Oncogene KRAS plays predominant roles in human cancers by regulating cell proliferation, differentiation, and migration. Recent progress revealed that directly target KRAS G12C with allosteric inhibitors that covalently bind to the switch Ⅱ pocket is feasible. Herein, series of pyrrolo[2,3-d]pyrimidine derivatives were designed and synthesized through systematic structural optimization, leading to the discovery of compound 2-((S)-1-acryloyl-4-(2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7-methyl-6-(8-methylnaphthalen-1-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile (50) with high KRAS/SOS1 inhibitory potency (IC50 = 0.21 μM) and strong anti-proliferation activities on cancer cells harboring KRAS p.G12C. Compound 50 also exhibited satisfactory selectivity, moderate pharmacokinetic characters, and good anticancer effects in vivo. Meaningfully, the identification of these compounds highlights the necessity of an appropriate conformational constraint for acquiring the applicable binding pose in the cryptic pocket of KRAS, and the results support efforts toward design of KRAS inhibitors with novel skeleton and binding mechanism could be beneficial for targeting the acquired drug resistance.