5804-49-9Relevant articles and documents
BICYCLIC HETEROARYL SUBSTITUTED COMPOUNDS
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, (2018/03/25)
Disclosed are compounds of Formula (I) to (VIII): (I) (II) (III) (IV) (V) (VI) (VII) (VIII); or a stereoisomer, tautomer, pharmaceutically acceptable salt, solvate or prodrug thereof, wherein R3 is a bicyclic heteroaryl group substituted with zero to 3 R3a; and R1, R2, R3a, R4, and n are defined herein. Also disclosed are methods of using such compounds as PAR4 inhibitors, and pharmaceutical compositions comprising such compounds. These compounds are useful in inhibiting or preventing platelet aggregation, and are useful for the treatment of a thromboembolic disorder or the primary prophylaxis of a thromboembolic disorder.
Discovery of the macrocycle 11-(2-pyrrolidin-1-yl-ethoxy)-14,19-dioxa-5,7, 26-triaza-tetracyclo[19.3.1.1(2,6).1(8,12)]heptacosa-1(25),2(26),3,5,8,10,12(27) ,16,21,23-decaene (SB1518), a potent Janus Kinase 2/Fms-like tyrosine kinase-3 (JAK2/FLT3) inhibitor for the treatment of myelofibrosis and lymphoma
William, Anthony D.,Lee, Angeline C.-H.,Blanchard, Stéphanie,Poulsen, Anders,Teo, Ee Ling,Nagaraj, Harish,Tan, Evelyn,Chen, Dizhong,Williams, Meredith,Sun, Eric T.,Goh, Kee Chuan,Ong, Wai Chung,Goh, Siok Kun,Hart, Stefan,Jayaraman, Ramesh,Pasha, Mohammed Khalid,Ethirajulu, Kantharaj,Wood, Jeanette M.,Dymock, Brian W.
experimental part, p. 4638 - 4658 (2011/09/14)
Discovery of the activating mutation V617F in Janus Kinase 2 (JAK2 V617F), a tyrosine kinase critically involved in receptor signaling, recently ignited interest in JAK2 inhibitor therapy as a treatment for myelofibrosis (MF). Herein, we describe the design and synthesis of a series of small molecule 4-aryl-2-aminopyrimidine macrocycles and their biological evaluation against the JAK family of kinase enzymes and FLT3. The most promising leads were assessed for their in vitro ADME properties culminating in the discovery of 21c, a potent JAK2 (IC50 = 23 and 19 nM for JAK2 WT and JAK2V617F, respectively) and FLT3 (IC50 = 22 nM) inhibitor with selectivity against JAK1 and JAK3 (IC50 = 1280 and 520 nM, respectively). Further profiling of 21c in preclinical species and mouse xenograft and allograft models is described. Compound 21c (SB1518) was selected as a development candidate and progressed into clinical trials where it is currently in phase 2 for MF and lymphoma.
Bicyclic compositions and methods for modulating a kinase cascade
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Page/Page column 75, (2008/06/13)
The invention relates to compounds and methods for modulating one or more components of a kinase cascade.
