1464153-40-9

Upstream product

• 99768-12-4 4-methoxycarbonylphenylboronic acid 
• 1464153-39-6 ethyl 4-(3-bromoimidazo[1,2-a]pyrazin-6-yl)benzoate 
• 1464153-37-4 ethyl 4-(imidazo[1,2-a]pyrazin-6-yl)benzoate 
• 4334-88-7 p-ethoxycarbonylphenylboronic acid 
• 912773-24-1 6-bromo-imidazo[1,2-a]pyrazine 

Downstream Products

• 1464153-42-1 (4-(3-bromoimidazo[1,2-a]pyrazin-6-yl)phenyl)(4-methylpiperazin-1-yl)methanone 
• 1464150-90-0 (4-(3-(4-(difluoromethyl)phenyl)imidazo[1,2-a]pyrazin-6-yl)phenyl)(4-methylpiperazin-1-yl)methanone 
• 1464150-41-1 4-(6-(4-(4-methylpiperazine-1-carbonyl)phenyl)imidazo[1,2-a]pyrazin-3-yl)benzonitrile 
• 1464150-89-7 N-hydroxy-4-(6-(4-(4-methylpiperazine-1-carbonyl)phenyl)imidazo[1,2-a]pyrazin-3-yl)benzamide 
• 1464154-38-8 4-(6-(4-(4-methylpiperazine-1-carbonyl)phenyl)imidazo[1,2-a]pyrazin-3-yl)-N-((tetrahydro-2H-pyran-2-yl)oxy)benzamide 
• 1464154-37-7 4-(6-(4-(4-methylpiperazine-1-carbonyl)phenyl)imidazo[1,2-a]pyrazin-3-yl)benzoic acid 
• 1464154-32-2 ethyl 4-(6-(4-(4-methylpiperazine-1-carbonyl)phenyl)imidazo[1,2-a]pyrazin-3-yl)benzoate 
• 1464150-36-4 (4-(3-(4-hydroxyphenyl)imidazo[l,2-a]pyrazin-6-yl)phenyl)(4-methylpiperazin-l-yl)methanone 
• 1464153-47-6 (4-(3-bromoimidazo[1,2-a]pyrazin-6-yl)phenyl)(morpholino)methanone 
• 1464150-37-5 (4-(3-(4-hydroxyphenyl)imidazo[1,2-a]pyrazin-6-yl)phenyl)(morpholino)methanone 

Relevant academic research and scientific papers

Optimization of Selective Mitogen-Activated Protein Kinase Interacting Kinases 1 and 2 Inhibitors for the Treatment of Blast Crisis Leukemia

Chronic myeloid leukemia (CML) is a myeloproliferative disease caused by bcr-abl1, a constitutively active tyrosine kinase fusion gene responsible for an abnormal proliferation of leukemic stem cells (LSCs). Inhibition of BCR-ABL1 kinase activity offers long-term relief to CML patients. However, for a proportion of them, BCR-ABL1 inhibition will become ineffective at treating the disease, and CML will progress to blast crisis (BC) CML with poor prognosis. BC-CML is often associated with excessive phosphorylated eukaryotic translation initiation factor 4E (eIF4E), which renders LSCs capable of proliferating via self-renewal, oblivious to BCR-ABL1 inhibition. In vivo, eIF4E is exclusively phosphorylated on Ser209 by MNK1/2. Consequently, a selective inhibitor of MNK1/2 should reduce the level of phosphorylated eIF4E and re-sensitize LSCs to BCR-ABL1 inhibition, thus hindering the proliferation of BC LSCs. We report herein the structure-activity relationships and pharmacokinetic properties of a selective MNK1/2 inhibitor clinical candidate, ETC-206, which in combination with dasatinib prevents BC-CML LSC self-renewal in vitro and enhances dasatinib antitumor activity in vivo.

Design, synthesis and biological evaluation of imidazopyridazine derivatives containing isoquinoline group as potent MNK1/2 inhibitors

Mitogen-activated protein kinase (MAPK)-interacting kinases (MNKs) are located at the meeting-point of ERK and p38 MAPK signaling pathways, which can phosphorylate eukaryotic translation initiation factor 4E (eIF4E) at the conserved serine 209 exclusively. MNKs modulate the translation of mRNA involved in tumor-associated signaling pathways. Consequently, selective inhibitors of MNK1/2 could reduce the level of phosphorylated eIF4E. Series of imidazopyrazines, imidazopyridazines and imidazopyridines derivatives were synthesized and evaluated as MNK1/2 inhibitors. Several compounds exhibited great inhibitory activity against MNK1/2 and selected compounds showed moderate to excellent anti-proliferative potency against diffuse large B-cell lymphoma (DLBCL) cell lines. In particular, compound II-5 (MNK1 IC50 = 2.3 nM; MNK2 IC50 = 3.4 nM) exhibited excellent enzymatic inhibitory potency and proved to be the most potent compound against TMD-8 and DOHH-2 cell lines with IC50 value of 0.3896 μM and 0.4092 μM respectively. These results demonstrated that compound II-5 could be considered as a potential MNK1/2 inhibitor for further investigation.

BICYCLIC HETEROCYCLIC DERIVATIVES AS MNK1 AND MNK2 MODULATORS AND USES THEREOF

The present invention relates to certain compounds (e.g., imidazopyrazine, imidazopyridine, imidazopyridazine and imidazpyrimidine compounds) that act as inhibitors of the MAP kinase interacting kinases MNK2a, MNK2b, MNK1a, and MNK1b. The present invention further relates to pharmaceutical compositions comprising these compounds, and to the use of the compounds for the preparation of a medicament for the prophylaxis and treatment of diseases (e.g., proliferative diseases (e.g., cancer), inflammatory diseases, Alzheimer's disease), as well as methods of treating these diseases.

BICYCLIC HETEROCYCLIC DERIVATIVES AS MNK1 AND MNK2 MODULATORS AND USES THEREOF

The present invention relates to certain compounds (e.g., imidazopyrazine, imidazopyridine, imidazopyridazine and imidazpyrimidine compounds) that act as inhibitors of the MAP kinase interacting kinases MNK2a, MNK2b, MNK1a, and MNK1b. The present invention further relates to pharmaceutical compositions comprising these compounds, and to the use of the compounds for the preparation of a medicament for the prophylaxis and treatment of diseases (e.g., proliferative diseases (e.g., cancer), inflammatory diseases, Alzheimer's disease), as well as methods of treating these diseases