Small molecule potentiators of metabotropic glutamate receptors I

1. A compound of formula I

wherein

X 2 is C—R 2 ;

X 3 is C—R 3 ;

X 4 is C—R 4 ;

Y 1 is N, C or C—R 5 ;

Y 2 is N, C or C—R 6 ;

Y 3 is N, C or C—R 7 ;

Y 4 is N, C or C—R 8 ;

provided that only the moiety Y 1 , Y 2 , Y 3 or Y 4 to which Z is bound to C and further provided at most one of Y 1 , Y 2 , Y 3 or Y 4 is N;

Z is O, S, S(O), S(O) 2 or NR z ;

R z is hydrogen, C 1 -C 4 -haloalkyl, C 3 -C 6 -cycloalkyl, C 3 -C 6 -cycloalkylmethyl, or C 1 -C 4 -alkyl, which is unsubstituted or carries one radical selected from the group consisting of C 1 -C 4 -alkoxy and NR Z1 R Z2 ;

where R Z1 and R Z2 are independently of each other selected from the group consisting of hydrogen, C 3 -C 6 -cycloalkyl, C 3 -C 6 -cycloalkylmethyl, C 1 -C 4 -alkyl and C 1 -C 4 -alkoxy-C 1 -C 4 -alkyl, or

R Z1 and R Z2 together with the nitrogen to which they are attached form a 5- or 6-membered N-bound saturated heterocycle, which, in addition to the nitrogen atom, may comprise a further heteroatom, selected from the group consisting of O, S and N as ring member and which is unsubstituted or carries 1, 2, 3 or 4 C 1 -C 4 -alkyl radicals;

or R Z is a radical SO 2 R Z3 or a radical S(O) 2 NR Z4 R Z5 ;

where R Z3 is C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy-C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, C 3 -C 6 -cycloalkyl, C 3 -C 6 -cycloalkylmethyl, phenyl or benzyl, wherein the phenyl ring in the last two mentioned radicals itself is unsubstituted or carries 1, 2, 3, 4 or 5 identical or different radicals 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,

R Z4 and R Z5 have one of the meanings given for R Z1 and R Z2 ;

Q is CH 2 or CH 2 CH 2 , where one or two of the hydrogen atoms in CH 2 or CH 2 CH 2 may be replaced by halogen, C 1 -C 4 -alkyl or C 1 -C 4 -haloalkyl;

R 1 is halogen, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, C 1 -C 6 -alkoxy, C 1 -C 4 -haloalkoxy, C 3 -C 3 -cycloalkyl, a radical NR 1a R 1b , C-bound 3- to 7-membered, saturated heterocyclyl having 1 or 2 nitrogen atoms and 0 or 1 heteroatoms, selected from the group consisting of O and S, as ring members, aryl, aryl-CH 2 , aryloxy, hetaryl, hetaryloxy or hetaryl-CH 2 , wherein the heterocyclyl, aryl and hetaryl ring in the last seven radicals themselves are unsubstituted or carry 1, 2, 3, 4 or 5 identical or different radicals R 1c ;

R 1a is hydrogen, C 1 -C 8 -alkyl, C 1 -C 8 -haloalkyl, C 1 -C 4 -alkoxy-C 1 -C 4 -alkyl, C 3 -C 8 -cycloalkyl, C 1 -C 8 -alkylcarbonyl, C 1 -C 8 -alkoxycarbonyl, benzyl, phenyl or 5- or 6-membered hetaryl, wherein the phenyl and hetaryl rings in the last three radicals itself are unsubstituted or carry 1, 2, 3, 4 or 5 identical or different radicals R 1c ;

R 1b is hydrogen or C 1 -C 4 -alkyl; or

NR 1a R 1b is a 3- to 10-membered mono- or bicyclic N-bound saturated heterocycle, which, in addition to the nitrogen atom, may comprise a further heteroatom, selected from the group consisting of O, S and N as ring member and which is unsubstituted or carries 1, 2, 3 or 4 radicals R 1c ;

R 1c is selected from the group consisting of halogen, CN, OH, C 1 -C 4 -alkyl, C 3 -C 6 -cycloalkyl, C 1 -C 4 -haloalkyl, C 1 -C 4 -alkoxy and C 1 -C 4 -haloalkoxy;

R 2 is hydrogen;

R 3 and R 4 are, independently of each other, selected from the group consisting of hydrogen, halogen, C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, C 3 -C 6 -cycloalkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -alkoxy-C 1 -C 4 -alkyl, phenyl, C 1 -C 4 -haloalkoxy, a radical (CH 2 ) n NR′R″, where R′ and R″ have one of the meanings given for R Z1 and R Z2 and wherein n is 0, 1, 2, 3 or 4,

or C-bound 3- to 10-membered, saturated heterocyclyl having 1 or 2 nitrogen atoms and 0 or 1 heteroatoms, selected from the group consisting of O and S, as ring members, where the heterocyclyl itself is unsubstituted or carries 1, 2, 3, 4 or 5 identical or different radicals R 6c , where R 6c has one of the meanings given for R 1c ;

R 5 is hydrogen, halogen, CN, C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -alkoxy-C 1 -C 4 -alkyl, C 1 -C 4 -haloalkoxy, (CH 2 ) n NR′R″, where R′ and R″ have one of the meanings given for R Z1 and R Z2 and wherein n is 0, 1, 2, 3 or 4,

or C-bound 3- to 10-membered, saturated heterocyclyl having 1 or 2 nitrogen atoms and 0 or 1 heteroatoms, selected from the group consisting of O and S, as ring members, where the heterocyclyl itself is unsubstituted or carries 1, 2, 3, 4 or 5 identical or different radicals R 6c , where R 6c has one of the meanings given for R 1c ;

R 6 , R 7 , Ware, independently of each other, selected from the group consisting of hydrogen, halogen, CN, C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -haloalkoxy, C 1 -C 4 -alkoxy-C 1 -C 4 -alkyl, (CH 2 ) n NR′R″, where R′ and R″ have one of the meanings given for R Z1 and R Z2 and wherein n is 0, 1, 2, 3 or 4,

or C-bound 3- to 10-membered, saturated heterocyclyl having 1 or 2 nitrogen atoms and 0 or 1 heteroatoms, selected from the group consisting of O and S, as ring members, where the heterocyclyl itself is unsubstituted or carries 1, 2, 3, 4 or 5 identical or different radicals R 6c , where R 6c has one of the meanings given for R 1c ;

R a is C 3 -C 6 -cycloalkyl, C 1 -C 6 -haloalkyl or C 1 -C 6 -alkyl, which is unsubstituted or carries one radical selected from the group consisting of C 1 -C 4 -alkoxy, C 1 -C 4 -haloalkoxy and a radical NR a1R a2 ,

where R a1 and R a2 are independently of each other selected from the group consisting of hydrogen, C 1 -C 4 -alkyl, C 3 -C 6 -cycloalkyl, C 3 -C 6 -cycloalkylmethyl and C 1 -C 4 -alkoxy-C 1 -C 4 -alkyl,

a radical NR a3 R a4 or a radical N═C(R a5)R a6 , where

R a3 and R a5 are independently of each other selected from the group consisting of hydrogen, C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, C 3 -C 6 -cycloalkyl, C 3 -C 6 -cycloalkylmethyl and C 1 -C 4 -alkoxy-C 1 -C 4 -alkyl;

R a4 and R a6 are independently of each other selected from the group consisting of hydrogen, C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, C 3 -C 6 -cycloalkyl, C 3 -C 6 -cycloalkylmethyl, C 1 -C 4 -alkoxy-C 1 -C 4 -alkyl, C-bound 3- to 10-membered, saturated heterocyclyl, 3- to 10-membered, saturated heterocyclylmethyl, where heterocyclyl in the last two mentioned radicals has 1 or 2 nitrogen atoms and 0 or 1 heteroatoms, selected from the group consisting of O and S, as ring members,

aryl, aryl-CH 2 , hetaryl and hetaryl-CH 2 , wherein the heterocycicyl, aryl and hetaryl rings ring in the last six radicals themselves are unsubstituted or carry 1, 2, 3, 4 or 5 identical or different radicals R ac , where R ac has one of the meanings given for R 1c ;

R b is hydrogen, halogen or C 1 -C 4 -alkyl;

or a pharmaceutically acceptable salt or N-oxide thereof.

2. The compound of claim 1 , wherein R 1 is phenyl or phenoxy, wherein the phenyl ring in these radicals itself is unsubstituted or carries 1, 2, 3, 4 or 5 identical or different radicals R 1c .

3. The compound of claim 1 , wherein R 1 is linear C 1 -C 6 -alkyl, branched C 3 -C 6 -alkyl, C 1 -C 6 -alkoxy, C 1 -C 4 -haloalkoxy, halogen, C 3 -C 6 -cycloalkyl or C 1 -C 6 -haloalkyl.

4. The compound of claim 1 , wherein R 1 is a radical NR 1a R 1b or C-bound 3- to 7-membered, saturated heterocyclyl having 1 or 2 nitrogen atoms and 0 or 1 heteroatoms, selected from the group consisting of O and S, as ring members, where the heterocyclyl itself is unsubstituted or carries 1, 2, 3, 4 or 5 identical or different radicals R 1c .

5. The compound of claim 1 , wherein Z is O or NH.

6. The compound of claim 1 , wherein X 3 is C—R 3 , wherein R 3 is hydrogen, chlorine, methyl or methoxy.

7. The compound of claim 1 , wherein X 4 is C—R 4 , wherein R 4 is hydrogen, chlorine, methyl or methoxy.

8. The compound of claim 6 , wherein X 2 is C—H, X 3 is C—R 3 and X 4 is C—R 4 , wherein R 3 and R 4 are, independently selected from the group consisting of hydrogen, chlorine, methyl and methoxy.

9. The compound of claim 1 , wherein Y 1 is C—R 5 , Y 2 is C, Y 3 is C—R 7 and Y 4 is N or C—R 8 .

10. The compound of claim 1 , wherein Y 1 is C—R 5 , Y 3 is C, Y 2 is C—R 6 and Y 4 is N or C—R 8 .

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

12. The compound of claim 1 , wherein R 6 , R 7 and R 8 , where present, are hydrogen.

13. The compound of claim 1 , wherein R a is C 3 -C 6 -alkyl or C 2 -C 6 -alkyl which carries one radical selected from the group consisting of C 1 -C 4 -alkoxy, C 1 -C 4 -haloalkoxy and the radical NR a1 R a2 , where R a1 and R a2 are independently of each other selected from the group consisting of hydrogen, C 1 -C 4 -alkyl, C 3 -C 6 -cycloalkyl, C 3 -C 6 -cycloalkylmethyl and C 1 -C 4 -alkoxy-C 1 -C 4 -alkyl.

14. The compound of claim 1 , wherein R a is a radical NR a3 R a4 , where

R a3 is selected from the group consisting of hydrogen, C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, C 3 -C 6 -cycloalkyl, C 3 -C 6 -cycloalkylmethyl and C 1 -C 4 -alkoxy-C 1 -C 4 -alkyl;

R a4 is selected from the group consisting of hydrogen, C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, C 3 -C 6 -cycloalkyl, C 3 -C 6 -cycloalkylmethyl, C 1 -C 4 -alkoxy-C 1 -C 4 -alkyl, C-bound 3- to 7-membered, saturated heterocyclyl, 3- to 7-membered, saturated heterocyclylmethyl, where heterocyclyl in the last two mentioned radicals has 1 or 2 nitrogen atoms and 0 or 1 heteroatoms, selected from the group consisting of O and S, as ring members, aryl, aryl-CH 2 , hetaryl and hetaryl-CH 2 , wherein the heterocycicyl, aryl and hetaryl rings ring in the last six radicals themselves are unsubstituted or carry 1, 2, 3, 4 or 5 identical or different radicals R ac , where R ac has one of the meanings given for R 1c .

15. The compound of claim 1 , wherein R b is hydrogen.

16. The compound of claim 1 of the formula Ia

wherein Z, Q, R 1 , R 3 , R 4 , R 5 and R a are as defined above.

17. A pharmaceutical composition comprising a carrier and a compound of claim 1 .

18. The compound of claim 1 , selected from the group consisting of

2-butyl-5-((2,6-dimethyl-4-phenylpyridin-3-yl)methoxy)isoindolin-1-one;

5-((2,6-dimethyl-4-phenylpyridin-3-yl)methoxy)-2-(2-(trifluoromethoxy)ethyl)isoindolin-1-one;

5-((4-phenoxypyridin-3-yl)methoxy)-2-propylisoindolin-1-one;

2-butyl-5-((2-chloro-4-phenylpyridin-3-yl)methoxy)isoindolin-1-one;

2-butyl-5-((2-chloro-4-iodopyridin-3-yl)methoxy)isoindolin-1-one;

5-(4-Phenyl-pyridin-3-ylmethoxy)-2-propyl-2,3-dihydro-isoindol-1-one;

5-(4-Phenyl-pyridin-3-ylmethoxy)-2-(2-trifluoromethoxy-ethyl)-2,3-dihydro-isoindol-1-one;

[3-(1-oxo-2-propyl-2,3-dihydro-1H-isoindo1-5-yloxymethyl)-pyridin-4-yl]-carbamic acid tert-butyl ester, trifluoroacetate;

2-Butyl-5-(2,6-dimethyl-4-phenyl-pyridin-3-ylmethoxy)-2,3-dihydroisoindol-1-one;

5-(2,6-Dimethyl-4-phenyl-pyridin-3-ylmethoxy)-2-(2-trifluoromethoxyethyl)-2,3-dihydro-isoindol-1-one, trifluoroacetate;

5-(2,6-Dimethyl-4-phenyl-pyridin-3-ylmethoxy)-2-ethyl-2,3-dihydroisoindol-1-one;

5-[(4-methoxypyridin-3-yl)methoxy]-2-propyl-2,3-dihydro-1H-isoindol-1-one;

2-butyl-5-((2,6-dimethyl-4-phenylpyridin-3-yl)methylamino)isoindolin-1-one;

2-butyl-5-((4-(trifluoromethyl)pyridin-3-yl)methylamino)isoindolin-1-one;

2-butyl-5-((4-phenylpyridin-3-yl)methylamino)isoindolin-1-one;

2-butyl-5-((4-phenoxypyridin-3-yl)methylamino)isoindolin-1-one;

2-butyl-5-((2-chloro-4-(trifluoromethyl)pyridin-3-yl)methylamino)-isoindolin-1-one;

5-((4-aminopyridin-3-yl)methylamino)-2-butylisoindolin-1-one;

2-butyl-5-((4-(phenylamino)pyridin-3-yl)methylamino)isoindolin-1-one;

4-(3-((2-butyl-1-oxoisoindolin-5-ylamino)methyl)pyridin-4-yl)benzonitrile;

2-butyl-5-((4-(4-(trifluoromethyl)phenyl)pyridin-3-yl)methylamino)-isoindolin-1-one;

7-chloro-2-cyclopropyl-5-{[(2,6-dimethyl-4-phenylpyridin-3-yl)methyl]amino}-2,3-dihydro-1H-isoindol-1-one;

7-chloro-5-({[2-chloro-4-(trifluoromethyl)pyridin-3-yl]methyl}amino)-2-cyclopropyl-2,3-dihydro-1H-isoindol-1-one;

2-butyl-5-({[4-(morpholin-4-yl)pyridin-3-yl]methyl}amino)-2,3-dihydro-1H-isoindol-1-one;

2-butyl-5-({[4-(4-methylpiperazin-1-yl)pyridin-3-yl]methyl}amino)-2,3-dihydro-1H-isoindol-1 -one;

2-butyl-5-({[2-chloro-4-(trifluoromethyl)pyridin-3-yl]methyl}amino)-7-methyl-2,3-dihydro-1H-isoindol-1-one;

2-butyl-7-chloro-5-({[2-chloro-4-(trifluoromethyl)pyridin-3-yl]methyl}amino)-2,3-dihydro-1H-isoindol-1-one;

5-({[2-chloro-4-(trifluoromethyl)pyridin-3-yl]methyl}amino)-7-methyl-2-(2,2,2-trifluoroethyl)-2,3-dihydro-1H-isoindol-1-one;

5-({[2-chloro-4-(trifluoromethyl)pyridin-3-yl]methyl}amino)-7-methyl-2-propyl-2,3-dihydro-1H-isoindol-1-one;

5-({[2-chloro-4-(trifluoromethyl)pyridin-3-yl]methyl}amino)-2-ethyl-7-methyl-2,3-dihydro-1H-isoindol-1-one;

2-butyl-5-{[(2-chloro-4-methylpyridin-3-yl)methyl]amino}-2,3-dihydro-1H-isoindol-1-one;

2-butyl-5-{[(2,4-dichloropyridin-3-yl)methyl]amino}-2,3-dihydro-1H-isoindol-1-one;

5-({[2-chloro-4-(trifluoromethyl)pyridin-3-yl]methyl}amino)-2-(2-methoxyethyl)-7-methyl-2,3-dihydro-1H-isoindol-1-one;

2-butyl-5-{[(2,4-dichloro-6-methylpyridin-3-yl)methyl]amino}-2,3-dihydro-1H-isoindol-1-one;

5-({[2-chloro-4-(trifluoromethyl)pyridin-3-yl]methyl}amino)-2-(2-methoxyethyl)-2,3-dihydro-1H-isoindol-1-one;

5-((4-(benzylamino)pyridin-3-yl)methylamino)-2-butylisoindolin-1-one;

N-(3-((2-butyl-1-oxoisoindolin-5-ylamino)methyl)pyridin-4-yl)pivalamide;

2,6-dimethyl-3-((1-oxo-2-(2-(trifluoromethoxy)ethyl)-isoindolin-5-yloxy)-methyl)-4-phenylpyridine 1-oxide;

7-Methyl-5-[(4-morpholin-4-yl-pyridin-3-ylmethyl)-amino]-2-(2,2,2-trifluoro-ethyl)-2,3-dihydro-isoindol-1-one;

2-Butyl-7-methyl-5-[(4-morpholin-4-yl-pyridin-3-ylmethyl)-amino]-2,3-dihydro-isoindol-1-one;

7-Methyl-5-[(4-morpholin-4-yl-pyridin-3-ylmethyl)-amino]-2-propyl-2,3-dihydro-isoindol-1-one;

2-Ethyl-7-methyl-5-[(4-morpholin-4-yl-pyridin-3-ylmethyl)-amino]-2,3-dihydro-isoindol-1-one;

2-Butyl-5-[(2-methyl-4-morpholin-4-yl-pyridin-3-ylmethyl)-amino]-2,3-dihydro-isoindol-1-one;

2-Butyl-5-[(4-[1,4]oxazepan-4-yl-pyridin-3-ylmethyl)-amino]-2,3-dihydro-isoindol-1-one;

2-Butyl-5-({4-[(3-methoxy-propyl)-methyl-amino]-pyridin-3-ylmethyl}-amino)-2,3-dihydro-isoindol-1-one;

2-Butyl-5-({4-[ethyl-(2-methoxy-ethyl)-amino]-pyridin-3-ylmethyl}-amino)-2,3-dihydro-isoindol-1-one;

2-Butyl-5-({4-[(2-methoxy-ethyl)-methyl-amino]-pyridin-3-ylmethyl}-amino)-2,3-dihydro-isoindol-1-one;

2-Butyl-5-(4-methoxy-pyridin-3-ylmethoxy)-2,3-dihydro-isoindol-1-one; and

2-Butyl-5-(4-morpholin-4-yl-pyridin-3-ylmethoxy)-2,3-dihydroisoindol-1-one,

or a pharmaceutically acceptable salt or N-oxide thereof.

19. A method for treating a medical disorder, selected from the group consisting of anxiety, depression, schizophrenia, and epilepsy in a mammalian, said method comprising administering an effective amount of at least one compound of claim 1 to a subject in need thereof.