A phenylpropanoid compound, a preparation method and application thereof

Abstract

This invention belongs to the field of chemical medicine, specifically relating to a phenylpropanoid compound, its preparation method, and its application. The phenylpropanoid compound specifically refers to the compound, solvate, optically pure isomer, stereoisomer, or pharmaceutically acceptable salt thereof, or mixtures thereof, represented by general formula (Ⅰ), wherein X is selected from O or N; R1, R2, R3, R4, and R5 are the same or different, and are independently selected from hydrogen, hydroxyl, halogen, alkoxy, and alkylthio groups; R 13 Selected from hydrogen or C1-C4 alkyl, or R 13 Connect R5 to form a loop; R 14 The compounds are selected from cycloalkyl groups with 5-6 substituted carbon atoms. The phenylpropanoid compounds synthesized in this invention exhibit significant inhibitory effects on glioma cells, and their inhibitory effect is superior to that of the positive control drugs temozolomide and the original chlorogenic acid. Simultaneously, some of the synthesized phenylpropanoid compounds significantly improve neuronal cell survival rates, and their protective effect is superior to that of the positive control drug edaravone, demonstrating potential for treating stroke.

Description

Technical Field

[0001] This invention belongs to the field of chemical medicine, specifically relating to a phenylpropanoid compound, its preparation method, and its application. Background Technology

[0002] Gliomas are the most common primary malignant brain tumors. Because gliomas diffusely and infiltrate surrounding tissues, complete surgical removal is often impossible. After three cycles of temozolomide (TMZ) treatment, gliomas develop resistance, leading to high postoperative recurrence rates and short average survival. Therefore, new treatment methods for TMZ-resistant gliomas are urgently needed in clinical practice.

[0003] Ischemic stroke is the most common type of stroke. Neuroprotective agents such as edaravone, edaravone dexborneol, urokinase, butylphthalide, and cinnarizine maleate are important treatments for acute ischemic stroke (AIS). However, comparisons of relevant clinical guidelines at home and abroad reveal significant differences in recommendations regarding the use of neuroprotective agents in AIS. International guidelines do not mention or recommend drugs with neuroprotective effects for the treatment of AIS. Furthermore, none of the five neuroprotective agents mentioned above are marketed or used abroad, and their efficacy and safety require further confirmation through more high-quality clinical trials. Therefore, there is an urgent need to develop stroke drugs with higher safety and better efficacy.

[0004] Chlorogenic acid is a phenylpropanoid compound that can promote cancer cell apoptosis, inhibit cancer cell proliferation, metastasis, and invasion, and reduce cancer cell metabolism. Studies have shown that chlorogenic acid can inhibit tumor cell proliferation, induce apoptosis, inhibit the activation of MAPK kinase-4 phosphorylation, and upregulate cellular antioxidant enzymes, thus exhibiting multiple effects such as antitumor, antioxidant, and antiviral activity. Chlorogenic acid can promote the production of intracellular reactive oxygen species (ROS), which have a significant inhibitory effect on cancer cell growth. Chlorogenic acid can promote the transformation of macrophage M1 cells, enhancing its inhibitory effect on glioblastoma. Simultaneously, chlorogenic acid has a significant protective effect against oxidative stress damage to endothelial cells, showing great potential for the treatment of acute ischemic stroke. However, the poor stability and pharmacokinetic properties of chlorogenic acid limit its clinical application, necessitating structural modification to improve its pharmacokinetic properties and biological activity. Summary of the Invention

[0005] To address the above shortcomings, this invention provides a phenylpropanoid compound, its preparation method, and its application.

[0006] To solve the above-mentioned technical problems, the technical solution adopted by the present invention is as follows:

[0007] A phenylpropanoid compound is a compound, solvate, optically pure isomer, stereoisomer, or pharmaceutically acceptable salt thereof, or a mixture thereof, represented by the following general formula (I):

[0008]

[0009] Equation (Ⅰ)

[0010] Where X is selected from O or N;

[0011] key This indicates whether the key is a single or double key;

[0012] R1, R2, R3, R4, and R5 may be the same or different, and are independently selected from hydrogen, hydroxyl, halogen, alkoxy, and alkylthio groups;

[0013] R 13 Selected from hydrogen or C1-C4 alkyl, or R 13 Connect R5 to form a loop;

[0014] R 14 Selected from cycloalkyl groups having 5-6 carbon atoms with substituents.

[0015] In some implementations, the R 14 The substituents are selected from those shown in formula (II-A) or formula (II-B):

[0016]

[0017] R6 is selected from hydrogen, C1-C4 alkyl, alkoxycarbonyl, carboxyl, ethynyl, vinyl, and cyano.

[0018] R7, R8, R 10 R 11 R 12 Whether the groups are the same or different, they are independently selected from amino, carboxyl, oxydimethyl, alkoxycarbonyl, and C1-C4 alkyl groups protected by hydrogen, hydroxyl, amino, or tert-butoxycarbonyl.

[0019] R9 is selected from hydrogen, carboxyl, amide, or R8 and R9 can be cyclically formed through hydroxyl and carboxyl groups, respectively.

[0020] In some embodiments, R2 and R3 may be the same or different, and are independently selected from hydrogen, hydroxyl, and alkoxy groups having 1-5 carbon atoms;

[0021] R1, R4, and R5 may be the same or different, and are independently selected from hydrogen, hydroxyl, and halogen;

[0022] R 13 Selected from hydrogen or C1-C2 alkyl.

[0023] In some embodiments, R6 is selected from hydrogen, C1-C4 alkyl, alkoxycarbonyl, ethynyl, and carboxyl.

[0024] R7, R8, R 10 R 11 R 12 Whether the groups are the same or different, they are independently selected from hydrogen, hydroxyl, amino, alkoxycarbonyl or C1-C4 alkyl;

[0025] R9 is selected from hydrogen, substituted or unsubstituted amide groups, or R8 and R9 are cyclized through hydroxyl and carboxyl groups, respectively.

[0026] In some implementations, the R 14 When selected from formula (Ⅱ-A), R7, R8, R 10 R 11 R 12 Whether the same or different, they are independently selected from hydrogen, hydroxyl, amino or C1-C4 alkyl;

[0027] R2 and R3 are independently selected from hydrogen or hydroxyl groups;

[0028] X is selected from O or N.

[0029] In some embodiments, compounds selected from those shown in formula (III) or formula (IV) are used:

[0030]

[0031] Among them, R2 and R3 may be the same or different, and are independently selected from hydrogen and hydroxyl; R6 is selected from hydrogen, C1-C4 alkyl, carboxyl, ethynyl, and cyano.

[0032] R7 is selected from amino groups protected by hydrogen, hydroxyl, amino, or tert-butoxycarbonyl.

[0033] In formula (Ⅲ) R 10 Selected from hydrogen, tert-butoxycarbonyl-protected amino, carboxyl, oxydimethyl, and C1-C4 alkyl groups.

[0034] In some embodiments, compounds selected from those shown in formula (V) are used:

[0035]

[0036] R2 and R3 may be the same or different, and are independently selected from hydrogen and hydroxyl groups;

[0037] R6 is selected from hydrogen or alkoxycarbonyl;

[0038] R7, R 12 Whether the amino groups are the same or different, they are independently selected from those protected by hydrogen, hydroxyl, amino, or tert-butoxycarbonyl groups;

[0039] R 10Selected from hydrogen, alkoxycarbonyl, tert-butoxycarbonyl protected amino groups, oxy subunits, and C1-C4 alkyl groups.

[0040] In some embodiments, compounds selected from those shown in formula (VI) are used:

[0041]

[0042] Y is either O or N.

[0043] R1, R2, R3, R4, and R5 may be the same or different, and are independently selected from hydrogen, hydroxyl, halogen, alkoxy, and alkylthio groups; R 13 Selected from: hydrogen, C1-C4 alkyl, or R 13 Connect R5 to form a loop;

[0044] R 15 Selected from: hydrogen, benzyl, or -CO-YR 15 - It forms a ring with the hydroxyl group on the same carbon atom of the six-membered ring;

[0045] When Y is N, -YR 15 The following groups can be selected.

[0046]

[0047] In some embodiments, the compound is selected from:

[0048]

[0049] In some embodiments, when the substituents of the compound produce configurational isomers, all configurational isomers are included.

[0050] Another object of the present invention is to provide a method for preparing the phenylpropanoid compounds, comprising reacting caffeic acid or chlorogenic acid with substituted cycloalkyl groups in the presence of a catalyst.

[0051] In some embodiments, when preparing the compound represented by formula (III) or (IV), the substituted cycloalkyl group is a substituted cycloalcohol, and the catalyst is triethylamine.

[0052] In some implementations, the following steps are included:

[0053] (1) Dissolve caffeic acid in a solvent, add oxaloyl chloride and a catalytic amount of DMF:

[0054] (2) Dissolve the substituted cyclic alcohol and triethylamine in THF and add them to the reaction system of step (1). The reaction is then completed.

[0055] In some embodiments, the solvent is one or more of THF and DCM; the reaction temperature is 20-50°C, the reaction time is 12-24 h; the molar ratio of caffeic acid to oxaloyl chloride is 1:(1-3), and the amount of DMF is 5-10 drops; the molar ratio of caffeic acid to cycloalcohol and triethylamine is 1:((1-4):((1-2)).

[0056] In some implementations, after the reaction is completed by TLC monitoring, the mixture is filtered, the filtrate is mixed with silica gel, and the product is obtained by column chromatography.

[0057] In some embodiments, the eluent for column chromatography separation is a mixture of petroleum ether and ethyl acetate, with an elution gradient of petroleum ether:ethyl acetate = 10:1, 8:1, 5:1, 3:1, 1:1.

[0058] In some embodiments, when preparing the compound represented by formula (V), the substituted cycloalkyl group is a substituted cycloamine, and the catalyst is N,N'-dicyclohexylcarbodiimide.

[0059] Preferably, the reaction is carried out at 40–90°C for 2–16 hours in a sealed tube.

[0060] The reaction was carried out in anhydrous THF;

[0061] The molar ratio of caffeic acid to N,N'-dicyclohexylcarbodiimide and cyclic amine is 1:(1~2):(1~2);

[0062] After the reaction is complete, the mixture is filtered, and the filtrate is passed through a silica gel column and eluted to obtain the corresponding product.

[0063] In some embodiments, the eluent used for elution is a mixture of dichloromethane and methanol, and the elution gradient is dichloromethane:methanol = 200:1, 150:1, 100:1, 50:1, 25:1, 20:1.

[0064] In some embodiments, when preparing the compound represented by formula (VI), the substituted cycloalkyl group is various four-membered heterocyclic amines and primary amines, and the catalyst is (benzotriazol-1-yloxy)tris(1-pyrrolidinyl)phosphine hexafluorophosphate and N,N-diisopropylethylamine.

[0065] In some implementations, the following steps are included:

[0066] (1) Chlorogenic acid was dissolved in anhydrous THF, and amines, N,N-diisopropylethylamine and (benzotriazol-1-yloxy)tris(1-pyrrolidinyl)phosphine hexafluorophosphate were added. The reaction was carried out at room temperature for 2 to 16 hours to obtain the intermediate.

[0067] (2) Dissolve the intermediate in acetone, add potassium carbonate and iodomethane to the solution, and react at 20-50°C for 12-24 hours.

[0068] In some embodiments, the molar ratio of chlorogenic acid to amines, N,N-diisopropylethylamine and (benzotriazol-1-yloxy)tris(1-pyrrolidinyl)phosphine hexafluorophosphate is 1:(1-2):(1-4):(1-2);

[0069] In some embodiments, after the reaction in step (1) or step (2) is completed, the mixture is filtered, the filtrate is passed through a silica gel column, and eluted to obtain the corresponding product.

[0070] In some embodiments, the eluent used for elution is a mixture of dichloromethane and methanol, with a gradient of dichloromethane:methanol volume ratios of 200:1, 150:1, 100:1, 50:1, 25:1, 20:1, and 10:1.

[0071] Another object of the present invention is to provide a pharmaceutical preparation, wherein the raw materials of the pharmaceutical preparation include the phenylpropanoid compound or the phenylpropanoid compound prepared by the preparation method, and pharmaceutically acceptable excipients.

[0072] Another object of the present invention is to provide the application of the phenylpropanoid compound or the phenylpropanoid compound prepared by the preparation method or the pharmaceutical preparation thereon in the preparation of antitumor drugs.

[0073] In some embodiments, the tumor refers to a glioma.

[0074] In some embodiments, the phenylpropanoid compound is selected from:

[0075]

[0076] Another object of the present invention is to provide the use of the phenylpropanoid compound or the phenylpropanoid compound prepared by the preparation method or the pharmaceutical preparation described herein in the preparation of a drug for treating cardiovascular and cerebrovascular diseases or nerve damage.

[0077] In some embodiments, the cardiovascular and cerebrovascular disease is selected from stroke or its complications.

[0078] In some embodiments, the drug can significantly improve neuronal cell survival.

[0079] In some embodiments, the phenylpropanoid compound is selected from:

[0080]

[0081] Compared with the prior art, the positive and beneficial effects of the present invention are as follows:

[0082] (1) After screening the synthesized phenylpropanoid compounds for various glioma cell activity, these compounds showed significant inhibitory effects on glioma cells, and the inhibitory effect was better than that of the positive control drugs temozolomide and chlorogenic acid prototype.

[0083] (2) After screening the activity of primary cortical neurons in rats with hypoxia-glucose injury model using the synthesized phenylpropanoid compounds, these compounds showed that they could improve the survival rate of neurons, demonstrating neuroprotective effects. Moreover, the protective effects were superior to those of the positive control drug edaravone, and they have the potential to treat stroke. Attached Figure Description

[0084] Figure 1 The graph shows the relationship between the survival rate of compound III-1 and its concentration in GL261 cells at 24h, 48h, and 72h.

[0085] Figure 2 The graph shows the relationship between the survival rate of compound IV-1 and its concentration in GL261 cells after 24 hours.

[0086] Figure 3 The graph shows the relationship between the survival rate of compound III-3 and its concentration in GL261 cells after 24 hours.

[0087] Figure 4 The graph shows the relationship between the 24-hour survival rate of GL261 cells and their concentration of compound III-4.

[0088] Figure 5 The graph shows the relationship between the survival rate of compound III-5 and its concentration in GL261 cells after 24 hours.

[0089] Figure 6 The graph shows the relationship between the survival rate of compound III-2 and its concentration in GL261 cells after 24 hours.

[0090] Figure 7 The graph shows the relationship between the survival rate of the compound temozolomide and its concentration in GL261 cells at 24h, 48h, and 72h.

[0091] Figure 8 The graph shows the relationship between the survival rate of chlorogenic acid in GL261 cells at 24h, 48h and 72h and its concentration.

[0092] Figure 9 The graph shows the relationship between the survival rate of compound III-1 and its concentration in U251 cells at 24h, 48h, and 72h.

[0093] Figure 10 The graph shows the relationship between the survival rate of compound IV-1 and its concentration in U251 cells after 24 hours.

[0094] Figure 11The graph shows the relationship between the survival rate of compound III-3 and its concentration in U251 cells after 24 hours.

[0095] Figure 12 The graph shows the relationship between the survival rate of compound III-4 and its concentration in U251 cells after 24 hours.

[0096] Figure 13 The graph shows the relationship between the survival rate of compound III-5 and its concentration in U251 cells after 24 hours.

[0097] Figure 14 The graph shows the relationship between the survival rate of compound III-2 and its concentration in U251 cells after 24 hours.

[0098] Figure 15 The graph shows the relationship between the survival rate of the compound temozolomide and its concentration in U251 cells at 24h, 48h, and 72h.

[0099] Figure 16 The graph shows the relationship between the survival rate of the compound chlorogenic acid in U251 cells at 24h, 48h and 72h and its concentration.

[0100] Figure 17 The graph shows the relationship between the survival rate of compound III-1 and its concentration in U87 cells after 24 hours.

[0101] Figure 18 The graph shows the relationship between the survival rate of compound IV-1 and its concentration in U87 cells after 24 hours.

[0102] Figure 19 The graph shows the relationship between the survival rate of compound III-3 and its concentration in U87 cells after 24 hours.

[0103] Figure 20 The graph shows the relationship between the survival rate of compound III-4 and its concentration in U87 cells after 24 hours.

[0104] Figure 21 The graph shows the relationship between the survival rate of compound III-5 and its concentration in U87 cells after 24 hours.

[0105] Figure 22 The graph shows the relationship between the survival rate of compound III-2 and its concentration in U87 cells after 24 hours.

[0106] Figure 23 The graph shows the relationship between the 24-hour survival rate of the compound temozolomide and its concentration in U87 cells.

[0107] Figure 24 The graph shows the relationship between the survival rate of the compound chlorogenic acid in U87 cells and its concentration after 24 hours.

[0108] Figure 25 The graph shows the relationship between the survival rate of compound III-1 and its concentration in C6 cells after 24 hours.

[0109] Figure 26 The graph shows the relationship between the survival rate of compound IV-1 and its concentration in C6 cells after 24 hours.

[0110] Figure 27 The graph shows the relationship between the survival rate of compound III-3 and its concentration in C6 cells after 24 hours.

[0111] Figure 28 The graph shows the relationship between the survival rate of compound III-4 and its concentration in C6 cells after 24 hours.

[0112] Figure 29 The graph shows the relationship between the survival rate of compound III-5 and its concentration in C6 cells after 24 hours.

[0113] Figure 30 The graph shows the relationship between the survival rate of compound III-2 in C6 cells after 24 hours and its concentration.

[0114] Figure 31 The graph shows the relationship between the survival rate of the compound temozolomide in C6 cells after 24 hours and its concentration.

[0115] Figure 32 The graph shows the relationship between the 24-hour survival rate of C6 cells and the concentration of the compound chlorogenic acid.

[0116] Figure 33 The 1H NMR spectrum of compound III-1;

[0117] Figure 34 The image shows the carbon NMR spectrum of compound III-1.

[0118] Figure 35 The 1H NMR spectrum of compound III-4;

[0119] Figure 36 The image shows the carbon NMR spectrum of compound III-4.

[0120] Figure 37 The 1H NMR spectrum of compound III-5;

[0121] Figure 38 The image shows the carbon NMR spectrum of compound III-5.

[0122] Figure 39 The 1H NMR spectrum of compound III-7;

[0123] Figure 40 The 1H NMR spectrum of compound III-10;

[0124] Figure 41 The 1H NMR spectrum of compound III-11;

[0125] Figure 42The 1H NMR spectrum of compound III-13;

[0126] Figure 43 The 1H NMR spectrum of compound III-15;

[0127] Figure 44 The 1H NMR spectrum of compound IV-1;

[0128] Figure 45 The image shows the carbon NMR spectrum of compound IV-1.

[0129] Figure 46 The image shows the 1H NMR spectrum of compound V-1.

[0130] Figure 47 The image shows the carbon NMR spectrum of compound V-1.

[0131] Figure 48 The image shows the 1H NMR spectrum of compound V-2.

[0132] Figure 49 The 1H NMR spectrum of compound V-3;

[0133] Figure 50 The 1H NMR spectrum of compound V-5;

[0134] Figure 51 The 1H NMR spectrum of compound V-6;

[0135] Figure 52 The 1H NMR spectrum of compound V-8;

[0136] Figure 53 The 1H NMR spectrum of compound V-9;

[0137] Figure 54 The image shows the 1H NMR spectrum of compound VI-1.

[0138] Figure 55 The image shows the carbon NMR spectrum of compound VI-1.

[0139] Figure 56 The 1H NMR spectrum of compound VI-2;

[0140] Figure 57 The 1H NMR spectrum of compound VI-7;

[0141] Figure 58 The 1H NMR spectrum of compound VI-8;

[0142] Figure 59 The 1H NMR spectrum of compound VI-9;

[0143] Figure 60The 1H NMR spectrum of compound VI-10;

[0144] Figure 61 The image shows the 1H NMR spectrum of compound VI-11. Detailed Implementation

[0145] The present invention will be further described in detail below with reference to specific embodiments. The following embodiments are not intended to limit the present invention, but only to illustrate the present invention. Unless otherwise specified, the experimental methods used in the following embodiments are generally performed under conventional conditions. Unless otherwise specified, the materials and reagents used in the following embodiments are commercially available.

[0146] Example 1

[0147]

[0148] The synthesis method of (Ⅲ-1) is as follows:

[0149] Caffeic acid (2.00 g, 11.11 mmol) was dissolved in anhydrous THF (50 mL), and 7 drops of DMF were added. Oxaloyl chloride (2.82 g, 22.22 mmol) was added dropwise to the reaction system under ice bath conditions, and the mixture was stirred for 1.5 hours. 1-Methylcyclohexanol (5.06 g, 44.44 mmol) and triethylamine (2.24 g, 22.22 mmol) were dissolved in anhydrous THF (8 mL), and added dropwise to the reaction system under constant pressure using a dropping funnel under ice bath conditions. After the addition was complete, the mixture was transferred to 40 °C and reacted for 18 hours. After the reaction was completed by TLC monitoring, the white solid was filtered, and the filtrate was mixed with silica gel and subjected to dry column chromatography (eluent: ethyl acetate: petroleum ether = (0–18%): (100%–82%)), yielding 1.09 g of a yellow oily product, with a yield of 35.6% and a purity of 96.8%. m / z HRMS(ESI)found[M+H] + 277.1438, requires 277.1435.

[0150] 1 H NMR(600MHz,MeOD)δ(ppm)7.45(d,J=15.8Hz,1H),7.02(d,J=2.1Hz,1H),6.92(dd,J=8.1,2.1Hz,1H),6.77(d,J= 8.2Hz,1H),6.20(d,J=15.9Hz,1H),2.23(m,2H),1.63-1.53(m,5H),1.52(s,3H),1.48(m,2H),1.36-1.29(m,1H). 13C NMR (151MHz, MeOD) δ (ppm) 168.68, 149.39, 146.83, 145.81, 127.88, 122.76, 117.13, 116.53, 115.05, 82.98, 37.79, 26.49, 26.11, 23.21.

[0151] Example 2

[0152]

[0153] The synthesis method of (Ⅲ-2) is as follows:

[0154] III-1 (0.39 g, 1.41 mmol) was dissolved in anhydrous ethanol (10 mL), and Pd / C catalyst (100 mg) was added. The air was replaced with a hydrogen balloon, and the reaction was carried out at room temperature with stirring for 5 hours under a hydrogen atmosphere. After the reaction was completed, the Pd / C catalyst was filtered through diatomaceous earth, and the filter cake was washed once with ethanol. The filtrate was concentrated to obtain 0.37 g of an oily product, with a yield of 94.1% and a purity of 94.5%. [m / z HRMS (ESI) found [MH]] - 277.1446, requires 277.1445.

[0155] 1 H NMR(600MHz,MeOD)δ(ppm)6.66(d,J=8.0Hz,1H),6.64(d,J=2.1Hz,1H),6.52(dd,J=8.0,2.2Hz,1H),2.75(t,J= 7.7Hz,2H),2.52(t,J=7.7Hz,2H),2.23(m,2H),1.63-1.53(m,5H),1.52(s,3H),1.48(m,2H),1.36-1.29(m,1H). 13 C NMR (151MHz, MeOD) δ (ppm) 177.01, 146.23, 144.63, 133.79, 120.51, 116.44, 116.38, 82.98, 37.79, 37.19, 31.50, 26.49, 26.11, 23.21.

[0156] Example 3

[0157]

[0158] The synthesis method of (Ⅲ-3) is as follows:

[0159] Caffeic acid (1.00 g, 5.56 mmol) was dissolved in anhydrous THF (20 mL), and 7 drops of DMF were added. Oxaloyl chloride (1.41 g, 11.11 mmol) was added dropwise to the reaction system under ice bath conditions, and the mixture was stirred for 1.5 hours. 1-Ethynylcyclohexanol (2.76 g, 22.22 mmol) and triethylamine (1.12 g, 11.11 mmol) were dissolved in anhydrous THF (5 mL), and added dropwise to the reaction system under constant pressure using a dropping funnel under ice bath conditions. After the addition was complete, the mixture was transferred to 40 °C and reacted for 18 hours. After the reaction was completed by TLC monitoring, the white solid was filtered, and the filtrate was mixed with silica gel and subjected to dry column chromatography (eluent: ethyl acetate: petroleum ether = (0–18%): (100%–82%)), yielding 0.74 g of a yellow oily product, with a yield of 46.6% and a purity of 91.1%. m / z HRMS(ESI)found[MH] - 285.1127, requires 285.1132.

[0160] 1 H NMR (600MHz, Methanol-d4) δ (ppm) 7.50 (d, J = 15.8Hz, 1H), 7.03 (d, J = 2.1Hz, 1H), 6.94 (dd, J = 8.2, 2.1Hz, 1H), 6.78 (d, J = 8. 2Hz,1H),6.21(d,J=15.8Hz,1H),2.99(s,1H),2.16(m,2H),2.00-1.92(m,2H),1.67(m,4H),1.59-1.51(m,1H),1.41(m,1H). 13 C NMR(151MHz,Methanol-d4)δ(ppm)167.43,149.63,146.85,146.81,127.74, 122.99,116.54,115.92,115.15,84.65,76.48,76.06,38.26,26.22,23.60.

[0161] Example 4

[0162]

[0163] The synthesis method of (Ⅲ-4) is as follows:

[0164] Caffeic acid (0.50 g, 2.78 mmol) was dissolved in anhydrous THF (15 mL), and 7 drops of DMF were added. Oxaloyl chloride (0.71 g, 5.55 mmol) was added dropwise to the reaction system under ice bath conditions, and the mixture was stirred for 1.5 hours. 1-Ethylcyclohexanol (1.45 g, 11.11 mmol) and triethylamine (0.56 g, 5.55 mmol) were dissolved in anhydrous THF (5 mL), and added dropwise to the reaction system under constant pressure using a dropping funnel under ice bath conditions. After the addition was complete, the mixture was transferred to 40 °C and reacted for 18 hours. After the reaction was completed by TLC monitoring, the white solid was filtered, the filtrate was mixed with silica gel, and dry-mounted for column chromatography (eluent: ethyl acetate: petroleum ether = (0–18%): (100%–82%)), yielding 0.23 g of a white solid product, with a yield of 28.6% and a purity of 92.2%. m / z HRMS (ESI) found [MH] - 289.1439, requires 289.1445.

[0165] 1 H NMR (600MHz, Methanol-d4) δ (ppm) 7.46 (d, J = 15.8 Hz, 1H), 7.02 (d, J = 2.1 Hz, 1H) ,6.93(dd,J=8.2,2.1Hz,1H),6.77(d,J=8.1Hz,1H),6.21(d,J=15.9Hz,1H),2.31 -2.24(m,2H),1.96(q,J=7.5Hz,2H),1.63(dq,J=12.6,4.1Hz,1H),1.55(tt,J=8 .0,4.0Hz,4H),1.41(dt,J=13.9,7.9Hz,2H),1.33(m,1H),0.85(t,J=7.5Hz,3H). 13 C NMR (151MHz, Methanol-d4) δ (ppm) 168.55, 149.42, 146.84, 145.90, 127.88, 122.79, 116.91, 116.54, 115.06, 85.58, 35.43, 31.47, 26.77, 23.04, 7.69.

[0166] Example 5

[0167]

[0168] The synthesis method of (Ⅲ-5) is as follows:

[0169] Caffeic acid (0.40 g, 2.22 mmol) was dissolved in anhydrous THF (15 mL), and 5 drops of DMF were added. Oxaloyl chloride (0.56 g, 4.44 mmol) was added dropwise to the reaction system under ice bath conditions, and the mixture was stirred for 1.5 hours. Trans-4-methylcyclohexanol (1.00 g, 8.89 mmol) and triethylamine (0.45 g, 4.44 mmol) were dissolved in anhydrous THF (5 mL), and added dropwise to the reaction system under constant pressure using a dropping funnel under ice bath conditions. After the addition was complete, the mixture was transferred to 40 °C and reacted for 18 hours. After the reaction was completed by TLC monitoring, the white solid was filtered, and the filtrate was mixed with silica gel and subjected to dry column chromatography (eluent: ethyl acetate: petroleum ether = (0–18%): (100%–82%)), yielding 0.19 g of a white solid product, with a yield of 31.0% and a purity of 93.5%. m / z HRMS (ESI) found [MH] - 275.1290, requires 275.1288.

[0170] 1 H NMR (600MHz, Methanol-d4) δ (ppm) 7.50 (d, J = 15.9Hz, 1H), 7.02 (d, J = 2.1Hz, 1H), 6.93(dd,J=8.2,2.1Hz,1H),6.77(d,J=8.2Hz,1H),6.22(d,J=15.9Hz,1H),4.71( tt,J=11.1,4.4Hz,1H),2.00(ddd,J=13.0,4.9,2.5Hz,2H),1.77(dt,J=13.2,3.1 Hz,2H),1.42(m,3H),1.08(tdd,J=13.6,11.4,3.4Hz,2H),0.92(d,J=6.6Hz,3H). 13 C NMR (151MHz, Methanol-d4) δ (ppm) 168.91, 149.55, 146.85, 146.59, 127.79, 122.90, 116.52, 115.73, 115.10, 74.76, 34.22, 33.04, 32.87, 22.26.

[0171] Example 6

[0172]

[0173] The synthesis method of (Ⅳ-1) is as follows:

[0174] Caffeic acid (0.50 g, 2.78 mmol) was dissolved in anhydrous THF (15 mL), and 5 drops of DMF were added. Oxaloyl chloride (0.56 g, 5.55 mmol) was added dropwise to the reaction system under ice bath conditions, and the mixture was stirred for 1.5 hours. 1-Methylcyclopentanol (1.11 g, 11.11 mmol) and triethylamine (0.56 g, 5.55 mmol) were dissolved in anhydrous THF (5 mL), and added dropwise to the reaction system under constant pressure using a dropping funnel under ice bath conditions. After the addition was complete, the mixture was transferred to 40 °C and reacted for 18 hours. After the reaction was completed by TLC monitoring, the white solid was filtered, and the filtrate was mixed with silica gel and subjected to dry column chromatography (eluent: ethyl acetate: petroleum ether = (0–18%): (100%–82%)), yielding 0.15 g of a white solid product, with a yield of 20.6% and a purity of 93.7%. m / z HRMS (ESI) found [MH] - 261.1135, requires 261.1132.

[0175] 1 H NMR(600MHz,MeOD)δ(ppm)7.43(d,J=15.8Hz,1H),7.01(d,J=2.1Hz,1H),6.91(dd,J=8.2,2.1Hz,1H),6.77(d ,J=8.1Hz,1H),6.18(d,J=15.8Hz,1H),2.21-2.14(m,2H),1.79-1.72(m,4H),1.70-1.64(m,2H),1.59(s,3H). 13 C NMR (151MHz, MeOD) δ (ppm) 168.97, 149.37, 146.79, 145.89, 127.86, 122.78, 116.97, 116.51, 115.05, 91.11, 40.20, 24.77.

[0176] Example 7

[0177]

[0178] The synthesis method of (Ⅲ-6) is as follows:

[0179] Caffeic acid (0.20 g, 1.11 mmol) was dissolved in anhydrous THF (10 mL), and 5 drops of DMF were added. Oxaloyl chloride (0.28 g, 2.22 mmol) was added dropwise to the reaction system under ice bath conditions, and the mixture was stirred for 1.5 hours. 4-Hydroxycyclohexanone (0.51 g, 4.44 mmol) and triethylamine (0.22 g, 2.22 mmol) were dissolved in anhydrous THF (5 mL), and added dropwise to the reaction system under constant pressure using a dropping funnel under ice bath conditions. After the addition was complete, the mixture was transferred to 40 °C and reacted for 18 hours. After the reaction was completed by TLC monitoring, the white solid was filtered, and the filtrate was mixed with silica gel and subjected to dry column chromatography (eluent: ethyl acetate: petroleum ether = (0–18%): (100%–82%)), yielding 0.10 g of a white solid product, with a yield of 32.7% and a purity of 98.6%. m / z HRMS (ESI) found [M+H] + 277.1063, requires 277.1071.

[0180] 1 H NMR(600MHz,MeOD)δ(ppm)7.58(d,J=15.9Hz,1H),7.06(d,J=2.1Hz,1H),6.96(dd,J=8.3,2.2Hz,1H),6.78(dd,J=8.1,3.5Hz,1H),6.30(d,J=15.9 Hz,1H),5.24(tt,J=6.4,3.7Hz,1H),2.58(m,1H),2.51(m,1H),2.40(m,1 H),2.32(m,1H),2.18-2.10(m,2H),2.07-2.00(m,1H),1.84-1.79(m,1H).

[0181] Example 8

[0182]

[0183] The synthesis method of (Ⅲ-7) is as follows:

[0184] Caffeic acid (0.50 g, 2.78 mmol) was dissolved in anhydrous THF (20 mL), and 5 drops of DMF were added. Oxaloyl chloride (0.71 g, 5.56 mmol) was added dropwise to the reaction system under ice bath conditions, and the mixture was stirred for 1.5 hours. (1S,2S)-N-Boc-2-aminocyclohexanol (1.20 g, 5.56 mmol) and triethylamine (0.56 g, 5.56 mmol) were dissolved in anhydrous THF (5 mL), and added dropwise to the reaction system under ice bath conditions using a constant pressure dropping funnel. After the addition was complete, the mixture was transferred to 40 °C and reacted for 18 hours. After the reaction was completed by TLC monitoring, the white solid was filtered, and the filtrate was mixed with silica gel and subjected to dry column chromatography (eluent: ethyl acetate: petroleum ether = (0–18%): (100%–82%)) to obtain 0.35 g of a colorless oily product, with a yield of 33.8% and a purity of 94.6%. m / z HRMS(ESI)found[MH] - 376.1767 requires 376.1765.

[0185] 1 H NMR (600MHz, MeOD) δ (ppm) 7.54 (d, J = 15.8Hz, 1H), 7.02 (d, J = 2.1Hz, 1H), 6.92 (dd, J = 8.2, 2.1Hz, 1H), 6.76 (d, J = 8.1Hz, 1H), 6.21 (d, J =15.9Hz,1H),4.64(td,J=10.3,4.4Hz,1H),3.55(td,J=10.4,4.5Hz,1H),2.06(m,1H),1.93(m,1H),1.81-1.71(m,2H),1.35(m,13H).

[0186] Example 9

[0187]

[0188] The synthesis method of (Ⅲ-8) is as follows:

[0189] Caffeic acid (0.48 g, 2.67 mmol) was dissolved in anhydrous THF (10 mL), and 5 drops of DMF were added. Oxaloyl chloride (0.68 g, 5.33 mmol) was added dropwise to the reaction system under ice bath conditions, and the mixture was stirred for 1.5 hours. (1R,2R)-N-Boc-2-aminocyclohexanol (1.13 g, 5.33 mmol) and triethylamine (0.27 g, 2.67 mmol) were dissolved in anhydrous THF (5 mL), and added dropwise to the reaction system under ice bath conditions using a constant pressure dropping funnel. After the addition was complete, the mixture was transferred to 40 °C and reacted for 18 hours. After the reaction was completed by TLC monitoring, the white solid was filtered, and the filtrate was mixed with silica gel and subjected to dry column chromatography (eluent: ethyl acetate: petroleum ether = (0–33%): (100%–67%)) to obtain 0.53 g of a colorless oily product, with a yield of 53.0% and a purity of 97.5%. m / z HRMS(ESI)found[MH] - 376.1763, requires 376.1765.

[0190] 1 H NMR (600MHz, Methanol-d4) δ (ppm) 7.54 (d, J = 15.9Hz, 1H), 7.02 (d, J = 2.0Hz, 1H), 6.92 (dd, J = 8.2, 2.1Hz, 1H), 6.76 (d, J = 8.2Hz, 1H), 6.21 (d, J = 15.9Hz,1H),4.64(td,J=10.4,4.4Hz,1H),3.55(m,1H),2.09-2.02(m,1 H), 1.92 (dd, J = 8.8, 4.3Hz, 1H), 1.81-1.71 (m, 2H), 1.48-1.30 (m, 13H).

[0191] Example 10

[0192]

[0193] The synthesis method of (Ⅲ-9) is as follows:

[0194] Caffeic acid (0.50 g, 2.78 mmol) was dissolved in anhydrous THF (20 mL), and 5 drops of DMF were added. Oxaloyl chloride (0.71 g, 5.56 mmol) was added dropwise to the reaction system under ice bath conditions, and the mixture was stirred for 1.5 hours. Trans-N-Boc-4-aminocyclohexanol (1.20 g, 5.56 mmol) and triethylamine (0.56 g, 5.56 mmol) were dissolved in anhydrous THF (5 mL), and added dropwise to the reaction system under ice bath conditions using a constant pressure dropping funnel. After the addition was complete, the mixture was transferred to 40 °C and reacted for 18 hours. After the reaction was completed by TLC monitoring, the white solid was filtered, and the filtrate was mixed with silica gel and subjected to dry column chromatography (eluent: ethyl acetate: petroleum ether = (0–33%): (100%–67%)), yielding 0.50 g of a white solid product, with a yield of 47.7% and a purity of 94.9%. m / z HRMS(ESI)found[MH] - 376.1770, requires 376.1765.

[0195] 1 H NMR(600MHz, Methanol-d4)δ(ppm)7.54(d,J=15.9Hz,1H),7.04(d,J=2.0Hz,1H),6.94(dd,J=8.2,2.1Hz,1H),6.77(d,J=8.2Hz,1H),6.26(d,J=15.9H z,1H),4.80(tt,J=10.7,4.2Hz,1H),3.37(tt,J=10.9,3.7Hz,1H),2.07-2. 01(m,2H),1.99-1.93(m,2H),1.56(m,2H),1.43(s,9H),1.37-1.31(m,2H).

[0196] Example 11

[0197]

[0198] The synthesis method of (Ⅲ-10) is as follows:

[0199] Caffeic acid (0.25 g, 1.39 mmol) was dissolved in anhydrous THF (8 mL), and 3 drops of DMF were added. Oxaloyl chloride (0.35 g, 2.78 mmol) was added dropwise to the reaction system under ice bath conditions, and the mixture was stirred for 1.5 hours. Trans-1,2-cyclohexanediol (0.32 g, 2.78 mmol) and triethylamine (0.14 g, 1.39 mmol) were dissolved in anhydrous THF (3 mL), and added dropwise to the reaction system under constant pressure using a dropping funnel under ice bath conditions. After the addition was complete, the mixture was transferred to 40 °C and reacted for 18 hours. After the reaction was completed by TLC monitoring, the white solid was filtered, and the filtrate was mixed with silica gel and subjected to dry column chromatography (eluent: ethyl acetate: petroleum ether = (0–33%): (100%–67%)), yielding 0.25 g of a white solid product, with a yield of 64.7% and a purity of 99.9%. m / z HRMS(ESI)found[M+H] + 279.1216 requires 279.1227.

[0200] 1 H NMR (600MHz, Methanol-d4) δ (ppm) 7.56 (d, J = 15.8Hz, 1H), 7.04 (d, J = 2.1Hz, 1H), 6.94 (dd, J = 8.1, 2.1Hz, 1H), 6.77 (d, J = 8.1Hz, 1H), 6 .28(d,J=15.8Hz,1H),4.68-4.62(m,1H),3.59(ddd,J=10.3,8.7,4.5Hz,1H),2.07-1.97(m,2H),1.77-1.69(m,2H),1.43-1.30(m,4H).

[0201] Example 12

[0202]

[0203] The synthesis method of (Ⅲ-11) is as follows:

[0204] Caffeic acid (0.50 g, 2.78 mmol) was dissolved in anhydrous THF (15 mL), and 5 drops of DMF were added. Oxaloyl chloride (0.71 g, 5.56 mmol) was added dropwise to the reaction system under ice bath conditions, and the mixture was stirred for 1.5 hours. Cis-4-hydroxycyclohexanecarboxylic acid (1.60 g, 11.11 mmol) and triethylamine (0.56 g, 5.56 mmol) were dissolved in anhydrous THF (5 mL), and added dropwise to the reaction system under constant pressure using a dropping funnel under ice bath conditions. After the addition was complete, the mixture was transferred to 40 °C and reacted for 18 hours. After the reaction was completed by TLC monitoring, the white solid was filtered, and the filtrate was mixed with silica gel and subjected to dry column chromatography (eluent: methanol: dichloromethane = (0–10%):(100%–90%)), yielding 0.10 g of a white solid product, with a yield of 11.8% and a purity of 92.84%. m / z HRMS(ESI)found[MH] - 305.1027 requires 305.1030.

[0205] 1 H NMR (600MHz, Methanol-d4) δ (ppm) 7.55 (d, J = 15.8Hz, 1H), 7.06 (d, J = 2.1Hz, 1H), 6.96 (dd, J = 8.2, 2.1Hz, 1H), 6.79 (d, J = 8.1 Hz,1H),6.28(d,J=15.9Hz,1H),5.02(tt,J=5.2,2.9Hz,1H),2.49-2.40(m,1H),1.90(m,4H),1.78(m,2H),1.74-1.67(m,2H).

[0206] Example 13

[0207]

[0208] The synthesis method of (Ⅲ-12) is as follows:

[0209] Caffeic acid (0.14 g, 0.79 mmol) was dissolved in anhydrous THF (5 mL), and 3 drops of DMF were added. Oxaloyl chloride (0.20 g, 1.57 mmol) was added dropwise to the reaction system under ice bath conditions, and the mixture was stirred for 1.5 hours. α-Hydroxy-cyclohexylcarboxylic acid (0.45 g, 3.16 mmol) and triethylamine (0.16 g, 1.57 mmol) were dissolved in anhydrous THF (2 mL), and added dropwise to the reaction system under constant pressure using a dropping funnel under ice bath conditions. After the addition was complete, the mixture was transferred to 40 °C and reacted for 18 hours. After the reaction was completed by TLC monitoring, the white solid was filtered, the filtrate was mixed with silica gel, and dry-mounted for column chromatography (eluent: methanol: dichloromethane = (0–3%):(100%–97%)), yielding 0.08 g of a white solid product, with a yield of 33.1% and a purity of 88.7%. m / z HRMS (ESI) found [MH] - 305.1024 requires 305.1030.

[0210] 1 H NMR(600MHz, Methanol-d4)δ(ppm)7.55(d,J=15.9Hz,1H),7.06(d,J=2.1Hz,1H),6.96(dd,J=8.2,2.1Hz,1H), 6.79(d,J=8.2Hz,1H),6.30(d,J=15.9Hz,1H),2.25-2.18(m,2H),1.84(m,2H),1.65(m,5H),1.41-1.34(m,1H).

[0211] Example 14

[0212]

[0213] The synthesis method of (Ⅲ-13) is as follows:

[0214] 3-Hydroxycinnamic acid (1.00 g, 6.10 mmol) was dissolved in anhydrous THF (30 mL), and 7 drops of DMF were added. Oxaloyl chloride (1.55 g, 12.20 mmol) was added dropwise to the reaction system under ice bath conditions, and the mixture was stirred for 1.5 hours. 1-Methylcyclohexanol (2.78 g, 24.40 mmol) and triethylamine (1.23 g, 12.20 mmol) were dissolved in anhydrous THF (7 mL), and added dropwise to the reaction system under ice bath conditions using a constant pressure dropping funnel. After the addition was complete, the mixture was transferred to 40 °C and reacted for 18 hours. After the reaction was completed by TLC monitoring, the white solid was filtered, and the filtrate was mixed with silica gel and subjected to dry column chromatography (eluent: ethyl acetate: petroleum ether = (0–25%): (100%–75%)), yielding 0.20 g of product, with a yield of 12.7% and a purity of 96.3%. m / z HRMS (ESI) found [MH] - 259.1339, requires 259.1339.

[0215] 1 H NMR (600MHz, Methanol-d4) δ (ppm) 7.51 (d, J = 15.9Hz, 1H), 7.21 (t, J = 7.9Hz, 1H), 7.03 (dt, J = 7.7, 1.3Hz, 1H), 6.98 (t, J = 2.1Hz, 1H), 6 .82(ddd,J=8.1,2.5,0.9Hz,1H),6.38(d,J=15.9Hz,1H),2.23(m,2H),1.64-1.53(m,5H),1.53(s,3H),1.49(m,2H),1.38-1.30(m,1H).

[0216] Example 15

[0217]

[0218] The synthesis method of (Ⅲ-14) is as follows:

[0219] Cinnamic acid (0.50 g, 3.38 mmol) was dissolved in anhydrous THF (20 mL), and 5 drops of DMF were added. Oxaloyl chloride (0.86 g, 6.76 mmol) was added dropwise to the reaction system under ice bath conditions, and the mixture was stirred for 1.5 hours. 1-Methylcyclohexanol (1.54 g, 13.51 mmol) and triethylamine (0.68 g, 6.76 mmol) were dissolved in anhydrous THF (5 mL), and added dropwise to the reaction system under ice bath conditions using a constant pressure dropping funnel. After the addition was complete, the mixture was transferred to 40 °C and reacted for 18 hours. After the reaction was completed by TLC monitoring, the white solid was filtered, and the filtrate was mixed with silica gel and subjected to column chromatography (eluent: ethyl acetate: petroleum ether = (0–3%): (100%–97%)) using a dry method, yielding 0.10 g of product, with a yield of 12.1% and a purity of 94.4%. m / z HRMS (ESI) found [M+H] + 245.1531, requires 245.1537.

[0220] 1 H NMR (600MHz, Methanol-d4) δ (ppm) 7.59 (d, J = 16.0Hz, 1H), 7.57-7.54 (m, 2H), 7.38 (m, 3H), 6.45 (d, J=16.0Hz,1H),2.27-2.20(m,2H),1.63-1.53(m,5H),1.53(s,3H),1.52-1.45(m,2H),1.33(m,1H).

[0221] Example 16

[0222]

[0223] The synthesis method of (Ⅲ-15) is as follows:

[0224] 3,4-Dihydroxybenzoic acid (1.00 g, 6.49 mmol) was dissolved in anhydrous THF (30 mL), and 7 drops of DMF were added. Oxaloyl chloride (1.65 g, 12.99 mmol) was added dropwise to the reaction system under ice bath conditions, and the mixture was stirred for 1.5 hours. 1-Methylcyclohexanol (2.96 g, 25.97 mmol) and triethylamine (1.31 g, 12.99 mmol) were dissolved in anhydrous THF (5 mL), and added dropwise to the reaction system under constant pressure using a dropping funnel under ice bath conditions. After the addition was complete, the mixture was transferred to 40 °C and reacted for 18 hours. After the reaction was completed by TLC monitoring, the white solid was filtered, and the filtrate was mixed with silica gel and subjected to column chromatography (eluent: ethyl acetate: petroleum ether = (0–20%): (100%–80%)) to obtain 0.44 g of the product, with a yield of 27.1% and a purity of 92.3%. m / z HRMS(ESI)found[MH] -249.1131, requires 249.1132.

[0225] 1 H NMR (600MHz, Methanol-d4) δ (ppm) 7.42 (d, J = 2.1Hz, 1H), 7.38 (dd, J = 8.3, 2.1Hz, 1H), 6.79 (d ,J=8.3Hz,1H),2.31(m,2H),1.67-1.56(m,5H),1.55(s,3H),1.49(m,2H),1.36-1.32(m,1H).

[0226] Example 17

[0227]

[0228] The synthesis method of (V-1) is as follows:

[0229] Caffeic acid (1.00 g, 5.56 mmol) was dissolved in anhydrous THF (20 mL). N,N'-dicyclohexylcarbodiimide (1.15 g, 5.56 mmol) and (1R,2R)-2-aminocyclohexanol (0.64 g, 5.56 mmol) were added sequentially to the solution. The tube was sealed and the reaction was carried out at 75 °C for 3.5 h. After the reaction was completed, the white solid was filtered, and the filtrate was mixed with silica gel and dry-mounted for column chromatography (eluent: methanol: dichloromethane = (0–5%):(100%–95%)). 1.00 g of the product was obtained, with a yield of 65.0% and a purity of 97.6%. [m / z HRMS (ESI) found [M+H]] + 278.1388, requires 278.1387.

[0230] 1 H NMR (600MHz, MeOD) δ (ppm) 7.39 (d, J = 15.6Hz, 1H), 7.01 (d, J = 2.1Hz, 1H), 6.90 (dd, J = 8.2, 2.1Hz, 1H), 6.76 (d, J = 8.1Hz, 1H), 6.40 (d, J = 15.6Hz,1H),3.67(ddd,J=10.9,9.5,4.3Hz,1H),3.39(td,J=9.8,4.3Hz,1H),2.05-1.93(m,2H),1.78-1.67(m,2H),1.40-1.26(m,4H). 13C NMR (151MHz, MeOD) δ (ppm) 169.50, 148.74, 146.75, 142.15, 128.46, 122.10, 118.83, 116.49, 115.10, 74.19, 56.48, 35.49, 32.69, 25.73, 25.40.

[0231] Example 18

[0232]

[0233] The synthesis method of (V-2) is as follows:

[0234] Caffeic acid (0.18 g, 1.00 mmol) was dissolved in anhydrous THF (4 mL). N,N'-dicyclohexylcarbodiimide (0.21 g, 1.00 mmol) and (1S,2S)-2-aminocyclohexanol (0.12 g, 1.00 mmol) were added sequentially to the solution. The tube was sealed and the reaction was carried out at 75 °C for 3.5 hours. After the reaction was completed, the white solid was filtered, and the filtrate was mixed with silica gel and dry-mounted for column chromatography (eluent: methanol: dichloromethane = (0–5%):(100%–95%)). 0.27 g of the product was obtained, with a yield of 97.5% and a purity of 91.8%. m / z HRMS (ESI) found [M+H] + 278.1388, requires 278.1387.

[0235] 1 H NMR (600MHz, Methanol-d4) δ (ppm) 7.39 (d, J = 15.6Hz, 1H), 7.00 (d, J = 2.0Hz, 1H), 6.90 (dd, J = 8.2, 2.1Hz, 1H), 6.76 (d, J = 8.1Hz, 1H), 6.40 ( d,J=15.6Hz,1H),3.67(ddd,J=11.0,9.5,4.3Hz,1H),3.39(td,J=9.8,4.3Hz,1H),2.04-1.94(m,2H),1.77-1.68(m,2H),1.36-1.24(m,4H).

[0236] Example 19

[0237]

[0238] The synthesis method of (V-3) is as follows:

[0239] Caffeic acid (0.18 g, 1.00 mmol) was dissolved in anhydrous THF (4 mL). N,N'-dicyclohexylcarbodiimide (0.21 g, 1.00 mmol) and methyl 1-aminocyclohexanecarboxylate (0.16 g, 1.00 mmol) were added sequentially to the solution. The tube was sealed and the reaction was carried out at 75 °C for 3.5 h. After the reaction was completed, the white solid was filtered, and the filtrate was mixed with silica gel and dry-mounted for column chromatography (eluent: methanol: dichloromethane = (0–5%):(100%–95%)). 0.25 g of the product was obtained, with a yield of 78.4% and a purity of 97.7%. [m / z HRMS (ESI) found [M+H]] + 320.1487, requires 320.1493.

[0240] 1 H NMR (600MHz, Methanol-d4) δ (ppm) 7.33 (d, J = 15.6Hz, 1H), 7.01 (d, J = 2.1Hz, 1H), 6.91 (dd, J = 8.2, 2.1Hz, 1H), 6.76 (d, J = 8.1Hz, 1H), 6.50 (d,J=15.7Hz,1H),3.67(s,3H),2.05(dd,J=13.4,4.5Hz,2H),1.87(ddd,J=14.1,11.0,3.9Hz,2H),1.66-1.53(m,5H),1.40-1.33(m,1H).

[0241] Example 20

[0242]

[0243] The synthesis method of (V-4) is as follows:

[0244] 4-Aminocyclohexanone hydrochloride (0.15 g, 1.00 mmol) was dissolved in anhydrous THF (4 mL). Triethylamine (0.10 g, 1.00 mmol) was added to the solution, and the mixture was stirred at room temperature for 5 minutes. Then, caffeic acid (0.18 g, 1.00 mmol) and N,N'-dicyclohexylcarbodiimide (0.21 g, 1.00 mmol) were added sequentially, and the mixture was sealed and reacted at 75 °C for 3.5 hours. After the reaction was completed by TLC monitoring, the white solid was filtered, and the filtrate was mixed with silica gel and dry-mounted for column chromatography (eluent: methanol:dichloromethane = (0–5%):(100%–95%)). The product yielded 0.06 g, with a yield of 22.2% and a purity of 95.2%. m / z HRMS (ESI) found [M+H] + 276.1226, requires 276.1231.

[0245] 1 H NMR (600MHz, Methanol-d4) δ (ppm) 7.42 (d, J = 15.6Hz, 1H), 7.01 (d, J = 2.0Hz, 1H), 6.90 (dd, J = 8.1, 2.0Hz, 1H), 6.77 (d ,J=8.1Hz,1H),6.38(d,J=15.7Hz,1H),4.26(m,1H),2.57-2.49(m,2H),2.20(m,2H),1.79(m,2H),1.64-1.45(m,2H).

[0246] Example 21

[0247]

[0248] The synthesis method of (V-5) is as follows:

[0249] Methyl trans-4-aminocyclohexane hydrochloride (0.19 g, 1.00 mmol) was dissolved in anhydrous THF (4 mL). Triethylamine (0.10 g, 1.00 mmol) was added to the solution, and the mixture was stirred at room temperature for 5 minutes. Then, caffeic acid (0.18 g, 1.00 mmol) and N,N'-dicyclohexylcarbodiimide (0.21 g, 1.00 mmol) were added sequentially, and the mixture was sealed and reacted at 75 °C for 3.5 hours. After the reaction was completed by TLC monitoring, the white solid was filtered, and the filtrate was mixed with silica gel and dry-mounted for column chromatography (eluent: methanol: dichloromethane = (0–4%):(100%–96%)). The product yielded 0.18 g, with a yield of 56.4% and a purity of 96.2%. m / z HRMS (ESI) found [M+H] + 320.1485, requires 320.1493.

[0250] 1 H NMR (600MHz, Methanol-d4) δ (ppm) 7.37 (d, J = 15.7Hz, 1H), 6.99 (d, J = 2.1Hz, 1H), 6.89 (dd, J = 8.2, 2.1Hz, 1H), 6.76 (d, J = 8. 1Hz,1H),6.33(d,J=15.6Hz,1H),3.73(m,1H),3.66(s,3H),2.31(m,1H),2.02(m,4H),1.58-1.49(m,2H),1.35-1.29(m,2H).

[0251] Example 22

[0252]

[0253] The synthesis method of (V-6) is as follows:

[0254] Caffeic acid (0.36 g, 2.00 mmol) was dissolved in anhydrous THF (8 mL). N,N'-dicyclohexylcarbodiimide (0.41 g, 2.00 mmol) and (1S,2R)-2-aminocyclohexylcarbamate tert-butyl ester (0.43 g, 2.00 mmol) were added sequentially to the solution. The tube was sealed and the reaction was carried out at 75 °C for 3.5 h. After the reaction was completed, the white solid was filtered, and the filtrate was mixed with silica gel and dry-mounted for column chromatography (eluent: methanol: dichloromethane = (0–5%):(100%–95%)). 0.60 g of the product was obtained, with a yield of 79.8% and a purity of 95.0%. m / z HRMS (ESI) found [M+H] + 377.2065, requires 377.2071.

[0255] 1 HNMR(600MHz,Methanol-d4)δ(ppm)7.38(d,J=15.7Hz,1H),7.00(d,J=2.1Hz,1H),6.90(dd,J=8.2,2.1Hz,1H ), 6.76 (d, J = 8.1Hz, 1H), 6.44 (d, J = 15.7Hz, 1H), 4.16 (s, 1H), 3.83 (s, 1H), 1.70-1.55 (m, 6H), 1.42 (m, 11H).

[0256] Example 23

[0257]

[0258] The synthesis method of (V-7) is as follows:

[0259] (1S,2R)-2-aminocyclohexanol hydrochloride (0.15 g, 1.00 mmol) was dissolved in anhydrous THF (4 mL). Triethylamine (0.10 g, 1.00 mmol) was added to the solution, and the mixture was stirred at room temperature for 5 minutes. Then, caffeic acid (0.18 g, 1.00 mmol) and N,N'-dicyclohexylcarbodiimide (0.21 g, 1.00 mmol) were added sequentially, and the mixture was sealed and reacted at 75 °C for 3.5 hours. After the reaction was completed by TLC monitoring, the white solid was filtered, and the filtrate was mixed with silica gel and subjected to dry column chromatography (eluent: methanol: dichloromethane = (0–4%):(100%–96%)) to obtain 0.19 g of product, with a yield of 67.9% and a purity of 98.0%. m / z HRMS (ESI) found [M+H] + 278.1377, requires 278.1387.

[0260] 1 H NMR(600MHz,Methanol-d4)δ(ppm)7.38(d,J=15.6Hz,1H),7.01(d,J=2.0Hz,1H),6.91(dd,J=8.2,2.1Hz,1H),6.76(d,J=8.1H z,1H),6.47(d,J=15.6Hz,1H),3.95-3.89(m,2H),1.84-1.78(m,1H),1.76-1.67(m,2H),1.67-1.55(m,3H),1.44-1.37(m,2H).

[0261] Example 24

[0262]

[0263] The synthesis method of (V-8) is as follows:

[0264] V-6 (0.16 g, 0.42 mmol) was dissolved in anhydrous DCM (3 mL), and trifluoroacetic acid (3 mL) was added to the solution. The mixture was stirred at room temperature for 2 hours. After the reaction was completed by TLC monitoring, the solution was concentrated to remove the solvent and trifluoroacetic acid. The solution was then diluted with methanol, mixed with silica gel, and subjected to dry column chromatography (eluent: methanol: dichloromethane = (0–9%):(100%–91%)), yielding 0.12 g of product, with a yield of 99.9% and a purity of 99.9%. m / z HRMS (ESI) found [M+H] + 277.1536, requires 277.1547.

[0265] 1 H NMR (600MHz, Methanol-d4) δ (ppm) 7.45 (d, J = 15.6Hz, 1H), 7.04 (d, J = 2.0Hz, 1H), 6.93 (dd, J = 8.1, 2.0Hz, 1H), 6.77 (d, J = 8.1Hz ,1H),6.58(d,J=15.6Hz,1H),4.43(m,1H),3.42(m,1H),1.82(m,3H),1.78-1.75(m,1H),1.70(m,2H),1.59(m,1H),1.50(m,1H).

[0266] Example 25

[0267]

[0268] The synthesis method of (V-9) is as follows:

[0269] Caffeic acid (0.36 g, 2.00 mmol) was dissolved in anhydrous THF (8 mL). N,N'-dicyclohexylcarbodiimide (0.41 g, 2.00 mmol) and cis-4-aminocyclohexanol (0.23 g, 2.00 mmol) were added sequentially to the solution. The tube was sealed and the reaction was carried out at 75 °C for 3.5 hours. After the reaction was completed, the white solid was filtered, and the filtrate was mixed with silica gel and dry-mounted for column chromatography (eluent: methanol: dichloromethane = (0–6%):(100%–94%)). 0.24 g of the product was obtained, with a yield of 43.3% and a purity of 99.4%. m / z HRMS (ESI) found [M+H] + 278.1387, requires 278.1387.

[0270] 1 H NMR(600MHz,Methanol-d4)δ(ppm)7.38(d,J=15.6Hz,1H),7.00(d,J=2.0Hz,1H),6.90(dd,J=8.1,2.1Hz,1H),6.76(d,J=8.1H z, 1H), 6.40 (d, J = 15.6Hz, 1H), 3.86 (tt, J = 5.4, 2.8Hz, 1H), 3.82 (tt, J = 8.8, 3.8Hz, 1H), 1.79-1.70 (m, 4H), 1.70-1.62 (m, 4H).

[0271] Example 26

[0272]

[0273] The synthesis method of (VI-1) is as follows:

[0274] first step:

[0275] Chlorogenic acid (2.00 g, 5.65 mmol) was dissolved in anhydrous THF (30 mL). Benzylamine (0.66 g, 6.22 mmol), N,N-diisopropylethylamine (1.45 g, 11.3 mmol), and (benzotriazol-1-yloxy)tris(1-pyrrolidinyl)phosphine hexafluorophosphate (2.94 g, 5.65 mmol) were added sequentially to the solution, and the reaction was carried out at room temperature for 16 hours. After the reaction was completed, the reaction solution was mixed with silica gel and subjected to dry column chromatography (eluent: methanol: dichloromethane = (0–6%):(100%–94%)), yielding 2.20 g of VI-1-intermediate, with a yield of 87.9% and a purity of 84.5%. m / z HRMS (ESI) found [M+H] + 444.1657, requires 444.1653.

[0276] Step Two:

[0277] VI-1-intermediate (2.2 g, 4.97 mmol) was dissolved in acetone (50 mL). Potassium carbonate (3.43 g, 24.8 mmol) and methyl iodide (3.53 g, 24.8 mmol) were added sequentially to the solution, and the reaction was carried out at 40 °C for 24 hours. After the reaction was completed, the white solid was filtered, and the filtrate was mixed with silica gel and subjected to dry column chromatography (eluent: methanol: dichloromethane = (0–3%):(100%–97%)), yielding 1.40 g of product, with a yield of 60.0% and a purity of 93.3%. m / z HRMS (ESI) found [M+H] + 472.1950, requires 472.1966.

[0278] 1 H NMR(600MHz,DMSO-d6)δ(ppm)8.35(t,J=6.4Hz,1H),7.60(d,J=15.9Hz,1H),7.35(d,J=2.1Hz,1H),7.32-7.28(m,2H) ,7.24(dd,J=8.3,2.0Hz,1H),7.23-7.19(m,3H),6.99(d,J=8.4Hz,1H),6.55(d,J=15.9Hz,1H),5.69(d,J=3.9Hz,1H), 5.66(s,1H),5.30(ddd,J=11.3,9.7,5.1Hz,1H),5.04(d,J=5.9Hz,1H),4.32-4.23(m,2H),4.11(p,J=3.2Hz,1H),3.81 (s,3H),3.80(s,3H),3.59(ddd,J=9.4,6.0,2.9Hz,1H),2.04-1.95(m,2H),1.92(m,1H),1.82(dt,J=14.5,3.3Hz,1H). 13 C NMR(151MHz,DMSO-d6)δ(ppm)173.67,166.14,150.80,148.88,144.36,139.57,128.10,126.84,126. 77,126.49,122.77,115.97,111.41,110.14,76.12,72.20,70.83,70.31,55.48,55.44,41.76,37.45.

[0279] Example 27

[0280]

[0281] The synthesis method of (VI-2) is as follows:

[0282] Chlorogenic acid (0.30 g, 0.85 mmol) was dissolved in anhydrous THF (10 mL). Methyl 3-oxopropyl ester hydrochloride (0.14 g, 0.93 mmol), N,N-diisopropylethylamine (0.23 g, 1.69 mmol), and (benzotriazol-1-yloxy)tris(1-pyrrolidinyl)phosphine hexafluorophosphate (0.44 g, 0.85 mmol) were added sequentially to the solution, and the reaction was carried out at room temperature for 3 hours. After the reaction was completed, the reaction solution was mixed with silica gel and dry-mounted for column chromatography (eluent: methanol: dichloromethane = (0–6%):(100%–94%)), yielding 0.21 g of product, with a yield of 54.2% and a purity of 97.4%. m / z HRMS (ESI) found [M+H] + 452.1538, requires 452.1552.

[0283] 1 H NMR(600MHz,Methanol-d4)δ(ppm)7.57(d,J=16.2Hz,1H),7.05(d,J=2.0Hz,1H),6.95(dt,J=8.4,1.6Hz,1H),6.78(d, J=8.1Hz,1H),6.29(dd,J=15.9,2.0Hz,1H),5.36(tdd,J=10.6,7.6,5.0Hz,1H),4.72(td,J=10.6,8.7Hz,1H),4.62(ddd ,J=12.7,10.4,6.0Hz,1H),4.22(p,J=3.4Hz,1H),4.14(dt,J=18.9,9.7Hz,1H),4.06(ddd,J=18.2,10.3,5.9Hz,1H),3 .73(d,J=14.0Hz,3H),3.69(dd,J=9.4,3.1Hz,1H),3.47(tq,J=9.1,6.1Hz,1H),2.22(m,1H),2.06(m,2H),2.00(m,1H).

[0284] Example 28

[0285]

[0286] The synthesis method of (VI-3) is as follows:

[0287] Chlorogenic acid (0.30 g, 0.85 mmol) was dissolved in anhydrous THF (10 mL). 3-Methoxyazacyclobutane hydrochloride (0.12 g, 0.93 mmol), N,N-diisopropylethylamine (0.23 g, 1.69 mmol), and (benzotriazol-1-yloxy)tris(1-pyrrolidinyl)phosphine hexafluorophosphate (0.44 g, 0.85 mmol) were added sequentially to the solution, and the reaction was carried out at room temperature for 3 hours. After the reaction was completed, the reaction solution was mixed with silica gel and dry-mounted for column chromatography (eluent: methanol:dichloromethane = (0–6%):(100%–94%)), yielding 0.21 g of product, with a yield of 57.5% and a purity of 97.5%. m / z HRMS (ESI) found [M+H] + 424.1589, requires 424.1603.

[0288] 1 H NMR (600MHz, Methanol-d4) δ (ppm) 7.47 (d, J = 15.9Hz, 1H), 6.96 (d, J = 2.1Hz, 1H), 6.85 (dd, J = 8.3, 2.2Hz, 1 H),6.68(d,J=8.2Hz,1H),6.18(d,J=15.9Hz,1H),5.26(ddt,J=10.7,8.9,4.4Hz,1H),4.59(tdd,J=11.5,6 .1,1.5Hz,1H),4.25-4.18(m,1H),4.12(dq,J=6.8,3.5Hz,1H),4.09-4.04(m,1H),4.04-3.98(m,1H),3.67 (m,1H),3.61-3.57(m,1H),3.16(d,J=9.0Hz,3H),2.15-2.08(m,1H),1.99-1.93(m,2H),1.93-1.86(m,1H).

[0289] Example 29

[0290]

[0291] The synthesis method of (VI-4) is as follows:

[0292] Chlorogenic acid (0.30 g, 0.85 mmol) was dissolved in anhydrous THF (10 mL). 3-Fluorozylidene hydrochloride (0.11 g, 0.93 mmol), N,N-diisopropylethylamine (0.23 g, 1.69 mmol), and (benzotriazol-1-yloxy)tris(1-pyrrolidinyl)phosphine hexafluorophosphate (0.44 g, 0.85 mmol) were added sequentially to the solution, and the reaction was carried out at room temperature for 3 hours. After the reaction was completed, the reaction solution was mixed with silica gel and dry-mounted for column chromatography (eluent: methanol:dichloromethane = (0–6%):(100%–94%)), yielding 0.3 g of product, with a yield of 86.1% and a purity of 90.1%. m / z HRMS (ESI) found [M+H] + 412.1410 requires 412.1403.

[0293] 1 H NMR (600MHz, Methanol-d4) δ (ppm) 7.57 (dd, J = 15.9, 3.2 Hz, 1H), 7.05 (d, J = 2.0 Hz,1H),6.95(dt,J=8.3,1.6Hz,1H),6.78(d,J=8.1Hz,1H),6.29(dd,J=15.9,3 .1Hz,1H),5.40-5.21(m,2H),4.61-4.49(m,1H),4.25(m,2H),3.99(m,1H),3.6 9-3.67(m,1H),2.24-2.19(m,1H),2.08(m,1H),2.04(m,1H),2.02-1.94(m,1H).

[0294] Example 30

[0295]

[0296] The synthesis method of (VI-5) is as follows:

[0297] Chlorogenic acid (0.20 g, 0.56 mmol) was dissolved in anhydrous THF (10 mL). 3-(Boc-amino)azacyclobutane hydrochloride (0.13 g, 0.62 mmol), N,N-diisopropylethylamine (0.15 g, 1.13 mmol), and (benzotriazol-1-yloxy)tris(1-pyrrolidinyl)phosphine hexafluorophosphate (0.29 g, 0.56 mmol) were added sequentially to the solution, and the reaction was carried out at room temperature for 16 hours. After the reaction was completed, the reaction solution was mixed with silica gel and dry-mounted for column chromatography (eluent: methanol: dichloromethane = (0–6%):(100%–94%)), yielding 0.11 g of product, with a yield of 38.7% and a purity of 94.5%. m / z HRMS (ESI) found [M+H] + 509.2128 requires 509.2130.

[0298] 1 H NMR (600MHz, Methanol-d4) δ (ppm) 7.58 (d, J = 15.9 Hz, 1H), 7.06 (d, J = 2.0 Hz, 1H), 6.95 (dd,J=8.3,2.1Hz,1H),6.79(d,J=8.1Hz,1H),6.29(d,J=15.9Hz,1H),5.37(td,J=10. 2,4.6Hz,1H),4.80-4.74(m,1H),4.38-4.30(m,2H),4.23(q,J=3.4Hz,1H),3.86-3.76 (m,1H),3.72-3.65(m,2H),2.24(m,1H),2.11-2.04(m,2H),2.01(m,1H),1.43(m,9H).

[0299] Example 31

[0300]

[0301] The synthesis method of (VI-6) is as follows:

[0302] Chlorogenic acid (0.20 g, 0.56 mmol) was dissolved in anhydrous THF (10 mL). 3,3-Difluoroazacyclobutane hydrochloride (0.08 g, 0.62 mmol), N,N-diisopropylethylamine (0.15 g, 1.13 mmol), and (benzotriazol-1-yloxy)tris(1-pyrrolidinyl)phosphine hexafluorophosphate (0.29 g, 0.56 mmol) were added sequentially to the solution, and the reaction was carried out at room temperature for 16 hours. After the reaction was completed, the reaction solution was mixed with silica gel and dry-mounted for column chromatography (eluent: methanol:dichloromethane = (0–6%):(100%–94%)), yielding 0.20 g of product, with a yield of 82.5% and a purity of 97.9%. m / z HRMS (ESI) found [M+H] + 430.1315, requires 430.1308.

[0303] 1 H NMR (600MHz, Methanol-d4) δ (ppm) 7.57 (d, J = 15.9 Hz, 1H), 7.05 ( d, J = 2.1 Hz, 1H), 6.95 ( dd, J =8.2,2.1Hz,1H),6.78(d,J=8.1Hz,1H),6.28(d,J=15.9Hz,1H),5.36(ddd,J=10.9,9.3,4.7 Hz,1H),4.81(m,1H),4.33-4.28(m,1H),4.24(q,J=3.4Hz,1H),3.72(m,2H),3.69(m,1H),2. 24(ddd,J=13.1,4.7,2.3Hz,1H), 2.08(dd,J=3.6,1.4Hz,2H), 2.01(dd,J=13.2,10.9Hz,1H).

[0304] Example 32

[0305]

[0306] The synthesis method of (VI-7) is as follows:

[0307] Chlorogenic acid (0.20 g, 0.56 mmol) was dissolved in anhydrous THF (10 mL). 2-oxa-6-azaspiro[3.3]heptane (0.06 g, 0.62 mmol), N,N-diisopropylethylamine (0.15 g, 1.13 mmol), and (benzotriazol-1-yloxy)tris(1-pyrrolidinyl)phosphine hexafluorophosphate (0.29 g, 0.56 mmol) were added sequentially to the solution, and the reaction was carried out at room temperature for 16 hours. After the reaction was completed, the reaction solution was mixed with silica gel and subjected to dry column chromatography (eluent: methanol: dichloromethane = (0–6%):(100%–94%)), yielding 0.21 g of product, with a yield of 86.7% and a purity of 90.7%. m / z HRMS (ESI) found [M+H] + 436.1608, requires 436.1603.

[0308] 1 H NMR (600MHz, Methanol-d4) δ (ppm) 7.56 (d, J = 15.8Hz, 1H), 7.05 (d, J = 2.1Hz, 1H), 6.95 (d d,J=8.2,2.1Hz,1H),6.78(d,J=8.2Hz,1H),6.27(d,J=15.8Hz,1H),5.34(ddd,J=10.6,9 .1,4.6Hz,1H),4.78-4.75(m,3H),4.72(m,1H),4.68(m,2H),4.21(q,J=3.5Hz,1H),4.15 -4.06(m,2H),3.68(dd,J=9.2,3.1Hz,1H),2.21-2.17(m,1H),2.03(m,2H),1.99(m,1H).

[0309] Example 33

[0310]

[0311] The synthesis method of (VI-8) is as follows:

[0312] first step:

[0313] Quinic acid (0.50 g, 2.60 mmol) was dissolved in anhydrous DCM (10 mL), cooled to -15 °C, and triethylamine (1.37 g, 14.31 mmol) was added. The mixture was stirred for 5 minutes. Then, trimethylchlorosilane (1.46 g, 13.53 mmol) was added, and the mixture was reacted at -5 °C for 6 hours. Hexane (10 mL) was added to the solution, and the mixture was filtered. The filter cake was washed once with hexane, and the filtrates were combined and concentrated to give intermediate VI-a 1.22 g, with a yield of 84.9%.

[0314] Step Two:

[0315] Intermediate VI-a (1.22 g, 2.21 mmol) was dissolved in acetone (7 mL), and 2,2-dimethoxypropane (7 mL) was added. The mixture was cooled to -85 °C and stirred for 30 minutes. Trimethylsilyl trifluoromethanesulfonate (0.10 g, 0.41 mmol, dissolved in 1 mL LDCM) was added dropwise. The temperature was slowly raised to -45 °C over 3 hours, then to -30 °C, and reacted at -30 °C for 24 hours. The system was then cooled to -85 °C, and saturated sodium bicarbonate solution (23 mL) was added. The mixture was separated, and the aqueous phase was extracted with ethyl acetate. The organic phases were combined. The mixture was dried over anhydrous sodium sulfate, mixed with silica gel, and subjected to dry column chromatography (eluent: ethyl acetate: petroleum ether = (0–30%): (100%–70%)) to obtain intermediate VI-b 0.38 g, yield 63.7%.

[0316] Step 3:

[0317] 2-Fluorocinic acid (0.08 g, 0.47 mmol) was dissolved in anhydrous THF (3 mL), and 3 drops of DMF were added. Oxaloyl chloride (0.12 g, 0.94 mmol) was added dropwise under ice bath conditions, and the mixture was stirred for 2 hours. Intermediate VI-b (0.09 g, 0.31 mmol) was dissolved in anhydrous DCM (3 mL), and DMAP (5.73 mg, 0.047 mmol) and pyridine (0.9 mL) were added. The solvent in the prepared acyl chloride solution was evaporated to dryness, and the prepared DCM solution was added to the acyl chloride solution. The mixture was stirred at room temperature for 3.5 hours. The reaction was monitored by TLC until completion. The mixture was acidified with 1 M HCl, extracted twice with DCM, washed once with saturated sodium chloride solution, and dried over sodium sulfate. The sample was mixed with silica gel and dry-mounted for column chromatography (eluent: ethyl acetate: petroleum ether = (0-5%): (100%-95%)) to obtain intermediate VI-8-10.10 g, yield 78%. m / z HRMS (ESI) found [M+H] + 421.1659, requires 421.1658.

[0318] Step 4:

[0319] Intermediate VI-8-1 (0.10 g, 0.24 mmol) was dissolved in anhydrous THF (1.6 mL), and 1 M HCl (6.4 mL) was added. The mixture was stirred at room temperature for 3 days. The reaction was monitored by TLC until completion. The sample was extracted twice with ethyl acetate, washed once with saturated sodium chloride solution, and dried over sodium sulfate. The solution was mixed with silica gel and dry-mounted for column chromatography (eluent: ethyl acetate: petroleum ether = (0–50%):(100%–50%)), yielding 54 mg of product, with a yield of 66% and a purity of 96.2%. m / z HRMS (ESI) found [MH] -339.0889, requires 339.0885.

[0320] 1 H NMR (600MHz, Methanol-d4) δ (ppm) 7.85 (d, J = 16.2 Hz, 1H), 7.69 (td, J = 7.7, 1.7 Hz, 1H), 7.43 (dddd, J = 8.5, 7.1, 5.2 ,1.7Hz,1H),7.23(td,J=7.5,1.1Hz,1H),7.17(ddd,J=11.1,8.3,1.1Hz,1H),6.63(d,J=16.2Hz,1H),5.38(ddd,J=1 0.9,9.3,4.5Hz,1H),4.23(q,J=3.5Hz,1H),3.74(dd,J=9.3,3.2Hz,1H),2.30(ddd,J=13.4,4.5,2.7Hz,1H),2.14(d dd,J=14.8,4.0,2.6Hz,1H),2.08(dd,J=14.8,3.4Hz,1H),1.93(dd,J=13.4,10.8Hz,1H),1.64(s,3H),1.63(s,3H).

[0321] Example 34

[0322]

[0323] The synthesis method of (VI-9) is as follows:

[0324] The first and second steps are the same as in Example 33;

[0325] Step 3:

[0326] 4-Methylthiocinnamic acid (186 mg, 0.96 mmol) was dissolved in anhydrous THF (6 mL), 3 drops of DMF were added, and oxalyl chloride (0.24 g, 1.92 mmol) was added dropwise under ice bath conditions, and the mixture was stirred for 2 hours. Intermediate VI-b (174 mg, 0.64 mmol) was dissolved in anhydrous DCM (6.6 mL), and DMAP (12 mg, 0.096 mmol) and pyridine (2 mL) were added. The solvent in the prepared acyl chloride solution was evaporated to dryness, and the prepared DCM solution was added to the acyl chloride solution. The mixture was stirred at room temperature for 3.5 hours. The reaction was monitored by TLC until completion, acidified with 1 M HCl, extracted twice with DCM, washed once with saturated sodium chloride solution, and dried over sodium sulfate. The sample was mixed with silica gel and dry-mounted for column chromatography (eluent: ethyl acetate: petroleum ether = (0-10%): (100%-90%)) to obtain intermediate VI-9-1198 mg, yield 69%. m / z HRMS (ESI) found [M+H]+ 449.1628, requires 449.1629.

[0327] Step 4:

[0328] Intermediate VI-9-1 (198 mg, 0.44 mmol) was dissolved in anhydrous THF (3 mL), and 1 M HCl (12 mL) was added. The mixture was stirred at room temperature for 4 days. The reaction was monitored by TLC until completion. The sample was extracted twice with ethyl acetate, washed once with saturated sodium chloride solution, and dried over sodium sulfate. The solution was mixed with silica gel and dry-mounted for column chromatography (eluent: ethyl acetate: petroleum ether = (0–55%):(100%–45%)), yielding 100 mg of product, with a yield of 61.5% and a purity of 94.7%. m / z HRMS (ESI) found [MH] - 367.0860, requires 367.0856.

[0329] 1 H NMR (600MHz, Methanol-d4) δ (ppm) 7.56 (d, J=16.0Hz, 1H), 7.38 (d, J=8.5Hz, 2H), 7.15-7.10 (d, J= 8.5Hz,2H),6.36(d,J=16.0Hz,1H),5.26(ddd,J=10.7,9.2,4.5Hz,1H),4.13(q,J=3.5Hz,1H),3.6 3(dd,J=9.2,3.2Hz,1H),2.37(s,3H),2.18(ddd,J=13.4,4.5,2.6Hz,1H),2.03(ddd,J=14.7,4.1, 2.7Hz, 1H), 1.96 (dd, J=14.7, 3.4Hz, 1H), 1.81 (dd, J=13.4, 10.7Hz, 1H), 1.51 (s, 3H), 1.51 (s, 3H).

[0330] Example 35

[0331]

[0332] The synthesis method of (VI-10) is as follows:

[0333] The first and second steps are the same as in Example 33;

[0334] Step 3:

[0335] α-Methylcinnamic acid (77 mg, 0.48 mmol) was dissolved in anhydrous THF (3 mL), 3 drops of DMF were added, and oxalyl chloride (0.12 g, 0.95 mmol) was added dropwise under ice bath conditions, and the mixture was stirred for 2 hours. Intermediate VI-b (86 mg, 0.32 mmol) was dissolved in anhydrous DCM (3 mL), and DMAP (6 mg, 0.048 mmol) and pyridine (0.9 mL) were added. The solvent in the prepared acyl chloride solution was evaporated to dryness, and the prepared DCM solution was added to the acyl chloride solution. The mixture was stirred at room temperature for 3.5 hours. The reaction was monitored by TLC until completion. The solution was acidified with 1 M HCl, extracted twice with DCM, washed once with saturated sodium chloride solution, and dried over sodium sulfate. The solution was mixed with silica gel and dry-mounted for column chromatography (eluent: ethyl acetate: petroleum ether = (0–10%): (100%–90%)), yielding intermediate VI-10-178 mg, with a yield of 60%. m / z HRMS(ESI)found[M+H] + 417.1912 requires 417.1908.

[0336] Step 4:

[0337] Intermediate VI-10-1 (78 mg, 0.19 mmol) was dissolved in anhydrous THF (1.25 mL), and 1 M HCl (5 mL) was added. The mixture was stirred at room temperature for 3 days. The reaction was monitored by TLC until completion. The sample was extracted twice with ethyl acetate, washed once with saturated sodium chloride solution, and dried over sodium sulfate. The solution was mixed with silica gel and dry-mounted for column chromatography (eluent: ethyl acetate: petroleum ether = (0–50%):(100%–50%)), yielding 43 mg of product, with a yield of 68% and a purity of 98.5%. m / z HRMS (ESI) found [MH] - 335.1140, requires 335.1136.

[0338] 1H NMR (600MHz, Methanol-d4) δ (ppm) 7.77 (d, J = 1.9 Hz, 1H), 7.45-7.38 (m, 4H), 7.35-7.31 (m, 1 H),5.37(ddd,J=10.1,8.9,4.5Hz,1H),4.25(dt,J=4.6,3.4Hz,1H),3.77(dd,J=8.9,3.2Hz,1 H),2.29(ddd,J=13.5,4.5,2.5Hz,1H),2.15(ddd,J=14.6,4.6,2.5Hz,1H),2.11(d,J=1.5Hz ,3H),2.07(dd,J=14.6,3.5Hz,1H),1.96(dd,J=13.4,10.1Hz,1H),1.63(s,3H),1.62(s,3H).

[0339] Example 36

[0340]

[0341] The synthesis method of (VI-11) is as follows:

[0342] The first and second steps are the same as in Example 33;

[0343] Step 3:

[0344] Indole-2-carboxylic acid (155 mg, 0.96 mmol) was dissolved in anhydrous THF (6 mL), 3 drops of DMF were added, and oxalyl chloride (0.24 g, 1.93 mmol) was added dropwise under ice bath conditions, and the mixture was stirred for 2 hours. Intermediate VI-b (174 mg, 0.64 mmol) was dissolved in anhydrous DCM (6.6 mL), and DMAP (12 mg, 0.096 mmol) and pyridine (2 mL) were added. The solvent in the prepared acyl chloride solution was evaporated to dryness, and the prepared DCM solution was added to the acyl chloride solution. The mixture was stirred at room temperature for 3.5 hours. The reaction was monitored by TLC until completion. The solution was acidified with 1 M HCl, extracted twice with DCM, washed once with saturated sodium chloride solution, and dried over sodium sulfate. The solution was mixed with silica gel and dry-mounted for column chromatography (eluent: ethyl acetate: petroleum ether = (0–7%): (100%–93%)), yielding intermediate VI-11-1229 mg, with a yield of 86%. m / z HRMS(ESI)found[M+H] + 416.1707 requires 416.1704.

[0345] Step 4:

[0346] Intermediate VI-10-1 (229 mg, 0.55 mmol) was dissolved in anhydrous THF (3.75 mL), and 1 M HCl (15 mL) was added. The mixture was stirred at room temperature for 3 days. The reaction was monitored by TLC until completion. The sample was extracted twice with ethyl acetate, washed once with saturated sodium chloride solution, and dried over sodium sulfate. The solution was mixed with silica gel and dry-mounted for column chromatography (eluent: ethyl acetate: petroleum ether = (0–50%):(100%–50%)), yielding 68 mg of product, with a yield of 36.8% and a purity of 97.5%. m / z HRMS (ESI) found [MH] - 334.0932, requires 334.0932.

[0347] 1 H NMR (600MHz, Methanol-d4) δ (ppm) 7.63 (dd, J = 8.1, 1.2 Hz, 1H), 7.44 (dd, J = 8.5, 1.0 Hz, 1H), 7.26 (ddd, J = 8. 2,6.9,1.1Hz,1H),7.24(d,J=0.9Hz,1H),7.07(ddd,J=8.1,6.9,0.9Hz,1H),5.50(ddd,J=10.4,9.0,4.5Hz, 1H),4.27(q,J=3.7Hz,1H),3.83(dd,J=9.1,3.2Hz,1H),2.37(ddd,J=13.5,4.6,2.6Hz,1H),2.17(ddd,J=14 .7,4.4,2.5Hz,1H),2.10(dd,J=14.7,3.5Hz,1H),2.03(dd,J=13.5,10.5Hz,1H),1.64(s,3H),1.63(s,3H).

[0348] Example 37

[0349] In vitro bioactivity experiments of the compounds provided in Examples 1-36 in inhibiting glioma cells

[0350] 1. Experimental objective: To screen the inhibitory effects of the compounds provided in Examples 1-36 on glioma cells;

[0351] 2. Experimental cells: U251MG cells (human-derived cells), U87MG cells (human-derived cells), GL261 cells (mouse-derived cells), C6 cells (rat-derived cells);

[0352] 3. Culture media: DMEM medium (C11995500BT, Gibco), MEM medium (C11095500BT, Gibco), F12K medium (iCell-0007, Cyprocon), FBS (10099-141, Gibco), horse serum (domestic) (iCell-002b, Cyprocon), penicillin-streptomycin mixture (100×) (P1400, Solarbio), CCK8 (RM02823, Abclonal).

[0353] DMSO (D8371, Solarbio).

[0354] 4. Experimental methods and procedures:

[0355] (1) Cell culture and plating:

[0356] Four cell culture conditions: U251MG cells: 89% MEM + 10% FBS + 1% PS; U87MG: 89% MEM + 10% FBS + 1% PS; GL261: 89% DMEM + 10% FBS + 1% PS; C6: 81.5% F12K + 2.5% FBS + 15% HS + 1% PS.

[0357] U251MG, U87MG, GL261, and C6 cells were cultured to the logarithmic growth phase, digested, counted, and divided into 5 × 10⁶ cells per well. 3 10 cells were seeded into 96-well plates (GL261 cells were seeded at a ratio of 6 × 10⁶ cells per well). 3 C6 cells were seeded at a density of 8 × 10⁶ cells per well. 3 (Cells are plated), 100 μL of complete culture medium per well, and placed in a cell culture incubator. The next day, after the cells have adhered to the plate, drug intervention is performed.

[0358] (2) Cellular drug intervention:

[0359] The compounds provided in Examples 1-36 were dissolved in DMSO to prepare 200 mM solutions, and the drug stock solutions were prepared to prepare 500 μM solutions (1.5 mL + 3.75 μL). These solutions were then diluted to 1, 10, 50, 200, and 500 solutions (600 μL each). The culture medium in the 96-well plates was discarded using a vacuum pump, and drug-containing culture medium was added according to the concentration gradient. CCK8 assays were performed after 24 hours. The compounds were first screened using U251MG, U87MG, and GL261 cells. For compounds with good activity, further screening was performed using C6 cells.

[0360] (3) CCK8 detection:

[0361] Prepare CCK8 working solution (CCK8: basal medium = 1:10), prepare a total of 40 mL of working solution, discard the cell culture supernatant to be tested, add CCK8 working solution, incubate at 37℃ for 2 h, then use an ELISA reader to detect absorbance at 450 nm and calculate cell viability.

[0362] Cell viability (%) = (OD value of experimental group - OD value of blank culture medium) / (OD value of control group - OD value of blank culture medium) × 100%;

[0363] Calculating cell IC using SPSS and Graphpad 50 .

[0364] 5. Experimental Results

[0365] The inhibitory effects of the compounds provided in Examples 1-36 on three types of glioma cells are shown in Table 1, and the inhibitory effects of the selected compounds with better activity on four types of glioma cells are shown in Table 2.

[0366] The relationship between the survival rate and concentration of compounds III-1, IV-1, III-3, III-4, III-5, III-2, temozolomide, and chlorogenic acid on GL261 cells is shown in the figure. Figures 1-8 ;

[0367] The relationship between the survival rate and concentration of compounds III-1, IV-1, III-3, III-4, III-5, III-2, temozolomide, and chlorogenic acid on U251 cells is shown in the figure. Figures 9-16 ;

[0368] The relationship between the survival rate and concentration of compounds III-1, IV-1, III-3, III-4, III-5, III-2, temozolomide, and chlorogenic acid on U87 cells is shown in the figure. Figures 17-24 ;

[0369] The relationship between the survival rate and concentration of compounds III-1, IV-1, III-3, III-4, III-5, III-2, temozolomide, and chlorogenic acid on C6 cells is shown in the figure. Figures 25-32 .

[0370] Table 1. Inhibitory effects of the compounds provided in Examples 1-36 on three types of glioma cells.

[0371]

[0372]

[0373] Table 2 shows the inhibitory effects of the selected compounds with good activity on four types of glioma cells.

[0374]

[0375]

[0376] 6. Experimental conclusions

[0377] As shown in Table 1, according to the screening results of three glioma cell lines, namely U251MG, U87MG, and GL261, compounds III-1, III-2, III-3, III-4, III-5, III-8, III-13, III-15, and IV-1 have relatively low IC 50 values against these three glioma cell lines, and are far lower than those of chlorogenic acid and temozolomide. On this basis, these 9 compounds were screened against C6 cells. Finally, it was found that compounds III-1, III-2, III-3, III-4, III-5, and IV-1 have good inhibitory effects on these four glioma cell lines, with IC 50 values significantly lower than those of chlorogenic acid and temozolomide, as shown in Table 2.

[0378] Example 38

[0379] From the compounds provided in Examples 1 to 36, 8 compounds were selected for an in vitro activity screening experiment on the oxygen-glucose deprivation / reperfusion model.

[0380] 1. Experimental purpose: To study the cytotoxicity of compounds to primary rat cortical neurons in vitro and the protective effect on the injury of primary rat cortical neurons mediated by the oxygen-glucose deprivation / reperfusion model (OGD / R model).

[0381] 2. Screened compounds: III-1, III-2, V-1, V-5, VI-1, VI-6, VI-8, VI-11.

[0382] 3. Experimental reagents: Fetal bovine serum: Yeasen Biotech; DMEM high-glucose medium: Solarbio; DMEM glucose-free medium (without sodium pyruvate): Meilunbio; D-Hank’s solution: Solarbio; PBS: Solarbio; Trypsin: Solarbio; Cytarabine: Meilunbio; CCK8 (ultrasensitive type): Abbkine.

[0383] 4. Experimental animals: Clean-grade pregnant SD rats, 130 days old, female, purchased from Spf (Beijing) Biotechnology Co., Ltd., certificate number: SCXK (Beijing) 2024-0001, housed in the animal room of the Experimental Building on the Yangming Campus of Jiangxi University of Traditional Chinese Medicine. The indoor temperature was controlled at 23±2°C, with free access to food and water, and a 12-hour / 12-hour day-night cycle.

[0384] 5. Experimental methods and procedures:

[0385] (1) Extraction and culture of rat cortical neurons

[0386] SD rat pups (0-1 day) were used. After routine scalp disinfection, the scalp and skull were cut along the midline using ophthalmic scissors in the right hand. The entire brain tissue was quickly removed using ophthalmic forceps and placed in a glass culture dish containing D-Hank's solution on ice. The blood vessels and meninges on the surface of the brain tissue were carefully dissected with forceps, and the cerebellum and brainstem were removed. The brain tissue was then repeatedly rinsed with D-Hank's solution. The cerebral cortex was cut off with ophthalmic scissors and transferred to a sterile culture dish. The cerebral cortex was minced, and trypsin was added. The mixture of brain tissue and trypsin was repeatedly aspirated with a pipette and mixed thoroughly. The mixture was placed in a 37°C constant temperature water bath for digestion. After digestion, culture medium containing serum was added to stop the digestion. The cells were centrifuged at 1500 rpm for 5 min, the supernatant was discarded, and the cells were resuspended in fresh culture medium containing serum. The cells were filtered through a 200-mesh cell sieve, and the filtrate was inoculated into 10 cm... 2 Incubate cells in porous plastic culture dishes at 37°C in a 5% CO2 incubator for 24 hours. After cell attachment, change the medium. After 36 hours of culture, add cytarabine (3 μg / mL) to inhibit glial cell division and growth. Change the medium 12 hours after adding cytarabine. Thereafter, change half the medium every 3 days. After 7–14 days, experiments can be performed.

[0387] (2) Acute toxicity test of primary cortical neurons in rats

[0388] Cells grown to approximately day 7 were selected for an in vitro OGD / R model. Cell density was adjusted to 1 × 10⁻⁶ cells / day. 5 Cells were seeded at the specified density in 96-well plates and cultured at 37°C in a 5% CO2 incubator for 24 hours. Then, they were cultured for another 24 hours in DMEM containing 1% FBS and corresponding concentrations (3.125, 6.25, 12.5, 25, 50, 100 μM). 10 μL of CCK8 was added to each well, and the cells were cultured for another 0.5 hours in a 5% CO2 incubator. OD values ​​were measured using a microplate reader. 450 .

[0389] (3) Rats model of hypoxia-hypoglycemia injury in primary cortical neurons

[0390] Cells grown to approximately day 7 were selected for an in vitro OGD / R model. Cell density was adjusted to 1 × 10⁻⁶ cells / day. 5Cells were seeded at a density of [insert density here] in 96-well plates for 24 hours. Then, they were cultured in drug-containing DMEM glucose-free medium containing 1% FBS and corresponding concentrations (1.8, 3.75, 7.5, 15, 30, 60 μM or 0.9, 1.8, 3.75, 7.5, 15, 30 μM) for 24 hours in a tri-gas incubator containing 1% O2, 5% CO2, and 94% N2 to complete the hypoxic process. Subsequently, the cell culture medium was replaced with complete DMEM high-glucose medium, and the cells were cultured in a 5% CO2 incubator for 24 hours (this process did not involve drug administration) to complete the reglucose and reoxygenation process. After incubation, 10 μL of CCK8 was added to each well, and the cells were cultured in a 5% CO2 incubator for 0.5 hours. OD was measured using a microplate reader. 450 .

[0391] 6. Experimental Results and Conclusions

[0392] Table 3 Results of acute cytotoxicity

[0393]

[0394]

[0395] Note: Compared with the control group, the increase was P<0.05*, P<0.01**; compared with the control group, the decrease was P<0.05#, P<0.01##.

[0396] As shown in Table 3, most compounds did not exhibit cytotoxicity at a high concentration of 100 μM, demonstrating good safety for primary neurons. Only compound III-1 showed significant cytotoxicity at high concentrations. In subsequent OGD / R experiments, the concentration of compound III-1 was reduced.

[0397] Table 4 OGD / R Results

[0398]

[0399]

[0400] Note: Compared with the model group, P<0.05*, P<0.01**.

[0401] As shown in Table 4, compared with the model group OGD / R, most compounds showed significant primary neuroprotective effects at various concentrations. Compared with the positive control drug edaravone, compounds VI-1, V-1, and III-1 significantly improved neuronal survival and showed stronger neuroprotective effects.

[0402] The above description is only a preferred embodiment of the present invention. It should be noted that for those skilled in the art, several improvements and modifications can be made without departing from the principle of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.

Claims

1. A phenylpropanoid compound, characterized in that, The following are compounds, solvates, optically pure isomers, stereoisomers, or pharmaceutically acceptable salts thereof, and mixtures thereof, represented by general formula (Ⅰ): Where X is selected from O or N; key This indicates whether the key is a single or double key; R1, R2, R3, R4, and R5 may be the same or different, and are independently selected from hydrogen, hydroxyl, halogen, alkoxy, and alkylthio groups; R 13 Selected from hydrogen or C1-C4 alkyl, or R 13 Connect R5 to form a loop; R 14 Selected from cycloalkyl groups having 5-6 carbon atoms with substituents.

2. The phenylpropanoid compound according to claim 1, characterized in that, The R 14 The substituents are selected from those shown in formula (II-A) or formula (II-B): R6 is selected from hydrogen, C1-C4 alkyl, alkoxycarbonyl, carboxyl, ethynyl, vinyl, and cyano. R7, R8, R 10 R 11 R 12 Whether the groups are the same or different, they are independently selected from amino, carboxyl, oxydimethyl, alkoxycarbonyl, and C1-C4 alkyl groups protected by hydrogen, hydroxyl, amino, or tert-butoxycarbonyl. R9 is selected from hydrogen, carboxyl, amide, or R8 and R9 can be cyclically formed through hydroxyl and carboxyl groups, respectively.

3. The phenylpropanoid compound according to claim 1, characterized in that, R2 and R3 may be the same or different, and are independently selected from hydrogen, hydroxyl, and alkoxy groups having 1-5 carbon atoms; R1, R4, and R5 may be the same or different, and are independently selected from hydrogen, hydroxyl, and halogen; R 13 Selected from hydrogen or C1-C2 alkyl.

4. The phenylpropanoid compound according to claim 2, characterized in that, R6 is selected from hydrogen, C1-C4 alkyl, alkoxycarbonyl, ethynyl, and carboxyl. R7, R8, R 10 R 11 R 12 Whether the groups are the same or different, they are independently selected from hydrogen, hydroxyl, amino, alkoxycarbonyl or C1-C4 alkyl; R9 is selected from hydrogen, substituted or unsubstituted amide group, or R8 and R9 are cyclically formed by hydroxyl and carboxyl groups respectively.

5. The phenylpropanoid compound according to claim 2, characterized in that, The R 14 When selected from formula (Ⅱ-A), R7, R8, R 10 R 11 R 12 Whether the same or different, they are independently selected from hydrogen, hydroxyl, amino or C1-C4 alkyl; R2 and R3 are independently selected from hydrogen or hydroxyl groups; X is selected from O or N.

6. The phenylpropanoid compound according to claim 1, characterized in that, Compounds selected from those shown in formula (III) or (IV): Among them, R2 and R3 may be the same or different, and are independently selected from hydrogen and hydroxyl; R6 is selected from hydrogen, C1-C4 alkyl, carboxyl, ethynyl, and cyano. R7 is selected from amino groups protected by hydrogen, hydroxyl, amino, or tert-butoxycarbonyl. In formula (Ⅲ) R 10 Selected from hydrogen, tert-butoxycarbonyl-protected amino, carboxyl, oxydimethyl, and C1-C4 alkyl groups.

7. The phenylpropanoid compound according to claim 1, characterized in that, Selected from compounds represented by formula (V): R2 and R3 may be the same or different, and are independently selected from hydrogen and hydroxyl groups; R6 is selected from hydrogen or alkoxycarbonyl; R7, R 12 Whether the amino groups are the same or different, they are independently selected from those protected by hydrogen, hydroxyl, amino, or tert-butoxycarbonyl groups; R 10 Selected from hydrogen, alkoxycarbonyl, tert-butoxycarbonyl protected amino groups, oxy subunits, and C1-C4 alkyl groups.

8. The phenylpropanoid compound according to claim 1, characterized in that, Selected from compounds represented by formula (VI): Y is either O or N. R1, R2, R3, R4, and R5 may be the same or different, and are independently selected from hydrogen, hydroxyl, halogen, alkoxy, and alkylthio groups; R 13 Selected from: hydrogen, C1-C4 alkyl, or R 13 Connect R5 to form a loop; R 15 Selected from: hydrogen, benzyl, or -CO-YR 15 - It forms a ring with the hydroxyl group on the same carbon atom of the six-membered ring; When Y is N, -YR 15 The following groups can be selected.

9. The phenylpropanoid compound according to claim 1, characterized in that, The compound is selected from:

10. A method for preparing a phenylpropanoid compound according to any one of claims 1-9, characterized in that, This can be achieved by reacting caffeic acid or chlorogenic acid with substituted cycloalkyl groups under the action of a catalyst.

11. The preparation method according to claim 10, characterized in that, When preparing the compound of formula (III) or formula (IV) according to claim 6, the substituted cycloalkyl group is a substituted cycloalcohol, and the catalyst is triethylamine.

12. The preparation method according to claim 10, characterized in that, When preparing the compound of formula (V) according to claim 7, the substituted cycloalkyl group is a substituted cycloamine, and the catalyst is N,N'-dicyclohexylcarbodiimide.

13. The preparation method according to claim 10, characterized in that, When preparing the compound of formula (VI) according to claim 8, the substituted cycloalkyl group is various four-membered heterocyclic amines and primary amines, and the catalyst is (benzotriazol-1-yloxy)tris(1-pyrrolidinyl)phosphine hexafluorophosphate and N,N-diisopropylethylamine.

14. A pharmaceutical preparation, characterized in that, The raw materials of the pharmaceutical preparation include phenylpropanoid compounds as described in any one of claims 1-9 or phenylpropanoid compounds prepared by the preparation method described in any one of claims 10-13, as well as pharmaceutically acceptable excipients.

15. The use of the phenylpropanoid compound according to any one of claims 1-9, or the phenylpropanoid compound prepared by the preparation method according to any one of claims 10-13, or the pharmaceutical preparation according to claim 14, in the preparation of antitumor drugs.

16. The application according to claim 15, characterized in that, The tumor in question refers to a glioma.

17. The application according to claim 16, characterized in that, The phenylpropanoid compounds are selected from:

18. The use of the phenylpropanoid compound according to any one of claims 1-9, or the phenylpropanoid compound prepared by the preparation method according to any one of claims 10-13, or the pharmaceutical preparation according to claim 14, in the preparation of a medicament for treating cardiovascular and cerebrovascular diseases or nerve damage.

19. The application according to claim 18, characterized in that, The cardiovascular and cerebrovascular diseases mentioned are selected from stroke or its complications.

20. The application according to claim 18, characterized in that, The phenylpropanoid compounds are selected from:

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