Chromene derivatives and their applications

Abstract

The present invention belongs to the field of pharmaceutical technology, and in particular relates to chromene derivatives and their applications. The chromene derivatives, whose structural formulas are shown in Formula A or Formula B, are used to prepare anti-tumor drugs, and / or improve drug metabolism efficiency, / or reduce drug side effects, and / or inhibit drug-drug interactions. The chromene derivatives of the present invention utilize protein degradation-targeting chimera technology to alter the degradation mechanism of PROTAC compounds, labeling estrogen receptors through ubiquitination and degrading them via the 26S proteasome pathway, effectively reducing intracellular estrogen receptor concentrations.

Description

Technical Field

[0001] The present invention belongs to the field of medical technology, and in particular relates to chromene derivatives and applications thereof. Background Art

[0002] Estrogen receptors are protein molecules that are widely present in the cell membrane, cytoplasm, or nucleus. The classic form of nuclear receptors is located in the cell nucleus, while the protein is temporarily present in the cytoplasm after translation, allowing it to be detected in the cytoplasm. Estrogen diffuses into the cell nucleus and binds to the nuclear receptors, triggering gene regulatory mechanisms and regulating the transcription of downstream genes. Estrogen receptors play a crucial role in the development and progression of breast cancer. Approximately 70% of breast cancer patients express estrogen receptors in their tumor cells and respond well to hormone therapy.

[0003] In the clinical treatment of breast cancer, a variety of treatment strategies are currently used, including surgery, radiotherapy, chemotherapy, endocrine therapy, and targeted therapy. Endocrine therapy is a key treatment for estrogen receptor-positive breast cancer, and its drugs can be divided into several generations. First-generation drugs, such as tamoxifen, are selective estrogen receptor modulators that can competitively bind to estrogen receptors and block the effects of estrogen, but may cause adverse reactions such as endometrial thickening and thrombosis; second-generation drugs, such as letrazol and anastrozole, are aromatase inhibitors that reduce estrogen levels in the body by inhibiting aromatase activity. Long-term use may cause osteoporosis and joint pain; third-generation drugs, such as fulvestrant, are selective estrogen receptor degraders that can induce the degradation of selective estrogen receptors, thereby inhibiting tumor growth, but may be accompanied by side effects such as muscle pain.

[0004] Existing endocrine therapy drugs have achieved remarkable success in the treatment of breast cancer, but they still have side effects, including the gradual development of drug resistance and the side effects associated with treatment. The effectiveness of endocrine therapy is particularly limited for patients with estrogen receptor-negative breast cancer, prompting the medical community to seek a wider range of treatment strategies. Therefore, developing new treatments to overcome the limitations of existing drugs and provide more treatment options for estrogen receptor-negative patients has become an important direction in breast cancer research. Summary of the Invention

[0005] The technical solution of the present invention addresses the limitations of the existing technology that the treatment of breast cancer relies on blocking the binding of estrogen to its receptor, such as large side effects, unstable efficacy and drug resistance. It provides chromene derivative compounds and their applications, which utilize the ubiquitin-proteasome system to degrade targeted estrogen receptors.

[0006] The main objectives of the present invention are:

[0007] 1. Overcoming the limitations of selective estrogen receptor modulators;

[0008] 2. Overcome drug resistance caused by mutations and enhance biocompatibility;

[0009] 3. Inhibit uncontrolled cell proliferation caused by malignant diseases.

[0010] To achieve the above objectives, the present invention adopts the following technical solutions.

[0011] Chromene derivatives,

[0012] The general structural formula of the chromene derivative is shown in Formula A or Formula B:

[0013] Formula A: Formula B: In the formula A and formula B: Linker is a connecting group.

[0014] As a preference,

[0015] One end of the linking group is CH2CO-, and the other end is -O- or -NH- or -N-.

[0016] As a preference,

[0017] The connecting group is any one of the following structural formulas a to y;

[0018] Formula a: Formula b: Formula c: Formula d: Formula e: Formula f: Formula g: Formula h: Formula i: Formula j: Formula k: Formula I: Formula m: Formula n: Formula o: Formula p: Formula q: Formula r: Formula s: Formula t: Formula u: Formula v: Formula w: Formula x: Formula y: As a preference,

[0019] Based on the linking groups represented by the above formulas a to y, the chromene derivative compounds of the present invention include but are not limited to any one of the following:

[0020]

[0021]

[0022]

[0023]

[0024]

[0025]

[0026]

[0027]

[0028]

[0029]

[0030]

[0031]

[0032]

[0033]

[0034] Application of chromene derivatives: the chromene derivatives are used to prepare anti-tumor drugs, and / or improve drug metabolism efficiency and / or reduce drug side effects and / or inhibit drug-drug interactions.

[0035] As a preference,

[0036] The tumor is human breast cancer.

[0037] Estrogen receptors are ubiquitous proteins located primarily in the cell nucleus. After forming in the cytoplasm, they migrate to the nucleus and bind to estrogen, activating gene regulation and influencing gene transcription. Estrogen receptors play a key role in breast cancer, with tumor cells in approximately 70% of patients expressing these receptors and being sensitive to hormonal therapy. Current endocrine-based therapies have achieved significant success in treating breast cancer, but side effects persist, including the gradual development of treatment resistance and associated side effects. The effectiveness of endocrine therapy is particularly limited in patients with estrogen receptor-negative breast cancer, prompting the medical community to explore a broader range of treatment strategies. To address the limitations of selective estrogen receptor modulators (SERDs), a new generation of therapeutic agents—selective estrogen receptor downregulators (SERDs)—has been developed. SERDs not only antagonize estrogen receptors (ERs) but also promote ER degradation, thereby blocking ER signaling pathways and effectively inhibiting breast cancer cell proliferation. Although Fulvestrant, as the only clinically approved SERDs drug, has shown certain potential in the treatment of drug-resistant breast cancer, its oral bioavailability is low and it needs to be administered by injection, which to a certain extent limits the patient's medication compliance. To overcome these limitations, the present invention uses a new treatment strategy, protein hydrolysis targeting chimera (PROTAC) technology. In the cutting-edge exploration of breast cancer treatment, PROTAC technology focuses on degrading proteins that are critical to tumor development, especially estrogen receptors. By specifically eliminating ER, PROTAC molecules demonstrate their ability to overcome the limitations of traditional hormone therapy, bringing more efficient and safe treatment prospects to breast cancer patients. However, to achieve this goal, an in-depth understanding of the fine structure, functional properties of ER and its complex interaction mechanism with E3 ubiquitin ligase is indispensable. The compounds provided by the present invention significantly inhibited the proliferation of tumor cells by effectively degrading ERα in the breast cancer MCF-7 cell line experiment, opening up a new path for the innovation of breast cancer treatment strategies.

[0038] For the technology of the present invention, the core lies in the degradation mechanism of innovative compounds using protein degradation targeting chimera technology (PROTAC), which not only improves the therapeutic effect, but also enhances the safety and reliability of the treatment, providing a new strategy for the treatment of estrogen-related diseases such as breast cancer. The technical solution involved in the present invention includes a compound, which is composed of three main components: one is a ligand with specific binding ability to the target protein (i.e., estrogen receptor); the second is a ligand that can attract E3 ubiquitin ligase; and the third is a chemical chain connecting the two ligands. Through this structural design, the compound of the present invention can effectively promote the approach between the estrogen receptor and the E3 ubiquitin ligase, mark the estrogen receptor with the help of the ubiquitination mechanism, and then achieve its degradation through the 26S proteasome pathway, significantly reducing the content of estrogen receptor in the cell, thereby regulating the biological processes related to it. The compound involved in the present invention, by utilizing the PROTAC mechanism, exhibited significant anti-tumor activity in the ER-positive breast cancer cell line MCF-7. The compound effectively inhibits the proliferation of tumor cells by promoting the degradation of ERα protein, providing an innovative approach for the treatment strategy of breast cancer. Unlike traditional inhibitors, the PROTAC degraders of the present invention do not need to bind to the active site of the target protein, thereby circumventing the drug resistance problem caused by protein mutations. This advantage significantly improves the efficacy and scope of application of the compound. In addition, the compounds of the present invention involve multiple metabolic enzymes in the metabolic process and have rich metabolic pathways, which reduces the possibility of drug interactions. Therefore, the compounds of the present invention show higher safety and reliability during the treatment process, reducing the difference in therapeutic effects between patients. In view of the above advantages of the PROTAC compounds of the present invention, they have broad application potential in the field of drug development, especially in those disease areas that traditional small molecule drugs are difficult to deal with.

[0039] The advantages of this invention lie in its ability to alter the degradation mechanism of PROTAC compounds by utilizing protein degradation-targeting chimera technology. This allows the estrogen receptor to be labeled via ubiquitination and then degraded via the 26S proteasome, effectively reducing intracellular estrogen receptor concentrations. The PROTAC degraders of this invention do not require binding to the active site of the target protein, overcoming drug resistance and improving therapeutic efficacy and application range. Furthermore, the compounds have diverse metabolic pathways, reducing the risk of drug-drug interactions and improving the safety and reliability of treatment, thus promising broad application prospects. BRIEF DESCRIPTION OF THE DRAWINGS

[0040] Figure 1 The synthetic route of structure 1-2 described in Example 1 Figure 1 ;

[0041] Figure 2The synthetic route of structure 1-2 described in Example 1 Figure 2 ;

[0042] Figure 3 The synthetic route of structure 1-2 described in Example 1 Figure 3 ;

[0043] Figure 4 The synthetic route of structure 1-2 described in Example 1 Figure 4 ;

[0044] Figure 5 The NMR characterization results of structure 1-2 prepared in Example 1;

[0045] Figure 6 The synthetic route of structure 1-7 described in Example 2;

[0046] Figure 7 The NMR characterization results of structure 1-7 prepared in Example 2;

[0047] Figure 8 The synthetic route of structure 2-21 described in Example 3 Figure 1 ;

[0048] Figure 9 The synthetic route of structure 2-21 described in Example 3 Figure 2 ;

[0049] Figure 10 The synthetic route of structure 2-21 described in Example 3 Figure 3 ;

[0050] Figure 11 These are the NMR characterization results of structure 2-21 prepared in Example 3. DETAILED DESCRIPTION

[0051] The present invention is further described in detail below with reference to specific embodiments and the accompanying drawings. Those skilled in the art will be able to implement the present invention based on these descriptions. Furthermore, the embodiments of the present invention described below are generally only a portion of the embodiments of the present invention, rather than all of the embodiments. Therefore, all other embodiments derived by those skilled in the art based on the embodiments of the present invention without inventive effort should fall within the scope of protection of the present invention.

[0052] Unless otherwise specified, the raw materials used in the examples of the present invention are all commercially available or available to those skilled in the art; unless otherwise specified, the methods used in the examples of the present invention are all methods known to those skilled in the art.

[0053] Example 1

[0054] A synthesis of a chromene derivative compound, specifically the synthesis of N-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)ethoxy)ethyl)-2-(3-(2-(4-((S)-6-hydroxy-3-(3-hydroxyphenyl)-4-methyl-2H-chromen-2-yl)phenoxy)ethyl)cyclobutyl)acetamide, namely structure 1-2, and the specific synthetic route is as follows: Figures 1 to 4 As shown, the synthetic route of steps (1) to (7) is as follows Figure 1 As shown, the synthetic route of steps (8) to (14) is as follows Figure 2 As shown, the synthetic route of step (15) to step (16) is as follows Figure 3 As shown, the synthetic route of steps (17) to (19) is as follows Figure 4 shown.

[0055] The specific operations are as follows:

[0056] (1) 2-(3-methoxyphenyl)acetic acid and dichloromethane were mixed in a mass ratio of 1:7.98, and stirred under nitrogen atmosphere at 0°C to prepare a 2-(3-methoxyphenyl)acetic acid solution with a concentration of 0.60 M. Subsequently, phosphorus oxychloride and dimethylformamide were continuously added dropwise to the 2-(3-methoxyphenyl)acetic acid solution at a drop rate of 6.5434 mL / min under nitrogen atmosphere at 0°C and stirred for 1.5 h, wherein the amount of phosphorus oxychloride added was 71.6 g phosphorus oxychloride / 100 g of 2-(3-methoxyphenyl)acetic acid, and the amount of dimethylformamide added was 2.6432 g dimethylformamide / 100 g of 2-(3-methoxyphenyl)acetic acid. The ice-water bath was removed, and the reaction mixture was stirred for 30 min. The reaction was stirred for 3 h under nitrogen atmosphere at 45°C, and concentrated to obtain 2-(3-methoxyphenyl)acetyl chloride. 1,4-Dimethoxybenzyl alcohol, aluminum chloride, and dichloromethane were mixed uniformly in a mass ratio of 1:9.62:3.20 and stirred at 0°C for 30 minutes. 2-(3-methoxyphenyl)acetyl chloride was then added dropwise at a rate of 2.223 mL / min at -10°C and stirred for 1.5 hours. After the addition was complete, the mixture was stirred at 0°C for 1 hour. The mixture was added to ice water and extracted with dichloromethane. The organic layers were combined and washed sequentially with aqueous hydrochloric acid, saturated sodium bicarbonate solution, and brine. The resulting solution was dried over sodium sulfate, concentrated, and purified by silica gel column chromatography to obtain 1-(2,5-dimethoxyphenyl)-2-(3-methoxyphenyl)ethane-1-one (A-3).

[0057] (2) 1-(2,5-dimethoxyphenyl)-2-(3-methoxyphenyl)ethane-1-one, dichloromethane, and boron tribromide were mixed uniformly in a mass ratio of 1:5.47:3.38, stirred at -78°C for 30 minutes, then gradually heated to 0°C over 30 minutes, stirred at 0°C for 1 hour, and then cooled to -78°C and quenched with methanol. The reaction mixture was heated to 25°C, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain 1-(2,5-dihydroxyphenyl)-2-(3-hydroxyphenyl)ethane-1-one (A-4).

[0058] (3) 1-(2,5-dihydroxyphenyl)-2-(3-hydroxyphenyl)ethanone, dihydropyran, dichloromethane and pyridine p-toluenesulfonate were mixed uniformly in a mass ratio of 1:2.41:13.3:0.206, wherein the mixing process was carried out at an ambient temperature of 0°C. The mixture was stirred at an ambient temperature of 25°C for 2 hours, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain 1-(2-hydroxy-5-((tetrahydro-2H-pyran-2-yl)oxy)phenyl)-2-(3-((tetrahydro-2H-pyran-2-yl)oxy)phenyl)ethan-1-one (A-5).

[0059] (4) 1-[2-hydroxy-5-(oxanyloxy)phenyl]-2-[3-(oxanyloxy)phenyl]ethanone, 4-iodobenzaldehyde, 1,8-diazabicyclo[5.4.0]undec-7-ene, piperidine and n-butanol were mixed uniformly in a mass ratio of 1:0.52:0.063:2.03 and kept warm in a microwave reactor at 120°C for 30 minutes. The mixture was cooled to room temperature and n-pentane was added in an amount of 75.12 g / g of n-butanol. The mixture was stirred at 25°C for 12 hours and filtered to obtain 2-(4-(benzyloxy)phenyl)-6-((tetrahydro-2H-pyran-2-yl)oxy)-3-(3-((tetrahydro-2H-pyran-2-yl)oxy)phenyl)chromen-4-one (A-6).

[0060] (5) 2-(4-(benzyloxy)phenyl)-6-((tetrahydro-2H-pyran-2-yl)oxy)-3-(3-((tetrahydro-2H-pyran-2-yl)oxy)phenyl)chromen-4-one, tetrahydrofuran and methylmagnesium chloride were mixed in a mass ratio of 1:3.09:1.85, stirred for 30 minutes under a nitrogen atmosphere at a temperature of 0°C, then stirred for 1.5 hours at a temperature of 25°C, cooled to 0°C after stirring, and saturated chloride was used. The reaction mixture was quenched with ammonium and extracted with ethyl acetate. The organic phases were combined, concentrated in vacuo, and purified by column chromatography to obtain intermediate a-7. The intermediate a-7 was heated in an aqueous acetic acid solution with a volume ratio of 4:1 at 90°C for 16 hours. The aqueous phase was extracted with ethyl acetate, and the organic phases were combined, washed, dried, concentrated, and purified by silica gel column chromatography to obtain 2-(4-(benzyloxy)phenyl)-3-(3-hydroxyphenyl)-4-methyl-2H-chromen-6-ol (A7).

[0061] (6) 2-(4-(Benzyloxy)phenyl)-3-(3-hydroxyphenyl)-4-methyl-2H-chromen-6-ol, dihydropyran, dichloromethane and pyridinium p-toluenesulfonate were mixed uniformly in a mass ratio of 1:1.16:30.79:0.17 and stirred at 26°C for 4 hours. The mixture was extracted with dichloromethane, and the organic phases were combined, washed, dried, concentrated and purified by silica gel column chromatography to obtain 2-(4-(benzyloxy)phenyl)-4-methyl-6-((tetrahydro-2H-pyran-2-yl)oxy)-3-(3-((tetrahydro-2H-pyran-2-yl)oxy)phenyl)-2H-chromene (A-8).

[0062] (7) 2-(4-(Benzyloxy)phenyl)-4-methyl-6-((tetrahydro-2H-pyran-2-yl)oxy)-3-(3-((tetrahydro-2H-pyran-2-yl)oxy)phenyl)-2H-chromene, an organic mixed solution, 10% palladium / carbon and ammonium formate were mixed in a mass ratio of 1:50.73:50:0.21, stirred under a nitrogen atmosphere at 50°C for 0.5 h, repeated 11 times, concentrated in vacuo, and purified by silica gel column chromatography to obtain 4-(4-methyl-6-((tetrahydro-2H-pyran-2-yl)oxy)-3-(3-((tetrahydro-2H-pyran-2-yl)oxy)phenyl)-2H-chromene-2-yl)phenol (A-9).

[0063] (8) 2,2,2-Trichloroacetyl chloride, methyl methylbut-3-enoate, zinc-copper alloy, dimethyl ether and diethyl ether were mixed uniformly in a mass ratio of 1:0.2:0.41:2.01:4.35, stirred at 25°C for 24 h, filtered, concentrated in vacuo, and purified by silica gel column chromatography to obtain methyl 2-(2,2-dichloro-3-oxocyclobutyl) acetate (A-11).

[0064] (9) Metallic zinc, methyl 2-(2,2-dichloro-3-oxocyclobutyl) acetate, and glacial acetic acid solution were mixed uniformly in a mass ratio of 1.6:1:30.9, stirred at 100°C for 15 h, concentrated in vacuo, and the organic layers were combined and dried to obtain methyl 2-(3-oxocyclobutyl) acetate (A-12).

[0065] (10) Tert-butyl triphenylphosphine acetate, methyl 2-(3-oxocyclobutyl) acetate, and dichloromethane were mixed uniformly in a mass ratio of 2.7:1:9.3, stirred at 25°C for 12 h, concentrated in vacuo, and purified by silica gel column chromatography to obtain methyl 2-{3-[2-(tert-butoxy)-2-oxoethylmethylene]cyclobutyl} acetate (A-14).

[0066] (11) Palladium / carbon, methyl 2-{3-[2-(tert-butoxy)-2-oxoethylmethylene]cyclobutyl} acetate and methanol were mixed uniformly in a mass ratio of 0.15:1:5.98, stirred for 4 h under a hydrogen atmosphere at 25°C, filtered and concentrated under vacuum to obtain 2-{3-[2-(tert-butoxy)-2-oxoethyl]cyclobutyl} acetate (A-15).

[0067] (12) 2-{3-[2-(tert-butoxy)-2-oxoethyl]cyclobutyl}acetate, dichloromethane, and trifluoroacetic acid were mixed uniformly in a mass ratio of 1:3.86:2.16, stirred at 25°C for 12 h, concentrated in vacuo, and freeze-dried to obtain [3-(2-methoxy-2-oxoethyl)cyclobutyl]acetic acid (A-16).

[0068] (13) [3-(2-methoxy-2-oxoethyl)cyclobutyl]acetic acid, 2-methylpropyl chloroformate and N-methylmorpholine were mixed in a mass ratio of 1:13.72:1.47:1.63 and stirred at 25°C for 0.5 h to prepare intermediate a-18. Intermediate a-18, methanol and sodium borohydride were mixed in a mass ratio of 1:0.46:0.034 and stirred at -78°C for 1.5 h. The mixture was then slowly heated to 25°C, dried, concentrated in vacuo, and purified by silica gel column chromatography to obtain methyl 2-[3-(2-hydroxyethyl)cyclobutyl]acetate (A-18).

[0069] (14) Methyl 2-[3-(2-hydroxyethyl)cyclobutyl]acetate, dichloromethane, triethylamine, 4-dimethylaminopyridine, and methanesulfonyl chloride were mixed uniformly in a mass ratio of 1:33.25:0.91:0.35:1.66 at 0°C, and kept at 25°C for 16 h. The mixture was then quenched with a saturated aqueous ammonium chloride solution, and the organic phases were extracted, combined, dried, concentrated in vacuo, and purified by silica gel column chromatography to obtain methyl 2-(3-(2-(methylsulfonyloxy)ethyl)cyclobutyl)acetate (A-19).

[0070] (15) Methyl 2-(3-(2-(methylsulfonyloxy)ethyl)cyclobutyl)acetate, 4-(4-methyl-6-((tetrahydro-2H-pyran-2-yl)oxy)-3-(3-((tetrahydro-2H-pyran-2-yl)oxy)phenyl)-2H-chromen-2-yl)phenol, cesium carbonate and acrylonitrile were mixed uniformly in a mass ratio of 1:1.31:2.5:20.35, and the mixture was kept at 70°C for 3 hours. The organic phases were extracted, combined, dried, concentrated in vacuo and purified by silica gel column chromatography to obtain methyl 2-(3-(2-(4-(4-methyl-6-((tetrahydro-2H-pyran-2-yl)oxy)-3-(3-((tetrahydro-2H-pyran-2-yl)oxy)phenyl)-2H-chromen-2-yl)phenoxy)ethyl)cyclobutyl)acetate (A-20).

[0071] (16) Methyl 2-(3-(2-(4-(4-methyl-6-((tetrahydro-2H-pyran-2-yl)oxy)-3-(3-((tetrahydro-2H-pyran-2-yl)oxy)phenyl)-2H-chromen-2-yl)phenoxy)ethyl)cyclobutyl)acetate was added to a mixed solvent comprising 18 wt% toluene, 27 wt% water, and the balance glacial acetic acid. The mixture was kept at 100° C. for 48 h, concentrated in vacuo, and filtered through a reverse phase filter. Column chromatography purification gave a racemic mixture, which was further subjected to supercritical fluid chromatography to give (S)-2-(3-(2-(4-(6-hydroxy-3-(3-hydroxyphenyl)-4-methyl-2H-chromen-2-yl)phenoxy)ethyl)cyclobutyl)acetic acid (A-21-1) and (R)-2-(3-(2-(4-(6-hydroxy-3-(3-hydroxyphenyl)-4-methyl-2H-chromen-2-yl)phenoxy)ethyl)cyclobutyl)acetic acid (A-21-2).

[0072] (17) Tert-butyl [2-(2-{[(4-methylphenyl)sulfonyl]oxy}ethoxy)ethyl]carbamate, dimethylformamide, 2-(2,6-dioxopiperidine-3-yl)-4-hydroxyisoindole-1,3-dione, potassium carbonate and potassium iodide were mixed at a mass ratio of 1:9.44:0.77:1.16:0.05 at 25°C, and kept at 80°C for 16 hours. The mixture was extracted with ethyl acetate, and the organic phases were combined, dried, concentrated, and purified by silica gel column chromatography to obtain tert-butyl [2-(2-{[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindole-4-yl]oxy}ethoxy)ethyl]carbamate (A-24).

[0073] (18) Tert-butyl [2-(2-{[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]oxy}ethoxy)ethyl]carbamate and 4 mol hydrochloric acid / 1,4-dioxane solution were mixed at a mass ratio of 0.24:4.13, stirred at 25°C for 2 h, and concentrated under reduced pressure to obtain 4-[2-(2-aminoethoxy)ethoxy]-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione (A-25).

[0074] (19) [3-(2-{4-[(2S)-6-hydroxy-3-(3-hydroxyphenyl)-4-methyl-2H-chromen-2-yl]phenoxy}ethyl)cyclobutyl]acetic acid, dimethylformamide, 4-[2-(2-aminoethoxy)ethoxy]-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione, HATU, and DIEA were mixed in a mass ratio of 1:75.52:0.74:1.17:0.80. The mixture was stirred at 25° C. for 2 h and purified by preparative high performance liquid chromatography to obtain N-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindole-4-yl)oxy)ethoxy)ethyl)-2-(3-(2-(4-((S)-6-hydroxy-3-(3-hydroxyphenyl)-4-methyl-2H-chromen-2-yl)phenoxy)ethyl)cyclobutyl)acetamide (A-26).

[0075] The structure 1-2 compound prepared in Example 1 was subjected to nuclear magnetic resonance detection. Figure 5The specific characterization results are as follows: 1H NMR (400 MHz, DMSO) δ 11.11 (s, 1H), 9.44 (s, 1H), 8.95 (s, 1H), 7.75 (m, 2H), 7.51 (d, J = 8.5 Hz, 1H), 7.45 (d, J = 7.2 Hz, 1H), 7.23-7.08 (m, 3H), 6.78-6.71 (m, 3H), 6.70-6.60 (m, 3H), 6.47 (s, 2H), 5.83 (s, 1H), 5.08 (dd, J = 12.9, 5.3 Hz, 1H), 4.36-4.27 (m , 2H), 3.82~3.73(m, 4H), 3.48(t, J=5.7Hz, 2H), 3.18(d, J=5.7Hz, 2H), 2.92~2.83(m, 1H), 2.58(d, J=16.8Hz, 2H), 2.38~2.33(m, 1H) , 2.22~2.11 (m, 2H), 2.10~2.07 (m, 2H), 2.03 (s, 4H), 1.78~1.71 (m, 2H), 1.66 (dd, J=12.9, 6.4Hz, 1H), 1.27 (dd, J=18.8, 8.9Hz, 2H).

[0076] Example 2

[0077] A synthesis of a chromene derivative compound, specifically the synthesis of N-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)butyl)-2-(3-(2-(4-((S)-6-hydroxy-3-(3-hydroxyphenyl)-4-methyl-2H-chromen-2-yl)phenoxy)ethyl)cyclobutyl)acetamide, namely structures 1-7, and the specific synthetic route is as follows: Figure 6 shown.

[0078] The specific operations are as follows:

[0079] (1) 2-(2,6-dioxo-piperidin-3-yl)-4-fluoro-isoindole-1,3-dione, tert-butyl (4-aminobutyl) carbamate, N-methylpyrrolidone and diisopropylethylamine were mixed uniformly in a mass ratio of 1:0.75:10.3:1.16, stirred at 90°C for 16 h, extracted with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated in vacuo, and purified by C18 chromatography to obtain tert-butyl (4-{[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindole-4-yl]amino}butyl)amino) (B-3).

[0080] (2) Tert-butyl (4-{[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]amino}butyl) carbamate and 4 mol hydrochloric acid / 1,4-dioxane solution were mixed uniformly in a mass ratio of 1:14.38, stirred at 25°C for 2 h, and concentrated under reduced pressure to obtain 4-((4-aminobutyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (B-4).

[0081] (3) [3-(2-{4-[(2S)-6-hydroxy-3-(3-hydroxyphenyl)-4-methyl-2H-chromen-2-yl]phenoxy}ethyl)cyclobutyl]acetic acid, dimethylformamide, 4-[(4-aminobutyl)amino]-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione, HATU and DIEA were mixed in a mass ratio of 1.18:88.89:1:1.38:1.25. The mixture was mixed evenly, stirred at 25° C. for 2 h, and purified by preparative high performance liquid chromatography to obtain N-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl)amino)butyl)-2-(3-(2-(4-((S)-6-hydroxy-3-(3-hydroxyphenyl)-4-methyl-2H-chromen-2-yl)phenoxy)ethyl)cyclobutyl)acetamide (B-5). The compound structure 1-7 prepared in Example 2 was subjected to nuclear magnetic resonance detection, as shown in FIG. Figure 7The specific characterization results are as follows: 1H NMR (400 MHz, DMSO) δ 11.09 (s, 1H), 9.42 (s, 1H), 8.94 (s, 1H), 7.72 (dt, J = 23.0, 5.6 Hz, 1H), 7.60-7.49 (m, 1H), 7.21-7.05 (m, 4H), 7.01 (d, J = 7.0 Hz, 1H), 6.75 (d, J = 8.7 Hz, 3H), 6.70-6.59 (m, 3H), 6.54 (s, 1H), 6.50-6.44 (m, 2H), 5.82 (s, 1H), 5.04 (dd, J = 12.9, 5.4 Hz, 1H), 3.82-3.75 (m, 2 H), 3.29 (d, J=4.4Hz, 2H), 3.03 (dd, J=12.4, 6.5Hz, 2H), 2.87 (m, 1H), 2.57 ( dd, J=20.3, 6.0Hz, 2H), 2.38 (dd, J=12.0, 4.7Hz, 1H), 2.18 (d, J=7.9Hz, 1H) , 2.15~2.06 (m, 3H), 2.02 (s, 4H), 1.82~1.71 (m, 2H), 1.68 (dd, J=12.9, 6.5H z, 1H), 1.58~1.48 (m, 2H), 1.47~1.38 (m, 2H), 1.30 (dd, J=17.9, 8.8Hz, 2H).

[0082] Example 3

[0083] A synthesis of a chromene derivative compound, specifically 2-(2,6-dioxopiperidin-3-yl)-4-(3-((4-(3-(2-(4-((R)-6-hydroxy-3-(3-hydroxyphenyl)-4-methyl-2H-chromen-2-yl)phenoxy)ethyl)cyclobutane-1-carbonyl)piperazin-1-yl)methyl)azetidin-1-yl)isoindoline-1,3-dione, namely structure 2-21. The specific synthetic route is as follows: Figures 8-10 As shown, steps (1) to (5) are as follows Figure 8 As shown, steps (6) to (7) are as follows Figure 9 As shown, steps (8) to (13) are as follows Figure 10 shown.

[0084] The specific operations are as follows:

[0085] (1) Methyl 3-oxocyclobutane-1-carboxylate, dichloromethane, and (tert-butoxycarbonylmethylene)triphenylphosphine were mixed uniformly in a mass ratio of 1:13.3:4.41, stirred at 25°C for 20 h, concentrated in vacuo, and purified by silica gel column chromatography to obtain methyl 3-[2-(tert-butoxy)-2-oxoethylmethylene]cyclobutane-1-carboxylate (C-3).

[0086] (2) Methyl 3-[2-(tert-butoxy)-2-oxoethylmethylene]cyclobutane-1-carboxylate, methanol and 10% palladium / carbon were mixed in a mass ratio of 1:4.75:0.1, stirred at 25°C for 16 h, filtered using bentonite, concentrated in vacuo, and purified by silica gel column chromatography to obtain methyl 3-(2-(tert-butoxy)-2-oxoethyl)cyclobutane-1-carboxylate (C-4).

[0087] (3) At an ambient temperature of 0°C, methyl 3-[2-(tert-butoxy)-2-oxoethyl]cyclobutane-1-carboxylate, dichloromethane, and trifluoroacetic acid were uniformly mixed in a mass ratio of 1:3.5:3.92, stirred at an ambient temperature of 25°C for 3 h, and freeze-dried to obtain 2-(3-(methoxycarbonyl)cyclobutyl)acetic acid (C-5).

[0088] (4) Under nitrogen atmosphere and an ambient temperature of 25°C, [3-(methoxycarbonyl)cyclobutyl]acetic acid, dichloromethane, 2-methylpropyl chloride and N-methylmorpholine were mixed in a mass ratio of 1.18:88.89:1:1.38, and stirred at 25°C for 0.5h to prepare intermediate c-7. Subsequently, intermediate c-7, methanol and sodium borohydride were mixed in a mass ratio of 1:0.51:0.043 at a temperature of -78°C, and stirred at -78°C for 1.5h. The mixture was slowly heated to room temperature, diluted with toluene, washed with salt, dried, concentrated in vacuo, and purified by silica gel column chromatography to obtain methyl 3-(2-hydroxyethyl)cyclobutane-1-carboxylate (C-7).

[0089] (5) At an ambient temperature of 0°C, methyl 3-(2-hydroxyethyl)cyclobutane-1-carboxylate, dichloromethane, triethylamine, 4-dimethylaminopyridine and methanesulfonyl chloride were mixed uniformly in a mass ratio of 3:66.5:1.82:1.16:5.43, and kept at an ambient temperature of 25°C for 16 h. The reaction was quenched with saturated ammonium chloride and extracted with ethyl acetate. The organic layers were combined, washed with salt, dried, concentrated in vacuo, and purified by silica gel column chromatography to obtain methyl 3-(2-(methylsulfonyloxy)ethyl)cyclobutane-1-carboxylate (C-8).

[0090] (6) Methyl 3-(2-(methylsulfonyloxy)ethyl)cyclobutane-1-carboxylate, 4-(4-methyl-6-((tetrahydro-2H-pyran-2-yl)oxy)-3-(3-((tetrahydro-2H-pyran-2-yl)oxy)phenyl)-2H-chromen-2-yl)phenol, cesium carbonate and acrylonitrile were mixed in a mass ratio of 1:1.5:1.9:20.15 and heated at 70°C. The mixture was incubated for 3 h under ambient conditions, extracted with ethyl acetate, and the organic layers were combined, washed with salt, dried, concentrated in vacuo, and purified by silica gel column chromatography to obtain 3-(2-(4-(4-methyl-6-((tetrahydro-2H-pyran-2-yl)oxy)-3-(3-((tetrahydro-2H-pyran-2-yl)oxy)phenyl)-2H-chromen-2-yl)phenoxy)ethyl)cyclobutane-1-carboxylate (C-9).

[0091] (7) 3-(2-(4-(4-methyl-6-((tetrahydro-2H-pyran-2-yl)oxy)-3-(3-((tetrahydro-2H-pyran-2-yl)oxy)phenyl)-2H-chromen-2-yl)phenoxy)ethyl)cyclobutane-1-carboxylate was added to a mixed solvent comprising 18 wt% toluene, 27 wt% water, and the balance glacial acetic acid. The mixture was kept at 110° C. for 48 h, concentrated in vacuo, and filtered. The products were purified by reverse phase column chromatography and separated by supercritical fluid chromatography to give (S)-3-(2-(4-(6-hydroxy-3-(3-hydroxyphenyl)-4-methyl-2H-chromen-2-yl)phenoxy)ethyl)cyclobutane-1-carboxylic acid (C-10-1) and (R)-3-(2-(4-(6-hydroxy-3-(3-hydroxyphenyl)-4-methyl-2H-chromen-2-yl)phenoxy)ethyl)cyclobutane-1-carboxylic acid (C-10-2).

[0092] (8) Under nitrogen atmosphere and temperature of -60°C, oxalyl chloride, dichloromethane, dimethyl sulfoxide and benzyl 3-(hydroxymethyl)azetidine-1-carboxylate were mixed in a mass ratio of 0.64:13.3:1.77:1 and stirred at -60°C for 1.5 h. Subsequently, triethylamine (2.29 times the mass of benzyl 3-(hydroxymethyl)azetidine-1-carboxylate) was added. The mixture was gradually heated to 25°C and extracted with ethyl acetate. The organic layers were combined, washed with salt, dried, filtered, and concentrated in vacuo to obtain benzyl 3-formylazetidine-1-carboxylate (C-12).

[0093] (9) Benzyl 3-formylazetidin-1-carboxylate, tert-butylpiperazine-1-carboxylate, dichloromethane, glacial acetic acid, and sodium acetylborohydride were mixed uniformly in a mass ratio of 1:1.19:14.78:0.52:1.35, stirred at 25°C for 16 h, extracted with ethyl acetate, and the organic layers were combined, washed with salt, dried, filtered, and concentrated in vacuo. The mixture was purified by C18 chromatography to obtain tert-butyl 4-({1-[(benzyloxy)carbonyl]azetidin-3-yl}methyl)piperazine-1-carboxylate (C-14).

[0094] (10) Tert-butyl 4-({1-[(benzyloxy)carbonyl]azetidin-3-yl}methyl)piperazine-1-carboxylate, methanol, and 20% palladium / carbon by mass were mixed uniformly, stirred for 16 h under a hydrogen atmosphere, a pressure of 1 MPa, and a temperature of 50°C, filtered, and concentrated in vacuo to obtain tert-butyl 4-(azetidin-3-ylmethyl)piperazine-1-carboxylate (C-15).

[0095] (11) 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindole-1,3-dione, N-methylpyrrolidone, tert-butyl 4-(azetidin-3-ylmethyl)piperazine-1-carboxylate and diisopropylethylamine were mixed in a mass ratio of 1:10.28:1.01:1.16, stirred at 90°C for 16 h, extracted with ethyl acetate, and the organic layers were combined, washed with salt, dried, filtered, concentrated in vacuo, and purified by column chromatography (FCC) to obtain tert-butyl 4-({1-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindole-4-yl]azetidin-3-yl{methyl)piperazine-1-carboxylate (C-17).

[0096] (12) Tert-butyl 4-({1-[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]azetidin-3-yl{methyl)piperazine-1-carboxylate, toluene, and diatomaceous earth were mixed uniformly in a mass ratio of 1:79.27:10, stirred at 100°C for 24 h, and the solvent was removed in vacuo. The residue was purified by column chromatography (FCC) to prepare 2-(2,6-dioxopiperidin-3-yl)-4-[3-(piperazin-1-ylmethyl)azetidin-1-yl]isoindole-1,3-dione (C-18).

[0097] (13) (S)-3-(2-(4-(6-hydroxy-3-(3-hydroxyphenyl)-4-methyl-2H-chromen-2-yl)phenoxy)ethyl)cyclobutane-1-carboxylic acid, dimethylformamide, 2-(2,6-dioxopiperidin-3-yl)-4-[3-(piperazin-1-ylmethyl)azetidin-1-yl]isoindole-1,3-dione, HATU and DIEA were mixed in a mass ratio of 1:75.52:1:1.17:1.06. The mixture was mixed evenly, stirred at 25° C. for 2 h, and purified by high performance liquid chromatography to give 2-(2,6-dioxopiperidin-3-yl)-4-(3-((4-(3-(2-(4-((S)-6-hydroxy-3-(3-hydroxyphenyl)-4-methyl-2H-chromen-2-yl)phenoxy)ethyl)cyclobutane-1-carbonyl)piperazin-1-yl)methyl)azetidin-1-yl)isoindoline-1,3-dione (C-19).

[0098] The structure2-21 compound prepared in Example 3 was subjected to nuclear magnetic resonance detection. Figure 11 The specific characterization results are shown as follows: 1 HNMR (400MHz, DMSO) δ11.08 (s, 1H), 9.58 (s, 1H, TFA), 9.44 (s, 1H), 8.95 (s, 1H), 7.61 (t, J=7.8Hz , 1H), 7.20~7.11(m, 4H), 6.80~6.61(m, 7H), 6.47(s, 2H), 5.83(s, 1H), 5.05(dd, J=12.8, 5.5Hz, 1 H), 4.41~4.37(m, 3H), 3.97~3.95(m, 2H), 3.91~3.75(m, 3H), 3.30~3.18(m, 3H), 2.98~2.85(m, 4H) ), 2.60~2.56(m, 2H), 2.45~2.29(m, 4H), 2.25~2.19(m, 3H), 2.03~1.98(m, 4H), 1.85~1.68(m, 4H).

[0099] Application Example 1

[0100] The chromene derivative compounds provided in the present invention were subjected to partial performance tests, and the specific operations and characterization data are as follows.

[0101] ICW assay for MCF-7 cells: MCF-7 cells were cultured in 384-well cell culture plates in a humidified incubator with a 5% CO2 atmosphere at 37°C, with 6,000 cells per well in 40 μL of carbon-adsorbed serum-free phenol red medium. 0.2 μL of the test compound (at a 200X concentration) was added to the appropriate wells (maximum final concentration was 10 μM, with a 3-fold serial dilution, "9+0" concentration, where "0" is DMSO solvent). The cells were then incubated in the above environment for a further 24 hours. After fixing the cells with 40 μU / well of 8% paraformaldehyde (PFA: final concentration 4%) for 20 minutes at room temperature, the plates were washed twice with PSB and permeabilized with pre-chilled methanol for 10 minutes. The cells were then blocked in Odessery blocking buffer for 1 hour. A cocktail of primary antibodies for the detection of ERα (rabbit monoclonal, 1:1000, Cell Signaling Technology catalog #8644) and housekeeping protein GAPDH (mouse monoclonal, 1:2000, Cell Signaling Technology catalog #97166S) was added. The cells were incubated overnight at 4°C. The cells were then 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 1 hour at room temperature. After washing three times with TBST, the buffer was removed and the cells were incubated for 1 hour at room temperature. The plates were read at 700 nm and 800 nm on an infrared imaging system (LI-COR). TM ; LI-COR, Lincoln, NE), quantified the staining intensity of ERα and housekeeping protein in each well and exported for analysis. For each data point, ERα intensity was normalized to housekeeping protein intensity, and for each compound, all normalized intensity values ​​were normalized to vehicle control.

[0102] The reagents and instruments used in the experiment are listed in Tables 1 and 2.

[0103] Table 1

[0104]

[0105]

[0106] Table 2

[0107]

[0108] Specific steps of the experiment:

[0109] 1) MCF-7 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.

[0110] 2) The compound was diluted in 3-fold gradient using DMSO solvent; a total of "9+0" concentrations.

[0111] 3) Use Echo 550 to dispense 200 μL of the compound diluted in step 2) into the cell culture plate (final DMSO concentration: 0.5%) and place in a 37° C., 5% CO 2 incubator for further culturing for 24 h.

[0112] 4) Add 40 μL / well of 8% paraformaldehyde and incubate at room temperature for 20 minutes.

[0113] 5) After removing the paraformaldehyde, the plate was washed twice with PBS, and then 40 μL / well of cold methanol (HPLC grade) was added and incubated at room temperature for 10 minutes.

[0114] 6) Methanol was removed, and the cells were washed once with PBS. 20 μU of Odessey blocking buffer was added to the wells and incubated at room temperature for 1 hour.

[0115] 7) Remove the Odessery blocking buffer, add 20 μL / well of a mixture of primary (estrogen receptor α (D8H8) rabbit monoclonal antibody and GAPDH (D4C6R) mouse monoclonal antibody), and incubate at 4°C overnight.

[0116] 8) Remove the primary antibody, wash three times with PBS + 0.05% Tween-20, add 20 μL / 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.

[0117] 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 min. Then, read the fluorescence signal value using Odyssey CLx.

[0118] The experimental data corresponding to the compounds are shown in the following table:

[0119]

[0120]

[0121] Analyzing the above characterization data, among the compounds mentioned, including structure1-7, structureu rel-10, structureu rel-13, structureu rel-19, structureu re1-20, structureu rel-21, structureu re1-22, structureu re1-23, structureu re1-24 and structureu re1-25, their DC50 values ​​are all lower than 10nM, and the Dmax values ​​of most compounds exceed 75%. In particular, compounds structu re1-24 and structu re1-25 have Dmax values ​​even exceeding 90%. Based on these data, the compounds provided by the present invention, as PROTAC degraders targeting estrogen receptor (ER), show significant degradation efficiency and anti-tumor activity in the ER-positive breast cancer cell line MCF-7, indicating that they have the potential for treating ER-positive breast cancer.

[0122] Application Example 2

[0123] Cytochrome P450 Inhibition Assay: Compounds 1-19, 1-20, 1-21, 1-22, 1-23, 1-24, and 1-25 were subjected to drug metabolizing enzyme phenotyping (CYP inhibition assay). This assay utilizes an in vitro test system to evaluate the effects of the test compounds on the activities of seven isoenzymes of human liver microsomal cytochrome P450 (CYP): CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. Specific probe substrates for CYP450 isozymes were incubated with human liver microsomes and different concentrations (10 μM, 3.33 μM, 1.11 μM, 0.37 μM, 0.123 μM, 0.041 μM, 0.0137 μM, 0 μM) of the test compound. Reduced nicotinamide adenine dinucleotide phosphate (NADPH) was added to initiate the reaction. After the reaction, the samples were processed and the metabolites produced by the probe substrate were quantitatively detected by liquid chromatography-tandem mass spectrometry (LC-MS / MS). Cytochrome P450 inhibition

[0124] The reagents and instruments used for the test are shown in Tables 3 and 4 below.

[0125] Table 3

[0126]

[0127]

[0128] Table 4

[0129]

[0130]

[0131] The specific steps of the test are as follows:

[0132] 1) Prepare 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).

[0133] 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.

[0134] 3) Dissolve 16 μL of 10 mM test compound or positive inhibitor stock solution in 24 μL of organic solvent, and then dilute with 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.

[0135] 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 diluted test compound or positive inhibitor solution was added.

[0136] The concentration of the mixed solution of positive control inhibitor and human liver microsomes was characterized as follows.

[0137]

[0138] 5) Prepare substrate solution (the prepared concentration is 4 times the final concentration).

[0139] The specific data characterization of the substrate solution preparation is as follows.

[0140]

[0141] 6) The substrate solution prepared in step 5) was then dispensed into a 96-well reaction plate: 30 μL of the mixed solution of the compound and human liver microsomes was dispensed into a 96-well plate, and then 15 μL of the substrate solution was added.

[0142] 7) Preheat the solution obtained in step 6) and 8 mM NADPH solution at 37° C. for 10 min.

[0143] 8) Add 15 μL of preheated NADPH solution to the reaction plate obtained in step 6), mix well, and start the reaction.

[0144] 9) Incubate the reaction plate at 37°C. CYP3A4 reacts for 5 minutes; CYP1A2, 2B6, 2C8, 2C9, and 2D6 reacts for 10 minutes; and CYP2C19 reacts for 20 minutes. At the end of the reaction, add 120 μL of acetonitrile containing the internal standard to terminate the reaction. Characterization data for the corresponding compounds are as follows:

[0145]

[0146]

[0147] Drug-metabolizing enzyme phenotyping, including CYP inhibition studies, aims to assess the inhibitory effects of compounds on cytochrome P450 (CYP450) enzyme activity. The CYP450 enzyme family is a group of enzymes primarily found in the liver and other tissues, playing a key role in the metabolism of drugs and exogenous compounds. Among the CYP450 enzymes involved in drug metabolism, the CYP1, CYP2, and CYP3 families are particularly important, while CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4 / 5 are the primary drug-metabolizing enzymes. The core of drug-metabolizing enzyme phenotyping lies in determining the types, quantities, and relative contributions of the metabolic enzymes involved in drug clearance. When a drug acts as a potent inhibitor or inducer of a CYP enzyme, it may interact with other drugs metabolized by the same CYP enzyme, potentially reducing drug efficacy or increasing the risk of adverse reactions. Therefore, in the early stages of drug development, the molecular structure of the drug is usually adjusted to reduce its interaction with CYP enzymes, thereby reducing the possibility of drug-drug interactions.

[0148] Analysis of the above characterization results shows that the IC50 values ​​of the provided compound structure1-22 for all CYP450 enzymes are greater than 10μM; and the IC50 values ​​of structure1-19, structure1-20, structure1-21, structure1-23, structure1-24, and structure1-25 for most CYP450 enzymes are also greater than 10μM. This indicates that the inhibitory effects of structure1-19, structure1-20, structure1-21, structure1-22, structure1-23, structure1-24, and structure1-25 on CYP450 enzymes are essentially negligible. Therefore, the compounds involved in the present invention involve a wide variety of enzymes in the metabolic process and have diverse metabolic pathways, thereby reducing the possibility of potential drug-drug interactions, helping to reduce individual differences in the treatment process, and ensuring higher safety and reliability.

Claims

1. A chromene derivative, characterized in that The general structural formula of the chromene derivative is shown in Formula A or Formula B: Formula A: ; Formula B: ; In the formula A and formula B: Linker is a connecting group; The connecting group is any one of the following structural formulas a to y; Formula a: ; Formula b: ; Formula c: ; Formula d: ; Formula e: ; Formula f: ; Formula g: ; Formula h: ; Formula i: ; Formula j: ; Formula k: ; Formula 1: ; Formula m: ; Formula n: ; Formula o: ; Formula p: ; Formula q: ; Formula r: ; Formula s: ; Formula t: ; Formula u: ; Formula v: ; Formula w: ; Formula x: ; Formula y: .

2. The use of a chromene derivative according to any one of claims 1, wherein The chromene derivative is used for preparing anti-tumor drugs.

3. The use according to claim 2, characterized in that The tumor is human breast cancer.

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