Quinoline derivatives as NK3 anatgonists
A compound, -NH2 technology, applied in anti-inflammatory agents, anti-tumor drugs, drug combinations, etc., can solve problems such as limited evaluation
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Embodiment 1
[0136] Example 1.3-(cyanomethyl)-2-phenyl-N-[(1S)-1-phenylpropyl]quinoline-4-carboxamide
[0137]
[0138] According to Scheme 1, the title compound was prepared.
[0139] plan 1:
[0140]
[0141] at RT and N 2 EDC (58 mg, 0.30 mmol) was added to 3-(cyanomethyl)-2-phenylquinoline-4-carboxylic acid (1c) (57.6 mg, 0.20 mmol), HOBT hydrate (46 mg, 0.30 mmol) ), 4-methylmorpholine (40 μL, 0.30 mmol) in dichloromethane (10 mL). Then, (S)-1-phenylpropylamine (25.4 mg, 0.21 mmol) was added and the reaction mixture was stirred at RT for 12 h. The reaction mixture was further diluted with dichloromethane (30 mL), washed sequentially with 5% citric acid, 10% aqueous sodium bicarbonate and brine. The organic phase was separated, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by chromatography eluting with 10-35% ethyl acetate / hexanes to afford the title compound (50 mg, 62%) as a pale yellow solid. 1 H NMR (300MHz, CDCl 3 )δ0.96(t, ...
Embodiment 2
[0147] Example 2.3-(cyanomethyl)-2-phenyl-N-[(1S)-1-phenylethyl]quinoline-4-carboxamide
[0148]
[0149] Using a method similar to that described in Example 1, the title compound was prepared except that (1S)-1-phenylethylamine (25.4 mg, 0.21 mmol) was used as the amine component.
[0150] Scenario 2:
[0151]
[0152] Through the reaction shown in Scheme 2, the title compound (2) (30 mg, 38%) was obtained as a white solid. 1 H NMR (300MHz, CDCl 3 )δ1.56(d, 3H), 4.73(s, 2H), 5.39(m, 1H), 6.48(d, 1H), 7.31(d, 2H), 7.34(d, 2H), 7.39(m, 1H ), 7.78(m, 2H), 7.84(m, 2H), 8.08(m, 1H), 8.30(m, 2H), 8.42(m, 2H). MS APCI, m / z=392 (M+1). LCMS: 2.21 min.
Embodiment 3
[0153] Example 3. Methyl (2R)-({[3-(cyanomethyl)-2-phenylquinolin-4-yl]carbonyl}amino)(phenyl)acetate
[0154]
[0155] Using a method similar to that described in Example 1, the title compound was prepared except that (2R)-methyl amino(phenyl)acetate (42.2 mg, 0.21 mmol) was used as the amine component.
[0156] Option 3:
[0157]
[0158] Through the reaction shown in Scheme 3, the title compound (3) (40 mg, 46%) was obtained as a white solid. 1 H NMR (300MHz, CDCl 3 )δ3.78(s, 3H), 3.83(s, 2H), 5.87(d, 1H), 6.72(d, 1H), 6.74(d, 2H), 7.04(d, 2H), 7.06(m, 1H ), 7.37 (m, 2H), 7.41 (m, 2H), 7.76 (m, 1H), 7.84 (m, 2H), 8.04-8.19 (m, 2H). MS APCI, m / z=436 (M+1). LCMS: 2.20 min.
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