JAK-STAT Signaling Pathway is an intramolecular base catalyst a cyclic mechanism

Anilinoquinoline carbonitrile 86 4 3, JAK-STAT Signaling Pathway developed by us and is a 9.10, orally active, irreversible inhibitor of EGFR kinase. This compound has formed a Michael acceptor in position 6, which is a covalent bond to Cys 773 in the pocket of the enzyme ATP binding EGFR. The water- Soluble dimethylamino group making up the end of the Michael acceptor is an intramolecular base catalyst a cyclic mechanism of five NONS the Michael addition of this high reactivity process.9 t with the EGFR with an enzyme catalyzes Improved bioavailability entered 86 powerful display antitumor activity of t-dependent EGFR born in Ngigen tumor models. However, since the effectiveness of 86 shows at least two SES abh Ngig tumor models, we continued our efforts to irreversible inhibitors with improved activity Tonnes compared with its 2-expressing tumors develop. These efforts are the subject of this release. EGFR and HER-2 share a 82% Sequenzidentit t NEN in the kinase-Dom is the identity t h yet Forth in the active site.11 We have a homology model of HER-2 kinase built in this study with the crystal structure of EGFR kinase in complex with erlotinib as a inhibitor.12 Cys 773 in EGFR is quinazolinebased as Cys 805 in HER 2 received, the development of an irreversible inhibitor of this kinase seemed proved feasible. The most notable difference in the ATP-binding region between these kinases is a single amino Urerest, ie Ser 783 in HER 2 vs. Cys 775 in EGFR. The high level of identity T between the ATP-binding regions of these two enzymes proposed to make heavy molecules that are selective for each other. Design an inhibitor that has shown improved efficacy appeared in his two models to be a realistic company. The binding models of our inhibitors showed that the aniline is part of a long lipophilic pocket. Since it introduced the green with the region of the binding pocket of the.
Th difference between the two kinases and there is m Was like, big e lipophilic groups at the para position of aniline, we explored different Changes the Part 4 arylamino to identify inhibitors in an empirical research activity of HER-2 molecules with improved Ten. Interestingly, several other groups13 15 independent Ngig discovered, for quinazoline inhibitors, big e lipophilic substituents improve activity of HER-2-t and improved in some F Fill two 2/EGFR SA activity.16, 17 Here we describe lead the synthesis and SAR of a series of 6,7-disubstituted quinoline 3 4-carbonitriles with a plurality of lipophilic substituents on the ring arylamino Clock. Compared to our EGFR kinase inhibitor 86, several of these compounds, such as 25o shows show improved activity T against HER-2 kinase, while maintaining a good performance for EGFR kinase. More importantly, this dual HER 2 and EGFR inhibitors, 25o showed in vivo efficacy in HER-2-dependent Ngigen improved tumor models. Most chemical-disubstituted 4 6.7 3 anilinoquinoline Carbons urenitrile Described here were from one of the three methods shown in Figures 1 3, is produced. In Scheme 1, 6 M Rz Chloro 4 nitroquinoline-carbonitriles 1a, b 9 reacted with a substituted aniline 2 and then reduced with iron and w Ssrigem ammonium chloride to the corresponding.