1-[(3RS,4RS)-1-Benzyl-4-methylpiperidin-3-yl]-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine hemihydrate

The benzyl residue in the title compound, C21H23N5·0.5H2O, is oriented at a dihedral angle of 83.8 (3)° towards the 1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine system. The piperidine ring adopts a chair conformation with the cis substituents displaying a torsion angle of −45.91 (16)°. In the crystal, molecules are accumulated as racemic dimers by two intermolecular hydrogen bonds between the pyrrolopyridine systems. Another hydrogen bond is formed between the imidazole ring and the cocrystallized water molecule, which is located on a twofold rotation axis

N-[(3RS,4SR)-1-Benzyl-4-methylpiperidin-3-yl]-1-(4-methylphenylsulfonyl)-5-nitro-1H-pyrrolo[2,3-b]pyridin-4-amine

The structure of the title compound, C27H29N5O4S, displays an intramolecular N—H...O hydrogen bond. The pyrrolo[2,3-b]pyridine core makes a dihedral angle of 85.5 (4)° with the benzyl residue and a dihedral angle of 89.4 (9)° with the tosyl ring. The nitro group is slightly twisted out of the plane of the planar pyrrolopyridine system [(—N—)C—C—N—O torsion angle = −4.61 (18)° and (—NH—)C—C—N—O = −6.46 (18)°]

2-(3-{(3R,4R)-4-Methyl-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]piperidin-1-yl}oxetan-3-yl)acetonitrile monohydrate

In the title compound, C18H24N6O·H2O, the piperidine ring adopts a chair conformation with an N—C—C—C torsion angle of 39.5 (5)° between the cis-related substituents. The pyrrole N—H group forms a water-mediated intermolecular hydrogen bond to one of the N atoms of the annelated pyrimidine ring. The water molecule connects two organic molecules and is disorderd over two positions (occupancies of 0.48 and 0.52). The crystal packing shows zigzag chains of alternating organic and water molecules running parallel to the a axis

Selective JAK3 Inhibitors with a Covalent Reversible Binding Mode Targeting a New Induced Fit Binding Pocket

Janus kinases (JAKs) are a family of cytoplasmatic tyrosine kinases that are attractive targets for the development of anti-inflammatory drugs given their roles in cytokine signaling. One question regarding JAKs and their inhibitors that remains under intensive debate is whether JAK inhibitors should be isoform selective. Since JAK3 functions are restricted to immune cells, an isoform-selective inhibitor for JAK3 could be especially valuable to achieve clinically more useful and precise effects. However, the high degree of structural conservation makes isoform-selective targeting a challenging task. Here, we present picomolar inhibitors with unprecedented kinome-wide selectivity for JAK3. Selectivity was achieved by concurrent covalent reversible targeting of a JAK3-specific cysteine residue and a ligand-induced binding pocket. We confirmed that in vitro activity and selectivity translate well into the cellular environment and suggest that our inhibitors are powerful tools to elucidate JAK3-specific functions.ISSN:2451-945