Salvianolic acid C derivatives, preparation methods and medical uses thereof

Abstract

The present invention discloses a salvianolic acid C derivative, its preparation method, and medical use. The salvianolic acid C derivative has a structure represented by the general formula (I): wherein X is O, S, NH, NOR, NR, or C, and R is a C1-C6 alkyl group; Y is O, S, NH, NOR, NR, or C, and R is a C1-C6 alkyl group; R1-R6 are each independently hydrogen, hydroxyl, methoxy, halogen, nitro, amino, benzyloxy, ethoxy, acid, carboxylate, or C1-C10 alkyl; and two adjacent substituents of R2 and R3, or R4 and R5, can be ‑OCH2O‑, C3 alkyl, to form a five-membered ring, or ‑CH2=CH2CH2=CH2‑, C4 alkyl, to form a six-membered ring. Pharmacological tests have shown that the salvianolic acid C derivative of the present invention has excellent cardiovascular pharmacological effects and can be used to further prepare cardiovascular prevention and treatment drugs.

Description

Technical Field

[0001] The present invention belongs to the technical field of pharmaceutical chemistry related to salvianolic acid C, and particularly relates to a salvianolic acid C derivative, a preparation method thereof, and an application thereof in preparing a drug for treating cardiovascular and cerebrovascular diseases. Background Art

[0002] Cardiovascular and cerebrovascular diseases (CVDs), encompassing both cardiovascular and cerebrovascular diseases, are common and pose a serious threat to human health. These diseases are characterized by high morbidity, mortality, disability, recurrence, and complications. In my country, CVD mortality rates exceed those of cancer and other diseases, making it the leading cause of death in the country. Therefore, finding effective treatments for CVD has become a primary clinical challenge.

[0003] In recent years, traditional Chinese medicine has gradually played an increasingly important role in the treatment of cardiovascular and cerebrovascular diseases and has also made breakthrough progress. The traditional Chinese medicine Danshen has the effects of removing blood stasis and relieving pain, promoting blood circulation and menstruation, clearing the heart and eliminating restlessness, cooling blood and eliminating carbuncle. It is widely used in the treatment of cardiovascular and cerebrovascular diseases such as angina pectoris, myocardial infarction, and stroke. The therapeutic effect of Danshen is related to its water-soluble phenolic acids, mainly including active ingredients such as danshensu and salvianolic acid. They have biological activities such as antioxidant, anti-inflammatory, anticoagulant, anti-apoptotic, improving microcirculation, and arterial vasodilation, and can have a good preventive and therapeutic effect on cardiovascular and cerebrovascular diseases (see Phytother. Res., 2007, 21(8):751-756.; Food Chem. Toxicol., 2008, 46(1):73-81.).

[0004] Salvianolic acid C (SAC) is a hydrophilic polyphenolic benzofuran derivative isolated from Salvia miltiorrhiza. It has multiple pharmacological activities and has excellent preventive and therapeutic effects on cardiovascular and cerebrovascular diseases. Related studies have shown that SAC has significant pharmacological effects such as antioxidant, oxidative stress inhibition, inflammation reduction, cell apoptosis reduction, anti-myocardial ischemia, anti-thrombosis, and reduction of myocardial ischemia and cerebral ischemia damage (see Drug Des. Devel. Ther., 2015, 9: 1063-1102.; Int. Immunopharmacol., 2018, 63: 299-310.). However, due to the presence of multiple hydrophilic groups such as carboxyl and phenolic hydroxyl groups in SAC, it has strong water solubility and poor lipid solubility. In addition, its phenolic hydroxyl groups are easily oxidized and unstable, resulting in a low bioavailability of only 5.60% and a half-life of only 48 minutes (see Fitoterapia, 2011, 82(6): 883-888.). At the same time, due to the presence of ester bonds in its molecular structure, it is unstable in aqueous solution, human plasma and blood, and is rapidly hydrolyzed by esterases in the body, resulting in premature nonspecific hydrolysis before it reaches the treatment tissue (see J. Med. Chem., 2011, 54(19): 6676-6690.). These factors have greatly limited the clinical development of salvianolic acid C as a drug for the prevention and treatment of cardiovascular and cerebrovascular diseases.

[0005]

[0006] At present, there have been reports that salvianolic acid C is used as a xanthine oxidase (XO) inhibitor to lower uric acid (see Eur J Med Chem. 2016, 124: 637-648.; Eur J Med Chem. 2018, 151: 849-860.), but there have been no reports on the effects of salvianolic acid C derivatives on cardiovascular and cerebrovascular diseases. Summary of the Invention

[0007] The present invention relates to salvianolic acid C derivatives or pharmaceutically acceptable salts thereof, and also to pharmaceutical compositions containing the salvianolic acid C derivatives and pharmaceutically acceptable salts thereof. Furthermore, the present invention also relates to methods for preparing the salvianolic acid C derivatives and pharmaceutically acceptable salts thereof. Furthermore, the present invention also relates to the use of the salvianolic acid C derivatives in medicine, including the preparation of drugs for preventing or treating cardiovascular and cerebrovascular diseases. Pharmacological tests have demonstrated that the salvianolic acid C derivatives of the present invention exhibit excellent cardiovascular pharmacological effects, increased lipid solubility, and enhanced therapeutic efficacy, and can be used to further prepare drugs for the prevention and treatment of cardiovascular and cerebrovascular diseases.

[0008] The salvianolic acid C derivative provided by the present invention has a structure represented by the general formula (I):

[0009]

[0010] in,

[0011] X is O, S, NH, NOR, NR, or C, and R is a C1-C6 alkyl group;

[0012] Y is O, S, NH, NOR, NR, or C, and R is a C1-C6 alkyl group;

[0013] R1 to R6 are each independently hydrogen, hydroxyl, methoxy, halogen, nitro, amino, benzyloxy, ethoxy, ether, carboxylate, or C1 to C10 alkyl;

[0014] Two adjacent substituents of R2 and R3, R4 and R5 can be -OCH2O-, C3 alkyl to form a five-membered ring, or -CH2=CH2CH2=CH2-, C4 alkyl to form a six-membered ring.

[0015] Furthermore, in the structure represented by the general formula (I),

[0016] X is O, S, NH, NR, C, and R is a C1-C6 alkyl group;

[0017] Y is O, S, NH, NR, or C, and R is a C1-C6 alkyl group;

[0018] R1 to R6 are each independently hydrogen, hydroxyl, methoxy, halogen, amino, benzyloxy, ethoxy, carboxylate, or C1 to C10 alkyl;

[0019] Two adjacent substituents of R2 and R3, R4 and R5 can be -OCH2O-, C3 alkyl to form a five-membered ring, or -CH2=CH2CH2=CH2-, C4 alkyl to form a six-membered ring.

[0020] Furthermore, in the structure represented by the general formula (I),

[0021] X is O, S, or NH;

[0022] Y is O, S, or NH;

[0023] R1 to R6 are each independently hydrogen, hydroxyl, methoxy, a halogen atom, amino, benzyloxy, ethoxy, or carboxylate.

[0024] Furthermore, the salvianolic acid C derivative is selected from any one of the following compounds:

[0025]

[0026]

[0027]

[0028]

[0029] The present invention also provides a method for preparing the above-mentioned salvianolic acid C derivative, and the preparation route is as follows:

[0030]

[0031] The specific preparation method comprises:

[0032] The compound represented by formula II is dissolved in dioxane and reacted with iodine chloride at 0°C to obtain the iodinated raw material compound represented by formula III; the iodinated raw material compound represented by formula III and the benzyne raw material compound represented by formula IV undergo a Sonogashira coupling reaction with a catalyst and further undergo cyclization under the catalysis of cuprous iodide to obtain the intermediate compound represented by formula V; the intermediate compound represented by formula V undergoes a condensation reaction with malonic acid to obtain the intermediate compound represented by formula VI; the intermediate compound represented by formula VI containing a carboxyl group is dissolved in a solvent of DMF or DCM, a condensing agent and an acid binding agent are added, and the reaction is carried out for 30 minutes. Then, the intermediate compound represented by formula VII substituted with different substituents is added, and the mixture is stirred and condensed at room temperature to obtain the target compound, a salvianolic acid C derivative.

[0033] The compound structural formula is as follows:

[0034]

[0035] in,

[0036] X is O, S, NH, NOR, NR, or C, and R is a C1-C6 alkyl group;

[0037] Y is O, S, NH, NOR, NR, or C, and R is a C1-C6 alkyl group;

[0038] R1 to R6 are each independently hydrogen, hydroxyl, methoxy, halogen, nitro, amino, benzyloxy, ethoxy, ether, carboxylate, or C1 to C10 alkyl;

[0039] Two adjacent substituents of R2 and R3, R4 and R5 can be -OCH2O-, C3 alkyl to form a five-membered ring, or -CH2=CH2CH2=CH2-, C4 alkyl to form a six-membered ring.

[0040] Furthermore, the catalyst is selected from one or more of RuCl2(PPh3)3, RhCl(PPh3)3, PdCl2(PPh3)2, and NiCl2(PPh3)2; the condensing agent is selected from one or more of DCC, DCI, EDCI, HATU, HBTU, TBTU, PyBOP, EDC, and BOP; the acid binding agent is selected from one or more of pyridine, triethylamine, diisopropylethylamine, DBU, sodium carbonate, potassium carbonate, cesium carbonate, sodium bis(trimethylsilyl)amide, sodium tert-butoxide, and potassium tert-butoxide; and the catalyst is preferably added in an amount of 0.06-0.08 equivalents, the condensing agent is preferably added in an amount of 1.2 equivalents, and the acid binding agent is preferably added in an amount of 3-4 equivalents.

[0041] Furthermore, the catalyst is RuCl2(PPh3)3, RhCl(PPh3)3 or PdCl2(PPh3)2; the condensing agent is DCC, EDCI, HBTU, TBTU or PyBOP; and the acid binding agent is pyridine, triethylamine, diisopropylethylamine, sodium carbonate, potassium carbonate or cesium carbonate.

[0042] Furthermore, the catalyst is PdCl2(PPh3)2; the condensation agent is EDCI, HBTU or PyBOP; and the acid binding agent is triethylamine or diisopropylethylamine.

[0043] Furthermore, the above preparation method further comprises: further subjecting the prepared target compound SAC derivative to phenolic hydroxyl methylation and / or hydrogenation debenzylation modification, thereby still obtaining the target compound SAC derivative shown in Formula I.

[0044] Specifically, the prepared SAC derivative in which R2 / R3 / R4 / R5 are phenolic hydroxyl groups is dissolved in acetonitrile, potassium carbonate and iodomethane are added, and then the temperature is raised to 85°C and refluxed for 24 hours to obtain a SAC derivative with improved lipid solubility after methylation of the phenolic hydroxyl groups. Under a hydrogen atmosphere, the SAC derivative in which R1 is a benzyloxy group is dissolved in a methanol solution, 10% Pd / C is added, and the mixture is stirred at room temperature for hydrogenation and debenzylation to obtain a SAC derivative in which R1 is a phenolic hydroxyl group.

[0045] The present invention also provides a pharmaceutical composition comprising a pharmaceutically effective dose of the above-mentioned salvianolic acid C derivative or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0046] The present invention also provides the use of the above-mentioned salvianolic acid C derivatives and pharmaceutically acceptable salts thereof, as well as corresponding pharmaceutical compositions in the preparation of drugs for treating cardiovascular and cerebrovascular diseases.

[0047] Furthermore, the cardiovascular and cerebrovascular diseases include hypertension, coronary heart disease, myocardial infarction, atherosclerosis, angina pectoris, thrombosis, myocarditis, cerebral stroke, arrhythmia, heart failure, cerebral hemorrhage, cerebral embolism, rheumatic heart disease, infectious heart disease, anemic heart disease and the like.

[0048] By analyzing the structure-activity relationship of salvianolic acid C, this invention uses its key skeleton, the 2-arylbenzo[b]furan ring, as the parent core. The ester bond at the C-9 position is replaced with a more hydrolytically stable amide bond to enhance its in vivo stability. The phenolic hydroxyl and carboxyl groups are further modified to increase the lipid solubility of the salvianolic acid C derivatives. The resulting series of novel salvianolic acid C derivatives exhibit strong lipid solubility, excellent stability, and easy blood-brain barrier (BBB) ​​penetration.

[0049] Experimental results on cardiomyocytes and neurons showed that salvianolic acid C derivatives have a protective effect against oxidative damage (t-BHP stimulation-induced model and oxygen-glucose deprivation model). In vivo experiments also showed that salvianolic acid C derivatives have a significant neuroprotective effect against cerebral ischemia-reperfusion injury in the SD rat MCAO model. This invention has certain guiding significance for the research on the preparation of drugs for the prevention or treatment of cardiovascular and cerebrovascular diseases. BRIEF DESCRIPTION OF THE DRAWINGS

[0050] Figure 1 The protective effect of salvianolic acid C derivatives on t-BHP-induced H9C2 cell injury (n = 3). Compared with the normal control group, ###P < 0.01; compared with the t-BHP-injured group, **P < 0.05, ***P < 0.01.

[0051] Figure 2 Salvianolic acid C derivatives protect against OGD (oxygen-glucose deprivation)-induced glial cell injury in rats. Compared with the normal control group, ###P<0.01; compared with the OGD-injured group, **P<0.05, ***P<0.01.

[0052] Figure 3 The neuroprotective effect of salvianolic acid C derivatives on cerebral ischemia-reperfusion injury in the MCAO model of SD rats was observed. Compared with the sham-operated group, ###P<0.01; compared with the MCAO model injury group, ***P<0.01. DETAILED DESCRIPTION

[0053] The following will clearly and completely describe the technical solutions in the embodiments of the present invention in conjunction with the accompanying drawings. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making creative efforts are within the scope of protection of the present invention.

[0054] As used herein, the term "pharmaceutically acceptable" refers to compounds, such as salts, that do not have unacceptable toxicity. Pharmaceutically acceptable salts include inorganic anions such as chloride, sulfate, sulfite, nitrate, nitrite, phosphate, hydrogen phosphate, and the like. Organic anions include acetate, propionate, cinnamate, tosylate, citrate, lactate, gluconate, and the like.

[0055] The salvianolic acid C derivatives described herein can be administered to patients in the form of a pharmaceutically acceptable salt or pharmaceutical composition. The complex must be mixed with an appropriate carrier or excipient to form a pharmaceutical composition to ensure an effective therapeutic dose. "Effective therapeutic dose" refers to the dose of the salvianolic acid C derivative required to achieve a therapeutic effect.

[0056] The salvianolic acid C derivatives and compositions containing them can be prepared into a variety of dosage forms, including solid dosage forms, semisolid dosage forms, liquid preparations, and aerosols (Remington's Pharmaceutical Sciences, Mack Publishing Company (1995), Philadelphia, PA, 19th ed. Specific dosage forms within these categories include tablets, pills, lozenges, granules, gels, ointments, solutions, suppositories, injections, inhalants, and sprays. These dosage forms can be used for local or systemic administration, as well as for immediate-release or sustained-release administration.

[0057] When salvianolic acid C derivatives and compositions containing these compounds are administered by injection, they can be formulated into solutions, suspensions, and emulsions using water-soluble or lipid-soluble solvents. Lipid-soluble solvents specifically include vegetable oils and similar oils, synthetic fatty acid glycerides, higher fatty acid esters, and proylene glycol esters. These compounds are more soluble in ethanol solutions and trace amounts of DMSO solutions.

[0058] When salvianolic acid C derivatives and compositions containing these compounds are administered orally, they can be prepared into complexes with pharmaceutically acceptable excipients using conventional techniques. These excipients can be used to prepare these compounds into a variety of dosage forms that can be administered to patients, such as tablets, pills, suspensions, gels, and the like. There are various methods for preparing oral dosage forms, such as first mixing the compound with a solid excipient, thoroughly grinding the mixture, adding appropriate excipients, and processing it into granules. Excipients that can be used to prepare oral dosage forms include: sugars such as lactose, sucrose, mannitol, or sorbitol; cellulosics such as corn starch, wheat starch, potato starch, gelatin, tamarind gum, methylcellulose, hydroxymethylcellulose, sodium carboxymethylcellulose, polyvinylpyrrolidone, and the like.

[0059] The salvianolic acid C derivatives and compositions containing them described herein can also be formulated into sprays. This dosage form is achieved using a pressurizer and a nebulizer or a dry powder inhaler. Suitable propellants for the sprayer include dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide, and dimethyl ether. The aerosol dosage can be adjusted using a valve in the sprayer.

[0060] The various dosage forms described herein are all related to the effective therapeutic dose of salvianolic acid C derivatives and compositions containing these compounds. The effective therapeutic dose of these compounds depends on the patient being treated. When determining the appropriate dose, the patient's weight, condition, route of administration, and the subjective judgment of the prescribing physician should all be considered. The therapeutically effective dose of salvianolic acid C derivatives and compositions containing these compounds should be determined by a competent and experienced prescribing physician.

[0061] Although the effective therapeutic dose of the salvianolic acid C derivatives and compositions containing these compounds may vary depending on the patient's condition, the appropriate dosage range is usually 10 mg to 10 g.

[0062] Example 1: Preparation of Compound 1

[0063] The specific synthesis method includes the following reaction steps:

[0064] [1] Synthesis of iodinated raw material 1a

[0065] Compound 4-methoxy-3-hydroxybenzaldehyde (10 mmol) was dissolved in pyridine solution (8 mL), cooled in an ice bath, and stirred to 0°C. Under light protection, iodine chloride (12 mmol) was weighed and dissolved in dioxane (16 mL). Dissolved thoroughly and then added dropwise to the pyridine reaction solution. After complete addition, the ice bath was removed, the temperature was raised to room temperature, and the reaction was monitored by TLC. The reaction was complete after 6 days. 50 mL of ice water was added to the solution, followed by quenching with concentrated hydrochloric acid. The pH was adjusted to 1. Saturated sodium thiosulfate solution was added and stirred thoroughly to remove iodine. Extraction was then performed with 100 mL of EA in three separate steps. The organic phases were combined, dried over anhydrous sodium sulfate, and the solvent removed under reduced pressure to yield a brownish-yellow crude oil. The crude product was purified by 300-400 mesh silica gel column chromatography (mobile phase ratio PE:EA = 10:1) to obtain 1a as a pale yellow solid (yield: 90%).

[0066] Iodinated raw material 1a 1 The H NMR data are as follows:

[0067] 1H NMR (500MHz, DMSO-d6) δ3.93 (s, 3H), 7.15 (d, J = 8.4Hz, 1H), 7.39 (d, J = 8.4Hz, 1H), 9.92 (s, 1H), 10.00 (s, 1H).

[0068]

[0069] [2] Synthesis of intermediate 1b

[0070] Weigh the iodide raw material 1a (10 mmol), add anhydrous DMF (30 mL) to fully dissolve, add 6% PdCl2 (PPh3) 2 (0.6 mmol) and 6% CuI (0.6 mmol) in sequence and mix well, add triethylamine (30 mmol). Then weigh 4-methoxyphenylacetylene (12 mmol), fully replace the argon, and then heat to 110 ° C to react. TLC monitors the reaction and the reaction is complete after 4 hours. The reaction is cooled to room temperature, 20 mL of water and 20 mL of EA are added, the mixed solution is filtered through a sand core funnel, the filter residue is removed, and the filter residue is washed with EA. 1 M dilute hydrochloric acid is used to adjust the pH to 7, 10 mL of water is added, and 20 mL of EA is used for extraction three times. The organic phases are combined, dried over anhydrous sodium sulfate, and the solvent is removed under reduced pressure to obtain a brown oily crude product. The crude product was purified by 300-400 mesh silica gel column chromatography (mobile phase ratio PE:EA=10:1) to obtain a light yellow solid 1b (yield: 70%).

[0071] Intermediate 1b 1 H NMR and 13 The C NMR data are as follows:

[0072] 1 H NMR (500MHz, CDCl3) δ3.85 (s, 3H), 4.10 (s, 3H), 6.84 (d, J = 8.3Hz, 1H), 6.94-7. 00(m,2H),7.62(d,J=8.3Hz,1H),7.64(s,1H),7.84-7.87(m,2H),10.02(s,1H).

[0073] 13 C NMR (125MHz, CDCl3) δ55.5,56.5,100.5,105.9,114.5,122.6,122.9,127.1,130.5,132.0,143.9,149.8,159.4,160.7,190.9.3)

[0074]

[0075] [3] Synthesis of intermediate 1c

[0076] Compound 1b (0.925 mmol) was weighed and dissolved thoroughly in pyridine (25 mL). Malonic acid (2.78 mmol) and piperidine (0.925 mmol) were added, and the mixture was heated to 110°C. The reaction was monitored by TLC and completed after 4 hours. The reaction mixture was cooled to room temperature, and 20 mL of ice-water was added. Concentrated hydrochloric acid was added with stirring to pH = 1, resulting in the precipitation of a large amount of yellow solid. The solid was filtered, washed with water 2-3 times, and then dried at 50°C to obtain 1c (yield: 87%) as a yellow solid.

[0077] Intermediate 1c 1 H NMR and 13 The C NMR data are as follows:

[0078] 1 H NMR(500MHz,DMSO-d6)δ3.83(s,3H),4.02(s,3H),6.59(d,J=16.1Hz,1H),6.97(d,J=8.5Hz,1H),7.05-7 .11(m,2H),7.57(d,J=8.6Hz,1H),7.75(s,1H),7.84(d,J=16.1Hz,1H),7.91-7.98(m,2H),12.25(s,1H).

[0079] 13 C NMR (125MHz, DMSO-d6) δ55.8,56.5,100.1,107.6,115.0,117.8,120.0,122.5,125.9,127.1,130.5,142.1,143.3,146.7,157.2,160.6,168.5.

[0080]

[0081] [4] Synthesis of compound 1

[0082] Intermediate 1c (0.84 mmol) and compound A (0.98 mmol) were weighed and dissolved in a mixture of DMF (5 mL) and DCM (10 mL). PyBOP (0.98 mmol) was weighed and added to the system to fully dissolve. Et3N (2.46 mmol) was added and stirred at room temperature. The reaction was monitored by TLC and completed after 12 hours. The pH was adjusted to 7 with 1M dilute hydrochloric acid. The product was extracted with 20 mL of DCM in three steps. The organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain a brownish-yellow crude oil. The crude product was purified by 300-400 mesh silica gel column chromatography (mobile phase ratio: DCM:MeOH = 80:1) to obtain compound 1 as a light yellow solid (yield: 67%).

[0083]

[0084] Compound 1 1 H NMR and 13 The C NMR data are as follows:

[0085] 1 H NMR (500MHz, CDCl3) δ2.98 (dd, J=6.1, 14.1Hz, 1H), 3.15 (dd, J=4.8, 13.9Hz, 1H), 3.67(s,3H),3.81(s,3H),3.88(s,3H),4.94(dd,J=5.9,12.5Hz,1H),6.20(d,J=1 5.6Hz,1H),6.45-6.51(m,2H),6.54(d,J=7.3Hz,1H),6.72(s,1H),6.78-6.83(m, 2H),6.88(d,J=8.8Hz,2H),6.94(d,J=8.3Hz,1H),7.59-7.68(m,3H),8.31(s,1H).

[0086] 13 C NMR (125MHz, CDCl3) δ37.1,52.6,53.9,55.3,56.0,98.5,106.3,114.1,115.3,116.2,116.9,119.5,121.0,122.5,1 23.9,126.7,127.7,130.7,140.1,143.3,143.8,144.3,146.3,157.1,160.2,167.2,172.4.HRMS(ESI,positive)m / z calcd for C29H28NO8[M+H]+:518.1809,found:518.1816.

[0087]

[0088] Example 2: Preparation of Compound 2

[0089] The specific synthesis method includes the following reaction steps:

[0090] [1] The synthesis of iodinated raw material 1a, intermediate 1b and intermediate 1c is shown in Example 1.

[0091] [2] Synthesis of compound 2

[0092] The experimental procedure was similar to that of Example 1, except that the following compounds were added: Intermediate 1c (0.82 mmol), Compound B (0.98 mmol), PyBOP (0.98 mmol), and Et3N (2.46 mmol). The crude product was purified by 300-400 mesh silica gel column chromatography (mobile phase ratio: DCM:MeOH = 80:1) to afford Compound 1 as a pale yellow solid (yield: 69%).

[0093]

[0094] Compound 2 1 H NMR and 13 The C NMR data are as follows:

[0095] 1 H NMR(500MHz,DMSO-d6)δ2.90(dd,J=8.6,13.9Hz,1H),2.99(m,1H),3.64(s,3H),3.84(s, 3H),4.02(s,3H),4.62(dd,J=8.0,14.0Hz,1H),6.69(d,J=8.4Hz,2H),6.82(d,J=15.9Hz ,1H),6.98(d,J=8.4Hz,1H),7.05(d,J=8.4Hz,2H),7.11(d,J=8.8Hz,2H),7.42(d,J=8.4 Hz,1H),7.63(t,J=7.9Hz,2H),7.90(d,J=8.8Hz,2H),8.40(d,J=7.8Hz,1H),9.27(s,1H).

[0096] 13 C NMR (125MHz, DMSO-d6) δ36.9,52.3,54.5,55.8,56.5,100.1,107.6,115.1,115.6,120.4,120.6,122.5,125.7, 127.0,127.5,129.7,130.5,137.9,143.5,146.3,156.6,157.0,160.6,165.9,172.8.HRMS(ESI,positive)m / z calcd for C29H28NO7[M+H] + :502.1860,found:502.1893.

[0097]

[0098] Example 3: Preparation of Compound 3

[0099] The specific synthesis method includes the following reaction steps:

[0100] [1] The synthesis of iodinated raw material 1a, intermediate 1b and intermediate 1c is shown in Example 1.

[0101] [2] Synthesis of compound 3

[0102] The experimental procedure was similar to that of Example 1, except that the following compounds were added: Intermediate 1c (0.75 mmol), Compound C (0.90 mmol), PyBOP (0.90 mmol), and Et3N (2.25 mmol). The crude product was purified by 300-400 mesh silica gel column chromatography (mobile phase ratio: DCM:MeOH = 80:1) to afford Compound 1 as a pale yellow solid (yield: 70%).

[0103]

[0104] Compound 3 1 H NMR and 13 The C NMR data are as follows:

[0105] 1 H NMR(500MHz,DMSO-d6)δ3.01(dd,J=8.9,13.8Hz,1H),3.12(dd,J=5.7,13.8Hz,1H),3.64(s, 3H),3.83(s,3H),4.00(s,3H),4.70(dt,J=7.2,14.2Hz,1H),6.80(d,J=15.9Hz,1H),6.97(d ,J=8.4Hz,1H),7.05-7.15(m,2H),7.19-7.24(m,1H),7.26(t,J=4.1Hz,2H),7.28-7.33(m,2 H),7.41(d,J=8.5Hz,1H),7.62(d,J=17.1Hz,2H),7.84-7.92(m,2H),8.46(d,J=7.8Hz,1H).

[0106] 13 C NMR (125MHz, DMSO-d6) δ37.5,52.4,54.2,55.8,56.5,100.0,107.6,115.1,120.3,120.6,122.5,125.6,127.0, 127.1,128.8,129.5,129.8,137.6,137.9,143.5,146.3,157.0,160.6,165.9,172.6.HRMS(ESI,positive)m / z calcd for C29H28NO6[M+H] +:486.1911,found:486.1930.

[0107]

[0108] Example 4: Preparation of Compound 4

[0109] The specific synthesis method includes the following reaction steps:

[0110] [1] Synthesis of compound 4

[0111] Compound 4 was synthesized based on Example 1. Compound 1 (0.17 mmol) was weighed and dissolved in acetonitrile (10 mL). Potassium carbonate (0.67 mmol) and CH3I (0.67 mmol) were added, and the mixture was heated to 85°C and refluxed for reaction. The reaction was monitored by TLC and the reaction was completed after 24 hours. Cooled to room temperature and acetonitrile was removed by distillation under reduced pressure. 10 mL of water and 10 mL of EA were added, the mixed solution was filtered through a sand core funnel, the filter residue was removed, and the filter residue was washed twice with 5 mL of EA. The pH was adjusted to 7 with 1 M dilute hydrochloric acid, and 20 mL of EA was used for three extractions. The organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain a brown-yellow oily crude product. The crude product was purified by 300-400 mesh silica gel column chromatography (mobile phase ratio of DCM:MeOH=100:1) to obtain off-white solid compound 4 (yield: 84%).

[0112] Compound 4 1 H NMR and 13 The C NMR data are as follows:

[0113] 1 H NMR (500MHz, CDCl3) δ3.16 (dd, J=3.6, 13.9Hz, 1H), 3.22 (dd, J=5.5, 14.0, Hz, 1H), 3.78 (s, 3H ),3.82(s,3H),3.84(s,3H),3.86(s,3H),4.06(s,3H),5.05(d,J=4.8Hz,1H),6.19(d,J=6.7H z,1H),6.44(d,J=15.6Hz,1H),6.60-6.70(m,2H),6.77(dd,J=8.1,13.1,Hz,2H),6.97(d,J=8 .6Hz,2H),7.13(s,1H),7.34(d,J=8.2Hz,1H),7.84(d,J=8.6Hz,2H),7.89(d,J=15.4Hz,1H).

[0114] 13C NMR (125MHz, CDCl3) δ37.9,52.8,53.9,55.8,56.2,56.6,99.3,107.0,111.6,112.9,114.7,120.5,121.8,123.0 ,124.6,127.2,128.7,131.0,140.1,144.1,146.8,148.5,149.3,157.8,160.7,172.7.HRMS(ESI,positive)m / z calcd for C31H32NO8[M+H] + :546.2122,found:546.2144.

[0115]

[0116] Example 5: Preparation of Compound 5

[0117] The specific synthesis method includes the following reaction steps:

[0118] [1] Synthesis of compound 5

[0119] Compound 5 was synthesized based on Example 2, using the same experimental procedures as in Example 4. Compound 2 (0.22 mmol) was dissolved in acetonitrile (10 mL), and potassium carbonate (0.44 mmol) and CH3I (0.44 mmol) were added. The crude product was purified by 300-400 mesh silica gel column chromatography (mobile phase ratio: DCM:MeOH = 100:1) to obtain Compound 4 as an off-white solid (yield: 91%).

[0120] Compound 5 1 H NMR and 13 The C NMR data are as follows:

[0121] 1H NMR (500MHz, CDCl3) δ3.16 (dd, J=3.6, 13.9Hz, 1H), 3.22 (dd, J=5.5, 14.0Hz, 1H), 3.78 (s, 3H ),3.82(s,3H),3.84(s,3H),3.86(s,3H),4.06(s,3H),5.05(d,J=4.8Hz,1H),6.19(d,J=6.7H z,1H),6.44(d,J=15.6Hz,1H),6.60-6.70(m,2H),6.77(dd,J=8.1,13.1Hz,2H),6.97(d,J=8 .6Hz,2H),7.13(s,1H),7.34(d,J=8.2Hz,1H),7.84(d,J=8.6Hz,2H),7.89(d,J=15.4Hz,1H).

[0122] 13 C NMR (125MHz, CDCl3) δ37.2,52.5,53.5,55.3,55.4,56.3,99.1,106.6,114.0,114.3,120.2,122.7,12 4.2,126.8,127.9,130.4,130.7,139.6,143.7,146.4,157.4,158.7,160.4.HRMS(ESI,positive)m / z calcd for C30H30NO7[M+H] + :516.2017,found:516.2019

[0123]

[0124] Example 6: Preparation of Compounds 6 and 7

[0125] The specific synthesis method includes the following reaction steps:

[0126] [1] Synthesis of iodinated raw material 2a

[0127] In a 200 mL reaction flask, 3,4-dihydroxybenzaldehyde (58 mmol) dissolved in DMF (80 mL) was added. Under magnetic stirring, NaHCO₃ (80 mmol), NaI (17.4 mmol), and benzyl chloride (14 mL) were weighed and added sequentially. The reaction was heated to 40°C and monitored by TLC. The reaction was complete after 48 hours. The reaction was stopped, cooled to room temperature, filtered through a fritted funnel, and the residue removed. The residue was then washed twice with 20 mL of EA. A small amount of 1N dilute hydrochloric acid was added to the filtrate to adjust the pH to 7. 150 mL of water was then added to the filtrate, and the mixture was extracted with 200 mL of EA in three separate extractions. The organic phases were combined, dried over anhydrous sodium sulfate, and the solvent removed under reduced pressure to yield a brownish-yellow crude oil. The crude product was recrystallized from methanol to obtain a white solid (yield: 65%), which was directly used in the next reaction.

[0128] Next, the product from the previous step (10 mmol) was weighed and dissolved in pyridine (8 mL), placed in an ice bath and cooled with stirring to 0°C. Under light protection, iodine chloride (12 mmol) was weighed and dissolved in dioxane (16 mL), fully dissolved, and added dropwise to the pyridine solution. After all additions were complete, the ice bath was removed, the temperature was raised to room temperature, and the reaction was monitored by TLC. The reaction was complete after 6 days. 50 mL of ice water was added to the solution, followed by quenching with concentrated hydrochloric acid, adjusting the pH to 1. Saturated sodium thiosulfate solution was added and stirred thoroughly to remove iodine. Three extractions were performed with 100 mL of EA. The organic phases were combined, dried over anhydrous sodium sulfate, and the solvent removed under reduced pressure to obtain a brownish-yellow oily crude product. The crude product was purified by 300-400 mesh silica gel column chromatography (mobile phase ratio PE:EA = 8:1) to obtain a white solid iodinated raw material 2a (yield: 87%).

[0129] Iodinated raw material 2a 1 The H NMR data are as follows:

[0130] 1 H NMR (500MHz, CDCl3) δ5.22(s,2H),6.36(s,1H),6.97(d,J=8.7Hz,1H),7.40(m,5H),7.55(d,J=8.6Hz,1H),10.03(s,1H).

[0131]

[0132] [2] Synthesis of intermediate 2b

[0133] The experimental procedure was similar to that used in the synthesis of intermediate 1b in Example 1. Iodinated starting material 2a (10 mmol), PdCl2(PPh3)2 (0.6 mmol), CuI (0.6 mmol), Et3N (30 mmol), and 4-methoxyphenylacetylene (12 mmol) were dissolved in 30 mL of DMF. Silica gel column chromatography (PE:EA = 10:1) afforded 2b as a yellow-green solid (yield: 69%).

[0134] Intermediate 2b 1 H NMR and 13 The C NMR data are as follows:

[0135] 1 H NMR (500MHz, CDCl3) δ3.82(s,3H),5.40(s,2H),7.04(d,J=8.3Hz,1H),7.07(d,J=8.5Hz,2H),7.37(t,J=7.3Hz,1H ),7.43(t,J=7.4Hz,2H),7.50-7.60(m,3H),7.76(s,1H),7.86-7.89(m,2H),7.95(d,J=8.5Hz,2H),10.02(s,1H).

[0136] 13 C NMR (125MHz, CDCl3) δ55.8,70.7,100.1,109.1,118.0,120.3,122.5,125.6,1 27.2,128.3,128.7,129.4,130.9,137.1,142.0,143.9,158.2,162.6,190.9.

[0137]

[0138] [3] Synthesis of intermediate 2c

[0139] The experimental procedure was similar to that of the synthesis of intermediate 1c in Example 1. Intermediate 2b (2 mmol) was weighed and dissolved in pyridine (50 mL). Malonic acid (6 mmol) and piperidine (2 mmol) were added to obtain yellow solid 2c (yield: 88%).

[0140] Intermediate 2c 1 H NMR and 13 The C NMR data are as follows:

[0141] 1H NMR (500MHz, DMSO-d6) δ3.82(s,3H),5.40(s,2H),6.59(d,J=16.1Hz,1H),7.04(d,J=8.5Hz,1H),7.07(d,J=8.9Hz,2H),7.37(t,J =7.3Hz,1H),7.43(t,J=7.4Hz,2H),7.50-7.60(m,3H),7.76(s,1H),7.84(d,J=16.0Hz,1H),7.95(d,J=8.8Hz,2H),12.34(s,1H).

[0142] 13 C NMR(125MHz,DMSO-d6)δ55.8,70.7,100.1,109.2,115.0,118.0,120.2,122.5,125.6, 127.2,128.4,128.6,129.0,130.7,137.1,141.9,143.6,145.7,157.2,160.6,168.5.

[0143]

[0144] [4] Synthesis of compound 6

[0145] Compound 6 was synthesized according to the experimental procedures of Example 1. Intermediate 2c (0.84 mmol), compound A (1.00 mmol), PyBOP (1.00 mmol), and Et3N (3.60 mmol) were dissolved in a mixture of DMF (5 mL) and DCM (10 mL). The resulting brownish-yellow crude product was purified by 300-400 mesh silica gel column chromatography (mobile phase ratio: DCM:MeOH = 80:1) to obtain Compound 6 as a yellow-green solid (yield: 66%).

[0146] Compound 6 1 H NMR and 13 The C NMR data are as follows:

[0147] 1H NMR (500MHz, CDCl3) δ3.01 (dd, J=5.5, 14.0Hz, 1H), 3.18 (dd, J=5.1, 14.1Hz, 1H), 3.68 (s, 3H), 3 .79(s,3H),4.94(dd,J=5.7,12.2Hz,1H),5.16(s,2H),6.12(d,J=15.5Hz,1H),6.38(d,J=5.7Hz ,1H),6.57-6.47(m,2H),6.72(s,1H),6.79(s,1H),6.83(d,J=8.0Hz,1H),6.88(d,J=8.7Hz,3H) ,7.34-7.30(m,1H),7.37(dd,J=4.3,11.3Hz,2H),7.43(d,J=7.1Hz,2H),7.65(d,J=8.7Hz,3H).

[0148] 13 C NMR (125MHz, CDCl3) δ37.0,52.5,53.9,55.3,70.9,98.5,108.5,114.1,115.2,116.2,119.8,121.0,122.6,123.7,126.8,127.5,1 27.7,128.1,128.6,131.1,136.6,140.0,143.6,143.9,144.3,145.4,157.2,160.2,167.0,172.2.HRMS(ESI,positive)m / zcalcd for C 35 H 32 NO8[M+H] + :594.2122,found:594.2123.

[0149]

[0150] [4] Synthesis of compound 7

[0151] Compound 6 (0.17 mmol) was weighed and dissolved in methanol (10 mL). 10% Pd / C was added under a hydrogen atmosphere and stirred at room temperature for 4 hours. After the reaction, the reaction solution was filtered to remove the catalyst and concentrated by vacuum distillation to obtain a yellow-green solid compound 7 (yield: 95%).

[0152] Compound 7 1 H NMR and 13 The C NMR data are as follows:

[0153] 1H NMR (500MHz, CDCl3) δ3.05(dd,J=5.3,14.1Hz,1H),3.14(dd,J=5.1,14.1Hz,1H),3.63(s,3H),3.79(s,3H),4.94(dd,J=5.7,12.2Hz,1H),6.10(d,J= 15.5Hz,1H),6.35(d,J=5.7Hz,1H),6.47-6.53(m,2H),6.71(s,1H),6.79( s,1H),6.82(d,J=8.0Hz,1H),6.86(d,J=8.7Hz,3H),7.63(d,J=8.7Hz,3H).

[0154] 13 C NMR (125MHz, CDCl3) δ37.0,52.5,54.0,55.1,97.3,107.9,113.5,114.9,115.8,118.8,120.7,122.1,123.2,126. 1,127.9,130.8,136.0,142.9,143.1,143.5,144.0,144.7,156.9,160.4,167.0,172.3.HRMS(ESI,positive)m / z calcd for C 28 H 26 NO8[M+H] + :504.2432,found:504.2433.

[0155]

[0156] Example 7: Preparation of Compounds 8 and 9

[0157] The specific synthesis method includes the following reaction steps:

[0158] [1] The synthesis of iodinated raw material 2a, intermediate 2b and intermediate 2c is shown in Example 6.

[0159] [2] Synthesis of compound 8

[0160] Compound 8 was synthesized according to the experimental procedures of Example 1. A mixture of intermediate 2c (0.81 mmol), compound B (0.97 mmol), PyBOP (0.97 mmol), and Et3N (2.43 mmol) in DMF (5 mL) and DCM (10 mL) was separated by silica gel column chromatography (DCM:CH3OH = 80:1) to afford Compound 8 as a pale yellow solid (yield: 70%).

[0161] Compound 8 1H NMR and 13 The C NMR data are as follows:

[0162] 1 H NMR(500MHz,DMSO-d6)δ2.90(dd,J=8.6,13.9Hz,1H),3.00(dd,J=5.7,13.9Hz,1H),3.64(s,3H),3.8 3(s,3H),4.62(dd,J=8.0,14.0Hz,1H),5.39(s,2H),6.69(d,J=8.4Hz,2H),6.82(d,J=15.9Hz,1H),7. 02-7.08(m,3H),7.11(d,J=8.9Hz,2H),7.38(dd,J=7.8,14.5Hz,2H),7.44(t,J=7.4Hz,2H),7.55(d, J=7.3Hz,2H),7.63(t,J=7.9Hz,2H),7.89-7.90(d,J=8.8Hz,2H),8.41(d,J=7.8Hz,1H),9.27(s,1H).

[0163] 13 C NMR (125MHz, DMSO-d6) δ36.8,52.3,54.5,55.8,70.7,100.1,109.2,115.1,115.6,120.6,120.9,122.4,125.5,127.0,127.5,12 8.4,128.6,129.0,130.0,130.5,137.1,137.8,143.7,145.2,156.5,157.0,160.6,165.8,172.8.HRMS(ESI,positive)m / zcalcd for C 35 H 32 NO7[M+H] + :578.2173,found:578.2182.

[0164]

[0165] [3] Synthesis of compound 9

[0166] The experimental procedure for removing the benzyl moiety was similar to that of Example 6 to obtain a pale yellow solid compound 9 (yield: 93%).

[0167] Compound 9 1 H NMR and 13 The C NMR data are as follows:

[0168] 1H NMR(500MHz,DMSO-d6)δ2.85(dd,J=8.3,13.9Hz,1H),3.00(dd,J=6.0,13.9Hz,1H ),3.61(s,3H),3.79(s,3H),4.60(dd,J=8.0,14.0Hz,1H),6.63(d,J=8.4Hz,2H),7 .01-7.07(m,3H),7.10(d,J=8.7Hz,2H),7.53(d,J=7.1Hz,2H),7.62(t,J=7.8Hz,2 H),7.83-7.90(d,J=8.7Hz,2H),8.40(d,J=7.8Hz,1H),9.24(s,1H),11.01(s,1H).

[0169] 13 C NMR (125MHz, DMSO-d6) δ36.9,52.4,53.9,55.4,100.1,109.0,114.9,115.2,120.1,120.3,122.0,125.2,12 8.1,129.0,130.0,130.5,136.9,143.3,145.0,156.5,157.0,160.1,166.3,172.7.HRMS(ESI,positive)m / z calcd for C28H26NO7[M+H]+:488.2361,found:488.2371.

[0170]

[0171] Example 8: Preparation of Compounds 10 and 11

[0172] The specific synthesis method includes the following reaction steps:

[0173] [1] The synthesis of iodinated raw material 2a, intermediate 2b and intermediate 2c is shown in Example 6.

[0174] [2] Synthesis of compound 10

[0175] Compound 10 was synthesized following the experimental procedures of Example 1. A mixture of intermediate 2c (0.75 mmol), compound C (0.90 mmol), PyBOP (0.90 mmol), and Et3N (2.25 mmol) in DMF (5 mL) and DCM (10 mL) was separated by silica gel column chromatography (DCM:MeOH = 80:1) to afford Compound 10 as a pale yellow solid (yield: 72%).

[0176] Compound 10 1 H NMR and13 The C NMR data are as follows:

[0177] 1 H NMR(500MHz, CDCl3)δ3.20(dd,J=5.5,13.9Hz,1H),3.27(dd,J=5.8,13.8Hz,1H),3.77(s,3H),3.86(s,3H),5.06-5 .12(m,1H),5.36(s,2H),6.22(d,J=7.7Hz,1H),6.42(d,J=15.6Hz,1H),6.79(d,J=8.4Hz,1H),6.98(dd,J=2.3,9.4 ,Hz,2H),7.14(s,2H),7.15(s,1H),7.25-7.27(m,1H),7.28(d,J=2.8Hz,1H),7.30(d,J=1.7Hz,1H),7.30-7.34(m, 1H),7.36(d,J=7.2Hz,1H),7.42(d,J=7.1Hz,2H),7.51(d,J=7.2Hz,2H),7.82-7.85(m,2H),7.88(d,J=15.6Hz,1H).

[0178] 13 C NMR (125MHz, CDCl3) δ38.0,52.4,53.4,55.4,98.9,108.8,114.3,118.2,120.4,122.7,124.0,126.7 126.8,127.1,127.4,127.5,128.2,128.5,128.6,128.6,128.7,129.0,129.4,131.0,1 36.0.136.7,139.6,144.0,145.4,157.3,160.4,165.8,172.3.HRMS(ESI,positive)m / z calcd for C 35 H 32 NO6[M+H] + :562.2224,found:562.2230.

[0179]

[0180] [2] Synthesis of compound 11

[0181] The experimental procedure for removing the benzyl moiety was referred to Example 6 to obtain a light yellow solid compound 11 (yield: 96%).

[0182] Compound 11 1 H NMR and13 The C NMR data are as follows:

[0183] 1 H NMR (500MHz, CDCl3) δ3.22 (dd, J=5.6, 13.9Hz, 1H), 3.27 (dd, J=5.8, 13.8Hz, 1H), 3.75 (s, 3H), 3.87(s,3H),5.01-5.12(m,1H),6.19(d,J=7.8Hz,1H),6.38(d,J=14.9Hz,1H),6.76(d,J=8.2H z,1H),6.93(dd,J=2.3,9.4,Hz,2H),7.12(s,2H),7.16(s,1H),7.24-7.27(m,1H),7.28(d,J=2 .5Hz,1H),7.29(d,J=1.7Hz,1H),7.30-7.35(m,1H),7.81-7.86(m,2H),7.89(d,J=15.0Hz,1H).

[0184] 13 C NMR (125MHz, CDCl3) δ38.0,52.3,53.2,55.0,109.2,114.0,117.9,120.4,121.9,123.8,126.1,126.8,127.5,128.2,128.5, 128.6,128.9,129.2,131.0,135.8.136.3,139.3,143.7,145.1,156.8,159.9,165.8,172.6.HRMS(ESI,positive)m / zcalcd for C28H26NO6[M+H] + :472.2224,found:472.2230.

[0185]

[0186] Example 9: Preparation of Compound 12

[0187] [1] The synthesis of iodinated starting material 2a, intermediate 2b, intermediate 2c and intermediate 2d is shown in Example 6.

[0188] [2] Synthesis of compound 12

[0189] Compound 12 was synthesized based on compound 6 from Example 6 by first methylating the phenolic hydroxyl group and then removing the benzyl group. The experimental procedures for methylating the phenolic hydroxyl group were similar to those for the synthesis of compound 4 in Example 4: Intermediate 2d (0.20 mmol), potassium carbonate (0.79 mmol), and CHCl (0.79 mmol) were added to acetonitrile (10 mL). The crude product obtained after extraction and concentration under reduced pressure was directly used in the next step of the benzyl removal reaction. The experimental procedures for removing the benzyl moiety were similar to those of Example 6, ultimately yielding compound 12 as an off-white solid (yield: 75%).

[0190] Compound 12 1 H NMR and 13 The C NMR data are as follows:

[0191] 1 H NMR (500MHz, CDCl3) δ3.07-3.24(m,2H),3.72(s,3H),3.77(s,3H),3.82(s, 3H),3.86(s,3H),4.99-5.06(m,1H),6.22(dd,J=4.3,7.5Hz,1H),6.42(d,J =15.6Hz,1H),6.59-6.72(m,2H),6.74-6.85(m,2H),6.95-7.00(m,2H),7.1 1-7.16(m,1H),7.28(d,J=8.3Hz,1H),7.80-7.84(m,2H),7.85-7.91(m,1H).

[0192] 13 C NMR (125MHz, CDCl3) δ37.6,52.4,53.6,55.4,55.9,58.5,98.9,108.8,111.8,114.3,114.5,115.6,118.2,120.4,120.9,122.8,1 24.0,128.2,129.0,131.0,136.6,139.6,144.0,144.8,145.6,146.6,157.4,160.4,165.9,172.4.HRMS(ESI,positive)m / zcalcd for C30H30NO8[M+H] + :532.2224,found:532.2230.

[0193]

[0194] Example 10: Preparation of Compound 13

[0195] The specific synthesis method includes the following reaction steps:

[0196] [1] The synthesis of iodinated raw material 2a, intermediate 2b, intermediate 2c and intermediate 3d is shown in Examples 6 and 7.

[0197] [2] Synthesis of compound 13

[0198] Compound 13 was synthesized based on compound 8 from Example 7. Phenolic hydroxymethylation was first performed, followed by benzyl removal. The experimental procedures for phenolic hydroxymethylation were similar to those for the synthesis of compound 4 in Example 4: intermediate 3d (0.15 mmol), potassium carbonate (0.60 mmol), and CH3I (0.60 mmol) were added to acetonitrile (10 mL). The crude product obtained after extraction and concentration under reduced pressure was directly used in the next step of benzyl removal. The experimental procedures for benzyl removal were similar to those of Example 6, ultimately yielding compound 13 as an off-white solid (yield: 84%).

[0199] Compound 13 1 H NMR and 13 The C NMR data are as follows:

[0200] 1 H NMR(500MHz,DMSO-d6)δ2.90(dd,J=8.6,13.9Hz,1H),2.99(dd,J=5.7,13.9Hz,1H), 3.35(s,3H),3.64(s,3H),3.84(s,3H),4.61(td,J=5.9,8.2Hz,1H),6.66-6.71(m,2H ),6.82(d,J=15.9Hz,1H),7.02-7.05(m,2H),7.09-7.13(m,2H),7.54(m,1H),7.62(d ,J=15.9Hz,1H),7.64(s,1H),7.88-7.92(m,2H),8.40(d,J=7.8Hz,1H),9.26(s,1H).

[0201] 13 C NMR (125MHz, DMSO-d6) δ36.8,52.3,54.5,55.8,100.1,109.2,115.1,115.6,120.6,120.9,122.4,125.5,128.6 ,129.0,130.0,130.5,137.1,138.0,143.8,145.2,156.5,157.0,160.6,165.8,172.8.HRMS(ESI,positive)m / z calcd for C29H27NO7[M+H] +:502.4330,found:502.4332.

[0202]

[0203] Example 11: Preparation of Compound 14

[0204] The specific synthesis method includes the following reaction steps:

[0205] [1] The synthesis of iodinated raw material 1a is carried out according to Example 1.

[0206] [2] Synthesis of intermediate 3b

[0207] The experimental procedures were similar to those used in the synthesis of intermediate 1b in Example 1. Iodinated starting material 1a (10 mmol), PdCl2(PPh3)2 (0.6 mmol), CuI (0.6 mmol), Et3N (30 mmol), and phenylacetylene (12 mmol) were dissolved in 30 mL of DMF. Silica gel column chromatography (PE:EA = 10:1) afforded 3b as a pale yellow solid (yield: 74%).

[0208] Intermediate 3b 1 H NMR and 13 The C NMR data are as follows:

[0209] 1 H NMR (500MHz, CDCl3) δ4.11 (s, 3H), 6.87 (d, J = 8.3Hz, 1H), 7.27-7.43 (m, 1H), 7.43-7.51 (m,2H),7.64(d,J=8.2Hz,1H),7.78(s,1H),7.93(dd,J=1.3,8.4Hz,2H),10.03(s,1H).

[0210] 13 C NMR (125MHz, CDCl3) δ56.4,102.0,106.1,122.9,125.4,128.9,129.3,129.7,129.9,132.0,144.0,149.8,159.0,190.8.

[0211]

[0212] [3] Synthesis of intermediate 3c

[0213] The experimental procedure was similar to that of the synthesis of intermediate 1c in Example 1. Intermediate 3b (2 mmol) was weighed and dissolved in pyridine (50 mL). Malonic acid (6 mmol) and piperidine (2 mmol) were added to obtain yellow solid 3c (yield: 84%).

[0214] Intermediate 3c 1 H NMR and 13 The C NMR data are as follows:

[0215] 1 H NMR (500MHz, DMSO-d6) δ4.02(s,3H),6.59(d,J=16.1Hz,1H),6.99(dd,J=2.1,8.4Hz,1H),7.42(t,J=7.3Hz,1H),7.5 1(t,J=7.6Hz,2H),7.59(d,J=8.4Hz,1H),7.85(d,J=16.1Hz,1H),7.91(s,1H),8.01(d,J=7.4Hz,2H),12.32(s,1H).

[0216] 13 C NMR (125MHz, DMSO-d6) δ56.6,101.9,108.0,118.1,120.3,125.4,125.9,129.5,129.6,129.9,130.1,141.9,143.6,146.8,156.9,168.5.

[0217]

[0218] [4] Synthesis of compound 14

[0219] Compound 14 was synthesized by following the experimental procedure for compound 1 in Example 1. Intermediate 3c (0.83 mmol), compound A (1.00 mmol), PyBOP (1.00 mmol), and Et3N (2.49 mmol) were dissolved in a mixture of DMF (5 mL) and DCM (10 mL) to obtain compound 14 as a pale yellow solid (yield: 68%).

[0220] Compound 14 1 H NMR and 13 The C NMR data are as follows:

[0221] 1H NMR(500MHz,DMSO-d6)δ2.85(dd,J=8.4,13.9,Hz 1H),2.94(dd,J=5.9,13.9Hz,1H),3.65(s,3H),4.03(s,3H),4.61(dd,J=7.9,14. 1Hz,1H),6.50(d,J=6.2Hz,1H),6.64(s,2H),6.86(d,J=15.9Hz,1H),7.02(d,J=8 .5Hz,1H),7.46(t,J=7.9Hz,2H),7.55(t,J=7.7Hz,2H),7.65(d,J=15.8Hz,1H),7 .80(s,1H),7.97(d,J=7.4Hz,2H),8.38(d,J=7.8Hz,1H),8.79(d,J=35.3Hz,2H).

[0222] 13 C NMR(125MHz,DMSO-d6)δ37.1,52.3,54.5,56.5,60.2,101.9,108.0,115.9,116.9,120.3,120.7,121,0,125.3,125.8, 128.2,129.4,129.6,129.7,129.8,137.8,143.8,144.5,145.5,146.4,156.7,165.8,172.8.HRMS(ESI,positive)m / z calcd forC28H26NO7[M+H] + :488.1704,found:488.1756.

[0223]

[0224] Example 12: Preparation of Compound 15

[0225] The specific synthesis method includes the following reaction steps:

[0226] [1] The synthesis of iodinated raw material 1a, intermediate 3b, and intermediate 3c was carried out according to Example 11.

[0227] [2] Synthesis of compound 15

[0228] Compound 15 was synthesized by following the experimental procedure for compound 1 in Example 1. Intermediate 3c (0.83 mmol), compound B (1.00 mmol), PyBOP (1.00 mmol), and Et3N (2.49 mmol) were dissolved in a mixture of DMF (5 mL) and DCM (10 mL) to obtain compound 15 as a pale yellow solid (yield: 71%).

[0229] Compound 15 1 H NMR and 13 The C NMR data are as follows:

[0230] 1 H NMR (500MHz, CDCl3) δ3.20 (dd, J=5.6, 13.9Hz, 1H), 3.27 (dd, J=5.8, 13.9Hz, 1H), 3.7 7(s,3H),4.05(s,3H),5.10(dt,J=5.7,7.6Hz,1H),6.29(d,J=7.8Hz,1H),6.45(d,J=1 5.6Hz,1H),6.77(d,J=8.4Hz,1H),7.13-7.19(m,2H),7.25-7.27(m,2H),7.28-7.32(m ,2H),7.34(d,J=8.4Hz,1H),7.36-7.39(m,1H),7.42-7.48(m,2H),7.86-7.92(m,3H).

[0231] 13 C NMR (125MHz, CDCl3) δ38.0,52.4,53.5,56.3,100.5,107.0,118.3,120.4,124.2,125.2,127.2,128.6,128 .8,129.0,129.4,129.9,130.4,136.0,139.5,143.9,146.5,157.1,165.9,172.3.HRMS(ESI,positive)m / z calcd for C28H26NO6[M+H] + :472.1755,found:472.1771.

[0232]

[0233] Example 13: Preparation of Compound 16

[0234] The specific synthesis method includes the following reaction steps:

[0235] [1] The synthesis of iodinated raw material 1a, intermediate 3b, and intermediate 3c was carried out according to Example 11.

[0236] [2] Synthesis of compound 16

[0237] Compound 16 was synthesized by following the experimental procedure for compound 1 in Example 1. Intermediate 3c (0.80 mmol), compound C (0.96 mmol), PyBOP (0.96 mmol), and Et3N (2.40 mmol) were dissolved in a mixture of DMF (5 mL) and DCM (10 mL) to obtain compound 16 as a pale yellow solid (yield: 76%).

[0238] Compound 16 1 H NMR and 13 The C NMR data are as follows:

[0239] 1 H NMR (500MHz, CDCl3) δ3.20 (dd, J=13.9, 5.6Hz, 1H), 3.27 (dd, J=5.8, 13.9Hz, 1H), 3.7 7(s,3H),4.05(s,3H),5.10(dt,J=5.7,7.6Hz,1H),6.29(d,J=7.8Hz,1H),6.45(d,J=1 5.6Hz,1H),6.77(d,J=8.4Hz,1H),7.13-7.19(m,2H),7.25-7.27(m,2H),7.28-7.32(m ,2H),7.34(d,J=8.4Hz,1H),7.36-7.39(m,1H),7.42-7.48(m,2H),7.86-7.92(m,3H).

[0240] 13 C NMR (125MHz, CDCl3) δ38.0,52.4,53.5,56.3,100.5,107.0,118.3,120.4,124.2,125.2,127.2,128.6,128 .8,129.0,129.4,130.0,130.4,136.0,139.5,143.9,146.5,157.1,165.9,172.3.HRMS(ESI,positive)m / z calcd for C28H26NO5[M+H] + :456.1805,found:456.1819.

[0241]

[0242] Example 14: Preparation of Compound 17

[0243] The specific synthesis method includes the following reaction steps:

[0244] [1] Synthesis of compound 17

[0245] Compound 17 was synthesized based on Example 11. The specific experimental steps were similar to those for the synthesis of compound 4 in Example 4. Compound 14 (0.30 mmol), potassium carbonate (1.20 mmol), and CH3I (1.20 mmol) were added to acetonitrile (10 mL) to obtain compound 17 as an off-white solid (yield: 80%).

[0246] Compound 17 1 H NMR and 13 The C NMR data are as follows:

[0247] 1 H NMR (500MHz, CDCl3) δ3.15 (dd, J=5.3, 14.0Hz, 1H), 3.22 (dd, J=5.9, 14.0Hz1H), 3.78 ( s,3H),3.81(s,3H),3.84(s,3H),4.05(s,3H),5.05(dt,J=5.6,7.5Hz,1H),6.25(d,J=7 .6Hz,1H),6.45(d,J=15.6Hz,1H),6.63-6.71(m,2H),6.78(dd,J=3.4,8.2Hz,2H),7.26 (s,1H),7.33-7.39(m,2H),7.45(dd,J=4.7,10.4Hz,2H),7.90(dd,J=5.4,12.4Hz,3H).

[0248] 13 C NMR (125MHz, CDCl3) δ37.5,52.4,53.6,55.8,55.9,56.3,100.5,107.0,111.2,112.5,118.3,120.4,121.4,124.2,125. 2,128.4,128.8,129.0,129.8,130.3,139.5,143.9,146.5,148.2,148.9,157.2,165.8,172.4.HRMS(ESI,positive)m / z calcd forC30H30NO7[M+H] + :516.2017,found:516.2039.

[0249]

[0250] Example 15: Preparation of Compound 18

[0251] The specific synthesis method includes the following reaction steps:

[0252] [1] Synthesis of compound 18

[0253] Compound 18 was synthesized based on Example 12. The specific experimental steps were similar to those for the synthesis of compound 4 in Example 4. Compound 15 (0.27 mmol), potassium carbonate (0.54 mmol), and CH3I (0.54 mmol) were added to acetonitrile (10 mL) to obtain compound 18 as an off-white solid (yield: 92%).

[0254] Compound 18 1 H NMR and 13 The C NMR data are as follows:

[0255] 1 H NMR(500MHz,DMSO-d6)δ2.10(dd,J=13.9,8.7Hz,1H),2.21(dd,J=13.9,5.7Hz,1H),2.7 9(s,3H),2.85(s,3H),3.17(s,3H),3.80(dd,J=13.9,8.3Hz,1H),5.99(t,J=12.4Hz,3H ),6.16(d,J=8.4Hz,1H),6.32(d,J=8.6Hz,2H),6.60(t,J=7.6Hz,2H),6.69(t,J=7.7Hz ,2H),6.79(d,J=15.9Hz,1H),6.93(s,1H),7.11(d,J=7.3Hz,2H),7.58(d,J=7.8Hz,1H).

[0256] 13 C NMR(125MHz,DMSO-d6)δ36.7,52.4,54.4,55.4,56.5,101.8,108.0,114.2,120.6,120.9,125.3,125.7,129.4, 129.4,129.6,129.7,129.8,130.6,137.8,143.8,146.4,156.7,158.5,165.8,172.7.HRMS(ESI,positive)m / z calcd for C29H28NO6[M+H] + :486.1911,found:486.1943.

[0257]

[0258] Example 16: Preparation of Compound 19

[0259] The specific synthesis method includes the following reaction steps:

[0260] [1] The synthesis of iodinated raw material 1a is carried out according to Example 1.

[0261] [2] Synthesis of intermediate 4b

[0262] The experimental procedure was similar to that used in the synthesis of intermediate 1b in Example 1. Iodinated starting material 1a (10 mmol), PdCl2(PPh3)2 (0.6 mmol), CuI (0.6 mmol), Et3N (30 mmol), and p-methylphenylacetylene (12 mmol) were dissolved in 30 mL of DMF. Silica gel column chromatography (PE:EA = 10:1) afforded 4b as a pale yellow solid (yield: 75%).

[0263] Intermediate 4b 1 H NMR and 13 The C NMR data are as follows:

[0264] 1 H NMR (500MHz, CDCl3) δ2.41 (s, 3H), 4.12 (s, 3H), 6.87 (d, J = 8.3Hz, 1H), 7.19-7. 32(m,2H),7.64(d,J=8.2Hz,1H),7.74(s,1H),7.78-7.90(m,2H),10.05(s,1H).

[0265] 13 C NMR (125MHz, CDCl3) δ21.5,56.4,101.3,105.9,122.9,125.4,127.0,129.6,130.1,131.9,139.5,143.9,149.7,159.3,190.8.

[0266]

[0267] [3] Synthesis of intermediate 4c

[0268] The experimental procedure was similar to that of the synthesis of intermediate 1c in Example 1. Intermediate 4b (2 mmol) was weighed and dissolved in pyridine (50 mL). Malonic acid (6 mmol) and piperidine (2 mmol) were added to obtain yellow solid 3c (yield: 84%).

[0269] Intermediate 4c 1 H NMR and 13 The C NMR data are as follows:

[0270] 1H NMR (500MHz, DMSO-d6) δ2.37(s,3H),4.02(s,3H),6.59(d,J=16.1Hz,1H),6.99(d,J=8.5Hz,1H),7.3 3(d,J=8.0Hz,2H),7.59(d,J=8.4Hz,1H),7.85(t,J=8.0Hz,2H),7.91(d,J=8.2Hz,2H),12.32(s,1H).

[0271] 13 C NMR (125MHz, DMSO-d6) δ21.4,56.5,101.1,107.8,117.9,120.1,125.4,126.0,127.2,130.1,130.2,139.4,142.0,143.4,146.8,157.1,168.5.

[0272]

[0273] [4] Synthesis of compound 19

[0274] Compound 19 was synthesized by following the experimental procedure of Compound 1 in Example 1. A mixture of Intermediate 4c (0.90 mmol), Compound A (1.08 mmol), PyBOP (1.08 mmol), and Et3N (2.70 mmol) in DMF (5 mL) and DCM (10 mL) gave Compound 19 as a pale yellow solid (yield: 66%).

[0275] Compound 19 1 H NMR and 13 The C NMR data are as follows:

[0276] 1 H NMR (500MHz, CDCl3) δ2.36 (s, 3H), 3.00 (dd, J = 6.1, 14.3, Hz, 1H), 3.17 (dd, J = 5.4, 14.3 Hz,1H),3.69(s,3H),3.89(s,3H),4.95(dd,J=5.9,13.1Hz,1H),6.16(d,J=15.7Hz,1H), 6.43(d,J=7.5Hz,2H),6.48-6.52(m,2H),6.80(d,J=2.3Hz,2H),6.83(d,J=8.1Hz,1H), 6.94(d,J=8.4Hz,1H),7.19(t,J=6.7Hz,2H),7.64(dd,J=3.7,11.8Hz,3H),8.36(s,1H).

[0277] 13 C NMR (125MHz, CDCl3) δ21.9,37.5,53.0,54.3,56.5,99.8,107.0,115.7,116.6,117.4,120.1,121.5,124.3,125.6,1 27.4,128.1,129.8,131.0,139.5,140.5,143.9,144.3,144.7,146.9,157.7,167.6,172.8.HRMS(ESI,positive)m / z calcd for C29H28NO7[M+H] + :502.1860,found:502.1891.

[0278]

[0279] Example 17: Preparation of Compound 20

[0280] The specific synthesis method includes the following reaction steps:

[0281] [1] The synthesis of iodinated raw material 1a, intermediate 4b, and intermediate 4c was carried out according to Example 16.

[0282] [2] Synthesis of compound 20

[0283] Compound 20 was synthesized by following the experimental procedure for compound 1 in Example 1. Intermediate 4c (0.88 mmol), compound B (1.06 mmol), PyBOP (1.06 mmol), and Et3N (2.64 mmol) were dissolved in a mixture of DMF (5 mL) and DCM (10 mL) to obtain compound 20 as a pale yellow solid (yield: 70%).

[0284] Compound 20 1 H NMR and 13 The C NMR data are as follows:

[0285] 1H NMR (500MHz, DMSO-d6) δ2.38(s,3H),2.91(dd,J=8.6,13.9Hz,1H),3.00(dd,J=5.8,13.9Hz,1H ),3.64(s,3H),4.02(s,3H),4.61(td,J=6.0,8.2Hz,1H),6.67-6.72(m,2H),6.86(d,J=15.9Hz, 1H),7.00(d,J=8.4Hz,1H),7.05(d,J=8.5Hz,2H),7.36(d,J=8.0Hz,2H),7.43(d,J=8.5Hz,1H), 7.62(d,J=15.9Hz,1H),7.74(s,1H),7.86(d,J=8.2Hz,2H),8.45(d,J=7.8Hz,1H),9.28(s,1H).

[0286] 13 C NMR (125MHz, DMSO-d6) δ21.4,36.9,52.3,54.6,56.5,101.1,107.8,115.6,120.6,120.8,125.3,125.9,127.1, 127.5,129.4,130.2,130.5,137.8,139.4,143.7,146.3,156.6,156.9,165.9,172.8.HRMS(ESI,positive)m / z calcd for C29H28NO6[M+H] + :486.1911,found:486.1965.

[0287]

[0288] Example 18: Preparation of Compound 21

[0289] The specific synthesis method includes the following reaction steps:

[0290] [1] The synthesis of iodinated raw material 1a, intermediate 4b, and intermediate 4c was carried out according to Example 16.

[0291] [2] Synthesis of compound 21

[0292] Compound 21 was synthesized by following the experimental procedure for compound 1 in Example 1. Intermediate 4c (0.70 mmol), compound C (0.84 mmol), PyBOP (0.84 mmol), and Et3N (2.10 mmol) were dissolved in a mixture of DMF (5 mL) and DCM (10 mL) to obtain compound 21 as a pale yellow solid (yield: 73%).

[0293] Compound 21 1 H NMR and 13 The C NMR data are as follows:

[0294] 1 H NMR(500MHz, CDCl3) δ2.40(s,3H),3.21(dd,J=5.4,13.9Hz,1H),3.27(dd,J=5.8,13.9Hz ,1H),3.77(s,3H),4.07(s,3H),5.09(dt,J=5.6,7.6Hz,1H),6.17(d,J=7.7Hz,1H),6.43 (d,J=15.6Hz,1H),6.78(d,1H),7.13-7.16(m,2H),7.22(s,1H),7.27(dd,J=2.4,4.0Hz, 2H),7.32-7.28(m,2H),7.35(d,J=8.6Hz,1H),7.79-7.84(m,2H),7.89(d,J=15.7Hz,1H).

[0295] 13 C NMR (125MHz, CDCl3) δ21.4,38.0,52.4,53.4,56.3,99.8,106.8,118.2,120.3,124.3,125.1,125.2,127.1,127.2,128.4,1 28.6,129.0,129.4,129.5,129.5,130.5,136.0,139.2,139.6,143.8,146.5,157.5,165.8,172.2.HRMS(ESI,positive)m / z calcdfor C29H28NO5[M+H] + :470.1962,found:470.1995.

[0296]

[0297] Example 19: Preparation of Compound 22

[0298] The specific synthesis method includes the following reaction steps:

[0299] [1] Synthesis of compound 22

[0300] Compound 22 was synthesized based on Example 16. The experimental procedures were similar to those of Example 4. Compound 19 (0.17 mmol), potassium carbonate (0.67 mmol) and CH3I (0.67 mmol) were added to acetonitrile (10 mL) to obtain an off-white solid compound 22 (yield: 73%).

[0301] Compound 22 1 H NMR and 13 The C NMR data are as follows:

[0302] 1 H NMR(500MHz, CDCl3) δ2.40(s,3H),3.21(dd,J=5.4,13.9Hz,1H),3.27(dd,J=5.8,13.9Hz ,1H),3.77(s,3H),4.07(s,3H),5.09(dt,J=5.6,7.6Hz,1H),6.17(d,J=7.7Hz,1H),6.43 (d,J=15.6Hz,1H),6.78(d,1H),7.13-7.16(m,2H),7.22(s,1H),7.27(dd,J=2.4,4.0Hz, 2H),7.32-7.28(m,2H),7.35(d,J=8.6Hz,1H),7.79-7.84(m,2H),7.89(d,J=15.7Hz,1H).

[0303] 13 C NMR (125MHz, CDCl3) δ21.4,38.0,52.4,53.4,56.3,99.8,106.8,118.2,120.3,124.3,125.1,125.2,127.1,127.2,128.4,1 28.6,129.0,129.4,129.5,129.5,130.5,136.0,139.2,139.6,143.8,146.5,157.5,165.8,172.2.HRMS(ESI,positive)m / z calcdfor C29H28NO5[M+H] + :470.1962,found:470.1995.

[0304]

[0305] Example 20: Preparation of Compound 23

[0306] The specific synthesis method includes the following reaction steps:

[0307] [1] Synthesis of compound 23

[0308] Compound 23 was synthesized based on Example 17. The experimental procedures were similar to those of Example 4. Compound 20 (0.17 mmol), potassium carbonate (0.67 mmol) and CH3I (0.67 mmol) were added to acetonitrile (10 mL) to obtain an off-white solid compound 20 (yield: 90%).

[0309] Compound 23 1 H NMR and 13 The C NMR data are as follows:

[0310] 1 H NMR (500MHz, DMSO-d6) δ2.37(s,3H),2.92(dd,J=8.7,13.9Hz,1H),2.99(dd,J=5.8,13.9Hz,1H),3. 39(s,3H),3.63(s,3H),4.01(s,3H),4.58(dd,J=8.0,13.9Hz,1H),6.70(d,J=8.4Hz,2H),6.96(d,J= 16.0Hz,1H),6.99(d,J=8.4Hz,1H),7.07(d,J=8.4Hz,2H),7.35(d,J=8.1Hz,2H),7.41(d,J=8.3Hz, 2H),7.60(d,J=15.9Hz,1H),7.84(s,1H),7.89(d,J=8.1Hz,2H),8.65(d,J=7.6Hz,1H),9.36(s,1H).

[0311] 13 C NMR (125MHz, DMSO-d6) δ21.4,36.9,52.3,54.7,56.5,101.4,107.8,115.6,120.8,120.9,125.3,126.2,127.2, 127.6,129.3,130.2,130.5,137.8,139.4,143.7,146.3,156.6,157.0,166.0,172.8.HRMS(ESI,positive)m / z calcd for C30H30NO6[M+H] + :500.2068,found:500.2130.

[0312]

[0313] Example 21: Preparation of Compound 24

[0314] The specific synthesis method includes the following reaction steps:

[0315] [1] Synthesis of intermediate 5b

[0316] Under argon, phenylacetylene (5.00 mmol) was added to an Et3N (5 mL) solution consisting of 2-bromo-3-formylphenyl acetate (2.50 mmol), CuI (0.30 mmol), PdCl2(PPh3)2 (0.10 mmol), and P(t-Bu)3·HBF4 (0.20 mmol). The mixture was stirred at room temperature. TLC monitored the reaction, which was complete after 18 h. 20 mL of water and 20 mL of EA were added, and the mixture was filtered through a fritted funnel. The residue was removed and washed with EA. Extraction was performed with 20 mL of EA in three separate steps. The organic phases were combined, dried over anhydrous sodium sulfate, and the solvent removed under reduced pressure to yield the crude product. The crude product was purified by 300-400 mesh silica gel column chromatography (mobile phase ratio PE:EA = 20:1) to afford 5b as a pale yellow solid (yield: 20%).

[0317] Intermediate 5b 1 H NMR and 13 The C NMR data are as follows:

[0318] 1 H NMR (500MHz, CDCl3) δ7.40–7.49(m,4H),7.67-7.75(m,3H),7.79(s,1H),7.94(d,J=7.4Hz,1H),10.3(s,1H).

[0319] 13 C NMR (125MHz, CDCl3) δ101.4,116.7,123.9,125.4,128.2,128.9,129.0,129.1,129.4,129.8,155.4,159.4,194.3.

[0320]

[0321] [3] Synthesis of compound 24

[0322] First, Intermediate 5c was synthesized following the experimental procedures for Intermediate 1c in Example 1. Intermediate 5b (2 mmol) was weighed and dissolved in pyridine (50 mL). Malonic acid (6 mmol) and piperidine (2 mmol) were then added to afford a yellow solid, 5c. The crude product was then purified and directly used in the next reaction.

[0323]

[0324] Compound 24 was synthesized by referring to the experimental procedure for compound 1 in Example 1. Intermediate 5c (0.83 mmol), compound A (1.00 mmol), PyBOP (1.00 mmol), and Et3N (2.49 mmol) were dissolved in a mixture of DMF (5 mL) and DCM (10 mL) to obtain compound 24 as a pale yellow solid (yield: 73%).

[0325] Compound 24 1 H NMR and 13 The C NMR data are as follows:

[0326] 1 H NMR(500MHz,DMSO-d6)δ2.83(dd,J=8.0,13.9Hz,1H),2.87(dd,J=7.7,13.9Hz,1H),3.65(s,3H ),4.61(dd,J=7.9,14.1Hz,1H),6.50(d,J=6.2Hz,1H),6.64(s,2H),6.83(d,J=15.9Hz,1H),7.2 2(d,J=8.5Hz,1H),7.32(d,J=7.2Hz,1H),7.42~7.52(m,2H),7.55(t,J=7.7Hz,2H),7.60(d,J= 15.8Hz,1H),7.80(s,1H),7.97(d,J=7.4Hz,2H),8.36(d,J=7.8Hz,1H),8.81(d,J=35.3Hz,2H).

[0327] 13 C NMR (125MHz, DMSO-d6) δ37.1,52.3,56.5,60.2,101.9,108.0,110.8,116.9,120,0,120.3,120.9,120.7,125.3,12 5.8,128.2,129.4,129.6,129.7,129.8,137.8,144.5,145.5,146.4,156.7,165.8,172.8.HRMS(ESI,positive)m / z calcd for C27H24NO6[M+H] + :458.4704,found:458.4756.

[0328]

[0329] Example 22: Protective Effects of Compounds 1-5, Compound 7, Compound 9, Compound 11, and Compounds 12-24 on t-BHP-Induced Cardiomyocyte Injury

[0330] The cultured h9c2 cells were randomly divided into 24 groups: normal control group, t-BHP injury group, t-BHP+10 μM salvianolic acid C and 10 μM salvianolic acid C derivatives compounds 1-5, compound 7, compound 9, compound 11, and compounds 12-24. 4 Cells were seeded at a density of 100 μL / well in a 96-well plate and incubated in a 37°C incubator until cell growth reached 70%-80%. Drug pretreatment was then added according to experimental grouping for 24 hours. The supernatant was removed, and each well was stimulated with complete medium containing 150 μM t-BHP for 24 hours (the normal control group was not stimulated with t-BHP). After removing the supernatant, 100 μL / well of the prepared CCK-8 working solution was added and incubated at 37°C for 1 hour. The absorbance of each well at a wavelength of 450 nm was then measured using an enzyme-linked immunosorbent assay (ELISA) to calculate cell viability. Cell viability (%) = absorbance of sample group / absorbance of blank control group × 100%.

[0331] The experimental results are shown in Figure 1 Comparing the control group with the t-BHP-induced injury group, the cell survival rate in the t-BHP-induced injury group was lower than that in the control group (P<0.01). Compared with the t-BHP-induced injury group, the salvianolic acid C derivative-treated group had a significantly higher survival rate (P<0.05).

[0332] Furthermore, the aforementioned salvianolic acid C derivatives, compounds 1-5, 7, 9, 11, and 12-24, showed a certain degree of protective effect against t-BHP-induced oxidative damage in cardiomyocytes. Compared with the normal control group, the viability of H9C2 cells in the t-BHP-injured group was significantly reduced (P < 0.01); compared with the model group, compound 7 significantly increased the survival rate of H9C2 cells after treatment (P < 0.01).

[0333] Example 23: Protective effect of compound 7 on OGD (oxygen-glucose deprivation) model-induced glial cell injury in rats

[0334] In vitro, OGD injury is a typical model of I / R (ischemia-reperfusion) injury: astrocytes were washed three times with PBS and resuspended in glucose-free DMEM / F12 medium, and the cells were grown for 12 hours in a hypoxic chamber containing a mixture of 0.1% O2, 94.9% N2, and 5% CO2. After hypoxia, the cells were transferred back to normal culture medium and cultured in an atmosphere of 95% air and 5% CO2 for 6 hours.

[0335] Astrocyte cultures were randomly divided into the following four experimental groups: (1) Sham group using phosphate buffered saline (PBS) and no damage; (2) OGD model group with OGD damage + PBS; (3) OGD damage + compound 7 group; (4) OGD damage + salvianolic acid C group.

[0336] Cell culture, cell counting, and cell processing were performed according to the above grouping. Flow cytometry was then used to analyze cell apoptosis. The flow cytometry experimental steps were as follows: After digestion with EDTA-free trypsin, the cells were collected by centrifugation at 300g and 4°C for 5 minutes. During the centrifugation, 1× Binding Buffer was prepared by diluting 4× Binding Buffer (4 mL Binding Buffer + 12 mL deionized water) 4-fold with deionized water. The cells were washed twice with 4°C pre-cooled PBS, each time centrifuged at 300g and 4°C for 5 minutes. 250 μl of 1× Binding Buffer was added to resuspend the cells and adjust the concentration to 1×10 6 cells / ml. Transfer 100 μL of cell suspension to a 5 mL flow cytometry tube, add 5 μL of Annexin FITC and 10 μL of PI, and mix gently. Incubate at room temperature for 15 minutes, protected from light. Finally, add 400 μL of 1× Binding Buffer, mix thoroughly, and analyze the sample within 1 hour.

[0337] Furthermore, the results of flow cytometry detection of astrocyte apoptosis showed that compared with the sham operation group, the astrocyte apoptosis in the OGD group was significantly increased (p≤0.01); compared with the model group, compound 7 treatment significantly reduced cell apoptosis (p≤0.01).

[0338] Example 24: Neuroprotective effect of compound 7 on cerebral ischemia-reperfusion injury in SD rats with MCAO model

[0339] Establishment of the MCAO model: Anesthesia was performed intraperitoneally with 50 mg / kg sodium pentobarbital at a dose of 0.33-0.35 ml / 100 g. After skin preparation and disinfection with iodine, blunt dissection was performed after skin incision. The carotid artery was identified along the right sternocleidomastoid tendon, and the arterial sheath was carefully dissected, avoiding injury to the vagus nerve. The common carotid artery (CCA), external carotid artery (ECA), and internal carotid artery (ICA) were then isolated, and the common and external carotid arteries were ligated. The CCA and ICA were clamped with an artery clamp. A small incision was made in the ECA 5 mm from the bifurcation with ophthalmic scissors. A pre-prepared suture corresponding to 180-220 g body weight was slowly inserted into the ICA. At the intersection of the ICA and ECA, the ICA artery clamp was removed, the insertion angle was adjusted, and the suture was slowly advanced toward the cranial end of the ICA to a depth of (18.0 ± 0.5) mm (i.e., the black mark on the suture). The suture was secured to the ECA, the CCA artery clamp was released, the excess suture was trimmed, and the fascia and skin were sutured. After 2 hours of ischemia, the suture was removed and the ECA proximal to the bifurcation was ligated. The sham group underwent the same surgical procedures as the model group, except that no suture was inserted. Successful MCAO modeling was indicated by unsteady standing, left limb paralysis, and lateral rotation when the tail was lifted.

[0340] Rats were randomly divided into three groups using a random number table: sham group, MCAO model group, and MCAO + Compound 7 group, with 10 rats in each group. The sham group did not undergo MCAO, while the I / R + Compound 7 group received oral administration of 10 mg / kg Compound 7 after MCAO for 14 consecutive days. Reperfusion was performed 120 minutes after MCAO. Ten rats survived in the sham group and five in the MCAO group, while eight survived in the MCAO + Compound 7 group. Neurological function was assessed in the rats. Surviving rats were sacrificed 14 days later, and brain tissue was removed for TTC (2,3,5-triphenyltetrazolium chloride) staining and infarct size calculation.

[0341] Neurological function score: After 24 hours of the rat cerebral ischemia-reperfusion model, the behavioral changes of the rats were observed, and the neurological function of the rats was evaluated according to Longa's five-point system: no nerve damage was scored as 0 points; inability to fully extend the contralateral forepaw was scored as 1 point; turning in circles to the outside was scored as 2 points; falling to the contralateral side was scored as 3 points; inability to walk spontaneously and loss of consciousness was scored as 4 points.

[0342] TTC staining: Rat brain tissue was serially sectioned coronally at a thickness of 2 mm per slice. The sections were placed in a 1% TTC solution and incubated in the dark at 37°C for 20 minutes. The sections were then fixed in a 4% paraformaldehyde solution for 24 hours. The sections were removed, neatly arranged, and images were recorded. Normal brain tissue appears bright red, while infarcted brain tissue appears white. The infarct area and total area of ​​each slice were measured using Image J software. The infarct volume of each slice was calculated as: infarct area × slice thickness; the total infarct volume was the sum of the infarct volumes of each slice. The percentage of infarct volume was calculated as: infarct volume / total brain volume × 100%.

[0343] Furthermore, the results showed that compared with the sham operation group, the construction of the cerebral ischemia-reperfusion model induced neurological damage in rats; compared with the model group, treatment with compound 7 could reduce the neurological function score and reduce the cerebral infarction volume (P<0.01), indicating that compound 7 can effectively alleviate cerebral ischemia-reperfusion injury.

[0344] The compounds of the present invention, their preparation methods, and applications are described herein with reference to specific embodiments and examples, and many details are described and illustrated. However, it should be understood that the specific embodiments and examples provided herein are merely exemplary and do not limit the scope of the present invention. In fact, it will be apparent to those skilled in the art that the present invention may also be implemented in other specific ways, and that such modifications, variations, or adjustments do not depart from the spirit and purpose of the present invention and are therefore intended to be encompassed within the scope of the present invention.

Claims

1. A salvianolic acid C derivative, characterized in that: The salvianolic acid C derivative is selected from the following compounds:

2. The method for preparing the salvianolic acid C derivative according to claim 1, comprising: The compound represented by formula II is dissolved in dioxane and reacted with iodine chloride at 0°C to obtain the iodinated raw material compound represented by formula III; The iodine raw material compound represented by formula III and the benzyne raw material compound represented by formula IV undergo Sonogashira coupling reaction in the presence of a catalyst and further undergo cyclization in the presence of cuprous iodide to prepare the intermediate compound represented by formula V; The compound represented by the intermediate formula V undergoes a condensation reaction with malonic acid to prepare the compound represented by the intermediate formula VI; The carboxyl-containing intermediate compound represented by formula VI is dissolved in a solvent such as DMF or DCM, a condensing agent and an acid-binding agent are added, and the reaction is carried out for 30 minutes. Then, the compound represented by formula VII is added, and the mixture is stirred at room temperature for condensation to obtain a SAC derivative. Under a hydrogen atmosphere, the SAC derivative wherein R1 is a benzyloxy group is dissolved in a methanol solution, 10% Pd / C is added, and the mixture is stirred at room temperature for hydrogenation and debenzylation to obtain the salvianolic acid C derivative according to claim 1. The compound structural formula is as follows: in, X is O; Y is NH; R1 is benzyloxy; R2 is a methoxy group; R3 is hydrogen; R4 is a hydroxyl group; R5 is a hydroxyl group; R6 is methoxy.

3. The preparation method according to claim 2, wherein: The catalyst is selected from one or more of RuCl2(PPh3)3, RhCl(PPh3)3, PdCl2(PPh3)2, and NiCl2(PPh3)2; the condensing agent is selected from one or more of DCC, DCI, EDCI, HATU, HBTU, TBTU, PyBOP, EDC, and BOP; and the acid binding agent is selected from one or more of pyridine, triethylamine, diisopropylethylamine, DBU, sodium carbonate, potassium carbonate, cesium carbonate, sodium bis(trimethylsilyl)amide, sodium tert-butoxide, and potassium tert-butoxide.

4. The preparation method according to claim 3, wherein: The catalyst is RuCl2(PPh3)3, RhCl(PPh3)3 or PdCl2(PPh3)2; the condensation agent is DCC, EDCI, HBTU, TBTU or PyBOP; and the acid binding agent is pyridine, triethylamine, diisopropylethylamine, sodium carbonate, potassium carbonate or cesium carbonate.

5. The preparation method according to claim 4, characterized in that: The catalyst is PdCl2(PPh3)2; the condensation agent is EDCI, HBTU or PyBOP; and the acid binding agent is triethylamine or diisopropylethylamine.

6. A pharmaceutical composition comprising a pharmaceutically effective dose of the salvianolic acid C derivative or a pharmaceutically acceptable salt thereof according to claim 1, and a pharmaceutically acceptable carrier.

7. Use of the salvianolic acid C derivative and its pharmaceutically acceptable salt according to claim 1 in the preparation of a medicament for treating coronary heart disease, myocardial infarction, angina pectoris, myocarditis, arrhythmia, heart failure, rheumatic heart disease, infectious heart disease or anemic heart disease.

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