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2-aminopyrimidine compounds and their applications

An aminopyrimidine and compound technology, applied in the field of 2-aminopyrimidine compounds, can solve problems such as poor selectivity

Active Publication Date: 2021-04-27
JINAN UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] At present, although there are many small molecule inhibitors of FGFRs in clinical research, their selectivity is poor, and side effects caused by off-targets have been frequently reported in clinical practice.

Method used

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  • 2-aminopyrimidine compounds and their applications
  • 2-aminopyrimidine compounds and their applications
  • 2-aminopyrimidine compounds and their applications

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0072] Example 1. N-(3,5-dichloro-2-((-5-((2,6-dichloro-3,5-dimethoxybenzyl)oxy)pyrimidin-2-yl)amino ) Synthesis of phenyl) acrylamide

[0073]

[0074] The synthetic route is as follows:

[0075]

[0076] Step 1. Synthesis of 2-chloro-5-((2,6-dichloro-3,5-dimethoxybenzyl)oxy)pyrimidine

[0077] In a 250ml flask, add 2,6-dichloro-3,5-dimethoxybenzyl bromide (6.3g, 21mmol), 2-chloro-5-hydroxypyrimidine (2.61g, 20mmol), tetra-tert-butyl Ammonium iodide (1.48g, 4mmol), K 2 CO 3 (5.53g, 40mmol) and 80ml DMF were reacted at 60°C for 2h. The reaction solution was poured into ice and stirred for 1 h, suction filtered with a Buchner funnel, the filter cake was washed with water several times, and vacuum-dried at 50° C. to obtain 6.31 g of solid, yield: 90.25%. 1 H NMR (400MHz, DMSO-d 6 ): δ(ppm)8.68(s,2H),7.02(s,1H),5.42(s,2H),3.95(s,6H).

[0078] Step 2. Synthesis of N-(2-chloro-4-fluorophenyl)acetamide

[0079] Acetic anhydride (20ml) and 2-chloro-4-fluoro-aniline (4.2...

Embodiment 2

[0094] Example 2. N-(3-chloro-2-((-5-((2,6-dichloro-3,5-dimethoxybenzyl)oxy)pyrimidin-2-yl)amino)-5 Synthesis of -fluorophenyl)acrylamide

[0095]

[0096] The synthetic route is as follows:

[0097]

[0098] Step 1. Synthesis of tert-butyl-(2-amino-3,5-dichlorophenyl)-carbamate

[0099] In a water bath, di-tert-butyl dicarbonate (0.46ml, 10mmol) was added dropwise to 3,5-dichloro-1,2-phenylenediamine (1.7703g, 10mmol), triethylamine (1.5ml) and tetrahydrofuran (12ml) of the mixed solution, after the dropwise addition, the mixed system was reacted at room temperature for 12h. Ethyl acetate was added and water was mixed to separate the liquids, and then the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and 1.1967 g of solids were obtained by column chromatography, yield: 43.2%. 1 H NMR (400MHz, DMSO) δ8.64(s, 1H), 7.39(d, J=1.5Hz, 1H), 7.13(d, J=2.4Hz, 1H), 5.24(s, 2H), 1.47(s ,9H).

[0100] S...

Embodiment 3

[0106] Example 3. N-(3-chloro-2-((5-((2,6-dichloro-3,5-dimethoxy)oxy)pyrimidin-2-yl)amino-5-trifluoromethane Synthesis of phenyl)acrylamide

[0107]

[0108] Final Product Characterization: 1 H NMR (500MHz, DMSO-d 6 ):δ(ppm)9.81(s,1H),8.72(s,1H),8.43(s,1H),8.27(s,2H),7.67(s,1H),7.00(s,1H),6.62( dd,J=17.0,10.2Hz,1H),6.27(d,J=17.0Hz,1H),5.78(d,J=10.4Hz,1H),5.25(s,2H),3.94(s,6H). HRMS(ESI)C23H18Cl3F3N4O4[M+H] + :579.03984.

[0109] The synthesis method refers to Example 2.

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Abstract

The invention relates to a 2-aminopyrimidine compound with a structure of formula I and a pharmaceutically acceptable salt thereof or a stereoisomer thereof or a prodrug molecule thereof, belonging to the technical field of chemistry and medicine. The compound can highly selectively inhibit the kinase activity of FGFR4 protein, but not inhibit the kinase activity of other members of the FGFRs family (FGFR1, FGFR2, FGFR3). It can effectively inhibit the growth of tumor cells caused by abnormal FGFR4 signaling pathway, and can be used to prevent and treat transitional proliferative diseases such as tumors caused by abnormal FGFR4 signaling pathway in humans and other mammals.

Description

technical field [0001] The invention relates to the technical field of chemistry and medicine, in particular to 2-aminopyrimidine compounds and applications thereof. Background technique [0002] Fibroblast growth factor receptors (FGFRs) belong to the receptor tyrosine kinase superfamily (RTK), which includes four subtypes (FGFR1, FGFR2, FGFR3 and FGFR4). Each subtype has the common structural features of RTKs: an extracellular region that binds to the ligand, a transmembrane region, and an intracellular region containing a kinase domain. The FGFRs family has 18 human-derived ligands, which are widely distributed in various tissues of the human body and can selectively bind to receptors. Co-receptors (HSPG or KLB) can enhance the binding of receptors to corresponding ligands. When the ligand specifically binds to the receptor, FGFR is induced to dimerize and then autophosphorylate, making its domain change from an inactive state to an active state. The activated FGFR phos...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D239/47C07D401/12A61K31/506A61K31/505A61P35/00
CPCC07D239/47C07D401/12
Inventor 丁克陆小云莫程李学强任小梅张章涂正超罗金凤杰弗里.布鲁斯.斯美而亚当.逢.帕特森
Owner JINAN UNIVERSITY
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