2,4-Diaminopyrimidine inhibitors of c-Met kinase bearing benzoxazepine anilines

• Published in: Bioorganic & medicinal chemistry letters Vol. 21; no. 2; pp. 660 - 663
• Main Authors: Zificsak, Craig A., Theroff, Jay P., Aimone, Lisa D., Albom, Mark S., Angeles, Thelma S., Brown, Rebecca A., Galinis, Deborah, Grobelny, Jennifer V., Herbertz, Torsten, Husten, Jean, Kocsis, Laura S., LoSardo, Christine, Miknyoczki, Sheila J., Murthy, Seetha, Rolon-Steele, Damaris, Underiner, Ted L., Wells-Knecht, Kevin J., Worrell, Candace S., Zeigler, Kelli S., Dorsey, Bruce D.
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 15.01.2011
• Subjects: Administration, Oral; animal models; Animals; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacokinetics; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; c-Met; Diaminopyrimidine; Humans; Inhibitors; Kinase; metabolites; Mice; Mice, Nude; Neoplasms - drug therapy; nitrogen; Protein Kinase Inhibitors - chemistry; Protein Kinase Inhibitors - pharmacokinetics; Protein Kinase Inhibitors - pharmacology; Protein Kinase Inhibitors - therapeutic use; Proto-Oncogene Proteins c-met - antagonists & inhibitors; Proto-Oncogene Proteins c-met - metabolism; Pyrimidines - chemistry; Pyrimidines - pharmacokinetics; Pyrimidines - pharmacology; Pyrimidines - therapeutic use; Xenograft Model Antitumor Assays; c-Met; Inhibitors; Kinase; Diaminopyrimidine
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2010.12.013

Elaboration of the SAR around a series of 2,4-diaminopyrimidines led to a number of c-Met inhibitors in which kinase selectivity was modulated by substituents appended on the C4-aminobenzamide ring and the nature of the C2-aminoaryl ring. Further lead optimization of the C2-aminoaryl group led to benzoxazepine analogs whose pharmaceutical properties were modulated by the nature of the substituent on the benzoxazepine nitrogen. Tumor stasis (with partial regressions) were observed when an orally bioavailable analog was evaluated in a GTL-16 tumor xenograft mouse model. Subsequent PK/PD studies suggested that a metabolite contributed to the overall in vivo response.