N4-Aryl-6-substitutedphenylmethyl-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamines as receptor tyrosine kinase inhibitors

Abstract

Six novel N4-substitutedphenyl-6-substitutedphenylmethyl-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamines were synthesized as multiple receptor tyrosine kinase (RTK) inhibitors and antitumor agents. An improvement in the inhibitory potency against epidermal growth factor receptor (EGFR), vascular endothelial growth factor receptor 1 (VEGFR-1) and vascular endothelial growth factor receptor 2 (VEGFR-2) assays and in the A431 cellular proliferation assay was observed for compounds 8–13 over the previously reported 5–7. Three compounds (8, 9, and 13) demonstrated potent, multiple RTK inhibition and were more potent or equipotent compared to the lead compounds 5 and 7 and the standard compounds. Compounds 10 and 12 showed potent inhibition of VEGFR-2 over EGFR, platelet-derived growth factor receptor-β (PDGFR-β) and VEGFR-1. The results indicate that the RTK inhibitory profile could be modulated with slight variations to the N4-aryl-6-substitutedphenylmethyl-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamino scaffold.

Discovery and preclinical evaluation of 7-benzyl-N-(substituted)-pyrrolo[3,2-d]pyrimidin-4-amines as single agents with microtubule targeting effects along with triple-acting angiokinase inhibition as antitumor agents

“…11, 36, 37 Thus, it was of interest to explore the effect of structural variations in 1 on activity against the RTKs VEGFR-2, PDGFR-β and EGFR, in addition to cytotoxic MT effects with the goal of identifying single molecules as MTAs with multiple angiokinase inhibitory potential. The clinical successes of the triple angiokinase inhibitor nintedanib in combination with docetaxel 38–41 makes a compelling argument for triple angiokinase inhibitors with MTAs in single molecular entities.…”

Design, synthesis and evaluation of 2-amino-4-m-bromoanilino-6-arylmethyl-7H-pyrrolo[2,3-d]pyrimidines as tyrosine kinase inhibitors and antiangiogenic agents1

“…The 2-NH 2 group in our compounds provides a third H-bonding moiety in the Hinge region of RTKs, and was anticipated to increase binding and consequently potency against RTKs. This has recently been shown to be true in most instances, but is dependent on the nature of the scaffold and its substitutions 16,17…”

Design, synthesis and biological activity of N4-phenylsubstituted-7H-pyrrolo[2,3-d]pyrimidin-4-amines as dual inhibitors of aurora kinase A and epidermal growth factor receptor kinase

“…Gangjee et al. 13 , 17 previously reported 4,6-disubstituted pyrrolo[2,3- d ]pyrimidines and 4,7-disubstituted pyrrolo[2,3- d ]pyrimidines as multi-targeted inhibitors of EGFR, platelet derived growth factor receptor kinase β (PDGFRβ) and vascular endothelial growth factor receptor kinase (VEGFR). Cheng et al.…”