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Preparation method and application of irreversible alkyne heterocyclic compound FGFR inhibitor

A compound and solvate technology, applied in the field of irreversible alkyne heterocyclic compounds FGFR inhibitors

Pending Publication Date: 2022-02-18
YA THERAPEUTICS INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] Although the development of FGFR inhibitors has attracted many companies at home and abroad, although two FGFR inhibitors have been marketed, due to their prospects in the treatment of various malignant tumors, it is still necessary to develop new compounds

Method used

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  • Preparation method and application of irreversible alkyne heterocyclic compound FGFR inhibitor
  • Preparation method and application of irreversible alkyne heterocyclic compound FGFR inhibitor
  • Preparation method and application of irreversible alkyne heterocyclic compound FGFR inhibitor

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0085] Example 1: (S)-1-(1-acryloylpyrrolidin-3-yl)-3-(3,5-dimethoxy-2,6-difluorophenylethynyl)-4-amino- Preparation of 7-Hydroxy-1H-pyrrole[2,3-d]pyridazine (Compound 1)

[0086]

[0087] Step 1: Synthesis of Compound 1b

[0088] Add compound 3-cyano-1H-pyrrole-2-carboxylate ethyl ester 1a (1.64g, 10.0mmol), hydrazine hydrate 5mL, and ethanol 50mL into the reaction flask, heat up to reflux reaction overnight with stirring. After cooling to room temperature, the solvent was evaporated to dryness under reduced pressure. The residue was purified by column chromatography to obtain compound 1b (0.64 g, 43% yield) as a white solid. LC / MS(ESI):m / z=151.1[M+H] + .

[0089] Step 2: Synthesis of Compound 1c

[0090] Add compound 1b (0.6g, 4.0mmol) and 10mL of N,N-dimethylformamide to the reaction flask, add NBS (1.07g, 6.0mmol) in batches, and react at 50°C for 4 hours under stirring. After cooling to room temperature, the reaction solution was poured into 50 mL of water and ex...

Embodiment 2

[0099] Example 2: (S)-1-(1-but-2-ynoylpyrrolidin-3-yl)-3-(3,5-dimethoxy-2,6-difluorophenylethynyl)- Preparation of 4-amino-7-hydroxy-1H-pyrrole[2,3-d]pyridazine (compound 2)

[0100]

[0101] Compound 2 (112 mg, yield 52%) was obtained as a yellow solid by a method similar to that of Example 1 (the intermediate was replaced by but-2-ynoyl chloride). LC / MS(ESI):m / z=482.0[M+H] + .

Embodiment 3

[0102] Example 3: (S)-1-(1-acryloylpyrrolidin-3-yl)-3-(3,5-dimethoxy-2,6-dichlorophenylethynyl)-4-amino- Preparation of 7-Hydroxy-1H-pyrrole[2,3-d]pyridazine (Compound 3)

[0103]

[0104] Compound 3 (95 mg, yield 41%) was obtained as an off-white solid by a method similar to that of Example 1 (the intermediate was replaced with 3,5-dimethoxy-2,6-dichlorophenylacetylene). LC / MS(ESI):m / z=503.0[M+H] + .

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Abstract

The invention discloses a preparation method and application of an irreversible alkyne heterocyclic compound FGFR inhibitor. The invention relates to a compound as shown in a general formula (I) and a pharmaceutically acceptable salt thereof, a pharmaceutical composition containing the compound and / or the pharmaceutically acceptable salt thereof, and application of the compound or the pharmaceutically acceptable salt in drugs for treating or preventing FGFR kinase related diseases, especially tumors. The inhibitor is a template compound containing alkyne heterocyclic rings. The invention also discloses a preparation method of the pharmaceutical composition of the compound or the pharmaceutically acceptable salt thereof.

Description

Technical field: [0001] The present invention relates to an irreversible acetylenic heterocyclic compound FGFR inhibitor; a pharmaceutical composition containing the acetylenic heterocyclic compound or a pharmaceutically acceptable salt thereof; a preparation method of the acetylenic heterocyclic compound or a pharmaceutically acceptable salt thereof The acetylenic heterocyclic compound or its pharmaceutically acceptable salt, or the pharmaceutical composition containing the acetylenic heterocyclic compound or its pharmaceutically acceptable salt is prepared for the treatment and / or prevention of FGFR-related diseases, Especially the use in the medicine of tumor. Background technique: [0002] Fibroblast Growth Factor Receptor (FGFR) is a kind of receptor tyrosine kinase (RTK), and the FGFR family mainly includes four subtypes: FGFR1-, FGFR2, FGFR3 and FGFR4. FGFR1 is a transmembrane protein that belongs to receptor tyrosine kinases and consists of three main parts: the ext...

Claims

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Application Information

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IPC IPC(8): C07D487/04A61K31/5025A61P35/00
CPCC07D487/04A61P35/00
Inventor 梁永宏许志勇严文广
Owner YA THERAPEUTICS INC