Compounds as metabotropic glutamate receptor antagonists

1. A compound of formula (I):

wherein

E, J and L are N; M is CH; and G=C;

R 1 and R 2 are each independently H, halogen, C 1-6 -alkyl optionally substituted by one or more F or C 1-6 -alkoxy, or C 1-6 -alkoxy optionally substituted by one or more F;

R 3 is H, —C(CH 3 ) 2 OH, or linear C 1-4 -alkyl or C 3-4 -cycloalkyl each of the latter three is optionally substituted by one or more substituent(s) selected from the group consisting of 1 to 6 F and 1 to 2 OH;

A is selected from the group consisting of aryl and 5 or 6-membered heteroaryl each of which is optionally substituted by one to four R a ;

R a is F, OH, amino, C 1-6 -alkyl optionally substituted by OH, C 1-6 -alkoxy, C 3-4 -cycloalkyl, —CO—R b , SO 2 —R c or SO 2 —NR d R e ;

R b is amino;

R c is OH or C 1-6 -alkyl;

R d and R e are the same or different and are selected from the group consisting of:

H;

straight or branched C 1-6 -alkyl optionally substituted by one or more substituent(s) selected from the group consisting of F, cyano, OH, di(C 1-6 -alkyl)amino, C 3-6 -cycloalkyl, 5 or 6-membered heterocycloalkyl, aryl and 5 or 6-membered heteroaryl;

C 3-6 -cycloalkyl;

aryl; and

5 or 6-membered heteroaryl;

or R d and R e together with the nitrogen atom to which they are attached, form a heterocyclic ring of 4 to 6 ring members which is optionally substituted by OH or C 1-6 -alkyl;

or a pharmaceutically acceptable salt thereof.

2. A compound of claim 1 having formula (I-a):

3. The compound of claim 2 , wherein:

R 1 is halo or CF 3 ;

R 2 is H, halo, or C 1-6 -alkyl or C 1-6 -alkoxy each of the latter two is optionally substituted by one or more F;

R 3 is H, linear C 1-4 -alkyl, or C 3-4 -cycloalkyl each of the latter two is optionally substituted by 1 to 6 F;

A is selected from the group consisting of aryl and 5 or 6-membered heteroaryl each of which is optionally substituted by one to four R a ;

R a is amino or SO 2 —NR d R e ; wherein R d and R e are each H;

or a pharmaceutically acceptable salt thereof.

4. The compound of claim 3 , wherein:

R 1 is Cl, F or CF 3 ;

R 2 is H, F, Cl, methyl, OEt, CHF 2 , CF 3 , OCF 3 or OCH 2 CF 3 ;

R 3 is H, methyl or cyclopropyl, each of the latter two is optionally substituted by 2 or 3 F;

A is selected from the group consisting of phenyl, thiophenyl, pyridinyl, pyrimidinyl and pyrazolyl, each of which is optionally substituted by one R a ;

R a is amino or SO 2 —NR d R e ; wherein R d and R e are each H;

or a pharmaceutically acceptable salt thereof.

5. The compound of claim 4 , selected from the group consisting of:

4-{5-[7-Trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidin-3-yl]-[1,2,4]oxadiazol-3-yl}-benzenesulfonamide;

3-{5-[7-Trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidin-3-yl]-[1,2,4]oxadiazol-3-yl}-benzenesulfonamide;

3-(3-Pyridin-3-yl-[1,2,4]oxadiazol-5-yl)-7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine;

4-{5-[7-Difluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidin-3-yl]-[1,2,4]oxadiazol-3-yl}-benzenesulfonamide;

3-{5-[7-Difluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidin-3-yl]-[1,2,4]oxadiazol-3-yl}-benzenesulfonamide;

3-{5-[5-(4-Chloro-phenyl)-7-cyclopropyl-pyrazolo[1,5-a]pyrimidin-3-yl]-[1,2,4]oxadiazol-3-yl}-benzenesulfonamide;

3-{5-[7-Cyclopropyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidin-3-yl]-[1,2,4]oxadiazol-3-yl}-benzenesulfonamide;

4-{5-[5-(4-Chloro-phenyl)-7-cyclopropyl-pyrazolo[1,5-a]pyrimidin-3-yl]-[1,2,4]oxadiazol-3-yl}-benzenesulfonamide;

4-{5-[7-Cyclopropyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidin-3-yl]-[1,2,4]oxadiazol-3-yl}-benzenesulfonamide; and

3-{5-[5-(4-Chloro-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidin-3-yl]-[1,2,4]oxadiazol-3-yl}-benzenesulfonamide.

6. The compound of claim 4 , selected from the group consisting of:

4-{5-[5-(4-Chloro-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidin-3-yl]-[1,2,4]oxadiazol-3-yl}-benzenesulfonamide;

4-{3-[7-Trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidin-3-yl]-[1,2,4]oxadiazol-5-yl}-benzenesulfonamide;

3-{3-[7-Trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidin-3-yl]-[1,2,4]oxadiazol-5-yl}-benzenesulfonamide;

3-(5-{5-[3-(2,2,2-Trifluoro-ethoxy)-4-trifluoromethyl-phenyl]-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidin-3-yl}-[1,2,4]oxadiazol-3-yl)-benzenesulfonamide;

3-{5-[5-(3-Methyl-4-trifluoromethyl-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidin-3-yl]-[1,2,4]oxadiazol-3-yl}-benzenesulfonamide;

4-{5-[5-(3-Methyl-4-trifluoromethyl-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidin-3-yl]-[1,2,4]oxadiazol-3-yl}-benzenesulfonamide;

3-{5-[5-(4-Chloro-phenyl)-7-difluoromethyl-pyrazolo[1,5-a]pyrimidin-3-yl]-[1,2,4]oxadiazol-3-yl}-benzenesulfonamide;

5-{5-[5-(4-Chloro-phenyl)-7-cyclopropyl-pyrazolo[1,5-a]pyrimidin-3-yl]-[1,2,4]oxadiazol-3-yl}-thiophene-2-sulfonic acid amide;

5-{5-[5-(3-Methyl-4-trifluoromethyl-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidin-3-yl]-[1,2,4]oxadiazol-3-yl}-thiophene-2-sulfonic acid amide; and

5-(5-{5-[3-(2,2,2-Trifluoro-ethoxy)-4-trifluoromethyl-phenyl]-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidin-3-yl}-[1,2,4]oxadiazol-3-yl)-thiophene-2-sulfonic acid amide.

7. The compound of claim 4 , selected from the group consisting of:

5-{5-[7-Cyclopropyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidin-3-yl]-[1,2,4]oxadiazol-3-yl}-thiophene-2-sulfonic acid amide;

4-{5-[7-Trifluoromethyl-5-(3-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidin-3-yl]-[1,2,4]oxadiazol-3-yl}-benzenesulfonamide;

3-{5-[7-Trifluoromethyl-5-(3-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidin-3-yl]-[1,2,4]oxadiazol-3-yl}-benzenesulfonamide;

5-{5-[7-Trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidin-3-yl]-[1,2,4]oxadiazol-3-yl}-thiophene-2-sulfonic acid amide;

5-{5-[5-(4-Chloro-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidin-3-yl]-[1,2,4]oxadiazol-3-yl}-thiophene-2-sulfonic acid amide;

5-{5-[5-(4-Chloro-phenyl)-7-difluoromethyl-pyrazolo[1,5-a]pyrimidin-3-yl]-[1,2,4]oxadiazol-3-yl}-thiophene-2-sulfonic acid amide;

5-{5-[7-Methyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidin-3-yl]-[1,2,4]oxadiazol-3-yl}-thiophene-2-sulfonic acid amide;

5-{5-[7-Difluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidin-3-yl]-[1,2,4]oxadiazol-3-yl}-thiophene-2-sulfonic acid amide;

5-{5-[5-(4-Chloro-phenyl)-7-methyl-pyrazolo[1,5-a]pyrimidin-3-yl]-[1,2,4]oxadiazol-3-yl}-thiophene-2-sulfonic acid amide; and

5-{3-[7-Trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidin-3-yl]-[1,2,4]oxadiazol-5-yl}-thiophene-2-sulfonic acid amide.

8. The compound of claim 4 , selected from the group consisting of:

5-{5-[7-Trifluoromethyl-5-(3-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidin-3-yl]-[1,2,4]oxadiazol-3-yl}-pyridin-2-ylamine;

5-{5-[7-Trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidin-3-yl]-[1,2,4]oxadiazol-3-yl}-pyridin-2-ylamine;

5-{5-[7-Difluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidin-3-yl]-[1,2,4]oxadiazol-3-yl}-pyridin-2-ylamine;

5-{5-[5-(3-Methyl-4-trifluoromethyl-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidin-3-yl]-[1,2,4]oxadiazol-3-yl}-pyridin-2-ylamine;

3-{5-[5-(4-Chloro-phenyl)-7-methyl-pyrazolo[1,5-a]pyrimidin-3-yl]-[1,2,4]oxadiazol-3-yl}-benzenesulfonamide;

5-{5-[7-Trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidin-3-yl]-[1,2,4]oxadiazol-3-yl}-pyrimidin-2-ylamine;

3-{5-[5-(4-Chloro-phenyl)-pyrazolo[1,5-a]pyrimidin-3-yl]-[1,2,4]oxadiazol-3-yl}-benzenesulfonamide;

5-{5-[5-(4-Trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidin-3-yl]-[1,2,4]oxadiazol-3-yl}-thiophene-2-sulfonic acid amide;

3-{5-[5-(4-Trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidin-3-yl]-[1,2,4]oxadiazol-3-yl}-benzenesulfonamide; and

4-{5-[7-Trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidin-3-yl]-[1,2,4]oxadiazol-3-yl}-pyridin-2-ylamine.

9. The compound of claim 4 , selected from the group consisting of:

4-{5-[5-(4-Trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidin-3-yl]-[1,2,4]oxadiazol-3-yl}-pyridin-2-ylamine;

5-{5-[5-(4-Chloro-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidin-3-yl]-[1,2,4]oxadiazol-3-yl}-pyridin-2-ylamine;

5-{5-[5-(4-Chloro-phenyl)-7-difluoromethyl-pyrazolo[1,5-a]pyrimidin-3-yl]-[1,2,4]oxadiazol-3-yl}-pyridin-2-ylamine;

5-{5-[5-(4-Chloro-3-methyl-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidin-3-yl]-[1,2,4]oxadiazol-3-yl}-pyridin-2-ylamine;

5-{5-[7-Difluoromethyl-5-(3-methyl-4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidin-3-yl]-[1,2,4]oxadiazol-3-yl}-pyridin-2-ylamine;

5-{5-[5-(3,4-Dichloro-phenyl)-7-difluoromethyl-pyrazolo[1,5-a]pyrimidin-3-yl]-[1,2,4]oxadiazol-3-yl}-pyridin-2-ylamine;

5-{5-[5-(3,4-Dichloro-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidin-3-yl]-[1,2,4]oxadiazol-3-yl}-pyridin-2-ylamine;

5-{5-[7-Difluoromethyl-5-(3-ethoxy-4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidin-3-yl]-[1,2,4]oxadiazol-3-yl}-pyridin-2-ylamine; and

5-{5-[5-(3-Ethoxy-4-trifluoromethyl-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidin-3-yl]-[1,2,4]oxadiazol-3-yl}-pyridin-2-ylamine.

10. The compound of claim 4 , selected from the group consisting of:

5-(5-{5-[3-(2,2,2-Trifluoro-ethoxy)-4-trifluoromethyl-phenyl]-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidin-3-yl}-[1,2,4]oxadiazol-3-yl)-pyridin-2-ylamine;

5-(5-{7-Difluoromethyl-5-[3-(2,2,2-trifluoro-ethoxy)-4-trifluoromethyl-phenyl]-pyrazolo[1,5-a]pyrimidin-3-yl}-[1,2,4]oxadiazol-3-yl)-pyridin-2-ylamine;

5-{5-[5-(3-Chloro-4-trifluoromethyl-phenyl)-7-difluoromethyl-pyrazolo[1,5-a]pyrimidin-3-yl]-[1,2,4]oxadiazol-3-yl}-pyridin-2-ylamine;

5-{5-[5-(3-Chloro-4-trifluoromethyl-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidin-3-yl]-[1,2,4]oxadiazol-3-yl}-pyridin-2-ylamine;

5-{5-[7-Difluoromethyl-5-(3-fluoro-4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidin-3-yl]-[1,2,4]oxadiazol-3-yl}-pyridin-2-ylamine;

5-{5-[5-(3-Fluoro-4-trifluoromethyl-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidin-3-yl]-[1,2,4]oxadiazol-3-yl}-pyridin-2-ylamine;

5-{5-[5-(3,4-Difluoro-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidin-3-yl]-[1,2,4]oxadiazol-3-yl}-pyridin-2-ylamine;

5-{5-[5-(4-Chloro-3-methyl-phenyl)-7-difluoromethyl-pyrazolo[1,5-a]pyrimidin-3-yl]-[1,2,4]oxadiazol-3-yl}-pyridin-2-ylamine; and

5-{5-[5-(3,4-Difluoro-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidin-3-yl]-[1,2,4]oxadiazol-3-yl}-pyrimidin-2-ylamine.

11. The compound of claim 4 , selected from the group consisting of:

5-{5-[5-(3-Fluoro-4-trifluoromethyl-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidin-3-yl]-[1,2,4]oxadiazol-3-yl}-pyrimidin-2-ylamine;

5-{5-[5-(3-Chloro-4-trifluoromethyl-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidin-3-yl]-[1,2,4]oxadiazol-3-yl}-pyrimidin-2-ylamine;

5-{5-[5-(3,4-Dichloro-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidin-3-yl]-[1,2,4]oxadiazol-3-yl}-pyrimidin-2-ylamine;

5-{5-[5-(4-Chloro-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidin-3-yl]-[1,2,4]oxadiazol-3-yl}-pyrimidin-2-ylamine;

5-{5-[5-(3-Methyl-4-trifluoromethyl-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidin-3-yl]-[1,2,4]oxadiazol-3-yl}-pyrimidin-2-ylamine;

5-{5-[5-(4-Chloro-3-methyl-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidin-3-yl]-[1,2,4]oxadiazol-3-yl}-pyrimidin-2-ylamine;

4-{5-[5-(4-Chloro-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidin-3-yl]-[1,2,4]oxadiazol-3-yl}-pyridin-2-ylamine;

4-{5-[5-(3,4-Dichloro-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidin-3-yl]-[1,2,4]oxadiazol-3-yl}-pyridin-2-ylamine; and

4-{5-[5-(3-Methyl-4-trifluoromethyl-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidin-3-yl]-[1,2,4]oxadiazol-3-yl}-pyridine-2-ylamine.

12. The compound of claim 1 , wherein E and J are N, G is C and one of L or M is N and the other is CH.

13. The compound of claim 1 , wherein A is aryl optionally substituted by one to four R a .

14. A pharmaceutical composition comprising compound of formula I

wherein

E, J and L are N; M is CH; and G=C;

R 1 and R 2 are each independently H, halogen, C 1-6 -alkyl optionally substituted by one or more F or C 1-6 -alkoxy, or C 1-6 -alkoxy optionally substituted by one or more F;

R 3 is H, —C(CH 3 ) 2 OH, or linear C 1-4 -alkyl or C 3-4 -cycloalkyl each of the latter three is optionally substituted by one or more substituent(s) selected from the group consisting of 1 to 6 F and 1 to 2 OH;

A is selected from the group consisting of aryl and 5 or 6-membered heteroaryl each of which is optionally substituted by one to four R a ;

R a is F, OH, amino, C 1-6 -alkyl optionally substituted by OH, C 1-6 -alkoxy, C 3-4 -cycloalkyl, —CO—R b , SO 2 —R c or SO 2 —NR d R e ;

R b is amino;

R c is OH or C 1-6 -alkyl;

R d and R e can be the same or different and are selected from the group consisting of:

H;

straight or branched C 1-6 -alkyl optionally substituted by one or more substituent(s) selected from the group consisting of F, cyano, OH, di(C 1-6 -alkyl)amino, C 3-6 -cycloalkyl, 5 or 6-membered heterocycloalkyl, aryl and 5 or 6-membered heteroaryl;

C 3-6 -cycloalkyl;

aryl; and

5 or 6-membered heteroaryl;

or R d and R e together with the nitrogen atom to which they are attached, form a heterocyclic ring of 4 to 6 ring members which is optionally substituted by OH or C 1-6 -alkyl;

or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.