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Preparation method and application of pyrazino[2,3-c]quinoline-2(1H)-one compounds used as mTOR inhibitors

A compound and selected technology, applied in the fields of anti-inflammatory agent, organic chemistry, drug combination, etc., can solve the problem that the regulation mechanism of mTORC2 is not very clear.

Active Publication Date: 2018-12-07
NANKAI UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Since there is no specific inhibitor for mTORC2, the regulatory mechanism of mTORC2 is not very clear

Method used

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  • Preparation method and application of pyrazino[2,3-c]quinoline-2(1H)-one compounds used as mTOR inhibitors
  • Preparation method and application of pyrazino[2,3-c]quinoline-2(1H)-one compounds used as mTOR inhibitors
  • Preparation method and application of pyrazino[2,3-c]quinoline-2(1H)-one compounds used as mTOR inhibitors

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preparation example Construction

[0052] The starting materials used in the preparation of the compounds of the present invention are known, can be prepared according to known methods, or are commercially available.

[0053] The invention also relates to novel intermediates and / or starting materials. Particular preference is given to reaction conditions and novel intermediates which are the same or similar to those mentioned in the examples.

[0054] Both intermediates and final products can be worked up and / or purified according to conventional methods including pH adjustment, extraction, filtration, drying, concentration, chromatography, trituration, crystallization, and the like.

[0055] In addition, the compounds of the present invention can be prepared by various methods known in the art or variations on the methods described herein.

[0056] The following examples are only used to illustrate the present invention, and do not limit the protection scope of the present invention in any way.

Embodiment 1

[0057] Example 1: 2-(4-(9-(6-aminopyridin-3-yl)-8-fluoro-2-oxopyrazino[2,3-c]quinoline-1(2 H )-yl) piperidin-1-yl) preparation of acetonitrile

[0058]

[0059] Step 1.1: Preparation of tert-butyl 4-((6-bromo-7-fluoro-3-nitroquinolin-4-yl)amino)piperidine-1-carboxylate

[0060]

[0061]In a 250mL two-necked bottle, 6-bromo-4-chloro-7-fluoro-3-nitroquinoline (20g, 65.5 mmol) and tert-butyl 4-aminopiperidine-1-carboxylate (14.4g, 72.0 mmol) was dissolved in 150 mL DMF to obtain a yellow solution. DIEA (22.5 mL) was added and stirred overnight at room temperature. Add 1 L of water and continue stirring for 0.5 hours, then filter, wash the filter residue with water and ethanol until the filtrate is colorless, and dry under reduced pressure at 60 degrees Celsius to obtain 21 g of a yellow solid with a yield of 68.4%. 1 H NMR (400 MHz, Chloroform- d ) δ 9.38(d, J = 8.6 Hz, 1H), 9.34 (s, 1H), 8.36 (d, J = 7.0 Hz, 1H), 7.68 (d, J = 9.0Hz, 1H), 4.29 – 4.16 (m, 1H), 4.06...

Embodiment 2

[0077] Example 2: (R)-2-(3-(9-(6-aminopyridin-3-yl)-8-fluoro-2-oxopyrazino[2,3-c]quinoline-1( 2 H )-yl) piperidin-1-yl) preparation of acetonitrile

[0078]

[0079] Step 2.1: Preparation of (R)-tert-butyl 3-((6-bromo-7-fluoro-3-nitroquinolin-4-yl)amino)piperidine-1-carboxylate

[0080]

[0081] Referring to step 1.1, the yield was 82%. 1 H NMR (400 MHz, Chloroform- d ) δ 9.51 (d, J = 8.7 Hz,1H), 9.34 (s, 1H), 8.42 (d, J = 7.0 Hz, 1H), 7.68 (d, J = 9.0 Hz, 1H), 4.26(tp, J = 7.0, 3.3 Hz, 1H), 3.80 (d, J = 13.4 Hz, 1H), 3.46 (q, J = 6.2 Hz,3H), 2.18 – 2.08 (m, 1H), 1.93 – 1.78 (m, 2H), 1.71 – 1.60 (m, 1H), 1.43 (s,9H); 13 C NMR (101 MHz, CDCl 3 ) Δ 162.06, 159.50, 154.76, 151.66, 151.54, 149.03,148.61, 131.25, 127.57, 117.63, 115.99, 115.77, 109.10, 108.86, 80.70, 53.72,31.64, 22.48.

[0082] Step 2.2: Preparation of tert-butyl (R)-3-((3-amino-6-bromo-7-fluoroquinolin-4-yl)amino)piperidine-1-carboxylate

[0083]

[0084] Referring to step 1.2, the yiel...

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Abstract

The invention discloses a preparation method and application of pyrazino[2,3-c]quinoline-2(1H)-one compounds used as mTOR inhibitors. The invention relates to the method for preparing substituted pyrazino[2,3-c]quinoline-2(1H)-one compounds (formula I) or a pharmaceutically acceptable salt thereof. The compounds are suitable for treating proliferative diseases (such as benign neoplasm, caner, inflammatory diseases, autoimmune diseases and diabetic retinopathy) and metabolic diseases. The invention provides novel small molecules for inhibiting one or more of mTORC1, mTORC2 and PI3K-related protein.

Description

technical field [0001] The present invention relates to novel pyrazino[2,3-c]quinoline-2(1 H )-ketones and pharmaceutical compositions thereof, especially pyrazino[2,3-c]quinoline-2 (1 H )-ketones and pharmaceutical compositions thereof. The invention also relates to methods and uses of these compounds and compositions in the treatment of hyperproliferative disorders (eg, benign neoplasms, cancer, inflammatory diseases, autoimmune diseases, diabetic retinopathy) and metabolic diseases. Background technique [0002] mTOR is a highly conserved serine / threonine kinase. It belongs to the phosphoinositide 3-kinase-related kinase family (PIKK) and is ubiquitously expressed in eukaryotic cells. According to different protein compositions, mTOR can be divided into two categories, namely, mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2), which have different biological functions. The two isoforms of mTOR play important roles in cellular regulation. mTORC1 affects cell prolife...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/04A61K31/4985A61K31/5377A61K31/506A61P35/00A61P29/00A61P37/02A61P9/10A61P3/10A61P3/00
CPCC07D471/04Y02P20/55
Inventor 向荣范艳郭庆祥李永涛张超黄志王鑫刘艳华
Owner NANKAI UNIV
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