A kind of pyrimidine small molecule compound and its application
A small molecular compound and compound technology, applied in the field of biomedicine, can solve the problems of high toxicity and side effects, poor kinase inhibitory activity, etc., and achieve high inhibitory activity, good anti-osteosarcoma effect, and relieve wet macular degeneration or uveitis.
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Embodiment 1
[0027] Example 1: Chemical synthesis of compounds 3a-3i
[0028] The synthetic route is as follows:
[0029]
[0030] The general process is as follows:
[0031] The nucleophilic substitution reaction with 6-aminoindazole takes 1a-1i as raw material to generate intermediate 2a-2i. Then 4-(4-methylpiperazine)aniline undergoes a nucleophilic substitution reaction with the obtained intermediate 2a-i to generate the final product 3a-3i.
[0032] Taking the synthesis of compound 3a as an example, the specific process is as follows:
[0033] 2,4-Dichloro-5-fluoropyrimidine (333.94 mg, 2 mmol) and N,N-diisopropylethylamine (DIPEA) (516.96 mg, 4 mmol) were dissolved in DMF (4 mL) and cooled to 0 °C . To the mixture was added 6-aminoindazole (266.3 mg, 2 mmol) in DMF (2 mL) dropwise. The reaction mixture was stirred at 0°C for about 1 hour. Next, the ice bath was removed, the reaction mixture was stirred at room temperature, and the reaction was monitored by TLC, the resulting...
Embodiment 2
[0071] Example 2: Chemical synthesis of compounds 5a-5j
[0072] The synthetic route is as follows:
[0073]
[0074] The general process is as follows:
[0075] Nucleophilic substitution of 2,4-dichloro-5-methylpyrimidine (1d) with various substituted amines gave intermediates 4a-4j. Then 4-(4-methylpiperazine)aniline undergoes a nucleophilic substitution reaction with the resulting intermediates 4a-4j to generate final products 5a-5j.
[0076] Taking the synthesis of compound 5a as an example, the specific process is as follows:
[0077] N,N-Diisopropylethylamine (DIPEA) (516.96 mg, 4 mmol) was dissolved in DMF (4 mL) and cooled to 0 °C. To the mixture was added 5-aminoindole (264.3 mg, 2 mmol) in DMF (2 mL) dropwise. The reaction mixture was stirred at 0°C for about 1 hour. Next, the ice bath was removed, the reaction mixture was stirred at room temperature, and the reaction was monitored by TLC. After the reaction was completed, the resulting mixture was extracted...
Embodiment 3
[0123] Example 3: Chemical synthesis of compounds 6a-6m
[0124] The synthetic routes of compounds 6a-6m are as follows:
[0125]
[0126] The general synthetic route is as follows:
[0127] 2,4-Dichloro-5-methylpyrimidine (1d) reacts with 6-aminoindazole to produce intermediate 2d, which undergoes nucleophilic substitution with various substituted amines to generate final products 6a-6m.
[0128] Taking the synthesis of compound 6a as an example, the specific synthesis is as follows:
[0129] Compound 2d was prepared according to Example 1. Compound 2d (259.7 mg, 1 mmol) and 4-(4-methylpiperazine)aniline (191.27 mg, 1 mmol) were dissolved in 4 ml of methanol, and TFA (148.56 μL, 2 mmol) was added. , warmed to 80 °C, and monitored the reaction by TLC. After the reaction was completed, it was cooled to room temperature, the resulting mixture was adjusted to neutral pH with saturated sodium bicarbonate, extracted with ethyl acetate (3×25 mL), washed with saturated brine, w...
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