CN116554158A - Isoindolinyl-piperazinyl urea compound, and preparation method and application thereof - Google Patents

Isoindolinyl-piperazinyl urea compound, and preparation method and application thereof Download PDF

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CN116554158A
CN116554158A CN202310424098.2A CN202310424098A CN116554158A CN 116554158 A CN116554158 A CN 116554158A CN 202310424098 A CN202310424098 A CN 202310424098A CN 116554158 A CN116554158 A CN 116554158A
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compound
acid
isoindolinyl
cancer
piperazinyl
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徐学军
杨玉坡
杨争艳
段超群
徐红运
裴梦富
刘亚青
李岑
汤善顺
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Henan Radiomedical Science And Technology Co ltd
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Abstract

The invention provides an isoindolinyl-piperazinyl urea compound, a preparation method and application thereof, and the isoindolinyl-piperazinyl urea compound contains a mother nucleus group with biological activity, which is further chemically modified to generate a plurality of compounds with higher biological activity, so that the wide application of the compound in biological medicine and the development prospect of pharmaceutical preparations are expanded. The compound can obviously inhibit proliferation of cells such as breast cancer, liver cancer, pancreatic cancer, gastric cancer and the like at low dose (nanomole), and can effectively inhibit growth of transplanted tumors in mice, so that the compound has a prospect of being developed into antitumor drugs.

Description

Isoindolinyl-piperazinyl urea compound, and preparation method and application thereof
Technical Field
The invention belongs to the field of tumor targeted therapy, and particularly relates to an isoindolinyl-piperazinyl urea compound, a preparation method and application thereof.
Background
Cancer has become a significant cause of premature death and reduced life in the global population. In 2020, there are about 1930 tens of thousands of diagnosed cancer cases worldwide, and nearly 1000 tens of thousands die from cancer. Experts predict that by 2035, cancer patients worldwide will increase by half. Whereas the incidence and mortality of cancer in China are high in a global proportion. About 48.2 ten thousand new cancer cases and about 32.1 ten thousand cancer death cases in 2022 are 2 times and 5 times of those in the United states respectively. Breast cancer has replaced lung cancer and is the first cancer worldwide. Up to 226 ten thousand new cases of breast cancer are worldwide. About 90.57 ten thousand people worldwide were diagnosed with liver cancer in 2020, with about 83.02 ten thousand of death cases. It is expected that the number of diagnosed primary liver cancer and the number of deaths may increase by more than 55% by 2040 years. In addition, the incidence of gastric cancer, pancreatic cancer, and the like is also high, and prognosis is still poor. At present, although the clinical treatment mode of cancer is greatly advanced, due to the heterogeneity and continuous evolution of tumors, the reaction rate of most drugs is low, and drug resistance is easy to occur, so that effective therapeutic drugs are still very lacking. The conventional cytotoxic chemotherapeutics taxol, cisplatin, carboplatin, capecitabine and the like have the advantages of wide anticancer spectrum and good curative effect, but have large toxic and side effects and are easy to resist early. Therefore, active research and development of new anticancer drugs has important clinical significance.
The isoindolinyl-piperazinyl urea compounds with novel structural formulas are synthesized. Through analysis of some biological technologies, the compounds can obviously inhibit proliferation of breast cancer, liver cancer, pancreatic cancer and gastric cancer cells at very low dose, and the drug effect of resisting the breast cancer in animals is close to that of albumin-bound taxol, and has no obvious toxic or side effect. Therefore, further development of such compounds would be of great significance in the application of tumor therapy.
Disclosure of Invention
The invention aims to provide an isoindolinyl-piperazinyl urea compound, and a preparation method and application thereof.
Based on the above purpose, the invention adopts the following technical scheme:
an isoindolinyl-piperazinyl urea compound with a structural formula shown in a general formula I:
wherein R is 1 Selected from H, F, cl, br, I, -CN, -CH 3 、-CF 3 、-OCH 3 、-OCF 3 、or-SO 2 NH 2 ；
R 2 Selected from H, F, cl, br, I, -CN, -CH 3 、-CF 3 、-OCH 3 、-OCF 3 、-COOH、OH、
R 3 Selected from H, F, cl, br, I, -CN, -CH 3 、-CF 3 、-OCH 3 、-OCF 3 -COOH or OH;
R 4 selected from H, F, cl, br, I, -CN, -CH 3 、-CF 3 、-OCH 3 、-OCF 3 -COOH or OH;
R 5 selected from H, F, cl, br, I, -CN, -CH 3 、-CF 3 、-OCH 3 、-OCF 3 -COOH or OH;
w, X, G, Q, V, M are each independently selected from C or N;
k is selected from O, NH or CH 2 ；
n＝0,1,2。
The isoindolinyl-piperazinyl urea compound is specifically a compound with the following structure:
and a biologically acceptable salt of the isoindolinyl-piperazinyl urea compound with at least one of acetic acid, dihydrofolate, benzoic acid, citric acid, sorbic acid, propionic acid, oxalic acid, fumaric acid, maleic acid, hydrochloric acid, malic acid, phosphoric acid, sulfurous acid, sulfuric acid, vanilloid, tartaric acid, ascorbic acid, boric acid, lactic acid, and ethylenediamine tetraacetic acid.
The preparation method of the isoindolinyl-piperazinyl urea compound has the following synthetic route:
the specific synthesis steps are as follows:
(1) Dissolving a compound 1, a compound 2 and potassium carbonate in DMF, stirring at 65-75 ℃ for complete reaction, diluting the reaction solution with ethyl acetate, washing with saturated saline, and spin-drying an organic phase to obtain a compound 3;
(2) Dissolving the compound 3 in methanol, adding an ethyl acetate solution of hydrogen chloride, stirring at room temperature, and spin-drying the reaction solution to obtain a compound 4;
(3) Dissolving the compound 5 in dichloromethane, sequentially adding pyridine and triphosgene at-5 ℃, stirring at room temperature to react completely, adding hydrochloric acid and dichloromethane for extraction, drying an organic phase, and spin-drying to obtain a compound 6;
(4) And dissolving the compound 4, the compound 6 and DIEA in THF, stirring at room temperature, completely reacting, spin-drying the reaction solution, and performing column chromatography to obtain the target compound.
Preferably, in step (1), the molar ratio of compound 1, compound 2 and potassium carbonate is 1:1:1.2; in the step (2), the molar ratio of the compound 3 to the hydrogen chloride is 1:10; in the step (3), the molar ratio of the compound 5, triphosgene and pyridine is 1:0.5:1.5; in step (4), the molar ratio of compound 4, compound 6 and DIEA was 1:1.2:3.
The application of the isoindolinyl-piperazinyl urea compound and the biologically acceptable salt thereof in preparing antitumor drugs.
Preferably, the antitumor drug is a drug for treating breast cancer, liver cancer, pancreatic cancer, gastric cancer and the like.
In particular, the method comprises the steps of, the invention synthesizes isoindolinyl-piperazinyl urea compounds IT B-1, ID B-1, isoindolinyl-piperazinyl urea compounds with brand new structures ID B-1, IY A-1, IY B-1, ID B-1, IT B-1, IY A-1, IY B-1, IY C-1 ID B-1, IY A-1, IY B-1 ID B-1, IT B-1, IY A-1, IY B-1, IY C-1. Detecting proliferation inhibition of the compound on various cancer cells by a CCK-8 method; the effect of the compounds on breast cancer growth in vivo was examined by a nude mouse engraftment tumor model.
The results show that the method has the advantages of, the compounds of the present invention IT B-1, ID B-1, IY A-1, IY B-1, ID B-1, IT B-1, IY A-1, IY B-1, IY C-1, ID A-1, ID B-1, ID C-1, IT A-1, IT B-1, IT C-1, IY A-1, IY C-1, IY A-1, and the like IY B-1, IY C-1, ID A-1, ID B-1, ID C-1IY A-1, IY230409A-1, IY230410A-1, IY A-1, and IY A-1, etc. can effectively inhibit proliferation of cells such as breast cancer, liver cancer, pancreatic cancer, and gastric cancer, and significantly inhibit the growth of breast cancer in mice.
In summary, the present invention provides a novel isoindolinyl-piperazinyl urea compound and its derivatives for use in tumor therapy and potential molecular mechanisms.
Drawings
FIG. 1 is a graph showing the evaluation of the antitumor effect of IT230308B-1 (RDp 034) in mice using albumin-bound Paclitaxel (Paclitaxel) as a positive control and a solvent as a blank control.
Detailed Description
In order to make the technical purpose, technical scheme and beneficial effect of the present invention more clear, the technical scheme of the present invention is further described below with reference to the accompanying drawings and specific embodiments.
In the process according to the invention for the synthesis of the compounds of the formula I, the various starting materials used for the reaction are preparable by the person skilled in the art according to the prior art, or can be prepared by methods known from the literature, or can be obtained commercially. The intermediates, raw materials, reagents, reaction conditions and the like used in the above reaction schemes may be appropriately changed according to the knowledge already known to those skilled in the art.
In the present invention, unless otherwise specified, wherein: (i) The temperature is expressed in degrees centigrade (DEG C), and the operation is performed in a room temperature environment; more specifically, the room temperature is 20-30 ℃; (ii) Drying the organic solvent by a common drying method, evaporating the solvent by a rotary evaporator under reduced pressure, wherein the bath temperature is not higher than 50 ℃; the volume ratio of the developing agent to the eluent is equal; (iii) the reaction process is followed by Thin Layer Chromatography (TLC); (iv) The final product had satisfactory proton nuclear magnetic resonance (1H-NMR).
EXAMPLE 1 Synthesis of all Compounds reference the following scheme
The specific synthesis method is exemplified by a compound IT230308B-1, and the structural formula is as follows:
the compound IT230308B-1 is named (4- (4- (2, 2-trifluomethoxy) benzyl) piperaziin-1-yl) (5- ((5- (3- (4- (trifluormethyl) phenyl) -1,2, 4-oxazil-5-yl) oxy) pyraziin-2-yl) metane, and the synthetic route is as follows:
step 1.Tert-butyl 5- ((5- (3- (4- (trifluoromethyl) phenyl) -1,2, 4-oxazo-l-5-yl)
pyrazin-2-yl) oxy) isoinoline-2-carboxylate (Compound 3)
Compound 1 (2.0 g,8.50mmol,1.0 eq), compound 2 (2.78 g,8.50mmol,1.0 eq) and potassium carbonate (1.41 g,10.2mmol,1.2 eq) were dissolved in 30mL DMF and reacted at 70℃for 3 hours, after which the reaction was monitored by TLC. The reaction was diluted with 200mL ethyl acetate, washed three times with saturated brine (200 mL x 3), the organic phase dried and spun-dried and the crude product purified by column (PE/ea=10/1 to 3/1) to give 3.5g of compound 3 as a white solid in 78.3% yield.
1 H NMR(CDCl 3 ,300MHz)δ:9.05(d,J＝1.1Hz,1H),8.70(d,J＝1.1Hz,1H),8.38(d,J＝8.2Hz,2H),7.84(d,J＝8.4Hz,2H),7.35(s,1H),6.95(d,J＝10.0Hz,2H),4.83(s,4H),1.59(s,9H).
Step 2. (4- (2- (piperidine-1-yl) ethoxy) phenyl) methane-nol (Compound 4)
Compound 3 (3.2 g,6.09mmol,1.0 eq) was dissolved in 20mL of methanol, cooled to 0deg.C, 4M hydrogen chloride in ethyl acetate (15.2 mL,60.9mmol,10 eq) was added, and the reaction was allowed to warm to room temperature naturally for 2 hours, and TLC monitoring showed complete reaction of starting material and new points had occurred. The reaction solution was directly dried by spin to obtain 2.75g of Compound 4 as a white solid in 97.8% yield.
1 H NMR(CDCl 3 ,300MHz)δ:9.05(d,J＝1.1Hz,1H),8.70(d,J＝1.1Hz,1H),8.38(d,J＝8.2Hz,2H),7.84(d,J＝8.4Hz,2H),7.35(s,1H),6.95(d,J＝10.0Hz,2H),4.83(s,4H)
Step 3.4- (4- (2, 2-trifluomethoxy) benzyl) piperazine-1-carbonyl chloride (6)
Compound 5 (4.0 g,14.58mmol,1.0 eq) was dissolved in 30mL of dichloromethane, cooled to 0deg.C, and triphosgene (2.16 g,7.29mmol,0.5 eq) and pyridine (1.73 g,21.87mmol,1.5 eq) were added sequentially and reacted for 1 hour at room temperature, followed by TLC monitoring the reaction. The reaction was poured into 1M dilute aqueous hydrochloric acid (150 mL), extracted 3 times with dichloromethane (100 mL x 3), the organic phases combined, dried over anhydrous sodium sulfate and spin-dried to give 710mg of compound (6) as a yellow solid in 92.1% yield.
1 H NMR(CDCl 3 ,400MHz)δ:7.60(s,2H),7.15(d,J＝7.9Hz,2H),4.83-4.78(m,2H),4.35(s,2H),3.57(s,5H),3.17(s,4H),1.34-1.22(m,1H).
Step 4. (4- (4- (2, 2-trifluomethoxy) benzyl) piperazin-1-yl) (5- ((5- (3- (4- (trifluormethyl) phenyl)
-1,2,4-oxadiazol-5-yl)pyrazin-2-yl)oxy)isoindolin-2-yl)methanone(IT230308B-1)
Compound 4 (1.0 g,2.17mmol,1.0 eq), compound 6 (0.87 g,2.60mmol,1.2 eq) and DIEA (0.84 g,6.50mmol,3.0 eq) were dissolved in 25mL THF and reacted at room temperature for 4 hours, after which the reaction was monitored by TLC. The reaction was directly spin-dried over column (DCM/meoh=60:1 to 20:1) to give 1.02g of t230308b-1 as a yellow solid in 65% yield.
1 H NMR(CDCl 3 ,300MHz)δ:9.05(d,J＝1.1Hz,1H),8.70(d,J＝1.1Hz,1H),8.38(d,J＝8.2Hz,2H),7.84(d,J＝8.4Hz,2H),7.38(d,J＝8.6Hz,2H),7.35(s,1H),7.16(d,J＝12.2Hz,2H),6.95(d,J＝10.0Hz,2H),4.83(s,4H),4.39(s,3H),3.66(m,2H),3.55(s,2H),3.43(s,4H),2.53(s,4H).
Examples 2, IT230308B-1, IT230309B-1, IT230310B-1, ID230308B-1, ID230309B-1, ID230310B-1, IY230307A-1, IY230308A-1, IY230309A-1, IY230309B-1, IY230310B-1, IY230312B-1, ID230312B-1, IT230312B-1, IT230313B-1, IY230320A-1, IY230320B-1, IY230320C-1, ID230320A-1, ID230320B-1, ID230320C-1, IT230320A-1, IT230320B-1 inhibition of proliferation of cells such as breast cancer, liver cancer, pancreatic cancer and gastric cancer by IT230320C-1, IY230320A-1, IY230320B-1, IY230320C-1, ID230320A-1, ID230320B-1, ID230320C-1 IY230320A-1, IY230409A-1, IY230410A-1, IY230320A-1 and IY230320A-1
MDA-MB-468, hepG2, bxPC-3 and MKN-45 cells in the logarithmic growth phase were collected, counted and the cell suspension concentration was adjusted to 5X 10 4 Each mL was added to 96-well cell culture plates at a volume of 100. Mu.L per well. The compound IT2303 of the invention is compared with DMSO as a solvent08B-1, IT230309B-1, IT230310B-1, ID230308B-1, ID230309B-1, ID230310B-1, IY230307A-1, IY230308A-1, IY230309A-1, IY230309B-1, IY230310B-1, IY230312B-1, ID230312B-1, IT230312B-1, IT230313B-1, IY230320A-1, IY230320B-1, IY230320C-1, ID230320A-1, ID230320B-1, ID230320C-1, IT230320A-1, IT230320B-1 IT230320C-1, IY230320A-1, IY230320B-1, IY230320C-1, ID230320A-1, ID230320B-1, ID230320C-1 IY230320A-1, I IY230320A-1, IY230409A-1, IY230410A-1, IY230320A-1 and the like are diluted with DMSO and added to a culture well, the final concentrations of the compounds in the system were set to 0.1, 0.3, 1, 3, 10, 30, 100 and 300 (. Mu. Mol/L), respectively. After further culturing for 48h, 10 μl of CCK-8 solvent was added to each well, incubated at 37deg.C for 1h, and the OD value at an absorption wavelength of 450nm was measured, the results were recorded, and the cell growth curve was drawn with the dose of the compound as abscissa and the absorbance as ordinate. The statistics of half-maximal inhibition (IC 50 value) of tumor cells by the compounds are shown in table 1 below:
table 1.CCK-8 detection IT230308B-1, IT230309B-1, IT230310B-1, ID230308B-1, ID230309B-1, ID230310B-1, IY230307A-1, IY230308A-1, IY230309A-1, IY230309B-1, IY230310B-1, IY230312B-1, ID230312B-1, IT230312B-1, IT230313B-1, IY230320A-1, IY230320B-1, IY230320C-1, ID230320A-1, ID230320B-1, ID230320C-1, IT230320A-1, IT230320B-1 inhibition of proliferation of cells such as breast cancer, liver cancer, pancreatic cancer and gastric cancer by IT230320C-1, IY230320A-1, IY230320B-1, IY230320C-1, ID230320A-1, ID230320B-1, ID230320C-1 IY230320A-1, IY230409A-1, IY230410A-1, IY230320A-1 and IY230320A-1
The table shows: IT 230310A-1, IT230310B-1, IT 230310C-1, IY 230310A-1, IY230310B-1, IY 230310C-1, ID 230310A-1 ID230310B-1, ID 230310C-1 IY 230310A-1, IY 230310A-1 IT 230310A-1, IT230310B-1, IT 230310C-1, IY 230310A-1, IY230310B-1, IY 230310C-1, ID 230310A-1, ID230310B-1, ID 230310C-1 IY 230310A-1, I IY 230310A-1, IY230409A-1, IY230410A-1, IY 230310A-1 and the like have good proliferation inhibition effect on breast cancer, liver cancer, pancreatic cancer, gastric cancer and the like, in particular to the tumor inhibiting activity of gastric cancer and breast cancer cells, and the application takes IT230310B-1 as an example to further study the in vivo anti-tumor effect of the compounds.
Example 3, anti-tumor efficacy of IT230308B-1 (RDp 034) in mice.
SPF grade, 20 BALB/c-nude female nude mice of 6 week old and 18-22g weight were purchased from St Bei Fu (Beijing) Biotechnology Co., ltd. Taking MDA-MB-468 cell transplanted tumor tissue which is successfully inoculated subcutaneously before, washing blood dirt by using PBS, cutting into small blocks of 1.5 mm, sucking the small tumor blocks by using a puncture needle, wiping the abdomen of an animal by using an alcohol cotton ball, directly penetrating the skin, and injecting the tumor blocks. The inoculated animals are put back into the original cage for feeding, so that the environment is kept clean, and the infection is avoided. After 1 week of tumor cell inoculation, the inoculation site was observed for the formation of milky white nodules. The major and minor diameters of the tumor were measured with a vernier caliper, and the result was obtained according to the formula (tumor volume=major diameter×minor diameter 2 X 0.5) calculate tumor volume. The tumor volume reaches 100-150mm 3 Time-based grouping and givingMedicine. 18 mice meeting the experimental volume requirements were randomly divided into 3 groups of 6 mice each. The dose of IT230308B-1 (RDp 034) was 5mg/kg per mouse by intraperitoneal injection, the solvent control (10% DMSO+90% corn oil, SUS control) was a blank control, and 5mg/kg of albumin-bound Paclitaxel (Paclitaxel) was a positive control, and 100. Mu.L of each injection was administered 1 time per day for 10 consecutive days. Tumor volume and body weight of mice were measured every other day, and the results are shown in FIG. 1.
The results of FIG. 1A show that on day ten of dosing, the tumor volumes of RDp034 mg/kg and Paclitoxel 5mg/kg were significantly smaller than the placebo group. The results in FIG. 1B show that the difference in the volumes of the transplants from the day after dosing was increasing in the RDp034 mg/kg group and the Paclitoxel 5mg/kg group versus the placebo group. From day six of dosing, the rate of graft tumor growth of Paclitaxel increased, gradually exceeding the tumor volume of RDp034 group. The results in fig. 1C show that the mice in the Paclitaxel group had significantly reduced body weight on day ten, while the mice in the RDp034 group had no significantly reduced body weight. These data indicate that RDp034 has close anticancer efficacy to Paclitaxel in vivo, is not easily resistant to drugs and has few side effects.
In conclusion, the results show that, IT230308B-1, IT230309B-1, IT230310B-1, ID230308B-1, ID230309B-1, ID230310B-1, IY230307A-1, IY230308A-1, IY230309A-1, IY230309B-1, IY230310B-1, IY230312B-1, ID230312B-1, IT230312B-1, IT230313B-1, IY230320A-1, IY230320B-1, IY230320C-1, ID230320A-1, ID230320B-1, ID230320C-1, IT230320A-1, IT230320B-1, IT230320C-1 IY230320A-1, IY230320B-1, IY230320C-1, ID230320A-1, ID230320B-1, ID230320C-1 IY230320A-1, IY230409A-1, IY230410A-1, IY230320A-1, and IY230320A-1, etc. can significantly inhibit proliferation of cells such as breast cancer, liver cancer, pancreatic cancer, stomach cancer, etc., and compared with taxol, IT230320B-1 has better curative effect and safety in mice. Therefore, the medicine has good anticancer effect and development potential.
According to the general way of drug development (conventional anti-tumor in-vitro screening is carried out firstly and then targeted research is carried out), the compound can be applied to cancer treatment drugs related to abnormal cell proliferation, and the anti-tumor drugs can be prepared by salifying with human bodies or mixing with a medicinal carrier.
Finally, what should be said is: the above embodiments are only for illustrating the technical solution of the present invention, and any equivalent replacement of the present invention and modification or partial replacement without departing from the spirit and scope of the present invention should be covered in the scope of the claims of the present invention.

Claims (7)

1. An isoindolinyl-piperazinyl urea compound is characterized by having a structural formula shown in a general formula I:
wherein R is 1 Selected from H, F, cl, br, I, -CN, -CH 3 、-CF 3 、-OCH 3 、-OCF 3 、or-SO 2 NH 2 ；
R 2 Selected from H, F, cl, br, I, -CN, -CH 3 、-CF 3 、-OCH 3 、-OCF 3 、-COOH、OH、
R 3 Selected from H, F, cl, br, I, -CN, -CH 3 、-CF 3 、-OCH 3 、-OCF 3 -COOH or OH;
R 4 selected from H, F, cl, br, I, -CN, -CH 3 、-CF 3 、-OCH 3 、-OCF 3 -COOH or OH;
R 5 selected from H, F, cl, br, I, -CN, -CH 3 、-CF 3 、-OCH 3 、-OCF 3 -COOH or OH;
w, X, G, Q, V, M are each independently selected from C or N;
k is selected from O, NH or CH 2 ；
n＝0,1,2。
2. The isoindolinyl-piperazinyl urea compound according to claim 1, characterized in that it is specifically a compound of the following structure:
3. the biologically acceptable salt of an isoindolinyl-piperazinyl urea of claim 1 or 2 with at least one of acetic acid, dihydrofolate, benzoic acid, citric acid, sorbic acid, propionic acid, oxalic acid, fumaric acid, maleic acid, hydrochloric acid, malic acid, phosphoric acid, sulfurous acid, sulfuric acid, vanillic acid, tartaric acid, ascorbic acid, boric acid, lactic acid, and ethylenediamine tetraacetic acid.
4. The method for preparing the isoindolinyl-piperazinyl urea compound according to claim 1, wherein the synthetic route is as follows:
the specific synthesis steps are as follows:
(1) Dissolving a compound 1, a compound 2 and potassium carbonate in DMF, stirring at 65-75 ℃ for complete reaction, diluting the reaction solution with ethyl acetate, washing with saturated saline, and spin-drying an organic phase to obtain a compound 3;
(2) Dissolving the compound 3 in methanol, adding an ethyl acetate solution of hydrogen chloride, stirring at room temperature, and spin-drying the reaction solution to obtain a compound 4;
(3) Dissolving the compound 5 in dichloromethane, sequentially adding pyridine and triphosgene at-5 ℃, stirring at room temperature to react completely, adding hydrochloric acid and dichloromethane for extraction, drying an organic phase, and spin-drying to obtain a compound 6;
(4) And dissolving the compound 4, the compound 6 and DIEA in THF, stirring at room temperature, completely reacting, spin-drying the reaction solution, and performing column chromatography to obtain the target compound.
5. The method for producing isoindolinyl-piperazinyl urea according to claim 4, wherein in the step (1), the molar ratio of the compound 1, the compound 2 and the potassium carbonate is 1:1:1.2; in the step (2), the molar ratio of the compound 3 to the hydrogen chloride is 1:10; in the step (3), the molar ratio of the compound 5, triphosgene and pyridine is 1:0.5:1.5; in step (4), the molar ratio of compound 4, compound 6 and DIEA was 1:1.2:3.
6. Use of the isoindolinyl-piperazinyl urea compounds and the biologically acceptable salts thereof according to any of claims 1 to 3 for the preparation of antitumor drugs.
7. The use according to claim 6, characterized in that: the antitumor drug is a drug for treating breast cancer, liver cancer, pancreatic cancer and gastric cancer.
CN202310424098.2A 2023-04-13 2023-04-20 Isoindolinyl-piperazinyl urea compound, and preparation method and application thereof Pending CN116554158A (en)

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