900506-24-3

Upstream product

• 24376-18-9 3,4-dinitrobenzoyl chloride 
• 131858-37-2 4-(bromomethyl)-2-fluoro-1-nitrobenzene 
• 1094554-37-6 1-(3-fluoro-4-nitrobenzyl)-4-methylpiperazine 
• 896466-70-9 1-(3,4-dinitrobenzyl)-4-methylpiperazine 

Downstream Products

• 1542265-53-1 2-(4-chloro-3-iodophenyl)-6-((4-methylpiperazin-1-yl)methyl)-1H-benzo[d]imidazole 
• 1542265-10-0 N-cyclobutyl-6-(2-(2-methyl-5-(6-((4-methylpiperazin-1-yl)methyl)-1H-benzo[d]imidazol-2-yl)phenyl)ethynyl)pyridazin-3-amine 
• 1542265-50-8 2-(3-iodo-4-methylphenyl)-6-((4-methylpiperazin-1-yl)methyl)-1H-benzo[d]imidazole 
• 1542265-14-4 N-cyclopropyl-5-(2-(2-methyl-5-(6-((4-methylpiperazin-1-yl)methyl)-1H-benzo[d]imidazol-2-yl)phenyl)ethynyl)pyrimidin-2-amine 
• 1542265-13-3 N-isopropyl-6-(2-(2-methyl-5-(6-((4-methylpiperazin-1-yl)methyl)-1H-benzo[d]imidazol-2-yl)phenyl)ethynyl)pyridazin-3-amine 

Relevant academic research and scientific papers

Discovery of a Candidate Containing an (S)-3,3-Difluoro-1-(4-methylpiperazin-1-yl)-2,3-dihydro-1 H-inden Scaffold as a Highly Potent Pan-Inhibitor of the BCR-ABL Kinase including the T315I-Resistant Mutant for the Treatment of Chronic Myeloid Leukemia

BCR-ABL kinase inhibition is an effective strategy for the treatment of chronic myeloid leukemia (CML). Herein, we report compound 3a-P1, bearing a difluoro-indene scaffold, as a novel potent pan-inhibitor against BCR-ABL mutants, including the most refractory T315I mutant. As the privileged (S)-isomer compared to its (R)-isomer 3a-P2, 3a-P1 exhibited potent antiproliferative activities against K562 and Ku812 CML cells and BCR-ABL and BCR-ABLT315I BaF3 cells, with IC50 values of 0.4, 0.1, 2.1, and 4.7 nM, respectively. 3a-P1 displayed a good safety profile in a battery of assays, including single-dose toxicity, hERG K+, and genotoxicity. It also showed favorable mice pharmacokinetic properties with a good oral bioavailability (32%), a reasonable half-life (4.61 h), and a high exposure (1386 h·ng/mL). Importantly, 3a-P1 demonstrated a higher potency than ponatinib in a mice xenograft model of BaF3 harboring BCR-ABLT315I. Overall, the results indicate that 3a-P1 is a promising drug candidate for the treatment of CML to overcome the imatinib-resistant T315I BCR-ABL mutation.

Pyrazole spleen tyrosine kinase inhibitor as well as preparation method and application thereof

The invention discloses a pyrazole spleen tyrosine kinase inhibitor, a preparation method thereof, a pharmaceutical composition containing the same, and application of the pyrazole spleen tyrosine kinase inhibitor and the pharmaceutical composition in the preparation of drugs for treating Syk-mediated diseases including cancers, inflammatory diseases and the like.

N-aryl-2-aminobenzimidazoles: Novel, efficacious, antimalarial lead compounds

From the phenotypic screening of the AstraZeneca corporate compound collection, N-aryl-2-aminobenzimidazoles have emerged as novel hits against the asexual blood stage of Plasmodium falciparum (Pf). Medicinal chemistry optimization of the potency against Pf and ADME properties resulted in the identification of 12 as a lead molecule. Compound 12 was efficacious in the P. berghei (Pb) model of malaria. This compound displayed an excellent pharmacokinetic profile with a long half-life (19 h) in rat blood. This profile led to an extended survival of animals for over 30 days following a dose of 50 mg/kg in the Pb malaria model. Compound 12 retains its potency against a panel of Pf isolates with known mechanisms of resistance. The fast killing observed in the in vitro parasite reduction ratio (PRR) assay coupled with the extended survival highlights the promise of this novel chemical class for the treatment of malaria.

Protein Kinase Inhibitors

The present invention relates to compounds of Formula I: as well as pharmaceutically acceptable salts, hydrates, isomers, or solvates thereof, wherein the variables are described herein. The present invention further relates to pharmaceutical compositions which comprise the compounds of Formula I, and to methods for inhibiting protein kinase and methods of treating diseases, such as cancers, inflammation.

PYRAZOLYLBENZO[D]IMIDAZOLE DERIVATIVES

A compound represented by the general Formula (I), whereinhydrogen atoms shown as attached to pyrazole and benzimidazole rings are attached to one of nitrogen atoms of the pyrazole or benzimidazole ring, respectively; R1 represents -X-Q-P, wherein X is absent or represents –CH2-, –C(O)-, or –C(O)NH-(CH2)k-, wherein k is 0, 1 or 2; Q is selected from the group consisting of Q1, Q2, Q3, Q4 and Q5; P is absent or represents straight-or branched-chain C1-C3 alkyl, –(CH2)l-NR2R3, or–(CH2)m-C(O)-NR2R3, wherein l and m independently of each other represent 0, 1 or 2, with the proviso that when B in Q1 represents oxygen atom, then P is absent;and R2and R3 independently represent C1 or C2 alkyl, or R2 and R3 together with nitrogen atom to which they are both attached form a 6- membered saturated heterocyclicring, wherein one of carbon atoms can be replaced with oxygen, -NH-or –N(C1-C2)alkyl-; and acid addition salts thereof. The compound can be useful in the treatment of cancer diseases. (I)

PHARMACEUTICAL COMPOUNDS

The use of a compound for the manufacture of a medicament for the prophylaxis or treatment of: A. a disease state or condition mediated by a kinase which is BCR-abl, VEGFR, PDGFR, EGFR, Flt3, JAK (e.g. JAK2 or JAK3), C-abl, PDKl , Chk (e.g. Cbkl or Chk2),

PYRAZOLE COMPOUNDS THAT MODULATE THE ACTIVITY OF CDK, GSK AND AURORA KINASES

The invention provides a compound of the formula (I): or a salt, solvate, tautomer or N-oxide thereof, wherein M is selected from a group D1 and a group D2: and R', E, A and X are as defined in the claims. Also provided are pharmaceutical compositions con