Substituted Pyrazole Derivatives As Selective CDK12/13 Inhibitors
a technology of substituting pyrazole and cdk12/13 inhibitors, which is applied in the field of substituting pyrazole derivatives, can solve the problems of sensitivity to platinum salts and parp1/2 inhibitors, defects in dna repair,
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example 1
Synthesis of 2-(4-(1-acryloyl-1,2,3,6-tetrahydropyridin-4-yl)phenyl)-N-(5-cyclopropyl-1H-pyrazol-3-yl)propanamide. (Compound 1)
[0293]
Step i: Synthesis of tert-butyl 4-(4-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)phenyl)-3,6-dihydropyridine-1(2H)-carboxylate
[0294]To a degas solution of tert-butyl 5-(2-(4-bromophenyl)propanamido)-3-cyclopropyl-1H-pyrazole-1-carboxylate (1.5 g, 3.45 mmol) (Intermediate-2) in 1,4-dioxane (40 mL), Cesium carbonate (2.25 g, 6.9 mmol) dissolved in water (2.0 M solution) and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (1.5 g, 4.8 mmol) were added and resultant solution was degassed for 10 min. Pd(PPh3)4 (0.2 g, 5 mol %) was added and mixture was heated at 100° C. for 4 h. Reaction mass filtered through celite and organic layer was separated, washed with brine and dried over anhydrous sodium sulphate to yield crude title compound. Crude was further purified using flash chromatography using...
example 2
Synthesis of N-(4-(4-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-1-oxopropan-2-yl)phenyl)cyclohexyl)acrylamide (Compound 10 and Compound 11)
[0298]
Step-i: Synthesis of tert-butyl 5-(2-(4-(4-((tert-butoxycarbonyl)amino)cyclohexyl)phenyl) propanamido)-3-cyclopropyl-1H-pyrazole-1-carboxylate
[0299]PtO2 (0.1 g) was added to a degassed solution of tert-butyl 5-(2-(4′-((tert-butoxycarbonyl)amino)-2′,3′,4′,5′-tetrahydro-[1,1′-biphenyl]-4-yl)propanamido)-3-cyclopropyl-1H-pyrazole-1-carboxylate (0.3 g, 0.66 mmol) (synthesis carried out as described in Example-1) in methanol (30 mL). The reaction mixture was subjected to hydrogenation at 60 psi in Parr shaker for 20 h at room temperature. Reaction mass was filtered through celite bed and washed the celite bed with methanol. The filtrate was concentrated under reduced pressure to afford the title compound (0.2 g, 66%). LCMS: m / z=553.1 (M+H)+.
Step-ii: Synthesis of 2-(4-(4-aminocyclohexyl)phenyl)-N-(5-cyclopropyl-1H-pyrazol-3-yl)propanamide
[0300]TFA...
example 3
Synthesis of (S,E)-N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(4-(1-(4-(diethylamino)but-2-enoyl)-1,2,3,6-tetrahydropyridin-4-yl)phenyl)propanamide (Compound 14)
[0306]
[0307]To a solution of (S)—N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(4-(1,2,3,6-tetrahydropyridin-4-yl)phenyl)propanamide (0.25 g, 0.75 mmol) (synthesis carried out as described in Example-1) and 1,8-Bis(dimethylamino)naphthalene (Proton sponge) (0.2 g, 0.93 mmol) in DCM (20 mL) was added (E)-4-bromobut-2-enoyl chloride (0.15 g, 0.82 mmol) at 0° C. and reaction stirred for 1 h at room temperature. The reaction mass was diluted with DCM and water, organic layer was separated and aqueous layer was further extracted with DCM. Combined organic layer was dried over sodium sulphate and concentrated to afford crude compound. Crude was further purified using flash chromatography using 0-5% MeOH in DCM mixture as eluent to afford title compound (0.25 g, 38%). LCMS: m / z=484.0 (M+H)+.
Step-ii: Synthesis of (S,E)-N-(5-cyclopropyl-1H-pyrazol-3-...
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