Aza-substituted xanthones or chlorinated xanthone derivatives and their applications

Abstract

The present invention relates to azasubstituted xanthones or chlorinated xanthone derivatives and their applications. Using xanthone as a raw material, diverse structural modifications are carried out on the side chain outside the seven-membered ring of xanthone through different chemical reactions to obtain xanthone derivatives with the following general structure; the antibacterial activity test results show that derivatives 1, 8, and 27 have broad-spectrum and highly efficient inhibitory activities against the mycelia of the tested phytopathogenic fungi, and derivatives 1, 2, 8, 9, 20, and 27 show strong inhibitory effects on the germination of the spores of the tested phytopathogenic fungi. Therefore, they are expected to be used in the preparation of new, highly efficient, and broad-spectrum agricultural antibacterial agents.

Description

Technical Field

[0001] The present invention belongs to the technical field of fungicide synthesis and its application, and particularly relates to nitrogen-substituted xanthinin or chlorinated xanthinin derivatives and their preparation methods and applications. Background Art

[0002] Xanthatin is a natural sesquiterpene lactone isolated from Xanthium strumarium L. of the genus Xanthium in the Compositae family, and has become the focus of research in recent years due to its wide range of biological activities. In particular, the discovery that this compound has excellent insecticidal and antibacterial activities makes its application in the agricultural field have certain prospects. Among them, the literature [Meng Xueying, Shen Huimin. Structural modification of xanthatin from Xanthium extract and determination of its insecticidal activity. Journal of Gansu Agricultural University, 2015, (3): 102-112.] reported that xanthatin and some of its derivatives not only have good contact insecticidal activity against adult female Tetranychus urticae, but also have good contact, stomach toxicity and antifeedant effects on Mythimna separata. The literature [Kawazu K, Nakajima S, Ariwa M. Xanthumin and 8-epi-xanthatin as insect development inhibitors from Xanthium canadense Mill. Experientia, 1979, 35(10): 1294-1295.] reported that a xanthatin analogue has a growth inhibitory effect on Drosophila larvae. The literature [Hu Dongyan. Isolation, identification and antibacterial activity study of the chemical constituents of Xanthium. Gansu Agricultural University, 2012.] found that xanthatin has a certain growth inhibitory effect on Rhizoctonia solani of pepper and Botrytis cinerea of tomato. The literature [Saha D, Kumar R, Ghosh S, et al. Control of foliar diseases of tea with Xanthium strumarium leaf extract. Industrial Crops & Products, 2012, 37(1): 376-382.] studied the antifungal activities of xanthatin against Colletotrichum camelliae, Phyllosticta theae, Cercospora theae and Cercospora sp., and the best inhibitory effect was on Colletotrichum camelliae, followed by Cercospora theae. The literature [Pinel B, Landreau A, Seraphin D, et al. Synthesis of reduced xanthatin derivatives and in vitro evaluation of their antifungal activity. Journal of Enzyme Inhibition and Medicinal Chemistry, 2005, 20(6): 575-579.] reported the in vitro antifungal activities of xanthatin against Candida glabrata, Candida albicans and Aspergillus fumigatus.In addition, the literature [Zhi X Y, Song L L, Liang J, et al. Synthesis and in vitro antifungal activity of new Michael-type amino derivatives of xanthatin, a natural sesquiterpene lactone from Xanthium strumarium L. Bioorganic & Medicinal Chemistry Letters. 2022, 55:128481] and the literature [Zhi X Y, Jiang L Y, Li T, et al. Natural product-based semisynthesis and biological evaluation of thiol / amino-Michael adducts of xanthatin derived from Xanthium strumarium as potential pesticidal agents. Bioorganic Chemistry, 2020, 97:103696.] reported that the products obtained by modifying the exocyclic double bond of the five-membered ring of xanthatin showed strong inhibitory germination activity against some plant pathogenic fungal spores.

[0003] In summary, it can be found that although there are already literatures reporting the antibacterial activities of xanthatin and some of its derivatives at the present stage, there are still problems such as weak antibacterial effect and narrow antibacterial activity spectrum. In particular, there is a lack of research on the derivatives with carbonyl modification on the outer side chain of the seven-membered ring of xanthatin and their antibacterial effects, which greatly restricts the in-depth research and development and utilization of the antibacterial effects of such substances and their derivatives. Summary of the Invention

[0004] The technical problem to be solved by the present invention is: how to provide a modification of xanthatin to improve the antibacterial activity or broad-spectrum property of xanthatin derivatives.

[0005] The technical solution of the present invention is: a xanthatin derivative or a pharmaceutically acceptable salt thereof, and the derivative has the structural formula shown in Formula I:

[0006]

[0007] In Formula I, X, R 1 and Y are any one of the following combinations (1) to (27):

[0008] (1): X = N, R 1= OH, Y = H (E - configuration);

[0009] (2): X = N, R 1 = a, Y = H (E - configuration);

[0010] (3): X = N, R 1 = b, Y = H (E - configuration);

[0011] (4): X = N, R 1 = c, Y = H (E - configuration);

[0012] (5): X = N, R 1 = d, Y = H (E - configuration);

[0013] (6): X = N, R 1 = f, Y = H (E - configuration);

[0014] (7): X = N, R 1 = g, Y = H (E - configuration);

[0015] (8): X = N, R 1 = OH, Y = H (Z - configuration);

[0016] (9): X = N, R 1 = a, Y = H (Z - configuration);

[0017] (10): X = N, R 1 = b, Y = H (Z - configuration);

[0018] (11): X = N, R 1 = c, Y = H (Z - configuration);

[0019] (12): X = N, R 1 = d, Y = H (Z - configuration);

[0020] (13): X = N, R 1 = f, Y = H (Z - configuration);

[0021] (14): X = N, R 1 = f, Y = H (Z - configuration);

[0022] (15): X = N, R 1 = g, Y = H (E - configuration);

[0023] (16): X = N, R 1 = h, Y = H (E - configuration);

[0024] (17): X = N, R 1 = i, Y = H (E - configuration);

[0025] (18): X = N, R 1 = j, Y = H (E - configuration);

[0026] (19): X = N, R 1 = k, Y = H (E - configuration);

[0027] (20): X = N, R 1 = g, Y = H (Z - configuration);

[0028] (21): X = N, R 1 = h, Y = H (Z - configuration);

[0029] (22): X = N, R 1 = i, Y = H (Z - configuration);

[0030] (23): X = N, R 1 = j, Y = H (Z - configuration);

[0031] (24): X = N, R 1 = k, Y = H (Z - configuration);

[0032] (25): X = N, R 1 = l, Y = H (E - configuration);

[0033] (26): X = N, R 1 = m, Y = H (E - configuration);

[0034] (27): X = O, Y = Cl (E - configuration);

[0035] Wherein, a - m are respectively the following groups:

[0036]

[0037] Preferably, the derivative is any one of the following structural formulas:

[0038]

[0039]

[0040] Application of xanthone derivatives or pharmaceutically acceptable salts thereof in anti - phytopathogenic fungi.

[0041] Further, the plant pathogenic fungus is any one of Cytospora mandshurica, Fusarium graminearum, Alternaria solani, Fusariu m solani, Colletotrichum orbiculare, Fusarium oxysporu m, or Botrytis cinerea.

[0042] A preparation containing the xanthin derivative or a pharmaceutically acceptable salt thereof described above.

[0043] Compared with the prior art, the present invention has the following beneficial effects:

[0044] 1. In the present invention, different substituents are introduced into the outer side chain of the seven-membered ring of xanthin, thereby preparing several xanthin derivatives with rich and novel structures, filling the research gap in the systematic structural modification of the outer side chain of the seven-membered ring of xanthin, and greatly enriching the structural diversity of such compounds. Some of the prepared xanthin derivatives have high bactericidal activity. In particular, derivatives 1, 8, and 27 have broad-spectrum and high-efficiency inhibitory activities against the mycelia of the tested plant pathogenic fungi, and derivatives 1, 2, 8, 9, 20, and 27 show strong inhibitory effects on the germination of spores of some of the tested plant pathogenic fungi. The above derivatives have great application potential.

[0045] 2. Some of the xanthone derivatives involved in the present invention have improved antibacterial activity compared to the parent xanthone, thus confirming that modifying the outer side chain of the seven-membered ring of xanthone helps to improve the antibacterial activity of this substance, providing ideas for further in-depth research and development of such compounds as new agricultural fungicides. Specifically: Derivatives 3, 5, 6, 8, 10, 12, 13, 25, and 27 have strong inhibitory effects on the mycelial growth of Valsa mali, and the antibacterial effect is higher than that of the substrate xanthone; the inhibitory effects of derivatives 8 and 27 on Gibberella zeae are higher than those of the parent xanthone; the inhibitory activities of derivatives 1, 8, 10, 12, 25, and 27 against Alternaria solani are superior to those of xanthone; the inhibitory activity of derivative 27 on the mycelial growth of Fusarium solani is higher than that of the parent xanthone; the inhibitory activities of derivatives 1, 5, 9, 11, 12, 25, and 27 against Colletotrichum orbiculare are higher than those of xanthone; the inhibitory activities of derivatives 1, 8, 9, and 27 against Fusarium oxysporum f. sp. capsici are higher than those of xanthone. In addition, the inhibitory effects of derivatives 2, 4, 9, 15, and 27 on the spore germination of Fusarium solani are stronger than those of the parent compound xanthone; the inhibitory activities of derivatives 1, 8, 9, and 20 on the spore germination of Botrytis cinerea are superior to those of xanthone; the inhibitory activities of derivatives 1 and 8 on the spore germination of Colletotrichum orbiculare are also higher than those of xanthone. BRIEF DESCRIPTION OF THE DRAWINGS

[0046] Figure 1 1H NMR spectrum of Compound 1;

[0047] Figure 2 13C NMR spectrum of Compound 1;

[0048] Figure 3 1H NMR spectrum of Compound 8;

[0049] Figure 4 13C NMR spectrum of Compound 8;

[0050] Figure 5 1H NMR spectrum of Compound 25;

[0051] Figure 6 13C NMR spectrum of Compound 25;

[0052] Figure 7 1H NMR spectrum of Compound 27;

[0053] Figure 8 13C NMR spectrum of Compound 27. DETAILED DESCRIPTION OF THE INVENTION

[0054] The experimental methods in the following examples are all conventional methods unless otherwise specified. The test materials used in the following examples are all obtained from commercial channels unless otherwise specified.

[0055] Example 1

[0056] Preparation Route and Structural Characterization Data of Aza-Substituted Xanthin / Chlorinated Xanthin Derivatives of the Present Invention

[0057] The following are the preparation routes of derivatives 1 and 8:

[0058] Take a certain amount of xanthin (1 mmol) and a certain amount of hydroxylamine hydrochloride (5 mmol) and dissolve them in anhydrous ethanol (6 mL). After stirring at room temperature for 4.5 h, the reaction is complete. The desired target products 1 and 8 are obtained by silica gel thin layer chromatography separation.

[0059] The reaction formula is as follows:

[0060]

[0061] The physical and chemical properties of compound 1 are as follows:

[0062] 1) White solid, melting point 123.9 - 124.5 °C, yield 44.1%;

[0063] 2) The characteristics of the nuclear magnetic resonance spectrum of this compound:

[0064] Using deuterated chloroform as the solvent and TMS as the internal standard, the attribution of each peak is as follows: – 1 1H NMR (500 MHz, CDCl3): δ = 6.48 (d, J = 16.5 Hz, 1H, 2-H), 6.32 (d, J = 16.5 Hz, 1H, 3-H), 6.19 (d, J = 3.0 Hz, 1H, 13-H), 6.03 (dd, J = 3.5, 9.0 Hz, 1H, 5-H), 5.48 (d, J = 3.0 Hz, 1H, 13-H), 4.26–4.31 (m, 1H, 8-H), 3.12–3.16 (m, 1H, 9-H), 2.69–2.75 (m, 1H, 10-H), 2.51–2.57 (m, 1H, 7-H), 2.34–2.38 (m, 1H, 6-H), 2.15–2.21 (m, 1H, 6-H), 2.06 (s, 3H, 15-H), 1.81–1.87 (m, 1H, 9-H), 1.17 (d, J = 7.5 Hz, 3H, 14-H). – 13 13C NMR (125 MHz, CDCl3): δ = 170.01, 156.86, 145.31, 139.53, 138.51, 131.57, 123.08, 118.75, 81.88, 47.80, 36.71, 29.12, 26.81, 18.88, 9.75;

[0065] 3) The characteristics of the high-resolution mass spectrum of this compound:

[0066] Electrospray ionization was used: m / z = 262.1448 (calcd. 262.1443 for C 15 H 20 NO3, [M+H] + ).

[0067] The physical and chemical properties of Compound 8 are as follows:

[0068] 1) White solid, melting point 171.4 - 172.3 °C, yield 42.1%;

[0069] 2) The characteristics of the nuclear magnetic resonance spectrum of this compound:

[0070] Using deuterated chloroform as the solvent and TMS as the internal standard, the attribution of each peak is as follows: – 1 1H NMR (500 MHz, CDCl3): δ = 7.06 (d, J = 16.5 Hz, 1H, 2-H), 6.53 (d, J = 16.5 Hz, 1H, 3-H), 6.20 (d, J = 3.5 Hz, 1H, 13-H), 6.12 (dd, J = 3.5, 9.5 Hz, 1H, 5-H), 5.48 (d, J = 3.0 Hz, 1H, 13-H), 4.27–4.32 (m, 1H, 8-H), 3.20–3.25 (m, 1H, 9-H), 2.71–2.77 (m, 1H, 10-H), 2.52–2.57 (m, 1H, 7-H), 2.36–2.40 (m, 1H, 6-H), 2.17–2.23 (m, 1H, 6-H), 2.05 (s, 3H, 15-H), 1.82–1.88 (m, 1H, 9-H), 1.19 (d, J = 7.5 Hz, 3H, 14-H). – 13 13C NMR (125 MHz, CDCl3): δ = 169.90, 153.42, 145.81, 141.63, 139.44, 133.76, 118.76, 114.24, 81.80, 47.71, 36.66, 28.97, 26.91, 18.87, 16.99;

[0071] 3) The characteristics of the high-resolution mass spectrum of this compound:

[0072] Electrospray ionization was used: m / z = 262.1444 (calcd. 262.1443 for C 15 H 20 NO3, [M+H] + )。

[0073] The following is the preparation route of derivatives 2 - 7 and 9 - 14:

[0074] A certain amount of Compound 1 / 8 (1 mmol), a certain amount of halogenated hydrocarbon (2 mmol), a certain amount of sodium hydroxide (2 mmol), and a catalytic amount of potassium iodide (0.1 mmol) were dissolved in N,N-dimethylformamide (DMF, 2 mL). The reaction was stirred under an ice-salt bath, monitored by TLC, and after the reaction was complete, silica gel thin-layer chromatography was prepared for separation to obtain the desired target products 2-7 and 9-14.

[0075] The reaction equation is as follows:

[0076]

[0077] Compounds 2-7 and 9-14 correspond one-to-one with the sequence numbers of the substituent R 2 respectively.

[0078] The physical and chemical properties of Compound 2 are as follows:

[0079] 1) White solid, melting point 104.7 - 105.6 °C, yield 70.5%;

[0080] 2) The characteristics of the nuclear magnetic resonance spectrum of this compound:

[0081] Using deuterated chloroform as the solvent and TMS as the internal standard, the attribution of each peak is as follows: – 1 1H NMR (400 MHz, CDCl3): δ = 6.46 (d, J = 16.0 Hz, 1H, 2-H), 6.33 (d, J = 16.4 Hz, 1H, 3-H), 6.19 (d, J = 3.2 Hz, 1H, 13-H), 6.02 (dd, J = 3.6, 9.2 Hz, 1H, 5-H), 5.47 (d, J = 2.8 Hz, 1H, 13-H), 4.25–4.31 (m, 1H, 8-H), 3.92 (s, 3H, -OCH3), 3.13–3.19 (m, 1H, 9-H), 2.67–2.74 (m, 1H, 10-H), 2.50–2.56 (m, 1H, 7-H), 2.33–2.38 (m, 1H, 6-H), 2.14–2.21 (m, 1H, 6-H), 1.99 (s, 3H, 15-H), 1.80–1.87 (m, 1H, 9-H), 1.16 (d, J = 7.2 Hz, 3H, 14-H). – 13 13C NMR (100 MHz, CDCl3): δ = 169.96, 155.77, 145.41, 139.53, 138.07, 131.31, 123.24, 118.66, 81.88, 61.84, 47.80, 36.66, 29.05, 26.76, 18.85, 10.23;

[0082] 3) The characteristics of the high-resolution mass spectrum of this compound:

[0083] Electrospray ionization was used: m / z = 276.1597 (calcd. 276.1600 for C 16 H 22 NO3, [M+H] + )

[0084] The physical and chemical properties of Compound 3 are as follows:

[0085] 1) Light yellow solid, melting point 70.5 - 71.4 °C, yield 34.5%;

[0086] 2) The characteristics of the nuclear magnetic resonance spectrum of this compound:

[0087] Using deuterated chloroform as the solvent and TMS as the internal standard, the attribution of each peak is as follows: – 1 1H NMR (400 MHz, CDCl3): δ = 6.45 (d, J = 16.4 Hz, 1H, 2-H), 6.35 (d, J = 16.4 Hz, 1H, 3-H), 6.19 (d, J = 3.6 Hz, 1H, 13-H), 6.01 (dd, J = 3.6, 9.2 Hz, 1H, 5-H), 5.47 (d, J = 2.8 Hz, 1H, 13-H), 4.25–4.31 (m, 1H, 8-H), 4.14 (t, J = 7.2 Hz, 2H), 3.14–3.19 (m, 1H, 9-H), 2.67–2.74 (m, 1H, 10-H), 2.50–2.56 (m, 1H, 7-H), 2.32–2.37 (m, 1H, 6-H), 2.13–2.21 (m, 1H, 6-H), 2.00 (s, 3H, 15-H), 1.79–1.86 (m, 1H, 9-H), 1.63–1.70 (m, 2H), 1.38–1.45 (m, 2H), 1.16 (d, J = 7.2 Hz, 3H, 14-H), 0.96 (t, J = 7.6 Hz, 3H, -CH3). – 13 13C NMR (100 MHz, CDCl3): δ = 169.98, 155.51, 145.49, 139.55, 137.82, 131.14, 123.48, 118.65, 81.91, 74.09, 47.82, 36.66, 31.21, 29.04, 26.75, 19.20, 18.86, 13.93, 10.34;

[0088] 3) The characteristics of the high-resolution mass spectrum of this compound:

[0089] Electrospray ionization was used: m / z = 340.1895 (calcd. 340.1889 for C 19 H27 NO3Na, [M+Na] + )。

[0090] The physical and chemical properties of Compound 4 are as follows:

[0091] 1) White solid, melting point 62.9 - 63.7 °C, yield 19.8%;

[0092] 2) The characteristics of the nuclear magnetic resonance spectrum of this compound:

[0093] Using deuterated chloroform as the solvent and TMS as the internal standard, the attribution of each peak is as follows: – 1 1H NMR (400 MHz, CDCl3): δ = 6.44 (d, J = 16.4 Hz, 1H, 2-H), 6.33 (d, J = 16.4 Hz, 1H, 3-H), 6.19 (d, J = 3.2 Hz, 1H, 13-H), 6.01 (dd, J = 3.2, 9.2 Hz, 1H, 5-H), 5.47 (d, J = 2.8 Hz, 1H, 13-H), 4.25–4.31 (m, 1H, 8-H), 4.12 (t, J = 6.8 Hz, 2H), 3.12–3.19 (m, 1H, 9-H), 2.67–2.74 (m, 1H, 10-H), 2.50–2.56 (m, 1H, 7-H), 2.32–2.37 (m, 1H, 6-H), 2.13–2.21 (m, 1H, 6-H), 1.99 (s, 3H, 15-H), 1.79–1.86 (m, 1H, 9-H), 1.64–1.71 (m, 2H), 1.29–1.35 (m, 6H), 1.16 (d, J = 7.2 Hz, 3H, 14-H), 0.90 (t, J = 6.8 Hz, 3H, -CH3). – 13 13C NMR (100 MHz, CDCl3): δ = 169.98, 155.44, 145.49, 139.56, 137.68, 131.04, 123.57, 118.65, 81.91, 74.36, 47.83, 36.66, 31.64, 29.09, 29.04, 26.74, 25.65, 22.59, 18.86, 14.03, 10.33;

[0094] 3) The characteristics of the high-resolution mass spectrum of this compound:

[0095] Using electrospray ionization: m / z = 346.2383 (calcd. 346.2382 for C 21 H 32 NO3, [M+H] + )。

[0096] The physical and chemical properties of Compound 5 are as follows:

[0097] 1) Pale yellow liquid, yield 20.4%;

[0098] 2) Characteristics of the nuclear magnetic resonance spectrum of this compound:

[0099] Using deuterated chloroform as the solvent and TMS as the internal standard, the attribution of each peak is as follows: – 1 H NMR(400MHz,CDCl3):δ=6.45(d,J=16.4Hz,1H,2-H),6.34(d,J=16.4Hz,1H,3-H),6.19(d,J=3.2Hz,1H,13-H),6.01(dd,J=3.2,8.8Hz,1H,5-H),5.47(d,J=3.2Hz,1H,13-H),4.25–4.31(m,1H,8-H),4.21(t,J=6.4Hz,2H),3.49(t,J=6.4Hz,2H),3.34(s,3H,-OCH3),3.13–3.19(m,1H,9-H),2.67–2.74(m,1H,10-H),2.50–2.56(m,1H,7-H),2.33–2.38(m,1H,6-H),2.14–2.21(m,1H,6-H),2.00(s,3H,15-H),1.97(t,J=6.4Hz,2H),1.79–1.87(m,1H,9-H),1.16(d,J=7.2Hz,3H,14-H).– 13 C NMR(100MHz,CDCl3):δ=169.98,155.72,145.46,139.54,137.87,131.18,123.44,118.67,81.90,71.04,69.50,58.65,47.82,36.66,29.43,29.05,26.75,18.86,10.35;

[0100] 3) Characteristics of the high-resolution mass spectrum of this compound:

[0101] Using electrospray ionization: m / z=356.1841(calcd.356.1838for C 19 H 27 NO4Na,[M+Na] + )。

[0102] The physical and chemical properties of Compound 6 are as follows:

[0103] 1) Yellow solid, melting point 94.2 - 95.2℃, yield 28.0%;

[0104] 2) NMR spectrum characteristics of the compound:

[0105] Using deuterated chloroform as the solvent and TMS as the internal standard, the assignments of each peak are as follows: – 1 1H NMR (400 MHz, CDCl3): δ = 6.45 (d, J = 16.0 Hz, 1H, 2-H), 6.34 (d, J = 16.4 Hz, 1H, 3-H), 6.19 (d, J = 3.2 Hz, 1H, 13-H), 6.01 (dd, J = 3.6, 9.2 Hz, 1H, 5-H), 5.47 (d, J = 3.2 Hz, 1H, 13-H), 4.25–4.31 (m, 1H, 8-H), 3.94 (d, J = 7.2 Hz, 2H), 3.14–3.19 (m, 1H, 9-H), 2.67–2.74 (m, 1H, 10-H), 2.50–2.57 (m, 1H, 7-H), 2.33–2.38 (m, 1H, 6-H), 2.14–2.21 (m, 1H, 6-H), 2.03 (s, 3H, 15-H), 1.79–1.87 (m, 1H, 9-H), 1.17–1.22 (m, 1H), 1.16 (d, J = 7.6 Hz, 3H, 14-H), 0.53–0.58 (m, 2H), 0.27–0.31 (m, 2H). – 13 13C NMR (100 MHz, CDCl3): δ = 169.98, 155.55, 145.48, 139.55, 137.83, 131.12, 123.53, 118.67, 81.91, 78.90, 47.83, 36.66, 29.04, 26.75, 18.87, 10.45, 10.23, 3.04, 3.01;

[0106] 3) High-resolution mass spectrometry characteristics of the compound:

[0107] Electrospray ionization was used: m / z = 316.1917 (calcd. 316.1913 for C 19 H 26 NO3, [M + H] + ).

[0108] The physical and chemical properties of Compound 7 are as follows:

[0109] 1) White solid, melting point 68.5 - 69.3 °C, yield 70.2%;

[0110] 2) NMR spectrum characteristics of the compound:

[0111] Using deuterated chloroform as the solvent and TMS as the internal standard, the assignments of each peak are as follows: – 11H NMR(500 MHz, CDCl3): δ = 7.34–7.38 (m, 4H, Ar-H), 7.28–7.31 (m, 1H, Ar-H), 6.45 (d, J = 16.5 Hz, 1H, 2-H), 6.33 (d, J = 16.5 Hz, 1H, 3-H), 6.18 (d, J = 3.5 Hz, 1H, 13-H), 6.01 (dd, J = 3.5, 9.5 Hz, 1H, 5-H), 5.46 (d, J = 3.0 Hz, 1H, 13-H), 5.16 (s, 2H, -OCH2-), 4.25–4.30 (m, 1H, 8-H), 3.11–3.17 (m, 1H, 9-H), 2.67–2.73 (m, 1H, 10-H), 2.50–2.55 (m, 1H, 7-H), 2.32–2.36 (m, 1H, 6-H), 2.13–2.20 (m, 1H, 6-H), 2.04 (s, 3H, 15-H), 1.79–1.85 (m, 1H, 9-H), 1.15 (d, J = 7.5 Hz, 3H, 14-H).– 13 13C NMR(125 MHz, CDCl3): δ = 169.94, 156.26, 145.45, 139.53, 138.17, 137.81, 131.33, 128.37, 127.93, 127.80, 123.31, 118.64, 81.87, 76.08, 47.80, 36.64, 29.03, 26.75, 18.85, 10.58;

[0112] 3) High-resolution mass spectrometry characteristics of the compound:

[0113] Electrospray ionization was used: m / z = 352.1916 (calcd. 352.1913 for C 22 H 26 NO3, [M + H] + ).

[0114] The physical and chemical properties of Compound 9 are as follows:

[0115] 1) White solid, melting point 113.0 - 113.8 °C, yield 40.7%;

[0116] 2) NMR spectrum characteristics of the compound:

[0117] Using deuterated chloroform as the solvent and TMS as the internal standard, the assignments of each peak are as follows:– 11H NMR (500 MHz, CDCl3): δ = 6.94 (d, J = 16.5 Hz, 1H, 2-H), 6.50 (d, J = 16.5 Hz, 1H, 3-H), 6.19 (d, J = 3.5 Hz, 1H, 13-H), 6.10 (dd, J = 3.5, 9.5 Hz, 1H, 5-H), 5.48 (d, J = 3.0 Hz, 1H, 13-H), 4.26–4.31 (m, 1H, 8-H), 3.89 (s, 3H, -CH3), 3.16–3.22 (m, 1H, 9-H), 2.70–2.76 (m, 1H, 10-H), 2.51–2.56 (m, 1H, 7-H), 2.36–2.39 (m, 1H, 6-H), 2.16–2.23 (m, 1H, 6-H), 2.03 (s, 3H, 15-H), 1.81–1.86 (m, 1H, 9-H), 1.18 (d, J = 7.5 Hz, 3H, 14-H).– 13 13C NMR (125 MHz, CDCl3): δ = 169.89, 152.65, 145.84, 141.55, 139.45, 133.69, 118.76, 114.76, 81.81, 61.59, 47.73, 36.66, 28.92, 26.90, 18.89, 17.00;

[0118] 3) High-resolution mass spectrometry characteristics of the compound:

[0119] Electrospray ionization was used: m / z = 276.1604 (calcd. 276.1600 for C 16 H 22 NO3, [M + H] + ).

[0120] The physical and chemical properties of Compound 10 are as follows:

[0121] 1) Pale yellow liquid, yield 21.4%;

[0122] 2) NMR spectrum characteristics of the compound:

[0123] Using deuterated chloroform as the solvent and TMS as the internal standard, the assignments of each peak are as follows:– 11H NMR (400 MHz, CDCl3): δ = 6.96 (d, J = 16.4 Hz, 1H, 2-H), 6.50 (d, J = 16.8 Hz, 1H, 3-H), 6.20 (d, J = 3.2 Hz, 1H, 13-H), 6.10 (dd, J = 3.6, 9.2 Hz, 1H, 5-H), 5.48 (d, J = 2.8 Hz, 1H, 13-H), 4.26–4.32 (m, 1H, 8-H), 4.11 (t, J = 6.8 Hz, 2H), 3.15–3.20 (m, 1H, 9-H), 2.70–2.77 (m, 1H, 10-H), 2.51–2.58 (m, 1H, 7-H), 2.36–2.41 (m, 1H, 6-H), 2.15–2.23 (m, 1H, 6-H), 2.03 (s, 3H, 15-H), 1.81–1.88 (m, 1H, 9-H), 1.64–1.71 (m, 2H), 1.37–1.45 (m, 2H), 1.18 (d, J = 7.2 Hz, 3H, 14-H), 0.97 (t, J = 7.2 Hz, 3H, -CH3). – 13 13C NMR (100 MHz, CDCl3): δ = 169.91, 152.40, 145.84, 141.39, 139.44, 133.47, 123.55, 118.76, 114.99, 81.81, 73.86, 47.71, 36.68, 31.21, 28.97, 26.91, 19.23, 17.04, 13.98;

[0124] 3) High-resolution mass spectrometry characteristics of the compound:

[0125] Electrospray ionization was used: m / z = 318.2074 (calcd. 318.2069 for C 19 H 28 NO3, [M + H] + ).

[0126] The physicochemical properties of Compound 11 are as follows:

[0127] 1) White solid, melting point 51.3 - 51.9 °C, yield 20.2%;

[0128] 2) NMR spectral characteristics of the compound:

[0129] Using deuterated chloroform as the solvent and TMS as the internal standard, the assignments of each peak are as follows: – 11H NMR (500 MHz, CDCl3): δ = 6.96 (d, J = 16.5 Hz, 1H, 2-H), 6.50 (d, J = 16.5 Hz, 1H, 3-H), 6.19 (d, J = 3.5 Hz, 1H, 13-H), 6.10 (dd, J = 3.5, 9.5 Hz, 1H, 5-H), 5.48 (d, J = 3.0 Hz, 1H, 13-H), 4.27–4.32 (m, 1H, 8-H), 4.10 (t, J = 6.5 Hz, 2H), 3.16–3.20 (m, 1H, 9-H), 2.70–2.76 (m, 1H, 10-H), 2.51–2.56 (m, 1H, 7-H), 2.36–2.40 (m, 1H, 6-H), 2.16–2.23 (m, 1H, 6-H), 2.04 (s, 3H, 15-H), 1.82–1.87 (m, 1H, 9-H), 1.65–1.71 (m, 2H), 1.30–1.37 (m, 6H), 1.18 (d, J = 7.5 Hz, 3H, 14-H), 0.90 (t, J = 7.0 Hz, 3H, -CH3). – 13 13C NMR (125 MHz, CDCl3): δ = 169.87, 152.43, 145.84, 141.37, 139.45, 133.47, 118.73, 115.02, 81.79, 74.15, 47.72, 36.68, 31.64, 29.05, 28.97, 26.91, 25.66, 22.60, 18.86, 17.02, 14.01;

[0130] 3) High-resolution mass spectrometry characteristics of the compound:

[0131] Using electrospray ionization: m / z = 346.2381 (calcd. 346.2382 for C 21 H 32 NO3, [M + H] + ).

[0132] The physical and chemical properties of Compound 12 are as follows:

[0133] 1) Pale yellow liquid, yield 75.2%;

[0134] 2) NMR spectrum characteristics of the compound:

[0135] Using deuterated chloroform as the solvent and TMS as the internal standard, the assignments of each peak are as follows: – 11H NMR (400 MHz, CDCl3): δ = 6.95 (d, J = 16.4 Hz, 1H, 2-H), 6.50 (d, J = 16.8 Hz, 1H, 3-H), 6.20 (d, J = 3.2 Hz, 1H, 13-H), 6.10 (dd, J = 3.6, 9.2 Hz, 1H, 5-H), 5.48 (d, J = 3.2 Hz, 1H, 13-H), 4.26–4.32 (m, 1H, 8-H), 4.18 (t, J = 6.4 Hz, 2H), 3.50 (t, J = 6.4 Hz, 2H), 3.34 (s, 3H, -OCH3), 3.16–3.21 (m, 1H, 9-H), 2.70–2.77 (m, 1H, 10-H), 2.50–2.57 (m, 1H, 7-H), 2.36–2.41 (m, 1H, 6-H), 2.16 - 2.23 (m, 1H, 6-H), 2.03 (s, 3H, 15-H), 1.93–2.00 (m, 2H), 1.81–1.88 (m, 1H, 9-H), 1.18 (d, J = 7.6 Hz, 3H, 14-H). – 13 13C NMR (100 MHz, CDCl3): δ = 169.90, 152.64, 145.81, 139.43, 137.84, 133.55, 131.16, 123.46, 118.77, 114.93, 81.80, 69.61, 58.64, 47.71, 36.67, 29.43, 26.91, 18.87, 10.35;

[0136] 3) High-resolution mass spectrometry characteristics of the compound:

[0137] Electrospray ionization was used: m / z = 356.1835 (calcd. 356.1838 for C 19 H 27 NO4Na, [M+Na] + ).

[0138] The physical and chemical properties of Compound 13 are as follows:

[0139] 1) Pale yellow solid, melting point 102.1 - 102.7 °C, yield 24.3%;

[0140] 2) NMR spectrum characteristics of the compound:

[0141] Using deuterated chloroform as the solvent and TMS as the internal standard, the assignments of each peak are as follows: – 11H NMR (400 MHz, CDCl3): δ = 7.00 (d, J = 16.4 Hz, 1H, 2-H), 6.51 (d, J = 16.4 Hz, 1H, 3-H), 6.20 (d, J = 3.2 Hz, 1H, 13-H), 6.10 (dd, J = 3.6, 9.2 Hz, 1H, 5-H), 5.48 (d, J = 3.2 Hz, 1H, 13-H), 4.27–4.33 (m, 1H, 8-H), 3.92 (d, J = 6.8 Hz, 2H, -OCH2-), 3.17–3.24 (m, 1H, 9-H), 2.70–2.77 (m, 1H, 10-H), 2.51–2.57 (m, 1H, 7-H), 2.37–2.41 (m, 1H, 6-H), 2.16–2.24 (m, 1H, 6-H), 2.04 (s, 3H, 15-H), 1.81–1.89 (m, 1H, 9-H), 1.14–1.22 (m, 1H), 1.19 (d, J = 7.6 Hz, 3H, 14-H), 0.53–0.58 (m, 2H), 0.28–0.32 (m, 2H).– 13 13C NMR (100 MHz, CDCl3): δ = 169.91, 152.50, 145.89, 141.46, 139.44, 133.50, 123.55, 118.76, 115.05, 81.83, 78.68, 47.73, 36.67, 28.95, 26.90, 18.89, 17.09, 10.27, 3.08;

[0142] 3) High-resolution mass spectrometry characteristics of the compound:

[0143] Electrospray ionization was used: m / z = 316.1909 (calcd. 316.1913 for C 19 H 26 NO3, [M + H] + ).

[0144] The physical and chemical properties of Compound 14 are as follows:

[0145] 1) Pale yellow liquid, yield 37.9%;

[0146] 2) NMR spectrum characteristics of the compound:

[0147] Using deuterated chloroform as the solvent and TMS as the internal standard, the attribution of each peak is as follows: – 11H NMR (500 MHz, CDCl3): δ = 7.34–7.39 (m, 4H, Ar-H), 7.29–7.32 (m, 1H, Ar-H), 6.99 (d, J = 16.5 Hz, 1H, 2-H), 6.50 (d, J = 16.5 Hz, 1H, 3-H), 6.19 (d, J = 3.5 Hz, 1H, 13-H), 5.98–6.09 (m, 1H), 5.47 (d, J = 3.0 Hz, 1H, 13-H), 5.14 (s, 2H, -OCH2-), 4.25–4.30 (m, 1H, 8-H), 3.15–3.17 (m, 1H, 9-H), 2.67–2.75 (m, 1H, 10-H), 2.50–2.55 (m, 1H, 7-H), 2.33–2.37 (m, 1H, 6-H), 2.16–2.22 (m, 1H, 6-H), 2.04 (s, 3H, 15-H), 1.80–1.85 (m, 1H, 9-H), 1.16 (d, J = 7.0 Hz, 3H, 14-H).– 13 13C NMR (125 MHz, CDCl3): δ = 169.92, 153.20, 145.84, 141.77, 139.45, 138.01, 133.77, 131.37, 128.39, 128.08, 123.35, 118.79, 115.00, 81.82, 75.89, 47.72, 36.67, 28.95, 26.93, 18.90, 17.09, 10.62;

[0148] 3) High-resolution mass spectrometry characteristics of the compound:

[0149] Electrospray ionization was used: m / z = 352.1911 (calcd. 352.1913 for C 22 H 26 NO3, [M + H] + ).

[0150] The following is the preparation route for derivatives 15-19 and 20-24:

[0151] A certain amount of compound 1 / 8 (1 mmol) and the corresponding substituted aromatic isocyanate (1.2 mmol) were dissolved in acetone (2 mL), and the reaction was stirred at 56 °C. The reaction was monitored by TLC. After the reaction was complete, silica gel thin-layer chromatography was prepared for separation to obtain the desired target products 15-19 and 20-24.

[0152] The reaction formula is as follows:

[0153]

[0154] Compounds 15 - 19 and 20 - 24 correspond one - to - one with the substituent R 3 respectively.

[0155] The physical and chemical properties of Compound 15 are as follows:

[0156] 1) White solid, melting point 62.1 - 63.0 °C, yield 77.4%;

[0157] 2) The characteristics of the nuclear magnetic resonance spectrum of this compound:

[0158] Using deuterated chloroform as the solvent and TMS as the internal standard, the attribution of each peak is as follows: – 1 1H NMR(500MHz,CDCl3):δ=8.23(s,1H,-NH-),7.31–7.34(m,2H,Ar - H),7.24(t,J=7.5Hz,1H,Ar - H),6.95(d,J=7.5Hz,1H,Ar - H),6.69(d,J=16.5Hz,1H,2 - H),6.40(d,J=16.5Hz,1H,3 - H),6.21(d,J=3.5Hz,1H,13 - H),6.15(dd,J=3.5,9.0Hz,1H,5 - H),5.50(d,J=3.0Hz,1H,13 - H),4.28–4.33(m,1H,8 - H),3.17–3.21(m,1H,9 - H),2.74–2.80(m,1H,10 - H),2.53–2.58(m,1H,7 - H),2.38–2.42(m,1H,6 - H),2.36(s,3H,-CH3),2.21–2.25(m,4H,6 - H and 15 - H),1.85–1.90(m,1H,9 - H),1.21(d,J=7.5Hz,3H,14 - H).– 13 13C NMR(125MHz,CDCl3):δ=169.83,160.55,151.98,145.04,142.67,139.32,139.09,136.96,134.22,128.96,125.08,121.25,120.23,118.93,116.71,81.65,47.67,36.69,29.1226.94,21.53,18.93,11.95;

[0159] 3) The characteristics of the high - resolution mass spectrum of this compound:

[0160] Using electrospray ionization: m / z=417.1790(calcd.417.1790for C 23 17 26 H14N2O4Na,[M + Na]++ )。

[0161] The physical and chemical properties of Compound 16 are as follows:

[0162] 1) Pale yellow solid, melting point 74.1 - 75.0 °C, yield 71.5%;

[0163] 2) The characteristics of the nuclear magnetic resonance spectrum of this compound:

[0164] Using deuterated chloroform as the solvent and TMS as the internal standard, the assignments of each peak are as follows: – 1 1H NMR(500MHz,CDCl3):δ=8.20(s,1H,-NH-),7.40(s,1H,Ar-H),7.38(s,1H,Ar-H),7.15(s,1H,Ar-H),7.14(s,1H,Ar-H),6.68(d,J=16.5Hz,1H,2-H),6.40(d,J=16.5Hz,1H,3-H),6.21(d,J=3.5Hz,1H,13-H),6.14(dd,J=3.5,9.5Hz,1H,5-H),5.49(d,J=3.0Hz,1H,13-H),4.28–4.33(m,1H,8-H),3.17–3.21(m,1H,9-H),2.74–2.79(m,1H,10-H),2.53–2.58(m,1H,7-H),2.38–2.42(m,1H,6-H),2.32(s,3H,-CH3),2.22(s,3H),2.19–2.25(m,1H),1.84–1.90(m,1H,9-H),1.21(d,J=7.5Hz,3H,14-H).– 13 13C NMR(125MHz,CDCl3):δ=169.80,160.49,152.11,145.02,142.59,139.30,134.44,134.15,133.87,129.61,121.26,119.72,118.89,81.62,47.64,36.66,29.09,26.91,20.82,18.89,11.89;

[0165] 3) The characteristics of the high-resolution mass spectrum of this compound:

[0166] Using electrospray ionization: m / z=417.1790(calcd.417.1790for C 23 H 26 N2O4Na,[M+Na] + )。

[0167] The physical and chemical properties of Compound 17 are as follows:

[0168] 1) Pale yellow solid, melting point 66.9 - 67.8 °C, yield 77.5%;

[0169] 2) The characteristics of the nuclear magnetic resonance spectrum of this compound:

[0170] Using deuterated chloroform as the solvent and TMS as the internal standard, the attribution of each peak is as follows: – 1 1H NMR (400 MHz, CDCl3): δ = 8.15 (s, 1H, -NH-), 7.42 (s, 1H, Ar-H), 7.40 (s, 1H, Ar-H), 6.89 (s, 1H, Ar-H), 6.87 (s, 1H, Ar-H), 6.68 (d, J = 16.4 Hz, 1H, 2-H), 6.40 (d, J = 16.0 Hz, 1H, 3-H), 6.20 (d, J = 3.6 Hz, 1H, 13-H), 6.14 (dd, J = 3.2, 9.2 Hz, 1H, 5-H), 5.49 (d, J = 2.8 Hz, 1H, 13-H), 4.27–4.33 (m, 1H, 8-H), 3.80 (s, 3H, -OCH3), 3.14–3.20 (m, 1H, 9-H), 2.73–2.80 (m, 1H, 10-H), 2.52–2.58 (m, 1H, 7-H), 2.37–2.42 (m, 1H, 6-H), 2.22 (s, 3H), 2.19–2.25 (m, 1H), 1.83–1.90 (m, 1H, 9-H), 1.21 (d, J = 7.6 Hz, 3H, 14-H). – 13 13C NMR (100 MHz, CDCl3): δ = 169.82, 160.50, 156.52, 152.47, 145.01, 142.58, 139.30, 134.15, 130.06, 121.64, 121.25, 118.90, 114.29, 81.63, 55.51, 53.45, 47.64, 36.66, 29.10, 26.91, 18.89, 11.88;

[0171] 3) The characteristics of the high-resolution mass spectrum of this compound:

[0172] Using electrospray ionization: m / z = 433.1721 (calcd. 433.1734 for C 23 H 26 N2O5Na, [M + Na] + ).

[0173] The physical and chemical properties of Compound 18 are as follows:

[0174] 1) Pale yellow solid, melting point 79.8 - 81.4 °C, yield 70.0%;

[0175] 2) The characteristics of the nuclear magnetic resonance spectrum of this compound:

[0176] Using deuterated chloroform as the solvent and TMS as the internal standard, the attribution of each peak is as follows: – 1 1H NMR (500 MHz, CDCl3): δ = 8.19 (s, 1H, -NH-), 7.14 (s, 2H, Ar-H), 6.76 (s, 1H, Ar-H), 6.68 (d, J = 16.0 Hz, 1H, 2-H), 6.39 (d, J = 16.5 Hz, 1H, 3-H), 6.21 (d, J = 3.0 Hz, 1H, 13-H), 6.14 (dd, J = 3.0, 9.0 Hz, 1H, 5-H), 5.49 (d, J = 3.0 Hz, 1H, 13-H), 4.28–4.32 (m, 1H, 8-H), 3.17–3.21 (m, 1H, 9-H), 2.73–2.79 (m, 1H, 10-H), 2.53–2.58 (m, 1H, 7-H), 2.38–2.42 (m, 1H, 6-H), 2.31 (s, 6H, Ar-(C H 3) 2), 2.22 (s, 3H), 2.18–2.25 (m, 1H), 1.84–1.90 (m, 1H, 9-H), 1.21 (d, J = 7.5 Hz, 3H, 14-H). – 13 13C NMR (125 MHz, CDCl3): δ = 169.81, 160.46, 151.94, 145.04, 142.61, 139.34, 138.86, 136.88, 134.16, 126.01, 121.29, 118.89, 117.35, 81.64, 47.67, 36.69, 29.14, 26.94, 21.40, 18.92, 11.93;

[0177] 3) The characteristics of the high-resolution mass spectrum of this compound:

[0178] Using electrospray ionization: m / z = 431.1949 (calcd. 431.1947 for C 24 H 28 N2O4Na, [M+Na] + ).

[0179] The physical and chemical properties of Compound 19 are as follows:

[0180] 1) White solid, melting point 70.4 - 71.2 °C, yield 40.0%;

[0181] 2) NMR spectrum characteristics of the compound:

[0182] Using deuterated chloroform as the solvent and TMS as the internal standard, the assignments of each peak are as follows: – 1 1H NMR (400 MHz, CDCl3): δ = 8.28 (s, 1H, -NH-), 7.48 (s, 1H, Ar-H), 7.46 (s, 1H, Ar-H), 7.32 (s, 1H, Ar-H), 7.30 (s, 1H, Ar-H), 6.70 (d, J = 16.4 Hz, 1H, 2-H), 6.39 (d, J = 16.4 Hz, 1H, 3-H), 6.21 (d, J = 3.2 Hz, 1H, 13-H), 6.16 (dd, J = 3.2, 9.2 Hz, 1H, 5-H), 5.50 (d, J = 3.2 Hz, 1H, 13-H), 4.27–4.33 (m, 1H, 8-H), 3.15–3.20 (m, 1H, 9-H), 2.73–2.81 (m, 1H, 10-H), 2.53–2.59 (m, 1H, 7-H), 2.38–2.43 (m, 1H, 6-H), 2.23 (s, 3H), 2.18–2.26 (m, 1H), 1.84–1.91 (m, 1H, 9-H), 1.21 (d, J = 7.2 Hz, 3H, 14-H). – 13 13C NMR (100 MHz, CDCl3): δ = 169.79, 160.88, 151.89, 144.98, 142.95, 139.26, 135.67, 134.43, 129.13, 120.99, 120.80, 118.93, 81.59, 47.62, 36.66, 29.11, 26.93, 18.89, 11.94;

[0183] 3) High-resolution mass spectrum characteristics of the compound:

[0184] Electrospray ionization was used: m / z = 437.1250 (calcd. 437.1244 for C 22 H 23 N2O4 35 ClNa, [M+Na] + ); 439.1236 (calcd. 439.1215 for C 22 H 23 N2O4 37 ClNa, [M+Na] + ).

[0185] The physical and chemical properties of Compound 20 are as follows:

[0186] 1) White solid, melting point 60.3 - 61.2 °C, yield 66.3%;

[0187] 2) The characteristics of the nuclear magnetic resonance spectrum of this compound:

[0188] Using deuterated chloroform as the solvent and TMS as the internal standard, the attribution of each peak is as follows: – 1 1H NMR (500 MHz, CDCl3): δ = 8.36 (s, 1H, -NH-), 7.30–7.34 (m, 2H, Ar-H), 7.24 (t, J = 7.5 Hz, 1H, Ar-H), 7.05 (d, J = 16.0 Hz, 1H, 2-H), 6.94 (d, J = 7.5 Hz, 1H, Ar-H), 6.68 (d, J = 16.5 Hz, 1H, 3-H), 6.20–6.21 (m, 2H), 5.48 (d, J = 3.0 Hz, 1H, 13-H), 4.28–4.32 (m, 1H, 8-H), 3.23–3.25 (m, 1H, 9-H), 2.74–2.79 (m, 1H, 10-H), 2.51–2.56 (m, 1H, 7-H), 2.38–2.42 (m, 1H, 6-H), 2.36 (s, 3H, -CH3), 2.23 (s, 1H), 2.19 (s, 3H, -CH3), 1.81–1.87 (m, 1H, 9-H), 1.18 (d, J = 7.5 Hz, 3H, 14-H). – 13 13C NMR (125 MHz, CDCl3): δ = 169.75, 157.21, 152.17, 145.49, 142.64, 139.28, 136.46, 134.19, 128.91, 125.03, 121.21, 118.81, 116.78, 114.37, 81.62, 47.55, 36.49, 28.83, 27.00, 21.49, 18.87, 17.17, 11.91;

[0189] 3) The characteristics of the high-resolution mass spectrum of this compound:

[0190] Using electrospray ionization: m / z = 395.1970 (calcd. 395.1971 for C 23 H 27 N2O4, [M + H] + ).

[0191] The physical and chemical properties of Compound 21 are as follows:

[0192] 1) White solid, melting point 85.3 - 85.9 °C, yield 66.3%;

[0193] 2) The characteristics of the nuclear magnetic resonance spectrum of this compound:

[0194] Using deuterated chloroform as the solvent and TMS as the internal standard, the assignments of each peak are as follows: – 1 1H NMR (500 MHz, CDCl3): δ = 8.33 (s, 1H, -NH-), 7.39 (s, 1H, Ar-H), 7.38 (s, 1H, Ar-H), 7.16 (s, 1H, Ar-H), 7.14 (s, 1H, Ar-H), 7.05 (d, J = 16.0 Hz, 1H, 2-H), 6.67 (d, J = 16.5 Hz, 1H, 3-H), 6.21 (s, 1H), 6.20 (s, 1H), 5.48 (d, J = 2.5 Hz, 1H, 13-H), 4.28–4.32 (m, 1H, 8-H), 3.19–3.24 (m, 1H, 9-H), 2.74–2.79 (m, 1H, 10-H), 2.51–2.56 (m, 1H, 7-H), 2.38–2.42 (m, 1H, 6-H), 2.32 (s, 3H, -CH3), 2.22–2.26 (m, 1H, 6-H), 2.19 (s, 3H, 15-H), 1.81–1.86 (m, 1H, 9-H), 1.18 (d, J = 7.5 Hz, 3H, 14-H). – 13 13C NMR (125 MHz, CDCl3): δ = 169.75, 157.18, 152.33, 145.64, 145.44, 139.28, 136.44, 134.49, 133.85, 129.59, 119.81, 118.81, 114.38, 81.62, 47.55, 36.49, 28.81, 26.99, 20.83, 18.86, 17.17;

[0195] 3) High-resolution mass spectrometry characteristics of the compound:

[0196] Electrospray ionization was used: m / z = 417.1791 (calcd. 417.1790 for C 23 H 26 N2O4Na, [M+Na] + ).

[0197] The physical and chemical properties of Compound 22 are as follows:

[0198] 1) Pale yellow solid, melting point 68.5 - 69.3 °C, yield 45.5%;

[0199] 2) NMR spectrum characteristics of the compound:

[0200] Using deuterated chloroform as the solvent and TMS as the internal standard, the assignments of each peak are as follows: – 11H NMR (500 MHz, CDCl3): δ = 8.26 (s, 1H, -NH-), 7.41 (s, 1H, Ar-H), 7.40 (s, 1H, Ar-H), 7.06 (d, J = 16.5 Hz, 1H, 2-H), 6.90 (s, 1H, Ar-H), 6.88 (s, 1H, Ar-H), 6.67 (d, J = 16.5 Hz, 1H, 3-H), 6.20 (s, 1H, Ar-H), 6.19 (s, 1H), 5.48 (d, J = 3.5 Hz, 1H, 13-H), 4.27–4.32 (m, 1H, 8-H), 3.80 (s, 3H, -OCH3), 3.24 (s, 1H, 9-H), 2.74–2.79 (m, 1H, 10-H), 2.51–2.56 (m, 1H, 7-H), 2.39–2.41 (m, 1H, 6-H), 2.22–2.26 (m, 1H, 6-H), 2.19 (s, 3H, 15-H), 1.81–1.86 (m, 1H, 9-H), 1.18 (d, J = 7.5 Hz, 3H, 14-H).– 13 13C NMR (125 MHz, CDCl3): δ = 169.74, 157.16, 156.53, 152.68, 145.66, 145.42, 139.29, 136.41, 130.10, 121.75, 118.80, 114.40, 114.29, 81.62, 55.51, 47.55, 36.49, 28.83, 27.00, 18.86, 17.16;

[0201] 3) High-resolution mass spectrometry characteristics of the compound:

[0202] Electrospray ionization was used: m / z = 433.1740 (calcd. 433.1739 for C 23 H 26 N2O5Na, [M + Na] + ).

[0203] The physical and chemical properties of Compound 23 are as follows:

[0204] 1) Pale yellow solid, melting point 72.9 - 73.6 °C, yield 77.4%;

[0205] 2) NMR spectrum characteristics of the compound:

[0206] Using deuterated chloroform as the solvent and TMS as the internal standard, the assignments of each peak are as follows:– 11H NMR (500 MHz, CDCl3): δ = 8.32 (s, 1H, -NH-), 7.14 (s, 2H, Ar-H), 7.05 (d, J = 16.0 Hz, 1H, 2-H), 6.77 (s, 1H, Ar-H), 6.68 (dd, J = 3.2, 16.5 Hz, 1H, 5-H), 6.21 (s, 1H), 6.20 (s, 1H), 5.49 (d, J = 3.0 Hz, 1H, 13-H), 4.28–4.33 (m, 1H, 8-H), 3.24–3.25 (m, 1H, 9-H), 2.74–2.79 (m, 1H, 10-H), 2.51–2.56 (m, 1H, 7-H), 2.39–2.42 (m, 1H, 6-H), 2.31 (s, 6H, Ar-(CH3)2), 2.22 (s, 1H, 6-H), 2.19 (s, 3H, 15-H), 1.81–1.88 (m, 1H, 9-H), 1.18 (d, J = 7.5 Hz, 3H, 14-H). – 13 13C NMR (125 MHz, CDCl3): δ = 169.76, 160.43, 157.11, 152.15, 145.45, 142.59, 139.28, 138.82, 136.43, 134.17, 125.97, 121.23, 118.82, 117.42, 114.39, 81.63, 47.55, 36.48, 28.81, 26.99, 21.38, 18.87, 17.17, 11.91;

[0207] 3) High-resolution mass spectrometry characteristics of the compound:

[0208] Electrospray ionization was used: m / z = 409.2127 (calcd. 409.2127 for C 24 H 29 N2O4, [M + H] + ).

[0209] The physical and chemical properties of Compound 24 are as follows:

[0210] 1) White solid, melting point 61.6 - 62.5 °C, yield 90.0%;

[0211] 2) NMR spectrum characteristics of the compound:

[0212] Using deuterated chloroform as the solvent and TMS as the internal standard, the assignments of each peak are as follows: – 11H NMR (500 MHz, CDCl3): δ = 8.42 (s, 1H, -NH-), 7.48 (s, 1H, Ar-H), 7.46 (s, 1H, Ar-H), 7.31 (s, 1H, Ar-H), 7.30 (s, 1H, Ar-H), 7.03 (d, J = 16.0 Hz, 1H, 2-H), 6.69 (d, J = 16.0 Hz, 1H, 3-H), 6.22 (s, 1H), 6.20 (s, 1H), 5.49 (d, J = 3.0 Hz, 1H, 13-H), 4.28–4.33 (m, 1H, 8-H), 3.22–3.24 (m, 1H, 9-H), 2.74–2.80 (m, 1H, 10-H), 2.52–2.56 (m, 1H, 7-H), 2.39–2.42 (m, 1H, 6-H), 2.23 (s, 1H, 6-H), 2.19 (s, 3H, 15-H), 1.81–1.87 (m, 1H, 9-H), 1.18 (d, J = 7.5 Hz, 3H, 14-H).– 13 13C NMR (125 MHz, CDCl3): δ = 169.71, 157.55, 152.07, 145.79, 145.62, 142.93, 139.27, 136.70, 135.75, 134.41, 129.11, 120.88, 118.83, 114.24, 81.58, 47.55, 36.51, 28.87, 27.03, 18.87, 17.15, 11.94;

[0213] 3) High-resolution mass spectrometry characteristics of the compound:

[0214] Electrospray ionization was used: m / z = 415.1427 (calcd. 415.1425 for C 22 H 24 N2O4 35 Cl, [M + H] + ); 417.1407 (calcd. 417.1395 for C 22 H 24 N2O4 37 Cl, [M + H] + ).

[0215] The following is the preparation route of derivatives 25 and 26:

[0216] Take a certain amount of xanthostrumarin (1 mmol) and thiosemicarbazide (1 mmol) and dissolve them in anhydrous ethanol (5 mL), add two drops of glacial acetic acid, stir and react at 80 °C for 3.5 h, and then separate by preparative silica gel thin-layer chromatography to obtain the desired target product 25;

[0217] A certain amount of compound 25 (1 mmol) and 2-bromoacetophenone (1.2 mmol) were dissolved in anhydrous ethanol (3 mL), and the mixture was stirred at 75 °C for 0.5 h. Then, the desired target product 26 was obtained by preparative silica gel thin-layer chromatography.

[0218] The reaction equation is as follows:

[0219]

[0220] The physicochemical properties of compound 25 are as follows:

[0221] 1) Pale yellow solid, melting point 112.1 - 113.0 °C, yield 91.8%;

[0222] 2) The characteristics of the nuclear magnetic resonance spectrum of this compound:

[0223] Using deuterated chloroform as the solvent and TMS as the internal standard, the assignments of each peak are as follows: – 1 H NMR (400 MHz, CDCl3): δ = 8.75 (s, 1H, -NH-), 7.30 (s, 1H), 6.57 (d, J = 16.4 Hz, 1H, 2-H), 6.47 (s, 1H), 6.32 (d, J = 16.0 Hz, 1H, 3-H), 6.20 (d, J = 3.2 Hz, 1H, 13-H), 6.09 (dd, J = 3.2, 9.2 Hz, 1H, 5-H), 5.49 (d, J = 2.8 Hz, 1H, 13-H), 4.26–4.33 (m, 1H, 8-H), 3.11–3.18 (m, 1H, 9-H), 2.71–2.78 (m, 1H, 10-H), 2.52–2.58 (m, 1H, 7-H), 2.36–2.41 (m, 1H, 6-H), 2.16–2.24 (m, 1H, 6-H), 2.05 (s, 3H, 15-H), 1.82–1.89 (m, 1H, 9-H), 1.19 (d, J = 7.2 Hz, 3H, 14-H). – 13 C NMR (100 MHz, CDCl3): δ = 178.67, 169.87, 148.91, 145.22, 140.29, 139.35, 132.98, 125.37, 118.85, 81.71, 47.70, 36.66, 29.13, 26.88, 18.89, 11.54;

[0224] 3) The characteristics of the high-resolution mass spectrum of this compound:

[0225] Electrospray ionization was used: m / z = 320.1434 (calcd. 320.1433 for C 16 H22 N3O2S, [M+H] + )。

[0226] The physical and chemical properties of Compound 26 are as follows:

[0227] 1) Orange solid, melting point 110.1 - 111.0 °C, yield 31.7%;

[0228] 2) The characteristics of the nuclear magnetic resonance spectrum of this compound:

[0229] Using deuterated chloroform as the solvent and TMS as the internal standard, the attribution of each peak is as follows: – 1 1H NMR (400 MHz, CDCl3): δ = 7.75 (d, J = 1.2 Hz, 1H, Ar-H), 7.73 (s, 1H, Ar-H), 7.39–7.43 (m, 2H, Ar-H), 7.31–7.34 (m, 1H, Ar-H), 6.83 (s, 1H), 6.41–6.50 (m, 2H), 6.20 (d, J = 3.2 Hz, 1H, 13-H), 6.06 (dd, J = 3.2, 9.2 Hz, 1H, 5-H), 5.48 (d, J = 2.8 Hz, 1H, 13-H), 4.27–4.33 (m, 1H, 8-H), 3.19–3.25 (m, 1H, 9-H), 2.69–2.76 (m, 1H, 10-H), 2.52–2.58 (m, 1H, 7-H), 2.37–2.42 (m, 1H, 6-H), 2.16–2.24 (m, 1H, 6-H), 2.09 (s, 3H, 15-H), 1.82–1.89 (m, 1H, 9-H), 1.20 (d, J = 7.2 Hz, 3H, 14-H). – 13 13C NMR (100 MHz, CDCl3): δ = 169.97, 169.34, 150.25, 148.72, 145.54, 139.51, 137.68, 131.50, 128.75, 128.13, 125.96, 118.71, 103.45, 81.90, 47.84, 36.67, 29.70, 29.09, 26.80, 21.34, 18.92, 11.68;

[0230] 3) The characteristics of the high-resolution mass spectrum of this compound:

[0231] Using electrospray ionization: m / z = 420.1739 (calcd. 420.1740 for C 24 H 26 N3O2S, [M+H] + )。

[0232] The preparation route of derivative 27 is as follows:

[0233] Take a certain amount of xanthostrumarin (1 mmol) and N-chlorosuccinimide (NCS, 2 mmol) and dissolve them in anhydrous tetrahydrofuran (THF, 3 mL). Stir and react at 70 °C for 3 h, and then obtain the desired target product 27 by preparative silica gel thin layer chromatography;

[0234] The reaction formula is as follows:

[0235]

[0236] The physical and chemical properties of compound 27 are as follows:

[0237] 1) Orange waxy liquid, yield 67.1%;

[0238] 2) The characteristics of the nuclear magnetic resonance spectrum of this compound:

[0239] Using deuterated chloroform as the solvent and TMS as the internal standard, the attribution of each peak is as follows: – 1 1H NMR (400 MHz, CDCl3): δ = 7.27 (s, 1H, 2-H), 6.31 (dd, J = 3.2, 8.4 Hz, 1H, 5-H), 6.21 (d, J = 3.2 Hz, 1H, 13-H), 5.50 (d, J = 2.8 Hz, 1H, 13-H), 4.27–4.33 (m, 1H, 8-H), 2.98–3.04 (m, 1H, 9-H), 2.76–2.83 (m, 1H, 10-H), 2.62–2.68 (m, 1H, 7-H), 2.46 (s, 3H, 15-H), 2.31–2.38 (m, 1H, 6-H), 2.20–2.26 (m, 1H, 6-H), 1.90–1.97 (m, 1H, 9-H), 1.20 (d, J = 7.6 Hz, 3H, 14-H). – 13 13C NMR (100 MHz, CDCl3): δ = 193.34, 169.78, 141.47, 139.45, 133.30, 129.98, 119.02, 81.41, 47.07, 36.85, 33.01, 29.70, 27.10, 26.92, 18.93;

[0240] 3) The characteristics of the high-resolution mass spectrum of this compound:

[0241] Using electrospray ionization: m / z = 303.0771 (calcd. 303.0764 for C 15 1 17 35 17ClO3Na, [M+Na] +); 305.0742 (calcd. 305.0735 for C 15 H 17 37 ClO3Na, [M+Na] + )。

[0242] Example 2

[0243] Antibacterial activity determination test of the present invention:

[0244] This example is the antibacterial activity test of the nitrogen-substituted xanthatin / chlorinated xanthatin derivatives (1-27) prepared in Example 1:

[0245] 1. Tested plant pathogenic fungi: Valsa mali, Fusarium graminearum, Alternaria solani, Fusarium solani, Colletotrichum orbiculare, Fusarium oxysporum, and Botrytis cinerea.

[0246] 2. Tested samples and reagents:

[0247] Tested samples: nitrogen-substituted xanthatin / chlorinated xanthatin derivatives 1-27 prepared in Example 1;

[0248] Control agents: raw material xanthatin, 99% hymexazol technical, 98% pyraclostrobin technical, and 98% difenoconazole technical;

[0249] Solvents: DMSO (dimethyl sulfoxide, chromatographically pure), acetone (analytically pure), and the emulsifier is Tween-80 (superior grade pure).

[0250] 3. Antibacterial activity test methods and results:

[0251] (1) Using the mycelial growth rate assay method to test the inhibitory effect of the Xanthinacin heptacyclic outer chain modified derivative prepared in Example 1 on the mycelial growth of six phytopathogenic fungi: All the test samples were dissolved in acetone and then mixed with the melted PDA medium, and poured into sterile petri dishes, about 15 mL per dish, to prepare a drug-containing medium with a concentration of 100 μg / mL (the content of acetone in the drug-containing medium does not exceed 0.5%, v / v). After the medium cooled and solidified, the pre-activated test strains were punched into 4-mm-diameter mycelial discs along the colony edge and inoculated in the center of the drug-containing medium. Each drug was repeated 3 times, and at the same time, a blank control test without the drug was set up. Cultivate at an appropriate temperature until the colony diameter of the blank control group reached 2 / 3 of the petri dish diameter. Use the cross method to measure the colony diameters of each treatment group and the control group, and calculate the mycelial growth inhibition rate of each drug treatment group according to Formula -1, and calculate the corresponding standard deviation, etc. The test results are shown in Table -1.

[0252] Mycelial growth inhibition rate = (average colony diameter of the control group - average colony diameter of the treatment group) / (average colony diameter of the control group - 4 mm) × 100% (Formula -1)

[0253] Table -1 Inhibitory activity of aza-substituted xanthinacin / chlorinated xanthinacin derivatives (1-27) on the mycelial growth of six phytopathogenic fungi

[0254]

[0255]

[0256] It can be found from Table -1 that in the mycelial growth inhibition test, at the test concentration of 100 μg / mL, derivatives 3, 5, 6, 8, 10, 12, 13, 25, and 27 showed strong inhibitory effects on the mycelial growth of Valsa mali, and their antibacterial rates were all greater than 90%, better than the positive control agent hymexazol, and comparable to the antibacterial rate of the positive control agent pyraclostrobin; the antibacterial activities of derivatives 8 and 27 against Gibberella zeae were the most prominent, and their antibacterial rates were higher than those of the two positive control agents; the inhibition rate of derivative 27 against Fusarium solani was as high as about 94%, better than the parent xanthinacin and the positive control agents hymexazol and pyraclostrobin; the antibacterial activities of derivatives 1, 8, 11, and 27 against Colletotrichum orbiculare were relatively prominent, and their antibacterial rates were better than those of xanthinacin and hymexazol. In particular, the antibacterial rate of derivative 27 was as high as 100%, comparable to the control agent pyraclostrobin; in addition, the antibacterial rates of 1, 8, and 27 against Fusarium oxysporum f. sp. capsici were relatively high, especially the antibacterial activity of compound 27 was much higher than that of the parent xanthinacin and the two positive control agents.

[0257] In summary, it can be found that most of the tested derivatives showed a certain inhibitory effect on the apple tree canker pathogen. In particular, the antibacterial activities of derivatives 1, 8, and 27 were the most prominent, and they showed a strong inhibitory effect on the mycelia of 6 tested plant pathogenic fungi, indicating that they have a broad-spectrum and highly efficient antibacterial effect. Therefore, it is expected to be further developed for the preparation of new agricultural antibacterial agents.

[0258] (2) The spore germination method was used to test the inhibitory germination activity of the Xanthinin heptacyclic ring outer chain modified derivatives prepared in Example 1 against the spores of four plant pathogenic fungi: a. Preparation of spore suspension: The pathogenic bacteria were cultured on PDA medium at 25 ± 1 °C for 2 weeks, and then the colonies were gently scraped off with a spatula, rinsed with sterile water, and filtered through double-layer gauze to remove hyphae and medium. The spores were washed repeatedly with sterile water 3 times and finally diluted to the required spore concentration (under a 100-fold microscope, there were approximately 20 - 40 spores in each field of view) with sterile water; b. Preparation of medicament: The sample to be tested was dissolved in a certain amount of DMSO, and a 1 mg / mL stock solution was prepared by diluting with a 0.1% Tween-80 sterile aqueous solution. Then, according to the activity of the medicament, 5 - 7 series of mass concentrations were set, and the final content of the organic solvent did not exceed 2% (v / v); c. Medicament treatment: The prepared sample solution was mixed evenly with the spore suspension in equal volume to obtain the required final concentration. A 2% DMSO plus 0.1% Tween-80 sterile aqueous solution was used as the control group. The above mixture was aspirated with a micropipette and dropped on a concave slide, placed in a petri dish with shallow water, covered, and cultured in an incubator at an appropriate temperature. The germination of spores on the slide was observed under a microscope. When the germ tube after spore germination was longer than the short diameter of the spore, it was considered germinated. When the spore germination rate of the blank control was greater than 90%, the spore germination rate of each treatment group was observed and calculated (Formula - 2), and at the same time, the corrected spore germination inhibition rate of each treatment group was calculated using Formula - 3, and the median inhibitory concentration, 95% confidence interval, etc. of each compound were obtained. The test results are shown in Table - 2.

[0259] Spore germination rate = number of germinated spores / total number of counted spores × 100% (Formula - 2);

[0260] Corrected spore germination inhibition rate = (average spore germination rate of the control group - average spore germination rate of the treatment group) / average spore germination rate of the control group × 100% (Formula - 3).

[0261] Table - 2 Inhibitory germination effect of aza - substituted Xanthinin / chloro - Xanthinin derivatives (1 - 27) on the spores of four plant pathogenic fungi

[0262]

[0263]

[0264] It can be seen from the results in Table-2 that derivatives 2, 9 and 27 have particularly strong inhibitory effects on the germination of Fusarium solani spores, and their median inhibitory concentrations are 31.75, 11.06 and 18.79 μg / mL respectively -1 , and their inhibitory activities are higher than that of the parent xanthinin, and much higher than that of the positive control agent difenoconazole; derivatives 1, 2, 8, 9 and 20 have relatively strong inhibitory effects on the germination of Botrytis cinerea spores. In particular, the median inhibitory concentration of derivative 1 on the germination of Botrytis cinerea spores is only 1.11 μg / mL -1 , which is far better than the commercial positive control agent difenoconazole and has great application potential; the median inhibitory concentrations of derivatives 1, 2, 8, 9 and 20 on the spores of Colletotrichum orbiculare are 17.09, 61.07, 14.89, 28.39 and 63.39 μg / mL respectively -1 , and their inhibitory activities are all higher than that of difenoconazole. In summary, it can be concluded that some of the xanthinin heptacyclic ring outer chain modified derivatives prepared in the present invention have relatively strong inhibitory activities on the germination of plant pathogenic fungal spores. In particular, derivatives 1, 2, 8, 9, 20 and 27 show highly efficient and broad-spectrum inhibitory effects, and thus are expected to be used to prepare novel agricultural fungal spore germination inhibitors.

Claims

1. Xanthane derivatives or pharmaceutically acceptable salts thereof, characterized in that, The derivative is any one of the following structural formulas: 、 、 、 、 。 2. A preparation containing the xanthones derivative described in claim 1 or a pharmaceutically acceptable salt thereof.

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