Heterocyclic compound used as MNK inhibitor
A compound and solvate technology, applied in the treatment or prevention of related diseases mediated by MNK, into the field of MNK inhibitors, can solve problems such as drug resistance
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Embodiment 1
[0168] 1-tert-butoxyacyl-5-(6-acetamidopyrimidin-4-ylamino)-6-methoxyindazole
[0169]
[0170] first step
[0171] 1-tert-butyloxyacyl-5-bromo-6-methoxyindazole
[0172] Compound 5-bromo-6-methoxy-1H-indazole 1a (4g, 17.6mmol), triethylamine (5.3g, 52.8mmol), di-tert-butyl dicarbonate (7.7g, 35.2mmol), 4 - Dimethylaminopyridine (7.7 g, 35.2 mmol) and tetrahydrofuran (40 mL) were mixed, and reacted at room temperature under argon protection for 1 hour. The mixture was precipitated under reduced pressure to obtain a crude product, which was purified by chromatography (petroleum ether / ethyl acetate=4:1) to obtain the target product 1-tert-butyloxyacyl-5-bromo-6-methoxyindazole 1b (2.8g , 8.59 mmol, yellow solid). Yield: 49%.
[0173] MS m / z(ESI): 327&329[M+1];
[0174] second step
[0175] 1-tert-butoxyacyl-5-(6-acetamidopyrimidin-4-ylamino)-6-methoxyindazole
[0176]Compound 1-tert-butoxyacyl-5-bromo-6-methoxyindazole 1b (24.0mg, 0.08mmol), N-(6-aminopyrimidin-4-yl)ac...
Embodiment 2
[0180] 5-(6-Acetamidopyrimidin-4-ylamino)-6-methoxy-1H-indazole
[0181]
[0182] Compound 1-tert-butoxyacyl-5-(6-acetamidopyrimidin-4-ylamino)-6-methoxyindazole 2a (10 mg, 0.025 mmol) and dichloromethane (2.0 mL), trifluoroacetic acid (1.0 mL) were mixed and stirred at room temperature for 3 hours. The mixture was quenched with 5 mL of saturated aqueous sodium bicarbonate, diluted with 5 mL of dichloromethane, the organic phase was separated, the aqueous phase was extracted with dichloromethane (10 mL×2), and the combined organic phases were washed with saturated brine (20 mL×2). Dry the organic phase with anhydrous sodium sulfate, filter to remove the desiccant, and desolvate under reduced pressure to obtain a crude product, which is purified by preparing a silica gel plate (dichloromethane / methanol=10:1) to obtain the target product 5-(6-Acetamidopyrimidine- 4-ylamino)-6-methoxy-1H-indazole 2 (5 mg, 0.017 mmol, yellow solid). Yield: 68%.
[0183] MS m / z(ESI): 299[M+1]...
Embodiment 3
[0186] 1-tert-butoxyacyl-5-(6-cyclopropanylaminopyrimidin-4-ylamino)-6-methoxyindazole
[0187]
[0188] Synthesis steps refer to Example 1. The target product 1-tert-butoxyacyl-5-(6-cyclopropyl Amidopyrimidin-4-ylamino)-6-methoxyindazole 3 (1.0 g, 2.4 mmol, yellow solid). Yield: 80%.
[0189] MS m / z(ESI): 425[M+1];
[0190] 1 H NMR (400MHz, CDCl 3 )δ8.78(s,1H),8.70(s,1H),8.51(s,1H),8.11(s,1H),7.75(s,1H),7.62(s,1H),7.46(s,1H ), 4.03(s,3H), 1.73(s,9H), 1.60-1.52(m,1H), 0.95-0.93(m,4H).
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