Compound for targeted degradation of focal adhesion kinase and application of compound

A compound and hydrate technology, applied in the field of biomedicine and drug synthesis, can solve the problems of prone to drug resistance and unable to block the function of FAK skeleton

Active Publication Date: 2020-11-06
SHENYANG PHARMA UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the action sites of these inhibitors are mainly concentrated in the ATP-binding pocket of the FAK kinase domain. They are ATP competitive inhibitors, which can only affect or block the function of the kinase domain, but cannot block the FAK-independent backbone function of FAK, and are easy to drug resistance

Method used

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  • Compound for targeted degradation of focal adhesion kinase and application of compound
  • Compound for targeted degradation of focal adhesion kinase and application of compound
  • Compound for targeted degradation of focal adhesion kinase and application of compound

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0111]

[0112] 1 H NMR (600MHz, CDCl 3 )δ10.00(s,1H),8.14(s,1H),7.51–7.48(m,1H),7.44 (d,J=5.8Hz,1H),7.39(d,J=8.7Hz,2H), 7.35–7.27(m,3H),7.18(d,J=7.1Hz,1H),6.97(s,1H),6.84(d,J=8.7Hz,2H),6.80(d,J=8.5Hz,1H ),6.70(t,J=5.7Hz,1H),5.96(s,1H),5.13(s,1H),4.90(dd,J=11.4,4.4Hz,1H),4.66(s,1H),3.94 (d,J=5.8Hz,2H),3.62–3.52(m,9H),3.45–3.42(m,1H),3.24(s,3H),3.15(s,4H),2.97(s,4H), 2.86–2.77(m,2H),2.72–2.64(m,6H),2.11(dd,J=8.8,3.9Hz, 1H).HRMS calcd for C 45 h 52 f 3 N 11 o 9 S,[M+H] + ,980.3695; found 980.3712.

Embodiment 2

[0114]

[0115] 1 H NMR (600MHz, CDCl 3 )δ10.76(s,1H),8.14(s,1H),7.72(s,1H),7.50–7.46(m,1H),7.45–7.41(m,3H),7.34–7.27(m,3H) ,7.08(d,J=7.1Hz,1H),6.97(d,J=8.6Hz,1H),6.82(d,J=8.7Hz,3H),6.41(t,J=4.9Hz,1H),5.99 (s,1H),5.12(s,1H),4.88(dd,J=12.0,5.4Hz,1H),4.65(d,J=11.3Hz,1H),3.66(t,J=5.6Hz, 2H) ,3.51–3.44(m,6H),3.22(s,3H),3.15(s,4H),2.96(s,3H),2.80–2.65(m,7H), 2.50–2.46(m,4H),2.09 (dd,J=7.8,5.3Hz,1H),1.82–1.78(m,2H).HRMS calcd for C 45 h 52 f 3 N 11 o 8 S,[M+H] + ,964.3746; found 964.3788.

Embodiment 3

[0117]

[0118] 1 H NMR (600MHz, CDCl 3 )δ10.40(s,1H),8.15(s,1H),7.71(s,1H),7.49–7.45(m,1H),7.44(d,J=6.6Hz,1H),7.40(d,J =9.0Hz, 2H), 7.34–7.27(m, 3H), 7.09 (d, J=7.1Hz, 1H), 6.90(d, J=8.6Hz, 1H), 6.85(d, J=8.9Hz, 2H ),6.52(t,J=5.5Hz,1H),6.00(s,1H),5.13(s,1H),4.87(dd,J=11.5,4.1Hz,1H),4.64(d,J=11.5Hz ,1H),3.73–3.69(m,4H),3.67–3.64(m,4H),3.47–3.44(m,2H),3.22(s,3H), 3.17(s,4H),2.96(s,3H ),2.80–2.65(m,9H),2.10–2.06(m,1H).HRMS calcd for C 43 h 49 f 3 N 10 o 8 S,[M+H] + ,923.3480; found 923.3513.

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Abstract

The invention belongs to the technical field of medicines, and provides a compound represented by a general formula (I) and a geometrical isomer or pharmaceutically acceptable salt, hydrate, solvate and prodrug thereof, and preparation methods thereof. The compound has good degradation activity on focal adhesion kinase (FAK). The compound and the geometrical isomer thereof or the pharmaceuticallyacceptable salt, hydrate, solvate or prodrug thereof are represented by the general formula I, wherein Y, L, X, Z and R1 are shown in the claims and the specification.

Description

technical field [0001] The present invention relates to the field of biomedicine and drug synthesis, and relates to a class of compounds targeted to degrade focal adhesion kinase (FAK) proteins, as well as pharmaceutically acceptable salts, hydrates, solvates or prodrugs of the compounds, and their preparation methods and its use as a therapeutic agent, especially as a FAK degradation agent. Background technique [0002] Focal adhesion kinase (FAK) is an intracellular non-receptor tyrosine kinase that belongs to the superfamily of tyrosine protein kinases and was first discovered in 1992 by Schaller et al. The structure of FAK can be divided into four parts: the middle kinase catalytic domain, the amino-terminal FERM (4.1-ezrin-radixin-moesin) domain, the carboxy-terminal local adhesion targeting domain (focal adhesion targeting, FAT) and rich Proline-rich regions (PRRs). Among them, the kinase domain is mainly responsible for regulating the kinase activity of FAK, while t...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/14A61P35/00A61K31/506
CPCC07D401/14A61P35/00
Inventor 赵冬梅王瑞峰程卯生于思佳赵相欣吴天啸秦桥花陈以轩
Owner SHENYANG PHARMA UNIVERSITY
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