Substituted pyrazolo[1,5-a]pyrimidine compounds as trk kinase inhibitors
A technology of compounds and substituents, applied in anti-inflammatory agents, drug combinations, organic chemistry, etc., to achieve excellent pharmacodynamic properties, high metabolic stability, and good Trk inhibitory activity
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[0092]
[0093] The present invention also provides the preparation method of the compound described in general formula (I), it comprises:
[0094] For where X is The compound of general formula (I), make the corresponding compound of formula II react with the compound of formula III in the presence of coupling agent and / or base to obtain the compound of formula IVa;
[0095]
[0096] where R 5 Independently, halogen, hydroxy, methoxy, ethoxy, propoxy, OTs, OMs and the like.
[0097] Formula IVa and Formula HNR a R b Compound reaction preparation where X is A compound of general formula (I).
[0098] If necessary, any protecting groups are added or removed, and if necessary, salts or solvates are formed.
[0099] For where X is The compound of general formula (I), make the corresponding compound of formula II generate isothiocyanate and have formula HNR a R b The compound reaction, or react with HNR after the compound of formula II reacts with thiophosgene a ...
Embodiment 1
[0147] 3-((5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrrolo[1,5-a]pyrimidin-3-yl)amino)-4 -((S)-3-Hydroxypyrrolidin-1-yl)cyclobut-3-ene-1,2-dione
[0148] Intermediate A is (R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)amino) - 4-Methoxycyclobut-3-ene-1,2-dione (0.5 g, 1.18 mmol) or an equivalent of intermediate B was dissolved in methanol (10 mL) and (S)-3-hydroxypyrrole was added Alkane hydrochloride (0.2g, 2.36mmol), reacted in a closed container under microwave conditions at 80°C for 1.5h, cooled to room temperature, a solid was produced, filtered, and the filtrate was suspended to dryness, then added a small amount of dichloromethane, and stood A solid was precipitated, and 0.12 g of product was obtained by filtration (yield 21%). 1 H-NMR (400MHz, CDCl 3 )δ: 6.31(s,1H), 8.17(d,2H), 7.0(m,1H), 6.91(m,1H), 6.76(m,1H), 6.22(s,1H), 5.97(s,1H ),5.30(s,1H),4.56(d,1H),3.91-3.53(m,5H),2.5(m,1H),2.13-2.08(m,6H), MS m / z 481.2(M+1 ) + . The st...
Embodiment 1A
[0151] 3-((5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)amino)- 4-((S)-3-Hydroxypyrrolidin-1-yl)cyclobut-3-ene-1,2-dione sulfate
[0152] At room temperature, to 3-((5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl )amino)-4-((S)-3-hydroxypyrrolidin-1-yl)cyclobut-3-ene-1,2-dione (0.48g, 1.0mmol) in methanol (20mL) was added Sulfuric acid in methanol (5 mL, 1 mmol). The resulting solution was stirred for 1 hour, then concentrated to give 3-((5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrrolo[1,5-a] as a yellow solid Pyrimidin-3-yl)amino)-4-((S)-3-hydroxypyrrolidin-1-yl)cyclobut-3-ene-1,2-dione sulfate 0.42g (yield 72%) . The structural formula is as follows:
[0153]
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