CN105683168A - Arylamino pyramidine compound and application thereof, and pharmaceutical compositions and pharmaceutically acceptable compositions prepared therefrom - Google Patents

Arylamino pyramidine compound and application thereof, and pharmaceutical compositions and pharmaceutically acceptable compositions prepared therefrom Download PDF

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CN105683168A
CN105683168A CN201580002151.3A CN201580002151A CN105683168A CN 105683168 A CN105683168 A CN 105683168A CN 201580002151 A CN201580002151 A CN 201580002151A CN 105683168 A CN105683168 A CN 105683168A
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phenyl
amino
pyrimidine
acrylamide
groups
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CN105683168B (en
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兰炯
崔玉敏
张亮
金云舟
周福生
程鹏飞
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Shanghai Haiyan Pharmaceutical Technology Co Ltd
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Shanghai Haiyan Pharmaceutical Technology Co Ltd
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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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • 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
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/42—One nitrogen atom
    • 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
    • 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

Abstract

Provided are an arylamino pyramidine compound having an inhibiting effect on EGFR tyrosine kinases, and pharmaceutically acceptable salt, stereoisomer, solvent compound, or prodrug of said arylamino pyramidine compound; also provided are pharmaceutical compositions and pharmaceutically acceptable compositions containing the arylamino pyramidine compound, and applications thereof.

Description

Fragrant amino pyrimidines and its application and pharmaceutical composition prepared therefrom and Pharmaceutical composition Technical field
The present invention relates to pharmaceutical technology field, more particularly to a kind of fragrant amino pyrimidines and its application as EGFR tyrosine kinase inhibitors, and pharmaceutical composition prepared therefrom and Pharmaceutical composition.
Background technology
Lung cancer is global incidence highest cancer, first in the lung cancer in China incidence of disease occupies all cancers, it is also Chinese morbidity and mortality highest cancer, in lung cancer in China patient, 30% patient has EGFR mutation, wherein L858R and the deletion mutation of exons 19 account for more than 90%, and this kind of patient is more sensitive to EGFR inhibitor.Existing to have listed first generation EGFR inhibitor such as Tarceva, Gefitinib works well to this kind of patient, can make wherein more than 60% patient's tumor regression, hence it is evident that extension patient's progression free survival phase.But most humans obtained resistance at 6-12 months, and first generation EGFR inhibitor will no longer work, and this kind of patient is currently in no medicine upstate.Clinical discovery is produced to first generation EGFR inhibitor has 50% to detect EGFR T790M mutation in the patient of resistance.First generation EGFR inhibitor, Gefitinib and Tarceva in T790M mutational cell lines H1975, are all higher than 3uM, basic without activity.
Lung cancer patient is evident in efficacy is better than first generation EGFR inhibitor to EGFR mutation for the irreversible pan-EGFR inhibitor of the second generation (Afatinib (BIBW2992)) of exploitation listing at present.But second generation inhibitor also has very strong Wild type EGFR inhibitory activity simultaneously, inhibitory activity to Wild type EGFR is significantly higher than resistance T790M mutation, the toxic side effects such as patient's fash are serious and poor to resistance patient's curative effect, and only fraction first generation EGFR inhibitor resistance patient produces response to this kind of medicine.
In order to reduce the inhibitory activity to Wild type EGFR while improving active to resistance EGFR T790M inhibition from mutation, the lower third generation EGFR mutant selective depressants of active higher, the selective more preferably, toxicity of exploitation have great importance.
The content of the invention
It is an object of the invention to provide a kind of fragrant amino pyrimidines or its pharmaceutically acceptable salt, stereoisomer, solvated compoundses or its prodrug.
It is a further object to provide the pharmaceutical composition for including above-mentioned fragrant amino pyrimidines or its pharmaceutically acceptable salt, stereoisomer, solvated compoundses or its prodrug.
Third object of the present invention is to provide the medicine that above-mentioned fragrant amino pyrimidines prepare regulation and control EGFR tyrosine kinase activities, or prepares the application on treatment EGFR relevant disease medicines.
First aspect present invention provides a kind of new fragrant amino pyrimidines or its pharmaceutically acceptable salt, stereoisomer, solvated compoundses or its prodrug, shown in the fragrant amino pyrimidines structure such as formula (I)：
In formula (I), A is selected from：Substituted or unsubstituted C6-10Aryl, substituted or unsubstituted C5-8Heteroaryl, substituted or unsubstituted C3-8Cycloalkyl, substituted or unsubstituted C3-8Heterocyclylalkyl, substituted or unsubstituted 8-14 members condensed ring group；Wherein, described " substitution " refers to that one or more of group hydrogen is selected from the substituent of the following group and replaced：Nitro, halogen, cyano group, C1-6The C of alkyl, halo1-6Alkyl, C1-6The C of alkoxy, halo1-6Alkoxy；
Z1Selected from NR9Or CR10R11；Wherein, R9Selected from hydrogen or C1-6Alkyl；R10、R11It is each independently selected from hydrogen, halogen, C1-6Alkyl；Or R10And R11C is collectively forming with the carbon atom being connected3-8Cycloalkyl or C3-8Heterocyclylalkyl；
Z2、Z3It is each independently selected from CR12Or N；Wherein, R12Selected from hydrogen, halogen, nitro, amino, C1-6Alkyl-substituted amino, C1-6Amino, cyano group, the C of acyl group substitution1-6The C of alkyl, halo1-6Alkyl, C1-6The C of alkoxy, halo1-6Alkoxy；
R1Selected from hydrogen or C1-6Alkyl；Or, R1Constituted together with A and their connected nitrogen-atoms selected from following group：Substituted or unsubstituted C5-8Heteroaryl, substituted or unsubstituted C3-8Heterocyclylalkyl or substituted or unsubstituted 8-14 members condensed ring group, wherein, described " substitution " refers to that one or more of group hydrogen is selected from the substituent of the following group and replaced：Nitro, halogen, cyano group, C1-6The C of alkyl, halo1-6Alkyl, C1-6The C of alkoxy, halo1-6Alkoxy；
R2Selected from hydrogen, halogen, C1-6Alkyl, halo C1-6Alkyl or C1-6Alkoxy；
R3、R4、R5It is each independently selected from：Hydrogen, halogen, nitro, amino, C1-6Alkyl-substituted amino, C1-6Amino, the C of acyl group substitution1-6Alkyl-substituted diaminourea, cyano group, C1-6The C of alkyl, halo1-6Alkyl, C1-6Alkoxy, C1-6The C of alkoxy substitution1-6Alkoxy, C6-10The C of aryl substitution1-6The C of alkoxy, halo1-6Alkoxy ,-O-C6-10Aryl ,-CO-C3-6Heterocyclylalkyl ,-CO-NR13R14、C3-6Heteroaryl, C3-6Heterocyclylalkyl, C3-6Heterocyclylalkyl-CO-C1-6Alkyl, C3-6Heterocyclylalkyl-N-C1-6Alkyl, C3-6Heterocyclylalkyl-C1-6Alkyl, C3-6Heterocyclylalkyl-C3-6Heterocyclylalkyl；Optionally, the C6-10Aryl, C3-6Heteroaryl or C3-6Heterocyclylalkyl can be replaced by one or more substituents being selected from the group：Nitro, halogen, cyano group, C1-6The C of alkyl, halo1-6Alkyl, C1-6The C of alkoxy, halo1-6Alkoxy, C1-6Alkyl-substituted amino；Wherein, R13、R14It is each independently selected from hydrogen or C1-6Alkyl；
R7、R8It is each independently selected from：Hydrogen, halogen, C1-6Alkyl, C3-8Cycloalkyl, C3-8Heterocyclylalkyl, C6-10Aryl or C5-8Heteroaryl.
In another preference, Z1Selected from NR9Or CR10R11；R9Selected from hydrogen or methyl；R10、R11It is each independently selected from hydrogen or methyl.
In another preference, Z2、Z3It is each independently selected from CH or N.
In another preference, R1Selected from hydrogen or methyl, or R1Piperidines is constituted together with A and their connected nitrogen-atoms.
In another preference, R2Selected from hydrogen, fluorine, chlorine, methyl, ethyl, propyl group, isopropyl, trifluoromethyl.
In another preference, R3For hydrogen, halogen, C1-6Alkoxy (preferably methoxyl group).
In another preference, R3For hydrogen or methoxyl group.
In another preference, R4For hydrogen, halogen, C1-6Alkoxy (preferably methoxyl group).
In another preference, R4For hydrogen, fluorine, chlorine or methoxyl group.
In another preference, R5For hydrogen, halogen, amino, C1-6Alkyl-substituted diaminourea, C1-6Alkyl, C1-6Alkoxy, C3-6Heterocyclylalkyl ,-CO-C3-6Heterocyclylalkyl ,-CO-NR13R14、C3-6Heterocyclylalkyl-C3-6Heterocyclylalkyl, the C3-6Heterocyclylalkyl can be replaced by one or more substituents being selected from the group：C1-6The C of alkyl, halo1-6Alkyl, C1-6Alkyl-substituted amino.
In another preference, R5For hydrogen, fluorine, chlorine, diethyl amido, N, N, N '-trimethyl ethylenediamine base, methyl, ethyl, propyl group, methoxyl group, ethyoxyl, C6Heterocyclylalkyl ,-CO-C6Heterocyclylalkyl ,-CO-N (CH2CH3)2、C6Heterocyclylalkyl-C6Heterocyclylalkyl, the C6Heterocyclylalkyl can be replaced by one or more substituents being selected from the group：Methyl, ethyl, propyl group, fluoro ethyl, N (CH3)2、N(CH2CH3)2。
In another preference, R5For hydrogen, fluorine, chlorine, diethyl amido, N, N, N '-trimethyl ethylenediamine base, methyl, ethyl, propyl group, methoxyl group, ethyoxyl, morpholinyl, piperazinyl, piperidyl ,-CO- morpholinyls ,-CO- piperazinyls ,-CO- piperidyls ,-CO-N (CH2CH3)2, piperidyl-piperazinyl, piperidyl-morpholinyl, the morpholinyl, piperazinyl, piperidyl can be replaced by one or more substituents being selected from the group：Methyl, ethyl, propyl group, fluoro ethyl, N (CH3)2、N(CH2CH3)2。
In another preference, R5For methoxyl group or be select the following group structure：
In another preference, the fragrant amino pyrimidines are the compound shown in formula (II)：
In formula (II), A, Z2、Z3、R1、R2、R3、R4、R5、R7、R8And R9As defined in formula (I).
In another preference, the fragrant amino pyrimidines are the compound shown in formula (III)：
In formula (III), A, Z2、Z3、R1、R2、R3、R4、R5、R7、R8、R10And R11As defined in formula (I).
In another preference, in formula (I) compound, formula (II) compound or formula (III) compound that the present invention is provided, R7、R8It is each independently hydrogen.
In another preference, in formula (I) compound, formula (II) compound or formula (III) compound that the present invention is provided, A is phenyl.
In another preference, the fragrant amino pyrimidines are the compound shown in formula a：
Wherein, Z1、Z2、Z3、R1、R2、R3、R4、R5、R7、R8As defined in formula (I).
In another preference, in formula (I) compound, formula (II) compound or formula (III) compound that the present invention is provided, A is phenyl, moreover, R7、R8It is each independently hydrogen.
In another preference, in formula (I) compound, formula (II) compound or formula (III) compound that the present invention is provided, R1Piperidines is constituted together with A and their connected nitrogen-atoms.
In another preference, the fragrant amino pyrimidines are the compound shown in formula b：
Wherein, Z1、Z2、Z3、R2、R3、R4、R5、R7、R8As defined in formula (I).
In another preference, the present invention formula (I) compound, formula (II) compound or formula (III) compound for providing wherein, R1Piperidines is constituted together with A and their connected nitrogen-atoms, moreover, R7、R8It is each independently hydrogen.
In another preference, the invention provides selected from following compound, or its pharmaceutically acceptable salt, stereoisomer, solvated compoundses or its prodrug：
N- (3- (3- (2- ((2- methoxyl groups -4- (4- methylpiperazine-1-yls) phenyl) amino) pyrimidine-4-yl) urea groups) phenyl) acrylamide (cpd-1)；
N- (3- (3- (2- ((4- (4- methylpiperazine-1-yls) phenyl) amino) pyrimidine-4-yl) urea groups) phenyl) acrylamide (cpd-2)；
N- (3- (3- (2- ((5- methoxypyridine -2- bases) amino) pyrimidine-4-yl) urea groups) phenyl) acrylamide (cpd-3)；
N- (3- (3- (2- ((the chloro- 4- of 3- ((3- luorobenzyls) oxygen) phenyl) amino) pyrimidine-4-yl) urea groups) phenyl) acrylamide (cpd-4)；
N- (3- (3- (2- ((2- methoxyl groups -4- (4- (4- methylpiperazine-1-yls) piperidin-1-yl) phenyl) amino) pyrimidine-4-yl) urea groups) phenyl) acrylamide (cpd-5)；
N- (3- (3- (2- ((6- morpholinoes pyridin-3-yl) amino) pyrimidine-4-yl) urea groups) phenyl) acrylamide (cpd-6)；
N- (3- (3- (2- ((2,4- Dimethoxyphenyls) amino) pyrimidine-4-yl) urea groups) phenyl) acrylamide (cpd-7)；
N- (3- (3- (2- ((the chloro- 4- fluorophenyls of 3-) amino) pyrimidine-4-yl) urea groups) phenyl) acrylamide (cpd-8)；
N- (3- (3- (2- ((2- methoxyl groups -4- (4- morpholines piperidin-1-yl) phenyl) amino) pyrimidine-4-yl) urea groups) phenyl) acrylamide (cpd-9)；
N- (3- (3- (2- ((4- (4- (dimethylamino) piperidin-1-yl) -2- anisyls) amino) pyrimidine-4-yl) urea groups) phenyl) Acrylamide (cpd-10)；
N- (3- (3- (2- ((4- (piperidin-1-yl) phenyl) amino) pyrimidine-4-yl) urea groups) phenyl) acrylamide (cpd-11)；
N- (3- (3- (2- ((4- (dimethylamino) phenyl) amino) pyrimidine-4-yl) urea groups) phenyl) acrylamide (cpd-12)；
N- (3- (3- (2- ((5- morpholino pyridine -2- bases) amino) pyrimidine-4-yl) urea groups) phenyl) acrylamide (cpd-13)；
N- (3- (3- (2- ((2- methoxyl group -4- morphlinophenyls) amino) pyrimidine-4-yl) urea groups) phenyl) acrylamide (cpd-14)；
N- (3- (3- (2- ((2- methoxyl groups -4- (morpholine -4- carbonyls) phenyl) amino) pyrimidine-4-yl) urea groups) phenyl) acrylamide (cpd-15)；
N- (3- (3- (2- ((2- methoxyl groups -4- (4- methyl piperazine -1- carbonyls) phenyl) amino) pyrimidine-4-yl) urea groups) phenyl) acrylamide (cpd-16)；
4- ((4- (3- (3- acryloyl groups amide phenyl) urea groups) pyrimidine -2-base) amino)-N, N- diethyl -3- methoxy benzamides (cpd-17)；
N- (3- (3- (2- ((4- (2- methoxy ethoxies) phenyl) amino) pyrimidine-4-yl) urea groups) phenyl) acrylamide (cpd-18)；
N- (3- (3- (2- ((2- methoxyl groups -4- (piperidin-1-yl) phenyl) amino) pyrimidine-4-yl) urea groups) phenyl) acrylamide (cpd-19)；
N- (3- (3- (2- ((4- (4- (2- fluoro ethyls) piperazine -1- bases) -2- anisyls) amino) pyrimidine-4-yl) urea groups) phenyl) acrylamide (cpd-20)；
N- (3- (3- (2- ((4- (diethylamino) -2- methoxyphenyls) amino) pyrimidine-4-yl) urea groups) phenyl) acrylamide (cpd-21)；
N- (3- (3- (2- ((4- (4- (diethylamino) piperidin-1-yl) -2- anisyls) amino) pyrimidine-4-yl) urea groups) phenyl) acrylamide (cpd-22)；
N- (3- (3- (2- ((4- (4- ethyl piperazidine -1- bases) -2- methoxyphenyls) amino) pyrimidine-4-yl) urea groups) phenyl) acrylamide (cpd-23)；
N- (3- (3- (2- (4- tolyls) amino) pyrimidine-4-yl) urea groups) phenyl) acrylamide (cpd-24)；
N- (3- (3- (2- ((5- (4- methylpiperazine-1-yls) pyridine -2- bases) amino) pyrimidine-4-yl) urea groups) phenyl) acrylamide (cpd-25)；
N- (3- (3- (2- ((4- fluorophenyls) amino) pyrimidine-4-yl) urea groups) phenyl) acrylamide (cpd-26)；
N- (3- (3- (2- ((4- ethoxyl phenenyls) amino) pyrimidine-4-yl) urea groups) phenyl) acrylamide (cpd-27)；
N- (3- (3- (2- ((2- methoxyphenyls) amino) pyrimidine-4-yl) urea groups) phenyl) acrylamide (cpd-28)；
N- (3- (3- (2- ((4- chlorphenyls) amino) pyrimidine-4-yl) urea groups) phenyl) acrylamide (cpd-29)；
N- (3- (3- (2- ((3,4,5- trimethoxyphenyls) amino) pyrimidine-4-yl) urea groups) phenyl) acrylamide (cpd-30)；
N- (3- (3- (2- ((4- morphlinophenyls) amino) pyrimidine-4-yl) urea groups) phenyl) acrylamide (cpd-31)；
N- (3- (3- (2- ((4- (4- (dimethylamino) piperidin-1-yl) -2- anisyls) amino) pyrimidine-4-yl) -3- methyl urea groups) phenyl) acrylamide (cpd-32)；
3- acrylamidos-N- (2- (2- methoxyl groups -4- (4- morpholino -1- bases) phenyl amino) pyrimidine-4-yl) piperidines -1- formamides (cpd-33)；
3- acrylamidos-N- (2- (2- methoxyl groups -4- (4- methylpiperazine-1-yls) phenyl amino) pyrimidine-4-yl) piperidines -1- formamides (cpd-34)；
3- acrylamidos-N- (2- (2- methoxyl groups -4- (1- methyl piperidine -4- bases) phenyl amino) pyrimidine-4-yl) piperidines -1- formamides (cpd-35)；
3- acrylamidos-N- (2- (4- ((2- (dimethylamino) ethyl) (methyl) amino) -2- Methoxyphenylaminos) pyrimidine-4-yl) piperidines -1- formamides (cpd-36)；
N- (3- (2- (2- (2- methoxyl groups -4- (4- methylpiperazine-1-yls) phenyl amino) pyrimidine-4-yl) -2- methylpropionylaminos) phenyl) acrylamide (cpd-37)；
1- (3- acryloyl groups amide groups) -3- (2- (2- methoxyl groups -4- (4- propylpiperazine -1- bases) phenyl amino) pyrimidine-4-yl) urea (cpd-38)；
3- (3- acryloyl groups amide groups) -1- (2- (4- ((2- (dimethylamino) ethyl) (methyl) amino) -2- Methoxyphenylaminos) pyrimidine-4-yl) -1- MUs (cpd-39)；Or
1- (3- acryloyl groups amide groups) -3- (the chloro- 2- of 5- (2- methoxyl groups -4- (4- morpholinoes piperidin-1-yl) phenyl amino) pyrimidine-4-yl) urea (cpd-40).
In the above-mentioned fragrant amino pyrimidines that the present invention is provided, described alkyl, as group or a part for other groups, such as alkyl of halogen substitution, the alkyl of hydroxyl substitution, can be straight chain or side chain.For example, C1-6Alkyl represents the alkyl with 1 to 6 carbon, including but not limited to methyl, ethyl, propyl group, isopropyl, normal-butyl, isobutyl group, sec-butyl, the tert-butyl group, n-pentyl, n-hexyl.
In the above-mentioned fragrant amino pyrimidines that the present invention is provided, " alkoxy " refers to alkyl and the generation group after oxygen atom link, including but not limited to methoxyl group, ethyoxyl, isopropoxy, ring propoxyl group etc..
In the above-mentioned fragrant amino pyrimidines that the present invention is provided, " diaminourea " refers to the diaminourea being connected by alkyl, such as ethylenediamine, propane diamine, butanediamine；Moreover, the amino of end can be replaced by alkyl, and such as N, N, N '-trimethyl butanediamine base.
In the above-mentioned fragrant amino pyrimidines that the present invention is provided, " amino " refers to NH2。
In the above-mentioned fragrant amino pyrimidines that the present invention is provided, " the C1-6Alkyl-substituted amino " refers to NH2In one or two hydrogen by C1-6Alkyl replaces.Including but not limited to NH (CH3)、N(CH3)2、N(CH2CH3)2Deng.
In the above-mentioned fragrant amino pyrimidines that the present invention is provided, " halogen " refers to fluorine, chlorine, bromine and iodine.It is preferred that fluorine and chlorine.
In the above-mentioned fragrant amino pyrimidines that the present invention is provided, " aryl " refers to monocyclic or fusion the aromatic hydrocarbon ring (such as phenyl and naphthyl) for including six to ten carbon atoms.
In the above-mentioned fragrant amino pyrimidines that the present invention is provided, " heteroaryl " refers to the aromatic ring system of any fusion or non-condensed, wherein at least one ring is to be selected from heteroatomic the five of nitrogen, oxygen and sulphur containing 1-4 to arrive octatomic ring, and preferably at least one hetero atom is selected from nitrogen.Heteroaryl includes but is not limited to thienyl, furyl, imidazole radicals, pyrazolyl, thiazolyl, oxazolyl, isoxazolyl, pyridine radicals, pyrimidine radicals, pyrazinyl, pyridazinyl, benzimidazolyl, benzopyrazoles base, indyl etc..
In the above-mentioned fragrant amino pyrimidines that the present invention is provided, " cycloalkyl " refers to the undersaturated monocyclic, condensed ring in saturation or part or bridged ring for including the carbon atom specified number.For example, C3-8Cycloalkyl refers to the cycloalkyl of three to eight carbon, including cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl etc..
In the above-mentioned fragrant amino pyrimidines that the present invention is provided, " Heterocyclylalkyl " refers to the cycloalkyl defined in the present invention, and the carbon atom on wherein one or more rings is by oxygen, nitrogen ,-NR-, sulphur, carbonyl ,-S (O)-or-S (O)2- Etc. substituent group；Heterocyclylalkyl includes but is not limited to morpholinyl, piperazinyl, piperidyl, thio-morpholinyl etc..
In the above-mentioned fragrant amino pyrimidines that the present invention is provided, " C1-6Acyl group " includes formoxyl, acetyl group, propiono, bytyry, valeryl, caproyl.
In the above-mentioned fragrant amino pyrimidines that the present invention is provided, " condensed ring group " refers to two or more carbocyclic rings or heterocycle with polycyclic organic compound, such as naphthalene, anthracene, anthraquinone, phenanthrene formed by shared ring side.
In the above-mentioned fragrant amino pyrimidines that the present invention is provided, " pharmaceutically acceptable salt " includes pharmaceutically acceptable acid-addition salts and pharmaceutically acceptable base addition salts." pharmaceutically acceptable acid-addition salts " be refer to retain free alkali biological effectiveness and without other side effects, the salt formed with inorganic acid or organic acid.Inorganic acid salt includes but is not limited to hydrochloride, hydrobromate, sulfate, phosphate etc.；Acylate includes but is not limited to formates, acetate, propionate, glycollate, gluconate, lactate, oxalates, maleate, succinate, fumarate, tartrate, citrate, glutamate, aspartate, benzoate, mesylate, tosilate and salicylate etc..These salt can be prepared by method known in the art." pharmaceutically acceptable base addition salts ", the including but not limited to salt of inorganic base such as sodium salt, sylvite, calcium salt and magnesium salts etc..The including but not limited to salt of organic base, such as ammonium salt, triethylamine salt, lysine salt, arginine salt etc..These salt can be prepared by method known in the art.
Formula (I) compound of the present invention may have more than one crystal formation, including various crystal formations and its mixture.
" solvate " referred in the present invention refers to the compound and the complex of solvent formation of the present invention.They reaction or Precipitation or are crystallized out from solvent in a solvent.For example, the complex that one and water are formed is referred to as " hydrate ".The solvate of formula (I) compound belongs within the scope of the invention.
The compound of the present invention can contain one or more chiral centres, and exist with different optical active forms.When compound contains a chiral centre, compound includes enantiomter.Mixture of the present invention including both isomers and isomers, such as racemic mixture.Enantiomter can be split by method known in the art, the method such as crystallization and chiral chromatogram.When formula (I) compound contains more than one chiral center, there may be diastereoisomer.The present invention includes the mixture of the optically pure specific isomers and diastereoisomer split.Diastereoisomer can be split by method known in the art, such as crystallize and prepare chromatogram.
The present invention includes the prodrug of above-claimed cpd.Prodrug includes known amino protecting group and carboxyl-protecting group, is hydrolyzed in physiological conditions or obtains parent compound via enzyme reaction release.Medicament preparation can refer to (Saulnier, M.G. before specific；Frennesson, D.B.；Deshpande, M.S.；Hansel, S.B and Vysa, D.M.Bioorg.Med.Chem Lett.1994,4,1985-1990；And Greenwald, R.B.；Choe, Y.H.；Conover, C.D.；Shum, K.；Wu, D.；Royzen, M.J.Med.Chem.2000,43,475.).
The compound that second aspect of the present invention is provided in the preparation method of above-mentioned fragrant amino pyrimidines, the present invention can easily be prepared by a variety of synthetic operations, and these operations are that one of ordinary skill in the art skillfully grasp.The specific preparation method of these compounds can include but is not limited to flow described below.
The preferred synthetic route of formula (I) compound of the present invention has following three kinds, and particular compound can refer to following synthetic routes and be prepared in following examples, in specific operation process, the step in method can be extended or be merged as needed.
Synthetic route 1
Step 1-1：The Z that pyrimidine is 41H reacts with aminated compounds, changes into corresponding amides compound, and reaction needs at a certain temperature, to carry out using suitable alkali and appropriate solvent, alkali used can be but not limited to triethylamine.
Step 1-2：The chlorine that pyrimidine is 2 is replaced with amine, needs at a certain temperature, to carry out using suitable catalyst and appropriate solvent.Using acid catalysis, catalyst can be but not limited to TFA or p-methyl benzenesulfonic acid.Using Buchwald-Hartwig amination methods, palladium catalyst used can be but not limited to Pd2(dba)3, part used can be but not limited to XantPhos, and alkali used can be but not limited to cesium carbonate.
Step 1-3：The nitro compound is converted into corresponding amine compound and can reduced in acid condition with metal (can be but not limited to iron powder, zinc powder) or stannous chloride；Or under palladium carbon catalysis, hydrogenating reduction.
Step 1-4：The amine compound can be condensed into acid amides with corresponding acyl chlorides in the basic conditions, or with corresponding carboxylic acid be condensed into acid amides in the presence of condensing agent.
Synthetic route 2
Step 2-1：The Z that pyrimidine is 41H reacts with aminated compounds, changes into corresponding amides compound, and reaction needs at a certain temperature, to carry out using suitable alkali and appropriate solvent, alkali used can be but not limited to triethylamine.
Step 2-2：The nitro compound is converted into corresponding amine compound and can reduced in acid condition with metal (can be but not limited to iron powder, zinc powder) or stannous chloride；Or under palladium carbon catalysis, hydrogenating reduction.
Step 2-3：The amine compound can be condensed into acid amides with corresponding acyl chlorides in the basic conditions, or in condensation In the presence of agent acid amides is condensed into corresponding carboxylic acid.
Step 2-4：The chlorine that pyrimidine is 2 is replaced with amine, needs at a certain temperature, to carry out using suitable catalyst and appropriate solvent.Using acid catalysis, catalyst can be but not limited to TFA or p-methyl benzenesulfonic acid.Using Buchwald-Hartwig amination methods, palladium catalyst used can be but not limited to Pd2(dba)3, part used can be but not limited to XantPhos (4,5- double (diphenylphosphine) -9,9- dimethyl xanthenes), and alkali used can be but not limited to cesium carbonate.
Synthetic route 3
Step 3-1：The chlorine that pyrimidine is 2 is replaced with amine, needs at a certain temperature, to carry out using suitable catalyst and appropriate solvent.Using acid catalysis, catalyst can be but not limited to TFA or p-methyl benzenesulfonic acid.Using Buchwald-Hartwig amination methods, palladium catalyst used can be but not limited to Pd2(dba)3, part used can be but not limited to XantPhos, and alkali used can be but not limited to cesium carbonate.
Step 3-2：The Z that pyrimidine is 41H reacts with aminated compounds, changes into corresponding amides compound, and reaction needs at a certain temperature, to carry out using suitable alkali and appropriate solvent, alkali used can be but not limited to triethylamine.
Step 3-3：The nitro compound is converted into corresponding amine compound and can reduced in acid condition with metal (can be but not limited to iron powder, zinc powder) or stannous chloride；Or under palladium carbon catalysis, hydrogenating reduction.
Step 3-4：The amine compound can be condensed into acid amides with corresponding acyl chlorides in the basic conditions, or with corresponding carboxylic acid be condensed into acid amides in the presence of condensing agent.
Third aspect present invention provides a kind of pharmaceutical composition, and it includes any of above-claimed cpd or multiple compounds or its pharmaceutically acceptable salt, solvate or prodrug, and also includes pharmaceutically acceptable carrier.
A kind of pharmaceutical composition that the present invention is provided, the composition includes the above-mentioned fragrant amino pyrimidines of therapeutically effective amount, such as above-mentioned formula (I) compound, formula (II) compound or formula (III) compound, or above-mentioned example compound, or its pharmaceutically acceptable salt, stereoisomer, solvated compoundses or its prodrug；And pharmaceutically acceptable carrier.
Generally, the compounds of this invention or its pharmaceutically acceptable salt can form suitable formulation with one or more pharmaceutical carriers and apply.These formulations are applied to oral, rectally, local administration, intraoral administration and other parenteral routes and applied (for example, subcutaneous, muscle, vein etc.).For example, the formulation for being adapted to be administered orally includes capsule, tablet, granule and syrup etc..The compound of the invention included in these preparations can be solid powder or particle；Solution or suspension in aqueous or non-aqueous liquid；Water-In-Oil or oil-in-water emulsion etc..Above-mentioned formulation can be by active ingredient Thing is made with one or more carriers or auxiliary material via general practice of pharmacy.Above-mentioned carrier needs compatible with reactive compound or other auxiliary materials.For solid pharmaceutical preparation, conventional non-toxic carrier includes but is not limited to mannitol, lactose, starch, magnesium stearate, cellulose, glucose, sucrose etc..Carrier for liquid preparation includes water, physiological saline, D/W, ethylene glycol and polyethylene glycol etc..Reactive compound can be with above-mentioned carrier formation solution or suspension.
Fourth aspect present invention provides above-claimed cpd or its pharmaceutically acceptable salt, solvate or prodrug can be used for the medicine of preparation regulation and control EGFR tyrosine kinase activities, or prepares the application in the medicine for the treatment of EGFR relevant diseases.
Preferably, the EGFR relevant diseases are cancer, diabetes, disease of immune system, nerve degenerative diseases or angiocardiopathy.
As preferred, the cancer be non-small cell lung cancer, head and neck cancer, breast cancer, kidney, cancer of pancreas, cervix cancer, cancer of the esophagus, cancer of pancreas, prostate cancer, carcinoma of urinary bladder, colorectal cancer, oophoroma, stomach cancer, brain cancer including spongioblastoma etc., or any combination of them.
The above-claimed cpd of the present invention or its can pharmaceutically acceptable salt, solvate or its prodrug can be additionally used in the disease for preparing treatment EGFR unconventionality expressions, or for preparing using the disease during EGFR modulators for treatment with acquired resistance.
Preferably, the acquired resistance is drug resistance, such as T790M caused by the T790 mutation encoded by EGFR extron 20s.
In the present invention, EGFR conditioning agents refer to the small molecule tyrosine kinase inhibitors of targeting EGFR, such as Gefitinib, Tarceva, Conmana, Lapatinib or Afatinib.
The Pharmaceutical composition of the present invention, includes any of the above-claimed cpd or multiple compounds or its pharmaceutically acceptable salt, solvate or prodrug of therapeutically effective amount, and the one or more being selected from the group in medicine：Gefitinib, Tarceva, Conmana, Lapatinib, XL647, NVP-AEE-788, ARRY-334543, EKB-569, BIBW2992, HKI272, BMS-690514, CI-1033, ZD6474, PF00299804, WZ4002, Cetuximab, Herceptin, Pa Ni dashes forward monoclonal antibody, matuzumab, Buddhist nun's trastuzumab, prick the wooden monoclonal antibody in Shandong, handkerchief trastuzumab, MDX-214, CDX-110, IMC-11F8, Zemab, Her2 vaccines PX 1041, HSP90 inhibitor, CNF2024, KOS-953, Ah's spiramvcin, IPI-504, SNX-5422, NVP-AUY922, or its combination.In addition to the compound or its pharmaceutically acceptable salt, solvate or prodrug of the present invention, the other drugs in above-mentioned Pharmaceutical composition are antineoplastic well known to those skilled in the art.
" therapeutically effective amount " refers to that function can be produced to people and/or animal or amount that is active and by people and/or animal being received.
The compounds of this invention or the therapeutically effective amount of its pharmaceutically acceptable salt, solvate or its prodrug contained in pharmaceutical composition of the present invention or the Pharmaceutical composition is preferably 0.1mg-5g/kg (body weight).
Described Pharmaceutical composition can be used for the disease for the treatment of EGFR unconventionality expressions, such as cancer, diabetes, disease of immune system, nerve degenerative diseases or angiocardiopathy.
The disease of the acquired resistance is that the T790 mutation caused by the T790 mutation encoded by EGFR extron 20s, or comprising EGFR extron 20s coding are caused.
In another preference, the T790 of described EGFR extron 20s coding is T790M.
The present invention compound in some diseases can with other drugs use in conjunction, to reach expected therapeutic effect.The example of one use in conjunction is for treating advanced NSCLC.For example, by the formula of therapeutically effective amount Compound shown in I and mTOR inhibitors combination (such as rapamycin)；Or be combined with Met inhibitor (including Met antibody MetMAb and Met micromolecular inhibitor PF02341066)；Or it is combined (such as OSI-906) with IGF1R inhibitor；Or with heat shock protein inhibitors combination etc..
The invention discloses the preparation method of a class compound and compound, medicine composition and therapeutic scheme, those skilled in the art can use for reference present disclosure, be suitably modified technological parameter realization.In particular, all similar replacements and change are apparent to those skilled in the art, and they are considered as being included in the present invention.Product, method and the application of the present invention is described by preferred embodiment, related personnel substantially can not departing from present invention, method described herein and application are modified in spirit and scope or suitably change is with combining, to realize and apply the technology of the present invention.
It should be understood that within the scope of the present invention, can be combined with each other between above-mentioned each technical characteristic of the invention and each technical characteristic specifically described in below (eg embodiment), so as to constitute new or preferred technical scheme.
Embodiment
A kind of inventor in-depth study by long-term, it has unexpectedly been found that fragrant amino pyrimidines, as the inhibitor of a class EGFR Catastrophic selections, has the advantages that toxic side effect is low.Specifically, the fragrant amino pyrimidines that the present invention is provided, as the inhibitor of a class EGFR Catastrophic selections, vitro enzyme, cell experiment show that it can suppress L858R-T790M enzymes and double mutant clone H1975 propagation under nanomolar concentration；And the suppression to Wild type EGFR and cell line A431 is then relatively weak.Its Catastrophic selection substantially reduces the toxic side effect produced because suppressing Wild type EGFR, it is adaptable to the case of secondary resistance is produced in current EGFR-TKI treatments, is the ideal substitute of first and second generation EGFR tyrosine kinase inhibitor.
In order that those skilled in the art more fully understands technical scheme, with reference to specific embodiment, the present invention is described in further detail.
In the present invention, the structure of compound by nuclear magnetic resonance (1H NMR) and/or LC-MS mass spectrum (LC-MS) determine.1HNMR displacements (δ) are provided with the unit of hundred a ten thousandths (ppm).1H NMR measure is to use Bruker AVANCE-400 nuclear magnetic resonance spectrometers, is inside designated as tetramethylsilane (TMS).
Product purity is determined to be determined by LC-MS.LC-MS measure is with Agilent 1200HPLC System/6140MS LC-MS mass spectrograph (manufacturers：Agilent), pillar Waters X-Bridge, 150 × 4.6mm, 3.5 μm.
Preparative high-performance liquid chromatographic (pre-HPLC) Waters PHW007, pillar XBridge C18,4.6*150mm, 3.5um.
Post instrument, the disposable silicagel column of Agela 4g, 12g, 20g, 40g, 80g, 120g are crossed using ISCO Combiflash-Rf75 or Rf200 types are automatic.
Tlc silica gel plate uses Yantai Huanghai Sea HSGF254 or Qingdao GF254 silica gel plates, thin-layered chromatography (TLC), the specification that the silica gel plate that detection reaction is used is used is 0.15mm~0.2mm, and the specification that thin-layered chromatography isolates and purifies the silica gel plate use that product is used is 0.4mm~0.5mm.Silica gel is carrier typically using the mesh silica gel of Yantai Huanghai Sea silica gel 200~300.Alkali alumina post is carrier with the mesh alkali alumina of FCP200~300 typically using traditional Chinese medicines chromatography.
The known initiation material of the present invention can be used or synthesized according to methods known in the art, or can be in ABCR GmbH＆Co.KG, Acros Organics, Aldrich Chemical Company, splendid remote chemistry scientific and technological (Accela ChemBio Inc) and up to the place's purchase of the companies such as auspicious chemicals.
Without specified otherwise in embodiment, reaction is carried out under nitrogen or argon atmospher.Argon atmospher or blanket of nitrogen refer to that reaction bulb connects the argon gas or nitrogen balloon of an about 1L volume.
Nitrogen atmosphere refers to that reaction bulb connects the hydrogen balloon of an about 1L volume, Parker-20H type hydrogen generators.Hydrogenation is generally vacuumized, and is filled with hydrogen, is operated 3 times repeatedly.
Without specified otherwise in embodiment, solution refers to the aqueous solution.
The monitoring of reaction process in embodiment uses thin-layered chromatography (TLC), and the system of solvent is selected from used in reaction：One or more in dichloromethane and methanol system, n-hexane and ethyl acetate system, petroleum ether and ethyl acetate system and acetone system；The volume ratio of solvent is adjusted according to the polarity difference of compound.
The system of the eluant, eluent for the column chromatography that purifying compound is used or the system of the solvent of thin-layered chromatography may be selected from：A, dichloromethane and methanol system, one or more in B, n-hexane and ethyl acetate system and C, dichloromethane and acetone system, the volume ratio of solvent is adjusted according to the polarity difference of compound, can also add the acid reagents such as the alkalescence such as a small amount of triethylamine or acetic acid and be adjusted.
In the present invention, DMF：Dimethylformamide, DMSO：Dimethyl sulfoxide (DMSO), THF：Tetrahydrofuran, DIEA：DIPEA, EA：Ethyl acetate, PE：Petroleum ether.
In following examples, room temperature refers to about 25 DEG C.
Preparation Example
Intermediate 1：The preparation of 2- methoxyl groups -4- (4- (4- methylpiperazine-1-yls) piperidin-1-yl) aniline
Step 1：By tert-butyl group 4- oxo-piperidine -1- t-butyl formates (5g, 29.2mmol) with sodium cyanoborohydride (2.8g, 43.8mmol) it is placed in 500mL stand up reaction bottle, add methanol 200ml dissolvings, 1- methyl piperazines (3.2g, 32.1mmol) and glacial acetic acid (1ml) are added afterwards and keep reaction system to stay overnight at room temperature.TLC detects extent of reaction, and after after substrate completely reaction, reaction solution is extracted three times with ethyl acetate/aqueous systems, isolates organic layer, through water and saturated common salt water washing, after anhydrous sodium sulfate drying, is concentrated under reduced pressure to give crude product.4- (4- methylpiperazine-1-yls) piperidines -1- t-butyl formates (6.5g, 79%) are obtained through the purifying of Combi-Flash column chromatographies.MS m/z(ESI):284.1[M+H]+
Step 2：At room temperature, 4- (4- methylpiperazine-1-yls) piperidines -1- t-butyl formates (6.5g, 22.9mmol) are added in 100ml hydrochloric acid dioxane solutions, 4h is stirred vigorously at room temperature.After reaction terminates, reaction solution is concentrated under reduced pressure, 1- methyl -4- (piperidin-4-yl) piperazine (4.2g, 100%) is obtained.MS m/z(ESI):184.1[M+H]+
Step 3：By 1- methyl -4- (piperidin-4-yl) piperazines (4.2g, 22.9mmol), the fluoro- 2- methoxyl groups -1- nitrobenzene (4.69g of 4-, 25.2mmol) with potassium carbonate (9.48g, 68.7mmol) it is placed in 250mL stand up reaction bottle, adding DMF (100mL) is partly dissolved substrate, keeps reaction system to heat 4h at 100 DEG C.TLC detects extent of reaction, after after substrate completely reaction, filter off insoluble matter, it is concentrated under reduced pressure to give yellow solid 1- (1- (3- methoxyl group -4- nitrobenzophenones) piperidin-4-yl) -4- methyl piperazines, target product 4a (6g, 78%) is obtained through the purifying of Combi-Flash column chromatographies.MS m/z(ESI):335.1[M+H]+
Step 4：At room temperature, palladium carbon (0.6g, 10%wt) is added to 1- (1- (3- methoxyl group -4- nitrobenzophenones) piperidines -4- Base) -4- methyl piperazines (6g, 17.9mmol) 200ml methanol solutions in, room temperature is stirred vigorously 20h in a hydrogen atmosphere.After reaction terminates, palladium carbon is filtered off, filtrate decompression is concentrated, product 2- methoxyl groups -4- (4- (4- methylpiperazine-1-yls) piperidin-1-yl) aniline, be directly used in next step reaction.MS m/z(ESI):305.1[M+H]+
Intermediate 2：The preparation of 3- amino -6- morpholine yl pyridines
Step 1：At room temperature, the bromo- 5- nitropyridines (2g, 10mmol) of 2- are added in 10ml morpholine solutions, 4h is stirred vigorously at room temperature.After reaction terminates, there is yellow solid precipitation.After filtering, with 50ml petroleum ether yellow solids, 4- (5- nitropyridine -2- bases) morpholine (1.9g, 92%) is obtained.MS m/z(ESI):210.1[M+H]+
Step 2：At room temperature, palladium carbon (100mg, 10%wt) is added in the 60ml methanol solutions of 4- (5- nitropyridine -2- bases) morpholine (1g, 9.1mmol), room temperature is stirred vigorously 20h in a hydrogen atmosphere.After reaction terminates, palladium carbon is filtered off, filtrate decompression is concentrated, product 3- amino -6- morpholine yl pyridines are obtained, be directly used in next step reaction.MS m/z(ESI):180.1[M+H]+
Intermediate 3：The preparation of 2- methoxyl groups -4- (4- morpholino -1- bases) aniline
Step 1：By 4- oxo-piperidine -1- t-butyl formates (5g, 29.2mmol) with sodium cyanoborohydride (2.8g, 43.8mmol) it is placed in 500mL stand up reaction bottle, add methanol 200ml dissolvings, morpholine (2.8g, 32.1mmol) and glacial acetic acid (1ml) are added afterwards and keep reaction system to stay overnight at room temperature.TLC detects extent of reaction, and after after substrate completely reaction, reaction solution is extracted three times with ethyl acetate/aqueous systems, isolates organic layer, through water and saturated common salt water washing, after anhydrous sodium sulfate drying, is concentrated under reduced pressure to give crude product.4- morpholino piperidines -1- t-butyl formates (6g, 76%) are obtained through the purifying of Combi-Flash column chromatographies.MS m/z(ESI):271.1[M+H]+
Step 2：At room temperature, 4- morpholino piperidines -1- t-butyl formates (6g, 22.2mmol) are added in 100ml hydrochloric acid dioxane solutions, 4h is stirred vigorously at room temperature.After reaction terminates, reaction solution is concentrated under reduced pressure, 4- (piperidin-4-yl) morpholine (3.8g, 100%) is obtained.MS m/z(ESI):171.1[M+H]+
Step 3：By 4- (piperidin-4-yl) morpholines (3.8g, 22.2mmol), the fluoro- 2- methoxyl groups -1- nitrobenzene (4.18g of 4-, 24.42mmol) with potassium carbonate (9.19g, 66.6mmol) it is placed in 250mL stand up reaction bottle, adding DMF (50mL) is partly dissolved substrate, keeps reaction system to heat 4h at 100 DEG C.TLC detects extent of reaction, after after substrate completely reaction, insoluble matter is filtered off, yellow solid is concentrated under reduced pressure to give, 4- (1- (3- methoxyl group -4- nitrobenzophenones) piperidin-4-yl) morpholine (5.8g, 81%) is obtained through the purifying of Combi-Flash column chromatographies.MS m/z(ESI):322.1[M+H]+
Step 4：At room temperature, by palladium carbon (0.58g, in the 200ml methanol solutions for 10%wt) being added to 4- (1- (3- methoxyl group -4- nitrobenzophenones) piperidin-4-yl) morpholine (5.8g, 18.1mmol), room temperature is stirred vigorously 20h in a hydrogen atmosphere.Reaction After end, palladium carbon is filtered off, filtrate decompression is concentrated, product 2- methoxyl groups -4- (4- morpholino -1- bases) aniline, be directly used in next step reaction.MS m/z(ESI):292.2[M+H]+
Intermediate 4：1- (4- amino -3- methoxyphenyls)-N, the preparation of N- lupetidine -4- amine
Step 1：By N, N- lupetidine -4- amine (5g, 39mmol) with the fluoro- 2- methoxyl groups -1- nitrobenzene (10.95g of 4-, 58.6mmol) with potassium carbonate (16.15g, 117mmol) it is placed in 500mL stand up reaction bottle, adding DMF (150mL) is partly dissolved substrate, keeps reaction system to heat 4h at 100 DEG C.TLC detects extent of reaction, after after substrate completely reaction, filters off insoluble matter, it is concentrated under reduced pressure to give yellow solid, 1- (3- methoxyl group -4- nitrobenzophenones)-N, N- lupetidine -4- amine (7.5g, 69%) are obtained through the purifying of Combi-Flash column chromatographies.MS m/z(ESI):280.1[M+H]+
Step 2：At room temperature, palladium carbon (0.75g, 10%wt) is added to 1- (3- methoxyl group -4- nitrobenzophenones)-N, N- lupetidine -4- amine (7.5g, in 200ml methanol solutions 26.8mmol), room temperature is stirred vigorously 20h in a hydrogen atmosphere.After reaction terminates, palladium carbon is filtered off, filtrate decompression is concentrated, product 1- (4- amino -3- methoxyphenyls)-N, N- lupetidine -4- amine, be directly used in next step reaction.MS m/z(ESI):250.2[M+H]+
Intermediate 5：The preparation of 2- methoxyl group -4- morpholino aniline
Step 1：The fluoro- 2- methoxyl groups -1- nitrobenzene (4.4g, 25.7mmol) of 4- and cesium carbonate (18.1g, 51.4mmol) are placed in 250mL stand up reaction bottle, adding DMF (100mL) is partly dissolved substrate.Morpholine (3.3mL, 38.6mmol) is added afterwards and keeps reaction system to heat 2h at 100 DEG C.TLC detects extent of reaction, after after substrate completely reaction, reaction solution is extracted three times with ethyl acetate/aqueous systems, isolate organic layer, through water and saturated common salt water washing, after anhydrous sodium sulfate drying, crude product 4- (3- methoxyl group -4- nitrobenzophenones) morpholine is concentrated under reduced pressure to give, the next step is directly used in.MS m/z(ESI):238.1[M+H]+
Step 2：At room temperature, palladium carbon (500mg, 10%wt) is added in the 100ml methanol solutions of 4- (3- methoxyl group -4- nitrobenzophenones) morpholine, room temperature is stirred vigorously reaction and stayed overnight in a hydrogen atmosphere.After reaction terminates, palladium carbon is filtered off, filtrate decompression concentration, product 2- methoxyl group -4- morpholines aniline (4.5g, two step yields 84%) is directly used in next step reaction.MS m/z(ESI):209.1[M+H]+
Intermediate 6：The preparation of 2- amino -5- (4- morpholinyls) pyridine
Step 1：At room temperature, the bromo- 2- nitropyridines (1g, 5mmol) of 5- are added in 10ml morpholine solutions, 4h is stirred vigorously at room temperature.After reaction terminates, there is yellow solid precipitation.It is solid with 50ml petroleum ethers yellow after filtering Body, obtains 4- (6- nitropyridine -3- bases) morpholine (530mg, 53%).MS m/z(ESI):210.1[M+H]+
Step 2：At room temperature, palladium carbon (60mg, 10%wt) is added in the 30ml methanol solutions of 4- (6- nitropyridine -3- bases) morpholine (600mg, 2.86mmol), room temperature is stirred vigorously 20h in a hydrogen atmosphere.After reaction terminates, palladium carbon is filtered off, filtrate decompression is concentrated, product 2- amino -5- (4- morpholinyls) pyridine is obtained, be directly used in next step reaction.MS m/z(ESI):180.1[M+H]+
Intermediate 7：The preparation of 2- methoxyl groups -4- (piperidin-1-yl) aniline
Step 1：The fluoro- 2- methoxyl groups -1- nitrobenzene (1.9g, 11.1mmol) of 4- and potassium carbonate (4.6g, 33.3mmol) are placed in 60mL stand up reaction bottle, adding DMF (60mL) is partly dissolved substrate.Piperidines (950mg, 11.1mmol) is added afterwards and keeps reaction system to heat 6h at 100 DEG C.TLC detects extent of reaction, and after after substrate completely reaction, reaction solution is extracted three times with ethyl acetate/aqueous systems, isolates organic layer, through water and saturated common salt water washing, after anhydrous sodium sulfate drying, is concentrated under reduced pressure to give crude product.1- (3- methoxyl group -4- nitrobenzophenones) piperidines (2.2g, 85%) is obtained through the purifying of Combi-Flash column chromatographies.MS m/z(ESI):237.1[M+H]+
Step 2：At room temperature, palladium carbon (200mg, 10%wt) is added in the 60ml methanol solutions of 1- (3- methoxyl group -4- nitrobenzophenones) piperidines (2g, 8.44mmol), room temperature is stirred vigorously 20h in a hydrogen atmosphere.After reaction terminates, palladium carbon is filtered off, filtrate decompression is concentrated, product 2- methoxyl groups -4- (piperidin-1-yl) aniline, be directly used in next step reaction.MS m/z(ESI):207.1[M+H]+
Intermediate 8：The preparation of 4- (4- (2- fluoro ethyls) piperazine -1- bases) -2- aminoanisoles
Step 1：The fluoro- 2- methoxyl groups -1- nitrobenzene (5g, 29.2mmol) of 4- and potassium carbonate (12.1g, 87.7mmol) are placed in 500mL stand up reaction bottle, adding DMF (100mL) is partly dissolved substrate.1- tert-butoxycarbonyl-piperazines (8.2g, 43.8mmol) are added afterwards and keep reaction system to heat 4h at 100 DEG C.TLC detects extent of reaction, and after after substrate completely reaction, reaction solution is extracted three times with ethyl acetate/aqueous systems, isolates organic layer, through water and saturated common salt water washing, after anhydrous sodium sulfate drying, is concentrated under reduced pressure to give crude product.4- (3- methoxyl group -4- nitrobenzophenones) piperazine -1- carboxylic acid tert-butyl esters (8.1g, 82%) are obtained through the purifying of Combi-Flash column chromatographies.MS m/z(ESI):338.2[M+H]+
Step 2：At room temperature, 4- (3- methoxyl group -4- nitrobenzophenones) piperazine -1- carboxylic acid tert-butyl esters (8g, 23.7mmol) are added in 100ml hydrochloric acid dioxane solutions, 1h is stirred vigorously at room temperature.After reaction terminates, reaction solution is concentrated under reduced pressure, 1- (3- methoxyl group -4- nitrobenzophenones) piperazine (5.6g, 95%) is obtained.MS m/z(ESI):238.1[M+H]+
Step 3：1- (3- methoxyl group -4- nitrobenzophenones) piperazines (500mg, 2.1mmol) and potassium carbonate (900mg, 6.3mmol) are placed in 25mL tube sealing reaction bottle, adding acetonitrile (6mL) is partly dissolved substrate.The bromo- 2- fluoroethanes (290mg, 2.3mmol) of 1- are added afterwards and keep reaction system to heat 7h at 80 DEG C.TLC detects extent of reaction, treats bottom After thing reaction completely, insoluble matter is filtered off, yellow solid 1- (2- fluoro ethyls) -4- (3- methoxyl group -4- nitrobenzophenones) piperazine (350mg, 59%) is concentrated under reduced pressure to give.MS m/z(ESI):284.1[M+H]+
Step 4：At room temperature, by palladium carbon (35mg, in the 50ml methanol solutions for 10%wt) being added to 1- (2- fluoro ethyls) -4- (3- methoxyl group -4- nitrobenzophenones) piperazine (350mg, 1.24mmol), room temperature is stirred vigorously 20h in a hydrogen atmosphere.After reaction terminates, palladium carbon is filtered off, filtrate decompression is concentrated, product 4- (4- (2- fluoro ethyls) piperazine -1- bases) -2- aminoanisoles, be directly used in next step reaction.MS m/z(ESI):254.1[M+H]+
Intermediate 9：N1, N1The preparation of-diethyl -3- methoxybenzene -1,4- diamines
Step 1：By diethylamine (1g, 13.7mmol) with the fluoro- 2- methoxyl groups -1- nitrobenzene (3.84g of 4-, 20.5mmol) with potassium carbonate (5.67g, 41.1mmol) it is placed in 500mL stand up reaction bottle, adding DMF (50mL) is partly dissolved substrate, keeps reaction system to heat 4h at 100 DEG C.TLC detects extent of reaction, after after substrate completely reaction, filters off insoluble matter, is concentrated under reduced pressure to give yellow solid, and N, N- diethyl -3- methoxyl group -4- nitroanilines (1.8g, 58%) are obtained through the purifying of Combi-Flash column chromatographies.MS m/z(ESI):225.1[M+H]+
Step 2：At room temperature, palladium carbon (0.22g, 10%wt) is added in N, the 200ml methanol solutions of N- diethyl -3- methoxyl group -4- nitroanilines (1.8g, 8.04mmol), room temperature is stirred vigorously 20h in a hydrogen atmosphere.After reaction terminates, palladium carbon is filtered off, filtrate decompression is concentrated, product N1, N1- diethyl -3- methoxybenzenes-Isosorbide-5-Nitrae-diamines, are directly used in next step reaction.MS m/z(ESI):195.1[M+H]+
Intermediate 10：The preparation of 1- (4- amino -3- methoxyphenyls)-N, N- diethyl phenylpiperidines -4- amine
Step 1：By 4- oxo-piperidine -1- t-butyl formates (5g, 29.2mmol) with sodium cyanoborohydride (2.8g, 43.8mmol) it is placed in 500mL stand up reaction bottle, add methanol 200ml dissolvings, diethylamine (2.3g, 32.1mmol) and glacial acetic acid (1ml) are added afterwards and keep reaction system to stay overnight at room temperature.TLC detects extent of reaction, and after after substrate completely reaction, reaction solution is extracted three times with ethyl acetate/aqueous systems, isolates organic layer, through water and saturated common salt water washing, after anhydrous sodium sulfate drying, is concentrated under reduced pressure to give crude product.4- (diethylamino) piperidines -1- t-butyl formates (5.2g, 70%) are obtained through the purifying of Combi-Flash column chromatographies.MS m/z(ESI):257.2[M+H]+
Step 2：At room temperature, 4- (diethylamino) piperidines -1- t-butyl formates (5.2g, 20.2mmol) are added in 100ml hydrochloric acid dioxane solutions, 4h is stirred vigorously at room temperature.After reaction terminates, reaction solution is concentrated under reduced pressure, N, N- diethyl phenylpiperidines -4- amine (3.1g, 100%) is obtained.MS m/z(ESI):157.1[M+H]+
Step 3：By N, the fluoro- 2- methoxyl groups -1- nitrobenzene (4.53g, 24.2mmol) of N- diethyls phenylpiperidines -4- amine (3.1g, 20.2mmol) 4- and potassium carbonate (8.36g, 60.6mmol) it is placed in 250mL stand up reaction bottle, adds DMF (100mL) Substrate is partly dissolved, keeps reaction system to heat 4h at 100 DEG C.TLC detects extent of reaction, after after substrate completely reaction, filters off insoluble matter, it is concentrated under reduced pressure to give yellow solid, N, N- diethyl -1- (3- methoxyl group -4- nitrobenzophenones) piperidines -4- amine (5g, 80%) are obtained through the purifying of Combi-Flash column chromatographies.MS m/z(ESI):308.1[M+H]+
Step 4：At room temperature, palladium carbon (0.5g, 10%wt) is added to N, N- diethyl -1- (3- methoxyl group -4- nitrobenzophenones) piperidines -4- amine (5g, in 200ml methanol solutions 17.9mmol), room temperature is stirred vigorously 20h in a hydrogen atmosphere.After reaction terminates, palladium carbon is filtered off, filtrate decompression is concentrated, product 1- (4- amino -3- methoxyphenyls)-N, N- diethyl phenylpiperidines -4- amine, be directly used in next step reaction.MS m/z(ESI):278.1[M+H]+
Intermediate 11：The preparation of 4- (4- ethyl piperazidine -1- bases) -2- aminoanisoles
Step 1：The fluoro- 2- methoxyl groups -1- nitrobenzene (5g, 29.2mmol) of 4- and potassium carbonate (12.1g, 87.7mmol) are placed in 500mL stand up reaction bottle, adding DMF (100mL) is partly dissolved substrate.1- tert-butoxycarbonyl-piperazines (8.2g, 43.8mmol) are added afterwards and keep reaction system to heat 4h at 100 DEG C.TLC detects extent of reaction, and after after substrate completely reaction, reaction solution is extracted three times with ethyl acetate/aqueous systems, isolates organic layer, through water and saturated common salt water washing, after anhydrous sodium sulfate drying, is concentrated under reduced pressure to give crude product.4- (3- methoxyl group -4- nitrobenzophenones) piperazine -1- carboxylic acid tert-butyl esters (8.1g, 82%) are obtained through the purifying of Combi-Flash column chromatographies.MS m/z(ESI):338.2[M+H]+
Step 2：At room temperature, 4- (3- methoxyl group -4- nitrobenzophenones) piperazine -1- carboxylic acid tert-butyl esters (8g, 23.7mmol) are added in 100ml hydrochloric acid dioxane solutions, 1h is stirred vigorously at room temperature.After reaction terminates, reaction solution is concentrated under reduced pressure, 1- (3- methoxyl group -4- nitrobenzophenones) piperazine (5.6g, 95%) is obtained.MS m/z(ESI):238.1[M+H]+
Step 3：1- (3- methoxyl group -4- nitrobenzophenones) piperazines (500mg, 2.1mmol) and potassium carbonate (900mg, 6.3mmol) are placed in 50mL stand up reaction bottle, adding acetonitrile (6mL) is partly dissolved substrate.Bromoethane (253mg, 2.3mmol) is added afterwards and keeps reaction system to heat 7h at 80 DEG C.TLC detects extent of reaction, after after substrate completely reaction, filters off insoluble matter, is concentrated under reduced pressure to give yellow solid 1- ethyls -4- (3- methoxyl group -4- nitrobenzophenones) piperazine (400mg, 72%).MS m/z(ESI):266.3[M+H]+
Step 4：At room temperature, palladium carbon (30mg, 10%wt) is added in the 50ml methanol solutions of 1- ethyls -4- (3- methoxyl group -4- nitrobenzophenones) piperazine (270mg, 1mmol), room temperature is stirred vigorously 20h in a hydrogen atmosphere.After reaction terminates, palladium carbon is filtered off, filtrate decompression is concentrated, product 4- (4- ethyl piperazidine -1- bases) -2- aminoanisoles, be directly used in next step reaction.MS m/z(ESI):236.3[M+H]+
Intermediate 12：The preparation of 5- (4- methylpiperazine-1-yls) pyridine -2- amine
Step 1：At room temperature, N methyl piperazine (30ml) is added in the 80ml dichloromethane solutions of the bromo- 2- nitropyridines (5g, 21.6mmol) of 5-, 2h is stirred vigorously at 45 DEG C.After after substrate completely reaction, it is diluted with water, is extracted three times with methylene chloride/water system, isolate organic layer, through water and saturated common salt water washing, after anhydrous sodium sulfate drying, Be concentrated under reduced pressure to obtain yellow solid 1- methyl -4- (6- nitropyridine -3- bases) piperazine (2.5g, 52%).MS m/z(ESI):223.1[M+H]+
Step 2：At room temperature, palladium carbon (250mg, 10%wt) is added in the 60ml methanol solutions of 1- methyl -4- (6- nitropyridine -3- bases) piperazine (2.5g, 11.2mmol), room temperature is stirred vigorously 20h in a hydrogen atmosphere.After reaction terminates, palladium carbon is filtered off, filtrate decompression is concentrated, product 5- (4- methylpiperazine-1-yls) pyridine -2- amine, be directly used in next step reaction.MS m/z(ESI):193.1[M+H]+
Intermediate 13：The preparation of 4- amino-N, N- diethyl -3- methoxy benzamides
Step 1：4- nitro -3- methoxy benzoic acids (5g, 25.4mmol) are added to 50ml SOCl2In, dropwise addition 4 is dripped is stirred vigorously 3h at DMF, 90 DEG C.TLC detects extent of reaction, and after after substrate completely reaction, the yellow solid 3- methoxyl group -4- nitrobenzoyl chlorides obtained after product concentration are directly used in next step reaction.
Step 2：At 0 DEG C, DIPEA (4mL, 25.1mmol) and diethylamine (2.7mL, 25.1mmol) are added in the 50ml THF solutions of 3- methoxyl group -4- nitrobenzoyl chlorides (5.4g, 25.1mmol), 3h is stirred vigorously at room temperature.TLC detects extent of reaction, after after substrate completely reaction, is diluted with water, and pH is to alkalescence for regulation, is extracted three times with ethyl acetate/aqueous systems, isolates organic layer, through water and saturated common salt water washing, after anhydrous sodium sulfate drying, is concentrated under reduced pressure to give crude product 6.6g.Compound N, N- diethyl -3- methoxyl group -4- nitrobenzamides (5.5g, 86%) are obtained through the purifying of Combi-Flash column chromatographies.MS m/z(ESI):253.1[M+H]+
Step 3：Pd/C (200mg) is added in N, the 50ml methanol solutions of N- diethyl -3- methoxyl group -4- nitrobenzamides (1g, 3.97mmol).At room temperature, 16h is stirred vigorously in atmosphere of hydrogen.After reaction terminates, filtering, filtrate concentration obtains compound 4- amino-N, N- diethyl -3- methoxy benzamides (840mg, 95%), product is directly used in next step.MS m/z(ESI):223.2[M+H]+
Intermediate 14：The preparation of (4- amino -3- methoxyphenyls) (morpholino) ketone
Step 1：4- nitro -3- methoxy benzoic acids (5g, 25.4mmol) are added to 50ml SOCl2In, dropwise addition 4 is dripped is stirred vigorously 3h at DMF, 90 DEG C.TLC detects extent of reaction, and after after substrate completely reaction, the yellow solid 3- methoxyl group -4- nitrobenzoyl chlorides obtained after product concentration are directly used in next step reaction.
Step 2：At 0 DEG C, DIPEA (4mL, 25.1mmol) and morpholine (2.2g, 25.1mmol) are added in the 50ml THF solutions of 3- methoxyl group -4- nitrobenzoyl chlorides (5.5g, 25.4mmol), 3h is stirred vigorously at room temperature.TLC detects extent of reaction, after after substrate completely reaction, it is diluted with water, pH is adjusted to alkalescence, is extracted three times with ethyl acetate/aqueous systems, isolates organic layer, through water and saturated common salt water washing, after anhydrous sodium sulfate drying, compound (3- methoxyl group -4- nitrobenzophenones) (morpholino) ketone (6.6g, 98%) is concentrated under reduced pressure to give.MS m/z(ESI):267.1[M+H]+
Step 3：In the 50ml methanol solutions that Pd/C (200mg) is added to (3- methoxyl group -4- nitrobenzophenones) (morpholino) ketone (1g, 3.76mmol).At room temperature, in H216h is stirred vigorously in atmosphere.After reaction terminates, filter, filter Liquid is concentrated, and obtains compound (4- amino -3- methoxyphenyls) (morpholino) ketone (900mg, 99%), product is directly used in next step.MS m/z(ESI):237.2[M+H]+
Intermediate 15：The preparation of (4- amino -3- methoxyphenyls) (4- methylpiperazine-1-yls) ketone
Step 1：4- nitro -3- methoxy benzoic acids (3g, 15.2mmol) are added to 50ml SOCl2In, dropwise addition 4 is dripped is stirred vigorously 3h at DMF, 90 DEG C.TLC detects extent of reaction, and after after substrate completely reaction, the yellow solid 3- methoxyl group -4- nitrobenzoyl chlorides obtained after product concentration are directly used in next step reaction.
Step 2：At 0 DEG C, in the 50ml dichloromethane solutions that N methyl piperazine (1.5g, 15.2mmol) is added to 3- methoxyl group -4- nitrobenzoyl chlorides (3.3g, 15.2mmol), 3h is stirred vigorously at room temperature.TLC detects extent of reaction, after after substrate completely reaction, it is diluted with water, pH is adjusted to alkalescence, is extracted three times with ethyl acetate/aqueous systems, isolates organic layer, through water and saturated common salt water washing, after anhydrous sodium sulfate drying, compound (3- methoxyl group -4- nitrobenzophenones) (4- methylpiperazine-1-yls) ketone (3.0g, 71%) is concentrated under reduced pressure to give.MS m/z(ESI):280.0[M+H]+
Step 3：In the 50ml methanol solutions that Pd/C (150mg) is added to (3- methoxyl group -4- nitrobenzophenones) (4- methylpiperazine-1-yls) ketone (1g, 3.58mmol).At room temperature, 16h is stirred vigorously in atmosphere of hydrogen.After TLC detection reactions terminate, filtering, filtrate concentration obtains (4- amino -3- methoxyphenyls) (4- methylpiperazine-1-yls) ketone (780mg, 87%), product is directly used in next step.
Embodiment 1：The preparation of N- (3- (3- (2- ((2- methoxyl groups -4- (4- methylpiperazine-1-yls) phenyl) amino) pyrimidine-4-yl) urea groups) phenyl) acrylamide (cpd-1)
Step 1：The synthesis of the chloro- 4- pyrimidines isocyanates of 2-
At 0 DEG C, 4- amino -2- chlorine pyrimidines (4.8g, 37.0mmol) are added to triphosgene (5.5g, in 200ml THF solutions 18.5mmol), then DIPEA (DIEA) (6.23g, 48.2mmol) is slowly added dropwise.4h is stirred vigorously at room temperature.TLC detects extent of reaction, and after after substrate completely reaction, the chloro- 4- pyrimidines isocyanates of product 2- is directly used in next step reaction.
Step 2：The synthesis of 1- (2- chlorine pyrimidine-4-yl) -3- (3- nitrobenzophenones) urea
At room temperature, triethylamine (TEA) (11g, 110mmol) and 3- nitroanilines (5.6g, 40.3mmol) are added to 2- In the 200ml THF solutions of chloro- 4- pyrimidines isocyanates (5.7g, 36.6mmol), 20h is stirred vigorously at room temperature.After reaction terminates, 500ml water is added to reaction system, there is yellow solid precipitation.Yellow solid is washed with 500ml ethyl acetate, is then beaten with 30ml ethyl acetate, is filtrated to get compound 1- (2- chlorine pyrimidine-4-yl) -3- (3- nitrobenzophenones) urea (2.8g).Yield：30%, purity：86%, MS m/z (ESI):294.1[M+H]+
Step 3：The synthesis of 1- (2- ((2- methoxyl groups -4- (4- methylpiperazine-1-yls) phenyl) amino) pyrimidine-4-yl) -3- (3- nitrobenzophenones) urea
By 2- methoxyl groups -4- (4- methylpiperazine-1-yls) aniline (739mg, 3.34mmol) with trifluoroacetic acid (TFA) (1.14g, 10mmol) it is added to compound 1- (2- chlorine pyrimidine-4-yl) -3- (3- nitrobenzophenones) urea (980mg, 3.34mmol) 20ml butanol solutions in, be stirred vigorously 7h at 130 DEG C.After reaction terminates, system is cooled to room temperature, filters to obtain brown solid.Brown solid is washed with 30ml ethanol, compound 1- (2- ((2- methoxyl groups -4- (4- methylpiperazine-1-yls) phenyl) amino) pyrimidine-4-yl) -3- (3- nitrobenzophenones) urea (700mg) is obtained, product is directly used in next step.Yield：44%, purity：74%, MS m/z (ESI):479.2[M+H]+
Step 4：The synthesis of 1- (3- aminophenyls) -3- (2- ((2- methoxyl groups -4- (4- methylpiperazine-1-yls) phenyl) amino) pyrimidine-4-yl) urea
By stannous chloride (554mg, 2.93mmol) it is added to 1- (2- ((2- methoxyl groups -4- (4- methylpiperazine-1-yls) phenyl) amino) pyrimidine-4-yl) -3- (3- nitrobenzophenones) urea (700mg, in 60ml methanol and 40mlDMF mixed solution 1.46mmol), 4h is stirred vigorously at 90 DEG C.After reaction terminates, system is cooled to room temperature, adds equivalent sodium bicarbonate solid.Mixture is stirred vigorously 30min, insoluble matter is filtered off.Filtrate decompression is concentrated to give brown solid compound 1- (3- aminophenyls) -3- (2- ((2- methoxyl groups -4- (4- methylpiperazine-1-yls) phenyl) amino) pyrimidine-4-yl) urea (300mg), product is directly used in next step.Yield：45%, purity：70%, MS m/z (ESI):449.2[M+H]+
Step 5：The synthesis of N- (3- (3- (2- ((2- methoxyl groups -4- (4- methylpiperazine-1-yls) phenyl) amino) pyrimidine-4-yl) urea groups) phenyl) acrylamide (cpd-1)
By triethylamine (70mg, 0.67mmol) it is added to 1- (3- aminophenyls) -3- (2- ((2- methoxyl groups -4- (4- methylpiperazine-1-yls) phenyl) amino) pyrimidine-4-yl) urea (100mg, in the mixed solution of 2ml THF and 2mlDMF 0.23mmol), it is stirred vigorously at 0 DEG C.By acryloyl chloride (25mg, 0.27mmol), at 0 DEG C, it is slowly dropped in reaction solution.Keep 0 DEG C of stirring 4h.TLC detects extent of reaction, after after substrate completely reaction, it is diluted with water, extracted three times with ethyl acetate/aqueous systems, isolate organic layer, through water and saturated common salt water washing, after anhydrous sodium sulfate drying, be concentrated under reduced pressure to obtain yellow solid, and compound N-(3- (3- (2- ((2- methoxyl groups -4- (4- methylpiperazine-1-yls) phenyl) amino) pyrimidine-4-yl) urea groups) phenyl) acrylamide (cpd-1) (2.4mg) is purified to obtain through preparing liquid phase separation.Yield：2%, purity：100%, MS m/z (ESI):503.2[M+H]+；1H NMR(400MHz,DMSO-d6):δ 10.52 (s, 1H), 10.14 (s, 1H), (9.61 s, 1H), 8.30 (d, 1H), (8.10 d, 1H), 7.94 (s, 1H), 7.48 (d, J=8.7Hz, 1H), 7.35 (d, J=8.7Hz, 1H), 7.15 (t, J=5.5Hz, 1H), 6.64 (s, 2H), 6.47-6.43 (m, 2H), 6.26 (d, J=16.9Hz, 1H), 5.75 (d, J=12.0Hz, 1H), 5.33 (m, 1H), 3.75 (s, 3H), 3.11 (m, 4H), 2.47 (m, 4H), 2.33 (s, 3H).
Embodiment 2：The preparation of N- (3- (3- (2- ((4- (4- methylpiperazine-1-yls) phenyl) amino) pyrimidine-4-yl) urea groups) phenyl) acrylamide (cpd-2)
Step 1：The synthesis of 1- (2- ((4- (4- methylpiperazine-1-yls) phenyl) amino) pyrimidine-4-yl) -3- (3- nitrobenzophenones) urea
By 4- (4- methylpiperazine-1-yls) aniline (392mg, 2.00mmol) with trifluoroacetic acid (700mg, 6.0mmol) it is added to 1- (2- chlorine pyrimidine-4-yl) -3- (3- nitrobenzophenones) urea (600mg, in 14ml butanol solutions 2.00mmol), 7h is stirred vigorously at 130 DEG C.After reaction terminates, system is cooled to room temperature, filters to obtain brown solid.Brown solid is washed with 50ml ethanol, 1- (2- ((4- (4- methylpiperazine-1-yls) phenyl) amino) pyrimidine-4-yl) -3- (3- nitrobenzophenones) urea (500mg) is obtained, product is directly used in next step.Yield：56%, purity：72%, MS m/z (ESI):449.2[M+H]+
Step 2：The synthesis of 1- (2- ((4- (4- methylpiperazine-1-yls) phenyl) amino) pyrimidine-4-yl) -3- (3- aminophenyls) urea
By stannous chloride (755mg, 3.33mmol) it is added to 1- (2- ((4- (4- methylpiperazine-1-yls) phenyl) amino) pyrimidine-4-yl) -3- (3- nitrobenzophenones) urea (500mg, 10ml methanol 1.11mmol) is with 5ml DMSO mixed solution, 4h is stirred vigorously at 90 DEG C.After reaction terminates, system is cooled to room temperature, adds equivalent sodium bicarbonate solid.Mixture is stirred vigorously 30min, insoluble matter is filtered off.Filtrate decompression is concentrated to give brown solid 1- (2- ((4- (4- methylpiperazine-1-yls) phenyl) amino) pyrimidine-4-yl) -3- (3- aminophenyls) urea (180mg), product is directly used in next step.Yield：39%, purity：72%, MS m/z (ESI):419.2[M+H]+
Step 3：The synthesis of N- (3- (3- (2- ((4- (4- methylpiperazine-1-yls) phenyl) amino) pyrimidine-4-yl) urea groups) phenyl) acrylamide (cpd-2)
By triethylamine (131mg, 1.29mmol) it is added to (2- ((4- (4- methylpiperazine-1-yls) phenyl) amino) pyrimidine-4-yl) -3- (3- aminophenyls) urea (180mg, in 5ml THF solutions 0.43mmol), it is stirred vigorously at 0 DEG C.By acryloyl chloride (60mg, 0.65mmol), at 0 DEG C, it is slowly dropped in reaction solution.Keep 0 DEG C of stirring 4h.TLC detects extent of reaction, after after substrate completely reaction, it is diluted with water, extracted three times with ethyl acetate/aqueous systems, isolate organic layer, through water and saturated common salt water washing, after anhydrous sodium sulfate drying, be concentrated under reduced pressure to obtain yellow solid, and compound N-(3- (3- (2- ((4- (4- methylpiperazine-1-yls) phenyl) amino) pyrimidine-4-yl) urea groups) phenyl) acrylamide (cpd-2) (12.4mg) is purified to obtain through preparing liquid phase separation.Yield：6%, purity：95%, MS m/z (ESI):473.0[M+H]+；1H NMR(400MHz,DMSO-d6):δ 10.31 (s, 1H), 10.17 (s, 1H), 9.55 (s, 1H), 9.20 (s, 1H), 8.18 (d, J=5.6Hz, 1H), 7.94 (s, 1H), 7.46 (dd, J=13.8,9.1Hz, 3H), 7.19 (t, J=8.1Hz, 1H), 6.89 (d, J=9.0Hz, 2H), 6.75 (d, J=5.6Hz, 2H), 6.47 (dd, J=17.0,10.1Hz, 1H), 6.26 (dd, J=16.9,2.0Hz, 1H), 5.75 (dd, J=10.1,2.0Hz, 1H), 3.09 (m, 4H), 2.53 (m, 4H), 2.33 (s, 3H).
Embodiment 3：The preparation of N- (3- (3- (2- ((5- methoxypyridine -2- bases) amino) pyrimidine-4-yl) urea groups) phenyl) acrylamide (cpd-3)
Step 1：The synthesis of 1- (2- ((5- methoxypyridine -2- bases) amino) pyrimidine-4-yl) -3- (3- nitrobenzophenones) urea
By 2- amino -5- methoxypyridines (414mg, 3.34mmol) with trifluoroacetic acid (1.14g, 10mmol) it is added to 1- (2- chlorine pyrimidine-4-yl) -3- (3- nitrobenzophenones) urea (980mg, in 20ml butanol solutions 3.34mmol), 7h is stirred vigorously at 130 DEG C.After reaction terminates, system is cooled to room temperature, filters to obtain brown solid.Brown solid is washed with 30ml ethanol, compound 1- (2- ((5- methoxypyridine -2- bases) amino) pyrimidine-4-yl) -3- (3- nitrobenzophenones) (650mg) is obtained, product is directly used in next step.Yield：51%, purity：78%, MS m/z (ESI):382.1[M+H]+
Step 2：The synthesis of 1- (2- ((5- methoxypyridine -2- bases) amino) pyrimidine-4-yl) -3- (3- aminophenyls) urea
By stannous chloride (1157mg, 5.13mmol) it is added to 1- (2- ((5- methoxypyridine -2- bases) amino) pyrimidine-4-yl) -3- (3- nitrobenzophenones) urea (650mg, in 60ml methanol and 40mlDMF mixed solution 1.71mmol), 4h is stirred vigorously at 90 DEG C.After reaction terminates, system is cooled to room temperature, adds equivalent sodium bicarbonate solid.Mixture is stirred vigorously 30min, insoluble matter is filtered off.Filtrate decompression is concentrated to give brown solid 1- (2- ((5- methoxypyridine -2- bases) amino) pyrimidine-4-yl) -3- (3- aminophenyls) urea (500mg), product is directly used in next step.Yield：83%, purity：78%, MS m/z (ESI):352.1[M+H]+
Step 3：The synthesis of N- (3- (3- (2- ((5- methoxypyridine -2- bases) amino) pyrimidine-4-yl) urea groups) phenyl) acrylamide (cpd-3)
By triethylamine (172mg, 1.7mmol) it is added to 1- (2- ((5- methoxypyridine -2- bases) amino) pyrimidine-4-yl) -3- (3- aminophenyls) urea (200mg, in the mixed solution of 2ml THF and 2mlDMF 0.56mmol), it is stirred vigorously at 0 DEG C.By acryloyl chloride (62mg, 0.68mmol), at 0 DEG C, it is slowly dropped in reaction solution.Keep 0 DEG C of stirring 4h.TLC detects extent of reaction, after after substrate completely reaction, it is diluted with water, extracted three times with ethyl acetate/aqueous systems, organic layer is isolated, through water and saturated common salt water washing, after anhydrous sodium sulfate drying, be concentrated under reduced pressure to obtain yellow solid, and N- (3- (3- (2- ((5- methoxypyridine -2- bases) amino) pyrimidine-4-yl) urea groups) phenyl) acrylamide (cpd-3) (26.3mg) is purified to obtain through preparing liquid phase separation.Yield：2%, purity：94.5%, MS m/z (ESI):406.0[M+H]+；1H NMR(400MHz,DMSO-d6):δ 10.17 (s, 1H), 9.85 (s, 1H), 9.49 (s, 1H), 9.37 (s, 1H), 8.49 (d, J=2Hz, 1H), 8.21 (d, J=5.6Hz, 1H), 7.90 (t, J=2.4Hz, 2H), 7.44 (d, J=8Hz, 1H), 7.22 (t, J=8.4Hz, 1H), 6.95 (d, J=5.2Hz, 2H), 6.78 (d, J=8.4Hz, 1H), 6.45 (t, J=12.4Hz, 1H), 6.25 (dd, J=2Hz, 1H), 5.75 (dd, J=1.6Hz, 1H), 3.81 (s, 3H).
Embodiment 4：The preparation of N- (3- (3- (2- ((the chloro- 4- of 3- ((3- luorobenzyls) oxygen) phenyl) amino) pyrimidine-4-yl) urea groups) phenyl) acrylamide (cpd-4)
Step 1：The synthesis of 1- (2- ((the chloro- 4- of 3- ((3- luorobenzyls) epoxide) phenyl) amino) pyrimidine-4-yl) -3- (3- nitrobenzophenones) urea
By the chloro- 4- of 3- ((3- luorobenzyls) oxygen) aniline (414mg, 3.34mmol) with trifluoroacetic acid (1.14g, 10mmol) it is added to 1- (2- chlorine pyrimidine-4-yl) -3- (3- nitrobenzophenones) urea (980mg, in 20ml butanol solutions 3.34mmol), 7h is stirred vigorously at 130 DEG C.After reaction terminates, system is cooled to room temperature, filters to obtain brown solid.Brown solid is washed with 30ml ethanol, 1- (2- ((the chloro- 4- of 3- ((3- luorobenzyls) epoxide) phenyl) amino) pyrimidine-4-yl) -3- (3- nitrobenzophenones) urea (650mg) is obtained, product is directly used in next step.Yield：51%, purity：78%, MS m/z (ESI):382.1[M+H]+
Step 2：The synthesis of 1- (2- ((the chloro- 4- of 3- ((3- luorobenzyls) epoxide) phenyl) amino) pyrimidine-4-yl) -3- (3- aminophenyls) urea
By stannous chloride (1157mg, 5.13mmol) it is added to 1- (2- ((the chloro- 4- of 3- ((3- luorobenzyls) epoxide) phenyl) amino) pyrimidine-4-yl) -3- (3- nitrobenzophenones) urea (650mg, in 60ml methanol and 40mlDMF mixed solution 1.71mmol), 4h is stirred vigorously at 90 DEG C.After reaction terminates, system is cooled to room temperature, adds equivalent sodium bicarbonate solid.Mixture is stirred vigorously 30min, insoluble matter is filtered off.Filtrate decompression is concentrated to give brown solid 1- (2- ((the chloro- 4- of 3- ((3- luorobenzyls) epoxide) phenyl) amino) pyrimidine-4-yl) -3- (3- aminophenyls) urea (500mg), product is directly used in next step.Yield：83%, purity：78%, MS m/z (ESI):352.1[M+H]+
Step 3：The synthesis of N- (3- (3- (2- ((the chloro- 4- of 3- ((3- luorobenzyls) oxygen) phenyl) amino) pyrimidine-4-yl) urea groups) phenyl) acrylamide (cpd-4)
By triethylamine (172mg, 1.7mmol) it is added to 1- (2- ((the chloro- 4- of 3- ((3- luorobenzyls) epoxide) phenyl) amino) pyrimidine-4-yl) -3- (3- aminophenyls) urea (200mg, in the mixed solution of 2ml THF and 2mlDMF 0.56mmol), it is stirred vigorously at 0 DEG C.By acryloyl chloride (62mg, 0.68mmol), at 0 DEG C, it is slowly dropped in reaction solution.Keep 0 DEG C of stirring 4h.TLC detects extent of reaction, after after substrate completely reaction, it is diluted with water, extracted three times with ethyl acetate/aqueous systems, isolate organic layer, through water and saturated common salt water washing, after anhydrous sodium sulfate drying, be concentrated under reduced pressure to obtain yellow solid, and N- (3- (3- (2- ((the chloro- 4- of 3- ((3- luorobenzyls) oxygen) phenyl) amino) pyrimidine-4-yl) urea groups) phenyl) acrylamide (cpd-4) (26.3mg) is purified to obtain through preparing liquid phase separation.Yield：2%, purity：100%, MS m/z (ESI):533.1[M+H]+；1H NMR(400MHz,DMSO-d6):δ 10.17 (s, 1H), 9.85 (s, 1H), 9.49 (s, 1H), 9.37 (s, 1H), (8.49 d, J=2Hz, 1H), 8.21 (d, J=5.6Hz, 1H), 7.90 (t, J=2.4Hz, 2H), 7.44 (d, J=8Hz, 1H), (7.22 t, J=8.4Hz, 1H), 6.95 (d, J=5.2Hz, 2H), 6.78 (d, J=8.4Hz, 1H), 6.45 (t, J=12.4Hz, 1H), (6.25 t, J=2Hz, 1H), 5.75 (t, J=1.6Hz, 1H), 3.81 (s, 3H).
Embodiment 5：The preparation of N- (3- (3- (2- ((2- methoxyl groups -4- (4- (4- methylpiperazine-1-yls) piperidin-1-yl) phenyl) amino) pyrimidine-4-yl) urea groups) phenyl) acrylamide (cpd-5)
Step 1：The synthesis of 1- (2- ((2- methoxyl groups -4- (4- (4- methylpiperazine-1-yls) piperidin-1-yl) phenyl) amino) pyrimidine-4-yl) -3- (3- nitrobenzophenones) urea
By 2- methoxyl groups -4 (4- (4- methyl piperazines) piperidines) aniline (338mg, 1.12mmol) with trifluoroacetic acid (380mg, 3.33mmol) it is added to 1- (2- chlorine pyrimidine-4-yl) -3- (3- nitrobenzophenones) urea (328mg, in 20ml butanol solutions 1.12mmol), 7h is stirred vigorously at 130 DEG C.After reaction terminates, system is cooled to room temperature, filters to obtain brown solid.Brown solid is washed with 30ml ethanol, 1- (2- ((2- methoxyl groups -4- (4- (4- methylpiperazine-1-yls) piperidin-1-yl) phenyl) amino) pyrimidine-4-yl) -3- (3- nitrobenzophenones) urea (281mg) is obtained, product is directly used in next step.Yield：45%, purity：79%, MS m/z (ESI):562.1[M+H]+
Step 2：The synthesis of 1- (2- ((2- methoxyl groups -4- (4- (4- methylpiperazine-1-yls) piperidin-1-yl) phenyl) amino) pyrimidine-4-yl) -3- (3- aminophenyls) urea
By stannous chloride (339mg, 1.5mmol) it is added to 1- (2- ((2- methoxyl groups -4- (4- (4- methylpiperazine-1-yls) piperidin-1-yl) phenyl) amino) pyrimidine-4-yl) -3- (3- nitrobenzophenones) urea (281mg, in 60ml methanol and 40mlDMF mixed solution 0.5mmol), 4h is stirred vigorously at 90 DEG C.After reaction terminates, system is cooled to room temperature, adds equivalent sodium bicarbonate solid.Mixture is stirred vigorously 30min, insoluble matter is filtered off.Filtrate decompression is concentrated to give brown solid 1- (2- ((2- methoxyl groups -4- (4- (4- methylpiperazine-1-yls) piperidin-1-yl) phenyl) amino) pyrimidine-4-yl) -3- (3- aminophenyls) urea (200mg), product is directly used in next step.Yield：76%, purity：82%, MS m/z (ESI):532.1[M+H]+
Step 3：The synthesis of N- (3- (3- (2- ((2- methoxyl groups -4- (4- (4- methylpiperazine-1-yls) piperidin-1-yl) phenyl) amino) pyrimidine-4-yl) urea groups) phenyl) acrylamide (cpd-5)
By triethylamine (114mg, 1.13mmol) it is added to 1- (2- ((2- methoxyl groups -4- (4- (4- methylpiperazine-1-yls) piperidin-1-yl) phenyl) amino) pyrimidine-4-yl) -3- (3- aminophenyls) urea (200mg, in the mixed solution of 2ml THF and 2mlDMF 0.38mmol), it is stirred vigorously at 0 DEG C.By acryloyl chloride (42mg, 0.46mmol), at 0 DEG C, it is slowly dropped in reaction solution.Keep 0 DEG C of stirring 4h.TLC detects extent of reaction, after after substrate completely reaction, it is diluted with water, extracted three times with ethyl acetate/aqueous systems, isolate organic layer, through water and saturated common salt water washing, after anhydrous sodium sulfate drying, be concentrated under reduced pressure to obtain yellow solid, and N- (3- (3- (2- ((2- methoxyl groups -4- (4- (4- methylpiperazine-1-yls) piperidin-1-yl) phenyl) amino) pyrimidine-4-yl) urea groups) phenyl) acrylamide (cpd-5) (3.3mg) is purified to obtain through preparing liquid phase separation.Yield：1.5%, purity：94%, MS m/z (ESI):586.1[M+H]+；1H NMR(400MHz,DMSO-d6):δ 11.02 (s, 1H), 10.13 (s, 1H), 8.28 (s, 1H), 8.09 (d, J=5.6Hz, 1H), 7.89 (s, 1H), 7.48 (d, J=8.4Hz, 1H), 7.31 (t, J=9.2Hz, 1H), 7.13 (m, J=7.2Hz, 1H), (6. m, 6H), 6.27 (t, J=2Hz, 1H), 5.74 (m, 1H), 3.74 (s, 3H), 3.66 (m, 1H), 2.66 (m, 4H), 2.33 (m, 4H), 2.14 (s, 3H), 1.82 (m, 4H), 1.50 (m, 4H).
Embodiment 6：The preparation of N- (3- (3- (2- ((6- morpholinoes pyridin-3-yl) amino) pyrimidine-4-yl) urea groups) phenyl) acrylamide (cpd-6)
Step 1：The synthesis of 1- (2- ((6- morpholinoes pyridin-3-yl) amino) pyrimidine-4-yl) -3- (3- nitrobenzophenones) urea
By 6- morpholino pyridine -3- amine (427mg, 2.38mmol) with trifluoroacetic acid (815mg, 7.15mmol) it is added to 1- (2- chlorine pyrimidine-4-yl) -3- (3- nitrobenzophenones) urea (700mg, in 8ml butanol solutions 2.38mmol), 7h is stirred vigorously at 130 DEG C.After reaction terminates, system is cooled to room temperature, filters to obtain brown solid.Brown solid 1- (2- ((6- morpholinoes pyridin-3-yl) amino) pyrimidine-4-yl) -3- (3- nitrobenzophenones) urea (120mg) is purified to obtain with column chromatography.Yield：10%, purity：85%, MS m/z (ESI):436.1[M+H]+
Step 2：The synthesis of 1- (2- ((6- morpholinoes pyridin-3-yl) amino) pyrimidine-4-yl) -3- (3- aminophenyls) urea
By stannous chloride (190mg, 0.82mmol) it is added to 1- (2- ((6- morpholinoes pyridin-3-yl) amino) pyrimidine-4-yl) -3- (3- nitrobenzophenones) urea (120mg, in 3ml methanol and 3mlDMF mixed solution 0.27mmol), 7h is stirred vigorously at 90 DEG C.After reaction terminates, system is cooled to room temperature, adds equivalent sodium bicarbonate solid.Mixture is stirred vigorously 30min, insoluble matter is filtered off.Filtrate decompression is concentrated to give brown solid 1- (2- ((6- morpholinoes pyridin-3-yl) amino) pyrimidine-4-yl) -3- (3- aminophenyls) urea (120mg), product is directly used in next step.Yield：90%, purity：70%, MS m/z (ESI):406.2[M+H]+
Step 3：The synthesis of N- (3- (3- (2- ((6- morpholinoes pyridin-3-yl) amino) pyrimidine-4-yl) urea groups) phenyl) acrylamide (cpd-6)
By triethylamine (90mg, 0.9mmol) it is added to 1- (2- ((6- morpholinoes pyridin-3-yl) amino) pyrimidine-4-yl) -3- (3- aminophenyls) urea (120mg, in 5ml THF solutions 0.30mmol), it is stirred vigorously at 0 DEG C.By acryloyl chloride (27mg, 0.30mmol), at 0 DEG C, it is slowly dropped in reaction solution.Keep 0 DEG C of stirring 4h.TLC detects extent of reaction, after after substrate completely reaction, it is diluted with water, extracted three times with ethyl acetate/aqueous systems, organic layer is isolated, through water and saturated common salt water washing, after anhydrous sodium sulfate drying, be concentrated under reduced pressure to obtain yellow solid, and N- (3- (3- (2- ((6- morpholinoes pyridin-3-yl) amino) pyrimidine-4-yl) urea groups) phenyl) acrylamide (cpd-6) (1.66mg) is purified to obtain through preparing liquid phase separation.Yield：2%, purity：97%, MS m/z (ESI):461.3[M+H]+。
Embodiment 7：The preparation of N- (3- (3- (2- ((2,4- Dimethoxyphenyls) amino) pyrimidine-4-yl) urea groups) phenyl) acrylamide (cpd-7)
Step 1：The synthesis of 1- (2- ((2,4- Dimethoxyphenyls) amino) pyrimidine-4-yl) -3- (3- nitrobenzophenones) urea
By 2,4- dimethoxyanilines (261mg, 1.7mmol) with trifluoroacetic acid (582mg, 5.1mmol) it is added to 1- (2- chlorine pyrimidine-4-yl) -3- (3- nitrobenzophenones) urea (500mg, 1.7mmol) 8ml butanol solutions in, be stirred vigorously 7h at 130 DEG C.After reaction terminates, system is cooled to room temperature, filters to obtain brown solid.Brown solid is washed with 30ml ethanol, 1- (2- ((2,4- Dimethoxyphenyl) amino) pyrimidine-4-yl) -3- (3- nitrobenzophenones) urea (120mg) is obtained, product is directly used in next step.Yield：18%, purity：76%, MS m/z (ESI):411.1[M+H]+
Step 2：The synthesis of 1- (2- ((2,4- Dimethoxyphenyls) amino) pyrimidine-4-yl) -3- (3- aminophenyls) urea
By stannous chloride (231mg, 1.0mmol) it is added to 1- (2- ((2,4- Dimethoxyphenyls) amino) pyrimidine-4-yl) -3- (3- nitrobenzophenones) urea (140mg, in 3ml methanol and 3mlDMF mixed solution 0.34mmol), 4h is stirred vigorously at 90 DEG C.After reaction terminates, system is cooled to room temperature, adds equivalent sodium bicarbonate solid.Mixture is stirred vigorously 30min, insoluble matter is filtered off.Filtrate decompression is concentrated to give brown solid 1- (2- ((2,4- Dimethoxyphenyl) amino) pyrimidine-4-yl) -3- (3- aminophenyls) urea (100mg), product is directly used in next step.Yield：90%, purity：69%, MS m/z (ESI):381.2[M+H]+
Step 3：The synthesis of N- (3- (3- (2- ((2,4- Dimethoxyphenyls) amino) pyrimidine-4-yl) urea groups) phenyl) acrylamide (cpd-7)
By triethylamine (100mg, 0.9mmol) it is added to 1- (2- ((2,4- Dimethoxyphenyls) amino) pyrimidine-4-yl) -3- (3- aminophenyls) urea (100mg, in 5ml THF solutions 0.3mmol), it is stirred vigorously at 0 DEG C.By acryloyl chloride (30mg, 0.3mmol), at 0 DEG C, it is slowly dropped in reaction solution.Keep 0 DEG C of stirring 4h.TLC detects extent of reaction, after after substrate completely reaction, it is diluted with water, extracted three times with ethyl acetate/aqueous systems, organic layer is isolated, through water and saturated common salt water washing, after anhydrous sodium sulfate drying, be concentrated under reduced pressure to obtain yellow solid, and N- (3- (3- (2- ((2,4- Dimethoxyphenyl) amino) pyrimidine-4-yl) urea groups) phenyl) acrylamide (cpd-7) (19.08mg) is purified to obtain through preparing liquid phase separation.Yield：15%, purity：100%, MS m/z (ESI):435.3[M+H]+；1H NMR(400MHz,DMSO-d6):δ 10.45 (s, 1H), 10.12 (s, 1H), 9.59 (s, 1H), 8.35 (s, 1H), 8.11 (d, J=5.6Hz, 1H), 7.88 (s, 1H), 7.45 (dd, J=14.0,8.5Hz, 2H), 7.12 (t, J=8.1Hz, 1H), 6.69-6.35 (m, 5H), 6.25 (dd, J=17.0,1.9Hz, 1H), 5.74 (dd, J=10.1,1.9Hz, 1H), 3.75 (s, 3H), 3.73 (s, 3H).
Embodiment 8：The preparation of N- (3- (3- (2- ((the chloro- 4- fluorophenyls of 3-) amino) pyrimidine-4-yl) urea groups) phenyl) acrylamide (cpd-8)
Step 1：The synthesis of 1- (2- ((the chloro- 4- fluorophenyls of 3-) amino) pyrimidine-4-yl) -3- (3- nitrobenzophenones) urea
By the chloro- 4- fluoroanilines (162mg of 3-, 1.12mmol) with trifluoroacetic acid (380mg, 3.33mmol) it is added to 1- (2- chlorine pyrimidine-4-yl) -3- (3- nitrobenzophenones) urea (328mg, 1.12mmol) 20ml butanol solutions in, be stirred vigorously 7h at 130 DEG C.After reaction terminates, system is cooled to room temperature, filters to obtain brown solid.Brown solid is washed with 30ml ethanol, 1- (2- ((the chloro- 4- fluorophenyls of 3-) amino) pyrimidine-4-yl) -3- (3- nitrobenzophenones) urea (230mg) is obtained, product is directly used in next step.Yield：51%, purity：74%, MS m/z (ESI):403.1[M+H]+
Step 2：The synthesis of 1- (2- ((the chloro- 4- fluorophenyls of 3-) amino) pyrimidine-4-yl) -3- (3- aminophenyls) urea
By stannous chloride (388mg, 1.72mmol) it is added to 1- (2- ((the chloro- 4- fluorophenyls of 3-) amino) pyrimidine-4-yl) -3- (3- nitrobenzophenones) urea (230mg, in 60ml methanol and 40mlDMF mixed solution 0.57mmol), 4h is stirred vigorously at 90 DEG C.After reaction terminates, system is cooled to room temperature, adds equivalent sodium bicarbonate solid.Mixture is stirred vigorously 30min, insoluble matter is filtered off.Filtrate decompression is concentrated to give brown solid 1- (2- ((the chloro- 4- fluorophenyls of 3-) amino) pyrimidine-4-yl) -3- (3- aminophenyls) urea (200mg), product is directly used in next step.Yield：94%, purity：80%, MS m/z (ESI):373.1[M+H]+
Step 3：The synthesis of N- (3- (3- (2- ((the chloro- 4- fluorophenyls of 3-) amino) pyrimidine-4-yl) urea groups) phenyl) acrylamide (cpd-8)
By triethylamine (163mg, 1.61mmol) it is added to 1- (2- ((the chloro- 4- fluorophenyls of 3-) amino) pyrimidine-4-yl) -3- (3- aminophenyls) urea (200mg, in 2ml THF 0.54mmol) and 2ml DMF mixed solution, it is stirred vigorously at 0 DEG C.By acryloyl chloride (58mg, 0.65mmol), at 0 DEG C, it is slowly dropped in reaction solution.Keep 0 DEG C of stirring 4h.TLC detects extent of reaction, after after substrate completely reaction, it is diluted with water, extracted three times with ethyl acetate/aqueous systems, organic layer is isolated, through water and saturated common salt water washing, after anhydrous sodium sulfate drying, be concentrated under reduced pressure to obtain yellow solid, and N- (3- (3- (2- ((the chloro- 4- fluorophenyls of 3-) amino) pyrimidine-4-yl) urea groups) phenyl) acrylamide (cpd-8) (3.7mg) is purified to obtain through preparing liquid phase separation.Yield：1.6%, purity：96.8%, MS m/z (ESI):427.0[M+H]+；1H NMR(400MHz,DMSO-d6):δ 10.17 (s, 1H), 9.91 (s, 1H), 9.62 (s, 1H), 9.47 (s, 1H), 8.28 (d, J=6Hz, 1H), 8.01 (m, 1H), 7.93 (s, 1H), 7.64 (m, 1H), 7.42 (d, J=8.4Hz, 1H), 7.33 (t, J=8.8Hz, 1H), 7.25 (t, J=8Hz, 1H), 7.08 (m, 2H), 6.47 (m, 1H), 6.26 (m, 1H), 5.75 (m, 1H).
Embodiment 9：The preparation of N- (3- (3- (2- ((2- methoxyl groups -4- (4- morpholines piperidin-1-yl) phenyl) amino) pyrimidine-4-yl) urea groups) phenyl) acrylamide (cpd-9)
Step 1：The synthesis of 1- (2- ((2- methoxyl groups -4- (4- morpholino -1- bases) phenyl) amino) pyrimidine-4-yl) -3- (3- nitrobenzophenones) urea
By 2- methoxyl groups -4 (4- morpholines piperidines) aniline (326mg, 1.12mmol) with trifluoroacetic acid (380mg, 3.33mmol) it is added to 1- (2- chlorine pyrimidine-4-yl) -3- (3- nitrobenzophenones) urea (328mg, in 20ml butanol solutions 1.12mmol), 7h is stirred vigorously at 130 DEG C.After reaction terminates, system is cooled to room temperature, filters to obtain brown solid.Brown solid is washed with 30ml ethanol, 1- (2- ((2- methoxyl groups -4- (4- morpholino -1- bases) phenyl) amino) pyrimidine-4-yl) -3- (3- nitrobenzophenones) urea (270mg) is obtained, product is directly used in next step.Yield：49%, purity：65%, MS m/z (ESI):549.1[M+H]+
Step 2：The synthesis of 1- (2- ((2- methoxyl groups -4- (4- morpholino -1- bases) phenyl) amino) pyrimidine-4-yl) -3- (3- aminophenyls) urea
Stannous chloride (339mg, 1.5mmol) is added to 1- (2- ((2- methoxyl groups -4- (4- morpholino -1- bases) phenyl) ammonia Base) pyrimidine-4-yl) in the 60ml methanol of -3- (3- nitrobenzophenones) ureas (270mg, 0.49mmol) and 40mlDMF mixed solution, 4h is stirred vigorously at 90 DEG C.After reaction terminates, system is cooled to room temperature, adds equivalent sodium bicarbonate solid.Mixture is stirred vigorously 30min, insoluble matter is filtered off.Filtrate decompression is concentrated to give brown solid 1- (2- ((2- methoxyl groups -4- (4- morpholino -1- bases) phenyl) amino) pyrimidine-4-yl) -3- (3- aminophenyls) urea (200mg), product is directly used in next step.Yield：79%, purity：75%, MS m/z (ESI):519.1[M+H]+
Step 3：The synthesis of N- (3- (3- (2- ((2- methoxyl groups -4- (4- morpholines piperidin-1-yl) phenyl) amino) pyrimidine-4-yl) urea groups) phenyl) acrylamide (cpd-9)
By triethylamine (114mg, 1.13mmol) it is added to 1- (2- ((2- methoxyl groups -4- (4- morpholino -1- bases) phenyl) amino) pyrimidine-4-yl) -3- (3- aminophenyls) urea (200mg, in the mixed solution of 2ml THF and 2mlDMF 0.38mmol), it is stirred vigorously at 0 DEG C.By acryloyl chloride (42mg, 0.46mmol), at 0 DEG C, it is slowly dropped in reaction solution.Keep 0 DEG C of stirring 4h.TLC detects extent of reaction, after after substrate completely reaction, it is diluted with water, extracted three times with ethyl acetate/aqueous systems, isolate organic layer, through water and saturated common salt water washing, after anhydrous sodium sulfate drying, be concentrated under reduced pressure to obtain yellow solid, and N- (3- (3- (2- ((2- methoxyl groups -4- (4- morpholines piperidin-1-yl) phenyl) amino) pyrimidine-4-yl) urea groups) phenyl) acrylamide (cpd-9) (70.98mg) is purified to obtain through preparing liquid phase separation.Yield：32.7%, purity：99%, MS m/z (ESI):573.3[M+H]+；1H NMR(400MHz,DMSO-d6):(the s of δ 10.28, 1H), 10.19 (s, 1H), 10.10 (s, 1H), 9.87 (s, 1H), 8.12 (d, J=8Hz, 1H), 7.94 (s, 1H), 7.50 (d, J=8Hz, 1H), 7.36 (d, J=8Hz, 1H), 7.18 (t, J=8Hz, 1H), 6.75 (s, 1H), 6.69 (d, J=4Hz, 1H), 6.28 (m, 3H), 6.25 (m, 1H), 5.75 (m, 1H), 4.03 (d, J=12Hz, 2H), 3.89 (d, J=12Hz, 2H), 3.89 (s, 3H), 3.69 (t, J=12Hz, 2H), 3.51 (d, J=12Hz, 2H), 3.38 (s, 1H), 3.14 (m, 2H), 2.65 (m, 2H), 2.15 (d, J=12Hz, 2H), 1.70 (m, 2H).
Embodiment 10：The preparation of N- (3- (3- (2- ((4- (4- (dimethylamino) piperidin-1-yl) -2- anisyls) amino) pyrimidine-4-yl) urea groups) phenyl) acrylamide (cpd-10)
Step 1：The synthesis of 1- (2- ((4- (4- (dimethylamino) piperidin-1-yl) -2- methoxyphenyls) amino) pyrimidine-4-yl) -3- (3- nitrobenzophenones) urea
By 1- (4- amino -3- methoxyphenyls)-N, N- lupetidine -4- amine (279mg, 1.12mmol) with trifluoroacetic acid (380mg, 3.33mmol) it is added to 1- (2- chlorine pyrimidine-4-yl) -3- (3- nitrobenzophenones) urea (328mg, in 20ml butanol solutions 1.12mmol), 7h is stirred vigorously at 130 DEG C.After reaction terminates, system is cooled to room temperature, filters to obtain brown solid.Brown solid is washed with 30ml ethanol, 1- (2- ((4- (4- (dimethylamino) piperidin-1-yl) -2- methoxyphenyls) amino) pyrimidine-4-yl) -3- (3- nitrobenzophenones) urea (230mg) is obtained, product is directly used in next step.Yield：41%, purity：65%, MS m/z (ESI):507.1[M+H]+
Step 2：The synthesis of 1- (2- ((4- (4- (dimethylamino) piperidin-1-yl) -2- methoxyphenyls) amino) pyrimidine-4-yl) -3- (3- aminophenyls) urea
By stannous chloride (305mg, 1.35mmol) it is added to 1- (2- ((4- (4- (dimethylamino) piperidin-1-yl) -2- methoxyphenyls) amino) pyrimidine-4-yl) -3- (3- nitrobenzophenones) urea (230mg, in 60ml methanol and 40mlDMF mixed solution 0.45mmol), 4h is stirred vigorously at 90 DEG C.After reaction terminates, system is cooled to room temperature, adds equivalent sodium bicarbonate solid.Mixture is stirred vigorously 30min, insoluble matter is filtered off.Filtrate decompression is concentrated to give brown solid 1- (2- ((4- (4- (dimethylamino) piperidin-1-yl) -2- methoxyphenyls) amino) pyrimidine-4-yl) -3- (3- aminophenyls) urea (180mg), product is directly used in next step.Yield：84%, purity：78%, MS m/z (ESI):477.2[M+H]+
Step 3：The synthesis of N- (3- (3- (2- ((4- (4- (dimethylamino) piperidin-1-yl) -2- anisyls) amino) pyrimidine-4-yl) urea groups) phenyl) acrylamide (cpd-10)
By triethylamine (114mg, 1.13mmol) it is added to 1- (2- ((4- (4- (dimethylamino) piperidin-1-yl) -2- methoxyphenyls) amino) pyrimidine-4-yl) -3- (3- aminophenyls) urea (180mg, in the mixed solution of 2ml THF and 2mlDMF 0.38mmol), it is stirred vigorously at 0 DEG C.By acryloyl chloride (42mg, 0.46mmol), at 0 DEG C, it is slowly dropped in reaction solution.Keep 0 DEG C of stirring 4h.TLC detects extent of reaction, after after substrate completely reaction, it is diluted with water, extracted three times with ethyl acetate/aqueous systems, isolate organic layer, through water and saturated common salt water washing, after anhydrous sodium sulfate drying, be concentrated under reduced pressure to obtain yellow solid, and compound N-(3- (3- (2- ((4- (4- (dimethylamino) piperidin-1-yl) -2- anisyls) amino) pyrimidine-4-yl) urea groups) phenyl) acrylamide (cpd-10) (25.36mg) is purified to obtain through preparing liquid phase separation.Yield：12.6%, purity：99%, MS m/z (ESI):531.3[M+H]+；1H NMR(400MHz,DMSO-d6):δ 10.25 (m, 3H), 10.00 (s, 1H), 9.49 (m, 1H), 8.14 (d, J=4Hz, 1H), 7.93 (s, 1H), 7.48 (m, 2H), 7.20 (m, 1H), 7.82 (s, 1H), 6.70 (d, J=4Hz, 1H), 6.57 (m, 2H), 6.28 (t, J=12Hz, 1H), 5.74 (t, J=12Hz, 1H), 4.04 (d, J=20Hz, 2H), 3.99 (s, 3H), 3.33 (m, 1H), 2.79 (s, 6H), 2.70 (t, J=12Hz, 2H), 2.08 (d, J=12Hz, 2H), 1.72 (m, 2H).
Embodiment 11：The preparation of N- (3- (3- (2- ((4- (piperidin-1-yl) phenyl) amino) pyrimidine-4-yl) urea groups) phenyl) acrylamide (cpd-11)
Step 1：The synthesis of 1- (2- ((4- (piperidin-1-yl) phenyl) amino) pyrimidine-4-yl) -3- (3- nitrobenzophenones) urea
By 4- (piperidin-1-yl)-aniline (197mg, 1.12mmol) with trifluoroacetic acid (380mg, 3.33mmol) it is added to 1- (2- chlorine pyrimidine-4-yl) -3- (3- nitrobenzophenones) urea (328mg, in 20ml butanol solutions 1.12mmol), 7h is stirred vigorously at 130 DEG C.After reaction terminates, system is cooled to room temperature, filters to obtain brown solid.Brown solid is washed with 30ml ethanol, 1- (2- ((4- (piperidin-1-yl) phenyl) amino) pyrimidine-4-yl) -3- (3- nitrobenzophenones) urea (230mg) is obtained, product is directly used in next step.Yield：47%, purity：80%, MS m/z (ESI):434.2[M+H]+
Step 2：1- (2- ((4- (piperidin-1-yl) phenyl) amino) pyrimidine-4-yl) -3- (3- aminophenyls) urea is synthesized
By stannous chloride (380mg, 1.59mmol) it is added to 1- (2- ((4- (piperidin-1-yl) phenyl) amino) pyrimidine-4-yl) -3- (3- nitrobenzophenones) urea (230mg, 60ml methanol 0.53mmol) is with 40ml DMF mixed solution, 4h is stirred vigorously at 90 DEG C.After reaction terminates, system is cooled to room temperature, adds equivalent sodium bicarbonate solid.Will mixing Thing is stirred vigorously 30min, filters off insoluble matter.Filtrate decompression is concentrated to give brown solid 1- (2- ((4- (piperidin-1-yl) phenyl) amino) pyrimidine-4-yl) -3- (3- aminophenyls) urea (200mg), product is directly used in next step.Yield：94%, purity：85%, MS m/z (ESI):404.2[M+H]+
Step 3：The synthesis of N- (3- (3- (2- ((4- (piperidin-1-yl) phenyl) amino) pyrimidine-4-yl) urea groups) phenyl) acrylamide (cpd-11)
By triethylamine (155mg, 1.50mmol) it is added to 1- (2- ((4- (piperidin-1-yl) phenyl) amino) pyrimidine-4-yl) -3- (3- aminophenyls) urea (200mg, in 2ml THF 0.50mmol) and 2ml DMF mixed solution, it is stirred vigorously at 0 DEG C.By acryloyl chloride (54mg, 0.6mmol), at 0 DEG C, it is slowly dropped in reaction solution.Keep 0 DEG C of stirring 4h.TLC detects extent of reaction, after after substrate completely reaction, it is diluted with water, extracted three times with ethyl acetate/aqueous systems, isolate organic layer, through water and saturated common salt water washing, after anhydrous sodium sulfate drying, be concentrated under reduced pressure to obtain yellow solid, and N- (3- (3- (2- ((4- (piperidin-1-yl) phenyl) amino) pyrimidine-4-yl) urea groups) phenyl) acrylamide (cpd-11) (1.80mg) is purified to obtain through preparing liquid phase separation.Yield：0.8%, purity：93.7%, MS m/z (ESI):458.3[M+H]+；1H NMR(400MHz,DMSO-d6):δ 10.28 (s, 1H), 10.14 (s, 1H), 9.52 (s, 1H), 9.17 (s, 1H), 8.16 (d, J=5.2Hz, 1H), 7.91 (s, 1H), 7.45 (m, 3H), 7.18 (t, J=7.6Hz, 1H), 6.85 (d, J=8.8Hz, 2H), 6.72 (d, J=5.2Hz, 1H), 6.45 (m, 1H), 6.28 (m, 1H), 5.76 (m, 1H), 3.02 (m, 4H), 1.61 (m, 4H), 1.51 (m, 2H).
Embodiment 12：The preparation of N- (3- (3- (2- ((4- (dimethylamino) phenyl) amino) pyrimidine-4-yl) urea groups) phenyl) acrylamide (cpd-12)
Step 1：The synthesis of 1- (2- ((4- (dimethylamino) phenyl) amino) pyrimidine-4-yl) -3- (3- nitrobenzophenones) urea
By 4- amino-N, accelerine (152mg, 1.12mmol) with trifluoroacetic acid (380mg, 3.33mmol) it is added to 1- (2- chlorine pyrimidine-4-yl) -3- (3- nitrobenzophenones) urea (328mg, in 20ml butanol solutions 1.12mmol), 7h is stirred vigorously at 130 DEG C.After reaction terminates, system is cooled to room temperature, filters to obtain brown solid.Brown solid is washed with 30ml ethanol, 1- (2- ((4- (dimethylamino) phenyl) amino) pyrimidine-4-yl) -3- (3- nitrobenzophenones) urea (221mg) is obtained, product is directly used in next step.Yield：50%, purity：78%, MS m/z (ESI):394.3[M+H]+
Step 2：The synthesis of 1- (2- ((4- (dimethylamino) phenyl) amino) pyrimidine-4-yl) -3- (3- aminophenyls) urea
By stannous chloride (380mg, 1.68mmol) it is added to 1- (2- ((4- (dimethylamino) phenyl) amino) pyrimidine-4-yl) -3- (3- nitrobenzophenones) urea (221mg, in 60ml methanol and 40mlDMF mixed solution 0.56mmol), 4h is stirred vigorously at 90 DEG C.After reaction terminates, system is cooled to room temperature, adds equivalent sodium bicarbonate solid.Mixture is stirred vigorously 30min, insoluble matter is filtered off.Filtrate decompression is concentrated to give brown solid 1- (2- ((4- (dimethylamino) phenyl) amino) pyrimidine-4-yl) -3- (3- aminophenyls) urea (195mg), product is directly used in next step.Yield：96%, purity：79%, MS m/z (ESI):364.2[M+H]+
Step 3：The synthesis of N- (3- (3- (2- ((4- (dimethylamino) phenyl) amino) pyrimidine-4-yl) urea groups) phenyl) acrylamide (cpd-12)
By triethylamine (163mg, 1.61mmol) it is added to 1- (2- ((4- (dimethylamino) phenyl) amino) pyrimidine-4-yl) -3- (3- aminophenyls) urea (195mg, in 2ml THF 0.54mmol) and 2ml DMF mixed solution, it is stirred vigorously at 0 DEG C.By acryloyl chloride (58mg, 0.65mmol), at 0 DEG C, it is slowly dropped in reaction solution.Keep 0 DEG C of stirring 4h.TLC detects extent of reaction, after after substrate completely reaction, it is diluted with water, extracted three times with ethyl acetate/aqueous systems, isolate organic layer, through water and saturated common salt water washing, after anhydrous sodium sulfate drying, be concentrated under reduced pressure to obtain yellow solid, and N- (3- (3- (2- ((4- (dimethylamino) phenyl) amino) pyrimidine-4-yl) urea groups) phenyl) acrylamide (cpd-12) (14.20mg) is purified to obtain through preparing liquid phase separation.Yield：6.3%, purity：99.7%, MS m/z (ESI):418.2[M+H]+；1H NMR(400MHz,DMSO-d6):δ 10.42 (s, 1H), 10.14 (s, 1H), 9.56 (s, 1H), 9.09 (s, 1H), 8.14 (d, J=5.2Hz, 1H), 7.92 (s, 1H), 7.47 (d, J=8Hz, 1H), 7.35 (d, J=8.8Hz, 2H), 7.13 (t, J=8Hz, 1H), 6.67 (m, 4H), 6.45 (m, 1H), 6.25 (m, 1H), 5.75 (m, 1H), 2.83 (s, 6H).
Embodiment 13：The preparation of N- (3- (3- (2- ((5- morpholino pyridine -2- bases) amino) pyrimidine-4-yl) urea groups) phenyl) acrylamide (cpd-13)
Step 1：The synthesis of 1- (2- chlorine pyrimidine-4-yl) -3- (3- aminophenyls) urea
1- (2- chlorine pyrimidine-4-yl) -3- (3- nitrobenzophenones) ureas (6.0g, 20mmol) are placed in 250mL stand up reaction bottle, adding THF/ water (75mL/50mL) mixed solution dissolves substrate.At room temperature, ammonium chloride (5.3g, 100mmol) and reduced iron powder (8.9g, 160mmol) are sequentially added into the reaction bulb of stirring, reaction system is then heated to 65 DEG C and 5h is kept stirring for.TLC detects extent of reaction, after after substrate completely reaction, is filtered to remove unnecessary iron powder, filter cake is eluted three times with ethyl acetate.Filtrate is extracted three times with ethyl acetate/aqueous systems, organic layer is isolated, through water and saturated common salt water washing, after anhydrous sodium sulfate drying, 1- (2- chlorine pyrimidine-4-yl) -3- (3- aminophenyls) urea (5.4g) is concentrated under reduced pressure to give, next step reaction is directly used in.
Step 2：The synthesis of N- (3- (3- (2- chlorine pyrimidine-4-yl) urea groups) phenyl) acrylamide
1- (2- chlorine pyrimidine-4-yl) -3- (3- aminophenyls) ureas (5.4g, 20mmol) are placed in 100mL stand up reaction bottle, adding dichloromethane (50mL) dissolves substrate.At 0 DEG C, triethylamine (4.3mL, 30mmol) and acryloyl chloride (2.0mL, 24mmol) are sequentially added into the reaction bulb of stirring, reaction system is then maintained 0 DEG C and continues to stir 1h.TLC detects extent of reaction, and after after substrate completely reaction, reaction solution is extracted three times with THF/ aqueous systems, is isolated after organic layer, saturated common salt water washing, anhydrous sodium sulfate drying, is concentrated under reduced pressure to give crude product.N- (3- (3- (2- chlorine pyrimidine-4-yl) urea groups) phenyl) acrylamide (5.2g) is beaten to obtain through alcohol reflux, is directly used in next Step reaction.Yield：80% (two steps), purity：90%, MS m/z (ESI):318.1[M+H]+.
Step 3：The synthesis of N- (3- (3- (2- ((5- morpholino pyridine -2- bases) amino) pyrimidine-4-yl) urea groups) phenyl) acrylamide (cpd-13)
At room temperature, by Pd2(dba)3(30mg; 0.03mmol); BINAP (2; the double diphenyl phosphines -1 of 2'-; 1'- dinaphthalenes) (40mg; 0.06mmol); t-BuONa (91mg; 0.96mmol) with 5- morpholino pyridine -2- amine (102mg; 0..57mmol) it is added to N- (3- (3- (2- chlorine pyrimidine-4-yl) urea groups) phenyl) acrylamide (200mg; in 5ml dioxane solutions 0.63mmol), under nitrogen protection, 120 DEG C of tube sealing is stirred vigorously 8h.After reaction terminates, filtering, the filtrate that is concentrated under reduced pressure obtains yellow solid, and N- (3- (3- (2- ((5- morpholino pyridine -2- bases) amino) pyrimidine-4-yl) urea groups) phenyl) acrylamide (cpd-13) (5.17mg) is obtained to prepare liquid phase purifying.Yield：3%, purity：97.67%, MS m/z (ESI):461.2[M+H]+；1H NMR(400MHz,DMSO-d6):(the s of δ 10.57, 1H), 10.17 (s, 1H), 9.80 (s, 1H), 9.70 (s, 1H), 8.23 (d, J=5.6Hz, 1H), 7.86 (d, J=12.3Hz, 3H), 7.50 (d, J=8.0Hz, 1H), 7.44-7.33 (m, 1H), 7.25 (t, J=8.1Hz, 1H), 7.10 (d, J=7.8Hz, 1H), 6.73 (d, J=5.5Hz, 1H), 6.46 (dd, J=17.0, 10.2Hz, 1H), 6.26 (d, J=16.9Hz, 1H), 5.75 (d, J=10.3Hz, 1H), 3.76-3.70 (m, 4H), 3.06-3.00 (m, 4H).
Embodiment 14：The preparation of N- (3- (3- (2- ((2- methoxyl group -4- morphlinophenyls) amino) pyrimidine-4-yl) urea groups) phenyl) acrylamide (cpd-14)
By N- (3- (3- (2- chlorine pyrimidine-4-yl) urea groups) phenyl) acrylamide (200mg, 0.62mmol) with 2- methoxyl group -4- morpholino aniline (131mg, 0.62mmol) it is placed in 50mL stand up reaction bottle, adding n-butanol (10mL) is partly dissolved substrate.Trifluoroacetic acid (215mg, 1.89mmol) is added afterwards, and keeps reaction system to heat 3h at 110 DEG C.After question response terminates, room temperature is cooled to, after after substrate completely reaction, reaction solution is extracted three times with ethyl acetate/aqueous systems, isolates organic layer, through saturated sodium bicarbonate and saturated common salt water washing, after anhydrous sodium sulfate drying, is concentrated under reduced pressure to give crude product.Through Prep-HPLC column chromatographies [H2O(10mM NH4HCO3):CH3CN=65:35~5:95] purifying obtains N- (3- (3- (2- ((2- methoxyl group -4- morphlinophenyls) amino) pyrimidine-4-yl) urea groups) phenyl) acrylamide (cpd-14) 5 (15.85mg).Yield：5%, purity：100%, MS m/z (ESI):490.7[M+H]+；1H NMR(400MHz,DMSO-d6):δ 10.47 (s, 1H), 10.13 (s, 1H), 9.59 (s, 1H), 8.29 (s, 1H), 8.10 (d, J=5.6Hz, 1H), 7.92 (s, 1H), 7.47 (d, J=8.3Hz, 1H), 7.39 (d, J=8.6Hz, 1H), 7.14 (t, J=8.1Hz, 1H), 6.60 (dd, J=12.7,4.0Hz, 2H), 6.49-6.42 (m, 3H), 6.25 (dd, J=17.0,2.0Hz, 1H), 5.74 (dd, J=10.1,2.0Hz, 1H), 3.81-3.70 (m, 7H), 3.13-3.02 (m, 4H).
Embodiment 15：The preparation of N- (3- (3- (2- ((2- methoxyl groups -4- (morpholine -4- carbonyls) phenyl) amino) pyrimidine-4-yl) urea groups) phenyl) acrylamide (cpd-15)
By (4- amino -3- methoxyphenyls) (morpholino) ketone (200mg, 0.63mmol) with TFA (216mg, 1.89mmol) it is added to N- (3- (3- (2- chlorine pyrimidine-4-yl) urea groups) phenyl) acrylamide (149mg, in 4ml butanol solutions 0.63mmol), 6h is stirred vigorously at 120 DEG C.After reaction terminates, system is cooled to room temperature, adds appropriate saturated solution of sodium bicarbonate, is extracted three times with ethyl acetate/aqueous systems, organic layer is concentrated under reduced pressure to give crude product.N- (3- (3- (2- ((2- methoxyl groups -4- (morpholine -4- carbonyls) phenyl) amino) pyrimidine-4-yl) urea groups) phenyl) acrylamide (cpd-15) (66.7mg) is purified to obtain through preparing liquid phase separation.Yield：21%, purity：99%, MS m/z (ESI):518.2[M+H]+；1H NMR (400MHz, DMSO) δ 10.18 (s, 1H), 9.90 (s, 1H), 9.76 (s, 1H), 8.26 (d, J=5.9Hz, 1H), 8.09 (d, J=8.1Hz, 1H), 7.93 (s, 1H), 7.41 (d, J=7.6Hz, 1H), 7.25 (t, J=8.1Hz, 1H), 7.05 (ddd, J=9.7,7.2,1.6Hz, 5H), 6.46 (dd, J=16.9,10.1Hz, 1H), 6.26 (dd, J=17.0,1.9Hz, 1H), 5.76 (dd, J=10.1,1.9Hz, 1H), 3.56 (d, J=36.0Hz, 11H).
Embodiment 16：The preparation of N- (3- (3- (2- ((2- methoxyl groups -4- (4- methyl piperazine -1- carbonyls) phenyl) amino) pyrimidine-4-yl) urea groups) phenyl) acrylamide (cpd-16)
By (4- amino -3- methoxyphenyls) (4- methylpiperazine-1-yls) ketone (200mg, 0.63mmol) with TFA (216mg, 1.89mmol) it is added to N- (3- (3- (2- chlorine pyrimidine-4-yl) urea groups) phenyl) acrylamide (157mg, in 4ml butanol solutions 0.63mmol), 6h is stirred vigorously at 120 DEG C.After reaction terminates, system is cooled to room temperature, adds appropriate saturated solution of sodium bicarbonate, is extracted three times with ethyl acetate/aqueous systems, organic layer is concentrated under reduced pressure to give crude product.N- (3- (3- (2- ((2- methoxyl groups -4- (4- methyl piperazine -1- carbonyls) phenyl) amino) pyrimidine-4-yl) urea groups) phenyl) acrylamide (cpd-16) (17.31mg) is purified to obtain through preparing liquid phase separation.Yield：5%, purity：100%, MS m/z (ESI):531.2[M+H]+；1H NMR(400MHz,CDCl3) δ 10.17 (s, 1H), 9.91 (s, 1H), 9.54 (s, 1H), 8.26 (d, J=5.8Hz, 2H), 8.15 (t, J=8.6Hz, 1H), 7.92 (s, 1H), 7.42 (d, J=8.2Hz, 1H), 7.25 (t, J=8.1Hz, 1H), 7.15-6.89 (m, 5H), 6.47 (dd, J=16.9,10.1Hz, 1H), 6.27 (dd, J=17.0,1.9Hz, 1H), 5.93-5.44 (m, 1H), (3.89 s, 4H), 3.44 (d, J=57.3Hz, 5H), 2.32 (s, 5H), 2.21 (s, 4H).
Embodiment 17：4- ((4- (3- (3- acryloyl groups amide phenyl) urea groups) pyrimidine -2-base) amino)-N, the preparation of N- diethyl -3- methoxy benzamides (cpd-17)
By 4- amino-N, N- diethyl -3- methoxy benzamides (200mg, 0.63mmol) with TFA (216mg, 1.89mmol) it is added to N- (3- (3- (2- chlorine pyrimidine-4-yl) urea groups) phenyl) acrylamide (140mg, in 4ml butanol solutions 0.63mmol), 6h is stirred vigorously at 110 DEG C.After reaction terminates, system is cooled to room temperature, adds appropriate saturated solution of sodium bicarbonate, is extracted three times with ethyl acetate/aqueous systems, organic layer is concentrated under reduced pressure to give crude product.4- ((4- (3- (3- acryloyl groups amide phenyl) urea groups) pyrimidine -2-base) amino)-N, N- diethyl -3- methoxy benzamides (cpd-17) (8.14mg) is obtained through preparing plate and the purifying of Combi-Flash reversed phase column chromatographies.Yield：2%, purity：95%, MS m/z (ESI):504.2[M+H]+；1H NMR (400MHz, DMSO) δ 10.16 (s, 1H), 9.92 (s, 1H), 9.53 (s, 1H), 8.60-8.21 (m, 2H), 8.10 (t, J=8.7Hz, 1H), 7.90 (s, 1H), 7.42 (d, J=8.0Hz, 1H), 7.25 (t, J=8.1Hz, 1H), 7.01 (s, 4H), 6.46 (dd, J=17.0,10.2Hz, 1H), 6.26 (d, J=16.9Hz, 1H), 5.75 (d, J=10.4Hz, 1H), 3.88 (s, 3H), 3.29 (s, 4H), 1.12 (s, 6H).
Embodiment 18：The preparation of N- (3- (3- (2- ((4- (2- methoxy ethoxies) phenyl) amino) pyrimidine-4-yl) urea groups) phenyl) acrylamide (cpd-18)
By 4- (2- methoxy ethoxies) aniline (105mg, 0.63mmol) with trifluoroacetic acid (216mg, 1.9mmol) it is added to N- (3- (3- (2- chlorine pyrimidine-4-yl) urea groups) phenyl) acrylamide (200mg, in 5ml butanol solutions 0.63mmol), 4h is stirred vigorously at 110 DEG C.After reaction terminates, system is cooled to room temperature, and be concentrated under reduced pressure to obtain brown solid.N- (3- (3- (2- ((4- (2- methoxy ethoxies) phenyl) amino) pyrimidine-4-yl) urea groups) phenyl) acrylamide (cpd-18) (4.70mg) is obtained through preparing liquid phase purifying.Yield：2%, purity：96.2%, MS m/z (ESI):449.2[M+H]+；1H NMR(400MHz,DMSO-d6):δ 10.16 (d, J=17.1Hz, 2H), 9.49 (s, 1H), 9.24 (s, 1H), 8.18 (d, J=5.6Hz, 1H), 7.92 (s, 1H), 7.48 (dd, J=20.8,8.4Hz, 3H), 7.19 (t, J=8.1Hz, 1H), 6.84 (dd, J=28.6,7.3Hz, 4H), 6.46 (dd, J=17.0,10.1Hz, 1H), 6.25 (dd, J=17.0,2.0Hz, 1H), 5.75 (dd, J=10.1,2.0Hz, 1H), 4.06-4.00 (m, 2H), 3.73-3.58 (m, 2H), 3.32 (s, 3H).
Embodiment 19：The preparation of N- (3- (3- (2- ((2- methoxyl groups -4- (piperidin-1-yl) phenyl) amino) pyrimidine-4-yl) urea groups) phenyl) acrylamide (cpd-19)
By 2- methoxyl groups -4- (piperidin-1-yl) aniline (130mg, 0.63mmol) with trifluoroacetic acid (216mg, 1.9mmol) it is added to N- (3- (3- (2- chlorine pyrimidine-4-yl) urea groups) phenyl) acrylamide (200mg, in 4ml butanol solutions 0.63mmol), 4h is stirred vigorously at 110 DEG C.After reaction terminates, system is cooled to room temperature, and be concentrated under reduced pressure to obtain brown solid.N- (3- (3- (2- ((2- methoxyl groups -4- (piperidin-1-yl) phenyl) amino) pyrimidine-4-yl) urea groups) phenyl) acrylamide (cpd-19) (41.19mg) is obtained through preparing liquid phase purifying.Yield：14%, purity：98.65%, MS m/z (ESI):488.3[M+H]+；1H NMR(400MHz,DMSO-d6):(the s of δ 10.47, 1H), 10.14 (d, J=18.9Hz, 1H), 9.58 (s, 1H), 8.38-8.19 (m, 1H), 8.10 (d, J=5.5Hz, 1H), 7.90 (s, 1H), 7.48 (d, J=7.9Hz, 1H), 7.35 (t, J=7.9Hz, 1H), 7.15 (dd, J=17.7, 9.7Hz, 1H), 6.66-6.55 (m, 2H), 6.54-6.36 (m, 3H), 6.25 (dd, J=17.0, 1.9Hz, 1H), 5.74 (dd, J=10.1, 1.9Hz, 1H), 3.74 (s, 3H), 3.15-3.05 (m, 4H), 1.66-1.50 (m, 6H).
Embodiment 20：The preparation of N- (3- (3- (2- ((4- (4- (2- fluoro ethyls) piperazine -1- bases) -2- anisyls) amino) pyrimidine-4-yl) urea groups) phenyl) acrylamide (cpd-20)
By N- (3- (3- (2- chlorine pyrimidine-4-yl) urea groups) phenyl) acrylamide (200mg, 0.62mmol) with 4- (4- (2- fluoro ethyls) piperazine -1- bases) -2- aminoanisoles (157mg, 0.62mmol) it is placed in 50mL stand up reaction bottle, adding n-butanol (10mL) is partly dissolved substrate.Trifluoroacetic acid (215mg, 1.89mmol) is added afterwards, and keeps reaction system to heat 3h at 110 DEG C.After question response terminates, room temperature is cooled to, after after substrate completely reaction, reaction solution is extracted three times with ethyl acetate/aqueous systems, isolates organic layer, through saturated sodium bicarbonate and saturated common salt water washing, after anhydrous sodium sulfate drying, is concentrated under reduced pressure to give crude product.Through Prep-HPLC column chromatographies [H2O(10mM NH4HCO3):CH3CN=65:35~5:95] purifying obtains N- (3- (3- (2- ((4- (4- (2- fluoro ethyls) piperazine -1- bases) -2- anisyls) amino) pyrimidine-4-yl) urea groups) phenyl) acrylamide (cpd-20) (22.42mg).Yield：6.8%, purity：100%, MS m/z (ESI):535.2[M+H]+；1H NMR(400MHz,DMSO-d6):δ 10.48 (s, 1H), 10.13 (s, 1H), 9.58 (s, 1H), 8.28 (s, 1H), 8.10 (d, J=5.6Hz, 1H), 7.93 (s, 1H), 7.47 (d, J=8.4Hz, 2H), 7.35 (d, J=9.2Hz, 1H), 7.13 (t, J=8Hz, 1H), 6.61 (m, 2H), 6.47 (m, 3H), 6.25 (m, 1H), 5.75 (m, 1H), 4.66 (m, 1H), 4.52 (m, 1H), 3.75 (s, 1H), 3.13 (m, 4H), 2.73 (m, 1H), 2.65 (m, 1H), 2.51 (m, 4H).
Embodiment 21：The preparation of N- (3- (3- (2- ((4- (diethylamino) -2- methoxyphenyls) amino) pyrimidine-4-yl) urea groups) phenyl) acrylamide (cpd-21)
By N- (3- (3- (2- chlorine pyrimidine-4-yl) urea groups) phenyl) acrylamide (200mg, 0.62mmol) and N, N- diethyl -3- methoxybenzenes -1,4- diamines (157mg, 0.62mmol) it is placed in 50mL stand up reaction bottle, adding n-butanol (10mL) is partly dissolved substrate.Trifluoroacetic acid (215mg, 1.89mmol) is added afterwards, and keeps reaction system to heat 3h at 110 DEG C.After question response terminates, room temperature is cooled to, after after substrate completely reaction, reaction solution is extracted three times with ethyl acetate/aqueous systems, isolates organic layer, through saturated sodium bicarbonate and saturated common salt water washing, after anhydrous sodium sulfate drying, is concentrated under reduced pressure to give crude product.Through Prep-HPLC column chromatographies [H2O(10mM NH4HCO3):CH3CN=65:35~5:95] purifying obtains N- (3- (3- (2- ((4- (diethylamino) -2- methoxyphenyls) amino) pyrimidine-4-yl) urea groups) phenyl) acrylamide (cpd-21) (86.24mg).Yield：29.2%, purity：100%, MS m/z (ESI):476.2[M+H]+；1H NMR(400MHz,DMSO-d6):δ 10.66 (s, 1H), 10.12 (s, 1H), 9.61 (s, 1H), 8.24 (s, 1H), 8.07 (d, J=5.6Hz, 1H), 7.94 (s, 1H), 7.49 (d, J=8Hz, 1H), 7.18 (d, J=8.4Hz, 1H), 7.07 (t, J=8Hz, 1H), 6.28 (m, 6H), 5.74 (m, 1H), 3.72 (t, 3H), 3.32 (m, 4H), 1.08 (m, 6H).
Embodiment 22：The preparation of N- (3- (3- (2- ((4- (4- (diethylamino) piperidin-1-yl) -2- anisyls) amino) pyrimidine-4-yl) urea groups) phenyl) acrylamide (cpd-22)
By N- (3- (3- (2- chlorine pyrimidine-4-yl) urea groups) phenyl) acrylamide (200mg, 0.62mmol) with 1- (4- amino -3- methoxyphenyls)-N, N- diethyl phenylpiperidines -4- amine (157mg, 0.62mmol) it is placed in 50mL stand up reaction bottle, adding n-butanol (10mL) is partly dissolved substrate.Trifluoroacetic acid (215mg, 1.89mmol) is added afterwards, and keeps reaction system to heat 3h at 110 DEG C.After question response terminates, room temperature is cooled to, after after substrate completely reaction, reaction solution is extracted three times with ethyl acetate/aqueous systems, isolates organic layer, through saturated sodium bicarbonate and saturated common salt water washing, after anhydrous sodium sulfate drying, is concentrated under reduced pressure to give crude product.Through Prep-HPLC column chromatographies [H2O(10mM NH4HCO3):CH3CN=65:35~5:95] purifying obtains N- (3- (3- (2- ((4- (4- (diethylamino) piperidin-1-yl) -2- anisyls) amino) pyrimidine-4-yl) urea groups) phenyl) acrylamide (cpd-22) (26.31mg).Yield：7.6%, purity：100%, MS m/z (ESI):559.3[M+H]+；1H NMR(400MHz,DMSO-d6):δ10.45(s,1H), (10.12 s, 1H), 9.61 (s, 1H), (8.25 s, 1H), 8.09 (d, J=8Hz, 1H), 7.88 (s, 1H), 7.48 (d, 8Hz, 1H), 7.34 (d, J=8.4Hz, 1H), 7.14 (m, 1H), 6.56 (m, 5H), 6.43 (m, 1H), 5.73 (m, 1H), 3.74 (s, 3H), 3.65 ((d, J=12Hz, 2H), 2.62 (m, 4H), 2.55 (s, 3H), 1.75 (d, J=11.2Hz, 2H), 1.51 (m, 2H), 0.97 (t, J=7.2Hz, 6H).
Embodiment 23：The preparation of N- (3- (3- (2- ((4- (4- ethyl piperazidine -1- bases) -2- methoxyphenyls) amino) pyrimidine-4-yl) urea groups) phenyl) acrylamide (cpd-23)
By 4- (4- ethyl piperazidine -1- bases) -2- aminoanisoles (150mg, 0.63mmol) with trifluoroacetic acid (216mg, 1.9mmol) it is added to N- (3- (3- (2- chlorine pyrimidine-4-yl) urea groups) phenyl) acrylamide (200mg, in 3ml butanol solutions 0.63mmol), 3h is stirred vigorously at 110 DEG C.After reaction terminates, system is cooled to room temperature, and be concentrated under reduced pressure to obtain brown solid.N- (3- (3- (2- ((4- (4- ethyl piperazidine -1- bases) -2- methoxyphenyls) amino) pyrimidine-4-yl) urea groups) phenyl) acrylamide (cpd-23) (60.25mg) is obtained through preparing liquid phase purifying.Yield：19%, purity：98.21%, MS m/z (ESI):517.2[M+H]+；1H NMR(400MHz,DMSO-d6):(the s of δ 10.48, 1H), 10.12 (s, 1H), 9.58 (s, 1H), 8.28 (s, 1H), 8.10 (d, J=5.6Hz, 1H), 7.93 (s, 1H), 7.48 (d, J=8.2Hz, 1H), 7.36 (t, J=7.9Hz, 1H), 7.13 (t, J=8.1Hz, 1H), 6.59 (dd, J=13.9, 3.8Hz, 2H), 6.51-6.31 (m, 3H), 6.25 (dd, J=17.0, 2.0Hz, 1H), 5.74 (dd, J=10.1, 2.0Hz, 1H), 3.75 (s, 3H), 3.12 (s, 4H), 2.50 (s, 4H), 2.39 (d, J=6.6Hz, 2H), 1.05 (t, J=7.2Hz, 3H).
Embodiment 24：N- (3- (3- (2- (4- tolyls) amino) pyrimidine-4-yl) urea groups) phenyl) acrylamide (cpd-24) preparation
By N- (3- (3- (2- chlorine pyrimidine-4-yl) urea groups) phenyl) acrylamide (200mg, 0.62mmol) with 4- methylanilines (67mg, 0.62mmol) it is placed in 50mL stand up reaction bottle, adding n-butanol (10mL) is partly dissolved substrate.Trifluoroacetic acid (215mg, 1.89mmol) is added afterwards, and keeps reaction system to heat 3h at 110 DEG C.After question response terminates, room temperature is cooled to, after after substrate completely reaction, reaction solution is extracted three times with ethyl acetate/aqueous systems, isolates organic layer, through saturated sodium bicarbonate and saturated common salt water washing, after anhydrous sodium sulfate drying, is concentrated under reduced pressure to give crude product.Through Prep-HPLC column chromatographies [H2O(10mM NH4HCO3):CH3CN=65:35~5:95] purifying obtains target product N- (3- (3- (2- (4- tolyls) amino) pyrimidine-4-yl) urea groups) phenyl) acrylamide (cpd-24) (97.43 mg).Yield：40%, purity：97.42%, MS m/z (ESI):389.1[M+H]+；1H NMR(400MHz,DMSO-d6):δ 10.16 (s, 1H), 10.12 (s, 1H), 9.55 (s, 1H), 9.40 (s, 1H), 8.21 (d, J=6Hz, 1H), 7.91 (s, 1H), 7.53 (d, J=8Hz, 2H), 7.45 (d, J=8Hz, 1H), 7.21 (t, J=8Hz, 1H), 7.09 (d, J=8.4Hz, 2H), 6.88 (m, 2H), 6.46 (m, 1H), 6.25 (m, 1H), 5.75 (m, 1H), 2.25 (s, 3H).
Embodiment 25：The preparation of N- (3- (3- (2- ((5- (4- methylpiperazine-1-yls) pyridine -2- bases) amino) pyrimidine-4-yl) urea groups) phenyl) acrylamide (cpd-25)
By N- (3- (3- (2- chlorine pyrimidine-4-yl) urea groups) phenyl) acrylamide (200mg, 0.62mmol) with 5- (4- methylpiperazine-1-yls) pyridine -2- amine (69mg, 0.62mmol) it is placed in 50mL stand up reaction bottle, adding n-butanol (10mL) is partly dissolved substrate.Trifluoroacetic acid (215mg, 1.89mmol) is added afterwards, and keeps reaction system to heat 3h at 110 DEG C.After question response terminates, room temperature is cooled to, after after substrate completely reaction, reaction solution is extracted three times with ethyl acetate/aqueous systems, isolates organic layer, through saturated sodium bicarbonate and saturated common salt water washing, after anhydrous sodium sulfate drying, is concentrated under reduced pressure to give crude product.After reaction terminates, filtering, the filtrate that is concentrated under reduced pressure obtains yellow solid, and N- (3- (3- (2- ((5- (4- methylpiperazine-1-yls) pyridine -2- bases) amino) pyrimidine-4-yl) urea groups) phenyl) acrylamide (cpd-25) (16.04mg) is obtained to prepare liquid phase purifying.Yield：4%, purity：98.37%, MS m/z (ESI):474.1[M+H]+；1H NMR(400MHz,DMSO-d6):(the s of δ 10.63, 1H), 10.18 (s, 1H), 9.76 (s, 1H), 8.39-8.16 (m, 2H), 7.86 (dd, J=10.8, 7.4Hz, 3H), 7.51 (d, J=8.0Hz, 1H), 7.37 (dd, J=9.1, 2.9Hz, 1H), 7.25 (t, J=8.1Hz, 1H), 7.09 (d, J=8.4Hz, 1H), 6.73 (d, J=5.6Hz, 1H), 6.57-6.39 (m, 1H), 6.26 (dd, J=17.0, 1.9Hz, 1H), 5.75 (dd, J=10.1, 1.9Hz, 1H), 3.06 (d, J=4.4Hz, 4H), 2.48-2.40 (m, 4H), 2.22 (s, 3H).
Embodiment 26：The preparation of N- (3- (3- (2- ((4- fluorophenyls) amino) pyrimidine-4-yl) urea groups) phenyl) acrylamide (cpd-26)
By N- (3- (3- (2- chlorine pyrimidine-4-yl) urea groups) phenyl) acrylamide (200mg, 0.62mmol) with para-fluoroaniline (69mg, 0.62mmol) it is placed in 50mL stand up reaction bottle, adding n-butanol (10mL) is partly dissolved substrate.Trifluoroacetic acid (215mg, 1.89mmol) is added afterwards, and keeps reaction system to heat 3h at 110 DEG C.After question response terminates, room temperature is cooled to, after after substrate completely reaction, reaction solution is extracted three times with ethyl acetate/aqueous systems, isolates organic layer, through saturated sodium bicarbonate and saturated common salt water washing, after anhydrous sodium sulfate drying, be concentrated under reduced pressure to give Crude product.Through Prep-HPLC column chromatographies [H2O(10mM NH4HCO3):CH3CN=65:35~5:95] purifying obtains N- (3- (3- (2- ((4- fluorophenyls) amino) pyrimidine-4-yl) urea groups) phenyl) acrylamide (cpd-26) (8.22mg).Yield：3.4%, purity：97.42%, MS m/z (ESI):393.1[M+H]+；1H NMR(400MHz,DMSO-d6):δ 10.16 (s, 1H), 9.99 (s, 1H), 9.46 (d, J=5.2Hz, 1H), 7.92 (s, 1H), 7.69 (m, 2H), 7.43 (d, J=8.4Hz, 1H), 7.23 (t, J=8Hz, 1H), 7.11 (t, J=8.8Hz, 2H), 7.00 (m, 2H), 6.47 (m, 1H), 6.26 (d, J=16.8Hz, 1H), 5.75 (m, J=7.8Hz, 1H).
Embodiment 27：The preparation of N- (3- (3- (2- ((4- ethoxyl phenenyls) amino) pyrimidine-4-yl) urea groups) phenyl) acrylamide (cpd-27)
By N- (3- (3- (2- chlorine pyrimidine-4-yl) urea groups) phenyl) acrylamide (200mg, 0.62mmol) with p-ethoxyaniline (85mg, 0.62mmol) it is placed in 50mL stand up reaction bottle, adding n-butanol (10mL) is partly dissolved substrate.Trifluoroacetic acid (215mg, 1.89mmol) is added afterwards, and keeps reaction system to heat 3h at 110 DEG C.After question response terminates, room temperature is cooled to, after after substrate completely reaction, reaction solution is extracted three times with ethyl acetate/aqueous systems, isolates organic layer, through saturated sodium bicarbonate and saturated common salt water washing, after anhydrous sodium sulfate drying, is concentrated under reduced pressure to give crude product.Through Prep-HPLC column chromatographies [H2O(10mM NH4HCO3):CH3CN=65:35~5:95] purifying obtains N- (3- (3- (2- ((4- ethoxyl phenenyls) amino) pyrimidine-4-yl) urea groups) phenyl) acrylamide (cpd-27) (38.46mg).Yield：12.7%, purity：100%, MS m/z (ESI):419.2[M+H]+；1H NMR(400MHz,DMSO-d6):δ 10.20 (s, 1H), 10.14 (s, 1H), 9.50 (s, 1H), 9.23 (s, 1H), 8.18 (d,), J=5.6Hz 7.91 (s, 1H), 7.50 (m, 3H), 7.19 (t, J=8Hz, 1H), 6.82 (m, 4H), 6.25 (m, 1H), 5.74 (m, 1H), 3.95 (m, 2H), 3.30 (s, 3H), 1.31 (t, J=2.8Hz, 3H).
Embodiment 28：The preparation of N- (3- (3- (2- ((2- methoxyphenyls) amino) pyrimidine-4-yl) urea groups) phenyl) acrylamide (cpd-28)
By 2- aminoanisoles (116mg, 0.63mmol) with TFA (216mg, 1.89mmol) it is added to N- (3- (3- (2- chlorine pyrimidine-4-yl) urea groups) phenyl) acrylamide (200mg, in 4ml butanol solutions 0.63mmol), 6h is stirred vigorously at 110 DEG C.After reaction terminates, system is cooled to room temperature, adds appropriate saturated solution of sodium bicarbonate, is extracted three times with ethyl acetate/aqueous systems, organic layer is concentrated under reduced pressure to give crude product.Purified through preparing liquid phase separation N- (3- (3- (2- ((2- methoxyphenyls) amino) pyrimidine-4-yl) urea groups) phenyl) acrylamide (cpd-28) (11.68mg).Yield：5%, purity：100%, MS m/z (ESI):405.1[M+H]+；1H NMR (400MHz, DMSO) δ 10.12 (d, J=18.3Hz, 1H), (9.55 s, 1H), 8.40-8.10 (m, 1H), 7.90 (d, J=7.5Hz, 1H), 7.37 (t, J=35.9Hz, 1H), 7.19 (t, J=8.1Hz, 1H), 7.13-7.02 (m, 1H), 7.01-6.86 (m, 1H), 6.78 (d, J=6.9Hz, 1H), 6.46 (dd, J=16.9,10.1Hz, 1H), (6.26 d, J=16.9Hz, 1H), 5.82-5.65 (m, 1H), 3.82 (s, 2H), 2.07 (s, 1H).
Embodiment 29：The preparation of N- (3- (3- (2- ((4- chlorphenyls) amino) pyrimidine-4-yl) urea groups) phenyl) acrylamide (cpd-29)
By 4- chloroanilines (80mg, 0.63mmol) with trifluoroacetic acid (216mg, 1.9mmol) it is added to N- (3- (3- (2- chlorine pyrimidine-4-yl) urea groups) phenyl) acrylamide (200mg, in 4ml butanol solutions 0.63mmol), 3h is stirred vigorously at 110 DEG C.After reaction terminates, system is cooled to room temperature, and be concentrated under reduced pressure to obtain brown solid.N- (3- (3- (2- ((4- chlorphenyls) amino) pyrimidine-4-yl) urea groups) phenyl) acrylamide (cpd-29) (9.37mg) is obtained through preparing liquid phase purifying.Yield：4%, purity：100.0%, MS m/z (ESI):409.0[M+H]+；1H NMR(400MHz,DMSO-d6):δ 10.18 (s, 1H), 9.93 (s, 1H), 9.61 (s, 1H), 9.49 (s, 1H), 8.27 (d, J=5.6Hz, 1H), 7.93 (s, 1H), 7.75 (dd, J=9.0,2.8Hz, 2H), 7.32 (tt, J=16.2,8.1Hz, 4H), 7.04 (dd, J=14.7,6.6Hz, 2H), 6.46 (dd, J=17.0,10.1Hz, 1H), 6.26 (dd, J=17.0,1.8Hz, 1H), 5.75 (dd, J=10.1,1.8Hz, 1H).
Embodiment 30：The preparation of N- (3- (3- (2- ((3,4,5- trimethoxyphenyls) amino) pyrimidine-4-yl) urea groups) phenyl) acrylamide (cpd-30)
By 3,4,5- trimethoxy-anilines (116mg, 0.63mmol) with TFA (216mg, 1.89mmol) it is added to N- (3- (3- (2- chlorine pyrimidine-4-yl) urea groups) phenyl) acrylamide (200mg, in 4ml butanol solutions 0.63mmol), 6h is stirred vigorously at 110 DEG C.After reaction terminates, system is cooled to room temperature, adds appropriate saturated solution of sodium bicarbonate, is extracted three times with ethyl acetate/aqueous systems, organic layer is concentrated under reduced pressure to give crude product.N- (3- (3- (2- ((3 are purified to obtain through preparing liquid phase separation, 4,5- trimethoxyphenyls) amino) pyrimidine-4-yl) urea groups) phenyl) acrylamide (cpd-30) (50.84mg).Yield：17%, purity：100%, MS m/z (ESI):465.1[M+H]+；1H NMR (400MHz, DMSO) δ 10.20 (d, J=31.9Hz, 1H), 9.50 (s, 1H), 9.34 (s, 1H), 8.24 (d, J=5.6Hz, 1H), 7.93 (s, 1H), 7.45 (d, J=8.2Hz, 1H), 7.21 (t, J=8.1Hz, 1H), 7.11-6.92 (m, 2H), 6.86 (d, J=5.6Hz, 1H), 6.46 (dd, J=17.0,10.1Hz, 1H), 6.26 (dd, J=17.0,1.9Hz, 1H), 5.75 (dd, J=10.1,2.0Hz, 1H), 3.74 (s, 6H), 3.61 (s, 3H).
Embodiment 31：The preparation of N- (3- (3- (2- ((4- morphlinophenyls) amino) pyrimidine-4-yl) urea groups) phenyl) acrylamide (cpd-31)
By N- (3- (3- (2- Chloropyrimide -4- bases) urea groups) phenyl) acrylamide (200mg, 0.63mmol) with 4- morpholinyl phenylamines (112mg, 0.62mmol) it is placed in 50mL stand up reaction bottle, adding n-butanol (10mL) is partly dissolved substrate.Trifluoroacetic acid (215mg, 1.89mmol) is added afterwards, and keeps reaction system to heat 6h at 110 DEG C.After question response terminates, room temperature is cooled to, after after substrate completely reaction, reaction solution is extracted three times with ethyl acetate/aqueous systems, isolates organic layer, through saturated sodium bicarbonate and saturated common salt water washing, after anhydrous sodium sulfate drying, is concentrated under reduced pressure to give crude product.Through Prep-HPLC column chromatographies [H2O(10mM NH4HCO3):CH3CN=65:35~5:95] purifying obtains N- (3- (3- (2- ((4- morphlinophenyls) amino) pyrimidine-4-yl) urea groups) phenyl) acrylamide (cpd-31) (4.22mg).Yield：2%, purity：100%, MS m/z (ESI):460.7[M+H]+；1H NMR(400MHz,DMSO-d6):δ 10.28 (s, 1H), 10.16 (s, 1H), 9.22 (s, 1H), 8.17 (d, J=5.6Hz, 1H), 7.93 (s, 1H), 7.56-7.39 (m, 3H), 7.19 (t, J=8.1Hz, 1H), 6.89-6.74 (m, 4H), 6.46 (dd, J=16.9,10.1Hz, 1H), 6.26 (dd, J=17.0,1.9Hz, 1H), 5.75 (dd, J=10.1,1.9Hz, 1H), 3.80-3.67 (m, 4H), 3.08-2.97 (m, 4H).
Embodiment 32：The preparation of N- (3- (3- (2- ((4- (4- (dimethylamino) piperidin-1-yl) -2- anisyls) amino) pyrimidine-4-yl) -3- methyl urea groups) phenyl) acrylamide (cpd-32)
Step 1：The synthesis of the chloro- 4- methylaminopyrimidins of 2-
30% methylamine alcohol solution (7.63g, 73.8mmol) is added to 2,4- dichloro pyrimidines (11g, 73.8mmol) In the mixed solution of 200ml ethanol and 80ml methanol, 3h is stirred vigorously at 80 DEG C.After reaction terminates, system is cooled to room temperature, is concentrated under reduced pressure, and the chloro- 4- methylaminopyrimidins (3.4g) of 2-, yield are purified to obtain through column chromatography：32%, purity：99%, MS m/z (ESI):144.1[M+H]+
Step 2：The synthesis of N- (4- (4- (dimethylamino) piperidin-1-yl) -2- methoxyphenyls)-N-4- methylpyrimidine -2,4- diamines
By 1- (4- amino -3- methoxyphenyls)-N, N- lupetidine -4- amine (1.39g, 5.57mmol) with trifluoroacetic acid (1.91g, 16.72mmol) it is added to the chloro- 4- methylaminopyrimidins (800mg of 2-, in 15ml butanol solutions 5.57mmol), 2h is stirred vigorously at 130 DEG C.After reaction terminates, system is cooled to room temperature, it is diluted with water, extracted three times with ethyl acetate/aqueous systems, organic layer is isolated, through water and saturated common salt water washing, after anhydrous sodium sulfate drying, be concentrated under reduced pressure to obtain brown solid, and N- (4- (4- (dimethylamino) piperidin-1-yl) -2- methoxyphenyls)-N-4- methylpyrimidines -2,4- diamines (1.4g) is obtained through column chromatographic isolation and purification.Yield：24%, purity：86%, MS m/z (ESI):357.2[M+H]+
Step 3：The synthesis of 1- (2- (4- (4- (dimethylamino) piperidin-1-yl) -2- Methoxyphenylaminos) pyrimidine-4-yl) -1- methyl -3- (3- nitrobenzophenones) urea
By the different hydrogen acid ether (hydrogen acid ester) (500mg of 3- nitrobenzene, 3mmol) it is added to N- (4- (4- (dimethylamino) piperidin-1-yl) -2- methoxyphenyls)-N-4- methylpyrimidines -2,4- diamines (700mg, 15ml1 2mmol), in 2- dichloroethanes (DCE) solution, 5h is stirred vigorously at 80 DEG C.After reaction terminates, system is cooled to room temperature, it is concentrated under reduced pressure, 1- (2- (4- (4- (dimethylamino) piperidin-1-yl) -2- Methoxyphenylaminos) pyrimidine-4-yl) -1- methyl -3- (3- nitrobenzophenones) urea (100mg) is purified to obtain through column chromatography.Yield：11%, purity：74%, MS m/z (ESI):521.2[M+H]+
Step 4：The synthesis of 1- (2- (4- (4- (dimethylamino) piperidin-1-yl) -2- Methoxyphenylaminos) pyrimidine-4-yl) -1- methyl -3- (3- aminophenyls) urea
At room temperature, by palladium carbon (10mg, 10%wt) it is added to 1- (2- (4- (4- (dimethylamino) piperidin-1-yl) -2- Methoxyphenylaminos) pyrimidine-4-yl) -1- methyl -3- (3- nitrobenzophenones) urea (90mg, in 20ml methanol solutions 0.17mmol), room temperature is stirred vigorously 3h in a hydrogen atmosphere.After reaction terminates, filter off palladium carbon, filtrate decompression is concentrated, 1- (2- (4- (4- (dimethylamino) piperidin-1-yl) -2- Methoxyphenylaminos) pyrimidine-4-yl) -1- methyl -3- (3- aminophenyls) urea is obtained, next step reaction is directly used in.Yield：92%, purity：70%, MS m/z (ESI):491.3[M+H]+
Step 5：The synthesis of N- (3- (3- (2- ((4- (4- (dimethylamino) piperidin-1-yl) -2- anisyls) amino) pyrimidine-4-yl) -3- methyl urea groups) phenyl) acrylamide (cpd-32)
By triethylamine (60mg, 0.55mmol) it is added to 1- (2- (4- (4- (dimethylamino) piperidin-1-yl) -2- Methoxyphenylaminos) pyrimidine-4-yl) -1- methyl -3- (3- aminophenyls) urea (90mg, in 2ml dichloromethane (DCM) solution 0.18mmol), it is stirred vigorously at 0 DEG C.By acryloyl chloride (20mg, 0.22mmol), at 0 DEG C, it is slowly dropped in reaction solution.Keep 0 DEG C of stirring 2h.TLC detects extent of reaction, after after substrate completely reaction, it is diluted with water, extracted three times with ethyl acetate/aqueous systems, isolate organic layer, through water and saturated common salt water washing, after anhydrous sodium sulfate drying, be concentrated under reduced pressure to obtain yellow solid, and N- (3- (3- (2- ((4- (4- (dimethylamino) piperidin-1-yl) -2- anisyls) amino) pyrimidine-4-yl) -3- methyl urea groups) phenyl) acrylamide (cpd-32) (3.38mg) is purified to obtain through preparing liquid phase separation.Yield：4%, purity：100.0%, MS m/z (ESI):545.0[M+H]+；1H NMR(400MHz,DMSO-d6):δ 11.81 (s, 1H), 10.09 (s, 1H), 8.51 (s, 1H), 8.24 (s, 1H), 7.83 (s, 1H), 7.49 (s, 1H), 7.25 (s, 1H), 7.12-7.05 (m, 1H), 6.55-6.24 (m, 5H), 5.75 (s, 1H), 5.32 (s, 1H), 3.71 (s, 3H), 3.56 (s, 2H), 3.29 (s, 3H), 2.72 (s, 2H), 2.19 (s, 6H), 2.00 (d, J=7.3Hz, 1H), 1.81 (s, 2H), 1.45 (s, 2H).
Embodiment 33：The preparation of 3- acrylamidos-N- (2- (2- methoxyl groups -4- (4- morpholino -1- bases) phenyl amino) pyrimidine-4-yl) piperidines -1- formamides (cpd-33)
Step 1：The synthesis of the chloro- 4- isocyanic acids pyrimidines of 2-
At 0 DEG C, in the 200ml THF solutions that 4- amino -2- chlorine pyrimidines (4.8g, 37.0mmol) are added to triphosgene (5.5g, 18.5mmol), DIPEA (6.23g, 48.2mmol) is then slowly added dropwise.4h is stirred vigorously at room temperature.TLC detects extent of reaction, and after after substrate completely reaction, product is directly used in next step reaction.
Step 2：The synthesis of 1- ((2- chlorine pyrimidine-4-yl) carbamoyl) piperidines -3- carbamates
At room temperature, triethylamine (10g, 97mmol) and 3- t-butoxycarbonyl aminos piperidines (7.1g, 35.4mmol) are added to the chloro- 4- isocyanic acids pyrimidine (5.0g of 2-, in 100ml THF solutions 32.2mmol), 18h is stirred vigorously at room temperature.After reaction terminates, 150ml ethyl acetate is added to reaction system, with 150ml water washing organic phases, saturated common salt water washing, after anhydrous sodium sulfate drying, be concentrated under reduced pressure to obtain yellow solid, and compound as white solid (3.5g) is obtained through column chromatographic isolation and purification.Yield：31%, purity：90%, MS m/z (ESI):356.2[M+H]+。
Step 3：The synthesis of 3- amino-N- (2- chlorine pyrimidine-4-yl) piperidines -1- formamides
1- ((2- chlorine pyrimidine-4-yl) carbamoyl) piperidines -3- carbamates (3.5g, 9.9mmol) are dissolved in 50ml hydrochloric acid dioxane solutions, 2h are stirred vigorously down at room temperature.After reaction terminates, be concentrated under reduced pressure to obtain compound as white solid (2.4g), and product is directly used in next step.Yield：94%, purity：85%, MS m/z (ESI):256.1[M+H]+。
Step 4：The synthesis of 3- acrylamidos-N- (2- chlorine pyrimidine-4-yl) piperidines -1- formamides
In the 50ml THF solutions that triethylamine (2.5g, 24.6mmol) is added to 3- amino-N- (2- chlorine pyrimidine-4-yl) piperidines -1- formamides (2.1g, 8.21mmol), it is stirred vigorously at 0 DEG C.By acryloyl chloride (820mg, 9.1mmol), at 0 DEG C, it is slowly dropped in reaction solution.0 DEG C of stirring 3h is kept, room temperature is slowly increased to, continues to stir 20h.After TLC detects that extent of reaction, reaction terminate, 80ml ethyl acetate is added to reaction system, with 50ml water washing organic phases, saturated common salt water washing, after anhydrous sodium sulfate drying, be concentrated under reduced pressure to obtain yellow solid, and compound as white solid (640mg) is obtained through column chromatographic isolation and purification.Yield：24%, purity：92%, MS m/z (ESI):310.1[M+H]+。
Step 5：The synthesis of 3- acrylamidos-N- (2- (2- methoxyl groups -4- (4- morpholino -1- bases) phenyl amino) pyrimidine-4-yl) piperidines -1- formamides (cpd-33)
By 2- methoxyl groups -4- (4- morpholino -1- bases) aniline (141mg, 0.48mmol) with trifluoroacetic acid (166mg, 1.45mmol) it is added to 3- acrylamidos-N- (2- chlorine pyrimidine-4-yl) piperidines -1- formamides (150mg, in 3ml butanol solutions 0.48mmol), 2h is stirred vigorously at 120 DEG C.After reaction terminates, system is cooled to room temperature, and be concentrated under reduced pressure to obtain brown solid.Cpd-33 (51.49mg) is obtained through preparing liquid phase purifying.Yield：20%, purity：100.0%, MS m/z (ESI):565.3[M+H]+；1H NMR(400MHz,DMSO-d6):(the d of δ 9.39, J=16.5Hz, 1H), 8.63-8.28 (m, 1H), 8.02 (d, J=5.9Hz, 2H), 7.36-7.13 (m, 1H), 6.64 (d, J=2.3Hz, 2H), 6.50 (dd, J=8.7, 2.3Hz, 2H), 6.07 (d, J=16.9Hz, 1H), 5.72-5.57 (m, 1H), 4.11-3.65 (m, 7H), 3.64-3.47 (m, 5H), 3.15-2.82 (m, 1H), 2.64 (t, J=12.2Hz, 2H), 2.48 (s, 4H), 2.24 (s, 1H), 1.86 (d, J=11.2Hz, 2H), 1.47 (d, J=8.7Hz, 5H), 1.23 (s, 2H).
Embodiment 34：The preparation of 3- acrylamidos-N- (2- (2- methoxyl groups -4- (4- methylpiperazine-1-yls) phenyl amino) pyrimidine-4-yl) piperidines -1- formamides (cpd-34)
By 2- methoxyl groups -4- (4- methylpiperazine-1-yls) aniline (107mg, 0.48mmol) with trifluoroacetic acid (166mg, 1.45mmol) it is added to 3- acrylamidos-N- (2- chlorine pyrimidine-4-yl) piperidines -1- formamides (150mg, in 3ml butanol solutions 0.48mmol), 2h is stirred vigorously at 120 DEG C.After reaction terminates, system is cooled to room temperature, and be concentrated under reduced pressure to obtain brown solid.Compound cpd-34 (48.53mg) is obtained through preparing liquid phase purifying.Yield：21%, purity：100.0%.MS m/z(ESI):495.2[M+H]+；1H NMR(400MHz,DMSO-d6):δ 9.42 (d, J=15.2Hz, 1H), 8.63-8.31 (m, 1H), 8.27-7.97 (m, 2H), 7.23 (s, 1H), 6.66 (dd, J=14.1,4.0Hz, 2H), 6.56-6.26 (m, 2H), 6.07 (d, J=16.7Hz, 1H), 5.73-5.58 (m, 1H), 3.78 (d, J=29.9Hz, 5H), 3.51 (s, 1H), 3.24-2.81 (m, 6H), 2.44 (s, 4H), 2.21 (d, J=8.1Hz, 3H), 1.62 (d, J=32.5Hz, 2H), 1.30 (d, J=52.4Hz, 2H).
Embodiment 35：The preparation of 3- acrylamidos-N- (2- (2- methoxyl groups -4- (1- methyl piperidine -4- bases) phenyl amino) pyrimidine-4-yl) piperidines -1- formamides (cpd-35)
By 2- methoxyl groups -4- (1- methyl piperidine -4- bases) aniline (85mg, 0.39mmol) with trifluoroacetic acid (135mg, 1.16mmol) it is added to 3- acrylamidos-N- (2- chlorine pyrimidine-4-yl) piperidines -1- formamides (120mg, 0.39mmol) In 3ml butanol solutions, 2h is stirred vigorously at 130 DEG C.After reaction terminates, system is cooled to room temperature, and be concentrated under reduced pressure to obtain brown solid.Cpd-35 (6.76mg) is obtained through preparing liquid phase purifying.Yield：4%, purity：94.53%.MS m/z(ESI):494.0[M+H]+；1H NMR(400MHz,DMSO-d6):δ 9.36 (d, J=20.0Hz, 0H), 8.08 (dd, J=41.4,35.9Hz, 1H), 7.67 (d, J=37.5Hz, 0H), 6.93 (s, 0H), 6.84-6.65 (m, 1H), 6.05 (d, J=15.8Hz, 0H), 5.64 (s, 0H), (3.81 s, 1H), 3.01 (s, 0H), 2.86 (d, J=9.8Hz, 1H), 2.67 (s, 1H), 2.30 (d, J=21.1Hz, 1H), (2.19 s, 3H), 1.95 (t, J=10.1Hz, 1H), 1.71 (s, 2H), 1.64-1.54 (m, 1H).
Embodiment 36：The preparation of 3- acrylamidos-N- (2- (4- ((2- (dimethylamino) ethyl) (methyl) amino) -2- Methoxyphenylaminos) pyrimidine-4-yl) piperidines -1- formamides (cpd-36)
Step 1：The synthesis of N- (2- (dimethylamino) ethyl) -3- methoxyl group -4- nitroanilines
By N, N,-dimethyl-ethylenediamine (8.36g, 81.9mmol) with potassium carbonate (12.1g, in the DMF for 122.8mmol) being added to the 200ml of the fluoro- 2- methoxyl groups -1- nitrobenzene (7g, 40.9mmol) of 4-, 24h is stirred vigorously at 50 DEG C.TLC detects extent of reaction, after after substrate completely reaction, add 200ml water, extracted three times with ethyl acetate/aqueous systems, isolate organic layer, crude product is concentrated under reduced pressure to give, N- (2- (dimethylamino) ethyl) -3- methoxyl group -4- nitroanilines (6.5g) are purified to obtain through Combi-Flash column chromatographies.Yield：63%, purity：100%.MS m/z(ESI):254.1[M+H]+。
Step 2：The synthesis of N1- (2- (dimethylamino) ethyl) -3- methoxybenzene -1,4- diamines
By reduced iron powder (256mg, 4.74mmol) it is added to N- (2- (dimethylamino) ethyl) -3- methoxyl group -4- nitroanilines (150mg, 3ml ethanol and 6 0.59mmol) drips in solution, instill one and drip hydrochloric acid, 4h is stirred vigorously at 100 DEG C.TLC detects extent of reaction, and after after substrate completely reaction, filtering, filtrate decompression is concentrated to give N1- (2- (dimethylamino) ethyl) -3- methoxybenzenes-Isosorbide-5-Nitrae-diamines (120mg).Yield：95%, purity：70%.MS m/z(ESI):224.2[M+H]+。
Step 3：The synthesis of 3- acrylamidos-N- (2- (4- ((2- (dimethylamino) ethyl) (methyl) amino) -2- Methoxyphenylaminos) pyrimidine-4-yl) piperidines -1- formamides
At 0 DEG C, by 3- acrylamidos-N- (2- chlorine pyrimidine-4-yl) piperidines -1- formamides (100mg, 0.32mmol) with TEA (66mg, 0.65mmol) it is added to N1- (2- (dimethylamino) ethyl) -3- methoxybenzenes -1,4- diamines (110mg, in 2ml dichloromethane solutions 0.48mmol), 2h is stirred vigorously at 0 DEG C.After reaction terminates, it is diluted with water, is extracted three times with methylene chloride/water system, organic layer is concentrated under reduced pressure to give crude product.Purified through preparing liquid phase separation cpd-36(41.19mg).Yield：26%, purity：97%.MS m/z(ESI):497.2[M+H]+；1H NMR (400MHz, DMSO the) (d of δ 9.40, J=15.8Hz, 1H), 8.54 (d, J=62.8Hz, 1H), 8.23 (d, J=30.0Hz, 2H), 8.03 (d, J=27.3Hz, 2H), 7.33-7.01 (m, 1H), 6.95-6.49 (m, 2H), 6.52-6.18 (m, 4H), 6.06 (dt, J=17.2, 8.5Hz, 1H), 5.65 (d, J=9.2Hz, 1H), 4.02-3.58 (m, 6H), 3.47 (s, 4H), 2.91 (s, 4H), 2.62 (d, J=42.9Hz, 2H), 2.33 (s, 7H), 1.62 (d, J=43.4Hz, 2H), 1.35 (s, 1H), 1.26-0.84 (m, 1H).
Embodiment 37：The preparation of the trifluoroacetate of N- (3- (2- (2- (2- methoxyl groups -4- (4- methylpiperazine-1-yls) phenyl amino) pyrimidine-4-yl) -2- methylpropionylaminos) phenyl) acrylamide (cpd-37)
Step 1：The synthesis of 2- (2- chlorine pyrimidine-4-yl) diethyl malonate
Diethyl malonate (6.5.0g, 40.0mmol) is placed in 500mL stand up reaction bottle, adding dry toluene (100mL) mixed solution dissolves it.At room temperature, sodium hydride (4.4g, 80.0mmol) is added into the reaction bulb of stirring, reaction system is then continuously stirred at room temperature 0.5h.2,4- dichloro pyrimidines (5.0g, 34.0mmol) are added in reaction system afterwards, reaction system adds Pd with after nitrogen displacement air three times2(dba)3(600mg, 0.68mmol) and P (t-Bu)3(280mg, 1.36mmol), uses nitrogen displacement air three times again afterwards.Reaction system is heated to 80 DEG C, and continues to stir 16h.TLC detects extent of reaction, after after substrate completely reaction, is filtered to remove precipitation, filter cake is eluted three times with ethyl acetate.Filtrate decompression is concentrated to give crude product, through Combi-Flash [EA:PE=5:95-50:50] column chromatography purifying obtains target compound yellow oily (2.9g, 10.0mmol).Yield：26.6%；Purity：90%.
Step 2：The synthesis of 2- (2- chlorine pyrimidine-4-yl) ethyl acetate
2- (2- chlorine pyrimidine-4-yl) diethyl malonate (2.9g, 10.0mmol) is placed in 250mL stand up reaction bottle, DMSO/H is added2O (100mL/2mL) mixed solution dissolves substrate.At room temperature, sodium chloride (600mg, 10.0mmol) is sequentially added into the reaction bulb of stirring, reaction system is then heated to 140 DEG C and 5h is kept stirring for.TLC detects extent of reaction, and after after substrate completely reaction, ethyl acetate/aqueous systems are extracted three times, organic layer is isolated, through water and saturated common salt water washing, after anhydrous sodium sulfate drying, target compound (1.4g, 7.0mmol) is concentrated under reduced pressure to give, next step reaction is directly used in.
Step 3：The synthesis of 2- (2- chlorine pyrimidine-4-yl) -2 Methylpropionic acid ethyl ester
2- (2- chlorine pyrimidine-4-yl) ethyl acetate (1.4g, 7.0mmol) is placed in 100mL stand up reaction bottle, adding acetone (50mL) dissolves substrate.At room temperature, potassium carbonate (2.9g, 21.0mmol) and iodomethane (1.5g, 10.5mmol) are sequentially added into the reaction bulb of stirring, reaction system is then heated to 60 DEG C and 5h is kept stirring for.TLC detects extent of reaction, after after substrate completely reaction, is filtered to remove precipitation, filter cake is eluted three times with ethyl acetate, Filtrate decompression is concentrated to give crude product, through Combi-Flash [EA:PE=5:95-50:50] column chromatography purifying obtains target compound colorless oil (900mg, 4.0mmol).Yield：39% (two steps)；Purity：90%；MS m/z(ESI):229.1[M+H]+。
Step 4：The synthesis of 2- (2- chlorine pyrimidine-4-yl) -2 Methylpropionic acid
2- (2- chlorine pyrimidine-4-yl) -2 Methylpropionic acid ethyl ester (900mg, 4.0mmol) is placed in 50mL stand up reaction bottle, adding methanol (5mL) is partly dissolved substrate.1N sodium hydrate aqueous solutions (5mL) are added afterwards, and keep reaction system to be continuously stirred at room temperature 6h.TLC detects extent of reaction, after after substrate completely reaction, reaction solution once, separates water-yielding stratum with ethyl acetate/aqueous systems extraction, with pH value to 5 in 2N aqueous hydrochloric acid solutions, extracted three times with ethyl acetate/aqueous systems, isolate organic layer, saturated common salt water washing, after anhydrous sodium sulfate drying, crude product 2- (2- chlorine pyrimidine-4-yl) -2 Methylpropionic acid (450mg, 2.25mmol) is concentrated under reduced pressure to give, the next step is direct plungeed into.Yield：56%；Purity：95%.MS m/z(ESI):201.7[M+H]+。
Step 5：The synthesis of N- (3- aminophenyls) -2- (2- chlorine pyrimidine-4-yl) -2- methyl propanamides
2- (2- chlorine pyrimidine-4-yl) -2 Methylpropionic acid (450mg, 2.25mmol) is placed in 50mL stand up reaction bottle, adding thionyl chloride (5mL) is partly dissolved substrate.Reaction system is heated to 80 DEG C afterwards and continues to stir 1h.After question response terminates, vacuum distillation removes unnecessary thionyl chloride and obtains acyl chlorides crude product.Acyl chlorides crude product is slowly added into dichloromethane (10mL) solution of benzene -1,3- diamines (365mg, 3.38mmol) and triethylamine (0.63mL, 4.5mmol) at 0 DEG C, keeps reaction system persistently to stir 1h at 0 DEG C.TLC detects extent of reaction, and after after substrate completely reaction, reaction solution is extracted three times with methylene chloride/water system, isolate after organic layer, saturated common salt water washing, anhydrous sodium sulfate drying, crude product (700mg) is concentrated under reduced pressure to give, the next step is direct plungeed into.
Step 6：The synthesis of N- (3- (2- (2- chlorine pyrimidine-4-yl) -2- methylpropionylaminos) phenyl) acrylamide
N- (3- aminophenyls) -2- (2- chlorine pyrimidine-4-yl) -2- methyl propanamides (700mg) are placed in 50mL stand up reaction bottle, adding dichloromethane (10mL) dissolves substrate.Triethylamine (1mL) and acryloyl chloride (0.5mL) are sequentially added at 0 DEG C afterwards, and keeps reaction system persistently to stir 1h at 0 DEG C.TLC detects extent of reaction, and reaction solution is extracted three times with methylene chloride/water system, isolates after organic layer, saturated common salt water washing, anhydrous sodium sulfate drying, be concentrated under reduced pressure to give crude product (710mg, 0.91mmol), direct plunge into the next step.Yield：40% (two steps)；Purity：44%；MS m/z(ESI):345.7[M+H]+。
Step 7：The trifluoroacetate synthesis of N- (3- (2- (2- (2- methoxyl groups -4- (4- methylpiperazine-1-yls) phenyl amino) pyrimidine-4-yl) -2- methylpropionylaminos) phenyl) acrylamide
By N- (3- (2- (2- chlorine pyrimidine-4-yl) -2- methylpropionylaminos) phenyl) acrylamide (710mg, 0.91mmol) with 2- methoxyl groups -4- (4- methylpiperazine-1-yls) aniline (402mg, 1.82mmol) it is placed in 50mL stand up reaction bottle, adding n-butanol (10mL) is partly dissolved substrate.Trifluoroacetic acid (620mg, 5.46mmol) is added afterwards, and keeps reaction system to heat 16h at 130 DEG C.After question response terminates, room temperature is cooled to, crude product is concentrated under reduced pressure to give.Through Prep-HPLC column chromatographies [H2O (0.05%TFA):CH3CN=65:35~5:95] purifying obtains target product cpd-37 trifluoroacetate (10.38mg, 0.016mmol).Yield：1.8%；Purity：95%；MS m/z(ESI):530.7[M+H]+；1H NMR (400MHz, CDCl3):δ 9.18 (s, 1H), 8.47-8.34 (m, 2H), 8.03 (d, J=8.7Hz, 1H), 7.50 (s, 1H), 7.32 (d, J=9.9Hz, 2H), 7.25 (s, 1H), 7.17 (t, J=8.1Hz, 1H), 6.80 (d, J=5.2Hz, 1H), 6.52-6.37 (m, 3H), 6.16 (d, J=8.7Hz, 1H), 5.73 (t, J=5.8Hz, 1H), 3.87 (s, 3H), 3.23 (s, 4H), 3.12 (s, 4H), 2.74 (s, 3H), 1.68 (s, 6H).
Embodiment 38：1- (3- acryloyl groups amide groups) -3- (2- (2- methoxyl groups -4- (4- propylpiperazine -1- bases) phenyl amino) Pyrimidine-4-yl) urea (cpd-38) preparation
Preparation method be the same as Example 23, the difference is that changing 4- (4- ethyl piperazidine -1- bases) -2- aminoanisoles in step into 4- (4- propylpiperazine -1- bases) -2- aminoanisoles (the similar intermediate 11 of preparation method).MS m/z(ESI):531[M+H]+；1H NMR (400MHz, DMSO the) (s of δ 10.47, 1H), 10.12 (s, 1H), 9.57 (s, 1H), 8.26 (s, 1H), 8.10 (d, J=5.5Hz, 1H), 7.93 (s, 1H), 7.47 (d, J=7.7Hz, 1H), 7.35 (d, J=8.4Hz, 1H), 7.13 (t, J=8.0Hz, 1H), 6.59 (d, J=6.8Hz, 2H), 6.48-6.41 (m, 2H), 6.25 (d, J=18.8Hz, 1H), 5.74 (d, J=11.6Hz, 1H), 3.75 (s, 3H), 3.29 (s, 4H), 3.11 (s, 4H), 2.32-2.25 (m, 2H), 1.48 (dd, J=14.7, 7.4Hz, 2H), 0.89 (t, J=7.4Hz, 3H)
Embodiment 39：The preparation of 3- (3- acryloyl groups amide groups) -1- (2- (4- ((2- (dimethylamino) ethyl) (methyl) amino) -2- Methoxyphenylaminos) pyrimidine-4-yl) -1- MUs (cpd-39)
Preparation method be the same as Example 32, the difference is that by 1- (4- amino -3- methoxyphenyls)-N in step 2, N- lupetidine -4- amine changes N into1- (2- (dimethylamino) ethyl) -3- methoxyl groups-N1Methylbenzene -1,4- diamines (the similar intermediate 4 of preparation method).MS m/z(ESI):519[M+H]+；1H NMR (400MHz, DMSO the) (s of δ 12.02, 1H), 10.11 (s, 1H), 8.52 (s, 1H), 8.23 (d, J=5.7Hz, 1H), 7.84 (s, 1H), 7.48 (d, J=7.8Hz, 1H), 7.13 (d, J=8.6Hz, 1H), 7.01 (s, 1H), 6.45 (dd, J=16.4, 10.6Hz, 2H), 6.40-6.17 (m, 3H), 6.13 (d, J=9.0Hz, 1H), 5.80-5.68 (m, 1H), 3.70 (s, 3H), 3.33 (d, J=6.9Hz, 5H), 2.86 (s, 3H), 2.27 (t, J=6.8Hz, 2H), 2.14 (s, 6H)
Embodiment 40：The preparation of 1- (3- acryloyl groups amide groups) -3- (the chloro- 2- of 5- (2- methoxyl groups -4- (4- morpholinoes piperidin-1-yl) phenyl amino) pyrimidine-4-yl) urea (cpd-40)
Preparation method be the same as Example 9, unlike by initiation material 1- (2- chlorine pyrimidine-4-yl) -3- (3- Nitrobenzophenone) urea changes 1- (2,5- dichloropyridine -4- bases) -3- (3- nitrobenzophenones) urea into.MS m/z(ESI):607[M+H]+；1H NMR (400MHz, CDCl3 the) (s of δ 10.82, 1H), 10.13 (s, 1H), 8.76 (s, 1H), 8.64 (s, 1H), 8.21 (s, 1H), 7.85 (s, 1H), 7.53 (d, J=8.0Hz, 1H), 7.24 (d, J=8.6Hz, 1H), 7.12 (s, 1H), 6.65-6.31 (m, 4H), 6.24 (dd, J=17.0, 1.9Hz, 1H), 5.76-5.71 (m, 1H), 3.71 (s, 3H), 3.62 (s, 1H), 3.60-3.56 (m, 5H), 2.59 (t, J=11.6Hz, 2H), 2.47 (s, 4H), 2.22 (d, J=10.9Hz, 1H), 1.83 (d, J=11.7Hz, 2H), 1.50-1.41 (m, 2H)
Embodiment 41：Enzyme platform (z-lyte) drug screening
Agents useful for same is purchased from Invitrogen in following z-lyte method of testings.
Determinand is determined to double-mutant EGFR kinases T790M/L858R kinases (Invitrogen using z-lyte methods, PV4879), the inhibitory action of Wild type EGFR kinases (EGFR WT) (Invitrogen, PV3872) kinase activity.
The working concentration of each component is in 10 μ L T790M/L858R kinase reactions：25 μM of ATP, 0.08ng/ μ L T790M/L858R kinases, 2 μM of Tyr04 substrates (Invitrogen, PV3193).Add the above embodiment of the present invention prepare compound (i.e. determinand) afterwards DMSO concentration be 2%.
The working concentration of each component is in 10 μ L EGFR WT kinase reactions：10 μM of ATP, 0.8ng/ μ L T790M WT kinases, 2 μM of Tyr04 substrates (Invitrogen, PV3193).The concentration for adding DMSO after determinand is 2%.
Water gradient dilution of the room-temperature dissolution 10mM medicine storing liquid through 4%DMSO is to 10-0.005 μM of final concentration.The mixture of the T790M/L858R kinases (or EGFR WT kinases) and Tyr04 substrates of the 2.5 μ L reacted buffer solution dilution of determinand solution and 5 μ L is added in per hole, the ATP for adding 2.5 μ L starts reaction.C1 holes replace ATP with reaction buffer, and C2 holes are added without any medicine, and by specification description in C3 holes adds the substrate of phosphorylation.After room temperature shaker reaction 60min.5 μ L Development Reagent B (Invitrogen is diluted with TR-FRET dilution buffers) are added, 60min is reacted in room temperature shaker.The read plate on VictorX5 fluorescence microplate readers (PerkinElmer), measure excitation wavelength is 405nm, and launch wavelength is 450nm and 520nm light absorbs.(for example, C3520nmRepresent readings of the C3 holes in 520nm).Inhibiting rate computational methods are as follows：
1st, ER=Coumarin Emission (450nm)/Fluorescein Emission (520nm)
2nd, phosphoric acid rate=(1- ((ER × C3520nm-C3450nm)/((C1450nm-C3450nm)+ER×(C3520nm-C1520nm)))) × 100%
3rd, inhibiting rate (IR)=(1- (the phosphoric acid rate of test compound)/(C2 phosphoric acid rate)) × 100%
With the softwares of XLFIT 5.0 (IDBS companies of Britain) the Fitting Calculation half-inhibition concentration IC50.Example compound is shown in Table 1- tables 2 to the inhibitory activity or selection inhibitory activity of enzyme.
Table 1- enzyme inhibition activities
Compound number T790M/L858R(IC<sub>50</sub>/μM) EGFR WT(IC<sub>50</sub>/μM)
cpd-1 0.017 0.017
cpd-2 0.048 0.143
cpd-5 0.005 0.080
cpd-7 0.058 0.348
cpd-9 0.004 0.086
cpd-10 0.002 0.045
cpd-14 0.015 0.225
cpd-19 0.028 0.273
cpd-20 0.022 0.158
cpd-21 0.012 0.183
cpd-22 0.002 0.036
cpd-23 0.013 0.039
cpd-31 0.087 0.644
cpd-32 0.028 0.054
cpd-38 0.010 0.042
cpd-39 0.019 0.049
cpd-40 0.037 0.641
BIBW2992 0.005 0.001
CO1686 0.008 0.074
The selection inhibitory activity of table 2- enzymes
Compound number To the selection inhibitory activity [IC of enzyme50(EGFR WT)/IC50(T790M/L858R)]
cpd-5 16
cpd-9 21.5
cpd-10 22.5
cpd-14 15
cpd-15 >7.8
cpd-17 >10
cpd-19 9.8
cpd-21 15.3
cpd-22 18
cpd-40 17.3
BIBW2992 0.2
CO1686 9.25
It can be seen that from table 1, table 2, the example compound of the present invention shows stronger inhibitory activity to EGFR mutant enzymes (T790M/L858R and L858R), and it is weaker to EGFR wild-type enzymes (EGFR WT) inhibitory activity, compared with positive control BIBW2992 (Afatinib), compound of the invention has obvious selection inhibitory activity to EGFR mutant enzymes.The selection inhibitory activity of the few examples compound of the present invention has been even more than positive control CO1686 (referring specifically to document Cancer Discovery, doi:10.1158/2159-8290.CD-13-0314).
Embodiment 42：MTT (3- (4,5- dimethylthiazoles -2) -2,5- diphenyltetrazolium bromide bromides) method detects cytoactive
MTT method of testings step is carried out using method well known to those skilled in the art, and agents useful for same is commercially available in method obtains.
First, pancreatin/EDTA (Gibco, 25200-056) of culture medium and addition 0.25% is removed.
After washing once, 1.5mL pancreatin/EDTA digestion attached cells are added, to cell separation, 3.5mL culture mediums is then added and terminates digestion.The cell suspending liquid digested is moved into 15mL centrifuge tubes, supernatant is abandoned after 1300rpm centrifugations 3min, and with fresh culture medium suspension cell.
Then cell count, and diluting cells are to following concentration：A431 and H1975 cells are per ml2.78 ten thousand, and NIH3T3 is per ml3.33 ten thousand.Cell kind is entered into 96 orifice plates (BD 3072), per the μ L of hole 90, overnight incubation.
A431 cell culture mediums are：10%FBS (Gibco, 10099-141) DMEM (Hyclone SH30243.01B)；
NIH3T3 cell culture mediums are：10%FBS (Gibco, 10099-141) DMEM (Hyclone SH30243.01B)；
H1975 cell culture mediums are：10%FBS (Gibco, 10099-141) RPMI-1640 (Hyclone SH30809.01B)；
20 μ L10mM testing compounds are taken, according to following concentration gradient (2000,666.67,222.22,74.07,24.69,8.23,2.74,0.91 μM) dilution 10X medicines, and add per the μ l medicines of hole 10 in Tissue Culture Plate, add serum free medium (final concentration of：10,3.333,1.111,0.370,0.123,0.041,0.014,0.005 μM), wherein DMSO final concentration of 0.5%.
Cell is put into after incubator, culture 72h after dosing, 10 μ L 5mg/ml MTT (Sigma, M5655) solution is added per hole, 96 orifice plates are then put into 37 DEG C of 5%CO2Incubator is incubated 4h.
Flat board is centrifuged under conditions of 2000rpm, 5min again, is removed after supernatant, 150 μ L DMSO are added per hole, and flat board to all crystal violets are shaken in shaking table and is dissolved (about 10-20min).492nm light absorbs finally are determined using fluorescence microplate reader, IC is calculated using the softwares of XLFIT 5.0 (IDBS companies of Britain)50.Example compound is shown in Table 3 to table 6 to the inhibitory activity or selection inhibitory activity of cell.
The histamine result (H1975 cells) of table 3- compound on intracellular activity
Compound number H1975 cells (IC50/μM)
cpd-9 0.037
cpd-19 0.075
cpd-21 0.086
cpd-22 0.031
cpd-23 0.070
BIBW2992 0.088
CO1686 0.029
The histamine result (A431 cells) of table 4- compound on intracellular activity
Compound number A431 cells (IC50/μM)
cpd-9 >10
cpd-10 3.379
cpd-19 >10
cpd-21 >10
cpd-23 >10
cpd-31 >10
cpd-32 3.577
BIBW2992 0.029
CO1686 2.892
The selectivity of table 5- compound on intracellular
Compound number To the selection inhibitory activity [IC of cell50(A431 cells)/IC50(H1975 cells)]
cpd-9 >270
cpd-19 >133
cpd-21 >116
cpd-23 >143
BIBW2992 0.33
CO1686 99.7
Toxic test results of the table 6- compounds to NIH3T3 cells
Compound number NIH3T3 cells MTT tests (IC50/μM)
cpd-1 4.199
cpd-2 7.261
cpd-5 4.246
cpd-7 >10
cpd-9 >10
cpd-10 >10
cpd-14 >10
cpd-15 6.291
cpd-19 >10
cpd-21 >10
cpd-22 4.263
cpd-25 >10
cpd-31 9.689
cpd-32 3.103
BIBW2992 2.750
CO1686 2.295
It can be seen that from table 3-5, the compound of the present invention shows stronger inhibitory activity to EGFR mutant cells (H1975 cells), and weaker inhibitory activity is shown to EGFR wild-type cells (A431 cells), compared with positive control BIBW2992, compound of the invention has obvious selection inhibitory activity to EGFR mutant cells.And the few examples compound of the present invention has been even more than positive control CO1686 to the selection inhibitory activity of EGFR mutant cells.
As can be seen from Table 6, compound of the invention has higher IC50 values to NIH3T3 cells, thus it is shown that less toxicity.
Embodiment 43：EGFR T790M inhibitor cytoactives ELISA method is determined
Collocation method and the cell processing of reagent, solution in following methods and lysate preparation process, ELISA detecting steps are according to R＆D DYC3570, and R＆D DYC1095E and R＆D DYC1095BE specification are operated.
First, reagent and solution
Cell lysis buffer solution：1%NP-40,20mM Tris (pH 8.0), 137mM NaCl, 10%glycerol, 1mM NaVO3, 2mM EDTA.
Cell pyrolysis liquid：The μ g/mL Aprotinins of cell lysis buffer solution+10 (Aprotinin) (Sigma), the bright suppression albumen peptases (Leupeptin) (Sigma) of 10 μ g/mL are now with the current.
1x PBSs：NaCl:0.137M, KCl:0.0027M, Na2PO4-12H2O:0.01M, KH2PO4:0.0015M, pH7.4.
Lavation buffer solution：PBS containing 0.05%Tween-20.
Detect antibody diluent：20mM Tris, 137mM NaCl, 0.05%Tween-20,0.1%BSA, pH7.2-7.4.
Confining liquid：PBS containing 1%BSA.
ELISA kit：R＆D DYC3570, R＆D DYC1095E and R＆D DYC1095BE.
2nd, H1975 cells
2.1H1975 it is prepared by cell processing and lysate
(1) by H1975 cells with 1 × 104The density kind in/hole is into 96 orifice plates, per 90 microlitres of hole 10%FBS, 1640 culture mediums, 37 DEG C, 5%CO2Overnight incubation.
(2) testing compound is diluted according to medicine dilution process in MTT experiment, the compound after 10 μ L are diluted or the DMSO after dilution are added in the corresponding aperture of cell wall panel, DMSO final concentration of 0.5%, 37 DEG C, 5%CO2 Culture 1 hour.Cell controls are used as using the cell culture system of pure DMSO processing.
(3) sop up and 100 μ L cell pyrolysis liquids are added after culture medium, shrouding molding is placed in -80 DEG C of refrigerator overnights.Blank control is used as using cell lysis buffer solution.
2.2ELISA detecting step
Specification is given according to R＆D DYC1095E or R＆D DYC1095BE to be operated.
(1) R＆D captures antibody ((DYC1095BE or DYC1095E)) PBS 1:180 dilutions, the μ L/ holes of antibody 100 diluted add ELISA reaction plates (Corning costar 42592), and 25 DEG C of shaking table coatings are stayed overnight；
(2) 360 μ L lavation buffer solutions are washed 3 times；
(3) 300 μ L confining liquids are added, 25 DEG C of shaking tables are incubated 2 hours；
(4) 360 μ L lavation buffer solutions are washed 3 times；
(5) 40 μ L cell lysis buffer solutions and 60 μ L cell pyrolysis liquids are added, 25 DEG C of shaking tables are incubated 2 hours；
(6) 360 μ L lavation buffer solutions are washed 3 times；
(7) detection antibody adds 100 μ L per hole with detection antibody diluent with kit explanation regulation dilution proportion, and 25 DEG C of shaking table lucifuges are incubated 1 hour；
(8) 360 μ L lavation buffer solutions are washed 3 times；
(9) by the A reagents and B reagents in tmb substrate (R＆D DY999) with 1:1 is mixed, and per the μ L of hole 100,25 DEG C of shaking table lucifuges are incubated 20 minutes；
(10)2N H2SO450 μ L are added per hole；
(11) determine the OD 450 in the case of cell controls, blank control and drug-treated respectively with ELIASA read plate (Thermo Multiskan K3) to be worth and OD570 values, and corresponding OD570 values are subtracted with the values of OD 450 of same holes and respectively obtain ODCell、ODBlankAnd ODDrug-treated。
2.3 data analysis
Inhibiting rate (%)=100% × (ODCell-ODDrug-treated)/(ODCell-ODBlank)
2.4 will calculate obtained inhibiting rate calculates IC with the softwares of XLFIT 5.050Value, referring to table 7.
3rd, A431 cells
3.1A431 processing and the testing procedure of cell
(1) by A431 cells with 1 × 104The density kind in/hole is into 96 orifice plates, per 90 microlitres of hole, 37 DEG C of the DMEM culture mediums containing 10%FBS, 5%CO2Overnight incubation.
(2) A431 cell culture mediums are replaced by 90 microlitres of plasma-free DMEM mediums, continue overnight incubation.
(3) testing compound is diluted according to medicine dilution process in MTT experiment, the compound after 10 μ L are diluted or the DMSO after dilution are added in the corresponding aperture of cell wall panel, DMSO final concentration of 0.5%, 37 DEG C, 5%CO2Culture 1 hour.Then 10 microlitre of 2 μ g/L EGF is added in every hole in addition to cell control well, adding 10 microlitres of serum-free DMEM in cell hole cultivates 45 minutes；Cell to be added without EGF and drug-treated is compareed as cell controls using being added without the cell of only addition EGF processing of medicine as EGF.
(4) sop up and 100 μ L cell pyrolysis liquids are added after culture medium, shrouding molding is placed in -80 DEG C of refrigerator overnights.
3.2ELISA detecting step
Operated with reference to R＆D DYC3570E specifications.
(1) R＆D captures antibody (DYC3570E) PBS 1:180 dilutions, the μ L/ holes of antibody 100 diluted add ELISA reaction plates (Corning costar 42592), and 25 DEG C of shaking table coatings are stayed overnight；
(2) 360 μ L lavation buffer solutions are washed 3 times；
(3) 200 μ L confining liquids are added, 25 DEG C of shaking tables are incubated 2 hours；
(4) 360 μ L lavation buffer solutions are washed 3 times；
(5) 40 μ L cell lysis buffer solutions and 60 μ L cell pyrolysis liquids are added, 25 DEG C of shaking tables are incubated 2 hours；
(6) 360 μ L lavation buffer solutions are washed 3 times；
(7) detection antibody adds 100 μ L per hole with detection antibody diluent with kit explanation regulation dilution proportion, and 25 DEG C of shaking table lucifuges are incubated 1 hour；
(8) 360 μ L lavation buffer solutions are washed 3 times；
(9) by the A reagents and B reagents in tmb substrate (R＆D DY999) with 1:1 is mixed, and per the μ L of hole 100,25 DEG C of shaking table lucifuges are incubated 20 minutes；
(10)2N H2SO450 μ L are added per hole；
(11) determine the OD 450 in the case of cell controls, blank control and drug-treated respectively with ELIASA read plate (Thermo Multiskan K3) to be worth and OD570 values, and corresponding OD570 values are subtracted with the values of OD 450 of same holes and respectively obtain ODEGF、ODMedicine、ODCell。
3.3 data analysis
Inhibiting rate (%)=100% × (ODEGF-ODMedicine)/(OD EGF-ODCell)
3.4 will calculate obtained inhibiting rate calculates IC with the softwares of XLFIT 5.050Value, referring to table 7.
The cytoactive ELISA method measurement result of table 7
As can be seen from Table 7, compared with positive control BIBW2992, example compound of the invention has obvious selection inhibitory activity to cellular level target spot.And the selection inhibitory activity of few examples compound has been even more than positive control CO1686, highest improves 6 times.
Shown from vitro enzyme, cell growth inhibition test, the compounds of this invention goes out stronger inhibitory activity to EGFR mutant enzymes, cells show, and go out weaker inhibitory activity to EGFR wild-type enzymes, cells show, therefore such compound has preferably selection inhibitory activity and relatively low cytotoxicity to the T790M EGFR being mutated.
All documents referred in the present invention are all incorporated as reference in this application, are individually recited just as each document as with reference to such.In addition, it is to be understood that after the above-mentioned instruction content of the present invention has been read, those skilled in the art can make various changes or modifications to the present invention, and these equivalent form of values equally fall within the application appended claims limited range.

Claims (10)

  1. A kind of fragrant amino pyrimidines or its pharmaceutically acceptable salt, stereoisomer, solvated compoundses or its prodrug, the structure of the compound is as shown in formula I：
    In formula,
    A is selected from：Substituted or unsubstituted C6-10Aryl, substituted or unsubstituted C5-8Heteroaryl, substituted or unsubstituted C3-8Cycloalkyl, substituted or unsubstituted C3-8Heterocyclylalkyl, substituted or unsubstituted 8-14 members condensed ring group；
    Z1Selected from NR9Or CR10R11；Wherein, R9Selected from hydrogen or C1-6Alkyl；R10、R11It is each independently selected from hydrogen, halogen, C1-6Alkyl；Or R10And R11C is collectively forming with the carbon atom being connected3-8Cycloalkyl or C3-8Heterocyclylalkyl；
    Z2、Z3It is each independently selected from CR12Or N；Wherein, R12Selected from hydrogen, halogen, nitro, amino, C1-6Alkyl-substituted amino, C1-6Amino, cyano group, the C of acyl group substitution1-6The C of alkyl, halo1-6Alkyl, C1-6The C of alkoxy, halo1-6Alkoxy；
    R1Selected from hydrogen or C1-6Alkyl；Or, R1Constituted together with A and their connected nitrogen-atoms selected from following group：Substituted or unsubstituted C5-8Heteroaryl, substituted or unsubstituted C3-8Heterocyclylalkyl or substituted or unsubstituted 8-14 members condensed ring group；
    In above-mentioned group, described " substitution " refers to that one or more of group hydrogen is selected from the substituent of the following group and replaced：Nitro, halogen, cyano group, C1-6The C of alkyl, halo1-6Alkyl, C1-6The C of alkoxy, halo1-6Alkoxy；
    R2Selected from hydrogen, halogen, C1-6Alkyl, halo C1-6Alkyl or C1-6Alkoxy；
    R3、R4、R5It is each independently selected from：Hydrogen, halogen, nitro, amino, C1-6Alkyl-substituted amino, C1-6Amino, the C of acyl group substitution1-6Alkyl-substituted diaminourea, cyano group, C1-6The C of alkyl, halo1-6Alkyl, C1-6Alkoxy, C1-6The C of alkoxy substitution1-6Alkoxy, C6-10The C of aryl substitution1-6The C of alkoxy, halo1-6Alkoxy ,-O-C6-10Aryl ,-CO-C3-6Heterocyclylalkyl ,-CO-N R13R14、C3-6Heteroaryl, C3-6Heterocyclylalkyl, C3-6Heterocyclylalkyl-CO-C1-6Alkyl, C3-6Heterocyclylalkyl-N-C1-6Alkyl, C3-6Heterocyclylalkyl-C1-6Alkyl, C3-6Heterocyclylalkyl-C3-6Heterocyclylalkyl；Optionally, the C6-10Aryl, C3-6Heteroaryl or C3-6Heterocyclylalkyl can be replaced by one or more substituents being selected from the group：Nitro, halogen, cyano group, C1-6The C of alkyl, halo1-6Alkyl, C1-6The C of alkoxy, halo1-6Alkoxy, C1-6Alkyl-substituted amino；Wherein, R13、R14It is each independently selected from hydrogen or C1-6Alkyl；
    R7、R8It is each independently selected from：Hydrogen, halogen, C1-6Alkyl, C3-8Cycloalkyl, C3-8Heterocyclylalkyl, C6-10Aryl or C5-8Heteroaryl.
  2. Compound as claimed in claim 1 or its pharmaceutically acceptable salt, stereoisomer, solvated compoundses or its prodrug, wherein, shown in the structure such as formula (II) of the compound：
    In formula, A, Z2、Z3、R1、R2、R3、R4、R5、R7、R8And R9As defined in claim 1.
  3. Compound as claimed in claim 1 or its pharmaceutically acceptable salt, stereoisomer, solvated compoundses or its prodrug, wherein, shown in the structure such as formula (III) of the compound：
    In formula, A, Z2、Z3、R1、R2、R3、R4、R5、R7、R8、R10And R11As defined in claim 1.
  4. Compound or its pharmaceutically acceptable salt, stereoisomer, solvated compoundses or its prodrug as described in claim any one of 1-3, wherein, (I) A is phenyl ring, or (II) A and R1And their connected nitrogen-atoms constitute piperidines together.
  5. Compound as claimed in claim 1 or its pharmaceutically acceptable salt, stereoisomer, solvated compoundses or its prodrug, wherein, the compound is selected from the group：
    N- (3- (3- (2- ((2- methoxyl groups -4- (4- methylpiperazine-1-yls) phenyl) amino) pyrimidine-4-yl) urea groups) phenyl) acrylamide；
    N- (3- (3- (2- ((4- (4- methylpiperazine-1-yls) phenyl) amino) pyrimidine-4-yl) urea groups) phenyl) acrylamide；
    N- (3- (3- (2- ((5- methoxypyridine -2- bases) amino) pyrimidine-4-yl) urea groups) phenyl) acrylamide；
    N- (3- (3- (2- ((the chloro- 4- of 3- ((3- luorobenzyls) oxygen) phenyl) amino) pyrimidine-4-yl) urea groups) phenyl) acrylamide；
    N- (3- (3- (2- ((2- methoxyl groups -4- (4- (4- methylpiperazine-1-yls) piperidin-1-yl) phenyl) amino) pyrimidine-4-yl) urea groups) phenyl) acrylamide；
    N- (3- (3- (2- ((6- morpholinoes pyridin-3-yl) amino) pyrimidine-4-yl) urea groups) phenyl) acrylamide；
    N- (3- (3- (2- ((2,4- Dimethoxyphenyls) amino) pyrimidine-4-yl) urea groups) phenyl) acrylamide；
    N- (3- (3- (2- ((the chloro- 4- fluorophenyls of 3-) amino) pyrimidine-4-yl) urea groups) phenyl) acrylamide；
    N- (3- (3- (2- ((2- methoxyl groups -4- (4- morpholines piperidin-1-yl) phenyl) amino) pyrimidine-4-yl) urea groups) phenyl) acrylamide；
    N- (3- (3- (2- ((4- (4- (dimethylamino) piperidin-1-yl) -2- anisyls) amino) pyrimidine-4-yl) urea groups) phenyl) acrylamide；
    N- (3- (3- (2- ((4- (piperidin-1-yl) phenyl) amino) pyrimidine-4-yl) urea groups) phenyl) acrylamide；
    N- (3- (3- (2- ((4- (dimethylamino) phenyl) amino) pyrimidine-4-yl) urea groups) phenyl) acrylamide；
    N- (3- (3- (2- ((5- morpholino pyridine -2- bases) amino) pyrimidine-4-yl) urea groups) phenyl) acrylamide；
    N- (3- (3- (2- ((2- methoxyl group -4- morphlinophenyls) amino) pyrimidine-4-yl) urea groups) phenyl) acrylamide；
    N- (3- (3- (2- ((2- methoxyl groups -4- (morpholine -4- carbonyls) phenyl) amino) pyrimidine-4-yl) urea groups) phenyl) acrylamide；
    N- (3- (3- (2- ((2- methoxyl groups -4- (4- methyl piperazine -1- carbonyls) phenyl) amino) pyrimidine-4-yl) urea groups) phenyl) acrylamide；
    4- ((4- (3- (3- acryloyl groups amide phenyl) urea groups) pyrimidine -2-base) amino)-N, N- diethyl -3- methoxy benzamides；
    N- (3- (3- (2- ((4- (2- methoxy ethoxies) phenyl) amino) pyrimidine-4-yl) urea groups) phenyl) acrylamide；
    N- (3- (3- (2- ((2- methoxyl groups -4- (piperidin-1-yl) phenyl) amino) pyrimidine-4-yl) urea groups) phenyl) acrylamide；
    N- (3- (3- (2- ((4- (4- (2- fluoro ethyls) piperazine -1- bases) -2- anisyls) amino) pyrimidine-4-yl) urea groups) phenyl) acrylamide；
    N- (3- (3- (2- ((4- (diethylamino) -2- methoxyphenyls) amino) pyrimidine-4-yl) urea groups) phenyl) acrylamide；
    N- (3- (3- (2- ((4- (4- (diethylamino) piperidin-1-yl) -2- anisyls) amino) pyrimidine-4-yl) urea groups) phenyl) acrylamide；
    N- (3- (3- (2- ((4- (4- ethyl piperazidine -1- bases) -2- methoxyphenyls) amino) pyrimidine-4-yl) urea groups) phenyl) acrylamide；
    N- (3- (3- (2- (4- tolyls) amino) pyrimidine-4-yl) urea groups) phenyl) acrylamide；
    N- (3- (3- (2- ((5- (4- methylpiperazine-1-yls) pyridine -2- bases) amino) pyrimidine-4-yl) urea groups) phenyl) acrylamide；
    N- (3- (3- (2- ((4- fluorophenyls) amino) pyrimidine-4-yl) urea groups) phenyl) acrylamide；
    N- (3- (3- (2- ((4- ethoxyl phenenyls) amino) pyrimidine-4-yl) urea groups) phenyl) acrylamide；
    N- (3- (3- (2- ((2- methoxyphenyls) amino) pyrimidine-4-yl) urea groups) phenyl) acrylamide；
    N- (3- (3- (2- ((4- chlorphenyls) amino) pyrimidine-4-yl) urea groups) phenyl) acrylamide；
    N- (3- (3- (2- ((3,4,5- trimethoxyphenyls) amino) pyrimidine-4-yl) urea groups) phenyl) acrylamide；
    N- (3- (3- (2- ((4- morphlinophenyls) amino) pyrimidine-4-yl) urea groups) phenyl) acrylamide；
    N- (3- (3- (2- ((4- (4- (dimethylamino) piperidin-1-yl) -2- anisyls) amino) pyrimidine-4-yl) -3- methyl urea groups) phenyl) acrylamide；
    3- acrylamidos-N- (2- (2- methoxyl groups -4- (4- morpholino -1- bases) phenyl amino) pyrimidine-4-yl) piperidines -1- formamides；
    3- acrylamidos-N- (2- (2- methoxyl groups -4- (4- methylpiperazine-1-yls) phenyl amino) pyrimidine-4-yl) piperidines -1- formamides；
    3- acrylamidos-N- (2- (2- methoxyl groups -4- (1- methyl piperidine -4- bases) phenyl amino) pyrimidine-4-yl) piperidines -1- formamides；
    3- acrylamidos-N- (2- (4- ((2- (dimethylamino) ethyl) (methyl) amino) -2- Methoxyphenylaminos) pyrimidine-4-yl) piperidines -1- formamides；
    N- (3- (2- (2- (2- methoxyl groups -4- (4- methylpiperazine-1-yls) phenyl amino) pyrimidine-4-yl) -2- methylpropionylaminos) phenyl) acrylamide；
    1- (3- acryloyl groups amide groups) -3- (2- (2- methoxyl groups -4- (4- propylpiperazine -1- bases) phenyl amino) pyrimidine-4-yl) Urea；
    3- (3- acryloyl groups amide groups) -1- (2- (4- ((2- (dimethylamino) ethyl) (methyl) amino) -2- Methoxyphenylaminos) pyrimidine-4-yl) -1- MUs；Or
    1- (3- acryloyl groups amide groups) -3- (the chloro- 2- of 5- (2- methoxyl groups -4- (4- morpholinoes piperidin-1-yl) phenyl amino) pyrimidine-4-yl) urea.
  6. A kind of pharmaceutical composition, the composition includes：Compound or its pharmaceutically acceptable salt, stereoisomer, solvated compoundses or its prodrug described in any one of claim 1 to 5；And pharmaceutically acceptable carrier.
  7. The application of compound or its pharmaceutically acceptable salt, stereoisomer, solvated compoundses or its prodrug in preparing regulation and control EGFR tyrosine kinase activities or treating the medicine of EGFR relevant diseases described in any one of claim 1 to 5.
  8. Application as claimed in claim 7, wherein, described EGFR relevant diseases are selected from：Cancer, diabetes, disease of immune system, nerve degenerative diseases, angiocardiopathy, use during EGFR modulators for treatment have acquired resistance disease.
  9. Application as claimed in claim 8, wherein, the disease of the acquired resistance is that the T790 mutation encoded by EGFR extron 20s are caused or caused comprising the T790 mutation that EGFR extron 20s are encoded.
  10. A kind of Pharmaceutical composition, the Pharmaceutical composition includes：Compound or its pharmaceutically acceptable salt, stereoisomer, solvated compoundses or its prodrug described in claim any one of 1-5；And it is selected from the group the one or more in medicine：Gefitinib, Tarceva, Conmana, Lapatinib, XL647, NVP-AEE-788, ARRY-334543, EKB-569, BIBW2992, HKI272, BMS-690514, CI-1033, ZD6474, PF00299804, WZ4002, Cetuximab, Herceptin, Pa Ni dashes forward monoclonal antibody, matuzumab, Buddhist nun's trastuzumab, prick the wooden monoclonal antibody in Shandong, handkerchief trastuzumab, MDX-214, CDX-110, IMC-11F8, Zemab, Her2 vaccines PX 1041, HSP90 inhibitor, CNF2024, KOS-953, Ah's spiramvcin, IPI-504, SNX-5422, NVP-AUY922, or its combination.
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