Parthenolide derivative as well as pharmaceutical composition, preparation method and application thereof

Abstract

The invention belongs to the technical field of medicines, and discloses parthenolide derivatives (general formula I), pharmaceutically acceptable salts thereof, a preparation method thereof, a pharmaceutical composition thereof and an application thereof, especially an application of the parthenolide derivatives in preparation of anti-tumor and immunotherapy medicines. # imgabs0 #

Description

Technical Field

[0001] The present invention belongs to the field of medical technology, and specifically relates to a new class of parthenolide derivatives and salts thereof, a pharmaceutical composition containing them, and use thereof in preparing anti-tumor and anti-inflammatory immune drugs. Background Art

[0002] Parthenolide (PTL) belongs to the geranyl lactone class of compounds and is commonly found in tansy, a plant of the Asteraceae family, and Magnoliaceae plant Micheliolide (MCL). Micheliolide (MCL) belongs to the guaiac class of compounds and is found in high concentrations in Magnoliaceae plants such as Coptidis chinensis and Taiwan Michelia. Micheliolide can be obtained by acid-catalyzed conversion of parthenolide. Both PTL and MCL exhibit broad anticancer activity and strong anti-inflammatory activity, with low toxicity and high safety, and therefore have broad research prospects. Studies have shown that PTL and MCL can exert anti-tumor effects by interfering with multiple inflammatory signaling pathways, including the NF-κB signaling pathway, the STAT3 signaling pathway, the JNK signaling pathway, and so on. From a structural analysis, both have a key α-methylene-γ-valerolactone structure, which can covalently bind to key proteins in the inflammatory pathway to regulate their physiological activity. Although PTL and MCL have strong anticancer activity and low toxicity, these compounds have low water solubility, poor plasma stability, low in vivo bioavailability, and their pharmacokinetic properties have greatly limited their clinical application. Therefore, how to improve the drug properties of these compounds while maintaining or even improving their pharmacological activity is the focus of current research. At present, a number of PTL and MCL-related derivatives have entered clinical evaluation or are on the market as anti-tumor drugs. LC-1 (DMAPT) is the fumarate salt of the dimethylamine addition product of PTL, and the compound is currently in the clinical research stage. ACT001 ( Figure 1 ) is the fumarate salt of the dimethylamine addition product of MCL. Currently, 6 Phase II clinical trials and 2 Phase I clinical trials in children are being conducted worldwide. Figure 1 ) can inhibit the activity of farnesyl transferase. It was registered and marketed in Kazakhstan as early as 1996 for the treatment of breast cancer, liver cancer, etc.

[0003] However, the water solubility of parthenolide is poor, and the plasma concentration of the drug in the body is too low after ingestion, which affects its pharmacological effects in vivo. The prodrug dimethylamine derivative LC-1 ( Figure 1), although the water solubility of the molecule is increased after salt formation, its in vivo antitumor activity still needs large-scale clinical verification. Yang et al. reported 11 ester derivatives of the oxidation product of parthenolide (melampomagnolide B, MMB) (Eur J Med Chem, 2017, 127, 296-304). Compared with the in vitro antitumor effects of PTL and MMB, some compounds showed better cell growth inhibition effects on tumor cell lines HL60 and KG1a, but there was no in vivo antitumor activity result data.

[0004] Bommagani et al. reported a series of ester derivatives of MMB and indolecarboxylic acid, benzofurancarboxylic acid and benzothiophenecarboxylic acid (Eur J Med Chem, 2017, 136, 393-405), and screened the tumor cell lines in NCI60. Compared with PTL cytotoxicity, the two ester derivatives had better cytotoxic effects (on leukemia cell line GI 50 0.05-0.40 μM), but there is no in vivo anti-tumor activity data.

[0005] Since parthenolide derivatives have good in vivo safety, with the in-depth study of their mechanism of action and targets, parthenolide is used as a lead anti-tumor or immunomodulatory drug. The present invention synthesizes a new class of parthenolide epoxy ring-opening dehydrate derivatives and conducts biological activity screening. Summary of the invention

[0006] The technical problem solved by the present invention is to use the oxidation product of parthenolide (melampomagnolide B, MMB, Figure 1 ) as raw materials and the corresponding organic acid for esterification to first obtain a series of MMB ester derivatives, the ester derivatives are epoxide-opened under the catalysis of p-toluenesulfonic acid, and finally the molecules are dehydrated and added with amines to obtain the compounds of the present invention, and pharmaceutically acceptable salts thereof, preparation methods, pharmaceutical compositions and uses thereof in the preparation of anti-tumor and anti-inflammatory immune drugs.

[0007] In order to solve the technical problem of the present invention, the present invention provides the following technical solutions:

[0008] The first aspect of the technical solution of the present invention is to provide the parthenolide derivatives and pharmaceutically acceptable salts thereof represented by the following general formula:

[0009]

[0010] in:

[0011] R1 is C 1-4 Alkyl, C 3-6 Cycloalkyl, halocycloalkyl, oxocycloalkyl, C 3-6 Heterocycloalkyl, Ar-SC1-2 Alkyl, Ar-OC 1-2 Alkyl, YNC 1-2 Alkyl, Ar, Ar-CH=CH-;

[0012] Y is phthalimide, tetrahydroisoquinolinyl;

[0013] R2 and R3 are combined to form =C, or

[0014] R2 is hydrogen and R3 is CH2N(CH3)2.

[0015] The C 1-4 The alkyl group is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl;

[0016] The Ar is selected from aryl selected from phenyl, furanyl, thienyl, pyrrolyl, isoxazolyl, thiazolyl, pyrimidinyl, pyridyl, pyrazinyl, naphthyl, chromonyl, quinolyl, isoquinolyl, anthraquinone;

[0017] The substituents on Ar are selected from halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, nitrile, methylmercapto, phenyl, methylenedioxolyl;

[0018] The C 1-4 Alkoxy means methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy;

[0019] The substituent of the substituted alkane or cycloalkane is selected from halogen, methyl, and carbonyl;

[0020] The positions of the benzene ring substituents are para, meta, or ortho, and the number of the substituents is mono-, di- or poly-substitution.

[0021] The most preferred parthenolide derivatives and pharmaceutically acceptable salts thereof are selected from the following compounds:

[0022]

[0023]

[0024]

[0025] The second aspect of the technical solution of the present invention is to provide a method for preparing the compounds described in the above table:

[0026]

[0027] Reaction step a: first, PTL is oxidized in an oxidant to generate MMB; reaction step b: MMB is esterified with an organic acid under the action of a coupling agent; reaction step c: MMB ester undergoes epoxy ring opening dehydration under the catalysis of Lewis acid to obtain a dehydrated compound; reaction step d: the compound of general formula (I) and a secondary amine are added to obtain the compound of general formula (I).

[0028] The most preferred reaction steps and reaction conditions are: (a) SeO2 / t-BuOOH / DCM; (b) R1COOH / EDCI / DMAP / DCM; (c) PTSA / DCM; (d) HNMe2 / DCM.

[0029] The pharmaceutically acceptable salts include inorganic or organic acid salts formed by the compound and an organic acid or an inorganic acid. The inorganic acid salts include hydrochlorides, hydrobromides, sulfates or bisulfates, nitrates, phosphates or biphosphates, etc.; the organic acid salts include formate, acetate, trifluoroacetate, benzoate, succinate, fumarate, maleate, lactate, citrate, tartrate, succinate, gluconate, methanesulfonate, benzenesulfonate, p-toluenesulfonate, etc.

[0030] The third aspect of the technical solution of the present invention is to provide a pharmaceutical composition, which comprises the parthenolide derivatives and pharmaceutically acceptable salts thereof described in the first aspect of the present invention and a pharmaceutically acceptable carrier or excipient.

[0031] The compounds of the present invention can be administered orally in the form of capsules, tablets, powders, granules, syrups or similar dosage forms, or parenterally by injection, ointment, suppository or similar dosage forms. These pharmaceutical preparations can be prepared by ordinary methods using adjuvants well known in the art, such as adhesives, excipients, stabilizers, disintegrants, flavoring agents, lubricants, etc. Although the dosage varies with the symptoms and age of the patient, the nature and severity of the disease or disorder and the route and mode of administration, for adult patients, the compounds of the present invention are normally administered in a total daily dose of 1 to 1000 mg, preferably 5 to 500 mg, as a single dose, or in divided doses; for example, twice or three times a day; for intravenous injection, 0.1 to 100 mg, preferably 0.5 to 50 mg, can be administered once or three times a day.

[0032] The present invention also provides a pharmaceutical composition comprising the above-mentioned parthenolide derivative of formula (I), characterized in that the pharmaceutical composition comprises the parthenolide derivative and a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4 and a pharmaceutically acceptable carrier or excipient.

[0033] When the compound of the present invention is used as a medicine, it can be used directly or in the form of a pharmaceutical composition. The pharmaceutical composition contains 0.1%-99%, preferably 0.5%-90% of the compound of the present invention, and the rest is a pharmaceutically acceptable, non-toxic and inert pharmaceutical carrier and / or excipient to humans and animals or is used in combination with other anticancer drugs. The pharmaceutical composition of the present invention can be prepared into injections, tablets, capsules, pills, powders, etc.

[0034] The pharmaceutical composition of the present invention can be in the form of a controlled-release dosage form, a sustained-release dosage form, or various microparticle delivery systems.

[0035] The fourth aspect of the technical solution of the present invention provides the use of the parthenolide derivative of formula (I) and its pharmaceutically acceptable salt described in the first aspect or the pharmaceutical composition described in the third aspect in the preparation of a drug for preventing or treating tumors or inflammatory immune diseases, wherein the tumor is preferably non-small cell lung cancer, colon cancer, gastric cancer, leukemia, lymphoma, glioma, liver cancer, etc., but not limited to the above tumors. The inflammatory immune disease is preferably selected from rheumatoid arthritis, diabetic nephropathy, organ fibrosis, psoriasis, neuromyelitis optica, but not limited to the above immune diseases.

[0036] Beneficial technical effects

[0037] The present invention focuses on providing a parthenolide derivative having a general formula (I), wherein a hydroxyl group is introduced into the 14-carbon of parthenolide, and the hydroxyl group is esterified to obtain an ester derivative, and the MMB ester is subjected to the action of Lewis acid to obtain a ring-opening dehydration product, and the unsaturated double bond of the lactone ring of the product and a secondary amine are added to form an amine. Preliminary activity screening shows that the anti-tumor activity of some of these derivatives is higher than that of parthenolide, suggesting that these derivatives have good anti-tumor prospects. BRIEF DESCRIPTION OF THE DRAWINGS

[0038] Figure 1 The structural formula of PTL and related derivatives DETAILED DESCRIPTION

[0039] English name and abbreviation:

[0040] DCM: dichloromethane

[0041] DMA: dimethylamine

[0042] DMAP: 4-dimethylaminopyridine

[0043] EA: Ethyl acetate

[0044] IC 50 : Half inhibitory concentration

[0045] 5-FU: 5-fluorouracil

[0046] TBHP: tert-butyl peroxide

[0047] EDCI: 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride

[0048] PTL: Parthenolide

[0049] MCL: Michelolide

[0050] MMB: melampomagnolide B

[0051] PTSA: p-Toluenesulfonic acid

[0052] The present invention discloses a new class of parthenolide derivatives, including their salts, solvates, prodrugs and pharmaceutical compositions. Those skilled in the art can refer to the content of this article and appropriately improve the process parameters to achieve the desired effect. It should be noted that all similar substitutions and modifications are obvious to those skilled in the art, and they are all considered to be included in the present invention. The methods and applications of the present invention have been described through preferred embodiments, and relevant personnel can obviously modify or appropriately change and combine the methods and applications described herein without departing from the content, spirit and scope of the present invention to implement and apply the technology of the present invention.

[0053] The present invention will be further described below in conjunction with embodiments:

[0054] General synthesis method of compounds:

[0055] The reaction formula is as follows:

[0056]

[0057] Reagents and conditions: (a) SeO2 / t-BuOOH / DCM; (b) R1COOH / EDCI / DMAP / DCM; (c) PTSA / DCM; (d) HNMe2 / DCM.

[0058] Synthesis of intermediate MMB

[0059]

[0060] To a 200mL round-bottom flask, add parthenolide (5mmol), selenium dioxide (2mmol), 70% TBHP (10mmol) and 70mL of dichloromethane in sequence. Set the oil bath temperature to 45°C and stir for 4h. After the reaction is completed, the reaction solution is filtered through diatomaceous earth, the filtrate is concentrated to dryness by rotary evaporator, and flash column chromatography is used for purification (mobile phase is petroleum ether-ethyl acetate) to obtain 620mg of light pink solid MMB, with a yield of 46.9%. 1H NMR (400MHz, CDCl3): δ6.24 (d, J = 3.6 Hz, 1H, = CH), 5.65 (d, J = 8.0 Hz, 1H, = CH), 5. 55(d,J=3.2Hz,1H,=CH),4.16(s,1H,=CCH),4.10(d,J=0.7Hz,=CCH),3.86(t,J= 9.4Hz,COO-CH),2.86(d,J=9.4Hz,2H,=CCH,HCO-),2.57-2.07(m,6H,-CH2-),1. 76-1.62(m,1H,-CH-),1.55(s,3H,-CH3),1.21-1.04(m,1H,-CH-).HRMS(ESI)m / z calcd.for C 15 H 21 O4[M+H + ]265.1434, found 265.1426.

[0061] General synthesis method of compounds:

[0062] 1) Synthesis of MMB ester

[0063] R1COOH (1mmol), EDCI (3mmol), DMAP (0.3mmol), MMB (1mmol) and DCM 5mL were added to the reaction bottle and stirred at room temperature until TLC showed that the reaction was complete. The reaction solution was diluted with 20mL DCM, and then 20mL distilled water was added and stirred for 10 minutes, and the dichloromethane phase was separated. The organic phase was first washed with a saturated sodium bicarbonate solution and then with a saturated saline solution, dried over anhydrous sodium sulfate overnight, concentrated, and the residue was separated by column chromatography (eluent: ethyl acetate-petroleum ether) to obtain solid MMB carboxylate.

[0064] 2) Synthesis of ring-opening dehydrated compounds

[0065] MMB ester (1 mmol) was dissolved in 10 mL of dichloromethane, p-toluenesulfonic acid monohydrate (2 mmol) was added, and the mixture was stirred under reflux at 45 ° C for 4 h. The reaction was complete when monitored by TLC. The reaction solution was diluted with 20 mL of dichloromethane, washed once with a saturated aqueous NaHCO3 solution (20 mL), washed three times with a saturated aqueous NaCl solution (20 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated and subjected to rapid silica gel column chromatography (eluent: DCM-EA) to obtain the ring-opened dehydrated compound.

[0066] 3) Synthesis of compounds of formula I

[0067] The above compound (1 mmol) was dissolved in 5 mL DCM, dimethylamine tetrahydrofuran solution (3 mmol) was added, and the mixture was stirred at room temperature for 5 hours. The product was concentrated to remove excess dimethylamine, and column chromatography was performed to obtain the compound of formula I.

[0068] Example 1 Synthesis of M73

[0069] 1) 5-nitrofuran-2-carboxylate of MMB

[0070]

[0071] 5-Nitrofuran-2-carboxylic acid (157 mg, 1 mmol), EDCI (575 mg, 3 mmol), DMAP (37 mg, 0.3 mmol), MMB (264 mg, 1 mmol) and 5 mL of DCM were added to the reaction flask and stirred at room temperature until TLC showed that the reaction was complete. The reaction solution was diluted with 20 mL of DCM, and then 20 mL of distilled water was added and stirred for 10 minutes, and the dichloromethane phase was separated. The organic phase was first washed with a saturated sodium bicarbonate solution and then with a saturated saline solution, dried over anhydrous sodium sulfate overnight, concentrated, and the residue was separated by column chromatography (eluent: ethyl acetate-petroleum ether) to obtain 327 mg of a white solid with a yield of 81%. 1 H NMR (400MHz, CDCl3) δ7.38–7.33(m,1H,Ar-H),7.31(d,J=3.7Hz,1H,Ar-H),6.25(d,J=3.5Hz,1H ,=CH),5.83(d,J=8.0Hz,1H,=CH),5.56(d,J=3.1Hz,1H,=CH),4.96(d,J=12.2Hz,1H,=CCH),4.7 5(d,J=12.3Hz,1H,=CCH),3.87(t,J=9.3Hz,1H,COO-CH),2.86(d,J=9.4Hz,2H,=CCH,HCO-),2.5 8–2.15(m,6H,-CH2-),1.74(dd,J=16.8,9.8Hz,1H,-CH-),1.56(s,3H,-CH3),1.14(s,1H,-CH-). 13 C NMR (126MHz, CDCl3) δ169.67,169.40,156.97,144.53,139.71,139.01,127.78,120.70,120.43 ,119.52,81.07,68.38,63.46,60.13,42.86,36.67,25.82,24.47,23.87,18.20.HRMS(ESI)m / zC 20 H22 O8N[M+H] + Theoretical value: 404.1340, measured value: 404.1333.

[0072] 2)M73 synthesis

[0073]

[0074] The 5-nitrofuran-2-carboxylate of MMB (403 mg, 1 mmol) was dissolved in 10 mL of dichloromethane, and p-toluenesulfonic acid monohydrate (380 mg, 2 mmol) was added. The mixture was stirred and refluxed at 45°C for 4 h. The reaction was complete after monitoring by TLC. The reaction solution was diluted with 20 mL of dichloromethane, washed once with a saturated aqueous NaHCO3 solution (20 mL), and washed three times with a saturated aqueous NaCl solution (20 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated and purified by rapid silica gel column chromatography (eluent: DCM-EA) to obtain 375 mg of a white solid with a yield of 93%. 1 H NMR (400MHz, CDCl3) δ7.35(d,J=3.8Hz,1H),7.31(d,J=3.8Hz,1H),6.30(s,1H),5.79(t,J=6.8Hz,1H),5.66(s,1H),5.54(t,J=8.7Hz,1H),4.79(d,J =4.6Hz,2H),4.49(d,J=6.5Hz,1H),4.38(t,J=6.0Hz,1H),3.04–2.75(m,4 H),2.23–2.13(m,1H),2.03–1.92(m,1H),1.82(s,3H),1.77–1.63(m,1H). 13 C NMR (101MHz, CDCl3) δ169.44,156.91,144.66,139.23,135.31,132.07,130.17,125.11,123.14,1 19.26,111.62,84.68,74.43,70.69,40.25,32.17,28.60,24.44,20.52,14.22.ESI-MS:404[M+H] +

[0075] Example 2 Synthesis of M74

[0076] 1) MMB anthraquinone-2-carboxylate

[0077]

[0078] Anthraquinone-2-carboxylic acid (252 mg, 1 mmol), EDCI (575 mg, 3 mmol), DMAP (37 mg, 0.3 mmol), MMB (264 mg, 1 mmol) and 5 mL of DCM were added to the reaction flask and stirred at room temperature until TLC showed that the reaction was complete. The reaction solution was diluted with 20 mL of DCM, and then 20 mL of distilled water was added and stirred for 10 minutes, and the dichloromethane phase was separated. The organic phase was first washed with a saturated sodium bicarbonate solution and then with a saturated saline solution, dried over anhydrous sodium sulfate overnight, concentrated, and the residue was separated by column chromatography (eluent: ethyl acetate-petroleum ether) to obtain 209 mg of light green solid, with a yield of 42%. 1 H NMR (400MHz, CDCl3) δ8.91 (d, J=0.8Hz, 1H, Ar-H), 8.43–8.37 (m, 2H, Ar-H), 8.33 (ddd, J=6.2, 5.0, 3.3Hz, 2H, A r-H),7.86–7.80(m,2H,Ar-H),6.24(d,J=3.5Hz,1H,=CH),5.83(t,J=8.3Hz,1H,=CH),5.56(d,J=3.2Hz,1H,=C H),4.99(d,J=12.4Hz,1H,=CH),4.77(d,J=12.4Hz,1H,=CCH),3.86(t,J=9.3Hz,1H,COO-CH),2.88(t,J=7.2Hz ,2H,=CCH,HCO-),2.55–2.14(m,6H,-CH2-),1.77–1.68(m,1H,-CH-),1.55(s,3H,-CH3),1.14(s,1H,-CH-).13C NMR (126MHz, CDCl3) δ182.69,182.52,169.48,165.00,138.69,136.50,134.99,134.85,134.83,134.79,134.68,133.81,133.57,133 .55,131.86,128.80,127.95,127.71,120.83,81.15,67.97,63.53,60.20,42.89,36.76,25.88,24.46,24.13,18.23.HRMS(ESI)m / zC 30 H 27 O7[M+H] + Theoretical value: 499.1751, measured value: 499.1751.

[0079] 2) Synthesis of M74

[0080]

[0081] Anthraquinone-2-carboxylate of MMB (499 mg, 1 mmol) was dissolved in 10 mL of dichloromethane, p-toluenesulfonic acid monohydrate (380 mg, 2 mmol) was added, and the mixture was stirred under reflux at 45°C for 4 h. The reaction was complete after monitoring by TLC. The reaction solution was diluted with 20 mL of dichloromethane, washed once with a saturated aqueous NaHCO3 solution (20 mL), washed three times with a saturated aqueous NaCl solution (20 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated and subjected to rapid silica gel column chromatography (eluent: DCM-EA) to obtain 174 mg of a light yellow solid with a yield of 35%. 1 H NMR (400MHz, CDCl3) δ8.93 (s, 1H), 8.44 (d, J = 8.0Hz, 2H), 8.40 (d, J = 8.0Hz, 1H), 8.3 6-8.31(m,2H),7.86-7.84(m,2H),6.28(d,J=2.9Hz,1H),5.81(t,J=6.7Hz,1H),5.6 7-5.53(m,2H),4.84(s,2H),4.51(d,J=6.5Hz,1H),4.41(t,J=5.8Hz,1H),3.10-2.7 1(m,4H),2.26-2.18(m,2H),1.98(t,J=13.6Hz,1H),1.83(s,3H),1.80-1.68(m,2H). 13 C NMR (101MHz, CDCl3) δ182.51,182.32,169.42,164.90,139.25,136.26,135.14,135.03,134.61,134.58,134.54,133.64,133.41,133.35,1 32.66,129.18,128.54,127.72,127.50,127.49,125.33,123.01,84.5 9,74.59,69.82,40.34,32.08,28.57,24.28,20.46.ESI-MS:499[M+H] +

[0082] Example 3 Synthesis of M106

[0083] 1) MMB quinoline-6-carboxylate

[0084]

[0085] Quinoline-6-carboxylic acid (173 mg, 1 mmol), EDCI (575 mg, 3 mmol), DMAP (37 mg, 0.3 mmol), MMB (264 mg, 1 mmol) and 5 mL of DCM were added to the reaction flask and stirred at room temperature until TLC showed that the reaction was complete. The reaction solution was diluted with 20 mL of DCM, and then 20 mL of distilled water was added and stirred for 10 minutes, and the dichloromethane phase was separated. The organic phase was first washed with a saturated sodium bicarbonate solution and then with a saturated saline solution, dried over anhydrous sodium sulfate overnight, concentrated, and the residue was separated by column chromatography (eluent: ethyl acetate-petroleum ether) to obtain 327 mg of a white solid with a yield of 78%. 1 H NMR (400MHz, CDCl3) δ9.00(s,1H),8.55(s,1H),8.27(d,J=8.0Hz,1H),8.15(d,J=8.8Hz, 1H),7.49(dd,J=8.4,4.1Hz,1H),6.21(d,J=3.4Hz,1H),5.81(t,J=8.6Hz,1H),5.53(d,J =3.4Hz,1H),4.97(d,J=12.5Hz,1H),4.77(d,J=12.5Hz,1H),3.87(t,J=9.3Hz,2H),3.16 –2.86(m,2H),2.58–2.08(m,6H),1.76–1.66(m,1H),1.55(s,3H),1.12(t,J=13.1Hz,1H). 13 C NMR (101MHz, CDCl3) δ169.62,165.94,152.61,149.94,139.56,137.73,135.44,132.90,131.14,129.86,129.11,128 .95,128.19,127.57,125.32,122.84,122.13,84.81,74.51,69.51,40.52,32.00,28.57,24.53,20.72.HRMS(ESI)m / z C 25 H 26 NO5[M+H] + Theoretical value: 420.1806, measured value: 420.1819.

[0086] 2)M106 synthesis

[0087]

[0088] MMB quinoline-6-carboxylate (420 mg, 1 mmol) was dissolved in 10 mL of dichloromethane, p-toluenesulfonic acid monohydrate (380 mg, 2 mmol) was added, and the mixture was stirred at reflux at 45°C for 4 h. The reaction was complete after monitoring by TLC. The reaction solution was diluted with 20 mL of dichloromethane, washed once with a saturated aqueous NaHCO3 solution (20 mL), washed three times with a saturated aqueous NaCl solution (20 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated and subjected to rapid silica gel column chromatography (eluent: DCM-EA) to obtain 201 mg of a white solid with a yield of 48%. 1 H NMR(400MHz, CDCl3)δ9.02(s,1H),8.57(s,1H),8.31–8.24(m,2H),8.17(d,J= 8.8Hz,1H),7.53–7.45(m,1H),6.24(s,1H),5.80(t,J=7.0Hz,1H),5.58–5.53 (m,2H),4.83(s,2H),4.51(d,J=6.2Hz,1H),4.46(d,J=5.6Hz,1H),3.02–2.78 (m,4H),2.33–2.14(m,2H),2.05–1.93(m,1H),1.82(s,3H),1.79–1.68(m,1H). 13 C NMR (101MHz, CDCl3) δ169.62,165.94,152.61,149.94,139.56,137.73,135.44,132.90,131.14,129.86,129.11,128 .95,128.19,127.57,125.32,122.84,122.13,84.81,74.51,69.51,40.52,32.00,28.57,24.53,20.72.HRMS(ESI)m / z C 25 H 26 NO5[M+H] + Theoretical value: 420.1806, measured value: 420.1812.

[0089] Example 4 Synthesis of M75

[0090] 1) MMB chromone-2-carboxylate

[0091]

[0092] Chromone-2-carboxylic acid (190 mg, 1 mmol), EDCI (575 mg, 3 mmol), DMAP (37 mg, 0.3 mmol), MMB (264 mg, 1 mmol) and 5 mL of DCM were added to the reaction flask and stirred at room temperature until TLC showed that the reaction was complete. The reaction solution was diluted with 20 mL of DCM, and then 20 mL of distilled water was added and stirred for 10 minutes, and the dichloromethane phase was separated. The organic phase was first washed with a saturated sodium bicarbonate solution and then with a saturated saline solution, dried over anhydrous sodium sulfate overnight, concentrated, and the residue was separated by column chromatography (eluent: ethyl acetate-petroleum ether) to obtain 92 mg of a light yellow solid with a yield of 21.7%. 1 H NMR (400MHz, CDCl3) δ8.19(d,J=8.0Hz,1H),7.76(t,J=8.0Hz,1H),7.58(d,J=8.0Hz,1H),7 .47(t,J=8.0Hz,1H),7.12(s,1H),6.24(d,J=3.4Hz,1H),5.85(t,J=8.6Hz,1H),5.56(d,J= 3.4Hz,1H),4.95(d,J=12.2Hz,1H),4.81(d,J=12.2Hz,1H),3.88(t,J=9.3Hz,1H),3.01-2. 81(m,2H),2.60-2.14(m,6H),1.76(t,J=13.0Hz,1H),1.57(s,3H),1.15(t,J=13.0Hz,1H). 13 C NMR (126MHz, CDCl3) δ178.49,169.39,160.54,156.10,151.86,138.69,135.20,133.96,126.34,125.97,12 4.56,120.76,118.97,81.05,69.04,63.46,60.16,42.88,36.66,25.78,24.47,24.12,18.21.HRMS(ESI)m / z C 25 H 25 O7[M+H] + Theoretical value: 437.1578, measured value: 437.1595.

[0093] 2)M75 synthesis

[0094]

[0095] The chromone-2-carboxylate of MMB (436 mg, 1 mmol) was dissolved in 10 mL of dichloromethane, and p-toluenesulfonic acid monohydrate (380 mg, 2 mmol) was added. The mixture was stirred and refluxed at 45°C for 4 h. The reaction was complete after monitoring by TLC. The reaction solution was diluted with 20 mL of dichloromethane, washed once with a saturated aqueous NaHCO3 solution (20 mL), and washed three times with a saturated aqueous NaCl solution (20 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated and subjected to rapid silica gel column chromatography (eluent: DCM-EA) to obtain 161 mg of a white solid with a yield of 37%. 1 H NMR (400MHz, CDCl3) δ8.20(d,J=8.0Hz,1H),7.75(t,J=8.0Hz,1H),7.58(d,J=8.0Hz,1H),7.47( t,J=8.0Hz,1H),7.12(s,1H),6.28(d,J=2.9Hz,1H),5.81(t,J=6.9Hz,1H),5.62(d,J=2.9Hz,1H ),5.56(t,J=8.6Hz,1H),4.83(s,2H),4.50(d,J=6.3Hz,1H),4.40(t,J=5.8Hz,1H),3.04-2.76( m,4H),2.76-2.40(m,1H),2.27-2.18(m,1H),2.03-1.91(m,1H),1.83(s,3H),1.77-1.67(m,1H). 13 C NMR (101MHz, CDCl3) δ178.41,169.44,160.56,156.08,152.05,139.43,135.56,135.03,132.01,130.16,126.22,125.9 7,125.16,124.58,123.01,118.86,115.18,84.72,74.51,70.95,40.47,32.04,28.63,24.38,20.60.ESI-MS:437[M+H] + .

[0096] Example 5 Synthesis of M97

[0097] 1) MMB 5-methylisoxazole-4-carboxylate

[0098]

[0099] 5-Methylisoxazole-4-carboxylic acid (127 mg, 1 mmol), EDCI (575 mg, 3 mmol), DMAP (37 mg, 0.3 mmol), MMB (264 mg, 1 mmol) and 5 mL of DCM were added to the reaction bottle and stirred at room temperature until TLC showed that the reaction was complete. The reaction solution was diluted with 20 mL of DCM, and then 20 mL of distilled water was added and stirred for 10 minutes, and the dichloromethane phase was separated. The organic phase was first washed with a saturated sodium bicarbonate solution and then with a saturated saline solution, dried over anhydrous sodium sulfate overnight, concentrated, and the residue was separated by column chromatography (eluent: ethyl acetate-petroleum ether) to obtain 134 mg of a white solid with a yield of 36%. 1 H NMR (400MHz, CDCl3) δ8.45(s,1H),6.25(d,J=3.5Hz,1H),5.73(t,J=8.5Hz,1H),5.55(d,J=3.5Hz,1H),4.83(d,J=12.5Hz,1H),4.66(d, J=12.5Hz,1H),3.86(t,J=9.3Hz,1H),2.97-2.75(m,2H),2.70(s,3H),2.60-2.07(m,6H),1.71(m,1H),1.55(s,3H),1.16-1.01(m,1H). 13 CNMR (101MHz, CDCl3) δ174.78,169.33,161.39,150.08,138.68,134.60,130.91,120.55,109.31 ,81.05,66.60,63.37,60.02,42.69,36.69,25.68,24.23,23.95,18.09,12.76.ESI-MS:374[M+H] + .

[0100] 2)M97 synthesis

[0101]

[0102] The 5-methylisoxazole-4-carboxylate of MMB (373 mg, 1 mmol) was dissolved in 10 mL of dichloromethane, and p-toluenesulfonic acid monohydrate (380 mg, 2 mmol) was added. The mixture was stirred and refluxed at 45°C for 4 h. The reaction was complete after monitoring by TLC. The reaction solution was diluted with 20 mL of dichloromethane, washed once with a saturated aqueous NaHCO3 solution (20 mL), and washed three times with a saturated aqueous NaCl solution (20 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated and subjected to rapid silica gel column chromatography (eluent: DCM-EA) to obtain 272 mg of a white solid with a yield of 73%. 1H NMR (400MHz, CDCl3) δ8.46(s,1H),6.27(d,J=2.9Hz,1H),5.71(t,J=7.0Hz,1H),5.59–5.48(m,2H),4.69(s,2H),4.49(d,J=6.2Hz,1H),4.38(t ,J=5.8Hz,1H),2.98–2.83(m,3H),2.82–2.72(m,1H),2.70(s,3H),2.2 6–2.12(m,2H),1.91(t,J=13.6Hz,1H),1.81(s,3H),1.73–1.62(m,1H). 13 C NMR (101MHz, CDCl3) δ174.65,169.58,161.48,150.09,139.47,135.41,132.68,128.81,125.23, 122.81,109.44,84.78,74.43,68.37,40.42,31.83,28.48,24.11,20.63,12.70.HRMS(ESI)m / zC 20 H 24 NO6[M+H] + Theoretical value: 374.1598, measured value: 374.1599.

[0103] Example 6 Synthesis of M77

[0104] 1) N-phthalimidoacetate of MMB

[0105]

[0106] N-phthalimidoacetic acid (205 mg, 1 mmol), EDCI (575 mg, 3 mmol), DMAP (37 mg, 0.3 mmol), MMB (264 mg, 1 mmol) and 5 mL of DCM were added to the reaction flask and stirred at room temperature until TLC showed that the reaction was complete. The reaction solution was diluted with 20 mL of DCM, and then 20 mL of distilled water was added and stirred for 10 minutes. The dichloromethane phase was separated, and the organic phase was first washed with a saturated sodium bicarbonate solution and then with a saturated saline solution, dried over anhydrous sodium sulfate overnight, concentrated, and the residue was separated by column chromatography (eluent: ethyl acetate-petroleum ether) to obtain 181 mg of a white solid with a yield of 40%. 1H NMR (400MHz, CDCl3) δ8.29–8.04(m,1H,Ar-H),7.83(dd,J=7.1,1.8Hz,1H,Ar-H),7.78–7.63(m,2H,A r-H),6.23(d,J=3.4Hz,1H,=CH),5.86(t,J=8.4Hz,1H,=CH),5.57(d,J=3.1Hz,1H,=CH),5.09–4.63(m ,2H,=CCH),3.87(t,J=9.3Hz,1H,COO-CH),2.88(t,J=10.1Hz,2H,=CCH,HCO-),2.96–2.15(m,8H,N-C H2-,-CH2-),1.73(dd,J=10.9,8.7Hz,1H,-CH-),1.56(s,3H,-CH3),1.14(t,J=13.3Hz,1H,-CH-).13C NMR (126MHz, CDCl3) δ169.29,163.86,138.45,134.91,134.35,132.96,132.66,132.26,131.42 ,120.62,80.93,68.44,63.32,59.98,42.77,36.54,25.56,24.29,23.88,17.99.HRMS(ESI)m / z C 25 H 26 O7N[M+H] + Theoretical value: 452.1704, measured value: 452.1673.

[0107] 2)M77 synthesis

[0108]

[0109] The N-phthalimidoacetate of MMB (451 mg, 1 mmol) was dissolved in 10 mL of dichloromethane, and p-toluenesulfonic acid monohydrate (380 mg, 2 mmol) was added. The mixture was stirred and refluxed at 45°C for 4 h. The reaction was complete after monitoring by TLC. The reaction solution was diluted with 20 mL of dichloromethane, washed once with a saturated aqueous NaHCO3 solution (20 mL), and washed three times with a saturated aqueous NaCl solution (20 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated and purified by rapid silica gel column chromatography (eluent: DCM-EA) to obtain 207 mg of a white solid with a yield of 46%. 1H NMR (400MHz, CDCl3) δ7.93–7.85(m,2H),7.81–7.73(m,2H),6.26(s,1H),5. 68(t,J=6.9Hz,1H),5.59(s,1H),5.52(t,J=8.7Hz,1H),4.60(s,2H),4.49–4 .43(m,3H),4.35(t,J=5.8Hz,1H),2.95–2.80(m,3H),2.73(t,J=13.8Hz,1H) ,2.16–2.08(m,1H),1.87(t,J=13.8Hz,1H),1.81(s,3H),1.68–1.57(m,1H). 13 C NMR (101MHz, CDCl3) δ169.46,167.49,167.20,139.28,135.21,134.41,132.34,131.99,129.26,125. 24,123.74,122.91,84.61,74.40,69.87,40.36,38.97,31.82,28.47,24.08,20.46.ESI-MS:452[M+H] + .

[0110] Example 7 Synthesis of M91

[0111] 1) 4-Chlorophenoxyacetic acid ester of MMB

[0112]

[0113] 4-Chlorophenoxyacetic acid (187 mg, 1 mmol), EDCI (575 mg, 3 mmol), DMAP (37 mg, 0.3 mmol), MMB (264 mg, 1 mmol) and 5 mL of DCM were added to the reaction flask and stirred at room temperature until TLC showed that the reaction was complete. The reaction solution was diluted with 20 mL of DCM, and then 20 mL of distilled water was added and stirred for 10 minutes. The dichloromethane phase was separated, and the organic phase was first washed with a saturated sodium bicarbonate solution and then with a saturated saline solution, dried over anhydrous sodium sulfate overnight, concentrated, and the residue was separated by column chromatography (eluent: ethyl acetate-petroleum ether) to obtain 221 mg of a white solid with a yield of 51%. 1H NMR (500MHz, CDCl3) δ7.26(d,J=8.0Hz,2H),6.83(d,J=8.0Hz,2H,Ar-H),6.25(s,1H),5.68(d,J=7.4Hz,1H),5.51(s,1H),4.77(d,J=12.2Hz,1 H),4.65-4.53(m,3H),3.83(t,J=9.0Hz,1H),2.79(d,J=9.1Hz,2H),2.35-2.21(m,6H),1.63(s,1H),1.54(s,3H,-CH3),1.09(t,J=12.7Hz,1H). 13 C NMR (126MHz, CDCl3) δ169.44,168.64,156.42,138.76,134.39,132.03,129.73,127.08,120.58,11 6.06,81.06,67.67,65.64,63.40,60.10,42.80,36.67,25.67,24.41,24.02,18.16.HRMS(ESI)m / z C 23 H 26 O6Cl[M+H] + Theoretical value: 433.1412, measured value: 433.1406.

[0114] 2)M91 synthesis

[0115]

[0116] The 4-chlorophenoxyacetic acid ester of MMB (433 mg, 1 mmol) was dissolved in 10 mL of dichloromethane, and p-toluenesulfonic acid monohydrate (380 mg, 2 mmol) was added. The mixture was stirred and refluxed at 45°C for 4 h. The reaction was complete after monitoring by TLC. The reaction solution was diluted with 20 mL of dichloromethane, washed once with a saturated aqueous NaHCO3 solution (20 mL), and washed three times with a saturated aqueous NaCl solution (20 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated and subjected to rapid silica gel column chromatography (eluent: DCM-EA) to obtain 277 mg of a white solid with a yield of 64%. 1H NMR (400MHz, CDCl3) δ7.25(d,J=8.3Hz,2H),6.82(d,J=8.3Hz,2H),6.27(d,J=2.4Hz ,1H),5.66(t,J=6.9Hz,1H),5.58(d,J=2.4Hz,1H),5.51(t,J=8.8Hz,1H),4.62(s,4 H),4.47(d,J=6.3Hz,1H),4.35(t,J=5.8Hz,1H),2.93–2.79(m,3H),2.70(t,J=13.2 Hz,1H),2.13–2.04(m,1H),1.87(t,J=13.2Hz,1H),1.81(s,3H),1.67–1.54(m,1H). 13 C NMR (101MHz, CDCl3) δ169.44,168.56,156.36,139.35,135.34,132.33,129.57,129.34,126.93,125 .13,122.86,115.99,84.64,74.34,69.53,65.68,40.33,31.77,28.44,24.20,20.43.HRMS(ESI)m / z C 23 H 26 O6[M+H] + Theoretical value: 433.1424, measured value: 433.1432.

[0117] Example 8 Synthesis of M124

[0118] 1) MMB 2-(4-chlorophenoxy)-2-methylpropionate

[0119]

[0120] 2-(4-Chlorophenoxy)-2-methylpropanoic acid (229 mg, 1 mmol), EDCI (575 mg, 3 mmol), DMAP (37 mg, 0.3 mmol), MMB (264 mg, 1 mmol) and 5 mL of DCM were added to the reaction bottle and stirred at room temperature until TLC showed that the reaction was complete. The reaction solution was diluted with 20 mL of DCM, and then 20 mL of distilled water was added and stirred for 10 minutes, and the dichloromethane phase was separated. The organic phase was first washed with a saturated sodium bicarbonate solution and then with a saturated saline solution, dried over anhydrous sodium sulfate overnight, concentrated, and the residue was separated by column chromatography (eluent: ethyl acetate-petroleum ether) to obtain 138 mg of a white solid, with a yield of 30%. 1H NMR (400MHz, CDCl3) δ7.19(d,J=8.9Hz,2H),6.74(d,J=8.9Hz,2H),6.24(d,J=3.5H z,1H),5.61(d,J=7.8Hz,1H),5.47(d,J=3.5Hz,1H),4.70(d,J=12.1Hz,1H),4.49( d,J=12.1Hz,1H),3.79(t,J=9.3Hz,1H),2.84-2.76(m,1H),2.66(d,J=9.4Hz,1H), 2.39-2.02(m,6H),1.66-1.60(m,4H),1.58(s,3H),1.50(s,3H),1.06-0.93(m,1H). 13 C NMR (101MHz, CDCl3) δ173.90,169.41,154.22,138.83,134.52,132.04,129.34,127.22,120.36,119.84,80 .95,79.53,67.81,63.23,59.95,42.75,36.60,26.12,25.58,24.84,24.48,23.92,18.06.ESI-MS:461[M+H] + ; HRMS (ESI) m / z C 25 H 30 ClO6[M+H] + Theoretical value: 461.1725, measured value: 461.1725.

[0121] 2)M124 synthesis

[0122]

[0123] MMB 2-(4-chlorophenoxy)-2-methylpropanoate (461 mg, 1 mmol) was dissolved in 10 mL of dichloromethane, p-toluenesulfonic acid monohydrate (380 mg, 2 mmol) was added, and the mixture was stirred at reflux at 45°C for 4 h. The reaction was complete after monitoring by TLC. The reaction solution was diluted with 20 mL of dichloromethane, washed once with a saturated aqueous NaHCO3 solution (20 mL), and washed three times with a saturated aqueous NaCl solution (20 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated and purified by rapid silica gel column chromatography (eluent: DCM-EA) to obtain 203 mg of a white solid with a yield of 44%. 1H NMR (400MHz, CDCl3) δ7.17(d,J=8.5Hz,2H),6.73(d,J=8.5Hz,2H),6.25(d,J=3.0 Hz,1H),5.64–5.55(m,2H),5.47(t,J=8.6Hz,1H),4.54(q,J=12.1Hz,2H),4.45(d, J=6.1Hz,1H),4.31(t,J=5.7Hz,1H),2.96–2.73(m,3H),2.58(t,J=13.4Hz,1H),2 .45–2.11(m,1H),1.98–1.89(m,1H),1.78(s,3H),1.58(s,6H),1.53–1.42(m,1H). 13 CNMR(101MHz, CDCl3)δ174.04,169.58,154.15,139.45,135.51,132.49,129.51,129.29,127.21,125.0 5,122.95,120.01,84.61,79.54,74.32,70.33,40.47,31.67,28.49,25.75,25.09,24.46.HRMS(ESI)m / z C 25 H 30 ClO6[M+H] + Theoretical value: 461.1725, measured value: 461.1725.

[0124] Example 9 Synthesis of M76

[0125] 1) p-Fluorophenylthioacetate of MMB

[0126]

[0127] Add p-fluorophenylthioacetic acid (186 mg, 1 mmol), EDCI (575 mg, 3 mmol), DMAP (37 mg, 0.3 mmol), MMB (264 mg, 1 mmol) and 5 mL of DCM to the reaction flask and stir at room temperature until TLC shows that the reaction is complete. After the reaction solution is diluted with 20 mL of DCM, 20 mL of distilled water is added and stirred for 10 minutes, the dichloromethane phase is separated, the organic phase is first washed with a saturated sodium bicarbonate solution, then with a saturated saline solution, dried over anhydrous sodium sulfate overnight, concentrated, and the residue is separated by column chromatography (eluent: ethyl acetate-petroleum ether) to obtain 242 mg of a white solid with a yield of 56%. 1H NMR (400MHz, DMSO-d6) δ7.55–7.37(m,2H,Ar-H),7.19(t,J=8.9Hz,2H,Ar-H),6.03(d,J=3.5Hz,1H,= CH),5.51(t,J=7.5Hz,2H,=CH),4.59(d,J=12.6Hz,1H,=CCH),4.41(d,J=12.6Hz,1H,=CCH),4.07(t, J=9.3Hz,1H,COO-CH),3.89(s,2H,SCH),3.03–2.84(m,1H,=CCH),2.77(d,J=9.5Hz,1H,HCO-),2.30– 2.01(m,6H,-CH2-),1.57(dd,J=12.7,5.8Hz,1H,-CH-),1.45(s,3H,-CH3),0.91–0.76(m,1H,-CH-). 13 C NMR (126MHz, DMSO) δ170.04,169.73,162.76,160.82,140.27,135.23,132.05,131.98,130.18,119.87,11 6.85,116.68,81.22,67.87,63.22,60.60,42.34,36.88,36.12,25.13,24.28,23.80,18.07.HRMS(ESI)m / z C 23 H 26 O5FS[M+H] + Theoretical value: 433.1479, measured value: 433.1473.

[0128] 2)M76 synthesis

[0129]

[0130] The p-fluorophenylthioacetate of MMB (462 mg, 1 mmol) was dissolved in 10 mL of dichloromethane, and p-toluenesulfonic acid monohydrate (380 mg, 2 mmol) was added. The mixture was stirred and refluxed at 45°C for 4 h. The reaction was complete after monitoring by TLC. The reaction solution was diluted with 20 mL of dichloromethane, washed once with a saturated aqueous NaHCO3 solution (20 mL), washed three times with a saturated aqueous NaCl solution (20 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated and subjected to rapid silica gel column chromatography (eluent: DCM-EA) to obtain 222 mg of a white solid with a yield of 48%. 1H NMR (400MHz, CDCl3) δ7.40(dd,J=8.6,5.2Hz,2H),6.99(t,J=8.5Hz,2H),6.25(d,J=2.9Hz,1H),5.63–5.56(m,2H),5.49(t,J=8.6Hz,1H),4.47(m,3 H),4.35(t,J=5.7Hz,1H),3.57(s,2H),2.95-2.75(m,3H),2.74-2.60(m,1 H),2.08-2.00(m,1H),1.91-1.79(m,1H),1.78(s,3H),1.67-1.51(m,1H). 13 C NMR (101MHz, CDCl3) δ170.00,169.92,162.96(d,J=248.0Hz),139.93,135.82,133.87(d,J=8.2Hz),133.01,130.14,129.4 2,125.67,123.29,116.80(d,J=21.9Hz),85.15,74.83,70.05,40.88. 38.30,32.24,28.92,24.71,20.95.ESI-MS:433[M+H] + .

[0131] Example 10 Synthesis of M95

[0132] 1) 2R-tetrahydrofuran ester of MMB

[0133]

[0134] 2R-tetrahydrofurancarboxylic acid (116 mg, 1 mmol), EDCI (575 mg, 3 mmol), DMAP (37 mg, 0.3 mmol), MMB (264 mg, 1 mmol) and 5 mL of DCM were added to the reaction flask and stirred at room temperature until TLC showed that the reaction was complete. The reaction solution was diluted with 20 mL of DCM, and then 20 mL of distilled water was added and stirred for 10 minutes, and the dichloromethane phase was separated. The organic phase was first washed with a saturated sodium bicarbonate solution and then with a saturated saline solution, dried over anhydrous sodium sulfate overnight, concentrated, and the residue was separated by column chromatography (eluent: ethyl acetate-petroleum ether) to obtain 134 mg of a white solid with a yield of 37%. 1H NMR (400MHz, CDCl3) δ6.24(d,J=3.5Hz,1H),5.70(t,J=8.3Hz,1H),5.55(d,J= 3.2Hz,1H),4.79(d,J=12.3Hz,1H),4.49-4.40(m,2H),4.03-3.95(m,1H),3.9 5-3.88(m,1H),3.84(t,J=9.3Hz,1H),2.94-2.79(m,2H),2.51-2.10(m,7H),2 .04-1.86(m,3H),1.67(t,J=12.8Hz,1H),1.54(s,3H),1.10(t,J=12.8Hz,1H). 13 C NMR (101MHz, CDCl3) δ173.28,169.43,138.76,134.79,131.29,120.45,81.06,76.73,69.52,6 6.98,63.34,60.01,42.72,36.68,30.35,25.70,25.41,24.36,23.93,18.07.ESI-MS:363[M+H] + .

[0135] 2)M95 synthesis

[0136]

[0137] The 2R-tetrahydrofuranate of MMB (362 mg, 1 mmol) was dissolved in 10 mL of dichloromethane, and p-toluenesulfonic acid monohydrate (380 mg, 2 mmol) was added. The mixture was stirred and refluxed at 45°C for 4 h. The reaction was complete when monitored by TLC. The reaction solution was diluted with 20 mL of dichloromethane, washed once with a saturated aqueous NaHCO3 solution (20 mL), and washed three times with a saturated aqueous NaCl solution (20 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated and purified by rapid silica gel column chromatography (eluent: DCM-EA) to obtain 199 mg of a white solid with a yield of 55%. 1H NMR (400MHz, CDCl3) δ6.28(s,1H),5.70–5.64(m,2H),5.63(s,1H),5.53(t,J=8.6Hz,1H),4.57–4.51(m,2H),4.49–4.42(m,2H),4.38(t,J=5.8Hz ,1H),4.00(q,J=7.3Hz,1H),3.91(q,J=7.1Hz,1H),2.96–2.80(m,3H),2. 73(t,J=12.7Hz,1H),2.31–1.86(m,7H),1.81(s,3H),1.72–1.60(m,1H). 13 CNMR(101MHz, CDCl3)δ173.28,169.64,139.52,135.15,132.77,128.79,125.36,122.85,84.8 3,82.60,74.52,69.45,69.05,40.32,32.03,30.26,28.51,25.34,24.36,20.70.HRMS(ESI)m / z C 20 H 27 O6[M+H] + Theoretical value: 363.1802, measured value: 363.1803.

[0138] Example 11 Synthesis of M94

[0139] 1) MMB (3,3-difluorocyclobutyl) formate

[0140]

[0141] 3,3-Difluorocyclobutanecarboxylic acid (136 mg, 1 mmol), EDCI (575 mg, 3 mmol), DMAP (37 mg, 0.3 mmol), MMB (264 mg, 1 mmol) and 5 mL of DCM were added to the reaction flask and stirred at room temperature until TLC showed that the reaction was complete. The reaction solution was diluted with 20 mL of DCM, and then 20 mL of distilled water was added and stirred for 10 minutes, and the dichloromethane phase was separated. The organic phase was first washed with a saturated sodium bicarbonate solution and then with a saturated saline solution, dried over anhydrous sodium sulfate overnight, concentrated, and the residue was separated by column chromatography (eluent: ethyl acetate-petroleum ether) to obtain 187 mg of a white solid with a yield of 49%. 1H NMR (400MHz, CDCl3) δ6.26(d,J=3.5Hz,1H),5.70(t,J=8.3Hz,1H),5.54(d,J=3.5Hz,1H),4.71(d,J=12.4Hz,1H),4.51(d,J= 12.4Hz,1H),3.85(t,J=9.3Hz,1H),3.21-2.65(m,7H),2.54-2.06(m,6H),1.79-1.59(m,1H),1.54(s,3H),1.15-1.01(m,1H). 13 C NMR(101MHz, CDCl3) δ173.13(t,J=2.7Hz),169.36,138.78,134.63,131.24,120.43,118.71(dd,J=283.6,271.5Hz),81.05,67.39 ,63.36,60.03,42.73,38.91(td,J=24.6,4.8Hz),36.67,26.63(dd,J=13.7,5.9Hz),25.69,24.37,23.94,18.08.ESI-MS:383[M+H] + .

[0142] 2)M94 synthesis

[0143]

[0144] MMB (3,3-difluorocyclobutyl) formate (382 mg, 1 mmol) was dissolved in 10 mL of dichloromethane, p-toluenesulfonic acid monohydrate (380 mg, 2 mmol) was added, and the mixture was stirred under reflux at 45°C for 4 h. The reaction was complete after monitoring by TLC. The reaction solution was diluted with 20 mL of dichloromethane, washed once with a saturated aqueous NaHCO3 solution (20 mL), washed three times with a saturated aqueous NaCl solution (20 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated and subjected to rapid silica gel column chromatography (eluent: DCM-EA) to obtain 92 mg of a white solid with a yield of 24%. 1 H NMR (400MHz, CDCl3) δ6.28(s,1H),5.66(t,J=7.0Hz,1H),5.58(s,1H),5.53(t,J=8.8Hz,1H),4.55(s,2H),4.48(d,J=6.3Hz,1 H),4.38(t,J=5.8Hz,1H),3.05–2.60(m,10H),2.16–2.08(m,1H),1.89(t,J=13.5Hz,1H),1.81(s,3H),1.67(d,J=11.6Hz,1H). 13C NMR (101MHz, CDCl3) δ173.16,169.63,139.57,135.38,132.67,128.84,125.18,122.65,84.80,7 4.43,69.15,40.37,38.81(t,J=24.5Hz),31.84,28.44,26.61(dd,J=14.0,5.7Hz),24.18,20.66.

[0145] Example 12 Synthesis of M110

[0146] 1) MMB (E)-3-(3-trifluoromethylbenzene) acrylate

[0147]

[0148] (E)-3-(3-trifluoromethylphenyl)acrylic acid (216 mg, 1 mmol), EDCI (575 mg, 3 mmol), DMAP (37 mg, 0.3 mmol), MMB (264 mg, 1 mmol) and 5 mL of DCM were added to a reaction flask and stirred at room temperature until TLC showed that the reaction was complete. The reaction solution was diluted with 20 mL of DCM, and then 20 mL of distilled water was added and stirred for 10 minutes. The dichloromethane phase was separated, and the organic phase was first washed with a saturated sodium bicarbonate solution and then with a saturated saline solution, dried over anhydrous sodium sulfate overnight, concentrated, and the residue was separated by column chromatography (eluent: ethyl acetate-petroleum ether) to obtain 407 mg of a white solid with a yield of 88%. 1 H NMR (400MHz, CDCl3) δ7.81–7.61(m,4H),7.53(t,J=7.8Hz,1H),6.49(d,J=16.0Hz,1 H),6.26(d,J=3.4Hz,1H),5.76(t,J=8.4Hz,1H),5.57(d,J=3.4Hz,1H),4.81(d,J=1 2.5Hz,1H),4.62(d,J=12.5Hz,1H),3.87(t,J=9.3Hz,1H),2,97–2.87(m,2H),2.57– 2.11(m,6H),1.76–1.65(m,1H),1.56(s,3H),1.13(t,J=12.9Hz,1H).HRMS(ESI)m / z C 25 H 26 F3O6[M+H] + Theoretical value: 463.1727, measured value: 463.1731.

[0149] 2)M110 synthesis

[0150]

[0151] MMB (E)-3-(3-trifluoromethylbenzene) acrylate (462 mg, 1 mmol) was dissolved in 10 mL of dichloromethane, p-toluenesulfonic acid monohydrate (380 mg, 2 mmol) was added, and the mixture was stirred under reflux at 45°C for 4 h. The reaction was complete after monitoring by TLC. The reaction solution was diluted with 20 mL of dichloromethane, washed once with a saturated aqueous NaHCO3 solution (20 mL), washed three times with a saturated aqueous NaCl solution (20 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated and purified by rapid silica gel column chromatography (eluent: DCM-EA) to obtain 375 mg of a white solid with a yield of 81%. 1 H NMR (400MHz, CDCl3) δ7.81–7.61(m,4H),7.53(t,J=7.8Hz,1H),6.50(d,J=16.0Hz ,1H),6.28(s,1H),5.77–5.69(m,1H),5.61(s,1H),5.56(t,J=8.8Hz,1H),4.66(s, 2H),4.50(d,J=5.9Hz,1H),4.40(t,J=5.8Hz,1H),2.98–2.82(m,3H),2.79(t,J=1 3.6Hz,1H),2.30–2.05(m,2H),2.00–1.89(m,1H),1.82(s,3H),1.76–1.62(m,1H). 13 C NMR (101MHz, CDCl3δ169.60,166.27,143.57,139.59,135.24,135.10,132.98,131.61(q,J=32.4Hz),131.20,129.65,128.62,126.96(q,J=3.6H z),125.45,124.74(q,J=3.8Hz),123.84(q,J=270.9Hz),122.81,119.78 ,84.82,74.46,68.80,40.44,32.00,28.57,24.34,20.57.HRMS(ESI)m / z C 25 H 25 F3O5Na[M+Na] + Theoretical value: 485.1546, measured value: 485.1558.

[0152] Example 13M102 Synthesis

[0153] 1) MMB (E)-3-(3-methylmercaptophenyl) acrylate

[0154]

[0155] (E)-3-(3-methylmercaptophenyl)acrylic acid (194 mg, 1 mmol), EDCI (575 mg, 3 mmol), DMAP (37 mg, 0.3 mmol), MMB (264 mg, 1 mmol) and 5 mL of DCM were added to a reaction flask and stirred at room temperature until TLC showed that the reaction was complete. The reaction solution was diluted with 20 mL of DCM, and then 20 mL of distilled water was added and stirred for 10 minutes. The dichloromethane phase was separated, and the organic phase was first washed with a saturated sodium bicarbonate solution and then with a saturated saline solution, dried over anhydrous sodium sulfate overnight, and concentrated. The residue was separated by column chromatography (eluent: ethyl acetate-petroleum ether) to obtain 189 mg of a white solid with a yield of 43%. 1 H NMR (400MHz, CDCl3) δ7.64(d,J=16.0Hz,1H),7.42(d,J=8.1Hz,2H),7.22(d,J=8.1Hz,2H),6 .36(d,J=16.0Hz,1H),6.25(d,J=3.4Hz,1H),5.74(t,J=8.4Hz,1H),5.55(d,J=3.4Hz,1H),4. 78(d,J=12.5Hz,1H),4.59(d,J=12.5Hz,1H),3.87(t,J=9.3Hz,1H),3.01-2.90(m,1H),2.89 (d,J=9.4Hz,1H),2.55-2.11(m,9H),1.74-1.63(m,1H),1.55(s,3H),1.12(t,J=12.9Hz,1H). 13 C NMR (101MHz, CDCl3) δ169.49,166.86,145.10,142.54,138.91,135.17,130.87,130.67,128.59,126.07,120 .45,116.31,81.17,66.98,63.43,60.06,42.83,36.75,25.99,24.72,23.99,18.13,15.20.ESI-MS:441[M+H] + .

[0156] 2)M102 synthesis

[0157]

[0158] MMB (E)-3-(3-methylmercaptophenyl) acrylate (440 mg, 1 mmol) was dissolved in 10 mL of dichloromethane, p-toluenesulfonic acid monohydrate (380 mg, 2 mmol) was added, and the mixture was stirred under reflux at 45°C for 4 h. The reaction was complete after monitoring by TLC. The reaction solution was diluted with 20 mL of dichloromethane, washed once with a saturated aqueous NaHCO3 solution (20 mL), washed three times with a saturated aqueous NaCl solution (20 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated and purified by rapid silica gel column chromatography (eluent: DCM-EA) to obtain 211 mg of a white solid with a yield of 48%. 1 H NMR (400MHz, CDCl3) δ7.64(d,J=16.0Hz,1H),7.43(d,J=8.1Hz,2H),7.23(d,J=8.1Hz,2H),6.38(d,J =16.0Hz,1H),6.27(d,J=2.9Hz,1H),5.72(t,J=6.9Hz,1H),5.61(d,J=2.9Hz,1H),5.56(t,J=8.6Hz,1 H),4.64(d,J=4.2Hz,2H),4.49(d,J=6.4Hz,1H),4.40(t,J=5.9Hz,1H),2.98–2.86(m,3H),2.78(t,J= 13.5Hz,1H),2.50(s,3H),2.21–2.14(m,1H),1.94(t,J=13.5Hz,1H),1.82(s,3H),1.74–1.64(m,1H). 13 C NMR (101MHz, CDCl3) δ169.51,166.87,144.78,142.35,139.50,135.05,133.12,130.71,128.49,128.40,126 .01,125.52,122.82,116.55,84.71,74.39,68.65,40.36,31.99,28.53,24.37,20.42,15.15.HRMS(ESI)m / z C 25 H 29 O5S[M+H] + Theoretical value: 441.1730, measured value: 441.1721.

[0159] Example 14 Synthesis of M104

[0160] 1) MMB (E)-3-(4-biphenyl) acrylate

[0161]

[0162] (E)-3-(4-biphenyl)acrylic acid (224 mg, 1 mmol), EDCI (575 mg, 3 mmol), DMAP (37 mg, 0.3 mmol), MMB (264 mg, 1 mmol) and 5 mL of DCM were added to a reaction flask and stirred at room temperature until TLC showed that the reaction was complete. The reaction solution was diluted with 20 mL of DCM, and then 20 mL of distilled water was added and stirred for 10 minutes, and the dichloromethane phase was separated. The organic phase was first washed with a saturated sodium bicarbonate solution and then with a saturated saline solution, dried over anhydrous sodium sulfate overnight, concentrated, and the residue was separated by column chromatography (eluent: ethyl acetate-petroleum ether) to obtain 419 mg of a white solid with a yield of 89%. 1 H NMR (400MHz, CDCl3) δ7.78(d,J=16.0Hz,1H),7.65(q,J=8.6Hz,6H),7.50(t,J=7.6Hz,2H),7.42(t,J=7.3Hz,1H ),6.50(d,J=16.0Hz,1H),6.31(d,J=3.5Hz,1H),5.80(t,J=7.8Hz,1H),5.62(d,J=3.3Hz,1H),4.85(d,J=12.6Hz ,1H),4.66(d,J=12.6Hz,1H),3.92(t,J=9.4Hz,1H),3.09–2.99(m,1H),2.95(d,J=9.4Hz,1H),2.60–2.33(m,4H) ,2.26(ddd,J=28.0,13.1,7.3Hz,2H),1.80–1.67(m,1H),1.61(s,3H),1.18(t,J=12.8Hz,1H).ESI-MS:471[M+H] + .

[0163] 2)M104 synthesis

[0164]

[0165] MMB (E)-3-(4-biphenyl) acrylate (470 mg, 1 mmol) was dissolved in 10 mL of dichloromethane, p-toluenesulfonic acid monohydrate (380 mg, 2 mmol) was added, and the mixture was stirred at reflux at 45°C for 4 h. The reaction was complete after monitoring by TLC. The reaction solution was diluted with 20 mL of dichloromethane, washed once with a saturated aqueous NaHCO3 solution (20 mL), washed three times with a saturated aqueous NaCl solution (20 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated and purified by rapid silica gel column chromatography (eluent: DCM-EA) to obtain 255 mg of a white solid with a yield of 48%. 1H NMR (400MHz, CDCl3) δ7.74 (d, J=16.0Hz, 1H), 7.61 (q, J=8.2, 7.4Hz, 6H), 7.50–7.42 (m ,2H),7.37(t,J=7.5Hz,1H),6.47(d,J=16.0Hz,1H),6.28(s,1H),5.73(t,J=6.9Hz,1H) ,5.66–5.50(m,2H),4.73–4.53(m,2H),4.50(d,J=6.5Hz,1H),4.41(d,J=5.8Hz,1H),3. 01–2.74(m,4H),2.34–2.11(m,2H),2.01–1.90(m,1H),1.82(s,3H),1.74–1.64(m,1H). 13 C NMR (101MHz, CDCl3) δ169.60,166.87,144.93,143.41,140.17,139.59,135.13,133.26,133.18,129.05,128.74,128.52, 128.05,127.72,127.16,125.60,122.90,117.58,84.83,74.50,68.79,40.45,32.11,28.63,24.46,20.55.HRMS(ESI)m / z C 30 H 31 O5[M+H] + Theoretical value: 471.2166, measured value: 471.2188.

[0166] Example 15 Synthesis of M99

[0167] 1) MMB (E)-3-(2,4-dichlorophenyl) acrylate

[0168]

[0169] (E)-3-(2,4-dichlorophenyl)acrylic acid (217 mg, 1 mmol), EDCI (575 mg, 3 mmol), DMAP (37 mg, 0.3 mmol), MMB (264 mg, 1 mmol) and 5 mL of DCM were added to the reaction flask and stirred at room temperature until TLC showed that the reaction was complete. The reaction solution was diluted with 20 mL of DCM, and then 20 mL of distilled water was added and stirred for 10 minutes. The dichloromethane phase was separated, and the organic phase was first washed with a saturated sodium bicarbonate solution and then with a saturated saline solution, dried over anhydrous sodium sulfate overnight, concentrated, and the residue was separated by column chromatography (eluent: ethyl acetate-petroleum ether) to obtain 282 mg of a white solid with a yield of 61%. 1H NMR (400MHz, CDCl3) δ8.04(d,J=16.0Hz,1H),7.53(d,J=8.5Hz,1H),7.45(d,J=2.0Hz,1H ),7.29-7.27(m,1H),6.40(d,J=16.0Hz,1H),6.25(d,J=3.3Hz,1H),5.76(t,J=8.5Hz,1H ),5.56(d,J=3.3Hz,1H),4.80(d,J=12.4Hz,1H),4.63(d,J=12.4Hz,1H),3.87(t,J=9.3H z,1H),3.04-2.85(m,2H),2.64-2.12(m,6H),1.80-1.49(m,4H),1.14(t,J=12.8Hz,1H). 13 C NMR (101MHz, CDCl3) δ169.45,166.03,140.25,138.88,136.81,135.74,134.96,131.18,131.09,130.23,128.49, 127.81,120.54,120.46,81.14,67.20,63.44,60.07,42.84,36.75,25.95,24.68,24.01,18.15.ESI-MS:463[M+H] + .

[0170] 2)M99 synthesis

[0171]

[0172] MMB (E)-3-(2,4-dichlorophenyl)acrylate (463 mg, 1 mmol) was dissolved in 10 mL of dichloromethane, p-toluenesulfonic acid monohydrate (380 mg, 2 mmol) was added, and the mixture was stirred under reflux at 45°C for 4 h. The reaction was complete after monitoring by TLC. The reaction solution was diluted with 20 mL of dichloromethane, washed once with a saturated aqueous NaHCO3 solution (20 mL), washed three times with a saturated aqueous NaCl solution (20 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated and subjected to rapid silica gel column chromatography (eluent: DCM-EA) to obtain 171 mg, with a yield of 37%. 1H NMR (400MHz, CDCl3) δ8.02(d,J=16.1Hz,1H),7.54(d,J=8.4Hz,1H),7.45(s,1H),7.27(d,J=8.4Hz ,1H),6.41(d,J=16.1Hz,1H),6.27(d,J=2.6Hz,1H),5.73(t,J=6.8Hz,1H),5.61(d,J=2.6Hz,1H),5 .55(t,J=8.8Hz,1H),4.66(s,2H),4.50(d,J=6.2Hz,1H),4.39(t,J=5.8Hz,1H),2.98–2.85(m,3H), 2.78(t,J=13.6Hz,1H),2.23–2.14(m,1H),1.94(t,J=13.6Hz,1H),1.82(s,3H),1.74–1.64(m,1H). 13 C NMR (101MHz, CDCl3) δ169.51,166.03,139.90,139.46,136.64,135.60,135.14,132.92,131.11,130.12,128.59,1 28.41,127.70,125.40,122.82,120.78,84.71,74.39,68.90,40.36,31.99,29.73,28.51,24.31.ESI-MS:463[M+H] + .

[0173] Example 16 Synthesis of M78

[0174] 1) MMB (E)-3-(3,4-dichlorophenyl) acrylate

[0175]

[0176] (E)-3-(3,4-dichlorophenyl)acrylic acid (217 mg, 1 mmol), EDCI (575 mg, 3 mmol), DMAP (37 mg, 0.3 mmol), MMB (264 mg, 1 mmol) and 5 mL of DCM were added to the reaction flask and stirred at room temperature until TLC showed that the reaction was complete. The reaction solution was diluted with 20 mL of DCM, and then 20 mL of distilled water was added and stirred for 10 minutes. The dichloromethane phase was separated, and the organic phase was first washed with a saturated sodium bicarbonate solution and then with a saturated saline solution, dried over anhydrous sodium sulfate overnight, concentrated, and the residue was separated by column chromatography (eluent: ethyl acetate-petroleum ether) to obtain 292 mg of a white solid with a yield of 63%. 1H NMR (400MHz, CDCl3) δ7.61-7.53(m,2H),7.47(d,J=8.4Hz,1H),7.33(dd,J=8.4,2.1Hz ,1H),6.40(d,J=16.0Hz,1H),6.25(d,J=3.6Hz,1H),5.74(t,J=8.4Hz,1H),5.55(d,J= 3.6Hz,1H),4.78(d,J=12.5Hz,1H),4.61(d,J=12.5Hz,1H),3.86(t,J=9.3Hz,1H),3.0 1-2.81(m,2H),2.55-2.09(m,6H),1.75-1.62(m,1H),1.55(s,3H),1.21-1.05(m,1H). 13 C NMR (101MHz, CDCl3) δ169.42,166.09,142.84,138.87,134.89,134.57,134.25,133.41,131.09,130.97,129.78, 127.17,120.40,119.42,81.12,67.08,63.39,60.05,42.78,36.71,25.85,24.56,23.96,18.10.ESI-MS:463[M+H] + .

[0177] 2)M78 synthesis

[0178]

[0179] MMB (E)-3-(3,4-dichlorophenyl)acrylate (463 mg, 1 mmol) was dissolved in 10 mL of dichloromethane, p-toluenesulfonic acid monohydrate (380 mg, 2 mmol) was added, and the mixture was stirred under reflux at 45°C for 4 h. The reaction was complete after monitoring by TLC. The reaction solution was diluted with 20 mL of dichloromethane, washed once with a saturated aqueous NaHCO3 solution (20 mL), washed three times with a saturated aqueous NaCl solution (20 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated and subjected to rapid silica gel column chromatography (eluent: DCM-EA) to obtain 241 mg of a white solid with a yield of 52%. 1H NMR (400MHz, CDCl3) δ7.54-7.61(m,2H),7.47(d,J=8.3Hz,1H),7.34(d,J=8.3Hz,1H),6.42(d, J=16.0Hz,1H),6.28(d,J=2.8Hz,1H),5.72(t,J=7.0Hz,1H),5.61(d,J=2.8Hz,1H),5.55(t,J= 8.7Hz,1H),4.64(s,2H),4.50(d,J=6.2Hz,1H),4.40(t,J=5.8Hz,1H),2.97–2.85(m,3H),2.77 (t,J=14.1Hz,1H),2.22–2.14(m,1H),1.94(t,J=14.1Hz,1H),1.82(s,3H),1.75–1.64(m,1H). 13 C NMR (101MHz, CDCl3) δ169.46,166.13,142.60,139.47,135.20,134.50,134.26,133.39,132.89,131.02,129.71,1 28.57,127.07,125.38,122.80,119.59,84.65,74.36,68.74,40.39,31.87,28.49,24.27,20.40.ESI-MS:463[M+H] + .

[0180] Example 17 Synthesis of M120

[0181] 1) MMB (E)-3-(2,6-dichlorophenyl) acrylate

[0182]

[0183] (E)-3-(2,6-dichlorophenyl)acrylic acid (217 mg, 1 mmol), EDCI (575 mg, 3 mmol), DMAP (37 mg, 0.3 mmol), MMB (264 mg, 1 mmol) and 5 mL of DCM were added to the reaction flask and stirred at room temperature until TLC showed that the reaction was complete. The reaction solution was diluted with 20 mL of DCM, and then 20 mL of distilled water was added and stirred for 10 minutes. The dichloromethane phase was separated, and the organic phase was first washed with a saturated sodium bicarbonate solution and then with a saturated saline solution, dried over anhydrous sodium sulfate overnight, concentrated, and the residue was separated by column chromatography (eluent: ethyl acetate-petroleum ether) to obtain 394 mg of a white solid with a yield of 85%. 1H NMR (400MHz, CDCl3) δ7.83(d,J=16.4Hz,1H),7.36(d,J=8.0Hz,2H),7.20(t,J=8.0Hz,1H) ,6.60(d,J=16.4Hz,1H),6.25(d,J=3.4Hz,1H),5.77(t,J=8.5Hz,1H),5.57(d,J=3.4Hz,1H ),4.81(d,J=12.4Hz,1H),4.65(d,J=12.4Hz,1H),3.87(t,J=9.3Hz,1H),3.00–2.82(m,2H) ,2.53–2.13(m,6H),1.75–1.62(m,1H),1.56(s,3H),1.14(t,J=13.0Hz,1H).HRMS(ESI)m / z C 24 H 25 Cl2O5[M+H] + Theoretical value: 463.1074, measured value: 463.1077.

[0184] 2)M120 synthesis

[0185]

[0186] MMB (E)-3-(2,6-dichlorophenyl)acrylate (463 mg, 1 mmol) was dissolved in 10 mL of dichloromethane, p-toluenesulfonic acid monohydrate (380 mg, 2 mmol) was added, and the mixture was stirred under reflux at 45°C for 4 h. The reaction was complete after monitoring by TLC. The reaction solution was diluted with 20 mL of dichloromethane, washed once with a saturated aqueous NaHCO3 solution (20 mL), washed three times with a saturated aqueous NaCl solution (20 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated and subjected to rapid silica gel column chromatography (eluent: DCM-EA) to obtain 245 mg of a white solid with a yield of 53%. 1H NMR(400MHz, CDCl3) δ7.81(d,J=16.4Hz,1H),7.36(d,J=8.0Hz,2H),7.20(t,J=8.0Hz,1H), 6.61(d,J=16.4Hz,1H),6.27(d,J=3.0Hz,1H),5.75(t,J=6.8Hz,1H),5.61(d,J=2.6Hz,1H) ,5.56(t,J=8.7Hz,1H),4.67(d,J=4.7Hz,2H),4.49(d,J=6.5Hz,1H),4.39(t,J=5.8Hz,1H) ,3.00–2.74(m,4H),2.26–2.06(m,2H),2.00–1.89(m,1H),1.82(s,3H),1.75–1.60(m,1H). 13 CNMR(101MHz, CDCl3)δ169.59,166.12,139.53,138.87,135.13,135.06,133.00,131.84,130.15,128.99 ,128.91,126.44,125.58,122.96,84.87,74.55,69.37,40.37,32.28,28.67,24.52,20.61.HRMS(ESI)m / z C 24 H 25 Cl2O5[M+H] + Theoretical value: 463.1074, Measured value: 463.1082. Example 18 Synthesis of M112

[0187] 1) MMB (E)-3-(2-methoxyphenyl) acrylate

[0188]

[0189] (E)-3-(2-methoxyphenyl)acrylic acid (178 mg, 1 mmol), EDCI (575 mg, 3 mmol), DMAP (37 mg, 0.3 mmol), MMB (264 mg, 1 mmol) and 5 mL of DCM were added to the reaction flask and stirred at room temperature until TLC showed that the reaction was complete. The reaction solution was diluted with 20 mL of DCM, and then 20 mL of distilled water was added and stirred for 10 minutes. The dichloromethane phase was separated, and the organic phase was first washed with a saturated sodium bicarbonate solution and then with a saturated saline solution, dried over anhydrous sodium sulfate overnight, concentrated, and the residue was separated by column chromatography (eluent: ethyl acetate-petroleum ether) to obtain 403 mg of a white solid with a yield of 95%. 1H NMR (400MHz, CDCl3) δ7.99(d,J=16.1Hz,1H),7.48(d,J=7.7Hz,1H),7.36(t,J=7.0Hz,1H),7.01–6.89(m ,2H),6.51(d,J=16.1Hz,1H),6.24(d,J=3.5Hz,1H),5.75(t,J=8.4Hz,1H),5.55(d,J=3.5Hz,1H),4.78(d ,J=12.5Hz,1H),4.61(d,J=12.5Hz,1H),3.89(s,3H),3.86(d,J=9.3=4Hz,1H),3.08–2.97(m,1H),2.91(d ,J=9.4Hz,1H),2.55–2.42(m,2H),2.42–2.28(m,2H),2.28–2.13(m,2H),1.74–1.61(m,2H),1.56(s,3H). 13 C NMR (101MHz, CDCl3) δ169.49,167.26,158.53,141.20,138.78,135.23,131.86,130.87,129.23,123.06,120.78,12 0.43,117.83,111.23,81.11,66.97,63.38,60.02,55.53,42.78,36.68,26.02,24.82,23.92,18.07.HRMS(ESI)m / z C 25 H 29 O6[M+H] + Theoretical value: 425.1959, measured value: 425.1961.

[0190] 2)M112 synthesis

[0191]

[0192] MMB (E)-3-(2-methoxyphenyl)acrylate (424 mg, 1 mmol) was dissolved in 10 mL of dichloromethane, p-toluenesulfonic acid monohydrate (380 mg, 2 mmol) was added, and the mixture was stirred at reflux at 45°C for 4 h. The reaction was complete after monitoring by TLC. The reaction solution was diluted with 20 mL of dichloromethane, washed once with a saturated aqueous NaHCO3 solution (20 mL), washed three times with a saturated aqueous NaCl solution (20 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated and subjected to rapid silica gel column chromatography (eluent: DCM-EA) to obtain 284 mg of a white solid with a yield of 67%. 1H NMR (400MHz, CDCl3) δ8.00(d,J=16.1Hz,1H),7.49(d,J=7.9Hz,1H),7.36(t,J=7.9Hz,1H),7.01–6.89( m,2H),6.54(d,J=16.1Hz,1H),6.27(d,J=2.6Hz,1H),5.73(t,J=6.9Hz,1H),5.63(d,J=2.6Hz,1H),5.56 (t,J=8.7Hz,1H),4.65(s,2H),4.49(d,J=6.5Hz,1H),4.39(t,J=5.9Hz,1H),3.89(s,3H),3.00–2.85(m, 3H),2.80(t,J=13.7Hz,1H),2.21–2.14(m,1H),1.96(t,J=13.7Hz,1H),1.82(s,3H),1.74–1.64(m,1H). 13 CNMR(101MHz, CDCl3)δ169.64,167.39,158.54,140.96,139.59,134.93,133.33,131.83,129.25,128.43,125.72,12 3.27,122.91,120.87,118.32,111.29,84.91,74.55,68.87,55.59,40.35,32.28,28.66,24.54,20.60.HRMS(ESI)m / z C 25 H 29 O6[M+H] + Theoretical value: 425.1959, measured value: 425.1954.

[0193] Example 19 Synthesis of M108

[0194] 1) MMB (E)-3-(4-methoxyphenyl) acrylate

[0195]

[0196] (E)-3-(4-methoxyphenyl)acrylic acid (178 mg, 1 mmol), EDCI (575 mg, 3 mmol), DMAP (37 mg, 0.3 mmol), MMB (264 mg, 1 mmol) and 5 mL of DCM were added to a reaction flask and stirred at room temperature until TLC showed that the reaction was complete. The reaction solution was diluted with 20 mL of DCM, and then 20 mL of distilled water was added and stirred for 10 minutes. The dichloromethane phase was separated, and the organic phase was first washed with a saturated sodium bicarbonate solution and then with a saturated saline solution, dried over anhydrous sodium sulfate overnight, concentrated, and the residue was separated by column chromatography (eluent: ethyl acetate-petroleum ether) to obtain 412 mg of a white solid with a yield of 97%. 1 H NMR (400MHz, CDCl3) δ7.65(d,J=15.9Hz,1H),7.46(d,J=8.2Hz,2H),6.91(d,J=8.2Hz,2H),6.32–6 .24(m,2H),5.74(t,J=8.4Hz,1H),5.56(d,J=3.1Hz,1H),4.78(d,J=12.5Hz,1H),4.59(d,J=12.5Hz ,1H),3.88(d,J=9.3Hz,1H),3.84(s,3H),3.04–2.94(m,1H),2.90(d,J=9.4Hz,1H),2.55–2.40(m, 2H),2.41–2.26(m,2H),2.29–2.12(m,2H),1.73–1.67(m,1H),1.56(s,3H),1.13(t,J=12.9Hz,1H). 13 C NMR (101MHz, CDCl3) δ169.54,167.10,161.75,145.40,138.91,135.27,130.78,129.97,126.95,120.49,11 4.86,114.54,81.19,66.89,63.45,60.08,55.53,42.84,36.76,26.01,24.75,23.99,18.14.HRMS(ESI)m / z C 25 H 29 O6[M+H] + Theoretical value: 425.1959, measured value: 425.1963.

[0197] 2)M108 synthesis

[0198]

[0199] MMB (E)-3-(4-methoxyphenyl)acrylate (424 mg, 1 mmol) was dissolved in 10 mL of dichloromethane, p-toluenesulfonic acid monohydrate (380 mg, 2 mmol) was added, and the mixture was stirred under reflux at 45°C for 4 h. The reaction was complete after monitoring by TLC. The reaction solution was diluted with 20 mL of dichloromethane, washed once with a saturated aqueous NaHCO3 solution (20 mL), washed three times with a saturated aqueous NaCl solution (20 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated and purified by rapid silica gel column chromatography (eluent: DCM-EA) to obtain 233 mg of a white solid, with a yield of 55%. 1 H NMR (400MHz, CDCl3) δ7.69(d,J=15.9Hz,1H),7.51(d,J=8.5Hz,2H),6.95(d,J=8.5Hz,2H),6.3 8–6.29(m,2H),5.75(t,J=6.5Hz,1H),5.65(d,J=2.5Hz,1H),5.60(t,J=8.6Hz,1H),4.67(d,J= 4.0Hz,2H),4.53(d,J=6.3Hz,1H),4.43(t,J=5.8Hz,1H),3.88(s,3H),3.02–2.90(m,3H),2.82 (t,J=13.5Hz,1H),2.27–2.16(m,1H),1.99(t,J=13.5Hz,1H),1.86(s,3H),1.79–1.67(m,1H). 13 C NMR (101MHz, CDCl3) δ169.63,167.18,161.68,145.14,139.61,135.08,133.28,129.92,128.38,127.05,125 .63,122.88,115.18,114.52,84.84,74.49,68.65,55.52,40.42,32.11,28.61,24.47,20.55.HRMS(ESI)m / zC 25 H 29 O6[M+H] + Theoretical value: 425.1959, measured value: 425.1973.

[0200] Example 20 Synthesis of M114

[0201] 1) MMB (E)-3-(2,5-dimethoxyphenyl) acrylate

[0202]

[0203] (E)-3-(2,5-dimethoxyphenyl)acrylic acid (208 mg, 1 mmol), EDCI (575 mg, 3 mmol), DMAP (37 mg, 0.3 mmol), MMB (264 mg, 1 mmol) and 5 mL of DCM were added to the reaction flask and stirred at room temperature until TLC showed that the reaction was complete. The reaction solution was diluted with 20 mL of DCM, and then 20 mL of distilled water was added and stirred for 10 minutes. The dichloromethane phase was separated, and the organic phase was first washed with a saturated sodium bicarbonate solution and then with a saturated saline solution, dried over anhydrous sodium sulfate overnight, concentrated, and the residue was separated by column chromatography (eluent: ethyl acetate-petroleum ether) to obtain 427 mg of a white solid with a yield of 94%. 1 H NMR (400MHz, CDCl3) δ7.97(d,J=16.1Hz,1H),7.01(s,1H),6.93(d,J=9.0Hz,1H),6.85(d,J=9.0Hz,1H),6.48(d ,J=16.1Hz,1H),6.24(d,J=1.9Hz,1H),5.75(t,J=8.3Hz,1H),5.55(d,J=1.9Hz,1H),4.78(d,J=12.5Hz,1H),4.6 1(d,J=12.5Hz,1H),3.88(d,J=10.0Hz,1H),3.85(s,3H),3.79(s,3H),3.08–2.97(m,1H),2.91(d,J=9.5Hz,1H), 2.48(m,2H),2.40–2.27(m,2H),2.27–2.13(m,2H),1.69(t,J=12.0Hz,1H),1.56(s,3H),1.14(t,J=13.0Hz,1H). 13 C NMR (101MHz, CDCl3) δ169.46,167.11,153.52,152.99,140.92,138.79,135.19,130.93,123.55,120.42,118.00,117.5 4,113.43,112.47,81.10,66.99,63.38,60.01,56.07,55.83,42.78,36.68,26.01,24.81,23.92,18.06.HRMS(ESI)m / z C 26 H 31 O7[M+H] + Theoretical value: 455.2064, measured value: 425.2069.

[0204] 2)M114 synthesis

[0205]

[0206] MMB (E)-3-(2,5-dimethoxyphenyl)acrylate (455 mg, 1 mmol) was dissolved in 10 mL of dichloromethane, p-toluenesulfonic acid monohydrate (380 mg, 2 mmol) was added, and the mixture was stirred at reflux at 45°C for 4 h. The reaction was complete after monitoring by TLC. The reaction solution was diluted with 20 mL of dichloromethane, washed once with a saturated aqueous NaHCO3 solution (20 mL), washed three times with a saturated aqueous NaCl solution (20 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated and subjected to rapid silica gel column chromatography (eluent: DCM-EA) to obtain 341 mg of a white solid with a yield of 75%. 1 H NMR (400MHz, CDCl3) δ7.97(d,J=16.1Hz,1H),7.03(d,J=3.0Hz,1H),6.92(dd,J=9.0,2.9Hz,1H),6.85(d,J=9.0 Hz,1H),6.50(d,J=16.1Hz,1H),6.27(d,J=2.9Hz,1H),5.73(t,J=6.8Hz,1H),5.62(d,J=2.9Hz,1H),5.56(t,J=8 .7Hz,1H),4.64(d,J=3.0Hz,2H),4.49(d,J=6.5Hz,1H),4.39(t,J=5.9Hz,1H),3.84(s,3H),3.79(s,3H),2.97– 2.86(m,3H),2.79(t,J=13.6Hz,1H),2.21–2.14(m,1H),1.95(t,J=13.6Hz,1H),1.82(s,3H),1.74–1.64(m,1H). 13 C NMR (101MHz, CDCl3) δ169.55,167.16,153.53,152.93,140.60,139.51,134.87,133.23,128.37,125.62,123.72,122.83 ,118.44,117.32,113.53,112.45,84.82,74.46,68.78,56.08,55.82,40.27,32.18,28.58,24.44,20.53.HRMS(ESI)m / z C 26 H 31 O7[M+H] + Theoretical value: 455.2064, measured value: 455.2065.

[0207] Example 21 Synthesis of M86

[0208] 1) MMB (E)-3-(2,6-dimethoxyphenyl) acrylate

[0209]

[0210] (E)-3-(2,6-dimethoxyphenyl)acrylic acid (208 mg, 1 mmol), EDCI (575 mg, 3 mmol), DMAP (37 mg, 0.3 mmol), MMB (264 mg, 1 mmol) and 5 mL of DCM were added to the reaction flask and stirred at room temperature until TLC showed that the reaction was complete. The reaction solution was diluted with 20 mL of DCM, and then 20 mL of distilled water was added and stirred for 10 minutes. The dichloromethane phase was separated, and the organic phase was first washed with a saturated sodium bicarbonate solution and then with a saturated saline solution, dried over anhydrous sodium sulfate overnight, concentrated, and the residue was separated by column chromatography (eluent: ethyl acetate-petroleum ether) to obtain 272 mg of a white solid with a yield of 60%. 1 H NMR (400MHz, CDCl3) δ8.17(d,J=16.2Hz,1H),7.28(t,J=7.1Hz,1H),6.84(d,J=16.2Hz,1H),6. 56(d,J=8.4Hz,2H),6.20(d,J=3.5Hz,1H),5.75(t,J=8.2Hz,1H),5.54(d,J=3.5Hz,1H),4.75(d ,J=12.5Hz,1H),4.61(d,J=12.5Hz,1H),3.88-3.84(m,7H),3.15-3.04(m,1H),2.93(d,J=9.4Hz ,1H),2.54–2.12(m,6H),1.68-1.62(m,1H),1.56(s,3H),1.14(t,J=12.8Hz,1H).HRMS(ESI)m / z C 26 H 31 O7[M+H] + Theoretical value: 455.2064, measured value: 455.2072.

[0211] 2)M86 synthesis

[0212]

[0213] MMB (E)-3-(2,6-dimethoxyphenyl)acrylate (455 mg, 1 mmol) was dissolved in 10 mL of dichloromethane, p-toluenesulfonic acid monohydrate (380 mg, 2 mmol) was added, and the mixture was stirred under reflux at 45°C for 4 h. The reaction was complete after monitoring by TLC. The reaction solution was diluted with 20 mL of dichloromethane, washed once with a saturated aqueous NaHCO3 solution (20 mL), washed three times with a saturated aqueous NaCl solution (20 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated and subjected to rapid silica gel column chromatography (eluent: DCM-EA) to obtain 414 mg of a white solid with a yield of 91%. 1 H NMR(400MHz, CDCl3)δ8.16(d,J=16.3Hz,1H),7.30–7.24(m,1H),6.88(d,J=16.3Hz,1H),6.56(d, J=8.4Hz,2H),6.26(d,J=3.0Hz,1H),5.73(t,J=6.7Hz,1H),5.64(d,J=2.6Hz,1H),5.56(t,J=8.7H z,1H),4.64(d,J=4.9Hz,2H),4.48(d,J=6.7Hz,1H),4.39(t,J=5.9Hz,1H),3.87(s,6H),2.96–2. 75(m,4H),2.17(ddd,J=14.3,5.4,3.2Hz,1H),2.12–1.90(m,2H),1.82(s,3H),1.74–1.60(m,1H). 13 C NMR (101MHz, CDCl3) δ169.66,168.50,160.18,139.61,136.29,134.74,133.54,131.62,128.39,125.89,122 .98,120.11,112.18,103.80,84.97,74.61,68.99,55.91,40.33,32.44,28.76,24.71,20.61.HRMS(ESI)m / z C 26 H 31 O7[M+H] + Theoretical value: 455.2064, measured value: 455.2072.

[0214] Example 22 Synthesis of M118

[0215] 1) MMB (E)-3-(4-nitrophenyl)acrylate

[0216]

[0217] (E)-3-(4-nitrophenyl)acrylic acid (173 mg, 1 mmol), EDCI (575 mg, 3 mmol), DMAP (37 mg, 0.3 mmol), MMB (264 mg, 1 mmol) and 5 mL of DCM were added to a reaction flask and stirred at room temperature until TLC showed that the reaction was complete. The reaction solution was diluted with 20 mL of DCM, and then 20 mL of distilled water was added and stirred for 10 minutes. The dichloromethane phase was separated, and the organic phase was first washed with a saturated sodium bicarbonate solution and then with a saturated saline solution, dried over anhydrous sodium sulfate overnight, concentrated, and the residue was separated by column chromatography (eluent: ethyl acetate-petroleum ether) to obtain 352 mg of a white solid with a yield of 84%. 1 H NMR (400MHz, CDCl3) δ7.72–7.63(m,3H),7.60(d,J=8.1Hz,2H),6.50(d,J=16.0Hz,1H ),6.25(d,J=3.5Hz,1H),5.75(t,J=8.3Hz,1H),5.55(d,J=3.5Hz,1H),4.80(d,J=12.5 Hz,1H),4.63(d,J=12.5Hz,1H),3.87(t,J=9.3Hz,1H),3.00–2.91(m,1H),2.88(d,J=9 .4Hz,1H),2.57–2.11(m,6H),1.77–1.65(m,1H),1.56(s,3H),1.13(t,J=13.0Hz,1H). 13 C NMR (101MHz, CDCl3) δ169.36,165.85,143.15,138.84,138.40,134.75,132.77,131.15,128.51,121.02,12 0.32,118.32,113.72,81.05,67.21,63.33,59.98,42.73,36.63,25.80,24.56,23.91,18.03.HRMS(ESI)m / z C 25 H 26 NO5[M+H] + Theoretical value: 420.1806, measured value: 420.1798.

[0218] 2) Synthesis of M118

[0219]

[0220] MMB's (E)-3-(4-nitrophenyl)acrylate (419 mg, 1 mmol) was dissolved in 10 mL of dichloromethane, p-toluenesulfonic acid monohydrate (380 mg, 2 mmol) was added, and the mixture was stirred under reflux at 45°C for 4 h. The reaction was complete after monitoring by TLC. The reaction solution was diluted with 20 mL of dichloromethane, washed once with a saturated aqueous NaHCO3 solution (20 mL), and washed three times with a saturated aqueous NaCl solution (20 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated and purified by rapid silica gel column chromatography (eluent: DCM-EA) to obtain 268 mg of a white solid with a yield of 64%. 1 H NMR (400MHz, CDCl3) δ7.25(d,J=8.3Hz,2H),6.82(d,J=8.3Hz,2H),6.27(d,J=2.4Hz ,1H),5.66(t,J=6.9Hz,1H),5.58(d,J=2.4Hz,1H),5.51(t,J=8.8Hz,1H),4.62(s,4 H),4.47(d,J=6.3Hz,1H),4.35(t,J=5.8Hz,1H),2.93–2.79(m,3H),2.70(t,J=13.2 Hz,1H),2.13–2.04(m,1H),1.87(t,J=13.2Hz,1H),1.81(s,3H),1.67–1.54(m,1H). 13 C NMR (101MHz, CDCl3) δ169.44,168.56,156.36,139.35,135.34,132.33,129.57,129.34,126.93,125. 13,122.86,115.99,84.64,74.34,69.53,65.68,40.33,31.77,28.44,24.20,20.43.ESI-MS:420[M+H] + .

[0221] Example 23 Synthesis of M122

[0222] 1) MMB (E)-3-(3,4-methylenedioxyphenyl) acrylate

[0223]

[0224] (E)-3-(3,4-methylenedioxyphenyl)propylene (192 mg, 1 mmol), EDCI (575 mg, 3 mmol), DMAP (37 mg, 0.3 mmol), MMB (264 mg, 1 mmol) and 5 mL of DCM were added to the reaction flask and stirred at room temperature until TLC showed that the reaction was complete. The reaction solution was diluted with 20 mL of DCM, and then 20 mL of distilled water was added and stirred for 10 minutes. The dichloromethane phase was separated, and the organic phase was first washed with a saturated sodium bicarbonate solution and then with a saturated saline solution, dried over anhydrous sodium sulfate overnight, concentrated, and the residue was separated by column chromatography (eluent: ethyl acetate-petroleum ether) to obtain 329 mg of a white solid with a yield of 75%. 1 H NMR(400MHz, CDCl3) δ7.60(d,J=15.8Hz,1H),7.01-6.98(m,2H),6.82(d,J=7.8Hz,1H),6.24( d,J=15.8Hz,1H),6.00(s,2H),5.74(t,J=8.5Hz,1H),5.56(d,J=3.1Hz,1H),4.78(d,J=12.5Hz ,1H),4.59(d,J=12.5Hz,1H),3.87(t,J=9.3Hz,1H),3.05–2.91(m,1H),2.89(d,J=9.4Hz,1H), 2.54–2.13(m,6H),1.69(t,J=11.1Hz,1H),1.56(s,3H),1.13(t,J=12.6Hz,1H).HRMS(ESI)m / z C 25 H 27 O7[M+H] + Theoretical value: 439.1751, measured value: 439.1754.

[0225] 2) Synthesis of M122

[0226]

[0227] MMB (E)-3-(3,4-methylenedioxyphenyl)acrylate (438 mg, 1 mmol) was dissolved in 10 mL of dichloromethane, p-toluenesulfonic acid monohydrate (380 mg, 2 mmol) was added, and the mixture was stirred under reflux at 45°C for 4 h. The reaction was complete after monitoring by TLC. The reaction solution was diluted with 20 mL of dichloromethane, washed once with a saturated aqueous NaHCO3 solution (20 mL), washed three times with a saturated aqueous NaCl solution (20 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated and subjected to rapid silica gel column chromatography (eluent: DCM-EA) to obtain 350 mg of a white solid with a yield of 80%. 1H NMR(400MHz, CDCl3)δ7.60(d,J=15.9Hz,1H),7.04–6.97(m,2H),6.81(d,J=7.9Hz,1H),6.3 0–6.19(m,2H),6.00(s,2H),5.71(t,J=6.8Hz,1H),5.61(d,J=2.5Hz,1H),5.56(t,J=8.6Hz ,1H),4.63(d,J=4.1Hz,2H),4.49(d,J=6.4Hz,1H),4.39(t,J=5.8Hz,1H),2.95–2.83(m,3H ),2.83–2.72(m,1H),2.21–2.12(m,1H),2.00–1.88(m,2H),1.82(s,3H),1.74–1.63(m,1H). 13 C NMR (101MHz, CDCl3) δ197.59,169.47,165.97,139.03,137.28,136.20,135.09,132.56,131.67,130.22,128.99 ,126.73,126.19,122.76,81.68,68.14,41.78,33.07,31.66,29.82,26.98,25.20,22.72,21.50.HRMS(ESI)m / zC 25 H 27 O7[M+H] + Theoretical value: 439.1751, measured value: 439.1755.

[0228] Example 24 Synthesis of M127

[0229] 1) 2-Methyl-5-pyrimidinecarboxylate of MMB

[0230]

[0231] 2-Methyl-5-pyrimidinecarboxylic acid (138 mg, 1 mmol), EDCI (575 mg, 3 mmol), DMAP (37 mg, 0.3 mmol), MMB (264 mg, 1 mmol) and 5 mL of DCM were added to the reaction bottle and stirred at room temperature until TLC showed that the reaction was complete. The reaction solution was diluted with 20 mL of DCM, and then 20 mL of distilled water was added and stirred for 10 minutes, and the dichloromethane phase was separated. The organic phase was first washed with a saturated sodium bicarbonate solution and then with a saturated saline solution, dried over anhydrous sodium sulfate overnight, concentrated, and the residue was separated by column chromatography (eluent: ethyl acetate-petroleum ether) to obtain 342 mg of a white solid with a yield of 89%. 1H NMR (400MHz, CDCl3) δ9.17(s,2H),6.27(s,1H),5.80(t,J=8.3Hz,1H),5.56(s,1H),4.95(d,J=12.3Hz,1H),4.76(d,J=12.3Hz,1H),3. 87(t,J=9.2Hz,1H),2.92–2.79(m,5H),2.59–2.32(m,4H),2.31–2.15(m,2H),1.79–1.68(m,1H),1.56(s,3H),1.13(t,J=12.8Hz,1H). 13 C NMR (126MHz, CDCl3) δ172.37,169.30,163.77,158.24,138.65,134.42,131.66,121.16,120.6 6,81.03,67.52,63.41,60.04,42.77,36.68,26.50,25.72,24.27,24.02,18.12.HRMS(ESI)m / z C 21 H 25 O5N2[M+H] + Theoretical value: 385.1758, measured value: 358.1759.

[0232] 2) Synthesis of M-127

[0233]

[0234] The 2-methyl-5-pyrimidinecarboxylate of MMB (384 mg, 1 mmol) was dissolved in 10 mL of dichloromethane, and p-toluenesulfonic acid monohydrate (380 mg, 2 mmol) was added. The mixture was stirred and refluxed at 45°C for 4 h. The reaction was complete after monitoring by TLC. The reaction solution was diluted with 20 mL of dichloromethane, washed once with a saturated aqueous NaHCO3 solution (20 mL), and washed three times with a saturated aqueous NaCl solution (20 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated and purified by rapid silica gel column chromatography (eluent: DCM-EA) to obtain 326 mg of a white solid with a yield of 85%. 1H NMR (400MHz, CDCl3) δ9.17(s,2H),6.28(s,1H),5.76(t,J=6.3Hz,1H),5.63–5.48(m,2H),4.80(s,2H),4.49(d,J=6.4Hz,1H ),4.40(t,J=4.9Hz,1H),3.00–2.78(m,7H),2.20(d,J=14.9Hz,1H),1.93(t,J=13.7Hz,1H),1.82(s,3H),1.76–1.62(m,1H). 13 CNMR (126MHz, CDCl3) δ172.27,169.44,163.84,158.22,139.40,135.47,132.51,129.26,125.27 ,122.98,121.32,84.70,74.54,69.32,40.48,31.96,28.58,26.48,24.21,20.65.HRMS(ESI)m / z C 21 H 25 O5N2[M+H] + Theoretical value: 385.1758, measured value: 358.1761.

[0235] Example 25 Synthesis of M126

[0236] 1) 2-Naphthoate of MMB

[0237]

[0238] 2-Naphthoic acid (172 mg, 1 mmol), EDCI (575 mg, 3 mmol), DMAP (37 mg, 0.3 mmol), MMB (264 mg, 1 mmol) and 5 mL of DCM were added to the reaction flask and stirred at room temperature until TLC showed that the reaction was complete. The reaction solution was diluted with 20 mL of DCM, and then 20 mL of distilled water was added and stirred for 10 minutes, and the dichloromethane phase was separated. The organic phase was first washed with a saturated sodium bicarbonate solution and then with a saturated saline solution, dried over anhydrous sodium sulfate overnight, concentrated, and the residue was separated by column chromatography (eluent: ethyl acetate-petroleum ether) to obtain 381 mg of a white solid with a yield of 91%. 1H NMR (400MHz, CDCl3) δ8.58(s,1H),8.04(d,J=8.6Hz,1H),7.95(d,J=8.6Hz,1H),7.89(d,J=8.4Hz,2H),7.59(d t,J=19.7,7.3Hz,2H),6.23(d,J=3.5Hz,1H),5.83(t,J=8.6Hz,1H),5.54(d,J=3.5Hz,1H),4.98(d,J=12.5Hz, 1H),4.78(d,J=12.5Hz,1H),3.89(t,J=9.3Hz,1H),3.03(t,J=11.2Hz,1H),2.93(d,J=9.4Hz,1H),2.59–2.40( m,3H),2.36(t,J=11.9Hz,1H),2.30–2.14(m,2H),1.73(t,J=11.2Hz,1H),1.57(s,3H),1.15(t,J=13.1Hz,1H). 13 C NMR (126MHz, CDCl3) δ169.47,166.61,138.77,135.78,135.16,132.59,131.31,130.87,129.49,128.65,128.51,127.96, 127.12,127.00,125.21,120.66,81.15,67.35,63.47,60.11,42.90,36.78,25.96,24.71,24333.04,18.16.HRMS(ESI)m / z C 26 H 27 O5[M+H] + Theoretical value: 419.1853, measured value: 419.1856.

[0239] 2) Synthesis of M126

[0240]

[0241] The 2-naphthoate of MMB (418 mg, 1 mmol) was dissolved in 10 mL of dichloromethane, p-toluenesulfonic acid monohydrate (380 mg, 2 mmol) was added, and the mixture was stirred under reflux at 45°C for 4 h. The reaction was complete after monitoring by TLC. The reaction solution was diluted with 20 mL of dichloromethane, washed once with a saturated aqueous NaHCO3 solution (20 mL), washed three times with a saturated aqueous NaCl solution (20 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated and purified by rapid silica gel column chromatography (eluent: DCM-EA) to obtain 347 mg of a white solid with a yield of 83%. 1H NMR (400MHz, CDCl3) δ8.59(s,1H),8.04(d,J=8.1Hz,1H),7.95(d,J=8.1Hz,1H),7.89(d, J=8.4Hz,2H),7.58(dt,J=20.2,7.1Hz,2H),6.24(s,1H),5.81(t,J=6.9Hz,1H),5.62–5. 52(m,2H),5.30(s,1H),4.83(s,2H),4.51(d,J=6.3Hz,1H),4.45(t,J=5.6Hz,1H),3.08– 2.77(m,4H),2.28(d,J=14.8Hz,1H),2.03–1.94(m,1H),1.83(s,3H),1.80–1.65(m,1H). 13 C NMR (126MHz, CDCl3) δ169.60,166.66,139.53,135.75,135.26,133.18,132.61,131.24,129.46,128.70,128.58,128.46, 127.96,127.37,126.97,125.52,125.25,122.99,84.71,74.51,69.45,40.54,32.13,28.66,24.62,20.54.HRMS(ESI)m / z C 26 H 27 O5[M+H] + Theoretical value: 419.1853, measured value: 419.1855.

[0242] Example 26 Synthesis of M137

[0243] 1) Quinoline-4-carboxylate of MMB

[0244]

[0245] Quinoline-4-carboxylic acid (173 mg, 1 mmol), EDCI (575 mg, 3 mmol), DMAP (37 mg, 0.3 mmol), MMB (264 mg, 1 mmol) and 5 mL of DCM were added to the reaction flask and stirred at room temperature until TLC showed that the reaction was complete. The reaction solution was diluted with 20 mL of DCM, and then 20 mL of distilled water was added and stirred for 10 minutes, and the dichloromethane phase was separated. The organic phase was first washed with a saturated sodium bicarbonate solution and then with a saturated saline solution, dried over anhydrous sodium sulfate overnight, concentrated, and the residue was separated by column chromatography (eluent: ethyl acetate-petroleum ether) to obtain 357 mg of a white solid with a yield of 85%. 1H NMR (400MHz, CDCl3) δ9.07 (d, J = 4.4Hz, 1H), 8.81 (d, J = 8.5Hz, 1H), 8.25 (d, J = 8.5Hz, 1H), 7.94 (d, J = 4. 4Hz,1H),7.85(t,J=7.8Hz,1H),7.73(t,J=7.8Hz,1H),6.26(d,J=3.1Hz,1H),5.88(t,J=8.5Hz,1H),5.5 5(d,J=3.1Hz,1H),5.06(d,J=12.5Hz,1H),4.89(d,J=12.5Hz,1H),3.91(t,J=9.3Hz,1H),3.04–2.90(m, 2H),2.67–2.36(m,4H),2.35–2.17(m,2H),1.78(t,J=12.6Hz,1H),1.61(s,3H),1.18(t,J=13.1Hz,1H). 13 C NMR (126MHz, CDCl3) δ169.18,165.76,149.59,138.54,134.44,131.38,130.09,128.55,125.40,125.10 ,122.12,120.41,80.94,67.77,63.32,59.92,42.68,36.61,25.72,24.41,23.92,18.01.HRMS(ESI)m / z C 25 H 26 O5N[M+H] + Theoretical value: 420.1805, measured value: 420.1816.

[0246] 2)M137 synthesis

[0247]

[0248] MMB quinoline-4-carboxylate (419 mg, 1 mmol) was dissolved in 10 mL of dichloromethane, p-toluenesulfonic acid monohydrate (380 mg, 2 mmol) was added, and the mixture was stirred at reflux at 45°C for 4 h. The reaction was complete after monitoring by TLC. The reaction solution was diluted with 20 mL of dichloromethane, washed once with a saturated aqueous NaHCO3 solution (20 mL), washed three times with a saturated aqueous NaCl solution (20 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated and subjected to rapid silica gel column chromatography (eluent: DCM-EA) to obtain 364 mg of a white solid with a yield of 87%. 1H NMR (400MHz, CDCl3) δ9.04(d,J=4.5Hz,1H),8.75(d,J=7.1Hz,1H),8.23(d,J=8.4Hz,1H),7.91(d,J=4.5Hz,1H), 7.80(ddd,J=8.4,6.9,1.5Hz,1H),7.68(ddd,J=8.3,6.9,1.5Hz,1H),6.23(dd,J=3.0,1.0Hz,1H),5.83(t,J=6.9 Hz,1H),5.61–5.52(m,1H),5.51(d,J=2.6Hz,1H),4.88(s,2H),4.51(d,J=6.2Hz,1H),4.42(t,J=5.7Hz,1H),3.0 1–2.83(m,4H),2.27(ddd,J=14.4,5.7,2.9Hz,1H),2.04–1.93(m,1H),1.82(d,J=1.3Hz,3H),1.79–1.66(m,1H). 13 C NMR (126MHz, CDCl3) δ169.44,165.86,149.52,148.82,139.39,135.47,133.00,132.56,130.23,129.92,129.46,128 .61,125.55,125.22,125.21,122.85,122.13,84.70,74.50,69.86,40.45,31.90,28.56,24.47,20.64.HRMS(ESI)m / z C 25 H 26 O5N[M+H] + Theoretical value: 420.1805, measured value: 420.1826.

[0249] Example 27 Synthesis of M138

[0250] 1) Nicotinic acid ester of MMB

[0251]

[0252] Nicotinic acid (123 mg, 1 mmol), EDCI (575 mg, 3 mmol), DMAP (37 mg, 0.3 mmol), MMB (264 mg, 1 mmol) and 5 mL of DCM were added to the reaction flask and stirred at room temperature until TLC showed that the reaction was complete. The reaction solution was diluted with 20 mL of DCM, and then 20 mL of distilled water was added and stirred for 10 minutes. The dichloromethane phase was separated, and the organic phase was first washed with a saturated sodium bicarbonate solution and then with a saturated saline solution, dried over anhydrous sodium sulfate overnight, concentrated, and the residue was separated by column chromatography (eluent: ethyl acetate-petroleum ether) to obtain 325 mg of a white solid with a yield of 88%. 1 H NMR (400MHz, CDCl3) δ9.24(s,1H),8.81(d,J=4.8Hz,1H),8.31(d,J=7.8Hz,1H),7.44(t, J=6.6Hz,1H),6.26(s,1H),5.81(t,J=8.5Hz,1H),5.56(s,1H),4.94(d,J=12.5Hz,1H),4 .78(d,J=12.5Hz,1H),3.88(t,J=9.3Hz,1H),2.97–2.83(m,2H),2.59–2.43(m,2H),2.43 –2.31(m,2H),2.30–2.15(m,2H),1.79–1.69(m,1H),1.57(s,3H),1.14(t,J=13.1Hz,1H). 13 C NMR (126MHz, CDCl3) δ169.24,164.96,153.68,150.83,138.57,137.20,134.55,131.12,125.82,12 3.49,120.49,80.95,67.31,63.30,59.95,42.69,36.60,25.66,24.29,23.88,18.01.HRMS(ESI)m / z C 21 H 24 O5N[M+H] + Theoretical value: 370.1649, measured value: 370.1660.

[0253] 2)M138 synthesis

[0254]

[0255] Nicotinate of MMB (369 mg, 1 mmol) was dissolved in 10 mL of dichloromethane, p-toluenesulfonic acid monohydrate (380 mg, 2 mmol) was added, and the mixture was stirred under reflux at 45°C for 4 h. The reaction was complete after monitoring by TLC. The reaction solution was diluted with 20 mL of dichloromethane, washed once with a saturated aqueous NaHCO3 solution (20 mL), washed three times with a saturated aqueous NaCl solution (20 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated and subjected to rapid silica gel column chromatography (eluent: DCM-EA) to obtain 306 mg of a white solid with a yield of 83%. 1 HNMR(400MHz, CDCl3) δ9.27(d,J=2.3Hz,1H),8.84(dd,J=4.9,1.8Hz,1H),8.35(dt,J=7.9,2.0Hz,1H) ,7.47(dd,J=7.9,4.9Hz,1H),6.30(dd,J=3.0,1.3Hz,1H),5.81(t,J=7.0Hz,1H),5.67–5.52(m,2H),4. 83(s,2H),4.53(d,J=6.2Hz,1H),4.45(t,J=5.7Hz,1H),3.03–2.89(m,3H),2.89–2.79(m,1H),2.26(dd d,J=14.4,5.7,2.9Hz,1H),2.04–1.93(m,1H),1.86(s,3H),1.74(dddd,J=14.8,11.9,5.9,3.0Hz,1H). 13 C NMR (126MHz, CDCl3) δ169.45,164.97,153.35,150.61,139.40,137.53,135.38,132.65,129.02,126. 22,125.29,123.65,122.91,84.64,74.47,69.34,40.45,31.93,28.53,24.30,20.57.HRMS(ESI)m / zC 21 H 24 O5N[M+H] + Theoretical value: 370.1649, measured value: 370.1662.

[0256] Example 28 Synthesis of M139

[0257] 1) Pyrazine-2-carboxylate of MMB

[0258]

[0259] Pyrazine-2-carboxylic acid (124 mg, 1 mmol), EDCI (575 mg, 3 mmol), DMAP (37 mg, 0.3 mmol), MMB (264 mg, 1 mmol) and 5 mL of DCM were added to the reaction flask and stirred at room temperature until TLC showed that the reaction was complete. The reaction solution was diluted with 20 mL of DCM, and then 20 mL of distilled water was added and stirred for 10 minutes, and the dichloromethane phase was separated. The organic phase was first washed with a saturated sodium bicarbonate solution and then with a saturated saline solution, dried over anhydrous sodium sulfate overnight, concentrated, and the residue was separated by column chromatography (eluent: ethyl acetate-petroleum ether) to obtain 315 mg of a white solid with a yield of 85%. 1 H NMR (400MHz, CDCl3) δ9.31 (s, 1H), 8.78 (d, J = 2.3Hz, 1H), 8.70 (d, J = 2.3Hz, 1H), 6.21 (d, J=3.4Hz,1H),5.85(t,J=8.4Hz,1H),5.51(d,J=3.4Hz,1H),5.05(d,J=12.3Hz,1H),4.80 (d,J=12.3Hz,1H),3.87(t,J=9.4Hz,1H),3.15–3.01(m,1H),2.90(d,J=9.4Hz,1H),2.59 –2.28(m,4H),2.29–2.14(m,2H),1.77–1.67(m,1H),1.56(s,3H),1.14(t,J=13.1Hz,1H). 13 C NMR (126MHz, CDCl3) δ169.38,163.83,147.96,146.30,144.56,143.14,138.86,134.30,132.48 ,120.14,80.99,68.45,63.25,59.93,42.75,36.55,25.76,24.67,23.95,18.01.HRMS(ESI)m / z C 20 H 23 O5N2[M+H] + Theoretical value: 371.1602, measured value: 371.1602.

[0260] 2) Synthesis of M139

[0261]

[0262] The pyrazine-2-carboxylate of MMB (370 mg, 1 mmol) was dissolved in 10 mL of dichloromethane, p-toluenesulfonic acid monohydrate (380 mg, 2 mmol) was added, and the mixture was stirred under reflux at 45°C for 4 h. The reaction was complete after monitoring by TLC. The reaction solution was diluted with 20 mL of dichloromethane, washed once with a saturated aqueous NaHCO3 solution (20 mL), washed three times with a saturated aqueous NaCl solution (20 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated and subjected to rapid silica gel column chromatography (eluent: DCM-EA) to obtain 355 mg of a white solid with a yield of 96%. 1 H NMR(400MHz, CDCl3)δ9.31(d,J=1.7Hz,1H),8.80–8.75(m,1H),8.74–8.68(m,1H) ),6.26(d,J=3.1Hz,1H),5.80(t,J=6.7Hz,1H),5.66(d,J=2.7Hz,1H),5.59–5.50 (m,1H),4.90–4.85(m,2H),4.49(d,J=6.4Hz,1H),4.41(t,J=5.8Hz,1H),3.03–2. 77(m,4H),2.27–2.11(m,1H),2.08–1.97(m,1H),1.81(s,3H),1.77–1.66(m,1H). 13 C NMR (126MHz, CDCl3) δ169.63,163.95,147.97,146.39,144.57,143.43,139.57,135.37,132.32, 129.88,125.25,122.89,84.77,74.43,70.76,40.38,32.10,28.63,24.67,20.55.HRMS(ESI)m / z C 20 H 23 O5N2[M+H] + Theoretical value: 371.1601, Measured value: 371.1607. Example 29 Synthesis of M140

[0263] 1) MMB benzoate

[0264]

[0265] Benzoic acid (122 mg, 1 mmol), EDCI (575 mg, 3 mmol), DMAP (37 mg, 0.3 mmol), MMB (264 mg, 1 mmol) and DCM 5 mL were added to the reaction flask and stirred at room temperature until TLC showed that the reaction was complete. The reaction solution was diluted with 20 mL DCM, and then 20 mL distilled water was added and stirred for 10 minutes. The dichloromethane phase was separated, and the organic phase was first washed with a saturated sodium bicarbonate solution and then with a saturated saline solution, dried over anhydrous sodium sulfate overnight, concentrated, and the residue was separated by column chromatography (eluent: ethyl acetate-petroleum ether) to obtain 295 mg of a white solid with a yield of 80%. 1 H NMR (400MHz, CDCl3) δ8.06(d,J=8.1Hz,2H),7.62(t,J=7.4Hz,1H),7.49(t,J=7.6Hz,2H), 6.27(d,J=3.5Hz,1H),5.83(t,J=8.5Hz,1H),5.56(d,J=3.5Hz,1H),4.94(d,J=12.6Hz,1H ),4.77(d,J=12.6Hz,1H),3.91(t,J=9.3Hz,1H),3.05–2.97(m,1H),2.94(d,J=9.5Hz,1H) ,2.61–2.33(m,4H),2.34–2.17(m,2H),1.80–1.69(m,1H),1.60(s,3H),1.23–1.12(m,1H). 13 C NMR (126MHz, CDCl3) δ169.33,166.28,138.62,134.97,133.31,130.65,129.81,129.61,128.54 ,120.45,81.00,67.04,63.32,59.98,42.74,36.64,25.78,24.53,23.87,18.03.HRMS(ESI)m / z C 22 H 25 O5[M+H] + Theoretical value: 369.1702, measured value: 369.1697.

[0266] 2) Synthesis of M140

[0267]

[0268] The benzoate of MMB (368 mg, 1 mmol) was dissolved in 10 mL of dichloromethane, and p-toluenesulfonic acid monohydrate (380 mg, 2 mmol) was added. The mixture was stirred and refluxed at 45°C for 4 h. The reaction was complete after monitoring by TLC. The reaction solution was diluted with 20 mL of dichloromethane, washed once with a saturated aqueous NaHCO3 solution (20 mL), and washed three times with a saturated aqueous NaCl solution (20 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated and purified by rapid silica gel column chromatography (eluent: DCM-EA) to obtain 313 mg of a white solid with a yield of 85%. 1 HNMR (400MHz, CDCl3) δ8.03(d,J=7.7Hz,2H),7.58(t,J=7.3Hz,1H),7.45(t,J=7.6 Hz,2H),6.24(d,J=2.9Hz,1H),5.77(t,J=6.9Hz,1H),5.60–5.52(m,2H),4.77(s,2H ),4.49(d,J=6.3Hz,1H),4.42(t,J=5.8Hz,1H),3.03–2.86(m,3H),2.80(t,J=13.5 Hz,1H),2.28–2.19(m,1H),1.97(t,J=13.5Hz,1H),1.82(s,3H),1.77–1.63(m,1H). 13 C NMR (126MHz, CDCl3) δ169.61,166.47,139.50,135.25,133.33,133.10,130.16,129.72,128.67, 128.63,125.49,122.95,84.67,74.50,69.28,40.51,32.07,28.62,24.56,20.54.HRMS(ESI)m / z C 22 H 25 O5[M+H] + Theoretical value: 369.1697, measured value: 369.1697.

[0269] Example 30 Synthesis of M141

[0270] 1) 4-Chlorobenzoate of MMB

[0271]

[0272] 4-Chlorobenzoic acid (156 mg, 1 mmol), EDCI (575 mg, 3 mmol), DMAP (37 mg, 0.3 mmol), MMB (264 mg, 1 mmol) and 5 mL of DCM were added to the reaction flask and stirred at room temperature until TLC showed that the reaction was complete. The reaction solution was diluted with 20 mL of DCM, and then 20 mL of distilled water was added and stirred for 10 minutes, and the dichloromethane phase was separated. The organic phase was first washed with a saturated sodium bicarbonate solution and then with a saturated saline solution, dried over anhydrous sodium sulfate overnight, concentrated, and the residue was separated by column chromatography (eluent: ethyl acetate-petroleum ether) to obtain 383 mg of a white solid with a yield of 95%. 1 H NMR(400MHz, CDCl3) δ7.96(d,J=8.3Hz,2H),7.43(d,J=8.3Hz,2H),6.25(d,J=3 .4Hz,1H),5.78(t,J=8.4Hz,1H),5.53(d,J=3.4Hz,1H),4.90(d,J=12.5Hz,1H), 4.72(d,J=12.5Hz,1H),3.87(t,J=9.3Hz,1H),2.99–2.87(m,2H),2.57–2.30(m, 4H),2.29–2.13(m,2H),1.77–1.66(m,1H),1.56(s,3H),1.13(t,J=13.0Hz,1H). 13 C NMR (126MHz, CDCl3) δ169.27,165.44,139.83,138.62,134.78,131.01,130.82,128.91,128.24 ,120.46,80.97,67.18,63.31,59.95,42.71,36.62,25.74,24.43,23.88,18.02.HRMS(ESI)m / zC 22 H 24 O5Cl[M+H] + Theoretical value: 403.1312, measured value: 403.1315.

[0273] 2) Synthesis of M141

[0274]

[0275] The 4-chlorobenzoate of MMB (402 mg, 1 mmol) was dissolved in 10 mL of dichloromethane, and p-toluenesulfonic acid monohydrate (380 mg, 2 mmol) was added. The mixture was stirred and refluxed at 45°C for 4 h. The reaction was complete after monitoring by TLC. The reaction solution was diluted with 20 mL of dichloromethane, washed once with a saturated aqueous NaHCO3 solution (20 mL), and washed three times with a saturated aqueous NaCl solution (20 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated and purified by rapid silica gel column chromatography (eluent: DCM-EA) to obtain 354 mg of a white solid with a yield of 88%. 1 H NMR(400MHz, CDCl3) δ7.96(d,J=8.3Hz,2H),7.42(d,J=8.3Hz,2H),6.26(d, J=3.0Hz,1H),5.75(t,J=7.0Hz,1H),5.60–5.52(m,2H),4.75(s,2H),4.50(d ,J=6.2Hz,1H),4.41(t,J=5.8Hz,1H),3.01–2.85(m,3H),2.79(t,J=13.4Hz ,1H),2.27–2.18(m,1H),2.01–1.90(m,1H),1.82(s,3H),1.77–1.64(m,1H). 13 C NMR (126MHz, CDCl3) δ169.55,165.63,139.84,139.49,135.37,132.94,131.11,129.00,128.78, 128.59,125.41,122.96,84.64,74.47,69.32,40.53,31.98,28.59,24.46,20.52.HRMS(ESI)m / z C 22 H 24 O5Cl[M+H] + Theoretical value: 403.1307, measured value: 403.1309.

[0276] Example 31 Synthesis of M142

[0277] 1) Thiophene-2-carboxylate of MMB

[0278]

[0279] Thiophene-2-carboxylic acid (128 mg, 1 mmol), EDCI (575 mg, 3 mmol), DMAP (37 mg, 0.3 mmol), MMB (264 mg, 1 mmol) and 5 mL of DCM were added to the reaction flask and stirred at room temperature until TLC showed that the reaction was complete. The reaction solution was diluted with 20 mL of DCM, and then 20 mL of distilled water was added and stirred for 10 minutes, and the dichloromethane phase was separated. The organic phase was first washed with a saturated sodium bicarbonate solution and then with a saturated saline solution, dried over anhydrous sodium sulfate overnight, concentrated, and the residue was separated by column chromatography (eluent: ethyl acetate-petroleum ether) to obtain 360 mg of a white solid with a yield of 96%. 1 H NMR (400MHz, CDCl3) δ7.80(d,J=4.9Hz,1H),7.58(d,J=5.0Hz,1H),7.11(t,J=4.4Hz,1H),6.23( d,J=3.3Hz,1H),5.79(t,J=8.5Hz,1H),5.52(d,J=3.3Hz,1H),4.87(d,J=12.5Hz,1H),4.71(d,J =12.5Hz,1H),3.86(t,J=9.3Hz,1H),3.03–2.94(m,1H),2.90(d,J=9.4Hz,1H),2.56–2.41(m,2H ),2.41–2.27(m,2H),2.30–2.13(m,2H),1.76–1.65(m,1H),1.56(s,3H),1.13(t,J=13.0Hz,1H). 13 CNMR(126MHz, CDCl3)δ169.35,161.91,138.66,134.80,133.81,133.15,132.85,131.16,127.9 6,120.43,80.97,67.19,63.30,59.97,42.78,36.61,25.79,24.64,23.88,18.03.HRMS(ESI)m / z C 20 H 23 O5S[M+H] + Theoretical value: 375.1266, measured value: 375.1262.

[0280] 2)M142 synthesis

[0281]

[0282] MMB thiophene-2-carboxylate (374 mg, 1 mmol) was dissolved in 10 mL of dichloromethane, p-toluenesulfonic acid monohydrate (380 mg, 2 mmol) was added, and the mixture was stirred under reflux at 45°C for 4 h. The reaction was complete after monitoring by TLC. The reaction solution was diluted with 20 mL of dichloromethane, washed once with a saturated aqueous NaHCO3 solution (20 mL), washed three times with a saturated aqueous NaCl solution (20 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated and purified by rapid silica gel column chromatography (eluent: DCM-EA) to obtain 329 mg of a white solid with a yield of 88%. 1 H NMR(400MHz, CDCl3) δ7.81(d,J=4.6Hz,1H),7.57(d,J=5.0Hz,1H),7.15–7.08(m ,1H),6.25(d,J=3.0Hz,1H),5.76(t,J=7.0Hz,1H),5.59–5.51(m,2H),4.74(s,2H ),4.49(d,J=6.4Hz,1H),4.41(t,J=5.7Hz,1H),3.03–2.85(m,3H),2.79(t,J=13 .5Hz,1H),2.26–2.15(m,1H),2.03–1.92(m,1H),1.82(s,3H),1.78–1.66(m,1H). 13 C NMR (126MHz, CDCl3) δ169.65,162.07,139.49,135.23,133.81,133.53,132.89,132.75,128.88, 128.03,125.39,122.96,84.68,74.50,69.63,40.47,32.18,28.62,24.59,20.59.HRMS(ESI)m / zC 20 H 23 O5S[M+H] + Theoretical value: 375.1261, Measured value: 375.1263. Example 32 Synthesis of M143

[0283] 1) MMB butyrate

[0284]

[0285] n-Butyric acid (88 mg, 1 mmol), EDCI (575 mg, 3 mmol), DMAP (37 mg, 0.3 mmol), MMB (264 mg, 1 mmol) and 5 mL of DCM were added to the reaction flask and stirred at room temperature until TLC showed that the reaction was complete. The reaction solution was diluted with 20 mL of DCM, and then 20 mL of distilled water was added and stirred for 10 minutes. The dichloromethane phase was separated, and the organic phase was first washed with a saturated sodium bicarbonate solution and then with a saturated saline solution, dried over anhydrous sodium sulfate overnight, concentrated, and the residue was separated by column chromatography (eluent: ethyl acetate-petroleum ether) to obtain 194 mg of a white solid with a yield of 58%. 1 H NMR (400MHz, CDCl3) δ6.26(d,J=3.5Hz,1H),5.69(t,J=8.2Hz,1H),5.54(d,J=3 .5Hz,1H),4.67(d,J=12.5Hz,1H),4.46(d,J=12.5Hz,1H),3.85(t,J=9.3Hz,1H ),2.96–2.83(m,2H),2.51–2.35(m,2H),2.34–2.26(m,4H),2.26–2.13(m,2H), 1.73–1.59(m,3H),1.55(s,3H),1.11(t,J=12.7Hz,1H),0.95(t,J=7.4Hz,3H). 13 C NMR (126MHz, CDCl3) δ173.35,169.35,138.78,135.02,130.62,120.27,81.02,66.51,63. 30,59.94,42.69,36.65,36.15,25.78,24.52,23.84,18.44,18.01,13.69.HRMS(ESI)m / z C 19 H 27 O5[M+H] + Theoretical value: 335.1858, measured value: 335.1850.

[0286] 2)M143 synthesis

[0287]

[0288] The n-butyrate of MMB (334 mg, 1 mmol) was dissolved in 10 mL of dichloromethane, p-toluenesulfonic acid monohydrate (380 mg, 2 mmol) was added, and the mixture was stirred under reflux at 45°C for 4 h. The reaction was complete after monitoring by TLC. The reaction solution was diluted with 20 mL of dichloromethane, washed once with a saturated aqueous NaHCO3 solution (20 mL), washed three times with a saturated aqueous NaCl solution (20 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated and purified by rapid silica gel column chromatography (eluent: DCM-EA) to obtain 287 mg of a white solid with a yield of 86%. 1 HNMR (400MHz, CDCl3) δ6.27 (d, J = 2.9 Hz, 1H), 5.65 (t, J = 6.8 Hz, 1H), 5.59 (d, J = 2. 6Hz,1H),5.53(t,J=8.7Hz,1H),4.49(d,J=12.8Hz,3H),4.38(t,J=5.7Hz,1H),2. 98–2.79(m,3H),2.73(td,J=14.4,2.9Hz,1H),2.30(t,J=7.4Hz,2H),2.18–2.07( m,1H),1.96–1.84(m,1H),1.80(s,3H),1.72–1.60(m,3H),0.95(t,J=7.4Hz,3H). 13 C NMR (126MHz, CDCl3) δ173.56,169.60,139.61,135.16,133.21,128.33,125.54,122.84,84 .76,74.49,68.50,40.45,36.37,32.00,28.57,24.41,20.53,18.57,13.81.HRMS(ESI)m / z C 19 H 27 O5[M+H] + Theoretical value: 335.1853, measured value: 335.1855.

[0289] Example 33 Synthesis of M162

[0290]

[0291] MMB (6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-acetate (498 mg, 1 mmol) was dissolved in 10 mL of dichloromethane, p-toluenesulfonic acid monohydrate (380 mg, 2 mmol) was added, and the mixture was stirred at reflux at 45°C for 4 h. The reaction was complete after monitoring by TLC. The reaction solution was diluted with 20 mL of dichloromethane, washed once with a saturated aqueous NaHCO3 solution (20 mL), washed three times with a saturated aqueous NaCl solution (20 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated and purified by rapid silica gel column chromatography (eluent: DCM-EA) to obtain 374 mg of a yellow solid with a yield of 75%. 1 H NMR (400MHz, CDCl3) δ6.59(s,1H),6.49(s,1H),6.26(s,1H),5.71–5.64(m,1H),5.63–5 .56(m,1H),5.53(t,J=8.9Hz,1H),4.59(s,2H),4.47(d,J=6.2Hz,1H),4.38(d,J=5.3Hz, 1H),3.84(s,3H),3.82(s,3H),3.75(s,2H),3.45(s,2H),2.93–2.84(m,7H),2.74(t,J= 14.4Hz,1H),2.23–2.07(m,1H),1.92(t,J=13.3Hz,1H),1.83–1.77(m,3H),1.66(s,1H). 13 C NMR (126MHz, CDCl3) δ170.16,169.55,147.85,147.50,139.51,135.28,132.84,128.91,125.59,125.42,122.95,120.7 0,111.50,109.44,84.78,74.51,68.90,56.07,56.03,54.95,50.83,40.44,31.98,28.57,24.41,20.58.HRMS(ESI)m / z C 28 H 36 O5N[M+H] + Theoretical value: 498.2486, measured value: 498.2489.

[0292] Example 34 Synthesis of M165

[0293] 1) MMB pyrrole-2-carboxylate

[0294]

[0295] Pyrrole-2-carboxylic acid (111 mg, 1 mmol), EDCI (575 mg, 3 mmol), DMAP (37 mg, 0.3 mmol), MMB (264 mg, 1 mmol) and 5 mL of DCM were added to the reaction bottle and stirred at room temperature until TLC showed that the reaction was complete. The reaction solution was diluted with 20 mL of DCM, and then 20 mL of distilled water was added and stirred for 10 minutes, and the dichloromethane phase was separated. The organic phase was first washed with a saturated sodium bicarbonate solution and then with a saturated saline solution, dried over anhydrous sodium sulfate overnight, concentrated, and the residue was separated by column chromatography (eluent: ethyl acetate-petroleum ether) to obtain 318 mg of a white solid with a yield of 89%. 1 H NMR (400MHz, CDCl3) δ9.17(s,1H),6.99(s,1H),6.90(s,1H),6.28(s,1H),6.24( s,1H),5.75(t,J=8.0Hz,1H),5.53(s,1H),4.86(d,J=12.2Hz,1H),4.66(d,J=12. 1Hz,1H),3.86(t,J=9.6Hz,1H),3.05–2.94(m,1H),2.89(d,J=10.1Hz,1H),2.52 –2.08(m,6H),1.69(t,J=10.2Hz,1H),1.60–1.52(m,3H),1.12(t,J=13.0Hz,1H). 13 C NMR (126MHz, CDCl3) δ169.47,160.85,138.76,135.16,130.50,123.44,122.31,120.52,115.64 ,110.79,81.11,66.36,63.37,60.06,42.79,36.72,25.88,24.57,23.92,18.10.HRMS(ESI)m / zC 20 H 24 O5N[M+H] + Theoretical value: 358.1649, measured value: 358.1644.

[0296] 2)M165 synthesis

[0297]

[0298] The pyrrole-2-carboxylate of MMB (357 mg, 1 mmol) was dissolved in 10 mL of dichloromethane, and p-toluenesulfonic acid monohydrate (380 mg, 2 mmol) was added. The mixture was stirred and refluxed at 45°C for 4 h. The reaction was complete when monitored by TLC. The reaction solution was diluted with 20 mL of dichloromethane, washed once with a saturated aqueous NaHCO3 solution (20 mL), and washed three times with a saturated aqueous NaCl solution (20 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated and purified by rapid silica gel column chromatography (eluent: DCM-EA) to obtain 307 mg of a white solid with a yield of 86%. 1 H NMR(400MHz, CDCl3)δ9.21(s,1H),7.00–6.96(m,1H),6.93–6.88(m,1H),6.28(dd,J=3.7,2 .5Hz,1H),6.25(d,J=3.1Hz,1H),5.73(t,J=6.8Hz,1H),5.59–5.51(m,2H),4.80–4.65(m,2 H),4.48(d,J=6.5Hz,1H),4.44–4.36(m,1H),2.91(p,J=7.6,6.8Hz,3H),2.78(t,J=13.3Hz ,1H),2.19(d,J=14.2Hz,1H),1.94(t,J=13.8Hz,1H),1.81(s,3H),1.69(t,J=14.2Hz,1H). 13 C NMR (126MHz, CDCl3) δ169.58,160.96,139.46,135.04,133.19,128.37,125.54,123.31,122.93, 122.56,115.48,110.73,84.70,74.48,68.53,40.40,32.16,28.60,24.45,20.50.HRMS(ESI)m / z C 20 H 24 O5N[M+H] + Theoretical value: 358.1649, measured value: 358.1646.

[0299] Example 35M163 Synthesis

[0300]

[0301] M137 (419 mg, 1 mmol) was dissolved in 5 mL DCM, dimethylamine tetrahydrofuran solution (3 mol) was added, and the mixture was stirred at room temperature for 5 hours. The product was concentrated to remove excess dimethylamine, and column chromatography (mobile phase: DCM-CH3OH) gave 372 mg of white solid, with a yield of 80%. ESI-MS: 465 [M+H]+ .

[0302] Pharmacological experiments

[0303] Experimental Example: In vitro antitumor activity test of parthenolide derivatives

[0304] MTT assay to determine tumor cell survival rate

[0305] After digesting the cells in the logarithmic growth phase with trypsin, a single cell suspension of a certain concentration was prepared. According to the difference in cell growth rate, 1500-3000 cells / well were inoculated in a 96-well plate, and 100 μl of cell suspension was added to each well. The next day, fresh culture medium containing different concentrations of drugs and corresponding solvent controls was added, and 100 μl was added to each well (DMSO final concentration <0.1%). Four dose groups (0.05, 0.5, 5, 50 μmol / L) were set for each test compound, and three parallel wells were set for each group. After continuing to culture at 37°C, 5% CO2 for 96 hours, the supernatant was discarded, and 200 μL of freshly prepared serum-free culture medium containing 0.5 mg / mL MTT was added to each well. Continue to culture for 4 h, discard the supernatant, add 200 μL DMSO to each well to dissolve the MTT formazan precipitate, shake and mix with a micro-oscillator, and measure the optical density (OD) with a microplate reader at a detection wavelength of 570 nm. The tumor cells treated with the solvent control were used as the control group, and the inhibition rate of the drug on the tumor cells was calculated according to the following formula, and the IC was calculated according to the median effect equation 50 value:

[0306]

[0307] The results of in vitro antitumor screening of parthenolide derivatives are shown in Table 1.

[0308] Table 1. MTT screening results of parthenolide derivatives

[0309]

[0310]

[0311] As can be seen from Table 1, the cytotoxicity screening of MMB ester ring-opening dehydrate derivatives found that most derivatives had significantly better anti-tumor activity than the lead compound parthenolide and the positive drug 5-fluorouracil. The IC value of derivative M108 against PANC-1 cancer cells was 50 The value reached 30nM, which is more than 400 times more active than PTL.

Claims

1. A class of parthenolide derivatives represented by the following general formula (I) and pharmaceutically acceptable salts thereof: in: R1 is C 1-4 Alkyl, C 3-6 Cycloalkyl, halocycloalkyl, oxocycloalkyl, C 3-6 Heterocycloalkyl, Ar-SC 1-2 Alkyl, Ar-OC 1-2 Alkyl, YNC 1-2 Alkyl, Ar, Ar-CH=CH-; Ar is phenyl, furanyl, thienyl, pyrrolyl, isoxazolyl, thiazolyl, pyrimidinyl, pyridyl, pyrazinyl, naphthyl, chromonyl, quinolyl, isoquinolyl, anthraquinone; Ar may be substituted by a substituent; The substituents on Ar are selected from halogen, C 1-4 Alkyl, haloC 1-4 Alkyl, C 1-4 Alkoxy, nitrile, methylmercapto, phenyl, nitro, methylenedioxolyl; Y is phthalimide, tetrahydroisoquinolinyl; R2 and R3 are combined to form =C, or R2 is hydrogen and R3 is CH2N(CH3)2.

2. The parthenolide derivative and pharmaceutically acceptable salt thereof according to claim 1, characterized in that: C 1-4 The alkyl group is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl; C 1-4 Alkoxy means methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy and tert-butoxy.

3. The parthenolide derivative and pharmaceutically acceptable salt thereof according to claim 2, characterized in that: The positions of the benzene ring substituents are para, meta, or ortho, and the number of substituents is mono-, di-, or poly-substituted.

4. The parthenolide derivative and pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, characterized in that: The compound is selected from the following:

5. The method for preparing the parthenolide derivative according to any one of claims 1 to 4, characterized in that: The preparation method of the compound is as follows: Reaction step a: first, PTL is oxidized in an oxidant to generate MMB; reaction step b: MMB is esterified with an organic acid under the action of a coupling agent; reaction step c: MMB ester is epoxidized to form a dehydrated compound under the catalysis of Lewis acid; reaction step d: the dehydrated product is subjected to addition reaction with a secondary amine to obtain a compound of formula (I); The definitions of R1, R2 and R3 are the same as those of any one of claims 1 to 4.

6. A pharmaceutical composition, characterized in that The pharmaceutical composition comprises the parthenolide derivative according to any one of claims 1 to 4 and a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient.

7. The pharmaceutical composition according to claim 6, characterized in that The pharmaceutical composition is selected from injections, tablets, capsules, pills and powders.

8. The pharmaceutical composition according to claim 6, characterized in that The pharmaceutical composition is selected from controlled-release dosage forms, sustained-release dosage forms, and various microparticle delivery systems.

9. Use of the parthenolide derivative and a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4 in the preparation of a medicament for preventing or treating tumors or inflammatory immune diseases.

10. The use according to claim 9, characterized in that The tumors include non-small cell lung cancer, colon cancer, gastric cancer, leukemia, lymphoma, and glioma; the inflammatory immune diseases include rheumatoid arthritis, diabetic nephropathy, organ fibrosis, ulcerative colitis, neuromyelitis optica, psoriasis, etc.

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