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Epidermal growth factor receptor inhibitor and preparation and application thereof

A technology selected from, C1-C8, applied in the field of medicine, can solve the problems of poor selectivity and low tolerance dose of EGFRT790M mutants

Active Publication Date: 2020-01-03
JIANGSU VCARE PHARMATECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The second-generation EGFR irreversible inhibitors, such as canertinib and afatinib, can overcome drug resistance, but these molecules have poor selectivity for EGFR T790M mutants, and their inhibitory effect on wild-type EGFR is lower than that of wild-type EGFR. Strong, low tolerated dose in vivo

Method used

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  • Epidermal growth factor receptor inhibitor and preparation and application thereof
  • Epidermal growth factor receptor inhibitor and preparation and application thereof
  • Epidermal growth factor receptor inhibitor and preparation and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0114] N-(5-((5-chloro-4-((2-(isopropylsulfonyl)pyridin-3-yl)aminopyrimidin-2-yl)amino)-2-((2-(dimethyl Synthesis of amino)ethyl)(methyl)amino)-6-methoxypyridin-3-yl)acrylamide

[0115]

[0116] Step 1: Synthesis of 6-bromo-2-methoxy-3-nitropyridine

[0117]

[0118] At room temperature, sequentially add 2,6-dibromo-3-nitropyridine (40.00g, 141.90mmol), THF (520ml) into the four-necked flask, cool down to 0-5°C, add sodium methoxide (30%, 28.11g , 156.08mmol), 3h reaction terminated. Pour the reaction solution into ice water (500ml), add MTBE (500ml x3) for extraction, combine the organic phases, wash with saturated brine (200ml), concentrate the organic phases, and crystallize the crude product to obtain 19.89g of a light yellow solid, with a yield of 60% . 1 H NMR (400MHz, Chloroform-d) δ 8.15 (d, J = 8.2Hz, 1H), 7.22 (d, J = 8.2Hz, 1H), 4.14 (s, 3H).

[0119] Step 2: Synthesis of 6-bromo-2-methoxypyridin-3-amine

[0120]

[0121] At room temperature, 6-bromo-2...

Embodiment 2

[0156] N-(5-((5-chloro-4-((2-(isopropylsulfonyl)pyridin-3-yl)amino)pyrimidin-2-yl)amino)-2-((2-(dimethyl Synthesis of (amino)ethyl)(methyl)amino)-6-ethoxypyridin-3-yl)acrylamide

[0157]

[0158] N-(5-((5-chloro-4-((2-(isopropylsulfonyl)pyridin-3-yl)amino)pyrimidin-2-yl)amino)-2-((2-(dimethyl The preparation method of (amino) ethyl) (methyl) amino)-6-ethoxypyridin-3-yl) acrylamide is similar to that of Example 1.

[0159] 1 H NMR (400MHz, DMSO-d 6 )8.61(s,1H),8.36(d,J=4.0Hz,1H),8.24(s,1H),8.06(s,1H),7.48(s,1H),6.43(dd,J=17.0,10.2 Hz,1H),6.21-6.14(m,1H),5.75-5.68(m,1H),4.29(q,J=7.0Hz,2H),3.86(dt,J=13.5,6.8Hz,1H),3.18 (t, J=6.3Hz, 2H), 2.85(s, 3H), 2.46(d, J=6.7Hz, 2H), 2.19(s, 6H), 1.23(s, 9H). MS(ESI)m / z:618.1[M+H] + .

Embodiment 3

[0161] N-(5-((5-chloro-4-((2-(isopropylsulfonyl)pyridin-3-yl)amino)pyrimidin-2-yl)amino)-2-((2-(dimethyl Synthesis of (amino)ethyl)(methyl)amino)-6-isopropoxypyridin-3-yl)acrylamide

[0162]

[0163] N-(5-((5-chloro-4-((2-(isopropylsulfonyl)pyridin-3-yl)amino)pyrimidin-2-yl)amino)-2-((2-(dimethyl The preparation method of (amino)ethyl) (methyl)amino)-6-isopropoxypyridin-3-yl)acrylamide is similar to that of Example 1.

[0164] 1 H NMR (400MHz, DMSO-d 6 )9.87(br,1H),9.75(br,1H),8.98(br,1H),8.52(s,1H),8.36(d,J=3.8Hz,1H),8.25(s,1H),8.05( s,1H),7.47(s,1H),6.43(dd,J=17.0,10.2Hz,1H),6.21-6.13(m,1H),5.76-5.69(m,1H),5.14(p,J= 6.1Hz, 1H), 3.85(dt, J=13.8, 6.9Hz, 1H), 3.17(t, J=6.4Hz, 2H), 2.84(s, 3H), 2.46-2.42(m, 2H), 2.18( s, 6H), 1.21 (dd, J = 10.5, 6.5Hz, 12H). MS(ESI)m / z:632.1[M+H] + .

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Abstract

The invention relates to 2-aminopyrimidine derivatives with a structure of a formula (I), a pharmaceutical composition containing the compounds of the formula (I) and application of the compounds in preparation of drugs for prevention or treatment of epidermal growth factor receptor (EGFR) kinase-related diseases, especially application of the compounds in prevention or treatment of cancers related to epidermal growth factor receptor kinase. Substituents in the formula (I) are the same as defined in the description.

Description

technical field [0001] The application belongs to the technical field of medicine, and specifically relates to 2-aminopyrimidine derivatives and their application for preparing antitumor drugs. [0002] This application claims the priority of Chinese patent CN201810704813.7 (application date June 27, 2018, invention name EGFR inhibitor and its preparation and application). Background technique [0003] Epidermal Rrowth Factor Receptor (EGFR) is a transmembrane receptor protein with tyrosine kinase activity widely distributed on the cell membrane of human tissues, and is a member of the erbB receptor family of tyrosine kinases. By binding to the ligand epidermal growth factor (EGF), EGFR forms a homodimer on the cell membrane, or forms a heterodimer with other receptors in the family (such as erbB2, erbB3, or erbB4) and is activated, causing Phosphorylation of key tyrosine residues in EGFR cells activates the kinase domain and further activates multiple downstream signaling ...

Claims

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Application Information

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IPC IPC(8): C07D401/14C07D401/12A61K31/506A61P35/00A61P35/02
CPCC07D401/14C07D401/12A61P35/00A61P35/02
Inventor 龚彦春孟磊郭其润刘永强
Owner JIANGSU VCARE PHARMATECH
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