Pyridine ring-containing amphiphilic cumin-quaternary ammonium salt hybrid and preparation method and antibacterial application thereof

Abstract

The application discloses a series of pyridine ring-containing amphiphilic osthole-quaternary ammonium salt hybrids and a preparation method and antibacterial application thereof. The series of compounds are prepared by taking coumarin derivative osthole as a lead compound, introducing a pyridine ring and a cationic quaternary ammonium salt fragment at a C-7 position, so as to obtain a series of pyridine ring-containing amphiphilic osthole-quaternary ammonium salt hybrids, and the structural general formula is shown in the following formula (I). The series of compounds have strong in-vivo and in-vitro antibacterial activities on staphylococcus aureus and clinically isolated methicillin-resistant staphylococcus aureus, and are equivalent to the glycopeptide antibiotic vancomycin. Through structural modification, the water solubility and antibacterial activity of osthole are improved, and the series of compounds have the characteristics of low in-vivo toxicity, hemolytic activity and reduced probability of bacterial drug resistance. Therefore, the pyridine ring-containing amphiphilic osthole-quaternary ammonium salt hybrids have the potential of being further developed into new antibacterial drugs.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of pharmaceutical chemistry, and specifically relates to an amphiphilic pyridine ring-containing cumin-quaternary ammonium salt hybrid and a preparation method and antibacterial application thereof. BACKGROUND

[0002] In the 1940s, Fleming discovered penicillin, which opened up the era of antibiotics for the treatment of bacterial infections, but due to misuse and abuse, bacteria gradually developed drug resistance (T.M. Uddin, A.J. Chakraborty, A. Khusro, et al. Antibiotic resistance in microbes: History, mechanisms, therapeutic strategies and future prospects. Journal of Infection and Public Health, 2021, 14, 1750-1766.). In the 1960s, methicillin-resistant Staphylococcus aureus (MRSA) was found in hospitalized patients (F.F. Barrett, R.F. McGehee, M. Finland, Methicillin-resistant Staphylococcus aureus at Boston City Hospital. Bacteriologic and epidemiologic observations. New England Journal of Medicine, 1968, 279, 441-448.). MRSA can cause high mortality outbreak diseases such as pneumonia, sepsis and osteomyelitis, and has strong virulence and drug resistance (H.F. Chambers, F.R. DeLeo, Waves of resistance: Staphylococcus aureus in the antibiotic era. Nature Reviews Microbiology, 2009, 7, 629-641.). Therefore, there is an urgent need to develop new antibacterial drugs to combat MRSA.

[0003] In recent years, in the field of developing new antibiotics, antimicrobial peptides (AMPs) have attracted much attention due to their rapid bactericidal speed and broad-spectrum antibacterial effect (M. Zasloff, Antimicrobial peptides of multicellular organisms. Nature, 2002, 415, 389-395.). However, AMPs also have the characteristics of high preparation cost, high cytotoxicity and poor stability due to their large molecular weight, which limits the application of AMPs in clinic (R. E. W. Hancock, H. G. Sahl, Antimicrobial and host-defense peptides as new anti-infective therapeutic strategies. Nature Biotechnology, 2006, 24, 1551-1557.). In addition, osthole, one of the natural derivatives of coumarin, has multiple activities such as anti-tumor, inhibition of epileptic seizures and stimulation of osteoblast differentiation (J. Liang, J. Zhou, Y. Xu, et al. Osthole inhibits ovarian carcinoma cells through LC3-mediated autophagy and GSDME-dependent pyroptosis except for apoptosis. European Journal of Pharmacology, 2020, 874, 172990.). In addition, osthole also has certain antibacterial activity, but because of its poor water solubility, the activity is relatively poor, and it needs to be further modified (C. Sun, Y. Gui, R. Hu, et al. Preparation and pharmacokinetics evaluation of solid self-microemulsifying drug delivery system (S-SMEDDS) of osthole. AAPS PharmSciTech, 2018, 19, 2301-2310). At the same time, there are few reports on the antibacterial activity of osthole on zoonotic pathogens. Previously, we measured the antibacterial activity of osthole on some clinical MRSA isolates by micro-broth dilution method, and the minimum inhibitory concentration (MICs) was ≥64 μg / mL, which was not ideal. SUMMARY

[0004] The application discloses a pyridine ring-containing amphiphilic cumin-quaternary ammonium salt hybrid and a preparation method and antibacterial application thereof.

[0005] Technical scheme: In order to achieve the above application purposes, the technical scheme adopted by the application is as follows.

[0006] The pyridine ring-containing amphiphilic cumin-quaternary ammonium salt hybrid has the structure shown in the following formula (I):

[0007]

[0008] Wherein, n = 3, 4 or 5, and R is Wherein, R 1 and R 2 are independently selected from H, a phenyl group or a C1-C6 alkyl group, and ring A is a 4-6 membered heterocyclic alkyl group containing one or two heteroatoms.

[0009] As a preferred scheme, the ring A is a 6-membered heterocyclic alkyl group containing two heteroatoms, wherein the heteroatoms include one O atom in addition to the N atom connected to the mother nucleus.

[0010] As a preferred compound, the n and R are one of the following combinations:

[0011] (1) n = 3, R 1 = H, R 2 = -(CH2)2CH3; (2) n = 4, R 1 = H, R 2 = -(CH2)2CH3;

[0012] (3) n = 5, R 1 = H, R2 = -(CH2)2CH3; (4) n = 3, R 1 = R 2 = -(CH2)2CH3;

[0013] (5) n = 4, R 1 = R 2 = -(CH2)2CH3; (6) n = 5, R 1 = R 2 = -(CH2)2CH3;

[0014] (7) n = 3, R 1 = H, R 2 = -(CH2)3CH3; (8) n = 4, R 1 = H, R 2 = -(CH2)3CH3;

[0015] (9) n = 5, R 1 = H, R 2 = -(CH2)3CH3; (10) n = 3, R 1 = R 2 = -CH(CH3)2;

[0016] (11) n = 4, R 1 = R 2 = -CH(CH3)2; (12) n = 5, R 1 = R 2 = -CH(CH3)2;

[0017] (13) n = 3, R 1 = H, R 2 = -(CH2)4CH3; (14) n = 4, R 1 = H, R 2 = -(CH2)4CH3;

[0018] (15) n = 5, R 1 = H, R 2 = -(CH2)4CH3; (16) n = 3, R 1 = R 2 = (CH2)3CH3;

[0019] (17) n = 4, R 1 = R 2 = (CH2)3CH3; (18) n = 5, R 1 = R 2 = (CH2)3CH3;

[0020] (19) n = 3, R 1 = H, R2= -(CH2)5CH3; (20) n = 4, R 1 = H, R2= -(CH2)5CH3;

[0021] (21) n = 5, R 1= H, R2= -(CH2)5CH3; (22) n = 3, R 1 = R 2 = -CH2CH(CH3)2;

[0022] (23) n = 4, R 1 = R 2 = -CH2CH(CH3)2; (24) n = 5, R 1 = R 2 = -CH2CH(CH3)2;

[0023] (25) n = 3, R is (26) n = 4, R is

[0024] (27) n = 5, R is (28) n = 3, R 1 = -CH3, R 2 = -C6H6;

[0025] (29) n = 4, R 1 = -CH3, R 2 = -C6H6; (30) n = 5, R 1 = -CH3, R 2 = -C6H6.

[0026] The above specific selection represents compounds 1-30 in the following examples (each compound corresponds to the combination selection of the same serial number as described above).

[0027] The application also provides a preparation method of the amphiphilic cymene-quaternary ammonium salt hybrid, comprising the following steps:

[0028] (1) taking cymene as a substrate, converting the methoxyl group thereof into a phenolic hydroxyl group under the action of boron tribromide to obtain an intermediate a;

[0029] (2) reacting the intermediate a with different dibromoalkanes under alkaline conditions to synthesize an intermediate b;

[0030] (3) reacting the intermediate b with 4-mercaptopyridine under alkaline conditions and catalyzed by a catalyst to synthesize an intermediate c;

[0031] (4) reacting the intermediate c with a small-molecule peptide mimic d again to generate the amphiphilic cymene-quaternary ammonium salt hybrid containing a pyridine ring, and the reaction formula is as shown below:

[0032]

[0033] wherein R and n are as defined above.

[0034] Preferably, in step (1), the molar ratio of the reaction of cnidilin and boron tribromide is 1:1-1:5, the reaction temperature is -40-0℃, and the reaction solvent is anhydrous dichloromethane.

[0035] Preferably, in step (2), the base in the basic condition is K2CO3, the molar ratio of intermediate a and the base is 1:1-1:3, the molar ratio of intermediate a and dibromoalkane is 1:1.5-1:3, the reaction temperature is 45-60℃, and the reaction solvent is anhydrous acetone.

[0036] Preferably, in step (3), the base in the basic condition is K2CO3, the catalyst is KI, the molar ratio of intermediate b and the base is 1:1.3-1.7, the molar ratio of intermediate b and the catalyst is 1:0.01-0.03, the molar ratio of intermediate b and 4-mercaptopyridine is 1:1.3-1.7, the reaction temperature is 45-60℃, and the reaction solvent is anhydrous acetone.

[0037] Preferably, in step (4), the preparation method of intermediate d comprises the following steps: substitution reaction of amine RH and bromoacetyl bromide under basic conditions to generate small molecule peptidomimetic d.

[0038]

[0039] wherein R is as defined above.

[0040] Further preferably, the preparation method of intermediate d is as follows:

[0041]

[0042] wherein R 1 and R 2 are as defined above.

[0043] Further preferably, the molar ratio of the amine RH with different carbon chain lengths and bromoacetyl bromide is 1:1.5-1:2.5, the selected base for the reaction is K2CO3, the reaction temperature is 0℃ to room temperature, the reaction time is 2-8h, and the reaction solvent is anhydrous dichloromethane.

[0044] Preferably, in step (4), the molar ratio of intermediate c and intermediate d is 1:2-1:3, the reaction temperature is 70-80℃, and the reaction solvent is anhydrous acetonitrile.

[0045] The application finally provides the use of the pyridine ring-containing amphiphilic cumin-quaternary ammonium salt hybrid in the preparation of antibacterial drugs. Preferably, in the preparation of drugs for inhibiting Staphylococcus aureus (Staphylococcus aureus ATCC 29213) and various clinical methicillin-resistant Staphylococcus aureus (Methicillin-resistant Staphylococcus aureus, MRSA).

[0046] In order to solve the defects of the prior art, the application designs and synthesizes a series of pyridine ring-containing amphiphilic cumin-quaternary ammonium salt hybrids by simulating the chemical structure and biological function of antibacterial peptides. The application introduces AMP mimics into the cumin mother nucleus to construct a cumin-AMP mimic hybrid. The design strategy takes the benzene ring and isopentenyl group of cumin as a hydrophobic group, introduces an alkane chain and 4-mercapto pyridine as a connecting module, introduces AMP mimics, and constructs a cumin-AMP mimic hybrid with similar charge distribution, hydrophobicity and amphiphilicity to AMP, aiming to obtain a pyridine ring-containing amphiphilic cumin-AMP mimic hybrid with high antibacterial activity and low toxicity. The benzene ring and isopentenyl group in the cumin derivative serve as a hydrophobic part that facilitates the insertion of the compound into the phospholipid bilayer of bacteria, and the hydrophilic cationic part facilitates the interaction with the negatively charged bacterial cell membrane, thereby killing the bacteria. The application evaluates the antibacterial activity of all target compounds and finds that all target compounds exhibit good in vitro antibacterial activity against Staphylococcus aureus ATCC 29213 and clinical methicillin-resistant Staphylococcus aureus (MRSA) with a minimum inhibitory concentration (MIC≤128 μg / mL). In particular, the in vitro and in vivo anti-MRSA activities of preferred compounds 15 and 23 are comparable to those of the positive control drug vancomycin. In addition, the target compounds have low hemolytic activity, in vivo toxicity, good water solubility and stability. Therefore, such compounds have broad clinical application prospects.

[0047] Technical effects: The pyridine ring-containing amphiphilic cumin-quaternary ammonium salt hybrid prepared by the application has good in vivo and in vitro bacteriostatic effect on Staphylococcus aureus ATCC 29213 and various methicillin-resistant Staphylococcus aureus (MRSA) and other gram-positive bacteria, improves water solubility, reduces biological toxicity, and has a high yield, and is expected to be further developed into a potential antibacterial drug in clinical use. BRIEF DESCRIPTION OF DRAWINGS

[0048] Figure 1 The dynamic bactericidal curve of compounds 15 and 23.

[0049] Figure 2 The in vivo blood routine and blood biochemical index of compounds 15 and 23 in a subcutaneous abscess model.

[0050] Figure 3 Changes in bacterial load on mouse skin in response to compounds 15 and 23 - subcutaneous abscess model.

[0051] Figure 4 The blood routine and blood biochemical indexes of compounds 15 and 23 in vivo - sepsis model.

[0052] Figure 5 Changes in bacterial load on mouse skin in the presence of compounds 15 and 23 - sepsis model.

[0053] Figure 6 Changes in mouse survival rate in response to compounds 15 and 23 - sepsis model.

[0054] Figure 7 Compound 15 1 H-NMR spectrum.

[0055] Figure 8 Compound 15 13 C-NMR spectrum.

[0056] Figure 9 Compound 23 1 H-NMR spectrum.

[0057] Figure 10 Compound 23 13 C-NMR spectrum. DETAILED DESCRIPTION

[0058] The present invention is further described in detail below through examples.

[0059] Example 1 Preparation of Intermediate a

[0060] An appropriate amount of substrate osthole (1 mmol) and boron tribromide (BBr3) (1.3 mmol) were weighed and placed in a 25 mL round-bottom flask. 3 mL of anhydrous dichloromethane was added to dissolve the mixture. The mixture was stirred at -40°C and detected by thin layer chromatography (TLC) until the reaction was complete. The reaction solution was filtered, washed thoroughly with dichloromethane, and the filtrate was concentrated under reduced pressure. Intermediate a was separated by column chromatography.

[0061] Example 2 Preparation of Intermediate b1-3

[0062] An appropriate amount of intermediate a (1 mmol) and potassium carbonate (3 mmol) were weighed and placed in a 25 mL round-bottom flask. 3 mL of acetone was added to dissolve them, and then 1,3-dibromoethane / 1,4-dibromopropane / 1,5-dibromobutane (3 mmol) were added. The mixture was heated and stirred at 50°C. The reaction was detected by thin layer chromatography (TLC) until the end. The mixture was extracted with ethyl acetate (3×30 mL). The organic layers were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography to obtain intermediate b1-3.

[0063] The physicochemical properties of intermediate b1 are as follows:

[0064] 1) White solid;

[0065] 2) The NMR spectrum of the compound ( 1 H NMR, 400 MHz) characteristics:

[0066] Using CDCl3 as solvent, the peaks are attributed to: Yield: 68%, 1 H NMR (400MHz CDCl3) δ: 7.81 (d, J = 8.4Hz, 1H, -Ph), 7.68 (d, J = 8.4Hz, 1H, -Ph), 7.01 (d, J = 8.4Hz, 1H, -Ph), 6.45 (d, J = 8.4Hz, 1H, -Ph), 5.75 (m, 1H, -C H =CH2), 4.08 (t, J = 7.2Hz, 2H, -OCH2-), 3.50 (t, J = 7.2Hz, 2H, -CH2Br), 3.30 (t, J = 6. 0Hz,2H,-CH2-),2.13(m,2H,-CH2-),1.83(s,3H,-CH3),1.67(s,3H,CH3); MS(ESI)C 17 H 20 BrO3[M+H] + calcd=351.05; found=351.11.

[0067] The physicochemical properties of intermediate b2 are as follows:

[0068] 1) White solid;

[0069] 2) The NMR spectrum of the compound ( 1 H NMR, 400 MHz) characteristics:

[0070] Using CDCl3 as solvent, the peaks are attributed to: Yield: 78%, 1H NMR (400MHz CDCl3) δ: 7.80 (d, J = 8.4Hz, 1H, -Ph), 7.69 (d, J = 8.4Hz, 1H, -Ph), 7.02 (d, J = 8.4Hz, 1H, -Ph), 6.47 (d, J = 8.4Hz, 1H, -Ph), 5.72 (m, 1H, -C H =CH2),4.07(t,J=7.2Hz,2H,-OCH2-),3.52(t,J=7.2Hz,2H,-CH2Br),3.33(t,J=6.0Hz,2H,-C H2-),2.01(m,2H,-CH2-),1.85(m,2H,-CH2-),1.83(s,3H,-CH3),1.67(s,3H,CH3); MS(ESI)C 18 H 22 BrO3[M+H] + calcd=365.07; found=365.09.

[0071] The physicochemical properties of intermediate b3 are as follows:

[0072] 1) White solid;

[0073] 2) The NMR spectrum of the compound ( 1 H NMR, 400 MHz) characteristics:

[0074] CDCl3 was used as solvent, and the peaks were assigned as follows: Yield: 80%, 1 H NMR (400MHz CDCl3) δ: 7.82 (d, J = 8.4Hz, 1H, -Ph), 7.66 (d, J = 8.4Hz, 1H, -Ph), 7.00 (d, J = 8.4Hz, 1H, -Ph), 6.44 (d, J = 8.4Hz, 1H, -Ph), 5.73 (m, 1H, -C H =CH2),4.06(t,J=7.2Hz,2H,-OCH2-),3.51(t,J=7.2Hz,2H,-CH2Br),3.32(t,J=6.0Hz,2H,-CH2-),2.1 0(m,2H,-CH2-),1.92(m,2H,-CH2-),1.83(s,3H,-CH3),1.67(s,3H,CH3),1.29(m,2H,-CH2-);MS(ESI)C 19 H 24 BrO3[M+H] + calcd=379.08; found=379.13.

[0075] Preparation of intermediate c1-3 in example 3

[0076] An appropriate amount of intermediate b (1 mmol), potassium carbonate (1.5 mmol) and potassium iodide (0.02 mmol) were weighed into a 25 mL round-bottom flask, 3 mL of acetone was added to dissolve them, then 4-mercaptopyridine (1.5 mmol) was added, and the mixture was heated and stirred at 50°C. The reaction was detected by thin layer chromatography (TLC) until it was completed. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Column chromatography was used to separate intermediate c1-3.

[0077] The physical and chemical properties of intermediate c1 are as follows:

[0078] 1) white solid;

[0079] 2) the nuclear magnetic resonance spectrum of the compound (H NMR, 400 MHz) is characterized by: 1 H NMR, 400 MHz) is characterized by:

[0080] Yield: 68%, in CDCl3 solvent, where each peak is assigned: 1 H NMR (400 MHz, DMSO) δ: 8.34 (d, J = 6.0 Hz, 2H, -Ph), 7.97 (d, J = 9.6 Hz, 1H, -CH=CH-), 7.54 (d, J = 8.8 Hz, 1H, -Ph), 7.28 (d, J = 6.4 Hz, 1H, -Ph), 7.04 (d, J = 8.8 Hz, 1H, -Ph), 6.27 (d, J = 9.2 Hz, 1H, -CH=CH-), 5.13 (t, J = 7.2 Hz, 1H, -CH=C(CH3)2), 4.21 (t, J = 6.0 Hz, 2H, -CH2-), 3.44 (d, J = 7.2 Hz, 2H, -CH2-), 3.23 (t, J = 7.2 Hz, 2H, -CH2-), 2.10-2.16 (m, 2H, -CH2-), 1.76 (s, 3H, -CH3), 1.58 (s, 3H, -CH3).

[0081] The physical and chemical properties of intermediate c2 are as follows:

[0082] 1) white solid;

[0083] 2) the nuclear magnetic resonance spectrum of the compound (H NMR, 400 MHz) is characterized by: 1 H NMR, 400 MHz) is characterized by:

[0084] Yield: 68%, in DMSO solvent, where each peak is assigned: 1H NMR(400MHz DMSO)δ:8.33(d,J=6.0Hz,2H,-Ph),7.95(d,J=9.6Hz,1H,-CH=CH-),7.53(d,J=8.4Hz,1H,-Ph),7.2 6(d,J=6.4Hz,2H,-Ph),7.03(d,J=8.8Hz,1H,-Ph),6.26(d,J=9.2Hz,1H,-CH=CH-),5.09(t,J=7.2Hz ,1H,-CH=C(CH3)2),4.14(t,J=6.0Hz,2H,-CH2-),3.37(d,J=7.2Hz,2H,-CH2-),3.13(t,J=7.2Hz,2H ,-CH2-),1.89-1.94(m,2H,-CH2-),1.81-1.86(m,2H,-CH2-),1.74(s,3H,-CH3),1.59(s,3H,-CH3).

[0085] The physicochemical properties of intermediate c3 are as follows:

[0086] 1) White solid;

[0087] 2) The NMR spectrum of the compound ( 1 H NMR, 400 MHz) characteristics:

[0088] Using CDCl3 as solvent, the peaks are attributed to: Yield: 68%, 1 H NMR(400MHz CDC13)δ:8.37(d,J=6.0Hz,2H,-Ph),7.59(d,J=9.6Hz,1H,-Ph),7.25(d,J=8.8Hz,1H,-CH=CH-),7.10(d,J =6.0Hz,2H,-Ph),6.78(d,J=8.4Hz,1H,-Ph),6.22(d,J=9.6Hz,1H,-CH=CH-),5.21(t,J=7.2Hz,1H,-CH=C(C H3)2),4.05(t,J=6.0Hz,2H,-CH2-),3.53(d,J=7.2Hz,2H,-CH2-),3.00(t,J=7.2Hz,2H,-CH2-),1.87-1.9 3(m,2H,-CH2-),1.84(s,3H,-CH3),1.78-1.82(m,2H,-CH2-),1.69-1.73(m,2H,-CH2-),1.66(s,3H,-CH3).

[0089] Example 4 Preparation of Intermediate d

[0090] The corresponding amine (1 mmol) was weighed into a 50 mL round-bottom flask, 2 mL of anhydrous dichloromethane was added to dissolve it, and then potassium carbonate (1.5 mmol) was added. At 0°C, bromoacetyl bromide (1.5 mmol) was slowly added to the reaction solution, and the reaction was continued for half an hour. Then the reaction was transferred to room temperature, and thin layer chromatography (TLC) was used to detect the end of the reaction. Ethyl acetate was used for extraction, anhydrous sodium sulfate was used for drying, and column chromatography was used for separation to obtain the corresponding intermediate d.

[0091] Example 5 Compound 1

[0092] Intermediate c1-3 (1 mmol) and intermediate d (3 mmol) were weighed into a 25 mL round-bottom flask, 2 mL of anhydrous acetonitrile was added to dissolve it, and then the reaction was stirred at 78°C. Thin layer chromatography (TLC) was used to detect the end of the reaction, and preparative thin layer chromatography (dichloromethane:methanol = 20:1) was used for separation to obtain the pure target compound.

[0093] The physicochemical properties of compound 1 are as follows:

[0094] 1), white solid;

[0095] 2), the nuclear magnetic resonance spectrum of the compound 1 H / 13 C NMR, 400 MHz) characteristics:

[0096] In DMSO as solvent, each peak is assigned as follows: 1 H NMR (400 MHz DMSO) δ: 8.63 (d, J = 7.2 Hz, 2H, -Ph), 8.58 (t, J = 5.6 Hz, 1H, -NH-), 7.98-8.02 (m, 3H, -Ph, -CH=CH-), 7.56 (d, J = 8.4 Hz, 1H, -Ph), 7.06 (d, J = 8.4 Hz, 1H, -Ph), 6.28 (d, J = 9.2 Hz, 1H, -CH=CH-), 5.26 (s, 2H, -CH2-), 5.14 (t, J = 7.2 Hz, 1H, -CH=C(CH3)2), 4.25 (t, J = 5.6 Hz, 2H, -CH2-), 3.49-3.45 (m, 4H, -CH2-), 3.06-3.11 (m, 2H, -CH2-), 3.19-3.25 (m, 2H, -CH2-), 1.77 (s, 3H, -CH3), 1.60 (s, 3H, -CH3), 1.42-1.51 (m, 2H, -CH2-), 0.86 (t, J = 7.2 Hz, 3H, -CH3); 13C NMR(100MHz DMSO)δ:164.36,162.44,160.22,158.70,152.18,144.67,143.86,131.69,127.20,122.11,121.38,121.30, 116.29,112.79,112.39,108.64,66.76,59.98,40.85,27.32,25.48,22.19,21.54,17.75,11.37; HRMS(ESI)C 27 H 33 N2O4S[M-Br] + calcd=481.2156; found=481.2162.

[0097] Example 5 Compound 2

[0098] Compound 2 was synthesized using the method described in Example 4. The physicochemical properties of compound 2 are as follows:

[0099] 1) White solid;

[0100] 2) The NMR spectrum of the compound ( 1 H / 13 C NMR, 400 MHz) characteristics:

[0101] With DMSO as solvent, the peaks are attributed to: 1 H NMR(400MHz DMSO)δ:8.62(d,J=6.8Hz,2H,-Ph),8.59(t,J=5.6Hz,1H,-NH-),7.97(m,3H,-Ph,-CH=CH-),7.54(d,J=8.8Hz ,1H,-Ph),7.05(d,J=8.8Hz,1H,-Ph),6.26(d,J=9.2Hz,1H,-CH=CH-),5.26(s,2H,-CH2-),5.11(t,J=7.2Hz,1 H,-CH=C(CH3)2),4.16(t,J=5.6Hz,2H,-CH2-),3.37-3.41(m,4H,-CH2-),3.07-3.12(m,2H,-CH2-),1.89-1.9 7(m,4H,-CH2-),1.75(s,3H,-CH3),1.60(s,3H,-CH3),1.42-1.51(m,2H,-CH2-),0.86(t,J=7.2Hz,3H,-CH3); 13C NMR(100MHz DMSO)δ:164.37,162.76,160.25,158.93,152.18,144.69,143.76,131.63,127.14,122.14,121.28,121.20,116.15 ,112.61,112.23,108.70,67.70,59.92,40.82,30.10,27.69,25.44,24.24,22.13,21.50,17.70,11.33; HRMS(ESI)C 28 H 35 N2O4S[M-Br] + calcd=495.2312; found=495.2317.

[0102] Example 6 Compound 3

[0103] Compound 3 was synthesized using the method described in Example 4. The physicochemical properties of compound 3 are as follows:

[0104] 1) Light yellow solid;

[0105] 2) The NMR spectrum of the compound ( 1 H / 13 C NMR, 400 MHz) characteristics:

[0106] CD3OD was used as solvent, and the peaks were assigned to 1 H NMR(400MHz CD3OD)δ:8.47(d,J=7.2Hz,2H,-Ph),7.84-7.87(m,3H,-Ph,-CH=CH-),7.42(d,J=8.8Hz,1H,-Ph),6.98(d,J=8.4Hz,1H, -Ph),6.21(d,J=9.2Hz,1H,-CH=CH-),5.24(s,2H,-CH2-),5.17(t,J=7.2Hz,1H,-CH=C(CH3)2),4.13(t,J=6.0Hz,2H,-CH 2-),3.50(d,J=7.2Hz,2H,-CH2-),3.33(d,J=7.2Hz,2H,-CH2-),3.19(t,J=7.2Hz,2H,-CH2-),1.87-1.96(m,4H,-CH2-) ,1.82(s,3H,-CH3),1.72-1.79(m,2H,-CH2-),1.65(s,3H,-CH3),1.54-1.60(m,2H,-CH2-),0.93(t,J=7.6Hz,3H,-CH3); 13C NMR (100 MHz CD3OD) δ: 166.60, 166.21, 163.48, 161.16, 153.97, 146.30, 146.24, 144.69, 133.18, 128.21, 123.54, 122.76, 122.59, 118.60, 114.38, 113.11, 109.94, 69.60, 61.43, 42.76, 32.36, 29.84, 28.66, 26.45, 26.03, 23.54, 22.87, 18.23, 11.69; HRMS (ESI) C 29 H 37 N2O4S [M-Br] + calcd = 509.2469; found = 509.2476.

[0107] Example 7 Compound 4

[0108] Compound 4 was synthesized using the method described in Example 4. The physicochemical properties of compound 4 are as follows:

[0109] 1) light yellow solid;

[0110] 2) the nuclear magnetic resonance spectrum of the compound (1H, 400 MHz) is characterized by: 1 H, 400 MHz) is characterized by:

[0111] in CD3OD as solvent, wherein each peak is assigned as: 1H NMR (400 MHz, CD3OD) δ: 8.45 (d, J = 7.2 Hz, 2H, -Ph), 7.89 (d, J = 7.2 Hz, 2H, -Ph), 7.86 (d, J = 9.6 Hz, 1H, -CH=CH-), 7.45 (d, J = 8.8 Hz, 1H, -Ph), 7.02 (d, J = 8.4 Hz, 1H, -Ph), 6.23 (d, J = 9.6 Hz, 1H, -CH=CH-), 5.56 (s, 2H, -CH2-), 5.17-5.21 (m, 1H, -CH=C(CH3)2), 4.28 (t, J = 6.0 Hz, 2H, -CH2-), 3.55 (d, J = 7.2 Hz, 2H, -CH2-), 3.50 (t, J = 7.2 Hz, 2H, -CH2-), 3.32-3.36 (m, 4H, -CH2-), 2.32-2.38 (m, 2H, -CH2-), 1.83 (s, 3H, -CH3), 1.73-1.79 (m, 2H, -CH2-), 1.64 (s, 3H, -CH3), 1.57-1.61 (m, 2H, -CH2-), 1.00 (t, J = 7.6 Hz, 3H, -CH3), 0.88 (t, J = 7.6 Hz, 3H, -CH3). HRMS (ESI) C 30 H 39 N2O4S[M-Br] + calcd = 523.2625; found = 523.2635.

[0112] Example 8 Compound 5

[0113] Compound 5 was synthesized using the method described in Example 4. The physicochemical properties of compound 5 are as follows:

[0114] 1) white solid;

[0115] 2) the nuclear magnetic resonance spectrum (H / 1 H / 13 C NMR, 400 MHz) characteristics of the compound are as follows:

[0116] in DMSO, in which each peak is assigned as follows: 1H NMR (400 MHz DMSO) δ: 8.61 (d, J = 7.2 Hz, 2H, -Ph), 8.00 (d, J = 7.2 Hz, 2H, -Ph), 7.97 (d, J = 9.6 Hz, 1H, -CH=CH-), 7.54 (d, J = 8.8 Hz, 1H, -Ph), 7.05 (d, J = 8.8 Hz, 1H, -Ph), 6.26 (d, J = 9.6 Hz, 1H, -CH=CH-), 5.61 (s, 2H, -CH2-), 5.11 (t, J = 7.2 Hz, 1H, -CH=C(CH3)2), 4.17 (t, J = 5.6 Hz, 2H, -CH2-), 3.38-3.42 (m, 4H, -CH2-), 3.23-3.28 (m, 4H, -CH2-), 1.90-1.96 (m, 4H, -CH2-), 1.75 (s, 3H, -CH3), 1.65-1.72 (m, 2H, -CH2-), 1.61 (s, 3H, -CH3), 1.45-1.55 (m, 2H, -CH2-), 0.91 (t, J = 7.2 Hz, 3H, -CH3), 0.80 (t, J = 7.2 Hz, 3H, -CH3); 13 C NMR (100 MHz DMSO) δ: 164.21, 162.85, 160.25, 158.94, 152.18, 144.70, 144.01, 143.95, 131.63, 127.11, 122.12, 121.29, 121.20, 116.16, 112.61, 112.23, 108.72, 67.72, 59.46, 48.28, 47.54, 30.14, 27.71, 25.43, 24.25, 21.51, 21.29, 20.34, 17.75, 11.11, 11.03; HRMS (ESI) C 31 H 41 N2O4S[M-Br] + calcd = 537.2782; found = 537.2790.

[0117] Example 9 Compound 6

[0118] Compound 6 was synthesized using the method described in Example 4. The physicochemical properties of compound 6 are as follows:

[0119] 1) white solid;

[0120] 2) the nuclear magnetic resonance spectrum (H / 1 H / 13 C NMR, 400 MHz) characteristics of the compound are as follows:

[0121] With CD3OD as solvent, the peaks are attributed to: 1 H NMR(400MHz CD3OD)δ:8.44(d,J=6.8Hz,2H,-Ph),7.84-7.87(m,3H,-Ph,-CH=CH-),7.43(d,J=8.8Hz,1H,-Ph),6.99(d,J=8.8Hz,1H ,-Ph),6.21(d,J=9.6Hz,1H,-CH=CH-),5.56(s,2H,-CH2-),5.17(t,J=7.2Hz,1H,-CH=C(CH3)2),4.13(t,J=6.0Hz,2H,- CH2-),3.50(d,J=6.8Hz,2H,-CH2-),3.33-3.36(m,6H,-CH2-),1.87-1.95(m,4H,-CH2-),1.82(s,3H,-CH3),1.75-1.7 7(m,4H,-CH2-),1.65(s,3H,-CH3),1.57-1.63(m,2H,-CH2-),1.00(t,J=7.2Hz,3H,-CH3), 0.88(t,J=7.2Hz,3H,-CH3); 13 C NMR(100MHz CD3OD)δ:166.55,165.88,163.47,161.16,153.87,146.28,145.10,144.99,133.20,128.15,123.41,122.72,122.57,118.61,114.36, 113.11,109.92,69.68,61.07,50.24,50.19,32.36,29.89,28.66,26.46,26.03,22.84,22.78,21.73,18.24,11.66,11.55; HRMS(ESI)C 32 H 43 N2O4S[M-Br] + calcd=551.2938; found=551.2943.

[0122] Example 10 Compound 7

[0123] Compound 7 was synthesized using the method described in Example 4. The physicochemical properties of compound 7 are as follows:

[0124] 1) White solid;

[0125] 2) The NMR spectrum of the compound ( 1 H / 13 C NMR, 400 MHz) characteristics:

[0126] In DMSO, where each peak is assigned as: 1 H NMR (400 MHz DMSO) δ: 8.63 (d, J = 6.8 Hz, 2H, -Ph), 8.56 (t, J = 5.6 Hz, 1H, -NH), 8.00 (d, J = 6.8 Hz, 2H, -Ph), 7.98 (s, 1H, -CH=CH-), 7.56 (d, J = 8.8 Hz, 1H, -Ph), 7.06 (d, J = 8.8 Hz, 1H, -CH=CH-), 6.28 (d, J = 9.6 Hz, 1H, -CH=CH-), 5.25 (s, 2H, -CH2-), 5.14 (t, J = 6.8 Hz, 1H, -CH=C(CH3)2), 4.25 (t, J = 5.6 Hz, 2H, -CH2-), 3.45-3.49 (m, 4H, -CH2-), 3.10-3.15 (m, 2H, -CH2-), 2.20-2.23 (t, J = 7.2 Hz, 2H, -CH2-), 1.77 (s, 3H, -CH3), 1.60 (s, 3H, -CH3), 1.41-1.45 (m, 2H, -CH2-), 1.30-1.34 (m, 2H, -CH2-), 0.86-0.90 (t, J = 7.2 Hz, 3H, -CH3); 13 C NMR (100 MHz DMSO) δ: 164.32, 162.44, 160.22, 158.69, 152.18, 144.67, 143.86, 131.69, 127.18, 122.12, 121.40, 121.29, 116.28, 112.80, 112.40, 108.71, 66.60, 59.98, 38.69, 30.94, 27.33, 25.44, 21.58, 19.48, 17.77, 13.60; HRMS (ESI) C 28 H 35 N2O4S[M-Br] + calcd = 495.2312; found = 495.2316.

[0127] Example 11 Compound 8

[0128] Compound 8 was synthesized using the method described in Example 4, and the physicochemical properties of compound 8 are as follows:

[0129] 1) white solid;

[0130] 2) the nuclear magnetic resonance spectrum of the compound (H / 1 H / 13 C NMR, 400 MHz) characteristics:

[0131] In CD3OD as solvent, where each peak is assigned as: 1 H NMR (400 MHz CD3OD) δ: 8.47 (d, J = 7.2 Hz, 2H, -Ph), 7.87 (d, J = 7.6 Hz, 2H, -Ph), 7.84 (d, J = 9.6 Hz, 1H, -CH=CH-), 7.43 (d, J = 8.8 Hz, 1H, -Ph), 7.00 (d, J = 8.8 Hz, 1H, -Ph), 6.21 (d, J = 9.6 Hz, 1H, -CH=CH-), 5.24 (s, 2H, -CH2-), 5.14 (t, J = 7.2 Hz, 1H, -CH=C(CH3)2), 4.18 (t, J = 5.6 Hz, 2H, -CH2-), 3.48 (d, J = 6.8 Hz, 2H, -CH2-), 3.37 (t, J = 6.8 Hz, 2H, -CH2-), 3.23-3.27 (m, 2H, -CH2-), 2.03-2.09 (m, 4H, -CH2-), 1.81 (s, 3H, -CH3), 1.63 (s, 3H, -CH3), 1.51-1.57 (m, 2H, -CH2-), 1.36-1.41 (m, 2H, -CH2-), 0.92 (t, J = 7.6 Hz, 3H, -CH3); 13 C NMR (100 MHz CD3OD) δ: 166.44, 166.12, 163.42, 161.00, 153.96, 146.25, 146.21, 144.75, 133.28, 128.21, 123.57, 122.69, 122.59, 118.60, 114.44, 113.19, 109.93, 69.18, 61.41, 40.72, 32.37, 32.07, 29.39, 25.98, 22.84, 21.07, 18.27, 18.23, 14.01; HRMS (ESI) C 29 H 37 N2O4S [M-Br] + calcd = 509.2469; found = 509.2479.

[0132] Example 12 Compound 9

[0133] Compound 9 was synthesized using the method described in Example 4, and the physicochemical properties of compound 9 are as follows:

[0134] 1), white solid;

[0135] 2), the nuclear magnetic resonance spectrum of the compound (400 MHz) is characterized as: 1 H NMR, 400 MHz) is characterized as:

[0136] In CD3OD as solvent, where each peak is assigned as: 1 H NMR (400 MHz CD3OD) δ: 8.47 (d, J = 6.8 Hz, 2H, -Ph), 7.85 (d, J = 7.2 Hz, 3H, -Ph, -CH=CH-), 7.43 (d, J = 8.8 Hz, 1H, -Ph), 6.99 (d, J = 8.4 Hz, 1H, -Ph), 6.21 (d, J = 9.6 Hz, 1H, -CH=CH-), 5.19-5.25 (m, 3H, -CH2-, -CH=C(CH3)2), 4.14-4.16 (m, 2H, -CH2-), 3.50 (s, 2H, -CH2-), 3.33 (d, J = 6.8 Hz, 2H, -CH2-), 3.23-3.27 (m, 2H, -CH2-), 1.89-1.94 (m, 4H, -CH2-), 1.82 (s, 3H, -CH3), 1.75-1.77 (m, 2H, -CH2-), 1.65 (s, 3H, -CH3), 1.49-1.55 (m, 2H, -CH2-), 1.35-1.41 (m, 2H, -CH2-), 0.92 (t, J = 7.6 Hz, 3H, -CH3); HRMS (ESI) C 30 H 39 N2O4S [M-Br] + calcd = 523.2625; found = 523.2628.

[0137] Example 13 Compound 10

[0138] Compound 10 was synthesized using the method described in Example 4, and the physicochemical properties of compound 10 are as follows:

[0139] 1) light brown solid;

[0140] 2) the nuclear magnetic resonance spectrum of this compound 1 H / 13 C NMR, 400 MHz) characteristics:

[0141] In DMSO as solvent, where each peak is assigned as: 1H NMR (400 MHz DMSO) δ: 8.62 (d, J = 7.2 Hz, 2H, -Ph), 8.03 (d, J = 7.2 Hz, 2H, -Ph), 7.98 (d, J = 9.6 Hz, 1H, -CH=CH-), 7.56 (d, J = 8.8 Hz, 1H, -Ph), 7.07 (d, J = 8.4 Hz, 1H, -Ph), 6.28 (d, J = 9.2 Hz, 1H, -CH=CH-), 5.58 (s, 2H, -CH2-), 5.14 (t, J = 7.2 Hz, 1H, -CH=C(CH3)2), 4.26 (t, J = 6.0 Hz, 2H, -CH2-), 3.83-3.89 (m, 1H, -CH-), 3.54-3.59 (m, 1H, -CH-), 3.45-3.50 (m, 4H, -CH2-), 2.20-2.25 (m, 2H, -CH2-), 1.77 (s, 3H, -CH3), 1.60 (s, 3H, -CH3), 1.27 (d, J = 6.8 Hz, 6H, -CH3), 1.25 (d, J = 6.4 Hz, 6H, -CH3). 13 CNMR (100 MHz DMSO) δ: 162.82, 162.35, 160.22, 158.70, 152.18, 144.65, 144.04, 131.70, 127.20, 122.09, 121.37, 116.29, 112.79, 112.40, 108.76, 66.74, 60.48, 47.97, 45.42, 27.35, 27.32, 25.43, 21.57, 20.21, 20.17, 20.13, 20.09, 17.75; HRMS (ESI) C 30 H 39 N2O4S[M-Br] + calcd = 523.2625; found = 523.2632.

[0142] Example 14 Compound 11

[0143] Compound 11 was synthesized using the method described in Example 4. The physicochemical properties of compound 11 are as follows:

[0144] 1) Light brown solid;

[0145] 2) The nuclear magnetic resonance spectrum (H / 1 H / 13 C NMR, 400 MHz) characteristics of the compound:

[0146] In DMSO as solvent, each peak is assigned: 1H NMR(400MHz DMSO)δ:8.59(d,J=6.8Hz,2H,-Ph),8.00(d,J=6.8Hz,2H,-Ph),7.97(d,J=9.6Hz,1H,-CH=CH-),7.54(d,J=8.8Hz,1H,-P h),7.05(d,J=8.4Hz,1H,-Ph),6.26(d,J=9.2Hz,1H,-CH=CH-),5.55(s,2H,-CH2-),5.12(t,J=7.2Hz,1H,-CH=C(CH3)2), 4.17(t,J=5.6Hz,2H,-CH2-),3.82-3.87(m,1H,-CH-),3.53-3.60(m,1H,-CH-),3.38-3.42(m,4H,-CH2-),1.91-1.96(m ,4H,-CH2-),1.75(s,3H,-CH3),1.61(s,3H,-CH3),1.27(d,J=6.8Hz,6H,-CH3),1.25(d,J=6.4Hz,6H,-CH3); HRMS(ESI)C 31 H 41 N2O4S[M-Br] + calcd=537.2782; found=537.2786.

[0147] Example 15 Compound 12

[0148] Compound 12 was synthesized using the method described in Example 4. The physicochemical properties of compound 12 are as follows:

[0149] 1) Light brown solid;

[0150] 2) The NMR spectrum of the compound ( 1 H / 13 C NMR, 400 MHz) characteristics:

[0151] With CD3OD as solvent, the peaks are attributed to: 1H NMR(400MHz CD3OD)δ:8.44(d,J=6.8Hz,2H,-Ph),7.85(d,J=7.2Hz,3H,-Ph,-CH=CH-),7.43(d,J=8.4Hz,1H,-Ph),6.99(d,J=8.8Hz,1H,-Ph ),6.21(d,J=9.6Hz,1H,-CH=CH-),5.53(s,2H,-CH2-),5.18(t,J=7.2Hz,1H,-CH=C(CH3)2),4.13(t,J=4.4Hz,2H,-CH2-),3.95 -3.98(m,1H,-CH-),3.60-3.67(m,1H,-CH-),3.51(d,J=6.0Hz,2H,-CH2-),3.33(d,J=7.2Hz,2H,-CH2-),1.88-1.97(m,4H,-CH 2-),1.82(s,3H,-CH3),1.74-1.78(m,2H,-CH2-),1.65(s,3H,-CH3),1.36(d,J=6.4Hz,6H,-CH3),1.33(t,J=6.8Hz,6H,-CH3); 13 C NMR(100MHz CD3OD)δ:164.86,162.96,161.98,159.67,152.47,144.78,143.63,143.46,131.68,126.70,126.59,121.88,121.23,11 7.09,112.85,111.57,108.44,68.14,60.58,30.83,28.35,27.14,24.93,24.54,24.49,21.35,19.20,19.14; HRMS(ESI)C 32 H 43 N2O4S[M-Br] + calcd=551.2938; found=551.2947.

[0152] Example 16 Compound 13

[0153] Compound 13 was synthesized using the method described in Example 4. The physicochemical properties of compound 13 are as follows:

[0154] 1) White solid;

[0155] 2) The NMR spectrum of the compound ( 1 H NMR, 400 MHz) characteristics:

[0156] DMSO was used as solvent, and the peaks were attributed to: 1H NMR (400 MHz DMSO) δ: 8.63 (d, J = 7.2 Hz, 2H, -Ph), 8.57 (t, J = 5.6 Hz, 1H, -NH-), 7.98 (m, 3H, -Ph, -CH=CH-), 7.56 (d, J = 8.8 Hz, 1H, -Ph), 7.06 (d, J = 8.8 Hz, 1H, -Ph), 6.28 (d, J = 9.6 Hz, 1H, -CH=CH-), 5.25 (s, 2H, -CH2-), 5.14 (t, J = 7.2 Hz, 1H, -CH=C(CH3)2), 4.25 (t, J = 5.6 Hz, 2H, -CH2-), 3.45-3.49 (m, 4H, -CH2-), 3.09-3.14 (m, 2H, -CH2-), 2.19-2.25 (m, 2H, -CH2-), 1.77 (s, 3H, -CH3), 1.60 (s, 3H, -CH3), 1.43-1.46 (m, 2H, -CH2-), 1.27-1.29 (m, 4H, -CH2-), 0.85 (t, J = 6.8 Hz, 3H, -CH3); 13 C NMR (100 MHz DMSO) δ: 164.30, 162.44, 160.22, 158.70, 152.18, 144.67, 143.85, 131.68, 127.20, 122.1, 121.3, 116.3, 112.8, 112.3, 108.6, 66.6, 59.9, 28.5, 27.3, 25.4, 21.7, 21.5, 17.7, 13.8; HRMS (ESI) C 29 H 37 N2O4S[M-Br] + calcd = 509.2469; found = 509.2476.

[0157] Example 17 Compound 14

[0158] Compound 14 was synthesized using the method described in Example 4, and the physicochemical properties of compound 14 are as follows:

[0159] 1) white solid;

[0160] 2) the nuclear magnetic resonance spectrum (H / 1 H / 13 C NMR, 400 MHz) characteristics of the compound are as follows:

[0161] In CD3OD solvent, the peaks are assigned as follows: 1H NMR (400 MHz, CD3OD) δ: 8.61 (d, J = 7.2 Hz, 2H, -Ph), 8.54 (t, J = 5.6 Hz, 1H, -NH-), 7.99 (d, J = 5.2 Hz, 2H, -Ph), 7.96 (d, J = 8.0 Hz, 1H, -CH=CH-), 7.54 (d, J = 8.4 Hz, 1H, -Ph), 7.05 (d, J = 8.8 Hz, 1H, -Ph), 6.26 (d, J = 9.2 Hz, 1H, -CH=CH-), 5.24 (s, 2H, -CH2-), 5.11 (t, J = 7.2 Hz, 1H, -CH=C(CH3)2), 4.16 (t, J = 5.6 Hz, 2H, -CH2-), 3.37-3.41 (m, 4H, -CH2-), 3.09-3.14 (m, 2H, -CH2-), 1.89-1.97 (m, 4H, -CH2-), 1.75 (s, 3H, -CH3), 1.60 (s, 3H, -CH3), 1.41-1.48 (m, 2H, -CH2-), 1.26-1.29 (m, 4H, -CH2-), 0.85 (t, J = 7.2 Hz, 3H, -CH3); 13 C NMR (100 MHz, CD3OD) δ: 164.3, 162.7, 160.2, 158.9, 152.1, 144.6, 143.7, 131.6, 127.1, 122.1, 121.2, 116.1, 112.6, 112.2, 108.7, 67.7, 59.9, 48.1, 47.4, 30.1, 28.5, 27.7, 25.4, 24.2, 21.8, 21.5, 17.7, 13.8; HRMS (ESI) C 30 H 39 N2O4S[M-Br] + calcd = 523.2625; found = 523.2629.

[0162] Example 18 Compound 15

[0163] Compound 15 was synthesized using the method described in Example 4, and the physicochemical properties of compound 15 are as follows:

[0164] 1) white solid;

[0165] 2) the nuclear magnetic resonance spectrum of the compound 1 H / 13 C NMR, 400 MHz) characteristics:

[0166] In CD3OD as solvent, each peak is assigned: 1H NMR(400MHz CD3OD)δ:8.46(d,J=7.2Hz,2H,-Ph),7.84-7.87(m,3H,-Ph,-CH=CH-),7.43(d,J=8.8Hz,1H,-Ph),6.98(d,J=8.4Hz,2H,-Ph),6 .21(d,J=9.2Hz,1H,-CH=CH-),5.23(s,2H,-CH2-),5.17(t,J=7.2Hz,1H,-CH=C(CH3)2),4.13(t,J=6.0Hz,2H,-CH2-),3.50(d, J=7.2Hz,2H,-CH2-),3.33(d,J=7.2Hz,2H,-CH2-),3.22(t,J=7.2Hz,2H,-CH2-),1.87-1.96(m,4H,-CH2-),1.82(s,3H,-CH3), 1.72-1.80(m,2H,-CH2-),1.65(s,3H,-CH3),1.52-1.59(m,2H,-CH2-),1.32-1.38(m,4H,-CH2-),0.90(t,J=6.8Hz,3H,-CH3); 13 C NMR(100MHz CD3OD)δ:165.10,164.65,161.98,159.66,152.47,144.78,143.31,143.11,131.68,126.64,122.06,121.24,121.10,117.11,1 12.90,111.62,108.39,68.25,59.92,39.51,30.84,28.70,28.46,27.12,24.92,24.51,21.93,21.38,16.78,12.87; HRMS(ESI)C 31 H 41 N2O4S[M-Br] + calcd=537.2782; found=537.2789.

[0167] Example 19 Compound 16

[0168] Compound 16 was synthesized using the method described in Example 4. The physicochemical properties of compound 16 are as follows:

[0169] 1) White solid;

[0170] 2) The NMR spectrum of the compound ( 1 H / 13 C NMR, 400 MHz) characteristics:

[0171] With CD3OD as solvent, the peaks are attributed to: 1 H NMR(400MHz CD3OD)δ:8.46(d,J=7.2Hz,2H,-Ph),7.89(d,J=7.2Hz,2H,-Ph),7.86(d,J=9.6Hz,1H,-CH=CH-),7.45(d,J=8.8Hz,1H,-Ph),7.02(d,J=8.8Hz,1H, -Ph),6.23(d,J=9.6Hz,1H,-CH=CH-),5.55(s,2H,-CH2-),5.18(t,J=7.2Hz,1H,-CH=C(CH3)2),4.28(t,J=5.6Hz,2H,-CH2-),3.55(d,J=7.2Hz,2H ,-CH2-),3.50(t,J=7.2Hz,2H,-CH2-),3.35-3.40(m,4H,-CH2-),2.32-2.38(m,2H,-CH2-),1.83(s,3H,-CH3),1.70-1.73(m,2H,-CH2-),1.64(s, 3H,-CH3),1.53-1.58(m,2H,-CH2-),1.41-1.46(m,2H,-CH2-),1.29-1.35(m,2H,-CH2-),1.01(t,J=7.6Hz,3H,-CH3),0.91(t,J=7.2Hz,3H,-CH3); 13 C NMR(100MHz CD3OD)δ:166.08,165.70,163.33,160.71,153.97,146.20,146.16,145.18,133.46,126.45,123.45,122.78,122.67,118.72,114. 69,113.42,109.88,67.94,61.17,47.97,47.73,31.71,30.69,29.10,28.91,25.97,22.89,21.16,18.27,14.17,14.09; HRMS(ESI)C 32 H 43 N2O4S[M-Br] + calcd=551.2938; found=551.2948.

[0172] Example 20 Compound 17

[0173] Compound 17 was synthesized using the method described in Example 4. The physicochemical properties of compound 17 are as follows:

[0174] 1) White solid;

[0175] 2), the nuclear magnetic resonance spectrum of the compound 1 H / 13 C NMR, 400MHz) characteristics:

[0176] In DMSO as solvent, where each peak is assigned: 1 H NMR (400MHz DMSO) δ: 8.60 (d, J = 7.2 Hz, 2H, -Ph), 8.00 (d, J = 7.2 Hz, 2H, -Ph), 7.97 (d, J = 9.6 Hz, 1H, -CH=CH-), 7.54 (d, J = 8.4 Hz, 1H, -Ph), 7.05 (d, J = 8.4 Hz, 1H, -Ph), 6.26 (d, J = 9.6 Hz, 1H, -CH=CH-), 5.59 (s, 2H, -CH2-), 5.11 (t, J = 7.2 Hz, 1H, -CH=C(CH3)2), 4.17 (t, J = 5.6 Hz, 2H, -CH2-), 3.38-3.42 (m, 4H, -CH2-), 3.26-3.30 (m, 4H, -CH2-), 1.91-1.96 (m, 4H, -CH2-), 1.75 (s, 3H, -CH3), 1.64-1.68 (m, 2H, -CH2-), 1.61 (s, 3H, -CH3), 1.45-1.50 (m, 2H, -CH2-), 1.32-1.38 (m, 2H, -CH2-), 1.21-1.27 (m, 2H, -CH2-), 0.94 (t, J = 7.2 Hz, 3H, -CH3), 0.85 (t, J = 7.2 Hz, 3H, -CH3); 13 C NMR (100MHz DMSO) δ: 164.09, 162.83, 160.25, 158.93, 152.18, 144.69, 143.99, 143.91, 143.91, 131.67, 127.16, 122.10, 121.30, 121.19, 116.17, 112.65, 112.22, 108.79, 67.78, 59.38, 46.30, 45.68, 30.14, 29.24, 27.70, 25.47, 24.32, 21.52, 19.59, 19.51, 17.72, 13.75, 13.66; HRMS (ESI) C 33 H 45 N2O4S[M-Br] + calcd = 565.3095; found = 565.3102.

[0177] Compound 18 of Example 21

[0178] Compound 18 was synthesized by the method described in Example 4, and the physicochemical properties of compound 18 were as follows:

[0179] 1) white solid;

[0180] 2) the nuclear magnetic resonance spectrum of the compound 1 H / 13 C NMR, 400MHz) characteristics:

[0181] In CD3OD solvent, each peak is assigned: 1 H NMR (400MHz CD3OD) δ: 8.45 (d, J = 7.2 Hz, 2H, -Ph), 7.85 (d, J = 7.6 Hz, 3H, -Ph, -CH=CH-), 7.43 (d, J = 8.4 Hz, 1H, -Ph), 6.99 (d, J = 8.4 Hz, 1H, -Ph), 6.21 (d, J = 9.2 Hz, 1H, -Ph), 5.56 (s, 2H, -CH2-), 5.17 (t, J = 8.0 Hz, 1H, -CH=C(CH3)2), 4.13 (t, J = 6.0 Hz, 2H, -CH2-), 3.51 (s, 2H, -CH2-), 3.33-3.40 (m, 6H, -CH2-), 1.88-1.96 (m, 4H, -CH2-), 1.82 (s, 3H, -CH3), 1.70-1.78 (m, 4H, -CH2-), 1.65 (s, 3H, -CH3), 1.52-1.59 (m, 2H, -CH2-), 1.43-1.49 (m, 2H, -CH2-), 1.29-1.37 (m, 2H, -CH2-), 1.01 (t, J = 7.6 Hz, 3H, -CH3), 0.91 (t, J = 7.2 Hz, 3H, -CH3); 13 C NMR (100MHz CD3OD) δ: 165.06, 164.24, 162.01, 159.66, 152.46, 144.85, 143.62, 143.40, 131.69, 126.66, 121.96, 121.21, 121.10, 117.08, 112.87, 111.59, 108.39, 68.16, 46.35, 46.29, 30.87, 30.20, 29.22, 28.35, 27.18, 24.95, 24.51, 21.35, 19.64, 16.76, 12.74, 12.65; HRMS (ESI) C 34 H 47 N2O4S[M-Br] + calcd = 579.3251; found = 579.3260.

[0182] Example 22 Compound 19

[0183] Compound 19 was synthesized by the method described in Example 4, and the physical and chemical properties of compound 19 are as follows:

[0184] 1) white solid;

[0185] 2) the nuclear magnetic resonance spectrum of the compound 1 H / 13 C NMR, 400MHz) characteristics:

[0186] In DMSO as solvent, each peak is assigned: 1 H NMR (400MHz DMSO) δ: 8.63 (d, J = 6.8 Hz, 2H, -Ph), 8.59 (t, J = 5.6 Hz, 1H, -NH-), 7.98 (m, 3H, -Ph, -CH=CH-), 7.56 (d, J = 8.4 Hz, 1H, -Ph), 7.06 (d, J = 8.4 Hz, 1H, -Ph), 6.28 (d, J = 9.6 Hz, 1H, -CH=CH-), 5.26 (s, 2H, -CH2-), 5.14 (t, J = 7.2 Hz, 1H, -CH=C(CH3)2), 4.25 (t, J = 5.6 Hz, 2H, -CH2-), 3.45-3.49 (m, 4H, -CH2-), 3.09-3.14 (m, 2H, -CH2-), 2.20-2.25 (m, 2H, -CH2-), 1.77 (s, 3H, -CH3), 1.60 (s, 3H, -CH3), 1.40-1.47 (m, 2H, -CH2-), 1.22-1.30 (m, 6H, -CH2-), 0.85 (t, J = 6.8 Hz, 3H, -CH3); 13 C NMR (100MHz DMSO) δ: 164.30, 162.44, 160.22, 158.70, 152.18, 144.67, 143.85, 131.68, 127.20, 122.11, 121.38, 121.30, 116.29, 112.79, 112.39, 108.65, 66.69, 59.96, 36.55, 30.90, 28.82, 27.34, 26.00, 25.44, 22.02, 21.57, 17.76, 13.91; HRMS (ESI) C 30 H 39 N2O4S[M-Br] + calcd = 523.2625; found = 523.2629.

[0187] Example 23 Compound 20

[0188] Compound 20 was synthesized by the method described in Example 4, and the physicochemical properties of compound 20 were as follows:

[0189] 1) white solid;

[0190] 2) the nuclear magnetic resonance spectrum of the compound (H NMR, 400MHz) was characterized as follows: 1 H / 13 C NMR, 400MHz) was characterized as follows:

[0191] In CD3OD solvent, each peak is assigned as follows: 1 H NMR (400MHz CD3OD) δ: 8.47 (d, J = 7.2 Hz, 2H, -Ph), 7.85 (m, 3H, -NH-, -Ph), 7.44 (d, J = 8.4 Hz, 1H, -CH=CH-), 7.00 (d, J = 8.4 Hz, 1H, -Ph), 6.21 (d, J = 9.6 Hz, 1H, -CH=CH-), 5.24 (s, 2H, -CH2-), 5.14 (t, J = 7.2 Hz, 1H, -CH=C(CH3)2), 4.18 (t, J = 5.6 Hz, 2H, -CH2-), 3.48 (d, J = 6.8 Hz, 2H, -CH2-), 3.37-3.41 (t, J = 6.8 Hz, 2H, -CH2-), 3.22-3.26 (m, 2H, -CH2-), 2.03-2.06 (m, 4H, -CH2-), 1.81 (s, 3H, -CH3), 1.63 (s, 3H, -CH3), 1.51-1.56 (m, 2H, -CH2-), 1.36-1.39 (m, 2H, -CH2-), 1.31-1.34 (m, 4H, -CH2-), 0.89 (t, J = 6.4 Hz, 3H, -CH3); 13 C NMR (100MHz CD3OD) δ: 166.43, 166.12, 163.43, 161.00, 153.96, 146.26, 146.21, 144.73, 133.28, 128.13, 123.57, 122.69, 118.60, 114.45, 113.18, 109.88, 69.26, 61.48, 41.09, 32.65, 32.11, 30.27, 29.42, 27.71, 25.98, 25.84, 23.63, 22.85, 18.28, 14.44; HRMS (ESI) C 31 H 41 N2O4S [M-Br] + calcd = 537.2782; found = 537.2792.

[0192] Example 24 Compound 21

[0193] Compound 21 was synthesized using the method described in Example 4. The physicochemical properties of compound 21 are as follows:

[0194] 1) yellow liquid;

[0195] 2) the nuclear magnetic resonance spectrum of the compound (H NMR, 400 MHz, CD3OD) is characterized by: 1 H / 13 C NMR, 400 MHz) is characterized by:

[0196] In CD3OD solvent, each peak is assigned as follows: 1 H NMR (400 MHz, CD3OD) δ: 8.46 (d, J = 7.2 Hz, 2H, -Ph), 7.84-7.87 (m, 3H, -Ph, -CH=CH-), 7.43 (d, J = 8.4 Hz, 1H, -Ph), 6.98 (d, J = 8.8 Hz, 1H, -Ph), 6.21 (d, J = 9.2 Hz, 1H, -CH=CH-), 5.23 (s, 2H, -CH2-), 5.17 (t, J = 7.2 Hz, 1H, -CH=C(CH3)2), 4.13 (t, J = 6.0 Hz, 2H, -CH2-), 3.50 (d, J = 7.2 Hz, 2H, -CH2-), 3.33 (d, J = 7.2 Hz, 2H, -CH2-), 3.22 (t, J = 7.2 Hz, 2H, -CH2-), 1.87-1.96 (m, 4H, -CH2-), 1.82 (s, 3H, -CH3), 1.72-1.80 (m, 2H, -CH2-), 1.65 (s, 3H, -CH3), 1.51-1.58 (m, 2H, -CH2-), 1.34-1.39 (m, 6H, -CH2-), 0.89 (t, J = 6.8 Hz, 3H, -CH3); 13 C NMR (100 MHz, CD3OD) δ: 165.10, 164.65, 161.98, 159.66, 152.47, 144.78, 143.32, 143.16, 131.70, 126.74, 122.03, 121.24, 121.08, 117.13, 112.87, 111.60, 108.45, 68.08, 59.87, 39.55, 31.14, 30.87, 28.76, 28.34, 27.10, 26.18, 24.93, 24.54, 22.15, 21.35, 16.77, 12.88; HRMS (ESI) C 32 H 43 N2O4S [M-Br] +calcd=551.2938; found=551.2945.

[0197] Example 25 Compound 22

[0198] Compound 22 was synthesized using the method described in Example 4. The physicochemical properties of compound 22 are as follows:

[0199] 1) White solid;

[0200] 2) The NMR spectrum of the compound ( 1 H / 13 C NMR, 400 MHz) characteristics:

[0201] With CD3OD as solvent, the peaks are attributed to: 1 H NMR(400MHz CD3OD)δ:8.45(d,J=7.2Hz,2H,-Ph),7.90(d,J=7.2Hz,2H,-Ph),7.85(d,J=9.6Hz,1H,-CH=CH-),7.45(d,J=8.4Hz,1H,-Ph),7 .02(d,J=8.8Hz,1H,-Ph),6.23(d,J=9.6Hz,1H,-CH=CH-),5.59(s,2H,-CH2-),5.18-5.21(m,1H,-CH=C(CH3)2),4.28(t,J=6. 0Hz,2H,-CH2-),3.55(d,J=7.2Hz,2H,-CH2-),3.50(t,J=7.2Hz,2H,-CH2-),3.24-3.27(m,4H,-CH2-),2.32-2.38(m,2H,-CH2 -),2.00-2.14(m,2H,-CH2-),1.83(s,3H,-CH3),1.64(s,3H,-CH3),1.02(d,J=6.4Hz,6H,-CH3),0.89(d,J=6.8Hz,6H,-CH3); 13 C NMR(100MHz CD3OD)δ:166.52,166.13,163.33,160.71,153.97,146.22,145.16,133.46,128.28,123.48,122.78,122.69,118.70,114.6 8,113.43,109.83,67.92,55.89,55.20,29.13,28.94,27.68,26.01,22.90,20.55,20.47,20.39,20.31,18.30; HRMS(ESI)C 32 H 43N2O4S[M-Br] + calcd = 551.2938; found = 551.2947.

[0202] Example 26 Compound 23

[0203] Compound 23 was synthesized using the method described in Example 4. The physical and chemical properties of compound 23 are as follows:

[0204] 1) white solid;

[0205] 2) the nuclear magnetic resonance spectrum of the compound 1 H / 13 C NMR, 400MHz) characteristics:

[0206] in DMSO, where each peak is assigned: 1 H NMR (400MHz DMSO) δ: 8.61 (d, J = 7.2 Hz, 2H, -Ph), 8.00 (d, J = 7.2 Hz, 2H, -Ph), 7.97 (d, J = 9.6 Hz, 1H, -CH=CH-), 7.54 (d, J = 8.8 Hz, 1H, -Ph), 7.05 (d, J = 8.8 Hz, 1H, -Ph), 6.26 (d, J = 9.6 Hz, 1H, -CH=CH-), 5.62 (s, 2H, -CH2-), 5.11 (t, J = 7.2 Hz, 1H, -CH=C(CH3)2), 4.17 (t, J = 5.6 Hz, 2H, -CH2-), 3.39-3.42 (m, 4H, -CH2-), 3.15-3.18 (m, 4H, -CH2-), 2.02-2.08 (m, 1H, -CH-), 1.90-1.97 (m, 5H, -CH-, -CH2-), 1.75 (s, 3H, -CH3), 1.60 (s, 3H, -CH3), 0.94 (d, J = 6.8 Hz, 6H, -CH3), 0.82 (d, J = 6.4 Hz, 6H, -CH3); 13 C NMR (100MHz DMSO) δ: 164.90, 162.92, 160.25, 158.94, 152.18, 144.69, 144.02, 143.97, 131.63, 127.16, 122.16, 121.30, 121.22, 116.17, 112.61, 112.24, 108.81, 67.74, 59.53, 53.89, 53.35, 30.14, 27.70, 27.04, 25.93, 25.45, 24.26, 21.48, 20.00, 19.93, 19.87, 19.81, 17.74; HRMS (ESI) C 33H 45 N2O4S[M-Br] + calcd=565.3095; found=565.3101

[0207] Example 27 Compound 24

[0208] Compound 24 was synthesized using the method described in Example 4. The physicochemical properties of compound 24 are as follows:

[0209] 1) White solid;

[0210] 2) The NMR spectrum of the compound ( 1 H / 13 C NMR, 400 MHz) characteristics:

[0211] With CD3OD as solvent, the peaks are attributed to: 1 H NMR(400MHz CD3OD)δ:8.60(d,J=7.2Hz,2H,-Ph),7.96-7.99(m,3H,-Ph,-CH=CH-),7.53(d,J=8.4Hz,1H,-Ph),7.04(d,J=8.8Hz,1H,-Ph) ,6.26(d,J=9.6Hz,1H,-CH=CH-),5.63(s,2H,-CH2-),5.14(t,J=7.2Hz,1H,-CH=C(CH3)2),4.11(t,J=6.0Hz,2H,-CH2-),3.4 1(d,J=7.2Hz,2H,-CH2-),3.32(s,2H,-CH2-),3.15(t,J=6.8Hz,4H,-CH2-),1.92-2.07(m,2H,-CH-),1.80-1.86(m,4H,-CH2 -),1.77(s,3H,-CH3),1.64-1.68(m,2H,-CH2-),1.62(s,3H,-CH3),0.94(t,J=6.8Hz,6H,-CH3), 0.82(t,J=6.4Hz,6H,-CH3); 13C NMR (100 MHz CD3OD) δ: 164.93, 163.03, 160.26, 159.04, 152.19, 144.71, 143.98, 143.90, 131.59, 127.16, 122.10, 121.32, 121.21, 116.17, 112.57, 112.20, 108.81, 68.29, 59.50, 53.88, 53.26, 30.48, 28.13, 27.09, 25.98, 25.88, 25.47, 24.70, 21.54, 20.03, 19.99, 19.89, 19.78, 17.72; HRMS (ESI) C 34 H 47 N2O4S[M-Br] + calcd = 579.3251 ; found = 579.3256

[0212] Example 28 Compound 25

[0213] Compound 25 was synthesized using the method described in Example 4. The physical and chemical properties of compound 25 are as follows:

[0214] 1) white solid;

[0215] 2) the nuclear magnetic resonance spectrum of the compound (H NMR, 400 MHz) is characterized by: 1 H / 13 C NMR, 400 MHz) is characterized by:

[0216] in DMSO, where each peak is assigned as: 1 H NMR (400 MHz DMSO) δ: 8.60 (d, J = 6.8 Hz, 2H, -Ph), 8.03 (d, J = 7.2 Hz, 2H, -Ph), 7.98 (d, J = 9.6 Hz, 1H, -CH=CH-), 7.56 (d, J = 8.8 Hz, 1H, -Ph), 7.06 (d, J = 8.8 Hz, 1H, -Ph), 6.28 (d, J = 9.6 Hz, 1H, -CH=CH-), 5.62 (s, 2H, -CH2-), 5.14 (t, J = 7.2 Hz, 1H, -CH=C(CH3)2), 4.25 (t, J = 6.0 Hz, 2H, -CH2-), 3.69-3.71 (m, 2H, -CH2-), 3.60-3.62 (m, 2H, -CH2-), 3.45-3.49 (m, 8H, -CH2-), 2.21-2.26 (m, 2H, -CH2-), 1.77 (s, 3H, -CH3), 1.60 (s, 3H, -CH3). 13C NMR(100MHz DMSO)δ:163.66,162.70,160.22,158.69,152.18,144.67,143.94,131.69,127.21,122.19,121.38,121.31,116.29 ,112.80,112.40,108.65,66.69,65.84,65.70,59.59,44.67,42.22,27.41,27.30,25.47,21.60,17.78; HRMS(ESI)C 28 H 33 N2O5S[M-Br] + calcd=509.2105; found=509.2112.

[0217] Example 29 Compound 26

[0218] Compound 26 was synthesized using the method described in Example 4. The physicochemical properties of compound 26 are as follows:

[0219] 1) White solid;

[0220] 2) The NMR spectrum of the compound ( 1 H / 13 C NMR, 400 MHz) characteristics:

[0221] With DMSO as solvent, the peaks are attributed to: 1 H NMR(400MHz DMSO)δ:8.58(d,J=6.8Hz,2H,-Ph),8.01(d,J=7.2Hz,2H,-Ph),7.97(d,J=9.6Hz,1H,-CH=CH-),7.54(d,J=8.8 Hz,1H,-Ph),7.05(d,J=8.4Hz,1H,-Ph),6.26(d,J=9.2Hz,1H,-CH=CH-),5.61(s,2H,-CH2-),5.11(t,J=7.2Hz ,1H,-CH=C(CH3)2),4.16(t,J=5.6Hz,2H,-CH2-),3.69-3.71(m,2H,-CH2-),3.60-3.62(m,2H,-CH2-),3.47-3 .49(m,4H,-CH2-),3.38-3.41(m,4H,-CH2-),1.90-1.96(m,4H,-CH2-),1.75(s,3H,-CH3),1.60(s,3H,-CH3); 13C NMR (100 MHz DMSO) δ: 163.68, 163.00, 160.25, 158.94, 152.18, 144.70, 143.88, 143.83, 131.63, 127.19, 122.24, 121.21, 116.15, 112.62, 108.75, 67.71, 65.84, 65.71, 59.55, 44.73, 42.23, 30.21, 27.76, 25.47, 24.27, 21.61, 17.76; HRMS (ESI) C 29 H 35 N2O4S [M-Br] + calcd = 523.2261; found = 523.2279.

[0222] Example 30 Compound 27

[0223] Compound 27 was synthesized using the method described in Example 4. The physical and chemical properties of compound 27 are as follows:

[0224] 1) white solid;

[0225] 2) the nuclear magnetic resonance spectrum of the compound (H NMR, 400 MHz) is characterized by: 1 H NMR, 400 MHz) is characterized by:

[0226] in DMSO, where each peak is assigned 1 H NMR (400 MHz DMSO) δ: 8.43 (d, J = 7.2 Hz, 2H, -Ph), 7.84-7.88 (m, 3H, -Ph, -CH=CH-), 7.42 (d, J = 8.8 Hz, 1H, -CH=CH-), 6.98 (d, J = 8.8 Hz, 1H, -Ph), 6.21 (d, J = 9.2 Hz, 1H, -Ph), 5.57 (s, 2H, -CH2-), 5.17 (t, J = 7.2 Hz, 1H, -CH=C(CH3)2), 4.13 (t, J = 6.0 Hz, 2H, -CH2-), 3.77-3.79 (m, 2H, -CH2-), 3.69-3.71 (m, 2H, -CH2-), 3.55-3.61 (m, 4H, -CH2-), 3.50 (d, J = 7.2 Hz, 2H, -CH2-), 3.33 (d, J = 7.2 Hz, 2H, -CH2-), 1.88-1.96 (m, 4H, -CH2-), 1.82 (s, 3H, -CH3), 1.72-1.80 (m, 2H, -CH2-), 1.65 (s, 3H, -CH3); HRMS (ESI) C 30 H 37 N2O5S [M-Br]+ calcd=537.2418; found=537.2426.

[0227] Example 31 Compound 28

[0228] Compound 28 was synthesized using the method described in Example 4. The physicochemical properties of compound 28 are as follows:

[0229] 1) Light yellow solid;

[0230] 2) The NMR spectrum of the compound ( 1 H NMR, 400 MHz) characteristics:

[0231] DMSO was used as solvent, and the peaks were attributed to: 1 H NMR(400MHz DMSO)δ:8.59(d,J=6.8Hz,2H,-Ph),7.97-8.02(m,3H,-Ph,-CH=CH-),7.55-7.57(m,5H,-Ph) ,7.46-7.50(m,1H,-Ph),7.06(d,J=8.8Hz,1H,-Ph),6.28(d,J=9.6Hz,1H,-CH=CH-),5.14-5 .17(m,3H,-CH=C(CH3)2,-CH2-),4.25(t,J=5.6Hz,2H,-CH2-),3.45-3.49(m,4H,-CH2-),3. 24(s,3H,-CH3),2.19-2.25(m,2H,-CH2-),1.77(s,3H,-CH3),1.60(s,3H,-CH3).HRMS(ESI)C 31 H 33 N2O4S[M-Br] + calcd=529.2156; found=529.2159.

[0232] Example 32 Compound 29

[0233] Compound 29 was synthesized using the method described in Example 4. The physicochemical properties of compound 29 are as follows:

[0234] 1) White solid;

[0235] 2) The NMR spectrum of the compound ( 1 H NMR, 400 MHz) characteristics:

[0236] With CD3OD as solvent, the peaks are attributed to: 1H NMR(400MHz CD3OD)δ:8.42(d,J=7.2Hz,2H,-Ph),7.84-7.87(m,3H,-Ph,-CH=CH-),7.43-7.58(m,6H,-Ph ),7.00(d,J=8.8Hz,1H,-Ph),6.21(d,J=9.6Hz,1H,-Ph),5.14-5.17(m,3H,-CH=C(CH3)2,-C H2-),4.18(t,J=5.6Hz,2H,-CH2-),3.48(d,J=7.2Hz,2H,-CH2-),3.36(t,J=6.4Hz,2H,-CH2 -),3.32(s,3H,-CH3),2.05(s,4H,-CH2-),1.80(s,3H,-CH3),1.63(s,3H,-CH3).HRMS(ESI)C 32 H 35 N2O4S[M-Br] + calcd=543.2312; found=543.2317.

[0237] Example 33 Compound 30

[0238] Compound 30 was synthesized using the method described in Example 4. The physicochemical properties of compound 30 are as follows:

[0239] 1) Light yellow solid;

[0240] 2) The NMR spectrum of the compound ( 1 H NMR, 400 MHz) characteristics:

[0241] With CDCl3 as solvent, the peaks are attributed to: 1H NMR (400 MHz, CD3OD) δ: 8.59 (d, J = 6.4 Hz, 2H, -Ph), 7.96-7.99 (m, 3H, -Ph, -CH=CH-), 7.55-7.58 (m, 4H, -Ph), 7.53 (s, 1H, -Ph), 7.47-7.50 (m, 1H, -Ph), 7.03 (d, J = 8.4 Hz, 1H, -Ph), 6.25 (d, J = 9.6 Hz, 1H, -CH=CH-), 5.13-5.18 (m, 3H, -CH=C(CH3)2, -CH2-), 4.10 (t, J = 6.0 Hz, 2H, -CH2-), 3.41 (d, J = 6.8 Hz, 4H, -CH2-), 3.23 (s, 3H, -CH3), 1.78-1.86 (m, 4H, -CH2), 1.76 (s, 3H, -CH3), 1.64-1.67 (m, 2H, -CH2-), 1.61 (s, 3H, -CH3); HRMS (ESI) C 33 H 37 N2O4S[M-Br] + calcd = 557.2469; found = 557.2471.

[0242] Application Example 1: In vitro antibacterial activity determination

[0243] 1. Test bacteria:

[0244] Staphylococcus aureus ATCC 29213; Escherichia coli ATCC 25922; Methicillin-resistant Staphylococcus aureus (MRSA).

[0245] 2. Samples and reagents:

[0246] The samples were: osthole, vancomycin, meropenem, and compounds 1-30 prepared in the examples.

[0247] 3. Test method:

[0248] According to the standard of the American National Clinical Laboratory Standard Association (CLSI), using a 96-well plate, the in vitro antibacterial activity of osthole and compounds 1-30 of the application and the clinical antibacterial drug vancomycin was tested by the method of doubling dilution, and the drug concentration of the minimum completely clear well was observed by the naked eye as the MIC value.

[0249] Table 1. MIC values of the amphiphilic osthole-quaternary ammonium salt hybrid 1-30 of the application against 10 strains of MRSA clinical isolates

[0250]

[0251]

[0252] a Sa: Staphylococcus aureus ATCC 29213; b M11-23:10 clinical MRSA strain; c Ec: Escherichia coli ATCC25922; d SI: Selectivity coefficient (HC 50 / MICs of S. aureus); e ND: not determined. f Van: vancomycin; k MEM: Meropenem. The experiment was repeated at least 3 times.

[0253] As can be seen from Table 1, the amphiphilic osthole-quaternary ammonium salt hybrids prepared by the present invention have good antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA). Compounds 15-20 and 22-23 all exhibited better antibacterial activity than the parent compound, with minimum inhibitory concentrations of ≤4 μg / mL. In particular, compounds 15 and 23 had the best antibacterial effects, with MIC values ​​of 0.5-1 μg / mL, which are close to or equivalent to the positive drug vancomycin. In addition, they all had relatively stable antibacterial activity against 10 clinically isolated MRSA strains. Therefore, they are expected to become clinical antibacterial drugs against methicillin-resistant Staphylococcus aureus.

[0254] Application Example 2: Time-kill kinetics experiment of compounds 15 and 23:

[0255] 1. Test bacteria:

[0256] Staphylococcus aureus ATCC 29213; MRSA-11 (clinical isolate).

[0257] 2. Samples and reagents:

[0258] The samples were vancomycin and compounds 15 and 23 prepared in Examples.

[0259] 3. Test method:

[0260] A single colony of the drug-resistant Staphylococcus aureus strain MRSA-11 was picked and placed in 1 mL of LB liquid medium and cultured in a shaker (200 rpm, 37°C) for 16-18 hours. The bacterial solution was then diluted 1000 times with LB liquid medium and cultured for another 2.5 hours until the bacterial solution was diluted to 1×10 5CFU / mL. Then different concentrations of compound 15 or 23 (4xMIC, 8xMIC) were added into the bacterial solution, vancomycin (8xMIC) was used as positive control, and blank group without drug was set. The solution was incubated in a shaker (200 rpm, 37°C), and 100 μL of each group was taken at 0 h, 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h after drug addition, centrifuged at 3500 rpm, 4°C for 3 min, the supernatant was removed, washed three times, resuspended with 100 μL of 1xPBS buffer solution, diluted by ten times, counted by plate, three parallel controls were set for each group, incubated in a 37°C constant temperature incubator overnight, and the number of colonies was counted the next day. The results are shown in the following table and figures. 10 CFU / mL, and the results are shown in the following table and figures. Figure 1 A, B.

[0261] Figure 1 A, B show that compound 15 and 23 can completely kill MRSA-11 within 8 h and 6 h respectively under the action of 8xMIC, and have stronger bactericidal effect than the positive control drug vancomycin under the same concentration. In addition, under the condition of 4xMIC, the number of colonies of MRSA-11 also gradually decreases with the extension of time, showing a good inhibitory effect. The results show that the pyridine ring-containing amphiphilic cniducin-quaternary ammonium salt hybrid 15 and 23 have strong bactericidal effect on MRSA-11, and have dose dependence, and are expected to develop into a clinical rapid antibacterial drug.

[0262] Example 3: Drug resistance induction experiment of compound 15 and 23:

[0263] First, the MIC values of compound 15, 23 and the positive control norfloxacin were determined, and then a single S. aureus colony was placed in MHB broth (1.0 mL) containing a sub-inhibitory concentration (1 / 2 MIC) of compound 15, 23 and norfloxacin, and incubated on a shaker (200 rpm, 37°C) for 12 hours. Then, the bacteria were inoculated on a fresh MHA plate containing a sub-inhibitory concentration (1 / 2 MIC) of compound 15, 23 and norfloxacin, and incubated at 37°C for 24 hours. When S. aureus formed single colonies, the above steps were repeated for more than 20 generations, and the MIC values of compound 15 and 23 were recorded by CLSI broth dilution method, and the results are shown in the following table and figures. Figure 1 C.

[0264] From Figure 1 The results show that compound 15 and 23 do not show any drug resistance when S. aureus grows for 20 generations, while the positive control drug norfloxacin shows obvious drug resistance when S. aureus grows for 19 generations, and the MIC value increases from 1 to 128 μg / mL.

[0265] Example 4: In vivo safety evaluation experiment - subcutaneous abscess model

[0266] 1. Reagents:

[0267] Example 15 and 23 prepared by the compounds, 0.9% NaCl.

[0268] 2. Test animals

[0269] SPF KM mice (purchased from Beijing Sbielfo Biotechnology Co., Ltd., body weight 19-22 g, 4-6 weeks old).

[0270] 3. Test method

[0271] Take 55 mice and divide them into groups of 5 each, Control group (0.9% NaCl), 15 (5mg / kg, 10mg / kg, 20mg / kg, 40mg / kg, 80mg / kg), 23 (5mg / kg, 10mg / kg, 20mg / kg, 40mg / kg, 80mg / kg), and inject 60 μL of 0.9% NaCl and different concentrations of compounds 15 or 23 into the back of the mice, respectively. Observe the mice for abnormalities (such as redness, hardness, ulceration, etc.) 24 hours later. The mice in the highest dose group that did not cause adverse reactions were sacrificed, and their blood was taken for routine blood tests and blood biochemical tests to evaluate whether compounds 15 and 23 have in vivo toxicity in mice, and the results are shown in Figure 2 .

[0272] By subcutaneously injecting different concentrations of compounds into mice, it was found that when the concentration of compound 15 was ≤20mg / kg and the concentration of compound 23 was ≤30mg / kg, the mice's skin did not show any adverse reactions (such as redness, hardness, ulceration, etc.). Therefore, routine blood tests and blood biochemical tests were performed on the mice at this dose. Figure 2 The blood samples were subjected to routine blood tests and blood biochemical tests, and the test items included white blood cell count (WBC), red blood cell count (RBC), hemoglobin (HGB), hematocrit (HCT), mean corpuscular volume (MCV), and platelet count (PLT). The statistical results showed that there was no significant difference in the results compared with the Control group (0.9% NaCl) after subcutaneously injecting compounds 15 and 23 (20mg / kg) into KM mice. At the same time, by collecting serum for blood biochemical tests, including albumin (ALB), urea (UREA) and creatinine (CREA), there was no significant difference in the corresponding indicators of liver and kidney function in mice compared with the Control group (0.9% NaCl) after subcutaneously injecting compounds 15 and 23 (20mg / kg) into KM mice. The results showed that compounds 15 and 23 had certain in vivo safety.

[0273] Example 5: In vivo anti-MRSA infection activity test of compounds 15 and 23 - subcutaneous abscess model

[0274] 1. Test bacteria:

[0275] MRSA-11 (clinical isolate)

[0276] 2. Samples and reagents:

[0277] The samples were: vancomycin and the compounds 15 and 23 prepared in the examples, 0.9% NaCl.

[0278] 3. Test animals:

[0279] SPF KM mice (purchased from Beijing Sbielfo Biotechnology Co., Ltd., body weight 19-22 g, 4-6 weeks old).

[0280] 4. Test method:

[0281] Thirty KM mice were taken, and their backs were depilated. The mice were grouped, with 6 mice in each group, which were blank group (no injection of MRSA-11 bacterial solution, no injection of drug solution), model group (only injection of MRSA-11 bacterial solution), compound 15 (4 mg / kg, 8 mg / kg), compound 23 (4 mg / kg, 8 mg / kg), and positive control vancomycin (4 mg / kg, 8 mg / kg). The mice were anesthetized, and MRSA-11 bacterial solution (60 μL, 1 x 10 8 CFU / mL) was injected subcutaneously on their backs. After 2 h, 60 μL of different concentrations of the compounds, positive drug vancomycin, and 0.9% NaCl were injected into the skin infection site. After 24 h of administration, the mice were sacrificed by dislocation, and then the mouse infected skin was aseptically separated, ground, and counted on a counting plate. The 24 h skin bacterial load of the mice was read, and the results are shown in Figure 3

[0282] The results showed that, compared with the model group, the number of MRSA cells in the skin of the mice treated with the compounds 15 and 23 and vancomycin was significantly reduced (P < 0.0001), and the treatment effect of the compounds 15, 23, and vancomycin (8 mg / kg) was the most significant (P < 0.0001), with a decrease of about 3.828 log 10 CFU / g, 4.252 log 10 CFU / g, and 3.96 log 10 CFU / g in the tissue bacterial load relative to the model group; and the tissue bacterial loads of the compounds 15, 23, and vancomycin (4 mg / kg) were reduced by about 1.882 log 10 CFU / g, 1.948 log​10 CFU / g and 1.578 log 10 CFU / g, showing moderate antibacterial effect, and the antibacterial effects of the three were comparable. Therefore, it was confirmed that the amphiphilic cnidium-chitosan hybrid 15 and 23 containing pyridine ring had a good therapeutic effect on MRSA-infected mouse skin abscesses, which was comparable to that of vancomycin at the same dose, and was expected to be developed into an anti-MRSA drug.

[0283] Example 6: In vivo safety evaluation experiment-sepsis model

[0284] 1. Reagents:

[0285] Example 15 and 23 prepared in the example, 0.9% NaCl.

[0286] 2. Test animals

[0287] SPF BALB / c mice (purchased from Beijing Vital River Laboratory Animal Technology Co., Ltd., body weight 17-19 g, 6-8 weeks old).

[0288] 3. Test method

[0289] 66 BALB / c mice were taken for grouping, 6 in each group, Control group (0.9% NaCl), 15 (5 mg / kg, 10 mg / kg, 20 mg / kg, 30 mg / kg, 40 mg / kg), 23 (5 mg / kg, 10 mg / kg, 20 mg / kg, 30 mg / kg, 40 mg / kg), then the mice were injected intraperitoneally with 100 μL of 0.9% NaCl and different concentrations of compounds 15 or 23 twice, and the interval was 5 h. After 48 h, observe whether the skin of the mice has any abnormalities (such as redness, hardness, ulceration, etc.). The mice in the maximum dose group that did not show adverse reactions and death were sacrificed, and their blood was taken for routine blood test and blood biochemical index test to evaluate whether the compounds 15 and 23 had in vivo toxicity to mice, and the results are shown in Figure 4 .

[0290] By intraperitoneal injection of different concentrations of compounds, it was found that when the concentration of compound 15 was ≤10 mg / kg and the concentration of compound 23 was ≤30 mg / kg, the skin of the mice did not show adverse reactions, and the survival rate was 100%. Therefore, the mice at this dose were subjected to routine blood test and blood biochemical index test. Figure 3The blood samples were subjected to routine blood test and blood biochemical analysis, and the test items included white blood cell count (WBC), red blood cell count (RBC), hemoglobin (HGB), hematocrit (HCT), mean corpuscular volume (MCV) and platelet count (PLT). The statistical results showed that there was no significant difference in each result after intraperitoneal injection of compound 15 (10 mg / kg) and 23 (30 mg / kg) into BALB / c mice compared with the Control group (0.9% NaCl). At the same time, the blood biochemical test was carried out by collecting serum, including albumin (ALB), urea (UREA) and creatinine (CREA), and there was no obvious difference in the corresponding indicators of liver and kidney function of the mice after intraperitoneal injection of compound 15 (10 mg / kg) and 23 (30 mg / kg) into BALB / c mice compared with the Control group (0.9% NaCl), which indicated that compounds 15 and 23 had certain in vivo safety.

[0291] Example 7: In vivo anti-MRSA infection activity experiment of compound 23 - sepsis model

[0292] 1. Test bacteria:

[0293] MRSA-11 (clinical isolate)

[0294] 2. Samples and reagents:

[0295] The samples were: vancomycin and compounds 15 and 23 prepared in the examples, and 0.9% NaCl.

[0296] 3. Test animals:

[0297] SPF BALB / c mice (purchased from Beijing Vital River Laboratory Animal Technology Co., Ltd., body weight 17-19 g, 6-8 weeks old).

[0298] 4. Test method of sublethal bacterial concentration and minimum lethal bacterial concentration:

[0299] Forty-two BALB / c mice were taken and grouped, with 6 mice in each group, which were blank group (no injection of MRSA-11 bacterial solution and no injection of drug solution), model group (5×10 7 CFU / mL, 1×10 8 CFU / mL, 5×10 8 CFU / mL, 1×10 9 CFU / mL, 5×10 9 CFU / mL, 1×10 10 CFU / mL). Different concentrations of MRSA-11 bacterial solution (100 μL) were intraperitoneally injected, and continuous observation was carried out for seven days.

[0300] The results show that when the injected bacteria concentration is ≤5x10 8 CFU / mL, the mice do not die. When the injected bacteria concentration is ≥1x10 9 CFU / mL, the survival rate of the mice is 0%. Therefore, 5x10 8 CFU / mL is taken as the sub-lethal bacteria concentration, and 1x10 9 CFU / mL is taken as the minimum lethal bacteria concentration.

[0301] 5. In vivo anti-MRSA testing method at sub-lethal bacteria concentration:

[0302] Take 45 BALB / c mice, and group the mice, 9 mice in each group, which are respectively a blank group (without injecting MRSA-11 bacteria solution and without injecting the drug solution), a model group (only injecting MRSA-11 bacteria solution), a positive control vancomycin group (10 mg / kg), and compound 23 (10 mg / kg, 20 mg / kg). Inject the MRSA-11 bacteria solution (100 μL, 5x10 8 CFU / mL) into the abdominal cavity of the mice, and 1 h later, inject 100 μL of different concentrations of the compound, the positive drug vancomycin, and 0.9% NaCl into the skin infection site. 5 h later, perform the second injection, and the injection liquid is the same as the first time. 48 h after the second injection, euthanize the mice by dislocation, then dissect the liver, kidney, and spleen of the mice, grind them, count them on a dipstick, and read the bacterial load of the skin of the mice, and the results are shown in Table 2. Figure 5

[0303] The results show that compared with the model group, the number of MRSA cells in the liver, kidney, and spleen of the mice after treatment with compound 23 and vancomycin is significantly reduced (P<0.0001), and the treatment effect of compound 23 (20 mg / kg) and vancomycin (10 mg / kg) is the most significant (P<0.0001), and the bacterial load of the liver, kidney, and spleen is significantly reduced compared with the model group; therefore, it is proved that the pyridine ring-containing amphiphilic cnidilide-quaternary ammonium salt hybrid 23 has a good treatment effect on sepsis of MRSA-infected mice, and is expected to be developed into an anti-MRSA drug.

[0304] 6. In vivo anti-MRSA testing method at minimum lethal bacteria concentration:

[0305] Take 72 BALB / c mice, and group the mice, 9 mice in each group, which are respectively a blank group (without injecting MRSA-11 bacteria solution and without injecting the drug solution), a model group (only injecting MRSA-11 bacteria solution), a positive control vancomycin group (5 mg / kg, 10 mg / kg, 15 mg / kg), and compound 23 (10 mg / kg, 20 mg / kg, 30 mg / kg). Inject the MRSA-11 bacteria solution (100 μL, 1x10 9 ​CFU / mL), 1 h later, 100 μL of different concentrations of compounds, positive drug vancomycin and 0.9% NaCl were injected into the skin infection sites respectively. 5 h later, the second injection was performed, and the injection liquid was the same as the first time. After injection, continuous observation was performed for seven days, and the results are shown in Table 2. Figure 6

[0306] The results show that all the mice in the model group died within two days, while the survival rate of the mice was significantly improved after treatment with compound 23 and vancomycin, and the treatment effect of compound 23 (30 mg / kg) and vancomycin (15 mg / kg) was the most significant, which could improve the survival rate of mice to 100%; therefore, it is further indicated that the pyridine ring-containing amphiphilic cumin-quaternary ammonium salt hybrid 23 has a significant in vivo antibacterial effect on sepsis of MRSA-infected mice, and has great potential in the development of a new type of anti-MRSA drug.​

Claims

1. An amphiphilic osthole-quaternary ammonium salt hybrid containing a pyridine ring, the structure of which is shown in the following formula (I): in, n=3, 4 or 5, R is Among them, R 1 and R 2 Independently selected from H, phenyl or C1-C6 alkyl, ring A is a 4-6 membered heterocycloalkyl containing one or two heteroatoms; said ring A is a 6 membered heterocycloalkyl containing two heteroatoms, wherein the heteroatoms include an O atom in addition to the N atom connecting the parent nucleus.

2. The amphiphilic osthole-quaternary ammonium salt hybrid containing a pyridine ring according to claim 1, characterized in that: The n, R is one of the following combinations: (1) n=3, R 1 = H, R 2 = -(CH2)2CH3;(2) n = 4,R 1 = H, R 2 = -(CH2)2CH3; (3) n = 5, R 1 = H, R2= -(CH2)2CH3;(4) n = 3, R 1 = R 2 = -(CH2)2CH3; (5) n = 4, R 1 =R 2 = -(CH2)2CH3;(6) n = 5, R 1 =R 2 = -(CH2)2CH3; (7) n = 3, R 1 = H, R 2 = -(CH2)3CH3;(8) n = 4, R 1 = H, R 2 = -(CH2)3CH3; (9) n = 5, R 1 = H, R 2 = -(CH2)3CH3;(10) n = 3, R 1 = R 2 = -CH(CH3)2; (11) n = 4, R 1 =R 2 = -CH(CH3)2;(12) n = 5, R 1 =R 2 = -CH(CH3)2; (13) n = 3, R 1 = H, R 2 = -(CH2)4CH3;(14) n = 4, R 1 = H, R 2 = -(CH2)4CH3; (15) n = 5, R 1 = H, R 2 = -(CH2)4CH3;(16) n = 3, R 1 = R 2 = (CH2)3CH3; (17) n = 4, R 1 =R 2 = (CH2)3CH3;(18) n = 5, R 1 =R 2 = (CH2)3CH3; (19) n = 3, R 1 = H, R2= -(CH2)5CH3;(20) n = 4, R 1 = H, R2= -(CH2)5CH3; (21) n = 5, R 1 = H, R2= -(CH2)5CH3;(22) n = 3, R 1 = R 2 = -CH2CH(CH3)2; (23) n = 4, R 1 =R 2 = -CH2CH(CH3)2;(24) n = 5, R 1 =R 2 = -CH2CH(CH3)2; (25)n=3, R is (26)n=4,R is (27)n=5, R is (28)n=3,R 1 =-CH3,R 2 =-C6H6; (29) n = 4, R 1 = -CH3, R 2 = -C6H6;(30) n = 5, R 1 = -CH3, R 2 = -C6H6.

3. The method for preparing the pyridine ring-containing amphiphilic osthole-quaternary ammonium salt hybrid according to claim 1 or 2, characterized in that: The following steps are involved: (1) Using osthole as a substrate, its methoxy group was converted into a phenolic hydroxyl group under the action of boron tribromide to obtain intermediate a; (2) Intermediate a reacts with different dibromoalkanes under alkaline conditions to synthesize intermediate b; (3) Intermediate b reacts with 4-mercaptopyridine under alkaline conditions and a catalyst to synthesize intermediate c; (4) Intermediate c then reacts with a small molecule peptide mimetic d to generate an amphiphilic osthole-quaternary ammonium salt hybrid containing a pyridine ring. The reaction formula is as follows: Wherein, R and n are the same as those described in claim 1 or 2.

4. The method for preparing the amphiphilic osthole-quaternary ammonium salt hybrid containing a pyridine ring according to claim 3, wherein: In step (1), the reaction molar ratio of osthole to boron tribromide is 1:1-1:5, the reaction temperature is -40-0°C, and the reaction solvent is anhydrous dichloromethane.

5. The method for preparing the amphiphilic osthole-quaternary ammonium salt hybrid containing a pyridine ring according to claim 3, wherein: In step (2), the base in the alkaline conditions is K2CO3, the reaction molar ratio of intermediate a to the base is 1:1-1:3, the molar ratio of intermediate a to dibromoalkane is 1:1.5-1:3, the reaction temperature is 45-60°C, and the reaction solvent is anhydrous acetone.

6. The method for preparing the amphiphilic osthole-quaternary ammonium salt hybrid containing a pyridine ring according to claim 3, wherein: In step (3), the base in the alkaline conditions is K2CO3, the catalyst is KI, the reaction molar ratio of the intermediate b to the base is 1:1.3-1.7, the reaction molar ratio of the intermediate b to the catalyst is 1:0.01-0.03, the reaction molar ratio of the intermediate b to 4-mercaptopyridine is 1:1.3-1.7, the reaction temperature is 45-60°C, and the reaction solvent is anhydrous acetone.

7. The method for preparing the amphiphilic osthole-quaternary ammonium salt hybrid containing a pyridine ring according to claim 3, characterized in that: In step (4), the preparation method of the intermediate d comprises the following steps: amine RH and bromoacetyl bromide undergo a substitution reaction under alkaline conditions to generate a small molecule peptide mimetic d: Wherein, R is the same as that described in claim 1 or 2.

8. The method for preparing the amphiphilic osthole-quaternary ammonium salt hybrid containing a pyridine ring according to claim 3, wherein: In step (4), the molar ratio of intermediate c to intermediate d is 1:1.5-1:3, the reaction temperature is 80-90°C, and the reaction solvent is anhydrous acetonitrile.

9. Use of the pyridine ring-containing amphiphilic osthole-quaternary ammonium salt hybrid according to claim 1 or 2 in the preparation of antibacterial drugs, characterized in that: The antibacterial drug can inhibit Staphylococcus aureus or methicillin-resistant Staphylococcus aureus.

Images