IP Library › Granted Patent US 10,189,782

Granted Patent B2

US 10,189,782 · App. 15/586,343 · Granted Jan 29, 2019

Derivatives of indole for the treatment of cancer, viral infections and lung diseases

Inventors: Cecile Bougeret (Nevers, FR); Catherine Guillou (Gif-sur-Yvette, FR); Julien Rouleau (Gif-sur-Yvette, FR); Julie Rivollier (Villebon-sur-Yvette, FR); Denis Carniato (Marcoussis, FR)

Assignees: BIOKINESIS; CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE

C07D209/18 A61K31/404 A61K31/444 A61K31/4439 A61K31/496 A61K31/675 A61K31/683 A61K31/685 A61K45/06 C07C211/63 C07D209/26 C07D401/06 C07D401/14 C07D403/06 C07D405/14 C07F9/09 C07F9/40 C07F9/5728

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Quick Facts

Patent No.: US 10,189,782
App. No.: 15/586,343
Granted: Jan 29, 2019
Kind: B2

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Abstract

The present invention relates to a new class of indole derivatives, having a particular MKlp2 inhibition profile and useful as a therapeutic agent, in particular for the treatment of cancer, viral infections and lung diseases.

Claims (142)

1. A compound of formula (I):

wherein:

X represents a nitrogen atom, or a N+-O— unit;

R 1 and R 1 ′ are such that one is H and the other represents a halogen or one —NR 11 R 12 unit wherein R 11 and R 12 represent H or a (C 1 -C 6 )alkyl group;

R 2 represents:

a radical (C 1 -C 6 )alkoxy, (C 3 -C 6 )cycloalkoxy, aryloxy, (C 1 -C 6 )alkyl-aryloxy, said radical being optionally substituted with halogen, or a radical thio-(C 1 -C 6 )alkyl, thio-aryl, or thio-(C 1 -C 6 )alkyl-aryl, said radical being optionally substituted with halogen or a (C 1 -C 6 )alkoxy group;

a —NR 4 R 5 unit, a O—(C 1 -C 6 )alkyl-NR 4 R 5 unit or a S—(C 1 -C 6 )alkyl-NR 4 R 5 unit wherein R 4 and R 5 represent II or a (C 1 -C 6 )alkyl group, with the proviso that at least one among R 4 and R 5 is not H;

a NHCOR 6 unit wherein R 6 represents (C 1 -C 6 )alkyl group;

an aryl group, optionally substituted with a halogen, a trifluoromethyl group, or a (C 1 -C 3 )alkoxy group; or

a halogen;

and

R 3 represents a hydrogen, a (C 1 -C 3 )alkyl group, a (C 1 -C 3 )alkoxy group or a halogen;

and the compounds of formula (I), in which the nitrogen atom of the indole core is substituted by a group selected from the group consisting of a COR 7 and a CO 2 R 7 group, wherein R 7 represents:

a (C 1 -C 6 )alkyl group, optionally substituted by at least a hydroxy group, a (C 1 -C 6 )alkyloxy group, a (C 1 -C 6 ) n polyalkyloxy group wherein n is 1<n<6, a phosphate or pyrophosphate group and a salt thereof or (C 1 -C 3 )alkyl ester thereof, a R 8 group, a —NHCO 2 R 8 unit, a COR 8 group, or a CO 2 R 8 group, wherein R 8 is:

a (C 1 -C 6 )alkyl group;

an aryl or a (C 1 -C 6 )alkylaryl;

a —NR 9 R 10 unit wherein R 9 and R 10 represent a hydrogen or a (C 1 -C 6 )alkyl group;

a NH—NR 9 R 10 unit wherein R 9 and R 10 are as defined above;

or a pharmaceutically acceptable salt thereof.

2. The compound according to claim 1 , wherein the compound has the formula (Ia):

wherein X, R 1 , R 1′ , R 2 , and R 3 are such as defined in claim 1 .

3. The compound according to claim 1 , wherein the compound has the formula (Ib):

wherein X, R 1 , R 1′ , R 2 , and R 3 are such as defined in claim 1 .

4. The compound according to claim 1 , wherein R 1 ′ is H.

5. The compound according to claim 1 , wherein R 1 represents a halogen selected from the group consisting of a bromine and a chlorine.

6. The compound according to claim 1 , wherein R 1 is H.

7. The compound according to claim 1 , wherein R 1 ′ is a halogen selected from a bromine, a chlorine or a fluorine.

8. The compound according to claim 1 , wherein R 2 represents:

a radical (C 1 -C 6 )alkoxy, or phenoxy, said radical being optionally substituted with halogen;

a halogen;

a R 4 —N—R 5 unit or a S—(C 1 -C 6 )alkyl-NR 4 R 5 unit, wherein R 4 and R 5 represent H or a (C 1 -C 6 )alkyl group, with the proviso that at least one among R 4 and R 5 is not H;

a NHCOR 6 unit wherein R 6 represents (C 1 -C 6 )alkyl group;

a radical thio-(C 1 -C 6 )alkyl, thio-aryl, or thio-(C 1 -C 6 )alkyl-aryl, said radical being optionally substituted with halogen or a (C 1 -C 6 )alkoxy group; or

an aryl group optionally substituted with halogen, or a trifluoromethyl group.

9. The compound according to claim 1 , wherein R 2 represents:

a radical (C 1 -C 6 )alkoxy selected from the group consisting of a methoxy group, an ethoxy group, and an isopropoxy group, or a phenoxy group, optionally substituted with fluorine or trifluoromethyl;

a halogen selected from the group consisting of a fluorine and a chlorine;

a R 4 —N—R 5 unit or a S—(C 1 -C 6 )alkyl-NR 4 R 5 unit wherein R 4 and R 5 represent a methyl or an ethyl group;

a NHCOR 6 unit wherein R 6 represents a tert-butyl group;

a radical selected from the group consisting of a thio-methyl group, a thio-ethyl group, a thio-benzyl group and a thio-phenyl group, optionally substituted with fluorine or a trifluoromethyl group; or

a phenyl group optionally substituted with bromine or a trifluoromethyl group.

10. The compound according to claim 1 , wherein said compound is selected from the group consisting of:

(Z)-2-(5-chloro-1H-indol-3-yl)-3-(4-chloropyridin-3-yl)-acrylonitrile;

(Z)-2-(5-bromo-1H-indol-3-yl)-3-(4-chloropyridin-3-yl)-acrylonitrile;

(Z)-2-(5-bromo-1H-indol-3-yl)-3-(4-methoxypyridin-3-yl)-acrylonitrile;

(E)-2-(5-bromo-1H-indol-3-yl)-3-(4-methoxypyridin-3-yl)-acrylonitrile;

(Z)-2-(5-chloro-1H-indol-3-yl)-3-(4-(dimethylamino)pyridin-3-yl)-acrylonitrile;

(Z)-2-(5-chloro-1H-indol-3-yl)-3-(4-dimethylamino)pyridine-3-yl)-acrylonitrile, hydrochloride;

(Z)-2-(5-bromo-1H-indol-3-yl)-3-(4-(dimethylamino)pyridin-3-yl)-acrylonitrile;

(Z)-2-(5-chloro-1H-indol-3-yl)-3-(4-methoxypyridin-3-yl)-acrylonitrile;

(E)-2-(5-chloro-1H-indol-3-yl)-3-(4-methoxypyridin-3-yl)-acrylonitrile;

(Z)-2-(5-chloro-1H-indol-3-yl)-3-(4-phenoxypyridin-3-yl)-acrylonitrile;

(Z)-2-(5-bromo-1H-indol-3-yl)-3-(4-phenoxypyridin-3-yl)-acrylonitrile;

(Z)-2-(5-bromo-1H-indol-3-yl)-3-(4-ethoxypyridin-3-yl)-acrylonitrile;

(Z)-2-(5-bromo-1H-indol-3-yl)-3-(4-isopropoxypyridin-3-yl)-acrylonitrile;

(Z)-2-(5-bromo-1H-indol-3-yl)-3-(4-(methylthio)pyridin-3-yl)-acrylonitrile;

(Z)-2-(5-bromo-1H-indol-3-yl)-3-(4-(ethylthio)pyridin-3-yl)-acrylonitrile;

(Z)-2-(5-bromo-1H-indol-3-yl)-3-(4-(3-bromophenyl)pyridin-3-yl)-acrylonitrile;

(Z)-3-(4-(3-bromophenyl)pyridin-3-yl)-2-(5-chloro-1H-indol-3-yl)-acrylonitrile;

(Z)-2-(5-bromo-1H-indol-3-yl)-3-(4-(phenylthio)pyridin-3-yl)-acrylonitrile;

(Z)-3-(4-(benzylthio)pyridin-3-yl)-2-(5-bromo-1H-indol-3-yl)-acrylonitrile;

(Z)-2-(5-bromo-1H-indol-3-yl)-3-(4-(3,4-dimethoxy)thio)pyridin-3-yl)-acrylonitrile;

(Z)-2-(5-bromo-1H-indol-3-yl)-3-(4-(4-fluorophenoxy)pyridin-3-yl)-acrylonitrile;

(Z)-2-(5-chloro-1H-indol-3-yl)-3-(4-(4-fluorophenoxy)pyridin-3-yl)-acrylonitrile;

(Z)-2-(5-bromo-1H-indol-3-yl)-3-(4-(diethylamino)pyridin-3-yl)-acrylonitrile;

(Z)-2-(5-bromo-1H-indol-3-yl)-3-(4-(4-(trifluoromethyl)phenyl)pyridin-3-yl)-acrylonitrile;

(Z)-2-(5-chloro-1H-indol-3-yl)-3-(4-(4-(trifluoromethyl))phenyl)pyridin-3-yl)-acrylonitrile;

(Z)-2-(5-chloro-1H-indol-3-yl)-3-(4-((4-fluorophenyl)thio)pyridin-3-yl)-acrylonitrile;

(Z)-2-(5-bromo-1H-indol-3-yl)-3-(4-((4-fluorophenyl)thio)pyridin-3-yl)-acrylonitrile;

(Z)-2-(5-chloro-1H-indol-3-yl)-3-(4-methoxypyridin-3-yl)-acrylonitrile;

(Z)-2-(5-bromo-1H-indol-3-yl)-3-(4-(2-(dimethylamino)ethylthio)pyridin-3-yl)-acrylonitrile;

(Z)-2-(6-bromo-1H-indol-3-yl)-3-(4-methoxypyridin-3-yl)acrylonitrile;

(Z)-2-(6-fluoro-1H-indol-3-yl)-3-(4-methoxypyridin-3-yl)acrylonitrile;

(Z)-2-(6-chloro-1H-indol-3-yl)-3-(4-methoxypyridin-3-yl)acrylonitrile;

(Z)-3-(2-(5-chloro-1H-indol-3-yl)-2-cyanovinyl)-4-methoxypyridine-1-oxide;

(Z)-2-(1-acetyl-5-bromo-1H-indol-3-yl)-3-(4-methoxypyridin-3-yl)acrylonitrile;

(Z)-2-(5-bromo-1-pivaloyl-1H-indol-3-yl)-3-(4-methoxypyridin-3-yl)acrylonitrile;

(Z)-methyl

3-(5-bromo-3-(1-cyano-2-(4-methoxypyridin-3-yl)vinyl)-1H-indol-1-yl)-3-oxopropanoate;

(Z)-2-(5-bromo-1-(2-(dimethylamino)acetyl)-1H-indol-3-yl)-3-(4-methoxypyridin-3-yl)acrylonitrile;

and their pharmaceutically acceptable salt.

11. The compound according to claim 1 , wherein said compound is selected from the group consisting of: