Chromene derivative and application thereof

Abstract

The invention belongs to the technical field of medicines, and particularly relates to a chromene derivative and application thereof. The structural formula of the chromene derivative is shown as a formula A or a formula B, and the chromene derivative is used for preparing anti-tumor drugs and / or improving drug metabolism efficiency and / or reducing drug side effects and / or inhibiting drug-drug interaction. According to the chromene derivative disclosed by the invention, the degradation mechanism of a PROTAC compound is changed by utilizing a protein degradation targeting chimera technology, an estrogen receptor is marked through a ubiquitination process, and the concentration of the estrogen receptor in a cell is effectively reduced by degrading through a 26S proteasome pathway.

Description

Technical Field

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

[0002] Estrogen receptor is a protein molecule that is widely present in the cell membrane, cytoplasm or nucleus. The classic form of nuclear receptor is located in the nucleus, and its protein is temporarily present in the cytoplasm after translation, so it can be detected in the cytoplasm. Estrogen diffuses to the nucleus and binds to the nuclear receptor, triggering the gene regulation mechanism, thereby regulating the transcription process of downstream genes. Estrogen receptor plays a vital role in the occurrence and progression of breast cancer. About 70% of breast cancer patients express estrogen receptors in their tumor cells, and the patients 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. The first generation of drugs, such as tamoxifen, is a selective estrogen receptor modulator that can competitively bind to estrogen receptors and block the effects of estrogen, but may cause adverse reactions such as endometrial thickening and thrombosis; the second generation of drugs, such as lepzostry 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; the third generation of drugs, such as fulvestrant, is a selective estrogen receptor degrader 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 made remarkable achievements in the treatment of breast cancer, but there are still side effects, including patients' gradual resistance to treatment and side effects associated with treatment. Especially for estrogen receptor-negative breast cancer patients, the effectiveness of endocrine therapy is limited, which has prompted 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 of breast cancer research. Summary of the invention

[0005] The technical solution of the present invention aims at the limitations of the prior art 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, and provides chromene derivative compounds and their applications, which utilize the ubiquitin-proteasome system to degrade targeted estrogen receptors.

[0006] The main purpose of the present invention is:

[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: Formula: Formula u: Formula v: Formula w: Formula x: Formula y: As a preference,

[0019] Based on the linking groups shown in 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 tables:

[0020]

[0021]

[0022]

[0023]

[0024]

[0025]

[0026]

[0027]

[0028]

[0029]

[0030]

[0031]

[0032]

[0033]

[0034] Application of chromene derivatives, wherein the chromene derivatives are used for preparing anti-tumor drugs, and / or improving drug metabolism efficiency and / or reducing drug side effects and / or inhibiting drug-drug interactions.

[0035] As a preference,

[0036] The tumor is human breast cancer.

[0037] Estrogen receptors are proteins that are widely present in cells and are mainly located in the cell nucleus. After being formed in the cytoplasm, they move to the cell nucleus and bind to estrogen, activating gene regulation and affecting gene transcription. Estrogen receptors play a key role in breast cancer. About 70% of patients' tumor cells express this receptor and are sensitive to hormone therapy. At present, endocrine therapy drugs have achieved remarkable results in the treatment of breast cancer. However, their side effects still exist, including patients' gradual resistance to treatment and the side effects associated with treatment. Especially for the group of breast cancer patients with negative estrogen receptors, the effectiveness of endocrine therapy is limited, which has prompted the medical community to seek a wider range of treatment strategies. In response to the limitations of selective estrogen receptor modulators, a new generation of therapeutic drugs, selective estrogen receptor downregulators (SERDs), have been developed. SERDs can not only antagonize estrogen receptors (ER), but also promote the degradation of ER, thereby blocking the ER signaling pathway and effectively inhibiting the proliferation of breast cancer cells. 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 limits the patient's medication compliance to a certain extent. To overcome these limitations, the present invention uses a new treatment strategy, namely, proteolysis targeted chimera (PROTAC) technology. In the frontier 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 and bring more efficient and safe treatment prospects to breast cancer patients. However, to achieve this goal, it is indispensable to deeply understand the fine structure, functional properties and complex interaction mechanism of ER with E3 ubiquitin ligase. 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 targeted chimera technology (PROTAC), which not only improves the treatment effect, but also enhances the safety and reliability of the treatment, and provides a new strategy for the treatment of estrogen-related diseases such as breast cancer. The technical scheme 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 (ie, 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 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, and then regulating the biological processes related to it. The compound involved in the present invention, by utilizing the PROTAC mechanism, exhibits 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 being able to circumvent 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 a variety of 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-mentioned 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 the present invention are: the present invention changes the degradation mechanism of PROTAC compounds by utilizing protein degradation targeted chimera technology, labels estrogen receptors through ubiquitination, and degrades through the 26S proteasome pathway, effectively reducing the concentration of estrogen receptors in cells. The PROTAC degrader of the present invention does not need to bind to the active site of the target protein, can overcome the problem of drug resistance, improve the therapeutic effect and application range, and at the same time, the metabolic pathways of the compound are diverse, reducing the risk of drug-drug interactions, improving the safety and reliability of treatment, and has 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] Fig. 9 The synthetic route of structure 2-21 described in Example 3 Figure 2 ;

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

[0050] Fig.11 This is the NMR characterization result of structure 2-21 prepared in Example 3. DETAILED DESCRIPTION

[0051] The present invention is further described in detail below in conjunction with specific embodiments and the accompanying drawings. A person of ordinary skill in the art will be able to implement the present invention based on these descriptions. In addition, the embodiments of the present invention involved in the following description are generally only embodiments of a part of the present invention, rather than all embodiments. Therefore, based on the embodiments of the present invention, all other embodiments obtained by a person of ordinary skill in the art without making creative work 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-chromene-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 uniformly mixed in a mass ratio of 1:7.98, and stirred in a nitrogen atmosphere at a temperature of 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 a nitrogen atmosphere at a temperature of 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 in a nitrogen atmosphere at a temperature of 45°C for 3 h, and concentrated to obtain 2-(3-methoxyphenyl)acetyl chloride. 1,4-dimethoxy, aluminum chloride and dichloromethane were mixed uniformly in a mass ratio of 1:9.62:3.20, stirred for 30 minutes at a temperature of 0°C, and then 2-(3-methoxyphenyl)acetyl chloride was continuously added at a drop rate of 2.223 mL / min at a temperature of -10°C and stirred for 1.5 hours. After the addition was completed, it was stirred for 1 hour at a temperature of 0°C. The mixture was added to ice water, extracted with dichloromethane, the organic layers were combined, washed with hydrochloric acid aqueous solution, saturated sodium bicarbonate solution and brine in sequence, and 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, and stirred continuously at -78°C for 30 min, then gradually heated to 0°C within 30 min, and stirred at 0°C for 1 h, 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 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)ethane-1-one (A-5).

[0059] (4) 1-[2-hydroxy-5-(oxacyclohexyloxy)phenyl]-2-[3-(oxacyclohexyloxy)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 the mixture was kept warm in a microwave reactor at 120°C for 30 min. 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 h, 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 0°C, then stirred for 1.5 hours at 25°C, cooled to 0°C after stirring, and heated to 40°C with saturated chloride. 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 a temperature of 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 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-chromene-6-ol, dihydropyran, dichloromethane and pyridinium p-toluenesulfonate were mixed in a mass ratio of 1:1.16:30.79:0.17 and stirred at 26°C for 4 h. The mixture was extracted with dichloromethane, and the organic phases were combined, washed, dried, concentrated and purified by silica 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 for 0.5 h under a nitrogen atmosphere at 50° C., repeated 11 times, concentrated in vacuo, and purified by silica 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 but-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 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 in a mass ratio of 2.7:1:9.3, stirred at 25°C for 12 h, concentrated in vacuo, and purified by silica 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 in a mass ratio of 0.15:1:5.98, stirred for 4 h in 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 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 for 0.5 h at 25°C 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 for 1.5 h at -78°C. The mixture was then slowly heated to 25°C, dried, concentrated in vacuo, and purified by silica column chromatography to obtain methyl 2-[3-(2-hydroxyethyl)cyclobutyl]acetate (A-18).

[0069] (14) Under the environmental condition of temperature of 0°C, methyl 2-[3-(2-hydroxyethyl)cyclobutyl]acetate, dichloromethane, triethylamine, 4-dimethylaminopyridine and methanesulfonyl chloride were mixed in a mass ratio of 1:33.25:0.91:0.35:1.66, and kept warm at the environmental condition of temperature of 25°C for 16 hours. Then, saturated aqueous ammonium chloride solution was used for quenching, and the organic phases were extracted and 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 in a mass ratio of 1:1.31:2.5:20.35, and the mixture was kept at 70°C for 3 h. 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, wherein the mixed solvent components were 18 wt % toluene, 27 wt % water, and the balance was glacial acetic acid, and the mixture was kept at a temperature of 100° C. for 48 h, concentrated in vacuo, and filtered through a reverse phase. 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-dioxopiperidin-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 the mixture was kept at 80°C for 16 h. 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-dioxopiperidin-3-yl)-1,3-dioxoisoindol-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 in 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-dioxoisoindol-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-chromene-2-yl)phenoxy)ethyl)cyclobutyl)acetamide, namely, structure 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, combined the organic phases, dried with 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-dioxoisoindol-4-yl]amino}butyl)amino) (B-3).

[0080] (2) Tert-butyl (4-{[2-(2,6-dioxopiperidine-3-yl)-1,3-dioxoisoindol-4-yl]amino}butyl) carbamate and 4 mol hydrochloric acid / 1,4-dioxane solution were mixed 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-dioxopiperidine-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 2h, 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 structure 1-7 compound 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 the synthesis of 2-(2,6-dioxopiperidin-3-yl)-4-(3-((4-(3-(2-(4-((R)-6-hydroxy-3-(3-hydroxyphenyl)-4-methyl-2H-chromene-2-yl)phenoxy)ethyl)cyclobutane-1-carbonyl)piperazin-1-yl)methyl)azetidin-1-yl)isoindoline-1,3-dione, namely structure 2-21, the specific synthesis route is as follows Figures 8 to 10 As shown, steps (1) to (5) are as follows Figure 8 As shown, steps (6) to (7) are as follows Fig. 9 As shown, steps (8) to (13) are as follows Fig.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 for 3 h at an ambient temperature of 25°C, and freeze-dried to obtain 2-(3-(methoxycarbonyl)cyclobutyl)acetic acid (C-5).

[0088] (4) In a nitrogen atmosphere at 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 for 0.5 h at an ambient temperature of 25°C 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, stirred for 1.5 h at a temperature of -78°C, 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, 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, wherein the mixed solvent components were 18 wt % toluene, 27 wt % water, and the balance was glacial acetic acid, and the mixture was kept at a temperature of 110° C. for 48 h, concentrated in vacuo, and filtered. The product was purified by reverse phase column chromatography and separated by supercritical fluid chromatography to obtain (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, stirred at -60°C for 1.5 h, and then 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-butyl piperazine-1-carboxylate, dichloromethane, glacial acetic acid and sodium acetylborhydride were mixed 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, the organic layers were combined, washed with salt, dried, filtered, concentrated in vacuo, and 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 ratio 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, 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 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 obtain 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 structure 2-21 compound prepared in Example 3 was subjected to NMR detection. Fig.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 of degradation of MCF-7 cells: MCF-7 cells were cultured in a 384-well cell culture plate in a humidified incubator with a carbon dioxide atmosphere of 5% and a temperature of 37°C, wherein each well of the cell culture plate contained 6,000 cells and the culture medium was 40 μL of carbon-adsorbed serum-free phenol red medium. 0.2 μL of the test compound (at a concentration of 200X) was added to the appropriate wells (the highest final concentration was 10 μM, 3-fold gradient dilution, "9+0" concentration, "0" was DMSO solvent). The cells were then incubated in the above environment for 24 hours. After adding 40 μU of 8% paraformaldehyde (PFA: final concentration 4%) to fix the cells at room temperature for 20 minutes, the plate was washed twice with PSB, and pre-cooled methanol was added to permeabilize the cells 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 h at room temperature. After washing three times with TBST, the buffer was removed and 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 a 384-well cell culture plate (Coring #356663) at 6000 cells / well / 40 μL using phenol red-free DMEM complete medium (phenol red-free DMEM + 10% Charcoal-FBS + 1% P / S) and placed at 37°C, 5% CO 2 Leave to adhere overnight.

[0110] 2) The compound was diluted 3-fold 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 it at 37°C and 5% CO. 2 Continue culturing in the incubator for 24 h.

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

[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 min.

[0114] 6) Methanol was removed, and the cells were washed once with PBS, and then 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 primary (estrogen receptor α (D8H8) rabbit monoclonal antibody and GAPDH (D4C6R) mouse monoclonal antibody) mixed solution, 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, and then read the fluorescence signal value with 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 structureu re1-24 and structureu re1-25, their Dmax values ​​even exceed 90%. Based on these data, the compounds provided by the present invention, as PROTAC degraders targeting estrogen receptors (ER), show significant degradation efficiency and anti-tumor activity in 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: The above compounds, Structure 1-19, Structure 1-20, Structure 1-21, Structure 1-22, Structure 1-23, Structure 1-24 and Structure 1-25, were subjected to drug metabolizing enzyme phenotype identification (CYPinhibition experiment). This assay uses an in vitro test system to evaluate the effects of the test compounds on the activities of seven isoenzymes (CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 and CYP3A4) of human liver microsomal cytochrome P450 (CYP). Specific probe substrates of 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, and 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 400-fold 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 of substrate solution preparation are as follows.

[0140]

[0141] 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.

[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 min; CYP1A2, 2B6, 2C8, 2C9, 2D6 react for 10 min; CYP2C19 reacts for 20 min. At the end of the reaction, add 120 μL of acetonitrile containing internal standard to terminate the reaction. The corresponding detection characterization data of the compounds are as follows:

[0145]

[0146]

[0147] The purpose of drug metabolism enzyme phenotyping and CYP inhibition experiments is to evaluate the inhibitory effect of compounds on cytochrome P450 (CYP450) enzyme activity. The CYP450 enzyme system is a group of enzymes that mainly exist in the liver and other tissues. They play 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, CYP2C 19, CYP2 D6 and CYP3A4 / 5 are the main drug metabolism enzymes. The core of drug metabolism enzyme phenotyping is to explore the types, quantities and relative contributions of metabolic enzymes involved in the drug clearance process. When a drug becomes a potent inhibitor or inducer of a CYP enzyme, it may interact with other drugs metabolized by the same CYP enzyme, which may lead to a reduction in drug efficacy or an increased 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] Analyzing the above characterization results, the IC50 values ​​of the provided compound structure 1-22 for all CYP450 enzymes are greater than 10UM; and the IC50 values ​​of structure 1-19, structure 1-20, structure 1-21, structure 1-23, structure 1-24 and structure 1-25 for most CYP450 enzymes are also greater than 10μM. This shows that the inhibitory effects of the compounds structure 1-19, structure 1-20, structure 1-21, structure 1-22, structure 1-23, structure 1-24 and structure 1-25 on CYP450 enzymes are basically negligible. Therefore, the compounds involved in the present invention involve a wide variety of enzymes in the metabolic process and the metabolic pathways are also diversified, 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.

2. The chromene derivative according to claim 1, characterized in that One end of the linking group is CH2CO-, and the other end is -O- or -NH- or -N-.

3. The chromene derivative according to claim 1 or 2, characterized in that 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 I: Formula m: Formula n: Formula o: Formula p: Formula q: Formula r: Formula: Formula: Formula u: Formula v: Formula w: Formula x: Formula y:

4. The use of a chromene derivative according to any one of claims 1 to 3, characterized in that: The chromene derivatives are used for preparing anti-tumor drugs, and / or improving drug metabolism efficiency and / or reducing drug side effects and / or inhibiting drug-drug interactions.

5. The use according to claim 4, characterized in that: The tumor is human breast cancer.

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