A class of magnolol derivatives, their preparation methods and applications

Abstract

This invention discloses a class of magnolol derivatives or pharmaceutically acceptable salts thereof with structures as shown in formulas VI and V, where R is selected from H and R' is selected from C1-C4 alkyl groups. Experiments have shown that, compared with magnolol, the magnolol derivatives or pharmaceutically acceptable salts of this invention exhibit enhanced anti-hepatocellular carcinoma activity and can significantly inhibit the migration of hepatocellular carcinoma cells. This invention also discloses the application of the magnolol derivatives or pharmaceutically acceptable salts thereof in the preparation of drugs for treating hepatocellular carcinoma.

Description

Technical Field

[0001] This invention belongs to the field of medicinal chemistry, specifically relating to a class of magnolol derivatives and their preparation methods, as well as their application in the preparation of antitumor drugs, particularly in the preparation of drugs that inhibit the proliferation and metastasis of liver cancer cells. Background Technology

[0002] As one of the most serious cancer diseases in the world, liver cancer has become a major challenge to human public health due to its high incidence and mortality rates. Although surgical resection of the lesion can cure early-stage liver cancer, most patients are diagnosed with liver cancer at an advanced stage because the disease is characterized by early metastasis and late onset of clinical symptoms, missing the optimal time for surgery and the tumor already having metastasized.

[0003] Sorafenib, as a first-line anti-liver cancer drug, can slow tumor progression by reducing tumor angiogenesis and promoting tumor cell apoptosis. However, long-term use of sorafenib can lead to drug resistance and serious adverse reactions, making the overall treatment effect unsatisfactory. Therefore, the development of novel anti-liver cancer drugs is imperative.

[0004] Magnolia officinalis, the main active ingredient of the traditional Chinese medicine Magnolia officinalis, has been proven to have therapeutic effects on various tumors. In vitro activity studies have shown that it has the strongest inhibitory effect on liver cancer cell lines and can inhibit liver cancer metastasis. Magnolia officinalis resources are widely distributed in my country, making magnolia officinalis raw material inexpensive and readily available. Therefore, developing novel anti-liver cancer drugs based on magnolia officinalis has a significant advantage. Summary of the Invention

[0005] The purpose of this invention is to address the shortcomings of existing technologies by providing a class of magnolol derivatives and their application in the treatment of liver cancer.

[0006] The objective of this invention is achieved through the following technical solution:

[0007] A class of magnolol derivatives or their pharmaceutically acceptable salts with structures as shown in formulas VI and V that have medicinal uses:

[0008] Where R is selected from

[0009] R1 is selected from H, halogen, cyano (CN), C1-C4 alkyl, C1-C4 alkoxy, halogen-substituted C1-C4 alkyl, and m is an integer from 1 to 3;

[0010] X is selected from oxygen or sulfur atom, and R2 is selected from H, halogen, C1-C4 alkyl, C1-C4 alkoxy;

[0011] R3 is selected from H, halogens, C1-C4 alkyl groups, and C1-C4 alkoxy groups;

[0012] R4 is selected from H, halogen, C1-C4 alkyl, C1-C4 alkoxy, n is an integer from 1 to 3, or R4 and benzene ring together form a 5-membered heterocycle containing two oxygen atoms;

[0013] R' is selected from H and C1-C4 alkyl groups.

[0014] Preferably, R1 is selected from H, F, Cl, cyano, methyl, methoxy, trifluoromethyl, and m is an integer from 1 to 3;

[0015] X is selected from oxygen or sulfur atoms, and R2 is selected from H or Cl.

[0016] R3 is selected from H, F, Cl, methyl, and methoxy.

[0017] R4 is selected from H, F, Cl, methyl, methoxy, and n is an integer from 1 to 3, or R4 and the benzene ring together form a 5-membered heterocycle containing two oxygen atoms;

[0018] R' is selected from H, methyl, or ethyl.

[0019] More preferably, m = 1, R1 is selected from H, para-substituted F, Cl, cyano, methyl, methoxy, trifluoromethyl; m = 3, R1 is selected from 3,4,5-trimethoxy;

[0020] X is selected from oxygen or sulfur atoms, and R2 is selected from H or Cl.

[0021] R3 is selected from H, F, Cl, methyl, and methoxy.

[0022] Selected from

[0023] R' is selected from H, methyl, or ethyl.

[0024] As one preferred embodiment of the present invention, a magnolol derivative or a pharmaceutically acceptable salt thereof with the structure shown in Formula I is used.

[0025]

[0026] R1 and m are as described above.

[0027] As a preferred embodiment of the present invention, a magnolol derivative or a pharmaceutically acceptable salt thereof with the structure shown in Formula II is used.

[0028]

[0029] X and R2 are as described above.

[0030] As one preferred embodiment of the present invention, a magnolol derivative or a pharmaceutically acceptable salt thereof with the structure shown in Formula III is used.

[0031]

[0032] R3 is as described above.

[0033] As one preferred embodiment of the present invention, a magnolol derivative or a pharmaceutically acceptable salt thereof with the structure shown in Formula IV is used.

[0034]

[0035] R4 and n are as described above.

[0036] The halogens described in this invention are fluorine, chlorine, bromine, and iodine; the C1-C4 alkyl groups are selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and tert-butyl; the C1-C4 alkoxy groups are selected from methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, and tert-butoxy; the halogen-substituted C1-C4 alkyl groups may be those in which at least one hydrogen atom is replaced by at least one halogen selected from fluorine, chlorine, bromine, and iodine.

[0037] Specifically, the magnolol derivatives described in this invention are selected from compounds with the following structures:

[0038]

[0039]

[0040]

[0041] The chemical names of the above magnolol derivatives are as follows:

[0042] (4-(5,5'-diallyl-2,2'-dihydroxy-[1,1'-biphenyl]-3-methyl)piperazin-1-yl)(thiophen-2-yl)methyl ketone (compound II 1);

[0043] (4-(5,5'-diallyl-2,2'-dihydroxy-[1,1'-biphenyl]-3-methyl)piperazin-1-yl)(furan-2-yl)methyl ketone (compound II 2);

[0044] (5-Chlorothiophene-2-yl)(4-(5,5'-diallyl-2,2'-dihydroxy-[1,1'-biphenyl]-3-yl)methyl)piperazin-1-yl)methyl ketone (compound II 3);

[0045] (4-(5,5'-diallyl-2,2'-dihydroxy-[1,1'-biphenyl]-3-methyl)piperazin-1-yl)(phenyl)methyl ketone (compound I1);

[0046] (4-(5,5'-diallyl-2,2'-dihydroxy-[1,1'-biphenyl]-3-methyl)piperazin-1-yl)(4-fluorophenyl)methyl ketone (compound I2);

[0047] (4-(5,5'-diallyl-2,2'-dihydroxy-[1,1'-biphenyl]-3-methyl)piperazin-1-yl)(3,4,5-trimethoxyphenyl)methyl ketone (compound I3);

[0048] (4-(5,5'-diallyl-2,2'-dihydroxy-[1,1'-biphenyl]-3-methyl)piperazin-1-yl)(4-(trifluoromethyl)phenyl)methyl ketone (compound I4);

[0049] 4-(4-(5,5'-diallyl-2,2'-dihydroxy-[1,1'-biphenyl]-3-yl)methyl)piperazine-1-carbonyl)benzonitrile (compound I 5);

[0050] (4-Chlorophenyl)(4-(5,5'-diallyl-2,2'-dihydroxy-[1,1'-biphenyl]-3-yl)methyl)piperazin-1-yl)methyl ketone (compound I6);

[0051] (4-(5,5'-diallyl-2,2'-dihydroxy-[1,1'-biphenyl]-3-methyl)piperazin-1-yl)(p-tolyl)methyl ketone (compound I7);

[0052] (4-(5,5'-diallyl-2,2'-dihydroxy-[1,1'-biphenyl]-3-methyl)piperazin-1-yl)(4-methoxyphenyl)methyl ketone (compound I8);

[0053] (E)-1-(4-((5,5'-diallyl-2,2'-dihydroxy-[1,1'-biphenyl]-3-methyl)piperazin-1-yl)-3-phenylpropyl-2-en-1-one (compound III1);

[0054] (E)-1-(4-((5,5'-diallyl-2,2'-dihydroxy-[1,1'-biphenyl]-3-methyl)piperazin-1-yl)-3-(4-fluorophenyl)malondialdehyde-2-en-1-one (compound III2);

[0055] Ethyl 6-allyl-8-(5-allyl-2-hydroxyphenyl)-2-oxo-2H-chromene-3-carboxylic acid (compound V1);

[0056] 6-Allyl-8-(5-Allyl-2-hydroxyphenyl)-2-oxo-2H-chromene-3-carboxylic acid (compound V2);

[0057] 5,5'-Diallyl-3-((benzylamino)methyl)-[1,1'-biphenyl]-2,2'-diol (compound IV 1);

[0058] 5,5'-Diallyl-3-((3,4-dichlorobenzyl)amino)-[1,1'-biphenyl]-2,2'-diol (compound IV 2);

[0059] 5,5'-diallyl-3-((3,4,5-trimethoxybenzyl)amino)-[1,1'-biphenyl]-2,2'-diol (compound IV 3);

[0060] 5,5'-Diallyl-3-((3,4-difluorobenzyl)amino)-[1,1'-biphenyl]-2,2'-diol (compound IV 4);

[0061] 5,5'-Diallyl-3-((4-chlorobenzyl)amino)-[1,1'-biphenyl]-2,2'-diol (compound IV 5);

[0062] 5,5'-Diallyl-3-((4-fluorobenzyl)amino)-[1,1'-biphenyl]-2,2'-diol (compound IV 6);

[0063] 5,5'-Diallyl-3-((3,4-dimethoxybenzyl)amino)-[1,1'-biphenyl]-2,2'-diol (compound IV 7);

[0064] 5,5'-Diallyl-3-(((benzo[d][1,3]dioxol-5-methyl)amino)methyl)-[1,1'-biphenyl]-2,2'-diol (compound IV 8);

[0065] 5,5'-diallyl-3-((3,4-dimethylbenzyl)amino)-[1,1'-biphenyl]-2,2'-diol (compound IV 9).

[0066] Pharmaceutically acceptable salts of the magnolol derivatives include hydrochloride, citrate, and maleate.

[0067] Another object of the present invention is to provide a method for preparing magnolol derivatives with structures as shown in Formula VI, wherein R is selected from... At that time, the synthesis route is as follows:

[0068]

[0069] Wherein, "R" is selected from R1, m, X, R2, and R3 are as described above;

[0070] When R is selected At that time, the synthesis route is as follows:

[0071]

[0072] R4 and n are as described above.

[0073] When R is selected The preparation method of magnolol derivatives includes the following steps:

[0074] Step (1): Using THF as the reaction solvent and magnolol as the starting material, magnolol, paraformaldehyde, triethylamine, and anhydrous magnesium chloride are dissolved in the reaction solvent and refluxed under argon or nitrogen protection to obtain intermediate 1; at room temperature, intermediate 1 is reduced by sodium borohydride to obtain intermediate 2; using anhydrous dichloromethane as the solvent, intermediate 2 reacts with thionyl chloride under argon or nitrogen protection to obtain intermediate 3.

[0075] The molar ratio of magnolol to paraformaldehyde is 1:5 to 1:10, preferably 1:5; the molar ratio of magnolol to triethylamine is 1:0.5 to 1:1.01; the molar ratio of magnolol to anhydrous magnesium chloride is 1:3 to 1:9, preferably 1:3; the molar ratio of intermediate 1 to sodium borohydride is 1:4.5 to 1:5, preferably 1:5; and the molar ratio of intermediate 2 to thionyl chloride is 1:4.5 to 1:5, preferably 1:5.

[0076] Step (2): Anhydrous dichloromethane is used as the reaction solvent, with the structure shown in the formula. The substituted or unsubstituted benzoic acid shown reacts with thionyl chloride under reflux to give a structure as shown in the formula. Intermediate 4a is shown; using anhydrous acetonitrile as the reaction solvent and anhydrous potassium carbonate as the acid-binding agent, N-boc piperazine reacts with intermediate 4a at room temperature to obtain the structure shown in the formula. Intermediate 5a, as shown, was reacted at room temperature with dichloromethane as the reaction solvent in the presence of trifluoroacetic acid to remove the BOC protecting group, yielding intermediate 6a.

[0077] Wherein, the molar ratio of substituted or unsubstituted benzoic acid to thionyl chloride is 1:5 to 1:9; the molar ratio of intermediate 4a to anhydrous potassium carbonate is 1:0.5 to 1:5; the molar ratio of intermediate 4a to N-boc piperazine is 1:1 to 1:2; and the volume ratio of dichloromethane to trifluoroacetic acid is 3:1.

[0078] Step (3): Using acetonitrile as the reaction solvent, in the presence of cesium carbonate, at room temperature, intermediate 3 reacts with intermediate 6a to obtain magnolol derivative;

[0079] The molar ratio of intermediate 3 to intermediate 6a is 1:2 to 1:5; the molar ratio of intermediate 3 to cesium carbonate is 1:5.

[0080] When R is selected The preparation method of magnolol derivatives includes the following steps:

[0081] Step (1): Preparation of intermediate 3;

[0082] Step (2): Using anhydrous dichloromethane as a solvent, the structure is shown in the formula. The reaction with thionyl chloride under reflux yields a structure as shown in the formula. Intermediate 4b is shown; using anhydrous acetonitrile as the reaction solvent and anhydrous potassium carbonate as the acid-binding agent, N-boc piperazine reacts with intermediate 4b at room temperature to give the structure shown in the formula. Intermediate 5b, as shown, was reacted at room temperature with dichloromethane as the reaction solvent in the presence of trifluoroacetic acid to remove the boc protecting group, yielding the structure shown in the formula. Intermediate 6b;

[0083] Among them, the aforementioned The molar ratio of intermediate 4b to thionyl chloride is 1:2.5 to 1:5; the molar ratio of intermediate 4b to anhydrous potassium carbonate is 1:0.3 to 1:1.5; the molar ratio of intermediate 4b to N-boc piperazine is 1:1 to 1:2; and the volume ratio of dichloromethane to trifluoroacetic acid is 3:1.

[0084] Step (3): Using acetonitrile as the reaction solvent, in the presence of cesium carbonate, at room temperature, intermediate 3 reacts with intermediate 6b to obtain magnolol derivative;

[0085] The molar ratio of intermediate 3 to intermediate 6b is 1:2 to 1:5; the molar ratio of intermediate 3 to cesium carbonate is 1:5.

[0086] When R is selected The preparation method of magnolol derivatives includes the following steps:

[0087] Step (1): Preparation of intermediate 3;

[0088] Step (2): Anhydrous dichloromethane is used as the reaction solvent, with the structure shown in the formula. The reaction with thionyl chloride under reflux yields the structure shown in the formula. Intermediate 4c is shown; using anhydrous acetonitrile as the reaction solvent and anhydrous potassium carbonate as the acid-binding agent, N-boc piperazine reacts with intermediate 4c at room temperature to give the structure shown in the formula. Intermediate 5c, as shown, was reacted at room temperature with dichloromethane as the reaction solvent in the presence of trifluoroacetic acid to remove the boc protecting group, yielding the structure shown in the formula. The intermediate 6c shown;

[0089] Among them, the aforementioned The molar ratio of intermediate 4c to thionyl chloride is 1:6 to 1:7; the molar ratio of intermediate 4c to anhydrous potassium carbonate is 1:1 to 1:2.5; the molar ratio of intermediate 4b to N-boc piperazine is 1:1 to 1:2; and the volume ratio of dichloromethane to trifluoroacetic acid is 3:1.

[0090] Step (3): Using acetonitrile as the reaction solvent, in the presence of cesium carbonate, at room temperature, intermediate 3 reacts with intermediate 6c to obtain magnolol derivative;

[0091] The molar ratio of intermediate 3 to intermediate 6c is 1:2 to 1:5; the molar ratio of intermediate 3 to cesium carbonate is 1:5.

[0092] When R is selected The preparation method of magnolol derivatives includes the following steps:

[0093] Step (1): Using THF as the reaction solvent and magnolol as the starting material, magnolol, paraformaldehyde, triethylamine, and anhydrous magnesium chloride are dissolved in the reaction solvent and refluxed under argon or nitrogen protection to obtain intermediate 1.

[0094] The molar ratio of magnolol to paraformaldehyde is 1:5 to 1:10, preferably 1:5; the molar ratio of magnolol to triethylamine is 1:0.5 to 1:1.01; and the molar ratio of magnolol to anhydrous magnesium chloride is 1:3 to 1:9, preferably 1:3.

[0095] Step (2): Using anhydrous dichloromethane as the reaction solvent, in the presence of anhydrous magnesium sulfate, at room temperature, intermediate 1 and the structure shown in the formula are reacted. The reaction was completed, and sodium borohydride was added for reduction to obtain magnolol derivatives.

[0096] Among them, intermediate 1 and The molar ratio of intermediate 1 to anhydrous magnesium sulfate is 1:5; the molar ratio of intermediate 1 to sodium borohydride is 1:2.

[0097] Another object of the present invention is to provide a method for preparing magnolol derivatives with structures as shown in Formula V, wherein when R' is selected from C1-C4 alkyl groups, the synthetic route is as follows:

[0098]

[0099] include:

[0100] Step (1): Using THF as the reaction solvent and magnolol as the starting material, magnolol, paraformaldehyde, triethylamine, and anhydrous magnesium chloride are dissolved in the reaction solvent and refluxed under argon or nitrogen protection to obtain intermediate 1.

[0101] The molar ratio of magnolol to paraformaldehyde is 1:5 to 1:10, preferably 1:5; the molar ratio of magnolol to triethylamine is 1:0.5 to 1:1.01; and the molar ratio of magnolol to anhydrous magnesium chloride is 1:3 to 1:9, preferably 1:3.

[0102] Step (2): Using anhydrous ethanol as the reaction solvent, intermediate 1 is refluxed with malonate diester in the presence of piperidine to obtain magnolol derivative.

[0103] Wherein, the molar ratio of intermediate 1 to dimalonate is 1:1 to 1:5, preferably 1:1.5; the dimalonate is selected from dimethyl malonate, diethyl malonate, di-n-propyl malonate, diisopropyl malonate, di-n-butyl malonate, diisobutyl malonate, and di-tert-butyl malonate; the molar ratio of intermediate 1 to piperidine is 1:1 to 1:1.5.

[0104] After the reaction was complete, ice water was added to the reaction solution, and the mixture was extracted 2-3 times with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and then evaporated to dryness to obtain the target compound.

[0105] When R' is selected from H, the synthesis route is:

[0106]

[0107] include:

[0108] Step (1): Using THF as the reaction solvent and magnolol as the starting material, magnolol, paraformaldehyde, triethylamine, and anhydrous magnesium chloride are dissolved in the reaction solvent and refluxed under argon or nitrogen protection to obtain intermediate 1.

[0109] Step (2): Using anhydrous ethanol as the reaction solvent, intermediate 1 is refluxed with diethyl malonate in the presence of piperidine to obtain ethyl 6-allyl-8-(5-allyl-2-hydroxyphenyl)-2-oxo-2H-chromene-3-carboxylate; ethyl 6-allyl-8-(5-allyl-2-hydroxyphenyl)-2-oxo-2H-chromene-3-carboxylate is dissolved in a 1% sodium hydroxide ethanol solution and refluxed at 85°C for 2-4 hours. 38% concentrated hydrochloric acid is added until the system becomes acidic to obtain the target compound.

[0110] Experiments have shown that, compared with magnolol, the magnolol derivatives or their pharmaceutically acceptable salts described in this invention have enhanced anti-hepatocellular carcinoma activity and can significantly inhibit the migration of hepatocellular carcinoma cells.

[0111] Therefore, another object of the present invention is to provide the use of the said magnolol derivative or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating liver cancer.

[0112] Preferably, the application is the use of the magnolol derivative or a pharmaceutically acceptable salt thereof in the preparation of a medicament for inhibiting the proliferation and / or migration of liver cancer cells.

[0113] Another object of the present invention is to provide a pharmaceutical composition which is any pharmaceutically acceptable dosage form made of the said magnolol derivative or a pharmaceutically acceptable salt thereof as the active ingredient and pharmaceutically acceptable excipients. Attached Figure Description

[0114] Figure 1 The results show the inhibitory effect of magnolol derivatives on the migration ability of HepG2 liver cancer cells. Detailed Implementation

[0115] The technical solution of the present invention will be further described below through specific embodiments.

[0116] Example 1

[0117] Synthesis of 5,5'-diallyl-2,2'-dihydroxy-[1,1'-biphenyl]-3-carboxaldehyde (intermediate 1)

[0118]

[0119] At room temperature, magnolol (5.0 g, 18.77 mmol) was dissolved in 25 mL of tetrahydrofuran, and paraformaldehyde (2.82 g, 93.86 mmol), anhydrous magnesium chloride (5.36 g, 56.32 mmol), and triethylamine (2.61 mL) were added. The mixture was stirred at room temperature for 15 min until completely dissolved, then purged with argon gas and refluxed at 70 °C for 12 h. The reaction was monitored by TLC until completion, and the reaction was quenched with ice water. The mixture was extracted three times with 30 mL of dichloromethane each time, and the organic layers were combined. The organic layer was dried with anhydrous sodium sulfate, and dichloromethane was removed under reduced pressure. The purified product was obtained by silica gel column chromatography with gradient elution using dichloromethane and methanol in a volume ratio of (100:1)–(50:1). The purified product was 2.79 g of yellow oil, with a yield of 50.49%, and was identified as intermediate 1.

[0120] 1 H NMR (300MHz, DMSO-d6) δ10.07(s,1H),7.55(d,J=2.3Hz,1H),7.34(d,J=2.3Hz,1H),7.01(dd,J=8.2,2.3Hz,1H),6.95(d, J=2.3Hz,1H),6.85(d,J=8.2Hz,1H),6.06-5.84(m,2H),5.20-4.96(m,4H),3.40(d,J=6.8Hz,2H),3.28(d,J=6.8Hz,2H); 13 CNMR(75MHz,Chloroform-d)δ197.28,155.77,152.21,140.02,137.79,136.62,133.27,132.80,1 32.77,131.23,130.07,127.65,124.48,120.60,118.25,116.90,115.83,39.46,38.98; HR-ESI-MS m / z calcd for C 19 H 18 O3[M+Na] + 317.1148, found 317.1192.

[0121] Example 2

[0122] Synthesis of 5,5'-diallyl-3-(hydroxymethyl)-[1,1'-biphenyl]-2,2'-diol (intermediate 2)

[0123]

[0124] Intermediate 1 (500 mg, 1.699 mmol) was dissolved in 15 mL of methanol, and sodium borohydride (321 mg, 8.493 mmol) was added. The reaction was carried out at room temperature for 10 h. After the reaction was completed by TLC monitoring, saturated sodium bicarbonate aqueous solution was added to quench the reaction. The mixture was extracted three times with dichloromethane, and the organic layers were combined. The organic layer was dried over anhydrous sodium sulfate, and the organic phase was collected and evaporated to dryness under reduced pressure. The mixture was purified by silica gel column chromatography with dichloromethane and methanol in a volume ratio of (50:1) to (20:1). The purified solid was 480 mg, with a yield of 95.35%, and was identified as intermediate 2.

[0125] 1 H NMR(300MHz,Chloroform-d)δ8.01(s,1H),7.24(s,1H),7.16-7.07(m,3H),7.00-6.87(m,2H),6. 13-5.84(m,2H),5.24-4.98(m,4H),4.79(s,2H),3.40(d,J=6.7Hz,2H),3.35(d,J=6.7Hz,2H); 13C NMR(75MHz,Chloroform-d)δ151.23,150.33,137.72,137.51,133.02,132.70,131.51,131.47,1 29.58,128.19,126.03,125.98,125.27,117.23,115.93,115.75,63.88,39.44,39.37; HR-ESI-MS m / z calcd for C 19 H 20 O3[M+Na] + 319.1305, found 319.1352.

[0126] Example 3

[0127] Synthesis of 5,5'-diallyl-3-(chloromethyl)-[1,1'-biphenyl]-2,2'-diol (intermediate 3)

[0128]

[0129] Intermediate 2 (200 mg, 0.675 mmol) was dissolved in 15 mL of anhydrous dichloromethane. Under argon protection, 245.05 μL of thionyl chloride was slowly added dropwise. The reaction was carried out at room temperature for 5 h, and the reaction was monitored by TLC. After the reaction was completed, ice water was added to quench the reaction. The mixture was extracted three times with dichloromethane, and the organic phases were combined. The organic phase was dried over anhydrous sodium sulfate and evaporated to dryness to obtain 200 mg of intermediate 3, a white oily liquid with a yield of 94.14%.

[0130] 1 H NMR(300MHz,Chloroform-d)δ8.05(s,1H),7.20(s,1H),7.17-7.07(m,3H),7.00-6.87(m,2H),6 .13-5.87(m,2H),5.24-4.98(m,4H),4.90(s,2H),3.40(d,J=6.7Hz,2H),3.35(d,J=6.7Hz,2H); 13 C NMR(75MHz,Chloroform-d)δ155.23,150.33,137.75,137.61,133.12,132.70,132.51,131.47,1 29.58,128.19,126.05,125.99,125.37,117.23,115.93,115.75,67.29,39.54,39.37; HR-ESI-MS m / z calcd for C 19 H 19 ClO2[M+Na] + 337.0966, found 337.0950.

[0131] Example 4

[0132] Synthesis of (4-(5,5'-diallyl-2,2'-dihydroxy-[1,1'-biphenyl]-3-methyl)piperazin-1-yl)(thiophen-2-yl)methyl ketone (compound II 1)

[0133] At room temperature, thiophene-2-carboxylic acid (100 mg, 0.78 mmol) was dissolved in 10 mL of anhydrous dichloromethane, and thionyl chloride (283 μL, 3.902 mmol) was added. The mixture was refluxed under argon protection for 6 h, and the reaction was monitored by TLC. After the reaction was complete, the solvent was evaporated to dryness to give 90 mg of 2-thiopheneformyl chloride, with a yield of 88.36%. At room temperature, 1-Boc-piperazine (200 mg, 1.074 mmol) and 2-thiopheneformyl chloride (68.143 mg, 1.07 mmol) were dissolved in 20 mL of anhydrous acetonitrile, and 50 mg of anhydrous potassium carbonate was added. The mixture was reacted at room temperature for 2 h. After the reaction was complete, the potassium carbonate was removed by filtration, and the solvent was evaporated to dryness to give 4-(thiophene-2-carbonyl)piperazine-1-carboxylic acid tert-butyl ester. 4-(thiophene-2-carbonyl)piperazine-1-carboxylic acid tert-butyl ester was dissolved in 15 mL of anhydrous dichloromethane, and 5 mL of trifluoroacetic acid was added. The reaction was carried out at room temperature for 4 h, and the reaction was monitored by TLC. After the reaction was completed, saturated sodium bicarbonate solution was added to quench the reaction until no more bubbles were generated. The product was extracted three times with dichloromethane, and the organic phases were combined and dried with anhydrous sodium sulfate. The organic phase was taken and evaporated to dryness to obtain 150 mg of piperazine-1-yl(thiophene-2-yl) methyl ketone, with a yield of 71.17%. The product did not require further purification and was directly used for the next reaction.

[0134] Intermediate 3 (200 mg, 0.635 mmol) was dissolved in 20 mL of anhydrous acetonitrile, and anhydrous cesium carbonate (1 g, 3.177 mmol) was added. Piperazin-1-yl(thiophen-2-yl) methyl ketone (200 mg, 1.271 mmol) was added under stirring. The reaction was carried out at room temperature for 9 h, and the reaction was monitored by TLC. After the reaction was completed, the solvent was evaporated, and silica gel column chromatography was performed with gradient elution using dichloromethane and methanol in a volume ratio of 100:1-30:1 to obtain compound II1, a pale yellow solid, 190 mg, with a yield of 63.01%, which was identified as (4-(5,5'-diallyl-2,2'-dihydroxy-[1,1'-biphenyl]-3-methyl)piperazin-1-yl)(thiophen-2-yl) methyl ketone.

[0135] 1H NMR(300MHz,Chloroform-d)δ7.49(dd,J=5.0,1.1Hz,1H),7.30(dd,J=3.7,1.2Hz,1H),7.19-7.11(m,3H),7.08-7.01(m,2H),6.89( 1 3CNMR(75MHz,Chloroform-d)δ163.59,152.40,151.32,137.94,137.51,136.41,132.56,132.27,131.74,131.13,129.38,129.17,1 29.09,128.40,126.86,126.50,126.29,120.31,118.45,115.90,115.53,61.46,53.49,52.44(2C),44.68,39.54,39.43; HR-ESI-MS m / z calcd for C 28 H 30 N₂O₃S[M+H] + 475.2050, found 475.2050.

[0136] Example 5

[0137] Synthesis of (4-(5,5'-diallyl-2,2'-dihydroxy-[1,1'-biphenyl]-3-methyl)piperazin-1-yl)(furan-2-yl)methyl ketone (compound II 2)

[0138] Referring to Example 4, thiophene-2-carboxylic acid was replaced with furan-2-carboxylic acid. At room temperature, furan-2-carboxylic acid (200 mg, 1.585 mmol) was dissolved in 10 mL of anhydrous dichloromethane, and thionyl chloride (283 μL, 3.902 mmol) was added. The mixture was refluxed under argon protection for 6 h, and the reaction was monitored by TLC. After the reaction was complete, the solvent was evaporated to dryness, yielding 190 mg of furan-2-carboxylic acid (91.84%). At room temperature, 1-Boc-piperazine (285 mg, 1.532 mmol) and furan-2-carboxylic acid (200 mg, 1.532 mmol) were dissolved in 20 mL of anhydrous acetonitrile, and 150 mg of anhydrous potassium carbonate was added. The mixture was reacted at room temperature for 2 h. After the reaction was complete, the potassium carbonate was removed by filtration, and the solvent was evaporated to dryness, yielding tert-butyl-4-(furan-2-carbonyl)piperazine-1-carboxylic acid ester. tert-butyl 4-(furan-2-carbonyl)piperazine-1-carboxylic acid ester was dissolved in 15 mL of anhydrous dichloromethane, and 5 mL of trifluoroacetic acid was added. The reaction was carried out at room temperature for 4 h, and the reaction was monitored by TLC. After the reaction was completed, saturated sodium bicarbonate solution was added to quench the reaction until no more bubbles were generated. The product was extracted three times with dichloromethane, dried over anhydrous sodium sulfate, and the organic phase was evaporated to dryness to obtain 193 mg of furan-2-yl(piperazine-1-yl) methyl ketone, with a yield of 69.90%. The product did not require further purification and was directly used for the next reaction.

[0139] Intermediate 3 (200 mg, 0.635 mmol) was dissolved in 20 mL of anhydrous acetonitrile, and anhydrous cesium carbonate (1.035 g, 3.177 mmol) was added. Furan-2-yl(piperazin-1-yl) methyl ketone (229 mg, 1.271 mmol) was added under stirring. The reaction was carried out at room temperature for 9 h, and the reaction was monitored by TLC. After the reaction was completed, the solvent was evaporated, and silica gel column chromatography was performed with gradient elution using dichloromethane and methanol in a volume ratio of 100:1-20:1 to purify compound II2, a white solid (190 mg, 0.414 mmol), with a yield of 65.22%. It was identified as (4-(5,5'-diallyl-2,2'-dihydroxy-[1,1'-biphenyl]-3-methyl)piperazin-1-yl)(furan-2-yl) methyl ketone.

[0140] 1H NMR(300MHz,Chloroform-d)δ7.70(dd,J=7.5,1.8Hz,1H),7.25(d,J=1.7Hz,1H),7 .18(dd,J=25.6,1.8Hz,2H),7.09(dd,J=7.0,1.8Hz,1H),7.03(dd,J=7.5,1.3Hz,1H ),6.86(d,J=7.5Hz,1H),6.54(t,J=7.7Hz,1H),6.08-5.89(m,2H),5.12-5.04(m,4 H),3.69-3.60(m,4H),3.41(d,J=6.5Hz,2H),3.39(d,J=6.5Hz,2H),2.79(brs,4H); 13 C NMR(75MHz,Chloroform-d)δ158.93,152.45,151.40,147.60,143.95,137.96,137.54,132.52,132.21,131.69,131.1 5,129.36,128.40,126.54,126.30,120.40,118.45,117.11,115.88,115.53,111.51,61.45,39.54,39.44; HR-ESI-MS m / z calcd for C 28 H 30 N₂O₄[M+H] + 459.2278, found 459.2269.

[0141] Example 6

[0142] Synthesis of (5-chlorothiophene-2-yl)(4-(5,5'-diallyl-2,2'-dihydroxy-[1,1'-biphenyl]-3-yl)methyl)piperazin-1-yl)methyl ketone (compound II 3)

[0143] Referring to Example 4, the starting material thiophene-2-carboxylic acid was replaced with 5-chlorothiophene-2-carboxylic acid. At room temperature, 200 mg (1.230 mmol) of 5-chlorothiophene-2-carboxylic acid was dissolved in 10 mL of anhydrous dichloromethane, and 283 μL (3.902 mmol) of thionyl chloride was added. The mixture was refluxed under argon protection for 6 h, and the reaction was monitored by TLC. After the reaction was complete, the solvent was evaporated to obtain 173 mg (0.956 mmol) of 5-chlorothiophene-2-carbonyl chloride, with a yield of 77.69%. At room temperature, 1-Boc-piperazine (103 mg, 0.552 mmol) and 5-chlorothiophene-2-carbonyl chloride (100 mg, 0.552 mmol) were dissolved in 20 mL of anhydrous acetonitrile. 100 mg of anhydrous potassium carbonate was added, and the mixture was reacted at room temperature for 2 h. After the reaction was complete, the potassium carbonate was removed by filtration, and the solvent was evaporated to dryness to obtain 4-(5-chlorothiophene-2-carbonyl)piperazine-1-carboxylic acid tert-butyl ester. 4-(5-chlorothiophene-2-carbonyl) was dissolved in 15 mL of anhydrous dichloromethane. tert-butyl piperazine-1-carboxylate was added to 5 mL of trifluoroacetic acid and reacted at room temperature for 4 h. The reaction was monitored by TLC. After the reaction was completed, saturated sodium bicarbonate solution was added to quench the reaction until no bubbles were generated. The product was extracted three times with dichloromethane, dried over anhydrous sodium sulfate, and the organic phase was collected and evaporated to dryness to give (5-chlorothiophene-2-yl)(piperazine-1-yl)methyl ketone (69 mg, 0.299 mmol), a pale yellow solid with a yield of 98.94%. The product did not require further purification and was directly used for the next reaction.

[0144] Intermediate 3 (200 mg, 0.635 mmol) was dissolved in 20 mL of anhydrous acetonitrile, and anhydrous cesium carbonate (1.035 g, 3.177 mmol) was added. Then, (5-chlorothiophene-2-yl)(piperazin-1-yl) methyl ketone (293 mg, 1.271 mmol) was added under stirring. The reaction was carried out at room temperature for 9 h, and the reaction was monitored by TLC. After the reaction was complete, the solvent was evaporated, and the solution was purified by silica gel column chromatography using a gradient elution with dichloromethane and methanol in a volume ratio of 100:1–20:1 to obtain compound II3 as a yellow solid (210 mg, 0.413 mmol), with a yield of 64.93%. It was identified as (5-chlorothiophene-2-yl)(4-(5,5'-diallyl-2,2'-dihydroxy-[1,1'-biphenyl]-3-yl)methyl)piperazin-1-yl) methyl ketone.

[0145] 1H NMR(300MHz,Chloroform-d)δ7.16(s,2H),7.13(d,J=2.3Hz,1H),7.07(d,J=3.9Hz,1H),7.02(d,J=8.6Hz,1H),6.88(d,J=2.1Hz,1H),6 .87(d,J=3.9Hz,1H),6.09-5.90(m,2H),5.16-5.05(m,4H),3.83(brs,6H),3.41(d,J=6.7Hz,2H),3.37(d,J=6.7Hz,2H),2.67(brs,4H); 13 C NMR(75MHz,Chloroform-d)δ162.30,152.39,151.32,137.94,137.52,135.23,134.53,132.56,132.28,131.72,131.17,129.38,12 8.88,128.46,126.51,126.28,126.16,120.33,118.40,115.93,115.57,61.36,53.56,52.32(2C),45.00,39.54,39.43; HR-ESI-MS m / z calcd for C 28 H 30 ClN2O3S[M+H] + 509.1660, found 509.1658.

[0146] Example 7

[0147] Synthesis of (4-(5,5'-diallyl-2,2'-dihydroxy-[1,1'-biphenyl]-3-methyl)piperazin-1-yl)(phenyl)methyl ketone (compound I1)

[0148] Referring to Example 4, the raw material thiophene-2-carboxylic acid was replaced with benzoic acid. Benzoic acid (200 mg, 1.638 mmol) was dissolved in 10 mL of anhydrous dichloromethane at room temperature, and thionyl chloride (595 μL, 8.188 mmol) was added. The mixture was refluxed for 6 h under argon protection, and the reaction was monitored by TLC. After the reaction was complete, the solvent was evaporated to obtain benzoyl chloride (166 mg, 1.181 mmol), with a yield of 72.11%. At room temperature, 1-Boc-piperazine (133 mg, 0.711 mmol) and benzoyl chloride (100 mg, 0.711 mmol) were dissolved in 20 mL of anhydrous acetonitrile, and 100 mg of anhydrous potassium carbonate was added. The mixture was refluxed at room temperature. After 2 hours of reaction, potassium carbonate was removed by filtration, and the solvent was evaporated to dryness to obtain 4-benzoylpiperazine-1-carboxylic acid tert-butyl ester. 15 mL of anhydrous dichloromethane was added to dissolve 4-benzoylpiperazine-1-carboxylic acid tert-butyl ester, and 5 mL of trifluoroacetic acid was added. The reaction was carried out at room temperature for 4 hours, and the reaction was monitored by TLC. After the reaction was completed, saturated sodium bicarbonate solution was added to quench the reaction until no bubbles were generated. The product was extracted three times with dichloromethane, dried over anhydrous sodium sulfate, and the organic phase was collected and evaporated to dryness to obtain phenyl(piperazine-1-yl) methyl ketone (59 mg, 0.256 mmol), a white solid with a yield of 84.60%. The product did not require further purification and was directly used for the next reaction.

[0149] Intermediate 3 (200 mg, 0.635 mmol) was dissolved in 20 mL of anhydrous acetonitrile, and anhydrous cesium carbonate (1.035 g, 3.177 mmol) was added. Then, phenyl(piperazin-1-yl) methyl ketone (242 mg, 1.271 mmol) was added under stirring. The reaction was carried out at room temperature for 9 h. The reaction was monitored by TLC. After the reaction was completed, the solvent was evaporated and purified by silica gel column chromatography with gradient elution using dichloromethane and methanol in a volume ratio of 100:1-20:1 to obtain compound I1 (210 mg, 0.448 mmol), a white solid with a yield of 70.54%. It was identified as (4-(5,5'-diallyl-2,2'-dihydroxy-[1,1'-biphenyl]-3-methyl)piperazin-1-yl)(phenyl) methyl ketone.

[0150] 1 H NMR(300MHz,Chloroform-d)δ7.52-7.42(m,5H),7.25(d,J=1.7Hz,1H),7.21-7.17(m,2H),7.10-7.07(m,1H),6.85(d,J=7.5H z,1H),6.08-5.89(m,2H),5.13-5.02(m,4H),3.69-3.65(m,6H),3.43(d,J=6.5Hz,2H),3.37(d,J=6.5Hz,2H),2.80(brs,4H); 13CNMR(75MHz,Chloroform-d)δ170.03,153.41,150.81,138.08,137.46,135.39,132.87,131.97,131.02,130.51,129 .37,129.15,128.86,128.33,127.17,126.14,125.96,125.45,115.68,54.81,53.02,45.25,39.56,39.55; HR-ESI-MS m / z calcd for C 30 H 32 N₂O₃[M+H] + 469.2486, found 469.2489.

[0151] Example 8

[0152] Synthesis of (4-(5,5'-diallyl-2,2'-dihydroxy-[1,1'-biphenyl]-3-methyl)piperazin-1-yl)(4-fluorophenyl)methyl ketone (compound I2)

[0153] Referring to Example 4, the starting material thiophene-2-carboxylic acid was replaced with 4-fluorobenzoic acid. At room temperature, 4-fluorobenzoic acid (200 mg, 1.427 mmol) was dissolved in 10 mL of anhydrous dichloromethane, and thionyl chloride (595 μL, 8.188 mmol) was added. The mixture was refluxed under argon protection for 6 h, and the reaction was monitored by TLC. After the reaction was complete, the solvent was evaporated to obtain 4-fluorobenzoyl chloride (169 mg, 1.066 mmol), with a yield of 74.67%. At room temperature, 1-Boc-piperazine (117 mg, 0.631 mmol) and p-fluorobenzoyl chloride (100 mg, 0.631 mmol) were dissolved in 20 mL of anhydrous acetonitrile, and 100 mg of anhydrous potassium carbonate was added. The mixture was reacted at room temperature for 2 h. After the reaction was complete, potassium carbonate was removed by filtration, and the solvent was evaporated to dryness to obtain 4-(4-fluorobenzoyl)piperazine-1-carboxylic acid tert-butyl ester. 15 mL of anhydrous dichloromethane was added to dissolve the 4-(4-fluorobenzoyl)piperazine-1-carboxylic acid tert-butyl ester, followed by the addition of 5 mL of trifluoroacetic acid. The reaction was carried out at room temperature for 4 h, and the reaction was monitored by TLC. After the reaction was complete, saturated sodium bicarbonate solution was added to quench the reaction until no more bubbles were generated. The mixture was extracted three times with dichloromethane, dried over anhydrous sodium sulfate, and the organic phase was collected and evaporated to dryness to obtain a white solid ((4-fluorophenyl)(piperazine-1-yl) methyl ketone, 55 mg, 0.264 mmol) with a yield of 81.44%. The product did not require further purification and was directly used in the next reaction.

[0154] Intermediate 3 (200 mg, 0.635 mmol) was dissolved in 20 mL of anhydrous acetonitrile, and anhydrous cesium carbonate (1.035 g, 3.177 mmol) was added. Then, (4-fluorophenyl)(piperazin-1-yl) methyl ketone (265 mg, 1.271 mmol) was added under stirring. The reaction was carried out at room temperature for 9 h, and the reaction was monitored by TLC. After the reaction was completed, the solvent was evaporated, and silica gel column chromatography was performed with gradient elution using dichloromethane and methanol in a volume ratio of 100:1-20:1 to obtain compound I2 as a white solid (260 mg, 0.534 mmol), with a yield of 84.11%. It was identified as (4-(5,5'-diallyl-2,2'-dihydroxy-[1,1'-biphenyl]-3-methyl)piperazin-1-yl)(4-fluorophenyl) methyl ketone.

[0155] 1 H NMR(300MHz,Chloroform-d)δ7.46-7.40(m,2H),7.17-7.08(m,5H),7.02(d,J=8.8Hz,1H),6.88(d,J=2.2Hz,1H),6.12-5 .87(m,2H),5.18-5.03(m,4H),3.85(s,2H),3.53(brs,4H),3.41(d,J=6.7Hz,2H),3.37(d,J=6.7Hz,2H),2.98(brs,4H); 13 C NMR(75MHz,Chloroform-d)δ169.42,163.56(d,J CF =250.5Hz),152.42,151.33,137.94,137.53,132.54,132.25,131.73,131.17,131.12,129.48(d,J CF =8.5Hz,2C),129.38,128.43,126.51,126.30,120.34,118.41,115.91,115.74(d,J CF =21.7Hz,2C),115.56,61.39,52.37,53.55,47.13,41.74,39.54,39.43; HR-ESI-MS m / z calcd for C 30 H 31 FN2O3[M+H] + 487.2391, found 487.2353.

[0156] Example 9

[0157] Synthesis of (4-(5,5'-diallyl-2,2'-dihydroxy-[1,1'-biphenyl]-3-methyl)piperazin-1-yl)(3,4,5-trimethoxyphenyl)methyl ketone (compound I3)

[0158] Referring to Example 4, the starting material thiophene-2-carboxylic acid was replaced with 3,4,5-trimethoxybenzoic acid. At room temperature, 3,4,5-trimethoxybenzoic acid (200 mg, 0.943 mmol) was dissolved in 10 mL of anhydrous dichloromethane, and thionyl chloride (595 μL, 8.188 mmol) was added. The mixture was refluxed under argon protection for 6 h, and the reaction was monitored by TLC. After the reaction was complete, the solvent was evaporated to obtain 3,4,5-trimethoxybenzoyl chloride (195 mg, 0.845 mmol), with a yield of 89.70%. At room temperature, 1-Boc-piperazine (80.75 mg, 0.434 mmol) and 3,4,5-trimethoxybenzoyl chloride (100 mg, 0.434 mmol) were dissolved in 20 mL of anhydrous acetonitrile, and 100 mg of anhydrous potassium carbonate was added. The mixture was reacted at room temperature for 2 h. After the reaction was complete, potassium carbonate was removed by filtration, and the solvent was evaporated to dryness to obtain 4-(3,4,5-trimethoxybenzoyl)piperazine-1-carboxylic acid tert-butyl ester. 15 mL of anhydrous dichloromethane was added to dissolve the 4-(3,4,5-trimethoxybenzoyl)piperazine-1-carboxylic acid tert-butyl ester. 5 mL of trifluoroacetic acid was added, and the reaction was carried out at room temperature for 4 h. The reaction was monitored by TLC. After the reaction was complete, saturated sodium bicarbonate solution was added to quench the reaction until no bubbles were generated. The mixture was extracted three times with dichloromethane, dried over anhydrous sodium sulfate, and the organic phase was collected and evaporated to dryness to obtain piperazine-1-yl(3,4,5-trimethoxyphenyl) methyl ketone (53 mg, 0.189 mmol), a white solid with a yield of 71.93%. The product did not require further purification and was directly used in the next reaction.

[0159] Intermediate 3 (200 mg, 0.635 mmol) was dissolved in 20 mL of anhydrous acetonitrile, and anhydrous cesium carbonate (1.035 g, 3.177 mmol) was added. Piperazin-1-yl(3,4,5-trimethoxyphenyl) methyl ketone (356 mg, 1.271 mmol) was added under stirring. The reaction was carried out at room temperature for 9 h, and the reaction was monitored by TLC. After the reaction was completed, the solvent was evaporated, and silica gel column chromatography was performed with gradient elution using dichloromethane and methanol in a volume ratio of 100:1-50:1 to obtain compound I3 as a white solid (290 mg, 0.519 mmol), with a yield of 81.71%. It was identified as (4-(5,5'-diallyl-2,2'-dihydroxy-[1,1'-biphenyl]-3-methyl)piperazin-1-yl)(3,4,5-trimethoxyphenyl) methyl ketone.

[0160] 1H NMR(300MHz,Chloroform-d)δ7.31-7.12(m,3H),6.99(dd,J=7.5,1.3Hz,1H),6.87(d,J=7.5Hz,1H),6.67(s,2H),6.18-5.99(m,2 H),5.15-4.98(m,4H),3.84(s,6H),3.76(s,3H),3.70-3.63(m,6H),3.40(d,J=6.5Hz,2H),3.36(d,J=6.5Hz,2H),2.82(brs,4H); 13 CNMR(75MHz,Chloroform-d)169.68,153.47,151.72,150.91,142.97,138.10,137.46,133.11,131.65,130.85,130.47,129.39 ,128.98,128.38,126.04,125.98,125.58,116.00,115.68,105.43,60.81,56.26,54.93,52.80,45.32,39.56,39.55; HR-ESI-MS m / zcalcd for C 33 H 38 N₂O₆[M+H] + 559.2803, found 559.2807.

[0161] Example 10

[0162] Synthesis of (4-(5,5'-diallyl-2,2'-dihydroxy-[1,1'-biphenyl]-3-methyl)piperazin-1-yl)(4-(trifluoromethyl)phenyl)methyl ketone (compound I4)

[0163] Referring to Example 4, the starting material thiophene-2-carboxylic acid was replaced with 4-(trifluoromethyl)benzoic acid. At room temperature, 4-(trifluoromethyl)benzoic acid (200 mg, 1.052 mmol) was dissolved in 10 mL of anhydrous dichloromethane, and thionyl chloride (595 μL, 8.188 mmol) was added. The mixture was refluxed under argon protection for 6 h, and the reaction was monitored by TLC. After the reaction was complete, the solvent was evaporated to obtain 4-(trifluoromethyl)benzoyl chloride (177 mg, 0.849 mmol), with a yield of 80.67%. At room temperature, 1-Boc-piperazine (89.30 mg, 0.479 mmol) and 4-(trifluoromethyl)benzoyl chloride (100 mg, 0.479 mmol) were dissolved in 20 mL of anhydrous acetonitrile, and 100 mg of anhydrous potassium carbonate was added. The mixture was reacted at room temperature for 2 h. After the reaction was complete, potassium carbonate was removed by filtration, and the solvent was evaporated to dryness to obtain tert-butyl 4-(4-(trifluoromethyl)benzoyl)piperazine-1-carboxylic acid ester. 15 mL of anhydrous dichloromethane was added to dissolve the tert-butyl 4-(4-(trifluoromethyl)benzoyl)piperazine-1-carboxylic acid ester, and 5 mL of trifluoroacetic acid was added. The reaction was carried out at room temperature for 4 h, and the reaction was monitored by TLC. After the reaction was complete, saturated sodium bicarbonate solution was added to quench the reaction until no bubbles were generated. The mixture was extracted three times with dichloromethane, dried over anhydrous sodium sulfate, and the organic phase was collected and evaporated to dryness to obtain piperazine-1-yl(4-(trifluoromethyl)phenyl) ketone (53 mg, 0.205 mmol), a white solid with a yield of 73.55%. The product did not require further purification and was directly used for the next reaction.

[0164] Intermediate 3 (200 mg, 0.635 mmol) was dissolved in 20 mL of anhydrous acetonitrile, and anhydrous cesium carbonate (1.035 g, 3.177 mmol) was added. Piperazin-1-yl(4-(trifluoromethyl)phenyl) ketone (328 mg, 1.271 mmol) was added under stirring. The reaction was carried out at room temperature for 9 h, and the reaction was monitored by TLC. After the reaction was completed, the solvent was evaporated, and silica gel column chromatography was performed with gradient elution using dichloromethane and methanol in a volume ratio of 100:1-30:1 to obtain compound I4 as a white solid (197 mg, 0.367 mmol), with a yield of 57.79%. It was identified as (4-(5,5'-diallyl-2,2'-dihydroxy-[1,1'-biphenyl]-3-methyl)piperazin-1-yl)(4-(trifluoromethyl)phenyl) ketone.

[0165] 1H NMR(300MHz,Chloroform-d)δ7.79(d,J=7.5Hz,2H),7.78-7.75(m,2H),7.31-7.24(m,1H),7.23-7.16(m,2H),7.09-7.03(m,1H),6.85(d,J= 7.5Hz,1H),6.15-5.91(m,2H),5.17-5.01(m,4H),3.87(s,2H),3.55(brs,4H),3.42(d,J=6.7Hz,2H),3.37(d,J=6.7Hz,2H),2.99(brs,4H); 13 C NMR(75MHz,Chloroform-d)δ170.14,153.44,151.37,138.08,137.46,134.66,134.09,132.96,131.65,130.47,129.37,128.93,128 .32,126.65,126.05,125.71,125.58,123.91(q,J=267.8Hz),116.02,115.88,115.68,54.95,52.81,45.40,39.54,39.43; HR-ESI-MS m / z calcd for C 31 H 31 F3N2O3[M+H] + 537.2360, found 537.2365.

[0166] Example 11

[0167] Synthesis of 4-(4-(5,5'-diallyl-2,2'-dihydroxy-[1,1'-biphenyl]-3-yl)methyl)piperazine-1-carbonyl)benzonitrile (compound I5)

[0168] Referring to Example 4, the raw material thiophene-2-carboxylic acid was replaced with 4-cyanobenzoic acid. 4-Cyanobenzoic acid (200 mg, 1.359 mmol) was dissolved in 10 mL of anhydrous dichloromethane at room temperature, and thionyl chloride (595 μL, 8.188 mmol) was added. The mixture was refluxed for 6 h under argon protection, and the reaction was monitored by TLC. After the reaction was complete, the solvent was evaporated to obtain 4-cyanobenzoyl chloride (139 mg, 0.839 mmol), with a yield of 61.76%. At room temperature, 1-Boc-piperazine (112 mg, 0.604 mmol) and 4-cyanobenzoyl chloride (100 mg, 0.604 mmol) were dissolved in 20 mL of anhydrous acetonitrile, and... 100 mg of anhydrous potassium carbonate was added, and the reaction was carried out at room temperature for 2 h. After the reaction was completed, the potassium carbonate was removed by filtration, and the solvent was evaporated to dryness to obtain 4-(4-cyanobenzoyl)piperazine-1-carboxylic acid tert-butyl ester. 15 mL of anhydrous dichloromethane was added to dissolve 4-(4-cyanobenzoyl)piperazine-1-carboxylic acid tert-butyl ester. 5 mL of trifluoroacetic acid was added, and the reaction was carried out at room temperature for 4 h. The reaction was monitored by TLC. After the reaction was completed, saturated sodium bicarbonate solution was added to quench the reaction until no bubbles were generated. The product was extracted three times with dichloromethane, dried over anhydrous sodium sulfate, and the organic phase was collected and evaporated to dryness to obtain a white solid (4-(piperazine-1-carbonyl)benzonitrile, 61 mg, 0.83 mmol) with a yield of 89.37%. The product did not require further purification and was directly used for the next reaction.

[0169] Intermediate 3 (200 mg, 0.635 mmol) was dissolved in 20 mL of anhydrous acetonitrile, and anhydrous cesium carbonate (1.035 g, 3.177 mmol) was added. 4-(piperazine-1-carbonyl)benzonitrile (274 mg, 1.271 mmol) was added under stirring. The reaction was carried out at room temperature for 9 h, and the reaction was monitored by TLC. After the reaction was complete, the solvent was evaporated, and silica gel column chromatography was performed using gradient elution with dichloromethane and methanol in a volume ratio of 100:1–30:1 to purify compound I5, a white solid (169 mg, 0.342 mmol), in a yield of 53.89%. It was identified as 4-(4-(5,5'-diallyl-2,2'-dihydroxy-[1,1'-biphenyl]-3-yl)methyl)piperazine-1-carbonyl)benzonitrile.

[0170] 1H NMR(300MHz,Chloroform-d)δ7.69(d,J=8.3Hz,2H),7.49(d,J=8.3Hz,2H),7.20-7.09(m,3H),6.99(d,J=8.0Hz,1H ),6.88(d,J=2.1Hz,1H),6.13-5.85(m,2H),5.20-4.96(m,4H),3.81(s,4H),3.53-3.25(m,6H),2.96-2.24(m,4H); 13 C NMR(75MHz,Chloroform-d)δ168.23,152.42,151.30,139.51,137.92,137.51,132.55,132.29,131.73,131.22,129.3 8,128.51,127.81,126.51,126.28,120.34,118.37,118.06,115.95,115.61,113.74,61.28,39.52,39.41; HR-ESI-MS m / z calcd for C 31 H 31 N3O3[M+H] + 494.2438, found 494.2439.

[0171] Example 12

[0172] Synthesis of (4-chlorophenyl)(4-(5,5'-diallyl-2,2'-dihydroxy-[1,1'-biphenyl]-3-yl)methyl)piperazin-1-yl)methyl ketone (compound I6)

[0173] Referring to Example 4, the starting material thiophene-2-carboxylic acid was replaced with 4-chlorobenzoic acid. At room temperature, 4-chlorobenzoic acid (200 mg, 1.277 mmol) was dissolved in 10 mL of anhydrous dichloromethane, and thionyl chloride (595 μL, 8.188 mmol) was added. The mixture was refluxed under argon protection for 6 h, and the reaction was monitored by TLC. After the reaction was complete, the solvent was evaporated to obtain 4-chlorobenzoyl chloride (150 mg, 0.857 mmol), with a yield of 67.10%. At room temperature, 1-Boc-piperazine (106 mg, 0.571 mmol) and 4-chlorobenzoyl chloride (100 mg, 0.571 mmol) were dissolved in 20 mL of anhydrous acetonitrile, and 100 mg of anhydrous potassium carbonate was added. The mixture was reacted at room temperature for 2 h. After the reaction was complete, potassium carbonate was removed by filtration, and the solvent was evaporated to dryness to obtain 4-(4-chlorobenzoyl)piperazine-1-carboxylic acid tert-butyl ester. 15 mL of anhydrous dichloromethane was added to dissolve 4-(4-chlorobenzoyl)piperazine-1-carboxylic acid tert-butyl ester, and 5 mL of trifluoroacetic acid was added. The reaction was carried out at room temperature for 4 h, and the reaction was monitored by TLC. After the reaction was complete, saturated sodium bicarbonate solution was added to quench the reaction until no bubbles were generated. The product was extracted three times with dichloromethane, dried over anhydrous sodium sulfate, and the organic phase was evaporated to dryness to obtain (4-chlorophenyl)(piperazine-1-yl) methyl ketone (49 mg, 0.218 mmol), a white solid with a yield of 70.83%. The product did not require further purification and was directly used for the next reaction.

[0174] Intermediate 3 (200 mg, 0.635 mmol) was dissolved in 20 mL of anhydrous acetonitrile, and anhydrous cesium carbonate (1.035 g, 3.177 mmol) was added. Then, (4-chlorophenyl)(piperazin-1-yl) methyl ketone (285 mg, 1.271 mmol) was added under stirring. The reaction was carried out at room temperature for 9 h, and the reaction was monitored by TLC. After the reaction was complete, the solvent was evaporated, and silica gel column chromatography was performed using gradient elution with dichloromethane and methanol in a volume ratio of 100:1–30:1 to purify compound I6, a white solid (183 mg, 0.36 mmol), with a yield of 57.26%. It was identified as (4-chlorophenyl)(4-(5,5'-diallyl-2,2'-dihydroxy-[1,1'-biphenyl]-3-yl)methyl)piperazin-1-yl) methyl ketone.

[0175] 1H NMR(300MHz,Chloroform-d)δ7.74-7.65(m,2H),7.53-7.43(m,2H),7.25(d,J=1.6Hz,1H),7.21-7.16(m,2H),7.09-7.04(m,1H),6.85(d,J= 7.5Hz,1H),6.15-5.85(m,2H),5.17-5.01(m,4H),3.87(s,2H),3.55(brs,4H),3.41(d,J=6.5Hz,2H),3.36(d,J=6.5Hz,2H),2.99(brs,4H); 13 C NMR(75MHz,Chloroform-d)δ169.83,153.43,151.10,138.63,138.08,137.46,134.00,132.93,131.97,130.43,129.78,129. 46,129.31,129.01,128.48,126.11,126.00,125.54,115.97,115.88,115.68,54.95,52.81,45.26,39.59,39.55; HR-ESI-MS m / z calcd for C 30 H 31 ClN2O3[M+H] + 503.2096, found 503.2099.

[0176] Example 13

[0177] Synthesis of (4-(5,5'-diallyl-2,2'-dihydroxy-[1,1'-biphenyl]-3-methyl)piperazin-1-yl)(p-tolyl)methyl ketone (compound I7)

[0178] Referring to Example 4, the starting material thiophene-2-carboxylic acid was replaced with 4-methylbenzoic acid. At room temperature, 4-methylbenzoic acid (200 mg, 1.469 mmol) was dissolved in 10 mL of anhydrous dichloromethane, and thionyl chloride (595 μL, 8.188 mmol) was added. The mixture was refluxed for 6 h under argon protection, and the reaction was monitored by TLC. After the reaction was complete, the solvent was evaporated to obtain 4-methylbenzoyl chloride (171 mg, 1.106 mmol), with a yield of 75.30%. At room temperature, 1-Boc-piperazine (120 mg, 0.647 mmol) and 4-methylbenzoyl chloride (100 mg, 0.647 mmol) were dissolved in 20 mL of anhydrous acetonitrile, and 100 mg of anhydrous potassium carbonate was added. The reaction was carried out at room temperature. After 2 hours of reaction, potassium carbonate was removed by filtration, and the solvent was evaporated to dryness to obtain 4-(4-methylbenzoyl)piperazine-1-carboxylic acid tert-butyl ester. 15 mL of anhydrous dichloromethane was added to dissolve the 4-(4-methylbenzoyl)piperazine-1-carboxylic acid tert-butyl ester, followed by the addition of 5 mL of trifluoroacetic acid. The reaction was carried out at room temperature for 4 hours, monitored by TLC. After the reaction was complete, saturated sodium bicarbonate solution was added to quench the reaction until no more bubbles were generated. The mixture was extracted three times with dichloromethane, dried over anhydrous sodium sulfate, and the organic phase was evaporated to dryness to obtain piperazine-1-yl(p-tolyl) methyl ketone (47 mg, 0.230 mmol), a white solid with a yield of 70.04%. The product did not require further purification and was directly used in the next reaction step.

[0179] Intermediate 3 (200 mg, 0.635 mmol) was dissolved in 20 mL of anhydrous acetonitrile, and anhydrous cesium carbonate (1.035 g, 3.177 mmol) was added. Piperazin-1-yl(p-tolyl) methyl ketone (260 mg, 1.271 mmol) was added under stirring. The reaction was carried out at room temperature for 9 h, and the reaction was monitored by TLC. After the reaction was completed, the solvent was evaporated, and silica gel column chromatography was performed with gradient elution using dichloromethane and methanol in a volume ratio of 100:1-50:1 to obtain compound I7 as a white solid (199 mg, 0.412 mmol), with a yield of 64.90%. It was identified as (4-(5,5'-diallyl-2,2'-dihydroxy-[1,1'-biphenyl]-3-methyl)piperazin-1-yl)(p-tolyl) methyl ketone.

[0180] 1H NMR(300MHz,Chloroform-d)δ7.70-7.61(m,2H),7.25(d,J=1.7Hz,1H),7.22-7.15(m,4H),7.09-7.03(m,1H),6.85(d,J=7.5Hz,1H),6.1 8-5.85(m,2H),5.28-4.90(m,4H),3.85(s,2H),3.50(brs,4H),3.43(d,J=6.5Hz,2H),3.37(d,J=6.5Hz,2H),2.99(brs,4H),2.42(s,3H); 13 C NMR(300MHz,Chloroform-d)δ169.99,153.44,150.83,141.34,138.10,137.46,134.06,132.87,131.97,130.48,129.39 ,129.11,128.35,126.14,125.96,125.46,115.98,115.91,115.68,54.95,52.81,45.26,39.59,39.56,21.35; HR-ESI-MS m / zcalcd for C 31 H 34 N₂O₃[M+H] + 483.2642, found 483.2645.

[0181] Example 14

[0182] Synthesis of (4-(5,5'-diallyl-2,2'-dihydroxy-[1,1'-biphenyl]-3-methyl)piperazin-1-yl)(4-methoxyphenyl)methyl ketone (compound I8)

[0183] Referring to Example 4, the starting material thiophene-2-carboxylic acid was replaced with 4-methoxybenzoic acid. At room temperature, 4-methoxybenzoic acid (200 mg, 1.315 mmol) was dissolved in 10 mL of anhydrous dichloromethane, and thionyl chloride (595 μL, 8.188 mmol) was added. The mixture was refluxed under argon protection for 6 h, and the reaction was monitored by TLC. After the reaction was complete, the solvent was evaporated to obtain 4-methoxybenzoyl chloride (173 mg, 1.014 mmol), with a yield of 77.15%. At room temperature, 1-Boc-piperazine (109 mg, 0.586 mmol) and 4-methoxybenzoyl chloride (100 mg, 0.586 mmol) were dissolved in 20 mL of anhydrous acetonitrile, and 100 mg of anhydrous potassium carbonate was added. The mixture was reacted at room temperature for 2 h. After the reaction was complete, potassium carbonate was removed by filtration, and the solvent was evaporated to dryness to obtain 4-(4-methoxybenzoyl)piperazine-1-carboxylic acid tert-butyl ester. 15 mL of anhydrous dichloromethane was added to dissolve the 4-(4-methoxybenzoyl)piperazine-1-carboxylic acid tert-butyl ester, followed by the addition of 5 mL of trifluoroacetic acid. The reaction was carried out at room temperature for 4 h, and the reaction was monitored by TLC. After the reaction was complete, saturated sodium bicarbonate solution was added to quench the reaction until no more bubbles were generated. The mixture was extracted three times with dichloromethane, dried over anhydrous sodium sulfate, and the organic phase was collected and evaporated to dryness to obtain (4-methoxyphenyl)(piperazine-1-yl) methyl ketone (59 mg, 0.268 mmol), a white solid with a yield of 85.82%. The product did not require further purification and was directly used in the next reaction.

[0184] Intermediate 3 (200 mg, 0.635 mmol) was dissolved in 20 mL of anhydrous acetonitrile, and anhydrous cesium carbonate (1.035 g, 3.177 mmol) was added. Then, (4-methoxyphenyl)(piperazin-1-yl) methyl ketone (280 mg, 1.271 mmol) was added under stirring. The reaction was carried out at room temperature for 9 h, and the reaction was monitored by TLC. After the reaction was completed, the solvent was evaporated, and silica gel column chromatography was performed with gradient elution using dichloromethane and methanol in a volume ratio of 100:1 to 50:1 to purify compound I8, a white solid (213 mg, 0.427 mmol), with a yield of 67.24%. It was identified as (4-(5,5'-diallyl-2,2'-dihydroxy-[1,1'-biphenyl]-3-methyl)piperazin-1-yl)(4-methoxyphenyl) methyl ketone.

[0185] 1H NMR(300MHz,Chloroform-d)δ7.57(d,J=7.7Hz,2H),7.25(d,J=1.7Hz,1H),7.2 0(dd,J=18.0,1.8Hz,2H),7.06(dt,J=7.5,1.3Hz,1H),7.02-6.97(m,2H),6.85 (d,J=7.5Hz,1H),6.08-5.88(m,2H),5.17-4.99(m,4H),3.87(s,2H),3.51(brs ,4H),3.41(d,J=6.6Hz,2H),3.35(d,J=6.6Hz,2H),2.99(brs,4H),3.84(s,3H); 13 C NMR(75MHz,Chloroform-d)δ170.12,162.73,153.46,151.10,138.08,137.46,132.87,131.98,131.15,130.48,129.81,129.67, 129.37,128.35,126.11,126.00,125.54,115.97,115.88,115.68,113.86,55.33,54.95,52.81,45.30,39.59,39.56; HR-ESI-MS m / z calcd for C 31 H 34 N₂O₄[M+H] + 499.2591, found 499.2595.

[0186] Example 15

[0187] Synthesis of (E)-1-(4-((5,5'-diallyl-2,2'-dihydroxy-[1,1'-biphenyl]-3-methyl)piperazin-1-yl)-3-phenylpropyl-2-en-1-one (compound III1)

[0188] Referring to Example 4, the starting material thiophene-2-carboxylic acid was replaced with cinnamic acid. At room temperature, cinnamic acid (200 mg, 1.350 mmol) was dissolved in 10 mL of anhydrous dichloromethane, and thionyl chloride (595 μL, 8.188 mmol) was added. The mixture was refluxed under argon protection for 6 h, and the reaction was monitored by TLC. After the reaction was complete, the solvent was evaporated to obtain cinnamyl chloride (190 mg, 1.140 mmol), with a yield of 84.48%. At room temperature, 1-Boc-piperazine (126 mg, 0.675 mmol) and cinnamyl chloride (100 mg, 0.675 mmol) were dissolved in 20 mL of anhydrous acetonitrile, and 100 mg of anhydrous potassium carbonate was added. The mixture was reacted at room temperature for 2 h. After the reaction was complete... Potassium carbonate was removed by filtration, and the solvent was evaporated to dryness to obtain tert-butyl-4-cinnamoylpiperazine-1-carboxylic acid ester. 15 mL of anhydrous dichloromethane was added to dissolve the tert-butyl-4-cinnamoylpiperazine-1-carboxylic acid ester, followed by the addition of 5 mL of trifluoroacetic acid. The reaction was carried out at room temperature for 4 h, and the reaction was monitored by TLC. After the reaction was completed, saturated sodium bicarbonate solution was added to quench the reaction until no more bubbles were generated. The mixture was extracted three times with dichloromethane, dried over anhydrous sodium sulfate, and the organic phase was collected and evaporated to dryness to obtain (E)-3-phenyl-1-(piperazin-1-yl)propyl-2-en-1-one (52 mg, 0.240 mmol), a white solid with a yield of 76.07%. The product did not require further purification and was directly used in the next reaction.

[0189] Intermediate 3 (200 mg, 0.635 mmol) was dissolved in 20 mL of anhydrous acetonitrile, and anhydrous cesium carbonate (1.035 g, 3.177 mmol) was added. Then, (E)-3-phenyl-1-(piperazin-1-yl)propyl-2-en-1-one (275 mg, 1.271 mmol) was added under stirring. The reaction was carried out at room temperature for 9 h, and the reaction was monitored by TLC. After the reaction was complete, the solvent was evaporated, and the solution was analyzed by silica gel column chromatography. Gradient elution was performed using dichloromethane and methanol in a volume ratio of 100:1-30:1 to purify compound III1, a white solid (227 mg, 0.459 mmol), with a yield of 72.24%. It was identified as (E)-1-(4-((5,5'-diallyl-2,2'-dihydroxy-[1,1'-biphenyl]-3-methyl)piperazin-1-yl)-3-phenylpropyl-2-en-1-one.

[0190] 1H NMR(300MHz,Chloroform-d)δ7.72(d,J=15.4Hz,1H),7.54(td,J=5.4,4.9,3.1Hz,2H),7.45-7.35(m,3H),7.23-7.12(m,3H),7.07-7.00(m,1H) ,6.95-6.80(m,2H),6.13-5.88(m,2H),5.20-5.01(m,4H),3.86(s,2H), 3.74(s,4H),3.42(d,J=6.7Hz,2H),3.38(d,J=6.7Hz,2H),2.69(s,4H). 13 C NMR(75MHz,Chloroform-d)δ165.46,152.42,151.39,143.62,137.95,137.53,135.01,132.56,132.24,131.72,131.15,129.9 1,129.38,128.89,128.41,127.86,126.52,126.32,120.35,118.45,116.41,115.90,115.54,61.44,39.54,39.44.HR-ESI-MS m / z calcd for C 32 H 34 N₂O₃[M+H] + 495.2642, found 495.2645.

[0191] Example 16

[0192] Synthesis of (E)-1-(4-((5,5'-diallyl-2,2'-dihydroxy-[1,1'-biphenyl]-3-methyl)piperazin-1-yl)3-(4-fluorophenyl)malondialdehyde-2-en-1-one (compound III2)

[0193] Referring to Example 4, the starting material thiophene-2-carboxylic acid was replaced with (E)-3-(4-fluorophenyl)acrylic acid. At room temperature, (E)-3-(4-fluorophenyl)acrylic acid (200 mg, 1.204 mmol) was dissolved in 10 mL of anhydrous dichloromethane, and thionyl chloride (595 μL, 8.188 mmol) was added. The mixture was refluxed under argon protection for 6 h, and the reaction was monitored by TLC. After the reaction was complete, the solvent was evaporated to obtain (E)-3-(4-fluorophenyl)acryloyl chloride (193 mg, 1.046 mmol), with a yield of 86.86%. At room temperature, 1-Boc-piperazine (112 mg, 0.602 mmol) and (E)-3-(4-fluorophenyl)acryloyl chloride (100 mg, 0.602 mmol) were dissolved in 20 mL of anhydrous acetonitrile, and 100 mg of anhydrous potassium carbonate was added. The mixture was reacted at room temperature for 2 h. After the reaction was complete... The potassium carbonate was removed by filtration, and the solvent was evaporated to dryness to obtain tert-butyl(E)-4-(3-(4-fluorophenyl)acryloyl)piperazine-1-carboxylic acid ester. 15 mL of anhydrous dichloromethane was added to dissolve the tert-butyl(E)-4-(3-(4-fluorophenyl)acryloyl)piperazine-1-carboxylic acid ester, and 5 mL of trifluoroacetic acid was added. The reaction was carried out at room temperature for 4 h, and the reaction was monitored by TLC. After the reaction was completed, saturated sodium bicarbonate solution was added to quench the reaction until no bubbles were generated. The mixture was extracted three times with dichloromethane, dried over anhydrous sodium sulfate, and the organic phase was collected and evaporated to dryness to obtain (E)-3-(4-fluorophenyl)-1-(piperazine-1-yl)propen-2-en-1-one (61 mg, 0.260 mmol), a white solid with a yield of 87.07%. The product did not require further purification and was directly used in the next reaction.

[0194] Intermediate 3 (200 mg, 0.635 mmol) was dissolved in 20 mL of anhydrous acetonitrile, and anhydrous cesium carbonate (1.035 g, 3.177 mmol) was added. Then, (E)-3-(4-fluorophenyl)-1-(piperazin-1-yl)propen-2-en-1-one (298 mg, 1.271 mmol) was added under stirring. The reaction was carried out at room temperature for 9 h, and the reaction was monitored by TLC. After the reaction was complete, the solvent was evaporated, and the solution was analyzed by silica gel column chromatography. Gradient elution was performed using dichloromethane and methanol in a volume ratio of 100:1-30:1 to purify compound III2, a white solid (266 mg, 0.519 mmol), with a yield of 81.68%. It was identified as (E)-1-(4-((5,5'-diallyl-2,2'-dihydroxy-[1,1'-biphenyl]-3-methyl)piperazin-1-yl)-3-(4-fluorophenyl)malondialdehyde-2-en-1-one.

[0195] 1H NMR(300MHz,Chloroform-d)δ7.70-7.64(m,2H),7.52(d,J=15.4Hz,1H),7.2 5(t,J=1.3Hz,1H),7.22-7.16(m,2H),7.15-7.09(m,3H),7.06(dd,J=7.3,1.6 Hz,1H),6.85(d,J=7.5Hz,1H),6.05-5.93(m,2H),5.13-5.04(m,4H),3.76(s ,2H),3.70(s,4H),3.45(d,J=6.7Hz,2H),3.39(d,J=6.7Hz,2H),2.70(s,4H); 13 C NMR(300MHz,Chloroform-d)δ166.48,161.49(d,J=252.4Hz),153.46,151.10 ,142.28,138.10,137.46,132.88,131.70,130.46,130.34(d,J=7.8Hz),129. 39,129.34,129.31,128.48,126.06,126.00,125.54,119.78,116.08(d,J=20 .1Hz),116.00,115.88,115.68,54.95,53.16,45.48,39.60,39.55; HR-ESI-MS m / z calcd for C 32 H 33 FN2O3[M+H] + 513.2548, found 513.2550.

[0196] Example 17

[0197] Synthesis of ethyl 6-allyl-8-(5-allyl-2-hydroxyphenyl)-2-oxo-2H-chromene-3-carboxylate (compound V1)

[0198] Intermediate 1 (100 mg, 0.340 mmol) was dissolved in 20 mL of anhydrous ethanol, and 50 μL of piperidine and diethyl malonate (81.6 mg, 0.51 mmol) were added. The mixture was refluxed at 80 °C overnight. The reaction was monitored by TLC. After the reaction was completed, the mixture was diluted with ice water and extracted three times with dichloromethane. The extract was dried over anhydrous sodium sulfate, and the organic phase was collected and evaporated to dryness. The mixture was then subjected to silica gel column chromatography with dichloromethane-methanol at a volume ratio of 50:1 as the eluent to give compound V1, 90 mg of off-white powder, with a yield of 67.85%. The compound was identified as ethyl 6-allyl-8-(5-allyl-2-hydroxyphenyl)-2-oxo-2H-chromene-3-carboxylic acid.

[0199] 1 H NMR(300MHz,Chloroform-d)δ8.57(s,1H),7.50(d,J=2.1Hz,1H),7.42(d,J=2.1Hz,1H),7.02(d,J=2.2Hz,1H),6.95(dd,J=8.3,2.2Hz,1H),6.80( d,J=8.3Hz,1H),6.09-5.87(m,2H),5.28-4.96(m,4H),4.38(q,J=7.1Hz, 2H), 3.48 (d, J = 6.8Hz, 2H), 3.36 (d, J = 6.8Hz, 2H), 1.38 (t, J = 7.1Hz, 3H); 13 C NMR(75MHz,Chloroform-d)δ163.22,157.45,152.06,151.07,149.33,137.76,137.18,136.87,136.17,131.71,130. 87,130.06,128.31,127.51,122.23,118.07,117.90,117.15,116.46,115.69,61.97,39.36,39.22,14.23; HR-ESI-MS m / z calcd for C 24 H 22 O5[M+Na] + 413.1359, found 413.1360.

[0200] Example 18

[0201] Synthesis of 6-allyl-8-(5-allyl-2-hydroxyphenyl)-2-oxo-2H-chromene-3-carboxylic acid (compound V2)

[0202] Ethyl 6-allyl-8-(5-allyl-2-hydroxyphenyl)-2-oxo-2H-benzofuran-3-carboxylic acid (100 mg, 0.256 mmol) was dissolved in 15 mL of 1% sodium hydroxide ethanol and refluxed at 85 °C for 2 h. Then, 2 mL of 38% concentrated hydrochloric acid was added, and the mixture was slowly cooled to room temperature. The precipitate was removed by filtration, and the filtrate was evaporated to dryness and subjected to silica gel column chromatography with dichloromethane-methanol-acetic acid in a volume ratio of 15:1:1 as the eluent. The purified compound V2 was obtained as a pale yellow powder, 90 mg, with a yield of 96.97%, and was identified as 6-allyl-8-(5-allyl-2-hydroxyphenyl)-2-oxo-2H-chromene-3-carboxylic acid.

[0203] 1H NMR(300MHz,Chloroform-d)δ8.96(s,1H),7.63(d,J=2.1Hz,1H),7.56(d,J=2.2Hz,1H),7.11(dd,J=8.2,2.2Hz,1H), 7.07(d,J=2.1Hz,1H),6.87(d,J=8.2Hz,1H),6.09-5.93(m,2H),5.28-5.07(m,4H),3.55(d,J=6.7Hz,2H),3.40(d,J=6 .7Hz, 2H); 13CNMR (75MHz, Chloroform-d) δ164.34,162.75,151.94,151.46,150.59,138.50,138.44,137.45,135.65 ,132.55,131.10,130.49,129.20,127.80,121.59,118.68,117.67,116.28,115.96,114.51,39.28,39.19; HR-ESI-MS m / z calcd for C 22 H 18 O5[M+Na]+385.1046,found385.1058.

[0204] Example 19

[0205] Synthesis of 5,5'-diallyl-3-((benzylamino)methyl)-[1,1'-biphenyl]-2,2'-diol (compound IV1)

[0206] At room temperature, intermediate 1 (200 mg, 0.679 mmol) was dissolved in 20 mL of anhydrous dichloromethane, and anhydrous magnesium sulfate (409 mg, 3.40 mmol) was added. Phenylmethylamine (146 mg, 1.359 mmol) was slowly added dropwise under stirring. The reaction was carried out at room temperature for 5 h, and the reaction was monitored by TLC. After the reaction was completed, sodium borohydride (51.41 mg, 1.359 mmol) was added, and the reaction was continued for 9 h. After the reaction was completed, the reaction was quenched with water, and the mixture was extracted three times with dichloromethane. The dichloromethane layers were combined, the solvent was evaporated, and the mixture was purified by silica gel column chromatography with a dichloromethane to methanol volume ratio of 100:1-20:1 as the eluent. The purified compound IV1 was a white powder, which was identified as 5,5'-diallyl-3-((benzylamino)methyl)-[1,1'-biphenyl]-2,2'-diol.

[0207] 1H NMR(300MHz,Chloroform-d)δ7.35-7.27(m,5H),7.24(dd,J=15.0,1.8Hz,2H),7.19(d,J=1.0Hz,1H),7.09(dd,J=7.5,1.8Hz,1H),6 .87(d,J=7.5Hz,1H),6.05-5.92(m,2H),5.10-5.04(m,4H),3.97(s,2H),3.88(s,2H),3.38(d,J=6.6Hz,2H),3.36(d,J=6.6Hz,2H); 13 C NMR(75MHz,Chloroform-d)δ154.04,150.79,139.49,138.10,137.48,132.82,131.81,130.51,129.92,129.36,128. 85,128.81,128.08,127.17,126.81,126.53,125.60,116.02,115.90,115.67,52.79,49.60,39.64,39.57; HR-ESI-MS m / z calcd forC 26 H 27 NO2[M+H]+386.2115, found 386.2117.

[0208] Example 20

[0209] Synthesis of 5,5'-diallyl-3-((3,4-dichlorobenzyl)amino)-[1,1'-biphenyl]-2,2'-diol (compound IV2)

[0210] Referring to Example 19, phenylmethylamine was replaced with (3,4-dichlorophenyl)methylamine. At room temperature, intermediate 1 (200 mg, 0.679 mmol) was dissolved in 20 mL of anhydrous dichloromethane, and anhydrous magnesium sulfate (409 mg, 3.40 mmol) was added. (3,4-dichlorophenyl)methylamine (239 mg, 1.359 mmol) was slowly added dropwise under stirring. The reaction was carried out at room temperature for 5 h, and the reaction was monitored by TLC. After the reaction was completed, sodium borohydride (51.41 mg, 1.359 mmol) was added, and the reaction was continued for 9 h. After the reaction was completed, the reaction was quenched with water, and the mixture was extracted three times with dichloromethane. The dichloromethane layers were combined, the solvent was evaporated, and the mixture was purified by silica gel column chromatography with a dichloromethane to methanol volume ratio of 100:1-20:1 as the eluent to obtain compound IV2, a white powder, which was identified as 5,5'-diallyl-3-((3,4-dichlorobenzyl)amino)-[1,1'-biphenyl]-2,2'-diol.

[0211] 1 H NMR(300MHz,Chloroform-d)δ7.42(d,J=7.5Hz,1H),7.39(s,1H),7.27-7.22(m,3H),7.19(s,1H),7.09(d,J=6.8,1H),6.86(d ,J=7.5Hz,1H),6.12-5.85(m,2H),5.25-4.94(m,4H),4.07(s,2H),3.92(s,2H),3.38(d,J=6.2Hz,2H),3.36(d,J=6.2Hz,2H); 13 CNMR(75MHz,Chloroform-d)δ150.79,139.51,138.11,137.50,132.82,132.27,131.60,130.53,130.30,129.85,129. 64,129.39,128.63,127.76,126.59,126.33,125.60,116.02,115.88,115.67,52.58,49.55,39.59,39.56; HR-ESI-MS m / z calcd for C 26 H 25 Cl2NO2[M+H]+454.1335,found 454.1340.

[0212] Example 21

[0213] Synthesis of 5,5'-diallyl-3-((3,4,5-trimethoxybenzyl)amino)-[1,1'-biphenyl]-2,2'-diol (compound IV3)

[0214] Referring to Example 19, phenylmethylamine was replaced with (3,4,5-trimethoxyphenyl)methylamine. At room temperature. Intermediate 1 (200 mg, 0.679 mmol) was dissolved in 20 mL of anhydrous dichloromethane, and anhydrous magnesium sulfate (409 mg, 3.40 mmol) was added. Then, (3,4,5-trimethoxyphenyl)methylamine (268 mg, 1.359 mmol) was slowly added dropwise under stirring. The reaction was carried out at room temperature for 5 h, and the reaction was monitored by TLC. After the reaction was complete, sodium borohydride (51.41 mg, 1.359 mmol) was added, and the reaction was continued for another 9 h. After the reaction was complete, the reaction was quenched with water, and the mixture was extracted three times with dichloromethane. The dichloromethane layers were combined, the solvent was evaporated, and the mixture was purified by silica gel column chromatography using a dichloromethane to methanol volume ratio of 100:1-20:1 as the eluent to obtain compound IV3, a white powder, which was identified as 5,5'-diallyl-3-((3,4,5-trimethoxybenzyl)amino)-[1,1'-biphenyl]-2,2'-diol.

[0215] 1 H NMR(300MHz,Chloroform-d)δ7.25(s,1H),7.21-7.18(m,2H),7.09(d,J=7.5Hz,1H),6.85(d,J=7.5Hz,1H),6.58( s,2H),6.07-5.90(m,2H),5.13-5.02(m,4H),3.99(s,2H),3.89(s,2H),3.81(s,6H),3.74(s,3H),3.39(d,J=6.8Hz 2H),3.36(d,J=6.8Hz2H); 13 C NMR(75MHz,Chloroform-d)δ153.24,150.79,138.25,138.08,137.46,136.04,132.33,130.51,129.74,129.37, 128.34,126.24,126.14,115.91,115.88,115.68,107.81,60.80,56.20,52.63,49.47,39.59,39.55; HR-ESI-MS m / z calcd for C 29 H 33 NO5[M+H]+476.2431,found 476.2440.

[0216] Example 22

[0217] Synthesis of 5,5'-diallyl-3-((3,4-difluorobenzyl)amino)-[1,1'-biphenyl]-2,2'-diol (compound IV4)

[0218] Referring to Example 19, phenylmethylamine was replaced with (3,4-difluorophenyl)methylamine. At room temperature. Intermediate 1 (200 mg, 0.679 mmol) was dissolved in 20 mL of anhydrous dichloromethane, and anhydrous magnesium sulfate (409 mg, 3.40 mmol) was added. Then, (3,4-difluorophenyl)methylamine (195 mg, 1.359 mmol) was slowly added dropwise under stirring. The reaction was carried out at room temperature for 5 h, and the reaction was monitored by TLC. After the reaction was complete, sodium borohydride (51.41 mg, 1.359 mmol) was added, and the reaction was continued for another 9 h. After the reaction was complete, water was added to quench the reaction, and the mixture was extracted three times with dichloromethane. The dichloromethane layers were combined, the solvent was evaporated, and the mixture was purified by silica gel column chromatography using a dichloromethane to methanol volume ratio of 100:1-20:1 as the eluent to obtain compound IV4, a white powder, which was identified as 5,5'-diallyl-3-((3,4-difluorobenzyl)amino)-[1,1'-biphenyl]-2,2'-diol.

[0219] 1 H NMR(300MHz,Chloroform-d)δ7.27-7.23(m,2H),7.21-7.19(m,1H),7.16-7.12(m,2H),7.11-7.07(m,2H),6.85(d,J=7.5 13C NMR(75MHz,Chloroform-d)δ153.22,151.01(d,J=252.1Hz),150.79,149.15(d,J=257.0Hz),138.09,137.49,137.20,132.86,132.03,130.56, 129.89,129.35,128.63,126.65,126.36,125.60,123.87,117.27(d,J=19.7Hz),116.26(d,J=20.0Hz),116.02,115.88,115.67; HR-ESI-MSm / z calcd for C 26 H 25 F2NO2[M+H]+422.1926,found 422.1930.

[0220] Example 23

[0221] Synthesis of 5,5'-diallyl-3-((4-chlorobenzyl)amino)-[1,1'-biphenyl]-2,2'-diol (compound IV 5)

[0222] Referring to Example 19, phenylmethylamine was replaced with (4-chlorophenyl)methylamine. At room temperature, intermediate 1 (200 mg, 0.679 mmol) was dissolved in 20 mL of anhydrous dichloromethane, and anhydrous magnesium sulfate (409 mg, 3.40 mmol) was added. (4-chlorophenyl)methylamine (192 mg, 1.359 mmol) was slowly added dropwise under stirring. The reaction was carried out at room temperature for 5 h, and the reaction was monitored by TLC. After the reaction was completed, sodium borohydride (51.41 mg, 1.359 mmol) was added, and the reaction was continued for 9 h. After the reaction was completed, the reaction was quenched with water, and the mixture was extracted three times with dichloromethane. The dichloromethane layers were combined, the solvent was evaporated, and the mixture was purified by silica gel column chromatography with a dichloromethane to methanol volume ratio of 100:1-20:1 as the eluent to obtain compound IV5, a white powder, which was identified as 5,5'-diallyl-3-((4-chlorobenzyl)amino)-[1,1'-biphenyl]-2,2'-diol.

[0223] 1 H NMR(300MHz,Chloroform-d)δ7.37(d,J=7.5Hz,2H),7.29(d,J=7.5Hz,2H),7.26-7.23(m,2H),7.19(d,J=1.1Hz,1H),7.10-7.06(m, 1H),6.85(d,J=7.5Hz,1H),6.07-5.88(m,2H),5.14-4.98(m,4H),4.02(s,2H),3.88(s,2H),3.38(d,J=6.2,2H),3.36(d,J=6.2,2H); 13 CNMR(75MHz,Chloroform-d)δ153.65,150.79,138.77,138.09,137.49,132.68,132.27,131.95,130.51,129.91,129. 76,129.35,128.73,128.40,126.65,126.61,125.54,116.04,115.88,115.67,52.88,49.55,39.62,39.56; HR-ESI-MS m / z calcd forC 26 H 26 ClNO2[M+H]+420.1725,found420.1729.

[0224] Example 24

[0225] Synthesis of 5,5'-diallyl-3-((4-fluorobenzyl)amino)-[1,1'-biphenyl]-2,2'-diol (compound IV 6)

[0226] Referring to Example 19, phenylmethylamine was replaced with (4-fluorophenyl)methylamine. At room temperature, intermediate 1 (200 mg, 0.679 mmol) was dissolved in 20 mL of anhydrous dichloromethane, and anhydrous magnesium sulfate (409 mg, 3.40 mmol) was added. (4-fluorophenyl)methylamine (170 mg, 1.359 mmol) was slowly added dropwise under stirring. The reaction was carried out at room temperature for 5 h, and the reaction was monitored by TLC. After the reaction was completed, sodium borohydride (51.41 mg, 1.359 mmol) was added, and the reaction was continued for 9 h. After the reaction was completed, the reaction was quenched with water, and the mixture was extracted three times with dichloromethane. The dichloromethane layers were combined, the solvent was evaporated, and the mixture was purified by silica gel column chromatography with a dichloromethane to methanol volume ratio of 100:1-20:1 as the eluent to obtain compound IV6, a white powder, which was identified as 5,5'-diallyl-3-((4-fluorobenzyl)amino)-[1,1'-biphenyl]-2,2'-diol.

[0227] 1 H NMR(300MHz,Chloroform-d)δ7.28-7.23(m,4H),7.20-7.19(m,1H),7.08(dt,J=7.5,1.3Hz,1H),7.06-7.03(m,2H),6.85(d ,J=7.5Hz,1H),6.08-5.84(m,2H),5.18-4.89(m,4H),4.01(s,2H),3.88(s,2H),3.38(6.2Hz,2H),3.36(d,J=6.2Hz,2H); 13C NMR (75MHz, Chloroform-d) δ162.23 (d, J = 262.0Hz), 153.97, 150.79, 138.08, 137.48, 136.57, 132.27, 131.81, 130.56, 130.18, 129. 95,129.37,128.75,126.80,126.68,125.56,116.04,115.90,115.67,115.40(d,J=20.1Hz),52.44,49.60,39.62,39.56; HR-ESI-MS m / z calcdfor C 26 H 26 FNO2[M+H]+404.2020,found 404.2025.

[0228] Example 25

[0229] Synthesis of 5,5'-diallyl-3-((3,4-dimethoxybenzyl)amino)-[1,1'-biphenyl]-2,2'-diol (compound IV 7)

[0230] Referring to Example 19, phenylmethylamine was replaced with (3,4-dimethoxyphenyl)methylamine. At room temperature, intermediate 1 (200 mg, 0.679 mmol) was dissolved in 20 mL of anhydrous dichloromethane, and anhydrous magnesium sulfate (409 mg, 3.40 mmol) was added. Then, (3,4-dimethoxyphenyl)methylamine (227 mg, 1.359 mmol) was slowly added dropwise under stirring. The reaction was carried out at room temperature for 5 h, and the reaction was monitored by TLC. After the reaction was completed, sodium borohydride (51.41 mg, 1.359 mmol) was added, and the reaction was continued for another 9 h. After the reaction was completed, the reaction was quenched with water, and the mixture was extracted three times with dichloromethane. The dichloromethane layers were combined, the solvent was evaporated, and the mixture was purified by silica gel column chromatography with a dichloromethane to methanol volume ratio of 100:1-20:1 as the eluent to obtain compound IV7, a white powder, which was identified as 5,5'-diallyl-3-((3,4-dimethoxybenzyl)amino)-[1,1'-biphenyl]-2,2'-diol.

[0231] 1 H NMR(300MHz,Chloroform-d)δ7.25(d,J=22.7Hz,2H),7.19(s,1H),7.08(d,J=7.5Hz,1H),6.95(d,J=7.5Hz,1H),6.87(s,1H),6.86(d,J=7.5Hz,1H),6.84 (d,J=7.6Hz,1H),6.07-5.89(m,2H),5.11-4.99(m,4H),4.00(s,2H),3.90(s ,2H),3.82(s,3H),3.81(s,3H),3.38(d,J=6.8Hz,2H),3.36(d,J=6.8Hz,2H); 13 C NMR(75MHz,Chloroform-d)δ153.63,150.79,149.03,148.65,138.09,137.47,134.27,132.96,132.03,130.54,129.89,129.38,128 .66,126.63,126.24,125.56,122.05,116.01,115.88,115.67,112.16,111.88,55.87,55.82,52.53,49.55,39.60,39.55; HR-ESI-MS m / z calcd for C 28 H 31 NO4[M+H]+446.2326,found 446.2330.

[0232] Example 26

[0233] Synthesis of 5,5'-diallyl-3-(((benzo[d][1,3]dioxo-5-methyl)amino)methyl)-[1,1'-biphenyl]-2,2'-diol (compound IV 8)

[0234] Referring to Example 19, phenylmethylamine was replaced with benzo[d][1,3]dioxanol-5-ylmethylamine. At room temperature, intermediate 1 (200 mg, 0.679 mmol) was dissolved in 20 mL of anhydrous dichloromethane, and anhydrous magnesium sulfate (409 mg, 3.40 mmol) was added. Benzo[d][1,3]dioxanol-5-ylmethylamine (205 mg, 1.359 mmol) was slowly added dropwise under stirring. The reaction was carried out at room temperature for 5 h, and the reaction was monitored by TLC. After the reaction was complete, sodium borohydride (51.41 mg, 1.359 mmol) was added, and the reaction was continued... The reaction was continued for 9 hours. After the reaction was completed, water was added to quench the reaction, and the mixture was extracted three times with dichloromethane. The dichloromethane layers were combined, the solvent was evaporated, and the mixture was purified by silica gel column chromatography with dichloromethane and methanol in a volume ratio of 100:1-20:1 as the eluent to obtain compound IV8, a white powder, which was identified as 5,5'-diallyl-3-(((benzo[d][1,3]dioxol-5-methyl)amino)methyl)-[1,1'-biphenyl]-2,2'-diol.

[0235] 1 H NMR(300MHz,Chloroform-d)δ7.24(dd,J=14.7,2.0Hz,2H),7.20-7.18(m,1H),7.08(dd,J=7.5,1.8Hz,1H),6.87-6.85(m,2H),6.84(d,J=1.8Hz, 1H),6.75(d,J=7.5Hz,1H),6.04-5.94(m,2H),5.93(s,2H),5.17-4.91(m ,4H),4.01(s,2H),3.90(s,2H),3.38(d,J=6.4,2H),3.36(d,J=6.4,2H); 13 C NMR(75MHz,Chloroform-d)δ150.79,147.50,138.11,137.48,134.20,132.96,132.03,130.59,129.94,129.35,128. 65,126.63,125.60,122.07,116.02,115.88,115.67,109.31,108.51,101.44,52.75,49.55,39.62,39.56; HR-ESI-MS m / z calcd for C 27 H 27 NO4[M+H]+ 430.2013, found 430.2015.

[0236] Example 27

[0237] Synthesis of 5,5'-diallyl-3-((3,4-dimethylbenzyl)amino)-[1,1'-biphenyl]-2,2'-diol (compound IV 9)

[0238] Referring to Example 19, phenylmethylamine was replaced with (3,4-dimethylphenyl)methylamine. At room temperature, intermediate 1 (200 mg, 0.679 mmol) was dissolved in 20 mL of anhydrous dichloromethane, and anhydrous magnesium sulfate (409 mg, 3.40 mmol) was added. Benzo[d][1,3]dioxanol-5-ylmethylamine (205 mg, 1.359 mmol) was slowly added dropwise under stirring. The reaction was carried out at room temperature for 5 h. After the reaction was completed by TLC monitoring, sodium borohydride (51.41 mg, 1.359 mmol) was added, and the reaction was continued for 9 h. After the reaction was completed, the reaction was quenched with water, and the mixture was extracted three times with dichloromethane. The dichloromethane layers were combined, the solvent was evaporated, and the mixture was purified by silica gel column chromatography with dichloromethane and methanol in a volume ratio of 100:1-20:1 to obtain compound IV9, a white powder, which was identified as 5,5'-diallyl-3-((3,4-dimethylbenzyl)amino)-[1,1'-biphenyl]-2,2'-diol.

[0239] 1 H NMR(300MHz,Chloroform-d)δ7.26-7.22(m,2H),7.19(d,J=1.1Hz,1H),7.16-7.06(m,4H),6.85(d,J=7.5Hz,1H),6.07-5. 91(m,2H),5.16-4.99(m,4H),3.96(s,2H),3.88(s,2H),3.38(d,J=6.1,2H),3.36(d,J=6.1,2H),2.29(s,3H),2.23(s,3H); 13 C NMR(75MHz,Chloroform-d)δ153.19,150.79,138.09,137.49,137.47,136.85,136.07,132.27,131.95,130.51,129.85,129.37,129 .13,128.63,127.80,126.80,126.36,125.70,125.56,116.02,115.90,115.70,52.85,49.55,39.62,39.56,20.10,19.70; HR-ESI-MS m / z calcdfor C28 H 31 NO2[M+H] + 414.2428, found 414.2430.

[0240] Example 28

[0241] The HepG2 human hepatocellular carcinoma cell line (purchased from the Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences) was cultured in RPMI-1640 medium containing 10% fetal bovine serum (FBS) under standard conditions (37°C, 5% CO2). The medium was replaced with fresh FBS every other day. When the cell density reached approximately 80%, the cells were digested with 0.25% trypsin-EDTA digestion solution, centrifuged, and resuspended in RPMI-1640 medium containing 10% FBS. The cell suspension was then cultured at 8 × 10⁻⁶ cells / day. 3 Seeds were planted at a density of cells / well in 96-well plates and cultured overnight in a standard culture environment at 37°C. The culture medium was then discarded, and 100 μL of 1640 medium with drug concentrations of 1, 2, 5, 10, 25, and 50 μmol / L were added to each test well. A blank medium without added drug was used as a control group. The plates were incubated in a standard culture environment for 24 h. Using a pipette, 10 μL of 5 mg / mL 3-(4,5-dimethylthiazol-2)-2,5-diphenyltetrazol bromide (MTT) was added to each test well under light-protected conditions. The plates were then cultured for another 4 h in a cell culture incubator at 37°C under light-protected conditions. After incubation, the 96-well plates were removed, and the culture medium in each well was discarded using a pipette. 150 μL of LDMSO was added to each test well to dissolve formazan within the cells. Finally, the absorbance of each test well was measured using a microplate reader with the following parameters: wavelength: 570 nm; oscillation mode: 30 s oscillation before testing; test mode: rapid. Record the absorbance values ​​of each well and calculate the cell viability using the following formula:

[0242] Cell viability (%) = (Experimental group absorbance - Blank / zero-adjustment group) / (Control group absorbance - Blank / zero-adjustment group) × 100%

[0243] Table 1. Inhibitory activity of the magnolol derivatives of the present invention against liver cancer cells.

[0244]

[0245] As shown in Table 1, most magnolol derivatives exhibited enhanced anti-hepatocellular carcinoma activity, with some derivatives showing higher bioactivity than the positive control drug sorafenib. This suggests that these compounds may have potential therapeutic effects on hepatocellular carcinoma and have promising application prospects.

[0246] Example 29

[0247] Once the HepG2 cells in the cell culture flasks had reached confluence, the cells were digested with 0.25% trypsin containing EDTA, centrifuged at 1000 rpm for 5 min, counted using a cell counter, and then RPMI-1640 medium containing 10% fetal bovine serum was added to achieve a cell suspension concentration of 1×10⁻⁶. 5 Cells were seeded at a density of 200,000 cells / well in 6-well cell culture plates (2 mL per well). The 6-well plates were incubated for 24 hours. After incubation, the culture medium was aspirated from the 6-well plates, and 2 mL of drug-containing medium of a specific concentration was added to each well, with each well labeled. The control group cells were cultured in RPMI-1640 medium without fetal bovine serum, while the drug-treated groups were cultured in RPMI-1640 medium containing magnolol (5 mol / L, 10 mol / L, 20 mol / L) or compound III1 (1 mol / L, 2 mol / L, 3 mol / L). After drug administration, the control and drug-treated groups were scratched with a pipette tip, washed twice with PBS, and cell migration images were taken at 0 h and 48 h under an inverted microscope. The experimental results are shown below. Figure 1 .

[0248] It can be seen that, compared with magnolol, compound III1 can significantly inhibit the migration of HepG2 liver cancer cells at a lower concentration, indicating that the magnolol derivative of the present invention has a potential anti-liver cancer metastasis effect and may have great application value in anti-liver cancer metastasis.

Claims

1. A class of magnolol derivatives or their pharmaceutically acceptable salts with structures as shown in formulas VI and V: ， ； in, R is selected from , , , ; R1 is selected from H, halogen, cyano, C1-C4 alkyl, C1-C4 alkoxy, halogen-substituted C1-C4 alkyl, and m is an integer from 1 to 3; X is selected from oxygen or sulfur atom, and R2 is selected from H, halogen, C1-C4 alkyl, C1-C4 alkoxy; R3 is selected from H, halogens, C1-C4 alkyl groups, and C1-C4 alkoxy groups; R4 is selected from H, halogen, C1-C4 alkyl, C1-C4 alkoxy, n is an integer from 1 to 3, or R4 and benzene ring together form a 5-membered heterocycle containing two oxygen atoms; R' is selected from H and C1-C4 alkyl groups.

2. The magnolol derivative or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: R1 is selected from H, F, Cl, cyano, methyl, methoxy, trifluoromethyl, and m is an integer from 1 to 3; X is selected from oxygen or sulfur atoms, and R2 is selected from H or Cl. R3 is selected from H, F, Cl, methyl, and methoxy. R4 is selected from H, F, Cl, methyl, methoxy, and n is an integer from 1 to 3, or R4 and the benzene ring together form a 5-membered heterocycle containing two oxygen atoms; R' is selected from H, methyl, or ethyl.

3. The magnolol derivative or a pharmaceutically acceptable salt thereof according to claim 2, characterized in that: For m=1, R1 is selected from H, para-substituted F, Cl, cyano, methyl, methoxy, and trifluoromethyl; for m=3, R1 is selected from 3,4,5-trimethoxy. X is selected from oxygen or sulfur atoms, and R2 is selected from H or Cl. R3 is selected from H, F, Cl, methyl, and methoxy. Selected from , ; R' is selected from H, methyl, or ethyl.

4. A magnolol derivative or a pharmaceutically acceptable salt thereof, characterized in that: The magnolol derivatives mentioned above are selected from compounds with the following structures: 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 。 5. A method for preparing a magnolol derivative with the structure shown in Formula VI according to claim 1, wherein R is selected from... , , At that time, the synthesis route is as follows: ， ， ； in, R'' is selected from , , R1, m, X, R2, and R3 are as described in claim 1; When R is selected At that time, the synthesis route is as follows: ； Wherein, R4 and n are as described in claim 1.

6. The method for preparing magnolol derivatives according to claim 5, characterized in that: When R is selected The preparation method of magnolol derivatives includes the following steps: Step (1): Using THF as the reaction solvent and magnolol as the starting material, magnolol, paraformaldehyde, triethylamine, and anhydrous magnesium chloride are dissolved in the reaction solvent and refluxed under argon or nitrogen protection to obtain intermediate 1; at room temperature, intermediate 1 is reduced by sodium borohydride to obtain intermediate 2; using anhydrous dichloromethane as the solvent, intermediate 2 reacts with thionyl chloride under argon or nitrogen protection to obtain intermediate 3. The molar ratio of magnolol to paraformaldehyde is 1:5 to 1:10; the molar ratio of magnolol to triethylamine is 1:0.5 to 1:1.01; the molar ratio of magnolol to anhydrous magnesium chloride is 1:3 to 1:9; the molar ratio of intermediate 1 to sodium borohydride is 1:4.5 to 1:5; and the molar ratio of intermediate 2 to thionyl chloride is 1:4.5 to 1:

5. Step (2): Anhydrous dichloromethane is used as the reaction solvent, with the structure shown in the formula. The substituted or unsubstituted benzoic acid shown reacts with thionyl chloride under reflux to give a structure as shown in the formula. Intermediate 4a is shown; using anhydrous acetonitrile as the reaction solvent and anhydrous potassium carbonate as the acid-binding agent, N-boc piperazine reacts with intermediate 4a at room temperature to obtain the structure shown in the formula. Intermediate 5a, as shown, was reacted at room temperature with dichloromethane as the reaction solvent in the presence of trifluoroacetic acid to remove the BOC protecting group, yielding intermediate 6a. ; Wherein, the molar ratio of substituted or unsubstituted benzoic acid to thionyl chloride is 1:5 to 1:9; the molar ratio of intermediate 4a to anhydrous potassium carbonate is 1:0.5 to 1:5; the molar ratio of intermediate 4a to N-boc piperazine is 1:1 to 1:2; and the volume ratio of dichloromethane to trifluoroacetic acid is 3:

1. Step (3): Using acetonitrile as the reaction solvent, in the presence of cesium carbonate, at room temperature, intermediate 3 reacts with intermediate 6a to obtain magnolol derivative; Wherein, the molar ratio of intermediate 3 to intermediate 6a is 1:2 to 1:5; the molar ratio of intermediate 3 to cesium carbonate is 1:5; When R is selected The preparation method of magnolol derivatives includes the following steps: Step (1): Preparation of intermediate 3; Step (2): Using anhydrous dichloromethane as a solvent, the structure is shown in the formula. The reaction with thionyl chloride under reflux yields a structure as shown in the formula. Intermediate 4b is shown; using anhydrous acetonitrile as the reaction solvent and anhydrous potassium carbonate as the acid-binding agent, N-boc piperazine reacts with intermediate 4b at room temperature to give the structure shown in the formula. Intermediate 5b, as shown, was reacted at room temperature with dichloromethane as the reaction solvent in the presence of trifluoroacetic acid to remove the boc protecting group, yielding the structure shown in the formula. Intermediate 6b; Among them, the aforementioned The molar ratio of intermediate 4b to thionyl chloride is 1:2.5 to 1:5; the molar ratio of intermediate 4b to anhydrous potassium carbonate is 1:0.3 to 1:1.5; the molar ratio of intermediate 4b to N-boc piperazine is 1:1 to 1:2; and the volume ratio of dichloromethane to trifluoroacetic acid is 3:

1. Step (3): Using acetonitrile as the reaction solvent, in the presence of cesium carbonate, at room temperature, intermediate 3 reacts with intermediate 6b to obtain magnolol derivative; Wherein, the molar ratio of intermediate 3 to intermediate 6b is 1:2 to 1:5; the molar ratio of intermediate 3 to cesium carbonate is 1:5; When R is selected The preparation method of magnolol derivatives includes the following steps: Step (1): Preparation of intermediate 3; Step (2): Anhydrous dichloromethane is used as the reaction solvent, with the structure shown in the formula. The reaction with thionyl chloride under reflux yields the structure shown in the formula. Intermediate 4c is shown; using anhydrous acetonitrile as the reaction solvent and anhydrous potassium carbonate as the acid-binding agent, N-boc piperazine reacts with intermediate 4c at room temperature to give the structure shown in the formula. Intermediate 5c, as shown, was reacted at room temperature with dichloromethane as the reaction solvent in the presence of trifluoroacetic acid to remove the boc protecting group, yielding the structure shown in the formula. The intermediate 6c shown; Among them, the aforementioned The molar ratio of intermediate 4c to thionyl chloride is 1:6 to 1:7; the molar ratio of intermediate 4c to anhydrous potassium carbonate is 1:1 to 1:2.5; the molar ratio of intermediate 4b to N-boc piperazine is 1:1 to 1:2; and the volume ratio of dichloromethane to trifluoroacetic acid is 3:

1. Step (3): Using acetonitrile as the reaction solvent, in the presence of cesium carbonate, at room temperature, intermediate 3 reacts with intermediate 6c to obtain magnolol derivative; Wherein, the molar ratio of intermediate 3 to intermediate 6c is 1:2 to 1:5; the molar ratio of intermediate 3 to cesium carbonate is 1:5; When R is selected The preparation method of magnolol derivatives includes the following steps: Step (1): Using THF as the reaction solvent and magnolol as the starting material, magnolol, paraformaldehyde, triethylamine, and anhydrous magnesium chloride are dissolved in the reaction solvent and refluxed under argon or nitrogen protection to obtain intermediate 1. The molar ratio of magnolol to paraformaldehyde is 1:5 to 1:10; the molar ratio of magnolol to triethylamine is 1:0.5 to 1:1.01; and the molar ratio of magnolol to anhydrous magnesium chloride is 1:3 to 1:

9. Step (2): Using anhydrous dichloromethane as the reaction solvent, in the presence of anhydrous magnesium sulfate, at room temperature, intermediate 1 and the structure shown in the formula are reacted. The reaction was completed, and sodium borohydride was added for reduction to obtain magnolol derivatives. Among them, intermediate 1 and The molar ratio of intermediate 1 to anhydrous magnesium sulfate is 1:5; the molar ratio of intermediate 1 to sodium borohydride is 1:

2.

7. The method for preparing magnolol derivatives according to claim 6, characterized in that: When R is selected In step (1), the molar ratio of magnolol to paraformaldehyde is 1:

5.

8. The method for preparing magnolol derivatives according to claim 6, characterized in that: When R is selected In step (1), the molar ratio of magnolol to paraformaldehyde is 1:5; the molar ratio of magnolol to anhydrous magnesium chloride is 1:

3.

9. A method for preparing a magnolol derivative with the structure shown in Formula V according to claim 1, characterized in that: When R' is selected from C1-C4 alkyl groups, the synthetic route is as follows: ； include: Step (1): Using THF as the reaction solvent and magnolol as the starting material, magnolol, paraformaldehyde, triethylamine, and anhydrous magnesium chloride are dissolved in the reaction solvent and refluxed under argon or nitrogen protection to obtain intermediate 1. The molar ratio of magnolol to paraformaldehyde is 1:5 to 1:10; the molar ratio of magnolol to triethylamine is 1:0.5 to 1:1.01; and the molar ratio of magnolol to anhydrous magnesium chloride is 1:3 to 1:

9. Step (2): Using anhydrous ethanol as the reaction solvent, intermediate 1 is refluxed with malonate diester in the presence of piperidine to obtain magnolol derivative. Wherein, the molar ratio of intermediate 1 to dimalonate is 1:1 to 1:5; the dimalonate is selected from dimethyl malonate, diethyl malonate, di-n-propyl malonate, diisopropyl malonate, di-n-butyl malonate, diisobutyl malonate, and di-tert-butyl malonate; the molar ratio of intermediate 1 to piperidine is 1:1 to 1:1.

5. When R' is selected from H, the synthesis route is: ； include: Step (1): Using THF as the reaction solvent and magnolol as the starting material, magnolol, paraformaldehyde, triethylamine, and anhydrous magnesium chloride are dissolved in the reaction solvent and refluxed under argon or nitrogen protection to obtain intermediate 1. Step (2): Using anhydrous ethanol as the reaction solvent, intermediate 1 is refluxed with diethyl malonate in the presence of piperidine to obtain ethyl 6-allyl-8-(5-allyl-2-hydroxyphenyl)-2-oxo-2H-chromene-3-carboxylate; ethyl 6-allyl-8-(5-allyl-2-hydroxyphenyl)-2-oxo-2H-chromene-3-carboxylate is dissolved in a 1% sodium hydroxide ethanol solution and refluxed at 85°C for 2-4 hours. 38% concentrated hydrochloric acid is added until the system becomes acidic to obtain the target compound.

10. The use of the magnolol derivative or a pharmaceutically acceptable salt thereof according to any one of claims 1-4 in the preparation of a medicament for treating liver cancer.

11. The application according to claim 10, characterized in that: The application described herein refers to the use of the magnolol derivative or its pharmaceutically acceptable salt in the preparation of drugs that inhibit the proliferation and / or migration of liver cancer cells.

12. A pharmaceutical composition, characterized in that: It is any pharmaceutically acceptable dosage form made with magnolol derivatives or their pharmaceutically acceptable salts as active ingredients and pharmaceutically acceptable excipients, as described in any one of claims 1-4.

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