The study describes the discovery and development of two clinical candidate IRAK4 inhibitors, BAY1834845 (zabedosertib) and BAY1830839, derived from a high-throughput screening hit in Bayer's compound library. The initial hit, compound 5, was optimized through structure-activity relationship (SAR) studies to improve potency, selectivity, and pharmacokinetic (PK) profiles. Key modifications included replacing the nitrophenyl group with a trifluoromethylpyridine moiety and introducing substituents at the 6-position of the indazole core. These changes enhanced potency and selectivity while maintaining good permeability and metabolic stability. Cocrystal structures of compound 5 and a subsequent compound, 16, provided insights into binding modes and selectivity factors. The final compounds, BAY1830839 and BAY1834845, showed high potency against IRAK4, excellent selectivity, and promising PK profiles across preclinical species. Both compounds demonstrated significant anti-inflammatory efficacy in various pharmacodynamic models, including IL-1β-induced and TLR-driven inflammation in mice. BAY1834845 also reduced psoriasis-like inflammation induced by imiquimod in mice. The study highlights the importance of SAR exploration and the development of improved synthetic methods for optimizing IRAK4 inhibitors.The study describes the discovery and development of two clinical candidate IRAK4 inhibitors, BAY1834845 (zabedosertib) and BAY1830839, derived from a high-throughput screening hit in Bayer's compound library. The initial hit, compound 5, was optimized through structure-activity relationship (SAR) studies to improve potency, selectivity, and pharmacokinetic (PK) profiles. Key modifications included replacing the nitrophenyl group with a trifluoromethylpyridine moiety and introducing substituents at the 6-position of the indazole core. These changes enhanced potency and selectivity while maintaining good permeability and metabolic stability. Cocrystal structures of compound 5 and a subsequent compound, 16, provided insights into binding modes and selectivity factors. The final compounds, BAY1830839 and BAY1834845, showed high potency against IRAK4, excellent selectivity, and promising PK profiles across preclinical species. Both compounds demonstrated significant anti-inflammatory efficacy in various pharmacodynamic models, including IL-1β-induced and TLR-driven inflammation in mice. BAY1834845 also reduced psoriasis-like inflammation induced by imiquimod in mice. The study highlights the importance of SAR exploration and the development of improved synthetic methods for optimizing IRAK4 inhibitors.