Starting from previously identified thiazole-2-carboxamides exemplified by compound 1/6, two new series of RORγt inverse agonists with significantly improved aqueous solubility, ADME parameters and oral PK properties were discovered. These scaffolds were identified from a bioisosteric amide replacement approach. Amongst the variety of heterocycles explored, a 1,3,4-oxadiazole led to compounds with the best overall profile for SAR development and in vivo exploration. In an ex vivo mouse PD model, concentration dependent efficacy was demonstrated and compounds 3/5 and 6/3 were profiled in a 5-day rat tolerability study.

中文翻译：

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通过生物等位酰胺替代方法发现和优化新的恶二唑取代的噻唑RORγt反向激动剂。

从先前确定的以化合物1/6为例的噻唑-2-羧酰胺开始，发现了两个新的RORγt反向激动剂系列，它们的水溶性，ADME参数和口服PK性能大大改善。这些支架是通过生物等位酰胺替代方法鉴定的。在探索的各种杂环中，1,3,4-恶二唑导致化合物具有用于SAR开发和体内探索的最佳总体特征。在离体小鼠PD模型中，证实了浓度依赖性功效，并在5天的大鼠耐受性研究中分析了化合物3/5和6/3。