Imidazopyrazine derivatives, process for preparation thereof, and their uses as luciferins

Patent metadata

Field	Value
Publication number	US-11938199-B2
Application number	US-201816607058-A
Country	US
Kind code	B2
Filing date	Apr 30, 2018
Priority date	Apr 28, 2017
Publication date	Mar 26, 2024
Grant date	Mar 26, 2024

Abstract

The present invention is in the field of bioluminescence in biology and/or medicine. In particular, the invention provides imidazopyrazine derivatives, processes for preparation thereof, and their uses as luciferins.

First claim

The invention claimed is:

1. A kit comprising:
i) A compound of following formula:

wherein:
R 1 represents H or a group selected from C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 6 -C 10 aryl, aralkyl and C 5 -C 10 -membered heteroaryl groups, said C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 6 -C 10 aryl, aralkyl and C 5 -C 10 -membered heteroaryl groups are optionally substituted by at least one Y 1 group;
R 2 represents a group selected from C 6 -C 10 aryl and C 5 -C 10 -membered heteroaryl groups, said C 6 -C 10 aryl and C 5 -C 10 -membered heteroaryl groups are optionally substituted by at least one Y 2 group;
or R 1 and R 2 together form with the two carbon atom to which they are respectively attached a C 5 -C 7 cycloalkene group, a C 4 -C 7 heterocycloalkene group, or a C 6 -C 10 arene, said C 5 -C 7 cycloalkene group and C 4 -C 7 heterocycloalkene groups are fused with a C 6 -C 10 arene, said C 5 -C 7 cycloalkene group, C 4 -C 7 heterocycloalkene group, C 6 -C 10 arene, C 5 -C 7 cycloalkene group and C 4 -C 7 heterocycloalkene groups are optionally substituted by at least one Y 12 group;
R 3 represents H, a C 1 -C 6 alkyl, an aralkyl group, a hetaralkyl group or a heterocycloalkyl-CH 2 — group, said C 1 -C 6 alkyl, aralkyl group, hetaralkyl group and heterocycloalkyl-CH 2 — group are optionally substituted by at least one Y 3 group;
R 4 represents H or a group selected from C 1 -C 6 alkyl and C 3 -C 7 cycloalkyl groups, said C 1 -C 6 alkyl and C 3 -C 7 cycloalkyl groups are optionally substituted by at least one Y 4 group;
R 5 represents a —C(═O)R a group or a —C(═O)OR a group, said C(═O)R a group and —C(═O)OR a group are optionally substituted by at least one Y 5 group;
R a represents H, a C 1 -C 6 alkyl group, a C 3 -C 7 cycloalkyl group, a C 6 -C 10 aryl, or an aralkyl group, said C 1 -C 6 alkyl group, C 3 -C 7 cycloalkyl group, C 6 -C 10 aryl, and aralkyl group are optionally substituted by at least one Y a group;
Z represents a C 6 -C 10 aryl, a C 5 -C 10 -membered heteroaryl groups, a C 1 -C 6 alkyl, a C 3 -C 7 cycloalkyl, a C 4 -C 7 heterocycloalkyl, said C 6 -C 10 aryl, C 5 -C 10 -membered heteroaryl groups, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl and C 4 -C 7 heterocycloalkyl are optionally substituted by at least one Y Z group;
said Y 1 , Y 2 , Y 12 , Y 3 , Y 4 , Y 5 , Y a and Y Z groups are each independently selected from:
a C 1 -C 6 alkyl;
a C 3 -C 7 cycloalkyl;
a C 6 -C 10 aryl;
a C 5 -C 10 -membered heteroaryl group;
an halogen;
a —CF 3 group;
a —CN group;
a —OR i group;
a —OSO 3 H group;
a —NR i R ii group;
a guanidinyl group;
a —C(═O)OR a group, R a is as defined above;
R i and R ii each independently represent H, a C 1 -C 6 alkyl group, a C 3 -C 10 cycloalkyl group, an aralkyl group; or together form with the nitrogen atom to which they are attached a C 4 -C 7 heterocycloalkyl group;
and

ii) a solution comprising a strong acid.

2. A compound of following formula:

wherein:
R 1 represents H or a group selected from C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 6 -C 10 aryl, aralkyl and C 5 -C 10 -membered heteroaryl groups, said C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 6 -C 10 aryl, aralkyl and C 5 -C 10 -membered heteroaryl groups are optionally substituted by at least one Y 1 group;
R 2 represents a group selected from C 6 -C 10 aryl and C 5 -C 10 -membered heteroaryl groups, said C 6 -C 10 aryl and C 5 -C 10 -membered heteroaryl groups are optionally substituted by at least one Y 2 group;
or R 1 and R 2 together form with the two carbon atom to which they are respectively attached a C 5 -C 7 cycloalkene group, a C 4 -C 7 heterocycloalkene group, or a C 6 -C 10 arene, said C 5 -C 7 cycloalkene group and C 4 -C 7 heterocycloalkene groups are fused with a C 6 -C 10 arene, said C 5 -C 7 cycloalkene group, C 4 -C 7 heterocycloalkene group, C 6 -C 10 arene, C 5 -C 7 cycloalkene group and C 4 -C 7 heterocycloalkene groups are optionally substituted by at least one Y 12 group;
R 3 represents H, a C 1 -C 6 alkyl, an aralkyl group, a hetaralkyl group or a heterocycloalkyl-CH 2 — group, said C 1 -C 6 alkyl, aralkyl group, hetaralkyl group and heterocycloalkyl-CH 2 — group are optionally substituted by at least one Y 3 group;
R 4 represents H or a group selected from C 1 -C 6 alkyl and C 3 -C 7 cycloalkyl groups, said C 1 -C 6 alkyl and C 3 -C 7 cycloalkyl groups are optionally substituted by at least one Y 4 group;
R 5 represents a —C(═O)R a group or a —C(═O)OR a group, said C(═O)R a group and —C(═O)OR a group are optionally substituted by at least one Y 5 group;
R a represents H, a C 1 -C 6 alkyl group, a C 3 -C 7 cycloalkyl group, a C 6 -C 10 aryl, or an aralkyl group, said C 1 -C 6 alkyl group, C 3 -C 7 cycloalkyl group, C 6 -C 10 aryl, and aralkyl group are optionally substituted by at least one Y a group;
Z represents a C 6 -C 10 aryl, a C 5 -C 10 -membered heteroaryl groups, a C 1 -C 6 alkyl, a C 3 -C 7 cycloalkyl, a C 4 -C 7 heterocycloalkyl, said C 6 -C 10 aryl, C 5 -C 10 -membered heteroaryl groups, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl and C 4 -C 7 heterocycloalkyl are optionally substituted by at least one Y Z group;
said Y 1 , Y 2 , Y 12 , Y 3 , Y 4 , Y 5 , Y a and Y Z groups are each independently selected from:
a C 1 -C 6 alkyl;
a C 3 -C 7 cycloalkyl;
a C 6 -C 10 aryl;
a C 5 -C 10 -membered heteroaryl group;
an halogen;
a —CF 3 group;
a —CN group;
a —OR i group;
a —OSO 3 H group;
a —NR i R ii group;
a guanidinyl group;
a —C(═O)OR a group, R a is as defined above;
R i and R ii each independently represent H, a C 1 -C 6 alkyl group, a C 3 -C 10 cycloalkyl group, an aralkyl group; or together form with the nitrogen atom to which they are attached a C 4 -C 7 heterocycloalkyl group;
with the proviso that when R 1 and R 4 represent H, then:
R 2 is not unsubstituted phenyl, or 4-hydroxy-phenyl, or
R 3 is not unsubstituted benzyl, or
Z is not unsubstituted phenyl, 4-hydroxy-phenyl, or unsubstituted furan.

3. A compound of following formula:

wherein:
R 1 represents H or a group selected from C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 6 -C 10 aryl, aralkyl and C 5 -C 10 -membered heteroaryl groups, said C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 6 -C 10 aryl, aralkyl and C 5 -C 10 -membered heteroaryl groups are optionally substituted by at least one Y 1 group;
R 2 represents a group selected from C 6 -C 10 aryl and C 5 -C 10 -membered heteroaryl groups, said C 6 -C 10 aryl and C 5 -C 10 -membered heteroaryl groups are optionally substituted by at least one Y 2 group;
R 3 represents an aralkyl group, said aralkyl group is optionally substituted by at least one Y 3 group;
R 4 represents H or a group selected from C 1 -C 6 alkyl and C 3 -C 7 cycloalkyl groups, said C 1 -C 6 alkyl and C 3 -C 7 cycloalkyl groups are optionally substituted by at least one Y 4 group;
Z represents a prow of following formula:

Assignees

• Pasteur Institut
• Centre Nat Rech Scient

Inventors

• Janin Yves-Louis
• Coutant Eloi Paul
• Hervin Vincent
• Gagnot Glwadys
• Jacob Yves
• Goyard Sophie
• Rose Thierry

Classifications

• A61K49/0013 Primary

  Luminescence · CPC title

• C07D487/04 Primary

  Ortho-condensed systems · CPC title

• G01N21/763

  Bioluminescence · CPC title

• G01N33/573

  for enzymes or isoenzymes · CPC title

• C07D241/16

  Halogen atoms; Nitro radicals · CPC title