Chinese Journal of Organic Chemistry >
Synthesis and Activity Evaluation of Novel 3,4-Dihydro-benzo[b]-oxazepin-5(2H)-one Derivatives as Protein Kinases Inhibitors
Received date: 2016-11-02
Revised date: 2017-01-09
Online published: 2017-02-15
Supported by
Project supported by the National Natural Science Foundation of China (Nos. 81520108028, 81273430, 21402010, 21672230, 41506187, 81302692, 41476063, 4167060562, 8160131016), and the National Natural Science Foundation of China-Shandong Joint Fund for Marine Science Research Centers (No. U1406402), the Shanghai Science and Technology Committee Project (Nos. 14431901100, 15431901000), the State Key Laboratory of Drug Research/Shanghai Institute of Materia Medica Projects (No. SIMM1501ZZ-03), the Institutes for Drug Discovery and Development, Chinese Academy of Sciences (No. CASIMM0120152039).
A series of novel 3,4-dihydro-benzo[b]oxazepin-5(2H)-one derivatives were designed and synthesized as potent protein-tyrosine kinases (PTKs, e.g. ErbB1, ErbB2, c-Met, ALK, FGFR1, RET, KDR) inhibitors. All compounds were characterized by NMR and MS. E-7-[(2,5-dihydroxy)phenylmethylene]amino-3,4-dihydro-benzo[b]oxazepin-5(2H)-one (8k) and E-7-[(2,3,4-trihydroxy)phenylmethylene]amino-3,4-dihydro-benzo[b]oxazepin-5(2H)-one (8n) were further characterized by X-ray single-crystal analysis. The synthesized compounds were further tested for their inhibitory activity on PTKs. The results display compounds with catechol-substitution display the most potent inhibitory activities toward PTKs. The IC50 values for E-7-[(3,4-dihydroxy)phenylmethylene]amino-3,4-dihydro-benzo[b]oxazepin-5(2H)-one (8i) against ErbB1, ErbB2 are 1.0 and 0.33 μmol/L, respectively. The IC50 value for 8n against RET is 0.7 μmol/L, while the IC50 value for 7-[(3,4-dihydroxyphenyl)methyl]amino-2,3,4,5-tetrahydro-benzo[b]oxazepin-5-ol (10b) against ErbB2 is 1.02 μmol/L.
Hou Guige , Jiang Chengshi , Liu Hongchun , Tong Linjiang , Peng Xia , Ji Yinchun , Geng Meiyu , Xiao Wei , Gong Jingxu , Guo Yuewei . Synthesis and Activity Evaluation of Novel 3,4-Dihydro-benzo[b]-oxazepin-5(2H)-one Derivatives as Protein Kinases Inhibitors[J]. Chinese Journal of Organic Chemistry, 2017 , 37(6) : 1463 -1472 . DOI: 10.6023/cjoc201611005
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