Substituted pyrimidine compound, pharmaceutical composition thereof and use of the compound

A compound and application technology, applied in the field of chemical medicine, to achieve the effect of reducing rash and diarrhea, improving diseases and disorders, and high metabolic stability

Active Publication Date: 2021-11-23
南京雷正医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] Most of the EGFR gene mutations occur in exons 18-21, and most of the mutations are non-frameshift deletion mutations in exon 19 and L858R point mutations in exon 21. Patients with these two types of mutations, the effect of targeted drugs generally very good

Method used

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  • Substituted pyrimidine compound, pharmaceutical composition thereof and use of the compound
  • Substituted pyrimidine compound, pharmaceutical composition thereof and use of the compound
  • Substituted pyrimidine compound, pharmaceutical composition thereof and use of the compound

Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0103]

[0104] Another aspect of the present invention also provides a method for preparing a compound of general formula (I), which is implemented by one of the following reaction schemes:

[0105] Reaction scheme one:

[0106]

[0107] Reaction 1

[0108] As shown in Reaction Formula 1, using isopropyl 2,4-dichloropyrimidine-5-carboxylate as a raw material, reacting with compound A under the action of a catalyst to obtain intermediate a through Friedel-Crafts reaction; intermediate a is substituted with compound B Reaction obtains compound C; Wherein, R 1 selected from hydrogen, C 1 -C 4 Alkyl, deuterated methyl, C 3 -C 6 Cycloalkyl, R 2 , R 3 , the definition of Z is identical with the definition in general formula (I),

[0109] In the above reaction, the preparation of the intermediate a is carried out under the action of a Lewis acid, and the Lewis acid can be selected from, but not limited to, iron trichloride, aluminum trichloride, zinc chloride, trifluori...

Embodiment 1

[0219] Example 1: Isopropyl-2-((5-acrylamido-4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxyphenyl)amino) -4-(1-Deuteromethyl-1H-indol-3-yl)pyrimidine-5-carboxylate

[0220]

[0221] Intermediate 2b (24mg, 0.073mmol) was dissolved in acetonitrile (2mL), and intermediate 1a (25mg, 0.087mmol) and p-toluenesulfonic acid monohydrate (4mg, 0.022mmol) were added successively, under nitrogen protection, heated to 80 °C for 18 hours. After the reaction solution was concentrated, it was purified by column to obtain 15 mg of gray solid with a yield of 35.3%.

[0222] ESI-MS m / z:589.4[M+H] + , 1 H-NMR (DMSO-d 6 ,400MHz),10.12(s,1H),8.84(s,1H),8.64(d,J=8.0Hz,2H),8.17(s,1H),7.73(s,1H),7.48(d,J= 8.0Hz,1H),7.19(t,J=8.0Hz,1H),7.05-7.01(m,2H),6.46-6.40(m,1H),6.29-6.20(m,1H),5.77(d,J =8.0Hz,1H),5.03-4.96(m,1H),3.87(s,3H),2.89(t,J=8.0Hz,2H),2.72(s,3H),2.32(t,J=8.0Hz ,2H),2.21(s,6H),1.12(d,J=8.0Hz,6H).

Embodiment 1A

[0223] Example 1A: Isopropyl-2-((5-acrylamido-4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxyphenyl)amino) -4-(1-Deuteromethyl-1H-indol-3-yl)pyrimidine-5-carboxylate succinate

[0224]

[0225] Isopropyl-2-((5-acrylamido-4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxyphenyl)amino)-4- (1-Deuteromethyl-1H-indol-3-yl)pyrimidine-5-carboxylate (400mg, 0.68mmol) in tetrahydrofuran (4mL) was slowly added dropwise with succinic acid (84.2mg, 0.71mmol) Tetrahydrofuran (1 mL) solution. Keep stirring for 12 hours. The solid precipitated, was filtered while it was hot, and dried in vacuo to obtain 320 mg of a light yellow solid with a yield of 66.7%.

[0226] ESI-MS m / z:589.4[M+H] + , 1 H-NMR (DMSO-d 6 ,400MHz),10.11(s,1H),8.83(s,1H),8.62(d,J=8.0Hz,2H),8.17(s,1H),7.73(s,1H),7.46(d,J= 8.0Hz,1H),7.18(t,J=8.0Hz,1H),7.05-6.09(m,2H),6.46-6.41(m,1H),6.29-6.20(m,1H),5.77(d,J =8.0Hz,1H),5.03-4.96(m,1H),3.87(s,3H),2.89(t,J=8.0Hz,2H),2.72(s,3H),2.41(s,2H),2.32 (t,J=8.0Hz,2H),2.21(...

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Abstract

The present invention relates to a substituted pyrimidine compound, its pharmaceutical composition and the use of the compound. It has excellent inhibitory activity on mutant EGFR and mutant HER2, and the substituted pyrimidine compounds with general formula (I) and pharmaceutically acceptable salts thereof have excellent pharmacodynamic properties, metabolic stability and / or better Blood-brain barrier permeability.

Description

technical field [0001] The invention belongs to the field of chemical medicine. The invention relates to a class of substituted pyrimidine compounds and pharmaceutical compositions of the compounds. In addition, the invention also relates to compounds for treating diseases and conditions related to kinase activity including mutant EGFR and mutant HER2 activities, Pharmaceutical compositions and methods. Background technique [0002] Epidermal growth factor receptor (EGFR) is a membrane surface receptor with tyrosine kinase activity widely present in human epidermal cells and stromal cells. In normal cells, the activity of EGFR tyrosine kinase (EGFR-TK) is precisely controlled, but when the gene site is mutated, its activity will continue to increase, thereby inducing tumors (Chong et al. Nature Med.2013; 19(11): 1389 -1400). [0003] Lung cancer consists of non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC) and neuroendocrine tumors. It has been reported th...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D401/14C07D403/04C07F9/6558A61P35/00A61K31/506A61K31/685A61K31/5377
CPCA61P35/00C07D401/14C07D403/04C07F9/65583
Inventor 范晶晶唐春雷范为正范文华张立勋
Owner 南京雷正医药科技有限公司
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