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Inhibitors of fibroblast growth factor receptor

A pharmacy and compound technology, applied in growth factors/growth regulators, receptors/cell surface antigens/cell surface determinants, medical preparations containing active ingredients, etc., and can solve problems such as lack of evidence

Active Publication Date: 2018-12-11
BLUEPRINT MEDICINES
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although alternative splicing has been found, there is no evidence that the C-terminal half of the IgIII domain of the protein varies between three alternative forms, such as those shown for FGFR 1-3

Method used

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  • Inhibitors of fibroblast growth factor receptor
  • Inhibitors of fibroblast growth factor receptor
  • Inhibitors of fibroblast growth factor receptor

Examples

Experimental program
Comparison scheme
Effect test

example 1

[0143] Example 1: Synthesis of N-(2-((6-(2,6-dichloro-3,5-dimethoxyphenyl)-8-methyl-7-oxo-7,8-di Hydropyrido[2,3-d]pyrimidin-2-yl)amino)-3-methylphenyl)acrylamide Compound 43

[0144]

[0145]

[0146] Step 1: Synthesis of 4-(methylamino)-2-(methylthio)pyrimidine-5-carboxylic acid ethyl ester

[0147]

[0148] Stir 4-chloro-2-(methylthio)pyrimidine-5-carboxylic acid ethyl ester (5.0 g, 21.5 mmol) and 29% methylamine (5.75 g, 53.72 mmol) in tetrahydrofuran (THF) (100 mL) at room temperature , methanol (MeOH) solution) mixture for 2 hours. Then, the reaction mixture was concentrated, followed by the addition of sodium bicarbonate (NaHCO 3) (20 mL aqueous solution), and the resulting solution was extracted with ethyl acetate (EtOAc) (3 x 50 mL). The combined organic layers were washed with water and brine, dried over sodium sulfate, filtered and concentrated to give ethyl 4-(methylamino)-2-(methylthio)pyrimidine-5-carboxylate (4.68 g) as a pale yellow solid , 96...

Embodiment 2

[0176] Example 2: Synthesis of N-(2-((6-(2,6-dichloro-3,5-dimethoxyphenyl)quinazolin-2-yl)amino)-3- Methoxyphenyl)acrylamide Compound 30

[0177]

[0178] Step 1: Synthesis of (2-amino-5-bromophenyl)methanol

[0179]

[0180] To a solution of 2-amino-5-bromobenzoic acid (10.0 g, 46.3 mmol) in THF (150 mL) at room temperature was added BH3-THF (1 M, 231 mL) and the reaction mixture was stirred overnight. An aliquot of the reaction mixture was analyzed by LCMS and indicated that the reaction had gone to completion. The reaction was quenched with water (150 mL) and extracted with EtOAc (3 x 500 mL). The organic layers were separated, combined, washed with water (200 mL) and brine (200 mL), dried over sodium sulfate, filtered and concentrated to give the title compound (10 g, crude material), which was used in the next step without further purification . MS(ES+)C 7 H 8 BrNO required value: 201, experimental value: 202, 204 [M+H] + .

[0181] Step 2: Synthesis of 2...

example 3

[0205] Example 3: Synthesis of Compound 25

[0206]

[0207] Synthesis of 6-(2,6-Dichloro-3,5-dimethoxyphenyl)-N-(2-methyl-6-nitrophenyl)quinazolin-2-amine

[0208]

[0209] 2-Chloro-6-(2,6-dichloro-3,5-dimethoxyphenyl)quinazoline (35) (5 g, 13.5 mmol), 2-methyl-6-nitroaniline ( 3.09g, 20.3mmol), Cs 2 CO 3 (13.2g, 40.6mmol),, Pd 2 (dba) 3 (1.24 g, 1.35 mmol) and 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (Xphos) (1.29 g, 2.71 mmol) were dissolved in DMA (100 ml) and mixed with N 2 Purge for 5 minutes. The reaction mixture was heated to 110°C for 3 hours. After cooling to room temperature, the reaction mixture was diluted with DCM (500 ml) and washed 3 times with 10% HCl (3 x 300 ml) and 3 times with brine. The organic mixture was dried over sodium sulfate and loaded directly onto silica gel and purified using a 0-100% EtOAc / Hexane gradient. 6-(2,6-Dichloro-3,5-dimethoxyphenyl)-N-(2-methyl-6-nitrophenyl)quinazolin-2-amine was recovered as a yellow so...

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Abstract

Described herein are FGFR inhibitors, pharmaceutical compositions comprising these compounds, and methods of using these compounds and compositions for inhibiting tyrosine kinase activity.

Description

[0001] claim priority [0002] This application claims priority to U.S. Patent Serial No. 61 / 670,379 filed on July 11, 2012 and U.S. Patent Serial No. 61 / 746,666 filed on December 28, 2012, the entire contents of which are hereby incorporated by reference in This is all incorporated into the present invention. technical field [0003] Described herein are compounds, methods of making the compounds, pharmaceutical compositions, and methods of using the compounds and compositions for inhibiting tyrosine kinase activity. Background technique [0004] Fibroblast growth factor receptor 4 (FGFR-4) refers to a protein encoded by the FGFR-4 gene in humans. This protein is a member of the fibroblast growth factor receptor family, and the amino acid sequence among members is highly conserved throughout evolution. Elements 1-4 of the FGFR family differ from each other in their ligand affinity and tissue distribution. A full-length representative protein consists of an extracellular ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D239/42C07D239/84C07D471/04C07D475/00C07D487/04A61K31/437A61K31/505A61K31/506A61K31/517A61K31/519A61P35/00
CPCC07D239/42C07D239/48C07D239/84C07D401/04C07D401/12C07D471/04C07D475/00C07D487/04C07D475/04C07D295/155A61K31/4375A61K31/517A61K31/519A61P1/16A61P25/00A61P35/00A61P3/06A61K31/437C07K14/71
Inventor 小尼尔·比富尔科娜塔莎·布鲁杰孟布赖恩·L·霍道什约瑟夫·L·基姆昌德拉塞卡·V·曼德拉史蒂文·M·翁劳斯基
Owner BLUEPRINT MEDICINES
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