Heterocyclic pyrazole derivatives as type III receptor tyrosine kinase inhibitors
A technology of heterocyclic groups and compounds applied in the field of heterocyclic pyrazole derivatives as type III receptor tyrosine kinase inhibitors
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example 1
[0105] Example 1: Synthesis of Formula (I) Compounds
[0106] Exemplary heterocyclic pyrazole compounds are listed in Table 1. Table 2 provides its 1 H NMR and mass data.
[0107] Table 1. Heterocyclic pyrazole compounds
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[0118] Table 2. 1 H NMR and mass data
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example 2
[0134] Example 2: Evaluation of the inhibitory activity of compounds of formula (I) in an in vitro biochemical assay
[0135] Various compounds of formula I were tested for inhibitory activity against various receptor tyrosine kinases. Brief descriptions of the different assays are described below.
[0136] FLT3 kinase assay
[0137] Inhibition of FLT3 kinase activity by test compounds disclosed herein was assessed by AlphaScreen (PerkinElmer, Akron, Ohio, USA). The standard analysis conditions are assay buffer (10 μM ATP, 10 mM MOPs, pH 7.0, 0.21 mM EDTA, 0.5% glycerol, 1 mg / mL BSA, 0.01% 2-mercaptoethanol, 0.001% Brij35, 10 mM MgCl 2 1.5ng recombinant FLT3 kinase (SignalChem, Richmond, BC, Canada) and 6ng biotin-conjugated poly-(Glu 4:Tyr 1) (Cisbio, Bedford, MA, USA) in a final volume of 25 μL. Reactions were incubated at 30°C for 30 minutes and stopped by adding 5 μL of 50 mM EDTA. The resulting products were analyzed using the AlphaScreen kit and counted with the Ensp...
example 3
[0151] Example 3: Evaluation of the Antiproliferative Activity of Compounds of Formula (I) against Groups of Human Cancer Cell Lines with Different Signal Transduction Dependencies
[0152] As mentioned above, the compounds of the present invention are useful in the treatment of protein kinase-associated diseases or disorders. A protein kinase-associated disease can be cancer, an autoimmune disease, or an angiogenic disorder. Cancer can be lung, colon, colorectal, breast, prostate, liver, pancreas, bladder, stomach, kidney, salivary gland, ovary, uterus, cervix, oral cavity, skin , brain cancer, lymphoma or leukemia.
[0153] Inhibition of cell growth by compounds was measured using the CellTiter™-96 assay. The cytotoxicity of the compounds of the present invention was evaluated in a panel of cell lines with different signaling pathway dependencies, including MV4-11 human acute myeloid leukemia cells with FLT3-ITD mutation, Molm-14 human acute myeloid leukemia cells with FLT...
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