Design and synthesis of bridged piperidine and piperazine isosteres

3-((Hetera)cyclobutyl)azetidines, “Stretched” Analogues of Piperidine, Piperazine, and Morpholine: Advanced Building Blocks for Drug Discovery

“…1 H NMR (400 MHz, D 2 O): δ 4.10−4.01 (m, 2H), 3.96 (t, J = 8.8 Hz, 2H), 3.81−3.71 (m, 2H), 3.50 (dd, J = 9.2, 5.2 Hz, 2H), 3.16 (sext, J = 8.4 Hz, 1H), 2.85−2.73 (m, 1H), 1.29 (s, 9H). 13 tert-Butyl 3-(Thietan-3-yl)azetidine-1-carboxylate (15). To a solution of tert-butyl 3-(1,3-dibromopropan-2-yl)azetidine-1-carboxylate (13; 41.1 g, 115 mmol) in a mixture of CH 3 CN (1 L) and H 2 O (100 mL), Na 2 S•5H 2 O (38.6 g, 230 mmol) was added, and the reaction mixture was stirred at 50 °C for 12 h. Then it was allowed to cool to rt and was concentrated under vacuum.…”

“…Being inspired by these successful examples, we have designed four novel piperidine, piperazine, and morpholine surrogates, 4 – 7 , which are based on the structural modifications mentioned above (i.e., the use of four-membered rings and incorporation of sulfone and carboxylic acid functionalities) (Figure ). It should be noted that a number of fused, bridged, and spirocyclic analogues of the parent saturated six-membered heterocycles were described in the literature. − These bicyclic ring systems have already proven their value for medicinal chemistry: − some of them can be found in the structures of marketed drugs, for example, boceprevir, gliclazide, and ledipasvir . Nevertheless, all these surrogates were obtained by introducing additional conformational restriction to the piperidine, piperazine, and morpholine rings; in contrast, molecules 4 – 7 are more flexible as compared to the parent structures due to the presence of a rotatable bond.…”

Discovery of BMS-986318, a Potent Nonbile Acid FXR Agonist for the Treatment of Nonalcoholic Steatohepatitis

“…Despite falling within our desired range of FXR potency, compound 5 lacked the requisite microsomal metabolic stability for advancement to further profiling ( t 1/2 = 13 min in HLM). In an attempt to block potential oxidative metabolism of the piperidine linker, we explored bicyclic analogs that would hopefully improve metabolic stability while maintaining potency . Among the analogs we explored, the azabicyclo[3.2.1]­octane analog 6 gave a modest improvement in mouse liver microsomal (MLM) stability but no improvement in HLM stability relative to piperidine 5 .…”