Fibroblast growth factor receptor 2 (FGFR2) has gained recognition as a compelling therapeutic target in oncology. We present LHQ766, a novel orally bioavailable FGFR2 inhibitor demonstrating exceptional potency and selectivity, through optimization of our previously reported FGFR2 inhibitor 7. The structures and purity of all target compounds were confirmed by 1H NMR, 13C NMR, HRMS and HPLC analyses. Compound LHQ766 exhibited strong enzymatic inhibition (IC50 = 7.3 nM against FGFR2), good kinase selectivity (selective over FGFR1/3/4 and 72 other tyrosine kinases), and remarkable cellular potency (IC50 = 0.5 nM in BaF3-FGFR2 cells). Mechanistic studies through computational modeling and mass spectrometry revealed LHQ766's covalent binding mode with FGFR2. The compound demonstrated dose-dependent suppression of FGFR2 signaling pathways and selective anti-proliferative effects in FGFR2-driven cancer models. As a key advancement over lead compound 7, LHQ766 showed substantially optimized pharmacokinetic properties, achieving 35.9 % oral bioavailability in rats. These findings positioned LHQ766 as a promising lead compound for targeted FGFR2 therapy.

The reversible interconversion between a carbon-carbon double bond and a diradical species represents a fundamental challenge in organic chemistry, with implications for molecular design and electronic materials. While steric strain and external stimulus can induce partial twisting of a carbon-carbon double bond, achieving stable diradical states through controlled, reversible bond twisting remains a significant challenge. Here, we report a strategy in which Lewis acid coordination enables the controlled twisting of C=C bonds to form diradical species with torsional angles of over 70 degrees. Through coordination of Al(ORF)(3) (RF = C(CF3)(3)) or SiEt3+ to bianthrone derivatives, we isolate twisted adducts characterized by X-ray crystallography, EPR spectroscopy, and magnetic studies. The process is reversible-competitive displacement of Lewis acids by CH3CN restores folded alkenes, as monitored by UV-vis and NMR spectroscopy. This work provides a strategy for manipulating carbon-carbon double-bond topology with potential applications in reversibly responsive molecular systems.

Although the thiocarbonyl group is typically attacked at sulfur due to orbital control, strong sigma-electron-withdrawing groups can invert this reactivity, rendering the carbon electrophilic. Herein, we demonstrate that (CF3S)(2)C=S, despite bearing two strongly electron-withdrawing CF3S groups, still exhibits electrophilicity primarily at the sulfur atom toward Grignard reagents. Strikingly, the stoichiometric ratio governs the pathway. Excess Grignard reagent affords sulfur addition products, whereas excess (CF3S)(2)C=S yields unprecedented tris(trifluoromethylthio)alkenes.

Polar polyolefins find widespread applications owing to their superior properties. Conventional synthesis methods incorporated polar groups into the side chains of polyolefins, offering effective pathways for diverse functional applications. In contrast, reports on main-chain polar polyolefins remain relatively scarce, and systematic studies of their properties are particularly underdeveloped. Here, we report a hydrogen-bonding-enhanced main-chain polar polyolefin (H-PO) synthesized via efficient polymerization of alpha,omega-dihydroxy telechelic polyolefins (tPO) and hexamethylene diisocyanate (HDI), incorporating 3.6-10.6 carbamate linkages per 1000C into the polyolefin backbone. The resulting H-PO shows high molecular weight (M n up to 120.6 kDa), excellent strength, elongation (up to 3048%), and toughness (up to 268 MJm-3). Notably, manganese-catalyzed hydrogenolysis allows closed-loop recycling of tPO macromonomers and HDI precursors (>= 95% yield). This approach uniquely combines high performance and easy synthesis of high-molecular-weight polyolefins with efficient circularity within a single material through main-chain polar linkages. It offers a new way to design high-performance, sustainable olefin polymer materials by utilizing multifunctional linkages for closed-loop recycling and enhanced properties.