Quinonoid diterpene stilbene ester adducts, methods of making and uses in treating melanoma

Abstract

The application belongs to the field of organic synthesis and medicinal chemistry, and relates to synthesis and AhR inhibitory activity research of quinoid diterpenyl benzene styrene alcohol ester adducts. The compound of the application has a structure shown in general formula (I), tanshinone is used as a raw material, and quinoid diterpenyl benzene styrene alcohol ester adducts are synthesized through eight steps. The raw material of the application is easy to obtain, and the reaction is easy to control. The application has important reference significance for preparing benzene 1,4-dioxane hemiacetal compounds. The prepared quinoid diterpenyl benzene styrene alcohol ester adducts have significant AhR inhibitory activity, and can be used as tumor immunotherapy drugs for further drug preparation.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of medicine, and relates to a synthesis method of a quinoid diterpenylphenylpropanol ester adduct and application thereof in treating melanoma. BACKGROUND

[0002] Malignant melanoma is a tumor caused by pathological changes of melanocytes in human skin, mucosa and retina, and significant changes in pigmented skin lesions occur in months or years. Although the incidence of melanoma is low, it has high malignancy, is prone to metastasis, and has a high mortality rate. Regional and distant metastatic melanoma (stages III and IV, respectively) have different prognoses, but the quality of life is poor. The 5-year survival rate of stage III is 13-69%, and that of stage IV is as low as 6%. Although PD-1 and PD-L1 antibodies have been used to treat melanoma, some patients still cannot benefit from antibody drug therapy due to poor therapeutic efficacy and high price.

[0003] In the tumor microenvironment, IDO1-Trp activation causes the expression of downstream inflammatory factors and immune checkpoint-related proteins, thereby causing tumor cell immunosuppression. However, all research and development projects targeting IDO1 have failed, and more and more researchers have shifted their focus to the downstream pathway of IDO1, the Kyn-AhR pathway. AhR is a transcription factor widely present in cells. In a calm state, AhR is located in the cytoplasm in the form of a complex. After the exogenous ligand enters the cytoplasm, it binds to the complex, and AhR is transported to the nucleus in a transport-dependent manner, binds to the common transcription recognition sequence XRE in the nucleus, and causes downstream gene transcription. Previous studies have mainly focused on the activation of AhR by environmental pollutants such as aromatic hydrocarbons, which causes the expression of cancer genes and increases the risk of cancer in humans. However, with the discovery that AhR ligands from vegetables in the diet and AhR ligands metabolized by intestinal flora are both normal physiological sources, the function of AhR has become increasingly clear. Due to the ligand dependence of AhR, different ligands bind to AhR, causing the expression of different downstream genes and exhibiting different physiological functions in tumor proliferation and metastasis. Currently, research and development of AhR inhibitors are being actively carried out, and pharmaceutical companies represented by Bayer are focusing on the research and development of AhR inhibitors. Therefore, the synthesis and design of new AhR compounds with novel skeletons are of great significance for the future development of tumor drugs.

[0004] In order to find AhR inhibitory ligands and develop drugs that are more effective in treating melanoma, we synthesized a quinoid diterpenylphenylpropanol ester adduct and evaluated its in vivo and in vitro pharmacodynamics. The results show that the new monomeric compound has the functions of inhibiting tumor growth, promoting CD8 + T cell immunological function, providing a new idea for the development of new drugs. SUMMARY

[0005] The present application aims to provide a kind of quinoid diterpenoid styrene alcohol ester class adducts;

[0006] Another object of the present application is to provide a preparation method of the compounds;

[0007] Still another object of the present application is to provide a pharmaceutical composition comprising an effective dose of a kind of quinoid diterpenoid styrene alcohol ester class adducts and a pharmaceutical carrier and / or excipient;

[0008] Still another object of the present application is to provide a kind of quinoid diterpenoid styrene alcohol ester class adducts in the preparation for treating and / or preventing melanoma drugs.

[0009] The present application provides the following technical solutions:

[0010] The first aspect of the present application provides a kind of quinoid diterpenoid styrene alcohol ester class adducts, characterized in that, has the following structure general formula:

[0011]

[0012] R is 1,2,3 arbitrary substituent on benzene ring,

[0013] The position of the one substituent is:

[0014]

[0015] The position of the two substituents is:

[0016]

[0017] The position of the three substituents is:

[0018]

[0019] Wherein R1,R2,R3 each is independently selected from: hydrogen, alkyl, hydroxyl, mercapto, methoxy, acetoxy, amino, nitro, halogen, carboxyl and the like.

[0020] The above-mentioned quinoid diterpenoid styrene alcohol ester class adducts, characterized in that, R is selected from: hydrogen, methoxy, acetoxy.

[0021] The above-mentioned quinoid diterpenoid styrene alcohol ester class adducts, characterized in that, the compound is selected from the following compounds

[0022]

[0023] The second aspect of the present application provides a preparation method of a quinoid diterpene stilbene ester adduct, characterized in that the method comprises the following steps:

[0024]

[0025] Route

[0026] (1) Synthesis of compound III:

[0027] Compound II is dissolved in toluene, zinc triflate is added, and the mixture is heated and stirred in a sealed tube at 120°C for 22 hours. After cooling to room temperature, ethyl acetate is added to dissolve the mixture, and saturated sodium bicarbonate solution is added for extraction. The organic phase is washed with saturated brine, dried over anhydrous sodium sulfate, filtered to remove the drying agent, concentrated under reduced pressure, and subjected to silica gel column chromatography to obtain compound III.

[0028] (2) Synthesis of compound V:

[0029] Compound III is dissolved in acetone, and Pd / C is added for reduction under a hydrogen atmosphere to obtain intermediate IV. Since intermediate IV is easily oxidized, it is not separated and purified, and directly subjected to the next reaction. Under argon protection, potassium carbonate and methyl 2,3-dibromopropionate are added, and the mixture is refluxed for 10 hours. After cooling to room temperature, Pd / C and potassium carbonate are removed by filtration to obtain a filtrate. After concentration under reduced pressure, ethyl acetate is added for extraction, and 10% (w / w) acetic acid-water is added for extraction. The organic phase is washed with saturated brine, dried over anhydrous sodium sulfate, filtered to remove the drying agent, concentrated under reduced pressure, and subjected to silica gel column chromatography to obtain compound V.

[0030] (3) Synthesis of compound VI:

[0031] Compound V is dissolved in tetrahydrofuran solution, and 25% (w / w) sodium hydroxide solution is added dropwise at room temperature. After the dropwise addition is completed, the mixture is reacted for 0.5 hours, and TLC detection shows that the reaction is completed. 10% (w / w) acetic acid-water is added to quench the reaction, and dichloromethane is added for extraction. The organic phase is washed with saturated brine, dried over anhydrous sodium sulfate, filtered to remove the drying agent, concentrated under reduced pressure, and subjected to silica gel column chromatography to obtain compound VI.

[0032] (4) Synthesis of compound VII:

[0033] Compound VI was dissolved in anhydrous dichloromethane, (COCl)2and 3 drops of DMF were added dropwise at room temperature, after the dropwise addition was completed, the reaction was carried out for 0.5 hours, then the above solution was added dropwise to a solution of 8-aminoquinoline in anhydrous dichloromethane containing triethylamine, after the dropwise addition was completed, the reaction was carried out for 10 minutes, after the reaction was completed as detected by TLC, 10% (w / w) acetic acid-water was added to quench the reaction, dichloromethane was used for extraction, the organic phase was washed with saturated brine respectively, dried over anhydrous sodium sulfate, the drying agent was filtered off, concentrated under reduced pressure, and column chromatography on silica gel was performed to obtain compound VII.

[0034] (5) Synthesis of compound VIII:

[0035] Compound VII was dissolved in toluene, Pd(OAc)2, AgOAc and iodobenzene compounds with different R were added, the reaction was carried out at 110°C for 50 hours, after the reaction was completed as detected by TLC, water was added to quench the reaction, dichloromethane was used for extraction, the organic phase was washed with saturated brine respectively, dried over anhydrous sodium sulfate, the drying agent was filtered off, concentrated under reduced pressure, and column chromatography on silica gel was performed to obtain compound VIII.

[0036] (6) Synthesis of compound IX:

[0037] Compound VIII was dissolved in 1,4-dioxane, 6M HCl was added, and hydrolysis was carried out at 110°C for 7 hours, after the reaction was completed as detected by TLC, dichloromethane was added for dissolution after concentration under reduced pressure, water was used for extraction, the organic phase was washed with saturated brine respectively, dried over anhydrous sodium sulfate, the drying agent was filtered off, concentrated under reduced pressure, and column chromatography on silica gel was performed to obtain compound IX.

[0038] (7) Synthesis of compound I:

[0039] Compound IX was dissolved in tetrahydrofuran, acetic acid and lead tetraacetate were added under the protection of argon, the reaction was carried out for 5 hours in the dark, after the reaction was completed as detected by TLC, the filtrate was obtained after filtration, ethyl acetate was added for dissolution after concentration under reduced pressure, saturated sodium bicarbonate was used for extraction, the organic phase was washed with saturated brine respectively, dried over anhydrous sodium sulfate, the drying agent was filtered off, concentrated under reduced pressure, and column chromatography on silica gel was performed to obtain compound I.

[0040] In the preparation method, R is the same as the above definition, and is preferably selected from hydrogen, alkyl, hydroxyl, mercapto, methoxy, amino, nitro, halogen, and carboxyl; more preferably, R is selected from hydrogen, methoxy, and acetoxy.

[0041] The third aspect of the present application relates to a pharmaceutical composition containing a pharmaceutically effective dose and a pharmaceutically acceptable carrier.

[0042] The present application also relates to pharmaceutical compositions comprising a compound of the present application as an active ingredient and a conventional pharmaceutical excipient or adjuvant. Generally, the pharmaceutical composition of the present application contains 0.1 to 95% by weight of the compound of the present application. In a unit dosage form, the compound of the present application is generally contained in an amount of 0.1 to 100 mg, and preferably, a unit dosage form contains 4 to 50 mg.

[0043] The pharmaceutical composition of the compound of the present application can be prepared according to the methods known in the art. For this purpose, if necessary, the compound of the present application can be combined with one or more solid or liquid pharmaceutical excipients and / or adjuvants to form a suitable administration form or dosage form which can be used as a human or veterinary medicine.

[0044] The compound of the present application or the pharmaceutical composition containing it can be administered in a unit dosage form, and the administration route can be gastrointestinal or non-gastrointestinal, such as oral, intramuscular, subcutaneous, nasal, oral mucosal, dermal, peritoneal or rectal, etc.

[0045] The administration route of the compound of the present application or the pharmaceutical composition containing it can be injection administration. Injection includes intravenous injection, intramuscular injection, subcutaneous injection, intradermal injection and intracavitary injection, etc.

[0046] The administration route of the compound of the present application or the pharmaceutical composition containing it can be dermal administration. It includes external solution, lotion, liniment, ointment, plaster, paste, patch, etc.

[0047] The administration dosage form can be a liquid dosage form, a solid dosage form or a semi-solid dosage form. The liquid dosage form can be a solution (including true solution and colloidal solution), an emulsion (including o / w type, w / o type and multiple emulsion), a suspension, an injection (including water injection, powder injection and infusion), eye drops, nose drops, lotion and liniment, etc.; the solid dosage form can be a tablet (including ordinary tablet, enteric-coated tablet, buccal tablet, dispersible tablet, chewable tablet, effervescent tablet, oral disintegrating tablet), a capsule (including hard capsule, soft capsule, enteric-coated capsule), a granule, a powder, a pellet, a drop, a suppository, a film, a patch, an aerosol (powder) mist, a spray, etc.; the semi-solid dosage form can be an ointment, a gel, a paste, etc.

[0048] To achieve the purpose of medication and enhance the therapeutic effect, the quinoid diterpene-styryl phenyl alcohol ester adduct or the pharmaceutical composition of the present application can be administered by any known administration method.

[0049] The dosage of the pharmaceutical composition of the compound of the present application can vary widely depending on the nature and severity of the disease to be prevented or treated, the individual condition of the patient or animal, the route of administration and the dosage form, etc. Generally, the suitable dosage of the compound of the present application per day is in the range of 0.001-150 mg / kg body weight, preferably 0.1-100 mg / kg body weight, more preferably 1-60 mg / kg body weight, and most preferably 2-30 mg / kg body weight. The above-mentioned dosage can be administered in one dosage unit or divided into several dosage units, depending on the clinical experience of the physician and the administration regimen including the use of other therapeutic means.

[0050] The dosage of the pharmaceutical composition of the compound of the present application depends on many factors, such as the nature and severity of the disease to be prevented or treated, the gender, age, weight, character and individual response of the patient or animal, the route of administration, the administration frequency, the purpose of treatment, and thus the therapeutic dosage of the present application can vary widely. Generally, the dosage of the pharmaceutical ingredient used in the present application is well known to those skilled in the art. The actual amount of the drug contained in the final preparation of the compound composition of the present application can be appropriately adjusted to achieve the therapeutically effective amount required to achieve the prevention or treatment purposes of the present application. The suitable dosage of the compound of the present application per day is in the range of 0.001-100 mg / kg body weight, preferably 0.1-60 mg / kg body weight, more preferably 1-30 mg / kg body weight, and most preferably 2-15 mg / kg body weight. The compound of the present application for adult patients is 10-500 mg per day, preferably 20-100 mg per day, which can be taken at one time or divided into 2-3 times; the dosage for children is 5-30 mg per kg body weight, preferably 10-20 mg per kg body weight. The above-mentioned dosage can be administered in a single dosage form or divided into several, for example, two, three or four dosage forms, which is limited by the clinical experience of the administering physician and the administration regimen of the therapeutic means. The compound or composition of the present application can be taken alone or in combination with other therapeutic drugs or symptomatic drugs.

[0051] The fourth aspect of the present experiment relates to the use of a quinoid diterpenoid-stilbene ester adduct in the treatment of melanoma.

[0052] The present application discloses for the first time that the quinoid diterpenoid-stilbene ester adduct compound 1-2 (LZY17 / 18) has an inhibitory effect on the AhR protein of tumor cells and can inhibit the AhR nuclear translocation in tumor cells. It can stop the growth of melanoma in mice and has a good tumor inhibition effect.

[0053] Beneficial technical effects:

[0054] 1.The quinoid diterpenylphenanthrene alcohol ester adduct of the present application has a novel structure, is not reported in the literature, can significantly inhibit the activity of AhR, and has the potential to be further developed as a new drug for treating melanoma.

[0055] 2.The quinoid diterpenylphenanthrene alcohol ester adduct of the present application is simple to separate after synthesis.

[0056] 3.The quinoid diterpenylphenanthrene alcohol ester adduct of the present application can reduce the activity and nuclear translocation of AhR in tumor cells, inhibit the expression of AhR downstream genes in tumor cells, including but not limited to IL-6, PD-L1, AhRR, etc.

[0057] In addition, the compound can also inhibit the growth of tumors in the ectopic inoculation B16F10 mouse model, and has an anti-tumor effect. BRIEF DESCRIPTION OF DRAWINGS

[0058] Figure 1 Effect of compound 1-2 (LZY-17 / 18) and compound 3-4 on the activity of AhR;

[0059] Figure 2 Effect of compound 1-2 (LZY17 / 18) on the nuclear translocation of U87, B16F10 AhR;

[0060] Figure 3 Effect of compound 1-2 (LZY17 / 18) on the expression of downstream genes of U87, B16F10;

[0061] Figure 4 Effect of compound 1-2 (LZY17 / 18) on the ectopic inoculation B16F10 model of mice; DETAILED DESCRIPTION

[0062] The following examples and pharmacological activity experiments are used to further illustrate, but this does not mean any limitation to the present application. Unless otherwise specified, the raw materials and reagents used in the following examples are commercially available or can be prepared by known methods.

[0063] Example 1: Synthesis method of compound I, comprising the following steps

[0064] (1) Synthesis of compound III

[0065] Compound II (4.16 g, 20.0 mmol) was dissolved in toluene (120 mL), zinc triflate (740 mg, 2.0 mmol) was added, and the reaction was stirred at 120 °C in a sealed tube for 22 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure, dissolved in ethyl acetate, and extracted with saturated sodium bicarbonate (100 mL). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (petroleum ether: ethyl acetate = 20:1) to obtain compound III (1.67 g, 30% yield) as a red-brown crystal.

[0066]

[0067] The structural characterization data of the product are as follows 1 H NMR (500 MHz, CD3OD): δ 9.15 (d, J = 9.0 Hz, 1H), 8.32 (d, J = 9.0 Hz, 1H), 7.48 (d, J = 9.0 Hz, 1H), 7.33 (d, J = 9.0 Hz, 1H), 7.16 (s, 1H), 3.05 (m, 1H), 2.59 (s, 3H), 2.47 (s, 3H), 1.21 (d, J = 7.0 Hz, 3H), 1.21 (d, J = 7.0 Hz, 3H). 13 C NMR (125 MHz, CD3OD): δ

[0068] 182.5, 181.8, 146.2, 139.8, 135.9, 135.4, 134.4, 133.7, 133.0, 132.2, 131.6, 126.7, 125.1, 124.2, 27.2, 21.7, 21.7, 20.9, 15.0. HR-ESI-MS m / z: [M+H] + Calcd for C 19 H 19 O2 279.1376; Found 279.1380.

[0069] (2) Synthesis of compound V

[0070] Compound III (1.67 g, 6.0 mmol) was dissolved in acetone (30 mL) and 10% Pd / C (167 mg) was added and reduced under hydrogen atmosphere to give intermediate IV which was not isolated and purified due to its easy oxidation and was directly used for the next reaction. Potassium carbonate (993.6 mg, 7.2 mmol) and methyl 2,3-dibromopropionate (898.68 μL, 7.2 mmol) were added under argon atmosphere and the reaction was refluxed for 8 h, cooled to room temperature and filtered to remove Pd / C and potassium carbonate to give the filtrate. 10% (w / w) acetic acid-water was added to neutralize the potassium carbonate (30 mL) and the organic phase was extracted with ethyl acetate (3 x 30 mL), dried over anhydrous sodium sulfate, filtered to remove the drying agent and concentrated under reduced pressure. The crude product was chromatographed on silica gel column (petroleum ether: ethyl acetate = 20:1) to give compound V (1.16 g, 53% yield) as a pale yellow solid.

[0071]

[0072] Product structure characterization data (±)-5a: 1 H NMR (500 MHz, CDC13): δ 9.26 (d, J = 9.0 Hz, 1H), 7.89 (br d, J = 9.0 Hz, 1H), 7.63 (d, J = 9.0 Hz, 1H), 7.37 (d, J = 9.0 Hz, 1H), 7.36 (s, 1H), 5.08 (dd, J = 4.5 Hz, 3.0 Hz, 1H), 4.72 (dd, J = 11.0 Hz, 4.5 Hz, 1H), 4.58 (dd, J = 11.0 Hz, 3.0 Hz, 1H), 3.81 (s, 3H), 3.48 (m, 1H), 2.64 (s, 3H), 2.52 (s, 3H), 1.39 (d, J = 7.0 Hz, 3H), 1.37 (d, J = 7.0 Hz, 3H). 13 C NMR (125 MHz, CDC13): δ 169.1, 140.8, 138.4, 137.0, 133.7, 131.6, 131.5, 128.3, 128.1, 127.4, 126.9, 125.9, 121.6, 119.8, 118.4, 71.7, 64.4, 52.9, 27.3, 22.9, 22.5, 21.1, 15.6.(±)-5b: 1H NMR (500 MHz, CDC13): δ 9.47 (d, J = 9.0 Hz, 1H), 7.90 (br d, J = 9.0 Hz, 1H), 7.63 (d, J = 9.0 Hz, 1H), 7.42 (d, J = 9.0 Hz, 1H), 7.33 (s, 1H), 5.12 (dd, J = 6.0 Hz, 3.0 Hz, 1H), 4.61 (dd, J = 11.0 Hz, 3.0 Hz, 1H), 4.51 (dd, J = 11.0 Hz, 6.0 Hz, 1H), 3.86 (s, 3H), 3.39 (m, 1H), 2.65 (s, 3H), 2.53 (s, 3H), 1.33 (d, J = 6.9 Hz, 3H), 1.32 (d, J = 7.0 Hz, 3H). 13 C NMR (125 MHz, CDC13): δ 168.7, 139.8, 139.0, 136.9, 133.7, 131.6, 131.4, 128.6, 128.2, 127.7, 126.8, 126.0, 121.7, 119.8, 118.1, 72.0, 64.4, 52.9, 27.1, 22.8, 22.7, 21.1, 15.6. HR-ESI-MS m / z: [M+H] + Calcd for C 23 H 25 O4 365.1747; Found 365.1747.

[0073] (3) Synthesis of compound VI

[0074] Compound V (1.16 g, 3.2 mmol) was dissolved in tetrahydrofuran solution (30 mL), 25% (w / w) sodium hydroxide solution (20 mL) was added at room temperature, after dropwise addition was completed, the reaction was carried out for 0.5 hours, TLC detection reaction was completed, 10% (w / w) acetic acid-water (30 mL) was added to quench the reaction, dichloromethane (3 x 30 mL) was extracted. The organic phase was washed with saturated brine respectively, dried over anhydrous sodium sulfate, the drying agent was filtered off, concentrated under reduced pressure, silica gel column chromatography, the crude product was subjected to silica gel column chromatography (petroleum ether: ethyl acetate = 6: 1), to obtain light yellow solid compound VI (963.6 mg, yield 86%).

[0075]

[0076] Structural characterization data of the product (±)-6a: 1H NMR (500 MHz, DMSO-d6): δ 13.59 (br s, 1H), 9.22 (d, J = 9.0 Hz, 1H), 7.88 (d, J = 9.0 Hz, 1H), 7.72 (d, J = 9.0 Hz, 1H), 7.43 (s, 1H), 7.38 (d, J = 9.0 Hz, 1H), 5.24 (br s, 1H), 4.78 (dd, J = 11.5 Hz, 3.0 Hz, 1H), 4.48 (dd, J = 11.5 Hz, 3.0 Hz, 1H), 3.41 (m, 1H), 2.58 (s, 3H), 2.46 (s, 3H), 1.33 (d, J = 7.0 Hz, 3H), 1.33 (d, J = 7.0 Hz, 3H). 13 C NMR (125 MHz, DMSO-d6): δ 169.9, 140.5, 138.6, 136.4, 133.4, 131.2, 130.9, 128.1, 127.5, 127.0, 126.4, 125.5, 120.9, 118.9, 117.7, 71.1, 64.6, 26.6, 22.7, 22.1, 20.6, 15.2. (±)-6b: 1 H NMR (500 MHz, DMSO-d6): δ 13.42 (br s, 1H), 9.50 (d, J = 9.0 Hz, 1H), 7.89 (d, J = 9.5 Hz, 1H), 7.72 (d, J = 9.5 Hz, 1H), 7.39 (s, 1H), 7.38 (d, J = 9.0 Hz, 1H), 5.25 (br s, 1H), 4.53 (d, J = 4.0 Hz, 2H), 3.32 (m, 1H), 2.59 (s, 3H), 2.47 (s, 3H), 1.28 (d, 7.0 Hz, 3H), 1.26 (d, 7.0 Hz, 3H). 13 C NMR (125 MHz, DMSO-d6): δ 169.5, 140.0, 139.0, 136.3, 133.3, 131.0, 130.9, 128.2, 127.7, 127.0, 126.8, 126.0, 121.1, 119.0, 117.1, 71.1, 64.5, 26.4, 22.6, 22.5, 20.6, 15.2. HR-ESI-MS m / z: [M+H] + Calcd for C 22 H 23 O4 351.1591; Found 351.1588.

[0077] (4) Synthesis of compound VII

[0078] Compound VI (963.6 mg, 2.75 mmol) was dissolved in dry dichloromethane (20 mL) and (COCl)2(281 μl, 3.3 mmol) and 3 drops of DMF were added dropwise at room temperature. After 0.5 h of reaction, the above prepared solution was added dropwise to a solution of 8-aminoquinoline (476 mg, 3.3 mmol) in dry dichloromethane (20 mL) containing triethylamine (573 μl, 4.1 mmol). After 10 min of reaction, the reaction was quenched by the addition of 10% (w / w) acetic acid-water (20 mL) and extracted with dichloromethane (3 x 30 mL). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, the drying agent was filtered off and concentrated under reduced pressure. The crude product was chromatographed on a silica gel column (petroleum ether: ethyl acetate = 10:1) to give compound VII (1.18 g, 90% yield) as a pale yellow solid.

[0079]

[0080] Product (±)-7a: 1 H NMR (500 MHz, CDC13): δ 11.23 (s, 1H), 9.34 (d, J = 9.0 Hz, 1H), 8.83 (dd, J = 6.0 Hz, 3.2 Hz, 1H), 8.79 (dd, J = 4.0 Hz, 2.0 Hz, 1H), 8.17 (dd, J = 8.5 Hz, 2.0 Hz, 1H), 7.91 (br d, J = 9.0 Hz, 1H), 7.66 (d, J = 9.0 Hz, 1H), 7.58 (d, J = 2.5 Hz, 1H), 7.57 (s, 1H), 7.47 (dd, J = 8.0 Hz, 4.0 Hz, 1H), 7.45 (s, 1H), 7.41 (d, J = 9.0 Hz, 1H), 5.15 (dd, J = 7.5 Hz, 3.0 Hz, 1H), 5.00 (dd, J = 11.0 Hz, 3.0 Hz, 1H), 4.57 (dd, J = 11.0 Hz, 7.5 Hz, 1H), 3.92 (m, 1H), 2.64 (s, 3H), 2.52 (s, 3H), 1.64 (d, J = 7.0 Hz, 3H), 1.51 (d, J = 7.0 Hz, 3H). 13C NMR (125 MHz, CDC13): δ 166.2, 148.5, 141.2, 138.9, 137.9, 136.9, 136.4, 133.9, 133.7, 131.6, 131.5, 128.5, 128.2, 128.1, 127.8, 127.4, 126.8, 126.0, 122.6, 121.9, 121.9, 120.0, 118.4, 116.9, 73.6, 65.1, 27.3, 23.2, 23.2, 21.1, 15.5. (±)-7b: 1 H NMR (500 MHz, CDC13) δ 11.25 (s, 1H), 9.64 (d, J = 9.0 Hz, 1H), 8.82 (dd, J = 7.0 Hz, 2.0 Hz, 1H), 8.20 (dd, J = 4.0 Hz, 2.0 Hz, 1H), 8.08 (dd, J = 8.5 Hz, 2.0 Hz, 1H), 7.96 (d, J = 9.0 Hz, 1H), 7.67 (d, J = 9.0 Hz, 1H), 7.54 (m, 2H), 7.40 (s, 1H), 7.37 (d, J = 9.0 Hz, 1H), 7.32 (dd, J = 8.0 Hz, 4.0 Hz, 1H), 5.22 (dd, J = 6.5 Hz, 3.0 Hz, 1H), 4.81 (dd, J = 11.0 Hz, 3.0 Hz, 1H), 4.68 (dd, J = 11.0 Hz, 6.5 Hz, 1H), 3.45 (m, 1H), 2.71 (s, 3H), 2.55 (s, 3H), 1.35 (d, J = 7.0 Hz, 3H), 1.31 (d, J = 7.0 Hz, 3H). 13 C NMR (125 MHz, CDC13): δ 166.3, 148.4, 139.7, 139.3, 138.8, 137.3136.1, 133.7, 133.7, 131.7, 131.4, 128.6, 128.1, 127.9, 127.6, 127.2, 127.0, 126.3, 122.5, 121.8, 121.7, 120.1, 118.9, 116.8, 74.0, 64.8, 27.1, 22.8, 22.6, 21.1, 15.6. HR-ESI-MS m / z: [M+H] + Calcd for C 31 H 29 O3N2 477.2173; Found 477.2174.

[0081] (5) Synthesis of compound VIII

[0082] Compound VII (1.18 g, 2.48 mmol) was dissolved in toluene (40 mL), Pd(OAc)4(56 mg, 0.25 mmol), AgOAc (908.82 mg, 5.45 mmol) and R-substituted iodobenzene (9.9 mmol) were added and the reaction was carried out at 110 °C for 50 h. After completion of the reaction as monitored by TLC, the reaction was quenched with water (20 mL) and extracted with dichloromethane (3 x 30 mL). The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (petroleum ether: ethyl acetate = 10:1) to give compound VIII as a yellow solid (yield 40-45%).

[0083]

[0084] Product structure characterization data (±)-8a (yield 23%): 1 H NMR (500 MHz, CDC13): δ 11.07 (s, 1H), 9.48 (d, J = 9.0 Hz, 1H), 8.78 (m, 1H), 8.73 (dd, J = 2.0 Hz, 4.0 Hz, 1H), 8.14 (dd, J = 2.0 Hz, 8.0 Hz, 1H), 7.97 (br d, J = 9.5 Hz, 1H), 7.72 (d, J = 9.5 Hz, 1H), 7.54 (d, J = 1.0 Hz, 1H), 7.53 (s, 1H), 7.46 (s, 1H), 7.43 (dd, J = 8.0 Hz, 4.0 Hz, 1H), 7.40 (d, J = 9.0 Hz, 1H), 6.98 (d, J = 2.0 Hz, 1H), 6.92 (dd, J = 8.5 Hz, 2.0 Hz, 1H), 6.56 (d, J = 8.5 Hz, 1H), 6.29 (dd, J = 3.0 Hz, 1H), 5.26 (d, J = 3.0 Hz, 1H), 3.83 (m, 1H), 3.63 (s, 3H), 3.50 (s, 3H), 2.66 (s, 3H), 2.52 (s, 3H), 1.56 (d, J = 7.0 Hz, 3H), 1.55 (d, J = 7.0 Hz, 3H). 13C NMR (125 MHz, CDC13): δ 165.5, 148.7, 148.6, 148.4, 140.6, 138.8, 138.1, 136.6, 136.3, 133.9, 133.6, 131.6, 131.5, 128.6, 128.5, 128.4, 128.3, 128.0, 127.2, 126.9, 126.0, 122.5, 122.1, 121.9, 119.8, 119.7, 117.9, 116.5, 110.7, 109.8, 75.8, 75.0, 55.6, 55.5, 27.6, 23.4, 22.4, 21.0, 15.5. (±)-8b (yield 17%): 1 H NMR (500 MHz, CDC13) δ 10.89 (s, 1H), 9.63 (d, J = 9.0 Hz, 1H), 8.83 (m, 1H), 8.61 (dd, J = 2.0 Hz, 4.0 Hz, 1H), 8.12 (br d, J = 8.5 Hz, 1H), 7.97 (br d, J = 9.5 Hz, 1H), 7.74 (d, J = 9.5 Hz, 1H), 7.54 (s, 1H), 7.53 (br s, 2H), 7.42 (dd, J = 8.0 Hz, 4.2 Hz, 1H), 7.33 (d, J = 9.0 Hz, 1H), 6.99 (d, J = 2.0 Hz, 1H), 6.94 (dd, J = 8.5 Hz, 2.0 Hz, 1H), 6.60 (d, J = 8.5 Hz, 1H), 6.01 (d, J = 3.0 Hz, 1H), 5.29 (d, J = 3.0 Hz, 1H), 3.62 (s, 3H), 3.54 (s, 3H), 3.57 (m, 1H), 2.67 (s, 3H), 2.51 (s, 3H), 1.45 (d, J = 7.0 Hz, 3H), 1.36 (d, J = 7.0 Hz, 3H). 13 C NMR (125 MHz, CDC13): δ 165.5, 148.7, 148.6, 148.4, 140.6, 138.8, 138.1, 136.6, 136.3, 133.9, 133.6, 131.6, 131.5, 128.6, 128.5, 128.4, 128.3, 128.0, 127.2, 126.9, 126.0, 122.5, 122.1, 121.9, 119.8, 119.7, 117.9, 116.5, 110.7, 109.8, 75.8, 75.0, 55.6, 55.5, 27.6, 23.4, 22.4, 21.0, 15.5. (±)-8b (yield 17%): + Calcd for C39 H 37 O5N2 613.2697; Found 613.2689.

[0085] Product structure characterization data (±)-8c (yield 25%): 1 H NMR (500 MHz, CDC13): δ 11.06 (s, 1H), 9.45 (d, J = 9.0 Hz, 1H), 8.75 (m, 2H), 8.15 (dd, J = 1.5 Hz, 8.0 Hz, 1H), 7.96 (br d, J = 9.0 Hz, 1H), 7.71 (d, J = 9.0 Hz, 1H), 7.55 (d, J = 1.0 Hz, 1H), 7.54 (s, 1H), 7.45 (s, 1H), 7.45 (dd, J = 4.0 Hz, 8.0 Hz, 1H), 7.39 (d, J = 9.0 Hz, 1H), 7.31 (dd, J = 2.0 Hz, 8.5 Hz, 2H), 6.62 (dd, J = 2.0 Hz, 9.0 Hz, 2H), 6.29 (d, J = 3.0 Hz, 1H), 5.24 (d, J = 3.0 Hz, 1H), 3.86 (m, 1H), 3.57 (s, 3H), 2.66 (s, 3H), 2.52 (s, 3H), 1.55 (d, J = 7.0 Hz, 3H), 1.53 (d, J = 7.0 Hz, 3H). 13 CNMR (125 MHz, CDC13): δ 165.4, 159.4, 148.4, 140.8, 138.9, 138.2, 136.7, 136.2, 133.9, 133.7, 131.6, 131.5, 128.7, 128.5, 128.5, 128.4, 128.3, 128.0, 128.0, 127.3, 127.0, 126.1, 122.4, 122.1, 121.9, 119.7, 117.8, 116.7, 113.8, 113.8, 75.8, 75.1, 55.1, 27.6, 23.3, 22.5, 21.1, 15.6. (±)-8d (yield 18%): 1H NMR (500 MHz, CDC13): δ 10.82 (s, 1H), 9.60 (d, J = 8.5 Hz, 1H), 8.75 (dd, J = 3.5 Hz, 5.5 Hz, 1H), 8.58 (dd, J = 1.5 Hz, 4.0 Hz, 1H), 8.13 (dd, J = 1.5 Hz, 8.0 Hz, 1H), 7.96 (br d, J = 9.0 Hz, 1H), 7.73 (d, J = 9.0 Hz, 1H), 7.53 (s, 1H), 7.53 (d, J = 2.0 Hz, 1H), 7.50 (s, 1H), 7.41 (dd, J = 4.0 Hz, 8.0 Hz, 1H), 7.31 (dd, J = 9.0 Hz, 2.5 Hz, 3H), 6.64 (dd, J = 2.0 Hz, 9.0 Hz, 2H), 6.02 (d, J = 3.0 Hz, 1H), 5.28 (d, J = 3.0 Hz, 1H), 3.56 (s, 3H), 3.50 (m, 1H), 2.69 (s, 3H), 2.51 (s, 3H), 1.40 (d, J = 7.0 Hz, 3H), 1.31 (d, J = 7.0 Hz, 3H). 13 CNMR (125 MHz, CDC13): δ 165.5, 159.4, 148.4, 139.8, 139.4, 138.8, 137.0, 136.0, 133.7, 133.6, 131.6, 131.5, 128.7, 128.5, 128.5, 128.3, 128.3, 127.8, 127.8, 127.1, 126.9, 126.0, 122.3, 121.7, 121.4, 119.9, 119.5, 116.8, 113.7, 113.7, 76.7, 75.5, 55.0, 27.3, 22.8, 22.4, 21.0, 15.5. HR-ESI-MS m / z: [M + H] + Calcd for C 38 H 35 O4N2583.2591; Found 583.2592.

[0086] Product structure characterization data (±)-8e (yield 27%): 1H NMR (500 MHz, CDC13): δ 11.03 (s, 1H), 9.47 (d, J = 9.0 Hz, 1H), 8.76 (dd, J = 6.5 Hz, 2.5 Hz, 1H), 8.72 (dd, J = 4.0 Hz, 1.5 Hz, 1H), 8.13 (dd, J = 8.5 Hz, 1.5 Hz, 1H), 7.97 (d, J = 9.0 Hz, 1H), 7.72 (d, J = 9.0 Hz, 1H), 7.54 (m, 2H), 7.47 (s, 1H), 7.41 (dd, J = 4.0 Hz, 8.0 Hz, 2H), 7.39 (m, 2H), 7.10 (m, 3H), 6.36 (d, J = 3.0 Hz, 1H), 5.26 (d, J = 4.0 Hz, 1H), 3.83 (m, 1H), 2.67 (s, 3H), 2.52 (s, 3H), 1.54 (d, J = 7.0 Hz, 3H), 153 (d, J = 7.0 Hz, 3H). 13 C NMR (125 MHz, CDC13): δ 165.3, 148.4, 140.9, 138.8, 138.3, 136.8, 136.3, 136.2, 133.9, 133.6, 131.6, 131.6, 128.7, 128.5, 128.4, 128.4, 128.4, 128.3, 128.0, 127.4, 127.0, 127.0, 127.0 126.1, 122.4, 122.2, 121.8, 119.7, 117.9, 116.8, 75.8, 75.5, 27.6, 23.2, 22.5, 21.1, 15.6. (±)-8f (yield 18%): 1 H NMR (500 MHz, CDC13): δ 10.80 (s, 1H), 9.59 (d, J = 8.5 Hz, 1H), 8.76 (dd, J = 5.5 Hz, 3.5 Hz, 1H), 8.54 (dd, J = 4.0 Hz, 1.5 Hz, 1H), 8.11 (dd, J = 8.0 Hz, 1.5 Hz, 1H), 7.97 (d, J = 9.0 Hz, 1H), 7.74 (d, J = 9.0 Hz, 1H), 7.53 (overlap, 2H), 7.52 (s, 1H), 7.40 (overlap, 3H), 7.30 (d, J = 8.5 Hz, 1H), 7.14 (m, 2H), 7.09 (m, 1H) 6.08 (d, J = 3.0 Hz, 1H), 5.31 (d, J = 3.0 Hz, 1H), 3.54 (m, 1H), 2.69 (s, 3H), 2.51 (s, 3H), 1.42 (d, J = 7.0 Hz, 3H), 1.33 (d, J = 7.0 Hz, 3H). 13C NMR (125 MHz, CDC13): δ 165.4, 148.5, 140.0, 139.6, 138.8, 137.0, 136.4, 136.1, 133.8, 133.7, 131.7, 131.6, 128.8, 128.4, 128.4, 128.4, 127.9, 127.3, 127.2, 127.0, 126.9, 126.9, 126.9, 126.1, 122.4, 121.8, 121.6, 120.1, 119.7, 116.8, 76.8, 76.1, 27.4, 22.9, 22.5, 21.1, 15.6. HR-ESI-MS m / z: [M+H] + Calcd for C 37 H 33 O3N2 553.2486; Found 553.2461.

[0087] Product structure characterization data (±)-8g (yield 27%): 1 H NMR (500 MHz, DMSO-d6): δ 10.50 (s, 1H), 9.51 (d, J = 8.5 Hz, 1H), 8.63 (dd, J = 1.5 Hz, 4.2 Hz, 1H), 8.58 (dd, J = 1.5 Hz, 7.5 Hz, 1H), 8.39 (dd, J = 1.5 Hz, 8.5 Hz, 1H), 7.96 (d, J = 9.0 Hz, 1H), 7.82 (d, J = 9.5 Hz, 1H), 7.69 (br d, J = 8.0 Hz, 1H), 7.62 (dd, J = 4.0 Hz, 8.5 Hz, 1H), 7.57 (m, 1H), 7.57 (s, 1H), 7.33 (d, J = 9.0 Hz, 1H), 7.22 (dd, J = 2.0 Hz, 9.0 Hz, 2H), 6.60 (dd, J = 2.0 Hz, 9.0 Hz, 2H), 5.90 (d, J = 3.0 Hz, 1H), 5.71 (d, J = 3.0 Hz, 1H), 3.46 (m, 1H), 2.63 (s, 3H), 2.47 (s, 3H), 1.34 (d, J = 7.0 Hz, 3H), 1.26 (d, J = 7.0 Hz, 3H). 13CNMR (125 MHz, DMSO-d6): δ 165.0, 157.5, 148.9, 139.4, 139.3, 137.8, 136.7, 136.4, 133.6, 133.2, 131.3, 131.2, 128.4, 127.9, 127.9 127.7, 127.4, 127.1, 127.0, 126.8, 126.2, 125.6, 122.6, 122.4, 121.2, 119.1, 118.7, 116.1, 115.2, 115.2, 75.9, 74.5, 26.8, 22.6, 22.2, 20.6, 15.2. (±)-8h (yield 18%): 1 H NMR (500 MHz, DMSO-d6): δ 10.91 (s, 1H), 9.37 (d, J = 9.0 Hz, 1H), 9.37 (d, J = 9.0 Hz, 1H), 8.86 (d, J = 1.5 Hz, 4.0 Hz, 1H), 8.60 (d, J = 1.5 Hz, 7.5 Hz, 1H), 8.38 (d, J = 1.5 Hz, 8.5 Hz, 1H), 7.95 (d, J = 9.5 Hz, 1H), 7.80 (d, J = 9.5 Hz, 1H), 7.71 (d, J = 1.5 Hz, 8.5 Hz, 1H), 7.65 (dd, J = 4.5 Hz, 8.0 Hz, 1H), 7.59 (t, J = 8.0 Hz, 1H), 7.56 (s, 1H), 7.39 (d, J = 9.0 Hz, 1H), 7.22 (dd, J = 2.0 Hz, 9.0 Hz, 2H), 6.55 (dd, J = 2.0 Hz, 9.0 Hz, 2H), 6.16 (d, J = 3.5 Hz, 1H), 5.59 (d, J = 3.5 Hz, 1H), 3.79 (m, 1H), 2.59 (s, 3H), 2.45 (s, 3H), 1.52 (d, J = 7.0 Hz, 3H), 1.51 (d, J = 7.0 Hz, 3H). 13 CNMR (125 MHz, DMSO-d6): δ 164.9, 157.5, 149.1, 140.0, 138.7, 137.7, 136.8, 136.2, 133.6, 133.0, 131.3, 131.0, 128.4, 128.4, 128.4, 127.8, 127.6, 127.6, 127.1, 127.1, 126.3, 125.5, 122.6, 122.6, 121.6, 118.9, 117.7, 115.6, 115.1, 115.1, 74.9, 74.2, 27.1, 22.9, 22.2, 20.5, 15.2. HR-ESI-MS m / z: [M+H] +Calcd for C 37 H 33 O4N2 569.2435; Found 569.2430.

[0088] (6) Synthesis of compound IX:

[0089] Compound VIII (0.99 mmol) was dissolved in 1,4-dioxane (5 mL), 6M HC1 (5 mL) was added and hydrolysis was carried out at 110°C for 7 hours. After the reaction was completed by TLC, the solvent was evaporated, dissolved in dichloromethane (10 mL), extracted with water (3 x 10 mL), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered off the drying agent, concentrated under reduced pressure, and the crude product was chromatographed on a silica gel column (petroleum ether: ethyl acetate = 6: 1) to obtain compound IX as a light yellow solid (yield 70%).

[0090]

[0091] Structural characterization data of the product cis-(±)-9a: 1 H NMR (500 MHz, DMSO-d6): δ 13.13 (brs, 1H), 9.39 (d, J = 9.0 Hz, 1H), 7.90 (d, J = 9.0 Hz, 1H), 7.75 (d, J = 9.0 Hz, 1H), 7.47 (s, 1H), 7.36 (d, J = 9.0 Hz, 1H), 7.22 (d, J = 2.0 Hz, 1H), 7.14 (dd, J = 8.5 Hz, 2.0 Hz, 1H), 6.99 (d, J = 8.5 Hz, 1H), 5.78 (d, J = 3.5 Hz, 1H), 5.38 (d, J = 3.5 Hz, 1H), 3.75 (s, 3H), 3.73 (s, 3H), 3.44 (m, 1H), 2.58 (s, 3H), 2.45 (s, 3H), 1.37 (d, J = 7.0 Hz, 3H), 1.32 (d, J = 7.0 Hz, 3H). 13 C NMR (125 MHz, DMSO-d6): δ 168.5, 148.7, 148.4, 140.1, 138.4, 136.2, 133.5, 131.3, 131.0, 128.1, 128.1, 127.5, 127.1, 126.7, 125.3, 121.1, 119.1, 118.9, 117.9, 111.5, 110.5, 74.0, 74.0, 55.5, 55.4, 26.9, 22.8, 22.1, 20.5, 15.2. cis-(±)-9b: 1H NMR (500 MHz, DMSO-d6): δ 13.26 (br s, 1H), 9.58 (d, J = 9.0 Hz, 1H), 7.91 (br d, J = 9.0 Hz, 1H), 7.75 (d, J = 9.0 Hz, 1H), 7.45 (s, 1H), 7.40 (d, J = 9.0 Hz, 1H), 7.13 (d, J = 2.0 Hz, 1H), 7.02 (dd, J = 8.5 Hz, 2.0 Hz, 1H), 6.90 (d, J = 8.5 Hz, 1H), 5.77 (d, J = 3.5 Hz, 1H), 5.38 (d, J = 3.5 Hz, 1H), 3.69 (s, 3H), 3.64 (s, 3H), 3.35 - 3.41 (m, 1H), 2.60 (s, 3H), 2.48 (s, 3H), 1.33 (d, J = 7.0 Hz, 3H), 1.23 (d, J = 7.0 Hz, 3H). 13 C NMR (125 MHz, DMSO-d6): δ 168.4, 148.7, 148.3, 139.6, 138.4, 136.2, 133.5, 131.2, 131.0, 128.3, 127.6, 127.0, 126.8, 125.8, 121.2, 119.0, 118.9, 117.8, 111.5, 111.0, 74.2, 73.3, 55.4, 55.3, 26.9, 22.7, 22.0, 20.6, 15.2. HR-ESI-MS m / z: [M-H] - Calcd for C 30 H 29 O6 485.1970; Found 485.1968.

[0092] cis-(±)-9c: 1 H NMR (500 MHz, DMSO-d6): δ 9.35 (d, J = 9.0 Hz, 1H), 7.90 (br d, J = 9.0 Hz, 1H), 7.75 (d, J = 9.0 Hz, 1H), 7.50 (dd, J = 2.0 Hz, 9.0 Hz, 2H), 7.47 (s, 1H), 7.35 (d, J = 9.0 Hz, 1H), 6.97 (d, J = 9.0 Hz, 2H), 5.82 (d, J = 3.5 Hz, 1H), 5.34 (d, J = 3.5 Hz, 1H), 3.74 (s, 3H), 3.47 (m, 1H), 2.58 (s, 3H), 2.50 (s, 3H), 1.36 (d, J = 7.0 Hz, 3H), 1.32 (d, J = 7.0 Hz, 3H). 13C NMR (125 MHz, DMSO-de): d 168.4, 159.2, 140.1, 138.4, 136.2, 133.4, 131.3, 131.0, 128.2, 128.2, 128.2, 127.9, 127.5, 127.1, 126.8, 125.3, 121.1, 1 18.9, 1 17.8, 1 13.8, 1 13.8, 73.9, 73.9, 55.1, 26.9, 22.8, 22.2, 20.5, 15.2. cis-(±)-9d: 1 H NMR (500 MHz, DMSO-de): d 9.56 (d, J = 9.0 Hz, 1 H), 7.92 (d, J = 9.0 Hz, 1 H), 7.75 (d, J = 9.0 Hz, 1 H), 7.46 (s, 3H), 7.40 (dd, J = 2.0 Hz, 9.0 Hz, 3H), 6.90 (m, 2H), 5.79 (d, 3.0 Hz, 1 H), 5.46 (d, J = 3.0 Hz, 1 H), 3.70 (s, 3H), 3.34 (m, 1 H), 2.60 (s, 3H), 2.48 (s, 3H), 1.31 (d, J = 7.0 Hz, 3H), 1.22 (d, J = 7.0 Hz, 3H). 13 C NMR (125 MHz, DMSO-de): d

[0093] 168.2 159.2, 139.6, 138.5, 136.2, 133.5, 131.1, 131.0, 128.3, 128.2, 128.2, 128.2, 127.6, 127.0, 126.7, 125.8, 121.2, 118.9, 117.8, 113.7, 113.7, 74.1, 73.3, 55.1, 26.8, 22.6, 22.1, 20.6, 15.2. HR-ESI-MS m / z: [M-H] - Calcd for C 29 H 27 O5 455.1864; Found 455.1864.

[0094] Product structure characterization data cis-(±)-9e: 1H NMR (500 MHz, DMSO-d6): δ 9.37 (d, J = 8.5 Hz, 1H), 7.90 (d, J = 9.0 Hz, 1H), 7.75 (d, J = 9.0 Hz, 1H), 7.59 (d, J = 7.5 Hz, 2H), 7.48 (s, 1H), 7.41 (d, J = 7.5 Hz, 2H), 7.36 (d, J = 8.5 Hz, 1H), 7.36 (m, 1H), 5.87 (d, J = 3.0 Hz, 1H), 5.36 (br s, 1H), 3.48 (m, 1H), 2.58 (s, 3H), 2.45 (s, 3H), 1.36 (d, J = 7.0 Hz, 3H), 1.31 (d, J = 7.0 Hz, 3H). 13 C NMR (125 MHz, DMSO-d6): δ 168.4, 140.2, 138.5, 136.3, 136.1, 133.5, 131.3, 131.0, 128.4, 128.4, 128.3, 128.2, 127.5, 127.1, 126.8, 126.7, 126.7, 125.3, 121.1, 118.9, 117.9, 74.5, 74.2, 26.8, 22.8, 22.2, 20.5, 15.2. cis-(±)-9f: 1 H NMR (500 MHz, DMSO-d6): δ 9.52 (d, J = 8.5 Hz, 1H), 7.92 (d, J = 9.0 Hz, 1H), 7.76 (d, J = 9.0 Hz, 1H), 7.49 (d, J = 7.0 Hz, 1H), 7.47 (br s, 1H), 7.47 (s, 1H), 7.35 (m, 4H), 5.83 (d, J = 3.0 Hz, 1H), 5.53 (d, J = 3.0 Hz, 1H), 3.50 (m, 1H), 2.60 (s, 3H), 2.48 (s, 3H), 1.32 (d, J = 7.0 Hz, 3H), 1.25 (d, J = 7.0 Hz, 3H). 13 C NMR (125 MHz, DMSO-d6): δ 168.2, 139.7, 138.7, 136.3, 136.1, 133.5, 131.2, 131.0, 128.4, 128.4, 128.3, 128.3, 127.6, 127.0, 126.8, 126.6, 126.6, 125.8, 121.2, 118.9, 117.8, 74.1, 73.8, 26.8, 22.6, 22.1, 20.6, 15.2. HR-ESI-MS m / z: [M-H] - Calcd for C 28 H 25O4 425.1758; Found 425.1757.

[0095] Product structure characterization data cis-(±)-9g: 1 H NMR (500 MHz, DMSO-d6): δ 9.37 (d, J = 9.0 Hz, 1H), 7.87 (d, J = 9.0 Hz, 1H), 7.72 (d, J = 9.0 Hz, 1H), 7.42 (s, 1H), 7.36 (dd, J = 2.0 Hz, 8.71 Hz, 2H), 7.34 (d, J = 9.0 Hz, 1H), 6.70 (dd, J = 2.0 Hz, 8.5 Hz, 2H), 5.79 (d, J = 3.5 Hz, 1H), 5.09 (br s, 1H), 3.47 (m, 1H), 2.57 (s, 3H), 2.44 (s, 3H), 1.34 (d, J = 7.0 Hz, 3H), 1.30 (d, J = 7.0 Hz, 3H). 13 C NMR (125 MHz, DMSO-d6): δ 172.5, 157.3, 140.0, 138.9, 136.3, 133.3, 131.2, 131.0, 128.5, 128.5, 128.2, 127.7, 127.1, 126.7, 125.4, 120.9, 126.2, 118.9, 117.5, 115.0, 115.0, 74.5, 74.3, 26.8, 22.8, 22.3, 20.5, 15.2. cis-(±)-9h: 1 H NMR (500 MHz, DMSO-d6): δ 9.37 (d, J = 9.0 Hz, 1H), 7.87 (d, J = 9.0 Hz, 1H), 7.72 (d, J = 9.0 Hz, 1H), 7.42 (s, 1H), 7.36 (dd, J = 2.0 Hz, 8.71 Hz, 2H), 7.34 (d, J = 9.0 Hz, 1H), 6.70 (dd, J = 2.0 Hz, 8.5 Hz, 2H), 5.79 (d, J = 3.5 Hz, 1H), 5.09 (br s, 1H), 3.47 (m, 1H), 2.57 (s, 3H), 2.44 (s, 3H), 1.34 (d, J = 7.0 Hz, 3H), 1.30 (d, J = 7.0 Hz, 3H). 13C NMR (125 MHz, DMSO-d6): δ 168.4, 157.3, 139.9, 138.5, 136.2, 133.4, 131.0, 131.0, 129.3, 128.5, 128.5, 128.4, 127.7, 127.0, 126.6, 126.2, 121.0, 118.9, 117.6, 114.9, 114.9, 74.7, 73.8, 26.8, 22.7, 22.1, 20.6, 15.2. HR-ESI-MS m / z: [M+H] - Calcd for C 28 H 27 O5 443.1853; Found 443.1848.

[0096] Product structure characterization data cis-(±)-9i: 1 H NMR (500 MHz, DMSO-d6): δ 9.37 (d, J = 9.0 Hz, 1H), 7.88 (d, J = 9.5 Hz, 1H), 7.73 (d, J = 9.5 Hz, 1H), 7.58 (d, J = 9.0 Hz, 2H), 7.44 (s, 1H), 7.35 (d, J = 9.0 Hz, 1H), 7.10 (d, J = 9.0 Hz, 2H), 5.93 (d, J = 3.5 Hz, 1H), 5.14 (br s, 1H), 3.47 (m, 1H), 2.58 (s, 3H), 2.44 (s, 3H), 1.34 (d, J = 7.0 Hz, 3H), 1.30 (d, J = 7.0 Hz, 3H). 13 C NMR (125 MHz, DMSO-d6): δ 169.3, 168.4, 150.2, 140.0, 139.0, 136.5, 134.2, 133.4, 131.3, 131.0, 128.3, 128.2, 128.2, 127.6, 127.1, 126.8, 125.4, 121.7, 121.7, 121.0, 118.9, 117.7, 74.6, 74.4, 26.7, 22.8, 22.4, 20.9, 20.6, 15.3. cis-(±)-9j: 1H NMR (500 MHz, DMSO-d6): δ 9.69 (d, J = 9.0 Hz, 1H), 7.91 (d, J = 9.5 Hz, 1H), 7.75 (d, J = 9.5 Hz, 1H), 7.51 (d, J = 9.0 Hz, 2H), 7.45 (s, 1H), 7.38 (d, J = 9.0 Hz, 1H), 7.07 (d, J = 9.0 Hz, 2H), 5.89 (d, J = 3.5 Hz, 1H), 5.22 (br s, 1H), 3.47 (m, 1H), 2.60 (s, 3H), 2.48 (s, 3H), 1.32 (d, J = 7.0 Hz, 3H), 1.24 (d, J = 7.0 Hz, 3H). 13 C NMR (125 MHz, DMSO-d6): δ 169.2, 168.2, 150.1, 140.3, 138.5, 136.1, 134.5, 133.4, 131.0, 131.0, 128.4, 128.2, 128.2, 127.7, 127.0, 126.7, 126.2, 121.6, 121.6, 121.1, 119.0, 117.6, 74.9, 73.8, 26.8, 22.7, 22.3, 20.9, 20.6, 15.2. HR-ESI-MS m / z: [M+H] - Calcd for C 30 H 29 O6 485.1958; Found 485.1959.

[0097] (7) Synthesis of compound I:

[0098] Compound IX (0.69 mmol) was dissolved in tetrahydrofuran, acetic acid (0.07 mmol) and lead tetraacetate (1.04 mmol) were added under argon protection, and the reaction was carried out for 5 hours in the dark. After the reaction was completed by TLC detection, the filtrate was obtained after filtration, dissolved in ethyl acetate after concentration under reduced pressure, extracted with saturated sodium bicarbonate solution, and the organic phase was dried with saturated brine, anhydrous sodium sulfate, filtered to remove the drying agent, and concentrated under reduced pressure. The crude product was chromatographed on a silica gel column (petroleum ether: ethyl acetate = 10:1) to obtain compound I as a light yellow solid (yield 30%).

[0099]

[0100] Structural characterization data of the product cis-(±)-1a: 1H NMR(500MHz,CDCl3):δ9.43(d,J=9.0Hz,1H),7.92(d,J=9.0Hz,1H),7.65(d,J=9.0Hz,1H),7.36(s,1H),7.34(d,J=9.0Hz,1H),7.05(dd,J=9.0Hz,2.0Hz,1H),7.05(d,J=2.0Hz,1H),6.83(d,J=9.0Hz,1H),6.64(d,J=4.0Hz,1H),5.33(d,J=4.0Hz,1H),3.86(s,3H),3.74(s,3H),3.38(m,1H),2.65(s,3H),2.50(s,3H),2.12(s,3H),1.32(d,J=7.0Hz,3H),1.30(d,J=7.0Hz,3H). 13 C NMR(125MHz,CDCl3):δ169.6,149.4,149.2,140.0,137.0,136.8,133.8,131.6,131.6,128.6,128.2,128.1,128.0,126.9,125.7,121.9,119.6,119.5,118.6,111.1,109.8,89.7,75.0,56.0,56.0,27.4,22.6,22.6,21.2,21.0,15.6.cis-(±)-1b: 1 H NMR(500MHz,CDCl3):δ9.24(d,J=9.0Hz,1H),7.90(d,J=9.0Hz,1H),7.65(d,J=9.0Hz,1H),7.41(s,1H),7.39(d,J=9.0Hz,1H),7.03(dd,J=8.5Hz,2.0Hz,1H),6.99(d,J=2.0Hz,1H),6.84(d,J=8.5Hz,1H),6.68(d,J=4.0Hz,1H),5.21(d,J=4.0Hz,1H),3.86(s,3H),3.80(s,3H),3.49(m,1H),2.64(s,3H),2.51(s,3H),2.12(s,3H),1.37(d,J=7.0Hz,3H),1.33(d,J=7.0Hz,3H). 13C NMR (125 MHz, CDC13): δ 169.6, 149.4, 149.2, 138.7, 138.1, 136.6, 133.9, 131.6, 131.5, 128.7, 128.4, 127.9, 127.7, 126.8, 125.8, 121.7, 119.7, 119.6, 119.0, 111.2, 109.9, 89.8, 74.9, 56.0, 56.0, 27.3, 23.0, 22.5, 21.2, 21.0, 15.5. HR-ESI-MS m / z: [M+Na] + Calcd for C 31 H 32 O6Na 523.2091; Found 523.2089.

[0101] Product structure characterization data cis-(±)-1c: 1 H NMR (500 MHz, CDC13): δ 9.24 (d, J = 9.0 Hz, 1H), 7.90 (br d, J = 9.0 Hz, 1H), 7.65 (d, J = 9.0 Hz, 1H), 7.41 (s, 1H), 7.39 (dd, J = 2.0 Hz, 8.5 Hz, 2H), 6.89 (dd, J = 2.0 Hz, 9.5 Hz, 2H), 6.66 (d, J = 4.0 Hz, 1H), 5.21 (d, J = 4.0 Hz, 1H), 3.79 (s, 3H), 3.47 (m, 1H), 2.64 (s, 3H), 2.51 (s, 3H), 1.36 (d, J = 7.0 Hz, 1H), 1.31 (d, J = 7.0 Hz, 1H). 13 C NMR (125 MHz, CDC13): δ 169.6, 160.1, 138.7, 138.1, 136.7, 133.9, 131.6, 131.5, 128.7, 128.4, 128.4, 128.1, 127.9, 127.7, 126.8, 125.8, 121.7, 119.7, 119.0, 114.2, 114.2, 89.9, 74.8, 55.4, 27.2, 23.0, 22.6, 21.2, 21.0, 15.5. cis-(±)-1d: 1H NMR (500 MHz, CDC13): δ 9.41 (d, J = 9.0 Hz, 1H), 7.92 (d, J = 9.0 Hz, 1H), 7.66 (d, J = 9.0 Hz, 1H), 7.42 (dd, J = 2.0 Hz, 9.0 Hz, 2H), 7.37 (s, 1H), 7.35 (d, J = 9.0 Hz, 1H), 6.87 (dd, J = 2.0 Hz, 9.0 Hz, 2H), 6.64 (d, J = 4.0 Hz, 1H), 5.35 (d, J = 4.0 Hz, 1H), 3.78 (s, 3H), 3.38 (m, 1H), 2.65 (s, 3H), 2.51 (s, 3H), 2.11 (s, 3H), 1.32 (d, J = 7.0 Hz, 3H), 1.30 (d, J = 7.0 Hz, 3H). 13 C NMR (125 MHz, CDC13): δ 169.6, 159.9, 140.1, 137.0, 136.8, 133.8, 131.6, 131.6, 128.6, 128.2, 128.2, 128.2, 128.0, 127.8, 126.9, 125.8, 121.9, 119.6, 118.5, 114.3, 114.3, 89.8, 74.9, 55.4, 27.3, 22.7, 22.5, 21.2, 21.0, 15.6. HR-ESI-MS m / z: [M + Na] + Calcd for C 30 H 30 O5Na493.1986; Found 493.1973.

[0102] Product structure characterization data cis-(±)-1e: 1 H NMR (500 MHz, CDC13): δ 9.43 (d, J = 9.0 Hz, 1H), 7.93 (br d, J = 9.0 Hz, 1H), 7.67 (d, J = 9.0 Hz, 1H), 7.49 (m, 2H), 7.37 (s, 1H), 7.35 (m, 4H), 6.67 (d, J = 4.0 Hz, 1H), 5.44 (d, J = 4.0 Hz, 1H), 3.36 (m, 1H), 2.66 (s, 3H), 2.51 (s, 3H), 2.11 (s, 3H), 1.31 (d, J = 7.0 Hz, 3H), 1.28 (d, J = 7.0 Hz, 3H). 13C NMR (125 MHz, CDC13): δ 169.7, 140.1, 136.9, 136.9, 135.9, 133.8, 131.6, 131.6, 128.9, 128.9, 128.9, 128.7, 128.2, 128.1, 126.9, 126.7, 126.7 125.9, 122.0, 119.5, 118.5, 89.7, 75.2, 27.3, 22.7, 22.5, 21.2, 21.0, 15.6. trans-(±)-1f: 1 H NMR (500 MHz, CDC13) δ 9.22 (d, J = 9.0 Hz, 1H), 7.91 (br d, J = 9.5 Hz, 1H), 7.65 (d, J = 9.0 Hz, 1H), 7.46 (m, 2H), 7.42 (s, 1H), 7.37 (m, 4H), 6.68 (d, J = 4.0 Hz, 1H), 5.29 (d, J = 4.0 Hz, 1H), 3.50 (m, 1H), 2.64 (s, 3H), 2.51 (s, 3H), 2.11 (s, 3H), 1.37 (d, J = 7.0 Hz, 3H), 1.34 (d, J = 7.0 Hz, 3H). 13 C NMR (125 MHz, CDC13): δ 169.7, 140.1, 136.9, 136.9, 135.9, 133.8, 131.6, 131.6, 128.9, 128.9, 128.9, 128.7, 128.2, 128.1, 126.9, 126.7, 126.7 125.9, 122.0, 119.5, 118.5, 89.7, 75.2, 27.3, 22.7, 22.5, 21.2, 21.0, 15.6. trans-(±)-1f: + Calcd for C 29 H 28 O4Na 463.1880; Found 463.1871.

[0103] Product structure characterization data cis-(±)-1g: 1H NMR (500 MHz, DMSO-d6): δ 9.40 (d, J = 9.0 Hz, 1H), 7.94 (d, J = 9.5 Hz, 1H) 7.66 (d, J = 9.5 Hz, 1H), 7.50 (dd, J = 1.5 Hz, 8.0 Hz, 2H), 7.37 (s, 1H), 7.36 (d, J = 9.5 Hz, 1H), 7.08 (dd, J = 2.0 Hz, 9.0 Hz, 2H), 6.65 (d, J = 3.5 Hz, 1H), 5.45 (d, J = 3.5 Hz, 1H), 3.36 (m, 1H), 2.66 (s, 3H), 2.51 (s, 3H), 2.29 (s, 3H), 2.12 (s, 3H), 1.30 (d, J = 7.0 Hz, 3H), 1.29 (d, J = 7.0 Hz, 3H). 13 C NMR (125 MHz, CDC13): δ 169.6, 169.5, 151.0, 139.9, 136.9, 136.8, 133.9, 133.4, 131.7, 131.6, 128.7, 128.2, 128.2, 127.9, 127.9, 126.9, 125.8, 122.1, 122.1, 122.0, 119.5, 118.6, 89.5, 74.8, 27.3, 22.7, 22.4, 21.3, 21.2, 21.0, 15.6. cis-(±)-1h: 1 H NMR (500 MHz, DMSO-d6): δ 9.22 (d, J = 8.5 Hz, 1H), 7.92 (d, J = 9.0 Hz, 1H), 7.66 (d, J = 9.0 Hz, 1H), 7.49 (dd, J = 2.5 Hz, 8.5 Hz, 2H), 7.43 (s, 1H), 7.39 (d, J = 9.0 Hz, 1H), 7.11 (m, 2H), 6.65 (d, J = 4.0 Hz, 1H), 5.28 (d, J = 4.0 Hz, 1H), 3.48 (m, 1H), 2.64 (s, 3H), 2.51 (s, 3H), 2.30 (s, 3H), 2.12 (s, 3H), 1.37 (d, J = 7.0 Hz, 3H), 1.34 (d, J = 7.0 Hz, 3H). 13C NMR (125 MHz, DMSO-d6): δ 169.5, 169.5, 151.1, 138.6, 138.0, 136.6, 133.9, 133.7, 131.6, 131.5, 128.7, 128.2, 127.9, 127.7, 126.7, 125.8, 122.1, 121.8, 119.7, 119.2, 89.7, 74.8, 27.2, 22.9, 22.7, 21.3, 21.1, 21.0, 15.5. HR-ESI-MS m / z: [M+H] + Calcd for C 31 H 31 O6 499.2115; Found 499.2110.

[0104] Example 2: Inhibition of AhR activity by compounds 1-4

[0105] Experimental method:

[0106] The dioxin-responsive element (DRE) and CYP1A1 core promoter sequence were constructed into the reporter gene plasmid (pGL3-basic) to obtain the recombinant vector pCL-CR2. Hepa 1 cells were transfected with pCL-CR2, and the stably transfected cell line CBG2.8D was obtained by G418 resistance screening. The CBG2.8D stable transfection cell line was inoculated in a 96-well white plate at a concentration of 4x10 5 After 24 hours of culture, the supernatant was aspirated and replaced with culture medium containing different concentrations of samples, with 3 wells in each group as controls. After 24 hours of continuous culture, the culture solution was discarded. Each well was washed once with 100 μL of PBS, and after the PBS was removed, 50 ul of luciferase lysis solution was added, shaken at room temperature for 20 minutes, and then detected for luciferase intensity.

[0107] Experimental results:

[0108] As the concentration of the compound in the culture system increased, the AhR activity decreased, and the inhibitory concentrations of compounds 1-4 on AhR were determined to be 0.32 μM, 0.29 μM, 1.97 μM, and 2.86 μM, respectively.

[0109] Example 3: Inhibition of nuclear translocation by compounds

[0110] Experimental method:

[0111] U87 and B16F10 cells with high expression of AhR were selected as tool cell lines. U87 and B16F10 cells in the exponential growth phase were trypsinized to prepare a cell suspension, which was diluted with medium to 1 x 10 5 The monomer compound was diluted with medium to concentrations of 10 μM and 30 μM, respectively, and negative and positive controls were set up (no test substance was added and kynurenine was added to a final concentration of 150 μM). The medium was removed, and 1 mL of medium containing the test substance at different concentrations was added to each well. The cells were incubated for 10 hours. The culture dishes were removed, and kynurenine was added to the test substance group to prepare a system with a final kynurenine concentration of 150 μM. Kynurenine was added to the positive control dish to a final concentration of 150 μM. The cells were incubated for 48 hours. The culture dishes were removed, and the supernatant was removed and washed with PBS three times. 4% tissue cell fixative was added, and the cells were fixed at room temperature for 15 minutes. After fixation, the cells were washed with PBS three times at a slow speed for 5 minutes each time. 1 mL of 0.3% Triton X-100 was added to each well, and the cells were fixed at room temperature for 20 minutes. The supernatant was removed. 3% BSA blocking solution was added, and the cells were blocked at room temperature for 1 hour. The supernatant was removed. 100 μL of AhR antibody diluted in 1% BSA was added to each well, and the cells were incubated in a humidified box at 4°C overnight. After rewarming for 0.5 hours, the cells were washed with PBST three times for 5 minutes each time. Fluorescent secondary antibody was added, and the cells were stained at room temperature in the dark for 45 minutes. The cells were washed with PBST three times on a shaker for 5 minutes each time. Nucleus dye hochest was added, and the cells were stained at room temperature in the dark for 20 minutes. After washing with PBS three times, the expression of the protein was observed under a fluorescence microscope.

[0112] Experimental results:

[0113] After kynurenine agonizes AhR protein in U87 and B16F10 cells, the AhR protein is transferred to the nucleus. However, the AhR protein remains in the cytoplasm after treatment with the compound, and the effect is dose-dependent.

[0114] Example 4: Effect of the compound on the expression of AhR downstream genes in U87 and B16F10 cells

[0115] Experimental method:

[0116] U87 and B16F10 cells in the logarithmic growth phase were trypsinized to prepare a single cell suspension, which was diluted with medium to 5 x 10 5U87 cells were inoculated in 6-well plates at 1 cell per dish, and when the cells reached 40-50% confluence, a monomer compound medium containing a final concentration of 10 μM was added. After 10 hours, kynurenine was added to the culture dish to adjust the medium concentration to contain 150 μM kynurenine and 10 μM monomer compound. At the same time, a blank control group (without compound and kynurenine) and a positive control group (containing only kynurenine) were set up. After 24 hours of incubation in the incubator, the cells were collected. The expression of AHR downstream genes such as AhRR, CYP1B1, PD-L1, IL6, etc. in tumor cells was detected by qPCR technology.

[0117] Experimental results:

[0118] After U87 cells were stimulated by kynurenine, the expression of IDO2, AhRR, CYP1B1, IL-6 and PD-L1 genes in the cells increased significantly. After the tumor cells were treated with the compound, the expression of the above genes decreased, and there was a statistically significant difference. After B16F10 cells were stimulated by kynurenine, AhR, IDO, AhRR and IL-6 genes were significantly up-regulated. After treatment with the compound, the stimulating effect of kynurenine was reversed, and AhR, IDO, AhRR and IL-6 genes were significantly down-regulated. It is proved that the compound can inhibit the expression of AhR downstream genes of U87 and B16F10 cells, and stop the expression of inflammation-related genes and immune escape-related genes.

[0119] Experimental method:

[0120] The pharmacodynamic effect of the compound on melanoma was evaluated by using a C57BL / 6 mouse model inoculated with B16F10 melanoma cells. Each C57BL / 6 mouse was injected with 2x10 6 B16F10 tumor cells on the right scapula. On the first day after modeling, the animals were divided into groups for administration, including a control group (model), a cyclophosphamide group (CTX), a compound 0.3 mg / kg group, and a compound 1 mg / kg group, with 7 animals in each group. The model group was given an equal volume of solvent control group 0.5% sodium carboxymethyl cellulose, and the cyclophosphamide group was given intraperitoneal injection at a dose of 100 mg / kg once a week for a total of two times. The experiment was ended on the 15th day after modeling, and the changes in mouse body weight, tumor volume and tumor weight were evaluated according to methods known in the art.

[0121] Experimental results:

[0122] The compound can maintain the body weight of mice during administration, and is safe and non-toxic. The compound can inhibit the growth of tumors in mice, and the tumor inhibition rate of the 0.3 mg / kg group was 32.89% and the tumor inhibition rate of the 1 mg / kg group was 55.79% at the end of the experiment after 15 days, indicating that the compound has a good tumor inhibition effect.

Claims

1. A class of quinone diterpenoid styrene alcohol ester adducts, characterized in that... having the structure shown in Schemes (IA) and (IB): R is 1, 2, 3 arbitrary substituents on the benzene ring, the position of the one substituent is: the position of the two substituents is: the position of the three substituents is: wherein R1, R2, R3 are each independently selected from the group consisting of: hydrogen, hydroxyl, mercapto, methoxy, acetoxy, amino, nitro, halogen, carboxyl.

2. The compound according to claim 1, characterized in that, R is selected from the group consisting of: hydrogen, methoxy, acetoxy.

3. The compound of any one of claims 1-2, wherein the compound is selected from the group consisting of:

4. Process for the preparation of a compound according to any one of claims 1 to 3, characterized in that, comprising the following steps: Scheme (1) synthesis of compound III: Compound II is reacted with zinc triflate at 120°C for 22h to obtain compound III; (2) synthesis of compound V: Compound III is reduced with Pd / C and H2 to obtain intermediate IV, which is reacted with methyl 2,3-dibromopropionate under the condition of potassium carbonate and protection of argon to obtain compound V; (3) synthesis of compound VI: Compound V is hydrolyzed under alkaline condition to obtain compound VI; (4) synthesis of compound VII: Compound VI is reacted with (COCl)2 under the catalysis of DMF to obtain acyl chloride, which is then reacted with 8-aminoquinoline under the condition of triethylamine to obtain compound VII; (5) synthesis of compound VIII: Compound VII is reacted with Pd(OAc)2, AgOAc and different iodo benzene compounds substituted with R at 110°C to obtain compound VIII; (6) synthesis of compound IX: Compound VIII is hydrolyzed under acidic condition at 110°C to obtain compound IX; (7) synthesis of compound I: Compound IX is reacted with acetic acid under the catalysis of lead tetraacetate in the dark to obtain compound I, wherein R is defined as in any one of claims 1-3.

5. The preparation method according to claim 4, characterized in that, Compound II in step (1): zinc triflate = 1:0.1; purified by silica gel column chromatography, and the eluent used is petroleum ether / ethyl acetate with a volume ratio of 20:

1.

6. The preparation method according to claim 4, characterized in that, Compound III in step (2): Pd / C: potassium carbonate: methyl 2,3-dibromopropionate = 1:0.1:1.2:1.2; purified by silica gel column chromatography, and the eluent used is petroleum ether / ethyl acetate with a volume ratio of 20:

1.

7. The preparation method according to claim 4, characterized in that, Compound VI in step (3) is purified by silica gel column chromatography, and the eluent used is petroleum ether / ethyl acetate with a volume ratio of 6:

1.

8. The preparation method according to claim 4, characterized in that, Compound VI in step (4): (COCl)2: triethylamine: 8-aminoquinoline = 1:1.2:1.5:1.2; purified by silica gel column chromatography, and the eluent used is petroleum ether / ethyl acetate with a volume ratio of 10:

1.

9. The preparation method according to claim 4, characterized in that, Compound VII in step (5): Pd(OAc)2: AgOAc: different iodo benzene compounds substituted with R = 1:0.1-0.2:2.5:4; purified by silica gel column chromatography, and the eluent used is petroleum ether / ethyl acetate with a volume ratio of 10:

1.

10. The method of claim 4, wherein, The compound IX in step (6) is purified by silica gel column chromatography using petroleum ether / ethyl acetate as eluent with a volume ratio of 6:

1.

11. The preparation method according to claim 4, characterized in that, The compound IX in step (7): Pb(OAc)4 = 1:1.5, purified by silica gel column chromatography using petroleum ether / ethyl acetate as eluent with a volume ratio of 10:

1.

12. A pharmaceutical composition, characterized by, an effective amount of a compound of any one of claims 1-3 and a pharmaceutically acceptable carrier.

13. Pharmaceutical composition according to claim 12, characterized in that The dosage form of the composition is selected from the group consisting of tablets, capsules, pills, granules, oral liquids and suspensions.

14. Use of a compound of any one of claims 1-3 in the manufacture of a medicament for treating melanoma.

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