Substitution at the 7-position of the chromen-4-one pharmacophore of 8-(dibenzo[b,d]thiophen-4-yl)-2-morpholino-4H-chromen-4-one NU7441, a potent and selective DNA-dependent protein kinase (DNA-PK) inhibitor, with allyl, n-propyl or methyl enabled the resolution by chiral HPLC of atropisomers. Biological evaluation against DNA-PK of each pair of atropisomers showed a marked difference in potency, with biological activity residing exclusively in the laevorotatory enantiomer.

Amino-substituted biphenyls were obtained by Suzuki cross-coupling of 2,6-dibromoaniline with a phenylboronic acid (substituted with Me, NO2, OH, OMe or Cl) preferably assisted by microwave irradiation. Conversion of the amino group into a thiol preceded a base-induced intramolecular substitution, also facilitated by microwave heating, to generate the second C-S bond of the target dibenzothiophene. The 1-, 2-, 3- or 4-substituted 6-halodibenzothiophenes obtained were subjected to a palladium-mediated coupling with 2-morpholin-4-yl-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4H-chromen-4-one to give the respective 6-, 7-, 8- or 9-substituted dibenzothiophen-4-ylchromenones. These compounds were evaluated as inhibitors of DNA-dependent protein kinase (DNA-PK) and compared to the parent 8-(dibenzo[b,d]thiophen-4-yl)-2-morpholin-4-yl-4H-chromen-4-one. Notably, derivatives bearing hydroxy or methoxy substituents at C-8 or C-9 retained activity, whereas substitution at C-7 lowered activity. Substitution with chloro at C-6 was not detrimental to activity, but a chloro group at C-7 or C-8 reduced potency. The data indicate permissive elaboration of hydroxyl at C-8 or C-9, enabling the possibility of improved pharmaceutical properties, whilst retaining potency against DNA-PK.

Introduction of an O-alkoxyphenyl substituent at the 8-position of the 2-morpholino-4H-chromen-4-one pharmacophore enabled regions of the ATP-binding site of DNA-dependent protein kinase (DNA-PK) to be probed further. Structure-activity relationships have been elucidated for inhibition of DNA-PK and PI3K (p110 alpha), with N-(2-(cyclopropylmethoxy)-4-(2-morpholino-4-oxo-4H-chromen-8-yl)phenyl)-2-morpholinoacetamide 11a being identified as a potent and selective DNA-PK inhibitor (IC50 = 8 nM). (C) 2010 Elsevier Ltd. All rights reserved.

The synthesis of trifluoromethyl-substituted pyridylboronic acids and pyrazolylboronic esters is described via lithiation-boronation protocols (Schemes 1, 3 and 4). A study of their palladium-catalysed cross-couplings with heteroaryl halides is presented. CF3-substituted aryl/heteroaryl-pyridines are thereby obtained (51-98% yields). Analogous cross-couplings have yielded heteroaryl-3-(trifluoromethyl)pyrazoles (60-85% yields); homocoupling of the pyrazolylboronic esters is suppressed by the addition of potassium formate, although competing protodeboronation is observed. Halogenation of the 4-position of selected pyrazole coupling products allows for further cross-couplings to yield tetra-substituted pyrazolyl derivatives (Scheme 5). X-Ray crystal structures are reported for selected pyridylboronic acids, pyrazolylboronic esters and derived trifluoromethyl-substituted heterobiaryl systems. These multi-ring CF3-substituted systems are of interest as building blocks for drug discovery and materials chemistry.

A general method for the synthesis of functionalized pyridazinylboronic acids/esters is described involving a directed ortho metalation (DoM)-boronation protocol (Schemes 1 and 2). A comprehensive study of the reactivity of the C-B bond in palladium -catalyzed cross-couplings with aryl/heteroaryl halides is presented. Aryl-/heteroarylpyridazines are thereby obtained in synthetically viable yields (typically 40-75%) although in some cases competing protodeboronation has been observed. A series of pyridazin-3(2H)-one derivatives, including 4,6-diaryl/heteroaryl derivatives, have been obtained from the corresponding 3-methoxypyridazines in straightforward procedures (Schemes 3 and 4). Several X-ray crystal structures of aryl-/heteroarylpyridazines and derived pyridazin-3(2H)-one derivatives are reported. These multi-ring systems are of considerable interest in contemporary N-heterocyclic chemistry.

We report the synthesis of (2,6-diinethoxy-3-pyridyl)boronic acid (2), (2,3-dimethoxy-4-pyridyl)boronic acid (4), (2,6-difluoro-3-pyridyl)boronic acid (6), (2,6-dichloro-3-pyridyl)boronic acid (8) and (2,3-dichloro-4-pyridyl)boronic acid (10) by directed ortho-metalation reactions on the corresponding disubstituted pyridine precursor, followed by the reaction with triisopropyl borate (TPB) or trimethyl borate. The reactivity of the pyridylboronic acids with heteroaryl halides in Suzuki-Miyaura cross-coupling reactions has been evaluated. New highly functionahzed heteroarylpyridine derivatives have thereby been obtained in moderate to high yields. The reaction of 8 and 3-amino-2-chloropyridine yielded the rare 5H-pyrrolo[2,3-b:4,5-b']dipyridine (i.e. 1,5-diazacarbazole) ring system by sequential cross-coupling and intramolecular cychsation reactions. The X-ray crystal structures are reported for the pyridylboronic acids 2, 4, 8 and 10. ((c) Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2008).

We report the synthesis of 2-chloro-5-pyrimidylboronic acid (6) and 2-amino-5-pyrimidylboronic acid (8) by lithium-halogen exchange followed by reaction with triisopropylborate. Their reactivity with heteroaryl halides in Suzuki-Miyaura cross-coupling reactions has been evaluated. New highly functionalized 5-heteroarylpyrimidine derivatives 24-33 (heteroaryl = quinoline, pyridine, pyrimidine, pyrazine, thiophene, benzothiazole) have been obtained in synthetically useful yields. The X-ray structure of 6 reveals extensive intermolecular O-H center dot center dot center dot N hydrogen bonding in the crystal. ((c) Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2007).