Protein kinase degradation agent and application thereof

A technology of selecting compounds, applied in medical preparations containing active ingredients, metabolic diseases, drug combinations, etc.

Pending Publication Date: 2021-08-20
SHANGHAI INST OF ORGANIC CHEM CHINESE ACAD OF SCI +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Currently, there are several non-selective FLT3 inhibitors such as midostaurin, and selective inhibitors such as Gilteritinib, Quizartinib and Crenolanib (CP-868596), etc. On the market or under research, but the rapid emergence of FTT3 mutation resistance is still an unsolved clinical medical problem

Method used

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  • Protein kinase degradation agent and application thereof
  • Protein kinase degradation agent and application thereof
  • Protein kinase degradation agent and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0150] Example 1: N-(4-((7-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl )amino)-2-oxyethyl)-6-methylquinazolin-4-yl)oxy)-3-fluorophenyl)-6-ethyl-1,2-dimethyl-4-oxo Substituent-1,4-dihydroquinoline-3-carboxamide (HS-1)

[0151]

[0152]

[0153] Step 1: Preparation of diethyl 2-(1-(((4-ethylphenyl)amino)ethylene)malonate (2)

[0154]

[0155] p-Ethylaniline (2.42g, 20mmol) and dimethyl acetylmalonate (2.02g, 10mmol) were dissolved in 50mL of n-pentane, a catalytic amount of p-toluenesulfonic acid (20mg) was added, and the mixture was refluxed overnight. Cool down to room temperature, add a small amount of saturated NaHCO 3 , extracted twice with EA, combined the organic phases, washed once with saturated brine, anhydrous Na 2 SO 4 It was dried, filtered and spin-dried, and 2.68 g (87.8%) of solid was obtained by column chromatography. 1 H NMR(400MHz,d6-DMSO)δ10.98(s,1H),7.23(d,J=8.0Hz,2H),7.14(d,J=8.0Hz,2H),4.10(m,4H),2.63 -2.58 (q, J=8.0Hz, 2H), 2....

Embodiment 2

[0177] Example 2: N-(4-((7-((6-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-4-yl) Amino)-6-oxohexyl)oxy)-6-methoxyquinazolin-4-yl)oxy)-3-fluorophenyl)-6-ethyl-1,2-dimethyl-4 -Oxo-1,4-dihydroquinoline-3-carboxamide (HS-2)

[0178]

[0179] The synthesis method is as in Example 1.

[0180] 1H NMR (400MHz, DMSO-d6) δ11.02(d, J=7.3Hz, 2H), 9.80(s, 1H), 8.56(s, 1H), 8.09(d, J=2.2Hz, 1H), 7.96 (dd,J=12.9,2.3Hz,1H),7.86-7.78(m,2H),7.67(dd,J=8.9,2.3Hz,1H),7.59(s,1H),7.51(d,J=1.7 Hz, 3H), 7.48-7.40(m, 2H), 5.15(dd, J=13.3, 5.1Hz, 1H), 4.46-4.31(m, 2H), 4.24(t, J=6.5Hz, 2H), 3.98 (s,3H),3.84(s,3H),2.91(ddd,J=17.7,13.4,5.4Hz,1H),2.78(q,J=7.6Hz,2H),2.65(s,3H),2.60( d,J=17.5Hz,1H),2.43(t,J=7.4Hz,2H),2.35(dd,J=13.1,4.5Hz,1H),2.02(dd,J=12.0,6.5Hz,1H), 1.88(t,J=7.4Hz,2H),1.79-1.67(m,2H),1.60-1.49(m,2H),1.25(t,J=7.5Hz,3H). 13 C NMR (151MHz, DMSO) δ173.93, 173.28, 171.77, 171.51, 168.30, 166.19, 164.55, 155.75, 154.79, 153.17, 152.55, 152.23, 150.84, 149.43, 139.98, 138.689, 139.689...

Embodiment 3

[0181] Example 3: N-(4-((7-((6-((2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindoline-4-yl) Amino)-6-oxohexyl)oxy)-6-methoxyquinazolin-4-yl)oxy)-3-fluorophenyl)-6-ethyl-1,2-dimethyl-4 -Oxo-1,4-dihydroquinoline-3-carboxamide (HS-3)

[0182]

[0183] The synthesis method is as in Example 1.

[0184] 1 H NMR(400MHz,DMSO-d6)δ11.06(s,1H),10.99(s,1H),10.31(s,1H),8.55(s,1H),8.33(d,J=8.3Hz,1H) ,8.09(d,J=2.2Hz,1H),7.97(dd,J=13.0,2.3Hz,1H),7.83(d,J=8.9Hz,1H),7.68(dd,J=8.9,2.3Hz, 1H),7.62-7.54(m,2H),7.53-7.39(m,3H),7.31-7.23(m,1H),5.09(dd,J=13.2,5.2Hz,1H),4.47(d,J= 17.7Hz, 1H), 4.36(d, J=17.7Hz, 1H), 4.22(t, J=6.5Hz, 2H), 3.98(s, 3H), 3.84(s, 3H), 2.89(ddd, J= 17.2,13.6,5.5Hz,1H),2.77(q,J=7.6Hz,2H),2.64(s,4H),2.49-2.34(m,3H),2.06-1.99(m,1H),1.88(t , J=7.4Hz, 2H), 1.76(t, J=7.6Hz, 2H), 1.56(d, J=7.5Hz, 2H), 1.25(s, 3H). 13 CNMR (151MHz, DMSO) δ 173.92, 173.24, 171.72, 171.22, 169.68, 166.19, 164.53, 155.76, 154.79, 153.18, 152.52, 152.24, 150.84, 149.42, 143.08, 138.98, 98, 9) ( J=28....

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Abstract

The invention provides a protein kinase degradation agent and application thereof, and particularly provides a compound with a structure as shown in a formula (I) defined in the description or pharmaceutically acceptable salt thereof, or a stereoisomer or a prodrug molecule thereof. The compound can degrade proteins such as AXL and FLT3 in a targeted ubiquitination manner, so that the compound can be used for treating indications related to abnormal expression of AXL and FLT3 kinase.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to a class of compounds targeting ubiquitination to degrade proteins such as AXL and FLT3, as well as pharmaceutical compositions and applications thereof. Background technique [0002] Protein kinases are key regulators of cellular function, constituting one of the largest and most functionally diverse gene families. Protein kinases direct the movement, localization, and overall function of many proteins through the phosphorylation of substrate proteins and are involved in virtually all cellular activities. Abnormal expression, activation, and localization of protein kinases are closely related to the occurrence and development of various diseases, and are important driving factors for various diseases such as tumors and inflammation. Therefore, the human kinase group is a resource bank of potential therapeutic targets, and the development of drugs targeting kinases will be a ma...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/14A61K31/517A61P9/00A61P3/10A61P9/12A61P21/00A61P25/16A61P25/28A61P35/00A61P35/02
CPCC07D401/14A61P9/00A61P3/10A61P9/12A61P21/00A61P25/16A61P25/28A61P35/00A61P35/02
Inventor 丁克马大为张章贺胜宋志强何蕊白玉黄晶黄维雪周凤涛汪永星
Owner SHANGHAI INST OF ORGANIC CHEM CHINESE ACAD OF SCI
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