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Pyrimidine heterocyclic compound and its preparation method and application

A compound and drug technology, applied in the field of EGFR-mediated diseases, can solve the problems of increased affinity and decreased affinity of adenosine phosphate, and achieve the effect of good safety and toxicity parameters

Active Publication Date: 2021-09-28
SHANGHAI KECHOW PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The most prevalent EGFR activating mutations (L858R and dele746_A750) result in increased affinity for small molecule tyrosine kinase inhibitors such as gefitinib and erlotinib relative to wild-type (WT) EGFR, as well as increased affinity for Decreased affinity for adenosine phosphate (ATP)

Method used

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  • Pyrimidine heterocyclic compound and its preparation method and application
  • Pyrimidine heterocyclic compound and its preparation method and application
  • Pyrimidine heterocyclic compound and its preparation method and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0073] Example 1: 2-acrylamide-N-(2-(dimethylamino)ethyl)-5-methoxy-N-methyl-4-((4-(1-methyl-1H-ind Synthesis of Indol-3-yl)pyrimidin-2-yl)amino)aniline

[0074]

[0075] Step 1: Synthesis of methyl 5-methoxy-4-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-2-nitrobenzoate:

[0076] Compound 3-(2-chloropyrimidin-4-yl)-1-methylindole (2.4g, 9.85mmol) and methyl 4-amino-5-methoxy-2-nitrobenzoate (2.67g , 11.82mmol) was added to the reaction flask, then 1,4-dioxane (20mL) was added, p-toluenesulfonic acid (2.03g, 11.82mmol) was added under stirring, and heated to 85°C for 48 hours, After the reaction was completed, it was cooled to room temperature, a solid was precipitated, filtered, the filter cake was washed with acetonitrile, and dried to obtain a yellow solid (4.0 g, yield: 93.7%). 1 H NMR (400MHz, CDCl 3 ):δ9.66(s,1H),8.44(d,J=4Hz,1H),8.21-8.19(m,1H), 8.17(s,1H),7.94(s,1H),7.44-7.41(m ,2H),7.28(s,1H),7.17(s,1H),4.06(s,3H),3.95(s,3H),3.93(s,3H).

[0077] Step 2: S...

Embodiment 2

[0085] Embodiment 2: N-(2-(dimethylamino)ethyl)-2-(3-(dimethylamino)propionylamino)-5-methoxy-N-methyl-4-(( Synthesis of 4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)benzamide

[0086]

[0087] Compound 2-acrylamide-N-(2-(dimethylamino)ethyl)-5-methoxy-N-methyl-4-((4-(1-methyl- 1H-indol-3-yl)pyrimidin-2-yl)amino)aniline (200mg, 0.38mmol) was added to the reaction flask, then ethanol (5mL) was added to dissolve, and 30% dimethylamine ethanol solution (2mL) was added under stirring ), stirred and reacted at room temperature for 30 minutes, after the completion of the reaction detected by TLC, concentrated, and purified by TLC to obtain the target compound as an off-white solid (100 mg, yield: 46.06%). 1 H NMR (400MHz, CDCl 3 )δ10.27(s,1H),9.16(s,1H),8.39(d,J=5.3Hz,2H),8.21(s,1H),7.80(s,1H),7.42–7.37(m,1H ),7.31(dd,J=8.9,5.2Hz,2H),7.17(d,J=5.3Hz,1H),6.77(s,1H),3.94(s,3H),3.87(s,3H),3.10 (s,3H),2.81(m,6H),2.55(s,6H),2.04(m,8H).MS(ESI)m / z573.32[M+H].

Embodiment 3

[0088]Example 3: N-(5-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-2-(2,2,2-trifluoroacetyl )-4-(trifluoromethoxy) phenyl) acrylamide synthesis:

[0089]

[0090] Step 1: 2,2,2-Trifluoro-1-(4-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)oxy)-2-nitro -Synthesis of 5-(trifluoromethoxy)phenyl)ethanone:

[0091] The compound 3-(2-chloropyrimidin-4-yl)-1-methylindole (1.5g, 6.16mmol) and 1-(4-amino-2-nitro-5-(trifluoromethoxy) Phenyl)-2,2,2-trifluoroethanone (1.96g, 6.16mmol) was added into the reaction flask, then 2-pentanol (100mL) was added, and p-toluenesulfonic acid monohydrate ( 1.27g, 7.39mmol), heated to 105°C for 2.5 hours, after the reaction, cooled to room temperature, precipitated solid, filtered, washed the filter cake with acetonitrile, dried to obtain a yellow solid (2.3g, yield: 71%). 1 H NMR (400MHz, CDCl 3 ):δ9.46(s,1H),8.56(d,1H),8.17(m,1H),7.59(m,1H),7.56(s,1H),7.50(s,1H),7.42-7.41( m,2H),7.19(s,1H),3.69(s,3H).

[0092] Step 2: 1-(2-Amino-4-((4-(1-me...

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Abstract

The present invention relates to compounds of formula (I) and pharmaceutically acceptable salts, prodrugs and solvates thereof, which are useful in the treatment of cancer and inflammation in mammals. The invention also discloses the preparation method of the compound of formula (I) and the pharmaceutical composition containing the compound.

Description

technical field [0001] The present invention relates to certain fluorinated heterocyclic compounds and pharmaceutically acceptable salts thereof, which can be used to treat epidermal growth factor receptors induced by certain variant forms (such as L858R activating mutants, Exon19 deletion activating mutants, and T790M resistant mutant) for the treatment and prevention of diseases or conditions mediated. Such compounds and their salts are useful in the treatment or prevention of many different cancers. The present invention also relates to pharmaceutical compositions comprising said compounds and their salts, intermediates in the preparation of said compounds, and to methods of using said compounds and their salts in the treatment of various forms of EGFR-mediated diseases. Background technique [0002] EGFR is a transmembrane protein tyrosine kinase member of the erbB receptor family. When bound to a growth factor ligand such as epidermal growth factor (EGF), the receptor...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D471/04C07D403/04C07D403/14C07D401/14A61K31/506A61P35/00
CPCC07D401/14C07D403/04C07D403/14C07D471/04
Inventor 田红旗黄功超程瑛
Owner SHANGHAI KECHOW PHARMA