CN117736213A - Dihydropyrroloquinazoline spiro indolone compound, application, pharmaceutical composition and synthetic method - Google Patents

Dihydropyrroloquinazoline spiro indolone compound, application, pharmaceutical composition and synthetic method Download PDF

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CN117736213A
CN117736213A CN202311763847.0A CN202311763847A CN117736213A CN 117736213 A CN117736213 A CN 117736213A CN 202311763847 A CN202311763847 A CN 202311763847A CN 117736213 A CN117736213 A CN 117736213A
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范学森
刘康莉
闫胜楠
张新迎
王悦
何兴
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Henan Normal University
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Henan Normal University
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Abstract

The invention belongs to the technical field of chemical medicaments and synthesis, and particularly relates to a dihydropyrroloquinazoline spiro indolone compound, application, a pharmaceutical composition and a synthesis method. The compound provided by the invention has the activity of inhibiting the proliferation of two cancer cells, namely Hela and A-549, and the compound can be used as an active ingredient of anticancer drugs such as cervical cancer, lung cancer and the like. Especially, part of the compounds can obviously inhibit the growth and proliferation of A-549, which suggests that the compounds have potential medicinal value and provide a new structural unit for drug screening; meanwhile, the synthesis method of the invention takes 1- (aryl) azomethine substituted indoline compounds and 3-diazonium-2-indolone compounds as raw materials to synthesize by a one-pot method. The synthesis method has the advantages of simple and easily obtained raw materials, simple and convenient operation, mild conditions, wide substrate application range, high atom economy and the like.

Description

Dihydropyrroloquinazoline spiro indolone compound, application, pharmaceutical composition and synthetic method
Technical Field
The invention belongs to the technical field of chemical medicaments and synthesis, and particularly relates to a dihydropyrroloquinazoline spiro indolone compound, application, a pharmaceutical composition and a synthesis method.
Background
Indoles (including indoles, indolines, indolones, isoindolones, and the like) are widely found in natural products, pharmaceuticals, pesticides, dyes, and pigments. Among the various indole derivatives, spiroindolones are not only common in nature, but also have various important biological activities such as antiviral, anticancer, anti-inflammatory and bactericidal activities, and are one of the advantageous structures of drug design.
The spiro indolone derivative combines indolone and heterocycle, which is one of the effective ways to find anticancer active molecules. In recent years, the anticancer activity of spiroindolones has attracted attention, and many compounds such as Spirotryprostatins A and B, MI-888, isopterodine have shown excellent anticancer activity. In view of the pharmaceutically active effects of spirocyclic indolone derivatives, new chemical structure expansion new drug screening molecular libraries are continually designed based on spirocyclic indolones.
On the other hand, in view of the importance of spiroindolones, various reliable and efficient processes for preparing such compounds have been developed successively, but the existing processes often require the use of highly functionalized substrates and severe reaction conditions, which are not only tedious and cumbersome to handle, but also generate a large amount of by-products and waste.
Therefore, the novel spiro indolone compound has an innovative molecular structure, provides a novel compound with anticancer activity, researches a synthesis method with simple and easily available raw materials and mild reaction conditions, realizes high-efficiency and low-cost synthesis of the novel compound, and has important theoretical significance and application value for promoting development of innovative medicaments.
Disclosure of Invention
In order to solve the problems in the prior art, one of the purposes of the invention is to provide a dihydropyrrolo quinazoline spiro indolone compound which has anticancer activity.
The second object of the invention is to provide the application of the dihydropyrrolo quinazoline spiro indolone compound in preparing anticancer drugs.
The invention further aims to provide a pharmaceutical composition for treating lung cancer, and the active ingredient of the pharmaceutical composition is the dihydropyrrolo quinazoline spiro indolone compound.
The fourth object of the invention is to provide a method for synthesizing the dihydropyrrolo quinazoline spiro indolone compounds.
In order to achieve the above purpose, the technical scheme adopted by the invention is as follows:
the chemical structural general formula of the dihydropyrrolo quinazoline spiro indolone compound is as follows:
wherein R is 1 Is hydrogen, C 1-4 Alkyl, C 1-4 Alkoxy or halogen, R 1 Is a mono-or poly-substituted; r is R 2 Is phenyl, substituted phenyl, thienyl or naphthyl, and the substituent on the benzene ring of the substituted phenyl is C 1-4 Alkyl, C 1-4 Alkoxy, halogen or methylenedioxy; r is R 3 Is hydrogen, C 1-4 Alkyl, C 1-4 Alkoxy or halogen, R 3 Is a mono-or poly-substituted; r is R 4 Is hydrogen, C 1-4 Alkyl, substituted C 1-4 Alkyl, phenyl or substituted phenyl, substituted C 1-4 The substituent of the alkyl is phenyl, and the substituent on the benzene ring of the substituted phenyl is C 1-4 Alkyl or C 1-4 An alkoxy group.
Optionally, the R 1 Is halogen; r is R 2 Is phenyl or substituted phenyl, and the substituent on the benzene ring of the substituted phenyl is halogen or methylenedioxy; r is R 3 Is hydrogen; r is R 4 Is methyl.
Preferably, the chemical structural formula of the compound is
The application of the compound in preparing anticancer drugs, wherein the compound is used as an active ingredient of the drugs.
The design experiment of the invention verifies that the compound provided by the invention has the activity of inhibiting the proliferation of two cancer cells, namely Hela and A-549, and the compound can be used as an active ingredient of anticancer drugs such as cervical cancer, lung cancer and the like. Especially, part of the compounds can obviously inhibit the growth and proliferation of A-549, and the compounds are suggested to be used as active ingredients of anticancer drugs to have the effects of preventing, treating and inhibiting the progress deterioration of lung cancer.
The synthesis method of the compound comprises the steps of taking 1- (aryl) azomethine substituted indoline compounds and 3-diazonium-2-indolone compounds as raw materials.
Optionally, the synthesis method specifically comprises mixing 1- (aryl) azoquinazolinone compound 1, 3-diazonium-2-indolinone compound 2, a catalyst, an additive and a solvent, and heating to react to obtain the dihydropyrroloquinazoline spiro indolinone compound 3, wherein the reaction equation is as follows:
optionally, the additive is selected from acetic acid, pivalic acid, 1-adamantanecarboxylic acid, benzoic acid, potassium acetate, sodium acetate, silver fluoride, silver hexafluoroantimonate, silver acetate, or a mixture of two or more;
alternatively, the solvent is selected from 1, 2-dichloroethane, dichloromethane, acetonitrile, toluene, tetrahydrofuran or methanol;
alternatively, the catalyst is dichloro bis (4-cymene) ruthenium (II), dichloro (pentamethyl cyclopentadienyl) rhodium (III) dimer or dichloro (pentamethyl cyclopentadienyl) iridium (III) dimer.
Preferably, the additive is acetic acid; the solvent is dichloroethane; the catalyst is dichloro bis (4-cymene) ruthenium (II);
optionally, the feeding mole ratio of the 1- (aryl) azomethine substituted indoline compound 1 to the 3-diazonium-2-indolinone compound 2 to the catalyst to the additive is 1:1-2:0.015-0.04:1-3;
preferably, the 1- (aryl) azomethine substituted indoline compound 1, 3-diazonium-2-indolinone compound 2, the catalyst and the additive are added in a molar ratio of 1:1.5:0.025:2;
optionally, the reaction temperature is 60-100 ℃; the reaction time is 3-5 h; the reaction is carried out in an air or inert gas atmosphere;
preferably, the reaction temperature is 80 ℃; the reaction time is 4h; the reaction is carried out in an air atmosphere.
Compared with the prior art, the invention has the following advantages:
(1) The dihydro-pyrrolo-quinazoline spiro indolone compound provided by the invention has activity of inhibiting proliferation of two cancer cells, namely Hela and A-549, through screening compounds with various substituents and through anticancer cell activity test verification, the compound provided by the invention has anticancer activity on cervical cancer and lung cancer, especially has obvious in vitro antiproliferation effect on human non-small cell lung cancer cells A-549, has potential medicinal value, and provides a new structural unit for drug screening;
(2) According to the synthesis method provided by the invention, 1- (aryl) azomethine substituted indoline compounds and 3-diazonium-2-indolone are used as starting materials, and a dihydropyrrole condensed quinazoline structure and a spiro skeleton of indoline can be simultaneously constructed through one-pot tandem reaction, so that the dihydropyrrole quinazoline spiroindolone compounds are synthesized, the synthesis process is simple and efficient, and the economy of reaction atoms is high;
(3) The synthetic method provided by the invention has wide substrate application range and good functional group tolerance; the raw materials are cheap and easy to obtain, the reaction conditions are mild, and the operation is simple.
Drawings
In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings that are required to be used in the embodiments or the description of the prior art will be briefly described below, and it is obvious that the drawings in the following description are only embodiments of the present invention, and that other drawings can be obtained according to the provided drawings without inventive effort for a person skilled in the art.
FIG. 1 is an X-ray single crystal diffraction pattern of compound 3aa of example 1.
Detailed Description
The above-described matters of the present invention will be described in further detail by way of examples, but it should not be construed that the scope of the above-described subject matter of the present invention is limited to the following examples, and all techniques realized based on the above-described matters of the present invention are within the scope of the present invention.
Example 1
To a 15mL reaction tube, the compounds 1a, 2a, the catalyst, the additive and the solvent were added in this order, the reaction tube was sealed, and the mixture was placed in an oil bath to be heated and stirred for reaction. After the reaction was completed, cooled to room temperature, quenched by adding saturated sodium bicarbonate solution, extracted three times with ethyl acetate, combined with the organic phase, dried over anhydrous sodium sulfate, filtered, concentrated, and separated by silica gel column (petroleum ether/ethyl acetate=1/1) to give a yellow solid product 3aa.
By changing the reaction conditions of the catalyst, additives, solvent, gas atmosphere, etc., a series of results were obtained as shown in table 1.
TABLE 1 Synthesis of 3aa under different conditions a
The optimum synthesis process conditions were determined based on the data screening shown in table 2 above.
Example 2
1a (44.5 mg,0.2 mmol), 2a (52.0 mg,0.3 mmol) and [ Ru (p-cymene) Cl were successively introduced into a 15mL pressure-resistant tube 2 ] 2 (3.06 mg,0.005 mmol), acetic acid (23. Mu.L, 0.4 mmol) and 1, 2-dichloroethane (2 mL), then the reaction tube was sealed and placed in an oil bath at 80℃for reaction for 4h. After the reaction was completed, the reaction system was cooled to room temperature, quenched with saturated sodium bicarbonate solution, extracted three times with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and separated by a silica gel column (petroleum ether/ethyl acetate=1/1) to give 3aa (60.2 mg, 82%) as a yellow solid. Characterization data for this compound were: 1 H NMR(400MHz,CDCl 3 ):δ7.62-7.59(m,2H),7.39-7.37(m,3H),7.32-7.25(m,2H),7.09-7.04(m,2H),6.88-6.84(m,2H),6.39(d,J＝7.6Hz,1H),4.04(td,J 1 ＝10.0Hz,J 2 ＝6.4Hz,1H),3.87(td,J 1 ＝9.6Hz,J 2 ＝7.2Hz,1H),3.25-3.19(m,5H). 13 C{ 1 H}NMR(100MHz,CDCl 3 ):δ177.1,156.8,143.5,141.3,135.53,135.49,129.5,129.1,128.4,127.9,125.2,124.5,124.3,123.3,123.2,116.3,108.2,67.6,50.9,28.7,26.5.HRMS(ESI)m/z:[M+H] + Calcd for C 24 H 20 N 3 O + 366.1601；Found 366.1605.
example 3
Method and procedure according to example 2 a,b Various dihydropyrrolo quinazoline spiro indolone compounds 3 can be synthesized by changing the reactant 1 and the reactant 2, and specific results are as follows:
a reaction conditions: 1 (0.2 mmol), 2 (0.3 mmol), [ Ru (p-cymene) Cl 2 ] 2 (0.005 mmol), acetic acid (0.4 mmol), 1, 2-dichloroethane (2 mL), 80 ℃ for 4h, air atmosphere; b the yield was isolated.
Representative product characterization data are as follows:
1,5-Dimethyl-3'-phenyl-5',6'-dihydrospiro[indoline-3,1'-pyrrolo[3,2,1-ij]quinazolin]-2-one(3ab)
1 H NMR(400MHz,CDCl 3 ):δ7.62-7.60(m,2H),7.39-7.37(m,3H),7.08-7.07(m,3H),6.86(t,J＝7.6Hz,1H),6.74-6.72(m,1H),6.40(d,J＝8.0Hz,1H),4.13(td,J 1 ＝10.0Hz,J 2 ＝6.8Hz,1H),3.88(td,J 1 ＝9.6Hz,J 2 ＝7.6Hz,1H),3.27-3.16(m,5H),2.29(s,3H). 13 C{ 1 H}NMR(150MHz,CDCl 3 ):δ177.1,156.7,141.3,141.1,135.6,135.6,132.8,129.5,129.3,128.4,128.0,125.9,124.4,124.3,123.3,116.5,107.9,67.7,50.9,28.7,26.5,21.2.HRMS(ESI)m/z:[M+H] + Calcd for C 25 H 22 N 3 O + 380.1757；Found 380.1753.
5-Methoxy-1-methyl-3'-phenyl-5',6'-dihydrospiro[indoline-3,1'-pyrrolo[3,2,1-ij]quinazol in]-2-one(3ac)
1 H NMR(400MHz,CDCl 3 ):δ7.62-7.59(m,2H),7.39-7.37(m,3H),7.08(d,J＝7.2Hz,1H),6.90-6.82(m,3H),6.75(d,J＝8.4Hz,1H),6.41(d,J＝7.6Hz,1H),4.05(td,J 1 ＝10.0Hz,J 2 ＝6.0Hz,1H),3.87(td,J 1 ＝10.0Hz,J 2 ＝7.6Hz,1H),3.75(s,3H),3.26-3.19(m,5H). 13 C{ 1 H}NMR(150MHz,CDCl 3 ):δ176.9,156.8,156.6,141.3,137.1,136.6,135.5,129.5,128.4,127.9,124.5,124.3,123.2,116.3,113.6,112.4,108.6,67.9,55.9,50.9,28.7,26.5.HRMS(ESI)m/z:[M+H] + Calcd for C 25 H 22 N 3 O 2 + 396.1707；Found 396.1712.
5-Fluoro-1-methyl-3'-phenyl-5',6'-dihydrospiro[indoline-3,1'-pyrrolo[3,2,1-ij]quinazolin]-2-one(3ad)
1 H NMR(600MHz,CDCl 3 ):δ7.61-7.59(m,2H),7.40-7.39(m,3H),7.10(d,J＝7.2Hz,1H),7.03-6.99(m,2H),6.89(t,J＝7.8Hz,1H),6.77(dd,J 1 ＝8.4Hz,J 2 ＝4.2Hz,1H),6.40(d,J＝7.2Hz,1H),4.06(td,J 1 ＝10.2Hz,J 2 ＝6.0Hz,1H),3.88(td,J 1 ＝10.2Hz,J 2 ＝7.8Hz,1H),3.28-3.19(m,5H). 13 C{ 1 H}NMR(150MHz,CDCl 3 ):δ176.9,159.9(d, 1 J C-F ＝239.6Hz),157.0,141.2,139.5,136.9(d, 3 J C-F ＝8.1Hz),135.3,129.6,128.6,128.5,127.9,124.7,124.6,123.0,115.7,115.3(d, 2 J C-F ＝23.9Hz),113.3(d, 2 J C-F ＝24.0Hz),108.7(d, 3 J C-F ＝7.7Hz),67.8,50.9,28.7,26.6. 19 F NMR(565MHz,CD 3 COCD 3 ):δ-121.35(td,J 1 ＝8.5Hz,J 2 ＝4.0Hz).HRMS(ESI)m/z:[M+H] + Calcd for C 24 H 19 FN 3 O + 384.1507；Found384.1509.
5-Chloro-1-methyl-3'-phenyl-5',6'-dihydrospiro[indoline-3,1'-pyrrolo[3,2,1-ij]quinazolin]-2-one(3ae)
1 H NMR(400MHz,CDCl 3 ):δ7.61-7.59(m,2H),7.40-7.38(m,3H),7.28-7.24(m,2H),7.10(d,J＝7.2Hz,1H),6.89(t,J＝7.6Hz,1H),6.78(d,J＝8.0Hz,1H),6.39(d,J＝7.6Hz,1H),4.04(td,J 1 ＝10.0Hz,J 2 ＝6.8Hz,1H),3.88(td,J 1 ＝10.0Hz,J 2 ＝7.6Hz,1H),3.25-3.19(m,5H). 13 C{ 1 H}NMR(150MHz,CDCl 3 ):δ176.7,156.9,142.1,141.1,137.1,135.3,129.6,129.0,128.7,128.6,128.5,127.9,125.7,124.7,124.6,123.1,115.6,109.2,67.6,50.9,28.7,26.6.HRMS(ESI)m/z:[M+H] + Calcd for C 24 H 19 ClN 3 O + 400.1211；Found400.1208.
5-Bromo-1-methyl-3'-phenyl-5',6'-dihydrospiro[indoline-3,1'-pyrrolo[3,2,1-ij]quinazolin]-2-one(3af)
1 H NMR(400MHz,CDCl 3 ):δ7.62-7.59(m,2H),7.44-7.37(m,5H),7.11-7.10(m,1H),6.89(t,J＝7.6Hz,1H),6.74(d,J＝8.0Hz,1H),6.40(d,J＝7.6Hz,1H),4.04(td,J 1 ＝10.0Hz,J 2 ＝6.8Hz,1H),3.90(td,J 1 ＝10.0Hz,J 2 ＝7.2Hz,1H),3.26-3.19(m,5H). 13 C{ 1 H}NMR(100MHz,CDCl 3 ):δ176.6,156.9,142.6,141.1,137.4,135.3,131.9,129.6,128.7,128.52,128.47,127.9,124.7,124.6,123.1,115.9,115.6,109.7,67.5,50.8,28.7,26.6.HRMS(ESI)m/z:[M+H] + Calcd for C 24 H 19 BrN 3 O + 444.0706；Found 444.0703.
5-Iodo-1-methyl-3'-phenyl-5',6'-dihydrospiro[indoline-3,1'-pyrrolo[3,2,1-ij]quinazolin]-2-one(3ag)
1 H NMR(400MHz,CDCl 3 ):δ7.63-7.59(m,3H),7.53(d,J＝1.6Hz,1H),7.41-7.39(m,3H),7.11(d,J＝7.2Hz,1H),6.89(t,J＝7.6Hz,1H),6.64(d,J＝8.0Hz,1H),6.39(d,J＝7.6Hz,1H),4.04(td,J 1 ＝10.0Hz,J 2 ＝6.8Hz,1H),3.89(td,J 1 ＝10.0Hz,J 2 ＝7.2Hz,1H),3.26-3.19(m,5H). 13 C{ 1 H}NMR(100MHz,CDCl 3 ):δ176.4,156.9,143.3,141.1,137.9,137.7,135.3,134.0,129.6,128.7,128.5,127.9,124.7,124.6,123.1,115.6,110.3,85.9,67.4,50.8,28.7,26.5.HRMS(ESI)m/z:[M+H] + Calcd for C 24 H 19 IN 3 O + 492.0567；Found492.0575.
6-Methoxy-1-methyl-3'-phenyl-5',6'-dihydrospiro[indoline-3,1'-pyrrolo[3,2,1-ij]quinazolin]-2-one(3ah)
1 H NMR(400MHz,CDCl 3 ):δ7.61-7.59(m,2H),7.39-7.37(m,3H),7.15(d,J＝8.0Hz,1H),7.07(d,J＝7.6Hz,1H),6.86(t,J＝7.6Hz,1H),6.56(dd,J 1 ＝8.0Hz,J 2 ＝2.0Hz,1H),6.44-6.40(m,2H),4.05(td,J 1 ＝10.0Hz,J 2 ＝6.0Hz,1H),3.88-3.82(m,4H),3.27-3.16(m,5H). 13 C{ 1 H}NMR(150MHz,CDCl 3 ):δ177.5,160.9,156.6,144.9,141.4,135.6,129.4,128.42,128.36,128.0,127.9,125.8,124.4,124.2,123.2,116.6,106.9,96.2,67.2,55.6,50.9,28.7,26.5.HRMS(ESI)m/z:[M+H] + Calcd for C 25 H 22 N 3 O 2 + 396.1707；Found 396.1714.6-Fluoro-1-methyl-3'-phenyl-5',6'-dihydrospiro[indoline-3,1'-pyrrolo[3,2,1-ij]quinazolin]-2-one(3ai)
1 H NMR(400MHz,CDCl 3 ):δ7.60-7.58(m,2H),7.39-7.38(m,3H),7.20(dd,J 1 ＝8.4Hz,J 2 ＝5.6Hz,1H),7.09(d,J＝7.2Hz,1H),6.88(t,J＝7.6Hz,1H),6.73(td,J 1 ＝10.0Hz,J 2 ＝2.0Hz,1H),6.59(dd,J 1 ＝8.8Hz,J 2 ＝2.4Hz,1H),6.38(d,J＝7.6Hz,1H),4.06(td,J 1 ＝10.0Hz,J 2 ＝6.0Hz,1H),3.85(td,J 1 ＝9.6Hz,J 2 ＝7.6Hz,1H),3.26-3.17(m,5H). 13 C{ 1 H}NMR(150MHz,CDCl 3 ):δ177.3,163.7(d, 1 J C-F ＝243.8Hz),156.9,145.2(d, 3 J C-F ＝12.5Hz),141.3,135.4,131.0,129.6,128.6,128.5,127.9,126.4(d, 3 J C-F ＝9.9Hz),124.6,124.5,123.1,116.0,109.2(d, 2 J C-F ＝21.5Hz),97.0(d, 2 J C-F ＝27.6Hz),67.1,50.9,28.7,26.6. 19 FNMR(376MHz,CDCl 3 ):δ-111.17--111.23(m).HRMS(ESI)m/z:[M+H] + Calcd forC 24 H 19 FN 3 O + 384.1507；Found 384.1511.
6-Chloro-1-methyl-3'-phenyl-5',6'-dihydrospiro[indoline-3,1'-pyrrolo[3,2,1-ij]quinazolin]-2-one(3aj)
1 H NMR(400MHz,CDCl 3 ):δ7.62-7.59(m,2H),7.44-7.37(m,5H),7.10(d,J＝7.6Hz,1H),6.89(t,J＝7.6Hz,1H),6.74(d,J＝8.0Hz,1H),6.40(d,J＝8.0Hz,1H),4.05(td,J 1 ＝10.0Hz,J 2 ＝6.4Hz,1H),3.89(td,J 1 ＝9.6Hz,J 2 ＝7.6Hz,1H),3.26-3.19(m,5H). 13 C{ 1 H}NMR(100MHz,CDCl 3 ):δ176.6,156.9,142.6,141.1,137.4,135.3,131.9,129.6,128.7,128.51,128.47,127.9,124.7,124.6,123.1,115.9,115.6,109.7,67.5,50.8,28.7,26.6.HRMS(ESI)m/z:[M+H] + Calcd for C 24 H 19 ClN 3 O + 400.1211；Found 400.1217.
1,7-Dimethyl-3'-phenyl-5',6'-dihydrospiro[indoline-3,1'-pyrrolo[3,2,1-ij]quinazolin]-2-one(3ak)
1 H NMR(400MHz,CDCl 3 ):δ7.61-7.59(m,2H),7.38-7.37(m,3H),7.09-7.06(m,2H),7.01(d,J＝7.6Hz,1H),6.93(t,J＝7.6Hz,1H),6.86(t,J＝7.6Hz,1H),6.41(d,J＝7.6Hz,1H),4.03(td,J 1 ＝10.0Hz,J 2 ＝6.4Hz,1H),3.86(td,J 1 ＝10.0Hz,J 2 ＝7.6Hz,1H),3.49(s,3H),3.25-3.18(m,2H),2.58(s,3H). 13 C{ 1 H}NMR(100MHz,CDCl 3 ):δ177.8,156.5,141.3,141.0,136.3,135.6,132.7,129.4,128.39,128.37,127.9,124.4,124.2,123.3,123.2,119.7,116.6,67.0,50.9,29.9,28.7,19.1.HRMS(ESI)m/z:[M+H] + Calcd for C 25 H 22 N 3 O + 380.1757；Found 380.1753.
7-Methoxy-1-methyl-3'-phenyl-5',6'-dihydrospiro[indoline-3,1'-pyrrolo[3,2,1-ij]quinazolin]-2-one(3al)
1 H NMR(400MHz,CDCl 3 ):δ7.61-7.59(m,2H),7.38-7.37(m,3H),7.08-7.06(m,1H),6.99(t,J＝7.6Hz,1H),6.89-6.84(m,3H),6.42(d,J＝7.6Hz,1H),4.02(td,J 1 ＝10.0Hz,J 2 ＝6.4Hz,1H),3.90-3.83(m,4H),3.48(s,3H),3.24-3.18(m,2H). 13 C{ 1 H}NMR(100MHz,CDCl 3 ):δ177.4,156.6,145.3,141.2,137.1,135.5,131.3,129.4,128.4,127.9,124.5,124.2,123.8,123.2,117.9,116.5,113.1,67.6,56.2,50.9,29.8,28.7.HRMS(ESI)m/z:[M+H] + Calcd for C 25 H 22 N 3 O 2 + 396.1707；Found 396.1717.
7-Fluoro-1-methyl-3'-phenyl-5',6'-dihydrospiro[indoline-3,1'-pyrrolo[3,2,1-ij]quinazolin]-2-one(3am)
1 H NMR(400MHz,CDCl 3 ):δ7.61-7.58(m,2H),7.40-7.38(m,3H),7.10(d,J＝7.2Hz,1H),7.07-6.98(m,3H),6.89(t,J＝7.6Hz,1H),6.41(d,J＝7.6Hz,1H),4.06(td,J 1 ＝10.0Hz,J 2 ＝6.4Hz,1H),3.87(td,J 1 ＝10.0Hz,J 2 ＝7.2Hz,1H),3.43(d,J＝2.8Hz,3H),3.26-3.20(m,2H). 13 C{ 1 H}NMR(100MHz,CDCl 3 ):δ176.7,156.8,147.7(d, 1 J C-F ＝241.9Hz),141.1,138.2(d, 5 J C-F ＝3.1Hz),135.4,130.1(d, 3 J C-F ＝8.8Hz),129.6,128.6,128.5,127.9,124.6,124.5,123.9(d, 3 J C-F ＝5.4Hz),123.1,121.1(d, 4 J C-F ＝3.0Hz),116.9(d, 2 J C-F ＝19.0Hz),115.9,67.6(d, 4 J C-F ＝2.4Hz),50.8,29.0(d, 4 J C-F ＝5.4Hz),28.7. 19 F NMR(376MHz,CDCl 3 ):δ-137.02--137.05(m).HRMS(ESI)m/z:[M+H] + Calcd for C 24 H 19 FN 3 O + 384.1507；Found 384.1512.
7-Chloro-1-methyl-3'-phenyl-5',6'-dihydrospiro[indoline-3,1'-pyrrolo[3,2,1-ij]quinazolin]-2-one(3an)
1 H NMR(400MHz,CDCl 3 ):δ7.60-7.58(m,2H),7.40-7.38(m,3H),7.22(d,J＝8.4Hz,1H),7.16-7.14(m,1H),7.10(d,J＝7.2Hz,1H),6.96(t,J＝8.0Hz,1H),6.89(t,J＝7.6Hz,1H),6.41(d,J＝7.6Hz,1H),4.05(td,J 1 ＝10.0Hz,J 2 ＝6.4Hz,1H),3.88(td,J 1 ＝9.6Hz,J 2 ＝7.2Hz,1H),3.58(s,3H),3.26-3.20(m,2H). 13 C{ 1 H}NMR(150MHz,CDCl 3 ):δ177.3,156.8,141.1,139.4,138.3,135.3,131.3,129.6,128.6,128.5,127.9,124.7,124.5,124.1,124.0,123.1,115.9,115.5,67.2,50.8,29.9,28.7.HRMS(ESI)m/z:[M+H] + Calcd forC 24 H 19 ClN 3 O + 400.1211；Found 400.1223.
7-Bromo-1-methyl-3'-phenyl-5',6'-dihydrospiro[indoline-3,1'-pyrrolo[3,2,1-ij]quinazolin]-2-one(3ao)
1 H NMR(600MHz,CDCl 3 ):δ7.60-7.58(m,2H),7.40-7.38(m,4H),7.18(dd,J 1 ＝7.2Hz,J 2 ＝1.2Hz,1H),7.10(d,J＝7.2Hz,1H),6.91-6.88(m,2H),6.41(d,J＝7.8Hz,1H),4.05(td,J 1 ＝10.2Hz,J 2 ＝6.0Hz,1H),3.88(td,J 1 ＝9.6Hz,J 2 ＝7.2Hz,1H),3.60(s,3H),3.26-3.20(m,2H). 13 C{ 1 H}NMR(150MHz,CDCl 3 ):δ177.5,156.8,141.1,140.8,138.7,135.3,134.6,129.6,128.6,128.5,127.9,124.7,124.6,124.5,123.2,115.9,102.4,67.2,50.9,30.1,28.7.HRMS(ESI)m/z:[M+H] + Calcd for C 24 H 19 BrN 3 O + 444.0706；Found 444.0689.1,5,7-Trimethyl-3'-phenyl-5',6'-dihydrospiro[indoline-3,1'-pyrrolo[3,2,1-ij]quinazolin]-2-one(3ap)
1 H NMR(400MHz,CDCl 3 ):δ7.62-7.60(m,2H),7.39-7.36(m,3H),7.07(dd,J 1 ＝7.6Hz,J 2 ＝0.8Hz,1H),6.90-6.85(m,2H),6.82(s,1H),6.42(d,J＝8.0Hz,1H),4.02(td,J 1 ＝10.0Hz,J 2 ＝6.4Hz,1H),3.88(td,J 1 ＝9.6Hz,J 2 ＝7.2Hz,1H),3.47(s,3H),3.25-3.19(m,2H),2.53(s,3H),2.22(s,3H). 13 C{ 1 H}NMR(100MHz,CDCl 3 ):δ177.8,156.4,141.3,138.6,136.4,135.6,133.1,132.7,129.4,128.4,128.3,128.0,124.4,124.2,124.0,123.3,119.3,116.8,67.1,50.9,29.9,28.7,20.8,18.9.HRMS(ESI)m/z:[M+H] + Calcd for C 26 H 24 N 3 O + 394.1914；Found 394.1916.
4-Chloro-1-methyl-3'-phenyl-5',6'-dihydrospiro[indoline-3,1'-pyrrolo[3,2,1-ij]quinazolin]-2-one(3aq)
1 H NMR(400MHz,CDCl 3 ):δ7.62-7.60(m,2H),7.40-7.38(m,3H),7.23(t,J＝8.4Hz,1H),7.08(d,J＝7.2Hz,1H),6.99(d,J＝8.4Hz,1H),6.86(t,J＝7.6Hz,1H),6.77(d,J＝8.0Hz,1H),6.41(d,J＝7.6Hz,1H),4.30(td,J 1 ＝10.0Hz,J 2 ＝6.8Hz,1H),3.91(td,J 1 ＝9.2Hz,J 2 ＝7.2Hz,1H),3.25-3.18(m,5H). 13 C{ 1 H}NMR(100MHz,CDCl 3 ):δ176.8,156.4,145.0,141.2,135.6,132.5,131.8,130.2,129.5,128.5,127.8,124.5,124.5,124.1,122.6,114.3,106.8,68.1,50.4,28.6,26.8.HRMS(ESI)m/z:[M+H] + Calcd for C 24 H 19 ClN 3 O + 400.1211；Found 400.1216.
4-Bromo-1-methyl-3'-phenyl-5',6'-dihydrospiro[indoline-3,1'-pyrrolo[3,2,1-ij]quinazolin]-2-one(3ar)
1 H NMR(400MHz,CDCl 3 ):δ7.65-7.62(m,2H),7.40-7.39(m,3H),7.17-7.16(m,2H),7.08(d,J＝7.2Hz,1H),6.86(t,J＝7.6Hz,1H),6.82-6.80(m,1H),6.39(d,J＝7.6Hz,1H),4.07(td,J 1 ＝10.0Hz,J 2 ＝6.0Hz,1H),3.92-3.85(m,1H),3.26-3.17(m,5H). 13 C{ 1 H}NMR(100MHz,CDCl 3 ):δ176.7,156.3,145.3,141.3,133.5,130.4,129.5,128.48,128.45,127.8,127.1,124.54,124.45,122.7,121.2,114.2,107.3,69.0,50.4,28.6,26.7.HRMS(ESI)m/z:[M+H] + Calcd for C 24 H 19 BrN 3 O + 444.0706；Found 444.0702.
1-Ethyl-3'-phenyl-5',6'-dihydrospiro[indoline-3,1'-pyrrolo[3,2,1-ij]quinazolin]-2-one(3as)
1 H NMR(400MHz,CDCl 3 ):δ7.62-7.60(m,2H),7.39-7.37(m,3H),7.30-7.26(m,2H),7.08-7.02(m,2H),6.88-6.84(m,1H),6.38(d,J＝7.6Hz,1H),4.03(td,J 1 ＝9.6,Hz,J 2 ＝6.8Hz,1H),3.91-3.79(m,2H),3.73-3.68(m,1H),3.25-3.19(m,2H),1.30(t,J＝7.6Hz,3H). 13 C{ 1 H}NMR(100MHz,CDCl 3 ):δ176.7,156.8,142.5,141.2,135.9,135.5,129.5,129.0,128.4,127.9,125.3,124.5,124.3,123.1,123.0,116.6,108.3,67.5,50.9,34.9,28.7,12.7.HRMS(ESI)m/z:[M+H] + Calcd for C 25 H 22 N 3 O + 380.1757；Found 380.1755.
1-Benzyl-3'-phenyl-5',6'-dihydrospiro[indoline-3,1'-pyrrolo[3,2,1-ij]quinazolin]-2-one(3at)
1 H NMR(400MHz,CDCl 3 ):δ7.64-7.62(m,2H),7.40-7.39(m,3H),7.34-7.22(m,6H),7.16(td,J 1 ＝8.0Hz,J 2 ＝1.2Hz,1H),7.10(d,J＝7.2Hz,1H),7.02(t,J＝7.2Hz,1H),6.88(t,J＝7.6Hz,1H),6.71(d,J＝8.0Hz,1H),6.39(d,J＝7.6Hz,1H),5.13(d,J＝16.0Hz,1H),4.67(d,J＝15.6Hz,1H),4.06(td,J 1 ＝10.0,Hz,J 2 ＝6.4Hz,1H),3.88(td,J 1 ＝10.0,Hz,J 2 ＝7.6Hz,1H),3.26-3.20(m,2H). 13 C{ 1 H}NMR(100MHz,CDCl 3 ):δ177.2,156.8,142.6,141.3,136.0,135.6,129.5,128.9,128.8,128.54,128.46,128.0,127.6,127.4,125.3,124.6,124.4,123.4,123.1,116.5,109.2,67.7,50.9,44.0,28.8.HRMS(ESI)m/z:[M+H] + Calcd for C 30 H 24 N 3 O + 442.1914；Found 442.1919.
1-(4-Methylbenzyl)-3'-phenyl-5',6'-dihydrospiro[indoline-3,1'-pyrrolo[3,2,1-ij]quinazolin]-2-one(3au)
1 H NMR(400MHz,CDCl 3 ):δ7.64-7.62(m,2H),7.40-7.39(m,3H),7.28-7.21(m,3H),7.16(td,J 1 ＝7.6Hz,J 2 ＝0.8Hz,1H),7.12-7.09(m,3H),7.01(t,J＝7.6Hz,1H),6.87(t,J＝7.6Hz,1H),6.72(d,J＝8.0Hz,1H),6.38(d,J＝7.6Hz,1H),5.11(d,J＝15.6Hz,1H),4.61(d,J＝15.6Hz,1H),4.07(td,J 1 ＝10.0Hz,J 2 ＝6.0Hz,1H),3.88(td,J 1 ＝10.0Hz,J 2 ＝7.6Hz,1H),3.27-3.20(m,2H),2.30(s,3H). 13 C{ 1 H}NMR(100MHz,CDCl 3 ):δ177.1,156.8,142.7,141.3,137.2,135.5,133.0,129.52,129.46,128.9,128.5,128.4,128.0,127.4,125.2,124.6,124.4,123.3,123.1,116.6,109.3,67.6,50.9,43.8,28.8,21.1.HRMS(ESI)m/z:[M+H] + Calcd for C 31 H 26 N 3 O + 456.2070；Found 456.2078.
1-Phenethyl-3'-phenyl-5',6'-dihydrospiro[indoline-3,1'-pyrrolo[3,2,1-ij]quinazolin]-2-one(3av)
1 H NMR(600MHz,CDCl 3 ):δ7.61-7.59(m,2H),7.39-7.38(m,3H),7.28-7.25(m,6H),7.21-7.19(m,1H),7.07(d,J＝7.2Hz,1H),7.04(t,J＝7.8Hz,1H),6.84-6.82(m,2H),6.21(d,J＝7.2Hz,1H),4.12-4.07(m,1H),4.03(td,J 1 ＝10.2Hz,J 2 ＝6.0Hz,1H),3.86(td,J 1 ＝9.6Hz,J 2 ＝7.2Hz,1H),3.80-3.75(m,1H),3.24-3.18(m,2H),3.04-3.00(m,2H). 13 C{ 1 H}NMR(150MHz,CDCl 3 ):δ176.9,156.8,142.7,141.3,138.3,135.7,135.6,129.5,129.0,128.6,128.44,128.37,127.9,126.6,125.4,124.5,124.3,123.2,123.1,116.4,108.3,67.5,50.9,41.6,33.7,28.8.HRMS(ESI)m/z:[M+H] + Calcd for C 31 H 26 N 3 O + 456.2070；Found456.2076.
1,3'-Diphenyl-5',6'-dihydrospiro[indoline-3,1'-pyrrolo[3,2,1-ij]quinazolin]-2-one(3aw)
1 H NMR(400MHz,CDCl 3 ):δ7.64-7.61(m,2H),7.49-7.48(m,4H),7.41-7.34(m,5H),7.22(td,J 1 ＝8.0Hz,J 2 ＝1.2Hz,1H),7.11-7.08(m,2H),6.92-6.86(m,2H),6.52(d,J＝8.0Hz,1H),4.04(td,J 1 ＝10.0Hz,J 2 ＝6.8Hz,1H),3.89(td,J 1 ＝9.6Hz,J 2 ＝7.6Hz,1H),3.26-3.20(m,2H). 13 C{ 1 H}NMR(100MHz,CDCl 3 ):δ176.2,156.9,143.3,141.2,135.6,135.3,134.6,129.53,129.46,128.9,128.6,128.5,127.9,127.8,126.6,125.6,124.6,124.4,123.8,123.1,116.7,109.5,67.7,50.8,28.8.HRMS(ESI)m/z:[M+H] + Calcd for C 29 H 22 N 3 O + 428.1757；Found 428.1758.
3'-Phenyl-5',6'-dihydrospiro[indoline-3,1'-pyrrolo[3,2,1-ij]quinazolin]-2-one(3ax)
1 H NMR(400MHz,CDCl 3 ):δ8.52(br s,1H),7.64-7.62(m,2H),7.39-7.38(m,3H),7.23-7.16(m,2H),7.08(d,J＝7.2Hz,1H),7.00(t,J＝7.6Hz,1H),6.90-6.84(m,2H),6.46(d,J＝7.2Hz,1H),4.05(td,J 1 ＝10.0Hz,J 2 ＝6.0Hz,1H),3.88(td,J 1 ＝9.6Hz,J 2 ＝7.6Hz,1H),3.29-3.15(m,2H). 13 C{ 1 H}NMR(100MHz,CDCl 3 ):δ179.3,156.7,141.1,140.5,136.3,135.5,129.5,129.0,128.5,128.4,128.0,125.4,124.6,124.4,123.3,123.2,116.2,110.1,68.0,50.9,28.7.HRMS(ESI)m/z:[M+H] + Calcd for C 23 H 18 N 3 O + 352.1444；Found352.1443.
1,8'-Dimethyl-3'-phenyl-5',6'-dihydrospiro[indoline-3,1'-pyrrolo[3,2,1-ij]quinazolin]-2-one(3ba)
1 H NMR(400MHz,CDCl 3 ):δ7.61-7.59(m,2H),7.38-7.36(m,3H),7.32-7.26(m,2H),7.06(t,J＝7.6Hz,1H),6.91(s,1H),6.85(d,J＝7.6Hz,1H),6.20(s,1H),4.01(td,J 1 ＝9.6Hz,J 2 ＝6.4Hz,1H),3.88(td,J 1 ＝9.6Hz,J 2 ＝7.2Hz,1H),3.23-3.15(m,5H),2.17(s,3H). 13 C{ 1 H}NMR(100MHz,CDCl 3 ):δ177.3,156.7,143.4,139.1,135.7,135.6,134.3,129.4,129.0,128.5,128.4,127.9,125.14,125.13,123.3,123.2,115.9,108.2,67.6,51.0,28.7,26.5,21.3.HRMS(ESI)m/z:[M+H] + Calcd for C 25 H 22 N 3 O + 380.1757；Found 380.1759.
8'-Methoxy-1-methyl-3'-phenyl-5',6'-dihydrospiro[indoline-3,1'-pyrrolo[3,2,1-ij]quinazolin]-2-one(3ca)
1 H NMR(600MHz,CDCl 3 ):δ7.61-7.59(m,2H),7.38-7.37(m,3H),7.29(t,J＝7.8Hz,1H),7.26-7.25(m,1H),7.06(t,J＝7.2Hz,1H),6.85(d,J＝7.8Hz,1H),6.70(s,1H),5.94(d,J＝1.2Hz,1H),4.04(td,J 1 ＝10.2Hz,J 2 ＝6.0Hz,1H),3.88(td,J 1 ＝9.6Hz,J 2 ＝7.2Hz,1H),3.63(s,3H),3.24-3.17(m,5H). 13 C{ 1 H}NMR(150MHz,CDCl 3 ):δ177.1,157.8,156.7,143.5,135.5,135.3,129.7,129.4,129.1,128.4,127.9,125.1,123.3,116.6,111.2,108.2,108.2,67.7,56.0,51.0,28.8,26.5.HRMS(ESI)m/z:[M+H] + Calcd for C 25 H 22 N 3 O 2 + 396.1707；Found 396.1713.
8'-Fluoro-1-methyl-3'-phenyl-5',6'-dihydrospiro[indoline-3,1'-pyrrolo[3,2,1-ij]quinazolin]-2-one(3da)
1 H NMR(400MHz,CDCl 3 ):δ7.61-7.58(m,2H),7.39-7.37(m,3H),7.31(td,J 1 ＝7.6Hz,J 2 ＝1.2Hz,1H),7.26-7.24(m,1H),7.07(td,J 1 ＝7.6Hz,J 2 ＝0.8Hz,1H),6.86(d,J＝8.0Hz,1H),6.82-6.79(m,1H),6.12(dd,J 1 ＝9.2Hz,J 2 ＝2.0Hz,1H),4.06(td,J 1 ＝10.0Hz,J 2 ＝6.4Hz,1H),3.88(td,J 1 ＝10.0Hz,J 2 ＝7.2Hz,1H),3.23-3.16(m,5H). 13 C{ 1 H}NMR(100MHz,CDCl 3 ):δ176.7,160.5(d, 1 J C-F ＝240.0Hz),156.7,143.4,137.5,135.3,135.0,130.1(d, 3 J C-F ＝8.7Hz),129.6,129.4,128.5,127.9,125.1,123.5,116.8(d, 3 J C-F ＝7.7Hz),112.1(d, 2 J C-F ＝24.9Hz),109.8(d, 2 J C-F ＝24.5Hz),108.4,67.6,51.1,28.6(d, 4 J C-F ＝2.3Hz),26.5. 19 F NMR(376MHz,CDCl 3 ):δ-118.34(t,J＝8.6Hz).HRMS(ESI)m/z:[M+H] + Calcd for C 24 H 19 FN 3 O + 384.1507；Found 384.1510.
8'-Chloro-1-methyl-3'-phenyl-5',6'-dihydrospiro[indoline-3,1'-pyrrolo[3,2,1-ij]quinazolin]-2-one(3ea)
1 H NMR(400MHz,CDCl 3 ):δ7.60-7.58(m,2H),7.40-7.38(m,3H),7.32(td,J 1 ＝8.0Hz,J 2 ＝0.8Hz,1H),7.25(d,J＝7.6Hz,1H),7.10-7.06(m,2H),6.86(d,J＝7.6Hz,1H),6.38(s,1H),4.07(td,J 1 ＝10.0Hz,J 2 ＝6.0Hz,1H),3.88(td,J 1 ＝9.6Hz,J 2 ＝7.2Hz,1H),3.24-3.17(m,5H). 13 C{ 1 H}NMR(100MHz,CDCl 3 ):δ176.6,156.6,143.4,140.2,135.1,134.9,130.2,129.7,129.4,129.0,128.5,127.9,125.1,124.7,123.5,123.2,117.2,108.4,67.4,51.0,28.5,26.5.HRMS(ESI)m/z:[M+H] + Calcd for C 24 H 19 ClN 3 O + 400.1211；Found400.1215.
8'-Bromo-1-methyl-3'-phenyl-5',6'-dihydrospiro[indoline-3,1'-pyrrolo[3,2,1-ij]quinazolin]-2-one(3fa)
1 H NMR(600MHz,CDCl 3 ):δ7.59-7.58(m,2H),7.39-7.38(m,3H),7.32(td,J 1 ＝7.8Hz,J 2 ＝0.6Hz,1H),7.25(d,J＝7.2Hz,1H),7.20(s,1H),7.08(t,J＝7.2Hz,1H),6.86(d,J＝7.2Hz,1H),6.51(s,1H),4.05(td,J 1 ＝9.6Hz,J 2 ＝6.0Hz,1H),3.87(td,J 1 ＝10.2Hz,J 2 ＝7.8Hz,1H),3.25-3.18(m,5H). 13 C{ 1 H}NMR(150MHz,CDCl 3 ):δ176.5,156.5,143.4,140.6,135.1,134.9,130.6,129.7,129.4,128.5,127.8,127.5,126.0,125.1,123.5,117.7,116.2,108.4,67.3,51.0,28.4,26.5.HRMS(ESI)m/z:[M+H] + Calcd for C 24 H 19 BrN 3 O + 444.0706；Found 444.0700.
7'-Methoxy-1-methyl-3'-phenyl-5',6'-dihydrospiro[indoline-3,1'-pyrrolo[3,2,1-ij]quinazolin]-2-one(3ga)
1 H NMR(400MHz,CDCl 3 ):δ7.60-7.58(m,2H),7.38-7.36(m,3H),7.31-7.25(m,2H),7.06(t,J＝7.2Hz,1H),6.84(d,J＝8.0Hz,1H),6.43-6.36(m,2H),4.07(td,J 1 ＝9.6Hz,J 2 ＝7.2Hz,1H),3.91-3.84(m,1H),3.78(s,3H),3.20-3.14(m,5H). 13 C{ 1 H}NMR(100MHz,CDCl 3 ):δ177.3,156.6,156.1,143.6,142.7,135.63,135.60,129.4,129.0,128.4,127.9,125.1,125.0,123.3,114.8,109.6,108.1,107.3,67.3,55.6,51.2,26.4,26.3.HRMS(ESI)m/z:[M+H] + Calcd for C 25 H 22 N 3 O 2 + 396.1707；Found 396.1714.
7'-Chloro-1-methyl-3'-phenyl-5',6'-dihydrospiro[indoline-3,1'-pyrrolo[3,2,1-ij]quinazolin]-2-one(3ha)
1 H NMR(400MHz,CDCl 3 ):δ7.60-7.58(m,2H),7.41-7.38(m,3H),7.30(td,J 1 ＝7.6Hz,J 2 ＝0.8Hz,1H),7.24(d,J＝7.6Hz,1H),7.07(t,J＝7.6Hz,1H),6.86-6.82(m,2H),6.35(d,J＝8.0Hz,1H),4.10(td,J 1 ＝9.6Hz,J 2 ＝6.8Hz,1H),3.91(td,J 1 ＝9.6Hz,J 2 ＝7.6Hz,1H),3.27-3.21(m,5H). 13 C{ 1 H}NMR(100MHz,CDCl 3 ):δ176.7,156.5,143.5,142.7,135.14,135.10,130.2,129.7,129.3,128.5,127.8,126.8,125.2,125.1,124.4,123.4,114.6,108.3,67.4,50.8,28.2 26.5.HRMS(ESI)m/z:[M+H] + Calcd for C 24 H 19 ClN 3 O + 400.1211；Found400.1214.
7'-Bromo-1-methyl-3'-phenyl-5',6'-dihydrospiro[indoline-3,1'-pyrrolo[3,2,1-ij]quinazolin]-2-one(3ia)
1 H NMR(400MHz,CDCl 3 ):δ7.60-7.57(m,2H),7.40-7.38(m,3H),7.31(td,J 1 ＝7.2Hz,J 2 ＝0.8Hz,1H),7.24(d,J＝7.2Hz,1H),7.07(t,J＝7.6Hz,1H),6.99(d,J＝8.0Hz,1H),6.85(d,J＝8.0Hz,1H),6.28(d,J＝8.0Hz,1H),4.10(td,J 1 ＝10.0Hz,J 2 ＝6.8Hz,1H),3.91(td,J 1 ＝10.0Hz,J 2 ＝7.6Hz,1H),3.25-3.18(m,5H). 13 C{ 1 H}NMR(100MHz,CDCl 3 ):δ176.6,156.5,143.5,142.4,135.09,135.05,129.7,129.3,129.2,128.5,127.9,127.1,125.3,125.1,123.4,118.7,115.2,108.3,67.4,50.5,30.0,26.5.HRMS(ESI)m/z:[M+H] + Calcd for C 24 H 19 BrN 3 O + 444.0706；Found 444.0718.
9'-Methoxy-1-methyl-3'-phenyl-5',6'-dihydrospiro[indoline-3,1'-pyrrolo[3,2,1-ij]quinazolin]-2-one(3ja)
1 H NMR(400MHz,CDCl 3 ):δ7.63-7.60(m,2H),7.41-7.39(m,3H),7.26(td,J 1 ＝7.6Hz,J 2 ＝1.2Hz,1H),7.20-7.18(m,1H),7.05(d,J＝8.0Hz,1H),7.01(td,J 1 ＝7.6Hz,J 2 ＝0.4Hz,1H),6.84(d,J＝8.0Hz,1H),6.41(d,J＝8.4Hz,1H),4.15(td,J 1 ＝10.0Hz,J 2 ＝5.2Hz,1H),3.79(td,J 1 ＝10.0Hz,J 2 ＝8.0Hz,1H),3.53(s,3H),3.31(s,3H),3.27-3.19(m,1H),3.15-3.07(m,1H). 13 C{ 1 H}NMR(100MHz,CDCl 3 ):δ177.8,155.2,142.9,142.3,136.0,135.5,129.5,128.6,128.4,128.0,124.5,124.3,122.7,120.7,107.8,106.7,105.6,65.2,56.4,51.4,27.9,26.5.HRMS(ESI)m/z:[M+H] + Calcd for C 25 H 22 N 3 O 2 + 396.1707；Found396.1704.
9'-Fluoro-1-methyl-3'-phenyl-5',6'-dihydrospiro[indoline-3,1'-pyrrolo[3,2,1-ij]quinazolin]-2-one(3ka)
1 H NMR(600MHz,CDCl 3 ):δ7.59-7.57(m,2H),7.38-7.37(m,3H),7.28-7.26(m,1H),7.21(d,J＝7.2Hz,1H),7.03-6.99(m,2H),6.84(d,J＝7.8Hz,1H),6.53(dd,J 1 ＝10.2Hz,J 2 ＝8.4Hz,1H),4.10(td,J 1 ＝9.6Hz,J 2 ＝5.4Hz,1H),3.87(td,J 1 ＝10.2Hz,J 2 ＝7.8Hz,1H),3.27(s,3H),3.23-3.17(m,1H),3.15-3.10(m,1H). 13 C{ 1 H}NMR(100MHz,CDCl 3 ):δ176.6,157.8(d, 1 J C-F ＝245.1Hz),155.3,142.8(d, 3 J C-F ＝9.4Hz),142.7,135.4,135.1,129.7,129.2,128.5,127.9,125.0(d, 3 J C-F ＝9.4Hz),124.6,123.7(d, 4 J C-F ＝2.9Hz),123.1,110.5(d, 2 J C-F ＝21.8Hz),108.4,104.6(d, 2 J C-F ＝20.5Hz),64.6,51.6,28.0,26.6. 19 F NMR(376MHz,CDCl 3 ):δ-119.29--119.33(m).HRMS(ESI)m/z:[M+H] + Calcd for C 24 H 19 FN 3 O + 384.1507；Found 384.1511.
8',9'-Difluoro-1-methyl-3'-phenyl-5',6'-dihydrospiro[indoline-3,1'-pyrrolo[3,2,1-ij]quinazolin]-2-one(3la)
1 H NMR(600MHz,CDCl 3 ):δ7.58-7.56(m,2H),7.39-7.37(m,3H),7.29(td,J 1 ＝7.8Hz,J 2 ＝1.2Hz,1H),7.21-7.20(m,1H),7.03(td,J 1 ＝7.8Hz,J 2 ＝1.2Hz,1H),6.91(dd,J 1 ＝9.0Hz,J 2 ＝7.2Hz,1H),6.85(d,J＝7.8Hz,1H),4.08(td,J 1 ＝10.2Hz,J 2 ＝5.4Hz,1H),3.87(td,J 1 ＝10.2Hz,J 2 ＝7.8Hz,1H),3.27(s,3H),3.19-3.12(m,2H). 13 C{ 1 H}NMR(100MHz,CDCl 3 ):δ176.2,155.3,147.4(dd, 1 J C-F ＝239.2Hz, 2 J C-F ＝11.3Hz),145.6(dd, 1 J C-F ＝253.8Hz, 2 J C-F ＝20.8Hz),142.6,137.5(d, 3 J C-F ＝6.5Hz),135.0,134.9,129.8,129.4,128.5,127.9,124.6,123.3,123.1(dd, 3 J C-F ＝6.5Hz, 4 J C-F ＝3.3Hz),113.4(d, 2 J C-F ＝20.7Hz),108.5,106.1(d, 2 J C-F ＝17.0Hz),64.7,51.1,28.0,26.6. 19 F NMR(376MHz,CDCl 3 ):δ-142.40(dd,J 1 ＝20.3Hz,J 2 ＝7.1Hz),-142.69(dd,J 1 ＝19.9Hz,J 2 ＝9.8Hz).HRMS(ESI)m/z:[M+H] + Calcd for C 24 H 18 F 2 N 3 O + 402.1412；Found 402.1414.
1-Methyl-3'-(p-tolyl)-5',6'-dihydrospiro[indoline-3,1'-pyrrolo[3,2,1-ij]quinazolin]-2-one(3ma)
1 H NMR(600MHz,CDCl 3 ):δ7.49(d,J＝7.8Hz,2H),7.29(td,J 1 ＝7.8Hz,J 2 ＝1.2Hz,1H),7.26-7.25(m,1H),7.18(d,J＝7.8Hz,2H),7.08-7.04(m,2H),6.86-6.84(m,2H),6.39(d,J＝7.2Hz,1H),4.05(td,J 1 ＝10.2Hz,J 2 ＝6.0Hz,1H),3.88(td,J 1 ＝10.2Hz,J 2 ＝7.2Hz,1H),3.24-3.18(m,5H),2.35(s,3H). 13 C{ 1 H}NMR(150MHz,CDCl 3 ):δ177.2,156.8,143.5,141.4,139.5,135.7,132.7,129.0,128.4,127.9,125.1,124.4,124.3,123.3,123.2,116.3,108.1,67.6,50.9,28.7,26.5,21.4.HRMS(ESI)m/z:[M+H] + Calcd for C 25 H 22 N 3 O + 380.1757；Found 380.1768.
3'-(4-(Tert-butyl)phenyl)-1-methyl-5',6'-dihydrospiro[indoline-3,1'-pyrrolo[3,2,1-ij]quinazolin]-2-one(3na)
1 H NMR(600MHz,CDCl 3 ):δ7.53(d,J＝8.4Hz,2H),7.39(d,J＝7.8Hz,2H),7.30-7.25(m,2H),7.08-7.03(m,2H),6.87-6.83(m,2H),6.40(d,J＝7.2Hz,1H),4.07(td,J 1 ＝10.2Hz,J 2 ＝6.0Hz,1H),3.92(td,J 1 ＝10.2Hz,J 2 ＝7.2Hz,1H),3.26-3.18(m,5H),1.29(s,9H). 13 C{ 1 H}NMR(150MHz,CDCl 3 ):δ177.2,156.8,152.6,143.5,141.5,135.7,132.7,129.0,128.4,127.6,125.3,125.1,124.4,124.3,123.3,123.2,116.3,108.1,67.6,50.9,34.8,31.2,28.7,26.5.HRMS(ESI)m/z:[M+H] + Calcd for C 28 H 28 N 3 O + 422.2227；Found 422.2230.
1-Methyl-3'-(4-(methylthio)phenyl)-5',6'-dihydrospiro[indoline-3,1'-pyrrolo[3,2,1-ij]quinazolin]-2-one(3oa)
1 H NMR(600MHz,CDCl 3 ):δ7.53(d,J＝8.4Hz,2H),7.29(td,J 1 ＝7.8Hz,J 2 ＝1.2Hz,1H),7.26-7.24(m,3H),7.08-7.04(m,2H),6.87-6.84(m,2H),6.38(d,J＝7.8Hz,1H),4.05(td,J 1 ＝10.2Hz,J 2 ＝6.0Hz,1H),3.89(td,J 1 ＝10.2Hz,J 2 ＝7.2Hz,1H),3.27-3.18(m,5H),2.46(s,3H). 13 C{ 1 H}NMR(100MHz,CDCl 3 ):δ177.1,156.4,143.5,141.3,140.6,135.5,132.0,129.1,128.43,128.38,126.0,125.1,124.5,124.3,123.3,123.2,116.3,108.2,67.6,50.9,28.7,26.5,15.5.HRMS(ESI)m/z:[M+H] + Calcd for C 25 H 22 N 3 OS + 412.1478；Found 412.1480.
3'-(4-Fluorophenyl)-1-methyl-5',6'-dihydrospiro[indoline-3,1'-pyrrolo[3,2,1-ij]quinazolin]-2-one(3pa)
1 H NMR(600MHz,CDCl 3 ):δ7.62-7.60(m,2H),7.30(td,J 1 ＝7.8Hz,J 2 ＝1.2Hz,1H),7.25(d,J＝7.8Hz,1H),7.09-7.05(m,4H),6.88-6.85(m,2H),6.39(d,J＝7.2Hz,1H),4.04(td,J 1 ＝10.2Hz,J 2 ＝6.0Hz,1H),3.86(td,J 1 ＝9.6Hz,J 2 ＝7.2Hz,1H),3.28-3.18(m,5H). 13 C{ 1 H}NMR(150MHz,CDCl 3 ):δ177.0,163.4(d, 1 J C-F ＝248.3Hz),155.9,143.5,141.2,135.4,131.6,130.0(d, 3 J C-F ＝8.7Hz),129.2,128.4,125.1,124.6,124.4,123.4,123.2,116.3,115.5(d, 2 J C-F ＝21.2Hz),108.2,67.6,50.9,28.8,26.5. 19 F NMR(565MHz,DMSO-d 6 ):δ-111.51--111.56(m).HRMS(ESI)m/z:[M+H] + Calcd for C 24 H 19 FN 3 O + 384.1507；Found384.1510.
3'-(4-Chlorophenyl)-1-methyl-5',6'-dihydrospiro[indoline-3,1'-pyrrolo[3,2,1-ij]quinazolin]-2-one(3qa)
1 H NMR(400MHz,CDCl 3 ):δ7.58-7.55(m,2H),7.38-7.35(m,2H),7.31(td,J 1 ＝8.0Hz,J 2 ＝1.2Hz,1H),7.25(d,J＝8.8Hz,1H),7.10-7.04(m,2H),6.89-6.85(m,2H),6.39(d,J＝7.6Hz,1H),4.04(td,J 1 ＝10.0Hz,J 2 ＝6.4Hz,1H),3.86(td,J 1 ＝10.0Hz,J 2 ＝7.2Hz,1H),3.27-3.20(m,5H). 13 C{ 1 H}NMR(100MHz,CDCl 3 ):δ176.9,155.8,143.5,141.1,135.6,135.3,133.9,129.4,129.2,128.7,128.4,125.1,124.7,124.4,123.4,123.2,116.3,108.3,67.6,50.9,28.8,26.5.HRMS(ESI)m/z:[M+H] + Calcd for C 24 H 19 ClN 3 O + 400.1211；Found400.1212.
3'-(4-Bromophenyl)-1-methyl-5',6'-dihydrospiro[indoline-3,1'-pyrrolo[3,2,1-ij]quinazolin]-2-one(3ra)
1 H NMR(400MHz,CDCl 3 ):δ7.54-7.48(m,4H),7.31(td,J 1 ＝8.0Hz,J 2 ＝1.2Hz,1H),7.24(d,J＝7.6Hz,1H),7.10-7.05(m,2H),6.89-6.85(m,2H),6.39(d,J＝7.6Hz,1H),4.04(td,J 1 ＝10.0Hz,J 2 ＝6.4Hz,1H),3.86(td,J 1 ＝10.0Hz,J 2 ＝7.2Hz,1H),3.27-3.21(m,5H). 13 C{ 1 H}NMR(100MHz,CDCl 3 ):δ176.9,155.8,143.5,141.1,135.3,134.3,131.7,129.6,129.2,128.4,125.1,124.8,124.4,123.9,123.4,123.2,116.3,108.3,67.6,50.8,28.8,26.5.HRMS(ESI)m/z:[M+H] + Calcd for C 24 H 19 BrN 3 O + 444.0706；Found 444.0713.
3'-([1,1'-Biphenyl]-4-yl)-1-methyl-5',6'-dihydrospiro[indoline-3,1'-pyrrolo[3,2,1-ij]quinazolin]-2-one(3sa)
1 H NMR(400MHz,CDCl 3 ):δ7.68(d,J＝8.4Hz,2H),7.61-7.56(m,4H),7.43(t,J＝8.0Hz,2H),7.36-7.27(m,3H),7.09-7.05(m,2H),6.89-6.84(m,2H),6.41(d,J＝7.6Hz,1H),4.10(td,J 1 ＝10.0Hz,J 2 ＝6.4Hz,1H),3.94(td,J 1 ＝10.0Hz,J 2 ＝7.6Hz,1H),3.26-3.20(m,5H). 13 C{ 1 H}NMR(100MHz,CDCl 3 ):δ177.1,156.6,143.5,142.4,141.4,140.5,135.6,134.4,129.1,128.9,128.5,128.4,127.7,127.19,127.17,125.2,124.5,124.4,123.4,123.2,116.3,108.2,67.7,51.0,28.8,26.5.HRMS(ESI)m/z:[M+H] + Calcd for C 30 H 24 N 3 O + 442.1914；Found 442.1918.
1-Methyl-3'-(m-tolyl)-5',6'-dihydrospiro[indoline-3,1'-pyrrolo[3,2,1-ij]quinazolin]-2-one(3ta)
1 H NMR(400MHz,CDCl 3 ):δ7.42-7.38(m,2H),7.31-7.25(m,3H),7.18(d,J＝7.6Hz,1H),7.09-7.04(m,2H),6.88-6.83(m,2H),6.39(d,J＝7.2Hz,1H),4.07-4.01(m,1H),3.88(td,J 1 ＝10.0Hz,J 2 ＝7.6Hz,1H),3.25-3.19(m,5H),2.34(s,3H). 13 C{ 1 H}NMR(100MHz,CDCl 3 ):δ177.1,156.9,143.5,141.3,138.3,135.6,135.4,130.2,129.1,128.6,128.4,128.2,125.2,124.8,124.4,124.3,123.3,123.2,116.3,108.2,67.6,50.9,28.7,26.5,21.4.HRMS(ESI)m/z:[M+H] + Calcd for C 25 H 22 N 3 O + 380.1757；Found 380.1758.
3'-(3-Fluorophenyl)-1-methyl-5',6'-dihydrospiro[indoline-3,1'-pyrrolo[3,2,1-ij]quinazolin]-2-one(3ua)
1 H NMR(400MHz,CDCl 3 ):δ7.41-7.29(m,4H),7.26-7.24(m,1H),7.10-7.05(m,3H),6.90-6.85(m,2H),6.39(d,J＝7.6Hz,1H),4.06(td,J 1 ＝9.6Hz,J 2 ＝6.0Hz,1H),3.88(td,J 1 ＝10.0Hz,J 2 ＝7.2Hz,1H),3.28-3.22(m,5H). 13 C{ 1 H}NMR(100MHz,CDCl 3 ):δ176.9,162.6(d, 1 J C-F ＝245.3Hz),155.6(d, 4 J C-F ＝1.8Hz),143.5,141.1,137.5(d, 3 J C-F ＝7.3Hz),135.3,130.2(d, 3 J C-F ＝7.7Hz),129.2,128.4,125.1,124.7,124.4,123.7(d, 4 J C-F ＝3.1Hz),123.4,123.2,116.6(d, 2 J C-F ＝20.9Hz),116.2,115.3(d, 2 J C-F ＝23.8Hz),108.3,67.6,50.8,28.8,26.5. 19 F NMR(376MHz,CDCl 3 ):δ-112.22--112.27(m).HRMS(ESI)m/z:[M+H] + Calcd for C 24 H 19 FN 3 O + 384.1507；Found 384.1513.
3'-(3-Chlorophenyl)-1-methyl-5',6'-dihydrospiro[indoline-3,1'-pyrrolo[3,2,1-ij]quinazolin]-2-one(3va)
1 H NMR(600MHz,CDCl 3 ):δ7.61(t,J＝1.8Hz,1H),7.50(dt,J 1 ＝7.8Hz,J 2 ＝1.2Hz,1H),7.37-7.30(m,3H),7.25(d,J＝7.8Hz,1H),7.10-7.06(m,2H),6.89-6.85(m,2H),6.39(d,J＝7.8Hz,1H),4.06(td,J 1 ＝10.2Hz,J 2 ＝6.0Hz,1H),3.87(td,J 1 ＝9.6Hz,J 2 ＝7.2Hz,1H),3.27-3.20(m,5H). 13 C{ 1 H}NMR(150MHz,CDCl 3 ):δ176.9,155.5,143.5,141.1,137.2,135.3,134.5,129.8,129.7,129.2,128.4,128.2,126.1,125.2,124.8,124.4,123.4,123.3,116.2,108.3,67.6,50.8,28.8,26.5.HRMS(ESI)m/z:[M+H] + Calcd forC 24 H 19 ClN 3 O + 400.1211；Found 400.1217.
3'-(3-Bromophenyl)-1-methyl-5',6'-dihydrospiro[indoline-3,1'-pyrrolo[3,2,1-ij]quinazolin]-2-one(3wa)
1 H NMR(600MHz,CDCl 3 ):δ7.77(t,J＝1.8Hz,1H),7.55(d,J＝7.2Hz,1H),7.52(dt,J 1 ＝7.8Hz,J 2 ＝1.2Hz,1H),7.30(td,J 1 ＝7.8Hz,J 2 ＝1.2Hz,1H),7.28-7.24(m,2H),7.10-7.06(m,2H),6.89-6.85(m,2H),6.39(d,J＝7.8Hz,1H),4.05(td,J 1 ＝10.2Hz,J 2 ＝6.0Hz,1H),3.87(td,J 1 ＝9.6Hz,J 2 ＝7.2Hz,1H),3.27-3.19(m,5H). 13 C{ 1 H}NMR(150MHz,CDCl 3 ):δ176.9,155.4,143.5,141.1,137.4,135.3,132.6,131.0,130.0,129.2,128.4,126.5,125.2,124.8,124.4,123.4,123.2,122.6,116.2,108.3,67.6,50.8,28.8,26.5.HRMS(ESI)m/z:[M+H] + Calcd for C 24 H 19 BrN 3 O + 444.0706；Found 444.0714.
3'-(2-Fluorophenyl)-1-methyl-5',6'-dihydrospiro[indoline-3,1'-pyrrolo[3,2,1-ij]quinazolin]-2-one(3xa)
1 H NMR(600MHz,CDCl 3 ):δ7.56-7.54(m,1H),7.39-7.35(m,1H),7.30-7.26(m,2H),7.17(t,J＝7.8Hz,1H),7.12-7.04(m,3H),6.88-6.84(m,2H),6.40(d,J＝7.8Hz,1H),3.92(t,J＝7.8Hz,2H),3.25-3.22(m,5H). 13 C{ 1 H}NMR(150MHz,CDCl 3 ):δ177.0,159.4(d, 1 J C-F ＝247.2Hz),152.0,143.3,140.7,135.6,131.4(d, 3 J C-F ＝7.2Hz),130.9,129.1,128.6,125.2,124.8,124.7(d, 4 J C-F ＝3.0Hz),124.5,123.4,123.2,116.1,115.8(d, 2 J C-F ＝21.8Hz),108.2,67.6,49.3(d, 5 J C-F ＝2.7Hz),28.6,26.5. 19 F NMR(376MHz,CDCl 3 ):δ-112.22--112.27(m).HRMS(ESI)m/z:[M+H] + Calcd for C 24 H 19 FN 3 O + 384.1507；Found 384.1510.1-Methyl-3'-(thiophen-2-yl)-5',6'-dihydrospiro[indoline-3,1'-pyrrolo[3,2,1-ij]quinazolin]-2-one(3ya)
1 H NMR(400MHz,CDCl 3 ):δ7.47(d,J＝2.4Hz,1H),7.34-7.28(m,2H),7.22(d,J＝7.2Hz,1H),7.08-7.02(m,3H),6.87-6.83(m,2H),6.34(d,J＝7.6Hz,1H),4.37(td,J 1 ＝10.0Hz,J 2 ＝6.4Hz,1H),4.25-4.18(m,1H),3.34-3.26(m,2H),3.22(s,3H). 13 C{ 1 H}NMR(100MHz,CDCl 3 ):δ177.1,150.3,143.4,141.2,137.8,135.6,129.0,128.3,128.2,127.9,127.0,125.2,124.6,124.3,123.3,123.1,116.4,108.2,67.6,51.1,28.9,26.5.HRMS(ESI)m/z:[M+H] + Calcd for C 22 H 18 N 3 OS + 372.1165；Found 372.1168.
1-Methyl-3'-(naphthalen-2-yl)-5',6'-dihydrospiro[indoline-3,1'-pyrrolo[3,2,1-ij]quinazoli n]-2-one(3za)
1 H NMR(600MHz,CDCl 3 ):δ8.12(s,1H),7.87-7.83(m,3H),7.71(dd,J 1 ＝8.4Hz,J 2 ＝1.2Hz,1H),7.52-7.48(m,2H),7.33-7.30(m,2H),7.11-7.08(m,2H),6.90-6.86(m,2H),6.42(d,J＝7.8Hz,1H),4.11(td,J 1 ＝10.2Hz,J 2 ＝6.0Hz,1H),3.92(td,J 1 ＝10.2Hz,J 2 ＝7.8Hz,1H),3.28-3.20(m,5H). 13 C{ 1 H}NMR(150MHz,CDCl 3 ):δ177.1,156.9,143.5,141.3,135.5,133.7,132.9,129.1,128.52,128.47,128.2,127.8,127.7,126.9,126.5,125.2,125.1,124.6,124.4,123.4,123.2,116.4,108.2,67.7,51.0,28.8,26.5.HRMS(ESI)m/z:[M+H] + Calcd for C 28 H 22 N 3 O + 416.1757；Found 416.1758.
3'-(Benzo[d][1,3]dioxol-5-yl)-1-methyl-5',6'-dihydrospiro[indoline-3,1'-pyrrolo[3,2,1-ij]quinazolin]-2-one(3#a)
1 H NMR(600MHz,CDCl 3 ):δ7.29(t,J＝7.8Hz,1H),7.24(d,J＝7.2Hz,1H),7.12(d,J＝8.4Hz,1H),7.08-7.04(m,3H),6.85(t,J＝7.2Hz,2H),6.81(d,J＝8.4Hz,1H),6.38(d,J＝7.8Hz,1H),5.95(d,J＝3.0Hz,2H),4.07(td,J 1 ＝9.6Hz,J 2 ＝6.0Hz,1H),3.93-3.88(m,1H),3.27-3.18(m,5H). 13 C{ 1 H}NMR(150MHz,CDCl 3 ):δ177.1,156.3,148.6,147.6,143.5,141.4,135.6,129.4,129.1,128.4,125.1,124.5,124.3,123.3,123.2,122.1,116.3,108.7,108.23,108.17,101.3,77.3,77.1,76.9,67.6,51.028.7,26.5.HRMS(ESI)m/z:[M+H] + Calcd for C 25 H 20 N 3 O 3 + 410.1499；Found 410.1502.
example 4
The anti-cancer activity of the compounds provided by the present invention was assessed by cell anti-proliferative activity studies using CCK8 assay.
Specifically, cells were first seeded at a density of 5000 cells per well in 96-well plates containing 100. Mu.L of medium per well at 37℃and 5% CO 2 Incubate overnight in the ambient. The next day, 100. Mu.L of test compound diluted with medium (concentration 0.03 nM-30. Mu.M) was added to each well, followed by cells at 37℃and 5% CO 2 Incubate for 72 hours in the environment. Then, 10. Mu.L of CCK8 was added to each well, and the 96-well plate was incubated at 37℃for 2 hours. Absorbance was measured at 450nm (630 nm as reference wavelength) using EnVision multilatelbel Reader (Perkinermer) and IC was calculated using GraphPad Prism 6.0 software 50 Values. All experiments were run in triplicate and repeated three times. Two cancer cells, hela and A-549, were selected as subjects, and 5-fluorouracil (5-FU) was used as a positive control for the drug.
The results of the anticancer activity of some compounds are shown in table 2 below:
TABLE 2
The results in Table 2 show that the dihydropyrrolo quinazoline spiro indolone compound 3 provided by the invention can inhibit proliferation activity of two cancer cells of Hela and A-549, and particularly has obvious antiproliferative effect on A-549 cancer cells by the compounds 3fa, 3ha, 3pa, 3va and 3#a, wherein the activity of the 3fa, 3ha, 3pa and 3#a is higher than that of a positive control drug 5-fluorouracil (5-FU), and the medicinal value of the compounds for preventing/treating/inhibiting progress deterioration of cancers, particularly lung cancer is suggested.
Finally, it should be noted that: the above embodiments are only for illustrating the technical solution of the present invention, and are not limiting; although the invention has been described in detail with reference to the foregoing embodiments, it will be understood by those of ordinary skill in the art that: the technical scheme described in the foregoing embodiments can be modified or some technical features thereof can be replaced by equivalents; such modifications and substitutions do not depart from the spirit and scope of the technical solutions of the embodiments of the present invention.

Claims (10)

1. The dihydro-pyrrolo-quinazoline spiro indolone compound is characterized by having a chemical structural general formula:
wherein R is 1 Is hydrogen, C 1-4 Alkyl, C 1-4 Alkoxy or halogen, R 1 Is a mono-or poly-substituted; r is R 2 Is phenyl, substituted phenyl, thienyl or naphthyl, and the substituent on the benzene ring of the substituted phenyl is C 1-4 Alkyl, C 1-4 Alkoxy, halogen or methylenedioxy; r is R 3 Is hydrogen, C 1-4 Alkyl, C 1-4 Alkoxy or halogen, R 3 Is a mono-or poly-substituted; r is R 4 Is hydrogen, C 1-4 Alkyl, substituted C 1-4 Alkyl, phenyl or substituted phenyl, substituted C 1-4 The substituent of the alkyl is phenyl, and the substituent on the benzene ring of the substituted phenyl is C 1-4 Alkyl or C 1-4 An alkoxy group.
2. The dihydropyrrolo quinazoline spiroindolone compound according to claim 1, wherein R 1 Is halogen; r is R 2 Is phenyl or substituted phenyl, and the substituent on the benzene ring of the substituted phenyl is halogen or methylenedioxy; r is R 3 Is hydrogen; r is R 4 Is methyl.
3. The dihydropyrrolo-quinazoline spiroindolone compound according to claim 2, wherein the compound has a chemical structural formula of
4. The use of a compound according to any one of claims 1 to 3 as an active ingredient of a medicament for the preparation of an anticancer drug.
5. The use according to claim 4, wherein the anticancer drug has the effects of preventing, treating, and inhibiting progression deterioration of lung cancer.
6. A pharmaceutical composition comprising the compound according to any one of claims 1 to 3 as an active ingredient.
7. The method for synthesizing the compound according to claim 1, which is characterized by comprising the steps of taking 1- (aryl) azomethine substituted indoline compounds and 3-diazonium-2-indolone compounds as raw materials.
8. The method of claim 7, comprising mixing 1- (aryl) azoquinazolinone 1, 3-diazonium-2-indolinone 2, catalyst, additive and solvent, heating to react to obtain dihydropyrroloquinazoline spiroindolinone 3, wherein the reaction equation is:
wherein R is 1 、R 2 、R 3 And R is 4 Is as claimed in claim 1.
9. The method of synthesis according to claim 8, wherein the additive is selected from acetic acid, pivalic acid, 1-adamantanecarboxylic acid, benzoic acid, potassium acetate, sodium acetate, silver fluoride, silver hexafluoroantimonate, silver acetate, or a mixture of two or more thereof;
the solvent is selected from 1, 2-dichloroethane, dichloromethane, acetonitrile, toluene, tetrahydrofuran or methanol;
the catalyst is dichloro bis (4-methyl isopropyl phenyl) ruthenium (II), dichloro (pentamethyl cyclopentadienyl) rhodium (III) dimer or dichloro (pentamethyl cyclopentadienyl) iridium (III) dimer.
10. The method of synthesis according to claim 8, wherein the additive is acetic acid; the solvent is dichloroethane; the catalyst is dichloro bis (4-cymene) ruthenium (II);
the molar ratio of the 1- (aryl) azomethine substituted indoline compound 1 to the 3-diazonium-2-indolinone compound 2 to the catalyst to the additive is 1:1-2:0.015-0.04:1-3.
Preferably, the feeding mole ratio of the 1- (aryl) azomethine substituted indoline compound 1 to the 3-diazonium-2-indolinone compound 2 to the catalyst to the additive is 1:1.5:0.025:2;
the reaction temperature is 60-100 ℃; the reaction time is 3-5 h; the reaction is carried out in an air or inert gas atmosphere;
preferably, the reaction temperature is 80 ℃; the reaction time is 4h; the reaction is carried out in an air atmosphere.
CN202311763847.0A 2023-12-21 2023-12-21 Dihydropyrroloquinazoline spiro indolone compound, application, pharmaceutical composition and synthetic method Pending CN117736213A (en)

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