Fused bicyclic derivatives of 2,4-diaminopyrimidine as c-Met inhibitors.
The HGF-c-Met signaling axis is an important paracrine mediator of epithelial-mesenchymal cell interactions involving the regulation of multiple cellular activities including cell motility, mitogenesis, morphogenesis, and angiogenesis. Dysregulation of c-Met signaling (e.g., overexpression or increased activation) is associated with the development of a wide range of tumor types; thus, inhibiting the HGF-c-Met pathway is predicted to lead to anti-tumor effects in many cancers. Elaboration of a 2-arylaminopyrimidine scaffold led to a series of potent c-Met inhibitors bearing a C4-2-amino-N-methylbenzamide group. Specifically, a series of C2-benzazepinone analogs demonstrated potent inhibition of c-Met in enzymatic and cellular assays. Kinase selectivity could be tuned by varying the nature of the alkyl group on the benzazepinone nitrogen.
Worldwide Discovery Research, Cephalon, Inc, 145 Brandywine Parkway, West Chester, PA 19380-4245, USA. lweinber@cephalon.com
Linda R
LR
Weinberg
Mark S
MS
Albom
Thelma S
TS
Angeles
Jean
J
Husten
Joseph G
JG
Lisko
Robert J
RJ
McHugh
Karen L
KL
Milkiewicz
Seetha
S
Murthy
Gregory R
GR
Ott
Jay P
JP
Theroff
Rabindranath
R
Tripathy
Ted L
TL
Underiner
Craig A
CA
Zificsak
Bruce D
BD
Dorsey
D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D001643:Bridged Bicyclo Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D045744:Cell Line, Tumor; D006801:Humans; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011743:Pyrimidines / Q000737:chemistry*; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; D001643:Bridged Bicyclo Compounds; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; C017205:2,4-diaminopyrimidine; D019859:Proto-Oncogene Proteins c-met