Factor XIa (FXIa) is an enzyme in the coagulation cascade thought to amplify 
thrombin generation but has a limited role in hemostasis. From preclinical 
models and human genetics, an inhibitor of FXIa has the potential to be an 
antithrombotic agent with superior efficacy and safety. Reversible and 
irreversible inhibitors of FXIa have demonstrated excellent antithrombotic 
efficacy without increased bleeding time in animal models (Weitz, J. I., Chan, 
N. C. Arterioscler. Thromb. Vasc. Biol. 2019, 39 (1), 7-12). Herein, we report 
the discovery of a novel series of macrocyclic FXIa inhibitors containing a 
pyrazole P2' moiety. Optimization of the series for (pharmacokinetic) PK 
properties, free fraction, and solubility resulted in the identification of 
milvexian (BMS-986177/JNJ-70033093, 17, FXIa Ki = 0.11 nM) as a clinical 
candidate for the prevention and treatment of thromboembolic disorders, suitable 
for oral administration.