CN102958921A - Urea compounds as well as preparation methods, intermediates and uses thereof - Google Patents

Urea compounds as well as preparation methods, intermediates and uses thereof Download PDF

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CN102958921A
CN102958921A CN2012800016600A CN201280001660A CN102958921A CN 102958921 A CN102958921 A CN 102958921A CN 2012800016600 A CN2012800016600 A CN 2012800016600A CN 201280001660 A CN201280001660 A CN 201280001660A CN 102958921 A CN102958921 A CN 102958921A
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methyl
pyrimidine
substituted
alkyl
unsubstituted
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CN102958921B (en
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张庆文
周后元
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Shanghai Institute of Pharmaceutical Industry
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    • 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
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Abstract

Disclosed are urea compounds represented by formula I or pharmaceutically acceptable salts, polymorphic forms, solvates or stereoisomers thereof; as well as preparation methods, intermediates and uses thereof. The urea compounds according to the present invention show various degrees of inhibitory activity against a variety of protein kinases in biological tests, and showed various degrees of activity against tumor cell growth and against angiogenesis in in vitro tests on resistance to the proliferation of human tumor cell line and human umbilical vein endothelial cells (HUVECs) respectively, and also exhibit good antitumor activity in vivo in animals.

Description

A kind of carbamide compounds, its preparation method, its intermediate and its application
A kind of carbamide compounds, its preparation method, its intermediate and its applied technical field
It is particularly related to a kind of carbamide compounds, its preparation method, its intermediate and its application.Background technology
Signal transduction between cell interior and cell（Signal transduction) regulate and control the every aspect of cell function.The exception of cell signalling is the molecular basis of the complicated cause of disease of many diseases.Most signal transduction pathways are by protein kinase（Protein kinase) mediation.The phosphorylation of human protein kinase catalytic serine, threonine or tyrosine residue, is played an important role in the growth of cell, metabolism, differentiation and apoptosis.Disregulated protein kinases can cause a series of diseases including tumour, diabetes, autoimmune disease, nerve degenerative diseases and inflammation.Therefore, kinases inhibitor turns into an important channel for treating above-mentioned many mankind's major diseases.
Human kinase protein group membership more than 500 kinds (such as Manning G Science, 2002,298 (5600):1912- 1934), including EGFR-TK and serine/threonine kinase.Some are important to be exemplified below as the protein kinase of drug targets：HER kinases（Such as EGFR and HER-2), VEGFR kinases（Such as VEGFR- 1, VEGFR-2 standing grain mouthful VEGFR-3), PDGFR kinases（Such as PDGFRc PDGFRp c-KIT, CSF-1R standing grain mouthful FLT-3), SRC kinases（Such as SRC, LCK, FYN and HCK), ALK, BCR-ABL, c-MET, TIE-2, FGFR- K RAF kinases（Such as BRAF and CRAF), Aurora A（Such as Aurora A and Aurora B), p38 a, and above-mentioned kinases mutant strain（Such as BCR-ABL T315I and BRAF V599E).
Angiogenesis（Angiogenesis) refer to from the brand-new blood vessel of existing angiogenesis.Normal angiogenesis is the normal physiological processes by tight control, betides embryonic development, wound healing and menstrual cycle.Angiogenesis may cause a variety of diseases such as diabetic retinopathy, rheumatoid arthritis, age-related macular degeneration, artery sclerosis and tumour once lacking of proper care.
Angiogenesis is the lifeline for maintaining tumour existence and progress, and solid tumor highly relies on angiogenesis persistently to obtain nutrition and oxygen.Therefore, the newborn compound of target vascular therapy turns into the big focus that antineoplastic is studied, and expected its may have advantage in terms of security and the resistance to the action of a drug.Multi-kinase inhibitor Sorafenib, Sutent and the Pazopanib listed at present is respectively provided with anti-angiogenic rebirth activity.
The target of current anti-angiogenic rebirth includes growth factor（Such as VEGF, platelet derived growth factor receptor, fibroblast growth factor and EGF）, receptor tyrosine kinase, transcription factor（Such as hypoxia inducible factor（Hypoxia inducible factor)), and participate in the molecule of MAPK and PI3K signal transduction pathways.Wherein protein kinase target mainly include VEGFR- 1, VEGFR-2 VEGFR-3 FGFR- 1, PDGFRc PDGFRp, C-KIT, FLT-3, EGFR and TIE-2 etc..
Urea structure type compound is received extensively and in-depth study in recent years as kinases inhibitor.（The Current Opinion in Drug Discovery ＆ Development such as Dumas J, 2004,7 (5):600-616. )
1st, Sorafenib：
Sorafenib（Sorafenib) it is first selective multi-kinase inhibitor for being approved by the FDA in the United States listing, its chemical structure characteristic is diaryl urea（diaryl urea).Sorafenib is to the Raf-1 (IC in RAF/MEK/ERK signal transduction pathways50, 6 nM), wild type BRAF (IC50, 22 nM), V599E anomaly BRAF (IC5Q, 38 nM) and it is respectively provided with remarkable inhibiting activity.In addition, Sorafenib also potent can suppress a variety of receptor tyrosine kinases significant to angiogenesis（RTK) : VEGFR-2 (IC5., 90nM), mouse VEGFR-2 (IC5., 15nM), mouse VEGFR-3 (IC5., 20 nM), mouse PDGFR-P (IC50, 57 nM), c-KIT (IC50, 68 nM) and standing grain B FLT-3 (IC50, 58 nM).In a word, Sorafenib had both targetted RAF/MEK/ER signal transduction pathways blocks tumor cells propagation, and the cascade of VEGFR-2/PDGFR-P signal transductions is targetted again and suppresses neonate tumour blood vessel.（The Cancer Research such as Wilhelm SM, 2004,64 (19):7099-7109 )
Sorafenib
2nd, other urea structure kinases inhibitors：
Tandutinib (MLN-518) is in acute myelocytic leukemia（AML 11 phases) are clinical.It is receptor kinase FLT-3, c-KIT and PDGFR potent inhibitor（IC5The 220nM of Q 170), there is high selectivity relative to p38 kinases, VEGFR-2 and FGFR（IC5Q >30 μ Μ (the Current Opinion in Drug Discovery ＆ Development such as Dumas J, 2004,7 (5):600-616. )
Boehringer Ingelheim once developed the clinical test that 2-substituted carbamide compound BIRB796 enters treatment autoimmune disease.BIRB796 is the α Μ Α Ρ kinase inhibitors of ρ 38.（The Journal of Medicinal Chemistry such as Regan J, 2003,46 (22):4676-4686. )
The isothiazole compounds CP-547632 of Pfizer's report is potent VEGFR-2 and FGFR-1 inhibitor, IC5QRespectively 11 and 9nM, relative to EGFR, PDGFRp and other associated kinases show selectivity.CP-547632 has the double activity of angiogenesis inhibiting and tumor cell proliferation：The angiogenesis that potent suppression VEGFR and FGF are induced in model in vivo；In the athymic mouse of lotus people's xenograft tumor, oral administration can suppress 85% tumour growth.(the Cancer Research such as Beebe JS, 2003,63 (21):7301-7309. ) Abbott Laboratories are in order to find new many kinases receptors EGFR-TKs（RTK) inhibitor, is found that ABT-869, already into clinical test by the extensive structure activity study in Aminoindazole series compound.ICs of the ABT-869 to VEGFR-2, FLT-3 and c-KIT50Respectively 4,5 standing grain Jie 16nM.（The Journal of Medicinal Chemistry such as Dai YJ, 2007,50 (7): 1584-1
(the Journal of Medicinal such as the Hasegawa M Chemistry, 2007,50 such as Hasegawa of GlaxoSmithKline PLC:4453-4470.) report TIE-2 the and VEGFR-2 dual tyrosine kinase inhibitor (IC for representative with compound 150Respectively 4.9 and 1.5nM), in PBS (phosphate buffered saline (PBS)s）Middle solubility is about 20 (^g/mL.
(the Journal of Medicinal Chemistry such as Niculescu-Duvaz D, 2009,52 (8) such as Niculescu-Duvaz:2255-2264.) using bicyclic pyridine, simultaneously imidazolidinone, as hinge area binding fragment, obtains the potent (IC of BRAF inhibitor 2
The content of the invention
The technical problems to be solved by the invention are to provide a kind of and the entirely different carbamide compounds of prior art or its pharmaceutically acceptable salt, polymorph, solvate or stereoisomer, its preparation method, its intermediate, and its application. The carbamide compounds of the present invention have different degrees of inhibitory activity, and human tumor cell lines and Human umbilical vein endothelial cells in vitro for multiple protein kinases in biology test（HUVEC) display, with different degrees of antitumor cell growth and anti-angiogenic rebirth activity, also shows that preferably antitumor activity in animal body respectively in proliferation activity experiment.
Therefore, the present invention relates to a kind of carbamide compounds or its pharmaceutically acceptable salt, polymorph, solvate or stereoisomer shown in formula I；
Wherein, R2It is substituted or unsubstituted C^Cs alkyl for hydrogen（It is preferred that alkyl, such as n-propyl, isopropyl, normal-butyl, isobutyl group, the tert-butyl group or n-hexyl）, substituted or unsubstituted C3〜C9Cycloalkyl（It is preferred that C3〜C8Cycloalkyl, such as cyclohexyl）, substituted or unsubstituted C6〜C14Aryl（It is preferred that C6〜C1QAryl, such as phenyl or naphthyl）, it is substituted or unsubstituted3Heteroaryl（It is preferred that C3〜C9Heteroaryl, further preferred C3〜C5Heteroaryl, still further preferably thiazolyl, such as thiazol-2-yl；Or pyridine radicals, such as pyridin-4-yl or pyridine -2- bases；Or isoxazolyl, such as isoxazole -3- bases）；Substituent in substituted alkyl is 49 yuan（It is preferred that 46 yuan）Saturated heterocyclyl, the hetero atom number of the saturated heterocyclyl is 14, and hetero atom is nitrogen, oxygen or sulphur, such as pyrrolidin-1-yl；Substituent in substituted cycloalkyl is halogen, alkyl or alkoxy；Substituent in substituted aryl or substituted heteroaryl is halogen (such as fluorine, chlorine, bromine or iodine）, cyano group, haloalkyl（Such as trifluoromethyl）, C^ alkyl（Preferably, when heteroaryl is isoxazole -3- bases, isoxazole -3- bases form alkyl isoxazole -3- bases, such as 5- methylisoxazoles -3- bases after being replaced by alkyl）, CH^ alkoxies, C2〜C3Alkenyl, C2〜C3Block base and（Connection (3The amine formyl of alkyl）Substituted pyridine epoxide（It is preferred that 2- (N- methylcarbamoyls) pyridine -4- epoxides）In one or more, the number of every kind of substituent is 0,1 or multiple, and the position of substituent can be commutable optional position on aryl or heteroaryl, when aryl is phenyl ring, ortho position for urea side chain of the position of substituent, meta or para position；Hetero atom in heteroaryl is nitrogen, oxygen or sulphur, and hetero atom number is 15；
Or, R2And with, R2Cyclization is substituted or unsubstituted 49 yuan to connected nitrogen-atoms together（It is preferred that 57 yuan）Saturated heterocyclic（Such as morpholine ring）, the saturated heterocyclic can be additionally containing 13 hetero atoms, and the hetero atom is nitrogen, oxygen or sulphur, if additionally including unsubstituted on nitrogen-atoms, the nitrogen-atoms or further being replaced by alkyl；Substituent in described substituted 49 yuan saturated heterocyclic is halogen, alkyl or alkoxy； R3For hydrogen or alkyl；
For hydrogen, C^ alkyl, alkoxy, halogen, amino or cyano group；
、、 /R5
I
Q is hydrogen, halogen（Such as fluorine, chlorine, bromine or iodine）OrRs ；Wherein, R5It is amino, hydroxyl, cyano group, halogen or C3 alkoxies with the substituent independently being on hydrogen, substituted or unsubstituted alkyl, the substituted alkyl；
Or R5And and R5, cyclization is substituted or unsubstituted 49 yuan to connected nitrogen-atoms together（It is preferred that 57 yuan）Saturated heterocyclic, the saturated heterocyclic can be additionally containing 13 hetero atoms, and the hetero atom is nitrogen, oxygen or sulphur
(such as morpholine ring or piperazine ring）；C^ (preferably C^Cs) alkyl that substituent in described substituted 49 yuan saturated heterocyclic is halogen, alkyl, alkoxy or hydroxyl replace, when the C^Cs that the substituent in described substituted 49 yuan saturated heterocyclic is alkyl, alkoxy or hydroxyl substitution is (during preferably alkyl, substituent can be connected on the carbon atom in saturated heterocyclic or nitrogen-atoms, when substituent is halogen, substituent can be connected on the carbon atom in saturated heterocyclic, preferably, described substituted or unsubstituted 49 yuan（It is preferred that 57 yuan）Saturated heterocyclic is 4- (2- ethoxys) piperazine -1- bases, morpholinyl or 4- methylpiperazine-1-yls；
R7For hydrogen, CH^ alkyl, C3 alkoxies or C3 alkylthio groups；
R8、 R9、 R1()And RuIt independently is hydrogen, C3 alkyl, C3 alkoxies, halogen or cyano group；
Urea side chain It is connected to 2', 3' or 4'.In the present invention, described compound I most preferably for following any structure:
A2 -13-3 A2 -14-3
In the B2M-20-2 present invention, described carbamide compounds I pharmaceutically acceptable salt is above-mentioned carbamide compounds and the salt of inorganic acid or organic acid formation, or above-mentioned carbamide compounds and inorganic base or the salt of organic base formation.
The crystal form of compound of formula I in the present invention can be polymorphic, and these crystal forms are included in the present invention. In addition, compound of formula I in the present invention such as and water forms hydrate, or can also form organic solvate, these hydrates and organic solvent compound are also included in the present invention with solvent formation solvate with organic solvent.
The compound of the present invention may contain asymmetric atom, especially asymmetric carbon atom, all therefore and stereoisomer of generation（Including pure stereoisomers, or the mixture being made up of the stereoisomer of various ratios）It is regarded as the part of the present invention.
The invention further relates to above-claimed cpd I preparation method, it is any one in following methods：Method one, when including hydroxyl in Q, compound IX slough the reaction of the protection group of hydroxyl, you can；Compound ' conventional by this area for the hydroxyl in Q groups
IX I
Method two, compound XI and QH Jin Hang Shrink are closed and reacted, you can；In compound XI, group X' is that this area Ci Lei Shrink close the leaving group commonly used in reaction, such as halogen（Such as chlorine, bromine or iodine）；
QH■
XI
Method three, when not including hydroxyl in Q, by compound Χ Π Ι and R R2NH carries out into urea reaction, you can;
In above-mentioned three kinds of methods, the method and condition of the reaction being related to can be the conventional method and condition in the reaction of this area respective classes；The definition of each group is the same as those described above unless otherwise indicated.
Therefore, the compound I in the present invention can be prepared according to prior art using the methodology of organic synthesis of any suitable.Below by the present invention, compound I preferred preparation method is illustrated： 1. contain free hydroxyl group in compound I（By taking 2- (piperazine -1- bases) ethanol as an example）When synthesis synthetic route 1:First closed with QH Shrink, then carry out into urea reaction
Compound Π and compound III Shrink is closed first（For example, under acid catalysis, compound II and compound III Jia Re Shrink are closed）, the acid-addition salts generated are through alkali（For example, sodium acetate）Neutralize to dissociate and obtain compound IV；Or first make compound II and alkali
(for example, sodium hydride）Reaction, then closed with compound m Shrink（For example, under reflux）, obtain compound IV (reactions steps a).If R3When being not hydrogen, then compound IV is alkylated through N-（For example, R3I, K2C03) obtain compound V (reactions steps b);If during hydrogen, then compound IV directly carries out next step reaction.Compound IV or V (is closed with the QH containing free hydroxyl group with 2- (Pai Qin Shrink（For example, in DMF, under 130 °C）Obtain compound VI (reactions steps c).Compound protects hydroxyl under DMAP catalysis with acetic anhydride acetylation）, obtain compound VII (reactions steps d).Compound VII is reduced through nitro（For example, electronation（Such as Fe-HOAc), catalytic hydrogenation）, obtain compound VIII (reaction e).Compound VIII and R^R^NH are into urea（For example, carbamate method, isocyanic acid ester process etc.）, obtain compound IX (reactions steps 0.Finally, compound IX reacts through dehydroxylation protection group（For example, in methyl alcohol through sodium hydrate aqueous solution saponification）, obtain compound I (reactions steps g).
Compound I is (containing trip hydroxyl in Q, by taking 2- (piperazine -1- bases) ethanol as an example）The synthetic route 2 of synthetic route 1:Urea reaction is first carried out into, then is closed with QH Shrink
Compound IV and compound V preparation are referring to synthetic route 1.Compound IV or compound V are reduced through nitro（For example, electronation（Such as Fe-HOAc), catalytic hydrogenation）, obtain compound X (reactions steps h).Compound X and R R2NH is into urea（For example, carbamate method, isocyanic acid ester process etc.）, obtain compound XI (reactions steps i).Finally, the compound XI and QH containing free hydroxyl group is (by taking 2- (piperazine -1- bases) ethanol as an example）Shrink is closed（For example, containing DIEA (diisopropyl ethyl amines）Under 80 °C of D）, obtain compound I (reactions steps j).Each group definition is the same as those described above, and contains free hydroxyl group in its Q.
V
Compound I is (containing trip hydroxyl in Q, by taking 2- (piperazine -1- bases) ethanol as an example）Synthetic route 2
(2. each group definition is the same as those described above other compounds I, and free hydroxyl group is free of in Q）Synthesis
(each group definition is the same as those described above other compounds I, but free hydroxyl group is not contained in Q）Synthesized using synthetic route 3 or synthetic route 4.
Synthetic route 3:First closed with QH Shrink, then carry out into urea reaction
Compound IV and compound V preparation are referring to synthetic route 1.Compound IV or compound V and the QH Shrink conjunctions for not containing free hydroxyl group（For example, in QH, under KI catalysis, heating；Or in QH DMSO solution, heating）, obtain compound Χ Π (reactions steps k).Compound Χ Π are reduced through nitro（For example, electronation（Such as Fe-HOAc), Catalytic hydrogenation etc.）, obtain compound Χ Π Ι (reactions steps 1).Finally, compound Χ Π Ι and R R2NH is into urea（For example, carbamate method, isocyanic acid ester process etc.）, obtain compound I (reactions steps m).Each group definition is the same as those described above, its
XIII
Compound I (is free of free hydroxyl group in Q）Synthetic route 3
Synthetic route 4:Urea reaction is first carried out into, then is closed with QH Shrink
Compound IV and compound V preparation are referring to synthetic route 1.Compound IV or compound V are reduced through nitro（For example, electronation（Such as Fe-HOAc), catalytic hydrogenation）, obtain compound X (reactions steps n).Compound X and R R2NH is into urea（For example, carbamate method, isocyanic acid ester process etc.）, obtain compound XI (reactions steps 0).Finally, compound XI and QH (does not contain free hydroxyl group）Shrink is closed（For example, in the DMF containing DIEA, under 80 °C）, obtain compound I (reactions steps p).Each group definition is the same as those described above, and free hydroxyl group is free of in wherein Q.
V
Compound I is (without trip hydroxyl in Q）Synthetic route 4
Wherein, the raw material or reagent being related in above-mentioned each method can be by commercially available, or prior art is prepared.
According to above-mentioned preparation method disclosed by the invention, those skilled in the art can use each particular compound being related in same principle and method, the general formula compound I that the present invention is made.
The invention further relates in the above method, the new midbody compound 55 for prepare compound I：Ni- (2- methyl -6- chlorine pyrimidine-4-yl) benzene -1,4- diamines（Α 1- Ν Η 2-0), 4- (2- methyl -6- chlorine pyrimidine-4-yls amido) anilino- formic acid (4- nitrobenzene) ester hydrochloride（Al-CAR-0), 2- methyl -6- morpholinyls-N- (4- nitrobenzophenones) pyrimidine -4- amine（Al-N02-2), ^- (2- methyl -6- morpholinyls pyrimidine-4-yl) benzene -1,4- diamines（Α 1- Ν Η 2-2), 4- (2- methyl -6- morpholinyl pyrimidine-4-yls amido) anilino- formic acid (4- nitrobenzene) ester hydrochloride（Al-CAR-2), the chloro- N- of 2- methyl -6- (3- nitrobenzophenones) pyrimidine -4- amine (A2-NO2-0), ^- (2- methyl -6- chlorine pyrimidine-4-yl) benzene -1,3- diamines（A2-NH2-0), 3- (2- methyl -6- chlorine pyrimidine-4-yls amido) anilino- formic acid (4- nitrobenzene) ester hydrochloride（A2-CAR-0), 2- methyl -6- morpholinyls-N- (3- nitrobenzophenones) pyrimidine -4- amine（A2-N02-2), ^- (2- methyl -6- morpholinyls pyrimidine-4-yl) benzene -1,3- diamines（A2-NH2-2), 3- (2- methyl -6- morpholinyl pyrimidine-4-yls amido) anilino- formic acid (4- nitrobenzene) ester hydrochloride（A2-CAR-2), 2- methyl -6- (4- methylpiperazine-1-yls)-N- (3- nitrobenzophenones) pyrimidine -4- amine（A2-N02-3 )、 N1- ^- methyl -6- (4- methylpiperazine-1-yls) pyrimidine-4-yl) benzene -1,3- diamines（A2-NH2-3), 3- (2- methyl -6- (4- methylpiperazine-1-yls) pyrimidine-4-yl amido) anilino- formic acid (4- nitrobenzene) ester hydrochloride（A2-CAR-3), 2- (4- (2- methyl -6- (4- nitrobenzene amido) pyrimidine-4-yl) piperazine -1- Base）Ethanol（Al-N02-1), 2- (4- (2- methyl -6- (4- nitrobenzene amido) pyrimidine-4-yls）Piperazine -1- bases）Ethyl acetate (A1-N02-1A), 2- (4- (2- methyl -6- (4- amino anilines）Pyrimidine-4-yl）Piperazine -1- bases）Ethyl acetate (A1-NH2-1A), 2- (4- (6- (4- (3- (the chloro- 4- fluorophenyls of 3-) urea groups) anilino-) -2- methylpyrimidine -4- bases) piperazine -1- bases)-ethyl acetate（A1-1-1A), 2- (4- (6- (4- (3- (3- (trifluoromethyl) -4- chlorphenyls) urea groups) anilino-) -2- methylpyrimidine -4- bases) piperazine -1- bases) ethyl acetate（Α 1-3-1 Α), 2- (4- (2- methyl -6- (4- (3- (3- cyano-phenyls) urea groups) anilino-) pyrimidine -4- bases) piperazine -1- bases) ethyl acetate（Α 1-4-1 Α), 2- (4- (2- methyl -6- (4- (3- (3- tolyls) urea) anilino-) pyrimidine-4-yl) piperazine -1- bases) ethyl acetate（A1-13-1A), 2- (4- (2- methyl -6- (4- (3- isobutyl groups urea groups) anilino-) pyrimidine-4-yl) piperazine -1- bases) ethyl acetate（A1-19-1A), 2- (4- (2- methyl -6- (3- nitrobenzene amido) pyrimidine-4-yl) piperazine -1- bases) ethanol (A2-N02-1), 2- (4- (2- methyl -6- (3- nitrobenzene amidos）Pyrimidine-4-yl）Piperazine -1- bases）Ethyl acetate (A2-N02-1A), 2- (4- (2- methyl -6- (3- aminobenzene amidos）Pyrimidine-4-yl）Piperazine -1- bases）Ethyl acetate (A2-NH2-1A), 2- (4- (2- methyl -6- (3- (3- (the chloro- 4- fluorophenyls of 3-) urea groups) anilino-) pyrimidine-4-yl) piperazine -1- bases)-ethyl acetate（A2-1-1A), 2- (4- (2- methyl -6- (3- (3- (3- (trifluoromethyl) -4- chlorphenyls) uride) anilino-) pyrimidine -4- bases) piperazine -1- bases) ethyl acetate（Α 2-3-1 Α), 2- (4- (2- methyl -6- (3- (3- (3- cyano-phenyls) urea groups) anilino-) pyrimidine -4- bases) piperazine -1- bases)-ethyl acetate（Α 2-4-1 Α), 2- (4- (2- methyl -6- (3- (3- (3- aminomethyl phenyls) urea groups) anilino-) pyrimidine -4- yls) piperazine -1- bases)-ethyl acetate（A2-13-1A), 2- (4- (2- methyl -6- (3- (3- isobutyl groups urea groups) anilino-) pyrimidine -4- bases）The base of piperazine -1）Ethyl acetate (A2-19-1A), the chloro- N of 6-, 2- dimethyl-N -s (3- nitrobenzophenones）Pyrimidine -4- amine (A2M-NO2-0), ^- (2- methyl -6- chlorine pyrimidine-4-yl)-N1- methylbenzene -1,3- diamines（A2M-NH2-0), 3- (methyl (2- methyl -6- chlorine pyrimidine-4-yl) amido) anilino- formic acid 4- nitrobenzene ester hydrochlorides（A2M-CAR-0), 2- methyl -6- morpholinyl-N-0 nitrobenzophenones) pyrimidine -4- amine（A2M-N02-2)、 N1- methyl -6- morpholinyls pyrimidine-4-yl) benzene -1,3- diamines（A2M-NH2-2), 3- (methyl (2- methyl -6- morpholinyls pyrimidine-4-yl) amidos）Anilino- formic acid 4- nitrobenzene ester hydrochloride (A2M-CAR-2), N, 2- dimethyl -6- (4- methylpiperazine-1-yls）- N- (3- nitrobenzophenones）Pyrimidine -4- amine (A2M-N02-3), N1- methyl-NJ- (2- methyl -6- (the small bases of 4- methyl piperazines）Pyrimidine-4-yl）Benzene -1,3- diamines (A2M-NH2-3), 3- (methyl (2- methyl -6- (4- methylpiperazine-1-yls) pyrimidine-4-yl) amidos）Anilino- formic acid 4- nitrobenzene ester hydrochlorides（A2M-CAR-3), the chloro- N- of 2- methyl -6- (3- nitro-4-methyls phenyl) pyrimidine -4- amine（A2N-NO2-0)、 N1^- methyl -6- chlorine pyrimidine-4-yl) -4- toluene -1,3- diamines（A2N-NH2-0), 5- (2- methyl -6- chlorine pyrimidine-4-yls amido) -2-aminotoluene base formic acid 4- nitrobenzene ester hydrochloride (A2N-CAR-0), 2- methyl-N- (4- methyl-3-nitros phenyl) -6- morpholine yl pyrimidines -4- amine（A2N-N02-2), 4- methyl-N1- (2- methyl -6- morpholinyl pyrimidine-4-yls）Benzene-1,3-diamines (A2N-NH2-2), 2- methyl-5- (2- methyl-6- morpholinyl pyrimidine-4-yls amido) anilino- formic acid 4- nitrobenzene ester hydrochloride (A2N-CAR-2), 2- methyl-N- (4- methyl-3-nitro phenyl）- 6- (4- methylpiperazine-1-yls）Pyrimidine -4- amine (A2N-N02-3), 4- methyl-N1^- methyl -6- (4- methylpiperazine-1-yls）Pyrimidine-4-yl）Benzene -1,3- diamines (A2N-NH2-3), 3- (trifluoromethyls）- 4- chloroanilino formic acid 4- nitro phenyl esters（3-CAR), 4- (pyrrolidin-1-yl) fourth amidocarbonic acid 4- nitrobenzene ester hydrochlorides（18-CAR), the chloro- N- of 2- methyl -6- (2- nitrobenzophenones) pyrimidine -4- amine (A3-NO2-0), ^- (2- methyl -6- chlorine pyrimidine-4-yl) benzene -1,2- diamines（A3-NH2-0), 2- methyl -6- morpholinyls-N- (2- nitrobenzophenones）Pyrimidine -4- amine（ A3-N02-2 )、 NJ- (2- methyl -6- morpholinyl pyrimidine-4-yls）Benzene -1,2- diamines (A3-NH2-2), 2- methyl -6- (4- methylpiperazine-1-yls)-N- (2- nitrobenzophenones) pyrimidine -4- amine（) or ^- (2- methyl -6- (the small base of 4- methyl piperazines) pyrimidine-4-yl) benzene -1,2- diamines A3-N02-3（A3-NH2-3), 6- chloro-n-methyls-N- (3- nitrobenzophenones）Pyrimidine -4- amine（B2M-NO2- 0), N- methyl -6- morpholinyls-N-0 nitrobenzophenones）Pyrimidine -4- amine (B2M-N02- 2) or N1- methyl-N1- ^- morpholinyls pyrimidine-4-yl) benzene -1,3- diamines（B2M-NH2-2)。
Preparing prevention the invention further relates to above-claimed cpd I or its pharmaceutically acceptable salt, polymorph, solvate or stereoisomer and/or treating mammal particularly people application with protein kinase mediated signal transduction pathway imbalance, or the medicine of the newborn related disease of abnormal vascular.Described disease includes but is not limited to tumour, diabetes, autoimmune disease, nerve degenerative diseases, diabetic retinopathy, age-related macular degeneration, artery sclerosis, psoriasis or inflammation.Described tumour includes but is not limited to the tumour or malignant hematologic disease of skin, brain, lung, lymphocyte, kidney, liver, stomach, colon, rectum, bladder, head, neck, mammary gland, thyroid gland, oesophagus, pancreas, prostate either gynemetrics（Such as leukaemia）.
Described protein kinase include EGFR-TK and serine/threonine kinase, and/or foregoing kinases various saltant types.Wherein, described EGFR-TK is preferably EGFR, HER-2, VEGFR-1, VEGFR-2, VEGFR-3 PDGFRc PDGFRP, c-KIT, CSF-1R, FLT-3, c-MET, FGFR-1, TIE-2, p38 a, SRC, LCK, FYN or HCK;Described serine/threonine kinase is preferably BRAF, CRAF, Aurora A or Aurora B;Described mutation type kinase is preferably BRAF V599E.
In the present invention, described compound of formula I is external to human tumor cell line and Human umbilical vein endothelial cells（HUVEC) there is growth inhibitory activity.The human tumor cell line includes but is not limited to A549 (human lung carcinoma cells）, HCT116 (people's colon-cancer cells）, CEM (human leukemia cells）With MCA-MB-435 (human melanoma cells）.
In the present invention, there is growth inhibitory activity to human tumour xenograft tumor in described compound of formula I body.The human tumour xenograft tumor includes but is not limited to transplant the A549 human lung cancers in nude mice.
Therefore the application the present invention relates to above-claimed cpd I or its pharmaceutically acceptable salt, polymorph, solvate or stereoisomer in the medicine with human tumour xenograft tumor inhibitory activity is prepared.Wherein, described human tumour xenograft tumor is preferably to transplant the A549 human lung cancers in nude mice.
The invention further relates to above-claimed cpd I or its pharmaceutically acceptable salt, polymorph, solvate or stereoisomer prepare with A549 human lung carcinoma cells, HCT116 people's colon-cancer cell, CEM human leukemia cells or Application in the medicine of MCA-MB-435 human melanoma cell inhibitory activity.
Prepared the invention further relates to described compound I or its pharmaceutically acceptable salt, polymorph, solvate or stereoisomer with Human umbilical vein endothelial cells（HUVEC) the application in the medicine of inhibitory activity.
Various forms of pharmaceutical compositions can be made in the carbamide compounds I or its pharmaceutically acceptable salt, polymorph, solvate or stereoisomer of the present invention with pharmaceutically acceptable carrier.The pharmaceutically acceptable carrier includes but is not limited to various common medicinal supplementary materials（Such as diluent, lubricant, disintegrant, adhesive and excipient）.According to therapeutic purposes, pharmaceutical composition can be made to various types of administration unit dosage forms, such as tablet, capsule, pill, pulvis, solution, suspension, emulsion agent, cream, syrup, granule, suppository and injection（Solution and suspension）Deng." alkyl " as used herein means to include the radical of saturated aliphatic alkyl with carbon number purpose straight chain and side chain is specified.For example, the definition of " d-do alkyl " for be included in have 1 in straight chain or branched structure, 2,3,4,5,6,7,8, the groups of 9 or 10 carbon atoms.For example, " d-do alkyl " specifically includes methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, sec-butyl, the tert-butyl group, n-pentyl, 2- methyl amyls, n-hexyl, n-heptyl, n-octyl, n-nonyl and positive decyl etc..
Term " cycloalkyl " refers to saturation or partly unsaturated monocyclic, polycyclic or bridge joint carbocyclic ring substituent.Ring with 3-20 carbon atom can be expressed as C3-C2.Cycloalkyl；Ring with 5-15 carbon atom can be expressed as C5-C15Cycloalkyl；Ring with 3-8 carbon atom can be expressed as C3-C8Cycloalkyl, etc..The term includes but is not limited to cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, suberyl, cyclooctyl, 1H- indenyls, 2, 3- indanyls, 1, 2, 3, 4- tetrahydrochysenes-naphthyl, 5, 6, 7, 8- tetrahydro-naphthalenyls, 8, 9- dihydro -7H- benzo ring heptene -6- bases, 6, 7, 8, 9- tetrahydrochysene -5H- benzocyclohepta alkenyls, 5, 6, 7, 8, 9, 10- hexahydros-benzo ring octenyl, fluorenyl, two rings [2.2.1] heptyl, two rings [2.2.1] heptenyl, two rings [2.2.2] octyl group, two rings [3.1.1] heptyl, two rings [3.2.1] octyl group, two rings [2.2.2] octenyl, two rings [3.2.1] octenyl, adamantyl, octahydro -4, 7- methylene -1H- indenyls and octahydro -2, 5- methylene-pentalene base etc..Naphthenic substituent can be connected on central element through any suitable carbon atom, and it can be further substituted with when permitted.
Term " alkoxy " represents there is the carbon number purpose ring-type or acyclic alkyl groups by what oxygen bridge was connected.Thus, the definition of " alkoxy " comprising above alkyl and cycloalkyl.
Term " alkenyl " refers to containing straight chain, side chain or the non-aromatic alkyl of ring-type for specifying number carbon atom and at least one carbon-carbon double bond.It is preferred that in the presence of a carbon-carbon double bond, and there may be up to four non-aromatic carbon-carbon double bonds.Thus, " C2-C1QAlkenyl " refers to the alkenyl with 2-10 carbon atom. "C2-C6Alkenyl " refers to the alkenyl with 2-6 carbon atom, including vinyl, acrylic, cyclobutenyl, 2- methyl butenes base and cyclohexenyl group.Straight chain, side chain or the loop section of alkenyl can contain double bond, and if being shown to be substituted alkenyl, then it can be substituted. Term " block base " refers to containing straight chain, side chain or the cyclic hydrocarbon group for specifying number carbon atom and at least one triple carbon-carbon bonds.Wherein there may be up to three triple carbon-carbon bonds.Thus, " C2-C1()Block base " refers to the block base with 2-10 carbon atom. "C2-C6Block base " refers to the block base with 2-6 carbon atom, including second block base, third piece of base, fourth block base and 3- methyl fourth block bases etc..
What " aryl " as used herein referred to any stabilization can include monocyclic, the bicyclic or three ring carbon rings of up to 7 atoms in each ring, and wherein at least one ring is aromatic rings.The example of above-mentioned aryl unit includes phenyl, naphthyl, tetralyl, 2,3- indanyls, xenyl, phenanthryl, anthryl or acenaphthenyl（aCenaphthyl).It is appreciated that be two ring substituents in aryl substituent, and in the case of one of ring is non-aromatic ring, connection is carried out by aromatic ring.
What term " heteroaryl " as used herein represented in each ring up to 7 atoms stablizes monocyclic, bicyclic or three rings, and wherein at least one ring is aromatic rings and the hetero atoms selected from 0, N and S containing 1-4.Heteroaryl within the range defined herein includes but is not limited to：Acridinyl, carbazyl, cinnolines base, quinoxalinyl, pyrazolyl, indyl, BTA base, furyl, thienyl, benzothienyl, benzofuranyl, quinolyl, isoquinolyl, oxazolyl, Yi Evil oxazolyls, indyl, pyrazinyl, pyridazinyl, pyridine radicals, pyrimidine radicals, pyrrole radicals, tetrahydroquinoline.As the definition of following heterocycle, " heteroaryl " is it should also be understood that be to include the N- oxide derivatives of any nitrogenous heteroaryl.Heteroaryl substituent is two ring substituents wherein and a ring is non-aromatic ring or not comprising in the case of heteroatomic, it will be understood that connection by aromatic ring or passes through the hetero atom comprising ring and carried out respectively.
In the present invention, term " heterocycle " as used herein or " heterocyclic radical " are represented containing 1-4 heteroatomic 5-10 members fragrance or nonaromatic heterocycles selected from 0, N and S, and including bicyclic groups.Therefore, " heterocyclic radical " includes above-mentioned heteroaryl and its dihydro or tetrahydrochysene analog.Other examples of " heterocyclic radical " include but is not limited to following：Benzimidazolyl, benzofuranyl, benzofuraxan base, benzopyrazoles base, BTA base, benzothienyl, benzoxazolyl, carbazyl, carboline base, cinnolines base, furyl, imidazole radicals, indolinyl, indyl, indazolyl, isobenzofuran-base, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl, naphthalene pyrimidine radicals, oxadiazolyl, oxazolyl, oxazoline, isoxazoline, oxygen cyclobutyl, pyranose, pyrazinyl, pyrazolyl, pyridazinyl, pyridopyridine base, pyridazinyl, pyridine radicals, pyrimidine radicals, pyrrole radicals, quinazolyl, quinolyl, quinoxalinyl, THP trtrahydropyranyl, tetrazole radical, tetrazolo pyridine radicals, thiadiazolyl group, thiazolyl, thienyl, triazolyl, azetidinyl, the alkyl dioxin of Isosorbide-5-Nitrae-, hexahydro azatropylidene base, piperazinyl, piperidyl, pyrrolidinyl, morpholinyl, thio-morpholinyl, dihydrobenzo imidazole radicals, dihydro benzo furyl, dihydrobenzo thienyl, Er hydrogen benzoxazolyls, dihydrofuran base, glyoxalidine base, indolinyl, dihydro-isoxazole base, dihydro isothiazolyl, Er Qing oxadiazolyls, dihydro-oxazole base, dihydro pyrazine base, pyrazoline base, dihydropyridine base, dihydro-pyrimidin base, pyrrolin base, EEDQ base, dihydro tetrazole radical, thiodiazoline base, dihydro-thiazolyl, dihydro-thiophene base, dihydro triazolyl, dihydro azetidinyl, methylenedioxyphenyl first Acyl group, tetrahydrofuran base and tetrahydro-thienyl and its N- oxides.Heterocyclyl substituent can be attached through carbon atom or hetero atom.
Term " halogen " represents fluorine, chlorine, bromine, iodine, astatine.
Term " haloalkyl " represents the alkyl of halogen optional position substitution.Thus, the definition of " haloalkyl " comprising above halogen and alkyl.
Term " saturated heterocyclyl " is represented containing 1-4 selected from 0, N or the heteroatomic 4-9 members nonaromatic heterocycles bases of S, and including bicyclic groups, unsaturated double-bond is not included wherein, saturated heterocyclyl substituent can be attached through carbon atom or hetero atom.Nitrogen therein, sulfur heteroatom can be aoxidized arbitrarily, and nitrogen heteroatom can also be by any quaternary ammoniated.For example, nafoxidine base, piperazinyl, morpholinyl, piperidyl, tetrahydrofuran base, THP trtrahydropyranyl, thio-morpholinyl, imidazolidine base, tetrahydro-thiazoles base, oxidation piperazinyl, oxyl base, thiomorpholine sulfoxide or thiomorpholine sulfone etc..
Without prejudice to the field on the basis of common sense, above-mentioned each optimum condition, can be combined, produce the preferred embodiments of the invention.
Unless otherwise specified, agents useful for same and raw material of the present invention are commercially available.
The positive effect of the present invention is：Present invention finds the brand-new carbamide compounds of a class shown in formula I, it possesses stronger antitumor cell growth and anti-angiogenic rebirth activity, it has stronger inhibitory activity for the protein kinase related to a variety of diseases, and preferably antitumor activity is also showed that in animal body.Embodiment
The present invention is further illustrated below by the mode of embodiment, but is not therefore limited the present invention among described scope of embodiments.The experimental method of unreceipted actual conditions in the following example, conventionally and condition, or is selected according to catalogue.
Part I Chemical Example
NMR is Varian companies INOVA-400, and hydrogen spectrum is determined under 400MHz；Mass spectrograph is Waters companies Micromass Q-Tof micro, electron spray ionisation（ESI).
1. A1 is serial
1. the 0 of 1 A1 series
The chloro- N- of 2- methyl -6- (4- nitrobenzophenones) pyrimidine -4- amine（ Al -NO2-0 )：
By 2- methyl -4,6- dichloro pyrimidines（81.56g, 0.5mol) and 4- nitroanilines（69.06g, 0.5mol) put into water (375mL) and acetone（In 125mL), 12mol/L hydrochloric acid is added（9mL) it is stirred at reflux 2h.It is cooled to after room temperature and filters, filter cake washing, dry yellow crystal 6- chloro-2-methyls-N- (4- nitrobenzophenones）Pyrimidine -4- amine hydrochlorates (A1-NO2-0.HC1) ( 123.9g, 82%)。
Take A1-NO2-0.HC1 (15.1g, 50mmol) to add in DMF (102mL), be heated to after 30 °C of stirring and dissolvings, add anhydrous sodium acetate（4.17g, 50mmol), 10min is stirred, is then added water（1L) stirring is cooled to room temperature, and filtration drying obtains crude product.Gained crude product is recrystallized with n-butanol, filtration drying obtains yellow needles A1-NO2-0 (12.56g, 95%)： iHNMR (DMSO-d6) 510.29(s,lH), 8.17-8.19(m, 2H), 7.89-7.91(m, 2H), 6.75(s,lH), 2.46(s,3H)
N1^- methyl -6- chlorine pyrimidine-4-yl) benzene -1,4- diamines（A1-NH2-0)
Al-NO2-0 (2.46g, lOmmol) is put into EtOH/H20(2:L) (72mL) and glacial acetic acid（2. 56g, 43mmol) in, the reduced iron powder through lmol/L hydrochloric acid activations is put under reflux（2.23g, 40mmol).Return stirring 30min, be cooled to after room temperature add ammoniacal liquor alkalize to pH be 9, filtered by diatomite.Filtrate is rotated, is added water into gained residue（15mL), it is extracted with ethyl acetate.Combined ethyl acetate rotates to obtain bois de rose crystalline A l-NH2-0 (2.23g, 95%) after anhydrous sodium sulfate drying：1Leg MR (DMSO-d6) 59.17(s,lH), 7.50(d, J=7.2Hz, 2H), 6.53-6.56(m:2H), 6.28 (s, lH), 4.91 (br s, 2H), 2.32 (s, 3H).
4- (2- methyl -6- chlorine pyrimidine-4-yls amido) anilino- formic acid (4- nitrobenzene) ester hydrochloride（A1-CAR-0) by p-nitrophenyl chloroformate ester（1.21g, 6mmol) it is dissolved in anhydrous methylene chloride（22mL).It is cooled to 0 °C, adds A1-NH2-0 (1.17g, 5mmol), rises to 20 °C of stirring 4.5h.Filter, wash, being dried in vacuo and to obtain yellow solid A1-CAR-0 (1.97g, 90%)：1Leg MR (DMSO-d6) S10.39 (s, lH), 9.76 (s, lH), 8.30-8.32 (m, 2H), 7.48-7.60 (m, 6H), 6.60 (s, lH), 2.42 (s, 3H)
1-(4- (2- methyl-6- chlorine pyrimidine-4-yls amido) phenyl)-3- (the chloro- 4- fluorophenyls of 3-) urea（ A1 - 1 -0 )
By the chloro- 4- fluoroanilines (0.32g, 2.2mmol) of A1-CAR-0 (0.87g, 2mmol), 3- and triethylamine（0.57g, 5.6mmol) it is added in dry DMF (8mL), stir 5h at 40 °C.After gained salmon pink reaction solution dchloromethane, successively with lmol/L sodium hydrate aqueous solutions and water washing, rotated after anhydrous sodium sulfate drying.Gained residue silica gel column chromatography, with ethyl acetate：Petroleum ether（3: 1-3：0) gradient elution, obtains near-white solid Al-l-0 (0.31g, 38%)：1Leg MR (DMS0-) 59.56 (s, lH), 8.83 (s, lH), 8.68 (s, lH), 7.78 (d, J=6.4Hz, lH), 7.41-7.49 (m, 4H), 7.30 (d, J=8.0Hz, lH), 6.52 (s, lH), 2.41 (s, 3H).
The 1 of 1.2 Al series
2- (4- (2- methyl -6- (4- nitrobenzene amido) pyrimidine-4-yl) piperazine -1- bases) ethanol（ A1-N02-1 ):
By 2- methyl -6- chloro- N- (4- nitrobenzophenones) pyrimidine -4- amine（0.51g, 1.9mmol) DMSO (30mL) is dissolved in, Add 2- (the small base of piperazine) ethanol（2g, 15.4mmol), it is heated to 130 °C of stirring 15min.It is cooled to room temperature, add water crystallization.Filtration drying obtains orange red solid（0.64g, 94%)： 1H-NMR (DMSO-d6) δ 9.72 (s, 1H), 8.15 (dd, J=2.0,7.2Hz, 2H), 7.88 (dd, J=2.0,7.2Hz, 2H), 5.94 (s, lH), 4.37 (t, J=5.2Hz, 1H), 3.50-3.56 (m, 4H), 2.54 (s, 2H), 2.48-2.51 (m, 4H), 2.44 (t, J=6Hz, 2H), 2.37 (s, 3H).
2- (4- (2- methyl-6- (4- nitrobenzene amido) pyrimidine-4-yl) piperazine-1-yl) ethyl acetate（ Al -N02- 1 A )：A1-N02-1 (0.36g, lmmol) is dissolved in DMSO (5mL), acetic anhydride is added（0.15g, 1.5mmol) and DMAP (0.02g, 0.16mmol), lh is stirred at room temperature, add water precipitation flocculent deposit.Filtration drying obtains yellow crystalline powder（0.37g, 93%)： 1H-NMR (DMSO-d6) δ 9.73 (s, lH), 8.15 (d, J=9.2Hz, 2H), 7.88 (d, J=9.2Hz, 2H), 5.94 (s, lH), 4.14 (t, J=5.6Hz, 2H), 3.52 (m, 4H), 2.60 (m, 2H), 2.50 (m, 4H), 2.37 (s, 3H), 2.02 (s, 3H).
2- (4- (2- methyl -6- (4- amino anilines) pyrimidine-4-yl) piperazine -1- bases) ethyl acetate（A1-NH2-1A):
A1-N02-1A (0.96g, 2.4mmol) heating stirring is dissolved in EtOH/H20(2:L) (45mL), adds the reduced iron powder through lmol/L hydrochloric acid activations（0.54g, 9.6mmol) and glacial acetic acid（0. 62g, 10.3mmol).Return stirring 30min, it is 8 to add ammoniacal liquor and alkalize to pH, is filtered while hot by diatomite.Rotate filtrate and remove ethanol, obtained aqueous solution is extracted with ethyl acetate.Drabon color crystalline powder is rotated to obtain after combined ethyl acetate, anhydrous sodium sulfate drying（0.76g, 85%)：1H-NMR (DMSO-de) δ 8.25 (s, 1H), 7.03 (dd, J=2.0,6.8Hz, 2H), 6.53 (dd, J=2.0,6.8Hz, 2H), 5.52 (s, 1H), 4.78 (s, 2H), 4.12 (t, J=5.6Hz, 2H), 3.37 (m, 4H), 2.56 (t, J=5.6Hz, 2H), 2.44 (m, 4H), 2.22 (s, 3H), 1.98 (s, 3H).
1-(the chloro- 4- fluorine of 3-)-3- (4- (2- methyl-6- (4- (2- ethoxys) piperazine-1-yl) pyrimidine-4-yl amido) phenyl) urea（Al-1-1) by A1-NH2-1A (0.43g, 1.2mmol) and p-nitrophenyl chloroformate ester（0.25g, 1.2mmol) it is dissolved in anhydrous CH2C12In (20mL), pyridine is added（0.14g, 1.8mmol), 5min is stirred at room temperature under nitrogen protection, the chloro- 4- fluoroanilines of 3- are then added（0.17g, 1.2mmol) and DIEA (0.53g, 4. lmmol) stirrings 48h.Hydrochloric acid (lmol/L is added into gained reactant under agitation, 24mL), flocculent deposit is separated out, filtration drying obtains 2- (4- (6- (4- (3- (the chloro- 4- fluorophenyls of 3-) urea groups) anilino-) -2- methylpyrimidine -4- bases) piperazine -1- bases)-ethyl acetate（), A1-1-1A it is golden yellow powder： 1H-NMR (DMSO-d6) δ 8.76 (s, 1 H), 8.73 (s, 1 H), 8.53 (s, 1 H), 7.78-7.80 (m, 1 H), 7.29-7.45 (m, 6H), 5.73 (s, l H), 4. 13 (m, 2H), 3.45 (m, 4H), 2.59 (m, 2H), 2.50 (m, 4H), 2.27 (s, 3H), 2.01 (s, 3H).
Al-l-lA (0.11g, 0.2mmol) is taken to be dissolved in methanol（LmL), lmol/L sodium hydrate aqueous solutions are added（0.6mL) solution stirring 3h.Revolving removes methanol, and ethyl acetate extracts gained residue, after anhydrous sodium sulfate drying and revolving, Silica gel column chromatography is separated, with methanol：Dichloromethane（1 :7) elute, obtain light brown powder A1-1-1 (0.09g, 87%)： 1H-NMR (DMSO-d6) δ 10.36 (s, 1H), 9.89 (s, 1H), 8.80 (s, 1H), 7.80 (dd, J=2.4,6.4Hz, lH), 7.33-7.43 (m, 5H), 7.28 (t, J=8.8Hz, lH), 5.76 (s, 1H), 4.41 (br s, 1H), 3.52 (m, 2H), 3.43 (m, 4H), 2.40-2.50 (m, 6H), 2.27 (s, 3H); MS-ESI: m/z 500(M+H) +.L- (3- (trifluoromethyl) -4- chlorphenyls) -3- (4- (2- methyl -6- (4- (2- ethoxys) piperazine -1- bases) pyrimidine -4- amino) phenyl) urea (A1-3-1):
With 3- (trifluoromethyl) -4- chloroanilines（0.47g, the chloro- 4- fluoroanilines of 3- 2.4mmol) are replaced, 2- (4- (6- (4- (3- (3- (trifluoromethyl) -4- chlorphenyls) urea groups) anilino-) -2- methylpyrimidine -4- bases) piperazine -1- bases) ethyl acetate (A1-3-1A) is prepared using the method similar to A1-1-1A.
A1-1-1A is replaced with Al-3-lA (0.12g, 0.2mmol), A1-3-1 is prepared using the method similar to A1-1-1, white powder is obtained（0.09g, 85%)： 1H-NMR (DMSO-d6) δ 9.05 (s, 1H), 8.75 (s, 1H), 8.62 (s, 1H, 8.10 (d, J=2.8Hz, lH), 7.58-7.62 (m, 2H), 7.45 (d, J=8.8Hz, 2H), 7.36 (d, J=8.8Hz, 2H), 5.73 (s, 1H), 4.36 (t, J=5.6Hz, lH), 3.53 (dd, J=6.0,12.0Hz, 2H), 3.44 (t, J=4.8Hz, 4H), 2.41-2.48 (m, 6H), 2.28 (s, 3H); MS-ESI:M/z 550 (M+H)+, 572 (M+Na)+.L- (3- cyano-phenyls) -3- (4- (2- methyl -6- (4- (2- ethoxys）Piperazine -1- bases）Pyrimidine-4-yl amido）Phenyl）Urea (A1-4-1)
With 3- cyano-anilines（0.24g, 2.0mmol) the chloro- 4- fluoroanilines of 3- are replaced, 2- (4- (2- methyl -6- (4- (3- (3- cyano-phenyls) urea groups is prepared using the method similar to A1-1-1A）Anilino-）Pyrimidine-4-yl）Piperazine -1- bases）Ethyl acetate (A1-4-1A).
A1-1-1A is replaced with A1-4-1A (0.1g, 0.2mmol), A1-4-1 is prepared using the method similar to A1-1-1, micro-yellow powder is obtained（0.06g, 63%)： 1H-NMR (DMSO-d6) δ 9.08 (s, lH), 8.79 (s, 1H), 8.76 (s, 1H), 7.96 (m, 1H), 7.65-7.67 (m, lH), 7.35-7.50 (m, 6H), 5.76 (s, 1H), 4.02 (m, 1H), 3.49-3.59 (m, 6H), 3.18 (m, 2H), 2.58 (m, 4H), 2.28 (s, 3H); MS-ESI: m/z 473(M+H)+.I-- p- methyl -6- (4- (2- ethoxys）Piperazine -1- bases）Pyrimidine-4-yl amido）Phenyl) -3- (3- aminomethyl phenyls）Urea (A1-13-1):
With 3- methylanilines（0.13g, 1.2mmol) the chloro- 4- fluoroanilines of 3- are replaced, 2- (4- (2- methyl -6- (4- (3- (3- tolyls are prepared using the method similar to A1-1-1A）Urea）Anilino-）Pyrimidine-4-yl）Piperazine-1-base）Ethyl acetate (A1-13-1A) ： 1H-NMR (CDC13) δ 7.99 (s, l H), 7.72 (br s, 2H), 7.33 (d, J=8.8Hz, l H), 7.26 (m, l H), 7.20-7.22 (m, 2H), 7.15 (t, J=7.6Hz, l H), 6.98 (d, J=8.8Hz, 2H), 6.85 (d, J=7.6Hz, l H), 5.51 (s, l H), 4.19 (m, 2H), 3.55 (m, 4H), 2.64 (t, J=6Hz, 2H), 2.51-2.56 (m, 4H), 2.40 (s, 3H), 2.29 (s, 3H), 2.05 (s, 3H) o
A1-1-1A is replaced with Al-13-lA (0.1g, 0.2mmol), Al-13-1 is prepared using the method similar to Al-1-1, white powder is obtained（0.06g, 66%)： 1H-NMR (DMSO-d6) δ 8.72 (s, 1 Η), 8.47 (s, 1H), 8.45 (s, 1H), 7.43 (d, J=8.8Hz, 2H), 7.35 (d, J=8.8Hz, 2H), 7.29 (m, 1H), 7.23 (d, J=8.8Hz, lH), 7.15 (t, J=8Hz, lH), 6.79 (d, J=6.8Hz, lH), 5.73 (s, 1H), 4.38 (br s, 1H), 3.54 (dd, J=6,8.8Hz, 2H), 3.45 (m, 4H), 2.42-2.48 (m, 6H), 2.28 (s, 6H); MS-ESI:M/z 462 (M+H)+, 923 (2M+H)+.
1-- P- methyl-6- (4- (2- ethoxys) piperazine-1- bases) pyrimidine-4-yl amido) phenyl)-3- isobutyl groups urea (Al-19-1):With isobutyl amine（0.24g, the chloro- 4- fluoroanilines of 3- 2.0mmol) are replaced, 2-(4- (2- methyl-6- (4- (3- isobutyl groups urea groups) anilino-) pyrimidine-4-yl) piperazine-1- bases) ethyl acetate (A1-19-1A) are prepared using the method similar to A1-1-1A.
A1-1-1A is replaced with Al-19-lA (0.09g, 0.2mmol), A1-19-1 is prepared using the method similar to A1-1-1, light yellow powder solid is obtained（0.06g, 70%)：1H-NMR (DMSO-de) δ 8.62 (s, l H), 8.20 (s, l H), 7.34 (d, J=8.8Hz, 2H), 7.28 (d, J=8.8Hz, 2H), 6.06 (t, J=8.8Hz, l H), 5.69 (s, l H), 4.35 (br s, 1 H), 3.5 1-3.55 (m, 2H), 3.43 (m, 4H), 2.92 (t, J=6.4Hz, 2H), 2.42-2.47 (m, 6H), 2.26 (s, 3H), 1 .69 (m, l H), 0.88 (s, 3H), 0.87 (s, 3H); MS-ESI:M/z 428 (M+H)+, 855 (2M+H)+.
The 2 of 1.3 Al series
2- methyl -6- morpholinyls-N- (4- nitrobenzophenones) pyrimidine -4- amine（A1-N02-2):
By A1-NO2-0.HC1 (36g, 0.12mol), morpholine（60 mL, 0.68mol) and several KI crystal be stirred at reflux 7.5h.Revolving, filtering gained residue, filter cake washing, dry crude product are beaten to obtain yellow solid A1-N02-2 (37.83g, 100%) through toluene： ^MR (DMSO-d6) 59.77 (s, lH), 8.14 (d, J=9.2Hz, 4H), 7.89 (d, J=9.2Hz, 4H), 5.95 (s, lH), 3.67 (t, J=4.8Hz, 4H), 3.49 (t, J=4.8Hz, 4H), 2.37 (s, 3H).
^- (2- methyl -6- morpholinyls pyrimidine-4-yl) benzene -1,4- diamines（A1-NH2-2)
By A1-N02-2 (6.3g, 20mmol), 7% palladium charcoal（Dry powder, 0.63g) put into methanol (180mL), hydrogenate 1.5h under 40 °C and 4bar pressure.It is cooled to after room temperature and filters, filter cake is extracted with DMF (30mL).Merging filtrate and DMF extract solutions, Jian Ya Nong Shrink, gained solid residue are beaten through cold absolute ethyl alcohol, obtain yellow crystal A1-NH2-2 (5.64g, 99%)：XHNMR (DMSO-d6) 58.30 (s, lH), 7.03 (d, J=8.4Hz, 4H), 6.53 (d, J=8.4Hz, 4H) 5.53 (s, lH), 4.79 (s, 2H), 3.62 (t, J=4.8Hz, 4H), 3.35 (t, J=4.8Hz, 4H), 2.23 (s, 3H).
4- (2- methyl -6- morpholinyl pyrimidine-4-yls amido) anilino- formic acid (4- nitrobenzene) ester hydrochloride（A1-CAR-2) by p-nitrophenyl chloroformate ester（2.42g, 12mmol) it is dissolved in anhydrous methylene chloride（30mL).It is cooled to 0 °C, A1-NH2-2 (2.80g, lOmmol) is put into batches, rises to 20 °C of stirring 3h.Filter, wash, being dried in vacuo and to obtain milk yellow powders A 1-CAR-0 (4.5g, 92%).
1- (the chloro- 4- fluorophenyls of 3-) -3- (4- (2- methyl -6- morpholinyl pyrimidine-4-yls amido) phenyl) urea（A1-1-2)
By the chloro- 4- fluoroanilines of A1-CAR-2 (0.49g, lmmol), 3-（0.16g, l .lmmol) and triethylamine（0.29g, 2.9mmol) it is added in dry DMF (4mL), stir 5.5h at 40 °C.By gained yellow reaction thing dichloromethane（LOOmL after) diluting, successively with lmol/L sodium hydrate aqueous solutions and water washing, rotated after anhydrous sodium sulfate drying.Gained residue silica gel column chromatography, with ethyl acetate：Ethanol（5 : 0〜5：1) gradient elution, obtains Light yellow crystals A1-1-2 (0.32g, 70%)：1Leg MR (DMSO-dg) 58.77 (s, lH), 8.75 (s, lH), 8.54 (s, lH), 7.74 (d, J=6.8Hz, lH), 7.29-7.45 (m, 6H), 5.73 (s, lH), 3.65 (m, 4H), 3.42 (m, 4H), 2.29 (s, 3H)； MS-ESI (m/z) 457 (M+H)+ , 913 (2M+H)+.L- (3- (trifluoromethyl) -4- chlorphenyls) -3- (4- (2- methyl -6- morpholinyl pyrimidine-4-yls amido) phenyl) urea（A1-3-2) with 3- (trifluoromethyl) -4- chloroanilines（0.22g, l lmmol) the chloro- 4- fluoroanilines of 3- are replaced, A1-3-2 is prepared using the method similar to A1-1-2, white crystals are obtained（0.13g, 25%):1Leg MR (DMSO-d6) 59.03 (s, lH), 8.79 (s, lH), 8.61 (s, lH), 8.09 (s, lH), 7.57-7.61 (m, 2H), 7.45 (d, J=8.4Hz, 2H), 7.35 (d, J=8.8Hz, 2H), 5.73 (s, lH), 3.65 (m, 4H), 3.41 (m, 4H), 2.28 (s, 3H); MS-ESI (m/z) 507 (M+H)+, 1013 (2M+H)+.L- (3- cyano-phenyls 3- (4- (2- methyl -6- morpholinyl pyrimidine-4-yls amido) phenyl) ureas（A1-4-2)
With 3- cyano-anilines（0.19g, 1.65mmol) the chloro- 4- fluoroanilines of 3- are replaced, A1-4-2 is prepared using the method similar to A1-1-2, white powder is obtained（0.25g, 39%)： ^MR (DMSO-d6) 58.91 (s, lH), 8.79 (s, lH), 8.62 (s, lH), 7.96 (s, lH), 7.66 (d, J=7.6Hz, lH), 7.35-7.50 (m, 6H), 5.74 (s, lH), 3.65 (m, 4H), 3.42 (m, 4H), 2.29 (s, 3H); MS-ESI (m/z) 430 (M+H)+, 859 (2M+H)+。
N- methyl -4- (4- (3- (3- (2- methyl -6- morpholinyl pyrimidine-4-yls amido) phenyl) urea groups) phenoxy group) B is than pyridine -2- formamides (A1-6-2) With 4- (4- amino-benzene oxygens)-N- picoline -2- formamides（0.27g, l.lmmol) the chloro- 4- fluoroanilines of 3- are replaced, A1-6-2 is prepared using the method similar to A1-1-2, near-white powder is obtained（0.49g, 89%)： 1HNMR (DMSO-d6) 58.76 (s, lH), 8.71 (s, lH), 8.68 (br s, lH), 8.50 (s, lH), 8.49 (s, lH), 7.57 (d, J=8.8Hz, 2H), 7.36-7.45 (m, 5H), 7.13-7.15 (m, 3H), 5.73 (s, lH), 3.65 (m, 4H), 3.42 (m, 4H), 2.80 (d, J=4.4 Hz, 3H):2.29(s,3H);MS-ESI (m/z) 555 (M+H)+, 577 (M+Na)+, 593 (M+K)+, 1109 (2M+H)+ , 1131 (2M+Na)+, 1147 (2M+K)+.L- (2- fluorophenyls) -3- (4- (2- methyl -6- morpholinyl pyrimidine-4-yls amido) phenyl) urea（A1-7-2)
With 2- fluoroanilines（0.18g, 1.65mmol) the chloro- 4- fluoroanilines of 3- are replaced, A1-7-2 is prepared using the method similar to A1-1-2, white powder (0.22g, 35%) is obtained：1Leg MR (DMSO-d6) 58.89 (s, lH), 8.77 (s, lH), 8.43 (s, lH), 8.13-8.17 (m, lH), 7.45 (d, J=8.8Hz, 2H), 7.36 (d, J=8.8Hz, 2H), 7.22 (m, lH), 7.13 (m, lH), 7.00 (m, lH), 5.73 (s, lH), 3.65 (m, 4H), 3.42 (m, 4H), 2.29 (s, 3H);MS-ESI (m/z) 423 (M+H)+, 445 (M+Na)+, 461 (M+K)+, 845 (2M+H)+, 867 (2M+Na)+, 883 (2M+K)+.L- (4- fluorophenyls) -3- (4- (2- methyl -6- morpholinyl pyrimidine-4-yls amido) phenyl) urea（A1-8-2)
With 4- fluoroanilines（0.18g, 1.65mmol) the chloro- 4- fluoroanilines of 3- are replaced, A1-8-2 is prepared using the method similar to A1-1-2, white solid is obtained（0.14g, 22%)：1Leg MR (DMSO-d6) 58.75 (s, lH), 8.58 (s, lH), 8.45 (s, lH), 7.33-7.46 (m, 6H), 7.09 (m, 2H), 5.72 (s, lH), 3.41 (m, 4H), 3.42 (m, 4H), 2.28 (s, 3H);MS-ESI (m/z) 423 (M+H)+, 445 (M+Na)+, 845 (2M+H)+, 867 (2M+Na)+, 883 (2M+K)+.L- (4- (2- methyl -6- morpholinyl pyrimidine-4-yls amido) phenyl) -3- (5- picoline -2- bases) urea（A1-10-2) with 5- picoline -2- amine（0.12g, l.lmmol) the chloro- 4- fluoroanilines of 3- are replaced, A1-10-2 is prepared using the method similar to A1-1-2, white solid is obtained（O.llg, 26% )：1Beautiful MR (DMSO-d6) S10.32 (s, lH), 9.22 (s, lH), 8.80 (s, lH), 8.10 (m, lH), 7.37-7.58 (m, 6H), 5.74 (s, lH), 3.65 (m, 4H), 3.42 (m, 4H), 2.29 (s, 3H), 2.23 (s, 3H); MS-ESI (m/z) 420 (M+H)+ o
1-cyclohexyl-3- (4- (2- methyl-6- morpholinyl pyrimidine-4-yls amido) phenyl) urea（ A1 - 11 -2 )
With cyclohexylamine（0.16g, 1.65mmol) the chloro- 4- fluoroanilines of 3- are replaced, A1-11-2 is prepared using the method similar to A1-1-2, near-white solid is obtained（0.39g, 63%)：1Leg MR (DMSO-d6) 58.66 (s, lH), 8.10 (s, lH), 7.30 (dd, J=8.8,24.8Hz, lH), 5.94 (d, J=7.6Hz, 1H), 3.64 (m, 4H), 3.47 (m, lH), 3.45 (m, 4H) 2.27(s,3H), l . l l-1.81(m, 10H); MS-ESI (m/z) 411 (M+H)+, 821 (2M+H)+。
N- (4- (2- methyl -6- morpholinyl pyrimidine-4-yls amido) phenyl) morpholine -4- formamides（ A 1 - 12-2 )
With morpholine（0.14g, 1.65mmol) the chloro- 4- fluoroanilines of 3- are replaced, A1-12-2 is prepared using the method similar to A1-1-2, near-white solid is obtained（0.26g, 43%)：1Leg MR (DMSO-d6) 58.72 (s, lH), 8.36 (s, lH), 7.39 (m, 4H), 5.71 (s, 1H), 3.59-3.66 (m, 8H), 3.40-3.42 (m, 8H), 2.28 (s, 3H)；MS-ESI (m/z) 399 (M+H)+, 797 (2M+H)+.
2. A2 is serial
The 0 of 2.1 A2 series
The chloro- N- of 2- methyl -6- (3- nitrobenzophenones) pyrimidine -4- amine（A2-NO2-0 )
By 2- methyl -4,6- dichloro pyrimidines（32.62g, 0.2mol) and 3- nitroanilines（27.62g, 0.2mol) put into water (150mL) and acetone（In 50mL), 12mol/L concentrated hydrochloric acids are added（4mL) it is stirred at reflux 2h.It is cooled to after room temperature and filters, filter cake washing, dry bright yellow solid A2-NO2-0.HC1 (50.6g, 84%).
A2-NO2-0.HC1 (16.42g, 54.5mmol) is taken to be dissolved in glacial acetic acid in 90 °C of stirrings（90mL) in standing grain Jie DMF (140mL), anhydrous sodium acetate C4.48g, 54.6mmol are added), filter while hot.Added water into filtrate（1.2L), stirring is cooled to room temperature, and filtration drying obtains crude product.Crude product recrystallizes to obtain yellow crystal through n-butanol（12.31g, 85%)： 1HNMR (DMSO-d6) 510.15 (s, lH), 8.73 (t, J=2.0Hz, 1H), 8.02 (dd, J=1.6,8.4Hz, 1H), 7.87 (dd, J=1.6,8.0Hz, 1H), 7.62 (t, J=8.4Hz, 1H), 6.70 (s, 1H), 2.50 (s, 3H).
3- (2- methyl -6- chlorine pyrimidine-4-yls amido) anilino- formic acid (4- nitrobenzene) ester hydrochloride（A2-CAR-0) by A2-NO2-0 (1.44g, 5.44mmol), the reduced iron powder through lmol/L hydrochloric acid activations（1.9g, 32.64mmol) and ammonium chloride（0.29g, 5.44 mmol) input EtOH (90mL), THF (30mL) standing grain B H2The in the mixed solvent of 0 (15mL) compositions, return stirring 3.5h, it is slightly cold after filtered by diatomite.Filtrate is rotated, by gained residue in water (50mL) and ethyl acetate（LOOmL distributed between), divide and take organic phase, aqueous phase is extracted with ethyl acetate again.Combined ethyl acetate, washs, after anhydrous sodium sulfate drying through saturated sodium-chloride water solution, rotates to obtain foam-like A2-NH2-0 (1.38g, 108%).
Above-mentioned gained A2-NH2-0 is dissolved in anhydrous methylene chloride（19mL).It is cooled to 0 °C, adds p-nitrophenyl chloroformate ester（1.42g, 7mmol) anhydrous methylene chloride（10mL) solution, is warmed to room temperature stirring 2.5h.Filter, wash, being dried in vacuo and to obtain yellow solid A2-CAR-0 (2.27g, 96%): 1HNMR (DMSO-d6) δ 10.45 (s, lH), 9.91 (s, lH), 8.29 (d, J=9.2Hz, 2H), 7.92 (s, 1H), 7.53 (d, J=8.8Hz, 2H), 7.37 (d, J=7.6Hz, 1H), 7.23-7.30 (m, 2H), 6.69 (s, lH), 2.43 (s, 3H). 1-(3- (2- methyl-6- chlorine pyrimidine-4-yls amido) phenyl)-3- (the chloro- 4- fluorophenyls of 3-) urea（A2- 1-0) by the chloro- 4- fluoroanilines of A2-CAR-0 (0.65g, 1.5mmol), 3-（0.24g, 1.65mmol) and triethylamine（0.46g, 4.5mmol) it is added in dry DMF (6mL), stir 5.5h at 40 °C.By gained reaction solution dichloromethane（After 90mL) diluting, successively with 0.5mol/L sodium hydrate aqueous solutions and water washing, rotated after anhydrous sodium sulfate drying.Gained residue silica gel column chromatography, with ethyl acetate：Petroleum ether（1 : 10-1：1) gradient elution, obtains slightly yellow solid A2-l-0 (0.36g, 60%)： iHNMR (DMSO-d6) δ 9.68 (s, lH), 8.80 (s, lH), 8.72 (s, lH), 7.78 (dd, J=2,8Hz, 2H), 7.29-7.3 l (m, 3H), 7.23 (t, J=8Hz, 1H), 7.1 l (d, J=8Hz, 1H), 6.63 (s, lH), 2.43 (s, 3H); MS-ESI (m/z) 406 (M+H)+.L- (3- (2- methyl -6- chlorine pyrimidine-4-yls amido) phenyl) -3- (3- (trifluoromethyl) -4- chlorphenyls) urea（A2-3-0) with 3- (trifluoromethyl) -4- chloroanilines（0.32g, 1.65mmol) the chloro- 4- fluoroanilines of 3- are replaced, A2-3-0 is prepared using the method similar to A2-1-0, faint yellow solid is obtained（0.12g, 18%)： 1HNMR (DMSO-d6) 59.70 (s, lH), 9.09 (s, lH), 8.81 (s, lH), 8.13 (s, lH), 7.83 (s, lH), 7.60 (m, 2H), 7.34 (d, J=8Hz, 1H), 7.22-7.26 (m, lH), 7.10 (d, J=8Hz, 1H), 6.64 (s, lH), 2.41 (s, 3H)； MS-ESI (m/z) 456 (M+H)+ ,478 (M+Na)+.
1-(3- (2- methyl-6- chlorine pyrimidine-4-yls amido) phenyl)-3- (4- (pyrrolidines-1-yl) butyl) urea（A2- 18-0) with 4- (pyrrolidin-1-yl) butyl- 1- amine（0.18g, 1.2mmol) the chloro- 4- fluoroanilines of 3- are replaced, A2-18-0 is prepared using the method similar to A2-1-0, yellow oil is obtained（0.12g, 30%)： ^MR (DMSO-d6) 59.62 (s, lH), 8.37 (s, lH), 7.68 (s, lH), 7.14-7.22 (m, 2H), 7.39 (d, J=8Hz, 1H), 6.61 (S, 1H), 6.11 (m, 1H), 3.08-3.09 (m, 2H), 2.40-2.43 (m, 6H), 2.38 (s, 3H), 1.66 (m, 4H), 1.45 (m, 4H); MS-ESI (m/z) 403 (M+H)+ ,827 (2M+Na)+.L- (3- (2- methyl -6- chlorine pyrimidine-4-yls amido) phenyl) -3- isobutyl group ureas（A2-19-0 )
With isobutyl amine（0.09g, 1.2mmol) the chloro- 4- fluoroanilines of 3- are replaced, A2-19-0 is prepared using the method similar to A2-1-0, white solid is obtained（0.13g, 39%)：1Leg MR (DMSO-d6) 59.62 (s, lH), 8.36 (s, lH), 7.68 (s, lH), 7.15-7.24 (m, 2H), 7.04 (d, J=8Hz, 1H), 6.61 (s, lH), 6.12-6.15 (m, lH), 2.91-2.94 (m, 2H), 2.43 (s, 3H), 1.70 (m, lH), 0.89 (s, 3H), 0.87 (s, 3H)；MS-ESI (m/z) 334 (M+H)+, 356 (M+Na)+, 689 (2M+Na)+. The 1 of the 2.2 bad lj of A2 systems
2- (4- (2- methyl-6- (3- nitrobenzene amido) pyrimidine-4-yl) piperazine-1-yl) ethyl acetate（ A2-N02- 1 A )：Take 2- methyl -6- chloro- N- (3- nitrobenzophenones) pyrimidine -4- amine（3.99g, 15mmol) DMSO (30mL) is dissolved in, 2- (the small base of piperazine) ethanol (15.6g, 0.12mol) is added, 15min is stirred at 130 °C.Add water crystallization, is filtrated to get salmon pink precipitates A2-N02-l.DMSO (lOmL) is dissolved in, acetic anhydride is added（2.30g, 0.023mol) and catalytic amount DMAP (0.15g, 1.2mmol), 5h is stirred at room temperature, add water crystallization, filtration drying obtains apricot powder（4.07g, 68%).
2- (4- (2- methyl-6- (3- aminobenzenes amido) pyrimidine-4-yl) piperazine-1-yl) ethyl acetate（The A of A2-NH2- 1) A2-N02-1A (0.96g, 2.4mmol) heating stirring is dissolved in EtOH/H20(2:L) (50mL), adds the reduced iron powder through lmol/L hydrochloric acid activations（0.54g, 9.6mmol) and glacial acetic acid（0. 62g, 10.3mmol).Return stirring 30min, it is 8 to add ammoniacal liquor and alkalize to pH, is filtered while hot by diatomite.Rotate filtrate and remove ethanol, obtained aqueous solution is extracted with ethyl acetate.Rotated after combined ethyl acetate, anhydrous sodium sulfate drying, obtain A2-NH2-1A (0.78g, 88%).
1- (the chloro- 4- fluorine of 3-) -3- (3- (2- methyl -6- (4- (2- ethoxys）Piperazine -1- bases）Pyrimidine radicals -4- base amidos）Phenyl）Urea (A2-1-1)
By A2-NH2-1A (0.78g, 2.1mmol) and p-nitrophenyl chloroformate ester（0.46g, 2.1mmol) it is dissolved in anhydrous CH2C12In (20mL), pyridine is added（0.25g, 3.2mmol), 5min is stirred at room temperature under nitrogen protection, the chloro- 4- fluoroanilines of 3- are then added（0.31g, 2.1mmol) and DIEA (0.96g, 7.4mmol) stirrings 48h.Under agitation into gained reactant add hydrochloric acid (lmol/L, 24mL), separate out flocculent deposit, filtration drying obtain 2- (4- (2- methyl-6-(3-(3-(3- chlorine -4- fluorophenyls) urea groups) anilino-) pyrimidine-4-yl) piperazine -1- bases)-ethyl acetate（), A2-1-1A it is light yellowish brown crystallization：(the s of ifi-NMR (DMSO-de) δ 8.88, 1 H), 8.80 (s, l H), 8.64 (s, l H), 7.81-7.83 (m, 1 H), 7.73 (s, 1 Η), (the m of 7.28-7.3 1, 2H), 7. (the m of 15-7. 17, 2H), 6.95-6.96 (m, l H), 5.94 (s, l H), 4. 13 (t, J=6Hz, 2H), 3.49 (t, J=4.8Hz, 4H), 2.59 (t, J=6Hz, 2H), 2.44-2.50 (m, 4H), 2.30 (, 3 Η), 2.00 (, 3 Η). MS-ESI:M/z 542 (M+H)+, 564 (M+Na)+.
A1-1-1A is replaced with A2-l-lA (0.11g, 0.2mmol), A2-1-1 is prepared using the method similar to Al-1-1, Beige powder A2-l-l (0.07g, 67%) is obtained： 1H-NMR (DMSO-d6) δ 8.90 (s, 1 Η), 8.84 (s, 1H), 8.68 (s, lH), 7.81 (dd, J=2.4,6.8Hz, 1H), 7.74 (s, 1H), 7.28-7.32 (m, 2H), 7.16-7.17 (m, 2H), 6.96 (d J=6.8Hz, 1H), 5.95 (s, 1H), 4.41 (br s, 1H), 3.51-3.56 (m, 6H), 3.17 (m, 2H), 2.59 (m, 4H), 2.30 (s, 3H); MS-ESI:M/z 500 (M+H)+, 999 (2M+H)+.L- (3- (trifluoromethyl) -4- chlorphenyls) -3- (3- (2- methyl -6- (4- (2- ethoxys) piperazine -1- bases) pyrimidine -4- amino) phenyl) urea (A2-3-1)
With 3- (trifluoromethyl) -4- chloroanilines（0.36g, the chloro- 4- fluoroanilines of 3- 1.8mmol) are replaced, 2- (4- (2- methyl -6- (3- (3- (3- (trifluoromethyl) -4- chlorphenyls) uride) anilino-) pyrimidine-4-yl) piperazine -1- bases) ethyl acetate (A2-3-1A) is prepared using the method similar to A2-1-1A.
A2-1-1A is replaced with A2-3-lA (0.18g, 0.3mmol), A2-3-1 is prepared using the method similar to A2-1-1, slightly yellow crystalline powder A2-3-1 (0.12g, 73%) is obtained： 1H-NMR (DMSO-d6) 59.38 (s, 1H), 8.96 (s, 2H), 8.17 (s, 1H), 7.75 (s, 1H), 7.60 (m, 2H), 7.24 (d, J=8.0Hz, 1H), 7.17 (t, J=8.4Hz, 1H), 6.99 (d J=8Hz, lH), 5.94 (s, 1H), 4.40 (br s, 1H), 3.43-3.59 (m, 6H), 3.17 (m, 2H), 2.59 (m, 4H), 2.31 (s, 3H); MS-ESI: m/z 550(M+H) +.L- (3- cyano-phenyls) -3- (3- (2- methyl -6- (4- (2- ethoxys）Piperazine -1- bases）Pyrimidine-4-yl amido）Phenyl）Urea (A2-4-1)
With 3- cyano-anilines（0.27g, the chloro- 4- fluoroanilines of 3- 2.3mmol) are replaced, 2- (4- (2- methyl -6- (3- (3- (3- cyano-phenyls) urea groups) anilino-) pyrimidine-4-yls are prepared using the method similar to A2-1-1A）Piperazine -1- bases)-ethyl acetate (A2-4-1A) is buff powder： 1H-NMR (CDC13) δ 8.63 (s, 1 H), 8.42 (s, l H), 7.86 (s, l H), 7.56 (d, J=8.4Hz, l H), 7.23-7.33 (m, 4H), 7.12 (t, J=8Hz, l H), 6.98 (d, J=8Hz, l H), 6.71 (dd, J=l .2,8Hz, 1 H), 5.89 (s, 1 H), 4.17-4.22 (m, 2H), 3.65-3.68 (m, 3H), 3.56-3.61 (m, l H), 2.46-2.69 (m, 6H), 2.42 (s, 3H), 2.05 (s, 3H).
A2-1-1A is replaced with A2-4-lA (0.15g, 0.3mmol), A2-4-1 is prepared using the method similar to A2-1-1, near-white crystalline powder A2-4-1 (0.09g, 63%) is obtained： 1H-NMR (DMSO-d6) δ 9.07 (s, 1H), 8.99 (s, 1H), 8.85 (s, 1H), 8.06 (s, 1H), 7.83 (s, 1H), 7.76 (d, J=8Hz, 1H), 7.49-7.60 (m, 2H), 7.24-7.30 (m, 2H), 7.08 (d, J=7.2Hz, 1H), 6.03 (s, 1H), 4.46 (br s, 1H), 3.59-3.65 (m, 6H), 3.27 (m, 2H), 2.55 (m, 4H), 2.40 (s, 3H); MS-ESI: m/z 473(M+H)+, 945(2M+H) +.I-P-p- methyl -6- (4- (2- ethoxys) piperazine -1- bases) pyrimidine-4-yl amido) phenyl) -3- (3- tolyls) urea（A2- With 3- methylanilines（0.23g, the chloro- 4- fluoroanilines of 3- 2.1mmol) are replaced, 2- (4- (2- methyl -6- (3- (3- (3- aminomethyl phenyls) urea groups) anilino-) pyrimidine-4-yls are prepared using the method similar to A2-1-1A）Piperazine -1- bases)-ethyl acetate (A2-13-1A):1H-NMR (DMSO-de) 58.86 (s, IH), 8.54 (s, lH), 8.51 (s, lH), 7.73 (s, lH):7.29 (s, lH), 7.21 (m, lH), 7.13-7.16 (m, 3H), 6.95-6.96 (m, lH), 6.78-6.79 (m, IH), 5.95 (s, lH), 4.13 (t, J=6 Hz, 2H), 3.48-3.50 (m, 4H), 2.59 (t, J=6 Hz, 2H), 2.45-2.49 (m, 4H), 2.30 (s, 3H), 2.28 (s, 3H), 2.01 (s, 3H). MS-ESI：M/z 504 (M+H)+, 1007 (2M+H)+.
A2-1-1A is replaced with A2-13-lA (0.1g, 0.2mmol), A2-13-1 is prepared using the method similar to A2-1-1, slightly yellow crystalline A 2-13-1 (0.09g, 90%) is obtained： 1H-NMR (DMSO-d6) δ 8.87 (s, 1H), 8.57 (s, 1H), 8.54 (s, IH), 7.73 (s, IH), 7.29 (s, 1H), 7.23 (d, J=8Hz, 1H), 7.13-7.16 (m, 3H), 6.95-6.97 (m, lH), 6.79 (d, J=7.6Hz, lH), 5.95 (s, 1H), 4.39 (br s, 1H), 3.50-3.56 (m, 6H), 3.17-3.18 (m, 2H), 2.46 (m, 4H), 2.30 (s, 3H), (2.28 s, 3H), MS-ESI: m/z 462(M+H) +.
1-p-p- methyl-6- (4- (2- ethoxys) piperazine-1- bases) pyrimidine-4-yl amido) phenyl)-3- isobutyl group ureas（A2-19-1 the chloro- 4- fluoroanilines of 3-) are replaced with isobutyl amine, 2- (4- (2- methyl -6-CH3- isobutyl groups urea groups) anilino-) pyrimidine-4-yl is prepared using the method similar to A2-1-1A) piperazine -1- bases) ethyl acetate（A2-19-1A) ： 1H-NMR (CDC13) δ 7.56 (s, 2H), 7.26 (s, lH), 7.15 (t, J=8.0Hz, 1H), 7.04 (d, J=8.0Hz, lH), 6.75-6.77 (m, 1H):5.85 (s, lH), 5.57 (m, lH), 4.21 (t, J=5.6Hz, 2H), 3.62 (m, 4H), 3.05 (t, J=6.0Hz, 2H), 2.65 (t, J=6.0Hz, 2H), 2.54 (t, J=5.2Hz, 4H), 2.42 (s, 3H), 2.07 (s, 3H), 1.79 (m, IH), 0.94 (s, 3H), 0.92 (s, 3H) o
A1-1-1A is replaced with A2-19-lA (0.38g, 0.8mmol), A2-19-1 is prepared using the method similar to Al-1-1, slightly yellow crystallization is obtained（0.26g, 76%)： 1H-NMR (DMSO-d6) 58.79 (s, lH), 8.28 (s, lH), 7.62 (s, lH), 7.06-7.09 (m, 2H), 6.89-6.93 (m, IH), 6.11-6.14 (m, lH), 5.90 (s, lH), 4.36 (br s, lH), 3.51-3.55 (m, 2H), 3.44-3.47 (m, 4H), 2.92 (t, J=6.4Hz, 2H), 2.41-2.45 (m, 6H), 2.29 (s, 3H), 1.69 (m, lH), 0.88 (s, 3H), 0.87 (s, 3H); MS-ESI:M/z 428 (M+H)+, 855 (2M+H)+.
The 2 of the 2.3 bad lj of A2 systems
2- methyl -6- morpholinyls-N- (3- nitrobenzophenones) pyrimidine -4- amine（A2-N02-2):
By A2-NO2-0.HC1 (9g, 0.03mol), morpholine（15mL, 0.17mol) and several KI crystal stirrings Flow back 8h.Revolving, filtering gained residue, filter cake washing, dry crude product obtain orange crystals A2-N02-2 (9.1g, 96%) through re crystallization from toluene： ^MR (DMSO-d6) 59.47 (s, lH), 8.75 (t, J=2.4Hz, 1H), 7.95-7.97 (m, 1H), 7.71-7.74 (m, 1H), 7.52 (t, J=8Hz, 1H), 5.83 (s, lH), 3.67 (t, J=4.8Hz, 4H), 3.47 (t, J=4.8Hz, 4H), 2.35 (s, 3H
^- (2- methyl -6- morpholinyls pyrimidine-4-yl) benzene -1,3- diamines（A2-NH2-2)
A2-N02-2 (6.3g, 20mmol), Raney Ni (about 1.5g) are put into absolute ethyl alcohol（In 180mL), 4h is hydrogenated under 60 °C and 4bar pressure.Filtering, filter cake DMF (50mL) and absolute ethyl alcohol（200mL) mixed solvent refluxing extraction.Merging filtrate and extract solution, are cooled to and crystallization are stirred at room temperature, and filter, be dried in vacuo to obtain pistac crystalline A 2-NH2-2 (3.87g, 68%)： ^MR (DMSO-d6) δ 8.59 (s, lH), 6.9 l (t, J=8.0Hz, 1H), 6.75 (t, J=2.0Hz, 1H), 6.67 (d, J=8.0Hz, 1H), 6.20 (d, J=8.0Hz, lH), 5.81 (s, 1H), 4.93 (s, 2H), 3.66 (m, 4H), 3.42 (t, J=4.8Hz, 4H), 2.29 (s, 3H).
3-(2- methyl-6- morpholinyl pyrimidine-4-yl amido) anilino- formic acid (4- nitrobenzene) ester hydrochloride（A2-CAR-2) by p-nitrophenyl chloroformate ester（1.22g, 6mmol) it is dissolved in anhydrous methylene chloride（26mL).It is cooled to 0 °C, point 3 batches of input A2-NH2-2 (1.40g, 5mmol) rise to 20 °C of stirring 3.5h.Filter, wash, being dried in vacuo and to obtain near-white solid A2-CAR-2 (2.15g, 88%): ^MR (DMSO-d6) 510.60 (s, lH), 10.05 (s, lH), 8.31-8.33 (m:2H), 7.68 (s, lH), 7.53-7.56 (m, 2H), 7.32-7.41 (m, 2H), 7.11 (d, J=7.2Hz, 1H), 6.03 (s, lH), 3.65 (m, 8H), 2.47 (s, 3H l- (the chloro- 4- fluorophenyls of 3-) -3- (3- (2- methyl -6- morpholinyl pyrimidine-4-yls amido) phenyl) urea（A2-1-2)
By the chloro- 4- fluoroanilines of A2-CAR-2 (0.98g, 2mmol), 3-（0.32g, 2.2mmol) and triethylamine（0.57g, 5.6mmol) it is added in dry DMF (8mL), stir 4.25h at 40 °C.By gained brown color reactant dichloromethane（After 90mL) diluting, successively with lmol/L sodium hydrate aqueous solutions and water washing, rotated after anhydrous sodium sulfate drying.Gained residue silica gel column chromatography, with ethyl acetate：Ethanol（100: 0-100：6) gradient elution, obtains white solid A2-1-2 (0.65g, 71%)：1Leg MR (DMSO-d6) 58.91 (s, lH), 8.78 (s, lH), 8.63 (s, lH), 7.80 (dd, J=2.4,6.8Hz, 1H), 7.72 (s, 1H), 7.26-7.33 (m, 2H), 7.15 (m, 2H), 6.97 (m, lH), 5.93 (s, lH), 3.66 (m, 4H), 3.46 (m, 4H), 2.30 (s, 3H); MS-ESI (m/z) 457 (M+H)+, 479 (M+Na)+, 913 (2M+H)+.L- (2,3- dichlorophenyl) -3- (3- (2- methyl -6- morpholinyl pyrimidine-4-yls amido) phenyl) urea（A2-2-2)
With 2,3- dichloroanilines（0.36g, 2.2mmol) the chloro- 4- fluoroanilines of 3- are replaced, A2-2-2 is prepared using the method similar to A2-1-2, white solid is obtained（0.09g, 9%)： ^MR (DMSO-d6) 59.38 (s, lH), 8.96 (s, lH), 8.43 (s, lH), 8.15-8.18 (m, 1H), 7.75 (m, 1H), 7.17-7.35 (m, 4H), 7.01 (d, J=8Hz, 2H), 5.93 (s, lH), 3.67 (m, 4H), 3.47 (m, 4H), 2.32 (s, 3H); MS-ESI (m/z) 473 (M+H)+, 495 (M+Na)+.L- (3- (trifluoromethyl) -4- chlorphenyls) -3- (3- (2- methyl -6- morpholinyl pyrimidine-4-yls amido) phenyl) urea（A2-3-2) with 3- (trifluoromethyl) -4- chloroanilines（0.43g, 2.2mmol) the chloro- 4- fluoroanilines of 3- are replaced, A2-3-2 is prepared using the method similar to A2-1-2, near-white solid is obtained（0.25g, 25%)： 1HNMR (DMSO-d6) 59.07 (s, lH), 8.95 (s, lH), 8.72 (s, lH), 8.13 (s, 1H), 7.77 (s, 1H), 7.61 (s, lH), 7.24 (d, J=8.8Hz, 1H), 7.18 (t, J=8.4Hz, lH), 6.98 (d, J=7.6Hz, 1H), 5.92 (S, 1H), 3.67 (m, 4H), 3.46 (m, 4H), 2.32 (s, 3H);MS-ESI (m/z) 507 (M+H)+, 529 (M+Na)+.L- (3- cyano-phenyls) -3- (3- (2- methyl -6- morpholinyl pyrimidine-4-yls amido) phenyl) urea（A2-4-2)
With 3- cyano-anilines（0.28g, 2.2mmol) the chloro- 4- fluoroanilines of 3- are replaced, A2-4-2 is prepared using the method similar to A2-1-2, white solid is obtained（0.40g, 47%)：1Leg MR (DMSO-d6) S8.94 (s, 2H), 8.72 (s, lH), 7.98 (s, 1H), 7.74 (s, 1H), 7.66 (d, J=8Hz, 1H), 7.49 (t, J=8Hz, 1H), 7.4 l (d, J=7.6Hz, lH), 7.16-7.22 (m, 2H), 6.99 (d, J=7.2Hz, 1H), 5.94 (s, 1H), 3.76 (m, 4H), 3.47 (m, 4H), 2.32 (s, 3H); MS-ESI (m/z).
N- methyl -4- (4- (3- (3- (2- methyl -6- morpholinyl pyrimidine-4-yls amido) phenyl) urea groups) phenoxy group) B is than pyridine -2- formamides (A2-6-2)
With 4- (4- amino-benzene oxygens)-N- picoline -2- formamides（0.54g, 2.2mmol) the chloro- 4- fluoroanilines of 3- are replaced, A2-6-2 is prepared using the method similar to A2-1-2, white powder is obtained（0.66g, 60%)： 1HNMR (DMSO-d6) 58.93 (s, lH), 8.75 (s, lH), 8.68 (m, lH), 8.61 (s, lH), 8.50 (d, J=5.2Hz, 1H), 7.58 (m, 2H), 7.41 (m, lH), 7.13-7.22 (m, 5H), 7.02 (m, 1H), 5.94 (s, lH), 3.67 (m, 4H), 3.47 (m, 4H), 2.81 (d, J=5.2Hz, 3H), 2.32 (s, 3H); MS-ESI (m/z) 555 (M+H)+, 1109 (2M+H)+.L- (3- (2- methyl -6- morpholinyl pyrimidine-4-yls amido) phenyl) -3- (5- picoline -2- bases) urea（A2-10-2) with 5- picoline -2- amine（0.18g, 1.65mmol) the chloro- 4- fluoroanilines of 3- are replaced, A2-10-2 is prepared using the method similar to A2- 1-2, pale yellow crystals are obtained（0.29g, 46%)： 1HNMR (DMSO-d6) 510.30 (s, lH), 9.25 (s, lH), 8.96 (s, 1H), 8.09 (s, 1H), 7.85 (s, lH), 7.57 (d, J=8Hz, 1H), 7.42 (J=8Hz, 1H), 7.16-7.25 (m, 2H), 7.03 (d, J=7.6Hz, 1H), 5.91 (s, 1H), 3.67 (m, 4H), 3.46 (m, 4H), 2.32 (s, 3H) 2.23(s,3H);MS-ESI (m/z) 420 (M+H)+, 839 (2M+H)+.
1-cyclohexyl-3- (3- (2- methyl-6- morpholinyl pyrimidine-4-yls amido) phenyl) urea（ A2- 11 -2 )
With cyclohexylamine（0.17g, 1.65mmol) the chloro- 4- fluoroanilines of 3- are replaced, A2-11-2 is prepared using the method similar to A2-1-2, white crystals are obtained（0.30g, 48%):1Leg MR (DMSO-d6) 58.84 (s, lH), 8.18 (s, lH), 7.60 (s, lH), 7.09 (d, 2H, J=5.2Hz), 6.91-6.93 (m, lH), 6.00 (d, J=7.6Hz, 1H), 5.90 (s, lH), 3.64-3.66 (m, 4H), 3.43_3.46 (m, 4H), 2.30 (s, 3H), 1.15-1.82 (m, 10H); MS-ESI (m/z) 411 (M+H)+, 843 (2M+Na)+.
N- (3-(2- methyl-6- morpholinyl pyrimidine-4-yls amido) phenyl) morpholine-4- formamides（ A2- 12-2 )
With morpholine（0.15g, 1.65mmol) the chloro- 4- fluoroanilines of 3- are replaced, A2-12-2 is prepared using the method similar to A2-1-2, white crystals are obtained（0.44g, 73%)：1Leg MR (DMSO-d6) S8.84 (s, lH), 8.45 (s, lH), 7.64 (s, 1H), 7.10-7.18 (m, 2H), 6.96 (d, lH, J=5.2Hz), 5.93 (s, 1H), 3.59-3.66 (m, 8H), 3.41-3.46 (m, 8H), 2.29 (s, 3H);MS-ESI (m/z) 399 (M+H)+, 421 (M+Na)+, 437 (M+K)+.I-P-p- methyl -6- morpholinyl pyrimidine-4-yls amido) phenyl) -3- (3- tolyls) urea（A2-13-2)
With 3- methylanilines（0.18g, 1.65mmol) the chloro- 4- fluoroanilines of 3- are replaced, A2-13-2 is prepared using the method similar to A2-1-2, white powder (0.32g, 51%) is obtained： ^MR (DMSO-d6) 58.92 (s, lH), 8.54 (s, lH), 8.51 (s, lH), 7.73 (s, lH), 7.30 (s, lH), 7.15-7.21 (m, 4H), 6.98 (d, lH, J=7.2Hz), 6.80 (d, lH, J=7.6Hz), 5.95 (s, lH), 3.67 (m, 4H), 3.47 (m, 4H), 2.32 (s, 3H), 2.28 (s, 3H); MS-ESI (m/z) 419 (M+H)+, 441 (M+Na)+.L- (3,5- bis- (trifluoromethyl) phenyl) -3- (3- (2- methyl -6- morpholinyl pyrimidine-4-yls amido) phenyl) urea（A2-14-2) with 3,5- bis- (trifluoromethyl) aniline（0.38g, 1.65mmol) the chloro- 4- fluoroanilines of 3- are replaced, A2-14-2 is prepared using the method similar to A2-1-2, buff powder (0.10g, 12%) is obtained： ^MR (DMSO-d6) 59.34 (s, lH), 9.00 (s, lH), 8.90 (s, lH), 8.13 (s, 2H), 7.79 (s, 1H), 7.62 (s, 1H), 7.20-7.24 (m, 2H), 7.00 (m, lH), 5.94 (s, 1H), 3.65 (m, 4H), 3.47 (m, 4H), 2.33 (s, 3H); MS-ESI (m/z) 541 (M+H)+, 1081 (2M+H)+.L- (2,5- difluorophenyl) -3- (3- (2- methyl -6- morpholinyl pyrimidine-4-yls amido) phenyl) urea（A2-15-2)
With 2,5- difluoroanilines（0.22g, 1.65mmol) the chloro- 4- fluoroanilines of 3- are replaced, A2-15-2 is prepared using the method similar to A2-1-2, faint yellow acicular crystal is obtained（0.08g, 12%)： ^MR (DMSO-d6) 59.06(s,lH),8.96(s,lH), 8.71(s,lH), 8.01-8.06(m, 1H), 7.76(s,lH), 7.16-7.3 l(m, 3H), 6.97(d, J=7.2Hz,lH), 6.78-6.82(m, 1H), 5.94(s, 1H), 3.66-3.68(m,4H), 3.46-3.48(m,4H), 2.32(s,3H); MS-ESI (m/z) 441 (M+H)+, 881 (2M+H)+.(2-methyl-5- fluorophenyl) -3- (3- (2- methyl -6- morpholinyl pyrimidine-4-yls amido) phenyl) urea（A2-16-2) with 2- methyl -5- fluoroanilines（0.22g, 1.76mmol) the chloro- 4- fluoroanilines of 3- are replaced, A2-16-2 is prepared using the method similar to A2- 1-2, white solid is obtained（0.23g, 35%)： 1HNMR (DMSO-d6) S8.93 (s, lH), 8.70 (s, lH), 8.59 (s, lH), 7.73 (t, J=2Hz, lH), 7.43 (dd, J=2,12Hz, lH), 7.13-7.17 (m, 3H), 7.00 (dd, J=2.4,8Hz, lH), 6.95-6.97 (m, lH), 5.95 (s, lH), 3.66-3.68 (m, 4H), 3.46-3.48 (m, 4H), 2.31 (s, 3H), 2.16 (s, 3H); MS-ESI (m/z) 437 (M+H)+, 873 (2M+H)+.
1-(3- (2- methyl-6- morpholinyl pyrimidine-4-yls amido) phenyl)-3- (thiazol-2-yl) urea（ A2- 17-2 )
With thiazolamine（0.17g, 1.65mmol) the chloro- 4- fluoroanilines of 3- are replaced, A2-17-2 is prepared using the method similar to A2-1-2, light yellow solid is obtained（0.27g, 44%):1Leg MR (DMSO-d6) 510.39 (br s, lH), 8.99 (s, lH), 8.87 (s, lH), 7.83 (s, lH), 7.37 (d, J=3.2Hz, lH), 7.26 (d, J=8.4Hz, lH), 7.10-7.2 l (m, 2H), 6.97 (d, J=8.4Hz, lH), 5.93 (s, lH), 3.65-3.69 (m, 4H), 3.44-3.48 (m, 4H), 2.31 (s, 3H);MS-ESI (m/z) 412 (M+H)+, 823 (2M+H)+.
1-(3- (2- methyl-6- morpholinyl pyrimidine-4-yls amido) phenyl)-3- (4- (pyrrolidines-1-yl) butyl) urea（A2- 18-2) with 4- (pyrrolidin-1-yl) butyl- 1- amine（0.26g, 1.8mmol) the chloro- 4- fluoroanilines of 3- are replaced, A2-18-2 is prepared using the method similar to A2-1-2, light yellow solid (0.31g, 46%) is obtained：1Beautiful MR (DMSO-d6) 58.83 (s, lH), 8.27 (s, lH), 7.62 (s, lH), 7.08-7.10 (m, 2H), 6.90-6.93 (m, 1H), 6.08 (m, 1H), 5.90 (s, lH), 3.65 (t, J=4.8Hz, 4H), 3.44 (t, J=4.8Hz, 4H), 3.07-3.09 (m, 2H), 2.38-2.42 (m, 6H), 2.30 (s, 3H), 1.65-1.67 (m, 4H), 1.46 (m, 4H);MS-ESI (m/z) 454 (M+H)+, 907 (2M+H)+.
1- isobutyl groups -3- (3- (2- methyl -6- morpholinyl pyrimidine-4-yls amido) phenyl) urea（A2-19-2)
With isobutyl amine（0.13g, 1.8mmol) the chloro- 4- fluoroanilines of 3- are replaced, A2-19-2 is prepared using the method similar to A2-1-2, white crystals are obtained（0.41g, 71%)：1Leg MR (DMSO-d6) 58.84 (s, lH), 8.27 (s, lH), 7.62 (s, lH), 7.09-7.10 (m, 2H), 6.91-6.93 (m, 1H), 6.11 (t, J=5.6Hz, 1H), 5.90 (s, lH), 3.65 (t, J=4.8Hz, 4H), 3.44 (t, J=4.8Hz, 4H), 2.92 (t, J=6.4Hz, 2H), 2.30 (s, 3H), 1.69 (m, lH), 0.88 (s, 3H), 0.81 (s, 3H); MS-ESI (m/z) 385 (M+H)+,769 (2M+H)+.The 3 of the 2.4 bad lj of A2 systems
2- methyl-6- (- 1-yl of 4- methyl piperazines)-N- (3- nitrobenzophenones) pyrimidine-4- amine（ A2-N02-3 )
By A2-NO2-0.HC1 (4.5g, 15mmol), 1- methyl piperazines（12g, 120mmol) and DMSO (30mL) 140 150 °C stir 0.5h.Gained reactant is cooled to room temperature, water is poured under agitation（In 225mL), continue to stir after lh and filter, filter cake washing, dry crude product obtain yellowish-brown crystalline A 2-N02-3 (4.9g, 100%) through 95% ethyl alcohol recrystallization： iHNMR (DMSO-d6) δ 9.44 (s, lH), 8.77 (t, J=2Hz, 1H), 7.96 (dd, J=2.4,8.4Hz, 1H), 7.73 (dd, J=2.4,8Hz, 1H), 7.53 (t, J=8Hz, 1H), 5.85 (s, lH), 3.50 (t, J=4.8Hz, 4H), 2.37 (t, J=4.8Hz, 4H), 2.35 (s, 3H), 2.22 (s, 3H).
NJ- (2- methyl-6- (- 1-yl of 4- methyl piperazines) pyrimidine-4-yl) benzene-1,3- diamines（ A2-NH2-3 )
By A2-N02-3 (3.3g, 10mmol), ammonium chloride（0.53g, 10mmol), the reduced iron powder through lmol/L hydrochloric acid activations（3.35g, 60mmol) put into by absolute ethyl alcohol（198mL), tetrahydrofuran（66mL) and water（33mL) in the mixed solvent of composition, return stirring 2h.Gained reactant is filtered by diatomite, filtrate is rotated.By gained residue in water（50mL) and ethyl acetate（LOOmL distributed between), divide and take organic phase, aqueous phase is extracted with ethyl acetate (2x50mL) again.Combined ethyl acetate, is washed through saturated sodium-chloride water solution, after anhydrous sodium sulfate drying, revolving.Gained residue is beaten in petroleum ether, filtration drying obtains yellowish pink crystalline A 2-NH2-3 (2.87g, 96%)：^MR (DMSO-de) δ 8.54 (s, lH), 6.90 (t, J=7.6Hz, 1H), 6.74 (t, J=2Hz, 1H), 6.66 (d, J=7.6Hz, 1H), 6.19 (dd, J=1.6,7.6Hz, 1H), 5.80 (s, lH), 4.93 (br s, 2H), 3.44 (t, J=4.8Hz, 4H), 2.36 (t, J=4.8Hz, 4H), 2.27 (s, 3H), 2.21 (s, 3H).
3_(2- methyl-6- (4- methylpiperazine-1-yls）Pyrimidine-4-yl amido）Anilino- formic acid (4- nitrobenzene）Ester hydrochloride (A2-CAR-3)
A2-NH2-3 (7.18g, 24mmol) is dissolved in anhydrous methylene chloride (200mL) and DMF (30mL), p-nitrophenyl chloroformate ester is added dropwise（5.81g, 28.8mmol) anhydrous methylene chloride（LOOmL) solution, is stirred at room temperature 5h.Filter, wash, being dried in vacuo and to obtain yellow solid A2-CAR-3 (9.36g, 78%)： MS-ESI (m/z) 464 (M+H)+, 927 (2M+H)+.L- (the chloro- 4- fluorophenyls of 3-) -3- (3- (2- methyl -6- (4- methylpiperazine-1-yls) pyrimidine-4-yl amido) phenyl) urea（A2-1-3) by the chloro- 4- fluoroanilines of A2-CAR-3 (0.75g, 1.5mmol), 3-（0.24g, 1.65mmol) and triethylamine（0.46g, 4.5mmol) it is added in dry DMF (6mL), stir 9h at 40 °C.By gained reactant dichloromethane（90mL) After dilution, successively with 0.5mol/L sodium hydrate aqueous solutions and water washing, rotated after anhydrous sodium sulfate drying.Gained residue silica gel column chromatography, with ethyl acetate：Ethanol（3: 0-3：1) gradient elution, obtains near-white crystalline A 2-1-3 (0.24g, 34%)：1Beautiful MR (DMSO-de) 58.88 (s, lH), 8.80 (s, lH), 8.65 (s, lH), 7.83 (dd, J=2.8,6.8Hz, 1H), 7.74 (s, lH), 7.27-7.32 (m, 2H), 7.16-7.17 (m, 2H), 6.95-6.96 (m, lH), 5.96 (s, lH), 3.50-3.5 l (m, 4H) 2.37 (t, J=4.4Hz, 4H), 2.30 (s, 3H), 2.21 (s, 3H); MS-ESI (m/z) 470 (M+H)+.L- (2,3- dichlorophenyl) -3- (3- (2- methyl -6- (4- methylpiperazine-1-yls) pyrimidine-4-yl amido) phenyl) urea（A2-2-3) with 2,3- dichloroanilines（0.27g, 1.65mmol) the chloro- 4- fluoroanilines of 3- are replaced, A2-2-3 is prepared using the method similar to A2-1-3, near-white solid is obtained（0.05g, 7%)：1Leg MR (DMSO-d6) S9.38 (s, lH), 8.90 (s, lH), 8.42 (s, lH), 8.16 (dd, J=2,8Hz, 1H), 7.74 (m, 1H), 7.16-7.33 (m, 4H), 6.97-6.99 (m, 1H), 5.93 (s, lH), 3.48 (t, J=4.8Hz, 4H), 2.35 (t, J=4.8Hz, 4H), 2.30 (s, 3H), 2.21 (s, 3H); MS-ESI (m/z) 486 (M+H)+.
1-CH trifluoromethyls) -4- chlorphenyls) -3- H2- methyl -6- (4- methylpiperazine-1-yls) pyrimidine-4-yl amido) phenyl) urea (A2-3-3)
With 3- (trifluoromethyl) -4- chloroanilines（0.32g, 1.65mmol) the chloro- 4- fluoroanilines of 3- are replaced, A2-3-3 is prepared using the method similar to A2-1-3, near-white solid (0.22g, 28%) is obtained： 1HNMR (DMSO-d6) 59.07 (s, lH), 8.89 (s, lH), 8.73 (s, lH), (8.13 s, 1H), 7.76 (s, 1H), 7.60 (s, 2H), (7.14-7.23 m, 2H), 6.96 (d, J=7.6Hz, 1 H), 5.92 (s, 1 H), 3.47-3.50 (m, 4H), 3.34-3.37 (m, 4H), 2.30 (s, 3H), 2.21 (s, 3H); MS-ESI (m/z) 520 (M+H)+.L- (3- cyano-phenyls 3- (3- (2- methyl -6- (4- methylpiperazine-1-yls) pyrimidine-4-yl amido) phenyl) ureas（A2-4-3) with 3- cyano-anilines（0.20g, 1.65mmol) the chloro- 4- fluoroanilines of 3- are replaced, A2-4-3 is prepared using the method similar to A2-1-3, Light yellow crystals powder is obtained（0.15g, 23%)： 1HNMR (DMSO-d6) 58.95 (s, lH), 8.89 (s, lH), 8.73 (s, lH), 7.99 (s, lH), 7.75 (s, lH), 7.64 (d, J=7.6Hz, 1H), 7.49 (t, J=7.6Hz, 1H), 7.41 (d, J=7.6Hz, lH), 7.16-7.18 (m, 2H), 6.96 (m, lH), 5.96 (s, lH), 3.50 (m, 4H), 2.37 (m, 4H), 2.30 (s, 3H), 2.21 (s, 3H); MS-ESI (m/z) 443(M+H)+。
1-cyclohexyl-3- (3- (2- methyl-6- (- 1-yl of 4- methyl piperazines) pyrimidine-4-yl amido) phenyl) urea（A2- 11-3) with cyclohexylamine（0.17g, 1.65mmol) the chloro- 4- fluoroanilines of 3- are replaced, using the method preparation similar to A2-1-3 A2-11-3, obtains white crystalline powder (0.27g, 42%)： 1HNMR (DMSO-d6) S8.88 (s, lH), 8.27 (s, lH), 7.69 (s, lH), 7.17 (m, 2H), 7.01 (s, lH), 6.09 (d, J=7.2Hz, 1H), 6.00 (s, lH), 3.57 (m, 4H), 3.35 (m, 4H), 2.21-2.59 (m, 9H), 1.25-1.92 (m, 8H); MS-ESI (m/z) 424 (M+H)+, 847 (2M+Na)+。
N- (3- (2- methyl -6- (4- methylpiperazine-1-yls) pyrimidine-4-yl amido) phenyl) morpholine -4- formamides（A2-12-3) with morpholine（0.15g, 1.65mmol) the chloro- 4- fluoroanilines of 3- are replaced, A2-12-3 is prepared using the method similar to A2-1-3, near-white solid is obtained（0.25g, 40%)：1Leg MR (DMSO-d6) S8.79 (s, lH), 8.45 (s, lH), 7.63 (s, 1H), 7.09-7.17 (m, 2H), 6.96 (dd, J=1.2,8Hz, lH), 5.92 (s, 1H), 3.60 (t, J=4.8Hz, 4H), 3.48 (m, 4H), 3.42 (t, J=4.8Hz, 4H), 2.38 (m, 4H), 2.28 (s, 3H), 2.22 (s, 3H); MS-ESI (m/z) 412 (M+H)+.I-P-p- methyl -6- (4- methylpiperazine-1-yls) pyrimidine-4-yl amido) phenyl) -3- (3- tolyls) urea（A2-13-3) with 3- methylanilines（0.18g, 1.65mmol) the chloro- 4- fluoroanilines of 3- are replaced, A2-13-3 is prepared using the method similar to A2-1-3, pale yellow powder is obtained（0.40g, 62%)：1Beautiful MR (DMSO-d6) S8.86 (s, lH), 8.53 (s, lH), 8.50 (s, lH), 7.73 (s, 1H), 7.30 (s, lH), 7.12-7.22 (m, 4H), 6.94-6.96 (m, lH), 6.78 (d, J=7.6Hz, 1H), 5.95 (s, lH), 3.49 (t, J=4.8Hz, 4H), 2.36 (t, J=4.8Hz, 4H), 2.29 (s, 3H), 2.27 (s, 3H), 2.20 (s, 3H); MS-ESI (m/z) 432 (M+H)+ ,863 (2M+H)+.L- (3,5- bis- (trifluoromethyl) phenyl) -3- H2- methyl -6- (4- methylpiperazine-1-yls) pyrimidine-4-yl amido) phenyl) urea (A2-14-3)
With 3,5- bis- (trifluoromethyl) aniline（0.38g, 1.65mmol) the chloro- 4- fluoroanilines of 3- are replaced, A2-14-3 is prepared using the method similar to A2-1-3, white powder is obtained（0.11g, 13%): 1HNMR (DMSO-d6) 59.37(s,lH), 8.91(s,lH):8.90 (s, lH), 8.12 (s, 2H), 7.79 (d, J=2Hz, 1H), 7.61 (s, lH), 7.16-7.24 (m, 2H), 6.97 (d, J=8.4Hz, 1H), 5.94 (s, lH), 3.49 (t, J=4.8Hz, 4H), 2.36 (t, J=4.8Hz, 4H), 2.30 (s, 3H), 2.21 (s, 3H); MS-ESI (m/z) 554 (M+H)+.L- (2,5- difluorophenyl) -3- (3- (2- methyl -6- (4- methylpiperazine-1-yls) pyrimidine-4-yl amido) phenyl) urea（A2-15-3) with 2,5- difluoroanilines（0.23g, 1.76mmol) the chloro- 4- fluoroanilines of 3- are replaced, A2-15-3 is prepared using the method similar to A2-1-3, white solid is obtained（0.14g, 21%)：1Leg MR (DMSO-d6) S9.05 (s, lH), 8.91 (s, lH), 8.70 (s, lH), (8.02-8.07 m, 1H), 7.77 (s, 1H), 7.24-7.30 (m, lH), (7.18 m, 2H), 6.93-6.94 (m, lH), 6.77-6.82 (m, 1H), (5.96 s, lH), 3.50 (m, 4H), 2.37 (m, 4H), 2.30 (s, 3H), 2.21 (s, 3H); MS-ESI (m/z) 454 (M+H)+,907 (2M+H)+.(- 5-fluorophenyl of 2- methyl)-3- (3- (2- methyl-6- (4- methylpiperazine-1-yls）Pyrimidine-4-yl amido）Phenyl）Urea (A2-16-3)
With 2- methyl -5- fluoroanilines（0.22g, 1.76mmol) the chloro- 4- fluoroanilines of 3- are replaced, A2-16-3 is prepared using the method similar to A2-1-3, milk yellow crystalline powder is obtained（0.53g, 79%)： ^MR (DMSO-d6) 58.88 (s, lH), 8.71 (s, lH), 8.59 (s, lH), 7.75 (s, 1H), 7.45 (d, J=12.0Hz, 1H), 7.16 (m, 3H), 7.01 (s, 1H), 6.95 (s, 1H), 5.97 (s, lH), 3.50 (m, 4H), 2.37 (m, 4H), 2.31 (s, 3H), 2.22 (s, 3H), 2.17 (s, 3H);MS-ESI (m/z) 450 (M+H)+, 899 (2M+H)+.I-P-p- methyl -6- (4- methylpiperazine-1-yls) pyrimidine-4-yl amido) phenyl) -3- (4- (pyrrolidin-1-yl) butyl) urea (A2-18-3)
With 4- (pyrrolidin-1-yl) butyl- 1- amine（0.26g, 1.8mmol) the chloro- 4- fluoroanilines of 3- are replaced, A2-18-3 is prepared using the method similar to A2-1-3, near-white solid (O.llg, 16%) is obtained： 1HNMR (DMSO-d6) 58.80 (s, lH), 8.31 (s, lH), 7.62 (s, 1H), 7.09-7.10 (m, 2H), 6.92-6.94 (m, 1H), 6.12 (m, 1H), 5.91 (s, lH), 3.48 (t, J=4.8Hz, 6H), 3.09-3.12 (m, 2H), 2.57 (m, 4H), 2.35-2.37 (m, 4H), 2.29 (s, 3H), 2.21 (s, 3H), 1.70-1.72 (m, 4H), 1.48-1.52 (m, 4H);MS-ESI (m/z) 467 (M+H)+, 933 (2M+H)+.
1- isobutyl groups -3- (3- (2- methyl -6- (4- methylpiperazine-1-yls) pyrimidine-4-yl amido) phenyl) urea（A2-19-3) with isobutyl amine（0.13g, 1.8mmol) the chloro- 4- fluoroanilines of 3- are replaced, A2-19-3 is prepared using the method similar to A2-1-3, white solid is obtained（0.29g, 48%):1Leg MR (DMSO-d6) 58.79 (s, lH), 8.27 (s, lH), 7.62 (s, lH), 7.08-7.10 (m, 2H), 6.91-6.93 (m, 1H), 6.12 (m, 1H), 5.90 (s, lH), 3.47 (m, 4H), 2.92 (m, 2H), 2.36 (m, 4H), 2.29 (s, 3H), 2.21 (s, 3H), 1.70 (m, 1H), 0.89 (s, 3H), 0.87 (s, 3H); MS-ESI (m/z) 398 (M+H)+, 795 (2M+H)+。
3. A2M is serial
The 0 of 3.1 A2M
The chloro- N of 6-, 2- dimethyl-N -s (3- nitrobenzophenones) pyrimidine -4- amine（A2M-NO2-0)
By A2-NO2-0.HC1 (10g, 33.2mmol) K2C03(13.8g, 99.6mmol) and iodomethane（5.67g, 40mmol) it is added in DMF (200mL), it is stirred overnight.Gained reactant is poured into frozen water（In 3L), 2h is stirred, filtering and washing drying obtains A2M-NO2-0 (9.26g, 100%)： 1H-NMR (DMSO-d6): δ 8.22-8.23 (m, 1H), 8.16-8.18 (m, lH), 7.83-7.85 (m, H), 7.75 (t, J=8Hz, 1H), 6.47 (s, lH), 3.46 (s, 3H), 2.39 (s, 3H) o
N1^- methyl -6- chlorine pyrimidine-4-yl)-N1- methylbenzene -1,3- diamines（A2M-NH2-0)
By A2M-NO2-0 (0.94g, 3.38mmol), the reduced iron powder through lmol/L hydrochloric acid activations（1.14g, 20.28mmol) and ammonium chloride（0.18g, 3.35mmol) add by absolute ethyl alcohol（60mL), tetrahydrofuran（20mL) and water（Then 10mL) the in the mixed solvent of composition, return stirring 2h is filtered while hot by diatomite, filtrate revolving.Stirring in gained residue is dissolved in water（20mL) and ethyl acetate（60mL), adjust pH to 8 with ammoniacal liquor, divide and take organic phase, aqueous phase is extracted with ethyl acetate again.Merge organic phase, wash, rotated after anhydrous sodium sulfate drying through saturated sodium-chloride water solution, obtain A2M-NH2-0 (0.83g, 99%).
3- (methyl (2- methyl -6- chlorine pyrimidine-4-yl) amido) anilino- formic acid 4- nitrobenzene ester hydrochlorides（A2M-CAR-0 A2M-NH2-0 (0.85g, 3.38mmol)) is dissolved in anhydrous methylene chloride（15 mL), 0 °C is cooled to, chloro-carbonic acid 4- nitro phenyl esters are added dropwise（0.82g, 4.06mmol) dichloromethane（10 mL) solution.After dripping off, 20 °C of stirring 2.5h are warming up to.Filter, dry, obtain A2M-CAR-0 (1.26g, 83%)： 1H-NMR (DMSO-d6):δ 10.60 (s, 1H), 8.31 (dd, J=2.4,7.2Hz, 2H), 7.54 (dd, J=2.4,6.8Hz, 2H), 7.49-7.51 (m, 3H), 7.06-7.09 (m, lH), 6.16 (s, lH), 3.41 (s, 3H), 2.42 (s, 3H)
1-(3- (methyl (2- methyl-6- chlorine pyrimidine-4-yl) amido) phenyl)-3- (the chloro- 4- fluorophenyls of 3-) urea（A2M-1-0) by the chloro- 4- fluoroanilines of 3-（0.22g, 1.54mmol) A2M-CAR-0 (0.63g, 1.4mmol) and triethylamine（0.42g, 4.2mmol) add in DMF (6mL), stir 9h at 40 °C.By gained reactant dichloromethane（90mL) dilute, successively with 0.5mol/L sodium hydrate aqueous solutions, water washing, rotated after anhydrous sodium sulfate drying.Gained residue silica gel column chromatography, with ethyl acetate：Petroleum ether（1 : 1〜1 :2) gradient elution, obtains A2M-1-0 (0.14g, 24%)： 1H-NMR (DMSO-de):δ 8.89 (s, 1H), 8.88 (s, 1H), 7.77-7.79 (m, lH), 7.50 (s, 1H), 7.36-7.44 (m, 2H), 7.30-7.32 (m, 2H), 6.96 (d, J=7.2Hz, 1H), 6.14 (s, 1H), 3.41 (s, 3H), 2.42 (s, 3H);MS-ESI m/z 420 (M+H)+, 839 (2M+H)+.L- (3- (methyl (2- methyl -6- chlorine pyrimidine-4-yl) amido) phenyl) -3- (3- (trifluoromethyl) -4- chlorphenyls) urea（A2M-3-0) with 3- (；Trifluoromethyl) -4- chloroanilines（0.30g, 1.54mmol) the chloro- 4- fluoroanilines of 3- are replaced, A2M-3-0 is prepared using the method similar to A2M-1-0, near-white solid is obtained（0.13g, 20%)： 1HNMR (DMSO-d6) δ 9.17 (s, 1H), 8.96 (s, 1H), 8.08 (d, J=1.6Hz, 1H), 7.60-7.62 (m, 2H), 7.51 (s, 1H), 7.40-7.43 (m, 2H), 6.97 (d, J=7.6Hz, 1H), 6.14 (s, 1H), 3.41 (s, 3H), 2.41 (s, 3H); MS-ESI (m/z) 470 (M+H)+。
The 2 of 3.2 A2M
2- methyl -6- morpholinyls-N- (3- nitrobenzophenones) pyrimidine -4- amine（A2M-N02-2)
By A2M-NO2-0 (5.02g, 18mmol), morpholine（9.42g, 108mmol) standing grain Jie DMSO (20mL) under nitrogen protection 140 °C stir 20min.Frozen water is poured into after gained reactant is cooled into 60 °C（Stirring 2h in 200mL), suction filtration, drying obtain A2M-N02-2 (5.61g, 95%)：1Beautiful MR (DMSO-d6) S8.13 (s, 1H), 8.02 (d, J=8.0Hz, 1H), 7.77 (d, J=8.0Hz, 1H), 7.66 (t, J=8.0Hz, 1H), 5.70 (s, 1H), 3.62 (t, J=4.8Hz, 4H), 3.45 (t, J=4.8Hz, 4H), 3.42 (s, 3H), 2.24 (s, 3H).
N1^- methyl -6- morpholinyls pyrimidine-4-yl) benzene -1,3- diamines（A2M-NH2-2)
By A2M-N02-2 (5.5g, 16.72mmol), the reduced iron powder through lmol/L hydrochloric acid activations（5.6g, lOOmmol) and ammonium chloride（0.89g, 16.72mmol) add by absolute ethyl alcohol（330mL), tetrahydrofuran（L lOmL) and water（Then 55mL) the in the mixed solvent of composition, return stirring 2h is filtered while hot by diatomite, filtrate revolving.Stirring in gained residue is dissolved in water（) and ethyl acetate lOOmL（200mL), adjust pH to 8 with ammoniacal liquor, divide and take organic phase, aqueous phase is extracted with ethyl acetate again.Merge organic phase, wash, rotated after anhydrous sodium sulfate drying through saturated sodium-chloride water solution, obtain light yellow solid A2M-NH2-2 (4.74g, 95%)： ^MR (DMSO-d6) 57.07 (t, J=8.0Hz, 1H), 6.45-6.49 (m, 2H), 6.37-6.39 (m, 1H), 5.34 (s, 1H), 5.13 (s, 2H), 3.58 (t, J=4.8Hz, 4H), 3.27 (m, 7H), 2.27 (s, 3H).
3- (methyl (2- methyl -6- morpholinyl pyrimidine-4-yls）Amido）Anilino- formic acid 4- nitrobenzene ester hydrochloride (A2M-CAR-2)
By A2M-NH2- 0 (4.63g, 15.48mmol) is dissolved in anhydrous methylene chloride（70 mL), 0 °C is cooled to, chloro-carbonic acid 4- nitro phenyl esters are added dropwise（3.74g, 18.55mmol) dichloromethane（50 mL) solution.After dripping off, 20 °C of stirring 2.5h are warming up to.Filter, dry, obtain light yellow solid A2M-CAR-0 (7.68g, 99%)： 1H-NMR (DMSO-de):(the s of δ 10.69,1H), 8.31 (dd, J=2,6.8Hz, 2H), 7.49-7.56 (m, 5H), 7.08-7.10 (m, 1H), 5.65 (s, 1H), 3.65 (m, 4 H), 3.58 (m, 4 H), 3.47 (s, 3H), 2.48 (s, 3H) o l- (the chloro- 4- fluorophenyls of 3-) -3- (3- (methyl (2- methyl -6- morpholinyls pyrimidine-4-yl) amido) phenyl) urea（A2M-1-2) by the chloro- 4- fluoroanilines of 3-（0.24g, 1.65mmol) A2M-CAR-2 (0.75g, 1.5mmol) and triethylamine（0.46g, 4.5mmol) add in DMF (6mL), stir 9h at 40 °C.By gained reactant dichloromethane（90mL) Dilution, successively with 0.5mol/L sodium hydrate aqueous solutions, water washing, is rotated after anhydrous sodium sulfate drying.Gained residue silica gel column chromatography, with ethyl acetate：Triethylamine（100:1) elute, obtain white solid A2M-1-2 (0.19g, 27%)： 1H-NMR (DMSO-de):5 8.83 (s, 1H), 8.78 (s, 1H), 7.79 (dd, J=2.4,6.8Hz, 1H), 7.46-7.47 (m, 1H), 7.28-7.36 (m, 3H), 7.23 (d, J=7.6Hz, 1H), 6.91 (d, J=7.2Hz, 1H), 5.51 (s, 1H), 3.59 (t, J=4.8Hz, 4H), 3.36 (s, 3H), 3.33 (m, 4H), 2.28 (s, 3H); MS-ESI m/z 471 (M+H)+.L- (3- (trifluoromethyl) -4- chlorphenyls) -3- (3- (methyl (2- methyl -6- morpholinyls pyrimidine-4-yl) amido) phenyl) urea (A2M-3-2)
With 3- (；Trifluoromethyl) -4- chloroanilines（0.32g, 1.65mmol) the chloro- 4- fluoroanilines of 3- are replaced, A2M-3-2 is prepared using the method similar to A2M-1-2, white solid is obtained（0.08g, 10%)： 1HNMR (DMSO-d6) δ 9.13 (s, 1H), 8.87 (s, 1H), 8.09 (s, 1H), 7.61-7.62 (m, 2H), 7.48 (s, 1H), 7.35 (t, J=8Hz, 1H), 7.25 (d, J=8Hz, 1H), 6.93 (d, J=7.6Hz, 1H), 5.51 (s, 1H), 3.59 (m, 4H), 3.37 (s, 3H), 3.26-3.37 (m, 4H), 2.28 (s, 3H); MS-ESI (m/z) 521 (M+H)+.L- (3- cyano-phenyls) -3- (3- (methyl (2- methyl -6- morpholinyls pyrimidine-4-yl) amido) phenyl) urea（A2M-4-2) with 3- cyano-anilines（0.19g, 1.65mmol) the chloro- 4- fluoroanilines of 3- are replaced, A2M-4-2 is prepared using the method similar to A2M-1-2, white solid (O.llg, 16%) is obtained：1Leg MR (DMSO-d6) δ 8.99 (s, 1H), 8.88 (s, 1H), 7.97 (m, 1H), 7.67 (d, J=8.8Hz, 1H), 7.47-7.51 (m, 2H), 7.42 (d, J=8Hz,
1H), 7.37 (t, J=8Hz, 1H), 7.25 (d, J=7.6Hz, 1H), 6.93 (d, J=8Hz, 1H), 5.52 (s,
1H), 3.60 (t, J=4.8Hz, 4H), 3.38 (s, 3H), 3.34-3.36 (m, 4H), 2.29 (s, 3H); MS-ESI
(m/z) 444 (M+H)+ ,887 (2M+H)+.L- (5- picoline -2- bases) -3- (3- (methyl (2- methyl -6- morpholinyls pyrimidine-4-yl) amido) phenyl) urea（A2M-10-2) with 5- picoline -2- amine（0.18g, 1.65mmol) the chloro- 4- fluoroanilines of 3- are replaced, A2M-10-2 is prepared using the method similar to A2M-1-2, white solid (0.23g, 35%) is obtained： 1HNMR (DMSO-d6) δ 10.45 (s, 1H), 9.26 (s, 1H), 8.09 (s, 1H), 7.31-7.57 (m, 5H), 6.91 (d, J=7.6Hz, 1H), 5.46 (s, 1H), 3.57 (t, J=4.8Hz, 4H), 3.35 (s, 3H), 3.30-3.33 (m, 4H), 2.26 (s, 3H), 2.21 (s, 3H); MS-ESI (m/z) 434 (M+H)+, 889 (2M+Na)+。 L- (3- tolyls) -3- (3- (methyl (2- methyl -6- morpholinyls pyrimidine-4-yl) amido) phenyl) urea（A2M-13-2) with 3- methylanilines（0.18g, 1.65mmol) the chloro- 4- fluoroanilines of 3- are replaced, A2M-13-2 is prepared using the method similar to A2M-1-2, white solid is obtained（0.35g, 54%)：1Leg MR (DMSO-d6) δ 8.69 (s, 1H), 8.55 (s, 1H), 7.48 (m, 1H), 7.30-7.35 (m, 2H), 7.19-7.22 (m, 2H), 7.14 (t, J=7.6Hz,
1H), 6.88 (dd, J=1.2,8.0Hz, 1H), 6.79 (d, J=7.2Hz, 1H), 5.51 (s, 1H), 3.59 (m,
4H), 3.37 (s, 3H), 3.32-3.36 (m, 4H), 2.28 (s, 3H), 2.27 (s, 3H); MS-ESI (m/z) 433
(M+H)+, 455 (M+Na)+, 471 (M+K)+.L- (4- (pyrrolidin-1-yls）Butyl) -3- (3- (methyl (2- methyl -6- morpholinyl pyrimidine-4-yls）Amido）Phenyl）Urea (A2M-18-2)
With 4- (pyrrolidin-1-yl) butyl- 1- amine（0.23g, 1.65mmol) the chloro- 4- fluoroanilines of 3- are replaced, A2M-18-2 is prepared using the method similar to A2M-1-2, white crystalline solid is obtained（0.25g, 36%)： 1HNMR (DMSO-d6) 57.21-7.29 (m, 3H), 7.03 (s, 1H), 6.86-6.88 (m, lH), 5.85 (s, 1H), 5.36 (s, 1H), 3.69 (t, J=4.8Hz, 4H), 3.41 (s, 3H), 3.38-3.41 (m, 4H), 3.23 (br s, 2H), 2.51-2.59 (m, 6H), 2.41 (s, 3H), 1.80-1.83 (m, 4H), 1.56-1.63 (m, 4H); MS-ESI (m/z) 468 (M+H)+ ,935 (2M+H)+。
1-isobutyl group-3- (3- (methyl (2- methyl-6- morpholinyls pyrimidine-4-yl) amido) phenyl) urea（A2M- 19-2) with isobutyl amine（0.12g, 1.65mmol) the chloro- 4- fluoroanilines of 3- are replaced, A2M-19-2 is prepared using the method similar to A2M-1-2, white solid is obtained（0.26g, 43%)：1Leg MR (DMSO-d6) 8.44 (s of δ, 1H), 7.42 (t, J=2.0Hz, lH), 7.24-7.28 (m, 1H), 7.15-7.17 (m, 1H), 6.79 (dd, J=1.2, 8.0Hz, 1H), 6.15 (t, J=6.0Hz, lH), 5.44 (s, 1H), 3.58 (t, J=4.8Hz, 4H), 3.34 (s, 3H), 3.3 l (t, J=4.8Hz, 4H), 2.90-2.93 (m, 2H), 2.27 (s, 3H), 1.69 (m, 1H), 0.87 (s, 3H), 0.86 (s, 3H); MS-ESI (m/z) 399 (M+H)+.L- (3- (methyl (2- methyl-6- 4-yl of-morpholine yl pyrimidines) amine) phenyl)-3- (5- methylisoxazole-3-yl) urea（A2M-20-2) by 3- amino -5- methylisoxazoles（0.26g, 2.7mmol) it is dissolved in anhydrous methylene chloride（12ml), phenyl chloroformate is added dropwise（0.42g, 2.7mmol), lh is stirred at room temperature.Add triethylamine（0.33g, 3.3mmol), add A2M-NH2- 2 (0.80g, 2.7mmol), triethylamine（0.66g, 6.5mmol), return stirring 3h.Let cool, add lmol/L sodium hydrate aqueous solutions（10ml), 10min is stirred.Point organic layer is taken, washed through saturated brine, after anhydrous sodium sulfate drying, Jian Ya Nong Shrink.Gained residue is handled with ethyl acetate, white solid is obtained.Flowed back and be dissolved in methanol（80ml), let cool, Add lmol/L hydrochloric acid（5ml), 2h is stirred.It is 9-10 with 0.5mol/L sodium hydrate aqueous solutions regulation pH, revolving removes methanol, filtering obtains faint yellow solid（0.20g, 18%)：1Beautiful MR (DMSO-d6) δ 9.63 (s, 1H), 9.38 (s, 1H), 7.52 (s, 1H), 7.34-7.43 (m, 2H), 6.98 (d, J=7.6Hz, 1H), 6.50 (s, 1H), 5.62 (s, 1H), 3.65 (t, J=4.4Hz, 4H), 3.52 (m, 4H), 3.43 (s, 3H), 2.41 (s, 3H), 2.36 (s, 3H); MS-ESI m/z 424 (M+H) +.
The 3 of 3.3 A2M
N, 2- dimethyl-6- (- 1-yl of 4- methyl piperazines)-N- (3- nitrobenzophenones) pyrimidine-4- amine（ A2M-N02-3 )
By A2M-NO2-0 (4.99g, 17.9mmol), 1- methyl piperazines（10.77g, 107.5mmol) standing grain Jie DMSO (20mL) under nitrogen protection 140 °C stir 20min.Gained reactant is cooled to after 80 °C, frozen water is poured under agitation（In 200mL), dichloromethane is used（2x l50mL) extract.Merge organic phase, washed through saturated sodium-chloride water solution, after anhydrous sodium sulfate drying, after revolving, drying A2M-N02-3 (6.02g, 98%)： 1H-NMR (DMSO-d6) 5 8.12 (t, J=2.0Hz, 1H), 8.00-8.02 (m, 1H), 7.75-7.77 (m, 1H), 7.65 (t, J=8.0Hz, 1H), 5.71 (s, 1H), 3.47 (t, J=5.2Hz, 4H), 3.41 (s, 3H), 2.32 (t, J=5.2Hz, 4H), 2.23 (s, 3H), 2.19 (s, 3H).
N1- methyl-^- (2- methyl-6- (- 1-yl of 4- methyl piperazines) pyrimidine-4-yl) benzene-1,3- diamines（A2M-NH2-3) by A2M-N02-3 (6.02g, 17.6mmol), the reduced iron powder through lmol/L hydrochloric acid activations（5.91g, 105.6mmol) and ammonium chloride（0.94g, 17.6mmol) add by absolute ethyl alcohol（360mL), tetrahydrofuran（120mL) and water（Then 60mL) the in the mixed solvent of composition, return stirring 2h is filtered while hot by diatomite, filtrate revolving.Stirring in gained residue is dissolved in water（) and ethyl acetate lOOmL（200mL), adjust pH to 8 with ammoniacal liquor, divide and take organic phase, aqueous phase is extracted with ethyl acetate again.Merge organic phase, wash, rotated after anhydrous sodium sulfate drying through saturated sodium-chloride water solution, obtain brown solid A2M-NH2-3 (4.73g, 86%)： 1H-NMR (DMSO-d6) 5 7.07 (t, J=8.0Hz, 1H), 6.45 (m, 2H), 6.37-6.39 (m, 1H), 5.34 (s, 1H), 5.13 (s, 2H), 3.29 (m, 7H), 2.29 (m, 4H), 2.26 (s, 3H), 2.16 (s, 3H).
3- (methyl (2- methyl -6- (4- methylpiperazine-1-yls) pyrimidine-4-yl) amidos）Anilino- formic acid 4- nitrobenzene ester hydrochloride (A2M-CAR-3)
A2M-NH2-3 (4.73g, 15.2mmol) is dissolved in anhydrous methylene chloride（70 mL), 0 °C is cooled to, chloro-carbonic acid 4- nitro phenyl esters are added dropwise（3.67g, 18.2mmol) dichloromethane（50 mL) solution.After dripping off, 20 °C of stirring 2.5h are warming up to.Filter, dry, obtain light yellow solid A2M-CAR-3 (7.89g, 100%)： 1H-NMR (DMSO-de):5 9.62 (s, 1H), 8.11 (d, J=9.2Hz, 2H), 7.48 (t, J=2Hz, 1H), 7.31-7.38 (m, 2H), 6.95 (d, J=9.2Hz, 2H), 6.88-6.91 (m, 1H), 5.64 (s, 1H), 3.46 (m, 4H), 3.39 (s, 3H), 3.03 (m, 4H), 2.75 (s, 3H), 2.32 (s, 3H).L- (the chloro- 4- fluorophenyls of 3-) -3-H methyl (2- methyl -6- (4- methylpiperazine-1-yls) pyrimidine-4-yl) amido) phenyl) urea (A2M-1-3)
By the chloro- 4- fluoroanilines of 3-（0.24g, 1.65mmol) A2M-CAR-3 (0.77g, 1.5mmol) and triethylamine（0.46g, 4.5mmol) add in DMF (6mL), stir 9h at 40 °C.By gained reactant dichloromethane（90mL) dilute, successively with 0.5mol/L sodium hydrate aqueous solutions, water washing, rotated after anhydrous sodium sulfate drying.Gained residue silica gel column chromatography, with ethyl acetate：Ethanol（5: 1〜1:1) gradient elution, obtains white solid A2M-1-3 (0.17g, 23%)： 1H-NMR (DMSO-de):δ 8.84 (s, 1H), 8.79 (s, 1H), 7.80 (dd, J=2.4,6.8Hz, 1H), 7.47 (s, 1H), 7.20-7.35 (m, 4H), 6.89-6.92 (m, 1H), 5.53 (s, 1H), 3.58 (m, 4H), 3.36 (s, 3H), 2.29 (t, J=4.8Hz, 4H), 2.26 (s, 3H), 2.17 (s, 3H). MS-ESI m/z 484 (M+H)+.L- (3- (trifluoromethyl) -4- chlorphenyls) -3- (3- (methyl (2- methyl -6- (4- methylpiperazine-1-yls) pyrimidine-4-yl) amido) phenyl) urea（A2M-3-3)
By 3- (trifluoromethyl) -4- chloroanilines（0.59g, 3mmol), A2M-CAR-3 (0.77g, 1.5mmol) and triethylamine（0.46g, 4.5mmol) add in DMF (6mL), stir 9h at 40 °C.By gained reactant dichloromethane
(90mL) dilutes, successively with 0.5mol/L sodium hydrate aqueous solutions, water washing, is rotated after anhydrous sodium sulfate drying.Gained residue silica gel column chromatography, with ethyl acetate：Ethanol（20: 1〜5：1) gradient elution, obtains near-white solid A2M-3-3
(0.20g, 25%)：1Beautiful MR (DMSO-d6) S9.13 (s, 1H), 8.87 (s, 1H), 8.09 (d, J=2.4Hz, 1H), 7.58-7.64 (m, 2H), 7.48 (s, 1H), 7.34 (t, J=8.0Hz, 1H), 7.24 (d, J=8.0Hz, 1H), 6.92 (d, J=8.0Hz, lH), 5.51 (s, 1H), 3.36 (m, 4H), 3.35 (s, 3H), 2.28-2.29 (m, 4H), 2.26 (s, 3H), 2.16 (s, 3H); MS-ESI (m/z) 534 (M+H)+ ,1067 (2M+H)+O l-(3- cyano-phenyls) -3- (3- (methyl (2- methyl -6- (4- methylpiperazine-1-yls）Pyrimidine-4-yl) amido）Phenyl) urea (A2M-4-3)
With 3- cyano-anilines（0.19g, 1.65mmol) the chloro- 4- fluoroanilines of 3- are replaced, A2M-4-3 is prepared using the method similar to A2M-1-3, white solid is obtained（0.06g, 9%)：1Leg MR (DMSO-d6) δ 9.01 (s, 1H), 8.88 (s, 1H), 7.96 (s, 1H), 7.64 (d, J=7.6Hz, 1H), 7.45-7.48 (m, 2H), 7.40 (d, J=7.2Hz 1H), 7.34 (t, J=8Hz, 1H), 7.22 (d, J=8.4Hz, 1H), 6.91 (d, J=7.6Hz, 1H), 5.53 (s, 1H), 3.49 (m, 4H), 3.36 (s, 3H), 2.28-2.29 (m, 4H), 2.26 (s, 3H), 2.16 (s, 3H); MS-ESI (m/z) 457 (M+H)+,913 (2M+H)+.L- (5- picoline -2- bases) -3- H methyl (2- methyl -6- (4- methylpiperazine-1-yls) pyrimidine-4-yl) amido) phenyl) urea (A2M-10-3)
With 5- picoline -2- amine（0.18g, 1.65mmol) the chloro- 4- fluoroanilines of 3- are replaced, A2M-10-3 is prepared using the method similar to A2M-1-3, white solid is obtained（0.23g, 34%)：1Beautiful MR (DMSO-d6) δ 10.48 (s, 1H), 9.25 (s, 1H), 8.10 (s, 1H), 7.52-7.57 (m, 2H), 7.30-7.40 (m, 3H), 6.92 (d, J=7.6Hz, 1H), 5.47 (s, 1H), 3.47 (m, 4H), 3.35 (s, 3H), 2.29 (t, J=4.4Hz, 4H), 2.26 (s, 3H), 2.22 (s, 3H), 2.16 (s, 3H); MS-ESI (m/z) 447 (M+H)+O l- (3- tolyls) -3- (3- (methyl (2- methyl -6- (4- methylpiperazine-1-yls）Pyrimidine-4-yl）Amido）Phenyl）Urea (A2M-13-3)
With 3- methylanilines（0.18g, 1.65mmol) the chloro- 4- fluoroanilines of 3- are replaced, A2M-13-3 is prepared using the method similar to A2M-1-3, white solid is obtained（0.13g, 19%)：1Beautiful MR (DMSO-d6) δ 8.70 (s, 1H), 8.56
(s, 1H), 7.49 (s, 1H), 7.33 (t, J=8Hz, 2H), 7.20 (d, J=8.4Hz, 2H), 7.14 (t, J=7.6Hz, 1H), 6.87-6.90 (m, 1H), 6.79 (d, J=6.8Hz, 1H), 5.53 (s, 1H), 3.38 (m, 4H), 3.36
(s, 3H), 2.30 (t, J=4.8Hz, 4H), 2.27 (s, 6H), 2.17 (s, 3H); MS-ESI (m/z) 446 (M+H)+.L- (3,5- bis- (trifluoromethyl) phenyl) -3- (3- (methyl (2- methyl -6- (4- methylpiperazine-1-yls) pyrimidine-4-yl) amido) phenyl) urea (A2M-14-3)
With 3,5- bis- (trifluoromethyl) aniline（0.69g, 3mmol) 3- (trifluoromethyl) -4- chloroanilines are replaced, A2M-14-3 is prepared using the method similar to A2M-3-3, near-white solid is obtained（0.06g, 7%)： 1HNMR (DMSO-d6) δ9.38
(s, 1H), 9.01 (s, 1H), 8.12 (s, 1H), 7.62 (s, lH), 7.50 (s, 1H), 7.36 (t, J=8.0Hz, 1H), 7.25 (d, J=8.4Hz, 1H), 6.94 (d, J=6.8Hz, lH), 5.53 (s, 1H), 3.37 (s, 3H), 3.35
(m, 4H), 2.27-2.29 (m, 4H) 2.28 (s, 3H), 2.15 (s, 3H); MS-ESI (m/z) 568 (M+H)+,1135 (2M+H)+.L- (4- (pyrrolidin-1-yl) butyl) -3-CH methyl (2- methyl -6- (4- methylpiperazine-1-yls) pyrimidine-4-yl) amido) phenyl) Urea (A2M-18-3)
With 4- (pyrrolidin-1-yl) butyl- 1- amine（0.23g, 1.65mmol) the chloro- 4- fluoroanilines of 3- are replaced, A2M-18-3, give light yellow oil are prepared using the method similar to A2M-1-3（0.24g, 33%)： 1HNMR (DMSO-d6) 58.68 (s, 1H), 7.43 (m, 1H), 7.17-7.27 (m, 2H), 6.77 (d, J=7.6Hz, 1H), 6.35 (br s, 1H), 5.43 (s, 1H), 3.74 (m, 6H), 3.34 (s, 3H), 3.07 (m, 2H), 2.39-2.43 (m, 4H), 2.28 (m, 4H), 2.26 (s, 3H), 2.15 (s, 3H), 1.65 (m, 4H), 1.45 (m, 4H); MS-ESI (m/z) 481 (M+H)+, 503 (M+Na)+ ,983 (2M+Na)+。
1-isobutyl group-3- (3- (methyl (2- methyl-6- (- 1-yl of 4- methyl piperazines) pyrimidine-4-yl) amido) phenyl) urea（A2M- 19-3) with isobutyl amine（0.12g, 1.65mmol) the chloro- 4- fluoroanilines of 3- are replaced, A2M-19-3 is prepared using the method similar to A2M-1-3, white crystalline solid is obtained（0.20g, 32%)： 1HNMR (DMSO-d6) 8.44 (s of δ, 1H), 7.42 (d, J=2.0Hz, lH), 7.26 (t, J=8.0Hz, 1H), 7.16 (dd, J=1.2, 8.0Hz, 1H), 6.78-6.80 (m, 1H), 6.16 (t, J=6.0Hz, lH), 5.44 (s, 1H), 3.35-3.37 (m, 4H), 3.33 (s, 3H), 2.9 l (t, J=6.0Hz, 2H), 2.27-2.29 (m, 4H), 2.26 (s, 3H), 2.16 (s, 3H), 1.69 (m, 1H), 0.87 (s, 3H), 0.86 (s, 3H); MS-ESI (m/z) 412 (M+H)+。
4. A2N is serial
The 1 of 4.1 A2N series
The chloro- N- of 2- methyl -6- (3- nitro-4-methyls phenyl) pyrimidine -4- amine hydrochlorates（A2N-NO2-0.HC1)
By 3- nitro-4-methyl aniline（30.43g, 0.2mol) and 2- methyl -4,6- dichloro pyrimidines（32.62g, 0.2mol) input water（150mL) and acetone（In 50mL), 12mol/L hydrochloric acid is added（4mL) it is stirred at reflux 2h.It is cooled to after room temperature and filters, filter cake washing, dry bright yellow solid A2N-NO2-0.HC1 (53.58g, 85%).
^- (2- methyl -6- chlorine pyrimidine-4-yl) -4- toluene -1,3- diamines（A2N-NH2-0)
By A2N-NO2-0.HC1 (3.67g, 11.7mmol), the reduced iron powder through lmol/L hydrochloric acid activations（3.92g, 70.0mmol) and ammonium chloride（1.25g, 23.4 mmol) in the mixed solvent being made up of ethanol (240mL), tetrahydrofuran (80mL) and water (40mL) is added, return stirring 2h is filtered while hot by diatomite.Filtrate rotates, into gained solid residue, adds water（LOOmL), pH is adjusted to 9 or so with ammoniacal liquor, then aqueous phase is extracted with ethyl acetate.Merge organic phase, rotated with after anhydrous sodium sulfate drying, obtain light yellow solid A2N-NH2-0 (2.64g, 81%)： 1H-NMR(DMSO-d6) 5 9.36 (s, 1H), 6.88 (d, J=8.0Hz, 1H), 6.78 (d, J=1.6Hz, 1H), 6.63 (d, J=8.0Hz, 1H), 6.52 (s, 1H), 4.85 (s, 2H), 2.40 (s, 3H), 2.03 (s, 3H).
5-(2- methyl-6- chlorine pyrimidine-4-yl amido) -2-aminotoluene base formic acid 4- nitrobenzene ester hydrochlorides（A2N-CAR-0) By p-nitrophenyl chloroformate ester（1.94g, 9.6mmol) it is dissolved in dichloromethane（20 mL).A2N-NH2-0 (2.00g, 8 mmol) dichloromethane is added dropwise at-10-5 °C（120 mL), 1.5h is stirred at room temperature after dripping off.Filtering vacuum is dried, and obtains near-white solid A2N-CAR-0 (3.27g, 91%)： 1H-NMR (DMSO-d6) δ 9.97 (br s, 1H), 9.71 (br s, 1H), 8.30 (dd, J=2.0,8.8Hz, 2H), 7.73 (s, 1H), 7.52 (dd, J=2.0,8.8Hz, 2H), 7.45 (d, J=7.6Hz, 1H), 7.21 (d, J=8.0Hz, 1H), 6.68 (s, 1H), 2.42 (s, 3H), 2.27 (s, 3H) o
1-(2- methyl-5- (2- methyl-6- chlorine pyrimidine-4-yl amidos）Phenyl) -3- (3- (trifluoromethyl) -4- chlorphenyls）Urea (A2N-3-0)
By A2N-CAR-C1 (0.67g, 1.5mmol) and 3- (trifluoromethyl) -4- chloroanilines（0.59g, 3 mmol) DMF (6 mL) is dissolved in, add triethylamine（0.46g, 4.5mmol), it is stirred overnight at 40 °C, dichloromethane (60mL) and the 0.5mol/LNaOH aqueous solution (20mL) is then added into gained reaction solution.Divide and take anhydrous sodium sulfate drying after organic phase, washing, rotate.Residue obtained by silica gel column chromatography, with ethyl acetate：Petroleum ether（2:1) elute, obtain white crystalline solid（0.10g, 14%)： 1H-NMR (DMSO-d6) δ 9.65 (s, 1H), 9.45 (s, 1H), 8.17 (s, 1H), 8.04 (s, 1H), 8.04 (s, 1H), 7.60 (s, 2H), 7.38 (d, J=7.6 Hz, 1H), 7.15 (d, J=8.4Hz, 1H), 6.61 (s, lH), 2.42 (s, 3H), 2.22 (s, 3H); MS-ESI m/z 470 (M+H)+ , 492 (M+Na)+。
1-(2- methyl-5- (2- methyl-6- chlorine pyrimidine-4-yls amido) phenyl)-3- (4- (pyrrolidines-1-yl) butyl) urea（A2N- 18-0) with 4- (the small base of pyrrolidines) the small amine of butane（0.40g, 3mmol) 3- (trifluoromethyl) -4- chloroanilines are replaced, A2N-18-0 is prepared using the method similar to A2N-3-0, light yellow solid (0.13g, 21%) is obtained： 1H-NMR (DMSO-d6) δ 9.58 (s, 1H, exchangeable), 7.98 (d, J=2.0Hz, 1H), 7.58 (s, 1H, exchangeable), 7.24 (d, J=7.6Hz, 1H), 7.07 (d, J=8.0Hz, 1H), 6.57 (s, 1H), 6.55 (m, 1H, exchangeable), 3.10 (d, J=6.0Hz, 2H), 2.42-2.44 (m, 6H), 2.40 (s, 3H), 2.15 (s, 3H), 1.67 (m, 4H), 1.47 (m, 4H); MS-ESI m/z 417 (M+H)+, 833 (2M+H)+.L- (3- (trifluoromethyl) -4- chlorphenyls) -3- (5- (6- (4- (2- ethoxys) piperazine -1- bases) -2- methylpyrimidine -4- bases amido) -2- tolyls) urea（A2N-3-1 )
Take A2N-3-0 (0.09g, 0.2 mmol), 2- (piperazine -1- bases) ethanol（0.16g, 1.2 mmol), DIEA (0.16g, 1.2 mmol) and n-butanol（3mL) mix, be warming up to 80 °C of stirring 7h, be cooled to after room temperature and rotate.Silicagel column Chromatography gained residue, with ethyl acetate：Ethanol（6:1〜3:1) gradient elution, obtains Tan solid A2N-3-1 (0.05g, 45%)： 1HNMR (DMSO-d6) δ 9.42 (s, 1H), 8.79 (s, 1H), 8.12 (s, 1H), 8.01 (s, 1H), 7.90 (d, J=2.0 Hz, 1H), 7.60 (s, 2H), 7.18 (dd, J=2.4,8.4Hz, 1H), 7.07 (d, J=8.4 Hz, 1H), 5.95 (s, lH), 4.36 (brs, 1H), 3.48 (m, 6H), 2.49 (m, 6H), 2.27 (s, 3H), 2.19 (s, 3H); MS-ESI m/z 564(M+H) +.
4.2A2N the 2 of series
2- methyl-N- (4- methyl-3-nitros phenyl) -6- morpholine yl pyrimidines -4- amine（A2N-N02-2)
By A2N-N02-C1.HC1 (5g, 15.9 mmol) and morpholine（8.29g, 95.2 mmol) it is added in DMSO (20mL), 140 °C of stirring 30min are heated to, mixture of ice and water is then poured into while hot under agitation（In 200mL), filtration drying obtains yellow solid A2N-N02-2 (5.11g, 98%)： 1H-NMR (DMSO-d6) 59.33 (s, 1H), 8.48 (d, J=2.0Hz, 1H), 7.77 (dd, J=2.4,8.4Hz, 1H), 7.36 (d, J=8.0Hz, 1H), 5.80 (s, 1H), 3.67 (t, J=4.8Hz, 4H), 3.46 (t, J=4.8Hz, 4H), 2.44 (s, 3H), 2.33 (s, 3H) o
4- methyl-N1- ^- methyl -6- morpholinyls pyrimidine-4-yl) benzene -1,3- diamines（A2N-NH2-2)
A2N-N02-2 (5.11g, 15.5 mmol) is added by ethanol (330mL), tetrahydrofuran（LlOmL) and water (55mL) composition in the mixed solvent, add ammonium chloride (0.83g, 15.5 mmol) and the reduced iron powder (5.21g, 93.0 mmol) with lmol/L hydrochloric acid activations, return stirring 2h is heated to, is then filtered while hot.Revolving reaction solution obtains white solid, adds water（LOOmL), pH is adjusted to 9 or so with ammoniacal liquor, add ethyl acetate (200mL) stirring, filter to obtain white solid；Rotated after organic filtrate anhydrous sodium sulfate drying, obtain second batch white solid.Merge two batches filter cake, be dried in vacuo to obtain white solid product A2N-NH2-2 (4.31g, 93%)： 1H-NMR (DMSO-d6) δ 8.50 (s, 1H), 6.81 (d, J=8.0Hz, 1H), 6.74 (m, 1H), 6.57-6.60 (m, 1H), 5.77 (s, 1H), 4.72 (s, 2H), 3.65 (t, J=4.8Hz, 4H), 3.40 (t, J=4.8Hz, 4H), 2.27 (s, 3H), 2.01 (s, 3H).
2_ methyl-5- (2- methyl-6- morpholinyl pyrimidine-4-yl amido）Anilino- formic acid 4- nitrobenzene ester hydrochloride (A2N-CAR-2)
A2N-NH2-2 (4.20g, 14.0 mmol) is dissolved in dichloromethane (70mL), is cooled to 0 °C of quick drop p-nitrophenyl chloroformate ester（3.40g, 16.8mmol) dichloromethane (70mL) solution.4h is stirred at room temperature after completion of dropping, filtration drying obtains light yellow product A2N-CAR-2 (6.44g, 92%): 1HNMR (DMSO-d6) δ 9.85 (brs, 2H), 8.31-8.34 (m, 2H), 7.53-7.56 (m, 2H), 7.30 (d, J=8.4Hz, 1H), 7.14 (d, J=8.0Hz, 1H), 5.98 (s, 1H), 3.61 (m, 8 H), 2.46 (s, 3H), 2.32 (s, 3H). 1- (3- (trifluoromethyl) -4- chlorphenyls) -3- (2- methyl -5- (2- methyl -6- morpholinyl pyrimidine-4-yls amido) phenyl) urea (A2N-3-2)
A2N-CAR-2 (0.75g, 1.5mmol) standing grain Jie 3- (trifluoromethyl) -4- chloroanilines (0.59g, 3mmol) are dissolved in DMF (6mL), triethylamine is added（0.46g, 4.5mmol), 40 °C of stirring 9h are incubated, sodium hydrate aqueous solution (20mL) are then added, then extracted with dichloromethane.Merge organic phase, after anhydrous sodium sulfate drying, revolving.Silica gel column chromatography purifying gained residue, uses ethyl acetate：Petroleum ether（1:1) elute, obtain slightly yellow solid A2N-3-2 (0.23g, 29%): 1HNMR (DMSO-d6) δ 9.41 (s, 1H), 8.84 (s, 1H), 8.13 (m, 1H), 8.00 (s, 1H), 7.91 (d, J=2Hz, 1H), 7.60 (m, 2H), 7.19 (dd, J=2.4,8.4Hz, 1H), 7.08 (d, J=8.4Hz, 1H), 5.95 (s, 1H), 3.64 (m, 4H), 3.46 (m, 4H), 2.28 (s, 3H), 2.19 (s, 3H); MS-ESIm/z521 (M+H)+.
^2- methyl-5- (2- methyl-6- morpholinyl pyrimidine-4-yl amido) phenyl) -3- (4- (pyrrolidin-1-yl) butyl) urea（A2N -18-2)
3- (trifluoromethyl) -4- chloroanilines are replaced with 4- (the small base of pyrrolidines) small amine of butane (0.40g, 3mmol), A2N-18-2 is prepared using the method similar to A2N-3-2, near-white solid is obtained（0.36g, 26%)： ^MR (DMSO-d6) δ 8.74 (s, 1H), 7.87 (s, 1H), 7.55 (s, 1H), 7.02 (d, J=8.0Hz, 2H), 6.50 (s, 1H), 5.98 (s, 1H), 3.65 (m, 4H), 3.47 (m, 4H), 3.10 (m, 2H), 2.44 (m, 6H), 2.27 (s, 3H), 2.13 (s, 3H), 1.67 (m, 4H), 1.47 (m, 4H); MS-ESIm/z 468 (M+H)+ ,935 (2M+H)+.
4.3 the 3 of A2N series
2- methyl-N- (4- methyl-3-nitros phenyl)-6- (- 1-yl of 4- methyl piperazines) pyrimidine-4- amine（A2N-N02-3) by A2N-N02-C1.HC1 (5g, 15.9mmol) with 1- methyl piperazines (9.53g, 95.2 mmol) it is added to DMSOC20mL) in, it is heated to 140 °C of stirring 0.5h, then it is poured into mixture of ice and water C200mL while hot under agitation) in, filtration drying, obtains yellow solid (5.43g, 100%)： 1H-NMR (DMSO-d6) δ 9.28 (s, 1H), 8.48 (d, J=2.4Hz, 1H), 7.76 (d, J=8.8Hz, 1H), 7.36 (d, J=8.8Hz, 1H), 5.81 (s, 1H), 3.49 (t, J=4.8Hz, 4H), 2.44 (s, 3H), 2.36 (t, J=4.8Hz, 4H), 2.32 (s, 3H), 2.21 (s, 3H).
4- methyl-N1^- methyl-6- (- 1-yl of 4- methyl piperazines) pyrimidine-4-yl) benzene-1,3- diamines（A2N-NH2-3) A2N-N02-3 (5.69g, 13.7mmol) is added by ethanol (330mL), tetrahydrofuran（LlOmL) and water (55mL) composition in the mixed solvent, add ammonium chloride (0.74g, 13.8mmol) and the reduced iron powder with lmol/L hydrochloric acid activations 2h is stirred in (4.75g, 85mmol), backflow, is then filtered while hot.Filtrate is rotated, ethyl acetate (200mL) and water are added into gained residue（LOOmL), adjust pH to 89 with ammoniacal liquor, divide and take organic phase, aqueous phase is extracted with ethyl acetate again, merge and rotated after organic phase, anhydrous sodium sulfate drying, obtain light yellow solid A2N-NH2-3 (4.83g, 93%)：^MR (DMSO-de) 5 8.45 (s, 1 Η), 6.80 (d, J=8.0Hz, 1H), 6.73 (d, J=1.6Hz, 1H), 6.58 (dd, J=2.0,8.0Hz, 1H), 5.76 (s, 1H), 4.72 (s, 2H), 3.42 (t, J=4.8Hz, 4H), 2.34 (t
J=4.8Hz, 4 H), 2.25 (s, 3H), 2.20 (s, 3H), 2.00 (s, 3H).
3- (trifluoromethyls）- 4- chloroanilino formic acid 4- nitro phenyl esters（3-CAR)
Take p-nitrophenyl chloroformate ester（1.21g, 6mmol) dichloromethane (15mL) is dissolved in, 3- (trifluoromethyl) -4- chloroanilines are slowly added dropwise below 0 °C（0.98g, 5mmol) dichloromethane (10mL) solution.2h is stirred at room temperature after completion of dropping, white solid 3-CAR (1.08g, 60%) is filtered to obtain： 1H-NMR (DMSO-d6) δ 10.84 (s, 1H), 8.31-8.34
(m, 2H), 8.05 (d, J=2.4Hz, 1H), 7.77-7.80 (m, 1H), 7.70-7.72 (m, 1H), 7.56-7.59
(m, 2H) o
4- (the small base of pyrrolidines) fourth amidocarbonic acid 4- nitrobenzene ester hydrochlorides（ 18-CAR)
By p-nitrophenyl chloroformate ester（2.42g, 12mmol) it is dissolved in dichloromethane（20mL), the dichloromethane of 4- (pyrrolidin-1-yl) butane -1- amine (1.34g, lOmmol) is slowly added dropwise at 0 °C or so（4h is stirred at room temperature after 20mL) solution, completion of dropping, rotates, ethyl acetate mashing is added into gained residue, white solid 18-CAR (2.60g, 76%) is filtered to obtain.
1- (3- (trifluoromethyl) -4- chlorphenyls) -3- (2- methyl -5- (2- methyl -6- (4- methylpiperazine-1-yls) pyrimidine-4-yl amido) phenyl) urea（A2N-3-3 )
Take A2N-NH2-3 (0.70g, 2.25mmol), 3-CAR (0.54g, 1.5 mmol) to be dissolved in DMF (6mL), add triethylamine（0.46g, 4.5 mmol), then 40 °C of stirring 9h of temperature control add dichloromethane (90mL) and the 0.5mol/LNaOH aqueous solution (20mL) into gained reaction solution.Divide and take anhydrous sodium sulfate drying after organic phase, washing, rotate, silica gel column chromatography purifying gained residue, with ethyl acetate：Ethanol（3: 1〜1 :1) gradient elution, obtains slightly yellow solid A2N-3-3 (0.14g, 18%)：1H-NMR (DMSO-de) δ 9.46 (s, lH), 8.86 (s, lH), 8.16 (d, J=2.0Hz, 1H), 8.04 (s, 1H), 7.91 (d, J=2.4Hz, 1H), 7.60 (m, 2H), 7.17 (dd, J=2.0,8.0Hz, 1H), 7.07 (d, J=8.0Hz, lH), 5.97 (s, lH), 3.49 (t, J=4.8 Hz, 4H), 2.34 (t, J=4.8 Hz, 4H), 2.27 (s, 3H), 2.193 (s, 3H), 2.186 (s, 3H);MS-ESI m/z 534 (M+H)+, 556 (M+ Na)+, 1089 (2M+Na)+, 532 (M-H)-, 568 (M+C1)-, l l l l (2M+COOH)-.L- (4- (pyrrolidin-1-yl) butyl 3- (2- methyl -5- (2- methyl -6- (4- methylpiperazine-1-yls) pyrimidine-4-yl amido) phenyl) Urea（A2N-18-3 )
3-CAR is replaced with 18-CAR (0.45g, 1.3 mmol), A2N -18-3 are prepared using the method similar to A2N-3-3, fawn crystallization is obtained（0.28g, 45%)：1Leg MR (DMSO-d6) δ 8.68 (s, 1H), 7.86 (d, J=2.4Hz, 1H), 7.55 (s, 1H), 6.98-7.02 (m, 2H), 6.50 (m, 1H), 5.97 (s, 1H), 3.48 (t, J=4.8Hz, 4H), 3.09 (m, 2H), 2.50-2.54 (m, 6H), 2.34 (t, J=4.8Hz, 4H), 2.25 (s, 3H), 2.20 (s, 3H), 2.12 (s, 3H), 1.69 (m, 4H), 1.48 (m, 4H); MS-ESI m/z 481 (M+H)+, 503 (M+Na)+, 961 (2M+H)+, 983 (2M+Na)+.
5. A3 series compounds
The 2 of 5.1 A3 series
The chloro- N- of 2- methyl -6- (2- nitrobenzophenones) pyrimidine -4- amine（A3-NO2-0)
By 60% sodium hydride（1.20g, 30mmol) THF (15mL) is dissolved in, ortho-nitraniline (1.38g, lOmmol) is added portionwise at 0 °C, 30min is stirred;Fast drop 2- methyl -4,6- dichloro pyrimidines again（1.63g, lOmmol) THF (15mL) solution, return stirring 2h after completion of dropping.Gained reactant is poured into mixture of ice and water while hot under agitation（In 200mL), filtering vacuum it is dry field gray product A3-NO2-0 (1.69g, 64%).
2- methyl -6- morpholinyls-N- (2- nitrobenzophenones) pyrimidine -4- amine（A3-N02-2)
A3-N02-C1 (1.59g, 6 mmol) and morpholine (3.14g, 36 mmol) are added in DMSO (lOmL), 4h is stirred at 140 °C under nitrogen protection, mixture of ice and water is then poured under agitation（In 200mL), filtering separates out solid, dry yellow solid A3-N02-2 (1.48g, 78%).
^- (2- methyl -6- morpholinyls pyrimidine-4-yl) benzene -1,2- diamines（A3-NH2-2)
By A3-N02-2 (1.48g, 4.7 mmol) and ammonium chloride（0.25g, 4.7 mmol) add by ethanol（120 mL):Tetrahydrofuran（40 mL) and water（20mL) in the mixed solvent of composition, adds the reduced iron powder through lmol/L hydrochloric acid activations（1.58g, 28.2 mmol), return stirring 2h is filtered while hot by diatomite, revolving, and water is added into gained solid residue（50mL), pH being adjusted to 9 or so with ammoniacal liquor, adding ethyl acetate mashing, filtration drying obtains pale solid A3-NH2-2 (0.83g, 62%)：1Leg MR (DMSO-d6) δ 7.95 (s, lH), 7.10 (d, J=7.2Hz, 1H), 6.92 (t, J=6.8Hz, lH), 6.77 (m, 1H), 6.58 (m, 1H), 5.40 (s, 1H), 4.77 (s, 2H), 3.60 (m, 4H), 3.23 (t, J=4.8Hz, 4H), 2.24 (s, 3H).L- (3- (trifluoromethyl) -4- chlorphenyls) -3- (2- (2- methyl -6- morpholinyl pyrimidine-4-yls amido) phenyl) urea（A3-3-2) A3-NH2-2 (0.32g, l lmmol) standing grain Jie 3-CAR (0.36g, lmmol) are dissolved in DMF (3 mL), triethylamine is added（0.31g, 3 mmol), it is stirred overnight at 0 °C, then adds dichloromethane into gained reaction solution (90mL) and the 0.5mol/LNaOH aqueous solution（20mL), divide and take organic phase, anhydrous sodium sulfate drying after washed several times with water, revolving.Silica gel column chromatography purifying gained residue, with ethyl acetate：Petroleum ether（3:1) elute, obtain white solid A3-3-2
(0.13g, 25%)：1Beautiful MR (DMSO-de) δ 9.59 (s, 1H), 8.35 (s, 1H), 8.13 (s, 1H), 8.06 (d, J=2.0Hz, 1H), 7.89-7.91 (m, 1H), 7.59 (m, 2H), 7.26 (d, J=8.0 Hz, 1H), 7.19 (t, J=7.2 Hz, 1H), 7.07 (dt, J=l .2,7.2 Hz, 1H), 5.37 (s, 1H), 3.55 (m, 4H), 3.32 (m, 4H), 2.24 (s, 3H); MS-EI: m/z 506(M).
1- (4- (；Pyrrolidin-1-yl) butyl) -3-00 methyl -6- morpholinyl pyrimidine-4-yls amido) phenyl) urea（A3-18-2) A3-NH2-2 (0.57g, 2mmol), 18-CAR (0.30g, lmmol) are dissolved in DMF (3 mL), triethylamine is added（0.31g, 3mmol), 40 °C are stirred overnight.Dichloromethane is added into gained reaction solution（90mL) with the 0.5mol/LNaOH aqueous solution（20mL), divide and take organic phase, anhydrous sodium sulfate drying after washing, revolving.Silica gel column chromatography purifying gained residue, with ethanol：Ethyl acetate：Triethylamine（150:50:1) elute, obtain Tan solid A3-18-2 (0.12g, 27%)： 1HNMR (DMSO-d6) 8.18 (s of δ, 1H), 7.82 (d, the Hz of J=8.4, 1H), 7.73 (s, 1H), 7.22 (d, the Hz of J=7.6, 1H), 7.11 (t, the Hz of J=8.0, 1H), 6.97 (m, 1H), 6.64 (t, the Hz of J=5.6, 1H), 5.35 (s, 1H), 3.60 (t, J=4.8Hz, 4H), 3.34 (t, J=4.8Hz, 4H), 3.07 (m, 2H), 2.44 (m, 6H), 2.25 (s, 3H), 1.68 (m, 4H), 1.43 (t, the Hz of J=3.2, 4H); MS-EI: m/z 453 (M).
The 3 of the 5.2 bad lj of A3 systems
2- methyl-6- (- 1-yl of 4- methyl piperazines)-N- (2- nitrobenzophenones) pyrimidine-4- amine（ A3-N02-3 )
By A3-N02-C1 (3.0g, 1 lmmol) and 1- methyl piperazines（6.67g, 66mmol) it is added in DMSO (25mL), stir 4h at 140 °C under nitrogen protection; then it is poured under agitation in mixture of ice and water; filtering separates out solid, dry yellow solid A3-N02-3 (3.12g, 84%).
NJ- (2- methyl-6- (- 1-yl of 4- methyl piperazines) pyrimidine-4-yl) benzene-1,2- diamines（ A3-NH2-3 )
By A3-N02-3 (2.6g, 8mmol) and ammonium chloride（0.36g, 8mmol) add by ethanol（90mL), tetrahydrofuran（30mL) and water（15mL) in the mixed solvent of composition, adds the reduced iron powder (2.52g, 48mmol) through lmol/L hydrochloric acid activations, return stirring 3h is filtered while hot, rotates.Added water into gained solid residue（80mL), adjust pH to 9 with ammoniacal liquor, add ethyl acetate（150mL) it is beaten, filtration drying obtains gray solid A3-NH2-3 (2.15g, 91%)：1H-NMR (DMSO-de) δ 7.90 (s, lH), 7.09 (d, J=7.6Hz, 1H), 6.91 (dt, J=1.6,7.6Hz, 1H), 6.75 (dd, J=1.2,7.6Hz, 1H), 6.56 (dt, J=0.8,6.8Hz, 1H), 5.39 (s, 1H), 4.76 (s, 2H), 3.37 (m, 4H), 3.30 (m, 4H), 2.22 (s, 3H), 2.18 (s, 3H). 1-CH trifluoromethyls) -4- chlorphenyls) -3- (2- (2- methyl -6- (4- methylpiperazine-1-yls) pyrimidine-4-yl amido) phenyl) urea (A3-3-3)
A3-NH2-3 (0.43g, 1.5mmol) and 3-CAR (0.54g, 1.5mmol) are dissolved in dry DMF (6mL), triethylamine is added（0.46g, 4.5mmol), it is stirred overnight at 40 °C.Dichloromethane (90mL) and 0.5%mol/L sodium hydrate aqueous solutions are added into gained reaction solution（20mL), divide and take organic phase, anhydrous sodium sulfate drying after washing, revolving.Silica gel column chromatography purifying gained residue, with ethanol：Ethyl acetate：Triethylamine（150:50:1) elute, obtain light gray solid A3-3-3 (0.27g, 35%)：1Leg MR (DMSO-d6) 59.54 (s, 1H), 8.27 (s, 1H), 8.08 (s, 1H), 8.07 (d, J=2.0Hz, 1H), 7.87 (the Hz of d, J=8.4,1H), 7.57 (m, 2H), 7.26 (d, J=7.6 Hz, 1H), 7.18 (d, J=7.2Hz, 1H), 7.07 (m, 1H), 5.35 (s, 1H), 3.36 (m, 4H), 2.23 (s, 3H), 2.21 (m, 4H), 2.10 (s, 3H); MS-ESI: m/z 520 (M+H)+ o
The 1 of the 5.3 bad lj of A3 systems
N1^- methyl -6- chlorine pyrimidine-4-yl) benzene -1,2- diamines（A3-NH2-0)
Take A3-NO2-0 (2.07g, 7.8mmol), ammonium chloride（0.83g, 15.6mmol) and reduced iron powder through lmol/L hydrochloric acid activations（2.63g, 46.8mmol) add by ethanol（120 mL):Tetrahydrofuran（40 mL) and water（Filtered while hot after the 20mL) in the mixed solvent of composition, return stirring 2h.Filtrate is rotated, water (50mL) is added into gained solid residue, adjusts pH to 9 with ammoniacal liquor, uses ethyl acetate（LOOmL, 3x50mL) extract.Merge extract solution, rotated with after anhydrous sodium sulfate drying, obtain dark green solid A3-NH2-0 (1.13g, 62%).
1- (3- (trifluoromethyl) -4- chlorphenyls) -3- (2- (6- (4- (2- ethoxys) piperazine -1- bases) -2- methylpyrimidine -4- bases amido) phenyl) urea（A3-3-1 )
A3-NH2-0 (0.47g, 2mmol) and 3-CAR (0.72g, 2mmol) are dissolved in DMF (lO mL), triethylamine is added（0.61g, 6mmol), it is stirred overnight at 40 °C.Dichloromethane is added into gained reaction solution（90mL) with 0.5%mol/L sodium hydrate aqueous solutions（20mL), divide and take organic phase, anhydrous sodium sulfate drying after washing, revolving.2- (piperazine -1- bases) ethanol (1.60g, 12mmol) and DIEA (1.60g, 12 mmol) are added into gained Xuan Zheng Nong Shrink liquid, is stirred overnight at 80 °C.Silica gel column chromatography gained reactant, with ethanol：Ethyl acetate（3:1) elute, obtain light yellow solid A3-3-1
(0.12g, 11%)：1HNMR (DMSO-de) δ 9.54 (s, 1H), 8.26 (s, 1H), 8.09 (s, 1H), 8.05 (s, 1H), 7.88 (d, J=8.4 Hz, 1H), 7.57 (s, 2H), 7.27 (the Hz of d, J=8.0, lH), 7.18 (m, 1H), 7.06 (m, 1H), 5.36 (s, 1H), 4.31 (t, J=5.2Hz, 1H), 3.48 (m, 2H), 3.36 (m 4H), 2.34 (m, 6H), 2.23 (s, 3H); MS-ESI: m/z 550 (M+H)+.
6. B is serial
6- chloro-n-methyls-N- (3- nitrobenzophenones) pyrimidine -4- amine（ B2M-NO2-0 )
By meta nitro aniline（17.0g, 0.12mol), 4,6- dichloro pyrimidines (18.3g, 0.12mol) add acetone (30ml) and water（In the mixed solvent 90ml), adds concentrated hydrochloric acid（2.5ml), flow back 2h.Let cool, suction filtration, filter cake washing is dried in vacuo to obtain crude product.Gained crude product is dissolved in glacial acetic acid（160ml) standing grain B DMF (250ml) in the mixed solvent, adds sodium acetate（7.8g, 0.095mol), 90 °C are warming up to, gained reaction solution is poured into water while hot（In 2L), lh is stirred.Filtering, washes filter cake, vacuum drying（70 °C, 5h), the chloro- N- of 6- (3- nitrobenzophenones) pyrimidine -4- amine is obtained, is yellow solid (26.7g, 89%).
By the chloro- N-0 nitrobenzophenones of 6-) pyrimidine -4- amine (5.0g, 20mmol) and potassium carbonate（7.2g, 52.1mmol) put into DMF (lOOml), add iodomethane（3.0g, 21.1mmol), 25 °C of stirring 10h.Reactant is poured into frozen water（In 1.2L), 2h is stirred.Suction filtration, filter cake washing, vacuum drying（70 °C, 5h) o obtains B2M-NO2- 0, it is yellow solid（4.8g, 91%)： mp 98.5-100.5 °C.
N- methyl -6- morpholinyls-N- (3- nitrobenzophenones) pyrimidine -4- amine（B2M-N02-2)
By B2M-NO2- 0 (5.0g, 17.9mmol) is dissolved in input DMSO (30ml), adds morpholine（9.4g, 0.12mol), 145 °C of stirring 0.5h.It is cooled to 50 °C, reaction solution is poured into frozen water (200ml), stirs lh.Filtering, washes filter cake, vacuum drying（70 °C, 5h), obtain B2M-N02- 2, it is yellow solid（5.8g, 98%)： mp 165.8-168.8°C.
N1- methyl-N1- ^- morpholinyls pyrimidine-4-yl) benzene -1,3- diamines（B2M-NH2-2)
By B2M-NO2- 2 (4.0g, 12.7mmol) are dissolved in ethanol（200ml), SnCl is added dropwise to dissolved clarification in 50 °C of stirrings2'2H20 (lO.Og, 44.3mmol) 6mol/L hydrochloric acid（Heated up after 15ml) solution, completion of dropping, flow back 2h.Let cool, part ethanol is removed in rotation, pH to 9 is adjusted with 2mol/L sodium hydrate aqueous solutions, with ethyl acetate：Ethanol（5:1) extract.Merge organic layer, washed successively with water, saturated brine, anhydrous sodium sulfate drying, subtract the dense Shrink of pressure, vacuum drying（70 °C, 7h), obtain B2M-NH2- 2, it is faint yellow solid（3.3g, 91%)： mp: 142-143.5 °C ; 1H-NMR(DMSO-d6) 5 8.31 (s, 1H), 7.17-7.27 (m, 1H), 6.55-6.64 (m, 3H), 5.46 (s, 1H), 3.75 (br s, 2H), 3.70 (t, J=4.8Hz, 4H), 3.37-3.43 (m, 4H), 3.41 (s, 3H).L- (3- (methyl (6- morpholinyls pyrimidine-4-yl) amido) phenyl) -3- (5- methylisoxazole -3- bases) urea（B2M-20-2) by 3- amino -5- methylisoxazoles（0.21g, 2.1mmol) it is dissolved in anhydrous methylene chloride（15ml), phenyl chloroformate is added dropwise（0.34g, 2.2mmol), lh is stirred at room temperature.Add triethylamine（0.65g, 6.4mmol), B2M-NH2- 2 (0.58g, 2.0mmol), return stirring 2h.Let cool, revolving removes solvent, add ethyl acetate（10ml) with 0.1mol/L sodium hydrate aqueous solutions（3ml), it is beaten lh.Filtering, washs filter cake, vacuum drying（80 °C, 3h), B2M-20-2 is obtained, is white solid（0.30g, 36%): 1H-NMR(DMSO-d6) δ 9.53 (s, 1H), 9.15 (s, 1H), 8.16 (d, J=0.8Hz, 1H), 7.47 (t, J=2.0Hz, 1H), 7.34-7.38 (m, 1H), (7.25-2.27 m, 1H), 6.93-6.95 (m, 1H), 6.51 (s, 1H), (5.66 s, 1H), 3.61 (t, J=4.8Hz, 4H), 3.36-3.38 (m, 4H), 3.36 (s, 3H) 2.35 (s, 3H); MS-ESI: m/z 410 (M+H)+.Part II Biological examples
External human tumor cell lines and human umbilical vein cells experiment
1.1 materials and methods
Sample preparation：After being dissolved with DMSO (Merck), solution or uniform suspension that PBS (-) is made into lOOO g/mL are added, then with PBS (-) dilution containing DMSO.
Cell line：A549 (human lung carcinoma cells）, HCT116 (people's colon-cancer cells）, CEM (human leukemia cells）With MCA-MB-435 (human melanoma cells）With HUVEC (Human umbilical vein endothelial cells）.Above cell line freezes and passed on by Shanghai Institute of Pharmaceutical Industry's Pharmacological Evaluation research center.
Nutrient solution：A549, HCT116, CEM standing grain Jie MCA-MB-435 are that DMEM+10%NBS+ is dual anti-, DMEM+10%FBS+ is dual anti-；HUVEC is that DMEM+10 15%FBS+ are dual anti-.
Full-automatic ELIASA：Model：WellscanMK-2, production firm： Labsystems.
Test method：Mtt assay.
A549, HCT116, CEM and MCA-MB-435:It is 4-5x l0 that 96 orifice plates, which add concentration per hole,4Individual/ml cell suspension Ι Ο Ο μ Ι, put 37 °C, 5% C02In incubator.After 24h, addition sample liquid, Ι Ο μ Ι/hole, if duplicate hole, 37 °C, 5% C02Lower effect 72h.Lysate Ι Ο Ο μ Ι/hole is added after the 5mg/ml μ 1 of MTT solution 20, effect 4h are added per hole, is put in incubator, 570nm OD values are surveyed with the full-automatic ELIASAs of Μ Κ -2 after dissolving.
HUVEC:It is l x lO that 96 orifice plates, which add concentration per hole,5Individual/ml the μ 1 of cell suspension 100, puts 37 °C, 5% C02In incubator.After 24h, addition sample liquid, Ι Ο μ Ι/hole, if duplicate hole, 37 °C, 5% C02Lower effect 48h.Lysate Ι Ο Ο μ Ι/hole is added after the 5mg/ml μ 1 of MTT solution 20, effect 4h are added per hole, is put in incubator, 570nm OD values are surveyed with the full-automatic ELIASAs of Μ Κ -2 after dissolving.
1.2 result of the test
Result of the test is shown in Table 1. In-vitro multiplication inhibitory action of the specific compound of formula I of table 1 to human tumor cells
A2-12-3 40.42 29.00 27.42 26.42 30.98
A2-13-3 90.18 97.58 92.60 100 100
A2-14-3 100 100 100 100 100
A2-15-3 0 48.20 14.18 69.59 25.76
A2-16-3 89.26 95.37 90.93 100 100
A2-18-3 3.94 8.97 10 41.20 21.10
A2-19-3 70.55 94.85 87.92 100 88.52
A2M-1-0 100 100 100 100 100
A2M-3-0 100 100 100 100 100
A2M-1-2 100 100 100 100 100
A2M-3-2 100 100 100 100 100
A2M-4-2 100 100 100 100 100
A2M-10-2 14.95 38.47 13.79 39.35 26.19
A2M-13-2 78.98 99.54 100 100 100
A2M-18-2 34.55 32.33 42.93 66.70 62.44
A2M-19-2 28.92 73.71 30.92 62.98 31.21
A2M-1-3 100 100 100 100 100
A2M-3-3 100 100 100 100 100
A2M-4-3 100 100 100 100 100
A2M-10-3 91.33 95.55 98.43 100 100
A2M-13-3 100 99.89 100 100 100
A2M-14-3 100 100 100 100 100
A2M-18-3 19.06 24.12 99.84 98.90 100
A2M-19-3 100 100 100 100 99.42
A2N-3-1 100 100 100 77.59 100
A2N-3-2 64.00 93.61 91.71 66.33 100
A2N-18-2 0.52 4.70 29.19 67.55 89.70
A2N-3-3 100 100 99.53 81.22 100
A2N-18-3 0 22.48 3.21 26.12 39.28
A3-3-1 100 100 100 100 100
A3-3-2 76.77 100 99.42 29.83 100
A3- 18-2 0 46.02 82.69 8.31 71.75
The external protein kinase of 100 100 100 77.76 100 Sorafenibs of A3-3-3 100 100 100 100 100 suppresses experiment
Rice is with Caliper mobility shift assay modes (referring to the Journal of Biomolecular such as Card A Screening, 2009,14 (l):10 compound of formula I 31-42.) are tested under Ι Ο μ Μ concentration, for ALK, Aurora A, EGFR, FGFR1, FLT-3, VEGFR-2, c-KIT, c-MET, PDGFRp under ATP Km concentration, the percent inhibition of 11 kinases such as TIE-2, p38 a.The positive control of detection is the blank group for being not added with sample, and negative control is EDTA groups, and reference compound is Staurosporine.Instrument is Caliper EZ Reader II.Kinase reaction condition is shown in Table 2. The kinase reaction condition of table 2
Using Invitrogen companies LanthaScreenTMMode is respectively under 0.5 μ Μ and 1.5 μ Μ ATP concentration, percent inhibition of 10 compound of formula I under Ι Ο μ Μ concentration for BRAF and BRAF V599E is tried, and tests IC of 4 compound of formula I for BRAF and BRAF V599E5Q.Operating method respectively refers to the file of Invitrogen companies offer《PV3848 BRAF Assay Validation》Standing grain Jie《PV3849 BRAF V599E Assay Validation》.
Kinases percent inhibition test result is shown in Table 3 and table 4, IC5QTest result is shown in Table 5.
Percent inhibition of 3 10 compound of formula I of table to protein kinase（%)
4 10 compounds of formula 11 of table are to protein kinase percent inhibition（It is continuous）（%)
BRAF
Sample ID VEGFR-2 c-KIT c-MET PDGFRP TIE-2 BRAF
V599E
A1-3-1 83 98 6 99 87 74 84
A2-3-0 96 85 96 99 102 103 104
A2-1-2 3 56 35 41 35 96 98
A2-1-3 59 83 33 96 91 -1.3 0.5
A2-3-2 15 23 14 46 49 99 105
A2-3-3 87 67 65 101 97 31 31
A2M-3-3 72 83 16 99 98 48 52
A2M-14-3 57 50 42 102 73 9 0
A2M-1-2 -15 13 4 60 26 98 104
A2N-3-1 -21 62 25 100 75 48 58
IC of 4 compound of formula I to protein kinase5Q (nM)
Internal anti-tumor activity test
5 compound of formula I are selected, using Sorafenib as positive control, using the Human lung cancer A549 model transplanted in nude mice, with the oral gastric infusion of 25mg/kg dosage 12 days, with based on relative tumour volume（RTV tumor control rate) is that leading indicator investigates its Anticancer effect in vivo, and by observing the changes of weight preliminary examinations of tested nude mice its toxic reactions.Results from vivo experiments is shown in Table 6.
Gross tumor volume calculation formula is： TV = ab2/ 2, wherein a are tumour major diameter (mm), and b is perpendicular tumour minor axis (mm).Relative tumour volume calculation formula is：RTV=Vt/Vo, Vo are when dividing cage（That is d0) measurement gained gross tumor volume, the gross tumor volume of (d4, d8, dl2, dl6) when Vt is measures each time.
The average RTV of the average RTV-administration group of blank control group
Tumor control rate l 00%
The average RTV of blank control group 65 compound of formula I of table are to transplanting in the tumor-inhibiting action of the A549 human lung cancers of nude mice
Compared (t inspections with blank control group）: *P<0.05, * * P<0.01.
Formula I is external to human tumor cell line and Human umbilical vein endothelial cells（HUVEC) there is growth inhibitory activity.The human tumor cell line includes but is not limited to A549 human lung carcinoma cells, HCT116 people's colon-cancer cell, CEM human leukemia cells and MCA-MB-435 human melanoma cells.
There is growth inhibitory activity to human tumour xenograft tumor in formula I body.The human tumour xenograft tumor includes but is not limited to transplant the A549 human lung cancers in nude mice.

Claims (1)

  1. Claim
    1st, a kind of carbamide compounds or its pharmaceutically acceptable salt, polymorph, solvate or stereoisomer shown in formula I；
    Wherein, R2It is substituted or unsubstituted C^Cs alkyl, substituted or unsubstituted C for hydrogen3〜C9Cycloalkyl, substituted or unsubstituted c6〜c14It is aryl, substituted or unsubstituted3Heteroaryl；Substituent in substituted alkyl is 49 yuan of saturated heterocyclyls, and the hetero atom number of the saturated heterocyclyl is 14, and hetero atom is nitrogen, oxygen or sulphur, such as pyrrolidin-1-yl；Substituent in substituted cycloalkyl is halogen, CH3Alkyl or CH3Alkoxy；Substituent in substituted aryl or substituted heteroaryl is halogen, cyano group, C^ haloalkyl, C^ alkyl, C^ alkoxies, C2〜C3Alkenyl, C2〜C3Block base and（Connect the amine formyl of alkyl）One or more in substituted pyridine epoxide, the number of every kind of substituent is 0,1 or multiple, the position of substituent can be commutable optional position on aryl or heteroaryl, when aryl is phenyl ring, and the position of substituent is the ortho position of urea side chain, meta or para position；Hetero atom in heteroaryl is nitrogen, oxygen or sulphur, and hetero atom number is 15；
    Or, R2And with, R2Cyclization is substituted or unsubstituted 49 yuan of saturated heterocyclics to connected nitrogen-atoms together, the saturated heterocyclic can be additionally containing 13 hetero atoms, the hetero atom is nitrogen, oxygen or sulphur, if additionally including unsubstituted on nitrogen-atoms, the nitrogen-atoms or being replaced by alkyl；Wherein, the substituent in described substituted 49 yuan saturated heterocyclic is halogen, alkyl or alkoxy；
    R3For hydrogen or alkyl；
    R4 is hydrogen, C^Cs alkyl, C3 alkoxies, halogen, amino or cyano group；
    、/、 /R5
    ^ N
    I
    Q be hydrogen, halogen orR6 ；Wherein, R5And R6The substituent independently being on hydrogen, substituted or unsubstituted C^Ce alkyl, the substituted alkyl is amino, hydroxyl, cyano group, halogen or alcoxyl Base；
    Or R5, R6 and and R5, cyclization is substituted or unsubstituted 49 yuan of saturated heterocyclics to connected nitrogen-atoms together, the saturated heterocyclic can be additionally containing 13 hetero atoms, and the hetero atom is nitrogen, oxygen or sulphur；Wherein, the substituent in described substituted 49 yuan saturated heterocyclic is halogen, C^Cs alkyl, alkoxy or the C^ alkyl of hydroxyl substitution, and substituent can be connected on the carbon atom in saturated heterocyclic or nitrogen-atoms；When the substituent in described substituted 49 yuan saturated heterocyclic is the alkyl of alkyl, alkoxy or hydroxyl substitution, substituent is connected on the carbon atom in saturated heterocyclic or nitrogen-atoms, when substituent is halogen, substituent is connected on the carbon atom in saturated heterocyclic
    R7For hydrogen, CH^ alkyl, alkoxy or alkylthio group；
    R8、 R9、 R1()And RuIt independently is hydrogen, C3 alkyl, C3 alkoxies, halogen or cyano group；
    Urea side chain It is connected to 2', 3' or 4'.
    2nd, carbamide compounds as claimed in claim 1 or its pharmaceutically acceptable salt, polymorph, solvate or stereoisomer, it is characterised in that：Work as R2For hydrogen, when being substituted or unsubstituted C^Cs alkyl, described C^Cs baked base is Ci.6 baked bases.
    3rd, carbamide compounds as claimed in claim 2 or its pharmaceutically acceptable salt, polymorph, solvate or stereoisomer, it is characterised in that：Work as R2For hydrogen, when being substituted or unsubstituted C^Cs alkyl, described C^Ce alkyl is n-propyl, isopropyl, normal-butyl, isobutyl group, the tert-butyl group or n-hexyl.
    4th, carbamide compounds as claimed in claim 1 or its pharmaceutically acceptable salt, polymorph, solvate or stereoisomer, it is characterised in that：Work as R2It is substituted or unsubstituted C for hydrogen3〜C9During cycloalkyl, described C3〜C9Cycloalkyl is C3〜C8Cycloalkyl.
    5th, carbamide compounds as claimed in claim 4 or its pharmaceutically acceptable salt, polymorph, solvate or stereoisomer, it is characterised in that：Work as R2It is substituted or unsubstituted C for hydrogen3〜C9During cycloalkyl, described C3〜C8Cycloalkyl is cyclohexyl.
    6th, carbamide compounds as claimed in claim 1 or its pharmaceutically acceptable salt, polymorph, solvate or stereoisomer, it is characterised in that：Work as R2For hydrogen, Ri is substituted or unsubstituted C6〜C14During aryl, described C6〜C14 Aryl is C6〜C10Aryl.
    7th, carbamide compounds as claimed in claim 6 or its pharmaceutically acceptable salt, polymorph, solvate or stereoisomer, it is characterised in that：Work as R2For hydrogen, Ri is substituted or unsubstituted C6〜C14During aryl, described C6〜C1()Aryl is phenyl or naphthyl.
    8th, carbamide compounds as claimed in claim 1 or its pharmaceutically acceptable salt, polymorph, solvate or stereoisomer, it is characterised in that：Work as R2It is substituted or unsubstituted for hydrogen3During heteroaryl, the wide C of described C13Heteroaryl is C3〜C9Heteroaryl.
    9th, carbamide compounds as claimed in claim 8 or its pharmaceutically acceptable salt, polymorph, solvate or stereoisomer, it is characterised in that：Work as R2It is substituted or unsubstituted for hydrogen3During heteroaryl, described C3〜C9Heteroaryl is C3〜C5Heteroaryl.
    10th, carbamide compounds as claimed in claim 9 or its pharmaceutically acceptable salt, polymorph, solvate or stereoisomer, it is characterised in that：Work as R2It is substituted or unsubstituted for hydrogen3During heteroaryl, described C3〜C5Heteroaryl is thiazolyl, pyridine radicals or isoxazolyl.
    11st, carbamide compounds as claimed in claim 10 or its pharmaceutically acceptable salt, polymorph, solvate or stereoisomer, it is characterised in that：Work as R2It is substituted or unsubstituted for hydrogen3During heteroaryl, described thiazolyl is thiazol-2-yl, and described pyridine radicals is pyridin-4-yl or pyridine -2- bases, and described isoxazolyl is isoxazole -3- bases；
    And/or, when the substituent in substituted heteroaryl is alkyl, and heteroaryl is isoxazole -3- bases, isoxazole -3- bases form 5- alkyl isoxazole -3- bases after being replaced by alkyl.
    12nd, the carbamide compounds or its pharmaceutically acceptable salt, polymorph, solvate or stereoisomer as described in any one of claim 13, it is characterised in that：Work as R2For hydrogen, when ^ is the ^ ^ alkyl of substitution, the substituent in alkyl is 46 yuan of saturated heterocyclyls.
    13rd, carbamide compounds as claimed in claim 12 or its pharmaceutically acceptable salt, polymorph, solvate or stereoisomer, it is characterised in that：Work as R2For hydrogen, for substituted ^ alkyl, when the substituent in alkyl is 46 yuan of saturated heterocyclyls, described saturated heterocyclyl is pyrrolidin-1-yl.
    14th, the carbamide compounds or its pharmaceutically acceptable salt, polymorphic as described in claim 1, any one of 6-11 Thing, solvate or stereoisomer, it is characterised in that：It is substituted or unsubstituted C when for hydrogen6〜C14Aryl, or it is substituted or unsubstituted3During heteroaryl, when the substituent in substituted aryl or substituted heteroaryl is halogen, described halogen is fluorine, chlorine, bromine or iodine.
    15th, the carbamide compounds or its pharmaceutically acceptable salt, polymorph, solvate or stereoisomer as described in claim 1, any one of 6-11, it is characterised in that：Work as R2It is substituted or unsubstituted C for hydrogen6〜C14Aryl, or it is substituted or unsubstituted3During the haloalkyl that the substituent in heteroaryl, substituted aryl or substituted heteroaryl is, described haloalkyl is trifluoromethyl.
    16th, the carbamide compounds or its pharmaceutically acceptable salt, polymorph, solvate or stereoisomer as described in claim 1, any one of 6-11, it is characterised in that：Work as R2It is substituted or unsubstituted C for hydrogen6〜C14Aryl, or it is substituted or unsubstituted3Substituent in heteroaryl, substituted aryl or substituted heteroaryl is（Connect the amine formyl of C3 alkyl）It is described during substituted pyridine epoxide（Connect the amine formyl of C3 alkyl）Substituted pyridine epoxide is 2- (N- methylcarbamoyls) pyridine -4- epoxides.
    17th, carbamide compounds as claimed in claim 1 or its pharmaceutically acceptable salt, polymorph, solvate or stereoisomer, it is characterised in that：As, R2And with R, R2Connected nitrogen-atoms is when cyclization is substituted or unsubstituted 49 yuan of saturated heterocyclics together, and described 49 yuan of saturated heterocyclics are 57 yuan.
    18th, carbamide compounds as claimed in claim 17 or its pharmaceutically acceptable salt, polymorph, solvate or stereoisomer, it is characterised in that：As, R2And with R, R2Connected nitrogen-atoms is when cyclization is substituted or unsubstituted 49 yuan of saturated heterocyclics together, and described 57 yuan of saturated heterocyclics are morpholine ring.
    19th, carbamide compounds as claimed in claim 1 or its pharmaceutically acceptable salt, polymorph, solvate or stereoisomer, it is characterised in that：When Q is halogen, described halogen is fluorine, chlorine, bromine or iodine.
    20th, carbamide compounds as claimed in claim 1 or its pharmaceutically acceptable salt, polymorph, solvate or stereoisomer, it is characterised in that：Work as R5And and R5、 R6Connected nitrogen-atoms is when cyclization is substituted or unsubstituted 49 yuan of saturated heterocyclics together, and described 49 yuan of saturated heterocyclics are 57 yuan.
    21st, carbamide compounds as claimed in claim 20 or its pharmaceutically acceptable salt, polymorph, solvate or stereoisomer, it is characterised in that：Work as R5And and R5、 R6Connected nitrogen-atoms is when cyclization is substituted or unsubstituted 49 yuan of saturated heterocyclics together, and described 57 yuan of saturated heterocyclics are morpholine ring or piperazine ring.
    22nd, as described in claim 1,20 or 21 carbamide compounds or its pharmaceutically acceptable salt, polymorph, Solvate or stereoisomer, it is characterised in that：Work as R5And and R5, cyclization is substituted or unsubstituted 49 yuan of saturated heterocyclics to connected nitrogen-atoms together, during the C^Ce alkyl that the substituent in described substituted 49 yuan saturated heterocyclic replaces for hydroxyl, the C^Ce alkyl of described hydroxyl substitution is the C^ alkyl that hydroxyl replaces.
    23rd, the carbamide compounds or its pharmaceutically acceptable salt, polymorph, solvate or stereoisomer as described in claim 1,20 or 21, it is characterised in that：Work as R5And and R5, connected nitrogen-atoms is when cyclization is substituted or unsubstituted 49 yuan of saturated heterocyclics together, described substituted or unsubstituted 49 yuan of saturated heterocyclics are 4- (2- ethoxys) piperazine -1- bases, morpholinyl or 4- methylpiperazine-1-yls.
    24th, carbamide compounds as claimed in claim 1 or its pharmaceutically acceptable salt, polymorph, solvate or stereoisomer, it is characterised in that：Described compound I is following any structure：
    A2N-3-0 A2N-18-0
    25th, the preparation method of carbamide compounds as claimed in claim 1, it is any one in following methods：Method one, when including hydroxyl in Q, compound IX slough the reaction of the protection group of hydroxyl, you can;In compound IX, Q' is the hydroxyl in Q groups by the group after the conventional hydroxyl protecting group protection in this area；
    IX
    Method two, compound XI and QH Jin Hang Shrink are closed and reacted, you can；In compound XI, group X' is that this area Ci Lei Shrink close the leaving group commonly used in reaction；
    XI
    Method three, when not including hydroxyl in Q, by compound Χ Π Ι and R R2NH carries out into urea reaction, you can;
    26th, any compound as follows：
    N1^- methyl -6- chlorine pyrimidine-4-yl) benzene -1,4- diamines（Α1-ΝΗ2-0)、
    4- (2- methyl -6- chlorine pyrimidine-4-yls amido) anilino- formic acid (4- nitrobenzene) ester hydrochloride（Al-CAR-0), 2- methyl -6- morpholinyls-N- (4- nitrobenzophenones) pyrimidine -4- amine（Al-N02-2)、
    ^- (2- methyl -6- morpholinyls pyrimidine-4-yl) benzene -1,4- diamines（Α1-ΝΗ2-2)、
    4- (2- methyl -6- morpholinyl pyrimidine-4-yls amido) anilino- formic acid (4- nitrobenzene) ester hydrochloride（Al-CAR-2)、
    The chloro- N- of 2- methyl -6- (3- nitrobenzophenones) pyrimidine -4- amine（A2-NO2-0)、
    NJ- (2- methyl -6- chlorine pyrimidine-4-yl) benzene -1,3- diamines（ A2-NH2-0 )、
    3- (2- methyl -6- chlorine pyrimidine-4-yls amido) anilino- formic acid (4- nitrobenzene) ester hydrochloride（A2-CAR-0), 2- methyl -6- morpholinyls-N- (3- nitrobenzophenones) pyrimidine -4- amine（A2-N02-2)、 ^- (2- methyl -6- morpholinyls pyrimidine-4-yl) benzene -1,3- diamines（A2-NH2-2)、
    3- (2- methyl -6- morpholinyl pyrimidine-4-yls amido) anilino- formic acid (4- nitrobenzene) ester hydrochloride（A2-CAR-2)、
    2- methyl-6- (- 1-yl of 4- methyl piperazines)-N- (3- nitrobenzophenones) pyrimidine-4- amine（ A2-N02-3 )、
    NJ- (2- methyl-6- (- 1-yl of 4- methyl piperazines) pyrimidine-4-yl) benzene-1,3- diamines（ A2-NH2-3 )、
    3- (2- methyl -6- (4- methylpiperazine-1-yls）Pyrimidine-4-yl amido）Anilino- formic acid (4- nitrobenzene）Ester hydrochloride (A2-CAR-3)
    2- (4- (2- methyl -6- (4- nitrobenzene amido) pyrimidine-4-yl) piperazine -1- bases) ethanol（ A1-N02-1 )、
    2- (4- (2- methyl-6- (4- nitrobenzene amido) pyrimidine-4-yl) piperazine-1-yl) ethyl acetate（The A of Al-N02- 1), 2- (4- (2- methyl -6- (4- amino anilines）Pyrimidine-4-yl）Piperazine -1- bases）Ethyl acetate (A1-NH2-1A), 2- (4- (6- (4- (3- (the chloro- 4- fluorophenyls of 3-) urea groups) anilino-) -2- methylpyrimidine -4- bases) piperazine -1- bases)-ethyl acetate
    (A1-1-1A)、
    2- (4- (6- (4- (3- (3- (trifluoromethyl) -4- chlorphenyls) urea groups) anilino-) -2- methylpyrimidine -4- bases) piperazine -1- bases) ethyl acetate (Α 1-3-1 Α),
    2- (4- (2- methyl -6- (4- (3- (3- cyano-phenyls) urea groups) anilino-) pyrimidine-4-yl) piperazine -1- bases) ethyl acetate
    (Α1-4-1Α)、
    2- (4- (2- methyl -6- (4- (3- (3- tolyls) urea) anilino-) pyrimidine-4-yl) piperazine -1- bases) ethyl acetate
    (A1-13-1A)、
    2- (4- (2- methyl -6- (4- (3- isobutyl groups urea groups) anilino-) pyrimidine-4-yl) piperazine -1- bases) ethyl acetate（A1-19-1A), 2- (4- (2- methyl -6- (3- nitrobenzene amido) pyrimidine-4-yl) piperazine -1- bases) ethanol（ A2-N02-1 )、
    2- (4- (2- methyl -6- (3- nitrobenzene amido) pyrimidine-4-yl) piperazine -1- bases) ethyl acetate（A2-N02-1A)、
    2- (4- (2- methyl -6- (3- aminobenzenes amido) pyrimidine-4-yl) piperazine -1- bases) ethyl acetate（A2-NH2-1A)、
    2- (4- (2- methyl -6- (3- (3- (the chloro- 4- fluorophenyls of 3-) urea groups) anilino-) pyrimidine-4-yl) piperazine -1- bases)-ethyl acetate
    (A2-1-1A)、
    2- (4- (2- methyl -6- (3- (3- (3- (trifluoromethyl) -4- chlorphenyls) uride) anilino-) pyrimidine-4-yl) piperazine -1- bases) ethyl acetate (Α 2-3-1 Α),
    2- (4- (2- methyl -6- (3- (3- (3- cyano-phenyls) urea groups) anilino-) pyrimidine-4-yl) piperazine -1- bases)-ethyl acetate (Α2-4-1Α)、
    2- (4- (2- methyl -6- (3- (3- (3- aminomethyl phenyls) urea groups) anilino-) pyrimidine-4-yl) piperazine -1- bases)-ethyl acetate
    (A2-13-1A)
    2- (4- (2- methyl -6- (3- (3- isobutyl groups urea groups) anilino-) pyrimidine-4-yl) piperazine -1- bases) ethyl acetate（A2-19-1A), the chloro- N of 6-, 2- dimethyl-N -s (3- nitrobenzophenones) pyrimidine -4- amine（ A2M-NO2-0)、
    ^- (2- methyl -6- chlorine pyrimidine-4-yl)-N1- methylbenzene -1,3- diamines（A2M-NH2-0)、
    3- (methyl (2- methyl -6- chlorine pyrimidine-4-yl) amido) anilino- formic acid 4- nitrobenzene ester hydrochlorides（A2M-CAR-0)、
    2- methyl -6- morpholinyls-N- (3- nitrobenzophenones) pyrimidine -4- amine（A2M-N02-2)、
    ^- (2- methyl -6- morpholinyls pyrimidine-4-yl) benzene -1,3- diamines（A2M-NH2-2)、
    3- (methyl (2- methyl -6- morpholinyls pyrimidine-4-yl) amidos）Anilino- formic acid 4- nitrobenzene ester hydrochlorides
    (A2M-CAR-2)、
    N, 2- dimethyl-6- (- 1-yl of 4- methyl piperazines)-N- (3- nitrobenzophenones) pyrimidine-4- amine（ A2M-N02-3 )、
    N1- methyl-^- (2- methyl -6- (the small base of 4- methyl piperazines) pyrimidine-4-yl) benzene -1,3- diamines（A2M-NH2-3 )、
    3- (methyl (2- methyl -6- (the small base of 4- methyl piperazines) pyrimidine-4-yl) amidos）Anilino- formic acid 4- nitrobenzene ester hydrochloride (A2M-CAR-3)
    The chloro- N- of 2- methyl -6- (3- nitro-4-methyls phenyl) pyrimidine -4- amine（ A2N-NO2-0 )、
    NJ- (2- methyl -6- chlorine pyrimidine-4-yl) -4- toluene -1,3- diamines（ A2N-NH2-0 )、
    5- (2- methyl -6- chlorine pyrimidine-4-yl amido 2-aminotoluene base formic acid 4- nitrobenzene ester hydrochlorides（A2N-CAR-0), 2- methyl-N- (4- methyl-3-nitros phenyl) -6- morpholine yl pyrimidines -4- amine（A2N-N02-2)、
    4- methyl-^- (2- methyl -6- morpholinyls pyrimidine-4-yl) benzene -1,3- diamines（ A2N-NH2-2 )、
    2_ methyl-5-(2- methyl -6- morpholinyl pyrimidine-4-yl amidos）Anilino- formic acid 4- nitrobenzene ester hydrochloride (A2N-CAR-2),
    2- methyl-N- (4- methyl-3-nitros phenyl)-6- (- 1-yl of 4- methyl piperazines) pyrimidine-4- amine（A2N-N02-3), 4- methyl-^- (2- methyl-6- (- 1-yl of 4- methyl piperazines) pyrimidine-4-yl) benzene-1,3- diamines（ A2N-NH2-3 )、
    3- (trifluoromethyls）- 4- chloroanilino formic acid 4- nitro phenyl esters（3-CAR)、
    4- (pyrrolidin-1-yl) fourth amidocarbonic acid 4- nitrobenzene ester hydrochlorides（ 18-CAR)、 The chloro- N- of 2- methyl -6- (2- nitrobenzophenones) pyrimidine -4- amine（A3-NO2-0)、
    NJ- (2- methyl -6- chlorine pyrimidine-4-yl) benzene -1,2- diamines（ A3-NH2-0 )、
    2- methyl -6- morpholinyls-N- (2- nitrobenzophenones) pyrimidine -4- amine（A3-N02-2)、
    ^- (2- methyl -6- morpholinyls pyrimidine-4-yl) benzene -1,2- diamines（A3-NH2-2)、
    2- methyl-6- (- 1-yl of 4- methyl piperazines)-N- (2- nitrobenzophenones) pyrimidine-4- amine（ A3-N02-3 )、
    NJ- (2- methyl-6- (- 1-yl of 4- methyl piperazines) pyrimidine-4-yl) benzene-1,2- diamines（ A3-NH2-3 )、
    6- chloro-n-methyls-N- (3- nitrobenzophenones) pyrimidine -4- amine（ B2M-NO2-0 )、
    N- methyl -6- morpholinyls-N- (3- nitrobenzophenones) pyrimidine -4- amine（ B2M-N02-2 )、
    Or N1- methyl-N1- ^- morpholinyls pyrimidine-4-yl) benzene -1,3- diamines（B2M-NH2-2)。
    27th, the application of compound I or its pharmaceutically acceptable salt, polymorph, solvate or stereoisomer as claimed in claim 1 in preparing prevention and/or treating being lacked of proper care with protein kinase mediated signal transduction pathway for mammal, or the medicine of the newborn related disease of abnormal vascular.
    28th, application as claimed in claim 27, it is characterised in that：Described disease is tumour, diabetes, autoimmune disease, nerve degenerative diseases, diabetic retinopathy, age-related macular degeneration, artery sclerosis, psoriasis or inflammation.
    29th, application as claimed in claim 28, it is characterised in that：Described tumour is the tumour or malignant hematologic disease of skin, brain, lung, lymphocyte, kidney, liver, stomach, colon, rectum, bladder, head, neck, mammary gland, thyroid gland, oesophagus, pancreas, prostate either gynemetrics.
    30th, application as claimed in claim 27, it is characterised in that：Described protein kinase be EGFR-TK, serine/threonine kinase, and/or foregoing kinases various saltant types.
    31st, application as claimed in claim 30, it is characterised in that：Described EGFR-TK is EGFR, HER-2, VEGFR-K VEGFR-2, VEGFR-3 PDGFRc PDGFRp, c-KIT, CSF-1R, FLT-3, c-MET, FGFR-K TIE-2, p38 a, SRC, LCK, FYN or HCK;Described serine/threonine kinase is BRAF, CRAF, Aurora A or Aurora B;Described mutation type kinase is BRAF V599E.
    32nd, the application of compound I or its pharmaceutically acceptable salt, polymorph, solvate or stereoisomer as claimed in claim 1 in the medicine with human tumour xenograft tumor inhibitory activity is prepared. 33rd, application as claimed in claim 32, it is characterised in that：Described human tumour xenograft tumor is to transplant the A549 human lung cancers in nude mice.
    34th, the application of compound I or its pharmaceutically acceptable salt, polymorph, solvate or stereoisomer as claimed in claim 1 in the medicine with A549 human lung carcinoma cells, HCT116 people's colon-cancer cell, CEM human leukemia cells or MCA-MB-435 human melanoma cell inhibitory activity is prepared.
    35th, the application of compound I or its pharmaceutically acceptable salt, polymorph, solvate or stereoisomer as claimed in claim 1 in the medicine with Human umbilical vein endothelial cells inhibitory activity is prepared.
    36th, the pharmaceutical composition of carbamide compounds I as claimed in claim 1 or its pharmaceutically acceptable salt, polymorph, solvate or stereoisomer is included.
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