CN105001208A - EGFR inhibitor and preparing method and application thereof - Google Patents

EGFR inhibitor and preparing method and application thereof Download PDF

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CN105001208A
CN105001208A CN201510475725.0A CN201510475725A CN105001208A CN 105001208 A CN105001208 A CN 105001208A CN 201510475725 A CN201510475725 A CN 201510475725A CN 105001208 A CN105001208 A CN 105001208A
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egf
methyl
elisa
egfr inhibitor
acceptable salt
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不公告发明人
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Nanjing Leikexing Biotechnology Co Ltd
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Nanjing Leikexing Biotechnology Co Ltd
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    • 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
    • C07D403/04—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 directly linked by a ring-member-to-ring-member bond

Abstract

The invention discloses an EGFR inhibitor. The EGFR inhibitor is of the structure shown in the formula (I) and is a compound including alpha, beta-unsaturated carboxylic acid amides. Meanwhile, the invention discloses a preparing method of the compound and the application of the compound serving as a protein tyrosine kinase inhibitor, especially the inhibiting function on T790M variant EGFR as the EGFR inhibitor, and the application on treating diseases such as the kidney cancer, the ling cancer, the prostate cancer, the pancreatic cancer the breast cancer and the spongiocytoma which are related to EGFR over expression. The structure is shown in the specification.

Description

A kind of EGF-R ELISA EGFR inhibitor and preparation method thereof and purposes
Technical field
The present invention relates to field of medicaments, be specifically related to a kind of EGF-R ELISA EGFR inhibitor and its production and use.
Background technology
EGF-R ELISA EGFR (Epidermal Growth Factor Receptor) is the one of ErbB receptor family, and be a kind of glycoprotein, belong to Tyrosylprotein kinase receptor, cytolemma is through, molecular weight 170KDa.EGFR is positioned at surface of cell membrane, activates EGF and TGF (transforming growth factor) with ligand binding.After activation, EGFR is activate it after dimer to be positioned at intracellular kinase pathway by conversion of monomer, guides the phosphorylation in downstream, comprises MPAK, Akt and JNK path, induced cell proliferation.Research shows in many noumenal tumours, there is EGFR high expression level or unconventionality expression, and the propagation of EGFR and tumour cell, vasculogenesis, tumor invasion, transfer and apoptotic suppression are relevant.The process LAN of EGFR plays an important role in the development of malignant tumour, has the overexpression of EGFR in the tissue such as kidney, lung cancer, prostate cancer, carcinoma of the pancreas, mammary cancer, glioma.
Protein tyrosine kinase is the enzyme that the phosphate group of ATP is transferred to the tyrosine residues of protein substrate by a class.Many growth factor receptor proteins are comprised EGF-R ELISA and are worked by phosphorylation, EGF-R ELISA EGFR Tyrosylprotein kinase makes EGF-R ELISA phosphorylation, clinically, EGFR tyrosine kinase inhibitor has been used to the treatment of cancer, as Gefitinib, Tarceva are used to treatment nonsmall-cell lung cancer and achieve certain curative effect.
But in many tumours, have the EGFR Tyrosylprotein kinase of anomaly, after pharmacological agent, EGFR Tyrosylprotein kinase is undergone mutation, or thus make drug failure, i.e. clinical signs go out resistance resistance.Within 2004, namely there are in Gefitinib is to Treatment for Non-small Cell Lung, occurred EGFR tyrosine-kinase enzyme mutant report (Science, 2004, Vol.304,1497-1500; New England Journal of Medicine 2004,350,2129-2139).Wherein a kind of variation occurs in residue on duty at the gate 790 site of EGFR Tyrosylprotein kinase, by the original L-threonine in this site (T) for L-MET (M) substitutes, be called as T790M variation, after variation, EGF Tyrosylprotein kinase R is no longer combined with Gefitinib, Tarceva, thus make medicine lose effect, there is resistance in patient.
In sum, the cancer therapy drug that exploitation is removed or reduction resistance produces is very necessary.
Summary of the invention
The present invention is directed to the EGFR Tyrosylprotein kinase of T790M variation, devise a series of inhibitor molecules, find compound T790M variation EGFR to high inhibit activities, and this compound has obvious restraining effect to cancer cells, this compound is a kind of new epidermal growth factor recipient tyrosine kinase inhibitor, comprise α, beta-unsaturated carboxylic acid amides or its pharmacy acceptable salt, this inhibitor can realize high reactivity to T790M/L858R variant EGFR to be suppressed, and can suppress or kill the tumour cell of EGFR T790M variation, be expected to become a kind of method for the treatment of related neoplasms.
A kind of EGF-R ELISA EGFR inhibitor and pharmacy acceptable salt thereof with logical formula I structure provided by the invention, this compounds contains α, beta-unsaturated carboxylic acid amide structure, and it can be used as a kind of irreversible EGFR inhibitor,
Wherein, B represents double bond or triple bond, and Ar is heterocyclic arene, is preferably
Wherein, X is the one in H, F, Cl and Br.
R 1for
In one;
R 2for any one in C1-C6 alkyl, N, N-dimethylaminomethyl, pyrrolidyl-1-methyl, piperidyl-1-methyl and morpholinyl-1-methyl.
Preferably, described compound comprises the compound had as table 1 structure:
Table 1-unsaturated carboxylic acid amides
Present invention also offers the preparation method of above-mentioned EGF-R ELISA EGFR inhibitor; as shown in Scheme 1; the method comprises the following steps: starting raw material is obtained by reacting intermediate II through multistep conventional chemical; intermediate II is successively through hydrogenating reduction, acidylate; or successively through nucleophilic substitution, hydrogenating reduction, acidylate, finally obtain corresponding general formula (I) compound.
The synthesis and preparation of Scheme 1 compound of Formula I
Present invention also offers a kind of pharmaceutical composition, described pharmaceutical composition comprises above-mentioned EGF-R ELISA EGFR inhibitor or its pharmacy acceptable salt, and its pharmaceutically acceptable carrier.
Described pharmaceutical composition is the form of tablet, capsule, granule or injection.
Described pharmaceutically acceptable carrier be selected from weighting agent, disintegrating agent, tackiness agent and lubricant one or more, include but not limited to any and whole solvents, dispersion medium, dressing, absorption delay agent etc., such medium and medicament are used for pharmaceutically active substances and are well known in the art.
Present invention also offers described EGF-R ELISA EGFR inhibitor or its pharmacy acceptable salt purposes as protein tyrosine kinase inhibitor;
Preferably, described protein tyrosine kinase inhibitor is epidermal growth factor receptor inhibitor;
More preferably, described epidermal growth factor receptor inhibitor is the inhibitor of the EGF-R ELISA to T790M variation.
Present invention also offers described EGF-R ELISA EGFR inhibitor or its pharmacy acceptable salt or the described pharmaceutical composition purposes in the medicine for the preparation for the treatment of EGF-R ELISA overexpression relative disease;
Preferably, described EGF-R ELISA overexpression relative disease is selected from as one or more in kidney, lung cancer, prostate cancer, carcinoma of the pancreas, mammary cancer and glioma.
EGF-R ELISA EGFR inhibitor provided by the invention or its pharmacy acceptable salt, and its pharmaceutical composition, the EGF-R ELISA that can effectively suppress T790M/L858R to make a variation, solve at EGFR targeted drug if Gefitinib, Tarceva sheet are to the resistance in oncotherapy, in vitro in enzymatic assay, the compound with general formula (I) reaches IC50=0.001 μM (see table 2) kinase whose inhibit activities; In vitro in cell experiment, the compound with general formula (I) all shows JEG-3 NCI-H1975, A549 and stronger kills activity (see table 3), be expected to become a more effective treatment EGF-R ELISA overexpression relative disease as the medicine of kidney, lung cancer, prostate cancer, carcinoma of the pancreas, mammary cancer, glioma etc., thus be expected to solve the resistance problems in EGFR target therapeutic agent.In addition, the compounds of this invention preparation technology is simple, and physico-chemical property is good, steady quality, is easy to carry out large-scale industrial production.
Embodiment
The present invention is further illustrated below by way of specific embodiment.
The method that preparation has the compound of general formula (I) comprises: starting raw material is obtained by reacting intermediate II through multistep conventional chemical; intermediate II is successively through hydrogenating reduction, acidylate; or successively through nucleophilic substitution, hydrogenating reduction, acidylate, finally obtain corresponding general formula (I) compound.What deserves to be explained is, general formula (I) compound includes but not limited to the following compound enumerated.
The fluoro-2-methoxyl group of embodiment 1:2-{4--5-[N, N dimethylamine methyl-(E)-acrylamido] } preparation of anilino-4-(1-methyl-3-indyl) pyrimidine (compound 101)
The preparation of 3-(the chloro-4-pyrimidyl of 2-)-1-skatole
2,4-dichloro pyrimidine (450g, 3.02mol) is dissolved in glycol dimethyl ether (6L), stirs under ice bath, add aluminum chloride in batches, react half an hour in stirred at ambient temperature afterwards.Drip N-skatole (400g, 3.05mol).Be heated to 80 DEG C of stirring reactions 4 hours afterwards.Liquid chromatograph mass spectrography (LCMS) detection reaction is complete.Stopped reaction, is down to room temperature, is slowly imported by reaction solution (18L) in frozen water, stirs rapidly, separates out a large amount of orange solid, suction filtration, and with cold water washing filter cake three times, gained filter cake is dried, and obtains light red solid crude product.Gained crude product is dissolved in (2ml/g) in methylene dichloride, and stirring at room temperature half an hour, in uniform suspension solid, suction filtration, a small amount of cold washed with dichloromethane filter cake, dries, obtain sterling 400g.Faint yellow solid, purity: 99%, yield: 54%.LC-MS(ESI):m/z244(M+H) +。
The preparation of the fluoro-2-anisidine of 4-
By fluoro-for 5-2-Nitroanisole (500g, 2.92mol) be dissolved in ethanol (2.4L) and water (0.8L), add ammonium chloride (78g, 1.46mol), 80 DEG C are heated under stirring, add reduced iron powder in batches, control temperature of reaction lower than 85 DEG C, stirring reaction 3 hours.LCMS detection reaction is complete.Stopped reaction, is down to room temperature, filters, a small amount of washing with alcohol filter cake, and filtrate concentrates.Gained resistates is dissolved in ethyl acetate (1L), a small amount of water washing, anhydrous sodium sulfate drying, filters, and filtrate step-down concentrates, dry, obtains product 408g, brown liquid, purity: 92%, yield: 99%.LC-MS(ESI):m/z 142(M+H) +。
The preparation of the fluoro-2-methoxyl group of 4--5-N-methyl-p-nitroaniline
Fluoro-for 4-2-anisidine (400g, 2.83mol) is dissolved in the vitriol oil, stirs under ice bath, add saltpetre (372g, 3.68mol) afterwards in batches, stirring reaction two hours under ice bath.LCMS detection reaction is complete.Stopped reaction, adjust pH in neutral (pH=7) with 30% aqueous sodium hydroxide solution, separate out a large amount of solid, suction filtration, a small amount of cold water washing filter cake, gained crude product is dry, obtains product.Brown solid, 134g, purity: 93%, yield: 25.4%.LC-MS(ESI):m/z 187(M+H) +。
The preparation of 2-(the fluoro-2-methoxyl group of 4--5-nitro) anilino-4-(1-methyl-3-indyl) pyrimidine (intermediate A)
By 3-(the chloro-4-pyrimidyl of 2-)-1-skatole (118g, 0.485mol) be dissolved in propyl carbinol (1.5L), in stirred at ambient temperature, add the fluoro-2-methoxyl group of 4--5-N-methyl-p-nitroaniline (90g, 0.485mol) with tosic acid (100g, 0.582mol), be heated to 105 DEG C afterwards, stirring reaction two hours.LCMS detection reaction is complete.Stopped reaction, is cooled to room temperature, and by reaction solution suction filtration, a small amount of cold washing with alcohol, filtration cakes torrefaction, obtains faint yellow solid 130g, purity: 98%, yield: 68%.LC-MS(ESI):m/z 394(M+H) +。
The preparation of 2-(the fluoro-2-methoxyl group of 4--5-amido) anilino-4-(1-methyl-3-indyl) pyrimidine
By 2-(the fluoro-2-methoxyl group of 4--5-nitro) anilino-4-(1-methyl-3-indyl) pyrimidine (310mg, 0.788mmol) be dissolved in methyl alcohol (5ml) and tetrahydrofuran (THF) (2ml), add 10%Pd/C (50mg), with hydrogen exchange three times, afterwards under 40Psi hydrogen-pressure, stirring reaction about 2 hours.LCMS detection reaction is complete.Filtering palladium charcoal, a small amount of methanol wash filter cake, filtrate reduced in volume is dry, obtains gray solid, 280mg, purity: 95%, yield: 96%.LC-MS(ESI):m/z 364(M+H) +；
The fluoro-2-methoxyl group of 2-{4--5-[N, N dimethylamine methyl-(E)-acrylamido] } preparation of anilino-4-(1-methyl-3-indyl) pyrimidine (compound 101)
By 2-(the fluoro-2-methoxyl group of 4--5-amido) anilino-4-(1-methyl-3-indyl) pyrimidine (intermediate A) (230mg, 0.633mmol) with (E)-4-dimethylin-2-butylene acid (105mg, 0.633mmol) be dissolved in tetrahydrofuran (THF) (5.0ml) and N, in dinethylformamide (0.8ml), add N, N-diisopropyl ethyl amine (368mg, 2.85mmol), stir under ice bath and add 2-(7-azo benzotriazole)-N in batches, N, N', N'-tetramethyl-urea phosphofluoric acid ester (HATU) (290mg, 0.76mmol), stirred at ambient temperature reacts 3 hours.LCMS detection reaction is complete.Dropped in the water that stirred by reaction solution, separate out a large amount of solid, suction filtration obtains head product 240mg, through purification by silica gel column chromatography (ethyl acetate: methyl alcohol=40:1 ~ 8:1), obtains brown solid, 50mg, purity: 99%, yield: 18%.LC-MS(ESI):m/z 475(M+H) +； 1H NMR(400MHz,CDCl 3)δppm 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),6.96-7.00(d,1H,J＝15.6Hz),7.17-7.18(d,1H,J＝5.2Hz),7.33(m,1H),7.37(m,1H),7.59(s,1H),8.09-8.11(d,1H,J＝6.8Hz),8.36-8.37(d,1H,J＝5.2Hz),8.77(s,1H),9.66(s,1H)。
Embodiment 2:2-{4-N, N-dimethyl amido-2-methoxyl group-5-[N, N dimethylamine methyl-(E)-acrylamido] } preparation of anilino-4-(1-methyl-3-indyl) pyrimidine (compound 102)
The preparation of 2-(4-N, N-dimethyl amido-2-methoxyl group-5-nitro) anilino-4-(1-methyl-3-indyl) pyrimidine
By 2-(the fluoro-2-methoxyl group of 4--5-nitro) anilino-4-(1-methyl-3-indyl) pyrimidine (400mg, 1.012mmol) be dissolved in N, in dinethylformamide (5ml), add dimethylamine (50mg, 1.113mmol) and N, N-diisopropyl ethyl amine (500mg, 4.048mmol), in 86 DEG C of stirring reactions 3 hours.LCMS detection reaction is complete.Be chilled to room temperature, dropped in the water that stirred by reaction solution, separate out a large amount of solid, suction filtration, a small amount of water washing filter cake, filter cake is added dropwise to after being dissolved in methylene dichloride and stirreds to obtain making beating process in sherwood oil, and gained solid suction filtration is dry.Obtain orange solid 410mg, purity: 93%, yield: 88%.LC-MS(ESI):m/z 419(M+H) +。
The preparation of 2-(4-N, N-dimethyl amido-2-methoxyl group-5-amido) anilino-4-(1-methyl-3-indyl) pyrimidine (intermediate B)
By 2-(4-N, N-dimethyl amido-2-methoxyl group-5-nitro) anilino-4-(1-methyl-3-indyl) pyrimidine (300mg, 0.718mmol) be dissolved in methyl alcohol (5ml), add 10%Pd/C (50mg), with hydrogen exchange three times, stirring reaction about 2 hours under 40Psi hydrogen-pressure afterwards.LCMS detection reaction is complete.Filtering palladium charcoal, filtrate reduced in volume is dry, obtains gray solid, 270mg, purity: 95%, yield: 96%.LC-MS(ESI):m/z 389(M+H) +。
2-{4-N, N-dimethyl amido-2-methoxyl group-5-[N, N dimethylamine methyl-(E)-acrylamido] } preparation of anilino-4-(1-methyl-3-indyl) pyrimidine (compound 102)
By 2-(4-N, N-dimethyl amido-2-methoxyl group-5-amido) anilino-4-(1-methyl-3-indyl) pyrimidine (intermediate B) (280mg, 0.72mmol) with (E)-4-dimethylin-2-butylene acid (120mg, 0.72mmol) be dissolved in tetrahydrofuran (THF) (6ml) and N, in dinethylformamide (1ml), add N, N-diisopropyl ethyl amine (420mg, 3.24mmol), stir under ice bath and add 2-(7-azo benzotriazole)-N in batches, N, N', N'-tetramethyl-urea phosphofluoric acid ester (HATU) (330mg, 0.865mmol), stirred at ambient temperature reacts 3 hours.LCMS detection reaction is complete.Dropped in the water that stirred by reaction solution, separate out a large amount of solid, suction filtration obtains crude product, through purification by silica gel column chromatography (ethyl acetate: methyl alcohol=40:1 ~ 8:1), obtains brown solid, 110mg, purity: 97%, yield: 32%.LC-MS(ESI):m/z500(M+H) +； 1H NMR(400MHz,CDCl 3)δppm 2.33(s,6H),2.65(s,6H),3.17-3.19(d,2H,J＝6Hz),3.89(s,3H),3.99(s,3H),6.22-6.26(d,1H,J＝15.2Hz),6.78(s,1H),6.93(m,1H),7.20(m,1H),7.30(s,1H),7.67(m,1H),8.06-8.08(m,1H),8.36-8.37(d,1H,J＝5.2Hz),8.65(s,1H),9.01(s,1H),9.76(s,1H).
Embodiment 3:2-{4-(1-methyl-N, N-dimethyl amido ethyl) amido-2-methoxyl group-5-(3 '-N, N-dimethylaminomethyl-acryloyl)-amido } preparation of anilino-4-(1-methyl-3-indyl) pyrimidine (compound 103)
2-{4-(1-methyl-N, N-dimethyl amido ethyl) amido-2-methoxyl group-5-nitro } preparation of anilino-4-(1-methyl-3-indyl) pyrimidine
By 2-(the fluoro-2-methoxyl group of 4--5-nitro) anilino-4-(1-methyl-3-indyl) pyrimidine (intermediate A) (150g, 0.381mol) be dissolved in methyl-sulphoxide (3L), in stirred at ambient temperature, add N, N, N-trimethylammonium quadrol (55g, 0.534mol) and N, N,-diisopropyl ethyl amine (123g, 0.953mol), be heated to 86 DEG C afterwards, stirring reaction three hours.LCMS detection reaction is complete.Stopped reaction, is cooled to room temperature, is slowly added by reaction solution in the frozen water (10L) that stirred, separates out a large amount of orange solid, suction filtration, filtration cakes torrefaction, obtain solid 170g, purity: 98%, yield: 94%.LC-MS(ESI):m/z 476(M+H) +。
2-{4-(1-methyl-N, N-dimethyl amido ethyl) amido-2-methoxyl group-5-amido } preparation of anilino-4-(1-methyl-3-indyl) pyrimidine (intermediate C)
By 2-{4-(1-methyl-N, N-dimethyl amido ethyl) amido-2-methoxyl group-5-nitro } anilino-4-(1-methyl-3-indyl) pyrimidine (170g, 0.357mol) be dissolved in ethanol (770ml) and water (260ml), in stirred at ambient temperature, add ammonium chloride (9.6g, 0.179mol), be heated to 85 DEG C afterwards, add reduced iron powder (90g, 1.609mol), stirring reaction eight hours in batches.LCMS detection reaction is complete.Stopped reaction, is cooled to room temperature, suction filtration, a small amount of washing with alcohol filter cake, and filtrate reduced in volume, obtains beige solid, through methylene dichloride and water making beating purifying, obtains gray solid 140g, purity: 98%, yield: 88%.LC-MS(ESI):m/z 446(M+H) +。
(E) preparation of-4-dimethyl amido-2-butylene acyl chloride hydrochloride (intermediate D)
By (E)-4-dimethyl amido-2-butylene acid hydrochloride (450mg, 2.69mmol) be dissolved in tetrahydrofuran (THF) (5ml), add two N, dinethylformamide, stir under ice bath, drip oxalyl chloride (320mg, 2.47mmol), stirring reaction 2 hours at 40 DEG C afterwards, gained solution sealing cooling is stand-by.
2-{4-(1-methyl-N, N-dimethyl amido ethyl) amido-2-methoxyl group-5-(3 '-N, N-dimethylaminomethyl-acryloyl)-amido } preparation of anilino-4-(1-methyl-3-indyl) pyrimidine (compound 103)
By 2-{4-(1-methyl-N, N-dimethyl amido ethyl) amido-2-methoxyl group-5-amido } anilino-4-(1-methyl-3-indyl) pyrimidine (intermediate C) (400mg, 0.898mmol) be dissolved in N-Methyl pyrrolidone (2ml), stir under ice bath, drip the intermediate solution D obtained by previous step, spend the night in 30 DEG C of stirring reactions afterwards.LCMS detection reaction is complete.Add 10% aqueous sodium hydroxide solution, pH is adjusted to about 10, separate out a large amount of solid, suction filtration, a small amount of water washing filter cake, filtration cakes torrefaction, obtains gray solid 480mg, purity: 99%, yield: 96%.LC-MS(ESI):m/z 557(M+H) +； 1H NMR(400MHz,CDCl 3)δppm 2.26-2.29(m,12H),2.70(s,3H),2.89(t,2H),3.13-315(t,2H),3.88(s,3H),4.01(s,3H),6.19-6.23(d,1H,J＝15.2Hz),6.79(s,1H),6.95-6.99(d,1H,J＝15.2Hz),7.19-7.20(d,1H,J＝5.2Hz),7.38-7.39(d,1H,J＝6.8Hz),7.71(s,1H),8.05-8.07(t,1H),8.37-8.38(d,1H,J＝5.2Hz),9.11(s,1H),9.83(s,1H),10.00(s,1H)。
Embodiment 4:2-{4-(1-methyl-N, N-dimethyl amido ethyl) amido-2-methoxyl group-5-(E)-crotonoyl amido } preparation of anilino-4-(1-methyl-3-indyl) pyrimidine (compound 104)
By 2-{4-(1-methyl-N, N-dimethyl amido ethyl) amido-2-methoxyl group-5-amido } anilino-4-(1-methyl-3-indyl) pyrimidine (intermediate C) (150mg, 0.337mmol) be dissolved in tetrahydrofuran (THF) (5ml) and N, in dinethylformamide (1ml), add (E)-2-butylene acid (35mg, 0.404mmol) and N, N-diisopropyl ethyl amine (174mg, 1.348mmol), stir under ice bath, add 2-(7-azo benzotriazole)-N in batches, N, N', N'-tetramethyl-urea phosphofluoric acid ester (HATU) (154mg, 0.404mmol), 3 hours are reacted in stirred at ambient temperature.LCMS detection reaction is complete.Stopped reaction, adds a small amount of shrend and goes out, and decompression steams tetrahydrofuran (THF), is dropped in the water that stirred by resistates, separates out a large amount of solid, suction filtration, a small amount of water washing filter cake, dry, obtains brown solid, 138mg, purity: 98%, yield: 80%.LC-MS(ESI):m/z 514(M+H) +； 1H NMR(400MHz,MeOD)δppm1.96-1.98(d,3H,J＝6.8Hz),2.72(s,3H),2.85(s,6H),3.25(m,2H),3.47(m,2H),3.89(s,3H),4.00(s,3H),6.17-6.21(d,1H,J＝15.2Hz),6.95(s,1H),7.08(m,1H),7.21(m,3H),7.44(m,1H),8.11(s,1H),8.25-8.26(d,1H,J＝5.2Hz),8.34-8.35(d,1H,J＝7.6Hz),8.58(s,1H)。
Embodiment 5:2-{4-(1-methyl-N, N-dimethyl amido ethyl) amido-2-methoxyl group-5-(E)-positive amylene amide group } preparation of anilino-4-(1-methyl-3-indyl) pyrimidine (compound 105)
By 2-{4-(1-methyl-N, N-dimethyl amido ethyl) amido-2-methoxyl group-5-amido } anilino-4-(1-methyl-3-indyl) pyrimidine (intermediate C) (150mg, 0.337mmol) be dissolved in tetrahydrofuran (THF) (5ml) and N, in dinethylformamide (1ml), add (E)-2-pentenoic acid (153mg, 1.17mmol) and N, N-diisopropyl ethyl amine (153mg, 1.17mmol), stir under ice bath, add 2-(7-azo benzotriazole)-N in batches, N, N', N'-tetramethyl-urea phosphofluoric acid ester (HATU) (155mg, 0.404mmol), 3 hours are reacted in stirred at ambient temperature.LCMS detection reaction is complete.Reaction solution is dropped in the water that stirred, separates out a large amount of gray solid, suction filtration, filtration cakes torrefaction, obtain gray solid product 140mg, content 96%, yield: 79%.LC-MS(ESI):m/z 527(M+H) +； 1H NMR(400MHz,MeOD)δppm 1.15(s,3H),1.36-1.37(m,3H),2.33(t,2H),2.72(m,2H),2.86(s,6H),3.47(t,2H),3.90(s,3H),4.01(s,3H),6.15-6.18(d,1H,J＝15.2Hz),6.95(s,1H),7.20-7.22(m,4H),7.44-7.46(m,1H),8.12(s,1H,),8.26-8.27(d,1H,J＝5.2HZ),8.35-8.37(d,1H,J＝7.2HZ)8.60(s,1H)。
Embodiment 6:2-{4-(1-methyl-N, N-dimethyl amido ethyl) amido-2-methoxyl group-5--butynamide base } preparation of anilino-4-(1-methyl-3-indyl) pyrimidine (compound 106)
By 2-{4-(1-methyl-N, N-dimethyl amido ethyl) amido-2-methoxyl group-5-amido } anilino-4-(1-methyl-3-indyl) pyrimidine (intermediate C) (150mg, 0.337mmol) be dissolved in tetrahydrofuran (THF) (5ml) and N, in dinethylformamide (1ml), add tetrolic acid (153mg, 1.17mmol) and N, N-diisopropyl ethyl amine (153mg, 1.17mmol), stir under ice bath, add 2-(7-azo benzotriazole)-N in batches, N, N', N'-tetramethyl-urea phosphofluoric acid ester (HATU) (155mg, 0.404mmol), 3 hours are reacted in stirred at ambient temperature.LCMS detection reaction is complete.Reaction solution is dropped in the water that stirred, separates out a large amount of gray solid, suction filtration, filtration cakes torrefaction, obtain gray solid, 70mg, purity: 96%, yield: 41%.LC-MS(ESI):m/z 511(M+H) +； 1H NMR(400MHz,MEOD)δppm2.07(s,3H),2.68-2.74(m,9H),2.98(m,2H),3.30(m,2H,),3.92(s,3H),3.97(s,3H),6.95(s,1H),7.27(m,3H),7.46(s,1H),8.28(m,3H)8.88(s,1H)。
Embodiment 7:2-{4-(1-methyl-N, N-dimethyl amido ethyl) amido-2-methoxyl group-5-pentyne amide group } preparation of anilino-4-(1-methyl-3-indyl) pyrimidine (compound 107)
By 2-{4-(1-methyl-N, N-dimethyl amido ethyl) amido-2-methoxyl group-5-amido } anilino-4-(1-methyl-3-indyl) pyrimidine (intermediate C) (150mg, 0.337mmol) be dissolved in tetrahydrofuran (THF) (5ml) and N, in dinethylformamide (1ml), add valerylene acid (170mg, 1.18mmol) and N, N-diisopropyl ethyl amine (153mg, 1.17mmol), stir under ice bath, add 2-(7-azo benzotriazole)-N in batches, N, N', N'-tetramethyl-urea phosphofluoric acid ester (HATU) (155mg, 0.404mmol), 3 hours are reacted in stirred at ambient temperature.LCMS detection reaction is complete.Reaction solution is dropped in the water that stirred, separates out a large amount of gray solid, suction filtration, filtration cakes torrefaction, obtain gray solid, 65mg, purity: 98%, yield: 41%.LC-MS(ESI):m/z 526(M+H) +； 1H NMR(400MHz,MEOD)δppm 1.18(t,3H),2.07(q,2H),2.35(s,6H),2.74(s,3H),2.95(m,2H),3.20(m,2H,),3.90(s,3H),3.87(s,3H),6.92(s,1H),7.30(m,3H),7.40(s,1H),8.30(m,3H)8.85(s,1H)。
Embodiment 8:2-{4-N, N-dimethyl amine base oxethyl-2-methoxyl group-5-(3 '-N, N-dimethylaminomethyl-acryloyl)-amido } preparation of anilino-4-(1-methyl-3-indyl) pyrimidine (compound 108)
2-{4-N, N-dimethyl amine base oxethyl-2-methoxyl group-5-nitro } preparation of anilino-4-(1-methyl-3-indyl) pyrimidine
Intermediate A (1.4g, 3.55mmol) is dissolved in methyl-sulphoxide (5ml), adds N, N-dimethyl amido ethanol (20mL) and cesium carbonate (1.8g, 5.52mmol), in 60 DEG C of stirring reactions 5 hours.LCMS detection reaction is complete.Be chilled to room temperature, dropped in the water that stirred by reaction solution, separate out a large amount of solid, suction filtration, 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 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-amido } preparation of anilino-4-(1-methyl-3-indyl) pyrimidine
By 2-{4-N, N-dimethyl amine base oxethyl-2-methoxyl group-5-nitro } anilino-4-(1-methyl-3-indyl) pyrimidine (1.1g, 2,38mmol) be dissolved in methyl alcohol (5ml), add 10%Pd/C (50mg), with hydrogen exchange three times, stirring reaction about 2 hours under 40Psi hydrogen-pressure afterwards.LCMS detection reaction is complete.Filtering palladium charcoal, filtrate reduced in volume is dry, obtains gray solid, 920mg, purity: 96%, yield: 90%.LC-MS(ESI):m/z 433(M+H) +。
2-{4-N, N-dimethyl amine base oxethyl-2-methoxyl group-5-(3 '-N, N-dimethylaminomethyl-acryloyl)-amido } preparation of anilino-4-(1-methyl-3-indyl) pyrimidine (compound 108)
By 2-{4-N, N-dimethyl amine base oxethyl-2-methoxyl group-5-amido } anilino-4-(1-methyl-3-indyl) pyrimidine (200mg, 0.462mmol) with (E)-4-dimethyl amido-2-butylene acyl chloride hydrochloride (intermediate D) (92mg, 0.554mmol) be dissolved in tetrahydrofuran (THF) (6ml) and N, in dinethylformamide (1.0ml), N is added in reaction solution, N-diisopropyl ethyl amine (209mg, 1.617mmol), stir under ice bath and add 2-(7-azo benzotriazole)-N in batches, N, N', N'-tetramethyl-urea phosphofluoric acid ester (HATU) (211mg, 0.554mmol) in reaction solution, 3 hours are reacted in stirred at ambient temperature.LCMS detection reaction is complete.Reaction solution drops in the water that stirred, and separates out a large amount of solid, suction filtration crude product, content 90%, crosses reversed-phase column purifying and obtains brown solid, 7mg, purity: 95%, yield: 3%.LC-MS(ESI):m/z 544(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),6.705-6.743(d,1H,J＝15.2Hz),6.939(s,1H),7.146–7.206(m,3H),7.515-7.535(m,1H),7.862(m,1H),8.296-8.309(m,2H),8.566(m,1H),8.883(m,1H),9.752(m,1H)。
Embodiment 9:2-{4-(1-methyl-N, N-dimethyl amido ethyl) amido-2-methoxyl group-5-(3 '-N, N-dimethylaminomethyl-acryloyl)-amido anilino-4-(1H-benzoglyoxaline-1-base) pyrimidine compound 109) preparation
By 2-{4-(1-methyl-N, N-dimethyl amido ethyl) amido-2-methoxyl group-5-amido } anilino-4-(1H-benzoglyoxaline-1-base) pyrimidine (215mg, 0.5mmol) be dissolved in N-Methyl pyrrolidone (2ml), stir under ice bath, drip intermediate solution D, spend the night in 30 DEG C of stirring reactions afterwards.LCMS detection reaction is complete.Add 10% aqueous sodium hydroxide solution, pH is adjusted to about 10, separate out a large amount of solid, suction filtration, a small amount of water washing filter cake, filtration cakes torrefaction, obtains gray solid 265mg, purity: 99%, yield: 96%.LC-MS(ESI):m/z 544(M+H) +； 1H NMR(400MHz,CDCl 3)δppm 2.30-2.32(12H),2.70(s,3H),2.89(t,2H),2.98(d,2H),3.13-315(t,2H),3.88(s,3H),6.18-6.22(d,1H,J＝15.2Hz),6.95-6.99(dt,1H,J＝15.2Hz),7.25-7.26(d,1H,J＝5.2Hz),7.40-7.41(d,1H,J＝6.8Hz),7.75(s,1H),8.06-8.08(t,1H),8.10(s,1H),8.41-8.42(d,1H,J＝5.2Hz),9.52(s,1H),10.11(s,1H)。
Embodiment 10: the compounds of this invention is to the external zymetology determination of activity of T790M EGFR
Utilize the EGFR-T790M kinase activity restraining effect of FRET technology to the compounds of this invention (compound 101-109 prepared by embodiment 1-9) to measure, adopt Life technologies company Z'-LYTE tMkinase Assay Kits (PV3193), and select the EGFR-T790M kinases solution in Tyrosine 4Peptide to carry out active determination test (the results are shown in Table 2).Testing sequence is as follows:
1. reagent prepares: carried out dissolving and being formulated into desired concn by the reagent in test kit;
2. compound solution preparation: the compounds of this invention solution serial dilution of 0.15mM is reached each concentration needed for test
3. kinases dissolves: is dissolved by EGFR-T790M kinases 96 orifice plates, and carry out gradient then the test kinase phosphoric acid kinase concentration that turns to about 17% ~ 36% as the concentration of use when testing.
4. kinase activity test: by the reagent prepared in kinases and 1,2 steps in order mixed being incorporated under room temperature (20-25 DEG C) condition add stop buffer after incubation 30s, detect by multi-functional microplate reader after the 30s that vibrates.
5. pair detected result carries out data processing, draws inhibiting rate and IC 50.
Table 2 compound is to T790M/L858R EGFR inhibit activities
Sample number into spectrum IC50(μM)
101 0.003
102 0.027
103 0.001
104 0.11
105 35.0
106 0.043
107 0.15
108 0.032
109 0.079
Embodiment 11: the compounds of this invention measures the inhibit activities of two kinds of lung cancer cell lines
1. test materials
1.1 cell strain
Human lung adenocarcinoma cell NCI-H1975 (EGFR-T790M high expression level), Non-small cell lung carcinoma cell A549 (EGFR high expression level).
1.2 main agents: DMEM in high glucose substratum, HyClone company, lot number NXJ0709,500ml/ bottle; Foetal calf serum, HyClone company, lot number NXC0582,500ml/ bottle; Tetrazolium bromide, sigma company, lot number MKBH7489V, 1g/ bottle; Methyl-sulphoxide, Chemical Reagent Co., Ltd., Sinopharm Group, lot number 20120705,500ml/ bottle; Trypsinase, prosperous Bioisystech Co., Ltd of Beijing ancient cooking vessel state, lot number 04D10151,25g/ bottle.
1.3 key instruments: CJ-1F type Medical purification worktable (center numbering 058, Suzhou Feng Shi laboratory animal equipment company limited); Table-type low-speed whizzer (center numbering 101, Kai Da industry development company limited of Hunan Province); DMIL type inverted microscope (center numbering 027, Leica); 3111 type CO2 incubators (center numbering 147, Thermo); MR-96A microplate reader (center numbering 007, Shenzhen steps auspicious); Aseptic syringe filter (millipore).
2. test method
2.1 cell cultures and inoculation
Tumor cell line 37 DEG C, under the saturated humidity environment of 5%CO2, containing cultivating in the DMEM in high glucose perfect medium of 10% foetal calf serum, going down to posterity.With 0.25% tryptic digestive juice digestion during inoculation, add cell culture medium and blow and beat uniformly cell suspension, cell is made 5 × 10 4the cell suspension of/ml, every hole 100 μ l is inoculated in 96 orifice plates.
2.2 trial-product preparation and CAs
Take a certain amount of the compounds of this invention, be mixed with the maximum concentration working fluid of 5000 μ g/ml with DMEM perfect medium, degerming with 0.22 μm of aseptic pin type metre filter, be then mixed with the working fluid of 1500,500,150,50,15 μ g/ml successively.Cis-platinum (DDP) DMEM perfect medium is mixed with the working fluid that concentration is 50,15,5,1.5,0.75,0.15 μ g/ml.After cell attachment, use the working fluid containing different concns trial-product and cis-platinum (DDP) instead, each concentration establishes 3 multiple holes.After after dosing 48 hours, every hole adds MTT solution, and (substratum is made into 5mg/ml, keep in Dark Place after filtration) 20 μ l, by supernatant liquor sucking-off after 4 hours, every hole adds MTT lysate DMSO150 μ l, concussion treats that Formazan dissolves completely, and microplate reader 492nm measures OD value, through the IC50 (nM) obtained in following table that converts.
Table 3 compound is to proliferation of lung cancer cells restraining effect
A549 NCI-H1975
Compound number IC50(nM) IC50(nM)
101 1.7 0.3
103 0.1 0.25
108 5.0 0.8

Claims (9)

1. have EGF-R ELISA EGFR inhibitor and the pharmacy acceptable salt thereof of general structure (I), its structure is a class α, beta-unsaturated carboxylic acid amides,
Wherein, B represents double bond or triple bond, and Ar is heterocyclic arene;
R 1for
in any one;
R 2for any one in C1-C6 alkyl, N, N-dimethylaminomethyl, pyrrolidyl-1-methyl, piperidyl-1-methyl and morpholinyl-1-methyl.
2. EGF-R ELISA EGFR inhibitor according to claim 1 and pharmacy acceptable salt thereof, is characterized in that, described Ar is
Wherein, X is the one in H, F, Cl and Br.
3. EGF-R ELISA EGFR inhibitor according to claim 1 and 2 and pharmacy acceptable salt thereof, is characterized in that, the compound of described general structure (I) comprises the one in numbering 101-109.
4. prepare the method for EGF-R ELISA EGFR inhibitor according to any one of claim 1-3 and pharmacy acceptable salt thereof for one kind; it is characterized in that comprising the steps: that starting raw material is obtained by reacting intermediate II through multistep conventional chemical; intermediate II is successively through hydrogenating reduction, acidylate; or successively through nucleophilic substitution, hydrogenating reduction, acidylate, finally obtain corresponding general formula (I) compound.
5. a pharmaceutical composition, is characterized in that, comprises the EGF-R ELISA EGFR inhibitor according to any one of claims 1 to 3 and pharmacy acceptable salt thereof, and pharmaceutically acceptable carrier.
6. pharmaceutical composition according to claim 5, is characterized in that, described pharmaceutical composition is the form of tablet, capsule, granule, sprays or injection.
7. the pharmaceutical composition according to claim 5 or 6, is characterized in that, described pharmaceutically acceptable carrier be selected from weighting agent, disintegrating agent, tackiness agent and lubricant one or more.
8. the EGF-R ELISA EGFR inhibitor according to any one of claims 1 to 3 and pharmacy acceptable salt thereof are as the purposes of protein tyrosine kinase inhibitor;
Preferably, described protein tyrosine kinase inhibitor is epidermal growth factor receptor inhibitor;
More preferably, described epidermal growth factor receptor inhibitor is the inhibitor of the EGF-R ELISA to T790M variation.
9. the EGF-R ELISA EGFR inhibitor according to any one of claims 1 to 3 and pharmacy acceptable salt thereof or the purposes of the pharmaceutical composition according to any one of claim 5 to 7 in the medicine for the preparation for the treatment of EGF-R ELISA overexpression relative disease;
Preferably, described EGF-R ELISA overexpression relative disease is selected from one or more in kidney, lung cancer, prostate cancer, carcinoma of the pancreas, mammary cancer and glioma.
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