NLRP3 is a receptor important for host responses to infection, yet also known to contribute to devastating diseases such as Alzheimer’s disease, diabetes, atherosclerosis and others, making inhibitors for NLRP3 sought after. One of the inhibitors currently in use is 2-aminoethoxy diphenylborinate (2APB). Unfortunately, in addition to inhibiting NLRP3, 2APB also displays non-selective effects on cellular Ca2+ homeostasis. Here, we use 2APB as a chemical scaffold to build a series of inhibitors, the NBC series, that inhibit NLRP3 inflammasome in vitro and in vivo without affecting Ca2+ homeostasis. The core chemical insights of this work is that oxazaborine ring is a critical feature of the NBC series, and the main biological insight that the use of NBC inhibitors led to was that NLRP3 inflammasome activation was independent of Ca2+. The NBC compounds represent useful tools to dissect NLRP3 function, and may lead to oxazaborine ring containing therapeutics.