CN105130907B - Pyrimidines and application thereof - Google Patents

Pyrimidines and application thereof Download PDF

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CN105130907B
CN105130907B CN201510454968.6A CN201510454968A CN105130907B CN 105130907 B CN105130907 B CN 105130907B CN 201510454968 A CN201510454968 A CN 201510454968A CN 105130907 B CN105130907 B CN 105130907B
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compound
phenyl
alkyl
pharmaceutically acceptable
diazanyl
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CN105130907A (en
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秦铭泽
宫平
赵燕芳
翟鑫
刘亚婧
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Shenyang Pharmaceutical University
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Shenyang Pharmaceutical University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/48—Two nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/47—One nitrogen atom and one oxygen or sulfur atom, e.g. cytosine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Abstract

The present invention relates to pyridine derivatives and their pharmaceutically acceptable salts, hydrate or prodrug, wherein substituent X, R shown in general formula I1、R2、R3, Ar there is the meaning that provides in the description.The present invention relates to the compounds of general formula I to have the function of inhibiting EGFR kinase mutants and such compound for treating and the purposes of the relevant disease of EGFR kinase activity.

Description

Pyrimidines and application thereof
Technical field
The present invention relates to new pyrimidines and its pharmaceutically acceptable salt, hydrate or its prodrug, they Preparation method and pharmaceutical composition containing the compound.The invention further relates to such compounds and its pharmaceutically acceptable Salt, hydrate or its prodrug prepare treatment in the drug of EGF-R ELISA (EGFR) kinase mutant associated disease Purposes.
Background technology
EGF-R ELISA (EGFR) is a member in tyrosine kinase receptor erbB families, can by with epidermis Growth factor combines the signal transduction to activation pathway downstream, and important work is played during cell growth, proliferation, migration etc. With.The overexpression of EGFR or mutation have been found closely related with the generation of a variety of solid tumors, such as lung neoplasm, forefront adenoncus Tumor, tumor of breast etc..Therefore, targeted inhibition EGFR kinase activity has been considered as the important means of oncotherapy.
Iressa (Iressa) and Erlotinib (Tarceva) are the irreversible EGFR inhibitors of the first generation, at present by FDA Approval was for previously receiving chemotherapy or being unsuitable for the Locally Advanced or Metastatic Nsclc (NSCLC) of chemotherapy Treatment.Particularly with EGFR Activating mutations in tumor tissues, (the 19th Exon deletion is mutated del E746_A750 or the 21st Exon replacement mutation L858R) positive patient, receiving treated with gefitinib initial stage, the state of an illness can be effectively controlled.So And there is the drug resistance to such drug, subsequent tumour rapid progress after treatment 10-16 is a month in about 70% patient.Pass through base Because detection means is found, the 20th exon produces secondary mutations in the EGFR gene of about 50% drug resistance patient, 790 The threonine of point sports methionine (T790M), which not only reduces EGFR inhibitor and the affinity of target, increases simultaneously The strong combination of kinases and ATP, to make ATP competitive types inhibitor be unable to reach effective treatment concentration in patient's body.The machine System is also the EGFR inhibitor acquired resistance mechanism being widely recognized as at present.
For the drug resistance for overcoming T790M mutation to generate, second generation non reversibility inhibitor is developed in succession, such as BIBW- 2992, HKI-272 and PF-0299804 etc..Such inhibitor is made by introducing the receptor of a Michael's addition in the molecule Form irreversible covalent bond with the Cys797 of ATP-binding site in EGFR, cause ATP not compete therewith.However, should Class EGFR-TKI has the structural framework of amido quinazoline similar with first generation inhibitor or quinoline, is acting on EGFR While T790M, also can with wild type (Wild Type, WT) EGFR covalent bonds in normal structure, to show dosage For example serious fash of restricted toxicity, diarrhea etc., cause patient that can not be resistant to and interrupt treatment.
In recent years, it is attracted wide attention by the third generation EGFR inhibitor of representative of CO-1686 and AZD-9291.With Two generation drugs are similar, such compound equally tool, can be with the mutational sites EGFR there are one the receptor structure of Michael's addition Cys797 covalent bonds.The difference is that third generation inhibitor using aminopyrimidine as structural framework, be spatially easier to The methionine in mutational site interacts, therefore with stronger EGFR T790M selectivity.Kinase activity test result shows CO-1686 and AZD-9291 inhibits EGFR Activating mutations and combines the IC of drug resistant mutants50It is below 25nM, while for wild There is type EGFR 10 times or more of selectivity, this selectivity to provide possibility to find safely and effectively treatment concentration.Currently, CO-1686 and AZD-9291 is in II phase clinical researches, and curative effect and safety need further to be verified.Therefore, urgently Exploitation is needed to be used for the treatment of NSCLC for the selective inhibitor of EGFR mutant.
Invention content：
The present invention relates to pyrimidines and its pharmaceutically acceptable salt, hydrate or prodrug shown in general formula I,
Wherein, X O, S or NH；
R1The C replaced for halogen or halogen1-C4Alkyl, preferably Cl, Br or CF3；
R2For H or (C1-C4) alkyl；
R3For
R4It is H or end by R5(the C of substitution1-C3) alkyl；
R5For by 1-2 (C1-C2) alkyl-substituted amino or 5-6 member saturated heterocyclyls, the heterocycle can optionally contain There are the 1-4 hetero atoms for being selected from N, O and S, and can be by 1-3 identical or different R6Substitution；
R6For (C1-C4) alkyl, (C1-C4) alkoxy or hydroxyl；
Preferably, R3For
R4For H or by R5Substituted methyl；
R5For dimethylamino, morpholinyl, piperidyl, piperazinyl or N methyl piperazine base；
Ar is phenyl, pyridyl group, pyrimidine radicals, pyrazinyl or indyl, and can be optionally identical or different by 1-3 R7Substitution；
R7For halogen, hydroxyl, amino, cyano, trifluoromethyl, trifluoromethoxy, (C1-C6) alkyl, (C1-C6) alkoxy, By 1-2 (C1-C2) alkyl-substituted amino, mesyl or by R8Substituted benzyl；
R8For halogen, hydroxyl, (C1-C6) alkyl or (C1-C6) alkoxy；
Represent substituent group junction.
Present invention is preferably related to pyrimidines shown in general formula I and its pharmaceutically acceptable salt, hydrates or preceding Medicine,
Wherein, X is O or NH；
R1For Cl or CF3；
R2For H or CH3。
R3For
R4For H or by end by R5(the C of substitution1-C3) alkyl；
R5For by 1-2 (C1-C2) alkyl-substituted amino or 5-6 member saturated heterocyclyls, the heterocycle can optionally contain There are the 1-4 hetero atoms for being selected from N, O and S, and can be by 1-3 identical or different R6Substitution；
R6For (C1-C4) alkyl, (C1-C4) alkoxy or hydroxyl；
Ar is phenyl, pyridyl group, pyrimidine radicals, pyrazinyl or indyl, and can be optionally identical or different by 1-3 R7Substitution；
R7For halogen, hydroxyl, amino, cyano, trifluoromethyl, trifluoromethoxy, (C1-C6) alkyl, (C1-C6) alcoxyl Base, by 1-2 (C1-C2) alkyl-substituted amino, mesyl or by R8Substituted benzyl；
R8For halogen, hydroxyl, (C1-C6) alkyl or (C1-C6) alkoxy；
The present invention be also preferably relate to pyrimidines and its pharmaceutically acceptable salt, hydrate shown in general formula I or Prodrug,
Wherein, X is O or NH；
R1For Cl or CF3；
R2For H or CH3；
R3For
R4For H or by R5Substituted methyl；
R5For dimethylamino, morpholinyl, piperidyl, piperazinyl or N methyl piperazine base.
Ar is phenyl, pyridyl group, pyrimidine radicals, pyrazinyl or indyl, and can be optionally identical or different by 1-3 R7Substitution；
R7For halogen, hydroxyl, amino, cyano, trifluoromethyl, trifluoromethoxy, (C1-C6) alkyl, (C1-C6) alkoxy, By 1-2 (C1-C2) alkyl-substituted amino, mesyl or the benzyl replaced by R8；
R8 is halogen, hydroxyl, (C1-C6) alkyl or (C1-C6) alkoxy；
It is specifically preferred according to the invention to be related to pyrimidines and its pharmaceutically acceptable salt, hydrate shown in general formula I Or prodrug,
Wherein, X is O or NH；
R1For Cl or CF3；
R2For H or CH3；
R3For
R4For H or by R5Substituted methyl；
R5For dimethylamino, morpholinyl, piperidyl, piperazinyl or N methyl piperazine base.
Ar is phenyl, pyridyl group or pyrazinyl, and optionally by 1-3 identical or different R7Substitution；
R7For halogen, hydroxyl, trifluoromethyl, trifluoromethoxy, (C1-C6) alkyl, (C1-C6) alkoxy or by R8Substitution Benzyl；
R8For halogen, (C1-C6) alkyl or (C1-C6) alkoxy.
The present invention is it is also particularly that be related to pyrimidines and its pharmaceutically acceptable salt, hydration shown in general formula I Object or prodrug,
Wherein, X is O or NH；
R1For Cl or CF3；
R2For H or CH3；
R3For
Ar is phenyl, pyridyl group or pyrazinyl, and can be optionally by R identical or different 1-37Substitution；
R7For halogen, hydroxyl, trifluoromethyl, trifluoromethoxy, (C1-C6) alkyl, (C1-C6) alkoxy or by R8Substitution Benzyl；
R8For halogen, (C1-C6) alkyl or (C1-C6) alkoxy.
The present invention is more particularly preferably related to pyrimidines and its pharmaceutically acceptable salt, water shown in general formula I Object or prodrug are closed,
Wherein, X is O or NH；
R1 is Cl or CF3；
R2For H or CH3；
R3For
Ar is phenyl, pyridyl group or pyrazinyl, and optionally by 1-3 identical or different R7Substitution；
R7For fluorine, methyl or methoxyl group.
The preferably following compound of compound of Formula I of the present invention and its pharmaceutically acceptable salt, hydrate or prodrug, but this A little compounds are not meant to any limitation of the invention：
Moreover, according to some usual methods of the art, the pyridine derivatives of formula of I of the present invention can be with Pharmaceutically acceptable salt is generated with acid.Pharmaceutically acceptable addition salts include inorganic acid and organic acid addition salt, with following sour addition Salt is particularly preferred：Hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-methyl benzenesulfonic acid, benzene sulfonic acid, two sulphur of naphthalene Acid, acetic acid, propionic acid, lactic acid, trifluoroacetic acid, maleic acid, citric acid, fumaric acid, oxalic acid, tartaric acid, benzoic acid etc..
In addition, the invention also includes the prodrugs of derivative of the present invention.The prodrug of derivative of the present invention is the derivative of general formula I Object, their own may have weaker activity even without activity, but upon administration, in physiological conditions (such as pass through Metabolism, solvolysis or other mode) it is converted to corresponding biologically active form.
" halogen " refers to fluorine, chlorine, bromine or iodine generation in the present invention；" alkyl " refers to the alkyl of linear chain or branched chain；" heterocycle " Refer to being selected from the heteroatomic monocycle of N, O, S or polycyclic cyclic annular system containing one or more, cyclic annular system is non-armaticity, Such as morpholinyl, piperidyl or piperazinyl etc..
The present invention can contain the pyridine derivatives of formula I above and its pharmaceutically acceptable salt, hydrate are used as activity Composition is prepared by mixing into composition with pharmaceutically acceptable excipient, and is prepared into clinically acceptable dosage form, above-mentioned tax Shape agent refers to that can be used for the diluent, adjuvant or carrier of pharmaceutical field.Above-mentioned dosage form refers to clinically common injection, piece Agent, capsule etc..
Iressa (Iressa) and Erlotinib (Tarceva) are a lines of the Patients with Non-small-cell Lung with Activating mutations Therapy, however the T790M mutation that the 20th exon of EGFR kinases generates make about 50% patient produce drug resistance.It opens at present Second generation inhibitor such as BIBW-2992, HKI-272 and PF-0299804 of hair etc. can effectively inhibit EGFR T790M mutant, However lacking selectivity for WT EGFR makes treatment generate dose-limiting toxicity.
It has been found that compound of the present invention has the function of significantly inhibiting at least one EGFR kinase mutants, There is potent inhibiting effect especially for the closely related EGFR T790M point mutation of the generation of drug resistance, while hardly Inhibit WT EGFR, this in current research and development the first generation and second generation inhibitor form a sharp contrast.In some embodiments In, a kind of Activating mutations of inhibition and (or) T790M of the compound selectivity provided are mutated.Activating mutations be L858R and delE746_A750." hardly inhibiting Wild type EGFR " refers to the IC that provided compound inhibits Wild type EGFR50At least It is 10 μM.
Simultaneously, it has been found that compound of the present invention can significantly inhibit H1975 (expression EGFR L858R/ T790M) the proliferation of tumor cell line, while to A549 (expression WT EGFR and K-Ras mutation) and A431 (expression WT EGFR) Cell line activity is weaker, further confirms compound involved in the present invention in the treatment of non-small cell lung cancer and overcomes EGFR There is development prospect in T790M resistant mutations.
Examples provided hereinafter and preparation example further elucidate and illustrate the present invention compound and its preparation side Method.It should be appreciated that the range of following examples and preparation example does not limit the scope of the invention in any way.
The preparation of I derivative of formula of the present invention is summarized and described to following synthetic route (route 1), and all raw materials are all Be prepared by way of described in these synthetic routes, by organic chemistry filed method well-known to the ordinarily skilled artisan or Person is commercially available.The all final derivatives of the present invention are all by method described in these synthetic routes or by similar with its Method prepare, these methods are that organic chemistry filed is well-known to the ordinarily skilled artisan.That is applied in these synthetic routes is complete Definition in the definition of portion's variable factor following article or such as claim.
Compound of formula I according to the invention can be prepared according to the method for route 1.
Compound of formula I according to the invention, works as R1For Cl, when X is NH, preparation method such as 2 institute of route of intermediate E -1 Show.
Work as R1For Cl, when X is O, the preparation method of intermediate E -2 is as shown in Scheme 3.
Work as R1For CF3, when X is NH, the preparation method of intermediate E -3 is as shown in Scheme 4.
Work as R1For CF3, when X is O, the preparation method of intermediate E -3 is as shown in Scheme 5.
Specific implementation mode：
Below in an example, the method for preparing the part compound is depicted.It will be appreciated that following methods and affiliated Other methods known to the those of ordinary skill in field can be adapted for the preparation of all compounds of the present invention.Implement Example is intended to elaboration rather than limits the scope of the invention.
Embodiment 1:(E)-N- (3- ((the chloro- 2- of 5- (2- (2- fluorobenzylidenes) diazanyl) pyrimidine-4-yl) amino) phenyl) Acrylamide (I-1)
Step 1：Tertiary butyl-(3- ((2,5- dichloro pyrimidine -4- bases) amino) phenyl) carbamate (E-1)
At room temperature, by 2,4,5- trichloropyrimidines (17.47g, 0.096mol), N-BOC-1,3- phenylenediamines (19.98g, 0.096mol) and potassium carbonate (19.91g, 0.144mol) is added in n,N-Dimethylformamide (10mL), is stirred to react 3 hours. After completion of the reaction, reaction solution is poured into ice water and is vigorously stirred, solid is precipitated, filtered, faint yellow solid is obtained after filtration cakes torrefaction 30.81g yield 90.80%.
Step 2：Tertiary butyl-(3- ((the chloro- 2- hydrazinopyrimidines -4- bases of 5-) amino) phenyl) carbamate
Second is added in tertiary butyl -3- ((2,5- dichloro pyrimidine -4- bases) amino) carbanilate (5g, 0.014mol) In alcohol (20mL), it is slowly added to hydrazine hydrate (2.06mL, 0.042mol), is warming up to back flow reaction 2 hours.Reaction solution is cooled to Room temperature filters, and pale solid 3.32g, yield 64.5% are obtained after filtration cakes torrefaction.
Step 3：Tertiary butyl-(E)-(3- ((the chloro- 2- of 5- (2- (2- fluorobenzylidenes) diazanyl) pyrimidine-4-yl) amino) benzene Base) carbamate
At room temperature, by tertiary butyl -3- ((the chloro- 2- hydrazinopyrimidines -4- bases of 5-) amino) carbanilic acid ester (1.0g, 3mmol) and 2- fluorobenzaldehydes (0.39g, 3.3mmol) are added into isopropanol (10mL), are warming up to back flow reaction 3 hours.It will Reaction solution is cooled to room temperature, and is stirred 1 hour, and solid is precipitated, and is filtered, and filtration cakes torrefaction obtains white solid 1.17g, yield 85.5%.
Step 4：(E)-N1(the chloro- 2- of 5- (2- (2- fluorobenzylidenes) diazanyl) pyrimidine-4-yl) -1,3- phenylenediamines
At room temperature, by tertiary butyl-(E) -3- ((the chloro- 2- of 5- (2- (2- fluorobenzylidenes) diazanyl) pyrimidine-4-yl) amino) Carbanilic acid ester (1.17g, 2.6mmol) be added in dichloromethane (10mL), be slowly dropped into trifluoroacetic acid (9.21g, 0.08mol), this temperature is maintained to continue to be stirred to react 5 hours.Solvent is evaporated off, water (20mL) is added into system, with unsaturated carbonate Potassium solution adjusts PH to 8, and solid is precipitated, and filters, and filtration cakes torrefaction obtains white solid 0.58g, yield 62.7%.
Step 5：(E)-N- (3- ((the chloro- 2- of 5- (2- (2- fluorobenzylidenes) diazanyl) pyrimidine-4-yl) amino) phenyl) third Acrylamide (I-1)
At 0 DEG C, by (E)-N1(the chloro- 2- of 5- (2- (2- fluorobenzylidenes) diazanyl) pyrimidine-4-yl) -1,3- phenylenediamines (0.1g, 0.28mmol) and n,N-diisopropylethylamine (0.04g, 0.31mmol) are added into dichloromethane (mL), to system In acryloyl chloride (0.025g, 0.28mmol) is slowly added dropwise.Drop finishes, and reaction solution is warming up to 25 DEG C, is stirred to react 1 hour.Instead After answering, organic layer uses saturated potassium carbonate, saturated salt solution and water washing, organic layer to be dried over anhydrous sodium sulfate successively, steams Do to obtain gray solid.Crude product is with methylene chloride/methanol (30:1) it is eluant, eluent, white solid is obtained after purification through silicagel column 0.087g, yield 75.7%.
ESI-MS m/z:411.1[M+H]+；1H NMR(600MHz,DMSO-d6)δ13.10(s,1H),10.67(s,1H), 10.27 (s, 1H), 8.54 (s, 1H), 8.32 (d, J=55.7Hz, 3H), 7.75 (d, J=5.9Hz, 1H), 7.52 (dd, J= 13.3,5.7Hz, 1H), 7.39 (t, J=7.9Hz, 1H), 7.32 (dd, J=16.3,8.2Hz, 3H), 6.63 (dd, J=16.9, 10.2Hz, 1H), 6.28 (d, J=16.9Hz, 1H), 5.76 (d, J=10.3Hz, 1H).
According to the synthetic method of embodiment 1, with the intermediate (E-1) in route 2 for raw material, after hydration hydrazine reaction, lead to It crosses and obtains corresponding intermediate G from different substituted benzaldehyde (acetophenone) condensation reactions, using Deprotection, amidation process The compound of embodiment I-2~I-8 is prepared.
Embodiment 2:(E)-N- (3- ((the chloro- 2- of 5- (2- (4- fluorobenzylidenes) diazanyl) pyrimidine-4-yl) amino) phenyl) Acrylamide (I-2)
ESI-MS m/z:411.2[M+H]+；1H NMR(400MHz,DMSO-d6)δ11.40(s,1H),10.34(s,1H), 9.06 (s, 1H), 8.17 (s, 1H), 8.13 (br, 2H), 7.72 (dd, J=8.6,5.7Hz, 2H), 7.58 (d, J=53.2Hz, 2H), 7.28 (dt, J=17.7,8.5Hz, 3H), 6.53 (dd, J=16.8,10.1Hz, 1H), 6.26 (dd, J=17.0, 1.9Hz, 1H), 5.74 (dd, J=10.3,1.6Hz, 1H).
Embodiment 3:(E)-N- (3- ((the chloro- 2- of 5- (2- (2,4 difluorobenzene methylene) diazanyl) -4- bases) amino) phenyl) Acrylamide (I-3)
ESI-MS m/z:429.1[M+H]+；1H NMR(400MHz,DMSO-d6)δ11.23(s,1H),10.16(s,1H), 8.94 (s, 1H), 8.23 (s, 1H), 8.16 (s, 1H), 7.99 (s, 1H), 7.92 (dd, J=15.5,8.6Hz, 1H), 7.73 (d, J=6.5Hz, 1H), 7.44 (d, J=7.7Hz, 1H), 7.31-7.35 (m, 2H), 7.13 (td, J=8.8,2.1Hz, 1H), 6.46 (dd, J=16.9,10.1Hz, 1H), 6.25 (dd, J=17.0,1.9Hz, 1H), 5.75 (m, 1H).
Embodiment 4：(E)-N- (4- ((the chloro- 2- of 5- (2- (1- (2- fluorophenyls) ethylidene) diazanyl) pyrimidine-4-yl) amino) Phenyl) acrylamide (I-4)
ESI-MS m/z:425.2[M+H]+。
Embodiment 5：(E)-N- (3- ((the chloro- 2- of 5- (2- (1- (4- fluorophenyls) ethylidene) diazanyl) pyrimidine-4-yl) amino) Phenyl) acrylamide (I-5)
ESI-MS m/z:425.3[M+H]+；1H NMR(400MHz,DMSO-d6)δ10.49(s,1H),10.28(s,1H), 9.30 (s, 1H), 8.22 (s, 1H), 8.10 (s, 1H), 7.93 (dd, J=7.3,6.0Hz, 2H), 7.71 (s, 1H), 7.48 (d, J =8.4Hz, 1H), 7.32-7.36 (m, 1H), 7.21-7.25 (m, 2H), 6.47 (dd, J=16.9,10.1Hz, 1H), 6.25 (dd, J=16.9,1.6Hz, 1H), 5.74 (dd, J=10.2,1.3Hz, 1H), 2.32 (s, 3H).
Embodiment 6：(E)-N- (3- ((the chloro- 2- of 5- (2- (1- (2,4 difluorobenzene base) ethylidene) diazanyl) pyrimidine-4-yl) Amino) phenyl) acrylamide (I-6)
ESI-MS m/z:443.5[M+H]+；1H NMR(400MHz,DMSO-d6)δ10.15(s,1H),10.02(s,1H), 8.90 (s, 1H), 8.18 (s, 1H), 8.10 (s, 1H), 7.78 (d, J=7.7Hz, 1H), 7.71 (td, J=8.9,7.0Hz, 1H), 7.39 (dd, J=8.4,0.8Hz, 1H), 7.24-7.31 (m, 2H), 7.09 (td, J=8.6,2.7Hz, 1H), 6.45 (dd, J=17.0,10.1Hz, 1H), 6.25 (dd, J=17.0,2.0Hz, 1H), 5.74 (dd, J=10.1,2.0Hz, 1H), 2.28(s,3H)。
Embodiment 7：(E)-N- (3- ((the chloro- 2- of 5- (2- (1- (4- aminomethyl phenyls) ethylidene) diazanyl) pyrimidine-4-yl) ammonia Base) phenyl) acrylamide (I-7)
ESI-MS m/z:421.5[M+H]+；1H NMR(400MHz,DMSO-d6)δ10.17(s,1H),9.94(s,1H), 8.92 (s, 1H), 8.17 (s, 1H), 8.07 (s, 1H), 7.92 (s, 1H), 7.74 (d, J=7.8Hz, 2H), 7.45 (dd, J= 8.1,1.3Hz, 1H), 7.31 (t, J=7.8Hz, 1H), 7.19 (d, J=7.9Hz, 2H), 6.45 (dd, J=16.9,10.1Hz, 1H), 6.26 (dd, J=16.9,1.9Hz, 1H), 5.73 (dd, J=10.3,1.7Hz, 1H), 2.32 (s, 3H), 2.26 (s, 3H)。
Embodiment 8：(E)-N- (3- ((the chloro- 2- of 5- (2- (1- (4- methoxyphenyls) ethylidene) diazanyl) pyrimidine-4-yl) Amino) phenyl) acrylamide (I-8)
ESI-MS m/z:437.2[M+H]+；1H NMR(400MHz,DMSO-d6)δ11.55(s,1H),10.36(s,1H), 10.34 (s, 1H), 8.29 (s, 1H), 7.80-7.96 (m, 3H), 7.58 (d, J=7.6Hz, 1H), 7.37-7.44 (m, 2H), 7.00 (d, J=9.0Hz, 2H), 6.50 (dd, J=17.0,10.1Hz, 1H), 6.28 (dd, J=16.9,1.8Hz, 1H), 5.78 (dd, J=10.1,1.8Hz, 1H), 3.82 (s, 3H), 2.37 (s, 3H).
Embodiment 9:(E)-N- (3- ((the chloro- 2- of 5- (2- (2- fluorobenzylidenes) diazanyl) pyrimidine-4-yl) oxygroup) phenyl) Acrylamide (I-9)
Step 1：Tertiary butyl-(3- ((2,5- dichloro pyrimidine -4- bases) oxygroup) phenyl) carbamate (E-2)
By 2,4,5- trichloropyrimidines (0.33g, 1.8mmol), N-BOC- m-aminophenols (0.38g, 1.8mmol) and carbonic acid Potassium (0.38g, 2.7mmol) is added in n,N-Dimethylformamide (10mL), is warming up to 50 DEG C and is stirred to react 2 hours.It has reacted Reaction solution is poured into ice water and is continued stirring 30 minutes, solid is precipitated, filtered, faint yellow solid is obtained after filtration cakes torrefaction by Bi Hou 0.25g, yield 39.2%.
Step 2：Tertiary butyl-(3- ((the chloro- 2- hydrazinopyrimidines -4- bases of 5-) oxygroup) phenyl) carbamate
Tertiary butyl-(3- ((2,5- dichloro pyrimidine -4- bases) oxygroup) phenyl) carbamate (0.5g, 1.4mmol) is added Enter in pyridine (8mL), at 25 DEG C be added dropwise hydrazine hydrate (0.07mL, 1.8mmol), drop finish be warming up to 50 DEG C react 2 hours.It is evaporated off Water (20mL) dichloromethane extraction (20mL) is added into system, organic layer is evaporated off and obtains yellow solid for pyridine.Crude product is with dichloro Methane/methanol (10:1) it is eluant, eluent, obtains light yellow solid 0.28g, yield 57.1% after purification through silicagel column.
Step 3：Tertiary butyl-(E)-(3- ((the chloro- 2- of 5- (2- (2- fluorobenzylidenes) diazanyl) pyrimidine-4-yl) oxygroup) benzene Base) carbamate
At room temperature, by tertiary butyl-(3- ((the chloro- 2- hydrazinopyrimidines -4- bases of 5-) oxygroup) phenyl) carbamate (1g, 2.8mmol) and 2- fluorobenzaldehydes (0.38g, 3.0mmol) are added into isopropanol (5mL), are warming up to back flow reaction 5 hours.It will Reaction solution is cooled to room temperature, and is stirred 1 hour, and solid is precipitated, and is filtered, and filtration cakes torrefaction obtains white solid 0.85g, yield 66.4%.
Step 4：(E) -3- ((the chloro- 2- of 5- (2- (2- fluorobenzylidenes) diazanyl) pyrimidine-4-yl) oxygroup) aniline
By tertiary butyl-(E)-(3- ((the chloro- 2- of 5- (2- (2- fluorobenzylidenes) diazanyl) pyrimidine-4-yl) oxygroup) phenyl) ammonia Carbamate (0.85g, 1.9mmol) be added in dichloromethane (10mL), be slowly added dropwise at 0 DEG C trifluoroacetic acid (6.52g, 0.057mol), drop finishes and reaction solution is risen to 25 DEG C is stirred to react 3 hours.Solvent is evaporated off, water (20mL) is added into system, with Unsaturated carbonate potassium solution adjusts PH to 7, and solid is precipitated, and filters, and filtration cakes torrefaction obtains white solid 0.49g, yield 72.1%.
Step 5：(E)-N- (3- ((the chloro- 2- of 5- (2- (2- fluorobenzylidenes) diazanyl) pyrimidine-4-yl) oxygroup) phenyl) third Acrylamide (I-9)
At 0 DEG C, by (E) -3- ((the chloro- 2- of 5- (2- (2- fluorobenzylidenes) diazanyl) pyrimidine-4-yl) oxygroup) aniline (0.1g, 0.28mmol) and n,N-diisopropylethylamine (0.04g, 0.31mmol) are added into dichloromethane (mL), to system In acryloyl chloride (0.025g, 0.28mmol) is slowly added dropwise.Drop finishes, and reaction solution is warming up to 25 DEG C, is stirred to react 2 hours.Instead After answering, organic layer uses saturated potassium carbonate, saturated salt solution and water washing, organic layer to be dried over anhydrous sodium sulfate successively, steams Do to obtain gray solid.Crude product is with methylene chloride/methanol (40:1) it is eluant, eluent, white solid is obtained after purification through silicagel column 0.088g, yield 73.3%.
ESI-MS m/z:412.2[M+H]+；1H NMR(400MHz,DMSO-d6)δ10.56(s,1H),10.32(s,1H), 8.26 (s, 1H), 8.13 (s, 1H), 7.78 (m, 1H), 7.41-7.46 (m, 1H), 7.56 (td, J=7.7,1.5Hz, 1H), 7.32 (t, J=1.4Hz, 1H), 7.22 (t, J=7.5Hz, 1H), 7.13-7.17 (m, 1H), 6.95-7.01 (m, 1H), 6.86 (dt, J=7.5,1.6Hz, 1H), 6.32 (dd, J=16.8,9.9Hz, 1H), 6.07 (dd, J=16.5,2.2Hz, 1H), 5.83 (dd, J=9.9,2.2Hz, 1H).
According to the synthetic method of embodiment 9, with the intermediate (E-2) in route 3 for raw material, after hydration hydrazine reaction, lead to It crosses and obtains corresponding intermediate G from different substituted aromatic aldehyde (ketone) condensation reactions, prepared using Deprotection, amidation process Obtain the compound of embodiment I-10~I-23.
Embodiment 10:(E)-N- (3- ((the chloro- 2- of 5- (2- (2- fluorobenzylidenes) diazanyl) pyrimidine-4-yl) oxygroup) phenyl) Acrylamide (I-10)
ESI-MS m/z:412.1[M+H]+；1H NMR(400MHz,DMSO-d6)δ10.75(s,1H),9.31(s,1H), 8.26 (s, 1H), 7.85 (s, 1H), 7.62-7.71 (m, 2H), 7.21-7.27 (m, 4H), 7.10 (dt, J=7.5,1.5Hz, 1H), 6.85 (dt, J=7.5,1.4Hz, 1H), 6.24 (dd, J=16.8,9.9Hz, 1H), 6.07 (dd, J=16.8,2.2Hz, 1H), 5.77 (dd, J=9.9,2.2Hz, 1H).
Embodiment 11：(E)-N- (4- ((the chloro- 2- of 5- (2- (2,4 difluorobenzene methylene) diazanyl) pyrimidine-4-yl) oxygroup) Phenyl) acrylamide (I-11)
ESI-MS m/z:430.2[M+H]+。
Embodiment 12：(E)-N- (3- ((the chloro- 2- of 5- (2- (1- (2- fluorophenyls) ethylidene) diazanyl) pyrimidine-4-yl) oxygen Base) phenyl) acrylamide (I-12)
ESI-MS m/z:426.0[M+H]+；1H NMR(400MHz,DMSO-d6)δ10.76.(s,1H),9.03(s,1H), 8.32 (s, 1H), 7.57-7.66 (m, 1H), 7.42-7.51 (m, 1H), 7.40 (td, J=7.5,1.5Hz, 1H), 7.30-7.33 (m, 2H), 7.16 (t, J=7.4Hz, 1H), 6.87 (dt, J=7.5,1.5Hz, 1H), 6.76 (dt, J=7.5,1.4Hz, 1H), 6.40 (dd, J=16.5,10.0Hz, 1H), 6.11 (dd, J=16.2,2.0Hz, 1H), 5.87 (dd, J=9.1,2.3Hz, 1H),2.76(s,3H)。
Embodiment 13：(E)-N- (3- ((the chloro- 2- of 5- (2- (1- (4- fluorophenyls) ethylidene) diazanyl) pyrimidine-4-yl) oxygen Base) phenyl) acrylamide (I-13)
ESI-MS m/z:426.1[M+H]+；1H NMR(400MHz,DMSO-d6)δ10.35(s,1H),8.96(s,1H), 8.31 (s, 1H), 7.62-7.70 (m, 2H), 7.55 (t, J=7.8Hz, 2H), 7.22-7.26 (m, 2H), 6.99 (dt, J= 7.3,1.6Hz, 1H), 6.77 (dt, J=7.2,1.7Hz, 1H), 6.37 (dd, J=16.8,9.6Hz, 1H), 6.12 (dd, J= 16.5,2.0Hz, 1H), 5.56 (dd, J=9.9,2.2Hz, 1H), 2.82 (s, 3H).
Embodiment 14：(E)-N- (3- ((the chloro- 2- of 5- (2- (1- (2,4 difluorobenzene base) ethylidene) diazanyl) pyrimidine-4-yl) Oxygroup) phenyl) acrylamide (I-14)
ESI-MS m/z:443.9[M+H]+。
Embodiment 15：(E)-N- (3- ((the chloro- 2- of 5- (2- (1- (4- aminomethyl phenyls) ethylidene) diazanyl) pyrimidine-4-yl) oxygen Base) phenyl) acrylamide (I-15)
ESI-MS m/z:422.0[M+H]+。
Embodiment 16：(E)-N- (3- ((the chloro- 2- of 5- (2- (1- (4- methoxyphenyls) ethylidene) diazanyl) pyrimidine-4-yl) Oxygroup) phenyl) acrylamide (I-16)
ESI-MS m/z:438.1[M+H]+。
Embodiment 17：(E)-N- (3- ((the chloro- 2- of 5- (2- (pyridine -2- methylenes) diazanyl) pyrimidine-4-yl) oxygroup) benzene Base) acrylamide (I-17)
ESI-MS m/z:395.2[M+H]+；1H NMR(400MHz,DMSO-d6)δ10.65(s,1H),9.13(s,1H), 8.45 (dd, J=7.5,1.4Hz, 1H), 8.37 (s, 1H), 8.20 (s, 1H), 7.75-7.79 (m, 1H), 7.76 (dd, J= 7.2,1.6Hz, 1H), 7.35-7.42 (m, 1H), 7.30 (t, J=1.6Hz, 1H), 7.22 (t, J=7.1Hz, 1H), 6.58- 6.61 (m, 2H), 6.32 (dd, J=16.8,10.0Hz, 1H), 6.11 (dd, J=16.8,2.2Hz, 1H), 5.37 (dd, J= 9.8,2.0Hz,1H)。
Embodiment 18：(E)-N- (4- ((the chloro- 2- of 5- (2- (pyridin-3-yl methylene) diazanyl) pyrimidine-4-yl) oxygroup) benzene Base) acrylamide (I-18)
ESI-MS m/z:395.1[M+H]+；1H NMR(400MHz,DMSO-d6)δ10.17(s,1H),8.89(s,1H), 8.52-7.56 (m, 1H), 8.47 (d, J=1.4Hz, 1H), 8.32 (s, 2H), 7.84 (dd, J=7.6,1.3Hz, 1H), 7.37 (t, J=7.5Hz, 1H), 7.25 (t, J=1.8Hz, 1H), 7.17-7.21 (m, 1H), 6.99 (dd, J=7.6,1.7Hz, 1H), 6.72-6.77 (m, 1H), 6.33 (dd, J=15.6,10.2Hz, 1H), 6.12 (dd, J=15.8,2.2Hz, 1H), 5.76 (dd, J=9.3,1.5Hz, 1H).
Embodiment 19：(E)-N- (3- ((the chloro- 2- of 5- (2- (pyridin-4-yl methylene) diazanyl) pyrimidine-4-yl) oxygroup) benzene Base) acrylamide (I-19)
ESI-MS m/z:395.1[M+H]+。
Embodiment 20：(E)-N- (3- ((the chloro- 2- of 5- (2- (1- (pyridine -2- bases) ethylidene) diazanyl) pyrimidine-4-yl) oxygen Base) phenyl) acrylamide (I-20)
ESI-MS m/z:409.0[M+H]+；1H NMR(400MHz,DMSO-d6)δ10.37(s,1H),8.59–8.63(m, 2H), 8.21 (s, 1H), 7.75 (dt, J=12.1,6.5Hz, 1H), 7.56-7.62 (m, 2H), 7.41 (t, J=2.2Hz, 1H), 7.26-7.31 (m, 1H), 7.02 (dd, J=7.5,1.4Hz, 1H), 6.62 (dt, J=7.5,1.6Hz, 1H), 6.29 (d, J= 15.6Hz, 1H), 6.07 (d, J=16.2Hz, 1H), 5.67 (dd, J=9.2,1.5Hz, 1H), 2.42 (s, 3H)
Embodiment 21：(E)-N- (3- ((the chloro- 2- of 5- (2- (1- (pyridin-3-yl) ethylidene) diazanyl) pyrimidine-4-yl) oxygen Base) phenyl) acrylamide (I-21)
ESI-MS m/z:408.9[M+H]+。
Embodiment 22：(E)-N- (3- ((the chloro- 2- of 5- (2- (1- (pyridin-4-yl) ethylidene) diazanyl) pyrimidine-4-yl) oxygen Base) phenyl) acrylamide (I-22)
ESI-MS m/z:409.0[M+H]+。
Embodiment 23：(E)-N- (3- ((the chloro- 2- of 5- (2- (1- (pyrazine -2- bases) ethylidene) diazanyl) pyrimidine-4-yl) oxygen Base) phenyl) acrylamide (I-23)
ESI-MS m/z:410.0[M+H]+。
Embodiment 24：(E)-N- (3- ((2- (2- (2- fluorobenzylidenes) diazanyl) -5- (trifluoromethyl) pyrimidine-4-yl) ammonia Base) phenyl) acrylamide (I-24)
Step 1：Tertiary butyl-(3- ((2- chloro- 5- (trifluoromethyl) pyrimidine-4-yl) amino) phenyl) carbamate (E- 3)
By 2,4-, bis- chloro- 5- trifluoromethyl pyrimidines (20g, 0.093mol), N-BOC-1,3- phenylenediamines (19.26g, 0.093mol) and potassium carbonate (19.17g, 0.139mol) is added in n,N-Dimethylformamide (10mL), and 25 DEG C are stirred to react 1 Hour, it rises to 50 DEG C and reacts 1 hour.Reaction solution is poured into ice water, solid is precipitated, is filtered, yellow solid is obtained after filtration cakes torrefaction 29.97g yield 83.5%.
Step 2：Tertiary butyl-(3- ((2- diazanyls -5- (trifluoromethyl) pyrimidine-4-yl) amino) phenyl) carbamate
At room temperature, by tertiary butyl-(3- ((2- chloro- 5- (trifluoromethyl) pyrimidine-4-yl) amino) phenyl) carbamate (5g, 0.013mol) is added in ethyl alcohol (30mL), is slowly added to hydrazine hydrate (1.875mL, 0.039mol), is warming up to back flow reaction 1.5 hour.Reaction solution is cooled to room temperature, petroleum ether (20mL) is added and is stirred 30 minutes, is filtered, grey is obtained after filtration cakes torrefaction Solid 3.87g, yield 78.2%.
Step 3：Tertiary butyl-(E)-(3- ((2- (2- (2- fluorobenzylidenes) diazanyl) -5- (trifluoromethyl) pyrimidine-4-yl) Amino) phenyl) carbamate
At room temperature, by tertiary butyl-(3- ((2- diazanyls -5- (trifluoromethyl) pyrimidine-4-yl) amino) phenyl) carbamic acid Ester (1g, 2.6mmol) and 2- fluorobenzaldehydes (0.36g, 2.9mmol) are added into ethyl alcohol (10mL), and it is small to be warming up to back flow reaction 5 When.Reaction solution is cooled to room temperature, solid is precipitated, is filtered, white solid 0.97g, yield 76.4% are obtained after filtration cakes torrefaction.
Step 4：(E)-N1(2- (2- (2- fluorobenzylidenes) diazanyl) -5- (trifluoromethyl) pyrimidine-4-yl) -1,3- benzene Diamines
By tertiary butyl-(E)-(3- ((2- (2- (2- fluorobenzylidenes) diazanyl) -5- (trifluoromethyl) pyrimidine-4-yl) ammonia Base) phenyl) carbamate (0.97g, 2.0mmol) is added in dry dichloromethane (15mL), trifluoro second is added dropwise at 0 DEG C Sour (7.45g, 0.065mol), drop finish, and are warming up to 25 DEG C and react 1.5 hours.Solvent is evaporated off, water (15mL) is added into system, PH to 7 is adjusted with unsaturated carbonate potassium solution, solid is precipitated, is filtered, filtration cakes torrefaction obtains white solid 0.56g, yield 71.8%.
Step 5:(E)-N- (3- ((2- (2- (2- fluorobenzylidenes) diazanyl) -5- (trifluoromethyl) pyrimidine-4-yl) amino) Phenyl) acrylamide (I-24)
At 0 DEG C, by (E)-N1(2- (2- (2- fluorobenzylidenes) diazanyl) -5- (trifluoromethyl) pyrimidine-4-yl) -1, 3- phenylenediamines (0.12g, 0.31mmol) and n,N-diisopropylethylamine (0.044g, 0.34mmol) are added to dry dichloromethane In alkane (mL), acryloyl chloride (0.028g, 0.31mmol) is slowly added dropwise into system.Drop finishes, and reaction solution is stirred to react at 0 DEG C 1 hour, after be warming up to 25 DEG C, continue to be stirred to react 1 hour.After completion of the reaction, organic layer uses saturated potassium carbonate, saturation food successively Brine and water washing, organic layer are dried over anhydrous sodium sulfate, and are evaporated to obtain gray solid.Crude product is with methylene chloride/methanol (45:1) For eluant, eluent, white solid 0.095g, yield 71.4% are obtained after purification through silicagel column.
ESI-MS m/z:444.9[M+H]+；1H NMR(400MHz,DMSO-d6)δ11.66(s,1H),8.54(s,1H), 8.16 (s, 1H), 7.89 (s, 1H), 7.56-7.62 (m, 1H), 7.36-7.43 (m, 2H), 7.32 (dd, J=7.8,1.5Hz, 1H), 7.17-7.28 (m, 3H), 7.13 (t, J=1.4Hz, 1H), 6.87 (s, 1H), 6.33 (dd, J=15.6,9.2Hz, 1H), 6.06 (dd, J=16.1,1.9Hz, 1H), 5.83 (dd, J=11.2,2.0Hz, 1H).
According to the synthetic method of embodiment 24, with the intermediate (E-3) in route 4 for raw material, after hydration hydrazine reaction, lead to Aromatic aldehyde (ketone) condensation reaction for crossing different substitutions obtains corresponding intermediate G, is prepared into using Deprotection, amidation process To the compound of embodiment I-25~I-38.
Embodiment 25：(E)-N- (3- ((2- (2- (4- fluorobenzylidenes) diazanyl) -5- (trifluoromethyl) pyrimidine-4-yl) ammonia Base) phenyl) acrylamide (I-25)
ESI-MS m/z:445.0[M+H]+；1H NMR(400MHz,DMSO-d6)δ10.62(s,1H),9.03(s,1H), 8.11 (s, 1H), 7.65 (s, 1H), 7.56-7.61 (m, 2H), 7.38-7.46 (m, 2H), 7.28 (d, J=8.1,3H), 7.20 (dt, J=7.9,1.7Hz, 1H), 6.97 (s, 1H), 6.32 (dd, J=16.9,9.9Hz, 1H), 6.11 (d, J=15.2Hz, 1H), 5.65 (dd, J=9.9,2.2Hz, 1H)
Embodiment 26：(E)-N- (3- ((2- (2- (2,4 difluorobenzene methylene) diazanyl) -5- (trifluoromethyl) pyrimidines -4- Base) amino) phenyl) acrylamide (I-26)
ESI-MS m/z:463.1[M+H]+。
Embodiment 27：(E)-N- (4- ((2- (2- (1- (2- fluorophenyls) ethylidene) diazanyl) -5- (trifluoromethyl) pyrimidines - 4- yls) amino) phenyl) acrylamide (I-27)
ESI-MS m/z:459.1[M+H]+；1H NMR(400MHz,DMSO-d6)δ10.57(s,1H),8.82(s,1H), 8.56 (s, 1H), 7.56-7.65 (m, 2H), 7.47 (s, 1H), 7.37-7.42 (m, 3H), 7.17 (td, J=7.1,1.6Hz, 1H), 7.02-7.10 (m, 2H), 6.34 (d, J=15.2,1H), 6.10 (d, J=16.3,1H), 5.77 (dd, J=10.1, 2.1Hz,1H),2.42(s,3H)。
Embodiment 28：(E)-N- (3- ((2- (2- (1- (4- fluorophenyls) ethylidene) diazanyl) -5- (trifluoromethyl) pyrimidines - 4- yls) amino) phenyl) acrylamide (I-28)
ESI-MS m/z:459.1[M+H]+。
Embodiment 29：(E) (((2- (2- (1- (2,4 difluorobenzene base) ethylidene) diazanyl) -5- (trifluoromethyl) is phonetic by 3- by-N- Pyridine -4- bases) amino) phenyl) acrylamide (I-29)
ESI-MS m/z:477.0[M+H]+。
Embodiment 30：(E) (((2- (2- (1- (4- aminomethyl phenyls) ethylidene) diazanyl) -5- (trifluoromethyl) is phonetic by 3- by-N- Pyridine -4- bases) amino) phenyl) acrylamide (I-30)
ESI-MS m/z:455.2[M+H]+。
Embodiment 31：(E) (((2- (2- (1- (4- methoxyphenyls) ethylidene) diazanyl) -5- (trifluoromethyl) is phonetic by 3- by-N- Pyridine -4- bases) amino) phenyl) acrylamide (I-31)
ESI-MS m/z:471.1[M+H]+。
Embodiment 32：(E)-N- (3- ((2- (2- (pyridine -2- methylenes) diazanyl) -5- (trifluoromethyl) pyrimidines -4- Base) amino) phenyl) acrylamide (I-32)
ESI-MS m/z:428.1[M+H]+；1H NMR(400MHz,DMSO-d6)δ10.68(s,1H),8.57(s,1H), 8.30 (d, J=7.4Hz, 1H), 8.29 (d, J=5.7Hz, 2H), 7.57-7.62 (m, 2H), 7.51 (s, 1H), 7.30-7.37 (m, 2H), 7.27 (t, J=6.8Hz, 1H), 7.11 (d, J=7.5Hz, 1H), 7.02 (t, J=1.4Hz, 1H), 6.52-6.58 (m, 1H), 6.22 (dd, J=15.7,2.2Hz, 1H), 5.85 (dd, J=9.7,1.9Hz, 1H).
Embodiment 33：(E)-N- (3- ((2- (2- (pyridin-3-yl methylene) diazanyl) -5- (trifluoromethyl) pyrimidines -4- Base) amino) phenyl) acrylamide (I-33)
ESI-MS m/z:428.0[M+H]+；1H NMR(400MHz,DMSO-d6)δ11.02(s,1H),8.98(s,1H), 8.47 (dd, J=8.2,1.6Hz, 1H), 8.42 (d, J=1.5Hz, 1H), 8.16-8.22 (m, 2H), 7.87 (d, J=8.2Hz, 1H), 7.35 (dt, J=16.5,7.7Hz, 2H), 7.22-7.28 (m, 3H), 7.07 (dt, J=7.5,1.4Hz, 1H), 6.29 (d, J=15.2,1H), 6.06 (d, J=15.6Hz, 1H), 5.67 (dd, J=10.1,1.8Hz, 1H).
Embodiment 34：(E)-N- (3- ((2- (2- (pyridin-3-yl methylene) diazanyl) -5- (trifluoromethyl) pyrimidines -4- Base) amino) phenyl) acrylamide (I-34)
ESI-MS m/z:428.1[M+H]+。
Embodiment 35：(E)-N- (3- ((2- (2- (1- (pyridine -2- bases) ethylidene) diazanyl) -5- (trifluoromethyl) pyrimidines - 4- yls) amino) phenyl) acrylamide (I-35)
ESI-MS m/z:442.0[M+H]+；1H NMR(400MHz,DMSO-d6)δ10.76(s,1H),8.58(s,1H), 8.62 (d, J=8.0Hz, 1H), 8.17 (s, 1H), 7.76-7.82 (m, 2H), 7.65 (td, J=7.8,2.0Hz, 1H), 7.53 (td, J=7.5,1.6Hz, 1H), 7.37-7.43 (m, 3H), 6.88 (t, J=1.8Hz, 1H), 6.32-6.37 (m, 1H), 6.16 (dd, J=16.8,2.3Hz, 1H), 5.72 (dd, J=9.9,2.2Hz, 1H), 2.43 (s, 3H).
Embodiment 36：(E)-N- (3- ((2- (2- (1- (pyridin-3-yl) ethylidene) diazanyl) -5- (trifluoromethyl) pyrimidines - 4- yls) amino) phenyl) acrylamide (I-36)
ESI-MS m/z:442.1[M+H]+。
Embodiment 37：(E)-N- (3- ((2- (2- (1- (pyridin-4-yl) ethylidene) diazanyl) -5- (trifluoromethyl) pyrimidines - 4- yls) amino) phenyl) acrylamide (I-37)
ESI-MS m/z:442.1[M+H]+。
Embodiment 38：(E)-N- (3- ((2- (2- (1- (pyrazine -2- bases) ethylidene) diazanyl) -5- (trifluoromethyl) pyrimidines - 4- yls) amino) phenyl) acrylamide (I-38)
ESI-MS m/z:442.9[M+H]+；1H NMR(400MHz,DMSO-d6)δ11.02(s,1H),9.97(s,1H), 8.76-8.82 (m, 2H), 8.58 (d, J=8.0Hz, 1H), 8.17 (s, 1H), 8.02 (s, 1H), 7.42 (d, J=7.5Hz, 1H), 7.22 (t, J=7.5Hz, 1H), 7.12 (d, J=7.7Hz, 1H), 6.98 (s, 1H), 6.52 (dd, J=15.6,9.8Hz, 1H), 6.11 (dd, J=16.0,1.7Hz, 1H), 5.56 (dd, J=10.2,1.5Hz, 1H), 2.32 (s, 3H).
Embodiment 39：(E)-N- (3- ((the chloro- 2- of 5- (2- ((E) -2- fluorobenzylidenes) diazanyl) pyrimidine-4-yl) amino) Phenyl) -4- (dimethylamino) but-2-enamides (I-39)
At room temperature, by (E)-N1(the chloro- 2- of 5- (2- (2- fluorobenzylidenes) diazanyl) pyrimidine-4-yl) -1,3- phenylenediamines (0.1g, 0.3mmol), n,N-diisopropylethylamine (0.097g, 0.75mmol), 4-dimethylaminopyridine (0.037g, It 0.3mmol) is added into dichloromethane (7mL), stirs 10 minutes, addition (E) -4- (dimethylamino) but-2-ene acid (0.05g, 0.3mmol), it continues at 25 DEG C and reacts 3 hours.Reaction solution is respectively washed with unsaturated carbonate potassium solution, saturated salt solution and water successively Once, organic layer is dried through anhydrous magnesium sulfate, and organic layer is evaporated off and obtains gray solid.Crude product is with methylene chloride/methanol (15:1) it is Eluant, eluent obtains white solid 0.067g, yield 47.9% through silicagel column after purification.
ESI-MS m/z:468.1[M+H]+；1H NMR(400MHz,DMSO-d6)δ11.23(s,1H),10.16(s,1H), 8.91 (s, 1H), 8.30 (s, 1H), 8.17 (s, 1H), 8.00 (s, 1H), 7.91 (t, J=7.5Hz, 1H), 7.73 (s, 1H), 7.45 (d, J=7.6Hz, 1H), 7.38 (dd, J=13.3,6.7Hz, 1H), 7.31 (t, J=8.0Hz, 1H), 7.23 (dd, J= 16.2,8.4Hz, 2H), 6.73 (m, 1H), 6.35 (d, J=15.4Hz, 1H), 3.29 (d, J=5.2Hz, 2H), 2.37 (s, 6H)。
According to the synthetic method of embodiment 39, with tertiary butyl-(3- ((the chloro- 2- hydrazinopyrimidines -4- bases of 5-) amino) phenyl) Carbamate is raw material, obtains corresponding intermediate G with 2,4- difluoro acetophenones and 4- methoxyacetophenone condensation reactions respectively, The compound of embodiment I-40 and I-41 is prepared using Deprotection, amidation process.
Embodiment 40：(E)-N- (3- ((the chloro- 2- of 5- (2- ((E) -1- (2,4- fluorophenyls) ethylidene) diazanyl) pyrimidine -4- Base) amino) phenyl) -4- (dimethylamino) but-2-enamides (I-40)
ESI-MS m/z:500.3[M+H]+；1H NMR(400MHz,DMSO-d6)δ10.17(s,1H),10.03(s,1H), 8.89 (s, 1H), 8.18 (s, 1H), 8.11 (s, 1H), 7.68-7.76 (m, 2H), 7.39 (d, J=7.8Hz, 1H), 7.27 (ddd, J=17.9,12.8,5.3Hz, 2H), 7.09 (dt, J=8.4,2.0Hz, 1H), 6.73 (dt, J=15.3,6.2Hz, 1H), 6.33 (d, J=15.1Hz, 1H), 3.22 (s, 2H), 2.29 (s, 3H), 2.28 (s, 6H).
Embodiment 41：(E)-N- (3- ((the chloro- 2- of 5- (2- ((E) -1- (4- methoxyphenyls) ethylidene) diazanyl) pyrimidines - 4- yls) amino) phenyl) -4- (dimethylamino) but-2-enamides (I-41)
ESI-MS m/z:494.5[M+H]+；1H NMR(400MHz,DMSO-d6)δ10.33(s,1H),9.87(s,1H), 8.87 (s, 1H), 8.16 (s, 1H), 8.11 (d, J=2.4Hz, 1H), 7.87 (br, 1H), 7.77 (d, J=7.7Hz, 2H), 7.46 (d, J=7.3Hz, 1H), 7.30-7.33 (m, 1H), 6.92 (d, J=7.9Hz, 2H), 6.73 (m, 1H), 6.43 (d, J= 15.3Hz, 1H), 3.79 (s, 3H), 3.69 (d, J=6.3Hz, 2H), 2.60 (s, 6H), 2.25 (s, 3H).
Embodiment 42：(E)-N- (3- ((the chloro- 2- of 5- (2- ((E) -4- fluorobenzylidenes) diazanyl) pyrimidine-4-yl) oxygroup) Phenyl) -4- (dimethylamino) but-2-enamides (I-42)
By (E) -3- ((the chloro- 2- of 5- (2- (4- fluorobenzylidenes) diazanyl) pyrimidine-4-yl) oxygroup) aniline (0.1g, 0.3mmol), n,N-diisopropylethylamine (0.097g, 0.75mmol), 4-dimethylaminopyridine (0.037g, 0.3mmol) are added Into dichloromethane (10mL), (E) -4- (dimethylamino) but-2-ene acid (0.05g, 0.3mmol) is added at 0 DEG C, is warming up to 25 DEG C are reacted 5 hours.Reaction solution is respectively washed once with unsaturated carbonate potassium solution, saturated salt solution and water successively, and organic layer is through anhydrous Magnesium sulfate is dried, and organic layer is evaporated off and obtains gray solid.Crude product is with methylene chloride/methanol (10:1) it is eluant, eluent, it is pure through silicagel column White solid 0.088g, yield 60.7% are obtained after change.
ESI-MS m/z:469.1[M+H]+；1H NMR(400MHz,DMSO-d6)δ10.37(s,1H),9.02(s,1H), 8.32 (s, 1H), 7.56 (s, 1H), 7.53-7.58 (m, 2H), 7.42 (t, J=6.7Hz, 2H), 7.22 (t, J=1.8Hz, 1H), 7.16 (t, J=7.2Hz, 1H), 7.06 (d, J=7.3Hz, 1H), 6.73-6.77 (m, 2H), 6.62 (d, J=15.6Hz, 1H), 3.72 (d, J=6.1, Hz, 2H), 2.42 (s, 6H).
According to the synthetic method of embodiment 42, with tertiary butyl-(3- ((the chloro- 2- hydrazinopyrimidines -4- bases of 5-) oxygroup) phenyl) Carbamate is raw material, obtains corresponding intermediate G with 2,4- difluoro acetophenones and 4- methoxyacetophenone condensation reactions respectively, The compound of embodiment I-43 and I-44 is prepared using Deprotection, amidation process.
Embodiment 43：(E)-N- (3- ((the chloro- 2- of 5- (2- ((E) -1- (2,4- fluorophenyls) ethylidene) diazanyl) pyrimidine -4- Base) oxygroup) phenyl) -4- (dimethylamino) but-2-enamides (I-43)
ESI-MS m/z:501.0[M+H]+；1H NMR(400MHz,DMSO-d6)δ10.52(s,1H),8.89(s,1H), 8.16 (s, 1H), 7.52-7.55 (m, 1H), 7.37-7.42 (m, 2H), 7.28 (td, J=8.2,1.6Hz, 1H), 7.16 (td, J =8.0,1.5Hz, 1H), 7.02 (d, J=7.8Hz, 1H), 6.62-6.68 (m, 2H), 6.48 (d, J=15.4Hz, 1H), 3.57 (d, J=6.1Hz, 2H), 2.73 (s, 3H), 2.56 (s, 6H).
Embodiment 44：(E)-N- (3- ((the chloro- 2- of 5- (2- ((E) -1- (4- methoxyphenyls) ethylidene) diazanyl) pyrimidines - 4- yls) oxygroup) phenyl) -4- (dimethylamino) but-2-enamides (I-44)
ESI-MS m/z:495.1[M+H]+。
Embodiment 45：(E) -4- (dimethylamino)-N- (3- ((2- (2- ((E) -4- fluorobenzylidenes) diazanyl) -5- (three Methyl fluoride) pyrimidine-4-yl) amino) phenyl) but-2-enamides (I-45)
By (E)-N1(2- (2- (4- fluorobenzylidenes) diazanyl) -5- (trifluoromethyl) pyrimidine-4-yl) -1,3- phenylenediamines (0.1g, 0.26mmol), n,N-diisopropylethylamine (0.083g, 0.64mmol), 4-dimethylaminopyridine (0.032g, 0.26mmol) be added in dichloromethane (5mL), be added with stirring (E) -4- (dimethylamino) but-2-ene acid (0.043g, 0.26mmol), reaction solution reacts 1.5 hours in 15 DEG C, then is warming up to 25 DEG C and reacts 2 hours.Organic layer saturated potassium carbonate is molten Liquid and water are respectively washed once, and organic layer is evaporated to obtain yellow-brown solid after drying.Crude product is with methylene chloride/methanol (15:1) it is elution Agent obtains white solid 0.076g, yield 58.5% through silicagel column after purification.
According to the synthetic method of embodiment 45, with tertiary butyl-(3- ((2- diazanyls -5- (trifluoromethyl) pyrimidine-4-yl) ammonia Base) phenyl) carbamate be raw material, respectively with 2,4- difluoro acetophenones, 4- methoxyacetophenones and 2- acetylpyridines into Row condensation reaction obtains corresponding intermediate G, and embodiment I-46 and I-48 is prepared using Deprotection, amidation process Compound.
Embodiment 46：(E)-N- (3- ((2- (2- ((E) -1- (2,4- fluorophenyls) ethylidene) diazanyl) -5- (trifluoromethyl) Pyrimidine-4-yl) amino) phenyl) -4- (dimethylamino) but-2-enamides (I-46)
ESI-MS m/z:534.1[M+H]+；1H NMR(400MHz,DMSO-d6)δ10.78(s,1H),8.56(s,1H), 8.22 (s, 1H), 7.65-7.70 (m, 1H), 7.42 (td, J=7.6,2.0Hz, 1H), 7.20-7.27 (m, 4H), 7.16 (d, J =6.8Hz, 1H), 6.96 (t, J=1.5Hz, 1H), 6.77 (dt, J=14.2,6.0Hz, 1H), 6.50 (d, J=14.6Hz, 1H), 3.41 (d, J=6.2Hz, 2H), 2.62 (s, 3H), 2.55 (s, 6H).
Embodiment 47：(E)-N- (3- ((2- (2- ((E) -1- (4- methoxyphenyls) ethylidene) diazanyl) -5- (fluoroforms Base) pyrimidine-4-yl) amino) phenyl) -4- (dimethylamino) but-2-enamides (I-47)
ESI-MS m/z:528.1[M+H]+。
Embodiment 48：(E) -4- (dimethylamino)-N- (3- ((2- (2- ((E) -1- (pyridine -2- bases) ethylidene) hydrazines Base) -5- (trifluoromethyl) pyrimidine-4-yl) amino) phenyl) but-2-enamides (I-48)
ESI-MS m/z:499.1[M+H]+；1H NMR(400MHz,DMSO-d6)δ10.31(s,1H),8.66(s,1H), 8.58 (dd, J=7.6,1.8Hz, 1H), 8.11 (s, 1H), 7.92 (td, J=6.8,1.5Hz, 1H), 7.86 (d, J=7.2Hz, 1H), 7.56 (td, J=7.0,2.2Hz, 1H), 7.37 (s, 1H), 7.16-7.22 (m, 2H), 7.10 (d, J=6.8Hz, 1H), 6.96 (t, J=1.3Hz, 1H), 6.85 (dt, J=16.2,5.7Hz, 1H), 6.62 (d, J=15.2Hz, 1H), 3.31 (d, J= 5.6Hz,2H),2.88(s,6H),2.30(s,3H)。
Embodiment 49：(E)-N- (3- ((2- (2- ((E)-(1- benzyl -1H- indol-3-yls) methylene) diazanyl) -5- chlorine Pyrimidine-4-yl) amino) phenyl) -4- (dimethylamino) but-2-enamides (I-49)
Step 1：(((2- (2- ((1- benzyl -1H- indol-3-yls) methylene) diazanyl) -5- chlorine is phonetic by 3- for tertiary butyl-(E) - Pyridine -4- bases) amino) phenyl) carbamate
At room temperature, by tertiary butyl-(3- ((the chloro- 2- hydrazinopyrimidines -4- bases of 5-) amino) phenyl) carbamate (0.8g, It 2.3mmol) is added into absolute ethyl alcohol (10mL), 1- benzyl -1H- indole -3-formaldehydes (0.64g, 2.7mmol), heating is added To back flow reaction 5 hours.Reaction, which finishes, is cooled to room temperature reaction solution, and solid is precipitated, and filters, and filtration cakes torrefaction obtains faint yellow solid 0.61g, yield 69.7%.
Step 2：(E)-N1(2- (2- ((1- benzyl -1H- indol-3-yls) methylene) diazanyl) -5- chlorine pyrimidine-4-yl) - 1,3- phenylenediamines
At 0 DEG C, by tertiary butyl-(E)-(3- ((2- (2- ((1- benzyl -1H- indol-3-yls) methylene) diazanyl) -5- Chlorine pyrimidine-4-yl) amino) phenyl) carbamate (0.61g, 1.1mmol) is added in dry dichloromethane (10mL), It is slowly dropped into trifluoroacetic acid (4.68g, 0.041mol), drop finishes, and reaction solution is warming up to 25 DEG C and reacts 2 hours.Solvent, Xiang Ti is evaporated off Water (20mL) is added in system, solution PH is adjusted to 8 with saturated potassium carbonate, solid is precipitated, filters, filtration cakes torrefaction obtains light yellow solid 0.38g, yield 81.4%.
(E)-N- (3- ((2- (2- ((E)-(1- benzyl -1H- indol-3-yls) methylene) diazanyl) -5- chlorine pyrimidine-4-yl) Amino) phenyl) -4- (dimethylamino) but-2-enamides (I-49)
By (E)-N1(2- (2- ((1- benzyl -1H- indol-3-yls) methylene) diazanyl) -5- chlorine pyrimidine-4-yl) -1,3- Phenylenediamine (0.1g, 0.2mmol), n,N-diisopropylethylamine (0.065g, 0.5mmol), 4-dimethylaminopyridine (0.024g, 0.2mmol) be added in dichloromethane (10mL), be added at 0 DEG C (E) -4- (dimethylamino) but-2-ene acid (0.033g, 0.2mmol), 25 DEG C are warming up to react 7 hours.Reaction solution respectively washes one with unsaturated carbonate potassium solution, saturated salt solution and water successively Secondary, organic layer is dried through anhydrous magnesium sulfate, and organic layer is evaporated off and obtains gray solid.Crude product is with methylene chloride/methanol (7:1) it is elution Agent obtains light yellow solid 0.082g, yield 70.9% after purification through silicagel column.
ESI-MS m/z:579.4[M+H]+；1H NMR(400MHz,DMSO-d6)δ10.67(s,1H),10.05(s,1H), 8.73 (s, 1H), 8.28 (s, 1H), 8.26 (d, J=7.9Hz, 1H), 8.10 (s, 1H), 7.85 (s, 1H), 7.81 (s, 1H), 7.45 (d, J=8.2Hz, 2H), 7.28-7.31 (m, 3H), 7.22-7.25 (m, 4H), 7.15-7.19 (m, 1H), 7.07 (t, J =7.5Hz, 1H), 6.69 (dt, J=15.3,5.9Hz, 1H), 6.25 (d, J=15.3Hz, 1H), 5.41 (s, 2H), 3.01 (d, J=5.4Hz, 2H), 2.13 (s, 6H).
According to the synthetic method of embodiment 49, with tertiary butyl-(3- ((the chloro- 2- hydrazinopyrimidines -4- bases of 5-) amino) phenyl) Carbamate is raw material, and carrying out condensation reaction with 1- (4- luorobenzyls) -1H- indole -3-formaldehydes obtains corresponding intermediate G, then The compound of embodiment I-50 is prepared by Deprotection, amidation process.
Embodiment 50：(E)-N- (3- ((the chloro- 2- of 5- (2- ((E)-(1- (4- luorobenzyls) -1H- indol-3-yls) methylene) Diazanyl) pyrimidine-4-yl) amino) phenyl) -4- (dimethylamino) but-2-enamides (I-50)
ESI-MS m/z:597.0[M+H]+。
According to the synthetic method of embodiment 42, with tertiary butyl-(3- ((the chloro- 2- hydrazinopyrimidines -4- bases of 5-) oxygroup) phenyl) Carbamate is raw material, is carried out respectively with 1- benzyl -1H- indole -3-formaldehydes and 1- (4- luorobenzyls) -1H- indole -3-formaldehydes Condensation reaction obtains corresponding intermediate G, and the change of embodiment I-51 and I-52 is prepared using Deprotection, amidation process Close object.
Embodiment 51：(E)-N- (3- ((2- (2- ((E)-(1- benzyl -1H- indol-3-yls) methylene) diazanyl) -5- chlorine Pyrimidine-4-yl) oxygroup) phenyl) -4- (dimethylamino) but-2-enamides (I-51)
ESI-MS m/z:580.0[M+H]+；1H NMR(400MHz,DMSO-d6)δ10.42(s,1H),9.78(s,1H), 8.52(s,1H),8.33(s,1H),8.26(s,1H),7.79–7.83(m,1H),7.50–7.55(m,1H),7.11–7.23(m, 10H), 6.98 (d, J=8.2Hz, 1H), 6.86 (d, J=8.0Hz, 1H), 6.62-6.70 (m, 1H), 6.50 (d, J= 14.7Hz, 1H), 5.86 (s, 1H), 5.43 (s, 1H), 3.52 (d, J=6.2Hz, 2H), 2.32 (s, 6H).
Embodiment 52：(E)-N- (3- ((2- (2- ((E)-(1- (4- luorobenzyls) -1H- indol-3-yls) methylene) hydrazines Base) -5- chlorine pyrimidine-4-yl) oxygroup) phenyl) -4- (dimethylamino) but-2-enamides (I-52)
ESI-MS m/z:598.1[M+H]+。
According to the method for embodiment 45, with tertiary butyl-(3- ((2- diazanyls -5- (trifluoromethyl) pyrimidine-4-yl) amino) benzene Base) carbamate be raw material, respectively with 1- benzyl -1H- indole -3-formaldehydes and 1- (4- luorobenzyls) -1H- indole -3-formaldehydes It carries out condensation reaction and obtains corresponding intermediate G, embodiment I-53 and I-54 is prepared using Deprotection, amidation process Compound.
Embodiment 53：(E)-N- (3- ((2- (2- ((E)-(1- benzyl -1H- indol-3-yls) methylene) diazanyl) -5- (three Methyl fluoride) pyrimidine-4-yl) amino) phenyl) -4- (dimethylamino) but-2-enamides (I-53)
ESI-MS m/z:613.1[M+H]+；1H NMR(400MHz,DMSO-d6)δ10.96(s,1H),10.03(s,1H), 8.35 (s, 1H), 8.17 (s, 1H), 7.87 (dd, J=7.0,1.6Hz, 1H), 7.62 (dd, J=7.1,1.5Hz, 1H), 7.12- 7.23 (m, 10H), 7.09 (d, J=7.2Hz, 1H), 6.85 (t, J=1.4Hz, 1H), 6.68-6.73 (m, 2H), 6.47 (d, J =14.6Hz, 1H), 5.31 (s, 2H), 3.55 (d, J=5.8Hz, 2H), 2.41 (s, 6H).
Embodiment 54：(E)-N- (3- ((2- (2- ((E)-(1- (4- luorobenzyls) -1H- indol-3-yls) methylene) hydrazines Base) -5- (trifluoromethyl) pyrimidine-4-yl) amino) phenyl) -4- (dimethylamino) but-2-enamides (I-53)
ESI-MS m/z:631.1[M+H]+。
The biological activity research of product of the present invention
Compound provided by the invention inhibits EGFR mutant and the activity research of WT EGFR
Inhibition EGFR T790M/L858R, EGFR have been carried out to the pyridine derivatives of formula I above according to the invention T790M/delE746_A750, EGFR T790M and the screening of WT activity of EGFR.Concrete operations are：
1) with 20mM Tris (pH7,5), 5mM MgCl2, 1mM EGTA, 5mM beta-glycerophosphates, 5% glycerine and 0.2mM DTT prepare kinase reaction buffer solution, 1.13XATP the and Tyr-Sox combination peptide substrates of 1X.
2) at 25 DEG C, take 5 each enzyme of μ L in 384 hole reaction plates, and be added 0.5 μ L 50%DMSO and 50% The compound through serial dilution prepared in DMSO, pre-incubation 30 minutes.
3) the ATP/Tyr-Sox peptide substrates mixtures that 45 μ L are added in each reacting hole start kinase reaction, in λ ex360/ It is monitored with the board-like readers of Synergy under λ em485, at the end of each analysis, checks the progress curve in each hole.
4) inhibition concentration curve is drawn, IC is calculated50Value.
Compound inhibits EGFR T790M/L858R, EGFR T790M/delE746_A750, EGFR T790M and WT The active testing of EGFR the results are shown in Table 1.
Table 1
It can be clearly seen that from above-mentioned test result, the claimed compounds of formula I of the present invention is mutated EGFR Body has significant inhibitory activity, hence it is evident that better than the inhibition to Wild type EGFR, it is seen that compound provided by the invention is EGFR Mutant selective depressant.
The present invention provides compound and inhibits proliferative activity o f tumor research:
External inhibition non-small cell lung cancer cell strain has been carried out to the pyridine derivatives of formula I above according to the invention The screening active ingredients of H1975, wherein H1975 cell strains express EGFR T790M/L858R.Concrete operations are：
1) cell recovery and after passing on 2-3 stabilization, makes it disappear from culture bottle bottom with trypsin solution (0.25%) Change is got off.After cell dissociation buffer is poured into centrifuge tube, culture solution is added later to terminate digestion.By centrifuge tube in 800r/min Lower centrifugation 10 minutes is added 5mL culture solutions after discarding supernatant liquid, blows and beats mixing cell, and it is thin to draw the addition of 10 μ L cell suspensions It is counted in born of the same parents' tally, adjustment cell concentration is 104A/hole.Except the holes A1 are that blank well is not added with extracellularly in 96 orifice plates, remaining is all 100 μ L cell suspensions are added.96 orifice plates are put into incubator and are cultivated 24 hours.
2) with 50 μ L dmso solution given the test agent, appropriate culture solution is then added, sample is made to be dissolved into 2mg/mL Then sample is diluted to 20,4,0.8,0.16,0.032 μ g/mL by liquid in 24 orifice plates.3 holes are added in each concentration, wherein Surrounding two rows, two row cell growing way is affected by environment larger, only and for blanc cell hole uses.96 orifice plates are put into incubator Cultivate 72h.
3) band medicine culture solution in 96 orifice plates is discarded, is rinsed cell twice with phosphate buffer solution (PBS), in every hole MTT (0.5mg/mL) 100 μ L are added to be put into incubator after 4 hours, discard MTT solution, 100 μ L of dimethyl sulfoxide (DMSO) are added. Oscillation makes survivaling cell fully be dissolved with MTT reaction products formazan on magnetic force oscillator, is put into measurement result in microplate reader.Pass through Bliss methods can find out drug IC50Value.Compound inhibits the Activity Results of H1975 tumor cell lines to be shown in Table 2.
Table 2
Compound number H1975IC50(μM) Compound number H1975IC50(μM)
I-1 0.29 I-29 0.82
I-2 0.43 I-30 0.73
I-3 0.38 I-31 1.11
I-4 0.56 I-32 0.032
I-5 0.39 I-33 0.027
I-6 0.30 I-34 0.41
I-7 0.74 I-35 0.058
I-8 1.06 I-36 0.065
I-9 0.40 I-37 0.48
I-10 0.069 I-38 0.017
I-11 0.85 I-39 0.59
I-12 2.03 I-40 0.48
I-13 0.56 I-41 0.99
I-14 0.17 I-42 0.67
I-15 1.68 I-43 0.065
I-16 0.57 I-44 0.31
I-17 0.068 I-45 0.81
I-18 0.11 I-46 0.57
I-19 0.26 I-47 0.42
I-20 0.055 I-48 0.39
I-21 0.66 I-49 0.26
I-22 1.32 I-50 0.17
I-23 0.039 I-51 0.12
I-24 0.22 I-52 0.63
I-25 0.31 I-53 0.056
I-26 0.40 I-54 0.045
I-27 2.02 Gefitinib 8.71
I-28 0.97
From the above it should be apparent that the compound of the claimed Formulas I of the present invention can significantly inhibit Ji Fei For the proliferation of Buddhist nun's drug-resistant cell strain H1975, be conducive to overcome resistance to caused by EGFR T790M mutation in treated with gefitinib Pharmacological property.
The compound of formula of I of the present invention can be administered alone, but typically be given with pharmaceutical carrier mixture, described medicinal The selection of carrier will be according to required route of administration and standard pharmaceutical practice, separately below with the various drug agent of such compound Type, for example, tablet, capsule, injection, aerosol, suppository, film, pill, externally-applied liniment and ointment preparation method, Illustrate its new opplication in pharmaceutical field.
Embodiment 55：Tablet
With compound (by taking 12 compound of embodiment as an example) 10g containing compound in claim 1, according to pharmacy one As after pressed disc method adds auxiliary material 20g mixings, be pressed into 100, every weight 300mg.
Embodiment 56：Capsule
With compound (by taking 36 compound of embodiment as an example) 10g containing compound in claim 1, according to pharmacy glue The requirement of wafer after auxiliary material 20g mixings, will be packed into Capsules, each capsule weight 300mg.
Embodiment 57：Injection
It is normal according to pharmacy with compound (by taking 1 compound of embodiment as an example) 10g containing compound in claim 1 Rule method carries out activated carbon adsorption, and after 0.65 μm of filtering with microporous membrane, hydro-acupuncture preparation, every dress is made in filling nitrogen gas tank 2mL, filling 100 bottles altogether.
Embodiment 58：Aerosol
With compound (by taking 22 compound of embodiment as an example) 10g containing compound in claim 1, with appropriate propylene glycol After dissolving, after distilled water and other spoke material are added, the clear solution of 500mL is made to obtain the final product.
Embodiment 59：Suppository
With compound (by taking 19 compound of embodiment as an example) 10g containing compound in claim 1, by finely ground addition The glycerin gelatine melted is added in appropriate glycerine after grinding well, grinding is uniform, is poured into the model for having applied lubricant, and suppository is made 50.
Embodiment 60：Film
With compound (by taking 13 compound of embodiment as an example) 10g containing compound in claim 1, by polyvinyl alcohol, It is dissolved by heating after the stirrings such as medicinal glycerin, water expansion, the filtering of 80 mesh screens, then 18 compound of embodiment is added in filtrate and is stirred Dissolving is mixed, film applicator is film-made 100.
Embodiment 61：Pill
With compound (by taking 17 compound of embodiment as an example) 10g containing compound in claim 1, with the matrix such as gelatin After 50g heating fusing mixings, instills in cryogenic liquid paraffin, 1000 ball of dripping pill is made altogether.
Embodiment 62：Externally-applied liniment
With compound (by taking 31 compound of embodiment as an example) 10g containing compound in claim 1, according to conventional dose The auxiliary materials 2.5g mixed grindings such as method and emulsifier, then add distilled water obtained to 200mL.
Embodiment 63：Ointment
With compound (by taking 47 compound of embodiment as an example) 10g containing compound in claim 1, finely ground rear and all scholars The oleaginous bases such as woods 500g grinds well obtained.
Although describing the present invention by particular embodiment, modification and equivalent variations are for being proficient in this field It will be apparent from for technical staff, and they are included within the scope of the invention.

Claims (11)

1. the compound and its pharmaceutically acceptable salt of general formula I,
Wherein,
X is O, S；
R1The C replaced for halogen or halogen1-C4Alkyl；
R2For H or (C1-C4) alkyl；
R3For
R4It is H or end by R5(the C of substitution1-C3) alkyl；
R5For by 1-2 (C1-C2) alkyl-substituted amino；
Ar is phenyl, pyridyl group, pyrimidine radicals, pyrazinyl or indyl, and optionally by 1-3 identical or different R7Substitution；
R7For halogen, hydroxyl, amino, cyano, trifluoromethyl, trifluoromethoxy, (C1-C6) alkyl, (C1-C6) alkoxy, by 1-2 A (C1-C2) alkyl-substituted amino；
Represent substituent group junction.
2. the compound and its pharmaceutically acceptable salt of general formula I,
Wherein,
X is O, S；
R1For Cl, Br or CF3；
R2For H or methyl；
R3For
R4It is H or end by R5(the C of substitution1-C3) alkyl；
R5For by 1-2 (C1-C2) alkyl-substituted amino；
Ar is phenyl, pyridyl group, pyrimidine radicals, pyrazinyl or indyl, and optionally by 1-3 identical or different R7Substitution；
R7For halogen, hydroxyl, amino, cyano, trifluoromethyl, trifluoromethoxy, (C1-C6) alkyl, (C1-C6) alkoxy, by 1-2 A (C1-C2) alkyl-substituted amino；
Represent substituent group junction.
3. compound as described in claim 1 and its pharmaceutically acceptable salt, wherein
R3For
R4For H or by R5Substituted methyl；R5For dimethylamino.
4. the compound as described in claim 1-3 any one and its pharmaceutically acceptable salt, wherein
Ar is phenyl, pyridyl group or pyrazinyl, and optionally by 1-3 identical or different R7Substitution；
R7For halogen, hydroxyl, trifluoromethyl, trifluoromethoxy, (C1-C6) alkyl, (C1-C6) alkoxy.
5. the compound as described in claim 1-3 any one and its pharmaceutically acceptable salt, wherein
R3For
6. compound as claimed in claim 4 and its pharmaceutically acceptable salt, wherein
R3For
7. compound and its pharmaceutically acceptable salt as described below：
8. a kind of Pharmaceutical composition, including the compound of any one of claim 1-7 and its pharmaceutically acceptable salt are made For active constituent and pharmaceutically acceptable excipient.
9. the compound and its pharmaceutically acceptable salt described in claim 1-5 any one or medicine according to any one of claims 8 The application in inhibiting EGFR mutant drugs is being prepared with composition.
10. application as claimed in claim 9, wherein EGFR mutant is T790M, Activating mutations body is L858R, delE746_ One or more of A750.
11. the compound and its pharmaceutically acceptable salt described in claim 1-7 any one or medicine according to any one of claims 8 With application of the composition in preparing treating cancer drug, the cancer is non-small cell lung cancer.
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Novel hydrazone moiety-bearing aminopyrimidines as selective inhibitors of epidermal growth factor receptor T790M mutant;Mingze Qin et al.;《European Journal of Medicinal Chemistry》;20150930;第104卷;115-126 *
Synthesis and Biological Evaluation of Novel 4-(2-Fluorophenoxy)-2-(1H-tetrazol-1-yl)pyridines Bearing Semicarbazone Moieties as Potent Antitumor Agents;Mingze Qin et al.;《Arch.Pharm.Chem.Life Sci.》;20121231;第346卷;840-850 *

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