Discovery of Aminopyrazole Derivatives as Potent Inhibitors of Wild-Type and Gatekeeper Mutant FGFR2 and 3.

Fibroblast growth factor receptors (FGFR) 2 and 3 have been established as drivers of numerous types of cancer with multiple drugs approved or entering late stage clinical trials. A limitation of current inhibitors is vulnerability to gatekeeper resistance mutations. Using a combination of targeted high-throughput screening and structure-based drug design, we have developed a series of aminopyrazole based FGFR inhibitors that covalently target a cysteine residue on the P-loop of the kinase. The inhibitors show excellent activity against the wild-type and gatekeeper mutant versions of the enzymes. Further optimization using SAR analysis and structure-based drug design led to analogues with improved potency and drug metabolism and pharmacokinetics properties.

Rhodium(II)-catalyzed alkyne amination of homopropargylic sulfamate esters: stereoselective synthesis of functionalized norcaradienes by arene cyclopropanation.

A rhodium(II) catalyzed nitrene-alkyne cycloaddition of stereochemically well-defined homopropargylic ethers is followed by arene cyclopropanation to afford unique tetracyclic norcaradiene products bearing a cyclic sulfamate. Products from the arene cyclopropanation (Buchner reaction) can be converted to fused cycloheptatrienes via a ring enlarging electrocyclization after nucleophilic ring opening of the cyclic sulfamate ester.

Enantioselective hydroarylation of bridged [3.2.1] heterocycles: an efficient entry into the homoepibatidine skeleton.

Achiral [3.2.1] bridged heterocycles containing a bridging amide can undergo enantioselective hydroarylation reactions under rhodium(I) catalysis. These reactions proceed in high yield and enantioselectivity in most cases, under mild reaction conditions and using commercially available Josiphos ligands. The phosphine ligand structure and the protecting group on the nitrogen both have significant effects on the selectivity and yield of the reactions.

An efficient synthesis of bridged heterocycles from an Ir(I) bis-amination/ring-closing metathesis sequence.

The amination of bis-allylic imidates using an Iridium(I) catalyst leads to the efficient formation of 2,6-divinyl heterocycles. Careful screening of amines, solvents, and conditions has led to the discovery of a system that favors formation of the desired cis products with synthetically useful levels of diastereoselectivity, and these results are further explained by computer based transition state energy calculations. Exposure of the heterocycles to ring-closing metathesis catalysts leads to the desired bridged heterocyclic systems.

Stereoselective C-glycosidations with achiral and enantioenriched allenylsilanes.

Allenylsilanes are used as carbon nucleophiles in highly stereoselective Lewis acid-promoted C-glycosidations, resulting in the introduction of an internal alkyne with an adjacent stereocenter. Both achiral and chiral allenylsilanes form the desired products with high diastereoselectivity, where the nucleophile adds exclusively to the α-face of the intermediate oxonium ion. Reactions with glucal and galactal afford dihydropyran products, while reactions with a ribose derivative yield dihydrofuran products.

Regioselective intramolecular dipolar cycloaddition of azides and unsymmetrical alkynes.

Enantioenriched allenylsilanes are used in three-component propargylation reactions with aldehydes and silyl ethers to form syn-homopropargylic ethers that contain an imbedded azide. These materials then undergo thermally induced intramolecular 1,3-dipolar cycloaddition reactions, resulting in unique fused ring systems containing 1,2,3-triazoles. The ability to modify all three components of the reaction allows for expedient access to compounds containing significant structural and stereochemical variation.

Synthesis of enantioenriched homopropargylic sulfonamides by a three component reaction of aldehydes, sulfonamides, and chiral allenylsilanes.

Enantioenriched allenylsilanes are used as carbon nucleophiles in three-component reactions with in situ generated N-sulfonylimines to selectively form syn-homopropargylic sulfonamides. The reactions proceed with a variety of aldehyde and sulfonamide reaction partners. These novel reaction products are obtained with useful levels of diastereoselectivity, and the axial chirality of the allenylsilane is fully transferred to point chirality, forming products with >97% ee.

Annulations of enantioenriched allenylsilanes with in situ generated iminium ions: stereoselective synthesis of diverse heterocycles.

Highly enantioenriched allenylsilanes participate in Lewis acid mediated annulations with in situ generated iminium ions derived from tert-butyl carbamate and methyl carbamate to selectively form functionalized 4,5-dihydropyrroles and 4,5-dihyrooxazines, respectively. The dihydropyrrole products were further elaborated in a stereocontrolled vinylsilane terminated cyclization with in situ generated oxonium ions, resulting in pyranopyrroles.

Preparation and use of enantioenriched allenylsilanes for the stereoselective synthesis of homopropargylic ethers.

A convenient procedure for the synthesis of highly enantioenriched allenylsilanes by Johnson orthoester Claisen rearrangement of 1-silyl propargylic alcohols is described. Allenylsilanes are then used as carbon nucleophiles in three-component, Lewis acid mediated additions to in situ generated oxonium ions, resulting in enantioenriched homopropargylic ethers.