Compound used as HPK1 kinase inhibitor and preparation method and application thereof
A compound and hydrate technology, applied in the field of HPK1 inhibitors and its preparation, to achieve high activity and high selectivity
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Embodiment 1
[0147] Example 1.3-((6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)amino)-5-phenylamino-1,2,4- Triazine-6-carboxamide
[0148]
[0149] Step 1: Add DIPEA (667mg, 5.16mmol) to a solution of ethyl 5-chloro-3-methylthio-1,2,4-triazine-6-carboxylate (600mg, 2.57mmol) in NMP (20ml) And aniline (287mg, 3.08mmol), react at room temperature for 1h. After the reaction, add water, extract three times with EA, combine the organic phase and wash with saturated brine, take the organic phase and dry it with anhydrous sodium sulfate, filter it with suction, spin dry to obtain 3-methylthio-5-phenylamino-1, Ethyl 2,4-triazine-6-carboxylate was directly used in the next reaction without further purification. MS(ESI):M / Z=291.09[M+H] + .
[0150] Step 2: Add 3-methylthio-5-phenylamino-1,2,4-triazine-6-carboxylic acid ethyl ester obtained in the previous step to 7N amine in methanol solution (20ml), and mix with room temperature Stir overnight. After the reaction, spin to dry unde...
Embodiment 2
[0152] Example 2.3-((6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)amino)-5-((2-(methoxymethyl )phenyl)amino)-1,2,4-triazine-6-carboxamide
[0153]
[0154] In a similar manner to that described in Example 1, using o-aminobenzyl alcohol as a raw material instead of aniline, a pale yellow product was finally prepared (yield: 2.1%). MS(ESI):M / Z=436.21[M+H] + . 1 H NMR (400MHz, DMSO-d 6 )δ11.43(s,1H),9.11(s,1H),8.42(s,1H),7.82(s,1H),7.61(d,J=7.1Hz,1H),7.43(s,1H), 7.33–7.26(m,2H),7.18–7.05(m,1H),6.81(s,1H),5.15(t,J=5.5Hz,1H),4.61(d,2H),3.71(s,3H) ,3.51(s,2H),2.85(t,J=5.1Hz,2H),2.74(d,2H),2.42(s,3H).
Embodiment 3
[0155] Example 3.3-((6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)amino)-5-((2-(methoxymethyl )phenyl)amino)-1,2,4-triazine-6-carboxamide
[0156]
[0157] In a similar manner to that described in Example 1, using 2-(methoxymethyl)aniline as a starting material instead of aniline, a pale yellow product was prepared (yield: 2.7%). MS(ESI):M / Z=450.22[M+H] + . 1 H NMR (400MHz, DMSO-d 6 )δ11.43(s,1H),9.03(s,1H),8.43(s,1H),7.83(s,1H),7.63(d,J=7.3Hz,1H),7.40(s,1H), 7.34–7.25(m,2H),7.17–7.05(m,1H),6.83(s,1H),4.83(s,2H),3.77(s,3H),3.50(s,2H),3.28(s, 2H) 2.85(t, J=5.4Hz, 2H), 2.83(d, 2H), 2.26(s, 3H).
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