CN112142645B

CN112142645B - Diketone indole compound containing urea structure and its preparing method and use

Info

Publication number: CN112142645B
Application number: CN202010267259.8A
Authority: CN
Inventors: 赵桂森; 董俊泽; 景永奎; 王悦桐; 于升平; 禚慧君
Original assignee: Shandong University
Current assignee: Shandong University
Priority date: 2019-06-27
Filing date: 2020-04-08
Publication date: 2021-12-24
Anticipated expiration: 2040-04-08
Also published as: CN112142645A

Abstract

The invention relates to a diketone indole compound containing a urea structure and a preparation method and application thereof. The compound has a structure shown in formula I. The invention also relates to a pharmaceutical composition containing the compound with the structure shown in the formula I. The invention also provides the application of the compound and a composition containing one or more compounds in preparing antitumor drugs.

Description

Diketone indole compound containing urea structure and its preparing method and use

Technical Field

The invention relates to the field of organic compound synthesis and medical application, in particular to a diketone indole compound containing a urea structure and a preparation method and application thereof.

Background

Cancer is the leading cause of death in the global population, with cancer deaths accounting for 13% of all deaths in 2005 (Smith, b.d.; Smith, g.l.; Hurria, a.; Hortobagyi, g.n.; Buchholz, t.a. future of cancer onset in the United States, burdens upper on an imaging, change natures, j.clin. oncol.2009,27, 2758-. Despite the great advances in cancer research, there is still a need to identify new target molecules and develop new therapeutic technologies, and the protein kinase family, which contains over 500 members, represents the major therapeutic target for drug development. Many small molecule kinase inhibitors such as sorafenib and imatinib have been approved for the treatment of cancer (Prakash, c.r.; Raja, s.indolinones as conditioning scfafold as kinase inhibitors: a review. mini. rev. med. chem.2012,12, 98-119.).

Isatin is an important natural product, widely distributed in the human and animal and plant bodies, and plays an important role in regulating biochemistry in various tissues (Hou, L.; Ju, C.; Zhang, J.; Song, J.; Ge, Y.; Wang, Y. Antituer effects of Isatin on human neuroblastoma cell line (SH-SY5Y) and the related mechanism. Eur. J. pharm.2008,589, 27-31.). In many organisms, isatin, an endogenous substance, has been reported in many literatures as to its chemical and pharmaceutical importance, and has anticancer, antibacterial, antiviral, antimalarial, anti-inflammatory, anticonvulsant, and antitubercular effects. The molecular structure of the polypeptide is chemically modified, and the polypeptide also has various biological activities (Popp, P.D. the Chemistry of Isatin. adv. heterocyclic. chem.1975,18, 51-58.). Some compounds based on the isatin structure, such as Semaxanib (Semaxanib), oantinib (Oratinib), Sunitinib (Sunitinib), and Nintedanib (Nintedanib), etc., have been approved by the FDA for marketing or use in preclinical studies and clinical trials (Khan, F.A.; Malik, A.Advances in pharmacology of inflammation and its derivatives: A review. Trop.J.Pharm.Res.2015,14, 1937-. The broad spectrum of biological activities coupled with extensive structural modifications and successful application in clinical practice has stimulated more researchers to study isatin and created a large number of structurally diverse derivatives.

Disclosure of Invention

The invention aims to provide a diketone indole compound with a urea structure and stronger antitumor activity; the invention also aims to provide a preparation method and application of the compound.

In order to achieve the purpose, the invention adopts the following technical scheme:

diketoindole compounds containing urea structure

A diketone indole compound containing a urea structure, or a pharmaceutically acceptable salt or ester thereof, wherein the structure is shown as the general formula I:

wherein R is¹Is alkyl, halogen substituted alkyl, benzene ring, halogen substituted benzene ring, benzyl, halogen substituted benzyl; r²Is hydrogen, halogen, cyano, trifluoromethyl, amino, or C_1～6An alkyl-substituted amino group;

preferably, wherein R¹Is methyl, 4-phenyl, 3, 4-dichlorobenzyl, 4-fluorobenzyl, 4-benzyl; r²Is hydrogen, 4-fluoro, 4-chloro, 3-chloro-4-cyano, 3-cyano, 4-cyano, 3-trifluoromethyl-4-cyano, 4-trifluoromethyl, 4-amino.

Further preferably, the diketone indole compound containing a urea structure is selected from the following compounds:

1- (4- (trifluoromethyl) phenyl) -3- (1-methyl-2, 3-indolidin-5-yl) urea (U1)

1- (3-cyanophenyl) -3- (1-methyl-2, 3-indolidin-5-yl) urea (U2)

1- (4-fluorophenyl) -3- (1-methyl-2, 3-indolidin-5-yl) urea (U3)

1- (4-cyanophenyl) -3- (1-methyl-2, 3-indolidin-5-yl) urea (U4)

1- (3-chloro-4-cyanophenyl) -3- (1-methyl-2, 3-indolidin-5-yl) urea (U5)

1- (3-trifluoromethyl-4-cyanophenyl) -3- (1-methyl-2, 3-indolidin-5-yl) urea (U6)

1- (4- (trifluoromethyl) phenyl) -3- (1- (3, 4-dichlorobenzyl) -2, 3-indolone-5-yl) urea (U7)

1- (3-cyanophenyl) -3- (1- (3, 4-dichlorobenzyl) -2, 3-indolidin-5-yl) urea (U8)

1- (4-fluorophenyl) -3- (1- (3, 4-dichlorobenzyl) -2, 3-indolidin-5-yl) urea (U9)

1- (4-cyanophenyl) -3- (1- (3, 4-dichlorobenzyl) -2, 3-indolidin-5-yl) urea (U10)

1- (3-chloro-4-cyanophenyl) -3- (1- (3, 4-dichlorobenzyl) -2, 3-indolidin-5-yl) urea (U11)

1- (4-cyano-3- (trifluoromethyl) phenyl) -3- (1- (3, 4-dichlorobenzyl) -2, 3-indolone-5-yl) urea (U12)

1- (4- (trifluoromethyl) phenyl) -3- (1- (4-fluorobenzyl) -2, 3-indolidin-5-yl) urea (U13)

1- (3-cyanophenyl) -3- (1- (4-fluorobenzyl) -2, 3-indolidin-5-yl) urea (U14)

1- (4-fluorophenyl) -3- (1- (4-fluorobenzyl) -2, 3-indolidin-5-yl) urea (U15)

1- (4-cyanophenyl) -3- (1- (4-fluorobenzyl) -2, 3-indolidin-5-yl) urea (U16)

1- (3-chloro-4-cyanophenyl) -3- (1- (4-fluorobenzyl) -2, 3-indolidin-5-yl) urea (U17)

1- (4-cyano-3- (trifluoromethyl) phenyl) -3- (1- (4-fluorobenzyl) -2, 3-indolone-5-yl) urea (U18)

The above-mentioned preferred 18 compounds are indicated by their corresponding symbols in parentheses after the names, and for the sake of descriptive convenience and simplicity of expression, the symbols in the above-mentioned parentheses will be directly used in the following description of the present specification.

Preparation method of di-diketone indole compound containing urea structure

The invention relates to a preparation method of a diketone indole compound containing a urea structure, which comprises the following steps:

taking isatin A as a raw material, and carrying out nitration reaction to generate an intermediate B; protecting carbonyl at the position of the intermediate B3 to obtain an intermediate C; carrying out substitution reaction on the intermediate C to obtain an intermediate D; the intermediate D is subjected to reduction reaction to obtain an intermediate E; p-nitrophenyl chloroformate F is used as a raw material and reacts with aniline containing different substituents to obtain an intermediate H; reacting the intermediate E with the intermediate H to obtain an intermediate I, and then carrying out deprotection to obtain a target compound U;

the synthetic route is as follows:

reagents and conditions: (i) fuming nitric acid and concentrated sulfuric acid at 0-5 ℃; (ii) p-toluenesulfonic acid, neopentyl glycol and cyclohexane, wherein the temperature is 80-90 ℃; (iii) potassium carbonate, 3, 4-dichlorobenzyl chloride/4-fluorobenzyl chloride, N, N-Dimethylformamide (DMF), 80-90 ℃ or sodium hydride, methyl iodide, N, N-Dimethylformamide (DMF), 0-5 ℃; (iv) hydrogen, 10% palladium on carbon, ethyl acetate, room temperature; (v) pyridine, dichloromethane, room temperature; (vi) pyridine, 80 ℃; (vii) 90% glacial acetic acid, concentrated hydrochloric acid, room temperature.

According to the preferable preparation method of the diketone indole compound containing the urea structure, the specific steps are as follows:

(1) the raw material A is slowly added into concentrated sulfuric acid and slowly stirred until dissolved. Dropwise adding fuming nitric acid under the condition of ice salt bath; stirring at room temperature after 15min, and detecting complete reaction by TLC after 1 h; pouring the reaction solution into ice water, stirring, gradually precipitating yellow solid, performing suction filtration, washing and drying a filter cake, and recrystallizing with ethyl acetate to obtain an intermediate B;

(2) adding the intermediate B, p-toluenesulfonic acid and neopentyl glycol into a reaction bottle by taking cyclohexane as a solvent, carrying out reflux reaction at 85 ℃ for 24 hours, detecting by TLC to complete the reaction, filtering a solid product, washing a filter cake with water, drying, and recrystallizing with ethyl acetate to obtain an intermediate C;

(3) placing the intermediate C in a reaction bottle, dissolving the intermediate C with DMF, slowly adding sodium hydride in an ice-water bath, stirring for 15min, adding iodomethane into the solution, stirring for 10min, continuously reacting for 3h at room temperature, detecting by TLC to complete the reaction, pouring the reaction solution into ice water, gradually precipitating pale yellow solid, performing suction filtration, washing a filter cake with water, drying, and purifying by column chromatography to obtain an intermediate D1;

(4) intermediate C and K₂CO₃Placing in a reaction flask, dissolving with DMF, adding 3, 4-dichlorobenzyl chloride or p-fluorobenzyl chloride into the above reaction solution, refluxing at 80 deg.C for 4 hr, detecting by TLC, cooling the reaction solution, pouring into water, adding dichloromethane for extraction, standingLayering, combining organic phases, and purifying by column chromatography to obtain intermediates D2 and D3;

(5) placing the intermediate D in a reaction bottle, dissolving the intermediate D with ethyl acetate, adding palladium carbon, connecting the reaction bottle with a hydrogen gas bag, vacuumizing the system, introducing hydrogen, reacting at room temperature overnight, detecting by TLC (thin layer chromatography) for complete reaction, filtering to remove the palladium carbon, evaporating under reduced pressure to remove a solvent, and performing column chromatography separation and purification to obtain an intermediate E;

(6) dissolving aniline and pyridine containing different substituents into a dichloromethane solution, slowly adding p-nitrophenyl chloroformate F under the condition of ice-water bath, removing the ice-water bath after 10min, reacting for 3H at room temperature, completely detecting by TLC (thin layer chromatography), pouring reaction liquid into water, extracting by dichloromethane, standing for layering, combining organic phases, drying, filtering, evaporating a solvent under reduced pressure to obtain an intermediate H, and putting the intermediate H into the next step without purification;

(7) placing the intermediate E and the intermediate H in a reaction bottle, dissolving the intermediate E and the intermediate H by pyridine, heating to 80 ℃, performing reflux reaction for 3 hours, detecting by TLC (thin layer chromatography) to complete the reaction, cooling the reaction liquid, performing reduced pressure evaporation to remove the solvent, and recrystallizing by using petroleum ether/ethyl acetate to obtain an intermediate I;

(8) and (3) placing the intermediate I into a reaction bottle, adding a small amount of concentrated hydrochloric acid by taking glacial acetic acid as a solvent, stirring at room temperature overnight, pouring the reaction solution into water, separating out a red solid, filtering the solid, washing a filter cake with water, drying the product, and recrystallizing with methanol to obtain the target compound U.

Application of diketone indole compound containing urea structure

Experiments show that most compounds have strong growth inhibition effect on human acute promyelocytic leukemia HL-60 cells, IC₅₀The values are low micromolar, such as compounds U8, U9, U10, U11, U15, U16 and U17, and are superior to the positive control AA-2 (chemical name: 1- (3, 4-dichlorobenzyl) -1H-indole-2, 3-dione).

Three compounds U7, U9 and U10 which have strong growth inhibition effect on HL-60 cells are selected from target compounds, and the apoptosis induction effect on the HL-60 cells is determined, experiments show that the three compounds all have strong apoptosis induction activity, wherein the compound U9 has the strongest activity, and has the apoptosis promotion induction effect on the HL-60 cells.

Therefore, the diketone indole compound containing the urea structure can be used for preparing anti-tumor drugs. The tumor is preferably human acute promyelocytic leukemia.

An anti-tumor pharmaceutical composition comprises the diketone indole compound containing the urea structure and one or more pharmaceutically acceptable carriers or excipients.

Drawings

FIG. 1 is a graph of the effect of compounds on the induction of HL-60 apoptosis (24 h); wherein (A) the apoptosis rate of AA-2 at different concentrations; (B) testing the apoptosis rate of a compound at different concentrations;

FIG. 2 is a graph showing the effect of Compound U9 on the induction of apoptosis of HL-60 cells.

Detailed Description

The following experimental examples are only for illustrating the technical effects of the present invention, but the experimental examples are not intended to limit the present invention.

Example 1:

(1) preparation of intermediate B

Raw material A (2g,13.59mmol) was slowly added to 20ml of concentrated sulfuric acid and magnetically stirred until isatin dissolved. Fuming nitric acid (1.24g, 17.67mmol) was added dropwise to the above solution under ice salt bath conditions. After 15min, the deicing salt bath is removed and stirred at room temperature, and after 1h, the TLC detection reaction is complete. The reaction solution was poured into 200ml of ice water, and a large amount of yellow solid was gradually precipitated by stirring. And (4) carrying out suction filtration, washing and drying a filter cake, and recrystallizing with ethyl acetate to obtain an intermediate B.

5-Nitro-2, 3-dione indole (intermediate B)

Yellow solid, 88% yield.¹H NMR(400MHz,DMSO-d₆)δ11.66(s,1H),8.45(dd,J＝8.7,2.4Hz,1H),8.22(d,J＝2.4Hz,1H),7.09(d,J＝8.7Hz,1H).

(2) Preparation of intermediate C

Intermediate B (1.35g,7.03mmol), neopentyl glycol (535mg,7.03mmol) and p-toluenesulfonic acid (484mg, 984. mu. mol) were added to 25ml of cyclohexane and reacted at 85 ℃ under reflux for 24 hours, whereupon a white solid insoluble in cyclohexane precipitated and was checked by TLC to completion. The solid product was filtered and the filter cake was washed with water, dried and recrystallized from ethyl acetate to give intermediate C.

5-Nitro-3- (5, 5-dimethyl-1, 3-dioxane-2-yl) -2-one indole (intermediate C)

White solid, yield 85%.¹H NMR(400MHz,DMSO-d₆)δ11.20(s,1H),8.28(dd,J＝8.7,2.4Hz,1H),8.08(d,J＝2.4Hz,1H),7.04(d,J＝8.7Hz,1H),4.49(d,J＝11.0Hz,2H),3.55(d,J＝11.2Hz,2H),1.34(s,3H),0.84(s,3H).

(3) Preparation of intermediate D

Intermediate C (500mg,1.8mmol) was placed in a 100ml reaction flask, 5ml DMF was added and stirred magnetically until dissolved. Sodium hydride (86.24mg,3.59mmol) was added slowly under ice water bath, and after stirring for 15min, methyl iodide (383mg,2.7mmol) was added dropwise to the above solution. Stirring for 10min, removing ice water bath, reacting at room temperature for 3h, and detecting by TLC to complete reaction. The reaction solution was poured into 50ml of ice water, and a pale yellow solid was gradually precipitated with stirring. Suction filtration, filter cake washing with water, drying and column chromatography purification (petroleum ether: ethyl acetate 2:1), product recrystallization with ethyl acetate, intermediate D1 was obtained.

1-methyl-5-nitro-3- (5, 5-dimethyl-1, 3-dioxan-2-yl) -2-one indole (intermediate D1)

White powdery solid, yield 90%.¹H NMR(400MHz,DMSO-d₆)δ8.39(dd,J＝8.7,2.3Hz,1H),8.10(d,J＝2.3Hz,1H),7.28(d,J＝8.7Hz,1H),4.50(d,J＝10.9Hz,2H),3.56(d,J＝11.1Hz,2H),3.18(s,3H),1.36(s,3H),0.86(s,3H).

Intermediate C (4g,14.37mmol) and K₂CO₃(2.98g,21.56mmol) was placed in a 100ml reaction flask, 20ml DMF was added and stirred magnetically until dissolved. 3, 4-dichlorobenzyl chloride (3.37g,17.25mmol) or p-fluorobenzyl chloride (2.5g,17.25mmol) is dropped into the reaction solution, reflux reaction is carried out for 4h at 80 ℃, and the reaction is detected to be complete by TLC. After the reaction solution was cooled, it was poured into 50ml of water, and extracted by adding methylene chloride (15 ml. times.3). Standing for layering, combining organic phases, drying, filtering, and purifying by column chromatography (petroleum ether: ethyl acetate: 5:1) to obtain intermediates D2 and D3.

1- (3, 4-dichlorobenzyl) -5-nitro-3- (5, 5-dimethyl-1, 3-dioxan-2-yl) -2-one indole (intermediate D2)

White powdery solid, yield 89%.¹H NMR(400MHz,DMSO-d₆)δ8.34(dd,J＝8.7,1.6Hz,1H),8.14(d,J＝2.2Hz,1H),7.64(d,J＝8.7Hz,2H),7.31(d,J＝8.8Hz,1H),7.22(dd,J＝8.3,2.0Hz,1H),4.98(s,2H),4.50(d,J＝11.0Hz,2H),3.61(d,J＝10.9Hz,2H),1.37(s,3H),0.87(s,3H).

1- (4-Fluorobenzyl) -5-nitro-3- (5, 5-dimethyl-1, 3-dioxan-2-yl) -2-one indole (intermediate D3)

White powdery solid, yield 90%.¹H NMR(400MHz,DMSO-d₆)δ8.33(dd,J＝8.7,2.3Hz,1H),8.13(d,J＝2.3Hz,1H),7.36(dd,J＝8.4,5.6Hz,2H),7.28(d,J＝8.8Hz,1H),7.21(t,J＝8.8Hz,2H),4.95(s,2H),4.52(d,J＝11.0Hz,2H),3.61(d,J＝11.1Hz,2H),1.37(s,3H),0.87(s,3H).

(4) Preparation of intermediate E

Intermediate D (640. mu. mol) was placed in a 50ml reaction flask, dissolved in 25ml ethyl acetate and added with 140mg of 60% palladium on carbon. Connecting the reaction bottle with a hydrogen bag, vacuumizing the system, introducing hydrogen, reacting at room temperature overnight, and detecting by TLC to complete the reaction. The palladium-carbon was removed by filtration, the solvent was distilled off under reduced pressure, and the product was purified by column chromatography (petroleum ether: ethyl acetate: 2:1) to give intermediate E.

1-methyl-5-amino-3- (5, 5-dimethyl-1, 3-dioxan-2-yl) -2-one indole (intermediate E1)

White powdery solid, yield 95%.¹H NMR(400MHz,DMSO-d₆)δ6.73(d,J＝2.0Hz,1H),6.67(d,J＝8.2Hz,1H),6.55(dd,J＝8.2,2.1Hz,1H),4.93(s,2H),4.50(d,J＝10.7Hz,2H),3.44(d,J＝10.8Hz,2H),2.98(s,3H),1.29(s,3H),0.82(s,3H).

1- (3, 4-dichlorobenzyl) -5-amino-3- (5, 5-dimethyl-1, 3-dioxan-2-yl) -2-one indole (intermediate E2)

White powdery solid, yield 77%.¹H NMR(400MHz,DMSO-d₆)δ7.63(d,J＝8.3Hz,1H),7.56(d,J＝1.6Hz,1H),7.21(dd,J＝8.3,1.7Hz,1H),6.91(d,J＝1.9Hz,1H),6.75(d,J＝8.3Hz,1H),6.68(t,J＝6.6Hz,1H),6.49(s,2H),4.79(s,2H),4.51(d,J＝10.9Hz,2H),3.52(d,J＝10.9Hz,2H),1.31(s,3H),0.85(s,3H).

1- (4-Fluorobenzyl) -5-amino-3- (5, 5-dimethyl-1, 3-dioxan-2-yl) -2-one indole (intermediate E3)

White powdery solid, yield 95%.¹H NMR(400MHz,DMSO-d₆)δ7.32(dd,J＝8.3,5.6Hz,2H),7.18(t,J＝8.8Hz,2H),6.74(d,J＝2.0Hz,1H),6.61(d,J＝8.3Hz,1H),6.47(dd,J＝8.3,2.1Hz,1H),4.95(s,2H),4.72(s,2H),4.52(d,J＝10.8Hz,2H),3.49(d,J＝10.9Hz,2H),1.30(s,3H),0.84(s,3H).

(5) Preparation of intermediate H

Aniline (4.50mmol) and pyridine (5.40mmol,427mg) containing various substituents were placed in a 50ml reaction flask, 20ml of dichloromethane was added, and after dissolving by magnetic stirring, p-nitrophenyl chloroformate (5.40mmol,1.09g) was slowly added under ice-water bath conditions. After 10min, removing the ice water bath, reacting for 3h at room temperature, and detecting by TLC to complete the reaction. The reaction solution was poured into 50ml of water, extracted with dichloromethane (25 ml. times.3), allowed to stand for separation, the organic phases were combined, dried, filtered, and the solvent was evaporated under reduced pressure to give a white solid which was directly put into the next step without purification.

(6) Preparation of intermediate I

Putting the intermediate E (314.78 mu mol) and the intermediate H (314.78 mu mol) into a reaction bottle, adding 20ml of pyridine, dissolving under magnetic stirring, heating to 80 ℃, refluxing for 3H, and detecting the reaction completion by TLC. After the reaction liquid is cooled, the solvent is evaporated under reduced pressure, and then the intermediate I is obtained by recrystallization with petroleum ether/ethyl acetate.

1- (4-cyanophenyl) -3- (1,5- ',5' -trimethyl-2-oxospiro [ indoline-3, 2' - [1,3] dioxan ] -5-yl) urea (intermediate I1)

White powdery solid, yield 78%.¹H NMR(400MHz,DMSO-d₆)δ9.19(s,1H),8.88(s,1H),7.72(d,J＝8.7Hz,2H),7.68(d,J＝2.0Hz,1H),7.63(d,J＝8.7Hz,2H),7.35(dd,J＝8.4,2.1Hz,1H),6.96(d,J＝8.5Hz,1H),4.52(d,J＝10.8Hz,2H),3.50(d,J＝10.8Hz,2H),3.06(s,3H),1.32(s,3H),0.84(s,3H).

1- (3-cyanophenyl) -3- (1,5- ',5' -trimethyl-2-oxospiro [ indoline-3, 2' - [1,3] dioxan ] -5-yl) urea (intermediate I2)

White powdery solid, yield 76%.¹H NMR(400MHz,DMSO-d₆)δ9.03(s,1H),8.89(s,1H),7.97(s,1H),7.68(d,J＝2.1Hz,2H),7.49(t,J＝7.9Hz,1H),7.42(d,J＝7.6Hz,1H),7.35(dd,J＝8.4,2.0Hz,1H),6.96(d,J＝8.3Hz,1H),4.52(d,J＝10.8Hz,2H),3.50(d,J＝10.8Hz,2H),3.06(s,3H),1.32(s,3H),0.84(s,3H).

1- (3-chloro-4-cyanophenyl) -3- (1,5- ',5' -trimethyl-2-oxospiro [ indoline-3, 2' - [1,3] dioxan ] -5-yl) urea (intermediate I3)

White powdery solid, yield 73%.¹H NMR(400MHz,DMSO-d₆)δ9.41(s,1H),9.01(s,1H),7.94(d,J＝1.9Hz,1H),7.84(d,J＝8.6Hz,1H),7.66(d,J＝2.0Hz,1H),7.47(dd,J＝8.7,1.9Hz,1H),7.36(dd,J＝8.4,2.1Hz,1H),6.97(d,J＝8.4Hz,1H),4.52(d,J＝10.9Hz,2H),3.49(d,J＝10.7Hz,3H),3.06(s,2H),1.32(s,3H),0.84(s,3H).

1- (1- (3, 4-dichlorobenzyl) -5',5' -dimethyl-2-oxospiro [ indoline-3, 2' - [1,3] dioxan ] -5-yl) -3- (4- (trifluoromethyl) phenyl) urea (intermediate I4)

White powdery solid, yield 74%.¹H NMR(400MHz,DMSO-d₆)δ9.07(s,1H),8.83(s,1H),7.76(d,J＝1.9Hz,1H),7.66(d,J＝4.2Hz,1H),7.64(d,J＝5.1Hz,4H),7.60(d,J＝1.6Hz,1H),7.26(dd,J＝8.5,2.0Hz,1H),7.23(dd,J＝8.3,1.6Hz,1H),6.94(d,J＝8.4Hz,1H),4.85(s,2H),4.53(d,J＝10.9Hz,2H),3.56(d,J＝10.8Hz,2H),1.33(s,3H),0.86(s,3H).

1- (1- (3, 4-dichlorobenzyl) -5',5' -dimethyl-2-oxospiro [ indoline-3, 2' - [1,3] dioxan ] -5-yl) -3- (4-cyanophenyl) urea (intermediate I5)

White powdery solid, yield 74%.¹H NMR(400MHz,DMSO-d₆)δ9.19(s,1H),8.89(s,1H),7.74(d,J＝2.1Hz,1H),7.73(s,1H),7.71(s,1H),7.63(t,J＝7.9Hz,3H),7.59(d,J＝1.7Hz,1H),7.26(dd,J＝8.5,2.0Hz,1H),7.23(dd,J＝8.3,1.7Hz,1H),6.94(d,J＝8.5Hz,1H),4.85(s,2H),4.52(d,J＝10.8Hz,2H),3.55(d,J＝10.9Hz,2H),1.33(s,3H),0.86(s,3H).

(7) Preparation of the target Compound

Intermediate I (421. mu. mol) was placed in a reaction flask, and 20ml of glacial acetic acid and 2ml of concentrated hydrochloric acid were added thereto, followed by stirring at room temperature overnight. The reaction solution was poured into 100ml of water, stirred to precipitate a large amount of red solid, the solid was filtered, and the filter cake was washed with water. Drying, filtering and recrystallizing by methanol to obtain a red solid product.

1- (4- (trifluoromethyl) phenyl) -3- (1-methyl-2, 3-indolidin-5-yl) urea (U1)

Red solid, yield 76%, Mp: 273-.¹H NMR(400MHz,DMSO-d₆)δ9.21(s,1H),8.92(s,1H),7.73(d,J＝2.0Hz,1H),7.65(d,J＝3.0Hz,4H),7.63(d,J＝1.8Hz,1H),7.10(d,J＝8.5Hz,1H),3.13(s,3H).¹³C NMR(100MHz,DMSO-d₆)δ184.13(s),158.69(s),152.92(s),146.71(s),143.84(s),135.61(s),128.47(s),126.54(q,2C,J＝3.7Hz),125.02(q,J＝269.3Hz),122.29(q,2C,J＝31.7Hz),118.41(s),117.87(s),115.24(s),111.32(s),26.49(s).HRMS(ESI)m/z for C₁₇H₁₂F₃N₃O₃[M-H]^-:calculated 362.0758found 362.0758.

1- (3-cyanophenyl) -3- (1-methyl-2, 3-indolidin-5-yl) urea (U2)

Red solid, yield 78%, Mp: 257-.¹H NMR(400MHz,DMSO-d₆)δ9.12(s,1H),8.95(s,1H),7.97(s,1H),7.72(d,J＝2.1Hz,1H),7.68(d,J＝9.0Hz,1H),7.63(dd,J＝8.5,2.2Hz,1H),7.50(t,J＝7.9Hz,1H),7.43(d,J＝7.6Hz,1H),7.10(d,J＝8.5Hz,1H),3.13(s,3H).¹³C NMR(100MHz,DMSO-d₆)δ184.13(s),158.69(s),153.05(s),146.73(s),141.00(s),135.59(s),130.66(s),128.51(s),125.88(s),123.47(s),121.37(s),119.34(s),117.87(s),115.30(s),112.04(s),111.32(s),26.50(s).HRMS(ESI)m/z for C₁₇H₁₂N₄O₃[M-H]^-:calculated 319.0837found 319.0835.

1- (4-fluorophenyl) -3- (1-methyl-2, 3-indolidin-5-yl) urea (U3)

Red solid, yield 69%, Mp: 253-.¹H NMR(400MHz,DMSO-d₆)δ8.86(s,2H),7.72(d,J＝2.1Hz,1H),7.61(dd,J＝8.5,2.2Hz,1H),7.46(dd,J＝9.0,4.9Hz,2H),7.13(t,J＝8.9Hz,2H),7.09(d,J＝8.5Hz,1H),3.37(s,3H).¹³C NMR(100MHz,DMSO-d₆)δ184.22(s),158.68(s),157.83(d,J＝236.0Hz)，153.28(s),146.39(s),136.41(d,J＝2.3Hz),136.11(s),128.05(s),120.47(d,2C,J＝7.7Hz),117.85(s),115.75(d,2C,J＝22.0Hz),114.88(s),111.31(s),26.48(s).HRMS(ESI)m/z for C₁₆H₁₂FN₃O₃[M-H]^-:calculated 312.0790found 312.0785.

1- (4-cyanophenyl) -3- (1-methyl-2, 3-indolidin-5-yl) urea (U4)

Red solid, yield 80%, Mp:257-260 ℃.¹H NMR(400MHz,DMSO-d₆)δ9.43(s,1H),9.11(s,1H),7.73(d,J＝8.6Hz,3H),7.63(d,J＝8.7Hz,3H),7.10(d,J＝8.4Hz,1H),3.13(s,3H).¹³C NMR(100MHz,DMSO-d₆)δ184.15(s),158.68(s),152.90(s),146.61(s),144.70(s),135.68(s),133.80(2C,s),127.82(s),119.82(s),118.20(2C,s),117.91(s),114.63(s),111.44(s),103.54(s),26.50(s).HRMS(ESI)m/z for C₁₇H₁₂N₄O₃[M-H]^-:calculated 319.0837found 319.0840.

1- (3-chloro-4-cyanophenyl) -3- (1-methyl-2, 3-indolidin-5-yl) urea (U5)

Red solid, yield 65%, Mp: 278-.¹H NMR(400MHz,DMSO-d₆)δ9.52(s,1H),9.10(s,1H),7.94(d,J＝1.8Hz,1H),7.85(d,J＝8.6Hz,1H),7.71(d,J＝2.1Hz,1H),7.65(dd,J＝8.5,2.1Hz,1H),7.47(dd,J＝8.7,1.8Hz,1H),7.11(d,J＝8.4Hz,1H),3.13(s,3H).¹³C NMR(100MHz,DMSO-d₆)δ184.04(s),158.70(s),152.58(s),147.03(s),145.82(s),136.53(s),135.53(s),135.12(s),128.83(s),118.41(s),117.88(s),117.33(s),116.97(s),115.57(s),111.34(s),104.16(s),26.51(s).HRMS(ESI)m/z for C₁₇H₁₁ClN₄O₃[M-H]^-:calculated 353.0447found 353.0434.

Red solid, yield 70%, Mp:282-285 ℃.¹H NMR(400MHz,DMSO-d₆)δ10.14(s,1H),9.53(s,1H),8.19(d,J＝1.5Hz,1H),8.04(d,J＝8.6Hz,1H),7.78(dd,J＝8.6,1.5Hz,1H),7.72(d,J＝2.1Hz,1H),7.64(dd,J＝8.5,2.2Hz,1H),7.12(d,J＝8.5Hz,1H),3.13(s,3H).¹³C NMR(100MHz,DMSO-d₆)δ184.04(s),158.71(s),152.70(s),147.15(s),145.13(s),136.80(s),135.05(s),129.06(s),122.85(q,J＝272.0Hz),121.51(s),117.90(s),116.51(s),115.94(q,J＝5.0Hz),115.78(s),111.34(s),105.00(s),100.28(s),26.52(s).HRMS(ESI)m/z for C₁₈H₁₁F₃N₄O₃[M-H]^-:calculated 387.0711found 387.0690.

Red solid, yield 80%, Mp: 249-.¹H NMR(400MHz,DMSO-d₆)δ9.19(s,1H),8.91(s,1H),7.79(dd,J＝5.5,1.9Hz,2H),7.64(d,J＝1.6Hz,4H),7.62(d,J＝8.4Hz,1H),7.50(dd,J＝8.5,2.2Hz,1H),7.46(dd,J＝8.4,1.8Hz,1H),6.89(d,J＝8.5Hz,1H),4.90(s,2H).¹³C NMR(100MHz,DMSO-d₆)δ183.47(s),159.06(s),152.92(s),145.21(s),143.83(s),137.38(s),135.72(s),131.76(s),131.18(s),130.59(s),129.85(s),129.13(s),128.23(s),128.18(s),126.53(q,2C,J＝4.0Hz),125.20(q,J＝269.3Hz),122.31(d,J＝32.2Hz),118.55(s),118.42(s),115.47(s),111.65(s),42.30(s).HRMS(ESI)m/z for C₂₃H₁₄Cl₂F₃N₃O₃[M-H]^-:calculated 506.0292found 506.0286.

Red solid, yield 78%, Mp: 268-.¹H NMR(400MHz,DMSO-d₆)δ9.11(s,1H),8.95(s,1H),7.96(s,1H),7.79(d,J＝2.0Hz,2H),7.67(d,J＝8.2Hz,1H),7.62(d,J＝8.3Hz,1H),7.48(d,J＝8.5Hz,2H),7.43(t,J＝5.6Hz,2H),6.88(d,J＝8.5Hz,1H),4.90(s,2H).¹³C NMR(100MHz,DMSO-d₆)δ183.46(s),159.06(s),153.05(s),145.22(s),140.99(s),137.37(s),135.70(s),131.76(s),131.18(s),130.65(s),130.59(s),129.85(s),128.23(s),127.83(s),125.89(s),123.47(s),121.37(s),119.32(s),118.54(s),115.54(s),112.06(s),111.63(s),42.30(s).HRMS(ESI)m/z for C₂₃H₁₄Cl₂N₄O₃[M-H]^-:calculated 463.0370found 463.0355.

Red solid, 73% yield, Mp: 264-.¹H NMR(400MHz,DMSO-d₆)δ8.77(s,2H),7.82–7.74(m,2H),7.62(d,J＝8.3Hz,1H),7.46(td,J＝8.4,3.4Hz,4H),7.12(t,J＝8.8Hz,2H),6.87(d,J＝8.5Hz,1H),4.90(s,2H).¹³C NMR(100MHz,DMSO-d₆)δ183.54(s),164.38(s),157.87(d,J＝237.0Hz),153.23(s),144.92(s),137.40(s),136.35(d,J＝2.3Hz),136.14(s),131.75(s),131.18(s),130.58(s),129.84(s),128.22(s),127.90(s),120.57(d,2C,J＝7.7Hz),118.51(s),115.75(d,2C,J＝22.2Hz),115.25(s),111.61(s),42.28(s).HRMS(ESI)m/z for C₂₂H₁₄Cl₂FN₃O₃[M-H]^-:calculated 456.0324found 456.0309.

Red solid in 83% yield, Mp:267- & 270 ℃.¹H NMR(400MHz,DMSO-d₆)δ9.79(s,1H),9.49(s,1H),7.78(s,2H),7.73(d,J＝8.5Hz,2H),7.64(s,1H),7.63–7.58(m,2H),7.50(d,J＝8.4Hz,1H),7.45(d,J＝8.8Hz,1H),6.91(d,J＝8.4Hz,1H),4.90(s,2H).¹³C NMR(100MHz,DMSO-d₆)δ183.45(s),159.05(s),152.83(s),145.20(s),144.64(s),137.37(s),135.69(s),133.77(2C,s),131.75(s),131.17(s),130.58(s),129.85(s),129.12(s),128.22(s),119.79(s),118.57(s),118.38(2C,s),115.19(s),111.69(s),103.68(s),42.31(s).HRMS(ESI)m/z for C₂₃H₁₄Cl₂N₄O₃[M-H]^-:calculated 463.0370found 463.0360.

Red solid, yield 75%, Mp 245-.¹H NMR(400MHz,DMSO-d₆)δ9.50(s,1H),9.09(s,1H),7.93(d,J＝1.8Hz,1H),7.85(d,J＝8.6Hz,1H),7.80–7.75(m,2H),7.62(d,J＝8.3Hz,1H),7.50(dd,J＝8.5,2.3Hz,1H),7.46(dd,J＝8.6,1.7Hz,2H),6.89(d,J＝8.5Hz,1H),4.90(s,2H).¹³C NMR(100MHz,DMSO-d₆)δ183.37(s),159.07(s),152.58(s),145.81(s),145.49(s),137.35(s),136.53(s),135.53(s),135.23(s),131.75(s),131.18(s),130.59(s),129.84(s),129.13(s),128.52(s),128.23(s),118.41(s),117.34(s),116.97(s),115.79(s),111.65(s),104.17(s),42.30(s).HRMS(ESI)m/z for C₂₃H₁₃Cl₃N₄O₃[M-H]^-:calculated 498.9955found 498.9946.

Red solid, yield 85%, Mp: 247-.¹H NMR(400MHz,DMSO-d₆)δ9.70(s,1H),9.15(s,1H),8.19(s,1H),8.04(d,J＝8.5Hz,1H),7.78(d,J＝1.9Hz,3H),7.62(d,J＝8.3Hz,1H),7.53(dd,J＝8.5,1.8Hz,1H),7.46(dd,J＝8.4,1.2Hz,1H),6.89(d,J＝8.5Hz,1H),4.91(s,2H).¹³C NMR(100MHz,DMSO-d₆)δ183.36(s),172.47(s),159.07(s),152.68(s),145.59(s),145.10(s),137.34(s),136.80(s),135.16(s),132.22(q,J＝32.3Hz),131.75(s),131.18(s),130.60(s),129.85(s),129.13(s),128.70(s),128.23(s),127.83(s),120.12(q,J＝283.5Hz),116.50(s),115.94(s),111.65(s),100.27(s),55.38(s).HRMS(ESI)m/z for C₂₄H₁₃Cl₂F₃N₄O₃[M-H]^-:calculated 531.0244found531.0226.

Red solid, yield 82%, Mp: 262-.¹H NMR(400MHz,DMSO-d₆)δ9.18(s,1H),8.90(s,1H),7.76(dd,J＝11.3,2.0Hz,1H),7.67–7.61(m,3H),7.54–7.44(m,3H),7.18(t,J＝8.8Hz,2H),6.91(t,J＝7.6Hz,1H),4.88(s,2H).¹³C NMR(100MHz,DMSO-d₆)δ183.70(s),162.04(d,J＝242Hz),158.87(s),152.91(s),145.47(s),143.82(s),135.70(s),132.25(d,J＝2.0Hz),130.00(d,2C,J＝8.2Hz),128.32(s),126.55(q,2C,J＝2.6Hz),125.02(q,J＝268.6Hz),122.30(q,J＝32.0Hz),118.41(2C,s),118.31(s),115.89(d,2C,J＝21.0Hz),115.48(s),111.81(s),42.66(s).HRMS(ESI)m/z for C₂₃H₁₅F₄N₃O₃[M-H]^-:calculated 456.0977found 456.0964.

1- (3-cyanophenyl) -3- (1- (4-fluorobenzyl) -2, 3-indolidin-5-yl) urea (U14)

Red solid, yield 70%, Mp: 230-.¹H NMR(400MHz,DMSO-d₆)δ9.14(s,1H),8.98(s,1H),7.96(s,1H),7.77(d,J＝2.1Hz,1H),7.67(d,J＝9.0Hz,1H),7.49(t,J＝7.6Hz,4H),7.43(d,J＝7.6Hz,1H),7.18(t,J＝8.8Hz,2H),6.92(d,J＝8.5Hz,1H),4.88(s,2H).¹³C NMR(100MHz,DMSO-d₆)δ183.70(s),172.51(s),162.04(d,J＝242.0Hz),158.86(s),153.04(s),145.47(s),140.99(s),135.71(s),132.25(d,J＝2.9Hz),130.65(s),130.00(d,2C,J＝8.2Hz),128.31(s),125.87(s),123.43(s),121.33(s),118.30(s),115.88(d,2C,J＝22.0Hz),115.49(s),112.05(s),111.80(s),42.67(s).HRMS(ESI)m/z for C₂₃H₁₅FN₄O₃[M-H]^-:calculated 413.1055found413.1037.

1- (4-fluorophenyl) -3- (1- (4-fluorobenzyl) -2, 3-indolidin-5-yl) urea (U15)

Red solid, yield 75%, Mp: 255-.¹H NMR(400MHz,DMSO-d₆)δ8.76(d,J＝3.0Hz,2H),7.78(d,J＝2.0Hz,1H),7.48(dd,J＝14.9,6.1Hz,4H),7.44(d,J＝5.0Hz,1H),7.18(t,J＝8.8Hz,2H),7.12(t,J＝8.8Hz,2H),6.91(d,J＝8.5Hz,1H),4.88(s,2H).¹³C NMR(100MHz,DMSO-d₆)δ183.77(s),162.04(d,J＝242.0Hz),158.86(s),157.87(d,J＝237.0Hz),153.23(s),145.20(s),136.34(d,J＝2.0Hz),136.13(s),132.27(d,J＝2.9Hz),130.00(d,2C,J＝8.2Hz),128.07(s),120.56(d,2C,J＝8.0Hz),118.28(s),115.89(d,2C,J＝21.0Hz),115.75(d,2C,J＝22.0Hz),115.27(s),111.78(s),42.66(s).HRMS(ESI)m/z for C₂₂H₁₅F₂N₃O₃[M-H]^-:calculated406.1009found 406.0989.

1- (4-cyanophenyl) -3- (1- (4-fluorobenzyl) -2, 3-indolidin-5-yl) urea (U16)

Red solid, yield 79%, Mp: 265-.¹H NMR(400MHz,DMSO-d₆)δ9.29(s,1H),8.97(s,1H),7.77(d,J＝2.2Hz,1H),7.73(d,J＝8.7Hz,2H),7.63(d,J＝8.8Hz,2H),7.51(dd,J＝8.0,2.5Hz,2H),7.48(s,1H),7.18(t,J＝8.8Hz,2H),6.93(d,J＝8.5Hz,1H),4.88(s,2H).¹³C NMR(100MHz,DMSO-d₆)δ183.67(s),162.04(d,J＝242.0Hz),158.87(s),152.74(s),145.58(s),144.56(s),135.53(s),133.75(2C,s),132.24(d,J＝3.0Hz),130.00(d,2C,J＝8.2Hz),128.42(s),119.77(s),118.59(2C,s),118.32(s),115.89(d,2C,J＝21.0Hz),115.57(s),111.82(s),103.81(s),42.67(s).HRMS(ESI)m/z for C₂₃H₁₅FN₄O₃[M-H]^-:calculated 413.1055found 413.1030.

Red solid, yield 76%, Mp: 253-.¹H NMR(400MHz,DMSO-d₆)δ9.50(s,1H),9.08(s,1H),7.92(d,J＝1.8Hz,1H),7.84(d,J＝8.6Hz,1H),7.76(d,J＝2.1Hz,1H),7.54–7.43(m,4H),7.18(t,J＝8.8Hz,2H),6.93(d,J＝8.5Hz,1H),4.88(s,2H).¹³C NMR(100MHz,DMSO-d₆)δ183.61(s),162.04(d,J＝242.0Hz),158.87(s),152.58(s),145.81(s),145.77(s),136.53(s),135.54(s),135.23(s),132.22(d,J＝2.9Hz),130.00(d,2C,J＝8.2Hz),128.65(s),118.40(s),118.33(s),117.32(s),116.97(s),115.89(d,2C,J＝21.0Hz),111.82(s),104.16(s),42.68(s).HRMS(ESI)m/z for C₂₃H₁₄ClFN₄O₃[M-H]^-:calculated 447.0666found 447.0652.

Red solid, yield 78%, Mp: 257-.¹H NMR(400MHz,DMSO-d₆)δ9.69(s,1H),9.14(s,1H),8.19(d,J＝1.4Hz,1H),8.04(d,J＝8.6Hz,1H),7.78(d,J＝10.6Hz,2H),7.54(dd,J＝8.5,2.2Hz,1H),7.49(dd,J＝8.4,5.6Hz,2H),7.18(t,J＝8.8Hz,2H),6.94(d,J＝8.5Hz,1H),4.88(s,2H).¹³C NMR(100MHz,DMSO-d₆)δ183.59(s),162.05(d,J＝242.0Hz),158.88(s),152.67(s),145.85(s),145.10(s),136.80(s),135.15(s),132.38(s),132.22(d,J＝3.0Hz),132.06(s),130.00(d,2C,J＝8.2Hz),128.82(s),125.28(q,J＝272.0Hz),121.48(s),118.32(s),116.52(s),115.97(q,J＝5.0Hz),115.88(d,2C,J＝22.0Hz),111.81(s),100.27(s),42.68(s).HRMS(ESI)m/z for C₂₄H₁₄F₄N₄O₃[M-H]^-:calculated 481.0929found 481.0910.

Example 2: growth inhibition experiment of compound on human acute promyelocytic leukemia HL-60 cells

Acute granulocyte leukemia cell line HL-60, inoculated in a culture medium containing 10% fetal calf serum, 100U/ml penicillin, 100U/ml streptomycin and 0.2% NaHCO₃In RPMI-1640 culture medium, was placed at 37 ℃ in 5% CO₂And culturing in an incubator with saturated humidity. Weighing trypan blue, adding a small amount of distilled water, grinding, adding double distilled water to dilute to 4%, filtering with filter paper, and storing at 4 ℃. When in use, the mother liquor is diluted to 0.4 percent by PBS, and the working solution is obtained. Taking HL-60 cells (5X 10)⁴Per mL) were seeded in 24-well plates, 2mL per well. Adding drugs with different concentrations for incubation to prepare single cell suspension, taking 50 mu L of cell suspension, adding 50 mu L of 0.4% trypan blue g working solution, mixing uniformly, observing under a microscope within 3min, wherein dead cells are dyed blue, and living cells are rejected. The total and dead cells were counted separately using a blood cell counting plate, and the growth inhibition rate was calculated: growth inhibition (%) was 1- (number of viable cells + number of dead cells)/total number of cells of control group × 100%; computing IC using software₅₀The value is obtained. The results are shown in Table 1.

TABLE 1 results of growth inhibitory Activity of target Compounds on HL-60 cells

As can be seen from the above table, the results of the growth inhibition effect on the acute myeloblastic leukemia cell line HL-60 show that the median growth inhibition concentration IC of most compounds₅₀The values are in the low micromolar range, where compounds U9, U10 and U15 inhibit the growth of HL-60 cells by more than 10 times that of the positive control AA-2(1- (3, 4-dichlorobenzyl) -1H-indole-2, 3-dione).

Example 3: experiment of apoptosis-inducing effect of compound on HL-60 cells

(1) Experiment of fluorescence double staining method of Acridine Orange (AO)/Ethidium Bromide (EB)

Taking HL-60 cells in logarithmic growth phase at 1 × 10⁵The density of each ml is inoculated in a 24-hole plate, 2ml is added in each hole, and the medicine to be tested with the corresponding concentration is added after the inoculation is finished. After 24h of drug treatment, 1ml of cell suspension was aspirated from each well and transferred to a 1.5ml EP tube, centrifuged at 1500rpm for ten minutes, the supernatant was discarded, and the cells were resuspended in 25 μ l PBS. Mu.l of each of 100. mu.g/ml Acridine Orange (AO) and Ethidium Bromide (EB) staining solutions were added to the cell suspension and mixed well, 20. mu.l of each staining solution was pipetted from the cell suspension and dropped onto a slide glass, the slide glass was mounted with a cover slip, and the cells were observed and photographed under a fluorescence microscope. When counted, cells that are resistant to EB staining and exhibit nuclear shrinkage, sprouting, foaming and apoptotic bodies are considered apoptotic cells. The percentage of the number of apoptotic cells to the total number of cells (greater than or equal to 300 cells) is the apoptosis rate (the apoptosis rate is the number of apoptotic cells/300 cells x 100%) when counting different regions under the mirror. The experimental result (figure 1) shows that compared with the positive control drug AA-2, three compounds selected and measured, namely, U7, U9 and U10 have stronger apoptosis induction activity, wherein the activity of the compound U9 is strongest.

(2) PI staining experiment

The suspension cells were counted at 10X 10⁴Adding the mixture into a 6-hole plate at a rate of 10 ml/hole; treating with drug for 24h, collecting all cells in a 10mL centrifuge tube, centrifuging at 1500r/s for 10min, discarding supernatant, re-suspending with 1mL PBS and transferring to an EP tube, centrifuging to discard supernatant, re-suspending with 700 μ L PBS, and dropwise adding into 10mL glacial ethanol overnight; the ice-ethanol is removed by centrifugation,resuspending with 600 μ L PBS containing 1mg/mLRNA enzyme, incubating at 37 deg.C for 30min, and adding PI staining solution; and detecting the sample by using a flow cytometer, and collecting 10000 cells for data analysis. The experimental results (figure 2) further show that the compound U9 has a pro-apoptosis inducing effect on HL-60 cells.

Claims

1. A diketone indole compound containing a urea structure or a pharmaceutically acceptable salt thereof, which is characterized in that the structure is shown as a general formula I:

wherein R is¹Is methyl, 3, 4-dichlorobenzyl, 4-fluorobenzyl, 4-chlorobenzyl; r²Is 4-fluoro, 4-chloro, 3-chloro-4-cyano, 3-cyano, 4-cyano, 3-trifluoromethyl-4-cyano, 4-trifluoromethyl, 4-amino.

2. The diketoindoles containing a urea structure as claimed in claim 1, wherein one of the following:

1- (1-methyl-2, 3-indolidin-5-yl) -3- (4- (trifluoromethyl) phenyl) urea (U1)

1- (3-cyanophenyl) -3- (1-methyl-2, 3-indolidin-5-yl) urea (U2)

1- (4-fluorophenyl) -3- (1-methyl-2, 3-indolidin-5-yl) urea (U3)

1- (4-cyanophenyl) -3- (1-methyl-2, 3-indolidin-5-yl) urea (U4)

1- (3-chloro-4-cyanophenyl) -3- (1-methyl-2, 3-indolidin-5-yl) urea (U5)

1- (1- (3, 4-dichlorobenzyl) -2, 3-indolidin-5-yl) -3- (4- (trifluoromethyl) phenyl) urea (U7)

1- (1- (3, 4-dichlorobenzyl) -2, 3-indolidin-5-yl) -3- (4-fluorophenyl) urea (U9)

1- (1- (4-fluorobenzyl) -2, 3-indolidin-5-yl) -3- (4- (trifluoromethyl) phenyl) urea (U13)

1- (3-cyanophenyl) -3- (1- (4-fluorobenzyl) -2, 3-indolidin-5-yl) urea (U14)

1- (1- (4-fluorobenzyl) -2, 3-indolidin-5-yl) -3- (4-fluorophenyl) urea (U15)

1- (4-cyanophenyl) -3- (1- (4-fluorobenzyl) -2, 3-indolidin-5-yl) urea (U16)

1- (4-cyano-3- (trifluoromethyl) phenyl) -3- (1- (4-fluorobenzyl) -2, 3-indolidin-5-yl) urea (U18).

3. The method for preparing a diketoindole compound having a urea structure according to claim 2, comprising the steps of:

the synthetic route is as follows:

4. The method for preparing the diketone indole compound containing the urea structure according to claim 3, comprising the following steps:

(1) slowly adding the raw material A into concentrated sulfuric acid, and slowly stirring until the raw material A is dissolved; dropwise adding fuming nitric acid under the condition of ice salt bath; stirring at room temperature after 15min, and detecting complete reaction by TLC after 1 h; pouring the reaction solution into ice water, stirring, gradually precipitating yellow solid, performing suction filtration, washing and drying a filter cake, and recrystallizing with ethyl acetate to obtain an intermediate B;

(4) intermediate C and K₂CO₃Placing the mixture into a reaction bottle, dissolving the mixture with DMF, adding 3, 4-dichlorobenzyl chloride or p-fluorobenzyl chloride into the reaction solution, carrying out reflux reaction for 4 hours at the temperature of 80 ℃, detecting by TLC to completely react, cooling the reaction solution, pouring the cooled reaction solution into water, adding dichloromethane for extraction, standing for layering, combining organic phases, and purifying by column chromatography to obtain intermediates D2 and D3;

(5) placing the intermediate D1-D3 in a reaction bottle, dissolving the intermediate with ethyl acetate, adding 10% palladium carbon, connecting the reaction bottle with a hydrogen bag, vacuumizing the system, introducing hydrogen, reacting overnight at room temperature, detecting by TLC (thin layer chromatography) to complete the reaction, filtering to remove the palladium carbon, evaporating the solvent under reduced pressure, and separating and purifying by column chromatography to obtain an intermediate E;

(8) and (3) placing the intermediate I into a reaction bottle, adding a small amount of concentrated hydrochloric acid by taking 90% glacial acetic acid as a solvent, stirring at room temperature overnight, pouring the reaction solution into water, separating out red solid, filtering the solid, washing a filter cake with water, drying the product, and recrystallizing with methanol to obtain the target compound U.

5. Use of the diketoindoles containing a urea structure according to claim 1 or 2 for the preparation of antitumor medicaments.

6. The use according to claim 5, wherein the neoplasm is human acute promyelocytic leukemia.

7. An antitumor pharmaceutical composition comprising the diketone indole compound containing a urea structure according to claim 1 or 2 and one or more pharmaceutically acceptable carriers or excipients.