A 2,3-dihydroquinazolinone compound, a preparation method and application thereof

Abstract

The application discloses a 2,3-dihydroquinazolinone compound and a preparation method and application thereof. A substituted 3-(but-3-en-1-yl)quinazolin-4(3H)-one of formula 1 is subjected to chemical reaction under reaction conditions to obtain a 2,3-dihydroquinazolinone compound with different substituents of formula 2; or a substituted N-cyano-N-[(1-vinyl-2-yl)phenyl]benzamide of formula 3 is subjected to chemical reaction under reaction conditions to obtain a 2,3-dihydroquinazolinone compound with different substituents of formula 4; the disclosed synthesis method is simple, safe and low in reaction cost. Moreover, the 2,3-dihydroquinazolinone compound prepared by the method has excellent inhibitory activity on tumor cells.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical synthesis, specifically to a method for preparing 2,3-dihydroquinazolinone compounds, the compounds obtained by this method, and their use in the preparation of pharmaceutical formulations. Background Technology

[0002] Compounds containing the 2,3-dihydroquinazolinone (DHQZ) group represent an important nitrogen-containing structural unit, formed by the fusion of a benzene ring and a six-membered ring, characterized by nitrogen atoms at positions 1 and 3, and a ketone group attached to a carbon atom at position 4. More importantly, this specific skeleton exhibits a wide range of pharmacological activities, including antibiotic, anti-fibrillary, anti-spermia, and analgesic effects. For example, Quinethazone, Fenquizone, and VU0092145, containing the DHQZ group, have shown antihypertensive activity. Figure 1 Furthermore, the polycyclic fused DHQZ compound Evodiamine also exhibits antitumor activity. Therefore, functionalizing DHQZ to obtain structurally diverse molecules has always been an important and challenging task in organic synthesis.

[0003]

[0004] Several synthetic methods for 2,3-dihydroquinazolinones have been reported in the literature to date. For example, copper catalysis has been reported to produce boron-based cyclized products with moderate to high efficiency from starting materials (Angew. Chem. Int. Ed., 2021). However, this method is applicable to primary alkyl groups and requires high stoichiometry of alkyl donors and harsh reaction conditions, which limits its applicability.

[0005] Furthermore, literature has demonstrated the successful formation of DHQZ groups under the catalysis of SmI3 (Org. Lett., 2014). However, this catalyst is expensive, which hinders its large-scale application.

[0006] (1) Angew. Chem. Int. Ed., 2021

[0007]

[0008] (2) Org. Lett., 2014

[0009]

[0010] In order to expand the application of the unique skeleton of DHQZ in organic and medicinal chemistry, it is necessary to develop a high-efficiency and rapid method for preparing the 2,3-dihydroquinazolinone compounds. SUMMARY

[0011] In view of the deficiencies of the prior art, the purpose of the present application is to provide a preparation method of 2,3-dihydroquinazolinone compounds, and to provide the compounds prepared by the method and the application of the compounds in pharmaceutical preparations.

[0012] In order to achieve the above purpose, the present application is implemented by the following technical solutions.

[0013] A new preparation method of 2,3-dihydroquinazolinone compounds comprises the following steps:

[0014] Substituted 3-(but-3-en-1-yl)quinazolin-4(3H)-one (1) undergoes chemical reaction under certain conditions to obtain 2,3-dihydroquinazolinone compounds (2) with different substituents, and the chemical reaction formula is shown in formula I:

[0015]

[0016] Alternatively, substituted N-cyano-N-[(1-vinyl-2-yl)phenyl]benzamide (3) undergoes chemical reaction under certain conditions to obtain 2,3-dihydroquinazolinone compounds (4) with different substituents, and the chemical reaction formula is shown in formula II:

[0017]

[0018]

[0019] R1, R2, R3 are independently H, halogen atom, C1-C10 aliphatic hydrocarbon and its substituent, C6-C20 aromatic hydrocarbon and its substituent;

[0020] The certain reaction conditions include catalyst, solvent, oxygen, reaction temperature, reaction time, reducing agent;

[0021] The catalyst includes organic metal compounds such as cuprous chloride CuCl, palladium acetate Pd(OAc)2, iron acetylacetate Fe(acac)3, cobalt acetylacetate Co(acac)2, or a mixture thereof;

[0022] The solvent is a common organic solvent, including water, ethanol, methanol, propanol, acetonitrile (ACN), N,N-dimethylformamide (DMF), tetrahydrofuran (THF), acetone (Acetone), butanone, hexanone, dichloromethane, or a mixture thereof;

[0023] ​The oxygen condition refers to that the reaction cannot be carried out under the condition of air or oxygen isolation;

[0024] The reaction temperature is related to the reaction time, and is -25-120 DEG C.

[0025] The reaction time is related to the above reaction condition, and is 0.1-24 hours.

[0026] The reducing agent is a common silane reducing agent, including tetramethyldisiloxane (TMDS), triethylsilane TES, t-butyl diphenyl silane, diphenyl silane Ph2SiH2, phenyl silane PhSiH3, or a mixture thereof.

[0027] Further, the application provides a synthesis method of 2,3-dihydroquinazolinone compounds, as shown in formula I and formula II, wherein,

[0028] R1, R2 and R3 are independently H, halogen atom, methyl, ethyl, propyl, isopropyl, cyclopropyl, allyl, propargyl, butyl, t-butyl, cyclohexyl, oxacyclohexyl, phenyl, substituted phenyl, benzyl, substituted benzyl;

[0029] The certain reaction condition includes a catalyst, a solvent, oxygen, a reaction temperature, a reaction time and a reducing agent.

[0030] The catalyst is cuprous chloride CuCl, palladium acetate Pd(OAc)2, iron acetylacetonate Fe(acac)3, cobalt acetylacetonate Co(acac)2 or a mixture thereof.

[0031] The solvent is ethanol, methanol, propanol or a mixture thereof.

[0032] The oxygen condition refers to that the reaction cannot be carried out under the condition of air or oxygen isolation.

[0033] The reaction temperature is related to the reaction time, and is 0-80 DEG C.

[0034] The reaction time is related to the above reaction condition, and is 0.1-12 hours.

[0035] The reducing agent is diphenyl silane Ph2SiH2, phenyl silane PhSiH3 or a mixture thereof.

[0036] Further, the application provides a synthesis method of 2,3-dihydroquinazolinone compounds, as shown in formula I and formula II, wherein,

[0037] R1, R2 and R3 are independently H, halogen atom, methyl, ethyl, propyl, isopropyl, cyclopropyl, phenyl.

[0038] Further, the application provides a synthesis method of the 2,3-dihydroquinazolinone compound, as shown in the formula I and the formula II, wherein the solvent is methanol or ethanol.

[0039] Further, the application provides a synthesis method of the 2,3-dihydroquinazolinone compound, as shown in the formula I and the formula II, wherein the reaction temperature is 15-80℃.

[0040] Further, the application provides a synthesis method of the 2,3-dihydroquinazolinone compound, as shown in the formula I and the formula II, wherein the reaction time is 0.1-4h.

[0041] The second object of the application is to provide a 2,3-dihydroquinazolinone compound by the above preparation method, which has the following structure:

[0042]

[0043]

[0044] The 2,3-dihydroquinazolinone compound prepared by the synthesis method can be used alone or prepared into a pharmaceutically acceptable salt by a conventional method.

[0045] The 2,3-dihydroquinazolinone compound and the pharmaceutically acceptable salt thereof prepared by the application have good proliferation inhibition activity on tumor cells, and thus can be applied to the preparation of a medicine for treating or preventing and relieving cancer, such as liver cancer, brain tumor, lung cancer or kidney cancer, or other cancers.

[0046] Compared with the prior art, the application has the following advantages:

[0047] The synthesis method of the 2,3-dihydroquinazolinone compound provided by the application has the advantages of cheap and easily available raw materials, mild reaction conditions, no need to avoid water and air, fast speed, simple operation, high regioselectivity, high yield and facilitation of industrial production. BRIEF DESCRIPTION OF DRAWINGS

[0048] Figure 1Structural diagrams of 3-(but-3-en-1-yl)quinazolin-4(3H)-one substituted with Formula 1, 2,3-dihydroquinazolinone compounds with different substituents of Formula 2, N-cyano-N-[(1-ethen-2-yl)phenyl]benzamide substituted with Formula 3, and 2,3-dihydroquinazolinone compounds with different substituents of Formula 4. DETAILED DESCRIPTION

[0049] The present application is further illustrated by the following examples without thereby limiting the present application to the scope of the examples. The experimental methods in the following examples, unless otherwise specified, are selected according to the conventional methods and conditions, or according to the commercial instruction.

[0050] Example 1. Preparation of compound 2a

[0051]

[0052] The reaction was carried out in a reaction flask equipped with a magnetic stir bar. After mixing the starting material 3-(3-methylbut-3-en-1-yl)quinazolin-4(3H)-one (1a, 214 mg, 1.0 mmol, 1.0 equiv), phenylsilane (PhSiH3, 1.05 mmol, 1.05 equiv) and Fe(acac)3(10 mol%) were dissolved in methanol (MeOH, 10.0 mL) at 50 °C for 30 min. Meanwhile, this reaction should be carried out in air. After the reaction was completed, the reaction mixture was quenched with saturated sodium chloride solution. The aqueous phase was extracted with ethyl acetate (EtOAc) and dried over Na2SO4. After concentration, the obtained residue was purified by column chromatography using petroleum ether (Pe) / ethyl acetate (6 / 1) as developing solvent to give the desired product 2a (179 mg, 79%). White solid, m.p.: 175.9-176.1 °C). 1 H NMR (400 MHz, Chloroform-d) δ 7.87 (dd, J = 7.8, 1.6 Hz, 1H), 7.29 - 7.21 (m, 1H), 6.83 (td, J = 7.6, 1.1 Hz, 1H), 6.71 (dd, J = 8.1, 1.0 Hz, 1H), 4.70 (s, 1H), 4.42 (s, 1H), 3.74 - 3.56 (m, 2H), 1.84 - 1.71 (m, 2H), 1.13 (d, J = 30.0 Hz, 6H). 13C NMR (101 MHz, Chloroform-d) δ 163.09, 148.80, 141.69, 131.82, 123.33, 116.08, 113.12, 42.57, 41.61, 36.42, 24.99, 21.96, 20.84. HRMS (ESI): calcd. for C 13 H 17 ON2[M+H] + 217.1342, find: 217.1347.

[0053] Example 2. Synthesis of different aryl substituted 2,3-dihydroquinazolinones (2b-2y)

[0054] Using the reaction condition of Example 1, 1 with different substituted groups, a number of 2,3-dihydroquinazolinones 2 were obtained. The reaction equation and the structure and yield of the products are as follows:

[0055]

[0056]

[0057] The structure confirmation of the prepared compounds is as follows:

[0058]

[0059] 3,3,8-trimethyl-1,2,3,3a,4,9-hexahydropyrrolo[2,1 -b]quinazolin-9-one (2b). White solid (yield: 75%, m.p.: 196.6-197.3 °C). 1 H NMR (400 MHz, Chloroform-d) δ 7.09 (t, J = 7.7 Hz, 1 H), 6.64 (d, J = 7.5 Hz, 1 H), 6.55 (d, J = 8.0 Hz, 1 H), 4.59 (s, 1 H), 4.10 (s, 1 H), 3.73-3.57 (m, 2H), 1.83-1.66 (m, 2H), 1.12 (d, J = 28.7 Hz, 6H). 13 C NMR (101 MHz, Chloroform-d) δ 163.09, 148.80, 141.69, 131.82, 123.33, 116.08, 113.12, 42.57, 41.61, 36.42, 24.99, 21.96, 20.84. HRMS (ESI): calcd. for C 14 H 19 N2O[M+H] +231.1498, found: 231.1499.

[0060]

[0061] 3,3,6-trimethyl-1,2,3,3a,4,9-hexahydropyrrolo[2,1-b]quinazolin-9-one (2c). White solid (yield: 68%, m.p.: 198.5-199.3 °C). 1 H NMR (400 MHz, Chloroform-d) δ 7.76 (d, J = 7.9 Hz, 1H), 6.66 (d, J = 7.0 Hz, 1H), 6.51 (s, 1H), 4.67 (s, 1H), 3.71-3.56 (m, 2H), 2.28 (s, 3H), 1.83-1.74 (m, 2H), 1.42 (d, J = 2.7 Hz, 1H), 1.12 (d, J = 30.7 Hz, 6H). 13 CNMR (101 MHz, Chloroform-d) δ 147.50, 143.78, 128.09, 120.70, 115.18, 41.97, 41.36, 36.22, 25.88, 24.64, 21.64, 20.62. HRMS (ESI): calcd. for C 14 H 19 ON2[M+H] + 231.1498, found: 231.1499.

[0062]

[0063] 3,3,5-trimethyl-1,2,3,3a,4,9-hexahydropyrrolo[2,1-b]quinazolin-9-one (2d). White solid (yield: 65%, m.p.: 130.0-131.1 °C). 1 H NMR (400 MHz, Chloroform-d) δ 7.76 (d, J = 7.9 Hz, 1H), 6.66 (d, J = 7.0 Hz, 1H), 6.51 (s, 1H), 4.67 (s, 1H), 3.71-3.56 (m, 2H), 2.28 (s, 3H), 1.83-1.74 (m, 2H), 1.42 (d, J = 2.7 Hz, 1H), 1.12 (d, J = 30.7 Hz, 6H). 13C NMR (101 MHz, Chloroform-d) δ 145.45, 134.03, 126.07, 125.47, 123.92, 122.19, 119.02, 117.22, 41.95, 41.40, 36.25, 35.45, 26.07, 24.75, 20.63, 16.62. HRMS (ESI): calcd. for C 14 H 19 ON2[M + H] + 231.1498, find: 231.1496.

[0064]

[0065] 8-fluoro-3,3-dimethyl-1,2,3,3a,4,9-hexahydropyrrolo[2,1-b]quinazolin-9-one (2e). White solid (yield: 78%, m.p.: 216.8-217.1 °C). 1 H NMR (400 MHz, Chloroform-d) δ 7.79 (dd, J = 8.7, 6.4 Hz, 1H), 6.45 (td, J = 8.6, 2.4 Hz, 1H), 6.32 (dd, J = 10.0, 2.3 Hz, 1H), 4.65 (s, 1H), 4.36 (s, 1H), 3.67-3.49 (m, 2H), 1.79-1.66 (m, 2H), 1.05 (d, J = 34.5 Hz, 6H). 13 C NMR (101 MHz, Chloroform-d) δ 167.24, 164.74, 161.83, 149.38, 149.27, 130.63, 130.52, 113.70, 106.87, 106.65, 101.39, 101.13, 41.98, 41.44, 36.16, 24.57, 20.57, 1.02. HRMS (ESI): calcd. for C 13 H 16 FN2O[M + H] + 235.1247 find: 235.1249.

[0066]

[0067] 7-fluoro-3,3-dimethyl-1,2,3,3a,4,9-hexahydropyrrolo[2,1-b]quinazolin-9-one (2f). White solid (yield: 71%, m.p.: 183.0-184.1 °C). 1 H NMR (400 MHz, Chloroform-d) δ 7.58 (dd, J = 8.8, 3.0 Hz, 1H), 7.00 (td, J = 8.4, 3.0 Hz, 1H), 6.67 (dd, J = 8.7, 4.2 Hz, 1H), 4.67 (s, 1H), 4.03 (s, 1H), 3.75-3.56 (m, 2H), 1.87-1.74 (m, 2H), 1.14 (d, J = 32.6 Hz, 6H). 13 C NMR (101 MHz, Chloroform-d) δ 161.54, 158.09, 155.72, 143.51, 143.49, 120.16, 119.93, 119.16, 119.09, 116.44, 116.37, 114.17, 113.93, 42.05, 41.34, 36.31, 24.70, 20.62. HRMS (ESI): calcd. for C 13 H 16 FN2O [M+H] + 235.1247, find: 235.1246.

[0068]

[0069] 6-fluoro-3,3-dimethyl-1,2,3,3a,4,9-hexahydropyrrolo[2,1-b]quinazolin-9-one (2f). White solid (yield: 71%, m.p.: 183.0-184.1 °C). 1 H NMR (400 MHz, Chloroform-d) δ 7.58 (dd, J = 8.8, 3.0 Hz, 1H), 7.00 (td, J = 8.4, 3.0 Hz, 1H), 6.67 (dd, J = 8.7, 4.2 Hz, 1H), 4.67 (s, 1H), 4.03 (s, 1H), 3.75-3.56 (m, 2H), 1.87-1.74 (m, 2H), 1.14 (d, J = 32.6 Hz, 6H). 13C NMR (101 MHz, Chloroform-d) δ 164.14, 161.56, 159.71, 150.03, 149.99, 133.54, 133.43, 110.63, 110.60, 107.32, 107.11, 106.54, 106.45, 42.37, 41.53, 36.29, 24.78, 20.71. HRMS (ESI): calcd. for C 13 H 16 OFN2[M+H] + 235.1247, find: 235.1250.

[0070]

[0071] 8-chloro-3,3-dimethyl-1,2,3,3a,4,9-hexahydropyrrolo[2,1-b]quinazolin-9-one (2h). White solid (yield: 79%, m.p.: 222.8-223.9 °C). 1 H NMR (400 MHz, Chloroform-d) δ 7.11 (t, J = 8.0 Hz, 1H), 6.87 (dd, J = 7.8, 1.1 Hz, 1H), 6.60 (dd, J = 8.1, 1.0 Hz, 1H), 4.62 (s, 1H), 4.09 (s, 1H), 3.77-3.60 (m, 2H), 1.85-1.69 (m, 2H), 1.13 (d, J = 31.1 Hz, 6H). 13 C NMR (101 MHz, Chloroform-d) δ 149.92, 132.32, 123.02, 113.84, 42.92, 41.67, 36.46, 25.04, 20.90. HRMS (ESI): calcd. for C 13 H 16 ClN2O[M+H] + 251.0943, find: 251.0941.

[0072]

[0073] 7-chloro-3,3-dimethyl-1,2,3,3a,4,9-hexahydropyrrolo[2,1-b]quinazolin-9-one (2h). White solid (yield: 79%, m.p.: 222.8-223.9 °C). 1H NMR (400 MHz, DMSO-d6) δ 7.28 (dd, J = 8.6, 2.6 Hz, 1H), 6.96 (s, 1H), 6.80 (d, J = 8.6 Hz, 1H), 4.64 (s, 1H), 4.14 (dd, J = 5.7, 3.5 Hz, 1H), 3.57 - 3.37 (m, 2H), 1.79 - 1.68 (m, 2H), 1.06 (d, J = 63.4 Hz, 6H). 13 CNMR (101 MHz, DMSO-d6) δ 160.66, 148.09, 132.93, 132.04, 129.12, 126.55, 121.43, 117.63, 116.87, 76.93, 42.09, 41.37, 35.81, 30.26, 28.83, 24.40, 23.71, 22.86, 20.79, 14.35, 11.26. HRMS (ESI): calcd. for C 13 H 16 OClN2[M+H] + 251.0952, find: 251.0954.

[0074]

[0075] 6-chloro-3,3-dimethyl-1,2,3,3a,4,9-hexahydropyrrolo[2,1-b]quinazolin-9-one (2j). White solid (yield: 63%, m.p.: 205.6-206.3 °C). 1 H NMR (400 MHz, Chloroform-d) δ 7.79 (d, J = 8.2 Hz, 1H), 6.80 (dd, J = 8.3, 2.0 Hz, 1H), 6.70 (d, J = 1.9 Hz, 1H), 4.71 (s, 1H), 4.34 (s, 1H), 3.66 (dtd, J = 19.5, 10.8, 9.5, 2.6 Hz, 2H), 1.79 (dt, J = 5.8, 3.1 Hz, 2H), 1.12 (d, J = 35.5 Hz, 6H). 13 CNMR (101 MHz, Chloroform-d) δ 161.76, 148.29, 138.84, 129.51, 119.70, 115.82, 114.51, 42.05, 41.45, 36.11, 24.56, 20.56. HRMS (ESI): calcd. for C 13 H 15 OClN22 [M+H] + 251.0952, find: 251.0957.

[0076]

[0077] 7-bromo-3,3-dimethyl-1,2,3,3a,4,9-hexahydropyrrolo[2,1-b]quinazolin-9-one(2k). White solid (yield: 74%, m.p.: 194.6-195.1 °C). 1 H NMR (400 MHz, Chloroform-d) δ 7.99 (d, J = 2.3 Hz, 1H), 7.34 (dd, J = 8.5, 2.4 Hz, 1H), 6.58 (d, J = 8.5 Hz, 1H), 4.68 (d, J = 1.3 Hz, 1H), 4.14 (s, 1H), 3.74-3.56 (m, 2H), 1.86-1.77 (m, 2H), 1.13 (d, J = 34.9 Hz, 6H). 13 C NMR (101 MHz, Chloroform-d) δ 161.19, 146.23, 135.57, 130.72, 119.14, 116.52, 111.61, 42.12, 41.42, 36.14, 24.62, 20.61. HRMS (ESI): calcd. for C 13 H 16 OBrN2[M+H] + 295.0447, find: 295.0450.

[0078]

[0079] 6-bromo-3,3-dimethyl-1,2,3,3a,4,9-hexahydropyrrolo[2,1-b]quinazolin-9-one(2l). White solid (yield: 61%, m.p.: 212.7-213.5 °C). The product was achieved by column chromatograph (Pe:EtOAc = 6: 1). 1H NMR (400 MHz, DMSO-d6) δ 7.49 (d, J = 8.3 Hz, 1H), 6.96 (d, J = 1.9 Hz, 1H), 6.84 (dd, J = 8.3, 1.9 Hz, 1H), 4.65 (s, 1H), 3.48 (dt, J = 10.2, 5.0 Hz, 1H), 1.71 (dd, J = 8.7, 5.7 Hz, 2H), 1.05 (d, J = 64.8 Hz, 6H). 13 C NMR (101 MHz, DMSO-d6) δ 161.10, 150.42, 129.48, 126.67, 120.52, 117.04, 115.46, 76.85, 42.05, 41.40, 35.71, 24.36, 20.72. HRMS (ESI): calcd. for C 13 H 16 OBrN2[M+H] + 295.0447, find: 295.0440.

[0080]

[0081] 3,3-dimethyl-7-(trifluoromethyl)-1,2,3,3a,4,9-hexahydropyrrolo[2,1-b]quinazolin-9-one (2m). White solid (yield: 68%, m.p.: 206.2-207.1 °C). 1 H NMR (400 MHz, Chloroform-d) δ 8.05 (d, J = 2.2 Hz, 1H), 7.38 (dd, J = 8.5, 2.2 Hz, 1H), 6.68 (d, J = 8.4 Hz, 1H), 4.76 (s, 1H), 4.69 (s, 1H), 3.68 - 3.51 (m, 2H), 1.80 - 1.64 (m, 2H), 1.07 (d, J = 38.7 Hz, 6H). 13 C NMR (101 MHz, Chloroform-d) δ 161.30, 149.93, 129.76, 129.73, 125.76, 125.72, 122.96, 121.32, 120.99, 116.45, 114.67, 42.15, 41.47, 35.93, 24.42, 20.48. HRMS (ESI): calcd. for C 14 H 16 OF3N2[M+H] +285.1215, find: 285.1213.

[0082]

[0083] 6,8-difluoro-3,3-dimethyl-1,2,3,3a,4,9-hexahydropyrrolo[2,1-b]quinazolin-9-on e(2n). White solid (yield: 69%, m.p.: 212.3-213.1 °C). 1 H NMR (400 MHz, Chloroform-d) δ 6.35-6.07 (m, 2H), 4.99 (s, 1H), 4.65 (s, 1H), 3.70-3.56 (m, 2H), 1.83-1.72 (m, 2H), 1.12 (d, J = 38.3 Hz, 6H). 13 C NMR (101 MHz, Chloroform-d) δ 166.70, 166.54, 165.15, 165.00, 164.20, 164.04, 162.56, 162.40, 159.20, 159.17, 151.31, 151.25, 151.17, 151.11, 97.62, 97.58, 97.37, 97.34, 96.10, 95.84, 95.58, 42.33, 41.54, 36.22, 24.64, 20.60. HRMS (ESI): calcd. for C 13 H 15 F2N2O [M+H] + 253.1153, find: 253.1149.

[0084]

[0085] 6,7-difluoro-3,3-dimethyl-1,2,3,3a,4,9-hexahydropyrrolo[2,1-b]quinazolin-9-on e(2o). White solid (yield: 64%, m.p.: 179.8-180.9 °C). 1 H NMR (400 MHz, Chloroform-d) δ 7.68 (t, J = 9.6 Hz, 1H), 6.51 (dd, J = 11.0, 6.2 Hz, 1H), 4.69 (s, 1H), 4.23 (s, 1H), 3.74-3.54 (m, 2H), 1.89-1.77 (m, 2H), 1.13 (d, J = 35.8 Hz, 6H).13 C NMR (101 MHz, Chloroform-d) δ 160.96, 144.43, 144.33, 116.66, 116.49, 103.69, 103.48, 42.08, 41.43, 36.22, 24.60, 20.59. HRMS (ESI): calcd. for C 13 H 15 OF2N2[M+H] + 253.1153 find: 253.1149.

[0086]

[0087] 3-methyl-1,2,3,3a,4,9-hexahydropyrrolo[2,1-b]quinazolin-9-one (2p). White solid (yield: 52%, m.p.: 159.3-160.2 °C). 1 H NMR (400 MHz, Chloroform-d) δ 7.80 (dd, J = 7.8, 1.6 Hz, 1H), 7.22-7.13 (m, 1H), 6.77 (qd, J = 7.6, 7.1, 1.1 Hz, 1H), 6.64 (ddd, J = 8.1, 2.4, 1.1 Hz, 1H), 4.96 (d, J = 5.3 Hz, 1H), 3.73-3.48 (m, 2H), 2.26-2.07 (m, 1H), 2.00-1.45 (m, 2H), 1.07 (dd, J = 24.9, 6.8 Hz, 3H). 13 C NMR (101 MHz, Chloroform-d) δ 162.61, 147.76, 132.92, 128.11, 128.09, 119.75, 119.41, 114.94, 75.62, 71.99, 43.32, 42.59, 40.92, 36.47, 29.91, 29.41, 15.54, 13.35. HRMS (ESI): calcd. for C 12 H 15 ON2[M+H] + 203.1185, find: 203.1179.

[0088]

[0089] 3,8-dimethyl-1,2,3,3a,4,9-hexahydropyrrolo[2,1-b]quinazolin-9-one(2q). White solid (yield: 69%, m.p.: 157.4-158.1 °C). 1 H NMR (400 MHz, Chloroform-d) δ 7.10 (t, J = 7.7 Hz, 1H), 6.67 (dd, J = 7.6, 3.1 Hz, 1H), 6.55 (dd, J = 8.0, 3.0 Hz, 1H), 4.71 (dd, J = 174.3, 6.7 Hz, 1H), 4.18 (d, J = 87.3 Hz, 1H), 3.94 - 3.48 (m, 2H), 2.67 (d, J = 2.3 Hz, 3H), 2.52 - 2.01 (m, 2H), 1.75 - 1.55 (m, 1H), 1.15 (dd, J = 18.9, 6.8 Hz, 3H). 13 C NMR (101 MHz, Chloroform-d) δ 163.06, 148.87, 148.50, 141.70, 141.66, 131.75, 123.72, 123.43, 116.61, 113.21, 113.14, 75.12, 71.17, 43.79, 43.51, 41.20, 36.90, 30.12, 30.00, 21.73, 15.82, 13.25. HRMS (ESI): calcd. for C 13 H 17 ON2[M+H] + 217.1342, find: 217.1342.

[0090]

[0091] 8-ethyl-3-methyl-1,2,3,3a,4,9-hexahydropyrrolo[2,1-b]quinazolin-9-one(2r). White solid (yield: 67%, m.p.: 150.6-151.3 °C). 1H NMR (400 MHz, Chloroform-d) δ 7.14 (t, J = 7.8 Hz, 1H), 6.71 (dt, J = 7.6, 1.7 Hz, 1H), 6.56 (ddd, J = 8.0, 3.2, 1.2 Hz, 1H), 5.04 - 4.39 (m, 1H), 4.05 (d, J = 15.6 Hz, 2H), 3.91 - 3.44 (m, 2H), 3.24 - 3.02 (m, 2H), 2.55 - 2.00 (m, 2H), 1.77 - 1.54 (m, 1H), 1.25 (td, J = 7.4, 3.3 Hz, 4H), 1.15 (dd, J = 18.6, 6.9 Hz, 3H). 13 C NMR (101 MHz, Chloroform-d) δ 148.99, 148.62, 148.02, 147.99, 131.95, 131.93, 122.27, 121.98, 113.24, 113.17, 75.02, 71.07, 43.94, 43.67, 41.21, 36.92, 30.16, 30.05, 27.30, 16.01, 15.99, 15.84, 13.22. HRMS (ESI): calcd. for C 14 H 19 ON2[M+H] + 231.1419 find: 231.1498.

[0092]

[0093] 3,6-dimethyl-1,2,3,3a,4,9-hexahydropyrrolo[2,1-b]quinazolin-9-one (2s). White solid (yield: 57%, m.p.: 162.5-163.1 °C). 1 H NMR (400 MHz, Chloroform-d) δ 7.76 (d, J = 7.9 Hz, 1H), 6.71 - 6.63 (m, 1H), 6.51 (t, J = 2.0 Hz, 1H), 5.13 - 4.46 (m, 1H), 2.27 (s, 3H), 2.21 - 2.09 (m, 1H), 2.08 - 1.45 (m, 2H), 1.14 (dd, J = 25.8, 6.8 Hz, 3H). 13C NMR (101 MHz, Chloroform-d) δ 147.50, 143.76, 128.09, 120.70, 115.18, 115.01, 41.95, 41.36, 36.22, 24.64, 21.63, 20.62. HRMS (ESI): calcd. for C 13 H 17 ON2[M + H] + 217.1342, find: 217.1344.

[0094]

[0095] 8-fluoro-3-methyl-1,2,3,3a,4,9-hexahydropyrrolo[2,1 -b]quinazolin-9-one (2t). White solid (yield: 51 %, m.p.: 151.0-151.7 °C). 1 H NMR (400 MHz, Chloroform-d) δ 7.22-7.06 (m, 1 H), 6.63-6.29 (m, 2H), 5.03-4.82 (m, 1 H), 4.75-4.49 (m, 1 H), 3.89-3.48 (m, 2H), 2.36-1.89 (m, 2H), 1.80-1.51 (m, 1 H), 1.15 (dd, J = 26.6, 6.9 Hz, 3H). 13 C NMR (101 MHz, Chloroform-d) δ 164.11, 161.54, 159.75, 150.27, 150.23, 148.51, 133.53, 133.49, 133.42, 133.38, 110.77, 110.74, 110.70, 110.67, 107.61, 107.39, 107.29, 107.07, 106.82, 71.52, 43.64, 43.08, 42.38, 41.23, 40.92, 36.57, 30.03, 30.00, 29.65, 15.66, 13.26. HRMS (ESI): calcd. for C 12 H 14 OFN2[M + H] + 221.1091, find: 221.1085.

[0096]

[0097] 6,7-difluoro-3-methyl-1,2,3,3a,4,9-hexahydropyrrolo[2,1-b]quinazolin-9-one (2u). White solid (yield: 48%, m.p.: 194.7-195.3 °C). 1 H NMR (400 MHz, DMSO-d6) δ 7.49 (dd, J = 10.8, 8.9 Hz, 1H), 7.02 (d, J = 95.7 Hz, 1H), 6.72 (ddd, J = 12.1, 6.7, 3.9 Hz, 1H), 4.97 (d, J = 5.2 Hz, 1H), 4.50 (d, J = 8.2 Hz, 0H), 3.58 - 3.39 (m, 2H), 2.24 - 1.95 (m, 2H), 1.69 - 1.49 (m, 1H), 1.07 (dd, J = 51.1, 6.8 Hz, 3H). 13 C NMR (101 MHz, DMSO-d6) δ 207.13, 160.32, 160.30, 159.87, 154.23, 154.18, 154.09, 154.04, 146.96, 146.86, 146.54, 146.45, 116.68, 103.81, 75.45, 72.19, 43.42, 42.34, 36.06, 29.72, 28.99, 15.47, 13.76. HRMS (ESI): calcd. for C 12 H 13 OF2N2[M+H] + 239.0997, find: 239.0988.

[0098]

[0099] 6,6-dimethyl-5,5a,6,12-tetrahydroindolo[2,1-b]quinazolin-12-one (2v). White solid (yield: 82%, m.p.: 189.6-193.0 °C). 1H NMR (400 MHz, Chloroform-d) δ 8.27 (dt, J = 8.0, 0.8 Hz, 1H), 8.04 (dd, J = 7.9, 1.6 Hz, 1H), 7.33 (ddd, J = 8.0, 7.2, 1.6 Hz, 1H), 7.29 - 7.23 (m, 1H), 7.19 (dd, J = 7.6, 1.4 Hz, 1H), 7.10 (td, J = 7.5, 1.1 Hz, 1H), 6.97 - 6.89 (m, 1H), 6.83 (dd, J = 8.1, 1.1 Hz, 1H), 5.18 (d, J = 1.6 Hz, 1H), 4.66 (s, 1H), 1.51 (s, 3H), 1.29 (s, 3H). 13 C NMR (101 MHz, Chloroform-d) δ 161.29, 146.91, 139.39, 138.48, 133.55, 128.67, 128.26, 124.34, 122.09, 120.19, 117.74, 116.16, 115.56, 79.73, 44.04, 24.85, 23.96. HRMS (ESI): calcd. for C 17 H 17 N2O[M+H] + 265.1342, find: 265.1338.

[0100]

[0101] 2-fluoro-6,6-dimethyl-5,5a,6,12-tetrahydroindolo[2,1-b]quinazolin-12-one (2w). White solid (yield: 79%, m.p.: 175.5-176.0 °C). 1 H NMR (400 MHz, Chloroform-d) δ 8.23 (dd, J = 8.7, 4.8 Hz, 1H), 8.02 (dd, J = 7.8, 1.6 Hz, 1H), 7.34 (ddd, J = 8.1, 7.2, 1.6 Hz, 1H), 6.98 - 6.91 (m, 2H), 6.89 (dd, J = 8.1, 2.6 Hz, 1H), 6.82 (dd, J = 8.1, 1.0 Hz, 1H), 5.20 (d, J = 1.4 Hz, 1H), 4.63 (s, 1H), 1.50 (s, 3H), 1.29 (s, 3H). 13C NMR (101 MHz, Chloroform-d) δ 161.11, 161.03, 158.69, 146.76, 140.65, 140.58, 135.45, 135.43, 133.63, 128.57, 120.28, 117.48, 117.17, 117.09, 115.57, 114.70, 114.47, 109.76, 109.52, 79.87, 44.23, 44.22, 24.61, 23.72. HRMS (ESI): calcd. for C 17 H 16 FN2O [M+H] + 283.1247, find: 283.1235.

[0102]

[0103] 2-bromo-6,6-dimethyl-5,5a,6,12-tetrahydroindolo[2,1-b]quinazolin-12-one (2x). White solid (yield: 80%, m.p.: 224.6-225.1 °C). 1 H NMR (400 MHz, Chloroform-d) δ 8.15 (d, J = 8.5 Hz, 1H), 8.02 (dd, J = 7.9, 1.6 Hz, 1H), 7.40-7.33 (m, 2H), 7.29 (d, J = 2.0 Hz, 1H), 5.18 (d, J = 1.5 Hz, 1H), 4.53 (s, 1H), 1.50 (s, 3H), 1.29 (s, 3H). 13 C NMR (101 MHz, Chloroform-d) δ 161.21, 146.78, 140.69, 138.46, 133.77, 131.19, 128.69, 125.48, 120.42, 117.57, 117.50, 116.71, 115.62, 79.76, 77.36, 77.04, 76.73, 44.23, 24.73, 23.86. HRMS (ESI): calcd. for C 17 H 16 BrN2O [M+H] + 343.0447, find: 343.0433.

[0104]

[0105] 6-(4-fluorophenyl)-6-methyl-5,5a,6,12-tetrahydroindolo[2,1-b]quinazolin-12-one (2y). White solid (yield: 80%, m.p.: 159.3-160.4 °C). 1 H NMR (400 MHz, Chloroform-d) δ 8.36 (d, J = 8.1 Hz, 1H), 8.03 (d, J = 7.8 Hz, 1H), 7.37 (t, J = 7.7 Hz, 1H), 7.28 (q, J = 7.4, 6.9 Hz, 1H), 7.16 - 7.03 (m, 4H), 7.03 - 6.90 (m, 3H), 6.69 (d, J = 8.1 Hz, 1H), 5.36 (d, J = 4.4 Hz, 1H), 3.53 (s, 1H), 1.96 (s, 3H). 13 C NMR (101 MHz, Chloroform-d) δ 161.15, 145.78, 140.66, 137.59, 133.44, 129.72, 129.64, 128.96, 128.62, 124.84, 123.76, 121.23, 119.35, 117.43, 116.07, 115.50, 115.29, 50.54, 24.97. HRMS (ESI): calcd. for C 22 H 18 FN2O [M+H] + 345.1404, find: 345.1397.

[0106] Example 3. Synthesis of 2,3-dihydroquinazolinones (4a-4x) with different substituents

[0107] Using the reaction conditions of Example 1, substituted N-cyano-N-[(1-ethen-2-yl)phenyl]benzamides (3) were subjected to chemical reactions under certain conditions to obtain 2,3-dihydroquinazolinones (4) with different substituents. The structures of the products were confirmed as follows:

[0108]

[0109] 6,6-dimethyl-6,12-dihydroindolo[2,1-b]quinazolin-12-one (4a). White solid (yield: 81%, m.p.: 144.2-144.8 °C). 1H NMR (400 MHz, Chloroform-d) δ 8.63-8.58 (m, 1H), 8.44-8.39 (m, 1H), 7.83-7.73 (m, 2H), 7.51 (ddd, J = 8.1, 6.2, 2.0 Hz, 1H), 7.45-7.40 (m, 2H), 7.37-7.32 (m, 1H), 1.64 (s, 6H). 13 C NMR (101 MHz, Chloroform-d) δ 164.77, 160.28, 147.60, 138.41, 137.94, 134.43, 128.51, 127.32, 126.94, 126.81, 126.72, 122.49, 121.50, 117.35, 45.28, 26.78. HRMS (ESI): calcd. for C 17 H 15 N2O[M+H] + 263.1185, find: 263.1186.

[0110]

[0111] 14,14-dimethyl-6,14-dihydrobenzo[g]indolo[2,1-b]quinazolin-6-one (4b). White solid (yield: 82%, m.p.: 199.7-200.4 °C). 1 H NMR (400 MHz, Chloroform-d) δ 9.17 (ddd, J = 6.0, 3.4, 1.4 Hz, 1H), 8.68 (dd, J = 8.3, 1.3 Hz, 1H), 8.35 (d, J = 8.7 Hz, 1H), 7.95-7.90 (m, 1H), 7.86 (dd, J = 8.7, 1.0 Hz, 1H), 7.75-7.65 (m, 2H), 7.49-7.42 (m, 2H), 7.40-7.33 (m, 1H), 1.71 (s, 6H). 13 C NMR (101 MHz, Chloroform-d) δ 164.84, 160.49, 146.45, 138.65, 138.29, 136.33, 130.09, 129.24, 128.52, 127.89, 126.87, 126.81, 125.46, 122.56, 121.97, 117.76, 117.57, 45.62, 26.84. HRMS (ESI): calcd. for C 21 H 17N2O[M+H] + 313.1342, find: 313.1345.

[0112]

[0113] 3-fluoro-6,6-dimethyl-6,12-dihydroindolo[2,1-b]quinazolin-12-one (4c). White solid (yield: 79%, m.p.: 188.6-189.2 °C). 1 H NMR (400 MHz, Chloroform-d) δ 8.67-8.45 (m, 1H), 8.39 (dd, J = 8.9, 6.2 Hz, 1H), 7.46-7.37 (m, 3H), 7.37-7.29 (m, 1H), 7.20 (ddd, J = 8.9, 8.1, 2.5 Hz, 1H), 1.62 (s, 6H). 13 C NMR (101 MHz, Chloroform-d) δ 167.81, 166.15, 165.28, 159.55, 150.04, 149.91, 138.26, 137.78, 129.57, 129.46, 128.54, 126.80, 122.50, 118.24, 118.22, 117.31, 115.48, 115.25, 113.00, 112.78, 45.38, 26.69. HRMS (ESI): calcd. for C 17 H 14 FN2O[M+H] + 281.1091, find: 281.1095.

[0114]

[0115] 3-chloro-6,6-dimethyl-6,12-dihydroindolo[2,1-b]quinazolin-12-one (4d). White solid (yield: 77%, m.p.: 153.1-153.6 °C). 1 H NMR (400 MHz, Chloroform-d) δ 8.59-8.54 (m, 1H), 8.33 (d, J = 8.5 Hz, 1H), 7.80 (d, J = 1.9 Hz, 1H), 7.47-7.44 (m, 1H), 7.44-7.40 (m, 2H), 7.38-7.34 (m, 1H), 1.63 (s, 6H). 13C NMR (101 MHz, Chloroform-d) δ 165.95, 159.65, 148.71, 138.15, 137.78, 130.18, 129.95, 128.93, 128.47, 128.23, 126.78, 122.42, 120.30, 117.26, 45.33, 26.62. HRMS (ESI): calcd. for C 17 H 14 ClN2O [M+H] + 297.0795, find: 297.0795.

[0116]

[0117] 3-bromo-6,6-dimethyl-6,12-dihydroindolo[2,1-b]quinazolin-12-one (4e). White solid (yield: 74%, m.p.: 167.5-168.6 °C). 1 H NMR (400 MHz, Chloroform-d) δ 8.53-8.46 (m, 1H), 8.17 (d, J = 8.5 Hz, 1H), 7.89 (d, J = 1.9 Hz, 1H), 7.53 (dd, J = 8.5, 1.9 Hz, 1H), 7.39-7.32 (m, 2H), 7.32-7.26 (m, 1H), 1.55 (s, 6H). 13 C NMR (101 MHz, Chloroform-d) δ 165.95, 159.65, 148.71, 138.15, 137.78, 130.18, 129.95, 128.93, 128.47, 128.23, 126.78, 122.42, 120.30, 117.26, 45.33, 26.62. HRMS (ESI): calcd. for C 17 H 14 OBrN2 [M+H] + 341.0290, find: 341.0282.

[0118]

[0119] bromo-6,6-dimethyl-6,12-dihydroindolo[2,1-b]quinazolin-12-one (4e). White solid (yield: 74%, m.p.: 167.5-168.6 °C). 1H NMR (400 MHz, Chloroform-d) δ 8.66-8.47 (m, 1H), 8.38 (dd, J = 7.9, 1.5 Hz, 1H), 8.04 (dd, J = 7.7, 1.5 Hz, 1H), 7.47-7.43 (m, 1H), 7.42 (q, J = 1.5 Hz, 1H), 7.38-7.36 (m, 1H), 7.33 (d, J = 7.9 Hz, 1H), 1.66 (s, 6H). 13 C NMR (101 MHz, Chloroform-d) δ 165.30, 159.71, 145.53, 138.16, 138.07, 128.52, 127.11, 126.96, 126.48, 123.10, 122.78, 122.59, 117.33, 45.65, 29.80, 26.92. HRMS (ESI): calcd. for C 17 H 14 OBrN2[M+H] + 341.0290, find: 341.0275.

[0120]

[0121] 8-fluoro-6,6-dimethyl-6,12-dihydroindolo[2,1-b]quinazolin-12-one (4g). White solid (yield: 77%, m.p.: 180.7-181.4 °C). 1 H NMR (400 MHz, DMSO-d6) δ 8.43 (dd, J = 8.8, 4.8 Hz, 1H), 8.26 (dd, J = 8.0, 1.6 Hz, 1H), 7.86 (ddd, J = 8.5, 7.0, 1.6 Hz, 1H), 7.76 (dd, J = 8.2, 1.2 Hz, 1H), 7.62 (dd, J = 8.4, 2.6 Hz, 1H), 7.60-7.51 (m, 1H), 7.28 (td, J = 9.1, 2.7 Hz, 1H), 1.58 (s, 6H). 13C NMR (101 MHz, DMSO-d6) δ 164.91, 162.32, 159.91, 159.58, 147.63, 140.97, 140.89, 134.99, 134.75, 134.73, 127.57, 127.22, 126.69, 121.40, 118.16, 118.07, 115.22, 114.99, 111.51, 111.26, 45.60, 45.58, 26.44. HRMS (ESI): calcd. for C 17 H 14 OFN2 [M+H] + 281.1091, find: 281.1085.

[0122]

[0123] 2-fluoro-14,14-dimethyl-6,14-dihydrobenzo[g]indolo[2,1-b]quinazolin-6-one (4h). White solid (yield: 83%, m.p.: 197.3-198.0 °C). 1 H NMR (400 MHz, Chloroform-d) δ 8.53 (ddd, J = 8.3, 4.7, 1.1 Hz, 1H), 8.38 (dd, J = 8.9, 6.1 Hz, 1H), 7.41 (dd, J = 9.7, 2.5 Hz, 1H), 7.24-7.17 (m, 1H), 7.18-7.01 (m, 2H), 1.63 (s, 6H). 13 C NMR (101 MHz, Chloroform-d) δ 164.42, 160.14, 146.27, 140.50, 140.42, 136.25, 129.96, 129.22, 127.82, 126.94, 126.85, 125.35, 121.77, 118.85, 118.77, 117.62, 115.16, 114.93, 110.33, 110.08, 45.75, 45.73, 26.64. HRMS (ESI): calcd. for C 21 H 16 OFN2 [M+H] + 331.1247, find: 331.1235.

[0124]

[0125] 3,8-difluoro-6,6-dimethyl-6,12-dihydroindolo[2,1-b]quinazolin-12-one (4i). White solid (yield: 47%, m.p.: 182.2-183.1 °C). 1 H NMR (400 MHz, Chloroform-d) δ 8.53 (ddd, J = 8.3, 4.7, 1.1 Hz, 1H), 8.38 (dd, J = 8.9, 6.1 Hz, 1H), 7.41 (dd, J = 9.7, 2.5 Hz, 1H), 7.24-7.17 (m, 1H), 7.18-7.01 (m, 2H), 1.63 (s, 6H). 13 C NMR (101 MHz, Chloroform-d) δ 167.73, 165.70, 165.21, 162.65, 160.20, 159.21, 149.86, 149.73, 140.01, 139.93, 134.14, 134.11, 129.42, 129.31, 118.60, 118.51, 118.05, 118.03, 115.53, 115.30, 115.18, 114.95, 112.97, 112.75, 110.27, 110.02, 45.50, 45.48, 26.48. HRMS (ESI): calcd. for C 17 H 13 OF2N2[M+H] + 299.0997, find: 299.0991.

[0126]

[0127] 3-bromo-8-fluoro-6,6-dimethyl-6,12-dihydroindolo[2,1-b]quinazolin-12-one (4j). White solid (yield: 55%, m.p.: 178.8-179.5 °C). 1 H NMR (400 MHz, DMSO-d6) δ 7.52 (dd, J = 8.9, 4.7 Hz, 1H), 7.27 (d, J = 8.5 Hz, 1H), 7.25-7.03 (m, 1H), 6.96-6.83 (m, 1H), 6.79 (dd, J = 8.5, 2.7 Hz, 1H), 6.42 (td, J = 9.2, 2.7 Hz, 1H), 0.73 (s, 6H). 13C NMR (101 MHz, DMSO-d6) δ 166.39, 162.38, 159.96, 159.09, 148.75, 140.89, 140.80, 134.57, 134.55, 130.15, 129.82, 128.62, 128.48, 120.59, 118.17, 118.09, 115.27, 115.04, 111.54, 111.30, 45.80, 45.78, 26.31. HRMS (ESI): calcd. for C 17 H 13 OBrFN2[M+H] + 359.0196, find: 359.0182.

[0128]

[0129] 6-(4-fluorophenyl)-6-methylindolo[2,1-b]quinazolin-12(6H)-one (4k). White solid (yield: 73%, m.p.: 154.6-155.1 °C). 1 H NMR (400 MHz, DMSO-d6) δ 9.15 (d, J = 8.1 Hz, 1H), 8.87 (dt, J = 8.2, 1.1 Hz, 1H), 8.25-8.07 (m, 2H), 7.99-7.93 (m, 2H), 7.86-7.75 (m, 4H), 7.48-7.41 (m, 2H), 2.02 (s, 3H). 13 C NMR (101 MHz, Chloroform-d) δ 163.32, 160.17, 147.60, 138.91, 137.61, 136.91, 134.35, 128.92, 128.57, 128.49, 127.66, 126.94, 126.89, 126.80, 124.09, 121.35, 117.46, 115.61, 115.40, 52.26, 29.72, 25.87. HRMS (ESI): calcd. for C 22 H 16 OFN2[M+H] + 343.1247, find: 343.1234.

[0130]

[0131] 14-(4-fluorophenyl)-14-methylbenzo[g]indolo[2,1-b]quinazolin-6(14H)-one (4l). White solid (yield: 75%, m.p.: 169.7-170.4 °C). 1 H NMR (400 MHz, Chloroform-d) δ 9.05 (dd, J = 7.9, 1.9 Hz, 1H), 8.77 (d, J = 7.9 Hz, 1H), 8.34 (d, J = 8.7 Hz, 1H), 7.96-7.86 (m, 2H), 7.74-7.64 (m, 2H), 7.54 (ddd, J = 8.4, 5.3, 3.6 Hz, 1H), 7.48-7.39 (m, 5H), 7.05-6.96 (m, 2H), 2.12 (s, 3H). 13 C NMR (101 MHz, Chloroform-d) δ 129.22, 129.02, 128.66, 128.58, 127.77, 127.08, 126.99, 126.84, 125.38, 124.33, 121.78, 117.73, 115.55, 115.34, 52.56, 26.38. HRMS (ESI): calcd. for C 26 H 18 FN2O [M+H] + 393.1404, find: 393.1379.

[0132]

[0133] 6-(4-chlorophenyl)-6-methylindolo[2,1-b]quinazolin-12(6H)-one (4m). White solid (yield: 67%, m.p.: 173.6-174.4 °C). 1 H NMR (400 MHz, Chloroform-d) δ 8.68 (d, J = 8.0 Hz, 1H), 8.55-8.33 (m, 1H), 7.86-7.66 (m, 2H), 7.49 (ddt, J = 8.6, 5.8, 2.0 Hz, 2H), 7.35 (td, J = 7.5, 1.1 Hz, 1H), 7.29 (dd, J = 13.7, 1.4 Hz, 5H), 2.03 (s, 3H). 13C NMR (101 MHz, Chloroform-d) δ 163.08, 160.11, 147.59, 140.42, 138.98, 136.65, 134.34, 133.57, 128.99, 128.80, 128.24, 127.67, 126.96, 126.90, 126.81, 124.08, 121.38, 117.48, 52.35, 25.67. HRMS (ESI): calcd. for C 22 H 16 OCIN2 [M+H] + 359.0952, find: 359.0939.

[0134]

[0135] 14-(4-chlorophenyl)-14-methylbenzo[g]indolo[2,1 -b]quinazolin-6(14H)-one (4n). White solid (yield: 68%, m.p.: 163.8-164.2 °C). 1 H NMR (400 MHz, Chloroform-d) δ 9.06-8.99 (m, 1 H), 8.76 (d, J = 8.1 Hz, 1 H), 8.32 (d, J = 8.7 Hz, 1 H), 7.92-7.81 (m, 2H), 7.72-7.61 (m, 2H), 7.53 (ddd, J = 8.3, 6.4, 2.5 Hz, 1 H), 7.46-7.35 (m, 4H), 7.34-7.25 (m, 2H), 2.11 (s, 3H). 13 C NMR (101 MHz, Chloroform-d) δ 163.12, 160.21, 146.25, 140.39, 139.28, 136.55, 136.26, 133.61, 129.95, 129.23, 129.09, 128.77, 128.33, 127.77, 127.12, 127.01, 126.86, 125.37, 124.30, 121.78, 117.76, 117.66, 52.66, 26.16. HRMS (ESI): calcd. for C 26 H 18 OCIN2 [M+H] + 409.1108, find: 409.1079.

[0136]

[0137] 1-fluoro-6-(4-fluorophenyl)-6-methylindolo[2,1-b]quinazolin-12(6H)-one (4o). White solid (yield: 57%, m.p.: 99.4-100.9 °C). 1 H NMR (400 MHz, Chloroform-d) δ 8.69 (d, J = 8.1 Hz, 1H), 7.65 (td, J = 8.2, 5.4 Hz, 1H), 7.54-7.45 (m, 2H), 7.37 (td, J = 7.5, 1.1 Hz, 1H), 7.31 (ddd, J = 8.9, 4.3, 2.3 Hz, 3H), 7.14 (ddd, J = 10.7, 8.1, 1.2 Hz, 1H), 7.04-6.94 (m, 2H), 2.03 (s, 3H). 13 C NMR (101 MHz, Chloroform-d) δ 164.26, 163.38, 163.27, 160.92, 160.63, 157.35, 157.31, 149.75, 138.78, 137.34, 137.31, 136.63, 134.66, 134.56, 129.04, 128.58, 128.50, 127.01, 124.06, 123.62, 123.58, 117.64, 115.63, 115.42, 113.76, 113.55, 111.07, 111.01, 52.30, 29.70, 25.81. HRMS (ESI): calcd. for C 22 H 15 OF2N2[M+H] + 361.1153, find: 361.1142.

[0138]

[0139] 3-fluoro-6-(4-fluorophenyl)-6-methylindolo[2,1-b]quinazolin-12(6H)-one (4p). White solid (yield: 49%, m.p.: 175.9-176.2 °C). 1H NMR (400 MHz, DMSO-d6) δ 8.52 (d, J = 8.0 Hz, 1H), 8.35 (dd, J = 8.9, 6.2 Hz, 1H), 7.62 - 7.49 (m, 2H), 7.40 (dd, J = 9.8, 4.8 Hz, 2H), 7.14 (t, J = 8.8 Hz, 2H), 2.01 (s, 3H). 13 C NMR (101 MHz, DMSO-d6) δ 165.65, 159.12, 149.88, 149.75, 138.73, 138.56, 138.53, 137.68, 129.86, 129.75, 129.32, 129.24, 129.09, 127.39, 124.65, 118.66, 116.99, 115.96, 115.87, 115.73, 115.66, 113.15, 112.93, 52.77, 25.19. HRMS (ESI): calcd. for C 22 H 15 OF2N2[M+H] + 361.1153, find: 361.1145.

[0140]

[0141] 6-(4-chlorophenyl)-1-fluoro-6-methylindolo[2,1-b]quinazolin-12(6H)-one (4q). White solid (yield: 55%, m.p.: 202.3-203.8 °C). 1 H NMR (400 MHz, Chloroform-d) δ 8.68 (dd, J = 8.1, 1.0 Hz, 1H), 7.64 (dd, J = 8.2, 5.4 Hz, 1H), 7.55 - 7.46 (m, 2H), 7.36 (td, J = 7.5, 1.1 Hz, 1H), 7.32 - 7.26 (m, 5H), 7.14 (ddd, J = 10.8, 8.1, 1.2 Hz, 1H), 2.02 (s, 3H). 13CNMR (101 MHz, Chloroform-d) δ 164.04, 163.25, 160.61, 157.34, 157.30, 149.68, 140.05, 138.79, 136.39, 134.74, 134.64, 133.68, 129.13, 128.84, 128.24, 127.08, 124.05, 123.62, 123.58, 117.66, 113.84, 113.63, 111.05, 110.99, 52.40, 25.57. HRMS (ESI): calcd. for C 22 H 15 OCIFN2 [M+H] + 377.0858, find: 377.0849.

[0142]

[0143] 6-(4-chlorophenyl)-3-fluoro-6-methylindolo[2,1-b]quinazolin-12(6H)-one (4r). White solid (yield: 56%, m.p.: 202.0-203.3 °C). 1 H NMR (400 MHz, Chloroform-d) δ 8.80-8.50 (m, 1H), 8.41 (dd, J = 8.9, 6.1 Hz, 1H), 7.50 (td, J = 7.8, 1.4 Hz, 1H), 7.42-7.34 (m, 2H), 7.30 (dd, J = 7.9, 1.4 Hz, 1H), 7.28-7.25 (m, 4H), 7.25-7.19 (m, 1H), 2.03 (s, 3H). 13 CNMR (101 MHz, Chloroform-d) δ 164.52, 159.39, 140.05, 138.83, 136.46, 133.71, 129.47, 129.36, 129.07, 128.85, 128.22, 127.05, 124.12, 118.06, 118.04, 117.46, 115.72, 115.49, 113.28, 113.06, 52.47, 25.61. HRMS (ESI): calcd. for C 22 H 15 OCIFN2 [M+H] + 377.0858, find: 377.0833.

[0144] Example 4. Preparation of hydrochloride salt (using compound 2a as an example)

[0145] Compound 2a (100 mg) was dissolved in 5 mL of ethyl acetate. Hydrochloric acid gas was bubbled into the solution until it was supersaturated. The solution was cooled to about 0°C, and crystals of the hydrochloride salt of compound 2a slowly precipitated.

[0146] Example 5. Proliferation inhibition activity of tumor cells - MTT method

[0147] The MTT method is also known as the MTT colorimetric method, which is a method for detecting cell survival and growth. The detection principle is that succinate dehydrogenase in the mitochondria of living cells can reduce exogenous MTT to water-insoluble blue-purple Formazan crystals, which can be deposited in cells, while dead cells do not have this function. Dimethyl sulfoxide (DMSO) can dissolve the Formazan in the cells, and the light absorption value of the Formazan can be measured by an enzyme-linked immunoassay instrument at a wavelength of 540 nm or 720 nm, which can indirectly reflect the number of living cells. Within a certain range of cell numbers, the amount of MTT crystals formed is directly proportional to the number of cells. This method has been widely used in the activity detection of some bioactive factors, large-scale screening of antitumor drugs, cytotoxicity tests, and determination of tumor radiosensitivity, etc. It has the characteristics of high sensitivity and economy.

[0148] Experimental method: Take tumor cell strains in the logarithmic growth phase (HepG2 liver cancer, U-87MG brain astrocytoma, H1299 human lung cancer cells, 786-O human renal clear cell carcinoma cells), inoculate 4000 cells per well in a 96-well culture solution, and set up a control group (DMSO) and a compound treatment group. The highest concentration of the compound is 50 μg / mL, which is diluted by 5 times in gradient, and a total of 5 concentrations, three replicate wells for each concentration. After the compound acts on the cells for 72 hours, the culture solution is discarded, 100 microliters of pre-cooled 10% trichloroacetic acid (TCA) solution is added to each well to fix the cells, and the culture solution is washed with deionized water for five times, and the trichloroacetic acid solution is removed. After drying in the air, 50 microliters of 1% acetic acid prepared SRB solution (4 mg / mL) is added to each well, and the plate is placed at room temperature for 20 minutes. After the liquid in each well is discarded, it is washed with 1% acetic acid for five times, and the unbound SRB dye is washed and dried in the air. 100 microliters of 10 mM Tris-base (tris-hydroxymethyl aminomethane) solution with pH = 10.5 is added to each well to dissolve it, and the plate is shaken for 5 minutes. The absorbance OD value is measured by an enzyme-labeled instrument at a wavelength of 515 nm.

[0149] The IC 50 values of the compounds are shown in the following table:

[0150] Table 1. IC 50 values of the compounds

[0151]

[0152]

[0153]

[0154] IC 50 : A <10 μM; 10 μM < B < 50 μM; 50 μM < C < 100 μM

[0155] It can be seen that the compound provided by the present application has good proliferation inhibition activity on tumor cells for different cell strains (HepG2 liver cancer, U-87MG brain astrocytoma, H1299 human lung cancer cells, 786-O human renal clear cell carcinoma cells), and thus can be applied in the preparation of drugs for treating, preventing and relieving cancer.

Claims

1. A method for preparing a 2,3-dihydroquinazolinone compound, characterized in that, Includes the following steps: The 3-(but-3-en-1-yl)quinazolin-4(3H)-one substituted with Formula 1 undergoes a chemical reaction under the reaction conditions to obtain 2,3-dihydroquinazolinone compounds with different substituents of Formula 2. 、 ； Alternatively, the N-cyano-N-[(1-vinyl-2-yl)phenyl]benzamide of formula 3 undergoes a chemical reaction under the reaction conditions to obtain 2,3-dihydroquinazolinone compounds of formula 4 with different substituents. 、 ； in, R1, R2, and R3 are independently H, halogen atoms, C1-C10 aliphatic hydrocarbons and their substituted products, and C6-C20 aromatic hydrocarbons and their substituted products. The reaction conditions include catalyst, solvent, oxygen, reaction temperature, reaction time, and reducing agent; The catalyst is iron acetylacetone; The solvent is one of water, ethanol, methanol, propanol, acetonitrile, N,N-dimethylformamide, tetrahydrofuran, acetone, butanone, hexanone, and dichloromethane, or a mixture thereof; The reaction temperature is -25℃ to 120℃; The reaction time is 0.1 to 24 hours; The reducing agent is one of tetramethyldisiloxane, triethylsilane, tert-butyldiphenylsilane, diphenylsilane, phenylsilane, or a mixture thereof.

2. The method for preparing 2,3-dihydroquinazolinone compounds as described in claim 1, characterized in that, R1, R2, and R3 are independently H, halogen atom, methyl, ethyl, propyl, isopropyl, cyclopropyl, allyl, propargyl, butyl, tert-butyl, cyclohexyl, oxacyclohexyl, phenyl, substituted phenyl, benzyl, or substituted benzyl.

3. The method for preparing 2,3-dihydroquinazolinone compounds as described in claim 2, characterized in that, R1, R2, and R3 are independently H, halogen atom, methyl, ethyl, propyl, isopropyl, cyclopropyl, and phenyl.

4. The method for preparing 2,3-dihydroquinazolinone compounds as described in claim 1, characterized in that, The solvent is one of ethanol, methanol, propanol, or a mixture thereof; The reaction temperature is 0℃~80℃; The reaction time is 0.1 to 12 hours.

5. The method for preparing 2,3-dihydroquinazolinone compounds as described in claim 4, characterized in that, The solvent is methanol or ethanol; The reaction temperature is 15℃~80℃; The reaction time is 0.1 to 4 hours.

6. The method for preparing 2,3-dihydroquinazolinone compounds as described in claim 1, characterized in that, The 2,3-dihydroquinazolinone compounds mentioned above have the following structures: ； ； 。

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