RAS is the most frequently mutated oncogene in cancer, with KRAS G12C mutations most commonly found in lung adenocarcinoma, colorectal cancer, and other solid tumor malignancies. Covalent inhibitors of KRASG12C have shown antitumor activity against advanced/metastatic KRAS G12C-mutated cancers. Here we report the identification of a new class of pyrazole based KRASG12C inhibitors discovered by structure based de-novo design. The compounds bind to the KRASG12C switch II pocket with a novel binding mode, exploiting unique interactions with the GDP-bound form of the KRASG12C protein. We describe the hit to lead and lead optimization by structure-based design of the novel chemical series leading to the discovery of NVP-JDQ443 (JDQ443), a novel, potent and selective, orally bioavailable KRASG12C covalent inhibitor. JDQ443 showed dose dependent antitumor efficacy in KRAS G12C-mutated cell-derived models and is currently in clinical development as monotherapy as well as in combination with TNO155, a SHP2 inhibitor (NCT04699188).