CN106243044A - Pyridine derivatives containing halo acrylamide side chain and preparation and application - Google Patents

Pyridine derivatives containing halo acrylamide side chain and preparation and application Download PDF

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CN106243044A
CN106243044A CN201610528620.1A CN201610528620A CN106243044A CN 106243044 A CN106243044 A CN 106243044A CN 201610528620 A CN201610528620 A CN 201610528620A CN 106243044 A CN106243044 A CN 106243044A
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amino
chlorine
piperazinyl
phenyl
acetyl group
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陈文腾
刘星雨
邵加安
陈恩
陈斌辉
唐湃
俞永平
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Zhejiang University ZJU
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/48—Two nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/47—One nitrogen atom and one oxygen or sulfur atom, e.g. cytosine
    • 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
    • C07D401/02—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 two hetero rings
    • C07D401/12—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 two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Abstract

The present invention provides a kind of pyridine derivatives containing halo acrylamide side chain shown in formula I, the invention also discloses its preparation method and application.Experiment proves, on a cellular level to tumor cell (the people epidermal carcinoma cell strain A431 of process LAN Wild type EGFR relevant to EGFR tyrosine kinase activity, human lung adenocarcinoma cell line H1975 to Gefitinib drug resistance) there is significant inhibited proliferation, particularly drug-resistant cell strain H1975 there is preferable inhibition, more weak to the inhibitory activity of low expression EGFR human colon cancer cell strain SW620, the EGFR kinases simultaneously suddenlyd change wild type and [L858R/T790M] also has preferable inhibition, and the EGFR Kinase Selectivity that suddenlys change [L858R/T790M] is high, corresponding antitumor cell medicine can be prepared.General structure is as follows:

Description

Pyridine derivatives containing halo acrylamide side chain and preparation and application
Technical field
The invention belongs to pharmaceutical field, be specifically related to a kind of pyrimidine derivatives containing halo acrylamide side chain, preparation side Method and application thereof.
Background technology
EGF-R ELISA (epidermal growth factor receptor, EGFR) is proto-oncogene HER1 Expression product, have part induction protein tyrosine kinase activity.The activation of proto-oncogene i.e. genovariation is to cause swelling One of reason that tumor occurs.EGFR plays an important role in cell cycle, grow with cell, breed, migrate relevant.Research table Bright, there are one or more EGFR family receptors process LAN or sudden changes in the malignant tumor section more than 60%.Although in the past time In between, EGFR inhibitor is developed rapidly in oncotherapy, but still leaves substantial amounts of research space, the sudden change institute of target spot Anti-tumor drugs targeting has been researched and proposed new challenge by the treatment Drug resistance caused, and irreversible inhibitor (includes Afatinib, Dacomitinib, Neratinib etc.) can be combined with covalent bond with EGFR tyrosine kinase, T790M can be resisted Sudden change, overcomes the drug resistance that T790M causes.Wherein, nearly FDA approved Boehringer Ingelheim (Boehringer Ingelheim) The afatinib sheet of exploitation lists with trade name Gilotrif, as a kind of oral, new first-line treatment medicine, it was demonstrated that permissible Non-for the transitivity of tumor EGF-R ELISA (EGFR) 19 exon disappearance or 21 exons sudden change (L858R) The treatment of small cell lung cancer (NSCLC) patient.Afatinib is first irreversible ErbB family blocker, the clinic that this medicine is positive Evidence, adds brand-new binding mode so that it is become a kind of outstanding therapeutic choice, is expected to provide it to be badly in need of for patients with lung cancer Clinical demand.
Summary of the invention
The technical problem to be solved is to provide a kind of pyridine derivatives containing halo acrylamide side chain, tool There is a following general structure I:
Wherein:
R1For halogen, methyl, methoxyl group, trifluoromethyl and nitrogen heterocyclic ring.
R2For methyl or acetyl group.
R3For hydrogen, halogen or trifluoromethyl.
X is oxygen atom or ammonia atom.
Y is trifluoromethyl, halogen atom.
One of the present invention acrylamide pyrimidine derivatives Han halo is following arbitrary compound:
N-[3-[[2-[[4-(4-acetyl group-1-piperazinyl) phenyl] amino]-5-(chlorine)-4-pyrimidine radicals] amino] benzene Base]-2-chloroacrylamide (embodiment 1)；
N-[3-[[2-[[4-(4-acetyl group-1-piperazinyl) phenyl] amino]-5-(chlorine)-4-pyrimidine radicals] amino] benzene Base]-2-fluoropropene amide (embodiment 2)；
N-[3-[[2-[[4-(4-acetyl group-1-piperazinyl) phenyl] amino]-5-(chlorine)-4-pyrimidine radicals] amino] benzene Base]-2-Phenyl Acrylamide (embodiment 3)；
N-[3-[[2-[[4-(4-acetyl group-1-piperazinyl)-2-methoxyphenyl] amino]-5-(chlorine)-4-pyrimidine radicals] Amino] phenyl]-2-trifluoromethyl acrylamide (embodiment 4)；
N-[3-[[2-[[4-(4-acetyl group-1-piperazinyl)-2-methoxyphenyl] amino]-5-(chlorine)-4-pyrimidine radicals] Amino] phenyl]-2-fluoropropene amide (embodiment 5)；
N-[3-[[2-[[4-(4-acetyl group-1-piperazinyl)-2-methoxyphenyl] amino]-5-(chlorine)-4-pyrimidine radicals] Amino] phenyl]-2-trifluoromethyl acrylamide (embodiment 6)；
N-[3-[[2-[[4-(4-acetyl group-1-piperazinyl)-2-methoxyphenyl] amino]-5-(chlorine)-4-pyrimidine radicals] Amino] phenyl]-2-chloroacrylamide (embodiment 7)；
N-[3-[[2-[[4-(4-acetyl group-1-piperazinyl) phenyl] amino]-5-(trifluoromethyl chlorine)-4-pyrimidine radicals] ammonia Base] phenyl]-2-fluoropropene amide (embodiment 8)；
[[[2-[[4-(4-acetyl group-1-piperazinyl)-2-methoxyphenyl] amino]-5-(trifluoromethyl)-4-is phonetic for 3-for N- Piperidinyl] amino] phenyl]-2-chloroacrylamide (embodiment 9)；
N-[3-[[2-[[4-(4-acetyl group-1-piperazinyl)-3-chlorphenyl] amino]-5-(chlorine)-4-pyrimidine radicals] amino] Phenyl]-2-fluoropropene amide (embodiment 10)；
N-[3-[[2-[[4-(4-methyl isophthalic acid-piperazinyl)-2-methoxyphenyl] oxygen]-5-(chlorine)-4-pyrimidine radicals] amino] Phenyl]-2-fluoropropene amide (embodiment 11)；
[[[2-[[4-(4-acetyl group-1-piperazinyl)-2-methoxyphenyl] amino]-5-(trifluoromethyl)-4-is phonetic for 3-for N- Piperidinyl] amino] phenyl]-2-trifluoromethyl acrylamide (embodiment 12)；
N-[3-[[2-[[4-(4-acetyl group-1-piperazinyl)-2-methoxyphenyl] oxygen]-5-(chlorine)-4-pyrimidine radicals] ammonia Base] phenyl]-2-fluoropropene amide (embodiment 13)；
N-[3-[[2-[[4-(4-acetyl group-1-piperazinyl)-3-fluorophenyl] oxygen]-5-(chlorine)-4-pyrimidine radicals] amino] benzene Base]-2-fluoropropene amide (embodiment 14)；
N-[3-[[2-[[4-(4-acetyl group-1-piperazinyl)-3-aminomethyl phenyl] oxygen]-5-(chlorine)-4-pyrimidine radicals] amino] Phenyl]-2-chloroacrylamide (embodiment 15)；
N-[2-[(2,2-dimethylamino) 5-[[4-(1-Methyl-1H-indole-3-base)-2-(5-chlorine)-pyrimidine radicals] ammonia Base] phenyl]-2-fluoropropene amide (embodiment 16)；
N-[3-[[2-[[4-(4-acetyl group-1-piperazinyl)-3-aminomethyl phenyl] amino]-5-(chlorine)-4-pyrimidine radicals] ammonia Base] phenyl]-2-fluoropropene amide (embodiment 17)；
N-[3-[[2-[[4-(4-acetyl group-1-piperazinyl)-3-aminomethyl phenyl] amino]-5-(chlorine)-4-pyrimidine radicals] ammonia Base] phenyl]-2-trifluoromethyl acrylamide (embodiment 18)；
N-[3-[[2-[[4-(4-methyl isophthalic acid-piperazinyl)-2-methoxyphenyl] oxygen]-5-(chlorine)-4-pyrimidine radicals] amino] Phenyl]-2-chloroacrylamide (embodiment 19)；
N-[2-[(2,2-dimethylamino) 5-[[4-(1-Methyl-1H-indole-3-base)-2-(5-chlorine)-pyrimidine radicals] ammonia Base] phenyl]-2-chloroacrylamide (embodiment 20)；
N-[3-[[2-[[4-(4-acetyl group-1-piperazinyl)-2-methoxyphenyl] oxygen]-5-(chlorine)-4-pyrimidine radicals] ammonia Base] phenyl]-2-chloroacrylamide (embodiment 21)；
N-[3-[[2-[[4-(4-acetyl group-1-piperazinyl)-3-fluorophenyl] amino]-5-(chlorine)-4-pyrimidine radicals] amino] Phenyl]-2-chloroacrylamide (embodiment 22)；
N-[2-[(2,2-dimethylamino) 5-[[4-(1-Methyl-1H-indole-3-base)-2-(5-chlorine)-pyrimidine radicals] ammonia Base] phenyl]-2-trifluoromethyl acrylamide (embodiment 23)；
N-[3-[[2-[[4-(4-acetyl group-1-piperazinyl) phenyl] amino]-5-(trifluoromethyl)-4-pyrimidine radicals] ammonia Base] phenyl]-2-chloroacrylamide (embodiment 24)；
N-[3-[[2-[[5-(4-acetyl group-1-piperazinyl) pyridine radicals] amino]-5-(chlorine)-4-pyrimidine radicals] amino] benzene Base]-2-chloroacrylamide (embodiment 25)；
N-[3-[[2-[[5-(4-acetyl group-1-piperazinyl) pyridine radicals] amino]-5-(chlorine)-4-pyrimidine radicals] amino] benzene Base]-2-fluoropropene amide (embodiment 26)；
N-[3-[[2-[[4-(4-acetyl group-1-piperazinyl)-3-trifluoromethyl] amino]-5-(chlorine)-4-pyrimidine Base] amino] phenyl]-2-chloroacrylamide (embodiment 27)；
N-[3-[[2-[[4-(4-acetyl group-1-piperazinyl)-3-trifluoromethyl] amino]-5-(chlorine)-4-pyrimidine Base] amino] phenyl]-2-fluoropropene amide (embodiment 28)；
N-[3-[[2-[[4-(4-acetyl group-1-piperazinyl)-3-chlorphenyl] amino]-5-(chlorine)-4-pyrimidine radicals] amino] Phenyl]-2-chloroacrylamide (embodiment 29)；
N-[3-[[2-[[4-(4-acetyl group-1-piperazinyl)-2-fluorophenyl] amino]-5-(chlorine)-4-pyrimidine radicals] amino] Phenyl]-2-chloroacrylamide (embodiment 30)；
N-[3-[[2-[[4-(4-acetyl group-1-piperazinyl) phenyl] oxygen]-5-(chlorine)-4-pyrimidine radicals] amino] phenyl]- 2-chloroacrylamide (embodiment 31)；
N-[3-[[2-[[4-(4-acetyl group-1-piperazinyl)-3-trifluoromethyl] oxygen]-5-(chlorine)-4-pyrimidine radicals] Amino] phenyl]-2-chloroacrylamide (embodiment 32)；
It is a further object to provide the system of described a kind of pyrimidine derivatives containing halo acrylamide side chain Preparation Method, is realized by following steps:
With 2,5-dichloro pyrimidine a is initiation material, and (3-aminophenyl) t-butyl carbamate (or (3-hydroxy benzenes Base) the amino tert-butyl ester) b react in n-butyl alcohol generation intermediate c, intermediate c reflux in n-butyl alcohol under dilute hydrochloric acid effect To 5-position substituted intermediate d, the tert. butyl protection group in intermediate d structure is under trifluoroacetic acid effect, and deprotection is dissociated The intermediate e of amino structure, the last acryloyl chloride condensation reaction with various halogen substiuted obtains target compound I；Reaction equation is:
Wherein substituent group is defined as above described in compound of Formula I, reaction condition: i) diisopropylethylamine, n-butyl alcohol, room Temperature；Ii) dilute hydrochloric acid, n-butyl alcohol, backflow；Iii) trifluoroacetic acid, dichloromethane, ice bath；Iv) acryloyl chloride Han halogen, triethylamine, Dichloromethane, ice bath is to room temperature.
Raw material involved in the present invention or intermediate, can directly buy, or prepares according to the literature method mentioned in embodiment.
Compound of formula I described in preparation method of the present invention, it is possible to use method described above prepares the chemical combination of the present invention Thing, it will be appreciated that when be given typical or preferred process condition (i.e. reaction temperature, the time, the mol ratio of reactant, solvent, Pressure etc.), it is also possible to use other process conditions, except as otherwise noted.Optimum reaction condition can be with concrete reaction used Thing or solvent and change, but these conditions can be determined by routine optimization process by those skilled in the art.Generally, may be used To use reaction scheme as above and technique to prepare the compounds of this invention, but the reagent being not limited in reaction condition and solvent.
It is also another object of the present invention to provide described containing halo acrylamide pyrimidine derivatives to prepare antitumor thin Application in born of the same parents and targeting EGFR kinases medicine, described tumor cell refer to process LAN EGFR people epidermal carcinoma cell strain A431, Human lung adenocarcinoma cell line H1975 and low expression EGFR human colon cancer cell strain SW620, described EGFR to Gefitinib drug resistance Kinases refers to the EGFR kinases that Wild type EGFR kinases and [L858R/T790M] suddenly change.
The invention provides a class brand-new containing halo acrylamide pyrimidine derivatives, the most halogen-containing acrylamide side Chain can be as novel irreversible covalent reaction functional group, and experimental data shows, its on a molecular scale to wild type and The EGFR tyrosine kinase that [L858R/T790M] suddenlys change has a preferably inhibitory action, and [L858R/T790M] is suddenlyd change EGFR Kinase Selectivity is high, also has the tumor cell relevant to EGFR tyrosine kinase activity significantly on a cellular level Inhibited proliferation, more weak to the inhibitory activity of low expression EGFR human colon cancer cell strain SW620, corresponding antitumor can be prepared Medicine, providing for the novel EGFR inhibitor overcoming Gefitinib drug resistance of design may.
Detailed description of the invention
Further illustrate the present invention below by the mode of embodiment, but the most therefore limit the present invention to described reality Execute among example scope, the experimental technique of unreceipted actual conditions in the following example, conventionally and condition, or according to business Product description selects.
Embodiment 1 N-[3-[[2-[[4-(4-acetyl group-1-piperazinyl) phenyl] amino]-5-(chlorine)-4-pyrimidine radicals] ammonia Base] phenyl]-2-chloroacrylamide；
The preparation of step 1:3-[2-[[4-(4-acetyl group-1-piperazinyl) phenyl] amino]-5-(chlorine)-4-pyrimidine radicals] aminobenzene
Raw material 1:3-[2-[[4-(4-acetyl group-1-piperazinyl) phenyl] amino]-5-(chlorine)-4-pyrimidine radicals] the tertiary fourth of formic acid Ester aminobenzene is prepared according to the method for document Cancer Discov.2013,12,1404-1415；
By 3-[2-[[4-(4-acetyl group-1-piperazinyl) phenyl] amino]-5-(chlorine)-4-pyrimidine radicals] t-butyl formate ammonia Base benzene (537mg, 1mmol) is dissolved in dichloromethane (2ml), drips trifluoroacetic acid (2ml) subsequently, and reaction is overnight.Question response is tied Shu Hou, obtains brownish red mucus by reactant liquor vacuum rotary steam, drips ether (5ml) subsequently, separates out solid in solution, and sucking filtration obtains Yellow solid (400mg), thick product yield is 95%, and this product directly carries out the next step.
Step 2:N-[3-[[2-[[4-(4-acetyl group-1-piperazinyl) phenyl] amino]-5-(chlorine)-4-pyrimidine radicals] ammonia Base] phenyl] preparation of-2-chloroacrylamide
Product obtained in the previous step (400mg) is dissolved in dichloromethane (5mL), is cooled to 0 DEG C-2 DEG C and instills 2-chlorine third Alkene acyl chlorides (124mg, 1mmol), drips triethylamine (235ul, 4mmol) subsequently, continues low-temp reaction overnight.Question response is complete, Adding water, extract with dichloromethane, take organic layer vacuum rotary steam, (flowing is CH to column chromatography chromatogram purification mutually2Cl2: MeOH= 100:1), reclaiming, be drying to obtain white solid product 130mg, productivity is 28.8%.1H NMR(500MHz,CDCl3)δ8.34 (s, 1H), 8.05 (d, J=13.0Hz, 2H), 7.43 (d, J=8.8Hz, 2H), 7.33 (d, J=5.3Hz, 2H), 7.14 (s, 1H), 6.86 (d, J=8.8Hz, 2H), 6.73 (d, J=1.0Hz, 1H), 5.92 (s, 1H), 3.79 3.74 (m, 2H), 3.64 3.59 (m, 2H), 3.14-3.05 (m, 4H), 2.14 (s, 3H) .ESI (M+H+): 562.1521.
According to embodiment 1 same procedure, use different material, prepare following compound.
Embodiment 2:N-[3-[[2-[[4-(4-acetyl group-1-piperazinyl) phenyl] amino]-5-(chlorine)-4-pyrimidine radicals] ammonia Base] phenyl]-2-fluoropropene amide
With reference to the method for embodiment 1, simply change the 2-chloropropene acyl chlorides in step 2 into 2-fluoropropene acyl chloride reaction and terminate After, it is evaporated to dry obtain crude product, obtains white solid through column chromatography purification (DCM/MeOH=100:1),1H NMR (500MHz,CDCl3) δ 8.07 (d, J=20.1Hz, 2H), 7.95 (s, 1H), 7.43-7.40 (m, 3H), 7.35 7.32 (m, 2H), 7.07 (d, J=33.0Hz, 2H), 6.87 (d, J=7.9Hz, 2H), 5.84 (d, J=48.4Hz, 1H), 5.27 (d, J= 14.8Hz,1H),3.77-3.61(m,4H),3.10-3.08(m,4H),2.14(s,3H).ESI(M+H+):510.1829。
Embodiment 3:N-[3-[[2-[[4-(4-acetyl group-1-piperazinyl) phenyl] amino]-5-(chlorine)-4-pyrimidine radicals] ammonia Base] phenyl]-2-Phenyl Acrylamide
With reference to the method for embodiment 1 into, simply the 2-chloropropene acyl chlorides in step 2 is changed 2-phenylacrylyl chloride reaction knot Shu Hou, is evaporated to dry obtain crude product, obtains white solid through column chromatography purification (DCM/MeOH=100:1).1H NMR (500MHz,DMSO)δ10.28(s,1H),9.11(s,1H),8.89(s,1H),8.09(s,1H),7.97(s,1H),7.48- 7.47 (m, 5H), 7.37-7.35 (m 5H), 6.76 (d, J=6.9Hz, 2H), 5.95 (s, 1H), 5.73 (s, 1H), 3.52 (m, 4H),2.98-2.92(m,4H),2.02(s,3H).ESI(M+H+):568.2236。
Embodiment 4:N-[3-[[2-[[4-(4-acetyl group-1-piperazinyl)-2-methoxyphenyl] amino]-5-(chlorine)-4- Pyrimidine radicals] amino] phenyl]-2-trifluoromethyl acrylamide
With reference to the method for embodiment 1, simply change the 2-chloropropene acyl chlorides in step 2 into 2-trifluoromethyl acryloyl chloride anti- After should terminating, it is evaporated to dry obtain crude product, obtains white solid through column chromatography purification (DCM/MeOH=100:1).1H NMR (500MHz, DMSO) δ 9.17 (s, 1H), 8.91 (s, 1H), 8.17 (s, 1H), 7.58 (d, J=8.8Hz, 1H), 7.51 (d, J=8.9Hz, 2H), 7.28 (s, 1H), 7.06 (d, J=7.9Hz, 1H), 6.92 6.82 (m, 3H), 3.60 3.55 (m, 4H), 3.09–3.02(m,2H),3.03–2.96(m,2H),2.04(s,3H).ESI(M+H+):560.1781。
Embodiment 5:N-[3-[[2-[[4-(4-acetyl group-1-piperazinyl)-2-methoxyphenyl] amino]-5-(chlorine)-4- Pyrimidine radicals] amino] phenyl]-2-fluoropropene amide
With reference to the method for embodiment 3, simply by raw material 3-[2-[[4-(4-acetyl group-1-piperazinyl) phenyl] amino]-5- (chlorine)-4-pyrimidine radicals] t-butyl formate aminobenzene changes 3-[2-[[4-(4-acetyl group-1-piperazinyl)-2-methoxyphenyl] ammonia into Base]-5-(chlorine)-4-pyrimidine radicals] t-butyl formate aminobenzene, after reaction terminates, it is evaporated to dry obtain crude product, pure through column chromatography Change (DCM/MeOH=100:1) and obtain white solid.1H NMR(500MHz,CDCl3) δ 8.11 (d, J=8.8Hz, 1H), 8.07 (s, 1H), 8.04 7.94 (m, 2H), 7.46-7.43 (t, 2H), 7.39 7.34 (m, 2H), 7.10 (s, 1H), 6.54 (d, J=2.3Hz, 1H), 6.42 (d, J=8.7Hz, 1H), 5.90-5.79 (m, 1H), 5.30-5.24 (m, 1H), 3.88 (s, 3H), 3.80 3.76 (m,2H),3.65–3.60(m,2H),3.12–3.06(m,4H),2.15(s,3H).ESI(M+H+):540.1928。
Embodiment 6:N-[3-[[2-[[4-(4-acetyl group-1-piperazinyl)-2-methoxyphenyl] amino]-5-(chlorine)-4- Pyrimidine radicals] amino] phenyl]-2-trifluoromethyl acrylamide
With reference to the method for embodiment 5, simply by raw material 3-[2-[[4-(4-acetyl group-1-piperazinyl) phenyl] amino]-5- (chlorine)-4-pyrimidine radicals] t-butyl formate aminobenzene changes 3-[2-[[4-(4-acetyl group-1-piperazinyl)-2-methoxyphenyl] ammonia into Base]-5-(chlorine)-4-pyrimidine radicals] t-butyl formate aminobenzene, after reaction terminates, it is evaporated to dry obtain crude product, pure through column chromatography Change (DCM/MeOH=100:1) and obtain white solid.1H NMR(500MHz,CDCl3) δ 8.11 (d, J=8.8Hz, 1H), 8.07 (s, 1H), 7.75 (s, 1H), 7.46 (d, J=8.1Hz, 1H), 7.38 (d, J=7.4Hz, 2H), 7.36-7.34 (m, 3H), 7.36-7.34 (m, 1H), 7.20 (d, J=7.6Hz, 1H), 7.09 (s, 1H), 6.52 (d, J=2.3Hz, 1H), 3.85 (s, 3H), 3.78- 3.76(m,2H),3.62-3.60(m,2H),3.08-3.05(m,4H),2.15(s,3H).ESI(M+H+):590.1890。
Embodiment 7:N-[3-[[2-[[4-(4-acetyl group-1-piperazinyl)-2-methoxyphenyl] amino]-5-(chlorine)-4- Pyrimidine radicals] amino] phenyl]-2-chloroacrylamide
With reference to the method for embodiment 1, simply by raw material 3-[2-[[4-(4-acetyl group-1-piperazinyl) phenyl] amino]-5- (chlorine)-4-pyrimidine radicals] t-butyl formate aminobenzene changes 3-[2-[[4-(4-acetyl group-1-piperazinyl)-2-methoxyphenyl] into Amino]-5-(chlorine)-4-pyrimidine radicals] t-butyl formate aminobenzene, after reaction terminates, it is evaporated to dry obtain crude product, through post layer Analysis purification (DCM/MeOH=100:1) obtains white solid.1H NMR(500MHz,CDCl3) δ 8.36 (s, 1H), 8.12 (d, J= 8.7Hz, 1H), 8.06 (s, 1H), 8.01 (d, J=11.8Hz, 1H), 7.46 (d, J=7.8Hz, 1H), 7.42 (d, J= 7.7Hz, 2H), 7.37 (d, J=8.0Hz, 1H), 7.11 (s, 1H), 6.74 (d, J=1.3Hz, 1H), 6.53 (d, J=2.1Hz, 1H), 6.42 (d, J=8.6Hz, 1H), 5.93 (d, J=1.3Hz, 1H), 3.88 (s, 3H), 3.79 3.76 (m, 2H), 3.64 3.61(m,2H),3.13–3.06(m,4H),2.15(s,3H).ESI(M+H+):566.1632。
Embodiment 8:N-[3-[[2-[[4-(4-acetyl group-1-piperazinyl) phenyl] amino]-5-(trifluoromethyl chlorine)-4- Pyrimidine radicals] amino] phenyl]-2-fluoropropene amide
With reference to the method for embodiment 3, simply by raw material 3-[2-[[4-(4-acetyl group-1-piperazinyl) phenyl] amino]-5- (chlorine)-4-pyrimidine radicals] t-butyl formate aminobenzene changes 3-[2-[[4-(4-acetyl group-1-piperazinyl) phenyl] amino]-5-into (trifluoromethyl)-4-pyrimidine radicals] t-butyl formate aminobenzene, after reaction terminates, it is evaporated to dry obtain crude product, through column chromatography Purification (DCM/MeOH=100:1) obtains white solid.1H NMR (500MHz, DMSO) δ 10.21 (d, J=6.4Hz, 1H), 9.67 (s, 1H), 8.53 (s, 1H), 8.32 (s, 1H), 7.78 (s, 1H), 7.41 (d, J=7.2Hz, 1H), 7.33 (d, J= 6.9Hz, 2H), 7.24 (d, J=6.9Hz, 1H), 7.05 (s, 1H), 6.93 (d, J=8.3Hz, 2H), 5.71 (dd, J=47.5, 2.8Hz, 1H), 5.43 (dd, J=15.3,3.1Hz, 1H), 3.60 (s, 4H), 3.11 (d, J=35.4Hz, 4H), 2.06 (s, 3H) .ESI (M+H+): 544.2081.
Embodiment 9:N-[3-[[2-[[4-(4-acetyl group-1-piperazinyl)-2-methoxyphenyl] amino]-5-(fluoroform Base)-4-pyrimidine radicals] amino] phenyl]-2-chloroacrylamide.
With reference to the method for embodiment 1, simply by raw material 3-[2-[[4-(4-acetyl group-1-piperazinyl) phenyl] amino]-5- (chlorine)-4-pyrimidine radicals] t-butyl formate aminobenzene changes 3-[2-[[4-(4-acetyl group-1-piperazinyl)-2-methoxyphenyl] ammonia into Base]-5-(trifluoromethyl)-4-pyrimidine radicals] t-butyl formate aminobenzene, after reaction terminates, it is evaporated to dry obtain crude product, through post layer Analysis purification (DCM/MeOH=100:1) obtains white solid.1H NMR(500MHz,CDCl3)δ8.40(s,1H),8.14(s,1H),8.08 (s, 1H), 7.62-7.58 (m, 1H), 7.44 (d, J=8.7Hz, 1H), 7.37 (t, 1H), 7.13 (s, 1H), 7.08 (s, 1H), 7.02 (d, J=8.5Hz, 1H), 6.85-6.81 (m, 1H), 6.74 (d, J=1.2Hz, 1H), 5.93 (d, J=1.2Hz, 1H), 3.80 3.77 (m,2H),3.64–3.61(m,2H),3.03–2.97(m,4H),2.14(s,3H),1.65(s,3H).ESI(M+H+):590.1990。
[[[2-[[4-(4-acetyl group-1-piperazinyl)-3-chlorphenyl] amino]-5-(chlorine)-4-is phonetic for 3-for embodiment 10:N- Piperidinyl] amino] phenyl]-2-fluoropropene amide
With reference to the method for embodiment 3, simply by raw material 3-[2-[[4-(4-acetyl group-1-piperazinyl) phenyl] amino]-5- (chlorine)-4-pyrimidine radicals] t-butyl formate aminobenzene change into 3-[2-[[4-(4-acetyl group-1-piperazinyl)-3-chlorphenyl] amino]- 5-(chlorine)-4-pyrimidine radicals] t-butyl formate aminobenzene, after reaction terminates, it is evaporated to dry obtain crude product, through column chromatography purification (DCM/MeOH=100:1) white solid is obtained.1H NMR(500MHz,DMSO)δ10.31(s,1H),9.44(s,1H),8.38(s, 1H), 7.86 (s, 1H), 7.37 (m, 2H), 7.14 (m, 3H), 5.68 (d, J=47.5Hz, 1H), 5.54 5.43 (m, 2H), 5.33 (d, J=14.1Hz, 1H), 3.60 (s, 4H), 2.97 (d, J=31.6Hz, 4H), 2.05 (s, 3H) .ESI (M+H+):544.1429。
[[[2-[[4-(4-methyl isophthalic acid-piperazinyl)-2-methoxyphenyl] oxygen]-5-(chlorine)-4-is phonetic for 3-for embodiment 11:N- Piperidinyl] amino] phenyl]-2-fluoropropene amide
With reference to the method for embodiment 3, simply by raw material 3-[2-[[4-(4-acetyl group-1-piperazinyl) phenyl] amino]-5- (chlorine)-4-pyrimidine radicals] t-butyl formate aminobenzene changes 3-[2-[[4-(4-methyl isophthalic acid-piperazinyl)-2-methoxyphenyl] into Oxygen]-5-(chlorine)-4-pyrimidine radicals] t-butyl formate aminobenzene, after reaction terminates, it is evaporated to dry obtain crude product, through column chromatography Purification (DCM/MeOH=100:1) obtains white solid.1H NMR(500MHz,CDCl3)δ8.23(s,1H),8.02(s,1H), 7.63 (d, J=7.0Hz, 2H), 7.51 (s, 1H), 7.46 (t, J=8.1Hz, 2H), 7.05 (d, J=7.5Hz, 1H), 6.45 (s,1H),6.20(s,1H),5.88-5.78(m,1H),5.31–5.23(m,1H),3.81(s,3H),3.11(m,4H),2.58 (m,4H),2.36(s,3H).ESI(M+H+):513.1819。
Embodiment 12:N-[3-[[2-[[4-(4-acetyl group-1-piperazinyl)-2-methoxyphenyl] amino]-5-(trifluoro Methyl)-4-pyrimidine radicals] amino] phenyl]-2-trifluoromethyl acrylamide
With reference to the method for embodiment 5, simply by raw material 3-[2-[[4-(4-acetyl group-1-piperazinyl) phenyl] amino]-5- (chlorine)-4-pyrimidine radicals] t-butyl formate aminobenzene changes 3-[2-[[4-(4-methyl isophthalic acid-piperazinyl)-2-methoxyphenyl] ammonia into Base]-5-(trifluoromethyl)-4-pyrimidine radicals] t-butyl formate aminobenzene, after reaction terminates, it is evaporated to the dry crude product that obtains, warp Column chromatography purification (DCM/MeOH=100:1) obtains white solid.1H NMR(500MHz,CDCl3)δ8.30(s,1H),8.04 (s,1H),7.85(s,1H),7.60(s,1H),7.45(t,1H),7.37(s,2H),6.87(s,1H),6.58(s,1H),6.49 (s, 1H), 6.34 (s, 1H), 3.86 (s, 3H), 3.75 (s, 2H), 3.61 (s, 2H), 3.07 (d, J=17.2Hz, 4H), 2.14 (s,3H).ESI(M+H+):624.6266。
Embodiment 13:N-[3-[[2-[[4-(4-acetyl group-1-piperazinyl)-2-methoxyphenyl] oxygen]-5-(chlorine)-4- Pyrimidine radicals] amino] phenyl]-2-fluoropropene amide
With reference to the method for embodiment 3, simply by raw material 3-[2-[[4-(4-acetyl group-1-piperazinyl) phenyl] amino]-5- (chlorine)-4-pyrimidine radicals] t-butyl formate aminobenzene changes 3-[2-[[4-(4-methyl isophthalic acid-piperazinyl)-2-methoxyphenyl] ammonia into Base]-5-(chlorine)-4-pyrimidine radicals] t-butyl formate aminobenzene, after reaction terminates, it is evaporated to dry obtain crude product, through column chromatography Purification (DCM/MeOH=100:1) obtains white solid.1H NMR(500MHz,CDCl3) δ 8.25 (s, 1H), 8.03 (d, J= 4.5Hz, 1H), 7.66 (d, J=7.4Hz, 2H), 7.49-7.45 (m, 3H), 7.06-7.04 (m, 1H), 6.46 (d, J= 1.9Hz,1H),6.19(s,1H),5.88-5.78(m,1H),5.29-5.25(m,1H),3.83(s,3H),3.78–3.73(m, 2H),3.64–3.58(m,2H),3.10–2.97(m,4H),2.14(s,3H).ESI(M+H+):541.1763。
Embodiment 14:N-[3-[[2-[[4-(4-acetyl group-1-piperazinyl)-3-fluorophenyl] oxygen]-5-(chlorine)-4-pyrimidine Base] amino] phenyl]-2-fluoropropene amide
With reference to the method for embodiment 3, simply by raw material 3-[2-[[4-(4-acetyl group-1-piperazinyl) phenyl] amino]-5- (chlorine)-4-pyrimidine radicals] t-butyl formate aminobenzene change into 3-[2-[[4-(4-methyl isophthalic acid-piperazinyl)-3-fluorophenyl] amino]- 5-(chlorine)-4-pyrimidine radicals] t-butyl formate aminobenzene, after reaction terminates, it is evaporated to dry obtain crude product, through column chromatography purification (DCM/MeOH=100:1) white solid is obtained.1H NMR(500MHz,CDCl3)δ8.15(s,1H),8.10–8.01(m,2H), 7.58 (d, J=14.5Hz, 1H), 7.44 7.33 (m, 2H), 7.29 (d, J=8.0Hz, 2H), 7.18 (s, 1H), 7.13 (s, 1H), 7.03 (d, J=8.4Hz, 1H), 6.83 (t, 1H), 5.89-5.79 (m, 1H), 5.28-5.25 (m, 1H), 3.78 (m, 2H),3.62(m,2H),3.01-2.97(m,4H),2.14(s,3H).ESI(M+H+):528.1725。
[[[2-[[4-(4-acetyl group-1-piperazinyl)-3-aminomethyl phenyl] oxygen]-5-(chlorine)-4-is phonetic for 3-for embodiment 15:N- Piperidinyl] amino] phenyl]-2-chloroacrylamide
With reference to the method for embodiment 1, simply by raw material 3-[2-[[4-(4-acetyl group-1-piperazinyl) phenyl] amino]-5- (chlorine)-4-pyrimidine radicals] t-butyl formate aminobenzene changes 3-[2-[[4-(4-methyl isophthalic acid-piperazinyl)-3-aminomethyl phenyl] ammonia into Base]-5-(chlorine)-4-pyrimidine radicals] t-butyl formate aminobenzene, after reaction terminates, it is evaporated to dry obtain crude product, through column chromatography Purification (DCM/MeOH=100:1) obtains white solid.1H NMR(500MHz,CDCl3)δ8.36(s,1H),8.06(s,2H), 7.52 (d, J=7.9Hz, 1H), 7.36 7.32 (m, 3H), 7.28 (s, 1H), 7.12 (s, 1H), 6.99 (s, 1H), 6.91 (d, J =8.4Hz, 1H), 6.74 (d, J=1.2Hz, 1H), 5.93 (d, J=1.2Hz, 1H), 3.75-3.71 (m, 2H), 3.61 3.57 (m,2H),2.87–2.80(m,4H),2.27(s,3H),2.15(s,3H).ESI(M+H+):540.1682。
Embodiment 16:N-[2-[(2,2-dimethylamino) 5-[[4-(1-Methyl-1H-indole-3-base)-2-(5-chlorine)- Pyrimidine radicals] amino] phenyl]-2-fluoropropene amide
With reference to the method for embodiment 3, simply by raw material 3-[2-[[4-(4-acetyl group-1-piperazinyl) phenyl] amino]-5- (chlorine)-4-pyrimidine radicals] t-butyl formate aminobenzene changes [(2,2-dimethylamino) 5-[[4-(1-Methyl-1H-indole-3-into Base)-2-(5-chlorine)-pyrimidine radicals] t-butyl formate amino, after reaction terminates, it is evaporated to dry obtain crude product, pure through column chromatography Change (DCM/MeOH=100:1) and obtain white solid.1H NMR(500MHz,CDCl3) δ 9.53 (s, 1H), 8.54 (d, J= 8.0Hz, 1H), 8.51 (d, J=2.4Hz, 1H), 8.36 (s, 1H), 8.29 (s, 1H), 7.71-7.69 (m, 1H), 7.39 (d, J =8.1Hz, 1H), 7.33 (t, 1H), 7.24 (d, J=7.5Hz, 1H), 7.22-7.20 (m, 2H), 5.86-5.76 (m, 1H), 5.26-5.23(m,1H),3.90(s,3H),2.67(s,6H).ESI(M+H+):465.1605。
Embodiment 17:N-[3-[[2-[[4-(4-acetyl group-1-piperazinyl)-3-aminomethyl phenyl] amino]-5-(chlorine)-4- Pyrimidine radicals] amino] phenyl]-2-fluoropropene amide
With reference to the method for embodiment 3, simply by raw material 3-[2-[[4-(4-acetyl group-1-piperazinyl) phenyl] amino]-5- (chlorine)-4-pyrimidine radicals] t-butyl formate aminobenzene changes 3-[2-[[4-(4-acetyl group-1-piperazinyl)-3-methylbenzene into Base] amino]-5-(chlorine)-4-pyrimidine radicals] t-butyl formate aminobenzene, after reaction terminates, it is evaporated to the dry crude product that obtains, warp Column chromatography purification (DCM/MeOH=100:1) obtains white solid.1H NMR(500MHz,CDCl3) δ 8.08 (d, J=9.8Hz, 2H), 7.95 (s, 1H), 7.49 (d, J=7.3Hz, 1H), 7.35-7.30 (m, 4H), 7.11 (s, 1H), 6.96 (s, 1H), 6.94–6.87(m,1H),5.90-5.80(m,1H),5.30-5.26(m,1H),3.75–3.72(m,2H),3.62–3.56(m, 2H),2.88–2.79(m,4H),2.28(s,3H),2.15(s,3H).ESI(M+H+):524.1978。
Embodiment 18:N-[3-[[2-[[4-(4-acetyl group-1-piperazinyl)-3-aminomethyl phenyl] amino]-5-(chlorine)-4- Pyrimidine radicals] amino] phenyl]-2-trifluoromethyl acrylamide
With reference to the method for embodiment 5, simply by raw material 3-[2-[[4-(4-acetyl group-1-piperazinyl) phenyl] amino]-5- (chlorine)-4-pyrimidine radicals] t-butyl formate aminobenzene changes 3-[2-[[4-(4-acetyl group-1-piperazinyl)-3 aminomethyl phenyls] into Amino]-5-(chlorine)-4-pyrimidine radicals] t-butyl formate aminobenzene, it is evaporated to dry obtain crude product, through column chromatography purification (DCM/MeOH=100:1) white solid is obtained.1H NMR(500MHz,CDCl3)δ8.08(s,1H),7.88(s,1H),7.45 (d, J=8.1Hz, 1H), 7.37 (d, J=2.4Hz, 1H), 7.33 (t, 1H), 7.30-7.28 (m 1H), 7.11 (s, 1H), 7.02 (d, J=7.8Hz, 1H), 6.98 (s, 1H), 6.92 (d, J=8.6Hz, 1H), 3.75 (t, 2H), 3.60 (t, 2H), 2.88–2.82(m,4H),2.27(s,3H),2.15(s,3H).ESI(M+H+):547.1962。
[[[2-[[4-(4-methyl isophthalic acid-piperazinyl)-2-methoxyphenyl] oxygen]-5-(chlorine)-4-is phonetic for 3-for embodiment 19:N- Piperidinyl] amino] phenyl]-2-chloroacrylamide
With reference to the method for embodiment 1, simply by raw material 3-[2-[[4-(4-acetyl group-1-piperazinyl) phenyl] amino]-5- (chlorine)-4-pyrimidine radicals] t-butyl formate aminobenzene changes 3-[2-[[4-(4-methyl isophthalic acid-piperazinyl)-2-methoxyphenyl] into Oxygen]-5-(chlorine)-4-pyrimidine radicals] t-butyl formate aminobenzene, after reaction terminates, it is evaporated to dry obtain crude product, through column chromatography Purification (DCM/MeOH=100:1) obtains white solid.1H NMR(500MHz,CDCl3)δ8.43(s,1H),8.23(s,1H), 7.63 (d, J=7.8Hz, 1H), 7.53 (t, 1H), 7.46 (t, 2H), 7.06-7.04 (m, 1H), 6.73 (d, J=1.3Hz, 1H), 6.45 (d, J=2.3Hz, 1H), 6.21 (s, 1H), 5.92 (d, J=1.4Hz, 1H), 3.82 (s, 3H), 3.15 3.04 (m,4H),2.61–2.54(m,4H),2.37(s,3H).ESI(M+H+):529.1519。
Embodiment 20:N-[2-[(2,2-dimethylamino) 5-[[4-(1-Methyl-1H-indole-3-base)-2-(5-chlorine)- Pyrimidine radicals] amino] phenyl]-2-chloroacrylamide
With reference to the method for embodiment 20 into, simply raw material 2-fluoropropene acyl chlorides is changed 2-chloropropene acyl chlorides, after reaction terminates, It is evaporated to dry obtain crude product, obtains white solid through column chromatography purification (DCM/MeOH=100:1).1H NMR(500MHz, CDCl3) δ 10.01 (s, 1H), 8.55 (d, J=8.0Hz, 1H), 8.50 (d, J=2.5Hz, 1H), 8.37 (s, 1H), 8.28 (s, 1H), 7.71-7.69 (m, 1H), 7.38 (d, J=8.1Hz, 1H), 7.36 7.30 (m, 1H), 7.26 (s, 1H), 7.24 (d, J= 7.1Hz, 1H), 7.20 (d, J=8.7Hz, 1H), 6.71 (d, J=1.3Hz, 1H), 5.91 (d, J=1.3Hz, 1H), 3.89 (s, 3H),2.69(s,6H).ESI(M+H+):481.1311。
Embodiment 21:N-[3-[[2-[[4-(4-acetyl group-1-piperazinyl)-2-methoxyphenyl] oxygen]-5-(chlorine)-4- Pyrimidine radicals] amino] phenyl]-2-chloroacrylamide
With reference to the method for embodiment 1, simply by raw material 3-[2-[[4-(4-acetyl group-1-piperazinyl) phenyl] amino]-5- (chlorine)-4-pyrimidine radicals] t-butyl formate aminobenzene changes 3-[2-[[4-(4-acetyl group-1-piperazinyl)-2-methoxyphenyl] into Oxygen]-5-(chlorine)-4-pyrimidine radicals] t-butyl formate aminobenzene, after reaction terminates, it is evaporated to dry obtain crude product, through column chromatography Purification (DCM/MeOH=100:1) obtains white solid.1H NMR(500MHz,CDCl3)δ8.47(s,1H),8.24(s,1H), 7.66 (d, J=7.6Hz, 1H), 7.51-7.45 (m, 3H), 7.06-7.04 (m, 1H), 6.72 (d, J=1.4Hz, 1H), 6.46 (d, J=2.2Hz, 1H), 6.20 (s, 1H), 5.93 (d, J=1.3Hz, 1H), 3.83 (s 3H), 3.79 3.72 (m, 2H), 3.63–3.57(m,2H),3.10–2.98(m,4H),2.14(s,3H).ESI(M+H+):557.1467。
[[[2-[[4-(4-acetyl group-1-piperazinyl)-3-fluorophenyl] amino]-5-(chlorine)-4-is phonetic for 3-for embodiment 22:N- Piperidinyl] amino] phenyl]-2-chloroacrylamide
With reference to the method for embodiment 1, simply by raw material 3-[2-[[4-(4-acetyl group-1-piperazinyl) phenyl] amino]-5- (chlorine)-4-pyrimidine radicals] t-butyl formate aminobenzene changes 3-[2-[[4-(4-acetyl group-1-piperazinyl)-3-fluorophenyl] ammonia into Base]-5-(chlorine)-4-pyrimidine radicals] t-butyl formate aminobenzene, after reaction terminates, it is evaporated to dry obtain crude product, through column chromatography Purification (DCM/MeOH=100:1) obtains white solid.1H NMR(500MHz,CDCl3)δ8.38(s,1H),8.12(s,1H), 8.06 (s, 1H), 7.60-7.56 (m, 1H), 7.42 (d, J=8.7Hz, 1H), 7.35 (t, 1H), 7.11 (s, 1H), 7.06 (s, 1H), 7.01-6.99 (m, 1H), 6.81 (t, 1H), 6.72 (d, J=1.2Hz, 1H), 5.91 (d, J=1.2Hz, 1H), 3.76 (t,3H),3.61(t,3H),3.00–2.95(m,4H),2.12(s,3H).ESI(M+H+):544.1431。
Embodiment 23:N-[2-[(2,2-dimethylamino) 5-[[4-(1-Methyl-1H-indole-3-base)-2-(5-chlorine)- Pyrimidine radicals] amino] phenyl]-2-trifluoromethyl acrylamide
With reference to the method for embodiment 20 into, simply raw material 2-fluorine propionyl chloride is changed 2-trifluoromethyl acryloyl chloride, reaction knot Shu Hou, is evaporated to dry obtain crude product, obtains white solid through column chromatography purification (DCM/MeOH=100:1).1H NMR (500MHz,CDCl3) δ 11.78 (s, 1H), 8.69 (d, J=7.6Hz, 1H), 8.40 (s, 1H), 8.24 (s, 1H), 8.16 (d, J =8.8Hz, 1H), 7.40 (d, J=7.7Hz, 1H), 7.37-7.35 (m, 1H), 7.34-7.33 (m, 1H), 7.31-7.30 (m, 1H), 7.19 (d, J=8.8Hz, 1H), 5.83 (s, 1H), 3.91 (s, 3H), 2.62 (s, 6H) .ESI (M+H+):515.1572。
[[[2-[[4-(4-acetyl group-1-piperazinyl) phenyl] amino]-5-(trifluoromethyl)-4-is phonetic for 3-for embodiment 24:N- Piperidinyl] amino] phenyl]-2-chloroacrylamide
With reference to the method for embodiment 15, simply by raw material 3-[2-[[4-(4-acetyl group-1-piperazinyl) phenyl] amino]- 5-(chlorine)-4-pyrimidine radicals] t-butyl formate aminobenzene changes 3-[2-[[4-(4-acetyl group-1-piperazinyl) phenyl] amino]-5-into (trifluoromethyl)-4-pyrimidine radicals] t-butyl formate aminobenzene, after reaction terminates, it is evaporated to dry obtain crude product, through column chromatography Purification (DCM/MeOH=100:1) obtains white solid.1H NMR(500MHz,CDCl3)δ8.31(s,1H),8.24(s,1H),7.81 (s, 1H), 7.49 (d, J=3.0Hz, 1H), 7.40 (d, J=8.9Hz, 2H), 7.33 (d, J=8.9Hz, 2H), 7.22 (t, 1H), 6.93 6.90 (m, 2H), 6.78 (s, 1H), 6.72 (d, J=1.3Hz, 1H), 5.91 (d, J=1.3Hz, 1H), 3.79 3.76 (m,2H),3.65-3.63(m,2H),3.19-3.14(m,4H),2.16(s,3H).ESI(M+H+):560.1793。
Embodiment 25:N-[3-[[2-[[5-(4-acetyl group-1-piperazinyl) pyridine radicals] amino]-5-(chlorine)-4-pyrimidine Base] amino] phenyl]-2-chloroacrylamide
With reference to the method for embodiment 1, simply by raw material 3-[2-[[4-(4-acetyl group-1-piperazinyl) phenyl] amino]-5- (chlorine)-4-pyrimidine radicals] t-butyl formate aminobenzene change into 3-[[2-[[5-(4-acetyl group-1-piperazinyl) pyridine radicals] amino]- 5-(chlorine)-4-pyrimidine radicals] amino] t-butyl formate aminobenzene, after reaction terminates, it is evaporated to dry obtain crude product, through post layer Analysis purification (DCM/MeOH=100:1) obtains white solid.1H NMR(500MHz,DMSO)δ10.18(s,1H),9.14(s, 1H), 8.90 (s, 1H), 8.27 (s, 1H), 8.10 (s, 1H), 7.92 (s, 1H), 7.84 (dd, J=9.1,2.6Hz, 1H), 7.46 (d, J=7.4Hz, 1H), 7.35 (d, J=24.0Hz, 1H), 7.31 (t, J=8.0Hz, 1H), 6.66 (d, J=7.9Hz, 1H), 6.41 (d, J=2.5Hz, 1H), 6.10 (d, J=2.6Hz, 1H), 3.54-3.51 (m, 4H), 3.41 3.38 (m, 2H), 3.31 (m,2H),2.04(s,3H).ESI(M+H+):527.1480。
Embodiment 26:N-[3-[[2-[[5-(4-acetyl group-1-piperazinyl) pyridine radicals] amino]-5-(chlorine)-4-pyrimidine Base] amino] phenyl]-2-fluoropropene amide
With reference to the method for embodiment 29 into, simply raw material 2-chloropropene acyl chlorides is changed 2-fluoropropene acyl chlorides, after reaction terminates, It is evaporated to dry obtain crude product, through column chromatography purification (DCM/MeOH=100:1), obtains white solid.1H NMR (500MHz,CDCl3) δ 8.27 (d, J=2.6Hz, 1H), 8.14 (s, 1H), 8.04 (s, 1H), 7.97 (d, J=2.5Hz, 1H), 7.82 (dd, J=9.0,2.7Hz, 1H), 7.38 7.28 (m, 3H), 7.11 (s, 1H), 6.89 (s, 1H), 6.63 (d, J= 9.0Hz, 1H), 5.84 (dd, J=47.8,3.4Hz, 1H), 5.27 (dd, J=15.2,3.4Hz, 1H), 3.78 3.72 (m, 2H),3.59-3.56(m,4H),3.47–3.40(m,2H),2.15(s,3H).ESI(M+H+):511.1760。
Embodiment 27:N-[3-[[2-[[4-(4-acetyl group-1-piperazinyl)-3-trifluoromethyl] amino]-5- (chlorine)-4-pyrimidine radicals] amino] phenyl]-2-chloroacrylamide
With reference to the method for embodiment 1, simply by raw material 3-[2-[[4-(4-acetyl group-1-piperazinyl) phenyl] amino]-5- (chlorine)-4-pyrimidine radicals] t-butyl formate aminobenzene changes 3-[2-[[4-(4-acetyl group-1-piperazinyl)-3-trifluoromethylbenzene into Base] amino]-5-(chlorine)-4-pyrimidine radicals] t-butyl formate aminobenzene, after reaction terminates, it is evaporated to the dry crude product that obtains, warp Column chromatography purification (DCM/MeOH=100:1) obtains white solid.1H NMR(500MHz,DMSO)δ10.21(s,1H),9.57 (s, 1H), 9.01 (s, 1H), 8.19 (s, 1H), 7.99 (d, J=7.8Hz, 1H), 7.92 (s, 1H), 7.82 (s, 1H), 7.49 (d, J=6.5Hz, 1H), 7.40 7.32 (m, 2H), 7.26 (d, J=8.3Hz, 1H), 6.41 (d, J=1.8Hz, 1H), 6.09 (s,1H),3.51(m,4H),2.77–2.69(m,4H),2.04(s,3H).ESI(M+H+):594.1390。
Embodiment 28:N-[3-[[2-[[4-(4-acetyl group-1-piperazinyl)-3-trifluoromethyl] amino]-5- (chlorine)-4-pyrimidine radicals] amino] phenyl]-2-fluoropropene amide
With reference to the method for embodiment 31, simply raw material 2-chlorpromazine chloride is changed into and 2-fluoropropene acyl chlorides, after reaction terminates, It is evaporated to dry obtain crude product, obtains white solid through column chromatography purification (DCM/MeOH=100:1).1H NMR(500MHz, DMSO) δ 10.32 (s, 1H), 9.57 (s, 1H), 9.02 (s, 1H), 8.19 (s, 1H), 7.99 (d, J=11.7Hz, 2H), 7.81 (s, 1H), 7.55 (d, J=6.3Hz, 1H), 7.34 (d, J=6.4Hz, 2H), 7.25 (d, J=8.0Hz, 1H), 5.69 (dd, J =47.6,3.0Hz, 1H), 5.42 (dd, J=15.4,3.0Hz, 1H), 3.51 (m, 4H), 2.75-2.70 (m, 4H), 2.04 (s, 3H).ESI(M+H+):578.1680。
[[[2-[[4-(4-acetyl group-1-piperazinyl)-3-chlorphenyl] amino]-5-(chlorine)-4-is phonetic for 3-for embodiment 29:N- Piperidinyl] amino] phenyl]-2-chloroacrylamide
With reference to the method for embodiment 1, simply by raw material 3-[2-[[4-(4-acetyl group-1-piperazinyl) phenyl] amino]-5- (chlorine)-4-pyrimidine radicals] t-butyl formate aminobenzene changes 3-[2-[[4-(4-acetyl group-1-piperazinyl)-3-chlorphenyl] ammonia into Base]-5-(chlorine)-4-pyrimidine radicals] t-butyl formate aminobenzene, after reaction terminates, it is evaporated to dry obtain crude product, through column chromatography Purification (DCM/MeOH=100:1) obtains white solid.1H NMR(500MHz,DMSO)δ10.20(s,1H),9.41(s,1H), 8.98 (s, 1H), 8.16 (s, 1H), 7.92 (s, 1H), 7.74 (s, 1H), 7.52 (dd, J=8.9,2.1Hz, 2H), 7.35 (d, J =4.8Hz, 2H), 6.91 (d, J=8.7Hz, 1H), 6.40 (d, J=2.2Hz, 1H), 6.08 (d, J=2.4Hz, 1H), 3.58 3.53(m,4H),2.88–2.83(m,2H),2.81–2.77(m,2H),2.03(s,3H).ESI(M+H+):560.1139。
[[[2-[[4-(4-acetyl group-1-piperazinyl)-2-fluorophenyl] amino]-5-(chlorine)-4-is phonetic for 3-for embodiment 30:N- Piperidinyl] amino] phenyl]-2-chloroacrylamide
With reference to the method for embodiment 1, simply by raw material 3-[2-[[4-(4-acetyl group-1-piperazinyl) phenyl] amino]-5- (chlorine)-4-pyrimidine radicals] t-butyl formate aminobenzene changes 3-[2-[[4-(4-acetyl group-1-piperazinyl)-2-chlorphenyl] ammonia into Base]-5-(chlorine)-4-pyrimidine radicals] t-butyl formate aminobenzene, after reaction terminates, it is evaporated to dry obtain crude product, through column chromatography Purification (DCM/MeOH=100:1) obtains white solid.1H NMR(500MHz,DMSO)δ10.13(s,1H),8.82(s,1H), 8.37 (s, 1H), 8.06 (s, 1H), 7.91 (s, 1H), 7.48 (d, J=8.9Hz, 1H), 7.43 (d, J=7.7Hz, 1H), 7.34 (d, J=8.2Hz, 1H), 7.18 (t, J=8.1Hz, 1H), 7.01 (d, J=2.6Hz, 1H), 6.81 (dd, J=8.8,2.5Hz, 1H), 6.43 (d, J=2.5Hz, 1H), 6.10 (d, J=2.5Hz, 1H), 3.57-3.56 (m, 4H), 3.15-3.06 (m, 4H), 2.05(s,3H).ESI(M+H+):560.1143。
Embodiment 31:N-[3-[[2-[[4-(4-acetyl group-1-piperazinyl) phenyl] oxygen]-5-(chlorine)-4-pyrimidine radicals] ammonia Base] phenyl]-2-chloroacrylamide
With reference to the method for embodiment 1, simply by raw material 3-[2-[[4-(4-acetyl group-1-piperazinyl) phenyl] amino]-5- (chlorine)-4-pyrimidine radicals] t-butyl formate aminobenzene changes 3-[2-[[4-(4-acetyl group-1-piperazinyl) phenyl] oxygen]-5-into (chlorine)-4-pyrimidine radicals] t-butyl formate aminobenzene, after reaction terminates, it is evaporated to dry obtain crude product, through column chromatography purification (DCM/MeOH=100:1) white solid is obtained.1H NMR(500MHz,DMSO)δ10.38(s,1H),9.56(s,1H),8.42 (s, 1H), 7.70 (d, J=7.9Hz, 1H), 7.62 (d, J=1.8Hz, 1H), 7.48 (t, J=8.2Hz, 1H), 7.25 (s, 2H), 7.07 (dd, J=8.0,1.9Hz, 1H), 6.69 (m, 2H), 6.43 (d, J=2.6Hz, 1H), 6.12 (d, J=2.6Hz, 1H),3.56-3.53(m,4H),3.03–2.85(m,4H),2.03(s,3H).ESI(M+H+):527.1363。
Embodiment 32:N-[3-[[2-[[4-(4-acetyl group-1-piperazinyl)-3-trifluoromethyl] oxygen]-5-(chlorine)- 4-pyrimidine radicals] amino] phenyl]-2-chloroacrylamide
With reference to the method for embodiment 1, simply by raw material 3-[2-[[4-(4-acetyl group-1-piperazinyl) phenyl] amino]-5- (chlorine)-4-pyrimidine radicals] t-butyl formate aminobenzene changes 3-[2-[[4-(4-acetyl group-1-piperazinyl)-3-trifluoromethyl] into Oxygen]-5-(chlorine)-4-pyrimidine radicals] t-butyl formate aminobenzene, after reaction terminates, it is evaporated to dry obtain crude product, pure through column chromatography Change (DCM/MeOH=100:1) and obtain white solid.1H NMR(500MHz,DMSO)δ10.39(s,1H),9.96(s,1H),8.53 (s, 1H), 7.73 (s, 1H), 7.71 7.66 (m, 2H), 7.65 (t, J=2.0Hz, 1H), 7.47 (t, J=8.1Hz, 1H), 7.22 (d, J=6.6Hz, 1H), 7.09 7.04 (m, 1H), 6.43 (d, J=2.6Hz, 1H), 6.11 (d, J=2.6Hz, 1H), 3.51- 3.50 (m, 4H), 2.78 2.72 (m, 2H), 2.69 (t, J=4.8Hz, 2H), 2.04 (s, 3H) .ESI (M+H+): 595.1250.
Effect example 1: the compounds of this invention is to A431, H1975, SW620 cell inhibitory effect determination of activity
The present embodiment is thin for Wild type EGFR high expressed people's epidermal carcinoma for measuring the compound that disclosed in this invention Born of the same parents strain A431, [L858R/T790M] EGFR point mutation human lung adenocarcinoma cell line H1975 and low expression EGFR human colon cancer cell The proliferation inhibition activity of strain SW620, the inhibitory activity half-inhibition concentration IC of compound on intracellular propagation50Represent.Test Scheme is as follows: Wild type EGFR high expressed people epidermal carcinoma cell strain A431, [L858R/T790M] EGFR point mutation human lung adenocarcinoma is thin Born of the same parents strain H1975 and low expression EGFR human colon cancer cell strain SW620 is all purchased from ATCC, with suitable cell concentration (A431: 20000 cell/ml culture medium；H1975:15000 cell/ml culture medium, SW620:20000 cell/ml culture medium) will Cell is inoculated on 384 well culture plates of White-opalescent；Afterwards cell is positioned over 37 DEG C, 5%CO2Environment in train Support, after 24 hours, in the cell culture medium cultivated, add the medicine of a series of Concentraton gradient, be typically chosen 10 concentration, it After cell is put back to former culture environment continues cultivate 48 hours, afterwards according to MTT detection method, measure test-compound pair The impact of A431, H1975 and SW620 cell proliferation, and calculate the inhibitory activity of the compound on intracellular propagation of variable concentrations, The IC of test-compound of the present invention50Data such as table 1 below.
Table 1
Having certain novelty in the compounds of this invention structure, Bioactivity evaluation result shows simultaneously, this Bright compound is to the people epidermal carcinoma cell strain A431 of process LAN EGFR, human lung adenocarcinoma cell line to Gefitinib drug resistance H1975 has obvious Inhibit proliferaton activity, and the proliferation inhibition activity of low expression EGFR human colon cancer cell strain SW620 is more weak.
Effect example 2: the compounds of this invention is to EGFRWT、EGFRL858R/T790MThe inhibitory action of tyrosine kinase activity
Enzymatic activity test uses Mobility shift assay method to carry out (Expert Opin Drug Discov.2008,3(6):607–621).After compound weighs, the DMSO being configured to 10mM stores liquid.Before test, according to required Concentration, the compound taking appropriate 10mM stores liquid, is dissolved in the water, is configured to the compound that respective concentration is ultimate density 5 times Working solution.And by the various kinases needed for reaction, EGFRWT、EGFRL858R/T790MBeing dissolved in concentration is desired concn 1.25 times In reaction buffer (62.5mM HEPES, pH7.5,0.001875%Brij-35,12.5mM MgCl2,2.5mM DTT), join Make the enzyme working solution that concentration is ultimate density 2.5 times.Peptide substrate by ATP and the FAM labelling needed for reaction is the most molten simultaneously Liquid, in the reaction buffer of 1.25X, is configured to substrate and ATP working solution that concentration is desired concn 2.5 times.Backward 384 Detection plate in hole adds 5 μ l compound working solutions, in blank (min), adds the EDTA of 5 μ l 250mM, to negative control (Max) add not drug containing in, but contain the working solution of the DMSO of same volume.It is simultaneously introduced 10 μ l enzyme working solutions, mixes gently After, incubated at room 10 minutes, backward each reacting hole in add substrate and the ATP working solution of 10 μ l, detection plate is placed in 28 degree Under the conditions of hatch 60 minutes, backward each reacting hole in add 25 μ l enzyme reaction stop liquid (100mM HEPES, pH7.5, 0.015%Brij-35,0.2%Coating Reagent#3,50mM EDTA), to stop enzyme reaction, afterwards Sptting plate is put The substrate conversion rate (substrate is by the ratio of tyrosine phosphorylation) in each reacting hole is gathered in Caliper EZ reader, and right Above-mentioned data are analyzed, and kinase whose suppression ratio is calculated and carries out as follows by compound: %inh=(Max- Conversion)/(Max-Min) × 100, wherein %inh is percent inhibition, and Max is that the substrate in negative control hole turns Changing rate, min is the substrate conversion rate in blank control wells, in conversion is each reacting hole adding variable concentrations compound Substrate conversion rate.%inh under calculated each concentration compound is imported in Xlift and is analyzed, it is thus achieved that be corresponding IC50, curve fitting formula is: Y=Bottom+ (Top-Bottom)/(1+10^ ((LogIC50-X) * Hillslope)).Table 2 For acquired results.
Table 2
The compound of the present invention is to EGFRWTThere is preferable inhibitory activity, particularly to EGFRL858R/T790MSuppression live Property is better than EGFRWT, illustrate that the selectivity of this compounds is preferable.

Claims (4)

1. the pyridine derivatives containing halo acrylamide side chain, it is characterised in that general structure I is as follows:
Wherein:
R1For halogen, methyl, methoxyl group, trifluoromethyl, or nitrogen heterocyclic ring,
R2For methyl or acetyl group,
R3For hydrogen, halogen or trifluoromethyl,
X is oxygen atom or ammonia atom,
Y is phenyl, trifluoromethyl, halogen atom.
A kind of pyrimidine derivatives containing halo acrylamide side chain the most according to claim 1, it is characterised in that described Compound of formula I is following arbitrary compound:
N-[3-[[2-[[4-(4-acetyl group-1-piperazinyl) phenyl] amino]-5-(chlorine)-4-pyrimidine radicals] amino] phenyl]-2- Chloroacrylamide (embodiment 1)；
N-[3-[[2-[[4-(4-acetyl group-1-piperazinyl) phenyl] amino]-5-(chlorine)-4-pyrimidine radicals] amino] phenyl]-2- Fluoropropene amide (embodiment 2)；
N-[3-[[2-[[4-(4-acetyl group-1-piperazinyl) phenyl] amino]-5-(chlorine)-4-pyrimidine radicals] amino] phenyl]-2- Phenyl Acrylamide (embodiment 3)；
N-[3-[[2-[[4-(4-acetyl group-1-piperazinyl)-2-methoxyphenyl] amino]-5-(chlorine)-4-pyrimidine radicals] amino] Phenyl]-2-trifluoromethyl acrylamide (embodiment 4)；
N-[3-[[2-[[4-(4-acetyl group-1-piperazinyl)-2-methoxyphenyl] amino]-5-(chlorine)-4-pyrimidine radicals] amino] Phenyl]-2-fluoropropene amide (embodiment 5)；
N-[3-[[2-[[4-(4-acetyl group-1-piperazinyl)-2-methoxyphenyl] amino]-5-(chlorine)-4-pyrimidine radicals] amino] Phenyl]-2-trifluoromethyl acrylamide (embodiment 6)；
N-[3-[[2-[[4-(4-acetyl group-1-piperazinyl)-2-methoxyphenyl] amino]-5-(chlorine)-4-pyrimidine radicals] amino] Phenyl]-2-chloroacrylamide (embodiment 7)；
N-[3-[[2-[[4-(4-acetyl group-1-piperazinyl) phenyl] amino]-5-(trifluoromethyl chlorine)-4-pyrimidine radicals] amino] Phenyl]-2-fluoropropene amide (embodiment 8)；
N-[3-[[2-[[4-(4-acetyl group-1-piperazinyl)-2-methoxyphenyl] amino]-5-(trifluoromethyl)-4-pyrimidine Base] amino] phenyl]-2-chloroacrylamide (embodiment 9)；
N-[3-[[2-[[4-(4-acetyl group-1-piperazinyl)-3-chlorphenyl] amino]-5-(chlorine)-4-pyrimidine radicals] amino] benzene Base]-2-fluoropropene amide (embodiment 10)；
N-[3-[[2-[[4-(4-methyl isophthalic acid-piperazinyl)-2-methoxyphenyl] oxygen]-5-(chlorine)-4-pyrimidine radicals] amino] benzene Base]-2-fluoropropene amide (embodiment 11)；
N-[3-[[2-[[4-(4-acetyl group-1-piperazinyl)-2-methoxyphenyl] amino]-5-(trifluoromethyl)-4-pyrimidine Base] amino] phenyl]-2-trifluoromethyl acrylamide (embodiment 12)；
N-[3-[[2-[[4-(4-acetyl group-1-piperazinyl)-2-methoxyphenyl] oxygen]-5-(chlorine)-4-pyrimidine radicals] amino] benzene Base]-2-fluoropropene amide (embodiment 13)；
N-[3-[[2-[[4-(4-acetyl group-1-piperazinyl)-3-fluorophenyl] oxygen]-5-(chlorine)-4-pyrimidine radicals] amino] phenyl]- 2-fluoropropene amide (embodiment 14)；
N-[3-[[2-[[4-(4-acetyl group-1-piperazinyl)-3-aminomethyl phenyl] oxygen]-5-(chlorine)-4-pyrimidine radicals] amino] benzene Base]-2-chloroacrylamide (embodiment 15)；
N-[2-[(2,2-dimethylamino) 5-[[4-(1-Methyl-1H-indole-3-base)-2-(5-chlorine)-pyrimidine radicals] amino] benzene Base]-2-fluoropropene amide (embodiment 16)；
N-[3-[[2-[[4-(4-acetyl group-1-piperazinyl)-3-aminomethyl phenyl] amino]-5-(chlorine)-4-pyrimidine radicals] amino] benzene Base]-2-fluoropropene amide (embodiment 17)；
N-[3-[[2-[[4-(4-acetyl group-1-piperazinyl)-3-aminomethyl phenyl] amino]-5-(chlorine)-4-pyrimidine radicals] amino] benzene Base]-2-trifluoromethyl acrylamide (embodiment 18)；
N-[3-[[2-[[4-(4-methyl isophthalic acid-piperazinyl)-2-methoxyphenyl] oxygen]-5-(chlorine)-4-pyrimidine radicals] amino] benzene Base]-2-chloroacrylamide (embodiment 19)；
N-[2-[(2,2-dimethylamino) 5-[[4-(1-Methyl-1H-indole-3-base)-2-(5-chlorine)-pyrimidine radicals] amino] benzene Base]-2-chloroacrylamide (embodiment 20)；
N-[3-[[2-[[4-(4-acetyl group-1-piperazinyl)-2-methoxyphenyl] oxygen]-5-(chlorine)-4-pyrimidine radicals] amino] benzene Base]-2-chloroacrylamide (embodiment 21)；
N-[3-[[2-[[4-(4-acetyl group-1-piperazinyl)-3-fluorophenyl] amino]-5-(chlorine)-4-pyrimidine radicals] amino] benzene Base]-2-chloroacrylamide (embodiment 22)；
N-[2-[(2,2-dimethylamino) 5-[[4-(1-Methyl-1H-indole-3-base)-2-(5-chlorine)-pyrimidine radicals] amino] benzene Base]-2-trifluoromethyl acrylamide (embodiment 23)；
N-[3-[[2-[[4-(4-acetyl group-1-piperazinyl) phenyl] amino]-5-(trifluoromethyl)-4-pyrimidine radicals] amino] benzene Base]-2-chloroacrylamide (embodiment 24)；
N-[3-[[2-[[5-(4-acetyl group-1-piperazinyl) pyridine radicals] amino]-5-(chlorine)-4-pyrimidine radicals] amino] phenyl]- 2-chloroacrylamide (embodiment 25)；
N-[3-[[2-[[5-(4-acetyl group-1-piperazinyl) pyridine radicals] amino]-5-(chlorine)-4-pyrimidine radicals] amino] phenyl]- 2-fluoropropene amide (embodiment 26)；
N-[3-[[2-[[4-(4-acetyl group-1-piperazinyl)-3-trifluoromethyl] amino]-5-(chlorine)-4-pyrimidine radicals] ammonia Base] phenyl]-2-chloroacrylamide (embodiment 27)；
N-[3-[[2-[[4-(4-acetyl group-1-piperazinyl)-3-trifluoromethyl] amino]-5-(chlorine)-4-pyrimidine radicals] ammonia Base] phenyl]-2-fluoropropene amide (embodiment 28)；
N-[3-[[2-[[4-(4-acetyl group-1-piperazinyl)-3-chlorphenyl] amino]-5-(chlorine)-4-pyrimidine radicals] amino] benzene Base]-2-chloroacrylamide (embodiment 29)；
N-[3-[[2-[[4-(4-acetyl group-1-piperazinyl)-2-fluorophenyl] amino]-5-(chlorine)-4-pyrimidine radicals] amino] benzene Base]-2-chloroacrylamide (embodiment 30)；
N-[3-[[2-[[4-(4-acetyl group-1-piperazinyl) phenyl] oxygen]-5-(chlorine)-4-pyrimidine radicals] amino] phenyl]-2-chlorine Acrylamide (embodiment 31)；
N-[3-[[2-[[4-(4-acetyl group-1-piperazinyl)-3-trifluoromethyl] oxygen]-5-(chlorine)-4-pyrimidine radicals] amino] Phenyl]-2-chloroacrylamide (embodiment 32).
The preparation method of a kind of pyrimidine derivatives containing halo acrylamide side chain the most according to claim 1 and 2, it is special Levy and be, realized by following steps:
With 2,5-dichloro pyrimidine a is initiation material, and (3-aminophenyl) t-butyl carbamate, or (3-hydroxy phenyl) The amino tert-butyl ester) b reacts generation intermediate c, intermediate c in n-butyl alcohol and refluxes in n-butyl alcohol under dilute hydrochloric acid effect and obtain 5-position substituted intermediate d, the tert. butyl protection group in intermediate d structure is under trifluoroacetic acid effect, and deprotection is dissociated The intermediate e of amino structure, last and halogen substiuted acryloyl chloride condensation reaction obtains target compound I, reaction equation:
Wherein the definition of substituent group is with claim 1, reaction condition: i) diisopropylethylamine, n-butyl alcohol, room temperature；Ii) dilute salt Acid, n-butyl alcohol, backflow；Iii) trifluoroacetic acid, dichloromethane, ice bath；Iv) acryloyl chloride Han halogen, triethylamine, dichloromethane, Ice bath is to room temperature.
A kind of pyrimidine derivatives containing halo acrylamide side chain the most according to claim 1 and 2 is to prepare antitumor thin Application in born of the same parents and targeting EGFR kinases medicine, it is characterised in that described tumor cell refers to people's epidermal carcinoma of process LAN EGFR Cell strain A431, human lung adenocarcinoma cell line H1975 to Gefitinib drug resistance, low expression EGFR human colon cancer cell strain SW620, described EGFR kinases refers to the EGFR kinases that Wild type EGFR kinases and [L858R/T790M] suddenly change.
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CN111004215B (en) * 2019-12-22 2022-08-09 华北理工大学 2, 4-substituted pyrimidine derivatives, preparation method thereof and application thereof in preparing antitumor drugs
CN113582995A (en) * 2021-08-17 2021-11-02 西安交通大学 9-9H-purine compound containing acrylamide amino fragment at 9-position, and salt and application thereof

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Application publication date: 20161221