KRAS G12C inhibitor and application thereof
An alkyl and compound technology, applied in the application field of cancer therapeutic agents, can solve the problem of no drug listing
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Embodiment 1
[0461] Example 1: 1-(4-(4-(5-methyl-1H-indazol-4-yl)furo[2,3-f]quinazolin-9-yl)piperazin-1-yl ) Synthesis of prop-2-en-1-one (compound 1-1-1)
[0462]
[0463] Step 1: Intermediate 1-6 (120 mg, 0.28 mmol), (5-methyl-1H-indazol-4-yl)boronic acid (80 mg, 0.45 mmol), cesium carbonate (92 mg, 0.28 mmol) and PdCl 2 dppf CH 2 Cl 2 (15 mg, 0.02 mmol) of 1,4-dioxane (12 mL) and water (1 mL) were replaced with nitrogen three times, and the reaction system was stirred at 90° C. for 12 hours. The reaction was quenched with water, the aqueous phase was extracted with ethyl acetate, the organic phase was separated and concentrated under reduced pressure, the residue was purified by Flash column chromatography (100% ethyl acetate) to obtain compound 1A (110 mg, yield: 56%) as yellow Oil. m / z:[M+H] + 485.0.
[0464] Step 2: A mixture of compound 1A (110 mg, 0.23 mmol) in dichloromethane (10 mL) and trifluoroacetic acid (1 mL) was stirred at room temperature for 1 hour, and concentra...
Embodiment 2
[0466] Example 2: (S)-2-(1-acryloyl-4-(4-(5-amino-2-chloro-3-fluorophenyl)furo[2,3-f]quinazoline-9 Synthesis of -yl)piperazin-2-yl)acetonitrile (compound 1-1-2)
[0467]
[0468] Step 1: To a solution of intermediate 1-5 (425 mg, 1.5 mmol) and triethylamine (0.62 ml, 4.5 mmol) in dichloromethane (10 mL) was added (S)-2-(1-acryloylpiperazine- 2-yl) acetonitrile hydrochloride (480 mg, 2.7 mmol), and the reaction solution was stirred at room temperature for 16 hours. Water was added to quench the reaction, the aqueous phase was extracted with dichloromethane, and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by Flash column chromatography (ethyl acetate / petroleum ether=0%-70%) to obtain compound 3A (160 mg, yield: 26%) as a light yellow solid. m / z: [M+H] + 426.0.
[0469] Step 2: Under nitrogen protection, compound 3A (0.11g, 0.26mmol), intermediate 2 (0.11g, 0.38mmol), PdCl 2 dppf CH 2 Cl 2 (3...
Embodiment 3
[0470] Example 3: 1-(4-(4-(5-methyl-1H-indazol-4-yl)-7-(((S)-1-methylpyrrolidin-2-yl)methyl) Synthesis of Furo[2,3-f]quinazolin-9-yl)piperazin-1-yl)prop-2-en-1-one (Compound 1-2-1)
[0471]
[0472] Step 1: Under ice-bath conditions, sodium hydrogen (60%, 56mg, 1.38mmol) was added in batches to a solution of N-methyl-L-prolinol (159mg, 1.38mmol) in DMF (12mL), and the reaction system was After stirring at 0°C for 1 hour, Intermediate 2-4 (63.5 mg, 0.13 mmol) was added to the above reaction solution, and the resulting mixture was stirred at room temperature for 2 hours. The reaction was quenched with ice water, the aqueous phase was extracted with ethyl acetate, the organic phase was separated and concentrated under reduced pressure, and the residue was purified by Flash column chromatography (dichloromethane / methanol=4 / 1) to obtain compound 4A (29 mg, yield : 40%) as a yellow oil. m / z:[M+H] + 545.8.
[0473] Step 2: Compound 4A (29 mg, 53.1 μmol), (5-methyl-1H-indazol-4...
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