Histone Deacetylases (HDACs) have become important targets for the treatment of cancer and other diseases. In previous studies we described the development of novel spirocyclic HDAC inhibitors based on the combination of privileged structures with hydroxamic acid moieties as zinc binding group. Herein, we report further explorations, which resulted in the discovery of a new class of spiro[2H-(1,3)-benzoxazine-2,4′-piperidine] derivatives. Several compounds showed good potency of around 100 nM and less in the HDAC inhibition assays, submicromolar IC₅₀ values when tested against tumour cell lines and a remarkable stability in human and mouse microsomes. Two representative examples exhibited a good pharmacokinetic profile with an oral bioavailability equal or higher than 35% and one of them studied in an HCT116 murine xenograft model showing a robust tumour growth inhibition. In addition, the two benzoxazines were found to have a minor affinity for the hERG potassium channel compared to their corresponding ketone analogues.

组蛋白脱乙酰基酶（HDAC）已成为治疗癌症和其他疾病的重要靶标。在以前的研究中，我们基于特权结构与异羟肟酸部分作为锌结合基团的组合，描述了新型螺环HDAC抑制剂的开发。在此，我们报告了进一步的探索，从而发现了新一类的螺[2 H-（1,3）-苯并恶嗪-2,4'-哌啶]衍生物。在HDAC抑制试验中，几种化合物显示出约100 nM的良好效价，而亚微摩尔IC ₅₀更低在针对肿瘤细胞系进行测试时具有很高的值，并且在人和小鼠微粒体中具有显着的稳定性。两个代表性实例显示出良好的药代动力学特征，口服生物利用度等于或高于35％，其中一个在HCT116鼠异种移植模型中研究，显示出强大的肿瘤生长抑制能力。另外，发现两种苯并恶嗪与其相应的酮类似物相比对hERG钾通道具有较小的亲和力。