959246-74-3Relevant academic research and scientific papers
Discovery of novel 2,4-diarylaminopyrimidine analogues (DAAPalogues) showing potent inhibitory activities against both wild-type and mutant ALK kinases
Song, Zilan,Yang, Yanhong,Liu, Zhiqing,Peng, Xia,Guo, Junfeng,Yang, Xinying,Wu, Kui,Ai, Jing,Ding, Jian,Geng, Meiyu,Zhang, Ao
, p. 197 - 211 (2015/02/19)
We have developed a series of new 2,4-diarylaminopyrimidine analogues (DAAPalogues) bearing a flexible amino acid side chain, different from the majority of the literature reported ALK inhibitors that often possess a structurally constrained arylpiperazine fragment or its equivalents in the solvent-interaction region. Extensive structural elaboration led to compound 15 possessing IC50 values of 2.7 and 15.3 nM, respectively, in the ALK wild-type and gate-keeper mutant L1196M enzymatic assays. This compound not only showed high proliferative inhibition against ALK-addicted cells across different oncogenic forms but also effectively suppressed several ALK secondary mutant cells, including the gate-keeper L1196M and F1174L. Significant antitumor efficacy was achieved in the ALK-driven SUP-M2 xenograft model.
Fused bicyclic derivatives of 2,4-diaminopyrimidine as c-Met inhibitors
Weinberg, Linda R.,Albom, Mark S.,Angeles, Thelma S.,Husten, Jean,Lisko, Joseph G.,McHugh, Robert J.,Milkiewicz, Karen L.,Murthy, Seetha,Ott, Gregory R.,Theroff, Jay P.,Tripathy, Rabindranath,Underiner, Ted L.,Zificsak, Craig A.,Dorsey, Bruce D.
, p. 164 - 167 (2011/03/17)
The HGF-c-Met signaling axis is an important paracrine mediator of epithelial-mesenchymal cell interactions involving the regulation of multiple cellular activities including cell motility, mitogenesis, morphogenesis, and angiogenesis. Dysregulation of c-Met signaling (e.g., overexpression or increased activation) is associated with the development of a wide range of tumor types; thus, inhibiting the HGF-c-Met pathway is predicted to lead to anti-tumor effects in many cancers. Elaboration of a 2-arylaminopyrimidine scaffold led to a series of potent c-Met inhibitors bearing a C4-2-amino-N-methylbenzamide group. Specifically, a series of C2-benzazepinone analogs demonstrated potent inhibition of c-Met in enzymatic and cellular assays. Kinase selectivity could be tuned by varying the nature of the alkyl group on the benzazepinone nitrogen.
2,4-Diaminopyrimidine inhibitors of c-Met kinase bearing benzoxazepine anilines
Zificsak, Craig A.,Theroff, Jay P.,Aimone, Lisa D.,Albom, Mark S.,Angeles, Thelma S.,Brown, Rebecca A.,Galinis, Deborah,Grobelny, Jennifer V.,Herbertz, Torsten,Husten, Jean,Kocsis, Laura S.,Losardo, Christine,Miknyoczki, Sheila J.,Murthy, Seetha,Rolon-Steele, Damaris,Underiner, Ted L.,Wells-Knecht, Kevin J.,Worrell, Candace S.,Zeigler, Kelli S.,Dorsey, Bruce D.
, p. 660 - 663 (2011/03/18)
Elaboration of the SAR around a series of 2,4-diaminopyrimidines led to a number of c-Met inhibitors in which kinase selectivity was modulated by substituents appended on the C4-aminobenzamide ring and the nature of the C2-aminoaryl ring. Further lead opt
FUSED BICYCLIC DERIVATIVES OF 2,4-DIAMINOPYRIMIDINE AS ALK AND C-MET INHIBITORS
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Page/Page column 462, (2008/12/05)
The present invention provides a compound of formula I or II or a pharmaceutically acceptable salt form thereof, wherein R1, R2, R3, R4, R5, A1, A2, A3, A4, and A5, are as defined herein. The compounds of formula I or II have ALK and/or c-Met inhibitory activity, and may be used to treat proliferative disorders.
