Imidazo[1,2-a]pyrazine modulators of adenosine a2a receptor

A technology of stereoisomers and tautomers, which is applied in the field of modulators of adenosine A2A receptors, can solve the problems of reduced cytotoxic activity and other issues

Inactive Publication Date: 2020-02-18
雷沃医疗有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

On the other hand, stimulation of adenosine may also lead to decreased cytotoxic activity, for example, CD8+ lymphocytes can reduce their secretion of IL-2, Th1 cytokines and IFN-γ, while NK cells can produce lower levels of GzmB, NKG2d, CD69 and CD27 [Sitkovsky Trends Immunol 2009;30:102-8]

Method used

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  • Imidazo[1,2-a]pyrazine modulators of adenosine a2a receptor
  • Imidazo[1,2-a]pyrazine modulators of adenosine a2a receptor
  • Imidazo[1,2-a]pyrazine modulators of adenosine a2a receptor

Examples

Experimental program
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Effect test

Embodiment 3

[0876] Example 3: 5-(2,6-Dimethylpyridin-4-yl)-6-phenylimidazo[1,2-a]pyrazin-8-amine

[0877]

[0878] The title compound was synthesized as described in Procedure B, Condition A, wherein (3-chloro-4-hydroxyphenyl)-boronic acid was replaced by 2,6-lutidine-4-boronic acid in step (c), Step (e) was then carried out in a 1:1 mixture of ethanol:water to afford the title compound as a pale yellow solid (18 mg, 17%). ESI-MS: 316.20 [M+H]+. 1 H NMR (300 MHz, DMSO-d6) δ 7.52 (s, 1H), 7.45 (s, 1H), 7.33-7.15 (m, 7H), 7.02 (s, 2H), 2.36 (s, 6H).

Embodiment 4

[0879] Example 4: 5-[2-methyl-6-(trifluoromethyl)pyridin-4-yl]-6-phenylimidazo[1,2-a]pyrazin-8-amine

[0880]

[0881] The title compound was synthesized as described in Procedure C, wherein phenylboronic acid was substituted for 2-furylboronic acid in step (c), and in DME:H 2 The reaction is carried out in a 4:1 mixture of O and step (d) is carried out at 60°C, in step (e) with 2-methyl-4-(tetramethyl-1,3,2-dioxaborin Alk-2-yl)-6(trifluoromethyl)pyridine (Procedure A1) in place of (3-chloro-4-hydroxyphenyl)-boronic acid afforded the title compound as formate salt (beige solid, 9 mg, 27 %). ESI-MS: 370.15 [M+H]+. 1 H NMR (400MHz, DMSO-d6) δ7.70(s, 1H), 7.67(d, J=1. 1 Hz, 1H), 7.58 (d, J = 1.0 Hz, 1H), 7.50 (s, 1H), 7.33 (br s, 2H), 7.26 (s, 5H), 2.54 (s, 3H).

Embodiment 5

[0882] Example 5: 4-[8-bromo-6-(furan-2-yl)imidazo[1,2-a]pyrazin-5-yl]-2-chlorophenol

[0883]

[0884] The title compound was synthesized following the procedure described in Procedure B, Condition A, wherein 2-furanboronic acid was substituted for phenylboronic acid in step (b), and this step was carried out overnight, and CHCl 3 : THF in a 3:1 mixture The reaction described in step (d) was carried out for 15 hours, and then chloroacetaldehyde was replaced by 2-bromo-1,1-dimethoxyethane in step (e) without Step (f), the title compound was obtained as a pale yellow solid (8 mg, 7%). ESI-MS: 391.4 [M+H]+. 1 H NMR (300MHz, CD3OD) δ9.05(s, 1H), 7.80(s, 1H), 7.62-7.56(m, 1H), 7.56-7.50(m, 1H), 7.33-7.27(m, 1H), 7.22-7.15 (m, 1H), 6.46-6.36 (m, 2H).

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Abstract

The present invention relates to the compound of formula (I) and salts, stereoisomers, tautomers, isotopologues,or N-oxides thereof. The present invention is further concerned with the use of such a compound or salt, stereoisomer, tautomer, isotopologues,or N-oxide thereof as medicament and a pharmaceutical composition comprising said compound.

Description

technical field [0001] The present invention relates to substituted imidazo[1,2-a]pyrazine compounds and their salts, stereoisomers, tautomers, isotopomers or N-oxides. The present invention also relates to the use of substituted imidazo[1,2-a]pyrazine compounds or their salts, stereoisomers, tautomers, isotopomers or N-oxides as medicines and compositions comprising The pharmaceutical composition of said compound. Background technique [0002] Cancer cells produce large numbers of mutated proteins, called neoantigens, which, when presented to the immune system, can lead to the natural eradication of tumors. However, to counteract this process, cancer cells also produce specific immunosuppressive metabolites that alter the microenvironment and impair immune cell function. One of the key metabolites that work in this way is adenosine. Its immunosuppressive function is mediated by adenosine receptors, which are members of the G protein-coupled receptor (GPCR) family and pos...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04A61K31/4985A61P35/00A61P25/00
CPCC07D487/04A61K45/06A61K31/4985A61P35/00A61P25/16A61P25/28A61K31/5377C07D519/00
Inventor 阿内塔·博博夫斯卡(内维特科夫卡)迈克尔·盖尔佐夫斯基马特乌斯·诺瓦克克劳德·科曼德尔乔安娜·塞雷梅塔-斯皮萨克马金·诺沃罗茨基艾丽西亚·奥巴拉安娜·杰拉克伊沃纳·洛津斯卡马塞琳娜·杜德克(内塞德拉克)安妮塔·雅尼加贾塞克·罗伊斯马雷克·沃诺夫斯基玛格达莱纳·扎斯塔沃纳亚当·拉齐米尔斯基马特乌斯·斯威斯基朱利安·扎克曼查尔斯-亨利·法布里提乌斯罗德里克·艾伦·波特乔安娜·福特
Owner 雷沃医疗有限公司
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