 9.3 Current Records of SyncroPatch 384i / 384

[0288] 1) Install and clean the head.

[0289] 2) Fill the chip with external and internal solutions. The junction potential is compensated.

[0290] 3) Add cells to the chip.

[0291] 4) Add seal enhancer solution to seal the cells and set the holding potential to -90 mV.

[0292] 5) Wash cells four times with external solution.

[0293] 6) 15 μM Escin in the internal solution will be permeated into the cells and acquire a whole-cell configuration.

[0294] 7) Simulation C slow and the number C slow Compensate for cell capacitance.

[0295] 8) Set the holding potential to -90 mV for 500 ms; record the current at 500 Hz and filter the current at 3 kHz. Measure the leakage current at -90 mV.

[0296] 9) Induce hERG current by depolarizing the membrane to +30 mV for 4.8 seconds, then bring the voltage back to -50 mV for 5.2 seconds to eliminate inactivation and measure the inactivation tail current. The sampling interval is 15 seconds. The maximum magnitude of the tail current will be used to determine the hERG current amplitude.

[0297] 10) Record the current for 120 seconds to assess current stability. Only stable cells with recording parameters that pass the acceptance criteria should be used for perfusion with the working solution.

[0298] 11) First, a blank vector was applied to the cells to create a baseline. After the hERG current had stabilized for at least 5 minutes, the test article was perfused. In the presence of the test compound, the hERG current was recorded for no less than 5 minutes at a single working concentration to reach steady state, and then 5 scans were captured. If steady state was not reached within 10 minutes, the steady-state value was replaced by the average peak current of the last 5 scans. The positive control cisapride was used in the experiment to ensure good performance of the cells and the operation as an integral part of the method validation. The hERG current inhibition in the presence of 5 concentrations of the test article was examined in 2 independent experiments (n=2) to determine the IC 50 .

[0299] 9.4 Data Acceptance Criteria

[0300] The following criteria will be used to determine data acceptability:

[0301] (1) Initial seal resistance is greater than 100 megohms (MΩ). This is the resistance formed between the cell membrane and the electrode during electrophysiological experiments. A high resistance value indicates a good seal quality, which can reduce noise and improve signal quality.

[0302] (2) Access resistance is less than 25 megohms. This refers to the resistance between the cell membrane and the electrode. Lower access resistance helps obtain clearer signals.

[0303] (3) At any given moment, the stable leak current is less than 50% of the control peak tail current. Leakage current refers to the current flowing through the cell membrane in the absence of a voltage change, while the control peak tail current refers to the current measured after a specific voltage pulse. This criterion ensures that leakage current does not significantly affect the experimental results.

[0304] (4) The hERG peak tail current amplitude is much larger than the prepulse current amplitude, and the absolute amplitude of the peak tail current is at least greater than 300 picoamperes (pA). This ensures that the measured current is mainly the hERG channel current, rather than other currents.

[0305] (5) The peak tail current amplitude should not decrease significantly by more than 30%. This means that during the experiment, the current amplitude should not decrease by more than 30%, which can exclude current changes caused by cell fatigue or other nonspecific factors.

[0306] The above standards are intended to ensure the accuracy and reproducibility of experiments and to evaluate the potential effects of drugs or compounds on hERG channels.

[0307] 9.5 Data Analysis:

[0308] Data meeting the above hERG current quality criteria will be further analyzed according to the following steps:

[0309] 1) The inhibition rate of the compound is calculated using the following formula. To plot the relationship between the inhibition rate of the compound and the compound concentration, please refer to Figure 8 、 Figure 9 、 Figure 10 、 Figure 11 、 Figure 12 .

[0310]

[0311] Note: Use Datacontrol 384 software to extract the peak current from the raw data.

[0312] inhibition).

[0313] 2) Dose-response curves of the compounds of Example 1, Example 4, Example 5, Example 6, and Comparative Example 1 and the relationship between hERG inhibition rate and test compound concentration were plotted using Graphpad Prism 8.0 (see Table 10), and the data were fitted to a sigmoidal dose-response curve with a variable slope.

[0314] 9.6 Data Interpretation Standards

[0315] A generally accepted ranking system that indicates the potency of a test sample to inhibit the hERG channel is as follows:

[0316] Low: IC50>10μM;

[0317] Moderate: 1μM <IC50<10μM;

[0318] High: IC50<1μM

[0319] Table 10: hERG detection data of Example 1, Example 4, Example 5, Example 6 and Comparative Example 1

[0320] Example hERG IC50 (μM) Example 1 >30 Example 4 >30 Example 5 >30 Example 6 23.69 Comparative Example 1 >30

[0321] Please refer to Figure 8 、 Figure 9 、 Figure 10 、 Figure 11 、 Figure 12 As shown in Table 10, the IC50 values ​​of the compounds of Examples 1, 4, 5, and 6 are all greater than 10 μM, indicating that the compounds of Examples 1, 4, 5, and 6 have no inhibitory effect on hERG, pose little risk to cardiac safety, and are very safe.

[0322] In summary, the compounds provided in this application include a ligand that specifically binds to a target protein (ie, an estrogen receptor), a ligand that recruits an E3 ubiquitin ligase, and a chemical chain linker that connects the two parts. The compounds provided in this application can bring the estrogen receptor closer to the E3 ubiquitin ligase, mark the estrogen receptor through the ubiquitination process, and then degrade it through the 26S proteasome pathway, thereby reducing the concentration of the estrogen receptor in the cell and regulating biological processes related to it. The compounds provided in this application exhibit significant anti-tumor activity through the PROTAC mechanism; they inhibit the proliferation of tumor cells by degrading Erα protein in the breast cancer MCF-7 cell line, providing a new strategy for the treatment of breast cancer.

[0323] Compared to traditional inhibitors, the ER-targeted PROTAC degraders provided in this application do not need to bind to the active site of the target protein, thus overcoming drug resistance caused by mutations. They also present a lower risk to cardiac safety and have a very good safety profile.

[0324] In addition, the metabolic process of the compound of the present application involves more metabolic enzymes and more metabolic pathways, which makes it difficult for potential drug-drug interactions to occur, reduces treatment deviations between patients, and has good safety and high reliability.

[0325] Each compound of the present application retains only one hydroxyl group, which effectively ensures the activity of the compound, facilitates the connection of the hydroxyl group to the ER protein, and further ensures the anti-tumor efficacy of the compound. On the contrary, if both hydroxyl groups are connected to the R2 group through a linker, the compound molecule will be too large, the space for interaction between the protein and the compound will be too crowded, which is not conducive to the interaction between the protein and the compound, and may also cause E3 ligase (E3 ubiquitin ligase) to collide at the other end, which will also cause the compound to be inactivated, thereby having no anti-tumor efficacy.

[0326] The above description is merely a preferred embodiment of the invention and does not constitute any form of limitation to the invention. Although the invention has been disclosed as a preferred embodiment as above, it is not intended to limit the invention. Any technician familiar with the profession can make some changes or modifications to equivalent embodiments of the technical contents disclosed above without departing from the scope of the technical solution of the invention. However, any simple modifications, equivalent changes and modifications made to the above embodiments based on the technical essence of the invention without departing from the content of the technical solution of the invention are still within the scope of the technical solution of the invention.

Claims

1. A compound, characterized in that The compound has the following structural formula (I): The Linker is selected from any one of the following structures:

2. The compound according to claim 1, wherein The compound is selected from any one of the following structures:

3. A PROTAC degrader targeting ER, characterized in that The ER-targeted PROTAC degrader includes the compound according to any one of claims 1-2.

4. Use of a compound according to any one of claims 1 to 2 or an ER-targeting PROTAC degrader according to claim 3 in the preparation of a medicament for preventing or treating breast tumors.

5. An anti-tumor drug comprising a pharmaceutical active ingredient and a pharmaceutical excipient, characterized in that: The pharmaceutically active ingredient comprises the compound according to any one of claims 1 to 2 or the ER-targeted PROTAC degrader according to claim 3.

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