A mixture of K2CO3 (6 g, 43.5 mmol), 8-bromo-3-chloroisoquinoline-5-yltrifluoromethanesulfonate (17 g), 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborane (7.30 g), and Pd(dppf)Cl2·CH2Cl2 (2.83 g, 3.48 mmol) in dioxane (200/20 mL) was stirred at 45°C for 3 hours. The mixture was diluted with 500 mL of ethyl acetate.
The mixture was washed twice with brine (200 mL). The organic layer was dried over Na₂SO₄. The organic layer was concentrated under vacuum. The residue was purified by silica gel column chromatography with petroleum ether:ethyl acetate = 20:1 to give the title compound BLU-945.
BLU-945 is a potent, highly selective, reversible, and orally active epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI). It can effectively inhibit EGFR with L858R and/or exon 19 deletion mutation, T790M mutation, and C797S mutation. BLU-945 can be used for research on lung cancer, including non-small cell lung cancer (NSCLC)[1].
IUPAC/Chemical Name: N-(2-((3S,4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl-3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinolin-3-amine.
According to clinical studies of BLU-945, common side effects of BLU-945 monotherapy include: rash, diarrhoea, nausea, vomiting, headache, dry skin, onychomycosis, and elevated alanine aminotransferase and aspartate aminotransferase.
Common side effects of the combination of BLU-945 and ositinib include: headache, nausea, fatigue, decreased appetite, vomiting, diarrhoea, dry skin, acne-like dermatitis and onychomycosis.
BLU-945 has inhibitory activity against the EGFRm/T790M double and EGFRm/T790M/C797Striple mutants with IC50 value range from 1.2-4.4 nM.
BLU-945 (0- 10 mM, 4 h) inhibit EGFR phosphorylation in the EGFR L858R/T790M/C797S, and EGFR ex19del/T790M/C797S mutant cell lines.
[1] Y. Elamin. “BLU-945 monotherapy and in combination with osimertinib (OSI) in previously treated patients with advanced EGFR-mutant (EGFRm) NSCLC in the phase 1/2 SYMPHONY study.” Journal of Clinical Oncology (2023).
[2] MEREDITH S. ENO*, THOMAS A. DINEEN Discovery of BLU-945, a Reversible, Potent, and Wild-Type-Sparing Next-Generation EGFR Mutant Inhibitor for Treatment-Resistant Non-Small-Cell Lung Cancer[J]. Journal of Medicinal Chemistry, 2022, 65 14: 9662-9677. DOI:
10.1021/acs.jmedchem.2c00704
