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PROTAC small molecular compound and application thereof

A technology of compounds and deuterated compounds, applied in medical preparations with non-active ingredients, medical preparations containing active ingredients, drug combinations, etc., can solve problems such as unclear specific mechanisms

Pending Publication Date: 2021-03-26
ZHUHAI YUFAN BIOTECHNOLOGIES CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This complex can ubiquitinate a series of proteins, but the specific mechanism is not clear

Method used

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  • PROTAC small molecular compound and application thereof
  • PROTAC small molecular compound and application thereof
  • PROTAC small molecular compound and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0209] The preparation of embodiment 1 compound C1

[0210]

[0211] In a 250ml round bottom flask, add 3-hydroxyphthalic anhydride (2g, 12.2mmol, 1.0equiv) and 3-amino-2,6-piperidinedione hydrochloride (2g, 12.2mmol, 1.0equiv) and An appropriate amount of toluene was added to the reaction system after being thoroughly mixed with triethylamine (1860 ul, 13.4 mmol, 1.1 equiv). After heating to reflux for 12h, stop heating. After the reaction system returned to room temperature, toluene was removed on a rotary evaporator. The crude product was purified by silica gel column chromatography (V methanol: V dichloromethane = 1:40) to obtain the final product 2-(2,6-dioxopiperidin-3-yl)-4-hydroxyiso-1 , 3-diketone 1.9032g, pale yellow solid, yield 57%.

[0212] NMR: 1 H NMR (400MHz, DMSO) δ11.15(s, 1H), 11.07(s, 1H), 7.62(t, J=7.7Hz, 1H), 7.29(d, J=7.1Hz, 1H), 7.22(d ,J=8.4Hz,1H),5.05(dd,J=12.8,5.1Hz,1H),3.04–2.73(m,1H),2.68–2.34(m,1H),2.17–1.73(m,1H). 13 C NMR (100MHz, DMSO)...

Embodiment 2

[0222] The preparation of embodiment 2 compound C2

[0223]

[0224] Dissolve C1 (12mg, 0.014mmol, 1.0equiv) in an appropriate amount of DMF, add potassium carbonate (3.9mg, 0.021mmol, 1.5equiv) and iodomethane (2.4mg, 0.017mmol, 1.2equiv) successively, stir overnight at room temperature, and wait After the reaction is complete, add an appropriate amount of ethyl acetate to dilute, extract with saturated saline for 3 times, take the organic phase and add anhydrous sodium sulfate to dry, filter through a sand core funnel, spin dry, and purify by silica gel column chromatography (V (methanol): V (di Chloromethane)=1:20) to obtain 2-58.2 mg of the final product, with a yield of 68%, LC-MS: m / z=861.

[0225] NMR: 1 H NMR (400MHz, DMSO) δ7.88(s, 1H), 7.84–7.77(m, 1H), 7.76(d, J=1.5Hz, 1H), 7.56–7.48(m, 3H), 7.45–7.36( m,2H),7.36–7.30(m,2H),6.09(s,2H),5.46(s,1H),5.21(s,2H),5.15(dd,J=13.0,5.4Hz,1H),4.42 (d,J=12.9Hz,1H),4.20(t,J=6.3Hz,2H), 3.93(d,J=13.5Hz,1H),3.29–3.09(m,3H),2.9...

Embodiment 3

[0226] The preparation of embodiment 3 compound C3

[0227]

[0228] 2-(2,6-dioxopiperidin-3-yl)-4-hydroxyiso-1,3-dione (300mg, 1.1mmol, 1.0equiv), potassium iodide (18.2mg, 0.1mmol, 0.1equiv ) and sodium bicarbonate (183.8 mg, 2.2 mmol, 2.0 equiv) were dissolved in DMF, and 10-bromo-1-decanol (314 mg, 1.32 mmol, 1.2 equiv) was added to the reaction system. Then heat the reaction system to 80°C, react overnight, stop heating, wait for the reaction system to cool down to room temperature, add an appropriate amount of ethyl acetate to dilute, and extract with saturated saline for 5 times, take the organic phase and add anhydrous sodium sulfate to dry, filter, spin Dry. The crude product was purified by silica gel column chromatography (V (petroleum ether): V (ethyl acetate) = 1: 2) to obtain 253.3 mg of the final product with a yield of 53%, LC-MS: m / z = 431.

[0229]

[0230] Dissolve 3-1 (190mg, 0.32mmol, 1.0equiv), PCC (190mg, 0.64mmol, 2.0equiv) in an appropriate amo...

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PUM

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Abstract

The invention discloses a compound with a general formula I, or a pharmaceutically acceptable salt, a stereoisomer, an ester, a prodrug, a solvate and a deuterated compound thereof, a composition containing the compound with the general formula I, and application of the compound with the general formula I or the pharmaceutically acceptable salt, stereoisomer, ester, prodrug, solvate and deuteratedcompound thereof in preparation of medicines for treating diseases related to serine / threonine kinase family (MAP4Ks), preferably medicines for treating diseases related to hematopoietic stem cell kinase 1 (HPK1).

Description

technical field [0001] The invention belongs to the field of biomedicine, and in particular relates to a PROTAC small molecule compound and its application. Background technique [0002] The protein degradation targeting chimera (PROTAC) technology originated from the discovery of the protein degradation process regulated by ubiquitin (Ub) by scientists. Eukaryotic cells are constantly struggling to maintain proper protein levels, producing and degrading thousands of proteins at any one time. A key factor in maintaining protein balance is a small protein molecule called ubiquitin. When it is linked to proteins, it causes these proteins to be transported to the proteasome for degradation. [0003] Targeted protein degradation is an emerging direction in the field of drug development. Protein-targeted degradation drugs try to design small molecules into a new type of drug. The role of traditional small molecules is to block the function of proteins, while the role of protei...

Claims

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Application Information

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IPC IPC(8): C07D417/14A61P29/00A61P35/00A61P35/02A61P37/06A61P13/12A61P19/02A61P17/06A61P3/10A61K31/4545
CPCC07D417/14A61P29/00A61P35/00A61P35/02A61P37/06A61P13/12A61P19/02A61P17/06A61P3/10A61K45/06A61K47/55A61K47/545A61K38/177A61K38/1774A61K38/1841
Inventor 廖学斌孙叔豪林星雨刘亚慧
Owner ZHUHAI YUFAN BIOTECHNOLOGIES CO LTD
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