Dibenzo-1,3-oxazocyclohexene isoquinoline-1(2h)-ketone compounds, preparation method and anti-plant fungal applications thereof

Abstract

The application discloses a kind of dibenzo-1,3-oxazinane hexane isomer quinoline-1 (2H) -ketone compound and its preparation method and application of anti-plant fungus, the structural formula of the compound is formula (I) wherein R 1 , R 2 , R 3 Each independently represent any one of H, C1-C4 alkyl, C1-C4 alkoxy, acetyl, cyano, fluorine, trifluoromethyl, hydroxyl.The preparation method is as follows: 3-biphenyl-1-hydroxypropyl pyridine-2 (1H) -ketone compound, hydrochloric acid is dissolved in organic solvent, and the target compound is obtained by reaction under ultraviolet light irradiation and then separation and purification.The application has the advantages of simple process, simple operation, high product yield and low production cost, and the obtained compound has good anti-plant fungal effect, and can be developed as a new pesticide with anti-plant fungal effect.

Description

Technical Field

[0001] This invention belongs to the field of heterocyclic compound technology, specifically relating to a class of dibenzo-1,3-oxazolidinylhexanoisoquinoline-1(2H)-one compounds, as well as the preparation method of the compound and its application in anti-plant fungi. Background Technology

[0002] Isoquinoline-1(2H)-ketones are an extremely important class of nitrogen-containing heterocyclic compounds, serving as crucial structural segments in many natural products. Due to their unique parent skeleton structure, they are widely used in the synthesis of drug molecules and various functional materials. These nitrogen-containing heterocyclic compounds typically possess a wide range of biological activities. In medicine, isoquinoline-1(2H)-ketones exhibit antitumor, antiviral, antibacterial, anti-inflammatory, anti-gastric ulcer, hepatoprotective, and therapeutic activities for central nervous system and cardiovascular diseases. In agriculture, isoquinoline-1(2H)-ketones can not only control plant diseases but also enhance plant resistance to abiotic stresses, while also possessing certain insecticidal and herbicidal effects. Furthermore, isoquinoline-1(2H)-ketones are also important pharmaceutical intermediates, present in many drug molecules. The synthesis of isoquinoline-1(2H)-ketone derivatives has attracted continuous attention from researchers over the past decade. In 2016, Ohwada's research group activated aromatic carbamate compounds with trifluoromethanesulfonic acid, and under heating conditions, obtained benzoquinone compounds through intramolecular cyclization. In 2017, Bolm's research group developed a method for synthesizing benzoquinone compounds through a rhodium(III)-catalyzed CH-activated cyclization reaction of 7-oxa / azabenzonorbornene with N-methoxybenzamide series. In 2018, Kamal's research group synthesized phenanthrenedihydrodibenzoquinone compounds in a one-pot reaction using naphthylamine, Michaelis-Menten acid, and benzaldehyde as raw materials under the catalysis of aminosulfonic acid. These methods require expensive transition metals or strong acids as catalysts, are difficult to recycle, and cause environmental pollution.

[0003] Plant infectious diseases can be classified into bacterial diseases, fungal diseases, viral diseases, and nematode diseases. Among these, fungal diseases are the most common and prevalent type of crop disease, exhibiting a wide variety of types and symptoms, causing significant yield reductions. Furthermore, fungal toxins can be toxic to animals and humans. Therefore, scientists have continuously developed numerous fungicides. However, due to the overuse or long-term use of some pesticides, many pathogenic fungi have developed resistance, and some pesticides themselves are toxic to humans. Therefore, there is an urgent need for new, safer, and more effective fungicides to replace them. Summary of the Invention

[0004] The purpose of this invention is to provide a class of dibenzo-1,3-oxazacyclohexaneisoquinoline-1(2H)-one compounds with antifungal activity against plant fungi.

[0005] Another object of the present invention is to provide a method for preparing dibenzo-1,3-oxazacyclohexaneisoquinoline-1(2H)-one compounds from 3-biphenyl-1-hydroxypropylpyridine-1(2H)-one compounds.

[0006] A further object of the present invention is to provide an application of dibenzo-1,3-oxazacyclohexaneisoquinoline-1(2H)-one compounds.

[0007] To achieve the above objectives, the dibenzo-1,3-oxazacyclohexaneisoquinoline-1(2H)-one compounds provided by the present invention have any one of the following structural formulas:

[0008]

[0009] In the formula R 1 R 2 R 3 Each of these can be independently represented by any one of H, C1-C4 alkyl, C1-C4 alkoxy, acetyl, cyano, fluorine, trifluoromethyl, or hydroxyl. R is preferred. 1 R represents any one of hydrogen, methoxy, fluorine, cyano, or hydroxyl. 2 R represents any one of hydrogen, methyl, acetyl, or fluorine. 3 It represents any one of hydrogen, trifluoromethyl, or methoxy.

[0010] The dibenzo-1,3-oxazacyclohexanoisoquinoline-1(2H)-one compounds of the present invention are further preferably any one of the following compounds:

[0011]

[0012]

[0013] The preparation method of the dibenzo-1,3-oxazacyclohexanisoquinoline-1(2H)-one compounds of the present invention is as follows: 3-biphenyl-1-hydroxypropylpyridine-2(1H)-one compounds of Formula I are dissolved in an organic solvent, irradiated with ultraviolet light at 300–365 nm for 30–90 minutes, followed by the addition of hydrochloric acid and stirring at room temperature for 30–120 minutes. After the reaction is completed, the reaction solution is distilled under reduced pressure and purified by column chromatography to obtain trans-dibenzo-1,3-oxazacyclohexanisoquinoline-1(2H)-one compounds; the reaction equation is as follows:

[0014]

[0015] Alternatively, the 3-biphenyl-1-hydroxypropylpyridine-2(1H)-one compound shown in Formula I is dissolved in hydrochloric acid in an organic solvent and irradiated with ultraviolet light at 300–365 nm for 30–120 minutes. After the reaction is complete, the reaction solution is distilled under reduced pressure and purified by column chromatography to obtain cis-dibenzo-1,3-oxazacyclohexaneisoquinoline-1(2H)-one compounds; the reaction equation is as follows:

[0016]

[0017] In the above preparation method, the preferred molar ratio of the 3-biphenyl-1-hydroxypropylpyridine-2(1H)-one compound to HCl in hydrochloric acid is 1:0.1 to 1.5;

[0018] In the above preparation method, the organic solvent is preferably any one of dioxane, toluene, and acetone.

[0019] This invention relates to the application of dibenzo-1,3-oxazacyclohexaneisoquinoline-1(2H)-one compounds in the preparation of antifungal drugs. When used, these compounds are taken as the active ingredient and combined with other excipients according to conventional preparation processes for various pesticide formulations to produce emulsifiable concentrates, powders, suspensions, masterbatches, liquids, etc. The plant fungus mentioned is any one of *Rhizoctonia solani*, *Phyllostachys edulis*, or *Phyllostachys aurea*.

[0020] The beneficial effects of this invention are as follows:

[0021] 1. The dibenzo-1,3-oxazacyclohexaneisoquinoline-1(2H)-one compounds of this invention all possess strong antifungal properties. Compounds 2b-α, 2b-β, 2f-α, 3b-β, 3b-α, 3e-β, and 3h-α of this invention all exhibit good antifungal activity against three tested strains. Among them, 2b-α, 2b-β, 2f-α, and 3e-β show significant antifungal activity against rice sheath blight pathogens, and all tested drugs show significant antifungal activity against apple anthracnose pathogens. 2f-α and 3b-β show significant antifungal activity against tomato early blight pathogens. If these compounds are used to prepare pesticides against plant fungi, it is expected that they will have good plant protection effects.

[0022] 2. This invention uses inexpensive and readily available 3-biphenyl-1-hydroxypropylpyridine-1(2H)-one compounds as raw materials and hydrochloric acid as a catalyst to synthesize a series of dibenzo-1,3-oxazacyclohexaneisoquinoline-1(2H)-one compounds. It has the advantages of short synthesis route, simple process, simple equipment, high product yield, low production cost and environmental protection. Detailed Implementation

[0023] The present invention will be further described in detail below with reference to the embodiments, but the scope of protection of the present invention is not limited to these embodiments.

[0024] Example 1

[0025] Method 1: 61.0 g (0.2 mol) of 3-([1,1'-biphenyl]-2-yl)-1-(3-hydroxypropyl)pyridine-1(2H)-one was dissolved in 40 L of dioxane. After irradiation with 313 nm ultraviolet light for 1 hour under argon protection, 20 mL of 1 mol / L hydrochloric acid was added, and the mixture was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was purified by column chromatography after vacuum distillation (the eluent was a mixture of CH2Cl2 and CH3OH in a volume ratio of 20:1) to obtain pure compounds 2a-α and 2a-β, with yields of 44% and 47%, respectively.

[0026]

[0027] Compound 2a-α is a white powder with a melting point of 151.4-152.0℃. It is readily soluble in organic solvents such as methanol, ethanol, and dichloromethane. The structural characterization results are as follows: 1 H NMR(600MHz,DMSO-d6)δ8.36(d,J=7.9Hz,1H),7.81(dd,J=23.3,7.2Hz,2H),7.41-7.33(m,4H),7.30(t ,J=7.6Hz,1H),4.99(d,J=3.0Hz,1H),4.63(dd,J=13.0,4.6Hz,1H),4.04(dd,J=11.2,4.6Hz,1H),3.87 (td,J=12.2,2.4Hz,1H),3.24(d,J=13.9Hz,1H),3.07(td,J=13.5,2.8Hz,1H),2.99(td,J=12.7,2.7Hz ,1H),2.60(d,J=13.7Hz,1H),2.12(td,J=13.5,4.3Hz,1H),1.74-1.61(m,1H),1.54(d,J=13.3Hz,1H); 13 C NMR(151MHz,DMSO-d6)δ166.7,138.6,135.0,134.5,134.1,127.9,127.4,127.3,127.1,12 6.0,124.6,124.1,123.5,84.3,67.7,44.4,42.1,33.8,29.2,26.0; HRMS(ESI): m / z[M+Na] + Theoretical value C 20 H 19NO2Na: 328.1313; Measured value: 328.1317.

[0028] Compound 2a-β is a white powder with a melting point of 156.0-156.5℃. It is readily soluble in organic solvents such as methanol, ethanol, and dichloromethane. The structural characterization results are as follows: 1 H NMR (600MHz, DMSO-d6) δ8.22(d,J=7.9Hz,1H),7.81(dd,J=23.4,7.5Hz,2H),7.47-7.30(m,4H),7.28(t,J=7.2Hz,1H),5.02(dd,J=9.1,5.2Hz,1H),4. 74-4.61(m,1H),4.00(d,J=15.0Hz,1H),3.67(t,J=12.6Hz,1H),3.24(d,J= 13.6Hz,1H),2.95-2.76(m,3H),1.80-1.67(m,2H),1.64(d,J=12.9Hz,1H); 13 C NMR(151MHz,DMSO-d6)δ167.0,138.0,135.0,134.4,134.0,127.9,127.4,127.3,127.1,12 6.0,124.6,124.1,123.5,84.5,65.9,44.9,39.0,33.5,30.5,24.8; HRMS(ESI): m / z[M+Na] + Theoretical value C 20 H 19 NO2Na: 328.1313; Measured value: 328.1315.

[0029] Method 2: Add 61.0 g (0.2 mol) of 3-biphenyl-1-hydroxypropylpyridine-1(2H)-one, 300 mL of 1 mol / L hydrochloric acid, and 40 L of dioxane to a photoreaction tube. Irradiate with 313 nm ultraviolet light for 1 hour under argon protection. After the reaction is completed, the reaction solution is distilled under reduced pressure and purified by column chromatography (eluent is a mixture of CH2Cl2 and CH3OH in a volume ratio of 20:1) to obtain pure compounds 3a-α and 3a-β, both in 43% yield.

[0030]

[0031] Compound 3a-α is a white powder with a melting point of 148.6-149.2℃. It is readily soluble in organic solvents such as methanol, ethanol, and dichloromethane. The structural characterization results are as follows: 1H NMR (600MHz, DMSO-d6) δ7.86 (t, J = 6.0 Hz, 2H), 7.38-7.27 (m, 5H), 7.24 (d, J = 7. 6Hz,1H),4.76(t,J=3.9Hz,1H),4.60(d,J=11.3Hz,1H),4.06(dd,J=11.1,4.1H z,1H),3.84(d,J=5.3Hz,1H),3.76(t,J=11.2Hz,1H),3.56-3.47(m,1H),2.77( t,J=11.3Hz,1H),2.12-1.88(m,1H),1.78-1.64(m,2H),1.51(d,J=13.1Hz,1H); 13 C NMR(151MHz,DMSO-d6)δ167.8,136.7,132.4,128.3,128.0,127.9,127.8,127.7,127.6 ,127.5,123.9,123.8,84.5,67.2,45.5,41.0,33.3,30.3,25.4; HRMS(ESI): m / z[M+Na] + Theoretical value C 20 H 19 NO2Na: 328.1313; Measured value: 328.1314.

[0032] Compound 3a-β is a white powder with a melting point of 148.1-148.6℃. It is readily soluble in organic solvents such as methanol, ethanol, and dichloromethane. The structural characterization results are as follows: 1 H NMR (400MHz, DMSO-d6) δ7.88 (t, J=7.4Hz, 2H), 7.41 -7.28(m,6H),4.87(dd,J=8.4,6.4Hz,1H),4.66(d,J=13.7Hz,1H),3.84(d,J=11.7Hz,1H),3.78(d,J=5.0Hz,1H), 3.63-3.53(m,1H),3.38-3.32(m,1H),2.91-2.74(m,1H),1.95-1.85(m,1H),1.65-1.53(m,2H),1.51-1.40(m,1H); 13 C NMR(151MHz,DMSO-d6)δ167.4,137.2,132.4,132.2,131.9,128.3,128.1,127.9,12 7.6,126.8,124.0,85.2,66.3,45.1,40.0,33.5,30.5,25.1; HRMS(APCI): m / z[M+H] +Theoretical value C 20 H 20 NO2: 306.1494; Measured value: 306.1489.

[0033] Example 2

[0034] In this embodiment, equimolar amounts of 3-([1,1'-biphenyl]-2-yl)-1-(3-hydroxypropyl)pyridin-1(2H)-one were used to replace the 3-([1,1'-biphenyl]-2-yl)-1-(3-hydroxypropyl)pyridin-1(2H)-one in Method 1 and Method 2 of Example 1, respectively. The other steps were the same as the corresponding methods in Example 1, and pure products of compounds 2b-α and 2b-β and compounds 3b-α and 3b-β were obtained, with yields of 47%, 45%, 40%, and 38%, respectively.

[0035]

[0036] Compound 2b-α is a white powder with a melting point of 193.5-194.1℃. It is readily soluble in organic solvents such as methanol, ethanol, and dichloromethane. The structural characterization results are as follows: 1 H NMR(600MHz,Chloroform-d)δ8.33(d,J=7.7Hz,1H),7.66(dd,J=8.5,5.7Hz,1H),7.59(d,J=8.2Hz,1H),7.33-7.22( m,2H),6.99(td,J=8.5,2.3Hz,1H),6.91(d,J=8.1Hz,1H),4.85(d,J=3.4Hz,1H),4.81(dd,J=13.2,4.8Hz,1H),4.08( dd,J=11.5,4.8Hz,1H),3.84(td,J=12.4,2.4Hz,1H),3.28(td,J=13.5,2.7Hz,1H),3.19(d,J=13.9Hz,1H),2.91(td, J=13.0,2.8Hz,1H),2.51(d,J=13.6Hz,1H),2.01(td,J=13.4,4.4Hz,1H),1.90-1.77(m,1H),1.51(d,J=13.7Hz,1H); 13C NMR(151MHz,Chloroform-d)δ167.4,162.6(d,J=247.3Hz),141.1(d,J=7.0Hz),134.3,134.2,131.0(d,J=3.0Hz),127.6,127.3,126.3 ,126.2(d,J=8.5Hz),124.4,114.1(d,J=21.2Hz),110.5(d,J=22.6Hz),85.0,68.7,45.2,43.1,34.1,30.1,26.3; HRMS(ESI):m / z[M+Na] + Theoretical value C 20 H 18 FNO2Na: 346.1214; Measured value: 346.1205.

[0037] Compound 2b-β is a white powder with a melting point of 149.6-150.5°C. It is readily soluble in organic solvents such as methanol, ethanol, and dichloromethane. The structural characterization results are as follows: 1 H NMR(600MHz,Chloroform-d)δ8.20(d,J=7.8Hz,1H),7.66(dd,J=8.5,5.7Hz,1H),7.59( d,J=7.4Hz,1H),7.33-7.20(m,2H),7.05-6.97(m,1H),6.94(d,J=9.6Hz,1H),4.97-4.6 9(m,2H),4.06(dd,J=11.2,4.4Hz,1H),3.65(td,J=12.1,2.0Hz,1H),3.23(d,J=13.7Hz ,1H),2.87-2.65(m,3H),1.99-1.86(m,1H),1.85-1.71(m,1H),1.60(d,J=13.3Hz,1H); 13 C NMR(151MHz,Chloroform-d)δ167.4,162.6(d,J=256.1Hz),140.2(d,J=7.2Hz),134.4,134.1,131.0(d,J=3.1Hz),127.7,127.4,126.3 ,126.2(d,J=2.5Hz),124.4,114.3(d,J=21.7Hz),110.5(d,J=22.7Hz),84.9,66.9,45.5,39.7,34.1,31.1,25.1; HRMS(ESI): m / z[M+Na] + Theoretical value C 20 H 18FNO2Na: 346.1214; Measured value: 346.1206.

[0038] Compound 3b-α is a white powder with a melting point of 185.3-185.8℃. It is readily soluble in organic solvents such as methanol, ethanol, and dichloromethane. The structural characterization results are as follows: 1 H NMR(400MHz,Chloroform-d)δ7.76-7.56(m,2H),7.33-7.14(m,3H),7.05-6.83(m, 2H),4.92-4.75(m,1H),4.61(dd,J=6.7,2.2Hz,1H),4.11(dd,J=11.5,4.8Hz,1H),3 .91(d,J=5.1Hz,1H),3.75(td,J=12.4,2.4Hz,1H),3.57-3.42(m,1H),2.71(td,J=1 2.9,2.9Hz,1H),2.13-1.83(m,2H),1.72(d,J=14.1Hz,1H),1.47(d,J=13.6Hz,1H); 13 C NMR(101MHz,Chloroform-d)δ168.7,162.6(d,J=249.0Hz),139.2(d,J=7.7Hz),132.2,131.4,129.3(d,J=3.0Hz),128.1,127.8,127.7 ,126.0(d,J=8.3Hz),123.6,114.9(d,J=21.5Hz),114.5(d,J=21.8Hz),85.5,68.4,46.1,42.0,34.2,30.5,25.8; HRMS(ESI): m / z[M+Na] + Theoretical value C 20 H 18 FNO2Na: 346.1214; Measured value: 346.1208.

[0039] Compound 3b-β is a white powder with a melting point of 193.4-193.9℃. It is readily soluble in organic solvents such as methanol, ethanol, and dichloromethane. The structural characterization results are as follows: 1H NMR(600MHz,Chloroform-d)δ7.76(dd,J=8.6,5.5Hz,1H),7.71(d,J=7.6Hz,1H),7.43(d,J=7.5Hz,1 H),7.34(t,J=7.4Hz,1H),7.30(t,J=7.4Hz,1H),7.06(td,J=8.5,2.5Hz,1H),6.93(dd,J=8.7,2.4Hz, 1H),4.97-4.87(m,1H),4.81(dd,J=8.7,6.2Hz,1H),4.08-3.91(m,2H),3.69-3.56(m,1H),3.22-3.0 6(m,1H),2.83(td,J=13.2,3.0Hz,1H),2.06-1.95(m,1H),1.93-1.79(m,2H),1.63(d,J=13.4Hz,1H); 13 C NMR(151MHz,Chloroform-d)δ168.4,162.4(d,J=248.5Hz),138.9(d,J=7.2Hz),132.0,131.2,129.3(d,J=2.9Hz),128.5,127.8,127.4 ,126.1(d,J=8.6Hz),123.7,115.0(d,J=21.2Hz),114.5(d,J=21.7Hz),86.0,67.3,45.6,40.2,35.2,30.5,25.4; HRMS(ESI): m / z[M+Na] + Theoretical value C 20 H 18 FNO2Na: 346.1214; Measured value: 346.1208.

[0040] Example 3

[0041] In this embodiment, equimolar amounts of 3-([1,1'-biphenyl]-2-yl)-1-(3-hydroxypropyl)pyridin-1(2H)-one were used to replace the 3-([1,1'-biphenyl]-2-yl)-1-(3-hydroxypropyl)pyridin-1(2H)-one in Method 1 and Method 2 of Example 1, respectively. The other steps were the same as the corresponding methods in Example 1, and pure products of compounds 2c-α and 2c-β and compounds 3c-α and 3c-β were obtained, with yields of 42%, 40%, 35%, and 34%, respectively.

[0042]

[0043] Compound 2c-α is a white powder with a melting point of 198.1-198.6℃. It is readily soluble in organic solvents such as methanol, ethanol, and dichloromethane. The structural characterization results are as follows: 1 H NMR(600MHz,Chloroform-d)δ8.30(d,J=7.9Hz,1H),7.64(d,J=8.5Hz,1H),7.59(d,J=7.6Hz,1H),7.27(t,J=7.3Hz,1H),7.2 2(td,J=7.8,1.3Hz,1H),6.84(dd,J=8.5,2.4Hz,1H),6.78-6.72(m,1H),4.85(d,J=3.3Hz,1H),4.81(dd,J=13.2,4.9Hz,1H) ,4.09(dd,J=11.4,4.9Hz,1H),3.84(td,J=12.4,2.5Hz,1H),3.79(s,3H),3.27(td,J=13.5,3.1Hz,1H),3.19(d,J=13.8Hz,1 H),2.91(td,J=13.0,2.9Hz,1H),2.60-2.52(m,1H),2.01(td,J=13.4,4.4Hz,1H),1.91-1.77(m,1H),1.51(d,J=13.7Hz,1H); 13 CNMR(151MHz,Chloroform-d)δ167.8,159.4,140.4,134.9,134.0,127.9,127.2,126.8,126.2,1 25.7,124.0,111.7,109.8,85.1,68.7,55.4,45.5,43.0,34.1,30.2,26.3; HRMS(ESI): m / z[M+Na] + Theoretical value C 21 H 21 NO3Na: 358.1414; Measured value: 358.1410.

[0044] Compound 2c-β is a white powder with a melting point of 181.3-181.9℃. It is readily soluble in organic solvents such as methanol, ethanol, and dichloromethane. The structural characterization results are as follows: 1H NMR(600MHz,Chloroform-d)δ8.16(d,J=7.9Hz,1H),7.64(d,J=8.5Hz,1H),7.58(d,J=7.6Hz,1H) ,7.26(t,J=7.4Hz,1H),7.22-7.19(m,1H),6.85(dd,J=8.5,2.4Hz,1H),6.79(d,J=1.7Hz,1H),4. 94-4.80(m,2H),4.06(dd,J=11.2,4.4Hz,1H),3.79(s,3H),3.66(td,J=12.1,2.1Hz,1H),3.23(d ,J=13.5Hz,1H),2.85-2.72(m,3H),2.00-1.88(m,1H),1.87-1.72(m,1H),1.59(d,J=13.2Hz,1H); 13 C NMR(151MHz,Chloroform-d)δ167.8,159.5,139.5,134.8,134.1,127.7,127.2,126.9,126.0,12 5.8,124.0,112.2,109.4,85.1,66.9,55.3,45.8,39.6,34.2,31.2,25.1; HRMS(ESI): m / z[M+Na] + Theoretical value: C 21 H 21 NO3Na 358.1414; Measured value: 358.1412.

[0045] Compound 3c-α is a white powder with a melting point of 168.2-168.8℃. It is readily soluble in organic solvents such as methanol, ethanol, and dichloromethane. The structural characterization results are as follows: 1 H NMR(600MHz,Chloroform-d)δ7.63(t,J=8.7Hz,2H),7.37-7.21(m,2H),7.21-7.08 (m,1H),6.93-6.80(m,1H),6.76(s,1H),4.86(d,J=12.7Hz,1H),4.62(d,J=4.1Hz, 1H),4.20-4.13(m,1H),3.92(d,J=4.6Hz,1H),3.78(s,4H),3.56-3.40(m,1H),2.8 5-2.66(m,1H),2.13-1.86(m,2H),1.72(d,J=13.8Hz,1H),1.47(d,J=13.2Hz,1H); 13C NMR(151MHz,Chloroform-d)δ169.1,159.7,138.5,132.8,131.0,127.6,127.4,127.3,125.8,12 5.5,123.1,113.8,112.7,85.7,68.5,55.4,46.3,42.0,34.5,30.7,25.8; HRMS(ESI): m / z[M+Na] + Theoretical value C 21 H 21 NO3Na: 358.1414; Measured value: 358.1411.

[0046] Compound 3c-β is a white powder with a melting point of 148.6-149.1℃. It is readily soluble in organic solvents such as methanol, ethanol, and dichloromethane. The structural characterization results are as follows: 1 H NMR(400MHz,Chloroform-d)δ7.66(d,J=8.7Hz,1H),7.62(d,J=7.6Hz,1H),7.34(d,J=7.6Hz,1H),7.25( t,J=7.4Hz,1H),7.17(t,J=7.4Hz,1H),6.84(dd,J=8.6,2.6Hz,1H),6.68(d,J=2.6Hz,1H),4.94-4.80(m ,1H),4.74(dd,J=8.8,6.2Hz,1H),3.99-3.85(m,2H),3.78(s,3H),3.57(td,J=12.3,2.0Hz,1H),3.13-3 .00(m,1H),2.76(td,J=13.1,3.2Hz,1H),2.00-1.88(m,1H),1.88-1.72(m,2H),1.54(d,J=12.8Hz,1H); 13 C NMR(101MHz,Chloroform-d)δ168.8,159.6,138.4,132.7,130.8,127.7,127.6,127.2,126.0,12 5.6,123.2,113.4,113.2,86.2,67.3,55.4,45.9,40.2,35.5,30.8,25.5; HRMS(ESI): m / z[M+Na] + Theoretical value C 21 H 21 NO3Na: 358.1414; Measured value: 358.1411.

[0047] Example 4

[0048] In this embodiment, equimolar amounts of 3-([1,1'-biphenyl]-2-yl)-1-(3-hydroxypropyl)pyridin-1(2H)-one were used to replace the 3-([1,1'-biphenyl]-2-yl)-1-(3-hydroxypropyl)pyridin-1(2H)-one in Method 1 and Method 2 of Example 1, respectively. The other steps were the same as the corresponding methods in Example 1, and pure products of compounds 2d-α and 2d-β and compounds 3d-α and 3d-β were obtained, with yields of 40%, 39%, 32%, and 32%, respectively.

[0049]

[0050] Compound 2d-α is a white powder with a melting point of 178.5-180.0℃. It is readily soluble in organic solvents such as methanol, ethanol, and dichloromethane. The structural characterization results are as follows: 1 H NMR(600MHz,Chloroform-d)δ8.51-8.45(m,1H),7.85(d,J=8.0Hz,1H),7.73(dd,J=7.1,1.9Hz,1H),7.68(d,J =8.0Hz,1H),7.54(s,1H),7.45-7.40(m,2H),4.96(d,J=3.2Hz,1H),4.88(dd,J=13.3,4.9Hz,1H),4.17(dd,J=1 1.5,4.9Hz,1H),3.93(td,J=12.3,2.5Hz,1H),3.39(td,J=13.5,3.1Hz,1H),3.27(d,J=14.0Hz,1H),3.00(td,J =13.0,2.9Hz,1H),2.68-2.58(m,1H),2.12(td,J=13.5,4.5Hz,1H),1.97-1.84(m,1H),1.59(d,J=13.7Hz,1H); 13 C NMR(151MHz,Chloroform-d)δ167.0,139.8,139.4,135.4,133.3,131.3,129.4,127.6,127.0,12 6.7,125.3,125.0,119.1,111.0,84.8,68.7,44.7,43.1,33.9,29.9,26.3; HRMS(ESI): m / z[M+Na] + Theoretical value C 21 H 18 N2O2Na: 353.1261; Measured value: 353.1256.

[0051] Compound 2d-β is a white powder with a melting point of 207.7-208.4℃. It is readily soluble in organic solvents such as methanol, ethanol, and dichloromethane. The structural characterization results are as follows: 1 H NMR(600MHz,Chloroform-d)δ8.39-8.27(m,1H),7.84(d,J=8.0Hz,1H),7.75-7.70(m,1H) ,7.68(d,J=8.0Hz,1H),7.57(s,1H),7.46-7.33(m,2H),4.97(dd,J=9.1,5.3Hz,1H),4.95 -4.86(m,1H),4.14(dd,J=11.2,4.4Hz,1H),3.73(td,J=12.1,2.0Hz,1H),3.29(d,J=13.7 Hz,1H),3.03-2.68(m,3H),2.06-1.95(m,1H),1.95-1.84(m,1H),1.67(d,J=14.2Hz,1H); 13 C NMR(151MHz,Chloroform-d)δ166.9,139.3,138.9,135.5,133.1,131.4,129.4,127.6,127.0,12 6.6,125.2,125.1,119.0,111.1,84.8,66.8,45.0,39.8,33.9,31.0,25.0; HRMS(ESI): m / z[M+Na] + Measured value C 21 H 18 N2O2Na: 353.1261; Theoretical value: 353.1259.

[0052] Compound 3d-α is a white powder with a melting point of 220.2-220.7℃. It is readily soluble in organic solvents such as methanol, ethanol, and dichloromethane. The structural characterization results are as follows: 1H NMR(600MHz,Chloroform-d)δ7.85(d,J=8.1Hz,1H),7.77(d,J=7.5Hz,1H),7.67-7.61( m,1H),7.59(s,1H),7.46-7.30(m,3H),4.90(d,J=12.0Hz,1H),4.68(d,J=3.0Hz,1H),4 .18(dd,J=11.4,4.5Hz,1H),3.99(d,J=5.0Hz,1H),3.89-3.77(m,1H),3.75-3.61(m,1H ),2.87-2.69(m,1H),2.17-1.91(m,2H),1.79(d,J=15.3Hz,1H),1.55(d,J=13.5Hz,1H); 13 C NMR(151MHz,Chloroform-d)δ168.1,137.9,137.6,132.6,131.6,131.4,131.1,129.9,128.1,12 8.0,124.7,124.6,118.7,111.4,85.2,68.4,45.7,42.1,33.7,30.4,25.7; HRMS(ESI): m / z[M+Na] + Theoretical value C 21 H 18 N2O2Na: 353.1261; Measured value: 353.1256.

[0053] Compound 3d-β is a white powder with a melting point of 210.6-211.1℃. It is readily soluble in organic solvents such as methanol, ethanol, and dichloromethane. The structural characterization results are as follows: 1 H NMR(600MHz,Chloroform-d)δ7.87(d,J=8.1Hz,1H),7.78(dd,J=5.3,3.8Hz,1H),7.64(dd,J=8.1 ,1.6Hz,1H),7.53(s,1H),7.49(dd,J=5.0,3.3Hz,1H),7.40(dd,J=5.8,3.3Hz,2H),4.99-4.87(m ,1H),4.83(dd,J=8.6,6.2Hz,1H),4.06-3.93(m,2H),3.65(td,J=12.3,2.2Hz,1H),3.32-3.19(m ,1H),2.85(td,J=13.2,3.2Hz,1H),2.09-1.94(m,1H),1.94-1.77(m,2H),1.64(d,J=13.4Hz,1H); 13C NMR(151MHz,Chloroform-d)δ167.8,137.7,132.4,131.8,131.5,131.0,130.3,128.1,127.8 ,124.9,124.6,118.7,111.3,85.8,67.4,45.3,40.3,34.7,30.4,25.4; HRMS(ESI): m / z[M+Na] + Theoretical value C 21 H 18 N2O2Na: 353.1261; Measured value: 353.1257.

[0054] Example 5

[0055] In this embodiment, equimolar amounts of 3-([1,1'-biphenyl]-2-yl)-1-(3-hydroxypropyl)pyridin-1(2H)-one were used to replace the 3-([1,1'-biphenyl]-2-yl)-1-(3-hydroxypropyl)pyridin-1(2H)-one in Method 1 and Method 2 of Example 1, respectively. The other steps were the same as the corresponding methods in Example 1, and pure products of compounds 2e-α and 2e-β and compounds 3e-α and 3e-β were obtained, with yields of 41%, 40%, 30%, and 29%, respectively.

[0056]

[0057] Compound 2e-α is a white powder with a melting point of 216.2-216.9℃. It is readily soluble in organic solvents such as methanol, ethanol, and dichloromethane. The structural characterization results are as follows: 1 H NMR (600MHz, DMSO-d6) δ9.63 (s, 1H), 8.27 (d, J = 7.9Hz, 1H), 7.65 (t, J = 8.4Hz, 2H), 7.30 (t, J = 7.4Hz, 1H), 7.19(t,J=7.7Hz,1H),6.77(dd,J=8.3,2.2Hz,1H),6.75-6.72(m,1H),4.98(d,J=3.1Hz,1H),4.62(dd,J=1 3.0,4.7Hz,1H),4.04(dd,J=11.3,4.7Hz,1H),3.87(td,J=12.0,2.4Hz,1H),3.17(d,J=13.8Hz,1H),3.04 -2.87(m,2H),2.47-2.42(m,1H),2.09(td,J=13.5,4.2Hz,1H),1.73-1.59(m,1H),1.54(d,J=13.6Hz,1H); 13C NMR(151MHz,DMSO-d6)δ166.8,157.5,140.3,134.9,133.9,126.9,125.9,125.8,125.6,12 5.3,123.6,114.1,110.4,84.3,67.7,44.6,42.1,33.8,29.2,26.0; HRMS(ESI): m / z[M+Na] + Theoretical value C 20 H 19 NO3Na: 344.1258; Measured value: 344.1259.

[0058] Compound 2e-β is a white powder with a melting point of 226.8-227.4℃. It is readily soluble in organic solvents such as methanol, ethanol, and dichloromethane. The structural characterization results are as follows: 1 H NMR(600MHz,DMSO-d6)δ9.69(s,1H),8.14(d,J=7.9Hz,1H),7.64(t,J=7.5Hz,2H),7 .28(t,J=7.5Hz,1H),7.18(t,J=7.5Hz,1H),6.84-6.70(m,2H),4.99(dd,J=9.1,5.0 Hz,1H),4.71-4.62(m,1H),4.00(dd,J=10.8,3.8Hz,1H),3.71-3.53(m,1H),3.18(d ,J=13.4Hz,1H),2.85(td,J=12.8,3.2Hz,1H),2.79-2.68(m,2H),1.80-1.58(m,3H); 13 C NMR(151MHz,DMSO-d6)δ167.1,157.6,139.7,134.8,133.9,127.0,125.9,125.8,125.6,12 5.2,123.6,114.1,110.5,84.5,65.9,45.1,39.0,33.5,30.5,24.9; HRMS(ESI): m / z[M+Na] + Theoretical value C 20 H 19 NO3Na: 344.1258; Measured value: 344.1259.

[0059] Compound 3e-α is a white powder with a melting point of 179.1-179.7℃. It is readily soluble in organic solvents such as methanol, ethanol, and dichloromethane. The structural characterization results are as follows: 1H NMR(600MHz, DMSO-d6)δ9.65(s,1H),7.70(dd,J=28.8,6.8Hz,2H),7.28(s,1H),7.17(s,2H),6.83-6.34(m,2H),4.76(s,1H),4.59(d,J= 8.5Hz,1H),4.06(d,J=7.3Hz,1H),3.89-3.67(m,2H),3.37(s,1H),2.78(s,1H),1.93(s,1H),1.79-1.55(m,2H),1.50(d,J=12.2Hz,1H); 13 C NMR(151MHz,DMSO-d6)δ168.0,157.7,138.4,132.8,127.6,127.3,126.7,126.6,125.5,12 3.6,122.8,114.9,113.9,84.5,67.3,45.7,41.0,33.6,30.4,25.4; HRMS(ESI): m / z[M+Na] + Theoretical value C 20 H 19 NO3Na: 344.1258; Measured value: 344.1257.

[0060] Compound 3e-β is a white powder with a melting point of 186.5-187.2℃. It is readily soluble in organic solvents such as methanol, ethanol, and dichloromethane. The structural characterization results are as follows: 1 H NMR (600MHz, DMSO-d6) δ9.65 (s, 1H), 7.74 (d, J = 7.7Hz, 1H), 7.67 (d, J = 8.5Hz, 1H), 7.30 (t, J = 7. 3Hz,1H),7.27-7.16(m,2H),6.75(dd,J=8.5,2.4Hz,1H),6.68(d,J=2.4Hz,1H),4.85(dd,J=8.5, 6.3Hz,1H),4.65(d,J=13.5Hz,1H),3.89-3.79(m,1H),3.70(d,J=4.8Hz,1H),3.62-3.53(m,1H) ,3.24-3.15(m,1H),2.87-2.73(m,1H),1.93-1.83(m,1H),1.66-1.55(m,2H),1.48-1.38(m,1H); 13C NMR(101MHz,DMSO-d6)δ167.5,157.6,138.8,132.9,130.7,127.5,126.9,126.6,125.5,12 3.4,122.9,115.0,114.5,85.2,66.3,45.2,39.4,33.8,30.5,25.2; HRMS(ESI): m / z[M+Na] + Theoretical value C 20 H 19 NO3Na: 344.1258; Measured value: 344.1259.

[0061] Example 6

[0062] In this embodiment, equimolar amounts of 3-([1,1'-biphenyl]-2-yl)-1-(3-hydroxypropyl)pyridin-1(2H)-one were used to replace the 3-([1,1'-biphenyl]-2-yl)-1-(3-hydroxypropyl)pyridin-1(2H)-one in Method 1 and Method 2 of Example 1, respectively. The other steps were the same as the corresponding methods in Example 1, and pure products of compounds 2f-α and 2f-β and compounds 3f-α and 3f-β were obtained, with yields of 42%, 44%, 31%, and 32%, respectively.

[0063]

[0064] Compound 2f-α is a white powder with a melting point of 180.2-180.8℃. It is readily soluble in organic solvents such as methanol, ethanol, and dichloromethane. The structural characterization results are as follows: 1 H NMR(600MHz,Chloroform-d)δ8.41(d,J=7.7Hz,1H),7.73(dd,J=7.6,1.3Hz,1H),7.60(s,1H),7.40-7.30(m ,2H),7.19-7.10(m,2H),4.92(d,J=3.4Hz,1H),4.89(dd,J=13.2,4.9Hz,1H),4.16(dd,J=11.4,4.9Hz,1H),3 .91(td,J=12.4,2.4Hz,1H),3.33(td,J=13.5,2.8Hz,1H),3.24(d,J=13.8Hz,1H),2.97(td,J=13.0,2.9Hz,1 H),2.71-2.62(m,1H),2.43(s,3H),2.07(td,J=13.4,4.4Hz,1H),1.97-1.83(m,1H),1.57(d,J=13.8Hz,1H); 13C NMR(151MHz,Chloroform-d)δ167.9,136.9,135.8,135.0,134.9,134.7,128.4,127.5,127.1,12 6.2,125.2,124.6,122.9,85.2,68.7,45.6,43.0,33.7,30.3,26.3,21.3; HRMS(ESI): m / z[M+Na] + Theoretical value C 21 H 21 NO2Na: 342.1465; Measured value: 342.1459.

[0065] Compound 2f-β is a white powder with a melting point of 182.5-183.0℃. It is readily soluble in organic solvents such as methanol, ethanol, and dichloromethane. The structural characterization results are as follows: 1 H NMR(600MHz,Chloroform-d)δ8.27(d,J=7.8Hz,1H),7.73(d,J=7.4Hz,1H),7.60(s,1H) ,7.35(t,J=7.3Hz,1H),7.31(t,J=7.1Hz,1H),7.24-7.12(m,2H),5.02-4.88(m,2H),4. 13(dd,J=11.1,4.8Hz,1H),3.73(td,J=12.1,2.1Hz,1H),3.29(d,J=13.7Hz,1H),2.94- 2.75(m,3H),2.43(s,3H),2.06-1.93(m,1H),1.92-1.81(m,1H),1.66(d,J=13.4Hz,1H); 13 C NMR(151MHz,Chloroform-d)δ167.9,137.1,135.0,134.9,134.7,128.5,127.6,127.2,126.1 ,125.2,124.6,122.9,85.3,66.9,46.0,39.6,33.8,31.3,25.1,21.3; HRMS(ESI): m / z[M+Na] + Theoretical value C 21 H 21 NO2Na: 342.1465; Measured value: 342.1460.

[0066] Compound 3f-α is a white powder with a melting point of 157.7-158.3℃. It is readily soluble in organic solvents such as methanol, ethanol, and dichloromethane. The structural characterization results are as follows: 1H NMR(600MHz,Chloroform-d)δ7.78(d,J=7.7Hz,1H),7.60(s,1H),7.39-7.30(m,2H),7.27(d,J=7.4 Hz,1H),7.20(d,J=7.6Hz,1H),7.11(d,J=7.5Hz,1H),4.92(d,J=11.9Hz,1H),4.68(d,J=3.2Hz,1H), 4.19(dd,J=11.2,3.9Hz,1H),3.98(d,J=4.6Hz,1H),3.82(t,J=11.3Hz,1H),3.71-3.51(m,1H),2.7 8(t,J=12.0Hz,1H),2.41(s,3H),2.18-1.91(m,2H),1.78(d,J=14.2Hz,1H),1.54(d,J=13.3Hz,1H); 13 C NMR(151MHz,Chloroform-d)δ169.2,137.5,134.0,132.9,132.8,132.0,129.0,128.1,127.8,12 7.6,127.5,124.7,123.8,85.7,68.5,46.4,42.0,33.7,30.9,25.8,21.4; HRMS(ESI): m / z[M+Na] + Theoretical value C 21 H 21 NO2Na: 342.1465; Measured value: 342.1463.

[0067] Compound 3f-β is a white powder with a melting point of 166.6-167.3°C. It is readily soluble in organic solvents such as methanol, ethanol, and dichloromethane. The structural characterization results are as follows: 1 H NMR(600MHz,Chloroform-d)δ7.77(d,J=7.7Hz,1H),7.62(s,1H),7.43(d,J=7.3Hz,1H),7.34( t,J=7.4Hz,1H),7.30(d,J=7.4Hz,1H),7.11(s,1H),4.93(dd,J=13.3,4.1Hz,1H),4.80(dd,J= 8.7,6.2Hz,1H),4.05-3.95(m,2H),3.66-3.63(m,1H),3.17(dt,J=13.7,4.0Hz,1H),2.83(td, J=13.1,2.7Hz,1H),2.41(s,3H),2.02-1.94(m,1H),1.92-1.75(m,2H),1.63(d,J=14.8Hz,2H);13 C NMR(151MHz,Chloroform-d)δ168.9,137.7,133.9,132.9,132.8,131.8,128.9,128.5,127.7,12 7.6,127.3,124.8,123.8,86.2,67.3,46.0,40.2,34.7,31.0,25.5,21.4; HRMS(ESI): m / z[M+Na] + Theoretical C 21 H 21 NO2Na: 342.1465; Measured value: 342.1463.

[0068] Example 7

[0069] In this embodiment, equimolar amounts of 3-([1,1'-biphenyl]-2-yl)-1-(3-hydroxypropyl)pyridin-1(2H)-one were used to replace the 3-([1,1'-biphenyl]-2-yl)-1-(3-hydroxypropyl)pyridin-1(2H)-one in Method 1 and Method 2 of Example 1, respectively. The other steps were the same as the corresponding methods in Example 1, and pure products of compounds 2g-α and 2g-β and compounds 3g-α and 3g-β were obtained, with yields of 40%, 41%, 32%, and 32%, respectively.

[0070]

[0071] Compound 2g-α is a white powder with a melting point of 154.8-155.5℃. It is readily soluble in organic solvents such as methanol, ethanol, and dichloromethane. The structural characterization results are as follows: 1 H NMR(600MHz,Chloroform-d)δ8.49-8.33(m,1H),7.74-7.60(m,1H),7.46(dd,J=9.8,1.9Hz,1H),7.42-7.30 (m,2H),7.22(dd,J=8.0,6.2Hz,1H),7.07-6.93(m,1H),4.92(d,J=3.5Hz,1H),4.88(dd,J=13.2,4.2Hz,1H), 4.16(dd,J=11.3,4.4Hz,1H),3.91(t,J=11.9Hz,1H),3.32(t,J=13.1Hz,1H),3.25(d,J=13.9Hz,1H),3.02-2 .93(m,1H),2.64(d,J=13.2Hz,1H),2.08(td,J=13.3,4.3Hz,1H),1.99-1.83(m,1H),1.58(d,J=13.5Hz,1H); 13C NMR (151MHz, Chloroform-d) δ 167.5, 162.4 (d, J = 244.1Hz), 136.9 (d, J = 7.7Hz), 135.0, 134.3 (d, J = 2.5Hz), 134.0 (d, J = 1.8Hz), 128.3, 127.3, 126.4, 124.8, 124.6 (d, J = 8.0Hz), 114.1 (d, J = 21.6Hz), 111.3 (d, J = 22.3Hz), 85.0, 68.7, 45.4, 43.0, 33.5, 30.3, 26.2; HRMS (ESI): m / z [M+Na] + Theoretical value C 20 H 18 FNO2Na: 346.1214; Measured value: 346.1205.

[0072] Compound 2g-β is a white powder with a melting point of 190.0-190.6℃. It is readily soluble in organic solvents such as methanol, ethanol, and dichloromethane. The structural characterization results are as follows: 1 H NMR(600MHz,Chloroform-d)δ8.32(d,J=7.0Hz,1H),7.68(d,J=6.7Hz,1H),7.48 (d,J=9.2Hz,1H),7.43-7.32(m,2H),7.28(s,1H),7.05(t,J=7.3Hz,1H),5.13-4. 75(m,2H),4.15(d,J=8.2Hz,1H),3.75(t,J=11.3Hz,1H),3.31(d,J=13.7Hz,1H), 3.04-2.70(m,3H),2.17-1.95(m,1H),1.94-1.83(m,1H),1.69(d,J=13.3Hz,1H); 13 C NMR (151MHz, Chloroform-d) δ167.5, 162.5 (d, J = 244.5Hz), 136.9 (d, J = 7.6Hz), 135.1, 133.9 (d, J = 1.5Hz), 133.5 (d, J = 2.7Hz), 128.4, 127.4, 126.3, 124.7, 124.6 (d, J = 8.4Hz), 114.2 (d, J = 21.6Hz), 111.4 (d, J = 22.6Hz), 85.1, 66.9, 45.7, 39.7, 33.7, 31.4, 25.1; HRMS (ESI): m / z [M+Na] + Measured value C 20 H 18FNO2Na: 346.1214; Theoretical value: 346.1209.

[0073] Compound 3g-α is a white powder with a melting point of 175.3-175.8℃. It is readily soluble in organic solvents such as methanol, ethanol, and dichloromethane. The structural characterization results are as follows: 1 H NMR(600MHz,Chloroform-d)δ7.66(d,J=7.6Hz,1H),7.50-7.39(m,1H),7.37-7.30(m,2H),7.28( d,J=7.4Hz,1H),7.25-7.18(m,1H),6.95(dt,J=8.2,4.1Hz,1H),4.88(d,J=11.8Hz,1H),4.64(d,J =3.2Hz,1H),4.15(dd,J=11.3,4.0Hz,1H),3.95(d,J=4.5Hz,1H),3.78(t,J=11.5Hz,1H),3.65-3 .49(m,1H),2.82-2.69(m,1H),2.09-1.90(m,2H),1.73(d,J=13.9Hz,1H),1.51(d,J=13.3Hz,1H); 13 C NMR (151MHz, Chloroform-d) δ 168.8, 162.7 (d, J = 244.5Hz), 135.1, 135.0 (d, J = 1.7Hz), 132.6, 132.0 (d, J = 2.1Hz), 129.3 (d, J = 6.6Hz), 128.9,127.8,127.7,124.0,114.9(d,J=21.8Hz),110.8(d,J=22.7Hz),85.6,68.5,46.3,42.0,33.4,30.8,25.8; HRMS(ESI): m / z[M+Na] + Theoretical value C 20 H 18 FNO2Na: 346.1214; Measured value: 346.1209.

[0074] Compound 3g-β is a white powder with a melting point of 163.4-163.9℃. It is readily soluble in organic solvents such as methanol, ethanol, and dichloromethane. The structural characterization results are as follows: 1H NMR(600MHz,Chloroform-d)δ7.70(d,J=7.7Hz,1H),7.52-7.42(m,2H),7.39-7.29(m,2H ),7.18(dd,J=8.2,5.8Hz,1H),6.97(td,J=8.3,2.4Hz,1H),4.99-4.86(m,1H),4.80(dd,J =8.8,6.2Hz,1H),4.08-3.92(m,2H),3.67-3.60(m,1H),3.20(dt,J=13.8,4.0Hz,1H),2. 83(td,J=13.2,3.1Hz,1H),2.05-1.93(m,1H),1.92-1.72(m,2H),1.63(d,J=13.6Hz,1H); 13 C NMR(151MHz,Chloroform-d)δ168.5,162.8(d,J=244.9Hz),135.1,132.4(d,J=2.5Hz),131.9(d,J=1.8Hz),131.8,129.3(d,J=7.9Hz), 129.2,127.8,127.5,124.1,114.(d,J=21.8Hz),111.1(d,J=22.9Hz),86.1,67.3,45.9,40.2,34.4,30.9,25.4; HRMS(ESI): m / z[M+Na] + Theoretical value C 20 H 18 FNO2Na: 346.1214; Measured value: 346.1206.

[0075] Example 8

[0076] In this embodiment, equimolar amounts of 3-([1,1'-biphenyl]-2-yl)-1-(3-hydroxypropyl)pyridin-1(2H)-one were used to replace the 3-([1,1'-biphenyl]-2-yl)-1-(3-hydroxypropyl)pyridin-1(2H)-one in Method 1 and Method 2 of Example 1, respectively. The other steps were the same as the corresponding methods in Example 1, and pure products of compounds 2h-α and 2h-β and compounds 3h-α and 3h-β were obtained, with yields of 40%, 39%, 30%, and 28%, respectively.

[0077]

[0078] Compound 2h-α is a white powder with a melting point of 181.2-181.8℃. It is readily soluble in organic solvents such as methanol, ethanol, and dichloromethane. The structural characterization results are as follows: 1H NMR(600MHz,Chloroform-d)δ8.43(d,J=7.7Hz,1H),8.36(d,J=1.5Hz,1H),7.92(dd,J=8.0,1.6Hz,1H),7.82(dd ,J=7.6,1.3Hz,1H),7.44-7.36(m,3H),4.94(d,J=3.3Hz,1H),4.88(dd,J=13.3,4.9Hz,1H),4.17(dd,J=11.4,4.9 Hz,1H),3.92(td,J=12.4,2.4Hz,1H),3.41(td,J=13.5,3.0Hz,1H),3.27(d,J=13.9Hz,1H),2.99(td,J=13.0,2.9 Hz,1H),2.72-2.68(m,1H),2.67(s,3H),2.12(td,J=13.4,4.4Hz,1H),1.97-1.86(m,1H),1.59(d,J=13.7Hz,1H); 13 C NMR(151MHz,Chloroform-d)δ197.8,167.3,143.8,136.4,135.4,134.8,134.2,128.3,127.7,127.5 ,126.3,124.9,124.2,123.4,85.0,68.7,45.0,43.1,34.4,30.1,26.7,26.3; HRMS(ESI): m / z[M+Na] + Theoretical value C 22 H 21 NO3Na: 370.1414; Measured value: 370.1411.

[0079] Compound 2h-β is a white powder with a melting point of 162.9-163.5℃. It is readily soluble in organic solvents such as methanol, ethanol, and dichloromethane. The structural characterization results are as follows: 1H NMR(600MHz,Chloroform-d)δ8.36(s,1H),8.29(d,J=7.7Hz,1H),7.94(d,J=7.7Hz ,1H),7.82(d,J=7.4Hz,1H),7.46-7.34(m,3H),4.98(dd,J=9.0,5.1Hz,1H),4.93( d,J=13.0Hz,1H),4.15(d,J=11.0Hz,1H),3.74(t,J=11.1Hz,1H),3.32(d,J=13.8H z,1H),3.00-2.80(m,3H),2.67(s,3H),2.07-1.88(m,2H),1.68(d,J=13.1Hz,1H); 13 C NMR(151MHz,Chloroform-d)δ197.7,167.3,142.9,136.6,135.4,134.9,134.1,128.4,127.8,127.5 ,126.3,124.9,124.3,123.4,85.0,66.9,45.3,39.7,34.5,31.2,26.7,25.1; HRMS(ESI): m / z[M+Na] + Theoretical value C 22 H 21 NO3Na: 370.1414; Measured value: 370.1413.

[0080] Compound 3h-α is a white powder with a melting point of 204.8-205.3℃. It is readily soluble in organic solvents such as methanol, ethanol, and dichloromethane. The structural characterization results are as follows: 1 H NMR(600MHz,Chloroform-d)δ8.39(d,J=1.3Hz,1H),7.92-7.80(m,2H),7.44-7.34(m,3H),7 .34-7.29(m,1H),4.91(d,J=12.8Hz,1H),4.70(d,J=3.1Hz,1H),4.20(dd,J=11.5,4.8Hz,1H ),4.01(d,J=5.1Hz,1H),3.83(td,J=12.5,2.3Hz,1H),3.74-3.65(m,1H),2.79(td,J=12.8, 2.5Hz,1H),2.65(s,3H),2.13-1.94(m,2H),1.79(d,J=13.9Hz,1H),1.55(d,J=13.6Hz,1H); 13C NMR(151MHz,Chloroform-d)δ197.7,168.6,142.1,137.0,133.5,132.0,131.9,128.9,128.2,128.0 ,127.7,127.6,124.1,124.0,85.5,68.5,45.9,42.1,34.2,30.4,26.7,25.8; HRMS(ESI): m / z[M+Na] + Theoretical value C 22 H 21 NO3Na: 370.1414; Measured value: 370.1409.

[0081] Compound 3h-β is a white powder with a melting point of 188.7-189.2℃. It is readily soluble in organic solvents such as methanol, ethanol, and dichloromethane. The structural characterization results are as follows: 1 H NMR(600MHz,Chloroform-d)δ8.40(s,1H),7.95-7.82(m,2H),7.47(d,J=7.5Hz, 1H),7.43-7.30(m,3H),4.93(dd,J=13.4,4.4Hz,1H),4.83(dd,J=8.6,6.2Hz,1H) ,4.00(d,J=5.4Hz,2H),3.71-3.59(m,1H),3.33-3.24(m,1H),2.84(td,J=13.1, 2.9Hz,1H),2.66(s,3H),2.08-1.95(m,1H),1.87(m,2H),1.64(d,J=13.6Hz,1H); 13 CNMR(151MHz,Chloroform-d)δ197.6,168.3,141.8,137.1,133.6,131.9,131.7,129.3,128.2,128. 0,127.9,127.5,124.2,124.1,86.0,67.3,45.4,40.2,35.1,30.4,26.7,25.4; HRMS(ESI): m / z[M+Na] + Theoretical value C 22 H 21 NO3Na: 370.1414; Measured value: 370.1403.

[0082] Example 9

[0083] In this embodiment, equimolar amounts of 3-([1,1'-biphenyl]-2-yl)-1-(3-hydroxypropyl)pyridin-1(2H)-one were used to replace the 3-([1,1'-biphenyl]-2-yl)-1-(3-hydroxypropyl)pyridin-1(2H)-one in Method 1 and Method 2 of Example 1, respectively. The other steps were the same as the corresponding methods in Example 1, and pure products of compounds 2i-α and 2i-β and compounds 3i-α and 3i-β were obtained, with yields of 40%, 42%, 34%, and 28%, respectively.

[0084]

[0085] Compound 2i-α is a white powder with a melting point of 149.9-150.5℃. It is readily soluble in organic solvents such as methanol, ethanol, and dichloromethane. The structural characterization results are as follows: 1 H NMR(600MHz,Chloroform-d)δ8.13(d,J=1.7Hz,1H),7.70(d,J=7.6Hz,1H),7.66(d,J=8.5Hz,1H),7.35(t,J=7.3Hz, 1H),7.31-7.26(m,2H),6.91(dd,J=8.5,2.4Hz,1H),4.93(d,J=3.6Hz,1H),4.88(dd,J=13.2,4.6Hz,1H),4.17(dd,J =11.4,4.7Hz,1H),3.97-3.90(m,1H),3.89(s,3H),3.36(td,J=13.4,2.7Hz,1H),3.26(d,J=13.9Hz,1H),2.97(td,J =12.9,2.6Hz,1H),2.68(d,J=13.8Hz,1H),2.10(td,J=13.4,4.4Hz,1H),1.99-1.88(m,1H),1.56(d,J=16.3Hz,1H); 13 CNMR(151MHz,Chloroform-d)δ167.9,159.3,137.8,136.4,134.9,127.9,127.4,126.8,125.8,1 23.8,122.9,113.0,111.9,85.2,68.7,55.4,45.5,43.0,34.0,30.2,26.3; HRMS(ESI): m / z[M+Na] + Theoretical value C 21 H 21 NO3Na: 358.1414; Measured value: 358.1420.

[0086] Compound 2i-β is a white powder with a melting point of 178.2-178.7℃. It is readily soluble in organic solvents such as methanol, ethanol, and dichloromethane. The structural characterization results are as follows: 1 H NMR(600MHz,Chloroform-d)δ7.98(d,J=1.8Hz,1H),7.70(d,J=7.7Hz,1H),7.65(d,J=8.5 Hz,1H),7.37(t,J=7.0Hz,1H),7.32-7.28(m,2H),6.90(dd,J=8.5,2.4Hz,1H),4.99-4.88 (m,2H),4.14(dd,J=11.1,4.1Hz,1H),3.87(s,3H),3.73(t,J=11.6Hz,1H),3.31(d,J=13. 6Hz,1H),2.99-2.79(m,3H),2.07-1.94(m,1H),1.93-1.84(m,1H),1.67(d,J=13.3Hz,1H); 13 C NMR(151MHz,Chloroform-d)δ167.9,159.3,136.9,136.5,134.9,127.7,127.5,126.9,125.8,12 3.8,122.9,113.2,111.7,85.2,66.9,55.4,45.8,39.8,34.1,31.2,25.1; HRMS(ESI): m / z[M+Na] + Theoretical value C 21 H 21 NO3Na: 358.1414; Measured value: 358.1418.

[0087] Compound 3i-α is a white powder with a melting point of 102.3-102.7℃. It is readily soluble in organic solvents such as methanol, ethanol, and dichloromethane. The structural characterization results are as follows: 1H NMR(600MHz,Chloroform-d)δ7.63(d,J=8.5Hz,2H),7.25(t,J=7.4Hz,1H),7.22-7.13(m ,2H),6.88(s,1H),6.81(dd,J=8.5,2.1Hz,1H),4.92-4.74(m,1H),4.61(d,J=3.6Hz,1H) ,4.12(dd,J=11.3,4.3Hz,1H),3.91(d,J=4.7Hz,1H),3.83-3.65(m,4H),3.60-3.41(m,1 H),2.79-2.67(m,1H),2.09-1.87(m,2H),1.71(d,J=13.8Hz,1H),1.47(d,J=13.3Hz,1H); 13 C NMR(151MHz,Chloroform-d)δ168.,159.8,136.0,133.6,133.0,127.9,127.8,127.3,125.7 ,125.1,123.4,113.0,85.6,68.5,55.3,46.5,42.0,34.1,30.8,25.8; HRMS(ESI): m / z[M+Na] + Theoretical value C 21 H 21 NO3Na: 358.1414; Measured value: 358.1416.

[0088] Compound 3i-β is a white powder with a melting point of 178.6-179.2℃. It is readily soluble in organic solvents such as methanol, ethanol, and dichloromethane. The structural characterization results are as follows: 1 H NMR(600MHz,Chloroform-d)δ7.71(t,J=7.7Hz,2H),7.34(t,J=7.5Hz,1H),7.23(t,J=7.4Hz, 1H),7.19(d,J=7.2Hz,1H),7.03(s,1H),6.88(dd,J=8.5,2.3Hz,1H),4.99-4.90(m,1H),4.81 (dd,J=8.8,6.2Hz,1H),4.04-3.95(m,2H),3.83(s,3H),3.68-3.60(m,1H),3.24-3.13(m,1H) ,2.83(td,J=13.1,3.0Hz,1H),2.04-1.92(m,1H),1.93-1.79(m,2H),1.63(d,J=14.3Hz,1H); 13CNMR(151MHz,Chloroform-d)δ168.7,160.0,135.8,133.4,133.1,128.1,127.8,127.2,125.6,1 25.2,123.5,113.3,112.8,86.2,67.3,55.3,46.0,40.2,35.1,30.8,25.5; HRMS(ESI): m / z[M+Na] + Theoretical value C 21 H 21 NO3Na: 358.1414; Theoretical value: 358.1419.

[0089] Example 10

[0090] In this embodiment, equimolar amounts of 3-([1,1'-biphenyl]-2-yl)-1-(3-hydroxypropyl)pyridin-1(2H)-one were used to replace the 3-([1,1'-biphenyl]-2-yl)-1-(3-hydroxypropyl)pyridin-1(2H)-one in Method 1 and Method 2 of Example 1, respectively. The other steps were the same as the corresponding methods in Example 1, and pure products of compounds 2j-α and 2j-β and compounds 3j-α and 3j-β were obtained, with yields of 38%, 38%, 32%, and 29%, respectively.

[0091]

[0092] Compound 2j-α is a white powder with a melting point of 171.8-172.5℃. It is readily soluble in organic solvents such as methanol, ethanol, and dichloromethane. The structural characterization results are as follows: 1 H NMR(600MHz,Chloroform-d)δ8.84(s,1H),7.80(dd,J=16.7,8.3Hz,2H),7.62(d,J=7.9Hz, 1H),7.55-7.36(m,2H),7.31(d,J=5.8Hz,1H),5.10-4.82(m,2H),4.17(dd,J=10.8,4.2Hz, 1H),4.02-3.84(m,1H),3.47-3.32(m,1H),3.26(d,J=14.0Hz,1H),3.09-2.90(m,1H),2.70 (d,J=13.6Hz,1H),2.10(td,J=13.4,4.3Hz,1H),2.03-1.82(m,1H),1.59(d,J=13.5Hz,1H); 13C NMR(151MHz,Chloroform-d)δ167.2,138.9,138.3,135.4,133.6,129.3(q,J=32.2Hz),128.8,127.6,124.9,124.8,124.4(q, J=272.1Hz), 124.1 (q, J=3.5Hz), 123.9 (q, J=3.8Hz), 123.2, 85.0, 68.7, 44.8, 43.0, 33.6, 30.2, 26.2; HRMS (ESI): m / z [M+Na] + Theoretical value C 21 H 18 F3NO2Na: 396.1182; Measured value: 396.1181.

[0093] Compound 2j-β is a white powder with a melting point of 155.5-156.0℃. It is readily soluble in organic solvents such as methanol, ethanol, and dichloromethane. The structural characterization results are as follows: 1 H NMR(600MHz,Chloroform-d)δ8.68(s,1H),7.58-7.73(m,2H),7.61(d,J=8.0 Hz,1H),7.49-7.38(m,2H),7.38-7.31(m,1H),5.00-4.88(m,2H),4.14(dd,J =11.2,4.5Hz,1H),3.74(td,J=12.1,2.1Hz,1H),3.30(d,J=13.7Hz,1H),2.9 8-2.82(m,3H),2.07-7.95(m,1H),1.95-1.84(m,1H),1.68(d,J=13.4Hz,1H); 13 C NMR(151MHz,Chloroform-d)δ167.1,138.2,138.1,135.5,133.5,129.3(q,J=32.1Hz),128.9,127.8,124.9,124.8,124.4(q, J=272.2Hz), 124.1 (q, J=3.5Hz), 123.8 (q, J=3.4Hz), 123.2, 85.0, 66.9, 45.2, 39.8, 33.7, 31.2, 25.0; HRMS (ESI): m / z [M+Na] + Theoretical value C 21 H 18 F3NO2Na: 396.1182; Measured value: 396.1188.

[0094] Compound 3j-α is a white powder with a melting point of 188.8-189.4℃. It is readily soluble in organic solvents such as methanol, ethanol, and dichloromethane. The structural characterization results are as follows: 1 H NMR(600MHz,Chloroform-d)δ7.79(d,J=7.9Hz,1H),7.72(d,J=7.1Hz,1H),7.56(s,1 H),7.51(d,J=7.8Hz,1H),7.38-7.20(m,3H),4.84(d,J=11.4Hz,1H),4.63(s,1H),4.1 2(d,J=8.1Hz,1H),3.93(s,1H),3.75(t,J=11.7Hz,1H),3.58(d,J=11.4Hz,1H),2.73 (t,J=12.2Hz,1H),2.07-1.84(m,2H),1.75(d,J=13.5Hz,1H),1.48(d,J=13.2Hz,1H); 13 C NMR(151MHz,Chloroform-d)δ168.1,137.2,136.4,132.7,131.7,130.0(q,J=32.3Hz),129.4,128.1,128.0(q,J=4.5Hz), 124.7(q,J=3.5Hz),124.6,124.1,124.0(q,J=272.1Hz),85.4,68.4,46.0,42.1,33.8,30.8,25.7; HRMS(ESI): m / z[M+Na] + calcd for C 21 H 18 F3NO2Na: 396.1182; found: 396.1180.

[0095] Compound 3j-β is a white powder with a melting point of 200.2-200.7℃. It is readily soluble in organic solvents such as methanol, ethanol, and dichloromethane. The structural characterization results are as follows: 1H NMR(600MHz,Chloroform-d)δ7.81(d,J=8.1Hz,1H),7.75(d,J=7.7Hz,1H),7.65(s,1H),7.53(d,J=8. 1Hz,1H),7.33(t,J=7.5Hz,1H),7.28(t,J=7.3Hz,1H),7.18(d,J=6.1Hz,1H),4.97-4.83(m,1H),4.76 (dd,J=8.7,6.1Hz,1H),4.03-3.82(m,2H),3.58(td,J=12.4,2.0Hz,1H),3.29-3.08(m,1H),2.77(td, J=13.2,3.1Hz,1H),2.07-1.90(m,1H),1.85-1.76(m,1H),1.75-1.63(m,1H),1.57(d,J=13.4Hz,1H); 13 CNMR(151MHz,Chloroform-d)δ167.9,137.1,136.3,132.6,131.8,130.3(q,J=32.7Hz),129.3,128.4,128.1,124.7,124.6(q ,J=3.4Hz),124.5(q,J=3.6Hz),124.2,124.1(q,J=272.1Hz),85.9,67.3,45.5,40.3,34.7,31.0,25.4; HRMS(ESI): m / z[M+Na] + Theoretical value C 21 H 18 F3NO2Na: 396.1182; Measured value: 396.1179.

[0096] Example 11

[0097] Application of the compounds of this invention in the preparation of antifungal drugs

[0098] The above compounds 2b-α, 2b-β, 2f-α, 3b-β, 3b-α, 3e-β, and 3h-α were used as active ingredients in efficacy tests against plant fungi. The specific test results are as follows:

[0099] 1. Test drug

[0100] Compounds: 2b-α, 2b-β, 2f-α, 3b-β, 3b-α, 3e-β and 3h-α.

[0101] 2. Test strains

[0102] Three strains were tested: rice sheath blight pathogen, apple rot pathogen, and tomato early blight pathogen.

[0103] 3. Assay for antifungal activity against plants

[0104] Preparation of test bacterial plates: Under aseptic conditions, pure culture test bacteria were inoculated onto sterile PDA medium plates using the dense wave streak method. The plates were incubated at 25°C for about one week until the plates were covered with bacterial growth.

[0105] Preparation and sterilization of the culture medium: The culture medium was PDA solid medium, with the following formula: 200g potato, 20g glucose, 20g agar, 1000mL tap water, and natural pH. Specific preparation process: Peel the potatoes and cut them into 5mm square pieces. Add tap water and boil for 20 minutes. Filter through 8 layers of gauze. Add the appropriate amount of glucose and agar powder to the filtrate, heat and stir until dissolved. Finally, add tap water to bring the volume to the appropriate level. Dispense into 250mL Erlenmeyer flasks and seal (100mL culture medium per flask). Sterilize in an autoclave at 115℃ for 30 minutes.

[0106] Preparation of the drug solution: Weigh 10.0 mg each of compounds 2b-α, 2b-β, 2f-α, 3b-β, 3b-α, 3e-β and 3h-α into a 1.5 mL sterile centrifuge tube, and add 1 mL of acetone to dissolve them.

[0107] Preparation of drug-containing culture medium: Heat the culture medium in the sterilized Erlenmeyer flask to melt and cool to about 50°C. Under aseptic conditions on a laminar flow hood, add the prepared drug solution to the flask and gently shake to distribute the drug solution evenly in the culture medium, thus preparing a 100 μg / mL drug-containing culture medium. Immediately pour the hot medium into 5 sterile petri dishes (20 mL of culture medium per dish) to make thin and uniform plates, and label them. Hymexazol is used as a positive control. Using the same procedure, prepare negative control plates of acetone (1 mL added directly to 100 mL of sterile culture medium) and label them.

[0108] Antimicrobial inhibition rate test: Under aseptic conditions, a certain number of mycelial cakes were punched out of the test bacteria plates using a sterile puncher. The mycelial cakes were then placed on the prepared drug-containing culture medium with the mycelium side down, one mycelial cake per plate (three replicates). The plates were marked and incubated in a constant temperature incubator at 25°C for 72 hours. The culture was then removed and the colony diameter was measured with calipers (two cross-sectional measurements were required, and the average of the measurements was taken for all three replicate plates). The antimicrobial inhibition rate was calculated according to the following formula. The calculation results are shown in Table 1.

[0109] Antibacterial inhibition rate = (negative control growth diameter - treatment growth diameter) / (negative control growth diameter - 4.5) × 100%

[0110] Table 1. Antifungal activity of each compound at a concentration of 100 μg / mL

[0111]

[0112]

[0113] As shown in Table 1, compounds 2b-α, 2b-β, 2f-α, 3b-β, 3b-α, 3e-β, and 3h-α of the present invention all exhibit good antibacterial activity against the three tested strains. Among them, 2b-α, 2b-β, 2f-α, and 3e-β show significant antibacterial activity against rice sheath blight pathogens, all tested drugs show significant antibacterial activity against apple anthracnose pathogens, and 2f-α and 3b-β show significant antibacterial activity against tomato early blight pathogens. Therefore, the dibenzo-1,3-oxazacyclohexaneisoquinoline-1(2H)-one compounds of the present invention all possess good antifungal activity against plant fungi.

Claims

1. A class of dibenzo-1,3-oxazacyclohexaneisoquinoline-1(2H)-one compounds, characterized in that... The compound has any one of the following structural formulas: In the formula R 1 R 2 R 3 Each can be independently represented by any one of H, C1-C4 alkyl, C1-C4 alkoxy, acetyl, cyano, fluorine, trifluoromethyl, or hydroxyl.

2. The dibenzo-1,3-oxazacyclohexaneisoquinoline-1(2H)-one compound according to claim 1, characterized in that: The R 1 R represents any one of hydrogen, methoxy, fluorine, cyano, or hydroxyl. 2 R represents any one of hydrogen, methyl, acetyl, or fluorine. 3 It represents any one of hydrogen, trifluoromethyl, or methoxy.

3. The dibenzo-1,3-oxazacyclohexaneisoquinoline-1(2H)-one compound according to claim 1, characterized in that... The compound is any one of the following formulas:

4. A method for preparing the dibenzo-1,3-oxazacyclohexaneisoquinoline-1(2H)-one compound according to claim 1, characterized in that: The 3-biphenyl-1-hydroxypropylpyridine-2(1H)-one compounds shown in Formula I were dissolved in an organic solvent and irradiated with ultraviolet light at 300–365 nm for 30–90 minutes. Hydrochloric acid was then added, and the mixture was stirred at room temperature for 30–120 minutes. After the reaction was complete, the reaction solution was distilled under reduced pressure and purified by column chromatography to obtain trans-dibenzo-1,3-oxazacyclohexaneisoquinoline-1(2H)-one compounds. The reaction equation is as follows: Alternatively, the 3-biphenyl-1-hydroxypropylpyridine-2(1H)-one compound shown in Formula I is dissolved in hydrochloric acid in an organic solvent and irradiated with ultraviolet light at 300–365 nm for 30–120 minutes. After the reaction is complete, the reaction solution is distilled under reduced pressure and purified by column chromatography to obtain cis-dibenzo-1,3-oxazacyclohexaneisoquinoline-1(2H)-one compounds; the reaction equation is as follows: In the formula R 1 R 2 R 3 Each can be independently represented by any one of H, C1-C4 alkyl, C1-C4 alkoxy, acetyl, cyano, fluorine, trifluoromethyl, or hydroxyl.

5. The method for preparing dibenzo-1,3-oxazacyclohexaneisoquinoline-1(2H)-one compounds according to claim 4, characterized in that: The molar ratio of the 3-biphenyl-1-hydroxypropylpyridine-2(1H)-one compound to HCl in hydrochloric acid is 1:0.1 to 1.

5.

6. The method for preparing dibenzo-1,3-oxazacyclohexaneisoquinoline-1(2H)-one compounds according to claim 4, characterized in that: The organic solvent is any one of dioxane, toluene, and acetone.

7. The use of the dibenzo-1,3-oxazacyclohexane-isoquinoline-1(2H)-one compound of claim 1 in the preparation of antifungal drugs.

8. The use of the dibenzo-1,3-oxazacyclohexaneisoquinoline-1(2H)-one compounds according to claim 7 in the preparation of antifungal drugs, characterized in that: The plant fungus mentioned is any one of rice sheath blight fungus, apple rot fungus, or tomato early blight fungus.

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