Imidazo[1,2-a]pyridin-6-yl-benzamide analogs as potent RAF inhibitors

Aaron Smith; Zhi-Jie Ni; Daniel Poon; Zilin Huang; Zheng Chen; Qiong Zhang; Laura Tandeske; Hanne Merritt; Kevin Shoemaker; John Chan; Susan Kaufman; Kay Huh; Jeremy Murray; Brent A Appleton; Sandra W Cowan-Jacob; Clemens Scheufler; Takanori Kanazawa; Johanna M Jansen; Darrin Stuart; Cynthia M Shafer

doi:10.1016/j.bmcl.2017.10.047

Imidazo[1,2-a]pyridin-6-yl-benzamide analogs as potent RAF inhibitors

Bioorg Med Chem Lett. 2017 Dec 1;27(23):5221-5224. doi: 10.1016/j.bmcl.2017.10.047. Epub 2017 Oct 20.

Authors

Aaron Smith¹, Zhi-Jie Ni¹, Daniel Poon¹, Zilin Huang¹, Zheng Chen¹, Qiong Zhang¹, Laura Tandeske¹, Hanne Merritt¹, Kevin Shoemaker¹, John Chan¹, Susan Kaufman¹, Kay Huh¹, Jeremy Murray¹, Brent A Appleton¹, Sandra W Cowan-Jacob², Clemens Scheufler², Takanori Kanazawa¹, Johanna M Jansen¹, Darrin Stuart¹, Cynthia M Shafer³

Affiliations

¹ Global Discovery Chemistry/Oncology & Exploratory Chemistry, Novartis Institutes for Biomedical Research, 5300 Chiron Way, Emeryville, CA 94608, United States.
² Novartis Institutes of Biomedical Research, Novartis Campus, CH-4056 Basel, Switzerland.
³ Global Discovery Chemistry/Oncology & Exploratory Chemistry, Novartis Institutes for Biomedical Research, 5300 Chiron Way, Emeryville, CA 94608, United States. Electronic address: cynthia.shafer@novartis.com.

PMID: 29107542
DOI: 10.1016/j.bmcl.2017.10.047

Abstract

A series of imidazo[1,2-a]pyridin-6-yl-benzamide analogs was designed as inhibitors of B-RAF^V600E. Medicinal chemistry techniques were employed to explore the SAR for this series and improve selectivity versus P38 and VEGFR2.

Keywords: Kinase; MAPK; RAF.

MeSH terms

Benzamides / chemical synthesis
Benzamides / chemistry
Benzamides / pharmacology*
Dose-Response Relationship, Drug
Heterocyclic Compounds, 2-Ring / chemical synthesis
Heterocyclic Compounds, 2-Ring / chemistry
Heterocyclic Compounds, 2-Ring / pharmacology*
Humans
Models, Molecular
Molecular Structure
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology*
Proto-Oncogene Proteins B-raf / antagonists & inhibitors*
Proto-Oncogene Proteins B-raf / metabolism
Structure-Activity Relationship

Substances

Benzamides
Heterocyclic Compounds, 2-Ring
Protein Kinase Inhibitors
Proto-Oncogene Proteins B-raf