Aminopyridyl/Pyrazinyl Spiro[indoline-3,4'-piperidine]-2-ones As Highly Selective and Efficacious c-Met/ALK Inhibitors

Jingrong Li; Nan Wu; Yuanxin Tian; Jiajie Zhang; Shuguang Wu

doi:10.1021/ml400203d

Aminopyridyl/Pyrazinyl Spiro[indoline-3,4'-piperidine]-2-ones As Highly Selective and Efficacious c-Met/ALK Inhibitors

ACS Med Chem Lett. 2013 Jul 12;4(8):806-10. doi: 10.1021/ml400203d. eCollection 2013 Aug 8.

Authors

Jingrong Li¹, Nan Wu², Yuanxin Tian¹, Jiajie Zhang¹, Shuguang Wu¹

Affiliations

¹ School of Pharmaceutical Sciences, Southern Medical University , 1838 North Guangzhou Boulevard, Guangzhou 510515, China.
² Department of Neurosurgery, Southwest Hospital, Third Military Medical University , Chongqing 400038, China.

Abstract

A series of novel aminopyridyl/pyrazinyl-substituted spiro[indoline-3,4'-piperidine]-2-ones were designed, synthesized, and tested in various in vitro/in vivo pharmacological and antitumor assays. 6-[6-Amino-5-[(1R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]-3-pyridyl]-1'-methylspiro[indoline-3,4'-piperidine]-2-one (compound 5b or SMU-B) was identified as a potent, highly selective, well-tolerated, and orally efficacious c-Met/ALK dual inhibitor, which showed pharmacodynamics effect by inhibiting c-Met phosphorylation in vivo and significant tumor growth inhibitions (>50%) in GTL-16 human gastric carcinoma xenograft models.

Keywords: Hepatocyte growth factor receptor (HGFR or c-Met); aminopyrazine; aminopyridine; anaplastic lymphoma kinase (ALK); cancer; inhibitor; small molecule; spiro[indoline-3,4′-piperidine]-2-one.