Substituted 6,5-fused bicyclic heteroaryl compounds
a technology of bicyclic heteroaryl compounds and substituted compounds, which is applied in the direction of organic chemistry, organic active ingredients, drug compositions, etc., can solve the problems of complexes lacked the ability to catalyze the methylation of the equivalent residue of h3-k27 of a peptidic substrate, disrupted control, and disease states, etc., to inhibit the conversion of h3-k27 and inhibit the activity of histone methyltransfer
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example 1
[0801]The compounds listed in Tables 1-6 were synthesized by reaction schemes depicted in the general schemes above or by methods described below.
Synthesis of Compound A-1: 1-cyclopentyl-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-(4-(morpholinomethyl)phenyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide
[0802]
Step 1: Synthesis of 3-(aminomethyl)-4,6-dimethylpyridin-2(1H)-one
[0803]
[0804]3-Cyano-2,4-dimethyl-2-hydroxypyridine (0.3 g, 2.0 mmol) was dissolved in MeOH (5 mL), to which catalytic amount of Raney Ni and of aqueous NH3 (0.3 mL) were added and the reaction mixture was stirred under hydrogen pressure (bladder pressure) for 3-4 h. After completion of the reaction, catalyst was filtered off and the filtrate was concentrated under reduced pressure. The residue was thoroughly dried to provide the desired product (0.3 g, quantitative yield).
Step 2: Synthesis of ethyl 6-hydroxy-1H-pyrazolo[3,4-b]pyridine-4-carboxylate
[0805]
[0806]A stirred solution of 1H-pyrazol-3-amine (45 g...
example 2
Bioassay Protocol and General Methods
Protocol for Wild-Type and Mutant PRC2 Enzyme Assays
[1382]General Materials.
[1383]S-adenosylmethionine (SAM), S-adenosylhomocyteine (SAH), bicine, KCl, Tween20, dimethylsulfoxide (DMSO) and bovine skin gelatin (BSG) were purchased from Sigma-Aldrich at the highest level of purity possible. Dithiothreitol (DTT) was purchased from EMD. 3H-SAM was purchased from American Radiolabeled Chemicals with a specific activity of 80 Ci / mmol 384-well streptavidin Flashplates were purchased from PerkinElmer.
[1384]Substrates.
[1385]Peptides representative of human histone H3 residues 21-44 containing either an unmodified lysine 27 (H3K27me0) or dimethylated lysine 27 (H3K27me2) were synthesized with a C-terminal G(K-biotin) linker-affinity tag motif and a C-terminal amide cap by 21st Century Biochemicals. The peptides were high-performance liquid chromatography (HPLC) purified to greater than 95% purity and confirmed by liquid chromatography mass spectrometry (L...
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