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Inhibitors of the fibroblast growth factor receptor

A technology of nucleophiles and compounds, applied in the field of fibroblast growth factor receptor inhibitors, can solve problems such as no evidence

Active Publication Date: 2015-04-22
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 the fibroblast growth factor receptor
  • Inhibitors of the fibroblast growth factor receptor
  • Inhibitors of the 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-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)-3-methylphenyl)propene Amide Compound 43

[0144]

[0145]

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

[0147]

[0148] Ethyl 4-chloro-2-(methylthio)pyrimidine-5-carboxylate (5.0 g, 21.5 mmol) and 29% methylamine (5.75 g, 53.72 mmol) in tetrahydrofuran (THF) (100 mL) were stirred at room temperature. , methanol (MeOH) solution) mixture for 2 h. Then, the reaction mixture was concentrated, followed by the addition of sodium bicarbonate (NaHCO 3) (20 mL in water), 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 afford ethyl 4-(methylamino)-2-(methylthio)pyrimidine-5-carboxylate (4.68 g) as a light yellow solid , 96%). MS(ES+)C ...

Embodiment 2

[0176] Embodiment 2: Synthesis of N-(2-((6-(2,6-dichloro-3,5-dimethoxyphenyl) quinazoline -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) was added BH3-THF (1M, 231 mL) at room temperature, and the reaction mixture was stirred overnight. An aliquot of the reaction mixture was analyzed by LCMS and indicated that the reaction had proceeded to completion. The reaction was quenched with water (150 mL), 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 directly in the next step without further purification . MS(ES+)C 7 h 8 Required value of BrNO: 201, experimental value: 202,204[M+H] + .

[0181] Step ...

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) (5g, 13.5mmol), 2-methyl-6-nitroaniline ( 3.09g, 20.3mmol), Cs 2 CO 3 (13.2g, 40.6mmol), Pd 2 (dba) 3 (1.24g, 1.35mmol) and 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (Xphos) (1.29g, 2.71mmol) were dissolved in DMA (100ml) and washed with N 2 Purify 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 (500ml), washed 3 times with 10% HCl (3 x 300ml), and washed 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 / hexanes gradient. 6-(2,6-Dichloro-3,5-dimethoxyphenyl)-N-(2-methyl-6-nitrophenyl)quinazolin-2-amine was recovered as a yellow sol...

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Abstract

Described herein are inhibitors of FGFR, pharmaceutical compositions including such compounds, and methods of using such compounds and compositions to inhibit the activity of tyrosine kinases.

Description

[0001] claim priority [0002] This application claims priority to U.S. Patent Serial No. 61 / 670,379, filed July 11, 2012, and U.S. Patent Serial No. 61 / 746,666, filed December 28, 2012, the entire contents of which are incorporated by reference at All of this is incorporated into the present invention. technical field [0003] Described herein are compounds, methods of preparing the compounds, pharmaceutical compositions, and methods of using the compounds and compositions to inhibit 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. Members 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 domain co...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D239/42C07D239/84C07D471/04C07D475/00C07D487/04A61K31/437A61K31/505A61K31/506A61K31/517A61K31/519A61P35/00
CPCC07D239/84C07D471/04C07D239/42A61K31/519A61K31/4375C07D295/155C07D487/04A61K31/517C07D475/00C07D239/48C07D401/04C07D401/12C07D475/04A61P1/16A61P25/00A61P35/00A61P3/06A61K31/437C07K14/71
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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