Isoindoline derivatives

Patent metadata

Field	Value
Publication number	US-9975873-B2
Application number	US-201515517769-A
Country	US
Kind code	B2
Filing date	Oct 6, 2015
Priority date	Oct 8, 2014
Publication date	May 22, 2018
Grant date	May 22, 2018

Abstract

The present invention relates to isoindoline derivatives according to formula (I), which are Positive Allosteric Modulators of D1 and accordingly of benefit as pharmaceutical agents for the treatment of diseases in which D1 receptors play a role.

First claim

The invention claimed is:

1. A compound of formula (I), or a pharmaceutically acceptable salt thereof;

wherein
R 1 is hydrogen, halogen, cyano or hydroxy; C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylsulfanyl, C 1-6 alkylsulfinyl, C 1-6 alkylsulfonyl, (C 1-6 -alkylsulfonyl)amino or (C 1-6 -alkylsulfonyl)amino(C 1-6 alkyl), any of which groups is optionally substituted by one or more substituents;
R 2 is hydrogen, cyano, halogen; or C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylsulfanyl, C 1-6 alkylsulfinyl, C 1-6 alkylsulfonyl, C 1-6 alkylsulfonylamino, (C 1-6 alkylsulfonyl)amino(C 1-6 alkyl), C 1-6 alkylamido, (C 1-6 alkylacyl)amino, (C 1-6 alkylacyl)amino(C 1-6 alkyl), or heteroaryl, any of which groups is optionally substituted by one or more substituents; or
R 1 and R 2 are linked together to form with the adjacent aromatic group a bicycle of formula (i):

wherein R 2b is hydrogen or C 1-6 alkylsulfonyl;
R 3 is halogen, C 1-6 alkyl, C 1-6 alkoxy or cyano;
R 4 is hydrogen, halogen, C 1-6 alkyl, hydroxy, C 1-6 alkoxy, C 1-6 alkylsulfonyl, C 1-6 alkoxycarbonyloxy or C 1-6 alkylaminocarbonyloxy;
R 5 is hydrogen, cyano, hydroxy or nitro; or C 1-6 alkyl; or C 1-6 alkoxy, C 1-6 -alkylsulfonyl, C 1-6 -alkylsulfonylamino; C 1-6 -alkylsulfonylamino(C 1-6 alkyl), heterocycle, C 1-6 alkylacylamino, C 1-6 alkylacylamino(C 1-6 alkyl); C 1-6 alkylureido(C 1-6 alkyl); C 1-6 alkylcarbamate(C 1-6 alkyl); amido; C 1-6 alkoxycarbonyl, C 1-6 alkoxycarbonyloxy(C 1-6 alkyl); amino group; N-cyano-S—(C 1-6 -alkyl)sulfonimidoyl, N,S-(di-C 1-6 -alkyl)sulfonimidoyl, aminosulfinyl; C 1-6 -alkylsulfinyl; aminosulfonyl; (di-C 1-6 -alkyl)(oxido)-λ 6 -sulfanylidene-amino; amino(C 1-6 alkyl), amido(C 1-6 alkyl) or amido(C 1-6 alkoxy); any of which groups is optionally substituted by one or more substituents;
R 6 is hydrogen or cyano;
R 7 is either hydrogen or (C 1-6 -alkylsulfonyl)amino;
X is either CR 9 or N; wherein R 9 is hydrogen, halogen or C 1-6 -alkyl substituted by hydroxy;
Z is CH or N; and
Y is CH 2 or NH.

2. The compound according to claim 1 represented by formula I-A, or a pharmaceutically acceptable salt thereof,

3. The compound according to claim 1 represented by formula I-B, or a pharmaceutically acceptable salt thereof,

4. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 1 is hydrogen, halogen, or hydroxy; or C 1-6 alkyl, C 1-6 alkoxy or (C 1-6 -alkylsulfonyl)amino(C 1-6 alkyl), any of which groups is optionally substituted by one or more substituents.

5. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 1 is hydrogen.

6. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 2 is cyano or halogen; or C 1-6 alkyl, which group is optionally substituted by one or more substituents.

7. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 4 is hydrogen.

8. The compound according to claim 1 or a pharmaceutically acceptable salt thereof wherein R 6 is hydrogen.

9. The compound according to claim 1 or a pharmaceutically acceptable salt thereof wherein R 7 is hydrogen.

10. The compound according to claim 1 or a pharmaceutically acceptable salt thereof wherein X is CH.

11. The compound according to claim 1 or a pharmaceutically acceptable salt thereof wherein Z is CH.

12. The compound as claimed in claim 2 represented by formula (I-A-A) or a pharmaceutically acceptable salt thereof;

wherein R 2 , R 3 and R 5 are as defined in claim 1 .

13. The compound according to claim 1 or a pharmaceutically acceptable salt thereof wherein R 2 is halogen or cyano.

14. The compound according to claim 1 or a pharmaceutically acceptable salt thereof wherein R 3 is halogen or cyano.

15. The compound according to claim 1 or a pharmaceutically acceptable salt thereof wherein R 2 is chloro or cyano.

16. The compound according to claim 1 or a pharmaceutically acceptable salt thereof wherein R 3 is chloro or cyano.

17. The compound according to claim 1 or a pharmaceutically acceptable salt thereof wherein
R 5 is hydrogen, hydroxy or nitro; or C 1-6 alkyl; C 1-6 alkoxy, C 1-6 -alkylsulfonyl, C 1-6 -alkylsulfonylamino; C 1-6 -alkylsulfonylamino(C 1-6 alkyl), heterocycle, C 1-6 alkylacylamino; amido; C 1-6 alkoxycarbonyl, amino group; aminosulfonyl; (di-C 1-6 -alkyl)(oxido)-λ 6 -sulfanylidene-amino or amido(C 1-6 alkoxy); any of which groups is optionally substituted by one or more substituents.

18. The compound according to claim 1 or a pharmaceutically acceptable salt thereof wherein
R 5 is hydrogen, hydroxy, nitro; (trifluoro)(hydroxyl)ethyl, (hydroxy)methyl, methoxy, methylsulfonyl, methylsulfonylamino, methylsulfonylaminomethyl, pyrazolyl, methylcarbonylamino, carbamoyl, methoxycarbonyl, amino, methylaminosulfonyl, isopropylaminosulfonyl, ethylaminosulfonyl, (trifluromethyl)methylaminosufonyl, triazolylaminosulfonyl, (methy)pyrazolylaminosulfonyl, (tetrahydropyranyl)methylsulfonyl, pyrrolidinylaminosulfonyl, piperidinylaminosulfonyl, azetidinylaminosulfonyl, (di-methyl)(oxido)-λ 6 -sulfanylidene-amino, methylaminocarbonylmethoxy, or dimethylaminocarbonylmethoxy.

19. The compound according to claim 1 , selected from the group consisting of
2-(2,6-dichlorophenyl)-1-(1-methyl-1,3-dihydro-2H-isoindol-2-yl)ethanone;
2-(2,6-dichlorophenyl)-1-[(1S)-1-methyl-1,3-dihydro-2H-isoindol-2-yl]ethanone;
2-(2,6-dichlorophenyl)-1-[(1R)-1-methyl-1,3-dihydro-2H-isoindol-2-yl]ethanone;
2-(2-chloro-6-iodophenyl)-1-(1-methyl-1,3-dihydro-2H-isoindol-2-yl)ethanone;
2-(2,4-dichloropyridin-3-yl)-1-(1-methyl-1,3-dihydro-2H-isoindol-2-yl)ethanone;
2-(2,6-dichlorophenyl)-1-(1-methyl-4-nitro-1,3-dihydro-2H-isoindol-2-yl)ethanone;
3-chloro-2-{2-[(1S)-1-methyl-1,3-dihydro-2H-isoindol-2-yl]-2-oxoethyl}benzonitrile;
2-(3,5-dichloro-2-methylpyridin-4-yl)-1-[(1S)-1-methyl-1,3-dihydro-2H-isoindol-2-yl]ethanone;
2-(3-bromo-5-chloropyridin-4-yl)-1-[(1S)-1-methyl-1,3-dihydro-2H-isoindol-2-yl]ethanone;
2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)-1-[(1S)-1-methyl-1,3-dihydro-2H-isoindol-2-yl]ethanone;
2-(3,5-dichloro-2-methoxypyridin-4-yl)-1-[(1S)-1-methyl-1,3-dihydro-2H-isoindol-2-yl]ethanone;
2-(3,5-dichloropyridin-4-yl)-1-[(1S)-1-methyl-1,3-dihydro-2H-isoindol-2-yl]ethanone;
N-{(1S)-2-[(2,6-dichlorophenyl)acetyl]-1-methyl-2,3-dihydro-1H-isoindol-4-yl}methanesulfonamide;
1-[(1S)-4-amino-1-methyl-1,3-dihydro-2H-isoindol-2-yl]-2-(2,6-dichlorophenyl)ethanone;
methyl 2-[(2,6-dichlorophenyl)acetyl]-1-methyl-2, 3-dihydro-1H-isoindole-4-carboxylate;
2-[2,6-dichloro-3-(hydroxymethyl)phenyl]-1-(1-methyl-1,3-dihydro-2H-isoindol-2-yl)ethanone;
2-[2,6-dichloro-3-(hydroxymethyl)phenyl]-1-[(1S)-1-methyl-1,3-dihydro-2H-isoindol-2-yl]ethanone;
2-(2,6-dichlorophenyl)-1-(4-hydroxy-1-methyl-1,3-dihydro-2H-isoindol-2-yl)ethanone;
2-[(2,6-dichlorophenyl)

Assignees

• Ucb Biopharma Sprl

Inventors

• Skolc David
• Ates Ali
• Jnoff Eric
• Valade Anne
• Mathieu Benoit
• Sands Zara

Classifications

• A61P25/16

  Anti-Parkinson drugs · CPC title

• C07D487/04

  Ortho-condensed systems · CPC title

• C07D401/06 Primary

  linked by a carbon chain containing only aliphatic carbon atoms · CPC title

• A61K31/4035

  Isoindoles, e.g. phthalimide · CPC title

• C07D209/44

  Iso-indoles; Hydrogenated iso-indoles · CPC title