Lactam compound, preparation method and use thereof

Abstract

Provided is a lactam compound, a tautomer, a stereoisomer, a racemate, a nonequal mixture of enantiomers, a geometric isomer, a solvate, a pharmaceutically acceptable salt thereof, or a solvate of the salt of the compound, and a pharmaceutical composition containing the compound. Also provided are the use of such compounds and their pharmaceutical compositions as drugs, especially as antiviral drugs.

Claims

1. A method for treating a viral disease, the method comprising administering to a subject a therapeutically effective amount of a pharmaceutical composition, wherein the viral disease is caused by respiratory syncytial virus (RSV), herpes simplex virus (HSV), enterovirus 71 (EV71), Coxsackie B virus, influenza virus (H1N1, H7N9), human immunodeficiency virus (HIV), or combinations thereof, wherein the pharmaceutical composition comprises a compound, or the tautomer, or the stereoisomer, or the racemate, or the nonequal mixture of enantiomers, or the geometric isomer, or the pharmaceutically acceptable salt thereof, wherein the compound has one of the following structures: ##STR00781## ##STR00782## ##STR00783## ##STR00784## ##STR00785## ##STR00786## ##STR00787## ##STR00788## wherein R.sub.2 is selected from following substituents: ##STR00789## ##STR00790## ##STR00791## ##STR00792## ##STR00793## ##STR00794## ##STR00795## ##STR00796## ##STR00797## ##STR00798## ##STR00799## ##STR00800## wherein R.sub.1 and R.sub.4 are selected from following substitutions: ##STR00801## ##STR00802## ##STR00803## ##STR00804## ##STR00805## ##STR00806## ##STR00807## ##STR00808## ##STR00809## ##STR00810## ##STR00811##

2. The method according to claim 1, wherein the disease is selected from the group consisting of respiratory diseases, pneumonia, gingival stomatitis, encephalitis, herpes and herpes pharyngitis, and enteritis.

3. The method according to claim 1, wherein the pharmaceutically acceptable salt is selected from the group consisting of hydrochloride, sulfate, phosphate, oxalate, maleate, methanesulfonate, succinate, citrate, fumarate, glucuronide, formate, acetate.

4. The method according to claim 1, wherein the compound, the tautomer, the stereoisomer, the racemate, the nonequal mixture of enantiomers, the geometric isomer, or the pharmaceutically acceptable salt thereof, possesses antiviral activity.

5. The method according to claim 1, wherein the pharmaceutical composition further comprises at least one drug having anti-viral activity, comprising virazole, rimantadine hydrochloride, amantadine hydrochloride, acyclovir, valaciclovir, ganciclovir, interferon, zidovudine, vidarabine, ribavirin, and tibivudine.

Description

DETAILED DESCRIPTION OF EMBODIMENTS

(1) In general, the invention of compounds can be obtained by method described in this invention, unless there is a further instructions, including the definition of substituent such as type I-VI, as shown in the following reaction scheme and implementation example for further example explains the content of the invention, in which R.sub.1, R.sub.2, R.sub.3 and R.sub.4, n, k, V, T is defined the same as any of the above place in the invention.

(2) ##STR00774##

(3) ##STR00775##

(4) ##STR00776##

(5) The compound concerned in this invention is obtained by reacting with a halogenated reagent under alkaline conditions with a quinolinone compound synthesized under scheme 1 or scheme 2 as a substrate.

(6) Take the compound 4-hydroxy-3-methoxyl-4-phenyl-3,4-dihydroquinolin-2 (1H)-one as an example, detailed synthetic method is described according to Scheme 1:

Example 1

(7) ##STR00777##

(8) Under the protection of nitrogen, 2-aminophenone (50 mg, 0.25 mmol) was dissolved in DCM (5 mL). Under the catalyzation of potassium carbonate, methoxyacetyl chloride (45 micron, 0.5 mmol, 2 eq) was added and reacted at room temperature for half an hour before quenching with water. The reaction mixture was extracted by ethyl acetate. The organic phase was removed by reduced pressure distillation. The dry residue was then dissolved in THF (10 mL). t-BuOK (225 mg, 2.5 mmol) was added for reaction at room temperature for 5 hours. The reaction solution was extracted with saturated ammonium chloride solution and ethyl acetate solution. The organic phase was removed by reduced pressure distillation, and the residues were purified by silica gel column chromatography (ethyl acetate/petroleum ether (v/v)=1/2) to obtain the white amorphous powder compound 4-hydroxy-3-methoxyl-4-phenyl-3,4-dihydroquinolin-2 (1H)-ketone (63 mg, 95%). .sup.1H NMR (500 MHz, CDCl.sub.3): δ ppm 3.54 (s, 3H), 4.00 (s, 1H), 6.85 (d, J=7.8 Hz, 1H), 7.07 (t, J=7.6 Hz, 1H), 7.26-7.34 (m, 7H), 8.4 (s, 1H), .sup.13C NMR (125 MHz, CDCl.sub.3): 59.8, 84.2, 115.4, 124.1, 126.5, 128.1, 128.3, 128.5, 129.5, 135.2, 140.2, 168.1. ESIMS m/z 270.02 [M+H].sup.+, 292.01 [M+Na].sup.+, 92% yield.

(9) Refer to the above synthetic process, 5-chloro-2-aminophenone, 5-iodine-2-aminophenone, 4′-bromo-2-aminophenone, 4′-chloro2-aminophenone, 4′-fluoro-2-aminophenone, phenyl 5-aminophenone, 5-methoxydiphenyl ketone, 5-hydroxydiphenyl ketone were used as raw materials to produce 6-chloro-4-hydroxy-3-methoxy-4-phenyl quinoline-2 (1H)-one, 6-iodine-4-hydroxy-3-methoxy-4-phenyl quinoline-2 (1H)-one, 4-(4-bromine phenyl)-4-hydroxy-3-methoxy quinoline-2 (1H)-one, 4-(4-chlorobenzene)-4-hydroxy-3-methoxy quinoline-2 (1H)-one, 4-(4-phenyl)-4-hydroxy-3-methoxy quinoline-2 (1H)-one, 3-methoxy-4-hydroxy-4-phenyl-1,6-nalidixic-2 (1H) one, 6-methoxy-4-hydroxy-3-methoxy-4-phenylquinolin-2 (1H)-one, 6-hydroxy-4-hydroxy-3-methoxy-4-phenylquinolin-2 (1H)-one.

Example 2

(10) ##STR00778##

(11) Under the protection of nitrogen, the compound 4-hydroxy-3-methoxyl-4-phenyl-3,4-dihydroquinolin-2 (1H)-one (100 mg) was dissolved in dry acetonitrile (5 mL). Under the catalyzation of potassium carbonate, the compound was added to benzyl bromide (3-4 eq) and reacted overnight at 60□. After TLC detection, the solvent was removed by reduced pressure distillation. Water and ethyl acetate were added to extract the production. Then the organic phase was condensed under reduced pressure and dried to obtain the target product. .sup.1H NMR (500 MHz, acetone-d.sub.6): δ ppm 3.48 (s, 3H), 4.29 (s, 1H), 4.84 (s, 1H), 5.12 (d, J=16.0 Hz, 1H), 5.24 (d, J=16.0 Hz, 1H), 7.05 (t, J=7.5 Hz, 1H), 7.08 (d, J=8.2 Hz, 1H), 7.20 (d, J=8.3 Hz, 2H), 7.26 (t, J=8.0 Hz, 1H), 7.33 (overlapped, 6H), 7.46 (d, J=8.3 Hz, 2H), .sup.13C NMR (125 MHz, acetone-d.sub.6): 44.1, 58.7, 76.2, 84.6, 115.2, 120.3, 123.2, 127.0, 127.6, 127.9, 128.1, 128.8, 129.0, 131.0, 131.4, 136.7, 137.9, 141.4, 167.4. ESIMS m/z 438.13/440.13 [M+H].sup.+/[M+2+H].sup.+ (1:1), 460.05/462.05 [M+Na].sup.+/[M+2+Na].sup.+ (1:1); HRESIMS m/z 438.0695 [M+H].sup.+ (calcd for C.sub.23H.sub.21O.sub.3NBr, 438.0699); 65% yield.

(12) Refer to the above synthetic process, 4-hydroxy-3-methoxyl-1-(3-methoxybenzyl)-4-phenyl-3,4-dihydroquinolin-2 (1H)-one, 4-hydroxy-3-methoxyl-1-(3-nitrobenzyl)-4-phenyl-3,4-dihydroquinolin-2 (1H)-one, 1-(3-chloro benzyl)-4-hydroxy-3-methoxyl-4-phenyl-3,4-dihydroquinolin-2 (1H)-one, 4-hydroxy-3-methoxyl-1-(3-methyl benzyl)-4-phenyl-3,4-dihydroquinolin-2 (1H)-one, 4-hydroxy-3-methoxyl-1-(4-methyl benzyl)-4-phenyl-3,4-dihydroquinolin-2 (1H)-one, 1-(3-fluoro benzyl)-4-hydroxy-3-methoxyl-4-phenyl-3,4-dihydroquinolin-2 (1H)-one, 1-(4-fluoro benzyl)-4-hydroxy-3-methoxyl-4-phenyl-3,4-dihydroquinolin-2 (1H)-one, 1-(4-bromo-2-fluoro benzyl)-4-hydroxy-3-methoxyl-4-phenyl-3,4-dihydroquinolin-2 (1H)-one, 1-(2-chloro-5-(three fluorinated methyl)benzyl)-4-hydroxy-3-methoxy-4-phenyl-3,4-dihydro quinoline-2 (1H)-one, 1-(4-bromo-2-fluoro benzyl)-4-hydroxy-3-methoxyl-4-phenyl-3,4-dihydroquinolin-2 (1H)-one, 1-(3,4-difluoro benzyl)-4-hydroxy-3-methoxyl-4-phenyl-3,4-dihydroquinolin-2 (1H)-one, 4-hydroxy-3-methoxy-4-phenyl-1-(4-(trifluoromethoxyl)benzyl)-3,4-dihydroquinolin-2 (1H)-one, 1-(3,5-difluoro benzyl)-4-hydroxy-3-methoxyl-4-phenyl-3,4-dihydroquinolin-2 (1H)-one, 1-(2-bromobenzyl)-4-hydroxy-3-methoxyl-4-phenyl-3,4-dihydroquinolin-2 (1H)-one, 1-(2,6-dichloro benzyl)-4-hydroxy-3-methoxyl-4-phenyl-3,4-dihydroquinolin-2 (1H)-one, 1-(4-chloro-2-fluoro benzyl)-4-hydroxy-3-methoxyl-4-phenyl-3,4-dihydroquinolin-2 (1H)-one, 1-(2-fluoro benzyl)-4-hydroxy-3-methoxyl-4-phenyl-3,4-dihydroquinolin-2 (1H)-one, 1-(2-chloro benzyl)-4-hydroxy-3-methoxyl-4-phenyl-3,4-dihydroquinolin-2 (1H)-one, 1-(2,5-difluoro benzyl)-4-hydroxy-3-methoxyl-4-phenyl-3,4-dihydroquinolin-2 (1H)-one, 4-hydroxy-3-methoxyl-1-(2-methyl benzyl)-4-phenyl-3,4-dihydroquinolin-2 (1H)-one, 4-hydroxy-3-methoxyl-4-phenyl-1-(2,4,5-trifluoro benzyl)-3,4-dihydroquinolin-2 (1H)-one, 1-(2,6-difluoro benzyl)-4-hydroxy-3-methoxyl-4-phenyl-3,4-dihydroquinolin-2 (1H)-one, 6-chloro-1-(3-chloro benzyl)-4-hydroxyl-3-methoxy-4-phenyl-3,4-dihydroquinoline-2(1H)-one, 6-chloro-1-(3-fluoro benzyl)-4-hydroxyl-3-methoxy-4-phenyl-3,4-dihydroquinoline-2(1H)-one, 6-chloro-1-(4-chloro benzyl)-4-hydroxyl-3-methoxy-4-phenyl-3,4-dihydroquinoline-2(1H)-one, 6-chloro-1-(4-fluoro benzyl)-4-hydroxyl-3-methoxy-4-phenyl-3,4-dihydroquinoline-2(1H)-one, 1-(4-bromobenzyl)-6-chloro-4-hydroxy-3-methoxyl-4-phenyl-3,4-dihydroquinolin-2 (1H)-one, 1-benzyl-6-chloro-4-hydroxyl-3-methoxy-4-phenyl-3,4-dihydroquinoline-2(1H)-one, 1-(4-methyl benzyl)-6-chloro-4-hydroxy-3-methoxyl-4-phenyl-3,4-dihydroquinolin-2 (1H)-one, 1-(2,6-dichloro benzyl)-6-chloro-4-hydroxy-3-methoxyl-4-phenyl-3,4-dihydroquinolin-2 (1H)-one, 1-(2-fluoro-4-chloro benzyl)-6-chloro-4-hydroxy-3-methoxyl-4-phenyl-3,4-dihydroquinolin-2 (1H)-one, 1-(2-cyano benzyl)-6-chloro-4-hydroxyl-3-methoxy-4-phenyl-3,4-dihydroquinoline-2(1H)-one, 1-(3,5-trifluoro methyl benzyl)-6-chloro-4-hydroxy-3-methoxy-4-phenyl-3,4-dihydro quinoline-2 (1H)-one, 1-(3,4-dichloro benzyl)-6-chloro-4-hydroxy-3-methoxyl-4-phenyl-3,4-dihydroquinolin-2 (1H)-one, 4-(4-chlorophenyl)-4-hydroxyl-1-(2-iodobenzyl)-3-methoxyl-3,4-dihydroquinoline-2(1H)-one, 4-(4-chlorophenyl)-4-hydroxyl-1-(2-chloro benzyl)-3-methoxyl-3,4-dihydroquinoline-2(1H)-one, 4-(4-fluorophenyl)-4-hydroxyl-1-(2-bromobenzyl)-3-methoxyl-3, 4-dihydroquinolin-2 (1H)-one, 4-(4-fluorophenyl)-4-hydroxyl-1-(2-iodobenzyl)-3-methoxyl-3,4-dihydroquinolin-2 (1H)-one, 4-(4-fluorophenyl)-4-hydroxyl-1-(2-fluoro benzyl)-3-methoxyl-3,4-dihydroquinoline-2(1H)-one, 4-(4-fluorophenyl)-4-hydroxyl-1-(2-chloro benzyl)-3-methoxyl-3,4-dihydroquinoline-2(1H)-one, 4-(4-fluorophenyl)-4-hydroxyl-1-(4-bromobenzyl)-3-methoxyl-3,4-dihydroquinolin-2 (1H)-one, 4-(4-fluorophenyl)-4-hydroxyl-1-(3-chloro benzyl)-3-methoxyl-3,4-dihydroquinolin-2 (1H)-one, 4-(4-bromophenyl)-4-hydroxyl-1-(2-bromobenzyl)-3-methoxyl-3,4-dihydroquinoline-2(1H)-one, 4-(4-bromophenyl)-4-hydroxyl-1-(2-iodobenzyl)-3-methoxyl-3,4-dihydroquinoline-2(1H)-one, 4-(4-bromophenyl)-4-hydroxyl-1-(4-fluoro benzyl)-3-methoxyl-3,4-dihydroquinoline-2(1H)-one, 4-(4-bromophenyl)-4-hydroxyl-1-(4-chloro benzyl)-3-methoxyl-3,4-dihydroquinoline-2(1H)-one, 4-(4-bromophenyl)-4-hydroxyl-1-(3-iodobenzyl)-3-methoxyl-3,4-dihydroquinoline-2(1H)-one, 1-(3-chloro benzyl)-4-hydroxy-6-iodine-3-methoxyl-4-phenyl-3,4-dihydroquinolin-2 (1H)-one, 1-ethyl6-iodine-3-methoxyl-4-phenylquinolin-2 (1H)-one, 1-(4-fluorophenyl)-6-iodine-3-methoxyl-4-phenylquinolin-2 (1H)-one, 5-bromo-1-(3-chloro benzyl)-4-hydroxy-3-methoxyl-4-phenyl-3,4-dihydroquinolin-2 (1H)-one, 1-(3-chloro benzyl)-4,6-dihydroxy-3-methoxyl-4-phenyl-3,4-dihydroquinolin-2 (1H)-one were synthesized.

Example 3

(13) ##STR00779##

Step 1) 6-Methyl-2-phenyl-4H-benzo[d][1,3]oxazin-4-one

(14) To a mixture of 2-Amino-5-methylbenzoic acid (0.45 g) and sodium carbonate (0.65 g) in THF being cooled to 0° C. was added benzoyl chloride (2 eq) and allowed to react at room temperature overnight. After the completion of the reaction, the reaction solution was diluted with water, stirred for 10 minutes, and filtered. The filter cake was washed twice with ethyl acetate. The compound was obtained as a white solid.

Step 2) N-(2-benzoyl-4-methylphenyl)benzamide

(15) To a solution of 6-Methyl-2-phenyl-4H-benzo[d][1,3]oxazin-4-one (0.093 g) in dichloromethane at −78° C. was added phenylmagnesium bromide (3-4 eq) dropwise. After being stirred for 2 hour at −78° C., the reaction mixture was quenched by addition of water. and extracted with dichloromethane. The organic phase was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, The compound was obtained as a yellow oil.

Step 3) (2-Amino-5-methylphenyl)(phenyl)methanone

(16) To a solution of N-(2-Benzoyl-4-methylphenyl)benzamide (1.32 g) in MeOH at room temperature was added NaOH (1.4 g) in water (2 mL) and heated to reflux overnight. The reaction solution was washed with water and extracted with ethyl acetate. The compound was obtained as a yellow oil.

Step 4) (5-Methyl-2-nitrophenyl) (phenyl)methanone

(17) To a solution of (2-Amino-5-methylphenyl) (phenyl)methanone (5.28 g) in toluene (200 mL) at 0° C. was added m-chloroperoxybenzoic acid (5 eq). The resulting mixture was heated to 120° C. and allowed to stir for 6 hours. After the completion of the reaction, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic phase is concentrated under reduced pressure and separated by column chromatography. The compound was obtained as a pale-yellow oil.

Step 5) (5-(Bromomethyl)-2-nitrophenyl) (phenyl)methanone

(18) To a solution of (5-methyl-2-nitrophenyl) (phenyl)methanone (2.41 g) in carbon tetrachloride (100 mL) under nitrogen was added, NBS (2.32 g) and AMBN (90 mg). And the mixture was stirred at 80° C. for 24 hours. After the completion of the reaction, the reaction mixture was diluted with water and extracted with dichloromethane. The organic phase was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=8/1), The compound was obtained as pale yellow oil.

Step 6) (5-((diethoxyphosphoryl)methyl)-2-nitrophenyl) (phenyl)methanone

(19) To a solution of 5-(bromomethyl)-2-nitrophenyl) (phenyl)methanone (2.1 g) in 1,4-dioxane (100 mL) at room temperature was added triethyl phosphite (10 eq) dropwise. After being stirred for 2 hour at −78° C., the reaction mixture was quenched by addition of water. and extracted with dichloromethane. The organic phase was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, The compound was obtained as a yellow oil.

Step 7) (E)-(5-(2-(2-methyl-5-(prop-1-en-2-yl)tetrahydrofuran-2-yl)vinyl)-2-nitrophenyl) (Phenyl) ketone

(20) To a solution of (5-((diethoxyphosphoryl)methyl)-2-nitrophenyl) (phenyl)methanone (0.8 g) in THF at 0° C. was added NaH (1.2 eq). After being stirred for 30 minutes at 0° C., the reaction mixture was added 2-methyl-5-(prop-1-en-2-yl) tetrahydrofuran-2-carbaldehyde (1.5 eq) and allowed to stir for 2 hours. After the completion of the reaction, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic phase was concentrated under reduced pressure.

(21) The residue was purified by silica gel column chromatography. The compound was obtained as a yellow oil.

Step 8) (E)-(2-Amino-5-(2-(2-methyl-5-(prop-1-en-2-yl)tetrahydrofuran-2-yl)vinyl)phenyl) (Benzene)-one

(22) To a solution of (E)-(5-(2-(2-methyl-5-(prop-1-en-2-yl)tetrahydrofuran-2-yl) vinyl)-2-nitrophenyl) (Phenyl)-one (0.1 g) in ethanol (10 mL) and water (5 mL) at room temperature was added Fe (6 eq) and ammonium chloride (6 eq) and heated to 90° C., then allowed to stir for 4 hours. The reaction solution was washed with water and extracted with ethyl acetate. The residue was purified by silica gel column chromatography, The compound was obtained as a yellow oil.

Step 9) (E)-N-(2-benzoyl-4-(2-(2-methyl-5-(prop-1-en-2-yl)tetrahydrofuran-2-yl)vinyl)phenyl)-2-methoxyacetamide

(23) To a solution of (E)-(2-Amino-5-(2-(2-methyl-5-(prop-1-en-2-yl)tetrahydrofuran-2-yl)vinyl)phenyl) (Benzene)-one (0.25 g) in dichloromethane at 0° C. was added DIPEA (1.2 eq). After being stirred for 30 minutes at 0° C., the reaction mixture was added 2-methoxyacetyl chloride (1.2 eq) and allowed to stir for 2 hours. After the completion of the reaction, the reaction mixture was diluted with water and extracted with dichloromethane. The organic phase was concentrated under reduced pressure. The residue was purified by silica gel column chromatography. The compound was obtained as a yellow oil.

Step 10) (E)-4-hydroxy-3-methoxy-4-phenyl-6-(2-(tetrahydrofuran-2-yl)vinyl)-3,4-dihydroquinolin-2(1H)-one

(24) To a solution of ((E)-N-(2-benzoyl-4-(2-(2-methyl-5-(prop-1-en-2-yl)tetrahydrofuran-2-yl) vinyl)phenyl)-2-methoxyacetamide (0.12 g) in THF (10 mL) at room temperature was added potassium t-butoxide (10 eq). After being stirred for 1 hour, the reaction mixture was quenched by addition of water. and extracted with ethyl acetate. The organic phase was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, The compound (E)-4-hydroxy-3-methoxy-4-phenyl-6-(2-(tetrahydrofuran-2-yl)vinyl)-3,4-dihydroquinolin-2(1H)-one was obtained as a white solid. ESIMS m/z 366.42.

Example 4

(25) Bicyclo[2.2.1]hept-5-ene-2-carbaldehyde was used as a reagent to react with the (5-((diethoxyphosphoryl)methyl)-2-nitrophenyl) (phenyl)methanone synthesized following Example 3, to give intermediate product (E)-(5-(2-(bicyclo[2.2.1]hept-5-en-2-yl)vinyl)-2-nitrophenyl) (phenyl)methanone, which was then subjected to reaction and post-treatment described in Example 3 to give final product (E)-6-(2-(bicyclo[2.2.1]hept-5-en-2-yl)vinyl)-4-hydroxy-3-methoxy-4-phenyl-3,4-dihydroquinolin-2(1H)-one. ESI-MS m/z 388.48 [M+H].sup.+.

Example 5

(26) 5-phenylfuran-2-carbaldehyde was used as a reagent to react with the (5-((diethoxyphosphoryl)methyl)-2-nitrophenyl) (phenyl)methanone synthesized following Example 3, to give intermediate product (E)-(2-nitro-5-(2-(5-phenylfuran-2-yl)vinyl)phenyl)(phenyl)methanone, which was then subjected to reaction and post-treatment described in Example 3 to give final product (E)-4-hydroxy-3-methoxy-4-phenyl-6-(2-(5-phenylfuran-2-yl) vinyl)-3,4-dihydroquinolin-2(1H)-one. ESI-MS m/z 438.50 [M+H].sup.+.

Example 6

(27) Cyclopentanecarbaldehyde was used as a reagent to react with the (5-((diethoxyphosphoryl)methyl)-2-nitrophenyl) (phenyl)methanone synthesized following Example 3, to give intermediate product (E)-(5-(2-cyclopentylvinyl)-2-nitrophenyl)(phenyl)methanone, which was then subjected to reaction and post-treatment described in Example 3 to give final product (E)-6-(2-cyclopentylvinyl)-4-hydroxy-3-methoxy-4-phenyl-3,4-dihydroquinolin-2(1H)-one. ESI-MS m/z 364.46 [M+H].sup.+

Example 7

(28) Cyclopentanone was used as a reagent to react with the (5-((diethoxyphosphoryl)methyl)-2-nitrophenyl) (phenyl)methanone synthesized following Example 3, to give intermediate product (5-(cyclopentylidenemethyl)-2-nitrophenyl)(phenyl)methanone, which was then subjected to reaction and post-treatment described in Example 3 to give final product 6-(cyclopentylidenemethyl)-4-hydroxy-3-methoxy-4-phenyl-3,4-dihydroquinolin-2(1H)-one. ESI-MS m/z 350.43 [M+H].sup.+

Example 8

(29) 3-methylcyclopentan-1-one was used as a reagent to react with the (5-((diethoxyphosphoryl)methyl)-2-nitrophenyl) (phenyl)methanone synthesized following Example 3, to give intermediate product (E)-(5-((3-methylcyclopentylidene)methyl)-2-nitrophenyl)(phenyl)methanone, which was then subjected to reaction and post-treatment described in Example 3 to give final product (E)-4-hydroxy-3-methoxy-6-((3-methylcyclopentylidene)methyl)-4-phenyl-3,4-dihydroquinolin-2(1H)-one. ESI-MS m/z 364.46 [M+H].sup.+

Example 9

(30) 1-cyclopentylpropan-1-one was used as a reagent to react with the (5-((diethoxyphosphoryl)methyl)-2-nitrophenyl) (phenyl)methanone synthesized following Example 3, to give intermediate product (E)-(5-(2-cyclopentylbut-1-en-1-yl)-2-nitrophenyl)(phenyl)methanone, which was then subjected to reaction and post-treatment described in Example 3 to give final product (E)-6-(2-cyclopentylbut-1-en-1-yl)-4-hydroxy-3-methoxy-4-phenyl-3,4-dihydroquinolin-2(1H)-one.

(31) ESI-MS m/z 392.51 [M+H].sup.+

Example 10

(32) 1-cyclopentylpropan-2-one was used as a reagent to react with the (5-((diethoxyphosphoryl)methyl)-2-nitrophenyl) (phenyl)methanone synthesized following Example 3, to give intermediate product (E)-(5-(3-cyclopentyl-2-methylprop-1-en-1-yl)-2-nitrophenyl)(phenyl)methanone, which was then subjected to reaction and post-treatment described in Example 3 to give final product (E)-6-(3-cyclopentyl-2-methylprop-1-en-1-yl)-4-hydroxy-3-methoxy-4-phenyl-3,4-dihydroquinolin-2(1H)-one. ESI-MS m/z 392.51 [M+H].sup.+

Example 11

(33) 5-methylhexan-3-one was used as a reagent to react with the (5-((diethoxyphosphoryl)methyl)-2-nitrophenyl) (phenyl)methanone synthesized following Example 3, to give intermediate product (Z)-(5-(2-ethyl-4-methylpent-1-en-1-yl)-2-nitrophenyl)(phenyl)methanone, which was then subjected to reaction and post-treatment described in Example 3 to give final product (Z)-6-(2-ethyl-4-methylpent-1-en-1-yl)-4-hydroxy-3-methoxy-4-phenyl-3,4-dihydroquinolin-2(1H)-one. ESI-MS m/z 380.50 [M+H].sup.+

Example 12

(34) 2,2,4-trimethylcyclopentan-1-one was used as a reagent to react with the (5-((diethoxyphosphoryl)methyl)-2-nitrophenyl) (phenyl)methanone synthesized following Example 3, to give intermediate product (E)-(2-nitro-5-((2,2,4-trimethylcyclopentylidene)methyl)phenyl)(phenyl)methanone, which was then subjected to reaction and post-treatment described in Example 3 to give final product (E)-4-hydroxy-3-methoxy-4-phenyl-6-((2,2,4-trimethylcyclopentylidene)methyl)-3,4-dihydroquinolin-2(1H)-one. ESI-MS m/z 392.51 [M+H].sup.+

Example 13

(35) Tetrahydrofuran-2-carbaldehyde was used as a reagent to react with the (5-((diethoxyphosphoryl)methyl)-2-nitrophenyl) (phenyl)methanone synthesized following Example 3, to give intermediate product (E)-(2-nitro-5-(2-(tetrahydrofuran-2-yl)vinyl)phenyl)(phenyl)methanone, which was then subjected to reaction and post-treatment described in Example 3 to give final product (E)-4-hydroxy-3-methoxy-4-phenyl-6-(2-(tetrahydrofuran-2-yl)vinyl)-3,4-dihydroquinolin-2(1H)-one. ESI-MS m/z 366.43 [M+H].sup.+

Example 14

(36) 2-methyldihydrofuran-3(2H)-one was used as a reagent to react with the (5-((diethoxyphosphoryl)methyl)-2-nitrophenyl) (phenyl)methanone synthesized following Example 3, to give intermediate product (Z)-(5-((2-methyldihydrofuran-3(2H)-ylidene)methyl)-2-nitrophenyl)(phenyl)methanone, which was then subjected to reaction and post-treatment described in Example 3 to give final product (Z)-4-hydroxy-3-methoxy-6-((2-methyldihydrofuran-3(2H)-ylidene)methyl)-4-phenyl-3,4-dihydroquinolin-2(1H)-one.

(37) ESI-MS m/z 366.43 [M+H].sup.+

Example 15

(38) Furan-2-carbaldehyde was used as a reagent to react with the (5-((diethoxyphosphoryl)methyl)-2-nitrophenyl) (phenyl)methanone synthesized following Example 3, to give intermediate product (E)-(5-(2-(furan-2-yl)vinyl)-2-nitrophenyl)(phenyl)methanone, which was then subjected to reaction and post-treatment described in Example 3 to give final product (E)-6-(2-(furan-2-yl)vinyl)-4-hydroxy-3-methoxy-4-phenyl-3,4-dihydroquinolin-2(1H)-one. ESI-MS m/z 362.40 [M+H].sup.+

Example 16

(39) 5-methylfuran-2-carbaldehyde was used as a reagent to react with the (5-((diethoxyphosphoryl)methyl)-2-nitrophenyl) (phenyl)methanone synthesized following Example 3, to give intermediate product (E)-(5-(2-(5-methylfuran-2-yl)vinyl)-2-nitrophenyl)(phenyl)methanone, which was then subjected to reaction and post-treatment described in Example 3 to give final product (E)-4-hydroxy-3-methoxy-6-(2-(5-methylfuran-2-yl)vinyl)-4-phenyl-3,4-dihydroquinolin-2(1H)-one. ESI-MS m/z 376.42 [M+H].sup.+

Example 17

(40) Furan-2,5-dicarbaldehyde was used as a reagent to react with the (5-((diethoxyphosphoryl)methyl)-2-nitrophenyl) (phenyl)methanone synthesized following Example 3, to give intermediate product (E)-5-(3-benzoyl-4-nitrostyryl)furan-2-carbaldehyde, which was then subjected to reaction and post-treatment described in Example 3 to give final product (E)-5-(2-(4-hydroxy-3-methoxy-2-oxo-4-phenyl-1-tetrahydroquinolin-6-yl)vinyl) furan-2-carbaldehyde. ESI-MS m/z 390.41 [M+H].sup.+

Example 18

(41) 5-formylfuran-2-carboxylic acid was used as a reagent to react with the (5-((diethoxyphosphoryl)methyl)-2-nitrophenyl) (phenyl)methanone synthesized following Example 3, to give intermediate product (E)-5-(3-benzoyl-4-nitrostyryl)furan-2-carboxylic acid, which was then subjected to reaction and post-treatment described in Example 3 to give final product (E)-5-(2-(4-hydroxy-3-methoxy-2-oxo-4-phenyl-1,2,3,4-tetrahydroquinolin-6-yl)vinyl)furan-2-carboxylic acid.

(42) ESI-MS m/z 406.41 [M+H].sup.+

Example 19

(43) 3-methylfuran-2-carbaldehyde was used as a reagent to react with the (5-((diethoxyphosphoryl)methyl)-2-nitrophenyl) (phenyl)methanone synthesized following Example 3, to give intermediate product (E)-(5-(2-(3-methylfuran-2-yl)vinyl)-2-nitrophenyl)(phenyl)methanone, which was then subjected to reaction and post-treatment described in Example 3 to give final product (E)-4-hydroxy-3-methoxy-6-(2-(3-methylfuran-2-yl)vinyl)-4-phenyl-3,4-dihydroquinolin-2(1H)-one.

(44) ESI-MS m/z 376.42 [M+H].sup.+

Example 20

(45) 5-ethylfuran-2-carbaldehyde was used as a reagent to react with the (5-((diethoxyphosphoryl)methyl)-2-nitrophenyl) (phenyl)methanone synthesized following Example 3, to give intermediate product (E)-(5-(2-(5-ethylfuran-2-yl)vinyl)-2-nitrophenyl)(phenyl)methanone, which was then subjected to reaction and post-treatment described in Example 3 to give final product (E)-6-(2-(5-ethylfuran-2-yl)vinyl)-4-hydroxy-3-methoxy-4-phenyl-3,4-dihydroquinolin-2(1H)-one.

(46) ESI-MS m/z 390.45 [M+H].sup.+

(47) 1-(5-(hydroxymethyl)furan-2-yl)ethan-1-one was used as a reagent to react with the (5-((diethoxyphosphoryl)methyl)-2-nitrophenyl) (phenyl)methanone synthesized following Example 3, to give intermediate product (E)-(5-(2-(5-(hydroxymethyl)furan-2-yl)prop-1-en-1-yl)-2-nitrophenyl)(phenyl)methanone, which was then subjected to reaction and post-treatment described in Example 3 to give final product (E)-4-hydroxy-6-(2-(5-(hydroxymethyl)furan-2-yl)prop-1-en-1-yl)-3-methoxy-4-phenyl-3,4-dihydroquinolin-2(1H)-one.

(48) ESI-MS m/z 406.45 [M+H].sup.+

Example 22

(49) (E)-3-(furan-2-yl)acrylaldehyde was used as a reagent to react with the (5-((diethoxyphosphoryl)methyl)-2-nitrophenyl) (phenyl)methanone synthesized following Example 3, to give intermediate product (5-((1E,3E)-4-(furan-2-yl)buta-1,3-dien-1-yl)-2-nitrophenyl)(phenyl)methanone, which was then subjected to reaction and post-treatment described in Example 3 to give final product 6-((1E,3E)-4-(furan-2-yl)buta-1,3-dien-1-yl)-4-hydroxy-3-methoxy-4-phenyl-3,4-dihydroquinolin-2(1H)-one.

(50) ESI-MS m/z 388.44 [M+H].sup.+

Example 23

(51) 1-(furan-2-yl)propan-1-one was used as a reagent to react with the (5-((diethoxyphosphoryl)methyl)-2-nitrophenyl) (phenyl)methanone synthesized following Example 3, to give intermediate product (E)-(5-(2-(furan-2-yl)but-1-en-1-yl)-2-nitrophenyl)(phenyl)methanone, which was then subjected to reaction and post-treatment described in Example 3 to give final product (E)-6-(2-(furan-2-yl)but-1-en-1-yl)-4-hydroxy-3-methoxy-4-phenyl-3,4-dihydroquinolin-2(1H)-one.

(52) ESI-MS m/z 390.45 [M+H].sup.+

Example 24

(53) 2,2,5,5-tetramethyldihydrofuran-3(2H)-one was used as a reagent to react with the (5-((diethoxyphosphoryl)methyl)-2-nitrophenyl) (phenyl)methanone synthesized following Example 3, to give intermediate product 2,2,5,5-tetramethyldihydrofuran-3(2H)-one, which was then subjected to reaction and post-treatment described in Example 3 to give final product (Z)-4-hydroxy-3-methoxy-4-phenyl-6-((2,2,5,5-tetramethyldihydrofuran-3(2H)-ylidene)methyl)-3,4-dihydroquinolin-2(1H)-one. ESI-MS m/z 408.51 [M+H].sup.+

Example 25

(54) 4,5-dimethylfuran-2-carbaldehyde was used as a reagent to react with the (5-((diethoxyphosphoryl)methyl)-2-nitrophenyl) (phenyl)methanone synthesized following Example 3, to give intermediate product (E)-(2-amino-5-(2-(4,5-dimethylfuran-2-yl)vinyl)phenyl)(phenyl)methanone, which was then subjected to reaction and post-treatment described in Example 3 to give final product (E)-6-(2-(4,5-dimethylfuran-2-yl)vinyl)-4-hydroxy-3-methoxy-4-phenyl-3,4-dihydroquinolin-2(1H)-one. ESI-MS m/z 390.45 [M+H].sup.+

Example 26

(55) 1-(5-(hydroxymethyl)furan-2-yl)ethan-1-one was used as a reagent to react with the (5-((diethoxyphosphoryl)methyl)-2-nitrophenyl) (phenyl)methanone synthesized following Example 3, to give intermediate product (E)-(5-(2-(5-(hydroxymethyl)furan-2-yl)prop-1-en-1-yl)-2-nitrophenyl)(phenyl)methanone, which was then subjected to reaction and post-treatment described in Example 3 to give final product (E)-4-hydroxy-6-(2-(5-(hydroxymethyl)furan-2-yl)prop-1-en-1-yl)-3-methoxy-4-phenyl-3,4-dihydroquinolin-2(1H)-one.

(56) ESI-MS m/z 406.45 [M+H].sup.+

Example 27

(57) (E)-3-(furan-2-yl)acrylaldehyde was used as a reagent to react with the (5-((diethoxyphosphoryl)methyl)-2-nitrophenyl) (phenyl)methanone synthesized following Example 3, to give intermediate product (5-((1E,3E)-4-(furan-2-yl)buta-1,3-dien-1-yl)-2-nitrophenyl)(phenyl)methanone, which was then subjected to reaction and post-treatment described in Example 3 to give final product 6-((1E,3E)-4-(furan-2-yl)buta-1,3-dien-1-yl)-4-hydroxy-3-methoxy-4-phenyl-3,4-dihydroquinolin-2(1H)-one. ESI-MS m/z 388.44 [M+H].sup.+

Example 28

(58) 1-(2,4-dimethylfuran-3-yl)ethan-1-one was used as a reagent to react with the (5-((diethoxyphosphoryl)methyl)-2-nitrophenyl) (phenyl)methanone synthesized following Example 3, to give intermediate product (E)-(5-(2-(2,4-dimethylfuran-3-yl)prop-1-en-1-yl)-2-nitrophenyl)(phenyl)methanone, which was then subjected to reaction and post-treatment described in Example 3 to give final product (E)-6-(2-(2,4-dimethylfuran-3-yl)prop-1-en-1-yl)-4-hydroxy-3-methoxy-4-phenyl-3,4-dihydroquinolin-2(1H)-one. ESI-MS m/z 404.48 [M+H].sup.+

(59) 5-chlorofuran-2-carbaldehyde was used as a reagent to react with the (5-((diethoxyphosphoryl)methyl)-2-nitrophenyl) (phenyl)methanone synthesized following Example 3, to give intermediate product (E)-(5-(2-(5-chlorofuran-2-yl)vinyl)-2-nitrophenyl)(phenyl)methanone, which was then subjected to reaction and post-treatment described in Example 3 to give final product (E)-6-(2-(5-chlorofuran-2-yl)vinyl)-4-hydroxy-3-methoxy-4-phenyl-3,4-dihydroquinolin-2(1H)-one. ESI-MS m/z 396.84 [M+H].sup.+

Example 30

(60) 1-(furan-2-yl)hexan-1-one was used as a reagent to react with the (5-((diethoxyphosphoryl)methyl)-2-nitrophenyl) (phenyl)methanone synthesized following Example 3, to give intermediate product (E)-(5-(2-(furan-2-yl)hept-1-en-1-yl)-2-nitrophenyl)(phenyl)methanone, which was then subjected to reaction and post-treatment described in Example 3 to give final product (E)-6-(2-(furan-2-yl)hept-1-en-1-yl)-4-hydroxy-3-methoxy-4-phenyl-3,4-dihydroquinolin-2(1H)-one. ESI-MS m/z 432.53 [M+H].sup.+

Example 31

(61) 1-(2,5-dimethylfuran-3-yl)ethan-1-one was used as a reagent to react with the (5-((diethoxyphosphoryl)methyl)-2-nitrophenyl) (phenyl)methanone synthesized following Example 3, to give intermediate product (E)-(5-(2-(2,5-dimethylfuran-3-yl)prop-1-en-1-yl)-2-nitrophenyl)(phenyl)methanone, which was then subjected to reaction and post-treatment described in Example 3 to give final product (E)-6-(2-(2,5-dimethylfuran-3-yl)prop-1-en-1-yl)-4-hydroxy-3-methoxy-4-phenyl-3,4-dihydroquinolin-2(1H)-one. ESI-MS m/z 404.48 [M+H].sup.+

Example 32

(62) 1-(5-(methoxymethyl)furan-2-yl)ethan-1-one was used as a reagent to react with the (5-((diethoxyphosphoryl)methyl)-2-nitrophenyl) (phenyl)methanone synthesized following Example 3, to give intermediate product (E)-(5-(2-(5-(methoxymethyl)furan-2-yl)prop-1-en-1-yl)-2-nitrophenyl)(phenyl)methanone, which was then subjected to reaction and post-treatment described in Example 3 to give final product (E)-4-hydroxy-3-methoxy-6-(2-(5-(methoxymethyl)furan-2-yl)prop-1-en-1-yl)-4-phenyl-3,4-dihydroquinolin-2(1H)-one.

(63) ESI-MS m/z 420.48 [M+H].sup.+

Example 33

(64) 2-methylfuran-3-carbaldehyde was used as a reagent to react with the (5-((diethoxyphosphoryl)methyl)-2-nitrophenyl) (phenyl)methanone synthesized following Example 3, to give intermediate product (E)-(5-(2-(2-methylfuran-3-yl)vinyl)-2-nitrophenyl)(phenyl)methanone, which was then subjected to reaction and post-treatment described in Example 3 to give final product (E)-4-hydroxy-3-methoxy-6-(2-(2-methylfuran-3-yl)vinyl)-4-phenyl-3,4-dihydroquinolin-2(1H)-one. ESI-MS m/z 376.42 [M+H].sup.+

Example 34

(65) 1-(4,5-dimethylfuran-2-yl)ethan-1-one was used as a reagent to react with the (5-((diethoxyphosphoryl)methyl)-2-nitrophenyl) (phenyl)methanone synthesized following Example 3, to give intermediate product (E)-(5-(2-(4,5-dimethylfuran-2-yl)prop-1-en-1-yl)-2-nitrophenyl)(phenyl)methanone, which was then subjected to reaction and post-treatment described in Example 3 to give final product (E)-6-(2-(4,5-dimethylfuran-2-yl)prop-1-en-1-yl)-4-hydroxy-3-methoxy-4-phenyl-3,4-dihydroquinolin-2(1H)-one. ESI-MS m/z 404.48 [M+H].sup.+

Example 35

(66) 1-(furan-2-yl)butan-1-one was used as a reagent to react with the (5-((diethoxyphosphoryl)methyl)-2-nitrophenyl) (phenyl)methanone synthesized following Example 3, to give intermediate product (E)-(5-(2-(furan-2-yl)pent-1-en-1-yl)-2-nitrophenyl)(phenyl)methanone, which was then subjected to reaction and post-treatment described in Example 3 to give final product (E)-6-(2-(furan-2-yl)pent-1-en-1-yl)-4-hydroxy-3-methoxy-4-phenyl-3,4-dihydroquinolin-2(1H)-one. ESI-MS m/z 404.48 [M+H].sup.+

Example 36

(67) 1-(furan-2-yl)pentan-1-one was used as a reagent to react with the (5-((diethoxyphosphoryl)methyl)-2-nitrophenyl) (phenyl)methanone synthesized following Example 3, to give intermediate product (E)-(5-(2-(furan-2-yl)hex-1-en-1-yl)-2-nitrophenyl)(phenyl)methanone, which was then subjected to reaction and post-treatment described in Example 3 to give final product (E)-6-(2-(furan-2-yl)hex-1-en-1-yl)-4-hydroxy-3-methoxy-4-phenyl-3,4-dihydroquinolin-2(1H)-one. ESI-MS m/z 418.51 [M+H].sup.+

Example 37

(68) 4-ethoxypent-4-enal was used as a reagent to react with the (5-((diethoxyphosphoryl)methyl)-2-nitrophenyl) (phenyl)methanone synthesized following Example 3, to give intermediate product (E)-(5-(5-ethoxyhexa-1,5-dien-1-yl)-2-nitrophenyl)(phenyl)methanone, which was then subjected to reaction and post-treatment described in Example 3 to give final product (E)-6-(5-ethoxyhexa-1,5-dien-1-yl)-4-hydroxy-3-methoxy-4-phenyl-3,4-dihydroquinolin-2(1H)-one. ESI-MS m/z 394.48 [M+H].sup.+

Example 38

(69) 1-(2,4-dimethylfuran-3-yl)ethan-1-one was used as a reagent to react with the (5-((diethoxyphosphoryl)methyl)-2-nitrophenyl) (phenyl)methanone synthesized following Example 3, to give intermediate product (E)-(5-(2-(2,4-dimethylfuran-3-yl)prop-1-en-1-yl)-2-nitrophenyl)(phenyl)methanone, which was then subjected to reaction and post-treatment described in Example 3 to give final product (E)-6-(2-(2,4-dimethylfuran-3-yl)prop-1-en-1-yl)-4-hydroxy-3-methoxy-4-phenyl-3,4-dihydroquinolin-2(1H)-one. ESI-MS m/z 404.48 [M+H].sup.+

Example 39

(70) 1-(furan-2-yl)heptan-1-one was used as a reagent to react with the (5-((diethoxyphosphoryl)methyl)-2-nitrophenyl) (phenyl)methanone synthesized following Example 3, to give intermediate product (E)-2-(1-(4-nitro-3-(1-phenylvinyl)phenyl)oct-1-en-2-yl)furan, which was then subjected to reaction and post-treatment described in Example 3 to give final product (E)-6-(2-(furan-2-yl)oct-1-en-1-yl)-4-hydroxy-3-methoxy-4-phenyl-3,4-dihydroquinolin-2(1H)-one. ESI-MS m/z 446.56 [M+H].sup.+

Example 40

(71) 1-(2,5-dimethylfuran-3-yl)ethan-1-one was used as a reagent to react with the (5-((diethoxyphosphoryl)methyl)-2-nitrophenyl) (phenyl)methanone synthesized following Example 3, to give intermediate product (E)-(5-(2-(2,5-dimethylfuran-3-yl)prop-1-yl-en-1-yl)-2-nitrophenyl)(phenyl)methanone, which was then subjected to reaction and post-treatment described in Example 3 to give final product (E)-6-(2-(2,5-dimethylfuran-3-yl)prop-1-en-1-yl)-4-hydroxy-3-methoxy-4-phenyl-3,4-dihydroquinolin-2(1H)-one. ESI-MS m/z 404.48 [M+H].sup.+

Example 41

(72) 3-(5-methylfuran-2-yl)butanal was used as a reagent to react with the (5-((diethoxyphosphoryl)methyl)-2-nitrophenyl) (phenyl)methanone synthesized following Example 3, to give intermediate product (E)-(5-(4-(5-methylfuran-2-yl)pent-1-en-1-yl)-2-nitrophenyl)(phenyl)methanone, which was then subjected to reaction and post-treatment described in Example 3 to give final product (E)-4-hydroxy-3-methoxy-6-(4-(5-methylfuran-2-yl)pent-1-en-1-yl)-4-phenyl-3,4-dihydroquinolin-2(1H)-one. ESI-MS m/z 418.51 [M+H].sup.+

Example 42

(73) S-(2-ethoxyallyl) methanethioate was used as a reagent to react with the (5-((diethoxyphosphoryl)methyl)-2-nitrophenyl) (phenyl)methanone synthesized following Example 3, to give intermediate product (E)-(5-(2-((2-ethoxyallyl)thio)vinyl)-2-nitrophenyl)(phenyl)methanone, which was then subjected to reaction and post-treatment described in Example 3 to give final product (E)-6-(2-((2-ethoxyallyl)thio)vinyl)-4-hydroxy-3-methoxy-4-phenyl-3,4-dihydroquinolin-2(1H)-one. ESI-MS m/z 412.52 [M+H].sup.+

Example 43

(74) 5-bromofuran-2-carbaldehyde was used as a reagent to react with the (5-((diethoxyphosphoryl)methyl)-2-nitrophenyl) (phenyl)methanone synthesized following Example 3, to give intermediate product (E)-(5-(2-(5-bromofuran-2-yl)vinyl)-2-nitrophenyl)(phenyl)methanone, which was then subjected to reaction and post-treatment described in Example 3 to give final product (E)-6-(2-(5-bromofuran-2-yl)vinyl)-4-hydroxy-3-methoxy-4-phenyl-3,4-dihydroquinolin-2(1H)-one. ESI-MS m/z 441.29 [M+H].sup.+

Example 44

(75) 5-(trifluoromethyl)furan-2-carbaldehyde was used as a reagent to react with the (5-((diethoxyphosphoryl)methyl)-2-nitrophenyl) (phenyl)methanone synthesized following Example 3, to give intermediate product (E)-(2-nitro-5-(2-(5-(trifluoromethyl)furan-2-yl)vinyl)phenyl)(phenyl)methanone, which was then subjected to reaction and post-treatment described in Example 3 to give final product (E)-4-hydroxy-3-methoxy-4-phenyl-6-(2-(5-(trifluoromethyl)furan-2-yl)vinyl)-3,4-dihydroquinolin-2(1H)-one. ESI-MS m/z 430.40 [M+H].sup.+

Example 45

(76) 4-bromofuran-2-carbaldehyde was used as a reagent to react with the (5-((diethoxyphosphoryl)methyl)-2-nitrophenyl) (phenyl)methanone synthesized following Example 3, to give intermediate product (E)-(5-(2-(4-bromofuran-2-yl)vinyl)-2-nitrophenyl)(phenyl)methanone, which was then subjected to reaction and post-treatment described in Example 3 to give final product (E)-6-(2-(4-bromofuran-2-yl)vinyl)-4-hydroxy-3-methoxy-4-phenyl-3,4-dihydroquinolin-2(1H)-one. ESI-MS m/z 441.29 [M+H].sup.+

Example 46

(77) Pyrrolidine-2-carbaldehyde was used as a reagent to react with the (5-((diethoxyphosphoryl)methyl)-2-nitrophenyl) (phenyl)methanone synthesized following Example 3, to give intermediate product (E)-(2-nitro-5-(2-(pyrrolidin-2-yl)vinyl)phenyl)(phenyl)methanone, which was then subjected to reaction and post-treatment described in Example 3 to give final product (E)-4-hydroxy-3-methoxy-4-phenyl-6-(2-(pyrrolidin-2-yl)vinyl)-3,4-dihydroquinolin-2(1H)-one. ESI-MS m/z 365.45 [M+H].sup.+

Example 47

(78) 2-methylpyrrolidine-2-carbaldehyde was used as a reagent to react with the (5-((diethoxyphosphoryl)methyl)-2-nitrophenyl) (phenyl)methanone synthesized following Example 3, to give intermediate product (E)-(5-(2-(2-methylpyrrolidin-2-yl)vinyl)-2-nitrophenyl)(phenyl)methanone, which was then subjected to reaction and post-treatment described in Example 3 to give final product (E)-4-hydroxy-3-methoxy-6-(2-(2-methylpyrrolidin-2-yl)vinyl)-4-phenyl-3,4-dihydroquinolin-2(1H)-one. ESI-MS m/z 379.47 [M+H].sup.+

Example 48

(79) 1-methylpyrrolidine-2-carbaldehyde was used as a reagent to react with the (5-((diethoxyphosphoryl)methyl)-2-nitrophenyl) (phenyl)methanone synthesized following Example 3, to give intermediate product (E)-(5-(2-(1-methylpyrrolidin-2-yl)vinyl)-2-nitrophenyl)(phenyl)methanone, which was then subjected to reaction and post-treatment described in Example 3 to give final product (E)-4-hydroxy-3-methoxy-6-(2-(1-methylpyrrolidin-2-yl)vinyl)-4-phenyl-3,4-dihydroquinolin-2(1H)-one. ESI-MS m/z 379.47 [M+H].sup.+

Example 49

(80) Hexahydro-1H-pyrrolizin-1-one was used as a reagent to react with the (5-((diethoxyphosphoryl)methyl)-2-nitrophenyl) (phenyl)methanone synthesized following Example 3, to give intermediate product (E)-(5-((hexahydro-1H-pyrrolizin-1-ylidene)methyl)-2-nitrophenyl)(phenyl)methanone, which was then subjected to reaction and post-treatment described in Example 3 to give final product (E)-6-((hexahydro-1H-pyrrolizin-1-ylidene)methyl)-4-hydroxy-3-methoxy-4-phenyl-3,4-dihydroquinolin-2(1H)-one.

(81) ESI-MS m/z391.48 [M+H].sup.+

Example 50

(82) 1-(cyclopropylmethyl)pyrrolidine-2-carbaldehyde was used as a reagent to react with the (5-((diethoxyphosphoryl)methyl)-2-nitrophenyl) (phenyl)methanone synthesized following Example 3, to give intermediate product (E)-(5-(2-(1-(cyclopropylmethyl)pyrrolidin-2-yl)vinyl)-2-nitrophenyl)(phenyl)methanone, which was then subjected to reaction and post-treatment described in Example 3 to give final product (E)-6-(2-(1-(cyclopropylmethyl)pyrrolidin-2-yl)vinyl)-4-hydroxy-3-methoxy-4-phenyl-3,4-dihydroquinolin-2(1H)-one.

(83) ESI-MS m/z 419.54 [M+H].sup.+

Example 51

(84) Octahydroindolizine-8-carbaldehyde was used as a reagent to react with the (5-((diethoxyphosphoryl)methyl)-2-nitrophenyl) (phenyl)methanone synthesized following Example 3, to give intermediate product (E)-(2-nitro-5-(2-(octahydroindolizin-8-yl)vinyl)phenyl)(phenyl)methanone, which was then subjected to reaction and post-treatment described in Example 3 to give final product (E)-4-hydroxy-3-methoxy-6-(2-(octahydroindolizin-8-yl)vinyl)-4-phenyl-3,4-dihydroquinolin-2(1H)-one. ESI-MS m/z 419.54 [M+H].sup.+

Example 52

(85) 2,2-dimethyl-3-(pyrrolidin-1-yl)propanal was used as a reagent to react with the (5-((diethoxyphosphoryl)methyl)-2-nitrophenyl) (phenyl)methanone synthesized following Example 3, to give intermediate product (E)-(5-(3,3-dimethyl-4-(pyrrolidin-1-yl)but-1-en-1-yl)-2-nitrophenyl)(phenyl)methanone, which was then subjected to reaction and post-treatment described in Example 3 to give final product (E)-6-(3,3-dimethyl-4-(pyrrolidin-1-yl)but-1-en-1-yl)-4-hydroxy-3-methoxy-4-phenyl-3,4-dihydroquinolin-2(H)-one.

(86) ESI-MS m/z 421.55 [M+H].sup.+

Example 53

(87) Piperidine-2-carbaldehyde was used as a reagent to react with the (5-((diethoxyphosphoryl)methyl)-2-nitrophenyl) (phenyl)methanone synthesized following Example 3, to give intermediate product (E)-(2-nitro-5-(2-(piperidin-2-yl)vinyl)phenyl)(phenyl)methanone, which was then subjected to reaction and post-treatment described in Example 3 to give final product (E)-4-hydroxy-3-methoxy-4-phenyl-6-(2-(piperidin-2-yl)vinyl)-3,4-dihydroquinolin-2(1H)-one. ESI-MS m/z 379.47 [M+H].sup.+

Example 53

(88) ##STR00780##

Step 1) 2-benzoyl-6-methyl-3-nitrophenyl acetate

(89) To a solution of (2-hydroxy-3-methyl-6-nitrophenyl)(phenyl)methanone (3.08 g, 12 mmol) and acetic anhydride (15 mL) in dichloromethane (30 mL) at 0° C. was added concentrated sulfuric acid (0.5 mL, 98%). After being stirred for 3 hours at 0° C., the completion of the reaction, the reaction mixture was diluted with water and extracted with dichloromethane. The organic phase was concentrated under reduced pressure. The residue was purified by silica gel column chromatography. The compound was obtained as a yellow oil.

Step 2) 2-Benzoyl-6-(bromomethyl)-3-nitrophenylacetate

(90) To a solution of 2-benzoyl-6-methyl-3-nitrophenyl acetate (2.41 g) in carbon tetrachloride (100 mL) under nitrogen was added, NBS (2.32 g) and AIBN (90 mg). And the mixture was stirred at 80° C. for 24 hours. After the completion of the reaction, the reaction mixture was diluted with water and extracted with dichloromethane. The organic phase was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=8/1) The compound was obtained as pale yellow oil.

Step 3) 2-Benzoyl-6-((diethoxyphosphoryl)methyl)-3-nitrophenylacetate

(91) Under nitrogen, dissolve 2-Benzoyl-6-(bromomethyl)-3-nitrophenylacetate in 1,4-dioxane (100 mL), add triethyl phosphite at room temperature (10 eq). The resulting mixture was heated to 125° C. and allowed to stir for 12 hours. After the completion of the reaction, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic phase was concentrated under reduced pressure. The residue was purified by silica gel column chromatography. The compound was obtained as a yellow oil.

Step 4) (3-Benzoyl-2-hydroxy-4-nitrobenzyl)phosphonic acid diethyl ester

(92) To a solution of 2-Benzoyl-6-((diethoxyphosphoryl)methyl)-3-nitrophenylacetate (1.32 g) in MeOH at room temperature was added Potassium carbonate (0.63, 4.6 mmol). The reaction mixture was stirred at room temperature for 10 mins. The reaction solution was washed with water and extracted with ethyl acetate. The compound was obtained as a yellow oil.

Step 5) (3-Benzoyl-2-(methoxymethoxy)-4-nitrobenzyl)phosphonic acid diethyl ester

(93) To a solution of (3-Benzoyl-2-hydroxy-4-nitrobenzyl)phosphonic acid diethyl ester (1.61 g, 4.1 mmol) and diisopropylethylamine (1.06 g, 8.2 mmol) in dichloromethane (30 mL) at 0° C. was added MOMCl (0.50 g, 6.2 mmol).

(94) After being stirred for 12 hours at 0° C., the completion of the reaction, the reaction mixture was diluted with water and extracted with dichloromethane. The organic phase was concentrated under reduced pressure. The residue was purified by silica gel column chromatography. The compound was obtained as a yellow oil.

Step 6) (E)-(3-(2-(furan-2-yl)vinyl)-2-(methoxymethoxy)-6 nitrophenyl) (phenyl)methanone

(95) To a solution of (3-Benzoyl-2-(methoxymethoxy)-4-nitrobenzyl)phosphonic acid diethyl ester (0.437 g, 1.0 mmol) in THF at 0° C. was added NaH (1.2 eq). After being stirred for 30 minutes at 0° C., the reaction mixture was added furan-2-carbaldehyde (1.5 eq) and allowed to stir for 2 hours. After the completion of the reaction, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic phase was concentrated under reduced pressure. The residue was purified by silica gel column chromatography. The compound was obtained as a yellow oil.

Step 7) (E)-(6-Amino-3-(2-(furan-2-yl)vinyl)-2-(methoxymethoxy)phenyl)(phenyl) methanone

(96) To a solution of (E)-(3-(2-(furan-2-yl)vinyl)-2-(methoxymethoxy)-6 nitrophenyl) (phenyl) methanone (0.219 g, 0.5 mmol) in ethanol (10 mL) and water (5 mL) at room temperature was added Fe (6 eq) and ammonium chloride (6 eq) and heated to 90° C., then allowed to stir for 4 hours. The reaction solution was washed with water and extracted with ethyl acetate. The residue was purified by silica gel column chromatography, The compound was obtained as a yellow oil.

Step 8) (E)-N-(2-benzoyl-4-(2-(furan-2-yl)vinyl)-3-(methoxymethoxy)phenyl)-2-methoxyacetamide

(97) To a solution of (E)-(6-Amino-3-(2-(furan-2-yl)vinyl)-2-(methoxymethoxy)phenyl) (phenyl) methanone (0.203 g, 0.50) in dichloromethane at 0° C. was added DIPEA (1.2 eq). After being stirred for 30 minutes at 0° C., the reaction mixture was added 2-methoxyacetyl chloride (1.2 eq) and allowed to stir for 2 hours. After the completion of the reaction, the reaction mixture was diluted with water and extracted with dichloromethane. The organic phase was concentrated under reduced pressure. The residue was purified by silica gel column chromatography. The compound was obtained as a yellow oil.

Step 9) (E)-6-(2-(Furan-2-yl)vinyl)-4-hydroxy-3-methoxy-5-(methoxymethoxy)-4-phenyl-3,4-dihydroquinoline-2(1H)-one

(98) To a solution of (E)-N-(2-benzoyl-4-(2-(furan-2-yl)vinyl)(methoxymethoxy)phenyl)-2-methoxyacetamide (0.15 g, 0.314 mmol) in THF (10 mL) at room temperature was added potassium t-butoxide (10 eq). After being stirred for 1 hour, the reaction mixture was quenched by addition of water. and extracted with ethyl acetate. The organic phase was concentrated under reduced pressure. The residue was purified by silica gel column chromatography. The compound was obtained as a white solid.

Step 10) (E)-6-(2-(Furan-2-yl)vinyl)-4,5-dihydroxy-3-methoxy-4-phenyl-3,4-dihydroquinoline-2(1H)-one

(99) To a solution of (E)-6-(2-(Furan-2-yl)vinyl)-4-hydroxy-3-methoxy-5-(methoxymethoxy)-4-phenyl-3,4-dihydroquinoline-2(1H)-one (0.11 g, 0.23 mmol) in THF at room temperature was added concentrated hydrochloric acid (0.5 mL, 36%). The reaction mixture was stirred at room temperature for 0.5 h. The reaction solution was washed with water and extracted with ethyl acetate. The compound was obtained as a white solid. ESIMS m/z 382.32.

Example 54

(100) Bicyclo[2.2.1]hept-5-ene-2-carbaldehyde was used as a reagent to react with the (3-Benzoyl-2-(methoxymethoxy)-4-nitrobenzyl)phosphonic acid diethyl ester synthesized following Example 53, to give intermediate product (E)-(3-(2-(bicyclo[2.2.1]hept-5-en-2-yl)vinyl)-2-(methoxymethoxy)-6-nitrophenyl) (phenyl)methanone, which was then subjected to reaction and post-treatment described in example 53 to give final product (E)-6-(2-(bicyclo[2.2.1]hept-5-en-2-yl)vinyl)-4,5-dihydroxy-3-methoxy-4-phenyl-3,4-dihydroquinolin-2(1H)-one. ESI-MS m/z 404.52 [M+H].sup.+.

Example 55

(101) 5-phenylfuran-2-carbaldehyde was used as a reagent to react with the (3-Benzoyl-2-(methoxymethoxy)-4-nitrobenzyl)phosphonic acid diethyl ester synthesized following Example 53, to give intermediate product (E)-(2-(methoxymethoxy)-6-nitro-3-(2-(5-phenylfuran-2-yl)vinyl)phenyl)(phenyl)methanone, which was then subjected to reaction and post-treatment described in example 53 to give final product (E)-4,5-dihydroxy-3-methoxy-4-phenyl-6-(2-(5-phenylfuran-2-yl)vinyl)-3,4-dihydroquinolin-2(1H)-one. ESI-MS m/z 454.50 [M+H].sup.+.

Example 56

(102) Cyclopentanecarbaldehyde was used as a reagent to react with the (3-Benzoyl-2-(methoxymethoxy)-4-nitrobenzyl)phosphonic acid diethyl ester synthesized following Example 53, to give intermediate product (E)-(3-(2-cyclopentylvinyl)-2-(methoxymethoxy)-6-nitrophenyl)(phenyl)methanone, which was then subjected to reaction and post-treatment described in example 53 to give final product (E)-6-(2-cyclopentylvinyl)-4,5-dihydroxy-3-methoxy-4-phenyl-3,4-dihydroquinolin-2(1H)-one. ESI-MS m/z 380.46 [M+H].sup.+.

Example 57

(103) Cyclopentanone was used as a reagent to react with the (3-Benzoyl-2-(methoxymethoxy)-4-nitrobenzyl)phosphonic acid diethyl ester synthesized following Example 53, to give intermediate product (3-(cyclopentylidenemethyl)-2-(methoxymethoxy)-6-nitrophenyl)(phenyl)methanone, which was then subjected to reaction and post-treatment described in example 53 to give final product 6-(cyclopentylidenemethyl)-4,5-dihydroxy-3-methoxy-4-phenyl-3,4-dihydroquinolin-2(1H)-one. ESI-MS m/z 366.43 [M+H].sup.+.

Example 58

(104) 3-methylcyclopentan-1-one was used as a reagent to react with the (3-Benzoyl-2-(methoxymethoxy)-4-nitrobenzyl)phosphonic acid diethyl ester synthesized following Example 53, to give intermediate product (E)-(2-(methoxymethoxy)-3-((3-methylcyclopentylidene)methyl)-6-nitrophenyl)(phenyl)methanone, which was then subjected to reaction and post-treatment described in example 53 to give final product (E)-4,5-dihydroxy-3-methoxy-6-((3-methylcyclopentylidene)methyl)-4-phenyl-3,4-dihydroquinolin-2(1H)-one. ESI-MS m/z 380.46 [M+H].sup.+.

Example 59

(105) 1-cyclopentylpropan-1-one was used as a reagent to react with the (3-Benzoyl-2-(methoxymethoxy)-4-nitrobenzyl)phosphonic acid diethyl ester synthesized following Example 53, to give intermediate product (E)-(3-(2-cyclopentylbut-1-en-1-yl)-2-(methoxymethoxy)-6-nitrophenyl)(phenyl)methanone, which was then subjected to reaction and post-treatment described in example 53 to give final product (E)-6-(2-cyclopentylbut-1-en-1-yl)-4,5-dihydroxy-3-methoxy-4-phenyl-3,4-dihydroquinolin-2(1H)-one. ESI-MS m/z 408.51 [M+H].sup.+.

Example 60

(106) 1-cyclopentylpropan-2-one was used as a reagent to react with the (3-Benzoyl-2-(methoxymethoxy)-4-nitrobenzyl)phosphonic acid diethyl ester synthesized following Example 53, to give intermediate product (E)-(3-(3-cyclopentyl-2-methylprop-1-en-1-yl)-2-(methoxymethoxy)-6-nitrophenyl)(phenyl)methanone, which was then subjected to reaction and post-treatment described in example 53 to give final product (E)-6-(3-cyclopentyl-2-methylprop-1-en-1-yl)-4,5-dihydroxy-3-methoxy-4-phenyl-3,4-dihydroquinolin-2(1H)-one. ESI-MS m/z 408.51 [M+H].sup.+.

Example 61

(107) 5-methylhexan-3-one was used as a reagent to react with the (3-Benzoyl-2-(methoxymethoxy)-4-nitrobenzyl)phosphonic acid diethyl ester synthesized following Example 53, to give intermediate product (Z)-(3-(2-ethyl-4-methylpent-1-en-1-yl)-2-(methoxymethoxy)-6-nitrophenyl)(phenyl)methanone, which was then subjected to reaction and post-treatment described in example 53 to give final product (Z)-6-(2-ethyl-4-methylpent-1-en-1-yl)-4,5-dihydroxy-3-methoxy-4-phenyl-3,4-dihydroquinolin-2(1H)-one. ESI-MS m/z 396.50 [M+H].sup.+.

Example 62

(108) 2,2,4-trimethylcyclopentan-1-one was used as a reagent to react with the (3-Benzoyl-2-(methoxymethoxy)-4-nitrobenzyl)phosphonic acid diethyl ester synthesized following Example 53, to give intermediate product (E)-(2-(methoxymethoxy)-6-nitro-3-((2,2,4-trimethylcyclopentylidene)methyl)phenyl)(phenyl)methanone, which was then subjected to reaction and post-treatment described in example 53 to give final product (E)-4,5-dihydroxy-3-methoxy-4-phenyl-6-((2,2,4-trimethylcyclopentylidene)methyl)-3,4-dihydroquinolin-2(1H)-one.

(109) ESI-MS m/z 408.51 [M+H].sup.+.

Example 63

(110) Tetrahydrofuran-2-carbaldehyde was used as a reagent to react with the (3-Benzoyl-2-(methoxymethoxy)-4-nitrobenzyl)phosphonic acid diethyl ester synthesized following Example 53, to give intermediate product (E)-(3-(3-methoxybut-1-en-1-yl)-2-(methoxymethoxy)-6-nitrophenyl)(phenyl)methanone, which was then subjected to reaction and post-treatment described in example 53 to give final product (E)-4,5-dihydroxy-3-methoxy-4-phenyl-6-(2-(tetrahydrofuran-2-yl)vinyl)-3,4-dihydroquinolin-2(1H)-one. ESI-MS m/z 382.43 [M+H].sup.+.

Example 64

(111) 2-methyldihydrofuran-3(2H)-one was used as a reagent to react with the (3-Benzoyl-2-(methoxymethoxy)-4-nitrobenzyl)phosphonic acid diethyl ester synthesized following Example 53, to give intermediate product (Z)-(2-(methoxymethoxy)-3-((2-methyldihydrofuran-3 (2H)-ylidene)methyl)-6-nitrophenyl)(phenyl)methanone, which was then subjected to reaction and post-treatment described in example 53 to give final product (Z)-4,5-dihydroxy-3-methoxy-6-((2-methyldihydrofuran-3(2H)-ylidene)methyl)-4-phenyl-3,4-dihydroquinolin-2(1H)-one.

(112) ESI-MS m/z 382.43 [M+H].sup.+.

Example 65

(113) Furan-2-carbaldehyde was used as a reagent to react with the (3-Benzoyl-2-(methoxymethoxy)-4-nitrobenzyl)phosphonic acid diethyl ester synthesized following Example 53, to give intermediate product (E)-(3-(2-(furan-2-yl)vinyl)-2-(methoxymethoxy)-6-nitrophenyl)(phenyl)methanone), which was then subjected to reaction and post-treatment described in example 53 to give final product (E)-6-(2-(furan-2-yl)vinyl)-4,5-dihydroxy-3-methoxy-4-phenyl-3,4-dihydroquinolin-2(1H)-one. ESI-MS m/z 378.40 [M+H].sup.+.

Example 66

(114) 5-methylfuran-2-carbaldehyde was used as a reagent to react with the (3-Benzoyl-2-(methoxymethoxy)-4-nitrobenzyl)phosphonic acid diethyl ester synthesized following Example 53, to give intermediate product (E)-(2-(methoxymethoxy)-3-(2-(5-methylfuran-2-yl) vinyl)-6-nitrophenyl)(phenyl)methanone, which was then subjected to reaction and post-treatment described in example 53 to give final product (E)-4,5-dihydroxy-3-methoxy-6-(2-(5-methylfuran-2-yl) vinyl)-4-phenyl-3,4-dihydroquinolin-2(1H)-one. ESI-MS m/z 392.42 [M+H].sup.+.

Example 67

(115) Furan-2,5-dicarbaldehyde was used as a reagent to react with the (3-Benzoyl-2-(methoxymethoxy)-4-nitrobenzyl)phosphonic acid diethyl ester synthesized following Example 53, to give intermediate product (E)-5-(3-benzoyl-2-(methoxymethoxy)-4-nitrostyryl) furan-2-carbaldehyde, which was then subjected to reaction and post-treatment described in example 53 to give final product (E)-5-(2-(4,5-dihydroxy-3-methoxy-2-oxo-4-phenyl-1,2,3,4-tetrahydroquinolin-6-yl) vinyl) furan-2-carbaldehyde. ESI-MS m/z 406.41 [M+H].sup.+.

Example 68

(116) 5-formylfuran-2-carboxylic acid was used as a reagent to react with the (3-Benzoyl-2-(methoxymethoxy)-4-nitrobenzyl)phosphonic acid diethyl ester synthesized following Example 53, to give intermediate product (E)-5-(3-benzoyl-2-(methoxymethoxy)-4-nitrostyryl) furan-2-carboxylic acid, which was then subjected to reaction and post-treatment described in example 53 to give final product (E)-5-(2-(4,5-dihydroxy-3-methoxy-2-oxo-4-phenyl-1,2,3,4-tetrahydroquinolin-6-yl)vinyl)furan-2-carboxylic acid. ESI-MS m/z 422.41 [M+H].sup.+.

Example 69

(117) 3-methylfuran-2-carbaldehyde was used as a reagent to react with the (3-Benzoyl-2-(methoxymethoxy)-4-nitrobenzyl)phosphonic acid diethyl ester synthesized following Example 53, to give intermediate product (E)-(2-(methoxymethoxy)-3-(2-(3-methylfuran-2-yl) vinyl)-6-nitrophenyl)(phenyl)methanone, which was then subjected to reaction and post-treatment described in example 53 to give final product (E)-4,5-dihydroxy-3-methoxy-6-(2-(3-methylfuran-2-yl) vinyl)-4-phenyl-3,4-dihydroquinolin-2(1H)-one. ESI-MS m/z 392.42 [M+H].sup.+.

Example 70

(118) 5-ethylfuran-2-carbaldehyde was used as a reagent to react with the (3-Benzoyl-2-(methoxymethoxy)-4-nitrobenzyl)phosphonic acid diethyl ester synthesized following Example 53, to give intermediate product (E)-(3-(2-(5-ethylfuran-2-yl)vinyl)-2-(methoxymethoxy)-6-nitrophenyl)(phenyl)methanone, which was then subjected to reaction and post-treatment described in example 53 to give final product (E)-6-(2-(5-ethylfuran-2-yl)vinyl)-4,5-dihydroxy-3-methoxy-4-phenyl-3,4-dihydroquinolin-2(1H)-one. ESI-MS m/z 406.45 [M+H].sup.+.

Example 71

(119) 1-(5-(hydroxymethyl)furan-2-yl)ethan-1-one was used as a reagent to react with the (3-Benzoyl-2-(methoxymethoxy)-4-nitrobenzyl)phosphonic acid diethyl ester synthesized following Example 53, to give intermediate product (E)-(3-(2-(5-(hydroxymethyl)furan-2-yl) prop-1-en-1-yl)-2-(methoxymethoxy)-6-nitrophenyl)(phenyl)methanone, which was then subjected to reaction and post-treatment described in example 53 to give final product (E)-4,5-dihydroxy-6-(2-(5-(hydroxymethyl)furan-2-yl)prop-1-en-1-yl)-3-methoxy-4-phenyl-3,4-dihydroquinolin-2(1H)-one.

(120) ESI-MS m/z 422.45 [M+H].sup.+.

Example 72

(121) (E)-3-(furan-2-yl)acrylaldehyde was used as a reagent to react with the (3-Benzoyl-2-(methoxymethoxy)-4-nitrobenzyl)phosphonic acid diethyl ester synthesized following Example 53, to give intermediate product (3-((1E,3E)-4-(furan-2-yl)buta-1,3-dien-1-yl)-2-(methoxymethoxy)-6-nitrophenyl)(phenyl)methanone, which was then subjected to reaction and post-treatment described in example 53 to give final product 6-((1E,3E)-4-(furan-2-yl) buta-,3-dien-1-yl)-4,5-dihydroxy-3-methoxy-4-phenyl-3,4-dihydroquinolin-2(1H)-one. ESI-MS m/z 404.44 [M+H].sup.+.

Example 73

(122) 1-(furan-2-yl)propan-1-one was used as a reagent to react with the (3-Benzoyl-2-(methoxymethoxy)-4-nitrobenzyl)phosphonic acid diethyl ester synthesized following Example 53, to give intermediate product (E)-(3-(2-(furan-2-yl)but-1-en-1-yl)-2-(methoxymethoxy)-6-nitrophenyl)(phenyl)methanone, which was then subjected to reaction and post-treatment described in example 53 to give final product (E)-6-(2-(furan-2-yl)but-1-en-1-yl)-4,5-dihydroxy-3-methoxy-4-phenyl-3,4-dihydroquinolin-2(1H)-one. ESI-MS m/z 406.45 [M+H].sup.+.

Example 74

(123) 2,2,5,5-tetramethyldihydrofuran-3(2H)-one was used as a reagent to react with the (3-Benzoyl-2-(methoxymethoxy)-4-nitrobenzyl)phosphonic acid diethyl ester synthesized following Example 53, to give intermediate product (Z)-(2-(methoxymethoxy)-6-nitro-3-((2,2,5,5-tetramethyldihydrofuran-3(2H)-ylidene)methyl)phenyl)(phenyl)methanone, which was then subjected to reaction and post-treatment described in example 53 to give final product (Z)-4,5-dihydroxy-3-methoxy-4-phenyl-6-((2,2,5,5-tetramethyldihydrofuran-3(2H)-ylidene)methyl)-3,4-dihydroquinolin-2(1H)-one. ESI-MS m/z 424.51 [M+H].sup.+.

Example 75

(124) 4,5-dimethylfuran-2-carbaldehyde was used as a reagent to react with the (3-Benzoyl-2-(methoxymethoxy)-4-nitrobenzyl)phosphonic acid diethyl ester synthesized following Example 53, to give intermediate product (E)-(6-amino-3-(2-(4,5-dimethylfuran-2-yl) vinyl)-2-(methoxymethoxy)phenyl)(phenyl)methanone, which was then subjected to reaction and post-treatment described in example 53 to give final product (E)-6-(2-(4,5-dimethylfuran-2-yl) vinyl)-4,5-dihydroxy-3-methoxy-4-phenyl-3,4-dihydroquinolin-2(1H)-one. ESI-MS m/z 406.45 [M+H].sup.+.

Example 76

(125) 1-(5-(hydroxymethyl)furan-2-yl)ethan-1-one was used as a reagent to react with the (3-Benzoyl-2-(methoxymethoxy)-4-nitrobenzyl)phosphonic acid diethyl ester synthesized following Example 53, to give intermediate product (E)-(3-(2-(5-(hydroxymethyl)furan-2-yl) prop-1-en-1-yl)-2-(methoxymethoxy)-6-nitrophenyl)(phenyl)methanone, which was then subjected to reaction and post-treatment described in example 53 to give final product (E)-4,5-dihydroxy-6-(2-(5-(hydroxymethyl)furan-2-yl)prop-1-en-1-yl)-3-methoxy-4-phenyl-3,4-dihydroquinolin-2(1H)-one.

(126) ESI-MS m/z 422.45 [M+H].sup.+.

Example 77

(127) (E)-3-(furan-2-yl)acrylaldehyde was used as a reagent to react with the (3-Benzoyl-2-(methoxymethoxy)-4-nitrobenzyl)phosphonic acid diethyl ester synthesized following Example 53, to give intermediate product (3-((1E,3E)-4-(furan-2-yl)buta-1,3-dien-1-yl)-2-(methoxymethoxy)-6-nitrophenyl)(phenyl)methanone, which was then subjected to reaction and post-treatment described in example 53 to give final product 6-((1E,3E)-4-(furan-2-yl)buta-1,3-dien-1-yl)-4,5-dihydroxy-3-methoxy-4-phenyl-3,4-dihydroquinolin-2(1H)-one. ESI-MS m/z 404.44 [M+H].sup.+.

Example 78

(128) 1-(2,4-dimethylfuran-3-yl)ethan-1-one was used as a reagent to react with the (3-Benzoyl-2-(methoxymethoxy)-4-nitrobenzyl)phosphonic acid diethyl ester synthesized following Example 53, to give intermediate product (E)-(3-(2-(2,4-dimethylfuran-3-yl) prop-1-en-1-yl)-2-(methoxymethoxy)-6-nitrophenyl)(phenyl)methanone, which was then subjected to reaction and post-treatment described in example 53 to give final product (E)-6-(2-(2,4-dimethylfuran-3-yl)prop-1-en-1-yl)-4,5-hydroxy-3-methoxy-4-phenyl-3,4-dihydroquinolin-2(1H)-one. ESI-MS m/z 420.48 [M+H].sup.+.

Example 79

(129) 5-chlorofuran-2-carbaldehyde was used as a reagent to react with the (3-Benzoyl-2-(methoxymethoxy)-4-nitrobenzyl)phosphonic acid diethyl ester synthesized following Example 53, to give intermediate product (E)-(3-(2-(5-chlorofuran-2-yl)vinyl)-2-(methoxymethoxy)-6-nitrophenyl)(phenyl)methanone, which was then subjected to reaction and post-treatment described in example 53 to give final product (E)-6-(2-(5-chlorofuran-2-yl)vinyl)-4,5di-hydroxy-3-methoxy-4-phenyl-3,4-dihydroquinolin-2(1H)-one. ESI-MS m/z 412.84 [M+H].sup.+.

Example 80

(130) 1-(furan-2-yl)hexan-1-one was used as a reagent to react with the (3-Benzoyl-2-(methoxymethoxy)-4-nitrobenzyl)phosphonic acid diethyl ester synthesized following Example 53, to give intermediate product (E)-(3-(2-(furan-2-yl)hept-1-en-1-yl)-2-(methoxymethoxy)-6-nitrophenyl) (phenyl)methanone, which was then subjected to reaction and post-treatment described in example 53 to give final product (E)-6-(2-(furan-2-yl)hept-1-en-1-yl)-4,5-dihydroxy-3-methoxy-4-phenyl-3,4-dihydroquinolin-2(1H)-one. ESI-MS m/z 448.53 [M+H].sup.+.

Example 81

(131) 1-(2,5-dimethylfuran-3-yl)ethan-1-one was used as a reagent to react with the (3-Benzoyl-2-(methoxymethoxy)-4-nitrobenzyl)phosphonic acid diethyl ester synthesized following Example 53, to give intermediate product (E)-(3-(2-(2,5-dimethylfuran-3-yl)prop-1-en-1-yl)-2-(methoxymethoxy)-6-nitrophenyl) (phenyl)methanone, which was then subjected to reaction and post-treatment described in example 53 to give final product (E)-6-(2-(2,5-dimethylfuran-3-yl) prop-1-en-1-yl)-4,5-dihydroxy-3-methoxy-4-phenyl-3,4-dihydroquinolin-2(1H)-one.

(132) ESI-MS m/z 420.48 [M+H].sup.+.

Example 82

(133) 1-(5-(methoxymethyl)furan-2-yl)ethan-1-one was used as a reagent to react with the (3-Benzoyl-2-(methoxymethoxy)-4-nitrobenzyl)phosphonic acid diethyl ester synthesized following Example 53, to give intermediate product (E)-(2-(methoxymethoxy)-3-(2-(5-(methoxymethyl) furan-2-yl) prop-1-en-1-yl)-6-nitrophenyl)(phenyl)methanone, which was then subjected to reaction and post-treatment described in example 53 to give final product (E)-4,5-dihydroxy-3-methoxy-6-(2-(5-(methoxymethyl)furan-2-yl)prop-1-en-1-yl)-4-phenyl-3,4-dihydroquinolin-2(1H)-one. ESI-MS m/z 436.48 [M+H].sup.+.

Example 83

(134) 2-methylfuran-3-carbaldehyde was used as a reagent to react with the (3-Benzoyl-2-(methoxymethoxy)-4-nitrobenzyl)phosphonic acid diethyl ester synthesized following Example 53, to give intermediate product (E)-(2-(methoxymethoxy)-3-(2-(2-methylfuran-3-yl) vinyl)-6-nitrophenyl)(phenyl)methanone, which was then subjected to reaction and post-treatment described in example 53 to give final product (E)-4,5-dihydroxy-3-methoxy-6-(2-(2-methylfuran-3-yl)vinyl)-4-phenyl-3,4-dihydroquinolin-2(1H)-one. ESI-MS m/z 392.42 [M+H].sup.+.

(135) Antiviral Activity Assay

(136) The compound was tested for antiviral activity based on cytopathic effects, with ribavirin as a positive control. The specific experimental scheme is as follows.

(137) Virus Proliferation

(138) The test virus was inoculated on the sensitive cells of the virus, and the cells were placed in a serum-free 1640 medium. The cells were then cultured at the temperature of 5% carbon dioxide and 37° C. until 90% of the cells were infected with the virus. After lesion, the cells were quantitatively divided and stored in the −80° C. refrigerator for later use.

(139) Virus Infectivity Titre

(140) Cell maintenance solution was used to conduct a series of gradient dilution of proliferating virus at 10 times the ratio. The virus was inoculated on hep-2 in 96-well plates and repeated vertically for 3 times as a control test. The cells were then cultured at a temperature of 37° C. with 5% carbon dioxide. After two to three days, the cell support fluid in the pore plate were absorbed and discarded, and 100 μL of 1% neutral red was added to the pore plate again. The staining solution was stained for 2 hours at 37° C., then the staining solution was absorbed and discarded, and the eluent was bleached at 37° C. for 10 minutes. OD value of the tested plate was measured with an enzyme reader at a wavelength of about 540 nm, and the lesion rate and cell specific distance were calculated by specific formula. The dilution index of the lesion rate with the cell specific distance higher than 50% was added together, and the TCID.sub.50 value of the virus was calculated by Reed-Muench method as 10.sup.−5.5/mL.
Cell survival rate=(OD value of each group−OD value of blank control group)/(OD value of normal cells−OD value of blank control group)
Cytopathic rate=1−cell survival rate
Cell specific distance=(>50% lesion rate−50%)/(>50% lesion rate−>50% lesion rate)

(141) Virus Inhibition Activity Assay

(142) Preparation of monolayer cells: the cells were degraded by trypsin and placed in 96 microporous plates. The cells could be cultured into monolayer cells for use.

(143) The tested compound were prepared and reserved according to the specification of 100 μL/tube. According to the molecular weight of test compound, dissolve each tube with a suitable solvent of 10 μL. The compound was diluted 10 times in a 2 percent cell culture solution (200 μL), with 10 gradients. They were then inoculated in 96 microporous plates containing monolayer cells. The 11th column was set as blank control group of virus, and the 12th column was set as blank control group of cells. The plate was then cultured at the temperature of 37° C. with 5% carbon dioxide. The cytopathic condition should be observed every day. When the virus control lesion was 90%, the cells in the pore plate were absorbed and discarded, and 100 μL of 1% neutral red was added to the pore plate again. The staining solution was stained for 2 hours at 37° C., then the staining solution was absorbed and discarded, and the eluent was bleached at 37° C. for 10 minutes. OD value of the tested plate was measured with an enzyme reader at a wavelength of about 540 nm. Finally, the cytologic lesion rate and cell survival rate were calculated by formula, and the Reed-Muench method was used to calculate the compound's 50% inhibitory concentration on virus (EC.sub.50) and 50% toxic concentration on cell (TC.sub.50).

(144) The data for the inhibitory activity against viruses are shown as follows:

(145) TABLE-US-00004 RSV HSV EV71 H1N1 H7N9 CoxB3 HIV TC50 Compd (EC50) μM (EC50) μM (EC50) μM (EC50) μM (EC50) μM (EC50) μM (EC50) μM μM 1 B C B C B B B ++ 2 C D B B A C D ++ 3 D D C D C C E ++ 4 D C B A B B C +++ 5 C B C B C B C +++ 9 C C B B C D D ++ 10 D C B C D C E ++ 12 C B D A B C D +++ 13 C B D C B C B +++ 17 C B D B D B D ++ 19 C C C D B B C ++ 22 D C B C C B C +++ 25 D C B B A B B +++ 29 B D C C B B B ++ 32 B C D C B C B ++ 36 C D C B B B C +++ 40 D B B B C D C ++ 43 A C B C B C C ++ 47 C D E C C B D +++ 49 D C C B C C D +++ 733 B C C D D C B ++ 734 C C B D C C B +++ 735 C D D B C D B ++ 736 B D C C B D C ++ 737 B C C D E B C ++ 743 C D C B E C B + 744 D C D D B E C ++ 745 A B C C D A C +++ 746 B C B B D E E ++ 747 A C D B D C D ++ 748 D C B D E B C +++ 751 A D B C D B B ++ 752 C D C E C C D ++ 753 B C D A B D C +++ 754 C E C B B D A +++ 758 B B D C C C B +++ 759 B A E D D B C + 760 C B B D E E D + 764 C B B C A D E +++ 773 D C C E D C B ++ 775 A D C B E B B ++ 781 B D D B C D C +++ 899 E E E A B C C +++ 914 B B A C D C D ++ 916 C E B B E E C + 919 D D C B B A B ++ 920 C C D C D B D ++ 924 B B D D C E D +++ 925 D C B E E C B ++ 926 C C B D D D B ++ 930 C B E C C B C +++ 939 C B A D B B C ++ 940 E E C E A D D ++ 944 A D D D D C C + 947 B A B D C B B ++ 948 B C C D C C D ++

(146) In the table, “A” means the compound concentration is less than 0.05 μM, “B” means the compound concentration is 0.05-5 μM, “C” means the compound concentration is 5-50 μM, and “D” means the compound concentration is 50-120 μM. “E” means more than 120 μM; “++++” means TC.sub.50 is more than 300 μM, “+++” means TC.sub.50 is between 100-300 μM, “++” means TC.sub.50 is between 50-100 μM, “+” means TC.sub.50 is between 10 to 50 μM.

(147) The activity test shows that the compound has a broad spectrum of antiviral activity, and the activity is stronger than or equal to the positive drug, showing a good application prospect.