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Biamino chloro pyrimidine compound containing m-chloroaniline substituent groups, and preparation method and applications thereof

A technology of compounds and hydrates, applied in the field of medicine, can solve problems such as drug resistance and adverse reactions

Inactive Publication Date: 2019-11-19
BEIJING SCITECH MQ PHARMA LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] An object of the present invention is to solve the problems of drug resistance and adverse reactions of kinase inhibitors in the prior art, and provide a compound represented by formula (I), its isomer, hydrate, solvate, and its pharmaceutically acceptable salts and their prodrugs,

Method used

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  • Biamino chloro pyrimidine compound containing m-chloroaniline substituent groups, and preparation method and applications thereof
  • Biamino chloro pyrimidine compound containing m-chloroaniline substituent groups, and preparation method and applications thereof
  • Biamino chloro pyrimidine compound containing m-chloroaniline substituent groups, and preparation method and applications thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0099] Example 1. (2-((5-chloro-2-((5-chloro-4-(4-(dimethylamino)piperidin-1-yl)-2-methoxyphenyl)amino)pyrimidine Preparation of -4-yl)amino)phenyl)dimethylphosphine oxide

[0100]

[0101] 28 mg (0.1 mmol) of 1-(4-amino-2-chloro-5-methoxyphenyl)-N,N-dimethylpiperidin-4-amine, (2-((2,5- Dichloropyrimidin-4-yl) amino) phenyl) 32 mg (0.1 mmol) of dimethylphosphine oxide, 17 mg (0.1 mmol) of p-toluenesulfonic acid were placed in a reaction flask, heated and stirred until the reaction was completed, and concentrated by rotary evaporation After column chromatography, 27 mg of the product was obtained, and the yield was 50%. 1 H NMR (400MHz, DMSO-d6) δ11.24(s,1H),8.46(s,1H),8.19(s,1H),8.16(s,1H),7.77(s,1H),7.60–7.53( m,1H),7.43(t,J=8.0,8.0Hz,1H),7.16–7.11(m,1H),6.81(s,1H),3.82(s,3H),3.35(s,1H),3.32 –3.28(m,2H),2.70–2.64(m,2H),2.22(s,6H),1.88–1.83(m,2H),1.79(s,3H),1.76(s,3H),1.60–1.52 (m,2H); MS:563[M+H] + .

Embodiment 2

[0102] Example 2. (2-((5-chloro-2-((5-chloro-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl ) phenyl) amino) pyrimidin-4-yl) amino) phenyl) dimethyl phosphine oxide

[0103]

[0104] With reference to the preparation method of Example 1, replace 1 -(4-Amino-2-chloro-5-methoxyphenyl)-N,N-dimethylpiperidin-4-amine. 1 HNMR(400MHz,DMSO-d6)δ11.22(s,1H),8.48–8.43(m,1H),8.15(s,1H),8.12(s,1H),7.79(s,1H),7.56(dd ,J=14.0,7.6Hz,1H),7.44(t,J=7.8,7.8Hz,1H),7.14(t,J=7.4,7.4Hz,1H),6.80(s,1H),3.82(s, 3H),3.33–3.31(m,2H),2.67(t,J=11.4,11.4Hz,2H),2.57–2.51(m,4H),2.37–2.26(m,5H),2.15(s,3H) ,1.85(d,J=12.2Hz,2H),1.79(s,3H),1.76(s,3H),1.63–1.54(m,2H).MS:618[M+H] + .

Embodiment 3

[0105] Example 3. (2-((2-((4-([1,4'-bipiperidin]-1'-yl)-5-chloro-2-methoxyphenyl)amino)-5- Preparation of chloropyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide

[0106]

[0107] Referring to the preparation method of Example 1, 1-(4-amino -2-Chloro-5-methoxyphenyl)-N,N-dimethylpiperidin-4-amine. 1 H NMR (400MHz, DMSO-d6) δ11.21(s, 1H), 8.45(s, 1H), 8.16–8.11(m, 2H), 7.78(s, 1H), 7.56(dd, J=13.8, 7.6 Hz,1H),7.44(t,J=8.0,8.0Hz,1H),7.14(t,J=7.4,7.4Hz,1H),6.80(s,1H),3.82(s,3H),3.34–3.31 (m,6H),2.67(t,J=11.4,11.4Hz,2H),2.38–2.31(m,1H),1.85–1.80(m,2H),1.79(s,3H),1.76(s,3H ),1.67–1.58(m,2H),1.53–1.48(m,4H),1.43–1.37(m,2H).MS:603[M+H] + .

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Abstract

The invention provides a biamino chloro pyrimidine compound containing m-chloroaniline substituent groups, and a preparation method and applications thereof, and more specifically relates to a compound represented by formula I, and isomers, hydrates, solvates, pharmaceutically acceptable salts, and a prodrug thereof, a preparation method of the above compounds, and applications of the compounds inpreparation of drugs taken as kinases inhibitors. The preparation method is used for solving a problem in the prior art that drug resistance is caused by conventional kinases inhibitors. The compoundpossesses excellent inhibition activity on mutant EGFRT790M and EGFRC797S kinases, and moderate inhibition activity on wild type EGFR kinases.

Description

technical field [0001] The invention belongs to the technical field of medicine, and relates to a diamino-substituted chloropyrimidine compound, a preparation method and an application thereof. Background technique [0002] Protein kinase is an important signal messenger for cell life activities, which can catalyze the transfer of the γ-phosphate group at the end of ATP to the hydroxyl receptor in the substrate amino acid residue (serine, threonine, tyrosine), thereby activating the target Protein (Johnson L.N., and Lewis R.J., Structural basis for control by phosphorylation, Cheminform, 2001, 101, 2209.). Protein kinases are involved in numerous physiological processes, including cell proliferation, survival, apoptosis, metabolism, transcription, and differentiation (Adams J.A., Kinetic and catalytic mechanisms of proteinkinases, Chemical reviews, 2001, 101, 2271.). Among the existing drug targets in the human body, members of the protein kinase family account for up to 10...

Claims

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Application Information

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IPC IPC(8): C07F9/6558A61K31/675A61P35/00A61P35/02
CPCA61P35/00A61P35/02C07F9/65583
Inventor 张强冯守业王中祥徐占强杨海龙张宏波周利凯
Owner BEIJING SCITECH MQ PHARMA LTD
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