CN106496196B - A kind of quinazoline, Pyridopyrimidine or double and pyrimidine derivatives egf inhibitor and preparation method thereof and purposes - Google Patents
A kind of quinazoline, Pyridopyrimidine or double and pyrimidine derivatives egf inhibitor and preparation method thereof and purposes Download PDFInfo
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- CN106496196B CN106496196B CN201610913806.9A CN201610913806A CN106496196B CN 106496196 B CN106496196 B CN 106496196B CN 201610913806 A CN201610913806 A CN 201610913806A CN 106496196 B CN106496196 B CN 106496196B
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- 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
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- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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Abstract
The present invention discloses a kind of selective depressant of the clinical mutant of EGFR protein tyrosine kinase, it has the structure such as formula (I), it is that one kind contains quinazoline, the compound of Pyridopyrimidine or double and pyrimidine double aromatic rings templates, also disclose the preparation method and its application as the selective depressant of the clinical mutant of EGFR protein tyrosine kinase of such compound, especially for the inhibiting effect of the EGF-R ELISA EGFR of T790M variation, related disease such as kidney is over-expressed in treatment and EGF-R ELISA EGFR, lung cancer, prostate cancer, cancer of pancreas, breast cancer, the application of spongiocytoma.
Description
Technical field
The present invention relates to field of medicaments, and in particular to a kind of quinazoline, Pyridopyrimidine or double and pyrimidine derivatives table
Epidermal growth factor inhibitors and its preparation method and application.
Background technique
EGF-R ELISA EGFR (Epidermal Growth Factor Receptor) is ErbB receptor family
One kind, be a kind of glycoprotein, belong to tyrosine kinase receptor, cell membrane perforation, molecular weight 170KDa.EGFR is located at cell
Film surface activates EGF and TGF (transforming growth factor) with ligand binding.After activation, EGFR is turned by monomer
It activates it to be located at intracellular kinase pathway after turning to dimer, guides the phosphorylation in downstream, including MPAK, Akt and JNK are logical
Road, induced cell proliferation.Research shows that high expression or unconventionality expression, EGFR and tumour in many entity tumors there are EGFR
The proliferation of cell, angiogenesis, tumor invasion, transfer and the inhibition of Apoptosis are related.The overexpression of EGFR is in malignant tumour
Development in play an important role, kidney, lung cancer, prostate cancer, cancer of pancreas, breast cancer, spongiocytoma etc. tissue in have
The overexpression of EGFR.
Protein tyrosine kinase is a kind of tyrosine residue that the phosphate group of ATP is transferred to protein substrate
Enzyme.Many growth factor receptor proteins include that EGF-R ELISA is worked by phosphorylation, epidermal growth factor receptor
Body EGFR tyrosine kinase makes EGF-R ELISA phosphorylation.Clinically, EGFR tyrosine kinase inhibitor has been used for
The treatment of cancer achieves certain curative effect as Gefitinib, Tarceva be used to treat non-small cell lung cancer.
However there are EGFR tyrosine-kinases after the EGFR tyrosine kinase or drug therapy of anomaly in many tumours
Enzyme mutates, so that drug failure, i.e. clinical signs be made to go out drug resistance or drug resistance.Have in Gefitinib within 2004
To occur EGFR tyrosine-kinase enzyme mutant in Treatment for Non-small Cell Lung report (Science, 2004, Vol.304,1497-
1500;New England Journal of Medicine 2004,350,2129-2139).One of which variation occurs
790 site of residue on duty at the gate of EGFR tyrosine kinase is that L- methionine (M) is replaced by the L-threonine (T) originally in the site
The variation of generation, referred to as T790M, EGF tyrosine kinase R is no longer in conjunction with Gefitinib, Tarceva after variation, to make drug
Effect is lost, drug resistance occurs in patient.
In conclusion the anticancer drug that exploitation removal or reduction drug resistance generate is very necessary.
Summary of the invention
The present invention is directed to the EGFR tyrosine kinase of T790M variation, devises a series of inhibitor molecules, it was found that right
T790M variation EGFR has the compound of high inhibitory activity, and the compound significantly inhibits cancer cell, should
Class compound contains quinazoline, Pyridopyrimidine or double and pyrimidine double aromatic rings templates and α, beta-unsaturated carboxylic acid amide
Functional group.The inhibitor can realize that high activity inhibits to T790M/L858R variant EGFR, and can inhibit or kill EGFR
The tumour cell of T790M variation, and it is lower to Wild type EGFR inhibitory activity, there is preferable selectivity, this characteristic can be with
Reduce the toxic side effect in oncotherapy.
A kind of quinazoline, Pyridopyrimidine or double and pyrimidine derivatives with general formula (I) structure provided by the invention
Egf inhibitor and its pharmaceutically acceptable salt, such compound contain α, beta-unsaturated carboxylic acid amide structure,
It can be used as a kind of irreversible EGFR inhibitor,
Wherein, X represents CH or N;Y represents CH or N;
R1For
Z is selected from any one in H, F, Cl, Br
R2For any one in methyl, ethyl, isopropyl;
R3For
In any one;
R4ForOrWherein R6For H, C1-C6 alkyl, N, N- dimethyl
Any one in amine methyl, pyrrolidinyl -1- methyl, piperidyl -1- methyl and morpholinyl -1- methyl;
Preferably, the compound includes with the compound such as 1 structure of table:
The compound of 1 general structure of table (I) includes one of number 201-210
The present invention also provides the preparation methods of above-mentioned EGFR protein tyrosine kinase selective depressant, such as Scheme 1
It is shown, method includes the following steps: starting material obtains intermediate A with phosphorus oxychloride reaction again after cyclization, it is intermediate
Body A successively passes through electrophilic addition, nucleophilic displacement of fluorine, hydrogenating reduction, acylation, finally obtains logical formula (I) compound represented accordingly
(shown in Scheme 1).
The synthesis and preparation of 1 compound of Formula I of Scheme
The present invention also provides a kind of pharmaceutical composition, described pharmaceutical composition includes above-mentioned quinazoline, Pyridopyrimidine
Or double and pyrimidine derivatives egf inhibitor or its pharmaceutically acceptable salt and its is pharmaceutically acceptable
Carrier.
Described pharmaceutical composition is the form of tablet, capsule, granule or injection.
The pharmaceutically acceptable carrier is selected from one of filler, disintegrating agent, adhesive and lubricant or a variety of,
Including but not limited to any and whole solvent, decentralized medium, coating, absorption delaying agent etc., such medium and medicament are used for
Pharmaceutically active substances are well known in the art.
The present invention also provides the quinazoline, Pyridopyrimidine or double and pyrimidine derivatives epidermal growth factor to inhibit
The purposes of agent or its pharmaceutically acceptable salt as protein tyrosine kinase inhibitor;
Preferably, the protein tyrosine kinase inhibitor is epidermal growth factor receptor inhibitor;
It is highly preferred that the epidermal growth factor receptor inhibitor is to the T790M EGF-R ELISA to make a variation
Inhibitor.
The present invention also provides the quinazoline, Pyridopyrimidine or double and pyrimidine derivatives epidermal growth factor to inhibit
Agent or its pharmaceutically acceptable salt or described pharmaceutical composition are over-expressed in preparation for treating EGF-R ELISA
Purposes in the drug of related disease;
Preferably, EGF-R ELISA overexpression related disease be selected from as kidney, lung cancer, prostate cancer,
One of cancer of pancreas, breast cancer and spongiocytoma are a variety of.
The selective depressant of the clinical mutant of EGFR protein tyrosine kinase provided by the invention or its pharmaceutically may be used
The salt of receiving and its pharmaceutical composition can effectively inhibit the EGF-R ELISA of T790M/L858R variation, solution
Certainly in EGFR targeted drug such as Gefitinib, Tarceva piece to the drug resistance in oncotherapy, in vitro in enzymatic assay, tool
There is the compound of logical formula (I) to reach IC50=10nM to the inhibitory activity of kinases (referring to table 2);Have very to Wild type EGFR
Good selectivity, can theoretically reduce the toxic side effect of drug well.In vitro in cell experiment, there is logical formula (I)
Compound all shows stronger killing activity to cancer cell line NCI-H1975, A549, is expected to become a more effectively treatment
EGF-R ELISA over-expresses related disease such as kidney, lung cancer, prostate cancer, cancer of pancreas, breast cancer, spongiocytoma
Deng drug, thus be expected to solve EGFR target therapeutic agent in resistance problems.
Specific embodiment
The present invention is further illustrated below by way of specific embodiment.
It includes: that starting material is anti-with phosphorus oxychloride again after cyclization that preparing, which has the method for the compound of logical formula (I),
Intermediate A should be obtained, intermediate A successively passes through electrophilic addition, nucleophilic displacement of fluorine, hydrogenating reduction, acylation, finally obtains corresponding logical
Formula (I) compound represented.It is worth noting that logical formula (I) compound includes but is not limited to following compounds enumerated.
Embodiment 1:2- { 4 '-fluoro- 5 '-[N, TMSDMA N dimethylamine methyl-(E)-acrylamido] -2 '-methoxyl groups } anilino- -
The preparation of 4- (1 "-methyl-1 H-3 "-indoles) quinazoline (compound 201)
The preparation of 2,4- dichloroquinazoline:
2,4- dihydroxy quinazoline (3.0g, 18.5mmol) is dissolved in phosphorus oxychloride (22ml), 108 DEG C of reflux are warming up to
Reaction about 3 hours, reaction solution gradually become brown color clarification shape liquid.LCMS detects fully reacting.Reaction solution is slowly added dropwise
Entering in trash ice stirring and a large amount of off-white powders are precipitated, filtrate decompression is concentrated and dried, obtain off-white powder, 3.1g, purity: 98%,
Yield: 83%.LC-MS(ESI):m/z 200(M+H)+。
The preparation of the chloro- 4- of 2- (1- methyl-1 H-3- indoles) quinazoline:
2,4- dichloroquinazoline (1.0g, 5.02mmol) is dissolved in glycol dimethyl ether (18ml), is stirred under ice bath,
Alchlor is added portionwise, is stirred to react half an hour at room temperature later.It is added dropwise N- methyl indol (650mg, 5.02mmol), it
After be heated to 85 DEG C and be stirred to react 3.5 hours.LCMS detects fully reacting.Stop reaction, is down to room temperature, reaction solution is slowly led
Enter in ice water, stir rapidly, a large amount of solids are precipitated, filter, washed filter cake three times with cold water, it is solid to obtain yellow for the drying of gained filter cake
Body, 950mg, purity: 90%, yield: 65%.LC-MS(ESI):m/z294(M+H)+。
The preparation of 2- { 4 '-fluoro- 5 '-nitro -2 '-methoxyl group } anilino- -4- (1 "-methyl-1 H-3 "-indoles) quinazoline:
The chloro- 4- of 2- (1- methyl-1 H-3- indoles) quinazoline (900mg, 3.06mmol) is dissolved in n-butanol (20ml),
Stir at room temperature, be added the fluoro- 2- methoxyl group -5- nitroaniline (570mg, 3.063mmol) of 4- and p-methyl benzenesulfonic acid (630mg,
3.67mmol), it is heated to 105 DEG C later, is stirred to react three hours.LCMS detects fully reacting.Stop reaction, is cooled to room
Temperature filters reaction solution, and a small amount of cold ethanol washing, filtration cakes torrefaction obtains faint yellow solid 600mg, purity: 80%, yield:
45%.LC-MS(ESI):m/z 445(M+H)+。
The preparation of 2- { 4 '-fluoro- 5 '-amido -2 '-methoxyl group } anilino- -4- (1 "-methyl-1 H-3 "-indoles) quinazoline:
By 2- { 4 '-fluoro- 5 '-nitro -2 '-methoxyl group } anilino- -4- (1 "-methyl-1 H-3 "-indoles) quinazoline
(330mg, 0.78mmol) is dissolved in methanol (5ml) and tetrahydrofuran (2ml), is added 10%Pd/C (50mg), is replaced with hydrogen
It three times, depresses, is stirred to react about 2 hours in 40Psi hydrogen later.LCMS detects fully reacting.Palladium charcoal is filtered out, a small amount of methanol is washed
Wash filter cake, filtrate decompression is concentrated and dried, obtain gray solid, 280mg, purity: 95%, yield: 96%.LC-MS(ESI):m/z
415(M+H)+;
2- { 4 '-fluoro- 5 '-[N, TMSDMA N dimethylamine methyl-(E)-acrylamido] -2 '-methoxyl groups } anilino- -4- (1 "-first
Base -1H-3 "-indoles) quinazoline (compound 201) preparation:
By 2- { 4 '-fluoro- 5 '-amido -2 '-methoxyl group } anilino- -4- (1 "-methyl-1 H-3 "-indoles) quinazoline
(245mg, 0.63mmol) and (E) -4- dimethylamino -2- butenoic acid (105mg, 0.633mmol) is dissolved in tetrahydrofuran (5.0ml)
In n,N-Dimethylformamide (0.8ml), N is added, N- diisopropyl ethyl amine (368mg, 2.85mmol) stirs under ice bath
It is added portionwise 2- (7- azo benzotriazole)-N, N, N', N'- tetramethylurea hexafluorophosphoric acid ester (HATU) (290mg,
0.76mmol), it is stirred to react at room temperature 3 hours.LCMS detects fully reacting.Reaction solution is added dropwise in the water that stirred, is analysed
A large amount of solids out filter to obtain head product 240mg, are purified by silica gel column chromatography (ethyl acetate: methanol=40:1~8:1), obtain brown
Color solid, 50mg, purity: 99%, yield: 18%.LC-MS(ESI):m/z 526(M+H)+;1H NMR(400MHz,CDCl3)δ
Ppm 2.30 (s, 6H), 3.14-3.15 (m, 2H), 3.88 (s, 3H), 3.95 (s, 3H), 6.16-6.20 (d, 1H, J=
15.2Hz), 6.68-6.71 (d, 1H, J=12Hz), 7.02 (s, 1H), 7.17 (m, 1H), 7.27 (m, 2H), 7.35 (m, 2H),
7.56-7.58 (d, 1H, J=8.4Hz), 7.66 (m, 1H), 7.78 (m, 1H), 8.08 (s, 1H), 8.14-8.16 (d, 1H, J=
7.6Hz), 8.27 (s, 1H), 8.29-8.31 (d, 1H, J=8.4Hz), 9.29 (s, 1H), 9.98 (s, 1H).
Embodiment 2:2- { 4 '-dimethylamino -5 '-[N, TMSDMA N dimethylamine methyl-(E)-acrylamido] -2 '-methoxyl groups }
The preparation of anilino- -4- (1 "-methyl-1 H-3 "-indoles) quinazoline (compound 202)
2- { 4 '-dimethylamino -5 '-nitro -2 '-methoxyl group } anilino- -4- (1 "-methyl-1 H-3 "-indoles) quinazoline
Preparation:
By 2- { 4 '-fluoro- 5 '-nitro -2 '-methoxyl group } anilino- -4- (1 "-methyl-1 H-3 "-indoles) quinazoline
(445mg, 1.0mmol) is dissolved in n,N-Dimethylformamide (5ml), and dimethylamine (50mg, 1.113mmol) and N, N- bis- is added
Diisopropylethylamine (500mg, 4.048mmol) is stirred to react 3 hours in 86 DEG C.LCMS detects fully reacting.It is cooled to room temperature,
Reaction solution is added dropwise in the water that stirred, a large amount of solids are precipitated, is filtered, a small amount of water washing filter cake, filter cake is dissolved in methylene chloride
After be added dropwise to stirred mashing processing in petroleum ether, obtained solid filter drying.Chinese red solid 455mg is obtained, purity:
93%, yield: 88%.LC-MS(ESI):m/z 469(M+H)+。
2- { 4 '-dimethylamino -5 '-amido -2 '-methoxyl group } anilino- -4- (1 "-methyl-1 H-3 "-indoles) quinazoline
Preparation:
By 2- { 4 '-dimethylamino -5 '-nitro -2 '-methoxyl group } anilino- -4- (1 "-methyl-1 H-3 "-indoles) quinoline azoles
Quinoline (410mg, 0.7mmol) is dissolved in methanol (5ml), is added 10%Pd/C (50mg), is replaced three times with hydrogen, Zhi Houyu
The pressure of 40Psi hydrogen is stirred to react about 2 hours.LCMS detects fully reacting.Palladium charcoal is filtered out, filtrate decompression is concentrated and dried, obtains grey
Color solid, 270mg, purity: 95%, yield: 96%.LC-MS(ESI):m/z 439(M+H)+。
2- { 4 '-dimethylamino -5 '-[N, TMSDMA N dimethylamine methyl-(E)-acrylamido] -2 '-methoxyl groups } anilino- -4-
The preparation of (1 "-methyl-1 H-3 "-indoles) quinazoline (compound 202)
By 2- { 4 '-dimethylamino -5 '-amido -2 '-methoxyl group } anilino- -4- (1 "-methyl-1 H-3 "-indoles) quinoline azoles
Quinoline (290mg, 0.7mmol) and (E) -4- dimethylamino -2- butenoic acid (120mg, 0.72mmol) be dissolved in tetrahydrofuran (6ml) and
In n,N-Dimethylformamide (1ml), N is added, N- diisopropyl ethyl amine (420mg, 3.24mmol) stirs in batches under ice bath
Addition 2- (7- azo benzotriazole)-N, N, N', N'- tetramethylurea hexafluorophosphoric acid ester (HATU) (330mg, 0.865mmol),
It is stirred to react at room temperature 3 hours.LCMS detects fully reacting.Reaction solution is added dropwise in the water that stirred, a large amount of solids are precipitated,
Crude product is filtered to obtain, (ethyl acetate: methanol=40:1~8:1) is purified by silica gel column chromatography, obtains brown solid, 110mg is pure
Degree: 97%, yield: 32%.LC-MS(ESI):m/z 550(M+H)+。
Embodiment 3:2- { 4- (1- methyl-N, N- dimethyl amido ethyl) amido -5 '-(3 '-N, N- dimethyl amido first
Base-acryloyl)-amido -2 '-methoxyl group anilino- -4- (1 "-methyl-1 H-3 "-indoles) quinazoline (compound 203) system
It is standby
2- { 4- (1- methyl-N, N- dimethyl amido ethyl) amido -5 '-nitro -2 '-methoxyl group } anilino- -4- (1 " -
Methyl-1 H-3 "-indoles) quinazoline preparation
By 2- { 4 '-fluoro- 5 '-nitro -2 '-methoxyl group } anilino- -4- (1 "-methyl-1 H-3 "-indoles) quinazoline
(400mg, 0.9mmol) is dissolved in dimethyl sulfoxide (7ml), is stirred at room temperature, be added N, N, N- trimethyl ethylenediamine (105mg,
1.0mmol) and N, N ,-diisopropyl ethyl amine (0.4ml) are heated to 86 DEG C later, are stirred to react three hours.LCMS detection is anti-
It should be complete.Stop reaction, be cooled to room temperature, reaction solution is slowly added into the ice water that stirred, a large amount of solids are precipitated, filters,
Filtration cakes torrefaction, gained crude product methylene chloride and petroleum ether mashing processing, obtain Chinese red solid 350mg, purity: 91%, yield:
70%.LC-MS(ESI):m/z 526(M+H)+。
2- { 4- (1- methyl-N, N- dimethyl amido ethyl) amido -5 '-amido -2 '-methoxyl group } anilino- -4- (1 " -
Methyl-1 H-3 "-indoles) quinazoline preparation
By 2- { 4- (1- methyl-N, N- dimethyl amido ethyl) amido -5 '-nitro -2 '-methoxyl group } anilino- -4-
(1 "-methyl-1 H-3 "-indoles) quinazoline (350mg, 0.667mmol) is dissolved in ethyl alcohol (7ml) and tetrahydrofuran (2ml), adds
Enter 10%Pd/C (50mg), is replaced three times with hydrogen, be stirred to react about 2 hours in the pressure of 40Psi hydrogen later.LCMS detection is anti-
It should be complete.Filtering out palladium charcoal, filtrate decompression is concentrated and dried, obtain gray solid, 280mg, purity: 91%, yield: 96%.LC-MS
(ESI):m/z 496(M+H)+;
2- { 4- (1- methyl-N, N- dimethyl amido ethyl) amido -5 '-(3 '-N, N- dimethylaminomethyl-propylene
Acyl)-amido -2 '-methoxyl group anilino- -4- (1 "-methyl-1 H-3 "-indoles) quinazoline (compound 203) preparation
By 2- { 4- (1- methyl-N, N- dimethyl amido ethyl) amido -5 '-amido -2 '-methoxyl group } anilino- -4-
(1 "-methyl-1 H-3 "-indoles) quinazoline (50mg, 0.101mmol) and 3-N, N- dimethylaminomethyl-acrylic acid hydrochloride
(49mg, 0.387mmol) is dissolved in tetrahydrofuran (3ml) and n,N-Dimethylformamide (0.5ml), and N, N- diisopropyl is added
Ethylamine (59mg, 0.455mmol), 2- (7- azo benzotriazole)-N, N, N', N'- tetra- is added portionwise in stirring under ice bath
Methylurea hexafluorophosphoric acid ester (HATU) (50mg, 0.121mmol) is stirred to react 3 hours at room temperature into reaction solution.LCMS inspection
Survey fully reacting.Reaction solution is added dropwise in the water that stirred, and a large amount of solids are precipitated, and is filtered, a small amount of water washing filter cake, dry, is obtained
Gray solid, 20mg, purity: 97%, yield: 50%.LC-MS(ESI):m/z 607(M+H)+;1H NMR(400MHz,DMSO)
δppm 1.23(m,2H),2.22(s,6H),2.30(s,6H),2.70(s,3H),2.93(m,2H),3.11(m,2H),3.87
(s, 3H), 3.95 (s, 3H), 6.24-6.28 (d, 1H, J=15.2Hz), 6.73-6.77 (d, 1H, J=15.2Hz), 7.02 (s,
1H), 7.17 (m, 1H), 7.27 (m, 2H), 7.35 (m, 2H), 7.56-7.58 (d, 1H, J=8.4Hz), 7.66 (m, 1H), 7.78
(m, 1H), 8.08 (s, 1H), 8.14-8.16 (d, 1H, J=7.6Hz), 8.27 (s, 1H), 8.29-8.31 (d, 1H, J=
8.4Hz),9.29(s,1H),9.98(s,1H).
Embodiment 4:2- { 4- (1- methyl-N, N- dimethyl amido ethyl) amido -5 '-(3 '-acryloyl)-amido -2 ' -
Methoxyl group } anilino- -4- (1 "-methyl-1 H-3 "-indoles) quinazoline (compound 204) preparation:
By 2- { 4- (1- methyl-N, N- dimethyl amido ethyl) amido -5 '-amido -2 '-methoxyl group } anilino- -4-
(1 "-methyl-1 H-3 "-indoles) quinazoline (160mg, 0.323mmol) is dissolved in tetrahydrofuran (4ml) and water (0.5ml), in
It stirs, is added dropwise 3- chlorpromazine chloride (49mg, 0.387mmol) under ice bath, drop Bi Jixu is stirred to react half an hour.LCMS detects raw material
Fully reacting.Sodium hydroxide (64mg, 1.615mmol) is added later, is heated to 80 DEG C, is stirred to react 16 hours.LCMS inspection
Survey fully reacting.Stop reaction, be cooled to room temperature, be concentrated under reduced pressure into residue about 60ml liquid, is added methanol (8ml), in room temperature
Lower stirring is subsequently added into water (300ml), and a large amount of solids are precipitated, and filters, is washed with water filter cake three times, gained crude product is through prep-
HPLC purifying, obtains faint yellow solid, 34mg, purity: 97%, yield: 20%.LC-MS(ESI):m/z 550(M+H)+;1H NMR
(400MHz,DMSO)δppm 2.20(s,6H),2.30(m,2H),2.72(s,3H),2.88(m,2H),3.86(s,3H),3.95
(s, 3H), 5.74-5.77 (t, 1H), 6.28-6.29 (d, 1H, J=2Hz), 6.38-6.41 (d, 1H, J=10.4Hz), 7.04
(s, 1H), 7.20 (m, 1H), 7.28 (m, 1H), 7.35 (m, 1H), 7.56-7.58 (d, 1H, J=8.4Hz), 7.64-7.66 (d,
1H, J=8.4Hz), 7.79 (m, 1H), 8.09 (s, 1H), 8.14-8.16 (d, 2H, J=8Hz), 8.28-8.31 (m, 2H),
9.35(s,1H),10.10(s,1H).
Embodiment 5:2- { 4- (1- methyl-N, N- dimethyl amido ethyl) amido -5 '-(3 '-crotonoyl)-amido -2 ' -
Methoxyl group } anilino- -4- (1 "-methyl-1 H-3 "-indoles) quinazoline (compound 205) preparation
By 2- { 4- (1- methyl-N, N- dimethyl amido ethyl) amido -5 '-amido -2 '-methoxyl group } anilino- -4-
(1 "-methyl-1 H-3 "-indoles) quinazoline (50mg, 0.101mmol) and (E) -2- butenoic acid (35mg, 0.404mmol) are dissolved in
In tetrahydrofuran (3ml) and n,N-Dimethylformamide (0.5ml), addition N, N- diisopropyl ethyl amine (59mg,
0.455mmol), 2- (7- azo benzotriazole)-N, N, N', N'- tetramethylurea hexafluoro phosphorus is added portionwise in stirring under ice bath
Acid esters (HATU) (50mg, 0.121mmol) is stirred to react 3 hours at room temperature into reaction solution.LCMS detects fully reacting.
Reaction solution is added dropwise in the water that stirred, and a large amount of solids are precipitated, and is filtered, a small amount of water washing filter cake, dry, obtains gray solid,
20mg, purity: 97%, yield: 50%.LC-MS(ESI):m/z 564(M+H)+。
Embodiment 6:2- { 4- (1- methyl-N, N- dimethyl amido ethyl) amido -5 '-(3 '-butine acyl) amido -2 '-first
Oxygroup } anilino- -4- (1 "-methyl-1 H-3 "-indoles) quinazoline (compound 206) preparation
By 2- { 4- (1- methyl-N, N- dimethyl amido ethyl) amido -5 '-amido -2 '-methoxyl group } anilino- -4-
(1 "-methyl-1 H-3 "-indoles) quinazoline (50mg, 0.101mmol) is dissolved in tetrahydrofuran (5ml) and n,N-Dimethylformamide
In (1ml), 2- tetrolic acid (153mg, 1.17mmol) and N, N- diisopropyl ethyl amine (153mg, 1.17mmol), Yu Bing is added
The lower stirring of bath, is added portionwise 2- (7- azo benzotriazole)-N, N, N', N'- tetramethylurea hexafluorophosphoric acid ester (HATU)
(155mg, 0.404mmol) is stirred to react 3 hours at room temperature.LCMS detects fully reacting.Reaction solution, which is added dropwise to, to be stirred
Water in, a large amount of gray solids are precipitated, filter, filtration cakes torrefaction obtains gray solid, 70mg, purity: 96%, yield: 41%.LC-
MS(ESI):m/z 562(M+H)+。
Embodiment 7:2- { 4-N, N- dimethyl amine base oxethyl -2- methoxyl group -5 '-(3 '-acryloyl)-amido -2 '-first
Oxygroup } anilino- -4- (1 "-methyl-1 H-3 "-indoles) quinazoline (compound 207) preparation:
2- { 4-N, N- dimethyl amine base oxethyl -2- methoxyl group -5- nitro } anilino- -4- (1- methyl -3- indyl)
The preparation of pyrimidine
Intermediate A (1.4g, 3.55mmol) is dissolved in dimethyl sulfoxide (5ml), N, N- dimethyl amido ethyl alcohol is added
(20mL) and cesium carbonate (1.8g, 5.52mmol), is stirred to react 5 hours in 60 DEG C.LCMS detects fully reacting.It is cooled to room temperature,
Reaction solution is added dropwise in the water that stirred, a large amount of solids are precipitated, is filtered, a small amount of water washing filter cake, it is solid that filtration cakes torrefaction obtains brown
Body 1.1g, purity: 96%, yield: 67%.LC-MS(ESI):m/z 463(M+H)+。1H NMR(400MHz,DMSO)δppm
2.25(s,6H),2.59–2.63(m,2H),3.74(s,3H),3.87(s,3H),4.01-4.08(m,2H),6.705(s,1H),
7.107-7.151(m,2H),7.240(s,1H),7.404-7.514(m,2H),7.756(s,1H),8.231-8.268(m,
2H), 8.401-8.421 (d, 1H, J=8.4Hz).
2- { 4-N, N- dimethyl amine base oxethyl -2- methoxyl group -5 '-nitro -2 '-methoxyl group } anilino- -4- (1 "-first
Base -1H-3 "-indoles) quinazoline preparation
By 2- { 4 '-fluoro- 5 '-nitro -2 '-methoxyl group } anilino- -4- (1 "-methyl-1 H-3 "-indoles) quinazoline
(400mg, 0.9mmol) is dissolved in dimethyl sulfoxide (7ml), is stirred at room temperature, and N, N- dimethyl amido ethyl alcohol (20mL) is added
With cesium carbonate (1.8g, 5.52mmol), it is stirred to react in 60 DEG C 5 hours.LCMS detects fully reacting.It is cooled to room temperature, will reacts
Drop adds in the water that stirred, and a large amount of solids are precipitated, and filters, and a small amount of water washing filter cake, filtration cakes torrefaction obtains brown solid 1.1g,
Purity: 96%, yield: 67%.LC-MS(ESI):m/z 527(M+H)+。
2- { 4-N, N- dimethyl amine base oxethyl -2- methoxyl group -5 '-amido -2 '-methoxyl group } anilino- -4- (1 "-first
Base -1H-3 "-indoles) quinazoline preparation
By 2- { 4-N, N- dimethyl amine base oxethyl -2- methoxyl group -5 '-nitro -2 '-methoxyl group } anilino- -4- (1 " -
Methyl-1 H-3 "-indoles) quinazoline (1.1g, 2,38mmol) is dissolved in methanol (5ml), and it is added 10%Pd/C (50mg), uses hydrogen
Gas is replaced three times, is stirred to react about 2 hours in the pressure of 40Psi hydrogen later.LCMS detects fully reacting.Filter out palladium charcoal, filtrate
Drying is concentrated under reduced pressure, obtains gray solid, 920mg, purity: 96%, yield: 90%.LC-MS(ESI):m/z 483(M+H)+。
2- { 4-N, N- dimethyl amine base oxethyl -2- methoxyl group -5 '-(3 '-acryloyl)-amido -2 '-methoxyl group } aniline
The preparation of base -4- (1 "-methyl-1 H-3 "-indoles) quinazoline (compound 207):
By 2- { 4-N, N- dimethyl amine base oxethyl -2- methoxyl group -5 '-amido -2 '-methoxyl group } anilino- -4- (1 " -
Methyl-1 H-3 "-indoles) quinazoline (160mg, 0.323mmol) is dissolved in tetrahydrofuran (4ml) and water (0.5ml), in ice bath
Lower stirring is added dropwise 3- chlorpromazine chloride (49mg, 0.387mmol), and drop Bi Jixu is stirred to react half an hour.LCMS detects raw material reaction
Completely.Sodium hydroxide (64mg, 1.615mmol) is added later, is heated to 80 DEG C, is stirred to react 16 hours.LCMS detection is anti-
It should be complete.Stop reaction, be cooled to room temperature, be concentrated under reduced pressure into residue about 60ml liquid, is added methanol (8ml), stirs at room temperature
It mixes, is subsequently added into water (300ml), a large amount of solids are precipitated, filter, be washed with water filter cake three times, gained crude product is pure through prep-HPLC
Change, obtains faint yellow solid, 36mg, purity: 97%, yield: 25%.LC-MS(ESI):m/z 536(M+H)+;
Embodiment 8:2- { 4-N, N- dimethyl amine base oxethyl -2- methoxyl group -5 '-(3 '-N, N- dimethylaminomethyl -
Acryloyl)-amido -2 '-methoxyl group anilino- -4- (1 "-methyl-1 H-3 "-indoles) quinazoline (compound 208) preparation
By 2- { 4-N, N- dimethyl amine base oxethyl -2- methoxyl group -5 '-amido -2 '-methoxyl group } anilino- -4- (1 " -
Methyl-1 H-3 "-indoles) quinazoline (200mg, 0.462mmol) and (E) -4- dimethyl amido -2- crotonic amide hydrochloride (in
Mesosome D) (92mg, 0.554mmol) be dissolved in tetrahydrofuran (6ml) and n,N-Dimethylformamide (1.0ml), in reaction solution
N is added, N- diisopropyl ethyl amine (209mg, 1.617mmol), 2- (three nitrogen of 7- azo benzo is added portionwise in stirring under ice bath
Azoles)-N, N, N', N'- tetramethylurea hexafluorophosphoric acid ester (HATU) (211mg, 0.554mmol) into reaction solution, stirs at room temperature
Mix reaction 3 hours.LCMS detects fully reacting.Reaction solution is added dropwise in the water that stirred, and a large amount of solids are precipitated, and filters crude product,
Content 90% crosses reverse phase column purification and obtains brown solid, 7mg, purity: 95%, yield: 3%.LC-MS(ESI):m/z 594(M+
H)+;1H NMR(400MHz,DMSO)δppm 2.191(s,6H),2.292(s,6H),2.595(m,2H),3.071-3.085(m,
2H), 3.861 (s, 3H), 3.908 (s, 3H), 4.18 (m, 2), 6.282-6.321 (d, 1H, J=15.6Hz), 7.12 (s, 1H),
7.27 (m, 1H), 7.35 (m, 4H), 7.55-7.57 (d, 1H, J=8.4Hz), 7.65 (m, 1H), 7.79 (m, 1H), 8.12 (s,
1H), 8.16-8.18 (d, 1H, J=7.6Hz), 8.27 (s, 1H), 8.29-8.31 (d, 1H, J=8.6Hz), 9.39 (s, 1H),
9.88(s,1H)。
Embodiment 9:2- { 4- (1- methyl-N, N- dimethyl amido ethyl) amido -5 '-(3 '-acryloyl)-amido -2 ' -
Methoxyl group } anilino- -4- (1 " H-3 "-indoles) quinazoline (compound 209) preparation:
The preparation of the chloro- 4- of 2- (1H-3- indoles) quinazoline:
2,4- dichloroquinazoline (2.0g, 10mmol) is dissolved in glycol dimethyl ether (40ml), is stirred under ice bath, point
It criticizes and alchlor is added, be stirred to react half an hour at room temperature later.It is added dropwise indoles (1.25g, 10mmol), is heated to 85 later
It DEG C is stirred to react 4 hours.LCMS detects fully reacting.Stop reaction, is down to room temperature, reaction solution is slowly imported in ice water, it is fast
Speed stirring, is precipitated a large amount of solids, filters, is washed filter cake three times with cold water, and the drying of gained filter cake obtains yellow solid, 1.95g is pure
Degree: 88%, yield: 60%.LC-MS(ESI):m/z 280(M+H)+。
The preparation of 2- { 4 '-fluoro- 5 '-nitro -2 '-methoxyl group } anilino- -4- (1 " H-3 "-indoles) quinazoline:
The chloro- 4- of 2- (1H-3- indoles) quinazoline (851mg, 3.0mmol) is dissolved in n-butanol (20ml), at room temperature
Stirring, the fluoro- 2- methoxyl group -5- nitroaniline (570mg, 3.063mmol) of addition 4- and p-methyl benzenesulfonic acid (630mg,
3.67mmol), it is heated to 105 DEG C later, is stirred to react three hours.LCMS detects fully reacting.Stop reaction, is cooled to room
Temperature filters reaction solution, and a small amount of cold ethanol washing, filtration cakes torrefaction obtains faint yellow solid 859mg, purity: 80%, yield:
67%.LC-MS(ESI):m/z 430(M+H)+。
2- { 4- (1- methyl-N, N- dimethyl amido ethyl) amido -5 '-amido -2 '-methoxyl group } anilino- -4- (1 " H-
3 "-indoles) quinazoline preparation
By 2- { 4- (1- methyl-N, N- dimethyl amido ethyl) amido -5 '-nitro -2 '-methoxyl group } anilino- -4- (1 "
H-3 "-indoles) quinazoline (301mg, 0.7mmol) is dissolved in ethyl alcohol (8ml) and tetrahydrofuran (2ml), 10%Pd/C is added
(50mg) is replaced three times with hydrogen, is stirred to react about 2 hours in the pressure of 40Psi hydrogen later.LCMS detects fully reacting.Filter
Palladium removing charcoal, filtrate decompression are concentrated and dried, and obtain gray solid, 280mg, purity: 91%, yield: 90%.LC-MS(ESI):m/z
482(M+H)+。
2- { 4- (1- methyl-N, N- dimethyl amido ethyl) amido -5 '-(3 '-acryloyl)-amido -2 '-methoxyl group } benzene
The preparation of amido -4- (1 "-methyl-1 H-3 "-indoles) quinazoline (compound 209):
By 2- { 4- (1- methyl-N, N- dimethyl amido ethyl) amido -5 '-amido -2 '-methoxyl group } anilino- -4- (1 "
H-3 "-indoles) quinazoline (155mg, 0.32mmol) is dissolved in tetrahydrofuran (4ml) and water (0.5ml), stirs under ice bath,
It is added dropwise 3- chlorpromazine chloride (49mg, 0.387mmol), drop Bi Jixu is stirred to react half an hour.LCMS detects raw material fully reacting.It
Sodium hydroxide (64mg, 1.615mmol) is added afterwards, is heated to 80 DEG C, is stirred to react 16 hours.LCMS detects fully reacting.
Stop reaction, be cooled to room temperature, be concentrated under reduced pressure into residue about 60ml liquid, is added methanol (8ml), stirs at room temperature, then
It is added water (300ml), a large amount of solids is precipitated, filter, be washed with water filter cake three times, gained crude product is purified through prep-HPLC, is obtained light
Yellow solid, 34mg, purity: 97%, yield: 20%.LC-MS(ESI):m/z 536(M+H)+;1H NMR(400MHz,DMSO)
δppm 2.20(s,6H),2.30(m,2H),2.72(s,3H),2.88(m,2H),3.86(s,3H),5.74-5.77(t,1H),
6.28-6.29 (d, 1H, J=2Hz), 6.38-6.41 (d, 1H, J=10.4Hz), 7.01 (s, 1H), 7.15 (m, 1H), 7.20
(m, 1H), 7.30 (m, 1H), 7.51-7.55 (d, 1H, J=8.4Hz), 7.60-7.63 (d, 1H, J=8.4Hz), 768 (m,
1H), 7.95 (s, 1H), 8.05-8.07 (d, 2H, J=8Hz), 8.18-8.21 (m, 2H), 9.15 (s, 1H), 9.95 (s, 1H)
Embodiment 10:2- { 4- (1- methyl-N, N- dimethyl amido ethyl) amido -5 '-(3 '-N, N- dimethyl amido first
Base-acryloyl)-amido -2 '-methoxyl group anilino- -4- (1 " H-3 "-indoles) quinazoline (compound 210) preparation
By 2- { 4- (1- methyl-N, N- dimethyl amido ethyl) amido -5 '-amido -2 '-methoxyl group } anilino- -4- (1 "
H-3 "-indoles) quinazoline (48mg, 0.10mmol) and 3-N, N- dimethylaminomethyl-acrylic acid hydrochloride (40mg,
It 0.3mmol) is dissolved in tetrahydrofuran (3ml) and n,N-Dimethylformamide (0.5ml), N, N- diisopropyl ethyl amine is added
(59mg, 0.455mmol), 2- (7- azo benzotriazole)-N, N, N', N'- tetramethylurea is added portionwise in stirring under ice bath
Hexafluorophosphoric acid ester (HATU) (40mg, 0.101mmol) is stirred to react 3 hours at room temperature into reaction solution.LCMS detection reaction
Completely.Reaction solution is added dropwise in the water that stirred, and a large amount of solids are precipitated, and is filtered, a small amount of water washing filter cake, dry, and it is solid to obtain grey
Body, 18mg, purity: 97%, yield: 50%.LC-MS(ESI):m/z 593(M+H)+。
Embodiment 11: the compounds of this invention is to the external zymetology determination of activity of T790M EGFR
Using FRET technology to the EGFR-T790M of the compounds of this invention (the compound 101-110 of embodiment 1-10 preparation)
Kinase activity inhibiting effect is measured, using Life technologies company Z'-LYTETM Kinase Assay Kits
(PV3193), and EGFR-T790M kinases solution in Tyrosine 4Peptide is selected to carry out active determination test (knot
2) fruit is shown in Table.Test procedure is as follows:
1. reagent prepares: the reagent in kit being dissolved and is formulated into required concentration;
2. compound solution is prepared: the compounds of this invention solution serial dilution of 0.15mM is reached each needed for test
Concentration
3. kinases dissolves: 96 orifice plates of EGFR-T790M kinases being dissolved, and carry out gradient then test kinase phosphorylation
For 17%~36% or so kinase concentration as test when the concentration that uses.
4. kinase activity is tested: the reagent prepared in kinases and 1,2 steps is mixed in order and at room temperature (20-25 DEG C)
Under the conditions of incubate 30s after be added terminate liquid, detected after vibrating 30s with multi-function microplate reader.
5. pair testing result carries out data processing, inhibiting rate and IC are obtained50。
2 compound of table is to T790M/L858R EGFR inhibitory activity
Sample number into spectrum | IC50(nM) |
201 | 20 |
202 | 47 |
203 | 2.5 |
204 | 18 |
205 | 53 |
206 | 65 |
207 | 12 |
208 | 15 |
209 | 1.2 |
210 | 0.5 |
Embodiment 12: the compounds of this invention measures the inhibitory activity of cancer cell line
1. test material
1.1 cell strain
Human lung adenocarcinoma cell NCI-H1975 (EGFR-T790M high expression), Non-small cell lung carcinoma cell A549 (EGFR high
Expression), people's epidermis cancer cell line (Wild type EGFR).
1.2 main agents: DMEM in high glucose culture medium, HyClone company, lot number NXJ0709,500ml/ bottle;Tire ox blood
Clearly, HyClone company, lot number NXC0582,500ml/ bottle;Thiazolyl blue, sigma company, lot number MKBH7489V, 1g/ bottle;Diformazan
Sulfoxide, Sinopharm Chemical Reagent Co., Ltd., lot number 20120705,500ml/ bottles;Trypsase, the prosperous biology of Beijing ancient cooking vessel state
Technology Co., Ltd., lot number 04D10151,25g/ bottle.
1.3 key instruments: (center number 058, Suzhou Feng Shi experimental animal equipment have CJ-1F type Medical purification workbench
Limit company);Table-type low-speed centrifuge (center number 101, Kai Da industry development Co., Ltd, Hunan Province);DMIL type is inverted micro-
Mirror (center number 027, Leica);3111 type CO2 incubators (center number 147, Thermo);MR-96A microplate reader (is compiled at center
Number 007, Shenzhen steps auspicious);Sterile syringe filter (millipore).
2. test method
2.1 cell culture and inoculation
For tumor cell line under 37 DEG C, the saturated humidity environment of 5%CO2, the DMEM in high glucose containing 10% fetal calf serum is complete
It cultivates, pass in culture medium.It is digested when inoculation with 0.25% tryptic digestive juice, adds cell culture medium piping and druming at uniform cell
Cell is made 5 × 10 by suspension4The cell suspension of/ml, every 100 μ l of hole are inoculated in 96 orifice plates.
2.2 test samples are prepared and cell growth inhibition assay
A certain amount of the compounds of this invention is weighed, is worked with the maximum concentration that DMEM complete medium is configured to 5000 μ g/ml
Then liquid is successively configured to the work of 1500,500,150,50,15 μ g/ml with 0.22 μm of sterile syringe filter filtration sterilization
Liquid.Cis-platinum (DDP) is configured to the working solution that concentration is 50,15,5,1.5,0.75,0.15 μ g/ml with DMEM complete medium.To
Use the working solution of test sample containing various concentration and cis-platinum (DDP) after cell is adherent instead, each concentration sets 3 multiple holes.Respectively at adding
After medicine after 48 hours, every hole adds 20 μ l of MTT solution (culture medium is made into 5mg/ml, is kept in dark place after filtering), by supernatant after 4 hours
Liquid is sucked out, and every hole adds MTT lysate DMSO150 μ l, and concussion is completely dissolved to Formazan, and microplate reader 492nm measures OD value, warp
Conversion obtains the IC50 (nM) in following table.
3 compound of table is to proliferation of lung cancer cells inhibiting effect
A549 | NCI-H1975 | |
Compound number | IC50(nM) | IC50(nM) |
203 | 16 | 2.0 |
204 | 25 | 6.0 |
205 | 120 | 10 |
Claims (10)
1. quinazoline, Pyridopyrimidine or double and pyrimidine derivatives epidermal growth factor of the one kind with general structure (I) press down
Preparation and its pharmaceutically acceptable salt,
Wherein, X represents CH or N;Y represents CH or N;
R1For
Z is selected from any one in H, F, Cl, Br;
R2For any one in methyl, ethyl, isopropyl;
R3For
In any one;
R4ForOrWherein R6For H, C1-C6 alkyl, N, N- dimethyl amine first
Any one in base, pyrrolidinyl -1- methyl, piperidyl -1- methyl and morpholinyl -1- methyl.
2. quinazoline according to claim 1, Pyridopyrimidine or double and pyrimidine derivatives epidermal growth factor inhibit
Agent and its pharmaceutically acceptable salt, which is characterized in that the compound of the general structure (I) include number 203,204,207,
208,209 or 210:
3. a kind of prepare quinazoline, Pyridopyrimidine or double and pyrimidine derivatives epidermal growth factor of any of claims 1 or 2
The method of sub- inhibitor and its pharmaceutically acceptable salt, it is characterised in that include the following steps: starting material through cyclization
Obtaining intermediate A with phosphorus oxychloride reaction again afterwards, intermediate A successively passes through electrophilic addition, nucleophilic displacement of fluorine, hydrogenating reduction, acylation,
Finally obtain logical formula (I) compound represented accordingly.
4. a kind of pharmaceutical composition, which is characterized in that include quinazoline of any of claims 1 or 2, Pyridopyrimidine or double
And pyrimidine derivatives egf inhibitor and its pharmaceutically acceptable salt and pharmaceutically acceptable carrier.
5. pharmaceutical composition according to claim 4, which is characterized in that described pharmaceutical composition is tablet, capsule, particle
The form of agent, spray or injection.
6. pharmaceutical composition according to claim 4, which is characterized in that the pharmaceutically acceptable carrier is selected from filling
One of agent, disintegrating agent, adhesive and lubricant are a variety of.
7. quinazoline of any of claims 1 or 2, Pyridopyrimidine or double and pyrimidine derivatives egf inhibitor
And its pharmaceutically acceptable salt is used to prepare the purposes of protein tyrosine kinase inhibitor.
8. purposes according to claim 7, it is characterised in that: the protein tyrosine kinase inhibitor is epidermal growth factor
Sub- acceptor inhibitor.
9. quinazoline of any of claims 1 or 2, Pyridopyrimidine or double and pyrimidine derivatives egf inhibitor
And its pharmaceutical composition described in any one of pharmaceutically acceptable salt or claim 4 to 6 is being prepared for treating epidermis
Growth factor receptors over-express the purposes in the drug of related disease.
10. purposes according to claim 9, it is characterised in that: the EGF-R ELISA over-expresses related disease
Disease is selected from one of kidney, lung cancer, prostate cancer, cancer of pancreas, breast cancer and spongiocytoma or a variety of.
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