Unlock instant, AI-driven research and patent intelligence for your innovation.

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

A compound and drug technology, applied in the field of chemical medicine, can solve the problems of low total yield and achieve the effects of low synthesis cost, good metabolic stability, and convenient synthesis method

Active Publication Date: 2022-07-12
山东轩硕医药科技有限公司
View PDF8 Cites 0 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0016] This route uses air-sensitive n-butyllithium ethyl and low temperature conditions of -78°C, and the overall yield is relatively low

Method used

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
View more

Image

Smart Image Click on the blue labels to locate them in the text.
Viewing Examples
Smart Image
  • Substituted pyrazolo[1,5-a]pyrimidine compounds as trk inhibitors
  • Substituted pyrazolo[1,5-a]pyrimidine compounds as trk inhibitors
  • Substituted pyrazolo[1,5-a]pyrimidine compounds as trk inhibitors

Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0104]

[0105] The present invention also provides the preparation method of the compound described in general formula (I), it comprises:

[0106] Preparation of intermediate (formula (II)):

[0107]

[0108] In some specific embodiments of the present invention, the intermediates include the following three types: compound (A), compound (B) and compound (C), and the respective preparation processes are as follows:

[0109] The preparation process of compound (A) (reaction formula 1):

[0110]

[0111] Reaction 1

[0112] As shown in reaction formula 1, the raw materials 2,5-difluorobenzaldehyde and methylamine are reductively aminated to obtain intermediate 1; intermediate 1 and 5-chloropyrazolo[1,5-a]pyrimidine are generated at high temperature Nucleophilic substitution gives intermediate 2; intermediate 2 is nitrated with nitric acid to give intermediate 3; intermediate 3 is reduced by zinc powder to give compound (A).

[0113] The preparation scheme of compound...

Embodiment 1

[0195] (S)-3-((5-((2,5-difluorobenzyl)(methyl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)amino)-4- (3-Hydroxypyrrolidin-1-yl)cyclobut-3-ene-1,2-dione

[0196] Structural formula:

[0197]

[0198] Intermediate A (60 mg, 0.21 mmol, 1 eq), (S)-3-ethoxy-4-(3-hydroxypyrrolidin-1-yl)but-3-ene-1,2-dione (purchased (53 mg, 0.25 mmol, 1.2 eq) from Yancheng Zhengchi Biotechnology Co., Ltd. was dissolved in 5 mL of ethanol, refluxed at 80 °C for 12 hours, cooled to room temperature, and the reaction solution was concentrated to obtain a solid. The crude product was purified by column chromatography to give a brown color Solid (S)-3-((5-((2,5-difluorobenzyl)(methyl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)amino)-4 -(3-Hydroxypyrrolidin-1-yl)cyclobut-3-ene-1,2-dione (30 mg, 32% yield). 1 H-NMR (400MHz, DMSO-d 6 )δ: 9.07(s,1H),8.64(d,J=8.0Hz,1H),7.87(s,1H),7.30–7.00(m,3H),6.66(d,J=8.0Hz,1H), 5.06(s,1H), 4.85(s,2H), 4.26(s,1H), 4.02-3.33(m,4H), 3.17(s,3H), 2.04-1.73(m,2H).MS(ESI) m / z 455.2[M+1...

Embodiment 1A

[0200] (S)-3-((5-((2,5-difluorobenzyl)(methyl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)amino)-4- (3-Hydroxypyrrolidin-1-yl)cyclobut-3-ene-1,2-dione sulfate

[0201] Structural formula:

[0202]

[0203] To (S)-3-(((5-((2,5-difluorobenzyl)(methyl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)amine at room temperature yl)-4-(3-hydroxypyrrolidin-1-yl)cyclobut-3-ene-1,2-dione (0.46 g, 1.0 mmol, 1 eq) in methanol (15 mL) was added Sulfuric acid (5 mL, 1 mmol, 1 eq). The resulting solution was stirred for 2 hours and then concentrated to give (S)-3-(((5-((2,5-difluorobenzyl)(methyl)amino)pyrazolo[1,5-a]pyrimidine as a yellow solid -3-yl)amino)-4-(3-hydroxypyrrolidin-1-yl)cyclobut-3-ene-1,2-dione sulfate (0.41 g, 72% yield).

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

PUM

No PUM Login to View More

Abstract

The present invention relates to a compound having the general formula (I) or a pharmaceutically acceptable salt thereof, a pharmaceutical composition and use thereof. The pyrazolo[1,5-a]pyrimidine derivative having the structure of general formula (I) is more convenient to synthesize and has good Trk family protein tyrosine kinase inhibitory activity.

Description

technical field [0001] The present 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] Trk (tropomyosin-related kinase) is a high-affinity receptor tyrosine kinase activated by a group of soluble growth factors called neurotrophins (NT). The Trk receptor family has three members: TrkA, TrkB and TrkC. Among the neurotrophins are (i) nerve growth factor (NGF) that activates TrkA; (ii) brain-derived neurotrophic factor (BDNF) and NT-4 / 5 that activate TrkB; and (iii) NT3 that activates TrkC. Trk is widely expressed in neuronal tissue and is involved in neuronal cell maintenance, signaling and survival (Current Opinion in Neurobiology, 2001, 11:272-280). [0003] Trk kinases were originally thought to be involved in the growth, differentiation, apoptosis, etc. of neuronal cells, and inhibitors ...

Claims

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

Application Information

Patent Timeline
no application Login to View More
Patent Type & Authority Patents(China)
IPC IPC(8): C07D487/04A61P35/00A61P29/00A61P25/00A61P35/02A61P25/04A61P25/06A61P11/06A61P1/04A61P1/00A61P13/10A61P17/00A61P33/02A61P19/08A61K31/519
CPCC07D487/04A61P35/00A61P29/00A61P25/00A61P35/02A61P25/04A61P25/06A61P11/06A61P1/04A61P1/00A61P13/10A61P17/00A61P33/02A61P19/08Y02A50/30
Inventor 范文华唐春雷范为正
Owner 山东轩硕医药科技有限公司