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

A compound, C1-C6 technology, applied in medical preparations containing active ingredients, drug combinations, organic chemistry, etc., can solve the problems of low drugability, insufficient inhibitory effect, low safety, etc., and achieve drug resistance Good, excellent Trk kinase inhibitory activity, high safety effect

Active Publication Date: 2022-05-24
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 uses thereof
  • Substituted pyrazolo[1,5-a]pyrimidine compounds and uses thereof
  • Substituted pyrazolo[1,5-a]pyrimidine compounds and uses thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0215] Example 1: 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 to the reaction flask 46.5 g (0.21 mol) of salt, 320 mL of anhydrous ethanol and 80 mL of tetrahydrofuran, and 71.3 g (0.705 mol) of triethylamine were added with stirring. The reaction mixture was heated to 50°C and stirred for about 5 hours, cooled to room temperature, water was added, and stirred for about 1 hour. After filtering, the filter cake was washed with water and dried to obtain 64.2 g of solid (purity>99%, molar yield: 92.3%). ESI-MS(m / z): 346.11([M+H] + ).

[0219] (b) (R)-phenyl 5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carbamic acid

[0220] To the reaction flask was added 20 g (58 mmol) of (R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)-3-nitropyrazolo[1,5-a]pyrim...

Embodiment 2

[0223] Example 2: 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] 5-Chloro-3-nitropyrazolo[1,5-a]pyrimidine 105mg (1.53mmol), ((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 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 give a white solid 155 mg (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]155 mg of 5-((2R,4S)-2-(2,5-difluorophenyl)-4-fluoropyrrolidin-1-yl)-3-nitropyrazolo[1,5-a]pyrimidine (0.43 mmol) was dissolved in a mixed solution of dichloromethane and methanol (V / V=1:1, 15 mL), 7 mL ...

Embodiment 3

[0233] Example 3: 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 an 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. The reaction system was stirred at 80°C overnight, 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 reverse-phase column (acetonitrile / water) to obtain 730 mg of 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 10 mL of an acetonitrile solution of 730 mg (8.02 mmol) of 2-fluoropyrazolo[1,5-a]pyrimidin-5-ol. The reaction system was heated at 85 The reaction was stirred at °C for 2 hours. LCMS de...

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Abstract

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

Description

technical field [0001] The present invention relates to the field of medicinal chemistry, in particular to a substituted pyrazolo[1,5-a]pyrimidine compound and use thereof. Background technique [0002] Tromyosin 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 three members, namely TrkA, TrkB and TrkC. Trk is widely expressed in neuronal tissue and is involved in the maintenance, signaling and survival of neuronal cells (Patapoutian, A. et al, Current Opinion in Neurobiology, 2001, 11:272-280). [0003] The literature shows that fusion, overexpression, activation, amplification and / or mutation of Trk is 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 Prevents tumor metastasis (Nakagawara, A. Cancer Letters, 2001, 169: 107-114; Meyer, ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
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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