Here we first time report an unprecedented and unnatural six-membered 1,5-oxaza spiroquinone scaffold with structural novelty, a convenient and efficient synthetic route was developed for the synthesis of new 1,5-oxaza spiroquinone derivatives (1a-1r) in high yields from readily available starting materials. The logic of the present work consists of (1) the identification of a promising unprecedented scaffold from privileged scaffolds of biological active molecules through our 'Chemistry-oriented Synthesis' (ChOS) approach, a compensatory strategy for target-based drug discovery, (2) the positioning of the identified 1,5-oxaza spiroquinone scaffold on neuroinflammation and neurodegenerative disease through nitric oxide (NO) inhibitory activity without cytotoxicity in hyper-activated microglia (IC<sub>50</sub> of NO production: 0.07-1.82 μM) to establish structure-activity relationship (SAR), (3) the investigation on the possibility as a selective kinase inhibitor related to neurodegenerative diseases (eg. JNK1, CDK2, DAPK1) through kinase full panel screening of the most potent compound 1n, and (4) the evaluation on in vivo efficacy of the compound 1n through Y-maze test.