A quinazolinone derivative, its preparation method and its application in anti-inflammatory and anti-tumor

Abstract

The present invention discloses a quinazolinone derivative, a preparation method thereof, and its application in anti-inflammatory and anti-tumor activities, belonging to the technical field of compounds. The quinazolinone derivatives of the present invention include ketone compounds and urea compounds, and are novel compound skeletons. To improve the toxicity that may be caused by the introduction of sulfur atoms, a carbonamide structure is introduced into the benzothiazole ring to obtain a novel compound skeleton. The compound is non-toxic and has excellent anti-inflammatory and anti-tumor activities.

Description

Technical Field

[0001] The present invention relates to the technical field of compounds, and in particular to a quinazolinone derivative, a preparation method thereof, and application thereof in anti-inflammatory and anti-tumor activities. Background Art

[0002] Quinazolinones are important drug scaffolds in drug discovery and have also demonstrated excellent anti-tumor efficacy. Existing 6-(2-amino-1H-benzo[d]imidazol-6-yl)quinazolin-4(3H)-one compounds have demonstrated anti-tumor activity, demonstrating broad-spectrum anti-tumor efficacy. Therefore, developing 6-(2-amino-1H-benzo[d]imidazol-6-yl)quinazolin-4(3H)-one derivatives is of great significance in broadening the scope of anti-tumor drugs. Summary of the Invention

[0003] The present invention aims to provide a quinazolinone derivative and its application in anti-tumor, in particular to provide a 6-(2-aminobenzo[d]thiazol-5-yl)quinazolin-4(3H)-one derivative.

[0004] In order to achieve the above object, the present invention is implemented through the following technical solutions:

[0005] A quinazolinone derivative, comprising a ketone compound represented by the general structural formula (I) and a urea compound represented by the general structural formula (II);

[0006]

[0007] In formula (I) and formula (II), R1 is selected from phenyl, N-morpholinoethyl, N,N-dimethylaminoethyl, 1-cyclohexylethyl, N-acetamidoethyl, butyl, cyclopropylmethyl, isopentyl, propyl, and 1-morpholino-1carbonylethyl;

[0008] In formula (I), R2 is selected from acetyl, propionyl, butyryl, benzoyl, and p-methoxybenzoyl;

[0009] In formula (II), R3 is selected from p-methylphenyl, 3,5-dimethylphenyl, benzyl, p-methoxyphenyl, 3-methoxyphenyl, 3-fluorophenyl, p-fluorophenyl, p-chlorophenyl, p-bromophenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 3,5-ditrifluoromethylphenyl, ethyl, isopropyl, butylcyclohexyl, and phenethyl.

[0010] Furthermore, the ketone compound represented by formula (I) includes N-(5-(3-benzyl-4-oxo-3,4-dihydroquinazolin-6-yl)benzo[d]thiazol-2-yl)butanamide or a pharmaceutically acceptable salt or solvate thereof.

[0011] Furthermore, the urea compound represented by formula II) includes 1-(5-(4-oxo-3,4-dihydroquinazolin-6-yl)benzo[d]thiazol-2-yl)urea or a pharmaceutically acceptable salt or solvate thereof.

[0012] Further, the urea compound represented by formula (II) is selected from 1-(5-(3-benzyl-4-oxo-3,4-dihydroquinazolin-6-yl)benzo[d]thiazol-2-yl)-3-(p-tolyl)urea, 1-benzyl-3-(5-(3-benzyl-4-oxo-3,4-dihydroquinazolin-6-yl)benzo[d]thiazol-2-yl)urea, 1-(5-(3-benzyl-4-oxo-3,4-dihydroquinazolin-6-yl)benzo[d]thiazol-2-yl)-3-(4-methoxyphenyl)urea, 1-(5-(3-benzyl-4-oxo-3,4-dihydroquinazolin-6-yl)benzo[d]thiazol-2-yl)-3-(3-methoxyphenyl)urea, 1-(5-(3-benzyl-4-oxo-3,4-dihydroquinazolin-6-yl)benzo[d]thiazol-2-yl)-3-(3-methoxyphenyl)urea, 4-oxo-3,4-dihydroquinazolin-6-yl)benzo[d]thiazol-2-yl)-3-(3-fluorophenyl)urea, 1-(5-(3-benzyl-4-oxo-3,4-dihydroquinazolin-6-yl)benzo[d]thiazol-2-yl)-3-(4-fluorophenyl)urea, 1-(5-(3-benzyl-4-oxo-3,4-dihydroquinazolin-6-yl)benzo[d]thiazol-2-yl)-3-(3-(trifluoromethyl)phenyl)urea, 1-(5-(3-benzyl-4-oxo-3,4-dihydroquinazolin-6-yl)benzo[d]thiazol-2-yl)-3-(4-(trifluoromethyl)phenyl)urea, 1-(5-(3-benzyl-4-oxo-3,4-dihydroquinazolin-6-yl)benzo[d]thiazol-2-yl)-3-(4-(trifluoromethyl)phenyl)urea, d]thiazol-2-yl)-3-(3,5-bis(trifluoromethyl)phenyl)urea, 1-(5-(3-benzyl-4-oxo-3,4-dihydroquinazolin-6-yl)benzo[d]thiazol-2-yl)-3-ethylurea, 1-(5-(3-benzyl-4-oxo-3,4-dihydroquinazolin-6-yl)benzo[d]thiazol-2-yl)-3-isopropylurea, 1-(5-(3-benzyl-4-oxo-3,4-dihydroquinazolin-6-yl)benzo[d]thiazol-2-yl)-3-butylurea, 1-(5-(3-benzyl-4-oxo-3,4-dihydroquinazolin-6-yl)benzo[d]thiazol-2-yl)-3-cyclohexylurea, 1-(5-(3-(2-morpholinoethyl)-4-oxo-3,4-dihydroquinazolin-6-yl)benzo[d]thiazol-2-yl)-3- oxo-3,4-dihydroquinazolin-6-yl)benzo[d]thiazol-2-yl)urea, 1-(4-methoxyphenyl)-3-(5-(3-(2-morpholinoethyl)-4-oxo-3,4-dihydroquinazolin-6-yl)benzo[d]thiazol-2-yl)urea, 1-(4-fluorophenyl)-3-(5-(3-(2-morpholinoethyl)-4-oxo-3,4-dihydroquinazolin-6-yl)benzo[d]thiazol-2-yl)urea, 1-(5-(3-(2-morpholinoethyl)-4-oxo-3,4-dihydroquinazolin-6-yl)benzo[d]thiazol-2-yl)urea4-dihydroquinazolin-6-yl)benzo[d]thiazol-2-yl)-3-(3-(trifluoromethyl)phenyl)urea, 1-(5-(3-(2-morpholinoethyl)-4-oxo-3,4-dihydroquinazolin-6-yl)benzo[d]thiazol-2-yl)-3-(4-(trifluoromethyl)phenyl)urea, 1-(5-(3-(2-(dimethylamino)ethyl)-4-oxo-3,4-dihydroquinazolin-6-yl)benzo[d]thiazol-2-yl)-3-(4-(trifluoromethyl)phenyl)urea (3-methoxyphenyl)urea, 1-(5-(3-(2-(dimethylamino)ethyl)-4-oxo-3,4-dihydroquinazolin-6-yl)benzo[d]thiazol-2-yl)-3-(4-methoxyphenyl)urea, 1-(5-(3-(2-(dimethylamino)ethyl)-4-oxo-3,4-dihydroquinazolin-6-yl)benzo[d]thiazol-2-yl)-3-(4-fluorophenyl)urea, 1-(5-(3-(2-cyclohexylethyl)-4- oxo-3,4-dihydroquinazolin-6-yl)benzo[d]thiazol-2-yl)-3-(3-methoxyphenyl)urea, 1-(5-(3-(2-cyclohexylethyl)-4-oxo-3,4-dihydroquinazolin-6-yl)benzo[d]thiazol-2-yl)-3-(4-fluorophenyl)urea, 1-(5-(3-butyl-4-oxo-3,4-dihydroquinazolin-6-yl)benzo[d]thiazol-2-yl)-3-(4-fluorophenyl)urea, 1-(5-(3-butyl-4-oxo-3,4-dihydroquinazolin-6-yl)benzo[d]thiazol-2-yl)-3-(4-fluorophenyl)urea, (3-(cyclopropylmethyl)-4-oxo-3,4-dihydroquinazolin-6-yl)benzo[d]thiazol-2-yl)-3-(4-fluorophenyl)urea, 1-(4-fluorophenyl)-3-(5-(3-isopentyl-4-oxo-3,4-dihydroquinazolin-6-yl)benzo[d]thiazol-2-yl)urea, 1-(4-fluorophenyl)-3-(5-(4-isopentyl-4-oxo-3,4-dihydroquinazolin-6-yl)benzo[d]thiazol-2-yl)urea.

[0013] The present invention also provides a method for preparing a quinazolinone derivative, comprising the following steps:

[0014] (1) Preparation of 5-(4,4,5-trimethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazol-2-amine: 2-amino-5-bromobenzothiazole is used as a raw material and reacted with diboronic acid pinacol ester in a molar mass ratio of 1:(1-2) in dioxane with a catalyst [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex at 100-110°C for 18h-30h to obtain 5-(4,4,5-trimethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazol-2-amine;

[0015]

[0016] (2) Preparation of 3-benzyl-6-bromoquinazolin-4(3H)-one: 2-amino-5-bromobenzoic acid, triethyl orthoformate, benzylamine, and iodine were added to anhydrous ethanol at a molar mass ratio of 1:(1-1.5):(1-1.5):(0.01-0.015), and the mixture was reacted at 75°C-85°C for 5h-7h to obtain 3-benzyl-6-bromoquinazolin-4(3H)-one by ring closure.

[0017]

[0018] Or 2-amino-5-bromobenzoic acid and formamide are reacted in a molar mass ratio of 1:(1-1.5) to obtain a 3-benzyl-6-bromoquinazolin-4(3H)-one intermediate, the intermediate and NaH are added to an organic solvent dimethylformamide (DMF), and then 2-chloro-1-morpholinethan-1-one is added dropwise, and stirred at room temperature for 18-36 hours to obtain 3-benzyl-6-bromoquinazolin-4(3H)-one;

[0019]

[0020] (3) Synthesis of 6-(2-aminobenzo[d]thiazol-5-yl)-3-benzylquinazolin-4(3H)-one intermediate: 5-(4,4,5-trimethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazol-2-amine obtained in step (1) and 3-benzyl-6-bromoquinazolin-4(3H)-one obtained in step (2) were added to dioxane and water in a molar mass ratio of (2-2.5):(1-1.5), and K2CO3 and dichloropalladium-carbon catalyst were added and reacted at 100°C-110°C for 4h-6h to obtain 6-(2-aminobenzo[d]thiazol-5-yl)-3-benzylquinazolin-4(3H)-one intermediate;

[0021]

[0022] (4) reacting the 6-(2-aminobenzo[d]thiazol-5-yl)-3-benzylquinazolin-4(3H)-one intermediate in step (3) with an acid chloride in an organic solvent of tetrahydrofuran (THF) and triethylamine at a molar mass ratio of 1:(1-1.5) at room temperature for 4-6 hours to obtain a compound of formula (I);

[0023]

[0024] Furthermore, in the preparation method of the compound of formula (I), the amount of the catalyst [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex added in step (1) is 3%-8% of the molar mass of 2-amino-5-bromobenzothiazole.

[0025] Furthermore, in the preparation method of the compound of formula (I) above, the molar mass ratio of K2CO3 to 3-benzyl-6-bromoquinazolin-4(3H)-one in step (3) is 3:1; the molar mass ratio of the catalyst dichloropalladium carbon to 3-benzyl-6-bromoquinazolin-4(3H)-one is 0.05:1.

[0026] The present invention also provides another method for preparing a quinazolinone derivative, comprising the following steps:

[0027] (1) Preparation of 5-(4,4,5-trimethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazol-2-amine: 2-amino-5-bromobenzothiazole is used as a raw material and reacted with diboronic acid pinacol ester in a molar mass ratio of 1:(1-2) in dioxane with a catalyst [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex at 100-110°C for 18h-30h to obtain 5-(4,4,5-trimethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazol-2-amine;

[0028]

[0029] (2) Preparation of 3-benzyl-6-bromoquinazolin-4(3H)-one: 2-amino-5-bromobenzoic acid, triethyl orthoformate, benzylamine, and iodine were added to anhydrous ethanol at a molar mass ratio of 1:(1-1.5):(1-1.5):(0.01-0.015), and the mixture was reacted at 75°C-85°C for 5h-7h to obtain 3-benzyl-6-bromoquinazolin-4(3H)-one by ring closure.

[0030]

[0031] Or 2-amino-5-bromobenzoic acid and formamide are reacted in a molar mass ratio of 1:(1-1.5) to obtain a 3-benzyl-6-bromoquinazolin-4(3H)-one intermediate, the intermediate and NaH are added to an organic solvent dimethylformamide (DMF), and then 2-chloro-1-morpholinethan-1-one is added dropwise, and stirred at room temperature for 18-36 hours to obtain 3-benzyl-6-bromoquinazolin-4(3H)-one;

[0032]

[0033] (3) Synthesis of 6-(2-aminobenzo[d]thiazol-5-yl)-3-benzylquinazolin-4(3H)-one intermediate: 5-(4,4,5-trimethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazol-2-amine obtained in step (1) and 3-benzyl-6-bromoquinazolin-4(3H)-one obtained in step (2) were added to dioxane and water in a molar mass ratio of (2-2.5):(1-1.5), and K2CO3 and dichloropalladium-carbon catalyst were added and reacted at 100°C-110°C for 4h-6h to obtain 6-(2-aminobenzo[d]thiazol-5-yl)-3-benzylquinazolin-4(3H)-one intermediate;

[0034]

[0035] (4) The 6-(2-aminobenzo[d]thiazol-5-yl)-3-benzylquinazolin-4(3H)-one intermediate in step (3) is reacted with isocyanate in a molar mass ratio of 1:(1-1.5) in dioxane at 75° C.-85° C. for 4 h-6 h to obtain a compound of formula (II);

[0036]

[0037] Furthermore, in the preparation method of the compound of formula (II), the amount of the catalyst [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex added in step (1) is 3%-8% of the molar mass of 2-amino-5-bromobenzothiazole.

[0038] Furthermore, in the preparation method of the compound of formula (II) above, the molar mass ratio of K2CO3 to 3-benzyl-6-bromoquinazoline-4(3H)-one in step (3) is 3:1; the molar mass ratio of the catalyst dichloropalladium carbon to 3-benzyl-6-bromoquinazoline-4(3H)-one is 0.05:1.

[0039] The invention also discloses application of a quinazolinone derivative in anti-inflammatory and anti-tumor effects.

[0040] The present invention discloses a quinazolinone derivative, a preparation method thereof, and an application thereof in anti-inflammatory and anti-tumor activities. The beneficial effects are as follows: the quinazolinone derivative of the present invention is a novel compound skeleton. In order to improve the toxicity that may be caused by the introduction of an S atom, a carbonamide structure is introduced into the benzothiazole ring to obtain a novel compound skeleton. The compound is non-toxic and has excellent anti-inflammatory and anti-tumor activities. BRIEF DESCRIPTION OF THE DRAWINGS

[0041] In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the following briefly introduces the drawings required for use in the embodiments or the description of the prior art. Obviously, the drawings described below are only some embodiments of the present invention. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying any creative work.

[0042] Figure 1 This is a diagram showing the effect of compound A29 of the present invention on the cell cycle of A549 cells;

[0043] Figure 2 This is a diagram showing the inhibitory effect of compound A29 on the ALK signaling pathway;

[0044] Figure 3 This is a diagram showing the effect of compound A29 on mitochondrial membrane potential;

[0045] Figure 4 This is a diagram showing the effect of compound A29 on cell apoptosis;

[0046] Figure 5 is a schematic diagram showing that compound A29 reduces the protein expression of Nrf2 and HO-1;

[0047] Figure 6 This is a diagram showing the inhibitory effect of compound A29 on the growth of tumor spheres. DETAILED DESCRIPTION

[0048] In order to enable those skilled in the art to better understand the present invention, the technical solution of the present invention will be clearly and completely described below in conjunction with the embodiments. Obviously, the embodiments described are only some embodiments of the present invention, not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without making any creative efforts shall fall within the scope of protection of the present invention.

[0049] Ketone compounds

[0050] Example 1

[0051] A method for preparing a quinazolinone derivative comprises the following steps:

[0052] (1) Preparation of 5-(4,4,5-trimethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazol-2-amine: 2-amino-5-bromobenzothiazole (2.29 g, 10 mmol), pinacol diboron (5.08 g, 20 mmol), AcOK (2.94 g,) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (0.4 g, 0.5 mmol) were added to dioxane (60 mL) and reacted at 100°C overnight. After the reaction, the solvent was removed and the residue was purified by column chromatography using dichloromethane / methanol to obtain a light yellow solid (2.23 g, 8 mmol, yield 80%).

[0053] (2) Preparation of 3-benzyl-6-bromoquinazolin-4(3H)-one: 2-amino-5-bromobenzoic acid (4.32 g, 20 mmol), triethyl orthoformate (3.86 g, 26 mmol), benzylamine (2.79 g, 26 mmol) and iodine (0.05 g, 0.2 mmol) were added to a three-necked flask, and anhydrous ethanol (60 mL) was added to reflux for 6 h. After the reaction was completed, the residue was concentrated and dissolved in ethyl acetate (100 mL). The ethyl acetate solution was washed three times with sodium hydroxide solution, dried over anhydrous magnesium sulfate, and dried to obtain 3-benzyl-6-bromoquinazolin-4(3H)-one as a light yellow solid with a yield of 85%.

[0054] (3) Synthesis of 6-(2-aminobenzo[d]thiazol-5-yl)-3-benzylquinazolin-4(3H)-one intermediate: The intermediate 3-benzyl-6-bromoquinazolin-4(3H)-one (1.26 g, 4 mmol) and 5-(4,4,5-trimethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazol-2-amine (2.21 g, 8 mmol) were added to 1,4-dioxane (20 mL) and stirred. K2CO3 (1.66 g, 12 mmol) and dichloropalladium on carbon (Pd(dppf)Cl2) (0.15 g, 0.2 mmol) were then added. The mixture was reacted at 100°C for 1 h, and then water (5 mL) was added and the reaction was continued for 4 h. After the reaction was completed, the solvent was removed and the residue was purified by dichloromethane / methanol column chromatography to obtain a light yellow solid with a yield of 79%.

[0055] (4) Synthesis of N-(5-(3-benzyl-4-oxo-3,4-dihydroquinazolin-6-yl)benzo[d]thiazol-2-yl)butanamide: The intermediate 6-(2-aminobenzo[d]thiazol-5-yl)-3-benzylquinazolin-4(3H)-one (100 mg, 0.26 mmol) and triethylamine (61.63 mg, 0.78 mmol) were added to THF (3 mL) at 0°C and stirred. Then, the acid chloride (0.34 mmol) was slowly added dropwise using a dropping funnel. After the addition was complete, the temperature was raised to room temperature and the reaction was continued for 5 h. After the reaction was completed, THF was removed and the residue was purified by dichloromethane / methanol column chromatography to obtain a white solid compound, namely, compound A1 of formula (I), with a yield of 56%, melting point: 259.1-259.8°C, HRMS (ESI): m / z 455.15201 [M+H] + .

[0056] Compound A1 1 H-NMR data are: δ12.43(s,1H),8.61(s,1H),8.40(d,J=2.2Hz,1H),8.20(dd,J=8.5,2.3Hz,1H),8.07–8.04(m,2H),7.78(d,J=8.5Hz,1H),7.66(dd,J=8.2,1.8Hz,1H),7.39(d,J=7.2Hz,2H),7.35(dd,J=8.5,6.8Hz,2H),7.31–7.27(m,1H),5.23(s,2H),2.48(t,J=7.4Hz,2H),1.65(h,J=7.3Hz,2H),0.92(t,J=7.4Hz,3H).

[0057] Compound A1 13 C-NMR data are: δ 172.74, 160.63, 159.26, 149.93, 148.49, 147.64, 139.28, 137.52, 137.29, 133.68, 131.79, 129.12, 129.12, 128.48, 128.18, 128.18, 128.17, 124.11, 122.87, 122.84, 122.46, 118.90, 49.47, 37.47, 18.49, 14.00.

[0058] Urea compounds

[0059] Example 2

[0060] A method for preparing a quinazolinone derivative comprises the following steps:

[0061] (1) Preparation of 5-(4,4,5-trimethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazol-2-amine: 2-amino-5-bromobenzothiazole (2.29 g, 10 mmol), pinacol diboron (5.08 g, 20 mmol), AcOK (2.94 g,) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (0.4 g, 0.5 mmol) were added to dioxane (60 mL) and reacted at 100°C overnight. After the reaction, the solvent was removed and the residue was purified by column chromatography using dichloromethane / methanol to obtain a light yellow solid (2.23 g, 8 mmol, yield 80%).

[0062] (2) Preparation of 3-benzyl-6-bromoquinazolin-4(3H)-one: 2-amino-5-bromobenzoic acid (4.32 g, 20 mmol), triethyl orthoformate (3.86 g, 26 mmol), benzylamine (2.79 g, 26 mmol) and iodine (0.05 g, 0.2 mmol) were added to a three-necked flask, and anhydrous ethanol (60 mL) was added to reflux for 6 h; after the reaction was completed, the residue was concentrated to obtain a residue, which was dissolved in ethyl acetate (100 mL); the ethyl acetate solution was washed three times with sodium hydroxide aqueous solution, dried over anhydrous magnesium sulfate, and dried to obtain 3-benzyl-6-bromoquinazolin-4(3H)-one as a light yellow solid with a yield of 85%;

[0063] (3) Synthesis of 6-(2-aminobenzo[d]thiazol-5-yl)-3-benzylquinazolin-4(3H)-one intermediate: The intermediate 3-benzyl-6-bromoquinazolin-4(3H)-one (1.26 g, 4 mmol) and 5-(4,4,5-trimethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazol-2-amine (2.21 g, 8 mmol) were added to 1,4-dioxane (20 mL) and stirred. K2CO3 (1.66 g, 12 mmol) and dichloropalladium on carbon (Pd(dppf)Cl2) (0.15 g, 0.2 mmol) were then added. The mixture was reacted at 100°C for 1 h, and then water (5 mL) was added and the reaction was continued for 4 h. After the reaction was completed, the solvent was removed and the residue was purified by dichloromethane / methanol column chromatography to obtain a light yellow solid with a yield of 79%.

[0064] (4) Synthesis of 1-(5-(3-benzyl-4-oxo-3,4-dihydroquinazolin-6-yl)benzo[d]thiazol-2-yl)-3-(p-tolyl)urea: The intermediate 6-(2-aminobenzo[d]thiazol-5-yl)-3-benzylquinazolin-4(3H)-one (100 mg, 0.26 mmol) and p-toluene isocyanate (45.08 mg, 0.34 mmol) were added to dioxane (2 mL) and reacted at 80°C for 4 h. After the reaction was completed, the solvent was removed and the residue was purified by dichloromethane / methanol column chromatography to obtain the compound A2 of formula (II) as a white solid in a yield of 95%. Melting point: 304.8-306.5°C. HRMS (ESI): m / z 518.16431 [M+H]. + .

[0065] Compound A2 1 H-NMR data are: δ10.98(s,1H),9.13(s,1H),8.59(s,1H),8.41(d,J=2.4Hz,1H),8.20(dd,J=8.5,2.3Hz,1H),8.00(d,J=8.3Hz,2H),7.78(d,J=8.4Hz,1H),7.62(dd,J=8.2,1.8Hz,1H),7.36(d,J=7.3Hz,2H),7.29(s,1H),7.14(d,J=8.6Hz,2H),5.23(s,2H),2.26(s,3H).

[0066] Compound A2 13 C-NMR data are: δ 160.64, 148.45, 147.63, 139.34, 137.40, 137.30, 136.30, 133.59, 132.47, 129.80, 129.80, 129.69, 129.12, 129.12, 128.49, 128.17, 128.17, 124.05, 122.66, 122.48, 122.26, 119.43, 119.43, 114.51, 49.44, 20.86.

[0067] Example 3

[0068] A method for preparing a quinazolinone derivative comprises the following steps:

[0069] (1) Same as step (1) in Example 2;

[0070] (2) The same as step (2) of Example 2, the product 3-benzyl-6-bromoquinazolin-4(3H)-one was a light yellow solid with a yield of 85%;

[0071] (3) The product, 6-(2-aminobenzo[d]thiazol-5-yl)-3-benzylquinazolin-4(3H)-one, was a light yellow solid in the same manner as in step (3) of Example 2. The yield was 79%.

[0072] (4) Synthesis of 1-benzyl-3-(5-(3-benzyl-4-oxo-3,4-dihydroquinazolin-6-yl)benzo[d]thiazol-2-yl)urea: The intermediate 6-(2-aminobenzo[d]thiazol-5-yl)-3-benzylquinazolin-4(3H)-one (100 mg, 0.26 mmol) and benzyl isocyanate (45.07 mg, 0.34 mmol) were added to dioxane (2 mL) and reacted at 80°C for 4 h. After the reaction was completed, the solvent was removed and the residue was purified by dichloromethane / methanol column chromatography to obtain the compound A3 of formula (II) as a white solid in a yield of 95%. Melting point: 170.8-172.9°C. HRMS (ESI): m / z 540.14545 [M+H]. + .

[0073] Compound A3 1 H-NMR data are: δ10.94(s,1H),8.60(s,1H),8.40(d,J=2.4Hz,1H),8.21(dd,J=8.5,2.3 Hz,1H),7.99(d,J=8.3Hz,1H),7.96(s,1H),7.78(d,J=8.4Hz,1H),7.60(dd,J=8.3 ,1.8Hz,1H),7.39(dd,J=8.4,1.5Hz,2H),7.36(d,J=7.3Hz,2H),7.34(d,J=2.5Hz, 4H),7.30(d,J=7.3Hz,1H),7.28–7.25(m,2H),5.23(s,2H),4.40(d,J=6.0Hz,2H).

[0074] Compound A3 13 C-NMR data are: δ 161.17, 160.65, 154.41, 148.46, 147.62, 139.83, 139.44, 137.31, 137.27, 133.63, 131.86, 129.13, 129.13, 128.90, 128.90, 128.49, 128.18, 128.18, 127.71, 127.71, 127.46, 124.02, 122.54, 122.48, 122.08, 118.23, 49.44, 43.47.

[0075] Example 4

[0076] A method for preparing a quinazolinone derivative comprises the following steps:

[0077] (1) Same as step (1) in Example 2;

[0078] (2) The same as step (2) of Example 2, the product 3-benzyl-6-bromoquinazolin-4(3H)-one was a light yellow solid with a yield of 85%;

[0079] (3) The product, 6-(2-aminobenzo[d]thiazol-5-yl)-3-benzylquinazolin-4(3H)-one, was a light yellow solid in the same manner as in step (3) of Example 2. The yield was 79%.

[0080] (4) Synthesis of 1-(5-(3-benzyl-4-oxo-3,4-dihydroquinazolin-6-yl)benzo[d]thiazol-2-yl)-3-(4-methoxyphenyl)urea: The intermediate 6-(2-aminobenzo[d]thiazol-5-yl)-3-benzylquinazolin-4(3H)-one (100 mg, 0.26 mmol) and p-methoxyphenyl isocyanate (50.41 mg, 0.34 mmol) were added to dioxane (2 mL) and reacted at 80°C for 4 h. After the reaction was completed, the solvent was removed and the residue was purified by dichloromethane / methanol column chromatography to obtain the compound A4 of formula (II) as a white solid in a yield of 96%. Melting point: 313.0-315.4°C. HRMS (ESI): m / z 534.15790 [M+H]. + .

[0081] Compound A4 1 H-NMR data are: δ10.88(s,1H),9.01(s,1H),8.62(s,1H),8.42(d,J=2.4Hz,1H),8.23(dd,J=8.5,2.4Hz,1H),8.02(d,J=8.2Hz,1H),8.00(s,1H),7.80(d,J=8.4Hz,1H),7. 64(dd,J=8.2,1.9Hz,1H),7.43(d,J=8.4Hz,2H),7.39(d,J=7.0Hz,2H),7.37(d,J= 7.3Hz, 2H), 7.30 (t, J = 7.2Hz, 1H), 6.92 (d, J = 9.1Hz, 2H), 5.24 (s, 2H), 3.74 (s, 3H).

[0082] Compound A4 13C-NMR data are: δ 160.65, 155.74, 148.52, 147.65, 139.37, 137.40, 137.31, 133.67, 129.14, 129.14, 128.53, 128.17, 128.17, 124.06, 122.72, 122.49, 122.26, 121.25, 121.25, 114.57, 114.57, 55.68, 49.45.

[0083] Example 5

[0084] A method for preparing a quinazolinone derivative comprises the following steps:

[0085] (1) Same as step (1) in Example 2;

[0086] (2) The same as step (2) of Example 2, the product 3-benzyl-6-bromoquinazolin-4(3H)-one was a light yellow solid with a yield of 85%;

[0087] (3) The product, 6-(2-aminobenzo[d]thiazol-5-yl)-3-benzylquinazolin-4(3H)-one, was a light yellow solid in the same manner as in step (3) of Example 2. The yield was 79%.

[0088] (4) Synthesis of 1-(5-(3-benzyl-4-oxo-3,4-dihydroquinazolin-6-yl)benzo[d]thiazol-2-yl)-3-(3-methoxyphenyl)urea: The intermediate 6-(2-aminobenzo[d]thiazol-5-yl)-3-benzylquinazolin-4(3H)-one (100 mg, 0.26 mmol) and 3-methoxyphenyl isocyanate (50.41 mg, 0.34 mmol) were added to dioxane (2 mL) and reacted at 80°C for 4 h. After the reaction was completed, the solvent was removed and the residue was purified by dichloromethane / methanol column chromatography to obtain the compound A5 of formula (II) as a white solid in a yield of 96%. Melting point: 327.4-329.7°C. HRMS (ESI): m / z 534.15790 [M+H]. + .

[0089] Compound A5 1H-NMR data: δ10.99 (s, 1H), 9.20 (s, 1H), 8.60 (s, 1H), 8.41 (d, J = 2.2 Hz, 1H), 8.19 (dd, J = 8.5, 2.3 Hz, 1H), 8.02–7.98 (m, 2H), 7.78 (d, J = 8.4 Hz, 1H), 7.62 (dd, J = 8.2, 1.8 Hz ,1H),7.40(d,J=7.0Hz,2H),7.37–7.34(m,2H),7.30(d,J=7.3Hz,1H),7.25–7.22(m ,2H),7.05(d,J=10.0Hz,1H),6.64(dd,J=8.5,2.6Hz,1H),5.23(s,2H),3.76(s,3H).

[0090] Compound A5 13 C-NMR data are: δ 160.64, 160.20, 149.38, 148.44, 147.63, 140.11, 139.29, 137.42, 137.29, 133.57, 131.42, 130.20, 129.12, 129.12, 128.95, 128.48, 128.30, 128.17, 128.17, 124.05, 122.69, 122.48, 122.31, 117.87, 111.61, 108.87, 105.10, 55.50, 49.44.

[0091] Example 6

[0092] A method for preparing a quinazolinone derivative comprises the following steps:

[0093] (1) Same as step (1) in Example 2;

[0094] (2) The same as step (2) of Example 2, the product 3-benzyl-6-bromoquinazolin-4(3H)-one was a light yellow solid with a yield of 85%;

[0095] (3) The product, 6-(2-aminobenzo[d]thiazol-5-yl)-3-benzylquinazolin-4(3H)-one, was a light yellow solid in the same manner as in step (3) of Example 2. The yield was 79%.

[0096] (4) Synthesis of 1-(5-(3-benzyl-4-oxo-3,4-dihydroquinazolin-6-yl)benzo[d]thiazol-2-yl)-3-(3-fluorophenyl)urea: The intermediate 6-(2-aminobenzo[d]thiazol-5-yl)-3-benzylquinazolin-4(3H)-one (100 mg, 0.26 mmol) and 3-fluorophenyl isocyanate (46.34 mg, 0.34 mmol) were added to dioxane (2 mL) and reacted at 80°C for 4 h. After completion of the reaction, the solvent was removed and the residue was purified by dichloromethane / methanol column chromatography to obtain the compound A6 of formula (II) as a white solid in a yield of 97%. Melting point: 302.3-305.5°C. HRMS (ESI): m / z 520.12372 [M+H]. + .

[0097] Compound A6 1 H-NMR data are: δ11.14(s,1H),9.43(s,1H),8.60(s,1H),8.41(d,J=2.4Hz,1H),8.2 0(dd,J=8.5,2.3Hz,1H),8.01(d,J=8.3Hz,1H),7.98(s,1H),7.79(d,J=8.4Hz,1 H),7.64(dd,J=8.3,1.9Hz,1H),7.54(d,J=11.6Hz,1H),7.39(d,J=6.8Hz,1H), 7.39–7.33(m,4H),7.31–7.25(m,2H),6.87(td,J=8.7,2.8Hz,1H),5.23(s,2H).

[0098] Compound A6 13 C-NMR data are: δ 163.60, 162.00, 160.63, 148.49, 147.67, 140.87, 139.25, 137.50, 137.30, 133.58, 130.99, 130.93, 129.12, 129.12, 128.51, 128.17, 128.17, 124.06, 122.81, 122.49, 122.39, 115.12, 109.72, 106.14, 49.43.

[0099] Example 7

[0100] A method for preparing a quinazolinone derivative comprises the following steps:

[0101] (1) Same as step (1) in Example 2;

[0102] (2) The same as step (2) of Example 2, the product 3-benzyl-6-bromoquinazolin-4(3H)-one was a light yellow solid with a yield of 85%;

[0103] (3) The product, 6-(2-aminobenzo[d]thiazol-5-yl)-3-benzylquinazolin-4(3H)-one, was a light yellow solid in the same manner as in step (3) of Example 2. The yield was 79%.

[0104] (4) Synthesis of 1-(5-(3-benzyl-4-oxo-3,4-dihydroquinazolin-6-yl)benzo[d]thiazol-2-yl)-3-(4-fluorophenyl)urea: The intermediate 6-(2-aminobenzo[d]thiazol-5-yl)-3-benzylquinazolin-4(3H)-one (100 mg, 0.26 mmol) and p-fluorophenyl isocyanate (46.34 mg, 0.34 mmol) were added to dioxane (2 mL) and reacted at 80°C for 4 h. After completion of the reaction, the solvent was removed and the residue was purified by dichloromethane / methanol column chromatography to obtain the compound A7 of formula (II) as a white solid in a yield of 97%. Melting point: 293.4-294.3°C. HRMS (ESI): m / z 544.11938 [M+Na] + .

[0105] Compound A7 1 H-NMR data are: δ11.01(s,1H),9.24(s,1H),8.60(s,1H),8.41(d,J=2.4Hz,1H),8.21(dd,J=8.5,2.3Hz,1H),8.01(d,J=8.2Hz,1H),7.99(s,1H),7.7 9(d,J=8.4Hz,1H),7.63(dd,J=8.2,1.9Hz,1H),7.56–7.54(m,2H),7.40 –7.35(m,4H),7.30(t,J=7.2Hz,1H),7.18(t,J=8.9Hz,2H),5.23(s,2H).

[0106] Compound A7 13 C-NMR data are: δ 160.65, 159.26, 157.68, 148.49, 147.65, 139.31, 137.45, 137.30, 135.26, 133.62, 129.13, 129.13, 128.52, 128.18, 128.18, 128.17, 124.06, 122.75, 122.48, 122.33, 121.35, 121.30, 116.03, 115.88, 49.45.

[0107] Example 8

[0108] A method for preparing a quinazolinone derivative comprises the following steps:

[0109] (1) Same as step (1) in Example 2;

[0110] (2) The same as step (2) of Example 2, the product 3-benzyl-6-bromoquinazolin-4(3H)-one was a light yellow solid with a yield of 85%;

[0111] (3) The product, 6-(2-aminobenzo[d]thiazol-5-yl)-3-benzylquinazolin-4(3H)-one, was a light yellow solid in the same manner as in step (3) of Example 2. The yield was 79%.

[0112] (4) Synthesis of 1-(5-(3-benzyl-4-oxo-3,4-dihydroquinazolin-6-yl)benzo[d]thiazol-2-yl)-3-(3-(trifluoromethyl)phenyl)urea: The intermediate 6-(2-aminobenzo[d]thiazol-5-yl)-3-benzylquinazolin-4(3H)-one (100 mg, 0.26 mmol) and 3-(trifluoromethyl)phenyl isocyanate (63.25 mg, 0.34 mmol) were added to dioxane (2 mL) and reacted at 80°C for 4 h. After the reaction was completed, the solvent was removed and the residue was purified by dichloromethane / methanol column chromatography to obtain the compound as a white solid, namely, compound A8 of formula (II), with a yield of 94%. Melting point: 293.4-294.3°C, 307.2-309.2°C, HRMS (ESI): m / z 594.11578 [M+Na] + .

[0113] Compound A8 1 H-NMR data are: δ11.32(s,1H),9.56(s,1H),8.60(s,1H),8.40(d,J=2.4Hz,1H),8.19(dd,J=8.4,2.2Hz,1H),8.06(s,1H),7.99(d,J=8.3Hz,1H),7.96(s,1H),7.78(d,J=8.4 Hz,1H),7.73(d,J=10.2Hz,1H),7.63(dd,J=8.2,1.8Hz,1H),7.55(t,J=7.9Hz,1H), 7.40(s,1H),7.39(s,2H),7.36(t,J=7.6Hz,2H),7.29(t,J=7.2Hz,1H),5.23(s,2H).

[0114] Compound A8 13C-NMR data are: δ 160.63, 148.47, 147.66, 140.03, 139.20, 137.51, 137.29, 133.53, 130.49, 130.17, 129.96, 129.75, 129.12, 129.12, 128.50, 128.17, 128.17, 127.31, 125.50, 124.05, 123.70, 123.02, 122.80, 122.48, 122.40, 121.89, 119.61, 115.30, 115.27, 49.43.

[0115] Example 9

[0116] A method for preparing a quinazolinone derivative comprises the following steps:

[0117] (1) Same as step (1) in Example 2;

[0118] (2) The same as step (2) of Example 2, the product 3-benzyl-6-bromoquinazolin-4(3H)-one was a light yellow solid with a yield of 85%;

[0119] (3) The product, 6-(2-aminobenzo[d]thiazol-5-yl)-3-benzylquinazolin-4(3H)-one, was a light yellow solid in the same manner as in step (3) of Example 2. The yield was 79%.

[0120] (4) Synthesis of 1-(5-(3-benzyl-4-oxo-3,4-dihydroquinazolin-6-yl)benzo[d]thiazol-2-yl)-3-(4-(trifluoromethyl)phenyl)urea: The intermediate 6-(2-aminobenzo[d]thiazol-5-yl)-3-benzylquinazolin-4(3H)-one (100 mg, 0.26 mmol) and 4-trifluoromethylphenylisocyanate (63.25 mg, 0.34 mmol) were added to dioxane (2 mL) and reacted at 80°C for 4 h. After completion of the reaction, the solvent was removed and the residue was purified by dichloromethane / methanol column chromatography to obtain the compound A9 of formula (II) as a white solid in a 94% yield. Melting point: 324.5-326.2°C. HRMS (ESI): m / z 594.11584. [M+Na] + .

[0121] Compound A9 1H-NMR data are: δ11.25(s,1H),9.60(s,1H),8.60(s,1H),8.40(d,J=2.2Hz,1H),8.1 9(dd,J=8.5,2.3Hz,1H),8.00(d,J=8.3Hz,1H),7.96(s,1H),7.78(d,J=8.4Hz,1 H),7.76(d,J=8.4Hz,2H),7.67(d,J=8.9Hz,2H),7.63(dd,J=8.2,1.8Hz,1H),7 .39(d,J=7.0Hz,2H),7.36(t,J=7.6Hz,2H),7.29(t,J=7.2Hz,1H),5.23(s,2H).

[0122] Compound A9 13 C-NMR data are: δ 160.62, 148.49, 147.66, 142.87, 139.19, 137.51, 137.30, 133.55, 129.12, 129.12, 128.50, 128.17, 128.17, 127.60, 126.64, 126.61, 125.80, 124.05, 124.05, 124.00, 122.83, 122.47, 122.47, 122.43, 119.05, 49.44.

[0123] Example 10

[0124] A method for preparing a quinazolinone derivative comprises the following steps:

[0125] (1) Same as step (1) in Example 2;

[0126] (2) The same as step (2) of Example 2, the product 3-benzyl-6-bromoquinazolin-4(3H)-one was a light yellow solid with a yield of 85%;

[0127] (3) The product, 6-(2-aminobenzo[d]thiazol-5-yl)-3-benzylquinazolin-4(3H)-one, was a light yellow solid in the same manner as in step (3) of Example 2. The yield was 79%.

[0128] (4) Synthesis of 1-(5-(3-benzyl-4-oxo-3,4-dihydroquinazolin-6-yl)benzo[d]thiazol-2-yl)-3-(3,5-bis(trifluoromethyl)phenyl)urea: The intermediate 6-(2-aminobenzo[d]thiazol-5-yl)-3-benzylquinazolin-4(3H)-one (100 mg, 0.26 mmol) and 3,5-bis(trifluoromethyl)phenyl isocyanate (86.23 mg,

[0129] The reaction mixture was stirred for 4 h at 80°C for 4 h. After the reaction, the solvent was removed and the residue was purified by dichloromethane / methanol column chromatography to obtain a white solid, Compound A10 of Formula (II), in a 96% yield. The yield was 96%. Melting point: 329.0-331.9°C. HRMS (ESI): m / z 662.10345 [M+Na]. + .

[0130] Compound A10 1 H-NMR data are: δ11.82(s,1H),9.93(s,1H),8.60(s,1H),8.36(d,J=17.5Hz,1H),8.26(s,2H),8.16(s,1H),7.99–7.86(m,2H),7.76(s,1H),7.70–7.61(m,3H),7.37(d,J=17.5Hz,4H),7.29(s,1H),5.23(s,2H).

[0131] Compound A10 13 C-NMR data are: δ 167.69, 160.61, 150.91, 148.52, 147.68, 141.66, 139.01, 137.61, 137.28, 133.47, 131.26, 131.05, 129.11, 129.11, 128.50, 128.15, 128.15, 124.64, 124.01, 123.72, 123.01, 122.83, 122.45, 121.03, 120.12, 118.96, 115.64, 113.27, 49.41.

[0132] Example 11

[0133] A method for preparing a quinazolinone derivative comprises the following steps:

[0134] (1) Same as step (1) in Example 2;

[0135] (2) The same as step (2) of Example 2, the product 3-benzyl-6-bromoquinazolin-4(3H)-one was a light yellow solid with a yield of 85%;

[0136] (3) The product, 6-(2-aminobenzo[d]thiazol-5-yl)-3-benzylquinazolin-4(3H)-one, was a light yellow solid in the same manner as in step (3) of Example 2. The yield was 79%.

[0137] (4) Synthesis of 1-(5-(3-benzyl-4-oxo-3,4-dihydroquinazolin-6-yl)benzo[d]thiazol-2-yl)-3-ethylurea: The intermediate 6-(2-aminobenzo[d]thiazol-5-yl)-3-benzylquinazolin-4(3H)-one (100 mg, 0.26 mmol) and ethyl isocyanate (61.63 mg, 0.34 mmol) were added to dioxane (2 mL) and reacted at 80°C for 4 h. After the reaction was completed, the solvent was removed and the residue was purified by dichloromethane / methanol column chromatography to obtain the compound A11 of formula (II) as a white solid in a yield of 33%. Melting point 279.0-280.9°C, HRMS (ESI): m / z 478.12912 [M+Na] + .

[0138] Compound A11 1 H-NMR data are: δ10.86(s,1H),8.61(s,1H),8.40(d,J=2.2Hz,1H),8.21(dd,J=8.5,2.2Hz,1H),7.98(d,J=8.2Hz,1H),7.95(s,1H),7.79(d,J=8.4Hz,1H),7.60(dd,J=8.2,1.9Hz,1H),7.36(dd,J=15.8,8.4Hz,4H),7.29(t,J=7.1Hz,1H),6.78(s,1H),5.23(s,2H),3.20(p,J=7.2Hz,2H),1.09(t,J=7.2Hz,3H).

[0139] Compound A11 13 C-NMR data are: δ 161.25, 160.65, 154.13, 148.48, 147.60, 139.48, 137.31, 137.22, 133.66, 131.86, 129.13, 129.13, 128.50, 128.17, 128.17, 124.00, 122.52, 122.47, 121.98, 118.13, 49.45, 31.61, 15.62.

[0140] Example 12

[0141] A method for preparing a quinazolinone derivative comprises the following steps:

[0142] (1) Same as step (1) in Example 2;

[0143] (2) The same as step (2) of Example 2, the product 3-benzyl-6-bromoquinazolin-4(3H)-one was a light yellow solid with a yield of 85%;

[0144] (3) The product, 6-(2-aminobenzo[d]thiazol-5-yl)-3-benzylquinazolin-4(3H)-one, was a light yellow solid in the same manner as in step (3) of Example 2. The yield was 79%.

[0145] (4) Synthesis of 1-(5-(3-benzyl-4-oxo-3,4-dihydroquinazolin-6-yl)benzo[d]thiazol-2-yl)-3-isopropylurea: The intermediate 6-(2-aminobenzo[d]thiazol-5-yl)-3-benzylquinazolin-4(3H)-one (100 mg, 0.26 mmol) and isopropyl isocyanate (28.76 mg, 0.34 mmol) were added to dioxane (2 mL) and reacted at 80°C for 4 h. After the reaction, the solvent was removed and the residue was purified by dichloromethane / methanol column chromatography to obtain the compound A12 of formula (II) as a white solid in a yield of 21%. Melting point: 282.1-283.4°C. HRMS (ESI): m / z 470.16266 [M+H]. + .

[0146] Compound A12 1 H-NMR data are: δ10.70 (s, 1H), 8.61 (s, 1H), 8.39 (d, J = 2.2 Hz, 1H), 8.20 (dd, J = 8.5, 2.2 Hz, 1H), 7.98 (d, J = 8.2 Hz, 1H), 7.95 (d, J = 1.9 Hz, 1H), 7.78 (d, J = 8.4 Hz, 1H), 7.59 (d d,J=8.2,1.9Hz,1H),7.40–7.38(m,2H),7.36(t,J=6.8Hz,2H),7.29(t,J=7.2Hz,1H ), 6.75 (d, J = 7.7Hz, 1H), 5.23 (s, 2H), 3.84 (p, J = 6.7Hz, 1H), 1.15 (d, J = 6.6Hz, 6H).

[0147] Compound A12 13 C-NMR data are: δ 161.15, 160.64, 153.50, 150.51, 148.46, 147.59, 139.47, 137.31, 137.21, 133.63, 131.85, 129.13, 129.13, 128.49, 128.30, 128.17, 128.17, 124.00, 122.50, 122.47, 121.97, 118.12, 49.44, 42.01, 23.15, 23.15.

[0148] Example 13

[0149] A method for preparing a quinazolinone derivative comprises the following steps:

[0150] (1) Same as step (1) in Example 2;

[0151] (2) The same as step (2) of Example 2, the product 3-benzyl-6-bromoquinazolin-4(3H)-one was a light yellow solid with a yield of 85%;

[0152] (3) The product, 6-(2-aminobenzo[d]thiazol-5-yl)-3-benzylquinazolin-4(3H)-one, was a light yellow solid in the same manner as in step (3) of Example 2. The yield was 79%.

[0153] (4) Synthesis of 1-(5-(3-benzyl-4-oxo-3,4-dihydroquinazolin-6-yl)benzo[d]thiazol-2-yl)-3-butylurea: The intermediate 6-(2-aminobenzo[d]thiazol-5-yl)-3-benzylquinazolin-4(3H)-one (100 mg, 0.26 mmol) and butyl isocyanate (50.34 mg, 0.34 mmol) were added to dioxane (2 mL) and reacted at 80°C for 4 h. After completion of the reaction, the solvent was removed and the residue was purified by dichloromethane / methanol column chromatography to obtain the compound A13 of formula (II) as a white solid in a yield of 41%. Melting point: 257.0-258.9°C. HRMS (ESI): m / z 506.16037 [M+Na] + .

[0154] Compound A13 1 H-NMR data are: δ10.78(s,1H),8.61(s,1H),8.40(s,1H),8.22(dd,J=8.4,2.1Hz,1H) ,7.99(d,J=8.1Hz,1H),7.95(s,1H),7.79(d,J=8.4Hz,1H),7.60(d,J=8.2Hz,1H ),7.39–7.35(m,4H),7.30(t,J=7.0Hz,1H),6.77(s,1H),5.24(s,2H),3.17(d,J =6.6Hz, 2H), 1.45 (d, J = 7.7Hz, 2H), 1.32 (q, J = 7.3Hz, 2H), 0.90 (t, J = 7.3Hz, 3H).

[0155] Compound A13 13C-NMR data are: δ 161.22, 160.65, 154.20, 148.49, 147.61, 139.48, 137.31, 137.22, 133.66, 131.89, 129.14, 129.14, 128.51, 128.17, 128.17, 124.74, 124.00, 122.53, 122.48, 121.99, 118.20, 49.44, 39.45, 30.28, 19.95, 14.12.

[0156] Example 14

[0157] A method for preparing a quinazolinone derivative comprises the following steps:

[0158] (1) Same as step (1) in Example 2;

[0159] (2) The same as step (2) of Example 2, the product 3-benzyl-6-bromoquinazolin-4(3H)-one was a light yellow solid with a yield of 85%;

[0160] (3) The product, 6-(2-aminobenzo[d]thiazol-5-yl)-3-benzylquinazolin-4(3H)-one, was a light yellow solid in the same manner as in step (3) of Example 2. The yield was 79%.

[0161] (4) Synthesis of 1-(5-(3-benzyl-4-oxo-3,4-dihydroquinazolin-6-yl)benzo[d]thiazol-2-yl)-3-cyclohexylurea: The intermediate 6-(2-aminobenzo[d]thiazol-5-yl)-3-benzylquinazolin-4(3H)-one (100 mg, 0.26 mmol) and cyclohexyl isocyanate (42.31 mg, 0.34 mmol) were added to dioxane (2 mL) and reacted at 80°C for 4 h. After the reaction, the solvent was removed and the residue was purified by dichloromethane / methanol column chromatography to obtain the compound A14 of formula (II) as a white solid in a yield of 52%. Melting point: 130.7-132.0°C. HRMS (ESI): m / z 510.19434 [M+H]. + .

[0162] Compound A14 1H-NMR data: δ10.73 (s, 1H), 8.60 (s, 1H), 8.39 (d, J = 2.2 Hz, 1H), 8.20 (dd, J = 8.5, 2.2 Hz, 1H), 7.98 (d, J = 8.2 Hz, 1H), 7.94 (d, J = 1.9 Hz, 1H), 7.78 (d, J = 8.5 Hz, 1H), 7.59 (dd, J = 8.2, 1.9 Hz, 1H ),7.39(d,J=6.8Hz,2H),7.35(t,J=7.6Hz,2H),7.29(t,J=7.2Hz,1H),6.89(d,J=8.2Hz,1H), 5.23(s,2H),3.57–3.52(m,1H),1.83(m,2H),1.66(dt,J=8.2,4.2Hz,2H),1.33–1.20(m,6H).

[0163] Compound A14 13 C-NMR data are: δ 161.22, 160.65, 153.48, 148.47, 147.59, 139.48, 137.31, 137.19, 133.64, 131.87, 129.13, 129.13, 129.11, 128.49, 128.17, 128.17, 123.99, 122.50, 122.47, 121.94, 118.11, 49.44, 49.44, 33.04, 33.04, 25.56, 24.72, 24.72.

[0164] Example 15

[0165] A method for preparing a quinazolinone derivative comprises the following steps:

[0166] (1) Same as step (1) in Example 2;

[0167] (2) The same as step (2) of Example 2, the product 3-benzyl-6-bromoquinazolin-4(3H)-one was a light yellow solid with a yield of 82%;

[0168] (3) The same as step (3) of Example 2, the product 6-(2-aminobenzo[d]thiazol-5-yl)-3-benzylquinazolin-4(3H)-one intermediate was a light yellow solid with a yield of 81%;

[0169] (4) Synthesis of 1-(5-(3-(2-morpholinylethyl)-4-oxo-3,4-dihydroquinazolin-6-yl)benzo[d]thiazol-2-yl)-3-phenylethylurea: The intermediate 6-(2-aminobenzo[d]thiazol-5-yl)-3-benzylquinazolin-4(3H)-one (100 mg, 0.25 mmol) and 2-phenylethyl isocyanate (46.95 mg, 0.5 mmol)) were added to dioxane (2 mL) and reacted at 80°C for 4 h. After the reaction was completed, the solvent was removed and the residue was purified by dichloromethane / methanol column chromatography to obtain the compound A15 of formula (II) as a white solid in a 90% yield. Melting point: 113.0-114.4°C. HRMS (ESI): m / z 555.21606 [M+H]. + .

[0170] Compound A15 1 H-NMR data are: δ10.85 (s, 1H), 8.39 (d, J = 2.4 Hz, 1H), 8.33 (s, 1H), 8.18 (dd, J = 8.5, 2.3 Hz, 1H), 7.98 (d, J = 8.3 Hz, 1H), 7.93 (s, 1H), 7.76 (d, J = 8.4 Hz, 1H), 7.59 (dd, J = 8.3, 1.9 Hz, 1H), 7.32 (t, J = 7.5 Hz,2H),7.26(d,J=8.4Hz,2H),7.23(t,J=7.3Hz,1H),6.84(s,1H),4.10(t,J=6.1Hz,2H),3.52(t ,J=4.6Hz,4H),3.42(d,J=6.9Hz,2H),2.80(t,J=7.2Hz,2H),2.61(t,J=6.1Hz,2H),2.44(s,4H).

[0171] Compound A15 13 C-NMR data are: δ 161.19, 160.70, 154.18, 150.45, 148.82, 147.61, 139.59, 139.13, 137.30, 133.45, 131.69, 129.20, 129.20, 128.91, 128.91, 128.36, 126.71, 123.89, 122.52, 122.29, 122.05, 118.07, 66.69, 56.80, 53.65, 43.11, 41.27, 40.40, 35.87.

[0172] Example 16

[0173] A method for preparing a quinazolinone derivative comprises the following steps:

[0174] (1) Same as step (1) in Example 2;

[0175] (2) The same as step (2) of Example 2, the product 3-benzyl-6-bromoquinazolin-4(3H)-one was a light yellow solid with a yield of 82%;

[0176] (3) The same as step (3) of Example 2, the product 6-(2-aminobenzo[d]thiazol-5-yl)-3-benzylquinazolin-4(3H)-one intermediate was a light yellow solid with a yield of 81%;

[0177] (4) Synthesis of 1-(3-methoxyphenyl)-3-(5-(3-(2-morpholinoethyl)-4-oxo-3,4-dihydroquinazolin-6-yl)benzo[d]thiazol-2-yl)urea: The intermediate 6-(2-aminobenzo[d]thiazol-5-yl)-3-benzylquinazolin-4(3H)-one (100 mg, 0.25 mmol) and 3-methoxyphenylisocyanate (55.93 mg, 0.5 mmol) were added to dioxane (2 mL) and reacted at 80°C for 4 h. After the reaction was completed, the solvent was removed and the residue was purified by dichloromethane / methanol column chromatography to obtain the compound A16 of formula (II) as a white solid in a yield of 93%. Melting point: 145.2-147.9°C. HRMS (ESI): m / z 557.19525 [M+H]. + .

[0178] Compound A16 1 H-NMR data are: δ11.04 (s, 1H), 9.25 (s, 1H), 8.40 (d, J = 2.4 Hz, 1H), 8.33 (s, 1H), 8.18 (dd, J = 8.4, 2.4 Hz, 1H), 8.03–7.95 (m, 2H), 7.75 (d, J = 8.4 Hz, 1H), 7.62 (dd, J = 8.2, 1. 8Hz,1H),7.28–7.20(m,2H),7.04(d,J=10.2Hz,1H),6.64(dd,J=8.4,3.0Hz,1H),4 .11(t,J=6.1Hz,2H),3.76(s,3H),3.53(t,J=4.7Hz,4H),2.63(s,2H),2.45(s,4H).

[0179] Compound A16 13C-NMR data are: δ 160.93, 160.67, 160.20, 152.58, 148.79, 147.67, 140.12, 139.00, 137.50, 133.39, 131.41, 130.20, 128.35, 123.95, 122.68, 122.32, 122.29, 117.74, 111.58, 108.85, 105.07, 66.65, 66.65, 56.80, 55.50, 55.50, 53.64, 43.06.

[0180] Example 17

[0181] A method for preparing a quinazolinone derivative comprises the following steps:

[0182] (1) Same as step (1) in Example 2;

[0183] (2) The same as step (2) of Example 2, the product 3-benzyl-6-bromoquinazolin-4(3H)-one was a light yellow solid with a yield of 82%;

[0184] (3) The same as step (3) of Example 2, the product 6-(2-aminobenzo[d]thiazol-5-yl)-3-benzylquinazolin-4(3H)-one intermediate was a light yellow solid with a yield of 81%;

[0185] (4) Synthesis of 1-(4-methoxyphenyl)-3-(5-(3-(2-morpholinoethyl)-4-oxo-3,4-dihydroquinazolin-6-yl)benzo[d]thiazol-2-yl)urea: The intermediate 6-(2-aminobenzo[d]thiazol-5-yl)-3-benzylquinazolin-4(3H)-one (100 mg, 0.25 mmol) and 4-methoxyphenylisocyanate (55.93 mg, 0.5 mmol) were added to dioxane (2 mL) and reacted at 80°C for 4 h. After completion of the reaction, the solvent was removed and the residue was purified by dichloromethane / methanol column chromatography to obtain the compound A17 of formula (II) as a white solid in a yield of 93%. Melting point: 258.6-260.8°C. HRMS (ESI): m / z 557.19543 [M+H]. + .

[0186] Compound A17 1H-NMR data are: δ10.95(s,1H),9.02(s,1H),8.39(d,J=2.4Hz,1H),8.32(s,1H),8. 17(dd,J=8.5,2.3Hz,1H),8.01–7.95(m,2H),7.75(d,J=8.4Hz,1H),7.60(dd,J =8.3,1.9Hz,1H),7.42(d,J=9.1Hz,2H),6.91(d,J=9.1Hz,2H),4.10(t,J=6.1H z, 2H), 3.73 (s, 3H), 3.52 (t, J = 4.7Hz, 4H), 2.62 (t, J = 6.1Hz, 2H), 2.44 (s, 4H).

[0187] Compound A17 13 C-NMR data are: δ 161.02, 160.69, 156.73, 155.73, 148.80, 147.63, 139.04, 137.44, 133.43, 131.73, 131.49, 129.25, 128.35, 123.92, 122.65, 122.28, 122.23, 121.26, 121.26, 117.82, 114.54, 114.54, 66.68, 66.68, 56.79, 55.65, 53.64, 53.64, 43.10.

[0188] Example 18

[0189] (1) Same as step (1) in Example 2;

[0190] (2) The same as step (2) of Example 2, the product 3-benzyl-6-bromoquinazolin-4(3H)-one was a light yellow solid with a yield of 82%;

[0191] (3) The same as step (3) of Example 2, the product 6-(2-aminobenzo[d]thiazol-5-yl)-3-benzylquinazolin-4(3H)-one intermediate was a light yellow solid with a yield of 81%;

[0192] (4) Synthesis of 1-(4-fluorophenyl)-3-(5-(3-(2-morpholinoethyl)-4-oxo-3,4-dihydroquinazolin-6-yl)benzo[d]thiazol-2-yl)urea: The intermediate 6-(2-aminobenzo[d]thiazol-5-yl)-3-benzylquinazolin-4(3H)-one (100 mg, 0.25 mmol) and p-fluorophenyl isocyanate (68.56 mg, 0.5 mmol) were added to dioxane (2 mL) and reacted at 80°C for 4 h. After completion of the reaction, the solvent was removed and the residue was purified by dichloromethane / methanol column chromatography to obtain the compound A18 of formula (II) as a white solid in a yield of 93%. Melting point: 158.8-160.1°C. HRMS (ESI): m / z 545.17560 [M+H]. + .

[0193] Compound A18 1 The H-NMR data are: δ11.11(s,1H),9.26(s,1H),8.41(d,J=2.4Hz,1H),8.35(s,1H),8. 20(dd,J=8.5,2.3Hz,1H),8.02(d,J=8.2Hz,1H),7.99(s,1H),7.77(d,J=8.4Hz ,1H),7.64(dd,J=8.2,1.9Hz,1H),7.57–7.54(m,2H),7.18(t,J=8.9Hz,2H),4. 12(t,J=6.1Hz,2H), 3.53(t,J=4.7Hz,4H), 2.63(t,J=6.1Hz,2H), 2.45(s,4H).

[0194] Compound A18 13 C-NMR data are: δ 160.67, 159.25, 157.66, 148.89, 147.71, 139.02, 137.53, 135.29, 133.45, 128.40, 123.97, 122.77, 122.33, 121.31, 121.26, 116.03, 115.89, 66.71, 66.71, 56.83, 53.67, 53.67, 43.10.

[0195] Example 19

[0196] A method for preparing a quinazolinone derivative comprises the following steps:

[0197] (1) Same as step (1) in Example 2;

[0198] (2) The same as step (2) of Example 2, the product 3-benzyl-6-bromoquinazolin-4(3H)-one was a light yellow solid with a yield of 82%;

[0199] (3) The same as step (3) of Example 2, the product 6-(2-aminobenzo[d]thiazol-5-yl)-3-benzylquinazolin-4(3H)-one intermediate was a light yellow solid with a yield of 81%;

[0200] (4) Synthesis of 1-(5-(3-(2-morpholinylethyl)-4-oxo-3,4-dihydroquinazolin-6-yl)benzo[d]thiazol-2-yl)-3-(3-(trifluoromethyl)phenyl)urea: The intermediate 6-(2-aminobenzo[d]thiazol-5-yl)-3-benzylquinazolin-4(3H)-one (100 mg, 0.26 mmol) and 3-(trifluoromethyl)phenylisocyanate (140.34 mg, 0.75 mmol) were added to dioxane (2 mL) and reacted at 80°C for 4 h. After the reaction was completed, the solvent was removed and the residue was purified by dichloromethane / methanol column chromatography to obtain the compound A19 of formula (II) as a white solid in a yield of 91%. Melting point: 156.3-157.9°C. HRMS (ESI): m / z 595.17236 [M+H]. + .

[0201] Compound A19 1 H-NMR data are: δ11.37 (s, 1H), 9.58 (s, 1H), 8.38 (d, J = 2.3 Hz, 1H), 8.32 (s, 1H), 8.16 (dd, J = 8.5, 2.3 Hz, 1H), 8.04 (d, J = 2.0 Hz, 1H), 7.99 (d, J = 8.2 Hz, 1H), 7.94 (s, 1H), 7.75 (d, J = 8.5 Hz ,1H),7.72–7.69(m,1H),7.62(dd,J=8.2,1.8Hz,1H),7.55(t,J=8.0Hz,1H),7.38(d,J=7. 7Hz, 1H), 4.10 (t, J = 6.1Hz, 2H), 3.52 (t, J = 4.6Hz, 4H), 2.62 (t, J = 6.1Hz, 2H), 2.44 (s, 4H).

[0202] Compound A19 13C-NMR data are: δ 160.68, 148.82, 147.66, 140.00, 138.89, 137.57, 133.38, 130.51, 130.36, 130.15, 129.94, 129.73, 128.36, 125.48, 123.93, 123.68, 123.00, 122.81, 122.39, 122.27, 119.63, 115.26, 115.23, 66.68, 66.68, 56.79, 53.64, 53.64, 43.09.

[0203] Example 20

[0204] A method for preparing a quinazolinone derivative comprises the following steps:

[0205] (1) Same as step (1) in Example 2;

[0206] (2) The same as step (2) of Example 2, the product 3-benzyl-6-bromoquinazolin-4(3H)-one was a light yellow solid with a yield of 82%;

[0207] (3) The same as step (3) of Example 2, the product 6-(2-aminobenzo[d]thiazol-5-yl)-3-benzylquinazolin-4(3H)-one intermediate was a light yellow solid with a yield of 81%;

[0208] (4) Synthesis of 1-(5-(3-(2-morpholinylethyl)-4-oxo-3,4-dihydroquinazolin-6-yl)benzo[d]thiazol-2-yl)-3-(4-(trifluoromethyl)phenyl)urea: The intermediate 6-(2-aminobenzo[d]thiazol-5-yl)-3-benzylquinazolin-4(3H)-one (100 mg, 0.26 mmol) and 4-trifluoromethylphenylisocyanate (140.34 mg,

[0209] 0.75 mmol) was added to dioxane (2 mL) and reacted at 80°C for 4 h. After completion of the reaction, the solvent was removed and the residue was purified by dichloromethane / methanol column chromatography to obtain a white solid, compound A20 of formula (II), in a 91% yield. Melting point: 152.8-155.2°C. HRMS (ESI): m / z 595.17206 [M+H] + .

[0210] Compound A20 1H-NMR data are: δ11.31(s,1H),9.61(s,1H),8.38(d,J=2.4Hz,1H),8.32(s,1H) ),8.16(dd,J=8.4,2.4Hz,1H),7.99(d,J=8.1Hz,1H),7.95(s,1H),7.75(d ,J=8.4Hz,3H),7.67(d,J=8.9Hz,2H),7.62(dd,J=8.3,1.9Hz,1H),4.10(t ,J=6.1Hz,2H),3.52(t,J=4.7Hz,4H),2.61(t,J=6.1Hz,2H),2.44(s,4H).

[0211] Compound 20 13 C-NMR data are: δ 160.68, 148.82, 147.66, 142.83, 138.89, 137.56, 133.38, 128.36, 127.58, 126.65, 126.62, 126.60, 126.57, 125.78, 123.99, 123.93, 123.38, 123.17, 122.82, 122.41, 122.27, 122.19, 119.05, 66.68, 66.68, 56.80, 53.64, 53.64, 43.10.

[0212] Example 21

[0213] A method for preparing a quinazolinone derivative comprises the following steps:

[0214] (1) Same as step (1) in Example 2;

[0215] (2) The same as step (2) of Example 2, the product 3-benzyl-6-bromoquinazolin-4(3H)-one was a light yellow solid with a yield of 74%;

[0216] (3) The product, 6-(2-aminobenzo[d]thiazol-5-yl)-3-benzylquinazolin-4(3H)-one, was a light yellow solid in the same manner as in step (3) of Example 2. The yield was 79%.

[0217] (4) Synthesis of 1-(5-(3-(2-(dimethylamino)ethyl)-4-oxo-3,4-dihydroquinazolin-6-yl)benzo[d]thiazol-2-yl)-3-(3-methoxyphenyl)urea: The intermediate 6-(2-aminobenzo[d]thiazol-5-yl)-3-benzylquinazolin-4(3H)-one (100 mg, 0.195 mmol) and 3-methoxyphenylisocyanate (87.28 mg, 0.585 mmol) were added to dioxane (2 mL) and reacted at 80°C for 4 h. After completion of the reaction, the solvent was removed and the residue was purified by dichloromethane / methanol column chromatography to obtain the compound A21 of formula (II) as a white solid in an 82% yield. Melting point: 125.1-127.5°C. HRMS (ESI): m / z 515.18518 [M+H]. + .

[0218] Compound A21 1 H-NMR data are: δ11.07(s,1H),9.27(s,1H),8.41(d,J=2.4Hz,1H),8.34(s,1H),8.20(dd,J=8.5,2.4Hz,1H),8.02(d,J=8.2Hz,1H),8.00(s,1H),7.76(d,J=8.4Hz,1H),7.64( dd,J=8.2,1.9Hz,1H),7.24(d,J=3.9Hz,2H),7.05(d,J=10.0Hz,1H),6.64(dd,J=8.2 ,2.8Hz,1H),4.10(t,J=6.1Hz,2H),3.76(s,3H),2.58(t,J=6.1Hz,2H),2.21(s,6H).

[0219] Compound A21 13 C-NMR data are: δ 161.10, 160.66, 160.19, 156.74, 148.79, 147.68, 140.16, 139.04, 137.51, 133.45, 131.41, 130.22, 128.38, 124.11, 123.97, 122.75, 122.35, 122.31, 117.73, 111.59, 108.85, 105.06, 57.75, 55.51, 45.69, 45.69, 43.93.

[0220] Example 22

[0221] A method for preparing a quinazolinone derivative comprises the following steps:

[0222] (1) Same as step (1) in Example 2;

[0223] (2) The same as step (2) of Example 2, the product 3-benzyl-6-bromoquinazolin-4(3H)-one was a light yellow solid with a yield of 74%;

[0224] (3) The product, 6-(2-aminobenzo[d]thiazol-5-yl)-3-benzylquinazolin-4(3H)-one, was a light yellow solid in the same manner as in step (3) of Example 2. The yield was 79%.

[0225] (4) Synthesis of 1-(5-(3-(2-(dimethylamino)ethyl)-4-oxo-3,4-dihydroquinazolin-6-yl)benzo[d]thiazol-2-yl)-3-(4-methoxyphenyl)urea: The intermediate 6-(2-aminobenzo[d]thiazol-5-yl)-3-benzylquinazolin-4(3H)-one (100 mg, 0.195 mmol) and 4-methoxyphenylisocyanate (87.28 mg, 0.585 mmol) were added to dioxane (2 mL) and reacted at 80°C for 4 h. After completion of the reaction, the solvent was removed and the residue was purified by dichloromethane / methanol column chromatography to obtain the compound A22 of formula (II) as a white solid in an 82% yield. Melting point: 274.4-276.8°C. HRMS (ESI): m / z 515.18518 [M+H]. + .

[0226] Compound A22 1 H-NMR data are: δ10.98(s,1H),9.08(s,1H),8.41(d,J=2.4Hz,1H),8.34(s,1H),8. 20(dd,J=8.5,2.3Hz,1H),8.02(d,J=8.2Hz,1H),7.99(d,J=1.9Hz,1H),7.76(d ,J=8.5Hz,1H),7.63(dd,J=8.2,1.8Hz,1H),7.44(d,J=9.0Hz,2H),6.93–6.91( m, 2H), 4.10 (t, J = 6.1Hz, 2H), 3.74 (s, 4H), 2.59 (t, J = 6.1Hz, 2H), 2.21 (s, 6H).

[0227] Compound A22 13C-NMR data are: δ 161.05, 160.67, 155.72, 152.63, 148.78, 147.67, 139.08, 137.46, 133.46, 131.81, 131.53, 129.25, 128.37, 123.96, 122.68, 122.35, 122.22, 121.22, 121.22, 117.83, 114.56, 114.56, 57.75, 55.67, 45.68, 45.68, 43.92.

[0228] Example 23

[0229] A method for preparing a quinazolinone derivative comprises the following steps:

[0230] (1) Same as step (1) in Example 2;

[0231] (2) The same as step (2) of Example 2, the product 3-benzyl-6-bromoquinazolin-4(3H)-one was a light yellow solid with a yield of 74%;

[0232] (3) The product, 6-(2-aminobenzo[d]thiazol-5-yl)-3-benzylquinazolin-4(3H)-one, was a light yellow solid in the same manner as in step (3) of Example 2. The yield was 79%.

[0233] (4) Synthesis of 1-(5-(3-(2-(dimethylamino)ethyl)-4-oxo-3,4-dihydroquinazolin-6-yl)benzo[d]thiazol-2-yl)-3-(4-fluorophenyl)urea: The intermediate 6-(2-aminobenzo[d]thiazol-5-yl)-3-benzylquinazolin-4(3H)-one (100 mg, 0.195 mmol) and p-fluorophenyl isocyanate (80.21 mg, 0.585 mmol) were added to dioxane (2 mL) and reacted at 80°C for 4 h. After completion of the reaction, the solvent was removed and the residue was purified by dichloromethane / methanol column chromatography to obtain the compound A23 of formula (II) as a white solid in an 81% yield. Melting point: 173.2-176.3°C. HRMS (ESI): m / z 503.16510 [M+H]. + .

[0234] Compound A23 1H-NMR data are: δ11.35(s,1H),9.62(s,1H),8.40(d,J=2.4Hz,1H),8.33(s,1H), 8.18(dd,J=8.5,2.2Hz,1H),8.01(d,J=8.2Hz,1H),7.97(d,J=1.9Hz,1H),7 .75(d,J=8.4Hz,1H),7.62(dd,J=8.2,1.8Hz,1H),7.57–7.55(m,2H),7.18( t,J=8.9Hz,2H), 4.09(t,J=6.1Hz,2H), 2.57(t,J=6.1Hz,2H), 2.20(s,6H).

[0235] Compound A23 13 C-NMR data are: δ 161.46, 160.65, 159.19, 157.60, 153.21, 148.77, 147.66, 139.07, 137.45, 135.46, 133.41, 131.44, 128.36, 123.94, 122.67, 122.34, 122.18, 121.25, 121.20, 117.65, 116.01, 115.86, 57.77, 45.71, 45.71, 43.96.

[0236] Example 24

[0237] A method for preparing a quinazolinone derivative comprises the following steps:

[0238] (1) Same as step (1) in Example 2;

[0239] (2) The same as step (2) of Example 2, the product 3-benzyl-6-bromoquinazolin-4(3H)-one was a light yellow solid with a yield of 80%;

[0240] (3) The same as step (3) of Example 2, the product 6-(2-aminobenzo[d]thiazol-5-yl)-3-benzylquinazolin-4(3H)-one intermediate was a light yellow solid with a yield of 84%;

[0241] (4) Synthesis of 1-(5-(3-(2-cyclohexylethyl)-4-oxo-3,4-dihydroquinazolin-6-yl)benzo[d]thiazol-2-yl)-3-(3-methoxyphenyl)urea: The intermediate 6-(2-aminobenzo[d]thiazol-5-yl)-3-benzylquinazolin-4(3H)-one (100 mg, 0.25 mmol) and 3-methoxyphenylisocyanate (110.62 mg, 0.5 mmol) were added to dioxane (2 mL) and reacted at 80°C for 4 h. After the reaction was completed, the solvent was removed and the residue was purified by dichloromethane / methanol column chromatography to obtain the compound A24 of formula (II) as a white solid in a yield of 97%. Melting point: 257.5-259.7°C. HRMS (ESI): m / z 554.21997 [M+H]. + .

[0242] Compound A24 1 H-NMR data are: δ10.93(s,1H),9.21(s,1H),8.41(s,1H),8.39(d,J=2.4Hz,1H),8.18(dd,J=8.5,2.3Hz,1H),8.01(d,J=8.2Hz,1H),7.98(s,1H),7.75(d,J=8.4Hz,1H),7.63(dd,J=8.2,1.9Hz,1H),7.23(d,J =8.2Hz,2H),7.04(d,J=7.5Hz,1H),6.64(dd,J=8.2,2.6Hz,1H),4.00(d,J=9.6Hz,2H),3.76(s,3H), 1.74(dd,J=12.7,3.6Hz,3H), 1.65(dt,J=12.5,3.4Hz,3H), 1.59(q,J=6.6Hz,4H), 1.19–1.15(m,2H).

[0243] Compound A24 13 C-NMR data are: δ 160.58, 160.19, 148.47, 147.65, 140.12, 139.07, 137.51, 133.37, 131.63, 130.22, 128.39, 123.92, 122.73, 122.35, 122.32, 111.58, 108.86, 105.05, 55.51, 44.53, 36.66, 35.24, 32.99, 32.99, 26.48, 26.11, 26.11.

[0244] Example 25

[0245] A method for preparing a quinazolinone derivative comprises the following steps:

[0246] (1) Same as step (1) in Example 2;

[0247] (2) The same as step (2) of Example 2, the product 3-benzyl-6-bromoquinazolin-4(3H)-one was a light yellow solid with a yield of 80%;

[0248] (3) The same as step (3) of Example 2, the product 6-(2-aminobenzo[d]thiazol-5-yl)-3-benzylquinazolin-4(3H)-one intermediate was a light yellow solid with a yield of 84%;

[0249] (4) Synthesis of 1-(5-(3-(2-cyclohexylethyl)-4-oxo-3,4-dihydroquinazolin-6-yl)benzo[d]thiazol-2-yl)-3-(4-fluorophenyl)urea: The intermediate 6-(2-aminobenzo[d]thiazol-5-yl)-3-benzylquinazolin-4(3H)-one (100 mg, 0.37 mmol) and p-fluorophenyl isocyanate (152.53 mg, 1.11 mmol) were added to dioxane (2 mL) and reacted at 80°C for 4 h. After the reaction was completed, the solvent was removed and the residue was purified by dichloromethane / methanol column chromatography to obtain the compound A25 of formula (II) as a white solid in a yield of 97%. Melting point: 297.2-299.7°C. HRMS (ESI): m / z 564.18176 [M+Na] + .

[0250] Compound A25 1 H-NMR data are: δ11.03 (s, 1H), 9.23 (s, 1H), 8.38 (d, J = 4.0 Hz, 2H), 8.15 (dd, J = 8.4, 2.4 Hz, 1H), 8.00–7.89 (m, 2H), 7.73 (d, J = 8.4 Hz, 1H), 7.60 (dd, J = 8.2, 1.8 Hz, 1H), 7.55 (dd, J = 9.1, 4.9 Hz, 2H), 7. 16(t,J=8.8Hz,2H),4.02–3.92(m,2H),1.72(d,J=12.9Hz,2H),1.63(dd,J=9.4,3.5Hz,2H),1.57 (q,J=6.8Hz,3H),1.25(ddt,J=12.4,8.7,4.3Hz,1H),1.19–1.08(m,3H),0.91(q,J=11.9Hz,2H).

[0251] Compound A25 13C-NMR data are: δ 161.04, 160.54, 159.24, 157.65, 152.85, 148.37, 147.64, 139.02, 137.48, 135.27, 133.26, 131.34, 128.34, 123.89, 122.65, 122.33, 122.25, 121.27, 121.21, 115.99, 115.84, 44.52, 36.65, 35.25, 32.97, 32.97, 26.46, 26.10, 26.10.

[0252] Example 26

[0253] A method for preparing a quinazolinone derivative comprises the following steps:

[0254] (1) Same as step (1) in Example 2;

[0255] (2) The same as step (2) of Example 2, the product 3-benzyl-6-bromoquinazolin-4(3H)-one was a light yellow solid with a yield of 85%;

[0256] (3) The same as step (3) of Example 2, the product 6-(2-aminobenzo[d]thiazol-5-yl)-3-benzylquinazolin-4(3H)-one intermediate was a light yellow solid with a yield of 82%;

[0257] (4) Synthesis of 1-(5-(3-butyl-4-oxo-3,4-dihydroquinazolin-6-yl)benzo[d]thiazol-2-yl)-3-(4-fluorophenyl)urea: The intermediate 6-(2-aminobenzo[d]thiazol-5-yl)-3-benzylquinazolin-4(3H)-one (100 mg, 0.28 mmol) and p-fluorophenyl isocyanate (117.37 mg, 0.86 mmol) were added to dioxane (2 mL) and reacted at 80°C for 4 h. After completion of the reaction, the solvent was removed and the residue was purified by dichloromethane / methanol column chromatography to obtain the compound A26 of formula (II) as a white solid in an 89% yield. Melting point: 330.5-332.7°C. HRMS (ESI): m / z 510.13553 [M+Na]. + .

[0258] Compound A26 1H-NMR data are: δ11.04(s,1H),9.26(s,1H),8.40(s,1H),8.39(d,J=2.4Hz,1H),8.18 (dd,J=8.5,2.3Hz,1H),8.01(d,J=8.2Hz,1H),7.97(s,1H),7.76(d,J=8.4Hz,1H ),7.62(dd,J=8.2,1.9Hz,1H),7.56–7.53(m,2H),7.17(t,J=8.8Hz,2H),3.99(t ,J=7.3Hz,2H),1.69(t,J=7.3Hz,2H),1.33–1.29(m,2H),0.91(t,J=7.4Hz,3H).

[0259] Compound A26 13 C-NMR data are: δ 160.69, 159.25, 157.66, 148.51, 147.64, 139.08, 137.51, 135.22, 133.40, 128.39, 123.91, 122.74, 122.33, 121.33, 121.28, 116.02, 116.02, 115.87, 115.87, 46.25, 31.18, 19.76, 14.02.

[0260] Example 27

[0261] A method for preparing a quinazolinone derivative comprises the following steps:

[0262] (1) Same as step (1) in Example 2;

[0263] (2) The same as step (2) of Example 2, the product 3-benzyl-6-bromoquinazolin-4(3H)-one was a light yellow solid with a yield of 85%;

[0264] (3) The same as step (3) of Example 2, the product 6-(2-aminobenzo[d]thiazol-5-yl)-3-benzylquinazolin-4(3H)-one intermediate was a light yellow solid with a yield of 82%;

[0265] (4) Synthesis of 1-(5-(3-(cyclopropylmethyl)-4-oxo-3,4-dihydroquinazolin-6-yl)benzo[d]thiazol-2-yl)-3-(4-fluorophenyl)urea: The intermediate 6-(2-aminobenzo[d]thiazol-5-yl)-3-benzylquinazolin-4(3H)-one (100 mg, 0.29 mmol) and p-fluorophenyl isocyanate (117.91 mg, 0.86 mmol) were added to dioxane (2 mL) and reacted at 80°C for 4 h. After completion of the reaction, the solvent was removed and the residue was purified by dichloromethane / methanol column chromatography to obtain the compound A27 of formula (II) as a white solid in an 89% yield. Melting point: 330.8-332.5°C. HRMS (ESI): m / z 508.11963 [M+Na] + .

[0266] Compound A27 1 H-NMR data are: δ11.06(s,1H),9.26(s,1H),8.45(s,1H),8.42(d,J=2.4Hz,1H),8.20(dd,J=8.5,2.3Hz,1H),8.01(d,J=8.2Hz,1H),7.99(s,1H),7.77(d,J=8.5Hz,1H),7.64(dd ,J=8.2,1.9Hz,1H),7.55(dd,J=9.1,4.9Hz,2H),7.18(t,J=8.8Hz,2H),3.87(d,J=7.2 Hz,2H),1.30(ddt,J=12.6,7.6,3.9Hz,1H),0.53–0.50(m,2H),0.45(t,J=4.3Hz,2H).

[0267] Compound A27 13 C-NMR data are: δ 160.78, 159.24, 157.66, 148.42, 147.71, 139.10, 137.50, 135.27, 133.45, 128.41, 123.96, 122.74, 122.41, 122.32, 121.31, 121.26, 116.02, 115.87, 50.61, 11.28, 4.00, 4.00.

[0268] Example 28

[0269] A method for preparing a quinazolinone derivative comprises the following steps:

[0270] (1) Same as step (1) in Example 2;

[0271] (2) The same as step (2) of Example 2, the product 3-benzyl-6-bromoquinazolin-4(3H)-one was a light yellow solid with a yield of 74%;

[0272] (3) The product, 6-(2-aminobenzo[d]thiazol-5-yl)-3-benzylquinazolin-4(3H)-one, was a light yellow solid in the same manner as in step (3) of Example 2. The yield was 79%.

[0273] (4) Synthesis of 1-(4-fluorophenyl)-3-(5-(3-isopentyl-4-oxo-3,4-dihydroquinazolin-6-yl)benzo[d]thiazol-2-yl)urea: The intermediate 6-(2-aminobenzo[d]thiazol-5-yl)-3-benzylquinazolin-4(3H)-one (100 mg, 0.27 mmol) and p-fluorophenyl isocyanate (112.96 mg, 0.82 mmol) were added to dioxane (2 mL) and reacted at 80°C for 4 h. After completion of the reaction, the solvent was removed and the residue was purified by dichloromethane / methanol column chromatography to obtain the compound A28 of formula (II) as a white solid in an 87% yield. Melting point: 331.2-332.7°C. HRMS (ESI): m / z 524.15082 [M+Na] + .

[0274] Compound A28 1 H-NMR data are: δ11.04(s,1H),9.24(s,1H),8.39(d,J=11.8Hz,2H),8.17(d,J=8.4Hz,1H),7.99(d,J=8.2Hz,1H),7.96(s,1H),7.75(d,J=8.5Hz,1H),7.61(d,J=8.3Hz,1H),7.54(t,J=6.7Hz,2H),7.17(t,J=8.6Hz,2H),3.99(t,J=7.0Hz,2H),1.58(t,J=6.4Hz,3H),0.93(s,6H).

[0275] Compound A28 13 C-NMR data are: δ 160.62, 159.25, 157.66, 148.43, 147.61, 139.06, 137.49, 135.22, 133.36, 131.99, 129.12, 128.37, 123.89, 122.71, 122.31, 122.31, 121.32, 121.27, 116.01, 116.01, 115.86, 115.86, 44.92, 38.09, 25.83, 22.74, 22.74.

[0276] Example 29

[0277] A method for preparing a quinazolinone derivative comprises the following steps:

[0278] (1) Same as step (1) in Example 2;

[0279] (2) The same as step (2) of Example 2, the product 3-benzyl-6-bromoquinazolin-4(3H)-one was a light yellow solid with a yield of 85%;

[0280] (3) The same as step (3) of Example 2, the product 6-(2-aminobenzo[d]thiazol-5-yl)-3-benzylquinazolin-4(3H)-one intermediate was a light yellow solid with a yield of 82%;

[0281] (4) Synthesis of 1-(4-fluorophenyl)-3-(5-(4-oxo-3-propyl-3,4-dihydroquinazolin-6-yl)benzo[d]thiazol-2-yl)urea: The intermediate 6-(2-aminobenzo[d]thiazol-5-yl)-3-benzylquinazolin-4(3H)-one (100 mg, 0.30 mmol) and p-fluorophenyl isocyanate (123.40 mg, 0.90 mmol) were added to dioxane (2 mL) and reacted at 80°C for 4 h. After completion of the reaction, the solvent was removed and the residue was purified by dichloromethane / methanol column chromatography to obtain the compound A29 of formula (II) as a white solid in an 86% yield. Melting point: 334.3-336.8°C. HRMS (ESI): m / z 496.11942 [M+Na] + .

[0282] Compound A29 1 H-NMR data are: δ11.04(s,1H),9.24(s,1H),8.39(s,1H),8.38(d,J=2.4Hz,1H), 8.16(dd,J=8.4,2.3Hz,1H),7.98(d,J=8.2Hz,1H),7.95(s,1H),7.75(d,J= 8.4Hz,1H),7.60(dd,J=8.2,1.9Hz,1H),7.55–7.52(m,2H),7.16(t,J=8.9H z, 2H), 3.95 (t, J = 7.2Hz, 2H), 1.72 (q, J = 7.3Hz, 2H), 0.89 (t, J = 7.4Hz, 3H).

[0283] Compound A29 13C-NMR data are: δ 160.70, 159.24, 157.66, 148.52, 147.63, 139.06, 137.49, 135.22, 133.37, 131.98, 129.11, 128.37, 123.90, 122.70, 122.32, 122.30, 121.32, 121.27, 116.01, 115.86, 48.02, 22.40, 11.30.

[0284] Proliferation inhibitory activity assay

[0285] (1) Experimental methods

[0286] Human non-small cell lung cancer cells (A549, HCC827, PC9, and H1975) were cultured in vitro in a cell culture incubator at 37°C and 5% CO2 until the logarithmic phase. These cells were seeded in a 96-well plate at a density of 3,000 cells / well, with 100 μL per well, and then incubated in a cell culture incubator for 24 hours. The compounds of the invention were then administered in culture medium at varying concentrations, with triplicate wells set up for each concentration as dosing groups. Blank control wells were also set up, including negative control wells seeded with cells and zero wells seeded with cells. The cells were then incubated for a further 72 hours.

[0287] The toxicity of inventive compounds 1-29 against the aforementioned tumor cells was determined using the MTT assay. To the treatment group, 20 μL of 5 mg mL MTT solution was added. Culture was continued under the same conditions for 4 h, after which the culture medium was discarded. 150 μL of DMSO-dissolved formazan was added to each well. The cells were shaken on a plate shaker for 10 min. The absorbance at 490 nm (OD) was measured using a microplate reader. The cell growth inhibition rate (IC50) was calculated using the following formula:

[0288]

[0289] Average OD value of drug-treated group: the average absorbance value measured after drug addition and incubation of each group;

[0290] Average OD value of negative control group: absorbance value measured in control wells with only cells but no drug added;

[0291] Average OD value of zero-adjusted wells: absorbance value measured in wells without cells or drugs.

[0292] (2) Experimental results

[0293] The experimental results are shown in Table 1: In the A549 cell line, (1) compared with the case where the R1 position was an aromatic ring, the anti-tumor activity of the compound was improved when the R1 substituent was a short-chain alkane or cycloalkane, with the short-chain alkane having the best activity; (2) the anti-tumor activity was significantly improved when the thiazole ring was connected to a carbonamide structure than when it was connected to an amide structure; (3) the activity of the thiazole ring carbonamide structure connected to a benzene ring was better than that of the carbonamide structure connected to a fatty group, and the activity was improved when the benzene ring on the carbonamide had a strong electron-withdrawing group F or a strong electron-donating group methoxy.

[0294] Table 1 Inhibitory activity of the compounds prepared in Examples 1-29 on tumor cell proliferation

[0295]

[0296]

[0297] Toxicity testing

[0298] Compounds 1 to 29 were used as test samples to detect the strong inhibitory activity on tumor cell proliferation and the IC 50 The toxicity of compounds <5 μM to normal human cells BEAS-2B is shown in Table 2:

[0299] Table 2 Inhibitory activity of compounds on normal human BEAS-2B cells

[0300]

[0301]

[0302] BEAS-2B is a normal cell, so the larger the IC50 value, the better the safety. From the data in Table 2, it can be seen that the compound 1-29 obtained in the present invention has low inhibitory activity on normal human cell proliferation, that is, it is non-toxic to normal human cells.

[0303] The effect of compound A29 on the A549 cell cycle was detected by flow cytometry. Figure 1 As shown, from Figure 1 It can be seen from the data that compound A29 of the present invention has a significant G1 cycle arrest effect on A549 cells, and thus has anti-tumor activity.

[0304] The mechanism of action of compound A29 of the present invention was studied using Western blot and Proteome Profiler Human Phospho-RTK array kit. The results are as follows: Figure 2 As shown, compound A29 can significantly inhibit the activity of the oncogenic ALK / PI3K / Akt signaling pathway, which once again demonstrates that the compound of the present invention has anti-tumor activity.

[0305] JC-1 dye was used to detect the depolarization of A549 mitochondrial membrane potential induced by compound A29 by flow cytometry and inverted fluorescence microscopy, thereby causing oxidative stress damage in tumor cells. The results are as follows Figure 3 shown.

[0306] The effect of compound A29 on apoptosis of A549 cells was detected by flow cytometry using an apoptosis kit. Figure 4 shown.

[0307] Proteins from the nucleus and cytoplasm of A549 cells were extracted and analyzed by Western blot. The results were as follows: Figure 5 As shown, in Figure 5 It was found that compound A29 effectively reduced the expression levels of Nrf2 proteins in the nucleus and cytoplasm, indicating that the compound of the present invention has significant anti-tumor activity.

[0308] The inhibitory effect of A29 on tumor spheres was detected using 3D cell culture technology, and the results were as follows: Figure 6 As shown, the present invention can effectively inhibit the growth of 3D tumor spheres, especially at higher concentrations, and has a certain decomposition effect on tumor spheres.

[0309] References herein to "embodiments" mean that a particular feature, structure, or characteristic described in connection with the embodiments may be included in at least one embodiment of the present invention. The appearance of this phrase in various places in the specification does not necessarily refer to the same embodiment, nor does it constitute a separate or alternative embodiment that is mutually exclusive of other embodiments. It is understood, both explicitly and implicitly, by those skilled in the art that the embodiments described herein may be combined with other embodiments.

[0310] Finally, it should be noted that the embodiments disclosed in the present invention are only preferred embodiments of the present invention, which are only used to illustrate the technical solutions of the present invention, rather than to limit them. Although the present invention has been described in detail with reference to the aforementioned embodiments, those skilled in the art should understand that the technical solutions described in the aforementioned embodiments can still be modified, or some of the technical features therein can be replaced by equivalents. However, these modifications or replacements do not deviate the essence of the corresponding technical solutions from the spirit and scope of the technical solutions of the various embodiments of the present invention.

Claims

1. A quinazolinone derivative, characterized in that: It is a urea compound represented by the general structural formula (II); The urea compound represented by formula (II) is selected from 1-(5-(3-benzyl-4-oxo-3,4-dihydroquinazolin-6-yl)benzo[d]thiazol-2-yl)-3-(p-tolyl)urea, 1-benzyl-3-(5-(3-benzyl-4-oxo-3,4-dihydroquinazolin-6-yl)benzo[d]thiazol-2-yl)urea, 1-(5-(3-benzyl-4-oxo-3,4-dihydroquinazolin-6-yl)benzo[d]thiazol-2-yl)-3-(4-methoxyphenyl)urea, 1-(5-(3-benzyl-4-oxo-3,4-dihydroquinazolin-6-yl)benzo[d]thiazol-2-yl)-3-(3-methoxyphenyl)urea, 1-(5-(3-benzyl-4-oxo-3,4-dihydroquinazolin-6-yl)benzo[d]thiazol-2-yl) -3,4-dihydroquinazolin-6-yl)benzo[d]thiazol-2-yl)-3-(3-fluorophenyl)urea, 1-(5-(3-benzyl-4-oxo-3,4-dihydroquinazolin-6-yl)benzo[d]thiazol-2-yl)-3-(4-fluorophenyl)urea, 1-(5-(3-benzyl-4-oxo-3,4-dihydroquinazolin-6-yl)benzo[d]thiazol-2-yl)-3-(3-(trifluoromethyl)phenyl)urea, 1-(5-(3-benzyl-4-oxo-3,4-dihydroquinazolin-6-yl)benzo[d]thiazol-2-yl)-3-(4-(trifluoromethyl)phenyl)urea, 1-(5-(3-benzyl-4-oxo-3,4-dihydroquinazolin-6-yl)benzo[d]thiazol-2-yl)-3-(4-(trifluoromethyl)phenyl)urea, oxazolin-2-yl)-3-(3,5-bis(trifluoromethyl)phenyl)urea, 1-(5-(3-benzyl-4-oxo-3,4-dihydroquinazolin-6-yl)benzo[d]thiazol-2-yl)-3-ethylurea, 1-(5-(3-benzyl-4-oxo-3,4-dihydroquinazolin-6-yl)benzo[d]thiazol-2-yl)-3-isopropylurea, 1-(5-(3-benzyl-4-oxo-3,4-dihydroquinazolin-6-yl)benzo[d]thiazol-2-yl)-3-butylurea, 1-(5-(3-benzyl-4-oxo-3,4-dihydroquinazolin-6-yl)benzo[d]thiazol-2-yl)-3-cyclohexylurea, 1-(5-(3-(2-morpholinoethyl)-4-oxo- -3,4-dihydroquinazolin-6-yl)benzo[d]thiazol-2-yl)-3-phenylethyl urea, 1-(3-methoxyphenyl)-3-(5-(3-(2-morpholinylethyl)-4-oxo-3,4-dihydroquinazolin-6-yl)benzo[d]thiazol-2-yl)urea, 1-(4-methoxyphenyl)-3-(5-(3-(2-morpholinylethyl)-4-oxo-3,4-dihydroquinazolin-6-yl)benzo[d]thiazol-2-yl)urea, 1-(4-fluorophenyl)-3-(5-(3-(2-morpholinylethyl)-4-oxo-3,4-dihydroquinazolin-6-yl)benzo[d]thiazol-2-yl)urea, 1-(5-(3-(2-morpholinylethyl)-4-oxo-3,4-dihydroquinazolin-6-yl)benzo[d]thiazol-2-yl)-3-(3-(trifluoromethyl)phenyl)urea, 1-(5-(3-(2-morpholinoethyl)-4-oxo-3,4-dihydroquinazolin-6-yl)benzo[d]thiazol-2-yl)-3-(4-(trifluoromethyl)phenyl)urea, 1-(5-(3-(2-(dimethylamino)ethyl)-4-oxo-3,4-dihydroquinazolin-6-yl)benzo[d]thiazol-2-yl)-3-(4-(trifluoromethyl)phenyl)urea (3-methoxyphenyl)urea, 1-(5-(3-(2-(dimethylamino)ethyl)-4-oxo-3,4-dihydroquinazolin-6-yl)benzo[d]thiazol-2-yl)-3-(4-methoxyphenyl)urea, 1-(5-(3-(2-(dimethylamino)ethyl)-4-oxo-3,4-dihydroquinazolin-6-yl)benzo[d]thiazol-2-yl)-3-(4-fluorophenyl)urea, 1-(5-(3-(2-cyclohexylethyl)-4- oxo-3,4-dihydroquinazolin-6-yl)benzo[d]thiazol-2-yl)-3-(3-methoxyphenyl)urea, 1-(5-(3-(2-cyclohexylethyl)-4-oxo-3,4-dihydroquinazolin-6-yl)benzo[d]thiazol-2-yl)-3-(4-fluorophenyl)urea, 1-(5-(3-butyl-4-oxo-3,4-dihydroquinazolin-6-yl)benzo[d]thiazol-2-yl)-3-(4-fluorophenyl)urea, 1-(5-(3-butyl-4-oxo-3,4-dihydroquinazolin-6-yl)benzo[d]thiazol-2-yl)-3-(4-fluorophenyl)urea, (3-(cyclopropylmethyl)-4-oxo-3,4-dihydroquinazolin-6-yl)benzo[d]thiazol-2-yl)-3-(4-fluorophenyl)urea, 1-(4-fluorophenyl)-3-(5-(3-isopentyl-4-oxo-3,4-dihydroquinazolin-6-yl)benzo[d]thiazol-2-yl)urea, 1-(4-fluorophenyl)-3-(5-(4-oxo-3-propyl-3,4-dihydroquinazolin-6-yl)benzo[d]thiazol-2-yl)urea.

2. A method for preparing the quinazolinone derivative according to claim 1, characterized in that: The following steps are involved: (1) Preparation of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazol-2-amine: 2-amino-5-bromobenzothiazole was used as a raw material and reacted with diboronic acid pinacol ester in a molar mass ratio of 1:(1-2) in dioxane with a catalyst [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex at 100-110°C for 18 h-30 h to obtain 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazol-2-amine; (2) Preparation of 3-benzyl-6-bromoquinazolin-4(3H)-one: 2-amino-5-bromobenzoic acid, triethyl orthoformate, benzylamine and iodine were added to anhydrous ethanol in a molar mass ratio of 1:(1-1.5):(1-1.5):(0.01-0.015), and the reaction was carried out at 75°C-85°C for 5h-7h to obtain 3-benzyl-6-bromoquinazolin-4(3H)-one by cyclization. (3) Synthesis of 6-(2-aminobenzo[d]thiazol-5-yl)-3-benzylquinazolin-4(3H)-one: 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazol-2-amine obtained in step (1) and 3-benzyl-6-bromoquinazolin-4(3H)-one obtained in step (2) were added to dioxane and water in a molar mass ratio of (2-2.5):(1-1.5), and then K2CO3 and dichloropalladium carbon catalyst were added and reacted at 100°C-110°C for 4h-6h to obtain 6-(2-aminobenzo[d]thiazol-5-yl)-3-benzylquinazolin-4(3H)-one; (4) 6-(2-aminobenzo[ d ]thiazol-5-yl)-3-benzylquinazolin-4(3H)-one is reacted with isocyanate in a molar mass ratio of 1:(1-1.5) in dioxane at 75°C-85°C for 4h-6h to obtain a quinazolinone derivative.

3. The method for preparing the quinazolinone derivative according to claim 2, wherein: The amount of the catalyst [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex added in step (1) is 3%-8% of the molar mass of 2-amino-5-bromobenzothiazole.

4. The method for preparing the quinazolinone derivative according to claim 2, wherein: In step (3), the molar mass ratio of K2CO3 to 3-benzyl-6-bromoquinazoline-4(3H)-one is 3:1; and the molar mass ratio of the catalyst dichloropalladium carbon to 3-benzyl-6-bromoquinazoline-4(3H)-one is 0.05:

1.

5. Use of a quinazolinone derivative in the preparation of an anti-non-small cell lung cancer cell drug, characterized in that: The quinazolinone derivative is the quinazolinone derivative according to claim 1 or the quinazolinone derivative obtained by the preparation method according to any one of claims 2 to 4.

Images