1020172-07-9

Rebastinib is an orally bioavailable tyrosine kinase inhibitor that inhibits Abl1 (IC₅₀ = 0.8 nM) as well as the gatekeeper mutant Abl1^T315I (IC₅₀ = 4 nM) and the activation loop mutant Abl1^H396P. It also inhibits the Src family kinases Src, Lyn, Fgr, and Hck and the tyrosine kinases KDR, FLT3, and Tie2 at nanomolar concentrations. Rebastinib inhibits mutant Abl1^T315I signaling and prolongs survival in a mouse Ba/F3 cell allograft model. Rebastinib also exhibits in vivo antineoplastic activity against cells with the T674I point mutation of FIP1-like-1-platelet-derived growth factor receptor α.

A conformational control inhibitor of Abl1 and Abl1-T315I with IC50s of 0.8 nM and 4 nM, respectively.

ChEBI: DCC-2036 is a member of the class of ureas that is urea in which one of the nitrogens bears a 3-tert-butyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl substituent, while the other bears a 2-fluoro-4-{[2-(methylcarbamoyl)pyridin-4-yl]oxy}phenyl substituent. It has a role as a tyrosine kinase inhibitor. It is a member of quinolines, a pyridinecarboxamide, a member of pyrazoles, an organofluorine compound and a member of phenylureas.

Example 1: 4-(4-amino-3-fluorophenoxy)-N-methylpyridine-2-carboxamide (7.0 g, 15.8 mmol), compound (CAS:1011464-72-4, 4.14 g, 15.8 mmol) and N,N-diisopropylethylamine (DIEA, 4.5 g, 34.9 mmol) were dissolved in dimethyl sulfoxide (DMSO 70 ml). The reaction mixture was heated in an oil bath at 70°C for 8 hours. After completion of the reaction, the mixture was poured into water (500 ml), stirred overnight and the solid was collected by filtration. The crude product was purified by successive crystallization from toluene and acetone to afford 1-(3-tert-butyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)-3-(2-fluoro-4-(2-(methylcarbamoyl)pyridin-4-yloxy)phenyl)urea as a white crystalline solid (4.06 g, 46% yield). The product was characterized by 1H NMR (DMSO-d6) and mass spectrometry (ESI): 1H NMR δ 8.90 (m, 2H), 8.79 (m, 1H), 8.52 (m, 2H), 8.2 (m, 3H), 7.96 (dd, J = 9,2 Hz, 1H), 7.63 (dd, J = 8,4 Hz, 1H), 7.40 (br s, 1H) 7.30 (dd, J = 3,12 Hz, 1H), 7.17 (m, 1H), 7.05 (d, J = 9 Hz, 1H), 6.50 (s, 1H), 2.80 (d, J = 5Hz), 1.32 (s, 9H); MS (ESI) m/z: 554 (M + H+).

[1] chan w w, wise s c, kaufman m d, et al. conformational control inhibition of the bcr-abl1 tyrosine kinase, including the gatekeeper t315i mutant, by the switch-control inhibitor dcc-2036. cancer cell, 2011, 19(4): 556-568.