Parthenolide ketone derivatives, pharmaceutical compositions thereof, and methods of preparation and use thereof

Abstract

The application belongs to the technical field of medicine, and discloses a parthenolide derivative (general formula I) and a pharmaceutically acceptable salt thereof, a preparation method of the parthenolide derivative, a pharmaceutical composition of the parthenolide derivative and purposes of the parthenolide derivative, in particular, purposes of the parthenolide derivative in preparation of anti-tumor and immunotherapy drugs.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical technology, specifically relating to a new class of ternolactone derivatives and their salts, pharmaceutical compositions containing them, and their use in the preparation of anti-inflammatory, immunomodulatory, and antitumor drugs. Background Technology

[0002] Natural product libraries are a source of diverse structural frameworks and bioactivities, which can be directly applied to the optimization of innovative drug structures. Sesquiterpenes are the most common metabolites found in secondary plant species, and their medicinal value has been confirmed by numerous clinical applications. This is because sesquiterpenes and their derivatives have great potential in treating a variety of diseases and have shown good efficacy in clinical trials. Parthenolide (PTL) belongs to the geraniol class of compounds and is commonly found in plants such as Artemisia argyi (Asteraceae) and Magnolia officinalis (Magnolia officinalis). Previous studies have shown that PTL possesses rich pharmacological activities, such as analgesia, anti-inflammation, antioxidant, antibacterial, antiviral, antiprotozoal, and anticancer bioactivities. Figure 1 These pharmacological activities are a research hotspot for PTL and its derivatives. Over the past two decades, PTL has shown promising therapeutic potential in numerous clinical cancer models and combination therapies, enriching the derivative library. However, the clinical application of PTL is limited by its narrow therapeutic window and low bioavailability. To improve the druggability of PTL and meet clinically acceptable toxicological requirements, a series of new PTL prodrugs have been prepared for subsequent clinical trials. DimethylaminoPTL (DMAPT), an effective hydrophilic PTL derivative, underwent Phase I clinical trials in acute myeloid leukemia and acute lymphoblastic leukemia. Although these clinical trials were terminated due to poor efficacy and limited therapeutic indications, this has motivated medicinal chemists to further optimize the structure of PTL to obtain candidate drugs with better efficacy, fewer side effects, and improved druggability.

[0003] Yang et al. reported 11 ester derivatives of melampomagnolide B (MMB) (Eur J Med Chem, 2017, 127, 296-304). Compared with PTL and MMB in vitro, some compounds showed better cell growth inhibition on tumor cell lines HL60 and KG1a, but no data were available on in vivo antitumor activity.

[0004] Bommagani et al. reported a series of ester derivatives of MMB and indolecarboxylic acid, benzofuran carboxylic acid, and benzothiophenecarboxylic acid (Eur J Med Chem, 2017, 136, 393-405), and screened tumor cell lines in NCI60. Compared with PTL cytotoxicity, the two ester derivatives showed better cytotoxic effects (against the leukemia cell line GI).50 The concentration ranged from 0.05 to 0.40 μM, but no data on in vivo antitumor activity were available.

[0005] Since parthenolide derivatives have good in vivo safety, and with the deepening research on their mechanism of action and targets, this invention synthesizes a new class of parthenolide epoxy ring-opening dehydration oxidation derivatives, using parthenolide as a lead compound for antitumor or immunomodulatory drugs, and conducts bioactivity screening. Summary of the Invention

[0006] The technical problem solved by this invention is the use of melampomagnolide B (MMB), an oxidation product of terpinol. Figure 1 The ester derivative of MMB is obtained by esterification of pyrazine carboxylic acid with pyrazine carboxylic acid. The ester derivative is then subjected to epoxy ring opening, molecular dehydration and oxidation under the catalysis of p-toluenesulfonic acid to obtain a ketone compound. After hydrolysis of the compound, the hydroxyl group reacts with the corresponding organic acid to obtain an ester derivative. Finally, the ester and amine are added to obtain the compound of general formula (I) of this invention, and its pharmaceutically acceptable salt, its preparation method, pharmaceutical composition and its use in the preparation of anti-inflammatory, immunomodulatory and antitumor drugs.

[0007] To solve the technical problem of this invention, the present invention provides the following technical solution:

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

[0009]

[0010] in:

[0011] R1 is C 1-4 Alkyl, substituted C 1-4 Alkyl, C 3-6 Cycloalkyl, substituted C 3-6 cycloalkyl, C 3-6 Heterocyclic alkyl, Ar-SC 1-2 Alkyl, Ar-OC 1-2 Alkyl, YNC 1-2 Alkyl group, Ar, Ar-CH=CH-;

[0012] Y is phthalimide group, tetrahydroisoquinoline group;

[0013] R2 and R3 can be combined to form C, or

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

[0015] The substituents mentioned above are selected from halogens, methyl groups, and carbonyl groups.

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

[0017] The Ar group is selected from aryl groups, which are selected from phenyl, furanyl, thiophene, pyrrolyl, isoxazolyl, thiazolyl, pyrimidinyl, pyridinyl, pyrazinyl, naphthyl, chromonel, quinolinyl, isoquinolinyl, and anthraquinonel.

[0018] The substituents on Ar are selected from halogens, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, nitrile, methimazole, phenyl, methylenedioxopentane;

[0019] The C mentioned 1-4 Alkyl groups include methyl methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, and tert-butoxy.

[0020] The substituted alkanes or cycloalkanes mentioned herein have substituents selected from halogens, methyl groups, and carbonyl groups;

[0021] The benzene ring substituents are located at para, meta, or ortho positions, and the number of substituents is monosubstituted, disubstituted, or polysubstituted.

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

[0023]

[0024]

[0025]

[0026] The second aspect of the present invention is to provide a method for preparing the compounds described in the table above:

[0027]

[0028] Reaction step a: First, PTL is oxidized by an oxidant to generate MMB; Reaction step b: MMB is esterified by pyrazine carboxylic acid under the action of a coupling agent; Reaction step c: MMB ester is dehydrated by ring-opening of an epoxy compound under Lewis acid catalysis; Reaction step d: The ring-opening dehydrated compound is oxidized to give a ketone; Reaction step e: The ester is hydrolyzed to give a hydroxymethyl compound; Reaction step f: The hydroxymethyl compound reacts with an organic acid to give the corresponding ester; Reaction step g: The ester is added to dimethylamine to give a compound of general formula (I).

[0029] The optimal reaction steps and conditions are: (a) SeO2 / t-BuOOH / DCM; (b) R1COOH / EDCI / DMAP / DCM; (c) PTSA / DCM; (d) HNMe2 / DCM; (e) LiOH / MeOH / THF;

[0030] (f) R2COOH / EDCI / DMAP / DCM; (g) (Me)2NH / DCM.

[0031] The pharmaceutically acceptable salts include inorganic or organic acid salts formed by the compound and organic or inorganic acids. Inorganic acid salts include hydrochloride, hydrobromide, sulfate or hydrogen sulfate, nitrate, phosphate or hydrogen phosphate, etc., while organic acid salts include formate, acetate, trifluoroacetate, benzoate, succinate, fumarate, maleate, lactate, citrate, tartrate, succinate, gluconate, methanesulfonate, benzenesulfonate, p-toluenesulfonate, etc.

[0032] A third aspect of the present invention is to provide a pharmaceutical composition comprising the ternolactone derivative described in the first aspect of the present invention, its pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier or excipient.

[0033] The compounds of the present invention can be administered orally, for example, in capsule, tablet, powder, granule, syrup or similar dosage forms, or non-gastrointestinally, by injection, ointment, suppository or similar dosage forms. These pharmaceutical preparations can be generated by conventional methods using adjuvants well known in the art, such as binders, excipients, stabilizers, disintegrants, flavoring agents, lubricants, etc. Although the dosage varies depending on symptoms and the patient's age, the nature and severity of the disease or disorder, and the route and manner of administration, for oral administration to adult patients, the normal dosage of the compounds of the present invention is 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 daily; for intravenous administration, a dose of 0.1 to 100 mg, preferably 0.5 to 50 mg, can be divided into one to three doses daily.

[0034] The present invention also provides a pharmaceutical composition comprising a ternolactone derivative of formula (I) above, characterized in that the pharmaceutical composition comprises a ternolactone derivative of any one of claims 1-4 and a pharmaceutically acceptable salt thereof, as well as a pharmaceutically acceptable carrier or excipient.

[0035] When used as a drug, the compounds of this invention 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 compounds of this invention, with the remainder being pharmaceutically acceptable, non-toxic, and inert pharmaceutically acceptable carriers and / or excipients for human and animal use, or in combination with other anticancer drugs. The pharmaceutical compositions of this invention can be prepared as injections, tablets, capsules, pills, powders, etc.

[0036] The pharmaceutical compositions of the present invention can be controlled-release dosage forms, sustained-release dosage forms, or various microparticle delivery systems.

[0037] The fourth aspect of this invention provides the use of the parthenolide derivative of formula (I) described in the first aspect and its pharmaceutically acceptable salt, or the pharmaceutical composition described in the third aspect, in the preparation of a medicament for the prevention or treatment of inflammatory, immune, or tumor diseases. The inflammatory and immune diseases are preferably rheumatoid arthritis, ulcerative colitis, diabetic nephropathy, organ fibrosis, psoriasis, neuromyelitis optica, and vitiligo, but are not limited to the aforementioned immune diseases and age-related diseases. The tumors are preferably non-small cell lung cancer, colon cancer, gastric cancer, leukemia, lymphoma, glioma, liver cancer, etc., but are not limited to the aforementioned tumors.

[0038] Beneficial technical effects

[0039] This invention focuses on providing parthenolide derivatives with the general formula (I). The main method involves introducing a carbonyl group at the 11-carbon position of the ring-opening dehydrated MMB derivative, followed by esterification of the hydroxyl group to obtain ester derivatives. Finally, the esterification product undergoes addition with a secondary amine to form an amination. Preliminary activity screening shows that these derivatives exhibit enhanced anti-inflammatory and immunomodulatory activity compared to parthenolide. This suggests that these derivatives hold promising potential for treating inflammatory and immune diseases. Attached Figure Description

[0040] Figure 1 The structural formulas of chrysanthemum lactone, chrysanthemum lactone dimethylamine adduct, and MMB compound.

[0041] Figure 2 Initial screening results of the inhibitory activity of all derivatives against IL6-STAT3 (4 concentrations, IC50) 50 value).

[0042] Figure 3 The results of secondary screening of the nine derivatives with good initial activity against IL6-STAT3 inhibition at different time points (1 hour, 3 hours) (6 concentrations, IC50) 50 value). Detailed Implementation

[0043] English names and abbreviations:

[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: Michelia lactone

[0051] MMB: melampomagnolide B

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

[0053] PTL: Trichoderma lactone

[0054] PTSA: p-Toluenesulfonic acid

[0055] TBHP: tert-butanol peroxide

[0056] This invention discloses a new class of parthenolide derivatives, including their salts, solvates, prodrugs, and pharmaceutical compositions. Those skilled in the art can refer to this document and appropriately modify the process parameters to achieve the desired results. It is particularly important to note that all similar substitutions and modifications are obvious to those skilled in the art and are considered to be included in this invention. The methods and applications of this invention have been described through preferred embodiments. Those skilled in the art will clearly be able to modify or appropriately change and combine the methods and applications described herein without departing from the content, spirit, and scope of this invention to realize and apply the technology of this invention.

[0057] The present invention will be further illustrated below with reference to the embodiments:

[0058] General synthetic methods for compounds:

[0059] The reaction formula is as follows:

[0060]

[0061] Reagents and conditions: (a) SeO2 / t-BuOOH / DCM; (b) R1COOH / EDCI / DMAP / DCM; (c) PTSA / DCM; (d) HNMe2 / DCM; (e) LiOH / MeOH / THF; (f) R2COOH / EDCI / DMAP / DCM; (g) (Me)2NH / DCM.

[0062] Intermediate synthesis method:

[0063] 1) MMB Synthesis

[0064]

[0065] To a 200 mL round-bottom flask, 5 mmol of ternolactone, 2 mmol of selenium dioxide, 10 mmol of 70% TBHP, and 70 mL of dichloromethane were added sequentially. The oil bath temperature was set at 45 °C, and the mixture was stirred for 4 h. After the reaction was complete, the reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated to dryness using a rotary evaporator. The solution was then purified by flash column chromatography (mobile phase: petroleum ether-ethyl acetate) to obtain 620 mg of pale pink solid MMB, with a yield of 46.9%. 1 H NMR (400MHz, CDCl3): 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,-CH2-),1.7 6-1.62(m,1H,-CH-),1.55(s,3H,-CH3),1.21-1.04(m,1H,-CH-).HRMS(ESI)m / zc C 15 H 21 O4[M+H] + Theoretical value: 265.1434, measured value: 265.1426.

[0066] 2) Synthesis of MMB pyrazine carbamate

[0067] Add 1 mmol of pyrazinic acid, 3 mmol of EDCI, 0.3 mmol of DMAP, 1 mmol of MMB, and 5 mL of DCM to a reaction flask and stir at room temperature until TLC shows the reaction is complete. Dilute the reaction solution with 20 mL of DCM, then add 20 mL of distilled water and stir for 10 minutes. Separate the dichloromethane phase. Wash the organic phase first with saturated sodium bicarbonate solution, then with saturated salt solution, dry overnight with anhydrous sodium sulfate, concentrate, and separate the residue by column chromatography (eluent: ethyl acetate-petroleum ether) to obtain solid MMB pyrazinic acid ester. 1H 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.

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

[0069] MMB pyrazine carboxylate (1 mmol) was dissolved in 10 mL of dichloromethane, and p-toluenesulfonic acid monohydrate (2 mmol) was added. The mixture was refluxed and stirred at 45 °C for 4 h. The reaction was monitored by TLC until complete. The reaction solution was diluted with 20 mL of dichloromethane, washed once with 20 mL of saturated NaHCO3 aqueous solution, washed three times with 20 mL of saturated NaCl aqueous solution, 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-opening dehydrated compound intermediate 1. 1H 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.

[0070] 4) Synthesis of intermediate 2

[0071] Intermediate 1 (1 mmol) was dissolved in 10 mL of dichloromethane, and Dysmartin oxidant (1.5 mmol) was added. The mixture was stirred at room temperature for 1 h, and the reaction was monitored by TLC until it was complete. The reaction solution was washed once with saturated Na2SO3 aqueous solution, once with saturated NaHCO3 aqueous solution, and three times with saturated NaCl aqueous solution. After drying with anhydrous Na2SO4, the solution was filtered, concentrated, and subjected to rapid silica gel column chromatography (eluent: DCM-EA) to obtain intermediate 2. 1H NMR (400MHz, CDCl3) δ9.37 (s, 1H), 8.83 (d, J = 2.4Hz, 1H), 8.75 (d, J = 2.4Hz, 1H), 6.36(t,J=9.6Hz,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,1 H),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 (126MHz, CDCl3) δ197.50,169.35,163.85,148.04,146.41,144.48,143.18,137.16,135.67, 135.20,131.87,127.68,122.78,81.60,69.46,41.64,32.88,29.76,25.27,21.45.HRMS(ESI)m / z C 21 H 21 O5N2[M+H] + Theoretical value: 369.1445, measured value: 369.1446.

[0072] 5) Synthesis of intermediate 3

[0073] 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 monitored by TLC until it was complete. The reaction solution was washed three times with saturated NaCl aqueous solution, dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated and subjected to rapid silica gel column chromatography (eluent: PE-EA) to obtain intermediate 3. 1 H 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 the corresponding esters

[0076] R1COOH (1 mmol), EDCI (3 mmol), DMAP (0.3 mmol), intermediate 3 (1 mmol), and 5 mL of DCM were added to a reaction flask and stirred at room temperature until TLC showed 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 washed first with saturated sodium bicarbonate solution, then with saturated salt solution, dried over anhydrous sodium sulfate overnight, concentrated, and the residue was separated by column chromatography (eluent: ethyl acetate-petroleum ether) to obtain solid trichoderma lactone carboxylic acid ester.

[0077] 2. Synthesis of Compounds of General Formula I

[0078] The above compound (1 mmol) was dissolved in 5 mL of DCM, and a dimethylamine tetrahydrofuran solution (3 mmol) was added. The mixture was stirred at room temperature for 5 hours. The product was concentrated to remove excess dimethylamine, and column chromatography was used to obtain compound of general formula I.

[0079] Example 1 M-0 Synthesis

[0080]

[0081] Intermediate 3 (262 mg, 1 mmol), Desmartin oxidant (636 mg, 1.5 mmol), and DCM (5 mL) were added to a reaction flask and stirred at room temperature until TLC showed the reaction was complete. The reaction solution was washed once with saturated Na₂SO₃ aqueous solution, once with saturated NaHCO₃ aqueous solution, and three times with saturated NaCl aqueous solution. After drying with anhydrous Na₂SO₄, the solution was filtered, concentrated, and the residue was separated by column chromatography (eluent: ethyl acetate-petroleum ether) to give 96 mg of white solid, yield 37%. 1 H NMR (400MHz, CDCl3) 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),2.7 1(dt,J=14.1,4.2Hz,1H),2.48(td,J=13.2,4.8Hz,1H),1.97–1.77(m,5H). 13C NMR (126MHz, CDCl3) 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 O4[M+H] + Theoretical value: 261.1121, measured value: 261.1121.

[0082] Example 2: Synthesis of M-150

[0083]

[0084] 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 a reaction flask and stirred at room temperature until TLC showed 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 washed first with saturated sodium bicarbonate solution, then with saturated salt solution, dried over anhydrous sodium sulfate overnight, concentrated, and the residue was separated by column chromatography (eluent: ethyl acetate-petroleum ether) to give 140 mg of white solid, yield 42%. 1 H NMR (400MHz, CDCl3) 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). 13C NMR (126MHz, CDCl3) δ197.61,173.34,169.41,137.24,136.07,134.99,132.78,126.07,12 2.64,81.57,67.15,41.66,36.18,32.79,29.65,25.01,21.43,18.43,13.68.HRMS(ESI)m / z C 19 H 25 O5[M+H] + Theoretical value: 333.1697, measured value: 333.1697.

[0086] Example 3: M-92 Synthesis

[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 a reaction flask and stirred at room temperature until TLC showed 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 washed first with saturated sodium bicarbonate solution, then with saturated salt solution, dried over anhydrous sodium sulfate overnight, concentrated, and the residue was separated by column chromatography (eluent: ethyl acetate-petroleum ether) to give 263 mg of white solid, yield 60.73%. 1 H NMR (400MHz, CDCl3) δ7.25(d,J=8.4Hz,2H),6.83(d,J=8.4Hz,2H),6.28(t,J=9.2Hz,1 H),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). 13C NMR (101MHz, CDCl3) 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 O6Cl[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 a reaction flask and stirred at room temperature until TLC showed 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 washed first with saturated sodium bicarbonate solution, then with saturated salt solution, dried over anhydrous sodium sulfate overnight, concentrated, and the residue was separated by column chromatography (eluent: ethyl acetate-petroleum ether) to give 263 mg of colorless oil, yield 39%. 1 H NMR (400MHz, CDCl3) δ7.17(d,J=7.6Hz,2H),6.72(d,J=9.3Hz,2H),6.30–6.21(m,2 H),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 ,8.7Hz,1H),2.04–1.95(m,1H),1.86(s,3H),1.78–1.67(m,1H),1.66–1.54(m,7H). 13C NMR (101MHz, CDCl3) δ197.68,173.99,169.47,154.10,137.21,135.69,135.29,132.11,129.33,127.56,127.30,1 22.93,119.92,81.60,79.55,77.48,77.16,76.84,69.21,41.68,32.74,29.74,25.57,25.30,21.55.HRMS(ESI)m / z C 28 H 23 ClO6[M+H] + Theoretical value: 459.1569, measured value: 459.1567.

[0092] Example 5: M-160 Synthesis

[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 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 washed first with saturated sodium bicarbonate solution, then with saturated salt solution, dried over anhydrous sodium sulfate overnight, concentrated, and the residue was separated by column chromatography (eluent: ethyl acetate-petroleum ether) to give 116 mg of white oil, yield 27%. 1 H NMR (400MHz, CDCl3) δ7.46–7.37(m,2H),7.05–6.96(m,2H),6.28(t,J=9.5Hz,1H),6.2 2(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=12.6Hz,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). 13C NMR (126MHz, CDCl3) δ197.80,169.45,169.43,162.61(d,J=248.2Hz),137.24,135.78,135.29,133.55,133.51,133.49,132.27,12 9.62(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 a reaction flask and stirred at room temperature until TLC showed 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 washed first with saturated sodium bicarbonate solution, then with saturated salt solution, dried over anhydrous sodium sulfate overnight, concentrated, and the residue was separated by column chromatography (eluent: ethyl acetate-petroleum ether) to give 409 mg of white solid, yield 91.06%. 1 H NMR (400MHz, CDCl3) δ7.89 (dd, J=5.3, 3.2Hz, 2H), 7.77 (dd, J=5.5, 3.2Hz, 2H), 6.31 (t, J=9.5 Hz,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=12.7H z,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). 13C NMR (101MHz, CDCl3) δ197.68,169.37,167.45,167.17,137.04,135.74,135.05,134.46,131.95, 126.89,123.75,122.87,81.64,68.48,41.60,38.94,32.65,29.70,24.85,21.43.HRMS(ESI)m / z C 25 H 24 NO7[M+H] + Theoretical value: 450.1547, measured value: 450.1569.

[0098] Example 7: M-96 Synthesis

[0099]

[0100] 2R-furanic 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 a reaction flask and stirred at room temperature until TLC showed 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 washed first with saturated sodium bicarbonate solution, then with saturated salt solution, dried over anhydrous sodium sulfate overnight, concentrated, and the residue was separated by column chromatography (eluent: ethyl acetate-petroleum ether) to give 133 mg of colorless oil, yield 37%. 1 H NMR (400MHz, CDCl3) 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). 13C NMR (101MHz, CDCl3) δ197.42, 173.14, 169.47, 137.17, 136.36, 134.71, 132.34, 126.52, 122.7 7,81.44,76.68,69.37,67.85,41.60,32.91,30.18,29.71,25.24,24.97,21.40.HRMS(ESI)m / z C 20 H 25 O6[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 a reaction flask and stirred at room temperature until TLC showed 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 washed first with saturated sodium bicarbonate solution, then with saturated salt solution, dried over anhydrous sodium sulfate overnight, concentrated, and the residue was separated by column chromatography (eluent: ethyl acetate-petroleum ether) to give 76 mg of colorless oil, yield 20%. 1 H NMR (400MHz, CDCl3) 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=12.7H z,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). 13C NMR (101MHz, CDCl3) δ197.75, 173.14, 169.40, 137.25, 135.88, 135.20, 132.44, 126.74, 122.81, 118.95 (t, J = 272.5Hz) ,81.59,67.89,41.72,38.86(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-trifluoromethylbenzene)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 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 washed first with saturated sodium bicarbonate solution, then with saturated salt solution, dried over anhydrous sodium sulfate overnight, concentrated, and the residue was separated by column chromatography (eluent: ethyl acetate-petroleum ether) to give 170 mg of white solid, yield 37%. 1 HNMR(400MHz, CDCl3)δ7.79–7.62(m,4H),7.54(t,J=7.8Hz,1H),6.51(d,J=16.0Hz,1H), 6.34(t,J=9.5Hz,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). 13C NMR (101MHz, CDCl3) 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 F3O5[M+H] + Theoretical value: 461.1570, measured value: 461.1582.

[0107] Example 10: Synthesis of M-154

[0108] 1) 3,4-Dacetylcaffeate of intermediate 3

[0109]

[0110] 3,4-Diacetylcaffeic 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 a reaction flask and stirred at room temperature until TLC showed 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 washed first with saturated sodium bicarbonate solution, then with saturated salt solution, dried over anhydrous sodium sulfate overnight, concentrated, and the residue was separated by column chromatography (eluent: ethyl acetate-petroleum ether) to give 132 mg of yellow solid, yield 26%. 1H NMR(400MHz, CDCl3)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,2H),6.21(s,1H),5.77–5.65(m,1H),5.56(s,1H),5.40(s,1H),4.75(d,J=1 2.8Hz,1H),4.63(d,J=12.8Hz,1H),3.38(q,J=11.6,10.3Hz,1H),3.07–2.97(m,1H),2.9 1–2.79(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] Intermediate 3, 3,4-diacetylcaffeate (508 mg, 1 mmol), was dissolved in a methanol-dichloromethane (2:1) mixed solvent (3 mL). Guanidine hydrochloride (310 mg, 3.25 mmol) and triethylamine (987 mg, 9.75 mmol) were added, and the mixture was stirred at room temperature. The reaction was monitored by TLC until complete. The reaction solution was diluted with 20 mL of dichloromethane, washed once with saturated NaHCO3 aqueous solution (20 mL), washed three times with saturated NaCl aqueous 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 give 318 mg of white solid, yield 75%. 1 H NMR(400MHz, CDCl3)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) ,2.97–2.85(m,1H),2.83–2.69(m,1H),2.36–2.24(m,1H),2.06–1.75(m,5H). 13C NMR (126MHz, CDCl3) δ197.68,170.29,167.24,146.86,145.81,144.14,137.20,136.67,135.22,132.75,127.24, 126.72,123.37,122.72,115.60,114.86,114.27,81.71,68.12,41.93,33.20,29.81,25.55,21.58.HRMS(ESI)m / z C 20 H 22 O5N[M+H] + Theoretical value: 356.1492, measured value: 356.1496.

[0114] Example 11 M-103 Synthesis

[0115]

[0116] (E)-3-(3-methylmercaptobenzene)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 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 washed first with saturated sodium bicarbonate solution, then with saturated salt solution, dried over anhydrous sodium sulfate overnight, concentrated, and the residue was separated by column chromatography (eluent: ethyl acetate-petroleum ether) to give 236 mg of white solid, yield 54%. 1 H NMR (400MHz, CDCl3) δ7.66(d,J=16.0Hz,1H),7.44(d,J=8.1Hz,2H),7.24(d,J=8.1Hz,2H),6.4 3–6.29(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). 13C NMR (101MHz, CDCl3) 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 O5S[M+H] + Theoretical value: 439.1574, measured value: 439.1579.

[0118] Example 12 M-105 Synthesis

[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 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 washed first with saturated sodium bicarbonate solution, then with saturated salt solution, dried over anhydrous sodium sulfate overnight, concentrated, and the residue was separated by column chromatography (eluent: ethyl acetate-petroleum ether) to give 150 mg of white solid, yield 32%. 1 H NMR (400MHz, CDCl3) δ7.75 (d, J=16.0Hz, 1H), 7.67–7.57 (m, 6H), 7.46 (t, J=7.5Hz, 2H), 7.38(t,J=7.5Hz,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). 13C NMR (101MHz, CDCl3) 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. 79,128.10,127.77,127.73,127.18,126.47,122.81,117.33,81.76,67.62,41.84,32.99,29.82,25.23,21.58.HRMS(ESI)m / z C 30 H 29 O5[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 a reaction flask and stirred at room temperature until TLC showed 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 washed first with saturated sodium bicarbonate solution, then with saturated salt solution, dried over anhydrous sodium sulfate overnight, concentrated, and the residue was separated by column chromatography (eluent: ethyl acetate-petroleum ether) to give 308 mg of white solid, yield 67%. 1 HNMR(400MHz, CDCl3)δ8.04(d,J=16.0Hz,1H),7.55(d,J=8.5Hz,1H),7.46(s,1H),7.32–7.27(m,1 H),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),5.5 5(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). 13C NMR (101MHz, CDCl3) δ197.81,169.48,166.05,140.26,137.31,136.88,135.99,135.75,135.25,132.68,131.10,1 30.27,128.51,127.84,126.66,122.85,120.63,81.76,67.80,41.82,32.92,29.81,25.16,21.56.HRMS(ESI)m / zC 24 H 23 Cl2O5[M+H] + Theoretical value: 461.0917, measured value: 461.0908.

[0124] Example 14 M-101 Synthesis

[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 a reaction flask and stirred at room temperature until TLC showed 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 washed first with saturated sodium bicarbonate solution, then with saturated salt solution, dried over anhydrous sodium sulfate overnight, concentrated, and the residue was separated by column chromatography (eluent: ethyl acetate-petroleum ether) to give 308 mg of white solid, yield 67%. 1 HNMR (400MHz, CDCl3) δ7.64–7.56(m,2H),7.49(s,1H),7.35(d,J=8.4Hz,1H),6.43(d,J=1 6.0Hz,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),3.0 7–2.98(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). 13C NMR (101MHz, CDCl3) δ197.74,169.38,166.05,142.85,137.25,135.94,135.16,134.61,134.16,133.42,132.56, 131.06,129.71,127.12,126.49,122.69,119.34,81.60,67.53,41.71,32.76,29.67,25.01,21.46.HRMS(ESI)m / z C 24 H 23 Cl2O5

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

[0129] Example 15 M-121 Synthesis

[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 a reaction flask and stirred at room temperature until TLC showed 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 washed first with saturated sodium bicarbonate solution, then with saturated salt solution, dried over anhydrous sodium sulfate overnight, concentrated, and the residue was separated by column chromatography (eluent: ethyl acetate-petroleum ether) to give 317 mg of white solid, yield 69%. 1 HNMR (400MHz, CDCl3) 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=8.0Hz, 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). 13C NMR (101MHz, CDCl3) 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 Cl2O5[M+H] + Theoretical value: 461.0917, measured value: 461.0927.

[0132] Example 16 M-113 Synthesis

[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 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 washed first with saturated sodium bicarbonate solution, then with saturated salt solution, dried over anhydrous sodium sulfate overnight, concentrated, and the residue was separated by column chromatography (eluent: ethyl acetate-petroleum ether) to give 279 mg of white solid, yield 66%. 1 H NMR (400MHz, CDCl3) 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= 7.7Hz,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, CDCl3)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 O6[M+H] + Theoretical value: 423.1802, Actual value: 423.1807.

[0135] Example 17 M-109 Synthesis

[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 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 washed first with saturated sodium bicarbonate solution, then with saturated salt solution, dried over anhydrous sodium sulfate overnight, concentrated, and the residue was separated by column chromatography (eluent: ethyl acetate-petroleum ether) to give 342 mg of white solid, yield 81%. 1 H NMR (400MHz, CDCl3) 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). 13C NMR (101MHz, CDCl3) 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 O6[M+H] + Theoretical value: 423.1802, Actual value: 423.1816.

[0138] Example 18 M-115 Synthesis

[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 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 washed first with saturated sodium bicarbonate solution, then with saturated salt solution, dried over anhydrous sodium sulfate overnight, concentrated, and the residue was separated by column chromatography (eluent: ethyl acetate-petroleum ether) to give 394 mg of white solid, yield 87%. 1HNMR (400MHz, CDCl3) 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= 8.1Hz,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, CDCl3)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 O7[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 a reaction flask and stirred at room temperature until TLC showed 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 washed first with saturated sodium bicarbonate solution, then with saturated salt solution, dried over anhydrous sodium sulfate overnight, concentrated, and the residue was separated by column chromatography (eluent: ethyl acetate-petroleum ether) to give 154 mg of white solid, yield 34%. 1 HNMR(400MHz, CDCl3)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 (101MHz, 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 O7[M+H] + Theoretical value: 453.1908, measured value: 453.1910.

[0144] Example 20: Synthesis of M-123

[0145]

[0146] (E)-3-(3,4-methylenedioxyphenyl)propene (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 a reaction flask and stirred at room temperature until TLC showed 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 washed first with saturated sodium bicarbonate solution, then with saturated salt solution, dried over anhydrous sodium sulfate overnight, concentrated, and the residue was separated by column chromatography (eluent: ethyl acetate-petroleum ether) to give 340 mg of white solid, yield 78%. 1 HNMR(400MHz, CDCl3)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,1H),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=9.6 Hz,1H),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 O7[M+H] + Theoretical value: 437.1599, measured value: 437.1606.

[0147] Example 21 M-119 Synthesis

[0148]

[0149] (E)-3-(3,4-methylenedioxyphenyl)propene (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 a reaction flask and stirred at room temperature until TLC showed 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 washed first with saturated sodium bicarbonate solution, then with saturated salt solution, dried over anhydrous sodium sulfate overnight, concentrated, and the residue was separated by column chromatography (eluent: ethyl acetate-petroleum ether) to give 230 mg of white solid, yield 55%. 1 HNMR (400MHz, CDCl3) 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=12.7Hz,1H),4.65(d,J=12.7Hz,1H),3.38(q,J=11.5Hz,1H),3.01–2.97(dd,J=11.5,5.3H z,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 (101MHz, CDCl3) δ197.78,169.38,165.84,143.15,138.39,137.27,135.87,135.23,132.78,132.49,128. 51,126.69,122.68,121.05,118.30,113.75,81.57,67.71,41.73,32.74,29.67,25.04,21.46.HRMS(ESI)m / z C 25 H 24 NO5[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 a reaction flask and stirred at room temperature until TLC showed 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 washed first with saturated sodium bicarbonate solution, then with saturated salt solution, dried over anhydrous sodium sulfate overnight, concentrated, and the residue was separated by column chromatography (eluent: ethyl acetate-petroleum ether) to give 100 mg of white solid, yield 25%. 1 H NMR (400MHz, CDCl3) 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,1H),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 (101MHz, CDCl3)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 NO8

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

[0155] Example 23 M-98 Synthesis

[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 a reaction flask and stirred at room temperature until TLC showed 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 washed first with saturated sodium bicarbonate solution, then with saturated salt solution, dried over anhydrous sodium sulfate overnight, concentrated, and the residue was separated by column chromatography (eluent: ethyl acetate-petroleum ether) to give 263 mg of colorless oil, yield 71%. 1 H NMR (400MHz, CDCl3)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 (101MHz, CDCl3) δ197.74,174.86,169.36,161.42,150.02,137.19,135.87,135.23,132.41,126.83,12 2.84,109.29,81.59,77.48,77.16,76.84,67.16,41.70,32.67,29.74,24.84,21.50,12.73.HRMS(ESI)m / z C 20 H 22 NO6[M+H] + Theoretical value: 372.1442, measured value: 372.1437.

[0159] Example 24 M-161 Synthesis

[0160]

[0161] 4-Benzopyranone-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 a reaction flask and stirred at room temperature until TLC showed 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 washed first with saturated sodium bicarbonate solution, then with saturated salt solution, dried over anhydrous sodium sulfate overnight, concentrated, and the residue was separated by column chromatography (eluent: ethyl acetate-petroleum ether) to give 326 mg of yellow solid, yield 75%. 1 H NMR (400MHz, CDCl3) 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 (126MHz, CDCl3) δ197.74,178.34,169.35,160.50,156.07,151.88,137.16,135.54,135.45,135.12,131.61,128. 09,126.31,126.00,124.58,123.03,118.86,115.27,81.66,69.75,41.78,32.80,29.84,25.20,21.57.HRMS(ESI)m / z C 25 H 23 O7[M+H] + Theoretical value: 435.1438, measured value: 435.1445.

[0162] Example 25 M-145 Synthesis

[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 a reaction flask and stirred at room temperature until TLC showed 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 washed first with saturated sodium bicarbonate solution, then with saturated salt solution, dried over anhydrous sodium sulfate overnight, concentrated, and the residue was separated by column chromatography (eluent: ethyl acetate-petroleum ether) to give 298 mg of white solid, yield 81%. 1 H 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 O5N[M+H] + Theoretical value: 368.1492, measured value: 368.1505.

[0165] Example 26 M-146 Synthesis

[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 a reaction flask and stirred at room temperature until TLC showed 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 washed first with saturated sodium bicarbonate solution, then with saturated salt solution, dried over anhydrous sodium sulfate overnight, concentrated, and the residue was separated by column chromatography (eluent: ethyl acetate-petroleum ether) to give 217 mg of white solid, yield 59%. 1 H NMR (400MHz, CDCl3) δ9.37 (s, 1H), 8.83 (d, J = 2.4Hz, 1H), 8.75 (d, J = 2.4Hz, 1H), 6.36(t,J=9.6Hz,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,1 H),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 (126MHz, CDCl3) δ197.50, 169.35, 163.85, 148.04, 146.41, 144.48, 143.18, 137.16, 135.67, 135.20,131.87,127.68,122.78,81.60,69.46,41.64,32.88,29.76,25.27,21.45.HRMS(ESI)m / z C 21 H 21 O5N2[M+H] + Theoretical value: 369.1445, measured value: 369.1446.

[0168] Example 27 M-144 Synthesis

[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 a reaction flask and stirred at room temperature until TLC showed 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 washed first with saturated sodium bicarbonate solution, then with saturated salt solution, dried over anhydrous sodium sulfate overnight, concentrated, and the residue was separated by column chromatography (eluent: ethyl acetate-petroleum ether) to give 238 mg of white solid, yield 57%. 1 H NMR (400MHz, CDCl3) 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=4.4 Hz,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 (126MHz, CDCl3) δ197.59,169.28,165.81,149.69,149.09,137.03,135.73,135.19,134.64,132.18,130.11,130. 05,128.49,127.22,125.34,125.01,122.74,122.04,81.51,68.53,41.63,32.72,29.70,25.12,21.44.HRMS(ESI)m / z C 25 H 24 O5N[M+H] + Theoretical value: 418.1649, measured value: 418.1665.

[0171] Example 28 M-107 Synthesis

[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 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 washed first with saturated sodium bicarbonate solution, then with saturated salt solution, dried over anhydrous sodium sulfate overnight, concentrated, and the residue was separated by column chromatography (eluent: ethyl acetate-petroleum ether) to give 271 mg of colorless oil, yield 65%. 1 H NMR (400MHz, CDCl3) 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,2 H),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= 8.2Hz,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 (101MHz, CDCl3) δ197.70,169.45,165.89,152.83,150.16,137.53,137.26,136.07,135.21,132.61,131.23,130. 08,128.89,127.89,127.54,126.93,122.78,122.20,81.58,68.46,41.84,32.97,29.83,25.29,21.54.HRMS(ESI)m / zC 25 H 24 O5N[M+H] + Theoretical value: 418.1649, measured value: 418.1651.

[0174] Example 29 M-147 Synthesis

[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 a reaction flask and stirred at room temperature until TLC showed 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 washed first with saturated sodium bicarbonate solution, then with saturated salt solution, dried over anhydrous sodium sulfate overnight, concentrated, and the residue was separated by column chromatography (eluent: ethyl acetate-petroleum ether) to give 187 mg of white solid, yield 51%. 1 H NMR (400MHz, CDCl3) 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,1H),6.16(d,J=1.8Hz,1H),5.78(dd,J=11.1,5.1Hz,1H),5.42(dd,J=4.1,1.7 Hz,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,1 H),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 (126MHz, CDCl3) δ197.48,169.41,166.28,137.12,136.13,135.00,133.37,132.61,129.85,1 29.60,128.58,126.64,122.69,81.53,68.20,41.70,32.96,29.76,25.22,21.45.HRMS(ESI)m / zC 22 H 23 O5[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 a reaction flask and stirred at room temperature until TLC showed 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 washed first with saturated sodium bicarbonate solution, then with saturated salt solution, dried over anhydrous sodium sulfate overnight, concentrated, and the residue was separated by column chromatography (eluent: ethyl acetate-petroleum ether) to give 144 mg of white solid, yield 36%. 1 H NMR(400MHz, CDCl3) 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 (126MHz, CDCl3) δ197.58,169.30,165.44,139.88,137.13,135.85,135.14,132.49,130.99,1 28.94,128.27,126.75,122.67,81.53,68.12,41.67,32.81,29.70,25.08,21.44.HRMS(ESI)m / zC 22 H 22 O5Cl[M+H] + Theoretical value: 401.1150, measured value: 401.1150.

[0180] Example 31 M-149 Synthesis

[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 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 washed first with saturated sodium bicarbonate solution, then with saturated salt solution, dried over anhydrous sodium sulfate overnight, concentrated, and the residue was separated by column chromatography (eluent: ethyl acetate-petroleum ether) to give 138 mg of white solid, yield 37%. 1 H NMR (400MHz, CDCl3) 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),4.86(d,J=12.5Hz,1H),4.75(d,J=12.5Hz,1H),3.40(q,J=12.4Hz,1H),3.03(t,J= 8.3Hz,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 (126MHz, CDCl3) δ197.44,169.41,161.87,137.11,136.06,134.97,133.87,133.15,132.82, 132.41,128.02,126.89,122.76,81.53,68.57,41.72,33.03,29.81,25.26,21.45.HRMS(ESI)m / z C 20 H 21 O5S[M+H] + Theoretical value: 373.1104, measured value: 373.1104.

[0183] Example 32 M-151 Synthesis

[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 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 washed first with saturated sodium bicarbonate solution, then with saturated salt solution, dried over anhydrous sodium sulfate overnight, concentrated, and the residue was separated by column chromatography (eluent: ethyl acetate-petroleum ether) to give 156 mg of white solid, yield 42%. 1 H NMR (400MHz, CDCl3) δ8.16–8.10(m,1H),7.56–7.49(m,1H),7.38–7.31(m,1 H), 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 (126MHz, CDCl3) δ197.67,169.50,162.51,137.25,136.15,135.18,133.34,133.19,132.74, 127.92,126.70,126.59,122.81,81.67,67.90,41.81,33.05,29.85,25.28,21.57.HRMS(ESI)m / z C 20 H 21 O5S[M+H] + Theoretical value: 373.1104, measured value: 373.1119.

[0186] Example 33 M-155 Synthesis

[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 a reaction flask and stirred at room temperature until TLC showed 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 washed first with saturated sodium bicarbonate solution, then with saturated salt solution, dried over anhydrous sodium sulfate overnight, concentrated, and the residue was separated by column chromatography (eluent: ethyl acetate-petroleum ether) to give 301 mg of white solid, yield 78%. 1 H NMR (400MHz, CDCl3) 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=12.5Hz,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 (126MHz, CDCl3) 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 O5S[M+H] + Theoretical value: 387.1261, measured value: 387.1262.

[0189] Example 34 M-156 Synthesis

[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 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 washed first with saturated sodium bicarbonate solution, then with saturated salt solution, dried over anhydrous sodium sulfate overnight, concentrated, and the residue was separated by column chromatography (eluent: ethyl acetate-petroleum ether) to give 224 mg of white solid, yield 54%. 1 H NMR (400MHz, CDCl3) δ7.79(d,J=3.8Hz,1H),7.65(d,J=3.8Hz,1H),6.34(t,J=9.6 Hz,1H),6.20(s,1H),5.84–5.72(m,1H),5.53(s,1H),5.42(s,1H),4.85(d,J=12.0 Hz,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 (126MHz, CDCl3) δ197.62,190.89,169.43,161.43,149.34,139.18,137.15,135.87,135.26,133.95, 132.16,131.88,127.30,122.99,81.62,68.92,41.80,32.98,29.89,27.12,25.24,21.56.HRMS(ESI)m / z C 22 H 23 O6S[M+H] + Theoretical value: 415.1210, measured value: 415.1225.

[0192] Example 35 M-152 Synthesis

[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 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 washed first with saturated sodium bicarbonate solution, then with saturated salt solution, dried over anhydrous sodium sulfate overnight, concentrated, and the residue was separated by column chromatography (eluent: ethyl acetate-petroleum ether) to give 285 mg of white solid, yield 70%. 1 H NMR (400MHz, CDCl3) δ7.60 (d, J = 4.1Hz, 1H), 6.95 (d, J = 4.1Hz, 1H), 6.32 (t, J = 9.5H z,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=12.7Hz,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 (126MHz, CDCl3) δ197.63,169.45,161.00,138.07,137.21,135.93,135.24,133.59,132.37, 131.33,127.63,127.09,122.91,81.67,68.56,41.81,33.00,29.88,25.22,21.57.HRMS(ESI)m / z C 20 H 20 O5ClS[M+H] + Theoretical value: 407.0714, measured value: 407.0720.

[0195] Example 36 M-158 Synthesis

[0196]

[0197] Methyl 5-carboxylic acid-2-thiophenecarboxylate (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 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 washed first with saturated sodium bicarbonate solution, then with saturated salt solution, dried over anhydrous sodium sulfate overnight, concentrated, and the residue was separated by column chromatography (eluent: ethyl acetate-petroleum ether) to give 366 mg of white solid, yield 85%. 1 H NMR (400MHz, CDCl3) 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), 4.7 6(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 (126MHz, CDCl3) δ197.55,169.44,161.98,161.33,139.31,138.32,137.17,135.93,135.20,133.58, 133.31,132.18,127.35,122.94,81.62,69.00,52.83,41.79,33.02,29.90,25.27,21.56.HRMS(ESI)m / z C 22 H 23 O7S[M+H] + Theoretical value: 431.1160, measured value: 431.1166.

[0198] Example 37 M-157 Synthesis

[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 a reaction flask and stirred at room temperature until TLC showed 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 washed first with saturated sodium bicarbonate solution, then with saturated salt solution, dried over anhydrous sodium sulfate overnight, concentrated, and the residue was separated by column chromatography (eluent: ethyl acetate-petroleum ether) to give 363 mg of white solid, yield 86%. 1 H NMR (400MHz, CDCl3) 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),4.89(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 (126MHz, CDCl3) δ197.57,169.47,162.55,142.27,138.68,137.18,136.01,135.15,132.88,132.39,131.15, 127.41,127.09,125.75,125.27,122.91,122.89,81.62,68.92,41.81,33.05,29.89,25.34,21.53.HRMS(ESI)m / z C 24 H 23 O5S[M+H] + Theoretical value: 423.1621, measured value: 423.1267.

[0201] Example 38 M-153 Synthesis

[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 a reaction flask and stirred at room temperature until TLC showed 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 washed first with saturated sodium bicarbonate solution, then with saturated salt solution, dried over anhydrous sodium sulfate overnight, concentrated, and the residue was separated by column chromatography (eluent: ethyl acetate-petroleum ether) to give 231 mg of white solid, yield 65%. 1 H NMR (400MHz, CDCl3) 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=12.7Hz,1H),4.69(d,J=12.7Hz,1H),3.39(q,J=11.8Hz,1H),3.01(t,J=8.1Hz,1 H),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 (126MHz, CDCl3) δ197.65,169.55,160.87,137.20,136.30,135.04,132.79,126.59,123.58, 122.83,122.33,115.63,110.78,81.60,67.59,41.77,33.10,29.81,25.32,21.54.HRMS(ESI)m / z C 20 H 22 O5N[M+H] + Theoretical value: 356.1492, measured value: 356.1496.

[0204] Example 39 M-159 Synthesis

[0205]

[0206] 201 mg, 1 mmol of p-sulfonamide benzoic acid, 575 mg, 3 mmol of EDCI, 37 mg, 0.3 mmol of DMAP, intermediate 3 (262 mg, 1 mmol), and 5 mL of DCM were added to a reaction flask and stirred at room temperature until TLC showed 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 washed first with saturated sodium bicarbonate solution, then with saturated salt solution, dried over anhydrous sodium sulfate overnight, concentrated, and the residue was separated by column chromatography (eluent: ethyl acetate-petroleum ether) to give 245 mg of white solid, yield 55%. 1 H NMR (400MHz, Methanol-d4) 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 (126MHz, METHANOL-D4) δ198.90,171.91,166.44,149.32,139.57,139.46,134.94,134.43,133. 94,131.18,127.54,127.48,123.16,83.03,69.66,43.27,34.56,30.79,25.79,21.59.HRMS(ESI)m / z C 22 H 24 O7NS[M+H] + Theoretical value: 446.1268, measured value: 446.1280.

[0207] Example 40: Synthesis of M-168

[0208]

[0209] M144 (417 mg, 1 mmol) was dissolved in 5 mL of DCM, and 3 mol of dimethylamine tetrahydrofuran solution was added. 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 208 mg of white solid, yield 45%. ESI-MS: 463 [M+H] + .

[0210] Pharmacological experiments

[0211] Experimental Example 1: Preliminary Screening Results of the In Vitro Anti-inflammatory Activity of Trichoderma lactone Derivatives

[0212] Using IL6 reporter HEK 293 cells, we screened the activity of parthenolide derivatives against the IL6-STAT3 signaling pathway to evaluate their potential anti-inflammatory biological activity. IL6 reporter HEK 293 is the HEK-Blue cell line for human IL-6R and STAT3 genes. TM IL-6 cells (InvivoGen) were preserved by the Institute of Materia Medica, Chinese Academy of Medical Sciences. The culture conditions included HEK-Blue. TM Selection (1:250), 10% FBS, and DMEM complete medium containing 100 μg / ml streptomycin and 100 U / ml penicillin. Napabucasin, a STAT3 inhibitor, was used as a positive control in this system. The specific method for detecting IL6-STAT3 pathway inhibitory activity is as follows:

[0213] 1) Plating: IL6 reporter HEK 293 cells were pipetted and counted, and plated in 96-well plates at a concentration of 25,000 cells / 160 μl.

[0214] 2) Dosing: Add the appropriate concentration of drug every other day, 20 μl / well.

[0215] 3) Stimulation: One hour after drug administration, add 20 μl of IL-6 stimulant at a final concentration of 5 ng / ml per well.

[0216] 4) Detection: After 18 hours, Quanti-blue reagent was used for detection. A new 96-well plate was prepared, 180 μl of Quanti-blue solution was added to each well, followed by 20 μl of cell culture supernatant. The plate was incubated at 37°C for 1 hour, and the OD value was measured at 655 nm.

[0217] 5) Calculate the inhibition rate using Excel and the IC using GraphPad Prism 8.0 software. 50 And draw a diagram.

[0218] Inhibition rate = (average absorbance of control group - average absorbance of treatment group) / average absorbance of control group x 100%

[0219] Table 1 shows the results, indicating that 19 derivatives, including M-0, M82, and M90, have an IC50 inhibitory activity against IL6-STAT3. 50 In 10 -6The M level was comparable in potency to that of the STAT3-positive inhibitor Napabucasin; 12 derivatives, including M92, M98, and M100, showed IC50 inhibitory activity against IL6-STAT3. 50 In 10 -7 M level is stronger than that of the STAT3-positive inhibitor Napabucasin.

[0220] Table 1. Results of the inhibitory activity of ternolactone derivatives against IL6-STAT3.

[0221]

[0222] Experiment Example 2: Re-screening activity and cytotoxicity results of nine initially screened active compounds, IL6-STAT3.

[0223] Initial screening inhibitory activity against the IL6-STAT3 pathway was 10 -7 Six derivatives of M were screened at different concentrations, and Quanti-Blue assays were performed at 1 hour and 3 hours after drug administration. Cell proliferation inhibition activity was assessed using CCK8 assays 24 hours after drug administration. As shown in Table 2, all six derivatives exhibited strong inhibitory activity against the IL6-STAT3 signaling pathway (IC50). 50 At the μM level, it has no significant effect on cell proliferation (IC50). 50 >10μM).

[0224] Table 2. Results of secondary screening and cytotoxicity of nine compounds with good initial screening activity against IL6-STAT3.

[0225]

Claims

1. A class of basilolone derivatives having the following general formula (I) and their pharmaceutically acceptable salts: in: R1 is C 1-4 Alkyl, substituted C 1-4 Alkyl, C 3-6 Cycloalkyl, substituted C 3-6 cycloalkyl, C 3-6 Heterocyclic alkyl, aryl, Ar-SC 1-2 Alkyl, Ar-OC 1-2 Alkyl, YNC 1-2 Alkyl group, Ar-CH=CH-; Ar is a phenyl or substituted phenyl group; the substituents on the benzene ring are selected from halogens, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, nitrile, methimazole, phenyl, methylenedioxy; Y is phthalimide group, tetrahydroisoquinoline group; R2 and R3 can be combined to form C, or R2 is hydrogen, and R3 is CH2N(CH3)2; The substituents mentioned above are selected from halogens, methyl groups, and carbonyl groups.

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

3. The parthenolide derivative and its pharmaceutically acceptable salt according to claim 1, characterized in that, The aryl group is selected from phenyl, furanyl, thiophene, isoxazolyl, pyrimidinyl, pyridyl, pyrazinyl, naphthyl, chromonel, quinolinyl, isoquinolinyl, and anthraquinone.

4. The ternolactone derivative and its pharmaceutically acceptable salt according to claim 2, characterized in that, The positions of the substituents on the benzene ring are para, meta, or ortho, and the number of substituents can be monosubstituted, disubstituted, or polysubstituted.

5. The ternolactone derivative and its pharmaceutically acceptable salt according to any one of claims 1-4, characterized in that, The compounds are selected from the following:

6. The method for preparing the chrysanthemum lactone derivative according to any one of claims 1-5, characterized in that, The preparation method of the compound is as follows: Reaction step a: First, PTL is oxidized by an oxidant to generate MMB; Reaction step b: MMB is esterified by pyrazine carboxylic acid under the action of a coupling agent; Reaction step c: MMB ester is dehydrated by ring-opening of epoxy under Lewis acid catalysis. Reaction step d: Oxidation of the ring-opening dehydrate to give a ketone; Reaction step e: Ester hydrolysis to give a hydroxymethyl compound; Reaction step f: The hydroxymethyl compound reacts with an organic acid to give the corresponding ester; Reaction step g: The ester is added to dimethylamine to give the compound of general formula (I).

7. A pharmaceutical composition, characterized in that, The pharmaceutical composition comprises a ternolactone derivative of any one of claims 1-5, 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 and sustained-release dosage forms.

10. The use of the ternolactone derivative of any one of claims 1-5 and its pharmaceutically acceptable salt in the preparation of a medicament for the prevention or treatment of tumors or inflammatory immune diseases.

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

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