阅读说明：本技术 具有神经保护作用的辣椒碱类化合物cp-x-y及其应用 (Capsaicin compound CP-X-Y with neuroprotective effect and application thereof ) 是由 张文曦 王辉 郭文博 王鹏龙 徐冰 于 2019-09-17 设计创作，主要内容包括：本发明提供了一类具有结构通式1的化合物及其在制备神经保护药物中的应用。本发明大部分衍生物对H-2O-2损伤的HBMEC-2(人脑微血管内皮细胞)、SH-SY5Y(神经母瘤细胞)表现出较好的保护作用,其中化合物CP-14-1及CP-22-2对两种细胞均表现出较好的促增殖作用(CP-14-1：EC-(50)(HBMEC-2,SH-SY5Y)＝3.16μM,2.45μM；CP-22-3：EC-(50)(HBMEC-2,SH-SY5Y)＝4.15μM,2.56μM)。结合流式细胞术研究结果表明化合物CP-14-1可减少细胞的早期凋亡。通过鹌鹑胚的整体实验表明CP-14-1对血管有明显的促生成作用。综上所述,CP-14-1作为辣椒碱系列衍生物之一,具有较好的神经保护活性以及促血管生长作用,具有进一步研究及开发意义。(The invention provides a compound with a structural general formula 1 and application thereof in preparing neuroprotective drugs. Most of the derivatives of the present invention are p-H 2 O 2 The damaged HBMEC-2 (human brain microvascular endothelial cells) and SH-SY5Y (neuroblastoma cells) show better protection effects, wherein the compounds CP-14-1 and CP-22-2 show better proliferation promoting effects on the two cells (CP-14-1: EC) 50 (HBMEC‑2,SH‑SY5Y)＝3.16μM,2.45μM；CP‑22‑3：EC 50 (HBMEC-2, SH-SY5Y) ═ 4.15 μ M,2.56 μ M). The results of the combined flow cytometry study showed that compound CP-14-1 reduced early apoptosis in cells. The integral experiment of quail embryo shows that CP-14-1 has obvious effect of promoting the growth of blood vessel. In conclusion, CP-14-1 as one of capsaicin derivatives has good neuroprotective activity and angiogenesis promoting effect, and has further research and development significance.)

1. a compound of the general formula 1 having neuroprotective effect,

wherein R is₁，R₂One selected from the following structures;

2. the compound vanillin amine salt with neuroprotective effect-2, 4, 5-trihydroxy cinnamic acid-ligustrazine (CP14-1-1) has the following structure

3. A process for the preparation of a compound according to claim 2, which process comprises:

the method comprises the following steps:

dissolving vanillin amine salt (mother nucleus of vanilloamide capsaicin structure) in an organic solvent A, and reacting with 2,4, 5-trihydroxy cinnamic acid under the action of a catalyst a to generate a compound CP-14-1.

4. The preparation process according to claim 3, wherein the organic solvent is as follows: an organic solvent A: n, N-Dimethylformamide (DMF), the catalyst/oxidant is as follows: catalyst a: 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI), 1-Hydroxybenzotriazole (HOBT); n, N-Diisopropylethylamine (DIPEA).

5. Use of a compound according to any one of claims 1 or 2, or a pharmaceutically acceptable salt thereof, in the manufacture of a neuroprotective medicament.

6. The use according to claim 5, wherein the neuroprotection is cerebral diseases such as ischemic stroke and Alzheimer's disease.

7. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claims 1 and 2, or a pharmaceutically acceptable salt thereof, in admixture with at least one pharmaceutically acceptable excipient.

8. The composition of claim 7, further comprising at least one conventional neuroprotective agent.

9. The composition of claim 8, wherein the neuroprotective agent is selected from edaravone, nimodipine, citicoline, vinpocetine, almag thiazole, aceglutamide, and nikkel.

Technical Field

The invention relates to a compound and application thereof, in particular to a compound with a neuroprotective effect and application thereof, belonging to the field of pharmaceutical chemistry.

Background

Ischemic stroke refers to cerebrovascular stenosis or occlusion, which leads to blockage of cerebral blood flow and leads to ischemic hypoxia, softening and even necrosis of brain tissues, thus causing cerebrovascular dysfunction. As one of three diseases causing human death, the traditional Chinese medicine composition has the characteristics of high morbidity, easy disability, high mortality, easy relapse, poor prognosis and the like. At present, the treatment for the disease mainly comprises the prevention and treatment of cerebral edema, the treatment of anti-platelet aggregation, the anticoagulation treatment, the thrombolytic treatment, the surgical treatment and the like, but the effect is not very ideal, certain toxic and side effects are accompanied, and the recurrence rate is high. The traditional Chinese medicine has the advantages of reducing the disability rate of patients and improving the life quality by treating the ischemic stroke with wind energy, along with small toxic and side effects, low required cost and the like. Ischemic brain diseases are the dominant disease species for the prevention and treatment of traditional Chinese medicine.

Capsaicin and analogs thereof are typical TRPV1 receptor agonists, have biological activities of analgesia, neural plasticity enhancement, neurotransmitter regulation, heart protection, blood vessel protection and the like, and have great research value in various diseases, particularly nervous system diseases. The subject group uses the compatibility principle of traditional Chinese medicines and the chemical combination principle of medicines for reference at the early stage, the traditional Chinese medicine active ingredients of phenolic acid and ligustrazine are introduced into the neuroprotective ingredients in the traditional Chinese medicines, and the initial pharmacodynamic evaluation finds that the neuroprotective effect of part of the synthesized compounds is obviously enhanced, and the compound has a certain curative effect on treating ischemic stroke. Therefore, the invention has important practical significance in that the active ingredients of the traditional Chinese medicine are used as raw materials for carrying out structural combination so as to obtain the lead compound for treating the ischemic stroke, which has high efficiency, low toxicity and definite action mechanism.

The invention adopts the principle of drug combination, selects a capsaicin vanilloylamine structure as a basic mother nucleus, introduces phenolic acid compounds by amido bonds, introduces ligustrazine by ether bonds, and designs and synthesizes 62 capsaicin-phenolic acid-ligustrazine derivatives. Then, with hydrogen peroxide (H)₂O₂) As an injury agent, human brain microvascular endothelial cells (HBMEC-2) and human neuroblastoma cells (SH-SY5Y) are used for establishing a nerve injury model for a cell line, and the neuroprotective activity of the derivative is evaluated. The angiogenesis promoting effect of the derivative is evaluated by a whole experiment of the quail embryo.

Disclosure of Invention

The invention aims to provide a compound with a structural general formula 1 and a preparation method thereof. The other object of the present invention is to provide a compound having a neuroprotective effect. The purpose of the invention is realized by the following technical scheme:

a compound having the structure of formula 1 or a pharmaceutically acceptable salt thereof,

further, the compound numbers and structural formulas of the invention are as follows:

the reaction route of the invention is as follows:

route 1 synthetic route of chloro-ligustrazine

Reaction conditions and reagents (a) NCS, BPO, CCl₄Strong light irradiation, 85 ℃,3h

Scheme 2 synthetic route for CP-X-1 derivatives

Reaction conditions and reagents (a) EDCI, DIEPA, HOBT, DMF,4h

Scheme 3 synthetic route for CP-X-2 derivatives (X ═ 1, 7-17)

Reaction conditions and reagents (a) K₂CO₃,DMF,80℃,4h

Scheme 4 synthetic route for CP-X-2 derivatives (X ═ 2-6,18-22)

Reaction conditions and reagents (a) MeOH, SoCl₂,1h；(b)K₂CO₃,DMF,80℃,3h；(c)NaOH,CHCl₂,2h；(d)EDCI,DIEPA, HOBT,DMF,4h

Scheme 5 synthetic route to CP-X-3 derivatives

Reaction conditions and reagents (a) Boc₂O,Et₃N, MeOH, room temperature, 4 h; (b) TMP, K₂CO₃,DMF,80℃,2h；(c)TFA(20％),CH₂Cl₂Room temperature, 1 h; (d) EDCI, DIEPA, Hobt, DMF, Room temperature, 4h

Scheme 6 synthetic route for CP-X-4 derivatives

The reaction conditions and reagents are (a) EDCI, DIEPA, Hobt, DMF,4 h; (b) TMP, K₂CO₃,DMF,80℃,4h

Most of the capsaicin-phenolic acid-ligustrazine derivatives of the invention are right for H₂O₂The damaged HBMEC-2 and SH-SY5Y show better protection effect, wherein the compounds CP-14-1 and CP-22-2 show better proliferation promoting effect on two cells (CP-14-1: EC)₅₀＝3.16μM,2.45μM；CP-22-2：EC₅₀＝4.15μM,2.56μM)。

Experimental example 1 MTT method for observing protective effect of CP-X-X of the compound of the invention on HBMEC-2 and SH-SY5Y cells

1. Apparatus and materials

CO2 incubator (U.S. Thermo 3111); biosafety cabinets (shanghai li kang HF safe 1500); microplate reader (Multiskan GO); desk type low speed centrifuge (Jingli brand LD5-2B type); inverted fluorescence microscopyA mirror (OlympusIX 71); full wavelength enzyme scanner (finland thermoelectric Multiskan GO); high pressure steam sterilization pots (Shanghai Boxun medical Bioinstruments GmbH); digital display constant temperature water bath (jintan crystal wave laboratory instrument factory); cell counter (Shanghai refining biochemical instrument factory); eppendorf pipette gun (Thermo Sammer Feishel science, USA); dragon Lab pipette gun (majongxing laboratory instruments ltd); 0.20 μm microfiltration membrane (Membrana, Germany); 25cm²Cell culture flasks (Corning); 96-well plates (Corning); centrifuge tubes (1.5mL, 15mL, 50mL, Axygen); pipette tips (1000. mu.L, 200. mu.L, 10. mu.L, Axygen).

DMEM medium; fetal bovine serum (FBS, Gibco); trypsin solution containing 0.25% EDTA (Gibco); hydrogen peroxide (H2O2 beijing chemical plant); penicillin streptomycin mixed solution (100 ×, Corning); phosphate buffer solution (PBS, Corning); dimethylsulfoxide (DMSO, Amresco); thiazole blue (MTT, Amresco); complete medium: 89% DMEM medium + 10% FBS + 1% streptomycin (100X).

Cell lines: human brain microvascular endothelial cells (HBMEC-2, purchased from Beijing coordination cell resource center);

cell lines: human neuroblastoma cell (SH-SY5Y, purchased from Beijing coordination cell resource center);

2. method of producing a composite material

2.1 culture of different cell lines

HBMEC-2, SH-SY5Y cells were cultured in DMEM containing 10% fetal bovine serum, and placed at 37 deg.C with 5% CO₂Incubation in an incubator. The cells all grow in an adherent state, the growth condition is observed under an inverted microscope, and subculture is carried out when the number of the cells is proper.

2.2 inhibition ratio of Primary Sieve cells

After the cell state is normal, when the cell density reaches 70% -80%, uniformly seeding the cells to a 96-well plate, wherein the cell concentration is 3.5 multiplied by 10 per 100 mu L of each well⁴each.mL^-1The 96-well plate was placed at 37 ℃ and incubation continued with 5% CO 2. After 24h, 100. mu.L of fresh cell culture medium was added to each well and the culture was continued for 24 h. Weighing a certain amount of sample to be detected, dissolving in DMSO to obtain 10% concentration⁴mu.M stock solution is taken for standby, DMEM cell culture solution is taken to dilute the stock solution of the sample to be tested to the required concentration of 0.78 mu.M, 1.56 mu.M, 3.13 mu.M, 6.25 mu.M and 12.5 mu.M, a 96-well plate is divided into a normal group, a model group and an administration group, 100 mu.L of sample solution to be tested with different concentrations is added into each well of the administration group, 100 mu.L of fresh culture solution is added into the normal group and the injury group, and the culture is continued for 24 h. H is to be₂O₂Dissolving in DMEM culture solution, diluting to desired concentration of 4.8mM, taking out 96-well plate, adding 40 μ L of H with above concentration into each well of injury group and administration group₂O₂Solution of H₂O₂The final concentration of the solution was 0.6mM, 40. mu.L of fresh culture medium was added to each well of the normal control group, and the cells were cultured for 4 hours to observe the morphology. The 96-well plate was removed, the supernatant was discarded, 100. mu.L of PBS was added to each well and washed twice, and 200. mu.L of DMEM medium and 20. mu.L of MTT (5 mg. multidot.mL) were added to each well^-1) Continuously culturing for 4h, discarding the MTT solution, adding 150 mu L DMSO into each hole, fully shaking, determining the absorbance value at 550nm after the blue crystal is uniformly dissolved, and calculating the cell survival rate (%) at different concentrations; cell survival (%) > injury OD/normal OD × 100%.

3. Results

Comparison of capsaicin series derivatives to 0.6mM H by the MTT method₂O₂The protective effect of damaging HBMEC-2 and SH-SY5Y cells is found, and most of compounds have H resistance₂O₂The damaged HBMEC-2 cells show certain protective effect. The proliferation rate of cells is higher than other concentrations of most compounds at the concentration of 6.25 mu M, which indicates that the capsaicin derivative possibly has the effects of promoting the inhibition at a low concentration and a high concentration. Wherein the compounds CP-14-1 and CP-22-2 show better proliferation promoting effect on two cells than other compounds (CP-14-1: EC)₅₀＝3.16μM,2.45μM；CP-22-2：EC₅₀＝4.15μM, 2.56μM)。

TABLE 1 EC of capsaicin derivative CP-X-X on HBMEC-2, SH-SY5Y minicells₅₀Value of

4. Conclusion

Through the determination of the biological activity of the derivative of the invention, most of the derivative is found to be in the pair of H₂O₂Damaged HBMEC-2 and SH-SY5Y cells have certain protective effect, wherein the protective activity of compounds CP-14-1 and CP-22-2 is better than that of other derivatives, (CP-14-1: EC)₅₀＝3.16μM,2.45μM；CP-22-2：EC₅₀4.15 μ M,2.56 μ M). The compounds can be used for the research of neuroprotective drugs.

Experimental example 2Annexin V-FITC/PI double staining method for observing influence of CP-14-1 compound on nerve cell apoptosis

1. Apparatus and materials

Thermo 3111 type CO₂An incubator; HFsafe biosafety cabinet; a Fresco cryo centrifuge (Thermo); olympus IX71 inverted fluorescence microscope; a flow cytometer; modified RPMI-1640, DMEM medium, fetal bovine serum, EDTA-free trypsin solution (Gibco), phosphate buffer (Saimer Feishell Biochemical Beijing Co., Ltd.); annexin V-FITC/PI kit (Solebao Biotechnology Co., Ltd.).

Human brain microvascular endothelial cells (HBMEC-2, purchased from Beijing coordination cell resource center);

human neuroblastoma cell (SH-SY5Y, purchased from Beijing coordination cell resource center);

experimental drugs: the compound CP-14-1 of the present invention.

2. Method of producing a composite material

2.1 culture of different cell lines

HBMEC-2, SH-SY5Y cells were cultured in DMEM containing 10% fetal bovine serum, and placed at 37 deg.C with 5% CO₂Incubation in an incubator. The cells all grow in an adherent state, the growth condition is observed under an inverted microscope, and subculture is carried out when the number of the cells is proper.

2.2Annexin V-FITC/PI double staining method for detecting influence of compound CP-14-1 on apoptosis of HBMEC-2/SH-SY5Y

After the cell state is good, when the cell density reaches 70% -80%, uniformly seeding the cells to a 24-pore plate, wherein the cell density is 3.5 multiplied by 10⁴each.mL^-1The 96-well plate was set at 37 ℃ and 5% CO₂And continuing the incubation. 400 μ L of CP-14 solutions with different concentrations were added to each well to give final concentrations of 1.56 μ M, 3.13 μ M, and 6.25 μ M, respectively. The plates were then returned to 5% CO₂And continuously culturing for 24 hours in an incubator at 37 ℃. H is to be₂O₂Dissolving in DMEM culture solution, and dividing 24-well plate into normal group, injury group and administration group, wherein 160 μ L of H is added into each well of injury group₂O₂Solution of H₂O₂The final concentration of the solution was 0.6 mM. 160. mu.L of fresh culture medium was added to each well of the normal group; after addition of the damaging agent, the plates were placed in a 5% incubator at 37 ℃ for further incubation. Digesting and collecting cells by using a trypsin solution without EDTA, 2400 r.min^-1Centrifuge for 10min, discard the supernatant, and add pre-cooled PBS and centrifuge again. The supernatant was discarded again and the cells were resuspended in 500. mu.L Buffer diluent at 2400 r.min^-1After centrifugation for 10min, the whole supernatant was discarded and 200. mu.L of Buffer diluent was added to resuspend the cells. Under the condition of keeping out of the sun, 5 mu L of annexin V-FITC is added into each group of samples, the mixture is evenly mixed and incubated for 10min in the sun, and finally 5 mu L of PI is added and incubated for 10min in the sun. Flow cytometry detection was performed within 1 h.

3. Results

Compound CP-14-1 vs. H₂O₂The damaged HBMEC-2 cells have the function of inhibiting apoptosis, and the apoptosis rate is reduced from 37.5% of a model group to 28.4%, 19.4% and 18.5% as shown in Table 2, wherein CP-14-1 mainly inhibits late apoptosis of the cells with small influence on early apoptosis of the cells. As shown in Table 3, the anti-apoptosis effect of the compound on SH-SY5Y cells is similar to that of HBMEC-2 cells, and the compound mainly affects late apoptosis of the cells, wherein the late apoptosis rate is reduced from 26.5% of a model group to 23.9%, 21% and 14%, but the early apoptosis rate is also obviously reduced when the concentration is 6.25 mu M. In conclusion, the compound CP-14-1 can achieve the neuroprotective effect by inhibiting early apoptosis and late apoptosis.

Table 2: method for detecting anti-apoptosis effect of CP-14-1 on HBMEC-2 cells by Annexin V-FITC/PI double staining method

Table 3: method for detecting anti-apoptosis effect of CP-14-1 on SH-SY5Y cells by Annexin V-FITC/PI double staining method

Note that: zone Q1 represents mechanical damage; region Q2 represents late apoptosis; region Q3 indicates normal; the region Q4 represents early apoptosis.

4. Conclusion

The compound CP-14-1 can achieve the neuroprotective effect by inhibiting early apoptosis and late apoptosis. The compound can be used for researching neuroprotective drugs.

Experimental example 3 Effect of inventive Compound CP-14-1 on quail embryo allantoic membrane angiogenesis

1. Apparatus and materials

Model 8204 BSS300 MP GTFS incubator (Grimbach, Germany), BJ-3CD upgraded vertical clean bench (Shanghai Bochner medical devices Co., Ltd.), model 320040 dissecting microscope (Olympus, Japan), ME55 one tenth electron analytical balance (Mettler-Toledo, Switzerland), Japanese yellow feather quail embryo eggs (supplied by Shandong sunshine farm). A disposable 1mL syringe, a hammer, a 3mm diameter punch, an ophthalmic scissors, a medical forceps, a gelatin sponge (Nanjing Jinling pharmaceutical factory), a glass slide, a culture dish, etc., a plastic dropper (2mL), a medical adhesive tape, physiological saline (Shijiazhuang four drugs Co., Ltd.), methanol, ethanol (Beijing chemical factory), deionized water.

Experimental drugs: the compound CP-14-1 of the present invention.

2. Method of producing a composite material

2.1 incubation of quail embryonated eggs

The quail embryo eggs are placed in an incubator, the temperature of the incubator is set to be 37 ℃, and the humidity is set to be 60%. When the laying device is placed, the air chambers of the embryonic eggs are upward, and a certain distance is kept between the embryonic eggs. Water is added into the incubator intermittently to ensure the humidity of the incubator.

2.2 preparation of the drug delivery vehicle

Before the windowing experiment, the gelatin sponge was evenly hammered out with a hammer and punched with a punch of 3mm diameter. Weighing a proper amount of sample CP-14-1 to be detected and preparing the sample CP-14-1 into 4 mg/mL by using thionyl chloride^-1The stock solution of (1) and gradually diluting the stock solution until the sample concentration is 2 mg/mL^-1、1mg·mL^-1、0.5mg·mL^-1And then standby. The CP-14 solution was applied to the gelatin sponge using a pipette gun, adding 4. mu.L per concentration. The drug loading rates of different groups of quail eggs are respectively 8 mug, 4 mug and 2 mug. The blank group (saline group) was filled with 4. mu.L of saline. Placing the gelatin sponge with the drug under an ultraviolet lamp, and disinfecting for 30 minutes.

2.3 windowing experiment

The superclean bench is irradiated by ultraviolet rays for 30 minutes and then wiped by alcohol for disinfection. After the quail embryo eggs are incubated for 7 days, the quail embryo eggs are taken out of the incubator, placed on a clean bench and subjected to subsequent operations in the clean bench. Wiping one end of the air chamber of the embryo egg with 70% alcohol for sterilization, lightly making a small hole at one end of the air chamber to reduce the pressure of the air chamber, and lightly removing the eggshell and the upper shell membrane with sterilized medical forceps without touching or tearing the lower shell membrane and the allantoic membrane. The opening area is 30mm²The method is suitable for the left and the right. The unfertilized eggs and the weakly fertilized embryonated eggs were discarded. The broken egg shells in the air chamber are removed by light blowing with an ear washing ball. A drop of sterile saline was applied to the lower shell membrane using a 1mL syringe, which allowed visualization of the vascularity of the allantoic membrane. Then, a small opening is opened by an injector at the place without blood vessels, and the physiological saline is infiltrated into the small opening. And carefully uncovering a small opening by using tweezers, so that the gelatin sponge and the allantoic membrane can be directly contacted. The steps are carefully operated, blood vessels on the allantoic membrane of the embryo are not damaged, and if the blood vessels are damaged in the operation process to cause bleeding, the quail egg cannot be subjected to subsequent experiments. Sealing with medical adhesive tape, and placing the medicated embryonated eggThe plastic tray is fixed and placed into an incubator for continuous incubation.

2.4 film removal and Observation

After 2 days of incubation, the embryonated egg is taken out, the sealing film is removed, the membrane is separated from the eggshell by an ophthalmic scissors after fixation, the eggshell is placed in a culture dish filled with physiological saline, a glass slide is placed under the membrane, the membrane is completely unfolded, the glass slide is quickly lifted after the membrane does not shake any more, and redundant water on the glass slide is wiped off. Finally, the film is observed by a dissecting microscope and photographed.

3. Results

As shown in FIG. 1, the quail embryo allantoic membrane in the normal saline group had thin blood vessels and low density. After administration, the blood vessel density of the allantoic membrane of the quail embryo is obviously increased, the blood vessels on part of the allantoic membrane are thick and strong, and the compound CP-14-1 has the effect of promoting angiogenesis. Under different drug loading, the increase condition of the blood vessel density on the allantoic membrane of the quail embryo has certain difference. Wherein, when the drug loading is 4 mug, the density of the blood vessel on the membrane is obviously larger than that of the blood vessel under other drug loading, which shows that the compound CP-14-1 has the function of promoting angiogenesis under the selected drug loading, wherein, when the drug loading is 4 mug, the angiogenesis promoting activity is optimal.

3. Conclusion

The compound CP-14-1 has good effect of promoting angiogenesis, and particularly, the number of blood vessels on the allantoic membrane is remarkably increased when the drug loading is 2 mu g or 4 mu g. The compound is shown to be used for research of angiogenesis promoting drugs.

Drawings

FIG. 1 is a graph showing the effect of CP-14-1, a compound obtained in example 14 of the present invention, on the neovascularization of quail embryo allantoic membrane. Wherein (A) is a blank group; (B) in the 2 mug quantity group; (C) in the 4. mu.g quantity group; (D) the amount was 8. mu.g.

Detailed Description

EXAMPLE 1 Synthesis of Compound CP-1-1

296.3mg (2.00mmol) cinnamic acid, 379.5mg (2.00mmol) vanillin amine hydrochloride, 286.9mg (1.50mmol) EDCI, 161.4mg (1.19mmol) HOBT, 191.2mg (1.48mmol) DIEPA are added sequentially in a 100mL round-bottomed flask; then adding a proper amount of N, N-dimethyl imide, and stirring at normal temperature for reaction for 4 hours. The reaction was detected by TLC [ V (dichloromethane): V (methanol) ═ 25:1] to be substantially complete, and the reaction solution was extracted with ethyl acetate, and the organic layer was collected, dried with an appropriate amount of saturated brine and anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. Silica gel column separation of the residue to give a white solid, melting point: 140.7-142.3 ℃, yield: 92.20 percent.

¹H NMR(400MHz,DMSO-d6)δ(ppm):8.84(s,1H,-OH),8.47(t,J＝5.7Hz,1H,-NH),7.56 (d,J＝7.3Hz,2H),7.46(d,J＝15.8Hz,1H),7.39(dq,J＝15.8,7.3Hz,3H),6.88(s,1H), 6.75-6.66(m,3H),4.29(d,J＝5.7Hz,2H,-CH₂),3.75(s,3H,-OCH₃)；¹³C NMR(100MHz, DMSO-d6)δ(ppm):164.72,147.45,145.54,138.74,134.93,130.02,129.41,128.92,127.49, 122.23,120.02,115.25,112.00,55.59,42.26.HR-MS(ESI)m/z:[M+H]⁺calcd for C₁₇H₁₇NO₃: 284.1242,found:284.1281.

EXAMPLE 2 Synthesis of Compound CP-2-1

328.4mg (2.00mmol) of o-hydroxycinnamic acid, 378.5mg (2.00mmol) of vanillin amine hydrochloride, 287.2mg (1.50mmol) of EDCI, 161.2mg (1.19mmol) of HOBT and 190.8mg (1.48mmol) of DIEPA were added sequentially in a 100mL round-bottomed flask; then adding a proper amount of N, N-dimethyl imide, and stirring at normal temperature for reaction for 4 hours. The reaction was detected by TLC [ V (dichloromethane): V (methanol) ═ 25:1] to be substantially complete, and the reaction solution was extracted with ethyl acetate, and the organic layer was collected, dried with an appropriate amount of saturated brine and anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. Silica gel column separation of the residue to give a white solid, melting point: 199.8-202.0 ℃, yield: 73.24 percent.

¹H NMR(400MHz,DMSO-d6)δ(ppm):10.01(s,1H,-OH),8.83(s,1H,-OH),8.43(t,J＝ 5.7Hz,1H,-NH),7.67(d,J＝15.7Hz,1H),7.41(d,J＝7.5Hz,1H),7.17(t,J＝7.5Hz,1H),6.89 (d,J＝8.3Hz,1H),6.87(s,1H),6.82(t,J＝7.5Hz,1H),6.70(dd,J＝10.6,5.3Hz,3H),4.27(d,J ＝5.7Hz,2H,-CH₂),3.75(s,3H,-OCH₃)；¹³C NMR(100MHz,DMSO-d6)δ(ppm):165.37, 156.23,147.42,145.46,134.62,130.41,130.25,128.11,121.69,121.62,119.96,119.32,116.06, 115.22,111.95,55.58,42.20.HR-MS(ESI)m/z:[M+H]⁺calcd for C₁₇H₁₇NO₄:300.1191,found: 300.1227.

EXAMPLE 3 Synthesis of Compound CP-3-1

328.3mg (2.00mmol) of m-hydroxycinnamic acid, 378.6mg (2.00mmol) of vanillin amine hydrochloride, 286.6mg (1.50mmol) of EDCI, 161.2mg (1.19mmol) of HOBT and 191.7mg (1.48mmol) of DIEPA are added in this order to a 100mL round-bottomed flask; then adding a proper amount of N, N-dimethyl imide, and stirring at normal temperature for reaction for 4 hours. The reaction was detected by TLC [ V (dichloromethane): V (methanol) ═ 25:1] to be substantially complete, and the reaction solution was extracted with ethyl acetate, and the organic layer was collected, dried with an appropriate amount of saturated brine and anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. Silica gel column separation of the residue to give a white solid, melting point: 150.2-151.8 ℃, yield: 81.14 percent.

¹H NMR(400MHz,DMSO-d6)δ(ppm):9.57(s,1H,-OH),8.86(s,1H,-OH),8.47(t,J＝5.7 Hz,1H,-NH),7.36(d,J＝15.7Hz,1H),7.20(t,J＝7.5Hz,1H),6.97(d,J＝7.5Hz,1H),6.93(s, 1H),6.87(s,1H),6.77(d,J＝7.9Hz,1H),6.72(d,J＝7.9Hz,1H),6.69(d,J＝7.9Hz,1H),6.60 (d,J＝15.7Hz,1H),4.28(d,J＝5.6Hz,2H,-CH₂),3.78(s,3H,-OCH₃)；¹³C NMR(100MHz, DMSO-d6)δ(ppm):164.75,157.68,147.45,145.53,138.94,136.19,130.03,129.91,121.96, 120.02,118.71,116.65,115.25,113.64,111.99,55.58,42.24.HR-MS(ESI)m/z:[M+H]⁺calcd for C₁₇H₁₇NO₄:300.1191,found:300.1243.

EXAMPLE 4 Synthesis of Compound CP-4-1

In a 100mL round-bottomed flask were added 329.0mg (2.00mmol) of p-hydroxycinnamic acid, 377.9mg (1.99mmol) of vanillin amine hydrochloride, 286.9mg (1.50mmol) of EDCI, 162.3mg (1.20mmol) of HOBT, 192.0mg (1.49mmol) of DIEPA in that order; then adding a proper amount of N, N-dimethyl imide, and stirring at normal temperature for reaction for 4 hours. The reaction was detected by TLC [ V (dichloromethane): V (methanol) ═ 25:1] to be substantially complete, and the reaction solution was extracted with ethyl acetate, and the organic layer was collected, dried with an appropriate amount of saturated brine and anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. Silica gel column separation of the residue to give a white solid, melting point: 195.3-197.0 ℃, yield: 84.56 percent.

¹H NMR(400MHz,DMSO-d6)δ(ppm):9.81(s,1H,-OH),8.82(s,1H,-OH),8.33(t,J＝5.7 Hz,1H,-NH),7.38(d,J＝8.4Hz,2H),7.34(s,1H),6.86(s,1H),6.79(d,J＝8.4Hz,2H),6.72(d, J＝8.0Hz,1H),6.68(d,J＝8.0Hz,1H),6.46(d,J＝15.7Hz,1H),4.27(d,J＝5.7Hz,2H,-CH₂), 3.74(s,3H,-OCH₃)；¹³C NMR(100MHz,DMSO-d6)δ(ppm):165.41,159.02,147.64,145.69, 139.06,130.44,129.40,126.13,120.16,118.86,115.94,115.44,112.16,55.79,42.38.HR-MS(ESI) m/z:[M+H]⁺calcd for C₁₇H₁₇NO₄:300.1191,found:300.1228.

EXAMPLE 5 Synthesis of Compound CP-5-1

398.2mg (2.00mmol) of 4-hydroxy-3-methoxycinnamic acid, 379.5mg (2.00mmol) of vanillin amine hydrochloride, 287.1mg (1.50mmol) of EDCI, 161.3mg (1.19mmol) of HOBT, 190.9mg (1.48mmol) of DIEPA are added sequentially in a 100mL round-bottomed flask; then adding a proper amount of N, N-dimethyl imide, and stirring at normal temperature for reaction for 4 hours. The reaction was detected by TLC [ V (dichloromethane): V (methanol) ═ 25:1] to be substantially complete, and the reaction solution was extracted with ethyl acetate, and the organic layer was collected, dried with an appropriate amount of saturated brine and anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. Silica gel column separation of the residue to give a white solid, melting point: 180.2-182.4 ℃, yield: 78.98 percent.

¹H NMR(400MHz,DMSO-d6)δ(ppm):9.41(s,1H,-OH),8.83(s,1H,-OH),8.31(t,J＝5.7 Hz,1H,-NH),7.35(d,J＝15.7Hz,1H),7.12(s,1H),6.99(d,J＝8.2Hz,1H),6.86(s,1H),6.79(d, J＝8.2,1H),6.72(d,J＝8.0Hz,1H),6.68(d,J＝8.0Hz,1H),6.50(d,J＝15.7Hz,1H),4.27(d,J＝ 5.7Hz,2H,-CH₂),3.80(s,3H,-OCH₃),3.74(s,3H,-OCH₃)；¹³C NMR(100MHz,DMSO-d6)δ (ppm):165.21,148.26,147.81,147.45,145.48,139.14,130.25,126.43,121.49,119.96,118.97, 115.67,115.24,111.95,110.81,55.59,55.51,42.21.HR-MS(ESI)m/z:[M+H]⁺calcd for C₁₈H₁₉NO₅:330.1297,found:330.1337.

EXAMPLE 6 Synthesis of Compound CP-6-1

388.3mg (2.00mmol) of 3-hydroxy-4-methoxycinnamic acid, 379.0mg (2.00mmol) of vanillin amine hydrochloride, 287.1mg (1.50mmol) of EDCI, 161.8mg (1.20mmol) of HOBT and 191.1mg (1.48mmol) of DIEPA are added in succession to a 100mL round-bottomed flask; then adding a proper amount of N, N-dimethyl imide, and stirring at normal temperature for reaction for 4 hours. The reaction was detected by TLC [ V (dichloromethane): V (methanol) ═ 25:1] to be substantially complete, and the reaction solution was extracted with ethyl acetate, and the organic layer was collected, dried with an appropriate amount of saturated brine and anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. Silica gel column separation of the residue to give a white solid, melting point: 154.7-156.5 ℃, yield: 89.12 percent.

¹H NMR(400MHz,DMSO-d6)δ(ppm):9.18(s,1H,-OH),8.84(s,1H,-OH),8.38(t,J＝5.7 Hz,1H,-NH),7.31(d,J＝15.6Hz,1H),6.98(s,1H),6.94(d,J＝6.3Hz,2H),6.86(s,1H),6.70(q, J＝7.9Hz,2H),6.45(d,J＝15.6Hz,1H),4.27(d,J＝4.9Hz,2H,-CH₂),3.79(s,3H,-OCH₃), 3.74(s,3H,-OCH₃)；¹³C NMR(100MHz,DMSO-d6)δ(ppm):165.05,149.16,147.44,146.68, 145.50,138.90,130.18,127.80,120.25,119.98,119.51,115.24,113.31,112.09,111.98,55.58, 42.19.HR-MS(ESI)m/z:[M+H]⁺calcd for C₁₈H₁₉NO₅:330.1297,found:330.1345.

EXAMPLE 7 Synthesis of Compound CP-7-1

In a 100mL round-bottomed flask were added 356.3mg (2.00mmol) of o-methoxycinnamic acid, 377.9mg (1.99mmol) of vanillin amine hydrochloride, 286.6mg (1.49mmol) of EDCI, 161.8mg (1.20mmol) of HOBT, and 192.2mg (1.49mmol) of DIEPA, in that order; then adding a proper amount of N, N-dimethyl imide, and stirring at normal temperature for reaction for 4 hours. The reaction was detected by TLC [ V (dichloromethane): V (methanol) ═ 25:1] to be substantially complete, and the reaction solution was extracted with ethyl acetate, and the organic layer was collected, dried with an appropriate amount of saturated brine and anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. Silica gel column separation of the residue to give a white solid, melting point: 150.9-151.3 ℃, yield: 82.14 percent.

¹H NMR(400MHz,DMSO-d6)δ(ppm):8.84(s,1H,-OH),8.44(t,J＝5.7Hz,1H,-NH),7.69 (d,J＝15.9Hz,1H),7.50(d,J＝7.5Hz,1H),7.35(t,J＝7.8Hz,1H),7.06(d,J＝8.3Hz,2H), 6.98(t,J＝7.5Hz,1H),6.77–6.65(m,3H),4.28(d,J＝5.7Hz,2H,-CH₂),3.85(s,3H,-OCH₃), 3.75(s,3H,-OCH₃)；¹³C NMR(100MHz,DMSO-d6)δ(ppm):165.11,157.51,147.44,145.51, 133.78,130.77,130.12,127.78,123.31,122.58,120.67,120.02,115.24,112.00,111.67,55.58, 55.52,42.24.HR-MS(ESI)m/z:[M+H]⁺calcd for C₁₈H₁₉NO₄:314.1348,found:314.1393.

EXAMPLE 8 Synthesis of Compound CP-8-1

355.9mg (2.00mmol) of m-methoxycinnamic acid, 377.8mg (1.99mmol) of vanillin amine hydrochloride, 287.3mg (1.50mmol) of EDCI, 160.9mg (1.19mmol) of HOBT and 191.7mg (1.48mmol) of DIEPA are added in succession to a 100mL round-bottomed flask; then adding a proper amount of N, N-dimethyl imide, and stirring at normal temperature for reaction for 4 hours. The reaction was detected by TLC [ V (dichloromethane): V (methanol) ═ 25:1] to be substantially complete, and the reaction solution was extracted with ethyl acetate, and the organic layer was collected, dried with an appropriate amount of saturated brine and anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. Silica gel column separation of the residue to give a white solid, melting point: 141.5-143.5 ℃, yield: 86.24 percent.

¹H NMR(400MHz,DMSO-d6)δ(ppm):8.85(s,1H,-OH),8.45(t,J＝5.7Hz,1H,-NH),7.43 (d,J＝15.7Hz,1H),7.32(t,J＝7.9Hz,1H),7.13(d,J＝7.9Hz,1H),7.11(s,1H),6.94(dd,J＝ 8.1Hz,1.9Hz,1H),6.87(s,1H),6.74-6.66(m,3H),4.29(d,J＝5.6Hz,2H,-CH₂),3.78(s,3H, -OCH₃),3.75(s,3H,-OCH₃)；¹³C NMR(100MHz,DMSO-d6)δ(ppm):164.70,159.58,147.46, 145.55,138.66,136.38,130.01,129.96,122.58,120.02,119.84,115.26,115.22,112.61,112.01, 55.59,55.09,42.28.HR-MS(ESI)m/z:[M+H]⁺calcd for C₁₈H₁₉NO₄:314.1348,found:314.1389.

EXAMPLE 9 Synthesis of Compound CP-9-1

In a 100mL round-bottomed flask were added 355.2mg (1.99mmol) of p-methoxycinnamic acid, 378.4mg (2.00mmol) of vanillin amine hydrochloride, 286.2mg (1.49mmol) of EDCI, 161.8mg (1.20mmol) of HOBT, and 193.3mg (1.50mmol) of DIEPA, in that order; then adding a proper amount of N, N-dimethyl imide, and stirring at normal temperature for reaction for 4 hours. The reaction was detected by TLC [ V (dichloromethane): V (methanol) ═ 25:1] to be substantially complete, and the reaction solution was extracted with ethyl acetate, and the organic layer was collected, dried with an appropriate amount of saturated brine and anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. Silica gel column separation of the residue to give a white solid, melting point: 172.1-173.2 ℃, yield: 83.57 percent.

¹H NMR(400MHz,DMSO-d6)δ(ppm):8.84(s,1H,-OH),8.37(t,J＝5.7Hz,1H,-NH),7.50 (d,J＝8.7Hz,2H),7.41(d,J＝15.7Hz,1H),6.97(d,J＝8.7Hz,2H),6.87(s,1H),6.72(d,J＝5.4 Hz,1H),6.69(d,J＝8.7Hz,1H),6.54(d,J＝15.7Hz,1H),4.28(d,J＝5.6Hz,2H,-CH₂),3.78(s, 3H,-OCH₃),3.75(s,3H,-OCH₃)；¹³C NMR(100MHz,DMSO-d6)δ(ppm):165.05,160.29, 147.45,145.51,138.45,130.17,129.06,127.50,119.99,119.74,115.24,114.38,111.97,55.58, 55.24,42.21.HR-MS(ESI)m/z:[M+H]⁺calcd for C₁₈H₁₉NO₄:314.1348,found:314.1392.

EXAMPLE 10 Synthesis of Compound CP-10-1

In a 100mL round-bottomed flask were added 415.5mg (2.00mmol) of 2, 3-dihydroxycinnamic acid, 379.2mg (2.00mmol) of vanillin amine hydrochloride, 287.0mg (1.50mmol) of EDCI, 161.3mg (1.19mmol) of HOBT, and 191.5mg (1.48mmol) of DIEPA in that order; then adding a proper amount of N, N-dimethyl imide, and stirring at normal temperature for reaction for 4 hours. The reaction was detected by TLC [ V (dichloromethane): V (methanol) ═ 25:1] to be substantially complete, and the reaction solution was extracted with ethyl acetate, and the organic layer was collected, dried with an appropriate amount of saturated brine and anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. Silica gel column separation of the residue to give a white solid, melting point: 193.9-197.6 ℃, yield: 90.7 percent;

¹H NMR(400MHz,DMSO-d6)δ(ppm):8.85(s,1H,-OH),8.50(t,J＝5.7Hz,1H,-NH),7.66 (d,J＝15.8Hz,1H),7.16-7.04(m,3H),6.87(s,1H),6.71(dd,J＝13.5Hz,8.9,3H),4.28(d,J＝5.7Hz,2H,-CH₂),3.82(s,3H,-OCH₃),3.75(s,3H,-OCH₃),3.74(s,3H,-OCH₃)；¹³C NMR(100 MHz,DMSO-d6)δ(ppm):164.85,152.85,147.45,147.37,145.54,133.17,130.02,128.52,124.36, 123.42,120.05,118.49,115.26,113.75,112.03,60.63,55.75,55.58,42.28.HR-MS(ESI)m/z: [M+H]⁺calcd for C₁₉H₂₁NO₅:344.1453,found:344.1493.

EXAMPLE 11 Synthesis of Compound CP-11-1

In a 100mL round-bottomed flask were added 416.3mg (2.00mmol) of 3, 4-dimethoxycinnamic acid, 377.9mg (1.99mmol) of vanillin amine hydrochloride, 287.5mg (1.50mmol) of EDCI, 160.9mg (1.19mmol) of HOBT, 191.7mg (1.48mmol) of DIEPA in that order; then adding a proper amount of N, N-dimethyl imide, and stirring at normal temperature for reaction for 4 hours. The reaction was detected by TLC [ V (dichloromethane): V (methanol) ═ 25:1] to be substantially complete, and the reaction solution was extracted with ethyl acetate, and the organic layer was collected, dried with an appropriate amount of saturated brine and anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. Silica gel column separation of the residue to give a white solid, melting point: 120.5-122.4 ℃, yield: 82.98 percent;

¹H NMR(400MHz,DMSO-d6)δ(ppm):8.84(s,1H,-OH),8.35(t,J＝5.7Hz,1H,-NH),7.38 (t,J＝15.8Hz,1H),7.15(s,1H),7.11(d,J＝8.4Hz,1H),6.98(d,J＝8.4Hz,1H),6.87(s,1H), 6.70(q,J＝8.4Hz,2H),6.57(d,J＝15.8Hz,1H),4.28(d,J＝5.7Hz,2H,-CH₂),3.79(s,3H, -OCH₃),3.78(s,3H,-OCH₃),3.75(s,3H,-OCH₃)；¹³C NMR(100MHz,DMSO-d6)δ(ppm): 165.05,150.07,148.88,147.45,145.50,138.79,130.18,127.73,121.29,119.97,115.24,111.97, 111.75,110.02,55.59,55.54,55.40,42.23.HR-MS(ESI)m/z:[M+H]⁺calcd for C₁₉H₂₁NO₅: 344.1453,found:344.1491.

EXAMPLE 12 Synthesis of Compound CP-12-1

In a 100mL round-bottomed flask were added 417.1mg (2.01mmol) of 3, 5-dihydroxycinnamic acid, 379.0mg (2.00mmol) of vanillin amine hydrochloride, 287.1mg (1.50mmol) of EDCI, 161.8mg (1.20mmol) of HOBT, 191.4mg (1.48mmol) of DIEPA in that order; then adding a proper amount of N, N-dimethyl imide, and stirring at normal temperature for reaction for 4 hours. The reaction was detected by TLC [ V (dichloromethane): V (methanol) ═ 25:1] to be substantially complete, and the reaction solution was extracted with ethyl acetate, and the organic layer was collected, dried with an appropriate amount of saturated brine and anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. Silica gel column separation of the residue to give a white solid, melting point: 153.1-154.9 ℃, yield: 86.19 percent;

¹H NMR(400MHz,DMSO-d6)δ(ppm):8.85(s,1H,-OH),8.43(t,J＝5.6Hz,1H,-NH),7.38 (d,J＝15.7Hz,1H),6.87(s,1H),6.73(d,J＝1.8Hz,2H),6.71(d,J＝5.2Hz,2H),6.67(d,J＝6.9 Hz,1H),6.51(s,1H),4.28(d,J＝5.7Hz,2H,-CH₂),3.76(s,6H,2*-OCH₃),3.75(s,3H,-OCH₃)；¹³C NMR(100MHz,DMSO-d6)δ(ppm):164.66,160.70,147.46,145.55,138.71,136.94,129.99, 122.84,120.02,115.26,112.01,105.40,101.47,55.59,55.25,42.29.HR-MS(ESI)m/z:[M+H]⁺ calcd for C₁₉H₂₁NO₅:344.1453,found:344.1496.

EXAMPLE 13 Synthesis of Compound CP-13-1

In a 100mL round-bottomed flask were added 416.3mg (2.00mmol) of 2, 5-dihydroxycinnamic acid, 379.5mg (2.00mmol) of vanillin amine hydrochloride, 286.8mg (1.50mmol) of EDCI, 161.1mg (1.19mmol) of HOBT, 191.9mg (1.48mmol) of DIEPA in that order; then adding a proper amount of N, N-dimethyl imide, and stirring at normal temperature for reaction for 4 hours. The reaction was detected by TLC [ V (dichloromethane): V (methanol) ═ 25:1] to be substantially complete, and the reaction solution was extracted with ethyl acetate, and the organic layer was collected, dried with an appropriate amount of saturated brine and anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. Silica gel column separation of the residue to give a white solid, melting point: 138.5-141.1 ℃, yield: 81.25 percent.

¹H NMR(400MHz,DMSO-d6)δ(ppm):8.85(s,1H,-OH),8.43(t,J＝5.7Hz,1H,-NH),7.66 (d,J＝15.9Hz,1H),7.06(d,J＝2.7Hz,1H),7.00(d,J＝9.0Hz,1H),6.94(dd,J＝9.0,2.7Hz, 1H),6.87(s,1H),6.71(dd,J＝15.9,7.9Hz,3H),4.27(d,J＝5.6Hz,2H,-CH₂),3.80(s,3H, -OCH₃),3.75(s,3H,-OCH₃),3.73(s,3H,-OCH₃)；¹³C NMR(100MHz,DMSO-d6)δ(ppm): 165.05,153.12,151.89,147.45,145.53,133.57,130.10,123.97,122.97,120.04,116.08,115.25, 112.94,112.41,112.03,56.00,55.59,55.41,42.28.HR-MS(ESI)m/z:[M+H]⁺calcd for C₁₉H₂₁NO₅:344.1453,found:344.1493.

EXAMPLE 14 Synthesis of Compound CP-14-1

477.8mg (2.01mmol) of 2,4, 5-trihydroxycinnamic acid, 379.2mg (2.00mmol) of vanillin amine hydrochloride, 287.2mg (1.50mmol) of EDCI, 161.6mg (1.20mmol) of HOBT and 191.1mg (1.48mmol) of DIEPA are added in sequence to a 100mL round-bottomed flask; then adding a proper amount of N, N-dimethyl imide, and stirring at normal temperature for reaction for 4 hours. The reaction was detected by TLC [ V (dichloromethane): V (methanol) ═ 25:1] to be substantially complete, and the reaction solution was extracted with ethyl acetate, and the organic layer was collected, dried with an appropriate amount of saturated brine and anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. Silica gel column separation of the residue to give a white solid, melting point: 204.7-206.8 ℃, yield: 85.38 percent.

¹H NMR(400MHz,DMSO-d6)δ(ppm):8.83(s,1H,-OH),8.30(s,1H,-NH),7.64(d,J＝ 15.9Hz,1H),7.06(s,1H),6.86(s,1H),6.71(s,2H),6.68(d,J＝8.0Hz,1H),6.58(d,J＝15.9Hz, 1H),4.26(d,J＝5.2Hz,2H,-CH₂),3.84(s,3H,-OCH₃),3.83(s,3H,-OCH₃),3.75(s,3H,-OCH₃), 3.73(s,3H,-OCH₃)；¹³C NMR(100MHz,DMSO-d6)δ(ppm):165.47,152.84,151.21,147.42, 145.47,142.83,133.44,130.28,119.97,119.84,115.22,114.58,111.99,110.80,97.95,56.28,56.02, 55.77,55.59,42.22.HR-MS(ESI)m/z:[M+H]⁺calcd for C₂₀H₂₃NO₆:344.1559,found:374.1615.

EXAMPLE 15 Synthesis of Compound CP-15-1

476.9mg (2.00mmol) of 3,4, 5-trimethoxycinnamic acid, 378.9mg (2.00mmol) of vanillin amine hydrochloride, 287.7mg (1.50mmol) of EDCI, 161.8mg (1.20mmol) of HOBT and 190.9mg (1.48mmol) of DIEPA are added in succession to a 100mL round-bottomed flask; then adding a proper amount of N, N-dimethyl imide, and stirring at normal temperature for reaction for 4 hours. The reaction was detected by TLC [ V (dichloromethane): V (methanol) ═ 25:1] to be substantially complete, and the reaction solution was extracted with ethyl acetate, and the organic layer was collected, dried with an appropriate amount of saturated brine and anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. Silica gel column separation of the residue to give a white solid, melting point: 178.0-180.7 ℃, yield: 81.58 percent;

¹H NMR(400MHz,DMSO-d6)δ(ppm):8.85(s,1H,-OH),8.40(s,1H,-NH),7.41(d,J＝ 15.7Hz,1H),6.90(s,2H),6.88(s,1H),6.70(q,J＝8.5Hz,2H),6.64(q,J＝15.7Hz,1H),4.29(d, J＝4.5Hz,2H,-CH₂),3.82(s,6H,2*-OCH₃),3.76(s,3H,-OCH₃),3.69(s,3H,-OCH₃)；.¹³C NMR (100MHz,DMSO-d6)δ(ppm):164.80,153.06,147.44,145.51,138.84,138.62,130.57,130.07, 121.62,119.98,115.23,111.99,104.91,60.08,55.85,55.59,42.27.HR-MS(ESI)m/z:[M+H]⁺ calcd for C₂₀H₂₃NO₆:344.1559,found:374.1591.

EXAMPLE 16 Synthesis of CP-16-1 Compound

To a 100mL round-bottomed flask were added 477.2mg (2.00mmol) of 2,3, 4-trimethoxycinnamic acid, 378.9mg (2.00mmol) of vanillin amine hydrochloride, 287.3mg (1.50mmol) of EDCI, 161.4mg (1.19mmol) of HOBT, 190.9mg (1.48mmol) of DIEPA in that order; then adding a proper amount of N, N-dimethyl imide, and stirring at normal temperature for reaction for 4 hours. The reaction was detected by TLC [ V (dichloromethane): V (methanol) ═ 25:1] to be substantially complete, and the reaction solution was extracted with ethyl acetate, and the organic layer was collected, dried with an appropriate amount of saturated brine and anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. Silica gel column separation of the residue to give a white solid, melting point: 175.8-176.4 ℃, yield: 90.17 percent;

¹H NMR(400MHz,DMSO-d6)δ(ppm):8.84(s,1H,-OH),8.41(s,1H,-NH),7.53(t,J＝ 15.9Hz,1H),7.27(d,J＝8.6Hz,1H),6.87(s,2H),6.71(s,2H),6.62(d,J＝15.9Hz,1H),4.27(d, J＝4.2Hz,2H,-CH₂),3.82(s,3H,-OCH₃),3.80(s,3H,-OCH₃),3.75(s,6H,2*-OCH₃)；¹³C NMR (100MHz,DMSO-d6)δ(ppm):165.17,154.50,152.20,147.44,145.51,141.91,133.44,130.16, 122.42,121.34,121.14,120.03,115.25,112.01,108.47,61.17,60.42,55.93,55.58,42.24.HR-MS (ESI)m/z:[M+H]⁺calcd for C₂₀H₂₃NO₆:344.1559,found:374.1599.

EXAMPLE 17 Synthesis of Compound CP-17-1

277.0mg (2.01mmol) of m-hydroxybenzoic acid, 378.3mg (2.00mmol) of vanillin amine hydrochloride, 286.3mg (1.49mmol) of EDCI, 161.5mg (1.20mmol) of HOBT and 190.9mg (1.48mmol) of DIEPA were sequentially added to a 100mL round-bottomed flask; then adding a proper amount of N, N-dimethyl imide, and stirring at normal temperature for reaction for 4 hours. The reaction was detected by TLC [ V (dichloromethane): V (methanol) ═ 25:1] to be substantially complete, and the reaction solution was extracted with ethyl acetate, and the organic layer was collected, dried with an appropriate amount of saturated brine and anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. Silica gel column separation of the residue to give a white solid, melting point: 141.7-144.2 ℃, yield: 81.25 percent;

¹H NMR(400MHz,DMSO-d6)δ(ppm):8.91(s,1H,-NH),8.82(s,1H,-OH),7.88(d,J＝7.3 Hz,2H),7.49(dt,J＝15.0,7.3Hz,3H),6.91(s,1H),6.72(s,2H),4.37(d,J＝5.9Hz,2H,-CH₂), 3.74(s,3H,-OCH₃)；¹³C NMR(100MHz,DMSO-d6)δ(ppm):166.04,147.40,145.41,134.51, 131.12,130.46,128.27,127.23,119.77,115.20,111.84,55.56,42.45.HR-MS(ESI)m/z:[M+H]⁺ calcd for C₁₅H₁₅NO₃:258.1085,found:258.1123.

EXAMPLE 18 Synthesis of CP-18-1 Compound

276.2mg (2.01mmol) of o-hydroxybenzoic acid, 378.7mg (2.00mmol) of vanillin amine hydrochloride, 286.9mg (1.50mmol) of EDCI, 161.2mg (1.20mmol) of HOBT and 190.9mg (1.48mmol) of DIEPA are sequentially added into a 100mL round-bottomed flask; then adding a proper amount of N, N-dimethyl imide, and stirring at normal temperature for reaction for 4 hours. The reaction was detected by TLC [ V (dichloromethane): V (methanol) ═ 25:1] to be substantially complete, and the reaction solution was extracted with ethyl acetate, and the organic layer was collected, dried with an appropriate amount of saturated brine and anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. Silica gel column separation of the residue to give a white solid, melting point: 165.4-167.3 ℃, yield: 78.92 percent;

¹H NMR(400MHz,DMSO-d6)δ(ppm):12.57(s,1H,-OH),9.22(t,J＝5.7Hz,1H,-NH), 8.87(s,1H,-OH),7.89(d,J＝7.6Hz,1H),7.40(t,J＝7.6Hz,1H),6.98–6.85(m,3H),6.73(s, 2H),4.40(d,J＝4.7Hz,2H,-CH₂),3.75(s,3H,-OCH₃)；¹³C NMR(100MHz,DMSO-d6)δ(ppm): 168.75,160.07,147.47,145.62,133.71,129.67,127.76,119.93,118.61,117.39,115.29,111.95, 55.59,42.23.HR-MS(ESI)m/z:[M+H]⁺calcd for C₁₅H₁₅NO₄:274.1035,found:274.1071.

EXAMPLE 19 Synthesis of Compound CP-19-1

277.0mg (2.01mmol) of m-hydroxybenzoic acid, 378.3mg (2.00mmol) of vanillin amine hydrochloride, 286.3mg (1.49mmol) of EDCI, 161.5mg (1.20mmol) of HOBT and 190.9mg (1.48mmol) of DIEPA were sequentially added to a 100mL round-bottomed flask; then adding a proper amount of N, N-dimethyl imide, and stirring at normal temperature for reaction for 4 hours. The reaction was detected by TLC [ V (dichloromethane): V (methanol) ═ 25:1] to be substantially complete, and the reaction solution was extracted with ethyl acetate, and the organic layer was collected, dried with an appropriate amount of saturated brine and anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. Silica gel column separation of the residue to give a white solid, melting point: 175.9-177.2 ℃, yield: 77.17 percent;

¹H NMR(400MHz,DMSO-d6)δ(ppm):9.61(s,1H,-OH),8.79(d,J＝9.2Hz,2H,-NH, -OH),7.34-7.20(m,3H),6.90(d,J＝7.8Hz,2H),6.70(s,2H),4.33(d,J＝5.9Hz,2H,-CH₂), 3.74(s,3H,-OCH₃)；¹³C NMR(100MHz,DMSO-d6)δ(ppm):166.10,157.30,147.38,145.37, 136.06,130.55,129.27,119.73,118.00,117.67,115.18,114.29,111.80,55.55,42.40.HR-MS(ESI) m/z:[M+H]⁺calcd for C₁₅H₁₅NO₄:274.1035,found:274.1074.

EXAMPLE 20 Synthesis of Compound CP-20-1

In a 100mL round-bottomed flask were added 276.5mg (2.00mmol) of p-hydroxybenzoic acid, 379.2mg (2.00mmol) of vanillin amine hydrochloride, 287.0mg (1.50mmol) of EDCI, 161.4mg (1.20mmol) of HOBT, and 190.6mg (1.48mmol) of DIEPA in that order; then adding a proper amount of N, N-dimethyl imide, and stirring at normal temperature for reaction for 4 hours. The reaction was detected by TLC [ V (dichloromethane): V (methanol) ═ 25:1] to be substantially complete, and the reaction solution was extracted with ethyl acetate, and the organic layer was collected, dried with an appropriate amount of saturated brine and anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. Silica gel column separation of the residue to give a white solid, melting point: 186.2-187.3 ℃, yield: 78.36 percent;

¹H NMR(400MHz,DMSO-d6)δ(ppm):9.94(s,1H,-OH),8.79(s,1H,-OH),8.64(t,J＝5.7 Hz,1H,-NH),7.75(d,J＝8.1Hz,2H),6.89(s,1H),6.79(d,J＝8.1Hz,2H),6.70(s,2H),4.33(d, J＝5.7Hz,2H,-CH₂),3.73(s,3H,-OCH₃)；¹³C NMR(100MHz,DMSO-d6)δ(ppm):165.75, 160.06,147.37,145.34,130.81,129.15,125.22,119.74,115.17,114.76,111.83,55.56,42.33. HR-MS(ESI)m/z:[M+H]⁺calcd for C₁₅H₁₅NO₄:274.1035,found:274.1068.

EXAMPLE 21 Synthesis of Compound CP-21-1

In a 100mL round-bottomed flask were added 336.4mg (2.00mmol) of 4-hydroxy-3-methoxybenzoic acid, 378.9mg (2.00mmol) of vanillin amine hydrochloride, 287.2mg (1.50mmol) of EDCI, 161.5mg (1.20mmol) of HOBT, and 191.3mg (1.48mmol) of DIEPA in that order; then adding a proper amount of N, N-dimethyl imide, and stirring at normal temperature for reaction for 4 hours. The reaction was detected by TLC [ V (dichloromethane): V (methanol) ═ 25:1] to be substantially complete, and the reaction solution was extracted with ethyl acetate, and the organic layer was collected, dried with an appropriate amount of saturated brine and anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. Silica gel column separation of the residue to give a white solid, melting point: 155.3-156.6 ℃, yield: 78.36 percent;

¹H NMR(400MHz,DMSO-d6)δ(ppm):9.52(s,1H,-OH),8.80(s,1H,-OH),8.67(t,J＝5.7 Hz,1H,-NH),7.46(s,1H),7.39(d,J＝8.2Hz,1H),6.89(s,1H),6.80(d,J＝8.2Hz,1H),6.71(s, 2H),4.35(d,J＝5.7Hz,2H,-CH₂),3.80(s,3H,-OCH₃),3.73(s,3H,-OCH₃)；¹³C NMR(100MHz, DMSO-d6)δ(ppm):165.71,149.42,147.38,147.10,145.37,130.79,125.50,120.78,119.80, 115.20,114.79,111.87,111.29,55.64,55.58,42.40.HR-MS(ESI)m/z:[M+H]⁺calcd for C₁₆H₁₇NO₅:304.1140,found:304.1179.

EXAMPLE 22 Synthesis of Compound CP-1-2

333.8mg (1.00mmol) of CP-1 and 277.9mg (2.01mmol) of K were sequentially added to a 100mL round-bottomed flask₂CO₃Then adding a proper amount of N, N-dimethyl imide, and stirring and reacting for 4 hours at 80 ℃. TLC [ V (dichloromethane): V (methanol) ═ 25:1]Detecting the reaction is almost complete, extracting the reaction solution by ethyl acetate, collecting an organic layer, drying by a proper amount of saturated saline and anhydrous sodium sulfate, and decompressing and evaporating to dryness. Silica gel column separation of the residue to give a white solid, melting point: 119.3-122.2 ℃, yield: 65.54 percent;

¹H NMR(400MHz,DMSO-d6)δ(ppm):8.54(s,1H,-NH),7.57(d,J＝6.8Hz,2H),7.48(d,J ＝15.8Hz,1H),7.44–7.33(m,3H),7.06(t,J＝8.0Hz,1H),6.96(s,1H),6.82(d,J＝8.0Hz,1H), 6.70(d,J＝15.8Hz,1H),5.10(s,2H,-CH₂),4.34(s,2H,-CH₂),3.74(s,3H,-OCH₃),2.50(s,3H, -CH₃),2.45(s,6H,2*-CH₃)；¹³C NMR(100MHz,DMSO-d6)δ(ppm):165.02,151.11,149.76, 149.42,148.35,146.94,145.77,139.06,135.11,132.82,129.64,129.13,127.72,122.33,119.75, 114.26,112.09,70.59,55.75,42.38,21.44,21.14,20.33.HR-MS(ESI)m/z:[M+H]⁺calcd for C₂₅H₂₇N₃O₃:418.2086,found:418.2116.

EXAMPLE 23 Synthesis of Compound CP-2-2

278mg (2.00mmol) of vanillin amine hydrochloride are weighed out in a reaction flask, dissolved in a suitable amount of MeOH and 0.2ml Et are added₃N, followed by 436mg (2.00mmol) Boc₂O, stirring for 1h at 60 ℃. The reaction was monitored by TCL for completion, the solvent was spun dry, dissolved in dichloromethane and pH adjusted to 7 by addition of hydrochloric acid. The reaction solution was extracted with water, and the organic layer was collected, dried with an appropriate amount of saturated saline and anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. Placing the obtained product in a reaction bottle, adding 200.4mg (1.20mmol) of chloro-ligustrazine and 345.1mg (2.5mmol) of K₂CO₃Dissolving in DMF, and stirring at 80 deg.C for 4 hr. The reaction was monitored by TCL for completion, and the reaction solution was extracted with ethyl acetate 3 times, the organic layer was collected, dried with an appropriate amount of saturated saline and anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. The resulting product was dissolved in 20ml of dichloromethane, 3ml of trifluoroacetic acid was slowly added, and the reaction was carried out for 1 hour under ice-bath conditions. After the reaction is completely carried out and the reaction solution is completely dried, 328.9mg (2.00mmol) of o-hydroxycinnamic acid, 286.5mg (1.50mmol) of EDCI, 162.9mg (1.20mmol) of Hobt and 193.5mg (1.50mmol) of DIEPA are added in sequence; adding a proper amount of DMF, and stirring at normal temperature for reaction for 4 h. TLC monitors the reaction to be complete and stops the reaction; the reaction solution was transferred to a separatory funnel, washed with 15mL of water and saturated brine in order, dehydrated with anhydrous sodium sulfate, and the product was separated on a silica gel column after concentration under reduced pressure to obtain a yellow solid. Melting point: 166.5-169.7 ℃, yield: 51.70 percent;

¹H-NMR(400MHz,DMSO-d6)δ(ppm):10.07(s,1H,-OH),8.53(s,1H),7.74(d,J＝16.0 Hz,1H),7.48(d,J＝7.5Hz,1H),7.23(t,J＝7.5Hz,1H),7.10(d,J＝8.0Hz,1H),7.00(s,1H), 6.95(d,J＝8.0Hz,1H),6.88(t,J＝8.1Hz,2H),6.77(d,J＝16.0Hz,1H),5.15(s,2H,-CH₂),4.38 (d,J＝4.8Hz,2H,-CH₂),3.74(s,3H,-OCH₃),2.55(s,3H,-CH₃),2.45(s,6H,2*-CH₃).¹³C-NMR (100MHz,DMSO-d6)δ(ppm):165.47,156.23,150.85,149.52,149.21,148.11,146.68,145.56, 134.74,132.86,130.39,128.13,121.67,121.53,119.49,119.30,116.06,114.12,111.89,70.40, 55.58,42.10,21.22,20.92,20.07.HR-MS(ESI)m/z:434.2074[M+H]+,calcd for C₂₅H₂₇N₃O₄: 433.2002.

EXAMPLE 24 Synthesis of Compound CP-3-2

278mg (2.00mmol) of vanillin amine hydrochloride are weighed into a reaction flask, dissolved in a suitable amount of MeOH, and 0.2ml Et is added₃N, followed by 436mg (2.00mmol) Boc₂O, stirring for 1h at 60 ℃. The reaction was monitored by TCL for completion, the solvent was spun dry, dissolved in dichloromethane and pH adjusted to 7 by addition of hydrochloric acid. The reaction solution was extracted with water, and the organic layer was collected, dried with an appropriate amount of saturated saline and anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. Placing the obtained product in a reaction bottle, adding 200.4mg (1.20mmol) of chloro-ligustrazine and 345.1mg (2.5mmol) of K₂CO₃Dissolving in DMF, and stirring at 80 deg.C for 4 hr. The reaction was monitored by TCL for completion, and the reaction solution was extracted with ethyl acetate 3 times, the organic layer was collected, dried with an appropriate amount of saturated saline and anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. The resulting product was dissolved in 20ml of dichloromethane, 3ml of trifluoroacetic acid was slowly added, and the reaction was carried out for 1 hour under ice-bath conditions. After the reaction is completely carried out and the reaction solution is completely dried, 328.9mg (2.00mmol) of m-hydroxycinnamic acid, 286.5mg (1.50mmol) of EDCI, 162.9mg (1.20mmol) of Hobt and 193.5mg (1.50mmol) of DIEPA are added in sequence; adding a proper amount of DMF, and stirring at normal temperature for reaction for 4 h. TLC monitors the reaction to be complete and stops the reaction; transferring the reaction solution to a separating funnel, washing with 15mL of water and saturated saline solution in sequence, dehydrating with anhydrous sodium sulfate, and separating the product on a silica gel column after decompression and concentration to obtain a light yellow solid with a melting point: 189.3-194.6 ℃, yield: 64.8 percent;

¹H-NMR(400MHz,DMSO-d6)δ(ppm):9.63(s,1H,-OH),8.57(s,1H,-NH),7.42(d,J＝ 15.7Hz,1H),7.26(t,J＝7.6Hz,1H),7.10(d,J＝8.1Hz,1H),7.03(d,J＝7.6Hz,1H),6.89-6.81 (m,2H),6.65(d,J＝15.7Hz,1H),5.15(s,2H,-CH₂),4.38(d,J＝5.0Hz,2H,-CH₂),3.79(s,3H, -OCH₃),2.55(s,3H,-CH₃),2.50(s,6H,2*-CH₃).¹³C-NMR(100MHz,DMSO-d6)δ(ppm): 164.84,157.69,150.92,149.56,149.21,148.16,146.73,145.57,139.06,136.16,132.62,129.93, 121.86,119.55,118.73,116.68,114.07,113.68,111.89,70.38,55.56,42.16,21.24,20.95,20.12. HR-MS(ESI)m/z:434.2066[M+H]+,calcd for C₂₅H₂₇N₃O₄:433.2002.

EXAMPLE 25 Synthesis of Compound CP-4-2

278mg (2.00mmol) of vanillin amine hydrochloride are weighed out in a reaction flask, dissolved in a suitable amount of MeOH and 0.2ml Et are added₃N, followed by 436mg (2.00mmol) Boc₂O, stirring for 1h at 60 ℃. The reaction was monitored by TCL for completion, the solvent was spun dry, dissolved in dichloromethane and pH adjusted to 7 by addition of hydrochloric acid. The reaction solution was extracted with water, and the organic layer was collected, dried with an appropriate amount of saturated saline and anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. Placing the obtained product in a reaction bottle, adding 200.4mg (1.20mmol) of chloro-ligustrazine and 345.1mg (2.5mmol) of K₂CO₃Dissolving in DMF, and stirring at 80 deg.C for 4 hr. The reaction was monitored by TCL for completion, and the reaction solution was extracted with ethyl acetate 3 times, the organic layer was collected, dried with an appropriate amount of saturated saline and anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. The resulting product was dissolved in 20ml of dichloromethane, 3ml of trifluoroacetic acid was slowly added, and the reaction was carried out for 1 hour under ice-bath conditions. After the reaction is completely carried out and the reaction solution is completely dried, 328.9mg (2.00mmol) of p-hydroxycinnamic acid, 286.5mg (1.50mmol) of EDCI, 162.9mg (1.20mmol) of Hobt and 193.5mg (1.50mmol) of DIEPA are added in sequence; adding a proper amount of DMF, and stirring at normal temperature for reaction for 4 h. TLC monitors the reaction to be complete and stops the reaction; transferring the reaction solution to a separating funnel, washing with 15mL of water and saturated saline solution in sequence, dehydrating with anhydrous sodium sulfate, concentrating under reduced pressure, and separating the product on a silica gel column to obtain a white solid with a melting point: 135.7-140.8 ℃, yield: 67.25 percent;

¹H-NMR(400MHz,DMSO-d6)δ(ppm):9.88(s,1H,-OH),8.45(s,1H,-NH),7.43(t,J＝ 10.9Hz,3H),7.09(d,J＝8.1Hz,1H),6.99(s,1H),6.85(d,J＝8.1Hz,3H),6.52(d,J＝15.7Hz, 1H),5.14(s,2H,-CH₂),4.37(d,J＝5.0Hz,2H,-CH₂),3.78(s,3H,-OCH₃),2.54(s,3H,-CH₃), 2.50(s,6H,2*-CH₃).¹³C-NMR(100MHz,DMSO-d6)δ(ppm):165.27,158.83,150.89,149.54, 149.19,148.13,146.67,145.56,138.94,132.83,129.20,125.88,119.47,118.53,115.72,114.06, 111.84,70.38,55.54,42.08,21.22,20.93,20.11.HR-MS(ESI)m/z:434.2060[M+H]⁺,calcd for C₂₅H₂₇N₃O₄:433.2002.

EXAMPLE 26 Synthesis of Compound CP-5-2

278mg (2.00mmol) of vanillin amine hydrochloride are weighed out in a reaction flask, dissolved in a suitable amount of MeOH and 0.2ml Et are added₃N, followed by 436mg (2.00mmol) Boc₂O, stirring for 1h at 60 ℃. The reaction was monitored by TCL for completion, the solvent was spun dry, dissolved in dichloromethane and pH adjusted to 7 by addition of hydrochloric acid. The reaction solution was extracted with water, and the organic layer was collected, dried with an appropriate amount of saturated saline and anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. Placing the obtained product in a reaction bottle, adding 200.4mg (1.20mmol) of chloro-ligustrazine and 345.1mg (2.5mmol) of K₂CO₃Dissolving in DMF, and stirring at 80 deg.C for 4 hr. The reaction was monitored by TCL for completion, and the reaction solution was extracted with ethyl acetate 3 times, the organic layer was collected, dried with an appropriate amount of saturated saline and anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. The resulting product was dissolved in 20ml of dichloromethane, 3ml of trifluoroacetic acid was slowly added, and the reaction was carried out for 1 hour under ice-bath conditions. After the reaction is completely carried out, adding 388.7mg (2.00mmol) of 3-methoxy-4-hydroxycinnamic acid, 286.5mg (1.50mmol) of EDCI, 162.9mg (1.20mmol) of Hobt and 193.5mg (1.50mmol) of DIEPA in turn; adding a proper amount of DMF, and stirring at normal temperature for reaction for 4 h. TLC monitors the reaction to be complete and stops the reaction; transferring the reaction solution to a separating funnel, washing with 15mL of water and saturated saline solution in sequence, dehydrating with anhydrous sodium sulfate, and separating the product on a silica gel column after decompression and concentration to obtain a light yellow solid with a melting point: 95.6-99.4 ℃, yield: 65.30 percent;

¹H-NMR(400MHz,DMSO-d6)δ(ppm):9.43(s,1H,-OH),8.38(s,1H,-NH),7.38(d,J＝ 15.7Hz,1H),7.13(s,1H),7.03(dd,J＝16.7,8.0Hz,2H),6.94(s,1H),6.81(d,J＝8.0Hz,2H), 6.52(d,J＝15.7Hz,1H),5.10(s,2H,-CH₂),4.33(d,J＝4.3Hz,2H,-CH₂),3.81(s,3H,-OCH₃), 3.74(s,3H,-OCH₃),2.50(s,3H,-CH₃),2.45(s,6H,2*-CH₃).¹³C-NMR(100MHz,DMSO-d6)δ (ppm):165.28,150.89,149.54,149.21,148.28,148.13,147.80,146.68,145.56,139.23,132.84, 126.39,121.50,119.47,118.85,115.65,114.07,111.86,110.82,70.39,55.57,55.53,42.11,21.24, 20.94,20.12.HR-MS(ESI)m/z:464.2190[M+H]+,calcd for C₂₆H₂₉N₃O₅:463.2107.

EXAMPLE 27 Synthesis of Compound CP-6-2

278mg (2.00mmol) of vanillin amine hydrochloride are weighed out in a reaction flask, dissolved in a suitable amount of MeOH and 0.2ml Et are added₃N, followed by 436mg (2.00mmol) Boc₂O, stirring for 1h at 60 ℃. The reaction was monitored by TCL for completion, the solvent was spun dry, dissolved in dichloromethane and pH adjusted to 7 by addition of hydrochloric acid. The reaction solution was extracted with water, and the organic layer was collected, dried with an appropriate amount of saturated saline and anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. Placing the obtained product in a reaction bottle, adding 200.4mg (1.20mmol) of chloro-ligustrazine and 345.1mg (2.5mmol) of K₂CO₃Dissolving in DMF, and stirring at 80 deg.C for 4 hr. The reaction was monitored by TCL for completion, and the reaction solution was extracted with ethyl acetate 3 times, the organic layer was collected, dried with an appropriate amount of saturated saline and anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. The resulting product was dissolved in 20ml of dichloromethane, 3ml of trifluoroacetic acid was slowly added, and the reaction was carried out for 1 hour under ice-bath conditions. After the reaction is completely carried out, 388.0mg (2.00mmol) of 3-hydroxy-4-methoxycinnamic acid, 286.5mg (1.50mmol) of EDCI, 162.9mg (1.20mmol) of Hobt and 193.5mg (1.50mmol) of DIEPA are added in sequence; adding a proper amount of DMF, and stirring at normal temperature for reaction for 4 h. TLC monitors the reaction to be complete and stops the reaction; transferring the reaction solution to a separating funnel, washing with 15mL of water and saturated saline solution in sequence, dehydrating with anhydrous sodium sulfate, concentrating under reduced pressure, and separating the product on a silica gel column to obtain a white solid with a melting point: 155.2-160.1 ℃, yield: 62.91 percent;

¹H-NMR(400MHz,DMSO-d6)δ(ppm):9.43(s,1H,-OH),8.38(s,1H,-NH),7.38(d,J＝ 15.7Hz,1H),7.13(s,1H),7.03(dd,J＝16.7,8.0Hz,2H),6.94(s,1H),6.81(d,J＝8.0Hz,2H), 6.52(d,J＝15.7Hz,1H),5.10(s,2H,-CH₂),4.33(d,J＝4.3Hz,2H,-CH₂),3.81(s,3H,-OCH₃), 3.74(s,3H,-OCH₃),2.50(s,3H,-CH₃),2.45(s,6H,2*-CH₃).¹³C-NMR(100MHz,DMSO-d6)δ (ppm):165.28,150.89,149.54,149.21,148.28,148.13,147.80,146.68,145.56,139.23,132.84, 126.39,121.50,119.47,118.85,115.65,114.07,111.86,110.82,70.39,55.57,55.53,42.11,21.24, 20.94,20.12.HR-MS(ESI)m/z:464.2190[M+H]+,calcd for C₂₆H₂₉N₃O₅:463.2107.

EXAMPLE 28 Synthesis of Compound CP-7-2

314.7mg (1.00mmol) of CP-7, 204.3mg (1.20mmol) of chloroligustrazine and 279.6mg (2.02mmol) of K are sequentially added into a 100mL round-bottomed bottle₂CO₃Then adding a proper amount of N, N-dimethyl imide, and stirring and reacting for 4 hours at 80 ℃. TLC [ V (dichloromethane): V (methanol) ═ 25:1]Detecting the reaction is almost complete, extracting the reaction solution by ethyl acetate, collecting an organic layer, drying by a proper amount of saturated saline and anhydrous sodium sulfate, and decompressing and evaporating to dryness. Silica gel column separation of the residue to give a white solid, melting point: 145.5-149.8 ℃, yield: 70.32 percent;

¹H NMR(400MHz,DMSO-d6)δ(ppm):8.51(s,1H,-NH),7.70(d,J＝15.9Hz,1H),7.52(d, J＝7.5Hz,1H),7.37(t,J＝7.5Hz,1H),7.06(t,J＝9.2Hz,2H),6.99(t,J＝9.2Hz,1H),6.95(s, 1H),6.81(d,J＝8.1Hz,1H),6.71(d,J＝15.9Hz,1H),5.10(s,2H,-CH₂),4.33(d,J＝5.0Hz,2H, -CH₂),3.86(s,3H,-OCH₃),3.74(s,3H,-OCH₃),2.50(s,3H,-CH₃),2.45(s,6H,2*-CH₃)；¹³C NMR(100MHz,DMSO-d6)δ(ppm):165.18,157.51,150.89,149.54,149.19,148.13,146.69, 145.56,133.88,132.71,130.80,127.80,123.27,122.48,120.67,119.53,114.06,111.90,111.67, 70.37,55.53,42.14,21.22,20.93,20.11.HR-MS(ESI)m/z:[M+H]⁺calcd for C₂₆H₂₉N₃O₄: 448.2192,found:448.2225.

EXAMPLE 29 Synthesis of Compound CP-8-2

315.0mg (1.00mmol) of CP-8, 205.9mg (1.21mmol) of chlorinated ligustrazine and 276.8mg (2.00mmol) of K are sequentially added into a 100mL round-bottomed bottle₂CO₃Then adding a proper amount of N, N-dimethyl imide, and stirring and reacting for 4 hours at 80 ℃. TLC [ V (dichloromethane): V (methanol) ═ 25:1]Detecting the reaction is almost complete, extracting the reaction solution by ethyl acetate, collecting an organic layer, drying by a proper amount of saturated saline and anhydrous sodium sulfate, and decompressing and evaporating to dryness. Silica gel column separation of the residue to give a white solid, melting point: 161.9-162.4 ℃, yield: 69.94 percent;

¹H NMR(400MHz,DMSO-d6)δ(ppm):8.52(s,1H,-NH),7.44(d,J＝15.8Hz,1H),7.33(d, J＝7.8Hz,1H),7.15(d,J＝7.8Hz,1H),7.13(s,1H),7.05(d,J＝8.1Hz,1H),6.95(s,2H),6.82 (d,J＝8.1,1H),6.70(d,J＝15.8Hz,1H),5.10(s,2H,-CH₂),4.34(d,J＝5.2Hz,2H,-CH₂),3.79 (s,3H,-OCH₃),3.74(s,3H,-OCH₃),2.50(s,3H,-CH₃),2.45(s,6H,2*-CH3)；¹³C NMR(100 MHz,DMSO-d6)δ(ppm):165.25,160.06,151.38,150.03,149.69,148.62,147.21,146.04,139.23, 136.83,133.08,130.44,122.96,120.34,120.02,115.72,114.55,113.10,112.38,70.86,56.04,55.58, 42.65,21.71,21.42,20.60.HR-MS(ESI)m/z:[M+H]⁺calcd for C₂₆H₂₉N₃O₄:448.2192,found: 448.2233.

EXAMPLE 30 Synthesis of Compound CP-9-2

314.8mg (1.00mmol) of CP-9, 204.4mg (1.20mmol) of chloroligustrazine and 276.3mg (2.00mmol) of K are sequentially added into a 100mL round-bottomed bottle₂CO₃Then adding a proper amount of N, N-dimethyl imide, and stirring and reacting for 4 hours at 80 ℃. TLC [ V (dichloromethane): V (methanol) ═ 25:1]Detecting the reaction is almost complete, extracting the reaction solution by ethyl acetate, collecting an organic layer, drying by a proper amount of saturated saline and anhydrous sodium sulfate, and decompressing and evaporating to dryness. Silica gel column separation of the residue to give a white solid, melting point: 136.6-137.2 ℃, yield: 73.13 percent;

¹H NMR(400MHz,DMSO-d6)δ(ppm):8.44(s,1H,-NH),7.52(d,J＝8.2Hz,2H),7.42(d,J ＝15.8Hz,1H),7.05(d,J＝8.2Hz,1H),6.98(d,J＝8.2Hz,2H),6.95(s,1H),6.91(d,J＝7.7,1H), 6.55(d,J＝15.8Hz,1H),5.10(s,2H,-CH₂),4.33(d,J＝4.6Hz,2H,-CH₂),3.79(s,3H,-OCH₃), 3.74(s,3H,-OCH₃),2.50(s,3H,-CH₃),2.45(s,6H,2*-CH₃)；¹³C NMR(100MHz,DMSO-d6)δ (ppm):165.11,160.29,150.88,149.54,149.20,148.13,146.69,145.55,138.53,132.76,129.06, 127.45,119.62,119.49,114.36,114.06,111.86,70.38,55.54,55.23,42.11,21.22,20.92,20.10. HR-MS(ESI)m/z:[M+H]⁺calcd for C₂₆H₂₉N₃O₄:448.2192,found:448.2225.

EXAMPLE 31 Synthesis of Compound CP-10-2

343.2mg (1.00mmol) of CP-10 and 204.2m are added into a 100mL round-bottomed bottle in sequenceg (1.20mmol) of chloroligustrazine and 279.3mg (2.02mmol) of K₂CO₃Then adding a proper amount of N, N-dimethyl imide, and stirring and reacting for 4 hours at 80 ℃. TLC [ V (dichloromethane): V (methanol) ═ 25:1]Detecting the reaction is almost complete, extracting the reaction solution by ethyl acetate, collecting an organic layer, drying by a proper amount of saturated saline and anhydrous sodium sulfate, and decompressing and evaporating to dryness. Silica gel column separation of the residue to give a white solid, melting point: 144.9-147.6 ℃, yield: 68.49 percent;

¹H NMR(400MHz,DMSO-d6)δ(ppm):8.56(s,1H,-NH),7.67(d,J＝15.9Hz,1H),7.13(t, J＝9.4Hz,2H),7.08(d,J＝8.5Hz,2H),6.96(s,1H),6.82(d,J＝8.5Hz,1H),6.71(d,J＝15.9Hz, 1H),5.10(s,2H,-CH₂),4.34(d,J＝4.4Hz,2H,-CH₂),3.83(s,3H,-OCH₃),3.75(s,6H,2* -OCH₃),2.50(s,3H,-CH₃),2.45(s,6H,2*-CH₃)；¹³C NMR(100MHz,DMSO-d6)δ(ppm): 164.94,152.85,150.91,149.56,149.20,148.15,147.38,146.73,145.56,133.28,132.62,128.49, 124.36,123.32,119.58,118.51,114.06,113.78,111.92,70.37,60.63,55.76,55.55,42.19,21.24, 20.94,20.12.HR-MS(ESI)m/z:[M+H]⁺calcd for C₂₇H₃₁N₃O₅:478.2297,found:478.2325.

EXAMPLE 32 Synthesis of Compound CP-11-2

344.1mg (1.00mmol) of CP-11, 205.1mg (1.21mmol) of ligustrazine chloride and 277.6mg (2.00mmol) of K are sequentially added into a 100mL round-bottomed bottle₂CO₃Then adding a proper amount of N, N-dimethyl imide, and stirring and reacting for 4 hours at 80 ℃. TLC [ V (dichloromethane): V (methanol) ═ 25:1]Detecting the reaction is almost complete, extracting the reaction solution by ethyl acetate, collecting an organic layer, drying by a proper amount of saturated saline and anhydrous sodium sulfate, and decompressing and evaporating to dryness. Silica gel column separation of the residue to give a white solid, melting point: 137.2-137.9 ℃, yield: 65.36 percent;

¹H NMR(400MHz,DMSO-d6)δ(ppm):8.46(s,1H,-NH),7.45(d,J＝15.8Hz,1H),7.42(d, J＝15.8Hz,1H),7.21(s,1H),7.16(d,J＝8.2Hz,1H),7.09(d,J＝8.2Hz,1H),7.03(d,J＝8.2Hz, 1H),6.99(s,1H),6.85(d,J＝8.0Hz,1H),5.14(s,2H,-CH₂),4.37(d,J＝4.8Hz,2H,-CH₂),3.83 (s,6H,2*-OCH₃),3.78(s,3H,-OCH₃),2.54(s,3H,-CH₃),2.49(s,6H,2*-CH₃)；¹³C NMR(100 MHz,DMSO-d6)δ(ppm):171.55,165.13,150.91,150.09,149.55,149.20,148.88,148.15,146.69, 145.57,138.89,132.77,127.69,121.33,119.85,119.48,114.04,111.85,111.73,110.01,70.38, 55.55,55.39,42.14,21.23,20.94,20.12.HR-MS(ESI)m/z:[M+H]⁺calcd for C₂₇H₃₁N₃O₅: 478.2297,found:478.2332.

EXAMPLE 33 Synthesis of Compound CP-12-2

343.9mg (1.00mmol) of CP-12, 204.9mg (1.20mmol) of chloroligustrazine and 280.3mg (2.03mmol) of K are sequentially added into a 100mL round-bottomed bottle₂CO₃Then adding a proper amount of N, N-dimethyl imide, and stirring and reacting for 4 hours at 80 ℃. TLC [ V (dichloromethane): V (methanol) ═ 25:1]Detecting the reaction is almost complete, extracting the reaction solution by ethyl acetate, collecting an organic layer, drying by a proper amount of saturated saline and anhydrous sodium sulfate, and decompressing and evaporating to dryness. Silica gel column separation of the residue to give a white solid, melting point: 134.6-136.9 ℃, yield: 61.47%;

¹H NMR(400MHz,DMSO-d6)δ(ppm):8.53(s,1H,-NH),7.71(d,J＝15.9Hz,1H),7.14– 7.08(m,2H),7.05(d,J＝8.1Hz,1H),6.99(s,2H),6.86(d,J＝8.1Hz,1H),6.77(d,J＝15.9Hz, 1H),5.14(s,2H,-CH₂),4.37(d,J＝4.9Hz,2H,-CH₂),3.85(s,3H,-OCH₃),3.78(s,6H,2* -OCH₃),2.54(s,3H,-CH₃),2.49(s,6H,2*-CH₃)；¹³C NMR(100MHz,DMSO-d6)δ(ppm): 165.12,153.11,151.89,150.91,149.55,149.19,148.15,146.71,145.56,133.67,132.68,123.92, 122.86,119.55,116.11,114.05,112.94,112.42,111.91,70.37,56.01,55.55,55.41,42.18,21.23, 20.94,20.12.HR-MS(ESI)m/z:[M+H]⁺calcd for C₂₇H₃₁N₃O₅:478.2297,found:478.2333.

EXAMPLE 34 Synthesis of Compound CP-13-2

343.4mg (1.00mmol) of CP-13, 204.2mg (1.20mmol) of chloroligustrazine and 275.8mg (2.00mmol) of K are sequentially added into a 100mL round-bottomed bottle₂CO₃Adding a proper amount of N, N-dimethyl imideAmine, 80 ℃ stirring and reacting for 4 h. TLC [ V (dichloromethane): V (methanol) ═ 25:1]Detecting the reaction is almost complete, extracting the reaction solution by ethyl acetate, collecting an organic layer, drying by a proper amount of saturated saline and anhydrous sodium sulfate, and decompressing and evaporating to dryness. Silica gel column separation of the residue to give a white solid, melting point: 150.5-152.7 ℃, yield: 66.82 percent;

¹H NMR(400MHz,DMSO-d6)δ(ppm):8.53(t,J＝5.3Hz,1H,-NH),7.71(d,J＝15.9Hz, 1H),7.10(dd,J＝9.0,8.1Hz,2H),7.05(d,J＝9.0Hz,1H),6.99(s,2H),6.85(d,J＝8.1Hz,1H), 6.76(d,J＝15.9Hz,1H),5.14(s,2H,-CH₂),4.37(d,J＝5.5Hz,2H,-CH₂),3.85(s,3H,-OCH₃), 3.78(s,6H,2*-OCH₃),2.54(s,3H,-CH₃),2.49(s,6H,2*-CH₃)；¹³C NMR(100MHz,DMSO-d6) δ(ppm):165.12,153.11,151.89,150.90,149.55,149.19,148.14,146.71,145.56,133.66,132.68, 123.92,122.86,119.55,116.10,114.04,112.93,112.41,111.91,70.37,56.00,55.55,55.41,42.18, 21.23,20.93,20.12.HR-MS(ESI)m/z:[M+H]⁺calcd for C₂₇H₃₁N₃O₅:478.2297,found:478.2331.

EXAMPLE 35 Synthesis of CP-14-2 Compound

374.2mg (1.00mmol) of CP-14, 204.6mg (1.20mmol) of ligustrazine chloride and 277.4mg (2.02mmol) of K are sequentially added into a 100mL round-bottomed bottle₂CO₃Then adding a proper amount of N, N-dimethyl imide, and stirring and reacting for 4 hours at 80 ℃. TLC [ V (dichloromethane): V (methanol) ═ 25:1]Detecting the reaction is almost complete, extracting the reaction solution by ethyl acetate, collecting an organic layer, drying by a proper amount of saturated saline and anhydrous sodium sulfate, and decompressing and evaporating to dryness. Silica gel column separation of the residue to give a white solid, melting point: 154.1-157.3 ℃, yield: 70.01 percent;

¹H NMR(400MHz,DMSO-d6)δ(ppm):8.37(d,J＝5.4Hz,1H,-NH),7.65(d,J＝15.9Hz, 1H),7.08(s,1H),7.04(d,J＝8.2Hz,1H),6.94(s,1H),6.80(d,J＝8.2Hz,1H),6.72(s,1H),6.59 (d,J＝15.9Hz,1H),5.10(s,2H,-CH₂),4.32(d,J＝5.4Hz,2H,-CH₂),3.86(s,3H,-OCH₃),3.84 (s,3H,-OCH₃),3.74(s,6H,2*-OCH₃),2.50(s,3H,-CH₃),2.45(s,6H,2*-CH₃)；¹³C NMR(100 MHz,DMSO-d6)δ(ppm):165.56,152.87,151.24,150.91,149.55,149.19,148.15,146.66,145.57, 142.83,133.56,132.88,119.71,119.49,114.53,114.04,111.87,110.80,97.93,70.38,56.29,56.02, 55.77,55.55,42.13,21.23,20.94,20.12.HR-MS(ESI)m/z:[M+H]⁺calcd for C₂₈H₃₃N₃O₆: 508.2403,found:508.2429.

EXAMPLE 36 Synthesis of Compound CP-15-2

Into a 100mL round-bottomed flask were added 375.0mg (1.00mmol) of CP-15, 204.2mg (1.20mmol) of chloroligustrazine, 274.9mg (1.99mmol) of K in that order₂CO₃Then adding a proper amount of N, N-dimethyl imide, and stirring and reacting for 4 hours at 80 ℃. TLC [ V (dichloromethane): V (methanol) ═ 25:1]Detecting the reaction is almost complete, extracting the reaction solution by ethyl acetate, collecting an organic layer, drying by a proper amount of saturated saline and anhydrous sodium sulfate, and decompressing and evaporating to dryness. Silica gel column separation of the residue to give a white solid, melting point: 180.1-181.9 ℃, yield: 72.84 percent;

¹H NMR(400MHz,DMSO-d6)δ(ppm):8.45(s,1H,-NH),7.41(d,J＝15.9Hz,1H),7.03(d, J＝8.1Hz,1H),6.95(s,1H),6.91(s,2H),6.81(d,J＝8.1Hz,1H),6.65(d,J＝15.9Hz,1H),5.10 (s,2H,-CH₂),4.33(d,J＝5.4Hz,2H,-CH₂),3.82(s,6H,2*-OCH₃),3.74(s,3H,-OCH₃),3.69(s, 3H,-OCH₃),2.50(s,3H,-CH₃),2.45(s,6H,2*-CH₃)；¹³C NMR(100MHz,DMSO-d6)δ(ppm): 164.68,152.86,150.71,149.35,148.99,147.95,146.49,145.36,138.75,138.43,132.46,130.33, 121.30,119.29,113.83,111.66,104.72,70.16,59.88,55.65,55.35,41.96,21.03,20.73,19.91. HR-MS(ESI)m/z:[M+H]⁺calcd.for C₂₈H₃₃N₃O₆：508.2434,found:508.2449..

EXAMPLE 37 Synthesis of Compound CP-16-2

374.2mg (1.00mmol) of CP-16, 203.6mg (1.20mmol) of chloroligustrazine and 279.6mg (2.02mmol) of K are sequentially added into a 100mL round-bottomed bottle₂CO₃Then adding a proper amount of N, N-dimethyl imide, and stirring and reacting for 4 hours at 80 ℃. TLC [ V (dichloromethane): V (methanol) ═ 25:1]Detection ofThe reaction was almost complete, the reaction solution was extracted with ethyl acetate, the organic layer was collected, dried with an appropriate amount of saturated saline and anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. Silica gel column separation of the residue to give a white solid, melting point: 174.2-175.3 ℃, yield: 71.24 percent;

¹H NMR(400MHz,DMSO-d6)δ(ppm):8.48(t,J＝5.7Hz,1H,-NH),7.57(d,J＝15.9Hz, 1H),7.29(d,J＝8.9Hz,1H),7.05(d,J＝8.2Hz,1H),6.95(d,J＝1.8Hz,1H),6.88(d,J＝8.9Hz, 1H),6.81(dd,J＝8.2,1.8Hz,1H),6.67-6.60(m,1H),5.10(s,2H,-CH₂),4.33(d,J＝5.8Hz,2H, -CH₂),3.83(s,3H,-OCH₃),3.81(s,3H,-OCH₃),3.77(s,3H,-OCH₃),3.74(s,3H,-OCH₃),2.50(s, 3H,-CH₃),2.45(d,J＝3.3Hz,6H,2*-CH₃)；¹³C NMR(100MHz,DMSO-d6)δ(ppm):165.26, 154.52,152.21,150.91,149.55,149.19,148.15,146.70,145.56,141.91,133.55,132.75,122.45, 121.31,121.02,119.55,114.05,111.89,108.45,70.38,61.16,60.42,55.93,55.54,42.15,21.23, 20.94,20.12.HR-MS(ESI)m/z:[M+H]⁺calcd for C₂₈H₃₃N₃O₆:508.2403,found:508.2449.

EXAMPLE 38 Synthesis of Compound CP-17-2

358.1mg (1.00mmol) of CP-17, 204.1mg (1.20mmol) of chlorinated ligustrazine and 275.8mg (2.00mmol) of K are sequentially added into a 100mL round-bottomed bottle₂CO₃Then adding a proper amount of N, N-dimethyl imide, and stirring and reacting for 4 hours at 80 ℃. TLC [ V (dichloromethane): V (methanol) ═ 25:1]Detecting the reaction is almost complete, extracting the reaction solution by ethyl acetate, collecting an organic layer, drying by a proper amount of saturated saline and anhydrous sodium sulfate, and decompressing and evaporating to dryness. Silica gel column separation of the residue to give a white solid, melting point: 125.7-127.4 ℃, yield: 64.82 percent;

¹H NMR(400MHz,DMSO-d6)δ(ppm):8.97(s,1H,-NH),7.89(d,J＝7.1Hz,2H),7.53(d,J ＝7.1Hz,1H),7.48(d,J＝7.1Hz,2H),7.04(d,J＝8.1Hz,1H),6.99(s,1H),6.84(d,J＝8.1Hz, 1H),5.09(s,2H,-CH₂),4.42(d,J＝5.4Hz,2H,-CH₂),3.73(s,3H,-OCH₃),2.50(s,3H,-CH₃), 2.45(s,6H,2*-CH₃)；¹³C NMR(100MHz,DMSO-d6)δ(ppm):166.12,150.90,149.55,149.16, 148.14,146.63,145.57,134.44,133.01,131.17,128.29,127.22,119.31,114.02,111.73,70.37, 55.52,42.40,21.23,20.93,20.12.HR-MS(ESI)m/z:[M+H]⁺calcd for C₂₃H₂₅N₃O₅:392.1929, found:392.1973.

EXAMPLE 39 Synthesis of Compound CP-18-2

278mg (2.00mmol) of vanillin amine hydrochloride are weighed out in a reaction flask, dissolved in a suitable amount of MeOH and 0.2ml Et are added₃N, followed by 436mg (2.00mmol) Boc₂O, stirring for 1h at 60 ℃. The reaction was monitored by TCL for completion, the solvent was spun dry, dissolved in dichloromethane and pH adjusted to 7 by addition of hydrochloric acid. The reaction solution was extracted with water, and the organic layer was collected, dried with an appropriate amount of saturated saline and anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. Placing the obtained product in a reaction bottle, adding 200.4mg (1.20mmol) of chloro-ligustrazine and 345.1mg (2.50mmol) of K₂CO₃Dissolving in DMF, and stirring at 80 deg.C for 4 hr. The reaction was monitored by TCL for completion, and the reaction solution was extracted with ethyl acetate 3 times, the organic layer was collected, dried with an appropriate amount of saturated saline and anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. The resulting product was dissolved in 20ml of dichloromethane, 3ml of trifluoroacetic acid was slowly added, and the reaction was carried out for 1 hour under ice-bath conditions. After the reaction is completely carried out, 276.5mg (2.00mmol) of o-hydroxybenzoic acid, 286.5mg (1.50mmol) of EDCI, 162.9mg (1.20mmol) of Hobt and 193.5mg (1.50mmol) of DIEPA are added in sequence; adding a proper amount of DMF, and stirring at normal temperature for reaction for 4 h. TLC monitors the reaction to be complete and stops the reaction; transferring the reaction solution to a separating funnel, washing with 15mL of water and saturated saline solution in sequence, dehydrating with anhydrous sodium sulfate, concentrating under reduced pressure, and separating the product on a silica gel column to obtain a white solid with a melting point: 166.6-170.1 ℃, yield: 66.25 percent;

¹H NMR(400MHz,DMSO-d6)δ(ppm):12.53(s,1H,-OH),9.26(s,1H,-NH),7.90(d,J＝ 7.8Hz,1H),7.41(t,J＝7.5Hz,1H),7.06(t,J＝7.8Hz,1H),7.01(s,1H),6.95-6.81(m,3H),5.10 (s,2H,-CH₂),4.46(d,J＝4.8Hz,2H,-CH₂),3.74(s,3H,-OCH₃),2.50(s,3H,-CH₃),2.45(s,6H, 2*-CH₃)；¹³C NMR(100MHz,DMSO-d6)δ(ppm):168.80,160.00,150.89,149.53,149.20, 148.13,146.79,145.52,133.70,132.22,127.77,119.45,118.61,117.36,115.27,114.05,111.84, 70.36,55.57,42.15,21.19,20.93,20.12.HR-MS(ESI)m/z:[M+H]⁺calcd for C₂₃H₂₇N₃O₄: 408.1898,found:407.1845.

EXAMPLE 40 Synthesis of Compound CP-19-2

278mg (2.00mmol) of vanillin amine hydrochloride are weighed out in a reaction flask, dissolved in a suitable amount of MeOH and 0.2ml Et are added₃N, followed by 436mg (2.00mmol) Boc₂O, stirring for 1h at 60 ℃. The reaction was monitored by TCL for completion, the solvent was spun dry, dissolved in dichloromethane and pH adjusted to 7 by addition of hydrochloric acid. The reaction solution was extracted with water, and the organic layer was collected, dried with an appropriate amount of saturated saline and anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. Placing the obtained product in a reaction bottle, adding 200.4mg (1.20mmol) of chloro-ligustrazine and 345.1mg (2.5mmol) of K₂CO₃Dissolving in DMF, and stirring at 80 deg.C for 4 hr. The reaction was monitored by TCL for completion, and the reaction solution was extracted with ethyl acetate 3 times, the organic layer was collected, dried with an appropriate amount of saturated saline and anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. The resulting product was dissolved in 20ml of dichloromethane, 3ml of trifluoroacetic acid was slowly added, and the reaction was carried out for 1 hour under ice-bath conditions. After the reaction is completely carried out, 276.5mg (2.00mmol) of m-hydroxybenzoic acid, 286.5mg (1.50mmol) of EDCI, 162.9mg (1.20mmol) of Hobt and 193.5mg (1.50mmol) of DIEPA are added in sequence; adding a proper amount of DMF, and stirring at normal temperature for reaction for 4 h. TLC monitors the reaction to be complete and stops the reaction; transferring the reaction solution to a separating funnel, washing with 15mL of water and saturated saline solution in sequence, dehydrating with anhydrous sodium sulfate, concentrating under reduced pressure, and separating the product on a silica gel column to obtain a white solid with a melting point: 179.2-184.3 ℃, yield: 58.73 percent;

¹H NMR(400MHz,DMSO-d6)δ(ppm):9.64(s,1H,-OH),8.86(s,1H,-NH),7.40-7.21(m, 3H),7.04(d,J＝8.0Hz,1H),6.97(s,1H),6.92(d,J＝7.5Hz,1H),6.82(d,J＝8.0Hz,1H),5.09 (s,2H,-CH₂),4.39(d,J＝4.8Hz,2H,-CH₂),3.73(s,3H,-OCH₃),2.50(s,3H,-CH₃),2.45(s,6H, 2*-CH₃)；¹³C NMR(100MHz,DMSO-d6)δ(ppm):166.18,157.31,150.91,149.55,149.14, 148.15,146.60,145.58,135.97,133.10,129.28,119.28,118.05,117.68,114.28,114.01,111.71, 70.38,55.51,42.35,21.24,20.94,20.12.HR-MS(ESI)m/z:[M+H]⁺calcd for C₂₃H₂₇N₃O₄: 408.1922,found:407.1845.

EXAMPLE 41 Synthesis of Compound CP-20-2

278mg (2.00mmol) of vanillin amine hydrochloride are weighed out in a reaction flask, dissolved in a suitable amount of MeOH and 0.2ml Et are added₃N, followed by 436mg (2.00mmol) Boc₂O, stirring for 1h at 60 ℃. The reaction was monitored by TCL for completion, the solvent was spun dry, dissolved in dichloromethane and pH adjusted to 7 by addition of hydrochloric acid. The reaction solution was extracted with water, and the organic layer was collected, dried with an appropriate amount of saturated saline and anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. Placing the obtained product in a reaction bottle, adding 200.4mg (1.20mmol) of chloro-ligustrazine and 345.1mg (2.5mmol) of K₂CO₃Dissolving in DMF, and stirring at 80 deg.C for 4 hr. The reaction was monitored by TCL for completion, and the reaction solution was extracted with ethyl acetate 3 times, the organic layer was collected, dried with an appropriate amount of saturated saline and anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. The resulting product was dissolved in 20ml of dichloromethane, 3ml of trifluoroacetic acid was slowly added, and the reaction was carried out for 1 hour under ice-bath conditions. After the reaction was completed and the reaction solution was spin-dried, 276.5mg (2.00mmol) of p-hydroxybenzoic acid, 286.5mg (1.50mmol) of EDCI, 162.9mg (1.20mmol) of Hobt, and 193.5mg (1.50mmol) of DIEPA were added in this order; adding a proper amount of DMF, and stirring at normal temperature for reaction for 4 h. TLC monitors the reaction to be complete and stops the reaction; transferring the reaction solution to a separating funnel, washing with 15mL of water and saturated saline solution in sequence, dehydrating with anhydrous sodium sulfate, concentrating under reduced pressure, and separating the product on a silica gel column to obtain a white solid with a melting point: 225.1-227.8 ℃, yield: 71.91 percent;

¹H NMR(400MHz,DMSO-d6)δ(ppm):9.97(s,1H,-OH),8.70(s,1H,-NH),7.76(d,J＝7.6 Hz,2H),7.04(d,J＝7.9Hz,1H),6.97(s,1H),6.81(d,J＝7.9Hz,3H),5.09(s,2H,-CH₂),4.38(d, J＝4.7Hz,2H,-CH₂),3.73(s,3H,-OCH₃),2.50(s,3H,-CH₃),2.45(s,6H,2*-CH₃)；¹³C NMR (100MHz,DMSO-d6)δ(ppm):165.81,160.09,150.90,149.55,149.13,148.14,146.55,145.59, 133.37,129.15,125.13,119.28,114.77,114.02,111.73,70.38,55.52,42.27,21.24,20.94,20.12. HR-MS(ESI)m/z:[M+H]⁺calcd for C₂₃H₂₇N₃O₄:408.1922,found:407.1845.

EXAMPLE 42 Synthesis of Compound CP-21-2

278mg (2.00mmol) of vanillin amine hydrochloride are weighed out in a reaction flask, dissolved in a suitable amount of MeOH and 0.2ml Et are added₃N, followed by 436mg (2.00mmol) Boc₂O, stirring for 1h at 60 ℃. The reaction was monitored by TCL for completion, the solvent was spun dry, dissolved in dichloromethane and pH adjusted to 7 by addition of hydrochloric acid. The reaction solution was extracted with water, and the organic layer was collected, dried with an appropriate amount of saturated saline and anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. Placing the obtained product in a reaction bottle, adding 200.4mg (1.20mmol) of chloro-ligustrazine and 345.1mg (2.5mmol) of K₂CO₃Dissolving in DMF, and stirring at 80 deg.C for 4 hr. The reaction was monitored by TCL for completion, and the reaction solution was extracted with ethyl acetate 3 times, the organic layer was collected, dried with an appropriate amount of saturated saline and anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. The resulting product was dissolved in 20ml of dichloromethane, 3ml of trifluoroacetic acid was slowly added, and the reaction was carried out for 1 hour under ice-bath conditions. After the reaction was completely carried out and the reaction solution was completely spin-dried, 336.2mg (2.00mmol) of 3-methoxy-4-hydroxybenzoic acid, 286.5mg (1.50mmol) of EDCI, 162.9mg (1.20mmol) of Hobt, and 193.5mg (1.50mmol) of DIEPA were sequentially added; adding a proper amount of DMF, and stirring at normal temperature for reaction for 4 h. TLC monitors the reaction to be complete and stops the reaction; transferring the reaction solution to a separating funnel, washing with 15mL of water and saturated saline solution in sequence, dehydrating with anhydrous sodium sulfate, concentrating under reduced pressure, and separating the product on a silica gel column to obtain a white solid with a melting point: 162.2-166.5 ℃, yield: 57.23 percent;

¹H NMR(400MHz,DMSO-d6)δ(ppm):9.53(s,1H,-OH),8.72(s,1H,-NH),7.46(s,1H), 7.39(d,J＝8.1Hz,1H),7.02(d,J＝9.6Hz,1H),6.96(s,1H),6.81(d,J＝8.1Hz,2H),5.08(s,2H, -CH₂),4.38(d,J＝4.5Hz,2H,-CH₂),3.81(s,3H,-OCH₃),3.72(s,3H,-OCH₃),2.62-2.38(m,12H, 4*-CH₃)；¹³C NMR(100MHz,DMSO-d6)δ(ppm):165.77,150.89,149.54,149.45,149.14, 148.13,147.11,146.58,145.58,133.34,125.40,120.76,119.32,114.79,114.05,111.77,111.29, 70.39,55.63,55.53,42.34,21.22,20.93,20.11.HR-MS(ESI)m/z:[M+H]⁺calcd for C₂₃H₂₇N₃O₄: 438.2028,found:437.1951.

EXAMPLE 43 Synthesis of Compound CP-22-2

278mg (2.00mmol) of vanillin amine hydrochloride are weighed out in a reaction flask, dissolved in a suitable amount of MeOH and 0.2ml Et are added₃N, followed by 436mg (2.00mmol) Boc₂O, stirring for 1h at 60 ℃. The reaction was monitored by TCL for completion, the solvent was spun dry, dissolved in dichloromethane and pH adjusted to 7 by addition of hydrochloric acid. The reaction solution was extracted with water, and the organic layer was collected, dried with an appropriate amount of saturated saline and anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. Placing the obtained product in a reaction bottle, adding 200.4mg (1.20mmol) of chloro-ligustrazine and 345.1mg (2.50mmol) of K₂CO₃Dissolving in DMF, and stirring at 80 deg.C for 4 hr. The reaction was monitored by TCL for completion, and the reaction solution was extracted with ethyl acetate 3 times, the organic layer was collected, dried with an appropriate amount of saturated saline and anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. The resulting product was dissolved in 20ml of dichloromethane, 3ml of trifluoroacetic acid was slowly added, and the reaction was carried out for 1 hour under ice-bath conditions. After the reaction was completely carried out and the reaction solution was completely spin-dried, 308.3mg (2.00mmol) of 3, 4-dihydroxybenzoic acid, 286.5mg (1.50mmol) of EDCI, 162.9mg (1.20mmol) of Hobt, and 193.5mg (1.50mmol) of DIEPA were sequentially added; adding a proper amount of DMF, and stirring at normal temperature for reaction for 4 h. TLC monitors the reaction to be complete and stops the reaction; transferring the reaction solution to a separating funnel, washing with 15mL of water and saturated saline solution in sequence, dehydrating with anhydrous sodium sulfate, concentrating under reduced pressure, and separating the product on a silica gel column to obtain a white solid with a melting point: 94.2-98.1 ℃, yield: 68.98 percent;

¹H NMR(400MHz,DMSO-d6)δ(ppm):9.45(s,1H,-OH),9.11(s,1H,-OH),8.62(s,1H, -NH),7.33(s,1H),7.24(d,J＝8.0Hz,1H),7.03(d,J＝8.0Hz,1H),6.96(s,1H),6.79(dd,J＝ 15.5,8.0Hz,2H),5.09(s,2H,-CH₂),4.37(s,2H,-CH₂),3.73(s,3H,-OCH₃),2.50(s,3H,-CH₃), 2.45(s,6H,2*-CH₃)；¹³C NMR(100MHz,DMSO-d6)δ(ppm):166.02,150.89,149.54,149.14, 148.33,148.14,146.55,145.59,144.82,133.47,125.73,119.26,118.96,115.14,114.83,114.04, 111.74,70.41,55.50,42.27,21.24,20.91,20.13.HR-MS(ESI)m/z:[M+H]⁺calcd for C₂₃H₂₇N₃O₄: 424.1846,found:423.1794.

EXAMPLE 44 Synthesis of Compound CP-2-3

598.2mg (2.00mmol) of o-hydroxycinnamic acid and 239.2mg (2.00mmol) of thionyl chloride are sequentially added into a 100mL round-bottomed bottle, an appropriate amount of methanol is added, and the mixture is reacted for 2 hours at normal temperature, wherein TLC [ V (dichloromethane): V (methanol): 25: 1)]Detecting reaction is basically complete, solvent is dried by spinning, and white solid is obtained by separating residue by a silica gel column; placing the obtained product in a 100mL round-bottom flask, adding 204.1(1.2mmol) of chloroligustrazine and 279.6mg (2.02mmol) of K₂CO₃Then adding a proper amount of N, N-dimethyl imide, and stirring and reacting for 4 hours at 80 ℃. TLC [ V (dichloromethane): V (methanol) ═ 25:1]Detecting that the reaction is basically complete, extracting the reaction solution by using ethyl acetate, collecting an organic layer, drying by using a proper amount of saturated saline and anhydrous sodium sulfate, and evaporating to dryness under reduced pressure; and then the obtained product is mixed with tetrahydrofuran: methanol: 10mL of water (3: 1: 1) was dissolved, 987.3mg (10%) of sodium hydroxide was added, and the mixture was reacted at 60 ℃ for 2 hours by TLC [ V (dichloromethane): V (methanol): 25:1]Detecting the reaction is basically complete, spin-drying the solvent, adding hydrochloric acid to adjust the pH value to 7, extracting with ethyl acetate, collecting an organic layer, drying with a proper amount of saturated saline solution and anhydrous sodium sulfate, and evaporating to dryness under reduced pressure; the resulting product was placed in a 100mL round-bottomed flask, 189.1mg (1.00mmol) of vanillin amine hydrochloride, 287.2mg (1.50mmol) of EDCI, 161.5mg (1.20mmol) of HOBT, 191.3mg (1.48mmol) of DIEPA, and an appropriate amount of N, N-dimethylimide were added and the reaction was stirred at room temperature for 4 hours. TLC [ V (dichloromethane): V (methanol) ═ 25:1]Detecting the reaction is almost complete, extracting the reaction solution by ethyl acetate, collecting an organic layer, drying by a proper amount of saturated saline and anhydrous sodium sulfate, and decompressing and evaporating to dryness. Silica gel column separation of the residue to give a white solid, melting point: 178.8-180.3 ℃, yield: 43.15 percent;

¹H NMR(400MHz,DMSO-d6)δ(ppm):8.85(s,1H,-OH),8.44(s,1H,-NH),7.70(d,J＝ 15.9Hz,1H),7.55(d,J＝7.5Hz,1H),7.37(t,J＝7.5Hz,1H),7.24(d,J＝8.2Hz,1H),7.02(t,J＝ 7.3Hz,1H),6.85(s,1H),6.68(dt,J＝23.8,11.9Hz,3H),5.25(s,2H,-CH₂),4.26(d,J＝4.9Hz, 2H,-CH₂),3.75(s,3H,-OCH₃),2.50(s,3H,-CH₃),2.47(s,6H,2*-CH₃)；¹³C NMR(100MHz, DMSO-d6)δ(ppm):165.38,156.82,151.65,149.84,148.85,147.91,145.98,145.65,133.62, 131.27,130.53,127.53,124.19,122.86,121.67,120.45,115.71,113.64,112.41,70.32,56.04,42.68, 21.75,21.48,20.64.HR-MS(ESI)m/z:[M+H]⁺calcd for C₂₅H₂₇N₃O₄:434.2035,found:434.2055.

EXAMPLE 45 Synthesis of Compound CP-3-3

598.4mg (2.00mmol) of m-hydroxycinnamic acid and 238.9mg (2.00mmol) of thionyl chloride are sequentially added into a 100mL round-bottomed bottle, an appropriate amount of methanol is added, and the mixture is reacted for 2 hours at normal temperature, wherein TLC [ V (dichloromethane): V (methanol): 25: 1)]Detecting reaction is basically complete, solvent is dried by spinning, and white solid is obtained by separating residue by a silica gel column; placing the obtained product in a 100mL round-bottom flask, adding 204.0mg (1.2mmol) of ligustrazine chloride and 278.2mg (2.01mmol) of K₂CO₃Then adding a proper amount of N, N-dimethyl imide, and stirring and reacting for 4 hours at 80 ℃. TLC [ V (dichloromethane): V (methanol) ═ 25:1]Detecting that the reaction is basically complete, extracting the reaction solution by using ethyl acetate, collecting an organic layer, drying by using a proper amount of saturated saline and anhydrous sodium sulfate, and evaporating to dryness under reduced pressure; and then the obtained product is mixed with tetrahydrofuran: methanol: 10mL of water (3: 1: 1) was dissolved, 993.5mg (10%) of sodium hydroxide was added, and the mixture was reacted at 60 ℃ for 2 hours by TLC [ V (dichloromethane): V (methanol): 25:1]Detecting the reaction is basically complete, spin-drying the solvent, adding hydrochloric acid to adjust the pH value to 7, extracting with ethyl acetate, collecting an organic layer, drying with a proper amount of saturated saline solution and anhydrous sodium sulfate, and evaporating to dryness under reduced pressure; the resulting product was placed in a 100mL round-bottomed flask, 189.6mg (1.00mmol) of vanillin amine hydrochloride, 287.4mg (1.50mmol) of EDCI, 161.3mg (1.20mmol) of HOBT, 192.1mg (1.49mmol) of DIEPA, and an appropriate amount of N, N-dimethylimide was added, and the reaction was stirred at room temperature for 4 hours. TLC [ V (dichloromethane): V (methanol) ═ 25:1]Detecting the reaction is almost complete, extracting the reaction solution by ethyl acetate, collecting an organic layer, drying by a proper amount of saturated saline and anhydrous sodium sulfate, and decompressing and evaporating to dryness. Silica gel column separation of the residue to give a white solid, melting point: 82.5-83.3 ℃, yield: 48.36 percent;

¹H NMR(400MHz,DMSO-d6)δ(ppm):8.85(s,1H,-OH),8.46(s,1H,-NH),7.43(d,J＝ 15.7Hz,1H),7.33(t,J＝7.7Hz,1H),7.25(s,1H),7.16(d,J＝7.4Hz,1H),7.05(d,J＝7.4Hz, 1H),6.88(s,1H),6.77–6.64(m,3H),5.19(s,2H,-CH₂),4.29(d,J＝5.0Hz,2H,-CH₂),3.75(s, 3H,-OCH₃),2.50(s,3H,-CH₃),2.45(s,6H,2*-CH₃)；¹³C NMR(100MHz,DMSO-d6)δ(ppm): 165.15,159.18,151.50,149.83,148.76,147.94,146.02,145.74,139.03,136.92,130.49,123.19, 120.72,120.48,116.39,115.73,114.16,112.47,69.84,56.07,42.74,21.73,21.44,20.64.HR-MS (ESI)m/z:[M+H]⁺calcd for C₂₅H₂₇N₃O₄:434.2035,found:434.2056.

EXAMPLE 46 Synthesis of Compound CP-4-3

597.4mg (1.99mmol) of p-hydroxycinnamic acid and 239.4mg (2.00mmol) of thionyl chloride are sequentially added into a 100mL round-bottomed bottle, an appropriate amount of methanol is added, and the mixture is reacted for 2 hours at normal temperature, wherein TLC [ V (dichloromethane): V (methanol): 25: 1)]Detecting reaction is basically complete, solvent is dried by spinning, and white solid is obtained by separating residue by a silica gel column; placing the obtained product in a 100mL round-bottom flask, adding 203.9mg (1.2mmol) of ligustrazine chloride and 278.3mg (2.01mmol) of K₂CO₃Then adding a proper amount of N, N-dimethyl imide, and stirring and reacting for 4 hours at 80 ℃. TLC [ V (dichloromethane): V (methanol) ═ 25:1]Detecting that the reaction is basically complete, extracting the reaction solution by using ethyl acetate, collecting an organic layer, drying by using a proper amount of saturated saline and anhydrous sodium sulfate, and evaporating to dryness under reduced pressure; and then the obtained product is mixed with tetrahydrofuran: methanol: 10mL of water (3: 1: 1) was dissolved, 997.1mg (10%) of sodium hydroxide was added, and the mixture was reacted at 60 ℃ for 2 hours by TLC [ V (dichloromethane): V (methanol): 25:1]Detecting the reaction is basically complete, spin-drying the solvent, adding hydrochloric acid to adjust the pH value to 7, extracting with ethyl acetate, collecting an organic layer, drying with a proper amount of saturated saline solution and anhydrous sodium sulfate, and evaporating to dryness under reduced pressure; the resulting product was placed in a 100mL round-bottomed flask, 189.1mg (1.00mmol) of vanillin amine hydrochloride, 287.4mg (1.50mmol) of EDCI, 161.8mg (1.20mmol) of HOBT, 193.7mg (1.50mmol) of DIEPA, and an appropriate amount of N, N-dimethylimide was added, and the reaction was stirred at room temperature for 4 hours. TLC [ V (dichloromethane): V (methanol) ═ 25:1]Detecting the reaction is almost complete, extracting the reaction solution by ethyl acetate, collecting an organic layer, drying by a proper amount of saturated saline and anhydrous sodium sulfate, and decompressing and evaporating to dryness. Silica gel column separation of the residue to give a white solid, melting point: 90.4-93.7 ℃, yield: 46.37 percent;

¹H NMR(400MHz,DMSO-d6)δ(ppm):8.86(s,1H,-OH),8.40(s,1H,-NH),7.52(d,J＝7.9 Hz,2H),7.43(d,J＝15.7Hz,1H),7.08(d,J＝7.9Hz,2H),6.88(s,1H),6.72(q,J＝7.9Hz,2H), 6.56(d,J＝15.7Hz,1H),5.20(s,2H,-CH₂),4.30(d,J＝4.5Hz,2H,-CH₂),3.76(s,3H,-OCH₃), 2.50(s,3H,-CH₃),2.46(s,6H,2*-CH₃)；¹³C NMR(100MHz,DMSO-d6)δ(ppm):165.02,159.37, 151.06,149.33,148.32,147.45,145.51,145.17,138.36,130.15,129.06,127.93,119.99,115.25, 115.17,111.98,69.39,55.58,42.23,21.26,20.97,20.16.HR-MS(ESI)m/z:[M+H]⁺calcd for C₂₅H₂₇N₃O₄:434.2035,found:434.2063.

EXAMPLE 47 Synthesis of Compound CP-5-3

In a 100mL round-bottomed flask were added 658.2mg (2.00mmol) of 4-hydroxy-3-methoxycinnamic acid and 238.9mg (2.00mmol) of thionyl chloride in this order, followed by addition of an appropriate amount of methanol, followed by reaction at room temperature for 2 hours by TLC [ V (dichloromethane): V (methanol): 25: 1)]Detecting reaction is basically complete, solvent is dried by spinning, and white solid is obtained by separating residue by a silica gel column; placing the obtained product in a 100mL round-bottom flask, adding 204.2mg (1.2mmol) of ligustrazine chloride and 279.2mg (2.02mmol) of K₂CO₃Then adding a proper amount of N, N-dimethyl imide, and stirring and reacting for 4 hours at 80 ℃. TLC [ V (dichloromethane): V (methanol) ═ 25:1]Detecting that the reaction is basically complete, extracting the reaction solution by using ethyl acetate, collecting an organic layer, drying by using a proper amount of saturated saline and anhydrous sodium sulfate, and evaporating to dryness under reduced pressure; and then the obtained product is mixed with tetrahydrofuran: methanol: 10mL of water (3: 1: 1) was dissolved, 987.3mg (10%) of sodium hydroxide was added, and the mixture was reacted at 60 ℃ for 2 hours by TLC [ V (dichloromethane): V (methanol): 25:1]Detecting the reaction is basically complete, spin-drying the solvent, adding hydrochloric acid to adjust the pH value to 7, extracting with ethyl acetate, collecting an organic layer, drying with a proper amount of saturated saline solution and anhydrous sodium sulfate, and evaporating to dryness under reduced pressure; the resulting product was placed in a 100mL round-bottomed flask, 189.6mg (1.00mmol) of vanillin amine hydrochloride, 287.3mg (1.50mmol) of EDCI, 161.9mg (1.20mmol) of HOBT, 191.6mg (1.48mmol) of DIEPA, and an appropriate amount of N, N-dimethylimide was added, and the reaction was stirred at room temperature for 4 hours. TLC [ V (dichloromethane): V (methanol) ═ 25:1]Detection reaction is basicAfter completion, the reaction solution was extracted with ethyl acetate, and the organic layer was collected, dried with an appropriate amount of saturated saline and anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. Silica gel column separation of the residue to give a white solid, melting point: 111.0-112.8 ℃, yield: 48.10 percent;

¹H NMR(400MHz,DMSO-d6)δ(ppm):8.89(s,1H,-OH),8.41(s,1H,-NH),7.44(d,J＝ 15.8Hz,1H),7.22(s,1H),7.17(q,J＝8.4Hz,2H),6.92(s,1H),6.75(q,J＝8.4Hz,2H),6.63(d, J＝15.8Hz,1H),5.20(s,2H,-CH₂),4.32(d,J＝5.0Hz,2H,-CH₂),3.82(s,3H,-OCH₃),3.80(s, 3H,-OCH₃),2.54(s,3H,-CH₃),2.50(s,6H,2*-CH₃)；¹³C NMR(100MHz,DMSO-d6)δ(ppm): 164.98,151.05,149.53,149.28,148.97,148.25,147.43,145.49,145.24,138.64,130.14,128.42, 121.09,120.29,119.96,115.23,113.70,111.97,110.38,70.09,55.58,55.48,42.22,21.24,20.94, 20.12.HR-MS(ESI)m/z:[M+H]⁺calcd for C₂₆H₂₉N₃O₅:464.2141,found:464.2165.

EXAMPLE 48 Synthesis of CP-6-3 Compound

658.7mg (2.00mmol) of 3-hydroxy-4-hydroxycinnamic acid and 239.2mg (2.00mmol) of thionyl chloride were sequentially added to a 100mL round-bottomed flask, followed by addition of an appropriate amount of methanol, and reaction was carried out at room temperature for 2 hours by TLC [ V (dichloromethane): V (methanol): 25: 1)]Detecting reaction is basically complete, solvent is dried by spinning, and white solid is obtained by separating residue by a silica gel column; placing the obtained product in a 100mL round-bottom flask, adding 204.5mg (1.2mmol) of chloro-ligustrazine and 278.1mg (2.00mmol) of K₂CO₃Then adding a proper amount of N, N-dimethyl imide, and stirring and reacting for 4 hours at 80 ℃. TLC [ V (dichloromethane): V (methanol) ═ 25:1]Detecting that the reaction is basically complete, extracting the reaction solution by using ethyl acetate, collecting an organic layer, drying by using a proper amount of saturated saline and anhydrous sodium sulfate, and evaporating to dryness under reduced pressure; and then the obtained product is mixed with tetrahydrofuran: methanol: 10mL of water (3: 1: 1) was dissolved, 993.3mg (10%) of sodium hydroxide was added, and the mixture was reacted at 60 ℃ for 2 hours by TLC [ V (dichloromethane): V (methanol): 25:1]Detecting the reaction is basically complete, spin-drying the solvent, adding hydrochloric acid to adjust the pH value to 7, extracting with ethyl acetate, collecting an organic layer, drying with a proper amount of saturated saline solution and anhydrous sodium sulfate, and evaporating to dryness under reduced pressure; placing the obtained product inA100 mL round-bottomed flask, 189.3mg (1.00mmol) of vanillin amine hydrochloride, 287.3mg (1.50mmol) of EDCI, 161.9mg (1.20mmol) of HOBT, 192.0mg (1.49mmol) of DIEPA, and an appropriate amount of N, N-dimethylimide were added, and the reaction was stirred at room temperature for 4 hours. TLC [ V (dichloromethane): V (methanol) ═ 25:1]Detecting the reaction is almost complete, extracting the reaction solution by ethyl acetate, collecting an organic layer, drying by a proper amount of saturated saline and anhydrous sodium sulfate, and decompressing and evaporating to dryness. Silica gel column separation of the residue to give a white solid, melting point: 121.4-125.2 ℃, yield: 48.35 percent;

¹H NMR(400MHz,DMSO-d6)δ(ppm):8.85(s,1H,-OH),8.39(s,1H,-NH),7.39(d,J＝ 15.7Hz,2H),7.16(d,J＝8.3Hz,1H),7.01(t,J＝8.3Hz,1H),6.88(s,1H),6.72(q,J＝8.3Hz, 2H),6.58(t,J＝15.7Hz,1H),5.17(s,2H,-CH₂),4.29(d,J＝4.9Hz,2H,-CH₂),3.78(s,3H, -OCH₃),3.76(s,3H,-OCH₃),2.51(s,3H,-CH₃),2.46(s,6H,2*-CH₃)；¹³C NMR(100MHz, DMSO-d6)δ(ppm):165.03,151.07,150.50,149.60,148.24,147.79,147.44,145.49,145.29, 138.66,130.19,127.70,121.90,120.10,119.94,115.23,112.51,112.15,111.95,70.15,55.63,55.58, 21.25,20.93,20.13.HR-MS(ESI)m/z:[M+H]⁺calcd for C₂₆H₂₉N₃O₅:464.2141,found:464.2188.

EXAMPLE 49 Synthesis of Compound CP-18-3

In a 100mL round-bottomed flask, 546.2mg (2.00mmol) of o-hydroxybenzoic acid and 239.8mg (2.00mmol) of thionyl chloride were sequentially added, and an appropriate amount of methanol was added to the flask, followed by reaction at room temperature for 2 hours, TLC [ V (dichloromethane): V (methanol): 25: 1)]Detecting reaction is basically complete, solvent is dried by spinning, and white solid is obtained by separating residue by a silica gel column; placing the obtained product in a 100mL round-bottom flask, adding 203.9mg (1.20mmol) of ligustrazine chloride and 277.9mg (2.00mmol) of K₂CO₃Then adding a proper amount of N, N-dimethyl imide, and stirring and reacting for 4 hours at 80 ℃. TLC [ V (dichloromethane): V (methanol) ═ 25:1]Detecting that the reaction is basically complete, extracting the reaction solution by using ethyl acetate, collecting an organic layer, drying by using a proper amount of saturated saline and anhydrous sodium sulfate, and evaporating to dryness under reduced pressure; and then the obtained product is mixed with tetrahydrofuran: methanol: 10mL of water (3: 1: 1) was dissolved, and 993.1mg (10%) of hydrogen and oxygen were addedDissolving sodium chloride, reacting at 60 deg.C for 2 hr, and TLC (V (dichloromethane): V (methanol): 25: 1)]Detecting the reaction is basically complete, spin-drying the solvent, adding hydrochloric acid to adjust the pH value to 7, extracting with ethyl acetate, collecting an organic layer, drying with a proper amount of saturated saline solution and anhydrous sodium sulfate, and evaporating to dryness under reduced pressure; the resulting product was placed in a 100mL round-bottomed flask, 189.1mg (1.00mmol) of vanillin amine hydrochloride, 286.9mg (1.50mmol) of EDCI, 161.5mg (1.20mmol) of HOBT, 191.9mg (1.49mmol) of DIEPA, and an appropriate amount of N, N-dimethylimide was added, and the reaction was stirred at room temperature for 4 hours. TLC [ V (dichloromethane): V (methanol) ═ 25:1]Detecting the reaction is almost complete, extracting the reaction solution by ethyl acetate, collecting an organic layer, drying by a proper amount of saturated saline and anhydrous sodium sulfate, and decompressing and evaporating to dryness. Silica gel column separation of the residue to give a white solid, melting point: 190.3-192.9 ℃, yield: 39.95 percent.

¹H NMR(400MHz,DMSO-d6)δ(ppm):8.92(s,1H,-NH),8.79(s,1H,-OH),7.85(d,J＝7.5 Hz,1H),7.50(t,J＝7.5Hz,1H),7.35(d,J＝8.2Hz,1H),7.08(d,J＝7.5Hz,1H),6.77(s,1H), 6.57(s,2H),5.34(s,2H,-CH₂),4.40(d,J＝5.2Hz,2H,-CH₂),3.63(s,3H,-OCH₃),2.42(s,3H, -CH₃),2.33(s,6H,2*-CH₃)；¹³C NMR(100MHz,DMSO-d6)δ(ppm):164.57,156.04,150.69, 148.24,148.19,147.32,145.31,144.70,132.34,130.75,129.78,122.92,121.11,119.26,115.10, 113.43,111.30,68.62,55.33,42.54,21.19,20.90,19.91.HR-MS(ESI)m/z:[M+H]⁺calcd for C₂₃H₂₅N₃O₄:408.1879,found:408.1904.

EXAMPLE 50 Synthesis of Compound CP-19-3

547.2mg (2.01mmol) of m-hydroxybenzoic acid, 239.2mg (2.00mmol) of thionyl chloride and an appropriate amount of methanol were sequentially added to a 100mL round-bottomed flask, and reacted at room temperature for 2 hours by TLC [ V (dichloromethane): V (methanol): 25: 1)]Detecting reaction is basically complete, solvent is dried by spinning, and white solid is obtained by separating residue by a silica gel column; placing the obtained product in a 100mL round-bottom flask, adding 204.3mg (1.20mmol) of chloro-ligustrazine and 279.6mg (2.02mmol) of K₂CO₃Then adding a proper amount of N, N-dimethyl imide, and stirring and reacting for 4 hours at 80 ℃. TLC [ V (dichloromethane): V (methanol) ═ 25:1]Detecting the reaction is almost complete, and using acetic acid for reaction liquidExtracting with ethyl ester, collecting organic layer, drying with appropriate amount of saturated saline solution and anhydrous sodium sulfate, and evaporating under reduced pressure; and then the obtained product is mixed with tetrahydrofuran: methanol: 10mL of water (3: 1: 1) was dissolved, and 997.5mg (10%) of sodium hydroxide was added to the solution, followed by reaction at 60 ℃ for 2 hours by TLC [ V (dichloromethane): V (methanol): 25: 1)]Detecting the reaction is basically complete, spin-drying the solvent, adding hydrochloric acid to adjust the pH value to 7, extracting with ethyl acetate, collecting an organic layer, drying with a proper amount of saturated saline solution and anhydrous sodium sulfate, and evaporating to dryness under reduced pressure; the resulting product was placed in a 100mL round-bottomed flask, 189.5mg (1.00mmol) of vanillin amine hydrochloride, 287.2mg (1.50mmol) of EDCI, 161.9mg (1.20mmol) of HOBT, 191.2mg (1.48mmol) of DIEPA, and an appropriate amount of N, N-dimethylimide were added and the reaction was stirred at room temperature for 4 hours. TLC [ V (dichloromethane): V (methanol) ═ 25:1]Detecting the reaction is almost complete, extracting the reaction solution by ethyl acetate, collecting an organic layer, drying by a proper amount of saturated saline and anhydrous sodium sulfate, and decompressing and evaporating to dryness. Silica gel column separation of the residue to give a white solid, melting point: 184.7-185.2 ℃, yield: 47.18 percent;

¹H NMR(400MHz,DMSO-d6)δ(ppm):8.94(s,1H,-NH),8.87(s,1H,-OH),7.60(s,1H), 7.53(d,J＝7.6Hz,1H),7.43(t,J＝7.6Hz,1H),7.23(d,J＝8.1Hz,1H),6.95(s,1H),6.76(s,2H), 5.25(s,2H,-CH₂),4.41(d,J＝5.2Hz,2H,-CH₂),3.79(s,3H,-OCH₃),2.55(s,H,-CH₃),2.49(s, 6H,2*-CH₃)；¹³C NMR(100MHz,DMSO-d6)δ(ppm):165.69,158.27,151.03,149.33,148.31, 147.40,145.44,145.23,136.01,130.38,129.48,119.94,119.81,117.62,115.21,113.42,111.87, 69.45,55.56,42.50,21.25,20.95,20.18.HR-MS(ESI)m/z:[M+H]⁺calcd for C₂₃H₂₅N₃O₄: 408.1879,found:408.1903.

EXAMPLE 51 Synthesis of Compound CP-20-3

In a 100mL round bottom flask were sequentially added 546.7mg (2.00mmol) of p-hydroxybenzoic acid, 239.2mg (2.00mmol) of thionyl chloride, and an appropriate amount of methanol, followed by reaction at room temperature for 2 hours by TLC [ V (dichloromethane): V (methanol): 25: 1)]Detecting reaction is basically complete, solvent is dried by spinning, and white solid is obtained by separating residue by a silica gel column; the resulting product was placed in a 100mL round bottom flask and 204.1mg (1.20mmol) of chloroligustrazine 279 was added.6mg(2.02mmol)K₂CO₃Then adding a proper amount of N, N-dimethyl imide, and stirring and reacting for 4 hours at 80 ℃. TLC [ V (dichloromethane): V (methanol) ═ 25:1]Detecting that the reaction is basically complete, extracting the reaction solution by using ethyl acetate, collecting an organic layer, drying by using a proper amount of saturated saline and anhydrous sodium sulfate, and evaporating to dryness under reduced pressure; and then the obtained product is mixed with tetrahydrofuran: methanol: 10mL of water (3: 1: 1) was dissolved, 992.5mg (10%) of sodium hydroxide was added, and the mixture was reacted at 60 ℃ for 2 hours by TLC [ V (dichloromethane): V (methanol): 25:1]Detecting the reaction is basically complete, spin-drying the solvent, adding hydrochloric acid to adjust the pH value to 7, extracting with ethyl acetate, collecting an organic layer, drying with a proper amount of saturated saline solution and anhydrous sodium sulfate, and evaporating to dryness under reduced pressure; the resulting product was placed in a 100mL round-bottomed flask, 189.8mg (1.00mmol) of vanillin amine hydrochloride, 287.6mg (1.50mmol) of EDCI, 161.5mg (1.20mmol) of HOBT, 191.9mg (1.49mmol) of DIEPA, and an appropriate amount of N, N-dimethylimide was added and the reaction was stirred at ambient temperature for 4 h. TLC [ V (dichloromethane): V (methanol) ═ 25:1]Detecting the reaction is almost complete, extracting the reaction solution by ethyl acetate, collecting an organic layer, drying by a proper amount of saturated saline and anhydrous sodium sulfate, and decompressing and evaporating to dryness. Silica gel column separation of the residue to give a white solid, melting point: 194.5-199.7 ℃, yield: 48.36 percent;

¹H NMR(400MHz,DMSO-d6)δ(ppm):8.86(s,1H,-OH),8.82(s,1H,-NH),7.91(d,J＝8.0 Hz,2H),7.14(d,J＝8.0Hz,2H),6.94(s,1H),6.75(s,2H),5.27(s,2H,-CH₂),4.40(d,J＝5.3Hz, 2H,-CH₂),3.79(s,3H,-OCH₃),2.54(s,3H,2*-CH3),2.50(s,6H,2*-CH₃)；¹³C NMR(100 MHz,DMSO-d6)δ(ppm):165.45,160.56,151.07,149.31,148.31,147.37,145.37,145.09,130.62, 129.03,127.14,119.74,115.17,114.26,111.81,69.38,55.55,42.38,21.24,20.95,20.14.HR-MS (ESI)m/z:[M+H]⁺calcd for C₂₃H₂₅N₃O₄:408.1879,found:408.1902.

EXAMPLE 52 Synthesis of Compound CP-21-3

605.9mg (2.00mmol) of 4-hydroxy-3-methoxybenzoic acid and 239.1mg (2.00mmol) of thionyl chloride are sequentially added into a 100mL round-bottomed bottle, an appropriate amount of methanol is added, reaction is carried out at normal temperature for 2h, and TLC [ V (dichloromethane): V (methanol): 25: 1)]The detection reaction is substantially completeSpin-drying the solvent, and separating the residue by a silica gel column to obtain a white solid; placing the obtained product in a 100mL round-bottom flask, adding 204.1mg (1.20mmol) of chloro-ligustrazine and 279.6mg (2.02mmol) of K₂CO₃Then adding a proper amount of N, N-dimethyl imide, and stirring and reacting for 4 hours at 80 ℃. TLC [ V (dichloromethane): V (methanol) ═ 25:1]Detecting that the reaction is basically complete, extracting the reaction solution by using ethyl acetate, collecting an organic layer, drying by using a proper amount of saturated saline and anhydrous sodium sulfate, and evaporating to dryness under reduced pressure; and then the obtained product is mixed with tetrahydrofuran: methanol: 10mL of water (3: 1: 1) was dissolved, 996.3mg (10%) of sodium hydroxide was added, and the mixture was reacted at 60 ℃ for 2 hours by TLC [ V (dichloromethane): V (methanol): 25:1]Detecting the reaction is basically complete, spin-drying the solvent, adding hydrochloric acid to adjust the pH value to 7, extracting with ethyl acetate, collecting an organic layer, drying with a proper amount of saturated saline solution and anhydrous sodium sulfate, and evaporating to dryness under reduced pressure; the resulting product was placed in a 100mL round-bottomed flask, 189.1mg (1.00mmol) of vanillin amine hydrochloride, 287.1mg (1.50mmol) of EDCI, 161.5mg (1.20mmol) of HOBT, 191.4mg (1.48mmol) of DIEPA, and an appropriate amount of N, N-dimethylimide was added, and the reaction was stirred at room temperature for 4 hours. TLC [ V (dichloromethane): V (methanol) ═ 25:1]Detecting the reaction is almost complete, extracting the reaction solution by ethyl acetate, collecting an organic layer, drying by a proper amount of saturated saline and anhydrous sodium sulfate, and decompressing and evaporating to dryness. Silica gel column separation of the residue to give a white solid, melting point: 165.2-169.4 ℃, yield: 78.36 percent;

¹H NMR(400MHz,DMSO-d6)δ(ppm):8.82(s,1H,-OH),8.80(s,1H,-NH),7.50(s,2H), 7.18(d,J＝8.2Hz,1H),6.90(s,1H),6.72(s,2H),5.19(s,2H,-CH₂),4.37(d,J＝5.0Hz,2H, -CH₂),3.79(s,3H,-OCH₃),3.75(s,3H,-OCH₃),2.50(s,3H,2*-CH₃),2.46(s,6H,2*-CH₃)；¹³C NMR(100MHz,DMSO-d6)δ(ppm):165.47,151.11,150.10,149.54,148.60,148.28,147.38, 145.40,145.18,130.61,127.40,120.29,119.79,115.20,112.73,111.84,110.97,70.03,55.61,55.57, 42.45,21.26,20.95,20.12.HR-MS(ESI)m/z:[M+H]⁺calcd for C₂₃H₂₅N₃O₄:438.1984,found: 438.2013.

EXAMPLE 53 Synthesis of Compound CP-2-4

328.9mg (2.00mmol) of o-phenylene are weighed outHydroxycinnamic acid, 278mg (2.00mmol) of vanillin amine hydrochloride were placed in a reaction flask, 20mL of dichloromethane were added, followed by 286.5mg (1.50mmol) of EDCI, 162.9mg (1.20mmol) of Hobt, 193.5mg (1.50mmol) of DIEPA, stirred at room temperature for 4h, TLC monitored that the reaction was complete, and the reaction was stopped; transferring the reaction solution to a separating funnel, extracting for 3 times by ethyl acetate, collecting an organic layer, washing with saturated saline solution in sequence, dehydrating by anhydrous sodium sulfate, concentrating under reduced pressure, and separating a product on a silica gel column. 400.8mg (2.40mmol) of chloroligustrazine and 345.1mg (2.50mmol) of K are added into the obtained product₂CO₃Dissolving in DMF, and stirring at 80 deg.C for 4 hr. TCL monitors the reaction is complete, the reaction solution is extracted by ethyl acetate for 3 times, an organic layer is collected, a proper amount of saturated saline and anhydrous sodium sulfate are dried and decompressed to dryness, and a product is separated on a silica gel column to obtain a white solid with a melting point: 177.2-182.3 ℃, yield: 58.66 percent;

¹H-NMR(400MHz,DMSO-d6)δ(ppm):8.51(s,1H,-NH),7.80–7.65(m,1H),7.55(d,J＝6.3Hz,1H),7.44–7.29(m,1H),7.24(d,J＝8.4Hz,1H),7.03(t,J＝7.1Hz,2H),6.93(s,1H), 6.80(d,J＝8.4Hz,1H),6.73–6.62(m,1H),5.43–5.23(m,2H,-CH₂),5.22–5.06(m,2H,-CH₂), 4.31(s,2H,-CH₂),3.73(s,3H,-OCH₃),2.76–2.26(m,18H,6*-CH₃).¹³C-NMR(100MHz, DMSO-d6)δ(ppm):165.02,156.35,151.13,150.86,149.52,149.33,149.19,148.34,148.12, 146.68,145.55,145.15,133.25,132.66,130.78,127.07,123.69,122.29,121.17,119.49,114.06, 113.15,111.84,70.37,69.83,55.53,42.11,20.93,20.49,20.11.HR-MS(ESI)m/z:568.2912 [M+H]+,calcd for C₃₃H₃₇N₅O₄:567.2846.

EXAMPLE 54 Synthesis of Compound CP-3-4

328.9mg (2.00mmol) of m-hydroxycinnamic acid, 278mg (2.00mmol) of vanillin amine hydrochloride are weighed out and placed in a reaction flask, 20mL of dichloromethane are added, 286.5mg (1.50mmol) of EDCI, 162.9mg (1.20mmol) of Hobt, 193.5mg (1.50mmol) of DIEPA are added, stirring is carried out at normal temperature for 4h, TLC monitors that the reaction is complete, and the reaction is stopped; transferring the reaction solution to a separating funnel, extracting with ethyl acetate for 3 times, collecting organic layers, washing with saturated saline solution in sequence,the product is separated on a silica gel column after dehydration with anhydrous sodium sulfate and concentration under reduced pressure. 400.8mg (2.40mmol) of chloroligustrazine and 345.1mg (2.50mmol) of K are added into the obtained product₂CO₃Dissolving in DMF, and stirring at 80 deg.C for 4 hr. TCL monitors the reaction is complete, the reaction solution is extracted by ethyl acetate for 3 times, an organic layer is collected, a proper amount of saturated saline and anhydrous sodium sulfate are dried and decompressed to dryness, and a product is separated on a silica gel column to obtain a white solid with a melting point: 163.6-168.4 ℃, yield: 45.72 percent;

¹H-NMR(400MHz,DMSO-d6)δ(ppm):8.53(s,1H,-NH),7.44(d,J＝15.7Hz,1H),7.34(t, J＝7.6Hz,1H),7.26(s,1H),7.17(d,J＝7.3Hz,1H),7.05(d,J＝8.0Hz,2H),6.95(s,1H),6.82 (d,J＝8.0Hz,1H),6.70(d,J＝15.7Hz,1H),5.19(s,2H,-CH₂),5.10(s,2H,-CH₂),4.34(d,J＝ 3.8Hz,2H,-CH₂),3.74(s,3H,-OCH₃),2.50(s,6H,2*-CH₃),2.46(s,12H,4*-CH₃).¹³C-NMR (100MHz,DMSO-d6)δ(ppm):165.24,159.17,151.51,151.39,150.03,149.83,149.68,148.76, 148.62,147.20,146.04,145.74,139.14,136.89,133.08,130.50,123.07,120.74,119.99,116.42, 114.53,114.16,112.35,70.85,69.83,56.03,42.65,21.73,21.44,21.42,20.65,20.60.HR-MS(ESI) m/z:568.2925[M+H]+,calcd for C₃₃H₃₇N₅O₄:567.2846.

EXAMPLE 55 Synthesis of Compound CP-4-4

328.9mg (2.00mmol) of p-hydroxycinnamic acid, 278mg (2.00mmol) of vanillin amine hydrochloride are weighed out and placed in a reaction flask, 20mL of dichloromethane are added, 286.5mg (1.50mmol) of EDCI, 162.9mg (1.20mmol) of Hobt, 193.5mg (1.50mmol) of DIEPA are added, stirring is carried out at normal temperature for 4h, TLC monitors that the reaction is complete, and the reaction is stopped; transferring the reaction solution to a separating funnel, extracting for 3 times by ethyl acetate, collecting an organic layer, washing with saturated saline solution in sequence, dehydrating by anhydrous sodium sulfate, concentrating under reduced pressure, and separating a product on a silica gel column. 400.8mg (2.40mmol) of chloroligustrazine and 345.1mg (2.50mmol) of K are added into the obtained product₂CO₃Dissolving in DMF, and stirring at 80 deg.C for 4 hr. TCL for monitoring reaction completion, extracting reaction solution with ethyl acetate for 3 times, collecting organic layer, and appropriate amount of saturated saline solution and anhydrous sulfuric acidDrying sodium, decompressing and evaporating to dryness, separating a product on a silica gel column to obtain a light yellow solid, wherein the melting point is as follows: 153.6-159.8 ℃, yield: 54.90 percent;

¹H-NMR(400MHz,DMSO-d6)δ(ppm):8.46(s,1H,-NH),7.52(d,J＝8.0Hz,2H),7.43(d, J＝15.7Hz,1H),7.19–7.01(m,3H),6.95(s,1H),6.82(d,J＝8.0Hz,1H),6.56(d,J＝15.7Hz, 1H),5.20(s,2H,-CH₂),5.10(s,2H,-CH₂),4.34(d,J＝4.5Hz,2H,-CH₂),3.74(s,3H,-OCH₃), 2.50(s,6H,2*-CH₃),2.46(s,12H,4*-CH₃).¹³C-NMR(100MHz,DMSO-d6)δ(ppm):165.10, 159.39,151.06,150.90,149.55,149.32,149.21,148.31,148.15,146.70,145.57,145.16,138.46, 132.75,129.08,127.90,119.87,119.51,115.17,114.07,111.87,70.38,69.39,55.55,42.13,21.25, 20.96,20.93,20.15,20.12.HR-MS(ESI)m/z:568.2907[M+H]+,calcd for C₃₃H₃₇N₅O₄:567.2846.

EXAMPLE 56 Synthesis of Compound CP-5-4

Weighing 388.7mg (2.00mmol) of 3-methoxy-4-hydroxycinnamic acid and 278mg (2.00mmol) of vanillin amine hydrochloride, placing the materials in a reaction bottle, adding 20mL of dichloromethane, then adding 286.5mg (1.50mmol) of EDCI, 162.9mg (1.20mmol) of Hobt and 193.5mg (1.50mmol) of DIEPA, stirring for 4h at normal temperature, monitoring the reaction by TLC to be complete, and stopping the reaction; transferring the reaction solution to a separating funnel, extracting for 3 times by ethyl acetate, collecting an organic layer, washing with saturated saline solution in sequence, dehydrating by anhydrous sodium sulfate, concentrating under reduced pressure, and separating a product on a silica gel column. 400.8mg (2.40mmol) of chloroligustrazine and 345.1mg (2.50mmol) of K are added into the obtained product₂CO₃Dissolving in DMF, and stirring at 80 deg.C for 4 hr. TCL monitors the reaction is complete, the reaction solution is extracted by ethyl acetate for 3 times, an organic layer is collected, a proper amount of saturated saline and anhydrous sodium sulfate are dried and decompressed to dryness, and a product is separated on a silica gel column to obtain a light yellow solid with a melting point: 149.4-153.7 ℃, yield: 57.31 percent;

¹H-NMR(400MHz,DMSO-d6)δ(ppm):8.41(s,1H,-NH),7.40(d,J＝15.7Hz,1H),7.18(s, 1H),7.16–7.09(m,2H),7.05(d,J＝7.6Hz,1H),6.94(s,1H),6.81(d,J＝8.1Hz,1H),6.58(d,J ＝15.7Hz,1H),5.16(s,2H,-CH₂),5.10(s,2H,-CH₂),4.33(d,J＝4.5Hz,2H,-CH₂),3.78(s,3H, -OCH₃),3.74(s,3H,-OCH₃),2.50(s,6H,2*-CH₃),2.45(s,12H,4*-CH₃).¹³C-NMR(100MHz, DMSO-d6)δ(ppm):165.05,151.00,150.84,149.48,149.29,149.21,148.98,148.22,148.11, 146.68,145.56,145.24,138.72,132.75,128.40,121.10,120.20,119.48,114.11,113.74,111.89, 110.43,70.39,70.09,55.58,55.52,55.46,42.11,21.17,20.87,20.10.HR-MS(ESI)m/z:598.3033 [M+H]+,calcd for C₃₄H₃₉N₅O₅:597.2951.

EXAMPLE 57 Synthesis of Compound CP-6-4

Weighing 388.7mg (2.00mmol) of 3-hydroxy-4-methoxycinnamic acid, 278mg (2.00mmol) of vanillin amine hydrochloride and placing in a reaction flask, adding 20mL of dichloromethane, then adding 286.5mg (1.50mmol) of EDCI, 162.9mg (1.20mmol) of Hobt and 193.5mg (1.50mmol) of DIEPA, stirring for 4h at normal temperature, monitoring by TLC that the reaction is complete, and stopping the reaction; transferring the reaction solution to a separating funnel, extracting for 3 times by ethyl acetate, collecting an organic layer, washing with saturated saline solution in sequence, dehydrating by anhydrous sodium sulfate, concentrating under reduced pressure, and separating a product on a silica gel column. 400.8mg (2.40mmol) of chloroligustrazine and 345.1mg (2.50mmol) of K are added into the obtained product₂CO₃Dissolving in DMF, and stirring at 80 deg.C for 4 hr. TCL monitors the reaction is complete, the reaction solution is extracted by ethyl acetate for 3 times, an organic layer is collected, a proper amount of saturated saline and anhydrous sodium sulfate are dried and decompressed to dryness, and a product is separated on a silica gel column to obtain a white solid with a melting point: 161.3-166.7 ℃, yield: 52.65 percent;

¹H-NMR(400MHz,DMSO-d6)δ(ppm):8.43(s,1H,-NH),7.38(d,J＝16.9Hz,1H),7.14(d, J＝8.2Hz,1H),7.02(dd,J＝15.5,8.2Hz,1H),6.94(s,1H),6.80(d,J＝7.8Hz,1H),6.57(d,J＝ 15.5Hz,1H),5.16(s,2H,-CH₂),5.09(s,2H,-CH₂),4.32(s,2H,-CH₂),3.76(s,3H,-OCH₃),3.73 (s,3H,-OCH₃),2.50(s,6H,2*-CH₃),2.44(s,12H,4*-CH₃).¹³C-NMR(100MHz,DMSO-d6)δ (ppm):165.61,151.54,151.37,151.02,150.09,150.03,149.70,148.71,148.62,148.29,147.18, 146.05,145.78,139.25,133.29,128.17,122.43,120.49,119.96,114.57,113.02,112.64,112.36, 70.89,70.65,56.15,56.07,42.62,21.74,21.43,21.39,20.62.HR-MS(ESI)m/z:598.3031[M+H]+, calcd for C₃₄H₃₉N₅O₅:597.2951.

EXAMPLE 58 Synthesis of Compound CP-18-4

276.5mg (2.00mmol) of o-hydroxybenzoic acid and 278mg (2.00mmol) of vanillin amine hydrochloride are weighed into a reaction bottle, 20mL of dichloromethane is added, 286.5mg (1.50mmol) of EDCI, 162.9mg (1.20mmol) of Hobt and 193.5mg (1.50mmol) of DIEPA are added, stirring is carried out for 4h at normal temperature, TLC monitors that the reaction is complete, and the reaction is stopped; transferring the reaction solution to a separating funnel, extracting for 3 times by ethyl acetate, collecting an organic layer, washing with saturated saline solution in sequence, dehydrating by anhydrous sodium sulfate, concentrating under reduced pressure, and separating a product on a silica gel column. 400.8mg (2.40mmol) of chloroligustrazine and 345.1mg (2.50mmol) of K are added into the obtained product₂CO₃Dissolving in DMF, and stirring at 80 deg.C for 4 hr. TCL monitors the reaction is complete, the reaction solution is extracted by ethyl acetate for 3 times, an organic layer is collected, a proper amount of saturated saline and anhydrous sodium sulfate are dried and decompressed to dryness, and a product is separated on a silica gel column to obtain a white solid with a melting point: 107.6-112.9 ℃, yield: 46.14 percent;

¹H-NMR(400MHz,DMSO-d6)δ(ppm):9.03(s,1H,-NH),7.85(d,J＝7.6Hz,1H),7.50(t, J＝7.6Hz,1H),7.36(d,J＝8.0Hz,1H),7.09(t,J＝8.0Hz,1H),6.91(d,J＝8.0Hz,1H),6.86(s, 1H),6.71(t,J＝7.6Hz,1H),5.36(s,2H,-CH₂),5.07(s,2H,-CH₂),4.47(d,J＝4.7Hz,2H,-CH₂), 3.62(s,3H,-OCH₃),2.79-2.33(m,18H,6*-CH₃).¹³C-NMR(100MHz,DMSO-d6)δ(ppm): 164.74,155.99,150.88,150.56,149.51,149.11,148.23,148.12,146.53,145.53,144.80,132.53, 132.28,130.66,123.05,121.09,118.82,113.93,113.44,111.23,70.37,68.58,55.31,55.28,42.37, 21.18,21.14,20.90,20.13,19.92,19.88.HR-MS(ESI)m/z:542.2761[M+H]+,calcd for C₃₄H₃₉N₅O₅:541.2689.

EXAMPLE 59 Synthesis of Compound CP-19-4

276.5mg (2.00mmol) were weighed out) M-hydroxybenzoic acid, 278mg (2.00mmol) of vanillin amine hydrochloride were placed in a reaction flask, 20mL of dichloromethane were added, followed by 286.5mg (1.50mmol) of EDCI, 162.9mg (1.20mmol) of Hobt, 193.5mg (1.50mmol) of DIEPA, stirred at room temperature for 4h, TLC monitored that the reaction was complete, and the reaction was stopped; transferring the reaction solution to a separating funnel, extracting for 3 times by ethyl acetate, collecting an organic layer, washing with saturated saline solution in sequence, dehydrating by anhydrous sodium sulfate, concentrating under reduced pressure, and separating a product on a silica gel column. 400.8mg (2.40mmol) of chloroligustrazine and 345.1mg (2.50mmol) of K are added into the obtained product₂CO₃Dissolving in DMF, and stirring at 80 deg.C for 4 hr. TCL monitors the reaction is complete, the reaction solution is extracted by ethyl acetate for 3 times, an organic layer is collected, a proper amount of saturated saline and anhydrous sodium sulfate are dried and decompressed to dryness, and a product is separated on a silica gel column to obtain a white solid with a melting point: 169.2-173.6 ℃, yield: 54.97 percent;

¹H-NMR(400MHz,DMSO-d6)δ(ppm):8.93(s,1H,-NH),7.55(s,1H),7.49(d,J＝7.7Hz, 1H),7.39(t,J＝7.7Hz,1H),7.19(d,J＝8.0Hz,1H),7.04(d,J＝8.0Hz,1H),6.97(s,1H),6.83(d, J＝7.7Hz,1H),5.20(s,2H,-CH₂),5.09(s,2H,-CH₂),4.41(d,J＝4.8Hz,2H,-CH₂),3.73(s,3H, -OCH₃),2.50(s,6H,2*-CH₃),2.44(s,12H,4*-CH₃).¹³C-NMR(100MHz,DMSO-d6)δ(ppm): 165.78,158.27,151.01,150.88,149.53,149.31,149.16,148.29,148.13,146.65,145.56,145.21, 135.93,132.94,129.49,119.93,119.36,117.66,114.05,113.44,111.79,70.38,69.45,55.55,42.44, 21.23,20.94,20.13.HR-MS(ESI)m/z:542.2761[M+H]+,calcd for C₃₄H₃₉N₅O₅:541.2689.

EXAMPLE 60 Synthesis of Compound CP-20-4

276.5mg (2.00mmol) of p-hydroxybenzoic acid, 278mg (2.00mmol) of vanillin amine hydrochloride are weighed into a reaction flask, 20mL of dichloromethane is added, 286.5mg (1.50mmol) of EDCI, 162.9mg (1.20mmol) of Hobt and 193.5mg (1.50mmol) of DIEPA are added, stirring is carried out for 4h at normal temperature, TLC monitors that the reaction is complete, and the reaction is stopped; transferring the reaction solution to a separating funnel, extracting with ethyl acetate for 3 times, collecting organic layers, washing with saturated saline solution sequentially, and removing anhydrous sodium sulfateDehydrating, concentrating under reduced pressure, and separating the product on silica gel column. 400.8mg (2.40mmol) of chloroligustrazine and 345.1mg (2.50mmol) of K are added into the obtained product₂CO₃Dissolving in DMF, and stirring at 80 deg.C for 4 hr. TCL monitors the reaction is complete, the reaction solution is extracted by ethyl acetate for 3 times, an organic layer is collected, a proper amount of saturated saline and anhydrous sodium sulfate are dried and decompressed to dryness, and a product is separated on a silica gel column to obtain a white solid with a melting point: 121.5-126.4 ℃, yield: 50.83 percent;

¹H-NMR(400MHz,DMSO-d6)δ(ppm):8.82(s,1H,-NH),7.87(d,J＝8.0Hz,2H),7.11(d,J ＝8.0Hz,2H),7.04(d,J＝8.0Hz,1H),6.97(s,1H),6.82(d,J＝7.7Hz,1H),5.23(s,2H,-CH₂), 5.09(s,2H,-CH₂),4.40(d,J＝4.7Hz,2H,-CH₂),3.73(s,3H,-OCH₃),2.50(s,6H,2*-CH₃),2.46 (s,12H,4*-CH₃).¹³C-NMR(100MHz,DMSO-d6)δ(ppm):165.52,160.59,151.06,150.87, 149.53,149.29,149.15,148.29,148.12,146.59,145.56,145.08,133.19,129.03,127.06,119.28, 114.27,114.04,111.73,70.38,69.38,55.49,42.32,21.23,20.93,20.11.HR-MS(ESI)m/z: 542.2735[M+H]+,calcd for C₃₄H₃₉N₅O₅:541.2689.

EXAMPLE 61 Synthesis of Compound CP-21-4

336.2mg (2.00mmol) of 3-methoxy-4-hydroxybenzoic acid and 278mg (2.00mmol) of vanillin amine hydrochloride are weighed into a reaction flask, 20mL of dichloromethane is added, 286.5mg (1.50mmol) of EDCI, 162.9mg (1.20mmol) of Hobt and 193.5mg (1.50mmol) of DIEPA are added, the mixture is stirred for 4h at normal temperature, TLC monitors that the reaction is complete, and the reaction is stopped; transferring the reaction solution to a separating funnel, extracting for 3 times by ethyl acetate, collecting an organic layer, washing with saturated saline solution in sequence, dehydrating by anhydrous sodium sulfate, concentrating under reduced pressure, and separating a product on a silica gel column. 400.8mg (2.40mmol) of chloroligustrazine and 345.1mg (2.50mmol) of K are added into the obtained product₂CO₃Dissolving in DMF, and stirring at 80 deg.C for 4 hr. TCL monitors the reaction is complete, the reaction solution is extracted by ethyl acetate for 3 times, an organic layer is collected, a proper amount of saturated saline and anhydrous sodium sulfate are dried and decompressed to dryness, and a product is separated on a silica gel column to obtain a white solid with a melting point: 99.8-104.1 deg.CThe yield is as follows: 42.35 percent;

¹H-NMR(400MHz,DMSO-d6)δ(ppm):8.83(s,1H,-NH),7.51(s,2H),7.19(d,J＝7.5Hz, 1H),7.04(d,J＝7.5Hz,1H),6.97(s,1H),6.83(d,J＝7.5Hz,1H),5.19(s,2H,-CH₂),5.09(s,2H, -CH₂),4.42(s,2H,-CH₂),3.79(s,3H,-OCH₃),3.73(s,3H,-OCH₃),2.50(s,6H,2*-CH₃),2.45(s, 12H,4*-CH₃).¹³C-NMR(100MHz,DMSO-d6)δ(ppm):165.53,151.07,150.87,150.13,149.52, 149.15,148.61,148.25,148.11,146.61,145.56,145.16,133.17,127.32,120.29,119.32,114.05, 112.75,111.77,110.99,70.39,70.03,55.63,55.58,42.39,21.22,20.93,20.08.HR-MS(ESI)m/z: 572.2879[M+H]+,calcd for C₃₄H₃₉N₅O₅:571.2795.

EXAMPLE 62 Synthesis of Compound CP-22-4

308.3mg (2.00mmol) of 3, 4-dihydroxybenzoic acid and 278mg (2.00mmol) of vanillin amine hydrochloride are weighed and placed in a reaction bottle, 20mL of dichloromethane is added, 286.5mg (1.50mmol) of EDCI, 162.9mg (1.20mmol) of Hobt and 193.5mg (1.50mmol) of DIEPA are added, the mixture is stirred for 4 hours at normal temperature, TLC monitors the reaction to be complete, and the reaction is stopped; transferring the reaction solution to a separating funnel, extracting for 3 times by ethyl acetate, collecting an organic layer, washing with saturated saline solution in sequence, dehydrating by anhydrous sodium sulfate, concentrating under reduced pressure, and separating a product on a silica gel column. 400.8mg (2.40mmol) of chloroligustrazine and 345.1mg (2.50mmol) of K are added into the obtained product₂CO₃Dissolving in DMF, and stirring at 80 deg.C for 4 hr. TCL monitors the reaction is complete, the reaction solution is extracted by ethyl acetate for 3 times, an organic layer is collected, a proper amount of saturated saline and anhydrous sodium sulfate are dried and decompressed to dryness, and a product is separated on a silica gel column to obtain a white solid with a melting point: 152.8-157.9 ℃, yield: 38.27 percent;

¹H-NMR(400MHz,DMSO-d6)δ(ppm):8.83(s,1H,-NH),7.70(s,1H),7.55(d,J＝8.1Hz, 1H),7.22(d,J＝8.1Hz,1H),7.04(d,J＝8.1Hz,1H),6.98(s,1H),6.84(d,J＝8.1Hz,1H),5.20(s, 2H,-CH₂),5.17(s,2H,-CH₂),5.10(s,2H,-CH₂),4.42(d,J＝4.2Hz,2H,-CH₂),3.74(s,3H, -OCH₃),2.50(s,6H,2*-CH₃),2.45(s,21H,7*-CH₃).¹³C-NMR(100MHz,DMSO-d6)δ(ppm): 165.45,151.01,150.97,150.87,150.62,149.53,149.48,149.45,149.16,148.18,148.12,147.53, 146.62,145.57,145.24,145.11,133.13,127.38,121.14,119.34,114.05,113.40,113.23,111.78, 70.39,70.10,55.55,55.51,42.40,21.23,21.19,20.88,20.05,20.01.HR-MS(ESI)m/z:692.3560 [M+H]+,calcd for C₃₄H₃₉N₅O₅:691.3482.