A series of new 6,7-disubstituted-4-(arylamino)quinoline-3-carbonitrile derivatives that function as irreversible inhibitors of human epidermal growth factor receptor-2 (HER-2) and epidermal growth factor receptor (EGFR) kinases have been prepared. These compounds demonstrated enhanced activities for inhibiting HER-2 kinase and the growth of HER-2 positive cells compared to our EGFR kinase inhibitor 86 (EKB-569). Three synthetic routes were used to prepare these compounds. They were prepared mostly by acylation of 6-amino-4-(arylamino)quinoline-3-carbonitriles with unsaturated acid chlorides or by amination of 4-chloro-6-(crotonamido)quinoline-3-carbonitriles with monocyclic or bicyclic anilines. The third route was developed to prepare a key intermediate, 6-acetamido-4-chloroquinoline-3-carbonitrile, that involved a safer cyclization step. We show that attaching a large lipophilic group at the para position of the 4-(arylamino) ring results in improved potency for inhibiting HER-2 kinase. We also show the importance of a basic dialkylamino group at the end of the Michael acceptor for activity, due to intramolecular catalysis of the Michael addition. This, along with improved water solubility, resulted in compounds with enhanced biological properties. We present molecular modeling results consistent with the proposed mechanism of inhibition. Binding studies of one compound, 25o (C-14 radiolabeled), showed that it binds irreversibly to HER-2 protein in BT474 cells. Furthermore, it demonstrated excellent oral activity, especially in HER-2 overexpressing xenografts. Compound 25o (HKI-272) was selected for further studies and is currently in phase I clinical trials for the treatment of cancer.

The reaction of l,l,l,3,3,3-hexafluoro-2-phenyl-2-propanol (RFOH) with either sec-butyllithium or n-butyllithium/IVJVrZV' JV'-tetramethylethylenediamine (TMEDA) provides 3, a reagent for the facile introduction of a bidentate ligand which is particularly effective in stabilizing the higher coordination states of nonmetallic elements. This reagent is used to prepare a series of spiro compounds in which two of these ligands are attached to hypervalent silicon (anionic lO-Si-5 species 6a-d, 13), phosphorus (10-P-5 phosphoranoxide salt 8), sulfur (the very unreactive sulfurane, 10-S-4 species 9), or iodine (10-1-3 species 15). Reaction of 3 with SiCL, gives the expected spirosilane, 12, an 8-SÍ-4 species which reacts with a variety of nucleophiles to give pentacoordinate silicon (lO-Si-5) species. For example, reaction of 12 with phenyllithium gives 6a. The much weaker nucleophile 4-(dimethylamino)pyridine gives a stable complex which involves nitrogen attack at silicon. Reaction of 3 with elemental sulfur gives disulfide diol 7a. Reaction with either 1,2-dibromoethane or elemental bromine gives bromo alcohol 11a, while I2 reacts with 3 to give iodo alcohol lib.

The optimization of a class of indole cPLA 2 alpha inhibitors is described herein. The importance of the substituent at C3 and the substitution pattern of the phenylmethane sulfonamide region are highlighted. Optimization of these regions led to the discovery of 111 (efipladib) and 121 (WAY-196025), which are shown to be potent, selective inhibitors of cPLA 2 alpha in a variety of isolated enzyme assays, cell based assays, and rat and human whole blood assays. The binding of these compounds has been further examined using isothermal titration calorimetry. Finally, these compounds have shown efficacy when dosed orally in multiple acute and chronic prostaglandin and leukotriene dependent in vivo models.

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