Tumor necrosis factor-alpha (TNF-alpha) is an important target for the treatment of inflammatory diseases. Targeting TNF-alpha inhibition, such as antibody drug infliximab and adalimumab, has emerged as an effective therapeutic strategy for managing the most difficult-to-treat chronic ulcerative colitis (UC). So far, there are no small molecule TNF-alpha inhibitors available on the market for the treatment of UC. Previously, we reported an indanone analogue (R)-STU104 showed considerable inhibitory activity on TNF-alpha production in both acute and chronic mouse models of UC with a favorable safety profile. However, further development potential of this compound was greatly limited due to its poor metabolic stability in human liver microsomes and suboptimal pharmacokinetic profiles in mice. Herein, we discovered a deuterated TNF-alpha small molecule modulator (R)-104-6D-01, which demonstrated promising clinical potential for the treatment of UC. This new compound exhibited enhanced oral bioavailability and exposure in pharmacokinetic studies, as well as superior anti-UC efficacy in a DSS-induced mouse UC model, compared with (R)-STU104 at a dosage of 30 mg/kg/d. Collectively, (R)-104-6D-01 proves to be a promising candidate of potential use in treating UC as an oral TNF-alpha small molecule modulator.