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Bicyclic heterocyclic derivatives, their preparation and therapeutic use

A compound and heteroaryl technology, applied in the fields of bicyclic heterocyclic derivatives, their preparation and therapeutic use, can solve the problems of limited cancer subgroups, lower rapalogue efficacy than expected, etc.

Active Publication Date: 2017-05-31
SANOFI SA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, despite some promising results, the efficacy of rapalogue in cancer therapy remains below expectations and appears to be limited to cancer subgroups

Method used

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  • Bicyclic heterocyclic derivatives, their preparation and therapeutic use
  • Bicyclic heterocyclic derivatives, their preparation and therapeutic use
  • Bicyclic heterocyclic derivatives, their preparation and therapeutic use

Examples

Experimental program
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preparation example Construction

[0293] The reaction scheme for the preparation of compounds of formula (XLI) via steps f) to k) is shown in Scheme 4 below (in an embodiment using compounds of formula (CII) in step k).

[0294]

[0295] Option 4 : Reaction scheme for the preparation of compounds of formula (XLI) starting from compounds of formula (XIII) via steps f) to k).

[0296] The method for preparing the above-mentioned compound of formula (XIII) carried out in the above-mentioned step c) or f) typically comprises the following steps:

[0297] a) make the following formula (XI) compound nucleophilic attack following formula (X) compound, obtain following formula (XII) compound,

[0298] Described formula (XI) is:

[0299]

[0300] where m, R 2 , R 3 and R 4 as defined above,

[0301] Described formula (X) is:

[0302]

[0303] LG 2 as defined above and LG 1 and LG 4 is independently a leaving group, such as a halogen atom such as a chlorine atom,

[0304] Described formula (XII) is: ...

Embodiment 1

[0477] 1-{4-[6-Ethyl-8,8-dimethyl-2-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-5-oxo- Synthesis of 5,6,7,8-tetrahydro-9-oxa-1,3,6-triazabenzocyclohepten-4-yl]-2-fluorophenyl}-3-methylurea

[0478]

[0479] Step 1.1: (preparation of formula (X) compound)

[0480] 4,6-Dichloro-2-methylthiopyrimidine-5-carbonyl chloride

[0481]

[0482]10 g of 4,6-dichloro-2-methylthiopyrimidine-5-carboxylic acid (41.83 mmol) were placed in 61 ml of thionyl chloride (836.54 mmol) under stirring. After 18 hours at 80° C., the thionyl chloride was distilled off and the residue was taken up twice with 15 ml of toluene and concentrated, yielding 10.77 g of 4,6-dichloro-2-methylthiopyrimidine-5-carbonyl chloride.

[0483] Step 1.2: (which corresponds to step a))

[0484] 4,6-Dichloro-2-methylthiopyrimidine-5-carboxylic acid ethyl-(2-hydroxy-2-methylpropyl)amide

[0485]

[0486] 4.9 g of 1-(ethylamino)-2-methylpropan-2-ol (41.82 mmol) and 17.5 ml of triethylamine (125.46 mmol) were placed i...

Embodiment 2

[0521] 1-{4-[6-Ethyl-8,8-dimethyl-2-((S)-3-methylmorpholin-4-yl)-5-oxo-5,6,7,8 -Synthesis of tetrahydro-9-oxa-1,3,6-triazabenzocyclohepten-4-yl]-2-fluorophenyl}-3-methylurea

[0522]

[0523] Step 2.1: (which corresponds to step e))

[0524] {4-[6-Ethyl-8,8-dimethyl-2-((S)-3-methylmorpholin-4-yl)-5-oxo-5,6,7,8-tetra tert-Butyl Hydrogen-9-Oxa-1,3,6-Triazabenzocyclohepten-4-yl]-2-fluorophenyl}carbamate

[0525]

[0526] 2.5 g of [4-(6-ethyl-2-methanesulfonyl-8,8-dimethyl-5-oxo-5,6,7,8-tetrahydro-9-oxa-1,3 , 6-Triazabenzocyclohepten-4-yl)-2-fluorophenyl]carbamate (19.66 mmol) in 20 ml of dioxane was placed in 4 microwave tubes respectively. A quarter of (S)-3-methylmorpholine (98.32 mmol) was added to each tube separately. The tubes were heated in a Biotage microwave machine at 100°C for 2 hours. The reaction medium is filtered and rinsed with MeOH. The solid was washed successively with water, acetonitrile and pentane. 3.7 g of {4-[6-ethyl-8,8-dimethyl-2-((S)-3-meth...

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Abstract

The present invention relates to a bicyclic heterocyclic derivative of general formula (I), its preparation method and therapeutic use.

Description

technical field [0001] The present invention relates to bicyclic heterocyclic derivatives and their preparation and therapeutic use. Background technique [0002] mTOR (mammalian target of rapamycin), also known as FRAP (FKBP12 and rapamycin-associated protein), is a 289-kDa serine / Threonine kinase, but mTOR does not phosphorylate phospholipids. [0003] The protein contains several domains including a C-terminal kinase domain, FKBP12-rapamycin binding domain, 20 N-terminal HEAT repeats involved in protein-protein interactions, FAT (FRAP-ATM-TRRAP ) domain and a C-terminal FAT domain, which are also present in other PIKKs (Wullschleger et al. (2006) Cell, 124, 471-484). [0004] The kinase mTOR is not only an important regulator of cell growth and proliferation, but also plays an important role in cell metabolism and angiogenesis. mTOR is activated by the PI3K / Akt axis and in turn phosphorylates downstream effectors of the PI3K / Akt signaling pathway, specifically ribosom...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D498/04A61K31/519
CPCC07D498/04C07D519/00A61P11/00A61P25/00A61P25/28A61P27/02A61P27/16A61P29/00A61P3/04A61P33/00A61P35/00A61P37/00A61P37/02A61P43/00A61P9/00A61P3/10A61K31/519
Inventor A·布朗O·克雷斯平Y·福里彻G·马西尼亚克N·马齐特E·尼古莱C·帕斯卡尔B·维瓦特F·维维安尼
Owner SANOFI SA