Isoquinolines as inhibitors of HPK1
An alkyl and compound technology, applied in the field of compounds that modulate HPK1 function, can solve problems such as damage to cells and surgical resection is not feasible
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[0572] Materials and methods
[0573] Method A: Experiments were performed on an Agilent 1100HPLC (equipped with an Agilent MSD mass spectrometer), using ESI as the ionization source, using an Agilent SunFire-C18 3.5 μm, 4.6x50 column and a flow rate of 2.0 ml / min. The solvent system was a gradient starting with 95% water and 0.05% TFA (solvent A) and 5% acetonitrile and 0.05% TFA (solvent B) to 100% solvent B in 1.3 minutes. The final solvent system was held constant for a further 1.2 minutes.
[0574] Method B: Experiments were performed on an Agilent 1200HPLC (equipped with an Agilent MSD mass spectrometer), using ESI as an ionization source, using an Agilent SunFire-C18 3.5 μm, 4.6x50 column and a flow rate of 2.0 ml / min. The solvent system was a gradient starting from 95% water and 0.01% TFA (solvent A) and 5% acetonitrile and 0.01% TFA (solvent B) to 5% solvent A and 95% solvent B in 1.4 minutes. The final solvent system was held constant for a further 1.0 minutes.
...
Embodiment I1
[0598] Intermediate 1: 6-Bromo-8-chloro-isoquinolin-3-amine
[0599]
[0600] Step 1: Methyl 2,2-diethoxyacetimidate
[0601]
[0602] To a stirred solution of diethoxyacetonitrile (7.0 g, 54.2 mmol) in dry methanol (50 mL) was added sodium methoxide in methanol (4.2 mL, 20%, 8.4 mmol). After the addition, the reaction mixture was stirred at room temperature for 48 hours. The reaction was concentrated to dryness and the residue was dissolved in chloroform, and the organic layer was washed with water, dried and concentrated to give methyl 2,2-diethoxyacetimidate (8.37 g, 95% yield), which As a colorless oil, it was used in the next step without further purification. 1 H NMR (400MHz, DMSO-d 6 ) δ 7.95 (s, 1H), 4.82 (s, 1H), 3.65 (s, 3H), 3.51 (q, J = 7.2Hz, 4H), 1.14 (t, J = 7.2Hz, 6H).
[0603] Step 2: 4-Bromo-2-chloro-phenyl)methanamine
[0604]
[0605] Add BH to a 50 mL round bottom flask 3 -THF (1.0M in THF, 32.5 mL, 32.5 mmol) and 4-bromo-2-chlorobenzonitril...
Embodiment I2
[0613] Intermediate 2: N-(6-bromo-8-chloro-3-isoquinolyl)cyclopropanecarboxamide
[0614]
[0615] To a cooled (0° C.) mixture of 6-bromo-8-chloro-isoquinolin-3-amine (900 mg, 2.1 mmol) and pyridine (166 mg, 2.1 mmol) in dichloromethane (10 mL) was added cyclopropane Carbonyl chloride (263 mg, 2.52 mmol). The reaction was stirred at 0 °C for 1 hour. The reaction mixture was added NH 4 Quenched with saturated aqueous Cl and extracted with dichloromethane. The organics were dried, filtered and concentrated. The crude product was purified by flash column chromatography (40% dichloromethane in petroleum ether) to give (N-(6-bromo-8-chloro-3-isoquinolinyl)cyclopropanecarboxamide (550 mg, 74% yield ) as a yellow solid. LCMS (ESI) [M+H] + = 324.9.
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