2, 3-dihydroquinazolinone compound as well as preparation method and application thereof

Abstract

The invention discloses a 2, 3-dihydroquinazolinone compound as well as a preparation method and application thereof. The preparation method comprises the following steps: carrying out chemical reaction on substituted 3-(butyl-3-ene-1-yl) quinazoline-4 (3H)-ketone in a formula 1 under reaction conditions to obtain 2, 3-dihydroquinazolinone compounds with different substituent groups in a formula 2; or, N-cyano-N-[(1-ethylene-2-yl) phenyl] benzamide substituted by a formula 3 is subjected to a chemical reaction under reaction conditions, and 2, 3-dihydroquinazolinone compounds substituted by a formula 4 and having different substituent groups are obtained; according to the synthesis method disclosed by the invention, the reaction system is simple and safe, and the reaction cost is low. Moreover, the 2, 3-dihydroquinazolinone compound prepared by the method disclosed by the invention has excellent inhibitory activity on tumor cells.

Description

Technical Field

[0001] The present invention relates to the field of drug synthesis, and in particular to a method for preparing a 2,3-dihydroquinazolinone compound, a compound prepared by the method, and use of the compound in preparing a drug preparation. Background Art

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

[0003]

[0004] So far, several synthetic methods for 2,3-dihydroquinazolinone have been reported in the literature. For example, it has been reported that using copper catalysis, the starting materials can produce boryl cyclization products with moderate to high efficiency (Angew. Chem. Int. Ed., 2021). However, this method is applicable to primary alkyl groups and requires high stoichiometric alkyl donors and harsh reaction conditions, which will limit its applicability.

[0005] In addition, there are documents proving that the formation of DHQZ groups is successful under the catalysis of SmI3 (Org. Lett., 2014). However, this catalyst is expensive and not conducive to 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 DHQZ skeleton in organic and medicinal chemistry, it is necessary to develop an efficient and rapid method to prepare this type of 2,3-dihydroquinazolinone compounds. Summary of the invention

[0011] In view of the deficiencies of the prior art, the object of the present invention is to provide a method for preparing a class of 2,3-dihydroquinazolinone compounds, and at the same time provide the compounds prepared by the method and the use of the compounds in pharmaceutical preparations.

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

[0013] A novel method for preparing 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 thereof is shown in Formula I:

[0015]

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

[0017]

[0018] in,

[0019] R1, R2, and R3 are independently H, halogen atoms, C1-C10 aliphatic hydrocarbons and their substituents, C6-C20 aromatic hydrocarbons and their substituents;

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

[0021] The catalyst includes an organic metal compound such as cuprous chloride CuCl, palladium acetate Pd(OAc)2, iron acetylacetonate Fe(acac)3, cobalt acetylacetonate Co(acac)2, etc., 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, butanone, hexanone, dichloromethane, or a mixture thereof;

[0023] The oxygen condition means that the reaction should not be carried out in the absence of air or oxygen;

[0024] The reaction temperature is related to the reaction time and is -25°C to 120°C;

[0025] The reaction time is related to the above reaction conditions and is 0.1 to 24 hours;

[0026] The reducing agent is a common silane reducing agent, including tetramethyldisiloxane (TMDS), triethylsilane TES, tert-butyldiphenylsilane, diphenylsilane Ph2SiH2, phenylsilane PhSiH3, or a mixture thereof.

[0027] Furthermore, the synthesis method of 2,3-dihydroquinazolinone compounds provided by the present invention is as shown in Formula I and Formula II, wherein:

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

[0029] The certain reaction conditions include catalyst, solvent, oxygen, reaction temperature, reaction time, and reducing agent;

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

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

[0032] The oxygen condition means that the reaction should not be carried out in the absence of air or oxygen;

[0033] The reaction temperature is related to the reaction time and is 0°C to 80°C;

[0034] The reaction time is related to the above reaction conditions and is 0.1 to 12 hours;

[0035] The reducing agent is diphenylsilane Ph2SiH2, phenylsilane PhSiH3, or a mixture thereof.

[0036] Furthermore, the present invention provides a method for synthesizing 2,3-dihydroquinazolinone compounds, as shown in Formula I and Formula II, wherein:

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

[0038] Furthermore, the synthesis method of 2,3-dihydroquinazolinone compounds provided by the present invention is as shown in Formula I and Formula II, wherein the solvent is methanol or ethanol.

[0039] Furthermore, the present invention provides a method for synthesizing 2,3-dihydroquinazolinone compounds, as shown in Formula I and Formula II, wherein the reaction temperature is 15°C to 80°C.

[0040] Furthermore, the present invention provides a method for synthesizing 2,3-dihydroquinazolinone compounds, as shown in Formula I and Formula II, wherein the reaction time is 0.1 to 4 hours.

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

[0042]

[0043]

[0044] The 2,3-dihydroquinazolinone compounds prepared by the synthesis method provided by the present invention can be used alone, or can be prepared into pharmaceutically acceptable salts by conventional methods. The pharmaceutically acceptable salts include hydrochloride, hydrobromide, hydroiodide, sulfate, bisulfate, phosphate, acetate, propionate, butyrate, oxalate, tartrate, methanesulfonate, p-toluenesulfonate, fumarate, taurate, citrate, succinate, or mixed salts thereof, etc.

[0045] The 2,3-dihydroquinazolinone compounds prepared by the present invention and their pharmaceutically acceptable salts have good activity in inhibiting the proliferation of tumor cells, and thus can be used in the preparation of drugs for treating, preventing and alleviating cancer, wherein the cancer is liver cancer, brain tumor, lung cancer or kidney cancer, or other cancers.

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

[0047] The present invention provides a method for synthesizing 2,3-dihydroquinazolinone compounds, which has cheap and readily available raw materials, mild reaction conditions, no need to avoid water and air, fast speed, simple operation, high regional selectivity, high yield, and is conducive to industrial production. At the same time, the 2,3-dihydroquinazolinone compounds prepared by the method described in the present invention have good proliferation inhibition activity on tumor cells, and thus can be used in the preparation of drugs for treating, preventing and alleviating cancer, or as lead compounds for designing candidate molecules with higher activity. BRIEF DESCRIPTION OF THE DRAWINGS

[0048] Figure 1It is a schematic diagram of the structures of 3-(but-3-en-1-yl)quinazolin-4(3H)-one substituted by formula 1, 2,3-dihydroquinazolinone compounds with different substituents by formula 2, N-cyano-N-[(1-vinyl-2-yl)phenyl]benzamide substituted by formula 3 and 2,3-dihydroquinazolinone compounds with different substituents by formula 4. DETAILED DESCRIPTION

[0049] The present invention is further described below by way of examples, but the present invention is not limited to the scope of the examples. The experimental methods in the following examples without specifying specific conditions are carried out according to conventional methods and conditions, or selected according to the product specifications.

[0050] Example 1. Preparation of Compound 2a

[0051]

[0052] The reaction was carried out in a reaction bottle equipped with a magnetic stirring bar. The starting materials 3-(3-methylbut-3-en-1-yl)quinazolin-4(3H)-one (1a, 214 mg, 1.0 mmol, 1.0 eq), phenylsilane (PhSiH3, 1.05 mmol, 1.05 eq) and Fe(acac) (10 mol%) were mixed and dissolved in methanol (MeOH, 10.0 ml), and the mixture was stirred at 50°C for 30 minutes. At the same time, this reaction should be carried out in the 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 the developing solvent to obtain the desired product 2a (179 mg, 79%). White solid, mp: 175.9-176.1°C). 1 H NMR(400MHz,Chloroform-d)δ7.87(dd,J=7.8,1.6Hz,1H),7.29-7.21(m,1H),6.83(td,J=7.6,1.1Hz,1H),6.71 (dd,J=8.1,1.0Hz,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=30.0Hz,6H). 13C NMR(101MHz,Chloroform-d)δ162.57,147.59,132.98,128.05,119.33,117.38,114.82,42.03,41.40,36.19,24.63,20.63.HRMS(ESI):calcd.for C 13 H 17 ON2[M+H] + 217.1342, found: 217.1347.

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

[0054] Using the reaction conditions of Example 1 and different substituent groups of 1, multiple 2,3-dihydroquinazolinone compounds 2 were obtained. The reaction equation and the structure and yield of the product are as follows:

[0055]

[0056]

[0057] The structure of the prepared compound was confirmed 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%,mp:196.6-197.3℃). 1 H NMR(400MHz,Chloroform-d)δ7.09(t,J=7.7Hz,1H),6.64(d,J=7.5Hz,1H),6.55(d,J=8.0Hz, 1H), 4.59 (s, 1H), 4.10 (s, 1H), 3.73-3.57 (m, 2H), 1.83-1.66 (m, 2H), 1.12 (d, J = 28.7Hz, 6H). 13 C NMR(101MHz,Chloroform-d)δ163.09,148.80,141.69,131.82,123.33,116.08,113.12,42.57,41.61,36.42,24.99,21.96,20.84.HRMS(ESI):calcd.for C 14 H 19 N2O[M+H] +231.1498,find:231.1493.

[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℃). 1 H NMR(400MHz,Chloroform-d)δ7.76(d,J=7.9Hz,1H),6.66(d,J=7.0Hz,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)δ147.50,143.78,128.09,120.70,115.18,41.97,41.36,36.22,25.88,24.64,21.64,20.62.HRMS(ESI):calcd.for C 14 H 19 ON2[M+H] + 231.1498,find: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℃). 1 H NMR(400 MHz,Chloroform-d)δ7.84-7.71(m,1H),7.15(d,J=7.3 Hz,1H),6.78(t,J=7.5 Hz,1H),4.67(s,1H),3.73-3.60(m,2H),2.17(s,3H),1.87-1.71(m,2H),1.16(d,J=28.9 Hz,6H). 13C NMR(101 MHz,Chloroform-d)δ145.45,134.03,126.07,125.47,123.92,122.19,119.02,117.22,41.95,41.40,36.25,35.45,26.07,24.75,20.63,16.62.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℃). 1 H NMR(400 MHz,Chloroform-d)δ7.79(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)δ167.24,164.74,161.83,149.38,149.27,130.63,130.52,113.70,106.87,106.65,101.39,101.13,41.98,41.44,36.16,24.57,20.57,1.02.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℃). 1 H NMR(400 MHz,Chloroform-d)δ7.58(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)δ161.54,158.09,155.72,143.51,143.49,120.16,119.93,119.16,119.09,116.44,116.37,114.17,113.93,42.05,41.34,36.31,24.70,20.62.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(2g).White solid(yield:64%,m.p.:202.1-203.0℃). 1 H NMR(400 MHz,Chloroform-d)δ7.16(td,J=8.2,5.5 Hz,1H),6.54-6.45(m,2H),4.65(s,1H),4.56(s,1H),3.72-3.57(m,2H),1.84-1.68(m,2H),1.12(d,J=34.0 Hz,6H). 13C NMR(101 MHz,Chloroform-d)δ164.14,161.56,159.71,150.03,149.99,133.54,133.43,110.63,110.60,107.32,107.11,106.54,106.45,42.37,41.53,36.29,24.78,20.71.HRMS(ESI):calcd.forC 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℃). 1 H NMR(400 MHz,Chloroform-d)δ7.11(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)δ149.92,132.32,123.02,113.84,42.92,41.67,36.46,25.04,20.90.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(2i).White solid(yield:69%,m.p:203.2-204.1℃). 1H NMR(400 MHz,DMSO-d6)δ7.28(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)δ160.66,148.09,132.93,132.04,129.12,126.55,121.43,117.63,116.87,76.93,42.09,41.37,35.81,30.26,28.83,24.40,23.71,22.86,20.79,14.35,11.26.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℃). 1 H NMR(400 MHz,Chloroform-d)δ7.79(d,J=8.2 Hz,1H),6.80(dd,J=8.3,2.0 Hz,1H),6.70(d,J=1.9Hz,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 C NMR(101MHz,Chloroform-d)δ161.76,148.29,138.84,129.51,119.70,115.82,114.51,42.05,41.45,36.11,24.56,20.56.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℃). 1 H NMR(400 MHz,Chloroform-d)δ7.99(d,J=2.3 Hz,1H),7.34(dd,J=8.5,2.4 Hz,1H),6.58(d,J=8.5Hz,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)δ161.19,146.23,135.57,130.72,119.14,116.52,111.61,42.12,41.42,36.14,24.62,20.61.HRMS(ESI):calcd.forC 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℃).The product was achievedby column chromatograph(Pe:EtOAc=6:1). 1H NMR(400 MHz,DMSO-d6)δ7.49(d,J=8.3Hz,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(101MHz,DMSO-d6)δ161.10,150.42,129.48,126.67,120.52,117.04,115.46,76.85,42.05,41.40,35.71,24.36,20.72.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]quinazoli n-9-one(2m).White solid(yield:68%,m.p.:206.2-207.1℃). 1 H NMR(400MHz,Chloroform-d)δ8.05(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)δ161.30,149.93,129.76,129.73,125.76,125.72,122.96,121.32,120.99,116.45,114.67,42.15,41.47,35.93,24.42,20.48.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℃). 1 H NMR(400MHz,Chloroform-d)δ6.35-6.07(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)δ166.70,166.54,165.15,165.00,164.20,164.04,162.56,162.40,159.20,159.17,151.31,151.25,151.17,151.11,97.62,97.58,97.37,97.34,96.10,95.84,95.58,42.33,41.54,36.22,24.64,20.60.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℃). 1 H NMR(400MHz,Chloroform-d)δ7.68(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(101MHz,Chloroform-d)δ160.96,144.43,144.33,116.66,116.49,103.69,103.48,42.08,41.43,36.22,24.60,20.59.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℃). 1 H NMR(400 MHz,Chloroform-d)δ7.80(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)δ162.61,147.76,132.92,128.11,128.09,119.75,119.41,114.94,75.62,71.99,43.32,42.59,40.92,36.47,29.91,29.41,15.54,13.35.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℃). 1 H NMR(400 MHz,Chloroform-d)δ7.10(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=2.3Hz,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(101MHz,Chloroform-d)δ163.06,148.87,148.50,141.70,141.66,131.75,123.72,123.43,116.61,113.21,113.14,75.12,71.17,43.79,43.51,41.20,36.90,30.12,30.00,21.73,15.82,13.25.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℃). 1H NMR(400 MHz,Chloroform-d)δ7.14(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=18.6,6.9Hz,3H). 13 C NMR(101 MHz,Chloroform-d)δ148.99,148.62,148.02,147.99,131.95,131.93,122.27,121.98,113.24,113.17,75.02,71.07,43.94,43.67,41.21,36.92,30.16,30.05,27.30,16.01,15.99,15.84,13.22.HRMS(ESI):calcd.for C 14 H 19 ON2[M+H] + 231.1419find: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℃). 1 H NMR(400 MHz,Chloroform-d)δ7.76(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)δ147.50,143.76,128.09,120.70,115.18,115.01,41.95,41.36,36.22,24.64,21.63,20.62.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℃). 1 H NMR(400 MHz,Chloroform-d)δ7.22-7.06(m,1H),6.63-6.29(m,2H),5.03-4.82(m,1H),4.75-4.49(m,1H),3.89-3.48(m,2H),2.36-1.89(m,2H),1.80-1.51(m,1H),1.15(dd,J=26.6,6.9 Hz,3H). 13 C NMR(101MHz,Chloroform-d)δ164.11,161.54,159.75,150.27,150.23,148.51,133.53,133.49,133.42,133.38,110.77,110.74,110.70,110.67,107.61,107.39,107.29,107.07,106.82,71.52,43.64,43.08,42.38,41.23,40.92,36.57,30.03,30.00,29.65,15.66,13.26.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℃). 1 H NMR(400 MHz,DMSO-d6)δ7.49(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=51.1,6.8Hz,3H). 13 C NMR(101 MHz,DMSO-d6)δ207.13,160.32,160.30,159.87,154.23,154.18,154.09,154.04,146.96,146.86,146.54,146.45,116.68,103.81,75.45,72.19,43.42,42.34,36.06,29.72,28.99,15.47,13.76.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℃). 1H NMR(400 MHz,Chloroform-d)δ8.27(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)δ161.29,146.91,139.39,138.48,133.55,128.67,128.26,124.34,122.09,120.19,117.74,116.16,115.56,79.73,44.04,24.85,23.96.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℃). 1 H NMR(400 MHz,Chloroform-d)δ8.23(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)δ161.11,161.03,158.69,146.76,140.65,140.58,135.45,135.43,133.63,128.57,120.28,117.48,117.17,117.09,115.57,114.70,114.47,109.76,109.52,79.87,44.23,44.22,24.61,23.72.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℃). 1 H NMR(400 MHz,Chloroform-d)δ8.15(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=2.0Hz,1H),5.18(d,J=1.5Hz,1H),4.53(s,1H),1.50(s,3H),1.29(s,3H). 13 C NMR(101MHz,Chloroform-d)δ161.21,146.78,140.69,138.46,133.77,131.19,128.69,125.48,120.42,117.57,117.50,116.71,115.62,79.76,77.36,77.04,76.73,44.23,24.73,23.86.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-on e(2y).White solid (yield: 80%, mp: 159.3-160.4℃). 1 H NMR(400MHz,Chloroform-d)δ8.36(d,J=8.1Hz,1H),8.03(d,J=7.8Hz,1H),7.37(t,J=7.7Hz,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=8.1Hz,1H),5.36(d,J=4.4Hz,1H),3.53(s,1H),1.96(s,3H). 13 C NMR(101MHz,Chloroform-d)δ161.15,145.78,140.66,137.59,133.44,129.72,129.64,128.96,128.62 ,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, found:345.1397.

[0106] Example 3. Synthesis of Differently Substituted 2,3-Dihydroquinazolinones (4a-4x)

[0107] Using the reaction conditions of Example 1, the substituted N-cyano-N-[(1-vinyl-2-yl)phenyl]benzamide (3) undergoes a chemical reaction under certain conditions to obtain 2,3-dihydroquinazolinone compounds (4) with different substituents. The structure and structure of the product are as follows:

[0108]

[0109] 6,6-dimethyl-6,12-dihydroindolo[2,1-b]quinazolin-12-one(4a).Whitesolid(yield:81%,mp:144.2-144.8℃). 1H NMR(400MHz,Chloroform-d)δ8.63-8.58(m,1H),8.44-8.39(m,1H),7.83-7.73(m,2H),7.51(ddd,J=8.1,6.2,2.0Hz,1H),7.45-7.40(m,2H),7.37-7.32(m,1H),1.64(s,6H). 13 C NMR(101MHz,Chloroform-d)δ164.77,160.28,147.60,138.41,137.94,134.43,128.51,127.32,126.94,126.81,126.72,122.49,121.50,117.35,45.28,26.78.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℃). 1 H NMR(400 MHz,Chloroform-d)δ9.17(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)δ164.84,160.49,146.45,138.65,138.29,136.33,130.09,129.24,128.52,127.89,126.87,126.81,125.46,122.56,121.97,117.76,117.57,45.62,26.84.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℃). 1 H NMR(400 MHz,Chloroform-d)δ8.67-8.45(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(101MHz,Chloroform-d)δ167.81,166.15,165.28,159.55,150.04,149.91,138.26,137.78,129.57,129.46,128.54,126.80,122.50,118.24,118.22,117.31,115.48,115.25,113.00,112.78,45.38,26.69.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℃). 1 H NMR(400 MHz,Chloroform-d)δ8.59-8.54(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) δ166.15,159.61,148.58,140.60,138.20,137.82,128.59,128.32 ,127.36,127.00,126.92,122.53,119.97,117.35,45.46,26.69.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%, mp: 167.5-168.6°C). 1 H NMR(400 MHz,Chloroform-d)δ8.53-8.46(m,1H),8.17(d,J8.5Hz,1H),7.89(d,J1.9). Hz,1H),7.53(dd,J8.5,1.9Hz,1H),7.39-7.32(m,2H),7.32-7.26(m,1H),1.55(s,6H). 13 C NMR(101). MHz,Chloroform-d)δ165.95,159.65,148.71,138.15,137.78,130.18,129.95,128.93 ,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(4f).White solid (yield: 68%, mp: 112.0-112.4°C). 1H NMR(400 MHz,Chloroform-d)δ8.66-8.47(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)δ165.30,159.71,145.53,138.16,138.07,128.52,127.11,126.96,126.48,123.10,122.78,122.59,117.33,45.65,29.80,26.92.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℃). 1 H NMR(400 MHz,DMSO-d6)δ8.43(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(101MHz,DMSO-d6)δ164.91,162.32,159.91,159.58,147.63,140.97,140.89,134.99,134.75,134.73,127.57,127.22,126.69,121.40,118.16,118.07,115.22,114.99,111.51,111.26,45.60,45.58,26.44.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℃). 1 H NMR(400 MHz,Chloroform-d)δ8.53(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(101MHz,Chloroform-d)δ164.42,160.14,146.27,140.50,140.42,136.25,129.96,129.22,127.82,126.94,126.85,125.35,121.77,118.85,118.77,117.62,115.16,114.93,110.33,110.08,45.75,45.73,26.64.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℃). 1 H NMR(400 MHz,Chloroform-d)δ8.53(ddd,J=8.3,4.7,1.1 Hz,1H),8.38(dd,J=8.9,6.1 Hz,1H),7.41(dd,J=9.7,2.5Hz,1H),7.24-7.17(m,1H),7.18-7.01(m,2H),1.63(s,6H). 13 C NMR(101 MHz,Chloroform-d)δ167.73,165.70,165.21,162.65,160.20,159.21,149.86,149.73,140.01,139.93,134.14,134.11,129.42,129.31,118.60,118.51,118.05,118.03,115.53,115.30,115.18,114.95,112.97,112.75,110.27,110.02,45.50,45.48,26.48.HRMS(ESI):calcd.forC 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℃). 1 H NMR(400 MHz,DMSO-d6)δ7.52(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=9.2,2.7Hz,1H),0.73(s,6H). 13C NMR(101MHz,DMSO-d6)δ166.39,162.38,159.96,159.09,148.75,140.89,140.80,134.57,134.55,130.15,129.82,128.62,128.48,120.59,118.17,118.09,115.27,115.04,111.54,111.30,45.80,45.78,26.31.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℃). 1 H NMR(400 MHz,DMSO-d6)δ9.15(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)δ163.32,160.17,147.60,138.91,137.61,136.91,134.35,128.92,128.57,128.49,127.66,126.94,126.89,126.80,124.09,121.35,117.46,115.61,115.40,52.26,29.72,25.87.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℃). 1 H NMR(400 MHz,Chloroform-d)δ9.05(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)δ129.22,129.02,128.66,128.58,127.77,127.08,126.99,126.84,125.38,124.33,121.78,117.73,115.55,115.34,52.56,26.38.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℃). 1 H NMR(400 MHz,Chloroform-d)δ8.68(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)δ163.08,160.11,147.59,140.42,138.98,136.65,134.34,133.57,128.99,128.80,128.24,127.67,126.96,126.90,126.81,124.08,121.38,117.48,52.35,25.67.HRMS(ESI):calcd.for C 22 H 16 OClN2[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℃). 1 H NMR(400 MHz,Chloroform-d)δ9.06-8.99(m,1H),8.76(d,J=8.1 Hz,1H),8.32(d,J=8.7Hz,1H),7.92-7.81(m,2H),7.72-7.61(m,2H),7.53(ddd,J=8.3,6.4,2.5 Hz,1H),7.46-7.35(m,4H),7.34-7.25(m,2H),2.11(s,3H). 13 C NMR(101 MHz,Chloroform-d)δ163.12,160.21,146.25,140.39,139.28,136.55,136.26,133.61,129.95,129.23,129.09,128.77,128.33,127.77,127.12,127.01,126.86,125.37,124.30,121.78,117.76,117.66,52.66,26.16.HRMS(ESI):calcd.for C 26 H 18 OClN2[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℃). 1 H NMR(400 MHz,Chloroform-d)δ8.69(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)δ164.26,163.38,163.27,160.92,160.63,157.35,157.31,149.75,138.78,137.34,137.31,136.63,134.66,134.56,129.04,128.58,128.50,127.01,124.06,123.62,123.58,117.64,115.63,115.42,113.76,113.55,111.07,111.01,52.30,29.70,25.81.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℃). 1H NMR(400 MHz,DMSO-d6)δ8.52(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)δ165.65,159.12,149.88,149.75,138.73,138.56,138.53,137.68,129.86,129.75,129.32,129.24,129.09,127.39,124.65,118.66,116.99,115.96,115.87,115.73,115.66,113.15,112.93,52.77,25.19.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℃). 1 H NMR(400MHz,Chloroform-d)δ8.68(dd,J=8.1,1.0Hz,1H),7.64(dd,J=8.2,5.4Hz,1H),7.55-7.46(m,2H),7.36(td,J=7.5,1.1Hz,1H),7.32-7.26(m,5H),7.14(ddd,J=10.8,8.1,1.2Hz,1H),2.02(s,3H). 13CNMR(101MHz,Chloroform-d)δ164.04,163.25,160.61,157.34,157.30,149.68,140.05,138.79,136.39,134.74,134.64,133.68,129.13,128.84,128.24,127.08,124.05,123.62,123.58,117.66,113.84,113.63,111.05,110.99,52.40,25.57.HRMS(ESI):calcd.forC 22 H 15 OClFN2[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℃). 1 H NMR(400MHz,Chloroform-d)δ8.80-8.50(m,1H),8.41(dd,J=8.9,6.1Hz,1H),7.50(td,J=7.8,1.4Hz,1H),7.42-7.34(m,2H),7.30(dd,J=7.9,1.4Hz,1H),7.28-7.25(m,4H),7.25-7.19(m,1H),2.03(s,3H). 13 C NMR(101MHz,Chloroform-d)δ164.52,159.39,140.05,138.83,136.46,133.71,129.47,129.36,129.07,128.85,128.22,127.05,124.12,118.06,118.04,117.46,115.72,115.49,113.28,113.06,52.47,25.61.HRMS(ESI):calcd.for C 22 H 15 OClFN2[M+H] + 377.0858,find:377.0833.

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

[0145] Compound 2a (100 mg) was dissolved in 5 mL of ethyl acetate. HCl gas was introduced at room temperature until the mixture was supersaturated. The temperature was lowered to about 0 degrees, and crystals were slowly precipitated, which was the hydrochloride of compound 2a.

[0146] Example 5. Tumor cell proliferation inhibition activity—MTT method

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

[0148] Experimental method: Take tumor cell lines in logarithmic growth phase (HepG2 liver cancer, U-87MG brain astrocytoblastoma, H1299 human lung cancer cells, 786-O human renal clear cell carcinoma cells), inoculate 4000 cells / well in 96-well culture medium, set up control group (DMSO) and compound treatment group. The highest compound concentration is 50μg / mL, 5-fold gradient dilution, a total of 5 concentrations, and three replicates for each concentration. After the compound acted on the cells for 72 hours, the culture medium was discarded, 100 μl of pre-cooled 10% trichloroacetic acid (TCA) solution was added to each well to fix the cells, and the cells were placed in a refrigerator at 4°C for 1 hour. The culture medium wells were washed five times with deionized water to remove the trichloroacetic acid solution. After drying in the air, 50 μl of SRB solution (4 mg / mL) prepared with 1% acetic acid was added to each well and placed at room temperature for 20 minutes. After the liquid in each well was discarded, it was washed five times with 1% acetic acid. After washing away the unbound SRB dye, it was air-dried. 100 μl of 10 mM Tris-base (trishydroxymethylaminomethane) solution with a pH of 10.5 was added to each well to dissolve it, and the plate was shaken for 5 minutes. The absorbance OD value was measured at a wavelength of 515 nm by an enzyme reader.

[0149] IC of the compound was determined 50 The values ​​are shown in the following table:

[0150] Table 1. Compound IC 50 value

[0151]

[0152]

[0153]

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

[0155] It can be seen that for different cell lines (HepG2 liver cancer, U-87MG brain astrocytoblastoma, H1299 human lung cancer cells, 786-O human renal clear cell carcinoma cells), the compounds provided by the present invention have good proliferation inhibitory activity on tumor cells, and therefore, can be used in the preparation of drugs for treating, preventing and alleviating cancer.

Claims

1. A method for preparing a 2,3-dihydroquinazolinone compound, characterized in that: The following steps are involved: The substituted 3-(but-3-en-1-yl)quinazolin-4(3H)-one of formula 1 undergoes a chemical reaction under reaction conditions to obtain a 2,3-dihydroquinazolinone compound having a different substituent of formula 2; Alternatively, the substituted N-cyano-N-[(1-vinyl-2-yl)phenyl]benzamide of formula 3 undergoes a chemical reaction under reaction conditions to obtain a substituted 2,3-dihydroquinazolinone compound having different substituents of formula 4; in, R1, R2, and R3 are independently H, halogen atoms, C1-C10 aliphatic hydrocarbons and their substituents, C6-C20 aromatic hydrocarbons and their substituents; The reaction conditions include catalyst, solvent, oxygen, reaction temperature, reaction time, and reducing agent; The catalyst is one of cuprous chloride, palladium acetate, ferric acetylacetonate, cobalt acetylacetonate, or a mixture thereof; The solvent is one of water, ethanol, methanol, propanol, acetonitrile, N,N-dimethylformamide, tetrahydrofuran, acetone, butanone, hexanone, dichloromethane, or a mixture thereof; The reaction temperature is -25°C to 120°C; 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 according to claim 1, characterized in that: R1, R2, and R3 are independently H, a 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 according to claim 2, characterized in that: R1, R2, and R3 are independently H, a halogen atom, a methyl group, an ethyl group, a propyl group, an isopropyl group, a cyclopropyl group, or a phenyl group.

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

5. The method for preparing 2,3-dihydroquinazolinone compounds according to claim 4, characterized in that: The solvent is methanol or ethanol; The reaction temperature is 15°C to 80°C; The reaction time is 0.1 to 4 hours.

6. The method for preparing 2,3-dihydroquinazolinone compounds according to claim 1, characterized in that: The 2,3-dihydroquinazolinone compound is a compound with the following structure:

7. The 2,3-dihydroquinazolinone compound or a pharmaceutically acceptable salt thereof prepared by the preparation method according to any one of claims 1 to 6, characterized in that: The pharmaceutically acceptable salt is hydrochloride, hydrobromide, hydroiodide, sulfate, bisulfate, phosphate, acetate, propionate, butyrate, oxalate, tartrate, methanesulfonate, p-toluenesulfonate, fumarate, taurate, citrate, succinate or a mixed salt thereof.

8. Use of the 2,3-dihydroquinazolinone compound or a pharmaceutically acceptable salt thereof as claimed in claim 7 in the preparation of a drug for treating, preventing and alleviating cancer.

9. The use according to claim 8, characterized in that: The cancer is liver cancer, brain tumor, lung cancer or kidney cancer.

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