Indolone derivative and application

Abstract

The invention relates to an indolone derivative and application thereof. In-vitro kinase and tumor cell inhibitory activity screening of the compounds shows that when three compounds 3-17a, 3-17d and 3-17k are at 10nM, the inhibition rate on AuroraB kinase exceeds 80%; one compound 3-19 has inhibitory activity on HELA human cervical cancer cells, and IC50 is 5.31 [mu] M; 10 compounds 3 to 17b, 3 to 17c, 3 to 17e, 3 to 17f, 3 to 17k, 3 to 17h, 3 to 17i, 3 to 17j, 3 to 19 and 3 to 17m have inhibitory activity on HGC27 human gastric cancer cells, and the IC50 (half maximal inhibitory concentration) is 4.044 mu M, 14.82 mu M, 2.821 mu M, 6.109 mu M, 2.052 mu M, 11.71 mu M, 4.52 mu M, 14.65 mu M, 4.38 mu M and 22.56 mu M respectively; 7 compounds 3 to 17b, 3 to 17e, 3 to 17f, 3 to 17k, 3 to 17j, 3 to 19 and 3 to 17m have inhibitory activity on HT-29 human colon cancer cells, and the IC50 (half maximal inhibitory concentration) is 2.696 mu M, 2.512 mu M, 18.27 mu M, 2.066 mu M, 6.05 mu M, 7.32 mu M and 20.87 mu M respectively; two compounds 3-17j and 3-19 have inhibitory activity on MCF7 human breast cancer cells, and the IC50 of the compounds 3-17j and 3-19 is 7.80 mu M and 8.96 mu M respectively.

Description

TECHNICAL FIELD

[0001] The present application relates to an indolone derivative and use. BACKGROUND

[0002] Cancer is a complex multi-gene disease that seriously affects human physical and mental health. In 2020, there were more than 19.3 million new cases and nearly 10 million deaths. At present, chemotherapy is still one of the most important treatments for cancer, but due to the continuous mutation and drug resistance of cancer cells, the efficacy of most chemotherapy drugs is getting worse and worse, so it is extremely urgent to develop new cancer treatment drugs.

[0003] Aurora kinase is a group of serine / threonine kinases that are essential for cell mitosis, including Aurora A, B and C three subtypes. In normal physiological conditions, Aurora B is widely expressed as a chromosome protein in rapidly proliferating tissues and cells, responsible for cell cycle checkpoint regulation and accurate cell division. However, in pathological conditions, Aurora B is overexpressed in various tumors, especially liver cancer, colon cancer, cervical cancer, breast cancer and prostate tumors. At present, at least 18 Aurora B inhibitors are in preclinical or clinical studies. Studies have shown that targeting Aurora B is beneficial to overcome drug resistance of EGFR-targeted drugs. As a new anti-tumor target, Aurora B has been relatively less studied, and there have been few reports on aurone Aurora B inhibitors.

[0004] Aurones are a subclass of flavonoids, which have simple chemical structures and a wide range of pharmacological activities. Literature shows that aurones have antibacterial, anti-inflammatory, antioxidant, antitumor, antiparasitic, anti-HCV, anti-Alzheimer's disease, and anti-diabetic activities. In recent years, some studies have found that aurones have certain cytotoxic effects on different cancer cell lines, and have also revealed their related mechanisms. Although the content of aurones in nature is relatively low, the discovery of lead compounds based on the antitumor activity of aurones has made some progress.

[0005] In the early stage, our research group screened aurone compounds for protein kinase targets, and the results showed that the aurone skeleton had good inhibitory activity on Aurora B kinase. On this basis, through comprehensive analysis of domestic and foreign literature and patents, our research group used aurone as a template and adopted a skeleton transition strategy to obtain more optimal indolone drugs. With the help of pharmacophore matching and other computer-aided drug molecule design methods, 15 indolone derivatives were synthesized, and their inhibitory activities on Aurora B kinase and four tumor cells were preliminarily studied, in order to discover new anti-tumor target drugs with high efficiency, low toxicity and good drugability.

[0006] REFERENCES

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[14] Zheng, X.; Wang, H.; Liu, Y.-M.; Yao, X.; Tong, M.; Wang, Y.-H.; Liao, D.-F., Synthesis, Characterization, and Anticancer Effect of Trifluoromethylated Aurone Derivatives. J Heterocyclic Chem, 2015, 52 (1), 296-301.

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[15] Xie, F.; Zhu, H.; Zhang, H.; Lang, Q.; Tang, L.; Huang, Q.; Yu, L., In vitro and in vivo characterization of a benzofuran derivative, a potential anticancer agent, as a novel Aurora B kinase inhibitor. Eur J Med Chem, 2015, 89, 310-9.

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[16] Velagapudi, U. K.; Langelier, M. F.; Delgado-Martin, C.; Diolaiti, M. E.; Bakker, S.; Ashworth, A.; Patel, B. A.; Shao, X.; Pascal, J. M.; Talele, T. T., Design and Synthesis of Poly(ADP-ribose)Polymerase Inhibitors: Impact of Adenosine Pocket-Binding Motif Appendage to the 3-Oxo-2,3-dihydrobenzofuran-7-carboxamide on Potency and Selectivity. J Med Chem, 2019, 62 (11), 5330-5357.

[0023]

[17] Uesawa, Y.; Sakagami, H.; Ikezoe, N.; Takao, K.; Kagaya, H.; Sugita, Y., Quantitative Structure-Cytotoxicity Relationship of Aurones. Anticancer Res, 2017, 37 (11), 6169-6176. SUMMARY

[0024] The present application aims to provide a kind of indolinone derivative and use, and the screening of the compound by in vitro kinase and tumor cell inhibition activity shows: there are three compounds 3-17a, 3-17d, 3-17k at 10nM, the inhibition rate of Aurora B kinase is more than 80%;There is 1 compound 3-19, and HELA human cervical cancer cell has inhibitory activity, IC 50 5.31 μM;There are 10 compounds 3-17b, 3-17c, 3-17e, 3-17f, 3-17k, 3-17h, 3-17i, 3-17j, 3-19, 3-17m, and HGC27 human gastric cancer cells have inhibitory activity, IC 50 4.044, 14.82, 2.821, 6.109, 2.052, 11.71, 4.52, 14.65, 4.38, 22.56 μM respectively;There are 7 compounds 3-17b, 3-17e, 3-17f, 3-17k, 3-17j, 3-19, 3-17m, and HT-29 human colon cancer cells have inhibitory activity, IC 50 2.696, 2.512, 18.27, 2.066, 6.05, 7.32, 20.87 μM respectively;There are 2 compounds 3-17j, 3-19, and MCF7 human breast cancer cells have inhibitory activity, IC 50 7.80, 8.96 μM respectively.

[0025] The indolinone derivative of the present application, the structural formula of the derivative is:

[0026]

[0027] Among them:

[0028] Compound 3-17a is (Z)-5-((6-(3-(3-chlorophenyl)urea)-2-indolinone-3-yl)methyl)-2,4-dimethyl-N-(2-(pyrrolidin-1-yl)ethyl)-1H-pyrrole-3-formamide;

[0029] Compound 3-17b is (Z)-5-((6-(3-(3-trifluoromethylphenyl)ureido)-2- indolinon-3-enyl)methyl)-2,4-dimethyl-N-(2-(pyrrolidin-l-yl)ethyl)-lH-pyrrole-3- carboxamide;

[0030] Compound 3-17c is (Z)-5-((6-(3-(3-cyanophenyl)ureido)-2-indolinon-3- enyl)methyl)-2,4-dimethyl-N-(2-(pyrrolidin-l-yl)ethyl)-lH-pyrrole-3-carboxamide;

[0031] Compound 3-17d is (Z)-5-((6-(3-(3-methylphenyl)ureido)-2-indolinon-3- enyl)methyl)-2,4-dimethyl-N-(2-(pyrrolidin-l-yl)ethyl)-lH-pyrrole-3-carboxamide;

[0032] Compound 3-17e is (Z)-5-((6-(3-(3-chlorophenyl)ureido)-2-indolinon-3- enyl)methyl)-N-(2-(diethylamino)ethyl)-2,4-dimethyl-lH-pyrrole-3-carboxamide;

[0033] Compound 3-17f is (Z)-5-((6-(3-(3-trifluoromethylphenyl)ureido)-2- indolinon-3-enyl)methyl)-N-(2-(diethylamino)ethyl)-2,4-dimethyl-lH-pyrrole-3- carboxamide;

[0034] Compound 3-17g is (Z)-5-((6-(3-(3-cyanophenyl)ureido)-2-indolinon-3- enyl)methyl)-N-(2-(diethylamino)ethyl)-2,4-dimethyl-lH-pyrrole-3-carboxamide;

[0035] Compound 3-17h is (Z)-5-((6-(3-(3-methylphenyl)ureido)-2-indolinon-3- enyl)methyl)-N-(2-(diethylamino)ethyl)-2,4-dimethyl-lH-pyrrole-3-carboxamide;

[0036] Compound 3-17i is (Z)-5-((6-(3-(3-methoxyphenyl)ureido)-2-indolinon-3- enyl)methyl)-N-(2-(diethylamino)ethyl)-2,4-dimethyl-lH-pyrrole-3-carboxamide;

[0037] Compound 3-17j is (Z)-5-((6-(3-(3-nitrophenyl)ureido)-2-indolinon-3- enyl)methyl)-N-(2-(diethylamino)ethyl)-2,4-dimethyl-lH-pyrrole-3-carboxamide;

[0038] Compound 3-17k is (Z)-5-((6-(3-(3-fluorophenyl)ureido)-2-indolinon-3-enyl)methyl)- N-(2-(diethylamino)ethyl)-2,4-dimethyl-1H-pyrrole-3-carboxamide;

[0039] Compound 3-17l is (Z)-N-(2-(diethylamino)ethyl)-2,4-dimethyl-5-((2-oxo-6-(5- propylamido-1H-pyrazol-3-yl)indol-3-enyl)methyl)-1H-pyrrole-3-carboxamide;

[0040] Compound 3-17m is (Z)-5-((6-((2-(cyclopropylamino)-2-acetyl)amino)-2-indolinon-3- enyl)methyl)-N-(2-(diethylamino)ethyl)-2,4-dimethyl-1H-pyrrole-3-carboxamide.

[0041] Compound 3-17n is (Z)-N-(3-(3-((1-(2-hydroxyethyl)-1H-pyrazol-4-yl)methylidene)-2- indolinon-6-yl)-1H-pyrazol-5-yl)propanamide;

[0042] Compound 3-19 is (Z)-N-(2-(diethylamino)ethyl)-2,4-dimethyl-5-((2-indolinon-3-enyl)methyl)- 1H-pyrrole-3-carboxamide.

[0043] Use of the indolinone derivatives 3-17a, 3-17d, 3-17k in the preparation of an Aurora B kinase inhibitor.

[0044] Use of the indolinone derivative 3-19 in the preparation of a medicament for treating HELA human cervical cancer.

[0045] Use of the indolinone derivatives 3-17b, 3-17c, 3-17e, 3-17f, 3-17k, 3-17h, 3-17i, 3-17j, 3-19, 3-17m in the preparation of a medicament for treating HGC27 human gastric cancer.

[0046] Use of the indolinone derivatives 3-17b, 3-17e, 3-17f, 3-17k, 3-17j, 3-19, 3-17m in the preparation of a medicament for treating HT29 human colon cancer.

[0047] Use of the indolinone derivatives 3-17j, 3-19 in the preparation of a medicament for treating MCF7 human breast cancer.

[0048] The present application relates to a kind of indolone derivatives and purposes, wherein preparation indolone derivatives intermediate 3-3a to 3-3g, 3-6a and 3-6b, 3-11, 3-14, 3-16 are carried out according to the following steps:

[0049] Synthesis of intermediate (3-3a to 3-3g):

[0050] Synthesis of intermediate 1-(3-chlorophenyl)-3-(2-indolin-6-yl)urea (3-3a):

[0051] Under inert atmosphere and temperature 0℃, 148mg 1mmol of 6-amino-2-indolone (3-1) is dissolved in dry dichloromethane solution 5ml, 0.187g 1mmol of 3-trifluoromethyl phenyl isocyanate (3-2b) is added, then raised to room temperature, stirred for 24h, after TLC detection reaction is completed, remove dichloromethane under reduced pressure, the residue is washed with 20mL water, then extracted with 20mL ethyl acetate for 3 times, sequentially washed with water, dried with anhydrous sodium sulfate, suction filtered, spin dried and purified by silica gel column chromatography, to obtain intermediate 1-(3-trifluoromethylphenyl)-3-(2-indolin-6-yl)urea 3-3b;

[0052] Synthesis of intermediate 1-(3-chlorophenyl)-3-(2-indolin-6-yl)urea (3-3a):

[0053] Under inert atmosphere and temperature 0℃, 148mg 1mmol of 6-amino-2-indolone (3-1) is dissolved in dry dichloromethane solution 5ml, 0.187g 1mmol of 3-trifluoromethyl phenyl isocyanate (3-2b) is added, then raised to room temperature, stirred for 24h, after TLC detection reaction is completed, remove dichloromethane under reduced pressure, the residue is washed with 20mL water, then extracted with 20mL ethyl acetate for 3 times, sequentially washed with water, dried with anhydrous sodium sulfate, suction filtered, spin dried and purified by silica gel column chromatography, to obtain intermediate 1-(3-trifluoromethylphenyl)-3-(2-indolin-6-yl)urea 3-3b;

[0054] Synthesis of intermediate 1-(3-chlorophenyl)-3-(2-indolin-6-yl)urea (3-3a):

[0055] In an inert atmosphere and at a temperature of 0°C, 148 mg of 1 mmol of 6-amino-2- indolinone (3-1) were dissolved in 5 ml of dry dichloromethane, 0.144 g of 1 mmol of 3- cyano phenyl isocyanate (3-2c) were added, then the temperature was raised to room temperature, stirring was carried out for 24 h, after the end of the reaction, ascertained by TLC, the dichloromethane was removed under reduced pressure, the residue was washed with 20 ml of water, then extracted with 20 ml of ethyl acetate three times, dried with water, with anhydrous sodium sulfate, filtered under suction, dried in a rotary evaporator and purified by column chromatography on silica gel, obtaining the intermediate 1-(3-cyano-phenyl)-3-(2-indolinyl-6-yl)urea 3-3c.

[0056] Synthesis of the intermediate 1-(3-methoxy-phenyl)-3-(2-indolinyl-6-yl)urea (3-3e):

[0057] In an inert atmosphere and at a temperature of 0°C, 148 mg of 1 mmol of 6-amino-2- indolinone (3-1) were dissolved in 5 ml of dry dichloromethane, 0.133 g of 1 mmol of 3- methyl phenyl isocyanate (3-2d) were added, then the temperature was raised to room temperature, stirring was carried out for 24 h, after the end of the reaction, ascertained by TLC, the dichloromethane was removed under reduced pressure, the residue was washed with 20 ml of water, then extracted with 20 ml of ethyl acetate three times, dried with water, with anhydrous sodium sulfate, filtered under suction, dried in a rotary evaporator and purified by column chromatography on silica gel, obtaining the intermediate 1-(3-methyl-phenyl)-3-(2-indolinyl-6-yl)urea 3-3d.

[0058] Synthesis of the intermediate 1-(3-methoxy-phenyl)-3-(2-indolinyl-6-yl)urea (3-3e):

[0059] In an inert atmosphere and at a temperature of 0°C, 148 mg of 1 mmol of 6-amino-2- indolinone (3-1) were dissolved in 5 ml of dry dichloromethane, 0.133 g of 1 mmol of 3- methyl phenyl isocyanate (3-2d) were added, then the temperature was raised to room temperature, stirring was carried out for 24 h, after the end of the reaction, ascertained by TLC, the dichloromethane was removed under reduced pressure, the residue was washed with 20 ml of water, then extracted with 20 ml of ethyl acetate three times, dried with water, with anhydrous sodium sulfate, filtered under suction, dried in a rotary evaporator and purified by column chromatography on silica gel, obtaining the intermediate 1-(3-methyl-phenyl)-3-(2-indolinyl-6-yl)urea 3-3d.

[0060] Synthesis of the intermediate 1-(3-methoxy-phenyl)-3-(2-indolinyl-6-yl)urea (3-3e):

[0061] In an inert atmosphere and at a temperature of 0°C, 148 mg of 1 mmol of 6-amino-2- indionone (3-1) were dissolved in 5 ml of dry dichloromethane, 0.164 g of 3-nitrophenyl isocyanate (3-2f, 1 mmol) was added, then it was brought to room temperature and stirred for 24 h. After the end of the reaction, monitored by TLC, the dichloromethane was removed under reduced pressure, the residue was washed with 20 ml of water and extracted with ethyl acetate (3 x 20 ml). After the water wash, drying with anhydrous sodium sulfate, suction filtration, spin drying and purification on a silica gel column, the intermediate 1-(3-nitrophenyl)-3-(2-indolin-6-yl)urea 3-3f was obtained.

[0062] Synthesis of the intermediate 1-(3-fluorophenyl)-3-(2-indolin-6-yl)urea (3-3g):

[0063] In an inert atmosphere and at a temperature of 0°C, 148 mg of 1 mmol of 6-amino-2- indionone (3-1) were dissolved in 5 ml of dry dichloromethane, 0.164 g of 3-nitrophenyl isocyanate (3-2f, 1 mmol) was added, then it was brought to room temperature and stirred for 24 h. After the end of the reaction, monitored by TLC, the dichloromethane was removed under reduced pressure, the residue was washed with 20 ml of water and extracted with ethyl acetate (3 x 20 ml). After the water wash, drying with anhydrous sodium sulfate, suction filtration, spin drying and purification on a silica gel column, the intermediate 1-(3-nitrophenyl)-3-(2-indolin-6-yl)urea 3-3f was obtained.

[0064] Synthesis of the intermediate (3-6a and 3-6b):

[0065] Synthesis of the intermediate 5-formyl-2,4-dimethyl-N-(2-(pyrrolidin-1-yl)ethyl)-1H- pyrrole-3-carboxamide (3-6a):

[0066] In an inert atmosphere and at a temperature of 0-4°C, 167 mg of 1 mmol of 5-formyl-2,4- dimethyl-1H-pyrazole-3-carboxylic acid (3-4), 1-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride 1.2 mmol and 1-hydroxybenzotriazole 1.2 mmol were sequentially dissolved in 3 ml of dichloromethane and stirred for 20 min, then 0.114 g of 1 mmol of 2-(pyrrolidin-1-yl)ethylamine (3-5a) was added, stirred for 30 min at a temperature of 0-4°C, then brought to room temperature and continuously stirred for 24 h. After the end of the reaction, monitored by TLC, the residue was washed with 30 ml of water and extracted with 30 ml of ethyl acetate 6 times, the collected organic phase was washed with 50 ml of water 3 times, then it was sequentially dried with anhydrous sodium sulfate, suction filtered, spin dried and purified on a silica gel column to obtain the intermediate 5-formyl-2,4-dimethyl-N-(2-(pyrrolidin-1-yl)ethyl)-1H-pyrrole-3- carboxamide 3-6a.

[0067] Synthesis of intermediate N-(2-(diethylamino)ethyl)-5-formyl-2,4-dimethyl-1H- pyrrole-3-carboxamide (3-6b):

[0068] Synthesis of intermediate N-(2-(diethylamino)ethyl)-5-formyl-2,4-dimethyl-1H- pyrrole-3-carboxamide (3-6b):

[0069] Synthesis of intermediate N-(3-(2-oxoindolin-6-yl)-1H-pyrazol-5-yl)propanamide (3-11):

[0070] Synthesis of intermediate N-(3-(2-oxoindolin-6-yl)-1H-pyrazol-5-yl)propanamide (3-11):

[0071] Synthesis of intermediate N-(3-(2-oxoindolin-6-yl)-1H-pyrazol-5-yl)propanamide (3-11):

[0072] Synthesis of intermediate N-(3-(2-oxoindolin-6-yl)-1H-pyrazol-5-yl)propanamide (3-11):

[0073] To a 50 mL round bottom flask were added 96 mg, 1 mmol of 1H-pyrazole-4-carboxaldehyde (3-12), 287 mg, 1.2 mmol of (2-bromoethoxy)-tert-butyldimethylsilane (3-13), and 165 mg, 1.2 mmol of K2CO3. To this was added 5 mL of acetonitrile and stirred at 80 °C for 4 h. After the reaction was complete, 15 mL of water was added to dilute the reaction mixture, which was then extracted with 15 mL of ethyl acetate three times. The combined organic phase was dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography to give the intermediate 1-(2-((tert-butyldimethylsilyloxy)ethyl)-1H-pyrazole-4-carboxaldehyde 3-14.

[0074] Synthesis of intermediate 1-(2-((tert-butyldimethylsilyloxy)ethyl)-1H-pyrazole-4-carboxaldehyde (3-14):

[0075] To a 50 mL round bottom flask were added 96 mg, 1 mmol of 1H-pyrazole-4-carboxaldehyde (3-12), 287 mg, 1.2 mmol of (2-bromoethoxy)-tert-butyldimethylsilane (3-13), and 165 mg, 1.2 mmol of K2CO3. To this was added 5 mL of acetonitrile and stirred at 80 °C for 4 h. After the reaction was complete, 15 mL of water was added to dilute the reaction mixture, which was then extracted with 15 mL of ethyl acetate three times. The combined organic phase was dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography to give the intermediate 1-(2-((tert-butyldimethylsilyloxy)ethyl)-1H-pyrazole-4-carboxaldehyde 3-14.

[0076] Synthesis of intermediate N-cyclopropyl-2-((2-oxoindolin-6-yl)amino)acetamide (3-16):

[0077] To a 50 mL round bottom flask were added 96 mg, 1 mmol of 1H-pyrazole-4-carboxaldehyde (3-12), 287 mg, 1.2 mmol of (2-bromoethoxy)-tert-butyldimethylsilane (3-13), and 165 mg, 1.2 mmol of K2CO3. To this was added 5 mL of acetonitrile and stirred at 80 °C for 4 h. After the reaction was complete, 15 mL of water was added to dilute the reaction mixture, which was then extracted with 15 mL of ethyl acetate three times. The combined organic phase was dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography to give the intermediate 1-(2-((tert-butyldimethylsilyloxy)ethyl)-1H-pyrazole-4-carboxaldehyde 3-14. BRIEF DESCRIPTION OF DRAWINGS

[0078] Figure 1 Synthetic scheme of 5 fragments (A-E) for the target compounds of the present application;

[0079] Figure 2 Synthetic scheme of the target compounds (F-I) of the present application. DETAILED DESCRIPTION

[0080] The present application is further illustrated by the following examples, but the present application is not limited to these examples.

[0081] Reagents: all reagents are commercially available and of analytical purity.

[0082] Example 1

[0083] Preparation of (Z)-5-((6-(3-(3-chlorophenyl)ureido)-2-indolinon-3-yl)methyl)-2,4- dimethyl-N-(2-(pyrrolidin-1-yl)ethyl)-1H-pyrrole-3-carboxamide (3-17a):

[0084] Dissolve 362 mg of 1-(3-chlorophenyl)-3-(2-indolin-6-yl)urea (3-3a) 1.2 mmol in 5 mL of methanol, add 1 mL of 50% concentration KOH aqueous solution, stir at room temperature for 15 min, then add 263 mg of 5-formyl-2,4-dimethyl-N-(2-(pyrrolidin-1-yl)ethyl)-1H-pyrrole-3-carboxamide (3-6a) 1 mmol, stir at room temperature overnight, after TLC shows that the reaction is completed, evaporate the methanol under reduced pressure, add 10 mL of hot water to the residue to dilute, adjust the pH to 7 with dilute hydrochloric acid, and a solid precipitates, filter and wash the precipitate, and recrystallize from methanol to obtain part of the target compound; if the target compound cannot be obtained by recrystallization from methanol, extract with 25 mL of water and 25 mL of ethyl acetate for 5 times, dry the combined organic phase with anhydrous sodium sulfate, rotary evaporate and purify by silica gel column chromatography to obtain the target compound 3-17a, yield 65%, orange solid, melting point 291.1-296.4°C;

[0085] 1 H NMR (500 MHz, DMSO-d6) δ 13.46 (s, 1H), 10.86 (s, 1H), 8.89 (s, 2H), 7.71 (s, 1H), 7.66 (d, J = 8.2 Hz, 1H), 7.50-7.44 (m, 2H), 7.33-7.24 (m, 3H), 7.02 (d, J = 7.4 Hz, 1H), 6.92 (d, J = 8.7 Hz, 1H), 2.56 (t, J = 6.9 Hz, 2H), 2.49-2.46 (m, 4H), 2.42 (s, 3H), 2.37 (s, 3H), 1.71-1.64 (m, 4H). 13C NMR (125 MHz, DMSO-d6) δ 169.95, 164.76, 152.26, 141.29, 139.11, 138.39, 134.87, 133.20, 130.42, 128.00, 125.74, 121.59, 121.45, 120.29, 119.58, 119.14, 117.56, 116.67, 115.54, 111.24, 100.15, 54.83, 53.53, 38.04, 23.21, 13.19, 10.47.

[0086] Example 2

[0087] Preparation of (Z)-5-((6-(3-(3-trifluoromethylphenyl)ureido)-2-indolinon-3- yl)methyl)-2,4-dimethyl-N-(2-(pyrrolidin-1-yl)ethyl)-1H-pyrrole-3-carboxamide (3-17b):

[0088] Dissolve 403 mg 1.2 mmol of 1-(3-trifluoromethylphenyl)-3-(2-indolin-6-yl)urea (3-3b) in 5 mL of methanol, add 1 mL of 50% concentration aqueous KOH solution, stir at room temperature for 15 min, then add 263 mg 1 mmol of 5-formyl-2,4-dimethyl-N-(2-(pyrrolidin-1-yl)ethyl)-1H-pyrrole-3-carboxamide (3-6a), stir at room temperature overnight, after TLC shows that the reaction is completed, evaporate the methanol under reduced pressure, add 10 mL of hot water to the residue to dilute, adjust the pH to 7 with dilute hydrochloric acid, and a solid precipitates, filter and wash the precipitate, and after recrystallization with methanol, part of the target compound is obtained; if pure target compound cannot be obtained by recrystallization with methanol, it can be extracted with 25 mL of water and 25 mL of ethyl acetate for 5 times, the combined organic phase is dried with anhydrous sodium sulfate, rotary evaporated and purified by silica gel column chromatography to obtain the target compound 3-17b, yield 71%, orange solid, melting point 267.1-273.5 °C;

[0089] 1 H NMR (500 MHz, DMSO-d6) δ 13.47 (s, 1H), 10.85 (s, 1H), 9.06 (s, 1H), 8.93 (s, 1H), 8.03 (s, 1H), 7.66 (d, J = 8.4 Hz, 1H), 7.61 - 7.42 (m, 4H), 7.33 - 7.28 (m, 2H), 6.94 (d, J = 8.4 Hz, 1H), 2.42 (s, 3H), 2.38 (s, 3H), 1.73 - 1.65 (s, 4H). 13C NMR (125 MHz, DMSO-d6) δ 169.93, 164.73, 152.38, 140.60, 139.10, 138.31, 134.87, 129.92, 129.40, 128.02, 125.73, 125.32, 123.16, 121.84, 121.62, 120.30, 119.64, 119.12, 118.04, 115.52, 114.11, 111.30, 100.23, 79.18, 54.83, 53.52, 38.03, 23.21, 13.18, 10.46.

[0090] Example 3

[0091] Preparation of (Z)-5-((6-(3-(3-cyanophenyl)ureido)-2-indolinon-3-yl)methyl)-2,4- dimethyl-N-(2-(pyrrolidin-l-yl)ethyl)-lH-pyrrole-3-carboxamide (3-17c):

[0092] Dissolve 352 mg 1.2 mmol of 1-(3-cyanophenyl)-3-(2-indolin-6-yl)urea (3-3c) in 5 mL of methanol, add 1 mL of 50% concentration aqueous KOH solution, stir at room temperature for 15 min, then add 263 mg 1 mmol of 5-formyl-2,4-dimethyl-N-(2-(pyrrolidin-l-yl)ethyl)-lH-pyrrole-3- carboxamide (3-6a), stir at room temperature overnight, after TLC shows that the reaction is completed, evaporate the methanol under reduced pressure, add 10 mL of hot water to the residue to dilute, adjust the pH to 7 with dilute hydrochloric acid, and a solid precipitates, filter and wash the precipitate, and recrystallize from methanol to obtain part of the target compound; if pure target compound cannot be obtained by recrystallization from methanol, extract with 25 mL of water and 25 mL of ethyl acetate for 5 times, dry the combined organic phase with anhydrous sodium sulfate, rotary evaporate, and purify by silica gel column chromatography to obtain the target compound 3-17c, yield 74%, orange solid, melting point 277.3-281.2 °C;

[0093] 1 H NMR (400 MHz, DMSO-d6) δ 13.41 (s, 1H), 10.80 (s, 1H), 8.98 (s, 1H), 8.92 (s, 1H), 7.92 (s, 1H), 7.61 (t, J = 7.6 Hz, 2H), 7.51 - 7.32 (m, 4H), 7.24 (s, 1H), 6.87 (d, J = 8.4 Hz, 1H), 3.30 - 3.22 (m, 2H) (overlap), 2.46 - 2.39 (m, 6H) (overlap), 2.34 (s, 6H), 1.62 (q, J = 3.3 Hz, 4H).13 C NMR (100 MHz, DMSO-d6) δ 169.92, 164.72, 152.27, 140.64, 139.09, 138.23, 134.87, 130.17, 128.01, 125.72, 125.28, 122.88, 121.61, 120.75, 120.28, 119.69, 119.11, 118.88, 115.49, 111.59, 111.28, 100.20, 54.80, 53.51, 38.00, 23.19, 13.17, 10.45.

[0094] Example 4

[0095] Preparation of (Z)-5-((6-(3-(3-methylphenyl)ureido)-2-indolon-3-yl)methyl)-2,4- dimethyl-N-(2-(pyrrolidin-l-yl)ethyl)-lH-pyrrole-3-carboxamide (3-17d):

[0096] Dissolve 338 mg 1.2 mmol of 1-(3-methylphenyl)-3-(2-indolin-6-yl)urea (3-3d) in 5 mL of methanol, add 1 mL of 50% concentration KOH aqueous solution, stir at room temperature for 15 min, then add 263 mg 1 mmol of 5-formyl-2,4-dimethyl-N-(2-(pyrrolidin-l-yl)ethyl)-lH-pyrrole-3-carboxamide (3-6a), stir at room temperature overnight, after TLC shows that the reaction is completed, evaporate the methanol under reduced pressure, add 10 mL of hot water to the residue to dilute, adjust the pH to 7 with dilute hydrochloric acid, and a solid precipitates, filter and wash the precipitate, and after recrystallization with methanol, part of the target compound is obtained; if recrystallization with methanol cannot obtain pure target compound, it can be extracted with 25 mL of water and 25 mL of ethyl acetate for 5 times, dry the combined organic phase with anhydrous sodium sulfate, rotary evaporate and purify with silica gel column chromatography to obtain the target compound 3-17d, yield 75%, orange solid, melting point 269.5-273.9 °C;

[0097] 1H NMR (400 MHz, DMSO-d6) δ 13.40 (s, 1H), 10.79 (s, 1H), 8.80 (s, 1H), 8.60 (s, 1H), 7.58 (d, J = 8.3 Hz, 1H), 7.41 (s, 2H), 7.26 (d, J = 7.6 Hz, 2H), 7.21 - 7.05 (m, 2H), 6.84 (d, J = 8.4 Hz, 1H), 6.74 (s, 1H), 2.46 - 2.39 (m, 9H), 2.36 (s, 3H), 2.32 (s, 3H), 2.22 (s, 4H), 1.66 - 1.59 (m, 4H). 13 C NMR (100 MHz, DMSO-d6) δ 169.96, 164.74, 152.39, 139.63, 139.13, 138.80, 137.92, 134.72, 128.61, 127.82, 125.71, 122.54, 121.35, 120.23, 119.22, 119.11, 118.71, 115.65, 115.37, 110.97, 99.91, 54.81, 53.51, 38.02, 23.20, 21.23, 13.16, 10.44.

[0098] Example 5

[0099] Preparation of (Z)-5-((6-(3-(3-chlorophenyl)ureido)-2-indolinon-3-yl)methyl)-N-(2- (diethylamino)ethyl)-2,4-dimethyl-1H-pyrrole-3-carboxamide (3-17e):

[0100] Dissolve 362 mg 1.2 mmol of 1-(3-methoxyphenyl)-3-(2-indolin-6-yl)urea (3-3e) in 5 mL of methanol, add 1 mL of 50% concentration aqueous KOH solution, stir at room temperature for 15 min, then add 266 mg 1 mmol of N-(2-(diethylamino)ethyl)-5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxamide (3-6b), stir at room temperature overnight, after TLC shows that the reaction is completed, evaporate the methanol under reduced pressure, add 10 mL of hot water to the residue to dilute, adjust the pH to 7 with dilute hydrochloric acid, and a solid precipitates, filter and wash the precipitate, and after recrystallization with methanol, part of the target compound is obtained; if recrystallization with methanol cannot obtain pure target compound, it can be extracted with 25 mL of water and 25 mL of ethyl acetate for 5 times, dry the combined organic phase with anhydrous sodium sulfate, rotary evaporate and purify by silica gel column chromatography to obtain the target compound 3-17e, yield 61%, orange solid, melting point 296.1-300.4 °C;

[0101] 1H NMR (500 MHz, DMSO-d6) δ 13.48 (s, 1H), 10.86 (s, 1H), 8.94 (s, 1H), 7.78 - 7.60 (m, 3H), 7.48 (s, 1H), 7.40 - 7.23 (m, 5H), 7.04 - 6.98 (m, 1H), 6.92 (d, J = 8.3 Hz, 1H), 3.28 (q, J = 6.2 Hz, 2H), 2.43 (s, 3H), 2.39 (s, 3H), 0.97 (t, J = 7.1 Hz, 6H). 13 C NMR (125 MHz, DMSO-d6) δ 169.95, 164.72, 152.27, 141.31, 139.12, 138.43, 134.95, 133.20, 130.40, 127.91, 125.73, 121.56, 120.10, 119.56, 119.13, 117.55, 116.65, 115.60, 111.22, 100.14, 51.67, 46.52, 36.96, 13.30, 11.90, 10.59.

[0102] Example 6

[0103] Preparation of (Z)-5-((6-(3-(3-trifluoromethylphenyl)ureido)-2-indolinon-3- yl)methyl)-N-(2-(diethylamino)ethyl)-2,4-dimethyl-1H-pyrrole-3-carboxamide (3-17f):

[0104] Dissolve 403 mg 1.2 mmol of 1-(3-trifluoromethylphenyl)-3-(2-indolin-6-yl)urea (3-3b) in 5 mL of methanol, add 1 mL of 50% concentration aqueous KOH solution, stir at room temperature for 15 min, then add 266 mg 1 mmol of N-(2-(diethylamino)ethyl)-5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxamide (3-6b), stir at room temperature overnight, after TLC shows that the reaction is completed, evaporate the methanol under reduced pressure, add 10 mL of hot water to the residue to dilute, adjust the pH to 7 with dilute hydrochloric acid, and a solid precipitates, filter and wash the precipitate, and recrystallize from methanol to obtain part of the target compound; if pure target compound cannot be obtained by recrystallization from methanol, extract with 25 mL of water and 25 mL of ethyl acetate for 5 times, dry the combined organic phase with anhydrous sodium sulfate, rotary evaporate and purify by silica gel column chromatography to obtain the target compound 3-17f, yield 67%, orange solid, melting point 281.5-286.0 °C;

[0105] 1H NMR (500 MHz, DMSO-d6) δ 13.48 (s, 1H), 10.86 (s, 1H), 9.04 (s, 1H), 8.91 (s, 1H), 8.03 (s, 1H), 7.66 (d, J = 8.3 Hz, 1H), 7.57 (d, J = 8.3 Hz, 1H), 7.54 - 7.47 (m, 2H), 7.37 (t, J = 5.6 Hz, 1H), 7.33 - 7.28 (m, 2H), 6.94 (d, J = 8.3 Hz, 1H), 3.28 (q, J = 6.5 Hz, 2H), 2.43 (s, 3H), 2.39 (s, 3H), 0.97 (t, J = 7.1 Hz, 6H). 13 C NMR (125 MHz, DMSO-d6) δ 169.93, 164.71, 152.37, 140.58, 139.11, 138.31, 134.98, 129.92, 129.65, 127.96, 127.47, 125.73, 121.85, 121.62, 120.12, 119.65, 119.13, 118.05, 115.57, 114.11, 111.30, 100.23, 51.68, 46.52, 36.96, 13.30, 11.89, 10.59.

[0106] Example 7

[0107] Preparation of (Z)-5-((6-(3-(3-cyanophenyl)ureido)-2-indolinon-3-yl)methyl)-N-(2- (diethylamino)ethyl)-2,4-dimethyl-1H-pyrrole-3-carboxamide (3-17g):

[0108] Dissolve 352 mg 1.2 mmol of 1-(3-cyanophenyl)-3-(2-indolin-6-yl)urea (3-3c) in 5 mL of methanol, add 1 mL of 50% concentration aqueous KOH solution, stir at room temperature for 15 min, then add 266 mg 1 mmol of N-(2-(diethylamino)ethyl)-5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxamide (3-6b), stir at room temperature overnight, after TLC shows that the reaction is completed, evaporate the methanol under reduced pressure, add 10 mL of hot water to the residue to dilute, adjust the pH to 7 with dilute hydrochloric acid, and a solid precipitates, filter and wash the precipitate, and recrystallize from methanol to obtain part of the target compound; if methanol recrystallization cannot obtain pure target compound, it can be extracted with 25 mL of water and 25 mL of ethyl acetate for 5 times, dry the combined organic phase with anhydrous sodium sulfate, rotary evaporate and purify by silica gel column chromatography to obtain the target compound 3-17g, yield 65%, orange solid, melting point 271.6-276.1 °C;

[0109] 1 H NMR (500 MHz, DMSO-d6) δ 13.48 (s, 1H), 10.87 (s, 1H), 9.34 - 8.76 (m, 2H), 7.98 (s, 1H), 7.71 - 7.61 (m, 2H), 7.55 - 7.28 (m, 5H), 6.97 - 6.90 (m, 1H), 3.33 - 3.25 (m, 4H), 2.61 - 2.52 (m, 4H, overlap), 2.43 (s, 3H), 2.39 (s, 3H), 0.99 (t, J = 7.1 Hz, 6H). 13 C NMR (125 MHz, DMSO-d6) δ 169.95, 164.78, 152.32, 140.69, 139.12, 138.31, 135.02, 130.20, 127.97, 125.74, 125.29, 122.90, 121.63, 120.75, 120.07, 119.68, 119.16, 118.91, 115.59, 111.60, 111.31, 100.21, 51.61, 46.54, 36.84, 13.32, 11.76, 10.60.

[0110] Example 8

[0111] Preparation of (Z)-5-((6-(3-(3-methylphenyl)ureido)-2-indolinon-3- yl)methyl)-N-(2-(diethylamino)ethyl)-2,4-dimethyl-1H-pyrrole-3-carboxamide (3-17h):

[0112] Dissolve 338 mg 1.2 mmol of 1-(3-methylphenyl)-3-(2-indolin-6-yl)urea (3-3d) in 5 mL of methanol, add 1 mL of 50% concentration aqueous KOH solution, stir at room temperature for 15 min, then add 266 mg 1 mmol of N-(2-(diethylamino)ethyl)-5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxamide (3-6b), stir at room temperature overnight, after TLC shows that the reaction is completed, evaporate the methanol under reduced pressure, add 10 mL of hot water to the residue to dilute, adjust the pH to 7 with dilute hydrochloric acid, and a solid precipitates, filter and wash the precipitate, and recrystallize from methanol to obtain part of the target compound; if recrystallization from methanol cannot obtain pure target compound, it can be extracted with 25 mL of water and 25 mL of ethyl acetate for 5 times, dry the combined organic phase with anhydrous sodium sulfate, rotary evaporate and purify by silica gel column chromatography to obtain the target compound 3-17h, yield 69%, orange solid, melting point 264.2-259.3°C;

[0113] 1H NMR (500 MHz, DMSO-d6) δ 13.47 (s, 1H), 10.85 (s, 1H), 8.80 (s, 1H), 8.61 (s, 1H), 7.64 (d, J = 8.3 Hz, 1H), 7.47 (s, 1H), 7.37 (t, J = 5.5 Hz, 1H), 7.31 (d, J = 8.3 Hz, 1H), 7.23 (d, J = 8.1 Hz, 1H), 7.15 (t, J = 7.8 Hz, 1H), 6.90 (d, J = 8.4 Hz, 1H), 6.79 (d, J = 7.5 Hz, 1H), 3.28 (q, J = 6.5 Hz, 2H), 2.58 - 2.51 (m, 4H, overlap), 2.43 (s, 3H), 2.39 (s, 3H), 2.28 (s, 3H), 0.98 (t, J = 7.1 Hz, 6H). 13 C NMR (125 MHz, DMSO-d6) δ 169.97, 164.75, 152.40, 139.61, 139.15, 138.80, 137.96, 134.88, 128.64, 127.80, 125.73, 122.59, 121.39, 120.06, 119.26, 119.15, 118.72, 115.70, 115.39, 111.00, 99.93, 51.66, 46.53, 36.94, 21.25, 13.30, 11.87, 10.59.

[0114] Example 9

[0115] Preparation of (Z)-5-((6-(3-(3-methoxyphenyl)ureido)-2-indolinon-3- yl)methyl)-N-(2-(diethylamino)ethyl)-2,4-dimethyl-1H-pyrrole-3-carboxamide (3-17i):

[0116] Dissolve 358 mg of 1.2 mmol of 1-(3-methoxyphenyl)-3-(2-indolin-6-yl)urea (3-3e) in 5 mL of methanol, add 1 mL of 50% concentration of KOH aqueous solution, stir at room temperature for 15 min, then add 266 mg of 1 mmol of N-(2-(diethylamino)ethyl)-5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxamide (3-6b), stir at room temperature overnight, after TLC shows that the reaction is completed, evaporate the methanol under reduced pressure, add 10 mL of hot water to the residue to dilute, adjust the pH to 7 with dilute hydrochloric acid, and a solid precipitates, filter and wash the precipitate, and after recrystallization with methanol, part of the target compound is obtained; if recrystallization with methanol cannot obtain pure target compound, it can be extracted with 25 mL of water and 25 mL of ethyl acetate for 5 times, dry the combined organic phase with anhydrous sodium sulfate, rotary evaporate and purify by silica gel column chromatography to obtain the target compound 3-17i, yield 71%, orange solid, melting point 292.0-296.4°C;

[0117] 1 H NMR (500 MHz, DMSO-d6) δ 13.48 (s, 1H), 10.84 (s, 1H), 8.80 (s, 1H), 8.70 (s, 1H), 7.65 (d, J = 8.2 Hz, 1H), 7.47 (s, 1H), 7.41-7.31 (m, 2H), 7.24-7.13 (m, 2H), 6.95-6.86 (m, 2H), 6.55 (d, J = 8.2 Hz, 1H), 3.73 (s, 3H), 3.33-2.25 (m, 2H, overlap), 2.56-2.51 (m, 6H, overlap), 2.43 (s, 3H), 2.39 (s, 3H), 0.98 (t, J = 7.1 Hz, 6H). 13 C NMR (125 MHz, DMSO-d6) δ 169.95, 164.76, 159.69, 152.33, 140.92, 139.15, 138.68, 134.90, 129.55, 127.82, 125.73, 121.43, 120.04, 119.32, 119.15, 115.68, 111.04, 110.51, 107.26, 103.92, 99.98, 54.93, 51.63, 46.54, 36.87, 13.30, 11.80, 10.60.

[0118] Example 10

[0119] (Z)-5-((6-(3-(3-nitrophenyl)ureido)-2-indolinon-3-yl)methyl)-N-(2-(diethylamino)ethyl)-2,4-dimethyl-1H-pyrrole-3-carboxamide (3-17j) was prepared according to the following procedure:

[0120] To a solution of 373 mg of 1.2 mmol of 1-(3-nitrophenyl)-3-(2-indolin-6-yl)urea (3-3f) in 5 mL of methanol, 1 mL of 50% aqueous KOH solution was added, and after stirring at room temperature for 15 min, 266 mg of 1 mmol of N-(2-(diethylamino)ethyl)-5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxamide (3-6b) was added, and stirred at room temperature overnight. After TLC showed that the reaction was completed, the methanol was removed under reduced pressure, and 10 mL of hot water was added to the residue to dilute it, and the pH was adjusted to 7 with dilute hydrochloric acid, and a solid was precipitated, which was filtered and washed, and after recrystallization from methanol, part of the target compound was obtained; if recrystallization from methanol cannot obtain pure target compound, it can be extracted with 25 mL of water and 25 mL of ethyl acetate for 5 times, and the combined organic phase was dried with anhydrous sodium sulfate, rotary evaporated and purified by silica gel column chromatography to obtain the target compound 3-17j, yield 67%, orange solid, melting point 295.8-299.2°C;

[0121] 1 H NMR (500 MHz, DMSO-d6) δ 13.44 (s, 1H), 10.83 (s, 1H), 9.30 (s, 1H), 9.04 (s, 1H), 8.60-8.51 (m, 1H), 7.78 (d, J = 8.1 Hz, 1H), 7.68 (d, J = 8.2 Hz, 1H), 7.63 (d, J = 8.3 Hz, 1H), 7.53 (q, J = 8.3 Hz, 1H), 7.45 (s, 1H), 7.36-7.27 (m, 2H), 6.92 (d, J = 8.3 Hz, 1H), 3.28-3.20 (m, 2H), 2.53-2.42 (m, 6H), 2.38 (s, 6H), 0.93 (t, J = 7.1 Hz, 6H). 13 C NMR (125 MHz, DMSO-d6) δ 169.96, 164.73, 163.38, 161.46, 148.26, 141.65, 139.17, 138.34, 134.56, 130.24, 127.45, 125.71, 121.60, 120.09, 119.61, 119.17, 115.58, 113.89, 111.19, 104.82, 104.70, 100.09, 51.68, 46.52, 36.96, 13.29, 11.89, 10.88.

[0122] Example 11

[0123] Preparation of (Z)-5-((6-(3-(3-fluorophenyl)ureido)-2-indolinon-3- yl)methyl)-N-(2-(diethylamino)ethyl)-2,4-dimethyl-1H-pyrrole-3-carboxamide (3-17k):

[0124] Dissolve 343 mg 1.2 mmol of 1-(3-fluorophenyl)-3-(2-indolin-6-yl)urea (3-3g) in 5 mL of methanol, add 1 mL of 50% concentration aqueous KOH solution, stir at room temperature for 15 min, then add 266 mg 1 mmol of N-(2-(diethylamino)ethyl)-5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxamide (3-6b), stir at room temperature overnight, after TLC shows that the reaction is completed, evaporate the methanol under reduced pressure, add 10 mL of hot water to the residue to dilute, adjust the pH to 7 with dilute hydrochloric acid, and a solid precipitates, filter and wash the precipitate, and after recrystallization with methanol, part of the target compound is obtained; if recrystallization with methanol cannot obtain pure target compound, it can be extracted with 25 mL of water and 25 mL of ethyl acetate for 5 times, dry the combined organic phase with anhydrous sodium sulfate, rotary evaporate and purify with silica gel column chromatography to obtain the target compound 3-17k, yield 67%, orange solid, melting point 282.5-287.6 °C;

[0125] 1 H NMR (500 MHz, DMSO-d6) δ 13.48 (s, 1H), 10.86 (s, 1H), 8.90 (s, 2H), 7.66 (d, J = 8.3 Hz, 1H), 7.53 - 7.47 (m, 2H), 7.39 - 7.26 (m, 3H), 7.12 (d, J = 8.2 Hz, 1H), 6.91 (d, J = 8.2 Hz, 1H), 6.78 (td, J = 8.5, 2.6 Hz, 1H), 3.28 (q, J = 6.5 Hz, 4H, overlap), 2.57 - 2.52 (m, 4H, overlap), 2.43 (s, 3H), 2.39 (s, 3H), 0.97 (t, J = 7.1 Hz, 6H). 13C NMR (125 MHz, DMSO-d6) δ 169.96, 164.73, 163.38, 161.46, 148.26, 141.65, 139.17, 138.34, 134.56, 130.24, 127.45, 125.71, 121.60, 120.09, 119.61, 119.17, 115.58, 113.89, 111.19, 104.82, 104.70, 100.09, 51.68, 46.52, 36.96, 13.29, 11.89, 10.88.

[0126] Example 12

[0127] Preparation of (Z)-N-(2-(diethylamino)ethyl)-2,4-dimethyl-5-((2-oxo-6-(5- propylamido-lH-pyrazol-3-yl)indol-3-enyl)methyl)-lH-pyrrole-3-carboxamide (3-17l):

[0128] Into a 50 mL round bottom flask, 271 mg 1 mmol of N-(3-(2-oxoindol-6-yl)-lH- pyrazol-5-yl)propanamide (3-11) and 266 mg 1 mmol of N-(2-(diethylamino)ethyl)-5- formyl-2,4-dimethyl-lH-pyrrole-3-carboxamide (3-6b) were dissolved in 5 mL of absolute ethanol, and a catalytic amount of tetrahydrofuran was added. The mixture was stirred at a temperature of 25-40 °C for 8 h. After the reaction was completed, 20 mL of water was added for dilution, and the mixture was extracted with 20 mL of ethyl acetate three times. The combined organic phase was dried with anhydrous sodium sulfate, rotary evaporated, and purified by silica gel column chromatography to obtain the target compound 3-17l, an orange solid, with a yield of 62%, melting point 282.5-287.6 °C;

[0129] 1 H NMR (500 MHz, DMSO-d6) δ 13.48 (s, 1H), 10.86 (s, 1H), 8.90 (s, 2H), 7.66 (d, J = 8.3 Hz, 1H), 7.53 - 7.47 (m, 2H), 7.39 - 7.26 (m, 3H), 7.12 (d, J = 8.2 Hz, 1H), 6.91 (d, J = 8.2 Hz, 1H), 6.78 (td, J = 8.5, 2.6 Hz, 1H), 3.28 (q, J = 6.5 Hz, 4H, overlap), 2.57 - 2.52 (m, 4H, overlap), 2.43 (s, 3H), 2.39 (s, 3H), 0.97 (t, J = 7.1 Hz, 6H). 13C NMR (125 MHz, DMSO-d6) δ 169.96, 164.73, 163.38, 161.46, 148.26, 141.65, 139.17, 138.34, 134.56, 130.24, 127.45, 125.71, 121.60, 120.09, 119.61, 119.17, 115.58, 113.89, 111.19, 104.82, 104.70, 100.09, 51.68, 46.52, 36.96, 13.29, 11.89, 10.88.

[0130] Example 13

[0131] Preparation of (Z)-5-((6-((2-(cyclopropylamino)-2-oxoacetyl)amino)-2- indolinon-3-yl)methyl)-N-(2-(diethylamino)ethyl)-2,4-dimethyl-1H-pyrrole-3- carboxamide (3-17m):

[0132] Into a 50 mL round bottom flask, 246 mg 1 mmol of N-cyclopropyl-2-((2-oxoindolin-6- yl)amino)acetamide (3-16) and 266 mg 1 mmol of N-(2-(diethylamino)ethyl)-5- formyl-2,4-dimethyl-1H-pyrrole-3-carboxamide (3-6b) were dissolved in 5 mL of absolute ethanol, a catalytic amount of tetrahydrofuran was added, and stirring was performed at a temperature of 25-40 °C for 8 h. After the reaction was completed, 20 mL of water was added for dilution, and extraction was performed 3 times with 20 mL of ethyl acetate. The combined organic phase was dried with anhydrous sodium sulfate, rotary evaporated, and purified by silica gel column chromatography to obtain the target compound 3-17m, which was an orange solid with a yield of 57% and a melting point of 273.5-276.2 °C;

[0133] 1 H NMR (400 MHz, DMSO-d6) δ 13.38 (s, 1H), 10.68 (s, 1H), 7.99 (s, 1H), 7.69 - 7.40 (m, 2H), 7.25 (s, 1H), 6.20 (d, J = 8.4 Hz, 1H), 6.11 (s, 2H), 3.60 (s, 2H), 3.41 - 3.38 (m, 2H), 2.91 - 2.69 (m, 6H), 2.70 - 2.59 (m, 1H), 2.42 (s, 3H), 2.36 (s, 3H), 1.09 (t, J = 7.3 Hz, 6H), 0.65 - 0.54 (m, 2H), 0.50 - 0.37 (m, 2H). 13CNMR (100 MHz, DMSO-d6) δ 171.11, 170.33, 165.27, 153.50, 148.40, 140.07, 133.82, 125.96, 125.73, 119.68, 119.03, 118.47, 117.09, 114.23, 109.55, 105.79, 94.05, 51.03, 46.80, 46.66, 22.27, 13.33, 10.60, 5.62.

[0134] Example 14

[0135] Preparation of (Z)-N-(3-(3-((l-(2-hydroxyethyl)-lH-pyrazol-4-yl)methylene)-2- indolinon-6-yl)-lH-pyrazol-5-yl)propanamide (3-17n):

[0136] Into a 50 mL round bottom flask, 271 mg 1 mmol of N-(3-(2-oxoindolin-6-yl)-lH- pyrazol-5-yl)propanamide (3-11) and 255 mg 1 mmol of l-(2-((tert-butyldimethylsilyloxy)ethyl)-lH-pyrazole-4-carbaldehyde (3-14) were dissolved in 5 mL of anhydrous ethanol, and a catalytic amount of tetrahydrofuran was added. The mixture was stirred at a temperature of 25-40 °C for 8 h. After the reaction was completed, 20 mL of water was added for dilution, and the mixture was extracted with 20 mL of ethyl acetate three times. The combined organic phase was dried with anhydrous sodium sulfate, rotary evaporated, and purified by silica gel column chromatography to obtain the target compound 3-17n, with a yield of 49%, orange solid, melting point 301.5-303.7 °C;

[0137] 1 H NMR (400 MHz, DMSO-d6) δ 12.78 (s, 1H), 10.53 (s, 2H), 8.86 (s, 1H), 8.26 (s, 1H), 7.74 (s, 1H), 7.65 (d, J = 8.4 Hz, 1H), 7.34 (d, J = 8.0 Hz, 1H), 7.14 (s, 1H), 6.86 (s, 1H), 4.96 (s, 1H), 4.24 (t, J = 5.6 Hz, 2H), 3.77 (d, J = 6.4 Hz, 2H), 2.31 (q, J = 7.5 Hz, 2H), 1.07 (t, J = 7.5 Hz, 3H). 13C NMR (100 MHz, DMSO-d6) δ 171.24, 169.54, 167.84, 143.42, 141.56, 140.40, 135.16, 133.59, 131.54, 120.98, 119.30, 118.00, 117.84, 117.00, 115.99, 105.54, 59.83, 54.52, 29.83, 9.70.

[0138] Example 15

[0139] Preparation of (Z)-N-(2-(diethylamino)ethyl)-2,4-dimethyl-5-((2-indolon-3- enyl)methyl)-lH-pyrrole-3-carboxamide (3-19):

[0140] Dissolve 160 mg 1.2 mmol of indole-2-one (3-18) in 5 mL of methanol, add 1 mL of 50% aqueous KOH solution, stir at room temperature for 15 min, then add 266 mg 1 mmol of N-(2-(diethylamino)ethyl)-5-formyl-2,4-dimethyl-lH-pyrrole-3- carboxamide (3-6b), stir at room temperature overnight, after TLC shows that the reaction is completed, evaporate the methanol under reduced pressure, extract with 20 mL of water and 20 mL of ethyl acetate for 3 times, dry the combined organic phase with anhydrous sodium sulfate, rotary evaporate and purify by silica gel column chromatography to obtain the target compound 3-19, yield 74%, orange solid, melting point 233.1-236.9 °C;

[0141] 1 H NMR (500 MHz, CDCl3) δ 13.26 (s, 1H), 9.00 (s, 1H), 7.43 (d, J = 7.5 Hz, 1H), 7.15 (t, J = 7.6 Hz, 1H), 7.05 (t, J = 7.5 Hz, 1H), 6.87 (d, J = 7.7 Hz, 1H), 6.73-6.68 (m, 1H), 3.54 (q, J = 5.4 Hz, 2H), 2.75-2.59 (m, 6H), 2.53 (s, 3H), 2.29 (s, 3H), 1.05 (t, J = 7.1 Hz, 6H). 13 C NMR (125 MHz, CDCl3) δ 170.17, 166.04, 137.68, 137.43, 129.58, 126.46, 126.40, 126.29, 123.22, 121.87, 119.84, 117.79, 114.64, 109.61, 51.52, 46.20, 36.79, 14.15, 11.34, 11.10.

[0142] Example 16

[0143] Use of the indolinone derivative in the preparation of an antitumor drug:

[0144] The compounds 3-17a-3-17n, 3-19 obtained in Examples 1-15 were taken as the research objects, and their inhibitory activities on Aurora B kinase were preliminarily studied;

[0145] Determination method:

[0146] The compound was diluted with dimethyl sulfoxide (DMSO) (item number: D4540, manufacturer: Sigma) to 100 times the detection concentration, and 100 nL of the compound was transferred to a 384 reaction plate (784075, Germany Greiner) using a Beckman Echo 655; 5 μL of a 2-fold kinase solution was prepared using a 1-fold kinase reaction buffer (1-fold buffer, 5 mM Mgcl2, 1 mM dithiothreitol (DTT), H2O, 1 mM MnCl2, 50 nM SEB), and a laser kinase (AURKB) (6 nM, 08-113, Carna) solution was transferred to the 384 reaction plate; centrifugation was performed at 1000 rpm for 60 seconds using a centrifuge, and incubation was performed at 25°C for 10 minutes; a 2-fold substrate (kinase TK: 1 uM) and adenosine triphosphate (ATP) 25 μM mixture was prepared using a kinase reaction buffer, and 5 μL of the substrate and adenosine triphosphate (ATP) mixture was added to the reaction plate to start the reaction; centrifugation was performed at 1000 rpm for 60 seconds using a centrifuge, and the plate was sealed using a sealing film; incubation was performed at 25°C for 50 minutes; 10 μL of a kinase detection reagent was added to each well of the reaction plate, centrifugation was performed at 1000 rpm for 1 minute, and incubation was performed at 25°C for 60 minutes; the fluorescence signals at 620 nm (cryptate) and 665 nm (XL665) were read using a BMG enzyme marker;

[0147] Data analysis was performed using Graphpad 8.0 software, and the following nonlinear fitting formula was used to obtain the IC 50 (half maximal inhibitory concentration)

[0148] Y = Bottom + (Top - Bottom) / (1 + 10^((LogIC 50 -X) * Hill Slope))

[0149] X: compound concentration log value Y: inhibition rate (% inhibition)

[0150] The results are shown in Table 1:

[0151] Table 1. Inhibitory activities of compounds 3-17a-3-17k, 3-17l-3-17n, 3-19 on Aurora B kinase

[0152]

[0153]

[0154] From Table 1, it can be seen that the compounds (Z)-5-((6-(3-(3-chlorophenyl)ureido)-2- indolinone-3-enyl)methyl)-2,4-dimethyl-N-(2-(pyrrolidin-1-yl)ethyl)-1H-pyrrole-3-carboxamide (3-17a), (Z)-5-((6-(3-(3-methylphenyl)ureido)-2-indolinone-3-enyl)methyl)-2,4-dimethyl-N-(2- (pyrrolidin-1-yl)ethyl)-1H-pyrrole-3-carboxamide (3-17d), (Z)-5-((6-(3-(3-fluorophenyl)ureido)- 2-indolinone-3-enyl)methyl)-N-(2-(diethylamino)ethyl)-2,4-dimethyl-1H-pyrrole-3-carboxamide (3-17k) can be used for preparing Aurora B kinase inhibitors in clinic.

[0155] Example 17

[0156] With the compounds 3-17a-3-17n, 3-19 obtained in Examples 1-15 as the research objects, their inhibitory activities on HELA human cervical cancer cells, Hgc27 human gastric cancer cells, HT-29 human colon cancer cells, and MCF7 human breast cancer cells were preliminarily studied.

[0157] (1) Screening model: HELA human cervical cancer cells, Hgc27 human gastric cancer cells, HT-29 human colon cancer cells, and MCF7 human breast cancer cells;

[0158] (2) Cell source: provided by the Chinese Academy of Sciences Cell Bank;

[0159] (3) Sample treatment: the samples were dissolved with dimethyl sulfoxide (DMSO) and stored at low temperature, and the concentration of dimethyl sulfoxide in the final system was controlled within the range that does not affect the detection activity;

[0160] (4) Determination method:

[0161] MTT method was used to detect the cell survival rate;

[0162] Cells in logarithmic growth phase were washed once with neutral phosphate buffer, trypsinized, terminated with culture medium (agar culture medium, purchased from Exploration Platform), counted, and inoculated in 96-well plates (100 μL / well) at a corresponding cell density, and incubated overnight; 3-17a-3-17n, 3-19 to be detected were added (20 μL / well), each compound was set at a concentration gradient, and each concentration was set at 3 replicate wells; incubated in a CO2 incubator at 37°C for 48 hours, the old culture medium was discarded, 100 μL of thiazolyl blue (MTT) was added, and incubated at 37°C for 2 hours; the absorbance value (OD) at 570 nm was measured using an MB microplate reader; the IC 50 value was obtained by nonlinear fitting of sample activity and sample concentration, the software used for calculation was Graphpad Prism 8, and the results are shown in Table 2:

[0163] Table 2. Anti-tumor activity results of compounds 3-17a-3-17n, 3-19

[0164]

[0165]

[0166] NI: represents that the inhibition rate of the compound on tumor cells is less than 50% at a concentration of 50 μM, so IC 50 is not tested.

[0167] As can be seen from the table, the compound (Z)-N-(2-(diethylamino)ethyl)-2,4-dimethyl-5-((2-indolone-3-enyl)methyl)-1H-pyrrole-3-carboxamide (3-19) can be used for the use in the preparation of a drug for treating HELA human cervical cancer cells in a clinic;

[0168] The use of the compound (Z)-5-((6-(3-(3-trifluoromethylphenyl)ureido)-2- indolinon-3-enyl)methyl)-2,4-dimethyl-N-(2-(pyrrolidin-1-yl)ethyl)-1H-pyrrole-3- carboxamide (3-17b), (Z)-5-((6-(3-(3-cyanophenyl)ureido)-2-indolinon-3-enyl)methyl)- 2,4-dimethyl-N-(2-(pyrrolidin-1-yl)ethyl)-1H-pyrrole-3-carboxamide (3-17c), (Z)-5- ((6-(3-(3-chlorophenyl)ureido)-2-indolinon-3-enyl)methyl)-N-(2-(diethylamino)ethyl)- 2,4-dimethyl-1H-pyrrole-3-carboxamide (3-17e), (Z)-5-((6-(3-(3- trifluoromethylphenyl)ureido)-2-indolinon-3-enyl)methyl)-N-(2-(diethylamino)ethyl)- 2,4-dimethyl-1H-pyrrole-3-carboxamide (3-17f), (Z)-5-((6-(3-(3-fluorophenyl)ureido)- 2-indolinon-3-enyl)methyl)-N-(2-(diethylamino)ethyl)-2,4-dimethyl-1H-pyrrole-3- carboxamide (3-17k), (Z)-5-((6-(3-(3-methylphenyl)ureido)-2-indolinon-3-enyl)methyl)- N-(2-(diethylamino)ethyl)-2,4-dimethyl-1H-pyrrole-3-carboxamide (3-17h), (Z)-5- ((6-(3-(3-methoxyphenyl)ureido)-2-indolinon-3-enyl)methyl)-N-(2-(diethylamino)ethyl)- 2,4-dimethyl-1H-pyrrole-3-carboxamide (3-17i), (Z)-5-((6-(3-(3-nitrophenyl)ureido)- 2-indolinon-3-enyl)methyl)-N-(2-(diethylamino)ethyl)-2,4-dimethyl-1H-pyrrole-3- carboxamide (3-17j), (Z)-N-(2-(diethylamino)ethyl)-2,4-dimethyl-5-((2-indolinon-3- enyl)methyl)-1H-pyrrole-3-carboxamide (3-19), (Z)-5-((6-((2-(cyclopropylamino)-2- acetyl)amino)-2-indolinon-3-enyl)methyl)-N-(2-(diethylamino)ethyl)-2,4-dimethyl- 1H-pyrrole-3-carboxamide (3-17m) for clinically preparing drugs for treating Hgc27 human gastric cancer;

[0169] The use of the compounds (Z)-5-((6-(3-(3-trifluoromethylphenyl)ureido)-2- indolinon-3-enyl)methyl)-2,4-dimethyl-N-(2-(pyrrolidin-1-yl)ethyl)-1H-pyrrole-3- carboxamide (3-17b), (Z)-5-((6-(3-(3-chlorophenyl)ureido)-2-indolinon-3-enyl)methyl)- N-(2-(diethylamino)ethyl)-2,4-dimethyl-1H-pyrrole-3-carboxamide (3-17e), (Z)-5-((6- (3-(3-trifluoromethylphenyl)ureido)-2-indolinon-3-enyl)methyl)-N-(2-(diethylamino) ethyl)-2,4-dimethyl-1H-pyrrole-3-carboxamide (3-17f), (Z)-5-((6-(3-(3- fluorophenyl)ureido)-2-indolinon-3-enyl)methyl)-N-(2-(diethylamino)ethyl)-2,4- dimethyl-1H-pyrrole-3-carboxamide (3-17k), (Z)-5-((6-(3-(3-nitrophenyl)ureido)-2- indolinon-3-enyl)methyl)-N-(2-(diethylamino)ethyl)-2,4-dimethyl-1H-pyrrole-3- carboxamide (3-17j), (Z)-N-(2-(diethylamino)ethyl)-2,4-dimethyl-5-((2-indolinon-3- enyl)methyl)-1H-pyrrole-3-carboxamide (3-19), (Z)-5-((6-((2-(cyclopropylamino)-2- acetyl)amino)-2-indolinon-3-enyl)methyl)-N-(2-(diethylamino)ethyl)-2,4-dimethyl- 1H-pyrrole-3-carboxamide (3-17m) for the clinical preparation of a medicament for the treatment of HT-29 human colon carcinoma;

[0170] The use of the compounds (Z)-5-((6-(3-(3-nitrophenyl)ureido)-2-indolinon-3- enyl)methyl)-N-(2-(diethylamino)ethyl)-2,4-dimethyl-1H-pyrrole-3-carboxamide (3- 17j), (Z)-N-(2-(diethylamino)ethyl)-2,4-dimethyl-5-((2-indolinon-3-enyl)methyl)-1H- pyrrole-3-carboxamide (3-19) for the clinical preparation of a medicament for the treatment of MCF7 human breast carcinoma.

Claims

1. An indole ketone derivative, characterized in that... The structural formula of the derivative is: Wherein: Compound 3-17a is (Z)-5-((6-(3-(3-chlorophenyl)ureido)-2-indolinone-3- enyl)methyl)-2,4-dimethyl-N-(2-(pyrrolidin-1-yl)ethyl)-1H-pyrrole-3-carboxamide; Compound 3-17b is (Z)-5-((6-(3-(3-trifluoromethylphenyl)ureido)-2-indolinone- 3-enyl)methyl)-2,4-dimethyl-N-(2-(pyrrolidin-1-yl)ethyl)-1H-pyrrole-3-carboxamide; Compound 3-17c is (Z)-5-((6-(3-(3-cyanophenyl)ureido)-2-indolinone-3-enyl) methyl)-2,4-dimethyl-N-(2-(pyrrolidin-1-yl)ethyl)-1H-pyrrole-3-carboxamide; Compound 3-17d is (Z)-5-((6-(3-(3-methylphenyl)ureido)-2-indolinone-3-enyl) methyl)-2,4-dimethyl-N-(2-(pyrrolidin-1-yl)ethyl)-1H-pyrrole-3-carboxamide; Compound 3-17e is (Z)-5-((6-(3-(3-chlorophenyl)ureido)-2-indolinone-3-enyl) methyl)-N-(2-(diethylamino)ethyl)-2,4-dimethyl-1H-pyrrole-3-carboxamide; Compound 3-17f is (Z)-5-((6-(3-(3-trifluoromethylphenyl)ureido)-2-indolinone- 3-enyl)methyl)-N-(2-(diethylamino)ethyl)-2,4-dimethyl-1H-pyrrole-3-carboxamide; Compound 3-17g is (Z)-5-((6-(3-(3-cyanophenyl)ureido)-2-indolinone-3-enyl) methyl)-N-(2-(diethylamino)ethyl)-2,4-dimethyl-1H-pyrrole-3-carboxamide; Compound 3-17h is (Z)-5-((6-(3-(3-methylphenyl)ureido)-2-indolinone-3-enyl) methyl)-N-(2-(diethylamino)ethyl)-2,4-dimethyl-1H-pyrrole-3-carboxamide; Compound 3-17i is (Z)-5-((6-(3-(3-methoxyphenyl)ureido)-2-indolinone-3-enyl) methyl)-N-(2-(diethylamino)ethyl)-2,4-dimethyl-1H-pyrrole-3-carboxamide; Compound 3-17j is (Z)-5-((6-(3-(3-nitrophenyl)ureido)-2-indolinone-3-enyl) methyl)-N-(2-(diethylamino)ethyl)-2,4-dimethyl-1H-pyrrole-3-carboxamide; Compound 3-17k is (Z)-5-((6-(3-(3-fluorophenyl)ureido)-2-indolinone-3-enyl) methyl)-N-(2-(diethylamino)ethyl)-2,4-dimethyl-1H-pyrrole-3-carboxamide; Compound 3-17l is (Z)-N-(2-(diethylamino)ethyl)-2,4-dimethyl-5-((2-oxo-6-(5- propylamido-lH-pyrazol-3-yl)indol-3-enyl)methyl)-lH-pyrrole-3-carboxamide; Compound 3-17m is (Z)-5-((6-((2-(cyclopropylamino)-2-oxoacetyl)amino)-2- indolinon-3-enyl)methyl)-N-(2-(diethylamino)ethyl)-2,4-dimethyl-lH-pyrrole-3- carboxamide. Compound 3-17n is (Z)-N-(3-(3-((l-(2-hydroxyethyl)-lH-pyrazol-4-yl)methyl)-2- indolinon-6-yl)-lH-pyrazol-5-yl)propanamide; Compound 3-19 is (Z)-N-(2-(diethylamino)ethyl)-2,4-dimethyl-5-((2-indolinon-3- enyl)methyl)-lH-pyrrole-3-carboxamide.

2. Use of the indolinone derivatives 3-17a, 3-17d, 3-17k according to claim 1 for the preparation of an Aurora B kinase inhibitor.

3. Use of the indolinone derivative 3-19 according to claim 1 for the preparation of a medicament for the treatment of HELA human cervical cancer.

4. Use of the indolinone derivatives 3-17b, 3-17c, 3-17e, 3-17f, 3-17k, 3-17h, 3- 17i, 3-17j, 3-19, 3-17m according to claim 1 for the preparation of a medicament for the treatment of HGC27 human gastric cancer.

5. Use of the indolinone derivatives 3-17b, 3-17e, 3-17f, 3-17k, 3-17j, 3-19, 3- 17m according to claim 1 for the preparation of a medicament for the treatment of HT29 human colon cancer.

6. Use of the indolinone derivatives 3-17j, 3-19 according to claim 1 for the preparation of a medicament for the treatment of MCF7 human breast cancer.

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