927880-90-8

RAF 265 is a multikinase inhibitor that has displayed BRAF inhibiting activity in clinical trials. It could be used in the treatment of a subpopulation of human melanoma tumors. Has cytotoxic effect o f on MDA-MB-231 cells. RAF265 when used with BEZ-235 inhibited ERK, PI3K signaling that reduced growth, proliferation and development of drug resistance in human thyroid cancer cells.

RAF265 (CHIR-265) is an oral, highly selective RAF and VEGFR kinase inhibitor with IC50 of of 5 to 10 μM.

ChEBI: 1-methyl-5-[[2-[5-(trifluoromethyl)-1H-imidazol-2-yl]-4-pyridinyl]oxy]-N-[4-(trifluoromethyl)phenyl]-2-benzimidazolamine is an aromatic ether.

Example 69: Preparation of 1-methyl-5-((2-(5-(trifluoromethyl)-1H-imidazol-2-yl)pyridin-4-yl)oxy)-N-(4-(trifluoromethyl)phenyl)-1H-benzo[d]imidazol-2-amine 1. 4-(Trifluoromethyl)phenyl isothiocyanate (200 mg, 1 mmol) was added to a solution of N1-methyl-4-[[2-[5-(trifluoromethyl)-1H-imidazol-2-yl]-4-pyridinyl]oxy]-1,2-benzenediamine (350 mg, 1 mmol) in 3 mL of acetonitrile. 2. The reaction mixture was stirred at room temperature for 20 min and the reaction progress was monitored by HPLC. 3. Triethylamine (0.3 mL, 2.2 mmol) was added to the reaction system followed by 2-chloro-1-methylpyridinium iodide (270 mg, 1.05 mmol). 4. The reaction mixture was heated to 50 °C and maintained at this temperature for 5 hours. 5. Upon completion of the reaction, the heating was stopped and 1.5 mL of water was added. 6. The mixture was continued to be stirred for 2 hours, after which the solid product was collected by filtration. 7. The solid was washed with acetonitrile/water (2:1, v/v, 3 x 1 mL) to give a final 317 mg (61% yield) of the target compound 1 -methyl-5-((2-(5-(trifluoromethyl)-1H-imidazol-2-yl)pyridin-4-yl)oxy)-N-(4-(trifluoromethyl)phenyl)-1H-benzo[d]imidazol-2-amine.

B-Raf

VEGFR2; RAF

[1]huang t1, karsy m, zhuge j, zhong m, liu d. b-raf and the inhibitors: from bench to bedside. j hematol oncol. 2013 apr 25;6:30. doi: 10.1186/1756-8722-6-30.
[2]garcia-gomez a1, ocio em, pandiella a, san miguel jf, garayoa m. raf265, a dual braf and vegfr2 inhibitor, prevents osteoclast formation and resorption. therapeutic implications. invest new drugs. 2013 feb;31(1):200-5. doi: 10.1007/s10637-012-9845-3. epub 2012 jul 7.
[3]su y1, vilgelm ae, kelley mc, hawkins oe, liu y, boyd kl, kantrow s, splittgerber rc, short sp, sobolik t, zaja-milatovic s, dahlman kb, amiri ki, jiang a, lu p, shyr y, stuart dd, levy s, sosman ja, richmond a. raf265 inhibits the growth of advanced human melanoma tumors. clin cancer res. 2012 apr 15;18(8):2184-98. doi: 10.1158/1078-0432.ccr-11-1122. epub 2012 feb 20.