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1.
ACS Med Chem Lett ; 6(8): 845-9, 2015 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-26288682

RESUMO

Early hit to lead work on a pyrrolopyridine chemotype provided access to compounds with biochemical and cellular potency against Janus kinase 2 (JAK2). Structure-based drug design along the extended hinge region of JAK2 led to the identification of an important H-bond interaction with the side chain of Tyr 931, which improved JAK family selectivity. The 4,5-dimethyl thiazole analogue 18 demonstrated high levels of JAK family selectivity and was identified as a promising lead for the program.

2.
ACS Med Chem Lett ; 6(8): 850-5, 2015 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-26288683

RESUMO

JAK2 kinase inhibitors are a promising new class of agents for the treatment of myeloproliferative neoplasms and have potential for the treatment of other diseases possessing a deregulated JAK2-STAT pathway. X-ray structure and ADME guided refinement of C-4 heterocycles to address metabolic liability present in dialkylthiazole 1 led to the discovery of a clinical candidate, BMS-911543 (11), with excellent kinome selectivity, in vivo PD activity, and safety profile.

3.
4.
J Am Chem Soc ; 128(41): 13370-1, 2006 Oct 18.
Artigo em Inglês | MEDLINE | ID: mdl-17031945

RESUMO

In this Communication, we report a system in which an achiral Lewis acid (activating the diene) works in concert with a chiral nucleophile (dienophile) to effect the first highly enantio- and regioselective catalytic inverse electron demand Diels-Alder [4 + 2] cycloaddition reaction to form biologically active quinoxalinones from ketene enolates and o-benzoquinone diimides in good to excellent yields with >99% ee.


Assuntos
Álcoois/química , Alcadienos/química , Benzoquinonas/química , Elétrons , Etilenos/química , Imidas/química , Cetonas/química , Catálise , Modelos Químicos , Estereoisomerismo
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