Design and synthesis of carbazole carboxamides as promising inhibitors of Bruton's tyrosine kinase (BTK) and Janus kinase 2 (JAK2)

Qingjie Liu; Douglas G Batt; Jonathan S Lippy; Neha Surti; Andrew J Tebben; Jodi K Muckelbauer; Lin Chen; Yongmi An; Chiehying Chang; Matt Pokross; Zheng Yang; Haiqing Wang; James R Burke; Percy H Carter; Joseph A Tino

doi:10.1016/j.bmcl.2015.07.102

Design and synthesis of carbazole carboxamides as promising inhibitors of Bruton's tyrosine kinase (BTK) and Janus kinase 2 (JAK2)

Bioorg Med Chem Lett. 2015 Oct 1;25(19):4265-9. doi: 10.1016/j.bmcl.2015.07.102. Epub 2015 Aug 6.

Authors

Affiliations

¹ Bristol-Myers Squibb Pharmaceutical Research Institute, PO Box 4000, Princeton, NJ 08543-4000, USA. Electronic address: qingjie.liu@bms.com.
² Bristol-Myers Squibb Pharmaceutical Research Institute, PO Box 4000, Princeton, NJ 08543-4000, USA.

PMID: 26320619
DOI: 10.1016/j.bmcl.2015.07.102

Abstract

Four series of disubstituted carbazole-1-carboxamides were designed and synthesised as inhibitors of Bruton's tyrosine kinase (BTK). 4,7- and 4,6-disubstituted carbazole-1-carboxamides were potent and selective inhibitors of BTK, while 3,7- and 3,6-disubstituted carbazole-1-carboxamides were potent and selective inhibitors of Janus kinase 2 (JAK2).

Keywords: Bruton’s tyrosine kinase (BTK); Carbazole; Janus kinase 2 (JAK2).

MeSH terms

Amides / chemical synthesis
Amides / chemistry
Amides / pharmacology*
Carbazoles / chemistry
Carbazoles / pharmacology*
Dose-Response Relationship, Drug
Drug Design*
Humans
Janus Kinase 2 / antagonists & inhibitors*
Janus Kinase 2 / metabolism
Molecular Structure
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology*
Protein-Tyrosine Kinases / antagonists & inhibitors*
Protein-Tyrosine Kinases / metabolism
Structure-Activity Relationship

Substances

Amides
Carbazoles
Protein Kinase Inhibitors
carbazole
Protein-Tyrosine Kinases
JAK2 protein, human
Janus Kinase 2