Psoralen derivative and use thereof

Abstract

The application discloses a psoralen derivative or a pharmaceutical salt thereof, and a structure general formula of the psoralen derivative is shown in the following formula: The psoralen derivative is obtained by optimizing the structure of psoralen, and the antibacterial activity test is carried out on common gram-positive bacteria such as drug-resistant staphylococcus aureus and gram-negative bacteria such as escherichia coli and klebsiella pneumoniae, and it is found that the compound or the pharmaceutical salt thereof has excellent anti-drug-resistant bacteria, anti-inflammatory and anti-tumor activities, and has good development value in preparation of anti-infection treatment drugs, anti-inflammatory drugs and anti-tumor drugs.

Description

Technical Field

[0001] The present invention belongs to the technical field of pharmaceutical chemistry, and in particular relates to a psoralen derivative or a pharmaceutically acceptable salt thereof and an application thereof. Background Art

[0002] Antibiotic resistance is one of the major health and well-being issues facing society today. Excessive or irrational use of quinolones can increase bacterial resistance, with methicillin-resistant Staphylococcus aureus, carbapenem-resistant Acinetobacter baumannii, and drug-resistant Klebsiella pneumoniae becoming the leading causes of nosocomial infections (Li Ping et al., Journal of Clinical Rational Drug Use, 2023, 4, 178-181; Niu Yinghui et al., Chinese Science and Technology Journal Database (Full Text Edition) Medicine and Health, 2022, 7, 262-264; Xing Lingyi et al., Journal of Tianjin University of Traditional Chinese Medicine, 2023, 1, 127-136). To address this global issue of antibiotic resistance, developing new antibiotics with different mechanisms of action from quinolones has become an effective solution.

[0003] With the emergence of a large number of drug-resistant pathogens, natural products have become a hot topic as antibacterial drugs. Psoralen, as a plant-based antibiotic, has a certain inhibitory effect on Gram-negative bacteria such as Shigella, Helicobacter pylori, and Enterobacter, as well as Gram-positive bacteria such as methicillin-resistant Staphylococcus aureus, Streptococcus faecalis, Bacillus, and Bacillus subtilis (Khatune NA, et al. Fitoterapia, 2004, 75(2), 228-230). However, the antibacterial activity of psoralen is relatively weak, and its structure needs to be optimized to enhance its antibacterial effect. Summary of the Invention

[0004] The present invention aims to provide a psoralen derivative, which solves the technical problem in the prior art that psoralen has low antibacterial activity against methicillin-resistant Staphylococcus aureus, Klebsiella pneumoniae and Escherichia coli.

[0005] Another object of the present invention is to provide a use of the psoralen derivative in the preparation of a medicament for treating infectious diseases.

[0006] In order to achieve the above object, the technical solution adopted by the present invention is as follows:

[0007] In a first aspect of the present invention, a psoralen derivative or a pharmaceutically acceptable salt thereof is provided. The general structural formula of the psoralen derivative is as follows:

[0008]

[0009] L is selected from -(CH2)n-, n is a positive integer selected from 1 to 10 (e.g., 1, 2, 3, 4, 5);

[0010] R1is selected from the group consisting of hydrogen, deuterium, hydroxyl, halogen (fluorine, chlorine, bromine, iodine), C1-C10alkyl, C1-C10alkoxy;

[0011] R2is selected from the group consisting of hydrogen, deuterium, hydroxyl, halogen (fluorine, chlorine, bromine, iodine), C1-C10alkyl, C1-C10alkoxy;

[0012] R3is selected from the group consisting of hydrogen, deuterium, hydroxyl, halogen (fluorine, chlorine, bromine, iodine), C1-C10alkyl, C1-C10alkoxy;

[0013] R4is selected from the group consisting of hydrogen, deuterium, hydroxyl, halogen (fluorine, chlorine, bromine, iodine), C1-C10alkyl, C1-C10alkoxy;

[0014] R5is selected from the group consisting of hydrogen, deuterium, hydroxyl, halogen (fluorine, chlorine, bromine, iodine), C1-C10alkyl, C1-C10alkoxy;

[0015] R6is selected from the group consisting of

[0016]

[0017] R7is selected from the group consisting of hydrogen, deuterium, halogen (fluorine, chlorine, bromine, iodine), C1-C10alkyl, C1-C10alkoxy;

[0018] R8is selected from the group consisting of hydrogen, deuterium, halogen (fluorine, chlorine, bromine, iodine), C1-C10alkyl, C1-C10alkoxy;

[0019] R9is selected from the group consisting of hydrogen, deuterium, halogen (fluorine, chlorine, bromine, iodine), C1-C10alkyl, C1-C10alkoxy;

[0020] R 10 is selected from the group consisting of hydrogen, deuterium, halogen (fluorine, chlorine, bromine, iodine), C1-C10alkyl, C1-C10alkoxy;

[0021] R 11 is selected from the group consisting of hydrogen, deuterium, halogen (fluorine, chlorine, bromine, iodine), C1-C10alkyl, C1-C10alkoxy.

[0022] More preferably, in the said psoralen derivative:

[0023] L is selected from the group consisting of -(CH2)n-, n is selected from 1, 2, 3, 4, 5;

[0024] R1is selected from the group consisting of hydrogen, deuterium, hydroxyl, fluorine, chlorine, bromine, iodine, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, t-butoxy, n-butoxy;

[0025] R2 is selected from hydrogen, deuterium, hydroxy, fluorine, chlorine, bromine, iodine, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, tert-butoxy, n-butoxy;

[0026] R3 is selected from hydrogen, deuterium, hydroxy, fluorine, chlorine, bromine, iodine, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, tert-butoxy, n-butoxy;

[0027] R4 is selected from hydrogen, deuterium, hydroxy, fluorine, chlorine, bromine, iodine, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, tert-butoxy, n-butoxy;

[0028] R5 is selected from hydrogen, deuterium, hydroxy, fluorine, chlorine, bromine, iodine, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, tert-butoxy, n-butoxy;

[0029] R6 is selected from

[0030]

[0031] R7 is selected from hydrogen, deuterium, fluorine, chlorine, bromine, iodine, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, tert-butoxy, n-butoxy;

[0032] R8 is selected from hydrogen, deuterium, fluorine, chlorine, bromine, iodine, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, tert-butoxy, n-butoxy;

[0033] R9 is selected from hydrogen, deuterium, fluorine, chlorine, bromine, iodine, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, tert-butoxy, n-butoxy;

[0034] R 10 is selected from hydrogen, deuterium, fluorine, chlorine, bromine, iodine, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, tert-butoxy, and n-butoxy;

[0035] R 11 is selected from hydrogen, deuterium, fluorine, chlorine, bromine, iodine, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, tert-butoxy, and n-butoxy.

[0036] Most preferably, the structure of the psoralen derivative is selected from one of the following structures:

[0037]

[0038]

[0039]

[0040] The second aspect of the present invention provides a use of the psoralen derivative or a pharmaceutically acceptable salt thereof in the preparation of an antibacterial drug.

[0041] The bacteria mentioned herein refer to methicillin-resistant Staphylococcus aureus, Klebsiella pneumoniae, Escherichia coli and the like.

[0042] The third aspect of the present invention provides a use of the psoralen derivative or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating infectious diseases.

[0043] The infectious diseases mentioned above refer to infectious diseases caused by drug-resistant bacteria, such as upper respiratory tract infection, pneumonia, cholecystitis, urinary tract infection, acute tonsillitis, bacterial dysentery, purulent meningitis, scarlet fever, tuberculosis, epidemic cerebrospinal meningitis, folliculitis, furuncle, etc.

[0044] The drug-resistant bacteria refer to methicillin-resistant Staphylococcus aureus, Klebsiella pneumoniae, and Escherichia coli.

[0045] The fourth aspect of the present invention provides a use of the psoralen derivative or a pharmaceutically acceptable salt thereof in the preparation of an anti-inflammatory drug.

[0046] The anti-inflammatory drug refers to an anti-leukemia drug.

[0047] The fifth aspect of the present invention provides a use of the psoralen derivative or a pharmaceutically acceptable salt thereof in the preparation of an anti-tumor drug.

[0048] The tumor is selected from lung adenocarcinoma or intestinal cancer.

[0049] Due to the adoption of the above technical solution, the present invention has the following advantages and beneficial effects:

[0050] The present invention obtains psoralen derivatives by optimizing the structure of psoralen. Antibacterial activity tests on common Gram-positive bacteria such as drug-resistant Staphylococcus aureus and Gram-negative bacteria such as Escherichia coli and Klebsiella pneumoniae reveal that the compounds have excellent activity against drug-resistant bacteria and have great development value in the preparation of anti-infection therapeutic drugs.

[0051] The compound of the present invention is a psoralen derivative or a pharmaceutically acceptable salt thereof. Psoralen has anti-inflammatory, anti-tumor and immunomodulatory effects (Li Xiaotian et al., Journal of Shanghai Jiao Tong University: Medical Edition, 2018, 2, 128-132; Zhang Yinhong et al., Chinese Journal of Laboratory Animals, 2017, 2, 207-210). Therefore, the compound of the present invention can be used to prepare anti-inflammatory, anti-tumor and immunomodulatory drugs.

[0052] The synthesis method of the psoralen derivatives of the present invention has high safety, mild reaction conditions and considerable yield, and is suitable for industrial production after further improvement. DETAILED DESCRIPTION

[0053] In order to explain the present invention more clearly, the present invention is further described below in conjunction with preferred embodiments. Those skilled in the art should understand that the following specific description is illustrative rather than restrictive and should not be used to limit the scope of protection of the present invention.

[0054] Example 1

[0055] Preparation of Intermediate Ia: tert-Butyl (1-(2-((7-oxo-7H-furo[3,2-g]furo[3,2-g]furan-9-yl)oxy)ethyl)piperidin-4-ylcarbamate

[0056]

[0057] To a 25 mL single-necked flask, 1-bromo-3-chloropropane (0.87 g, 5.49 mmol) and anhydrous acetonitrile (9 mL) were added, followed by stirring. 4-tert-Butyloxycarbonylaminopiperidine (1.00 g, 4.99 mmol) and potassium carbonate (0.86 g, 6.24 mmol) were added and the mixture was allowed to react at 70°C for 3 h. After cooling to room temperature, 9-hydroxy-7H-furo[3,2-g]chromen-7-one (1.00 g, 4.99 mmol) and anhydrous DMF (7 mL) were added. Potassium carbonate (0.86 g, 6.24 mmol) was then added, and the temperature was raised to 90°C for 5 h. The mixture was cooled to room temperature, filtered, and the solvent was evaporated. 50 mL of water was added, and the mixture was extracted three times with ethyl acetate. The mixture was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated. The mixture was purified by column chromatography to obtain a yellow solid in a 20% yield. 1 H NMR(600MHz,Methanol-d4)δ8.03(d,J=9.7Hz,1H),7.89(d,J=2.2Hz,1H),7.59(s,1 H),6.97(d,J=2.2Hz,1H),6.39(d,J=9.6Hz,1H),4.53(t,J=6.0Hz,2H),3.41(s,1H) ,3.07(d,J=11.7Hz,2H),2.86(dd,J=10.9,4.8Hz,2H),2.33(s,2H),2.11–2.03(m,2 H),1.91(d,J=13.1Hz,2H),1.58–1.49(m,2H),1.44(s,9H).HRMS(ESI,positive)m / z calcd forC 24 H 30 N2O6[M+H] + :443.2182; found443.2177.

[0058] Preparation of Intermediate IIa: 9-(3-(4-aminopiperidin-1-yl)propoxy)-7H-furo[3,2-g]thiophen-7-one

[0059]

[0060] Add intermediate Ia (141 mg, 0.319 mmol) to a 10 mL single-necked bottle, mix 1 mL of trifluoroacetic acid and 1 mL of dry dichloromethane, react at room temperature for 2 hours, and evaporate the solvent to obtain a yellow oily liquid, which is directly used in the next reaction.

[0061] Preparation of Compound 1: 9-(3,4-dihydropyranopyrano[2,3-c]pyridin-6-yl)methylamino)piperidin-1-ylpropoxy)-7H-furo[3,2-g]puran-7-one

[0062]

[0063] Intermediate IIa (100 mg, 0.292 mmol) and 3,4-dihydro-2H-pyrano[2,3-c]pyridine-6-carbaldehyde (43 mg, 0.263 mmol) were placed in a 10 mL single-necked flask and dissolved in 2 mL of anhydrous 1,3-dichloroethane. Then, sodium triacetoxyborohydride (186 mg, 0.876 mmol) was added and allowed to react at room temperature for 2 h. After completion of the reaction, 15 mL of saturated NaHCO₃ solution was added, and the mixture was extracted with dichloromethane (8 mL x 3). The organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and the solvent was evaporated. Purification by column chromatography afforded a white solid in a 19.6% yield. 1 H NMR(600MHz,Methanol-d4)δ8.06(d,J=9.6Hz,1H),8.01(s,1H),7.91(d,J=2.2Hz,1H),7.61(s,1H), 7.18(s,1H),6.99(d,J=2.2Hz,1H),6.41(d,J=9.6Hz,1H),4.55(t,J=5.9Hz,2H),4.28–4.23(m,2H),3 .93(s,2H),3.18(d,J=11.8Hz,2H),2.89(t,J=7.8Hz,2H),2.84(t,J=6.5Hz,2H),2.80–2.75(m,1H),2 .34–2.27(m,2H),2.10(dt,J=9.1,6.1Hz,2H),2.05(dtd,J=11.7,6.5,3.5Hz,4H),1.65–1.55(m,2H). 13C NMR(151MHz,Methanol-d4)δ161.23,151.69,148.12,147.15,145.31,143.27,137.65,132.56,131.29,126.51,123.42,1 16.66,113.85,113.67,106.63,71.78,66.48,54.48,53.60,51.62,29.83,26.67,23.75,21.18.HRMS(ESI,positive)m / z calcd forC 28 H 31 N3O5[M+H] + :490.2342; found 490.2336.

[0064] Example 2

[0065] Preparation of Compound 2: 9-(3-(4-chlorobenzyl)amino)piperidin-1-propoxy)-7H-furo[3,2-g]puran-7-one

[0066]

[0067] Referring to the preparation method of Compound 1 in Example 1, 4-chlorobenzaldehyde was used instead of 3,4-dihydro-2H-pyrano[2,3-C]pyridine-6-carbaldehyde to obtain a white solid with a yield of 30.8%. 1 H NMR(600MHz, Methanol-d4)δ8.02(d,J=9.6Hz,1H),7.89(d,J=2.3Hz,1H),7.57(s,1H),7.37– 7.30(m,4H),6.96(d,J=2.2Hz,1H),6.38(d,J=9.6Hz,1H),4.51(t,J=6.0Hz,2H),3.78(s,2H) ,3.04(dt,J=12.6,3.6Hz,2H),2.77–2.71(m,2H),2.54(tt,J=10.8,4.1Hz,1H),2.11(td,J=1 2.0,2.5Hz,2H),2.03(dq,J=7.8,6.0Hz,2H),1.99–1.92(m,2H),1.48(qd,J=12.3,3.7Hz,2H). 13C NMR(151MHz,Methanol-d4)δ161.16,148.05,147.08,145.22,143.19,138.12,132.54,131.33,129.77,128.15,1 26.44,116.60,113.67,106.62,71.96,54.71,53.69,53.43,52.07,49.06,30.92,27.00.HRMS(ESI,positive)m / z calcd for C 26 H 27 N2O4Cl[M+H] + :467.1737; found467.1732.

[0068] Example 3

[0069] Preparation of compound 3: 9-(3-(4-bromobenzyl)amino)piperidin-1-propoxy)-7H-furo[3,2-g]thiophen-7-one

[0070]

[0071] Referring to the preparation method of Compound 1 in Example 1, 4-bromobenzaldehyde was used instead of 3,4-dihydro-2H-pyrano[2,3-C]pyridine-6-carbaldehyde to obtain a white solid with a yield of 34.4%. 1H NMR(600MHz,Methanol-d4)δ8.05(d,J=9.6Hz,1H),7.90(d,J=2.2Hz,1H),7.61(s ,1H),7.56–7.50(m,2H),7.36–7.31(m,2H),6.98(d,J=2.2Hz,1H),6.40(d,J=9.6H z,1H),4.55(t,J=5.9Hz,2H),3.90(s,2H),3.25(d,J=12.2Hz,2H),2.98(t,J=7.8 Hz,2H),2.84–2.77(m,1H),2.42(s,2H),2.15–2.05(m,4H),1.66–1.57(m,2H).13C NMR(151MHz,Methanol-d4)δ161.20,148.08,147.17,145.30,143.25,136.79,131.38,131.22,130.41,126.52,12 1.16,116.65,113.91,113.68,106.65,71.67,54.44,53.21,51.56,48.76,29.61,26.44.HRMS(ESI,positive)m / z calcd forC26 H 27 BrN2O4[M+H] + :511.1232; found 511.1227.

[0072] Example 4

[0073] Preparation of Compound 4: 9-(3-(4-((4-iodobenzyl)amino)piperidin-1-yl)propoxy)-7H-furo[3,2-g]thiophen-7-one

[0074]

[0075] Referring to the preparation method of Compound 1 in Example 1, 4-iodobenzaldehyde was used instead of 3,4-dihydro-2H-pyrano[2,3-C]pyridine-6-carbaldehyde to obtain a white solid with a yield of 49.8%. 1 H NMR(600MHz, Methanol-d4)δ8.05(d,J=9.6Hz,1H),7.90(d,J=2.2Hz,1H),7.75–7.71(m ,2H),7.60(s,1H),7.23–7.18(m,2H),6.98(d,J=2.2Hz,1H),6.40(d,J=9.6Hz,1H),4.54 (t,J=5.8Hz,2H),3.89(s,2H),3.26(dd,J=12.7,4.4Hz,2H),3.02–2.96(m,2H),2.81(td ,J=10.6,5.2Hz,1H),2.44(t,J=12.1Hz,2H),2.14–2.06(m,4H),1.62(q,J=13.8Hz,2H). 13 C NMR(151MHz,Methanol-d4)δ161.18,147.99,147.21,145.32,143.19,137.66,135.85,131.07,130.83,126.52,1 16.62,114.04,113.68,106.70,93.03,71.43,54.23,53.45,51.16,48.58,28.54,25.99.HRMS(ESI,positive)m / z calcd for C 26 H 27 N2O4I[M+H] + :559.1094; found 559.1088.

[0076] Example 5

[0077] Preparation of Compound 5: 9-(3-(4-bromo-3,5-difluorobenzyl)amino)piperidin-1-ylpropoxy)-7H-furo[3,2-g]puro[3,2-g]thiophen-7-one

[0078]

[0079] Referring to the preparation method of Compound 1 in Example 1, 3,5-difluoro-4-bromobenzaldehyde was used instead of 3,4-dihydro-2H-pyrano[2,3-C]pyridine-6-carbaldehyde to obtain a white solid with a yield of 33.9%. 1 H NMR(600MHz,Methanol-d4)δ8.03(d,J=9.6Hz,1H),7.89(d,J=2.2Hz,1H),7.58(s,1H), 7.18–7.13(m,2H),6.97(d,J=2.2Hz,1H),6.39(d,J=9.6Hz,1H),4.53(t,J=5.9Hz,2H),3 .83(s,2H),3.26(d,J=12.4Hz,2H),3.06–3.01(m,2H),2.67(tt,J=10.3,3.9Hz,1H),2. 51(t,J=11.4Hz,2H),2.13(dq,J=7.5,5.9Hz,2H),2.07–2.00(m,2H),1.64–1.54(m,2H). 13 C NMR(151MHz,Methanol-d4)δ161.19,160.61,158.97,148.04,147.18,145.29,143.23,143.00,131.14,126.52,116.6 4,113.97,113.68,111.57,111.42,106.65,71.59,54.54,52.50,51.53,48.68,30.02,26.16.HRMS(ESI,positive)m / z calcd for C 26 H 25 BrN2O4[M+H] + :547.1044; found 547.1039.

[0080] Example 6

[0081] Preparation of Compound 6: 9-(3-(3-fluoro-4-iodobenzylamino)piperidin-1-ylpropoxy)-7H-furo[3,2-g]puro[3,2-g]thiophen-7-one

[0082]

[0083] Referring to the preparation method of Compound 1 in Example 1, 4-iodo-3-fluorobenzaldehyde was used instead of 3,4-dihydro-2H-pyrano[2,3-C]pyridine-6-carbaldehyde to obtain a white solid with a yield of 67.5%. 1 HNMR(600MHz,Methanol-d4)δ8.03(d,J=9.6Hz,1H),7.90(d,J=2.2Hz,1H),7.76(dd,J=8.0,6.6Hz,1H),7.59 (s,1H),7.22(dd,J=9.1,1.9Hz,1H),7.02(dd,J=8.0,1.9Hz,1H),6.97(d,J=2.2Hz,1H),6.39(d,J=9.6Hz,1H) ,4.54(t,J=5.8Hz,2H),3.86(s,2H),3.31–3.26(m,2H),3.05(t,J=7.7Hz,2H),2.75(ddt,J=10.1,7.8,3.9Hz ,1H),2.52(t,J=11.5Hz,2H),2.13(dq,J=11.9,6.0Hz,2H),2.10–2.05(m,2H),1.61(dd,J=14.4,10.8Hz,2H). 13 C NMR(151MHz,Methanol-d4)δ162.70,161.19,161.08,148.03,147.19,145.31,143.22,141.94,139.32,131.12,126.52,125.92,1 16.63,115.41,115.25,113.99,113.68,106.67,78.76,78.59,71.55,54.42,52.61,51.42,29.56,26.11.HRMS(ESI,positive)m / z calcd for C 26 H 25 F1I1N2O4[M+H] + : 577.0999; found 577.0994.

[0084] Example 7

[0085] Preparation of Compound 7: 9-(3-(4-chloro-3-fluorobenzylamino)piperidin-1-yl)propoxy)-7H-furo[3,2-g]thiophen-7-one

[0086]

[0087] Referring to the preparation method of Compound 1 in Example 1, 3-fluoro-4-chlorobenzaldehyde was used instead of 3,4-dihydro-2H-pyrano[2,3-C]pyridine-6-carbaldehyde to obtain a white solid with a yield of 27.4%. 1 HNMR(600MHz, Methanol-d4)δ7.97(d,J=9.6Hz,1H),7.86(d,J=2.2Hz,1H),7.51(s,1H),7.39(t,J=7.9 Hz,1H),7.27(dd,J=10.3,2.0Hz,1H),7.17–7.13(m,1H),6.93(d,J=2.2Hz,1H),6.35(d,J=9.6Hz,1H), 4.48(t,J=6.0Hz,2H),3.77(s,2H),3.06–2.98(m,2H),2.76–2.71(m,2H),2.51(tt,J=10.5,4.0Hz,1H) ,2.12(td,J=12.0,2.5Hz,2H),2.02(ddt,J=9.4,7.7,6.1Hz,2H),1.97–1.90(m,2H),1.51–1.42(m,2H). 13 C NMR(151MHz,Methanol-d4)δ161.15,158.72,157.09,148.04,147.09,145.21,143.19,141.36,141.32,131.31,130.16,126.44,124.85,12 4.82,118.78,118.67,116.60,116.18,116.04,113.70,113.66,106.61,71.91,54.70,53.57,51.99,30.89,26.91.HRMS(ESI,positive)m / z calcd for C 26 H 26 ClF1N2O4[M+H] + :485.1643; found 485.1638.

[0088] Example 8

[0089] Preparation of Compound 8: 9-(3-(4-bromo-2,3-difluorobenzyl)amino)piperidin-1-ylpropoxy)-7H-furo[3,2-g]puro[3,2-g]thiophen-7-one

[0090]

[0091] Referring to the preparation method of Compound 1 in Example 1, 2,3-difluoro-4-bromobenzaldehyde was used instead of 3,4-dihydro-2H-pyrano[2,3-C]pyridine-6-carbaldehyde to obtain a white solid with a yield of 23.7%. 1 H NMR (600MHz, Methanol-d4) δ7.97(d,J=9.5Hz,1H),7.86(d,J=2.2Hz,1H),7.50(s,1H),7.37(ddd,J=8.2, 6.1,1.9Hz,1H),7.18(ddd,J=8.6,6.8,1.9Hz,1H),6.93(d,J=2.2Hz,1H),6.35(d,J=9.5Hz,1H),4.48(t,J =6.0Hz,2H),3.82(d,J=1.4Hz,2H),3.02(dt,J=12.6,3.6Hz,2H),2.75–2.70(m,2H),2.51(tt,J=10.7,4. 2Hz, 1H), 2.12 (td, J=12.0, 2.5Hz, 2H), 2.02 (dq, J=7.8, 6.0Hz, 2H), 1.97–1.89 (m, 2H), 1.49–1.42 (m, 2H). 13 C NMR(151MHz,Methanol-d4)δ161.13,150.04,149.95,148.56,148.46,148.39,14 8.30,148.02,147.07,146.82,145.19,143.17,131.32,129.05,128.97,127.60,1 27.58,126.43,125.69,125.66,125.63,116.59,113.66,107.99,107.87,106.61 ,71.94,54.73,53.77,52.00,42.30,31.04,26.98.HRMS(ESI,positive)m / zcalcd for C 26 H 25 BrF2N2O4[M+H] + :547.1044; found 547.1039.

[0092] Example 9

[0093] Preparation of Compound 9: 9-(3-(4-bromo-2,5-difluorobenzyl)amino)piperidin-1-ylpropoxy)-7H-furo[3,2-g]puran-7-one

[0094]

[0095] Referring to the preparation method of Compound 1 in Example 1, 2,5-difluoro-4-bromobenzaldehyde was used instead of 3,4-dihydro-2H-pyrano[2,3-C]pyridine-6-carbaldehyde to obtain a white solid with a yield of 10.2%. 1 H NMR (600MHz, Methanol-d4) δ8.00(d,J=9.6Hz,1H),7.88(d,J=2.2Hz,1H),7.54(s,1H),7.40(d d,J=8.9,5.6Hz,1H),7.35(dd,J=9.0,6.2Hz,1H),6.95(d,J=2.2Hz,1H),6.36(d,J=9.6Hz,1H), 4.50(t,J=6.0Hz,2H),3.79(s,2H),3.03(dt,J=12.4,3.7Hz,2H),2.77–2.72(m,2H),2.52(tt,J =10.7,4.0Hz,1H),2.18–2.11(m,2H),2.07–1.99(m,2H),1.97–1.92(m,2H),1.52–1.42(m,2H). 13 CNMR(151MHz,Methanol-d4)δ161.18,157.36,156.33,155.74,154.73,148.08,147.09,145.22,143.22,131.34,1 26.45,119.76,119.57,116.62,106.60,71.95,54.72,53.75,51.99,42.26,31.05,26.96.HRMS(ESI,positive)m / z calcd for C 26 H 25 BrF2N2O4[M+H] + :547.1044; found 547.1039.

[0096] Example 10

[0097] Preparation of Compound 10: 9-(3-(4-bromo-3-fluorobenzyl)amino)piperidin-1-ylpropoxy)-7H-furo[3,2-g]puro[3,2-g]thiophen-7-one

[0098]

[0099] Referring to the preparation method of Compound 1 in Example 1, 3-fluoro-4-bromobenzaldehyde was used instead of 3,4-dihydro-2H-pyrano[2,3-C]pyridine-6-carbaldehyde to obtain a white solid with a yield of 13.9%. 1HNMR(600MHz, Methanol-d4)δ8.01(d,J=9.7Hz,1H),7.88(d,J=2.2Hz,1H),7.58–7.52(m,2H),7.26 (dd,J=9.8,2.0Hz,1H),7.11(dd,J=8.1,1.9Hz,1H),6.95(d,J=2.2Hz,1H),6.37(d,J=9.5Hz,1H),5. 50(s,1H),4.50(t,J=6.0Hz,2H),3.78(s,2H),3.09–3.02(m,2H),2.79–2.74(m,2H),2.54(tt,J=10. 7,4.1Hz,1H),2.19–2.12(m,2H),2.08–2.00(m,2H),1.98–1.92(m,2H),1.48(qd,J=12.5,3.7Hz,2H) 13 CNMR(151MHz,Methanol-d4)δ161.20,148.11,147.12,145.27,143.26,141.95,133.16,131.31,126.49,125.31,125.29,116.65,116. 11,115.96,113.78,113.68,106.61,106.47,71.87,54.65,53.39,51.90,48.76,48.45,48.03,30.67,26.77.HRMS(ESI,positive)m / z calcd for C 26 H 25 BrF1N2O4[M+H] + :529.1138; found 529.1139.

[0100] Example 11

[0101] Preparation of Compound 11: 9-(3-(4-(4-chloro-3,5-difluorobenzyl)amino)piperidin-1-propoxy)-7H-furo[3,2-g]puran-7-one

[0102]

[0103] Referring to the preparation method of Compound 1 in Example 1, 3,5-difluoro-4-chlorobenzaldehyde was used instead of 3,4-dihydro-2H-pyrano[2,3-C]pyridine-6-carbaldehyde to obtain a white solid with a yield of 10.8%. 1H NMR(600MHz,Chloroform-d)δ7.77(d,J=9.6Hz,1H),7.68(d,J=2.2Hz,1H),7.02– 6.96(m,2H),6.81(s,1H),6.36(d,J=9.5Hz,1H),4.53(t,J=6.2Hz,2H),3.78(s,2 H),3.01–2.95(m,2H),2.72(t,J=7.6Hz,2H),2.51(tt,J=10.2,4.6Hz,1H),2.14( s,2H),2.10–2.06(m,2H),1.94–1.88(m,2H),1.45(qd,J=13.1,11.7,6.7Hz,2H). 13 C NMR(151MHz,Chloroform-d)δ160.56,159.64,157.98,148.21,146.65,144.42,143.49,142.27,131.81,126.04,116.52,114.69, 113.26,111.22,111.07,107.65,106.78,72.35,54.87,53.81,53.44,52.17,50.59,49.59,32.19,27.46.HRMS(ESI,positive)m / z calcd for C 26 H 25 CIF2N2O4[M+H] + :503.1549; found503.1544.

[0104] Example 12

[0105] Preparation of Intermediate Ib: tert-Butyl (1-(2-((7-oxo-7H-furo[3,2-g]furo[3,2-g]furan-9-yl)oxy)ethyl)piperidin-4-ylcarbamate

[0106]

[0107] Referring to the preparation method of Compound Ia in Example 1, 1,3-dibromoethane was used instead of 1-bromo-3-chloropropane to obtain a yellow solid with a yield of 21.2%.

[0108] Preparation of Intermediate IIb: 9-(2-(4-aminopiperidin-1-yl)ethoxy)-7H-furo[3,2-g]furo[3,2-g]thiophen-7-one

[0109]

[0110] The procedure of Example 1 was followed to give 1.13 g of yellow oily liquid which was used directly for the next reaction.

[0111] Preparation of compound 12: 9-(2-(2-(3,4-dihydro-2H-pyrano[2,3-c]pyridin-6- yl)methylamino)piperidin-1-yl)ethoxy)-7H-furo[3,2-g]pyrano[3,2-g]pyran-7-one

[0112]

[0113] Intermediate IIb (0.548 mmol) and 3,4-dihydro-2H-pyrano[2,3-c]pyridine-6- carboxaldehyde (0.493 mmol) were added into a 10 mL vial, followed by the addition of 3 mL of anhydrous 1,2-dichloroethane and sodium triacetoxyborohydride (1.644 mmol), and the reaction was allowed to proceed at room temperature for 2 h. After the reaction was completed, a saturated NaHCO3solution was added, and the mixture was extracted with dichloromethane (15 mL x 3). The combined organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and the solvent was evaporated. The product was purified by column chromatography to give a white solid with a yield of 96.3%. 1 H NMR (600 MHz, Methanol-d4) δ 8.15 (s, 1H), 8.11 (d, J = 9.7 Hz, 1H), 7.96 (d, J = 2.2 Hz, 1H), 7.73 (s, 1H), 7.27 (s, 1H), 7.05 (d, J = 2.2 Hz, 1H), 6.45 (d, J = 9.6 Hz, 1H), 4.83 - 4.78 (m, 2H), 4.37 (s, 2H), 4.31 - 4.28 (m, 2H), 4.12 (d, J = 12.6 Hz, 2H), 3.77 (t, J = 4.7 Hz, 2H), 3.68 (tt, J = 11.8, 4.0 Hz, 1H), 3.48 (s, 2H), 2.87 (t, J = 6.4 Hz, 2H), 2.57 (d, J = 13.8 Hz, 2H), 2.25 (q, J = 13.0 Hz, 2H), 2.10 - 2.02 (m, 2H). 13C NMR (151 MHz, Methanol-d4) δ 160.76, 152.56, 147.90, 147.50, 145.25, 143.23, 141.23, 138.38, 132.85, 129.84, 126.63, 124.09, 116.67, 115.59, 115.23, 113.80, 113.71, 106.81, 67.54, 66.64, 54.43, 51.72, 51.03, 23.72, 20.99, 17.32, 15.89. HRMS (ESI, positive) m / z calcd for C 27 H 29 N3O5[M+H] + : 476.2185; found 476.2180.

[0114] Example 13

[0115] Preparation of compound 13: 9-(2-(4-chlorobenzyl)amino)piperidin-l-yl)ethoxy)-7H- furo[3,2-g]thiophen-7-one

[0116]

[0117] The preparation method of compound 12 in Reference Example 12 was referenced, 4- chlorobenzaldehyde was replaced by 3,4-dihydro-2H-pyrano[2,3-c]pyridine-6-carboxaldehyde to obtain white solid with a yield of 30.8%. 1 H NMR (600 MHz, Methanol-d4) δ 8.01 (d, J = 9.5 Hz, 1H), 7.88 (d, J = 2.2 Hz, 1H), 7.56 (s, 1H), 7.37 - 7.30 (m, 4H), 6.96 (d, J = 2.3 Hz, 1H), 6.37 (d, J = 9.6 Hz, 1H), 4.59 (t, J = 5.5 Hz, 2H), 3.78 (s, 2H), 3.16 - 3.10 (m, 2H), 2.90 (t, J = 5.5 Hz, 2H), 2.53 (tt, J = 10.8, 4.0 Hz, 1H), 2.24 (td, J = 12.0, 2.5 Hz, 2H), 1.94 (dd, J = 12.4, 4.0 Hz, 2H), 1.46 (qd, J = 12.2, 3.8 Hz, 2H). 13C NMR (151 MHz, Methanol-d4) δ 161.10, 148.04, 147.12, 145.25, 143.22, 138.15, 132.54, 131.41, 129.78, 128.14, 126.45, 116.63, 113.82, 113.66, 106.63, 71.05, 57.38, 53.62, 52.37, 49.03, 31.05. HRMS (ESI, positive) m / z calcd for C 25 H 25 ClN2O4[M+H] + : 453.1581; found 453.1576.

[0118] Example 14

[0119] Preparation of compound 14: 9-(2-(4-(4-bromobenzyl)amino)piperidin-l-yl)ethoxy)-7H- furazano[3,2-g]furan-7-one

[0120]

[0121] The preparation method of compound 12 in Reference Example 12 was referenced, 4-bromobenzaldehyde was used to replace 3,4-dihydro-2H-pyrano[2,3-c]pyridine-6-carboxaldehyde to obtain white solid with a yield of 20.2%. 1 H NMR (600 MHz, Methanol-d4) δ 7.97 (d, J = 9.6 Hz, 1H), 7.86 (d, J = 2.2 Hz, 1H), 7.51 (s, 1H), 7.48 - 7.43 (m, 2H), 7.30 - 7.25 (m, 2H), 6.93 (d, J = 2.2 Hz, 1H), 6.34 (d, J = 9.6 Hz, 1H), 4.55 (t, J = 5.5 Hz, 2H), 3.75 (s, 2H), 3.14 - 3.08 (m, 2H), 2.88 (t, J = 5.5 Hz, 2H), 2.54 (tt, J = 10.9, 4.0 Hz, 1H), 2.23 (td, J = 12.0, 2.5 Hz, 2H), 1.96 - 1.89 (m, 2H), 1.50 - 1.41 (m, 2H). 13C NMR (151MHz, Methanol-d4) δ161.04,147.96,147.10,145.20,143.15,138.38,131.33,131.19,130.16,126.41,120. 57,116.59,113.81,113.66,106.65,71.02,57.34,53.65,52.32,49.04,48.49,30.96.HRMS(ESI,positive)m / zcalcd for C 25 H 25 BrN2O4[M+H] + :497.1076; found 497.1070.

[0122] Example 15

[0123] Preparation of Compound 15: 9-(2-(4-(4-iodobenzyl)amino)piperidin-1-yl)ethoxy)-7H-furo[3,2-g]thiophen-7-one

[0124]

[0125] Referring to the preparation method of Compound 12 in Example 12, 4-iodobenzaldehyde was used instead of 3,4-dihydro-2H-pyrano[2,3-C]pyridine-6-carbaldehyde to obtain a white solid with a yield of 15.41%. 1 H NMR(600MHz, Methanol-d4)δ7.99(d,J=9.6Hz,1H),7.87(d,J=2.2Hz,1H),7.69–7.64(m, 2H),7.54(s,1H),7.17–7.12(m,2H),6.94(d,J=2.2Hz,1H),6.36(d,J=9.6Hz,1H),4.57(t ,J=5.5Hz,2H),3.75(s,2H),3.13(dt,J=12.3,3.7Hz,2H),2.90(t,J=5.5Hz,2H),2.55(tt ,J=10.9,4.0Hz,1H),2.24(td,J=12.0,2.5Hz,2H),1.97–1.89(m,2H),1.51–1.41(m,2H). 13C NMR (151 MHz, Methanol-d4) δ 161.06, 148.00, 147.11, 145.22, 143.19, 138.87, 137.32, 131.36, 130.34, 126.43, 116.62, 113.83, 113.67, 106.64, 91.79, 71.02, 57.33, 53.63, 52.31, 49.11, 48.47, 30.92. HRMS (ESI, positive) m / z calcd for C 25 H 25 IN2O4[M+H] + : 545.0937; found 545.0932

[0126] Example 16

[0127] Preparation of Compound 16: 9-(2-(4-bromo-3,5-difluorobenzyl)amino)piperidin-l-yl)ethoxy)-7H-furo[3,2-g]thiophene-7-one

[0128]

[0129] Referring to the preparation method of Compound 12 in Example 12, 3,4-dihydro-2H-pyrano[2,3-c]pyridine-6-carbaldehyde was substituted with 3,5-difluoro-4-bromobenzaldehyde to obtain a white solid with a yield of 45.6%. 1H NMR (600 MHz, Chloroform-d) δ 7.76 (d, J = 9.6 Hz, 1H), 7.67 (d, J = 2.2 Hz, 1H), 7.36 (s, 1H), 6.99–6.93 (m, 2H), 6.81 (d, J = 2.2 Hz, 1H), 6.34 (d, J = 9.6 Hz, 1H), 4.59 (t, J = 5.7 Hz, 2H), 3.76 (s, 2H), 3.02 (dt, J = 11.8, 4.0Hz, 2H), 2.90 (t, J = 5.7Hz, 2H), 2.48 (tt, J = 10. 2,4.0Hz,1H),2.21(td,J=11.6,2.5Hz,2H),1.90–1.83(m,2H),1.43–1.34(m,2H).13C NMR(151MHz,Chloroform-d)δ160.67,160.64,160.48,159.02,158.99,148.1 5,146.66,144.40,143.77,143.71,143.66,143.43,131.89,125.99,116.48, 114.66,113.30,111.22,111.20,111.08,111.05,106.79,95.63,95.47,95.3 0,71.40,57.81,53.89,52.58,50.54,49.56,32.50.HRMS(ESI,positive)m / z calcd for C 25 H 23 BrN2O4[M+H] + :533.0887; found 533.0882.

[0130] Example 17

[0131] Preparation of Compound 17: 9-(2-(4-(3-fluoro-4-iodobenzyl)amino)piperidin-1-yl)ethoxy)-7H-furo[3,2-g]thiophen-7-one

[0132]

[0133] Referring to the preparation method of compound 12 in Example 11, 3-fluoro-4-iodobenzaldehyde was used instead of 3,4-dihydro-2H-pyrano[2,3-C]pyridine-6-carbaldehyde to obtain a white solid with a yield of 28%. 1H NMR (600MHz, Methanol-d4) δ7.99(d,J=9.5Hz,1H),7.87(d,J=2.2Hz,1H),7.72(dd,J=8.0,6. 6Hz,1H),7.54(s,1H),7.17(dd,J=9.2,1.9Hz,1H),6.99–6.93(m,2H),6.36(d,J=9.6Hz,1H), 4.57(t,J=5.5Hz,2H),3.77(s,2H),3.13(dt,J=12.8,3.7Hz,2H),2.90(t,J=5.5Hz,2H),2.53 (tt,J=10.8,4.0Hz,1H),2.25(td,J=12.0,2.5Hz,2H),1.96–1.90(m,2H),1.50–1.39(m,2H). 13 C NMR(151MHz,Methanol-d4)δ162.66,161.08,161.04,148.02,147.12,145.23,143.20,143.04,142.99,139.16,131.36,126.44,125.76,1 25.74,116.62,115.24,115.07,113.84,113.66,106.64,78.27,78.11,70.97,57.34,53.58,52.30,48.76,31.01.HRMS(ESI,positive)m / z calcdfor C 25 H 24 FIN2O4[M+H] + :563.0843; found 563.0838.

[0134] Example 18

[0135] Preparation of Compound 18: 9-(2-(4-(4-chloro-3-fluorobenzyl)amino)piperidin-1-yl)ethoxy)-7H-furo[3,2-g]furo[3,2-g]thiophen-7-one

[0136]

[0137] Referring to the preparation method of Compound 12 in Example 12, 3,4-dihydro-2H-pyrano[2,3-C]pyridine-6-carbaldehyde was replaced with 3-fluoro-4-chlorobenzaldehyde to obtain a white solid with a yield of 17.5%. 1H NMR(600MHz, Methanol-d4)δ8.00(d,J=9.6Hz,1H),7.88(d,J=2.2Hz,1H),7.55(s,1H),7.40(t,J =7.9Hz,1H),7.28(dd,J=10.3,1.9Hz,1H),7.16(dd,J=8.2,1.9Hz,1H),6.95(d,J=2.2Hz,1H),6.3 7(d,J=9.6Hz,1H),4.58(t,J=5.5Hz,2H),3.78(s,2H),3.16–3.10(m,2H),2.91(t,J=5.5Hz,2H), 2.52(tt,J=10.8,4.1Hz,1H),2.25(td,J=12.0,2.5Hz,2H),1.97–1.90(m,2H),1.50–1.41(m,2H). 13 CNMR(151MHz,Methanol-d4)δ161.09,158.73,157.09,148.03,147.11,145.23,143.21,141.35,141.31,131.38,130.15,126.44,124.87,12 4.84,118.78,118.67,116.62,116.20,116.06,113.82,113.65,106.63,71.01,57.37,53.61,52.33,48.77,31.09.HRMS(ESI,positive)m / z calcd for C 25 H 24 CIF1N2O4[M+H] + :471.1487; found 471.1481

[0138] Example 19

[0139] Preparation of Compound 19: 9-(2-(4-bromo-2,3-difluorobenzyl)amino)piperidin-1-yl)ethoxy)-7H-furo[3,2-g]thiophen-7-one

[0140]

[0141] Referring to the preparation method of Compound 12 in Example 12, 2,3-difluoro-4-bromobenzaldehyde was used instead of 3,4-dihydro-2H-pyrano[2,3-C]pyridine-6-carbaldehyde to obtain a white solid with a yield of 14.3%. 1H NMR (600MHz, Methanol-d4) δ8.00(d,J=9.6Hz,1H),7.88(d,J=2.2Hz,1H),7.55(s,1H),7.39(ddd,J=8 .3,6.2,2.0Hz,1H),7.20(ddd,J=8.7,6.8,2.0Hz,1H),6.95(d,J=2.2Hz,1H),6.37(d,J=9.6Hz,1H),4. 59(t,J=5.5Hz,2H),3.85(d,J=1.5Hz,2H),3.15(dt,J=12.4,3.7Hz,2H),2.93(t,J=5.5Hz,2H),2.54( tt,J=10.7,4.0Hz,1H),2.30(td,J=11.9,2.5Hz,2H),1.95(dq,J=12.2,2.8Hz,2H),1.51–1.42(m,2H). 13 C NMR(151MHz,Methanol-d4)δ161.06,148.03,147.12,145.21,143.21,131.35,128.95,128.86,127.62,127.59,126.44,125.72,125.6 9,125.67,116.62,113.85,113.66,108.04,107.92,106.63,70.91,57.34,53.65,52.24,42.25,31.07.HRMS(ESI,positive)m / zcalcd for C 25 H 23 BrF2N2O4[M+H] + :533.0887; found533.0882.

[0142] Example 20

[0143] Preparation of Compound 20: 9-(2-(4-bromo-2,5-difluorobenzyl)amino)piperidin-1-yl)ethoxy)-7H-furo[3,2-g]puro[3,2-g]puran-7-one

[0144]

[0145] Referring to the preparation method of Compound 12 in Example 12, 2,5-difluoro-4-bromobenzaldehyde was used instead of 3,4-dihydro-2H-pyrano[2,3-C]pyridine-6-carbaldehyde to obtain a white solid with a yield of 10.9%. 1H NMR (600MHz, Methanol-d4) δ7.99(d,J=9.7Hz,1H),7.88(d,J=2.2Hz,1H),7.54(s,1H),7.40(dd, J=8.9,5.6Hz,1H),7.35(dd,J=9.0,6.2Hz,1H),6.95(d,J=2.2Hz,1H),6.36(d,J=9.6Hz,1H),5.50 (s,1H),4.58(t,J=5.5Hz,2H),3.80(s,2H),3.14(dt,J=12.5,3.8Hz,2H),2.93(t,J=5.4Hz,2H), 2.53(tt,J=10.6,4.0Hz,1H),2.29(td,J=12.0,2.5Hz,2H),1.98–1.91(m,2H),1.51–1.41(m,2H). 13 CNMR(151MHz,Methanol-d4)δ161.06,157.36,156.32,155.74,154.71,148.00,147.12,145.21,143.19,131.33,126.43,119.77,119.5 8,117.19,117.15,117.02,116.98,116.61,113.84,113.66,106.63,70.90,57.34,53.66,52.26,42.21,31.09.HRMS(ESI,positive)m / z calcd for C 25 H 23 BrF2N2O4[M+H] + :533.0887; found 533.0882.

[0146] Example 21

[0147] Preparation of Compound 21: 9-(2-(4-bromo-3-fluorobenzyl)amino)piperidin-1-yl)ethoxy)-7H-furo[3,2-g]furo[3,2-g]thiophen-7-one

[0148]

[0149] Referring to the preparation method of Compound 12 in Example 12, 3,4-dihydro-2H-pyrano[2,3-C]pyridine-6-carbaldehyde was replaced with 3-fluoro-4-bromobenzaldehyde to obtain a white solid with a yield of 15%. 1H NMR(600MHz, Methanol-d4)δ7.98(d,J=9.5Hz,1H),7.87(d,J=2.2Hz,1H),7.56–7.50(m,2H),7. 24(dd,J=9.9,2.0Hz,1H),7.09(dd,J=8.1,2.0Hz,1H),6.93(d,J=2.2Hz,1H),6.35(d,J=9.6Hz, 1H),4.56(t,J=5.5Hz,2H),3.76(s,2H),3.15–3.09(m,2H),2.89(t,J=5.5Hz,2H),2.52(tt,J=1 0.8,4.0Hz,1H),2.24(td,J=12.0,2.5Hz,2H),1.93(dq,J=12.6,3.1Hz,2H),1.50–1.40(m,2H). 13 C NMR(151MHz,Methanol-d4)δ161.06,159.77,158.14,147.98,147.10,145.20,143.16,142.15,142.10,133.12,131.34,126 .42,125.30,125.28,116.60,116.10,115.95,113.65,106.63,70.99,57.36,53.61,52.32,48.78.HRMS(ESI,positive)m / z calcd for C 25 H 24 BrF1N2O4[M+H] + :515.0981;found515.0976.

[0150] Example 22

[0151] Preparation of Compound 22 9-(2-(4-(4-chloro-3,5-difluorobenzyl)amino)piperidin-1-yl)ethoxy)-7H-furo[3,2-g]furo[3,2-g]puran-7-one

[0152]

[0153] Referring to the preparation method of Compound 12 in Example 12, 3,5-difluoro-4-chlorobenzaldehyde was used instead of 3,4-dihydro-2H-pyrano[2,3-C]pyridine-6-carbaldehyde to obtain a white solid with a yield of 41.2%. 1H NMR(600MHz, Methanol-d4)δ8.01(d,J=9.5Hz,1H),7.89(s,1H),7.57(s,1H),7.16( d,J=7.9Hz,2H),6.96(d,J=2.2Hz,1H),6.37(d,J=9.5Hz,1H),4.60(t,J=5.4Hz,2H), 3.80(s,2H),3.16(d,J=12.0Hz,2H),2.95(t,J=5.4Hz,2H),2.54(tt,J=10.7,4.0Hz ,1H),2.31(td,J=11.9,2.5Hz,2H),1.98–1.90(m,2H),1.47(qd,J=11.7,3.7Hz,2H). 13 C NMR(151MHz,Methanol-d4)δ161.09,159.48,159.45,157.82,148.04,147.13,145.24,143.22,142.02,131.32,126.46,116.63,11 3.89,113.66,111.61,111.59,111.47,111.45,106.63,70.85,57.30,53.48,52.23,48.69,48.45,31.02.HRMS(ESI,positive)m / z calcd for C 25 H 23 ClF2N2O4[M+H] + :489.1392; found 489.1387.

[0154] Example 23

[0155] Preparation of intermediate IIIa: 7-oxo-7H-furo[3,2-g]thiophen-9-yl 2-bromoacetate

[0156]

[0157] 8-Hydroxypsoralen (100 mg, 0.495 mmol) was added to a 10 mL single-necked flask and dissolved in 2.5 mL of dichloromethane. The mixture was then cooled to 0°C in an ice bath. Pyridine (66 μL, 0.816 mmol) and bromoacetyl bromide (109.82 mg, 0.544 mmol) were added separately and stirred for 15 minutes. The mixture was then warmed to room temperature and allowed to react for 20 minutes. After completion of the reaction, 30 mL of water was added to quench the reaction and the mixture was extracted with dichloromethane (30 mL x 3). The organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and the solvent was evaporated. The mixture was purified by column chromatography to obtain a white solid in a 36.6% yield.1 H NMR (600MHz, Chloroform-d) δ7.82(d,J=9.6Hz,1H),7.73(d,J=2.2Hz,1H),7.63(s,1H),6.89(d,J=2.2Hz,1H),6.42(d,J=9.6Hz,1H),4.31(s,2H).

[0158] Preparation of Intermediate Ic: 7-oxo-7H-furo[3,2-g]thien-9-yl-2-(4-((tert-butoxycarbonyl)amino)piperidin-1-yl)acetate

[0159]

[0160] Raw material IIIa (48 mg, 0.149 mmol) was placed in a 10 mL single-necked flask and dissolved in 2.5 mL of DMF. 4-tert-Butyloxycarbonylaminopiperidine (35.71 mg, 0.178 mmol) and potassium carbonate (35.71 mg, 0.178 mmol) were then added, respectively, and reacted at 90°C for 2 hours. After completion of the reaction, the mixture was cooled to room temperature, and water (30 mL) was added. Extraction was performed with ethyl acetate (20 mL x 3), and the mixture was washed with saturated brine (30 mL). The organic phase was dried over anhydrous sodium sulfate, and the solvent was evaporated. The product was purified by column chromatography to obtain a white solid in a 30.3% yield. 1 H NMR(600MHz,Chloroform-d)δ8.03(s,1H),7.78(d,J=9.6Hz,1H),7.71(d,J=2.1Hz,1H),7.41(s, 1H),6.83(d,J=2.1Hz,1H),6.37(d,J=9.5Hz,1H),5.24(d,J=13.1Hz,1H),5.08(d,J=12.8Hz,1H), 4.91(s,1H),4.48(d,J=13.3Hz,1H),4.14(d,J=13.4Hz,1H),3.79(s,1H),3.31(t,J=12.2Hz,1H), 2.80(t,J=13.0Hz,1H),2.10(d,J=12.1Hz,1H),1.98(d,J=12.5Hz,1H),1.88(s,1H),1.47(s,9H).

[0161] Preparation of intermediate IIc: 7-oxo-7H-furo[3,2-g]thiophen-9-yl 2-(4-aminopiperidin-1-yl)acetate

[0162]

[0163] Refer to the preparation method of Compound IIa in Example 1.

[0164] Preparation of compound 23: 7-oxo-7H-furan[3,2-g]thiophen-9-yl 2-(4-((4-bromo-3,5- difluorobenzyl)amino)piperidin-l-yl)acetate

[0165]

[0166] Intermediate IIc (54.2 mg, 0.158 mmol) and 4-bromo-3,5-difluorobenzaldehyde (31.45 mg, 0.142 mmol) were added to a 10 mL vial. Then, 2 mL of anhydrous 1,3-dichloroethane and NaBH(OAc)3(167.43 mg, 0.79 mmol) were added and the reaction was allowed to proceed at room temperature for 2.5 h. After the reaction was completed, saturated NaHCO3solution was added and the reaction mixture was extracted with dichloromethane (20 mL x 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate and the solvent was evaporated. The product was purified by column chromatography to give a white solid with a yield of 11.6%. 1 H NMR (600 MHz, Chloroform-d) δ 7.77 (d, J = 9.6 Hz, 1H), 7.70 (d, J = 2.2 Hz, 1H), 7.05 - 6.99 (m, 2H), 6.82 (d, J = 2.2 Hz, 1H), 6.35 (d, J = 9.5 Hz, 1H), 5.19 (d, J = 13.2 Hz, 1H), 5.13 (d, J = 13.2 Hz, 1H), 4.40 (d, J = 13.4 Hz, 1H), 4.14 (d, J = 13.9 Hz, 1H), 3.85 (s, 2H), 3.48 (s, 1H), 3.33 - 3.26 (m, 1H), 2.88 - 2.79 (m, 2H), 2.09 (d, J = 13.1 Hz, 1H), 1.96 (d, J = 13.0 Hz, 1H), 1.69 (d, J = 11.9 Hz, 1H), 1.41 (t, J = 9.9 Hz, 1H). 13 C NMR (75 MHz, Chloroform-d) δ 165.85, 161.54, 160.25, 158.24, 147.82, 146.86, 144.48, 143.15, 143.09, 130.99, 126.15, 116.51, 114.68, 114.03, 111.36, 111.06, 106.81, 95.80, 71.68, 53.92, 49.48, 44.21, 40.88, 32.77, 31.94, 29.69. HRMS (ESI, positive) m / z calcd for C 25 H 21 BrF2N2O5[M+H]+ :547.0675;found.547.0680.

[0167] Example 24

[0168] Preparation of Compound 24: 7-oxo-7H-furo[3,2-g]thiophen-9-yl 2-(4-((3-fluoro-4-iodobenzyl)amino)piperidin-1-yl)acetate

[0169]

[0170] Referring to the preparation method of Compound 23 in Example 23, 3-fluoro-4-iodobenzaldehyde was used instead of 3,5-difluoro-4-bromobenzaldehyde to obtain a white solid with a yield of 11.6%. 1 H NMR (600MHz, DMSO-d6) δ8.19–8.13(m,2H),7.77(t,J=7.4Hz,1H),7.64(s,1H),7.39(s,1H),7.11–7.05(m,2H),6.43(d,J=9.6Hz,1H) ,5.31–5.18(m,2H),4.12(d,J=11.8Hz,1H),3.84(s,3H),3.17–3.08(m,1H),2.81–2.70(m,2H),1.91(d,J=67.4Hz,3H),1.48(s,1H). 13 C NMR (75MHz, DMSO) δ165.81,163.88,160.23,157.86,148.30,146.49,145.80,141.37,140.84,139.33,131.19 ,126.37,116.78,114.62,113.72,107.37,70.15,53.60,45.46,45.01,33.72,29.81.HRMS(ESI,positive)m / z calcd forC 25 H 22 F1I1N2O5[M+H] + :577.0630; found 577.0635.

[0171] Example 25

[0172] Preparation of Compound 25: 7-oxo-7H-furo[3,2-g]thiophen-9-yl 2-(4-((4-chloro-3,5-difluorobenzyl)amino)piperidin-1-yl)acetate

[0173]

[0174] Referring to the preparation method of Compound 23 in Example 23, 3,5-difluoro-4-chlorobenzaldehyde was used instead of 3,5-difluoro-4-bromobenzaldehyde to obtain a white solid with a yield of 3.5%. 1 H NMR (600MHz, DMSO-d6) δ8.16(d,J=9.6Hz,2H),7.64(s,1H),7.45(s,1H),7.08(d,J=2.2Hz,1H),6.44(d,J=9.6Hz,1H),5.34– 5.17(m,2H),4.13(s,1H),3.87(s,2H),3.13(t,J=12.6Hz,1H),2.74(t,J=12.2Hz,1H),1.94(d,J=37.6Hz,2H),1.48(s,1H). 13 C NMR (151MHz, DMSO) δ160.63,158.99,157.93,157.35,152.49,149.21,146.61,140.34,114.38,112.84,1 12.47,107.35,105.75,94.17,71.06,57.50,53.85,52.32,48.43,31.72,29.45.HRMS(ESI,positive)m / z calcd for C 25 H 21 ClF2N2O5[M+H] + :503.1180; found 503.1185.

[0175] Example 26

[0176] Preparation of Intermediate IIIb: 9-(2-bromoethoxy)-7H-furo[3,2-g]thiophen-7-one

[0177]

[0178] 8-Hydroxypsoralen (500 mg, 2.48 mmol) was added to a 25 mL single-necked flask and dissolved in 4 mL of anhydrous DMF. Potassium carbonate (856.9 mg, 6.20 mmol) and 1-bromo-3-chloropropane (2.788 g, 14.84 mmol) were added separately and reacted at 100°C for 2 h. After the reaction was completed, the mixture was cooled to room temperature, water was added, and extraction was performed with ethyl acetate (20 mL x 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. Purification by column chromatography afforded a yellow solid in a 20% yield. 1HNMR(600MHz,Chloroform-d)δ8.26(d,J=9.8Hz,1H),7.63(d,J=2.3Hz,1H),7.22–7.19(m,1 H),6.92(dd,J=2.4,1.0Hz,1H),6.32(d,J=9.7Hz,1H),4.75–4.70(m,2H),3.75–3.70(m,2H).

[0179] Preparation of Intermediate IVa: tert-Butyl (3R,4R)-3-hydroxy-1-(2-(7-oxo-7H-furo[3,2-g]thiophen-9-oxy)ethyl)piperidin-4-yl)carbamate

[0180]

[0181] Compound IIIb (50 mg, 0.162 mmol) and anhydrous DMF (2.5 mL) were added to a 25 mL single-necked flask. After stirring to dissolve, trans-4-(Boc-amino)-3-hydroxypiperidine (38.48 mg, 0.178 mmol) and potassium carbonate (55.98 mg, 0.405 mmol) were added and reacted at 70°C for 4.5 h. After completion of the reaction, the mixture was cooled to room temperature, filtered, and the solvent was evaporated under reduced pressure. The residue was added with water and extracted with ethyl acetate (20 mL x 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. Purification by column chromatography afforded a white solid in a yield of 66.7%. 1 H NMR (600MHz, Chloroform-d) δ7.78(d,J=9.6Hz,1H),7.70(d,J=2.2Hz,1H),6.83(d,J=2.2Hz,1H),6.37(d,J=9.6Hz,1H),4.71(s,1H),4.63(q,J =7.0,5.4Hz,1H),4.58(d,J=4.9Hz,1H),3.59(s,1H),3.43(d,J=29.8Hz ,2H),2.96(s,1H),2.38(s,1H),2.25(s,1H),1.56(s,1H),1.45(s,10H).

[0182] Preparation of Intermediate Va: 9-(2-(3R,4R)-4-amino-3-hydroxypiperidin-1-yl)ethoxy)-7H-furo[3,2-g]thiophen-7-one

[0183]

[0184] The preparation method of compound IIa was referred to Example 1 and used directly in the next reaction without purification.

[0185] Preparation of Compound 26: 9-(2-(3R,4R)-4-(4-bromo-3,5-difluorobenzyl)amino)-3-hydroxypiperidin-1-yl)ethoxy)-7H-furo[3,2-g]thiophen-7-one

[0186]

[0187] Compound Va (31 mg, 0.09 mmol) and 4-bromo-3,5-difluorobenzaldehyde (21.9 mg, 0.099 mmol) were added to a 10 mL single-necked flask. 2 mL of anhydrous 1,3-dichloroethane and NaBH(OAc)3 (95.37 mg, 0.45 mmol) were added sequentially. The reaction was allowed to proceed at room temperature for 2.5 h. After completion of the reaction, saturated NaHCO3 solution was added, and the mixture was extracted with dichloromethane (20 mL x 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated. The mixture was purified by column chromatography to obtain a white solid in a yield of 16.6%. 1 HNMR(600MHz,Methanol-d4)δ8.03(d,J=9.6Hz,1H),7.89(d,J=2.2Hz,1H),7.59(s,1H),7.19–7.14(m,2H),6.97 (d,J=2.2Hz,1H),6.38(d,J=9.6Hz,1H),4.60(td,J=5.3,1.2Hz,2H),3.96(d,J=14.2Hz,1H),3.87(d,J=14.1Hz, 1H),3.57(td,J=9.3,4.3Hz,1H),3.35(s,3H),3.17(d,J=12.0Hz,1H),3.03(d,J=6.1Hz,2H),2.50(td,J=10.5,1 0.0,4.3Hz,1H),2.37(t,J=11.7Hz,1H),2.27(s,1H),2.06(dd,J=13.2,3.7Hz,1H),1.46(qd,J=11.5,3.9Hz,1H). 13 C NMR (75MHz, CDCl3) δ161.48,160.83,158.18,148.29,146.80,144.62,143.41,142.97,142.86,142.75,131.71,126.15,116.46,114.62 ,113.60,111.56,111.21,106.83,95.85,71.86,70.41,60.33,58.52,57.01,52.67,49.66,29.08,1.01.HRMS(ESI,positive)m / zcalcd for C25 H 23 BrF2N2O5[M+H] + : 549.0836; found 549.0831.

[0188] Example 27

[0189] Preparation of Compound 27: 9-(2-(3-fluoro-4-iodobenzyl)amino)-3- hydroxypiperidin-l-yl)ethoxy)-7H-furo[3,2-g]pyrimidin-7-one

[0190]

[0191] The procedure of Example 26 was followed for the preparation of Compound 26 using 3-fluoro-4-iodobenzaldehyde instead of 3,5-difluoro-4-bromobenzaldehyde to give a white solid in 6.1% yield. 1 H NMR (600 MHz, Methanol-d4) δ 8.04 (d, J = 9.6 Hz, 1H), 7.88 (d, J = 2.2 Hz, 1H), 7.74 (dd, J = 8.1, 6.7 Hz, 1H), 7.59 (s, 1H), 7.19 (dd, J = 9.2, 1.9 Hz, 1H), 7.00 - 6.95 (m, 2H), 6.39 (d, J = 9.6 Hz, 1H), 4.59 (td, J = 5.4, 1.9 Hz, 2H), 3.89 (d, J = 13.8 Hz, 1H), 3.75 (d, J = 13.7 Hz, 1H), 3.45 (td, J = 9.7, 4.6 Hz, 1H), 3.35 (s, 3H), 3.27 - 3.21 (m, 1H), 3.06 (d, J = 11.9 Hz, 1H), 2.93 (q, J = 4.9 Hz, 2H), 2.41 - 2.34 (m, 1H), 2.21 (t, J = 12.0 Hz, 1H), 2.08 (t, J = 10.5 Hz, 1H), 1.99 (dd, J = 12.9, 3.9 Hz, 1H). 13 C NMR (75 MHz, CDC13) δ 163.30, 160.78, 160.05, 148.15, 146.82, 144.64, 143.30, 142.26, 139.19, 131.65, 126.14, 116.42, 115.80, 115.48, 114.54, 113.56, 106.83, 71.69, 69.95, 60.34, 58.78, 57.05, 52.49, 49.39, 28.67. HRMS (ESI, positive) m / z calcd for C 25 H 24 F1I1N2O5[M+H]+ : 579.0792; found 579.0787.

[0192] Example 28

[0193] Preparation of Compound 28: 9-(2-(3R,4R)-4-(4-chloro-3,5-difluorobenzylamino)-3-hydroxypiperidin-1-yl)ethoxy)-7H-furo[3,2-g]thiophen-7-one

[0194]

[0195] Referring to the preparation method of compound 26 in Example 26, 3,5-difluoro-4-chlorobenzaldehyde was substituted for 3,5-difluoro-4-bromobenzaldehyde to obtain a white solid with a yield of 4.8%. 1 H NMR(600MHz, Methanol-d4)δ8.05(d,J=9.6Hz,1H),7.90(d,J=2.2Hz,1H),7.61(s,1H),7.26–7.19(m,2H), 6.98(d,J=2.2Hz,1H),6.39(d,J=9.6Hz,1H),4.61(td,J=5.3,1.4Hz,2H),3.98(d,J=14.1Hz,1H),3.88(d,J =14.1Hz,1H),3.58(td,J=9.4,4.4Hz,1H),3.37–3.33(m,1H),3.17(d,J=11.9Hz,1H),3.04(d,J=5.6Hz,2H ),2.55–2.48(m,1H),2.37(t,J=11.5Hz,1H),2.27(s,1H),2.07(dd,J=13.4,3.8Hz,1H),1.52–1.43(m,1H). 13 C NMR (151MHz, CDCl3) δ165.13,163.46,161.81,151.99,151.14,149.26,147.12,144.10,135.03,130.43,120.55,118.08,117. 57,115.93,115.79,111.76,110.61,74.40,72.90,63.27,62.23,60.69,55.34,52.54,52.40,31.08.HRMS(ESI,positive)m / z calcd for C 25 H 23 ClF2N2O5[M+H] + :505.1342; found 505.1336.

[0196] Example 29

[0197] Preparation of Intermediate VIa: tert-Butyl 4-((4-bromo-3,5-difluorobenzyl)amino)-3-methoxypiperidine-1-carboxylate

[0198]

[0199] (3S,4R)-N-Boc-4-amino-3-methoxypiperidine (0.17 mmol) and 4-bromo-3,5-difluorobenzaldehyde (0.157 mmol) were added to a 10 mL single-necked flask. 2 mL of anhydrous 1,3-dichloroethane was added with stirring, followed by the addition of sodium triacetoxyborohydride (0.85 mmol). The mixture was allowed to react at room temperature for 2.5 h. After completion of the reaction, saturated NaHCO₃ solution was added, and the mixture was extracted with dichloromethane (20 mL x 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated. The mixture was purified by column chromatography to obtain a white solid in a 45.3% yield. 1 H NMR(600MHz, Methanol-d4)δ7.14(d,J=8.3Hz,2H),4.30(d,J=15.2Hz,1H),4.07–3.93(m,1H),3.80(s,2H),3.42 (s,3H),3.36(s,1H),2.79(t,J=16.4Hz,1H),2.69(d,J=10.7Hz,1H),1.63(dd,J=10.0,4.2Hz,2H),1.47(s,9H).

[0200] Preparation of intermediate VIIa: N-(4-bromo-3,5-difluorobenzyl)-3-methoxypiperidin-4-amine

[0201]

[0202] The preparation method of compound IIa was referred to Example 1 and used directly in the next reaction without purification.

[0203] Preparation of Compound 29: 9-(2-(4-bromo-3,5-difluorobenzyl)amino)-3-methoxypiperidin-1-yl)ethoxy)-7H-furo[3,2-g]puran-7-one

[0204]

[0205] To a 25 mL single-necked flask, add raw material VIIa (60 mg, 0.179 mmol) and anhydrous DMF (2.5 mL). After stirring, add compound IIIb (55.3 mg, 0.179 mmol) and potassium carbonate (61.85 mg, 0.448 mmol). The reaction was allowed to react at 70°C for 3 h. After completion of the reaction, cool to room temperature, filter, and evaporate the solvent under reduced pressure. Water was added, and extraction was performed with ethyl acetate (20 mL x 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. Purification by column chromatography afforded a white solid in a yield of 6.9%. 1 HNMR(600MHz,Chloroform-d)δ7.78(d,J=9.6Hz,1H),7.69(d,J=2.2Hz,1H),7.39(s,1H),6.38(d,J=9.6Hz,1H),4.68(d,J=13.1Hz,2H),3.8 2–3.73(m,2H),3.42(s,3H),3.22(s,1H),3.05(s,2H),2.77(s,1H),2. 54(s,2H),2.12(d,J=11.7Hz,1H),1.76(s,3H),1.61(q,J=7.6Hz,1H). 13 C NMR (75MHz, CDCl3) δ161.46,160.38,158.11,148.09,146.60,144.34,143.80,143.41,131.81,125.98,116.48,114.67,1 13.30,111.26,110.96,106.80,95.35,71.60,57.66,56.64,54.59,53.47,53.09,49.36,27.64.HRMS(ESI,positive)m / z calcdfor C26H25BrF2N2O5[M+H] + :563.0983; found 563.0998.

[0206] Example 30

[0207] Preparation of Compound 30: 9-(2-(4-(3-fluoro-4-iodobenzyl)amino)-3-methoxypiperidin-1-yl)ethoxy)-7H-furo[3,2-g]furo[3,2-g]puran-7-one

[0208]

[0209] Referring to the preparation method of Compound 29 in Example 29, 3-fluoro-4-iodobenzaldehyde was used instead of 3,5-difluoro-4-bromobenzaldehyde to obtain a white solid with a yield of 7.2%. 1H NMR(600MHz,Chloroform-d)δ7.78(d,J=9.6Hz,1H),7.70–7.67(m,1H),7.67–7.63(m,1H),7 .39(s,1H),7.12(dd,J=8.9,1.9Hz,1H),6.92(dd,J=8.1,1.9Hz,1H),6.83(d,J=2.2Hz,1H),6 .36(d,J=9.6Hz,1H),4.72(ddp,J=16.4,11.0,4.9Hz,2H),3.85–3.74(m,2H),3.65(s,1H),3 .40(s,3H),3.28(s,1H),3.19–3.07(m,3H),2.89(s,1H),2.71(s,1H),1.86(d,J=5.8Hz,2H). 13 C NMR (75MHz, CDCl3) δ163.36,160.42,160.11,148.08,146.63,144.37,143.39,138.97,131.78,126.00,125.35,116.49,1 15.38,115.07,114.69,113.33,106.81,71.52,57.63,56.63,54.39,53.06,50.98,49.40,27.46.HRMS(ESI,positive)m / z calcd for C 26 H 26 F1I1N2O5[M+H] + :593.0948;found593.0943

[0210] Example 31

[0211] Preparation of Compound 31: 9-(2-(4-(4-chloro-3,5-difluorobenzyl)amino)-3-methoxypiperidin-1-yl)ethoxy)-7H-furo[3,2-g]furo[3,2-g]puran-7-one

[0212]

[0213] Referring to the preparation method of Compound 29 in Example 29, 3,5-difluoro-4-chlorobenzaldehyde was used instead of 3,5-difluoro-4-bromobenzaldehyde to obtain a white solid with a yield of 17.3%. 1H NMR (600 MHz, Methanol-d4) δ 8.01 (d, J = 9.5 Hz, 1H), 7.89 (s, 1H), 7.57 (s, 1H), 7.16 (d, J = 7.9 Hz, 2H), 6.96 (d, J = 2.2 Hz, 1H), 6.37 (d, J = 9.5 Hz, 1H), 4.60 (t, J = 5.4 Hz, 2H), 3.80 (s, 2H), 3.16 (d, J = 12.0 Hz, 2H), 2.95 (t, J = 5.4 Hz, 2H), 2.54 (tt, J = 10.7, 4.0 Hz, 1H), 2.31 (td, J = 11.9, 2.5 Hz, 2H), 1.98 - 1.90 (m, 2H), 1.47 (qd, J = 11.7, 3.7 Hz, 2H). 13 C NMR (75 MHz, MeOD) δ 161.03, 160.23, 156.93, 147.96, 147.09, 145.19, 143.15, 142.37, 131.26, 126.43, 116.61, 113.83, 113.65, 111.57, 111.24, 106.63, 75.50, 71.10, 57.17, 55.53, 54.83, 52.57, 51.33, 29.38, 26.65. HRMS (ESI, positive) m / z calcd for C 26 H 25 ClF2N2O5[M+H] + : 519.1498; found 519.1493.

[0214] Example 32

[0215] Preparation of compound 32: 9-(2-(4-bromo-3,5-difluorobenzyl)amino)-3- fluoropiperidin-l-yl)ethoxy)-7H-furo[3,2-g]pyrimido[3,2-g]pyrimin-7-one

[0216]

[0217] The preparation of compound 29 according to the procedure described in Example 29, using N-Boc-4-amino-3-fluoropiperidine instead of (3S,4R)-N-Boc-4-amino-3- methoxypiperidine, afforded a white solid in 37.7% yield. 1H NMR(600MHz, Methanol-d4)δ8.05(d,J=9.6Hz,1H),7.90(d,J=2.2Hz,1H),7.61(s,1H),7.20–7.1 2(m,2H),6.98(d,J=2.3Hz,1H),6.39(d,J=9.6Hz,1H),4.63(h,J=6.1Hz,2H),3.89(s,2H),3.48(t ,J=11.6Hz,1H),3.14(d,J=12.0Hz,1H),3.08–2.98(m,2H),2.75(dd,J=28.3,11.3Hz,1H),2.65( dd,J=37.0,13.2Hz,1H),2.49(t,J=11.6Hz,1H),1.87(dd,J=13.6,3.9Hz,1H),1.84–1.74(m,1H). 13 CNMR (75MHz, CDCl3) δ162.61,161.44,160.48,158.14,148.01,146.78,144.47,143.27,143.16,131.69,127.40,116. 46,114.61,113.56,111.00,106.85,86.76,75.56,71.47,61.65,57.19,51.45,49.00,26.79.HRMS(ESI,positive)m / z calcd forC 25 H 22 BrF3N2O4[M+H] + :551.0793; found551.0788.

[0218] Example 33

[0219] Preparation of compound 33: 9-(2-(3-fluoro-4-iodobenzyl)amino)piperidin-1-yl)ethoxy)-7H-furo[3,2-g]thiophen-7-one

[0220]

[0221] Referring to the preparation method of Compound 29 in Example 29, N-Boc-4-amino-3-fluoropiperidine and 3-fluoro-4-iodobenzaldehyde were used to replace (3S,4R)-N-Boc-4-amino-3-methoxypiperidine and 3,5-difluoro-4-bromobenzaldehyde, respectively, to obtain a yellow solid with a yield of 41.4%. 1H NMR(600MHz, Methanol-d4)δ8.03–7.98(m,2H),7.87(dd,J=5.8,2.2Hz,2H),7.75–7.69(m,1H),7.55(d,J=1.7Hz ,2H),7.23–7.14(m,1H),6.98(td,J=7.9,1.9Hz,1H),6.95(d,J=2.2Hz,2H),6.39–6.34(m,2H),4.64–4.52(m,5H ),3.95(t,J=4.8Hz,2H),3.88–3.81(m,2H),3.42(t,J=11.8Hz,1H),3.31(p,J=1.8Hz,4H),3.08(d,J=11.8Hz,1H ),3.01–2.91(m,2H),2.73–2.50(m,2H),2.43–2.36(m,1H),1.83(d,J=12.5Hz,1H),1.75(qd,J=12.2,3.9Hz,1H). 13 C NMR(75MHz,MeOD)δ163.37,161.51,161.27,160.14,147.69,147.10,145.44,142.84,139.17,131.05,126.37,116.4 5,115.30,113.82,113.53,106.62,86.09,78.57,74.85,70.94,60.95,56.73,51.39,26.07.HRMS(ESI,positive)m / z calcdfor C 25 H 23 F2I1N2O4[M+H] + : 581.0749; found 581.0743.

[0222] Example 34

[0223] Preparation of Compound 34: 9-(2-(4-chloro-3,5-difluorobenzyl)amino)-3-fluoropiperidin-1-yl)ethoxy)-7H-furo[3,2-g]puro[3,2-g]puran-7-one

[0224]

[0225] Referring to the preparation method of Compound 29 in Example 29, N-Boc-4-amino-3-fluoropiperidine and 3,5-difluoro-4-chlorobenzaldehyde were used to replace (3S,4R)-N-Boc-4-amino-3-methoxypiperidine and 3,5-difluoro-4-bromobenzaldehyde, respectively, to obtain a yellow solid with a yield of 27.8%. 1H NMR(600MHz, Methanol-d4)δ8.02–7.96(m,1H),7.87(dd,J=3.6,2.1Hz,1H),7.56–7.52(m,1H),7.15( dd,J=15.9,8.6Hz,2H),6.96–6.92(m,1H),6.39–6.33(m,1H),4.63–4.52(m,2H),3.94(t,J=4.8Hz,1H ),3.84(s,2H),3.44–3.37(m,1H),3.09–3.03(m,1H),3.01–2.91(m,2H),2.70–2.51(m,1H),2.44–2.3 7(m,1H),2.24(dtd,J=27.0,11.8,11.0,4.1Hz,1H),1.82(dd,J=13.2,3.9Hz,1H),1.79–1.69(m,1H). 13 C NMR(75MHz,MeOD)δ163.54,160.99,160.64,157.35,148.94,148.50,146.46,145.35,144.04,132.46,132.23,126.97,1 17.63,115.35,112.81,108.27,88.03,76.13,72.37,61.57,56.83,52.30,49.44,28.12,28.08.HRMS(ESI,positive)m / z calcd for C 25 H 22 ClF3N2O4[M+H] + :507.1298; found507.1293

[0226] Example 35

[0227] Preparation of Compound 35: 9-(2-(4-bromo-3,5-difluorobenzyl)amino)-3,3-difluoropiperidin-1-yl)ethoxy)-7H-furo[3,2-g]furo[3,2-g]thiophen-7-one

[0228]

[0229] Referring to the preparation method of Compound 29 in Example 29, N-Boc-4-amino-3,3-difluoropiperidine was used instead of (3S,4R)-N-Boc-4-amino-3-methoxypiperidine to obtain a white solid with a yield of 9.8%. 1H NMR(600MHz,Methanol-d4)δ8.06(d,J=9.6Hz,1H),7.91(d,J=2.2Hz,1H),7.60(s,1H),7 .18–7.13(m,2H),6.99(d,J=2.2Hz,1H),6.41(d,J=9.5Hz,1H),4.59–4.56(m,2H),4.00– 3.95(m,3H),3.94(s,2H),3.22(dt,J=13.7,9.6Hz,1H),3.03(d,J=13.8Hz,1H),3.00–2. 79(m,2H),2.70–2.63(m,1H),2.03(ddd,J=17.7,9.7,4.9Hz,1H),1.62(d,J=21.2Hz,1H). 13 C NMR(151MHz,MeOD)δ161.38,160.58,158.93,147.80,147.12,145.40,143.64,142.91,131.53,126.55,116.60,11 3.60,113.54,111.13,110.98,106.57,74.88,60.92,56.67,49.76,49.05,42.40,29.32.HRMS(ESI,positive)m / z calcd for C 25 H 21 BrF4N2O4,[M+H] + :569.0702;found569.0694.

[0230] Example 36

[0231] Preparation of Compound 36: 9-(2-(3,3-difluoro-4-(3-fluoro-4-iodobenzyl)amino)piperidin-1-yl)ethoxy)-7H-furo[3,2-g]puran-7-one

[0232]

[0233] Referring to the preparation method of Compound 29 in Example 29, (3S,4R)-N-Boc-4-amino-3-methoxypiperidine and 3,5-difluoro-4-bromobenzaldehyde were replaced by N-Boc-4-amino-3,3-difluoropiperidine and 3-fluoro-4-iodobenzaldehyde, respectively, to obtain a white solid with a yield of 64.8%. 1H NMR (600MHz, Methanol-d4) δ8.03(d,J=9.6Hz,1H),7.88(d,J=2.2Hz,1H),7.72(dd,J=8.1,6.6Hz,1 H),7.59(s,1H),7.19(dd,J=9.2,1.9Hz,1H),7.00–6.95(m,2H),6.39(d,J=9.6Hz,1H),4.60(t,J=5 .2Hz,2H),3.94–3.85(m,2H),3.25(q,J=10.1Hz,1H),2.99(ddt,J=6.8,5.0,2.3Hz,3H),2.89–2.77 (m,1H),2.68–2.59(m,1H),2.43(dd,J=12.5,9.8Hz,1H),1.95–1.88(m,1H),1.55(q,J=11.5Hz,1H). 13 C NMR (75MHz, CDCl3) δ163.40,160.40,160.15,148.13,146.69,144.36,143.84,143.46,139.06,139.03,131.67,125.98,125.33,125.29 ,124.10,120.85,116.50,115.33,115.02,114.70,113.50,106.83,79.00,71.41,56.71,50.86,50.55,29.46.HRMS(ESI,positive)m / z calcd forC 25 H 22 F3I1N2O4[M+H] + :599.0654;found599.0649.

[0234] Example 37

[0235] Preparation of Compound 37: 9-(2-(4-(4-chloro-3,5-difluorobenzyl)amino)-3,3-difluoropiperidin-1-yl)ethoxy)-7H-furo[3,2-g]puran-7-one

[0236]

[0237] Referring to the preparation method of Compound 29 in Example 29, (3S,4R)-N-Boc-4-amino-3-methoxypiperidine and 3,5-difluoro-4-bromobenzaldehyde were replaced by N-Boc-4-amino-3,3-difluoropiperidine and 3,5-difluoro-4-chlorobenzaldehyde, respectively, to obtain a light yellow solid with a yield of 26.6%. 1H NMR (600MHz, Methanol-d4) δ8.03 (ddd, J=9.6, 3.3, 1.9Hz, 1H), 7.89 (dd, J=2.2, 1.0Hz, 1H), 7.58 (d, J=2.3H z,1H),7.17(d,J=8.7Hz,2H),6.97(dd,J=2.3,1.2Hz,1H),6.39(dt,J=9.5,1.7Hz,1H),4.63–4.58(m,2H),3 .93(d,J=2.9Hz,2H),3.27(qd,J=9.7,4.7Hz,1H),3.05–2.98(m,3H),2.83(ddt,J=19.2,10.3,5.1Hz,1H),2 .71–2.61(m,1H),2.46(td,J=11.2,9.7,2.7Hz,1H),1.98–1.90(m,1H),1.58(tdd,J=14.0,9.7,3.6Hz,1H). 13 C NMR(75MHz,MeOD)δ161.10,160.19,156.89,147.87,147.04,145.17,143.08,142.75,131.23,126.35,123.83,117.34,116.5 3,113.76,113.58,111.26,110.93,106.61,71.00,56.79,56.39,50.38,49.75,49.73,28.47.HRMS(ESI,positive)m / zcalcd for C 25 H 21 ClF4N2O4,[M+H] + :525.1204; found 525.1199.

[0238] Example 38

[0239] Preparation of Compound 38: 9-(2-((3R,4R)-4-(((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)amino)-3-hydroxypiperidin-1-yl)ethoxy)naphtho[2,3-b]furan-7(8H)-one

[0240]

[0241] Referring to the preparation method of Compound 26 in Example 26, 3,4-dihydro-2H-pyrano[2,3-C]pyridine-6-carbaldehyde was used instead of 3,5-difluoro-4-bromobenzaldehyde to obtain a light yellow solid with a yield of 20.5%. 1H NMR(600MHz,Chloroform-d)δ7.79(d,J=9.6Hz,1H),7.72(d,J=2.2Hz,1H),7.39(s,1H),7.00(d,J=2.1Hz,1H),6.96(dd,J=8.3,2. 1Hz,1H),6.86–6.81(m,2H),6.37(d,J=9.6Hz,1H),5.31(s,1H),4.62(ddd,J=10.4,6.0,4.4Hz,1H),4.54(ddd,J=10.6,6.2,4.5Hz ,1H),4.23(s,4H),4.10(d,J=13.2Hz,1H),3.82(dd,J=13.6,8.6Hz,2H),3.43(dd,J=11.4,4.4Hz,1H),3.07(d,J=11.8Hz,1H),2.9 9–2.88(m,2H),2.64(td,J=10.3,9.2,4.4Hz,1H),2.26(t,J=11.7Hz,1H),2.15(t,J=10.4Hz,1H),2.07(s,1H),1.84–1.75(m,1H). 13 C NMR (151MHz, CDCl3) δ160.64,148.13,146.86,144.54,143.58,143.34,131.71,128.08,126.07,122.31,118.17,117.55,116 .42,114.57,113.47,106.79,71.54,68.61,64.31,64.24,60.15,58.93,56.98,52.08,48.90,27.31.HRMS(ESI,positive)m / z calcd for C 27 H 28 N2O7[M+H] + : 493.1975; found 493.1969.

[0242] Example 39

[0243] In vitro activity assay of compound 1-38 against drug-resistant bacteria

[0244] In vitro antibacterial activity was tested using the broth microdilution method against methicillin-resistant Staphylococcus aureus ATCC 33591 (MRSA), Klebsiella pneumoniae ATCC 10031 (sensitive quality control strain), and Escherichia coli ATCC 25922. Ceftazidime, gepotidacin, and psoralen were used as positive controls, and minimum inhibitory concentrations (MICs) were determined.

[0245] The experimental strains included Gram-positive bacteria: methicillin-resistant Staphylococcus aureus ATCC 33591 (MRSA); Gram-negative bacteria: Klebsiella pneumoniae ATCC 10031 (sensitive quality control strain) and Escherichia coli ATCC 25922.

[0246] The specific steps are as follows:

[0247] (1) Preparation of test compounds and culture medium: The test compound was prepared as a 10 mg / mL DMSO stock solution, and the culture medium was prepared according to the manufacturer's instructions.

[0248] (2) Gradual dilution of test compound concentration

[0249] Double dilution of the test compound solution: Aseptically, take 12.8μL of the drug solution and add it to the first well of a 96-well plate, then add 27.2μL of DMSO. Place 2-12uL of DMSO in 20 wells and mix well. Take 20uL from the first well and place it in the second well and mix well. Collect 20uL from the second well and place it in the third well. Repeat this process until the 11th well, then collect 20uL and discard it. Starting from the 12th well, only 20uL of DMSO is added to the growth and control well. Add 180uL of sterile water to the next well and mix well. Prepare the control drug in the same way. Place 10ul in each well of 96 sterile wells to prepare solutions of different concentrations as samples.

[0250] (3) Preparation of test strains and MIC experiments

[0251] Agar plates containing a single fungus were plated with 5 ml of sterile saline solution. The spectrophotometer showed approximately 80% transmittance. MHB liquid medium was diluted to a 1:200 ratio. 90 μL of the bacterial suspension was mixed with 10 μL of the test compound solution. Results were analyzed after incubation at 35°C for 16-20 hours in a standard biochemical incubator. Results were obtained for wells 1 through 12 at concentrations of 32, 16, 8, 4, 2, 1, 0.5, 0.25, 0.125, 0.0625, 0.03125, and 0 μg / mL. Dilutions of the same compound were performed in duplicate.

[0252] (4) Reading and judging the results:

[0253] Refer to the 2013 CLSI recommended standard: The MIC value is the lowest visible antimicrobial concentration that can completely inhibit the growth of microorganisms in a test tube or microdilution well. If only microorganisms growing in the wells can be identified, equipment can be used to help read and record the results of the microdilution experiment. When determining the growth endpoint, compare the growth of antimicrobial and non-antimicrobial microdilution wells or in vitro microorganisms. If the growth control well shows acceptable growth conditions (2mm button-shaped sediment or a mixture with a certain turbidity), the test is valid.

[0254] Table 1 Minimum inhibitory concentrations of compounds 1-25 against three strains

[0255]

[0256]

[0257] The results for compounds 1-25 are shown in Table 1. As can be seen from Table 1, with the exception of compounds 1, 2, 11, 12, and 25, the remaining 20 compounds exhibited significant antibacterial activity against methicillin-resistant Staphylococcus aureus. Compounds 16 and 22 exhibited moderate antibacterial activity against Klebsiella pneumoniae, with MIC values ​​of 4 μg / mL and 16 μg / mL, respectively. More importantly, compounds 16 and 17 exhibited an MIC of 1 μg / mL against methicillin-resistant Staphylococcus aureus, demonstrating a stronger antibacterial effect than gepotidacin. These results demonstrate that the compounds of the present invention, or pharmaceutically acceptable salts thereof, have potential for development as anti-infective drugs.

[0258] The results of in vitro anti-drug-resistant bacteria activity assays of compounds 26-38 are shown in Table 2:

[0259] Table 2 Minimum inhibitory concentrations of compounds 26-38 against three strains

[0260]

[0261] As can be seen from Table 2, most compounds have antibacterial activity against methicillin-resistant Staphylococcus aureus. Among them, compounds 26, 27, and 33 have better antibacterial activity against methicillin-resistant Staphylococcus aureus than gepotidacin. Compound 26 has the highest antibacterial activity, with an MIC value of 0.5 μg / mL. Compounds 28, 30, and 32 have activity comparable to gepacidacin, with an MIC value of 4 μg / mL. Some compounds have antibacterial activity against Klebsiella pneumoniae, with the better compounds being 26, 27, 28, 29, and 33. These results indicate that the compounds of the present invention or their pharmaceutically acceptable salts have potential for development as drugs against drug-resistant bacteria.

[0262] Example 40

[0263] In vitro anti-inflammatory activity test of some compounds of the present application

[0264] The mouse monocyte macrophage leukemia RAW264.7 (purchased from Wuhan Pons Life Science Co., Ltd.) was selected as the anti-inflammatory activity detection cell to evaluate the expression level of inflammatory factors such as TNF-α and IL-6, and the anti-inflammatory activity evaluation method adopted the inflammation-related physiological index level score IR, the value range of which was 0-100, and the IR scoring method was as follows: the culture medium with only cells was taken as the blank group, the cells not showing inflammation were induced to express inflammatory factors on the basis of the blank group to form the model group, the compound was added to the model group to form the experimental group, the inflammation-related index level of each group was detected, and the detection results were calculated according to the formula; IR = (model group and inflammation-related index level-experimental group and inflammation-related index level) / (model group and inflammation-related index level-blank group and inflammation-related index level) x 100% was calculated. In the IR calculation formula, the inflammation-related index level was quantitatively characterized by detecting the absorbance through the enzyme-linked immunosorbent assay method (ELISA).

[0265] The specific experimental method was as follows: the RAW264.7 cells were cultured in the DMEM medium, and after the cells grew to the logarithmic growth phase, they were counted and inoculated in the 96-well cell culture plate. After the cells completely adhered and grew, the old culture medium was discarded, and 0.5 μM and 1 μM of the compound prepared in the culture medium and the positive control compound 8-hydroxy psoralen were added to the well plate, and the cells were placed in the cell incubator for 2 hours. Lipopolysaccharide (LPS) was added for 4 hours to induce the secretion of inflammatory factors. The cell supernatant was collected, and the content of inflammatory factors such as TNF-α and IL-6 was determined according to the enzyme-linked immunosorbent assay kit instruction.

[0266] Table 3 Inhibition of IL-6 in RAW264.7 cells by some compounds of the examples

[0267]

[0268] Table 4 Inhibition of TNF-α in RAW264.7 cells by some compounds of the examples

[0269]

[0270] As can be seen from Tables 3 and 4, the compounds of the present application have good inhibition effect on IL-6 and TNF-α in mouse monocyte macrophage leukemia RAW264.7, especially the inhibition rate of TNF-α is 88.3-100% at high concentration, and the above research results show that the compounds of the present application or the pharmaceutical salts thereof can also be used for preparing anti-inflammatory drugs.

[0271] Example 41

[0272] In vitro antitumor activity test of some compounds of the present invention

[0273] Some of the compounds of the present invention were tested for tumor cell proliferation inhibition using the CCK-8 assay (e.g., Lü Qiujun, ed., "New Drug Pharmacology Research Methods," 2007: 242-243). Cell lines used were A549 (human lung adenocarcinoma cells) and HCT-116 (human intestinal carcinoma cells), and the culture medium consisted of DMEM + 10% FBS + dual antibodies.

[0274] In vitro activity test: 4-5×10 4 100 μL of cell suspension with a concentration of 100 μL / mL was placed in a 37°C, 5% CO2 incubator. After 24 hours, the sample solution was added at 10 μL / well, and duplicate wells were set up and incubated at 37°C, 5% CO2 for 72 hours. 20 μL of 5 mg / ml CCK-8 solution was added to each well, and after 4 hours, 100 μL / well of dissolution solution was added and placed in an incubator. After dissolution, the OD value at 570 nm was measured using a full-wavelength multifunctional microplate reader. The inhibition rate (IR) and half-maximal inhibitory concentration (IC) were calculated using Excel software. 50 ).

[0275] The inhibition rate (IR%) of the drug on cell growth was calculated according to the following formula:

[0276]

[0277] The test results are shown in Table 5, wherein the samples refer to the compounds prepared in the corresponding examples.

[0278] Table 5 In vitro antitumor activity of some of the compounds in the examples

[0279]

[0280] The above experimental results demonstrate that the compounds of the present invention possess excellent antitumor activity, particularly against colon cancer and lung cancer cell lines. For example, compound 22 exhibited activity in the hundreds of nanomolar range against both tumor cell lines. Therefore, the compounds of the present invention or their pharmaceutically acceptable salts can also be used to prepare antitumor drugs.

[0281] The above merely describes the preferred embodiments of the present application, and is not intended to limit the present application in any form. Although the present application has been disclosed with the preferred embodiments as above, it is not intended to limit the present application, and any person skilled in the art can make some changes or modifications to the above-mentioned technical content with the prompt as equivalent embodiments of equivalent changes without departing from the technical solution of the present application. Any simple modification, equivalent change and modification made to the above embodiments according to the technical essence of the present application, which does not depart from the technical solution of the present application, still belongs to the scope of the present application.

Claims

1. A psoralen derivative or a pharmaceutically acceptable salt thereof, characterized in that: The general structural formula of the psoralen derivative is shown below: L is selected from -(CH2)n-, n is selected from 1, 2, 3, 4, 5; R1 is selected from hydrogen, hydroxy, halogen, C1-C10 alkyl, C1-C10 alkoxy; R2 is selected from hydrogen, hydroxy, halogen, C1-C10 alkyl, C1-C10 alkoxy; R3 is selected from hydrogen, hydroxy, halogen, C1-C10 alkyl, C1-C10 alkoxy; R4 is selected from hydrogen, hydroxy, halogen, C1-C10 alkyl, C1-C10 alkoxy; R5 is selected from hydrogen, hydroxy, halogen, C1-C10 alkyl, C1-C10 alkoxy; R6 is selected from R7 is selected from hydrogen, halogen, C1-C10 alkyl, C1-C10 alkoxy; R8 is selected from hydrogen, halogen, C1-C10 alkyl, C1-C10 alkoxy; R9 is selected from hydrogen, halogen, C1-C10 alkyl, C1-C10 alkoxy; R 10 is selected from hydrogen, halogen, C1-C10 alkyl, C1-C10 alkoxy; R 11 Selected from hydrogen, halogen, C1-C10 alkyl, C1-C10 alkoxy.

2. The psoralen derivative or pharmaceutically acceptable salt thereof according to claim 1, characterized in that In the psoralen derivatives: L is selected from -(CH2)n-, R1 is selected from hydrogen, hydroxy, fluorine, chlorine, bromine, iodine, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, tert-butoxy, n-butoxy; R2 is selected from hydrogen, hydroxy, fluorine, chlorine, bromine, iodine, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, tert-butoxy, n-butoxy; R3 is selected from hydrogen, hydroxy, fluorine, chlorine, bromine, iodine, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, tert-butoxy, n-butoxy; R4 is selected from hydrogen, hydroxy, fluorine, chlorine, bromine, iodine, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, tert-butoxy, n-butoxy; R5 is selected from hydrogen, hydroxy, fluorine, chlorine, bromine, iodine, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, tert-butoxy, n-butoxy; R6 is selected from R7 is selected from hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, tert-butoxy, n-butoxy; R8 is selected from hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, tert-butoxy, n-butoxy; R9 is selected from hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, tert-butoxy, n-butoxy; R 10 is selected from hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, tert-butoxy, n-butoxy; R 11 Selected from hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, tert-butoxy, n-butoxy.

3. A psoralen derivative or a pharmaceutically acceptable salt thereof, characterized in that: The structure of the psoralen derivative is selected from one of the following structures:

4. Use of a psoralen derivative or a pharmaceutically acceptable salt thereof in the preparation of an antibacterial drug, characterized in that: The bacteria mentioned are methicillin-resistant Staphylococcus aureus, Klebsiella pneumoniae, and Escherichia coli; The structure of the psoralen derivative is selected from one of the following structures:

5. Use of the psoralen derivative or a pharmaceutically acceptable salt thereof according to claim 3 in the preparation of anti-inflammatory drugs.

6. Use of a psoralen derivative or a pharmaceutically acceptable salt thereof in the preparation of an anti-tumor drug, characterized in that: The tumor is selected from lung adenocarcinoma or colon cancer; The structure of the psoralen derivative is selected from one of the following structures:

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