The article describes the discovery of two clinical candidates for IRAK4 inhibitors, BAY1834845 (zabedosertib) and BAY1830839. Starting from a high-throughput screening hit from Bayer's compound library, these compounds were developed through a series of chemical modifications and optimization. The discovery process involved the use of an in-house docking model to exploit unique binding site features of IRAK4, leading to compounds with good potency and selectivity. Favorable DMPK profiles and activity in animal inflammation models led to the selection of these two compounds for clinical development. IRAK4 plays a critical role in innate immune signaling pathways, and its activation is associated with inflammatory and autoimmune disorders. Numerous IRAK4 inhibitors have been identified, but only a few have progressed to clinical development. The discovery of BAY1834845 and BAY1830839 represents a significant advancement in the development of IRAK4 inhibitors with high potency, selectivity, and favorable pharmacokinetic profiles. These compounds have shown significant anti-inflammatory effects in preclinical models, including in vivo studies in mice, and have advanced to clinical trials. The synthesis of these compounds involved a series of chemical reactions, including alkylation and coupling steps, to achieve the desired structure and properties. The compounds have been shown to be metabolically stable, highly permeable, and to exhibit excellent oral bioavailability. The study highlights the importance of structural optimization and the use of computational methods in the discovery of novel IRAK4 inhibitors.The article describes the discovery of two clinical candidates for IRAK4 inhibitors, BAY1834845 (zabedosertib) and BAY1830839. Starting from a high-throughput screening hit from Bayer's compound library, these compounds were developed through a series of chemical modifications and optimization. The discovery process involved the use of an in-house docking model to exploit unique binding site features of IRAK4, leading to compounds with good potency and selectivity. Favorable DMPK profiles and activity in animal inflammation models led to the selection of these two compounds for clinical development. IRAK4 plays a critical role in innate immune signaling pathways, and its activation is associated with inflammatory and autoimmune disorders. Numerous IRAK4 inhibitors have been identified, but only a few have progressed to clinical development. The discovery of BAY1834845 and BAY1830839 represents a significant advancement in the development of IRAK4 inhibitors with high potency, selectivity, and favorable pharmacokinetic profiles. These compounds have shown significant anti-inflammatory effects in preclinical models, including in vivo studies in mice, and have advanced to clinical trials. The synthesis of these compounds involved a series of chemical reactions, including alkylation and coupling steps, to achieve the desired structure and properties. The compounds have been shown to be metabolically stable, highly permeable, and to exhibit excellent oral bioavailability. The study highlights the importance of structural optimization and the use of computational methods in the discovery of novel IRAK4 inhibitors.