A kras inhibitor compound
A technology for compounds and compositions, applied in the field of novel KRASG12C inhibitor compounds, which can solve problems such as biochemical complexity
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Embodiment 1
[0075] Example 1SZ-014096
[0076]
[0077]
[0078] Step 1: Synthesis of compound 014004A2
[0079] Compound 2,6-dichloro-5-fluoronicotinic acid 014004A1 (16.0g, 76.4mmol) was dissolved in dichloromethane (200mL), and oxalyl chloride (12.1g, 95.2mmol) was added dropwise in an ice-water bath, followed by dropwise addition of catalytic Amount of DMF (0.2mL), reaction at room temperature (20°C) overnight and concentration under reduced pressure, the residue obtained was dissolved in 200mL 1,4-dioxane and cooled to zero, ammonia solution (28.0-30%, 14.4mL, 114.2 mmol) was slowly added dropwise to the reaction phase, stirred at zero for 30 minutes, concentrated under reduced pressure to remove the solvent, and the obtained white solid crude product was purified by silica gel column chromatography (dichloromethane / methanol=100:1) to obtain the white solid compound 014004A2 (9.0 g, yield 56.2%). LCMS(M+H) + m / z calculated 209.0, found 209.0.
[0080] Step 2: Synthesis of c...
Embodiment 2
[0105] Example 2SZ-014096B
[0106]
[0107] Step 1: Synthesis of SZ-014096B
[0108] Compound 014004A10B (100 mg, 0.2 mmol), 014096A2 (22 mg, 0.2 mmol), HATU (112 mg, 0.296 mmol) were dissolved in N, N-dimethylformamide (2.0 mL), and N, N-dimethoxy Isopropylethylamine (51 mg, 0.4 mmol). The reaction phase was stirred for two hours at room temperature (25°C). Concentrate under reduced pressure to remove N,N-dimethylformamide, and the concentrated residue is purified by preparative high performance liquid chromatography to obtain white solid compound SZ-014096B (23.0 mg, yield 19.3%). Liquid phase mass spectrometry [mobile phase: at 40 degrees centigrade column temperature, from 80% water (containing 0.02% ammonium acetate) and 20% acetonitrile to 30% water (containing 0.02% ammonium acetate) and 70% acetonitrile elution was maintained for 6.5 minutes. Column: waters XBridge C18 3.5um, 50x4.6mm] purity 99.14%, Rt=3.361min; LCMS (M+H) + m / z calculated 603.3, found 603.2....
Embodiment 3
[0109] Example 3SZ-014017A / B
[0110]
[0111] Step 1: Synthesis of 014086A1
[0112] The compound 4,6-dichloro-5-aminopyrimidine (10.0g, 60.98mmol) was dissolved in 200 ml of tetrahydrofuran, and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride was added (8.9g, 12.2mmol), isopropylmagnesium chloride (1N, 183mL, 366mmol) was added dropwise at zero, heated to 70 overnight under nitrogen protection. The reaction solution was cooled to room temperature, quenched with saturated ammonium chloride, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate=3:1 ) to give yellow solid 014086A1 (3.0 g, yield 27%). LCMS(M+H) + m / z calculated 180.1, found 180.1. 1 H NMR (DMSO-d 6 , 400MHz): δ8.34 (s, 1H), 5.06 (s, 2H), 3.29-3.20 (m, 2H), 1.17 (d, J=8.8Hz, 12H).
[0113] Step 2: Synthesis of 014086A2
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