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A novel series of 3-quinoline carboxamides has been discovered and optimized as selective inhibitors of the ataxia telangiectasia mutated (ATM) kinase. From a modestly potent HTS hit (4), we identified molecules such as 6-[6-(methoxymethyl)-3-pyridinyl]-4-{[(1R)-1-(tetrahydro-2H-pyran-4-yl)ethyl]amino}-3-quinolinecarboxamide (72) and 7-fluoro-6-[6-(methoxymethyl)pyridin-3-yl]-4-{[(1S)-1-(1-methyl-1H-pyrazol-3-yl)ethyl]amino}quinoline-3-carboxamide (74) as potent and highly selective ATM inhibitors with overall ADME properties suitable for oral administration. 72 and 74 constitute excellent oral tools to probe ATM inhibition in vivo. Efficacy in combination with the DSB-inducing agent irinotecan was observed in a disease relevant model.

Optimization of cellular lipophilic ligand efficiency (LLE) in a series of 2-anilino-pyrimidine IGF-1R kinase inhibitors led to the identification of novel 2-(pyrazol-4-ylamino)-pyrimidines with improved physicochemical properties. Replacement of the imidazo[1,2-a]pyridine group of the previously reported inhibitor 3 with the related pyrazolo[1,5-a]pyridine improved IGF-1R cellular potency. Substitution of the amino-pyrazole group was key to obtaining excellent kinase selectivity and pharmacokinetic parameters suitable for oral dosing, which led to the discovery of (2R)-1-[4-(4-{[5-chloro-4-(pyrazolo[1,5-a]pyridin-3-yl)-2-pyrimidinyl]amino}-3,5-dimethyl-1H-pyrazol-1-yl)-1-piperidinyl]-2-hydroxy-1-propanone (AZD9362, 28), a novel, efficacious inhibitor of IGF-1R.

A practical synthesis of 3,4-dihydro-3-methyl-2 H -1,3-benzothiazine-2-imine via intramolecular palladium-catalyzed C–S bond formation is presented and exemplified for both alkyl- and ­arylisothiocyanates.

We developed an efficient one-pot tandem carbamoyl chloride amination and palladium-catalyzed intramolecular urea cyclization, which furnished high-throughput access to imidazo[4,5-b]pyridine-2-one and related imidazo[4,5-c]pyridine-2-one ring systems. Moderate to excellent yields were reported.

Starting from suitably protected 3- and 4-aminobenzenesulfonamides, a practical two-step strategy for the synthesis of unsubstituted N-aryl and heteroarylaminobenzenesulfonamides was devised. Strong bases are tolerated during the N-arylation step. Overall moderate to excellent yields are reported.

A two-step synthesis of 3-(2-chloropyrimidin-4-yl)imidazo[1,2-a]pyridines is presented. The late stage elaboration of the imidazopyridine through a cyclocondensation allows a rapid access to a variety of substitution patterns. The intermediate enol ethers were obtained from inexpensive reagents in a ligand-free Heck coupling. This methodology has been extended to the formation of pyrazolo[1,5-a]pyridines via a formal 1,3-dipolar cycloaddition.

Herein, we report two synthetically useful and high yielding routes to so far unknown branched γ,γ′- and δ,δ′-difluoroalkylamines that can be of interest as building-blocks for medicinal chemistry programs.

The benzofuranone 2 , a potential intermediate for the synthesis of the marine natural product diazonamide A 1 , has been synthesised in eight steps from the N -protected tyrosine ester 3 .

The concise route to title compounds (III) and (V) is amenable to the introduction of both alkyl- and arylisothiocyanates.

The title compounds are prepared by Pd-catalyzed N-arylation of the sulfonamide and subsequent deprotection.

Two-dimensional crystals of a membrane protein, the proton ATPase from plant plasma membranes, have been obtained by a new strategy based on the use of functionalized, fluorinated lipids spread at the air-water interface. Monolayers of the fluorinated lipids are stable even in the presence of high concentrations of various detergents as was established by ellipsometry measurements. A nickel functionalized fluorinated lipid was spread into a monolayer at the air-water interface. The overexpressed His-tagged ATPase solubilized by detergents was added to the subphase. 2D crystals of the membrane protein, embedded in a lipid bilayer, formed as the detergent was removed by adsorption. Electron microscopy indicated that the 2D crystals were single layers with dimensions of 10 microm or more. Image processing yielded a projection map at 9 A resolution, showing three well-separated domains of the membrane-embedded proton ATPase.

The benzofuranone 2 , a potential intermediate for the synthesis of the marine natural product diazonamide A 1 , has been synthesised in eight steps from the N -protected tyrosine ester 3 .

A series of new fluorinated amphiphilic structures has been synthesized. The molecules were designed to prevent the insertion of hydrophobic compounds in between the fatty chains of the amphiphile. Derivatives of vitamin A analogues were prepared in order to perform two-dimensional crystallisation experiments with retinoic acid receptors.

Various approaches to the tyrosine-derived fragment of the marine secondary metabolite diazonamide A are described. Initial efforts were focused on the originally proposed structure of the natural product, and a feasibility study established that a model 4-aryltryptamine could be readily prepared. Protected 4-bromotryptamine underwent Pd0-catalyzed coupling with the boronic acid derived from 2-bromophenyl allyl ether by Claisen rearrangement, O-methylation and lithiation-boration. The resulting biaryl was elaborated into an alpha-diazo-beta-ketoester, dirhodium(II)-catalyzed reaction of which with N-Z-valinamide gave the desired tryptamine-oxazole following cyclodehydration of the intermediate ketoamide. A potential precursor to the benzofuran ring of the original structure of diazonamide A was prepared in eight steps from N-Z-tyrosine tert-butyl ester. Iodination, O-protection and Stille coupling gave the cinnamyl alcohol 25, converted via the bromide into the allyl aryl ether 27. Subsequent Claisen rearrangement and oxidative cleavage of the alkene gave the lactol 29, converted into the desired benzofuranone 31. The revision in the structure of diazonamide A to 2 resulted in the targeting of an alternative tyrosine-derived model benzofuranone 41 synthesized in four steps from N-Z-tyrosine methyl ester 36 by a route involving Claisen rearrangement of cinnamyl ether 37. Poor yields in this sequence prompted an investigation into the intramolecular Heck reaction as a route to benzofuranone 50. Coupling of 3-iodotyrosine 44 with 2-phenylbutenoic acid 48 gave ester 49 that readily underwent intramolecular Heck reaction to give benzofuranone 50, albeit with poor stereocontrol.