Dihydropyrroloquinazoline spiroindolinones, uses, pharmaceutical compositions, synthetic methods

Abstract

This invention belongs to the field of chemical pharmaceuticals and synthesis technology, specifically relating to dihydropyrroloquinazoline spiroindole ketones, their applications, pharmaceutical compositions, and synthetic methods. The compounds provided by this invention exhibit inhibitory activity against the proliferation of HeLa and A-549 cancer cells, suggesting that these compounds could serve as active ingredients in anticancer drugs for cervical cancer, lung cancer, and other cancers. In particular, some compounds significantly inhibit the growth and proliferation of A-549, indicating the potential pharmaceutical value of these compounds and providing new structural units for drug screening. Furthermore, the synthetic method of this invention uses a one-pot synthesis of 1-(aryl)methylimine-substituted indoline compounds and 3-diazo-2-indole ketone compounds as starting materials. This synthetic method has advantages such as readily available and simple starting materials, easy operation, mild conditions, wide substrate applicability, and high atom economy.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of chemical drugs and synthetic technology, and particularly relates to a dihydropyrroloquinazoline spiroindolinone compound, application, pharmaceutical composition and synthetic method. BACKGROUND

[0002] Indole skeleton (including indole, indoline, indolinone and isoindolinone) is widely present in natural products, drugs, pesticides, dyes and pigments. Among a large number of indole derivatives, spiroindolinone compounds 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 for drug design.

[0003] The spiroindolinone derivative combines indolinone and heterocycle together, and it is one of the effective ways to find anticancer active molecules. In recent years, the anticancer activity of spiroindolinone has attracted widespread attention, and many compounds such as spirotryprostatins A and B, MI-888 and isopteropodine have shown excellent anticancer activity. In view of the pharmaceutical activity of spiroindolinone derivatives, people are constantly designing new chemical structures based on spiroindolinone to expand the molecular library for new drug screening.

[0004] On the other hand, in view of the importance of spiroindolinone compounds, people have developed various reliable and effective methods for preparing the compounds, but the existing methods often need to use highly functionalized substrates and harsh reaction conditions, which are not only long in steps and complicated in operation, but also produce a large amount of by-products and waste.

[0005] Therefore, it is of important theoretical significance and application value to innovate the molecular structure of spiroindolinone compounds, provide new compounds with anticancer activity, and study a synthetic method with simple raw materials, mild reaction conditions and high-efficiency and low-cost synthesis of new compounds, so as to promote the research and development of innovative drugs. SUMMARY

[0006] In order to solve the problems in the prior art, one of the purposes of the present application is to provide a dihydropyrroloquinazoline spiroindolinone compound, which has anticancer activity.

[0007] The second purpose of the present application is to provide an application of the dihydropyrroloquinazoline spiroindolinone compound in preparing an anticancer drug.

[0008] The third purpose of the present application is to provide a pharmaceutical composition for treating lung cancer, wherein the active ingredient is the dihydropyrroloquinazoline spiroindolinone compound provided by the present application.

[0009] The fourth objective of this invention is to provide a method for synthesizing dihydropyrroloquinazolinospiroindole ketones.

[0010] To achieve the above objectives, the technical solution adopted by the present invention is as follows:

[0011] A dihydropyrroloquinazolinospiroindole compound with the following general chemical formula:

[0012]

[0013] Where R 1 For hydrogen, C 1-4 Alkyl, C 1-4 Alkoxy or halogen, R 1 For mono- or multi-element substitution; R 2 It is phenyl, substituted phenyl, thiophene, or naphthyl, and the substituent on the substituted phenyl ring is C. 1-4 Alkyl, C 1-4 Alkyl, halogen, or methylenedioxy; R 3 For hydrogen, C 1-4 Alkyl, C 1-4 Alkoxy or halogen, R 3 For mono- or multi-element substitution; R 4 For hydrogen, C 1-4 Alkyl, substituted C 1-4 Alkyl, phenyl, or substituted phenyl, C-substituted 1-4 The alkyl group is substituted with a phenyl group, and the substituent on the substituted phenyl ring is C. 1-4 Alkyl or C 1-4 Alkyl group.

[0014] Optionally, the R 1 It is a halogen; R 2 It is a phenyl group or a substituted phenyl group, wherein the substituent on the substituted phenyl ring is a halogen or a methylenedioxy group; R 3 It is hydrogen; R 4 It is a methyl group.

[0015] Preferably, the chemical structural formula of the above compound is as follows:

[0016]

[0017] The above-mentioned compounds are used in the preparation of anticancer drugs, and the compounds are used as active ingredients in the drugs.

[0018] The experiments designed in this invention verified that the compounds provided by this invention have inhibitory activity against the proliferation of HeLa and A-549 cancer cells, suggesting that the compounds of this invention can serve as active ingredients in anticancer drugs for cervical cancer, lung cancer, etc. In particular, some compounds can significantly inhibit the growth and proliferation of A-549, suggesting that these compounds, as active ingredients in anticancer drugs, have preventive, therapeutic, and inhibitory effects on the progression of lung cancer.

[0019] The above-mentioned compounds are synthesized using indoline compounds substituted with 1-(aryl)methylimine and 3-diazo-2-indole ketone compounds as raw materials.

[0020] Optionally, the above synthetic method specifically includes mixing a 1-(aryl)methylimine-substituted indoline compound 1, a 3-diazo-2-indolone compound 2, a catalyst, an additive, and a solvent, and reacting at elevated temperature to obtain a dihydropyrroloquinazolinospirindolone compound 3. The reaction equation is as follows:

[0021]

[0022] 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 of them;

[0023] Optionally, the solvent is selected from 1,2-dichloroethane, dichloromethane, acetonitrile, toluene, tetrahydrofuran, or methanol;

[0024] Optionally, the catalyst is a dichlorobis(4-methylisopropylphenyl)ruthenium(II), a dichloro(pentamethylcyclopentadienyl)rhodium(III) dimer, or a dichloro(pentamethylcyclopentadienyl)iridium(III) dimer.

[0025] Preferably, the additive is acetic acid; the solvent is dichloroethane; and the catalyst is dichlorobis(4-methylisopropylphenyl)ruthenium(II).

[0026] Optionally, the molar ratio of the 1-(aryl)methylimine-substituted indoline compound 1, the 3-diazo-2-indolone compound 2, the catalyst, and the additive is 1:1~2:0.015~0.04:1~3.

[0027] Preferably, the molar ratio of the 1-(aryl)methylimine-substituted indoline compound 1, the 3-diazo-2-indolone compound 2, the catalyst, and the additive is 1:1.5:0.025:2.

[0028] Optionally, the reaction temperature is 60–100°C; the reaction time is 3–5 h; and the reaction is carried out in an air or inert gas atmosphere.

[0029] Preferably, the reaction temperature is 80°C; the reaction time is 4 hours; and the reaction is carried out in an air atmosphere.

[0030] Compared with the prior art, the present invention has the following advantages:

[0031] (1) The dihydropyrroloquinazoline spiroindole ketone compounds provided by the present invention, through screening of compounds with various substituents and verification by anti-cancer cell activity test, show that the compounds provided by the present invention have the activity of inhibiting the proliferation of HeLa and A-549 cancer cells, suggesting that the compounds of the present invention have anti-cancer activity against cervical cancer and lung cancer, especially showing significant in vitro anti-proliferation activity against human non-small cell lung cancer cells A-549, and have potential pharmaceutical value, providing a new structural unit for drug screening;

[0032] (2) The synthesis method provided by the present invention uses 1-(aryl)methylimine-substituted indoline compounds and 3-diazo-2-indolone as starting materials. Through a one-pot tandem reaction, dihydropyrrolo-quinazoline and quinazoline structures and their spirocyclic skeleton with indoline can be constructed simultaneously to synthesize dihydropyrrolo-quinazoline spiroindolone compounds. The synthesis process is simple, efficient and has high atom economy.

[0033] (3) The synthesis method provided by the present invention has a wide range of applicable substrates and good functional group tolerance; the raw materials are inexpensive and readily available, the reaction conditions are mild, and the operation is simple. Attached Figure Description

[0034] To more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the drawings used in the description of the embodiments or the prior art will be briefly introduced below. Obviously, the drawings described below are only embodiments of the present invention. For those skilled in the art, other drawings can be obtained based on the provided drawings without creative effort.

[0035] Figure 1 This is the X-ray single-crystal diffraction pattern of compound 3aa in Example 1. Detailed Implementation

[0036] The following examples further illustrate the above-described content of the present invention, but it should not be construed as limiting the scope of the subject matter of the present invention to the following examples. All technologies implemented based on the above-described content of the present invention fall within the scope of the present invention.

[0037] Example 1

[0038]

[0039] Compounds 1a, 2a, catalyst, additive, and solvent were added sequentially to a 15 mL reaction tube. The reaction tube was sealed and placed in an oil bath with stirring. After the reaction was complete, the mixture was cooled to room temperature, and the reaction was quenched with saturated sodium bicarbonate solution. The mixture was extracted three times with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and separated by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give a yellow solid product 3aa.

[0040] By changing the reaction conditions such as catalyst, additives, solvent, and gas atmosphere, a series of results were obtained, as shown in Table 1.

[0041] Table 1 Synthesis of 3aa under different conditions a

[0042]

[0043]

[0044] The optimal synthesis process conditions were determined based on the data shown in Table 2 above.

[0045] Example 2

[0046]

[0047] Add 1a (44.5 mg, 0.2 mmol), 2a (52.0 mg, 0.3 mmol), [Ru(p-cymene)Cl2]2 (3.06 mg, 0.005 mmol), acetic acid (23 μL, 0.4 mmol), and 1,2-dichloroethane (2 mL) sequentially to a 15 mL pressure-resistant tube. Seal the tube and place it in an oil bath at 80 °C for 4 h. After the reaction, cool the reaction system to room temperature, quench the reaction with saturated sodium bicarbonate solution, extract three times with ethyl acetate, combine the organic phases, dry with anhydrous sodium sulfate, filter, concentrate the filtrate, and separate by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain a yellow solid product 3aa (60.2 mg, 82%). The characterization data of this compound are as follows: 1 H NMR (400MHz, CDCl3): 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, J1 = 10.0Hz, J2 = 6.4Hz, 1H), 3.87 (td, J1 = 9.6Hz, J2 = 7.2Hz, 1H), 3.25-3.19 (m, 5H). 13 C{ 1H}NMR (100MHz, CDCl3): 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 N3O + 366.1601; Found 366.1605.

[0048] Example 3

[0049] According to the method and steps of Example 2 a,b By changing reactant 1 and reactant 2, various dihydropyrroloquinazoline spiroindole ketone compounds 3 can be synthesized, as shown in the following results:

[0050]

[0051] a Reaction conditions: 1 (0.2 mmol), 2 (0.3 mmol), [Ru(p-cymene)Cl2]2 (0.005 mmol), acetic acid (0.4 mmol), 1,2-dichloroethane (2 mL), 80 °C, 4 h, air atmosphere; b Separation yield.

[0052] The representative product characterization data are as follows:

[0053] 1,5-Dimethyl-3'-phenyl-5',6'-dihydrospiro[indoline-3,1'-pyrrolo[3,2,1-ij]quinazolin]-2-one(3ab)

[0054] 1 H NMR (400MHz, CDCl3): 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,J1=10.0Hz,J2=6.8Hz,1H),3.88(td,J1=9.6Hz,J2=7.6Hz,1H),3.27-3.16(m,5H),2.29(s,3H). 13 C{1 H}NMR(150MHz,CDCl3):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 N3O + 380.1757;Found 380.1753.

[0055] 5-Methoxy-1-methyl-3'-phenyl-5',6'-dihydrospiro[indoline-3,1'-pyrrolo[3,2,1-ij]quinazol in]-2-one(3ac)

[0056] 1 H NMR(400MHz,CDCl3):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,J1=10.0Hz,J2=6.0Hz,1H),3.87(td,J1=10.0Hz,J2=7.6Hz,1H),3.75(s,3H),3.26-3.19(m,5H). 13 C{ 1 H}NMR(150MHz,CDCl3):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 N3O2 + 396.1707;Found 396.1712.

[0057] 5-Fluoro-1-methyl-3'-phenyl-5',6'-dihydrospiro[indoline-3,1'-pyrrolo[3,2,1-ij]quinazolin]-2-one(3ad)

[0058] 1 H NMR(600MHz,CDCl3):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,J1=8.4Hz,J2=4.2Hz,1H),6.40(d,J=7.2Hz,1H),4.06(td,J1=10.2Hz,J2=6.0Hz,1H),3.88(td,J1=10.2Hz,J2=7.8Hz,1H),3.28-3.19(m,5H). 13 C{ 1 H}NMR(150MHz,CDCl3):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,CD3COCD3):δ-121.35(td,J1=8.5Hz,J2=4.0Hz).HRMS(ESI)m / z:[M+H] + Calcd for C 24 H 19 FN3O + 384.1507;Found384.1509.

[0059] 5-Chloro-1-methyl-3'-phenyl-5',6'-dihydrospiro[indoline-3,1'-pyrrolo[3,2,1-ij]quinazolin]-2-one(3ae)

[0060] 1 H NMR(400MHz,CDCl3):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,J1=10.0Hz,J2=6.8Hz,1H),3.88(td,J1=10.0Hz,J2=7.6Hz,1H),3.25-3.19(m,5H). 13 C{ 1 H}NMR(150MHz,CDCl3):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 ClN3O + 400.1211;Found400.1208.

[0061] 5-Bromo-1-methyl-3'-phenyl-5',6'-dihydrospiro[indoline-3,1'-pyrrolo[3,2,1-ij]quinazolin]-2-one(3af)

[0062] 1H NMR(400MHz,CDCl3):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,J1=10.0Hz,J2=6.8Hz,1H),3.90(td,J1=10.0Hz,J2=7.2Hz,1H),3.26-3.19(m,5H). 13 C{ 1 H}NMR(100MHz,CDCl3):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 BrN3O + 444.0706;Found 444.0703.

[0063] 5-Iodo-1-methyl-3'-phenyl-5',6'-dihydrospiro[indoline-3,1'-pyrrolo[3,2,1-ij]quinazolin]-2-one(3ag)

[0064] 1 H NMR(400MHz,CDCl3):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,J1=10.0Hz,J2=6.8Hz,1H),3.89(td,J1=10.0Hz,J2=7.2Hz,1H),3.26-3.19(m,5H). 13 C{ 1H}NMR(100MHz,CDCl3):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 IN3O + 492.0567;Found492.0575.

[0065] 6-Methoxy-1-methyl-3'-phenyl-5',6'-dihydrospiro[indoline-3,1'-pyrrolo[3,2,1-ij]quinazolin]-2-one(3ah)

[0066] 1 H NMR(400MHz,CDCl3):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,J1=8.0Hz,J2=2.0Hz,1H),6.44-6.40(m,2H),4.05(td,J1=10.0Hz,J2=6.0Hz,1H),3.88-3.82(m,4H),3.27-3.16(m,5H). 13 C{ 1 H}NMR(150MHz,CDCl3):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 N3O2 +396.1707;Found396.1714.6-Fluoro-1-methyl-3'-phenyl-5',6'-dihydrospiro[indoline-3,1'-pyrrolo[3,2,1-ij]quinazolin]-2-one(3ai)

[0067] 1 H NMR(400MHz,CDCl3):δ7.60-7.58(m,2H),7.39-7.38(m,3H),7.20(dd,J1=8.4Hz,J2=5.6Hz,1H),7.09(d,J=7.2Hz,1H),6.88(t,J=7.6Hz,1H),6.73(td,J1=10.0Hz,J2=2.0Hz,1H),6.59(dd,J1=8.8Hz,J2=2.4Hz,1H),6.38(d,J=7.6Hz,1H),4.06(td,J1=10.0Hz,J2=6.0Hz,1H),3.85(td,J1=9.6Hz,J2=7.6Hz,1H),3.26-3.17(m,5H). 13 C{ 1 H}NMR(150MHz,CDCl3):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,CDCl3):δ-111.17--111.23(m).HRMS(ESI)m / z:[M+H] + CalcdforC 24 H 19 FN3O + 384.1507;Found 384.1511.

[0068] 6-Chloro-1-methyl-3'-phenyl-5',6'-dihydrospiro[indoline-3,1'-pyrrolo[3,2,1-ij]quinazolin]-2-one(3aj)

[0069] 1 H NMR(400MHz,CDCl3):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,J1=10.0Hz,J2=6.4Hz,1H),3.89(td,J1=9.6Hz,J2=7.6Hz,1H),3.26-3.19(m,5H). 13 C{ 1 H}NMR(100MHz,CDCl3):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 ClN3O + 400.1211;Found 400.1217.

[0070] 1,7-Dimethyl-3'-phenyl-5',6'-dihydrospiro[indoline-3,1'-pyrrolo[3,2,1-ij]quinazolin]-2-one(3ak)

[0071] 1H NMR(400MHz,CDCl3):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,J1=10.0Hz,J2=6.4Hz,1H),3.86(td,J1=10.0Hz,J2=7.6Hz,1H),3.49(s,3H),3.25-3.18(m,2H),2.58(s,3H). 13 C{ 1 H}NMR(100MHz,CDCl3):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 N3O + 380.1757;Found 380.1753.

[0072] 7-Methoxy-1-methyl-3'-phenyl-5',6'-dihydrospiro[indoline-3,1'-pyrrolo[3,2,1-ij]quinazolin]-2-one(3al)

[0073] 1 H NMR(400MHz,CDCl3):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,J1=10.0Hz,J2=6.4Hz,1H),3.90-3.83(m,4H),3.48(s,3H),3.24-3.18(m,2H). 13 C{ 1H}NMR(100MHz,CDCl3):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 N3O2 + 396.1707;Found 396.1717.

[0074] 7-Fluoro-1-methyl-3'-phenyl-5',6'-dihydrospiro[indoline-3,1'-pyrrolo[3,2,1-ij]quinazolin]-2-one(3am)

[0075] 1 H NMR(400MHz,CDCl3):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,J1=10.0Hz,J2=6.4Hz,1H),3.87(td,J1=10.0Hz,J2=7.2Hz,1H),3.43(d,J=2.8Hz,3H),3.26-3.20(m,2H). 13 C{ 1 H}NMR(100MHz,CDCl3):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 JC-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,CDCl3):δ-137.02--137.05(m).HRMS(ESI)m / z:[M+H] + Calcd for C 24 H 19 FN3O + 384.1507;Found 384.1512.

[0076] 7-Chloro-1-methyl-3'-phenyl-5',6'-dihydrospiro[indoline-3,1'-pyrrolo[3,2,1-ij]quinazolin]-2-one(3an)

[0077] 1 H NMR(400MHz,CDCl3):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,J1=10.0Hz,J2=6.4Hz,1H),3.88(td,J1=9.6Hz,J2=7.2Hz,1H),3.58(s,3H),3.26-3.20(m,2H). 13 C{ 1 H}NMR(150MHz,CDCl3):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] + CalcdforC 24 H 19 ClN3O + 400.1211;Found 400.1223.

[0078] 7-Bromo-1-methyl-3'-phenyl-5',6'-dihydrospiro[indoline-3,1'-pyrrolo[3,2,1-ij]quinazolin]-2-one(3ao)

[0079] 1 H NMR(600MHz,CDCl3):δ7.60-7.58(m,2H),7.40-7.38(m,4H),7.18(dd,J1=7.2Hz,J2=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,J1=10.2Hz,J2=6.0Hz,1H),3.88(td,J1=9.6Hz,J2=7.2Hz,1H),3.60(s,3H),3.26-3.20(m,2H). 13 C{ 1 H}NMR(150MHz,CDCl3):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 BrN3O + 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)

[0080] 1H NMR(400MHz,CDCl3):δ7.62-7.60(m,2H),7.39-7.36(m,3H),7.07(dd,J1=7.6Hz,J2=0.8Hz,1H),6.90-6.85(m,2H),6.82(s,1H),6.42(d,J=8.0Hz,1H),4.02(td,J1=10.0Hz,J2=6.4Hz,1H),3.88(td,J1=9.6Hz,J2=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,CDCl3):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 forC 26 H 24 N3O + 394.1914;Found 394.1916.

[0081] 4-Chloro-1-methyl-3'-phenyl-5',6'-dihydrospiro[indoline-3,1'-pyrrolo[3,2,1-ij]quinazolin]-2-one(3aq)

[0082] 1 H NMR(400MHz,CDCl3):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,J1=10.0Hz,J2=6.8Hz,1H),3.91(td,J1=9.2Hz,J2=7.2Hz,1H),3.25-3.18(m,5H). 13 C{ 1H}NMR(100MHz,CDCl3):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 ClN3O + 400.1211;Found 400.1216.

[0083] 4-Bromo-1-methyl-3'-phenyl-5',6'-dihydrospiro[indoline-3,1'-pyrrolo[3,2,1-ij]quinazolin]-2-one(3ar)

[0084] 1 H NMR(400MHz,CDCl3):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,J1=10.0Hz,J2=6.0Hz,1H),3.92-3.85(m,1H),3.26-3.17(m,5H). 13 C{ 1 H}NMR(100MHz,CDCl3):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 BrN3O + 444.0706;Found 444.0702.

[0085] 1-Ethyl-3'-phenyl-5',6'-dihydrospiro[indoline-3,1'-pyrrolo[3,2,1-ij]quinazolin]-2-one(3as)

[0086] 1 H NMR(400MHz,CDCl3):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,J1=9.6,Hz,J2=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,CDCl3):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 N3O + 380.1757;Found 380.1755.

[0087] 1-Benzyl-3'-phenyl-5',6'-dihydrospiro[indoline-3,1'-pyrrolo[3,2,1-ij]quinazolin]-2-one(3at)

[0088] 1H NMR(400MHz,CDCl3):δ7.64-7.62(m,2H),7.40-7.39(m,3H),7.34-7.22(m,6H),7.16(td,J1=8.0Hz,J2=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,J1=10.0,Hz,J2=6.4Hz,1H),3.88(td,J1=10.0,Hz,J2=7.6Hz,1H),3.26-3.20(m,2H). 13 C{ 1 H}NMR(100MHz,CDCl3):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] + Calcdfor C 30 H 24 N3O + 442.1914;Found 442.1919.

[0089] 1-(4-Methylbenzyl)-3'-phenyl-5',6'-dihydrospiro[indoline-3,1'-pyrrolo[3,2,1-ij]quinazolin]-2-one(3au)

[0090] 1H NMR(400MHz,CDCl3):δ7.64-7.62(m,2H),7.40-7.39(m,3H),7.28-7.21(m,3H),7.16(td,J1=7.6Hz,J2=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,J1=10.0Hz,J2=6.0Hz,1H),3.88(td,J1=10.0Hz,J2=7.6Hz,1H),3.27-3.20(m,2H),2.30(s,3H). 13 C{ 1 H}NMR(100MHz,CDCl3):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 N3O + 456.2070;Found 456.2078.

[0091] 1-Phenethyl-3'-phenyl-5',6'-dihydrospiro[indoline-3,1'-pyrrolo[3,2,1-ij]quinazolin]-2-one(3av)

[0092] 1H NMR(600MHz,CDCl3):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,J1=10.2Hz,J2=6.0Hz,1H),3.86(td,J1=9.6Hz,J2=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,CDCl3):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 N3O + 456.2070;Found456.2076.

[0093] 1,3'-Diphenyl-5',6'-dihydrospiro[indoline-3,1'-pyrrolo[3,2,1-ij]quinazolin]-2-one(3aw)

[0094] 1 H NMR(400MHz,CDCl3):δ7.64-7.61(m,2H),7.49-7.48(m,4H),7.41-7.34(m,5H),7.22(td,J1=8.0Hz,J2=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,J1=10.0Hz,J2=6.8Hz,1H),3.89(td,J1=9.6Hz,J2=7.6Hz,1H),3.26-3.20(m,2H). 13 C{ 1H}NMR(100MHz,CDCl3):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 N3O + 428.1757;Found 428.1758.

[0095] 3'-Phenyl-5',6'-dihydrospiro[indoline-3,1'-pyrrolo[3,2,1-ij]quinazolin]-2-one(3ax)

[0096] 1 H NMR(400MHz,CDCl3):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,J1=10.0Hz,J2=6.0Hz,1H),3.88(td,J1=9.6Hz,J2=7.6Hz,1H),3.29-3.15(m,2H). 13 C{ 1 H}NMR(100MHz,CDCl3):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 N3O + 352.1444;Found352.1443.

[0097] 1,8'-Dimethyl-3'-phenyl-5',6'-dihydrospiro[indoline-3,1'-pyrrolo[3,2,1-ij]quinazolin]-2-one(3ba)

[0098] 1 H NMR(400MHz,CDCl3):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,J1=9.6Hz,J2=6.4Hz,1H),3.88(td,J1=9.6Hz,J2=7.2Hz,1H),3.23-3.15(m,5H),2.17(s,3H). 13 C{ 1 H}NMR(100MHz,CDCl3):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 N3O + 380.1757;Found 380.1759.

[0099] 8'-Methoxy-1-methyl-3'-phenyl-5',6'-dihydrospiro[indoline-3,1'-pyrrolo[3,2,1-ij]quinazolin]-2-one(3ca)

[0100] 1H NMR(600MHz,CDCl3):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,J1=10.2Hz,J2=6.0Hz,1H),3.88(td,J1=9.6Hz,J2=7.2Hz,1H),3.63(s,3H),3.24-3.17(m,5H). 13 C{ 1 H}NMR(150MHz,CDCl3):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 N3O2 + 396.1707;Found 396.1713.

[0101] 8'-Fluoro-1-methyl-3'-phenyl-5',6'-dihydrospiro[indoline-3,1'-pyrrolo[3,2,1-ij]quinazolin]-2-one(3da)

[0102] 1 H NMR(400MHz,CDCl3):δ7.61-7.58(m,2H),7.39-7.37(m,3H),7.31(td,J1=7.6Hz,J2=1.2Hz,1H),7.26-7.24(m,1H),7.07(td,J1=7.6Hz,J2=0.8Hz,1H),6.86(d,J=8.0Hz,1H),6.82-6.79(m,1H),6.12(dd,J1=9.2Hz,J2=2.0Hz,1H),4.06(td,J1=10.0Hz,J2=6.4Hz,1H),3.88(td,J1=10.0Hz,J2=7.2Hz,1H),3.23-3.16(m,5H). 13 C{ 1H}NMR(100MHz,CDCl3):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,CDCl3):δ-118.34(t,J=8.6Hz).HRMS(ESI)m / z:[M+H] + Calcd for C 24 H 19 FN3O + 384.1507;Found 384.1510.

[0103] 8'-Chloro-1-methyl-3'-phenyl-5',6'-dihydrospiro[indoline-3,1'-pyrrolo[3,2,1-ij]quinazolin]-2-one(3ea)

[0104] 1 H NMR(400MHz,CDCl3):δ7.60-7.58(m,2H),7.40-7.38(m,3H),7.32(td,J1=8.0Hz,J2=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,J1=10.0Hz,J2=6.0Hz,1H),3.88(td,J1=9.6Hz,J2=7.2Hz,1H),3.24-3.17(m,5H). 13 C{ 1H}NMR(100MHz,CDCl3):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 ClN3O + 400.1211;Found400.1215.

[0105] 8'-Bromo-1-methyl-3'-phenyl-5',6'-dihydrospiro[indoline-3,1'-pyrrolo[3,2,1-ij]quinazolin]-2-one(3fa)

[0106] 1 H NMR(600MHz,CDCl3):δ7.59-7.58(m,2H),7.39-7.38(m,3H),7.32(td,J1=7.8Hz,J2=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,J1=9.6Hz,J2=6.0Hz,1H),3.87(td,J1=10.2Hz,J2=7.8Hz,1H),3.25-3.18(m,5H). 13 C{ 1 H}NMR(150MHz,CDCl3):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 BrN3O + 444.0706;Found 444.0700.

[0107] 7'-Methoxy-1-methyl-3'-phenyl-5',6'-dihydrospiro[indoline-3,1'-pyrrolo[3,2,1-ij]quinazolin]-2-one(3ga)

[0108] 1 H NMR(400MHz,CDCl3):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,J1=9.6Hz,J2=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,CDCl3):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 N3O2 + 396.1707;Found 396.1714.

[0109] 7'-Chloro-1-methyl-3'-phenyl-5',6'-dihydrospiro[indoline-3,1'-pyrrolo[3,2,1-ij]quinazolin]-2-one(3ha)

[0110] 1H NMR(400MHz,CDCl3):δ7.60-7.58(m,2H),7.41-7.38(m,3H),7.30(td,J1=7.6Hz,J2=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,J1=9.6Hz,J2=6.8Hz,1H),3.91(td,J1=9.6Hz,J2=7.6Hz,1H),3.27-3.21(m,5H). 13 C{ 1 H}NMR(100MHz,CDCl3):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 ClN3O + 400.1211;Found400.1214.

[0111] 7'-Bromo-1-methyl-3'-phenyl-5',6'-dihydrospiro[indoline-3,1'-pyrrolo[3,2,1-ij]quinazolin]-2-one(3ia)

[0112] 1 H NMR(400MHz,CDCl3):δ7.60-7.57(m,2H),7.40-7.38(m,3H),7.31(td,J1=7.2Hz,J2=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,J1=10.0Hz,J2=6.8Hz,1H),3.91(td,J1=10.0Hz,J2=7.6Hz,1H),3.25-3.18(m,5H). 13 C{ 1H}NMR(100MHz,CDCl3):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 BrN3O + 444.0706;Found 444.0718.

[0113] 9'-Methoxy-1-methyl-3'-phenyl-5',6'-dihydrospiro[indoline-3,1'-pyrrolo[3,2,1-ij]quinazolin]-2-one(3ja)

[0114] 1 H NMR(400MHz,CDCl3):δ7.63-7.60(m,2H),7.41-7.39(m,3H),7.26(td,J1=7.6Hz,J2=1.2Hz,1H),7.20-7.18(m,1H),7.05(d,J=8.0Hz,1H),7.01(td,J1=7.6Hz,J2=0.4Hz,1H),6.84(d,J=8.0Hz,1H),6.41(d,J=8.4Hz,1H),4.15(td,J1=10.0Hz,J2=5.2Hz,1H),3.79(td,J1=10.0Hz,J2=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,CDCl3):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 N3O2 +396.1707;Found396.1704.

[0115] 9'-Fluoro-1-methyl-3'-phenyl-5',6'-dihydrospiro[indoline-3,1'-pyrrolo[3,2,1-ij]quinazolin]-2-one(3ka)

[0116] 1 H NMR(600MHz,CDCl3):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,J1=10.2Hz,J2=8.4Hz,1H),4.10(td,J1=9.6Hz,J2=5.4Hz,1H),3.87(td,J1=10.2Hz,J2=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,CDCl3):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,CDCl3):δ-119.29--119.33(m).HRMS(ESI)m / z:[M+H] + Calcd for C 24 H 19 FN3O +384.1507;Found 384.1511.

[0117] 8',9'-Difluoro-1-methyl-3'-phenyl-5',6'-dihydrospiro[indoline-3,1'-pyrrolo[3,2,1-ij]quinazolin]-2-one(3la)

[0118] 1 H NMR(600MHz,CDCl3):δ7.58-7.56(m,2H),7.39-7.37(m,3H),7.29(td,J1=7.8Hz,J2=1.2Hz,1H),7.21-7.20(m,1H),7.03(td,J1=7.8Hz,J2=1.2Hz,1H),6.91(dd,J1=9.0Hz,J2=7.2Hz,1H),6.85(d,J=7.8Hz,1H),4.08(td,J1=10.2Hz,J2=5.4Hz,1H),3.87(td,J1=10.2Hz,J2=7.8Hz,1H),3.27(s,3H),3.19-3.12(m,2H). 13 C{ 1 H}NMR(100MHz,CDCl3):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. 19F NMR(376MHz,CDCl3):δ-142.40(dd,J1=20.3Hz,J2=7.1Hz),-142.69(dd,J1=19.9Hz,J2=9.8Hz).HRMS(ESI)m / z:[M+H] + Calcd for C 24 H 18 F2N3O + 402.1412;Found 402.1414.

[0119] 1-Methyl-3'-(p-tolyl)-5',6'-dihydrospiro[indoline-3,1'-pyrrolo[3,2,1-ij]quinazolin]-2-one(3ma)

[0120] 1 H NMR(600MHz,CDCl3):δ7.49(d,J=7.8Hz,2H),7.29(td,J1=7.8Hz,J2=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,J1=10.2Hz,J2=6.0Hz,1H),3.88(td,J1=10.2Hz,J2=7.2Hz,1H),3.24-3.18(m,5H),2.35(s,3H). 13 C{ 1 H}NMR(150MHz,CDCl3):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 N3O + 380.1757;Found 380.1768.

[0121] 3'-(4-(Tert-butyl)phenyl)-1-methyl-5',6'-dihydrospiro[indoline-3,1'-pyrrolo[3,2,1-ij]quinazolin]-2-one(3na)

[0122] 1 H NMR(600MHz,CDCl3):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,J1=10.2Hz,J2=6.0Hz,1H),3.92(td,J1=10.2Hz,J2=7.2Hz,1H),3.26-3.18(m,5H),1.29(s,9H). 13 C{ 1 H}NMR(150MHz,CDCl3):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 N3O + 422.2227;Found 422.2230.

[0123] 1-Methyl-3'-(4-(methylthio)phenyl)-5',6'-dihydrospiro[indoline-3,1'-pyrrolo[3,2,1-ij]quinazolin]-2-one(3oa)

[0124] 1H NMR(600MHz,CDCl3):δ7.53(d,J=8.4Hz,2H),7.29(td,J1=7.8Hz,J2=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,J1=10.2Hz,J2=6.0Hz,1H),3.89(td,J1=10.2Hz,J2=7.2Hz,1H),3.27-3.18(m,5H),2.46(s,3H). 13 C{ 1 H}NMR(100MHz,CDCl3):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 N3OS + 412.1478;Found412.1480.

[0125] 3'-(4-Fluorophenyl)-1-methyl-5',6'-dihydrospiro[indoline-3,1'-pyrrolo[3,2,1-ij]quinazolin]-2-one(3pa)

[0126] 1 H NMR(600MHz,CDCl3):δ7.62-7.60(m,2H),7.30(td,J1=7.8Hz,J2=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,J1=10.2Hz,J2=6.0Hz,1H),3.86(td,J1=9.6Hz,J2=7.2Hz,1H),3.28-3.18(m,5H). 13 C{ 1 H}NMR(150MHz,CDCl3):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-d6):δ-111.51--111.56(m).HRMS(ESI)m / z:[M+H] + Calcd for C 24 H 19 FN3O + 384.1507;Found384.1510.

[0127] 3'-(4-Chlorophenyl)-1-methyl-5',6'-dihydrospiro[indoline-3,1'-pyrrolo[3,2,1-ij]quinazolin]-2-one(3qa)

[0128] 1 H NMR(400MHz,CDCl3):δ7.58-7.55(m,2H),7.38-7.35(m,2H),7.31(td,J1=8.0Hz,J2=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,J1=10.0Hz,J2=6.4Hz,1H),3.86(td,J1=10.0Hz,J2=7.2Hz,1H),3.27-3.20(m,5H). 13 C{ 1 H}NMR(100MHz,CDCl3):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 H19 ClN3O + 400.1211;Found400.1212.

[0129] 3'-(4-Bromophenyl)-1-methyl-5',6'-dihydrospiro[indoline-3,1'-pyrrolo[3,2,1-ij]quinazolin]-2-one(3ra)

[0130] 1 H NMR(400MHz,CDCl3):δ7.54-7.48(m,4H),7.31(td,J1=8.0Hz,J2=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,J1=10.0Hz,J2=6.4Hz,1H),3.86(td,J1=10.0Hz,J2=7.2Hz,1H),3.27-3.21(m,5H). 13 C{ 1 H}NMR(100MHz,CDCl3):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 BrN3O + 444.0706;Found 444.0713.

[0131] 3'-([1,1'-Biphenyl]-4-yl)-1-methyl-5',6'-dihydrospiro[indoline-3,1'-pyrrolo[3,2,1-ij]quinazolin]-2-one(3sa)

[0132] 1H NMR(400MHz,CDCl3):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,J1=10.0Hz,J2=6.4Hz,1H),3.94(td,J1=10.0Hz,J2=7.6Hz,1H),3.26-3.20(m,5H). 13 C{ 1 H}NMR(100MHz,CDCl3):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 forC 30 H 24 N3O + 442.1914;Found 442.1918.

[0133] 1-Methyl-3'-(m-tolyl)-5',6'-dihydrospiro[indoline-3,1'-pyrrolo[3,2,1-ij]quinazolin]-2-one(3ta)

[0134] 1 H NMR(400MHz,CDCl3):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,J1=10.0Hz,J2=7.6Hz,1H),3.25-3.19(m,5H),2.34(s,3H). 13 C{ 1H}NMR(100MHz,CDCl3):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 N3O + 380.1757;Found 380.1758.

[0135] 3'-(3-Fluorophenyl)-1-methyl-5',6'-dihydrospiro[indoline-3,1'-pyrrolo[3,2,1-ij]quinazolin]-2-one(3ua)

[0136] 1 H NMR(400MHz,CDCl3):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,J1=9.6Hz,J2=6.0Hz,1H),3.88(td,J1=10.0Hz,J2=7.2Hz,1H),3.28-3.22(m,5H). 13 C{ 1 H}NMR(100MHz,CDCl3):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,CDCl3):δ-112.22--112.27(m).HRMS(ESI)m / z:[M+H] + Calcd forC 24 H 19 FN3O + 384.1507;Found 384.1513.

[0137] 3'-(3-Chlorophenyl)-1-methyl-5',6'-dihydrospiro[indoline-3,1'-pyrrolo[3,2,1-ij]quinazolin]-2-one(3va)

[0138] 1 H NMR(600MHz,CDCl3):δ7.61(t,J=1.8Hz,1H),7.50(dt,J1=7.8Hz,J2=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,J1=10.2Hz,J2=6.0Hz,1H),3.87(td,J1=9.6Hz,J2=7.2Hz,1H),3.27-3.20(m,5H). 13 C{ 1 H}NMR(150MHz,CDCl3):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 ClN3O + 400.1211;Found 400.1217.

[0139] 3'-(3-Bromophenyl)-1-methyl-5',6'-dihydrospiro[indoline-3,1'-pyrrolo[3,2,1-ij]quinazolin]-2-one(3wa)

[0140] 1 H NMR(600MHz,CDCl3):δ7.77(t,J=1.8Hz,1H),7.55(d,J=7.2Hz,1H),7.52(dt,J1=7.8Hz,J2=1.2Hz,1H),7.30(td,J1=7.8Hz,J2=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,J1=10.2Hz,J2=6.0Hz,1H),3.87(td,J1=9.6Hz,J2=7.2Hz,1H),3.27-3.19(m,5H). 13 C{ 1 H}NMR(150MHz,CDCl3):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 BrN3O + 444.0706;Found 444.0714.

[0141] 3'-(2-Fluorophenyl)-1-methyl-5',6'-dihydrospiro[indoline-3,1'-pyrrolo[3,2,1-ij]quinazolin]-2-one(3xa)

[0142] 1H NMR(600MHz,CDCl3):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,CDCl3):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,CDCl3):δ-112.22--112.27(m).HRMS(ESI)m / z:[M+H] + Calcd for C 24 H 19 FN3O + 384.1507;Found384.1510.1-Methyl-3'-(thiophen-2-yl)-5',6'-dihydrospiro[indoline-3,1'-pyrrolo[3,2,1-ij]quinazolin]-2-one(3ya)

[0143] 1H NMR(400MHz,CDCl3):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,J1=10.0Hz,J2=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,CDCl3):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 N3OS + 372.1165;Found 372.1168.

[0144] 1-Methyl-3'-(naphthalen-2-yl)-5',6'-dihydrospiro[indoline-3,1'-pyrrolo[3,2,1-ij]quinazoli n]-2-one(3za)

[0145] 1 H NMR(600MHz,CDCl3):δ8.12(s,1H),7.87-7.83(m,3H),7.71(dd,J1=8.4Hz,J2=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,J1=10.2Hz,J2=6.0Hz,1H),3.92(td,J1=10.2Hz,J2=7.8Hz,1H),3.28-3.20(m,5H). 13 C{ 1H}NMR(150MHz,CDCl3):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 N3O + 416.1757;Found 416.1758.

[0146] 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)

[0147] 1 H NMR(600MHz,CDCl3):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,J1=9.6Hz,J2=6.0Hz,1H),3.93-3.88(m,1H),3.27-3.18(m,5H). 13 C{ 1 H}NMR(150MHz,CDCl3):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 N3O3 +410.1499; Found 410.1502.

[0148] Example 4

[0149] The anticancer activity of the compounds provided in this invention was evaluated using CCK8 analysis through cell antiproliferative activity studies.

[0150] The specific method is as follows: First, cells were seeded at a density of 5000 cells per well into 96-well plates containing 100 μL of culture medium per well and incubated overnight at 37°C and 5% CO2. The next day, 100 μL of the test compound diluted with culture medium (concentration 0.03 nM–30 μM) was added to each well, and the cells were then incubated at 37°C and 5% CO2 for 72 hours. Then, 10 μL of CCK8 was added to each well, and the 96-well plate was incubated at 37°C for 2 hours. The absorbance was measured at 450 nm using an EnVision multilatelbel Reader (PerkinErmer) (with 630 nm as the reference wavelength), and the IC50 was calculated using GraphPad Prism 6.0 software. 50 Values. All experiments were performed with three parallel samples and repeated three times. Hela and A-549 cancer cells were selected as the research subjects, and 5-fluorouracil (5-FU) was used as a positive control.

[0151] The results of the anticancer activity of some compounds are shown in Table 2 below:

[0152] Table 2

[0153]

[0154]

[0155] The results in Table 2 show that the dihydropyrroloquinazoline spiroindole ketone compound 3 provided by this invention can inhibit the proliferation activity of HeLa and A-549 cancer cells. In particular, compounds 3fa, 3ha, 3pa, 3va, and 3#a have significant anti-proliferative effects on A-549 cancer cells. Among them, 3fa, 3ha, 3pa, and 3#a have higher activity than the positive control drug 5-fluorouracil (5-FU), suggesting the medicinal value of this type of compound in the prevention, treatment, and inhibition of the progression of cancer, especially lung cancer.

[0156] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, and not to limit them; although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand that modifications can still be made to the technical solutions described in the foregoing embodiments, or equivalent substitutions can be made to some of the technical features; and these modifications or substitutions do not cause the essence of the corresponding technical solutions to deviate from the spirit and scope of the technical solutions of the embodiments of the present invention.

Claims

1. A dihydropyrroloquinazoline spiroindolinone compound, characterized in that, The chemical structural formula is ； wherein R 1 is mono- or poly- substituted, R 1 is hydrogen, methyl, methoxy or halogen; R 2 is phenyl or substituted phenyl, the substituents on the phenyl ring of the substituted phenyl being halogen or methylenedioxy; R 3 is mono- or poly- substituted, R 3 is hydrogen, methyl, methoxy or halogen; R 4 is hydrogen, methyl.

2. The dihydropyrroloquinazoline spiroindolone compound of claim 1, wherein The chemical structural formula is or or or or .

3. Use of a compound according to any one of claims 1 or 2 for the preparation of an anti-cancer medicament, characterized in that, The compound is used as an effective pharmaceutical ingredient; the anticancer drug has the effects of preventing, treating and inhibiting the progression of cervical cancer and / or lung cancer.

4. A pharmaceutical composition, characterized by, The effective ingredient is the compound according to any one of claims 1 or 2.

5. A method of synthesizing a compound of claim 1, wherein, The 1-(aryl)methyl imine substituted indoline compound 1, 3-diazo-2-indolone compound 2, a catalyst, an additive and a solvent are mixed, and a dihydropyrroloquinazoline spiroindolone compound 3 is prepared by heating reaction, and the reaction equation is as follows: ； wherein R 1 , R 2 , R 3 and R 4 are as defined in claim 1 ; The additive is selected from acetic acid, tert-butyl acid, 1-adamantane acid, benzoic acid, potassium acetate, sodium acetate, silver fluoride, silver hexafluoroantimonate, silver acetate or two or more mixtures thereof; The solvent is selected from 1,2-dichloroethane, dichloromethane, acetonitrile, toluene, tetrahydrofuran or methanol; The catalyst is dichlorobis(4-methylisopropylphenyl)ruthenium(II), dichloro(pentamethylcyclopentadienyl)rhodium(III) dimer or dichloro(pentamethylcyclopentadienyl)iridium(III) dimer.

6. The method of synthesis of claim 5, wherein, The additive is acetic acid; the solvent is 1,2-dichloroethane; and the catalyst is dichlorobis(4-methylisopropylphenyl)ruthenium(II). The feeding molar ratio of the 1-(aryl)methyl imine substituted indoline compound 1, 3-diazo-2-indolone compound 2, the catalyst and the additive is 1: 1~2: 0.015~0.04: 1~3; The reaction temperature is 60~100 ℃; the reaction time is 3~5h; and the reaction is carried out in air or inert gas atmosphere; 7. The method of synthesis of claim 6, wherein, The feeding molar ratio of the 1-(aryl)methyl imine substituted indoline compound 1, 3-diazo-2-indolone compound 2, the catalyst and the additive is 1: 1.5: 0.025:

2.

8. The method of synthesis of claim 7, wherein, The reaction temperature is 80 ℃; the reaction time is 4h; and the reaction is carried out in air atmosphere.

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