CN106632273A - Pyrimidine compound containing azole heterocycle, composition and applications of pyrimidine compound and combination - Google Patents

Pyrimidine compound containing azole heterocycle, composition and applications of pyrimidine compound and combination Download PDF

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Publication number
CN106632273A
CN106632273A CN201611249447.8A CN201611249447A CN106632273A CN 106632273 A CN106632273 A CN 106632273A CN 201611249447 A CN201611249447 A CN 201611249447A CN 106632273 A CN106632273 A CN 106632273A
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amine
phenyl
compound
acrylamides
acceptable salt
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马晓东
宋振东
刘贺
黄珊珊
王长远
张建斌
刘克辛
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Dalian Medical University
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Dalian Medical University
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    • 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 invention relates to a pyrimidine compound containing an azole heterocycle, a composition and application of the pyrimidine compound and the combination. The pyrimidine compound containing the azole heterocycle is specifically a compound shown as a general formula (I), and substituent groups in the general formula (I) are defined in the description. The invention further relates to application of a compound shown as the general formula (I), or a pharmaceutically-acceptable salt thereof, or a medical composition containing the compound or the pharmaceutically-acceptable salt thereof to treatment of tumor diseases, in particular to treatment of non-small cell lung cancer and small cell lung cancer by inhibition of EGFR (Epidermal Growth Factor Receptor) protein tyrosine kinase. The general formula (I) is shown in the description.

Description

Pyrimidines containing azoles heterocycle, composition and application thereof
Technical field
The present invention relates to contain the pyrimidines of azoles heterocycle, composition and application thereof, belong to pharmaceutical technology field.
Background technology
Protein tyrosine kinase (protein tyrosine kinase, PTKs) is led to by the signal transduction of control cell Road adjusts a series of physiological and biochemical procedures such as growth, differentiation, the apoptosis of cell.Receptor type tyrosine kinase is a class across cell The relatively large kinases of film, ectodomain that it has ligand binding, membrane spaning domain and plays zymogenesis-in phosphorylation Specific tyrosine residue and the thus intracellular domain of impact cell propagation.(such as lung cancer, mammary gland in general human cancer Cancer, cancer of the stomach, oophoroma, lymthoma) have found the unconventionality expression of the kinases.Protein tyrosine kinase has become antineoplastic One of important target spot of research and development.
Epidermal growth factor recipient tyrosine kinase (epidermal growth factor receptor tyrosine Kinase, EGFR) it is one of earliest protein tyrosine kinase for finding, the intracellular region of EGFR has ATP-binding site, and EGFR suppresses Agent, so as to suppress the Phosphorylation events of EGFR, can block the conduction of downstream signal with competitiveness in combination with ATP-binding site, And then suppress the growth of tumour cell, break up and shift (Yun, et al.Cancer Cell 2007,11,217-227).EGFR It is elucidated with as the biochemical process of anti-tumor target, its crystal structure and active site are also clearer, as target spot Medicine Gefitinib (gefitinib), Erlotinib (erlotinib), Afatinib (afatinib) etc. be applied to Clinic, and with the further investigation of EGFR structures and activity relationship, many better outstanding EGFR inhibitors (EP0566226、WO9961428、WO0051587、WO0375947、WO0132651、WO9633980、WO9630347、 US7709479, US6716847, US6593333, US6251912, CN201080060451.4, CN201110191525.4 etc.) Have been observed that.But these medicines are inevitably present the problem of anti-drug resistance difference.Research shows：Amino acid The790 is arrived The mutation (T790M) of Met790 is the main inducing of such drug resistant.There is clinical case data display, about 60% patient's acquired resistance is all originated from caused by the mutation in T790M sites.Therefore exploitation anti-drug resistance is higher, toxicity is less, The higher new E GFR inhibitor of activity has extremely important realistic price.
Osimertinib (AZD9291) is oral irreversible, T790M Catastrophic selection EGFR inhibitors, thin in LoVo To the EGFRL858R/T790M and EGFR of the disappearances of Exon 19 in born of the same parentsWTIC50Respectively 11.44 and 493.8nM, in 2015 12 are approved by the FDA in the United States listing (WO2013014448) for treating EGFRT790MDrug-resistant type lung cancer.Rociletinib(CO- 1686, AVL-301) it is irreversible, the Catastrophic selection EGFR of another kindT790MInhibitor, acts in Cell free assay EGFRT790MAnd EGFRWTIC50Respectively 21.5nM and 303.3nM, is currently in third stage research research (WO 2012061299).Other such as HM61713, EGF816, PF-06747775, Avitinib, ASP8273 are also to enter clinical research New E GFR inhibitor (Ma et al., J.Med.Chem., 2016, DOI:10.1021/ Acs.jmedchem.5b00840.), the patent being related to is such as：US20120157426、US8563568B2、CN102740847、 CN102083800。
In view for the treatment of cancer is necessary to develop new better good medicine in the urgent need to, this area.
The content of the invention
An object of the present invention is to provide a kind of pyrimidines containing azoles heterocycle or its is pharmaceutically acceptable Salt, such compound has good antitumor activity.
Another object of the present invention is to provide containing the pyrimidines containing azoles heterocycle or its is pharmaceutically acceptable Salt pharmaceutical composition.
It is still another object of the present invention to provide pyrimidines containing azoles heterocycle or its is pharmaceutically acceptable Salt, or the purposes of the composition.
For this purpose, on the one hand, the present invention provides the compound or its pharmaceutically acceptable salt shown in a kind of formula (I), institute State the compound shown in formula (I) and there is following structure：
Wherein,
R1Selected from selecting chlorine, hydrogen, fluorine, trifluoromethyl or nitro；
R2Selected from hydrogen, chlorine, fluorine, methyl or methoxy；
Z is selected from-OCH2CH2-、-CH2- ,-NHC (=O) CH2-, direct singly-bound ,-OCH2CH2CH2-, when Z two ends are contained During hetero atom O or N, the hetero atom is connected with phenyl ring；
X is selected from CH or N；
Y is selected from CH or N.
Used as a kind of specific embodiment of the present invention, the compound shown in formula (I) of the present invention has I-1～I- Structure shown in 39：
Structural compounds as implied above are the pyrimidines containing azoles heterocycle, and antitumor activity screening of the present invention shows, Most of such compound has stronger suppression non-small cell lung cancer (NSCLC) ability of cell proliferation, and part of compounds shows Go out the anti-EGFR more more excellent than RociletinibT790MActivity.As the novel molecule of a class formation, the chemical combination in the present invention Thing has develops into the potentiality of new and effective EGFR inhibitor, to the tumor disease of therapy-related especially non-small cell lung cancer, ED-SCLC has larger using value.
Structure shown in aforementioned I-1～I-39 has respectively following title：
(I-1) N- [3- [[the chloro- 2- of 5- [[4- [2- (1H- imidazole radicals) ethyoxyl] phenyl] amine] -4- pyrimidine radicals] amine] benzene Base] -2- acrylamides；
(I-2) N- [3- [[the chloro- 2- of 5- [[4- [2- (1H- triazolyls) ethyoxyl] phenyl] amine] -4- pyrimidine radicals] amine] benzene Base] -2- acrylamides；
(I-3) N- [3- [[the fluoro- 2- of 5- [[4- [2- (1H- imidazole radicals) ethyoxyl] phenyl] amine] -4- pyrimidine radicals] amine] benzene Base] -2- acrylamides；
(I-4) N- [3- [[the chloro- 2- of 5- [[2- methoxyl group -4- (1H- imidazoles -1- methylene) phenyl] amine] -4- pyrimidine radicals] Amine] phenyl] -2- acrylamides；
(I-5) N- [3- [[the chloro- 2- of 5- [[4- [(1H- imidazole radicals) ethyoxyl] phenyl] amine] -4- pyrimidine radicals] amine] phenyl] - 2- acrylamides；
(I-6) N- [3- [[the fluoro- 2- of 5- [[4- [(1H- imidazole radicals) ethyoxyl] phenyl] amine] -4- pyrimidine radicals] amine] phenyl] - 2- acrylamides；
(I-7) N- [3- [[5- nitro -2- [[4- [2- (1H- imidazole radicals) acetylamino] phenyl] amine] -4- pyrimidine radicals] amine] Phenyl] -2- acrylamides；
(I-8) N- [3- [[5- nitro -2- [[4- [(1H- imidazole radicals)] phenyl] amine] -4- pyrimidine radicals] amine] phenyl] -2- third Acrylamide；
(I-9) N- [3- [[5- nitro -2- [[4- [3- (1H- imidazole radicals) propoxyl group] phenyl] amine] -4- pyrimidine radicals] amine] benzene Base] -2- acrylamides；
(I-10) N- [3- [[5- nitro -2- [[4- [3- (1H- tetrazole bases) propoxyl group] phenyl] amine] -4- pyrimidine radicals] Amine] phenyl] -2- acrylamides；
(I-11) N- [3- [[the chloro- 2- of 5- [[2- methyl -4- [2- (1H- imidazole radicals) ethyoxyl] phenyl] amine] -4- pyrimidines Base] amine] phenyl] -2- acrylamides；
(I-12) N- [3- [[the chloro- 2- of 5- [[the chloro- 4- of 3- [2- (1H- imidazole radicals) ethyoxyl] phenyl] amine] -4- pyrimidine radicals] Amine] phenyl] -2- acrylamides；
(I-13) N- [3- [[the chloro- 2- of 5- [[3- methoxyl group -4- [2- (1H- imidazole radicals) ethyoxyl] phenyl] amine] -4- pyrimidines Base] amine] phenyl] -2- acrylamides；
(I-14) N- [3- [[the fluoro- 2- of 5- [[2- methyl -4- [2- (1H- imidazole radicals) ethyoxyl] phenyl] amine] -4- pyrimidines Base] amine] phenyl] -2- acrylamides；
(I-15) N- [3- [[the fluoro- 2- of 5- [[the chloro- 4- of 3- [2- (1H- imidazole radicals) ethyoxyl] phenyl] amine] -4- pyrimidine radicals] Amine] phenyl] -2- acrylamides；
(I-16) N- [3- [[the fluoro- 2- of 5- [[3- methoxyl group -4- [2- (1H- imidazole radicals) ethyoxyl] phenyl] amine] -4- pyrimidines Base] amine] phenyl] -2- acrylamides；
(I-17) N- [3- [[the chloro- 2- of 5- [[2- methoxyl group -4- [2- (1H- imidazole radicals) ethyoxyl] phenyl] amine] -4- pyrimidines Base] amine] phenyl] -2- acrylamides；
(I-18) N- [3- [[the fluoro- 2- of 5- [[2- methoxyl group -4- [2- (1H- imidazole radicals) ethyoxyl] phenyl] amine] -4- pyrimidines Base] amine] phenyl] -2- acrylamides；
(I-19) N- [3- [[the chloro- 2- of 5- [[2- methyl -4- (1H- imidazoles -1- methylene) phenyl] amine] -4- pyrimidine radicals] Amine] phenyl] -2- acrylamides；
(I-20) N- [3- [[the chloro- 2- of 5- [[the chloro- 4- of 3- (1H- imidazoles -1- methylene) phenyl] amine] -4- pyrimidine radicals] amine] Phenyl] -2- acrylamides；
(I-21) N- [3- [[the chloro- 2- of 5- [[3- methoxyl group -4- (1H- imidazoles -1- methylene) phenyl] amine] -4- pyrimidine radicals] Amine] phenyl] -2- acrylamides；
(I-22) N- [3- [[5- nitro -2- [[2- methyl -4- (1H- imidazoles -1- methylene) phenyl] amine] -4- pyrimidine radicals] Amine] phenyl] -2- acrylamides；
(I-23) N- [3- [[5- nitro -2- [[the chloro- 4- of 3- (1H- imidazoles -1- methylene) phenyl] amine] -4- pyrimidine radicals] Amine] phenyl] -2- acrylamides；
(I-24) N- [3- [[5- nitro -2- [[3- methoxyl group -4- (1H- imidazoles -1- methylene) phenyl] amine] -4- pyrimidines Base] amine] phenyl] -2- acrylamides；
(I-25) N- [3- [[5- nitro -2- [[2- methoxyl group -4- (1H- imidazoles -1- methylene) phenyl] amine] -4- pyrimidines Base] amine] phenyl] -2- acrylamides；
(I-26) N- [3- [[5- nitro -2- [[2- methyl -4- [2- (1H- imidazole radicals) ethyoxyl] phenyl] amine] -4- pyrimidines Base] amine] phenyl] -2- acrylamides；
(I-27) N- [3- [[5- nitro -2- [[the chloro- 4- of 3- [2- (1H- imidazole radicals) ethyoxyl] phenyl] amine] -4- pyrimidines Base] amine] phenyl] -2- acrylamides；
(I-28) [[[5- nitro -2- [[2- methoxyl group -4- [2- (1H- imidazole radicals) ethyoxyl] phenyl] amine] -4- is phonetic for 3- for N- Piperidinyl] amine] phenyl] -2- acrylamides；
(I-29) [[[5- nitro -2- [[3- methoxyl group -4- [2- (1H- imidazole radicals) ethyoxyl] phenyl] amine] -4- is phonetic for 3- for N- Piperidinyl] amine] phenyl] -2- acrylamides；
(I-30) N- [3- [[5- nitro -2- [[2- methyl -4- [3- (1H- imidazole radicals) propoxyl group] phenyl] amine] -4- pyrimidines Base] amine] phenyl] -2- acrylamides；
(I-31) N- [3- [[5- nitro -2- [[the chloro- 4- of 3- [3- (1H- imidazole radicals) propoxyl group] phenyl] amine] -4- pyrimidines Base] amine] phenyl] -2- acrylamides；
(I-32) [[[5- nitro -2- [[3- methoxyl group -4- [3- (1H- imidazole radicals) propoxyl group] phenyl] amine] -4- is phonetic for 3- for N- Piperidinyl] amine] phenyl] -2- acrylamides；
(I-33) N- [3- [[5- trifluoromethyl -2- [[4- [2- (1H- imidazole radicals) ethyoxyl] phenyl] amine] -4- pyrimidine radicals] Amine] phenyl] -2- acrylamides；
(I-34) N- [3- [[2- [[4- [2- (1H- imidazole radicals) ethyoxyl] phenyl] amine] -4- pyrimidine radicals] amine] phenyl] -2- Acrylamide；
(I-35) N- [3- [[5- trifluoromethyl -2- [[4- [(1H- imidazole radicals) ethyoxyl] phenyl] amine] -4- pyrimidine radicals] Amine] phenyl] -2- acrylamides；
(I-36) N- [3- [[2- [[4- [(1H- imidazole radicals) ethyoxyl] phenyl] amine] -4- pyrimidine radicals] amine] phenyl] -2- third Acrylamide；
(I-37) N- [3- [[the chloro- 2- of 5- [[the fluoro- 4- of 3- (1H- imidazoles -1- methylene) phenyl] amine] -4- pyrimidine radicals] amine] Phenyl] -2- acrylamides；
(I-38) N- [3- [[the chloro- 2- of 5- [[the chloro- 4- of 3- [2- (1H- imidazole radicals) ethyoxyl] phenyl] amine] -4- pyrimidine radicals] Amine] phenyl] -2- acrylamides；
(I-39) N- [3- [[the chloro- 2- of 5- [[the fluoro- 4- of 3- [2- (1H- imidazole radicals) ethyoxyl] phenyl] amine] -4- pyrimidine radicals] Amine] phenyl] -2- acrylamides；
On the other hand, the present invention provides a kind of pharmaceutical composition, and it contains formula of the present invention (I) institute of effective dose The compound for showing or its pharmaceutically acceptable salt, and pharmaceutical carrier.
, due to their possibility purposes in medicine, the salt preferred agents of formula (I) compound can for compound of the present invention The salt of acceptance.The compound of the present invention is alkali, and salt form needed for it can be prepared by appropriate method known in the art, is wrapped Include and use mineral acid treatment free alkali, the inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid etc.；Or use at organic acid Reason free alkali, the organic acids such as acetic acid, trifluoroacetic acid, maleic acid, butanedioic acid, mandelic acid, fumaric acid, malonic acid, acetone Acid, oxalic acid, hydroxyacetic acid, salicylic acid, pyranose thuja acid (pyranosidy1acid), such as glucuronic acid or galacturonic acid, 'alpha '-hydroxy acids, such as citric acid or tartaric acid, such as amino acid, aspartic acid or glutamic acid, such as aromatic acid, benzoic acid or meat Cinnamic acid, such as sulfonic acid, p- toluenesulfonic acids, methanesulfonic acid, ethyl sulfonic acid etc..The embodiment of pharmaceutically acceptable salt include sulfate, Pyrosulfate, disulfate, sulphite, bisulfites, phosphate, chloride, bromide, iodide, acetate, propionic acid Salt, caprate, caprylate, acrylates, formates, isobutyrate, caproate, enanthate, propionate (propiolates), Oxalates, malonate, benzoate, chloro benzoate, methyl benzoic acid salt, dinitro-benzoate, hydroxy benzoate, Methoxy benzoic acid salt, phthalate, phenyl acetate salt, phenylpropionic acid salt, PB (phenylbutrates), Citrate, lactate, gamma hydroxybutyrate, hydroxyl acetate, tartrate, amygdalate and sulfonate, such as diformazan Benzene sulfonate, mesylate, propane sulfonic acid salt, naphthalene -1- sulfonate and naphthalene-2-sulfonic acid salt.
The pharmaceutical composition of the present invention usually contains a kind of the compounds of this invention.However, in some embodiments, this Bright pharmaceutical composition contains the compound for having more than a kind of present invention.In addition, the pharmaceutical composition of the present invention can also optionally include One or more other pharmaceutically active compound.
The present invention also provides the pyrimidines containing azoles heterocycle or its pharmaceutically acceptable carrier, the medicine Composition further suppresses the purposes of tumor proliferation by suppressing EGFR skin factors receptor tyrosine kinase.Specifically, the purposes Predominantly prepare for the purposes in the medicine for treating non-small cell lung cancer, ED-SCLC.
The present invention provides shown compound or its pharmaceutically acceptable salt, or pharmaceutical composition of the present invention exists Prepare the application in EGFR skin factor receptor protein tyrosine kinase inhibitor.
The present invention provides the compound or its pharmaceutically acceptable salt or medicine of the present invention shown in the formula (I) Purposes of the compositions in the medicine for preparing treatment tumour.Preferably, the tumour is selected from non-small cell lung cancer or cellule Lung cancer, further preferred non-small cell lung cancer.It is highly preferred that the purposes is mainly by suppressing EGFR skin factor receptor proteins What EGFR-TK was realized.
Description of the drawings
Fig. 1 causes the apoptotic results of H1975 for compound I-5 under 50nmol/L concentration.
Fig. 2 is to cause the apoptotic results of H1975 under the conditions of blank..
Fig. 3 causes the apoptotic results of H1975 for compound I-5 under 500nmol/L concentration.
Fig. 4 causes the apoptotic results of H1975 for compound I-5 under 200nmol/L concentration.
Fig. 5 is that blank condition and compound I-5 cause the apoptotic results of H1975 under 5～15 μM/L.
Specific embodiment
The explanation present invention is further described below in conjunction with specific embodiment, but these embodiments are not meant as limiting this Bright scope.
The experimental technique of unreceipted actual conditions in the embodiment of the present invention, generally according to normal condition, or according to raw material or Condition proposed by commodity manufacturer.The reagent in unreceipted concrete source, is the conventional reagent of market purchase.
The preparation of the target molecule of embodiment 1
Tlc silica gel plate is made using Yantai Huanghai Sea HSGF254 or Qingdao GF254 silica gel plates, thin-layered chromatography (TLC) The specification that silicon amine plate is adopted is 0.15mm-0.2mm, and it is 0.4mm- that thin-layer chromatography isolates and purifies the specification of product employing 0.5mm。
The raw material that the present invention is used is mainly purchased from commercially available from Chemical Reagent Co., Ltd., Sinopharm Group, Beijing coupling science and technology Co., Ltd, Aladdin chemical reagent Co., Ltd, up to companies such as auspicious chemicals.
Without specified otherwise in embodiment, solution refers to the aqueous solution.
Without specified otherwise in embodiment, the temperature of reaction is room temperature, is 20 DEG C -30 DEG C.
The technical solution used in the present invention is as follows：
The synthetic route of compound (I). reagent and condition:(a) meta nitro aniline, DIPEA, 1,4- dioxane, rt, 2h, 91%；b)DIPEA, 1,4- dioxane, 60 DEG C, 2h, 49-72%；(c)Fe- NH4Cl,MeOH-H2O, 80 DEG C to rt, 62-85%；(d) acryloyl chloride, NaHCO3, acetone, 10min, 43-68%, above-mentioned route In each substituent be defined as above.
The synthesis of I-b
I-a (23.44mmol) and DIPEA (4.5g, 35.16mmol) are taken in 50mL dioxane, 3- nitre is slowly added into Base aniline (3.8g, 23.44mmol), heats up 60 DEG C, and after reacting 5 hours, reaction is finished, and cooling adds 400mL water, separates out yellow White solid, suction filtration, drying obtains white solid, does not purify direct next step reaction.
The synthesis of I-c
I-b (23.44mmol) and trifluoroacetic acid (4.5g, 35.16mmol) are taken in 2-BuOH (50ml), is slowly added into and is taken For arylamine (I-f, 3.44mmol), heat up 100 DEG C, after reacting 8 hours, reaction is finished, saturated sodium bicarbonate solution is poured in cooling into In, solid is separated out, suction filtration, washing, drying silica gel column chromatography is separated, and obtains brown solid.
The synthesis of I-d
I-c (1.9g, 6.8mmol) and ammonium chloride (0.73g, 13.6mmol) are taken in reaction bulb, add MeOH (15mL) and Water (15mL), stirring is lower to add iron powder (1.5g, 27.2mmol), heats up 60 DEG C and reacts 2 hours, while hot suction filtration, and water mutually uses acetic acid Ethyl ester extracts (100mL × 3), combined ethyl acetate layer, and saturated common salt is washed once, and anhydrous sodium sulfate drying, evaporated under reduced pressure is obtained Yellow semisolid I-d.
The synthesis of object (I)
Take I-d (2.1g, 9.7mmol) to be dissolved in 20mL acetonitriles, add sodium acid carbonate (1.6g, 19.4mmol), and methyl Piperazine (1.2g, 11.64mmol), heats up 60 DEG C and reacts 5 hours, and solvent is drained after completion of the reaction, and add water 200mL, does not separate out solid Body, water is mutually extracted with ethyl acetate (100mL × 3), and combined ethyl acetate layer, saturated aqueous common salt washed once, anhydrous sodium sulfate It is dried, evaporated under reduced pressure obtains target molecule (I).
Target molecule is synthesized according to above method, the physicochemical data of synthesized target molecule is as follows：
(I-1) N- [3- [[the chloro- 2- of 5- [[4- [2- (1H- imidazole radicals) ethyoxyl] phenyl] amine] -4- pyrimidine radicals] amine] benzene Base] -2- acrylamides
1H NMR(400MHz,d6-DMSO):δ 4.12 (s, 2H), 4.31 (s, 2H), 5.75 (d, J=12.0Hz, 1H), 6.24 (d, J=16.8Hz, 1H), 6.44 (dd, J=12.0,16.8Hz, 1H), 6.70 (s, 2H), 6.90 (s, 1H), 7.22 (s, 1H),7.29-7.31(m,2H),7.44-7.49(m,3H),7.66(s,1H),7.87(s,1H),8.10(s,1H),8.90(s, 1H),9.18(s,1H),10.20(s,1H).MS(ESI)m/z 476.16[M+H]+。
(I-2) N- [3- [[the chloro- 2- of 5- [[4- [2- (1H- triazolyls) ethyoxyl] phenyl] amine] -4- pyrimidine radicals] amine] benzene Base] -2- acrylamides
1H NMR(400MHz,d6-DMSO):δ 4.07 (s, 2H), 4.26 (s, 2H), 5.70 (d, J=12.0Hz, 1H), 6.19 (d, J=16.8Hz, 1H), 6.39 (dd, J=12.0,16.8Hz, 1H), 6.64 (s, 2H), 6.84 (s, 1H), 7.17 (s, 1H),7.24-7.29(m,2H),7.44-7.48(m,2H),7.61(s,1H),7.82(s,1H),8.05(s,1H),8.84(s, 1H),9.13(s,1H),10.15(s,1H).MS(ESI)m/z 475.15[M+H]+。
(I-3) N- [3- [[the fluoro- 2- of 5- [[4- [2- (1H- imidazole radicals) ethyoxyl] phenyl] amine] -4- pyrimidine radicals] amine] benzene Base] -2- acrylamides
1H NMR(400MHz,d6-DMSO):δ 4.12 (t, J=4.0Hz, 2H)), 4.31 (t, J=4.0Hz, 2H), 5.75 (d, J=12.0Hz, 1H), 6.24 (d, J=16.8Hz, 1H), 6.44 (dd, J=12.0,16.8Hz, 1H), 6.74 (d, J= 8.0Hz, 2H), 6.91 (s, 1H), 7.24 (d, J=6.0Hz, 1H), 7.29 (d, J=12.0Hz, 2H), 7.42 (d, J= 8.4Hz, 1H), 7.53 (d, J=8.4Hz, 2H), 7.69 (s, 1H), 7.93 (s, 1H), 8.07 (s, 1H), 9.01 (s, 1H), 9.39(s,1H),10.15(s,1H).MS(ESI)m/z 460.19[M+H]+。
(I-4) N- [3- [[the chloro- 2- of 5- [[2- methoxyl group -4- (1H- imidazoles -1- methylene) phenyl] amine] -4- pyrimidine radicals] Amine] phenyl] -2- acrylamides
1H NMR(400MHz,d6-DMSO):δ 3.78 (s, 3H), 5.05 (s, 2H), 5.74 (dd, J=2.4,10.0Hz, 1H), 6.24 (dd, J=2.0,16.8Hz, 1H), 6.42 (dd, J=10.0,17.2Hz, 1H), 6.66 (d, J=8Hz, 1H), 6.88 (s, 1H), 6.97 (s, 1H), 7.15 (s, 1H), 7.20 (d, J=8.4Hz, 1H), 7.25 (s, 1H), 7.41 (d, J= 8.4Hz, 1H), 7.73 (s, 1H), 7.79 (s, 1H), 7.91 (d, J=6.0Hz, 1H), 7.92 (s, 1H), 8.11 (s, 1H), 8.95(s,1H),10.14(s,1H).MS(ESI)m/z 476.16[M+H]+。
(I-5) N- [3- [[the chloro- 2- of 5- [[4- [2- (1H- imidazole radicals) ethyoxyl] phenyl] amine] -4- pyrimidine radicals] amine] benzene Base] -2- acrylamides
1H NMR(400MHz,d6-DMSO):δ 5.02 (s, 2H), 5.75 (dd, J=2.4,10.0Hz, 1H), 6.25 (dd, J =2.0,16.8Hz, 1H), 6.47 (dd, J=10.0,17.2Hz, 1H), 6.86 (s, 1H), 7.04 (d, J=8.4Hz, 2H), 7.10 (s, 1H), 7.30 (d, J=6.0Hz, 2H), 7.50 (d, J=6.0Hz, 1H), 7.57 (d, J=8.4Hz, 2H), 7.67 (s,1H),7.85(s,1H),8.14(s,1H),8.97(s,1H),9.37(s,1H),10.18(s,1H).MS(ESI)m/z 446.14[M+H]+。
(I-6) N- [3- [[the fluoro- 2- of 5- [[4- [2- (1H- imidazole radicals) ethyoxyl] phenyl] amine] -4- pyrimidine radicals] amine] benzene Base] -2- acrylamides
1H NMR(400MHz,d6-DMSO):δ 5.04 (s, 2H), 5.76 (dd, J=2.0,10.0Hz, 1H), 6.26 (dd, J =2.0,16.8Hz, 1H), 6.50 (dd, J=10.0,16.8Hz, 1H), 6.88 (s, 1H), 7.03 (d, J=8.4Hz, 2H), 7.09 (s, 1H), 7.27 (d, J=6.0Hz, 1H), 7.43 (d, J=6.0Hz, 1H), 7.51 (d, J=6.0Hz, 1H), 7.64 (s,1H),7.69(s,1H),7.93(s,1H),8.11(s,1H),9.24(s,1H),9.46(s,1H),10.16(s,1H).MS (ESI)m/z 430.17[M+H]+。
(I-7) N- [3- [[5- nitro -2- [[4- [2- (1H- imidazole radicals) acetylamino] phenyl] amine] -4- pyrimidine radicals] amine] Phenyl] -2- acrylamides
1H NMR(400MHz,d6-DMSO):δ 5.07 (s, 2H), 5.71 (d, J=10.0Hz, 1H), 6.21 (d, J= 16.8Hz, 1H), 6.40 (dd, J=10.0,16.8Hz, 1H), 6.88 (s, 1H), 7.01 (s, 1H), 7.11 (d, J=8.4Hz, 2H), 7.27 (d, J=6.0Hz, 1H), 7.44 (d, J=6.0Hz, 1H), 7.52 (d, J=6.0Hz, 1H), 7.65 (d, J= 8.4Hz,2H),7.69(s,1H),7.83(s,1H),7.95(s,1H),8.51(s,1H),9.04(s,1H),10.32(s,1H) .MS(ESI)m/z 500.17[M+H]+。
(I-8) N- [3- [[5- nitro -2- [[4- [2- (1H- imidazole radicals)] phenyl] amine] -4- pyrimidine radicals] amine] phenyl] -2- Acrylamide
1H NMR(400MHz,d6-DMSO):δ 5.67 (d, J=10.0Hz, 1H), 6.19 (d, J=16.8Hz, 1H), 6.29 (dd, J=10.0,16.8Hz, 1H), 6.39 (s, 1H), 6.64 (d, J=8.4Hz, 2H), 6.84 (s, 1H), 7.01 (s, 1H), 7.21 (d, J=8.4Hz, 1H), 7.28 (d, J=6.0Hz, 1H), 7.38 (d, J=6.0Hz, 1H), 7.41 (s, 1H), 7.43 (s,1H),7.86(s,1H),8.02(s,1H),8.96(s,1H),9.23(s,1H),10.29(s,1H).MS(ESI)m/z 443.15[M+H]+。
(I-9) N- [3- [[5- nitro -2- [[4- [2- (1H- imidazole radicals) propoxyl group] phenyl] amine] -4- pyrimidine radicals] amine] benzene Base] -2- acrylamides
1H NMR(400MHz,d6-DMSO):δ 3.86 (m, 2H), 4.07 (t, J=4.0Hz, 2H), 4.57 (t, J= 4.0Hz, 2H), 5.72 (d, J=10.0Hz, 1H), 6.17 (d, J=16.8Hz, 1H), 6.21 (dd, J=10.0,16.8Hz, 1H), 6.39 (s, 1H), 6.64 (d, J=8.4Hz, 2H), 6.84 (s, 1H), 7.17 (d, J=8.4Hz, 2H), 7.24 (d, J= 6.0Hz, 1H), 7.44 (d, J=8.4Hz, 2H), 7.61 (s, 1H), 7.82 (s, 1H), 8.05 (s, 1H), 9.03 (s, 1H), 9.45(s,1H),10.27(s,1H).MS(ESI)m/z 501.20[M+H]+。
(I-10) N- [3- [[5- nitro -2- [[4- [2- (1H- tetrazole bases) propoxyl group] phenyl] amine] -4- pyrimidine radicals] Amine] phenyl] -2- acrylamides
1H NMR(400MHz,d6-DMSO):δ 3.87 (m, 2H), 4.10 (t, J=4.0Hz, 2H), 4.62 (t, J= 4.0Hz, 2H), 5.75 (d, J=10.0Hz, 1H), 6.18 (d, J=16.8Hz, 1H), 6.25 (dd, J=10.0,16.8Hz, 1H), 6.45 (s, 1H), 6.67 (d, J=8.4Hz, 1H), 6.87 (s, 1H), 7.20 (d, J=8.4Hz, 1H), 7.28 (d, J= 6.0Hz, 1H), 7.49 (d, J=8.4Hz, 2H), 7.71 (s, 1H), 7.88 (s, 1H), 8.15 (s, 1H), 9.13 (s, 1H), 9.55(s,1H),10.26(s,1H).MS(ESI)m/z 525.17[M+H]+。
(I-11) N- [3- [[the chloro- 2- of 5- [[2- methyl -4- [2- (1H- imidazole radicals) ethyoxyl] phenyl] amine] -4- pyrimidines Base] amine] phenyl] -2- acrylamides
1H NMR(400MHz,d6-DMSO):δ 3.66 (s, 3H), 4.13 (s, 2H), 4.35 (s, 2H), 5.76 (d, J= 12.0Hz, 1H), 6.24 (d, J=16.8Hz, 1H), 6.44 (dd, J=12.0,16.8Hz, 1H), 6.70 (s, 2H), 6.90 (s, 1H),7.22(s,1H),7.29-7.31(m,1H),7.44-7.49(m,3H),7.66(s,1H),7.87(s,1H),8.10(s, 1H),8.90(s,1H),9.19(s,1H),10.28(s,1H).MS(ESI),m/z:490.17[M+H]+。
(I-12) N- [3- [[the chloro- 2- of 5- [[the chloro- 4- of 3- [2- (1H- imidazole radicals) ethyoxyl] phenyl] amine] -4- pyrimidine radicals] Amine] phenyl] -2- acrylamides
1H NMR(400MHz,d6-DMSO):δ 4.19 (s, 2H), 4.41 (s, 2H), 5.75 (d, J=12.0Hz, 1H), 6.24 (d, J=16.8Hz, 1H), 6.44 (dd, J=12.0,16.8Hz, 1H), 6.76 (s, 2H), 6.90 (s, 1H), 7.22 (s, 1H),7.29-7.31(m,1H),7.44-7.49(m,3H),7.66(s,1H),7.87(s,1H),8.10(s,1H),8.96(s, 1H),9.28(s,1H),10.26(s,1H).MS(ESI),m/z:510.11[M+H]+。
(I-13) N- [3- [[the chloro- 2- of 5- [[3- methoxyl group -4- [2- (1H- imidazole radicals) ethyoxyl] phenyl] amine] -4- pyrimidines Base] amine] phenyl] -2- acrylamides
1H NMR(400MHz,d6-DMSO):δ 4.27 (s, 2H), 4.42 (s, 2H), 5.33 (s, 1H), 5.75 (d, J= 12.0Hz, 1H), 6.24 (d, J=16.8Hz, 1H), 6.44 (dd, J=12.0,16.8Hz, 1H), 6.70 (s, 2H), 6.90 (s, 1H),7.22(s,1H),7.29-7.31(m,1H),7.44-7.49(m,3H),7.66(s,1H),7.89(s,1H),8.15(s, 1H),8.97(s,1H),9.28(s,1H),10.36(s,1H).MS(ESI),m/z:506.16[M+H]+。
(I-14) N- [3- [[the fluoro- 2- of 5- [[2- methyl -4- [2- (1H- imidazole radicals) ethyoxyl] phenyl] amine] -4- pyrimidines Base] amine] phenyl] -2- acrylamides
1H NMR(400MHz,d6-DMSO):δ 3.76 (s, 3H), 4.23 (s, 2H), 4.35 (s, 2H), 5.76 (d, J= 12.0Hz, 1H), 6.24 (d, J=16.8Hz, 1H), 6.44 (dd, J=12.0,16.8Hz, 1H), 6.70 (s, 2H), 6.90 (s, 1H),7.22(s,1H),7.29-7.31(m,1H),7.44-7.49(m,3H),7.66(s,1H),7.77(s,1H),8.10(s, 1H),8.90(s,1H),9.14(s,1H),10.18(s,1H).MS(ESI),m/z:474.20[M+H]+。
(I-15) N- [3- [[the fluoro- 2- of 5- [[the chloro- 4- of 3- [2- (1H- imidazole radicals) ethyoxyl] phenyl] amine] -4- pyrimidine radicals] Amine] phenyl] -2- acrylamides
1H NMR(400MHz,d6-DMSO):δ 4.09 (s, 2H), 4.26 (s, 2H), 5.75 (d, J=12.0Hz, 1H), 6.24 (d, J=16.8Hz, 1H), 6.44 (dd, J=12.0,16.8Hz, 1H), 6.76 (s, 2H), 6.90 (s, 1H), 7.22 (s, 1H),7.29-7.31(m,1H),7.44-7.49(m,3H),7.74(s,1H),7.89(s,1H),8.20(s,1H),8.96(s, 1H),9.28(s,1H),10.36(s,1H).MS(ESI),m/z:494.14[M+H]+。
(I-16) N- [3- [[the fluoro- 2- of 5- [[3- methoxyl group -4- [2- (1H- imidazole radicals) ethyoxyl] phenyl] amine] -4- pyrimidines Base] amine] phenyl] -2- acrylamides
1H NMR(400MHz,d6-DMSO):δ 4.17 (s, 2H), 4.33 (s, 2H), 5.43 (s, 1H), 5.75 (d, J= 12.0Hz, 1H), 6.24 (d, J=16.8Hz, 1H), 6.44 (dd, J=12.0,16.8Hz, 1H), 6.70 (s, 2H), 6.90 (s, 1H),7.22(s,1H),7.29-7.31(m,1H),7.44-7.49(m,3H),7.66(s,1H),7.89(s,1H),8.15(s, 1H),9.05(s,1H),9.18(s,1H),10.27(s,1H).MS(ESI),m/z:490.19[M+H]+。
(I-17) N- [3- [[the chloro- 2- of 5- [[2- methoxyl group -4- [2- (1H- imidazole radicals) ethyoxyl] phenyl] amine] -4- pyrimidines Base] amine] phenyl] -2- acrylamides
1H NMR(400MHz,d6-DMSO):δ 4.17 (s, 2H), 4.42 (s, 2H), 5.53 (s, 1H), 5.75 (d, J= 12.0Hz, 1H), 6.24 (d, J=16.8Hz, 1H), 6.44 (dd, J=12.0,16.8Hz, 1H), 6.70 (s, 2H), 6.90 (s, 1H),7.22(s,1H),7.29-7.31(m,1H),7.44-7.49(m,3H),7.66(s,1H),7.89(s,1H),8.15(s, 1H),8.99(s,1H),9.18(s,1H),10.18(s,1H).MS(ESI),m/z:506.16[M+H]+。
(I-18) N- [3- [[the fluoro- 2- of 5- [[2- methoxyl group -4- [2- (1H- imidazole radicals) ethyoxyl] phenyl] amine] -4- pyrimidines Base] amine] phenyl] -2- acrylamides
1H NMR(400MHz,d6-DMSO):δ 4.09 (s, 2H), 4.22 (s, 2H), 5.37 (s, 1H), 5.75 (d, J= 12.0Hz, 1H), 6.24 (d, J=16.8Hz, 1H), 6.44 (dd, J=12.0,16.8Hz, 1H), 6.70 (s, 2H), 6.90 (s, 1H),7.22(s,1H),7.29-7.31(m,1H),7.44-7.49(m,3H),7.76(s,1H),7.90(s,1H),8.15(s, 1H),8.99(s,1H),9.21(s,1H),10.24(s,1H).MS(ESI),m/z:490.19[M+H]+。
(I-19) N- [3- [[the chloro- 2- of 5- [[2- methyl -4- (1H- imidazoles -1- methylene) phenyl] amine] -4- pyrimidine radicals] Amine] phenyl] -2- acrylamides
1H NMR(400MHz,d6-DMSO):δ 2.89 (s, 3H), 5.02 (s, 2H), 5.75 (dd, J=2.4,10.0Hz, 1H), 6.25 (dd, J=2.0,16.8Hz, 1H), 6.47 (dd, J=10.0,17.2Hz, 1H), 6.86 (s, 1H), 7.04 (d, J =8.4Hz, 2H), 7.10 (s, 1H), 7.30 (d, J=6.0Hz, 2H), 7.50 (d, J=6.0Hz, 1H), 7.57 (d, J= 8.4Hz,1H),7.67(s,1H),7.85(s,1H),8.14(s,1H),8.97(s,1H),9.37(s,1H),10.18(s,1H) .MS(ESI),MS(ESI),m/z:46016[M+H]+。
(I-20) N- [3- [[the chloro- 2- of 5- [[the chloro- 4- of 3- (1H- imidazoles -1- methylene) phenyl] amine] -4- pyrimidine radicals] amine] Phenyl] -2- acrylamides
1H NMR(400MHz,d6-DMSO):δ 5.02 (s, 2H), 5.75 (dd, J=2.4,10.0Hz, 1H), 6.25 (dd, J =2.0,16.8Hz, 1H), 6.47 (dd, J=10.0,17.2Hz, 1H), 6.86 (s, 1H), 7.14 (d, J=8.4Hz, 2H), 7.20 (s, 1H), 7.39 (d, J=6.0Hz, 2H), 7.58 (d, J=6.0Hz, 1H), 7.67 (d, J=8.4Hz, 1H), 7.77 (s,1H),7.89(s,1H),8.14(s,1H),8.97(s,1H),9.49(s,1H),10.28(s,1H).MS(ESI),m/z: 480.10[M+H]+。
(I-21) N- [3- [[the chloro- 2- of 5- [[3- methoxyl group -4- (1H- imidazoles -1- methylene) phenyl] amine] -4- pyrimidine radicals] Amine] phenyl] -2- acrylamides
1H NMR(400MHz,d6-DMSO):δ 3.78 (s, 3H), 5.05 (s, 2H), 5.74 (dd, J=2.4,10.0Hz, 1H), 6.24 (dd, J=2.0,16.8Hz, 1H), 6.42 (dd, J=10.0,17.2Hz, 1H), 6.66 (d, J=8Hz, 1H), 6.88 (s, 1H), 6.97 (s, 1H), 7.15 (s, 1H), 7.20 (d, J=8.4Hz, 1H), 7.25 (s, 1H), 7.41 (d, J= 8.4Hz, 1H), 7.73 (s, 1H), 7.79 (s, 1H), 7.91 (d, J=6.0Hz, 1H), 7.92 (s, 1H), 8.11 (s, 1H), 8.95(s,1H),10.14(s,1H).MS(ESI)m/z 476.16[M+H]+。
(I-22) N- [3- [[5- nitro -2- [[2- methyl -4- (1H- imidazoles -1- methylene) phenyl] amine] -4- pyrimidine radicals] Amine] phenyl] -2- acrylamides
1H NMR(400MHz,d6-DMSO):δ 2.89 (s, 3H), 5.02 (s, 2H), 5.75 (dd, J=2.4,10.0Hz, 1H), 6.25 (dd, J=2.0,16.8Hz, 1H), 6.47 (dd, J=10.0,17.2Hz, 1H), 6.86 (s, 1H), 7.04 (d, J =8.4Hz, 2H), 7.10 (s, 1H), 7.30 (d, J=6.0Hz, 2H), 7.50 (d, J=6.0Hz, 1H), 7.57 (d, J= 8.4Hz,1H),7.97(s,1H),8.05(s,1H),8.64(s,1H),9.17(s,1H),9.78(s,1H),10.38(s,1H) .MS(ESI),m/z:471.18[M+H]+。
(I-23) N- [3- [[5- nitro -2- [[the chloro- 4- of 3- (1H- imidazoles -1- methylene) phenyl] amine] -4- pyrimidine radicals] Amine] phenyl] -2- acrylamides
1H NMR(400MHz,d6-DMSO):δ 5.02 (s, 2H), 5.75 (dd, J=2.4,10.0Hz, 1H), 6.25 (dd, J =2.0,16.8Hz, 1H), 6.47 (dd, J=10.0,17.2Hz, 1H), 6.86 (s, 1H), 7.14 (d, J=8.4Hz, 2H), 7.20 (s, 1H), 7.39 (d, J=6.0Hz, 2H), 7.58 (d, J=6.0Hz, 1H), 7.67 (d, J=8.4Hz, 1H), 7.77 (s,1H),7.89(s,1H),8.14(s,1H),8.97(s,1H),9.69(s,1H),10.39(s,1H).MS(ESI),m/z: 491.13[M+H]+。
(I-24) N- [3- [[5- nitro -2- [[3- methoxyl group -4- (1H- imidazoles -1- methylene) phenyl] amine] -4- pyrimidines Base] amine] phenyl] -2- acrylamides
1H NMR(400MHz,d6-DMSO):δ 3.58 (s, 3H), 5.15 (s, 2H), 5.79 (dd, J=2.4,10.0Hz, 1H), 6.24 (dd, J=2.0,16.8Hz, 1H), 6.42 (dd, J=10.0,17.2Hz, 1H), 6.66 (d, J=8Hz, 1H), 6.88 (s, 1H), 6.97 (s, 1H), 7.15 (s, 1H), 7.20 (d, J=8.4Hz, 1H), 7.25 (s, 1H), 7.41 (d, J= 8.4Hz, 1H), 7.73 (s, 1H), 7.79 (s, 1H), 7.99 (d, J=6.0Hz, 1H), 8.02 (s, 1H), 8.51 (s, 1H), 9.15(s,1H),10.34(s,1H).MS(ESI),m/z:487.18[M+H]+。
(I-25) N- [3- [[5- nitro -2- [[2- methoxyl group -4- (1H- imidazoles -1- methylene) phenyl] amine] -4- pyrimidines Base] amine] phenyl] -2- acrylamides
1H NMR(400MHz,d6-DMSO):δ 3.78 (s, 3H), 5.05 (s, 2H), 5.74 (dd, J=2.4,10.0Hz, 1H), 6.24 (dd, J=2.0,16.8Hz, 1H), 6.42 (dd, J=10.0,17.2Hz, 1H), 6.66 (d, J=8Hz, 1H), 6.88 (s, 1H), 6.97 (s, 1H), 7.15 (s, 1H), 7.20 (d, J=8.4Hz, 1H), 7.25 (s, 1H), 7.41 (d, J= 8.4Hz, 1H), 7.73 (s, 1H), 7.79 (s, 1H), 7.91 (d, J=6.0Hz, 1H), 7.92 (s, 1H), 8.11 (s, 1H), 8.95(s,1H),10.14(s,1H).MS(ESI),m/z:487.18[M+H]+。
(I-26) N- [3- [[5- nitro -2- [[2- methyl -4- [2- (1H- imidazole radicals) ethyoxyl] phenyl] amine] -4- pyrimidines Base] amine] phenyl] -2- acrylamides
1H NMR(400MHz,d6-DMSO):δ 3.76 (s, 3H), 4.19 (s, 2H), 4.38 (s, 2H), 5.76 (d, J= 12.0Hz, 1H), 6.24 (d, J=16.8Hz, 1H), 6.44 (dd, J=12.0,16.8Hz, 1H), 6.70 (s, 2H), 6.90 (s, 1H),7.22(s,1H),7.29-7.31(m,1H),7.44-7.49(m,3H),7.86(s,1H),7.97(s,1H),8.40(s, 1H),8.99(s,1H),9.49(s,1H),10.38(s,1H).MS(ESI),m/z:501.19[M+H]+。
(I-27) N- [3- [[5- nitro -2- [[the chloro- 4- of 3- [2- (1H- imidazole radicals) ethyoxyl] phenyl] amine] -4- pyrimidines Base] amine] phenyl] -2- acrylamides
1H NMR(400MHz,d6-DMSO):δ 4.29 (s, 2H), 4.41 (s, 2H), 5.75 (d, J=12.0Hz, 1H), 6.24 (d, J=16.8Hz, 1H), 6.44 (dd, J=12.0,16.8Hz, 1H), 6.76 (s, 2H), 6.90 (s, 1H), 7.22 (s, 1H),7.29-7.31(m,1H),7.44-7.49(m,3H),7.66(s,1H),7.97(s,1H),8.40(s,1H),8.96(s, 1H),9.48(s,1H),10.36(s,1H).MS(ESI),m/z:521.14[M+H]+。
(I-28) [[[5- nitro -2- [[2- methoxyl group -4- [2- (1H- imidazole radicals) ethyoxyl] phenyl] amine] -4- is phonetic for 3- for N- Piperidinyl] amine] phenyl] -2- acrylamides
1H NMR(400MHz,d6-DMSO):δ 4.27 (s, 2H), 4.66 (s, 2H), 5.73 (s, 1H), 5.75 (d, J= 12.0Hz, 1H), 6.24 (d, J=16.8Hz, 1H), 6.44 (dd, J=12.0,16.8Hz, 1H), 6.70 (s, 2H), 6.90 (s, 1H),7.22(s,1H),7.29-7.31(m,1H),7.44-7.49(m,3H),7.86(s,1H),8.02(s,1H),8.65(s, 1H),9.10(s,1H),9.37(s,1H),10.40(s,1H).MS(ESI),m/z:517.19[M+H]+。
(I-29) [[[5- nitro -2- [[3- methoxyl group -4- [2- (1H- imidazole radicals) ethyoxyl] phenyl] amine] -4- is phonetic for 3- for N- Piperidinyl] amine] phenyl] -2- acrylamides
1H NMR(400MHz,d6-DMSO):δ 4.17 (s, 2H), 4.33 (s, 2H), 5.43 (s, 1H), 5.75 (d, J= 12.0Hz, 1H), 6.24 (d, J=16.8Hz, 1H), 6.44 (dd, J=12.0,16.8Hz, 1H), 6.70 (s, 2H), 6.90 (s, 1H),7.22(s,1H),7.29-7.31(m,1H),7.44-7.49(m,3H),7.66(s,1H),7.89(s,1H),8.15(s, 1H),9.05(s,1H),9.18(s,1H),10.27(s,1H).MS(ESI),m/z:517.19[M+H]+。
(I-30) N- [3- [[5- nitro -2- [[2- methyl -4- [3- (1H- imidazole radicals) propoxyl group] phenyl] amine] -4- pyrimidines Base] amine] phenyl] -2- acrylamides
1H NMR(400MHz,d6-DMSO):δ 3.91 (m, 2H), 4.09 (t, J=4.0Hz, 2H), 4.57 (t, J= 4.0Hz, 2H), 5.72 (d, J=10.0Hz, 1H), 6.17 (d, J=16.8Hz, 1H), 6.21 (dd, J=10.0,16.8Hz, 1H), 6.39 (s, 1H), 6.64 (d, J=8.4Hz, 2H), 6.84 (s, 1H), 7.17 (d, J=8.4Hz, 2H), 7.24 (d, J= 6.0Hz, 1H), 7.44 (d, J=8.4Hz, 2H), 7.61 (s, 1H), 7.82 (s, 1H), 8.05 (s, 1H), 9.18 (s, 1H), 9.64(s,1H),10.37(s,1H).MS(ESI),m/z:515.21[M+H]+。
(I-31) N- [3- [[5- nitro -2- [[the chloro- 4- of 3- [3- (1H- imidazole radicals) propoxyl group] phenyl] amine] -4- pyrimidines Base] amine] phenyl] -2- acrylamides
1H NMR(400MHz,d6-DMSO):δ 3.77 (m, 2H), 4.09 (t, J=4.0Hz, 2H), 4.67 (t, J= 4.0Hz, 2H), 5.78 (d, J=10.0Hz, 1H), 6.20 (d, J=16.8Hz, 1H), 6.29 (dd, J=10.0,16.8Hz, 1H), 6.39 (s, 1H), 6.64 (d, J=8.4Hz, 2H), 6.84 (s, 1H), 7.17 (d, J=8.4Hz, 2H), 7.24 (d, J= 6.0Hz, 1H), 7.44 (d, J=8.4Hz, 2H), 7.61 (s, 1H), 7.82 (s, 1H), 8.05 (s, 1H), 9.03 (s, 1H), 9.55(s,1H),10.38(s,1H).MS(ESI),m/z:535.15[M+H]+。
(I-32) [[[5- nitro -2- [[3- methoxyl group -4- [3- (1H- imidazole radicals) propoxyl group] phenyl] amine] -4- is phonetic for 3- for N- Piperidinyl] amine] phenyl] -2- acrylamides
1H NMR(400MHz,d6-DMSO):δ 3.66 (m, 2H), 4.12 (t, J=4.0Hz, 2H), 4.77 (t, J= 4.0Hz, 2H), 5.79 (d, J=10.0Hz, 1H), 6.18 (d, J=16.8Hz, 1H), 6.26 (dd, J=10.0,16.8Hz, 1H), 6.39 (s, 1H), 6.64 (d, J=8.4Hz, 2H), 6.84 (s, 1H), 7.17 (d, J=8.4Hz, 2H), 7.24 (d, J= 6.0Hz, 1H), 7.44 (d, J=8.4Hz, 2H), 7.61 (s, 1H), 7.82 (s, 1H), 8.05 (s, 1H), 9.13 (s, 1H), 9.49(s,1H),10.29(s,1H).MS(ESI),m/z:531.20[M+H]+。
(I-33) N- [3- [[5- trifluoromethyl -2- [[4- [2- (1H- imidazole radicals) ethyoxyl] phenyl] amine] -4- pyrimidine radicals] Amine] phenyl] -2- acrylamides；
1H NMR(400MHz,d6-DMSO):δ 4.12 (s, 2H), 4.31 (s, 2H), 5.75 (d, J=12.0Hz, 1H), 6.24 (d, J=16.8Hz, 1H), 6.44 (dd, J=12.0,16.8Hz, 1H), 6.70 (s, 2H), 6.90 (s, 1H), 7.22 (s, 1H),7.29-7.31(m,2H),7.44-7.49(m,3H),7.66(s,1H),7.87(s,1H),8.10(s,1H),8.90(s, 1H),9.18(s,1H),10.20(s,1H).MS(ESI)m/z 510.18[M+H]+。
(I-34) N- [3- [[2- [[4- [2- (1H- imidazole radicals) ethyoxyl] phenyl] amine] -4- pyrimidine radicals] amine] phenyl] -2- Acrylamide；
1H NMR(400MHz,d6-DMSO):δ 4.12 (s, 2H), 4.31 (s, 2H), 5.75 (d, J=12.0Hz, 1H), 6.24 (d, J=16.8Hz, 1H), 6.44 (dd, J=12.0,16.8Hz, 1H), 6.70 (s, 2H), 6.90 (s, 1H), 7.22 (s, 1H), 7.29-7.31 (m, 2H), 7.44-7.49 (m, 3H), 7.66 (s, 1H), 7.77 (dd, J=4.0Hz, 1H), 7.87 (s, 1H),8.10(s,1H),8.90(s,1H),9.18(s,1H),10.20(s,1H).MS(ESI)m/z 442.19[M+H]+。
(I-35) N- [3- [[5- trifluoromethyl -2- [[4- [(1H- imidazole radicals) ethyoxyl] phenyl] amine] -4- pyrimidine radicals] Amine] phenyl] -2- acrylamides；
1H NMR(400MHz,d6-DMSO):δ 4.12 (s, 2H), 4.31 (s, 2H), 5.75 (d, J=12.0Hz, 1H), 6.24 (d, J=16.8Hz, 1H), 6.44 (dd, J=12.0,16.8Hz, 1H), 6.70 (s, 2H), 6.90 (s, 1H), 7.22 (s, 1H),7.29-7.31(m,2H),7.44-7.49(m,3H),7.66(s,1H),7.87(s,1H),8.10(s,1H),8.90(s, 1H),9.18(s,1H),10.20(s,1H).MS(ESI)m/z 480.17[M+H]+。
(I-36) N- [3- [[2- [[4- [(1H- imidazole radicals) ethyoxyl] phenyl] amine] -4- pyrimidine radicals] amine] phenyl] -2- third Acrylamide；
1H NMR(400MHz,d6-DMSO):δ 4.12 (s, 2H), 4.31 (s, 2H), 5.75 (d, J=12.0Hz, 1H), 6.24 (d, J=16.8Hz, 1H), 6.44 (dd, J=12.0,16.8Hz, 1H), 6.70 (s, 2H), 6.90 (s, 1H), 7.22 (s, 1H), 7.29-7.31 (m, 2H), 7.44-7.49 (m, 3H), 7.66 (s, 1H), 7.77 (dd, J=4Hz, 1H), 7.87 (s, 1H), 8.10(s,1H),8.90(s,1H),9.18(s,1H),10.20(s,1H).MS(ESI)m/z 412.18[M+H]+。
(I-37) N- [3- [[the chloro- 2- of 5- [[the fluoro- 4- of 3- (1H- imidazoles -1- methylene) phenyl] amine] -4- pyrimidine radicals] amine] Phenyl] -2- acrylamides；
1H NMR(400MHz,d6-DMSO):δ 4.12 (s, 2H), 4.31 (s, 2H), 5.75 (d, J=12.0Hz, 1H), 6.24 (d, J=16.8Hz, 1H), 6.44 (dd, J=12.0,16.8Hz, 1H), 6.70 (s, 2H), 6.90 (s, 1H), 7.22 (s, 1H),7.29-7.31(m,2H),7.44-7.49(m,2H),7.66(s,1H),7.87(s,1H),8.10(s,1H),8.90(s, 1H),9.18(s,1H),10.20(s,1H).MS(ESI)m/z 464.13[M+H]+。
(I-38) N- [3- [[the chloro- 2- of 5- [[the chloro- 4- of 3- [2- (1H- imidazole radicals) ethyoxyl] phenyl] amine] -4- pyrimidine radicals] Amine] phenyl] -2- acrylamides；
1H NMR(400MHz,d6-DMSO):δ 4.12 (s, 2H), 4.31 (s, 2H), 5.75 (d, J=12.0Hz, 1H), 6.24 (d, J=16.8Hz, 1H), 6.44 (dd, J=12.0,16.8Hz, 1H), 6.70 (s, 2H), 6.90 (s, 1H), 7.22 (s, 1H),7.29-7.31(m,2H),7.44-7.49(m,2H),7.66(s,1H),7.87(s,1H),8.10(s,1H),8.90(s, 1H),9.18(s,1H),10.20(s,1H).MS(ESI)m/z 510.11[M+H]+。
(I-39) N- [3- [[the chloro- 2- of 5- [[the fluoro- 4- of 3- [2- (1H- imidazole radicals) ethyoxyl] phenyl] amine] -4- pyrimidine radicals] Amine] phenyl] -2- acrylamides；
1H NMR(400MHz,d6-DMSO):δ 4.12 (t, J=4.0Hz, 2H)), 4.31 (t, J=4.0Hz, 2H), 5.75 (d, J=12.0Hz, 1H), 6.24 (d, J=16.8Hz, 1H), 6.44 (dd, J=12.0,16.8Hz, 1H), 6.74 (d, J= 8.0Hz, 2H), 6.91 (s, 1H), 7.24 (d, J=6.0Hz, 1H), 7.29 (d, J=12.0Hz, 2H), 7.42 (d, J= 8.4Hz, 1H), 7.53 (d, J=8.4Hz, 1H), 7.69 (s, 1H), 7.93 (s, 1H), 8.07 (s, 1H), 9.01 (s, 1H), 9.39(s,1H),10.15(s,1H).MS(ESI)m/z 494.14[M+H]+。
Method of the target molecule into salt
The preparation method of inorganic acid salt：Take target molecule (1mmol) to be dissolved in 10mL absolute methanols, under ice bath, slowly drip Plus the 5mL absolute methanol solutions of inorganic acid (1mmol), completion of dropping, stir 30 minutes at a temperature of this, then normal temperature is evaporated off first Alcohol, obtains final product the inorganic acid salt of target molecule.Hydrochloride (I-5-1), the hydrobromate of compound I-5 are prepared for by the method (I-5-2), sulphate salt (I-5-3) and hydrobromate (I-5-4)；
The preparation method of acylate：Take target molecule (1mmol) to be dissolved in 10mL absolute methanols, under ice bath, slowly drip Plus the 5mL dry ethers of organic acid (1mmol), completion of dropping, stir 30 minutes at a temperature of this, then normal temperature is evaporated off solvent, Obtain final product the acylate of target molecule.Maleate (I-9-5), the succinate (I- of compound I-9 are prepared for by the method 9-6) and fumarate (I-9-7).
The preparation of two target molecule mixtures
The above-mentioned two target molecule of equimolar amounts (1mmol) is taken in absolute methanol (5mL), is stirred at room temperature 10 minutes, Normal temperature is evaporated off solvent, obtains final product the mixture of target molecule.(I-5)-(I-6), (I-5)-(I-9), (I- are prepared for by the method 6)-compositions of (I-10) three.
The target molecule evaluated biological activity of embodiment 2
1st, it is external to receptor tyrosine kinase inhibitory activity method of testing
Prepare kinase assay buffer
1. melt kinase assay buffer (Kinase Detection Buffer) in room temperature, see whether precipitation.
2. if there is precipitation, just often shake within 15 minutes and Jing in 37 DEG C of incubations (Kinase Detection Buffer), Dissolution precipitation.Or, supernatant is carefully siphoned away, remove precipitation.
Prepare kinase assay reagent
1. using front in equilibrium at room temperature kinase assay buffer (Kinase Detection Buffe) and (Kinase Detection Substrate)。
2. kinase assay buffer (Kinase Detection Buffer) is all poured into equipped with kinase assay substrate In the brown bottle of (Kinase Detection Substrate), freeze-dried powder substrate is dissolved, thus made kinase assay Reagent.
3. gently concussion, vortex or reverse mixing, becomes homogeneous solution, and substrate should dissolve in 1 minute.
4. should use immediately after kinase assay reagent is prepared, or packing is stored in -20 DEG C, it is believed that the reagent for preparing is passed through Several times freeze thawing Posterior circle signal activity is not all lost.
Make the calibration curve that ATP changes into ADP
1. the Ultra that kit is provided is diluted with 1 × kinase reaction buffer solution (kinase reaction buffer) Pure ATP and ADP, make 900 μ L, 50 μM of ADP of 50 μM of ATP and 500 μ L.
2. the 50 μM of ATP and 50 μM of ADP solution for previous step being prepared are mixed as table 1 Suo Shi in 384 orifice plate A1-A12, The concentration of the ATP and ADP of each conversion percentages is simulated, is mixed.
Table 1. prepares 50 μM of series A TP+ADP standard items
3. the ADP-Glo of 5 μ L is added per holeTMReagent is terminating kinase reaction.In incubation at room temperature 40 minutes.
4. add 10 μ L kinase assay reagents (Kinase Detection Reagent) that ADP is changed into into ATP per hole, and Introduce luciferase and luciferin to detect ATP.
5. in incubation at room temperature 30-60 minutes, measure fluorescent with multi-function microplate reader and record fluorescent value.
6. the calibration curve that ATP changes into ADP is drawn.
Determine the IC of kinase inhibitor50Value
1. 1 × kinase reaction buffer solution (kinase reaction are prepared according to promega kit specifications Buffer), 2.5 × 50ng/ μ L kinases and 2.5 × 0.5 μ g/ μ L substrates and 125 μM of ATP.
2. 3 μ L 1 × kinase reaction buffer solutions (kinase reaction buffer), 2 μ are added in without enzyme control wells L2.5 × 0.5 μ g/ μ L substrates and 125 μM of ATP.1 μ L 1 × kinase reaction buffer solution (kinase are added in negative control hole Reaction buffer), 2 μ L 2.5 × 50ng/ μ L kinases, the μ g/ μ L substrates of 2 μ L 2.5 × 0.5 and 125 μM of ATP.In test Add 15 × medicines to be measured of μ L in hole, 2 μ L 2.5 × 50ng/ μ L kinases, the μ g/ μ L substrates of 2 μ L 2.5 × 0.5 and 125 μM ATP。
3. flat board is mixed, is incubated 60 minutes.
4. the ADP-Glo of 5 μ L is added per holeTMReagent is terminating kinase reaction.In incubation at room temperature 40 minutes.
5. add 10 μ L kinase assay reagents (Kinase Detection Reagent) that ADP is changed into into ATP per hole, and Introduce luciferase and luciferin to detect ATP.In incubation at room temperature 30-60 minutes, measure fluorescent with multi-function microplate reader and remember Record fluorescent value.
6. interpretation of result, is as a result shown in table 2.
2nd, cell growth assay (MTT detection methods)
Cell is inoculated with：Exponential phase cell is collected, concentration of cell suspension is adjusted, with every hole 7 × 103Individual cell, per hole The μ L of volume 100 are inoculated into 96 orifice plates, and 4 multiple holes are set per group (edge hole is filled with aseptic PBS)；
Cell culture：After cell attachment, 0%FBS RPMI-1640 starvation 8h, control group is trained with 10%FBSRPMI-1640 Support, 37 DEG C, 5%CO2Continue to cultivate (empirically requiring to cultivate different time respectively) in incubator；
Colour generation：Three groups of cells add 10 μ L MTT solution (5mg/mL) after culture 72h, culture are terminated after 4h, often Hole adds the liquid of 100 μ L tri-, the low-speed oscillation 10min on shaking table crystallization is fully dissolved；
Colorimetric：Each hole shading value (OD values) is determined on enzyme-linked immunosorbent assay instrument, 570nm wavelength is selected, with acellular That is RPMl-1640 nutrient solutions blank well zeroing, surveys the absorbance in each hole.Experiment is in triplicate
Record result：Inhibitory rate of cell growth=(the experimental group absorbance of control group absorbance one)/control group extinction Angle value × 100%, cell proliferation rate=(experimental group absorbance/control group absorbance) × 100；
Draw cell growth curve：With the time as abscissa, inhibiting rate/rate of increase is that ordinate draws cell growth song Line.
Do figure for inhibitor concentration in GraphPad Prism mapping softwares in GraphPad softwares, so as to by Log [inhibitor] goes out IC relative to reaction, variable slope model assessment50。
As shown in table 2, table 2 shows that obtained compound is suppressing EGFR EGFR-TKs and antitumor thin to test result Active effect in born of the same parents' propagationa。
Table 2
Table 3
a:H1975 is EGFRT790MMutant clone, A431EGFRWTCell .b:IC50：Half effective inhibition concentration.
3rd, Apoptosis (flow cytometry)
3.1 experiment materials and reagent
H1975 cells, RAPI1640 basal mediums (Hyclone companies, cat:SH30022.01B), FBS hyclones (GIBCO companies, cat:16400-044), dual anti-(Beijing Xia Si bio tech ltd, prospeccat:SV30010), Low speed centrifuge (upper sea cowry grace bio tech ltd, cat:TDZ4B-WS), CO2Incubator (the rich news in Shanghai, cat:BC- J160S), superclean bench (rich news model SW-CJ-2FD in Shanghai), is inverted fluorescent electronic microscope (Leica DMI3000B).
3.2 experimental technique
3.2.1 Amplification Culture H1975 cell；
3.2.2 drug-treated：With variable concentrations drug-treated cell 48 hours.
3.2.3 after drug-treated cell with without EDTA collected by trypsinisation, PBS washed cells twice, collect cell 1 ～5 × 105Cell；
3.2.4 AnnexinV combination buffers (Binding Buffer) suspension cell of 500 μ L is added；
3.2.5 after adding 5 μ L AnnexinV-FITC to mix, 5 μ L propidium iodides (Propidium Iodide, (week are added Phase detection only adds 5uL propidium iodides), mix；
3.2.6 lucifuge, room temperature reaction 10min；
3.2.7 flow cytomery (Ex=488nm is used；Em=530nm) the situation in Apoptosis and cycle.
As shown in Fig. 1～Fig. 5, figure below shows that obtained compound I-5 causes H1975 under variable concentrations to test result Apoptotic result.
Above biologically active result shows that the molecule in the present invention is to EGFR and EGFRT790MKinases has strong suppression effect Really, majority of compounds reaches the active rank of nanomolar range, and has effective inhibition concentration IC of the nearly compound of half50 Value is less than 100nM, compound I-3 (9.1nM), I-5 (3.3nM), and I-6 (9.0nM) is to EGFRT790MIC50Even more reach 10nM Below, hence it is evident that better than Gefitinib and Rociletinib, additionally, compound involved in the present invention on Kinase Selectivity compared with Get well, especially compound I-5 (SI=303), its selectivity is the 13.8 of lead compound Rociletinib (SI=21.9) Times, as a result imply that compound I-5 effect it is more single-minded, it is thus possible to toxic and side effect can be less.Antiproliferation result Disclose, majority of compounds has very effective inhibitory action, wherein compound I-5 to drug resistance of lung cancer type cell H1975 (118nM) activity of Rociletinib (137nM) is substantially better than with I-9 (129nM), in addition, majority of compounds is normal to people The inhibitory action of bronchial epithelial cell HBE is weaker, in the case where its performance suppresses the valid density of H1975 cells, almost to normal Cell does not affect, it was demonstrated that the toxicity of such compound is less, and the result of fluidic cell apoptosis discloses I-5 can draw to H1975 Apoptosis is played, and apoptosis number is presented dose dependent.Indicate that this quasi-molecule has and greatly may develop into new and effective EGFR The potentiality of inhibitor, to the tumor disease of therapy-related, especially non-small cell lung cancer and ED-SCLC have larger application valency Value.
The above is only the preferred embodiments of the present invention, it is noted that for the ordinary skill people of the art For member, on the premise of without departing from the technology of the present invention principle, some improvements and modifications can also be made, these improvements and modifications Also should be regarded as protection scope of the present invention.

Claims (8)

1. a kind of compound or its pharmaceutically acceptable salt shown in formula (I), the compound shown in the formula (I) has Following structure：
Wherein,
R1Selected from selecting chlorine, hydrogen, fluorine, trifluoromethyl or nitro；
R2Selected from hydrogen, chlorine, fluorine, methyl or methoxy；
Z is selected from-OCH2CH2-、-CH2- ,-NHC (=O) CH2-, direct singly-bound ,-OCH2CH2CH2-, when hetero atom is contained at Z two ends During O or N, the hetero atom is connected with phenyl ring；
X is selected from CH or N；
Y is selected from CH or N.
2. the compound or its pharmaceutically acceptable salt shown in formula (I) as claimed in claim 1, wherein, the formula (I) compound shown in has the structure shown in I-1～I-39：
3. a kind of pharmaceutical composition, its contain the compound described in the claim 1 or 2 of effective dose shown in formula (I) or its Pharmaceutically acceptable salt, and pharmaceutical carrier.
4. the compound or its pharmaceutically acceptable salt shown in formula described in claim 1 or 2 (I), or described in claim 3 Application of the pharmaceutical composition in EGFR skin factor receptor protein tyrosine kinase inhibitor is prepared.
5. the compound or its pharmaceutically acceptable salt shown in formula described in claim 1 or 2 (I), or described in claim 3 Pharmaceutical composition prepare treatment tumour medicine in purposes.
6. purposes according to claim 5, wherein, the tumour in non-small cell lung cancer or ED-SCLC one Plant or various.
7. purposes according to claim 6, wherein, the tumour is non-small cell lung cancer.
8. the purposes according to any one of claim 5～7, wherein, the purposes mainly by suppress EGFR epidermises because What sub- receptor protein tyrosine kinase was realized.
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