Coumarin derivatives containing thioether quinoline and synthesis method and application thereof

Abstract

The present invention relates to the technical field of organic synthesis, and provides a thioether quinoline-containing coumarin derivative and a synthesis method and application thereof. The thioether quinoline-containing coumarin derivative of the present invention has a structure as shown in Formula I. Compared with the prior art, the thioether quinoline-containing coumarin derivative of the present invention has excellent broad-spectrum bactericidal activity against plant pathogenic bacteria, the raw materials for preparation are easily available, and the synthesis steps are simple and practical, providing a favorable guide for the creation of natural bionic bactericides.

Description

Technical Field

[0001] The invention relates to the technical field of organic synthesis, and more specifically to coumarin derivatives containing thioether quinoline and a synthesis method and application thereof. Background Art

[0002] Bacterial diseases of crops caused by plant pathogenic bacteria have always been a global problem. Diseases can have a serious impact on crops, leading to reduced yields and lower quality, thus causing significant losses to agricultural production. For many countries, controlling these diseases is crucial, and a variety of comprehensive management measures need to be taken, including reasonable planting systems, the use of disease control agents, and the cultivation of disease-resistant varieties, in order to reduce the adverse effects of diseases on crop production.

[0003] At present, chemical control of bacterial diseases of crops is mainly adopted, but the long-term and large-scale use of chemical pesticides is prone to drug resistance and environmental risks. In addition, with global warming and changes in planting structure, the degree of damage of bacterial diseases of crops continues to increase. The existing control agents for bacterial diseases are mainly copper preparations, antibiotics and thiazoles; copper agents are broad-spectrum fungicides that are often used to control a variety of plant bacterial diseases. They inhibit the growth and reproduction of bacteria by releasing copper ions; antibiotics can be used to control specific bacterial diseases, such as streptomycin and tetracycline antibiotics. They work by interfering with bacterial protein synthesis or other biochemical processes; however, excessive use of copper agents or antibiotics may lead to soil copper accumulation or environmental pollution. Therefore, it is urgent to create new bactericides with novel structures for the prevention and control of bacterial diseases of crops. Summary of the invention

[0004] In view of this, the purpose of the present invention is to provide a thioether quinoline-containing coumarin derivative and a synthesis method and application thereof. The thioether quinoline-containing coumarin derivative of the present invention has excellent broad-spectrum bactericidal activity against plant pathogenic bacteria, the preparation raw materials are easily available, and the synthesis steps are simple and practical, providing a favorable guide for the creation of natural bionic bactericides.

[0005] In order to achieve the above object, the present invention adopts the following technical solutions:

[0006] A coumarin derivative containing thioether quinoline having a structure as shown in formula I,

[0007]

[0008] In Formula I, R 1 is selected from one of hydrogen, halogen, C1-C5 alkyl, C1-C2 haloalkyl, C1-C3 alkoxy, nitro or cyano; R 2is selected from one of hydrogen, halogen, C1-C5 alkyl, C1-C2 haloalkyl, C1-C3 alkoxy, nitro or cyano; n is 3 or 4; p is selected from an integer of 1-4; q is selected from an integer of 1-5.

[0009] Finding lead compounds from natural products and using them as probes to design and synthesize natural biomimetic pesticides is one of the effective ways to create new pesticides. The compound with the structure shown in Formula I of the present invention has a novel structure and a variety of modifiable sites, which meets the creation potential of lead compounds.

[0010] Preferably, the halogen is selected from one of fluorine, chlorine, bromine or iodine; the C1-C5 alkyl is selected from one of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl or neopentyl; the C1-C2 haloalkyl is selected from one of trifluoromethane, difluorodichloromethane, trichloromethane, difluoromethane, dichloromethane, monofluoromethane, 1,2-difluoroethane, 1,2-methylfluoroethane, 1,2-dichloroethane or 1,2-tetrachloroethane; the C1-C3 alkoxy is selected from one of methoxy, ethoxy or n-propoxy.

[0011] Preferably, in Formula I, R 1 is hydrogen, p is 4; R 2 One selected from hydrogen, fluorine, chlorine, bromine, methyl, methoxy and trifluoromethane.

[0012] The present invention also provides a method for synthesizing the coumarin derivatives containing thioether quinoline, comprising the following steps:

[0013] The compound represented by formula II, potassium carbonate, the compound represented by formula III and an organic solvent are mixed and reacted at room temperature to obtain a coumarin derivative containing thioether quinoline;

[0014]

[0015] In formula II, R 1 is selected from one of hydrogen, halogen, C1-C5 alkyl, C1-C2 haloalkyl, C1-C3 alkoxy, nitro or cyano; X is selected from one of fluorine, chlorine, bromine or iodine; n is 3 or 4; p is selected from an integer of 1-4;

[0016] In Formula III, R 2 is selected from one of hydrogen, halogen, C1-C5 alkyl, C1-C2 haloalkyl, C1-C3 alkoxy, nitro or cyano; q is selected from an integer of 1-5.

[0017] Preferably, the synthesis method of the coumarin derivative containing thioether quinoline comprises: taking the compound shown in formula III and potassium carbonate and dissolving them in DMF, adding the compound shown in formula II, reacting at room temperature, pouring the system into ice water, stirring continuously, precipitating solid, filtering, washing and drying, and purifying by column chromatography to obtain the coumarin derivative containing thioether quinoline.

[0018] Preferably, the method for preparing the compound represented by formula II comprises: reacting the compound represented by formula IV, X(CH 2 ) n X, triethylamine and an organic solvent are mixed and reacted at room temperature to obtain a compound shown in formula II;

[0019] In Formula IV, R 1 is selected from one of hydrogen, halogen, C1-C5 alkyl, C1-C2 haloalkyl, C1-C3 alkoxy, nitro or cyano; p is selected from an integer of 1-4; X(CH 2 ) n In X, X is selected from fluorine, chlorine, bromine or iodine; and n is 3 or 4.

[0020] Preferably, the compound represented by formula IV, X(CH 2 ) n The molar ratio of X to triethylamine is 1:(3-4):(1.5-2); the preparation method of the compound represented by formula II comprises: dissolving the compound represented by formula IV and triethylamine in DMF, adding X(CH 2 ) n X, after reacting at room temperature, pour the system into ice water and stir continuously to precipitate solid, filter out with suction, wash and dry, then add a mixed solvent and stir overnight, then filter out with suction to obtain a compound shown in formula II; the mixed solvent is petroleum ether: ethyl acetate = 3:1, V / V.

[0021] Preferably, the preparation method of the compound represented by formula IV comprises: mixing the compound represented by formula V, Michaelis acid, a metal catalyst and an organic solvent, and reacting them at room temperature to obtain the compound represented by formula IV;

[0022] In Formula V, R 1 is selected from one of hydrogen, halogen, C1-C5 alkyl, C1-C2 haloalkyl, C1-C3 alkoxy, nitro or cyano; p is selected from an integer of 1-4.

[0023] Preferably, the preparation method of the compound represented by formula IV comprises: dissolving the compound represented by formula V, Michaelis acid and N-bromosuccinimide (NBS) in ethanol and water, reacting at room temperature for 6-12 hours, and after the reaction is completed, adding ethanol, heating to reflux for 10-30 minutes, cooling and filtering, washing and drying to obtain the compound represented by formula IV; the molar ratio of the compound represented by formula V, Michaelis acid and NBS is 1:(1.1-1.3):(0.1-0.3).

[0024] Preferably, the preparation method of the compound represented by formula III comprises: mixing the compound represented by formula VI with anhydrous pyridine and phosphorus pentasulfide, and reacting to obtain the compound represented by formula III;

[0025] In Formula VI, R 2 is selected from one of hydrogen, halogen, C1-C5 alkyl, C1-C2 haloalkyl, C1-C3 alkoxy, nitro or cyano; q is selected from an integer of 1-5.

[0026] Preferably, the preparation method of the compound shown in formula III comprises: dissolving the compound shown in formula VI in anhydrous pyridine, adding phosphorus pentasulfide, heating and refluxing the reaction, pouring the system into ice water, precipitating solid, filtering by suction, collecting the filter cake and dissolving it in sodium hydroxide solution, adjusting the pH to neutral with glacial acetic acid, precipitating solid, filtering by suction, washing, collecting the filter cake and drying to obtain the compound shown in formula III; the molar ratio of the compound shown in formula VI to phosphorus pentasulfide is 1:(2-3).

[0027] Preferably, the preparation method of the compound represented by formula VI comprises: mixing and reacting the compound represented by formula VII with 1,4-dioxane to obtain the compound represented by formula VI;

[0028] In formula VII, R 2 is selected from one of hydrogen, halogen, C1-C5 alkyl, C1-C2 haloalkyl, C1-C3 alkoxy, nitro or cyano; q is selected from an integer of 1-5.

[0029] Preferably, the preparation method of the compound represented by formula VI comprises: dissolving the compound represented by formula VII and sodium hydroxide in 1,4-dioxane, heating and refluxing for 4-8 hours, removing the solvent, adding water to dissolve, adjusting the pH to neutral with hydrochloric acid, precipitating solid, filtering, washing and drying to obtain the compound represented by formula VI; the molar ratio of the compound represented by formula VII to sodium hydroxide is 1:(2-3).

[0030] Preferably, the preparation method of the compound represented by formula VII comprises: mixing the compound represented by formula VIII with o-aminoacetophenone, triethylamine and an organic solvent to obtain the compound represented by formula VII;

[0031] In Formula VIII, R 2 is selected from one of hydrogen, halogen, C1-C5 alkyl, C1-C2 haloalkyl, C1-C3 alkoxy, nitro or cyano; q is selected from an integer of 1-5.

[0032] Preferably, the preparation method of the compound represented by formula VII comprises: dissolving o-aminoacetophenone and triethylamine in dichloromethane, adding the compound represented by formula VIII, and reacting at room temperature for 2-6 hours. After the reaction is completed, adding an extractant for extraction, collecting the organic phase, desolventizing under reduced pressure, and recrystallizing to obtain the compound represented by formula VII; the molar ratio of o-aminoacetophenone, triethylamine and the compound represented by formula VIII is 1:1:1; and the extractant is a mixture of dichloromethane and sodium chloride solution.

[0033] The present invention also provides the use of the coumarin derivatives containing thioether quinoline in inhibiting bacterial pathogens of crops and / or preventing and controlling diseases caused by bacterial pathogens of crops.

[0034] Preferably, the bacterial pathogens include one or more of Xanthomonas, Pseudomonas, Pectobacterium, Ralstonia, Acidovorax, Dickie's, Corynebacterium or Agrobacterium, Colletotrichum panacicola. Preferably, the bacterial diseases of plants caused by the Xanthomonas bacteria include rice bacterial leaf blight, rice bacterial streak, citrus canker, mango black spot, cotton angular spot, cabbage black rot, pepper bacterial leaf spot or pepper scab; the bacterial diseases of plants caused by the Pseudomonas bacteria include rice bacterial brown spot, tomato bacterial spot disease, cucumber bacterial angular spot or kiwifruit canker; the bacterial diseases of plants caused by the Pectobacterium bacteria include potato soft rot, Chinese cabbage soft rot, bacterial soft rot of Solanaceae crops or Cucurbitaceae crops. Bacterial soft rot; plant bacterial diseases caused by the Ralstonia bacteria include tobacco bacterial wilt, potato bacterial wilt, pepper bacterial wilt or tomato bacterial wilt; plant bacterial diseases caused by the Acidovibacterium bacteria include watermelon bacterial fruit spot or melon bacterial fruit spot; plant bacterial diseases caused by the Dickie's bacteria include rice base rot or banana soft rot; plant bacterial diseases caused by the Corynebacterium bacteria include tomato canker or potato ring rot; plant bacterial diseases caused by the Agrobacterium bacteria include fruit tree root cancer.

[0035] Compared with the prior art, the present invention has the following beneficial effects:

[0036] (1) The present invention provides a thioether quinoline-containing coumarin derivative and a synthetic route thereof. The thioether quinoline-containing coumarin derivative has excellent broad-spectrum bactericidal activity against plant pathogenic bacteria. The raw materials for preparation are easily available, and the synthetic steps are simple and practical, thereby providing a favorable lead compound for the creation of a natural bionic bactericide.

[0037] (2) The test examples show that the coumarin derivatives containing thioether quinoline provided by the present invention have high bactericidal activity against Xanthomonas oryzae and Bacterial fruit spot of melons. The bactericidal activity of compound A9 against Bacterial fruit spot of melons is better than that of the control agent kasugamycin. In addition, compounds A9 and A35 also have strong bactericidal activity against Xanthomonas oryzae and Bacterial fruit spot of melons, and their toxicity is better than that of the lead compound 3-CCA. The EC of A9 against Xanthomonas oryzae and Bacterial fruit spot of melons is higher than that of the lead compound 3-CCA. 50 The values ​​were 11.05 and 8.05 μg / mL, respectively; the EC values ​​of compound A35 against Xanthomonas oryzae and Psoralea corylifolia were 50 The values ​​were 14.87 and 15.42 μg / mL respectively. The pot experiment showed that compound A35 had excellent protective and therapeutic effects on melon bacterial fruit spot, and the effect was better than the control agent thiophanate-methyl. BRIEF DESCRIPTION OF THE DRAWINGS

[0038] Figure 1 is the hydrogen nuclear magnetic resonance spectrum of compound A9 of the present invention;

[0039] Figure 2 is the carbon nuclear magnetic resonance spectrum of compound A9 of the present invention;

[0040] Figure 3 is a high-resolution mass spectrum of compound A9 of the present invention;

[0041] Figure 4 is the hydrogen nuclear magnetic resonance spectrum of compound A35 of the present invention;

[0042] Figure 5 is the carbon nuclear magnetic resonance spectrum of compound A35 of the present invention;

[0043] Figure 6 is the nuclear magnetic resonance fluorine spectrum of compound A35 of the present invention;

[0044] Figure 7 It is the high-resolution mass spectrum of compound A35 of the present invention. DETAILED DESCRIPTION

[0045] The technical solution of the present invention will be clearly and completely described below in conjunction with the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0046] In order to further illustrate the present invention, the following examples are used to explain it in detail. The raw materials used in the following examples and comparative examples of the present invention are all commercially available products.

[0047] Example 1

[0048] The synthesis method of the thioether-containing quinoline coumarin derivatives of this embodiment comprises the following steps:

[0049] (1) Preparation of Intermediate 1

[0050] Intermediate 1 was prepared according to the method reported in reference 1 (Yang Rui, Ma Yanni, Huang Ting, Jie Wei, Zhang Xia, Huang Guoshuang, Liu Xiaodong. Synthesis and antibacterial activity of 4-thioether quinoline compounds. Organic Chemistry, 2018, 38(08): 2143-2150). o-Aminoacetophenone (4.50 mL, 37 mmol), triethylamine (5.14 mL, 37 mmol), and 20 mL of dichloromethane were sequentially placed in a 100 mL round-bottom flask and stirred in an ice bath for about 5 min. Subsequently, a solution of benzoyl chloride (4.29 mL, 37 mmol) in dichloromethane (10 mL) was added dropwise using a constant pressure dropping funnel. After the addition was completed, the reaction was continued at room temperature for 3 h. The reaction was monitored by thin layer chromatography (TLC) until it was complete (petroleum ether: ethyl acetate = 5:1, V / V). After the reaction is completed, an appropriate amount of water is added for extraction, the organic phase is collected, the solvent is removed by rotation, and recrystallization is performed with a mixed solvent of petroleum ether and ethyl acetate to obtain colorless transparent crystals (intermediate 1) with a yield of 90%. The reaction route is as follows:

[0051]

[0052] (2) Preparation of Intermediate 2

[0053] Intermediate 2 was prepared according to the method reported in Reference 1. Intermediate 1 (4.00 g, 17 mmol) was added to a 100 mL round-bottom flask containing 1,4-dioxane (40 mL), and solid sodium hydroxide (2.01 g, 51 mmol) was added in batches. The temperature was slowly raised to 110°C and refluxed for 3 h. After the reaction was completed, the solvent was removed by rotation, and the residue was dispersed in 100 mL of distilled water. The pH of the solution was adjusted to neutral with 1 mol / L hydrochloric acid, and a large amount of yellow precipitate was precipitated. The filter cake was washed with water several times, and then washed several times with a mixed solution (dichloromethane: ethyl acetate = 1:1, V / V), and dried to obtain a yellow solid (intermediate 2). The yield was 85%. The reaction route is as follows:

[0054]

[0055] (3) Preparation of Intermediate 3

[0056] Prepare intermediate 3 according to the method reported in document 1. Take intermediate 2 (2.00g, 9mmol) in a 100mL round-bottom flask, add 30mL anhydrous pyridine, stir in an ice bath for 10min, slowly add phosphorus pentasulfide (4.02g, 18mmol) in batches, after the addition is complete, heat to 110°C and continue to react for 5h. After the reaction is completed, cool the system to room temperature and pour into 200mL ice water. A yellow precipitate is precipitated. Continue stirring for 30min. After the precipitate is completely precipitated, filter it with suction, collect the filter cake, and obtain a crude product. The crude product is completely dissolved in 100mL sodium hydroxide solution with a mass fraction of 10%, and then adjust the pH to neutral with glacial acetic acid. A large amount of yellow precipitate is precipitated again. Filter it under reduced pressure, wash it with water and petroleum ether several times, collect the filter cake and dry it to obtain a yellow solid (intermediate 3). Yield: 87%, the reaction route is as follows:

[0057]

[0058] (4) Preparation of intermediate 4

[0059] Intermediate 4 was prepared according to the method reported in Reference 2 (Ruan Hongli, Zhang Jingyuan, Sun Sai, Yang Ying, Zhu Xiaolei, Lv Chengwei. Synthesis of coumarin-3-carboxylic acid by reaction of salicylaldehyde and Michael's acid catalyzed by N-bromosuccinimide. Organic Chemistry, 2017, 37(08): 2139-2144.). Salicylaldehyde (8.70mL, 82mmol), Michael's acid (12.98g, 90mmol), N-bromosuccinimide (NBS) (2.19g, 12mmol), 164mL water and 82mL ethanol were added to a 500mL round-bottom flask in sequence, and the reaction was carried out at room temperature for 10h, and the reaction was monitored by TLC. After the reaction was completed, 82mL of 20% ethanol was added to the reaction system and stirred at 100℃ for 10min. After sufficient cooling, the filter cake was collected and dried to obtain white intermediate 4 with a yield of 80%. The reaction route is as follows:

[0060]

[0061] (5) Preparation of Intermediate 5

[0062] Intermediate 5 was prepared according to the method reported in reference 3 (Feng Peng, Tingting Liu, Xiao Cao, Qifan Wang, Fang Liu, Liwei Liu, Ming He; Wei Xue. Antiviral activities of novel myricetin derivatives containing 1,3,4-oxadiazole bisthioether. Chemistry & Biodiversity. 2022, 3 (19): e202100939). Intermediate 4 (10.00 g, 53 mmol) and triethylamine (14.62 mL, 105 mmol) were added to a round-bottom flask containing 50 mL of DMF, stirred at room temperature for 10 min, and then 1,3-dibromopropane (14.62 mL, 210 mmol) was added, and the reaction was continued at room temperature for 6 h. After the reaction, the reaction mixture was poured into 300 mL of ice water and stirred continuously to precipitate a light yellow solid. When no solid precipitated, the mixture was filtered and the filter cake was collected and dried at room temperature. A mixed solvent (petroleum ether: ethyl acetate = 3:1, V / V) was added and stirred overnight. The mixture was then filtered and the filter cake was collected and dried at room temperature to obtain intermediate 5 with a yield of 82%. The reaction route is shown below:

[0063]

[0064] (6) Preparation of target compound

[0065] Taking A1 as an example, intermediate 3 (0.48 g, 2 mmol), K2 CO 3 (0.56g, 4mmol) and 10mL DMF were added to a 50mL round-bottom flask in sequence. After stirring at room temperature for 10min, intermediate 5 (0.63g, 2mmol) was added and the reaction was continued at room temperature for 5h. The reaction was monitored by TLC (petroleum ether: ethyl acetate = 3:1, V / V). After the reaction was completed, the reaction system was poured into 100mL ice water and stirred continuously until solids precipitated. When no solids precipitated, the crude product was filtered to obtain the crude product. The crude product was further purified by column chromatography (petroleum ether: ethyl acetate = 5:1, V / V) to obtain the target compound A1 as a white solid with a yield of 52%. The synthesis method of A37-A38 was carried out with reference to A1, and the reaction route is as follows:

[0066]

[0067]

[0068] Example 2

[0069] In this example, the structures of the compounds A1-A38 prepared in Example 1 were characterized, and the results were as follows:

[0070] 3-((2-phenylquinolin-4-yl)thio)propyl 2-oxo-2H-chromene-3-carboxylate(A1)White solid, mp123.2-124.0℃, yield 52%; 1 H NMR(400MHz,Chloroform-d)δ8.49(s,1H,Ph-H),8.16-8.11(m,2H,Ph-H),8.10(dd,J=5.2,3.4Hz,2H,Ph-H),7.74-7.70(m,2H,Ph-H),7.66(m,J =8.6,7.4,1.6Hz,1H,Ph-H),7.56-7.51(m,2H,Ph-H),7.46(dd,J=10.4,4.7Hz,2H,Ph-H),7.38-7.30(m,3H,Ph-H),4.54(t,J=6.0Hz,2H,-COO-CH 2 CH 2 CH 2 -S-),3.43(t,J=7.2Hz,2H,-COO-CH 2 CH 2 CH 2 -S-), 2.35-2.28(m,2H,-COO-CH 2 CH 2 CH2 -S-). 13 CNMR(125MHz,Chloroform-d)δ163.42(s),156.76(s),155.30(s),149.19(s),147.69(s),147.22(s),139.83(s),134.63(s),130.35(s),130.07(s),129.70(s),128.88(s),127.74(s),126.25(s),125.69(s),124.97(s),123.49(s),117.93(d,J=18.0Hz),116.89(s),114.53(s),64.25(s),27.78(s).HRMS(ESI)calcd for C 28 H 22 NO 4 S[M+H] + :468.12641,found468.12572.

[0071] 4-((2-phenylquinolin-4-yl)thio)butyl 2-oxo-2H-chromene-3-carboxylate(A2)White solid,m.p.113.6-114.6℃,yield 13%; 1 H NMR(400MHz,Chloroform-d)δ8.44(s,1H,Ph-H),8.15-8.08(m,4H,Ph-H),7.71(m,J=8.4,6.9,1.4Hz,1H,Ph-H),7.66-7.61(m,2H,Ph-H),7.54-7.49(m,4H,Ph-H),7.46-7.42(m,1H,Ph-H),7.34-7.28(m,2H,Ph-H),4.44(t,J=5.9Hz,2H,-COO-CH 2 CH 2 CH 2 CH 2 -S-),3.30(t,J=6.7Hz,2H,-COO-CH 2 CH 2 CH 2 CH 2 -S-),2.06(dt,J=6.5,3.3Hz,4H,-COO-CH 2 CH 2 CH 2 CH 2 -S-). 13C NMR(101MHz,Chloroform-d)δ162.22(s),155.56(d,J=1.4Hz),154.16(s),147.79(s),146.56(d,J=3.2Hz),138.77(s),133.40(s),129.24(s),128.89(s),128.41(d,J=17.4Hz),127.82(s),126.56(s),125.06(s),124.58(s),123.80(s),122.38(s),117.02(s),116.75(s),115.76(s),113.32(s),64.27(s),29.91(s),26.75(s),23.98(s).HRMS(ESI)calcd for C 29 H 24 NO 4 S[M+H] + :482.142055,found 482.14191.

[0072] 3-((2-(2-methoxyphenyl)quinolin-4-yl)thio)propyl 2-oxo-2H-chromene-3-carboxylate(A3)White solid,m.p.138.9-139.9℃,yield 69%; 1 H NMR(400MHz,Chloroform-d)δ8.46(s,1H,Ph-H),8.14-8.11(m,2H,Ph-H),7.81(dd,J=7.6,1.8Hz,1H,Ph-H),7.76(s,1H,Ph-H),7.72-7.68(m,1H,Ph-H),7.66-7.62(m,1H,Ph-H),7.54-7.50(m,2H,Ph-H),7.35-7.28(m,3H,Ph-H),7.06(td,J=7.5,0.9Hz,1H,Ph-H),6.96(d,J=8.1Hz,1H,Ph-H),4.53(t,J=6.0Hz,2H,-COO-CH 2 CH 2 CH 2 -S-),3.84(s,3H,Ph-OCH 3 ),3.34(t,J=7.1Hz,2H,-COO-CH 2 CH 2 CH 2-S-),2.35-2.29(m,2H,-COO-CH 2 CH 2 CH 2 -S-). 13 C NMR(101MHz,Chloroform-d)δ162.15(s),156.03(s),155.50(s),154.98(s),154.20(s),147.91(s),146.64(s),144.01(s),133.46(s),130.35(s),129.34(s),129.14(s),128.68-128.42(m),125.04(s),124.49(s),123.81(s),122.30(s),120.24(s),117.64(s),116.82(d,J=9.8Hz),115.76(s),110.41(s),63.08(s),54.74(s),26.53(d,J=6.8Hz).HRMS(ESI)calcdfor C 29 H 24 NO 5 S[M+H] + :498.13697,found 498.13677.

[0073] 4-((2-(2-methoxyphenyl)quinolin-4-yl)thio)butyl 2-oxo-2H-chromene-3-carboxylate(A4)White solid,m.p.119.1-120.7℃,yield 82%; 1 H NMR(400MHz,Chloroform-d)δ8.42(s,1H,Ph-H),8.14-8.09(m,2H,Ph-H),7.81(dd,J=7.6,1.8Hz,1H,Ph-H),7.72-7.66(m,2H,Ph-H),7.63(m,J=8.6,7.4,1.6Hz,1H,Ph-H),7.54-7.48(m,2H,Ph-H),7.39(m,J=8.3,7.5,1.8Hz,1H,Ph-H),7.35-7.28(m,2H,Ph-H),7.06(ddd,J=19.9,13.2,4.6Hz,2H,Ph-H),4.42(t,J=5.9Hz,2H,-COO-CH 2 CH 2 CH 2 CH 2-S-),3.86(s,3H,Ph-OCH 3 ),3.22(t,J=6.7Hz,2H,-COO-CH 2 CH 2 CH 2 CH 2 -S-),2.03(dd,J=5.9,2.5Hz,4H,-COO-CH 2 CH 2 CH 2 CH 2 -S-). 13 C NMR(101MHz,Chloroform-d)δ162.13(s),156.06(s),155.58(s),154.93(s),154.15(s),147.72(s),146.59(s),144.51(s),133.39(s),130.38(s),129.37(s),129.14(s),128.52(t,J=5.2Hz),124.96(s),124.45(s),123.80(s),122.30(s),120.30(s),117.46(s),116.97(s),116.76(s),115.74(s),110.54(s),64.20(s),54.78(s),29.66(s),26.69(s),23.87(s).HRMS(ESI)calcd for C 30 H 26 NO 5 S[M+H] + :512.152620,found 512.15216.

[0074] 3-((2-(o-tolyl)quinolin-4-yl)thio)propyl 2-oxo-2H-chromene-3-carboxylate(A5)White solid,m.p.91.2-92.3℃,yield 54%; 1H NMR(400MHz,Chloroform-d)δ8.46(s,1H,Ph-H),8.18-8.09(m,2H,Ph-H),7.69(m,2H,Ph-H),7.57-7.53(m,2H,Ph-H),7.45(d,J=7.6Hz,1H,Ph-H),7.39(s,1H,Ph-H),7.37-7.31(m,2H,Ph-H),7.23-7.14(m,3H,Ph-H),4.51(t,J=5.9Hz,2H,-COO-CH 2 CH 2 CH 2 -S-),3.36(t,J=7.1Hz,2H,-COO-CH 2 CH 2 CH 2 -S-),2.38(s,3H,Ph-OCH 3 ),2.31-2.25(m,2H,-COO-CH 2 CH 2 CH 2 -S-). 13 CNMR(101MHz,Chloroform-d)δ162.25(s),158.31(s),155.47(s),154.25(s),147.94(s),146.17(s),145.61(s),139.70(s),134.94(s),133.46(s),129.69(s),129.12(s),128.89(s),128.51(d,J=7.4Hz),127.39(s),125.21(s),124.87(s),124.12(s),123.82(s),122.32(s),116.86(d,J=8.1Hz),116.10(s),115.81(s),63.02(s),26.82(s),26.40(s),19.30(s).HRMS(ESI)calcd for C 29 H 24 NO 4 S[M+H] + :482.14206,found 482.14224.

[0075] 4-((2-(o-tolyl)quinolin-4-yl)thio)butyl 2-oxo-2H-chromene-3-carboxylate(A6)Whitesolid,m.p.129.0-130.5℃,yield 89%;1 H NMR(400MHz,Chloroform-d)δ8.46(s,1H,Ph-H),8.12(ddd,J=25.3,8.4,0.8Hz,2H,Ph-H),7.71(ddd,J=8.4,6.9,1.4Hz,1H,Ph-H),7.66-7.62(m,1H,Ph-H),7.57-7.51(m,2H,Ph-H),7.48-7.45(m,1H,Ph-H),7.35-7.27(m,6H,Ph-H),4.42(t,J=5.9Hz,2H,-COO-CH 2 CH 2 CH 2 CH 2 -S-),3.22(t,J=6.7Hz,2H,-COO-CH 2 CH 2 CH 2 CH 2 -S-),2.39(s,3H,Ph-OCH 3 ),2.03(dd,J=6.4,2.9Hz,4H,-COO-CH 2 CH 2 CH 2 CH 2 -S-). 13 C NMR(101MHz,Chloroform-d)δ162.22(s),158.25(s),155.53(s),154.18(s),147.80(s),146.11(s),139.78(s),134.91(s),133.41(s),129.81(s),129.10(s),128.85(s),128.47(d,J=3.1Hz),127.52(s),125.07(d,J=15.5Hz),124.07(s),123.81(s),122.32(s),117.02(s),116.78(s),116.09(s),115.78(s),64.25(s),29.74(s),26.72(s),23.95(s),19.31(s).HRMS(ESI)calcd for C 30 H 26 NO 4 S[M+H] + :496.15771,found 496.15711.

[0076] 3-((2-(2-bromophenyl)quinolin-4-yl)thio)propyl 2-oxo-2H-chromene-3-carboxylate(A7)White solid,m.p.110.2-111.9℃,yield 68%; 1 H NMR(400MHz,Chloroform-d)δ8.49(s,1H,Ph-H),8.16(dd,J=8.4,0.9Hz,1H,Ph-H),8.11(dd,J=8.4,0.6Hz,1H,Ph-H),7.73(ddd,J=8.4,6.9,1.4Hz,1H,Ph-H),7.68-7.62(m,2H,Ph-H),7.59-7.54(m,4H,Ph-H),7.39(td,J=7.5,1.2Hz,1H,Ph-H),7.36-7.31(m,2H,Ph-H),7.17-7.13(m,1H,Ph-H),4.53(t,J=5.9Hz,2H,-COO-CH 2 CH 2 CH 2 -S-),3.38(t,J=7.2Hz,2H,-COO-CH 2 CH 2 CH 2 -S-),2.35-2.28(m,2H,-COO-CH 2 CH 2 CH 2 -S-). 13 C NMR(101MHz,Chloroform-d)δ163.21(s),157.70(s),156.52(s),155.25(s),149.02(s),147.24(s),146.27(s),141.60(s),134.53(s),133.09(s),131.63(s),130.23(s),130.00(d,J=4.0Hz),129.63(s),127.75(s),126.62(s),125.55(s),124.89(s),123.44(s),121.76(s),117.88(d,J=9.0Hz),117.55(s),116.84(s),64.08(s),27.92(s),27.43(s).HRMS(ESI)calcd forC 30 H 26 NO 4 S[M+H] +:546.03692,found 546.03575.

[0077] 4-((2-(2-bromophenyl)quinolin-4-yl)thio)butyl 2-oxo-2H-chromene-3-carboxylate(A8)White solid,m.p.108.6-109.4℃,yield 21%; 1 H NMR(400MHz,Chloroform-d)δ8.46(s,1H,Ph-H),8.16(dd,J=8.4,0.8Hz,1H,Ph-H),8.10(dd,J=8.4,0.5Hz,1H,Ph-H),7.72(ddd,J=8.4,6.9,1.4Hz,1H,Ph-H),7.67-7.62(m,3H,Ph-H),7.59-7.55(m,1H,Ph-H),7.52(dd,J=7.8,1.5Hz,1H,Ph-H),7.48(s,1H,Ph-H),7.42(td,J=7.5,1.1Hz,1H,Ph-H),7.34(d,J=8.3Hz,1H,Ph-H),7.29(ddd,J=13.7,7.1,4.2Hz,3H,Ph-H),7.26(s,1H,Ph-H),4.42(t,J=5.8Hz,2H,-COO-CH 2 CH 2 CH 2 CH 2 -S-),3.24(t,J=6.7Hz,2H,-COO-CH 2 CH 2 CH 2 CH 2 -S-),2.03(dd,J=6.4,2.9Hz,4H,-COO-CH 2 CH 2 CH 2 CH 2 -S-). 13C NMR(101MHz,Chloroform-d)δ162.14(s),156.57(s),155.59(s),154.13(s),147.85(s),146.12(s),145.71(s),140.55(s),133.43(s),132.20(s),130.56(s),129.32-128.79(m),128.51(s),126.76(s),125.51(s),124.42(s),123.83(s),122.39(s),120.71(s),116.82(d,J=16.2Hz),116.42(s),115.76(s),64.29(s),29.62(s),26.71(s),24.12(s).HRMS(ESI)calcd for C 29 H 23 BrNO 4 S[M+H] + :560.05257,found560.05251.

[0078] 3-((2-(2-chlorophenyl)quinolin-4-yl)thio)propyl 2-oxo-2H-chromene-3-carboxylate(A9)White solid,m.p.116.9-118.0℃,yield 26%; 1 H NMR(400MHz,Chloroform-d)δ8.50(s,1H,Ph-H),8.16(dd,J=8.4,0.8Hz,1H,Ph-H),8.12(dd,J=8.4,0.5Hz,1H,Ph-H),7.73(ddd,J=8.4,6.9,1.3Hz,1H,Ph-H),7.70-7.64(m,2H,Ph-H),7.60-7.55(m,3H,Ph-H),7.34(dt,J=8.6,4.2Hz,4H,Ph-H),7.26-7.18(m,1H,Ph-H),4.53(t,J=5.9Hz,2H,-COO-CH 2 CH 2 CH 2 -S-),3.38(t,J=7.2Hz,2H,-COO-CH 2 CH 2 CH 2 -S-),2.34-2.27(m,2H,-COO-CH 2 CH 2 CH2 -S-). 13 C NMR(125MHz,Chloroform-d)δ163.26(s),156.62(s),156.43(s),155.30(s),149.10(s), 147.41(s),146.37(s),139.63(s),134.61(s),132.25(s),131.79(s),130.29(s),130.1 7-129.77(m),129.70(s),127.31(s),126.69(s),125.60(s),124.97(s),123.50(s),117 .92(d,J=9.8Hz),117.62(s),116.90(s),64.16(s),27.85(s),27.48(s).HRMS(ESI)calcd for C 28 H 21 ClNO 4 S[M+H] + :502.08743,found 502.08725.

[0079] The H NMR spectrum of compound A9 is shown in Figure 1 As shown, the carbon NMR spectrum is as follows Figure 2 As shown in the high-resolution mass spectrum Figure 3 shown.

[0080] 4-((2-(2-chlorophenyl)quinolin-4-yl)thio)butyl 2-oxo-2H-chromene-3-carboxylate(A10)White solid, mp122.3-124.0℃, yield 35%; 1 H NMR(400MHz,Chloroform-d)δ8.46(s,1H,Ph-H),8.15(dd,J=8.4,0.9Hz,1H,Ph-H) ,8.10(dd,J=8.4,0.6Hz,1H,Ph-H),7.75-7.67(m,2H,Ph-H),7.64(ddd,J=8.6,7.4 ,1.6Hz,1H,Ph-H),7.57(ddd,J=8.2,6.9,1.2Hz,1H,Ph-H),7.54-7.50(m,2H,Ph-H ),7.49-7.44(m,1H,Ph-H),7.41-7.29(m,4H,Ph-H),4.42(t,J=5.7Hz,2H,-COO-CH 2 CH 2 CH2 CH 2 -S-),3.24(t,J=6.6Hz,2H,-COO-CH 2 CH 2 CH 2 CH 2 -S-),2.08-1.99(m,4H,-COO-CH 2 CH 2 CH 2 CH 2 -S-). 13 C NMR(125MHz,Chloroform-d)(126MHz,)δ163.24(s),156.71(s),156.36(s),155.24(s),148.93(s),147.36(s),146.87(s),139.64(s),134.54(s),132.26(s),131.76(s),130.62-129.78(m),129.62(s),127.34(s),126.62(s),125.55(s),124.94(s),123.50(s),117.94(d,J=20.7Hz),117.60(s),116.86(s),65.40(s),30.76(s),27.83(s),25.17(s).HRMS(ESI)calcd for C 29 H 23 ClNO 4 S[M+H] + :516.10308,found 516.10234.

[0081] 3-((2-(2-fluorophenyl)quinolin-4-yl)thio)propyl 2-oxo-2H-chromene-3-carboxylate(A11)White solid,m.p.117.8-118.5℃,yield 24%; 1H NMR(400MHz,Chloroform-d)δ8.51(s,1H,Ph-H),8.13(td,J=8.5,0.7Hz,2H,Ph-H),8.05(td,J=7.8,1.9Hz,1H,Ph-H),7.75-7.70(m,2H,Ph-H),7.65(ddd,J=8.7,7.4,1.6Hz,1H,Ph-H),7.58-7.53(m,2H,Ph-H),7.36-7.30(m,3H,Ph-H),7.27(td,J=7.5,1.3Hz,1H,Ph-H),7.08(ddd,J=11.2,8.1,1.2Hz,1H,Ph-H),4.54(t,J=6.0Hz,2H,-COO-CH 2 CH 2 CH 2 -S-),3.39(t,J=7.1Hz,2H,-COO-CH 2 CH 2 CH 2 -S-),2.35-2.28(m,2H,-COO-CH 2 CH 2 CH 2 -S-). 13 C NMR(101MHz,Chloroform-d)δ162.13(s),159.53(d,J=249.2Hz),155.56(s),154.18(s),152.01(d,J=1.9Hz),147.94(s),146.54(s),145.58(s),133.48(s),130.47(d,J=3.0Hz),129.79(d,J=8.5Hz),129.21(s),128.92(s),128.56(s),126.83(d,J=11.9Hz),125.44(s),124.55(s),123.84(s),123.72(d,J=3.5Hz),122.34(s),116.83(d,J=14.5Hz),116.23(d,J=8.2Hz),115.78(s),115.08(d,J=22.8Hz),63.10(s),26.48(d,J=2.4Hz). 19 F NMR(377MHz,Chloroform-d)δ-117.11(s).HRMS(ESI)calcd for C 28 H 21 FNO 4 S[M+H] +:486.11698,found 486.11649.

[0082] 4-((2-(2-fluorophenyl)quinolin-4-yl)thio)butyl 2-oxo-2H-chromene-3-carboxylate(A12)White solid,m.p.110.8-112.1℃,yield 34%; 1 H NMR(400MHz,Chloroform-d)δ8.46(s,1H,Ph-H),8.15-8.09(m,2H,Ph-H),8.05(td,J=7.8,1.8Hz,1H,Ph-H),7.72(ddd,J=8.3,6.9,1.3Hz,1H,Ph-H),7.63(ddd,J=9.8,6.6,1.9Hz,2H,Ph-H),7.55(ddd,J=8.2,7.0,1.2Hz,1H,Ph-H),7.50(dd,J=7.8,1.4Hz,1H,Ph-H),7.41(tdd,J=7.1,5.0,1.8Hz,1H,Ph-H),7.34-7.27(m,3H,Ph-H),7.16(ddd,J=11.3,8.2,0.9Hz,1H,Ph-H),4.43(t,J=5.7Hz,2H,-COO-CH 2 CH 2 CH 2 CH 2 -S-),3.25(t,J=6.6Hz,2H,-COO-CH 2 CH 2 CH 2 CH 2 -S-),2.04(dt,J=6.1,3.2Hz,4H,-COO-CH 2 CH 2 CH 2 CH 2 -S-). 13C NMR(101MHz,Chloroform-d)δ162.07(s),159.57(d,J=249.1Hz),155.61(s),154.11(s),151.93(d,J=1.9Hz),147.77(s),146.48(s),146.09(s),133.40(s),130.44(d,J=3.0Hz),129.85(d,J=8.5Hz),129.18(s),128.87(s),128.49(s),126.82(d,J=11.9Hz),125.36(s),124.49(s),123.79(s),123.74(d,J=3.4Hz),122.33(s),116.81(d,J=18.0Hz),116.07(d,J=8.5Hz),115.74(s),115.20(d,J=22.8Hz),64.27(s),29.59(s),26.74(s),23.89(s). 19 FNMR(471MHz,Chloroform-d)δ-117.00(s).HRMS(ESI)calcd for C 29 H 23 FNO 4 S[M+H] + :500.13263,found 500.13254.

[0083] 3-((2-(2,4-dichlorophenyl)quinolin-4-yl)thio)propyl 2-oxo-2H-chromene-3-carboxylate(A13)White solid,m.p.120.4-122.4℃,yield 43%; 1 H NMR(400MHz,Chloroform-d)δ8.51(s,1H,Ph-H),8.16(dd,J=8.4,0.8Hz,1H,Ph-H),8.10(dd,J=8.4,0.5Hz,1H,Ph-H),7.74(ddd,J=8.4,6.9,1.3Hz,1H,Ph-H),7.69-7.64(m,2H,Ph-H),7.60-7.56(m,3H,Ph-H),7.38-7.32(m,4H,Ph-H),4.52(t,J=5.9Hz,2H,-COO-CH 2 CH 2 CH 2 -S-),3.39(t,J=7.2Hz,2H,-COO-CH2 CH 2 CH 2 -S-),2.33-2.26(m,2H,-COO-CH 2 CH 2 CH 2 -S-). 13 CNMR(101MHz,Chloroform-d)δ163.32(s),156.52(s),155.28(d,J=6.9Hz),149.12(s),147.33(s),146.65(s),138.13(s),135.16(s),134.64(s),132.99(s),132.67(s),130.16(d,J=7.5Hz),129.65(d,J=6.3Hz),127.57(s),126.77(s),125.57(s),124.95(s),123.45(s),117.83(d,J=12.4Hz),117.24(s),116.91(s),64.06(s),27.91(s),27.38(s).HRMS(ESI)calcd for C 28 H 20 Cl 2 NO 4 S[M+H] + :536.04846,found 536.04828.

[0084] 4-((2-(2,4-dichlorophenyl)quinolin-4-yl)thio)butyl 2-oxo-2H-chromene-3-carboxylate(A14)White solid,m.p.132.9-134.8℃,yield 17%; 1 H NMR(400MHz,Chloroform-d)δ8.48(s,1H,Ph-H),8.15(dd,J=8.3,0.8Hz,1H,Ph-H),8.08(d,J=8.0Hz,1H,Ph-H),7.72(ddd,J=8.3,7.0,1.3Hz,1H,Ph-H),7.68-7.62(m,2H,Ph-H),7.59-7.53(m,2H,Ph-H),7.51-7.46(m,2H,Ph-H),7.37-7.29(m,3H,Ph-H),4.42(t,J=5.7Hz,2H,-COO-CH 2 CH 2 CH 2 CH2 -S-),3.24(t,J=6.7Hz,2H,-COO-CH 2 CH 2 CH 2 CH 2 -S-),2.09-1.97(m,4H,-COO-CH 2 CH 2 CH 2 CH 2 -S-). 13 C NMR(101MHz,Chloroform-d)δ162.22(s),155.56(s),154.13(d,J=1.4Hz),147.93(s),146.16(d,J=9.7Hz),137.07(s),134.16(s),133.48(s),131.89(s),131.58(s),129.07(d,J=6.7Hz),128.80(s),128.51(s),126.58(s),125.66(s),124.43(s),123.84(s),122.39(s),116.80(d,J=14.7Hz),116.13(s),115.76(s),64.33(s),29.61(s),26.69(s),24.09(s).HRMS(ESI)calcd for C 29 H 22 Cl 2 NO 4 S[M+H] + :550.06411,found 550.06379.

[0085] 3-((2-(3,5-dichlorophenyl)quinolin-4-yl)thio)propyl 2-oxo-2H-chromene-3-carboxylate(A15)White solid,m.p.173.5-174.3℃,yield 22%; 1H NMR(400MHz,Chloroform-d)δ8.51(s,1H,Ph-H),8.13(ddd,J=17.8,8.4,0.7Hz,2H,Ph-H),8.00(d,J=1.9Hz,2H,Ph-H),7.76-7.71(m,2H,Ph-H),7.69-7.64(m,1H,Ph-H),7.58-7.53(m,2H,Ph-H),7.33(dd,J=11.2,4.4Hz,2H,Ph-H),7.25(d,J=1.9Hz,1H,Ph-H),4.53(t,J=5.9Hz,2H,-COO-CH 2 CH 2 CH 2 -S-),3.49(t,J=7.3Hz,2H,-COO-CH 2 CH 2 CH 2 -S-),2.33(dt,J=12.7,6.4Hz,2H,-COO-CH 2 CH 2 CH 2 -S-). 13 C NMR(101MHz,Chloroform-d)δ162.54(s),155.68(s),154.20(s),152.75(s),148.24(s),147.14(s),146.31(s),141.66(s),134.25(s),133.55(s),129.29(s),128.54(s),127.92(s),125.72(s),125.13(s),124.84(s),123.87(s),122.41(s),116.82(d,J=18.2Hz),115.79(s),112.68(s),63.15(s),26.74(s),26.49(s).HRMS(ESI)calcd for C 28 H 20 Cl 2 NO 4 S[M+H] + :536.048461,found 536.04857.

[0086] 4-((2-(3-methoxyphenyl)quinolin-4-yl)thio)butyl 2-oxo-2H-chromene-3-carboxylate(A16)White solid,m.p.86.0-87.8℃,yield10%;1 H NMR(400MHz,Chloroform-d)δ8.43(s,1H,Ph-H),8.15-8.09(m,2H,Ph-H),7.70(ddd,J=5.9,5.4,1.4Hz,2H,Ph-H),7.63(qd,J=5.5,1.6Hz,3H,Ph-H),7.54-7.48(m,2H,Ph-H),7.41(t,J=7.9Hz,1H,Ph-H),7.34-7.28(m,2H,Ph-H),6.99(dd,J=8.0,2.3Hz,1H,Ph-H),4.44(t,J=5.7Hz,2H,-COO-CH 2 CH 2 CH 2 CH 2 -S-),3.91(s,3H,Ph-OCH 3 ),3.29(t,J=6.6Hz,2H,-COO-CH 2 CH 2 CH 2 CH 2 -S-),2.05(dt,J=6.3,3.3Hz,4H,-COO-CH 2 CH 2 CH 2 CH 2 -S-). 13 C NMR(101MHz,Chloroform-d)δ162.18(s),159.04(s),155.56(s),155.31(s),154.15(s),147.75(s),146.52(d,J=10.8Hz),140.25(s),133.37(s),129.25(s),128.85(d,J=9.7Hz),128.50(s),125.11(s),124.66(s),123.78(s),122.38(s),118.94(s),117.00(s),116.75(s),115.74(s),114.19(s),113.38(s),111.88(s),64.24(s),54.40(s),29.90(s),26.76(s),23.97(s).HRMS(ESI)calcd for C 30 H 26 NO 5 S[M+H] + :512.15262,found 512.15207.

[0087] 3-((2-(m-tolyl)quinolin-4-yl)thio)propyl 2-oxo-2H-chromene-3-carboxylate(A17)Whitesolid,m.p.98.0-100.0℃,yield 54%; 1 H NMR(400MHz,Chloroform-d)δ8.48(s,1H,Ph-H),8.14(dd,J=12.2,4.6Hz,2H,Ph-H),7.93(s,1H,Ph-H),7.84(d,J=7.7Hz,1H,Ph-H),7.74-7.69(m,2H,Ph-H),7.65(ddd,J=8.6,7.4,1.6Hz,1H,Ph-H),7.55-7.50(m,2H,Ph-H),7.32(ddd,J=10.4,5.3,2.9Hz,3H,Ph-H),7.17(d,J=7.5Hz,1H,Ph-H),4.53(t,J=6.0Hz,2H,-COO-CH 2 CH 2 CH 2 -S-),3.43(t,J=7.1Hz,2H,-COO-CH 2 CH 2 CH 2 -S-),2.43(s,3H,Ph-OCH 3 ),2.35-2.28(m,2H,-COO-CH 2 CH 2 CH 2 -S-). 13 C NMR(101MHz,Chloroform-d)δ162.29(s),155.88(s),155.59(s),154.19(s),148.05(s),146.56(s),145.99(s),138.69(s),137.47(s),133.49(s),129.37-128.82(m),128.56(s),127.62(s),127.28(s),125.06(s),124.58(s),123.78(d,J=10.2Hz),122.38(s),116.81(d,J=13.1Hz),115.75(s),113.66(s),63.09(s),26.67(d,J=4.0Hz),20.53(s).HRMS(ESI)calcd for C 29 H 24 NO 4 S[M+H]+ :482.14206,found 482.14151.

[0088] 4-((2-(m-tolyl)quinolin-4-yl)thio)butyl 2-oxo-2H-chromene-3-carboxylate(A18)Whitesolid,m.p.89.8-90.9℃,yield 71%; 1 H NMR(400MHz,Chloroform-d)δ8.43(s,1H,Ph-H),8.15-8.09(m,2H,Ph-H),7.93(s,1H,Ph-H),7.84(d,J=7.7Hz,1H,Ph-H),7.70(ddd,J=8.3,6.9,1.4Hz,1H,Ph-H),7.65-7.60(m,2H,Ph-H),7.53-7.47(m,2H,Ph-H),7.39(t,J=7.6Hz,1H,Ph-H),7.33-7.24(m,3H,Ph-H),7.26(s,1H,Ph-H),4.44(t,J=5.8Hz,2H,-COO-CH 2 CH 2 CH 2 CH 2 -S-),3.29(t,J=6.7Hz,2H,-COO-CH 2 CH 2 CH 2 CH 2 -S-),2.46(s,3H,Ph-OCH 3 ),2.05(dt,J=6.3,3.2Hz,4H,-COO-CH 2 CH 2 CH 2 CH 2 -S-). 13C NMR(101MHz,Chloroform-d)δ163.21(s),156.69(d,J=18.2Hz),155.18(s),148.79(s),147.54(d,J=7.9Hz),139.76(s),138.57(s),134.41(s),130.20(d,J=7.4Hz),129.89(s),129.53(s),128.74(s),128.26(s),126.04(s),125.61(s),124.75(d,J=13.1Hz),123.42(s),118.03(s),117.78(s),116.77(s),114.50(s),65.28(s),30.95(s),27.78(s),24.99(s),21.61(s).HRMS(ESI)calcd for C 30 H 26 NO 4 S[M+H] + :496.15771,found 496.15757.

[0089] 4-((2-(3,5-dichlorophenyl)quinolin-4-yl)thio)butyl 2-oxo-2H-chromene-3-carboxylate(A19)White solid,m.p.130.8-132.8℃,yield 10%; 1 H NMR(400MHz,Chloroform-d)δ8.47(s,1H,Ph-H),8.14-8.06(m,2H,Ph-H),8.00(d,J=1.9Hz,1H,Ph-H),7.72(ddd,J=8.3,6.9,1.3Hz,1H,Ph-H),7.64(td,J=3.4,1.7Hz,1H,Ph-H),7.56-7.49(m,3H,Ph-H),7.41-7.28(m,4H,Ph-H),4.45(t,J=5.6Hz,2H,-COO-CH 2 CH 2 CH 2 CH 2 -S-),3.32(t,J=6.6Hz,2H,-COO-CH 2 CH 2 CH 2 CH 2 -S-),2.09-2.03(m,4H,-COO-CH 2 CH2 CH 2 CH 2 -S-). 13 C NMR(101MHz,Chloroform-d)δ163.36(s),156.65(s),155.18(s),153.57(s),149.01(s),148.72(s),147.26(s),142.65(s),135.44(s),134.52(s),130.33(s),129.53(s),129.10(s),126.75(s),126.06(s),125.83(s),124.88(s),123.46(s),117.95(s),117.75(s),116.82(s),113.54(s),65.39(s),30.97(s),27.74(s),24.97(s).HRMS(ESI)calcd forC 29 H 22 Cl 2 NO 4 S[M+H] + :550.06411,found 550.06440.

[0090] 4-((2-(3-bromophenyl)quinolin-4-yl)thio)butyl 2-oxo-2H-chromene-3-carboxylate(A20)White solid,m.p.132.0-133.8℃,yield 30%; 1 H NMR(400MHz,Chloroform-d)δ8.45(s,1H,Ph-H),8.28(t,J=1.8Hz,1H,Ph-H),8.11(ddd,J=15.8,8.4,0.7Hz,2H,Ph-H),8.02-7.98(m,1H,Ph-H),7.72(ddd,J=8.4,6.9,1.4Hz,1H,Ph-H),7.63(ddd,J=8.7,7.3,1.6Hz,1H,Ph-H),7.59(s,1H,Ph-H),7.57-7.48(m,3H,Ph-H),7.37(t,J=7.9Hz,1H,Ph-H),7.33-7.28(m,2H,Ph-H),4.44(t,J=5.8Hz,2H,-COO-CH 2 CH 2 CH 2 CH 2-S-),3.30(t,J=6.7Hz,2H,-COO-CH 2 CH 2 CH 2 CH 2 -S-),2.06(dt,J=6.1,3.1Hz,4H,-COO-CH 2 CH 2 CH 2 CH 2 -S-). 13 C NMR(101MHz,Chloroform-d)δ162.23(s),155.59(s),154.11(s),153.82(s),147.90(s),147.14(s),146.33(s),140.73(s),133.45(s),131.20(s),129.58(s),129.43-129.00(m),128.48(s),125.39(s),125.06(s),124.63(s),123.82(s),122.37(s),122.08(s),116.79(d,J=20.0Hz),115.75(s),112.79(s),64.29(s),29.86(s),26.69(s),23.90(s).HRMS(ESI)calcd for C 29 H 23 BrNO 4 S[M+H] + :560.05257,found 560.05229.

[0091] 3-((2-(3-chlorophenyl)quinolin-4-yl)thio)propyl 2-oxo-2H-chromene-3-carboxylate(A21)White solid,m.p.165.0-165.9℃,yield 63%; 1H NMR(400MHz,Chloroform-d)δ8.50(s,1H,Ph-H),8.15(dd,J=8.4,0.8Hz,1H,Ph-H),8.13-8.10(m,2H,Ph-H),7.99-7.96(m,1H,Ph-H),7.75-7.70(m,2H,Ph-H),7.66(ddd,J=8.6,7.4,1.6Hz,1H,Ph-H),7.57-7.52(m,2H,Ph-H),7.38-7.27(m,4H,Ph-H),4.53(t,J=5.9Hz,2H,-COO-CH 2 CH 2 CH 2 -S-),3.45(t,J=7.2Hz,2H,-COO-CH 2 CH 2 CH 2 -S-),2.35-2.28(m,2H,-COO-CH 2 CH 2 CH 2 -S-). 13 C NMR(101MHz,Chloroform-d)δ162.41(s),155.64(s),154.15(d,J=7.6Hz),148.16(s),146.53(d,J=19.7Hz),140.51(s),133.74(s),133.53(s),129.39-128.84(m),128.56(s),128.18(s),126.74(s),125.43(s),124.73(d,J=3.9Hz),123.86(s),122.39(s),116.81(d,J=15.4Hz),115.77(s),113.03(s),63.12(s),26.65(d,J=10.3Hz).HRMS(ESI)calcd for C 28 H 21 ClNO 4 S[M+H] + :502.08743,found 502.08754.

[0092] 4-((2-(3-chlorophenyl)quinolin-4-yl)thio)butyl 2-oxo-2H-chromene-3-carboxylate(A22)White solid,m.p.114.0-115.7℃,yield 57%; 1H NMR(400MHz,Chloroform-d)δ8.37(s,1H,Ph-H),8.08-8.01(m,3H,Ph-H),7.90(dt,J=7.3,1.6Hz,1H,Ph-H),7.65(ddd,J=8.4,6.9,1.4Hz,1H,Ph-H),7.59-7.54(m,2H,Ph-H),7.48-7.42(m,2H,Ph-H),7.39-7.31(m,2H,Ph-H),7.24(ddd,J=8.6,5.7,1.9Hz,2H,Ph-H),4.38(t,J=5.8Hz,2H,-COO-CH 2 CH 2 CH 2 CH 2 -S-),3.24(t,J=6.7Hz,2H,-COO-CH 2 CH 2 CH 2 CH 2 -S-),1.99(dt,J=6.5,3.3Hz,4H,-COO-CH 2 CH 2 CH 2 CH 2 -S-). 13 C NMR(101MHz,Chloroform-d)δ162.27(s),155.55(s),154.16(s),153.95(s),147.83(s),147.11(s),146.41(s),140.53(s),133.88(s),133.42(s),129.38-128.92(m),128.38(d,J=18.7Hz),126.71(s),125.39(s),124.66(d,J=9.7Hz),123.80(s),122.41(s),117.01(s),116.73(s),115.77(s),112.93(s),64.29(s),29.95(s),26.73(s),23.97(s).HRMS(ESI)calcd for C 29 H 23 ClNO 4 S[M+H] + :516.10308,found 516.10302.

[0093] 3-((2-(3-fluorophenyl)quinolin-4-yl)thio)propyl 2-oxo-2H-chromene-3-carboxylate(A23)White solid,m.p.155.0-156.1℃,yield 53%; 1 H NMR(400MHz,Chloroform-d)δ8.50(s,1H,Ph-H),8.13(ddd,J=12.6,8.4,0.7Hz,2H,Ph-H),7.89-7.83(m,2H,Ph-H),7.75-7.70(m,2H,Ph-H),7.66(ddd,J=8.7,7.4,1.6Hz,1H,Ph-H),7.58-7.52(m,2H,Ph-H),7.40(td,J=8.0,5.9Hz,1H,Ph-H),7.37-7.31(m,2H,Ph-H),7.03(tdd,J=8.4,2.6,0.8Hz,1H,Ph-H),4.54(t,J=5.9Hz,2H,-COO-CH 2 CH 2 CH 2 -S-),3.45(t,J=7.2Hz,2H,-COO-CH 2 CH 2 CH 2 -S-),2.35-2.28(m,2H,-COO-CH 2 CH 2 CH 2 -S-). 13 C NMR(101MHz,Chloroform-d)δ162.42(s),162.11(d,J=245.6Hz),155.65(s),154.19(d,J=2.0Hz),148.16(s),146.48(d,J=11.1Hz),140.99(d,J=7.5Hz),133.53(s),129.26(s),129.21(d,J=8.4Hz),129.11(s),128.56(s),125.40(s),124.73(s),123.86(s),122.38(s),122.20(d,J=2.8Hz),116.82(d,J=16.8Hz),115.78(s),115.07(d,J=21.3Hz),113.56(d,J=22.7Hz),113.05(s),63.14(s),26.63(d,J=8.8Hz). 19F NMR(377MHz,Chloroform-d)δ-112.66(s).HRMS(ESI)calcd for C 28 H 21 FNO 4 S[M+H] + :486.11698,found 486.11654.

[0094] 4-((2-(3-fluorophenyl)quinolin-4-yl)thio)butyl 2-oxo-2H-chromene-3-carboxylate(A24)White solid,m.p.128.8-130.8℃,yield 57%; 1 H NMR(400MHz,Chloroform-d)δ8.45(s,1H,Ph-H),8.15-8.08(m,2H,Ph-H),7.89-7.84(m,2H,Ph-H),7.71(ddd,J=8.4,6.9,1.3Hz,1H,Ph-H),7.66-7.61(m,2H,Ph-H),7.55-7.44(m,3H,Ph-H),7.33-7.28(m,2H,Ph-H),7.15-7.10(m,1H,Ph-H),4.44(t,J=5.8Hz,2H,-COO-CH 2 CH 2 CH 2 CH 2 -S-),3.30(t,J=6.7Hz,2H,-COO-CH 2 CH 2 CH 2 CH 2 -S-),2.06(dt,J=6.4,3.3Hz,4H,-COO-CH 2 CH 2 CH 2 CH 2 -S-). 13C NMR(101MHz,Chloroform-d)δ162.27(s),162.24(d,J=245.8Hz),155.56(s),154.16(s),154.06(d,J=2.7Hz),147.84(s),147.04(s),146.40(s),141.05(d,J=7.5Hz),133.42(s),129.29(d,J=8.0Hz),129.28(s),128.48(s),125.36(s),124.72(s),123.80(s),122.40(s),122.08(d,J=2.8Hz),117.01(s),116.74(s),115.76(s),115.17(d,J=21.4Hz),113.53(d,J=22.7Hz),112.97(s),64.30(s),29.93(s),26.73(s),23.97(s). 19 F NMR(377MHz,Chloroform-d)δ-112.60(s).HRMS(ESI)calcd for C 29 H 23 FNO 4 S[M+H] + :500.13263,found 500.13261.

[0095] 3-((2-(3-(trifluoromethyl)phenyl)quinolin-4-yl)thio)propyl 2-oxo-2H-chromene-3-carboxylate(A25)White solid,m.p.117.5-119.5℃,yield 18%; 1 H NMR(400MHz,Chloroform-d)δ8.49(s,1H,Ph-H),8.43(s,1H,Ph-H),8.29(d,J=7.5Hz,1H,Ph-H),8.16(ddd,J=13.8,8.4,0.7Hz,2H,Ph-H),7.77-7.72(m,2H,Ph-H),7.66(ddd,J=8.6,7.3,1.6Hz,1H,Ph-H),7.63-7.54(m,4H,Ph-H),7.36-7.31(m,2H,Ph-H),4.54(t,J=6.0Hz,2H,-COO-CH 2 CH 2 CH 2-S-),3.47(t,J=7.2Hz,2H,-COO-CH 2 CH 2 CH 2 -S-),2.36-2.29(m,2H,-COO-CH 2 CH 2 CH 2 -S-). 13 C NMR(101MHz,Chloroform-d)δ162.46(s),155.59(s),154.23(s),154.00(s),148.11(s),146.83(s),146.52(s),139.50(s),133.52(s),130.14(d,J=32.3Hz),129.84(s),129.27(d,J=13.9Hz),128.55(s),128.17(s),125.56(s),124.82(s),124.78(d,J=3.8Hz),123.87(s),123.58(d,J=3.9Hz),123.25(d,J=298.6Hz),122.47(s),117.02(s),116.76(s),115.78(s),113.14(s),63.09(s),26.75(d,J=5.2Hz). 19 F NMR(377MHz,Chloroform-d)δ-62.47(s).HRMS(ESI)calcd for C 29 H 21 F 3 NO 4 S[M+H] + :536.11379,found536.11369.

[0096] 4-((2-(3-(trifluoromethyl)phenyl)quinolin-4-yl)thio)butyl 2-oxo-2H-chromene-3-carboxylate(A26)White solid,m.p.117.0-118.7℃,yield 23%; 1H NMR(400MHz,Chloroform-d)δ8.45(s,1H,Ph-H),8.29(d,J=7.7Hz,1H,Ph-H),8.18-8.09(m,2H,Ph-H),7.73(ddd,J=15.0,8.0,4.6Hz,2H,Ph-H),7.63(dd,J=13.1,5.6Hz,3H,Ph-H),7.57-7.50(m,2H,Ph-H),7.30(dd,J=11.4,4.3Hz,2H,Ph-H),4.45(t,J=5.5Hz,2H,-COO-CH 2 CH 2 CH 2 CH 2 -S-),3.33(t,J=6.5Hz,2H,-COO-CH 2 CH 2 CH 2 CH 2 -S-),2.10-2.04(m,4H,-COO-CH 2 CH 2 CH 2 CH 2 -S-). 13 C NMR(101MHz,Chloroform-d)δ162.31(s),155.55(s),154.16(s),153.84(s),147.86(s),147.34(s),146.44(s),139.50(s),133.43(s),130.53(d,J=32.2Hz),129.73(s),129.25(d,J=15.8Hz),128.47(s),128.27(s),125.51(s),124.87(d,J=3.9Hz),124.75(s),123.81(s),123.48(d,J=3.7Hz),123.27(d,J=298.2Hz),122.44(s),117.03(s),116.74(s),115.76(s),112.87(s),64.32(s),30.00(s),26.72(s),24.00(s). 19 F NMR(377MHz,Chloroform-d)δ-62.47(s).HRMS(ESI)calcd for C 30 H 23 F 3 NO 4 S[M+H] +:550.12944,found550.12937.

[0097] 3-((2-(4-methoxyphenyl)quinolin-4-yl)thio)propyl 2-oxo-2H-chromene-3-carboxylate(A27)White solid,m.p.131.0-131.5℃,yield 9%; 1 H NMR(400MHz,Chloroform-d)δ8.48(s,1H,Ph-H),8.14-8.06(m,4H,Ph-H),7.71-7.63(m,3H,Ph-H),7.55-7.47(m,2H,Ph-H),7.33(dd,J=12.2,4.6Hz,2H,Ph-H),6.98-6.94(m,2H,Ph-H),4.53(t,J=6.0Hz,2H,-COO-CH 2 CH 2 CH 2 -S-),3.80(s,3H,Ph-OCH 3 ),3.42(t,J=7.2Hz,2H,-COO-CH 2 CH 2 CH 2 -S-),2.34-2.28(m,2H,-COO-CH 2 CH 2 CH 2 -S-). 13 C NMR(101MHz,Chloroform-d)δ163.31(s),160.77(s),156.58(s),156.11(s),155.21(s),149.00(s),134.46(s),129.93(d,J=2.6Hz),129.57(s),128.98(s),125.80(s),125.41(s),124.84(s),123.39(s),118.00(s),117.77(s),116.77(s),114.16(d,J=5.7Hz),64.14(s),55.27(s),27.78(s),1.00(s).HRMS(ESI)calcd for C 29 H 24 NO 5 S[M+H] + :498.13697,found 498.13656.

[0098] 4-((2-(4-methoxyphenyl)quinolin-4-yl)thio)butyl 2-oxo-2H-chromene-3-carboxylate(A28)White solid,m.p.138.0-139.8℃,yield 10%; 1 H NMR(400MHz,Chloroform-d)δ8.43(s,1H,Ph-H),8.13-8.10(m,1H,Ph-H),8.07(dd,J=7.0,1.9Hz,3H,Ph-H),7.71-7.62(m,3H,Ph-H),7.51-7.47(m,2H,Ph-H),7.31(dd,J=14.3,7.7Hz,2H,Ph-H),7.04-7.00(m,2H,Ph-H),4.44(t,J=5.7Hz,2H,-COO-CH 2 CH 2 CH 2 CH 2 -S-),3.87(s,3H,Ph-OCH 3 ),3.29(t,J=6.6Hz,2H,-COO-CH 2 CH 2 CH 2 CH 2 -S-),2.06(dd,J=6.2,2.9Hz,4H,-COO-CH 2 CH 2 CH 2 CH 2 -S-). 13 C NMR(101MHz,Chloroform-d)δ162.21(s),159.80(s),155.58(s),155.05(s),154.16(s),147.78(s),133.40(s),128.92(d,J=16.0Hz),128.51(s),127.87(s),124.73(s),124.36(s),123.80(s),122.38(s),117.01(s),116.76(s),115.75(s),113.21(s),112.95(s),64.27(s),54.39(s),29.91(s),26.76(s),24.01(s).HRMS(ESI)calcd for C 30 H 26 NO 5 S[M+H] +:512.15262,found512.15283.

[0099] 3-((2-(p-tolyl)quinolin-4-yl)thio)propyl 2-oxo-2H-chromene-3-carboxylate(29)Whitesolid,m.p.103.5-104.3℃,yield 30%; 1 H NMR(400MHz,Chloroform-d)δ8.47(s,1H,Ph-H),8.12(ddd,J=12.5,8.4,0.7Hz,2H,Ph-H),8.00(d,J=8.2Hz,2H,Ph-H),7.73-7.63(m,3H,Ph-H),7.55-7.49(m,2H,Ph-H),7.37-7.30(m,2H,Ph-H),7.24(d,J=7.9Hz,2H,Ph-H),4.53(t,J=6.0Hz,2H,-COO-CH 2 CH 2 CH 2 -S-),3.43(t,J=7.2Hz,2H,-COO-CH 2 CH 2 CH 2 -S-),2.33-2.29(m,5H,Ph-OCH 3 ,-COO-CH 2 CH 2 CH 2 -S-). 13 C NMR(101MHz,Chloroform-d)δ162.29(s),155.60(s),154.18(s),148.02(s),146.60(s),145.85(s),138.35(s),135.86(s),133.48(s),129.13(s),128.87(s),128.51(d,J=12.1Hz),126.45(d,J=5.5Hz),124.93(s),124.52(s),123.84(s),122.36(s),116.84(d,J=18.8Hz),115.76(s),113.32(s),63.14(s),26.69(d,J=11.6Hz),20.22(s).HRMS(ESI)calcd for C 29 H 24 NO 5 S[M+H] +:482.14206,found 482.14212.

[0100] 4-((2-(p-tolyl)quinolin-4-yl)thio)butyl 2-oxo-2H-chromene-3-carboxylate(A30)White solid,m.p.80.2-82.0℃,yield 45%; 1 H NMR(400MHz,Chloroform-d)δ8.43(s,1H,Ph-H),8.11(ddd,J=14.3,8.4,0.8Hz,2H,Ph-H),8.01-7.98(m,2H,Ph-H),7.69(ddd,J=8.4,6.9,1.4Hz,1H,Ph-H),7.66-7.61(m,2H,Ph-H),7.52-7.48(m,2H,Ph-H),7.34-7.28(m,4H,Ph-H),4.44(t,J=5.9Hz,2H,-COO-CH 2 CH 2 CH 2 CH 2 -S-),3.29(t,J=6.7Hz,2H,-COO-CH 2 CH 2 CH 2 CH 2 -S-),2.41(s,3H,Ph-OCH 3 ),2.05(dt,J=6.5,3.2Hz,4H,-COO-CH 2 CH 2 CH 2 CH 2 -S-). 13C NMR(101MHz,Chloroform-d)δ162.15(s),155.52(d,J=15.0Hz),154.11(s),147.81(s),146.43(d,J=18.3Hz),138.43(s),135.86(s),133.41(s),129.12(s),128.83(s),128.52(d,J=3.3Hz),126.40(d,J=4.0Hz),124.87(s),124.45(s),123.79(s),122.33(s),116.81(d,J=19.5Hz),115.72(s),113.07(s),64.24(s),29.80(s),26.72(s),23.93(s),20.32(s).HRMS(ESI)calcd for C 30 H 26 NO 4 S[M+H] + :496.15771,found 496.15737.

[0101] 3-((2-(4-bromophenyl)quinolin-4-yl)thio)propyl 2-oxo-2H-chromene-3-carboxylate(A31)White solid,m.p.142.1-143.5℃,yield 16%; 1 H NMR(400MHz,Chloroform-d)δ8.51(s,1H,Ph-H),8.13(ddd,J=18.5,8.4,0.7Hz,2H,Ph-H),8.04-7.95(m,2H,Ph-H),7.75-7.64(m,3H,Ph-H),7.62-7.47(m,4H,Ph-H),7.40-7.32(m,2H,Ph-H),4.53(t,J=5.9Hz,2H,-COO-CH 2 CH 2 CH 2 -S-),3.45(t,J=7.2Hz,2H,-COO-CH 2 CH 2 CH 2 -S-),2.31(dt,J=12.9,6.3Hz,2H,-COO-CH 2 CH 2 CH 2 -S-). 13C NMR(101MHz,Chloroform-d)δ162.49(s),154.42(s),154.21(s),148.22(s),146.50(s),133.65(s),130.85(s),129.15(d,J=7.2Hz),128.58(s),128.23(s),125.32(s),124.74(d,J=18.5Hz),124.16(s),123.95(s),122.85(s),122.42(s),115.88(s),63.13(s),28.68(s),26.61(s).HRMS(ESI)calcd forC 28 H 21 BrNO 4 S[M+H] + :546.03692,found 546.03701.

[0102] 4-((2-(4-bromophenyl)quinolin-4-yl)thio)butyl 2-oxo-2H-chromene-3-carboxylate(A32)White solid,m.p.106.7-108.6℃,yield 29%; 1 H NMR(400MHz,Chloroform-d)δ8.46(s,1H,Ph-H),8.11(ddd,J=20.8,8.4,0.7Hz,2H,Ph-H),8.02-7.99(m,2H,Ph-H),7.71(ddd,J=8.4,6.9,1.4Hz,1H,Ph-H),7.63(ddd,J=5.6,3.3,1.5Hz,4H,Ph-H),7.53(ddd,J=8.1,5.8,1.4Hz,2H,Ph-H),7.34-7.31(m,2H,Ph-H),4.44(d,J=3.9Hz,2H,-COO-CH 2 CH 2 CH 2 CH 2 -S-),3.31(t,J=6.6Hz,2H,-COO-CH 2 CH 2 CH 2 CH 2 -S-),2.06(dd,J=5.9,3.1Hz,4H,-COO-CH 2 CH 2 CH 2 CH 2 -S-).13 C NMR(101MHz,Chloroform-d)δ162.36(s),155.55(s),154.17(s),147.85(d,J=13.4Hz),147.02(s),146.45(s),137.59(s),133.46(s),130.94(s),129.13(d,J=14.9Hz),128.50(s),128.13(s),125.27(s),124.62(s),123.83(s),122.89(s),122.42(s),116.75(s),115.78(s),112.80(s),64.36(s),29.94(s),26.73(s),24.07(s).HRMS(ESI)calcd for C 29 H 23 BrNO 4 S[M+H] + :560.05257,found560.05231.

[0103] 3-((2-(4-chlorophenyl)quinolin-4-yl)thio)propyl 2-oxo-2H-chromene-3-carboxylate(A33)White solid,m.p.139.9-140.9℃,yield 21%; 1 H NMR(400MHz,Chloroform-d)δ8.50(s,1H,Ph-H),8.16-8.13(m,1H,Ph-H),8.10(d,J=8.3Hz,1H,Ph-H),8.08-8.04(m,2H,Ph-H),7.74-7.70(m,2H,Ph-H),7.67(ddd,J=7.5,5.3,1.5Hz,1H,Ph-H),7.58-7.51(m,2H,Ph-H),7.42-7.38(m,2H,Ph-H),7.38-7.31(m,2H,Ph-H),4.52(t,J=5.9Hz,2H,-COO-CH 2 CH 2 CH 2 -S-),3.45(t,J=7.2Hz,2H,-COO-CH 2 CH 2 CH 2 -S-),2.34-2.27(m,2H,-COO-CH 2 CH 2 CH 2-S-). 13 C NMR(101MHz,Chloroform-d)δ162.45(s),155.64(s),154.26(d,J=16.4Hz),148.18(s),146.46(d,J=3.2Hz),137.07(s),134.43(s),133.62(s),129.13(d,J=9.0Hz),128.56(s),127.91(d,J=5.2Hz),125.28(s),124.60(s),123.92(s),122.39(s),116.91(s),116.70(s),115.83(s),112.94(s),63.12(s),26.69(d,J=16.7Hz).HRMS(ESI)calcd for C 28 H 21 ClNO 4 S[M+H] + :502.08743,found 502.08685.

[0104] 4-((2-(4-chlorophenyl)quinolin-4-yl)thio)butyl 2-oxo-2H-chromene-3-carboxylate(A34)White solid,m.p.126.1-127.6℃,yield 13%; 1 H NMR(400MHz,Chloroform-d)δ8.46(s,1H,Ph-H),8.13(dd,J=8.4,0.9Hz,1H,Ph-H),8.10-8.05(m,3H,Ph-H),7.71(ddd,J=8.4,6.9,1.4Hz,1H,Ph-H),7.66-7.62(m,2H,Ph-H),7.52(ddd,J=7.2,6.3,1.3Hz,2H,Ph-H),7.49-7.45(m,2H,Ph-H),7.31(ddd,J=8.6,6.5,2.7Hz,2H,Ph-H),4.44(t,J=5.7Hz,2H,-COO-CH 2 CH 2 CH 2 CH 2 -S-),3.30(t,J=6.7Hz,2H,-COO-CH 2 CH 2 CH 2 CH 2 -S-),2.09-2.03(m,4H,-COO-CH2 CH 2 CH 2 CH 2 -S-). 13 C NMR(101MHz,Chloroform-d)δ162.34(s),155.55(s),154.19(d,J=5.2Hz),147.90(s),146.98(s),146.44(s),137.14(s),134.50(s),133.45(s),129.11(d,J=15.9Hz),128.50(s),127.91(d,J=12.9Hz),125.24(s),124.59(s),123.82(s),122.40(s),117.02(s),116.75(s),115.76(s),112.84(s),64.35(s),29.93(s),26.73(s),24.05(s).HRMS(ESI)calcd forC 29 H 23 ClNO 4 S[M+H] + :516.10308,found 516.10239.

[0105] 3-((2-(4-fluorophenyl)quinolin-4-yl)thio)propyl 2-oxo-2H-chromene-3-carboxylate(A35)White solid,m.p.135.6-136.5℃,yield 26%; 1 H NMR(400MHz,Chloroform-d)δ8.50(s,1H,Ph-H),8.15-8.08(m,4H,Ph-H),7.74-7.69(m,2H,Ph-H),7.69-7.65(m,1H,Ph-H),7.58-7.50(m,2H,Ph-H),7.38-7.31(m,2H,Ph-H),7.15-7.10(m,2H,Ph-H),4.53(t,J=5.9Hz,2H,-COO-CH 2 CH 2 CH 2 -S-),3.44(t,J=7.2Hz,2H,-COO-CH 2 CH 2 CH 2 -S-),2.30(dd,J=13.0,6.7Hz,2H,-COO-CH 2 CH2 CH 2 -S-). 13 C NMR(101MHz,Chloroform-d)δ162.66(d,J=249.1Hz),162.43(s),155.62(s),154.55(s), 154.18(s),148.17(s),146.40(d,J=17.6Hz),134.82(d,J=3.1Hz),133.60(s),129.08(d, J=8.2Hz),128.51(d,J=8.1Hz),125.15(s),124.48(s),123.91(s),122.39(s),116.91(s) ,116.71(s),115.80(s),114.66(d,J=21.6Hz),113.03(s),63.12(s),26.68(d,J=8.9Hz). 19 F NMR(376MHz,Chloroform-d)δ-112.38(s).HRMS(ESI)calcd for C 28 H 21 FNO 4 S[M+H] + :486.11698, found 486.11685.

[0106] The H NMR spectrum of compound A35 is shown in Figure 4 As shown, the carbon NMR spectrum is as follows Figure 5 As shown, the NMR fluorine spectrum is as Figure 6 As shown in the high-resolution mass spectrum Figure 7 shown.

[0107] 4-((2-(4-fluorophenyl)quinolin-4-yl)thio)butyl 2-oxo-2H-chromene-3-carboxylate(A36)White solid, mp117.4-118.9℃, yield 9%; 1H NMR(400MHz,Chloroform-d)δ8.46(s,1H,Ph-H),8.15-8.07(m,4H,Ph-H),7.70(ddd,J=8.4,6.9,1.3Hz,1H,Ph-H),7.67-7.61(m,2H,Ph-H),7.54-7.50(m,2H,Ph-H),7.34-7.29(m,2H,Ph-H),7.21-7.16(m,2H,Ph-H),4.45(t,J=5.8Hz,2H,-COO-CH 2 CH 2 CH 2 CH 2 -S-),3.30(t,J=6.7Hz,2H,-COO-CH 2 CH 2 CH 2 CH 2 -S-),2.06(dt,J=6.6,3.4Hz,4H,-COO-CH 2 CH 2 CH 2 CH 2 -S-). 13 C NMR(101MHz,Chloroform-d)δ162.75(d,J=249.1Hz),162.34(s),161.93(d,J=83.4Hz),155.57(s),154.46(s),154.18(s),147.89(s),146.84(s),146.46(s),133.45(s),129.26(d,J=3.2Hz),129.15(s),129.00(s),128.45(d,J=9.5Hz),125.11(s),124.48(s),123.83(s),122.40(s),117.04(s),116.76(s),115.77(s),114.75(d,J=21.5Hz),112.96(s),64.34(s),29.94(s),26.73(s),24.02(s). 19 F NMR(377MHz,Chloroform-d)δ-112.38(s).HRMS(ESI)calcd for C 29 H 23 FNO 4 S[M+H] + :500.13263,found 500.13193.

[0108] 3-((2-(4-(trifluoromethyl)phenyl)quinolin-4-yl)thio)propyl 2-oxo-2H-chromene-3-carboxylate(A37)White solid,m.p.156.3-158.2℃,yield 9%; 1 H NMR(400MHz,Chloroform-d)δ8.51(s,1H,Ph-H),8.26(d,J=8.2Hz,2H,Ph-H),8.15(dd,J=15.8,8.4Hz,2H,Ph-H),7.79(s,1H,Ph-H),7.76-7.65(m,4H,Ph-H),7.56(t,J=8.2Hz,2H,Ph-H),7.37-7.32(m,2H,Ph-H),4.54(t,J=5.9Hz,2H,-COO-CH 2 CH 2 CH 2 -S-),3.47(t,J=7.3Hz,2H,-COO-CH 2 CH 2 CH 2 -S-),2.35-2.28(m,2H,-COO-CH 2 CH 2 CH 2 -S-). 13 C NMR(101MHz,Chloroform-d)δ162.55(s),155.63(s),154.14(d,J=15.6Hz),148.19(s),146.78(s),146.54(s),142.04(s),133.62(s),129.97(d,J=32.3Hz),129.29(d,J=18.9Hz),128.54(s),127.02(s),125.60(s),124.85(s),124.62(d,J=3.7Hz),123.94(s),123.11(d,J=271.8Hz),122.45(s),117.06(s),116.74(s),115.81(s),113.17(s),63.15(s),26.76(d,J=14.5Hz). 19 F NMR(377MHz,Chloroform-d)δ-62.61(s).HRMS(ESI)calcd for C 29 H 21 F 3 NO 4S[M+H] + :536.11379,found 536.11363.

[0109] 4-((2-(4-(trifluoromethyl)phenyl)quinolin-4-yl)thio)butyl 2-oxo-2H-chromene-3-carboxylate(A38)White solid,m.p.91.2-92.5℃,yield 25%; 1 H NMR(400MHz,Chloroform-d)δ8.46(s,1H,Ph-H),8.24(d,J=8.2Hz,2H,Ph-H),8.16-8.09(m,2H,Ph-H),7.73(ddd,J=10.0,9.5,4.8Hz,3H,Ph-H),7.67-7.61(m,2H,Ph-H),7.53(ddd,J=9.1,8.2,1.1Hz,2H,Ph-H),7.30(t,J=7.7Hz,2H,Ph-H),4.44(t,J=5.7Hz,2H,-COO-CH 2 CH 2 CH 2 CH 2 -S-),3.32(t,J=6.7Hz,2H,-COO-CH 2 CH 2 CH 2 CH 2 -S-),2.09-2.04(m,4H,-COO-CH 2 CH 2 CH 2 CH 2 -S-). 13C NMR(101MHz,Chloroform-d)δ162.39(s),155.59(s),154.04(d,J=18.1Hz),148.04(s),147.35( s),146.37(s),142.08(d,J=0.9Hz),133.50(s),130.00(d,J=32.5Hz),129.24(d,J=15.2Hz),12 8.49(s),126.91(s),125.55(s),124.71(d,J=4.1Hz),123.84(s),123.14(d,J=272.3Hz),122.3 9(s),116.92(s),116.70(s),115.74(s),112.91(s),64.40(s),29.87(s),26.69(s),24.02(s). 19 F NMR(377MHz,Chloroform-d)δ-62.53(s).HRMS(ESI)calcd for C 30 H 23 F 3 NO 4 S[M+H] + :550.12944, found 550.12864.

[0110] Test Example 1 Bactericidal Activity Test

[0111] This test example tests the bactericidal activity of the compound obtained in Example 1, specifically comprising the following steps:

[0112] The bactericidal activity of the synthesized target compounds A1-A38, the lead compound 3-CCA and the commercial control agent kasugamycin against rice bacterial leaf blight, ginseng anthracnose (Colletotrichum panacicola) and melon bacterial fruit spot was tested by turbidity method. The test compound was dissolved in DMSO to a 10000 μg / mL mother solution, and then diluted with liquid culture medium to prepare a drug-containing culture medium with a final concentration of 50 μg / mL. 190 μL of drug-containing culture medium was added to a 96-well plate, followed by 10 μL of 0.6A bacterial suspension. The drug-containing and non-bacterial treatment was used as the background control, kasugamycin and 3-CCA were used as the positive agent control, the drug-free treatment was used as the negative control, and 1% DMSO was used as the solvent control. The 96-well plates were sealed with sealing film and placed in a shaker at 180 rpm and 28°C for culture. After 12 h of culture, when the bacterial solution in the negative control group became completely turbid, the OD of the bacterial solution was measured using an automatic microplate reader. 600The value of nm was used to calculate the inhibition rate of each compound on the test strain. Each test treatment was repeated 3 times. The calculation formula is shown below. The test results are shown in Table 1.

[0113] Light absorption increase ΔOD = treatment OD 600 nm-background control OD 600 nm (1)

[0114] P(%)=(A 0 -A 1 ) / A 0 ×100 (2)

[0115] In formula (2), P is the inhibition rate, A is 0 The increase in OD value of the negative control, A 1 Add value to compound OD value.

[0116] Table 1 Screening of bactericidal activity of coumarin derivatives containing thioether quinoline

[0117]

[0118]

[0119]

[0120] The results showed that these compounds were more effective against Xanthomonas oryzae and Bacterial fruit spot of melons. Compounds A9 and A13 were the most antibacterial derivatives against Xanthomonas oryzae and Bacterial fruit spot of melons, with inhibition rates of 90.68% (A9, Xanthomonas oryzae), 89.29% (A13, Xanthomonas oryzae), 93.71% (A9, Bacterial fruit spot of melons), and 84.10% (A13, Bacterial fruit spot of melons) at 50 μg / mL, which were higher than 3-CCA and comparable to the positive control kasugamycin. Compound A35 also had better antibacterial activity against Xanthomonas oryzae and Bacterial fruit spot of melons than 3-CCA, but lower than the positive control kasugamycin. Compound A25 was selective against Xanthomonas oryzae, and its antibacterial activity against Xanthomonas oryzae was better than 3-CCA, but lower than the positive control kasugamycin.

[0121] Test Example 2 Toxicity Determination

[0122] This test example studies the toxicity of the compound obtained in Example 1 to Xanthomonas oryzae and Bacterial fruit spot of melons. The test method is the same as that of Test Example 1. According to the preliminary test results, 5-7 concentrations are selected to test the toxicity of the highly active compound to Xanthomonas oryzae and Bacterial fruit spot of melons. The test results are shown in Table 2.

[0123] Table 2 Toxicity test of highly active compounds against Xanthomonas oryzae and Bacterial fruit spot pathogen of melon

[0124]

[0125]

[0126] Based on the initial screening of activity, the toxicity of highly active compounds against Xanthomonas oryzae and Bacterial fruit spot of melon was tested. The results showed that compound A9 had the strongest antibacterial activity against Xanthomonas oryzae and Bacterial fruit spot of melon. 50 The values ​​were 11.05 and 8.05 μg / mL, respectively, which were better than the lead structure 3-CCA and comparable to the control agent kasugamycin. Compound A35 also had excellent fungicidal activity, with an EC value of 1.05 and 8.05 μg / mL against Xanthomonas oryzae and Bacterial fruit spot of melon. 50 The values ​​were 14.87 and 15.42 μg / mL, respectively, and their intensity trends were the same as compound A9. The remaining compounds also had strong fungicidal effects, and their EC values ​​against rice bacterial blight and melon bacterial fruit spot were 50 Values ​​ranged from 11-32 μg / mL.

[0127] Test Example 3 Potted Plant Experiment

[0128] This test example studied the potted plant test of compound A9 obtained in Example 1 against melon bacterial fruit spot pathogen, including:

[0129] 1. Test materials: Hybrid melon: The variety is Yangjiaomi, purchased from China Vegetable Seed Technology Co., Ltd.

[0130] 2. Pot test method: Select full-grained melon seeds, soak them in 55°C hot water for 30 minutes for surface disinfection, then rinse them with sterilized distilled water for 3 times, place them in an incubator (25-28°C) to germinate until they turn white, sow them in a plastic pot filled with planting soil, and conduct a live pot test when they grow two true leaves. The test plants were randomly divided into two groups. OD 600=1 bacterial suspension was inoculated into melon cotyledons. After 24h, compound A9 dissolved in DMSO was diluted to a concentration of 100 and 200 μg / mL with distilled water containing 0.1% Tween-20, and the cotyledons and leaves were treated with the diluted A9 solution. Commercially available fungicides 20% thiophanate-methyl SC and 2% kasugamycin AS were used as positive controls, and sterile distilled water containing the same dose and Tween-20 was used as a negative control. In order to evaluate the protective effect, the bacterial suspension was inoculated 24 hours after the above-mentioned spraying of the agent solution. The treated seedlings continued to grow for 7d under standard conditions (light conditions of 25±2℃, 60±5% RH, 16h + dark conditions of 20±2℃, 75±5% RH, 8h). Disease indexes and control effects were evaluated according to the method of Tian et al (Tian, ​​Y., Zhao, Y., Wu, X., Liu, F., Hu, B., & Walcott, RR 2015. The type VI protein secretion system contributes to biofilm formation and seed-to-seedling transmission of Acidovorax citrulli on melon. Mol Plant Pathol, 16 (1), 38-47). Six plants were measured for each treatment, and each test condition was repeated 3 times. The test results are shown in Table 3.

[0131] Table 3 Protective and therapeutic effects of compound A9 on melon bacterial fruit spot pathogen

[0132]

[0133] Note: The data in the table are the average values ​​of 3 replicates. Different lowercase letters in the same column indicate significant differences at the 0.05 level.

[0134] The results showed that A9 had a high protective effect against melon bacterial fruit spot, with a protective effect of 61.50% at a test concentration of 200 μg / mL, which was lower than the control agent kasugamycin (67.57%), but better than the control agent thiophanate-methyl (51.89%). At the same time, compound A9 also had a certain therapeutic effect, with a therapeutic effect of 54.86% at a test concentration of 200 μg / mL, and its activity intensity was similar to the protective effect.

[0135] The above description of the disclosed embodiments enables those skilled in the art to implement or use the present invention. Various modifications to these embodiments will be apparent to those skilled in the art, and the general principles defined herein may be implemented in other embodiments without departing from the spirit or scope of the present invention. Therefore, the present invention will not be limited to the embodiments shown herein, but rather to the widest scope consistent with the principles and novel features disclosed herein.

Claims

1. A coumarin derivative containing thioether quinoline having a structure as shown in formula I, In formula I, R1 is selected from one of hydrogen, halogen, C1-C5 alkyl, C1-C2 haloalkyl, C1-C3 alkoxy, nitro or cyano; R2 is selected from one of hydrogen, halogen, C1-C5 alkyl, C1-C2 haloalkyl, C1-C3 alkoxy, nitro or cyano; n is 3 or 4; p is an integer selected from 1 to 4; q is an integer selected from 1-5.

2. The coumarin derivative containing thioether quinoline according to claim 1, characterized in that: The halogen is selected from one of fluorine, chlorine, bromine or iodine; The C1-C5 alkyl group is selected from one of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl or neopentyl; The C1-C2 haloalkyl group is selected from one of trifluoromethane, difluorodichloromethane, trichloromethane, difluoromethane, dichloromethane, monofluoromethane, 1,2-difluoroethane, 1,2-methylfluoroethane, 1,2-dichloroethane or 1,2-tetrachloroethane; The C1-C3 alkoxy group is selected from a methoxy group, an ethoxy group or a n-propoxy group.

3. The coumarin derivative containing thioether quinoline according to claim 1, characterized in that: In the formula I, R1 is hydrogen, p is 4; R2 is selected from one of hydrogen, fluorine, chlorine, bromine, methyl, methoxy, and trifluoromethane.

4. The method for synthesizing the coumarin derivatives containing thioether quinoline according to any one of claims 1 to 3, characterized in that: The steps include: The compound represented by formula II, potassium carbonate, the compound represented by formula III and an organic solvent are mixed and reacted at room temperature to obtain a coumarin derivative containing thioether quinoline; In formula II, R1 is selected from one of hydrogen, halogen, C1-C5 alkyl, C1-C2 haloalkyl, C1-C3 alkoxy, nitro or cyano; X is selected from one of fluorine, chlorine, bromine or iodine; n is 3 or 4; p is an integer selected from 1 to 4; In formula III, R2 is selected from one of hydrogen, halogen, C1-C5 alkyl, C1-C2 haloalkyl, C1-C3 alkoxy, nitro or cyano; q is an integer selected from 1-5.

5. The method for synthesizing coumarin derivatives containing thioether quinoline according to claim 4, characterized in that: The preparation method of the compound represented by formula II comprises: The compound represented by formula Ⅳ, X(CH2) n X, triethylamine and an organic solvent are mixed and reacted at room temperature to obtain a compound shown in formula II; In formula IV, R1 is selected from one of hydrogen, halogen, C1-C5 alkyl, C1-C2 haloalkyl, C1-C3 alkoxy, nitro or cyano; p is an integer selected from 1 to 4; X(CH2) n In X, X is selected from one of fluorine, chlorine, bromine or iodine; n is 3 or 4.

6. The method for synthesizing the coumarin derivatives containing thioether quinoline according to claim 5, characterized in that: The preparation method of the compound represented by formula IV comprises: The compound represented by formula V, Michler's acid, a metal catalyst and an organic solvent are mixed and reacted at room temperature to obtain a compound represented by formula IV; In formula V, R1 is selected from one of hydrogen, halogen, C1-C5 alkyl, C1-C2 haloalkyl, C1-C3 alkoxy, nitro or cyano; p is selected from an integer of 1-4.

7. The method for synthesizing coumarin derivatives containing thioether quinoline according to claim 4, characterized in that: The preparation method of the compound represented by formula III comprises: The compound represented by formula VI is mixed with anhydrous pyridine and phosphorus pentasulfide to react to obtain the compound represented by formula III; In formula VI, R2 is selected from one of hydrogen, halogen, C1-C5 alkyl, C1-C2 haloalkyl, C1-C3 alkoxy, nitro or cyano; q is an integer selected from 1-5.

8. The method for synthesizing coumarin derivatives containing thioether quinoline according to claim 7, characterized in that: The preparation method of the compound represented by formula VI comprises: The compound represented by formula VII is mixed with 1,4-dioxane and reacted to obtain the compound represented by formula VI; In formula VII, R2 is selected from one of hydrogen, halogen, C1-C5 alkyl, C1-C2 haloalkyl, C1-C3 alkoxy, nitro or cyano; q is an integer selected from 1 to 5; The preparation method of the compound represented by formula VII comprises: The compound represented by formula VIII is mixed with o-aminoacetophenone, triethylamine and an organic solvent to react to obtain a compound represented by formula VII; In formula VIII, R2 is selected from one of hydrogen, halogen, C1-C5 alkyl, C1-C2 haloalkyl, C1-C3 alkoxy, nitro or cyano; q is an integer selected from 1-5.

9. Use of the coumarin derivative containing thioether quinoline according to any one of claims 1 to 3 in inhibiting bacterial pathogens of crops and / or preventing and controlling diseases caused by bacterial pathogens of crops; The bacterial pathogens are one or more of rice bacterial blight pathogen, ginseng anthracnose pathogen and melon bacterial fruit spot pathogen.

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