Tyrosine Kinase Inhibitors. 16. 6,5,6-Tricyclic Benzothieno[3,2-d]pyrimidines and Pyrimido[5,4-b]- and -[4,5-b]indoles as Potent Inhibitors of the Epidermal Growth Factor Receptor Tyrosine Kinase

Abstract

Several elaborations of the fundamental anilinopyrimidine pharmacophore have been reported as potent and selective inhibitors of the epidermal growth factor receptor (EGFr) tyrosine kinase. This paper reports on a series of inhibitors whereby some 6,5-bicyclic heteroaromatic systems were fused through their C-2 and C-3 positions to this anilinopyrimidine pharmacophore. Although the resulting tricycles did not produce the enormous potency of some of the (5/6),6,6-bicyclic systems, the best of them had IC(50)s for the EGFr TK around 1 nM. Investigation of 4-position side chains in the indolopyrimidines confirmed that m-bromoaniline was an optimal substituent for potency. Investigation of substitution within the C-(benzo)ring of benzothienopyrimidines confirmed that introduction of an extra ring can change sharply the effects of substituents when compared to similar bicyclic nuclei, and only two substituents were found which even moderately enhanced inhibitory activity over the parent compound for this series.

Discovery of Potent Antiproliferative Agents Targeting EGFR Tyrosine Kinase Based on the Pyrido[3′,2′:4,5]thieno[3,2-<i>d</i>]pyrimidin-4-amine Scaffold

“…1,4,11) In this context, Showalter et al reported that fusing a third ring to 6-and 7-positions of the quinazoline ring enhanced the kinase inhibitory activity over the parent bicyclic analogues.…”

“…8,9) Consistent with this, some investigations showed that the isosteric replacement of the benzene ring of the quinazoline core with five-membered heteroaromatic rings is favorable. 10,11) The flexibility of the linking NH group between the heteroaryl core and the aniline ring permits the proper orientation of the aniline ring into the hydrophobic pocket, lying in the back of the ATP-binding site. 1) This hydrophobic pocket, often called "specificity pocket," is characteristic for each type of kinases, allowing for the design of selective ligands.…”

“…12) On the other side, the substituents present at positions 6 and 7 of the quinazoline core structure, often called "solubilizing tails," protrude from the ATP-binding site into the solvent. 1,4,11) In this context, Showalter et al reported that fusing a third ring to 6-and 7-positions of the quinazoline ring enhanced the kinase inhibitory activity over the parent bicyclic analogues. 11) On the other hand, the discovery of potent inhibitors of a particular kinase often commence with the screening of the archived inhibitors that were studied in previous reports.…”

Identification of a lead small-molecule inhibitor of the Aurora kinases using a structure-assisted, fragment-based approach

“…The tricyclic fragments 2 to 4 and compounds containing these pharmacophores also showed good LUDI scores of 411, 389, and 416, respectively. These three fragments have also been reported as potential kinase inhibitor scaffolds (24,34,35); however, their utility as components of an Aurora kinase inhibitor has not been reported. Therefore, compounds derived from these adeno-mimetic pharmacophores were of great interest to us for further development as Aurora kinase inhibitors.…”

“…Fragments 1 to 4 were prepared using conditions described in the literature (23,24). The fragments were further converted to chloro derivatives by either using Vilsmeier's reagent (oxalyl chloride/DMF) or reacting with neat POCl 3 in the presence of 1,4-dioxane to make them more amenable to further chemical modification.…”