Substituted imidazo-[1,5-a][1,2,4]triazolo[1,5-d][1,4] benzodiazepine derivatives

1. A compound of formula I

wherein

R 1 and R 1′ are each independently hydrogen, hydroxy, lower alkyl, lower alkynyl, halogen, lower alkoxy, cycloalkyl, or lower alkyl or alkoxy each of which is substituted by halogen;

X is —CH 2 —, —CH(CH 3 )—, —CH 2 —O—, —CRR′— or —C(O)—;

R 2 is —(CH 2 ) n -O-lower alkyl,

halogen,

—NHCH 3 ,

—N(CH 3 )C(O)-cycloalkyl,

—N(CH 3 )C(O)-lower alkyl,

—N(CH 3 )S(O 2 )CH 3 ,

—NHC(O)CH 2 OC(O)CH 3 ,

—CF 3 ,

cycloalkyl,

hydroxy,

—CH 2 OH,

cyano,

S(O) 2 CH 3 ,

—CH(OH)-lower alkyl,

aryl unsubstituted or substituted by lower alkoxy,

an aromatic or non aromatic heterocyclic ring, containing from 1 to 3 heteroatoms selected from the group consisting of N, O and S, and wherein the heterocyclic ring is unsubstituted or substituted by 1-4 substituents selected from the group consisting of lower alkyl, lower alkoxy, cycloalkyl, ═O, CF 3 , CN, C(O)O-lower alkyl, benzyl, phenyl, —CH 2 O-lower alkyl, CHO and 3-bromo-10-chloro-9H-imidazo[1,5-a][1,2,4]triazolo[1,5-d][1,4]benzodiazepin-6-ylmethyl,

—C(O)—O-lower alkyl,

—C(O)NH—(CH 2 ) n -cycloalkyl,

—C(O)NH—(CH 2 ) n -aromatic or non aromatic heterocyclic ring, wherein the heterocyclic ring contains from 1 to 3 heteroatoms selected from the group consisting of N, O and S,

—C(O)NH—(CH 2 ) n OH,

—C(O)-aromatic or non aromatic heterocyclic ring, wherein the heterocyclic ring contains from 1 to 3 heteroatoms selected from the group consisting of N, O and S, unsubstituted or substituted by lower alkyl,

—NH—C(O)H,

—N(CH 3 )—C(O)H,

—NH—C(O)-lower alkyl,

—NH—C(O)-cycloalkyl,

—NH—C(O)—O-lower alkyl,

—NH—C(O)—N-di-lower alkyl,

—NH—C(O)—CH 2 —O-lower alkyl,

—NH—C(O)—CH 2 —OH,

—NH—(CH 2 ) n -cycloalkyl,

—NH—(CH 2 ) n S(O) 2 CH 3 ,

—NH—(CH 2 ) n -aromatic or non aromatic heterocyclic ring, wherein the heterocyclic ring contains from 1 to 3 heteroatoms selected from the group consisting of N, O and S, or

—NH—(CH 2 ) n OH; or

X—R 2 is lower alkyl with the exception of methyl or is cycloalkyl, which is unsubstituted or substituted by lower alkyl or hydroxy,

an aromatic or non aromatic heterocyclic ring, which contains from 1 to 3 heteroatoms selected from the group consisting of N, O and S, or

—CHRR′;

R is hydroxy;

R′ is cycloalkyl, lower alkyl, lower alkyl substituted by halogen, phenyl or pyridinyl;

R 3 is hydrogen, halogen, C(O)O-lower alkyl, CH 2 OH, CHO, lower alkyl, or lower alkyl substituted by halogen; and

n is 0, 1 or 2;

or a pharmaceutically acceptable acid addition salt thereof.

2. The compound of claim 1 , wherein X is —CH 2 —.

3. The compound of claim 1 , in which R 2 is —(CH 2 ) n O-lower alkyl.

4. The compound of claim 3 , selected from the group consisting of

ethyl 3-chloro-6-methoxymethyl-9H-imidazo[1,5-a][1,2,4]triazolo[1,5-d][1,4]benzodiazepine-10-carboxylate and

ethyl 3-bromo-6-methoxymethyl-9H-imidazo[1,5-a][1,2,4]triazolo[1,5-d][1,4]benzodiazepine-10-carboxylate.

5. The compound of claim 2 , in which R 2 is an aromatic heterocyclic ring, containing from 1 to 3 heteroatoms selected from the group consisting of N, O and S, and wherein the heterocyclic ring is unsubstituted or substituted by 1-4 substituents selected from the group consisting of lower alkyl, ═O, CF 3 , C(O)O-lower alkyl, benzyl, phenyl, CH 2 O-lower alkyl and CHO.

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

3,10-dichloro-6-[1,2,3]triazol-2-ylmethyl-9H-imidazo[1,5-a][1,2,4]triazolo[1,5-d][1,4]benzodiazepine,

3,10-dichloro-6-[1,2,3]triazol-1-ylmethyl-9H-imidazo[1,5-a][1,2,4]triazolo[1,5-d][1,4]benzodiazepine,

3,10-dichloro-6-[1,2,4]triazol-1-ylmethyl-9H-imidazo[1,5-a][1,2,4]triazolo[1,5-d][1,4]benzodiazepine,

3,10-dichloro-6-pyrazol-1-ylmethyl-9H-imidazo[1,5-a][1,2,4]triazolo[1,5-d][1,4]benzodiazepine,

6-benzotriazol-2-ylmethyl-3,10-dichloro-9H-imidazo[1,5-a][1,2,4]triazolo[1,5-d][1,4]benzodiazepine,

6-benzotriazol-1-ylmethyl-3,10-dichloro-9H-imidazo[1,5-a][1,2,4]triazolo[1,5-d][1,4]benzodiazepine,

3,10-dichloro-6-indazol-2-ylmethyl-9H-imidazo[1,5-a][1,2,4]triazolo[1,5-d][1,4]benzodiazepine, and

3-bromo-10-chloro-6-(5-methyl-[1,2,4]oxadiazol-3-ylmethyl)-9H-imidazo[1,5-a][1,2,4]triazolo[1,5-d][1,4]benzodiazepine.

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

3-bromo-10-methyl-6-(pyridine-4-ylmethyl)-9H-imidazo[1,5-a][1,2,4]triazolo[1,5-d][1,4]benzodiazepine,

3-bromo-10-methyl-6-(3-methyl-isoxazol-5-ylmethyl)-9H-imidazo[1,5-a][1,2,4]triazolo[1,5-d][1,4]benzodiazepine,

3-bromo-10-methyl-6-(6-methyl-pyridin-3-ylmethyl)-9H-imidazo[1,5-a][1,2,4]triazolo[1,5-d][1,4]benzodiazepine,

3-bromo-10-methyl-6-[1,2,3 ]triazol-1-ylmethyl-9H-imidazo[1,5-a][1,2,4]triazolo[1,5-d][1,4]benzodiazepine,

3-chloro-10-methyl-6-(3-methyl-isoxazol-5-ylmethyl)-9H-imidazo[1,5-a][1,2,4]triazolo[1,5-d][1,4]benzodiazepine,

3-chloro-10-methyl-6-(6-methyl-pyridin-3-ylmethyl)-9H-imidazo[1,5-a][1,2,4]triazolo[1,5-d][1,4]benzodiazepine,

3-chloro-10-methyl-6-(2-methyl-pyridin-4-ylmethyl)-9H-imidazo[1,5-a][1,2,4]triazolo[1,5-d][1,4]benzodiazepine, and

3,10-dimethyl-6-(3-methyl-isoxazol-5-ylmethyl)-9H-imidazo[1,5-a][1,2,4]triazolo[1,5-d][1,4]benzodiazepine.

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

10-methyl-6-(pyridine-2-ylmethyl)-9H-imidazo[1,5-a][1,2,4]triazolo[1,5-d][1,4]benzodiazepine,

10-methyl-6-(pyridine-3-ylmethyl)-9H-imidazo[1,5-a][1,2,4]triazolo[1,5-d][1,4]benzodiazepine,

6-(imidazol-1-ylmethyl)-10-methyl-9H-imidazo[1,5-a][1,2,4]triazolo[1,5-d][1,4]benzodiazepine,

3-bromo-10-methyl-6-(6-oxo-6H-pyridazin-1-ylmethyl)-9H-imidazo[1,5-a][1,2,4]triazolo[1,5-d][1,4]benzodiazepine,

3-bromo-10-methyl-6-(3-methyl-[1,2,4]oxadiazol-5-ylmethyl)-9H-imidazo[1,5-a][1,2,4]triazolo[1,5-d][1,4]benzodiazepine,

3-chloro-10-methyl-6-[1,2,3]triazol-1-ylmethyl-9H-imidazo[1,5-a][1,2,4]triazolo[1,5-d][1,4]benzodiazepine,

10-methyl-6-(2-oxo-2H-pyridin-1-ylmethyl)-9H-imidazo[1,5-a][1,2,4]triazolo[1,5-d][1,4]benzodiazepine and

10-methyl-6-(2H-pyrazol-3-ylmethyl)-9H-imidazo[1,5-a][1,2,4]triazolo[1,5-d][1,4]benzodiazepine.

9. The compound of claim 2 , in which R 2 is a non aromatic heterocyclic ring, containing from 1 to 3 heteroatoms selected from the group consisting of N, O and S, and wherein the heterocyclic ring is unsubstituted or substituted by 1-4 substituents selected from the group consisting of lower alkyl, ═O, CF 3 , C(O)O-lower alkyl, benzyl, phenyl, CH 2 O-lower alkyl and CHO.

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

3-bromo-10-chloro-6-(2-oxo-pyrrolidin-1-ylmethyl)-9H-imidazo[1,5-a][1,2,4]triazolo[1,5-d][1,4]benzodiazepine,

3-bromo-10-chloro-6-(2-oxo-oxazolidin-3-ylmethyl)-9H-imidazo[1,5-a][1,2,4]triazolo[1,5-d][1,4]benzodiazepine,

3-bromo-10-chloro-6-(5-methoxymethyl-2-oxo-oxazolidin-3-ylmethyl)-9H-imidazo[1,5-a][1,2,4]triazolo[1,5-d][1,4]benzodiazepine,

3-bromo-10-chloro-6-(3-methyl-2-oxo-imidazolidin-1-ylmethyl)-9H-imidazo[1,5-a][1,2,4]triazolo[1,5-d][1,4]benzodiazepine,

3-bromo-10-chloro-6-(2-oxo-imidazolidin-1-ylmethyl)-9H-imidazo[1,5-a][1,2,4]triazolo[1,5-d][1,4]benzodiazepine,

3-bromo-10-chloro-6-(2,4-dioxo-thiazolidin-3-ylmethyl)-9H-imidazo[1,5-a][1,2,4]triazolo[1,5-d][1,4]benzodiazepine,

3-bromo-10-chloro-6-(2,5-dioxo-pyrrolidin-1-ylmethyl)-9H-imidazo[1,5-a][1,2,4]triazolo[1,5-d][1,4 ]benzodiazepine,

3-bromo-10-chloro-6-(2-oxo-thiazolidin-3-ylmethyl)-9H-imidazo[1,5-a][1,2,4]triazolo[1,5-d][1,4]benzodiazepine,

3-bromo-10-chloro-6-((5S)-5-methyl-2-oxo-oxazolidin-3-ylmethyl)-9H-imidazo[1,5-a][1,2,4]triazolo[1,5-d][1,4]benzodiazepine and

3,10-dichloro-6-(2-oxo-oxazolidin-3-ylmethyl)-9H-imidazo[1,5-a][1,2,4]triazolo[1,5-d][1,4]benzodiazepine.

11. The compound of claim 2 , in which R 2 is —C(O)NH—(CH 2 ) n -cycloalkyl or —C(O)NH—(CH 2 ) n -aromatic or non aromatic heterocyclic ring, wherein the heterocyclic ring contains from 1 to 3 heteroatoms selected from the group consisting of N, O and S.

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

3-bromo-10-chloro-6-cyclopentylcarbamoylmethyl-9H-imidazo[1,5-a][1,2,4]triazolo[1,5-d][1,4]benzodiazepine,

3-bromo-10-chloro-6-[(tetrahydro-pyran-4-ylcarbamoyl)-methyl]-9H-imidazo[1,5-a][1,2,4]triazolo[1,5-d][1,4]benzodiazepine,

3-bromo-10-chloro-6-{[(pyridin-3-ylmethyl)-carbamoyl]-methyl}-9 H-imidazo[1,5-a][1,2,4]triazolo[1,5-d][1,4]benzodiazepine

3-bromo-10-chloro-6-[(cyclopropylmethyl-carbamoyl)-methyl]-9H-imidazo[1,5-a][1,2,4]triazolo[1,5-d][1,4]benzodiazepine.

13. The compound of claim 2 , in which R 2 is —C(O)NH—(CH 2 ) n OH.

14. The compound of claim 13 , which compound is

3-bromo-10-chloro-6-[(2-hydroxy-ethylcarbamoyl)-methyl]-9H-imidazo[1,5-a][1,2,4]triazolo[1,5-d][1,4]benzodiazepine.

15. The compound of claim 2 , wherein R 2 is aryl, which is unsubstituted or substituted by lower alkoxy.

16. The compound of claim 15 , which compound is

3-Bromo-6-(2-methoxy-benzyl)-10-methyl-9H-imidazo[1,5-a][1,2,4]triazolo[1,5-d][1,4]benzodiazepine.

17. The compound of claim 1 , wherein X is —CH(CH 3 ).

18. The compound of claim 1 , wherein X is CH 2 O.

19. The compound of claim 1 , wherein X is CRR′.

20. The compound of claim 1 , wherein X is C(O).

21. The compound of claim 1 wherein X—R 2 is lower alkyl, except for methyl.

22. The compound of claim 1 , wherein X—R 2 is cycloalkyl, which is unsubstituted or substituted by lower alkyl or hydroxyl.

23. The compound of claim 1 , wherein X—R 2 is an aromatic or non aromatic heterocyclic ring, which contains from 1 to 3 heteroatoms selected from the group consisting of N, O and S.

24. The compound of claim 1 , wherein X—R 2 is —CHRR′ wherein R is hydroxy and R′ is cycloalkyl, lower alkyl, phenyl or pyridinyl.

25. The compound of claim 24 , selected from the group consisting of

3-bromo-10-chloro-6-(hydroxy-phenyl-ethyl)-9H-imidazo[1,5-a][1,2,4]triazolo[1,5-d][1,4]benzodiazepine and

3-bromo-10-chloro-6-(hydroxy-pyridin-3-yl-methyl)-9H-imidazo[1,5-a][1,2,4]triazolo[1,5-d][1,4]benzodiazepine.

26. The compound of claim 1 , wherein R 3 is hydrogen, halogen, lower alkyl, or lower alkyl substituted by halogen.

27. The compound of claim 1 , wherein R 3 is C(O)O-lower alkyl or CHO.

28. The compound of claim 1 , wherein R 3 is CH 2 OH.

29. A pharmaceutical composition comprising a compound of formula I

wherein

R′ and R 1′ are each independently hydrogen, hydroxy, lower alkyl, lower alkynyl, halogen, lower alkoxy, cycloalkyl, or lower alkyl or alkoxy each of which is substituted by halogen;

X is —CH 2 —, —CH(CH 3 )—, —CH 2 —O—, —CRR′— or —C(O)—;

R 2 is —(CH 2 ) n —O-lower alkyl,

halogen,

—NHCH 3 ,

—N(CH 3 )C(O)-cycloalkyl,

—N(CH 3 )C(O)-lower alkyl,

—N(CH 3 )S(O 2 )CH 3 ,

—NHC(O)CH 2 OC(O)CH 3 ,

—CF 3 ,

cycloalkyl,

hydroxy,

—CH 2 OH,

cyano,

S(O) 2 CH 3 ,

—CH(OH)-lower alkyl,

aryl unsubstituted or substituted by lower alkoxy,

an aromatic or non aromatic heterocyclic ring, containing from 1 to 3 heteroatoms selected from the group consisting of N, O and S, and wherein the heterocyclic ring is unsubstituted or substituted by 1-4 substituents selected from the group consisting of lower alkyl, lower alkoxy, cycloalkyl, ═O, CF 3 , CN, C(O)O-lower alkyl, benzyl, phenyl, —CH 2 O-lower alkyl, CHO and 3-bromo-10-chloro-9H-imidazo[1,5-a][1,2,4]triazolo[1,5-d][1,4]benzodiazepin-6-ylmethyl,

—C(O)—O-lower alkyl,

—C(O)NH—(CH 2 ) n -cycloalkyl,

—C(O)NH—(CH 2 ) n -aromatic or non aromatic heterocyclic ring, wherein the heterocyclic ring contains from 1 to 3 heteroatoms selected from the group consisting of N, O and S,

—C(O)NH—(CH 2 ) n OH,

—C(O)-aromatic or non aromatic heterocyclic ring, wherein the heterocyclic ring contains from 1 to 3 heteroatoms selected from the group consisting of N, O and S, unsubstituted or substituted by lower alkyl,

—NH—C(O)H,

—N(CH 3 )—C(O)H,

—NH—C(O)-lower alkyl,

—NH—C(O)-cycloalkyl,

—NH—C(O)—O-lower alkyl,

—NH—C(O)—N-di-lower alkyl,

—NH—C(O)—CH 2 —O-lower alkyl,

—NH—C(O)—CH 2 —OH,

—NH—(CH 2 ) n -cycloalkyl,

—NH—(CH 2 ) n S(O) 2 CH 3 ,

—NH—(CH 2 ) n -aromatic or non aromatic heterocyclic ring, wherein the heterocyclic ring contains from 1 to 3 heteroatoms selected from the group consisting of N, O and S, or

—NH—(CH 2 ) n OH; or

X—R 2 is lower alkyl with the exception of methyl or is cycloalkyl, which is unsubstituted or substituted by lower alkyl or hydroxy,

an aromatic or non aromatic heterocyclic ring, which contains from 1 to 3 heteroatoms selected from the group consisting of N, O and S, or

—CHRR′;

R is hydroxy;

R′ is cycloalkyl, lower alkyl, lower alkyl substituted by halogen, phenyl or pyridinyl;

R 3 is hydrogen, halogen, C(O)O-lower alkyl, CH 2 OH, CHO, lower alkyl, or lower alkyl substituted by halogen; and

n is 0, 1 or 2;

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