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Substituted pyrazolo [1, 5-a] pyrimidine compounds and application thereof

A compound and 5-a technology, applied in the field of substituted pyrazolo[1,5-a]pyrimidine compounds, can solve the problems of low safety, insufficient inhibitory effect, low drugability and the like, and achieve high safety, Excellent Trk kinase inhibitory activity, good effect against drug resistance

Active Publication Date: 2021-10-29
HANGZHOU BANGSHUN PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] The purpose of the present invention is to overcome the defects of existing compounds with insufficient inhibitory effect, low druggability and low safety, and provide a substituted pyrazolo[1,5-a ] Pyrimidine compounds and uses thereof

Method used

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  • Substituted pyrazolo [1, 5-a] pyrimidine compounds and application thereof
  • Substituted pyrazolo [1, 5-a] pyrimidine compounds and application thereof
  • Substituted pyrazolo [1, 5-a] pyrimidine compounds and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0215] Embodiment 1: the preparation of compound 1

[0216]

[0217] (a) (R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)-3-nitropyrazolo[1,5-a]pyrimidine

[0218] Add 40g (0.20mol) of 5-chloro-3-nitropyrazolo[1,5-a]pyrimidine, (R)-2-(2,5-difluorophenyl)pyrrolidine hydrochloride in the reaction flask Salt 46.5g (0.21mol), absolute ethanol 320mL and tetrahydrofuran 80mL, triethylamine 71.3g (0.705mol) was added under stirring. The reaction mixture was heated to 50° C. and stirred for about 5 hours, cooled to room temperature, added with water, and stirred for about 1 hour. Filter, wash the filter cake with water, and dry to obtain 64.2 g of solid (purity>99%, molar yield: 92.3%). ESI-MS(m / z):346.11([M+H] + ).

[0219] (b) Phenyl (R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carbamate

[0220] Add (R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)-3-nitropyrazolo[1,5-a]pyrimidine 20g (58mmol ) and THF 200mL, stirred at room temperature to dissolve. A...

Embodiment 2

[0223] Embodiment 2: the preparation of compound 2

[0224]

[0225] (a) 5-((2R,4S)-2-(2,5-difluorophenyl)-4-fluoropyrrolidin-1-yl)-3-nitropyrazolo[1,5-a] pyrimidine

[0226] 105 mg (1.53 mmol) of 5-chloro-3-nitropyrazolo[1,5-a]pyrimidine, ((2R,4S)-2-(2,5-difluorophenyl)-4-fluoropyrrole 130 mg (0.53 mmol) of alkane and 214 mg (2.12 mmol) of triethylamine were dissolved in 10 mL of ethanol, and the reaction system was stirred and reacted at 60° C. for 2 hours. The reaction system was concentrated under reduced pressure to obtain a residue, which was purified by reverse phase column ( Acetonitrile / water) to obtain white solid 155mg (molar yield: 81%).ESI-MS (m / z): 364.10 ([M+H] + ).

[0227] (b) 5-((2R,4S)-2-(2,5-difluorophenyl)-4-fluoropyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-amine

[0228]5-((2R,4S)-2-(2,5-difluorophenyl)-4-fluoropyrrolidin-1-yl)-3-nitropyrazolo[1,5-a]pyrimidine 155mg (0.43mmol) was dissolved in a mixed solution of dichloromethane and methanol (V / V=1...

Embodiment 3

[0233] Embodiment 3: the preparation of compound 3

[0234]

[0235] (a) 2-fluoropyrazolo[1,5-a]pyrimidin-5-ol

[0236] Under nitrogen, 1.2 g (12.03 mmol) of methyl propiolate was added to 15 mL of ethanol solution of 810 mg (8.02 mmol) of 3-fluoro-1H-pyrazol-5-amine and 5.3 g (16.04 mmol) of cesium carbonate In this process, the reaction system was stirred and reacted overnight at 80° C., and LCMS detection showed that the reaction was complete. The reaction system was concentrated under reduced pressure to obtain a residue, and the residue was purified by a reverse-phase column (acetonitrile / water) to obtain 730 mg of a yellow solid (molar yield: 61%). ESI-MS(m / z):154.04([M+H] + ).

[0237] (b) 5-Chloro-2-fluoropyrazolo[1,5-a]pyrimidine

[0238] Under nitrogen, 3 mL of phosphorus oxychloride was slowly added dropwise to 730 mg (8.02 mmol) of 2-fluoropyrazolo[1,5-a]pyrimidin-5-ol in 10 mL of acetonitrile solution. The reaction was stirred at °C for 2 hours. LCMS detec...

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Abstract

The invention discloses a substituted pyrazolo [1, 5-a] pyrimidine compound and application thereof. The compound shown in the formula I has a pyrazolo [1, 5-a] pyrimidine series structure, has a good inhibition effect on tropomyosin receptor (Trk) kinase, and also has a good inhibition effect on in-vitro tumor cell proliferation.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to a substituted pyrazolo[1,5-a]pyrimidine compound and its application. Background technique [0002] Tropomyosin receptor kinase (Trk) is a high-affinity receptor tyrosine kinase activated by a group of soluble growth factors called neurotrophins (NT). The Trk receptor family includes 3 members, TrkA, TrkB and TrkC. Trk is widely expressed in neuronal tissues and is related to the maintenance, signal transduction and survival of neuronal cells (Patapoutian, A. et al, Current Opinion in Neurobiology, 2001, 11:272-280). [0003] Literature has shown that fusion, overexpression, activation, amplification and / or mutation of Trk are associated with many cancers, and in preclinical models of cancer, non-selective small molecule inhibitors of TrkA, B and C can effectively inhibit tumor growth and Prevent tumor metastasis (Nakagawara, A. Cancer Letters, 2001, 169: 107-114; Meyer, J. e...

Claims

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Application Information

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IPC IPC(8): C07D487/04A61K31/519A61P35/00A61P29/00A61P25/00
CPCC07D487/04A61P35/00A61P29/00A61P25/00C07B2200/07
Inventor 杨欣崔荣张华玲孔祥文鲍粤华胡祖耀
Owner HANGZHOU BANGSHUN PHARM CO LTD
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