This paper presents the design and synthesis of 4-(3-hydroxyanilino)-6-(1H-1,2,3-triazol-4-yl)quinazolines of scaffold 9 as selective B-Raf/B-Raf^V600E and potent EGFR/VEGFR2 kinase inhibitors. Total 14 compounds of scaffold 9 having different side chains at the triazolyl group with/without fluoro substituents at the anilino group were synthesized and investigated. Among them, 9m with a 2-carbamoylethyl side chain and C-4′/C-6′ difluoro substituents was the most potent, which selectively inhibited B-Raf (IC₅₀: 57 nM) and B-Raf^V600E (IC₅₀: 51 nM) over C-Raf (IC₅₀: 1.0 μM). Compound 9m also actively inhibited EGFR (IC₅₀: 73 nM) and VEGFR2 (IC₅₀: 7.0 nM) but not EGFR^T790M and PDGFR-β (IC₅₀: >10 μM). Despite having good potency for B-Raf and B-Raf^V600E in the enzymatic assays, 9m was less active to inhibit melanoma A375 cells which proliferate due to constitutively activated B-Raf^600E. The inferior activity of 9m for A375 was similar to that of sorafenib (6), suggesting that 9m might bind to the inactive conformations of B-Raf and B-Raf^V600E. Docking simulations could thus be performed to reveal the binding poses of 9m in B-Raf, B-Raf^V600E, and VEGFR2 kinases.

本文介绍了支架9的 4-(3-羟基苯胺基)-6-(1 H -1,2,3-三唑-4-基)喹唑啉作为选择性 B-Raf/B-Raf ^V600E和有效的设计和合成EGFR/VEGFR2激酶抑制剂。合成并研究了在三唑基具有/不具有氟取代基的三唑基基团处具有不同侧链的支架9的总共14种化合物并进行了研究。其中，具有 2-氨基甲酰基乙基侧链和 C-4'/C-6' 二氟取代基的9m是最有效的，它选择性地抑制 B-Raf (IC ₅₀ : 57 nM) 和 B-Raf ^V600E (IC ₅₀ : 51 nM) 超过 C-Raf (IC ₅₀ : 1.0 μM)。化合物9m还积极抑制 EGFR (IC ₅₀ : 73 nM) 和 VEGFR2 (IC ₅₀ : 7.0 nM) 但不抑制EGFR ^T790M和 PDGFR-β (IC ₅₀ : >10 μM)。尽管在酶促测定中对 B-Raf 和 B-Raf ^V600E具有良好的效力，但9m对抑制由于组成型激活的 B-Raf ^600E而增殖的黑色素瘤 A375 细胞的活性较低。9m对 A375的较差活性类似于索拉非尼 ( 6 )，表明9m可能与 B-Raf 和 B-Raf ^V600E的无活性构象结合。因此可以进行对接模拟以揭示在 B-Raf、B-Raf ^V600E和 VEGFR2 激酶中为9m。