A series of 4-arylamido 5-methylisoxazole derivatives with quinazoline core was designed and synthesised based on conformational rigidification of a previous type II FMS inhibitor. Most of quinazoline analogues displayed activity against FLT3 and FLT3-ITD. Compound 7d, 5-methyl-N-(2-(3-(4-methylpiperazin-1-yl)-5-(trifluoromethyl)phenyl)quinazolin-7-yl)isoxazole-4-carboxamide, exhibited the most potent inhibitory activity against FLT3 (IC50= 106 nM) with excellent selectivity profiles over 36 other protein kinases including cKit and FMS kinase. Compound 7d was also active in FLT-ITD, with an IC50 value of 301 nM, and other FLT3 mutants showing potential as an AML therapeutics.

中文翻译：

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发现了5-甲基-N-（2-芳基喹唑啉-7-基）异恶唑-4-羧酰胺类似物作为高选择性FLT3抑制剂。

基于先前的II型FMS抑制剂的构象刚性，设计和合成了一系列具有喹唑啉核心的4-芳基氨基5-甲基异恶唑衍生物。大多数喹唑啉类似物表现出针对FLT3和FLT3-ITD的活性。化合物7d 5-甲基-N-（2-（3-（4-甲基哌嗪-1-基）-5-（三氟甲基）苯基）喹唑啉-7-基）异恶唑-4-羧酰胺表现出最强的抑制活性针对FLT3（IC50 = 106 nM）的抗性，具有优于其他36种蛋白激酶（包括cKit和FMS激酶）的选择性。化合物7d在FLT-ITD中也具有活性，IC50值为301 nM，其他FLT3突变体也显示出作为AML治疗药物的潜力。