Quinoid chalcone dimer compounds with isopentenyl in A ring and anti-tumor application of quinoid chalcone dimer compounds

Abstract

The invention relates to the technical field of medicines, and discloses a quinonoid chalcone dimer compound with an A ring having an isopentenyl group and an anti-tumor application of the quinonoid chalcone dimer compound. The compound provided by the invention has a structure shown in a general formula (I) or a pharmaceutically acceptable salt thereof, and the preparation method comprises the following steps: (1) synthesizing 3, 5-dihydroxy-2-acetyl-6, 6-diisopentenyl cyclohexane-2, 4-dienone, (2) synthesizing a quinone chalcone compound with an A ring having an isopentenyl group, and (3) synthesizing a quinoid chalcone compound with an A ring having an isopentenyl group. And (3) synthesizing the quinoid chalcone dimer compound with an A ring having an isopentenyl group. The compound provided by the invention is simple in preparation method and shows relatively good anti-tumor activity. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to the field of medical technology, and is concerned with a class of quinone chalcone dimer compounds with an isopentenyl group in the A ring, a preparation method, a pharmaceutical composition containing the compounds, and an application thereof in anti-tumor activity. Background Art

[0002] Isopentenyl groups are a common and important group in medicinal chemistry. Literature research reveals the presence of numerous isopentenyl phloroglucinol compounds in natural products. These compounds exhibit significant antitumor and other biological activities, making them a hot topic in medicinal chemistry research. Previous research by our group synthesized a class of isopentenylquinone chalcone compounds that exhibited modest antitumor activity. Furthermore, natural products such as quinone chalcone dimers and phloroglucinol dimers also exhibit a wide range of biological activities. To further identify promising lead compounds, we combined previous research with literature research to design and synthesize a class of quinone chalcone dimers with an isopentenyl group in the A ring and evaluated their antitumor activity. Summary of the Invention

[0003] The object of the present invention is to provide a class of quinone chalcone dimer compounds with an isopentenyl group in the A ring or pharmaceutically acceptable salts thereof.

[0004] Another object of the present invention is to provide a method for preparing the compound.

[0005] Another object of the present invention is to provide a pharmaceutical composition comprising an effective dose of a class of quinone chalcone dimer compounds having an isopentenyl group in ring A and a pharmaceutically acceptable carrier and / or excipient.

[0006] Another object of the present invention is to provide a class of quinone chalcone dimer compounds with an isopentenyl group in the A ring for use in preparing drugs for treating tumor diseases.

[0007] The present invention provides the following technical solutions:

[0008] The first aspect of the present invention provides a class of quinone chalcone dimer compounds having an isopentenyl group in ring A, characterized in that the compound has a structure represented by general formula (I) or a pharmaceutically acceptable salt thereof.

[0009]

[0010] Among them, (1) R A 1, 2, or 3 arbitrary monosubstituted, disubstituted, or polysubstituted groups on the benzene ring,

[0011] The R A When it is a single substituent, its position is as shown in R1:

[0012]

[0013] The R A When it is a disubstituted group, its position is as shown in R2 and R3:

[0014]

[0015] The R A When there are three substituents, their positions are as shown in R4, R5, and R6:

[0016]

[0017] wherein R1, R2, R3, R4, R5, and R6 are each independently selected from the group consisting of hydrogen, hydroxy, methoxy, methyl, methoxymethoxy, bromine, and chlorine;

[0018] (2)R B Selected from general formula (II)

[0019]

[0020] Among them, R C is one or two arbitrary single or multiple substituents on the benzene ring,

[0021] The R C When it is a single substituent, its position is as shown in R7:

[0022]

[0023] The R C When it is a disubstituted group, its position is as shown in R8 and R9:

[0024]

[0025] Wherein, R7, R8, and R9 are independently selected from the group consisting of hydrogen, hydroxy, methoxy, methoxymethoxy, bromine, and chlorine. The compound is selected from the following compounds:

[0026]

[0027]

[0028] The second aspect of the present invention provides a method for preparing a compound having a structure of general formula (I), characterized in that it comprises the following steps:

[0029] Synthesis route 1:

[0030]

[0031] Synthesis route 2:

[0032]

[0033] (1) Synthesis of 3,5-dihydroxy-2-acetyl-6,6-diisopentenylcyclohexa-2,4-dienone

[0034] 2,4,6-trihydroxyacetophenone was added to an alkaline aqueous solution and stirred in an ice-water bath to dissolve. 2 times the molar amount of 2,4,6-trihydroxyacetophenone was added to the aqueous solution. After 60 minutes, the pH was adjusted to 3 with dilute hydrochloric acid, and then extracted with ethyl acetate. The organic phase was washed and dried, and finally purified by normal phase silica gel column chromatography to obtain a yellow oily substance, 3,5-dihydroxy-2-acetyl-6,6-diisopentenylcyclohexa-2,4-dienone.

[0035] (2) Synthesis of a class of quinone chalcone compounds with an isopentenyl group in the A ring

[0036] An equal mass of potassium hydroxide and 3,5-dihydroxy-2-acetyl-6,6-diisopentenylcyclohexa-2,4-dienone was dissolved in aqueous ethanol. 3,5-dihydroxy-2-acetyl-6,6-diisopentenylcyclohexa-2,4-dienone and substituted benzaldehyde were then added at a molar ratio of 1:1.5. The mixture was stirred at 55°C for 11 hours, and completion of the reaction was monitored by high-performance liquid chromatography. The reaction was quenched with water, the pH was adjusted to neutral with dilute hydrochloric acid, and then extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution and purified water, dried over anhydrous sodium sulfate, filtered, evaporated to dryness under reduced pressure, and purified by reverse-phase column chromatography to obtain a class of quinone chalcone compounds with an isopentenyl group in Ring A.

[0037] (3) Synthesis of a class of quinone chalcone dimer compounds with an isopentenyl group on the A ring

[0038] Synthesis method 1:

[0039] A quinone-type chalcone compound having an isopentenyl group in its A ring is dissolved in acetonitrile, and then a catalytic amount of acetic acid and a 37% aqueous formaldehyde solution (2-20 times the molar amount of the isopentenyl quinone-type chalcone compound) are added. The mixture is stirred at room temperature and the reaction is monitored for completion by thin-layer chromatography. The mixture is quenched with water, extracted with ethyl acetate, and the organic layer is washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness under reduced pressure. Finally, the mixture is purified by normal-phase column chromatography to obtain a quinone-type chalcone dimer compound having an isopentenyl group in its A ring.

[0040] Synthesis method 2:

[0041] A class of quinone chalcone compounds with an isopentenyl group in Ring A is dissolved in acetic acid, followed by the addition of an aldehyde compound three times the molar amount of the isopentenyl quinone chalcone compound. The reaction is stirred at room temperature and monitored for completion by thin-layer chromatography. The mixture is quenched with water, extracted with ethyl acetate, and the organic layer is washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness under reduced pressure. Finally, the mixture is purified by normal-phase column chromatography to obtain a class of quinone chalcone dimer compounds with an isopentenyl group in Ring A.

[0042] Synthesis method three:

[0043] An equal amount of potassium hydroxide and 3,5-dihydroxy-2-acetyl-6,6-diisopentenylcyclohexa-2,4-dienone was dissolved in aqueous ethanol. 3,5-dihydroxy-2-acetyl-6,6-diisopentenylcyclohexa-2,4-dienone and substituted benzaldehyde were then added at a molar ratio of 1:3. The mixture was stirred at 55°C for 11 hours, concentrated under reduced pressure at 45°C for 2 hours, and monitored for completion by thin-layer chromatography. The reaction was quenched with water, the pH was adjusted to neutral with dilute hydrochloric acid, and then extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution and purified water, dried over anhydrous sodium sulfate, filtered, evaporated to dryness under reduced pressure, and purified by normal-phase column chromatography to obtain a class of quinone-type chalcone dimers with an isopentenyl group in Ring A.

[0044] The third aspect of the present invention relates to a pharmaceutical composition comprising a pharmaceutically effective dose of the compound as described in each case of general formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[0045] The present invention also relates to pharmaceutical compositions comprising a compound of the present invention as an active ingredient and conventional pharmaceutical excipients or adjuvants. Typically, the pharmaceutical compositions of the present invention contain 0.1-95% by weight of the compound of the present invention. The compound of the present invention is typically present in a unit dosage form in an amount of 0.1-100 mg, with preferred unit dosage forms containing 4-50 mg.

[0046] The pharmaceutical composition of the compounds of this invention can be prepared according to methods well known in the art. When used for this purpose, if necessary, the compounds of this invention can be combined with one or more solid or liquid pharmaceutical excipients and / or adjuvants to prepare suitable administration forms or dosage forms that can be used as human or veterinary medicines.

[0047] The compound of the present invention or the pharmaceutical composition containing the same can be administered in a unit dosage form, and the administration route can be enteral or parenteral, such as oral, intramuscular, subcutaneous, nasal, oral mucosa, skin, peritoneum or rectum.

[0048] The compound of the present invention or the pharmaceutical composition containing the same can be administered by injection, including intravenous injection, intramuscular injection, subcutaneous injection, intradermal injection and acupuncture injection.

[0049] The dosage form can be a liquid or solid dosage form. For example, liquid dosage forms can be true solutions, colloids, microparticles, emulsions, or suspensions. Other dosage forms include tablets, capsules, pellets, aerosols, pills, powders, solutions, suspensions, emulsions, granules, suppositories, and freeze-dried powder injections.

[0050] The compound of the present invention can be prepared into common preparations, sustained-release preparations, controlled-release preparations, targeted preparations and various microparticle delivery systems.

[0051] For example, in order to prepare a unit dosage form into a tablet, a wide variety of carriers well known in the art can be used. Examples of carriers include diluents and absorbents such as starch, dextrin, calcium sulfate, lactose, mannitol, sucrose, sodium chloride, glucose, urea, calcium carbonate, kaolin, microcrystalline cellulose, aluminum silicate, etc.; wetting agents and binders such as water, glycerol, polyethylene glycol, ethanol, propanol, starch paste, dextrin, syrup, honey, glucose solution, acacia paste, gelatin paste, sodium carboxymethylcellulose, shellac, methylcellulose, potassium phosphate, polyvinyl pyrrolidone, etc.; disintegrants such as dry starch, alginate, agar powder, brown seaweed starch, sodium bicarbonate and citric acid, calcium carbonate, polyoxyethylene sorbitan fatty acid ester, sodium lauryl sulfate, methylcellulose, ethylcellulose, etc.; disintegration inhibitors such as sucrose, tristearin, cocoa butter, hydrogenated oil, etc.; absorption accelerators such as quaternary ammonium salts, sodium lauryl sulfate, etc.; lubricants such as talc, silicon dioxide, corn starch, stearate, boric acid, liquid paraffin, polyethylene glycol, etc. The tablets can be further made into coated tablets, such as sugar-coated tablets, film-coated tablets, enteric-coated tablets, or double-layer tablets and multi-layer tablets.

[0052] For example, to prepare the dosing unit into a pill, various carriers known in the art can be widely used. Examples of carriers include diluents and absorbents, such as glucose, lactose, starch, cocoa butter, hydrogenated vegetable oil, polyvinyl pyrrolidone, glyceryl monostearate, kaolin, talc, etc.; binders, such as gum arabic, tragacanth gum, gelatin, ethanol, honey, liquid sugar, rice paste or flour paste, etc.; disintegrants, such as agar powder, dry starch, alginate, sodium lauryl sulfate, methylcellulose, ethylcellulose, etc.

[0053] For example, to prepare a dosing unit in the form of a capsule, the active ingredient compound of the present invention is mixed with the various carriers described above, and the resulting mixture is placed in a hard gelatin capsule or soft capsule. The active ingredient compound of the present invention can also be formulated into microcapsules and suspended in an aqueous medium to form a suspension, which can also be encapsulated in a hard capsule or formulated as an injection for use.

[0054] For example, the compounds of the present invention may be formulated into injectable formulations such as solutions, suspensions, emulsions, or freeze-dried powder injections. These formulations may be aqueous or non-aqueous and may contain one or more pharmacologically acceptable carriers, diluents, adhesives, lubricants, preservatives, surfactants, or dispersants. For example, the diluent may be selected from water, ethanol, polyethylene glycol, 1,3-propylene glycol, ethoxylated isostearyl alcohol, polyoxyethylene isostearyl alcohol, polyoxyethylene sorbitol esters, fatty acid esters, and the like. In addition, to prepare isotonic injections, an appropriate amount of sodium chloride, glucose, or glycerol may be added to the injectable formulation. Conventional cosolvents, buffers, pH regulators, and the like may also be added. These adjuvants are commonly used in the art.

[0055] In addition, if necessary, colorants, preservatives, perfumes, flavorings, sweeteners or other materials may be added to the pharmaceutical preparations.

[0056] To achieve the purpose of medication and enhance the therapeutic effect, the drug or pharmaceutical composition of the present invention can be administered by any known method of administration.

[0057] The dosage of the pharmaceutical composition of the present invention depends on many factors, such as the nature and severity of the disease to be prevented or treated, the sex, age, weight, personality and individual response of the patient or animal, the route of administration, the number of doses, and the therapeutic purpose. Therefore, the therapeutic dosage of the present invention can vary widely. Generally speaking, the dosage of the pharmaceutical ingredients of the present invention is well known to those skilled in the art. The dosage can be appropriately adjusted based on the actual amount of drug contained in the final formulation of the composition of the present invention to achieve the therapeutically effective amount required to achieve the preventive or therapeutic purpose of the present invention. The suitable daily dosage range of the compound of the present invention is: the amount of the compound of the present invention is 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 daily dosage of the compound of the present invention for adult patients is 10-500 mg, preferably 20-100 mg, which can be taken once or divided into 2-3 doses; the dosage for children is 5-30 mg per kg body weight, preferably 10-20 mg / kg body weight. The above dosage can be administered in a single dose or divided into several doses, such as two, three or four doses, depending on the clinical experience of the administering physician and the dosing regimen of the treatment. The compounds or compositions of the present invention can be taken alone or in combination with other therapeutic drugs or symptomatic drugs.

[0058] A fourth aspect of the present invention relates to the use of a quinone chalcone dimer compound having an isopentenyl group in Ring A, or a pharmaceutically acceptable salt thereof, in a medicament for preventing and / or treating a tumor disease. The tumor disease is selected from glioblastoma, melanoma, gastric cancer, lung cancer, breast cancer, kidney cancer, liver cancer, cervical cancer, and ovarian cancer.

[0059] Experiments have shown that a class of quinone chalcone dimer compounds with an isopentenyl group in the A ring of the present invention exhibits significant anti-tumor activity in an in vitro proliferation inhibition model for evaluating human glioma cells.

[0060] 1. The compound structure of the present invention is synthesized for the first time, and there are very few reports of similar structures in the literature. It has the potential to be further developed into a new anti-tumor drug.

[0061] 2. The compounds of the present invention exhibit good anti-tumor activity.

[0062] 3. The synthetic route of this type of compound is mature and simple to obtain.

[0063] Effective technical effects

[0064] 1. The present invention discloses a class of quinone chalcone dimer compounds with an isopentenyl group in Ring A, which have novel structures and have not been reported in the literature. They have the potential to be further developed into new drugs for anti-tumor diseases.

[0065] 2. The preparation method of the quinone chalcone dimer compound with an isopentenyl group in the A ring of the present invention is novel and the separation is simple.

[0066] 3. A class of quinone chalcone dimer compounds with an isopentenyl group in the A ring of the present invention has good anti-tumor activity and can significantly inhibit the proliferation of human glioma cells in vitro. There is currently no relevant report on the anti-tumor activity of this class of compounds. DETAILED DESCRIPTION

[0067] Example 1

[0068] The synthesis method of compound 1 comprises the following steps:

[0069] (1) Synthesis of 3,5-dihydroxy-2-acetyl-6,6-diisopentenylcyclohexa-2,4-dienone

[0070] 0.73 g of 2.2 eq of potassium hydroxide was added to 10 ml of water, and 1 g of 2,4,6-trihydroxyacetophenone was added and stirred to dissolve. 1.51 mL of 2.2 eq of bromoisoamylene was added to the aqueous solution, and the mixture was stirred at 0°C for 1 hour. The reaction was stopped, and the pH was adjusted to 3 with dilute hydrochloric acid. The mixture was then extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution and pure water, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness under reduced pressure. Finally, 603 mg of 3,5-dihydroxy-2-acetyl-6,6-diisopentenylcyclohexa-2,4-dienone was separated and purified by normal phase flash preparative column chromatography (petroleum ether:ethyl acetate = 95:5) to obtain 3,5-dihydroxy-2-acetyl-6,6-diisopentenylcyclohexa-2,4-dienone with a yield of 33.3%. The following reactions occurred in this process:

[0071]

[0072] The structural characterization data of the product are: HRESIMS: (m / z 305.1745[M+H] + ,calcd,305.1747); 1 HNMR (DMSO-d6, 500MHz)δ H :1.52(6H,s,2×CH3),1.54(6H,s,2×CH3),2.44(2H,m,-CH2CH=),2.45(3H,s,-CH3CO),2.53(2H,m,-C H2CH=),4.76(2H,t,J=7.5Hz,2×=CHCH2),5.53(1H,s,H-4),12.57(1H,s,5-OH),18.35(1H,s,3-OH).

[0073] (2) Synthesis of 4,4′-[(4-bromophenyl)methylene]bis[2-(4-bromocinnamoyl)-5-hydroxy-6,6-diisopentenylcyclohex-4-ene-1,3-dione]

[0074] Dissolve 0.5g of potassium hydroxide in 1ml of water-1.5ml of ethanol solution, then add 0.5g of 3,5-dihydroxy-2-acetyl-6,6-diisopentenylcyclohexa-2,4-dienone and 3eq (0.91g) of 4-bromobenzaldehyde. Stir at 55°C for 11h, then concentrate under reduced pressure at 45°C for 2h. Completion of the reaction is monitored by thin-layer chromatography. The reaction is quenched with water, the pH is adjusted to neutral with dilute hydrochloric acid, and then extracted with ethyl acetate. The organic layer is washed with saturated sodium chloride solution and purified water, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness under reduced pressure. Finally, the product is isolated and purified by normal phase flash preparative column chromatography (petroleum ether:ethyl acetate = 95:5) to obtain 66mg of 4,4′-[(4-bromophenyl)methylene]bis[2-(4-bromocinnamoyl)-5-hydroxy-6,6-diisopentenylcyclohex-4-ene-1,3-dione] in a yield of 7.3%. The following reactions occur during this process:

[0075] The structural characterization data of the product are: HRESIMS (m / z 1105.1509[M+H] + ,calcd,1105.1531); 1 HNMR (500MHz, pyridine-d5)δ H:1.63(6H,s,2×CH3),1.69(6H,s,2×CH3),1.70(6H,s,2×CH3),1.72(6H,s,2×CH3),2.94(2H,m,-CH2CH=),3.05(2H,m,-CH2CH=),3.16(4H,m,2×-CH2CH=),5.54(4H,s,4×=CHCH2),7.47(1H,overlap,-CH-),7.47(4H,overlap,H-3″,H-5″,H-3″″′,H-5″″′),7.46(2H,overlap,H-3″″″,H-5″″″),7.61(4H,d,J=8.5Hz,H-2″,H-6″,H-2″″′,H-6″″′),7.70(2H,d,J=8.5Hz,H-2″″″,H-6″″″),7.94(2H,d,J=16.0Hz,H-2′,H-2″″),9.00(2H,d,J=16.0Hz,H-3′,H-3″″). 13 C NMR(125MHz,chloroform-d)δ C:18.0(1×CH3),18.1(1×CH3),18.1(1×CH3),18.5(1×CH3),25.9(1×CH3),26.0(1×CH3),26.2(1×CH3),26. 3(1×CH3),34.9(-CH-),36.3(1×-CH2CH=),37.6(1×-CH2CH=),37.9(1×-CH2CH=),39.1(1×-CH2CH=),55.4( C-6″′),55.5(C-6),110.5(C-2″′),110.8(C-2),115.7(C-4″′),117.5(C-4),117.0(1×=CHCH2),117.3(1× =CHCH2),118.1(1×=CHCH2),118.8(1×=CHCH2),119.4(C-4″″″),124.0(C-2″″),124.2(C-2′),125.5(C-4″ ″′),125.5(C-4″),128.8(C-2″″″,C-6″″″),130.4(C-2″″′,C-6″″′),130.5(C-2″,C-6″),131.2(C-3″″″,C -5″″”),132.4(C-3″″′,C-5″″′),132.4(C-3″,C-5″),133.9(C-1″″′),134.1(C-1″),135.7(1×-C=CH),135 .8(1×-C=CH),135.9(1×-C=CH),136.7(1×-C=CH),137.8(C-1″″″),144.4(C-3″″),144.6(C-3′),172.5(C- 5″′), 173.4(C-5), 187.1(C-1″″), 187.8(C-1′), 187.8(C-3″′), 188.6(C-3), 202.1(C-1″′), 202.3(C-1).

[0076] Example 2

[0077] The synthesis method of compound 2 comprises the following steps:

[0078] (1) Synthesis of 3,5-dihydroxy-2-acetyl-6,6-diisopentenylcyclohexa-2,4-dienone

[0079] The preparation method is the same as that of compound 1.

[0080] (2) Synthesis of 4,4′-[(4-chlorophenyl)methylene]bis[2-(4-bromocinnamoyl)-5-hydroxy-6,6-diisopentenylcyclohex-4-ene-1,3-dione]

[0081] Dissolve 0.5g of potassium hydroxide in 1ml of water-1.5ml of ethanol solution, then add 0.5g of 3,5-dihydroxy-2-acetyl-6,6-diisopentenylcyclohexa-2,4-dienone and 3eq (0.69g) of 4-chlorobenzaldehyde. Stir at 55°C for 11h, then concentrate under reduced pressure at 45°C for 2h. Completion of the reaction is monitored by thin-layer chromatography. The reaction is quenched with water, the pH is adjusted to neutral with dilute hydrochloric acid, and then extracted with ethyl acetate. The organic layer is washed with saturated sodium chloride solution and purified water, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness under reduced pressure. Finally, the product is isolated and purified by normal phase flash preparative column chromatography (petroleum ether:ethyl acetate = 95:5) to obtain 62mg of 4,4′-[(4-chlorophenyl)methylene]bis[2-(4-bromocinnamoyl)-5-hydroxy-6,6-diisopentenylcyclohex-4-ene-1,3-dione] in a yield of 7.7%. The following reactions occur during this process:

[0082]

[0083] The structural characterization data of the product are: HRESIMS (m / z 973.3046[M+H] + ,calcd,973.3046); 1 H NMR (500 MHz, pyridine-d5) δ H :1.63(6H,s,2×CH3),1.69(6H,s,2×CH3),1.71(6H,s,2×CH3),1.72(6H,s,2×CH3),2.94(2H,m,-CH2CH=),3.06(2 H,m,-CH2CH=),3.16(4H,m,2×-CH2CH=),5.55(4H,s,4×=CHCH2),7.26(1H,s,-CH-),7.31(4H,d,J=8.0Hz,H-3″,H- 5″,H-3″″′,H-5″″′),7.46(2H,d,J=8.0Hz,H-3″″″,H-5″″″),7.54(4H,d,J=8.0Hz,H-2″,H-6″,H-2″″′,H-6″″′), 7.76(2H,d,J=8.0Hz,H-2″″″,H-6″″″),7.96(2H,d,J=16.0Hz,H-2′,H-2″″),8.99(2H,d,J=16.0Hz,H-3′,H-3″″). 13 C NMR (125MHz, chloroform-d)δ C:18.0(1×CH3),18.1(1×CH3),18.1(1×CH3),18.5(1×CH3),25.9(1×CH3),26.0(1×CH3),26.2(1×CH3),26. 3(1×CH3),34.8(-CH-),36.3(1×-CH2CH=),37.6(1×-CH2CH=),37.9(1×-CH2CH=),39.1(1×-CH2CH=),55.4( C-6″′),55.5(C-6),110.5(C-2″′),110.8(C-2),115.8(C-4″′),117.5(C-4),117.0(1×=CHCH2),117.3(1× =CHCH2),118.1(1×=CHCH2),118.8(1×=CHCH2),123.9(C-2″″),124.1(C-2′),128.3(C-3″″″,C-5″″″),128 .4(C-3″″′,C-5″″′),128.4(C-3″,C-5″),129.4(C-2″″″,C-6″″″),130.2(C-2″″′,C-6″″′),130.3(C-2″,C -6″),131.3(C-4″″″),133.5(C-1″″′),133.7(C-1″),135.7(C-4″″′),135.7(C-4″),135.9(1×-C=CH),136 .7(1×-C=CH),137.0(1×-C=CH),137.0(1×-C=CH),137.2(C-1″″″),144.3(C-3″″),144.5(C-3′),172.5(C- 5″′), 173.4(C-5), 187.1(C-1″″), 187.8(C-1′), 187.8(C-3″′), 188.6(C-3), 202.1(C-1″′), 202.2(C-1).

[0084] Example 3

[0085] The synthesis method of compound 3 comprises the following steps:

[0086] (1) Synthesis of 3,5-dihydroxy-2-acetyl-6,6-diisopentenylcyclohexa-2,4-dienone

[0087] The preparation method is the same as that of compound 1.

[0088] (2) Synthesis of 4,4′-(phenylmethylene)bis[2-(4-bromocinnamoyl)-5-hydroxy-6,6-diisopentenylcyclohex-4-ene-1,3-dione]

[0089] Dissolve 0.5g of potassium hydroxide in 1ml of water-1.5ml of ethanol solution, then add 0.5g of 3,5-dihydroxy-2-acetyl-6,6-diisopentenylcyclohexa-2,4-dienone and 3eq (0.5ml) of benzaldehyde. Stir and react at 55°C for 11h. Concentrate under reduced pressure at 45°C for 2h. Completion of the reaction is monitored by thin-layer chromatography. Quench with water, adjust the pH to neutral with dilute hydrochloric acid, and extract with ethyl acetate. The organic layer is washed with saturated sodium chloride solution and purified water, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness under reduced pressure. Finally, separate and purify using normal phase flash preparative column chromatography (petroleum ether:ethyl acetate = 95:5) to obtain 108mg of 4,4′-(phenylmethylene)bis[2-(4-bromocinnamoyl)-5-hydroxy-6,6-diisopentenylcyclohex-4-ene-1,3-dione] in a yield of 15.1%. The following reactions occur during this process:

[0090]

[0091] The structural characterization data of the product are: HRESIMS (m / z 871.4215[M+H] + ,calcd,871.4215); 1 H NMR (500 MHz, pyridine-d5) δ H :1.62(6H,s,2×CH3),1.72(18H,s,6×CH3),2.94(2H,m,-CH2CH=),3.06(2H,m,-CH2CH=),3.18(4H,m,2×-CH2CH=), 5.58(4H,s,4×=CHCH2),7.26(3H,t,J=8.0Hz,H-3″″″,4″″″,H-5″″″),7.28(4H,d,J=8.5Hz,H-3″,H-5″,H-3″″′,H- 5″″′),7.30(1H,s,-CH-),7.42(2H,t,J=8.5Hz,H-4″,H-4″″′),7.65(4H,d,J=8.5Hz,H-2″,H-6″,H-2″″′,H-6″″′) ,7.84(2H,d,J=8.0Hz,H-2″″″,H-6″″″),8.05(2H,d,J=16.0Hz,H-2′,H-2″″),9.05(2H,d,J=16.0Hz,H-3′,H-3″″). 13 C NMR (125MHz, chloroform-d)δ C:18.0(1×CH3),18.1(2×CH3),18.4(1×CH3),25.9(1×CH3),26.0(1×CH3),26.2(1×CH3),26.2(1×CH3),35 .2(-CH-),36.3(1×-CH2CH=),37.5(1×-CH2CH=),37.9(1×-CH2CH=),39.1(1×-CH2CH=),55.3(C-6″′),55 .4(C-6),110.6(C-2″′),110.9(C-2),116.2(C-4″′),117.8(C-4),117.2(1×=CHCH2),117.4(1×=CHCH2) ,118.2(1×=CHCH2),118.9(1×=CHCH2),123.5(C-2″″),123.6(C-2′),125.6(C-4″″″),126.9(C-2″″″,C-6 ″″″),127.0(C-4″″′),128.2(C-4″),129.0(C-2″″′,C-6″″′),129.1(C-2″,C-6″),129.1(C-3″″′,C-5″″ ′),129.2(C-3″,C-5″),131.0(C-3″″″,C-5″″″),135.5(C-1″″′),135.6(C-1″),135.1(1×-C=CH),135.2( 1×-C=CH),135.8(1×-C=CH),136.5(1×-C=CH),138.6(C-1″″″),145.8(C-3″″),145.9(C-3′),172.3(C-5 ″′),172.9(C-5),187.2(C-1″″),187.9(C-1′),187.9(C-3″′),188.8(C-3),202.1(C-1″′),202.2(C-1).

[0092] Example 4

[0093] The synthesis method of compound 4 comprises the following steps:

[0094] (1) Synthesis of 3,5-dihydroxy-2-acetyl-6,6-diisopentenylcyclohexa-2,4-dienone

[0095] The preparation method is the same as that of compound 1.

[0096] (2) Synthesis of 4,4′-[(4-methoxyphenyl)methylene]bis[2-(4-bromocinnamoyl)-5-hydroxy-6,6-diisopentenylcyclohex-4-ene-1,3-dione]

[0097] Dissolve 0.96g of potassium hydroxide in 2ml of water-3ml of ethanol solution, then add 0.96g of 3,5-dihydroxy-2-acetyl-6,6-diisopentenylcyclohexa-2,4-dienone and 3eq (1.15ml) of 4-methoxybenzaldehyde. Stir at 55°C for 11h, then concentrate under reduced pressure at 45°C for 2h. Completion of the reaction is monitored by thin-layer chromatography. The reaction is quenched with water, the pH is adjusted to neutral with dilute hydrochloric acid, and then extracted with ethyl acetate. The organic layer is washed with saturated sodium chloride solution and purified water, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness under reduced pressure. Finally, it is isolated and purified by normal phase flash preparative column chromatography (petroleum ether:ethyl acetate = 95:5) to obtain 287mg of 4,4′-[(4-methoxyphenyl)methylene]bis[2-(4-bromocinnamoyl)-5-hydroxy-6,6-diisopentenylcyclohex-4-ene-1,3-dione] in an 18.9% yield. The following reactions occur during this process:

[0098]

[0099] The structural characterization data of the product are: HRESIMS (m / z 963.4669[M+H] + ,calcd,963.4678); 1 H NMR (500 MHz, pyridine-d5) δ H :1.64(6H,s,2×CH3),1.71(6H,s,2×CH3),1.74(12H,s,4×CH3),2.98(2H,m,-CH2CH=),3.09(2H,m,-CH2CH=) ,3.20(4H,m,2×-CH2CH=),5.61(4H,s,4×=CHCH2),6.91(4H,d,J=8.5Hz,H-3″,H-5″,H-3″″′,H-5″″′),7.07(2 H,d,J=8.5Hz,H-3″″″,H-5″″″),7.32(1H,s,-CH-),7.62(4H,d,J=8.5Hz,H-2″,H-6″,H-2″″′,H-6″″′),7.78 (2H,d,J=8.5Hz,H-2″″″,H-6″″″),8.09(2H,d,J=16.0Hz,H-2′,H-2″″),9.02(2H,d,J=16.0Hz,H-3′,H-3″″).

[0100] 13 C NMR (125MHz, chloroform-d)δ C:18.0(1×CH3),18.1(1×CH3),18.1(1×CH3),18.4(1×CH3),25.9(1×CH3),26.0(1×CH3),26.2(1×CH3),26.2(1×C H3),34.5(-CH-),36.4(1×-CH2CH=),37.5(1×-CH2CH=),37.9(1×-CH2CH=),39.1(1×-CH2CH=),55.3(1×-OCH3), 55.3(1×-OCH3),55.4(1×-OCH3),55.6(C-6″′),55.6(C-6),110.2(C-2″′),110.6(C-2),113.4(C-4″′),113.6( C-4),114.5(C-2″″″,C-6″″″),114.6(C-3″″′,C-5″″′),114.6(C-3″,C-5″),117.3(1×=CHCH2),117.5(1×=CHCH2 ),118.4(1×=CHCH2),119.1(1×=CHCH2),121.0(C-2″″),121.0(C-2′),128.0(C-1″″′),128.1(C-1″),130.6(C- 1″″”),131.0(C-3″″″,C-5″″″),131.1(C-2″″′,C-6″″′),131.2(C-2″,C-6″),135.3(1×-C=CH),135.5(1×-C=CH ),135.7(1×-C=CH),136.4(1×-C=CH),145.9(C-3″″),146.0(C-3′),157.4(C-4″″″),162.2(C-4″,C-4″″′),172 .1(C-5″′),172.6(C-5),187.2(C-1″″),187.7(C-1′),187.7(C-3″′),188.8(C-3),202.1(C-1″′),202.2(C-1).

[0101] Example 5

[0102] The synthesis method of compound 5 comprises the following steps:

[0103] (1) Synthesis of 3,5-dihydroxy-2-acetyl-6,6-diisopentenylcyclohexa-2,4-dienone

[0104] The preparation method is the same as that of compound 1.

[0105] (2) Synthesis of 4,4′-[(4-methoxymethoxyphenyl)methylene]bis[2-(4-bromocinnamoyl)-5-hydroxy-6,6-diisopentenylcyclohex-4-ene-1,3-dione]

[0106] Take 0.5g of potassium hydroxide, add 1ml of water-1.5ml of ethanol solution to dissolve it, then add 0.5g of 3,5-dihydroxy-2-acetyl-6,6-diisopentenylcyclohexa-2,4-dienone and 3eq (0.82g) of 4-methoxymethoxybenzaldehyde, stir at 55℃ for 11h, concentrate under reduced pressure at 45℃ for 2h, and monitor the completion of the reaction by thin layer chromatography. The mixture was quenched with water, the pH was adjusted to neutral with dilute hydrochloric acid, and then extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, washed with pure water, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness under reduced pressure. Finally, the mixture was separated and purified by normal phase flash preparative column chromatography (petroleum ether: ethyl acetate = 95:5) to obtain 125 mg of 4,4′-[(4-methoxymethoxyphenyl)methylene]bis[2-(4-bromocinnamoyl)-5-hydroxy-6,6-diisopentenylcyclohex-4-ene-1,3-dione] with a yield of 14.4%. The following reactions occurred in this process:

[0107]

[0108] The structural characterization data of the product are: HRESIMS (m / z 1053.4979[M+H] + ,calcd,1053.4995); 1 HNMR (500MHz, pyridine-d5)δ H:1.63(6H,s,2×CH3),1.70(6H,s,2×CH3),1.73(12H,s,4×CH3),2.96(2H,m,-CH2CH=),3.08(2H,m,-CH2CH=),3.18(4H,m,2×-CH2CH=),3.36(6H,s,2×-OCH3),3.40(3H,s,1×-OCH3),5.20(4H,s,2×-OCH2O-),5.22(2H,s,1×-OCH2O-),5.60(4H,s,4×=CHCH2),7.11(4H,d,J=8.5Hz,H-3″,H-5″,H-3″″′,H-5″″′),7.27(2H,d,J=8.5Hz,H-3″″″,H-5″″″),7.30(1H,s,-CH-),7.63(4H,d,J=8.5Hz,H-2″,H-6″,H-2″″′,H-6″″′),7.79(2H,d,J=8.5Hz,H-2″″″,H-6″″″),8.08(2H,d,J=16.0Hz,H-2′,H-2″″),9.01(2H,d,J=16.0Hz,H-3′,H-3″″).

[0109] 13 C NMR(125MHz,chloroform-d)δ C:18.0(1×CH3),18.1(1×CH3),18.1(1×CH3),18.4(1×CH3),25.9(1×CH3),26.0(1×CH3),26.2(1×CH3),26. 2(1×CH3),34.6(-CH-),36.4(1×-CH2CH=),37.5(1×-CH2CH=),37.9(1×-CH2CH=),39.1(1×-CH2CH=),55.3( C-6″′),55.4(C-6),110.3(C-2″′),110.6(C-2),115.9(C-2″″″,C-6″″″),116.4(C-4″′),116.6(C-3″″′,C -5″″′),116.7(C-3″,C-5″),117.3(1×=CHCH2),117.5(1×=CHCH2),117.9(C-4),118.3(1×=CHCH2),119.0( 1×=CHCH2),121.5(C-2″″),121.5(C-2′),128.1(C-1″″″),129.0(C-1″″′),129.1(C-1″),130.9(C-3″″″,C -5″″”),131.0(C-2″″′,C-6″″′),131.1(C-2″,C-6″),135.4(1×-C=CH),135.5(1×-C=CH),135.7(1×-C=CH) ,136.4(1×-C=CH),145.7(C-3″″),145.8(C-3′),155.1(C-4″″″),159.7(C-4″″′),159.7(C-4″),172.1(C- 5″′), 173.2(C-5), 185.6(C-1″″), 187.7(C-1′), 187.7(C-3″′), 188.7(C-3), 202.1(C-1″′), 202.2(C-1).

[0110] Example 6

[0111] The synthesis method of compound 6 comprises the following steps:

[0112] (1) Synthesis of 3,5-dihydroxy-2-acetyl-6,6-diisopentenylcyclohexa-2,4-dienone

[0113] The preparation method is the same as that of compound 1.

[0114] (2) Synthesis of 4,4′-[(4-methoxymethoxyphenyl)methylene]bis[2-(4-bromocinnamoyl)-5-hydroxy-6,6-diisopentenylcyclohex-4-ene-1,3-dione]

[0115] The preparation method is the same as compound 5.

[0116] (2) Synthesis of 4,4′-[(4-hydroxyphenyl)methylene]bis[2-(4-bromocinnamoyl)-5-hydroxy-6,6-diisopentenylcyclohex-4-ene-1,3-dione]

[0117] Take 100 mg of 4,4′-[(4-methoxymethoxyphenyl)methylene]bis[2-(4-bromocinnamoyl)-5-hydroxy-6,6-diisopentenylcyclohex-4-ene-1,3-dione], add 4 mL of methanol and 2 mL of ethyl acetate to dissolve, then add 2 eq 36 mg of p-toluenesulfonic acid hydrate, stir at room temperature for 3 days, and monitor the completion of the reaction by thin layer chromatography. The product was quenched with water and extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution and purified water, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness under reduced pressure. The product was then separated and purified by normal phase rapid preparative column chromatography (petroleum ether: ethyl acetate = 80:20). Finally, 63 mg of 4,4′-[(4-hydroxyphenyl)methylene]bis[2-(4-bromocinnamoyl)-5-hydroxy-6,6-diisopentenylcyclohex-4-ene-1,3-dione] was obtained by high performance liquid phase semi-preparative column chromatography (methanol: water = 95:5). The yield was 72.0%. The following reactions occurred during the process:

[0118]

[0119] The structural characterization data of the product are: HRESIMS (m / z 921.4200[M+H] + ,calcd,921.4208); 1 H NMR (500 MHz, pyridine-d5) δ H :1.63(12H,s,4×CH3),1.71(6H,s,2×CH3),1.74(6H,s,2×CH3),2.98(2H,m,-CH2CH=),3.09(2H,m,-CH2 CH=),3.20(4H,m,2×-CH2CH=),5.62(4H,s,4×=CHCH2),7.09(4H,d,J=8.5Hz,H-3″,H-5″,H-3″″′,H-5″″′ ),7.22(2H,m,H-3″″″,H-5″″″),7.34(1H,s,-CH-),7.65(4H,d,J=8.5Hz,H-2″,H-6″,H-2″″′,H-6″″′), 7.76(2H,m,H-2″″″,H-6″″″),8.14(2H,d,J=16.0Hz,H-2′,H-2″″),9.04(2H,d,J=16.0Hz,H-3′,H-3″″).

[0120] 13 C NMR (125MHz, methanol-d4)δ C :18.3(2×CH3),18.4(2×CH3),25.9(2×CH3),26.3(2×CH3),33.3(-CH-),38.5(2×-CH2CH=),39.9(2×-CH2CH=),58.3(C-6,C-6″′ ),108.2(C-2,C-2″′),113.1(C-4,C-4″′),115.3(C-3″,C-5″,C-3″″′,C-5″″′,C-3″″″,C-5″″”),119.7(4×=CHCH2),121.0(C-2′ ,C-2″″),121.8(C-1″″″),124.5(C-1″,C-1″″′),129.5(C-2″,C-6″,C-2″″′,C-6″″′,C-2″″″,C-6″″”),131.6(4×-C=CH),133.9( C-3′, C-3″″), 155.1 (C-4″, C-4″″′, C-4″″″), 170.0 (C-5, C-5″′), 187.2 (C-1′, C-1″″), 189.0 (C-3, C-3″′), 201.1 (C-1, C-1″′).

[0121] Example 7

[0122] The synthesis method of compound 7 comprises the following steps:

[0123] (1) Synthesis of 3,5-dihydroxy-2-acetyl-6,6-diisopentenylcyclohexa-2,4-dienone

[0124] The preparation method is the same as that of compound 1.

[0125] (2) Synthesis of 2-(4-methoxymethoxycinnamoyl)-5-hydroxy-6,6-diisopentenylcyclohex-4-ene-1,3-dione

[0126] Dissolve 1g of potassium hydroxide in 2ml of water-3ml of ethanol solution, then add 1g of 3,5-dihydroxy-2-acetyl-6,6-diisopentenylcyclohexa-2,4-dienone and 1.2eq (655mg) of 4-methoxymethoxybenzaldehyde. Stir at 55°C for 10h. Completion of the reaction is monitored by HPLC. The mixture is quenched with water, the pH is adjusted to neutral with dilute hydrochloric acid, and then extracted with ethyl acetate. The organic layer is washed with saturated sodium chloride solution and purified water, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness under reduced pressure. Finally, 637mg of 2-(4-methoxymethoxycinnamoyl)-5-hydroxy-6,6-diisopentenylcyclohex-4-ene-1,3-dione is isolated and purified using normal phase flash preparative column chromatography (petroleum ether:ethyl acetate = 91:9) with a yield of 42.8%. The following reactions occur during this process:

[0127]

[0128] The structural characterization data of the product are: HRESIMS (m / z 453.2269[M+H] + ,calcd,453.2272); 1 H NMR (500 MHz, DMSO-d6) δ H :1.53(12H,s,4×CH3),2.47(2H,m,-CH2CH=),2.58(2H,m,-CH2CH=),3.39(3H, s,OCH3),4.80(2H,t,J=7.5Hz,2×=CHCH2),5.26(2H,s,-OCH2O),5.60(1H,s,H -4),7.11(2H,d,J=8.5Hz,H-3″,H-5″),7.64(2H,d,J=8.5Hz,H-2″,H-6″),7.8 0(1H,d,J=16.0Hz,H-2′),8.14(1H,d,J=16.0Hz,H-3′),18.99(1H,s,1′-OH).

[0129] 13 C NMR (125 MHz, DMSO-d6) δ C:17.8(2×CH3),25.7(2×CH3),37.0(2×-CH2CH=),55.8(OCH3),57.5(C-4),9 3.7(-OCH2O),100.1(C-6),107.0(C-2),116.6(C-3″,C-5″),118.3(2×=CHCH 2),121.2(C-2′),128.4(C-1″),130.3(C-2″,C-6″),134.1(2×-C=CH),143.3 (C-3′),158.9(C-4″),179.5(C-5),185.5(C-1′),190.9(C-1),196.3(C-3).

[0130] (3) Synthesis of 2-(4-hydroxycinnamoyl)-5-hydroxy-6,6-diisopentenylcyclohex-4-ene-1,3-dione

[0131] 637 mg of 2-(4-methoxymethoxycinnamoyl)-5-hydroxy-6,6-diisopentenylcyclohex-4-ene-1,3-dione was added to 268 mg of 1 eq of p-toluenesulfonic acid hydrate and dissolved in 15 mL of methanol. The mixture was stirred at room temperature for 1 day, and the reaction was monitored for completion by thin-layer chromatography. The mixture was quenched with water and extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution and purified water, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness under reduced pressure. Finally, 330 mg of 2-(4-hydroxycinnamoyl)-5-hydroxy-6,6-diisopentenylcyclohex-4-ene-1,3-dione was isolated and purified using normal phase flash preparative column chromatography (petroleum ether:ethyl acetate = 75:25) with a yield of 57.4%. The following reactions occurred during this process:

[0132]

[0133] The structural characterization data of the product are: HRESIMS (m / z 409.2001[M+H] + ,calcd,409.2010); 1 H NMR (500 MHz, DMSO-d6) δ H:1.52(12H,s,4×CH3),2.46(2H,m,-CH2CH=),2.56(2H,m,-CH2CH=),4.80(2H,t,J=7.5Hz,2×=CHCH2),5.55(1H,s,H-4),6.85(2H,d,J=8 .5Hz,H-3″,H-5″),7.54(2H,d,J=8.5Hz,H-2″,H-6″),7.75(1H,d,J=16.0Hz,H-2′),8.10(1H,d,J=16.0Hz,H-3′),18.97(1H,s,1′-OH).

[0134] (4) Synthesis of 4,4′-(phenylmethylene)bis[2-(4-bromocinnamoyl)-5-hydroxy-6,6-diisopentenylcyclohex-4-ene-1,3-dione]

[0135] 1.82 g of 2-(4-hydroxycinnamoyl)-5-hydroxy-6,6-diisopentenylcyclohex-4-ene-1,3-dione was dissolved in 100 mL of acetic acid, followed by the addition of 3 eq (1.36 mL) of benzaldehyde. The mixture was stirred at room temperature for 3 days, and the reaction was monitored for completion by thin-layer chromatography. The mixture was quenched with water and extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution and purified water, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness under reduced pressure. Finally, it was isolated and purified by normal phase flash preparative column chromatography (petroleum ether:ethyl acetate = 84:16) to obtain 555 mg of 4,4′-(phenylmethylene)bis[2-(4-bromocinnamoyl)-5-hydroxy-6,6-diisopentenylcyclohex-4-ene-1,3-dione] in a yield of 27.6%. The following reactions occurred during this process:

[0136]

[0137] The structural characterization data of the product are: HRESIMS (m / z 903.4128[M+H] + ,calcd,903.4114); 1 H NMR (500 MHz, pyridine-d5) δ H: 1.64 (6H, s, 2×CH3), 1.71 (6H, s, 2×CH3), 1.74 (12H, s, 4×CH3), 2.96 (2H, m, -CH2CH=), 3.08 (2H, m, -CH2CH=), 3.19 (4H, m, 2×-CH2CH=), 5.61 (4H, s, 4×=CHCH2), 7.11 (4H, d, J = 8.5 Hz, H-3″, H-5″, H-3″″′, H-5″″′), 7.37 (1H, s, -CH-), 7.41 (3H, t, J = 7.5 Hz, H-3″″″, H-4″″″, H-5″″″), 7.66 (4H, d, J = 8.5 Hz, H-2″, H-6″, H-2″″′, H-6″″′), 7.86 (2H, d, J = 7.5 Hz, H-2″″″, H-6″″″), 8.14 (2H, d, J = 15.5 Hz, H-2′, H-2″″), 9.03 (2H, d, J = 15.5 Hz, H-3′, H-3″″).

[0138] 13 C NMR (125 MHz, methanol-d4) δ C : 18.2 (2×CH3), 18.3 (2×CH3), 26.3 (4×CH3), 36.2 (-CH-), 37.6 (1×-CH 2CH=), 38.7 (2×-CH2CH=), 40.0 (1×-CH2CH=), 56.6 (C-6″′), 59.6 (C-6), 109.2 (C-2, C-2″′), 111.0 (C-4″′), 111.4 (C-4), 117.1 (4×=CHCH 2), 118.5 (C-3″″′, C-5″″′), 118.8 (C-3″, C-5″), 119.5 (C-2″″), 120.1 (C-2′), 126. 5 (C-4″″″), 126.8 (C-2″″″, C-6″″″), 128.1 (C-1″, C-1″″′), 128.1 (C-3″″″, C-5″″″), 129.0 (C-2″″′, C-6″″′), 129.2 (C-2″, C-6″), 132.4 (4×-C=CH), 136.3 (C-1″″″), 148.1 (C-3″″), 148.1 (C-3′), 162.3 (C-4″, C-4″″′), 172.5 (C-5″′), 173.3 (C-5), 187.9 (C-1″″), 187.9 (C-1′), 188.6 (C-3″′), 1 89.8 (C-3), 199.3 (C-1″′), 203.3 (C-1).

[0139] Pharmacological experiments

[0140] Experimental Example 1 In vitro screening model: Screening of compounds for in vitro proliferation inhibition activity against human glioma cells

[0141] 1 Materials and Methods

[0142] 1.1 Materials

[0143] Human glioma cells (U87) and culture medium MEM (NEAA) + 10% FBS + 1% P / S were products of Wuhan Pronos Life Science Technology Co., Ltd.; Alamar blue reagent (C7084) was purchased from Bioss.

[0144] 1.2 Methods

[0145] Cells were evenly plated in a 96-well plate at a density of 2000 cells per well. The test compound was then added at the appropriate concentration. After 24 hours, Alamar Blue detection reagent was added. After a 4-hour reaction, the fluorescence intensity at 530 nm and 590 nm was measured using a microplate reader. Cell viability was calculated by subtracting the background value. The inhibition curve was plotted using GraphPad with the log10 of the drug concentration as the horizontal axis and the cell viability as the vertical axis, and the corresponding IC was calculated. 50 value.

[0146] 2 Results

[0147] Table 4 Inhibitory effect of compounds on proliferation of human glioma cells cultured in vitro

[0148]

Claims

1. A compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, characterized in that: Among them, (1) R A 1, 2, or 3 arbitrary monosubstituted, disubstituted, or polysubstituted groups on the benzene ring, The R A When it is a single substituent, its position is as shown in R1: The R A When it is a disubstituted group, its position is as shown in R2 and R3: The R A When there are three substituents, their positions are as shown in R4, R5, and R6: wherein R1, R2, R3, R4, R5, and R6 are each independently selected from the group consisting of hydrogen, hydroxy, methoxy, methyl, methoxymethoxy, bromine, and chlorine; (2)R B Selected from general formula (II) Among them, R C is one or two arbitrary single or multiple substituents on the benzene ring, The R C When it is a single substituent, its position is as shown in R7: The R C When it is a disubstituted group, its position is as shown in R8 and R9: Wherein, R7, R8, and R9 are independently selected from the group consisting of hydrogen, hydroxy, methoxy, methoxymethoxy, bromine, and chlorine.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that The compound is selected from the following compounds:

3. A pharmaceutical composition, characterized in that Contains an effective dose of the compound according to any one of claims 1 to 2 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

4. The pharmaceutical composition according to claim 3, characterized in that The dosage form of the composition is selected from tablets, capsules, pills, granules, oral solutions and suspensions.

5. Use of the compound according to any one of claims 1 to 2 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating tumor diseases.

6. Use according to claim 5, characterized in that The tumor disease is selected from glioblastoma, melanoma, gastric cancer, lung cancer, breast cancer, kidney cancer, liver cancer, cervical cancer, and ovarian cancer.

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