Non brain penetrant A2A inhibitors and methods for use in the treatment of cancers

Inventor: Stefano Crosignani (Nivelles, BE)

Assignee: ITEOS BELGIUM SA

C07D487/14 C07D487/04

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Quick Facts

Patent No.: US 11,427,594
App. No.: 16/584,596
Granted: Aug 30, 2022
Kind: B2

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Abstract

The present invention relates to compounds of Formula (I) or pharmaceutically acceptable salts thereof. The invention further relates to the use of the compounds of Formula (I) as A2A inhibitors. The invention also relates to the use of the compounds of Formula (I) for the treatment and/or prevention of proliferative disorders, including cancers.

Claims (46)

1. A method of treating cancer, comprising administering to a patient in need thereof a therapeutically acceptable effective amount of compound selected from the group consisting of

(S)—N5-(2-(4-(2,4-difluoro-5-(2-(methylsulfinyl)ethoxy)phenyl)piperazin-1-yl)ethyl)-2-(furan-2-yl)-N5-methyl-[1,2,4]triazolo[1,5-a][1,3,5]triazine-5,7-diamine;

(R)—N5-(2-(4-(2,4-difluoro-5-(2-(methylsulfinyl)ethoxy)phenyl)piperazin-1-yl)ethyl)-2-(furan-2-yl)-N5-methyl-[1,2,4]triazolo[1,5-a][1,3,5]triazine-5,7-diamine;

5-(4-(2-(5-amino-8-(furan-2-yl)-1-methyl-2-oxo-1H-[1,2,4]triazolo[5,1-i]purin-3(2H)-yl)ethyl)piperazin-1-yl)-2,4-difluoro-N-methylbenzamide;

5-(4-(2-(5-amino-2-(furan-2-yl)-7H-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidin-7-yl)ethyl)piperazin-1-yl)-2,4-difluoro-N-methylbenzamide;

N5-(2-(4-(2,4-difluoro-5-(2-(methylsulfonyl)ethoxy)phenyl)piperazin-1-yl)ethyl)-2-(furan-2-yl)-N5-methyl-[1,2,4]triazolo[1,5-a][1,3,5]triazine-5,7-diamine;

N5-(2-(4-(2,4-difluoro-5-(2-(methylsulfonyl)ethoxy)phenyl)piperazin-1-yl)ethyl)-2-(furan-2-yl)-[1,2,4]triazolo[1,5-a][1,3,5]triazine-5,7-diamine;

(S)-5-amino-3-(2-(4-(2,4-difluoro-5-(2-(methylsulfinyl)ethoxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)-1-methyl-1H-[1,2,4]triazolo[5,1-i]purin-2(3H)-one;

(R)-5-amino-3-(2-(4-(2,4-difluoro-5-(2-(methylsulfinyl)ethoxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)-1-methyl-1H-[1,2,4]triazolo[5,1-i]purin-2(3H)-one;

5-amino-3-(2-(4-(2,4-difluoro-5-(2-(methylsulfonyl)ethoxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)-1-methyl-1H-[1,2,4]triazolo[5,1-i]purin-2(3H)-one;

(S)—N5-(2-(4-(2,4-difluoro-5-(2-(methylsulfinyl)ethoxy)phenyl)piperazin-1-yl)ethyl)-2-(furan-2-yl)-[1,2,4]triazolo[1,5-a][1,3,5]triazine-5,7-diamine;

(R)—N5-(2-(4-(2,4-difluoro-5-(2-(methylsulfinyl)ethoxy)phenyl)piperazin-1-yl)ethyl)-2-(furan-2-yl)-[1,2,4]triazolo[1,5-a][1,3,5]triazine-5,7-diamine;

(S)-7-(2-(4-(2,4-difluoro-5-(2-(methylsulfinyl)ethoxy)phenyl)piperazin-1-yl)ethyl)-2-(furan-2-yl)-7H-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidin-5-amine;

(R)-7-(2-(4-(2,4-difluoro-5-(2-(methylsulfinyl)ethoxy)phenyl)piperazin-1-yl)ethyl)-2-(furan-2-yl)-7H-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidin-5-amine;

(1s,4s)-4-(5-(4-(2-((7-amino-2-(furan-2-yl)-[1,2,4]triazolo[1,5-a][1,3,5]triazin-5-yl)amino)ethyl)piperazin-1-yl)-2,4-difluorophenoxy)tetrahydro-2H-thiopyran 1-oxide;

4-(5-(4-(2-((7-amino-2-(furan-2-yl)-[1,2,4]triazolo[1,5-a][1,3,5]triazin-5-yl)amino)ethyl)piperazin-1-yl)-2,4-difluorophenyl)thiomorpholine 1-oxide;

(R)—N5-(2-(4-(2,4-difluoro-5-(methylsulfinyl)phenyl)piperazin-1-yl)ethyl)-2-(furan-2-yl)-[1,2,4]triazolo[1,5-a][1,3,5]triazine-5,7-diamine;

(S)—N5-(2-(4-(2,4-difluoro-5-(methylsulfinyl)phenyl)piperazin-1-yl)ethyl)-2-(furan-2-yl)-[1,2,4]triazolo[1,5-a][1,3,5]triazine-5,7-diamine;

(4-(4-(2-((7-amino-2-(furan-2-yl)-[1,2,4]triazolo[1,5-a][1,3,5]triazin-5-yl)amino)ethyl)piperazin-1-yl)-3-fluorophenyl)(1-oxidothiomorpholino)methanone;

(1s,4s)-4-(4-(4-(2-((7-amino-2-(furan-2-yl)-[1,2,4]triazolo[1,5-a][1,3,5]triazin-5-yl)amino)ethyl)piperazin-1-yl)-3-fluorophenoxy)tetrahydro-2H-thiopyran 1-oxide;

5-amino-3-(2-(4-(2-fluoro-4-(2-(methylsulfinyl)ethoxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)-1-methyl-1H-[1,2,4]triazolo[5,1-i]purin-2(3H)-one; and

5-amino-3-(2-(4-(2,4-difluoro-5-((2-oxopyrrolidin-3-yl)oxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)-1-methyl-1H-[1,2,4]triazolo[5,1-i]purin-2(3H)-one;

or a pharmaceutically acceptable salt thereof.

2. A method of modulating A2A activity in a patient in need thereof, comprising administering to said patient a therapeutically acceptable effective amount of compound selected from the group consisting of