CN104817535A - Quinolinone derivative, and synthetic method and application thereof - Google Patents
Quinolinone derivative, and synthetic method and application thereof Download PDFInfo
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- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
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- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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Abstract
The invention discloses a quinolinone derivative, and a synthetic method and application thereof. The quinolinone derivative is 3-(1H-benzimidazole-2-yl)-6-methyl-2(1H)-quinolinone. The synthetic method for the quinolinone derivative comprises the following steps: with paratoluidine as a raw material, adding acetic anhydride for acylation in the presence of acetic acid or hydrochloric acid so as to obtain a compound 1; subjecting the compound 1 and phosphorus oxychloride to cyclization so as to obtain a compound 2; adding acid into the compound 2 for hydrolysis so as to obtain a compound 3; and subjecting the compound 3 and o-phenylenediamine for condensation reaction so as to obtain the quinolinone derivative. The method provided by the invention is simple, easy to operate and high in yield; and the obtained target derivative shows certain proliferation inhibition activity to a variety of cell lines, wherein the activity to human gastric carcinoma cell MGC-803 is highest. The quinolinone derivative has a structural formula as shown in a formula (I) which is described in the specification.
Description
Technical field
The present invention relates to medical art, be specifically related to a kind of qualone derivative and synthetic method thereof and application.
Background technology
2 (1H)-quinolinone structures are and the quinoline equally extensive alkaloid existed in natural product, compound containing 2 (1H)-quinolinone structures has multiple biological activity, on its ring or on side chain, introduce different substituting groups, the pharmacologically active of the wide spectrums such as such as antitumor, anti-oxidant, anti-inflammatory can be produced.Seek good activity, a kind of important method that lead compound parent nucleus that toxicity is low is current research and development anti-cancer agent, due to 2 (1H)-quinolinones have active better, structure is easy to features such as modifying, toxicity is low, in the design of its antitumor drug that is widely used and screening.Some compounds with 2 (1H)-quinolinone skeletons have entered clinical as antitumor drug, such as: many Weis are a kind of orally active small molecules multiple receptor tyrosine kinases inhibitors for Buddhist nun (Dovitinib), tumour cell can be directly acted on and provide blood vessel and the matrix of nutrition for tumour cell, by antiproliferative activity and anti-angiogenic existence activity, show antitumor action; Tipifarnib (Tipifanib) belongs to farnesyl transferase inhibitor, and it, by suppressing the protein of farnesylation, can prevent the activation of Ras oncogene, cell growth inhibiting, cell death inducing, and inhibiting angiogenesis.Have not yet to see the relevant report of 3-(1H-benzimidazolyl-2 radicals-Ji)-6-methyl-2 (1H)-quinolinone and synthesis and application.
Summary of the invention
The technical problem to be solved in the present invention is to provide a kind of new 2 (1H)-qualone derivatives and 3-(1H-benzimidazolyl-2 radicals-Ji)-6-methyl-2 (1H)-quinolinone, and its synthetic method and application.
The present invention relates to compound or its pharmacy acceptable salt shown in following formula (I):
Shown in above-mentioned formula (I), the chemical name of compound is 3-(1H-benzimidazolyl-2 radicals-Ji)-6-methyl-2 (1H)-quinolinone, and molecular weight is: 275.1.
Shown in above-mentioned formula (I), the synthesis thinking of compound is: take para-totuidine as raw material, under acetic acid or hydrochloric acid existent condition, add diacetyl oxide and carry out acidylate, obtain acylate (i.e. compound 1); Gained acylate closes ring with phosphorus oxychloride, obtains closing ring product (i.e. compound 2); Gained closes ring product acid adding and is hydrolyzed, and obtains hydrolysate (i.e. compound 3); Gained hydrolysate and O-Phenylene Diamine carry out condensation reaction, obtain target product (i.e. compound 4).Concrete synthetic route is as follows:
Reagent: (a) diacetyl oxide, acetic acid or hydrochloric acid; (b) DMF, phosphorus oxychloride; (c) acid; (d) O-Phenylene Diamine, methyl alcohol and/ethanol.
More specifically synthetic method, comprises the following steps:
1) take para-totuidine as raw material, under acetic acid or hydrochloric acid existent condition, add diacetyl oxide and react, the pH value of having reacted rear regulation system is 6 ~ 8, reactant suction filtration, and filter cake recrystallization, obtains compound 1;
2) gained compound 1 is dissolved in DMF, and add phosphorus oxychloride and carry out ring closure reaction, gained reactant is poured in frozen water, suction filtration, obtains compound 2;
3) gained compound 2 acid adding is hydrolyzed, and obtains compound 3;
4) gained compound 3 and O-Phenylene Diamine carry out condensation reaction under methyl alcohol and/or ethanol existent condition, obtain target product.
The step 1 of above-mentioned synthetic method) in, the concentration of described acetic acid can be 30 ~ 90 (v/v) %, the concentration of described hydrochloric acid can be 15 ~ 37w/w%, the consumption of described acetate and hydrochloride is respectively 0.9 ~ 1.2 times of para-totuidine amount of substance usually, or is greater than 1.2 times of para-totuidine amount of substance.The add-on of described diacetyl oxide is generally 0.9 ~ 1.2 times of para-totuidine amount of substance, or is greater than 1.2 times of para-totuidine amount of substance.In this step, due to exothermic heat of reaction, preferred reaction is carried out under condition of ice bath.Whether reaction can adopt thin-layer chromatography (TLC) tracing detection completely, and usually controlling the reaction times is that 1 ~ 4h is more suitable.The pH value of having reacted rear employing alkali lye regulation system is 6 ~ 8, and described alkali lye can be the aqueous solution of the alkaline matters such as sodium acetate, sodium carbonate, sodium phosphate, sodium bicarbonate or salt of wormwood, and the concentration of described alkali lye is preferably 5 ~ 30/w/w%; The aqueous solution of sodium acetate is preferably adopted to regulate.The filter cake collected adopts dehydrated alcohol and/or anhydrous methanol to carry out recrystallization usually.
The step 2 of above-mentioned synthetic method) in, the add-on of described phosphorus oxychloride is generally 0.9 ~ 1.2 times of compound 1 amount of substance, or is greater than 1.2 times of para-totuidine amount of substance.The consumption of described DMF can be determined as required, specifically can calculate by the amount of 10mmol compound 1 with 5 ~ 11ml.Described ring closure reaction carries out usually in a heated condition, preferably carries out under 60 ~ 90 DEG C of conditions, is more preferably and under 60 ~ 90 DEG C of conditions, carries out back flow reaction in reflux.Whether reaction can adopt TLC tracing detection completely, and usually controlling the reaction times is that 8 ~ 14h is more suitable.
The step 3 of above-mentioned synthetic method) in, acid used when being hydrolyzed can be 30 ~ 90 (v/v) % Glacial acetic acid, or the hydrochloric acid of 2 ~ 6mol/L, or the sulfuric acid of 2 ~ 6mol/L; The consumption of the described acid for being hydrolyzed is generally every 10mmol compound 2 50 ~ 80ml acid solution and is hydrolyzed.Described hydrolysis is carried out usually in a heated condition, preferably carries out under 60 ~ 90 DEG C of conditions, is more preferably and refluxes under 60 ~ 90 DEG C of conditions in reflux, and under said temperature condition, backflow can obtain settled solution.Whether hydrolysis can adopt TLC tracing detection completely, and usually controlling the reaction times is that 6 ~ 12h is more suitable.After hydrolysis completely, gained reactant cools, and have crystal to separate out, the crystal of precipitation is compound 3.
The step 4 of above-mentioned synthetic method) in, the consumption of described O-Phenylene Diamine is generally 0.9 ~ 1.2 times of compound 3 amount of substance, or is greater than 1.2 times of para-totuidine amount of substance.Described methyl alcohol is 70 ~ 100v/v% methyl alcohol, and described ethanol is 70 ~ 100v/v% ethanol; The consumption of described methyl alcohol and/or ethanol can be determined as required, specifically can calculate by the amount of 10mmol compound 3 with 50 ~ 80ml.Described condensation reaction is carried out usually in a heated condition, preferably carries out under 60 ~ 90 DEG C of conditions, is more preferably and under 60 ~ 90 DEG C of conditions, carries out back flow reaction in reflux.Whether condensation reaction can adopt TLC tracing detection completely, and usually controlling the reaction times is that 6 ~ 12h is more suitable.After having reacted, suction filtration after the cooling of gained reactant, collects filter cake and is target product.
The productive rate adopting synthetic method of the present invention to synthesize compound shown in above-mentioned (I) is more than 46%.
The present invention also comprises compound or its pharmacy acceptable salt shown in above-mentioned (I) and is preparing the application in antitumor drug.
Compared with prior art, the invention provides a kind of new 2 (1H)-qualone derivatives and 3-(1H-benzimidazolyl-2 radicals-Ji)-6-methyl-2 (1H)-quinolinone, and its synthetic method and application.Described synthetic method obtains product through acidylate, Guan Huan, hydrolysis, condensation four step, and method is simple to operation, and productive rate is high.The anti tumor activity in vitro research of applicant to compound of the present invention shows, it all shows certain proliferation inhibition activity to human cervical carcinoma cell Hela229, gastric carcinoma cells MGC-803, human hepatoma cell strain Hep G2 and BEL-7404 tetra-kinds of cell strains, wherein the highest for gastric carcinoma cells MGC-803 activity.
Accompanying drawing explanation
Fig. 1 is the hydrogen nuclear magnetic resonance spectrogram of the final product that the embodiment of the present invention 1 obtains;
Fig. 2 is the carbon-13 nmr spectra figure of the final product that the embodiment of the present invention 1 obtains;
Fig. 3 is the high resolution mass spectrum spectrogram of the final product that the embodiment of the present invention 1 obtains.
Embodiment
Below in conjunction with specific embodiment, the present invention is described in further detail, and to understand content of the present invention better, but the present invention is not limited to following examples.
Embodiment 1
1) by 10.7g (0.1mol) para-totuidine, 50ml water adds 250ml round-bottomed flask, dropwise add 8ml concentrated hydrochloric acid, 10.2g (0.1mol) diacetyl oxide, react 4 hours under ice bath, then be 7 by the pH value of the sodium acetate solution regulation system of 20w/w%, leave standstill, suction filtration, filter cake dehydrated alcohol recrystallization obtains compound 1 (white needle-like crystals, 13.3g, productive rate 89%).
2) by 3.5ml DMF and 17ml POCl
3mix under ice bath, add 2.24g (15mmol) compound 1 after stirring, gained solution is placed in reflux, be heated to 90 DEG C of backflows 10 hours, pour in 500ml frozen water after cooling, suction filtration obtains compound 2 (2.7g, productive rate 87%).
3) 2.05g (10mmol) compound 2 is dissolved in 80ml 70% Glacial acetic acid, gained solution is placed in reflux, and be heated to 90 DEG C of backflows 8 hours, cooling obtains compound 3 (yellow needle-like crystals, 1.70g, productive rate 91%).
4) join in 80ml anhydrous methanol by 1.87g (10mmol) compound 3 and 1.08g (10mmol) O-Phenylene Diamine, gained solution was placed in reflux, in 90 DEG C of backflows 8 hours, cooling, suction filtration, obtains yellow solid (2.48g, 90%).
Gained yellow solid product is identified:
(1) proton nmr spectra and carbon spectrum, their spectrogram respectively as illustrated in fig. 1 and 2.
1H NMR(500MHz,DMSO-d6)δ12.65(s,1H),12.40(s,1H),9.00(d,J＝1.7Hz,1H),7.74–7.70(m,1H),7.69(s,1H),7.68–7.63(m,1H),7.42(d,J＝8.4Hz,1H),7.33(d,J＝8.4Hz,1H),7.22–7.17(m,2H),2.36(s,3H).
13C NMR(126MHz,DMSO-d6)δ160.79,147.96,142.83,138.90,136.85,134.49,133.15,131.89,128.38,122.41,122.05,119.93,119.19,118.38,115.29,112.88,20.56.
(2) electrospray ionization mass spectrum, as shown in Figure 3, ESI-MS m/z:276.1 [M+H]
+.
Therefore, can determine that above-mentioned yellow solid product is 3-(1H-benzimidazolyl-2 radicals-Ji)-6-methyl-2 (1H)-quinolinone, its chemical structural formula is as follows:
Embodiment 2
1) by 10.7g (0.1mol) para-totuidine, 40ml Glacial acetic acid, adds 250ml round-bottomed flask, dropwise adds 10.2g (0.1mol) diacetyl oxide, react 4 hours under ice bath, then underpressure distillation is except desolventizing, then is 7 by the pH value of the sodium carbonate solution regulation system of 20w/w%, leaves standstill, suction filtration, filter cake dehydrated alcohol recrystallization obtains compound 1 (white needle-like crystals, 12.7g, productive rate 85%).
2) by 3.5ml DMF and 17ml POCl
3mix under ice bath, add 2.24g (15mmol) compound 1 after uniform stirring, gained solution is placed in reflux, be heated to 70 DEG C of backflows 14 hours, pour in 500ml frozen water after cooling, suction filtration obtains compound 2 (2.5g, productive rate 80%).
3) 2.05g (10mmol) compound 2 is dissolved in 80ml 90% Glacial acetic acid, gained solution is placed in reflux, and be heated to 60 DEG C of backflows 10 hours, cooling obtains compound 3 (yellow needle-like crystals, 1.50g, productive rate 80%).
4) add in 80ml80v/v% methyl alcohol by 1.87g (10mmol) compound 3 and 1.08g (10mmol) O-Phenylene Diamine, gained solution is placed in reflux, is heated to 90 DEG C of backflows 8 hours, cooling, suction filtration, obtains yellow solid (2.48g, 90%).
Gained yellow solid product is 3-(1H-benzimidazolyl-2 radicals-Ji)-6-methyl-2 (1H)-quinolinone through qualification.
Embodiment 3:
1) by 10.7g (0.1mol) para-totuidine, 50ml water adds 250ml round-bottomed flask, dropwise add 8ml concentrated hydrochloric acid, 10.2g (0.1mol) diacetyl oxide, reacts 4 hours under ice bath, is then 6 by the pH value of the sodium acetate solution regulation system of 20w/w%, leave standstill, suction filtration, filter cake dehydrated alcohol recrystallization obtains white needle-like crystals 1 (13.3g, productive rate 89%).
2) by 3.5ml DMF and 17ml POCl
3mix under ice bath, add 2.24g (15mmol) compound 1 after uniform stirring, gained solution is placed in reflux, be heated to 60 DEG C of backflows 10 hours, pour in 500ml frozen water after cooling, suction filtration obtains compound 2 (2.4g, productive rate 77%).
3) 2.05g (10mmol) compound 2 is dissolved in 80ml 4M aqueous hydrochloric acid, gained solution is placed in reflux, and be heated to 90 DEG C of backflows 10 hours, cooling obtains compound 3 (yellow needle-like crystals, 1.59g, productive rate 85%).
4) add in 100ml dehydrated alcohol by 1.87g (10mmol) compound 3 and 1.08g (10mmol) O-Phenylene Diamine, gained solution is placed in reflux, is heated to 80 DEG C of backflows 6 hours, cooling, suction filtration, obtains yellow solid (2.4g, 87%).
Gained yellow solid product is 3-(1H-benzimidazolyl-2 radicals-Ji)-6-methyl-2 (1H)-quinolinone through qualification.
Embodiment 4:
1) by 10.7g (0.1mol) para-totuidine, 50ml water adds 250ml round-bottomed flask, dropwise add 8ml concentrated hydrochloric acid, 10.2g (0.1mol) diacetyl oxide, react 4 hours under ice bath, then be 7.5 by the pH value of the sodium acetate solution regulation system of 20w/w%, leave standstill, suction filtration, filter cake anhydrous methanol recrystallization obtains compound 1 (white needle-like crystals, 13.3g, productive rate 89%).
2) by 3.5ml DMF and 17ml POCl
3mix under ice bath, add 2.24g (15mmol) compound 1 after uniform stirring, gained solution is placed in reflux, be heated to 90 DEG C of backflows 8 hours, pour in 500ml frozen water after cooling, suction filtration obtains compound 2 (2.6g, productive rate 83%).
3) 2.05g (10mmol) compound 2 is dissolved in 80ml 40% Glacial acetic acid, gained solution is placed in reflux, and be heated to 90 DEG C of backflows 6 hours, cooling obtains compound 3 (yellow needle-like crystals, 1.4g, productive rate 75%).
4) add in 80ml90v/v% ethanol by 1.87g (10mmol) compound 3 and 1.08g (10mmol) O-Phenylene Diamine, gained solution is placed in reflux, is heated to 60 DEG C of backflows 12 hours, cooling, suction filtration, obtains yellow solid (2.3g, 83%).
Gained yellow solid product is 3-(1H-benzimidazolyl-2 radicals-Ji)-6-methyl-2 (1H)-quinolinone through qualification.
Applicant has carried out anti tumor activity in vitro experiment to 3-of the present invention (1H-benzimidazolyl-2 radicals-Ji)-6-methyl-2 (1H)-quinolinone, specific as follows:
1, cell strain and cell cultures
Human cervical carcinoma cell Hela229, gastric carcinoma cells MGC-803, human hepatoma cell strain Hep G2 and BEL-7404 totally 4 kinds of cell strains are selected in this experiment.
All tumor cell lines are all cultivated in the RPMI-1640 nutrient solution containing the little ox blood of 10wt%, 100U/mL penicillin, 100U/mL Streptomycin sulphate, put 37 DEG C containing volumetric concentration 5%CO
2cultivate in incubator; Human normal cell line strain is then cultivated in the DMEM nutrient solution containing the little ox blood of 10wt%, 100U/mL penicillin, 100U/mL Streptomycin sulphate.
2, the preparation of testing compound
3-(1H-benzimidazolyl-2 radicals-Ji)-6-methyl-2 (1H)-quinolinone used is for purifying gained through column chromatography by the obtained product of method described in the embodiment of the present invention 1, purity >=95%, its DMSO liquid storage (concentration is 0.001mol/L) is diluted to five concentration gradients successively by RMPI1640 substratum, be respectively 40,20,10,5,2.5 μm of ol/L, wherein solubility promoter DMSO final concentration≤1%.First test the target product of 20 μm of ol/L for the inhibiting rate of tumor cell proliferation, be considered as primary dcreening operation result; Under testing different gradient concentration more respectively, target product is to the Proliferation Ability degree of various tumour cell, in order to the Fitting Calculation half-inhibition concentration, i.e. IC
50value.
3, cell growth inhibition test (mtt assay)
(1) tumour cell of taking the logarithm vegetative period, after tryptic digestion, the cell suspension that concentration is 5000/mL is mixed with the nutrient solution containing 10% calf serum, be inoculated in 96 well culture plates with every hole 190 μ L, make cell density to 1000 ~ 10000 to be measured/hole (the aseptic PBS of marginal pore fills);
(2) 5%CO
2, hatch 24h for 37 DEG C, be paved with at the bottom of hole to cell monolayer, every hole adds the medicine 10 μ L of finite concentration gradient, and each concentration gradient establishes 4 multiple holes;
(3) 5%CO
2, hatch 48 hours for 37 DEG C, observe under inverted microscope;
(4) every hole adds the MTT solution (5mg/mL PBS, i.e. 0.5%MTT) of 10 μ L, continues to cultivate 4h;
(5) stop cultivating, carefully suck nutrient solution in hole, every hole adds 150 μ L DMSO and fully dissolves first a ceremonial jade-ladle, used in libation precipitation, and after vibrator mixing, be 570nm at microplate reader wavelength, reference wavelength is the optical density value that 450nm measures each hole;
(6) zeroing hole (substratum, MTT, DMSO) is set simultaneously, control wells (the medicine dissolution medium of cell, same concentrations, nutrient solution, MTT, DMSO).
(7) according to the optical density value (OD value) recorded, judge viable cell quantity, OD value is larger, and cytoactive is stronger.
Utilize formula:
Growth of tumour cell inhibiting rate
Computerized compound is to the inhibiting rate of growth of tumour cell.Its test result as shown in the following Table 1.
Table 1: compound of the present invention when 20 μm of ol/L to the growth inhibition ratio (%) of different tumor cell line
For the cell strain of inhibiting rate more than 50% under primary dcreening operation concentration, carry out matching further by the inhibiting rate data of SPSS software to five concentration gradients, obtain the half-inhibition concentration (IC of product to different tumor line
50value, unit μm ol/L), compound of the present invention is for the IC of different cell strain
50be worth as shown in table 2.
Table 2: the IC of each cell strain of compound of the present invention
50value (μM)
From anti tumor activity in vitro test result, 3-of the present invention (1H-benzimidazolyl-2 radicals-Ji)-6-methyl-2 (1H)-quinolinone all shows certain proliferation inhibition activity to human cervical carcinoma cell Hela229, gastric carcinoma cells MGC-803, human hepatoma cell strain Hep G2 and BEL-7404 tetra-kinds of cell strains, wherein the highest for gastric carcinoma cells MGC-803 activity.
Claims (10)
1. compound shown in following formula (I) or its pharmacy acceptable salt:
2. the synthetic method of compound described in claim 1, is characterized in that: take para-totuidine as raw material, under acetic acid or hydrochloric acid existent condition, adds diacetyl oxide and carries out acidifying, obtain compound 1; Gained compound 1 closes ring with phosphorus oxychloride, obtains compound 2; Gained compound 2 acid adding is hydrolyzed, and obtains compound 3; Gained compound 3 and O-Phenylene Diamine carry out condensation reaction, obtain target product.
3. the synthetic method of compound described in claim 2, is characterized in that: comprise the following steps:
1) take para-totuidine as raw material, under acetic acid or hydrochloric acid existent condition, add diacetyl oxide and react, the pH value of having reacted rear regulation system is 6 ~ 8, reactant suction filtration, and filter cake recrystallization, obtains compound 1;
2) gained compound 1 is dissolved in DMF, and add phosphorus oxychloride and carry out ring closure reaction, gained reactant is poured in frozen water, suction filtration, obtains compound 2;
3) gained compound 2 acid adding is hydrolyzed, and obtains compound 3;
4) gained compound 3 and O-Phenylene Diamine carry out condensation reaction under methyl alcohol and/or ethanol existent condition, obtain target product.
4. synthetic method according to claim 3, is characterized in that: step 1) in, react and carry out under condition of ice bath.
5. synthetic method according to claim 3, is characterized in that: step 1) in, be 6 ~ 8 by the pH value of alkali lye regulation system.
6. synthetic method according to claim 3, is characterized in that: step 2) in, described ring closure reaction carries out under 60 ~ 90 DEG C of conditions.
7. synthetic method according to claim 3, is characterized in that: step 3) in, acid used when being hydrolyzed is 30 ~ 90 (v/v) % acetic acid, or the hydrochloric acid of 2 ~ 6mol/L, or the sulfuric acid of 2 ~ 6mol/L.
8. synthetic method according to claim 3, is characterized in that: step 3) in, described hydrolysis is carried out under 60 ~ 90 DEG C of conditions.
9. synthetic method according to claim 3, is characterized in that: step 4) in, described condensation reaction is carried out under 60 ~ 90 DEG C of conditions.
10. compound described in claim 1 or its pharmacy acceptable salt are preparing the application in antitumor drug.
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| CN105622574A (en) * | 2016-02-04 | 2016-06-01 | 桂林师范高等专科学校 | 3-benzimidazole-2(1H)-quinolinone derivative and preparation method and application thereof |
| CN108003150A (en) * | 2016-10-31 | 2018-05-08 | 河南工业大学 | The preparation method and applications of 4- heteroaryl qualone derivatives |
| CN110938061A (en) * | 2019-11-27 | 2020-03-31 | 渤海大学 | Synthesis of 2- (2-benzofuranyl) -2-quinoxalinecarboxylic acid derivatives |
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| CN1483028A (en) * | 2000-09-11 | 2004-03-17 | ϣ | Quinolinone derivatives as tyrosine kinase inhibitors |
| WO2004030620A2 (en) * | 2002-09-30 | 2004-04-15 | Bristol-Myers Squibb Company | Novel tyrosine kinase inhibitors |
| CN103570678A (en) * | 2013-11-01 | 2014-02-12 | 山西大学 | 2-quinolinone compound and preparation method and application thereof |
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| CN1483028A (en) * | 2000-09-11 | 2004-03-17 | ϣ | Quinolinone derivatives as tyrosine kinase inhibitors |
| WO2004030620A2 (en) * | 2002-09-30 | 2004-04-15 | Bristol-Myers Squibb Company | Novel tyrosine kinase inhibitors |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105622574A (en) * | 2016-02-04 | 2016-06-01 | 桂林师范高等专科学校 | 3-benzimidazole-2(1H)-quinolinone derivative and preparation method and application thereof |
| CN105622574B (en) * | 2016-02-04 | 2018-12-25 | 桂林医学院 | 3- benzimidazolyl-2 radicals (1H)-qualone derivative and its preparation method and application |
| CN108003150A (en) * | 2016-10-31 | 2018-05-08 | 河南工业大学 | The preparation method and applications of 4- heteroaryl qualone derivatives |
| CN110938061A (en) * | 2019-11-27 | 2020-03-31 | 渤海大学 | Synthesis of 2- (2-benzofuranyl) -2-quinoxalinecarboxylic acid derivatives |
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Application publication date: 20150805 |