Preparation and application of novel phosphorus-containing substance

Abstract

The invention discloses a novel phosphorus-containing substance, which is characterized in that the structural formula of the substance is shown in the specification, wherein R is selected from the following structures: the EC50 values of B12 and C2 for the treatment activity of TMV are respectively 197.53 mu g / mL and 171.83 mu g / mL, which are superior to that of a control drug ningnanmycin (237.41 mu g / mL). Besides, the substance C2 is subjected to an anti-TMV protection activity EC50 value test, and the test result is 238.22 [mu] g / mL, which is superior to that of a control drug NNM (268.71 [mu] g / mL).

Description

Technical Field

[0001] This invention relates to the preparation and application of a novel phosphorus-containing substance, belonging to the field of agricultural disease control. Background Technology

[0002] Plant viral diseases pose a significant threat to global agricultural production, causing economic losses exceeding tens of billions of US dollars annually. Tobacco mosaic virus (TMV), due to its high stability, ease of mechanical transmission, and cross-host infection capability (covering over 200 plant species including Solanaceae and Cucurbitaceae), is one of the most destructive pathogens. In major tobacco-producing areas, TMV can cause leaf mottling and necrosis, systemic stunting of plants, and severe yield losses. Current TMV control mainly relies on three methods: biological agents such as ningnanmycin, chemical inactivators like morpholine guanidine hydrochloride, and plant inducers. However, all have significant drawbacks: while ningnanmycin has environmental compatibility advantages, its control effect is limited, and field monitoring shows that TMV has developed resistance mutations; chemical inactivators have a single function, only inhibiting virus particle assembly and lacking systemic therapeutic activity, and high-concentration application can easily cause phytotoxicity; while inducers such as salicylic acid are severely affected by environmental stress and lack field stability. The existing technological system is insufficient to meet the comprehensive control requirements of "high efficiency, versatility, environmental friendliness, and resistance management."

[0003] Phosphorus-containing substances (compounds) are considered an important direction for antiviral agent development due to their strong modifiability, diverse targets, and excellent environmental degradability; however, some problems still exist in the current research. In terms of synthesis processes, traditional methods for preparing aminophosphates are complex and do not conform to the principles of green pesticide synthesis. Regarding bioactivity, the antiviral activity of reported phosphonate derivatives still needs further improvement. There is an urgent need to find novel antiviral compounds with multiple activities, possessing therapeutic, inactivating, and protective activities simultaneously.

[0004] Therefore, there is an urgent need in this field to develop a novel phosphorus-containing substance preparation system that simultaneously meets the following criteria through molecular structure innovation and breakthroughs in synthetic processes: functionally, it should achieve synergistic effects of therapeutic, passivating, and protective activities, significantly surpassing reference drugs such as ningnanmycin; synthetically, it should avoid multi-step synthesis, achieving atom-economical one-pot preparation; structurally, it should integrate vanillin radical scavenging fragments, sulfonamide systemic conduction structures, and phosphite virus-targeting groups to construct a novel α-aminophosphate molecular framework. Filling this technological gap will be of strategic significance for reconstructing the TMV prevention and control paradigm and ensuring safe crop production. Summary of the Invention

[0005] The technical problem to be solved by this invention is to provide a novel preparation method and application of phosphorus-containing substances to obtain novel agrochemicals with low drug resistance and high antiviral activity.

[0006] The technical solution of this invention is: a novel phosphorus-containing substance, the structural formula of which is shown below:

[0007] Where R is selected from the following structure:

[0008]

[0009] A method for preparing a novel phosphorus-containing substance, comprising the following steps:

[0010]

[0011]

[0012] The application of the novel phosphorus-containing substance in the preparation of agents to combat plant viral diseases.

[0013] The plant viral disease mentioned is TMV virus.

[0014] The beneficial effects of this invention are as follows: Substances C2 (76.9±3.4%) and B11 (73.7±5.5%) exhibit stronger therapeutic potential, with C2 also possessing high inactivation activity (87.7±3.5%). B12 in the B series demonstrates a unique protective activity advantage (78.3±5.4%), far exceeding that of ningnanmycin (62.5±6.3%). Notably, A4 (74.6±6.1% therapeutic activity) and A6 (71.3±2.5% protective activity) in the A series show outstanding performance in their respective functional dimensions, while C7 (69.7±3.5% therapeutic activity) in the C series has therapeutic activity close to that of ningnanmycin.

[0015] EC2 of the therapeutic activity of B12 and C2 against TMV 50 The values ​​were 197.53 and 171.83 μg / mL, respectively, which were superior to the control drug ningnanmycin (237.41 μg / mL). Furthermore, the protective activity against TMV of substance C2 was tested. 50 The concentration was tested and the result was 238.22 μg / mL, which was better than the control drug NNM (268.71 μg / mL). Detailed Implementation

[0016] Instruments and Chemicals

[0017] All chemical reagents (including benzaldehyde, diethyl phosphite, and various sulfonamides) were purchased from commercial suppliers. Nuclear magnetic resonance (NMR) spectra were measured using a Bruker BioSpin-AG-400 NMR spectrometer (Bruker Optics, Switzerland); high-resolution mass spectrometry (HRMS) data were acquired using an UltiMate 3000 HRMS spectrometer (Thermo Scientific, USA); cell turbidity was measured using 96-well plates (Nest Biotechnology Co., Ltd.).

[0018] Synthesis of substances A1-A12, B1-B12 and C1-C12

[0019] The synthesis steps of the target substances are as follows: Vanillin, aniline containing a sulfonamide structure, zinc acetate, and diethyl phosphite were added to a 100 mL round-bottom flask and refluxed. The mixture was reacted for 2 hours until complete, then a saturated salt solution (150 mL) was added, followed by extraction with dichloromethane (60 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum, then purified by column chromatography (eluent: dichloromethane / methanol, gradient ratio 100 / 1 to 50 / 1, v / v) to obtain the target product, with yields ranging from 37.3% to 83.7%. Finally, all target substances were further purified by column chromatography and analyzed by... 1 H NMR, 13 C NMR, 31 PNMR and HRMS analysis and characterization.

[0020] A1-C12 1 The H NMR data are as follows:

[0021] Diethyl((2-hydroxyphenyl)((3-(N-phenylsulfamoyl)phenyl)amino)methyl)phosphonate(A1).White solid, mp139.8-141.2; yield 81.98%. 1H NMR(400MHz,DMSO)δ10.14(s,1H),9.93(s,1H),7.44(d,J=7.7Hz,1H),7.27(s,1H),7.17(t,J=5.9Hz,3H),7.07(t,J=7.2Hz,3H),6.96(t,J=7.3Hz,1H),6.89(dd,J=15.7,7.9Hz,4H),6.77(t,J=7.4Hz,1H),5.23(dd,J=23.6,9.9Hz,1H),4.04(dd,J=7.1,2.3Hz,2H),3.85(dd,J=17.4,7.3Hz,1H),3.67(dd,J=16.3,9.2Hz,1H),1.15(t,J=7.1Hz,3H),1.01(t,J=7.0Hz,3H). 13 C NMR(101MHz,DMSO)δ155.58,148.37,140.78,138.43,129.95,129.47,129.10,123.97,122.75,119.88,119.45,117.08,115.25,114.72,111.31,62.89,62,70,46.86(d,J=156.9Hz),16.59,16.43. 31 P NMR(162MHz,DMSO)δ21.86.HRMS(ESI)[M+H] + calcd forC 23 H 28 N2O6PS + :491.14002,found:491.13870.

[0022] Diethyl((2-hydroxyphenyl)((4-(N-(pyridin-2-yl)sulfamoyl)phenyl)amino)methyl)phosphonate(A2).White solid,m.p.188.3-189.3;yield 90.47%. 1H NMR(400MHz,DMSO)δ11.13(s,1H),9.92(s,1H),8.05(d,J=4.1Hz,1H),7.72–7.48(m,4H),7.44(d,J=7.7Hz,1H),7.29–7.14(m,1H),7.08(t,J=7.9Hz,2H),6.85(d,J=9.6Hz,2H),6.78(dd,J=13.8,8.1Hz,3H),5.27(dd,J=23.5,9.6Hz,1H),4.03(dd,J=8.8,7.0Hz,2H),3.85(dd,J=17.4,7.2Hz,1H),3.66(dd,J=17.4,8.1Hz,1H),1.14(t,J=7.1Hz,3H),0.99(t,J=7.0Hz,3H). 13 C NMR(101MHz,DMSO)δ155.43,152.83,151.38,146.29,139.44,129.38,129.27,128.93,128.00,122.64,119.58,117.29,115.37,112.86,112.25,63.01,62.77,46.74(d,J=156.6 Hz),45.96(s),16.74,16.41. 31 P NMR(162 MHz,DMSO)δ22.57.HRMS(ESI)[M+H] + calcd forC 22 H 27 N3O6PS + :492.13527,found:492.13406.

[0023] Diethyl((2-hydroxyphenyl)((4-(N-(pyrimidin-2-yl)sulfamoyl)phenyl)amino)methyl)phosphonate(A3).White solid,m.p.190.0-191.8;yield 86.52%. 1H NMR(400MHz,DMSO)δ11.34(s,1H),9.93(s,1H),8.45(d,J=4.9 Hz,2H),7.67(d,J=9.0Hz,2H),7.45(d,J=7.7 Hz,1H),7.32–7.22(m,1H),7.09(t,J=7.0 Hz,1H),6.96(t,J=4.9Hz,1H),6.81(dd,J=22.5,13.5 Hz,4H),5.29(dd,J=23.4,9.5 Hz,1H),4.12–3.95(m,2H),3.85(dd,J=12.3,5.1 Hz,1H),3.67(dd,J=17.9,7.7 Hz,1H),1.14(t,J=7.1 Hz,3H),0.99(t,J=7.1 Hz,3H). 13 C NMR(101 MHz,DMSO)δ158.72,157.60,155.42,151.70,129.88,129.29,127.03,122.62,119.58,116.04,115.38,111.98,63.03,62.77,46.72(d,J=156.7 Hz),16.74,16.41. 31 P NMR(162MHz,DMSO)δ22.52.HRMS(ESI)[M+H] + calcd forC 21 H 26 N4O6PS + :493.13052,found:493.12933.

[0024] Diethyl((2-hydroxyphenyl)((4-(N-methylsulfamoyl)phenyl)amino)methyl)phosphonate(A4).White solid,m.p.149.5-149.6;yield 74.36%. 1H NMR(400 MHz,DMSO)δ9.97(s,1H),7.46(t,J=9.5 Hz,3H),7.24–7.14(m,1H),7.10(t,J=7.7Hz,1H),6.96(d,J=5.2 Hz,1H),6.86(d,J=9.0 Hz,3H),6.79(t,J=7.4 Hz,1H),5.31(dd,J=23.7,9.6Hz,1H),4.07(dd,J=15.2,7.1 Hz,2H),3.87(dd,J=17.4,7.2Hz,1H),3.69(dd,J=7.1,2.0 Hz,1H),2.32(d,J=5.1 Hz,3H),1.19(t,J=7.1 Hz,3H),1.01(t,J=7.1 Hz,3H). 13 CNMR(101 MHz,DMSO)δ155.49,151.21,129.27,128.74,126.33,122.70,119.60,115.36,112.52,63.08,62.84,46.77(d,J=156.9 Hz),29.12,16.76,16.40. 31 P NMR(162 MHz,DMSO)δ22.65.HRMS(ESI)[M+H] + calcd for C 18 H 26 N2O6PS + :429.12437,found:429.12329.

[0025] Diethyl(((4-(N,N-dimethylsulfamoyl)phenyl)amino)(2-hydroxyphenyl)methyl)phosphonate(A5).Faint yellow solid,m.p.140.1-142.9;yield 77.86%. 1H NMR(400MHz,DMSO)δ9.97(s,1H),7.51(d,J=7.7 Hz,1H),7.43(d,J=8.9 Hz,2H),7.38–7.32(m,1H),7.11(t,J=7.7 Hz,1H),6.90(dd,J=12.9,8.5 Hz,3H),6.81(t,J=7.4 Hz,1H),5.34(dd,J=23.5,9.5 Hz,1H),4.08(dd,J=15.2,7.2 Hz,2H),3.89(dd,J=17.4,7.2 Hz,1H),3.70(dd,J=16.3,9.2 Hz,1H),2.49(s,6H),1.20(t,J=7.1 Hz,3H),1.02(t,J=7.1Hz,3H). 13 C NMR(101 MHz,DMSO)δ155.40,151.75,129.71,129.28,122.65,121.40,119.57,115.38,112.49,63.06,62.80,46.70(d,J=156.8 Hz),38.07,16.74,16.39. 31 P NMR(162MHz,DMSO)δ22.55.HRMS(ESI)[M+H] + calcd for:C 19 H 28 N2O6PS + 443.14002,found:443.13885.

[0026] Diethyl((2-hydroxyphenyl)((4-(N-(thiazol-2-yl)sulfamoyl)phenyl)amino)methyl)phosphonate(A6).White solid,m.p.166.1-167.5;yield 83.41%. 1H NMR(400MHz,DMSO)δ9.95(s,1H),7.45(t,J=9.4 Hz,3H),7.15(d,J=4.6 Hz,1H),7.08(t,J=7.6Hz,2H),6.84(d,J=8.1 Hz,1H),6.79(d,J=8.9 Hz,3H),6.71(d,J=4.6 Hz,1H),5.27(dd,J=23.7,9.2 Hz,1H),4.05(dd,J=14.9,7.3 Hz,2H),3.86(dd,J=15.9,8.7 Hz,1H),3.67(dd,J=17.6,7.7 Hz,1H),1.18(t,J=7.0 Hz,3H),1.00(t,J=7.0 Hz,3H). 13 C NMR(101 MHz,DMSO)δ168.58,155.48,150.99,129.87,129.23,127.84,124.74,122.76,119.59,115.35,112.32,108.03,63.01,62.80,46.79(d,J=156.7 Hz),16.77,16.42. 31 PNMR(162 MHz,DMSO)δ22.67.HRMS(ESI)[M+H] + calcd for C 20 H 25 N3O6PS2 + :498.09169,found:498.09012.

[0027] Diethyl((2-hydroxyphenyl)((4-(N-(p-tolyl)sulfamoyl)phenyl)amino)methyl)phosphonate(A7).Offwhite solid,m.p.154.9-155.1;yield 88.61%. 1H NMR(400MHz,DMSO)δ9.79(s,1H),9.48(s,1H),7.50(d,J=8.2 Hz,2H),7.39(d,J=7.7 Hz,1H),7.27(d,J=8.1 Hz,2H),7.05(t,J=7.7 Hz,1H),6.80(d,J=8.1 Hz,1H),6.74(t,J=7.5Hz,1H),6.69(d,J=8.8 Hz,2H),6.55(d,J=8.9 Hz,2H),6.28–6.09(m,1H),5.11(dd,J=24.1,9.1 Hz,1H),4.03(dd,J=15.0,7.8 Hz,2H),3.81(dd,J=17.4,7.2Hz,1H),3.61(dd,J=17.8,7.6 Hz,1H),2.31(s,3H),1.16(t,J=7.1 Hz,3H),0.98(t,J=7.0 Hz,3H). 13 CNMR(101 MHz,DMSO)δ155.50,145.35,143.15,137.37,129.89,129.24,128.91,127.04,124.36,123.27,119.46,115.25,113.59,62.78,62.6247.21(d,J=156.4 Hz),21.41,16.77,16.42. 31 P NMR(162 MHz,DMSO)δ23.40.HRMS(ESI)[M+H] + calcd for C 24 H 30 N2O6PS + :505.15567,found:505.15408.

[0028] Diethyl((2-hydroxyphenyl)((4-(N-(5-methoxypyrimidin-2-yl)sulfamoyl)phenyl)amino)methyl)phosphonate(A8).Offwhite solid,m.p.188.6-189.3;yield68.42%. 1HNMR(400 MHz,DMSO)δ11.04(s,1H),9.94(s,1H),8.23(s,2H),7.63(d,J=9.0Hz,2H),7.44(d,J=7.7 Hz,1H),7.30–7.19(m,1H),7.08(t,J=7.7 Hz,1H),6.84(d,J=8.1 Hz,1H),6.82–6.73(m,3H),5.27(dd,J=23.5,9.5 Hz,1H),4.04(dd,J=11.9,5.1Hz,2H),3.85(dd,J=15.9,8.7 Hz,1H),3.76(s,3H),3.66(dd,J=16.3,9.2Hz,1H),1.15(t,J=7.1 Hz,3H),1.00(t,J=7.0 Hz,3H). 13 C NMR(101 MHz,DMSO)δ155.42,151.70,151.42,149.86,145.01,129.67,129.28,127.36,122.64,119.58,115.36,111.99,63.02,62.77,56.67,δ46.70(d,J=156.8 Hz),16.74,16.41. 31 P NMR(162 MHz,DMSO)δ22.54.HRMS(ESI)[M+H] + calcd forC 22 H 28 N4O7PS + :523.14108,found:523.14008.

[0029] Diethyl((2-hydroxyphenyl)((4-(N-(5-methylisoxazol-3-yl)sulfamoyl)phenyl)amino)methyl)phosphonate(A9).White solid,m.p.165.0-166.1;yield79.67%. 1HNMR(400 MHz,DMSO)δ10.96(s,1H),9.93(s,1H),7.49(d,J=9.0 Hz,2H),7.43(d,J=7.7 Hz,1H),7.36–7.29(m,1H),7.09(t,J=7.7 Hz,1H),6.81(t,J=15.0 Hz,4H),6.07(s,1H),5.26(dd,J=23.4,9.5 Hz,1H),4.04(dd,J=10.7,3.6 Hz,2H),3.85(dd,J=15.8,8.6 Hz,1H),3.66(dd,J=16.3,9.2 Hz,1H),2.26(s,3H),1.16(t,J=7.1 Hz,3H),1.00(t,J=7.0 Hz,3H). 13 C NMR(101 MHz,DMSO)δ170.43,158.27,155.35,151.91,129.30,128.90,126.21,122.52,119.61,115.38,112.40,95.71,63.03,62.77,δ46.68(d,J=156.6Hz),16.74,16.41,12.50. 31 P NMR(162MHz,DMSO)δ22.42.HRMS(ESI)[M+H] + calcd forC 21 H 27 N3O7PS + :496.13018,found:496.13022.

[0030] Diethyl(((3-(N-(3,4-dimethylisoxazol-5-yl)sulfamoyl)phenyl)amino)(2-hydroxyphenyl)methyl)phosphonate(A 10 ).Faint yellow solid,m.p.181.6-183.5;yield75.83%. 1H NMR(400 MHz,DMSO)δ10.54(s,1H),9.96(s,1H),7.48(d,J=7.7 Hz,1H),7.42(d,J=9.0 Hz,2H),7.39–7.32(m,1H),7.10(t,J=7.1 Hz,1H),6.87(t,J=7.8Hz,3H),6.79(t,J=7.5 Hz,1H),5.34(dd,J=23.4,9.5 Hz,1H),4.08(dd,J=13.8,5.8 Hz,2H),3.88(dd,J=14.3,3.2 Hz,1H),3.70(dd,J=18.9,6.7 Hz,1H),2.04(s,3H),1.55(s,3H),1.23–1.18(m,3H),1.02(t,J=7.1 Hz,3H). 13 C NMR(101 MHz,DMSO)δ161.67,156.55,155.44,152.02,129.27,128.78,126.61,122.48,119.59,115.39,112.59,104.85,63.10,62.85,46.80(d,J=156.8 Hz),16.73,16.38,10.69,6.15. 31 P NMR(162 MHz,DMSO)δ22.49.HRMS(ESI)[M+H] + calcd forC 22 H 29 N3O7PS + :510.14583,found:510.14484.

[0031] Diethyl((2-hydroxyphenyl)((6-(N-methylsulfamoyl)naphthalen-2-yl)amino)methyl)phosphonate(A 11 ).brownish red solid,m.p.167.7-171.2;yield76.41%. 1H NMR(400 MHz,DMSO)δ9.97(s,1H),8.11(s,1H),7.81(d,J=9.0 Hz,1H),7.64–7.55(m,2H),7.50(d,J=7.7 Hz,1H),7.37(dd,J=9.0,2.2 Hz,1H),7.28(q,J=5.0 Hz,1H),7.09(dd,J=14.0,6.1 Hz,2H),6.93–6.84(m,2H),6.79(dt,J=14.9,7.5 Hz,2H),5.40(dd,J=23.6,9.7 Hz,1H),4.08(dd,J=15.3,7.2 Hz,2H),3.89(dd,J=17.4,7.2 Hz,1H),3.70(dd,J=18.3,7.1 Hz,1H),2.37(d,J=5.1 Hz,3H),1.20(t,J=7.0 Hz,3H),1.02(d,J=7.0 Hz,3H). 13 C NMR(101 MHz,DMSO)δ155.60,148.10,136.77,131.64,130.22,129.14,128.03,126.91,125.51,125.16,123.26,122.99,120.34,119.58,115.37,103.81,62.97,62.78,46.93(d,J=156.7 Hz),29.12,16.81,16.45. 31 P NMR(162 MHz,DMSO)δ22.87.HRMS(ESI)[M+H] + calcd forC 22 H 28 N2O6PS + :479.14002,found:479.13873.

[0032] Diethyl(((4-(N-(3,6-dimethoxypyrazin-2-yl)sulfamoyl)phenyl)amino)(3-hydroxyphenyl)methyl)phosphonate(A 12 ).White solid,m.p.169.1-171.1;yield86.24%. 1HNMR(400 MHz,DMSO)δ10.65(s,1H),9.93(s,1H),8.09(s,1H),7.66(d,J=8.9Hz,2H),7.43(d,J=7.7 Hz,1H),7.32–7.23(m,1H),7.08(t,J=7.7 Hz,1H),6.87–6.72(m,4H),5.27(dd,J=23.5,9.5 Hz,1H),4.10–3.98(m,2H),3.87(s,3H),3.82(dd,J=12.3,5.0 Hz,1H),3.69(dd,J=11.2,4.0 Hz,1H),3.65(s,3H),1.16(t,J=7.1 Hz,3H),1.00(t,J=7.0 Hz,3H). 13 C NMR(101 MHz,DMSO)δ161.86,155.42,151.06,129.84,129.28,127.28,122.62,119.59,115.36,111.96,63.01,62.75,60.64,54.39,46.70(d,J=156.7 Hz),16.74,16.41. 31 P NMR(162 MHz,DMSO)δ22.49.HRMS(ESI)[M+H] + calcd for C 23 H 30 N4O8PS + :553.15165:,found:553.15039.

[0033] Diethyl((3-hydroxyphenyl)((3-(N-phenylsulfamoyl)phenyl)amino)methyl)phosphonate(B1).White solid,m.p.149.3-151.2;yield 79.67%. 1H NMR(400 MHz,DMSO)δ10.10(s,1H),9.42(s,1H),7.26(s,1H),7.16(dd,J=24.4,14.3 Hz,4H),7.06(d,J=7.5Hz,2H),6.98(t,J=7.4 Hz,2H),6.95–6.84(m,4H),6.69(d,J=7.9 Hz,1H),4.86(dd,J=24.3,9.2 Hz,1H),4.00(dd,J=15.2,7.2 Hz,2H),3.90(dd,J=12.3,5.1 Hz,1H),3.74(dd,J=16.4,9.4 Hz,1H),1.14(t,J=7.1 Hz,3H),1.07(t,J=7.1 Hz,3H). 13 C NMR(101MHz,DMSO)δ157.64,148.40,148.27 140.65,138.40,137.92,129.88,129.45,124.16,120.24,119.52,117.45,115.65,115.12,114.79,111.52,62.99,62.81 54.40(d,J=152.2Hz),16.74,16.50. 31 P NMR(162 MHz,DMSO)δ22.19.HRMS(ESI)[M+H] + calcd forC 23 H 28 N2O6PS + :491.14002,found:491.13885.

[0034] Diethyl((3-hydroxyphenyl)((4-(N-(pyridin-2-yl)sulfamoyl)phenyl)amino)methyl)phosphonate(B2).White solid,yield 83.04%,m.p.209.7-210.7; 1H NMR(400MHz,DMSO)δ11.08(s,1H),9.39(s,1H),8.05(d,J=4.0 Hz,1H),7.63(t,J=6.9 Hz,1H),7.55(s,2H),7.24–7.13(m,1H),7.09(dd,J=18.3,8.1 Hz,2H),6.93(d,J=8.9 Hz,2H),6.89–6.83(m,3H),6.66(d,J=7.7 Hz,1H),5.02(dd,J=24.1,9.4 Hz,1H),4.00(dd,J=15.3,8.1 Hz,2H),3.88(dd,J=15.9,8.7 Hz,1H),3.72(dd,J=18.0,7.8 Hz,1H),1.12(t,J=7.1 Hz,3H),1.05(t,J=7.1 Hz,3H). 13 C NMR(101MHz,DMSO)δ157.60,152.83,151.43,151.31,146.36,139.42,137.87,129.46,128.77,127.92,119.43,117.34,115.73,115.12,112.70,62.97,62.86,53.85(d,J=151.6 Hz),16.73,16.47. 31 P NMR(162 MHz,DMSO)δ22.13.HRMS(ESI)[M+H] + calcd for C 22 H 27 N3O6PS + :492.13527,found:492.13394.

[0035] Diethyl((3-hydroxyphenyl)((4-(N-(pyrimidin-2-yl)sulfamoyl)phenyl)amino)methyl)phosphonate(B3).Offwhite solid,m.p.192.5-192.9;yield 75.23%. 1HNMR(400 MHz,DMSO)δ8.45(s,1H),8.44(s,1H),7.65(d,J=9.0 Hz,3H),7.22(s,2H),7.11(t,J=7.9 Hz,1H),6.99–6.92(m,3H),6.89(d,J=9.0 Hz,2H),6.67(d,J=8.8 Hz,1H),5.04(dd,J=24.0,8.1 Hz,1H),4.00(dd,J=15.2,7.2 Hz,2H),3.88(dd,J=12.3,5.1 Hz,1H),3.73(dd,J=16.4,9.3 Hz,1H),1.11(t,J=7.1 Hz,3H),1.04(t,J=7.1 Hz,3H). 13 CNMR(101 MHz,DMSO)δ158.71,157.58,151.62,137.80,129.73,129.50,126.98,119.49,116.06,115.74,115.17,112.45,63.03,62.94,53.84(d,J=151.7 Hz),16.70,16.45. 31 PNMR(162 MHz,DMSO)δ22.08.HRMS(ESI)[M+H] + calcd for C 21 H 26 N4O6PS + :493.13052,found:493.13077.

[0036] Diethyl((3-hydroxyphenyl)((4-(N-methylsulfamoyl)phenyl)amino)methyl)phosphonate(B4).White solid,m.p.;180.7-181.7;yield 86.43%. 1H NMR(400 MHz,DMSO)δ9.40(s,1H),7.41(d,J=8.8 Hz,2H),7.13(dd,J=18.4,10.7 Hz,2H),6.94(dd,J=14.9,7.2 Hz,5H),6.66(d,J=7.9 Hz,1H),5.05(dd,J=24.3,9.5 Hz,1H),4.03(dd,J=14.0,6.5 Hz,2H),3.91(dd,J=17.5,7.2 Hz,1H),3.74(dd,J=16.4,9.3Hz,1H),2.30(d,J=5.1 Hz,3H),1.17(t,J=7.0 Hz,3H),1.07(t,J=7.0 Hz,3H). 13 C NMR(101 MHz,DMSO)δ157.60,151.27,138.05,129.46,128.57,126.15,119.48,115.75,115.10,112.95,62.99,62.88,53.88(d,J=151.7 Hz),29.13,16.77,16.50. 31 P NMR(162 MHz,DMSO)δ22.19.HRMS(ESI)[M+H] + calcd forC 18 H 26 N2O6PS + :429.12437,found:429.12320.

[0037] Diethyl(((4-(N,N-dimethylsulfamoyl)phenyl)amino)(3-hydroxyphenyl)methyl)phosphonate(B5).White solid,m.p.90.3 -91.4;yield 88.21%. 1H NMR(400MHz,DMSO)δ9.43(s,1H),7.38(d,J=8.9 Hz,2H),7.32–7.26(m,1H),7.13(t,J=7.6Hz,1H),6.97(d,J=8.9 Hz,4H),6.68(d,J=7.6 Hz,1H),5.06(dd,J=24.1,9.4 Hz,1H),4.04(dd,J=14.2,6.6 Hz,2H),3.90(dd,J=12.3,5.1 Hz,1H),3.74(dd,J=17.3,8.4 Hz,1H),2.49(s,6H),1.18–1.13(m,3H),1.07(t,J=7.1 Hz,3H). 13 CNMR(101 MHz,DMSO)δ157.64,151.81,137.92,129.50,121.28,119.49,115.70,115.15,114.83,112.93,62.99,62.89,53.86(d,J=151.7 Hz),38.10,16.76,16.48. 31 PNMR(162 MHz,DMSO)δ22.09.HRMS(ESI)[M+H] + calcd for C 19 H 28 N2O6PS + 443.14002:,found:443.13879.

[0038] Diethyl((3-hydroxyphenyl)((4-(N-(thiazol-2-yl)sulfamoyl)phenyl)amino)methyl)phosphonate(B6).Faint yellow solid,m.p.185.7-186.9;yield 83.78%. 1H NMR(400 MHz,DMSO)δ9.90(s,1H),7.44(t,J=8.9 Hz,3H),7.16(d,J=4.6 Hz,1H),7.12–7.04(m,2H),6.83(d,J=8.1 Hz,1H),6.77(t,J=7.5 Hz,3H),6.72(d,J=4.6Hz,1H),5.26(dd,J=23.7,9.4 Hz,1H),4.04(dd,J=11.4,4.1 Hz,2H),3.85(dd,J=15.9,8.7 Hz,1H),3.66(dd,J=16.9,8.7 Hz,1H),1.18(t,J=7.1 Hz,3H),1.00(t,J=7.0 Hz,3H). 13 C NMR(101MHz,DMSO)δ168.57,155.41,150.98,129.75–129.55(m),129.19,127.83,124.75,122.76,119.57,115.33,112.30,108.03,62.98,62.78,46.77(d,J=156.7 Hz),16.78,16.43. 31 PNMR(162 MHz,DMSO)δ22.65.HRMS(ESI)[M+H] + calcd for C 20 H 25 N3O6PS2 + :498.09169,found:498.09033.

[0039] Diethyl((3-hydroxyphenyl)((4-(N-(p-tolyl)sulfamoyl)phenyl)amino)methyl)phosphonate(B7).White solid,m.p.147.9-147.8;yield 82.12%. 1H NMR(400MHz,DMSO)δ9.51(s,1H),9.37(s,1H),7.54(d,J=8.2 Hz,2H),7.27(d,J=8.1 Hz,2H),7.10(t,J=7.9 Hz,1H),6.93(d,J=7.5 Hz,2H),6.73(d,J=8.9 Hz,2H),6.66(d,J=9.0Hz,2H),6.25–6.11(m,1H),4.84(dd,J=24.5,9.7 Hz,1H),4.02(dd,J=14.2,7.1 Hz,2H),3.88(dd,J=17.4,7.2 Hz,1H),3.70(dd,J=18.0,7.7 Hz,1H),2.30(s,3H),1.16(t,J=7.1 Hz,3H),1.04(t,J=7.1 Hz,3H). 13 C NMR(101 MHz,DMSO)δ157.57,145.33,143.17,138.55,137.40,129.87,129.33,127.20,127.15,124.31,119.60,115.78,114.94,113.94,62.91,62.73,54.58(d,J=151.5 Hz),21.39,16.75,16.46. 31 P NMR(162 MHz,DMSO)δ22.92.HRMS(ESI)[M+H] + calcd forC 24 H 28 N2O6PS + :503.14002,found:503.13889.

[0040] Diethyl((3-hydroxyphenyl)((4-(N-(5-methoxypyrimidin-2-yl)sulfamoyl)phenyl)amino)methyl)phosphonate(B8).White solid,m.p.109.8-109.9;yield73.71%. 1HNMR(400 MHz,DMSO)δ11.04(s,1H),9.40(s,1H),8.26(d,J=7.5 Hz,3H),7.60(dd,J=8.9,2.0 Hz,3H),7.20(dd,J=9.4,6.6 Hz,1H),7.11(t,J=7.8 Hz,1H),6.94(d,J=9.2 Hz,2H),6.87(d,J=9.0 Hz,2H),6.66(d,J=7.8 Hz,1H),6.56(d,J=8.8Hz,1H),5.03(dd,J=24.1,9.5 Hz,1H),4.00(dd,J=15.0,7.7 Hz,2H),3.89(dd,J=17.5,7.2 Hz,1H),3.76(s,3H),3.70(dd,J=18.1,7.8 Hz,1H),1.13(t,J=7.1 Hz,3H),1.05(t,J=7.0Hz,3H). 13 C NMR(101 MHz,DMSO)δ157.60,153.36,151.72,149.87,144.99,137.89,130.10,129.50,127.33,125.69,119.43,115.74,115.14,112.65,112.46,62.97,62.87,56.69,53.83(d,J=151.8 Hz),16.74,16.48. 31 P NMR(162 MHz,DMSO)δ22.12.HRMS(ESI)[M+H] + calcd for C 22 H 28 N4O7PS + :523.14108,found:523.14001.

[0041] Diethyl((3-hydroxyphenyl)((4-(N-(5-methylisoxazol-3-yl)sulfamoyl)phenyl)amino)methyl)phosphonate(B9).White solid,m.p.163.4-164.2;yield84.57%. 1H NMR(400 MHz,DMSO)δ10.97(s,1H),9.41(s,1H),7.49(d,J=9.0 Hz,2H),7.35–7.26(m,1H),7.12(t,J=7.8 Hz,1H),6.93(dd,J=16.7,8.8 Hz,4H),6.67(d,J=7.6Hz,1H),6.09(s,1H),5.06(dd,J=24.1,9.4 Hz,1H),4.02(t,J=11.2 Hz,2H),3.90(dd,J=17.5,7.2 Hz,1H),3.74(dd,J=16.4,9.4 Hz,1H),2.26(s,3H),1.14(d,J=7.1 Hz,3H),1.06(d,J=14.1 Hz,3H). 13 C NMR(101 MHz,DMSO)δ170.43,158.32,157.61,151.87,137.77,129.51,128.75,126.21,119.43,115.69,115.09,112.90,95.74,63.00,62.91,53.81(d,J=151.7 Hz),16.72,16.47,12.49. 31 P NMR(162 MHz,DMSO)δ22.03.HRMS(ESI)[M+H] + calcd for C 22 H 29 N3O7PS + :510.14583,found:510.14444.

[0042] Diethyl(((3-(N-(3,4-dimethylisoxazol-5-yl)sulfamoyl)phenyl)amino)(3-hydroxyphenyl)methyl)phosphonate(B 10 ).White solid,m.p.179.2-180.2;yield75.12%. 1HNMR(400 MHz,DMSO)δ10.53(s,1H),9.42(s,1H),7.38(d,J=9.0 Hz,2H),7.31(dd,J=9.3,6.7 Hz,1H),7.11(dd,J=7.7,2.8 Hz,1H),6.94(dd,J=13.4,8.8 Hz,5H),6.68(d,J=8.6 Hz,1H),5.08(dd,J=24.1,9.5 Hz,1H),4.06–3.99(m,2H),3.90(dd,J=8.9,5.9 Hz,1H),3.75(dd,J=16.5,9.4 Hz,1H),2.04(s,3H),1.54(s,3H),1.17(dd,J=4.7,2.4 Hz,3H),1.07(t,J=7.1 Hz,3H). 13 C NMR(101 MHz,DMSO)δ161.68,157.64,157.39,156.56,151.94,128.62,119.46,118.51,115.75,115.14,114.78,113.04,104.84,62.71,62.29,53.86(d,J=151.6 Hz),16.75,16.48,10.73,6.16. 31 P NMR(162 MHz,DMSO)δ22.06.HRMS(ESI)[M+H] + calcd forC 22 H 29 N3O7PS + :510.14583,found:510.14438.

[0043] Diethyl((3-hydroxyphenyl)((4-(N-(p-tolyl)sulfamoyl)phenyl)amino)methyl)phosphonate(B 11 ).Brownish red solid,m.p.186.9-187.3;yield:80.56%. 1HNMR(400MHz,DMSO)δ9.40(s,1H),8.11(s,1H),7.81(d,J=9.0 Hz,1H),7.63(d,J=8.8Hz,1H),7.56(d,J=10.5 Hz,1H),7.44(d,J=9.0 Hz,1H),7.28(q,J=5.0 Hz,1H),7.13(t,J=7.8 Hz,1H),7.10–6.98(m,4H),6.66(d,J=7.9 Hz,1H),5.14(dd,J=24.4,9.6 Hz,1H),4.06(dd,J=13.1,7.1 Hz,2H),3.93(dd,J=12.3,5.1 Hz,1H),3.77(dd,J=16.4,9.4 Hz,1H),2.37(d,J=5.1 Hz,3H),1.18(t,J=7.1 Hz,3H),1.09(t,J=7.0 Hz,3H). 13 C NMR(101MHz,DMSO)δ157.61,148.19,138.18,136.75,131.63,130.14,129.43,128.01,126.96,125.46,123.16,120.49,119.63,115.77,115.07,104.51,63.03,62.85,54.08(d,J=151.9Hz),29.13,16.80,16.52. 31 P NMR(162 MHz,DMSO)δ22.39.HRMS(ESI)[M+H] + calcd forC 22 H 28 N2O6PS + :479.14002,found:479.14008.

[0044] Diethyl(((4-(N-(3,6-dimethoxypyrazin-2-yl)sulfamoyl)phenyl)amino)(3-hydroxyphenyl)methyl)phosphonate(B 12 ).White solid,m.p.117.3-119.1;yield67.32%. 1HNMR(400 MHz,DMSO)δ10.65(s,1H),9.40(s,1H),8.09(s,1H),7.64(d,J=9.0Hz,2H),7.27–7.20(m,1H),7.10(t,J=7.8 Hz,1H),6.94(d,J=9.4 Hz,2H),6.88(d,J=9.0 Hz,2H),6.65(d,J=7.8 Hz,1H),5.04(dd,J=24.1,9.4 Hz,1H),4.02(dd,J=15.3,8.2 Hz,2H),3.94(dd,J=11.7,4.6 Hz,1H),3.87(s,3H),3.77–3.69(m,1H),3.65(s,3H),1.13(t,J=7.0 Hz,3H),1.05(t,J=7.0 Hz,3H). 13 C NMR(101MHz,DMSO)δ161.86,157.61,151.77,151.11,137.86,129.66,129.46,127.29,119.42,115.75,115.14,112.43,62.97,62.87,60.63,54.41,53.81(d,J=151.3 Hz),16.72,16.47. 31 P NMR(162 MHz,DMSO)δ22.03.HRMS(ESI)[M+H] + calcd forC 22 H 28 N2O6PS + :553.15165,found:553.15057.

[0045] Diethyl((4-hydroxyphenyl)((3-(N-phenylsulfamoyl)phenyl)amino)methyl)phosphonate(C1).White solid,yield 67.32%,m.p.187.5–189.5 1H NMR(400 MHz,DMSO)δ10.09(s,1H),9.42(s,1H),7.30(d,J=6.7 Hz,2H),7.24(s,1H),7.21–7.12(m,3H),7.05(d,J=7.6 Hz,2H),6.98(t,J=8.0 Hz,2H),6.91(d,J=8.1 Hz,1H),6.86(dd,J=9.7,6.0Hz,1H),6.72(d,J=8.4 Hz,2H),4.82(dd,J=23.6,9.9Hz,1H),3.98(dd,J=15.1,7.1 Hz,2H),3.87(dd,J=17.5,7.2 Hz,1H),3.70(dd,J=18.6,7.1 Hz,1H),1.13(t,J=7.0 Hz,3H),1.05(t,J=7.0 Hz,3H). 13 C NMR(101MHz,DMSO)δ155.58,148.24,140.78,138.43,129.97,129.45,123.98,122.75,119.89,119.45,117.10,115.26,114.73,111.31,62.90,62.71,46.86(d,J=156.9 Hz),16.75,16.43. 31 P NMR(162 MHz,DMSO)δ22.84.HRMS(ESI)[M+H] + calcd forC 23 H 28 N2O6PS + :491.14002,found:491.13916.

[0046] Diethyl((4-hydroxyphenyl)((4-(N-(pyridin-2-yl)sulfamoyl)phenyl)amino)methyl)phosphonate(C2).White solid,m.p.184.2-185.0;yield 71.34%. 1H NMR(400MHz,DMSO)δ11.05(s,1H),9.39(s,1H),8.05(d,J=4.0 Hz,1H),7.63(t,J=7.9 Hz,1H),7.52(d,J=9.0 Hz,2H),7.30(dd,J=8.6,1.9 Hz,2H),7.16–7.09(m,1H),7.05(d,J=8.5Hz,1H),6.84(d,J=9.0 Hz,2H),6.69(d,J=8.5 Hz,2H),4.97(dd,J=23.4,9.6 Hz,1H),3.97(dd,J=15.2,6.6 Hz,2H),3.83(dd,J=8.7,5.7 Hz,1H),3.66(dd,J=16.4,9.4 Hz,1H),1.11(t,J=7.1 Hz,3H),1.02(t,J=7.0 Hz,3H). 13 C NMR(101 MHz,DMSO)δ157.40,152.82,151.33,146.40,139.39,129.94,129.38,128.78,127.76,126.41,117.36,115.40,112.91,62.83,62.76,53.21(d,J=153.8 Hz),16.74,16.51. 31 P NMR(162 MHz,DMSO)δ22.34.HRMS(ESI)[M+H] + calcd forC 22 H 27 N3O6PS + :492.13527,found:492.13354.

[0047] Diethyl((4-hydroxyphenyl)((4-(N-(pyrimidin-2-yl)sulfamoyl)phenyl)amino)methyl)phosphonate(C3).White solid,m.p.146.0-146.1;yield 74.21. 1H NMR(400 MHz,DMSO)δ11.29(s,1H),9.40(s,1H),8.46(d,J=4.8 Hz,2H),7.61(d,J=9.0 Hz,2H),7.31(d,J=8.5 Hz,2H),7.20(t,J=13.0 Hz,1H),6.98(t,J=4.9 Hz,1H),6.86(d,J=9.0 Hz,2H),6.70(d,J=8.5 Hz,2H),4.99(dd,J=23.3,9.6 Hz,1H),3.98(dd,J=15.0,7.8 Hz,2H),3.85(dd,J=17.5,7.2 Hz,1H),3.68(dd,J=18.0,7.7 Hz,1H),1.11(t,J=7.1 Hz,3H),1.03(t,J=7.0 Hz,3H). 13 C NMR(101 MHz,DMSO)δ158.72,157.62,157.41,151.76,129.95,129.71,126.84,126.40,116.05,115.41,112.41,62.87,62.77,53.19(d,J=153.8 Hz),16.74,16.51. 31 P NMR(162 MHz,DMSO)δ22.52.HRMS(ESI)[M+H] + calcd forC 21 H 26 N4O6PS + :493.13052,found:493.12903.

[0048] Diethyl((4-hydroxyphenyl)((4-(N-methylsulfamoyl)phenyl)amino)methyl)phosphonate(C4).Pale brown solid,m.p.139.9-141.3;yield:86.45%. 1H NMR(400 MHz,DMSO)δ9.40(s,1H),7.39(d,J=8.9 Hz,2H),7.33(dd,J=8.6,2.0 Hz,2H),7.11(dd,J=9.6,6.1 Hz,1H),6.95(d,J=10.2 Hz,1H),6.90(d,J=8.9 Hz,2H),6.71(d,J=8.4 Hz,2H),5.75(s,1H),5.00(dd,J=23.6,9.7 Hz,1H),4.01(dd,J=13.8,6.2Hz,2H),3.86(dd,J=12.4,5.2 Hz,1H),3.70(dd,J=17.1,8.7 Hz,1H),2.29(d,J=5.1 Hz,3H),1.16(t,J=7.0 Hz,3H),1.05(t,J=7.0 Hz,3H). 13 C NMR(101 MHz,DMSO)δ157.40,151.27,129.90,128.56,126.51,126.12,115.40,112.94,62.87,62.85,53.26(d,J=153.9 Hz),29.11,16.78,16.52. 31 P NMR(162 MHz,DMSO)δ22.63.HRMS(ESI)[M+H] + calcd for C 18 H 26 N2O6PS + :429.12437,found:429.12332.

[0049] Diethyl(((4-(N,N-dimethylsulfamoyl)phenyl)amino)(4-hydroxyphenyl)methyl)phosphonate(C5).Pale brown solid,m.p.;134.2-123.4:yield:77.81%. 1H NMR(400MHz,DMSO)δ9.41(s,1H),7.41–7.31(m,4H),7.25(dd,J=9.5,6.0 Hz,1H),6.95(d,J=8.9 Hz,2H),6.72(d,J=8.4 Hz,2H),5.02(dd,J=23.4,9.6 Hz,1H),4.01(dd,J=14.0,6.4 Hz,2H),3.91–3.80(m,1H),3.69(dd,J=16.4,9.3 Hz,1H),2.48(s,6H),1.15(t,J=7.0 Hz,3H),1.04(t,J=7.0 Hz,3H). 13 C NMR(101 MHz,DMSO)δ157.46,151.80,129.94,129.55,126.43,121.21,115.44,112.93,62.89,62.82,53.24(d,J=154.0 Hz),38.09,16.75,16.50. 31 P NMR(162 MHz,DMSO)δ22.53.HRMS(ESI)[M+H] + calcd for C 19 H 28 N2O6PS + :441.12437,found:441.12305.

[0050] Diethyl((4-hydroxyphenyl)((4-(N-(thiazol-2-yl)sulfamoyl)phenyl)amino)methyl)phosphonate(C6).White solid,m.p.195.1-197.0;yield 5.32%. 1H NMR(400MHz,DMSO)δ12.43(s,1H),9.38(s,1H),7.42(d,J=8.9 Hz,2H),7.31(d,J=2.0 Hz,1H),7.29(d,J=2.0 Hz,1H),7.17(d,J=4.6 Hz,1H),7.03(dd,J=9.4,6.4 Hz,1H),6.83(d,J=8.9 Hz,2H),6.72(d,J=4.6 Hz,1H),6.69(d,J=8.5 Hz,2H),4.95(dd,J=23.6,9.6Hz,1H),4.00(dd,J=13.9,7.0 Hz,2H),3.77(ddd,J=68.8,17.4,8.7 Hz,2H),1.14(t,J=7.0 Hz,3H),1.04(t,J=7.0 Hz,3H). 13 C NMR(101 MHz,DMSO)δ158.72,157.62,151.76,129.95,127.69,126.84,126.40,124.76,116.05,115.41,112.42,108.01,62.84,62.77,54.09(s),52.42(s),16.77,16.51. 31 P NMR(162 MHz,DMSO)δ22.53.HRMS(ESI)[M+H] + calcdfor C 20 H 25 N3O6PS + :498.09169,found:498.0900.

[0051] Diethyl((4-hydroxyphenyl)((4-(N-(p-tolyl)sulfamoyl)phenyl)amino)methyl)phosphonate(C7).Pale brown solid,m.p.175.1-176.0;yield 88.46%. 1H NMR(400MHz,DMSO)δ9.47(s,1H),9.35(s,1H),7.51(d,J=8.2 Hz,2H),7.27(d,J=8.2Hz,4H),6.69(d,J=8.2 Hz,4H),6.62(d,J=9.0 Hz,2H),6.14(dd,J=10.0,6.3 Hz,1H),4.78(dd,J=23.9,10.0 Hz,1H),3.99(dd,J=15.9,8.7 Hz,2H),3.75(dd,J=72.7,18.0 Hz,2H),2.31(s,3H),1.14(t,J=7.1 Hz,3H),1.02(t,J=7.1 Hz,3H). 13 CNMR(101 MHz,DMSO)δ157.21,145.51,143.15,137.39,129.86,127.20,127.04,124.30,115.28,114.14,62.72,62.58,53.90(d,J=153.8 Hz),21.39,16.77,16.51. 31 P NMR(162 MHz,DMSO)δ23.36.HRMS(ESI)[M+H] + calcd forC 24 H 30 N2O6PS + :505.15567,found:505.15375.

[0052] Diethyl((4-hydroxyphenyl)((4-(N-(3-methoxypyrazin-2-yl)sulfamoyl)phenyl)amino)methyl)phosphonate(C8).White solid,m.p.188.6-190.5;yield78.45%. 1H NMR(400 MHz,DMSO)δ10.37(s,1H),9.40(s,1H),7.70(s,2H),7.64(d,J=8.8Hz,2H),7.33(d,J=1.7 Hz,1H),7.31(d,J=1.8 Hz,1H),7.19(dd,J=9.4,6.0 Hz,1H),6.87(d,J=9.0 Hz,2H),6.70(d,J=8.4 Hz,2H),5.00(dd,J=23.4,9.6 Hz,1H),3.99(dd,J=14.6,7.2 Hz,2H),3.91–3.81(m,4H),3.69(dd,J=16.4,9.3 Hz,1H),1.12(t,J=7.0Hz,3H),1.03(t,J=7.0 Hz,3H). 13 C NMR(101 MHz,DMSO)δ157.37,151.68,150.00,138.74,134.03,133.60,129.88,129.67,127.13,126.42,115.39,112.41,62.82,62.75,53.17(d,J=153.8 Hz),16.75,16.51. 31 P NMR(162MHz,DMSO)δ22.53.HRMS(ESI)[M+H] + calcd forC 22 H 28 N4O7PS + :523.14108,found:523.13940.

[0053] Diethyl(((4-(N-(5,6-dimethoxypyrimidin-4-yl)sulfamoyl)phenyl)amino)(4-hydroxyphenyl)methyl)phosphonate(C9).Faint yellow solid,m.p.161.4-161.8;yield56.27%. 1H NMR(400 MHz,DMSO)δ10.64(s,1H),9.47(s,1H),8.09(s,1H),7.65(d,J=8.9 Hz,2H),7.32(dd,J=8.5,1.8 Hz,2H),7.21(dd,J=9.5,6.0 Hz,1H),6.88(d,J=9.0 Hz,2H),6.71(d,J=8.4 Hz,2H),5.00(dd,J=23.4,9.5 Hz,1H),3.99(dd,J=14.7,7.2 Hz,2H),3.89–3.83(m,4H),3.70(dd,J=10.2,7.2 Hz,1H),3.65(s,3H),1.12(t,J=7.0 Hz,3H),1.03(t,J=7.0 Hz,3H). 13 C NMR(101 MHz,DMSO)δ161.85,157.41,151.77,151.11,129.94,129.68,127.28,126.38,115.40,112.42,62.85,62.78,60.63,54.39,53.18(d,J=153.8 Hz),16.72,16.49. 31 P NMR(162MHz,DMSO)δ22.51.HRMS(ESI)[M+H] + calcd for C 23 H 30 N2O8PS + :553.15365,found:553.15015.

[0054] Diethyl((4-hydroxyphenyl)((4-(N-(6-methoxypyridazin-3-yl)sulfamoyl)phenyl)amino)methyl)phosphonate(C 10 ).Faint yellow solid,m.p.157.7–157.7;yield65.23%. 1H NMR(400 MHz,DMSO)δ9.39(s,1H),7.56(d,J=7.9 Hz,1H),7.48(d,J=8.9Hz,2H),7.31(d,J=6.6 Hz,2H),7.23(d,J=9.7 Hz,1H),7.15–7.07(m,1H),6.85(d,J=8.9Hz,2H),6.70(d,J=8.5 Hz,2H),4.98(dd,J=23.5,9.6 Hz,1H),3.99(dd,J=14.7,7.1Hz,2H),3.85(dd,J=16.0,8.6Hz,4H),3.68(dd,J=16.4,9.3Hz,1H),1.13(t,J=7.1Hz,3H),1.03(t,J=7.0Hz,3H). 13 C NMR(101MHz,DMSO)δ157.36,151.29,129.94,128.36,126.46,115.39,112.79,62.83,62.74,54.81(s),53.23(d,J=153.9Hz),16.75,16.51. 31 P NMR(162MHz,DMSO)δ22.59.HRMS(ESI)[M+H] + calcd for C 22 H 28 N4O7PS + :523.14108,found:523.14108.

[0055] Diethyl

[0056] ((4-hydroxyphenyl)((4-(morpholinosulfonyl)phenyl)amino)methyl)phosphonate(C 11 ).Faint yellow solid,m.p.189.1-191.1;yield 68.51%. 1H NMR(400MHz,DMSO)δ9.44(s,1H),7.34(dd,J=16.3,12.4Hz,5H),6.97(d,J=8.9Hz,2H),6.73(d,J=8.4Hz,2H),5.04(dd,J=23.3,9.5Hz,1H),4.02(dd,J=13.8,7.0Hz,2H),3.88(dd,J=17.4,7.2Hz,1H),3.71(dd,J=18.0,7.8Hz,1H),3.62–3.54(m,4H),2.78–2.70(m,4H),1.16(t,J=7.1Hz,3H),1.06(t,J=7.0Hz,3H). 13 C NMR(101MHz,DMSO)δ157.41,152.09,129.96,129.97,126.36,120.66,115.43,112.94,65.71,62.86,62.79,53.21(d,J=153.7Hz),46.36,16.78,16.53. 31 P NMR(162MHz,DMSO)δ22.48.HRMS(ESI)[M+H] + calcd forC 21 H 30 N2O6PS + :485.15058,found:485.15079.

[0057] Diethyl(((3-(N-cyclohexyl-N-methylsulfamoyl)phenyl)amino)(4-hydroxyphenyl)methyl)phosphonate(C 12 ).Light pink solid,m.p.187.5–189.5;yield76.21%. 1HNMR(400MHz, DMSO)δ9.45(s,1H),7.61–7.53(m,1H),7.32–7.23(m,3H),7.01(t,J=8.6Hz,1H),6.81(d,J=8.4H z,1H),6.71(dd,J=12.5,7.9Hz,3H),5.13(dd,J=23.6,8.6Hz,1H),4.00(dd,J=15.0,7.8Hz,2H),3.88(dd,J=12. 3,5.2Hz,1H),3.73(dd,J=18.0,7.7Hz,1H),3.65–3.54(m,1H),2.75(s,3H),1.66(t,J=9.7Hz,2H),1.55–1.45( m,2H),1.39(t,J=10.2Hz,3H),1.23(dt,J=14.1,9.9Hz,5H),1.08(t,J=7.1Hz,3H),0.99(dd,J=8.0,4.7Hz,1H). 13 C NMR(101MHz,DMSO)δ157.81,144.59,137.55,134.51,130.27,122.14,119.03,116.95,115.28, 114.07,63.16,62.82,56.49,53.60(d,J=150.0Hz),30.02,29.04,25.71,25.26,16.66,16.45. 31 P NMR(162MHz,DMSO)δ22.42.HRMS(ESI)[M+H] + calcd forC 24 H 36 N2O6PS + :511.20262,found:511.20135.

[0058] Antiviral activity test

[0059] The inhibitory effect of the target substance on TMV was tested using the half-leaf necrotic spot method, with the commercial drug ningnanmycin used as a control. The test plants were *Nicotiana siceraria*, and the culture environment was an artificial intelligence-controlled greenhouse. The experimental procedure is as follows:

[0060] (1) Extraction of TMV

[0061] Take leaves of common tobacco plants that have been infected with the virus for three weeks or more. Cut the leaf mesophyll into small pieces and place them in a mortar. Add liquid nitrogen and grind finely, then weigh. Add 0.2 mol / L phosphate buffer (pH 7.2, containing 1% mercaptoethanol by volume) at a mass:volume ratio of 1:1.5. After thorough stirring, filter to obtain the initial extract. Add 8% (by volume) n-butanol to the initial extract, stir well, and centrifuge to obtain the supernatant. Add sodium chloride and polyethylene glycol at a volume equal to 1 / 25 of the supernatant volume, continue stirring, and centrifuge. Collect the precipitate, add 0.01 mol / L phosphate buffer, shake well, and centrifuge. Collect the supernatant. Repeat the above operation three times and combine the supernatants. All stirring processes are carried out under ice bath conditions. Centrifugation parameters are set to 4℃, 8000 rpm, and 20 min.

[0062] (2) Preparation of solvent and virus

[0063] Tween-80 (1%) solution: Dissolve 1.0 mL of Tween-80 in 499.0 mL of deionized water, mix thoroughly and set aside.

[0064] Preparation of the drug solution: Accurately weigh 2.00 mg of the target substance and place it in a 15 mL centrifuge tube. Add 30 μL LDMSO to dissolve it, and then add 4 mL of Tween-80 (1%) to prepare a drug solution with a concentration of 500 μg / mL.

[0065] Preparation of 250-fold virus: Pipette 49.8 mL of 0.01 M phosphate buffer and add 200 μL of TMV extraction solution. Refrigerate for later use.

[0066] Preparation of 500-fold virus: Pipette 49.9 mL of 0.01 M phosphate buffer and add 100 μL of TMV extraction solution to obtain 500-fold virus. Store in the refrigerator for later use.

[0067] (2) Therapeutic activity

[0068] Sampling: Select tobacco plants in the same growth cycle, remove apical dominance, and retain 3 to 5 healthy leaves that are of uniform size and growth.

[0069] Inoculation: Dip a brush in 500 times diluted TMV virus and gently sweep it over the leaves that have been evenly sprinkled with carborundum. After 30 minutes, rinse off the carborundum and let the leaves air dry in a cool, ventilated place.

[0070] Apply the medicine: Gently apply the medicine to the right side of the leaf with a brush, and apply DMSO to the left side as a control.

[0071] Calculation: After the drug application, culture for 2-3 days and count the number of spots on the left and right leaves respectively. Calculate the inhibition rate as shown in formula (3-4). Perform three parallel tests.

[0072]

[0073] (3) Protective activity

[0074] Sampling: Select tobacco plants in the same growth cycle, remove apical dominance, and retain 3 to 5 healthy leaves that are of uniform size and growth.

[0075] Application of the medicine: Use a brush to apply the medicine solution gently and evenly to the right side of the leaf, and apply DMSO to the left side as a blank control. Place in a greenhouse for 24 hours.

[0076] Inoculation: Dip a brush in 500 times diluted TMV virus and gently sweep it over the leaves that have been evenly sprinkled with carborundum. After 30 minutes, rinse off the carborundum and let the leaves air dry in a cool, ventilated place.

[0077] Calculation: After treatment, culture for 2-3 days and count the number of spots on the left and right leaves respectively. Calculate the inhibition rate as shown in formula (3-4). Perform three parallel tests.

[0078] (4) Passivation activity

[0079] Sampling: Select tobacco plants in the same growth cycle, remove apical dominance, and retain 3 to 5 healthy leaves that are of uniform size and growth.

[0080] Preparation: Take 1 mL of the drug solution and 250 times the amount of virus, mix them evenly, and inactivate for 30 minutes.

[0081] Inoculation: Take TMV virus diluted 500 times from the left leaf and virus diluted 250 times after inactivation from the right leaf. Gently sweep the leaves evenly sprinkled with carborundum with a brush. After 30 minutes, rinse off the carborundum and let them air dry in a cool, ventilated place.

[0082] Calculation: After treatment, culture for 2-3 days and count the number of spots on the left and right leaves respectively. Calculate the inhibition rate as shown in formula (3-4). Perform three parallel tests.

[0083] (5) Testing EC against TMV 50 value

[0084] The drug solution was prepared at a concentration of 500 μg / mL and then sequentially diluted to five concentration gradients: 250, 125, 62.5, and 31.25 μg / mL. The above steps were repeated, and the inhibition rate was calculated. The corresponding EC was then calculated using the formula. 50 The value was tested in parallel three times.

[0085] Table 1. Anti-TMV Activity Data of Substance AC

[0086]

[0087]

[0088] Anti-TMV activity studies showed that substances C2 (76.9±3.4%) and B11 (73.7±5.5%) exhibited strong therapeutic activity, with C2 also possessing high inactivation activity (87.7±3.5%). B12 in the B series demonstrated unique protective activity (78.3±5.4%), superior to ningnanmycin (62.5±6.3%). Notably, A4 (74.6±6.1%) and A6 (71.3±2.5%) in the A series showed superior therapeutic activity compared to the control drug ningnanmycin, while C7 (69.7±3.5%) in the C series showed therapeutic activity close to that of ningnanmycin.

[0089]

[0090] Experimental results showed that B12 and C2 had ECGs of therapeutic activity against TMV. 50 The values ​​were 197.53 and 171.83 μg / mL, respectively, which were superior to the control drug ningnanmycin (237.41 μg / mL). Furthermore, the protective activity against TMV of substance C2 was tested. 50 The value test result was 238.22 μg / mL, which was better than the control drug ningnanmycin (268.71 μg / mL).

Claims

1. A novel phosphorus-containing substance, characterized in that: The structural formula of the substance is shown below: Where R is selected from the following structure:

2. The method for preparing a novel phosphorus-containing substance as described in claim 1, characterized in that:

3. The application of the novel phosphorus-containing substance as described in claim 1 in the preparation of agents to combat plant viral diseases.

4. The application according to claim 1, characterized in that: The plant viral disease mentioned is Tobacco Mosaic Virus (TMV).

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