CN105669564B - Carbamide compounds, its preparation method, pharmaceutical composition, intermediate and its application - Google Patents

Carbamide compounds, its preparation method, pharmaceutical composition, intermediate and its application Download PDF

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CN105669564B
CN105669564B CN201610097258.7A CN201610097258A CN105669564B CN 105669564 B CN105669564 B CN 105669564B CN 201610097258 A CN201610097258 A CN 201610097258A CN 105669564 B CN105669564 B CN 105669564B
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methyl
pyrimidine
dmso
amido
urea
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CN105669564A (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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    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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Abstract

The invention discloses a kind of carbamide compounds or its pharmaceutically acceptable salt, polymorph, solvate or stereoisomer shown in formula I；With and preparation method thereof, its pharmaceutical composition, intermediate and its application.The carbamide compounds of the present invention are in biology test, there is different degrees of inhibitory activity for multiple protein kinases, and display is grown with different degrees of antitumor cell respectively and anti-angiogenic rebirth is active in human tumor cell lines and Human umbilical vein endothelial cells (HUVEC) proliferation test in vitro, also shows that preferable antitumor activity in animal body.

Description

Carbamide compounds, its preparation method, pharmaceutical composition, intermediate and its application
The application is the applying date：On April 11st, 2012, application number：CN201280001660.0, it is entitled：It is a kind of Carbamide compounds, the divisional application of its preparation method, wherein mesosome and its application.
Technical field
It is particularly related to a kind of carbamide compounds, its preparation method, pharmaceutical composition, intermediate and its application.
Background technology
Signal transduction (signal transduction) between cell interior and cell regulates and controls the Fang Fang of cell function Face face.The exception of cell signalling is the molecular basis of many disease complexity causes of disease.Most signal transduction pathways are by egg White kinases (protein kinase) mediation.The phosphorylation of human protein kinase catalytic serine, threonine or tyrosine residue, Played an important role in the growth of cell, metabolism, differentiation and apoptosis.Disregulated protein kinases can cause to include tumour, diabetes, A series of diseases including autoimmune disease, nerve degenerative diseases and inflammation.Therefore, kinases inhibitor becomes and controls Treat an important channel of above-mentioned many mankind's major diseases.
Human kinase protein group membership more than 500 kinds (.Science such as Manning G, 2002,298 (5600):1912- , including tyrosine kinase and serine/threonine kinase 1934).Some important protein kinases as drug targets are illustrated It is as follows：HER kinases (such as EGFR and HER-2), VEGFR kinases (such as VEGFR-1, VEGFR-2 and VEGFR-3), PDGFR kinases (such as PDGFR α, PDGFR β, c-KIT, CSF-1R and FLT-3), SRC kinases (such as SRC, LCK, FYN and HCK), ALK, BCR- ABL, c-MET, TIE-2, FGFR-1, RAF kinases (such as BRAF and CRAF), Aurora A (such as Aurora A and Aurora B), p 38 alpha, and the mutant strain (such as BCR-ABL T315I and BRAF V599E) of above-mentioned kinases.
Angiogenesis (angiogenesis) refers to from the brand-new blood vessel of existing angiogenesis.Normal angiogenesis is one It is subject to the normal physiological processes of tight control, betides embryonic development, wound healing and menstrual cycle.Angiogenesis is once lacked of proper care A variety of diseases such as diabetic retinopathy, rheumatoid arthritis, age-related macular degeneration, artery sclerosis and tumour may be caused Disease.
Angiogenesis is the lifeline for maintaining tumour existence and progress, and solid tumor highly relies on angiogenesis to continue acquisition Nutrition and oxygen.Therefore, the compound of target vascular therapy new life becomes a big hot spot of antitumor drug research, and expected its is being pacified There may be advantage in terms of full property and the resistance to the action of a drug.Multi-kinase inhibitor Sorafenib, Sutent and the Pa Zuopa listed at present Buddhist nun is respectively provided with anti-angiogenic rebirth activity.
At present the target of anti-angiogenic rebirth include growth factor (such as vascular endothelial growth factor, platelet derived growth because Sub- acceptor, fibroblast growth factor and epidermal growth factor), receptor tyrosine kinase, transcription factor (such as hypoxia inducible because Sub (hypoxia inducible factor)), and participate in the molecule of MAPK and PI3K signal transduction pathways.Wherein albumen swashs Enzyme target mainly include VEGFR-1, VEGFR-2, VEGFR-3, FGFR-1, PDGFR α, PDGFR β, c-KIT, FLT-3, EGFR and TIE-2 etc..
Urea structure type compound receives extensively and in-depth study in recent years as kinases inhibitor.(Dumas The .Current Opinion in Drug Discovery＆Development such as J, 2004,7 (5):600-616.)
1st, Sorafenib：
Sorafenib (sorafenib) is first selective multi-kinase inhibitor for being approved by the FDA in the United States listing, it is changed Architectural feature is diaryl urea (diaryl urea).Sorafenib is to the Raf-1 in RAF/MEK/ERK signal transduction pathways (IC50, 6nM), wild type BRAF (IC50, 22nM), V599E anomaly BRAF (IC50, 38nM) and it is respectively provided with remarkable inhibiting activity. In addition, Sorafenib also potent can suppress a variety of receptor tyrosine kinases (RTK) being of great significance to angiogenesis： VEGFR-2(IC50, 90nM), mouse VEGFR-2 (IC50, 15nM), mouse VEGFR-3 (IC50, 20nM), mouse PDGFR- β (IC50, 57nM)、c-KIT(IC50, 68nM) and FLT-3 (IC50,58nM).Turn in short, Sorafenib had both targeted RAF/MEK/ERK signals Guiding path blocks tumor cells are bred, and are targeted VEGFR-2/PDGFR- signal betas transductory cascade and suppressed neonate tumour blood vessel. (.Cancer such as Wilhelm SM Research, 2004,64 (19):7099-7109)
2nd, other urea structure kinases inhibitors：
The II phases that Tandutinib (MLN-518) is in acute myelocytic leukemia (AML) are clinical.It is receptor kinase Potent inhibitor (the IC of FLT-3, c-KIT and PDGFR50170~220nM), it is equal relative to p38 kinases, VEGFR-2 and FGFR There is high selectivity (IC50>30μM).(the .Current Opinion in Drug such as Dumas J Discovery＆ Development,2004,7(5):600-616.)
Boehringer Ingelheim once developed the clinical examination that 2-substituted carbamide compound BIRB796 enters treatment autoimmune disease Test.BIRB796 is p 38 alpha map kinase inhibitor.(the .Journal of Medicinal such as Regan J Chemistry, 2003, 46(22):4676-4686.)
The isothiazole compounds CP-547632 of Pfizer's report is potent VEGFR-2 and FGFR-1 inhibitor, IC50Respectively 11 and 9nM, selectivity is shown relative to EGFR, PDGFR β and other associated kinases.CP-547632 has angiogenesis inhibiting With the double activity of tumor cell proliferation：The angiogenesis that potent suppression VEGFR and FGF are induced in model in vivo；In lotus people In the athymic mouse of xenograft tumor, oral administration can inhibit 85% tumour growth.(the .Cancer such as Beebe JS Research,2003,63(21):7301-7309.)
Abbott Laboratories are in order to find new more kinases receptors tyrosine kinase (RTK) inhibitor, by Aminoindazole seriation Extensive structure activity study in compound is found that ABT-869, already into clinical test.ABT-869 is to VEGFR-2, FLT-3 With the IC of c-KIT50Respectively 4,5 and 16nM.(the .Journal of Medicinal such as Dai YJ Chemistry, 2007,50 (7):1584-1597.)
Hasegawa of GlaxoSmithKline PLC etc. (the .Journal of Medicinal Chemistry such as Hasegawa M, 2007,50:4453-4470.) report TIE-2 the and VEGFR-2 dual tyrosine kinase inhibitor for representative with compound 1 (IC50Respectively 4.9 and 1.5nM), solubility is about 200 μ g/mL in PBS (phosphate buffered saline (PBS)).
Niculescu-Duvaz etc. (the .Journal of Medicinal Chemistry such as Niculescu-Duvaz D, 2009,52(8):2255-2264.) using bicyclic pyridine, simultaneously imidazolidinone as hinge area binding fragment, obtains potent BRAF suppressions 2 (IC of preparation50 12nM)。
The content of the invention
The technical problems to be solved by the invention be to provide it is a kind of with the entirely different carbamide compounds of the prior art or its Pharmaceutically acceptable salt, polymorph, solvate or stereoisomer, its preparation method, its pharmaceutical composition, among it Body, and its application.The carbamide compounds of the present invention have different degrees of suppression in biology test for multiple protein kinases System activity, and shown respectively in human tumor cell lines and the experiment of Human umbilical vein endothelial cells (HUVEC) proliferation activity in vitro Show with different degrees of antitumor cell growth and anti-angiogenic rebirth activity, also show that in animal body preferably antitumor Activity.
Therefore, the present invention relates to a kind of carbamide compounds or its pharmaceutically acceptable salt, polymorphic shown in formula I Thing, solvate or stereoisomer；
Wherein, R2For hydrogen, R1For substituted or unsubstituted C1~C8Alkyl (preferably C1~C6Alkyl, such as n-propyl, isopropyl Base, normal-butyl, isobutyl group, the tert-butyl group or n-hexyl), substituted or unsubstituted C3~C9Cycloalkyl (preferably C3~C8Cycloalkyl, Such as cyclohexyl), substituted or unsubstituted C6~C14Aryl (preferably C6~C10Aryl, such as phenyl or naphthyl), substitution or it is unsubstituted C1~C13Heteroaryl (preferably C3~C9Heteroaryl, further preferred C3~C5Heteroaryl, still further preferably thiazolyl, such as thiophene Azoles -2- bases；Or pyridine radicals, such as pyridin-4-yl or pyridine -2- bases；Or isoxazolyl, such as isoxazole -3- bases)；Substitution Substituent in alkyl is 4~9 yuan of (preferably 4~6 yuan) saturated heterocyclyls, and the hetero atom number of the saturated heterocyclyl is 1~4 A, hetero atom is nitrogen, oxygen or sulphur, such as pyrrolidin-1-yl；Substituent in substituted cycloalkyl is halogen, C1~C3Alkyl or C1 ~C3Alkoxy；Substituent in substituted aryl or substituted heteroaryl is halogen (such as fluorine, chlorine, bromine or iodine), cyano group, C1~ C3Haloalkyl (such as trifluoromethyl), C1~C3Alkyl (preferably, when heteroaryl is isoxazole -3- bases, isoxazole -3- bases By C1~C35-C is formed after alkyl substitution1~C3Alkyl isoxazole -3- bases, such as 5- methylisoxazole -3- bases), C1~C3Alcoxyl Base, C2~C3Alkenyl, C2~C3Alkynyl and (connection C1~C3The amine formyl of alkyl) substitution pyridine epoxide (preferably 2- (N- Methylcarbamoyl) pyridine -4- epoxides) in one or more, the number of every kind of substituent is 0,1 or multiple, substituent Position can be commutable optional position on aryl or heteroaryl, and when aryl is phenyl ring, the position of substituent is urea side chain Ortho position, meta or para position；Hetero atom in heteroaryl is nitrogen, oxygen or sulphur, and hetero atom number is 1~5；
Or R1、R2And and R1、R2Connected nitrogen-atoms together cyclization for substituted or unsubstituted 4~9 yuan (preferably 5~ 7 yuan) saturated heterocyclic (such as morpholine ring), the saturated heterocyclic can additionally contain 1~3 hetero atom, the hetero atom is nitrogen, oxygen or Sulphur, it is unsubstituted on the nitrogen-atoms or further by C if additionally including nitrogen-atoms1~C6Alkyl substitutes；Substituted 4 Substituent in~9 yuan of saturated heterocyclics is halogen, C1~C3Alkyl or C1~C3Alkoxy；
R3For hydrogen or C1~C3Alkyl；
R4For hydrogen, C1~C3Alkyl, C1~C3Alkoxy, halogen, amino or cyano group；
Q for hydrogen, halogen (such as fluorine, chlorine, bromine or iodine) orWherein, R5And R6Independently be hydrogen, substitution or not Substituted C1~C6Alkyl, the substituted C1~C6Substituent on alkyl is amino, hydroxyl, cyano group, halogen or C1~C3 Alkoxy；
Or R5、R6And and R5、R6Connected nitrogen-atoms together cyclization for substituted or unsubstituted 4~9 yuan (preferably 5~ 7 yuan) saturated heterocyclic, the saturated heterocyclic can additionally contain 1~3 hetero atom, and the hetero atom is nitrogen, oxygen or sulphur (such as morpholine Ring or piperazine ring)；Substituent in substituted 4~9 yuan saturated heterocyclic is halogen, C1~C3Alkyl, C1~C3Alkoxy Or the C of hydroxyl substitution1~C6(preferably C1~C3) alkyl, when the substituent in substituted 4~9 yuan saturated heterocyclic is C1~ C3Alkyl, C1~C3Alkoxy or the C of hydroxyl substitution1~C6(preferably C1~C3) alkyl when, it is miscellaneous that substituent can be connected to saturation On nuclear carbon atom or nitrogen-atoms, when substituent is halogen, substituent can be connected on the carbon atom in saturated heterocyclic, compared with It is good, substituted or unsubstituted 4~9 yuan described (preferably 5~7 yuan) saturated heterocyclics are 4- (2- ethoxys) piperazine -1- bases, Quinoline base or 4- methylpiperazine-1-yls；
R7For hydrogen, C1~C3Alkyl, C1~C3Alkoxy or C1~C3Alkylthio group；
R8、R9、R10And R11It independently is hydrogen, C1~C3Alkyl, C1~C3Alkoxy, halogen or cyano group；
Urea side chainIt is connected to 2 ', 3 ' or 4 ' positions.
In the present invention, the compound I it is optimal for following any structure：
In the present invention, the pharmaceutically acceptable salt of the carbamide compounds I is above-mentioned carbamide compounds and inorganic acid Or the salt that organic acid is formed, or the salt that above-mentioned carbamide compounds and inorganic base or organic base are formed.
The crystal form of compound of formula I in the present invention can be polymorphic, these crystal forms are comprised in the present invention In.In addition, the compound of formula I in the present invention can also form solvate with solvent, such as and water forms hydrate, or with having Solvent forms organic solvent compound, these hydrates and organic solvent compound are also included in the present invention.
The compound of the present invention may contain asymmetric atom, especially asymmetric carbon atom, all therefore and produce vertical Body isomers (including pure stereoisomers, or the mixture being made of the stereoisomer of various ratios) it is regarded as this hair A bright part.
The invention further relates to the preparation method of above-claimed cpd I, it is any one in following methods：
Compound IX, when including hydroxyl in Q, slough the reaction of the protection group of hydroxyl by method one, you can；Chemical combination In thing IX, Q ' is the group after the hydroxyl in Q groups is protected by the hydroxyl protection base of this area routine；
Method two, condensation reaction is carried out by compound XI and QH, you can；In compound XI, group X ' is such for this area Common leaving group in condensation reaction, such as halogen (such as chlorine, bromine or iodine)；
Method three, when not including hydroxyl in Q, by compound XIII and R1R2NH reacted into urea, you can；
In above-mentioned three kinds of methods, the method and condition of the reaction being related to can be normal in the reaction of this area respective classes Rule method and condition；The definition of each group is unless otherwise indicated as described above.
Therefore, the compound I in the present invention can be prepared according to the prior art using the methodology of organic synthesis of any suitable. Below by the present invention, the preferable preparation method of compound I illustrates：
1. contain synthesis during free hydroxyl group (by taking 2- (piperazine -1- bases) ethanol as an example) in compound I
Synthetic route 1：First it is condensed with QH, then carries out into urea reaction
By compound II and compound III condensations, (for example, under acid catalysis, compound II and compound III is heated first Condensation), the acid-addition salts generated neutralize to dissociate through alkali (for example, sodium acetate) obtains compound IV；Or first make compound II React with alkali (for example, sodium hydride), then be condensed with compound III (for example, under reflux), obtain compound IV (reactions steps a).If R3When not being hydrogen, then compound IV is alkylated (for example, R through N-3I, K2CO3) obtain compound V (reactions steps b)；If R3 For hydrogen when, then compound IV directly carries out next step reaction.Compound IV or V with containing free hydroxyl group QH (with 2- (piperazine- 1- yls) exemplified by ethanol) condensation (for example, in DMF, at 130 DEG C) obtains compound VI (reactions steps c).Compound VI is through protecting Protect after free hydroxyl group (for example, protecting hydroxyl under DMAP catalysis with acetic anhydride acetylation), obtain compound VII (reactions steps d).Compound VII reduces (for example, electronation (such as Fe-HOAc), catalytic hydrogenation) through nitro, and it is (anti-to obtain compound VIII Answer step e).Compound VIII and R1R2NH obtains compound IX into urea (for example, carbamate method, isocyanic acid ester process etc.) (reactions steps f).Finally, compound IX is reacted (for example, in methyl alcohol through sodium hydrate aqueous solution soap through dehydroxylation protection group Change), obtain compound I (reactions steps g).Each group definition as described above, contains free hydroxyl group in wherein Q.
Compound I (containing free hydroxyl group in Q, by taking 2- (piperazine -1- bases) ethanol as an example) synthetic route 1
Synthetic route 2：Urea reaction is first carried out into, then is condensed with QH
The preparation of compound IV and compound V are referring to synthetic route 1.Compound IV or compound V reduce (example through nitro Such as, electronation (such as Fe-HOAc), catalytic hydrogenation), obtain compound X (reactions steps h).Compound X and R1R2NH is into urea (for example, carbamate method, isocyanic acid ester process etc.), obtains compound XI (reactions steps i).Finally, compound XI is with containing The QH (by taking 2- (piperazine -1- bases) ethanol as an example) of free hydroxyl group is condensed (for example, containing DIEA's (diisopropyl ethyl amine) In DMF, at 80 DEG C), obtain compound I (reactions steps j).Each group definition as described above, contains free hydroxyl group in wherein Q.
Compound I (containing free hydroxyl group in Q, by taking 2- (piperazine -1- bases) ethanol as an example) synthetic route 2
2. the synthesis of other compounds I (each group definition as described above, is free of free hydroxyl group in Q)
Other compounds I (each group definition as described above, but does not contain free hydroxyl group in Q) using synthetic route 3 or Synthetic route 4 synthesizes.
Synthetic route 3：First it is condensed with QH, then carries out into urea reaction
The preparation of compound IV and compound V are referring to synthetic route 1.Compound IV or compound V are free with not containing The QH condensations of hydroxyl (for example, in QH, under KI catalysis, are heated；Or in the DMSO solution of QH, heating), obtain compound XII (reactions steps k).Compound XII reduces (for example, electronation (such as Fe-HOAc), catalytic hydrogenation) through nitro, obtains Compound XIII (reactions steps l).Finally, compound XIII and R1R2NH is into urea (for example, carbamate method, isocyanic acid ester process Deng), obtain compound I (reactions steps m).Each group definition as described above, is free of free hydroxyl group in wherein Q.
Compound I (free hydroxyl group is free of in Q) synthetic route 3
Synthetic route 4：Urea reaction is first carried out into, then is condensed with QH
The preparation of compound IV and compound V are referring to synthetic route 1.Compound IV or compound V reduce (example through nitro Such as, electronation (such as Fe-HOAc), catalytic hydrogenation), obtain compound X (reactions steps n).Compound X and R1R2NH is into urea (for example, carbamate method, isocyanic acid ester process etc.), obtains compound XI (reactions steps o).Finally, compound XI and QH be (no Contain free hydroxyl group) condensation (for example, in DMF containing DIEA, at 80 DEG C), obtain compound I (reactions steps p).Each base Group is as defined above described, and free hydroxyl group is free of in wherein Q.
Compound I (free hydroxyl group is free of in Q) synthetic route 4
Wherein, the raw material involved in above-mentioned each method or reagent can be by commercially available, or the prior art is prepared.
Disclosed above-mentioned preparation method according to the present invention, those skilled in the art can use same principle and side Method, is made each particular compound involved in the general formula compound I of the present invention.
The invention further relates to the new midbody compound 55 in the above method, being used to prepare compound I：N1- (2- first Base -6- chlorine pyrimidine-4-yl) benzene -1,4- diamines (A1-NH2-0), 4- (2- methyl -6- chlorine pyrimidine-4-yls amido) anilino- formic acid (4- nitrobenzenes) ester hydrochloride (A1-CAR-0), 2- methyl -6- morpholinyls-N- (4- nitrobenzophenones) pyrimidine -4- amine (A1-NO2- 2)、N1- (2- methyl -6- morpholinyls pyrimidine-4-yl) benzene -1,4- diamines (A1-NH2-2), 4- (2- methyl -6- morpholines yl pyrimidines - 4- bases amido) anilino- formic acid (4- nitrobenzenes) ester hydrochloride (A1-CAR-2), the chloro- N- of 2- methyl -6- (3- nitrobenzophenones) be phonetic Pyridine -4- amine (A2-NO2-0), N1- (2- methyl -6- chlorine pyrimidine-4-yl) benzene -1,3- diamines (A2-NH2-0), 3- (2- methyl -6- Chlorine pyrimidine-4-yl amido) anilino- formic acid (4- nitrobenzenes) ester hydrochloride (A2-CAR-0), 2- methyl -6- morpholinyl-N- (3- Nitrobenzophenone) pyrimidine -4- amine (A2-NO2-2), N1- (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- nitrobenzenes) ester hydrochloride (A2-CAR-2), 2- Methyl -6- (4- methylpiperazine-1-yls)-N- (3- nitrobenzophenones) pyrimidine -4- amine (A2-NO2-3), N1- (2- methyl -6- (4- first Base piperazine -1- bases) pyrimidine-4-yl) benzene -1,3- diamines (A2-NH2-3), (2- methyl -6- (4- methylpiperazine-1-yls) is phonetic by 3- Pyridine -4- bases amido) anilino- formic acid (4- nitrobenzenes) ester hydrochloride (A2-CAR-3), 2- (4- (2- methyl -6- (4- nitroanilines Base) pyrimidine-4-yl) piperazine -1- bases) ethanol (A1-NO2-1), 2- (4- (2- methyl -6- (4- nitrobenzenes amido) pyrimidine-4-yl) Piperazine -1- bases) ethyl acetate (A1-NO2-1A), 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- methylpyrimidines -4- Base) piperazine -1- bases)-ethyl acetate (A1-1-1A), 2- (4- (6- (4- (3- (3- (trifluoromethyl) -4- chlorphenyls) urea groups) benzene Amido) -2- methylpyrimidine -4- bases) piperazine -1- bases) ethyl acetate (A1-3-1A), 2- (4- (2- methyl -6- (4- (3- (3- cyanogen Base phenyl) urea groups) anilino-) pyrimidine-4-yl) piperazine -1- bases) ethyl acetate (A1-4-1A), 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- nitrobenzenes amido) pyrimidine-4-yl) piperazine -1- bases) ethanol (A2-NO2-1), 2- (4- (2- methyl -6- (3- nitroanilines Base) pyrimidine-4-yl) piperazine -1- bases) ethyl acetate (A2-NO2-1A), 2- (4- (2- methyl -6- (3- aminobenzenes amido) pyrimidine - 4- yls) 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- (fluoroforms Base) -4- chlorphenyls) uride) anilino-) pyrimidine-4-yl) piperazine -1- bases) ethyl acetate (A2-3-1A), 2- (4- (2- methyl - 6- (3- (3- (3- cyano-phenyls) urea groups) anilino-) pyrimidine-4-yl) piperazine -1- bases)-ethyl acetate (A2-4-1A), 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-(3- nitrobenzophenones) pyrimidine -4- amine (A2M-NO2-0), N1- (2- methyl -6- chlorine is phonetic Pyridine -4- bases)-N1- methylbenzene -1,3- diamines (A2M-NH2-0), 3- (methyl (2- methyl -6- chlorine pyrimidine-4-yl) amido) aniline Base formic acid 4- nitrobenzenes ester hydrochloride (A2M-CAR-0), 2- methyl -6- morpholinyls-N- (3- nitrobenzophenones) pyrimidine -4- amine (A2M-NO2-2)、N1- (2- methyl -6- morpholinyls pyrimidine-4-yl) benzene -1,3- diamines (A2M-NH2-2), 3- (methyl (2- first Base -6- morpholinyls pyrimidine-4-yl) amido) anilino- formic acid 4- nitrobenzenes ester hydrochloride (A2M-CAR-2), N, 2- dimethyl -6- (4- methylpiperazine-1-yls)-N- (3- nitrobenzophenones) pyrimidine -4- amine (A2M-NO2-3), N1- methyl-N1- (2- methyl -6- (4- Methylpiperazine-1-yl) pyrimidine-4-yl) benzene -1,3- diamines (A2M-NH2-3), 3- (methyl (2- methyl -6- (4- methyl piperazines - 1- yls) pyrimidine-4-yl) amido) anilino- formic acid 4- nitrobenzenes ester hydrochloride (A2M-CAR-3), 2- methyl -6- chloro- N- (3- nitre Base -4- aminomethyl phenyls) pyrimidine -4- amine (A2N-NO2-0), N1- (2- 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 hydrochlorides (A2N-CAR-0), 2- methyl-N- (4- methyl-3-nitros phenyl) -6- morpholine yl pyrimidines -4- amine (A2N-NO2-2), 4- methyl - N1- (2- methyl -6- morpholinyls pyrimidine-4-yl) benzene -1,3- diamines (A2N-NH2-2), 2- methyl -5- (2- methyl -6- morpholinyls Pyrimidine-4-yl amido) anilino- formic acid 4- nitrobenzenes ester hydrochloride (A2N-CAR-2), 2- methyl-N- (4- methyl-3-nitro benzene Base) -6- (4- methylpiperazine-1-yls) pyrimidine -4- amine (A2N-NO2-3), 4- methyl-N1- (2- methyl -6- (4- methyl piperazines - 1- yls) pyrimidine-4-yl) benzene -1,3- diamines (A2N-NH2-3), 3- (trifluoromethyl) -4- chloroanilino formic acid 4- nitro phenyl esters (3-CAR), 4- (pyrrolidin-1-yl) fourth amidocarbonic acid 4- nitrobenzenes ester hydrochloride (18-CAR), 2- methyl -6- chloro- N- (2- nitre Base phenyl) pyrimidine -4- amine (A3-NO2-0), N1- (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-NO2-2), N1- (2- methyl -6- morpholinyls pyrimidine-4-yl) Benzene -1,2- diamines (A3-NH2-2), 2- methyl -6- (4- methylpiperazine-1-yls)-N- (2- nitrobenzophenones) pyrimidine -4- amine (A3- ) or N NO2-31- (2- methyl -6- (4- methylpiperazine-1-yls) pyrimidine-4-yl) benzene -1,2- diamines (A3-NH2-3), 6- Chloro-n-methyl-N- (3- nitrobenzophenones) pyrimidine -4- amine (B2M-NO2- 0), N- methyl -6- morpholinyls-N- (3- nitrobenzophenones) is phonetic Pyridine -4- amine (B2M-NO2- 2) or N1- methyl-N1- (6- morpholinyls pyrimidine-4-yl) benzene -1,3- diamines (B2M-NH2-2)。
The invention further relates to above-claimed cpd I or its pharmaceutically acceptable salt, polymorph, solvate or three-dimensional different Structure body is preparing prevention and/or is treating lacking of proper care with protein kinase mediated signal transduction pathway for mammal particularly people, or Application in the medicine of the newborn relevant disease of person's abnormal vascular.The disease include but not limited to tumour, diabetes, itself Immunity disease, nerve degenerative diseases, diabetic retinopathy, age-related macular degeneration, artery sclerosis, psoriasis or inflammation Disease.The tumour include but not limited to skin, brain, lung, lymphocyte, kidney, liver, stomach, colon, rectum, bladder, Head, neck, mammary gland, thyroid gland, oesophagus, pancreas, the prostate either tumour of gynemetrics or malignant hematologic disease (such as white blood Disease).
The protein kinase includes tyrosine kinase and serine/threonine kinase, and/or the various of foregoing kinases dash forward Modification.Wherein, the tyrosine kinase be preferably EGFR, HER-2, VEGFR-1, VEGFR-2, VEGFR-3, PDGFR α, PDGFR β, c-KIT, CSF-1R, FLT-3, c-MET, FGFR-1, TIE-2, p 38 alpha, SRC, LCK, FYN or HCK；The silk ammonia Acid/threonine kinase is preferably BRAF, CRAF, Aurora A or Aurora B；The mutation type kinase is preferably BRAF V599E。
In the present invention, the compound of formula I in vitro has human tumor cell line and Human umbilical vein endothelial cells (HUVEC) There is growth inhibitory activity.The human tumor cell line includes but not limited to A549 (human lung carcinoma cell), (people's intestinal cancer is thin by HCT116 Born of the same parents), CEM (human leukemia cell) and MCA-MB-435 (human melanoma cell).
In the present invention, there is growth inhibitory activity to human tumour xenograft tumor in the compound of formula I body.The people Tumor xenograft knurl includes but not limited to transplant in the A549 human lung cancers of nude mice.
Therefore the present invention relates to above-claimed cpd I or its pharmaceutically acceptable salt, polymorph, solvate or solid Application of the isomers in the medicine with human tumour xenograft tumor inhibitory activity is prepared.Wherein, the human tumour xenogenesis Transplantable tumor is preferably to transplant in the A549 human lung cancers of nude mice.
The invention further relates to above-claimed cpd I or its pharmaceutically acceptable salt, polymorph, solvate or three-dimensional different Structure body is black with A549 human lung carcinoma cells, HCT116 people's colon-cancer cell, CEM human leukemia cells or MCA-MB-435 people in preparation Application in the medicine of melanoma cell inhibitory activity.
The invention further relates to the compound I or its pharmaceutically acceptable salt, polymorph, solvate or solid Application of the isomers in the medicine with Human umbilical vein endothelial cells (HUVEC) inhibitory activity is prepared.
The carbamide compounds I or its pharmaceutically acceptable salt, polymorph, solvate or stereoisomer of the present invention Various forms of pharmaceutical compositions can be made with pharmaceutically acceptable carrier.The pharmaceutically acceptable carrier is included but not It is limited to various common medicinal supplementary materials (such as diluent, lubricant, disintegrant, adhesive and excipient)., can according to therapeutic purposes Various types of administration unit dosage forms are made in pharmaceutical composition, as tablet, capsule, pill, pulvis, solution, suspension, Emulsion agent, cream, syrup, granule, suppository and injection (solution and suspension) etc..
" 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, " C1-C10The definition of alkyl " either has 1,2,3,4,5,6,7,8,9 or 10 in branched structure to be included in straight chain The group of carbon atom.For example, " C1-C10Alkyl " specifically includes methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, secondary 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, and either part is unsaturated monocyclic, polycyclic or bridges carbocyclic ring substituent.With 3- The ring of 20 carbon atoms can be expressed as C3-C20Cycloalkyl；Ring with 5-15 carbon atom can be expressed as C5-C15Cycloalkanes Base；Ring with 3-8 carbon atom can be expressed as C3-C8Cycloalkyl, etc..The term includes but not limited to cyclopropyl, ring fourth Base, cyclopenta, cyclohexyl, suberyl, cyclooctyl, 1H- indenyls, indanyl, 1,2,3,4- tetrahydro-naphthalenyls, 5,6, 7,8- tetrahydro-naphthalenyls, 8,9- dihydro -7H- benzo ring heptene -6- bases, 6,7,8,9- tetrahydrochysene -5H- benzocycloheptas alkenyl, 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] are pungent Base, 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, adamantane Base, octahydro -4,7- methylene -1H- indenyls and octahydro -2,5- methylene-pentalene base etc..Naphthenic substituent can be with It is 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 connected. Thus, " alkoxy " includes the definition of above alkyl and cycloalkyl.
Term " alkenyl " refers to containing the straight chain, side chain or ring-type for specifying number carbon atom and at least one carbon-carbon double bond Non-aromatic alkyl.It is preferred that there are a carbon-carbon double bond, and there may be up to four non-aromatic carbon-carbon double bonds.Thus, " C2- C10Alkenyl " refers to the alkenyl with 2-10 carbon atom.“C2-C6Alkenyl " refers to the alkenyl with 2-6 carbon atom, including second Alkenyl, acrylic, cyclobutenyl, 2- methyl butenes base and cyclohexenyl group.Straight chain, side chain or the loop section of alkenyl can contain double Key, and if being shown to be substituted alkenyl, then it can be substituted.
Term " alkynyl " refers to containing the straight chain, side chain or ring-type for specifying number carbon atom and at least one triple carbon-carbon bonds Alkyl.Wherein there may be up to three triple carbon-carbon bonds.Thus, " C2-C10Alkynyl " refers to the alkynyl with 2-10 carbon atom. “C2-C6Alkynyl " refers to the alkynyl with 2-6 carbon atom, including acetenyl, propinyl, butynyl and 3- methylbutynyls etc. Deng.
" aryl " as used herein refer to any stabilization can be included in each ring the monocyclic, bicyclic of up to 7 atoms or Person's tricyclic carbocyclic ring, wherein at least one ring are 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 it is two in aryl substituent Ring substituents, 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 tricyclic, Wherein at least one ring is aromatic rings and the hetero atoms selected from O, N and S containing 1-4.Heteroaryl within the range defined herein Including but not limited to：Acridinyl, carbazyl, cinnoline base, quinoxalinyl, pyrazolyl, indyl, benzotriazole base, furyl, thiophene Fen base, benzothienyl, benzofuranyl, quinolyl, isoquinolyl, oxazolyl, isoxazolyls, indyl, pyrazinyl, pyridazine Base, pyridine radicals, pyrimidine radicals, pyrrole radicals, tetrahydroquinoline.As the definition of following heterocycle, " heteroaryl " is it should also be understood that be 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 is respectively by aromatic ring or ring-containing miscellaneous by wrapping Atom carries out.
In the present invention, term " heterocycle " as used herein or " heterocyclic radical " represent miscellaneous selected from O, N and S containing 1-4 The 5-10 members fragrance or nonaromatic heterocycles of atom, and including bicyclic groups.Therefore, " heterocyclic radical " include above-mentioned heteroaryl with And its dihydro or tetrahydrochysene analog.Other examples of " heterocyclic radical " include but not limited to following：Benzimidazolyl, benzofuran Base, benzofuraxan base, benzopyrazoles base, benzotriazole base, benzothienyl, benzoxazolyl, carbazyl, carboline base, cinnolines It is base, furyl, imidazole radicals, indolinyl, indyl, indazolyl, isobenzofuran-base, isoindolyl, isoquinolyl, different Thiazolyl, isoxazolyls, naphthalene pyrimidine radicals, oxadiazolyl, oxazolyl, oxazoline, isoxazolines, oxygen cyclobutyl, pyranose, pyrazine Base, pyrazolyl, pyridazinyl, pyridopyridine base, pyridazinyl, pyridine radicals, pyrimidine radicals, pyrrole radicals, quinazolyl, quinolyl, quinoline Quinoline base, THP trtrahydropyranyl, tetrazole radical, tetrazolo pyridine radicals, thiadiazolyl group, thiazolyl, thienyl, triazolyl, azetidin Alkyl, 1,4- alkyl dioxins, hexahydro azatropylidene base, piperazinyl, piperidyl, pyrrolidinyl, morpholinyl, thio-morpholinyl, dihydro Benzimidazolyl, dihydro benzo furyl, dihydrobenzo thienyl, Er hydrogen benzoxazolyl, dihydrofuran base, glyoxalidine Base, indolinyl, dihydro-isoxazole base, dihydro isothiazolyl, Er Qing oxadiazolyls, dihydro-oxazole base, dihydro pyrazine base, two Hydrogen pyrazolyl, dihydropyridine base, dihydro-pyrimidin base, pyrrolin base, dihydroquinoline base, dihydro tetrazole radical, thiodiazoline base, Dihydro-thiazolyl, dihydro-thiophene base, dihydro triazolyl, dihydro azetidinyl, methylenedioxyphenyl formoxyl, tetrahydrochysene furan Mutter 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, " haloalkyl " includes above halogen With the definition of alkyl.
Term " saturated heterocyclyl " represents that containing 1-4 is selected from the heteroatomic 4-9 members nonaromatic heterocycles base of O, N or S, and Including bicyclic groups, wherein not comprising unsaturated double-bond, saturated heterocyclyl substituent can be carried out through carbon atom or hetero atom Connection.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, each preferably up to the present invention Example.
Unless otherwise specified, the reagents and materials used in the present invention are commercially available.
The positive effect of the present invention is：Present invention finds a kind of brand-new carbamide compounds shown in formula I, It possesses stronger antitumor cell growth and anti-angiogenic rebirth activity, it with the relevant protein kinase of a variety of diseases for having Stronger inhibitory activity, also shows that preferable antitumor activity in animal body.
Embodiment
The present invention is further illustrated below by the mode of embodiment, but does not therefore limit the present invention to the reality Apply among a scope.The experimental method of actual conditions is not specified in the following example, according to conventional methods and conditions, or according to business Product specification selects.
Part I Chemical Example
Nuclear Magnetic Resonance is Varian companies INOVA-400, and hydrogen spectrum is measured under 400MHz；Mass spectrograph is Waters companies Micromass Q-Tof micro, electron spray ionisation (ESI).
1. A1 is serial
The 0 of 1.1 A1 series
The chloro- N- of 2- methyl -6- (4- nitrobenzophenones) pyrimidine -4- amine (A1-NO2-0)：
By 2- methyl -4,6- dichloro pyrimidine (81.56g, 0.5mol) and 4- nitroanilines (69.06g, 0.5mol) input water In (375mL) and acetone (125mL), add 12mol/L hydrochloric acid (9mL) and be stirred at reflux 2h.Filtered after being cooled to room temperature, filter cake water Wash, dry yellow crystal 6- chloro-2-methyls-N- (4- nitrobenzophenones) pyrimidine -4- amine hydrochlorates (A1-NO2-0.HCl) (123.9g, 82%).
Take A1-NO2-0.HCl (15.1g, 50mmol) to add in DMF (102mL), after being heated to 30 DEG C of stirring and dissolvings, add Enter anhydrous sodium acetate (4.17g, 50mmol), stir 10min, then plus water (1L) stirring is cooled to room temperature, and filtration drying obtains slightly Product.Gained crude product is recrystallized with n-butanol, filtration drying obtains yellow needles A1-NO2-0 (12.56g, 95%)：1HNMR (DMSO-d6)δ10.29(s,1H),8.17-8.19(m,2H),7.89-7.91(m,2H),6.75(s,1H),2.46(s,3H)
N1- (2- methyl -6- chlorine pyrimidine-4-yl) benzene -1,4- diamines (A1-NH2-0)
A1-NO2-0 (2.46g, 10mmol) is put into EtOH/H2O(2:1) (72mL) and glacial acetic acid (2.56g, 43mmol) In, the reduced iron powder (2.23g, 40mmol) through 1mol/L hydrochloric acid activations is put under reflux.30min is refluxed, is cooled to It is 9 that ammonium hydroxide is added after room temperature and is alkalized to pH, is filtered by diatomite.Filtrate is rotated, water (15mL) is added into gained residue, is used Ethyl acetate extracts.After combined ethyl acetate is dried over anhydrous sodium sulfate, rotate bois de rose crystalline A 1-NH2-0 (2.23g, 95%)：1HNMR(DMSO-d6) δ 9.17 (s, 1H), 7.50 (d, J=7.2Hz, 2H), 6.53-6.56 (m, 2H), 6.28 (s, 1H),4.91(br s,2H),2.32(s,3H)。
4- (2- methyl -6- chlorine pyrimidine-4-yls amido) anilino- formic acid (4- nitrobenzenes) ester hydrochloride (A1-CAR-0)
P-nitrophenyl chloroformate ester (1.21g, 6mmol) is dissolved in anhydrous methylene chloride (22mL).It is cooled to 0 DEG C, adds A1- NH2-0 (1.17g, 5mmol), rises to 20 DEG C of stirring 4.5h.Filter, wash, being dried in vacuo and to obtain yellow solid A1-CAR-0 (1.97g, 90%)：1HNMR(DMSO-d6)δ10.39(s,1H),9.76(s,1H,),8.30-8.32(m,2H),7.48-7.60 (m,6H),6.60(s,1H),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 anhydrous DMF (8mL), 5h is stirred at 40 DEG C.After gained salmon pink reaction solution is diluted with dichloromethane, 1mol/L sodium hydrate aqueous solutions and water washing are used successively, are 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 A1-1-0 (0.31g, 38%)：1HNMR (DMSO-d6) δ 9.56 (s, 1H), 8.83 (s, 1H), 8.68 (s, 1H), 7.78 (d, J=6.4Hz, 1H), 7.41-7.49 (m, 4H), 7.30 (d, J=8.0Hz, 1H), 6.52 (s, 1H), 2.41 (s, 3H).
The 1 of 1.2 A1 series
2- (4- (2- methyl -6- (4- nitrobenzenes amido) pyrimidine-4-yl) piperazine -1- bases) ethanol (A1-NO2-1)：
2- methyl -6- chloro- N- (4- nitrobenzophenones) pyrimidine -4- amine (0.51g, 1.9mmol) is dissolved in DMSO (30mL), is added Enter 2- (piperazine -1- bases) ethanol (2g, 15.4mmol), be heated to 130 DEG C of stirring 15min.It is cooled to room temperature, adds elutriation brilliant.Filtering Dry 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, 1H), 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- nitrobenzenes amido) pyrimidine-4-yl) piperazine -1- bases) ethyl acetate (A1-NO2-1A)：
A1-NO2-1 (0.36g, 1mmol) is dissolved in DMSO (5mL), adds acetic anhydride (0.15g, 1.5mmol) and DMAP (0.02g, 0.16mmol), is stirred at room temperature 1h, adds elutriation to go out flocculent deposit.Filtration drying obtain yellow crystalline powder (0.37g, 93%)：1H-NMR(DMSO-d6) δ 9.73 (s, 1H), 8.15 (d, J=9.2Hz, 2H), 7.88 (d, J=9.2Hz, 2H), 5.94 (s, 1H), 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-NO2-1A (0.96g, 2.4mmol) heating stirring is dissolved in EtOH/H2O(2:1) (45mL), adds through 1mol/ The reduced iron powder (0.54g, 9.6mmol) and glacial acetic acid (0.62g, 10.3mmol) of L hydrochloric acid activations.30min is refluxed, is added It is 8 that ammonium hydroxide, which alkalizes to pH, is filtered while hot by diatomite.Rotate filtrate and remove ethanol, obtained aqueous solution is extracted with ethyl acetate. Combined ethyl acetate, drabon color crystalline powder (0.76g, 85%) is rotated to obtain after anhydrous sodium sulfate drying：1H-NMR(DMSO- d6) 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- bases) pyrimidine-4-yl amido) benzene Base) urea (A1-1-1)
A1-NH2-1A (0.43g, 1.2mmol) and p-nitrophenyl chloroformate ester (0.25g, 1.2mmol) are dissolved in anhydrous CH2Cl2In (20mL), pyridine (0.14g, 1.8mmol) is added, 5min is stirred at room temperature under nitrogen protection, then adds the chloro- 4- of 3- Fluoroaniline (0.17g, 1.2mmol) and DIEA (0.53g, 4.1mmol) stirrings 48h.Added under agitation into gained reactant Hydrochloric acid (1mol/L, 24mL), separates out flocculent deposit, and filtration drying obtains 2- (4- (6- (4- (3- (the chloro- 4- fluorophenyls of 3-) urea groups) benzene Amido) -2- methylpyrimidine -4- bases) piperazine -1- bases)-ethyl acetate (A1-1-1A), for golden yellow powder：1H-NMR(DMSO- d6) δ 8.76 (s, 1H), 8.73 (s, 1H), 8.53 (s, 1H), 7.78-7.80 (m, 1H), 7.29-7.45 (m, 6H), 5.73 (s, 1H), 4.13 (m, 2H), 3.45 (m, 4H), 2.59 (m, 2H), 2.50 (m, 4H), 2.27 (s, 3H), 2.01 (s, 3H).
Take A1-1-1A (0.11g, 0.2mmol) to be dissolved in methanol (1mL), add 1mol/L sodium hydrate aqueous solutions (0.6mL) Solution stirs 3h.Revolving removes methanol, and ethyl acetate extracts gained residue, after being dried over anhydrous sodium sulfate and rotating, silica gel Column chromatography for separation, 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, 1H), 7.33- 7.43 (m, 5H), 7.28 (t, J=8.8Hz, 1H), 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)+。
1- (3- (trifluoromethyl) -4- chlorphenyls) -3- (4- (2- methyl -6- (4- (2- ethoxys) piperazine -1- bases) pyrimidine - 4- amino) phenyl) urea (A1-3-1)：
The chloro- 4- fluoroanilines of 3- are replaced with 3- (trifluoromethyl) -4- chloroanilines (0.47g, 2.4mmol), using similar to A1- The method of 1-1A prepares 2- (4- (6- (4- (3- (3- (trifluoromethyl) -4- chlorphenyls) urea groups) anilino-) -2- methylpyrimidines -4- Base) piperazine -1- bases) ethyl acetate (A1-3-1A).
A1-1-1A is replaced with A1-3-1A (0.12g, 0.2mmol), A1-3-1 is prepared using the method similar to A1-1-1, Obtain white powder (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, 1H), 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, 1H), 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)+。
1- (3- cyano-phenyls) -3- (4- (2- methyl -6- (4- (2- ethoxys) piperazine -1- bases) pyrimidine-4-yl amido) benzene Base) urea (A1-4-1)
The chloro- 4- fluoroanilines of 3- are replaced with 3- cyano-anilines (0.24g, 2.0mmol), using the method similar to A1-1-1A Prepare 2- (4- (2- methyl -6- (4- (3- (3- cyano-phenyls) urea groups) 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, Obtain micro-yellow powder (0.06g, 63%)：1H-NMR(DMSO-d6) δ 9.08 (s, 1H), 8.79 (s, 1H), 8.76 (s, 1H), 7.96 (m, 1H), 7.65-7.67 (m, 1H), 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)+。
1- (4- (2- methyl -6- (4- (2- ethoxys) piperazine -1- bases) pyrimidine-4-yl amido) phenyl) -3- (3- methylbenzenes Base) urea (A1-13-1)：
The chloro- 4- fluoroanilines of 3- are replaced with 3- methylanilines (0.13g, 1.2mmol), using the method similar to A1-1-1A Prepare 2- (4- (2- methyl -6- (4- (3- (3- tolyls) urea) anilino-) pyrimidine-4-yl) piperazine -1- bases) ethyl acetate (A1- 13-1A)：1H-NMR(CDCl3) δ 7.99 (s, 1H), 7.72 (br s, 2H), 7.33 (d, J=8.8Hz, 1H), 7.26 (m, 1H), 7.20-7.22 (m, 2H), 7.15 (t, J=7.6Hz, 1H), 6.98 (d, J=8.8Hz, 2H), 6.85 (d, J=7.6Hz, 1H), 5.51 (s, 1H), 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)。
A1-1-1A is replaced with A1-13-1A (0.1g, 0.2mmol), A1-13- is prepared using the method similar to A1-1-1 1, obtain white powder (0.06g, 66%)：1H-NMR(DMSO-d6) δ 8.72 (s, 1H), 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, 1H), 7.15 (t, J= 8Hz, 1H), 6.79 (d, J=6.8Hz, 1H), 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- (4- (2- methyl -6- (4- (2- ethoxys) piperazine -1- bases) pyrimidine-4-yl amido) phenyl) -3- isobutyl group ureas (A1-19-1)：
The chloro- 4- fluoroanilines of 3- are replaced with isobutyl amine (0.24g, 2.0mmol), using the method preparation similar to A1-1-1A 2- (4- (2- methyl -6- (4- (3- isobutyl groups urea groups) anilino-) pyrimidine-4-yl) piperazine -1- bases) ethyl acetate (A1-19- 1A)。
A1-1-1A is replaced with A1-19-1A (0.09g, 0.2mmol), A1-19- is prepared using the method similar to A1-1-1 1, obtain light yellow powder solid (0.06g, 70%)：1H-NMR(DMSO-d6) δ 8.62 (s, 1H), 8.20 (s, 1H), 7.34 (d, J=8.8Hz, 2H), 7.28 (d, J=8.8Hz, 2H), 6.06 (t, J=8.8Hz, 1H), 5.69 (s, 1H), 4.35 (br s, 1H), 3.51-3.55 (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,1H),0.88(s,3H),0.87(s,3H)；MS-ESI:m/z 428(M+H)+,855(2M+H)+。
The 2 of 1.3 A1 series
2- methyl -6- morpholinyls-N- (4- nitrobenzophenones) pyrimidine -4- amine (A1-NO2-2)：
A1-NO2-0.HCl (36g, 0.12mol), morpholine (60mL, 0.68mol) and several potassium iodide crystal are stirred back Flow 7.5h.Revolving, filtering gained residue, filter cake washing, dry crude product, yellow solid A1-NO2-2 is beaten to obtain through toluene (37.83g, 100%)：1HNMR(DMSO-d6) δ 9.77 (s, 1H), 8.14 (d, J=9.2Hz, 4H), 7.89 (d, J=9.2Hz, 4H), 5.95 (s, 1H), 3.67 (t, J=4.8Hz, 4H), 3.49 (t, J=4.8Hz, 4H), 2.37 (s, 3H).
N1- (2- methyl -6- morpholinyls pyrimidine-4-yl) benzene -1,4- diamines (A1-NH2-2)
By in A1-NO2-2 (6.3g, 20mmol), 7% palladium charcoal (dry powder, 0.63g) input methanol (180mL), at 40 DEG C and 1.5h is hydrogenated under 4bar pressure.Filtered after being cooled to room temperature, filter cake is extracted with DMF (30mL).Merging filtrate and DMF extracting solutions, It is concentrated under reduced pressure, obtained solid residue is beaten through cold absolute ethyl alcohol, obtains yellow crystal A1-NH2-2 (5.64g, 99%)：1HNMR (DMSO-d6) δ 8.30 (s, 1H), 7.03 (d, J=8.4Hz, 4H), 6.53 (d, J=8.4Hz, 4H), 5.53 (s, 1H), 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- nitrobenzenes) ester hydrochloride (A1-CAR- 2)
P-nitrophenyl chloroformate ester (2.42g, 12mmol) is dissolved in anhydrous methylene chloride (30mL).It is cooled to 0 DEG C, throws in batches Enter A1-NH2-2 (2.80g, 10mmol), rise to 20 DEG 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 (0.16g, 1.1mmol) of A1-CAR-2 (0.49g, 1mmol), 3- and triethylamine (0.29g, 2.9mmol) it is added in anhydrous DMF (4mL), 5.5h is stirred at 40 DEG C.By gained yellow reaction thing with dichloromethane (100mL) After dilution, successively with 1mol/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%)：1HNMR (DMSO-d6) δ 8.77 (s, 1H), 8.75 (s, 1H), 8.54 (s, 1H), 7.74 (d, J=6.8Hz, 1H), 7.29-7.45 (m, 6H),5.73(s,1H),3.65(m,4H),3.42(m,4H),2.29(s,3H)；MS-ESI(m/z)457(M+H)+,913(2M+ H)+。
1- (3- (trifluoromethyl) -4- chlorphenyls) -3- (4- (2- methyl -6- morpholinyl pyrimidine-4-yls amido) phenyl) urea (A1-3-2)
The chloro- 4- fluoroanilines of 3- are replaced with 3- (trifluoromethyl) -4- chloroanilines (0.22g, 1.1mmol), using similar to A1- The method of 1-2 prepares A1-3-2, obtains white crystals (0.13g, 25%)：1HNMR(DMSO-d6)δ9.03(s,1H),8.79(s, 1H), 8.61 (s, 1H), 8.09 (s, 1H), 7.57-7.61 (m, 2H), 7.45 (d, J=8.4Hz, 2H), 7.35 (d, J= 8.8Hz,2H),5.73(s,1H),3.65(m,4H),3.41(m,4H),2.28(s,3H)；MS-ESI(m/z)507(M+H)+, 1013(2M+H)+。
1- (3- cyano-phenyls) -3- (4- (2- methyl -6- morpholinyl pyrimidine-4-yls amido) phenyl) urea (A1-4-2)
The chloro- 4- fluoroanilines of 3- are replaced with 3- cyano-anilines (0.19g, 1.65mmol), using the method similar to A1-1-2 A1-4-2 is prepared, obtains white powder (0.25g, 39%)：1HNMR(DMSO-d6)δ8.91(s,1H),8.79(s,1H),8.62(s, 1H), 7.96 (s, 1H), 7.66 (d, J=7.6Hz, 1H), 7.35-7.50 (m, 6H), 5.74 (s, 1H), 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) pyrrole Pyridine -2- formamides (A1-6-2)
The chloro- 4- fluorobenzene of 3- is replaced with 4- (4- amino-benzene oxygens)-N- picoline -2- formamides (0.27g, 1.1mmol) Amine, prepares A1-6-2 using the method similar to A1-1-2, obtains near-white powder (0.49g, 89%)：1HNMR(DMSO-d6)δ 8.76 (s, 1H), 8.71 (s, 1H), 8.68 (br s, 1H), 8.50 (s, 1H), 8.49 (s, 1H), 7.57 (d, J=8.8Hz, 2H),7.36-7.45(m,5H),7.13-7.15(m,3H),5.73(s,1H),3.65(m,4H),3.42(m,4H),2.80(d,J =4.4Hz, 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)+。
1- (2- fluorophenyls) -3- (4- (2- methyl -6- morpholinyl pyrimidine-4-yls amido) phenyl) urea (A1-7-2)
The chloro- 4- fluoroanilines of 3- are replaced with 2- fluoroanilines (0.18g, 1.65mmol), using the method system similar to A1-1-2 Standby A1-7-2, obtains white powder (0.22g, 35%)：1HNMR(DMSO-d6)δ8.89(s,1H),8.77(s,1H),8.43(s, 1H), 8.13-8.17 (m, 1H), 7.45 (d, J=8.8Hz, 2H), 7.36 (d, J=8.8Hz, 2H), 7.22 (m, 1H), 7.13 (m,1H),7.00(m,1H),5.73(s,1H),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)+。
1- (4- fluorophenyls) -3- (4- (2- methyl -6- morpholinyl pyrimidine-4-yls amido) phenyl) urea (A1-8-2)
The chloro- 4- fluoroanilines of 3- are replaced with 4- fluoroanilines (0.18g, 1.65mmol), using the method system similar to A1-1-2 Standby A1-8-2, obtains white solid (0.14g, 22%)：1HNMR(DMSO-d6)δ8.75(s,1H),8.58(s,1H),8.45(s, 1H),7.33-7.46(m,6H),7.09(m,2H),5.72(s,1H),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)+。
1- (4- (2- methyl -6- morpholinyl pyrimidine-4-yls amido) phenyl) -3- (5- picoline -2- bases) urea (A1-10- 2)
The chloro- 4- fluoroanilines of 3- are replaced with 5- picoline -2- amine (0.12g, 1.1mmol), using similar to A1-1-2's Method prepares A1-10-2, obtains white solid (0.11g, 26%)：1HNMR(DMSO-d6)δ10.32(s,1H),9.22(s,1H), 8.80(s,1H),8.10(m,1H),7.37-7.58(m,6H),5.74(s,1H),3.65(m,4H),3.42(m,4H),2.29 (s,3H),2.23(s,3H)；MS-ESI(m/z)420(M+H)+。
1- cyclohexyl -3- (4- (2- methyl -6- morpholinyl pyrimidine-4-yls amido) phenyl) urea (A1-11-2)
The chloro- 4- fluoroanilines of 3- are replaced with cyclohexylamine (0.16g, 1.65mmol), using the method preparation similar to A1-1-2 A1-11-2, obtains near-white solid (0.39g, 63%)：1HNMR(DMSO-d6)δ8.66(s,1H),8.10(s,1H),7.30(dd, J=8.8,24.8Hz, 1H), 5.94 (d, J=7.6Hz, 1H), 3.64 (m, 4H), 3.47 (m, 1H), 3.45 (m, 4H), 2.27 (s,3H),1.11-1.81(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 (A1-12-2)
The chloro- 4- fluoroanilines of 3- are replaced with morpholine (0.14g, 1.65mmol), A1- is prepared using the method similar to A1-1-2 12-2, obtains near-white solid (0.26g, 43%)：1HNMR(DMSO-d6)δ8.72(s,1H),8.36(s,1H),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 pyrimidine (32.62g, 0.2mol) and 3- nitroanilines (27.62g, 0.2mol) input water In (150mL) and acetone (50mL), add 12mol/L concentrated hydrochloric acids (4mL) and be stirred at reflux 2h.Filtered after being cooled to room temperature, filter cake water Wash, dry bright yellow solid A2-NO2-0.HCl (50.6g, 84%).
A2-NO2-0.HCl (16.42g, 54.5mmol) is taken to be dissolved in glacial acetic acid (90mL) and DMF (140mL) in 90 DEG C of stirrings In, anhydrous sodium acetate (4.48g, 54.6mmol) is added, is filtered while hot.Adding water (1.2L) into filtrate, stirring is cooled to room temperature, Filtration drying obtains crude product.Crude product recrystallizes to obtain yellow crystal (12.31g, 85%) through n-butanol：1HNMR(DMSO-d6)δ10.15 (s, 1H), 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- nitrobenzenes) ester hydrochloride (A2-CAR-0)
By A2-NO2-0 (1.44g, 5.44mmol), the reduced iron powder (1.9g, 32.64mmol) through 1mol/L hydrochloric acid activations With ammonium chloride (0.29g, 5.44mmol) input EtOH (90mL), THF (30mL) and H2The in the mixed solvent of O (15mL) compositions, 3.5h is refluxed, is filtered after slightly cold by diatomite.Filtrate is rotated, by gained residue in water (50mL) and ethyl acetate Distributed between (100mL), divide and take organic phase, water is mutually extracted with ethyl acetate again.Combined ethyl acetate, it is water-soluble through saturated sodium-chloride After liquid washing, anhydrous sodium sulfate drying, foam-like A2-NH2-0 (1.38g, 108%) is rotated to obtain.
Above-mentioned gained A2-NH2-0 is dissolved in anhydrous methylene chloride (19mL).It is cooled to 0 DEG C, adds p-nitrophenyl chloroformate ester Anhydrous methylene chloride (10mL) solution of (1.42g, 7mmol), is warmed to room temperature stirring 2.5h.Filter, wash, being dried in vacuo yellow Color solid A2-CAR-0 (2.27g, 96%)：1HNMR(DMSO-d6) δ 10.45 (s, 1H), 9.91 (s, 1H), 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,1H),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 (0.24g, 1.65mmol) of A2-CAR-0 (0.65g, 1.5mmol), 3- and triethylamine (0.46g, 4.5mmol) is added in anhydrous DMF (6mL), and 5.5h is stirred at 40 DEG C.By gained reaction solution dichloromethane After (90mL) dilution, successively with 0.5mol/L sodium hydrate aqueous solutions and water washing, rotated after anhydrous sodium sulfate drying.Gained is residual Thing silica gel column chromatography is stayed, with ethyl acetate：Petroleum ether (1：10~1：1) gradient elution, obtain yellowish solid A2-1-0 (0.36g, 60%)：1HNMR(DMSO-d6) δ 9.68 (s, 1H), 8.80 (s, 1H), 8.72 (s, 1H), 7.78 (dd, J=2,8Hz, 2H), 7.29-7.31 (m, 3H), 7.23 (t, J=8Hz, 1H), 7.11 (d, J=8Hz, 1H), 6.63 (s, 1H), 2.43 (s, 3H)；MS- ESI(m/z)406(M+H)+。
1- (3- (2- methyl -6- chlorine pyrimidine-4-yls amido) phenyl) -3- (3- (trifluoromethyl) -4- chlorphenyls) urea (A2- 3-0)
The chloro- 4- fluoroanilines of 3- are replaced with 3- (trifluoromethyl) -4- chloroanilines (0.32g, 1.65mmol), using similar to The method of A2-1-0 prepares A2-3-0, obtains faint yellow solid (0.12g, 18%)：1HNMR(DMSO-d6)δ9.70(s,1H),9.09 (s, 1H), 8.81 (s, 1H), 8.13 (s, 1H), 7.83 (s, 1H), 7.60 (m, 2H), 7.34 (d, J=8Hz, 1H), 7.22- 7.26 (m, 1H), 7.10 (d, J=8Hz, 1H), 6.64 (s, 1H), 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- (pyrrolidin-1-yl) butyl) urea (A2-18- 0)
The chloro- 4- fluoroanilines of 3- are replaced with 4- (pyrrolidin-1-yl) butyl- 1- amine (0.18g, 1.2mmol), using similar to The method of A2-1-0 prepares A2-18-0, obtains yellow oil (0.12g, 30%)：1HNMR(DMSO-d6)δ9.62(s,1H), 8.37 (s, 1H), 7.68 (s, 1H), 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)+。
1- (3- (2- methyl -6- chlorine pyrimidine-4-yls amido) phenyl) -3- isobutyl groups urea (A2-19-0)
The chloro- 4- fluoroanilines of 3- are replaced with isobutyl amine (0.09g, 1.2mmol), using the method preparation similar to A2-1-0 A2-19-0, obtains white solid (0.13g, 39%)：1HNMR(DMSO-d6)δ9.62(s,1H),8.36(s,1H),7.68(s, 1H), 7.15-7.24 (m, 2H), 7.04 (d, J=8Hz, 1H), 6.61 (s, 1H), 6.12-6.15 (m, 1H), 2.91-2.94 (m, 2H),2.43(s,3H),1.70(m,1H),0.89(s,3H),0.87(s,3H)；MS-ESI(m/z)334(M+H)+,356(M+ Na)+,689(2M+Na)+。
The 1 of 2.2 A2 series
2- (4- (2- methyl -6- (3- nitrobenzenes amido) pyrimidine-4-yl) piperazine -1- bases) ethyl acetate (A2-NO2-1A)：
2- methyl -6- chloro- N- (3- nitrobenzophenones) pyrimidine -4- amine (3.99g, 15mmol) is taken to be dissolved in DMSO (30mL), 2- (piperazine -1- bases) ethanol (15.6g, 0.12mol) is added, 15min is stirred at 130 DEG C.Add elutriation brilliant, salmon pink is obtained by filtration Precipitate A 2-NO2-1.DMSO (10mL) is dissolved in, adds the DMAP of acetic anhydride (2.30g, 0.023mol) and catalytic amount (0.15g, 1.2mmol), is stirred at room temperature 5h, adds elutriation brilliant, filtration drying obtains apricot powder (4.07g, 68%).
2- (4- (2- methyl -6- (3- aminobenzenes amido) pyrimidine-4-yl) piperazine -1- bases) ethyl acetate (A2-NH2-1A)
A2-NO2-1A (0.96g, 2.4mmol) heating stirring is dissolved in EtOH/H2O(2:1) (50mL), adds through 1mol/ The reduced iron powder (0.54g, 9.6mmol) and glacial acetic acid (0.62g, 10.3mmol) of L hydrochloric acid activations.30min is refluxed, is added It is 8 that ammonium hydroxide, which alkalizes to pH, is filtered while hot by diatomite.Rotate filtrate and remove ethanol, obtained aqueous solution is extracted with ethyl acetate. Combined ethyl acetate, rotates after anhydrous sodium sulfate drying, obtains 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- bases amido) Phenyl) urea (A2-1-1)
A2-NH2-1A (0.78g, 2.1mmol) and p-nitrophenyl chloroformate ester (0.46g, 2.1mmol) are dissolved in anhydrous CH2Cl2In (20mL), pyridine (0.25g, 3.2mmol) is added, 5min is stirred at room temperature under nitrogen protection, then adds the chloro- 4- of 3- Fluoroaniline (0.31g, 2.1mmol) and DIEA (0.96g, 7.4mmol) stirrings 48h.Added under agitation into gained reactant Hydrochloric acid (1mol/L, 24mL), separates out flocculent deposit, and filtration drying obtains 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), crystallized for light yellowish brown：1H-NMR (DMSO-d6) δ 8.88 (s, 1H), 8.80 (s, 1H), 8.64 (s, 1H), 7.81-7.83 (m, 1H), 7.73 (s, 1H), 7.28- 7.31 (m, 2H), 7.15-7.17 (m, 2H), 6.95-6.96 (m, 1H), 5.94 (s, 1H), 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 (s, 3H), 2.00 (s, 3H).MS- ESI:m/z 542(M+H)+,564(M+Na)+。
A1-1-1A is replaced with A2-1-1A (0.11g, 0.2mmol), A2-1-1 is prepared using the method similar to A1-1-1, Obtain Beige powder A2-1-1 (0.07g, 67%)：1H-NMR(DMSO-d6) δ 8.90 (s, 1H), 8.84 (s, 1H), 8.68 (s, 1H), 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)+。
1- (3- (trifluoromethyl) -4- chlorphenyls) -3- (3- (2- methyl -6- (4- (2- ethoxys) piperazine -1- bases) pyrimidine - 4- amino) phenyl) urea (A2-3-1)
The chloro- 4- fluoroanilines of 3- are replaced with 3- (trifluoromethyl) -4- chloroanilines (0.36g, 1.8mmol), using similar to A2- The method of 1-1A prepares 2- (4- (2- methyl -6- (3- (3- (3- (trifluoromethyl) -4- chlorphenyls) uride) anilino-) pyrimidine -4- Base) piperazine -1- bases) ethyl acetate (A2-3-1A).
A2-1-1A is replaced with A2-3-1A (0.18g, 0.3mmol), A2-3-1 is prepared using the method similar to A2-1-1, Obtain yellowish crystalline powder A2-3-1 (0.12g, 73%)：1H-NMR(DMSO-d6) δ 9.38 (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, 1H), 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)+。
1- (3- cyano-phenyls) -3- (3- (2- methyl -6- (4- (2- ethoxys) piperazine -1- bases) pyrimidine-4-yl amido) benzene Base) urea (A2-4-1)
The chloro- 4- fluoroanilines of 3- are replaced with 3- cyano-anilines (0.27g, 2.3mmol), using the method similar to A2-1-1A Prepare 2- (4- (2- methyl -6- (3- (3- (3- cyano-phenyls) urea groups) anilino-) pyrimidine-4-yl) piperazine -1- bases)-acetic acid second Ester (A2-4-1A), is buff powder：1H-NMR(CDCl3) δ 8.63 (s, 1H), 8.42 (s, 1H), 7.86 (s, 1H), 7.56 (d, J=8.4Hz, 1H), 7.23-7.33 (m, 4H), 7.12 (t, J=8Hz, 1H), 6.98 (d, J=8Hz, 1H), 6.71 (dd, J =1.2,8Hz, 1H), 5.89 (s, 1H), 4.17-4.22 (m, 2H), 3.65-3.68 (m, 3H), 3.56-3.61 (m, 1H), 2.46-2.69(m,6H),2.42(s,3H),2.05(s,3H)。
A2-1-1A is replaced with A2-4-1A (0.15g, 0.3mmol), A2-4-1 is prepared using the method similar to A2-1-1, Obtain near-white crystalline powder A2-4-1 (0.09g, 63%)：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)+。
1- (3- (2- methyl -6- (4- (2- ethoxys) piperazine -1- bases) pyrimidine-4-yl amido) phenyl) -3- (3- toluene Base) urea (A2-13-1)
The chloro- 4- fluoroanilines of 3- are replaced with 3- methylanilines (0.23g, 2.1mmol), using the method similar to A2-1-1A Prepare 2- (4- (2- methyl -6- (3- (3- (3- aminomethyl phenyls) urea groups) anilino-) pyrimidine-4-yl) piperazine -1- bases)-acetic acid second Ester (A2-13-1A)：1H-NMR(DMSO-d6) δ 8.86 (s, 1H), 8.54 (s, 1H), 8.51 (s, 1H), 7.73 (s, 1H), 7.29 (s,1H),7.21(m,1H),7.13-7.16(m,3H),6.95-6.96(m,1H),6.78-6.79(m,1H),5.95(s,1H), 4.13 (t, J=6Hz, 2H), 3.48-3.50 (m, 4H), 2.59 (t, J=6Hz, 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 A2-13-1A (0.1g, 0.2mmol), A2-13- is prepared using the method similar to A2-1-1 1, obtain yellowish crystalline A 2-13-1 (0.09g, 90%)：1H-NMR(DMSO-d6) δ 8.87 (s, 1H), 8.57 (s, 1H), 8.54 (s, 1H), 7.73 (s, 1H), 7.29 (s, 1H), 7.23 (d, J=8Hz, 1H), 7.13-7.16 (m, 3H), 6.95-6.97 (m, 1H), 6.79 (d, J=7.6Hz, 1H), 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- (3- (2- 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- are prepared using the method similar to A2-1-1A (3- (3- isobutyl groups urea groups) anilino-) pyrimidine-4-yl) piperazine -1- bases) ethyl acetate (A2-19-1A)：1H-NMR(CDCl3)δ 7.56 (s, 2H), 7.26 (s, 1H), 7.15 (t, J=8.0Hz, 1H), 7.04 (d, J=8.0Hz, 1H), 6.75-6.77 (m, 1H), 5.85 (s, 1H), 5.57 (m, 1H), 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, 1H), 0.94 (s,3H),0.92(s,3H)。
A1-1-1A is replaced with A2-19-1A (0.38g, 0.8mmol), A2-19- is prepared using the method similar to A1-1-1 1, obtain yellowish crystallization (0.26g, 76%)：1H-NMR(DMSO-d6)δ8.79(s,1H),8.28(s,1H),7.62(s,1H), 7.06-7.09(m,2H),6.89-6.93(m,1H),6.11-6.14(m,1H),5.90(s,1H),4.36(br s,1H), 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,1H),0.88(s,3H),0.87(s,3H)；MS-ESI:m/z 428(M+H)+,855(2M+H)+。
The 2 of 2.3 A2 series
2- methyl -6- morpholinyls-N- (3- nitrobenzophenones) pyrimidine -4- amine (A2-NO2-2)：
A2-NO2-0.HCl (9g, 0.03mol), morpholine (15mL, 0.17mol) and several potassium iodide crystal are stirred at reflux 8h.Revolving, filtering gained residue, filter cake washing, dry crude product, orange crystals A2-NO2-2 is obtained through re crystallization from toluene (9.1g, 96%)：1HNMR(DMSO-d6) δ 9.47 (s, 1H), 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, 1H), 3.67 (t, J=4.8Hz, 4H), 3.47 (t, J= 4.8Hz,4H),2.35(s,3H)。
N1- (2- methyl -6- morpholinyls pyrimidine-4-yl) benzene -1,3- diamines (A2-NH2-2)
A2-NO2-2 (6.3g, 20mmol), Raney Ni (about 1.5g) are put into absolute ethyl alcohol (180mL), at 60 DEG C 4h is hydrogenated with 4bar pressure.Filtering, filter cake DMF (50mL) and absolute ethyl alcohol (200mL) mixed solvent refluxing extraction.Merge Filtrate and extracting solution, are cooled to room temperature stirring and crystallizing, filter, be dried in vacuo pistac crystalline A 2-NH2-2 (3.87g, 68%)：1HNMR(DMSO-d6) δ 8.59 (s, 1H), 6.91 (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, 1H), 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-yls amido) anilino- formic acid (4- nitrobenzenes) ester hydrochloride (A2-CAR- 2)
P-nitrophenyl chloroformate ester (1.22g, 6mmol) is dissolved in anhydrous methylene chloride (26mL).It is cooled to 0 DEG C, point 3 batches of throwings Enter A2-NH2-2 (1.40g, 5mmol), rise to 20 DEG C of stirring 3.5h.Filter, wash, being dried in vacuo and to obtain near-white solid A2- CAR-2 (2.15g, 88%)：1HNMR(DMSO-d6)δ10.60(s,1H),10.05(s,1H),8.31-8.33(m,2H),7.68 (s, 1H), 7.53-7.56 (m, 2H), 7.32-7.41 (m, 2H), 7.11 (d, J=7.2Hz, 1H), 6.03 (s, 1H), 3.65 (m, 8H),2.47(s,3H)。
1- (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 (0.32g, 2.2mmol) of A2-CAR-2 (0.98g, 2mmol), 3- and triethylamine (0.57g, 5.6mmol) it is added in anhydrous DMF (8mL), 4.25h is stirred at 40 DEG C.By gained brown color reactant dichloromethane After (90mL) dilution, successively with 1mol/L sodium hydrate aqueous solutions and water washing, rotated after anhydrous sodium sulfate drying.Gained remains Thing silica gel column chromatography, with ethyl acetate：Ethanol (100：0~100：6) gradient elution, obtain white solid A2-1-2 (0.65g, 71%)：1HNMR(DMSO-d6) δ 8.91 (s, 1H), 8.78 (s, 1H), 8.63 (s, 1H), 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,1H),5.93(s,1H),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)+。
1- (2,3- dichlorophenyls) -3- (3- (2- methyl -6- morpholinyl pyrimidine-4-yls amido) phenyl) urea (A2-2-2)
The chloro- 4- fluoroanilines of 3- are replaced with 2,3- dichloroanilines (0.36g, 2.2mmol), using the method similar to A2-1-2 A2-2-2 is prepared, obtains white solid (0.09g, 9%)：1HNMR(DMSO-d6)δ9.38(s,1H),8.96(s,1H),8.43(s, 1H), 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, 1H), 3.67(m,4H),3.47(m,4H),2.32(s,3H)；MS-ESI(m/z)473(M+H)+,495(M+Na)+。
1- (3- (trifluoromethyl) -4- chlorphenyls) -3- (3- (2- methyl -6- morpholinyl pyrimidine-4-yls amido) phenyl) urea (A2-3-2)
The chloro- 4- fluoroanilines of 3- are replaced with 3- (trifluoromethyl) -4- chloroanilines (0.43g, 2.2mmol), using similar to A2- The method of 1-2 prepares A2-3-2, obtains near-white solid (0.25g, 25%)：1HNMR(DMSO-d6)δ9.07(s,1H),8.95(s, 1H), 8.72 (s, 1H), 8.13 (s, 1H), 7.77 (s, 1H), 7.61 (s, 1H), 7.24 (d, J=8.8Hz, 1H), 7.18 (t, J =8.4Hz, 1H), 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)+。
1- (3- cyano-phenyls) -3- (3- (2- methyl -6- morpholinyl pyrimidine-4-yls amido) phenyl) urea (A2-4-2)
The chloro- 4- fluoroanilines of 3- are replaced with 3- cyano-anilines (0.28g, 2.2mmol), using the method system similar to A2-1-2 Standby A2-4-2, obtains white solid (0.40g, 47%)：1HNMR(DMSO-d6)δ8.94(s,2H),8.72(s,1H),7.98(s, 1H), 7.74 (s, 1H), 7.66 (d, J=8Hz, 1H), 7.49 (t, J=8Hz, 1H), 7.41 (d, J=7.6Hz, 1H), 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) pyrrole Pyridine -2- formamides (A2-6-2)
The chloro- 4- fluorobenzene of 3- is replaced with 4- (4- amino-benzene oxygens)-N- picoline -2- formamides (0.54g, 2.2mmol) Amine, prepares A2-6-2 using the method similar to A2-1-2, obtains white powder (0.66g, 60%)：1HNMR(DMSO-d6)δ8.93 (s, 1H), 8.75 (s, 1H), 8.68 (m, 1H), 8.61 (s, 1H), 8.50 (d, J=5.2Hz, 1H), 7.58 (m, 2H), 7.41 (m, 1H), 7.13-7.22 (m, 5H), 7.02 (m, 1H), 5.94 (s, 1H), 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)+。
1- (3- (2- methyl -6- morpholinyl pyrimidine-4-yls amido) phenyl) -3- (5- picoline -2- bases) urea (A2-10- 2)
The chloro- 4- fluoroanilines of 3- are replaced with 5- picoline -2- amine (0.18g, 1.65mmol), using similar to A2-1-2's Method prepares A2-10-2, obtains pale yellow crystals (0.29g, 46%)：1HNMR(DMSO-d6)δ10.30(s,1H),9.25(s, 1H), 8.96 (s, 1H), 8.09 (s, 1H), 7.85 (s, 1H), 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)
The chloro- 4- fluoroanilines of 3- are replaced with cyclohexylamine (0.17g, 1.65mmol), using the method preparation similar to A2-1-2 A2-11-2, obtains white crystals (0.30g, 48%)：1HNMR(DMSO-d6)δ8.84(s,1H),8.18(s,1H),7.60(s, 1H), 7.09 (d, 2H, J=5.2Hz), 6.91-6.93 (m, 1H), 6.00 (d, J=7.6Hz, 1H), 5.90 (s, 1H), 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)
The chloro- 4- fluoroanilines of 3- are replaced with morpholine (0.15g, 1.65mmol), A2- is prepared using the method similar to A2-1-2 12-2, obtains white crystals (0.44g, 73%)：1HNMR(DMSO-d6)δ8.84(s,1H),8.45(s,1H),7.64(s,1H), 7.10-7.18 (m, 2H), 6.96 (d, 1H, 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)+。
1- (3- (2- methyl -6- morpholinyl pyrimidine-4-yls amido) phenyl) -3- (3- tolyls) urea (A2-13-2)
The chloro- 4- fluoroanilines of 3- are replaced with 3- methylanilines (0.18g, 1.65mmol), using the method similar to A2-1-2 A2-13-2 is prepared, obtains white powder (0.32g, 51%)：1HNMR(DMSO-d6)δ8.92(s,1H),8.54(s,1H),8.51 (s, 1H), 7.73 (s, 1H), 7.30 (s, 1H), 7.15-7.21 (m, 4H), 6.98 (d, 1H, J=7.2Hz), 6.80 (d, 1H, J =7.6Hz), 5.95 (s, 1H), 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)+。
1- (3,5- bis- (trifluoromethyl) phenyl) -3- (3- (2- methyl -6- morpholinyl pyrimidine-4-yls amido) phenyl) urea (A2-14-2)
The chloro- 4- fluoroanilines of 3- are replaced with 3,5- bis- (trifluoromethyl) aniline (0.38g, 1.65mmol), using similar to A2- The method of 1-2 prepares A2-14-2, obtains buff powder (0.10g, 12%)：1HNMR(DMSO-d6)δ9.34(s,1H),9.00 (s,1H),8.90(s,1H),8.13(s,2H),7.79(s,1H),7.62(s,1H),7.20-7.24(m,2H),7.00(m, 1H),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)+。
1- (2,5- difluorophenyls) -3- (3- (2- methyl -6- morpholinyl pyrimidine-4-yls amido) phenyl) urea (A2-15-2)
The chloro- 4- fluoroanilines of 3- are replaced with 2,5- difluoroanilines (0.22g, 1.65mmol), using the side similar to A2-1-2 Method prepares A2-15-2, obtains faint yellow acicular crystal (0.08g, 12%)：1HNMR(DMSO-d6)δ9.06(s,1H),8.96(s, 1H), 8.71 (s, 1H), 8.01-8.06 (m, 1H), 7.76 (s, 1H), 7.16-7.31 (m, 3H), 6.97 (d, J=7.2Hz, 1H),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)+。
1- (2- methyl -5- fluorophenyls) -3- (3- (2- methyl -6- morpholinyl pyrimidine-4-yls amido) phenyl) urea (A2-16- 2)
The chloro- 4- fluoroanilines of 3- are replaced with 2- methyl -5- fluoroanilines (0.22g, 1.76mmol), using similar to A2-1-2's Method prepares A2-16-2, obtains white solid (0.23g, 35%)：1HNMR(DMSO-d6)δ8.93(s,1H),8.70(s,1H), 8.59 (s, 1H), 7.73 (t, J=2Hz, 1H), 7.43 (dd, J=2,12Hz, 1H), 7.13-7.17 (m, 3H), 7.00 (dd, J =2.4,8Hz, 1H), 6.95-6.97 (m, 1H), 5.95 (s, 1H), 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)
The chloro- 4- fluoroanilines of 3- are replaced with thiazolamine (0.17g, 1.65mmol), using the method similar to A2-1-2 A2-17-2 is prepared, obtains light yellow solid (0.27g, 44%)：1HNMR(DMSO-d6)δ10.39(br s,1H),8.99(s,1H), 8.87 (s, 1H), 7.83 (s, 1H), 7.37 (d, J=3.2Hz, 1H), 7.26 (d, J=8.4Hz, 1H), 7.10-7.21 (m, 2H), 6.97 (d, J=8.4Hz, 1H), 5.93 (s, 1H), 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- (pyrrolidin-1-yl) butyl) urea (A2-18-2)
The chloro- 4- fluoroanilines of 3- are replaced with 4- (pyrrolidin-1-yl) butyl- 1- amine (0.26g, 1.8mmol), using similar to The method of A2-1-2 prepares A2-18-2, obtains light yellow solid (0.31g, 46%)：1HNMR(DMSO-d6)δ8.83(s,1H), 8.27(s,1H),7.62(s,1H),7.08-7.10(m,2H),6.90-6.93(m,1H),6.08(m,1H),5.90(s,1H), 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)
The chloro- 4- fluoroanilines of 3- are replaced with isobutyl amine (0.13g, 1.8mmol), using the method preparation similar to A2-1-2 A2-19-2, obtains white crystals (0.41g, 71%)：1HNMR(DMSO-d6)δ8.84(s,1H),8.27(s,1H),7.62(s, 1H), 7.09-7.10 (m, 2H), 6.91-6.93 (m, 1H), 6.11 (t, J=5.6Hz, 1H), 5.90 (s, 1H), 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, 1H), 0.88 (s,3H),0.81(s,3H)；MS-ESI(m/z)385(M+H)+,769(2M+H)+。
The 3 of 2.4 A2 series
2- methyl -6- (4- methylpiperazine-1-yls)-N- (3- nitrobenzophenones) pyrimidine -4- amine (A2-NO2-3)
By A2-NO2-0.HCl (4.5g, 15mmol), 1- methyl piperazines (12g, 120mmol) and DMSO (30mL) 140 ~150 DEG C of stirring 0.5h.Gained reactant is cooled to room temperature, is poured under agitation in water (225mL), continues mistake after stirring 1h Filter, filter cake washing, dry crude product, yellowish-brown crystalline A 2-NO2-3 (4.9g, 100%) is obtained through 95% ethyl alcohol recrystallization：1HNMR (DMSO-d6) δ 9.44 (s, 1H), 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, 1H), 3.50 (t, J=4.8Hz, 4H), 2.37 (t, J=4.8Hz, 4H),2.35(s,3H),2.22(s,3H)。
N1- (2- methyl -6- (4- methylpiperazine-1-yls) pyrimidine-4-yl) benzene -1,3- diamines (A2-NH2-3)
By A2-NO2-3 (3.3g, 10mmol), ammonium chloride (0.53g, 10mmol), the reduced iron through 1mol/L hydrochloric acid activations The mixed solvent that powder (3.35g, 60mmol) input is made of absolute ethyl alcohol (198mL), tetrahydrofuran (66mL) and water (33mL) In, it is refluxed 2h.Gained reactant is filtered by diatomite, rotates filtrate.By gained residue in water (50mL) and second Distributed between acetoacetic ester (100mL), divide and take organic phase, water is mutually extracted with ethyl acetate (2 × 50mL) again.Combined ethyl acetate, Washed, after anhydrous sodium sulfate drying through saturated sodium-chloride water solution, revolving.Gained residue is beaten in petroleum ether, is filtered Dry yellowish pink crystalline A 2-NH2-3 (2.87g, 96%)：1HNMR(DMSO-d6) δ 8.54 (s, 1H), 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, 1H), 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- nitrobenzenes) ester hydrochloride Salt (A2-CAR-3)
A2-NH2-3 (7.18g, 24mmol) is dissolved in anhydrous methylene chloride (200mL) and DMF (30mL), chloro-carbonic acid is added dropwise Anhydrous methylene chloride (100mL) solution of p-nitrophenyl ester (5.81g, 28.8mmol), is stirred at room temperature 5h.Filtering, washing, vacuum Dry yellow solid A2-CAR-3 (9.36g, 78%)：MS-ESI(m/z)464(M+H)+,927(2M+H)+。
1- (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 (0.24g, 1.65mmol) of A2-CAR-3 (0.75g, 1.5mmol), 3- and triethylamine (0.46g, 4.5mmol) is added in anhydrous DMF (6mL), and 9h is stirred at 40 DEG C.By gained reactant with dichloromethane (90mL) After dilution, successively with 0.5mol/L sodium hydrate aqueous solutions and water washing, rotated after anhydrous sodium sulfate drying.Gained residue silicon Plastic column chromatography, with ethyl acetate：Ethanol (3：0~3：1) gradient elution, obtains near-white crystalline A 2-1-3 (0.24g, 34%)：1HNMR(DMSO-d6) δ 8.88 (s, 1H), 8.80 (s, 1H), 8.65 (s, 1H), 7.83 (dd, J=2.8,6.8Hz, 1H), 7.74 (s,1H),7.27-7.32(m,2H),7.16-7.17(m,2H),6.95-6.96(m,1H),5.96(s,1H),3.50-3.51 (m, 4H), 2.37 (t, J=4.4Hz, 4H), 2.30 (s, 3H), 2.21 (s, 3H)；MS-ESI(m/z)470(M+H)+。
1- (2,3- dichlorophenyls) -3- (3- (2- methyl -6- (4- methylpiperazine-1-yls) pyrimidine-4-yl amido) phenyl) Urea (A2-2-3)
The chloro- 4- fluoroanilines of 3- are replaced with 2,3- dichloroanilines (0.27g, 1.65mmol), using the side similar to A2-1-3 Method prepares A2-2-3, obtains near-white solid (0.05g, 7%)：1HNMR(DMSO-d6)δ9.38(s,1H),8.90(s,1H),8.42 (s, 1H), 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, 1H), 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- (3- (trifluoromethyl) -4- chlorphenyls) -3- (3- (2- methyl -6- (4- methylpiperazine-1-yls) pyrimidine-4-yl amine Base) phenyl) urea (A2-3-3)
The chloro- 4- fluoroanilines of 3- are replaced with 3- (trifluoromethyl) -4- chloroanilines (0.32g, 1.65mmol), using similar to The method of A2-1-3 prepares A2-3-3, obtains near-white solid (0.22g, 28%)：1HNMR(DMSO-d6)δ9.07(s,1H),8.89 (s, 1H), 8.73 (s, 1H), 8.13 (s, 1H), 7.76 (s, 1H), 7.60 (s, 2H), 7.14-7.23 (m, 2H), 6.96 (d, J= 7.6Hz,1H),5.92(s,1H),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)+。
1- (3- cyano-phenyls) -3- (3- (2- methyl -6- (4- methylpiperazine-1-yls) pyrimidine-4-yl amido) phenyl) urea (A2-4-3)
The chloro- 4- fluoroanilines of 3- are replaced with 3- cyano-anilines (0.20g, 1.65mmol), using the method similar to A2-1-3 A2-4-3 is prepared, obtains Light yellow crystals powder (0.15g, 23%)：1HNMR(DMSO-d6)δ8.95(s,1H),8.89(s, 1H), 8.73 (s, 1H), 7.99 (s, 1H), 7.75 (s, 1H), 7.64 (d, J=7.6Hz, 1H), 7.49 (t, J=7.6Hz, 1H), 7.41 (d, J=7.6Hz, 1H), 7.16-7.18 (m, 2H), 6.96 (m, 1H), 5.96 (s, 1H), 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- (4- methylpiperazine-1-yls) pyrimidine-4-yl amido) phenyl) urea (A2-11- 3)
The chloro- 4- fluoroanilines of 3- are replaced with cyclohexylamine (0.17g, 1.65mmol), using the method preparation similar to A2-1-3 A2-11-3, obtains white crystalline powder (0.27g, 42%)：1HNMR(DMSO-d6)δ8.88(s,1H),8.27(s,1H),7.69 (s, 1H), 7.17 (m, 2H), 7.01 (s, 1H), 6.09 (d, J=7.2Hz, 1H), 6.00 (s, 1H), 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)
The chloro- 4- fluoroanilines of 3- are replaced with morpholine (0.15g, 1.65mmol), A2- is prepared using the method similar to A2-1-3 12-3, obtains near-white solid (0.25g, 40%)：1HNMR(DMSO-d6)δ8.79(s,1H),8.45(s,1H),7.63(s,1H), 7.09-7.17 (m, 2H), 6.96 (dd, J=1.2,8Hz, 1H), 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 )+。
1- (3- (2- methyl -6- (4- methylpiperazine-1-yls) pyrimidine-4-yl amido) phenyl) -3- (3- tolyls) urea (A2-13-3)
The chloro- 4- fluoroanilines of 3- are replaced with 3- methylanilines (0.18g, 1.65mmol), using the method similar to A2-1-3 A2-13-3 is prepared, obtains pale yellow powder (0.40g, 62%)：1HNMR(DMSO-d6)δ8.86(s,1H),8.53(s,1H),8.50 (s, 1H), 7.73 (s, 1H), 7.30 (s, 1H), 7.12-7.22 (m, 4H), 6.94-6.96 (m, 1H), 6.78 (d, J=7.6Hz, 1H), 5.95 (s, 1H), 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)+。
1- (3,5- bis- (trifluoromethyl) phenyl) -3- (3- (2- methyl -6- (4- methylpiperazine-1-yls) pyrimidine-4-yl amine Base) phenyl) urea (A2-14-3)
The chloro- 4- fluoroanilines of 3- are replaced with 3,5- bis- (trifluoromethyl) aniline (0.38g, 1.65mmol), using similar to A2- The method of 1-3 prepares A2-14-3, obtains white powder (0.11g, 13%)：1HNMR(DMSO-d6)δ9.37(s,1H),8.91(s, 1H), 8.90 (s, 1H), 8.12 (s, 2H), 7.79 (d, J=2Hz, 1H), 7.61 (s, 1H), 7.16-7.24 (m, 2H), 6.97 (d, J=8.4Hz, 1H), 5.94 (s, 1H), 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)+。
1- (2,5- difluorophenyls) -3- (3- (2- methyl -6- (4- methylpiperazine-1-yls) pyrimidine-4-yl amido) phenyl) Urea (A2-15-3)
The chloro- 4- fluoroanilines of 3- are replaced with 2,5- difluoroanilines (0.23g, 1.76mmol), using the side similar to A2-1-3 Method prepares A2-15-3, obtains white solid (0.14g, 21%)：1HNMR(DMSO-d6)δ9.05(s,1H),8.91(s,1H),8.70 (s,1H),8.02-8.07(m,1H),7.77(s,1H),7.24-7.30(m,1H),7.18(m,2H),6.93-6.94(m,1H), 6.77-6.82(m,1H),5.96(s,1H),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)+。
1- (2- methyl -5- fluorophenyls) -3- (3- (2- methyl -6- (4- methylpiperazine-1-yls) pyrimidine-4-yl amido) benzene Base) urea (A2-16-3)
The chloro- 4- fluoroanilines of 3- are replaced with 2- methyl -5- fluoroanilines (0.22g, 1.76mmol), using similar to A2-1-3's Method prepares A2-16-3, obtains milk yellow crystalline powder (0.53g, 79%)：1HNMR(DMSO-d6)δ8.88(s,1H),8.71 (s, 1H), 8.59 (s, 1H), 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,1H),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)+。
1- (3- (2- methyl -6- (4- methylpiperazine-1-yls) pyrimidine-4-yl amido) phenyl) -3- (4- (pyrrolidines -1- Base) butyl) urea (A2-18-3)
The chloro- 4- fluoroanilines of 3- are replaced with 4- (pyrrolidin-1-yl) butyl- 1- amine (0.26g, 1.8mmol), using similar to The method of A2-1-3 prepares A2-18-3, obtains near-white solid (0.11g, 16%)：1HNMR(DMSO-d6)δ8.80(s,1H), 8.31(s,1H),7.62(s,1H),7.09-7.10(m,2H),6.92-6.94(m,1H),6.12(m,1H),5.91(s,1H), 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)
The chloro- 4- fluoroanilines of 3- are replaced with isobutyl amine (0.13g, 1.8mmol), using the method preparation similar to A2-1-3 A2-19-3, obtains white solid (0.29g, 48%)：1HNMR(DMSO-d6)δ8.79(s,1H),8.27(s,1H),7.62(s, 1H),7.08-7.10(m,2H),6.91-6.93(m,1H),6.12(m,1H),5.90(s,1H),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.HCl (10g, 33.2mmol), K2CO3(13.8g, 99.6mmol) and iodomethane (5.67g, 40mmol) it is added in DMF (200mL), is stirred overnight.Gained reactant is poured into frozen water (3L), stirs 2h, 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, 1H), 7.83-7.85 (m, H), 7.75 (t, J=8Hz, 1H), 6.47 (s, 1H), 3.46 (s, 3H), 2.39 (s, 3H).
N1- (2- methyl -6- chlorine pyrimidine-4-yl)-N1- methylbenzene -1,3- diamines (A2M-NH2-0)
By A2M-NO2-0 (0.94g, 3.38mmol), through 1mol/L hydrochloric acid activations reduced iron powder (1.14g, 20.28mmol) added with ammonium chloride (0.18g, 3.35mmol) by absolute ethyl alcohol (60mL), tetrahydrofuran (20mL) and water The in the mixed solvent of (10mL) composition, is refluxed 2h, is then filtered while hot by diatomite, filtrate revolving.Gained is remained Stirring is dissolved in water (20mL) and ethyl acetate (60mL) in thing, with ammonium hydroxide tune pH to 8, divides and takes organic phase, water mutually uses acetic acid second again Ester extracts.Merge organic phase, rotated after saturated sodium-chloride water solution washs, anhydrous sodium sulfate is dried, 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 (15mL), is cooled to 0 DEG C, chloromethane is added dropwise Dichloromethane (10mL) solution of sour 4- nitros phenyl ester (0.82g, 4.06mmol).After dripping off, 20 DEG C of stirring 2.5h are warming up to.Cross Filter, drying, 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, 1H), 6.16 (s, 1H), 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 (0.22g, 1.54mmol) of 3-, A2M-CAR-0 (0.63g, 1.4mmol) and triethylamine (0.42g, 4.2mmol) is added in DMF (6mL), and 9h is stirred at 40 DEG C.Gained reactant dichloromethane (90mL) is diluted, Successively with 0.5mol/L sodium hydrate aqueous solutions, water washing, rotated after being dried over anhydrous sodium sulfate.Gained residue silica gel column layer Analysis, with ethyl acetate：Petroleum ether (1:1~1:2) gradient elution, obtains A2M-1-0 (0.14g, 24%)：1H-NMR(DMSO-d6)：δ 8.89 (s, 1H), 8.88 (s, 1H), 7.77-7.79 (m, 1H), 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)+。
1- (3- (methyl (2- methyl -6- chlorine pyrimidine-4-yl) amido) phenyl) -3- (3- (trifluoromethyl) -4- chlorphenyls) Urea (A2M-3-0)
The chloro- 4- fluoroanilines of 3- are replaced with 3- (trifluoromethyl) -4- chloroanilines (0.30g, 1.54mmol), using similar to The method of A2M-1-0 prepares A2M-3-0, obtains near-white solid (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-NO2-2)
By A2M-NO2-0 (5.02g, 18mmol), morpholine (9.42g, 108mmol) and DMSO (20mL) under nitrogen protection 20min is stirred at 140 DEG C.Gained reactant is cooled to after 60 DEG C and is poured into stirring 2h in frozen water (200mL), filters, is dry, obtaining A2M-NO2-2 (5.61g, 95%)：1HNMR(DMSO-d6) δ 8.13 (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- (2- methyl -6- morpholinyls pyrimidine-4-yl) benzene -1,3- diamines (A2M-NH2-2)
By A2M-NO2-2 (5.5g, 16.72mmol), the reduced iron powder (5.6g, 100mmol) through 1mol/L hydrochloric acid activations Add with ammonium chloride (0.89g, 16.72mmol) and be made of absolute ethyl alcohol (330mL), tetrahydrofuran (110mL) and water (55mL) In the mixed solvent, be refluxed 2h, then filtered while hot by diatomite, filtrate revolving.It is molten by being stirred in gained residue In water (100mL) and ethyl acetate (200mL), with ammonium hydroxide tune pH to 8, divide and take organic phase, water is mutually extracted with ethyl acetate again.Close And organic phase, rotated after saturated sodium-chloride water solution washs, anhydrous sodium sulfate is dried, obtain light yellow solid A2M-NH2-2 (4.74g, 95%)：1HNMR(DMSO-d6) δ 7.07 (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- morpholinyls pyrimidine-4-yl) amido) anilino- formic acid 4- nitrobenzene ester hydrochlorides (A2M- CAR-2)
By A2M-NH2- 0 (4.63g, 15.48mmol) is dissolved in anhydrous methylene chloride (70mL), is cooled to 0 DEG C, and chloromethane is added dropwise Dichloromethane (50mL) solution of sour 4- nitros phenyl ester (3.74g, 18.55mmol).After dripping off, 20 DEG C of stirring 2.5h are warming up to. Filtering, drying, obtain light yellow solid A2M-CAR-0 (7.68g, 99%)：1H-NMR(DMSO-d6)：δ 10.69 (s, 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, 4H), 3.58 (m, 4H), 3.47 (s, 3H), 2.48 (s, 3H).
1- (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 (0.24g, 1.65mmol) of 3-, A2M-CAR-2 (0.75g, 1.5mmol) and triethylamine (0.46g, 4.5mmol) is added in DMF (6mL), and 9h is stirred at 40 DEG C.Gained reactant dichloromethane (90mL) is diluted, Successively with 0.5mol/L sodium hydrate aqueous solutions, water washing, rotated after being dried over anhydrous sodium sulfate.Gained residue silica gel column layer Analysis, with ethyl acetate：Triethylamine (100：1) elute, obtain white solid A2M-1-2 (0.19g, 27%)：1H-NMR(DMSO-d6)： δ 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)+。
1- (3- (trifluoromethyl) -4- chlorphenyls) -3- (3- (methyl (2- methyl -6- morpholinyls pyrimidine-4-yl) amido) benzene Base) urea (A2M-3-2)
The chloro- 4- fluoroanilines of 3- are replaced with 3- (trifluoromethyl) -4- chloroanilines (0.32g, 1.65mmol), using similar to The method of A2M-1-2 prepares A2M-3-2, obtains white solid (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)+。
1- (3- cyano-phenyls) -3- (3- (methyl (2- methyl -6- morpholinyls pyrimidine-4-yl) amido) phenyl) urea (A2M- 4-2)
The chloro- 4- fluoroanilines of 3- are replaced with 3- cyano-anilines (0.19g, 1.65mmol), using the method similar to A2M-1-2 A2M-4-2 is prepared, obtains white solid (0.11g, 16%)：1HNMR(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)+。
1- (5- picoline -2- bases) -3- (3- (methyl (2- methyl -6- morpholinyls pyrimidine-4-yl) amido) phenyl) urea (A2M-10-2)
The chloro- 4- fluoroanilines of 3- are replaced with 5- picoline -2- amine (0.18g, 1.65mmol), using similar to A2M-1-2 Method prepare A2M-10-2, obtain white solid (0.23g, 35%)：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)+。
1- (3- tolyls) -3- (3- (methyl (2- methyl -6- morpholinyls pyrimidine-4-yl) amido) phenyl) urea (A2M-13- 2)
The chloro- 4- fluoroanilines of 3- are replaced with 3- methylanilines (0.18g, 1.65mmol), using the method similar to A2M-1-2 A2M-13-2 is prepared, obtains white solid (0.35g, 54%)：1HNMR(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)+。
1- (4- (pyrrolidin-1-yl) butyl) -3- (3- (methyl (2- methyl -6- morpholinyls pyrimidine-4-yl) amido) benzene Base) urea (A2M-18-2)
The chloro- 4- fluoroanilines of 3- are replaced with 4- (pyrrolidin-1-yl) butyl- 1- amine (0.23g, 1.65mmol), using similar to The method of A2M-1-2 prepares A2M-18-2, obtains white crystalline solid (0.25g, 36%)：1HNMR(DMSO-d6)δ7.21- 7.29 (m, 3H), 7.03 (s, 1H), 6.86-6.88 (m, 1H), 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 groups -3- (3- (methyl (2- methyl -6- morpholinyls pyrimidine-4-yl) amido) phenyl) urea (A2M-19-2)
The chloro- 4- fluoroanilines of 3- are replaced with isobutyl amine (0.12g, 1.65mmol), using the method preparation similar to A2M-1-2 A2M-19-2, obtains white solid (0.26g, 43%)：1HNMR(DMSO-d6) δ 8.44 (s, 1H), 7.42 (t, J=2.0Hz, 1H), 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, 1H), 5.44 (s, 1H), 3.58 (t, J=4.8Hz, 4H), 3.34 (s, 3H), 3.31 (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)+。
1- (3- (methyl (2- methyl -6- morpholinyls pyrimidine-4-yl) amine) phenyl) -3- (5- methylisoxazole -3- bases) urea (A2M-20-2)
3- amino -5- methylisoxazoles (0.26g, 2.7mmol) are dissolved in anhydrous methylene chloride (12ml), chloro-carbonic acid is added dropwise Phenyl ester (0.42g, 2.7mmol), is stirred at room temperature 1h.Triethylamine (0.33g, 3.3mmol) is added, adds A2M-NH2-2 (0.80g, 2.7mmol), triethylamine (0.66g, 6.5mmol), is refluxed 3h.Let cool, it is water-soluble to add 1mol/L sodium hydroxides Liquid (10ml), stirs 10min.Divide and take organic layer, wash, after anhydrous sodium sulfate drying, be concentrated under reduced pressure through saturated brine.Use acetic acid Ethyl ester processing gained residue, obtains white solid.Flowed back and be dissolved in methanol (80ml), let cool, add 1mol/L hydrochloric acid (5ml), stirs 2h.It is 9-10 to adjust pH with 0.5mol/L sodium hydrate aqueous solutions, and revolving removes methanol, and filtering, obtains faint yellow Solid (0.20g, 18%)：1HNMR(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- (4- methylpiperazine-1-yls)-N- (3- nitrobenzophenones) pyrimidine -4- amine (A2M-NO2-3)
By A2M-NO2-0 (4.99g, 17.9mmol), 1- methyl piperazines (10.77g, 107.5mmol) and DMSO (20mL) Under nitrogen protection 20min is stirred at 140 DEG C.After gained reactant is cooled to 80 DEG C, frozen water (200mL) is poured under agitation In, extracted with dichloromethane (2 × 150mL).Merge organic phase, washed through saturated sodium-chloride water solution, anhydrous sodium sulfate drying Afterwards, rotate, A2M-NO2-3 (6.02g, 98%) is obtained after drying：1H-NMR(DMSO-d6) δ 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-N1- (2- methyl -6- (4- methylpiperazine-1-yls) pyrimidine-4-yl) benzene -1,3- diamines (A2M-NH2-3)
By A2M-NO2-3 (6.02g, 17.6mmol), through 1mol/L hydrochloric acid activations reduced iron powder (5.91g, 105.6mmol) added with ammonium chloride (0.94g, 17.6mmol) by absolute ethyl alcohol (360mL), tetrahydrofuran (120mL) and water The in the mixed solvent of (60mL) composition, is refluxed 2h, is then filtered while hot by diatomite, filtrate revolving.Gained is remained Stirring is dissolved in water (100mL) and ethyl acetate (200mL) in thing, with ammonium hydroxide tune pH to 8, divides and takes organic phase, water mutually uses acetic acid again Ethyl ester extracts.Merge organic phase, rotated after saturated sodium-chloride water solution washs, anhydrous sodium sulfate is dried, obtain brown solid A2M-NH2-3 (4.73g, 86%)：1H-NMR(DMSO-d6) δ 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) amido) anilino- formic acid 4- nitro phenyl esters Hydrochloride (A2M-CAR-3)
A2M-NH2-3 (4.73g, 15.2mmol) is dissolved in anhydrous methylene chloride (70mL), is cooled to 0 DEG C, chloromethane is added dropwise Dichloromethane (50mL) solution of sour 4- nitros phenyl ester (3.67g, 18.2mmol).After dripping off, 20 DEG C of stirring 2.5h are warming up to.Cross Filter, drying, obtain light yellow solid A2M-CAR-3 (7.89g, 100%)：1H-NMR(DMSO-d6)：δ 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).
1- (the chloro- 4- fluorophenyls of 3-) -3- (3- (methyl (2- methyl -6- (4- methylpiperazine-1-yls) pyrimidine-4-yl) amine Base) phenyl) urea (A2M-1-3)
By the chloro- 4- fluoroanilines (0.24g, 1.65mmol) of 3-, A2M-CAR-3 (0.77g, 1.5mmol) and triethylamine (0.46g, 4.5mmol) is added in DMF (6mL), and 9h is stirred at 40 DEG C.Gained reactant dichloromethane (90mL) is diluted, Successively with 0.5mol/L sodium hydrate aqueous solutions, water washing, rotated after being dried over anhydrous sodium sulfate.Gained residue silica gel column layer Analysis, with ethyl acetate：Ethanol (5：1~1:1) gradient elution, obtains white solid A2M-1-3 (0.17g, 23%)：1H-NMR (DMSO-d6)：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)+。
1- (3- (trifluoromethyl) -4- chlorphenyls) -3- (3- (methyl (2- methyl -6- (4- methylpiperazine-1-yls) pyrimidine - 4- yls) 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) is added in DMF (6mL), and 9h is stirred at 40 DEG C.Gained reactant dichloromethane (90mL) is diluted, Successively with 0.5mol/L sodium hydrate aqueous solutions, water washing, rotated after being dried over anhydrous sodium sulfate.Gained residue silica gel column layer Analysis, with ethyl acetate：Ethanol (20：1~5：1) gradient elution, obtains near-white solid A2M-3-3 (0.20g, 25%)：1HNMR (DMSO-d6) δ 9.13 (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, 1H), 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)+。
1- (3- cyano-phenyls) -3- (3- (methyl (2- methyl -6- (4- methylpiperazine-1-yls) pyrimidine-4-yl) amido) benzene Base) urea (A2M-4-3)
The chloro- 4- fluoroanilines of 3- are replaced with 3- cyano-anilines (0.19g, 1.65mmol), using the method similar to A2M-1-3 A2M-4-3 is prepared, obtains white solid (0.06g, 9%)：1HNMR(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)+。
1- (5- picoline -2- bases) -3- (3- (methyl (2- methyl -6- (4- methylpiperazine-1-yls) pyrimidine-4-yl) amine Base) phenyl) urea (A2M-10-3)
The chloro- 4- fluoroanilines of 3- are replaced with 5- picoline -2- amine (0.18g, 1.65mmol), using similar to A2M-1-3 Method prepare A2M-10-3, obtain white solid (0.23g, 34%)：1HNMR(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)+。
1- (3- tolyls) -3- (3- (methyl (2- methyl -6- (4- methylpiperazine-1-yls) pyrimidine-4-yl) amido) benzene Base) urea (A2M-13-3)
The chloro- 4- fluoroanilines of 3- are replaced with 3- methylanilines (0.18g, 1.65mmol), using the method similar to A2M-1-3 A2M-13-3 is prepared, obtains white solid (0.13g, 19%)：1HNMR(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)+。
1- (3,5- bis- (trifluoromethyl) phenyl) -3- (3- (methyl (2- methyl -6- (4- methylpiperazine-1-yls) pyrimidine -4- Base) amido) phenyl) urea (A2M-14-3)
3- (trifluoromethyl) -4- chloroanilines are replaced with 3,5- bis- (trifluoromethyl) aniline (0.69g, 3mmol), using similar A2M-14-3 is prepared in the method for A2M-3-3, obtains near-white solid (0.06g, 7%)：1HNMR(DMSO-d6) δ 9.38 (s, 1H), 9.01 (s, 1H), 8.12 (s, 1H), 7.62 (s, 1H), 7.50 (s, 1H), 7.36 (t, J=8.0Hz, 1H), 7.25 (d, J= 8.4Hz, 1H), 6.94 (d, J=6.8Hz, 1H), 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)+。
1- (4- (pyrrolidin-1-yl) butyl) -3- (3- (methyl (2- methyl -6- (4- methylpiperazine-1-yls) pyrimidine -4- Base) amido) phenyl) urea (A2M-18-3)
The chloro- 4- fluoroanilines of 3- are replaced with 4- (pyrrolidin-1-yl) butyl- 1- amine (0.23g, 1.65mmol), using similar to The method of A2M-1-3 prepares A2M-18-3, give light yellow oil (0.24g, 33%)：1HNMR(DMSO-d6) δ 8.68 (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 groups -3- (3- (methyl (2- methyl -6- (4- methylpiperazine-1-yls) pyrimidine-4-yl) amido) phenyl) urea (A2M-19-3)
The chloro- 4- fluoroanilines of 3- are replaced with isobutyl amine (0.12g, 1.65mmol), using the method preparation similar to A2M-1-3 A2M-19-3, obtains white crystalline solid (0.20g, 32%)：1HNMR(DMSO-d6) δ 8.44 (s, 1H), 7.42 (d, J= 2.0Hz, 1H), 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, 1H), 5.44 (s, 1H), 3.35-3.37 (m, 4H), 3.33 (s, 3H), 2.91 (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.HCl)
By 3- nitro-4-methyls aniline (30.43g, 0.2mol) and 2- methyl -4,6- dichloro pyrimidine (32.62g, 0.2mol) put into water (150mL) and acetone (50mL), add 12mol/L hydrochloric acid (4mL) and be stirred at reflux 2h.After being cooled to room temperature Filtering, filter cake washing, dry bright yellow solid A2N-NO2-0.HCl (53.58g, 85%).
N1- (2- methyl -6- chlorine pyrimidine-4-yl) -4- toluene -1,3- diamines (A2N-NH2-0)
By A2N-NO2-0.HCl (3.67g, 11.7mmol), through 1mol/L hydrochloric acid activations reduced iron powder (3.92g, 70.0mmol) added with ammonium chloride (1.25g, 23.4mmol) by ethanol (240mL), tetrahydrofuran (80mL) and water (40mL) group Into in the mixed solvent, be refluxed 2h, filtered while hot by diatomite.Filtrate rotates, and into obtained solid residue, adds Water (100mL), with ammonium hydroxide tune pH to 9 or so, then is extracted with ethyl acetate water phase.Merge organic phase, dried with anhydrous sodium sulfate After rotate, obtain light yellow solid A2N-NH2-0 (2.64g, 81%)：1H-NMR(DMSO-d6) δ 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-yls amido) -2-aminotoluene base formic acid 4- nitrobenzene ester hydrochlorides (A2N- CAR-0)
P-nitrophenyl chloroformate ester (1.94g, 9.6mmol) is dissolved in dichloromethane (20mL).In -10~-5 DEG C of dropwise additions The dichloromethane (120mL) of A2N-NH2-0 (2.00g, 8mmol), 1.5h is stirred at room temperature after dripping off.Filtering vacuum is dried, and is obtained closely 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).
1- (2- methyl -5- (2- methyl -6- chlorine pyrimidine-4-yls amido) phenyl) -3- (3- (trifluoromethyl) -4- chlorphenyls) Urea (A2N-3-0)
A2N-CAR-Cl (0.67g, 1.5mmol) and 3- (trifluoromethyl) -4- chloroanilines (0.59g, 3mmol) are dissolved in DMF (6mL), adds triethylamine (0.46g, 4.5mmol), is stirred overnight at 40 DEG C, then add two into gained reaction solution Chloromethanes (60mL) and 0.5mol/LNaOH aqueous solutions (20mL).Divide and take organic phase, anhydrous sodium sulfate is dried after washing, revolving. 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=7.6Hz, 1H), 7.15 (d, J=8.4Hz, 1H), 6.61 (s, 1H), 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- (pyrrolidin-1-yl) butyl) urea (A2N-18-0)
3- (trifluoromethyl) -4- chloroanilines are replaced with 4- (pyrrolidin-1-yl) butane -1- amine (0.40g, 3mmol), are used A2N-18-0 is prepared similar to the method for A2N-3-0, obtains light yellow solid (0.13g, 21%)：1H-NMR(DMSO-d6)δ9.58 (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)+。
1- (3- (trifluoromethyl) -4- chlorphenyls) -3- (5- (6- (4- (2- ethoxys) piperazine -1- bases) -2- methylpyrimidines - 4- bases amido) -2- tolyls) urea (A2N-3-1)
Take A2N-3-0 (0.09g, 0.2mmol), 2- (piperazine -1- bases) ethanol (0.16g, 1.2mmol), DIEA (0.16g, 1.2mmol) it is mixed with n-butanol (3mL), is warming up to 80 DEG C of stirring 7h, is rotated after being cooled to room temperature.Obtained by silica gel column chromatography 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=2.0Hz, 1H), 7.60 (s, 2H), 7.18 (dd, J=2.4,8.4Hz, 1H), 7.07 (d, J=8.4Hz, 1H), 5.95 (s, 1H), 4.36 (br s, 1H), 3.48 (m, 6H), 2.49 (m, 6H), 2.27 (s, 3H), 2.19 (s, 3H)；MS-ESI m/z 564(M+H)+。
The 2 of 4.2 A2N series
2- methyl-N- (4- methyl-3-nitros phenyl) -6- morpholine yl pyrimidines -4- amine (A2N-NO2-2)
A2N-NO2-Cl.HCl (5g, 15.9mmol) and morpholine (8.29g, 95.2mmol) are added to DMSO (20mL) In, 140 DEG C of stirring 30min are heated to, are then poured into while hot under agitation in mixture of ice and water (200mL), filtration drying, obtains Yellow solid A2N-NO2-2 (5.11g, 98%)：1H-NMR(DMSO-d6) δ 9.33 (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).
4- methyl-N1- (2- methyl -6- morpholinyls pyrimidine-4-yl) benzene -1,3- diamines (A2N-NH2-2)
A2N-NO2-2 (5.11g, 15.5mmol) is added by ethanol (330mL), tetrahydrofuran (110mL) and water The in the mixed solvent of (55mL) composition, adds ammonium chloride (0.83g, 15.5mmol) and the reduced iron with 1mol/L hydrochloric acid activations Powder (5.21g, 93.0mmol), is heated to being refluxed 2h, then filters while hot.Revolving reaction solution obtains white solid, adds water (100mL), with ammonium hydroxide tune pH to 9 or so, adds ethyl acetate (200mL) stirring, filters to obtain white solid；Organic filtrate is used Rotated after 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-yls amido) anilino- formic acid 4- nitrobenzene ester hydrochlorides (A2N-CAR-2)
A2N-NH2-2 (4.20g, 14.0mmol) is dissolved in dichloromethane (70mL), is cooled to 0 DEG C of quick drop chloro-carbonic acid to nitre Dichloromethane (70mL) solution of base phenyl ester (3.40g, 16.8mmol).4h is stirred at room temperature after being added dropwise, filtration drying, obtains shallow Yellow product A2N-CAR-2 (6.44g, 92%)：1HNMR(DMSO-d6) δ 9.85 (br s, 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, 8H), 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) and 3- (trifluoromethyl) -4- chloroanilines (0.59g, 3mmol) are dissolved in DMF (6mL), adds triethylamine (0.46g, 4.5mmol), keeps the temperature 40 DEG C of stirring 9h, then adds sodium hydrate aqueous solution (20mL), Extracted again with dichloromethane.Merge organic phase, after being dried with anhydrous sodium sulfate, revolving.Silica gel column chromatography purifying gained residue, Use ethyl acetate：Petroleum ether (1:1) elute, obtain yellowish solid A2N-3-2 (0.23g, 29%)：1HNMR(DMSO-d6)δ9.41 (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-ESI m/z 521(M+H)+。
1- (2- methyl -5- (2- methyl -6- morpholinyl pyrimidine-4-yls amido) phenyl) -3- (4- (pyrrolidin-1-yl) fourths Base) urea (A2N-18-2)
3- (trifluoromethyl) -4- chloroanilines are replaced with 4- (pyrrolidin-1-yl) butane -1- amine (0.40g, 3mmol), are used A2N-18-2 is prepared similar to the method for A2N-3-2, obtains near-white solid (0.36g, 26%)：1HNMR(DMSO-d6)δ8.74 (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-ESI m/z 468(M+H)+,935(2M+H)+。
The 3 of 4.3 A2N series
2- methyl-N- (4- methyl-3-nitros phenyl) -6- (4- methylpiperazine-1-yls) pyrimidine -4- amine (A2N-NO2-3)
A2N-NO2-Cl.HCl (5g, 15.9mmol) and 1- methyl piperazines (9.53g, 95.2mmol) are added to DMSO In (20mL), 140 DEG C of stirring 0.5h are heated to, is then poured into while hot under agitation in mixture of ice and water (200mL), is crossed and be filtered dry It is dry, obtain 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- (2- methyl -6- (4- methylpiperazine-1-yls) pyrimidine-4-yl) benzene -1,3- diamines (A2N-NH2-3)
A2N-NO2-3 (5.69g, 13.7mmol) is added by ethanol (330mL), tetrahydrofuran (110mL) and water The in the mixed solvent of (55mL) composition, adds ammonium chloride (0.74g, 13.8mmol) and the reduced iron with 1mol/L hydrochloric acid activations Powder (4.75g, 85mmol), reflux are stirred 2h, are then filtered while hot.Filtrate is rotated, ethyl acetate is added into gained residue (200mL) and water (100mL), with ammonium hydroxide tune pH to 8~9, divides and takes organic phase, and water is mutually extracted with ethyl acetate again, merges organic Phase, rotates after anhydrous sodium sulfate drying, obtains light yellow solid A2N-NH2-3 (4.83g, 93%)：1HNMR(DMSO-d6)δ8.45 (s, 1H), 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, 4H), 2.25 (s, 3H), 2.20 (s, 3H), 2.00 (s, 3H).
3- (trifluoromethyl) -4- chloroanilino formic acid 4- nitros phenyl esters (3-CAR)
Take p-nitrophenyl chloroformate ester (1.21g, 6mmol) to be dissolved in dichloromethane (15mL), 3- is slowly added dropwise below 0 DEG C Dichloromethane (10mL) solution of (trifluoromethyl) -4- chloroanilines (0.98g, 5mmol).2h, mistake are stirred at room temperature after being added dropwise Filter to obtain white solid 3-CAR (1.08g, 60%)：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).
4- (pyrrolidin-1-yl) fourth amidocarbonic acid 4- nitrobenzenes ester hydrochloride (18-CAR)
P-nitrophenyl chloroformate ester (2.42g, 12mmol) is dissolved in dichloromethane (20mL), is slowly added dropwise at 0 DEG C or so Dichloromethane (20mL) solution of 4- (pyrrolidin-1-yl) butane -1- amine (1.34g, 10mmol), is stirred at room temperature after being added dropwise 4h, revolving, ethyl acetate mashing is added into gained residue, filters to obtain white solid 18-CAR (2.60g, 76%).
((2- methyl -6- (4- methylpiperazine-1-yls) is phonetic by 2- methyl -5- by 1- (3- (trifluoromethyl) -4- chlorphenyls) -3- Pyridine -4- bases amido) phenyl) urea (A2N-3-3)
Take A2N-NH2-3 (0.70g, 2.25mmol), 3-CAR (0.54g, 1.5mmol) to be dissolved in DMF (6mL), add Triethylamine (0.46g, 4.5mmol), 40 DEG C of temperature control stirring 9h, then added into gained reaction solution dichloromethane (90mL) and 0.5mol/LNaOH aqueous solutions (20mL).Divide and take organic phase, anhydrous sodium sulfate is dried after washing, revolving, silica gel column chromatography purifying Gained residue, with ethyl acetate：Ethanol (3:1~1:1) gradient elution, obtains yellowish solid A2N-3-3 (0.14g, 18%) ：1H-NMR(DMSO-d6) δ 9.46 (s, 1H), 8.86 (s, 1H), 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, 1H), 5.97 (s, 1H), 3.49 (t, J=4.8Hz, 4H), 2.34 (t, J=4.8Hz, 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+Cl)-,1111(2M+ COOH)-。
1- (4- (pyrrolidin-1-yl) butyl) -3- (2- methyl -5- (2- methyl -6- (4- methylpiperazine-1-yls) pyrimidine - 4- bases amido) phenyl) urea (A2N-18-3)
3-CAR is replaced with 18-CAR (0.45g, 1.3mmol), A2N-18-3 is prepared using the method similar to A2N-3-3, Obtain fawn crystallization (0.28g, 45%)：1HNMR(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)
60% sodium hydride (1.20g, 30mmol) is dissolved in THF (15mL), ortho-nitraniline is added portionwise at 0 DEG C (1.38g, 10mmol), stirs 30min；The THF of fast drop 2- methyl -4,6- dichloro pyrimidines (1.63g, 10mmol) again (15mL) solution, 2h is refluxed after being added dropwise.Gained reactant is poured into mixture of ice and water (200mL) while hot under agitation In, 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-NO2-2)
A3-NO2-Cl (1.59g, 6mmol) and morpholine (3.14g, 36mmol) are added in DMSO (10mL), nitrogen is protected 4h are stirred at 140 DEG C under shield, are then poured under agitation in mixture of ice and water (200mL), filtering separates out solid, dry yellow Solid A3-NO2-2 (1.48g, 78%).
N1- (2- methyl -6- morpholinyls pyrimidine-4-yl) benzene -1,2- diamines (A3-NH2-2)
A3-NO2-2 (1.48g, 4.7mmol) and ammonium chloride (0.25g, 4.7mmol) are added by ethanol (120mL)：Four The in the mixed solvent of hydrogen furans (40mL) and water (20mL) composition, adds the reduced iron powder through 1mol/L hydrochloric acid activations (1.58g, 28.2mmol), is refluxed 2h, is filtered while hot by diatomite, and revolving, water is added into obtained solid residue (50mL), with ammonium hydroxide tune pH to 9 or so, adds ethyl acetate mashing, filtration drying, obtains pale solid A3-NH2-2 (0.83g, 62%)：1HNMR(DMSO-d6) δ 7.95 (s, 1H), 7.10 (d, J=7.2Hz, 1H), 6.92 (t, J=6.8Hz, 1H), 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).
1- (3- (trifluoromethyl) -4- chlorphenyls) -3- (2- (2- methyl -6- morpholinyl pyrimidine-4-yls amido) phenyl) urea (A3-3-2)
A3-NH2-2 (0.32g, 1.1mmol) and 3-CAR (0.36g, 1mmol) are dissolved in DMF (3mL), add three Ethamine (0.31g, 3mmol), is stirred overnight at 0 DEG C, and dichloromethane (90mL) and 0.5mol/ are then added into gained reaction solution LNaOH aqueous solutions (20mL), divide and take organic phase, and anhydrous sodium sulfate is dried 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%)：1HNMR(DMSO- d6) 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=8.0Hz, 1H), 7.19 (t, J=7.2Hz, 1H), 7.07 (dt, J=1.2,7.2Hz, 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- (2- (2- methyl -6- morpholinyl pyrimidine-4-yls amido) phenyl) urea (A3-18-2)
A3-NH2-2 (0.57g, 2mmol), 18-CAR (0.30g, 1mmol) are dissolved in DMF (3mL), add three second Amine (0.31g, 3mmol), 40 DEG C are stirred overnight.Dichloromethane (90mL) and 0.5mol/LNaOH water are added into gained reaction solution Solution (20mL), divides and takes organic phase, and anhydrous sodium sulfate is dried after washing, revolving.Silica gel column chromatography purifying gained residue, with second Alcohol：Ethyl acetate：Triethylamine (150:50:1) elute, obtain Tan solid A3-18-2 (0.12g, 27%)：1HNMR (DMSO-d6) δ 8.18 (s, 1H), 7.82 (d, J=8.4Hz, 1H), 7.73 (s, 1H), 7.22 (d, J=7.6Hz, 1H), 7.11 (t, J=8.0Hz, 1H), 6.97 (m, 1H), 6.64 (t, J=5.6Hz, 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, J =3.2Hz, 4H)；MS-EI：m/z 453(M).
The 3 of 5.2 A3 series
2- methyl -6- (4- methylpiperazine-1-yls)-N- (2- nitrobenzophenones) pyrimidine -4- amine (A3-NO2-3)
A3-NO2-Cl (3.0g, 11mmol) and 1- methyl piperazines (6.67g, 66mmol) are added in DMSO (25mL), 4h is stirred at 140 DEG C under nitrogen protection, is then poured under agitation in mixture of ice and water, filtering separates out solid, yellowly dry Color solid A3-NO2-3 (3.12g, 84%).
N1- (2- methyl -6- (4- methylpiperazine-1-yls) pyrimidine-4-yl) benzene -1,2- diamines (A3-NH2-3)
A3-NO2-3 (2.6g, 8mmol) and ammonium chloride (0.36g, 8mmol) are added by ethanol (90mL), tetrahydrofuran (30mL) and water (15mL) composition in the mixed solvent, add through 1mol/L hydrochloric acid activations reduced iron powder (2.52g, 48mmol), 3h is refluxed, is filtered while hot, is rotated.Into obtained solid residue plus water (80mL), with ammonium hydroxide tune pH to 9, Ethyl acetate (150mL) mashing is added, filtration drying obtains gray solid A3-NH2-3 (2.15g, 91%)：1H-NMR(DMSO- d6) δ 7.90 (s, 1H), 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- (3- (trifluoromethyl) -4- chlorphenyls) -3- (2- (2- methyl -6- (4- methylpiperazine-1-yls) pyrimidine-4-yl amine Base) phenyl) urea (A3-3-3)
A3-NH2-3 (0.43g, 1.5mmol) and 3-CAR (0.54g, 1.5mmol) are dissolved in anhydrous DMF (6mL), then Triethylamine (0.46g, 4.5mmol) is added, is stirred overnight at 40 DEG C.Into gained reaction solution add dichloromethane (90mL) and 0.5%mol/L sodium hydrate aqueous solutions (20mL), divide and take organic phase, and anhydrous sodium sulfate is dried after washing, revolving.Silica gel column layer Analysis purifying gained residue, with ethanol：Ethyl acetate：Triethylamine (150:50:1) elute, obtain light gray solid A3-3-3 (0.27g, 35%)：1HNMR(DMSO-d6) δ 9.54 (s, 1H), 8.27 (s, 1H), 8.08 (s, 1H), 8.07 (d, J=2.0Hz, 1H), 7.87 (d, J=8.4Hz, 1H), 7.57 (m, 2H), 7.26 (d, J=7.6Hz, 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)+。
The 1 of 5.3 A3 series
N1- (2- 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 through 1mol/L hydrochloric acid activations Reduced iron powder (2.63g, 46.8mmol) is added by ethanol (120mL)：The mixing of tetrahydrofuran (40mL) and water (20mL) composition In solvent, filtered while hot after being refluxed 2h.Filtrate is rotated, water (50mL) is added into obtained solid residue, with ammonium hydroxide tune PH to 9, is extracted with ethyl acetate (100mL, 3 × 50mL).Merge extracting solution, rotate, obtain blackish green after being dried with anhydrous sodium sulfate Color solid A3-NH2-0 (1.13g, 62%).
1- (3- (trifluoromethyl) -4- chlorphenyls) -3- (2- (6- (4- (2- ethoxys) piperazine -1- bases) -2- methylpyrimidines - 4- bases amido) phenyl) urea (A3-3-1)
A3-NH2-0 (0.47g, 2mmol) and 3-CAR (0.72g, 2mmol) are dissolved in DMF (10mL), add triethylamine (0.61g, 6mmol), is stirred overnight at 40 DEG C.Dichloromethane (90mL) and 0.5%mol/L hydrogen-oxygens are added into gained reaction solution Change sodium water solution (20mL), divide and take organic phase, anhydrous sodium sulfate is dried after washing, revolving.Added into gained concentrated by rotary evaporation liquid 2- (piperazine -1- bases) ethanol (1.60g, 12mmol) and DIEA (1.60g, 12mmol), are stirred overnight at 80 DEG 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-d6) δ 9.54 (s, 1H), 8.26 (s, 1H), 8.09 (s, 1H), 8.05 (s, 1H), 7.88 (d, J=8.4Hz, 1H), 7.57 (s, 2H), 7.27 (d, J=8.0Hz, 1H), 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)
Meta nitro aniline (17.0g, 0.12mol), 4,6- dichloro pyrimidines (18.3g, 0.12mol) are added into acetone (30ml) With the in the mixed solvent of water (90ml), concentrated hydrochloric acid (2.5ml) is added, flow back 2h.Let cool, filter, filter cake washing, is dried in vacuo Crude product.Gained crude product is dissolved in the in the mixed solvent of glacial acetic acid (160ml) and DMF (250ml), add sodium acetate (7.8g, 0.095mol), 90 DEG C are warming up to, gained reaction solution is poured into water (2L) while hot, stirs 1h.Filtering, washes filter cake, and vacuum is done Dry (70 DEG C, 5h), obtain the chloro- N- of 6- (3- nitrobenzophenones) pyrimidine -4- amine, are yellow solid (26.7g, 89%).
The chloro- N- of 6- (3- nitrobenzophenones) pyrimidine -4- amine (5.0g, 20mmol) and potassium carbonate (7.2g, 52.1mmol) are thrown Enter in DMF (100ml), add iodomethane (3.0g, 21.1mmol), 25 DEG C of stirring 10h.Reactant is poured into frozen water (1.2L) In, stir 2h.Filter, filter cake washing, is dried in vacuo (70 DEG C, 5h).Obtain B2M-NO2- 0, it is yellow solid (4.8g, 91%)： mp 98.5-100.5℃。
N- methyl -6- morpholinyls-N- (3- nitrobenzophenones) pyrimidine -4- amine (B2M-NO2-2)
By B2M-NO2- 0 (5.0g, 17.9mmol) is dissolved in input DMSO (30ml), addition morpholine (9.4g, 0.12mol), 145 DEG C of stirring 0.5h.It is cooled to 50 DEG C, reaction solution is poured into frozen water (200ml), stirs 1h.Filtering, washing filter Cake, is dried in vacuo (70 DEG C, 5h), obtains B2M-NO2- 2, it is yellow solid (5.8g, 98%)：mp 165.8-168.8℃.
N1- methyl-N1- (6- morpholinyls pyrimidine-4-yl) benzene -1,3- diamines (B2M-NH2-2)
By B2M-NO2- 2 (4.0g, 12.7mmol) are dissolved in ethanol (200ml), and 50 DEG C of stirrings to dissolved clarification, are added dropwise SnCl2· 2H26mol/L hydrochloric acid (15ml) solution of O (10.0g, 44.3mmol), heats up after being added dropwise, and flow back 2h.Let cool, portion is gone in rotation Divide ethanol, pH to 9 is adjusted with 2mol/L sodium hydrate aqueous solutions, with ethyl acetate：Ethanol (5:1) extract.Merge organic layer, according to Secondary to be washed with water, saturated brine, anhydrous sodium sulfate drying, is concentrated under reduced pressure, is dried in vacuo (70 DEG C, 7h), obtains B2M-NH2- 2, For faint yellow solid (3.3g, 91%)：mp：142-143.5℃；1H-NMR(DMSO-d6) δ 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).
1- (3- (methyl (6- morpholinyls pyrimidine-4-yl) amido) phenyl) -3- (5- methylisoxazole -3- bases) urea (B2M- 20-2)
3- amino -5- methylisoxazoles (0.21g, 2.1mmol) are dissolved in anhydrous methylene chloride (15ml), chloro-carbonic acid is added dropwise Phenyl ester (0.34g, 2.2mmol), is stirred at room temperature 1h.Add triethylamine (0.65g, 6.4mmol), B2M-NH2- 2 (0.58g, 2.0mmol), it is refluxed 2h.Let cool, revolving removes solvent, adds ethyl acetate (10ml) and 0.1mol/L sodium hydroxide water Solution (3ml), is beaten 1h.Filtering, wash filter cake, be dried in vacuo (80 DEG C, 3h), obtain B2M-20-2, be 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), the solution or uniform mixed that PBS (-) is made into 1000 μ g/mL is added Suspension, then with PBS (-) dilution containing DMSO.
Cell line：A549 (human lung carcinoma cell), HCT116 (people's colon-cancer cell), CEM (human leukemia cell) and MCA-MB- 435 (human melanoma cells) and HUVEC (Human umbilical vein endothelial cells).Above cell line is by Shanghai Institute of Pharmaceutical Industry Pharmacological Evaluation research center freezes and passes on.
Nutrient solution：A549, HCT116, CEM and MCA-MB-435 are that DMEM+10%NBS+ is dual anti-, DMEM+10%FBS+ is double It is anti-；HUVEC is dual anti-for DMEM+10~15%FBS+.
Full-automatic microplate reader：Model：WellscanMK-2, production firm：Labsystems.
Test method：Mtt assay.
A549, HCT116, CEM and MCA-MB-435：It is 4-5 × 10 that 96 orifice plates add concentration per hole4The cell of a/ml hangs 100 μ l of liquid, put 37 DEG C, 5%CO2In incubator.After 24h, addition sample liquid, 10 μ l/ holes, if duplicate hole, 37 DEG C, 5%CO2Under Act on 72h.The 20 μ l of MTT solution of 5mg/ml are added per hole, 100 μ l/ holes of lysate is added after acting on 4h, puts in incubator, it is molten After solution 570nm OD values are surveyed with the full-automatic microplate reader of MK-2.
HUVEC：It is 1 × 10 that 96 orifice plates, which add concentration per hole,5The 100 μ l of cell suspension of a/ml, put 37 DEG C, 5%CO2Culture In case.After 24h, addition sample liquid, 10 μ l/ holes, if duplicate hole, 37 DEG C, 5%CO2Lower effect 48h.Add 5mg/ml's per hole 20 μ l of MTT solution, add 100 μ l/ holes of lysate after acting on 4h, put in incubator, are surveyed after dissolving with the full-automatic microplate reader of MK-2 570nm OD values.
1.2 result of the test
Result of the test is shown in Table 1.
In-vitro multiplication inhibitory action of the 1 specific compound of formula I of table to human tumor cells
External protein kinase suppresses experiment
Using Caliper mobility shift assay modes (referring to the .Journal such as Card A of Biomolecular Screening,2009,14(1):10 compound of formula I 31-42.) are tested under 10 μM of concentration, in ATP Under Km concentration for ALK, Aurora A, EGFR, FGFR1, FLT-3, VEGFR-2, c-KIT, c-MET, PDGFR β, TIE-2, The percent inhibition of 11 kinases such as p 38 alpha.The positive control of detection is the blank group for being not added with sample, and negative control is EDTA groups, Reference compound is Staurosporine.Instrument is Caliper EZ Reader II.Kinase reaction condition is shown in Table 2.
2 kinase reaction condition of table
Kinases Kinase concentration (nM) ATP concentration (μM) Whether there is MnCl2 Reaction time
ALK 0.8 82 Nothing 1h
Aurora A 3.5 33 Nothing 1h
EGFR 8 2.3 Have 1h
FGFR-1 6 262 Nothing 1h
FLT-3 0.45 97 Nothing 1h
VEGFR-2 1.8 92 Nothing 1h
c-KIT 12 87 Nothing 40min
c-MET 4.5 75 Nothing 1h
PDGFRβ 6 38 Nothing 5h
TIE-2 6 157 Nothing 1h
p38α 6 195 Nothing 1h
Using Invitrogen companies LanthaScreenTMMode under 0.5 μM and 1.5 μM of ATP concentration, is tested respectively 10 compound of formula I for the percent inhibition of BRAF and BRAF V599E, and test 4 compound of formula I under 10 μM of concentration For the IC of BRAF and BRAF V599E50.Operating method respectively refers to the file of Invitrogen companies offer《PV3848 BRAF Assay Validation》With《PV3849 BRAF V599E Assay Validation》.
Kinases percent inhibition test result is shown in Table 3 and table 4, IC50Test result is shown in Table 5.
Percent inhibition (%) of 3 10 compound of formula I of table to protein kinase
Sample ID ALK Aurora A EGFR FGFR-1 FLT-3 p38α
A1-3-1 28 50 7 3 89 44
A2-3-0 65 95 98 95 92 2
A2-1-2 17 55 11 -7 56 4
A2-1-3 63 25 38 32 65 16
A2-3-2 26 15 2 0 47 30
A2-3-3 101 14 58 92 88 0
A2M-3-3 35 5 14 41 93 5
A2M-14-3 19 22 4 19 63 5
A2M-1-2 16 3 6 5 11 26
A2N-3-1 14 -6 0 -1 23 9
Percent inhibition (Continued) (%) of 4 10 compound of formula I of table to protein kinase
IC of 54 compound of formula I of table to protein kinase50(nM)
Sample ID BRAF BRAF V599E
A2-3-0 722 298
A2-1-2 1068 626
A2-3-2 271 142
A2M-1-2 366 232
Internal anti-tumor activity test
5 compound of formula I are selected, using Sorafenib as positive control, using transplanting in the Human lung cancer A549 mould of nude mice Type, with the oral gastric infusion of 25mg/kg dosage 12 days, using the tumor control rate based on relative tumour volume (RTV) to refer mainly to Mark investigates its Anticancer effect in vivo, and by observing the changes of weight preliminary examinations of tested nude mice its toxic reactions.Examination in vivo Test and the results are 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 for (i.e. d0) measurement gained gross tumor volume, Vt when dividing cage The gross tumor volume of (d4, d8, d12, d16) when measuring each time.
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 with blank control group (t inspections)：*P<0.05, * * P<0.01.
Formula Compound I there is growth to press down human tumor cell line and Human umbilical vein endothelial cells (HUVEC) in vitro System activity.The human tumor cell line includes but not limited to A549 human lung carcinoma cells, HCT116 people's colon-cancer cell, the white blood of CEM people Sick cell and MCA-MB-435 human melanoma cell.
There is growth inhibitory activity to human tumour xenograft tumor in formula Compound I body.The human tumour xenogenesis Transplantable tumor includes but not limited to transplant in the A549 human lung cancers of nude mice.

Claims (13)

1. a kind of carbamide compounds or its pharmaceutically acceptable salt；
2. the preparation method of carbamide compounds as claimed in claim 1, it includes the following steps：By A2-CAR-2 0.98g, 2- methyl -5- fluoroanilines 0.22g and triethylamine 0.57g are added in anhydrous DMF 8mL, and 4.25h is stirred at 40 DEG C；By gained palm fibre After yellow reaction thing is diluted with dichloromethane 90mL, successively with 1mol/L sodium hydrate aqueous solutions and water washing, anhydrous sodium sulfate Rotated after drying；Gained residue silica gel column chromatography, with ethyl acetate：Ethanol 100：0~100：6 gradient elutions, obtain white solid Body 0.23g；
3. compound as follows：
3- (2- methyl -6- morpholinyl pyrimidine-4-yls amido) anilino- formic acid (4- nitrobenzenes) ester hydrochloride (A2-CAR-2).
4. carbamide compounds as claimed in claim 1 or its pharmaceutically acceptable salt are preparing prevention and/or treatment lactation Animal is lacked of proper care with protein kinase mediated signal transduction pathway, or answering in the medicine of the newborn relevant disease of abnormal vascular With；The disease is tumour, diabetes, autoimmune disease, nerve degenerative diseases, diabetic retinopathy, old Year property macular degeneration, artery sclerosis, psoriasis or inflammation.
5. application as claimed in claim 4, it is characterised in that：The tumour is skin, lung, lymphocyte, kidney, liver Dirty, stomach, colon, rectum, bladder, head, neck, mammary gland, thyroid gland, oesophagus, the tumour of pancreas or prostate.
6. application as claimed in claim 4, it is characterised in that the tumour is the tumour or malignant hematologic disease of brain.
7. application as claimed in claim 4, it is characterised in that：The protein kinase is tyrosine kinase, serine/Soviet Union's ammonia Acid kinase, and/or the various saltant types of foregoing kinases.
8. application as claimed in claim 7, it is characterised in that：The tyrosine kinase for EGFR, HER-2, VEGFR-1, VEGFR-2、VEGFR-3、PDGFRα、PDGFRβ、c-KIT、CSF-1R、FLT-3、c-MET、FGFR-1、TIE-2、p38α、SRC、 LCK, FYN or HCK；The serine/threonine kinase is BRAF, CRAF, Aurora A or Aurora B；The mutation Type kinase is BRAF V599E.
9. carbamide compounds as claimed in claim 1 or its pharmaceutically acceptable salt have human tumour heterograft in preparation Application in the medicine of knurl inhibitory activity.
10. application as claimed in claim 9, it is characterised in that：The human tumour xenograft tumor is transplanting in nude mice A549 human lung cancers.
11. carbamide compounds as claimed in claim 1 or its pharmaceutically acceptable salt are thin with A549 human lung cancers in preparation Born of the same parents, HCT116 people's colon-cancer cell, CEM human leukemia cells or MCA-MB-435 human melanoma cell inhibitory activity medicine in Application.
12. carbamide compounds as claimed in claim 1 or its pharmaceutically acceptable salt have human umblilical vein endothelial in preparation Application in the medicine of cell inhibitory activity.
13. the pharmaceutical composition comprising carbamide compounds as claimed in claim 1 or its pharmaceutically acceptable salt.
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