Trifluoromethyl substituted quinazolinone compound as well as preparation method and application thereof

Abstract

The invention relates to the technical field of biological medicine, and discloses a trifluoromethyl substituted quinazolinone compound as well as a preparation method and application thereof. According to the method, quinazolinone and trifluoromethyl alkyne are adopted as reaction substrates, no transition metal catalyst is needed, and the trifluoromethyl substituted quinazolinone compound can be prepared only through conventional cheap inorganic base catalysis; the reaction yield can reach medium to excellent, the chemical selectivity and regioselectivity of the reaction are excellent, the reaction condition is mild, and the application range of the substrate is wide; the method is simple and convenient to operate, low in cost, few in side reaction, high in product purity, convenient to separate and purify and suitable for large-scale preparation; the obtained product has a very good application prospect in the field of biological medicines, and particularly has relatively good anti-tumor activity.

Description

Technical Field

[0001] The present invention relates to the field of biomedicine technology, and more specifically to a trifluoromethyl substituted quinazolinone compound, a preparation method and an application thereof. Background Art

[0002] Pharmacophore molecular hybridization is an important strategy for new drug discovery, which has attracted widespread interest and great attention from a wide range of organic synthetic chemists and medicinal chemists (X. Li, X. Li, F. Liu, S. Li, D. Shi, J. Med. Chem. 2021, 64, 10581-10605; B. Sharma, A. Agarwal, SKAwasthi, RSC Med. Chem. 2023, 14, 1227-1253; AK Singh, A. Kumar, H. Singh, P. Sonawane, H. Paliwal, S. Thareja, P. Pathak, M. Grishina, M. Jaremko, AE Emwas, JP Yadav, A. Verma, H. Khalilullah, P. Kumar, Pharmaceuticals 2022, 15, 1071). This technology develops new organic synthesis methods to combine two or more effective pharmacophores into one molecule through rational design, which often has a synergistic effect.

[0003] As a special strong electron-withdrawing fluorine-containing group, trifluoromethyl has many excellent properties and is commonly found in various new drugs and pesticide molecules. Due to the high electronegativity and small atomic radius of fluorine atoms, the introduction of trifluoromethyl into drug molecules can often improve the lipophilicity and drug metabolism of drugs (W. Zhu, J. Wang, S. Wang, Z. Gu, JL K.Izawa,H.Liu,VASoloshonok,J.FluorineChem.,2014,167,37-54;M.Bassetto,S.Ferla,F.Pert usati,FutureMed.Chem.,2015,7,527–546; F.Meyer,Chem.Commun.,2016,52,3077-3094;M.Inoue, Y. Sumii, N. Shibata, ACSOmega2020, 5, 10633-10640; ASNair, AKSingh, A. Kumar, S. Kumar, S. Sukumaran, VP Koyiparambath, LKPappachen, TMRangarajan, H. Kim, B. Mathew, Processes 2022, 10, 2054). Therefore, it is of great scientific significance and practical application value to study and develop simple and effective methods to introduce trifluoromethyl groups into quinazolinone and synthesize trifluoromethyl-substituted quinazolinone compounds.

[0004] Quinazolinone is an important class of nitrogen-containing alkaloid core skeletons, which are commonly found in many natural products and have a variety of important physiological and pharmaceutical activities (H. Li, G. Fu, W. Zhong, Euro. J. Med. Chem. 2023, 245, 114915; I. Khan, A. Ibrar, N. Abbas, A. Saeed, Euro. J. Med. Chem. 2014, 76, 193-244; UAKshirsagar, Org. Biomol. Chem. 2015, 13, 9336-9352). In particular, N3-substituted quinazolinone compounds have been reported to have anticancer, anti-inflammatory, antidiabetic, anticonvulsant, antiviral and antibacterial activities (MR Mangroo, MS Shahbaz, A. Anwar, SM Saad, KM Khan, NAKhan, R. Siddiqui, ACS Chem. Neurosci. 2020, 11, 2438-2449; X. Wang, J. Chai, X. Kong, F. Jin, M. .Chen, C.Yang, W.Xue, Bioorg.Med.Chem.2021,45,116330; B.Cheng, Z.Cai, Z.Luo, S.Luo, Z.Luo, Y.Cheng, Y.Yu, J.Guo, Y.Ju, Q.Gu, J.Xu, X.Jiang, G.Li, H.Zhou, J.Med.Chem.2022,65,15840-15855). Due to the structural characteristics of the quinazolinone molecule itself, it is easy to undergo enol and keto interconversion and is always in a dynamic equilibrium.This results in the generation of N1- and O-functionalized byproducts when the N3 position is directly substituted (E. Pitta, O. Balabon, MK Rogacki, J. Gomez, F. Cunningham, J. Joosens, K. Augustyns, P. van der Veken, R. Bates, Euro. J. Med. Chem. 2017, 125, 890-901; RE Hartung, MC Wall, S. Lebreton, M. Smrc Ina, M. Patek, Heterocycles, 2017, 94, 1305; G. S. Chen, S. Kalchar, C. Kuo, C. Chang, C. Usifoh, J. Chern, J. Org. Chem. 2003, 68, 2502-2505; M. Spulák, Z. Novák, K. Palát, J. rí Kune, J. Pourová, M. Pour, Tetrahedron 2013, 69, 1705-1711). In order to solve the above challenges, people use expensive transition metal catalysts to achieve artificial control of the selectivity in the reaction process. For example, the Cook group reported palladium-catalyzed coupling reactions of quinazolinone with allyl alcohol and olefins in 2015 and 2016, respectively (D. Kumar, S.R. Vemula, G.R. Cook, Green Chem. 2015, 17, 4300-4306; S.R. Vemula, D. Kumar, G.R. Cook, ACS Catal. 2016, 6, 5295-5301). In 2017, the Lu group reported palladium-catalyzed coupling reactions of quinazolinone with phenylmethylalkyne (C. Lu, D. Chen, H. Chen, H. Wang, H. Jin, X. Huang, J. Gao, Org. Biomol. Chem. 2017, 15, 5756-5763). In the same year, the Breit group achieved rhodium-catalyzed asymmetric addition reaction of quinazolinone with allene and allyl carbonate (Y. Zhou, B. Breit, Chem. Eur. J. 2017, 23, 18156-18160). In 2021, Kumar et al. achieved nickel-catalyzed reaction of quinazolinone with allyl alcohol and dimethyl carbonate (GN Vaidya, M. Nagpure, D. Kumar, ACS Sustainable Chem. Eng. 2021, 9, 1846-1855).In 2023, He et al. realized the asymmetric substitution reaction of quinazolinone and allyl carbonate catalyzed by iridium (J.Zou, Y.Yang, J.Gu, F.Liu, Z.Ye, W.Yi, Y.He, Angew.Chem.Int.Ed.2023,62,e202310320). However, expensive transition metal catalysts such as palladium, rhodium, and iridium greatly increase the reaction cost and produce heavy metal residue problems, which limits its application in modern drug research and development. Therefore, it is urgent to develop new efficient and highly selective green synthesis methods to construct a molecular library of quinazolinone N3-substituted derivatives with structural diversity to meet the needs of the green pharmaceutical industry. Summary of the invention

[0005] Based on this, in order to solve the above problems, the present invention provides a trifluoromethyl substituted quinazolinone compound, a preparation method and an application thereof.

[0006] In a first aspect, the present invention provides a trifluoromethyl substituted quinazolinone compound as shown in formula I,

[0007] The trifluoromethyl substituted quinazolinone compound shown in formula I:

[0008]

[0009] Among them, R 1 is selected from hydrogen, C1-C8 alkyl, C1-C8 alkoxy, halogen, nitro, trifluoromethyl; R 2 Selected from hydrogen, halogen, cyano, trifluoromethyl.

[0010] Preferably, the R 1 is selected from hydrogen, methyl, methoxy, fluorine, chlorine, bromine, iodine, nitro, trifluoromethyl; said R 2 Selected from bromine, iodine, cyano, trifluoromethyl.

[0011] Preferably, the trifluoromethyl substituted quinazolinone compound is one of the following compounds:

[0012] (Z)-3-(3,3,3-trifluoro-1-phenylprop-1-en-1-yl)quinazolin-4(3H)-one;

[0013] (Z)-5-Fluoro-3-(3,3,3-trifluoro-1-phenylprop-1-en-1-yl)quinazolin-4(3H)-one;

[0014] (Z)-5-chloro-3-(3,3,3-trifluoro-1-phenylprop-1-en-1-yl)quinazolin-4(3H)-one;

[0015] (Z)-6-Fluoro-3-(3,3,3-trifluoro-1-phenylprop-1-en-1-yl)quinazolin-4(3H)-one;

[0016] (Z)-6-Chloro-3-(3,3,3-trifluoro-1-phenylprop-1-en-1-yl)quinazolin-4(3H)-one;

[0017] (Z)-6-bromo-3-(3,3,3-trifluoro-1-phenylprop-1-en-1-yl)quinazolin-4(3H)-one;

[0018] (Z)-6-iodo-3-(3,3,3-trifluoro-1-phenylprop-1-en-1-yl)quinazolin-4(3H)-one;

[0019] (Z)-6-methoxy-3-(3,3,3-trifluoro-1-phenylprop-1-en-1-yl)quinazolin-4(3H)-one;

[0020] (Z)-7-Fluoro-3-(3,3,3-trifluoro-1-phenylprop-1-en-1-yl)quinazolin-4(3H)-one;

[0021] (Z)-7-Chloro-3-(3,3,3-trifluoro-1-phenylprop-1-en-1-yl)quinazolin-4(3H)-one;

[0022] (Z)-7-Bromo-3-(3,3,3-trifluoro-1-phenylprop-1-en-1-yl)quinazolin-4(3H)-one;

[0023] (Z)-7-methoxy-3-(3,3,3-trifluoro-1-phenylprop-1-en-1-yl)quinazolin-4(3H)-one indole;

[0024] (Z)-7-nitro-3-(3,3,3-trifluoro-1-phenylprop-1-en-1-yl)quinazolin-4(3H)-one;

[0025] (Z)-7-trifluoromethyl-3-(3,3,3-trifluoro-1-phenylprop-1-en-1-yl)quinazolin-4(3H)-one;

[0026] (Z)-8-Chloro-3-(3,3,3-trifluoro-1-phenylprop-1-en-1-yl)quinazolin-4(3H)-one;

[0027] (Z)-8-methyl-3-(3,3,3-trifluoro-1-phenylprop-1-en-1-yl)quinazolin-4(3H)-one;

[0028] (Z)-8-Trifluoromethyl-3-(3,3,3-trifluoro-1-phenylprop-1-en-1-yl)quinazolin-4(3H)-one;

[0029] (Z)-6,8-dichloro-3-(3,3,3-trifluoro-1-phenylprop-1-en-1-yl)quinazolin-4(3H)-one;

[0030] (Z)-6,8-dibromo-3-(3,3,3-trifluoro-1-phenylprop-1-en-1-yl)quinazolin-4(3H)-one;

[0031] (Z)-6-dichloro-8-methyl-3-(3,3,3-trifluoro-1-phenylprop-1-en-1-yl)quinazolin-4(3H)-one;

[0032] (Z)-3-(1-(4-bromophenyl)-3,3,3-trifluoroprop-1-enyl)quinazolin-4(3H)-one;

[0033] (Z)-3-(1-(4-iodophenyl)-3,3,3-trifluoroprop-1-enyl)quinazolin-4(3H)-one;

[0034] (Z)-3-(1-(4-cyanophenyl)-3,3,3-trifluoroprop-1-enyl)quinazolin-4(3H)-one;

[0035] (Z)-3-(1-(4-trifluoromethylphenyl)-3,3,3-trifluoroprop-1-enyl)quinazolin-4(3H)-one.

[0036] In a second aspect, a method for preparing a trifluoromethyl substituted quinazolinone compound comprises the following steps:

[0037] In an organic solvent, under alkaline conditions, reacting the quinazolinone compound represented by formula II with the trifluoromethylacetylene compound represented by formula III to obtain the trifluoromethyl-substituted quinazolinone compound represented by formula I;

[0038]

[0039] Quinazolinone compounds Trifluoromethylalkyne compounds Trifluoromethylsubstituted quinazolinone compounds

[0040] Among them, R 1 is selected from hydrogen, C1-C8 alkyl, C1-C8 alkoxy, halogen, nitro, trifluoromethyl; R 2 Selected from hydrogen, halogen, cyano, trifluoromethyl.

[0041] Preferably, the R 1 is selected from hydrogen, methyl, methoxy, fluorine, chlorine, bromine, iodine, nitro, trifluoromethyl; said R 2 Selected from bromine, iodine, cyano, trifluoromethyl.

[0042] Preferably, the molar ratio of the quinazolinone compound to the trifluoromethylalkyne compound is 1:1 to 1:3, the reaction temperature is 20 to 60° C., and the reaction time is 2 to 10 hours.

[0043] Preferably, the organic solvent is dimethyl sulfoxide, N,N-dimethylformamide, acetone or acetonitrile.

[0044] Preferably, the base is potassium carbonate, sodium carbonate, potassium acetate, potassium tert-butoxide, potassium hydroxide or 1,8-diazabicyclo[5.4.0]undec-7-ene.

[0045] In a third aspect, the present invention provides an application of the trifluoromethyl substituted quinazolinone compound shown in Formula I, and the trifluoromethyl substituted quinazolinone compound is used to prepare drugs for breast cancer, colon adenocarcinoma or colon cancer.

[0046] In a fourth aspect, the present invention provides a tumor cell inhibitor, wherein the inhibitor comprises the trifluoromethyl substituted quinazolinone compound represented by Formula I.

[0047] Compared with the prior art, the advantages of the embodiments of the present invention include:

[0048] First, trifluoromethyl-substituted quinazolinone compounds were prepared for the first time through base-catalyzed direct addition reaction, successfully integrating two effective pharmacophores, quinazolinone and trifluoromethyl, into one molecule;

[0049] Secondly, the preparation method of the trifluoromethyl substituted quinazolinone compound does not require pre-activation of the substrate, but directly undergoes an addition reaction; does not require the addition of any transition metal catalyst, can achieve excellent reaction yield, has very high chemical selectivity and regioselectivity, mild conditions, a wide range of substrate applications, simple operation, low cost, few side reactions, high product purity, is easy to separate and purify, and can be applied to large-scale preparation;

[0050] Thirdly, trifluoromethyl-substituted quinazolinone compounds have potential biological and pharmaceutical activities, especially good activity in the anti-tumor field, and therefore can be applied in the biomedical field and have very good application prospects. BRIEF DESCRIPTION OF THE DRAWINGS

[0051] Figure 1 This is the X-ray single crystal diffraction structure of (Z)-3-(3,3,3-trifluoro-1-phenylprop-1-en-1-yl)quinazolin-4(3H)-one 1.

[0052] Figure 2 This is the molecular structure diagram of the compound corresponding to the single crystal structure of (Z)-3-(3,3,3-trifluoro-1-phenylprop-1-en-1-yl)quinazolin-4(3H)-one 1.

[0053] Figure 3 Figure 3 is a heat map of the 48-hour growth inhibition rate of four tumor cells by representative compounds. DETAILED DESCRIPTION

[0054] The beneficial effects of the present invention will be described in detail below in conjunction with the embodiments of the accompanying drawings, aiming to help readers better understand the essence of the present invention, but shall not constitute any limitation on the implementation and protection scope of the present invention.

[0055] The inventors have discovered a new type of base-catalyzed direct addition reaction. In the absence of any transition metal catalyst, a quinazolinone compound is reacted with a trifluoromethyl acetylene compound to prepare a trifluoromethyl substituted quinazolinone compound. After the reaction is completed, separation and purification and structural characterization are performed to confirm that the desired target product is obtained. The method is convenient for separation and purification and can be applied to large-scale preparation.

[0056] Based on this, the present invention provides a new base-catalyzed direct addition method for preparing trifluoromethyl-substituted quinazolinone compounds, and evaluates the anti-tumor activity of trifluoromethyl-substituted quinazolinone compounds through activity screening, structure-activity relationship analysis, and in-depth action and mechanism studies.

[0057] The trifluoromethyl substituted quinazolinone compound has a structure shown in Formula I:

[0058]

[0059] Among them, R 1 is selected from hydrogen, C1-C8 alkyl, C1-C8 alkoxy, halogen, nitro, trifluoromethyl; R 2 Selected from hydrogen, halogen, cyano, trifluoromethyl.

[0060] Preferably, R 1 is selected from hydrogen, methyl, methoxy, fluorine, chlorine, bromine, iodine, nitro, trifluoromethyl; said R 2 Selected from bromine, iodine, cyano, trifluoromethyl.

[0061] Preferably, the trifluoromethyl-substituted quinazolinone compound is one of the following compounds:

[0062] (Z)-3-(3,3,3-trifluoro-1-phenylprop-1-en-1-yl)quinazolin-4(3H)-one;

[0063] (Z)-5-Fluoro-3-(3,3,3-trifluoro-1-phenylprop-1-en-1-yl)quinazolin-4(3H)-one;

[0064] (Z)-5-chloro-3-(3,3,3-trifluoro-1-phenylprop-1-en-1-yl)quinazolin-4(3H)-one;

[0065] (Z)-6-Fluoro-3-(3,3,3-trifluoro-1-phenylprop-1-en-1-yl)quinazolin-4(3H)-one;

[0066] (Z)-6-Chloro-3-(3,3,3-trifluoro-1-phenylprop-1-en-1-yl)quinazolin-4(3H)-one;

[0067] (Z)-6-bromo-3-(3,3,3-trifluoro-1-phenylprop-1-en-1-yl)quinazolin-4(3H)-one;

[0068] (Z)-6-iodo-3-(3,3,3-trifluoro-1-phenylprop-1-en-1-yl)quinazolin-4(3H)-one;

[0069] (Z)-6-methoxy-3-(3,3,3-trifluoro-1-phenylprop-1-en-1-yl)quinazolin-4(3H)-one;

[0070] (Z)-7-Fluoro-3-(3,3,3-trifluoro-1-phenylprop-1-en-1-yl)quinazolin-4(3H)-one;

[0071] (Z)-7-Chloro-3-(3,3,3-trifluoro-1-phenylprop-1-en-1-yl)quinazolin-4(3H)-one;

[0072] (Z)-7-Bromo-3-(3,3,3-trifluoro-1-phenylprop-1-en-1-yl)quinazolin-4(3H)-one;

[0073] (Z)-7-methoxy-3-(3,3,3-trifluoro-1-phenylprop-1-en-1-yl)quinazolin-4(3H)-one indole;

[0074] (Z)-7-nitro-3-(3,3,3-trifluoro-1-phenylprop-1-en-1-yl)quinazolin-4(3H)-one;

[0075] (Z)-7-trifluoromethyl-3-(3,3,3-trifluoro-1-phenylprop-1-en-1-yl)quinazolin-4(3H)-one;

[0076] (Z)-8-Chloro-3-(3,3,3-trifluoro-1-phenylprop-1-en-1-yl)quinazolin-4(3H)-one;

[0077] (Z)-8-methyl-3-(3,3,3-trifluoro-1-phenylprop-1-en-1-yl)quinazolin-4(3H)-one;

[0078] (Z)-8-Trifluoromethyl-3-(3,3,3-trifluoro-1-phenylprop-1-en-1-yl)quinazolin-4(3H)-one;

[0079] (Z)-6,8-dichloro-3-(3,3,3-trifluoro-1-phenylprop-1-en-1-yl)quinazolin-4(3H)-one;

[0080] (Z)-6,8-dibromo-3-(3,3,3-trifluoro-1-phenylprop-1-en-1-yl)quinazolin-4(3H)-one;

[0081] (Z)-6-dichloro-8-methyl-3-(3,3,3-trifluoro-1-phenylprop-1-en-1-yl)quinazolin-4(3H)-one; (Z)-3-(1-(4-bromophenyl)-3,3,3-trifluoroprop-1-en-1-yl)quinazolin-4(3H)-one;

[0082] (Z)-3-(1-(4-iodophenyl)-3,3,3-trifluoroprop-1-enyl)quinazolin-4(3H)-one;

[0083] (Z)-3-(1-(4-cyanophenyl)-3,3,3-trifluoroprop-1-enyl)quinazolin-4(3H)-one;

[0084] (Z)-3-(1-(4-trifluoromethylphenyl)-3,3,3-trifluoroprop-1-enyl)quinazolin-4(3H)-one; their structural formulas are as follows:

[0085]

[0086] The present invention provides a method for preparing a trifluoromethyl substituted quinazolinone as shown in formula I, the method comprising the following steps:

[0087] In an organic solvent, under alkaline conditions, reacting the quinazolinone compound represented by formula II with the trifluoromethylacetylene compound represented by formula III to obtain the trifluoromethyl-substituted quinazolinone compound represented by formula I;

[0088]

[0089] Among them, R 1 is selected from hydrogen, C1-C8 alkyl, C1-C8 alkoxy, halogen, nitro, trifluoromethyl; R 2 Selected from hydrogen, halogen, cyano, trifluoromethyl.

[0090] In the absence of any transition metal catalyst, a quinazolinone compound and a trifluoromethylalkyne compound undergo direct addition reaction to prepare a trifluoromethyl-substituted quinazolinone compound.

[0091] Preferably, R1 is selected from hydrogen, methyl, methoxy, fluorine, chlorine, bromine, iodine, nitro, trifluoromethyl; said R 2 Selected from bromine, iodine, cyano, trifluoromethyl.

[0092] In the above method, the molar ratio of the quinazolinone compound to the trifluoromethylalkyne compound is 1:1 to 1:3.

[0093] In the above method, the reaction temperature is 20 to 60° C. and the reaction time is 2 to 10 hours.

[0094] The base is potassium carbonate, sodium carbonate, potassium acetate, potassium tert-butoxide, potassium hydroxide or 1,8-diazabicyclo[5.4.0]undec-7-ene.

[0095] The organic solvent is dimethyl sulfoxide, N,N-dimethylformamide, acetone or acetonitrile.

[0096] The specific operation of the preparation method of the trifluoromethyl substituted quinazolinone compound can be as follows: quinazolinone, trifluoromethyl alkyne, and base are added to a reaction tube in sequence, and finally a solvent is added, and the reaction tube is sealed with a rubber stopper; the test tube is placed in an oil bath at 20 to 60° C. and stirred and heated for reaction for 2 to 10 hours, and TLC is used to detect the complete reaction during the reaction; after the reaction is completed, the solvent is spin-dried and directly separated by silica gel column chromatography to obtain a pure product trifluoromethyl substituted quinazolinone (compound shown in formula I).

[0097] Through the experiment of the proliferation inhibition activity of the trifluoromethyl substituted quinazolinone compound shown in Formula I on various human tumor cells, it is found that the trifluoromethyl substituted quinazolinone compound has an anti-tumor effect and can be used to prepare anti-tumor drugs. Therefore, the present invention also provides the use of the trifluoromethyl substituted quinazolinone compound shown in Formula I in anti-tumor drugs, which can be specifically used to prepare drugs against breast cancer, colon adenocarcinoma or colon cancer.

[0098] Some typical embodiments are described below.

[0099] Example 1

[0100] Quinazolinone (0.2mmol), trifluoromethylacetylene (0.4mmol) and potassium carbonate (25mol%) were added to the reaction tube in sequence, and finally the solvent N,N-dimethylformamide (2mL) was added, and the reaction tube was sealed with a rubber stopper. The test tube was placed in a 40°C oil bath and stirred and heated for 6 hours. During the reaction, TLC was used to detect the complete reaction. After the reaction was completed, the solvent was first spin-dried and directly separated by silica gel column chromatography to obtain the pure product (Z)-3-(3,3,3-trifluoro-1-phenylprop-1-en-1-yl)quinazolin-4(3H)-one (Compound 1).

[0101]

[0102] (Z)-3-(3,3,3-trifluoro-1-phenylprop-1-en-1-yl)quinazolin-4(3H)-one (Compound 1), yield: 85%; white solid; melting point 139-141°C; 1 HNMR (400MHz, CDCl3) δ8.32(dd,J=8.0,1.2Hz,1H),7.95(s,1H),7.90–7.75(m,2H),7.62–7.53(m,1H),7.51–7.33(m,5H),6.55(q,J=7.6Hz,1H); 13 CNMR(100MHz,CDCl3)δ160.1,148.1,145.3(q,J C-F =5.5Hz),145.1,135.3,133.6,131.5,129.6,128.2,128.1,127.4,126.3,122.3,121.7(q,J C-F =269.3Hz),116.9(q,J C-F =34.8Hz); 19 FNMR (376MHz, CDCl3) δ-58.76; HRMS (ESI) m / z: [M+Na] + forC 17 H 11 F3N2NaOcalcd:339.0716,found:339.0713.

[0103] Only the corresponding reactants were changed and Examples 2 to 24 were obtained using substantially the same method as Example 1.

[0104] Example 2

[0105] The reactant is 5-fluoro-quinazolin-4(3H)-one, and the product is (Z)-5-fluoro-3-(3,3,3-trifluoro-1-phenylprop-1-en-1-yl)quinazolin-4(3H)-one (Compound 2).

[0106]

[0107] (Z)-5-Fluoro-3-(3,3,3-trifluoro-1-phenylprop-1-en-1-yl)quinazolin-4(3H)-one (Compound 2), yield: 62%; white solid; melting point 139-140°C; 1HNMR (400MHz, CDCl3) δ7.93 (s, 1H), 7.80-7.73 (m, 1H), 7.60 (d, J = 8.4Hz, 1H), 7.51–7.39 (m, 5H), 7.25–7.13 (m, 1H), 6.53 (q, J = 7.6Hz, 1H); 13 CNMR (100MHz,CDCl3)δ161.6(d,J C-F =266.2Hz),156.9,150.0,146.0,145.2(q,J C-F =5.5Hz),135.8(d,J C-F =10.4Hz),133.5,131.6,129.6,126.3,124.0(d,J C-F =4.3Hz),121.9(q,J C-F =269.3Hz),117.1(q,J C-F =34.7Hz),115.0(d,J C-F =20.5Hz),112.0(d,J C-F =6.2Hz); 19 FNMR(376MHz, CDCl3)δ-58.66,-107.99; HRMS(ESI)m / z:[M+Na] + forC 17 H 10 F4N2NaOcalcd:357.0621,found:357.0623.

[0108] Example 3

[0109] The reactant is 5-chloro-quinazolin-4(3H)-one, and the product is (Z)-5-chloro-3-(3,3,3-trifluoro-1-phenylprop-1-en-1-yl)quinazolin-4(3H)-one (Compound 3).

[0110]

[0111] (Z)-5-chloro-3-(3,3,3-trifluoro-1-phenylprop-1-en-1-yl)quinazolin-4(3H)-one (Compound 3), yield: 70%; white solid; melting point 131-132°C; 1 HNMR (400MHz, CDCl3) δ7.95 (s, 1H), 7.74–7.65 (m, 2H), 7.54 (dd, J = 7.2, 2.0Hz, 1H), 7.50–7.35 (m, 5H), 6.52 (q, J = 7.6Hz, 1H); 13CNMR(100MHz,CDCl3)δ158.0,150.5,145.8,145.5(q,J C-F =5.5Hz),135.0,134.6,133.5,131.6,131.0,129.6,127.4,126.3,121.9(q,J C-F =269.3Hz),119.7,117.0(q,J C-F =34.7Hz); 19 FNMR (376MHz, CDCl3) δ-58.59; HRMS (ESI) m / z: [M+Na] + forC 17 H 10 ClF3N2NaOcalcd:373.0326,found:337.0330.

[0112] Example 4

[0113] The reactant is 6-fluoro-quinazolin-4(3H)-one, and the product is (Z)-6-fluoro-3-(3,3,3-trifluoro-1-phenylprop-1-en-1-yl)quinazolin-4(3H)-one (Compound 4).

[0114]

[0115] (Z)-6-Fluoro-3-(3,3,3-trifluoro-1-phenylprop-1-en-1-yl)quinazolin-4(3H)-one (Compound 4), yield: 68%; white solid; melting point 153-155°C; 1 HNMR (400MHz, CDCl3) δ8.00–7.87(m,2H),7.82(dd,J=8.8,4.8Hz,1H),7.62–7.30(m,6H),6.55(q,J=7.6Hz,1H); 13 CNMR (100MHz,CDCl3)δ161.7(d,J C-F =248.8Hz),159.4,145.1(q,J C-F =5.5Hz),144.8,144.4,133.4,131.7,130.6(d,J C-F =8.3Hz),129.6,126.3,123.9,123.6,121.9(q,J C-F =296.2Hz),117.1(q,J C-F =34.7Hz),112.5(d,J C-F =23.9Hz); 19FNMR(376MHz, CDCl3)δ-58.82,-110.67; HRMS(ESI)m / z:[M+Na] + for C 17 H 10 F4N2NaOcalcd:357.0621,found:357.0625.

[0116] Example 5

[0117] The reactant is 6-chloro-quinazolin-4(3H)-one, and the product is (Z)-6-chloro-3-(3,3,3-trifluoro-1-phenylprop-1-en-1-yl)quinazolin-4(3H)-one (Compound 5).

[0118]

[0119] (Z)-6-Chloro-3-(3,3,3-trifluoro-1-phenylprop-1-en-1-yl)quinazolin-4(3H)-one (Compound 5), yield: 76%; white solid; melting point 126-127°C; 1 HNMR (400MHz, CDCl3) δ8.27(d,J=2.0Hz,1H),7.93(s,1H),7.88–7.62(m,2H),7.60–7.33(m,5H),6.55(q,J=7.6Hz,1H); 13 CNMR(100MHz,CDCl3)δ159.4,146.9,145.5,145.3(q,J C-F =5.5Hz),136.0,134.5,133.6,132.0,130.1,129.9,127.1,126.6,123.7,122.2(q,J C-F =269.3Hz),117.4(q,J C-F =34.7Hz); 19 FNMR (376MHz, CDCl3) δ-58.79; HRMS (ESI) m / z: [M+Na] + forC 17 H 10 ClF3N2NaOcalcd:373.0326,found:373.0325.

[0120] Example 6

[0121] The reactant is 6-bromo-quinazolin-4(3H)-one, and the product is (Z)-6-bromo-3-(3,3,3-trifluoro-1-phenylprop-1-en-1-yl)quinazolin-4(3H)-one (Compound 6).

[0122]

[0123] (Z)-6-Bromo-3-(3,3,3-trifluoro-1-phenylprop-1-en-1-yl)quinazolin-4(3H)-one (Compound 6), yield: 79%; white solid; melting point 101-102°C; 1 HNMR (400MHz, CDCl3) δ8.44(d,J=2.0Hz,1H),8.11–7.85(m,2H),7.68(d,J=8.4Hz,1H),7.55–7.34(m,5H),6.55(q,J=7.2Hz,1H); 13 CNMR(100MHz,CDCl3)δ159.3,147.2,145.7,145.3(q,J C-F =5.4Hz),138.8,133.6,132.1,130.3,130.2,129.9,126.6,124.0,122.3,122.2(q,J C-F =269.5Hz),117.4(q,J C-F =34.8Hz); 19 FNMR (376MHz, CDCl3) δ-58.79; HRMS (ESI) m / z: [M+Na] + forC 17 H 10 BrF3N2NaOcalcd:416.9821,found:416.9822.

[0124] Example 7

[0125] The reactant is 6-iodo-quinazolin-4(3H)-one, and the product is (Z)-6-iodo-3-(3,3,3-trifluoro-1-phenylprop-1-en-1-yl)quinazolin-4(3H)-one (Compound 7).

[0126]

[0127] (Z)-6-iodo-3-(3,3,3-trifluoro-1-phenylprop-1-en-1-yl)quinazolin-4(3H)-one (Compound 7), yield: 55%; yellow oil; 1 HNMR (400MHz, CDCl3) δ8.69–8.58(m,1H),8.13-8.00(m,1H),7.94(s,1H),7.59–7.33(m,6H),6.55(q,J=7.6Hz,1H); 13CNMR(100MHz,CDCl3)δ158.6,147.3,145.5,145.0(q,J C-F =5.5Hz),144.0,136.2,133.2,131.7,129.8,129.5,126.2,123.7,121.8(q,J C-F =269.4Hz),117.0(q,J C-F =34.7Hz),92.9; HRMS(ESI)m / z:[M+Na] + forC 17 H 10 F3IN2NaO calcd:464.9682,found:464.9671.

[0128] Example 8

[0129] The reactant is 6-methoxy-quinazolin-4(3H)-one, and the product is (Z)-6-methoxy-3-(3,3,3-trifluoro-1-phenylprop-1-en-1-yl)quinazolin-4(3H)-one (Compound 8).

[0130]

[0131] (Z)-6-methoxy-3-(3,3,3-trifluoro-1-phenylprop-1-en-1-yl)quinazolin-4(3H)-one (Compound 8), yield: 73%; white solid; melting point 128-130°C; 1 HNMR (400MHz, CDCl3) δ7.86 (s, 1H), 7.73 (d, J = 8.8Hz, 1H), 7.68 (d, J = 3.2Hz, 1H), 7.51–7.34 (m, 6H), 6.54 (q, J = 7.6Hz, 1H), 3.90 (s, 3H); 13 CNMR(100MHz,CDCl3)δ160.0,159.4,145.4(q,J C-F =5.4Hz),142.9,142.6,133.6,131.5,129.6,129.5,126.3,125.3,123.1,121.9(q,J C-F =269.3Hz),116.8(q,J C-F =34.8Hz),106.9,56.0; 19 FNMR (376MHz, CDCl3) δ-58.80; HRMS (ESI) m / z: [M+Na] + forC 18 H 13F3N2NaO2calcd:369.0821,found:369.0824.

[0132] Example 9

[0133] The reactant is 7-fluoro-quinazolin-4(3H)-one, and the product is (Z)-7-fluoro-3-(3,3,3-trifluoro-1-phenylprop-1-en-1-yl)quinazolin-4(3H)-one (Compound 9).

[0134]

[0135] (Z)-7-Fluoro-3-(3,3,3-trifluoro-1-phenylprop-1-en-1-yl)quinazolin-4(3H)-one (Compound 9), yield: 80%; white solid; melting point 147-148°C; 1 HNMR (400MHz, CDCl3) δ8.37-8.26, (m, 1H), 7.94 (s, 1H), 7.53–7.35 (m, 6H), 7.32–7.21 (m, 1H), 6.54 (q, J = 7.6Hz, 1H); 13 CNMR (100MHz,CDCl3)δ167.0(d,J C-F =254.5Hz),159.4,150.3(d,J C-F =13Hz),146.3,145.1(q,J C-F =5.5Hz),133.4,131.7,130.3(d,J C-F =10.6Hz),129.6,126.3,121.9(q,J C-F =269.4Hz),119.0(d,J C-F =2.1Hz),117.0(q,J C-F =34.8Hz),116.9(d,J C-F =23.3Hz),113.7(d,J C-F =22.1Hz); 19 FNMR(376MHz, CDCl3)δ-58.77,-101.72; HRMS(ESI)m / z:[M+Na] + forC 17 H 10 F4N2NaOcalcd:357.0621,found:357.0621.

[0136] Example 10

[0137] The reactant is 7-chloro-quinazolin-4(3H)-one, and the product is (Z)-7-chloro-3-(3,3,3-trifluoro-1-phenylprop-1-en-1-yl)quinazolin-4(3H)-one (Compound 10).

[0138]

[0139] (Z)-7-Chloro-3-(3,3,3-trifluoro-1-phenylprop-1-en-1-yl)quinazolin-4(3H)-one (Compound 10), yield: 76%; white solid; melting point 146-147°C; 1 HNMR (400MHz, CDCl3) δ8.24(d,J=8.4Hz,1H),7.95(s,1H),7.80(d,J=2.0Hz,1H),7.60–7.33(m,6H),6.55(q,J=7.6Hz,1H); 13 CNMR(100MHz,CDCl3)δ159.5,149.1,146.2,145.1(q,J C-F =5.5Hz),141.7,133.4,131.7,129.6,128.9,128.8,127.8,126.3,121.9(q,J C-F =269.3Hz),120.7,117.0(q,J C-F =34.8Hz); 19 FNMR (376MHz, CDCl3) δ-58.77; HRMS (ESI) m / z: [M+Na] + forC 17 H 10 ClF3N2NaOcalcd:373.0326,found:373.0321.

[0140] Embodiment 11

[0141] The reactant is 7-bromo-quinazolin-4(3H)-one, and the product is (Z)-7-bromo-3-(3,3,3-trifluoro-1-phenylprop-1-en-1-yl)quinazolin-4(3H)-one (Compound 11).

[0142]

[0143] (Z)-7-Bromo-3-(3,3,3-trifluoro-1-phenylprop-1-en-1-yl)quinazolin-4(3H)-one (Compound 11), yield: 60%; yellow solid; melting point 138-140°C; 1HNMR (400MHz, CDCl3) δ8.16(d,J=8.4Hz,1H),8.05–7.87(m,2H),7.67(dd,J=8.4,1.6Hz,1H),7.56–7.34(m,5H),6.55(q,J=7.6Hz,1H); 13 CNMR(100MHz,CDCl3)δ159.6,149.1,146.2,145.1,(q,J C-F =5.4Hz),133.4,131.7,131.6,131.0,130.2,129.6,128.9,126.3,121.9(q,J C-F =269.1Hz),121.1,117.0(q,J C-F =34.8Hz); 19 FNMR (376MHz, CDCl3) δ-58.75; HRMS (ESI) m / z: [M+Na] + forC 17 H 10 BrF3N2NaOcalcd:416.9821,found:416.9819.

[0144] Example 12

[0145] The reactant is 7-methoxy-quinazolin-4(3H)-one, and the product is (Z)-7-methoxy-3-(3,3,3-trifluoro-1-phenylprop-1-en-1-yl)quinazolin-4(3H)-one indole (Compound 12).

[0146]

[0147] (Z)-7-methoxy-3-(3,3,3-trifluoro-1-phenylprop-1-en-1-yl)quinazoline-4(3H)-one indole (Compound 12), yield: 78%; white solid; melting point 147-149°C; 1 HNMR(400MHz, CDCl3)δ8.21(d,J=8.8Hz,1H),7.92(s,1H),7.61–7.35(m,5H),7.18 (d, J=2.4Hz, 1H), 7.11 (dd, J=8.8, 2.4Hz, 1H), 6.53 (q, J=7.6Hz, 1H), 3.95 (s, 3H); 13 CNMR(100MHz,CDCl3)δ165.4,159.7,150.4,145.8,145.5(q,J C-F=5.2Hz),133.8,131.6,129.6,129.1,126.3,122.0(q,J C-F =269.1Hz),117.9,116.8(q,J C-F =34.7Hz),115.7,109.1,56.0; 19 FNMR (376MHz, CDCl3) δ-58.72; HRMS (ESI) m / z: [M+Na] + forC 18 H 13 F3N2NaO2calcd:369.0821,found:369.0825.

[0148] Embodiment 13

[0149] The reactant is 7-nitro-quinazolin-4(3H)-one, and the product is (Z)-7-nitro-3-(3,3,3-trifluoro-1-phenylprop-1-en-1-yl)quinazolin-4(3H)-one (Compound 13).

[0150]

[0151] (Z)-7-nitro-3-(3,3,3-trifluoro-1-phenylprop-1-en-1-yl)quinazolin-4(3H)-one (Compound 13), yield: 67%; yellow solid; melting point 127-129°C; 1 HNMR (400MHz, CDCl3) δ8.63(d,J=2.0Hz,1H),8.47(d,J=8.8Hz,1H),8.31(dd,J=8.8,2.0Hz,1H),8.05(s,1H),7.56-7.40(m,5H),6.59(q,J=7.6Hz,1H); 13 CNMR(100MHz,CDCl3)δ158.9,152.1,148.7,147.0,144.7(q,J C-F =5.5Hz),133.0,132.0,129.7,129.4,126.4,126.3,123.7,121.9,121.8(q,J C-F =269.4Hz),117.3(q,J C-F =34.8Hz); 19 FNMR (376MHz, CDCl3) δ-58.79; HRMS (ESI) m / z: [M+Na] + forC 17 H 10F3N3NaO3calcd:384.0556,found:384.0571.

[0152] Embodiment 14

[0153] The reactant is 7-trifluoromethyl-quinazolin-4(3H)-one, and the product is (Z)-7-trifluoromethyl-3-(3,3,3-trifluoro-1-phenylprop-1-en-1-yl)quinazolin-4(3H)-one (Compound 14).

[0154]

[0155] (Z)-7-Trifluoromethyl-3-(3,3,3-trifluoro-1-phenylprop-1-en-1-yl)quinazolin-4(3H)-one (Compound 14), yield: 75%; white solid; melting point 105-106°C; 1 HNMR (400MHz, CDCl3) δ8.43(d,J=8.4Hz,1H),8.09(s,1H),8.01(s,1H),7.77(dd,J=8.4,1.2Hz,1H),7.63–7.35(m,5H),6.58(q,J=7.6Hz,1H); 13 CNMR(100MHz,CDCl3)δ159.3,148.2,146.3,144.9(q,J C-F =5.4Hz),136.8(q,J C-F =32.9Hz),133.2,131.8,129.7,128.6,126.3,125.7(q,J C-F =4Hz),124.7,124.2(q,J C-F =3.4Hz),123.4(q,J C-F =271.6Hz),121.9(q,J C-F =269.3Hz),117.2(q,J C-F =34.9Hz); 19 FNMR(376MHz, CDCl3)δ-58.80,-63.32; HRMS(ESI)m / z:[M+Na] + forC 18 H 10 F6N2NaOcalcd:407.0590,found:407.0596.

[0156] Embodiment 15

[0157] The reactant is 8-chloro-quinazolin-4(3H)-one, and the product is (Z)-8-chloro-3-(3,3,3-trifluoro-1-phenylprop-1-en-1-yl)quinazolin-4(3H)-one (Compound 15).

[0158]

[0159] (Z)-8-Chloro-3-(3,3,3-trifluoro-1-phenylprop-1-en-1-yl)quinazolin-4(3H)-one (Compound 15), yield: 89%; white solid; melting point 110-112°C; 1 HNMR (400MHz, CDCl3) δ8.23(dd,J=8.0,1.2Hz,1H),8.07(s,1H),7.92(dd,J=7.6,1.2Hz,1H),7.60–7.34(m,6H),6.56(q,J=7.2Hz,1H); 13 CNMR(100MHz,CDCl3)δ159.5,145.8,145.0(q,J C-F =5.5Hz),144.9,144.8,135.6,133.2,132.5,131.7,129.6,128.3,126.3,123.9,121.8(q,J C-F =269.3Hz),117.1(q,J C-F =34.8Hz); 19 FNMR (376MHz, CDCl3) δ-58.67; HRMS (ESI) m / z: [M+Na] + forC 17 H 10 ClF3N2NaOcalcd:373.0326,found:373.0325.

[0160] Example 16

[0161] The reactant is 8-methyl-quinazolin-4(3H)-one, and the product is (Z)-8-methyl-3-(3,3,3-trifluoro-1-phenylprop-1-en-1-yl)quinazolin-4(3H)-one (Compound 16).

[0162]

[0163] (Z)-8-methyl-3-(3,3,3-trifluoro-1-phenylprop-1-en-1-yl)quinazolin-4(3H)-one (Compound 16), yield: 60%; white solid; melting point 126-127°C; 1HNMR (400MHz, CDCl3) δ8.16(d,J=8.0Hz,1H),7.97(s,1H),7.69(d,J=7.2Hz,1H),7.55–7.36(m,6H),6.54(q,J=7.6Hz,1H),2.68(s,3H); 13 CNMR(100MHz,CDCl3)δ160.5,146.7,145.5(q,J C-F =5.4Hz),143.8,136.7,136.0,133.7,131.6,129.6,127.7,126.3,125.1,122.3,122.0(q,J C-F =270.4Hz),116.8(q,J C-F =34.9Hz),17.7; 19 FNMR (376MHz, CDCl3) δ-58.69; HRMS (ESI) m / z: [M+Na] + forC 18 H 13 F3N2NaOcalcd:353.0872,found:353.0871.

[0164] Embodiment 17

[0165] The reactant is 8-trifluoromethyl-quinazolin-4(3H)-one, and the product is (Z)-8-trifluoromethyl-3-(3,3,3-trifluoro-1-phenylprop-1-en-1-yl)quinazolin-4(3H)-one (Compound 17).

[0166]

[0167] (Z)-8-Trifluoromethyl-3-(3,3,3-trifluoro-1-phenylprop-1-en-1-yl)quinazolin-4(3H)-one (Compound 17), yield: 84%; colorless oil; 1 HNMR (400MHz, CDCl3) δ8.61–8.43(m,1H),8.16(d,J=7.2Hz,1H),8.08(s,1H),7.63(t,J=8.0Hz,1H),7.50–7.36(m,5H),6.57(q,J=7.6Hz,1H); 13 CNMR(100MHz,CDCl3)δ159.2,146.0,145.7,144.8(q,J C-F =5.4Hz),133.2,132.9(q,J C-F=5.2Hz),131.8,131.5,129.6,127.4(q,J C-F =30.8Hz),127.3,126.3,123.5,123.4(q,J C-F =272.1Hz),121.8(q,J C-F =269.4Hz),117.2(q,J C-F =34.9Hz); HRMS(ESI)m / z:[M+Na] + forC 18 H 10 F6N2NaO calcd:407.0590,found:407.0589.

[0168] Embodiment 18

[0169] The reactant is 6,8-dichloro-quinazolin-4(3H)-one, and the product is (Z)-6,8-dichloro-3-(3,3,3-trifluoro-1-phenylprop-1-en-1-yl)quinazolin-4(3H)-one (Compound 18).

[0170]

[0171] (Z)-6,8-dichloro-3-(3,3,3-trifluoro-1-phenylprop-1-en-1-yl)quinazolin-4(3H)-one (Compound 18), yield: 63%; yellow solid; melting point 149-151°C; 1 HNMR (400MHz, CDCl3) δ8.20 (s, 1H), 8.04 (s, 1H), 7.90 (s, 1H), 7.53-7.35 (m, 5H), 6.57 (q, J = 7.6Hz, 1H); 13 CNMR(100MHz,CDCl3)δ158.5,145.8,144.7(q,J C-F =5.4Hz),143.5,135.7,134.0,133.7,133.0,131.9,129.7,126.3,125.8,124.4,121.8(q,J C-F =269.5Hz),117.3(q,J C-F =35.0Hz); 19 FNMR (376MHz, CDCl3) δ-58.72; HRMS (ESI) m / z: [M+Na] + forC 17 H9ClF3N2NaOcalcd:406.9936,found:406.9935.

[0172] Embodiment 19

[0173] The reactant is 6,8-dibromo-quinazolin-4(3H)-one, and the product is (Z)-6,8-dibromo-3-(3,3,3-trifluoro-1-phenylprop-1-en-1-yl)quinazolin-4(3H)-one (Compound 19).

[0174]

[0175] (Z)-6,8-dibromo-3-(3,3,3-trifluoro-1-phenylprop-1-en-1-yl)quinazolin-4(3H)-one (Compound 19), yield: 66%; yellow solid; melting point 148-150°C; 1 HNMR (400MHz, CDCl3) δ8.25(d,J=2.0Hz,1H),8.08(d,J=2.0Hz,1H),7.91(s,1H),7.50–7.20(m,5H),6.42(q,J=7.6Hz,1H); 13 CNMR(100MHz,CDCl3)δ158.4,146.0,144.9,144.7(q,J C-F =5.5Hz),141.4,133.0,131.9,129.7,129.7,126.3,124.6,124.0,121.8(q,J C-F =269.4Hz),121.7,117.3(q,J C-F =34.9Hz); 19 FNMR (376MHz, CDCl3) δ-58.72; HRMS (ESI) m / z: [M+Na] + forC 17 H9Br2F3N2NaOcalcd:494.8926,found:494.8920.

[0176] Embodiment 20

[0177] The reactant is 6-chloro-8-methyl-quinazolin-4(3H)-one, and the product is (Z)-6-chloro-8-methyl-3-(3,3,3-trifluoro-1-phenylprop-1-en-1-yl)quinazolin-4(3H)-one (Compound 20).

[0178]

[0179] (Z)-6-Chloro-8-methyl-3-(3,3,3-trifluoro-1-phenylprop-1-en-1-yl)quinazolin-4(3H)-one (Compound 20), yield: 63%; green solid; melting point 134-135°C;1 HNMR (400MHz, CDCl3) δ8.12(d,J=2.4Hz,1H),7.95(s,1H),7.64(d,J=1.6Hz,1H),7.53–7.36(m,5H),6.55(q,J=7.6Hz,1H),2.65(s,3H); 13 CNMR(100MHz,CDCl3)δ159.5,145.3,145.2(q,J C-F =5.5Hz),144.0,139.0,136.1,133.5,133.4,131.7,129.6,126.3,124.4,123.3,121.9(q,J C-F =269.3Hz),116.9(q,J C-F =34.8Hz),17.6; 19 FNMR (376MHz, CDCl3) δ-58.72; HRMS (ESI) m / z: [M+Na] + forC 18 H 12 ClF3N2NaOcalcd:387.0482,found:387.0476.

[0180] Embodiment 21

[0181] The reactant is trifluoromethyl-(4-bromo)phenylacetylene, and the product is (Z)-3-(1-(4-bromophenyl)-3,3,3-trifluoroprop-1-enyl)quinazolin-4(3H)-one (Compound 21).

[0182]

[0183] (Z)-3-(1-(4-bromophenyl)-3,3,3-trifluoroprop-1-enyl)quinazolin-4(3H)-one (Compound 21), yield: 80%; white solid; melting point 117-118°C; 1 HNMR (400MHz, CDCl3) δ8.30(dd,J=8.0,1.2Hz,1H),7.94(s,1H),7.87-7.77(m,2H),7.71–7.48(m,3H),7.27(d,J=7.2Hz,2H),6.53(q,J=7.6Hz,1H); 13 CNMR(100MHz,CDCl3)δ160.1,148.0,144.8,144.7(q,J C-F=5.5Hz),135.4,132.9,132.7,128.3,128.2,127.8,127.5,126.3,121.8(q,J C-F =269.3Hz),122.2,117.3(q,J C-F =35.0Hz); 19 FNMR (376MHz, CDCl3) δ-58.78; HRMS (ESI) m / z: [M+Na] + forC 17 H 10 BrF3N2NaOcalcd:416.9821,found:416.9816.

[0184] Embodiment 22

[0185] The reactant is trifluoromethyl-(4-iodo)phenylacetylene, and the product is (Z)-3-(1-(4-iodophenyl)-3,3,3-trifluoroprop-1-enyl)quinazolin-4(3H)-one (Compound 22).

[0186]

[0187] (Z)-3-(1-(4-iodophenyl)-3,3,3-trifluoroprop-1-enyl)quinazolin-4(3H)-one (Compound 22), yield: 60%; white solid; melting point 113-114°C; 1 HNMR (400MHz, CDCl3) δ8.41–8.24(m,1H),7.93(s,1H),7.90–7.71(m,4H),7.64–7.34(m,1H),7.20-7.10(m,2H),6.53(q,J=7.6Hz,1H); 13 CNMR(100MHz,CDCl3)δ160.1,148.0,144.8(q,J C-F =5.5Hz),144.7,138.8,135.4,133.3,128.3,128.2127.8,127.4,122.2,121.8(q,J C-F =269.6Hz)117.3(q,J C-F =35Hz),98.3; 19 FNMR (376MHz, CDCl3) δ-58.76; HRMS (ESI) m / z: [M+Na] + forC 17 H 10 F3IN2NaOcalcd:464.9682,found:464.9675.

[0188] Embodiment 23

[0189] The reactant is trifluoromethyl-(4-cyano)phenylacetylene, and the product is (Z)-3-(1-(4-cyanophenyl)-3,3,3-trifluoroprop-1-enyl)quinazolin-4(3H)-one (Compound 23).

[0190]

[0191] (Z)-3-(1-(4-cyanophenyl)-3,3,3-trifluoroprop-1-enyl)quinazolin-4(3H)-one (Compound 23), yield: 43%; white solid; melting point 139-141°C; 1 HNMR (400MHz, CDCl3) δ8.29(d,J=7.2Hz,1H),7.96(s,1H),7.90-7.79(m,2H),7.73(d,J=8.4Hz,2H),7.71–7.43(m,3H),6.60(q,J=7.2Hz,1H); 13 CNMR(100MHz,CDCl3)δ160.1,148.0,144.4,144.1(q,J C-F =5.3Hz),138.0,135.7,133.3,128.5,128.3,127.4,127.1,122.1,121.5(q,J C-F =269.9Hz),119.7(q,J C-F =35.1Hz),117.9,115.2; 19 FNMR (376MHz, CDCl3) δ-58.72; 19 FNMR (376MHz, CDCl3) δ-58.96; HRMS (ESI) m / z: [M+Na] + forC 18 H 10 F3N3NaOcalcd:364.0668,found:364.0659.

[0192] Embodiment 24

[0193] The reactant is trifluoromethyl-(4-trifluoromethyl)phenylacetylene, and the product is (Z)-3-(1-(4-trifluoromethylphenyl)-3,3,3-trifluoroprop-1-enyl)quinazolin-4(3H)-one (Compound 24).

[0194]

[0195] (Z)-3-(1-(4-trifluoromethylphenyl)-3,3,3-trifluoroprop-1-enyl)quinazolin-4(3H)-one (Compound 24), yield: 64%; yellow oil; 1 HNMR (400MHz, CDCl3) δ8.36–8.24(m,1H),7.97(s,1H),7.88-7.78(m,2H),7.68(d,J=8.4Hz,2H),7.65–7.51(m,3H),6.60(q,J=7.2Hz,1H); 13 CNMR(100MHz,CDCl3)δ160.4,148.3,145.0,144.8(q,J C-F =5.0Hz),137.5,135.9,133.6(q,J C-F =33.0Hz),128.7,128.5,127.7,127.2,126.9(q,J C-F =3.7Hz),124.0(q,J C-F =270.9Hz),122.5,121.9(q,J C-F =204.1Hz),119.3(q,J C-F =35.1Hz); 19 FNMR(376MHz, CDCl3)δ-58.94,-63.13; HRMS(ESI)m / z:[M+Na] + forC 18 H 10 F6N2NaOcalcd:407.0590,found:407.0602.

[0196] Embodiment 25

[0197] Evaluation of the antitumor activity of newly synthesized trifluoromethyl substituted quinazolinone compounds. Human breast cancer cell line MDA-MB-231, human colon adenocarcinoma cell line SW480, human colon adenocarcinoma cell line LOVO, and human colon cancer cell line HCT-116 were treated with different concentrations of the compounds, and the inhibition rate of the compounds on cell proliferation was determined using the CCK8 kit after 48 hours. The results showed that various compounds of the present invention (such as compounds 6, 11, 20 and 22) had better inhibitory activity against various tumor cells than unmodified quinazolin-4 (3H) -one (Q), revealing that the bromine atoms at positions 6 and 7 of quinazolinone and the iodine atom at the para position of the trifluoromethyl alkynyl benzene ring are the key pharmacophores for the drug to take effect. All experimental data are mean ± standard error, with the blank solvent control group as the reference group (survival rate 100%).

[0198] Here, inhibition rate (%) = [A control - (A sample - A sample blank)] / A control × 100.

[0199] Figure 3 This is a heat map of the 48-hour growth inhibition rate of four tumor cells by representative compounds.

[0200] It can be seen that trifluoromethyl substituted quinazolinone compounds have inhibitory activity on the proliferation of various human tumor cells. Compound 6 showed the strongest inhibitory effect on the human colon cancer cell line HCT-116, inhibiting 78% of tumor cell proliferation.

[0201] The embodiments described above are merely descriptions of preferred implementation modes of the present invention and are not intended to limit the scope of the present invention. Without departing from the design spirit of the present invention, various modifications and improvements made to the technical solutions of the present invention by ordinary technicians in this field should all fall within the protection scope determined by the claims of the present invention.

Claims

1. The trifluoromethyl substituted quinazolinone compound shown in formula I: in, R 1 is selected from hydrogen, C1-C8 alkyl, C1-C8 alkoxy, halogen, nitro, trifluoromethyl; R 2 Selected from hydrogen, halogen, cyano, trifluoromethyl.

2. The trifluoromethyl-substituted quinazolinone compound according to claim 1, characterized in that: The R 1 is selected from hydrogen, methyl, methoxy, fluorine, chlorine, bromine, iodine, nitro, trifluoromethyl; said R 2 Selected from bromine, iodine, cyano, trifluoromethyl.

3. The trifluoromethyl-substituted quinazolinone compound according to claim 1, characterized in that: The trifluoromethyl substituted quinazolinone compound is specifically one of the following compounds: (Z)-3-(3,3,3-trifluoro-1-phenylprop-1-en-1-yl)quinazolin-4(3H)-one; (Z)-5-Fluoro-3-(3,3,3-trifluoro-1-phenylprop-1-en-1-yl)quinazolin-4(3H)-one; (Z)-5-chloro-3-(3,3,3-trifluoro-1-phenylprop-1-en-1-yl)quinazolin-4(3H)-one; (Z)-6-Fluoro-3-(3,3,3-trifluoro-1-phenylprop-1-en-1-yl)quinazolin-4(3H)-one; (Z)-6-Chloro-3-(3,3,3-trifluoro-1-phenylprop-1-en-1-yl)quinazolin-4(3H)-one; (Z)-6-bromo-3-(3,3,3-trifluoro-1-phenylprop-1-en-1-yl)quinazolin-4(3H)-one; (Z)-6-iodo-3-(3,3,3-trifluoro-1-phenylprop-1-en-1-yl)quinazolin-4(3H)-one; (Z)-6-methoxy-3-(3,3,3-trifluoro-1-phenylprop-1-en-1-yl)quinazolin-4(3H)-one; (Z)-7-Fluoro-3-(3,3,3-trifluoro-1-phenylprop-1-en-1-yl)quinazolin-4(3H)-one; (Z)-7-Chloro-3-(3,3,3-trifluoro-1-phenylprop-1-en-1-yl)quinazolin-4(3H)-one; (Z)-7-Bromo-3-(3,3,3-trifluoro-1-phenylprop-1-en-1-yl)quinazolin-4(3H)-one; (Z)-7-methoxy-3-(3,3,3-trifluoro-1-phenylprop-1-en-1-yl)quinazolin-4(3H)-one indole; (Z)-7-nitro-3-(3,3,3-trifluoro-1-phenylprop-1-en-1-yl)quinazolin-4(3H)-one; (Z)-7-trifluoromethyl-3-(3,3,3-trifluoro-1-phenylprop-1-en-1-yl)quinazolin-4(3H)-one; (Z)-8-Chloro-3-(3,3,3-trifluoro-1-phenylprop-1-en-1-yl)quinazolin-4(3H)-one; (Z)-8-methyl-3-(3,3,3-trifluoro-1-phenylprop-1-en-1-yl)quinazolin-4(3H)-one; (Z)-8-Trifluoromethyl-3-(3,3,3-trifluoro-1-phenylprop-1-en-1-yl)quinazolin-4(3H)-one; (Z)-6,8-dichloro-3-(3,3,3-trifluoro-1-phenylprop-1-en-1-yl)quinazolin-4(3H)-one; (Z)-6,8-dibromo-3-(3,3,3-trifluoro-1-phenylprop-1-en-1-yl)quinazolin-4(3H)-one; (Z)-6-dichloro-8-methyl-3-(3,3,3-trifluoro-1-phenylprop-1-en-1-yl)quinazolin-4(3H)-one; (Z)-3-(1-(4-bromophenyl)-3,3,3-trifluoroprop-1-enyl)quinazolin-4(3H)-one; (Z)-3-(1-(4-iodophenyl)-3,3,3-trifluoroprop-1-enyl)quinazolin-4(3H)-one; (Z)-3-(1-(4-cyanophenyl)-3,3,3-trifluoroprop-1-enyl)quinazolin-4(3H)-one; (Z)-3-(1-(4-trifluoromethylphenyl)-3,3,3-trifluoroprop-1-enyl)quinazolin-4(3H)-one.

4. The method for preparing the trifluoromethyl-substituted quinazolinone compound according to claim 1, characterized in that: The following steps are involved: In an organic solvent, under alkaline conditions, reacting the quinazolinone compound represented by formula II with the trifluoromethylacetylene compound represented by formula III to obtain the trifluoromethyl-substituted quinazolinone compound represented by formula I; Among them, R 1 is selected from hydrogen, C1-C8 alkyl, C1-C8 alkoxy, halogen, nitro, trifluoromethyl; R 2 Selected from hydrogen, halogen, cyano, trifluoromethyl.

5. The method according to claim 4, characterized in that The R 1 is selected from hydrogen, methyl, methoxy, fluorine, chlorine, bromine, iodine, nitro, trifluoromethyl; said R 2 Selected from bromine, iodine, cyano, trifluoromethyl.

6. The method according to claim 4, characterized in that The molar ratio of the quinazolinone compound to the trifluoromethylalkyne compound is 1:1 to 1:3, the reaction temperature is 20 to 60° C., and the reaction time is 2 to 10 hours.

7. The method according to claim 4, characterized in that The organic solvent is dimethyl sulfoxide, N,N-dimethylformamide, acetone or acetonitrile.

8. The method according to claim 4, characterized in that The base is potassium carbonate, sodium carbonate, potassium acetate, potassium tert-butoxide, potassium hydroxide or 1,8-diazabicyclo[5.4.0]undec-7-ene.

9. The use of the trifluoromethyl substituted quinazolinone compound according to claim 1, characterized in that: The trifluoromethyl substituted quinazolinone compound represented by formula I is used for preparing drugs for breast cancer, colon adenocarcinoma or colon cancer.

10. A tumor cell inhibitor, characterized in that The inhibitor comprises the trifluoromethyl-substituted quinazolinone compound according to claim 1.

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