[reaction: see text] (Trialkylsilyl)arylketenes combine with (trimethylsilyl)diazomethane in a new [4 + 1] annulation process leading to 2-indanone derivatives. The (trialkylsilyl)arylketene annulation substrates are available via the photochemical Wolff rearrangement of alpha-silyl-alpha-diazo ketones, which are themselves prepared by silylation of the corresponding diazo ketones. The mechanism of the annulation reaction is proposed to involve the formation of a 2,3-bis(silyl)cyclopropanone, which is in equilibrium with an oxyallylic cation. Electrocyclic closure of this intermediate forms the new cyclopentenone ring.
Fused pyrimidine derivatives R 0515Microwave-Assisted One-Pot Synthesis of 2,3-Disubstituted 3H-Quinazolin--4-ones. -Reaction of anthranilic acids with carboxylic acids or acid chlorides and subsequent microwave-promoted ring closure provides an efficient one-pot synthesis of the title skeleton, present in many natural compounds. -(LIU*, J.-F.; LEE, J.; DALTON, A. M.; BI, G.; YU, L.; BALDINO, C. M.; MCELORY, E.; BROWN, M.; Tetrahedron Lett. 46 (2005) 8, 1241-1244; ArQule, Inc., Woburn, MA 01801, USA; Eng.) -Mais 23-160
Utilization of hydrophobic motifs present in auto-inhibited protein kinases has resulted in the identification of a series of 5,6-dihydrobenzo [h]quinazolin-2-amines with activity as fibroblast growth factor receptor (FGFR) tyrosine kinase inhibitors. Herein we describe the combination of a proprietary in silico design process, a new screening paradigm using an array of biochemical and biophysical technologies in conjunction with an established parallel chemistry process for the identification and optimization of a series of novel FGFR inhibitors. These potent FGFR inhibitors exhibit a preference for the inactive form of the kinase, are non-ATP competitive, and exhibit robust cellular pharmacodynamic inhibition as well as in vitro anti-proliferative effects in cells dependent on FGFR and significant anti-tumor activity in appropriate xenograft models in vivo. The design strategy, synthesis, structure activity relationships and in vitro and in vivo biology of selected inhibitors will be presented.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3905. doi:1538-7445.AM2012-3905
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