The phosphoinositide 3-kinase (PI3K) pathway is aberrantly activated in many disease states, including tumor cells, either by growth factor receptor tyrosine kinases or by the genetic mutation and amplification of key pathway components. A variety of PI3K isoforms play differential roles in cancers. As such, the development of PI3K inhibitors from novel compound classes should lead to differential pharmacological and pharmacokinetic profiles and allow exploration in various indications, combinations, and dosing regimens. A screening effort aimed at the identification of PI3Kgamma inhibitors for the treatment of inflammatory diseases led to the discovery of the novel 2,3-dihydroimidazo[1,2-c]quinazoline class of PI3K inhibitors. A subsequent lead optimization program targeting cancer therapy focused on inhibition of PI3Kalpha and PI3Kbeta. Herein, initial structure-activity relationship findings for this class and the optimization that led to the identification of copanlisib (BAY 80-6946) as a clinical candidate for the treatment of solid and hematological tumors are described.

中文翻译：

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新型2,3-二氢咪唑并[1,2-c]喹唑啉PI3K抑制剂的发现与合成孔径雷达：鉴定帕潘西伯（BAY 80-6946）。

磷酸肌醇3-激酶（PI3K）途径在许多疾病状态（包括肿瘤细胞）中都被生长因子受体酪氨酸激酶或关键途径成分的遗传突变和扩增异常激活。多种PI3K亚型在癌症中起着不同的作用。因此，从新型化合物类别开发PI3K抑制剂应导致不同的药理和药代动力学特征，并允许探索各种适应症，组合和给药方案。旨在鉴定用于治疗炎性疾病的PI3Kgamma抑制剂的筛选工作导致发现了新型的3,3-二氢咪唑并[1,2-c]喹唑啉类PI3K抑制剂。随后针对癌症治疗的前导优化程序重点在于抑制PI3Kalpha和PI3Kbeta。在此处，