- Selectfluor-promoted regioselective chlorination/bromination of 2-aminopyridines and 2-aminodiazines using LiCl/LiBr
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Using LiCl as a chlorine source, the chlorination of 2-aminopyridines or 2-aminodiazines in the presence of Selectfluor and DMF is established under mild conditions. This method gives chlorinated pyridines or diazines in good to high yields with high regioselectivities. Also, this method is extended to the bromination of 2-aminopyridines or 2-aminodiazines by using LiBr. The regioselectivity of the chlorination reaction is strongly dependent upon the substituent pattern in either the 2-aminopyridines or 2-aminodiazines. The synthesis of Buparlisib from chlorinated pyridines was explored. A study of the mechanism revealed that this chlorination occurs via either a pyridine or diazine radical process.
- Hu, Jiao,Zhou, Gang,Tian, Yawei,Zhao, Xiaoming
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supporting information
p. 6342 - 6345
(2019/07/10)
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- Structure-activity relationship of 3,5-diaryl-2-aminopyridine ALK2 inhibitors reveals unaltered binding affinity for fibrodysplasia ossificans progressiva causing mutants
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There are currently no effective therapies for fibrodysplasia ossificans progressiva (FOP), a debilitating and progressive heterotopic ossification disease caused by activating mutations of ACVR1 encoding the BMP type I receptor kinase ALK2. Recently, a subset of these same mutations of ACVR1 have been identified in diffuse intrinsic pontine glioma (DIPG) tumors. Here we describe the structure-activity relationship for a series of novel ALK2 inhibitors based on the 2-aminopyridine compound K02288. Several modifications increased potency in kinase, thermal shift, or cell-based assays of BMP signaling and transcription, as well as selectivity for ALK2 versus closely related BMP and TGF-β type I receptor kinases. Compounds in this series exhibited a wide range of in vitro cytotoxicity that was not correlated with potency or selectivity, suggesting mechanisms independent of BMP or TGF-β inhibition. The study also highlights a potent 2-methylpyridine derivative 10 (LDN-214117) with a high degree of selectivity for ALK2 and low cytotoxicity that could provide a template for preclinical development. Contrary to the notion that activating mutations of ALK2 might alter inhibitor efficacy due to potential conformational changes in the ATP-binding site, the compounds demonstrated consistent binding to a panel of mutant and wild-type ALK2 proteins. Thus, BMP inhibitors identified via activity against wild-type ALK2 signaling are likely to be of clinical relevance for the diverse ALK2 mutant proteins associated with FOP and DIPG.
- Mohedas, Agustin H.,Wang, You,Sanvitale, Caroline E.,Canning, Peter,Choi, Sungwoon,Xing, Xuechao,Bullock, Alex N.,Cuny, Gregory D.,Yu, Paul B.
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p. 7900 - 7915
(2014/12/11)
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- PYRIDINE BENZAMIDES AND PYRAZINE BENZAMIDES USED AS PKD INHIBITORS
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The present invention pertains generally to the field of therapeutic compounds,. arid more specifically to certain pyridine benzamide and pyrazine benzamide compounds (I) (referred to herein as PDBA and PZBA compounds) which, inter alia, inhibit protein kinase D (PKD) (e.g., PKD1, PKD2, PKD3). The present invention also pertains to pharmaceutical compositions comprising such compounds, and the use of such compounds and compositions, both in vitro and in vivo, to inhibit PKD, and in the treatment of diseases and conditions that are mediated by PKD1 that are ameliorated by the inhibition of PKD, etc., including proliferative conditions such as cancer, etc.
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Page/Page column 106-107
(2008/12/06)
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