Oxindole derivatives carrying an amine-substituted piperidyl-acetidinyl substituent and use thereof for treating vasopressine-related diseases

Patent metadata

Field	Value
Publication number	US-9862704-B2
Application number	US-201415106662-A
Country	US
Kind code	B2
Filing date	Dec 19, 2014
Priority date	Dec 20, 2013
Publication date	Jan 9, 2018
Grant date	Jan 9, 2018

Abstract

The present invention relates to novel substituted oxindole derivatives of formula (I) wherein the variables are as defined in the claims and description; to pharmaceutical compositions comprising them, and to their use for the treatment of vasopressin-related disorders.

First claim

The invention claimed is:

1. A compound of formula (I)

wherein
X 1 is N or CH;
X 2 is C—R 1 or N;
R 1 and R 2 , independently of each other, are selected from the group consisting of hydrogen, halogen, cyano, C 1 -C 3 -alkyl, fluorinated C 1 -C 3 -alkyl, C 1 -C 3 -hydroxyalkyl, C 1 -C 3 -alkoxy and fluorinated C 1 -C 3 -alkoxy;
R 3 is selected from the group consisting of hydrogen, halogen, cyano, hydroxyl, C 1 -C 3 -alkyl, fluorinated C 1 -C 3 -alkyl, C 1 -C 3 -hydroxyalkyl, C 1 -C 3 -alkoxy and fluorinated C 1 -C 3 -alkoxy;
R 4 is C 1 -C 3 -alkoxy;
R 5 is hydrogen or C 1 -C 3 -alkoxy;
R 6 is cyano or halogen;
R 7 is selected from the group consisting of hydrogen, halogen and cyano;
R 8 and R 9 , independently of each other, are selected from the group consisting of hydrogen, cyano, C 1 -C 6 -haloalkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -haloalkenyl, C 2 -C 6 -alkynyl, C 2 -C 6 -haloalkynyl, C 3 -C 7 -cycloalkyl, C 3 -C 7 -halocycloalkyl and phenyl which may carry 1, 2 or 3 substituents selected from the group consisting of halogen, hydroxyl, cyano, C 1 -C 4 -alkoxy and C 1 -C 4 -haloalkoxy; or
R 8 and R 9 , together with the nitrogen atom they are bound to, form a 3-, 4-, 5-, 6- or 7-membered saturated, partially unsaturated or maximally unsaturated heterocyclic ring, where the heterocyclic ring may carry 1 or 2 substituents selected from the group consisting of cyano, C 1 -C 4 -alkyl and C 1 -C 4 -haloalkyl, where the nitrogen bound to R 8 and R 9 is the only heteroatom present in the 3-, 4-, 5-, 6- or 7-membered saturated, partially unsaturated or maximally unsaturated heterocyclic ring;
R 10 and R 11 , independently of each other and independently of each occurrence, are selected from the group consisting of halogen, C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, C 1 -C 4 -alkoxy and C 1 -C 4 -haloalkoxy, with the proviso that R 10 and R 11 are not halogen, C 1 -C 4 -alkoxy or C 1 -C 4 -haloalkoxy if they are bound to a carbon atom in α-position to a nitrogen ring atom; or
two non-geminal radicals R 10 form together a group —(CH 2 ) n —, where n is 1, 2, 3 or 4, where 1 or 2 hydrogen atoms in this group may be replaced a methyl group; or
two non-geminal radicals R 11 form together a group —(CH 2 ) n —, where n is 1, 2, 3 or 4, where 1 or 2 hydrogen atoms in this group may be replaced a methyl group;

a is 0, 1 or 2; and
b is 0, 1, 2, 3 or 4;
or a N-oxide, stereoisomer, or pharmaceutically acceptable salt thereof; or the above compound, wherein at least one of the atoms has been replaced by its stable, non-radioactive isotope.

2. The compound of claim 1 , wherein at least one hydrogen atom has been replaced by a deuterium atom.

3. The compound of claim 1 , wherein X 2 is C—R 1 and R 1 , R 2 and R 3 , independently of each other, are selected from the group consisting of hydrogen, halogen, C 1 -C 3 -alkyl, fluorinated C 1 -C 3 -alkyl, C 1 -C 3 -alkoxy and fluorinated C 1 -C 3 -alkoxy.

4. The compound of claim 3 , wherein R 1 , R 2 and R 3 , independently of each other, are selected from the group consisting of hydrogen, fluorine and methoxy.

5. The compound of claim 4 , wherein R 1 and R 2 , independently of each other, are selected from the group consisting of hydrogen, fluorine and methoxy.

6. The compound of claim 4 , wherein R 3 is hydrogen or fluorine.

7. The compound of claim 1 , wherein X 2 is N and R 2 and R 3 , independently of each other, are selected from the group consisting of hydrogen, halogen, C 1 -C 3 -alkyl, fluorinated C 1 -C 3 -alkyl, C 1 -C 3 -alkoxy and fluorinated C 1 -C 3 -alkoxy.

8. The compound of claim 7 , wherein R 2 is selected from the group consisting of hydrogen, fluorine and methoxy.

9. The compound of claim 7 , wherein R 3 is selected from the group consisting of hydrogen, fluorine and methoxy.

10. The compound of claim 1 , wherein R 4 is methoxy or ethoxy.

11. The compound of claim 1 , wherein R 5 is hydrogen or methoxy.

12. The compound of claim 1 , wherein R 6 is selected from the group consisting of cyano, fluorine and chlorine.

13. The compound of claim 1 , wherein R 7 is hydrogen or fluorine.

14. The compound of claim 1 , wherein
R 8 and R 9 , independently of each other, are selected from the group consisting of hydrogen, C 1 -C 4 -alkyl, C 1 -C 4 haloalkyl, C 3 -C 6 -cycloalkyl and C 3 -C 6 -halocycloalkyl; or
R 8 and R 9 , together with the nitrogen atom they are bound to, form a 3-, 4-, 5- or 6-membered saturated, partially unsaturated or maximally unsaturated heterocyclic ring, where the heterocyclic ring may carry 1 or 2 substituents selected from the group consisting of cyano, C 1 -C 4 -alkyl and C 1 -C 4 -haloalkyl.

15. The compound as claimed in claim 14 , wherein
R 8 and R 9 , independently of each other, are selected from the group consisting of C 1 -C 4 -alkyl, fluorinated C 1 -C 4 -alkyl, C 3 -C 6 -cycloalkyl and fluorinated C 3 -C 6 -cycloalkyl; or
R 8 and R 9 , together with the nitrogen atom they are bound to, form a 3-, 4-, 5- or 6-membered saturated heterocyclic ring, where the heterocyclic ring may carry 1 or 2 substituents selected from the group consisting of cyano, C 1 -C 4 -alkyl and C 1 -C 4 -haloalkyl.

16. The compound of claim 15 , wherein
R 8 and R 9 , independently of each other, are C 1 -C 4 -alkyl; or
R 8 and R 9 form together a group —(CH 2 ) n —, where n is 2, 3, 4, or 5, thus forming together with the nitrogen atom they are bound to a 3-, 4-, 5- or 6-membered saturated heterocyclic ring.

17. The compound of claim 1 , wherein each R 10 is independently halogen or C 1 -C 4 -alkyl, with the proviso that R 10 is not halogen if it is bound to a carbon atom in α-position to a nitrogen ring atom.

18. The compound of claim 1 , wherein each R 11 is independently halogen and/or C 1 -C 4 -alkyl, with the proviso that R 11 is not halogen if it is bound to a carbon atom in α-position to a nitrogen ring atom;
or two non-geminal radicals R 11 form together a group —CH 2 —.

19. The compound of claim 1 , wherein X 1 is N.

20. The compound of claim 1 , wherein X 1 is CH.

21. The compound of claim 1 , wherein X 2 is C—R 1 .

22. The compound claim 1 , wherein X 2 is N.

23. The compound of claim 1 , wherein a is 0 or 1.

24. The compound of claim 1 , wherein b is 0, 1 or 2.

25. A compound selected from the group consisting of
N-[(3S)-5-cyano-1-(2,4-dimethoxyphenyl)sulfonyl-3-(2-ethoxy-3-pyridyl)-2-oxo-indolin-3-yl]-3-[4-(1-piperidyl)-1-piperidyl]azetidine-1-carboxamide;
(S)—N-(5-cyano-1-((2,4-dimethoxyphenyl)sulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxoinodolin-3-yl)-3-(4-(dimethylamino)piperidin-1-yl)azetidine-1-carboxamide;
(S)—N-(5-cyano-1-((2,4-dimethoxyphenyl)sulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxoindolin-3-yl)-3-(4-(diethylamino)piperidin-1-yl)azetidine-1-carboxamide;
(S)—N-(5-cyano-1-((2,4-dimethoxyphenyl)sulfonyl)-3-(2-ethoxypyridin-3-yl)-2-oxoindolin-3-yl)-3-(4-(pyrrolidin-1-yl)piperidin-1-yl)azetidine-1-carboxamide;
(S)-3-([1,4′-bipiperidin]-1′-yl)-N-(5-cyano-1-((2,4-dimethoxyphenyl)sulfonyl)-3-(2-methoxypyridin-3-yl)-2-oxoindolin-3-yl)azetidine-1-carboxamide;
(S)—N-(5-cyano-((2,4-dimethoxyphenyl)sulfonyl)-3-(2-methoxypyridin-3-yl)-2-oxoindolin-3-yl)-3-(4-(pyrrolidin-1-

Assignees

• Abbvie Deutschland
• Abbvie Inc

Inventors

• Geneste Hervé
• Hornberger Wilfried
• Hutchins Charles W
• Jantos Katja
• Kling Andreas
• Laplanche Loic
• Van Gaalen Marcel

Classifications

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• C07D401/14 Primary

  containing three or more hetero rings · CPC title