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[Display omitted] We describe our efforts to introduce structural diversity to a previously described triazole-containing N1-carboline series of bromodomain and extra-terminal (BET) inhibitors. N9 carbolines were designed to retain favorable binding interactions that the N1-carbolines possess. A convergent synthetic route enabled modifications to reduce clearance, enhance physicochemical properties, and improve the overall in vitro profile. This work led to the identification of a potent BET inhibitor, (S)-2‐{8‐fluoro‐5‐[(3‐fluoropyridin‐2‐yl)(oxan‐4‐yl)methyl]‐7‐[4‐(2H 3)methyl‐1‐methyl‐1 H ‐1,2,3‐triazol‐5‐yl]‐5 H ‐pyrido[3,2‐b]indol‐3‐yl}propan‐2‐ol (10), a compound with enhanced oral exposure in mice. Subsequent evaluation in a mouse triple-negative breast cancer tumor model revealed efficacy at 4 mg/kg of N9-carboline 10. [ABSTRACT FROM AUTHOR]

[Display omitted] We describe our efforts to identify structurally diverse leads in the triazole-containing N1-carboline series of bromodomain and extra-terminal inhibitors. Replacement of the N5 "cap" phenyl moiety with various heteroaryls, coupled with additional modifications to the carboline core, provided analogs with similar potency, improved pharmacokinetic properties, and increased solubility compared to our backup lead, BMS-986225 (2). Rapid SAR exploration was enabled by a convergent, synthetic route. These efforts provided a potent BET inhibitor, 3-fluoropyridyl 12 , that demonstrated robust efficacy in a multiple myeloma mouse tumor model at 1 mg/kg. [ABSTRACT FROM AUTHOR]