CN108129460B - Methoxyphenylbenzo [ d ] aza-quinazoline compound and preparation and application thereof - Google Patents
Methoxyphenylbenzo [ d ] aza-quinazoline compound and preparation and application thereof Download PDFInfo
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Abstract
The invention discloses methoxyphenyl benzo [ d]Aza derivatives
A quinazoline compound, a preparation method and an application thereof. The invention provides methoxyphenyl benzo [ d]Aza derivatives
The quinazoline compound has obvious inhibition activity on human breast cancer cell strains MCF-7 and human lung cancer cell strains A-549, and is expected to be applied to preparation of medicaments for preventing or treating human breast cancer and human lung cancer. The invention provides the methoxyphenyl benzo [ d]Aza derivatives
Description
(I) technical field
The invention relates to a methoxyphenyl benzo [ d]Aza derivatives
A quinazoline compound, a preparation method thereof and application of the compound in preparing medicaments for preventing or treating tumor diseases.
(II) background of the invention
The quinazoline compounds have a plurality of good biological activities and are widely applied in the field of medicine, particularly, some quinazoline derivatives with special structures have obvious antiviral activity, antibacterial activity, antitumor activity and the like, and the quinazoline compounds are marketed as antitumor drugs. For example, Gefitinib (Gefitinib) and Erlotinib (Erlotinib) are marketed for the treatment of lung cancer, and Lapatinib (Lapatinib) is marketed for the treatment of breast cancer, both of which belong to the quinazoline class of compounds. Novel quinazoline compounds and their biological activities are also commonly reported in the literature (see y. -y. ke, h. -y. shiao, y. c. hsu, c. -y. chu, w. -c. wang, y. -c. lee, w. -h. lin, c. -h. chen, j. t. a. hsu, c. -w. chang, c. -w. lin, t. -k. yeh, y. -s. chao, m.s. coumar, h. -p. hsieh, chemed chem 2013,8, 136-148; a.garofalo, a.farce, s.ravez, a.lemoine, p.six, p.vachatte, l.gos, p.depenux, j.chem. 1204, d. chem. 1189). Of course most quinazoline compounds do not have anti-tumor activity.
Disclosure of the invention
The invention aims to provide a novel quinazoline compound-methoxyphenyl benzo [ d]Aza derivatives
The quinazoline compound has obvious inhibition rate on human breast cancer cell strains MCF-7 and human lung cancer cell strains A-549 under certain dosage; and the preparation method of the compound is simple and convenient, easy to operate, easy to obtain raw materials, low in production cost and suitable for industrial application.
In order to achieve the purpose, the invention adopts the following technical scheme:
in a first aspect, the present invention provides a methoxyphenyl benzo [ d ] of formula (I)]Aza derivatives
The quinazoline compound is a quinazoline compound which is a quinazoline compound,
in a second aspect, the present invention provides a methoxyphenyl benzo [ d ] of formula (I)]Aza derivatives
The preparation method of the fluoroquinazoline compound comprises the following steps: mixing a compound shown as a formula (II) and a compound shown as a formula (III), reacting at 25-120 ℃ in an organic solvent A under the action of a basic catalyst (TLC tracking monitoring, a developing agent is ethyl acetate/petroleum ether ═ 1: 3(v/v), preferably 40-100 ℃ for 0.5-12 h), separating and purifying a reaction liquid after the reaction is completed, and obtaining the compound shown as the formula (I)A compound; the organic solvent A is selected from one of the following: chloroform, toluene, methanol, ethanol, propanol, isopropanol, acetonitrile or N, N-dimethylformamide; the alkaline catalyst is selected from one of the following: pyridine, diethylamine, triethylamine, quinoline, N-dimethylaniline, 4-dimethylaminopyridine, 4-pyrrolidinylpyridine or sodium carbonate (preferably pyridine, diethylamine, triethylamine, N-dimethylaniline or 4-dimethylaminopyridine);
further, in the above process, the ratio of the compound of the formula (iii) to the compound of the formula (ii) to the amount of the substance charged as the basic catalyst is 1.0: 0.8 to 1.2: 1.0 to 8.0.
Further, in the above method, the amount of the organic solvent A is 10 to 50mL/g based on the mass of the compound represented by the formula (III).
Further, the method for separating and purifying the reaction solution in the above steps of the present invention comprises: after the reaction is completed, evaporating the solvent from the reaction solution, dissolving the concentrate with an organic solvent C to obtain a dissolved solution, adding column chromatography silica gel (preferably 300-400 mesh coarse pore (zcx.II) type column chromatography silica gel) in an amount which is 1.0-2.0 times the weight of the concentrate into the dissolved solution, uniformly mixing, evaporating the solvent, drying to obtain a mixture of the concentrate and the silica gel, packing the mixture into a column, and then mixing the mixture with the silica gel in a volume ratio of 1: taking a mixed solution of petroleum ether and ethyl acetate of 0.1-10 as an eluent, collecting an effluent containing a target component (preferably, ethyl acetate/petroleum ether is 1: 3(v/v) is taken as a developing agent for tracking detection, collecting the target component, preferably, collecting a component with an Rf value of 0.5), concentrating under reduced pressure, and drying (preferably, drying at 50 ℃) to obtain the compound shown in the formula (I); the organic solvent C is one of the following solvents: ethanol, chloroform, tetrahydrofuran or ethyl acetate. The organic solvent C is used in an amount capable of dissolving the residue.
The organic solvents A and C are organic solvents, so that the organic solvents used for distinguishing different steps are named for convenience, and the letters have no meanings.
In a third aspect,the invention also provides a methoxyphenyl benzo [ d ] shown in the formula (I)]Aza derivatives
The application of the fluoroquinazoline compound in preparing medicaments for preventing or treating tumor diseases, in particular to the application in preparing medicaments for preventing or treating human breast cancer.
Preferably, the medicament is a medicament for inhibiting the activity of the human breast cancer cell line MCF-7. The methoxyphenyl benzo [ d ] of the invention]Aza derivatives
The quinazoline compound has obvious inhibition effect on human breast cancer cell strain MCF-7.
The methoxyphenyl benzo [ d ] of the invention]Aza derivatives
The quinazoline compound also has a remarkable inhibiting effect on a human lung cancer cell strain A-549, and can be applied to preparation of medicaments for preventing or treating human lung cancer.
The invention has the following beneficial effects: (1) provides a novel quinazoline compound with good anti-cancer (especially human breast cancer or human lung cancer) activity, and is expected to be applied to the preparation of medicaments for preventing or treating human breast cancer or human lung cancer; (2) the invention provides methoxyphenyl benzo [ d]Aza derivatives
The preparation method of the quinazoline compound (I) is simple and easy to operate, the raw materials are easy to obtain, the production cost is low, and the quinazoline compound (I) is suitable for practical use.
(IV) detailed description of the preferred embodiments
The invention is further illustrated by reference to specific examples, which are intended to illustrate the invention, but not to limit it in any way.
The compound (II) can be prepared by the method described in Weinstock, J.et al.J.Med.chem.,1986, 29(11), 2315-2325. 4-chloroquinazoline (III) prepared by the method of reference (Rao, G. -W.et. ChemMedChem,2013,8(6), 928-one 933).
Example 1: methoxyphenyl benzo [ d ]]Aza derivatives
Preparation of a quiazoline (I)
Adding 0.943 g (5.73mmol) of 4-chloroquinazoline (III) and 2.39 g (6.87mmol) of compound (II), 3.62 g (45.76mmol) of pyridine and 9.5 ml of chloroform into a 50ml reaction bottle in sequence, heating to 40 ℃, performing TLC tracking detection (a developing agent is ethyl acetate/petroleum ether is 1: 3(v/v)), stirring for 10 hours, stopping the reaction, evaporating the reaction liquid to remove the solvent, adding 10 ml of ethyl acetate into the obtained concentrate to dissolve the concentrate to obtain a dissolved solution, adding 3.0 g of column chromatography silica gel (300-400 mesh column chromatography silica gel) into the dissolved solution, uniformly mixing, evaporating the solvent to obtain a mixture of a dried concentrate and the silica gel, filling the mixture into a column, and then performing column chromatography by using a volume ratio of 1: the eluent was eluted with 10 g of a mixed solution of petroleum ether and ethyl acetate (eluent: ethyl acetate/petroleum ether: 1: 3(v/v)), followed by TLC (eluent: 0.5 Rf), and the eluate was collected by TLC and concentrated to obtain a white solid product of formula (i) at 50 ℃ in a yield of 63.8%.1HNMR(400MHz,CDCl3):＝3.30(m,1H),3.45(m,1H),3.70(s,3H),3.78(s,3H),3.79(s,3H),4.12(m,2H),4.61(m,1H),5.05(t,J＝8.0Hz,1H),6.49(s,1H),6.8d,J＝8.4Hz,2H),7.04(d,J＝8.4Hz,2H),7.37(m,1H),7.68(m,1H),7.81(d,J＝8.0Hz,2H),7.87(d,J＝8.0Hz,2H),8.60ppm(s,1H)；IR(KBr):v＝2935,1611,1597,1566,1536,1507,938,828,768,687cm-1。
Example 2: methoxyphenyl benzo [ d ]]Aza derivatives
Preparation of a quiazoline (I)
0.943 g (5.73mmol) of 4-chloroquinazoline (III) and 1.59 g (4.57mmol) of compound (II), 1.67 g (22.83mmol) of diethylamine and 47 ml of toluene were successively introduced into a 100 ml three-necked flask, heated to 100 ℃ and checked by TLC tracing (the developing solvent was ethylEthyl acetate/petroleum ether ═ 1: 3(v/v)), stirring for 2 hours, stopping the reaction, evaporating the reaction solution to remove the solvent, adding 20 ml of ethanol into the obtained concentrate to dissolve the concentrate to obtain a dissolved solution, adding 2.5 g of column chromatography silica gel (300-400 mesh column chromatography silica gel) into the dissolved solution, uniformly mixing, evaporating the solvent to obtain a mixture of the dried concentrate and the silica gel, filling the mixture into a column, and then performing reaction in a volume ratio of 1: the mixed solution of petroleum ether and ethyl acetate of 5 was used as an eluent, elution was performed, follow-up detection by TLC (developing solvent ethyl acetate/petroleum ether ═ 1: 3(v/v)) was performed, an eluent containing the compound represented by formula (i) (Rf value 0.5) was collected by TLC detection, and the collected solution was concentrated and dried at 50 ℃ to obtain a white solid product represented by formula (i) with a yield of 79.7%.1HNMR and IR were the same as in example 1.
Example 3: methoxyphenyl benzo [ d ]]Aza derivatives
Preparation of a quiazoline (I)
Adding 0.943 g (5.73mmol) of 4-chloroquinazoline (III) and 1.99 g (5.72mmol) of compound (II), 0.58 g (5.73mmol) of triethylamine and 40 ml of ethanol into a 100 ml three-neck flask in sequence, heating to 60 ℃, performing TLC tracking detection (ethyl acetate/petroleum ether is used as a developing agent, 1: 3(v/v)), stirring for 8 hours, closing the reaction, evaporating the reaction liquid to remove the solvent, adding 20 ml of chloroform into the obtained concentrate to dissolve the concentrate to obtain a dissolved solution, adding 2.5 g of column chromatography silica gel (300-400 mesh silica gel column chromatography) into the dissolved solution, uniformly mixing, evaporating the solvent to obtain a mixture of a dried concentrate and the silica gel, filling the mixture into a column, and then performing column chromatography on the mixture according to the volume ratio of 10: the petroleum ether/ethyl acetate mixed solution of 1 was used as an eluent, elution was performed, follow-up detection by TLC (developing solvent ethyl acetate/petroleum ether: 1: 3(v/v)) was performed, an eluent containing the compound represented by formula (i) (Rf value 0.5) was collected according to TLC detection, and the collected solution was concentrated and dried at 50 ℃ to obtain a white solid product represented by formula (i) with a yield of 71.4%.1H NMR and IR were the same as in example 1.
Example 4: methoxyphenyl benzo [ d ]]Aza derivatives
Preparation of a quiazoline (I)
Adding 0.943 g (5.73mmol) of 4-chloroquinazoline (III) and 2.20 g (6.32mmol) of compound (II), 1.40 g (11.46mmol) of 4-dimethylaminopyridine and 30 ml of isopropanol into a 100 ml three-neck flask, stirring at room temperature and 25 ℃, performing TLC tracking detection (a developing agent is ethyl acetate/petroleum ether is 1: 3(v/v)), reacting for 12 hours, closing the reaction, evaporating the reaction liquid to remove the solvent, adding 20 ml of tetrahydrofuran into the obtained concentrate to dissolve the concentrate to obtain a dissolved solution, adding 4.0 g of column chromatography silica gel (300-400 mesh column chromatography silica gel) into the dissolved solution, uniformly mixing, evaporating the solvent to obtain a mixture of a dried concentrate and the silica gel, filling the mixture into a column, and then performing column chromatography on the mixture according to a volume ratio of 5: the petroleum ether/ethyl acetate mixed solution of 1 was used as an eluent, elution was performed, follow-up detection by TLC (developing solvent ethyl acetate/petroleum ether: 1: 3(v/v)) was performed, an eluent containing the compound represented by formula (i) (Rf value 0.5) was collected according to TLC detection, and the collected solution was concentrated and dried at 50 ℃ to obtain a white solid product represented by formula (i) with a yield of 88.7%.1H NMR and IR were the same as in example 1.
Example 5: methoxyphenyl benzo [ d ]]Aza derivatives
Preparation of a quiazoline (I)
Adding 0.943 g (5.73mmol) of 4-chloroquinazoline (III) and 1.79 g (5.15mmol) of compound (II), 1.04 g (8.58mmol) of N, N-dimethylaniline and 15 ml of N, N-dimethylformamide into a 50ml reaction bottle, heating to 120 ℃, performing TLC tracking detection (a developing agent is ethyl acetate/petroleum ether is 1: 3(v/v)), stirring for 0.5 hour, stopping the reaction, evaporating the reaction liquid to remove the solvent, adding 20 ml of tetrahydrofuran into the obtained concentrate to dissolve the concentrate to obtain a dissolved solution, adding 5.0 g of column chromatography silica gel (300-400 mesh column chromatography silica gel) into the dissolved solution, uniformly mixing, evaporating the solvent to obtain a mixture of the dried concentrate and the silica gel, filling the mixture into a column, and then filling the mixture into the column at a volume ratio of 1: eluting with petroleum ether/ethyl acetate mixed solution of 1 as eluent, tracking by TLC (developing solvent ethyl acetate/petroleum ether is 1: 3(v/v)), and collecting the eluent containing formula (II)The eluate of the compound represented by the formula (I) (Rf value: 0.5) was concentrated and dried at 50 ℃ to obtain a white solid product represented by the formula (I) in a yield of 63.1%.1H NMR and IR were the same as in example 1.
Example 6: methoxyphenyl benzo [ d ]]Aza derivatives
Preparation of a quiazoline (I)
Adding 0.943 g (5.73mmol) of 4-chloroquinazoline (III) and 2.39 g (6.87mmol) of compound (II), 3.62 g (45.76mmol) of pyridine and 20 ml of propanol into a 30 ml reaction bottle in sequence, heating to 40 ℃, performing TLC tracking detection (ethyl acetate/petroleum ether is used as a developing agent: 1: 3(v/v)), stirring for 10 hours, stopping the reaction, evaporating the reaction liquid to remove the solvent, adding 20 ml of ethyl acetate into the obtained concentrate to dissolve the concentrate to obtain a dissolved solution, adding 3.5 g of column chromatography silica gel (300-400 mesh silica gel column chromatography) into the dissolved solution, uniformly mixing, evaporating the solvent to obtain a mixture of a dried concentrate and the silica gel, filling the mixture into a column, and then performing column chromatography on the mixture according to the volume ratio of 1: the petroleum ether/ethyl acetate mixed solution of 1 was used as an eluent, elution was performed, follow-up detection by TLC (developing solvent ethyl acetate/petroleum ether: 1: 3(v/v)) was performed, an eluent containing the compound represented by formula (i) (Rf value 0.5) was collected according to TLC detection, and the collected solution was concentrated and dried at 50 ℃ to obtain a white solid product represented by formula (i) with a yield of 70.4%.1H NMR and IR were the same as in example 1.
Example 7: in vitro test for anti-cancer Activity
The compound (i) prepared in example 1 was tested for human breast cancer bioactivity.
The test method comprises the following steps: tetrazolium salt reduction (MTT process).
Cell lines: human breast cancer cell strain MCF-7. The tumor cell strain is purchased from cell banks of Shanghai Life sciences of Chinese academy of sciences.
The experimental procedure was as follows:
(1) preparation of samples: for soluble samples, each 1mg was dissolved in 40. mu.L DMSO, 2. mu.L was diluted with 1000. mu.L of medium to a concentration of 100. mu.g/mL, and then serially diluted with the culture medium to the use concentration.
(2) Culture of cells
1) The medium was prepared by adding 80 million units of penicillin, 1.0g of streptomycin, and 10% inactivated fetal bovine serum to 1000mL of DMEM medium (Gibco).
2) And (3) culturing the cells: inoculating tumor cells into culture medium, standing at 37 deg.C and 5% CO2Culturing in an incubator, and carrying out passage for 3-5 days.
3) Determination of the inhibition of tumor cell growth by samples
The 10 th generation cells were digested with EDTA-pancreatin digest and diluted to 1 × 10 with medium6Perml, 100. mu.L/well in 96-well cell culture plates, 37 ℃ 5% CO2Culturing in an incubator. After 24h of inoculation, 100. mu.L of 100. mu.g/mL, 10. mu.g/mL and 1. mu.g/mL samples diluted with medium were added to each well at 3 concentrations and placed at 37 ℃ in 5% CO2The culture was performed in an incubator, 5mg/mL MTT was added to the cell culture wells after 72h, 10. mu.L per well, incubated at 37 ℃ for 3h, DMSO was added, 150. mu.L per well, shaken with a shaker, and formazan was completely solubilized and colorimetric with a microplate reader at a wavelength of 570 nm. Using cells cultured in the same DMSO concentration medium without sample under the same conditions as a control, the IC of the sample on tumor cell growth was calculated50。
The results of the test are shown in table 1:
TABLE 1 inhibitory Effect of Compound (I) on the growth of cancer cell line MCF-7
Example 8: in vitro test for anti-cancer Activity
(1) The compound (i) prepared in example 1 was tested for human lung cancer bioactivity.
The test method comprises the following steps: tetrazolium salt reduction (MTT process).
Cell lines: human lung cancer cell strain A-549. The tumor cell strain is purchased from cell banks of Shanghai Life sciences of Chinese academy of sciences.
The experimental procedure was as follows:
1) preparation of samples: for soluble samples, each 1mg was dissolved in 40. mu.L DMSO, 2. mu.L was diluted with 1000. mu.L of medium to a concentration of 100. mu.g/mL, and then serially diluted with the culture medium to the use concentration.
2) Culture of cells
Preparation of culture medium, each 1000mL of DMEM culture medium (Gibco) contains 80 ten thousand units of penicillin, 1.0g of streptomycin and 10% inactivated fetal bovine serum.
② cultivation of cells, inoculating tumor cells into culture medium, standing at 37 deg.C and 5% CO2Culturing in an incubator, and carrying out passage for 3-5 days.
Measuring the inhibition of the sample on the growth of tumor cells
The 10 th generation cells were digested with EDTA-pancreatin digest and diluted to 1 × 10 with medium6Perml, 100. mu.L/well in 96-well cell culture plates, 37 ℃ 5% CO2Culturing in an incubator. After 24h of inoculation, 100. mu.L of 100. mu.g/mL, 10. mu.g/mL and 1. mu.g/mL samples diluted with medium were added to each well at 3 concentrations and placed at 37 ℃ in 5% CO2The culture was performed in an incubator, 5mg/mL MTT was added to the cell culture wells after 72h, 10. mu.L per well, incubated at 37 ℃ for 3h, DMSO was added, 150. mu.L per well, shaken with a shaker, and formazan was completely solubilized and colorimetric with a microplate reader at a wavelength of 570 nm. Using cells cultured in the same DMSO concentration medium without sample under the same conditions as a control, the IC of the sample on tumor cell growth was calculated50。
The results of the tests are shown in table 2:
TABLE 2 inhibitory Effect of Compound (I) on the growth of cancer cell line A-549
(2) Referring to the literature (Fernandes, C.et al.Bioorg.Med.chem.,2007,15(12),3974-3980), 4-chloro-6-nitroquinazoline was prepared, and the 4-chloroquinazoline was replaced by 4-chloro-6-nitroquinazoline according to example 1, and the other operations were the same as example 1, to synthesize a quinazoline compound (a) having the following structure:
the prepared quinazoline compound (a) is subjected to a biological activity test of a human lung cancer cell strain A-549 according to the method, and the test result shows that the anticancer activity of the quinazoline compound (a) on the human lung cancer cell strain A-549 is far lower than that of the compound (I). Specific results are shown in table 3:
TABLE 3 inhibitory Effect of Compound (a) on the growth of cancer cell line A-549
The anti-cancer activity in vitro test experiment shows that: methoxyphenyl benzo [ d ]]Aza derivatives
The quinazoline (I) has obvious inhibition effect on a human lung cancer cell strain A-549, and is obviously superior to the compound (a) with a similar structure.
Claims (7)
1. A methoxyphenyl benzo [ d ] shown in formula (I)]Aza derivatives
Fluoroquinazoline compounds:
2. a methoxyphenyl benzo [ d ] of the formula (I) as claimed in claim 1]Aza derivatives
The preparation method of the fluoroquinazoline compound is characterized by comprising the following steps:
mixing a compound shown as a formula (II) and a compound shown as a formula (III), reacting in an organic solvent A at 25-120 ℃ under the action of a basic catalyst, and after the reaction is completed, separating and purifying reaction liquid to obtain a compound shown as a formula (I); the organic solvent A is selected from one of the following: chloroform, toluene, methanol, ethanol, propanol, isopropanol, acetonitrile or N, N-dimethylformamide; the alkaline catalyst is selected from one of the following: pyridine, diethylamine, triethylamine, quinoline, N-dimethylaniline, 4-dimethylaminopyridine, 4-pyrrolidinylpyridine or sodium carbonate;
3. the method of claim 2, wherein: the ratio of the compound of formula (III) to the compound of formula (II) to the amount of the basic catalyst to be charged is 1.0: 0.8 to 1.2: 1.0 to 8.0.
4. The method of claim 2, wherein: the dosage of the organic solvent A is 10-50 mL/g based on the mass of the compound shown in the formula (III).
5. The method of claim 2, wherein: after the reaction is completed, evaporating the solvent from the reaction solution, dissolving the concentrate with an organic solvent C to obtain a dissolved solution, adding column chromatography silica gel of which the weight is 1.0-2.0 times that of the concentrate into the dissolved solution, uniformly mixing, evaporating the solvent, drying to obtain a mixture of the concentrate and the silica gel, filling the mixture into a column, and then mixing the mixture with the organic solvent C in a volume ratio of 1: taking a mixed solution of petroleum ether and ethyl acetate of 0.1-10 as an eluent, collecting an effluent containing a target component, concentrating under reduced pressure, and drying to obtain a compound shown in a formula (I); the organic solvent C is one of the following solvents: ethanol, chloroform, tetrahydrofuran or ethyl acetate.
6. The methoxyphenyl benzo [ d ] of the formula (I) as claimed in claim 1]Aza derivatives
Application of the fluoroquinazoline compound in preparing medicaments for preventing or treating human breast cancer.
7. The use according to claim 6, wherein the medicament is a medicament having the activity of inhibiting the activity of human breast cancer cell line MCF-7.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1061411A (en) * | 1990-11-06 | 1992-05-27 | 美国辉瑞有限公司 | Be used to strengthen the active quinazoline derivant of antineoplastic agent |
| CN1141633A (en) * | 1994-02-23 | 1997-01-29 | 辉瑞大药厂 | 4-heterocyclyl-substituted Quinazoline derivatives, method for prepn. of same and the use as anti-cancer agent |
| CN103275018A (en) * | 2013-04-26 | 2013-09-04 | 浙江工业大学 | 4-(3-chloro-4-substituted anilino)-6-substituted carbamonyl quinazoline compounds, and preparation method and applications thereof |
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| CN103254142B (en) * | 2013-04-26 | 2015-10-28 | 浙江工业大学 | 4-[4-(2-substituted-amino kharophen) anilino] quinazoline derivative and Synthesis and applications |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1061411A (en) * | 1990-11-06 | 1992-05-27 | 美国辉瑞有限公司 | Be used to strengthen the active quinazoline derivant of antineoplastic agent |
| CN1141633A (en) * | 1994-02-23 | 1997-01-29 | 辉瑞大药厂 | 4-heterocyclyl-substituted Quinazoline derivatives, method for prepn. of same and the use as anti-cancer agent |
| CN103275018A (en) * | 2013-04-26 | 2013-09-04 | 浙江工业大学 | 4-(3-chloro-4-substituted anilino)-6-substituted carbamonyl quinazoline compounds, and preparation method and applications thereof |
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