Described herein are phenoxy-pyridyl-pyrimidine compounds with inositol requiring enzyme 1 (IRE1) modulation activity or function having the Formula I structure:,or stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, and with the substituents and structural features described herein. Also described are pharmaceutical compositions and medicaments that include the Formula I compounds, as well as methods of using such IRE1 modulators, alone and in combination with other therapeutic agents, for treating diseases or conditions that are mediated or dependent upon estrogen receptors.本發明描述具有肌醇需求酶1 (IRE1)調節活性或功能的苯氧基-吡啶基-嘧啶化合物，其具有式I結構：，或其立體異構體、互變異構體或醫藥學上可接受之鹽，且該等化合物具有本文中所述之取代基及結構特徵。亦描述包括該等式I化合物之醫藥組合物及藥劑，以及單獨及與其他治療劑組合使用此類IRE1調節劑以治療雌激素受體介導性或依賴性疾病或病狀之方法。
