Indazolin‑<i>s</i>‑ylidene–N-Heterocyclic Carbene Complexes of Rhodium, Palladium, and Gold: Synthesis, Characterization, and Catalytic Hydration of Alkynes

A novel series of Indy-N-heterocyclic carbene ligands (Indy = indazolin-<i>s</i>-ylidene) have been developed and investigated. Via a mild Ag carbene transfer route, these new carbene ligands reacted with rhodium, palladium, and gold salts to yield the corresponding air-stable metal complexes. The product complexes were characterized by NMR spectroscopic methods and X-ray diffraction analysis. The electronic properties of these complexes were modified by the introduction of different substituents at the coordinated NHC ligands. Catalytic properties of the gold complex were evaluated in the hydration of alkynes to give the corresponding ketone products. This new type of gold N-heterocyclic carbene complex showed a high catalytic activity in the hydration of alkyne at room temperature

Indazolin‑<i>s</i>‑ylidene–N-Heterocyclic Carbene Complexes of Rhodium, Palladium, and Gold: Synthesis, Characterization, and Catalytic Hydration of Alkynes

A novel series of Indy-N-heterocyclic carbene ligands (Indy = indazolin-<i>s</i>-ylidene) have been developed and investigated. Via a mild Ag carbene transfer route, these new carbene ligands reacted with rhodium, palladium, and gold salts to yield the corresponding air-stable metal complexes. The product complexes were characterized by NMR spectroscopic methods and X-ray diffraction analysis. The electronic properties of these complexes were modified by the introduction of different substituents at the coordinated NHC ligands. Catalytic properties of the gold complex were evaluated in the hydration of alkynes to give the corresponding ketone products. This new type of gold N-heterocyclic carbene complex showed a high catalytic activity in the hydration of alkyne at room temperature

Effect of Ionic Strength on the Interfacial Forces between Oil/Brine/Rock Interfaces: A Chemical Force Microscopy Study

The presence of thin aqueous films and their stability have a profound effect on the interactions between oil/brine/rock interfaces. In a previous report, we proposed that hydration forces, originating from the overlap of hydrated layers of different surfaces in the presence of sodium chloride, played an important role at short range. In the present work, divalent ions were introduced to the liquid films and, the mechanisms in improving oil recovery from low-salinity brine and the low-salinity effect at the molecular level were revealed. Through a direct force-measuring technique of chemical force microscopy (CFM), the functionalized atomic force microscopy (AFM) tips felt a solid surface to mimic the oil/rock interactions in brine. It was found that not only did the van der Waals and electrostatic forces have a great effect on this process due to the interactions between the charged interfaces of oil/water and water/solid, but also some important additional interactions appeared at short range under a variety of salinity concentrations or compositions. Taking into account the important role of structural forces under a small distance, the force profiles were fitted well with the theory of extended Derjaguin–Landau–Verwey–Overbeek (denoted by EDLVO) through a double-exponential or Gaussian model. Interestingly, low adhesion appeared in the presence of sodium sulfate, because hydration forces contributed to the resultant force depending on the intrinsic properties of the solvent or solute molecules, while in the presence of calcium chloride, high adhesion emerged due to the dispersion interaction between water and hydrocarbon molecules, as well as the reorientation or restructuring of water molecules with tiny breakage of hydrogen bonds. Therefore, on the basis of the EDLVO theory, additional forces were suggested to play an important part in short range, proposing a better understanding of the effect of divalent ions on the thin liquid films in the process of increasing oil recovery

Small Molecule Reversible Inhibitors of Bruton’s Tyrosine Kinase (BTK): Structure–Activity Relationships Leading to the Identification of 7‑(2-Hydroxypropan-2-yl)-4-[2-methyl-3-(4-oxo-3,4-dihydroquinazolin-3-yl)phenyl]‑9<i>H</i>‑carbazole-1-carboxamide (BMS-935177)

Bruton’s tyrosine kinase (BTK) belongs to the TEC family of nonreceptor tyrosine kinases and plays a critical role in multiple cell types responsible for numerous autoimmune diseases. This article will detail the structure–activity relationships (SARs) leading to a novel second generation series of potent and selective reversible carbazole inhibitors of BTK. With an excellent pharmacokinetic profile as well as demonstrated in vivo activity and an acceptable safety profile, 7-(2-hydroxypropan-2-yl)-4-[2-methyl-3-(4-oxo-3,4-dihydro­quinazolin-3-yl)­phenyl]-9<i>H</i>-carbazole-1-carboxamide <b>6</b> (BMS-935177) was selected to advance into clinical development

Discovery of 6‑Fluoro-5‑(<i>R</i>)‑(3‑(<i>S</i>)‑(8-fluoro-1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3(4<i>H</i>)‑yl)-2-methylphenyl)-2‑(<i>S</i>)‑(2-hydroxypropan-2-yl)-2,3,4,9-tetrahydro‑1<i>H</i>‑carbazole-8-carboxamide (BMS-986142): A Reversible Inhibitor of Bruton’s Tyrosine Kinase (BTK) Conformationally Constrained by Two Locked Atropisomers

Bruton's tyrosine kinase (BTK), a nonreceptor tyrosine kinase, is a member of the Tec family of kinases. BTK plays an essential role in B cell receptor (BCR)-mediated signaling as well as Fcγ receptor signaling in monocytes and Fcε receptor signaling in mast cells and basophils, all of which have been implicated in the pathophysiology of autoimmune disease. As a result, inhibition of BTK is anticipated to provide an effective strategy for the clinical treatment of autoimmune diseases such as lupus and rheumatoid arthritis. This article details the structure–activity relationships (SAR) leading to a novel series of highly potent and selective carbazole and tetrahydrocarbazole based, reversible inhibitors of BTK. Of particular interest is that two atropisomeric centers were rotationally locked to provide a single, stable atropisomer, resulting in enhanced potency and selectivity as well as a reduction in safety liabilities. With significantly enhanced potency and selectivity, excellent in vivo properties and efficacy, and a very desirable tolerability and safety profile, <b>14f</b> (BMS-986142) was advanced into clinical studies

Identification of a Potent, Selective, and Efficacious Phosphatidylinositol 3‑Kinase δ (PI3Kδ) Inhibitor for the Treatment of Immunological Disorders

PI3Kδ plays an important role controlling immune cell function and has therefore been identified as a potential target for the treatment of immunological disorders. This article highlights our work toward the identification of a potent, selective, and efficacious PI3Kδ inhibitor. Through careful SAR, the successful replacement of a polar pyrazole group by a simple chloro or trifluoromethyl group led to improved Caco-2 permeability, reduced Caco-2 efflux, reduced hERG PC activity, and increased selectivity profile while maintaining potency in the CD69 hWB assay. The optimization of the aryl substitution then identified a 4′-CN group that improved the human/rodent correlation in microsomal metabolic stability. Our lead molecule is very potent in PK/PD assays and highly efficacious in a mouse collagen-induced arthritis model