CN104844580B - Pyrimidines, its preparation method and medical usage - Google Patents

Pyrimidines, its preparation method and medical usage Download PDF

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CN104844580B
CN104844580B CN201510184234.0A CN201510184234A CN104844580B CN 104844580 B CN104844580 B CN 104844580B CN 201510184234 A CN201510184234 A CN 201510184234A CN 104844580 B CN104844580 B CN 104844580B
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bases
amido
base
methyl
pyrimidine
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CN104844580A (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

Abstract

The invention belongs to drug field, and in particular to one kind pyrimidines, its stereoisomer or its pharmaceutically acceptable salt with formula (I) architectural feature, their preparation method and the application in antineoplastic is prepared.The Pharmacological experiment result shows that, such compound has good inhibitory action to EGF-R ELISA (EGFR) and its mutant, and can suppress the propagation of kinds of tumor cells, therefore can be used to prepare antineoplastic as EGFR inhibitor.

Description

Pyrimidines, its preparation method and medical usage
Technical field
The invention belongs to drug field, and in particular to a kind of pyrimidines, its preparation method and medical usage, special It is not the application in antineoplastic is prepared.
Background technology
Protein tyrosine kinase is the important regulating and controlling factor in intracellular signal transduction pathway, is swashed in known 518 kinds of albumen In enzyme, 90 kinds belong to protein tyrosine kinase.It can be catalyzed γ-phosphoric acid on ATP and be transferred on the tyrosine residue of substrate protein, Promote kinases to be transformed into activated conformation by inactive conformation, so as to activate downstream signaling molecule, further trigger a variety of of cell Biological effect, play an important role (Oncogene, 2000,19 (49) during cell growth, propagation, differentiation etc.： 5548-5557).In normal cell, the catalytic activity of protein tyrosine kinase is worked as the generation of its gene by strict regulation and control Therefore mutation or other change different time, the function of EGFR-TK will lack of proper care, and get muddled, enter so as to cause cell to breed regulation And the generation and development of induced tumor.Therefore, protein tyrosine kinase turns into the hot topic of tumor cells targeted therapy in recent years Target.
EGF-R ELISA (EGFR) is the important protein tyrosine kinase ErbB families of a class, and the family includes ErbB1 (EGFR/HER1), erbB2 (HER2), erbB3 (HER3), four members of erbB4 (HER4).When the extracellular acceptors of EGFR After ligand binding, cause homologous or Heterodimerization, then phosphorylation occurs for dimer, causes intracellular EGFR-TK Area is activated and combines an ATP molecule, promotes the specific tyrosine residue phosphorylation of intracellular region, then recognizes and combine successively Adaptor protein (such as Cbl, Shc, Grb2, Crk) with PTB domains or SH2 domains, and then activate downstream signal point Son.EGFR can be regulated and controled (EMBO by many signal paths such as Ras/MAPK, c-Src and PI3K/Akt to cell function J, 2000,19 (13)：3159-3167).EGFR dysfunction and lung cancer, breast cancer, colon cancer, stomach cancer, kidney, oophoroma, Generation development closely related (the Clin Cancer Res, 2006,12 of the kinds of tumors such as prostate cancer, glioblastoma (18)：5268-5272).Therefore, targeting EGFR antineoplastic object depth is paid close attention to by people in recent years.
First generation small molecule EGFR inhibitor mainly includes Gefitinib (gefitinib), Tarceva (erlotinib), Lapatinib (lapatinib) and Conmana (icotinib) etc..Such reversible EGFR inhibitor master If by competitive binding in the ATP binding pockets of kinase region, preventing ATP from being combined with EGFR, so that suppress its phosphorylation, Block signal transduction, and then inducing death of neoplastic cells.These medicines are in clinical treatment non-small cell lung cancer, breast cancer and pancreas Curative effect is protruded in the tumours such as cancer.However, clinical research shows, Partial tumors patient is after such drug therapy is received for a period of time Just occur bis- mutation of EGFR and/or Met gene magnifications, HGF overexpressions etc., so as to produce acquired resistance (J Biomed Biotechnol, 2011：165214).Wherein, the T790M mutation occurred in EGFR kinase regions are considered as main resistance Mechanism, the mutation can hinder inhibitor to be combined with kinase activity pocket, and strengthen combination (the N Engl J of ATP and active pocket Med, 2005,352 (8)：786-792；Proc Natl Acad Sci USA, 2008,105 (6)：2070-2075).Therefore, people Carried out the research and development of irreversible EGFR covalency inhibitors.
Irreversible EGFR inhibitor is mainly the Cys797 sulfydryls with EGFR kinase activity location proximate by electrophilic group Generation Michael additions and covalent bond, so as to occupy ATP binding pocket, prevent kinase activator.It is existing at present Multiple irreversible EGFR covalency inhibitors such as dacomitinib, neratinib, pelitinib, CO-1686 and AZD9291 are entered Enter clinical research, wherein afatinib is approved by the FDA in the United States listing in July, 2013, for treating metastatic non-small cell Lung cancer.
Although with target protein covalent bond, which occurs, for irreversible inhibitor can generally strengthen drug effect and extension action time, It can be easy to occur non-specific covalent bond with the nucleophilic group of non-target protein when its electrophilicity is too strong, be missed the target now so as to produce As.In addition, when medicine and the irreversible covalent bond of substrate protein generation, the haptenization of protein can be caused, so as to cause Autoimmune response (Chem Res Toxicol, 2008,21 (1)：84-92；Expert Opin Drug Discov, 2012,7 (7)：561-581).
It is noted that Taunton groups are confirmed containing alpha-cyano-α, the compound of beta-unsaturated carbonyl can be with Invertibity covalent bond occurs for p90 ribosome S 6 protein kinases (RSK), therefore helps to overcome or reduce irreversible covalent drug Adverse reaction (the Nat Chem Biol, 2012,8 (5) of initiation：471-476).
The content of the invention
The invention discloses a kind of pyrimidines, its stereoisomer or its pharmaceutically acceptable salt and medicine Purposes.The Pharmacological experiment result shows that, such compound has good to EGF-R ELISA (EGFR) and its mutant Inhibitory activity, and the propagation of kinds of tumor cells can be suppressed.Therefore it can be used to prepare antineoplastic as EGFR kinase inhibitor Thing.
The present invention discloses pyrimidines, its stereoisomer or its pharmaceutically acceptable salt shown in formula (I)：
Wherein：
R1Represent C1-C8Alkyl, C3-C6Cycloalkyl, C5-C10Aryl or C5-C10Aromatic heterocyclic, described alkyl, cycloalkyl, Aryl or aromatic heterocyclic are optionally monosubstituted to five substitutions, described substituent choosing by substituent that is following identical or differing From：Halogen, cyano group, nitro, trifluoromethyl, C1-C8Alkoxy, NR3R4、C(O)NR3R4Or C (O) OR5；
R2Represent hydrogen, halogen, NR3R4Or OR5；
R3And R4It may be the same or different, optionally certainly：Hydrogen, C1-C8Alkyl or R3And R4Together with the nitrogen-atoms connected with them 5-7 circle heterocycles groups are formed, the heterocyclic group optionally includes one or more other hetero atoms selected from O, S or N, and The heterocyclic group is optionally monosubstituted to five substitutions by following identical or different substituents, and the substituent is selected from：Halogen, Cyano group, nitro, hydroxyl, trifluoromethyl, amino, C1-C8Alkyl or C1-C8Alkoxy；
R5Represent hydrogen, C1-C8Alkyl, C3-C6Cycloalkyl, C5-C10Aryl or C5-C10Aromatic heterocyclic, described alkyl, cycloalkanes Base, aryl or aromatic heterocyclic are optionally monosubstituted to five substitutions, described substitution by substituent that is following identical or differing Base is selected from：Halogen, cyano group, nitro, hydroxyl, trifluoromethyl, amino, C1-C8Alkyl or C1-C8Alkoxy.
Further, pyrimidines, its stereoisomer or its pharmaceutically acceptable salt shown in formula (I) are led to, It is characterized in that：
R1Represent tertiary amyl, cyclopropyl, phenyl, 2- methoxyphenyls, 4- trifluoromethyls, pyrazolyl, pyrrole radicals, miaow Oxazolyl, furyl, pyridine radicals.
R2Represent N, N, N- trimethyl ethylenediamines base, N methyl piperazine base, morpholinyl.
Specifically, pyrimidines, its stereoisomer or the choosing of its pharmaceutically acceptable salt shown in formula (I) are led to From following compounds：
N- [2- [[2- (dimethylamino) ethyl] (methyl) amido] -4- methoxyl groups -5- [[4- (1- methyl indol -3- bases) Pyrimidine -2-base] amido] phenyl] -2- cyano group -3- (pyrroles -2- bases) acrylamide (LY-1)；
N- [2- [[2- (dimethylamino) ethyl] (methyl) amido] -4- methoxyl groups -5- [[4- (1- methyl indol -3- bases) Pyrimidine -2-base] amido] phenyl] -2- cyano group -3- (imidazoles -2- bases) acrylamide (LY-2)；
N- [2- [[2- (dimethylamino) ethyl] (methyl) amido] -4- methoxyl groups -5- [[4- (1- methyl indol -3- bases) Pyrimidine -2-base] amido] phenyl] -2- cyano group -3- (furans -2- bases) acrylamide (LY-3)；
N- [2- [[2- (dimethylamino) ethyl] (methyl) amido] -4- methoxyl groups -5- [[4- (1- methyl indol -3- bases) Pyrimidine -2-base] amido] phenyl] -2- cyano group -3- (2- methoxyphenyls) acrylamide (LY-4)；
N- [2- [[2- (dimethylamino) ethyl] (methyl) amido] -4- methoxyl groups -5- [[4- (1- methyl indol -3- bases) Pyrimidine -2-base] amido] phenyl] -2- cyano group -3- (pyridine -2- bases) acrylamide (LY-5)；
N- [2- [[2- (dimethylamino) ethyl] (methyl) amido] -4- methoxyl groups -5- [[4- (1- methyl indol -3- bases) Pyrimidine -2-base] amido] phenyl] -2- cyano group -3- (pyrazole-3-yl) acrylamide (LY-6)；
N- [2- [[2- (dimethylamino) ethyl] (methyl) amido] -4- methoxyl groups -5- [[4- (1- methyl indol -3- bases) Pyrimidine -2-base] amido] phenyl] -2- cyano group -3- (imidazol-4 yl) acrylamide (LY-7)；
N- [2- [[2- (dimethylamino) ethyl] (methyl) amido] -4- methoxyl groups -5- [[4- (1- methyl indol -3- bases) Pyrimidine -2-base] amido] phenyl] -2- cyano group -3- Phenyl Acrylamides (LY-8)；
N- [2- [[2- (dimethylamino) ethyl] (methyl) amido] -4- methoxyl groups -5- [[4- (1- methyl indol -3- bases) Pyrimidine -2-base] amido] phenyl] -2- cyano group -3- cyclopropyl acrylamides (LY-9)；
N- [2- [[2- (dimethylamino) ethyl] (methyl) amido] -4- methoxyl groups -5- [[4- (1- methyl indol -3- bases) Pyrimidine -2-base] amido] phenyl] -2- cyano group -3- tertiary amyls acrylamides (LY-10)；
N- [2- (4- methylpiperazine-1-yls) -4- methoxyl groups -5- [[4- (1- methyl indol -3- bases) pyrimidine -2-base] amine Base] phenyl] -2- cyano group -3- (pyrroles -2- bases) acrylamide (LY-11)；
N- [2- (4- methylpiperazine-1-yls) -4- methoxyl groups -5- [[4- (1- methyl indol -3- bases) pyrimidine -2-base] amine Base] phenyl] -2- cyano group -3- (imidazoles -2- bases) acrylamide (LY-12)；
N- [2- (4- methylpiperazine-1-yls) -4- methoxyl groups -5- [[4- (1- methyl indol -3- bases) pyrimidine -2-base] amine Base] phenyl] -2- cyano group -3- Phenyl Acrylamides (LY-13)；
N- [2- (4- methylpiperazine-1-yls) -4- methoxyl groups -5- [[4- (1- methyl indol -3- bases) pyrimidine -2-base] amine Base] phenyl] -2- cyano group -3- (pyridine -2- bases) acrylamide (LY-14)；
N- [2- (4- methylpiperazine-1-yls) -4- methoxyl groups -5- [[4- (1- methyl indol -3- bases) pyrimidine -2-base] amine Base] phenyl] -2- cyano group -3- (4- trifluoromethyls) acrylamide (LY-15)；
N- [2- (4- methylpiperazine-1-yls) -4- methoxyl groups -5- [[4- (1- methyl indol -3- bases) pyrimidine -2-base] amine Base] phenyl] -2- cyano group -3- (2- methoxyphenyls) acrylamide (LY-16)；
N- [2- (4- methylpiperazine-1-yls) -4- methoxyl groups -5- [[4- (1- methyl indol -3- bases) pyrimidine -2-base] amine Base] phenyl] -2- cyano group -3- (furans -2- bases) acrylamide (LY-17)；
N- [2- (4- methylpiperazine-1-yls) -4- methoxyl groups -5- [[4- (1- methyl indol -3- bases) pyrimidine -2-base] amine Base] phenyl] -2- cyano group -3- (pyrroles -2- bases) acrylamide (LY-18)；
N- [2- (morpholinyl) -4- methoxyl groups -5- [[4- (1- methyl indol -3- bases) pyrimidine -2-base] amido] phenyl] -2- Cyano group -3- (imidazoles -2- bases) acrylamide (LY-19)；
N- [2- (morpholinyl) -4- methoxyl groups -5- [[4- (1- methyl indol -3- bases) pyrimidine -2-base] amido] phenyl] -2- Cyano group -3- (furans -2- bases) acrylamide (LY-20)；
N- [2- (morpholinyl) -4- methoxyl groups -5- [[4- (1- methyl indol -3- bases) pyrimidine -2-base] amido] phenyl] -2- Cyano group -3- (2- methoxyphenyls) acrylamide (LY-21)；
N- [2- (morpholinyl) -4- methoxyl groups -5- [[4- (1- methyl indol -3- bases) pyrimidine -2-base] amido] phenyl] -2- Cyano group -3- (pyridine -2- bases) acrylamide (LY-22)；
N- [2- (morpholinyl) -4- methoxyl groups -5- [[4- (1- methyl indol -3- bases) pyrimidine -2-base] amido] phenyl] -2- Cyano group -3- (pyrazole-3-yl) acrylamide (LY-23)；
N- [2- (morpholinyl) -4- methoxyl groups -5- [[4- (1- methyl indol -3- bases) pyrimidine -2-base] amido] phenyl] -2- Cyano group -3- (imidazol-4 yl) acrylamide (LY-24)；
N- [2- (morpholinyl) -4- methoxyl groups -5- [[4- (1- methyl indol -3- bases) pyrimidine -2-base] amido] phenyl] -2- Cyano group -3- cyclopropyl acrylamide (LY-25).
The compound numbers being related to below in pharmacological evaluation are equal to the compound corresponding to code name herein.
Another object of the present invention is to provide the preparation method of compound shown in logical formula (I), it is characterised in that：2- nitre Base -5- fluoroanisoles obtain the fluoro- 5- nitroanilines of 2- methoxyl groups -4- through the obtained 2- methoxyl group -4- fluoroanilines 1,1 of reduction through nitrification 2.The coupling under alchlor effect obtains 1- methyl -3- (2- chlorine pyrimidine-4-yl) Yin to 2,4- dichloro pyrimidines with N- methyl indols Diindyl 3.3 and 2 reaction be made 1- methyl -3- [[2- (the fluoro- 5- nitros of 2- methoxyl groups -4-) anilino-] pyrimidine-4-yl] indoles 4,4 with Aminated compounds condensation is made intermediate 5,5 and is condensed to yield intermediate 7,7 in piperazine with cyanoacetic acid through the obtained intermediate 6,6 of reduction Under the catalysis of pyridine acetic acid LY-1~LY-25 is condensed to yield with aldehyde compound；Synthetic route is as follows：
Wherein, R1And R2Definition it is as claimed in claim 1.
It is a further object of the present invention to provide a kind of pharmaceutical composition, by the claim 1-5 of the upper effective dose for the treatment of Any one of compound or its pharmaceutically acceptable carrier or auxiliary material composition.
It is also another object of the present invention to provide the compound with logical formula (I) or its stereoisomer or its pharmaceutically may be used The salt of receiving and the composition that is made up of them anti-tumor aspect application, wherein described tumour is non-small cell lung Cancer, breast cancer, stomach cancer, the carcinoma of the rectum, liver cancer, prostate cancer, carcinoma of urinary bladder and oophoroma, head and neck neoplasm or glioblastoma.
Described compound includes the rotamer of compound shown in logical formula (I), optical isomer, racemic modification, non- Enantiomter or dynamic isomer, and any of above form mixture.
Embodiment
In order to which the present invention is furture elucidated, a series of embodiments are given below, these embodiments be entirely it is illustrative, it Only be used for the present invention specific descriptions, be not construed as limitation of the present invention.
Embodiment 1
The preparation of 2- methoxyl group -4- fluoroanilines (1)
2- nitro -5- fluoroanisoles (1.00g, 5.81mmol) and 5% palladium carbon (0.62g, 0.29mmol) are added into 35mL In THF, hydrogen stirring 5h is passed through at room temperature, and suction filtration is spin-dried for solvent, obtains light yellow solid 0.80g, yield 97%.
The preparation of the fluoro- 5- nitroanilines (2) of 2- methoxyl groups -4-
Under ice bath, 1 (1.00g, 5.42mmol) is dissolved in the 6.50mL concentrated sulfuric acids in batches, NaNO is added portionwise3(0.46g, 5.41mmol), continue to stir 4 hours, 2%NaOH solution adjusts neutral, dichloromethane extraction is spin-dried for solvent, obtains Orange red solid 0.64g, yield 64%.
The preparation of 1- methyl -3- (2- chlorine pyrimidine-4-yl) indoles (3)
2,4- dichloro pyrimidines (1.00g, 6.71mmol) are dissolved in 25mL glycol dimethyl ethers, ice bath cooling adds in batches Enter AlCl3(0.98g, 7.42mmol), temperature control is less than at 10 DEG C, adds N- methyl indols (0.83mL, 6.74mmol), removes ice Bath, back flow reaction 2h is cooled to room temperature, poured into 200mL frozen water, stirs 30min, and suction filtration, washing, recrystallized from acetonitrile is dried Obtain Off-white solid 0.88g, yield 54%.
The preparation of 1- methyl -3- [2- [(the fluoro- 5- nitros of 2- methoxyl groups -4-) anilino-] pyrimidine-4-yl] indoles (4)
By 3 (0.90g, 3.71mmol), 2 (0.69g, 3.72mmol) and one hydration p-methyl benzenesulfonic acid (0.84g, 4.44mmol) it is dissolved in 30mL sec-amyl alcohols, flow back 2.5h, is cooled to room temperature, separates out yellow solid, suction filtration, ethanol washing is dried Obtain yellow solid 1.23g, yield 85%.
1- methyl -3- [[2- [2- methoxyl groups -4- (N, N, N '-trimethyl ethylenediamine base) -5- nitros] anilino-] pyrimidine - 4- yls] indoles (5a) preparation
4 (0.50mg, 1.31mmol) and N, N, N '-trimethyl ethylenediamine (0.16mL, 1.30mmol) add sec-butyl alcohol and DIPEA (0.55mL, 3.22mmol), is passed through N2, flow back reaction overnight, is cooled to room temperature, suction filtration obtains red solid 0.48g, receives Rate 80%, mp：143~145.ESI-MS：476.4[M+H]+。
1- methyl -3- [[2- [2- methoxyl groups -4- (N, N, N '-trimethyl ethylenediamine base) -5- amino] anilino-] pyrimidine - 4- yls] indoles (6a) preparation
5a (0.50mg, 1.13mmol) and 5% palladium-carbon (0.11g, 0.06mmol) add tetrahydrofuran, are passed through hydrogen, room Temperature reaction 4h, suction filtration is spin-dried for filtrate and obtains yellow solid 590mg, yield 98%.
1- methyl -3- [[2- [2- methoxyl groups -4- (N, N, N '-trimethyl ethylenediamine base) -5- cyano-acetamides amido] aniline Base] pyrimidine-4-yl] indoles indoles (7a) preparation
Cyanoacetic acid (190mg, 2.24mmol), EDCHCl (859mg, 4.48mmol) and 6a (0.59g, 1.12mmol) DMF and DIPEA (1.20mL, 6.72mmol) is added, 4h is reacted at room temperature, is diluted with water, ultrasonic agitation, suction filtration, washing and drying is obtained Pale solid 0.45g, yield 78%, mp：124~126 DEG C.ESI-MS：513.4[M+H]+；1H-NMR (300MHz, DMSO- d6), 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), (s, the 1H) of 8.33 (d, 1H, J=5.34Hz), 8.67 (s, 1H), 8.99 (s, 1H), 10.32
N- [2- [[2- (dimethylamino) ethyl] (methyl) amido] -4- methoxyl groups -5- [[4- (1- methyl indol -3- bases) Pyrimidine -2-base] amido] phenyl] and -2- cyano group -3- (pyrroles -2- bases) acrylamide (LY-1) preparation
7 (0.03g, 0.06mmol) are dissolved in 5mL acetonitriles, add pyrrole aldehyde (5.60mg, 0.06mmol) and catalytic amount Piperidines acetic acid, react at room temperature 4h, add water, stir, suction filtration it is dry orange solid 0.02g, yield 58%, mp：131~133 DEG C. ESI-MS：590.4[M+H]+；1H-NMR (300MHz, DMSO-d6), 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
N- [2- [[2- (dimethylamino) ethyl] (methyl) amido] -4- methoxyl groups -5- [[4- (1- methyl indol -3- bases) Pyrimidine -2-base] amido] phenyl] and -2- cyano group -3- (imidazoles -2- bases) acrylamide (LY-2) preparation
With reference to LY-1 preparation method, reacted by 7a and imidazoles -2- formaldehyde and yellow powdery solid is made, yield 73%, mp：137~139 DEG C.ESI-MS：591.4[M+H]+；1H-NMR (300MHz, DMSO-d6), 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
N- [2- [[2- (dimethylamino) ethyl] (methyl) amido] -4- methoxyl groups -5- [[4- (1- methyl indol -3- bases) Pyrimidine -2-base] amido] phenyl] and -2- cyano group -3- (furans -2- bases) acrylamide (LY-3) preparation
With reference to LY-1 preparation method, reacted by 7a and furans -2- formaldehyde and yellow powdery solid is made, yield 81%, mp：174~176 DEG C.ESI-MS：591.4[M+H]+；1H-NMR (300MHz, DMSO-d6), 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
N- [2- [[2- (dimethylamino) ethyl] (methyl) amido] -4- methoxyl groups -5- [[4- (1- methyl indol -3- bases) Pyrimidine -2-base] amido] phenyl] and -2- cyano group -3- (2- methoxyphenyls) acrylamides (LY-4) preparation
With reference to LY-1 preparation method, reacted by 7a and Benzaldehyde,2-methoxy and yellow powdery solid, yield is made 73%, mp：197~199 DEG C.ESI-MS：631.4[M+H]+；1H-NMR (300MHz, DMSO-d6), 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), (s, the 1H) of 8.60 (s, 1H), 8.83 (s, 1H), 9.30 (s, 1H), 10.01
Embodiment 5
N- [2- [[2- (dimethylamino) ethyl] (methyl) amido] -4- methoxyl groups -5- [[4- (1- methyl indol -3- bases) Pyrimidine -2-base] amido] phenyl] and -2- cyano group -3- (pyridine -2- bases) acrylamide (LY-5) preparation
With reference to LY-1 preparation method, reacted by 7a and pyridine carboxaldehyde and yellow powdery solid, yield 78%, mp is made： 194~196 DEG C.ESI-MS：602.4[M+H]+；1H-NMR (300MHz, DMSO-d6), 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
N- [2- [[2- (dimethylamino) ethyl] (methyl) amido] -4- methoxyl groups -5- [[4- (1- methyl indol -3- bases) Pyrimidine -2-base] amido] phenyl] and -2- cyano group -3- (pyrazole-3-yl) acrylamide (LY-6) preparation
With reference to LY-1 preparation method, reacted by 7a and pyrazoles -3- formaldehyde and yellow powdery solid is made, yield 73%, mp：223~225 DEG C.ESI-MS：590.3[M+H]+；1H-NMR (300MHz, DMSO-d6), 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
N- [2- [[2- (dimethylamino) ethyl] (methyl) amido] -4- methoxyl groups -5- [[4- (1- methyl indol -3- bases) Pyrimidine -2-base] amido] phenyl] and -2- cyano group -3- (imidazol-4 yl) acrylamide (LY-7) preparation
With reference to LY-1 preparation method, reacted by 7a and imidazoles -4- formaldehyde and yellow powdery solid is made, yield 65%, mp：210~212 DEG C.ESI-MS：591.4[M+H]+；1H-NMR (300MHz, DMSO-d6), 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), (s, the 1H) of 8.25 (d, 1H, J=7.77Hz), 8.33 (d, 1H, J=5.25Hz), 8.64 (s, 1H), 9.20 (s, 1H), 10.14
Embodiment 8
N- [2- [[2- (dimethylamino) ethyl] (methyl) amido] -4- methoxyl groups -5- [[4- (1- methyl indol -3- bases) Pyrimidine -2-base] amido] phenyl] and -2- cyano group -3- Phenyl Acrylamides (LY-8) preparation
With reference to LY-1 preparation method, reacted by 7a and benzaldehyde and orange powder shape solid, yield 76%, mp is made：182 ~184 DEG C.ESI-MS：601.4[M+H]+；1H-NMR (300MHz, DMSO-d6), 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), (s, the 1H) of 8.33 (s, 1H), 8.35 (d, 1H, J=5.37Hz), 8.64 (s, 1H), 9.21 (s, 1H), 10.42
Embodiment 9
N- [2- [[2- (dimethylamino) ethyl] (methyl) amido] -4- methoxyl groups -5- [[4- (1- methyl indol -3- bases) Pyrimidine -2-base] amido] phenyl] -2- cyano group -3- cyclopropyl acrylamides (LY-9) preparation
With reference to LY-1 preparation method, reacted by 7a and the formaldehyde of ring third and shallow white solid, yield 84%, mp is made：192~ 194℃.ESI-MS：564.3[M+H]+；1H-NMR (300MHz, DMSO-d6), 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), (s, the 1H) of 8.59 (d, 1H, J=7.38Hz), 9.05 (s, 1H), 10.02
Embodiment 10
N- [2- [[2- (dimethylamino) ethyl] (methyl) amido] -4- methoxyl groups -5- [[4- (1- methyl indol -3- bases) Pyrimidine -2-base] amido] phenyl] and -2- cyano group -3- tertiary amyls acrylamides (LY-10) preparation
With reference to LY-1 preparation method, reacted by 7 with special penta formaldehyde and gray solid, yield 83%, mp is made：109~111 ℃.ESI-MS：581.5[M+H]+；1H-NMR (300MHz, DMSO-d6), 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
N- [2- (4- methylpiperazine-1-yls) -4- methoxyl groups -5- [[4- (1- methyl indol -3- bases) pyrimidine -2-base] amine Base] phenyl] -2- cyano group -3- (pyrroles -2- bases) acrylamide (LY-11) preparation
1- methyl -3- [2- [[4- (N methyl piperazine -1- bases) -2- methoxyl group -5- nitros] anilino-] pyrimidine-4-yl] Yin The preparation of diindyl (5b)
With reference to 5a preparation method, reacted by 4 with N methyl piperazine and red powder solid, yield 86% is made.1H- NMR (300MHz, DMSO-d6), 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).
1- methyl -3- [2- [[4- (N methyl piperazine -1- bases) -2- methoxyl group -5- amino] anilino-] pyrimidine-4-yl] Yin The preparation of diindyl (6b)
With reference to 6a preparation method, by 5b and H2White powdery solids, yield 97% are made in-Pd/C reactions.
[2- [[4- (N methyl piperazine -1- bases) -2- methoxyl group -5- cyano-acetamides amido] anilino-] is phonetic by 1- methyl -3- Pyridine -4- bases] indoles (7b) preparation
With reference to 7a preparation method, reacted by 6b and cyanoacetic acid and white solid, yield 68%, mp is made：230~232 ℃.ESI-MS：533.4[M+Na]+；1H-NMR (300MHz, DMSO-d6), 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)
N- [2- (4- methylpiperazine-1-yls) -4- methoxyl groups -5- [[4- (1- methyl indol -3- bases) pyrimidine -2-base] amine Base] phenyl] -2- cyano group -3- (pyrroles -2- bases) acrylamide (LY-11) preparation
With reference to LY-1 preparation method, reacted by 7b and pyrrole-2-aldehyde and yellow solid, yield 73%, mp is made：193 ~195 DEG C.ESI-MS：588.4[M+H]+；1H-NMR (300MHz, DMSO-d6), 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
N- [2- (4- methylpiperazine-1-yls) -4- methoxyl groups -5- [[4- (1- methyl indol -3- bases) pyrimidine -2-base] amine Base] phenyl] -2- cyano group -3- (imidazoles -2- bases) acrylamide (LY-12) preparation
With reference to LY-1 preparation method, reacted by 7b and imidazoles -2- formaldehyde and yellow solid, yield 57%, mp is made：190 ~192 DEG C.ESI-MS：589.4[M+H]+；1H-NMR (300MHz, DMSO-d6), 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), (s, the 1H) of 8.58 (s, 1H), 9.23 (s, 1H), 9.75
Embodiment 13
N- [2- (4- methylpiperazine-1-yls) -4- methoxyl groups -5- [[4- (1- methyl indol -3- bases) pyrimidine -2-base] amine Base] phenyl] -2- cyano group -3- Phenyl Acrylamides (LY-13) preparation
With reference to LY-1 preparation method, reacted by 7b and benzaldehyde and yellow solid, yield 66%, mp is made：240~241 ℃.ESI-MS：621.4[M+Na]+；1H-NMR (300MHz, DMSO-d6), 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
N- [2- (4- methylpiperazine-1-yls) -4- methoxyl groups -5- [[4- (1- methyl indol -3- bases) pyrimidine -2-base] amine Base] phenyl] -2- cyano group -3- (pyridine -2- bases) acrylamide (LY-14) preparation
With reference to LY-1 preparation method, reacted by 7b and benzaldehyde and orange solids, yield 68%, mp are made：220~222 ℃.ESI-MS：600.4[M+H]+；1H-NMR (300MHz, DMSO-d6), 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
N- [2- (4- methylpiperazine-1-yls) -4- methoxyl groups -5- [[4- (1- methyl indol -3- bases) pyrimidine -2-base] amine Base] phenyl] -2- cyano group -3- (4- trifluoromethyls) acrylamides (LY-15) preparation
With reference to LY-1 preparation method, orange solids processed, yield 67%, mp are reacted by 7b and 4- trifluoromethylated benzaldehydes： 239~240 DEG C.ESI-MS：667.4[M+H]+；1H-NMR (300MHz, DMSO-d6), 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
N- [2- (4- methylpiperazine-1-yls) -4- methoxyl groups -5- [[4- (1- methyl indol -3- bases) pyrimidine -2-base] amine Base] phenyl] -2- cyano group -3- (2- methoxyphenyls) acrylamides (LY-16) preparation
With reference to LY-1 preparation method, reacted by 7b and Benzaldehyde,2-methoxy and yellow solid, yield 76%, mp is made： 263~265 DEG C.ESI-MS：629.5[M+H]+；1H-NMR (300MHz, DMSO-d6), 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
N- [2- (4- methylpiperazine-1-yls) -4- methoxyl groups -5- [[4- (1- methyl indol -3- bases) pyrimidine -2-base] amine Base] phenyl] -2- cyano group -3- (furans -2- bases) acrylamide (LY-17) preparation
With reference to LY-1 preparation method, reacted by 7b and furtural and yellow solid, yield 74%, mp is made：237~ 239℃.ESI-MS：589.4[M+H]+；1H-NMR (300MHz, DMSO-d6), 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
N- [2- (4- methylpiperazine-1-yls) -4- methoxyl groups -5- [[4- (1- methyl indol -3- bases) pyrimidine -2-base] amine Base] phenyl] -2- cyano group -3- (pyrroles -2- bases) acrylamide (LY-18) preparation
1- methyl -3- [2- [[4- (morpholine -1- bases) -2- methoxyl group -5- nitros] anilino-] pyrimidine-4-yl] indoles (5c) Preparation
With reference to 5a preparation method, reacted by 4 with morpholine and red solid, yield 89%, mp is made：236~238 DEG C. ESI-MS：461.4[M+H]+；1H-NMR (300MHz, DMSO-d6), 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)
1- methyl -3- [2- [[4- (morpholine -1- bases) -2- methoxyl group -5- amino] anilino-] pyrimidine-4-yl] indoles (6c) Preparation
With reference to 6a preparation method, by 5c and H2White solid, yield 98%, mp is made in-Pd/C reactions：177~179 ℃.ESI-MS：431.3[M+H]+；1H-NMR (300MHz, DMSO-d6), 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), (s, the 1H) of 7.52 (s, 2H), 7.79 (s, 1H), 8.29 (s, 2H), 8.41
1- methyl -3- [2- [[4- (morpholine -1- bases) -2- methoxyl group -5- cyano-acetamides amido] anilino-] pyrimidine-4-yl] The preparation of indoles (7c)
With reference to 7a preparation method, reacted by 6c and cyanoacetic acid and white solid, yield 68%, mp is made：145~147 ℃.ESI-MS：498.4[M+H]+；1H-NMR (300MHz, DMSO-d6), 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), (s, the 1H) of 8.32 (d, 1H, J=5.34Hz), 8.58 (s, 1H), 8.76 (s, 1H), 9.34
N- [2- (4- methylpiperazine-1-yls) -4- methoxyl groups -5- [[4- (1- methyl indol -3- bases) pyrimidine -2-base] amine Base] phenyl] -2- cyano group -3- (pyrroles -2- bases) acrylamide (LY-18) preparation
With reference to LY-1 preparation method, reacted by 7c and pyrrole-2-aldehyde and yellow solid, yield 74%, mp is made：273 ~275 DEG C.ESI-MS：575.4[M+H]+；1H-NMR (300MHz, DMSO-d6), 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), (s, the 1H) of 8.62 (s, 1H), 9.25 (s, 1H), 9.61
Embodiment 19
N- [2- (morpholinyl) -4- methoxyl groups -5- [[4- (1- methyl indol -3- bases) pyrimidine -2-base] amido] phenyl] -2- The preparation of cyano group -3- (imidazoles -2- bases) acrylamide (LY-19)
With reference to LY-1 preparation method, reacted by 7c and imidazoles -2- formaldehyde and yellow solid, yield 64%, mp is made：195 ~196 DEG C.ESI-MS：598.4[M+Na]+；1H-NMR (300MHz, DMSO-d6), 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
N- [2- (morpholinyl) -4- methoxyl groups -5- [[4- (1- methyl indol -3- bases) pyrimidine -2-base] amido] phenyl] -2- The preparation of cyano group -3- (furans -2- bases) acrylamide (LY-20)
With reference to LY-1 preparation method, reacted by 7c and furans -2- formaldehyde and yellow solid, yield 87%, mp is made：269 ~271 DEG C.ESI-MS：598.4[M+Na]+；1H-NMR (300MHz, DMSO-d6), 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), (s, the 1H) of 8.43 (s, 1H), 8.58 (s, 1H), 9.23 (s, 1H), 9.76
Embodiment 21
N- [2- (morpholinyl) -4- methoxyl groups -5- [[4- (1- methyl indol -3- bases) pyrimidine -2-base] amido] phenyl] -2- The preparation of cyano group -3- (2- methoxyphenyls) acrylamides (LY-21)
With reference to LY-1 preparation method, reacted by 7c and Benzaldehyde,2-methoxy and yellow solid, yield 72%, mp is made： 264~266 DEG C.ESI-MS：638.3[M+Na]+；1H-NMR (300MHz, DMSO-d6), 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), (s, the 1H) of 8.34 (s, 1H), 8.72 (d, 1H, J=8.61Hz), 8.77 (d, 1H, J=8.22Hz), 9.39 (s, 1H), 9.91
Embodiment 22
N- [2- (morpholinyl) -4- methoxyl groups -5- [[4- (1- methyl indol -3- bases) pyrimidine -2-base] amido] phenyl] -2- The preparation of cyano group -3- (pyridine -2- bases) acrylamide (LY-22)
With reference to LY-1 preparation method, reacted by 7c and pyridine-2-formaldehyde and orange solids, yield 66%, mp are made：264 ~266 DEG C.ESI-MS：609.4[M+Na]+；1H-NMR (300MHz, DMSO-d6), 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
N- [2- (morpholinyl) -4- methoxyl groups -5- [[4- (1- methyl indol -3- bases) pyrimidine -2-base] amido] phenyl] -2- The preparation of cyano group -3- (pyrazole-3-yl) acrylamide (LY-23)
With reference to LY-1 preparation method, reacted by 7c and pyrazoles -3- formaldehyde and yellow solid, yield 67%, mp is made：259 ~261 DEG C.ESI-MS：598.4[M+Na]+；1H-NMR (300MHz, DMSO-d6), 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
N- [2- (morpholinyl) -4- methoxyl groups -5- [[4- (1- methyl indol -3- bases) pyrimidine -2-base] amido] phenyl] -2- The preparation of cyano group -3- (imidazol-4 yl) acrylamide (LY-24)
With reference to LY-1 preparation method, reacted by 7c and imidazoles -4- formaldehyde and yellow solid, yield 57%, mp is made：289 ~291 DEG C.ESI-MS：598.4[M+Na]+；1H-NMR (300MHz, DMSO-d6), 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), (s, the 1H) of 8.34 (d, 1H, J=5.40Hz), 8.64 (s, 1H), 9.29 (s, 1H), 9.70
Embodiment 25
N- [2- (morpholinyl) -4- methoxyl groups -5- [[4- (1- methyl indol -3- bases) pyrimidine -2-base] amido] phenyl] -2- The preparation of cyano group -3- cyclopropyl acrylamide (LY-25)
With reference to LY-1 preparation method, reacted by 7c and the formaldehyde of ring third and light yellow solid, yield 86%, mp is made：257~ 259℃.ESI-MS：550.4[M+H]+；1H-NMR (300MHz, DMSO-d6), 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 activities test of the compounds of this invention
Using Z '-LyteTMKinases testing cassete (invitrogenTM, Z '-LyteTM Kinase assay kit-Tyr 6peptide) tested.Enzyme and compound are first added on 384 orifice plates according to certain proportioning respectively, mixed, 30min is placed； Then ATP is added, is mixed, 2h is placed；Plus 5 μ L Development Regent, mix, 15min placed at room temperature, After 30min, 1h, detected with ELIASA；5 μ L Stop regent are added after 1h, are detected after mixing with ELIASA. Corresponding phosphorylation ratio is calculated, is mapped according to the concentration of compound with corresponding kinase inhibition rate, obtains dose-effect curve, Half-inhibition concentration (the IC of medicine is tried to achieve accordingly50).As a result it is as shown in table 1.
Inhibiting rate (%)=[1- (ASample sets-ASample blank group)/(AControl group-ABlank group)] × 100%
EGFR kinase inhibiting activities (the IC of the compounds of this invention of table 150：nM)
EGFR kinase inhibiting activity test results show that the compounds of this invention is to EGFR (WT), EGF (T790M), EGFR (L861Q), EGFR (L858R) has good inhibitory activity, wherein, LY-2, LY-5, LY-12 and LY-13 and positive drug WZ4002 and AZD9291 activity is quite.
Embodiment 40
The compounds of this invention cell inhibitory effect active testing
Part of compounds of the present invention is evaluated to 8 kinds of Non-small cell lung carcinomas, breasts using the blue colorimetric method (MTT) of tetramethyl nitrogen azoles The inhibitory activity of gland cancer, stomach cancer and colon cancer cell line propagation.Mtt assay be widely used in large-scale screening anti-tumor medicine, Cell toxicity test and tumour radiotherapy sensitivity measure etc..
Tumor cell line：A549 lung carcinoma cells (WT EGFR)；HCC827 lung carcinoma cells (EGFR del E746-A750)； A431 epithelial cells (EGFR of overexpression)；H1975 lung carcinoma cells (EGFR L858R/T790M)；MCF-7 breast cancer cells (not expressing EGFR and HER-2)；SK-Br-3 breast cancer cells (HER-2 overexpressions)；N87 stomach cancer cells be (overexpression EGFR)；LoVo colon cancer cells (EGFR of overexpression).
Experimental method：The cell in growth period of taking the logarithm is made into 4.5 × 105/mL cell suspensions, is seeded to 96 well culture plates In, per the μ L of hole 180, every group sets 5 parallel holes, is separately added into each 20 μ L of various concentrations tested material.It is placed in constant temperature CO2 incubators Culture 48 hours, tetramethyl nitrogen azoles indigo plant is added in 96 orifice plates, per the μ L of hole 20, continues to cultivate 4 hours.Supernatant is sucked, is added DMSO, per the μ L of hole 150, shakes 5 minutes on plate shaker.In wavelength it is to be determined at 570nm per hole with enzyme-linked immunosorbent assay instrument Trap, above experiment is respectively repeated 3 times.Calculate cell proliferation inhibition rate (inhibiting rate %=(negative control group OD values-tested group OD values)/negative control group OD values × 100%), linear regression equation is set up according to inhibiting rate and tries to achieve half-inhibition concentration IC50 Value.It the results are shown in Table 2.
Part of compounds anti-tumour cell proliferative activity (the IC of the present invention of table 250：μM)
Cytoactive test show the compounds of this invention to A549, HCC827, A431, H1975, MCF-7, SK-Br-3, N87 and LoVo have good proliferation inhibition activity.Wherein, LY-5, LY-6, LY-7, LY-8 and LY-9 to A549, A431, H1975, MCF-7, SK-Br-3, N87 and LoVo proliferation inhibition activity are better than or suitable with positive drug AZD9291.

Claims (7)

1. pyrimidines, its stereoisomer or its pharmaceutically acceptable salt shown in logical formula (I)：
Wherein：
R1Represent C1-C8Alkyl, C3-C6Cycloalkyl, C5-C10Aryl or C5-C10Aromatic heterocyclic, described alkyl, cycloalkyl, aryl Or aromatic heterocyclic is optionally monosubstituted to five substitutions by substituent that is following identical or differing, described substituent is selected from： Trifluoromethyl or methoxyl group；
R2Represent N, N, N- trimethyl ethylenediamines base, N methyl piperazine base or morpholinyl.
2. pyrimidines according to claim 1, its stereoisomer or its pharmaceutically acceptable salt, its feature It is：
R1Represent tertiary amyl, cyclopropyl, phenyl, 2- methoxyphenyls, 4- trifluoromethyls, pyrazolyl, pyrrole radicals, imidazole radicals, Furyl or pyridine radicals；
R2Represent N, N, N- trimethyl ethylenediamines base, N methyl piperazine base or morpholinyl.
3. pyrimidines according to claim 1, its stereoisomer or its pharmaceutically acceptable salt, its feature It is, the compound is selected from：
N- [2- [[2- (dimethylamino) ethyl] (methyl) amido] -4- methoxyl groups -5- [[4- (1- methyl indol -3- bases) pyrimidine - 2- yls] amido] phenyl] -2- cyano group -3- (pyrroles -2- bases) acrylamide；
N- [2- [[2- (dimethylamino) ethyl] (methyl) amido] -4- methoxyl groups -5- [[4- (1- methyl indol -3- bases) pyrimidine - 2- yls] amido] phenyl] -2- cyano group -3- (imidazoles -2- bases) acrylamide；
N- [2- [[2- (dimethylamino) ethyl] (methyl) amido] -4- methoxyl groups -5- [[4- (1- methyl indol -3- bases) pyrimidine - 2- yls] amido] phenyl] -2- cyano group -3- (furans -2- bases) acrylamide；
N- [2- [[2- (dimethylamino) ethyl] (methyl) amido] -4- methoxyl groups -5- [[4- (1- methyl indol -3- bases) pyrimidine - 2- yls] amido] phenyl] -2- cyano group -3- (2- methoxyphenyls) acrylamide；
N- [2- [[2- (dimethylamino) ethyl] (methyl) amido] -4- methoxyl groups -5- [[4- (1- methyl indol -3- bases) pyrimidine - 2- yls] amido] phenyl] -2- cyano group -3- (pyridine -2- bases) acrylamide；
N- [2- [[2- (dimethylamino) ethyl] (methyl) amido] -4- methoxyl groups -5- [[4- (1- methyl indol -3- bases) pyrimidine - 2- yls] amido] phenyl] -2- cyano group -3- (pyrazole-3-yl) acrylamide；
N- [2- [[2- (dimethylamino) ethyl] (methyl) amido] -4- methoxyl groups -5- [[4- (1- methyl indol -3- bases) pyrimidine - 2- yls] amido] phenyl] -2- cyano group -3- (imidazol-4 yl) acrylamide；
N- [2- [[2- (dimethylamino) ethyl] (methyl) amido] -4- methoxyl groups -5- [[4- (1- methyl indol -3- bases) pyrimidine - 2- yls] amido] phenyl] -2- cyano group -3- Phenyl Acrylamides；
N- [2- [[2- (dimethylamino) ethyl] (methyl) amido] -4- methoxyl groups -5- [[4- (1- methyl indol -3- bases) pyrimidine - 2- yls] amido] phenyl] -2- cyano group -3- cyclopropyl acrylamides；
N- [2- [[2- (dimethylamino) ethyl] (methyl) amido] -4- methoxyl groups -5- [[4- (1- methyl indol -3- bases) pyrimidine - 2- yls] amido] phenyl] -2- cyano group -3- tertiary amyl acrylamides；
N- [2- (4- methylpiperazine-1-yls) -4- methoxyl groups -5- [[4- (1- methyl indol -3- bases) pyrimidine -2-base] amido] benzene Base] -2- cyano group -3- (pyrroles -2- bases) acrylamide；
N- [2- (4- methylpiperazine-1-yls) -4- methoxyl groups -5- [[4- (1- methyl indol -3- bases) pyrimidine -2-base] amido] benzene Base] -2- cyano group -3- (imidazoles -2- bases) acrylamide；
N- [2- (4- methylpiperazine-1-yls) -4- methoxyl groups -5- [[4- (1- methyl indol -3- bases) pyrimidine -2-base] amido] benzene Base] -2- cyano group -3- Phenyl Acrylamides；
N- [2- (4- methylpiperazine-1-yls) -4- methoxyl groups -5- [[4- (1- methyl indol -3- bases) pyrimidine -2-base] amido] benzene Base] -2- cyano group -3- (pyridine -2- bases) acrylamide；
N- [2- (4- methylpiperazine-1-yls) -4- methoxyl groups -5- [[4- (1- methyl indol -3- bases) pyrimidine -2-base] amido] benzene Base] -2- cyano group -3- (4- trifluoromethyls) acrylamide；
N- [2- (4- methylpiperazine-1-yls) -4- methoxyl groups -5- [[4- (1- methyl indol -3- bases) pyrimidine -2-base] amido] benzene Base] -2- cyano group -3- (2- methoxyphenyls) acrylamide；
N- [2- (4- methylpiperazine-1-yls) -4- methoxyl groups -5- [[4- (1- methyl indol -3- bases) pyrimidine -2-base] amido] benzene Base] -2- cyano group -3- (furans -2- bases) acrylamide；
N- [2- (4- methylpiperazine-1-yls) -4- methoxyl groups -5- [[4- (1- methyl indol -3- bases) pyrimidine -2-base] amido] benzene Base] -2- cyano group -3- (pyrroles -2- bases) acrylamide；
N- [2- (morpholinyl) -4- methoxyl groups -5- [[4- (1- methyl indol -3- bases) pyrimidine -2-base] amido] phenyl] -2- cyanogen Base -3- (imidazoles -2- bases) acrylamide；
N- [2- (morpholinyl) -4- methoxyl groups -5- [[4- (1- methyl indol -3- bases) pyrimidine -2-base] amido] phenyl] -2- cyanogen Base -3- (furans -2- bases) acrylamide；
N- [2- (morpholinyl) -4- methoxyl groups -5- [[4- (1- methyl indol -3- bases) pyrimidine -2-base] amido] phenyl] -2- cyanogen Base -3- (2- methoxyphenyls) acrylamide；
N- [2- (morpholinyl) -4- methoxyl groups -5- [[4- (1- methyl indol -3- bases) pyrimidine -2-base] amido] phenyl] -2- cyanogen Base -3- (pyridine -2- bases) acrylamide；
N- [2- (morpholinyl) -4- methoxyl groups -5- [[4- (1- methyl indol -3- bases) pyrimidine -2-base] amido] phenyl] -2- cyanogen Base -3- (pyrazole-3-yl) acrylamide；
N- [2- (morpholinyl) -4- methoxyl groups -5- [[4- (1- methyl indol -3- bases) pyrimidine -2-base] amido] phenyl] -2- cyanogen Base -3- (imidazol-4 yl) acrylamide；
N- [2- (morpholinyl) -4- methoxyl groups -5- [[4- (1- methyl indol -3- bases) pyrimidine -2-base] amido] phenyl] -2- cyanogen Base -3- cyclopropyl acrylamides.
4. the preparation method of the pyrimidines described in claim 1, it is characterised in that：2- nitro -5- fluoroanisoles are through also The obtained 2- methoxyl group -4- fluoroanilines 1,1 of original through nitrification obtain the fluoro- dichloro pyrimidines of 5- nitroanilines 2,2,4- of 2- methoxyl groups -4- with The coupling under alchlor effect of N- methyl indols obtains the reaction of 1- methyl -3- (2- chlorine pyrimidine-4-yl) indoles 3,3 and 2 and is made 1- methyl -3- [[2- (the fluoro- 5- nitros of 2- methoxyl groups -4-) anilino-] pyrimidine-4-yl] indoles 4,4 is condensed with aminated compounds and made Intermediate 5,5 through reduction be made intermediate 6,6 and cyanoacetic acid be condensed to yield intermediate 7,7 under the catalysis of Piperidineacetic acid with Aldehyde compound is condensed to yield LY-1~LY-25；Synthetic route is as follows：
Wherein, R1And R2Definition it is as claimed in claim 1.
5. a kind of pharmaceutical composition, different by any one of the claim 1-3 of the upper effective dose for the treatment of pyrimidines, its solid Structure body or its pharmaceutically acceptable salt and pharmaceutically acceptable carrier or auxiliary material composition.
6. any one of claim 1-3 pyrimidines, its stereoisomer or its pharmaceutically acceptable salt and right It is required that application of the pharmaceutical composition described in 5 in antineoplastic is prepared.
7. purposes according to claim 6, described tumor disease is non-small cell lung cancer, breast cancer, stomach cancer, the carcinoma of the rectum, liver Cancer, prostate cancer, carcinoma of urinary bladder and oophoroma, head and neck neoplasm or glioblastoma.
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