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

Active Publication Date: 2020-09-08
南京雷正医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The present invention proposes a novel substituted pyrazolo[1,5-a]pyrimidine compound as a Trk kinase inhibitor to overcome the problems of insufficient stability and activity in the prior art and meet the growing clinical needs

Method used

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  • Substituted pyrazolo[1,5-a]pyrimidine compounds as trk kinase inhibitors
  • Substituted pyrazolo[1,5-a]pyrimidine compounds as trk kinase inhibitors
  • Substituted pyrazolo[1,5-a]pyrimidine compounds as trk kinase inhibitors

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preparation example Construction

[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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Abstract

The invention relates to a substituted pyrazolo [1,5-a] pyrimidine compound used as a Trk kinase inhibitor, or pharmacologically acceptable salt, a medicine composition and a purpose. A pyrazolo [1,5-a] pyrimidine derivative in the structure with a general formula (I) shown as the accompanying drawing has good Trk family protein tyrosine kinase inhibition activity and metabolism stability.

Description

technical field [0001] The invention belongs to the field of chemical medicine, and relates to a series of substituted pyrazolo[1,5-a]pyrimidine compounds, pharmaceutical compositions containing the compounds and uses of the compounds. Background technique [0002] Tropomyosin-related kinase (Trk) is a kind of nerve growth factor receptor, and its family has highly homologous tropomyosin-related kinase A (tropomyosin-related kinase A, TrkA), tropomyosin Globulin-related kinase B (TrkB) and tropomyosin-related kinase C (TrkC) are encoded by NTRK1, NTRK2 and NTRK3, respectively. Among the neurotrophic factors are (i) nerve growth factor (NGF) that activates TrkA, (ii) brain-derived neurotrophic factor (BDNF) and NT-4 / 5 that activate TrkB, and (iii) TrkC that activates NT3. Trk is widely expressed in neuronal tissues and is related to the maintenance, signal transduction and survival of neuronal cells (Current Opinion in Neurobiology, 2001, 11:272-280). [0003] Trk kinase w...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D487/04A61K31/519A61P35/00A61P29/00A61P25/28A61P35/02A61P19/02A61P17/06A61P13/10A61P1/18A61P25/06A61P11/06A61P1/04A61P1/00A61P17/00A61P33/02
CPCA61P1/00A61P1/04A61P1/18A61P11/06A61P13/10A61P17/00A61P17/06A61P19/02A61P25/06A61P25/28A61P29/00A61P33/02A61P35/00A61P35/02C07D487/04Y02A50/30
Inventor 范晶晶唐春雷范为正
Owner 南京雷正医药科技有限公司
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