MDM2 protein degradation targeting chimera and preparation method and application thereof
A MDM2 and protein degradation technology, applied in the field of medicine, to achieve the effects of delaying tumor growth, good MDM2 enzyme inhibitory activity, and broad-spectrum anti-tumor activity
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Embodiment 1
[0070] The synthesis of embodiment 1 compound 1
[0071] Step a. 2-(4-(2-(4-(tert-butyl)-2-ethoxyphenyl)-4,5-bis(4-chlorophenyl)-4,5-dihydro-1H -Synthesis of imidazole-1-carbonyl)-2-oxopiperazine methyl ester-1-yl)methyl acetate:
[0072] The compound (4-(tert-butyl)-2-ethoxyphenyl)-4,5-bis(4-chlorophenyl)-4,5-dihydro-1H-imidazole-1-carbonyl chloride (30mg , 0.054mmol), 2-(2-oxopiperazin-1-yl)methyl acetate (10mg, 0.06mmol) was dissolved in CH 2 Cl 2 (10 mL), TEA (2 mL) was added dropwise to the solution, stirred at room temperature for 1.5 hours, and purified by silica gel column chromatography (eluent, dichloromethane / methanol=100 / 1) to obtain 23 mg of white solid, yield 85%.
[0073] Step b. 2-(4-(2-(4-(tert-butyl)-2-ethoxyphenyl)-4,5-bis(4-chlorophenyl)-4,5-dihydro-1H -Synthesis of imidazole-1-carbonyl)-2-oxopiperazin-1-yl)acetic acid:
[0074] The compound 2-(4-(2-(4-(tert-butyl)-2-ethoxyphenyl)-4,5-bis(4-chlorophenyl)-4,5-dihydro-1H- Imidazole-1-carbonyl)-2-oxopip...
Embodiment 2～3
[0077] The synthesis of embodiment 2~3 compound 2~3
[0078] Operation is identical with embodiment 1 with feeding intake.
Embodiment 4
[0079] The synthesis of embodiment 4 compound 4
[0080] Step a. (2-(4-(tert-butyl)-2-ethoxyphenyl)-4,5-bis(4-chlorophenyl)-4,5-dihydro-1H-imidazole-1- base) (piperazin-1-yl) ketone synthesis:
[0081] The compound (4-(tert-butyl)-2-ethoxyphenyl)-4,5-bis(4-chlorophenyl)-4,5-dihydro-1H-imidazole-1-carbonyl chloride (60mg , 0.108mmol), piperazine (10.3mg, 0.12mmol) dissolved in CH 2 Cl 2 (10 mL), TEA (2 mL) was added dropwise, stirred at room temperature for 1.5 hours, and then purified by silica gel column chromatography (eluent, dichloromethane / methanol=100 / 0.5) to obtain 40 mg of white solid, yield 62%.
[0082] Step b. (Nonane-1,9-diylbis(piperazine-4,1-diyl))bis((2-(4-(tert-butyl)-2-ethoxyphenyl)-4 , 5-bis(4-chlorophenyl)-4,5-dihydro-1H-imidazol-1-yl)methanone) synthesis:
[0083] The compound (2-(4-(tert-butyl)-2-ethoxyphenyl)-4,5-bis(4-chlorophenyl)-4,5-dihydro-1H-imidazol-1-yl )(piperazin-1-yl)methanone (50mg, 0.086mmol), pimelic acid (6.9mg, 0.043mmol), HATU (14.4...
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