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-inflammatory, immune and anti-tumor drugs. Background Art

[0002] Natural product libraries are a source of discovering diverse structural skeletons and biological activities, which can be directly applied to the structural optimization of innovative drugs. Sesquiterpenes are the most common metabolites in secondary plants, and their medicinal value has been confirmed by a large number of clinical applications. Because sesquiterpenes and their derivatives have great potential in the treatment of various diseases and have shown good efficacy in clinical trials. Parthenolide (PTL) belongs to the class of geranyl lactone compounds and is commonly found in tansy, a plant of the Asteraceae family, and osmanthus, a plant of the Magnoliaceae family. Previous studies have shown that PTL has rich pharmacological activities, such as analgesic, anti-inflammatory, antioxidant, antibacterial, antiviral, antiprotozoal and anticancer biological activities ( Figure 1 ), these pharmacological activities are the research hotspots of PTL and its derivatives. In the past two decades, PTL has shown good therapeutic potential in many clinical cancer models and combination therapies, and these applications have enriched the derivative library. However, the clinical application of PTL is limited because it has defects such as a narrow therapeutic window and low bioavailability. In order to improve the drugability of PTL and meet clinically acceptable toxicological requirements, a series of new PTL prodrugs were prepared for subsequent clinical trials. Dimethylamino PTL (DMAPT) is an effective hydrophilic PTL derivative and has been used in Phase I clinical trials for acute myeloid leukemia and acute lymphoblastic leukemia. Although these clinical trials were terminated due to poor efficacy and limited therapeutic indications, this encouraged medicinal chemists to perform more structural optimization of PTL to obtain candidate drugs with good efficacy, low side effects and better drugability.

[0003] 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 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 GI50 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 dehydration oxidation 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 a raw material and esterified with pyrazinecarboxylic acid to obtain a pyrazinecarboxylate derivative of MMB, the ester derivative is subjected to epoxy ring opening, molecular dehydration and oxidation under the catalysis of p-toluenesulfonic acid to obtain a ketone compound, the compound is hydrolyzed and the hydroxyl group reacts with the corresponding organic acid to obtain an ester derivative, and finally the ester and amine are added to obtain the compound of the general formula (I) of the present invention, and its pharmaceutically acceptable salt, its preparation method, pharmaceutical composition and its use in the preparation of anti-inflammatory, immune and anti-tumor 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] R 1 C 1-4 Alkyl, substituted C 1-4 Alkyl, C 3-6 Cycloalkyl, substituted C 3-6 Cycloalkyl, C 3-6 Heterocycloalkyl, Ar-SC 1-2 Alkyl, Ar-OC 1-2 Alkyl, YNC 1-2 Alkyl, Ar, Ar-CH=CH-;

[0012] Y is phthalimide, tetrahydroisoquinolinyl;

[0013] R 2 , R 3 Combined to =C, or

[0014] R 2 is hydrogen, R 3 CH 2 N(CH3 ) 2 .

[0015] The above substituents are selected from halogen, methyl and carbonyl.

[0016] The C 1-4 The alkyl group is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl;

[0017] The Ar is selected from aryl selected from phenyl, furanyl, thienyl, pyrrolyl, isoxazolyl, thiazolyl, pyrimidinyl, pyridyl, pyrazinyl, naphthyl, chromonyl, quinolyl, isoquinolyl, anthraquinone;

[0018] The substituents on Ar are selected from halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, nitrile, methylmercapto, phenyl, methylenedioxolyl;

[0019] The C 1-4 Alkoxy means methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy;

[0020] The substituent of the substituted alkane or cycloalkane is selected from halogen, methyl, and carbonyl;

[0021] The positions of the benzene ring substituents are para, meta, or ortho, and the number of the substituents is mono-, di- or poly-substitution.

[0022] The most preferred parthenolide derivatives and pharmaceutically acceptable salts thereof are selected from the following compounds:

[0023]

[0024]

[0025]

[0026] 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:

[0027]

[0028] Reaction step a: first, PTL is oxidized in an oxidant to generate MMB; reaction step b: MMB is converted into an ester by pyrazine carboxylic acid under the action of a coupling agent; reaction step c: MMB ester is epoxidized to an hydrated compound under the catalysis of Lewis acid; reaction step d: the ketone is oxidized to the ketone; reaction step e: the ester is hydrolyzed to obtain a hydroxymethyl compound; reaction step f: the hydroxymethyl compound is reacted with an organic acid to obtain the corresponding ester; reaction step g: the ester and dimethylamine are added to obtain a compound of general formula (I).

[0029] The most preferred reaction steps and reaction conditions are: (a) SeO 2 / t-BuOOH / DCM; (b) R 1 COOH / EDCI / DMAP / DCM; (c)PTSA / DCM; (d)HNMe 2 / DCM(e)LiOH / MeOH / THF;

[0030] (f)R 2 COOH / EDCI / DMAP / DCM; (g)(Me) 2 NH / DCM.

[0031] 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.

[0032] 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.

[0033] 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.

[0034] 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.

[0035] 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.

[0036] 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.

[0037] The fourth aspect of the technical solution of the present invention is to provide 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 inflammatory immune or tumor diseases, wherein the inflammatory immune disease is preferably selected from rheumatoid arthritis, ulcerative colitis, diabetic nephropathy, organ fibrosis, psoriasis, neuromyelitis optica, vitiligo, but not limited to the above immune diseases and aging-related diseases. 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.

[0038] Beneficial technical effects

[0039] The present invention focuses on providing a parthenolide derivative having a general formula (I), wherein a carbonyl group is introduced into the 11-carbon of the MMB ring-opening dehydration derivative, and then the hydroxyl group is esterified to obtain an ester derivative, and finally the esterification product is added to a secondary amine to form an amine. Preliminary activity screening shows that the anti-inflammatory immune activity of some of these derivatives is higher than that of parthenolide, suggesting that these derivatives have a good prospect for treating inflammatory immune diseases. BRIEF DESCRIPTION OF THE DRAWINGS

[0040] Figure 1 Structural formulas of parthenolide, parthenolide dimethylamine adduct, and MMB compound.

[0041] Figure 2 The results of the preliminary screening of the inhibitory activity of all derivatives against IL6-STAT3 (4 concentrations, IC 50 value).

[0042] Figure 3 The results of re-screening of IL6-STAT3 inhibition of 9 derivatives with good initial activity at different time (1 hour, 3 hours) (6 concentrations, IC 50 value). DETAILED DESCRIPTION

[0043] English name and abbreviation:

[0044] DCM: dichloromethane

[0045] DMA: dimethylamine

[0046] DMAP: 4-dimethylaminopyridine

[0047] EA: Ethyl acetate

[0048] 5-FU: 5-fluorouracil

[0049] EDCI: 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride

[0050] MCL: Michelolide

[0051] MMB: melampomagnolide B

[0052] Napabucasin: 2-acetylfurano-1,4-naphthoquinone

[0053] PTL: Parthenolide

[0054] PTSA: p-Toluenesulfonic acid

[0055] TBHP: tert-butyl peroxide

[0056] 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.

[0057] The present invention will be further described below in conjunction with embodiments:

[0058] General synthesis method of compounds:

[0059] The reaction formula is as follows:

[0060]

[0061] Reagents and conditions: (a) SeO 2 / t-BuOOH / DCM; (b) R 1 COOH / EDCI / DMAP / DCM; (c)PTSA / DCM; (d)HNMe 2 / DCM (e) LiOH / MeOH / THF; (f) R 2COOH / EDCI / DMAP / DCM; (g)(Me) 2 NH / DCM.

[0062] Intermediate synthesis method:

[0063] 1) MMB synthesis

[0064]

[0065] 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%. 1 H NMR (400 MHz, CDCl 3 ): δ6.24(d,J=3.6Hz,1H,=CH),5.65(d,J=8.0Hz,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,-CH 2 -),1.76-1.62(m,1H,-CH-),1.55(s,3H,-CH 3 ),1.21-1.04(m,1H,-CH-).HRMS(ESI)m / zc C 15 H 21 O 4 [M+H] + Theoretical value: 265.1434, measured value: 265.1426.

[0066] 2) Synthesis of MMB pyrazine carboxylate

[0067] Pyrazinecarboxylic acid (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 pyrazinecarboxylate. 1 H NMR (400 MHz, CDCl 3 )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),2.59–2.2 8(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 (126 MHz, CDCl 3 )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 O 5 N 2 [M+H] + Theoretical value: 371.1602, measured value: 371.1602.

[0068] 3) Synthesis of the ring-opening dehydrated compound (intermediate 1)

[0069] MMB pyrazine carboxylate (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 and saturated NaHCO 3The mixture was washed once with aqueous solution (20 mL), three times with saturated NaCl solution (20 mL), and anhydrous Na 2 SO 4 After drying and filtering, the filtrate was concentrated and subjected to rapid silica gel column chromatography (eluent: DCM-EA) to obtain the ring-opened anhydrous compound intermediate 1. 1 H NMR (400 MHz, CDCl 3 )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 (126 MHz, CDCl 3 )δ169.63,163.95,147.97,146.39,144.57,143.43,139.57,135.37,132.32,129.88,1 25.25,122.89,84.77,74.43,70.76,40.38,32.10,28.63,24.67,20.55.HRMS(ESI)m / z C 20 H 23 O 5 N 2 [M+H] + Theoretical value: 371.1601, measured value: 371.1607.

[0070] 4) Synthesis of Intermediate 2

[0071] The intermediate 1 (1 mmol) was dissolved in 10 mL of dichloromethane, and Dess-Martin periodinane (1.5 mmol) was added. The mixture was stirred at room temperature for 1 h. The reaction was complete when monitored by TLC. The reaction solution was washed with saturated Na 2 SO 3 Wash once with aqueous solution and saturated NaHCO 3 Wash once with aqueous solution, three times with saturated NaCl solution, and then with anhydrous Na 2 SO 4 After drying and filtering, the filtrate was concentrated and purified by flash silica gel column chromatography (eluent: DCM-EA) to obtain intermediate 2. 1H NMR (400 MHz, CDCl 3 )δ9.37(s,1H),8.83(d,J=2.4Hz,1H),8.75(d,J=2.4Hz,1H),6.36(t,J=9.6 Hz,1H),6.25(s,1H),5.85(dd,J=11.2,5.0Hz,1H),5.62(s,1H),5.45(s,1H ),5.01(d,J=12.5Hz,1H),4.91(d,J=12.5Hz,1H),3.44(q,J=11.9Hz,1H),3 .14–3.06(m,1H),2.95–2.77(m,2H),2.39–2.29(m,1H),2.06–1.86(m,5H). 13 C NMR (126 MHz, CDCl 3 )δ197.50,169.35,163.85,148.04,146.41,144.48,143.18,137.16,135.67,135.20,1 31.87,127.68,122.78,81.60,69.46,41.64,32.88,29.76,25.27,21.45.HRMS(ESI)m / z C 21 H 21 O 5 N 2 [M+H] + Theoretical value: 369.1445, measured value: 369.1446.

[0072] 5) Synthesis of Intermediate 3

[0073] The intermediate 2 (1 mmol) was dissolved in 10 mL of a 1:1 mixed solvent of DCM:MeOH, and LiOH (1.5 mmol) was added. The mixture was stirred at room temperature for 1 h. The reaction was complete after monitoring by TLC. The reaction solution was washed three times with a saturated aqueous NaCl solution and anhydrous Na 2 SO 4 After drying and filtering, the filtrate was concentrated and subjected to rapid silica gel column chromatography (eluent: PE-EA) to obtain intermediate 3. 1H NMR(400MHz,Chloroform-d)δ6.34(t,J=11.4Hz,1H),6.19(s,1H),5.69–5.59(m,1H),5.54(s,1H),5.42(s,1H),4.13(s,2H), 3.36(q,J=12.5,11.6Hz,1H),3.08–2.95(m,1H),2.90–2.76(m,1H),2.74–2.61(m,1H),2.31–2.22(m,1H),1.96–1.76(m,5H).

[0074] General synthesis method:

[0075] 1. Synthesis of corresponding esters

[0076] R 1 COOH (1mmol), EDCI (3mmol), DMAP (0.3mmol), intermediate 3 (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. 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 solid parthenolide ketocarboxylic acid ester.

[0077] 2. Synthesis of compounds of formula I

[0078] 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.

[0079] Example 1 M-0 Synthesis

[0080]

[0081] Intermediate 3 (262 mg, 1 mmol), Dess-Martin periodinane (636 mg, 1.5 mmol) and DCM (5 mL) were added to the reaction flask and stirred at room temperature until TLC showed that the reaction was complete. 2 SO 3 Wash once with aqueous solution and saturated NaHCO 3 Wash once with aqueous solution, three times with saturated NaCl solution, and then with anhydrous Na 2 SO 4After drying, filtering and concentration, the residue was separated by column chromatography (eluent: ethyl acetate-petroleum ether) to obtain 96 mg of white solid with a yield of 37%. 1 H NMR (400 MHz, CDCl 3 )δ9.47(s,1H),6.62(dd,J=11.2,5.5Hz,1H),6.26(t,J=9.4Hz,1H),6.21(d,J=2.0Hz,1H),5.52(d,J=2.0Hz,1H),5.20(d,J=3.1Hz,1H),3.60 (q,J=11.7Hz,1H),3.14–3.01(m,1H),2.81(d,J=11.8Hz,1H),2.71(dt,J=14.1,4.2Hz,1H),2.48(td,J=13.2,4.8Hz,1H),1.97–1.77(m,5H). 13 C NMR (126 MHz, CDCl 3 )δ198.58,194.23,169.06,148.88,141.08,137.54,136.65,131.56,123.22,82.42,41.37,32.13,30.24,21.45,21.28.HRMS(ESI)m / z C 15 H 17 O 4 [M+H] + Theoretical value: 261.1121, measured value: 261.1121.

[0082] Example 2 Synthesis of M-150

[0083]

[0084] n-Butyric acid (88 mg, 1 mmol), EDCI (575 mg, 3 mmol), DMAP (37 mg, 0.3 mmol), intermediate 3 (262 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 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 140 mg of a white solid with a yield of 42%. 1 H NMR (400 MHz, CDCl 3)δ6.33(t,J=9.5Hz,1H),6.21(s,1H),5.66(dd,J=11.2,4.9Hz,1H),5.56(s,1H),5.40(s,1H),4.61(d,J=

[0085] 12.7Hz,1H),4.52(d,J=12.7Hz,1H),3.37(dt,J=14.5,11.1Hz,1H),3.07–2.94(m,1H),2.91–2.79(m,1H),2.77–2.65(m ,1H),2.32(t,J=7.4Hz,2H),2.20(dt,J=14.9,4.1Hz,1H),1.94–1.78(m,5H),1.74–1.60(m,2H),0.96(t,J=7.4Hz,3H). 13 C NMR (126 MHz, CDCl 3 )δ197.61,173.34,169.41,137.24,136.07,134.99,132.78,126.07,122.64,81. 57,67.15,41.66,36.18,32.79,29.65,25.01,21.43,18.43,13.68.HRMS(ESI)m / z C 19 H 25 O 5 [M+H] + Theoretical value: 333.1697, measured value: 333.1697.

[0086] Example 3 Synthesis of M-92

[0087]

[0088] p-Chlorophenoxyacetic acid (187 mg, 1 mmol), EDCI (575 mg, 3 mmol), DMAP (37 mg, 0.3 mmol), intermediate 3 (262 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 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 263 mg of a white solid with a yield of 60.73%. 1 H NMR (400 MHz, CDCl 3)δ7.25(d,J=8.4Hz,2H),6.83(d,J=8.4Hz,2H),6.28(t,J=9.2Hz,1H),6.21(s,1H ),5.65(dd,J=11.1,5.2Hz,1H),5.55(s,1H),5.35(s,1H),4.72(d,J=12.7Hz,1H) ,4.66–4.59(m,3H),3.34(q,J=11.5Hz,1H),3.02–2.91(m,1H),2.87–2.77(m,1H) ,2.73–2.61(m,1H),2.15(dt,J=14.9,4.0Hz,1H),1.88(s,3H),1.84–1.75(m,2H). 13 C NMR (101 MHz, CDCl 3 )δ197.71,169.33,168.50,156.31,137.10,135.59,135.26,131.93,129.60,127.17,127. 00,122.83,115.98,81.57,68.24,65.64,41.62,32.61,29.63,24.95,21.45.HRMS(ESI)m / z C 23 H 24 O 6 Cl[M+H] + Theoretical value: 431.1256, measured value: 431.1274.

[0089] Example 4 M-125 Synthesis

[0090]

[0091] 2-(4-Chlorophenoxy)isobutyric acid (215 mg, 1 mmol), EDCI (575 mg, 3 mmol), DMAP (37 mg, 0.3 mmol), intermediate 3 (262 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 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 263 mg of colorless oil, with a yield of 39%. 1 H NMR (400 MHz, CDCl 3)δ7.17(d,J=7.6Hz,2H),6.72(d,J=9.3Hz,2H),6.30–6.21(m,2H),5.63–5.53 (m,2H),5.32(s,1H),4.63(d,J=12.4Hz,1H),4.54(d,J=12.4Hz,1H),3.31(q,J =11.7Hz,1H),2.90(t,J=8.2Hz,1H),2.83–2.71(m,1H),2.60(dt,J=16.6,8.7 Hz,1H),2.04–1.95(m,1H),1.86(s,3H),1.78–1.67(m,1H),1.66–1.54(m,7H). 13 C NMR (101 MHz, CDCl 3 )δ197.68,173.99,169.47,154.10,137.21,135.69,135.29,132.11,129.33,127.56,127.30,122.93,11 9.92,81.60,79.55,77.48,77.16,76.84,69.21,41.68,32.74,29.74,25.57,25.30,21.55.HRMS(ESI)m / z C 28 H 23 C1O 6 [M+H] + Theoretical value: 459.1569, measured value: 459.1567.

[0092] Example 5 Synthesis of M-160

[0093]

[0094] 2-[(4-Fluorophenyl)thio]acetic acid (186 mg, 1 mmol), EDCI (575 mg, 3 mmol), DMAP (37 mg, 0.3 mmol), intermediate 3 (262 mg, 1 mmol) and DCM (5 mL) 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 116 mg of white oil, with a yield of 27%. 1 H NMR (400 MHz, CDCl 3)δ7.46–7.37(m,2H),7.05–6.96(m,2H),6.28(t,J=9.5Hz,1H),6.22(s,1H),5.66 –5.58(m,1H),5.56(s,1H),5.35(s,1H),4.61(d,J=12.8Hz,1H),4.52(d,J=12.6H z,1H),3.63–3.56(m,2H),3.33(q,J=12.1Hz,1H),3.01–2.91(m,1H),2.86–2.75( m,1H),2.72–2.57(m,1H),2.11(d,J=14.7Hz,1H),1.87(s,3H),1.83–1.71(m,2H). 13 C NMR (126 MHz, CDCl 3 )δ197.80,169.45,169.43,162.61(d,J=248.2Hz),137.24,135.78,135.29,133.55,133.51,133.49,132.27,129.62(d,J =3.4Hz), 126.85, 122.90, 116.46 (d, J = 22.05Hz), 81.67, 68.34, 41.72, 37.88, 32.70, 29.72, 25.02, 21.53. HRMS (ESI) m / zC 23 H 24 FS[M+H] + Theoretical value: 431.1323, measured value: 431.1325.

[0095] Example 6 Synthesis of M-93

[0096]

[0097] Phthaloylglycine (205 mg, 1 mmol), EDCI (575 mg, 3 mmol), DMAP (37 mg, 0.3 mmol), intermediate 3 (262 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 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 409 mg of a white solid with a yield of 91.06%. 1 H NMR (400 MHz, CDCl 3)δ7.89(dd,J=5.3,3.2Hz,2H),7.77(dd,J=5.5,3.2Hz,2H),6.31(t,J=9.5Hz,1H),6.20( s,1H),5.69(dd,J=11.1,5.2Hz,1H),5.57(s,1H),5.36(s,1H),4.71(d,J=12.7Hz,1H),4. 60(d,J=12.7Hz,1H),4.47(s,2H),3.35(q,J=11.7Hz,1H),3.01–2.96(m,1H),2.87–2.77( m,1H),2.75–2.63(m,1H),2.19(dt,J=16.0,4.4Hz,,1H),1.88(s,3H),1.85–1.76(m,2H). 13 C NMR (101 MHz, CDCl 3 )δ197.68,169.37,167.45,167.17,137.04,135.74,135.05,134.46,131.95,126.89,1 23.75,122.87,81.64,68.48,41.60,38.94,32.65,29.70,24.85,21.43.HRMS(ESI)m / z C 25 H 24 NO 7 [M+H] + Theoretical value: 450.1547, measured value: 450.1569.

[0098] Example 7 Synthesis of M-96

[0099]

[0100] 2R-furancarboxylic acid (116 mg, 1 mmol), EDCI (575 mg, 3 mmol), DMAP (37 mg, 0.3 mmol), intermediate 3 (262 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 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 133 mg of colorless oil, with a yield of 37%. 1 H NMR (400 MHz, CDCl 3)δ6.32(t,J=9.5Hz,1H),6.19(s,1H),5.66(dd,J=11.2,5.1Hz,1H),5.59(s,1H),5.39(s ,1H),4.67(d,J=12.6Hz,1H),4.54(d,J=12.6Hz,1H),4.45(dd,J=8.4,5.3Hz,1H),3.98(q ,J=7.2Hz,1H),3.94–3.85(q,J=7.2Hz,1H)),3.43–3.29(m,1H),3.02–2.94(m,1H),2.86- 2.74(m,1H),2.76-2.66(m,1H),2.31–2.13(m,2H), 2.03-1.89(m,3H), 1.85-1.76(m,5H). 13 C NMR (101 MHz, CDCl 3 )δ197.42,173.14,169.47,137.17,136.36,134.71,132.34,126.52,122.77,81.44, 76.68,69.37,67.85,41.60,32.91,30.18,29.71,25.24,24.97,21.40.HRMS(ESI)m / z C 20 H 25 O 6 [M+H] + Theoretical value: 361.1646, measured value: 361.1649.

[0101] Example 8 Synthesis of M-124

[0102]

[0103] 3,3-Difluorocyclobutanecarboxylic acid (136 mg, 1 mmol), EDCI (575 mg, 3 mmol), DMAP (37 mg, 0.3 mmol), intermediate 3 (262 mg, 1 mmol) and DCM (5 mL) 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. 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 76 mg of colorless oil, with a yield of 20%. 1 H NMR (400 MHz, CDCl 3)δ6.31(t,J=9.4Hz,1H),6.20(s,1H),5.66(dd,J=11.1,5.2Hz,1H),5.55(s,1H),5.39(s,1H),4.64(d,J=12.7Hz,1H),4.55(d,J=12.7Hz,1H),3. 36(dt,J=14.2,11.0Hz,1H),3.02–2.93(m,2H),2.88–2.76(m,5H),2.70( td,J=14.4,5.1Hz,1H),2.18(dt,J=14.7,4.2Hz,1H),1.88–1.72(m,5H). 13 C NMR (101 MHz, CDCl 3 )δ197.75,173.14,169.40,137.25,135.88,135.20,132.44,126.74,122.81,118.95(t,J=272.5Hz),81.59,6 7.89,41.72,38.86(t,J=30.6Hz),32.72,29.74,26.66(d,J=14.3Hz),26.25,24.92,21.49.ESI-MS:381[M+H] + .

[0104] Example 9 Synthesis of M-111

[0105]

[0106] (E)-3-(3-trifluoromethylphenyl)acrylic acid (216 mg, 1 mmol), EDCI (575 mg, 3 mmol), DMAP (37 mg, 0.3 mmol), intermediate 3 (262 mg, 1 mmol) and DCM (5 mL) 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 170 mg of a white solid with a yield of 37%. 1 HNMR (400MHz, CDCl 3)δ7.79–7.62(m,4H),7.54(t,J=7.8Hz,1H),6.51(d,J=16.0Hz,1H),6.34(t,J=9.5H z,1H),6.21(s,1H),5.73(dd,J=11.0,5.1Hz,1H),5.56(s,1H),5.40(s,1H),4.77(d, J=12.8Hz,1H),4.65(d,J=12.8Hz,1H),3.45–3.34(m,1H),3.03(t,J=8.0Hz,1H),2. 94–2.79(m,1H),2.79–2.65(m,1H),2.27(dt,J=14.7,4.2Hz,1H),1.96–1.79(m,5H). 13 C NMR (101 MHz, CDCl 3 )δ197.60,169.48,166.08,143.66,137.32,136.41,134.95,134.85,132.55,131.47(q,J=32.2Hz),131.20,129.65,126.94(d,J=3.8Hz ),126.31,124.63(d,J=4.0Hz),123.77(q,J=272.0Hz),122.61,119.53,81.52,67.51,41.73,32.87,29.73,24.95,21.43.HRMS(ESI)m / z C 25 H 24 F 3 O 5 [M+H] + Theoretical value: 461.1570, measured value: 461.1582.

[0107] Example 10 Synthesis of M-154

[0108] 1) 3,4-diacetyl caffeate of intermediate 3

[0109]

[0110] 3,4-diacetyl caffeic acid (264 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 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 132 mg of a yellow solid with a yield of 26%. 1 H NMR (400 MHz, CDCl 3 )δ7.64(d,J=16.3Hz,1H),7.43–7.34(m,2H),7.23(d,J=8.4Hz,1H),6.43–6.29(m,2 H),6.21(s,1H),5.77–5.65(m,1H),5.56(s,1H),5.40(s,1H),4.75(d,J=12.8Hz,1H ),4.63(d,J=12.8Hz,1H),3.38(q,J=11.6,10.3Hz,1H),3.07–2.97(m,1H),2.91–2. 79(m,1H),2.77–2.65(m,1H),2.30(d,J=2.2Hz,6H),2.30–2.21(m,1H),1.88(s,5H).

[0111] 2)M-154 synthesis

[0112]

[0113] The 3,4-diacetyl caffeic acid ester of intermediate 3 (508 mg, 1 mmol) was dissolved in a methanol-dichloromethane (2:1) mixed solvent (3 mL), and guanidine hydrochloride (310 mg, 3.25 mmol) and triethylamine (987 mg, 9.75 mmol) were added and stirred at room temperature. The reaction was complete when monitored by TLC. The reaction solution was diluted with 20 mL of dichloromethane and saturated NaHCO 3 The mixture was washed once with aqueous solution (20 mL), three times with saturated NaCl solution (20 mL), and anhydrous Na 2 SO 4 After drying and filtering, the filtrate was concentrated and subjected to rapid silica gel column chromatography (eluent: DCM-EA) to obtain 318 mg of white solid, with a yield of 75%. 1 H NMR (400 MHz, CDCl 3)δ7.62(d,J=16.1Hz,1H),7.15(s,1H),7.06–6.98(m,1H),6.95–6.89(m ,1H),6.47–6.38(m,1H),6.37–6.20(m,2H),5.75(s,1H),5.64(s,1H),5. 52(s,1H),4.79–4.64(m,2H),3.50–3.35(m,1H),3.18–3.03(m,1H),2.9 7–2.85(m,1H),2.83–2.69(m,1H),2.36–2.24(m,1H),2.06–1.75(m,5H). 13 C NMR (126 MHz, CDCl 3 )δ197.68,170.29,167.24,146.86,145.81,144.14,137.20,136.67,135.22,132.75,127.24,126.72,1 23.37,122.72,115.60,114.86,114.27,81.71,68.12,41.93,33.20,29.81,25.55,21.58.HRMS(ESI)m / z C 20 H 22 O 5 N[M+H] + Theoretical value: 356.1492, measured value: 356.1496.

[0114] Example 11 Synthesis of M-103

[0115]

[0116] (E)-3-(3-methylmercaptophenyl)acrylic acid (194 mg, 1 mmol), EDCI (575 mg, 3 mmol), DMAP (37 mg, 0.3 mmol), intermediate 3 (262 mg, 1 mmol) and DCM (5 mL) 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 236 mg of a white solid with a yield of 54%. 1 H NMR (400 MHz, CDCl 3)δ7.66(d,J=16.0Hz,1H),7.44(d,J=8.1Hz,2H),7.24(d,J=8.1Hz,2H),6.43–6.29(m ,2H),6.21(s,1H),5.72(dd,J=11.1,5.1Hz,1H),5.55(s,1H),5.41(s,1H),4.76(d,J=

[0117] 12.7Hz,1H),4.63(d,J=12.7Hz,1H),3.45–3.33(m,1H),3.04(t,J=8.1Hz,1H),2.89–2.81(m,1 H),2.74(dt,J=14.3,8.9Hz,1H),2.51(s,3H),2.27(dt,J=14.6,4.3Hz,1H),1.95–1.79(m,5H). 13 C NMR (101 MHz, CDCl 3 )δ197.69,169.44,166.77,145.05,142.54,137.27,136.10,135.08,132.76,130.57,130.54,128.51,128. 49,126.34,126.00,122.69,116.27,81.65,67.48,41.73,32.89,29.71,25.13,21.48,15.12.HRMS(ESI)m / z C 25 H 27 O 5 S[M+H] + Theoretical value: 439.1574, measured value: 439.1579.

[0118] Example 12 Synthesis of M-105

[0119]

[0120] (E)-3-(4-biphenyl)acrylic acid (224 mg, 1 mmol), EDCI (575 mg, 3 mmol), DMAP (37 mg, 0.3 mmol), intermediate 3 (262 mg, 1 mmol) and DCM (5 mL) 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 150 mg of a white solid with a yield of 32%. 1H NMR (400 MHz, CDCl 3 )δ7.75(d,J=16.0Hz,1H),7.67–7.57(m,6H),7.46(t,J=7.5Hz,2H),7.38(t,J=7.5 Hz,1H),6.48(d,J=16.0Hz,1H),6.35(t,J=9.6Hz,1H),5.74(dd,J=11.1,5.1Hz,1H) ,5.57(s,1H),5.42(s,1H),4.78(d,J=12.7Hz,1H),4.66(d,J=12.7Hz,1H),3.46–3 .33(m,1H),3.05(t,J=8.4Hz,1H),2.28(dt,J=14.6,4.1Hz,1H),1.98–1.84(m,5H). 13 C NMR (101 MHz, CDCl 3 )δ197.78,169.52,166.78,145.28,143.55,140.14,137.36,136.15,135.19,133.15,132.84,129.08,128.79,128.1 0,127.77,127.73,127.18,126.47,122.81,117.33,81.76,67.62,41.84,32.99,29.82,25.23,21.58.HRMS(ESI)m / z C 30 H 29 O 5 [M+H] + Theoretical value: 499.2010, measured value: 499.2028.

[0121] Example 13 M100 Synthesis

[0122]

[0123] (E)-3-(2,4-dichlorophenyl)acrylic acid (217 mg, 1 mmol), EDCI (575 mg, 3 mmol), DMAP (37 mg, 0.3 mmol), intermediate 3 (262 mg, 1 mmol) and DCM (5 mL) 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. 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 308 mg of a white solid with a yield of 67%. 1HNMR (400MHz, CDCl 3 )δ8.04(d,J=16.0Hz,1H),7.55(d,J=8.5Hz,1H),7.46(s,1H),7.32–7.27(m,1H),6.42(d,J= 16.0Hz,1H),6.33(t,J=9.6Hz,,1H),6.21(s,1H),5.73(dd,J=10.9,5.2Hz,1H),5.55(s,1H), 5.40(s,1H),4.78(d,J=12.7Hz,1H),4.66(d,J=12.7Hz,1H),3.45–3.32(m,1H),3.09–2.99(m ,1H),2.91-2.81(m,1H),2.80–2.67(m,1H),2.27(dt,J=14.4,4.0Hz,1H),1.89–1.82(m,5H). 13 C NMR (101 MHz, CDCl 3 )δ197.81,169.48,166.05,140.26,137.31,136.88,135.99,135.75,135.25,132.68,131.10,130.27,12 8.51,127.84,126.66,122.85,120.63,81.76,67.80,41.82,32.92,29.81,25.16,21.56.HRMS(ESI)m / zC 24 H 23 Cl 2 O 5 [M+H] + Theoretical value: 461.0917, measured value: 461.0908.

[0124] Example 14 Synthesis of M-101

[0125]

[0126] (E)-3-(3,4-dichlorophenyl)acrylic acid (217 mg, 1 mmol), EDCI (575 mg, 3 mmol), DMAP (37 mg, 0.3 mmol), intermediate 3 (262 mg, 1 mmol) and DCM (5 mL) 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. 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 308 mg of a white solid with a yield of 67%. 1 HNMR (400MHz, CDCl 3 )δ7.64–7.56(m,2H),7.49(s,1H),7.35(d,J=8.4Hz,1H),6.43(d,J=16.0Hz,1H),6. 33(t,J=9.5Hz,1H),6.22(s,1H),5.72(dd,J=11.1,5.2Hz,1H),5.56(s,1H),5.40(s, 1H),4.76(d,J=12.8Hz,1H),4.64(d,J=12.8Hz,1H),3.38(q,J=11.3Hz,1H),3.07–2. 98(m,1H),2.90–2.82(m,1H),2.79–2.67(m,1H),2.27(dt,J=14.8,4.8Hz,1H),1.91–

[0127] 1.81 (m, 5H). 13 C NMR (101 MHz, CDCl 3 )δ197.74,169.38,166.05,142.85,137.25,135.94,135.16,134.61,134.16,133.42,132.56,131.06,1 29.71,127.12,126.49,122.69,119.34,81.60,67.53,41.71,32.76,29.67,25.01,21.46.HRMS(ESI)m / z C 24 H 23 Cl 2 O 5

[0128] [M+H] + Theoretical value: 461.0917, measured value: 461.0906.

[0129] Example 15 Synthesis of M-121

[0130]

[0131] (E)-3-(2,6-dichlorophenyl)acrylic acid (217 mg, 1 mmol), EDCI (575 mg, 3 mmol), DMAP (37 mg, 0.3 mmol), intermediate 3 (262 mg, 1 mmol) and DCM (5 mL) 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. 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 317 mg of a white solid with a yield of 69%. 1 HNMR (400MHz, CDCl 3 )δ7.83(d,J=16.4Hz,1H),7.36(d,J=8.0Hz,2H),7.21(t,J=8.0Hz,1H),6.62(d,J=16.4Hz ,1H),6.34(t,J=9.6Hz,1H),6.19(s,1H),5.75(dd,J=11.2,5.0Hz,1H),5.56(s,1H),5.41 (s,1H),4.78(d,J=12.6Hz,1H),4.68(d,J=12.6Hz,1H),3.46–3.32(m,1H),3.03(t,J=8.0 Hz, 1H), 2.90–2.80 (m, 1H), 2.80–2.70 (m, 1H), 2.27 (dt, J = 14.6, 4.1Hz, 1H), 1.88 (s, 5H). 13 C NMR (101 MHz, CDCl 3 )δ197.65,169.51,166.03,139.11,137.24,136.16,135.12,135.07,132.58,131.70,130.26,129. 03,126.78,126.20,122.88,81.74,68.17,41.80,33.08,29.86,29.81,25.24,21.56.HRMS(ESI)m / z C 24 H 23 Cl 2 O 5 [M+H] + Theoretical value: 461.0917, measured value: 461.0927.

[0132] Example 16 Synthesis of M-113

[0133]

[0134] (E)-3-(2-methoxyphenyl)acrylic acid (178 mg, 1 mmol), EDCI (575 mg, 3 mmol), DMAP (37 mg, 0.3 mmol), intermediate 3 (262 mg, 1 mmol) and DCM (5 mL) 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 279 mg of a white solid with a yield of 66%. 1 H NMR (400 MHz, CDCl 3 )δ8.00(d,J=16.1Hz,1H),7.49(d,J=7.7Hz,1H),7.37(t,J=7.0Hz,1H),7.01–6.89(m,2H),6.54(d,J=16 .1Hz,1H),6.35(t,J=8.8Hz,1H),6.19(s,1H),5.73(dd,J=11.2,5.0Hz,1H),5.56(s,1H),5.41(s,1H),4. 76(d,J=12.7Hz,1H),4.64(d,J=12.7Hz,1H),3.88(s,3H),3.39(dt,J=14.1,11.2Hz,1H),3.04(t,J=7.7H z,1H),2.90–2.79(m,1H),2.75(dt,J=14.6,8.9Hz,1H),2.27(dt,J=14.6,4.0Hz,1H),1.94–1.80(m,5H). 13 CNMR (101MHz, CDCl 3 )δ197.58,169.50,167.18,158.47,141.11,137.26,136.28,134.97,132.84,131.90,129.17,126.35,123. 07,122.71,120.83,117.98,111.24,81.67,67.72,55.53,41.73,33.06,29.76,25.25,21.49.HRMS(ESI)m / z C 25 H 27 O 6 [M+H] +Theoretical value: 423.1802, actual value: 423.1807.

[0135] Example 17 Synthesis of M-109

[0136]

[0137] (E)-3-(4-methoxyphenyl)acrylic acid (178 mg, 1 mmol), EDCI (575 mg, 3 mmol), DMAP (37 mg, 0.3 mmol), intermediate 3 (262 mg, 1 mmol) and DCM (5 mL) 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 342 mg of a white solid with a yield of 81%. 1 H NMR (400 MHz, CDCl 3 )δ7.67(d,J=15.9Hz,1H),7.48(d,J=8.3Hz,2H),6.91(d,J=9.1Hz,2H),6.39–6.26(m,2H), 6.20(s,1H),5.72(dd,J=11.0,5.0Hz,1H),5.56(s,1H),5.41(s,1H),4.76(d,J=12.7Hz,1H) ,4.63(d,J=12.7Hz,1H),3.85(s,3H),3.39(q,J=11.8Hz,1H),3.04(t,J=8.3Hz,1H),2.89– 2.81(m,1H),2.74(dt,J=16.6,8.6Hz,1H),2.27(dt,J=14.5,4.2Hz,1H),1.91–1.79(m,5H). 13 C NMR (101 MHz, CDCl 3 )δ197.65,169.48,166.98,161.70,145.31,137.28,136.26,134.98,132.84,129.88,129.86,126.84,126. 21,122.69,114.83,114.48,114.46,81.64,67.41,55.45,41.74,32.95,29.73,25.13,21.48.HRMS(ESI)m / z C 25 H 27 O 6 [M+H]+ Theoretical value: 423.1802, actual value: 423.1816.

[0138] Example 18 Synthesis of M-115

[0139]

[0140] (E)-3-(2,6-dimethoxyphenyl)acrylic acid (208 mg, 1 mmol), EDCI (575 mg, 3 mmol), DMAP (37 mg, 0.3 mmol), intermediate 3 (262 mg, 1 mmol) and DCM (5 mL) 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 394 mg of a white solid with a yield of 87%. 1 HNMR (400MHz, CDCl 3 )δ7.98(d,J=16.1Hz,1H),7.02(s,1H),6.93(d,J=8.9Hz,1H),6.86(d,J=8.9Hz,1H),6.50(d,J=16.1Hz, 1H),6.35(t,J=9.6Hz,1H),6.19(s,1H),5.73(dd,J=11.3,5.0Hz,1H),5.56(s,1H),5.41(s,1H),4.76(d, J=12.6Hz,1H),4.64(d,J=12.7Hz,1H),3.84(s,3H),3.79(s,3H),3.39(q,J=11.8Hz,1H),3.04(t,J=8.1H z,1H),2.91–2.80(m,1H),2.75(dt,J=16.5,8.5Hz,1H),2.27(dt,J=14.3,4.1Hz,1H),1.92–1.83(m,5H). 13 CNMR (101MHz, CDCl 3)δ197.66,169.59,167.14,153.64,153.02,140.92,137.34,136.37,135.05,132.90,126.45,123.67,122.81, 118.28,117.49,113.67,112.54,81.75,67.79,56.15,55.92,41.82,33.13,29.85,25.31,21.58.HRMS(ESI)m / z C 26 H 29 O 7 [M+H] + Theoretical value: 453.1908, measured value: 453.1911.

[0141] Example 19 Synthesis of M-117

[0142]

[0143] (E)-3-(2,5-dimethoxyphenyl)acrylic acid (208 mg, 1 mmol), EDCI (575 mg, 3 mmol), DMAP (37 mg, 0.3 mmol), intermediate 3 (262 mg, 1 mmol) and DCM (5 mL) 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. 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 154 mg of a white solid with a yield of 34%. 1 HNMR (400MHz, CDCl 3 )δ8.16(d,J=16.3Hz,1H),7.33–7.24(m,1H),6.88(d,J=17.5Hz,1H),6.56(d,J=8.4Hz,2H ),6.41–6.32(m,1H),6.17(s,1H),5.73(dd,J=11.4,4.9Hz,1H),5.56(s,1H),5.42(s,1H) ,4.77(d,J=12.6Hz,1H),4.64(d,J=12.5Hz,1H),3.87(s,6H),3.49–3.29(m,1H),3.05(dd ,J=11.5,5.0Hz,1H),2.88–2.70(m,3H),2.27(dt,J=14.7,4.2Hz,1H),1.97–1.75(m,4H). 13 C NMR (101 MHz, CDCl3 )δ197.46,169.58,168.26,160.12,137.27,136.52,136.42,134.86,132.95,131.68,126.35,122. 70,119.75,111.95,103.71,81.68,67.90,55.82,41.75,33.23,29.80,25.41,21.51.HRMS(ESI)m / z C 26 H 29 O 7 [M+H] + Theoretical value: 453.1908, measured value: 453.1910.

[0144] Example 20 Synthesis of M-123

[0145]

[0146] (E)-3-(3,4-methylenedioxyphenyl)propylene (192 mg, 1 mmol), EDCI (575 mg, 3 mmol), DMAP (37 mg, 0.3 mmol), intermediate 3 (262 mg, 1 mmol) and DCM (5 mL) 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. 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 340 mg of a white solid with a yield of 78%. 1 HNMR (400MHz, CDCl 3)δ7.61(d,J=15.8Hz,1H),7.04–6.95(m,2H),6.81(d,J=8.0Hz,1H),6.33(t,J=9.6Hz,1 H),6.20(d,J=18.4Hz,1H),6.01(s,2H),5.77–5.64(m,1H),5.55(s,1H),5.40(s,1H),4. 75(d,J=12.7Hz,1H),4.62(d,J=12.7Hz,1H),3.38(q,J=12.0Hz,1H),3.02(t,J=9.6Hz,1 H),2.92–2.78(m,1H),2.77–2.65(m,1H),2.26(d,J=12.8Hz,1H),1.94–1.77(m,5H).13C NMR (101MHz, CDCl3) δ197.73,169.53,166.91,150.04,148.58,145.43,137.34,136.24,135.11,132.87,128.63,126. 33,124.82,122.79,115.37,108.76,106.54,101.79,81.73,67.50,41.81,33.00,29.81,25.19,21.57.HRMS(ESI)m / z C 25 H 25 O 7 [M+H] + Theoretical value: 437.1599, measured value: 437.1606.

[0147] Example 21 Synthesis of M-119

[0148]

[0149] (E)-3-(3,4-methylenedioxyphenyl)propylene (192 mg, 1 mmol), EDCI (575 mg, 3 mmol), DMAP (37 mg, 0.3 mmol), intermediate 3 (262 mg, 1 mmol) and DCM (5 mL) 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. 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 230 mg of a white solid with a yield of 55%. 1 HNMR (400MHz, CDCl 3)δ7.73–7.65(m,3H),7.61(d,J=8.0Hz,2H),6.52(d,J=16.1Hz,1H),6.33(t,J=9.5Hz,1H ),6.21(s,1H),5.73(dd,J=11.0,5.2Hz,1H),5.55(s,1H),5.40(s,1H),4.78(d,J=12.7H z,1H),4.65(d,J=12.7Hz,1H),3.38(q,J=11.5Hz,1H),3.01–2.97(dd,J=11.5,5.3Hz,1H ),2.92–2.82(m,1H),2.78–2.68(m,1H),2.27(dt,J=14.4,4.4Hz,1H),1.91–1.81(m,5H). 13 C NMR (101 MHz, CDCl 3 )δ197.78,169.38,165.84,143.15,138.39,137.27,135.87,135.23,132.78,132.49,128.51,126.6 9,122.68,121.05,118.30,113.75,81.57,67.71,41.73,32.74,29.67,25.04,21.46.HRMS(ESI)m / z C 25 H 24 NO 5 [M+H] + Theoretical value: 418.1649, measured value: 418.1653.

[0150] Example 22 M-90 Synthesis

[0151]

[0152] 5-Nitrofuran-2-carboxylic acid (157 mg, 1 mmol), EDCI (575 mg, 3 mmol), DMAP (37 mg, 0.3 mmol), intermediate 3 (262 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 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 100 mg of a white solid with a yield of 25%. 1 H NMR (400 MHz, CDCl 3)δ7.37(d,J=3.8Hz,1H),7.34(d,J=3.8Hz,1H),6.30(t,J=10.0Hz,1H),6.23(s, 1H),5.80(dd,J=11.0,5.2Hz,1H),5.61(s,1H),5.40(s,1H),4.89(d,J=12.5Hz,1 H),4.82(d,J=12.5Hz,1H),3.46–3.33(m,1H),3.04(t,J=7.8Hz,1H),2.93–2.82 (m,1H),2.78(dt,J=14.7,8.7Hz,1H),2.28(dt,J=14.5,4.1Hz,1H),1.89(s,5H). 13 C NMR (101 MHz, CDCl 3 )δ

[0153] 197.71,169.40,156.92,144.54,137.04,135.56,135.34,131.72,128.09,123.17 ,119.55,111.74,81.69,69.42,41.74,32.91,29.87,25.24,21.55.HRMS(ESI)m / zC 20 H 20 NO 8

[0154] [M+H] + Theoretical value: 402.1183, measured value: 402.1187.

[0155] Example 23 Synthesis of M-98

[0156]

[0157] 5-Methylisoxazole-4-carboxylic acid (127 mg, 1 mmol), EDCI (575 mg, 3 mmol), DMAP (37 mg, 0.3 mmol), intermediate 3 (262 mg, 1 mmol) and DCM (5 mL) 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. 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 263 mg of colorless oil, with a yield of 71%. 1 H NMR (400 MHz, CDCl 3 )δ

[0158] 8.45(s,1H),6.47–6.25(m,1H),6.19(s,1H),5.72(dd,J=11.0,5.1Hz,1 H),5.51(s,1H),5.39(s,1H),5.29(s,1H),4.81(d,J=12.7Hz,1H),4.69 (d,J=12.7Hz,1H),3.45–3.32(m,1H),3.03–2.96(m,1H),2.86(dt,J=14 .0,6.5Hz,1H),2.70(s,4H),2.25(dt,J=14.0,4.1Hz,1H),1.86(s,5H). 13 C NMR (101 MHz, CDCl 3 )δ197.74,174.86,169.36,161.42,150.02,137.19,135.87,135.23,132.41,126.83,122.84,109 .29,81.59,77.48,77.16,76.84,67.16,41.70,32.67,29.74,24.84,21.50,12.73.HRMS(ESI)m / z C 20 H 22 NO 6 [M+H] + Theoretical value: 372.1442, measured value: 372.1437.

[0159] Example 24 Synthesis of M-161

[0160]

[0161] 4-Benzopyrone-2-carboxylic acid (190 mg, 1 mmol), EDCI (575 mg, 3 mmol), DMAP (37 mg, 0.3 mmol), intermediate 3 (262 mg, 1 mmol) and DCM (5 mL) 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 326 mg of a yellow solid with a yield of 75%. 1 H NMR (400 MHz, CDCl 3)δ8.21(d,J=8.0Hz,1H),7.76(t,J=8.1Hz,1H),7.58(d,J=8.5Hz,1H),7.47(t,J=7.7Hz ,1H),7.13(s,1H),6.34(t,J=9.6Hz,1H),6.22(s,1H),5.86–5.76(m,1H),5.57(s,1H),5 .42(s,1H),4.93(d,J=14Hz,1H),4.84(d,J=12.4Hz,1H),3.41(q,J=12.0Hz,1H),3.08–2 .99(m,1H),2.95–2.85(m,1H),2.83–2.72(m,1H),2.36–2.26(m,1H),1.99–1.86(m,5H). 13 C NMR (126 MHz, CDCl 3 )δ197.74,178.34,169.35,160.50,156.07,151.88,137.16,135.54,135.45,135.12,131.61,128.09,126.3 1,126.00,124.58,123.03,118.86,115.27,81.66,69.75,41.78,32.80,29.84,25.20,21.57.HRMS(ESI)m / z C 25 H 23 O 7 [M+H] + Theoretical value: 435.1438, measured value: 435.1445.

[0162] Example 25 Synthesis of M-145

[0163]

[0164] Nicotinic acid (123 mg, 1 mmol), EDCI (575 mg, 3 mmol), DMAP (37 mg, 0.3 mmol), intermediate 3 (262 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 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 298 mg of a white solid with a yield of 81%. 1H NMR (400MHz, Chloroform-d) δ9.24 (s, 1H), 8.81 (d, J = 3.4Hz, 1H), 8.32 (d, J = 7.9Hz, 1H), 7.45 (d d, J=8.0, 4.8Hz, 1H), 6.38–6.27 (m, 1H), 6.19 (s, 1H), 5.78 (dd, J=11.1, 5.1Hz, 1H), 5.50 (s, 1H) ,5.42(s,1H),4.90(d,J=12.8Hz,1H),4.80(d,J=12.8Hz,1H),3.40(dt,J=14.4,11.1Hz,1H),3. 03(dd,J=10.8,6.0Hz,1H),2.93–2.71(m,2H),2.30(dt,J=14.5,4.1Hz,1H),1.97–1.75(m,5H). 13 C NMR(126MHz,CHLOROFORM-D)δ197.63,169.36,164.93,153.50,150.60,137.53,137.13,135.88,135.21, 132.29,127.05,126.04,123.72,122.85,81.58,68.25,41.72,32.83,29.79,25.08,21.51.HRMS(ESI)m / z C 21 H 22 O 5 N[M+H] + Theoretical value: 368.1492, measured value: 368.1505.

[0165] Example 26 Synthesis of M-146

[0166]

[0167] Pyrazine-2-carboxylic acid (124 mg, 1 mmol), EDCI (575 mg, 3 mmol), DMAP (37 mg, 0.3 mmol), intermediate 3 (262 mg, 1 mmol) and DCM (5 mL) 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. 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 217 mg of a white solid with a yield of 59%. 1 H NMR (400 MHz, CDCl 3)δ9.37(s,1H),8.83(d,J=2.4Hz,1H),8.75(d,J=2.4Hz,1H),6.36(t,J=9.6 Hz,1H),6.25(s,1H),5.85(dd,J=11.2,5.0Hz,1H),5.62(s,1H),5.45(s,1H ),5.01(d,J=12.5Hz,1H),4.91(d,J=12.5Hz,1H),3.44(q,J=11.9Hz,1H),3 .14–3.06(m,1H), 2.95–2.77(m,2H),2.39–2.29(m,1H), 2.06–1.86(m,5H). 13 C NMR (126 MHz, CDCl 3 )δ197.50,169.35,163.85,148.04,146.41,144.48,143.18,137.16,135.67,135.20,1 31.87,127.68,122.78,81.60,69.46,41.64,32.88,29.76,25.27,21.45.HRMS(ESI)m / z C 21 H 21 O 5 N 2 [M+H] + Theoretical value: 369.1445, measured value: 369.1446.

[0168] Example 27 Synthesis of M-144

[0169]

[0170] Quinoline-4-carboxylic acid (173 mg, 1 mmol), EDCI (575 mg, 3 mmol), DMAP (37 mg, 0.3 mmol), intermediate 3 (262 mg, 1 mmol) and DCM (5 mL) 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. 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 238 mg of a white solid with a yield of 57%. 1 H NMR (400 MHz, CDCl 3)δ9.04(d,J=4.4Hz,1H),8.73(d,J=8.6Hz,1H),8.19(d,J=8.6Hz,1H),7.90(d,J=4.4Hz,1H),7.79( t, J=7.8Hz, 1H), 7.67 (t, J=7.7Hz, 1H), 6.38–6.29 (m, 1H), 6.15 (s, 1H), 5.83 (dd, J=11.0, 5.1Hz, 1H) ,5.41(d,J=5.0Hz,2H), 4.98(d,J=12.6Hz,1H), 4.88(d,J=12.6Hz,1H), 3.42(q,J=11.7,11.3Hz,1H) ,3.05(t,J=8.3Hz,1H),2.94–2.83(m,1H),2.84–2.73(m,1H),2.39–2.27(m,1H),1.94–1.83(m,5H). 13 C NMR (126 MHz, CDCl 3 )δ197.59,169.28,165.81,149.69,149.09,137.03,135.73,135.19,134.64,132.18,130.11,130.05,128.4 9,127.22,125.34,125.01,122.74,122.04,81.51,68.53,41.63,32.72,29.70,25.12,21.44.HRMS(ESI)m / z C 25 H 24 O 5 N[M+H] + Theoretical value: 418.1649, measured value: 418.1665.

[0171] Example 28 Synthesis of M-107

[0172]

[0173] Quinoline-6-carboxylic acid (173 mg, 1 mmol), EDCI (575 mg, 3 mmol), DMAP (37 mg, 0.3 mmol), intermediate 3 (262 mg, 1 mmol) and DCM (5 mL) 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 271 mg of a colorless oil with a yield of 65%. 1H NMR (400 MHz, CDCl 3 )δ9.03(s,1H),8.60(s,1H),8.30(d,J=7.8Hz,2H),8.19(d,J=8.5Hz,2H),7.51(dd,J=8.5,4. 2Hz,2H),6.35(t,J=9.6Hz,1H),6.17(s,1H),5.82(dd,J=11.0,5.2Hz,1H),5.48(s,2H),5.44( s,1H),4.95(d,J=12.6Hz,2H),4.84(d,J=12.6Hz,1H), 3.41(q,J=11.3Hz,1H),3.07(t,J=8.2H z,1H),2.94–2.85(m,1H),2.79(dt,J=14.3,8.7Hz,1H),2.42–2.30(m,1H),1.95–1.86(m,5H). 13 C NMR (101 MHz, CDCl 3 )δ197.70,169.45,165.89,152.83,150.16,137.53,137.26,136.07,135.21,132.61,131.23,130.08,128.8 9,127.89,127.54,126.93,122.78,122.20,81.58,68.46,41.84,32.97,29.83,25.29,21.54.HRMS(ESI)m / zC 25 H 24 O 5 N[M+H] + Theoretical value: 418.1649, measured value: 418.1651.

[0174] Example 29 Synthesis of M-147

[0175]

[0176] Benzoic acid (122 mg, 1 mmol), EDCI (575 mg, 3 mmol), DMAP (37 mg, 0.3 mmol), intermediate 3 (262 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 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 187 mg of a white solid with a yield of 51%. 1H NMR (400 MHz, CDCl 3 )δ8.04(d,J=6.7Hz,2H),7.59(t,J=7.4Hz,1H),7.46(t,J=7.7Hz,2H),6.40–6.30(m,1 H),6.16(d,J=1.8Hz,1H),5.78(dd,J=11.1,5.1Hz,1H),5.42(dd,J=4.1,1.7Hz,2H),4 .89(d,J=12.6Hz,1H),4.77(d,J=12.6Hz,1H),3.48–3.34(m,1H),3.08–2.99(m,1H),2 .92–2.82(m,1H),2.82–2.72(m,1H),2.31(dt,J=14.6,4.0Hz,1H),1.92–1.82(m,5H). 13 C NMR (126 MHz, CDCl 3 )δ197.48,169.41,166.28,137.12,136.13,135.00,133.37,132.61,129.85,129.60,12 8.58,126.64,122.69,81.53,68.20,41.70,32.96,29.76,25.22,21.45.HRMS(ESI)m / zC 22 H 23 O 5 [M+H] + Theoretical value: 367.1540, measured value: 367.1540.

[0177] Example 30 Synthesis of M-148

[0178]

[0179] 4-Chlorobenzoic acid (156 mg, 1 mmol), EDCI (575 mg, 3 mmol), DMAP (37 mg, 0.3 mmol), intermediate 3 (262 mg, 1 mmol) and DCM (5 mL) 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. 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 144 mg of a white solid with a yield of 36%. 1 H NMR (400 MHz, CDCl 3)δ7.98(dd,J=8.5,1.6Hz,2H),7.44(dd,J=8.5,1.6Hz,2H),6.33(t,J=9.6Hz,1H),6 .19(d,J=1.8Hz,1H),5.76(dd,J=11.2,5.1Hz,1H),5.46(d,J=1.8Hz,1H),5.41(s,1H ),4.87(d,J=12.6Hz,1H),4.76(d,J=12.6Hz,1H),3.40(q,J=11.5Hz,1H),3.06–2.99 (m,1H),2.92–2.82(m,1H),2.82–2.69(m,1H),2.34–2.25(m,1H),1.92–1.81(m,5H). 13 C NMR (126 MHz, CDCl 3 )δ197.58,169.30,165.44,139.88,137.13,135.85,135.14,132.49,130.99,128.94,12 8.27,126.75,122.67,81.53,68.12,41.67,32.81,29.70,25.08,21.44.HRMS(ESI)m / zC 22 H 22 O 5 Cl[M+H] + Theoretical value: 401.1150, measured value: 401.1150.

[0180] Example 31 Synthesis of M-149

[0181]

[0182] Thiophene-2-carboxylic acid (128 mg, 1 mmol), EDCI (575 mg, 3 mmol), DMAP (37 mg, 0.3 mmol), intermediate 3 (262 mg, 1 mmol) and DCM (5 mL) 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 138 mg of a white solid with a yield of 37%. 1 H NMR (400 MHz, CDCl 3)δ7.83(d,J=4.3Hz,1H),7.59(d,J=5.0Hz,1H),7.13(t,J=4.3Hz,1H),6.35(t,J=9 .6Hz,1H),6.17(s,1H),5.77(dd,J=11.0,4.7Hz,1H),5.45(s,1H),5.43(s,1H),4.8 6(d,J=12.5Hz,1H),4.75(d,J=12.5Hz,1H),3.40(q,J=12.4Hz,1H),3.03(t,J=8.3H z,1H),2.92–2.82(m,1H),2.82–2.71(m,1H),2.34–2.25(m,1H),1.95–1.82(m,5H). 13 C NMR (126 MHz, CDCl 3 )δ197.44,169.41,161.87,137.11,136.06,134.97,133.87,133.15,132.82,132.41,1 28.02,126.89,122.76,81.53,68.57,41.72,33.03,29.81,25.26,21.45.HRMS(ESI)m / z C 20 H 21 O 5 S[M+H] + Theoretical value: 373.1104, measured value: 373.1104.

[0183] Example 32 Synthesis of M-151

[0184]

[0185] Thiophene-3-carboxylic acid (128 mg, 1 mmol), EDCI (575 mg, 3 mmol), DMAP (37 mg, 0.3 mmol), intermediate 3 (262 mg, 1 mmol) and DCM (5 mL) 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 156 mg of a white solid with a yield of 42%. 1 H NMR (400 MHz, CDCl 3)δ8.16–8.10(m,1H),7.56–7.49(m,1H),7.38–7.31(m,1H),6.34(t,J=9.5Hz,1H),6.16(s,1H),5.76(d,J=10.9Hz,1H),5.41(d,J=2.5Hz,2H), 4.85(d,J=12.8Hz,1H),4.71(d,J=12.8Hz,1H),3.48–3.28(m,1H),3.12 –2.97(m,1H),2.94–2.69(m,2H),2.37–2.21(m,1H),1.96–1.74(m,5H). 13 C NMR (126 MHz, CDCl 3 )δ197.67,169.50,162.51,137.25,136.15,135.18,133.34,133.19,132.74,127.92,1 26.70,126.59,122.81,81.67,67.90,41.81,33.05,29.85,25.28,21.57.HRMS(ESI)m / z C 20 H 21 O 5 S[M+H] + Theoretical value: 373.1104, measured value: 373.1119.

[0186] Example 33 Synthesis of M-155

[0187]

[0188] 4-Methyl-2-thiophenecarboxylic acid (142 mg, 1 mmol), EDCI (575 mg, 3 mmol), DMAP (37 mg, 0.3 mmol), intermediate 3 (262 mg, 1 mmol) and DCM (5 mL) 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. 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 301 mg of a white solid with a yield of 78%. 1 H NMR (400 MHz, CDCl 3)δ7.61(s,1H),7.17(s,1H),6.34(t,J=9.8Hz,1H),6.17(d,J=2.9Hz,1H),5.75(d,J=11.2Hz,1H),5.44(d,J=12.3Hz,2H),4.82(d,J=12.5 Hz,1H),4.71(d,J=12.5Hz,1H),3.39(q,J=12.9,12.5Hz,1H),3.06–2.98(m,1H),2.93–2.68(m,2H),2.36–2.16(m,4H),1.95–1.78(m,5H). 13 C NMR (126 MHz, CDCl 3 )δ197.56,169.55,162.06,138.91,137.25,136.20,135.84,135.09,132.75,132.59,128. 68,126.93,122.88,81.65,68.64,41.85,33.16,29.93,25.40,21.57,15.67.HRMS(ESI)m / z C 21 H 23 O 5 S[M+H] + Theoretical value: 387.1261, measured value: 387.1262.

[0189] Example 34 Synthesis of M-156

[0190]

[0191] 5-Acetyl-2-thiophenecarboxylic acid (170 mg, 1 mmol), EDCI (575 mg, 3 mmol), DMAP (37 mg, 0.3 mmol), intermediate 3 (262 mg, 1 mmol) and DCM (5 mL) 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 224 mg of a white solid with a yield of 54%. 1 H NMR (400 MHz, CDCl 3)δ7.79(d,J=3.8Hz,1H),7.65(d,J=3.8Hz,1H),6.34(t,J=9.6Hz,1H),6.20( s,1H),5.84–5.72(m,1H),5.53(s,1H),5.42(s,1H),4.85(d,J=12.0Hz,1H),4 .77(d,J=12.0Hz,1H),3.40(q,J=11.8Hz,1H),3.09–2.97(m,1H),2.95–2.82( m,1H),2.83–2.71(m,1H),2.59(s,3H),2.32–2.24(m,1H),1.96–1.80(m,5H). 13 C NMR (126 MHz, CDCl 3 )δ197.62,190.89,169.43,161.43,149.34,139.18,137.15,135.87,135.26,133.95,132.16,1 31.88,127.30,122.99,81.62,68.92,41.80,32.98,29.89,27.12,25.24,21.56.HRMS(ESI)m / z C 22 H 23 O 6 S[M+H] + Theoretical value: 415.1210, measured value: 415.1225.

[0192] Example 35 Synthesis of M-152

[0193]

[0194] 2-Chlorothiophene-5-carboxylic acid (163 mg, 1 mmol), EDCI (575 mg, 3 mmol), DMAP (37 mg, 0.3 mmol), intermediate 3 (262 mg, 1 mmol) and DCM (5 mL) 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 285 mg of a white solid with a yield of 70%. 1 H NMR (400 MHz, CDCl 3)δ7.60(d,J=4.1Hz,1H),6.95(d,J=4.1Hz,1H),6.32(t,J=9.5Hz,1H),6.18(s ,1H),5.74(dd,J=11.3,5.1Hz,1H),5.48(s,1H),5.40(s,1H),4.81(d,J=12.7 Hz,1H),4.71(d,J=12.7Hz,1H),3.38(q,J=11.9Hz,1H),3.04–2.96(m,1H),2. 90–2.80(m,1H),2.81–2.66(m,1H),2.25(d,J=14.8Hz,1H),1.94–1.79(m,5H). 13 C NMR (126 MHz, CDCl 3 )δ197.63,169.45,161.00,138.07,137.21,135.93,135.24,133.59,132.37,131.33,1 27.63,127.09,122.91,81.67,68.56,41.81,33.00,29.88,25.22,21.57.HRMS(ESI)m / z C 20 H 20 O 5 ClS[M+H] + Theoretical value: 407.0714, measured value: 407.0720.

[0195] Example 36 Synthesis of M-158

[0196]

[0197] 5-Carboxylic acid-2-thiophenecarboxylic acid methyl ester (186 mg, 1 mmol), EDCI (575 mg, 3 mmol), DMAP (37 mg, 0.3 mmol), intermediate 3 (262 mg, 1 mmol) and DCM (5 mL) 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 366 mg of a white solid with a yield of 85%. 1 H NMR (400 MHz, CDCl 3)δ7.75(s,2H),6.34(t,J=9.2Hz,1H),6.19(s,1H),5.81–5.70(m,1H),5.51(s,1H),5.42(s,1H),4.84(d,J=12.6Hz,1H),4.76(d,J=13 .0Hz,1H),3.92(s,3H),3.40(q,J=11.6,11.0Hz,1H),3.07–2.96(m,1H),2.93–2.67(m,2H),2.28(d,J=14.7Hz,1H),1.95–1.78(m,5H). 13 C NMR (126 MHz, CDCl 3 )δ197.55,169.44,161.98,161.33,139.31,138.32,137.17,135.93,135.20,133.58,133.31,1 32.18,127.35,122.94,81.62,69.00,52.83,41.79,33.02,29.90,25.27,21.56.HRMS(ESI)m / z C 22 H 23 O 7 S[M+H] + Theoretical value: 431.1160, measured value: 431.1166.

[0198] Example 37 Synthesis of M-157

[0199]

[0200] Benzothiophene-2-carboxylic acid (178 mg, 1 mmol), EDCI (575 mg, 3 mmol), DMAP (37 mg, 0.3 mmol), intermediate 3 (262 mg, 1 mmol) and DCM (5 mL) 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. 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 363 mg of a white solid with a yield of 86%. 1 H NMR (400 MHz, CDCl 3)δ8.09(s,1H),7.88(t,J=7.9Hz,2H),7.45(dt,J=21.3,7.2Hz,2H),6.35(t,J=9. 8Hz,1H),6.17(s,1H),5.80(dd,J=11.0,5.0Hz,1H),5.51(s,1H),5.44(s,1H),4.8 9(d,J=11.9Hz,1H),4.79(d,J=13.0Hz,1H),3.41(q,J=11.9,11.4Hz,1H),3.06(t ,J=8.4Hz,1H),2.92–2.69(m,2H),2.32(d,J=15.2Hz,1H),1.90(d,J=10.4Hz,5H). 13 C NMR (126 MHz, CDCl 3 )δ197.57,169.47,162.55,142.27,138.68,137.18,136.01,135.15,132.88,132.39,131.15,127.41,1 27.09,125.75,125.27,122.91,122.89,81.62,68.92,41.81,33.05,29.89,25.34,21.53.HRMS(ESI)m / z C 24 H 23 O 5 S[M+H] + Theoretical value: 423.1621, measured value: 423.1267.

[0201] Example 38 Synthesis of M-153

[0202]

[0203] Pyrrole-2-carboxylic acid (111 mg, 1 mmol), EDCI (575 mg, 3 mmol), DMAP (37 mg, 0.3 mmol), intermediate 3 (262 mg, 1 mmol) and DCM (5 mL) 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. 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 231 mg of a white solid with a yield of 65%. 1 H NMR (400 MHz, CDCl 3)δ9.25(s,1H),6.99(s,1H),6.91(s,1H),6.34(t,J=9.3Hz,1H),6.28(s,1H),6 .15(s,1H),5.74(dd,J=10.6,3.9Hz,1H),5.41(d,J=9.6Hz,2H),4.83(d,J=12.7 Hz,1H),4.69(d,J=12.7Hz,1H),3.39(q,J=11.8Hz,1H),3.01(t,J=8.1Hz,1H),2 .93–2.81(m,1H),2.81–2.68(m,1H),2.28(d,J=14.6Hz,1H),1.96–1.76(m,5H). 13 C NMR (126 MHz, CDCl 3 )δ197.65,169.55,160.87,137.20,136.30,135.04,132.79,126.59,123.58,122.83,1 22.33,115.63,110.78,81.60,67.59,41.77,33.10,29.81,25.32,21.54.HRMS(ESI)m / z C 20 H 22 O 5 N[M+H] + Theoretical value: 356.1492, measured value: 356.1496.

[0204] Example 39 Synthesis of M-159

[0205]

[0206] p-Sulfonamide benzoic acid (201 mg, 1 mmol), EDCI (575 mg, 3 mmol), DMAP (37 mg, 0.3 mmol), intermediate 3 (262 mg, 1 mmol) and DCM (5 mL) 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. 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 245 mg of a white solid with a yield of 55%. 1 H NMR (400 MHz, Methanol-d 4)δ8.18(d,J=7.1Hz,2H),8.02(d,J=8.2Hz,2H),6.55(t,J=9.4Hz,1H),6.05(s,1H),5.89–5.79(m,2H),5.53(s,1H),5.49(s,1H),4.95( d,J=13.2Hz,1H),4.87(s,1H),3.63(q,J=12.1Hz,1H),3.13–3.04(m,1H),3.03–2.78(m,2H),2.30(d,J=14.7Hz,1H),1.87–1.75(m,5H). 13 C NMR (126 MHz, METHANOL-D 4 )δ198.90,171.91,166.44,149.32,139.57,139.46,134.94,134.43,133.94,131.18, 1 27.54,127.48,123.16,83.03,69.66,43.27,34.56,30.79,25.79,21.59.HRMS(ESI)m / z C 22 H 24 O 7 NS[M+H] + Theoretical value: 446.1268, measured value: 446.1280.

[0207] Example 40 Synthesis of M-168

[0208] M144 (417 mg, 1 mmol) was dissolved in 5 mL DCM, and dimethylamine tetrahydrofuran solution (3 mol) was added. The mixture was stirred at room temperature for 5 hours. The product was concentrated to remove excess dimethylamine and then purified by column chromatography (mobile phase: DCM-CH 3 OH) to obtain 208 mg of white solid, yield 45%. ESI-MS: 463 [M+H] + .

[0209] Pharmacological experiments

[0210] Experimental Example 1 Preliminary screening results of in vitro anti-inflammatory activity of parthenolide derivatives

[0211] IL6 reporter HEK 293 cells were used to screen the activity of parthenolide derivatives on the IL6-STAT3 signaling pathway to evaluate the potential anti-inflammatory biological activity of this type of derivatives. IL6 reporter HEK 293 is a HEK-Blue RNA expressing human IL-6R and STAT3 genes. TMIL-6 cells (InvivoGen) were stored by the Institute of Materia Medica, Chinese Academy of Medical Sciences. The culture conditions were HEK-Blue TM Selection (1:250), DMEM complete medium with 10% FBS, 100 μg / ml streptomycin, and 100 U / ml penicillin. The STAT3 inhibitor Napabucasin was used as the positive control drug for this system screening. The specific method for detecting the inhibitory activity of the IL6-STAT3 pathway is as follows:

[0212] 1) Plate: IL6 reporter HEK 293 cells were blown down and counted, and plated on a 96-well plate at a concentration of 25,000 cells / 160 μl.

[0213] 2) Drug addition: Add drugs of corresponding concentration every other day, 20 μl / well

[0214] 3) Stimulation: 1 hour after drug addition, add IL-6 stimulator with a final concentration of 5 ng / ml, 20 μl / well

[0215] 4) Detection: After 18 hours, use Quanti-blue reagent for detection. Take a new 96-well plate, add 180μl Quanti-blue solution / well, add 20μl culture cell supernatant, incubate at 37℃ for 1 hour, and detect the OD value at a wavelength of 655nm.

[0216] 5) Inhibition rate was calculated using Excel, and IC was calculated using GraphPad Prism 8.0 software. 50 And draw the picture.

[0217] Inhibition rate = (average absorbance value of the control group - average absorbance value of the drug group) / average absorbance value of the control group x 100%

[0218] Table 1 The results show that 19 derivatives including M-0, M82, M90, etc. have IC inhibitory activity against IL6-STAT3 50 In 10 -6 M level, which is comparable to the STAT3 positive inhibitor Napabucasin; 12 derivatives including M92, M98, and M100 have IC inhibitory activity against IL6-STAT3. 50 In 10 -7 M level, stronger than the STAT3 positive inhibitor Napabucasin.

[0219] Table 1 Results of the inhibitory activity of parthenolide derivatives on IL6-STAT3

[0220]

[0221] Experimental Example 2: Results of rescreening of IL6-STAT3 activity and cytotoxicity of nine primary active compounds

[0222] The inhibitory activity of IL6-STAT3 pathway was initially screened at 10 -7 The derivatives of M were screened at 6 concentrations, and Quanti-blue detection was performed at 1 hour and 3 hours after drug addition, and cell proliferation inhibition activity was detected (CCK8 detection) 24 hours after drug addition. As shown in Table 2, all 6 derivatives have strong inhibitory activity on the IL6-STAT3 signaling pathway (IC 50 at μM level), but had no significant effect on cell proliferation itself (IC 50 >10 μM).

[0223] Table 2 Results of rescreening and cytotoxicity of nine compounds with good initial screening activity against IL6-STAT3

[0224]

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, substituted C 1-4 Alkyl, C 3-6 Cycloalkyl, substituted C 3-6 Cycloalkyl, C 3-6 Heterocycloalkyl, aryl, Ar-SC 1-2 Alkyl, Ar-OC 1-2 Alkyl, YNC 1-2 Alkyl, Ar-CH=CH-; Ar is phenyl or substituted phenyl; the substituents on the phenyl ring are selected from halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, nitrile, methylmercapto, phenyl, methylenedioxy; Y is phthalimide, tetrahydroisoquinolinyl; R2 and R3 are combined to form =C, or R2 is hydrogen, R3 is CH2N(CH3)2; The above substituents are selected from halogen, methyl and carbonyl.

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 1, characterized in that: Aryl is selected from phenyl, furanyl, thienyl, isoxazolyl, pyrimidinyl, pyridinyl, pyrazinyl, naphthyl, chromonyl, quinolyl, isoquinolyl, anthraquinone.

4. 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.

5. 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:

6. The method for preparing the parthenolide derivative according to any one of claims 1 to 5, 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 converted into an ester by pyrazine carboxylic acid under the action of a coupling agent; reaction step c: MMB ester is epoxidized to an hydrated compound under the catalysis of Lewis acid; reaction step d: the ketone is oxidized to the ketone; reaction step e: the ester is hydrolyzed to obtain a hydroxymethyl compound; reaction step f: the hydroxymethyl compound is reacted with an organic acid to obtain the corresponding ester; reaction step g: the ester and dimethylamine are added to obtain a compound of general formula (I).

7. A pharmaceutical composition, characterized in that The pharmaceutical composition comprises the parthenolide derivative according to any one of claims 1 to 5 and a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient.

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

9. The pharmaceutical composition according to claim 7, characterized in that The pharmaceutical composition is selected from controlled-release dosage forms, sustained-release dosage forms, and various microparticle delivery systems.

10. Use of the parthenolide derivative and a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5 in the preparation of a medicament for preventing or treating tumors or inflammatory immune diseases.

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

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