Dibenzo [b] [1, 8] naphthyridine-subunit-pyrrolidine-2, 3, 5-triketone compound as well as preparation method and application thereof

Abstract

The invention belongs to the technical field of compounds, and particularly discloses a dibenzo [b] [1, 8] naphthyridine-subunit-pyrrolidine-2, 3, 5-triketone compound as well as a preparation method and application of the dibenzo [b] [1, 8] naphthyridine-subunit-pyrrolidine-2, 3, 5-triketone compound. The structural formula of the compound is shown as (III), and in the formula, R1 is selected from C1-6 alkyl, naphthyl, phenyl or substituted phenyl; r2 is selected from C1-6 alkyl groups, phenyl groups, benzyl groups, chiral 2-hydroxy propyl groups or 2-hydroxy ethyl groups; r3 is selected from hydrogen, halogen and C1-6 alkyl; and R4 is selected from C1-6 alkyl and phenyl. The invention also discloses a preparation method of the compound and application of the compound in fluorescent dye and tumor cell imaging. # imgabs0 #

Description

Technical Field

[0001] The present invention belongs to the technical field of compounds, and specifically relates to a dibenzo[b][1,8]naphthyridine-ylidene-pyrrolidine-2,3,5-trione compound and a preparation method and application thereof. Background Art

[0002] The benzohydronaphthyridine core or the polysubstituted hydroquinoline core is a relatively important molecular structure, among which, it is an important pharmacophore in drug molecules. According to existing literature reports, polysubstituted benzohydronaphthyridine compounds and polysubstituted hydroquinoline compounds have certain biological activities. For example, European patent EP0430485A2 reports that compounds containing benzohydronaphthyridine structures have the potential to develop into acetylcholine autoenzyme inhibitors; The Lycopodium Alkaloids: Chemistry and Pharmacology. Vol 45. New York: Academic Press; 1994. p. 233–266 reports that polysubstituted hydroquinoline compounds inhibit the proliferation of HeLa cells and have potential anti-tumor activity; RSC Adv., 2015, 5, 94344–94350 reports that aminomaleimide compounds have aggregation-induced emission. Summary of the invention

[0003] The first purpose of the present invention is to provide a dibenzo[b][1,8]naphthyridine-ylidene-pyrrolidine-2,3,5-trione compound, which has both a benzonaphthyridine mother nucleus and a substituted quinoline mother nucleus, and also introduces a pyrrolidine structure. Therefore, the compound may have potential pharmaceutical activity. At the same time, due to the establishment of an ultra-long conjugated system, it has been tested that it also has the potential for application as a fluorescent dye.

[0004] The second object of the present invention is to provide a method for preparing the above-mentioned dibenzo[b][1,8]naphthyridine-ylidene-pyrrolidine-2,3,5-trione compounds, wherein aminomaleimide compounds are used as carbon attack points or carbon-nitrogen attack points to undergo a cycloaddition reaction with 2-halogenated quinoline-3-α,β-unsaturated carbonyl compounds in the form of a dinucleophilic reagent, and the compound is obtained by base-catalyzed tandem rearrangement cyclization.

[0005] The third object of the present invention is to provide the use of the above-mentioned dibenzo[b][1,8]naphthyridine-ylidene-pyrrolidine-2,3,5-trione compounds in fluorescent dyes and tumor cell imaging.

[0006] The technical solution of the present invention is as follows:

[0007] A dibenzo[b][1,8]naphthyridine-ylidene-pyrrolidine-2,3,5-trione compound of the present invention has a structural formula as shown in (III):

[0008]

[0009] Among them, R 1 Selected from C 1-6 Alkyl, naphthyl, phenyl or substituted phenyl, wherein the substituent in the substituted phenyl is halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, phenyl, phenoxy, nitro, cyano or trifluoromethyl; R 2 Selected from C 1-6 Alkyl, phenyl, benzyl, chiral 2-hydroxypropyl or 2-hydroxyethyl; R 3 Selected from hydrogen, halogen, C 1-6 Alkyl; R 4 Selected from C 1-6 Alkyl, phenyl.

[0010] The present invention also discloses a method for preparing the above-mentioned dibenzo[b][1,8]naphthyridine-ylidene-pyrrolidine-2,3,5-trione compound. The reaction formula is shown below, comprising the following steps: placing a solution mixed with a 2-halogenated quinoline-3-α,β-unsaturated carbonyl compound shown in formula (I), an aminomaleimide compound shown in formula (II) and a base, stirring and reacting at 25°C to 120°C for 0.5 to 36 hours to obtain a dibenzo[b][1,8]naphthyridine-ylidene-pyrrolidine-2,3,5-trione compound shown in formula (III).

[0011]

[0012] In one embodiment of the present invention, preferably, the molar feed ratio of the 2-halogenoquinoline-3-α,β-unsaturated carbonyl compound represented by formula (I), the aminomaleimide compound represented by formula (II) and the base is 1:1-3:1-3.

[0013] In one embodiment of the present invention, preferably, the base used in the reaction is one or more of potassium carbonate, cesium carbonate, potassium tert-butoxide, sodium tert-butoxide, potassium phosphate, potassium bicarbonate, sodium hydroxide or potassium hydroxide.

[0014] In one embodiment of the present invention, preferably, the solvent used in the reaction is one or more of toluene, tetrahydrofuran, N,N-dimethylformamide, dichloroethane, chlorobenzene, chloroform, ethyl acetate, ethanol, methanol, tert-butanol, 1,4-dioxane, acetonitrile or dimethyl sulfoxide.

[0015] In one embodiment of the present invention, preferably, N,N-dimethylformamide is used as solvent, cesium carbonate is used as base, and the reaction is carried out at 70-90° C. for 8-12 hours.

[0016] In one embodiment of the present invention, preferably, the method further comprises, after the reaction is completed, performing column chromatography separation on the reaction solution using petroleum ether / ethyl acetate in a volume ratio of 10:1-2:1 to obtain a dibenzo[b][1,8]naphthyridine-ylidene-pyrrolidine-2,3,5-trione compound as shown in (III).

[0017] The invention also discloses the application of the above dibenzo[b][1,8]naphthyridine-ylidene-pyrrolidine-2,3,5-trione compounds in fluorescent dyes.

[0018] The present invention also discloses the application of the above-mentioned dibenzo[b][1,8]naphthyridine-ylidene-pyrrolidine-2,3,5-trione compounds in tumor cell imaging.

[0019] Compared with the prior art, the present invention has the following beneficial effects:

[0020] The dibenzo[b][1,8]naphthyridine-ylidene-pyrrolidine-2,3,5-trione compound of the present invention has both a benzonaphthyridine mother core and a substituted quinoline mother core, and also introduces a pyrrolidine structure. Therefore, according to reports in existing literature on this type of mother core structure, the compound may show potential drug activity. At the same time, due to the establishment of an ultra-long conjugated system, it has been tested that it also has the potential for application as a fluorescent dye and also has application in tumor cell imaging.

[0021] At the same time, the present invention also discloses a preparation method of the above-mentioned compound, wherein an aminomaleimide compound is used as a carbon attack point or a carbon-nitrogen attack point, and a cycloaddition reaction is carried out with a 2-halogenated quinoline-3-α,β-unsaturated carbonyl compound in the form of a dinucleophilic reagent, and the compound is obtained by base-catalyzed tandem rearrangement cyclization. The compound has the characteristics of easy availability of raw materials, simple operation, high atom economy, etc. BRIEF DESCRIPTION OF THE DRAWINGS

[0022] Figure 1 The (E)-4-(1-(4-bromophenyl)-2-phenylbenzo[b][1,8]naphthyridine-4(1H)-ylidene)-1-ethylpyrrolidine-2,3,5-trione (III-3a) of Example 1 of the present invention is 1 H NMR spectrum;

[0023] Figure 2 Example 1 (E)-4-(1-(4-bromophenyl)-2-phenylbenzo[b][1,8]naphthyridine-4(1H)-ylidene)-1-ethylpyrrolidine-2,3,5-trione (III-3a) of the present invention 13C NMR spectrum;

[0024] Figure 3 The (E)-4-(1,2-diphenylbenzo[b][1,8]naphthyridine-4(1H)-ylidene)-1-ethylpyrrolidine-2,3,5-trione (III-3b) of Example 7 of the present invention is 1 H NMR spectrum;

[0025] Figure 4 The (E)-4-(1,2-diphenylbenzo[b][1,8]naphthyridine-4(1H)-ylidene)-1-ethylpyrrolidine-2,3,5-trione (III-3b) of Example 7 of the present invention is 13 C NMR spectrum;

[0026] Figure 5 The (E)-4-(1-(4-chlorophenyl)-2-phenylbenzo[b][1,8]naphthyridine-4(1H)-ylidene)-1-ethylpyrrolidine-2,3,5-trione (III-3c) of Example 8 of the present invention is 1 H NMR spectrum;

[0027] Figure 6 The (E)-4-(1-(4-chlorophenyl)-2-phenylbenzo[b][1,8]naphthyridine-4(1H)-ylidene)-1-ethylpyrrolidine-2,3,5-trione (III-3c) of Example 8 of the present invention is 13 C NMR spectrum;

[0028] Figure 7 The (E)-1-ethyl-4-(1-(4-fluorophenyl)-2-phenylbenzo[b][1,8]naphthyridine-4(1H)-ylidene)pyrrolidine-2,3,5-trione (III-3d) of Example 9 of the present invention is 1 H NMR spectrum;

[0029] Figure 8 The (E)-1-ethyl-4-(1-(4-fluorophenyl)-2-phenylbenzo[b][1,8]naphthyridine-4(1H)-ylidene)pyrrolidine-2,3,5-trione (III-3d) of Example 9 of the present invention is 13 C NMR spectrum;

[0030] Fig. 9 The (E)-1-ethyl-4-(1-(4-iodophenyl)-2-phenylbenzo[b][1,8]naphthyridine-4(1H)-ylidene)pyrrolidine-2,3,5-trione (III-3e) of Example 10 of the present invention is 1 H NMR spectrum;

[0031] Fig.10The (E)-1-ethyl-4-(1-(4-iodophenyl)-2-phenylbenzo[b][1,8]naphthyridine-4(1H)-ylidene)pyrrolidine-2,3,5-trione (III-3e) of Example 10 of the present invention is 13 C NMR spectrum;

[0032] Fig.11 The near infrared spectra of compounds III-3d, III-3n and III-3r of the present invention (A) and the imaging of living human brain glioma U251 cells (B), wherein (a) FITC channel: ex =488nm; (b) Bright field; (c) Merged image;

[0033] Fig.12 The imaging diagram of the compound III-3ag of the present invention in living human brain glioma U251 cells, wherein (A) FITC channel: ex =488nm; (B) Bright field; (C) Merged image. DETAILED DESCRIPTION

[0034] In order to make the above-mentioned objects, features and advantages of the present invention more obvious and easy to understand, the specific embodiments of the present invention are described in detail below with reference to the accompanying drawings.

[0035] Many specific details are set forth in the following description to facilitate a full understanding of the present invention. However, the present invention can be implemented in many other ways than those described herein, and those skilled in the art can make similar generalizations without violating the connotation of the present invention, so the present invention is not limited to the specific implementation disclosed below.

[0036] The raw materials used in the present invention, wherein the aminomaleimide compound shown in formula (I) can be prepared according to the method reported in the document RSC Adv. 2015, 5, 94344-94350. The 2-halogenated quinoline-3-α, β-unsaturated carbonyl compound shown in formula (II) can be prepared according to the method reported in the document Eur. J. Med. Chem. 2011, 46, 4448-4456; Org. Lett. 2019, 21, 8149-8152. There may be specific compounds that are not reported in the above literature, but they can still be prepared by adjusting the substrate raw materials according to the method of the above literature. The base and solvent used can be obtained commercially.

[0037] Example 1: Preparation of (E)-4-(1-(4-bromophenyl)-2-phenylbenzo[b][1,8]naphthyridine-4(1H)-ylidene)-1-ethylpyrrolidine-2,3,5-trione (III-3a)

[0038]

[0039] Compound I-1a (29.4 mg, 0.1 mmol) and II-2a (58.6 mg, 0.2 mmol) were added to ethanol (2 mL) as solvent, and cesium carbonate (48.9 mg, 0.15 mmol) was added. After stirring under reflux for 12 hours, the solvent was recovered by concentration under reduced pressure. After separation by column chromatography (petroleum ether / ethyl acetate = 5 / 1, v / v), 14.3 mg of product III-3a was obtained as a red oil with a yield of 26%.

[0040] Structural characterization of III-3a: red solid, mp: 145-146℃, 1 H NMR (400MHz, CDCl3): δ10.03(s,1H),8.51(s,1H),8.09(t,J=8.2Hz,1H),7.81(q,J=8.8Hz,2H),7.62–7.55(m,1H ),7.52(d,J=8.5Hz,2H),7.38–7.28(m,5H),7.11(d,J=8.6Hz,2H),3.72(q,J=6.4Hz,2H),1.27(t,J=7.1Hz,3H), such as Figure 1 as shown. 13 C NMR (100 MHz, CDCl3): δ 177.1, 171.2, 163.6, 156.5, 153.4, 149.7, 147.3, 143.3, 137.7, 134.6, 133.9, 132.0, 131.3, 130.0, 129.7, 129.3, 128.5, 128.1, 126.8, 125.5, 122.8, 116.3, 114.1, 101.4, 32.6, 13.8, as Figure 2 HRMS (ESI) m / z calculated for C 30 H 20 BrN3O3[M+H] + =550.0760,found=550.0756.

[0041] In Examples 2 to 9, the present invention investigates the effects of solvent, base, reaction temperature, and reaction time on the reaction, and uses Compound I-1a (29.4 mg, 0.1 mmol) and II-2a (58.6 mg, 0.2 mmol) as raw materials. After the reaction, the solvent is recovered by concentration under reduced pressure, and separated by column chromatography (petroleum ether / ethyl acetate = 5 / 1, v / v) to obtain Product III-3a and calculate the reaction yield, as shown in Table 1. As can be seen from Table 1, the preferred reaction conditions for preparing the compound of the present invention are: using N,N-dimethylformamide as solvent, cesium carbonate as base, and reacting at 70-90°C for 8-12h.

[0042] Table 1

[0043] Example Solvents Alkali Time / h Temperature(℃) Yield (%) Example 2 Ethanol Cesium carbonate 8 78 26 Example 3 Ethyl acetate Cesium carbonate 8 78 10 Example 4 Toluene Cesium carbonate 8 110 20 Example 5 N,N-Dimethylformamide Cesium carbonate 8 80 70 Example 6 N,N-Dimethylformamide Cesium carbonate 8 60 45 Example 7 N,N-Dimethylformamide Cesium carbonate 8 100 50 Example 8 N,N-Dimethylformamide Potassium carbonate 8 80 40 Example 9 N,N-Dimethylformamide Potassium carbonate 12 80 68

[0044] Example 10: Preparation of Ia

[0045]

[0046] Using N,N-dimethylformamide (2 mL) as solvent, I-1a (29.4 mg, 0.1 mmol) and II-2a' (67.4 mg, 0.2 mmol), and cesium carbonate (48.9 mg, 0.15 mmol) were added. After stirring at 80°C for 12 hours, the solvent was recovered by concentration under reduced pressure. After separation by column chromatography (petroleum ether / ethyl acetate = 5 / 1, v / v), 27.4 mg of product III-3a was obtained as a red oil with a yield of 68%.

[0047] Example 11: Preparation of (E)-4-(1,2-diphenylbenzo[b][1,8]naphthyridine-4(1H)-ylidene)-1-ethylpyrrolidine-2,3,5-trione (III-3b)

[0048]

[0049] Using N,N-dimethylformamide (2 mL) as solvent, I-1b (21.6 mg, 0.1 mmol) and II-2a (67.4 mg, 0.2 mmol), and cesium carbonate (48.9 mg, 0.15 mmol) were added. After stirring at 80 ° C for 8 hours, the solvent was recovered by concentration under reduced pressure. After separation by column chromatography (petroleum ether / ethyl acetate = 5 / 1, v / v), 32.0 mg of product III-3b was obtained as a red oil with a yield of 68%.

[0050] Structural characterization of II-3b: red solid, mp: 132-133℃, 1H NMR (400MHz, CDCl3): δ10.04(s,1H),8.52(s,1H),8.14(d,J=8.3Hz,1H),7.85–7.77(m,2H),7.60(ddd,J=8.1,6.0, 1.8Hz,1H),7.42–7.37(m,3H),7.34–7.27(m,5H),7.24–7.20(m,2H),3.79(q,J=7.2Hz,2H),1.31(t,J=7.2Hz,3H), such as Figure 3 as shown. 13 C NMR (100 MHz, CDCl3) δ 177.0, 171.6, 163.9, 157.1, 153.6, 149.9, 147.5, 143.3, 138.7, 134.9, 133.8, 129.8, 129.7, 129.6, 129.3, 128.8, 128.35, 128.33, 126.8, 125.6, 116.5, 114.4, 101.0, 32.7, 13.9, as Figure 4 HRMS (ESI) m / z calculated for C 30 H 21 N3O3[M+H] + =472.1655,found=472.1650

[0051] Example 12: Preparation of (E)-4-(1-(4-chlorophenyl)-2-phenylbenzo[b][1,8]naphthyridine-4(1H)-ylidene)-1-ethylpyrrolidine-2,3,5-trione (III-3c)

[0052]

[0053] Using N,N-dimethylformamide (2mL) as solvent, I-1c (25.0mg, 0.1mmol) and II-2a (67.4mg, 0.2mmol), and cesium carbonate (48.9mg, 0.15mmol) were added, and the reaction was stirred at 80°C for 8 hours, and then the solvent was recovered by concentration under reduced pressure. After separation by column chromatography (petroleum ether / ethyl acetate = 5 / 1, v / v), 32.0mg of product III-3c was obtained as a red oil with a yield of 66%.

[0054] Structural characterization of III-3c: red solid, mp: 152-153℃, 1H NMR (400MHz, CDCl3): δ10.05(s,1H),8.53(s,1H),8.14(d,J=8.3Hz,1H),7.90–7.78(m,2H),7.61(ddd,J=8.0,6.2,1.5Hz,1H ),7.39–7.37(m,1H),7.37–7.33(m,2H),7.33–7.27(m,4H),7.20–7.13(m,2H),3.77(q,J=7.2Hz,2H),1.30(t,J=7.2Hz,3H), such as Figure 5 as shown. 13 C NMR (100 MHz, CDCl3): δ 177.2, 171.3, 163.7, 156.7, 153.6, 149.8, 147.4, 143.4, 137.2, 134.8, 134.6, 134.0, 131.0, 130.0, 129.7, 129.3, 129.1, 128.6, 128.2, 126.9, 125.6, 116.3, 114.2, 101.4, 32.7, 13.8, as Figure 6 HRMS (ESI) m / z calculated for C 30 H 20 ClN3O3[M+H] + =506.1266,found=506.1270.

[0055] Example 13: Preparation of (E)-1-ethyl-4-(1-(4-fluorophenyl)-2-phenylbenzo[b][1,8]naphthyridine-4(1H)-ylidene)pyrrolidine-2,3,5-trione (III-3d)

[0056]

[0057] Using N,N-dimethylformamide (2 mL) as solvent, I-1d (23.4 mg, 0.1 mmol) and II-2a (67.4 mg, 0.2 mmol), and cesium carbonate (48.9 mg, 0.15 mmol) were added, and the reaction was stirred at 80 ° C for 8 hours, and then the solvent was recovered by concentration under reduced pressure. After separation by column chromatography (petroleum ether / ethyl acetate = 5 / 1, v / v), 48.9 mg of product III-3d was obtained as a red oil with a yield of 63%.

[0058] Structural characterization of III-3d: red solid, mp: 119-120℃, 1H NMR (400MHz, CDCl3) δ10.06(s,1H),8.53(s,1H),8.14(d,J=8.3Hz,1H),7.88–7.78(m,2H),7.65–7.57(m,1H) ,7.35–7.28(m,5H),7.23–7.17(m,2H),7.09(t,J=8.5Hz,2H),3.78(q,J=7.1Hz,2H),1.30(t,J=7.3Hz,3H), such as Figure 7 as shown. 13 C NMR (100 MHz, CDCl3) δ 171.4, 163.7, 160.9, 156.9, 153.6, 149.8, 147.5, 143.4, 134.8, 134.0, 131.4, 131.3, 129.9, 129.7, 129.2, 128.5, 128.2, 126.9, 125.6, 116.4, 116.1, 115.8, 114.2, 101.3, 32.7, 13.8, as Figure 8 as shown. 19 F NMR(377MHz,CDCl3)δ-110.22–-113.73(m).HRMS(ESI)m / z calculated for C 30 H 20 FN3O3[M+H] + =490.1561,found=490.1570.

[0059] Example 14: Preparation of (E)-1-ethyl-4-(1-(4-iodophenyl)-2-phenylbenzo[b][1,8]naphthyridine-4(1H)-ylidene)pyrrolidine-2,3,5-trione (III-3e)

[0060]

[0061] Using N,N-dimethylformamide (2 mL) as solvent, I-1e (34.2 mg, 0.1 mmol) and II-2a (67.4 mg, 0.2 mmol), and cesium carbonate (48.9 mg, 0.15 mmol) were added, and the reaction was stirred at 80 ° C for 8 hours, and then the solvent was recovered by concentration under reduced pressure. After separation by column chromatography (petroleum ether / ethyl acetate = 5 / 1, v / v), 40.6 mg of product III-3d was obtained as a red oil with a yield of 68%.

[0062] Structural characterization of III-3e: red solid, mp: 155-156℃, 1H NMR (400MHz, CDCl3): δ10.03(s,1H),8.50(s,1H),8.11(d,J=8.3Hz,1H),7.88–7.78(m,2H),7.72(d,J=8.5Hz,2 H),7.64–7.55(m,1H),7.39–7.27(m,5H),6.98(d,J=8.5Hz,2H),3.74(q,J=7.1Hz,2H),1.28(t,J=7.2Hz,3H), such as Fig. 9 as shown. 13 C NMR (100 MHz, CDCl3): δ 177.1, 171.2, 163.6, 156.5, 153.4, 149.7, 147.2, 143.3, 138.4, 138.0, 134.6, 133.9, 131.4, 130.0, 129.7, 129.3, 128.5, 128.2, 126.8, 125.5, 116.3, 114.2, 101.3, 94.4, 32.6, 13.8, as Fig.10 HRMS (ESI) m / z calculated for C 30 H 20 IN3O3[M+H] + =598.0622,found=598.0615.

[0063] Embodiment 15-47:

[0064] In Example 11-47, the present invention uses the aminomaleimide compound represented by formula (I) and the 2-chloroquinoline-3-α,β-unsaturated carbonyl compound represented by formula (II) as raw materials to prepare the substituent R 1 , R 2 , R 3 and R 4 Various variations of dibenzo[b][1,8]naphthyridine-ylidene-pyrrolidine-2,3,5-trione compounds are shown in Table 2. The reaction process is:

[0065] Using N,N-dimethylformamide (2 mL) as solvent, add aminomaleimide compound (0.1 mmol) represented by formula (I) and 2-chloroquinoline-3-α,β-unsaturated carbonyl compound (0.2 mmol) represented by formula (II) into a Shrek tube (15 mL), and add cesium carbonate (0.15 mmol). After stirring and reacting at 80° C. for 8-12 hours, the solvent is recovered by concentration under reduced pressure, and separated by column chromatography (petroleum ether / ethyl acetate=5 / 1, v / v) to obtain the target product represented by formula (III), as shown in Table 2.

[0066]

[0067] Table 2

[0068]

[0069]

[0070] The following is the structural characterization of Compound III of Example 11-45, as follows:

[0071] Structural characterization of III-3f: red solid, mp: 108-109℃, 1 H NMR (400MHz, CDCl3): δ10.04(s,1H),8.51(s,1H),8.13(d,J=8.4Hz,1H),7.83–7.79(m,2H),7.62–7.56(m,1H),7.30(qd,J =7.2, 3.4Hz, 5H), 7.18 (d, J = 8.1Hz, 2H), 7.08 (d, J = 8.3Hz, 2H), 3.77 (q, J = 7.2Hz, 2H), 2.39 (s, 3H), 1.30 (t, J = 7.2Hz, 3H). 13 C NMR (100MHz, CDCl3): δ176.9,171.6,163.9,157.3,153.5,149.9,147.6,143.2,138.8,136.1,135.0,133.7,129. 7,129.7,129.4,129.3,129.3,128.4,128.3,126.7,125.6,116.6,114.5,100.8,32.6,21.2,13.9.HRMS(ESI)m / z calculated for C 31 H 23 N3O3[M+H] + =486.1812,found=486.1816.

[0072] Structural characterization of III-3g: red solid, mp: 137-138℃, 11H NMR (400 MHz, CDCl3): δ 10.01 (s, 1H), 8.50 (s, 1H), 8.13 (d, J = 8.4 Hz, 1H), 7.82 (d, J = 3.4 Hz, 2H), 7.63–7.55 (m, 1H), 7.37–7.27 (m, 5H), 7.14–7.08 (m, 2H), 6.92–6.83 (m, 2H), 3.83 (s, 3H), 3.76 (d, J = 7.2 Hz, 2H), 1.30 (t, J = 7.1 Hz, 3H). 13 13C NMR (100 MHz, CDCl3): δ 176.9, 171.5, 163.9, 159.4, 157.5, 153.5, 149.9, 147.7, 143.2, 135.1, 133.7, 131.3, 130.6, 129.70, 129.66, 129.3, 128.4, 128.3, 126.7, 125.5, 116.6, 114.5, 113.9, 100.7, 55.4, 32.6, 13.9. HRMS (ESI) m / z calculated for C 31 H 23 N3O4 [M + H]+ + = 502.1761, found = 502.1755.

[0073] Structural characterization of III-3h: red solid, m.p.: 149 - 150 °C, 1 1H NMR (400 MHz, CDCl3): δ 10.04 (s, 1H), 8.52 (s, 1H), 8.14 (d, J = 8.4 Hz, 1H), 7.83 (d, J = 3.4 Hz, 2H), 7.63–7.58 (m, 1H), 7.36–7.29 (m, 5H), 7.24–7.20 (m, 2H), 7.16–7.08 (m, 2H), 3.78 (q, J = 7.2 Hz, 2H), 2.50 (s, 3H), 1.30 (t, J = 7.2 Hz, 3H). 13 13C NMR (100 MHz, CDCl3): δ 171.5, 163.9, 161.2, 157.1, 153.5, 149.8, 147.5, 143.3, 140.1, 135.3, 134.9, 133.8, 129.9, 129.8, 129.7, 129.3, 128.5, 128.3, 126.8, 125.8, 125.6, 116.5, 114.5, 101.0, 32.7, 15.3, 13.9. HRMS (ESI) m / z calculated for C 31 H23 N3O3S[M+H] + =518.1532,found=518.1539.

[0074] Structural characterization of III-3i: red solid, mp: 252-253℃, 1 H NMR (400MHz, CDCl3): δ10.07(s,1H),8.55(s,1H),8.13(d,J=8.2Hz,1H),7.87–7.76(m,2H),7.67(d,J=8.4Hz,2H ),7.61(t,J=7.4Hz,1H),7.38(d,J=8.3Hz,2H),7.36–7.27(m,5H),3.76(q,J=7.1Hz,2H),1.30(t,J=6.0Hz,3H). 13 C NMR (100MHz, CDCl3): δ171.2,163.5,156.3,153.5,149.7,147.2,143.5,141.8,134.4,134.1,130. 4,130.1,129.7,129.3,128.6,128.1,126.9,126.0,125.9,125.6,116.2,114.1,101.7,32.7,13.8. 19 F NMR(377MHz,CDCl3):δ-62.60.HRMS(ESI)m / z calculated for C 31 H 20 F3N3O3[M+H] + =506.1266,found=506.1270.

[0075] Structural characterization of III-3j: red solid, mp: 169-170℃, 1 H NMR (400MHz, CDCl3): δ10.06(s,1H),8.55(s,1H),8.12(d,J=8.2Hz,1H),7.89–7.82(m,1H),7.77(d,J=8.6Hz,1H),7.70(d,J=8. 5Hz,2H),7.61(t,J=7.5Hz,1H),7.39(d,J=8.5Hz,3H),7.29(dd,J=8.1,4.1Hz,4H),3.74(q,J=7.2Hz,2H),1.28(t,J=7.2Hz,3H). 13C NMR (100MHz, CDCl3): δ177.4,171.0,163.4,155.8,153.4,149.6,147.1,143.6,142.7,134.3,134.2,132.6,130. 9,130.3,129.8,129.2,128.7,128.0,127.0,125.5,117.7,116.1,113.9,112.8,102.1,32.8,13.8.HRMS(ESI)m / z calculated for C 31 H 20 N4O3[M+H] + =497.1608,found=497.1612.

[0076] Structural characterization of III-3k: red solid, mp: 145-146℃, 1 H NMR (400MHz, CDCl3): δ10.05(s,1H),8.54(s,1H),8.14(d,J=8.3Hz,1H),7.82(dd,J=8.0,5.5Hz,2H),7.61(t,J=7.2Hz,5H),7.4 7(t,J=7.5Hz,2H),7.40(d,J=7.3Hz,1H),7.36–7.33(m,2H),7.30(t,J=8.4Hz,5H),3.78(q,J=7.2Hz,2H),1.31(t,J=7.2Hz,3H). 13 C NMR (100MHz, CDCl3): δ177.0,171.5,163.8,157.1,153.5,149.8,147.5,143.3,141.5,139.5,137.7,134.9,133.8,129.9,1 29.8,129.7,129.3,128.9,128.4,128.3,128.0,127.3,127.1,126.8,125.6,116.5,114.5,101.0,32.7,13.9.HRMS(ESI)m / z calculated for C 36 H 25 N3O3[M+H] + =548.1968,found=548.1972.

[0077] Structural characterization of III-3l: red solid, mp: 239-240℃, 11H NMR (400 MHz, CDCl3): δ 10.04 (s, 1H), 8.51 (s, 1H), 8.14 (d, J = 8.4 Hz, 1H), 7.82 (d, J = 3.4 Hz, 2H), 7.59 (dt, J = 8.1, 3.9 Hz, 1H), 7.29 (ddd, J = 13.6, 8.3, 4.4 Hz, 6H), 7.17 (d, J = 7.6 Hz, 1H), 7.06–6.96 (m, 2H), 3.77 (d, J = 7.2 Hz, 2H), 2.31 (s, 3H), 1.30 (t, J = 7.2 Hz, 3H). 13 13C NMR (100 MHz, CDCl3): δ 176.9, 171.6, 163.9, 157.2, 153.9, 153.5, 149.9, 147.5, 143.2, 138.9, 138.5, 135.0, 133.7, 130.0, 129.7, 129.7, 129.5, 129.2, 128.5, 128.4, 128.3, 126.8, 125.6, 116.6, 114.5, 100.8, 77.3, 77.0, 76.7, 32.6, 21.2, 13.9. HRMS (ESI) m / z calculated for C 31 H 23 N3O3 [M + H] + = 486.1812, found = 486.1814.

[0078] Structural characterization of III-3m: red solid, m.p.: 262 - 263 °C, 1 1H NMR (400 MHz, CDCl3): δ 10.06 (s, 1H), 8.53 (s, 1H), 8.14 (d, J = 8.4 Hz, 1H), 7.88–7.80 (m, 2H), 7.61 (ddd, J = 8.1, 5.8, 2.1 Hz, 1H), 7.52 (ddd, J = 8.0, 1.7, 1.0 Hz, 1H), 7.44 (t, J = 1.9 Hz, 1H), 7.36–7.28 (m, 5H), 7.25 (d, J = 8.1 Hz, 1H), 7.15 (ddd, J = 8.0, 1.9, 0.9 Hz, 1H), 3.77 (q, J = 7.2 Hz, 2H), 1.30 (t, J = 7.1 Hz, 3H). 1313C NMR (100 MHz, CDCl3): δ 171.3, 168.5, 163.6, 156.5, 153.5, 149.7, 147.3, 143.4, 139.7, 134.5, 134.0, 132.9, 132.0, 130.0, 129.9, 129.7, 129.2, 128.5, 128.5, 128.2, 126.9, 125.6, 122.0, 116.3, 114.0, 101.6, 32.7, 13.8. HRMS (ESI) m / z calculated for C 30 H 20 BrN3O3 [M + H] + = 550.0760, found = 550.0777.

[0079] Structural characterization of III-3n: red solid, m.p.: 256 - 257 °C, 1 1H NMR (400 MHz, CDCl3): δ 10.06 (s, 1H), 8.53 (s, 1H), 8.14 (d, J = 8.3 Hz, 1H), 7.88–7.78 (m, 2H), 7.61 (ddd, J = 8.1, 6.1, 1.7 Hz, 1H), 7.38–7.29 (m, 6H), 7.11 (td, J = 8.3, 1.8 Hz, 1H), 7.03 (ddd, J = 17.3, 9.7, 5.0 Hz, 2H), 3.77 (q, J = 7.2 Hz, 2H), 1.30 (t, J = 7.2 Hz, 3H). 13 13C NMR (100 MHz, CDCl3): δ 171.3, 163.6, 161.2, 156.6, 153.6, 149.8, 147.3, 143.4, 139.8, 134.6, 134.0, 130.0, 129.9, 129.7, 129.2, 128.5, 128.2, 126.9, 125.6, 117.8, 117.5, 116.3, 116.2, 116.0, 114.1, 101.5, 32.7, 13.8. 19 19F NMR (377 MHz, CDCl3): δ -111.20 (dd, J = 15.1, 8.3 Hz). HRMS (ESI) m / z calculated for C 30 H 20 FN3O3 [M + H] + = 490.1561, found = 490.1567.

[0080] Structural characterization of III-3o: red solid, mp: 271-272℃, 1 H NMR (400MHz, CDCl3): δ10.05(s,1H),8.53(s,1H),8.14(d,J=8.3Hz,1H),7.89–7.79(m,2H),7.61(ddd,J=8.0,6.0, 1.7Hz,1H),7.40–7.32(m,3H),7.32–7.28(m,5H),7.13–7.08(m,1H),3.77(q,J=7.1Hz,2H),1.30(t,J=7.1Hz,3H). 13 C NMR (100MHz, CDCl3): δ177.6,171.3,163.6,156.5,153.6,149.7,147.3,143.4,139.6,134.5,134.4,134.0,130.1,130.0,1 29.73,129.72,129.2,129.1,128.5,128.2,128.0,126.9,125.6,116.3,114.1,101.5,32.7,13.8.HRMS(ESI)m / zcalculated for C 30 H 20 ClN3O3[M+H] + =506.1266,found=506.1273.

[0081] Structural characterization of III-3p: red solid, mp: 232-233℃, 1 H NMR (400MHz, CDCl3): δ10.02(s,1H),8.50(s,1H),8.13(d,J=8.4Hz,1H),7.82(dd,J=7.9,4.5Hz,2H),7.63–7.56(m,1H),7.36–7.26(m,6H) ),6.94–6.89(m,1H),6.82(dd,J=7.8,1.1Hz,1H),6.76(t,J=2.1Hz,1H),3.76(dd,J=14.2,7.1Hz,2H),3.73(s,3H),1.29(t,J=7.2Hz,3H). 13C NMR (100MHz, CDCl3): δ177.0,171.5,163.9,159.8,157.0,153.5,149.9,147.4,143.2,139.5,134.9,133.8,129.8,129.7 ,129.4,129.1,128.35,128.33,126.8,125.6,122.1,116.5,115.6,114.5,114.4,100.9,55.5,32.6,13.9.HRMS(ESI)m / z calculated for C 31 H 23 N3O4[M+H] + =502.1761,found=502.1770.

[0082] Structural characterization of III-3q: red solid, mp: 284-285℃, 1 H NMR (400MHz, CDCl3): δ10.11(s,1H),8.59(s,1H),8.28–8.23(m,1H),8.18–8.13(m,2H),7.88–7.82(m,1H),7.76(d,J=8. 5Hz,1H),7.63(dd,J=8.2,1.2Hz,1H),7.61–7.57(m,2H),7.35–7.28(m,5H),3.77(q,J=7.2Hz,2H),1.30(t,J=7.1Hz,3H). 13 C NMR (100MHz, CDCl3): δ177.4,171.0,163.3,155.9,153.5,149.6,148.2,147.2,143.7,139.7,135.9,134.2,130.2,1 29.8,129.6,129.3,128.8,128.0,127.0,125.6,125.3,123.7,119.6,116.1,113.8,102.3,32.8,13.8.HRMS(ESI)m / z calculated for C 30 H 20 N4O5[M+H] + =517.1506,found=517.1514.

[0083] Structural characterization of III-3r: red solid, mp: 239-240℃, 11H NMR (400 MHz, CDCl3): δ 10.07 (s, 1H), 8.54 (s, 1H), 8.14 (d, J = 8.3 Hz, 1H), 7.82 (ddd, J = 13.4, 10.5, 4.5 Hz, 2H), 7.63–7.57 (m, 1H), 7.44–7.38 (m, 1H), 7.36 (d, J = 8.0 Hz, 3H), 7.31 (d, J = 6.9 Hz, 2H), 7.20–7.13 (m, 3H), 3.79 (q, J = 7.2 Hz, 2H), 1.31 (t, J = 7.2 Hz, 3H). 13 13C NMR (100 MHz, CDCl3): δ 173.1, 171.3, 163.6, 157.0, 153.9, 149.9, 146.9, 143.4, 134.4, 133.9, 131.2, 131.1, 130.7, 130.1, 129.8, 128.6, 128.4, 128.2, 126.7, 125.7, 124.4, 124.4, 116.2, 116.0, 113.8, 101.7, 32.7, 13.8. 19 19F NMR (377 MHz, CDCl3) δ -118.51 (dd, J = 8.8, 6.1 Hz). HRMS (ESI) m / z calculated for C 30 H 20 FN3O3 [M + H] + = 490.1561, found = 490.1556.

[0084] Structural characterization of III-3s: red solid, m.p.: 257 - 258 °C, 1 1H NMR (400 MHz, CDCl3): δ 10.09 (s, 1H), 8.54 (s, 1H), 8.14 (d, J = 8.3 Hz, 1H), 7.85–7.75 (m, 2H), 7.60 (ddd, J = 8.0, 5.0, 1.3 Hz, 1H), 7.46 (dd, J = 8.0, 1.4 Hz, 1H), 7.38 (ddd, J = 9.1, 5.1, 1.4 Hz, 3H), 7.35–7.32 (m, 1H), 7.29 (ddd, J = 8.5, 4.2, 2.6 Hz, 3H), 7.24 (dd, J = 7.8, 1.7 Hz, 1H), 3.78 (q, J = 7.2 Hz, 2H), 1.30 (t, J = 7.2 Hz, 3H). 13C NMR (100MHz, CDCl3): δ177.2,171.4,163.7,156.9,153.9,150.0,146.8,143.4,136.8,134.2,133.9,133.2,131.3,130.4, 130.1,130.0,129.8,128.8,128.3,128.2,127.3,126.8,125.7,116.3,114.0,101.6,32.7,13.8.HRMS(ESI)m / zcalculated for C 30 H 20 ClN3O3[M+H] + =506.1266,found=506.1273.

[0085] Structural characterization of III-3t: red solid, mp: 232-233℃, 1 H NMR (400MHz, CDCl3): δ10.01(s,1H),8.47(s,1H),8.13(d,J=8.4Hz,1H),7.79(d,J=2.5Hz,2H),7.60–7.56(m,1H),7.40–7.30(m,4H),7.29–7.2 6(m,2H),7.17(dd,J=7.8,1.6Hz,1H),6.98(td,J=7.7,1.1Hz,1H),6.91 –6.86(m,1H),3.78(q,J=7.2Hz,2H),3.59(s,3H),1.31(t,J=7.2Hz,3H). 13 C NMR (100MHz, CDCl3): δ176.8,171.7,164.1,158.2,154.6,153.9,150.0,147.1,143.1,134.8,133.6,130.7,130.5,129. 9,129.7,128.7,128.3,128.0,127.7,126.6,125.7,120.4,116.7,114.4,111.8,100.6,55.5,32.6,13.9.HRMS(ESI)m / z calculated forC 31 H 23 N3O4[M+H] + =502.1761,found=502.1770.

[0086] Structural characterization of III-3u: red solid, mp: 231-232℃, 11H NMR (400 MHz, CDCl3): δ 10.06 (s, 1H), 8.52 (s, 1H), 8.15 (d, J = 8.4 Hz, 1H), 7.82 (d, J = 3.6 Hz, 2H), 7.60 (ddd, J = 8.1, 4.7, 3.1 Hz, 1H), 7.34–7.27 (m, 5H), 7.12 (q, J = 8.2 Hz, 2H), 6.83 (s, 1H), 3.79 (q, J = 7.2 Hz, 2H), 2.24 (s, 3H), 1.93 (s, 3H), 1.31 (t, J = 7.2 Hz, 3H). 13 13C NMR (100 MHz, CDCl3): δ 176.9, 171.7, 164.0, 157.3, 153.6, 150.1, 146.9, 143.3, 137.8, 136.3, 134.6, 133.8, 132.8, 130.5, 130.0, 130.0, 129.8, 129.7, 128.9, 128.4, 128.2, 126.8, 125.6, 116.6, 114.6, 100.7, 32.6, 20.7, 17.7, 13.9. HRMS (ESI) m / z calculated for C 32 H 25 N3O3 [M + H] + = 500.1968, found = 500.1978.

[0087] Structural characterization of III-3v: red solid, m.p.: 221 - 222 °C, 1 1H NMR (400 MHz, CDCl3) δ 10.05 (s, 1H), 8.51 (s, 1H), 8.14 (d, J = 8.4 Hz, 1H), 7.81 (d, J = 3.5 Hz, 2H), 7.60 (ddd, J = 8.1, 4.5, 3.3 Hz, 1H), 7.36–7.27 (m, 5H), 7.06 (s, 1H), 6.99 (d, J = 8.1 Hz, 1H), 6.92 (d, J = 8.0 Hz, 1H), 3.79 (q, J = 7.2 Hz, 2H), 2.35 (s, 3H), 1.93 (s, 3H), 1.31 (t, J = 7.2 Hz, 3H). 13C NMR (100MHz, CDCl3): δ176.9,171.7,164.0,157.5,153.6,150.2,147.0,143.3,139.2,135.5,135.4,134.7,133.7,131.4, 129.9,129.7,129.2,129.0,128.4,128.3,127.2,126.8,125.6,116.6,114.7,100.7,32.6,21.2,18.1,13.9.HRMS(ESI)m / z calculated forC 32 H 25 N3O3[M+H] + =500.1968,found=500.1976.

[0088] Structural characterization of III-3w: red solid, mp: 254-255℃, 1 H NMR (400MHz, CDCl3): δ10.06(s,1H),8.51(s,1H),8.14(d,J=8.4Hz,1H),7.81(dd,J=5.6,1.2Hz,2H),7.62–7.57(m,1H),7.35–7.26(m,5H), 7.19(d,J=7.5Hz,1H),7.09(t,J=7.7Hz,1H),6.92(d,J=7.7Hz,1H),3.79(q,J=7.2Hz,2H),2.28(s,3H),1.83(s,3H),1.31(t,J=7.2Hz,3H). 13 C NMR (100MHz, CDCl3): δ176.9,171.7,164.0,157.5,153.6,150.1,147.0,143.3,138.1,138.0,134.6,134.4,133.7,130.6, 129.9,129.7,128.9,128.4,128.2,127.2,126.8,125.7,125.6,116.6,114.6,100.7,32.6,20.3,15.0,13.9.HRMS(ESI)m / z calculated forC 32 H 25 N3O3[M+H] + =500.1968,found=500.1971.

[0089] Structural characterization of III-3x: red solid, mp: 283-284℃, 11H NMR (400 MHz, CDCl3): δ 10.09 (s, 1H), 8.59 (s, 1H), 8.13 (d, J = 8.2 Hz, 1H), 7.90 (d, J = 8.3 Hz, 2H), 7.72–7.67 (m, 1H), 7.58–7.48 (m, 3H), 7.48–7.35 (m, 3H), 7.30 (dd, J = 7.3, 0.8 Hz, 1H), 7.21–7.15 (m, 3H), 7.07 (t, J = 7.6 Hz, 2H), 3.80 (q, J = 7.2 Hz, 2H), 1.32 (dd, J = 9.5, 4.9 Hz, 3H). 13 13C NMR (100 MHz, CDCl3): δ 177.1, 171.6, 163.9, 158.1, 153.8, 150.0, 147.7, 143.3, 135.7, 134.6, 133.7, 130.9, 129.8, 129.7, 129.6, 128.5, 128.4, 128.3, 128.0, 127.7, 127.6, 126.8, 126.6, 125.7, 124.9, 122.5, 116.4, 114.4, 101.1, 32.7, 13.9. HRMS (ESI) m / z calculated for C 34 H 23 N3O3 [M + H] + = 522.1812, found = 522.1812.

[0090] Structural characterization of III-3y: red solid, m.p.: 258 - 259 °C, 1 1H NMR (400 MHz, CDCl3): δ 10.01 (s, 1H), 8.48 (s, 1H), 8.13 (d, J = 8.3 Hz, 1H), 7.90–7.80 (m, 2H), 7.60 (ddd, J = 8.1, 6.2, 1.6 Hz, 1H), 7.40–7.30 (m, 5H), 6.76 (dd, J = 14.8, 5.1 Hz, 2H), 6.58 (d, J = 2.1 Hz, 1H), 6.06 (d, J = 17.8 Hz, 2H), 3.76 (q, J = 7.2 Hz, 2H), 1.29 (t, J = 7.2 Hz, 3H). 13C NMR (100MHz, CDCl3): δ177.0,171.5,163.8,157.3,153.5,149.9,147.9,147.8,147.7,143.3,135.0,133.8,132.2,129. 8,129.7,129.1,128.4,128.3,126.8,125.6,123.2,116.5,114.4,110.7,107.9,102.0,101.0,32.6,13.9.HRMS(ESI)m / z calculated for C 31 H 21 N3O5[M+H] + =516.1554,found=516.1564.

[0091] Structural characterization of III-3z: red solid, mp: 186-187℃, 1 H NMR (400MHz, CDCl3): δ9.99(s,1H),8.48(s,1H),8.11(d,J=8.3Hz,1H),7.89–7.76(m,2H),7.56(t,J=7.1Hz,1H),7.31(td, J=7.6,3.4Hz,5H),7.01(d,J=8.9Hz,2H),6.62(d,J=8.9Hz,2H),3.76(q,J=7.1Hz,2H),2.98(s,6H),1.29(t,J=7.2Hz,3H). 13 C NMR (100MHz, CDCl3): δ176.6,171.7,164.1,157.9,153.2,149.9,149.9,147.9,143.1,135.4,133.5,129.9,129. 6,129.5,129.2,128.5,128.3,127.0,126.6,125.5,116.8,114.8,111.3,100.2,40.2,32.5,13.9.HRMS(ESI)m / z calculated for C 32 H 26 N4O3[M+H] + =515.2077,found=515.2081.

[0092] Structural characterization of III-3aa: red solid, mp: 277-278℃, 11H NMR (400 MHz, CDCl3): δ 10.09 (s, 1H), 8.60 (s, 1H), 8.16 (t, J = 6.8 Hz, 3H), 7.91 (dt, J = 6.5, 4.7 Hz, 2H), 7.61 (ddt, J = 9.5, 4.7, 2.0 Hz, 4H), 7.47–7.43 (m, 4H), 7.39–7.32 (m, 8H), 3.79 (q, J = 7.2 Hz, 2H), 1.32 (t, J = 7.2 Hz, 3H). 13 13C NMR (100 MHz, CDCl3): δ 177.1, 171.4, 165.5, 156.8, 153.6, 149.8, 147.4, 143.4, 140.4, 138.0, 137.3, 134.8, 134.0, 131.3, 130.0, 129.8, 129.4, 128.5, 128.2, 127.1, 126.9, 126.1, 125.6, 123.5, 120.5, 120.4, 116.4, 114.2, 109.4, 32.7, 13.9. HRMS (ESI) m / z calculated for C 42 H 28 N4O3 [M + H] + = 637.2234, found = 637.2229.

[0093] Structural characterization of III-3ad: red solid, m.p.: 109 - 110 °C, 1 1H NMR (400 MHz, CDCl3): δ 10.07 (s, 1H), 8.18 (s, 1H), 8.15–8.10 (m, 2H), 7.91 (dd, J = 8.0, 3.7 Hz, 2H), 7.74 (ddd, J = 8.4, 6.8, 1.3 Hz, 1H), 7.50 (tdd, J = 6.9, 4.2, 2.5 Hz, 4H), 4.97 (q, J = 7.0 Hz, 2H), 3.69 (q, J = 7.2 Hz, 2H), 1.45 (t, J = 7.0 Hz, 3H), 1.29 (t, J = 7.2 Hz, 3H). 13 13C NMR (100 MHz, CDCl3): δ 189.6, 167.4, 163.4, 147.9, 147.0, 141.4, 141.2, 140.6, 138.5, 132.1, 129.1, 128.5, 128.3, 127.6, 126.1, 125.4, 118.5, 112.2, 107.5, 39.6, 33.0, 14.6, 13.9. HRMS (ESI) m / z calculated for C26 H 21 N3O3[M+H] + =423.1582,found=423.1581.

[0094] Structural characterization of III-3af: red solid, mp: 142-143℃, 1 H NMR (400MHz, CDCl3): δ10.06(s,1H),8.56(s,1H),8.17(d,J=8.4Hz,1H),7.85(d,J=3.5Hz,2H),7.65–7.59(m,1H),7.5 1(t,J=7.3Hz,4H),7.37(d,J=6.9Hz,1H),7.33–7.27(m,5H),7.20(d,J=8.1Hz,2H),7.11(d,J=8.0Hz,2H),2.40(s,3H). 13 C NMR (100MHz, CDCl3): δ175.7,170.8,163.1,157.9,154.1,150.0,147.4,143.3,139.0,135.9,134.8,134.0,131.9,129.9,129.8 129.5,129.3,129.2,128.9,128.4,128.4,127.7,127.0,126.4,125.7,116.9,115.7,99.9,21.3.HRMS(ESI)m / z calculated for C 35 H 23 N3O3[M+H] + =534.1812,found=534.1805.

[0095] Structural characterization of III-3ag: red solid, mp: 144-145℃, 1 H NMR (400MHz, CDCl3): δ9.98(s,1H),8.47(s,1H),8.11(d,J=8.3Hz,1H),7.80(t,J=6.4Hz,2H),7.62–7.53(m,1H),7.48(d,J=7.3Hz ,2H),7.29(dd,J=11.2,7.6Hz,7H),7.24(d,J=7.3Hz,1H),7.18(d,J=8.1Hz,2H),7.09(d,J=8.1Hz,2H),4.86(s,2H),2.38(s,3H). 1313C NMR (100 MHz, CDCl3): δ 176.5, 171.1, 163.7, 157.4, 153.5, 149.8, 147.4, 143.1, 138.8, 136.7, 135.9, 134.9, 133.7, 129.7, 129.6, 129.4, 129.20, 129.16, 128.54, 128.47, 128.2, 127.7, 127.5, 126.7, 125.5, 116.5, 114.6, 100.6, 41.2, 21.2. HRMS (ESI) m / z calculated for C 36 H 25 N3O3 [M + H] + = 548.1968, found = 548.1971.

[0096] Structural characterization of III-(R)-3ah: red solid, m.p.: 139 - 140 °C, 1 1H NMR (400 MHz, CDCl3): δ 9.97 (s, 1H), 8.46 (s, 1H), 8.13 (d, J = 8.4 Hz, 1H), 7.83 (d, J = 3.4 Hz, 2H), 7.60 (dt, J = 8.1, 3.9 Hz, 1H), 7.35–7.28 (m, 5H), 7.18 (d, J = 8.1 Hz, 2H), 7.08 (d, J = 8.3 Hz, 2H), 4.13 (td, J = 6.9, 3.0 Hz, 1H), 3.80 (ddd, J = 21.5, 14.1, 5.2 Hz, 2H), 3.10 (s, 1H), 2.39 (s, 3H), 1.27 (d, J = 6.4 Hz, 3H). 13 13C NMR (100 MHz, CDCl3): δ 176.2, 172.7, 164.6, 157.7, 153.7, 149.9, 147.4, 143.2, 138.9, 135.9, 134.8, 133.9, 129.8, 129.7, 129.5, 129.3, 129.2, 128.4, 126.9, 125.6, 116.6, 115.1, 100.1, 67.1, 45.5, 21.3, 21.0. HRMS (ESI) m / z calculated for C 32 H 25 N3O4 [M + H] + = 516.1917, found = 516.1911.

[0097] Structural characterization of III-(S)-3ah: red solid, mp: 139-140℃, 1 H NMR (400MHz, CDCl3): δ9.97 (s, 1H), 8.46 (s, 1H), 8.13 (d, J = 8.3Hz, 1H), 7.8 3(d,J=3.5Hz,2H),7.60(dd,J=8.2,4.0Hz,1H),7.32(dt,J=10.8,4.3Hz,5H) ,7.18(d,J=8.1Hz,2H),7.08(d,J=8.2Hz,2H),4.19–4.08(m,1H),3.80(ddd ,J=21.5,14.1,5.0Hz,2H),3.10(s,1H),2.39(s,3H),1.27(d,J=6.5Hz,3H). 13 C NMR (100MHz, CDCl3): δ176.2,172.7,164.6,157.7,153.7,149.9,147.4,143.2,138.9,135.9,134.8,133.9,129. 9,129.7,129.5,129.30,129.2,128.4,126.9,125.6,116.6,115.1,100.1,67.1,45.5,21.3,21.0.HRMS(ESI)m / z calculated forC 32 H 25 N3O4[M+H] + =516.1917,found=516.1913.

[0098] Structural characterization of III-3ai: red solid, mp: 205-206℃, 1 H NMR (400MHz, CDCl3): δ9.98(s,1H),8.47(s,1H),8.13(d,J=8.4Hz,1H),7.83(d,J=3.4Hz,2H),7.60(dt,J=8.1,3.9 Hz,1H),7.36–7.28(m,5H),7.19(d,J=8.1Hz,2H),7.08(d,J=8.3Hz,2H),3.92(dt,J=9.3,4.2Hz,4H),2.39(s,3H). 13C NMR (100MHz, CDCl3): δ176.2,172.5,164.6,157.7,153.7,150.0,147.4,143.2,139.0,135.9,134.8,133.9,1 29.9,129.7,129.5,129.3,129.2,128.4,126.9,125.7,116.6,115.0,100.2,61.7,41.0,21.3.HRMS(ESI)m / z calculatedfor C 31 H 23 N3O4[M+H] + =502.1761,found=502.1757.

[0099] Structural characterization of III-3aj: red solid, mp: 243-244℃, 1 H NMR (400MHz, CDCl3): δ10.03(s,1H),8.51(s,1H),8.14(dd,J=9.1,6.1Hz,1H),7.46–7.38(m,2H),7.33–7.27( m,5H),7.18(d,J=8.1Hz,2H),7.06(d,J=8.2Hz,2H),3.77(q,J=7.2Hz,2H),2.39(s,3H),1.30(t,J=7.2Hz,3H). 13 C NMR (100MHz, CDCl3): δ177.0,171.5,163.9,157.3,153.4,151.0,148.3,143.3,138.9,135.9,134.9,132. 3,129.8,129.5,129.3,129.2,128.4,122.8,118.6,118.3,114.6,111.6,111.4,100.9,32.7,21.2,13.9. 19 F NMR(377MHz,CDCl3):δ-98.61–-103.02(m).HRMS(ESI)m / z calculated for C 31 H 22 FN3O3[M+H] + =504.1718,found=504.1728.

[0100] Structural characterization of III-3ak: red solid, mp: 280-281℃, 11H NMR (400 MHz, CDCl3): δ 9.87 (s, 1H), 8.46 (s, 1H), 7.86 (s, 1H), 7.71 (d, J = 8.8 Hz, 1H), 7.63 (dd, J = 8.8, 1.8 Hz, 1H), 7.30 (ddt, J = 11.3, 8.1, 3.9 Hz, 5H), 7.17 (d, J = 8.1 Hz, 2H), 7.08 (d, J = 8.3 Hz, 2H), 3.74 (q, J = 7.2 Hz, 2H), 2.53 (s, 3H), 2.37 (s, 3H), 1.28 (t, J = 7.2 Hz, 3H). 13 13C NMR (100 MHz, CDCl3): δ 176.7, 171.5, 163.9, 157.0, 153.4, 148.6, 147.0, 141.9, 138.7, 136.8, 136.5, 136.0, 135.0, 129.6, 129.3, 129.23, 129.19, 128.2, 127.9, 127.8, 125.6, 116.5, 114.6, 100.3, 32.5, 21.6, 21.2, 13.8. HRMS (ESI) m / z calculated for C 32 H 25 N3O3 [M + H] + = 500.1968, found = 500.1962.

[0101] Structural characterization of III-3am: red solid, m.p.: 269 - 270 °C, 1 1H NMR (400 MHz, CDCl3): δ 9.94 (s, 1H), 8.48 (s, 1H), 7.89 (d, J = 8.5 Hz, 1H), 7.43 (d, J = 8.5 Hz, 1H), 7.32 (ddd, J = 9.2, 6.6, 2.1 Hz, 5H), 7.19 (d, J = 8.1 Hz, 2H), 7.10 (d, J = 8.3 Hz, 2H), 3.78 (q, J = 7.2 Hz, 2H), 2.50 (s, 3H), 2.39 (s, 3H), 2.29 (s, 3H), 1.30 (t, J = 7.0 Hz, 3H). 13C NMR (100MHz, CDCl3): δ176.8,171.8,164.2,156.8,153.5,149.0,146.8,142.9,142.3,138.6,136.4,135.0,133.2,130 .4,129.7,129.4,129.3,129.2,128.3,126.5,124.3,115.8,114.6,100.3,32.6,21.2,21.1,13.9,12.6.HRMS(ESI)m / z calculated for C 33 H 27 N3O3[M+H] + =514.2125,found=514.2118.

[0102] Structural characterization of III-3an: red solid, mp: 230-231℃, 1 H NMR (400MHz, CDCl3): δ10.37(s,1H),8.57(s,1H),7.53(d,J=7.0Hz,1H),7.37–7.34(m,2H),7.33–7.27(m,4H),7.18(d,J =8.2Hz,2H),7.10(d,J=8.3Hz,2H),3.78(q,J=7.2Hz,2H),2.86(s,3H),2.38(s,3H),2.29(s,3H),1.31(t,J=7.2Hz,3H). 13 C NMR (100MHz, CDCl3): δ176.7,171.9,164.0,156.8,153.6,149.6,146.3,140.2,138.6,136.2,135.1,135.0,134.0,133. 2,129.7,129.4,129.23,129.15,128.3,126.5,125.6,116.0,114.6,100.3,32.6,21.2,18.9,17.0,13.9.HRMS(ESI)m / z calculated for C 33 H 27 N3O3[M+H] + =514.2125,found=514.2121.

[0103] Structural characterization of III-3ao: red solid, mp: 121-122℃, 1H NMR (400MHz, CDCl3): δ9.96 (s, 1H), 8.37 (s, 1H), 8.10 (d, J = 8.3Hz, 1H), 7.81–7.75 (m, 2H), 7.59–7.54 (m, 1H), 7.4 5(d,J=8.0Hz,2H),7.14(d,J=8.1Hz,2H),3.79(q,J=7.1Hz,2H),2.54(s,3H),2.44(s,3H),1.32(t,J=7.1Hz,3H). 13 C NMR (100MHz, CDCl3): δ176.8,171.8,164.2,156.6,153.6,149.7,147.9,143.1,139.8,135.9,133.7, 130.6,129.7,128.3,127.6,126.6,125.4,116.4,113.4,99.6,32.6,23.7,21.4,14.0.HRMS(ESI)m / z calculated for C 26 H 21 N3O3[M+H] + =424.1655,found=424.1650.

[0104] Example 48 Fluorescence Spectrum Analysis

[0105] Some of the above compounds (III) were selected for fluorescence spectral analysis. Experimental steps: Using a black flat-bottom 96-well plate, 5 mM solutions of dimethyl sulfoxide (DCM), ethanol (EtOH), toluene, 1,4-dioxane, dichloromethane and phosphate buffered saline (PBS) were placed in the well plate respectively, and excited in the range of 320 nm to 520 nm. At the corresponding excitation wavelength (λex = 420 nm), the maximum absorption intensity (I) and emission wavelength (λem) of compound (III) (3d, 3g, 3k, 3l, 3n, 3r, 3v, 3ag, 3ak) in organic solvents were obtained. As shown in Table 3, its emission wavelength is in the near-infrared spectral region, indicating that it can be used as a fluorescent dye.

[0106] Table 3

[0107]

[0108]

[0109] Example 45: In vivo imaging of human brain glioma U251 cells

[0110] Cell culture: Living human brain glioma U251 cells were cultured in heat-inactivated cell culture medium, and then the culture dish was placed in a cell incubator at 37°C, containing 5% CO2 and 95% air to allow the cells to grow attached to the wall. U251 cells were incubated with 10μM dibenzo[b][1,8]naphthyridine-ylidene-pyrrolidine-2,3,5-trione compounds for different 4h, and then treated with 4% paraformaldehyde (20min), washed 3 times with PBS, and imaged using a Leica STELLARIS5 laser confocal microscope.

[0111] like Fig.11 As shown, monofluoro-substituted dibenzo[b][1,8]naphthyridine-ylidene-pyrrolidine-2,3,5-trione compounds (3d, 3n, 3r) exhibited near-infrared photophysical properties (λex = 420 nm, λem ≈ 744 nm) in PBS, and showed good imaging effects after incubation with living human glioma U251 cells for 4 hours.

[0112] In addition, compound III-3ag was selected and imaged using a Leica STELLARIS5 laser confocal microscope after incubation in living human brain glioma U251 cells for 4 hours. Fig.12 As shown, it shows that it has a better imaging effect.

[0113] Therefore, the dibenzo[b][1,8]naphthyridine-ylidene-pyrrolidine-2,3,5-trione compounds III of the present invention can be used as fluorescent dyes to image living human glioma U251 cells, preliminarily showing that they have positive effects in biocompatibility and low toxicity, which provides possibilities for their potential biological applications.

[0114] The preferred embodiments of the present invention disclosed above are only used to help illustrate the present invention. The preferred embodiments do not describe all the details in detail, nor do they limit the invention to the specific implementation methods described. Obviously, many modifications and changes can be made according to the content of this specification. This specification selects and specifically describes these embodiments in order to better explain the principles and practical applications of the present invention, so that those skilled in the art can understand and use the present invention well. The present invention is limited only by the claims and their full scope and equivalents.

Claims

1. A dibenzo[b][1,8]naphthyridine-ylidene-pyrrolidine-2,3,5-trione compound, the structural formula of which is shown in (III): in, R 1 Selected from C 1-6 Alkyl, naphthyl, phenyl or substituted phenyl, wherein the substituent in the substituted phenyl is halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, phenyl, phenoxy, nitro, cyano or trifluoromethyl; R 2 Selected from C 1-6 Alkyl, phenyl, benzyl, chiral 2-hydroxypropyl or 2-hydroxyethyl; R 3 Selected from hydrogen, halogen, C 1-6 Alkyl; R 4 Selected from C 1-6 Alkyl, phenyl.

2. A method for preparing dibenzo[b][1,8]naphthyridin-ylidene-pyrrolidine-2,3,5-trione compounds as claimed in claim 1, characterized in that: The reaction formula is shown below, which comprises the following steps: placing a solution containing a 2-halogenoquinoline-3-α,β-unsaturated carbonyl compound represented by formula (I), an aminomaleimide compound represented by formula (II) and a base under stirring at 25° C. to 120° C. for 0.5 to 36 hours to obtain a dibenzo[b][1,8]naphthyridine-ylidene-pyrrolidine-2,3,5-trione compound represented by formula (III).

3. The method for preparing dibenzo[b][1,8]naphthyridin-ylidene-pyrrolidine-2,3,5-trione compounds according to claim 2, characterized in that: The molar feed ratio of the 2-halogenoquinoline-3-α,β-unsaturated carbonyl compound represented by formula (I), the aminomaleimide compound represented by formula (II) and the base is 1:1-3:1-3.

4. The method for preparing dibenzo[b][1,8]naphthyridin-ylidene-pyrrolidine-2,3,5-trione compounds according to claim 2, characterized in that: The base used in the reaction is one or more of potassium carbonate, cesium carbonate, potassium tert-butoxide, sodium tert-butoxide, potassium phosphate, potassium bicarbonate, sodium hydroxide or potassium hydroxide.

5. The method for preparing dibenzo[b][1,8]naphthyridin-ylidene-pyrrolidine-2,3,5-trione compounds according to claim 4, characterized in that: The solvent used in the reaction is one or more of toluene, tetrahydrofuran, N,N-dimethylformamide, dichloroethane, chlorobenzene, chloroform, ethyl acetate, ethanol, methanol, tert-butanol, 1,4-dioxane, acetonitrile or dimethyl sulfoxide.

6. The method for preparing dibenzo[b][1,8]naphthyridin-ylidene-pyrrolidine-2,3,5-trione compounds according to claim 5, characterized in that: Use N,N-dimethylformamide as solvent and cesium carbonate as base, and react at 70-90°C for 8-12h.

7. The method for preparing dibenzo[b][1,8]naphthyridin-ylidene-pyrrolidine-2,3,5-trione compounds according to claim 2, characterized in that: The method also includes, after the reaction is completed, using petroleum ether / ethyl acetate with a volume ratio of 10:1-2:1 to separate the reaction solution by column chromatography to obtain a dibenzo[b][1,8]naphthyridine-ylidene-pyrrolidine-2,3,5-trione compound as shown in (III).

8. Use of the dibenzo[b][1,8]naphthyridine-ylidene-pyrrolidine-2,3,5-trione compound according to claim 1 in fluorescent dyes.

9. Use of the dibenzo[b][1,8]naphthyridine-ylidene-pyrrolidine-2,3,5-trione compound of claim 1 in tumor cell imaging.

Images