CN104844580A - Miazines compound, preparation method and medical application thereof - Google Patents

Miazines compound, preparation method and medical application thereof Download PDF

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CN104844580A
CN104844580A CN201510184234.0A CN201510184234A CN104844580A CN 104844580 A CN104844580 A CN 104844580A CN 201510184234 A CN201510184234 A CN 201510184234A CN 104844580 A CN104844580 A CN 104844580A
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base
group
amido
phenyl
pyrimidine
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CN104844580B (en
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赖宜生
杨凤娇
马骏
罗明昊
张姗
张奕华
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China Pharmaceutical University
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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
    • C07D403/14—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 three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • 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
    • 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

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Abstract

The invention belongs to the medicine field, and concretely relates to a miazines compound having a structure of a formula (1), its pharmaceutically acceptable salt, a preparation method and an application of the compound for preparing an antitumor drug. The pharmacological experiment result shows that the compound has good inhibition effect to an epidermal growth factor acceptor (EGFR) and its mutant, can inhibit propagation of a plurality of tumor cells, and can be taken as an EGFR inhibitor used for preparing the antitumor drug.

Description

Pyrimidines, its preparation method and medicinal use
Technical field
The invention belongs to pharmaceutical field, be specifically related to a kind of pyrimidines, its preparation method and medicinal use, particularly prepare the application in antitumor drug.
Background technology
Protein tyrosine kinase is the important regulating and controlling factor in intracellular signal transduction pathway, and in known 518 kinds of protein kinases, 90 kinds belong to protein tyrosine kinase.It can catalysis ATP transfer on the tyrosine residues of substrate protein by γ-phosphoric acid, kinases is impelled to be transformed into activated conformation by inactive conformation, thus activation downstream signaling molecule, the multiple biological effect of further trigger cell, play an important role (Oncogene in the processes such as Growth of Cells, propagation, differentiation, 2000,19 (49): 5548-5557).In normal cell, the catalytic activity of protein tyrosine kinase is subject to strict regulation and control, but when its gene is undergone mutation or other makes a variation, therefore the function of Tyrosylprotein kinase just can lack of proper care, thus cause cell proliferation to regulate getting muddled, and then the generation of induced tumor and development.Therefore, protein tyrosine kinase has become the popular target of tumor cells targeted therapy in recent years.
EGF-R ELISA (EGFR) is the important protein tyrosine kinase ErbB family of a class, and this family comprises erbB1 (EGFR/HER1), erbB2 (HER2), erbB3 (HER3), erbB4 (HER4) four members.When after the binding of receptor and ligand outside EGFR born of the same parents, cause homology or Heterodimerization, then dimer generation phosphorylation, Bao Nei Tyrosylprotein kinase district is caused to be activated and in conjunction with an ATP molecule, impel the specific tyrosine residues phosphorylation of intracellular region, identify successively subsequently and combine the adaptor protein (as Cbl, Shc, Grb2, Crk etc.) with PTB structural domain or SH2 structural domain, and then activating downstream signaling molecule.EGFR can be undertaken regulating and controlling by many signal paths cellular function such as Ras/MAPK, c-Src and PI3K/Akt (EMBO J, 2000,19 (13): 3159-3167).The generation of the kinds of tumors such as the dysfunction of EGFR and lung cancer, mammary cancer, colorectal carcinoma, cancer of the stomach, kidney, ovarian cancer, prostate cancer, glioblastoma multiforme develops closely related (Clin CancerRes, 2006,12 (18): 5268-5272).Therefore, targeting EGFR antitumour drug object depth is paid close attention to by people in recent years.
First-generation small molecule EGFR inhibitor mainly comprises Gefitinib (gefitinib), Tarceva (erlotinib), lapatinibditosylate (lapatinib) and Conmana (icotinib) etc.Such reversible EGFR inhibitor, mainly by the ATP binding pocket of competitive binding in kinase region, stops ATP and EGFR to combine, thus suppresses its phosphorylation, retardance signal transduction, and then inducing death of neoplastic cells.These medicines curative effect in the tumours such as clinical treatment nonsmall-cell lung cancer, mammary cancer and carcinoma of the pancreas is given prominence to.But, clinical study shows, just there is EGFR bis-sudden changes and/or Met gene amplification, HGF overexpression etc. in Partial tumors patient, thus produce acquired resistance (J Biomed Biotechnol, 2011:165214) after accepting such pharmacological agent for some time.Wherein, the T790M sudden change occurring in EGFR kinase region is considered to main resistance mechanism, and this sudden change can hinder inhibitor to be combined with kinase activity pocket, and strengthens combination (the N Engl J Med of ATP and active pocket, 2005,352 (8): 786-792; Proc Natl Acad Sci USA, 2008,105 (6): 2070-2075).For this reason, people have carried out irreversible EGFR covalency inhibitor research and development.
Mainly there is Michael addition and covalent attachment by the Cys797 sulfydryl of electrophilic group and EGFR kinase activity location proximate in irreversible EGFR inhibitor, thus occupies the binding pocket of ATP, stops kinase activator.Have multiple irreversible EGFR covalency inhibitor such as dacomitinib, neratinib, pelitinib, CO-1686 and AZD9291 at present and enter clinical study, wherein afatinib is gone on the market in July, 2013 by U.S. FDA approval, is used for the treatment of Metastatic Nsclc.
Although irreversible inhibitor and target protein generation covalent attachment usually can strengthen drug effect and extend action time, can be easy to by force, with the nucleophilic group of non-target protein, non-specific covalent attachment occurs when its Electron Affinities is crossed, thus produce phenomenon of missing the target.In addition, when irreversible covalent attachment occurs for medicine and substrate protein, the haptenization of protein can be caused, thus cause autoimmune response (Chem Res Toxicol, 2008,21 (1): 84-92; Expert Opin Drug Discov, 2012,7 (7): 561-581).
It is worth mentioning that, Taunton group confirms containing alpha-cyano-α, reversibility covalent attachment can be there is in the compound of beta-unsaturated carbonyl with p90 ribosome S 6 protein kinase (RSK), therefore untoward reaction (the Nat Chem Biol overcoming or reduce the initiation of irreversible covalent drug is contributed to, 2012,8 (5): 471-476).
Summary of the invention
The invention discloses a kind of pyrimidines, its steric isomer or its pharmacy acceptable salt and medicinal use.The pharmacological results shows, this compounds his-and-hers watches skin growth factor acceptor (EGFR) and mutant thereof have good inhibit activities, and can suppress the propagation of kinds of tumor cells.Therefore can be used as EGFR kinase inhibitor for the preparation of antitumor drug.
The present invention open pyrimidines shown in formula (I), its steric isomer or its pharmacy acceptable salt:
Wherein:
R 1represent C 1-C 8alkyl, C 3-C 6cycloalkyl, C 5-C 10aryl or C 5-C 10aromatic heterocyclic, described alkyl, cycloalkyl, aryl or aromatic heterocyclic are optionally monosubstituted to five replacements by following identical or not identical substituting group, and described substituting group is selected from: halogen, cyano group, nitro, trifluoromethyl, C 1-C 8alkoxyl group, NR 3r 4, C (O) NR 3r 4or C (O) OR 5;
R 2represent hydrogen, halogen, NR 3r 4or OR 5;
R 3and R 4may be the same or different, certainly optional: hydrogen, C 1-C 8alkyl or R 3and R 45-7 unit heterocyclic group is formed together with the nitrogen-atoms connected with them, this heterocyclic group optionally comprises one or more other heteroatoms being selected from O, S or N, and this heterocyclic group is optionally monosubstituted to five replacements by following identical or different substituting group, and described substituting group is selected from: halogen, cyano group, nitro, hydroxyl, trifluoromethyl, amino, C 1-C 8alkyl or C 1-C 8alkoxyl group;
R 5represent hydrogen, C 1-C 8alkyl, C 3-C 6cycloalkyl, C 5-C 10aryl or C 5-C 10aromatic heterocyclic, described alkyl, cycloalkyl, aryl or aromatic heterocyclic are optionally monosubstituted to five replacements by following identical or not identical substituting group, and described substituting group is selected from: halogen, cyano group, nitro, hydroxyl, trifluoromethyl, amino, C 1-C 8alkyl or C 1-C 8alkoxyl group.
Further, the pyrimidines shown in general formula (I), its steric isomer or its pharmacy acceptable salt, is characterized in that:
R 1represent tertiary amyl, cyclopropyl, phenyl, 2-p-methoxy-phenyl, 4-trifluoromethyl, pyrazolyl, pyrryl, imidazolyl, furyl, pyridyl.
R 2represent N, N, N-trimethylammonium quadrol base, N methyl piperazine base, morpholinyl.
Specifically, the pyrimidines shown in general formula (I), its steric isomer or its pharmacy acceptable salt are selected from following compounds:
N-[2-[[2-(dimethylin) ethyl] (methyl) amido]-4-methoxyl group-5-[[4-(1-skatole-3-base) pyrimidine-2-base] amido] phenyl]-2-cyano group-3-(pyrroles-2-base) acrylamide (LY-1);
N-[2-[[2-(dimethylin) ethyl] (methyl) amido]-4-methoxyl group-5-[[4-(1-skatole-3-base) pyrimidine-2-base] amido] phenyl]-2-cyano group-3-(imidazoles-2-base) acrylamide (LY-2);
N-[2-[[2-(dimethylin) ethyl] (methyl) amido]-4-methoxyl group-5-[[4-(1-skatole-3-base) pyrimidine-2-base] amido] phenyl]-2-cyano group-3-(furans-2-base) acrylamide (LY-3);
N-[2-[[2-(dimethylin) ethyl] (methyl) amido]-4-methoxyl group-5-[[4-(1-skatole-3-base) pyrimidine-2-base] amido] phenyl]-2-cyano group-3-(2-p-methoxy-phenyl) acrylamide (LY-4);
N-[2-[[2-(dimethylin) ethyl] (methyl) amido]-4-methoxyl group-5-[[4-(1-skatole-3-base) pyrimidine-2-base] amido] phenyl]-2-cyano group-3-(pyridine-2-base) acrylamide (LY-5);
N-[2-[[2-(dimethylin) ethyl] (methyl) amido]-4-methoxyl group-5-[[4-(1-skatole-3-base) pyrimidine-2-base] amido] phenyl]-2-cyano group-3-(pyrazole-3-yl) acrylamide (LY-6);
N-[2-[[2-(dimethylin) ethyl] (methyl) amido]-4-methoxyl group-5-[[4-(1-skatole-3-base) pyrimidine-2-base] amido] phenyl]-2-cyano group-3-(imidazol-4 yl) acrylamide (LY-7);
N-[2-[[2-(dimethylin) ethyl] (methyl) amido]-4-methoxyl group-5-[[4-(1-skatole-3-base) pyrimidine-2-base] amido] phenyl]-2-cyano group-3-Phenyl Acrylamide (LY-8);
N-[2-[[2-(dimethylin) ethyl] (methyl) amido]-4-methoxyl group-5-[[4-(1-skatole-3-base) pyrimidine-2-base] amido] phenyl]-2-cyano group-3-cyclopropyl acrylamide (LY-9);
N-[2-[[2-(dimethylin) ethyl] (methyl) amido]-4-methoxyl group-5-[[4-(1-skatole-3-base) pyrimidine-2-base] amido] phenyl]-2-cyano group-3-tertiary amyl acrylamide (LY-10);
N-[2-(4-methylpiperazine-1-yl)-4-methoxyl group-5-[[4-(1-skatole-3-base) pyrimidine-2-base] amido] phenyl]-2-cyano group-3-(pyrroles-2-base) acrylamide (LY-11);
N-[2-(4-methylpiperazine-1-yl)-4-methoxyl group-5-[[4-(1-skatole-3-base) pyrimidine-2-base] amido] phenyl]-2-cyano group-3-(imidazoles-2-base) acrylamide (LY-12);
N-[2-(4-methylpiperazine-1-yl)-4-methoxyl group-5-[[4-(1-skatole-3-base) pyrimidine-2-base] amido] phenyl]-2-cyano group-3-Phenyl Acrylamide (LY-13);
N-[2-(4-methylpiperazine-1-yl)-4-methoxyl group-5-[[4-(1-skatole-3-base) pyrimidine-2-base] amido] phenyl]-2-cyano group-3-(pyridine-2-base) acrylamide (LY-14);
N-[2-(4-methylpiperazine-1-yl)-4-methoxyl group-5-[[4-(1-skatole-3-base) pyrimidine-2-base] amido] phenyl]-2-cyano group-3-(4-trifluoromethyl) acrylamide (LY-15);
N-[2-(4-methylpiperazine-1-yl)-4-methoxyl group-5-[[4-(1-skatole-3-base) pyrimidine-2-base] amido] phenyl]-2-cyano group-3-(2-p-methoxy-phenyl) acrylamide (LY-16);
N-[2-(4-methylpiperazine-1-yl)-4-methoxyl group-5-[[4-(1-skatole-3-base) pyrimidine-2-base] amido] phenyl]-2-cyano group-3-(furans-2-base) acrylamide (LY-17);
N-[2-(4-methylpiperazine-1-yl)-4-methoxyl group-5-[[4-(1-skatole-3-base) pyrimidine-2-base] amido] phenyl]-2-cyano group-3-(pyrroles-2-base) acrylamide (LY-18);
N-[2-(morpholinyl)-4-methoxyl group-5-[[4-(1-skatole-3-base) pyrimidine-2-base] amido] phenyl]-2-cyano group-3-(imidazoles-2-base) acrylamide (LY-19);
N-[2-(morpholinyl)-4-methoxyl group-5-[[4-(1-skatole-3-base) pyrimidine-2-base] amido] phenyl]-2-cyano group-3-(furans-2-base) acrylamide (LY-20);
N-[2-(morpholinyl)-4-methoxyl group-5-[[4-(1-skatole-3-base) pyrimidine-2-base] amido] phenyl]-2-cyano group-3-(2-p-methoxy-phenyl) acrylamide (LY-21);
N-[2-(morpholinyl)-4-methoxyl group-5-[[4-(1-skatole-3-base) pyrimidine-2-base] amido] phenyl]-2-cyano group-3-(pyridine-2-base) acrylamide (LY-22);
N-[2-(morpholinyl)-4-methoxyl group-5-[[4-(1-skatole-3-base) pyrimidine-2-base] amido] phenyl]-2-cyano group-3-(pyrazole-3-yl) acrylamide (LY-23);
N-[2-(morpholinyl)-4-methoxyl group-5-[[4-(1-skatole-3-base) pyrimidine-2-base] amido] phenyl]-2-cyano group-3-(imidazol-4 yl) acrylamide (LY-24);
N-[2-(morpholinyl)-4-methoxyl group-5-[[4-(1-skatole-3-base) pyrimidine-2-base] amido] phenyl]-2-cyano group-3-cyclopropyl acrylamide (LY-25).
The compound numbers related in pharmacological evaluation is below equal to the compound herein corresponding to code name.
Another object of the present invention is to provide the preparation method of compound shown in general formula (I), it is characterized in that: 2-nitro-5-fluoroanisole obtains the fluoro-5-N-methyl-p-nitroaniline 2 of 2-methoxyl group-4-through reducing obtained 2-methoxyl group-4-fluoroaniline 1,1 through nitrated.The coupling under aluminum chloride effect of 2,4-dichloro pyrimidine and N-skatole obtains 1-methyl-3-(2-chloropyrimide-4-base) indoles 3.3 and 2 react obtained 1-methyl-3-[[2-(the fluoro-5-nitro of 2-methoxyl group-4-) anilino] pyrimidine-4-yl] indoles 4,4 obtain intermediate 5 with aminated compounds condensation, 5 through reducing obtained intermediate 6,6 obtain intermediate 7 with cyanoacetic acid condensation, and 7 obtain LY-1 ~ LY-25 with aldehyde compound condensation under the catalysis of Piperidineacetic acid; Synthetic route is as follows:
Wherein, R 1and R 2definition as claimed in claim 1.
A further object of the present invention is to provide a kind of pharmaceutical composition, and the compound any one of the claim 1-5 of the upper significant quantity for the treatment of or its pharmaceutically acceptable carrier or auxiliary material form.
Another object of the present invention is to provide the application at anti-tumor aspect of the compound or its steric isomer or its pharmacy acceptable salt with general formula (I) and the composition be made up of them, and wherein said tumour is nonsmall-cell lung cancer, mammary cancer, cancer of the stomach, the rectum cancer, liver cancer, prostate cancer, bladder cancer and ovarian cancer, tumor of head and neck or glioblastoma multiforme.
Described compound comprises the conformer of compound shown in general formula (I), optically active isomer, racemic modification, diastereomer or tautomer, and the mixture of any above-mentioned form.
Embodiment
In order to illustrate the present invention further, provide a series of embodiment below, these embodiments are illustrative completely, and they are only used for specifically describing the present invention, not should be understood to limitation of the present invention.
Embodiment 1
The preparation of 2-methoxyl group-4-fluoroaniline (1)
Add in 35mL THF by 2-nitro-5-fluoroanisole (1.00g, 5.81mmol) and 5% palladium carbon (0.62g, 0.29mmol), pass into hydrogen under room temperature and stir 5h, suction filtration, is spin-dried for solvent, obtains light yellow solid 0.80g, yield 97%.
The preparation of the fluoro-5-N-methyl-p-nitroaniline (2) of 2-methoxyl group-4-
Under ice bath, 1 (1.00g, 5.42mmol) is dissolved in the 6.50mL vitriol oil in batches, adds NaNO in batches 3(0.46g, 5.41mmol), continues stirring 4 hours, and 2%NaOH solution is adjusted neutral, and dichloromethane extraction, is spin-dried for solvent, obtains Orange red solid 0.64g, yield 64%.
The preparation of 1-methyl-3-(2-chloropyrimide-4-base) indoles (3)
Be dissolved in by 2,4-dichloro pyrimidine (1.00g, 6.71mmol) in 25mL glycol dimethyl ether, ice bath cools, and adds AlCl in batches 3(0.98g, 7.42mmol), temperature control is lower than at 10 DEG C, add N-skatole (0.83mL, 6.74mmol), remove ice bath, back flow reaction 2h, is cooled to room temperature, pours in 200mL frozen water, stir 30min, suction filtration, washing, recrystallized from acetonitrile, dry Off-white solid 0.88g, yield 54%.
The preparation of 1-methyl-3-[2-[(the fluoro-5-nitro of 2-methoxyl group-4-) anilino] pyrimidine-4-yl] indoles (4)
By 3 (0.90g, 3.71mmol), 2 (0.69g, 3.72mmol) He one hydration tosic acid (0.84g, 4.44mmol) is dissolved in 30mL sec.-amyl alcohol, backflow 2.5h, be cooled to room temperature, separate out yellow solid, suction filtration, washing with alcohol, dry yellow solid 1.23g, yield 85%.
1-methyl-3-[[2-[2-methoxyl group-4-(N, N, N '-trimethylammonium quadrol base)-5-nitro] anilino] pyrimidine-4-yl] indoles (5a) preparation
4 (0.50mg, 1.31mmol) and N, N, N '-trimethylammonium quadrol (0.16mL, 1.30mmol) adds sec-butyl alcohol and DIPEA (0.55mL, 3.22mmol), passes into N 2, backflow reaction overnight, is cooled to room temperature, suction filtration, obtains red solid 0.48g, yield 80%, mp:143 ~ 145.ESI-MS：476.4[M+H] +。
1-methyl-3-[[2-[2-methoxyl group-4-(N, N, N '-trimethylammonium quadrol base)-5-amino] anilino] pyrimidine-4-yl] indoles (6a) preparation
5a (0.50mg, 1.13mmol) and 5% palladium-carbon (0.11g, 0.06mmol) add tetrahydrofuran (THF), pass into hydrogen, room temperature reaction 4h, suction filtration, are spin-dried for filtrate and obtain yellow solid 590mg, yield 98%.
The preparation of 1-methyl-3-[[2-[2-methoxyl group-4-(N, N, N '-trimethylammonium quadrol base)-5-cyano-acetamide amido] anilino] pyrimidine-4-yl] indoles indoles (7a)
Cyanoacetic acid (190mg, 2.24mmol), EDCHCl (859mg, 4.48mmol) and 6a (0.59g, 1.12mmol) adds DMF and DIPEA (1.20mL, 6.72mmol), room temperature reaction 4h, thin up, ultrasonic agitation, suction filtration, washing and drying obtains pale solid 0.45g, yield 78%, mp:124 ~ 126 DEG C.ESI-MS：513.4[M+H] +； 1H-NMR(300MHz，DMSO-d 6)，δ(ppm)：2.21(s，6H)，2.26(t，2H，J＝6.36Hz)，2.71(s，3H)，2.92(t，2H，J＝6.38Hz)，3.86(s，3H)，3.95(s，3H)，3.96(s，2H)，7.03(s，1H)，7.17(t，1H，J＝7.47Hz)，7.25(d，1H，J＝5.46Hz)，7.27(d，1H，J＝7.86Hz)，7.56(d，1H，J＝7.8Hz)，7.90(s，1H)，8.22(d，1H，J＝7.62Hz)，8.33(d，1H，J＝5.34Hz)，8.67(s，1H)，8.99(s，1H)，10.32(s，1H).
The preparation of N-[2-[[2-(dimethylin) ethyl] (methyl) amido]-4-methoxyl group-5-[[4-(1-skatole-3-base) pyrimidine-2-base] amido] phenyl]-2-cyano group-3-(pyrroles-2-base) acrylamide (LY-1)
7 (0.03g, 0.06mmol) are dissolved in 5mL acetonitrile, add the piperidines acetic acid of pyrrole aldehyde (5.60mg, 0.06mmol) and catalytic amount, room temperature reaction 4h, adds water, and stirs, suction filtration is dry obtains orange solid 0.02g, yield 58%, mp:131 ~ 133 DEG C.ESI-MS：590.4[M+H] +； 1H-NMR(300MHz，DMSO-d 6)，δ(ppm)：2.12(s，6H)，2.27(s，2H)，2.72(s，3H)，2.98(s，2H)，3.87(s，3H)，3.95(s，3H)，6.47(s，1H)，7.12(s，2H)，7.23(s，2H)，7.37(s，2H)，7.52(d，1H，J＝7.86Hz)，7.95(s，1H)，8.15(s，1H)，8.26(d，1H，J＝7.50Hz)，8.34(d，1H，J＝4.56Hz)，8.59(s，1H)，9.18(s，1H)，10.0(s，1H)，12.01(s，1H).
Embodiment 2
The preparation of N-[2-[[2-(dimethylin) ethyl] (methyl) amido]-4-methoxyl group-5-[[4-(1-skatole-3-base) pyrimidine-2-base] amido] phenyl]-2-cyano group-3-(imidazoles-2-base) acrylamide (LY-2)
With reference to the preparation method of LY-1, obtain yellow powdery solid by 7a and imidazoles-2-formaldehyde reaction, yield 73%, mp:137 ~ 139 DEG C.ESI-MS：591.4[M+H] +； 1H-NMR(300MHz，DMSO-d 6)，δ(ppm)：2.11(s，6H)，2.28(br，2H)，2.72(s，3H)，2.99(br，2H)，3.88(s，3H)，3.90(s，3H)，7.14(br，2H)，7.24(br，2H)，8.06(br，2H)，8.26(d，1H，J＝6.93Hz)，8.34(m，1H)，8.59(s，1H)，9.19(s，1H)，10.24(br，1H).
Embodiment 3
The preparation of N-[2-[[2-(dimethylin) ethyl] (methyl) amido]-4-methoxyl group-5-[[4-(1-skatole-3-base) pyrimidine-2-base] amido] phenyl]-2-cyano group-3-(furans-2-base) acrylamide (LY-3)
With reference to the preparation method of LY-1, obtain yellow powdery solid by 7a and furans-2-formaldehyde reaction, yield 81%, mp:174 ~ 176 DEG C.ESI-MS：591.4[M+H] +； 1H-NMR(300MHz，DMSO-d 6)，δ(ppm)：2.11(s，6H)，2.45(m，2H)，2.72(s，3H)，2.99(m，2H)，3.88(s，3H)，3.91(s，3H)，6.87(m，1H)，7.14(m，2H)，7.24(m，2H)，7.46(d，1H，J＝3.54Hz)，7.52(d，1H，J＝7.98Hz)，7.99(s，1H)，8.08(s，1H)，8.21(s，1H)，8.26(d，1H，J＝8.10Hz)，8.33(d，1H，J＝5.31Hz)，8.60(s，1H)，9.16(s，1H)，10.26(s，1H).
Embodiment 4
The preparation of N-[2-[[2-(dimethylin) ethyl] (methyl) amido]-4-methoxyl group-5-[[4-(1-skatole-3-base) pyrimidine-2-base] amido] phenyl]-2-cyano group-3-(2-p-methoxy-phenyl) acrylamide (LY-4)
With reference to the preparation method of LY-1, react obtained yellow powdery solid by 7a and Benzaldehyde,2-methoxy, yield 73%, mp:197 ~ 199 DEG C.ESI-MS：631.4[M+H] +； 1H-NMR(300MHz，DMSO-d 6)，δ(ppm)：1.29(s，2H)，2.42(s，2H)，2.98(s，4H)，3.73(s，4H)，3.80(s，3H)，3.87(s，3H)，7.15(br，2H)，7.24(br，2H)，7.49(s，1H)，7.59(s，1H)，7.90(s，1H)，8.01(s，2H)，8.27(s，1H)，8.34(s，1H)，8.60(s，1H)，8.83(s，1H)，9.30(s，1H)，10.01(s，1H).
Embodiment 5
The preparation of N-[2-[[2-(dimethylin) ethyl] (methyl) amido]-4-methoxyl group-5-[[4-(1-skatole-3-base) pyrimidine-2-base] amido] phenyl]-2-cyano group-3-(pyridine-2-base) acrylamide (LY-5)
With reference to the preparation method of LY-1, react obtained yellow powdery solid by 7a and pyridylaldehyde, yield 78%, mp:194 ~ 196 DEG C.ESI-MS：602.4[M+H] +； 1H-NMR(300MHz，DMSO-d 6)，δ(ppm)：2.11(s，6H)，2.27(br，2H)，2.74(s，3H)，3.00(br，2H)，3.90(s，3H)，3.92(s，3H)，7.16(br s，2H)，7.21～7.28(m，2H)，7.56(d，1H，J＝8.04Hz)，8.00(s，1H)，8.29(m，1H)，8.38(s，1H)，8.56(s，1H)，8.82(s，1H)，9.23(s，1H)，10.34(s，1H).
Embodiment 6
The preparation of N-[2-[[2-(dimethylin) ethyl] (methyl) amido]-4-methoxyl group-5-[[4-(1-skatole-3-base) pyrimidine-2-base] amido] phenyl]-2-cyano group-3-(pyrazole-3-yl) acrylamide (LY-6)
With reference to the preparation method of LY-1, obtain yellow powdery solid by 7a and pyrazoles-3-formaldehyde reaction, yield 73%, mp:223 ~ 225 DEG C.ESI-MS：590.3[M+H] +； 1H-NMR(300MHz，DMSO-d 6)，δ(ppm)：2.13(s，6H)，2.21(br，2H)，2.74(s，3H)，2.99(br，2H)，3.89(s，3H)，3.93(s，3H)，7.14(br s，2H)，7.16(m，2H)，7.22(d，1H，J＝7.83Hz)，7.25(d，1H，J＝4.65Hz)，7.54(d，1H，J＝7.86Hz)，7.99(d，1H，J＝7.80Hz)，8.22(s，1H)，8.56(d，1H，J＝6.93Hz)，8.35(d，1H，J＝5.19Hz)，8.67(s，1H)，9.19(s，1H)，10.44(s，1H).
Embodiment 7
The preparation of N-[2-[[2-(dimethylin) ethyl] (methyl) amido]-4-methoxyl group-5-[[4-(1-skatole-3-base) pyrimidine-2-base] amido] phenyl]-2-cyano group-3-(imidazol-4 yl) acrylamide (LY-7)
With reference to the preparation method of LY-1, obtain yellow powdery solid by 7a and imidazoles-4-formaldehyde reaction, yield 65%, mp:210 ~ 212 DEG C.ESI-MS：591.4[M+H] +； 1H-NMR(300MHz，DMSO-d 6)，δ(ppm)：2.12(s，6H)，2.26(m，2H)，2.72(s，3H)，2.99(m，2H)，3.87(s，3H)，3.92(s，3H)，7.13～7.16(m，2H)，7.20～7.25(m，1H)，7.52(d，1H，J＝7.68Hz)，7.96(d，1H，J＝5.25Hz)，8.04(s，1H)，8.15(s，1H)，8.25(d，1H，J＝7.77Hz)，8.33(d，1H，J＝5.25Hz)，8.64(s，1H)，9.20(s，1H)，10.14(s，1H).
Embodiment 8
The preparation of N-[2-[[2-(dimethylin) ethyl] (methyl) amido]-4-methoxyl group-5-[[4-(1-skatole-3-base) pyrimidine-2-base] amido] phenyl]-2-cyano group-3-Phenyl Acrylamide (LY-8)
With reference to the preparation method of LY-1, react obtained orange powder shape solid by 7a and phenyl aldehyde, yield 76%, mp:182 ~ 184 DEG C.ESI-MS：601.4[M+H] +； 1H-NMR(300MHz，DMSO-d 6)，δ(ppm)：2.11(s，6H)，2.25～2.27(m，2H)，2.75(s，3H)，2.97～3.01(m，2H)，3.89(s，3H)，3.93(s，3H)，7.15(br s，2H)，7.22(d，1H，J＝8.19Hz)，7.26(d，1H，J＝5.37Hz)，7.99(s，1H)，8.03(d，1H，J＝3.54Hz)，8.05(s，1H)，8.33(s，1H)，8.35(d，1H，J＝5.37Hz)，8.64(s，1H)，9.21(s，1H)，10.42(s，1H).
Embodiment 9
Prepared by N-[2-[[2-(dimethylin) ethyl] (methyl) amido]-4-methoxyl group-5-[[4-(1-skatole-3-base) pyrimidine-2-base] amido] phenyl]-2-cyano group-3-cyclopropyl acrylamide (LY-9)
With reference to the preparation method of LY-1, obtain shallow white solid by 7a and ring third formaldehyde reaction, yield 84%, mp:192 ~ 194 DEG C.ESI-MS：564.3[M+H] +； 1H-NMR(300MHz，DMSO-d 6)，δ(ppm)：2.13(s，6H)，2.21(m，2H)，2.70(s，3H)，2.95(m，2H)，3.87(s，3H)，3.90(s，3H)，7.09～7.16(m，3H)，7.23～7.29(m，2H)，7.53(d，1H，J＝7.38Hz)，7.96(s，1H)，8.25(d，1H，J＝7.65Hz)，8.32(d，1H，J＝4.89Hz)，8.59(d，1H，J＝7.38Hz)，9.05(s，1H)，10.02(s，1H).
Embodiment 10
The preparation of N-[2-[[2-(dimethylin) ethyl] (methyl) amido]-4-methoxyl group-5-[[4-(1-skatole-3-base) pyrimidine-2-base] amido] phenyl]-2-cyano group-3-tertiary amyl acrylamide (LY-10)
With reference to the preparation method of LY-1, obtain gray solid, yield 83%, mp:109 ~ 111 DEG C by 7 with special penta formaldehyde reaction.ESI-MS：581.5[M+H] +； 1H-NMR(300MHz，DMSO-d 6)，δ(ppm)：1.23(s，3H)，1.30(s，3H)，2.13(s，3H)，2.22～2.27(br s，6H)，2.71(s，4H)，3.87～3.92(m，6H)，3.95(br s，3H)，7.03(d，1H，J＝2.79Hz)，7.08～7.24(m，5H)，7.55(d，1H，J＝0.72Hz)，7.57(s，1H)，7.90(d，1H，J＝0.45Hz)，7.95(s，1H)，8.22～8.27(m，2H)，8.34(d，1H，J＝4.05Hz)，8.62(s，1H)，8.67(s，1H)，9.00(s，1H)，9.13(s，1H)，10.18(s，1H)，10.30(br s，1H).
Embodiment 11
The preparation of N-[2-(4-methylpiperazine-1-yl)-4-methoxyl group-5-[[4-(1-skatole-3-base) pyrimidine-2-base] amido] phenyl]-2-cyano group-3-(pyrroles-2-base) acrylamide (LY-11)
The preparation of 1-methyl-3-[2-[[4-(N methyl piperazine-1-base)-2-methoxyl group-5-nitro] anilino] pyrimidine-4-yl] indoles (5b)
With reference to the preparation method of 5a, react obtained red powder solid by 4 and N methyl piperazine, yield 86%. 1H-NMR(300MHz，DMSO-d 6)，δ(ppm)：2.25(s，3H)，3.08(s，4H)，3.87(s，3H)，4.05(s，3H)，6.84(s，1H)，7.13(t，1H，J＝7.50Hz)，7.23(d，1H，J＝5.73Hz)，7.26(d，1H，J＝8.58Hz)，7.52(d，1H，J＝7.92Hz)，8.18(s，1H)，8.32～8.37(m，3H)，8.78(s，1H)。
The preparation of 1-methyl-3-[2-[[4-(N methyl piperazine-1-base)-2-methoxyl group-5-is amino] anilino] pyrimidine-4-yl] indoles (6b)
With reference to the preparation method of 6a, by 5b and H 2the obtained white powdery solids of-Pd/C reaction, yield 97%.
The preparation of 1-methyl-3-[2-[[4-(N methyl piperazine-1-base)-2-methoxyl group-5-cyano-acetamide amido] anilino] pyrimidine-4-yl] indoles (7b)
With reference to the preparation method of 7a, react obtained white solid by 6b and cyanoacetic acid, yield 68%, mp:230 ~ 232 DEG C.ESI-MS：533.4[M+Na] +； 1H-NMR(300MHz，DMSO-d 6)，δ(ppm)：2.26(s，3H)，2.56(s，4H)，2.87(s，4H)，3.86(s，3H)，3.93(s，3H)，4.03(s，2H)，6.88(s，1H)，7.18(t，1H，J＝6.3Hz)，7.22(d，1H，J＝5.58Hz)，7.27(d，1H，J＝7.23Hz)，7.54(d，1H，J＝7.89Hz)，7.90(s，1H)，8.26(d，1H，J＝7.38Hz)，8.31(d，1H，J＝5.19Hz)，8.56(s，1H)，8.72(s，1H)，9.25(s，1H).
The preparation of N-[2-(4-methylpiperazine-1-yl)-4-methoxyl group-5-[[4-(1-skatole-3-base) pyrimidine-2-base] amido] phenyl]-2-cyano group-3-(pyrroles-2-base) acrylamide (LY-11)
With reference to the preparation method of LY-1, react obtained yellow solid by 7b and pyrrole-2-aldehyde, yield 73%, mp:193 ~ 195 DEG C.ESI-MS：588.4[M+H] +； 1H-NMR(300MHz，DMSO-d 6)，δ(ppm)：2.26(s，3H)，2.61(s，4H)，2.90(s，3H)，3.88(s，4H)，6.48(s，1H)，7.10(br，2H)，7.22(br，2H)，7.39(br，2H)，7.48～7.54(m，1H)，7.96(s，1H)，8.22～8.3(m，3H)，8.58(s，1H)，9.23(s，1H)，9.50(s，1H)，12.05(br，1H).
Embodiment 12
The preparation of N-[2-(4-methylpiperazine-1-yl)-4-methoxyl group-5-[[4-(1-skatole-3-base) pyrimidine-2-base] amido] phenyl]-2-cyano group-3-(imidazoles-2-base) acrylamide (LY-12)
With reference to the preparation method of LY-1, obtain yellow solid by 7b and imidazoles-2-formaldehyde reaction, yield 57%, mp:190 ~ 192 DEG C.ESI-MS：589.4[M+H] +； 1H-NMR(300MHz，DMSO-d 6)，δ(ppm)：2.26(s，3H)，2.62(s，4H)，2.92(s，4H)，3.88(s，3H)，3.90(s，3H)，7.11(s，1H)，7.13(t，1H，J＝7.38Hz)，7.24(m，2H)，7.52(m，3H)，8.00(s，1H)，8.07(s，1H)，8.27(d，1H，J＝7.71Hz)，8.33(d，1H，J＝4.95Hz)，8.58(s，1H)，9.23(s，1H)，9.75(s，1H).
Embodiment 13
The preparation of N-[2-(4-methylpiperazine-1-yl)-4-methoxyl group-5-[[4-(1-skatole-3-base) pyrimidine-2-base] amido] phenyl]-2-cyano group-3-Phenyl Acrylamide (LY-13)
With reference to the preparation method of LY-1, react obtained yellow solid by 7b and phenyl aldehyde, yield 66%, mp:240 ~ 241 DEG C.ESI-MS：621.4[M+Na] +； 1H-NMR(300MHz，DMSO-d 6)，δ(ppm)：2.26(s，3H)，2.60(br s，4H)，2.93(br s，4H)，3.89(s，3H)，3.93(s，3H)，7.06(s，1H)，7.16(d，1H，J＝7.59Hz)，7.21～7.26(m，2H)，7.52(d，1H，J＝8.10Hz)，7.63(s，1H)，7.65～7.69(m，2H)，8.00(s，1H)，8.04(s，1H)，8.06(s，1H)，8.27(d，1H，J＝7.89Hz)，8.33(d，1H，J＝5.49Hz)，8.41(s，1H)，8.62(s，1H)，9.25(s，1H)，9.79(s，1H).
Embodiment 14
The preparation of N-[2-(4-methylpiperazine-1-yl)-4-methoxyl group-5-[[4-(1-skatole-3-base) pyrimidine-2-base] amido] phenyl]-2-cyano group-3-(pyridine-2-base) acrylamide (LY-14)
With reference to the preparation method of LY-1, react obtained orange solids by 7b and phenyl aldehyde, yield 68%, mp:220 ~ 222 DEG C.ESI-MS：600.4[M+H] +； 1H-NMR(300MHz，DMSO-d 6)，δ(ppm)：2.26(s，3H)，2.61(br s，4H)，2.93(br s，4H)，3.88(s，3H)，3.91(s，3H)，7.11～7.14(m，2H)，7.23～7.26(m，2H)，7.52(d，1H，J＝7.35Hz)，7.59(br s，1H)，7.91(d，1H，J＝7.65Hz)，7.99～8.03(m，2H)，8.28(d，1H，J＝9.51Hz)，8.33(d，1H，J＝4.17Hz)，8.40(s，1H)，8.59(s，1H)，8.83(d，1H，J＝7.47Hz)，9.26(s，1H)，9.92(s，1H).
Embodiment 15
The preparation of N-[2-(4-methylpiperazine-1-yl)-4-methoxyl group-5-[[4-(1-skatole-3-base) pyrimidine-2-base] amido] phenyl]-2-cyano group-3-(4-trifluoromethyl) acrylamide (LY-15)
With reference to the preparation method of LY-1, react orange solids processed by 7b and 4-trifluoromethylated benzaldehyde, yield 67%, mp:239 ~ 240 DEG C.ESI-MS：667.4[M+H] +； 1H-NMR(300MHz，DMSO-d 6)，δ(ppm)：2.22(s，3H)，2.61(br s，4H)，2.93(br s，4H)，3.85(s，3H)，3.90(s，3H)，7.12(s，1H)，7.16(d，1H，J＝7.77Hz)，7.21～7.26(m，2H)，7.52(d，1H，J＝8.34Hz)，7.98(s，1H)，8.00(s，1H)，8.03(s，1H)，8.21(d，1H，J＝8.25Hz)，8.30(d，1H，J＝1.95Hz)，8.33(d，1H，J＝5.31Hz)，8.49(s，1H)，8.59(s，1H)，9.21(s，1H)，9.84(s，1H).
Embodiment 16
The preparation of N-[2-(4-methylpiperazine-1-yl)-4-methoxyl group-5-[[4-(1-skatole-3-base) pyrimidine-2-base] amido] phenyl]-2-cyano group-3-(2-p-methoxy-phenyl) acrylamide (LY-16)
With reference to the preparation method of LY-1, react obtained yellow solid by 7b and Benzaldehyde,2-methoxy, yield 76%, mp:263 ~ 265 DEG C.ESI-MS：629.5[M+H] +； 1H-NMR(300MHz，DMSO-d 6)，δ(ppm)：2.26(s，3H)，2.62(s，4H)，2.92(s，4H)，3.88(s，3H)，3.96(s，3H)，4.02(s，3H)，7.12(s，1H)，7.15(m，1H)，7.18(m，1H)，7.21(s，1H)，7.26(s，1H)，7.28(m，1H)，7.58(d，1H，J＝8.43Hz)，7.63(d，1H，J＝8.40Hz)，7.95(s，1H)，8.18(d，1H，J＝8.22Hz)，8.24(d，1H，J＝8.25Hz)，8.37(d，1H，J＝5.07Hz)，8.71(s，1H)，8.75(s，1H).
Embodiment 17
The preparation of N-[2-(4-methylpiperazine-1-yl)-4-methoxyl group-5-[[4-(1-skatole-3-base) pyrimidine-2-base] amido] phenyl]-2-cyano group-3-(furans-2-base) acrylamide (LY-17)
With reference to the preparation method of LY-1, react obtained yellow solid by 7b and furtural, yield 74%, mp:237 ~ 239 DEG C.ESI-MS：589.4[M+H] +； 1H-NMR(300MHz，DMSO-d 6)，δ(ppm)：2.26(s，3H)，2.62(s，4H)，2.92(s，4H)，3.88(s，3H)，3.97(s，3H)，6.88(m，1H)，7.10(s，1H)，7.17(d，1H，J＝5.85Hz)，7.21～7.25(m，2H)，7.48(d，1H，J＝3.54Hz)，7.52(d，1H，J＝8.31Hz)，8.01(s，1H)，8.21(s，1H)，8.27(d，1H，J＝8.25Hz)，8.32(d，1H，J＝5.16Hz)，8.57(s，1H)，9.19(s，1H)，9.70(s，1H).
Embodiment 18
The preparation of N-[2-(4-methylpiperazine-1-yl)-4-methoxyl group-5-[[4-(1-skatole-3-base) pyrimidine-2-base] amido] phenyl]-2-cyano group-3-(pyrroles-2-base) acrylamide (LY-18)
The preparation of 1-methyl-3-[2-[[4-(morpholine-1-base)-2-methoxyl group-5-nitro] anilino] pyrimidine-4-yl] indoles (5c)
With reference to the preparation method of 5a, react obtained red solid by 4 and morpholine, yield 89%, mp:236 ~ 238 DEG C.ESI-MS：461.4[M+H] +； 1H-NMR(300MHz，DMSO-d 6)，δ(ppm)：3.08(br s，4H)，3.75(br s，4H)，3.88(s，3H)，4.00(s，3H)，6.89(s，1H)，7.10～7.15(m，1H)，7.25(d，1H，J＝7.59Hz)，7.25(t，1H，J＝6.63Hz)，7.28(d，1H，J＝7.59Hz)，8.14(s，1H)，8.34～8.41(m，3H)，8.31(d，1H，J＝3.78Hz).
The preparation of 1-methyl-3-[2-[[4-(morpholine-1-base)-2-methoxyl group-5-is amino] anilino] pyrimidine-4-yl] indoles (6c)
With reference to the preparation method of 6a, by 5c and H 2the obtained white solid of-Pd/C reaction, yield 98%, mp:177 ~ 179 DEG C.ESI-MS：431.3[M+H] +； 1H-NMR(300MHz，DMSO-d 6)，δ(ppm)：1.35(s，2H)，2.49(s，1H)，2.84(s，4H)，3.59(s，1H)，3.75(br s，6H)，3.86(s，3H)，4.47(s，2H)，6.71(s，1H)，7.15(s，3H)，7.52(s，2H)，7.79(s，1H)，8.29(s，2H)，8.41(s，1H).
The preparation of 1-methyl-3-[2-[[4-(morpholine-1-base)-2-methoxyl group-5-cyano-acetamide amido] anilino] pyrimidine-4-yl] indoles (7c)
With reference to the preparation method of 7a, react obtained white solid by 6c and cyanoacetic acid, yield 68%, mp:145 ~ 147 DEG C.ESI-MS：498.4[M+H] +； 1H-NMR(300MHz，DMSO-d 6)，δ(ppm)：2.88(br s，4H)，3.80(br s，4H)，3.88(s，3H)，3.93(s，3H)，4.04(s，2H)，6.92(s，1H)，7.18(d，1H，J＝6.84Hz)，7.23(d，1H，J＝5.55Hz)，7.28(d，1H，J＝7.53Hz)，7.55(d，1H，J＝7.86Hz)，7.91(s，1H)，7.26(d，1H，J＝7.68Hz)，8.32(d，1H，J＝5.34Hz)，8.58(s，1H)，8.76(s，1H)，9.34(s，1H).
The preparation of N-[2-(4-methylpiperazine-1-yl)-4-methoxyl group-5-[[4-(1-skatole-3-base) pyrimidine-2-base] amido] phenyl]-2-cyano group-3-(pyrroles-2-base) acrylamide (LY-18)
With reference to the preparation method of LY-1, react obtained yellow solid by 7c and pyrrole-2-aldehyde, yield 74%, mp:273 ~ 275 DEG C.ESI-MS：575.4[M+H] +； 1H-NMR(300MHz，DMSO-d 6)，δ(ppm)：2.91(br s，3H)，3.83(br s，4H)，3.88(s，3H)，3.91(s，3H)，6.48(br s，1H)，7.14～7.17(m，2H)，7.22～7.28(m，2H)，7.53(d，1H，J＝8.07Hz)，8.00(s，1H)，8.22(s，1H)，8.27(d，1H，J＝8.04Hz)，8.34(d，1H，J＝3.96Hz)，8.62(s，1H)，9.25(s，1H)，9.61(s，1H).
Embodiment 19
The preparation of N-[2-(morpholinyl)-4-methoxyl group-5-[[4-(1-skatole-3-base) pyrimidine-2-base] amido] phenyl]-2-cyano group-3-(imidazoles-2-base) acrylamide (LY-19)
With reference to the preparation method of LY-1, obtain yellow solid by 7c and imidazoles-2-formaldehyde reaction, yield 64%, mp:195 ~ 196 DEG C.ESI-MS：598.4[M+Na] +； 1H-NMR(300MHz，DMSO-d 6)，δ(ppm)：2.92(br s，3H)，3.84(br s，4H)，3.89(s，3H)，3.92(s，3H)，7.08(br s，1H)，7.14～7.17(m，2H)，7.24～7.26(m，2H)，7.34(s，1H)，7.47(br s，2H)，7.54(d，1H，J＝7.56Hz)，8.01(s，1H)，8.05(s，1H)，8.27(d，1H，J＝8.07Hz)，8.34(d，1H，J＝5.37Hz)，8.63(s，1H)，9.28(s，1H)，9.79(s，1H).
Embodiment 20
The preparation of N-[2-(morpholinyl)-4-methoxyl group-5-[[4-(1-skatole-3-base) pyrimidine-2-base] amido] phenyl]-2-cyano group-3-(furans-2-base) acrylamide (LY-20)
With reference to the preparation method of LY-1, obtain yellow solid by 7c and furans-2-formaldehyde reaction, yield 87%, mp:269 ~ 271 DEG C.ESI-MS：598.4[M+Na] +； 1H-NMR(300MHz，DMSO-d 6)，δ(ppm)：2.92(s，4H)，3.88(s，4H)，3.89(s，3H)，3.90(s，3H)，6.70(s，1H)，7.06(m，2H)，7.15(m，2H)，7.47(s，1H)，7.50(s，1H)，8.03(s，1H)，8.14(d，1H，J＝3.18Hz)，8.27(s，1H)，8.30(s，1H)，8.34(s，1H)，8.40(s，1H)，8.43(s，1H)，8.58(s，1H)，9.23(s，1H)，9.76(s，1H).
Embodiment 21
The preparation of N-[2-(morpholinyl)-4-methoxyl group-5-[[4-(1-skatole-3-base) pyrimidine-2-base] amido] phenyl]-2-cyano group-3-(2-p-methoxy-phenyl) acrylamide (LY-21)
With reference to the preparation method of LY-1, react obtained yellow solid by 7c and Benzaldehyde,2-methoxy, yield 72%, mp:264 ~ 266 DEG C.ESI-MS：638.3[M+Na] +； 1H-NMR(300MHz，DMSO-d 6)，δ(ppm)：2.92(br s，4H)，3.86(br s，4H)，3.91(s，3H)，3.94(s，3H)，3.97(s，3H)，7.16～7.22(m，2H)，7.23～7.27(m，2H)，7.57～7.66(m，2H)，7.94(s，1H)，8.16(d，1H，J＝9.78Hz)，8.23(d，1H，J＝6.96Hz)，8.34(s，1H)，8.72(d，1H，J＝8.61Hz)，8.77(d，1H，J＝8.22Hz)，9.39(s，1H)，9.91(s，1H).
Embodiment 22
The preparation of N-[2-(morpholinyl)-4-methoxyl group-5-[[4-(1-skatole-3-base) pyrimidine-2-base] amido] phenyl]-2-cyano group-3-(pyridine-2-base) acrylamide (LY-22)
With reference to the preparation method of LY-1, react obtained orange solids by 7c and pyridine-2-formaldehyde, yield 66%, mp:264 ~ 266 DEG C.ESI-MS：609.4[M+Na] +； 1H-NMR(300MHz，DMSO-d 6)，δ(ppm)：2.10(s，8H)，2.23(s，3H)，2.73(s，5H)，2.99(s，4H)，3.92(s，13H)，6.91(m，8H)，7.57(s，2H)，7.92(m，2H)，8.11(m，2H)，8.23(s，1H)，8.32(s，1H)，8.60(s，1H)，8.73(s，1H)，9.28(s，1H)，10.42(s，1H).
Embodiment 23
The preparation of N-[2-(morpholinyl)-4-methoxyl group-5-[[4-(1-skatole-3-base) pyrimidine-2-base] amido] phenyl]-2-cyano group-3-(pyrazole-3-yl) acrylamide (LY-23)
With reference to the preparation method of LY-1, obtain yellow solid by 7c and pyrazoles-3-formaldehyde reaction, yield 67%, mp:259 ~ 261 DEG C.ESI-MS：598.4[M+Na] +； 1H-NMR(300MHz，DMSO-d 6)，δ(ppm)：2.93(br s，4H)，3.87(br s，4H)，3.89(s，3H)，3.93(s，3H)，7.10～7.29(m，6H)，7.54(d，1H，J＝7.71Hz)，8.01(s，1H)，8.28(d，1H，J＝10.32Hz)，8.34(d，1H，J＝5.55Hz)，8.76(s，1H)，9.26(s，1H)，9.82(br s，1H).
Embodiment 24
The preparation of N-[2-(morpholinyl)-4-methoxyl group-5-[[4-(1-skatole-3-base) pyrimidine-2-base] amido] phenyl]-2-cyano group-3-(imidazol-4 yl) acrylamide (LY-24)
With reference to the preparation method of LY-1, obtain yellow solid by 7c and imidazoles-4-formaldehyde reaction, yield 57%, mp:289 ~ 291 DEG C.ESI-MS：598.4[M+Na] +； 1H-NMR(300MHz，DMSO-d 6)，δ(ppm)：2.91(br s，4H)，3.88(br s，4H)，3.92(s，3H)，4.00(s，3H)，7.13～7.19(m，2H)，7.21～7.26(m，2H)，7.53(d，1H，J＝8.43Hz)，7.93(s，1H)，8.00(s，1H)，8.03(s，1H)，8.21(s，1H)，8.26(d，1H，J＝7.89Hz)，8.34(d，1H，J＝5.40Hz)，8.64(s，1H)，9.29(s，1H)，9.70(s，1H).
Embodiment 25
The preparation of N-[2-(morpholinyl)-4-methoxyl group-5-[[4-(1-skatole-3-base) pyrimidine-2-base] amido] phenyl]-2-cyano group-3-cyclopropyl acrylamide (LY-25)
With reference to the preparation method of LY-1, obtain light yellow solid by 7c and ring third formaldehyde reaction, yield 86%, mp:257 ~ 259 DEG C.ESI-MS：550.4[M+H] +； 1H-NMR(300MHz，DMSO-d 6)，δ(ppm)：2.90(br s，4H)，3.84(br s，4H)，3.92(s，4H)，7.06(s，1H)，7.11(s，1H)，7.17(s，1H)，7.24(s，1H)，7.27(s，1H)，7.53(d，1H，J＝7.71Hz)，7.98(s，1H)，8.30(s，1H)，8.36(s，1H)，8.59(s，1H)，9.18(s，1H)，9.53(s，1H).
Embodiment 39
The EGFR kinase inhibiting activity test of the compounds of this invention
Adopt Z '-Lyte tMkinases testing cassete (invitrogen tM, Z '-Lyte tMkinase assay kit-Tyr 6peptide) test.First enzyme and compound are added on 384 orifice plates according to certain proportioning respectively, mixing, place 30min; Then add ATP, mixing, place 2h; Add 5 μ L Development Regent, mixing, puts 15min in ambient temperatare, after 30min, 1h, detects by microplate reader; Add the Stop regent of 5 μ L after 1h, detect by microplate reader after mixing.Calculate corresponding phosphorylation ratio, the concentration according to compound is mapped with corresponding kinase inhibition rate, obtains dose response curve, tries to achieve the half-inhibition concentration (IC of medicine accordingly 50).Result is as shown in table 1.
Inhibiting rate (%)=[1-(A sample sets-A sample blank group)/(A control group-A blank group)] × 100%
EGFR kinase inhibiting activity (the IC of table 1 the compounds of this invention 50: nM)
EGFR kinase inhibiting activity test result shows, the compounds of this invention has good inhibit activities to EGFR (WT), EGF (T790M), EGFR (L861Q), EGFR (L858R), wherein, LY-2, LY-5, LY-12 and LY-13 are active suitable with positive drug WZ4002 and AZD9291.
Embodiment 40
The compounds of this invention cell inhibitory effect active testing
The blue colorimetry (MTT) of employing tetramethyl-nitrogen azoles evaluates the inhibit activities that part of compounds of the present invention is bred 8 kinds of Non-small cell lung carcinomas, mammary cancer, cancer of the stomach and colon cancer cell lines.Mtt assay has been widely used in large-scale screening anti-tumor medicine, cell toxicity test and tumour radiotherapy sensitivity and has measured.
Tumor cell line: A549 lung carcinoma cell (WT EGFR); HCC827 lung carcinoma cell (EGFR del E746-A750); A431 epithelial cell (EGFR of overexpression); H1975 lung carcinoma cell (EGFR L858R/T790M); MCF-7 breast cancer cell (not expressing EGFR and HER-2); SK-Br-3 breast cancer cell (HER-2 overexpression); N87 stomach cancer cell (EGFR of overexpression); LoVo colon cancer cell (EGFR of overexpression).
Experimental technique: the cell in vegetative period of taking the logarithm is made into 4.5 × 105/mL cell suspension, is seeded in 96 well culture plates, every hole 180 μ L, and often group establishes 5 parallel holes, adds each 20 μ L of different concns tested material respectively.Be placed in constant temperature CO2 incubator to cultivate 48 hours, tetramethyl-nitrogen azoles indigo plant added in 96 orifice plates, every hole 20 μ L, continue cultivation 4 hours.Suck supernatant liquor, add DMSO, every hole 150 μ L, jolting 5 minutes on plate shaker.Be the optical density in the every hole of mensuration, 570nm place at wavelength with enzyme-linked immunosorbent assay instrument, each repetition of above experiment 3 times.Calculate cell proliferation inhibition rate (inhibiting rate %=(negative control group OD value-tested group OD value)/negative control group OD value × 100%), set up linear regression equation according to inhibiting rate and try to achieve half-inhibition concentration IC50 value.The results are shown in Table 2.
Table 2 part of compounds anti-tumour cell proliferative activity of the present invention (IC 50: μM)
Cytoactive test display the compounds of this invention has good proliferation inhibition activity to A549, HCC827, A431, H1975, MCF-7, SK-Br-3, N87 and LoVo.Wherein, LY-5, LY-6, LY-7, LY-8 and LY-9 are better than A549, A431, H1975, MCF-7, SK-Br-3, N87 and LoVo proliferation inhibition activity or suitable with positive drug AZD9291.

Claims (9)

1. the pyrimidines shown in general formula (I), its steric isomer or its pharmacy acceptable salt:
Wherein:
R 1represent C 1-C 8alkyl, C 3-C 6cycloalkyl, C 5-C 10aryl or C 5-C 10aromatic heterocyclic, described alkyl, cycloalkyl, aryl or aromatic heterocyclic are optionally monosubstituted to five replacements by following identical or not identical substituting group, and described substituting group is selected from: halogen, cyano group, nitro, trifluoromethyl, C 1-C 8alkoxyl group, NR 3r 4, C (O) NR 3r 4or C (O) OR 5;
R 2represent hydrogen, halogen, NR 3r 4or OR 5;
R 3and R 4may be the same or different, certainly optional: hydrogen, C 1-C 8alkyl or R 3and R 45-7 unit heterocyclic group is formed together with the nitrogen-atoms connected with them, this heterocyclic group optionally comprises one or more other heteroatoms being selected from O, S or N, and this heterocyclic group is optionally monosubstituted to five replacements by following identical or different substituting group, and described substituting group is selected from: halogen, cyano group, nitro, hydroxyl, trifluoromethyl, amino, C 1-C 8alkyl or C 1-C 8alkoxyl group;
R 5represent hydrogen, C 1-C 8alkyl, C 3-C 6cycloalkyl, C 5-C 10aryl or C 5-C 10aromatic heterocyclic, described alkyl, cycloalkyl, aryl or aromatic heterocyclic are optionally monosubstituted to five replacements by following identical or not identical substituting group, and described substituting group is selected from: halogen, cyano group, nitro, hydroxyl, trifluoromethyl, amino, C 1-C 8alkyl or C 1-C 8alkoxyl group.
2. pyrimidines according to claim 1, its steric isomer or its pharmacy acceptable salt, is characterized in that:
R 1represent C 1-C 8alkyl, C 3-C 6cycloalkyl, C 5-C 10aryl or C 5-C 10aromatic heterocyclic, described alkyl, cycloalkyl, aryl or aromatic heterocyclic are optionally monosubstituted to five replacements by following identical or not identical substituting group, and described substituting group is selected from: trifluoromethyl or C 1-C 8alkoxyl group;
R 2represent hydrogen, halogen or NR 3r 4;
R 3and R 4may be the same or different, certainly optional: C 1-C 8alkyl or R 3and R 45-7 unit heterocyclic group is formed together with the nitrogen-atoms connected with them, this heterocyclic group optionally comprises one or more other heteroatoms being selected from O, S or N, and this heterocyclic group is optionally monosubstituted to five replacements by following identical or different substituting group, and described substituting group is selected from: trifluoromethyl, C 1-C 8alkyl or C 1-C 8alkoxyl group.
3. pyrimidines according to claim 1, its steric isomer or its pharmacy acceptable salt, is characterized in that:
R 1represent C 1-C 8alkyl, C 3-C 6cycloalkyl, C 5-C 10aryl or C 5-C 10aromatic heterocyclic, described alkyl, cycloalkyl, aryl or aromatic heterocyclic are optionally monosubstituted to five replacements by following identical or not identical substituting group, and described substituting group is selected from: trifluoromethyl or methoxyl group;
R 2represent NR 3r 4;
R 3and R 4may be the same or different, certainly optional: hydrogen, C 1-C 8alkyl or R 3and R 45-7 unit heterocyclic group is formed together with the nitrogen-atoms connected with them, this heterocyclic group optionally comprises one or more other heteroatoms being selected from O, S or N, and this heterocyclic group is optionally monosubstituted to five replacements by following identical or different substituting group, and described substituting group is selected from C 1-C 8alkyl.
4. pyrimidines according to claim 1, its steric isomer or its pharmacy acceptable salt, is characterized in that:
R 1represent tertiary amyl, cyclopropyl, phenyl, 2-p-methoxy-phenyl, 4-trifluoromethyl, pyrazolyl, pyrryl, imidazolyl, furyl or pyridyl;
R 2represent N, N, N-trimethylammonium quadrol base, N methyl piperazine base or morpholinyl.
5. pyrimidines according to claim 1, its steric isomer or its pharmacy acceptable salt, is characterized in that, described compound is selected from:
N-[2-[[2-(dimethylin) ethyl] (methyl) amido]-4-methoxyl group-5-[[4-(1-skatole-3-base) pyrimidine-2-base] amido] phenyl]-2-cyano group-3-(pyrroles-2-base) acrylamide;
N-[2-[[2-(dimethylin) ethyl] (methyl) amido]-4-methoxyl group-5-[[4-(1-skatole-3-base) pyrimidine-2-base] amido] phenyl]-2-cyano group-3-(imidazoles-2-base) acrylamide;
N-[2-[[2-(dimethylin) ethyl] (methyl) amido]-4-methoxyl group-5-[[4-(1-skatole-3-base) pyrimidine-2-base] amido] phenyl]-2-cyano group-3-(furans-2-base) acrylamide;
N-[2-[[2-(dimethylin) ethyl] (methyl) amido]-4-methoxyl group-5-[[4-(1-skatole-3-base) pyrimidine-2-base] amido] phenyl]-2-cyano group-3-(2-p-methoxy-phenyl) acrylamide;
N-[2-[[2-(dimethylin) ethyl] (methyl) amido]-4-methoxyl group-5-[[4-(1-skatole-3-base) pyrimidine-2-base] amido] phenyl]-2-cyano group-3-(pyridine-2-base) acrylamide;
N-[2-[[2-(dimethylin) ethyl] (methyl) amido]-4-methoxyl group-5-[[4-(1-skatole-3-base) pyrimidine-2-base] amido] phenyl]-2-cyano group-3-(pyrazole-3-yl) acrylamide;
N-[2-[[2-(dimethylin) ethyl] (methyl) amido]-4-methoxyl group-5-[[4-(1-skatole-3-base) pyrimidine-2-base] amido] phenyl]-2-cyano group-3-(imidazol-4 yl) acrylamide;
N-[2-[[2-(dimethylin) ethyl] (methyl) amido]-4-methoxyl group-5-[[4-(1-skatole-3-base) pyrimidine-2-base] amido] phenyl]-2-cyano group-3-Phenyl Acrylamide;
N-[2-[[2-(dimethylin) ethyl] (methyl) amido]-4-methoxyl group-5-[[4-(1-skatole-3-base) pyrimidine-2-base] amido] phenyl]-2-cyano group-3-cyclopropyl acrylamide;
N-[2-[[2-(dimethylin) ethyl] (methyl) amido]-4-methoxyl group-5-[[4-(1-skatole-3-base) pyrimidine-2-base] amido] phenyl]-2-cyano group-3-tertiary amyl acrylamide;
N-[2-(4-methylpiperazine-1-yl)-4-methoxyl group-5-[[4-(1-skatole-3-base) pyrimidine-2-base] amido] phenyl]-2-cyano group-3-(pyrroles-2-base) acrylamide;
N-[2-(4-methylpiperazine-1-yl)-4-methoxyl group-5-[[4-(1-skatole-3-base) pyrimidine-2-base] amido] phenyl]-2-cyano group-3-(imidazoles-2-base) acrylamide;
N-[2-(4-methylpiperazine-1-yl)-4-methoxyl group-5-[[4-(1-skatole-3-base) pyrimidine-2-base] amido] phenyl]-2-cyano group-3-Phenyl Acrylamide;
N-[2-(4-methylpiperazine-1-yl)-4-methoxyl group-5-[[4-(1-skatole-3-base) pyrimidine-2-base] amido] phenyl]-2-cyano group-3-(pyridine-2-base) acrylamide;
N-[2-(4-methylpiperazine-1-yl)-4-methoxyl group-5-[[4-(1-skatole-3-base) pyrimidine-2-base] amido] phenyl]-2-cyano group-3-(4-trifluoromethyl) acrylamide;
N-[2-(4-methylpiperazine-1-yl)-4-methoxyl group-5-[[4-(1-skatole-3-base) pyrimidine-2-base] amido] phenyl]-2-cyano group-3-(2-p-methoxy-phenyl) acrylamide;
N-[2-(4-methylpiperazine-1-yl)-4-methoxyl group-5-[[4-(1-skatole-3-base) pyrimidine-2-base] amido] phenyl]-2-cyano group-3-(furans-2-base) acrylamide;
N-[2-(4-methylpiperazine-1-yl)-4-methoxyl group-5-[[4-(1-skatole-3-base) pyrimidine-2-base] amido] phenyl]-2-cyano group-3-(pyrroles-2-base) acrylamide;
N-[2-(morpholinyl)-4-methoxyl group-5-[[4-(1-skatole-3-base) pyrimidine-2-base] amido] phenyl]-2-cyano group-3-(imidazoles-2-base) acrylamide;
N-[2-(morpholinyl)-4-methoxyl group-5-[[4-(1-skatole-3-base) pyrimidine-2-base] amido] phenyl]-2-cyano group-3-(furans-2-base) acrylamide;
N-[2-(morpholinyl)-4-methoxyl group-5-[[4-(1-skatole-3-base) pyrimidine-2-base] amido] phenyl]-2-cyano group-3-(2-p-methoxy-phenyl) acrylamide;
N-[2-(morpholinyl)-4-methoxyl group-5-[[4-(1-skatole-3-base) pyrimidine-2-base] amido] phenyl]-2-cyano group-3-(pyridine-2-base) acrylamide;
N-[2-(morpholinyl)-4-methoxyl group-5-[[4-(1-skatole-3-base) pyrimidine-2-base] amido] phenyl]-2-cyano group-3-(pyrazole-3-yl) acrylamide;
N-[2-(morpholinyl)-4-methoxyl group-5-[[4-(1-skatole-3-base) pyrimidine-2-base] amido] phenyl]-2-cyano group-3-(imidazol-4 yl) acrylamide;
N-[2-(morpholinyl)-4-methoxyl group-5-[[4-(1-skatole-3-base) pyrimidine-2-base] amido] phenyl]-2-cyano group-3-cyclopropyl acrylamide.
6. the preparation method of pyrimidines according to claim 1, is characterized in that: 2-nitro-5-fluoroanisole obtains the fluoro-5-N-methyl-p-nitroaniline 2 of 2-methoxyl group-4-through reducing obtained 2-methoxyl group-4-fluoroaniline 1,1 through nitrated.The coupling under aluminum chloride effect of 2,4-dichloro pyrimidine and N-skatole obtains 1-methyl-3-(2-chloropyrimide-4-base) indoles 3.3 and 2 react obtained 1-methyl-3-[[2-(the fluoro-5-nitro of 2-methoxyl group-4-) anilino] pyrimidine-4-yl] indoles 4,4 obtain intermediate 5 with aminated compounds condensation, 5 through reducing obtained intermediate 6,6 obtain intermediate 7 with cyanoacetic acid condensation, and 7 obtain LY-1 ~ LY-25 with aldehyde compound condensation under the catalysis of Piperidineacetic acid; Synthetic route is as follows:
Wherein, R 1and R 2definition as claimed in claim 1.
7. a pharmaceutical composition, any one of the claim 1-5 of the upper significant quantity for the treatment of, pyrimidines, its steric isomer or its pharmacy acceptable salt and pharmaceutically acceptable carrier or auxiliary material form.
8. pyrimidines, its steric isomer or its pharmacy acceptable salt any one of claim 1-5 and pharmaceutical composition according to claim 7 are preparing the application in antitumor drug.
9. purposes according to claim 8, described tumor disease is nonsmall-cell lung cancer, mammary cancer, cancer of the stomach, the rectum cancer, liver cancer, prostate cancer, bladder cancer and ovarian cancer, tumor of head and neck or glioblastoma multiforme.
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Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105237518A (en) * 2015-09-11 2016-01-13 中国药科大学 4-heterocycle substituted pyrimidine compound and uses thereof
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US10435388B2 (en) 2016-01-07 2019-10-08 Cs Pharmatech Limited Selective inhibitors of clinically important mutants of the EGFR tyrosine kinase
US10513509B2 (en) 2016-05-26 2019-12-24 Recurium Ip Holdings, Llc EGFR inhibitor compounds
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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006082129A1 (en) * 2005-02-04 2006-08-10 Boehringer Ingelheim International Gmbh Use of tyrosine kinase inhibitors for the treatment of chronic rhinosinusitis
WO2012158764A1 (en) * 2011-05-17 2012-11-22 Principia Biopharma Inc. Tyrosine kinase inhibitors
CN103087077A (en) * 2011-11-03 2013-05-08 上海希迈医药科技有限公司 Thienopyrimidine and furopyrimidine derivative, its preparation method and application in medicines
CN103360407A (en) * 2012-04-10 2013-10-23 上海希迈医药科技有限公司 Thiophene miazines derivate as well as preparation method and medical application thereof

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006082129A1 (en) * 2005-02-04 2006-08-10 Boehringer Ingelheim International Gmbh Use of tyrosine kinase inhibitors for the treatment of chronic rhinosinusitis
WO2012158764A1 (en) * 2011-05-17 2012-11-22 Principia Biopharma Inc. Tyrosine kinase inhibitors
CN103087077A (en) * 2011-11-03 2013-05-08 上海希迈医药科技有限公司 Thienopyrimidine and furopyrimidine derivative, its preparation method and application in medicines
CN103360407A (en) * 2012-04-10 2013-10-23 上海希迈医药科技有限公司 Thiophene miazines derivate as well as preparation method and medical application thereof

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US11098030B2 (en) 2016-05-26 2021-08-24 Recurium Ip Holdings, Llc EGFR inhibitor compounds
US10513509B2 (en) 2016-05-26 2019-12-24 Recurium Ip Holdings, Llc EGFR inhibitor compounds
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