Non-hinge-binding pyrazolo[1,5-a]pyrimidines as potent B-Raf kinase inhibitors.
As part of our research effort to discover B-Raf kinase inhibitors, we prepared a series of C-3 substituted N-(3-(pyrazolo[1,5-a]pyrimidin-7-yl)phenyl)-3-(trifluoromethyl)benzamides. X-ray crystallography studies revealed that one of the more potent inhibitors (10n) bound to B-Raf kinase without forming a hinge-binding hydrogen bond. With basic amine residues appended to C-3 aryl residues, cellular activity and solubility were enhanced over previously described compounds of this class.
Berger
Dan M
DM
Chemical Sciences, Wyeth Research, Pearl River, NY 10965, USA. bergerd@wyeth.com
Torres
Nancy
N
Dutia
Minu
M
Powell
Dennis
D
Ciszewski
Greg
G
Gopalsamy
Ariamala
A
Levin
Jeremy I
JI
Kim
Kyung-Hee
KH
Xu
Weixin
W
Wilhelm
James
J
Hu
YongBo
Y
Collins
Karen
K
Feldberg
Larry
L
Kim
Steven
S
Frommer
Eileen
E
Wojciechowicz
Donald
D
Mallon
Robert
R
D001549:Benzamides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D018360:Crystallography, X-Ray; D008958:Models, Molecular; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011720:Pyrazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D001549:Benzamides; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011743:Pyrimidines; D048493:Proto-Oncogene Proteins B-raf