CN104860891B - Fragrant amino pyrimidines and its application and pharmaceutical composition prepared therefrom and Pharmaceutical composition - Google Patents

Fragrant amino pyrimidines and its application and pharmaceutical composition prepared therefrom and Pharmaceutical composition Download PDF

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CN104860891B
CN104860891B CN201410064358.0A CN201410064358A CN104860891B CN 104860891 B CN104860891 B CN 104860891B CN 201410064358 A CN201410064358 A CN 201410064358A CN 104860891 B CN104860891 B CN 104860891B
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phenyl
amino
pyrimidine
acrylamide
urea groups
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CN104860891A (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 Hai Yan Pharmaceutical Technology Co., Ltd
Yangtze River Pharmaceutical Group Co Ltd
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Shanghai Hai Yan Pharmaceutical Technology Co Ltd
Yangtze River Pharmaceutical Group Co Ltd
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Priority to CN201580002151.3A priority patent/CN105683168B/en
Priority to PCT/CN2015/073045 priority patent/WO2015127873A1/en
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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
    • A61P37/00—Drugs for immunological or allergic disorders
    • 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

The invention discloses a kind of the fragrant amino pyrimidines and its pharmaceutically acceptable salt, stereoisomer, solvated compoundses or prodrug inhibited to EGFR EGFR-TKs, shown in formula I, the definition of each group refers to specification in formula.Additionally, pharmaceutical composition, Pharmaceutical composition and its application the invention also discloses the compound.

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 as EGFR junket ammonia The application of acid kinase inhibitor, 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, is also Chinese morbidity and mortality highest cancer, according to 2004-2005 Ministry of Public Health statistical report data, lung cancer 2004-2005 Annual death rate is more than 3/10000；And number of the infected is in ascendant trend year by year, additionally, In The Atmosphere Over China is seriously polluted, PM2.5 water It is flat higher following lung cancer morbidity rate to be caused higher.
In lung cancer in China patient, there is 30% patient EGFR to be mutated, and wherein L858R and the deletion mutation of exons 19 are accounted for More than 90%, the activity of EGFR after this kind of patient's mutation is higher, and patient is more sensitive to EGFR inhibitor.It is existing to have listed first For EGFR inhibitor such as Tarceva, Gefitinib is worked well to this kind of patient, and wherein more than 60% patient can be made to swell Knurl reduces, hence it is evident that extension patient's progression free survival phase.But most humans obtained resistance at 6-12 month, the first generation will for Buddhist nun No longer work, and this kind of patient is currently in without medicine upstate.The current irreversible pan-EGFR inhibitor of the second generation is in In the later phase clinical stage, they are mutated to EGFR, and lung cancer patient is evident in efficacy to be better than first generation EGFR inhibitor.But the second generation suppresses Agent is significantly higher than the toxic and side effects such as resistance T790M mutation, patient's fash to Wild type EGFR activity and seriously and to resistance patient treats Effect is poor, and only 7% resistance patient produces response to this kind of medicine.
In lung cancer patient, 90% or so patient has L858R and the deletion mutation of exons 19, EGFR after undergoing mutation Activity is raised, especially sensitive to EGFR inhibitor with both mutant cells growths survival height EGFR dependent signal path, Referred to as sensitizing mutation.The first generation EGFR inhibitor Gefitinib and Tarceva for having listed activity in this kind of sensitive cells It is very strong, sensitizing mutation cell growth can be suppressed in very low concentrations.Such as Gefitinib IC in lung cancer cell line HCC82750 It is 2.5nM, is 4-5nM in lung cancer cell line H3255, is 25nM in PC-9.Clinical discovery EGFR inhibitor resistance patient In 50% occur T790M mutation, first generation EGFR inhibitor Gefitinib and E Luo are replaced in T790M mutational cell lines H1975 Buddhist nun is all higher than 3uM, basic without activity.Albumin crystal diffraction investigation finds that T790M mutation occur the ATP-binding domain in EGFR Domain, the binding ability reduction that EGFR and Gefitinib and Tarceva after T790M mutation occur, and with ATP binding abilities Enhancing, the extension of ATP Dissociation times.Due to first generation EGFR inhibitor be reversible inhibitor, with ATP competition bindings to EGFR on, Then inhibitor is combined reduction to ATP with the increase of EGFR binding abilities, and T790M mutation activity of EGFR is substantially reduced.In order to have Effect suppresses T790M mutation, now many irreversible EGFR inhibitors of exploitation, and they can be with the cysteine of EGFRATP binding sites Irreversible binding, and do not fall off, being capable of the more effective activity that must suppress EGFRT790M.But with BIBW2992, pf299804 is generation The irreversible EGFR inhibitor of the second generation of table is similar with first generation EGFR inhibitor due to structure, so having very strong open country simultaneously Raw type EGFR, Her2 activity, the activity of suppression T790M mutation is far below and suppresses Wild type EGFR.Such as BIBW2992 suppresses resistance to The IC of medicine cell H197550It is 99nM, and suppresses Wild type EGFR Ba/f3 for 0.5nM.Suppress concentration needed for mdr cell growth Far above normal cell, often toxicity is difficult to tolerate under this dosage.
In order to preferably solve resistance problems, the inhibitor of exploitation Selective depression T790M EGFR is a preferably side To.WZ4002 is first T790M selective depressant, and it suppresses H1975IC50It is 47nM, suppresses the double mutation of T790M/L858R Ba/f3 cells IC50Be 8nM but suppress Wild type EGFR Ba/f3 in 113nM.Prior art still suffers from such demand, that is, open The hair more preferable novel compound of activity and selectivity.
The content of the invention
Inventor in-depth study by long-term, it has unexpectedly been found that a kind of fragrant amino pyrimidines, as one The irreversible inhibitor of class EGFR Catastrophic selections, has the advantages that toxic and side effect is low.
It is different it is an object of the invention to provide a kind of fragrant amino pyrimidines or its pharmaceutically acceptable salt, solid Structure body, solvated compoundses or its prodrug.
It is a further object to provide comprising above-mentioned fragrant amino pyrimidines or its is pharmaceutically acceptable The pharmaceutical composition of salt, stereoisomer, solvated compoundses or its prodrug.
Third object of the present invention is to provide above-mentioned fragrant amino pyrimidines and prepares regulation and control EGFR EGFR-TKs The medicine of activity, or prepare the application on treatment EGFR relevant disease medicines.
Specifically, the invention provides a kind of new fragrant amino pyrimidines or its pharmaceutically acceptable salt, Stereoisomer, solvated compoundses or its prodrug, shown in its structure such as formula (I)：
Wherein, 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 units condensed ring radical Group；Wherein, described " substitution " refers to that one or more hydrogen in group are selected from the substitution base of the following group and are replaced：Nitro, halogen Element, cyano group, C1-6The C of alkyl, halo1-6Alkyl, C1-6The C of alkoxy, halo1-6Alkoxy；
Z1Selected from NR9Or CR10R11；
Here, 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；
Here, R12Selected from hydrogen, halogen, nitro, amino, C1-6Alkyl-substituted amino, C1-6Amino, the cyanogen of acyl group substitution Base, C1-6The C of alkyl, halo1-6Alkyl, C1-6The C of alkoxy, halo1-6Alkoxy；
R1Selected from hydrogen or C1-6Alkyl；Or, R1Constituted selected from following group together with the nitrogen-atoms being connected with A and they： Substituted or unsubstituted C5-8Heteroaryl, substituted or unsubstituted C3-8Heterocyclylalkyl or substituted or unsubstituted 8-14 units are thick Cyclic group, wherein, described " substitution " refers to that one or more hydrogen in group are selected from the substitution base of the following group and are replaced：Nitre Base, 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, C1-6Acyl group takes The amino in generation, C1-6Alkyl-substituted diaminourea, cyano group, C1-6The C of alkyl, halo1-6Alkyl, C1-6Alkoxy, C1-6Alkoxy takes The C in generation1-6Alkoxy, C6-10The C of aryl substitution1-6The C of alkoxy, halo1-6Alkoxy ,-O-C6-10Aryl ,-CO-C3-6 Heterocyclylalkyl ,-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 C3-6The substitution base that Heterocyclylalkyl can be selected from the group by one or more replaces：Nitro, halogen, cyano group, C1-6The C of alkyl, halo1-6Alkyl, C1-6The C of alkoxy, halo1-6Alkoxy, C1-6Alkyl-substituted amino；
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 one embodiment of the present invention, formula (I) compound that the present invention is provided is the compound shown in formula (II)：
Wherein, in formula (II), A, Z2、Z3、R1、R2、R3、R4、R5、R7、R8And R9As defined in formula (I).
In one embodiment of the present invention, formula (I) compound that the present invention is provided is the chemical combination shown in formula (III) Thing：
Wherein, in formula (III), A, Z2、Z3、R1、R2、R3、R4、R5、R7、R8、R10And R11As defined in formula (I).
In one embodiment of the present invention, the present invention is provided formula (I) compound, formula (II) compound or formula (III) compound, wherein, R7、R8It is each independently hydrogen.
In one embodiment of the present invention, the present invention is provided formula (I) compound, formula (II) compound or formula (III) compound, wherein, A is benzene.
In one embodiment of the present invention, formula (I) compound that the present invention is provided is the compound shown in formula a：
Wherein, Z1、Z2、Z3、R1、R2、R3、R4、R5、R7、R8As defined in formula (I).
In one embodiment of the present invention, the present invention is provided formula (I) compound, formula (II) compound or formula (III) compound, wherein, A is benzene, and, R7、R8It is each independently hydrogen.
In one embodiment of the present invention, the present invention is provided formula (I) compound, formula (II) compound or formula (III) compound, wherein, R1Piperidines is constituted together with the nitrogen-atoms being connected with A and they.
In one embodiment of the present invention, formula (I) compound that the present invention is provided is the compound shown in formula b：
Wherein, Z1、Z2、Z3、R2、R3、R4、R5、R7、R8As defined in formula (I).
In one embodiment of the present invention, the present invention is provided formula (I) compound, formula (II) compound or formula (III) compound, wherein, R1Piperidines is constituted together with the nitrogen-atoms being connected with A and they, and, R7、R9It is each independently hydrogen.
The example compound of the above-mentioned fragrant amino pyrimidines provided as the present invention, the invention provides being selected from down The compound of row, 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) benzene Base) acrylamide (cpd-1)；
N- (3- (3- (2- ((4- (4- methylpiperazine-1-yls) phenyl) amino) pyrimidine-4-yl) urea groups) phenyl) acryloyl Amine (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) propylene Acid amides (cpd-4)；
N- (3- (3- (2- ((2- methoxyl groups -4- (4- (4- methylpiperazine-1-yls) piperidin-1-yl) phenyl) amino) pyrimidine - 4- yls) 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- Dimethoxyphenyl) 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) benzene Base) acrylamide (cpd-9)；
N- (3- (3- (2- ((4- (4- (dimethylamino) piperidin-1-yl) -2- anisyls) amino) pyrimidine-4-yl) ureas Base) 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) third 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- methoxyl groups Benzamide (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) propylene Acid amides (cpd-19)；
N- (3- (3- (2- ((4- (4- (2- fluoro ethyls) piperazine -1- bases) -2- anisyls) amino) pyrimidine-4-yl) ureas Base) phenyl) acrylamide (cpd-20)；
N- (3- (3- (2- ((4- (diethylamino) -2- methoxyphenyls) amino) pyrimidine-4-yl) urea groups) phenyl) third Acrylamide (cpd-21)；
N- (3- (3- (2- ((4- (4- (diethylamino) piperidin-1-yl) -2- anisyls) amino) pyrimidine-4-yl) ureas Base) phenyl) acrylamide (cpd-22)；
N- (3- (3- (2- ((4- (4- ethyl piperazidine -1- bases) -2- methoxyphenyls) amino) pyrimidine-4-yl) urea groups) benzene Base) 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) third 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- trimethoxyphenyl) 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) piperazine Pyridine -1- formamides (cpd-34)；
3- acrylamidos-N- (2- (2- methoxyl groups -4- (1- methyl piperidine -4- bases) phenyl amino) pyrimidine-4-yl) piperazine Pyridine -1- formamides (cpd-35)；
3- acrylamidos-N- (2- (4- ((2- (dimethylamino) ethyl) (methyl) amino) -2- methoxyphenyl ammonia Base) pyrimidine-4-yl) piperidines -1- formamides (cpd-36)；Or
N- (3- (2- (2- (2- methoxyl groups -4- (4- methylpiperazine-1-yls) phenyl amino) pyrimidine-4-yl) -2- methyl-props Acylamino-) phenyl) acrylamide (cpd-37).
In the above-mentioned fragrant amino pyrimidines that the present invention is provided, described alkyl, as group or other bases The alkyl of a part for group, such as halogen substitution, the alkyl of hydroxyl substitution, can be straight chain or side chain.For example, C1-6 Alkyl represents 1 to 6 alkyl of carbon, including but not limited to methyl, ethyl, propyl group, isopropyl, normal-butyl, isobutyl group, Zhong Ding Base, the tert-butyl group, n-pentyl, n-hexyl.
In the above-mentioned fragrant amino pyrimidines that the present invention is provided, " alkoxy " refers to that alkyl connects with oxygen atom Generation group after knot, 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 be connected by alkyl Diaminourea, such as ethylenediamine, propane diamine, butanediamine；And, the amino of end can be replaced by alkyl, such as N, N, N '-front three Base butanediamine base.
In the above-mentioned fragrant amino pyrimidines that the present invention is provided, " halogen " refers to fluorine, chlorine, bromine and iodine.It is especially excellent Choosing is fluorine and chlorine.
In the above-mentioned fragrant amino pyrimidines that the present invention is provided, " aryl " refers to comprising six to ten carbon atoms The monocyclic or aromatic hydrocarbon ring (such as phenyl and naphthyl) that condenses.
In the above-mentioned fragrant amino pyrimidines that the present invention is provided, " heteroaryl " refers to any condensing or non-condensed Aromatic ring system, wherein at least one ring is to arrive octatomic ring selected from heteroatomic the five of nitrogen, oxygen and sulphur containing 1-4, preferably at least One hetero atom is selected from nitrogen.Heteroaryl includes but is not limited to thienyl, furyl, imidazole radicals, pyrazolyl, thiazolyl, oxazole Base, 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 former comprising the carbon for specifying number The undersaturated monocyclic, condensed ring in saturation or part or bridged ring of son.For example, C3-8Cycloalkyl refers to three to eight cycloalkyl of carbon, Including cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl etc..
In the above-mentioned fragrant amino pyrimidines that the present invention is provided, " Heterocyclylalkyl " refers to defined in the present invention Cycloalkyl, the carbon atom on wherein one or more rings is by oxygen, nitrogen ,-NR-, sulphur, carbonyl ,-S (O)-or-S (O)2- wait group to take Generation；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, third Acyl group, bytyry, valeryl, caproyl.
In the above-mentioned fragrant amino pyrimidines that the present invention is provided, " condensed ring group " refers to two or more carbon The polycyclic organic compound that ring or heterocycle are formed with having ring side.Such as naphthalene, anthracene, anthraquinone, phenanthrene.
In the above-mentioned fragrant amino pyrimidines that the present invention is provided, " pharmaceutically acceptable salt " can connect including pharmacy The acid-addition salts and pharmaceutically acceptable base addition salts received." pharmaceutically acceptable acid-addition salts " are to refer to retain free alkali Biological effectiveness and without other side effects, the salt formed with inorganic acid or organic acid.Inorganic acid salt is included but is not limited to Hydrochloride, hydrobromate, sulfate, phosphate etc.；Acylate includes but is not limited to formates, acetate, propionate, ethanol Hydrochlorate, gluconate, lactate, oxalates, maleate, succinate, fumarate, tartrate, citrate, paddy ammonia Hydrochlorate, aspartate, benzoate, mesylate, tosilate and salicylate etc..These salt can be by this specialty It is prepared by known method.
The salt of pharmaceutically acceptable base addition salts, including but not limited to 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 by this specially It is prepared by method known to industry.
In compound of the invention, some formula (I) compounds there may be more than one crystal formation, and the present invention includes various Crystal formation and its mixture.
" solvate " referred in the present invention refers to the complex that compound of the invention is formed with solvent.They or Reaction or Precipitation or crystallized out from solvent in a solvent.For example, a complex formed with water is referred to as " water Compound ".The solvate of formula (I) compound belongs within the scope of the invention.
Compound shown in formula (I) of the present invention can contain one or more chiral centres, and with different optical activities Form is present.When compound contains a chiral centre, compound includes enantiomter.The present invention includes both isomeries The mixture of body and isomers, such as racemic mixture.Enantiomter can be split by method known in the art, for example The method such as crystallization and chiral chromatogram.When formula (I) compound contains more than one chiral center, there may be diastereo-isomerism Body.The present invention includes the mixture of the optically pure specific isomers and diastereoisomer for splitting.Diastereoisomer Can be split by method known in the art, such as crystallization and preparative chromatography.
Prodrug of the present invention including above-claimed cpd.Prodrug includes known amino protecting group and carboxyl-protecting group, in life It is hydrolyzed under the conditions of reason or obtains parent compound via enzyme reaction release.Medicament preparation can refer to before specific (Saulnier, M.G.；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.).
Second aspect, the invention provides the preparation method of above-mentioned fragrant amino pyrimidines, the chemical combination in the present invention Thing can easily be prepared by various synthetic operations, and these operations are that one of ordinary skill in the art skillfully grasp.These are changed The specific preparation method of compound can include but is not limited to flow hereinafter described.
The preferred synthetic route of formula (I) compound of the present invention has following three kinds, and particular compound can join in following examples Be prepared according to following synthetic routes, in specific operation process, the step in method can be extended as needed or Merge.
Synthetic route 1
Step 1-1：
The Z that pyrimidine is 41H reacts with aminated compounds, changes into corresponding amides compound, and reaction need to be in a constant temperature Under degree, can just be carried 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, can just enter using suitable catalyst and appropriate solvent OK.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, used Alkali can be but not limited to cesium carbonate.
Step 1-3：
The nitro compound is converted into corresponding amine compound (can be able to be but do not limited with metal in acid condition In iron powder, zinc powder) or stannous chloride reduced；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 in the presence of condensing agent with Corresponding carboxylic acid is condensed into acid amides.
Synthetic route 2
Step 2-1：
The Z that pyrimidine is 41H reacts with aminated compounds, changes into corresponding amides compound, and reaction need to be in a constant temperature Under degree, can just be carried 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 (can be able to be but do not limited with metal in acid condition In iron powder, zinc powder) or stannous chloride reduced；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 the presence of condensing agent with Corresponding carboxylic acid is condensed into acid amides.
Step 2-4：
The chlorine that pyrimidine is 2 is replaced with amine, needs at a certain temperature, can just enter using suitable catalyst and appropriate solvent OK.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 (4,5- is double (diphenylphosphine) -9,9- dimethyl xanthene), 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, can just enter using suitable catalyst and appropriate solvent OK.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, used Alkali 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 need to be in a constant temperature Under degree, can just be carried 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 (can be able to be but do not limited with metal in acid condition In iron powder, zinc powder) or stannous chloride reduced；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 in the presence of condensing agent with Corresponding carboxylic acid is condensed into acid amides.
The third aspect, the invention provides a kind of pharmaceutical composition, it includes compound or pharmacy described in any of the above-described Acceptable salt, solvate or prodrug, and also including pharmaceutically acceptable carrier.A kind of drug regimen that the present invention is provided Thing, 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, solvent Compound or its prodrug；And pharmaceutically acceptable carrier.
Generally, the compounds of this invention or its pharmaceutically acceptable salt can form suitable with one or more pharmaceutical carrier Formulation is applied.These formulations are applied to oral, rectally, local administration, intraoral administration and other parenteral routes and apply (example Such as, subcutaneous, muscle, vein etc.).For example, the suitable formulation being administered orally is including capsule, tablet, granule and syrup etc..This The compound of the invention included in a little preparations can be solid powder or particle；Solution in aqueous or non-aqueous liquid or Suspension；Water-In-Oil or oil-in-water emulsion etc..Above-mentioned formulation can be passed through by reactive compound and one or more carrier or auxiliary material It is made up of 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..For The carrier of liquid preparation is including water, physiological saline, D/W, ethylene glycol and polyethylene glycol etc..Reactive compound can be with Above-mentioned carrier forms solution or suspension.
Fourth aspect, the invention provides the compound described in any of the above-described or its pharmaceutically acceptable salt, solvent Compound or prodrug can be used to prepare the medicine of regulation and control EGFR tyrosine kinase activities, or the medicine for preparing treatment EGFR relevant diseases In application, preferably, the EGFR relevant diseases be cancer, diabetes, disease of immune system, nerve degenerative diseases Or angiocardiopathy.
Preferably, the cancer is non-small cell lung cancer, head and neck cancer, breast cancer, kidney, cancer of pancreas, cervix cancer, food Road cancer, cancer of pancreas, prostate cancer, carcinoma of urinary bladder, colorectal cancer, oophoroma, stomach cancer, brain cancer include spongioblastoma Deng, or any combination of them.
Any of the above-described compound or pharmaceutically acceptable salt thereof of the invention, solvate or its prodrug can also be used to prepare treatment The disease of EGFR unconventionality expressions, or there is the disease of acquired resistance for preparing during using EGFR modulators for treatment.
The acquired resistance is the drug resistance that the T790 mutation encoded by EGFR extron 20s cause, such as T790M.
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.
Pharmaceutical composition of the invention, including compound described in any of the above-described of therapeutically effective amount or its pharmaceutically may be used The salt of receiving, solvate or prodrug, and it is selected from the group one or more in medicine：Gefitinib, Tarceva, Ai Ke For Buddhist nun, Lapatinib, XL647, NVP-AEE-788, ARRY-334543, EKB-569, BIBW2992, HKl272, BMS- 690514th, CI-1033, ZD6474, PF00299804, wZ4002, Cetuximab, Herceptin, handkerchief Buddhist nun prominent monoclonal antibody, horse Trastuzumab, Buddhist nun's trastuzumab, the wooden monoclonal antibody in bundle Shandong, handkerchief trastuzumab, MDX-214, CDX-110, IMC-11F8, Zemab, Her2 Vaccine PX1041, HSP90 inhibitor, CNF2024, KOS-953, Ah's spiramvcin, IPI-504, SNX-5422, NVP- AUY922 or its combination.It is above-mentioned in addition to compound of the invention or its pharmaceutically acceptable salt, solvate or prodrug Other drugs in Pharmaceutical composition are antineoplastic well known to those skilled in the art.
" therapeutically effective amount " can produce function or activity to people and/or animal and can be connect by people and/or animal The amount received.
The compounds of this invention contained in described pharmaceutical composition of the invention or the Pharmaceutical composition or its pharmaceutically The therapeutically effective amount of acceptable salt, solvate or its prodrug is preferably 0.1mg-5g/kg (body weight).
Described Pharmaceutical composition can be used to treat the disease of EGFR unconventionality expressions, such as cancer, diabetes, immune system disease Disease, nerve degenerative diseases or angiocardiopathy.
The disease of the acquired resistance is that the T790 mutation encoded by EGFR extron 20s are caused, or bag Caused by the T790 mutation of the coding of extron 20 containing EGFR.
In another preference, the T790 of described EGFR extron 20s coding is T790M.
Compound of the invention expected can control curative effect with other drugs use in conjunction in some diseases to reach Really.The example of one use in conjunction is for treating advanced NSCLC.For example, by chemical combination shown in the formula I of therapeutically effective amount Thing and mTOR inhibitors combination (such as rapamycin)；Or with Met inhibitor (including Met antibody MetMAb and Met small molecule press down Preparation PF02341066) combination；Or it is combined (such as OSI-906) with IGF1R inhibitor；Or be combined with heat shock protein inhibitors Deng.Preparation method, medicine composition and therapeutic scheme the invention discloses a class compound and compound, people in the art Member can use for reference present disclosure, be suitably modified technological parameter realization.In particular, all similar replacements and change Apparent to those skilled in the art, they are considered as being included in the present invention.Product of the invention, method and Using being described by preferred embodiment, related personnel can substantially not depart from present invention, spirit and scope It is interior to realize and apply the technology of the present invention to method described herein and using being modified or suitably changing with combining.
It should be understood that within the scope of the present invention, above-mentioned each technical characteristic of the invention and have in below (eg embodiment) Can be combined with each other between each technical characteristic of body description, so as to constitute new or preferred technical scheme.
The present invention provide a kind of fragrant amino pyrimidines, as a class EGFR Catastrophic selections can not retroactive inhibition Agent, vitro enzyme, cell experiment show that it can suppress L858R-T790M enzymes and double mutant clone H1975 under nanomolar concentration Propagation；And the suppression to Wild type EGFR and cell line A431 is then relatively weak.Its Catastrophic selection is substantially reduced because of suppression Wild type EGFR processed and the toxic and side effect that produces, 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.
Specific embodiment
In order that those skilled in the art more fully understands technical scheme, with reference to specific embodiment pair The present invention is described in further detail.
In the present invention, the structure of compound be by nuclear magnetic resonance (1H NMR) and/or LC-MS mass spectrum (LC-MS) Determine.1HNMR displacements (δ) are given with the unit of hundred a ten thousandths (ppm).1The measure of H NMR is to use Bruker AVANCE- 400 nuclear magnetic resonance spectrometers, measure solvent is deuterated methanol (CD3OD), deuterochloroform (CDCl3), hexadeuterated dimethyl sulfoxide (DMSO-d6), Inside it is designated as tetramethylsilane (TMS).
Product purity is determined and determined by LC-MS.The measure of LC-MS Agilent1200HPLCSystem/6140MS liquid Matter is combined mass spectrograph (manufacturer：Agilent), pillar Waters X-Bridge, 150 × 4.6mm, 3.5 μm.
Preparative high-performance liquid chromatographic (pre-HPLC) Waters PHW007, pillar XBridgeC18,4.6*150mm, 3.5um。
Using ISCOCombiflash-Rf75 or Rf200 types it is automatic cross post instrument, Agela4g, 12g, 20g, 40g, 80g, The disposable silicagel columns of 120g.
Tlc silica gel plate uses Yantai Huanghai Sea HSGF254 or Qingdao GF254 silica gel plates, thin-layered chromatography (TLC), inspection The specification for surveying the silica gel plate use that reaction is used is 0.15mm~0.2mm, and thin-layered chromatography isolates and purifies the silica gel that product is used The specification that plate is used is 0.4mm~0.5mm.It is carrier that silica gel generally uses the mesh silica gel of Yantai Huanghai Sea silica gel 200~300.Alkalescence It is carrier that alumina column generally uses traditional Chinese medicines chromatography FCP200~300 mesh alkali alumina.
Known initiation material of the 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 science and technology (Accela ChemBio Inc) and bought up at 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 about 1L volumes.
Nitrogen atmosphere refers to that reaction bulb connects a hydrogen balloon for about 1L volumes, 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 the reaction process in embodiment uses thin-layered chromatography (TLC), reacts the system of used solvent It is selected from：In dichloromethane and methanol system, n-hexane and ethyl acetate system, petroleum ether and ethyl acetate system and acetone system One or more；The volume ratio of solvent is adjusted according to the polarity difference of compound.
The system of the solvent of the system or thin-layered chromatography of the eluant, eluent of the column chromatography that purifying compound is used may be selected from： One kind or many in A, dichloromethane and methanol system, B, n-hexane and ethyl acetate system and C, dichloromethane and acetone system Kind, the volume ratio of solvent is different according to the polarity of compound and be adjusted, it is also possible to add the alkalescence such as a small amount of triethylamine or The acid reagents such as acetic acid are adjusted.
In present specification, it is following write a Chinese character in simplified form expression be：
DMF：Dimethylformamide, DMSO：Dimethyl sulfoxide (DMSO), THF：Tetrahydrofuran, DIEA：DIPEA, EA：Ethyl acetate, PE：Petroleum ether.
In following examples, room temperature refers to 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) and sodium cyanoborohydride (2.8g, 43.8mmol) be positioned in the stand up reaction bottle of 500mL, add methyl alcohol 200ml dissolving, add afterwards 1- methyl piperazines (3.2g, 32.1mmol) and glacial acetic acid (1ml) and keep reaction system at ambient temperature overnight.Extent of reaction is detected by TLC, bottom is treated After thing reacts completely, reaction solution ethyl acetate/aqueous systems are extracted three times, isolate organic layer, through washing, saturated common salt washing Wash, after anhydrous sodium sulfate drying, be concentrated under reduced pressure to give crude product.4- (4- methyl piperazines are obtained through the purifying of Combi-Flash column chromatographies Piperazine -1- bases) piperidines -1- t-butyl formates (6.5g, 79%).Spectral data：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) is added to 100 In milliliter hydrochloric acid dioxane solution, it is stirred vigorously at room temperature 4 hours.After reaction terminates, reaction solution is concentrated under reduced pressure, obtains 1- Methyl -4- (piperidin-4-yl) piperazine (4.2g, 100%).Spectral data：MS m/z(ESI)：184.1[M+H]+
Step 3：
By 1- methyl -4- (piperidin-4-yl) piperazine (4.2g, 22.9mmol), the fluoro- 2- methoxyl groups -1- nitrobenzene of 4- (4.69g, 25.2mmol) and potassium carbonate (9.48g, 68.7mmol) are positioned in the stand up reaction bottle of 250mL, add DMF (100mL) is partly dissolved substrate, keeps reaction system to be heated 4 hours under 100 degrees celsius.Detected by TLC and reacted Progress, after substrate reacts completely, filters off insoluble matter, is concentrated under reduced pressure to give yellow solid 1- (1- (3- methoxyl group -4- nitrobenzene Base) piperidin-4-yl) -4- methyl piperazines, obtain target product 4a (6g, 78%) through the purifying of Combi-Flash column chromatographies.Wave spectrum Data：MS m/z (ESI)：335.1[M+H]+
Step 4：
At room temperature, by palladium carbon (0.6g, 10%wt) be added to 1- (1- (3- methoxyl group -4- nitrobenzophenones) piperidin-4-yl) - In 200 ml methanol solution of 4- methyl piperazines (6g, 17.9mmol), room temperature is stirred vigorously 20 hours in a hydrogen atmosphere.Instead After should terminating, palladium carbon is filtered off, filtrate decompression is concentrated, product 2- methoxyl groups -4- (4- (4- methylpiperazine-1-yls) piperidines -1- Base) aniline, it is directly used in next step reaction.Spectral data：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 10 milliliters of morpholine solutions, at room temperature acutely Stirring 4 hours.After reaction terminates, there is yellow solid to separate out.After filtering, with 50 milliliters of petroleum ether yellow solids, 4- is obtained (5- nitropyridine -2- bases) morpholine (1.9g, 92%).Spectral data：MS m/z (ESI)：210.1[M+H]+
Step 2：
At room temperature, palladium carbon (100mg, 10%wt) is added to 4- (5- nitropyridine -2- bases) morpholine (1g, 9.1mmol) 60 ml methanol solution in, room temperature is stirred vigorously 20 hours in a hydrogen atmosphere.After reaction terminates, palladium carbon is filtered off, by filtrate It is concentrated under reduced pressure, product 3- amino -6- morpholine yl pyridines are obtained, it is directly used in next step reaction.Spectral data：MS m/z (ESI)： 180.1[M+H]+
Intermediate 3
The preparation of 2- methoxyl groups -4- (4- morpholino -1- bases) aniline
Step 1：
4- oxo-piperidine -1- t-butyl formates (5g, 29.2mmol) and sodium cyanoborohydride (2.8g, 43.8mmol) are put It is placed in the stand up reaction bottle of 500mL, adds methyl alcohol 200mi dissolvings, morpholine (2.8g, 32.1mmol) and glacial acetic acid is added afterwards (1ml) and keep reaction system at ambient temperature overnight.Extent of reaction is detected by TLC, after substrate reacts completely, reaction Liquid ethyl acetate/aqueous systems are extracted three times, isolate organic layer, through washing, saturated common salt water washing, anhydrous sodium sulfate drying Afterwards, it is concentrated under reduced pressure to give crude product.4- morpholino piperidines -1- t-butyl formates are obtained through the purifying of Combi-Flash column chromatographies (6g, 76%).Spectral data：MS m/z (ESI)：271.1[M+H]+
Step 2：
At room temperature, 4- morpholinoes piperidines -1- t-butyl formates (6g, 22.2mmol) is added to 100 milliliters of hydrochloric acid dioxies In six ring solution, it is stirred vigorously at room temperature 4 hours.After reaction terminates, reaction solution is concentrated under reduced pressure, obtains 4- (piperidin-4-yl) Morpholine (3.8g, 100%).Spectral data：MSm/z (ESI)：171.1[M+H]+
Step 3：
By 4- (piperidin-4-yl) morpholine (3.8g, 22.2mmol), the fluoro- 2- methoxyl groups -1- nitrobenzene of 4- (4.18g, 24.42mmol) it is positioned in the stand up reaction bottle of 250mL with potassium carbonate (9.19g, 66.6mmol), adds DMF (50mL) to make bottom Thing is partly dissolved, and keeps reaction system to be heated 4 hours under 100 degrees celsius.Extent of reaction is detected by TLC, substrate is treated After reacting completely, insoluble matter is filtered off, be concentrated under reduced pressure to give yellow solid, 4- (1- are obtained through the purifying of Combi-Flash column chromatographies (3- methoxyl group -4- nitrobenzophenones) piperidin-4-yl) morpholine (5.8g, 81%).Spectral data：MS m/z (ESI)：322.1[M+ H]+
Step 4：
At room temperature, palladium carbon (0.58g, 10%wt) is added to 4- (1- (3- methoxyl group -4- nitrobenzophenones) piperidin-4-yl) In 200 ml methanol solution of morpholine (5.8g, 18.1mmol), room temperature is stirred vigorously 20 hours in a hydrogen atmosphere.Reaction knot Shu Hou, filters off palladium carbon, and filtrate decompression is concentrated, and product 2- methoxyl groups -4- (4- morpholino -1- bases) aniline is directly used in next Step reaction.Spectral data：MSm/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, the fluoro- 2- methoxyl groups -1- nitrobenzene of N- lupetidine -4- amine (5g, 39mmol) and 4- (10.95g, 58.6mmol) it is positioned in the stand up reaction bottle of 500mL with potassium carbonate (16.15g, 117mmol), adds DMF (150mL) to make bottom Thing is partly dissolved, and keeps reaction system to be heated 4 hours under 100 degrees celsius.Extent of reaction is detected by TLC, substrate is treated After reacting completely, insoluble matter is filtered off, be concentrated under reduced pressure to give yellow solid, 1- (3- first is obtained through the purifying of Combi-Flash column chromatographies Epoxide -4- nitrobenzophenones)-N, N- lupetidine -4- amine (7.5g, 69%).Spectral data：MSm/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-- dimethyl In the 200 ml methanol solution of piperidines -4- amine (7.5g, 26.8mmol), room temperature is stirred vigorously 20 hours in a hydrogen atmosphere.Instead After should terminating, palladium carbon is filtered off, filtrate decompression is concentrated, product 1- (4- amino -3- methoxyphenyls)-N, N- lupetidines - 4- amine, is directly used in next step reaction.Spectral data：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 positioned over In the stand up reaction bottle of 250mL, DMF (100mL) is added to be partly dissolved substrate.Morpholine (3.3mL, 38.6mmol) is added afterwards And keep reaction system to be heated 2 hours under 100 degrees celsius.Extent of reaction is detected by TLC, treats that substrate reacts completely Afterwards, reaction solution ethyl acetate/aqueous systems are extracted three times, isolate organic layer, through washing, saturated common salt water washing, anhydrous sulphur After sour sodium is dried, crude product 4- (3- methoxyl group -4- nitrobenzophenones) morpholine is concentrated under reduced pressure to give, is directly used in the next step.Ripple Modal data：MS m/z (ESI)：238.1[M+H]+
Step 2：
At room temperature, palladium carbon (500mg, 10%wt) is added to 100 milliliters of 4- (3- methoxyl group -4- nitrobenzophenones) morpholine In methanol solution, room temperature is stirred vigorously reaction overnight in a hydrogen atmosphere.After reaction terminates, palladium carbon is filtered off, filtrate decompression is concentrated, Product 2- methoxyl group -4- morpholines aniline (4.5g, two step yields 84%), are directly used in next step reaction.Spectral data：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 10 milliliters of morpholine solutions, are acutely stirred at room temperature Mix 4 hours.After reaction terminates, there is yellow solid to separate out.After filtering, with 50 milliliters of petroleum ether yellow solids, 4- (6- are obtained Nitropyridine -3- bases) morpholine (530mg, 53%).Spectral data：MS m/z (ESI)：210.1[M+H]+
Step 2：
At room temperature, by palladium carbon (60mg, 10%wt) be added to 4- (6- nitropyridine -3- bases) morpholine (600mg, In 30 ml methanol solution 2.86mmol), room temperature is stirred vigorously 20 hours in a hydrogen atmosphere.After reaction terminates, palladium is filtered off Carbon, filtrate decompression is concentrated, and obtains product 2- amino -5- (4- morpholinyls) pyridine, is directly used in next step reaction.Wave spectrum number According to：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 positioned over In the stand up reaction bottle of 60mL, DMF (60mL) is added to be partly dissolved substrate.Piperidines (950mg, 11.1mmol) is added afterwards And keep reaction system to be heated 6 hours under 100 degrees celsius.Extent of reaction is detected by TLC, treats that substrate reacts completely Afterwards, reaction solution ethyl acetate/aqueous systems are extracted three times, isolate organic layer, through washing, saturated common salt water washing, anhydrous sulphur After sour sodium is dried, crude product is concentrated under reduced pressure to give.1- (3- methoxyl group -4- nitrobenzene is obtained through the purifying of Combi-Flash column chromatographies Base) piperidines (2.2g, 85%).Spectral data：MS m/z (ESI)：237.1[M+H]+Step 2：
At room temperature, by palladium carbon (200mg, 10%wt) be added to 1- (3- methoxyl group -4- nitrobenzophenones) piperidines (2g, In 60 ml methanol solution 8.44mmol), room temperature is stirred vigorously 20 hours in a hydrogen atmosphere.After reaction terminates, palladium is filtered off Carbon, filtrate decompression is concentrated, product 2- methoxyl groups -4- (piperidin-1-yl) aniline, is directly used in next step reaction.Spectral data： 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 positioned over In the stand up reaction bottle of 500mL, DMF (100mL) is added to be partly dissolved substrate.1- tert-butoxycarbonyl-piperazines are added afterwards (8.2g, 43.8mmol) and reaction system is kept to be heated 4 hours under 100 degrees celsius.Extent of reaction is detected by TLC, After substrate reacts completely, reaction solution ethyl acetate/aqueous systems are extracted three times, isolate organic layer, through washing, saturated common salt Water washing, after anhydrous sodium sulfate drying, is concentrated under reduced pressure to give crude product.4- (3- first is obtained through the purifying of Combi-Flash column chromatographies Epoxide -4- nitrobenzophenones) piperazine -1- carboxylic acid tert-butyl esters (8.1g, 82%).Spectral data：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) is added to In 100 milliliters of hydrochloric acid dioxane solutions, it is stirred vigorously at room temperature 1 hour.After reaction terminates, reaction solution is concentrated under reduced pressure, obtained To 1- (3- methoxyl group -4- nitrobenzophenones) piperazine (5.6g, 95%).Spectral data：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 put It is placed in the tube sealing reaction of 25mL bottle, adds acetonitrile (6mL) to be partly dissolved substrate.The bromo- 2- fluoroethanes of 1- are added afterwards (290mg, 2.3mmol) and reaction system is kept to heat at 80 degrees celsius 7 hours.Extent of reaction is detected by TLC, is treated After substrate reacts completely, insoluble matter is filtered off, be concentrated under reduced pressure to give yellow solid 1- (2- fluoro ethyls) -4- (3- methoxyl group -4- nitros Phenyl) piperazine (350mg, 59%).Spectral data：MS m/z (ESI)：284.1[M+H]+
Step 4：
At room temperature, palladium carbon (35mg, 10%wt) is added to 1- (2- fluoro ethyls) -4- (3- methoxyl group -4- nitrobenzophenones) In 50 ml methanol solution of piperazine (350mg, 1.24mmol), room temperature is stirred vigorously 20 hours in a hydrogen atmosphere.Reaction knot Shu Hou, filters off palladium carbon, filtrate decompression is concentrated, product 4- (4- (2- fluoro ethyls) piperazine -1- bases) -2- aminoanisoles, directly For next step reaction.Spectral data：MS m/z (ESI)：254.1[M+H]+
Intermediate 9
N1, N1The preparation of-diethyl -3- methoxybenzenes-Isosorbide-5-Nitrae-diamines
Step 1：
By diethylamine (1g, 13.7mmol) and the fluoro- 2- methoxyl groups -1- nitrobenzene (3.84g, 20.5mmol) of 4- and potassium carbonate (5.67g, 41.1mmol) is positioned in the stand up reaction bottle of 500mL, adds DMF (50mL) to be partly dissolved substrate, keeps anti- System is answered to be heated 4 hours under 100 degrees celsius.Extent of reaction is detected by TLC, after substrate reacts completely, is filtered off not Molten thing, is concentrated under reduced pressure to give yellow solid, and N, N- diethyl -3- methoxyl group -4- nitre are obtained through the purifying of Combi-Flash column chromatographies Base aniline (1.8g, 58%).Spectral data：MS m/z (ESI)：225.1[M+H]+
Step 2：
At room temperature, palladium carbon (0.22g, 10%wt) is added to N, the diethyl -3- methoxyl group -4- nitroanilines of N-- bis- In the 200 ml methanol solution of (1.8g, 8.04mmol), room temperature is stirred vigorously 20 hours 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 anti- Should.Spectral data：MSm/z (ESI)：195.1[M+H]+
Intermediate 10
The preparation of 1- (4- amino -3- methoxyphenyls)-N, N- diethyl phenylpiperidines -4- amine
Step 1：
4- oxo-piperidine -1- t-butyl formates (5g, 29.2mmol) and sodium cyanoborohydride (2.8g, 43.8mmol) are put It is placed in the stand up reaction bottle of 500mL, adds methyl alcohol 200ml dissolvings, diethylamine (2.3g, 32.1mmol) and ice vinegar is added afterwards Sour (1ml) and keep reaction system at ambient temperature overnight.Extent of reaction is detected by TLC, after substrate reacts completely, instead Answer liquid ethyl acetate/aqueous systems to extract three times, isolate organic layer, through washing, saturated common salt water washing, anhydrous sodium sulfate is done After dry, crude product is concentrated under reduced pressure to give.4- (diethylamino) piperidines -1- formic acid is obtained through the purifying of Combi-Flash column chromatographies The tert-butyl ester (5.2g, 70%).Spectral data：MS m/z (ESI)：257.2[M+H]+
Step 2：
At room temperature, 4- (diethylamino) piperidines -1- t-butyl formates (5.2g, 20.2mmol) is added to 100 milliliters In hydrochloric acid dioxane solution, it is stirred vigorously at room temperature 4 hours.After reaction terminates, reaction solution is concentrated under reduced pressure, obtains N, N-- Two diethyl phenylpiperidines -4- amine (3.1g, 100%).Spectral data：MS m/z (ESI)：157.1[M+H]+
Step 3：
By N, the fluoro- 2- methoxyl groups -1- nitrobenzene of N-- bis--ethyl piperidine -4- amine (3.1g, 20.2mmol) 4- (4.53g, 24.2mmol) it is positioned in the stand up reaction bottle of 250mL with potassium carbonate (8.36g, 60.6mmol), adds DMF (100mL) to make bottom Thing is partly dissolved, and keeps reaction system to be heated 4 hours under 100 degrees celsius.Extent of reaction is detected by TLC, substrate is treated After reacting completely, insoluble matter is filtered off, be concentrated under reduced pressure to give yellow solid, N, N- are obtained through the purifying of Combi-Flash column chromatographies-Two Diethyl -1- (3- methoxyl group -4- nitrobenzophenones) piperidines -4- amine (5g, 80%).Spectral data：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) piperazine In the 200 ml methanol solution of pyridine -4- amine (5g, 17.9mmol), room temperature is stirred vigorously 20 hours in a hydrogen atmosphere.Reaction knot Shu Hou, filters off palladium carbon, filtrate decompression is concentrated, product 1- (4- amino -3- methoxyphenyls)-N, N- diethyl phenylpiperidines -4- amine, It is directly used in next step reaction.Spectral data：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 positioned over In the stand up reaction bottle of 500mL, DMF (100mL) is added to be partly dissolved substrate.1- tert-butoxycarbonyl-piperazines are added afterwards (8.2g, 43.8mmol) and reaction system is kept to be heated 4 hours under 100 degrees celsius.Extent of reaction is detected by TLC, After substrate reacts completely, reaction solution ethyl acetate/aqueous systems are extracted three times, isolate organic layer, through washing, saturated common salt Water washing, after anhydrous sodium sulfate drying, is concentrated under reduced pressure to give crude product.4- (3- first is obtained through the purifying of Combi-Flash column chromatographies Epoxide -4- nitrobenzophenones) piperazine -1- carboxylic acid tert-butyl esters (8.1g, 82%).Spectral data：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) is added to In 100 milliliters of hydrochloric acid dioxane solutions, it is stirred vigorously at room temperature 1 hour.After reaction terminates, reaction solution is concentrated under reduced pressure, obtained To 1- (3- methoxyl group -4- nitrobenzophenones) piperazine (5.6g, 95%).Spectral data：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 put It is placed in the stand up reaction bottle of 50mL, adds acetonitrile (6mL) to be partly dissolved substrate.Afterwards add bromoethane (253mg, 2.3mmol) and reaction system is kept to heat at 80 degrees celsius 7 hours.Extent of reaction is detected by TLC, treats that substrate is complete After full response, insoluble matter is filtered off, be concentrated under reduced pressure to give yellow solid 1- ethyls -4- (3- methoxyl group -4- nitrobenzophenones) piperazine (400mg, 72%).Spectral data：MSm/z(ESI)：266.3[M+H]+
Step 4：
At room temperature, palladium carbon (30mg, 10%wt) is added to 1- ethyls -4- (3- methoxyl group -4- nitrobenzophenones) piperazine In the 50 ml methanol solution of (270mg, 1mmol), room temperature is stirred vigorously 20 hours in a hydrogen atmosphere.After reaction terminates, filter Palladium carbon is gone, filtrate decompression is concentrated, product 4- (4- ethyl piperazidine -1- bases) -2- aminoanisoles are directly used in next step anti- Should.Spectral data：MSm/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 to 80 milliliter two of the bromo- 2- nitropyridines (5g, 21.6mmol) of 5- In chloromethanes solution, it is stirred vigorously under 45 degrees Celsius 2 hours.After substrate reacts completely, it is diluted with water, uses methylene chloride/water System is extracted three times, isolates organic layer, and through washing, saturated common salt water washing after anhydrous sodium sulfate drying, is concentrated under reduced pressure yellow Color solid 1- methyl -4- (6- nitropyridine -3- bases) piperazine (2.5g, 52%).Spectral data：MS m/z (ESI)：223.1[M+ H]+Step 2：
At room temperature, by palladium carbon (250mg, 10%wt) be added to 1- methyl -4- (6- nitropyridine -3- bases) piperazine (2.5g, In 60 ml methanol solution 11.2mmol), room temperature is stirred vigorously 20 hours in a hydrogen atmosphere.After reaction terminates, palladium is filtered off Carbon, filtrate decompression is concentrated, product 5- (4- methylpiperazine-1-yls) pyridine -2- amine, is directly used in next step reaction.Wave spectrum number According to：MSm/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) is added to 50 milliliters of SOCl2In, it is added dropwise 4 and drips DMF, 3h is stirred vigorously under 90 degrees Celsius.Extent of reaction is detected by TLC, after substrate reacts completely, the Huang obtained after product concentration Color solid 3- methoxyl group -4- nitrobenzoyl chlorides are directly used in next step reaction.
Step 2：
Under 0 degree Celsius, DIPEA (4mL, 25.1mmol) and diethylamine (2.7mL, 25.1mmol) are added to 3- methoxies In 50 milliliters of tetrahydrofuran solutions of base -4- nitrobenzoyl chlorides (5.4g, 25.1mmol), it is stirred vigorously at room temperature 3 hours.It is logical TLC detection extent of reactions are crossed, after substrate reacts completely, is diluted with water, regulation PH to alkalescence is extracted with ethyl acetate/aqueous systems Take three times, isolate organic layer, through washing, 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 are obtained through the purifying of Combi-Flash column chromatographies (5.5g, 86%).MS m/z (ESI)：253.1[M+H]+
Step 3：
Pd/C (200mg) is added to N, N-'s diethyl -3- methoxyl group -4- nitrobenzamides (1g, 3.97mmol) In 50 ml methanol solution.At room temperature, in H2It is stirred vigorously in atmosphere 16 hours.After reaction terminates, filtering, filtrate concentration is obtained 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, 25.4mm01) is added to 50 milliliters of SOCl2In, it is added dropwise 4 and drips DMF, 3h is stirred vigorously under 90 degrees Celsius.Extent of reaction is detected by TLC, after substrate reacts completely, the Huang obtained after product concentration Color solid 3- methoxyl group -4- nitrobenzoyl chlorides are directly used in next step reaction.
Step 2：
Under 0 degree Celsius, by DIPEA (4mL, 25.1mmol) and morpholine (2.2g, 25.1mmol) be added to 3- methoxyl groups- In 50 milliliters of tetrahydrofuran solutions of 4- nitrobenzoyl chlorides (5.5g, 25.4mmol), it is stirred vigorously at room temperature 3 hours.Pass through TLC detects extent of reaction, after substrate reacts completely, is diluted with water, regulation PH to alkalescence, is extracted with ethyl acetate/aqueous systems Three times, organic layer is isolated, through washing, saturated common salt water washing after anhydrous sodium sulfate drying, is concentrated under reduced pressure to give compound (3- methoxyl group -4- nitrobenzophenones) (morpholino) ketone (6.6g, 98%).MS m/z (ESI)：267.1[M+H]+
Step 3：
Pd/C (200mg) is added to the 50 of (3- methoxyl group -4- nitrobenzophenones) (morpholino) ketone (1g, 3.76mmol) In ml methanol solution.At room temperature, in H2It is stirred vigorously in atmosphere 16 hours.After reaction terminates, filtering, filtrate concentration must be changed 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) is added to 50 milliliters of SOCl2In, it is added dropwise 4 and drips DMF, 3h is stirred vigorously under 90 degrees Celsius.Extent of reaction is detected by TLC, after substrate reacts completely, the Huang obtained after product concentration Color solid 3- methoxyl group -4- nitrobenzoyl chlorides are directly used in next step reaction.
Step 2：
Under 0 degree Celsius, N methyl piperazine (1.5g, 15.2mmol) is added to 3- methoxyl group -4- nitrobenzoyl chlorides In 50 milliliters of dichloromethane solutions of (3.3g, 15.2mmol), it is stirred vigorously at room temperature 3 hours.By TLC detect react into Degree, after substrate reacts completely, is diluted with water, regulation PH to alkalescence, is extracted three times with ethyl acetate/aqueous systems, has isolated Machine layer, through washing, saturated common salt water washing after anhydrous sodium sulfate drying, is concentrated under reduced pressure to give compound (3- methoxyl group -4- nitre Base phenyl) (4- methylpiperazine-1-yls) ketone (3.0g, 71%).MS m/z (ESI)：280.0[M+H]+
Step 3：
By Pd/C (150mg) be added to (3- methoxyl group -4- nitrobenzophenones) (4- methylpiperazine-1-yls) ketone (1g, In 50 ml methanol solution 3.58mmol).At room temperature, in H2It is stirred vigorously in atmosphere 16 hours.TLC detection reactions terminate Afterwards, filter, filtrate concentration, obtain compound (4- amino -3- methoxyphenyls) (4- methylpiperazine-1-yls) ketone (780mg, 87%), product is directly used in next step.
Embodiment 1
N- (3- (3- (2- ((2- methoxyl groups -4- (4- methylpiperazine-1-yls) phenyl) amino) pyrimidine 4- yls) urea groups) benzene Base) acrylamide (cpd-1) preparation
Step 1：The synthesis of the chloro- 4- pyrimidines isocyanates of 2-
Under 0 degree Celsius, by 4- amino -2- chlorine pyrimidine (4.8g, 37.0mmol) be added to triphosgene (5.5g, In 200 milliliters of tetrahydrofuran (THF) solution 18.5mmol), N, N-- diisopropylethylamine (DIEA) are then slowly added dropwise (6.23g, 48.2mmol).It is stirred vigorously at room temperature 4 hours.Extent of reaction is detected by TLC, after substrate reacts completely, is produced The chloro- 4- pyrimidines isocyanates of thing 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 200 milliliters of tetrahydrofuran solutions of chloro- 4- pyrimidines isocyanates (5.7g, 36.6mmol), it is stirred vigorously at room temperature 20 hours. After reaction terminates, 500 milliliters of water are added to reaction system, there is yellow solid to separate out.Yellow is washed with 500 milliliters of ethyl acetate to consolidate Body, is then beaten with 30 milliliters of ethyl acetate, is filtrated to get compound 1- (2- chlorine pyrimidine-4-yl) -3- (3- nitrobenzophenones) urea (2.8g).Yield：30%, purity：86%, spectral data：MS m/z (ESI)：294.1[M+H]+
Step 3：1- (2- ((2- methoxyl groups -4- (4- methylpiperazine-1-yls) phenyl) amino) pyrimidine-4-yl) -3- (3- nitre Base phenyl) urea synthesis
By 2- methoxyl groups -4- (4- methylpiperazine-1-yls) aniline (739mg, 3.34mmol) and trifluoroacetic acid (TFA) (1.14g, 10mmol) is added to compound 1- (2- chlorine pyrimidine-4-yl) -3- (3- nitrobenzophenones) urea (980mg, 3.34mmol) 20 milliliters of butanol solutions in, be stirred vigorously under 130 degrees Celsius 7 hours.After reaction terminates, system is cooled to room temperature, filtering Obtain brown solid.Brown solid is washed with 30 milliliters of ethanol, compound 1- (2- ((2- methoxyl groups -4- (4- methyl piperazines -1- are obtained Base) phenyl) amino) pyrimidine-4-yl) -3- (3- nitrobenzophenones) urea (700mg), product is directly used in next step.Yield：44%, Purity：74%, spectral data：MS m/z (ESI)：479.2[M+H]+
Step 4：(2- ((2- methoxyl groups -4- (4- methylpiperazine-1-yls) phenyl) amino) is phonetic for 1- (3- aminophenyls) -3- Pyridine -4- bases) urea synthesis
Stannous chloride (554mg, 2.93mmol) is added to 1- (2- ((2- methoxyl groups -4- (4- methylpiperazine-1-yls) benzene Base) amino) pyrimidine-4-yl) and -3- (3- nitrobenzophenones) urea (700mg, 1.46mmol) 60 ml methanols with 40 milliliters of DMF's In mixed solution, it is stirred vigorously under 90 degrees Celsius 4 hours.After reaction terminates, system is cooled to room temperature, adds equivalent bicarbonate Sodium solid.Mixture is stirred vigorously 30 minutes, insoluble matter is filtered off.Filtrate decompression is concentrated to give brown solid compound 1- (3- Aminophenyl) -3- (2- ((2- methoxyl groups -4- (4- methylpiperazine-1-yls) phenyl) amino) pyrimidine-4-yl) urea (300mg), produces Product are directly used in next step.Yield：45%, purity：70%, spectral data：MS1m/z(ESI)：449.2[M+H]+
Step 5：N- (3- (3- (2- ((2- methoxyl groups -4- (4- methylpiperazine-1-yls) phenyl) amino) pyrimidine-4-yl) ureas Base) phenyl) triethylamine (70mg, 0.67mmol) is added to 1- (3- aminophenyls) -3- by the synthesis of acrylamide (cpd-1) 2 millis of (2- ((2- methoxyl groups -4- (4- methylpiperazine-1-yls) phenyl) amino) pyrimidine-4-yl) urea (100mg, 0.23mmol) Rise in tetrahydrofuran and 2 milliliters of mixed solutions of DMF, be stirred vigorously under 0 degree Celsius.By acryloyl chloride (25mg, 0.27mmol), In under 0 degree Celsius, it is slowly dropped in reaction solution.Kept for 0 degree Celsius stir 4 hours.Extent of reaction is detected by TLC, bottom is treated After thing reacts completely, it is diluted with water, is extracted three times with ethyl acetate/aqueous systems, isolate organic layer, through washing, saturated common salt Water washing, after anhydrous sodium sulfate drying, be concentrated under reduced pressure to obtain yellow solid, and compound N-(3- (3- are purified to obtain through preparing liquid phase separation (2- ((2- methoxyl groups -4- (4- methylpiperazine-1-yls) phenyl) amino) pyrimidine-4-yl) urea groups) phenyl) acrylamide (cpd- 1)(2.4mg).Yield：2%, purity：100%, spectral data：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
N- (3- (3- (2- ((4- (4- methylpiperazine-1-yls) phenyl) amino) pyrimidine-4-yl) urea groups) phenyl) acryloyl The preparation of amine (cpd-2)
Step 1：1- (2- ((4- (4- methylpiperazine-1-yls) phenyl) amino) pyrimidine-4-yl) -3- (3- nitrobenzophenones) urea Synthesis
4- (4- methylpiperazine-1-yls) aniline (392mg, 2.00mmol) and trifluoroacetic acid (700mg, 6.0mmol) are added Enter in 14 milliliters of butanol solutions of 1- (2- chlorine pyrimidine-4-yl) -3- (3- nitrobenzophenones) urea (600mg, 2.00mmol), It is stirred vigorously under 130 degrees Celsius 7 hours.After reaction terminates, system is cooled to room temperature, filters to obtain brown solid.With 50 milliliters of second Alcohol washs brown solid, obtains compound 1- (2- ((4- (4- methylpiperazine-1-yls) phenyl) amino) pyrimidine-4-yl) -3- (3- nitre Base phenyl) urea (500mg), product is directly used in next step.Yield：56%, purity：72%, spectral data：MS m/z (ESI)： 449.2[M+H]+
Step 2：1- (2- ((4- (4- methylpiperazine-1-yls) phenyl) amino) pyrimidine-4-yl) -3- (3- aminophenyls) urea Synthesis
Stannous chloride (755mg, 3.33mmol) is added to 1- (2- ((4- (4- methylpiperazine-1-yls) phenyl) amino) Pyrimidine-4-yl) -3- (3- nitrobenzophenones) urea (500mg, 1.11mmol) 10 ml methanols and 5 milliliters of DMSO mixed solutions In, it is stirred vigorously under 90 degrees Celsius 4 hours.After reaction terminates, system is cooled to room temperature, adds equivalent sodium bicarbonate solid. Mixture is stirred vigorously 30 minutes, insoluble matter is filtered off.Filtrate decompression is concentrated to give brown solid 1- (2- ((4- (4- methyl piperazines Piperazine -1- bases) phenyl) amino) pyrimidine-4-yl) -3- (3- aminophenyls) urea (180mg), product is directly used in next step.Yield： 39%, purity：72%, spectral data：MS m/z (ESI)：419.2[M+H]+
Step 3：N- (3- (3- (2- ((4- (4- methylpiperazine-1-yls) phenyl) amino) pyrimidine-4-yl) urea groups) phenyl) The synthesis of acrylamide (cpd-2)
Triethylamine (131mg, 1.29mmol) is added to (2- ((4- (4- methylpiperazine-1-yls) phenyl) amino) pyrimidine- 4- yls) -3- (3- aminophenyls) urea (180mg, 0.43mmol) 5 milliliters of tetrahydrofuran solutions in, acutely stirred under 0 degree Celsius Mix.By acryloyl chloride (60mg, 0.65 mmol), under 0 degree Celsius, it is slowly dropped in reaction solution.Keep 0 degree Celsius of stirring 4 Hour.Extent of reaction is detected by TLC, after substrate reacts completely, is diluted with water, extracted three times with ethyl acetate/aqueous systems, Organic layer is isolated, through washing, saturated common salt water washing, after anhydrous sodium sulfate drying, be concentrated under reduced pressure to obtain yellow solid, through preparing Liquid phase separation purifies to obtain compound N-(3- (3- (2- ((4- (4- methylpiperazine-1-yls) phenyl) amino) pyrimidine-4-yl) urea groups) Phenyl) acrylamide (cpd-2) (12.4mg).Yield：6%, purity：95%, spectral data：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.
N- (3- (3- (2- ((5- methoxypyridine -2- bases) amino) pyrimidine-4-yl) urea groups) phenyl) acrylamide (cpd- 3) preparation
Step 1：The synthesis of 1- (2- ((5- methoxypyridine -2- bases) amino) pyrimidine-4-yl) -3- (3- nitrobenzophenones) urea
2- amino -5- methoxypyridines (414mg, 3.34mmol) and trifluoroacetic acid (1.14g, 10mmol) are added to 1- In 20 milliliters of butanol solutions of (2- chlorine pyrimidine-4-yl) -3- (3- nitrobenzophenones) urea (980mg, 3.34mmol), 130 is Celsius It is stirred vigorously under degree 7 hours.After reaction terminates, system is cooled to room temperature, filters to obtain brown solid.With 30 milliliters of ethanol washing palm fibres Color solid, obtains compound 1- (2- ((5- methoxypyridine -2- bases) amino) pyrimidine-4-yl) -3- (3- nitrobenzophenones) (650mg), product is directly used in next step.Yield：51%, purity：78%, spectral data：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) be added to 1- (2- ((5- methoxypyridine -2- bases) amino) pyrimidine - 4- yls) in 60 ml methanols of -3- (3- nitrobenzophenones) urea (650mg, 1.71mmol) and the mixed solutions of 40 milliliters of DMF, 90 It is stirred vigorously under degree Celsius 4 hours.After reaction terminates, system is cooled to room temperature, adds equivalent sodium bicarbonate solid.Will mixing Thing is stirred vigorously 30 minutes, filters off insoluble matter.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%, spectral data：MS m/z (ESI)：352.1[M+H]+
Step 3：N- (3- (3- (2- ((5- methoxypyridine -2- bases) amino) pyrimidine-4-yl) urea groups) phenyl) acryloyl The synthesis of amine (cpd-3)
Triethylamine (172mg, 1.7mmol) is added to 1- (2- ((5- methoxypyridine -2- bases) amino) pyrimidine -4- Base) -3- (3- aminophenyls) urea (200mg, 0.56mmol) 2 milliliters of tetrahydrofurans and 2 milliliters of mixed solutions of DMF in, 0 takes the photograph It is stirred vigorously under family name's degree.By acryloyl chloride (62mg, 0.68mmol), under 0 degree Celsius, it is slowly dropped in reaction solution.Keep 0 Degree Celsius stirring 4 hours.Extent of reaction is detected by TLC, after substrate reacts completely, is diluted with water, with ethyl acetate/water body System's extraction three times, isolates organic layer, and through washing, saturated common salt water washing, after anhydrous sodium sulfate drying, be concentrated under reduced pressure to obtain yellow Solid, N- (3- (3- (2- ((5- methoxypyridine -2- bases) amino) pyrimidine-4-yl) urea groups) are purified to obtain through preparing liquid phase separation Phenyl) acrylamide (cpd-3) (26.3mg).Yield：2%, purity：94.5%, spectral data：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.
N- (3- (3- (2- ((the chloro- 4- of 3- ((3- luorobenzyls) oxygen) phenyl) amino) pyrimidine-4-yl) urea groups) phenyl) propylene The preparation of acid amides (cpd-4)
Step 1：1- (2- ((the chloro- 4- of 3- ((3- luorobenzyls) epoxide) phenyl) amino) pyrimidine -4- bases) -3- (3- nitrobenzene Base) urea synthesis
The chloro- 4- of 3- ((3- luorobenzyls) oxygen) aniline (414mg, 3.34mmol) and trifluoroacetic acid (1.14g, 10mmol) are added Enter in 20 milliliters of butanol solutions of 1- (2- chlorine pyrimidine-4-yl) -3- (3- nitrobenzophenones) urea (980mg, 3.34mmol), It is stirred vigorously under 130 degrees Celsius 7 hours.After reaction terminates, system is cooled to room temperature, filters to obtain brown solid.With 30 milliliters of second Alcohol washs brown solid, obtains 1- (2- ((the chloro- 4- of 3- ((3- luorobenzyls) epoxide) phenyl) amino) pyrimidine-4-yl) -3- (3- nitros Phenyl) urea (650mg), product is directly used in next step.Yield：51%, purity：78%, spectral data：MS m/z (ESI)： 382.1[M+H]+
Step 2：1- (2- ((the chloro- 4- of 3- ((3- luorobenzyls) epoxide) phenyl) amino) pyrimidine-4-yl) -3- (3- aminobenzenes Base) urea synthesis
Stannous chloride (1157mg, 5.13mmol) is added to 1- (2- ((the chloro- 4- of 3- ((3- luorobenzyls) epoxide) phenyl) Amino) pyrimidine-4-yl) -3- (3- nitrobenzophenones) urea (650mg, 1.71mmol) 60 ml methanols and 40 milliliters of DMF mixing In solution, it is stirred vigorously under 90 degrees Celsius 4 hours.After reaction terminates, system is cooled to room temperature, adds equivalent sodium acid carbonate to consolidate Body.Mixture is stirred vigorously 30 minutes, 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%, spectral data：MS m/z (ESI)：352.1[M+H]+
Step 3：N- (3- (3- (2- ((the chloro- 4- of 3- ((3- luorobenzyls) oxygen) phenyl) amino) pyrimidine-4-yl) urea groups) benzene Base) acrylamide (cpd-4) synthesis
Triethylamine (172mg, 1.7mmol) is added to 1- (2- ((the chloro- 4- of 3- ((3- luorobenzyls) epoxide) phenyl) amino) Pyrimidine-4-yl) -3- (3- aminophenyls) urea (200mg, 0.56mmol) 2 milliliters of tetrahydrofurans it is molten with the mixing of 2 milliliters of DMF In liquid, it is stirred vigorously under 0 degree Celsius.By acryloyl chloride (62mg, 0.68mmol), under 0 degree Celsius, reaction solution is slowly dropped to In.Kept for 0 degree Celsius stir 4 hours.Extent of reaction is detected by TLC, after substrate reacts completely, is diluted with water, use acetic acid Ethyl ester/aqueous systems are extracted three times, isolate organic layer, and through washing, saturated common salt water washing after anhydrous sodium sulfate drying, depressurizes Yellow solid is concentrated to give, N- (3- (3- (2- ((the chloro- 4- of 3- ((3- luorobenzyls) oxygen) phenyl) ammonia is purified to obtain through preparing liquid phase separation Base) pyrimidine-4-yl) urea groups) phenyl) acrylamide (cpd-4) (26.3mg).Yield：2%, purity：100%, spectral data： 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.
N- (3- (3- (2- ((2- methoxyl groups -4- (4- (4- methylpiperazine-1-yls) piperidin-1-yl) phenyl) amino) pyrimidine - 4- yls) urea groups) phenyl) and acrylamide (cpd-5) preparation
Step 1：1- (2- ((2- methoxyl groups -4- (4- (4- methylpiperazine-1-yls) piperidin-1-yl) phenyl) amino) pyrimidine - 4- yls) -3- (3- nitrobenzophenones) urea synthesis
By (4- (4- methyl piperazines) piperidines) aniline (338mg, 1.12mmol) of 2- methoxyl groups -4 and trifluoroacetic acid (380mg, 3.33mmol) it is added to 20 milliliters of positive fourths of 1- (2- chlorine pyrimidine-4-yl) -3- (3- nitrobenzophenones) urea (328mg, 1.12mmol) In alcoholic solution, it is stirred vigorously under 130 degrees Celsius 7 hours.After reaction terminates, system is cooled to room temperature, filters to obtain brown solid.With 30 milliliters of ethanol wash brown solid, obtain 1- (2- ((2- methoxyl groups -4- (4- (4- methylpiperazine-1-yls) piperidin-1-yl) benzene Base) amino) pyrimidine-4-yl) -3- (3- nitrobenzophenones) urea (281mg), product is directly used in next step.Yield：45%, purity： 79%, spectral data：MS m/z (ESI)：562.1[M+H]+
Step 2：1- (2- ((2- methoxyl groups -4- (4- (4- methylpiperazine-1-yls) piperidin-1-yl) phenyl) amino) pyrimidine - 4- yls) -3- (3- aminophenyls) urea synthesis
Stannous chloride (339mg, 1.5rmmol) is added to 1- (2- ((2- methoxyl groups -4- (4- (4- methyl piperazines -1- Base) piperidin-1-yl) phenyl) amino) pyrimidine-4-yl) and -3- (3- nitrobenzophenones) urea (281mg, 0.5mmol) 60 ml methanols In 40 milliliters of mixed solutions of DMF, it is stirred vigorously under 90 degrees Celsius 4 hours.After reaction terminates, system is cooled to room temperature, plus Enter equivalent sodium bicarbonate solid.Mixture is stirred vigorously 30 minutes, insoluble matter is filtered off.Filtrate decompression is concentrated to give into brown to consolidate Body 1- (2- ((2- methoxyl groups -4- (4- (4- methylpiperazine-1-yls) piperidin-1-yl) phenyl) amino) pyrimidine-4-yl) -3- (3- Aminophenyl) urea (200mg), product is directly used in next step.Yield：76%, purity：82%, spectral data：MS m/z (ESI)：532.1[M+H]+
Step 3：N- (3- (3- (2- ((2- methoxyl groups -4- (4- (4- methylpiperazine-1-yls) piperidin-1-yl) phenyl) ammonia Base) pyrimidine-4-yl) urea groups) phenyl) acrylamide (cpd-5) synthesis
Triethylamine (114mg, 1.13mmol) 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, 0.38mmol) 2 milliliters of tetrahydrochysene furans Mutter with the mixed solution of 2 milliliters of DMF, be stirred vigorously under 0 degree Celsius.It is Celsius in 0 by acryloyl chloride (42mg, 0.46mmol) Under degree, it is slowly dropped in reaction solution.Kept for 0 degree Celsius stir 4 hours.Extent of reaction is detected by TLC, treats that substrate is completely anti- Ying Hou, is diluted with water, and is extracted three times with ethyl acetate/aqueous systems, isolates organic layer, through washing, saturated common salt water washing, nothing Aqueous sodium persulfate dry after, be concentrated under reduced pressure to obtain yellow solid, through prepare liquid phase separation purify 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).Yield：1.5%, purity：94%, spectral data：MS m/z (ESI)：586.1[M+H]+；1H NMR (400MHz, DMS0-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.
N- (3- (3- (2- ((6- morpholinoes pyridin-3-yl) amino) pyrimidine-4-yl) urea groups) phenyl) acrylamide (cpd- 6) preparation
Step 1：The synthesis of 1- (2- ((6- morpholinoes pyridin-3-yl) amino) pyrimidine-4-yl) -3- (3- nitrobenzophenones) urea
6- morpholinoes pyridine -3- amine (427mg, 2.38mmol) and trifluoroacetic acid (815mg, 7.15mmol) are added to 1- In 8 milliliters of butanol solutions of (2- chlorine pyrimidine-4-yl) -3- (3- nitrobenzophenones) urea (700mg, 2.38mmol), 130 degrees Celsius Under be stirred vigorously 7 hours.After reaction terminates, system is cooled to room temperature, filters to obtain brown solid.Brown is purified to obtain with column chromatography Solid 1- (2- ((6- morpholinoes pyridin-3-yl) amino) pyrimidine-4-yl) -3- (3- nitrobenzophenones) urea (120mg).Yield： 10%, purity：85%, spectral data：MS m/z (ESI)：436.1[M+H1+
Step 2：The synthesis of 1- (2- ((6- morpholinoes pyridin-3-yl) amino) pyrimidine-4-yl) -3- (3- aminophenyls) urea
Stannous chloride (190mg, 0.82mmol) is added to 1- (2- ((6- morpholinoes pyridin-3-yl) amino) pyrimidine -4- Base) in 3 ml methanols of -3- (3- nitrobenzophenones) urea (120mg, 0.27mmol) and the mixed solutions of 3 milliliters of DMF, 90 is Celsius It is stirred vigorously under degree 7 hours.After reaction terminates, system is cooled to room temperature, adds equivalent sodium bicarbonate solid.Mixture is acute Strong stirring 30 minutes, filters off insoluble matter.Filtrate decompression is concentrated to give brown solid 1- (2- ((6- morpholinoes pyridin-3-yl) ammonia Base) pyrimidine-4-yl) -3- (3- aminophenyls) urea (120mg), product is directly used in next step.Yield：90%, purity：70%, Spectral data：MS m/z (ESI)：406.2[M+H]+
Step 3：N- (3- (3- (2- ((6- morpholinoes pyridin-3-yl) amino) pyrimidine-4-yl) urea groups) phenyl) acryloyl The synthesis of amine (cpd-6)
Triethylamine (901mg, 0.9mmol) is added to 1- (2- ((6- morpholinoes pyridin-3-yl) amino) pyrimidine -4- Base) -3- (3- aminophenyls) urea (120mg, 0.30mmol) 5 milliliters of tetrahydrofuran solutions in, be stirred vigorously under 0 degree Celsius. By acryloyl chloride (27mg, 0.30mmol), under 0 degree Celsius, it is slowly dropped in reaction solution.Keep 0 degree Celsius of stirring 4 small When.Extent of reaction is detected by TLC, after substrate reacts completely, is diluted with water, extracted three times with ethyl acetate/aqueous systems, point Organic layer is separated out, through washing, saturated common salt water washing, after anhydrous sodium sulfate drying, be concentrated under reduced pressure to obtain yellow solid, through preparation solution Phase separation purifies to obtain N- (3- (3- (2- ((6- morpholinoes pyridin-3-yl) amino) pyrimidine-4-yl) urea groups) phenyl) acrylamide (cpd-6)(1.66mg).Yield：2%, purity：97%, spectral data：MS m/z (ESI)：461.3[M+H1+.
Embodiment 7.
N- (3- (3- (2- ((2,4-- Dimethoxyphenyls) amino) pyrimidine-4-yl) urea groups) phenyl) acrylamide (cpd- 7) preparation
Step 1：The synthesis of 1- (2- ((2,4- Dimethoxyphenyls) amino) pyrimidine-4-yl) -3- (3- nitrobenzophenones) urea
2,4--, bis--aminoanisoles (261mg, 1.7mmol) and trifluoroacetic acid (582mg, 5.1mmol) are added to 1- In 8 milliliters of butanol solutions of (2- chlorine pyrimidine-4-yl) -3- (3- nitrobenzophenones) urea (500mg, 1.7mmol), 130 degrees Celsius Under be stirred vigorously 7 hours.After reaction terminates, system is cooled to room temperature, filters to obtain brown solid.Brown is washed with 30 milliliters of ethanol Solid, obtains 1- (2- ((2,4- bis- Dimethoxyphenyl) amino) pyrimidine-4-yl) -3- (3- nitrobenzophenones) urea (120mg), product It is directly used in next step.Yield：18%, purity：76%, spectral data：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
Stannous chloride (231mg, 1.0mmol) is added to 1- (2- ((2,4- Dimethoxyphenyl) amino) pyrimidine -4- Base) in 3 ml methanols of -3- (3- nitrobenzophenones) urea (140mg, 0.34mmol) and the mixed solutions of 3 milliliters of DMF, 90 is Celsius It is stirred vigorously under degree 4 hours.After reaction terminates, system is cooled to room temperature, adds equivalent sodium bicarbonate solid.Mixture is acute Strong stirring 30 minutes, filters off insoluble matter.Filtrate decompression is concentrated to give brown solid 1- (2- ((bis--methoxyphenyls of 2,4--) ammonia Base) pyrimidine-4-yl) -3- (3- aminophenyls) urea (100mg), product is directly used in next step.Yield：90%, purity：69%, Spectral data：MS m/z (ESI)：381.2[M+H]+
Step 3：N- (3- (3- (2- ((Dimethoxyphenyls of 2,4- bis-) amino) pyrimidine-4-yl) urea groups) phenyl) acryloyl The synthesis of amine (cpd-7)
By triethylamine (100mg, 0.9mmol) be added to 1- (2- ((2,4- Dimethoxyphenyl) amino) pyrimidine-4-yl)- In 5 milliliters of tetrahydrofuran solutions of 3- (3- aminophenyls) urea (100mg, 0.3mmol), it is stirred vigorously under 0 degree Celsius.By propylene Acyl chlorides (30mg, 0.3mmol), under 0 degree Celsius, is slowly dropped in reaction solution.Kept for 0 degree Celsius stir 4 hours.Pass through TLC detects extent of reaction, after substrate reacts completely, is diluted with water, and is extracted three times with ethyl acetate/aqueous systems, has isolated Machine layer, through washing, saturated common salt water washing, after anhydrous sodium sulfate drying, be concentrated under reduced pressure to obtain yellow solid, through preparing liquid phase separation Purify to obtain N- (3- (3- (2- ((2,4- Dimethoxyphenyls) amino) pyrimidine-4-yl) urea groups) phenyl) acrylamide (cpd-7) (19.08mg).Yield：15%, purity：100%, spectral data：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.
N- (3- (3- (2- ((the chloro- 4- fluorophenyls of 3-) amino) pyrimidine-4-yl) urea groups) phenyl) acrylamide (cpd-8) Prepare
Step 1：The synthesis of 1- (2- ((the chloro- 4- fluorophenyls of 3-) amino) pyrimidine-4-yl) -3- (3- nitrobenzophenones) urea
The chloro- 4- fluoroanilines (162mg, 1.12mmol) of 3- and trifluoroacetic acid (380mg, 3.33mmol) are added to 1- (2- Chlorine pyrimidine-4-yl) -3- (3- nitrobenzophenones) urea (328mg, 1.12mmol) 20 milliliters of butanol solutions in, under 130 degrees Celsius It is stirred vigorously 7 hours.After reaction terminates, system is cooled to room temperature, filters to obtain brown solid.Brown is washed with 30 milliliters of ethanol to consolidate Body, obtains 1- (2- ((the chloro- 4- fluorophenyls of 3-) amino) pyrimidine-4-yl) -3- (3- nitrobenzophenones) urea (2301mg), and product is directly used In next step.Yield：51%, purity：74%, spectral data：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) be added to 1- (2- ((the chloro- 4- fluorophenyls of 3-) amino) pyrimidine-4-yl)- In 60 ml methanols of 3- (3- nitrobenzophenones) urea (230mg, 0.57mmol) and 40 milliliters of mixed solutions of DMF, 90 degrees Celsius Under be stirred vigorously 4 hours.After reaction terminates, system is cooled to room temperature, adds equivalent sodium bicarbonate solid.Mixture is violent Stirring 30 minutes, filters off insoluble matter.By filtrate decompression be concentrated to give brown solid 1- (2- ((the chloro- 4- fluorophenyls of 3-) amino) pyrimidine- 4- yls) -3- (3- aminophenyls) urea (200mg), product is directly used in next step.Yield：94%, purity：80%, wave spectrum number According to：MS m/z (ESI)：373.1[M+H]+
Step 3：N- (3- (3- (2- ((the chloro- 4- fluorophenyls of 3-) amino) pyrimidine-4-yl) urea groups) phenyl) acrylamide (cpd-8) synthesis
By triethylamine (163mg, 1.61mmol) be added to 1- (2- ((the chloro- 4- fluorophenyls of 3-) amino) pyrimidine-4-yl)- In 2 milliliters of tetrahydrofurans and 2 milliliters of mixed solutions of DMF of 3- (3- aminophenyls) urea (200mg, 0.54mmol), 0 degree Celsius Under be stirred vigorously.By acryloyl chloride (58mg, 0.65mmol), under 0 degree Celsius, it is slowly dropped in reaction solution.Keep 0 Celsius Degree stirring 4 hours.Extent of reaction is detected by TLC, after substrate reacts completely, is diluted with water, extracted with ethyl acetate/aqueous systems Take three times, isolate organic layer, through washing, saturated common salt water washing is concentrated under reduced pressure that yellow is consolidated after anhydrous sodium sulfate drying Body, N- (3- (3- (2- ((the chloro- 4- fluorophenyls of 3-) amino) pyrimidine-4-yl) urea groups) phenyl) third is purified to obtain through preparing liquid phase separation Acrylamide (cpd-8) (3.7mg).Yield：1.6%, purity：96.8%, spectral data：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.
N- (3- (3- (2- ((2- methoxyl groups -4- (4- morpholines piperidin-1-yl) phenyl) amino) pyrimidine 4- yls) urea groups) benzene Base) acrylamide (cpd-9) preparation
Step 1：1- (2- ((2- methoxyl groups -4- (4- morpholino -1- bases) phenyl) amino) pyrimidine-4-yl) -3- (3- nitros Phenyl) urea synthesis
By (the 4- morpholines piperidines) aniline (326mg, 1.12mmol) of 2- methoxyl groups -4 and trifluoroacetic acid (380mg, 3.33mmol) it is added to 20 milliliters of positive fourths of 1- (2- chlorine pyrimidine-4-yl) -3- (3- nitrobenzophenones) urea (328mg, 1.12mmol) In alcoholic solution, it is stirred vigorously under 130 degrees Celsius 7 hours.After reaction terminates, system is cooled to room temperature, filters to obtain brown solid.With 30 milliliters of ethanol wash brown solid, obtain 1- (2- ((2- methoxyl groups -4- (4- morpholino -1- bases) phenyl) amino) pyrimidine -4- Base) -3- (3- nitrobenzophenones) urea (270mg), product is directly used in next step.Yield：49%, purity：65%, spectral data： MS m/z (ESI)：549.1[M+H]+
Step 2：1- (2- ((2- methoxyl groups -4- (4- morpholino -1- bases) phenyl) amino) pyrimidine -4- bases) -3- (3- ammonia Base phenyl) urea synthesis
Stannous chloride (339mg, 1.5mmol) is added to 1- (2- ((2- methoxyl groups -4- (4- morpholino -1- bases) phenyl) Amino) pyrimidine-4-yl) -3- (3- nitrobenzophenones) urea (270mg, 0.49mmol) 60 ml methanols and 40 milliliters of DMF mixing In solution, it is stirred vigorously under 90 degrees Celsius 4 hours.After reaction terminates, system is cooled to room temperature, adds equivalent sodium acid carbonate to consolidate Body.Mixture is stirred vigorously 30 minutes, insoluble matter is filtered off.By filtrate decompression be 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 down One step.Yield：79%, purity：75%, spectral data：MS m/z (ESI)：519.1[M+H]+
Step 3：N- (3- (3- (2- ((2- methoxyl groups -4- (4- morpholines piperidin-1-yl) phenyl) amino) pyrimidine-4-yl) ureas Base) phenyl) acrylamide (cpd-9) synthesis
Triethylamine (114mg, 1.13mmol) is added to 1- (2- ((2- methoxyl groups -4- (4- morpholino -1- bases) phenyl) Amino) pyrimidine-4-yl) -3- (3- aminophenyls) urea (200mg, 0.38mmol) 2 milliliters of tetrahydrofurans and 2 milliliters of DMF it is mixed Close in solution, be stirred vigorously under 0 degree Celsius.By acryloyl chloride (421mg, 0.46mmol), under 0 degree Celsius, it is slowly dropped to In reaction solution.Kept for 0 degree Celsius stir 4 hours.Extent of reaction is detected by TLC, after substrate reacts completely, is diluted with water, Extracted three times with ethyl acetate/aqueous systems, isolate organic layer, through washing, saturated common salt water washing, anhydrous sodium sulfate drying Afterwards, be concentrated under reduced pressure to obtain yellow solid, and N- (3- (3- (2- ((2- methoxyl groups -4- (4- morpholine piperazines are purified to obtain through preparing liquid phase separation Pyridine -1- bases) phenyl) amino) pyrimidine-4-yl) urea groups) phenyl) acrylamide (cpd-9) (70.98mg).Yield：32.7%, it is pure Degree：99%, spectral data：MS m/z (ESI)：573.3[M+H]+；1H NMR (400MHz, DMSO-d6)：δ 10.28 (s, 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.
N- (3- (3- (2- ((4- (4- (dimethylamino) piperidin-1-yl) -2- anisyls) amino) pyrimidine-4-yl) ureas Base) phenyl) acrylamide (cpd-10) preparation
Step 1：1- (2- ((4- (4- (dimethylamino) piperidin-1-yl) -2- methoxyphenyls) amino) pyrimidine -4- Base) -3- (3- nitrobenzophenones) urea synthesis
By 1- (4- amino -3- methoxyphenyls)-N, N--2 lupetidine -4- amine (279mg, 1.12mmol) and trifluoro Acetic acid (380mg, 3.33mmol) is added to 1- (2- chlorine pyrimidine-4-yl) -3- (3- nitrobenzophenones) urea (328mg, 1.12mmol) 20 milliliters of butanol solutions in, be stirred vigorously under 130 degrees Celsius 7 hours.After reaction terminates, system is cooled to room temperature, filtering Obtain brown solid.Brown solid is washed with 30 milliliters of ethanol, 1- (2- ((4- (4- (dimethylamino) piperidin-1-yl) -2- first is obtained Phenyl) amino) pyrimidine-4-yl) -3- (3- nitrobenzophenones) urea (230mg), product is directly used in next step.Yield： 41%, purity：65%, spectral data：MS m/z (ESI)：507.1[M+H]+
Step 2：1- (2- ((4- (4- (dimethylamino) piperidin-1-yl) -2- methoxyphenyls) amino) pyrimidine -4- Base) -3- (3- aminophenyls) urea synthesis
Stannous chloride (305mg, 1.35mmol) is added to 1- (2- ((4- (4- (dimethylamino) piperidin-1-yl) -2- Methoxyphenyl) amino) pyrimidine-4-yl) and -3- (3- nitrobenzophenones) urea (230mg, 0.45mmol) 60 ml methanols with 40 milli Rise in the mixed solution of DMF, be stirred vigorously under 90 degrees Celsius 4 hours.After reaction terminates, system is cooled to room temperature, addition etc. and works as Amount sodium bicarbonate solid.Mixture is stirred vigorously 30 minutes, 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%, spectral data：MS m/z (ESI)：477.2[M +H1+
Step 3：N- (3- (3- (2- ((4- (4- (dimethylamino) piperidin-1-yl) -2- anisyls) amino) pyrimidine - 4- yls) urea groups) phenyl) and acrylamide (cpd-10) synthesis
Triethylamine (114mg, 1.13mmol) is added to 1- (2- ((4- (4- (dimethylamino) piperidin-1-yl) -2- first Phenyl) amino) pyrimidine-4-yl) and -3- (3- aminophenyls) urea (180mg, 0.38mmol) 2 milliliters of tetrahydrofurans and 2 milli Rise in the mixed solution of DMF, be stirred vigorously under 0 degree Celsius.By acryloyl chloride (42mg, 0.46mmol), under 0 degree Celsius, delay Slowly it is added drop-wise in reaction solution.Kept for 0 degree Celsius stir 4 hours.Extent of reaction is detected by TLC, after substrate reacts completely, It is diluted with water, is extracted three times with ethyl acetate/aqueous systems, isolate organic layer, through washing, saturated common salt water washing, anhydrous sulphur After sour sodium is dried, be concentrated under reduced pressure to obtain yellow solid, and compound N-(3- (3- (2- ((4- (4- (two are purified to obtain through preparing liquid phase separation Methylamino) piperidin-1-yl) -2- anisyls) amino) pyrimidine-4-yl) urea groups) phenyl) acrylamide (cpd-10) (25.36mg).Yield：12.6%, purity：99%, spectral data：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.
N- (3- (3- (2- ((4- (piperidin-1-yl) phenyl) amino) pyrimidine-4-yl) urea groups) phenyl) acrylamide (cpd- 11) preparation
Step 1：The synthesis of 1- (2- ((4- (piperidin-1-yl) phenyl) amino) pyrimidine-4-yl) -3- (3- nitrobenzophenones) urea
4- (piperidin-1-yl)-aniline (197mg, 1.12mmol) and trifluoroacetic acid (380mg, 3.33mmol) are added to In 20 milliliters of butanol solutions of 1- (2- chlorine pyrimidine-4-yl) -3- (3- nitrobenzophenones) urea (328mg, 1.12mmol), 130 take the photograph It is stirred vigorously under family name's degree 7 hours.After reaction terminates, system is cooled to room temperature, filters to obtain brown solid.Washed with 30 milliliters of ethanol Brown solid, obtains 1- (2- ((4- (piperidin-1-yl) phenyl) amino) pyrimidine-4-yl) -3- (3- nitrobenzophenones) urea (230mg), Product is directly used in next step.Yield：47%, purity：80%, spectral data：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 synthesizes
By stannous chloride (380mg, 1.59mmol) be added to 1- (2- ((4- (piperidin-1-yl) phenyl) amino) pyrimidine- 4- yls) in 60 ml methanols of -3- (3- nitrobenzophenones) urea (230mg, 0.53mmol) and the mixed solutions of 40 milliliters of DMF, 90 It is stirred vigorously under degree Celsius 4 hours.After reaction terminates, system is cooled to room temperature, adds equivalent sodium bicarbonate solid.Will mixing Thing is stirred vigorously 30 minutes, 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%, spectral data：MS m/z (ESI)：404.2[M+H]+
Step 3：N- (3- (3- (2- ((4- (piperidin-1-yl) phenyl) amino) pyrimidine-4-yl) urea groups) phenyl) acryloyl The synthesis of amine (cpd-11)
Triethylamine (155mg, 1.50mmol) is added to 1- (2- ((4- (piperidin-1-yl) phenyl) amino) pyrimidine -4- Base) -3- (3- aminophenyls) urea (200mg, 0.50mmol) 2 milliliters of tetrahydrofurans and 2 milliliters of mixed solutions of DMF in, 0 takes the photograph It is stirred vigorously under family name's degree.By acryloyl chloride (54mg, 0.6mmol), under 0 degree Celsius, it is slowly dropped in reaction solution.Keep 0 Degree Celsius stirring 4 hours.Extent of reaction is detected by TLC, after substrate reacts completely, is diluted with water, with ethyl acetate/water body System's extraction three times, isolates organic layer, and through washing, saturated common salt water washing, after anhydrous sodium sulfate drying, be concentrated under reduced pressure to obtain yellow Solid, N- (3- (3- (2- ((4- (piperidin-1-yl) phenyl) amino) pyrimidine-4-yl) urea groups) are purified to obtain through preparing liquid phase separation Phenyl) acrylamide (cpd-11) (1.80mg).Yield：0.8%, purity：93.7%, spectral data：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.
N- (3- (3- (2- ((4- (dimethylamino) phenyl) amino) pyrimidine-4-yl) urea groups) phenyl) acrylamide (cpd- 12) preparation
Step 1：The conjunction of 1- (2- ((4- (dimethylamino) phenyl) amino) pyrimidine-4-yl) -3- (3- nitrobenzophenones) urea Into
By the dimethylaniline (152mg, 1.121mmol) of 4- amino-N, N-- bis- and trifluoroacetic acid (380mg, 3.33mmol) It is added in 20 milliliters of butanol solutions of 1- (2- chlorine pyrimidine-4-yl) -3- (3- nitrobenzophenones) urea (328mg, 1.12mmol), It is stirred vigorously under 130 degrees Celsius 7 hours.After reaction terminates, system is cooled to room temperature, filters to obtain brown solid.With 30 milliliters of second Alcohol washs brown solid, obtains 1- (2- ((4- (dimethylamino) phenyl) amino) pyrimidine-4-yl) -3- (3- nitrobenzophenones) urea (221mg), product is directly used in next step.Yield：50%, purity：78%, spectral data：MS m/z (ESI)：394.3[M+ H]+
Step 2：The conjunction of 1- (2- ((4- (dimethylamino) phenyl) amino) pyrimidine-4-yl) -3- (3- aminophenyls) urea Into
By stannous chloride (380mg, 1.68mm01) be added to 1- (2- ((4- (dimethylamino) phenyl) amino) pyrimidine- 4- yls) in 60 ml methanols of -3- (3- nitrobenzophenones) urea (221mg, 0.56mmol) and the mixed solutions of 40 milliliters of DMF, 90 It is stirred vigorously under degree Celsius 4 hours.After reaction terminates, system is cooled to room temperature, adds equivalent sodium bicarbonate solid.Will mixing Thing is stirred vigorously 30 minutes, filters off insoluble matter.Filtrate decompression is concentrated to give brown solid 1- (2- ((4- (dimethylamino) benzene Base) amino) pyrimidine-4-yl) -3- (3- aminophenyls) urea (195mg), product is directly used in next step.Yield：96%, purity： 79%, spectral data：MS m/z (ESI)：364.2[M+H]+
Step 3：N- (3- (3- (2- ((4- (dimethylamino) phenyl) amino) pyrimidine-4-yl) urea groups) phenyl) acrylamide (cpd-12) synthesis
Triethylamine (163mg, 1.61mmol) is added to 1- (2- ((4- (dimethylamino) phenyl) amino) pyrimidine -4- Base) -3- (3- aminophenyls) urea (195mg, 0.54mmol) 2 milliliters of tetrahydrofurans and 2 milliliters of mixed solutions of DMF in, 0 takes the photograph It is stirred vigorously under family name's degree.By acryloyl chloride (58mg, 0.65mmol), under 0 degree Celsius, it is slowly dropped in reaction solution.Keep 0 Degree Celsius stirring 4 hours.Extent of reaction is detected by TLC, after substrate reacts completely, is diluted with water, with ethyl acetate/water body System's extraction three times, isolates organic layer, and through washing, saturated common salt water washing, after anhydrous sodium sulfate drying, be concentrated under reduced pressure to obtain yellow Solid, N- (3- (3- (2- ((4- (dimethylamino) phenyl) amino) pyrimidine-4-yl) urea groups) benzene is purified to obtain through preparing liquid phase separation Base) acrylamide (cpd-12) (14.20mg).Yield：6.3%, purity：99.7%, spectral data：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.
N- (3- (3- (2- ((5- morpholino pyridine -2- bases) amino) pyrimidine-4-yl) urea groups) phenyl) acrylamide (cpd- 13) preparation
Step 1：The synthesis of 1- (2- chlorine pyrimidine-4-yl) -3- (3- aminophenyls) urea
The single port that 1- (2- chlorine pyrimidine-4-yl) -3- (3- nitrobenzophenones) urea (6.0g, 20mmol) is positioned over into 250mL is anti- Answer in bottle, add tetrahydrofuran/water (75mL/50mL) mixed solution to dissolve substrate.At ambient temperature, to the reaction of stirring Ammonium chloride (5.3g, 100mmol) and reduced iron powder (8.9g, 160mmol) are sequentially added in bottle, then reaction system is heated to 65 degrees Celsius and it is kept stirring for 5 hours.Extent of reaction is detected by TLC, after substrate reacts completely, unnecessary iron is filtered to remove Powder, filter cake ethyl acetate drip washing three times.Filtrate is extracted three times with ethyl acetate/aqueous systems, isolates organic layer, through washing, Saturated common salt water washing, after anhydrous sodium sulfate drying, is concentrated under reduced pressure to give 1- (2- chlorine pyrimidine-4-yl) -3- (3- aminophenyls) Urea (5.4g), is directly used in next step reaction.
Step 2：The synthesis of N- (3- (3- (2- chlorine pyrimidine-4-yl) urea groups) phenyl) acrylamide
The single port that 1- (2- chlorine pyrimidine-4-yl) -3- (3- aminophenyls) urea (5.4g, 20mmol) is positioned over into 100mL is anti- Answer in bottle, add dichloromethane (50mL) to dissolve substrate.Under 0 degrees celsius, sequentially added in the reaction bulb to stirring Triethylamine (4.3mL, 30mmoL) with acryloyl chloride (2.0mL, 24mmol), reaction system is then maintained 0 degree Celsius and is held Continuous stirring 1 hour.Extent of reaction is detected by TLC, after substrate reacts completely, reaction solution tetrahydrofuran/aqueous systems extraction Three times, organic layer is isolated, saturated common salt water washing after anhydrous sodium sulfate drying, is concentrated under reduced pressure to give crude product.Through ethanol Backflow is beaten to obtain N- (3- (3- (2- chlorine pyrimidine-4-yl) urea groups) phenyl) acrylamide (5.2g), is directly used in next step reaction. Yield：80% (two steps), purity：90%, spectral data：MS m/z (ESI)：318.1[M+H]+.
Step 3：N- (3- (3- (2- ((5- morpholino pyridine -2- bases) amino) pyrimidine-4-yl) urea groups) phenyl) acryloyl The synthesis of amine (cpd-13)
At room temperature, by Pd2(dba)3(30mg, 0.03mmol), BINAP (2,2 '-bis- diphenyl phosphine -1,1 '-dinaphthalene) (40mg, 0.06mmol), t-BuONa (91mg, 0.96mmol) and 5- morpholinoes pyridine -2- amine (102mg, 0..57mmol) add Enter 5 milliliters of dioxane to N- (3- (3- (2- chlorine pyrimidine-4-yl) urea groups) phenyl) acrylamide (200mg, 0.63mmol) In solution, under nitrogen protection, the degrees Celsius with vigorous of tube sealing 120 is stirred 8 hours.After reaction terminates, filtering, filtrate concentrated under reduced pressure obtains yellow Color solid, N- (3- (3- (2- ((5- morpholino pyridine -2- bases) amino) pyrimidine-4-yl) urea groups) are obtained to prepare liquid phase purifying Phenyl) acrylamide (cpd-13) (5.17mg).Yield：3%, purity：97.67%, spectral data：MS m/z (ESI)： 461.2[M+H]+；1H NMR (400MHz, DMSO-d6)：δ 10.57 (s, 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.
N- (3- (3- (2- ((2- methoxyl group -4- morphlinophenyls) amino) pyrimidine-4-yl) urea groups) phenyl) acrylamide (cpd-14) preparation
By N- (3- (3- (2- chlorine pyrimidine-4-yl) urea groups) phenyl) acrylamides (200mg, 0.62mmol) and 2- methoxies Base -4- morpholinoes aniline (131mg, 0.62mmol) is positioned in the stand up reaction bottle of 50mL, adds n-butanol (10mL) to make bottom Thing is partly dissolved.Trifluoroacetic acid (215mg, 1.89mmol) is added afterwards, and keeps reaction system to add under 110 degrees celsius Heat 3 hours.After question response terminates, room temperature is cooled to, after substrate reacts completely, reaction solution ethyl acetate/aqueous systems extraction Three times, organic layer is isolated, saturated sodium bicarbonate washing, saturated common salt water washing after anhydrous sodium sulfate drying, is concentrated under reduced pressure To crude product.Through Prep-HPLC column chromatographies [H2O(10mMNH4HCO3)：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%, spectral data：MS m/z (ESI)：490.7[M+H]+；1HNMR (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.
N- (3- (3- (2- ((2- methoxyl groups -4- (morpholine -4- carbonyls) phenyl) amino) pyrimidine-4-yl) urea groups) phenyl) third The preparation of acrylamide (cpd-15)
By (4- amino -3- methoxyphenyls) (morpholino) ketone (200mg, 0.63mmol) and TFA (216mg, 1.89mmol) it is added to 4 millis of N- (3- (3- (2- chlorine pyrimidine-4-yl) urea groups) phenyl) acrylamide (149mg, 0.63mmol) In rising butanol solution, be stirred vigorously 64 under 120 degrees Celsius, when.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, and organic layer is concentrated under reduced pressure to give crude product.Through preparation solution Phase separation purifies to obtain N- (3- (3- (2- ((2- methoxyl groups -4- (morpholine -4- carbonyls) phenyl) amino) pyrimidine-4-yl) urea groups) benzene Base) acrylamide (cpd-15) (66.7mg).Yield：21%, purity：99%, spectral data：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.
N- (3- (3- (2- ((2- methoxyl groups -4- (4- methyl piperazine -1- carbonyls) phenyl) amino) pyrimidine-4-yl) urea groups) Phenyl) acrylamide (cpd-16) preparation
By (4- amino -3- methoxyphenyls) (4- methylpiperazine-1-yls) ketone (200mg, 0.63mmol) and TFA (216mg, 1.89mmol) be added to N- (3- (3- (2- chlorine pyrimidine-4-yl) urea groups) phenyl) acrylamide (157mg, In 4 milliliters of butanol solutions 0.63mmol), it is stirred vigorously under 120 degrees Celsius 6 hours.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, and organic layer is concentrated under reduced pressure to give slightly Product.N- (3- (3- (2- ((2- methoxyl groups -4- (4- methyl piperazine -1- carbonyls) phenyl) ammonia is purified to obtain through preparing liquid phase separation Base) pyrimidine-4-yl) urea groups) phenyl) acrylamide (cpd-16) (17.31mg).Yield：5%, purity：100%, wave spectrum number According to：MS m/z (ESI)：531.2[M+H]+；1H NMR (400MHz, CDC13) 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, N- diethyl -3- methoxyl groups The preparation of benzamide (cpd-17)
By 4- amino-N, N- diethyl -3- methoxy benzamides (200mg, 0.63mmol) and TFA (216mg, 1.89mmol) it is added to 4 millis of N- (3- (3- (2- chlorine pyrimidine-4-yl) urea groups) phenyl) acrylamide (140mg, 0.63mmol) Rise in butanol solution, be stirred vigorously under 110 degrees Celsius 6 hours.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, and organic layer is concentrated under reduced pressure to give crude product.Through preparing plate 4- ((4- (3- (3- acryloyl groups amide phenyl) urea groups) pyrimidine -2-base) ammonia is obtained with the purifying of Combi-Flash reversed phase column chromatographies Base)-N, N- diethyl -3- methoxy benzamides (cpd-17) (8.14mg).Yield：2%, purity：95%, spectral data： 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.
N- (3- (3- (2- ((4- (2- methoxy ethoxies) phenyl) amino) pyrimidine-4-yl) urea groups) phenyl) acrylamide (cpd-18) preparation
4- (2- methoxy ethoxies) aniline (105mg, 0.63mmol) and trifluoroacetic acid (216mg, 1.9mmol) are added To 5 milliliters of butanol solutions of N- (3- (3- (2- chlorine pyrimidine-4-yl) urea groups) phenyl) acrylamide (200mg, 0.63mmol) In, it is stirred vigorously under 110 degrees Celsius 4 hours.After reaction terminates, system is cooled to room temperature, and be concentrated under reduced pressure to obtain brown solid.Through system Standby liquid phase purifying obtains N- (3- (3- (2- ((4- (2- methoxy ethoxies) phenyl) amino) pyrimidine-4-yl) urea groups) phenyl) Acrylamide (cpd-18) (4.70mg).Yield：2%, purity：96.2%, spectral data：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.
N- (3- (3- (2- ((2- methoxyl groups -4- (piperidin-1-yl) phenyl) amino) pyrimidine-4-yl) urea groups) phenyl) propylene The preparation of acid amides (cpd-19)
By 2- methoxyl groups -4- (piperidin-1-yl) aniline (130mg, 0.63mmol) and trifluoroacetic acid (216mg, 1.9mmol) It is added to 4 milliliters of n-butanols of N- (3- (3- (2- chlorine pyrimidine-4-yl) urea groups) phenyl) acrylamide (200mg, 0.63mmol) In solution, it is stirred vigorously under 110 degrees Celsius 4 hours.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) ureas are obtained through preparing liquid phase purifying Base) phenyl) acrylamide (cpd-19) (41.19mg).Yield：14%, purity：98.65%, spectral data：MSm/z(ESI)： 488.3[M+H]+；1H NMR (400MHz, DMSO-d6)：δ 10.47 (s, 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.
N- (3- (3- (2- ((4- (4- (2- fluoro ethyls) piperazine -1- bases) -2- anisyls) amino) pyrimidine-4-yl) ureas Base) phenyl) acrylamide (cpd-20) preparation
By N- (3- (3- (2- chlorine pyrimidine-4-yl) urea groups) phenyl) acrylamides (200mg, 0.62mmol) and 4- (4- (2- Fluoro ethyl) piperazine -1- bases) -2- aminoanisoles (157mg, 0.62mmol) are positioned in the stand up reaction bottle of 50mL, add just Butanol (10mL) is partly dissolved substrate.Trifluoroacetic acid (215mg, 1.89mmol) is added afterwards, and keeps reaction system 110 Heated 3 hours under degrees celsius.After question response terminates, room temperature is cooled to, after substrate reacts completely, reaction solution acetic acid second Ester/aqueous systems are extracted three times, isolate organic layer, saturated sodium bicarbonate washing, saturated common salt water washing, anhydrous sodium sulfate drying Afterwards, it is concentrated under reduced pressure to give crude product.Through Prep-HPLC column chromatographies [H2O(10mM NH4HCO3)：CH3CN=65：35~5：951 is pure Change 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%, spectral data：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.
N- (3- (3- (2- ((4- (diethylamino) -2- methoxyphenyls) amino) pyrimidine-4-yl) urea groups) phenyl) third The preparation of acrylamide (cpd-21)
By N- (3- (3- (2- chlorine pyrimidine-4-yl) urea groups) phenyl) acrylamides (200mg, 0.62mmol) and N, N- diethyl Base -3- methoxybenzenes-Isosorbide-5-Nitrae -- diamines (157mg, 0.62mmol) is positioned in the stand up reaction bottle of 50mL, plus 2 just-Butanol (10mL) is partly dissolved substrate.Trifluoroacetic acid (215mg, 1.89mmol) is added afterwards, and keeps reaction system Celsius 110 Under the conditions of degree heating 34, when.After question response terminates, room temperature is cooled to, after substrate reacts completely, reaction solution ethyl acetate/ Aqueous systems are extracted three times, isolate organic layer, and saturated sodium bicarbonate is washed, saturated common salt water washing, after anhydrous sodium sulfate drying, It is concentrated under reduced pressure to give crude product.Through Prep-HPLC column chromatographies [H2O(10mMNH4HCO3)：CH3CN=65：35~5：95] purify To 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%, spectral data：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.
N- (3- (3- (2- ((4- (4- (diethylamino) piperidin-1-yl) -2- anisyls) amino) pyrimidine-4-yl) ureas Base) phenyl) acrylamide (cpd-22) preparation
By N- (3- (3- (2- chlorine pyrimidine-4-yl) urea groups) phenyl) acrylamides (200mg, 0.62mmol) and 1- (4- ammonia Base -3- methoxyphenyls)-N, N- diethyls phenylpiperidines -4- amine (157mg, 0.62mmol) is positioned in the stand up reaction bottle of 50mL, Adding n-butanol (10mL) is partly dissolved substrate.Trifluoroacetic acid (215mg, 1.89mmol) is added afterwards, and keeps reactant Tie up to heating 31 under 110 degrees celsius, when.After question response terminates, room temperature is cooled to, after substrate reacts completely, reaction solution Extracted three times with ethyl acetate/aqueous systems, isolate organic layer, saturated sodium bicarbonate washing, saturated common salt water washing, anhydrous sulphur After sour sodium is dried, crude product is concentrated under reduced pressure to give.Through Prep-HPLC column chromatographies [H2O(10mM NH4HCO3)：CH3CN=65：35 ~5：95] purifying obtain N- (3- (3- (2- ((4- (4- (diethylamino) piperidin-1-yl) -2- anisyls) amino) pyrimidine - 4- yls) urea groups) phenyl) acrylamide (cpd-22) (26.31mg).Yield：7.6%, purity：100%, spectral data：MS M/z (ESI)：559.3[M+H]+；1H NMR (400MHz, DMSO-d6)：δ 10.45 (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 (1m, 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.
N- (3- (3- (2- ((4- (4- ethyl piperazidine -1- the bases) -2- methoxyphenyls) amino) base of pyrimidine 4.) urea groups) benzene Base) acrylamide (cpd-23) preparation
By 4- (4- ethyl piperazidine -1- bases) -2- aminoanisoles (150mg, 0.63mmol) and trifluoroacetic acid (216mg, 1.9mmol) it is added to 3 millis of N- (3- (3- (2- chlorine pyrimidine-4-yl) urea groups) phenyl) acrylamide (200mg, 0.63mmol) Rise in butanol solution, be stirred vigorously under 110 degrees Celsius 3 hours.After reaction terminates, system is cooled to room temperature, is concentrated under reduced pressure Brown solid.N- (3- (3- (2- ((4- (4- ethyl piperazidine -1- bases) -2- methoxyphenyls) ammonia is obtained through preparing liquid phase purifying Base) pyrimidine-4-yl) urea groups) phenyl) acrylamide (cpd-23) (60.25mg).Yield：19%, purity：98.21%, wave spectrum Data：MS m/z (ESI)：517.2[M+H]+；1H NMR (400MHz, DMSO-d6)：δ 10.48 (s, 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) acrylamides (200mg, 0.62mmol) and 4- methylbenzenes Amine (67mg, 0.62mmol) is positioned in the stand up reaction bottle of 50mL, adds n-butanol (10mL) to be partly dissolved substrate.Afterwards Trifluoroacetic acid (215mg, 1.89mmol) is added, and keeps reaction system to be heated 3 hours under 110 degrees celsius.Question response After end, room temperature is cooled to, after substrate reacts completely, reaction solution ethyl acetate/aqueous systems are extracted three times, are isolated organic Layer, saturated sodium bicarbonate washing, 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) (97.43mg).Yield：40%, it is pure Degree：97.42%, spectral data：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.
N- (3- (3- (2- ((5- (4- methylpiperazine-1-yls) pyridine -2- bases) amino) pyrimidine-4-yl) urea groups) phenyl) third The preparation of acrylamide (cpd-25)
By N- (3- (3- (2- chlorine pyrimidine-4-yl) urea groups) phenyl) acrylamides (200mg, 0.62mmol) and 5- (4- first Base piperazine -1- bases) pyridine -2- amine (69mg, 0.62mmol) is positioned in the stand up reaction bottle of 50mL, adds n-butanol (10mL) It is partly dissolved substrate.Trifluoroacetic acid (215mg, 1.89mmol) is added afterwards, and keeps reaction system in 110 degrees celsius Lower heating 3 hours.After question response terminates, room temperature is cooled to, after substrate reacts completely, reaction solution ethyl acetate/aqueous systems Extraction three times, isolates organic layer, and saturated sodium bicarbonate washing, saturated common salt water washing after anhydrous sodium sulfate drying, depressurizes dense Contracting obtains crude product.After reaction terminates, filtering, filtrate concentrated under reduced pressure obtains yellow solid, and N- (3- are obtained to prepare liquid phase purifying (3- (2- ((5- (4- methylpiperazine-1-yls) pyridine -2- bases) amino) pyrimidine-4-yl) urea groups) phenyl) acrylamide (cpd- 25)(16.041mg).Yield：4%, purity：98.37%, spectral data：MS m/z (ESI)：474.1[M+H]+；1H NMR (400MHz, DMSO-d6)：δ 10.63 (s, 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) acrylamides (200mg, 0.62mmol) and para-fluoroaniline (69mg, 0.62mmol) is positioned in the stand up reaction bottle of 50mL, adds n-butanol (10mL) to be partly dissolved substrate.Afterwards plus Enter trifluoroacetic acid (215mg, 1.89mmol), and keep reaction system to heat 34 under 110 degrees celsius, when.Question response knot Shu Hou, is cooled to room temperature, and after substrate reacts completely, reaction solution ethyl acetate/aqueous systems are extracted three times, are isolated organic Layer, saturated sodium bicarbonate washing, 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- fluorine Phenyl) amino) pyrimidine-4-yl) urea groups) phenyl) acrylamide (cpd-26) (8.22mg).Yield：3.4%, purity： 97.42%, spectral data：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.
N- (3- (3- (2- ((4- ethoxyl phenenyls) amino) pyrimidine-4-yl) urea groups) phenyl) acrylamide (cpd-27) Prepare
By N- (3- (3- (2- chlorine pyrimidine-4-yl) urea groups) phenyl) acrylamides (200mg, 0.62mmol) and to ethyoxyl Aniline (85mg, 0.62mmol) is positioned in the stand up reaction bottle of 50mL, adds n-butanol (10mL) to be partly dissolved substrate.It Trifluoroacetic acid (215mg, 1.89mmol) is added afterwards, and keeps reaction system to be heated 3 hours under 110 degrees celsius.Treat anti- After should terminating, room temperature is cooled to, after substrate reacts completely, reaction solution ethyl acetate/aqueous systems are extracted three times, have been isolated Machine layer, saturated sodium bicarbonate washing, 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- second Phenyl) amino) pyrimidine-4-yl) urea groups) phenyl) acrylamide (cpd-27) (38.46mg).Yield：12.7%, purity： 100%, spectral data：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.
N- (3- (3- (2- ((2- methoxyphenyls) amino) pyrimidine-4-yl) urea groups) phenyl) acrylamide (cpd-28) Prepare
2- aminoanisoles (116mg, 0.63mmol) and TFA (216mg, 1.89mmol) are added to N- (3- (3- (2- Chlorine pyrimidine-4-yl) urea groups) phenyl) and acrylamide (200mg, 0.63mmol) 4 milliliters of butanol solutions in, under 110 degrees Celsius It is stirred vigorously 6 hours.After reaction terminates, system is cooled to room temperature, adds appropriate saturated solution of sodium bicarbonate, uses acetic acid second Ester/aqueous systems are extracted three times, and organic layer is concentrated under reduced pressure to give crude product.N- (3- (3- (2- are purified to obtain through preparing liquid phase separation ((2- methoxyphenyls) amino) pyrimidine-4-yl) urea groups) phenyl) acrylamide (cpd-28) (11.68mg).Yield：5%, it is pure Degree：100%, spectral data：MSm/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)
4- chloroanilines (80mg, 0.63mmol) and trifluoroacetic acid (216mg, 1.9mmol) are added to N- (3- (3- (2- chlorine Pyrimidine-4-yl) urea groups) phenyl) and acrylamide (200mg, 0.63mmol) 4 milliliters of butanol solutions in, it is acute under 110 degrees Celsius Strong stirring 3 hours.After reaction terminates, system is cooled to room temperature, and be concentrated under reduced pressure to obtain brown solid.N- is obtained through preparing liquid phase purifying (3- (3- (2- ((4- chlorphenyls) amino) pyrimidine-4-yl) urea groups) phenyl) acrylamide (cpd-29) (9.37mg).Yield： 4%, purity：100.0%, spectral data：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.
N- (3- (3- (2- ((3,4,5- trimethoxyphenyls) amino) pyrimidine-4-yl) urea groups) phenyl) acrylamide (cpd-30) preparation
By 3,4,5- trimethoxy-anilines (116mg, 0.63mmol) are added to N- (3- with TFA (216mg, 1.89mmol) (3- (2- chlorine pyrimidine-4-yl) urea groups) phenyl) acrylamide (200mg, 0.63mmol) 4 milliliters of butanol solutions in, 110 take the photograph It is stirred vigorously under family name's degree 6 hours.After reaction terminates, system is cooled to room temperature, adds appropriate saturated solution of sodium bicarbonate, uses second Acetoacetic ester/aqueous systems are extracted three times, and organic layer is concentrated under reduced pressure to give crude product.N- (3- (3- are purified to obtain through preparing liquid phase separation (2- ((3,4,5- trimethoxyphenyl) amino) pyrimidine-4-yl) urea groups) phenyl) acrylamide (cpd-30) (50.84mg).Produce Rate：17%, purity：100%, spectral data：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.
N- (3- (3- (2- ((4- morphlinophenyls) amino) pyrimidine-4-yl) urea groups) phenyl) acrylamide (cpd-31) Prepare
By N- (3- (3- (2- Chloropyrimide -4- bases) urea groups) phenyl) acrylamides (200mg, 0.63mmol) and 4- morpholines Base aniline (112mg, 0.62mmol) is positioned in the stand up reaction bottle of 50mL, adds n-butanol (10mL) to make substrate part molten Solution.Trifluoroacetic acid (215mg, 1.89mmol) is added afterwards, and keeps reaction system to be heated 6 hours under 110 degrees celsius. After question response terminates, room temperature is cooled to, after substrate reacts completely, reaction solution ethyl acetate/aqueous systems are extracted three times, are separated Go out organic layer, saturated sodium bicarbonate washing, 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- Morphlinophenyl) amino) pyrimidine-4-yl) urea groups) phenyl) acrylamide (cpd-31) (4.22mg).Yield：2%, purity： 100%, spectral data：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.
N- (3- (3- (2- ((4- (4- (dimethylamino) piperidin-1-yl) -2- anisyls) amino) pyrimidine-4-yl) - 3- methyl urea groups) phenyl) acrylamide (cpd-32) preparation
Step 1：The synthesis of the chloro- 4- methylaminopyrimidins of 2-
30% methylamine alcohol solution (7.63g, 73.8mmol) is added to the 200 of 2,4- dichloro pyrimidines (11g, 73.8mmol) In the mixed solution of milliliter ethanol and 80 ml methanols, it is stirred vigorously under 80 degrees Celsius 3 hours.After reaction terminates, system cooling To room temperature, it is concentrated under reduced pressure, the chloro- 4- methylaminopyrimidins (3.4g) of 2-, yield is purified to obtain through column chromatography：32%, purity：99%, ripple Modal data：MS m/z (ESI)： 144.1[M+H]+
Step 2：N- (4- (4- (dimethylamino) piperidin-1-yl) -2- methoxyphenyls)-N-4- methylpyrimidines -2,4- The synthesis of diamines
By 1- (4- amino -3- methoxyphenyls)-N, N- lupetidine -4- amine (1.39g, 5.57mmol) and trifluoro second Sour (1.91g, 16.72mmol) is added to 15 milliliters of butanol solutions of the chloro- 4- methylaminopyrimidins (800mg, 5.57mmol) of 12- In, it is stirred vigorously under 130 degrees Celsius 2 hours.After reaction terminates, system is cooled to room temperature, is diluted with water, with ethyl acetate/water System is extracted three times, isolates organic layer, and through washing, saturated common salt water washing after anhydrous sodium sulfate drying, is concentrated under reduced pressure brown Color solid, N- (4- (4- (dimethylamino) piperidin-1-yl) -2- methoxyphenyls)-N-4- first is obtained through column chromatographic isolation and purification Yl pyrimidines -2,4- diamines (1.4g).Yield：24%, purity：86%, spectral data：MS m/z (ESI)：357.2[M+H]+
Step 3：1- (2- (4- (4- (dimethylamino) piperidin-1-yl) -2- Methoxyphenylaminos) pyrimidine-4-yl) - The synthesis of 1- methyl -3- (3- nitrobenzophenones) urea
By the different hydrogen acid ether (hydrogen acid ester) of 3- nitrobenzene (500mg, 3mmol) be added to N- (4- (4- (dimethylamino) piperidin-1-yl)- 2- methoxyphenyls)-N-4- methylpyrimidine -2,15 milliliters of 1,2- dichloroethanes (DCE) solution of 4- diamines (700mg, 2mmol) In, it is stirred vigorously under 80 degrees Celsius 5 hours.After reaction terminates, system is cooled to room temperature, is concentrated under reduced pressure, and is purified through column chromatography 1- (2- (4- (4- (dimethylamino) piperidin-1-yl) -2- Methoxyphenylaminos) pyrimidine-4-yl) -1- methyl -3- (3- nitre Base phenyl) urea (100mg).Yield：11%, purity：74%, spectral data：MS m/z (ESI)：521.2[M+H]+
Step 4：1- (2- (4- (4- (dimethylamino) piperidin-1-yl) -2- Methoxyphenylaminos) pyrimidine-4-yl) - The synthesis of 1- methyl -3- (3- aminophenyls) urea
At room temperature, palladium carbon (10mmg, 10%wt) is added to 1- (2- (4- (4- (dimethylamino) piperidin-1-yl) -2- Methoxyphenylamino) pyrimidine-4-yl) -1- methyl -3- (3- nitrobenzophenones) urea (90mg, 0.17mmol) 20 ml methanols In solution, room temperature is stirred vigorously 3 hours in a hydrogen atmosphere.After reaction terminates, palladium carbon is filtered off, filtrate decompression is concentrated, obtained 1- (2- (4- (4- (dimethylamino) piperidin-1-yl) -2- Methoxyphenylaminos) pyrimidine-4-yl) -1- methyl -3- (3- ammonia Base phenyl) urea, it is directly used in next step reaction.Yield：92%, purity：70%, spectral data：MS m/z (ESI)：491.3[M +H]+
Step 5：N- (3- (3- (2- ((4- (4- (dimethylamino) piperidin-1-yl) -2- anisyls) amino) pyrimidine - 4- yls) -3- methyl urea groups) phenyl) and acrylamide (cpd-32) synthesis
Triethylamine (60mg, 0.55rmmol) is added to 1- (2- (4- (4- (dimethylamino) piperidin-1-yl) -2- first Methoxy phenyl) pyrimidine-4-yl) -1- methyl -3- (3- aminophenyls) urea (90mg, 0.18mmol) 2 milliliters of dichloromethane (DCM) in solution, it is stirred vigorously under 0 degree Celsius.By acryloyl chloride (20mg, 0.22mmol), under 0 degree Celsius, it is slowly added dropwise To in reaction solution.Kept for 0 degree Celsius stir 2 hours.Extent of reaction is detected by TLC, after substrate reacts completely, is added water dilute Release, extracted three times with ethyl acetate/aqueous systems, isolate organic layer, through washing, saturated common salt water washing, anhydrous sodium sulfate is done After dry, be concentrated under reduced pressure to obtain yellow solid, and N- (3- (3- (2- ((4- (4- (dimethylamino) piperazines are purified to obtain through preparing liquid phase separation Pyridine -1- bases) -2- anisyls) amino) pyrimidine-4-yl) -3- methyl urea groups) phenyl) acrylamide (cpd-32) (3.38mg). Yield：4%, purity：100.0%, spectral data：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
3- acrylamidos-N- (2- (2- methoxyl groups -4- (4- morpholino -1- bases) phenyl amino) pyrimidine-4-yl) piperidines - The preparation of 1- formamides (cpd-33)
Step 1：The synthesis of the chloro- 4- isocyanic acids pyrimidines of 2-
Under 0 degree Celsius, by 4- amino -2- chlorine pyrimidine (4.8g, 37.0rmol) be added to triphosgene (5.5g, In 200 milliliters of tetrahydrofuran solutions 18.5mmol), be then slowly added dropwise DIPEA (6.23g, 48.2mmol).It is stirred vigorously at room temperature 4 hours.Extent of reaction is detected by TLC, after substrate reacts completely, 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 in 100 milliliters of tetrahydrofuran solutions of the chloro- 4- isocyanic acids pyrimidines (5.0g, 32.2mmol) of 2-, 18 are stirred vigorously at room temperature small When.After reaction terminates, 150 milliliters of ethyl acetate are added to reaction system, with 150 milliliters of water washing organic phases, saturated aqueous common salt Washing, after anhydrous sodium sulfate drying, be concentrated under reduced pressure to obtain yellow solid, and compound as white solid is obtained through column chromatographic isolation and purification (3.5g).Yield：31%, purity：90%, spectral data：MS m/z (ESI)：356.2[M+H]+.
Step 3：The synthesis of 3- amino-N- (2- chlorine pyrimidine-4-yl) piperidines -1- formamides
By 1- ((2- chlorine pyrimidine-4-yl) carbamoyl) piperidines -3- carbamates (3.5g, 9.9mmol) It is dissolved in 50 milliliters of hydrochloric acid dioxane solutions, is stirred vigorously down 2 hours at room temperature.After reaction terminates, it is concentrated under reduced pressure white Solid chemical compound (2.4g), product is directly used in next step.Yield：94%, purity：85%, spectral data：MS m/z (ESI)： 256.1[M+H]+。
Step 4：The synthesis of 3- acrylamidos-N- (2- chlorine pyrimidine-4-yl) piperidines -1- formamides
Triethylamine (2.5g, 24.6mmol) is added to 3- amino-N- (2- chlorine pyrimidine-4-yl) piperidines -1- formamides In 50 milliliters of tetrahydrofuran solutions of (2.1g, 8.21mmol), it is stirred vigorously under 0 degree Celsius.By acryloyl chloride (820mg, 9.1mmol), under 0 degree Celsius, it is slowly dropped in reaction solution.Kept for 0 degree Celsius stir 3 hours, be slowly increased to room temperature, after Continuous stirring 20 hours.After detecting that extent of reaction, reaction terminate by TLC, 80 milliliters of ethyl acetate are added to reaction system, with 50 Milliliter water washing organic phase, saturated common salt water washing, after anhydrous sodium sulfate drying, be concentrated under reduced pressure to obtain yellow solid, through column chromatography Isolate and purify to obtain compound as white solid (640mg).Yield：24%, purity：92%, spectral data：MS m/z (ESI)： 310.1[M+H]+。
Step 5：3- acrylamidos-N- (2- (2- methoxyl groups -4- (4- morpholino -1- bases) phenyl amino) pyrimidine -4- Base) piperidines -1- formamides (cpd-33) synthesis
By 2- methoxyl groups -4- (4- morpholino -1- bases) aniline (141mg, 0.48mmol) and trifluoroacetic acid (166mg, 1.45mmol) it is added to the 3 of 3- acrylamidos-N- (2- chlorine pyrimidine-4-yl) piperidines -1- formamides (150mg, 0.48mmol) In milliliter butanol solution, it is stirred vigorously under 120 degrees Celsius 2 hours.After reaction terminates, system is cooled to room temperature, is concentrated under reduced pressure Obtain brown solid.Cpd-33 (51.49mg) is obtained through preparing liquid phase purifying.Yield：20%, purity：100.0%, wave spectrum number According to：MS m/z (ESI)：565.3[M+H]+；1H NMR (400MHz, DMSO-d6)：δ 9.39 (d, 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.
3- acrylamidos-N- (2- (2- methoxyl groups -4- (4- methylpiperazine-1-yls) phenyl amino) pyrimidine-4-yl) piperazine The preparation of pyridine -1- formamides (cpd-34)
By 2- methoxyl groups -4- (4- methylpiperazine-1-yls) aniline (107mg, 0.48mmol) and trifluoroacetic acid (166mg, 1.45mmol) it is added to the 3 of 3- acrylamidos-N- (2- chlorine pyrimidine-4-yl) piperidines -1- formamides (150mg, 0.48mmol) In milliliter butanol solution, it is stirred vigorously under 120 degrees Celsius 2 hours.After reaction terminates, system is cooled to room temperature, is concentrated under reduced pressure Obtain brown solid.Compound cpd-34 (48.53mg) is obtained through preparing liquid phase purifying.Yield：21%, purity：100.0%.Ripple Modal data：MSm/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.
3- acrylamidos-N- (2- (2- methoxyl groups -4- (1- methyl piperidine -4- bases) phenyl amino) pyrimidine-4-yl) piperazine The preparation of pyridine -1- formamides (cpd-35)
By 2- methoxyl groups -4- (1- methyl piperidine -4- bases) aniline (85mg, 0.39mmol) and trifluoroacetic acid (135mg, 1.16mol) it is added to the 3 of 3- acrylamidos-N- (2- chlorine pyrimidine-4-yl) piperidines -1- formamides (120mg, 0.39mmol) In milliliter butanol solution, it is stirred vigorously under 130 degrees Celsius 2 hours.After reaction terminates, system is cooled to room temperature, is concentrated under reduced pressure Obtain brown solid.Cpd-35 (6.76mg) is obtained through preparing liquid phase purifying.Yield：4%, purity：94.53%.Spectral data：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.
3- acrylamidos-N- (2- (4- ((2- (dimethylamino) ethyl) (methyl) amino) -2- methoxyphenyl ammonia Base) pyrimidine-4-yl) piperidines -1- formamides (cpd-36) preparation
Step 1：The synthesis of N- (2- (dimethylamino) ethyl) -3- methoxyl group -4- nitroanilines
By N, N ,-dimethyl-ethylenediamine (8.36g, 81.9mmol) and potassium carbonate (12.1g, 122.8 mmol) are added to 4- In the DMF of 200 milliliters of fluoro- 2- methoxyl groups -1- nitrobenzene (7g, 40.9mmol), 24h is stirred vigorously under 50 degrees Celsius.Pass through TLC detects extent of reaction, after substrate reacts completely, adds 200 milliliters of water, is extracted three times with ethyl acetate/aqueous systems, separates Go out organic layer, be concentrated under reduced pressure to give crude product, through Combi-Flash column chromatographies purify N- (2- (dimethylamino) ethyl)- 3- methoxyl group -4- nitroanilines (6.5g).Yield：63%, purity：100%.Spectral data：MS m/z (ESI)：254.1[M+ H]+。
Step 2：The synthesis of N1- (2- (dimethylamino) ethyl) -3- methoxybenzenes-Isosorbide-5-Nitrae-diamines
Reduced iron powder (256mg, 4.74mmol) is added to N- (2- (dimethylamino) ethyl) -3- methoxyl group -4- nitre 3 milliliters of ethanol of base aniline (150mg, 0.59mmol) and 6 drip in solution, instill one and drip hydrochloric acid, under 100 degrees Celsius acutely Stirring 4 hours.Extent of reaction is detected by TLC, after substrate reacts completely, filtering, filtrate decompression is concentrated to give N1- (2- (two Methylamino) ethyl) -3- methoxybenzenes-Isosorbide-5-Nitrae-diamines (120mg).Yield：95%, purity：70%.Spectral data：MS m/z (ESI)：224.2[M+H]+。
Step 3：3- acrylamidos-N- (2- (4- ((2- (dimethylamino) ethyl) (methyl) amino) -2- methoxyl groups Phenyl amino) pyrimidine-4-yl) piperidines -1- formamides synthesis
Under 0 degree Celsius, by 3- acrylamidos-N- (2- chlorine pyrimidine-4-yl) piperidines -1- formamides (100mg, 0.32mmol) N1- (2- (dimethylamino) ethyl) -3- methoxybenzenes-Isosorbide-5-Nitrae-two are added to TEA (66mg, 0.65mmol) In 2 milliliters of dichloromethane solutions of amine (110mg, 0.48mmol), it is stirred vigorously under 0 degree Celsius 2 hours.After reaction terminates, plus Water dilutes, and is extracted three times with methylene chloride/water system, and organic layer is concentrated under reduced pressure to give crude product.Purified through preparing liquid phase separation Obtain cpd-36 (41.19mg).Yield：26%, purity：97%.Spectral data：MSm/z (ESI)：497.2[M+H]+；1H NMR (400MHz, DMSO) δ 9.40 (d, 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.
N- (3- (2- (2- (2- methoxyl groups -4- (4- methylpiperazine-1-yls) phenyl amino) pyrimidine-4-yl) -2- methyl-props Acylamino-) phenyl) acrylamide (cpd-37) trifluoroacetate preparation
Step 1：The synthesis of 2- (2- chlorine pyrimidine-4-yl) diethyl malonate
Diethyl malonate (6.5.0g, 40.0mmol) is positioned in the stand up reaction bottle of 500mL, dry toluene is added (100mL) mixed solution dissolves it.At ambient temperature, to stirring reaction bulb in add sodium hydride (4.4g, 80.0mmol), reaction system is persistently then stirred into half an hour at ambient temperature.Afterwards by 2,4- dichloro pyrimidines (5.0g, 34.0mmol) add in reaction system, reaction system adds Pd with after nitrogen displacement air three times2(dba)3(600mg, 0.68mmol) with P (t-Bu)3(280mg, 1.36mmol), uses nitrogen displacement air three times again afterwards.Reaction system is heated to 80 degrees Celsius, and continue stirring 16 hours.Extent of reaction is detected by TLC, after substrate reacts completely, it is heavy to be filtered to remove Form sediment, filter cake ethyl acetate drip washing three times.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 positioned over the stand up reaction bottle of 250mL In, add DMSO/H2O (100mL/2mL) mixed solution dissolves substrate.At ambient temperature, to stirring reaction bulb according to Secondary addition sodium chloride (600mg, 10.0mmol), is then heated to reaction system 140 degrees Celsius and is kept stirring for 5 hours.It is logical TLC detection extent of reactions are crossed, after substrate reacts completely, ethyl acetate/aqueous systems are extracted three times, organic layer are isolated, through water Wash, saturated common salt water washing, after anhydrous sodium sulfate drying, be concentrated under reduced pressure to give target compound (1.4g, 7.0mmol), directly For next step reaction.
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 positioned in the stand up reaction bottle of 100mL, plus Entering acetone (50mL) dissolves substrate.At ambient temperature, to stirring reaction bulb in sequentially add potassium carbonate (2.9g, 21.0mmol) with iodomethane (1.5g, 10.5mmol), reaction system is then heated to 60 degrees Celsius and is kept stirring for 5 hours. Extent of reaction is detected by TLC, after substrate reacts completely, precipitation, filter cake ethyl acetate drip washing three times, filtrate is filtered to remove Crude product is concentrated under reduced pressure to give, through Combi-Flash [EA：PE=5：95-50：50] column chromatography purifying obtain target compound without Color oily (900mg, 4.0mmol).Yield：39% (two steps)；Purity：90%；Spectral data：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 positioned over the single port reaction of 50mL In bottle, methyl alcohol (5mL) is added to be partly dissolved substrate.1N sodium hydrate aqueous solutions (5mL) is added afterwards, and keeps reaction system Persistently stir 6 hours at ambient temperature.Extent of reaction, after substrate reacts completely, reaction solution acetic acid second are detected by TLC Ester/aqueous systems extraction once, separates water-yielding stratum, with pH value to 5 in 2N aqueous hydrochloric acid solutions, three is extracted with ethyl acetate/aqueous systems It is secondary, isolate organic layer, saturated common salt water washing, after anhydrous sodium sulfate drying, (2- chlorine is phonetic to be concentrated under reduced pressure to give crude product 2- Pyridine -4- bases) -2 Methylpropionic acid (450mg, 2.25mmol), direct plunge into the next step.Yield：56%；Purity：95%.Wave spectrum Data：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 positioned over the stand up reaction bottle of 50mL In, add thionyl chloride (5mL) to be partly dissolved substrate.Reaction system is heated to 80 degrees Celsius afterwards and to continue stirring 1 small When.After question response terminates, vacuum distillation removes unnecessary thionyl chloride and obtains acyl chlorides crude product.By acyl chlorides under 0 degrees celsius Crude product is slowly added into the dichloromethane of benzene -1,3- diamines (365mg, 3.38mmol) and triethylamine (0.63mL, 4.5mmol) In (10mL) solution, reaction system is kept persistently to be stirred under 0 degrees celsius 1 hour.Extent of reaction is detected by TLC, is treated After substrate reacts completely, reaction solution is extracted three times with methylene chloride/water system, isolates organic layer, saturated common salt water washing, nothing After aqueous sodium persulfate is dried, crude product (700mg) is concentrated under reduced pressure to give, direct plunges into the next step.
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 positioned over the list of 50mL In mouth reaction bulb, dichloromethane (10mL) is added to dissolve substrate.Afterwards triethylamine is sequentially added under 0 degrees celsius (1mL) and acryloyl chloride (0.5mL), and keep reaction system persistently to be stirred under 0 degrees celsius 1 hour.Detected by TLC Extent of reaction, reaction solution is extracted three times with methylene chloride/water system, isolates organic layer, saturated common salt water washing, anhydrous slufuric acid After sodium is dried, crude product (710mg, 0.91mmol) is concentrated under reduced pressure to give, direct plunges into the next step.Yield：40% (two steps)； Purity：44%；Spectral data：MS m/z (ESI)：345.7[M+H]+。
Step 7：N- (3- (2- (2- (2- methoxyl groups -4- (4- methylpiperazine-1-yls) phenyl amino) pyrimidine-4-yl) -2- Methylpropionylamino) phenyl) acrylamide trifluoroacetate synthesis
By N- (3- (2- (2- chlorine pyrimidine-4-yl) -2- methylpropionylaminos) phenyl) acrylamide (710mg, The single port that 50mL 0.91mmol) is positioned over 2- methoxyl groups -4- (4- methylpiperazine-1-yls) aniline (402mg, 1.82mmol) is anti- Answer in bottle, add n-butanol (10mL) to be partly dissolved substrate.Trifluoroacetic acid (620mg, 5.46mmol) is added afterwards, and is kept Reaction system is heated 16 hours under 130 degrees celsius.After question response terminates, room temperature is cooled to, is concentrated under reduced pressure to give thick product Thing.Through Prep-HPLC column chromatographies [H2O (0.05%TFA)：CH3CN=65：35~5：95] purifying obtains target product cpd-37's Trifluoroacetate (10.38mg, 0.016mmol).Yield：1.8%；Purity：95%；Spectral data：MS m/z (ESI)：530.7 [M+H]+；1H NMR (400MHz, CDC13)：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 38Enzyme platform (z-lyte) drug screening
Agents useful for same is purchased from Invitrogen in following z-lyte method of testings.
Using z-lyte methods determine determinand to double-mutant EGFR kinases T790M/L858R kinases (Invitrogen, PV4879), Wild type EGFR kinases T790M WT (Invitrogen, PV3872) kinases, single mutation type EGFR kinases L858R swash The inhibitory action of enzyme (Invitrogen, PV4128) activity.
The working concentration of each component is in T790M/L858R kinase reactions：25 μM of AT P, 0.08ng/ μ LT790M/ L858R kinases, 2 μM of Tyr04 substrates (Invitrogen, PV3193).The concentration of DMSO is 2% after addition determinand.
The working concentration of each component is in T790M WT kinase reactions：10 μM of ATP, 0.8ng/ μ LT790M WT kinases, 2 μ MTyr04 substrates (Invitrogen, PV3193).The concentration of DMSO is 2% after addition determinand.
The medicine storing liquid of room-temperature dissolution 10mM is through the water gradient dilution of 4%DMSO to 10-0.005 μM of final concentration.Per hole (or T790M WT swash the T790M/L858R kinases of the reacted buffer solution dilution of the determinand solution and 5 μ L of 2.5 μ L of middle addition Enzyme) with the mixture of Tyr04 substrates, the ATP for adding 2.5 μ L starts reaction.After room temperature shaker reacts 60 minutes.Add 5 μ LDevelopment Reagent B (Invitrogen is diluted with TR-FRET dilution buffers), in room temperature shaker reaction 60 minutes.The read plate on VictorX5 fluorescence microplate readers (PerkinElmer), determines excitation wavelength for 340nm launch wavelengths are 500nm and 520nm light absorbs.
The inhibiting rate of ratio calculation compound according to 520nm/500nm to enzymatic activity.With XLFIT5.0 softwares (Britain IDBS companies) the Fitting Calculation half-inhibition concentration IC50。
Table 1- enzyme inhibition activities
The selection inhibitory activity of table 2- enzymes
Table 3-L858R enzyme inhibition activities
Inhibitory action of the determinand to EGFR L858R kinase activities is determined using z-lyte methods.L858R kinase reactions The working concentration of middle each component is：50 μM of ATP, 0.25ng/ μ LL858R kinases, 2 μM of Tyr04 substrates (Invitrogen, PV3193).The concentration of DMSO is 2% after addition determinand.
The medicine storing liquid of room-temperature dissolution 10mM is diluted to final concentration of 1 μM through the water of 4%DMSO.2.5 μ are added in per hole The mixture of the EGFR L858R kinases and Tyr04 substrates of the determinand solution of L and the reacted buffer solution dilutions of 5 μ L, then add The ATP for entering 2.5 μ L starts reaction.After room temperature shaker reacts 60 minutes.Add 5 μ L Development Reagent B (Invitrogen is diluted with TR-FRET dilution buffers), reacts 60 minutes in room temperature shaker.In VictorX5 fluorescence Read plate on ELIASA (PerkinElmer), it is that 340nm launch wavelengths are 500nm and 520nm light absorbs to determine excitation wavelength.
The inhibiting rate of ratio calculation compound according to 520nm/500nm to enzymatic activity.Estimate that half presses down with below equation Concentration IC50 processed：IC50=【(1-IH%)/IH%】×1μM.The IC50 values of the L858R of CO1686 are according to above-mentioned T790M/L858R The actual measurement of kinases identical method of testing is obtained, and result of calculation is as shown in table 3：
Table 3
From table 1, table 2 and table 3 as can be seen that with positive control CO1686 (referring specifically to document Cancer Discovery,doi：10.1158/2159-8290.CD-13-0314) compare, example compound of the invention is mutated to EGFR Type enzyme (T790M/L858R and L858R) shows stronger inhibitory activity, and EGFR wild-type enzymes (EGFR WT) are suppressed to live Property it is weaker, therefore compound of the invention to EGFR mutant enzymes have preferably selection inhibitory activity.
Embodiment 39.MTT (3- (4,5- dimethylthiazole -2) -2,5- diphenyltetrazolium bromide bromides) method detection cell is lived Property
MTT method of testings step is carried out using method well known to those skilled in the art, agents useful for same Jun Ke cities in method Buy.
First, the 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, be subsequently adding 3.5mL trainings Support base and terminate digestion.The cell suspending liquid that will have been digested moves to 15mL centrifuge tubes, and 1300rpm abandons supernatant after being centrifuged 3 minutes, and With fresh culture medium suspension cell.
Then cell count, and diluting cells are to following concentration：A431 and H1975 cells/mls 2.78 ten thousand, NIH3T3 Every milliliter 3.33 ten thousand.Cell kind is entered into 96 orifice plates (BD3072), 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)；
Take 20 μ L10mM testing compounds, 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 hole 10ul medicines in Tissue Culture Plate, adding serum-free training Support base (final concentration of：10,3.333,1.111,0.370,0.123,0.041,0.014,0.005 μM), wherein DMSO final concentrations It is 0.5%.
Cell is put into incubator after dosing, after culture 72 hours, added per hole the 5mg/ml of 10 μ L MTT (Sigma, Then 96 orifice plates are put into 37 DEG C of 5%CO by M5655) solution2Incubator is incubated 4 hours.
Flat board is centrifuged under conditions of 2000rpm, 5min again, after removing supernatant, 150 μ L DMSO is added per hole, and shaking Flat board to all crystal violets are shaken in bed to dissolve (about 10-20 minutes).492nm light absorbs finally are determined using fluorescence microplate reader, IC is calculated using XLFIT5.0 softwares (IDBS companies of Britain)50。
The histamine result (H1975 cells) of table 4- compound on intracellular activity
The histamine result (A431 cells) of table 5- compound on intracellular activity
The selectivity of table 6- compound on intracellular
Toxic test results of the table 7- compounds to NIH3T3 cells
From table 4-6 can be seen that compound of the invention EGFR mutant cells (H1975 cells) are shown it is stronger Inhibitory activity, and weaker inhibitory activity is shown to EGFR wild-type cells (A431 cells), therefore compound pair of the invention EGFR mutant cells have preferably selection inhibitory activity.
As can be seen from Table 7, compared with positive control CO1686, compound of the invention has to NIH3T3 cells IC50 values higher, thus it is shown that less toxicity.
Shown from vitro enzyme, cell growth inhibition test, the compounds of this invention EGFR mutant enzymes, cells show are gone out compared with Strong inhibitory activity, and go out weaker inhibitory activity to EGFR wild-type enzymes, cells show, therefore such compound is prominent to T790M The EGFR of change has preferably selection inhibitory activity and relatively low cytotoxicity.
The all documents referred in the present invention are all incorporated as reference in present application, independent just as each document It is incorporated as with reference to such.In addition, it is to be understood that after above-mentioned instruction content of the invention has been read, those skilled in the art can Made various changes or modifications with to the present invention, these equivalent form of values equally fall within the model that the application appended claims are limited Enclose.

Claims (7)

1. a kind of fragrant amino pyrimidines or its pharmaceutically acceptable salt, stereoisomer, the structure of the compound As shown in formula I：
In formula, A is selected from phenyl ring；
Z1Selected from NR9；
Wherein R9Selected from hydrogen or C1-6Alkyl；
Z2、Z3It is each independently selected from CR12Or N；
Wherein R12Selected from hydrogen；
R1Selected from hydrogen or C1-6Alkyl；
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, C1-6The ammonia of acyl group substitution Base, C1-6Alkyl-substituted diaminourea, cyano group, C1-6The C of alkyl, halo1-6Alkyl, C1-6Alkoxy, C1-6Alkoxy substitution C1-6Alkoxy, C6-10The C of aryl substitution1-6The C of alkoxy, halo1-6Alkoxy ,-O-C6-10Aryl ,-CO-C3-6Heterocycle Alkyl ,-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, C3-6 Heteroaryl or C3-6The substitution base that Heterocyclylalkyl can be selected from the group by one or more replaces：Nitro, halogen, cyano group, C1-6 The C of alkyl, halo1-6Alkyl, C1-6The C of alkoxy, halo1-6Alkoxy, C1-6Alkyl-substituted amino；
R13、R14It is each independently selected from hydrogen or C1-6Alkyl；
R7、R8It is each independently selected from hydrogen.
2. compound as claimed in claim 1 or its pharmaceutically acceptable salt, stereoisomer, it is selected from following composition Group：
N- (3- (3- (2- ((2- methoxyl groups -4- (4- methylpiperazine-1-yls) phenyl) amino) pyrimidine-4-yl) urea groups) phenyl) third 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- Base) 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) third 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) acryloyl Amine；
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- methoxybenzene first Acid amides；
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) acryloyl Amine；
N- (3- (3- (2- ((4- (4- (2- fluoro ethyls) piperazine -1- bases) -2- anisyls) amino) pyrimidine-4-yl) urea groups) benzene Base) acrylamide；
N- (3- (3- (2- ((4- (diethylamino) -2- methoxyphenyls) amino) pyrimidine-4-yl) urea groups) phenyl) acryloyl Amine；
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) third 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) acryloyl Amine；
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；Or
N- (3- (3- (2- ((4- (4- (dimethylamino) piperidin-1-yl) -2- anisyls) amino) pyrimidine-4-yl) -3- first Base urea groups) phenyl) acrylamide.
3. a kind of pharmaceutical composition, the composition includes：
Compound or its pharmaceutically acceptable salt, stereoisomer described in claim 1 or 2；And it is pharmaceutically acceptable Carrier.
4. the compound described in claim 1 or 2 is preparing regulation and control EGFR tyrosine kinase activities or treatment EGFR correlation diseases Application in the medicine of disease.
5. application as claimed in claim 4, wherein, described EGFR relevant diseases are selected from：Cancer, diabetes, immune system Disease, nerve degenerative diseases, angiocardiopathy, use during EGFR modulators for treatment with acquired resistance disease.
6. application as claimed in claim 5, wherein, the disease of the acquired resistance is encoded by EGFR extron 20s Caused by T790 mutation, or caused by the T790 mutation comprising EGFR extron 20s coding.
7. a kind of Pharmaceutical composition, the Pharmaceutical composition includes：
Compound or its pharmaceutically acceptable salt, stereoisomer described in claim 1 or 2；
And be selected from the group in medicine one or more：Gefitinib, Tarceva, Conmana, Lapatinib, XL647, NVP-AEE-788, ARRY-334543, EKB-569, BIBW2992, HKI272, BMS-690514, CI-1033, ZD6474, PF00299804, WZ4002, Cetuximab, Herceptin, handkerchief Buddhist nun prominent monoclonal antibody, matuzumab, Buddhist nun's trastuzumab, Zha Lu Wooden monoclonal antibody, handkerchief trastuzumab, MDX-214, CDX-110, IMC-11F8, Zemab, Her2 vaccine PX 1041, HSP90 inhibitor, CNF2024, KOS-953, Ah's spiramvcin, IPI-504, SNX-5422, NVP-AUY922 or its combination.
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