CN102942561A - 4-amino quinazoline heterocyclic compound and purpose of 4-amino quinazoline heterocyclic compound - Google Patents
4-amino quinazoline heterocyclic compound and purpose of 4-amino quinazoline heterocyclic compound Download PDFInfo
- Publication number
- CN102942561A CN102942561A CN2012104384181A CN201210438418A CN102942561A CN 102942561 A CN102942561 A CN 102942561A CN 2012104384181 A CN2012104384181 A CN 2012104384181A CN 201210438418 A CN201210438418 A CN 201210438418A CN 102942561 A CN102942561 A CN 102942561A
- Authority
- CN
- China
- Prior art keywords
- cxm
- quinazoline
- indazole
- fluoro
- benzyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 0 **1(CCCC2=CCC(CC(Cc3cccc(F)c3)*N=C3)C3=C2)CC1 Chemical compound **1(CCCC2=CCC(CC(Cc3cccc(F)c3)*N=C3)C3=C2)CC1 0.000 description 3
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
Abstract
The invention provides a compound shown as the formula (I) and a preparation method of the compound as well as a purpose of the compound in the antitumor drug preparation.
Description
Technical field
The present invention relates to 4-amido quinazoline heterogeneous ring compound of therapeutic activity and preparation method thereof, contain the pharmaceutical composition of these compounds, and described compound or the purposes of pharmaceutical composition in the preparation antitumor drug.
Technical background
Cancer/malignant tumour is one of chief threat of human health, most of tumours all with the external environment factor analysis, cancer is died from more than every year 5000000 people being arranged in the whole world.Although more existing treatment ways can make the patient cure such as surgical operation, radiotherapy, chemotherapy etc. now, curative ratio is not high.At present, using chemoprophylaxis and treatment is one of most effectual way of uniform tumour.
EGF-R ELISA (EGFR) signal transduction pathway is playing an important role aspect generation, propagation and the existence of tumour cell.Therefore, EGFR is an important target of antitumor drug always.So far, the test of inside and outside and clinical studies show, as a kind of promising antitumor drug, the EGFR-TK inhibitor is that separately application or assimilation chemotherapy combined radiotherapy all show significant antitumor action.The antitumor drug that has gone on the market such as Gefitinib (Gefitinib), erlotinib (Erlotinib), lapatinibditosylate (Lapatinib) etc. are first-generation EGFR-TK inhibitor.Find in the clinical practice that tumour patient is lower to the susceptibility of first-generation EGFR-TK inhibitor, about 10% North America patient and Yue 20% asian patients have response to them.At present, the s-generation has entered clinical experimental stage.An advantage of s-generation EGFR inhibitor is irreversibly covalent attachment of they and target, and like this, medicine just can be applied to the whole link of Urogastron signal transduction pathway, and improves the blocking-up efficient of medicine.This non-reversibility is in conjunction with killing those to the tumour cell of first-generation EGFR inhibitor resistance.Another advantage is many targets property.The signal conduction of tumour cell has diversity, and s-generation EGFR inhibitor can also stop the signal transduction pathway of the ErbB family as HER-2 except stoping the EGFR signal transduction pathway.S-generation EGFR inhibitor is attractive at clinical I and the interim test-results of II, particularly just at the BIBW2992 of II clinical trial phase.
Along with further illustrating of mechanism of action, will have more this type of medicine enter clinical, for the treatment of tumour provides more wide development space.For example, the compound of similar BIBW2992 has been described in the patent applications such as WO0250043, US20050085495, US20090306378, they have valuable pharmacological character, especially the signal transmission that mediates by Tyrosylprotein kinase is had inhibition and the signal transmission that mediates by EGF-R ELISA (EGF-R) is had inhibition.Therefore, these compounds are specially adapted to treat tumor disease, lung and respiratory tract disease and gi tract, bile duct and gallbladder disease.
The inventor is based on the exploitation of multiple receptor tyrosine kinases inhibitor, design and synthesize new 4-Aminoquinazolines compounds, it irreversibly suppresses the various approach of EGFR and relevant HER-2 and inhibition cell mitogen, thereby is used for the treatment of tumor disease by suppressing tumor-blood-vessel growth.
Summary of the invention
An object of the present invention is to provide new 4-amido quinazoline heterogeneous ring compound.
Another object of the present invention provides the pharmaceutical composition that contains above-claimed cpd and pharmaceutically acceptable carrier.
A further object of the present invention provides above-claimed cpd or the purposes of pharmaceutical composition in the preparation antitumor drug, described tumour is preferably by the kinase mediated disease of albumen TYR, such as mammary cancer, nonsmall-cell lung cancer, ovarian cancer, cancer of the stomach, carcinoma of the pancreas etc.
According to an aspect of the present invention, provide the compound shown in the formula (I):
Wherein, R
1And R
2Represent independently hydrogen, halogen, C
1-4The C that alkyl, halogen replace
1-4Alkyl, C
1-4The C that alkoxyl group, halogen replace
1-4Alkoxyl group, itrile group, ester group, nitro, amino, amide group, sulfoamido, phenyl or CH
3SO
2CH
2CH
2NHCH
2-Ar; Wherein Ar represents phenyl, furyl, thienyl, pyrryl and thiazolyl, and Ar can be selected from halogen, C by one or two
1-4Alkyl and C
1-4The group of alkoxyl group replaces; Perhaps
R
1, R
2Independently expression:
X-(CH
2)
n-R
4
Wherein X represents N, O or S; N represents 0 to 6 integer; R
4Expression hydrogen, C
1-4The C that alkyl, halogen replace
1-4Alkyl, C
1-4The C that alkoxyl group, halogen replace
1-4Alkoxyl group, furyl, tetrahydrofuran base, morpholinyl, pyranyl, THP trtrahydropyranyl, pyrryl, pyridyl, oxazolinyl, thiazolyl or thienyl; Perhaps
R
1, R
2Independently expression:
R wherein
5Expression H, N, N-dimethyl amine ylmethyl, N, N-diethylamide ylmethyl or N, N-dipropylamine ylmethyl;
R
3Expression hydrogen or C
1-4Alkyl.
In preferred embodiment, the compound shown in the formula (I), wherein:
R
1And R
2Represent independently hydrogen, C
1-4Alkoxyl group, nitro, amino, amide group; Perhaps
R
1, R
2Represent independently following structure:
X-(CH
2)
n-R
4
Wherein X represents O or S; N represents 0 to 4 integer, for example 0,1,2,3 or 4; R
4Expression hydrogen, C
1-4Alkyl, C
1-4Alkoxyl group, 3-tetrahydrofuran base, morpholinyl, 4-THP trtrahydropyranyl, 2-pyrryl, oxazolinyl, thiazolyl or thienyl; Perhaps,
R
1, R
2Represent independently following structure:
R wherein
5Expression H, N, N-dimethyl amine ylmethyl, N, N-diethylamide ylmethyl or N, N-dipropylamine ylmethyl;
R
3Expression hydrogen.
The preferred compound of the present invention is selected from:
N-{4-[1-(3-fluoro-benzyl)-1H-indazole-5-base amido]-quinazoline-6-yl }-acrylamide (CXM-01);
(E)-N-{4-[1-(3-fluoro-benzyl)-1H-indazole-5-base amido]-7-methoxyl group-quinazoline-6-yl }-4-(dimethylamino) but-2-enamides (CXM-02);
(E)-N-{4-[1-(3-fluoro-benzyl)-1H-indazole-5-base amido]-7-oxyethyl group-quinazoline-6-yl }-4-(dimethyl amido)-but-2-enamides (CXM-03);
7-(2-methoxy ethoxy)-N-[1-(3-fluoro-benzyl)-1H-indazole-5-yl]-6-nitro-quinazoline-4-amine (CXM-04);
(E)-N-{4-[1-(3-fluoro-benzyl)-1H-indazole-5-base amido]-7-(3-methoxy ethoxy)-quinazoline-6-yl }-4-(dimethyl amido)-but-2-enamides (CXM-05);
N-{4-[1-(3-fluoro-benzyl)-1H-indazole-5-base amido]-7-(2-methoxyethoxy)-quinazoline-6-yl }-acrylamide (CXM-06);
N-{4-[1-(3-fluoro-benzyl)-1H-indazole-5-base amido]-7-[3-(4-morpholino) propoxy-]-quinazoline-6-yl }-acrylamide (CXM-07);
(E)-N-{4-[1-(3-fluoro-benzyl)-1H-indazole-5-base amido]-7-[3-(4-morpholino) propoxy-]-quinazoline-6-yl }-4-(dimethyl amido)-but-2-enamides (CXM-08);
(E)-N-{7-[(S)-tetrahydrofuran (THF)-3-base oxygen base]-4-[1-(3-fluoro-benzyl)-1H-indazole-5-base amido]-quinazoline-6-yl }-4-dimethyl amido-but-2-enamides (CXM-09);
(E)-N-{4-[1-(3-fluoro-benzyl)-1H-indazole-5-base amido]-7-(itrile group)-quinazoline-6-yl }-4-dimethyl amido-but-2-enamides (CXM-10);
(E)-N-{7-[(tetrahydrochysene-2H-pyrans-4-yl)-methylthio group]-4-[1-(3-fluoro-benzyl)-1H-indazole-5-base amido]-quinazoline-6-yl }-4-dimethyl amido-but-2-enamides (CXM-11);
(E)-N-{4-[1-(3-fluoro-benzyl)-1H-indazole-5-base amido]-quinazoline-6-yl }-4-dimethyl amido-but-2-enamides (CXM-12);
N-{4-[1-(3-fluoro-benzyl)-1H-indazole-5-base amido]-7-methoxyl group-quinazoline-6-yl }-acrylamide (CXM-13);
N-{4-[1-(3-fluoro-benzyl)-1H-indazole-5-base amido]-7-oxyethyl group-quinazoline-6-yl }-acrylamide (CXM-14);
N-{7-[(S)-tetrahydrofuran (THF)-3-base oxygen base]-4-[1-(3-fluoro-benzyl)-1H-indazole-5-base amido]-quinazoline-6-yl }-acrylamide (CXM-15);
N-{4-[1-(3-fluoro-benzyl)-1H-indazole-5-base amido]-7-itrile group-quinazoline-6-yl }-acrylamide (CXM-16);
N-{7-[(tetrahydrochysene-2H-pyrans-4-yl)-methylthio group]-4-[1-(3-fluoro-benzyl)-1H-indazole-5-base amido]-quinazoline-6-yl }-acrylamide (CXM-17);
N-{4-[1-(3-fluoro-benzyl)-1H-indazole-5-base amido]-quinazoline-7-yl }-acrylamide (CXM-18);
(E)-N-{4-[1-(3-fluoro-benzyl)-1H-indazole-5-base amido]-6-methoxyl group-quinazoline-7-yl }-4-dimethyl amido-but-2-enamides (CXM-19);
(E)-N-{4-[1-(3-fluoro-benzyl)-1H-indazole-5-base amido]-6-oxyethyl group-quinazoline-7-yl }-4-dimethyl amido-but-2-enamides (CXM-20);
(E)-N-{4-[1-(3-fluoro-benzyl)-1H-indazole-5-base amido]-6-(2-methoxy ethoxy)-quinazoline-7-yl }-4-dimethyl amido-but-2-enamides (CXM-21);
N-{4-[1-(3-fluoro-benzyl)-1H-indazole-5-base amido]-6-(2-methoxy ethoxy)-quinazoline-7-yl }-acrylamide (CXM-22);
N-{4-[1-(3-fluoro-benzyl)-1H-indazole-5-base amido]-6-[3-(4-morpholino) propoxy-]-quinazoline-7-yl }-acrylamide (CXM-23);
(E)-N-{4-[1-(3-fluoro-benzyl)-1H-indazole-5-base amido]-6-[3-(4-morpholino) propoxy-]-quinazoline-7-yl }-4-dimethyl amido-but-2-enamides (CXM-24)
(E)-N-{6-[(S)-tetrahydrofuran (THF)-3-base oxygen base]-4-[1-(3-fluoro-benzyl)-1H-indazole-5-base amido]-quinazoline-7-yl }-4-dimethyl amido-but-2-enamides (CXM-25);
(E)-N-{4-[1-(3-fluoro-benzyl)-1H-indazole-5-base amido]-6-itrile group-quinazoline-7-yl }-4-dimethyl amido-but-2-enamides (CXM-26);
(E)-N-{6-[(tetrahydrochysene-2H-pyrans-4-yl)-methylthio group]-4-[1-(3-fluoro-benzyl)-1H-indazole-5-base amido]-quinazoline-7-yl }-4-dimethyl amido-but-2-enamides (CXM-27);
(E)-N-{4-[1-(3-fluoro-benzyl)-1H-indazole-5-base amido]-quinazoline-7-yl }-4-dimethyl amido-but-2-enamides (CXM-28);
N-{4-[1-(3-fluoro-benzyl)-1H-indazole-5-base amido]-6-methoxyl group-quinazoline-7-yl }-acrylamide (CXM-29);
N-{4-[1-(3-fluoro-benzyl)-1H-indazole-5-base amido]-6-oxyethyl group-quinazoline-7-yl }-acrylamide (CXM-30);
N-{6-[(S)-tetrahydrofuran (THF)-3-base oxygen base]-4-[1-(3-fluoro-benzyl)-1H-indazole-5-base amido]-quinazoline-7-yl }-acrylamide (CXM-31);
N-{4-[1-(3-fluoro-benzyl)-1H-indazole-5-base amido]-6-itrile group-quinazoline-7-yl }-acrylamide (CXM-32);
N-{6-[(tetrahydrochysene-2H-pyrans-4-yl)-methylthio group]-4-[1-(3-fluoro-benzyl)-1H-indazole-5-base amido]-quinazoline-7-yl }-acrylamide (CXM-33).
Compound of the present invention can be the form of tautomer, steric isomer or its pharmacy acceptable salt.
In the present invention, unless specify in addition, following term has following implication.
" halogen " refers to fluorine, chlorine, bromine and iodine, preferred fluorine, chlorine or bromine.
" C
1-4Alkyl " nail base, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, sec-butyl and the tertiary butyl; Preferable methyl, ethyl, propyl group, sec.-propyl or butyl; More preferably methyl.
" C
1-4Alkoxyl group " refer to methoxyl group, oxyethyl group, positive propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy and tert.-butoxy; Preferred methoxyl group, oxyethyl group, propoxy-, isopropoxy or butoxy; More preferably methoxyl group.
" ester group " nail perester radical, acetate groups, propionic acid ester group, butyric acid ester group etc., preferred acetate groups.
" amide group " nail amide group, acetamido, propionamido-etc.; Preferred α, β-unsaturated propionic acid amide.
" sulfoamido " nail sulfoamido, ethyl sulfonamide base, sulfonyl propyl amido, sec.-propyl sulfoamido etc.; Preferred methylsulfonyl amido.
" phenyl " can be by the phenyl of the replacements such as alkyl, alkoxyl group, alkoxy methyl, ester group, sulfonate group, hydroxyl, the phenyl that preferred alkoxyl group, alkoxy methyl, ester group, hydroxyl replace.
" furyl " comprises 2-furyl and 3-furyl." tetrahydrofuran base " comprises 2-tetrahydrofuran base and 3-tetrahydrofuran base.Also comprise the furyl and the tetrahydrofuran base that are replaced by groups such as alkyl, alkoxyl group, alkoxy methyl, ester group, sulfonate group, hydroxyls.
" pyranyl " comprises 2-pyranyl, 3-pyranyl and 4-pyranyl." THP trtrahydropyranyl " comprises 2-THP trtrahydropyranyl, 3-THP trtrahydropyranyl and 4-THP trtrahydropyranyl.Also comprise the pyranyl and the THP trtrahydropyranyl that are replaced by groups such as alkyl, alkoxyl group, alkoxy methyl, ester group, sulfonate group, hydroxyls.
" thienyl " comprises 2-thienyl and 3-thienyl.Also comprise the thienyl that is replaced by alkyl, alkoxyl group, alkoxy methyl, ester group, sulfonate group, hydroxyl etc.
" steric isomer " comprises cis-trans-isomer, enantiomer and conformer.
" pharmacy acceptable salt " refers to relatively nontoxic formula of the present invention (I) compound and the acid salt of organic acid or inorganic formation.These salt can in the end separate and the preparation of purification compound process situ, perhaps by compound is made with its free alkali form and suitable inorganic or organic acid reaction.Described mineral acid or organic acid are selected from Hydrogen bromide, hydrochloric acid, sulfuric acid, sulfurous acid, acetic acid, oxalic acid, valeric acid, oleic acid, palmitinic acid, stearic acid, lauric acid, boric acid, phenylformic acid, lactic acid, phosphoric acid, toluic acid, citric acid, toxilic acid, fumaric acid, succsinic acid, tartrate, phenylformic acid, methylsulfonic acid, gluconic acid, lactobionic acid and lauryl sulfonic acid.
According to a further aspect in the invention, provide a kind of pharmaceutical composition that contains compound of the present invention and pharmaceutically acceptable carrier.
The compound of the present invention administration that can separately or mutually combine, also can with other pharmaceutically acceptable active compound Combined Preparation.Described compound can pharmaceutical composition form bestow the human or animal who needs by oral, rectum, parenteral, topical.
Described pharmaceutical composition mixes the pharmaceutically acceptable carrier of active compound and one or more usually according to conventional methods, makes suitable formulation.Described pharmaceutically acceptable carrier refers to the inert support of pharmaceutical field routine.
For example, be used for oral solid dosage and comprise capsule, tablet, pill, powder and granule etc.Except the active ingredient beyond the region of objective existence, pharmaceutical composition can comprise following one or more carriers: thinner, such as starch, lactose, sucrose, glucose, N.F,USP MANNITOL or silicic acid; Tackiness agent is such as Walocel MT 20.000PV, alginate, gelatin, Polyvinylpyrolidone (PVP), sucrose and gum arabic; Dispersion agent is such as polyoxyethylene glycol, polyvinylpyrrolidone; Wetting Agent for Printing Inks, for example glycerine; Disintegrating agent is such as agar, calcium carbonate, yam starch or tapioca (flour), alginic acid, some composition silicate and yellow soda ash; Retarding solvent is such as paraffin; Absorb accelerator, such as quaternary ammonium compound; Wetting agent is such as hexadecanol and glyceryl monostearate; Sorbent material is such as kaolin; Lubricant, for example talcum powder, calcium stearate, Magnesium Stearate, solid polyethylene glycol, sodium lauryl sulphate; Other assistant agents are such as buffer reagent, tinting material, perfume compound, sweeting agent etc.In addition, can comprise coating material and prepare coated preparation.Can comprise the preparation sustained release preparations such as polymeric material and Wax, make active compound to discharge in mode certain part in digestive tube that postpones.
The liquid dosage form that is used for oral administration comprises emulsion, solution, suspension, syrup or tincture.Except the active ingredient beyond the region of objective existence, pharmaceutical composition can comprise following one or more carriers: thinner such as water or other solvent, solubilizing agent and emulsifying agent, such as ethanol, Virahol, ethyl-carbonate, ethyl acetate, propylene glycol, 1, the mixture of 3-butyleneglycol, dimethyl formamide and oil, particularly Oleum Gossypii semen, peanut oil, maize germ, sweet oil, Viscotrol C and sesame oil or these materials; Suspending agent is such as ethoxylation isooctadecane alcohol, polyoxyethylene sorbitol and Isosorbide Dinitrate, Microcrystalline Cellulose, aluminum methylate and agar.Can comprise assistant agent in addition, such as wetting agent, emulsifying agent, suspension agent, sweeting agent, correctives and spices.
The formulation that is used for administered parenterally comprises intravenously, subcutaneous, intramuscular injection preparation.Except the active ingredient beyond the region of objective existence, pharmaceutical composition can comprise physiologically acceptable aseptic moisture or anhydrous solution, dispersion liquid, suspension or emulsion, and is used for again being dissolved into aseptic Injectable solution or the sterilized powder of dispersion liquid.Suitable moisture and nonaqueous carrier, thinner, solvent comprise water, ethanol, polyvalent alcohol and suitable mixture thereof.
The formulation that is used for topical comprises ointment, powder, propellant, drops and inhalation.Activeconstituents under aseptic condition with physiologically acceptable carrier and any sanitas, buffer reagent, or the propelling agent that may need in case of necessity is mixed together.
According to a further aspect in the invention, the application in the preparation antitumor drug of compound of the present invention or pharmaceutical composition is provided, described tumour is preferably by the kinase mediated disease of albumen TYR, such as mammary cancer, nonsmall-cell lung cancer, ovarian cancer, cancer of the stomach, carcinoma of the pancreas etc.
Embodiment
By following examples the present invention is described in further detail, but should not be construed as limiting the scope of the invention.
Embodiment 1Preparation N-{4-[1-(3-fluoro-benzyl)-1H-indazole-5-base amido]-quinazoline-6-base--acrylamide (Compound C XM-01)
5-nitro indazole (163.1g, 1mol), cesium carbonate (358.4g, 1.1mol) are dissolved in DMF (0.5L), in 70-80 ℃ of reaction 2h, then add 3-fluoro benzyl bromide (225.6g, 1.2mol) and continue reaction, until the thin-layer chromatography detection reaction is complete.Reaction solution is cooled to room temperature, filters, and with DMF (0.3L) washing leaching cake.Filtrate adds entry (0.13-0.15L) in the time of 15-20 ℃, place 4h, filter, filter cake is used DMF/ water mixture (0.2L successively, v/v 2: 1), water (0.2L) and cold CAN (ceric ammonium nitrate)/water mixture (0.15L, v/v 3: 1) washing, be lower than under 45 ℃ the temperature dry, get 5-nitro-1-(3-luorobenzyl)-indazole crystallization (compound 1), yield 56%.
1H-MR (400MHz, CDCl
3) δ 5.62 (s, 2H), 6.85 (d, 1H, J=9.4Hz), 6.93 (m, 2H), (7.28 m, 1H), 7.40 (d, 1H, J=9.2Hz), 8.21 (dd, 1H, J=10Hz and 2Hz), 8.24 (s, 1H), 8.70 (d, 1H, J=2Hz); MS:272 (M+H)
+HPLC retention time: 6.95min (YMC ODS-A 3 μ m, 4.6 * 50mm post, the 10min gradient, 2.5ml/min).
Add compound 1 (271.2g, 1mol) in hydrogenation reaction cauldron, THF (0.8L), 5% palladium carbon (2.7g, the 0.1wt% of compound 1) be as catalyzer, reacts 2h in 30-35 ℃, 15psi.Reaction solution is cooled to room temperature, filters, with THF (0.1L) washing leaching cake.Filter cake is added stirring among the THF (0.5L), filter.Merging filtrate, air distillation be to volume required (0.55L), and under 55-60 ℃ at 1h with interior adding heptane (1.5L), obtain soup compound.Soup compound is cooled to room temperature in 1.5h, places 1h, filter, filter cake washs with THF/ heptane (1L, v/v 1: 4), and 40 ℃ of forced air dryings get 1-(3-fluoro-benzyl)-1H-indazole-5-base amine (compound 2), yield 80%.mp：130℃。HPLC retention time: 9.05min.
In 105-110 ℃ of back flow reaction 3h, reaction solution is slowly poured in the frozen water (0.9L) and is separated out the flakey solid with 6-nitro-quinazoline ketone (191.1g, 1mol) and phosphorus oxychloride (0.15L), filter, drying gets 4-chloro-6-nitro-quinazoline (compound 3), yield 80%.
1H-MR(400MHz，CDCl
3)：δ9.20(s，2H)，8.72(dd，1H，J＝2.57Hz，9.16Hz)，8.25(d，1H，J＝9.16Hz).
With compound 2 (241.2g, 1mol) with compound 3 (209.6g, 1mol) be dissolved in Virahol (1.5L), back flow reaction 3h, separate out yellow solid, filter vacuum-drying, get yellow solid N-[1-(3-fluoro-benzyl)-1H-indazole-5-yl]-6-nitro-quinazoline-4-amine (compound 4), yield 73%.
1H-MR(400MHz，CDCl
3)：δ10.08(s，br，1H)，8.76-8.70(m，2H)，8.36(s，1H)，8.27-8.21(m，1H)，8.14-8.05(m，1H)，7.35-7.32(m，1H)，7.12-7.03(m，1H)，7.05-6.96(m，1H)，6.83-6.80(m，1H)，6.78-6.68(m，2H)，6.54-6.51(m，1H)，4.99(s，2H).
With compound 4 (414.4g, 1mol), iron powder (279.2g, 5mol) adds in Glacial acetic acid (0.05L) and the methyl alcohol (1L), back flow reaction 4h, reacting liquid filtering is removed iron powder, and filtrate adds ethyl acetate (0.5L), then uses successively an amount of sodium hydrogen carbonate solution and water washing, separate organic phase, anhydrous magnesium sulfate drying, concentrated, get yellow solid N
4-[1-(3-fluoro-benzyl)-1H-indazole-5-yl]-quinazoline-4,6-diamines (compound 5), yield 64%.
1H-MR(400MHz，DMSO)：δ9.43(s，1H)，8.32(s，1H)，8.14-8.10(m，1H)，7.76-7.71(m，1H)，7.35-7.32(m，1H)，7.13-7.10(m，1H)，7.08-6.99(m，3H)，6.83-6.70(m，3H)，6.54-6.44(m，1H)，5.19(s，2H).
Under 0-5 ℃ of temperature to compound 5 (384.4g, add triethylamine (151.8g 1mol), 1.5mol), acrylate chloride (90.5g, 1mol), tetrahydrofuran (THF) (1.3L), slowly rise to room temperature, reaction 3h, reaction solution extracts with ethyl acetate (1.5L), separate organic phase, anhydrous magnesium sulfate drying, concentrated, enriched material separates (moving phase: ethyl acetate and sherwood oil) through silica gel column chromatography, get faint yellow solid N-{4-[1-(3-fluoro-benzyl)-1H-indazole-5-base amido]-quinazoline-6-base--acrylamide (title compound CXM-01), yield 70%.
1H-MR(400MHz，CDCl
3)：δ8.38(s，1H)，8.22-8.14(m，2H)，8.14-8.10(m，1H)，7.99-7.94(m，1H)，7.35-7.32(m，1H)，7.12-7.05(m，2H)，6.83-6.77(m，3H)，6.54-6.52(m，1H)，6.48-6.36(d，J＝5.9Hz，2H)，5.71-5.67(t，J＝5.9Hz，2H)，6.5.09(s，2H).
Embodiment 2Preparation (E)-N-{4-[1-(3-fluoro-benzyl)-1H-indazole-5-base amido]-7-methoxyl group-quinazoline-6-base--4-(dimethylamino) but-2-enamides (Compound C XM-02)
2-amino-4-chloro-phenylformic acid (171.6g, 1mol) is dissolved in methane amide (972.8g, 21.6mol), back flow reaction 5h, reacting liquid filtering, dry cake gets 7-chloroquine oxazolone (compound 6).
Compound 6 (180.6g, 1mol) is slowly added in the nitration mixture (0.4L contains the vitriol oil and nitrosonitric acid, v/v 1: 1) under ice bath, be heated to 90 ℃ of reaction 4h.The reaction solution of clarification is slowly poured in the frozen water (3L), separated out light-yellow precipitate, filter, filter cake gets 6-nitro-7-chloroquine oxazolone crystal (compound 7) with hot Glacial acetic acid (2L) recrystallization.
With compound 7 (225.6g, 1mol) and phosphorus oxychloride (0.375L) back flow reaction 4h, reaction solution is poured in the frozen water, filters, and dry cake gets 6-nitro-4,7-dichloroquinazoline (compound 8).
With compound 8 (170.1g, 0.7mol) be dissolved in the Virahol (0.75L), add 1-(3-fluoro-benzyl)-1H-indazole-5-base amine (compound 2,168.8g, 0.7mol), back flow reaction 4h filters, the vacuum-drying filter cake gets N-[1-(3-fluoro-benzyl)-1H-indazole-5-yl]-7-chloro-6-nitro-quinazoline-4-amine (compound 9).
Compound 9 (448.8g, 1mol) is dissolved among the anhydrous THF (2.5L), adds sodium methylate (63.74g, 1.18mol), back flow reaction 18h.Reaction solution adds Glacial acetic acid (70.86g, 1.18mol), washing, then use ethyl acetate (0.5L) extraction 3 times, the organic phase concentrating under reduced pressure, drying gets N-[1-(3-fluoro-benzyl)-1H-indazole-5-yl]-7-methoxyl group-6-nitro-quinazoline-4-amine (compound 10).
With compound 10 (444.4g, 1mol), iron powder (279.2g, 5mol), Glacial acetic acid (0.25L), methyl alcohol (2.5L) mix, back flow reaction 3h, reacting liquid filtering is removed iron powder, filtrate is diluted with ethyl acetate (0.5L), use successively the washing of saturated sodium bicarbonate solution (1L) and water (0.2L), the organic phase anhydrous magnesium sulfate drying, concentrated, get light yellow solid compound 11, yield 73%.
Compound 11 (414.4g, 1mol) is dissolved among the anhydrous THF (2.5L), drips successively diisopropyl ethyl amine (0.15L) and 3-N in 0 ℃, N-dimethylamino methyl acrylate chloride (147.6g, 1mol) is in 0-5 ℃ of reaction 3h.Add ethyl acetate-water (v/v to reaction solution, 4: 1) mixture (1L), water layer washs 3 times with ethyl acetate (0.5L), merge organic phase, anhydrous magnesium sulfate drying, concentrated, silica gel column chromatography separates, get solid (E)-N-{4-[1-(3-fluoro-benzyl)-1H-indazole-5-base amido]-7-methoxyl group-quinazoline-6-base--4-(dimethylamino) but-2-enamides (title compound CXM-02), yield 67%.
1H-NMR(400MHz，CDCl
3)：δ8.36(s，1H)，8.20-8.14(m，1H)，8.12-8.10(m，1H)，7.50-7.46(m，1H)，7.36-7.33(m，1H)，7.10-7.05(m，2H)，6.83-6.77(m，3H)，6.75-6.73(d，J＝2.5Hz，1H)，6.54-6.52(d，J＝2.5Hz，1H)，6.38-6.36(m，1H)，4.99-4.94(m，2H)，3.83(s，3H)，3.03(m，2H)，2.27-2.18(m，6H).
Embodiment 3Preparation (E)-N-{4-[1-(3-fluoro-benzyl)-1H-indazole-5-base amido]-7-oxyethyl group-quinazoline-6-yl }-4-(dimethyl amido)-but-2-enamides (Compound C XM-03)
Preparation method's similar embodiment 2, different is that sodium methylate is replaced with sodium ethylate.End product is title compound CXM-03.
1H-NMR(400MHz，CDCl
3)：δ8.37(s，1H)，8.21-8.13(m，1H)，8.11-8.08(m，1H)，7.51-7.48(m，1H)，7.37-7.32(m，1H)，7.11-7.06(m，2H)，6.82-6.75(m，3H)，6.70-6.68(d，J＝2.5Hz，1H)，6.50-6.48(d，J＝2.5Hz，1H)，6.40-6.35(m，1H)，5.03-4.96(m，2H)，3.85(s，3H)，3.03(m，2H)，2.27-2.18(m，6H)，1.33-1.30(m，3H).
Embodiment 4Preparation 7-(2-methoxy ethoxy)-N-[1-(3-fluoro-benzyl)-1H-indazole-5-yl]-6-nitro-quinazoline-4-amine (Compound C XM-04)
4-chloro-6-nitro-quinazoline-7-base-acetic ester (267g, lmol) and 1-(3-fluoro-benzyl)-1H-indazole-5-amine (241.1g, 1mol) is dissolved in the Virahol (1L) back flow reaction 3h.Reacting liquid filtering, filter cake washs with ethyl acetate (0.3L), 45 ℃ of vacuum-dryings are spent the night, and get light yellow solid 4-[1-(3-fluoro-benzyl)-1H-indazole-5-base amido]-6-nitro-quinazoline-7-base-acetic ester (compound 12), yield 93%.
1H-NMR(400MHz，CDCl
3)：δ8.74(s，1H)，8.36-8.32(m，1H)，8.14-8.08(m，2H)，7.35-7.30(m，1H)，7.12-7.08(m，2H)，6.83-6.77(m，3H)，6.54-6.49(m，1H)，5.03-4.99(m，2H)，2.08(m，3H).
With compound 12 (472.1g, 1mol) be dissolved in the methyl alcohol (5L), drip strong aqua (0.5L), room temperature reaction 5h, reacting liquid filtering, filtrate is concentrated, enriched material and filter cake merge, use recrystallizing methanol, get yellow solid 4-[1-(3-fluoro-benzyl)-1H-indazole-5-base amido]-6-nitro-quinazoline-7-hydroxyl (compound 13), yield 95%.
1H-NMR(400MHz，CDCl
3)：δ8.60(s，1H)，8.36-8.32(m，1H)，8.14-8.10(m，1H)，7.76-7.72(m，1H)，7.35-7.32(m，1H)，7.12-7.05(m，2H)，6.83-6.77(m，3H)，6.54-6.50(m，1H)，5.05-5.00(m，2H).
With compound 13 (430.1g, 1mol) and 2-methoxyl group monobromethane (185.9,1.5mol) be dissolved among the DMF (15L), add tetrabutylammonium iodide (36.9g, 0.1mol) and salt of wormwood (138.2g, 1mol), filtered while hot is spent the night in 60 ℃ of reactions, filtrate decompression boils off solvent, the residuum recrystallizing methanol gets title compound CXM-04, yield 71%.
1H-NMR(400MHz，CDCl
3)：δ8.66(s，1H)，8.36-8.33(m，1H)，8.14-8.11(m，1H)，7.78-7.75(m，2H)，7.37-7.33(m，1H)，7.11-7.07(m，2H)，7.06-7.01(m，1H)，6.85-6.75(m，3H)，6.56-6.51(m，1H)，5.07-5.02(m，2H)，4.11-4.07(m，2H)，3.79-3.73(m，2H)，3.24(s，3H).
Embodiment 5Preparation (E)-N-{4-[1-(3-fluoro-benzyl)-1H-indazole-5-base amido]-7-(3-methoxy ethoxy)-quinazoline-6-yl }-4-(dimethyl amido)-but-2-enamides (Compound C XM-05)
Preparation method's similar embodiment 2, different is that compound 10 is replaced with Compound C XM-04.End product is title compound CXM-05.
1H-NMR(400MHz，CDCl
3)：δ8.37(s，1H)，8.15-8.12(m，1H)，7.50-7.45(m，1H)，7.36-7.32(m，1H)，7.12-7.05(m，2H)，6.83-6.77(m，3H)，6.75-6.72(d，J＝2.5Hz，1H)，6.54-6.51(m，1H)，6.38-6.34(d，J＝2.5Hz，1H)，4.99-4.96(m，2H)，4.10-4.06(m，2H)，3.78-3.74(m，2H)，3.24(s，3H)，3.03-3.00(d，J＝3.8Hz，2H)，2.28(s，6H).
Embodiment 6Preparation N-{4-[1-(3-fluoro-benzyl)-1H-indazole-5-base amido]-7-(2-methoxyethoxy)-quinazoline-6-yl }-acrylamide (Compound C XM-06)
Preparation method's similar embodiment 5, different is with 3-N, N-dimethylamino methyl acrylate chloride replaces with acrylate chloride.End product is title compound CXM-06.
1H-NMR(400MHz，CDCl
3)：δ8.36(s，1H)，8.14-8.11(m，2H)，7.51-7.46(m，1H)，7.35-7.32(m，1H)，7.12-7.05(m，2H)，6.84-6.78(m，3H)，6.54-6.51(m，1H)，6.48-6.44(q，J＝10.1，16.8Hz，1H)，6.17-6.14(dd，J＝2.1，7.1Hz，2H)，5.71-5.68(dd，J＝2.1，7.1Hz，2H)，4.99-4.96(m，2H)，4.11-4.06(m，2H)，3.79-3.74(m，2H)，3.24(s，3H).
Embodiment 7Preparation N-{4-[1-(3-fluoro-benzyl)-1H-indazole-5-base amido]-7-[3-(4-morpholino) propoxy-]-quinazoline-6-yl }-acrylamide (Compound C XM-07)
Preparation method's similar embodiment 6, different is that 2-methoxyl group monobromethane is replaced with 3-(N-morpholine)-n-propyl chloride.End product is title compound CXM-07.
1H-NMR(400MHz，CDCl
3)：δ8.34(s，1H)，8.15-8.12(m，2H)，7.50-7.46(m，1H)，7.36-7.32(m，1H)，7.10-7.05(m，2H)，6.83-6.77(m，3H)，6.53-6.50(m，1H)，6.46-6.42(q，J＝10.1，16.8Hz，1H)，6.15-6.12(dd，J＝2.1，7.1Hz，2H)，5.70-5.66(dd，J＝2.1，7.1Hz，2H)，5.00-4.98(m，2H)，3.94-3.90(m，2H)，3.67-3.64(m，4H)，2.37-2.35(m，6H)，1.81-1.75(m，2H).
Embodiment 8Preparation (E)-N-{4-[1-(3-fluoro-benzyl)-1H-indazole-5-base amido]-7-[3-(4-morpholino) propoxy-]-quinazoline-6-yl }-4-(dimethyl amido)-but-2-enamides (Compound C XM-08)
Preparation method's similar embodiment 7, different is that acrylate chloride is replaced with 3-N, N-dimethylamino methyl acrylate chloride.End product is title compound CXM-08.
1H-NMR(400MHz，CDCl
3)：δ8.36(s，1H)，8.14-8.10(m，2H)，7.51-7.48(m，1H)，7.35-7.31(m，1H)，7.12-7.08(m，2H)，6.84-6.78(m，3H)，6.54-6.50(m，1H)，6.40-6.37(d，J＝2.5Hz，1H)，6.29-6.26(d，J＝2.5Hz，1H)，4.99-4.96(m，2H)，3.67-3.63(m，4H)，3.94-3.90(m，2H)，3.03-2.99(m，2H)，2.37-2.32(m，6H)，2.27(s，6H).
Embodiment 9Preparation (E)-N-{7-[(S)-tetrahydrofuran (THF)-3-base oxygen base]-4-[1-(3-fluoro-benzyl)-1H-indazole-5-base amido]-quinazoline-6-yl }-4-dimethyl amido-but-2-enamides (Compound C XM-09)
Under the ice bath with compound 13 (430.1g, 1mol) be dissolved in the methylene dichloride (2L), add (S)-tetrahydrofuran base-3-alcohol (105.7g, 1.2mol), triphenyl phosphorus (280g, 1mol), diethylazodicarboxylate (261.2g, 1.5mol), stirring at room 10h, reacting liquid filtering, with methylene dichloride (1.0L) extraction 3 times, organic phase pressure reducing and steaming solvent, drying under reduced pressure gets 7-[(R)-tetrahydrofuran (THF)-3-base oxygen base]-N-[1-(3-fluoro-benzyl)-1H-indazole-5-yl]-6-nitro-quinazoline-4-amine (compound 14).
Reference example 2, compound 14 get 7-[(S through nitro-reduction reaction)-tetrahydrofuran (THF)-3-base oxygen base]-N
4-[1-(3-fluoro-benzyl)-1H-indazole-5-yl]-quinazoline-4,6-diamines (compound 15), again with 3-N, N dimethylamine ylmethyl acrylate chloride carries out acylation reaction, gets title compound CXM-09.
1H-NMR(400MHz，CDCl
3)：δ8.37(s，1H)，8.15-8.11(m，2H)，7.52-7.47(m，1H)，7.36-7.32(m，1H)，7.12-7.05(m，2H)，6.83-6.78(m，3H)，6.75-6.70(d，J＝2.5Hz，1H)，6.54-6.50(m，1H)，6.41-6.38(d，J＝2.5Hz，1H)，5.00-4.97(m，2H)，4.26-4.22(m，1H)，4.05-4.01(m，2H)，3.80-3.70(m，2H)，3.03-2.99(m，2H)，2.36-2.34(m，1H)，2.27(s，6H)，2.11-2.09(m，1H).
Embodiment 10Preparation (E)-N-{4-[1-(3-fluoro-benzyl)-1H-indazole-5-base amido]-7-(itrile group)-quinazoline-6-yl }-4-dimethyl amido-but-2-enamides (Compound C XM-10)
Compound 13 (430.1g, 1mol), cuprous cyanide (89.6g, 1mol) be added among the DMF (2L) stirring and refluxing reaction 20h, reaction solution diatomite filtration, add 2N hydrochloric acid (0.2L) in the filtrate, with methylene dichloride (0.5L) extraction 3 times, separate organic phase, the pressure reducing and steaming solvent, drying under reduced pressure gets 4-[1-(3-fluoro-benzyl)-1H-indazole-5-base amido]-6-nitro-quinazoline-7-acetonitrile (compound 16).
Reference example 2; compound 16 is through nitro-reduction reaction; obtain 4-[1-(3-fluoro-benzyl)-1H-indazole-5-base amido]-6-amino-quinazolines-7-acetonitrile (compound 17); again with 3-N; N-dimethylamino methyl acrylate chloride carries out acylation reaction, gets title compound CXM-10.
1H-NMR(400MHz，CDCl
3)：δ8.40-8.36(m，2H)，8.24-8.20(m，1H)，8.16-8.14(m，1H)，7.37-7.33(m，1H)，7.12-7.05(m，2H)，6.83-6.77(m，3H)，6.74-6.70(d，J＝2.5Hz，1H)，6.53-6.50(m，1H)，6.40-6.37(d，J＝2.5Hz，1H)，4.99-4.96(m，2H)，3.03-2.99(m，2H)，2.27(s，6H).
Embodiment 11Preparation (E)-N-{7-[(tetrahydrochysene-2H-pyrans-4-yl)-methylthio group]-4-[1-(3-fluoro-benzyl)-1H-indazole-5-base amido]-quinazoline-6-yl }-4-dimethyl amido-but-2-enamides (Compound C XM-11)
4-(brooethyl)-tetrahydrochysene-2H-pyrans (177.9g, lmol) spend the night with thiocarbamide (190g, 2.5mol) back flow reaction, the reaction solution concentrating under reduced pressure gets solid concentrates, join (2.37L) back flow reaction 2h in the 30%NaOH aqueous solution, then regulate pH to 3.Mixing solutions separates organic phase with ethyl acetate (0.5L) extraction 3 times, and anhydrous sodium sulfate drying is concentrated, gets faint yellow oily thing 4-(thiomethyl) tetrahydrochysene-2H-pyrans (compound 18).
Cryosel slowly joins sodium hydrogen (96g, 4mol) in tetrahydrofuran (THF) (2L) solution of compound 13 (430.1g, 1mol) under bathing, and then stirring at room 0.5h adds compound 18 (396.2g, 3mol), stirring at room 4h.Reaction solution adds the purified water extraction and goes out, then use ethyl acetate (0.5L) extraction 3 times, separate organic phase, the pressure reducing and steaming solvent, drying under reduced pressure gets yellow solid 7-[(tetrahydrochysene-2H-pyrans-4-yl)-methylthio group]-N-[1-(3-fluoro-benzyl)-1H-indazole-5-yl]-6-nitro-quinazoline-4-amine (compound 19).
Reference example 2, compound 19 get 7-[(tetrahydrochysene-2H-pyrans-4-yl through nitro-reduction reaction)-methylthio group]-N
4-[1-(3-fluoro-benzyl)-1H-indazole-5-yl]-quinazoline-4,6-diamines (compound 20), again with 3-N, N-dimethylamino methyl acrylate chloride carries out acylation reaction, gets title compound CXM-11.
1H-NMR(400MHz，CDCl
3)：δ8.38(s，1H)，8.14-8.12(m，2H)，7.91-7.87(m，1H)，7.35-7.32(m，1H)，7.13-7.05(m，2H)，6.83-6.77(m，3H)，6.74-6.70(d，J＝2.5Hz，1H)，6.53-6.50(m，1H)，6.40-6.36(d，J＝2.5Hz，1H)，4.99-4.96(m，2H)，3.65-3.62(m，2H)，3.55-3.53(m，2H)，3.05-3.03(m，2H)，2.73-2.70(m，2H)，2.26(s，6H)，1.87-1.85(m，1H)，1.68-1.64(m，2H)，1.43-1.40(m，2H).
Embodiment 12Preparation (E)-N-{4-[1-(3-fluoro-benzyl)-1H-indazole-5-base amido]-quinazoline-6-base--4-dimethyl amido-but-2-enamides (Compound C XM-12)
Preparation method's similar embodiment 1, different is that acrylate chloride is replaced with 3-N, N-dimethylamino methyl acrylate chloride.End product is title compound CXM-12.
1H-NMR(400MHz，CDCl
3)：δ8.36(s，1H)，8.22-8.21(m，2H)，8.14-8.10(m，1H)，7.99-7.96(m，1H)，7.35-7.32(m，1H)，7.12-7.05(m，2H)，6.84-6.78(m，3H)，6.75-6.70(d，J＝2.5Hz，1H)，6.38-6.34(d，J＝2.5Hz，1H)，5.01-4.99(m，2H)，3.05-3.03(m，2H)，2.27(s，6H).
Embodiment 13Preparation N-{4-[1-(3-fluoro-benzyl)-1H-indazole-5-base amido]-7-methoxyl group-quinazoline-6-base--acrylamide (Compound C XM-13)
Preparation method's similar embodiment 2, different is with 3-N, N-dimethylamino methyl acrylate chloride replaces with acrylate chloride.End product is title compound CXM-13.
1H-NMR(400MHz，CDCl
3)：δ8.38-8.35(s，1H)，8.14-8.11(m，2H)，7.51-7.46(m，1H)，7.35-7.32(m，1H)，7.11-7.04(m，2H)，6.84-6.78(m，3H)，6.54-6.51(m，1H)，6.48-6.45(dd，J＝2.5Hz，8.9Hz，1H)，6.17-6.14(d，J＝5.8Hz，1H)，5.71-5.68(t，J＝5.8Hz，1H)，4.99-4.96(m，2H)，3.73(s，3H).
Embodiment 14Preparation N-{4-[1-(3-fluoro-benzyl)-1H-indazole-5-base amido]-7-oxyethyl group-quinazoline-6-base--acrylamide (Compound C XM-14)
Preparation method's similar embodiment 13, different is that sodium methylate is replaced with sodium ethylate.End product is title compound CXM-14.
1H-NMR(400MHz，CDCl
3)：δ8.38(s，1H)，8.14-8.11(m，2H)，7.50-7.48(m，1H)，7.37-7.32(m，1H)，7.12-7.05(m，2H)，6.83-6.77(m，3H)，6.54-6.50(m，1H)，6.50-6.48(dd，J＝2.5Hz，9.0Hz，1H)，6.18-6.15(d，J＝5.8Hz，1H)，5.70-5.68(t，J＝5.8Hz，1H)，5.00-4.96(m，2H)，3.98-3.94(m，2H)，1.33(t，J＝7.1Hz，3H).
Embodiment 15Preparation N-{7-[(S)-tetrahydrofuran (THF)-3-base oxygen base]-4-[1-(3-fluoro-benzyl)-1H-indazole-5-base amido]-quinazoline-6-base--acrylamide (Compound C XM-15)
Preparation method's similar embodiment 9, different is with 3-N, N-dimethylamino methyl acrylate chloride replaces with acrylate chloride.End product is title compound CXM-15.
1H-NMR(400MHz，CDCl
3)：δ8.37(s，1H)，8.15-8.11(m，2H)，7.52-7.47(m，1H)，7.36-7.32(m，1H)，7.11-7.05(m，2H)，6.83-6.78(m，3H)，6.53-6.50(m，1H)，6.48-6.44(dd，J＝2.5Hz，9.0Hz，1H)，6.17-6.14(d，J＝5.8Hz，1H)，5.71-5.68(t，J＝5.8Hz，1H)，5.00-4.97(m，2H)，4.26-4.22(m，1H)，4.05-4.01(m，2H)，3.78-3.70(m，2H)，2.37-2.34(m，1H)，2.11-2.08(m，1H).
Embodiment 16Preparation N-{4-[1-(3-fluoro-benzyl)-1H-indazole-5-base amido]-7-itrile group-quinazoline-6-yl }-acrylamide (Compound C XM-16)
Preparation method's similar embodiment 10, different is with 3-N, N-dimethylamino methyl acrylate chloride replaces with acrylate chloride.End product is title compound CXM-16.
1H-NMR(400MHz，CDCl
3)：δ8.41-8.35(m，2H)，8.24-8.21(m，1H)，8.14-8.12(m，1H)，7.35-7.31(m，1H)，7.10-7.05(m，2H)，6.83-6.77(m，3H)，6.54-6.50(m，1H)，6.47-6.43(dd，J＝2.5Hz，9.0Hz，1H)，6.17-6.13(d，J＝5.8Hz，1H)，5.71-5.68(t，J＝5.8Hz，1H)，4.99-4.96(m，2H).
Embodiment 17Preparation N-{7-[(tetrahydrochysene-2H-pyrans-4-yl)-methylthio group]-4-[1-(3-fluoro-benzyl)-1H-indazole-5-base amido]-quinazoline-6-base--acrylamide (Compound C XM-17)
Preparation method's similar embodiment 11, different is with 3-N, N-dimethylamino methyl acrylate chloride replaces with acrylate chloride.End product is title compound CXM-17.
1H-NMR(400MHz，CDCl
3)：δ8.37(s，1H)，8.15-8.11(m，2H)，7.91-7.88(m，1H)，7.36-7.32(m，1H)，7.12-7.05(m，2H)，6.84-6.76(m，3H)，6.54-6.50(m，1H)，6.48-6.43(dd，J＝2.5Hz，9.0Hz，1H)，6.18-6.14(d，J＝5.8Hz，1H)，5.70-5.67(t，J＝5.8Hz，1H)，5.00-4.96(m，2H)，3.66-3.62(m，2H)，3.56-3.53(m，2H)，2.74-2.70(m，2H)，1.88-1.85(m，1H)，1.68-1.65(m，2H)，1.44-1.40(m，2H).
Embodiment 18Preparation N-{4-[1-(3-fluoro-benzyl)-1H-indazole-5-base amido]-quinazoline-7-base--acrylamide (Compound C XM-18)
Preparation method's similar embodiment 1, different is to replace 6-nitro-quinazoline ketone with 7-nitro-quinazoline ketone.End product is title compound CXM-18.Mass spectrum (ESI
+): m/z=438,439[M+H]
+
Embodiment 19Preparation (E)-N-{4-[1-(3-fluoro-benzyl)-1H-indazole-5-base amido]-6-methoxyl group-quinazoline-7-base--4-dimethyl amido-but-2-enamides (Compound C XM-19)
Preparation method's similar embodiment 2, different is to replace 2-amino-4-chloro-benzoic acid as starting material with 2-amino-5-chloro-benzoic acid.End product is title compound CXM-19.Mass spectrum (ESI
+): m/z=525,526[M+H]
+
Embodiment 20Preparation (E)-N-{4-[1-(3-fluoro-benzyl)-1H-indazole-5-base amido]-6-oxyethyl group-quinazoline-7-base--4-dimethyl amido-but-2-enamides (Compound C XM-20)
Preparation method's similar embodiment 19, different is that sodium methylate is replaced with sodium ethylate.End product is title compound CXM-20.Mass spectrum (ESI
+): m/z=539,540[M+H]
+
Embodiment 21Preparation (E)-N-{4-[1-(3-fluoro-benzyl)-1H-indazole-5-base amido]-6-(2-methoxy ethoxy)-quinazoline-7-base--4-dimethyl amido-but-2-enamides (Compound C XM-21)
Preparation method's similar embodiment 4 and 5, different is that starting raw material 4-chloro-6-nitro-quinazoline-7-base-acetic ester is replaced with 4-chloro-7-nitro-quinazoline-6-base-acetic ester.End product is title compound CXM-21.Mass spectrum (ESI
+): m/z=569,570[M+H]
+
Embodiment 22Preparation N-{4-[1-(3-fluoro-benzyl)-1H-indazole-5-base amido]-6-(2-methoxy ethoxy)-quinazoline-7-base--acrylamide (Compound C XM-22)
Preparation method's similar embodiment 21, different is with 3-N, N-dimethylamino methyl acrylate chloride replaces with acrylate chloride.End product is title compound CXM-22.Mass spectrum (ESI
+): m/z=569,570[M+H]
+
Embodiment 23Preparation N-{4-[1-(3-fluoro-benzyl)-1H-indazole-5-base amido]-6-[3-(4-morpholino) propoxy-]-quinazoline-7-base--acrylamide (Compound C XM-23)
Preparation method's similar embodiment 7, different is to replace 4-chloro-6-nitro-quinazoline-7-base-acetic ester as starting raw material with 4-chloro-7-nitro-quinazoline-6-base-acetic ester.End product is title compound CXM-23.Mass spectrum (ESI
+): m/z=581,582[M+H]+.
Embodiment 24Preparation (E)-N-{4-[1-(3-fluoro-benzyl)-1H-indazole-5-base amido]-6-[3-(4-morpholino) propoxy-]-quinazoline-7-base--4-dimethyl amido-but-2-enamides (Compound C XM-24)
Preparation method's similar embodiment 8, different is to replace 4-chloro-6-nitro-quinazoline-7-base-acetic ester as starting raw material with 4-chloro-7-nitro-quinazoline-6-base-acetic ester.End product is title compound CXM-24.Mass spectrum (ESI
+): m/z=638,639[M+H]
+
Embodiment 25Preparation (E)-N-{6-[(S)-tetrahydrofuran (THF)-3-base oxygen base]-4-[1-(3-fluoro-benzyl)-1H-indazole-5-base amido]-quinazoline-7-base--4-dimethyl amido-but-2-enamides (Compound C XM-25)
Preparation method's similar embodiment 9, different is to replace 4-chloro-6-nitro-quinazoline-7-base-acetic ester as starting raw material with 4-chloro-7-nitro-quinazoline-6-base-acetic ester.End product is title compound CXM-25.Mass spectrum (ESI
+): m/z=581,582[M+H]
+
Embodiment 26Preparation (E)-N-{4-[1-(3-fluoro-benzyl)-1H-indazole-5-base amido]-6-itrile group-quinazoline-7-base--4-dimethyl amido-but-2-enamides (Compound C XM-26)
Preparation method's similar embodiment 10, different is to replace 4-chloro-6-nitro-quinazoline-7-base-acetic ester as starting raw material with 4-chloro-7-nitro-quinazoline-6-base-acetic ester.End product is title compound CXM-26.Mass spectrum (ESI
+): m/z=581,582[M+H]
+
Embodiment 27Preparation (E)-N-{6-[(tetrahydrochysene-2H-pyrans-4-yl)-methylthio group]-4-[1-(3-fluoro-benzyl)-1H-indazole-5-base amido]-quinazoline-7-yl }-4-dimethyl amido-but-2-enamides (Compound C XM-27)
Preparation method's similar embodiment 11, different is to replace 4-chloro-6-nitro-quinazoline-7-base-acetic ester as starting raw material with 4-chloro-7-nitro-quinazoline-6-base-acetic ester.End product is title compound CXM-27.Mass spectrum (ESI
+): m/z=625,626[M+H]
+
Embodiment 28Preparation (E)-N-{4-[1-(3-fluoro-benzyl)-1H-indazole-5-base amido]-quinazoline-7-yl }-4-dimethyl amido-but-2-enamides (Compound C XM-28)
Preparation method's similar embodiment 12, different is to replace 6-nitro-quinolinone as starting raw material with 7-nitroquinoline ketone.End product is title compound CXM-28.Mass spectrum (ESI
+): m/z=495,496[M+H]
+
Embodiment 29Preparation N-{4-[1-(3-fluoro-benzyl)-1H-indazole-5-base amido]-6-methoxyl group-quinazoline-7-yl }-acrylamide (Compound C XM-29)
Preparation method's similar embodiment 13, different is to replace 2-amino-4-chloro-phenylformic acid as starting raw material with 2-amino-5-chloro-phenylformic acid.End product is title compound CXM-29.Mass spectrum (ESI
+): m/z=468,469[M+H]
+
Embodiment 30Preparation N-{4-[1-(3-fluoro-benzyl)-1H-indazole-5-base amido]-6-oxyethyl group-quinazoline-7-yl }-acrylamide (Compound C XM-30)
Preparation method's similar embodiment 14, different is to replace 2-amino-4-chloro-phenylformic acid as starting raw material with 2-amino-5-chloro-phenylformic acid.End product is title compound CXM-30.Mass spectrum (ESI
+): m/z=482,483[M+H]
+
Embodiment 31Preparation N-{6-[(S)-tetrahydrofuran (THF)-3-base oxygen base]-4-[1-(3-fluoro-benzyl)-1H-indazole-5-base amido]-quinazoline-7-yl }-acrylamide (Compound C XM-31)
Preparation method's similar embodiment 15, different is to replace 4-chloro-6-nitro-quinazoline-7-base-acetic ester as starting raw material with 4-chloro-7-nitro-quinazoline-6-base-acetic ester.End product is title compound CXM-31.Mass spectrum (ESI
+): m/z=524,525[M+H]
+
Embodiment 32Preparation N-{4-[1-(3-fluoro-benzyl)-1H-indazole-5-base amido]-6-itrile group-quinazoline-7-yl }-acrylamide (Compound C XM-32)
Preparation method's similar embodiment 16, different is to replace 4-chloro-6-nitro-quinazoline-7-base-acetic ester as starting raw material with 4-chloro-7-nitro-quinazoline-6-base-acetic ester.End product is title compound CXM-32.Mass spectrum (ESI
+): m/z=463,464[M+H]
+
Embodiment 33Preparation N-{6-[(tetrahydrochysene-2H-pyrans-4 base)-methylthio group]-4-[1-(3-fluoro-benzyl)-1H-indazole-5-base amido]-quinazoline-7-yl }-acrylamide (Compound C XM-33)
Operation steps is with embodiment 17, and different is to replace 4-chloro-6-nitro-quinazoline-7-base-acetic ester as starting raw material with 4-chloro-7-nitro-quinazoline-6-base-acetic ester.End product is title compound CXM-33.Mass spectrum (ESI
+): m/z=568,569[M+H]
+
Embodiment 34Compound of the present invention is to different enzymeinhibition active testings
1, experiment material:
Compound C XM01 of the present invention～CXM33; TK-biotin substrate (Cat.62TKOPEC, Cisbio); ATP (Cat.PV3227, Invitrogen); Enzyme: FGFR1 (Cat.PV3146, Invitrogen), PDGFR beta (Cat.P3082, Invitrogen), EGFR (Cat.PV3872, Invitrogen), KDR (Cat.K2643, Sigma), HER2 (Cat.PV3366, Invitrogen); Streptavidin-XL665 (Cat.62TKOPEC, Cisbio); TK antibody europium cryptate (Cat.62TKOPEC, Cisbio); HTRF kinEASE TK kit (Cat.62TKOPEC, Cisbio); ENVISION detector: Perkinelmer (Cat.2104-0010, PerkinElmer).
2, experimental technique:
Use HTRF kinEASE TK kit and detect 33 compounds of the present invention to FGFR1, PDGFR, KDR, EGFR and HER2 enzymeinhibition activity.
1) reagent preparation
By preparing FGFR1, PDGF, KDR, EGFR and five kinds of kinases reagent of HER2 shown in the table 1.
Five kinds of each components of kinase whose reaction system of table 1 and concentration table
Contain 200 μ L, 5 * Enzymebuffer among 1 * FGFR1 Enzymatic Buffer:1mL, 1 * Kinase Buffer, 5 μ L 1M MgCl
2, 1 μ L 1M DTT, 794 μ L ddH
2O.
Contain 200 μ L, 5 * Enzymebuffer among 1 * PDGFR Enzymatic Buffer:1mL, 1 * Kinase Buffer, 5 μ L 1M MgCl
2, 1 μ L 1M DTT, 20 μ L SEB, 1 μ L 1M MnCl
2, 773 μ LddH
2O.
Contain 200 μ L, 5 * Enzymebuffer among 1 * KDR Enzymatic Buffer:1mL, 1 * Kinase Buffer, 5 μ L 1M MgCl
2, 1 μ L 1M DTT, 1 μ L 1M MnCl
2, 793 μ L ddH
2O.
Contain 200 μ L, 5 * Enzymebuffer among 1 * EGFR Enzymatic Buffer:1mL, 1 * Kinase Buffer, 5 μ L 1M MgCl
2, 1 μ L 1M DTT, 1 μ L 1M MnCl
2, 793 μ L ddH
2O.
Contain 200 μ L, 5 * Enzymebuffer among 1 * HER2 Enzymatic Buffer:1mL, 1 * Kinase Buffer, 5 μ L 1M MgCl
2, 1 μ L 1M DTT, 3.2 μ L SEB, 1 μ L 1M MnCl
2, 789.8 μ LddH
2O.
5 * Substrate-TK and ATP working fluid
The concrete concentration of Substrate-TK and ATP sees Table 1.
With to reaction density 5 times of 1 * Kinase Buffer dilution Substrate-TK and ATP.
5 * Enzyme working fluid: the concentration of agents useful for same sees Table 1 during five kinds of kinases concentration optimization screenings.Prepare respectively 5 * enzyme working fluid of 5 kinds of enzymes with 1 * kinase buffer.
The concentration of 4 * Streptavidin-XL665 working fluid: Sa-XL665 in reaction sees Table 1.With DetectionBuffer preparation 4 * Streptavidin-XL665 working fluid.
4 * TK-Antibody-cryptate working fluid: TK-Antibody-Cryptate is diluted 100 times as working fluid with Detection Buffer.
After all reagent prepare according to the method described above, outside dezymotizing, equilibrate to after the room temperature beginning application of sample.
A) (the DMSO excessive concentration can exert an influence to reaction at first to use the 1X kinase buffer of five kinds of enzymes configuring to prepare respectively 2.5% DMSO solution, the final concentration of control DMSO is 1%), then use 2.5% DMSO solution dilution testing compound corresponding to five kinds of enzymes, the final concentration of each determinand is 2 μ M and 0.2 μ M.
Except control wells, add the good testing compound solution of dilution of 4 μ l in all reacting holes, add 2.5% DMSO solution corresponding to five kinds of enzymes of the previous preparation of 4 μ l in the control wells.
B) add the TK-biotin substrate solution (consumption of substrate sees Table 1 during five kinds of enzymes screenings) of the corresponding concentration of substrate of five kinds of enzymes that 2 μ l had before prepared in all reacting holes.
Five kinds of enzyme solution (consumption of five kinds of enzymes sees Table 1) of the corresponding concentration that c) adding 2 μ l had before prepared in all reacting holes except negative hole, negative hole is supplied volume with the corresponding 1Xkinase buffer of five kinds of enzymes of 2 μ l.With shrouding film shrouding, incubated at room 10min behind the mixing allows compound and enzyme fully act on combination.
D) the ATP solution that adds five kinds of enzyme corresponding concentration of 2 μ l in all reacting holes starts kinase reaction, and wherein PDGFR β and KDR enzyme reaction time are 20min, and the FGFR1 enzyme reaction time is 25min, and the enzyme reaction time of EGFR and HER2 is 30min.Corresponding ATP concentration and the reaction times sees Table 1 during five kinds of enzyme screenings.
E) 5min begins to prepare five kinds of enzymes detection liquid before kinase reaction finishes.Streptavidin-XL665 and TKantibody europium cryptate (1: 100) that detection buffer in the use test kit prepares respectively five kinds of enzyme corresponding concentration detect liquid.Corresponding detection reagent concentration sees Table 1 during five kinds of enzyme screenings.
F) after kinase reaction finishes, in all reacting holes, add the corresponding Streptavidin-XL665 solution that dilutes of five kinds of enzymes of 5 μ l, add immediately the good TK antibody europiumcryptate of dilution behind the mixing and detect liquid.
G) shrouding mixing behind the room temperature reaction 1h, detects fluorescent signal (320nm stimulates, 665nm, 615nm emission) with the ENVISION detector.Calculating the inhibiting rate in each hole by complete active hole and background signal hole, averages in multiple hole, and the picture analysis software PRISM 5.0 with specialty carries out the match that half suppresses activity (IC50) to each testing compound simultaneously.
Emittance (ER)=665nm transmits/and 615nm transmits
Inhibiting rate=(ER
Positive-ER
Sample)/(ER
Positive-ER
Negative) * 100%
Experiment application of sample schema is as follows:
3, results and analysis
Table 2-table 6 show respectively compound of the present invention when 2 μ M and 0.2 μ M concentration to FGFR1, PDGFR, KDR, EGFR and HER2 enzymeinhibition rate.
Table 2 compound of the present invention when 2 μ M and 0.2 μ M concentration to the inhibiting rate of FGFR1
From the results shown in Table 2, Compound C XM-02, CXM-04, CXM-05, CXM-09, CXM-15, CXM-18, CXM-20, CXM-22, CXM-26, CXM-27, CXM-30, CXM-31, CXM-33 have showed than positive control Ah handkerchief for the better or suitable activity of Buddhist nun at concentration 2 μ M and 0.2 μ M.
Table 3 compound of the present invention when 2 μ M and 0.2 μ M concentration to the inhibiting rate of PDGFR beta
From the results shown in Table 3, Compound C XM-03, CXM-24, CXM-33 show with positive control Ah handkerchief for the suitable activity of Buddhist nun at concentration 2 μ M and 0.2 μ M.
Table 4 compound of the present invention when 2 μ M and 0.2 μ M concentration to the inhibiting rate of KDR
From the results shown in Table 4, Compound C XM-01, CXM-02, CXM-09, CXM-23, CXM-24, CXM-30, CXM-31, CXM-32 have showed than positive control Ah handkerchief for the better or suitable activity of Buddhist nun at concentration 2 μ M and 0.2 μ M.
Table 5 compound of the present invention when 2 μ M and 0.2 μ M concentration to the EGFR inhibiting rate
From the results shown in Table 5, Compound C XM-01, CXM-02, CXM-09, CXM-23, CXM-24, CXM-30, CXM-31, CXM-32 have showed than positive control Ah handkerchief for the better or suitable activity of Buddhist nun at concentration 2 μ M and 0.2 μ M.
Table 6 compound of the present invention when 2 μ M and 0.2 μ M concentration to the inhibiting rate of HER2
From the results shown in Table 6, Compound C XM-01, CXM-02, CXM-03, CXM-09, CXM-12, CXM-15, CXM-18, CXM-20, CXM-24 have showed than positive control Ah handkerchief for the better or suitable activity of Buddhist nun at concentration 2 μ M and 0.2 μ M.
Embodiment 35The test the compounds of this invention is to the IC of different tumor cell lines
50Value
1, experiment material
Compound C XM-30 of the present invention, 33,02,05,12,09,24; Positive control BIBW-2992, lapatinibditosylate: available from the flourish large medication chemistry company limited in Hangzhou; Non-small cell cancer cells NCI-H322M, prostate cancer cell DU145: available from the ATCC of American Type Culture Collecti; Liver cancer cell Hep3B, breast cancer cell MDA-MB-231, ovarian cancer cell SK-OV-3, hypopharyngeal cancer people swallow squamous cell carcinoma FaDu, pernicious glioblastoma cells U-87MG: available from Shanghai cell biological institute of the Chinese Academy of Sciences; The CCK-8 detection kit: available from Cat# CK04-13, Dojindo company.
2, experimental technique:
1) cell cultures
Each cell strain is cultivated with following corresponding perfect medium, and cell is placed at 37 ℃, 100% relative humidity, 5%CO
2Grow in the incubator, select the cell of logarithmic phase to carry out experiment test.
Being formulated as follows shown in the table 7 of substratum.
Table 7
| Cell strain | Substratum |
| NCI-H322M | RPMI?1640+10％FBS |
| Hep3B | DMEM+10％FBS |
| ACHN | RPMI?1640+10％FBS |
| MDA-MB-231 | RPMI?1640+10％FBS |
| DU-145 | F12+10％FBS |
| SK-OV-3 | RPMI?1640+10％FBS |
| FaDu | RPMI?1640+10％FBS |
| U-87MG | EMEM+10％FBS |
A) collect the logarithmic phase cell, counting is with perfect medium Eddy diffusion cell;
B) adjust cell concn to suitable concn, inoculate 96 orifice plates, 100 μ l cell suspensions are inoculated in every hole;
C) cell is at 37 ℃, 100% relative humidity, 5%CO
2Hatch 24h in the incubator.
2) IC
50Experiment
A) collect the logarithmic phase cell, counting with perfect medium Eddy diffusion cell, is adjusted cell concn to suitable concn (determining according to cell density optimization Test result), inoculates 96 orifice plates, and every hole adds 100 μ l cell suspensions.Cell is at 37 ℃, 100% relative humidity, 5%CO
2Hatch 24h in the incubator.
B) with substratum testing compound is diluted to 5 μ M ﹠amp; 0.5 μ M adds cell by 25 μ l/ holes, the compound final concentration is 1 μ M to 0.1 μ M.
C) cell places 37 ℃, 100% relative humidity, 5%CO
2Hatch 72h in the incubator.
D) substratum is abandoned in suction, adds the perfect medium that contains 10%CCK-8 and places 37 ℃ of incubators to hatch 2-4h.
E) measure the absorbancy at 450nm wavelength place after the light shaking at SpectraMax M5 Microplate Reader, with 650nm place absorbancy (OA) as reference, the calculating inhibiting rate.
3) data are calculated
Growth of tumour cell inhibiting rate %=[(Ac-As)/(Ac-Ab)] * 100%
As: the absorbancy of sample (cell+CCK-8+ testing compound)
Ac: the absorbancy of negative control (cell+CCK-8+DMSO)
Ab: the absorbancy of positive control (substratum+CCK-8+DMSO)
Method to specifications detects compound of the present invention and positive control respectively to the vitro cytotoxicity IC50 value of different cell strains (non-small cell cancer cells NCI-H322M, liver cancer cell Hep3B, breast cancer cell MDA-MB-231, prostate cancer cell DU145, ovarian cancer cell SK-OV-3, hypopharyngeal cancer people swallow squamous cell carcinoma FaDu, pernicious glioblastoma cells U-87MG) with the CCK-8 detection kit.Be from 10 μ M to 0 μ M with DMSO diluted compounds effect final concentration, comprise 10 μ M, 2 μ M, 0.4 μ M, 0.08 μ M, 0.016 μ M, 0.0032 μ M, 0.00064 μ M, 0.000128 μ M and 0 μ M.
3, results and analysis
Experimental result is as shown in table 7.
Table 7 compound is to the vitro cytotoxicity IC of different tumor cell lines
50Value
As can be seen from Table 7, Compound C XM-02, CXM-12, CXM-24 show than positive control drug BIBW-2992, biological activity that lapatinibditosylate is higher; Compound C XM-30, CXM-09, CXM-33 show than positive control BIBW-2992, biological activity that lapatinibditosylate is suitable; Compound C XM-05 shows than positive control BIBW-2992, the lower slightly biological activity of lapatinibditosylate.
Embodiment 36The pharmacokinetics behavioral study of the compounds of this invention in the rat body
1, experiment material:
Animal: 96 of cleaning level SD rats, female, body weight＞200 grams;
Reagent: compound of the present invention: CXM-02, CXM-30, CXM-33, CXM-12, CXM-09, CXM-24; Positive reference substance: lapatinibditosylate (the flourish large medication chemistry company limited in Hangzhou product), BIBW-2992 (Hangzhou Products Co., Ltd of flourish large medication chemistry company limited product);
Instrument: liquid chromatograph (Agilent1100 of Agilent company); Mass spectrograph (API4000, Applied biosystems), electric spray ion source (ESI), series connection quadrupole mass analyzer.Data handling system is Analyst software (Applied biosystems, software version number 1.5.1).
2, experimental technique:
With 48 of rats, be divided at random 8 groups, 6 every group, bestow 6 compounds of the present invention and 2 positive control sample according to the 2mg/kg body weight through single intravenous injection respectively.Simultaneously, with 48 of rats, be divided at random 8 groups, 6 every group, bestow 6 compounds of the present invention and 2 positive reference substances according to the 5mg/kg body weight through single oral respectively.Before administration, 5min after the administration, 15min, 30min, 1h, 2h, 4h, 6h, 8h and 24h, every animal is respectively through the about 0.2mL of eye socket vein (behind the isoflurane anesthesia) blood sampling, heparin sodium anti-freezing.Blood sample places on ice, and within 30min centrifugal separation plasma (centrifugal condition: 8000r/min, 6min, 4 ℃).Deposit in-80 ℃ before the plasma analysis of collecting.
Adopt liquid chromatography-mass spectrography-mass spectrum (LC/MS/MS) coupling method to measure the concentration of tested material in the rat plasma.Plasma Concentration the data pharmacokinetics process software WinNonlin 5.2 non-compartment models according to gained calculate relevant pharmacokinetic parameter.
3, results and analysis
Experimental result is shown in following table 8 and table 9:
Table 8 rat single dose intravenous gives the main pharmacokinetic parameters of compound of the present invention and 2 positive reference substances
Table 9 rat single oral gives the main pharmacokinetic parameters of compound of the present invention and positive reference substance
Can find out that from the result of table 8 and table 9 Compound C XM-33, CXM-02, CXM-24 show than positive control drug BIBW-2992, lapatinibditosylate oral administration biaavailability preferably; Compound C XM-09, CXM-30, CXM-12 show the oral administration biaavailability close or lower slightly with positive control drug BIBW-2992, lapatinibditosylate.The main pharmacokinetic parameter of 6 compound single dose intravenous has surpassed the upper limit of apparatus measures, so the preparation way of inapplicable this compounds of mode of intravenously administrable.
Claims (8)
1. the compound shown in the formula (I):
Wherein, R
1And R
2Represent independently hydrogen, halogen, C
1-4The C that alkyl, halogen replace
1-4Alkyl, C
1-4The C that alkoxyl group, halogen replace
1-4Alkoxyl group, itrile group, ester group, nitro, amino, amide group, sulfoamido, phenyl or CH
3SO
2CH
2CH
2NHCH
2-Ar; Wherein Ar represents phenyl, furyl, thienyl, pyrryl and thiazolyl, and Ar can be selected from halogen, C by one or two
1-4Alkyl and C
1-4The group of alkoxyl group replaces; Perhaps
R
1, R
2Independently expression:
X-(CH
2)
n-R
4
Wherein X represents N, O or S; N represents 0 to 6 integer; R
4Expression hydrogen, C
1-4The C that alkyl, halogen replace
1-4Alkyl, C
1-4The C that alkoxyl group, halogen replace
1-4Alkoxyl group, furyl, tetrahydrofuran base, morpholinyl, pyranyl, THP trtrahydropyranyl, pyrryl, pyridyl, oxazolinyl, thiazolyl or thienyl; Perhaps
R
1, R
2Independently expression:
R wherein
5Expression H, N, N-dimethyl amine ylmethyl, N, N-diethylamide ylmethyl or N, N-dipropylamine ylmethyl;
R
3Expression hydrogen or C
1-4Alkyl.
2. compound as claimed in claim 1, wherein,
R
1And R
2Represent independently hydrogen, C
1-4Alkoxyl group, nitro, amino, amide group; Perhaps
R
1, R
2Independently expression:
X-(CH
2)
n-R
4
Wherein X represents O or S; N represents 0 to 4 integer; R
4Expression hydrogen, C
1-4Alkyl, C
1-4Alkoxyl group, 3-tetrahydrofuran base, morpholinyl, 4-THP trtrahydropyranyl, 2-pyrryl, oxazolinyl, thiazolyl or thienyl; Perhaps,
R
1, R
2Independently expression:
R wherein
5Expression H, N, N-dimethyl amine ylmethyl, N, N-diethylamide ylmethyl or N, N-dipropylamine ylmethyl;
R
3Expression hydrogen.
3. compound as claimed in claim 1, wherein said compound is selected from:
N-{4-[1-(3-fluoro-benzyl)-1H-indazole-5-base amido]-quinazoline-6-yl }-acrylamide (CXM-01);
(E)-N-{4-[1-(3-fluoro-benzyl)-1H-indazole-5-base amido]-7-methoxyl group-quinazoline-6-yl }-4-(dimethylamino) but-2-enamides (CXM-02);
(E)-N-{4-[1-(3-fluoro-benzyl)-1H-indazole-5-base amido]-7-oxyethyl group-quinazoline-6-yl }-4-(dimethyl amido)-but-2-enamides (CXM-03);
7-(2-methoxy ethoxy)-N-[1-(3-fluoro-benzyl)-1H-indazole-5-yl]-6-nitro-quinazoline-4-amine (CXM-04);
(E)-N-{4-[1-(3-fluoro-benzyl)-1H-indazole-5-base amido]-7-(3-methoxy ethoxy)-quinazoline-6-yl }-4-(dimethyl amido)-but-2-enamides (CXM-05);
N-{4-[1-(3-fluoro-benzyl)-1H-indazole-5-base amido]-7-(2-methoxyethoxy)-quinazoline-6-yl }-acrylamide (CXM-06);
N-{4-[1-(3-fluoro-benzyl)-1H-indazole-5-base amido]-7-[3-(4-morpholino) propoxy-]-quinazoline-6-yl }-acrylamide (CXM-07);
(E)-N-{4-[1-(3-fluoro-benzyl)-1H-indazole-5-base amido]-7-[3-(4-morpholino) propoxy-]-quinazoline-6-yl }-4-(dimethyl amido)-but-2-enamides (CXM-08);
(E)-N-{7-[(S)-tetrahydrofuran (THF)-3-base oxygen base]-4-[1-(3-fluoro-benzyl)-1H-indazole-5-base amido]-quinazoline-6-yl }-4-dimethyl amido-but-2-enamides (CXM-09);
(E)-N-{4-[1-(3-fluoro-benzyl)-1H-indazole-5-base amido]-7-(itrile group)-quinazoline-6-yl }-4-dimethyl amido-but-2-enamides (CXM-10);
(E)-N-{7-[(tetrahydrochysene-2H-pyrans-4-yl)-methylthio group]-4-[1-(3-fluoro-benzyl)-1H-indazole-5-base amido]-quinazoline-6-yl }-4-dimethyl amido-but-2-enamides (CXM-11);
(E)-N-{4-[1-(3-fluoro-benzyl)-1H-indazole-5-base amido]-quinazoline-6-yl }-4-dimethyl amido-but-2-enamides (CXM-12);
N-{4-[1-(3-fluoro-benzyl)-1H-indazole-5-base amido]-7-methoxyl group-quinazoline-6-yl }-acrylamide (CXM-13);
N-{4-[1-(3-fluoro-benzyl)-1H-indazole-5-base amido]-7-oxyethyl group-quinazoline-6-yl }-acrylamide (CXM-14);
N-{7-[(S)-tetrahydrofuran (THF)-3-base oxygen base]-4-[1-(3-fluoro-benzyl)-1H-indazole-5-base amido]-quinazoline-6-yl }-acrylamide (CXM-15);
N-{4-[1-(3-fluoro-benzyl)-1H-indazole-5-base amido]-7-itrile group-quinazoline-6-yl }-acrylamide (CXM-16);
N-{7-[(tetrahydrochysene-2H-pyrans-4-yl)-methylthio group]-4-[1-(3-fluoro-benzyl)-1H-indazole-5-base amido]-quinazoline-6-yl }-acrylamide (CXM-17);
N-{4-[1-(3-fluoro-benzyl)-1H-indazole-5-base amido]-quinazoline-7-yl }-acrylamide (CXM-18);
(E)-N-{4-[1-(3-fluoro-benzyl)-1H-indazole-5-base amido]-6-methoxyl group-quinazoline-7-yl }-4-dimethyl amido-but-2-enamides (CXM-19);
(E)-N-{4-[1-(3-fluoro-benzyl)-1H-indazole-5-base amido]-6-oxyethyl group-quinazoline-7-yl }-4-dimethyl amido-but-2-enamides (CXM-20);
(E)-N-{4-[1-(3-fluoro-benzyl)-1H-indazole-5-base amido]-6-(2-methoxy ethoxy)-quinazoline-7-yl }-4-dimethyl amido-but-2-enamides (CXM-21);
N-{4-[1-(3-fluoro-benzyl)-1H-indazole-5-base amido]-6-(2-methoxy ethoxy)-quinazoline-7-yl }-acrylamide (CXM-22);
N-{4-[1-(3-fluoro-benzyl)-1H-indazole-5-base amido]-6-[3-(4-morpholino) propoxy-]-quinazoline-7-yl }-acrylamide (CXM-23);
(E)-N-{4-[1-(3-fluoro-benzyl)-1H-indazole-5-base amido]-6-[3-(4-morpholino) propoxy-]-quinazoline-7-yl }-4-dimethyl amido-but-2-enamides (CXM-24);
(E)-N-{6-[(S)-tetrahydrofuran (THF)-3-base oxygen base]-4-[1-(3-fluoro-benzyl)-1H-indazole-5-base amido]-quinazoline-7-yl }-4-dimethyl amido-but-2-enamides (CXM-25);
(E)-N-{4-[1-(3-fluoro-benzyl)-1H-indazole-5-base amido]-6-itrile group-quinazoline-7-yl }-4-dimethyl amido-but-2-enamides (CXM-26);
(E)-N-{6-[(tetrahydrochysene-2H-pyrans-4-yl)-methylthio group]-4-[1-(3-fluoro-benzyl)-1H-indazole-5-base amido]-quinazoline-7-yl }-4-dimethyl amido-but-2-enamides (CXM-27);
(E)-N-{4-[1-(3-fluoro-benzyl)-1H-indazole-5-base amido]-quinazoline-7-yl }-4-dimethyl amido-but-2-enamides (CXM-28);
N-{4-[1-(3-fluoro-benzyl)-1H-indazole-5-base amido]-6-methoxyl group-quinazoline-7-yl }-acrylamide (CXM-29);
N-{4-[1-(3-fluoro-benzyl)-1H-indazole-5-base amido]-6-oxyethyl group-quinazoline-7-yl }-acrylamide (CXM-30);
N-{6-[(S)-tetrahydrofuran (THF)-3-base oxygen base]-4-[1-(3-fluoro-benzyl)-1H-indazole-5-base amido]-quinazoline-7-yl }-acrylamide (CXM-31);
N-{4-[1-(3-fluoro-benzyl)-1H-indazole-5-base amido]-6-itrile group-quinazoline-7-yl }-acrylamide (CXM-32);
N-{6-[(tetrahydrochysene-2H-pyrans-4-yl)-methylthio group]-4-[1-(3-fluoro-benzyl)-1H-indazole-5-base amido]-quinazoline-7-yl }-acrylamide (CXM-33).
4. compound as claimed in claim 1, wherein said compound is the form of tautomer, steric isomer or its pharmacy acceptable salt.
5. compound as claimed in claim 4, wherein said pharmacy acceptable salt is described compound and the sour acid salt that forms, and described acid is selected from Hydrogen bromide, hydrochloric acid, sulfuric acid, sulfurous acid, acetic acid, oxalic acid, valeric acid, oleic acid, palmitinic acid, stearic acid, lauric acid, boric acid, phenylformic acid, lactic acid, phosphoric acid, toluic acid, citric acid, toxilic acid, fumaric acid, succsinic acid, tartrate, phenylformic acid, methylsulfonic acid, gluconic acid, lactobionic acid and lauryl sulfonic acid.
6. a pharmaceutical composition comprises each described compound of claim 1 to 4 and pharmaceutically acceptable carrier.
7. each described compound of claim 1 to 4 is in the purposes of preparation in the medicine, and described medicine is used for the treatment of by the kinase mediated disease of albumen TYR.
8. purposes claimed in claim 7, wherein said disease is mammary cancer, nonsmall-cell lung cancer, ovarian cancer, cancer of the stomach or carcinoma of the pancreas.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2012104384181A CN102942561A (en) | 2012-11-06 | 2012-11-06 | 4-amino quinazoline heterocyclic compound and purpose of 4-amino quinazoline heterocyclic compound |
| PCT/CN2013/086514 WO2014071824A1 (en) | 2012-11-06 | 2013-11-04 | 4-quinazolinamine heterocyclic compound and use thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2012104384181A CN102942561A (en) | 2012-11-06 | 2012-11-06 | 4-amino quinazoline heterocyclic compound and purpose of 4-amino quinazoline heterocyclic compound |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN102942561A true CN102942561A (en) | 2013-02-27 |
Family
ID=47725577
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2012104384181A Pending CN102942561A (en) | 2012-11-06 | 2012-11-06 | 4-amino quinazoline heterocyclic compound and purpose of 4-amino quinazoline heterocyclic compound |
Country Status (2)
| Country | Link |
|---|---|
| CN (1) | CN102942561A (en) |
| WO (1) | WO2014071824A1 (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2014071824A1 (en) * | 2012-11-06 | 2014-05-15 | 深圳海王药业有限公司 | 4-quinazolinamine heterocyclic compound and use thereof |
| CN110963972A (en) * | 2019-11-21 | 2020-04-07 | 苏州明锐医药科技有限公司 | Quinazoline derivative, preparation method and pharmaceutical application thereof |
| CN113164776A (en) * | 2018-09-25 | 2021-07-23 | 黑钻治疗公司 | Tyrosine kinase inhibitor compositions, methods of making and methods of using the same |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1997003069A1 (en) * | 1995-07-13 | 1997-01-30 | Glaxo Group Limited | Heterocyclic compounds and pharmaceutical compositions containing them |
| CN101094840A (en) * | 2004-12-29 | 2007-12-26 | 韩美药品株式会社 | Quinazoline derivatives for inhibiting cancer cell growth and method for the preparation thereof |
| CN101273033A (en) * | 2005-09-20 | 2008-09-24 | 阿斯利康(瑞典)有限公司 | 4- (iH-indazol-s-yl-amino)-quinazoline compounds as ERBB receptor tyrosine kinase inhibitors for the treatment of cancer |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| RS49779B (en) * | 1998-01-12 | 2008-06-05 | Glaxo Group Limited, | Byciclic heteroaromatic compounds as protein tyrosine kinase inhibitors |
| CN102311438A (en) * | 2010-06-30 | 2012-01-11 | 和记黄埔医药（上海）有限公司 | Quinazoline compound |
| CN102942561A (en) * | 2012-11-06 | 2013-02-27 | 深圳海王药业有限公司 | 4-amino quinazoline heterocyclic compound and purpose of 4-amino quinazoline heterocyclic compound |
-
2012
- 2012-11-06 CN CN2012104384181A patent/CN102942561A/en active Pending
-
2013
- 2013-11-04 WO PCT/CN2013/086514 patent/WO2014071824A1/en active Application Filing
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1997003069A1 (en) * | 1995-07-13 | 1997-01-30 | Glaxo Group Limited | Heterocyclic compounds and pharmaceutical compositions containing them |
| CN101094840A (en) * | 2004-12-29 | 2007-12-26 | 韩美药品株式会社 | Quinazoline derivatives for inhibiting cancer cell growth and method for the preparation thereof |
| CN101273033A (en) * | 2005-09-20 | 2008-09-24 | 阿斯利康(瑞典)有限公司 | 4- (iH-indazol-s-yl-amino)-quinazoline compounds as ERBB receptor tyrosine kinase inhibitors for the treatment of cancer |
Non-Patent Citations (3)
| Title |
|---|
| HANS-JOACHIM BOHM，ET AL.，: "fluorine in medicinal chemistry", 《CHEMBIOCHEM》 * |
| 桑鹏，等: "氟在药物设计与开发中的应用", 《化学通报》 * |
| 王江，等: "氟原子在药物分子设计中的应用", 《有机化学》 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2014071824A1 (en) * | 2012-11-06 | 2014-05-15 | 深圳海王药业有限公司 | 4-quinazolinamine heterocyclic compound and use thereof |
| CN113164776A (en) * | 2018-09-25 | 2021-07-23 | 黑钻治疗公司 | Tyrosine kinase inhibitor compositions, methods of making and methods of using the same |
| CN110963972A (en) * | 2019-11-21 | 2020-04-07 | 苏州明锐医药科技有限公司 | Quinazoline derivative, preparation method and pharmaceutical application thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| WO2014071824A1 (en) | 2014-05-15 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN104592242B (en) | Icotinib hydrochloride crystal forms, medicine composition and application | |
| CN105315259B (en) | Pyridine amine pyrimidine derivates, its preparation method and application | |
| CN102731485B (en) | 4-(substituted benzene amino) quinazoline derivant and preparation method thereof, pharmaceutical composition and purposes | |
| ES2425068T3 (en) | Pyrido [2,3-d] pyrimidin-7-one compounds as PI3K-alpha inhibitors for cancer treatment | |
| CN105705493B (en) | Quinazoline derivant, its preparation method, pharmaceutical composition and application | |
| CN107929276A (en) | A kind of taxol and CDKS kinase inhibitor drug combination compositions | |
| CN106478605A (en) | Pyrimidines, its preparation method and medical usage | |
| CN107163026A (en) | Salt of pyridine amine pyrimidine derivates and its preparation method and application | |
| CN103172641B (en) | Heterocyclic amino and alkoxy-replaced quinazoline derivative and application thereof | |
| CN106749097B (en) | A kind of chloro- 2- aminobenzothiazole analog derivative of 6- and its preparation method and application | |
| CN102942561A (en) | 4-amino quinazoline heterocyclic compound and purpose of 4-amino quinazoline heterocyclic compound | |
| CN105566305B (en) | The polymorph and its preparation method and application of 4- (substituted anilinic) quinazoline derivant xylenesulfonate | |
| CN101845051B (en) | Nitrogen-containing heterocyclic thienopyridine compounds and preparation method and application thereof | |
| CN102584828B (en) | Tetramethyleneimine [3,4-d] pyrimidine derivatives, preparation method and application thereof | |
| CN106831707A (en) | As the benzheterocycle analog derivative and its medical application of c Met kinase inhibitors | |
| CN114174269B (en) | Pyrimidine compounds acting on EGFR and ERBB2 | |
| CN104402861A (en) | Benzene sulfonamide derivatives, preparation method, and treatment application | |
| CN102268014B (en) | Condensed heteroaryl derivative and its preparation method and use | |
| JP7223684B2 (en) | Antitumor effect enhancer using pyrazolo[3,4-d]pyrimidine compound | |
| CN105384738A (en) | Heterocyclic compound as protein kinase inhibitor and preparation method and application thereof | |
| CN101845052B (en) | Nitrogen-containing heterocyclic ring thienopyridine ketone derivative, preparation method and application thereof | |
| CN107827877A (en) | Dialkyl amido quinazoline compounds and its application in antineoplastic is prepared | |
| CN105646461B (en) | S configuration 4- (substituted anilinic) quinazoline derivant and its preparation method and application | |
| CN103601722B (en) | New antitumoral compounds | |
| CN101805355B (en) | Thienopyridone derivative, preparation method and uses thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C12 | Rejection of a patent application after its publication | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20130227 |