Isoindoline derivatives, pharmaceutical compositions containing them, and their use in therapy

1. An isoindoline derivative of formula (I)

wherein

R is R 1 -W-A 1 -Q-Y-A 2 -X 1 - or —CN;

R 1 is hydrogen, C 1 -C 6 -alkyl, C 3 -C 12 -cycloalkyl-C 1 -C 4 -alkyl, halogenated C 1 -C 6 -alkyl, tri-(C 1 -C 4 -alkyl)-silyl-C 1 -C 4 -alkyl, hydroxy-C 1 -C 4 -alkyl, C 1 -C 6 -alkoxy-C 1 -C 4 -alkyl, amino-C 1 -C 4 -alkyl, C 1 -C 6 -alkylamino-C 1 -C 4 -alkyl, di-C 1 -C 6 -alkylamino-C 1 -C 4 -alkyl, C 1 -C 6 -alkylcarbonylamino-C 1 -C 4 -alkyl, C 1 -C 6 -alkyloxycarbonylamino-C 1 -C 4 -alkyl, C 1 -C 6 -alkylaminocarbonylamino-C 1 -C 4 -alkyl, di-C 1 -C 6 -alkylaminocarbonylamino-C 1 -C 4 alkyl, C 1 -C 6 -alkylsulfonylamino-C 1 -C 4 -alkyl, (optionally substituted C 6 -C 12 -aryl-C 1 -C 6 -alkyl)amino-C 1 -C 4 -alkyl, optionally substituted C 6 -C 12 -aryl-C 1 -C 4 -alkyl, optionally substituted C 3 -C 12 -heterocyclyl-C 1 -C 4 -alkyl, C 3 -C 12 -cycloalkyl, C 1 -C 6 -alkylcarbonyl, C 1 -C 6 -alkoxycarbonyl, halogenated C 1 -C 6 -alkoxycarbonyl, C 6 -C 12 -aryloxycarbonyl, aminocarbonyl, C 1 -C 6 -alkylaminocarbonyl, (halogenated C 1 -C 4 -alkyl)aminocarbonyl, C 6 -C 12 -arylaminocarbonyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, optionally substituted C 6 -C 12 -aryl, hydroxy, C 1 -C 6 -alkoxy, halogenated C 1 -C 6 -alkoxy, C 1 -C 6 -hydroxyalkoxy, C 1 -C 6 -alkoxy-C 1 -C 4 -alkoxy, amino-C 1 -C 4 -alkoxy, C 1 -C 6 -alkylamino-C 1 -C 4 -alkoxy, di-C 1 -C 6 -alkylamino-C 1 -C 4 -alkoxy, C 1 -C 6 -alkylcarbonylamino-C 1 -C 4 -alkoxy, C 6 -C 12 -arylcarbonylamino-C 1 -C 4 -alkoxy, C 1 -C 6 -alkoxycarbonylamino-C 1 -C 4 -alkoxy, C 6 -C 12 aryl-C 1 -C 4 -alkoxy, C 1 -C 6 -alkylsulfonylamino-C 1 -C 4 -alkoxy, (halogenated C 1 -C 6 -alkyl)sulfonylamino-C 1 -C 4 -alkoxy, C 6 -C 12 -arylsulfonylamino-C 1 -C 4 -alkoxy, (C 6 -C 12 aryl-C 1 -C 6 -alkyl) sulfonylamino-C 1 -C 4 -alkoxy, C 3 -C 12 -heterocyclylsulfonylamino-C 1 -C 4 -alkoxy, C 3 -C 12 -heterocyclyl-C 1 -C 4 -alkoxy, C 6 -C 12 -aryloxy, C 3 -C 12 -heterocyclyloxy, C 1 -C 6 -alkylthio, halogenated C 1 -C 6 -alkylthio, C 1 -C 6 -alkylamino, (halogenated C 1 -C 6 -alkyl)amino, di-C 1 -C 6 -alkylamino, di-(halogenated C 1 -C 6 -alkyl)amino, C 1 -C 6 -alkylcarbonylamino, (halogenated C 1 -C 6 -alkyl)carbonylamino, C 6 -C 12 -arylcarbonylamino, C 1 -C 6 -alkylsulfonylamino, (halogenated C 1 -C 6 -alkyl)sulfonylamino, C 6 -C 12 -arylsulfonylamino or optionally substituted C 3 -C 12 -heterocyclyl;

W is —NR 8 — or a bond;

A 1 is optionally substituted C 1 -C 4 -alkylene or a bond;

Q is —S(O) 2 — or —C(O)—;

Y is —NR 9 — or a bond;

A 2 is optionally substituted C 1 -C 4 -alkylene, C 1 -C 4 -alkylene-CO—, —CO—C 1 -C 4 -alkylene, C 1 -C 4 -alkylene-O—C 1 -C 4 -alkylene, C 1 -C 4 -alkylene-NR 10 —C 1 -C 4 -alkylene, optionally substituted C 2 -C 4 -alkenylene, optionally substituted C 2 -C 4 -alkynylene, optionally substituted C 6 -C 12 -arylene, optionally substituted C 6 -C 12 -heteroarylene or a bond;

X 1 is —O—, —NR 11 —, —S—, optionally substituted C 1 -C 4 -alkylene, optionally substituted C 2 -C 4 -alkenylene, or optionally substituted C 2 -C 4 -alkynylene, wherein -Y-A 2 -X 1 - comprises at least 2, 3 or 4 atoms in the main chain;

R 2 is hydrogen, halogen, C 1 -C 6 -alkyl, halogenated C 1 -C 4 -alkyl, hydroxy-C 1 -C 4 -alkyl, —CN, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, optionally substituted C 6 -C 12 -aryl, hydroxy, C 1 -C 6 -alkoxy, halogenated C 1 -C 6 -alkoxy, C 1 -C 6 -alkoxycarbonyl, C 2 -C 6 -alkenyloxy, C 6 -C 12 -aryl-C 1 -C 4 -alkoxy, C 1 -C 6 -alkylcarbonyloxy, C 1 -C 6 -alkylthio, C 1 -C 6 -alkylsulfinyl, C 1 -C 6 -alkylsulfonyl, aminosulfonyl, amino, C 1 -C 6 -alkylamino, C 2 -C 6 -alkenylamino, nitro or optionally substituted C 3 -C 12 -heterocyclyl, or two radicals R 2 together with the ring atoms of A to which they are bound form a 5- or 6 membered ring;

R 3 is hydrogen, halogen, C 1 -C 6 -alkyl or C 1 -C 6 -alkoxy, or two radicals R 3 together with the carbon atom to which they are attached form a carbonyl group;

R 4 is hydrogen, C 1 -C 6 -alkyl, C 3 -C 12 -cycloalkyl-C 1 -C 4 -alkyl, halogenated C 1 -C 4 -alkyl, hydroxy-C 1 -C 4 -alkyl, C 1 -C 6 -alkoxy-C 1 -C 4 -alkyl, amino-C 1 -C 4 -alkyl, CH 2 CN, C 6 -C 12 -aryl-C 1 -C 4 -alkyl, C 3 -C 12 -cycloalkyl, —CHO, C 1 -C 4 -alkylcarbonyl, (halogenated C 1 -C 4 -alkyl)carbonyl, C 6 -C 12 -arylcarbonyl, C 1 -C 4 -alkoxycarbonyl, C 6 -C 12 -aryloxycarbonyl, C 1 -C 6 -alkylaminocarbonyl, C 2 -C 6 -alkenyl, —C(═NH)NH 2 , —C(═NH)NHCN, C 1 -C 6 -alkylsulfonyl, C 6 -C 12 -arylsulfonyl, amino, —NO or C 3 -C 12 -heterocyclyl;

X 2 is >CR 12a R 12b ;

X 3 is a bond;

R 5 is optionally substituted C 6 -C 12 -aryl, optionally substituted C 3 -C 12 -cycloalkyl, or optionally substituted C 3 -C 12 -heterocyclyl;

R 6 is hydrogen or C 1 -C 6 -alkyl;

R 7 is hydrogen or C 1 -C 6 -alkyl;

R 8 is hydrogen or C 1 -C 6 -alkyl;

R 9 is hydrogen, C 1 -C 6 -alkyl, C 3 -C 12 -cycloalkyl, amino-C 1 -C 6 -alkyl, optionally substituted C 6 -C 12 -aryl-C 1 -C 4 -alkyl or C 3 -C 12 -heterocyclyl; or

R 9 , R 1 together are C 1 -C 4 -alkylene; or

R 9 is C 1 -C 4 -alkylene that is bound to a carbon atom in A 2 and A 2 is C 1 -C 4 -alkylene or to a carbon atom in X 1 and X 1 is C 1 -C 4 -alkylene;

R 10 is hydrogen, C 1 -C 6 -alkyl or C 1 -C 6 -alkylsulfonyl;

R 11 is hydrogen or C 1 -C 6 -alkyl, or

R 9 , R 11 together are C 1 -C 4 -alkylene,

R 12a is hydrogen, optionally substituted C 1 -C 6 -alkyl, C 1 -C 6 -alkylamino-C 1 -C 4 -alkyl, di-C 1 -C 6 -alkylamino-C 1 -C 4 -alkyl, C 3 -C 12 -heterocyclyl-C 1 -C 6 -alkyl, optionally substituted C 6 -C 12 -aryl or hydroxy;

R 12b is hydrogen or C 1 -C 6 -alkyl, or

R 12a , R 12b together are optionally substituted C 1 -C 4 -alkylene, wherein one —CH 2 — of C 1 -C 4 -alkylene may be replaced by an oxygen atom or —NR 14 —;

R 13a is hydrogen, optionally substituted C 1 -C 6 -alkyl, C 1 -C 6 -alkylamino-C 1 -C 4 -alkyl, di-C 1 -C 6 -alkylamino-C 1 -C 4 -alkyl, C 3 -C 12 -heterocyclyl-C 1 -C 6 -alkyl, optionally substituted C 6 -C 12 -aryl or hydroxy;

R 13b is hydrogen or C 1 -C 6 -alkyl, or

R 13a , R 13b together are optionally substituted C 1 -C 4 -alkylene, wherein one —CH 2 - of C 1 -C 4 -alkylene may be replaced by an oxygen atom or —NR 15 —;

R 14 is hydrogen or C 1 -C 6 -alkyl; and

R 15 is hydrogen or C 1 -C 6 -alkyl;

or a physiologically tolerated salt thereof.

2. A compound as claimed in claim 1 , wherein R is R 1 -W-A 1 -Q-Y-A 2 -X 1 -.

3. A compound as claimed in claim 1 , wherein R 1 is C 1 -C 6 -alkyl, C 3 -C 12 -cycloalkyl-C 1 -C 4 -alkyl, C 3 -C 12 -cycloalkyl, or optionally substituted C 3 -C 12 -heterocyclyl.

4. A compound as claimed in claim 1 , wherein A 1 is a bond.

5. A compound as claimed in claim 1 , wherein W is a bond and Y is a bond, or wherein W is a bond and Y is —NR 9 —.

6. A compound as claimed in claim 1 , wherein X 1 is —O— and A 2 is C 1 -C 4 -alkylene, or X 1 is C 1 -C 4 -alkylene and A 2 is a bond.

7. A compound as claimed in claim 1 , wherein R 1 -W-A 1 -Q-Y-A 2 -X 1 - is R 1 -S(O) 2 -NR 9 -A 2 -X 1 - or R 1 —S(O) 2 —X 1 —.

8. A compound as claimed in claim 1 , having formula

9. A compound as claimed in claim 1 , wherein R 2 is hydrogen or halogen.

10. A compound as claimed in claim 1 , wherein R 3 is hydrogen or C 1 -C 6 -alkyl, or two radicals R 3 together with the carbon atom to which they are attached form a carbonyl group.

11. A compound as claimed in claim 1 , wherein R 4 is hydrogen, C 1 -C 6 -alkyl, C 3 -C 12 -cycloalkyl-C 1 -C 4 -alkyl, halogenated C 1 -C 4 -alkyl, C 3 -C 12 -cycloalkyl, (halogenated C 1 -C 4 -alkyl)carbonyl, or C 3 -C 12 -heterocyclyl.

12. A compound as claimed in claim 1 , wherein R 12a is hydrogen or C 1 -C 6 -alkyl and R 12b is hydrogen or C 1 -C 6 -alkyl, or wherein R 12a , R 12b together are optionally substituted C 1 -C 4 -alkylene.

13. A compound as claimed in claim 1 , having formula

wherein

R 17a , R 17b , R 17c , R 17d , R 17e independently are hydrogen, halogen, or halogenated C 1 -C 6 -alkyl, or having formula

wherein

R 17b , R 17c , R 17d , R 17e independently are hydrogen, halogen, or halogenated C 1 -C 6 -alkyl.

14. A compound as claimed in claim 1 , wherein

R is R 1 -W-A 1 -Q-Y-A 2 -X 1 -;

R 1 is C 1 -C 6 -alkyl, C 3 -C 12 -cycloalkyl-C 1 -C 4 -alkyl, C 3 -C 12 -cycloalkyl, or optionally substituted C 3 -C 12 -heterocyclyl;

W is a bond;

A 1 is a bond;

Q is —S(O) 2 —;

Y is —NR 9 - or a bond;

A 2 is C 1 -C 4 -alkylene;

X 1 is —O— or C 1 -C 4 -alkylene;

R 2 is hydrogen or halogen;

R 3 is hydrogen or C 1 -C 6 -alkyl, or two radicals R 3 together with the carbon atom to which they are attached form a carbonyl group;

R 4 is hydrogen, C 1 -C 6 -alkyl, C 3 -C 12 -cycloalkyl-C 1 -C 4 -alkyl, halogenated C 1 -C 4 -alkyl, C 3 -C 12 -cycloalkyl, (halogenated C 1 -C 4 -alkyl)carbonyl, or C 3 -C 12 -heterocyclyl;

X 2 is CR 12a R 12b ;

X 3 is a bond;

R 5 is optionally substituted phenyl;

R 9 is hydrogen;

R 12a is hydrogen; and

R 12b is hydrogen.

15. A compound as claimed in claim 1 which is:

N-[2-(3-benzyl-1-oxo-isoindolin-5-yl)oxyethyl]-1-methyl-imidazole-4-sulfonamide;

N-[(3-benzyl-1-oxo-isoindolin-5-yl)methyl]-1-methyl-imidazole-4-sulfonamide;

[2-(3-Benzyl-1-oxo-2,3-dihydro-1H-isoindol-5-yloxy) -ethyl]-carbamic acid tert-butyl ester;

N-[(3-benzylisoindolin-5-yl)methyl]-1-methyl-imidazole-4-sulfonamide;

N-[2-(3-benzylisoindolin-5-yl)oxyethyl]-1-methyl-imidazole-4-sulfonamide;

N-[2-(3-benzyl-1-oxo-isoindolin-5-yl)oxyethyl]-1-methyl-pyrazole-4-sulfonamide;

N-[2-(3-benzylisoindolin-5-yl)oxyethyl]-1-methyl-pyrazole-4-sulfonamide;

N-[2-(3-benzyl-3-methyl-1-oxo-isoindolin-5-yl)oxyethyl]-1-methyl-imidazole-4-sulfonamide;

N-[2-(3-benzyl-3-methyl-1-oxo-isoindolin-5-yl)oxyethyl]-1-ethyl-pyrazole-4-sulfonamide;

N-[2-(3-benzyl-3-methyl-isoindolin-5-yl)oxyethyl]-1-methyl-pyrazole-4-sulfonamide;

N-[2-(3-benzyl-3-methyl-isoindolin-5-yl)oxyethyl]-1-methyl-imidazole-4-sulfonamide;

N-[2-[3-benzyl-2-(2,2,2-trifluoroacetyl)isoindolin-5-yl]oxyethyl]-1-methyl-pyrazole-4-sulfonamide;

N-[2-(3-benzyl-2-methyl-isoindolin-5-yl)oxyethyl]-1-methyl-pyrazole-4-sulfonamide;

N-[2-(3-benzyl-2-methyl-isoindolin-5-yl)oxyethyl]-1-methyl-imidazole-4-sulfonamide;

N-[2-[3-benzyl-2-(2,2,2-trifluoroethyl)isoindolin-5-yl]oxyethyl]-1-methyl-pyrazole-4-sulfonamide;

N-[2-[3-benzyl-2-(oxetan-3-yl)isoindolin-5-yl]oxyethyl]-1-methyl-pyrazole-4-sulfonamide;

N-[2-(3-benzyl-3-methyl-1-oxo-isoindolin-5-yl)oxyethyl]-1-cyclopropyl-methanesulfonamide;

N-[2-(3-benzyl-3-methyl-isoindolin-5-yl)oxyethyl]-1-cyclopropyl-methanesulfonamide;

N-[2-(3-benzyl-6-fluoro-1-oxo-isoindolin-5-yl)oxyethyl]-1-methyl-imidazole-4-sulfonamide;

N-(2-(3-benzyl-6-fluoro-2-methylisoindolin-5-yloxy)ethyl)-1-cyclopropyl-methanesulfonamide;

1-Methyl-1H-imidazole-4-sulfonic acid [2-(3-benzyl-6-fluoro-2,3-dihydro-1H-isoindol-5-yloxy) -ethyl]-amide;

N-[2-(3-Benzyl-6-fluoro-1-oxo-2,3-dihydro-1H-isoindol-5-yloxy)-ethyl]-C-cyclopropyl-methanesulfonamide;

N-[2-(3-Benzyl-6-fluoro-2,3-dihydro-1H-isoindol-5-yloxy)-ethyl]-C-cyclopropyl-methanesulfonamide;

Ethanesulfonic acid [2-(3-benzyl-6-fluoro-1-oxo-2,3-dihydro-1H-isoindol-5-yloxy) -ethyl]-amide;

Ethanesulfonic acid [2-(3-benzyl-6-fluoro-2,3-dihydro-1H-isoindol-5-yloxy)-ethyl]-amide;

N-(3-Benzyl-1-oxo-2,3-dihydro-1H-isoindol-5-ylmethyl)-C-cyclopropyl-methanesulfonamide;

Ethanesulfonic acid (3-benzyl-1-oxo-2,3-dihydro-1H-isoindol-5-ylmethyl)-amide;

Propane-1-sulfonic acid (3-benzyl-1-oxo-2,3-dihydro-1H-isoindol-5-ylmethyl)-amide;

N-(3-Benzyl-2,3-dihydro-1H-isoindol-5-ylmethyl)-C-cyclopropyl-methanesulfonamide;

Ethanesulfonic acid (3-benzyl-2,3-dihydro-1H-isoindol-5-ylmethyl)-amide; or

Propane-1-sulfonic acid (3-benzyl-2,3-dihydro-1H-isoindol-5-ylmethyl)-amide;

or a physiologically tolerated salt thereof.

16. A pharmaceutical composition which comprises a carrier and a compound of claim 1 .

17. A method for treating a neurologic or psychiatric disorder or pain in a mammalian patient in need thereof which comprises administering to the patient a therapeutically effective amount of a compound of claim 1 , wherein the neurologic disorder is selected from the group consisting of dementia, cognitive impairment, and attention deficit disorder, and wherein the psychiatric disorder is selected from the group consisting of anxiety disorder, depression, bipolar disorder, schizophrenia, and psychosis.

18. A compound as claimed in claim 1 which is:

N-[2-(3-benzyl-3-methyl-isoindolin-5-yl)oxyethyl]-1-methyl-pyrazole-4-sulfonamide or a physiologically tolerated salt thereof.

19. A compound as claimed in claim 1 which is:

N-[2-(3-benzyl-2-methyl-isoindolin-5-yl)oxyethyl]-1-methyl-pyrazole-4-sulfonamide or a physiologically tolerated salt thereof.

20. A compound as claimed in claim 1 which is:

N-[2-(3-benzyl-3-methyl-isoindolin-5-yl)oxyethyl]-1-methyl-imidazole-4-sulfonamide or a physiologically tolerated salt thereof.