Compounds as inhibitors of the YAP/TAZ-TEAD interaction and their use in the treatment of malignant mesothelioma

1. A compound of formula (I)

or a pharmaceutically acceptable salt thereof, wherein:

R 1 is alkyl or alkyl-R 7 or -aryl-R 7 ;

R 2 , R 3 , R 4 , R 5 are independently H, halo, —B(O—R 11 ) 2 , alkyl, alkoxyl, hydroxycarbonyl, —COOR 11 , —CO—NR 8 R 9 or aryl;

R 6 is H or alkyl; or

R 1 and R 6 are bound together to form a 5 or 6-member heterocycle;

R 7 is hydroxyl, alkylhydroxyl, —NR 8 R 9 , —CO—X—R 10 , —CF 3 , aryl;

R 8 and R 9 are independently H, alkyl or form together with the nitrogen atom a 3 to 6-member cyclic group;

X is —O— or —NR 11 —;

R 10 is H, alkyl or hydroxyalkyl;

R 11 is H or alkyl.

2. A compound of formula:

or a pharmaceutically acceptable salt thereof, wherein:

R 1 is H, alkyl or alkyl-R 7 or -aryl-R 7 ;

R 2 , R 4 , R 5 are independently H, halo, —B(O—R 11 ) 2 , alkyl, alkoxyl, hydroxycarbonyl, —COOR 11 , —CO—NR 8 R 9 or aryl;

R 3 is halo, alkyl, alkoxyl, or hydroxycarbonyl;

R 6 is H or alkyl; or

R 1 and R 6 are bound together to form a 5 or 6-member heterocycle;

R 7 is hydroxyl, alkylhydroxyl, —NR 8 R 9 , —CO—X—R 10 , —CN, —CF 3 , aryl;

R 8 and R 9 are independently H, alkyl or form together with the nitrogen atom a 3 to 6-member cyclic group;

X is —O— or —NR 11 —;

R 10 is H, alkyl or hydroxyalkyl;

R 11 is H or alkyl.

3. A compound of formula:

or a pharmaceutically acceptable salt thereof, wherein:

R 1 is H, alkyl or alkyl-R 7 or -aryl-R 7 ;

R 2 , R 3 , R 4 , are independently H, halo, —B(O—R 11 ) 2 , alkyl, alkoxyl, hydroxycarbonyl, —COOR 11 , —CO—NR 8 R 9 or aryl;

R 5 is halo, alkyl, alkoxyl, or hydroxycarbonyl;

R 6 is H or alkyl; or

R 1 and R 6 are bound together to form a 5 or 6-member heterocycle;

R 7 is hydroxyl, alkylhydroxyl, —NR 8 R 9 , —CO—X—R 10 , —CN, —CF 3 , aryl;

R 8 and R 9 are independently H, alkyl or form together with the nitrogen atom a 3 to 6-member cyclic group;

X is —O— or —NR 11 —;

R 10 is H, alkyl or hydroxyalkyl;

R 11 is H or alkyl.

4. A compound of formula:

or a pharmaceutically acceptable salt thereof, wherein:

R 1 is H, alkyl or alkyl-R 7 or -aryl-R 7 ;

R 2 , R 3 , R 5 are independently H, halo, —B(O—R 11 ) 2 , alkyl, alkoxyl, hydroxycarbonyl, —COOR 1 , —CO—NR 8 R 9 or aryl;

R 4 is halo, alkyl, alkoxyl, or hydroxycarbonyl;

R 6 is H or alkyl; or

R 1 and R 6 are bound together to form a 5 or 6-member heterocycle;

R 7 is hydroxyl, alkylhydroxyl, —NR 8 R 9 , —CO—X—R 10 , —CN, —CF 3 , aryl;

R 8 and R 9 are independently H, alkyl or form together with the nitrogen atom a 3 to 6-member cyclic group;

X is —O— or —NR 11 —;

R 10 is H, alkyl or hydroxyalkyl;

R 11 is H or alkyl.

5. The compound of claim 1 , which is selected from the group consisting of:

4-[(E)-[(1,1-dioxo-1,2-benzothiazol-3-yl)-methyl-hydrazono]methyl]-2-methoxy-phenol

4-[(E)-[(1,1-dioxo-1,2-benzothiazol-3-yl)-(2-hydroxyethyl)hydrazono]methyl]-2-methoxy-phenol

4-[(E)-[(1,1-dioxo-1,2-benzothiazol-3-yl)-ethyl-hydrazono]methyl]-2-methoxy-phenol

4-[(E)-[(1,1-dioxo-1,2-benzothiazol-3-yl)-(2-morpholinoethyl)hydrazono]methyl]-2-methoxy-phenol hydrochloride

4-[(E)-[(1,1-dioxo-1,2-benzothiazol-3-yl)-(3-hydroxypropyl)hydrazono]methyl]-2-methoxy-phenol

4-[(E)-[3-(dimethylamino)propyl-(1,1-dioxo-1,2-benzothiazol-3-yl)hydrazono]methyl]-2-methoxy-phenol hydrochloride

4-[(E)-[(1,1-dioxo-1,2-benzothiazol-3-yl)-(2-methoxyethyl)hydrazono]methyl]-2-methoxy-phenol

3-[(1,1-dioxo-1,2-benzothiazol-3-yl)-[(E)-(4-hydroxy-3-methoxy-phenyl)methylene amino]amino]propanoic acid

2-[(1,1-dioxo-1,2-benzothiazol-3-yl)-[(E)-(4-hydroxy-3-methoxy-phenyl)methylene amino]amino]-N-(2-hydroxyethyl)acetamide

4-[(E)-[(1,1-dioxo-1,2-benzothiazol-3-yl)-(3-methoxypropyl)hydrazono]methyl]-2-methoxy-phenol

4-[(E)-[(1,1-dioxo-1,2-benzothiazol-3-yl)-isopropyl-hydrazono]methyl]-2-methoxy-phenol

4-[(E)-[(1,1-dioxo-1,2-benzothiazol-3-yl)-(2,2,2-trifluoroethyl)hydrazono]methyl]-2-methoxy-phenol

4-[(1,1-dioxo-1,2-benzothiazol-3-yl)-[(E)-(4-hydroxy-3-methoxy-phenyl) methyleneamino]amino]benzoic acid

and pharmaceutically acceptable salts thereof.

6. The compound of claim 2 , which is selected from the group consisting of:

4-[(E)-[2-hydroxyethyl-(5-methoxy-1,1-dioxo-1,2-benzothiazol-3-yl)hydrazono]methyl]-2-methoxy-phenol

2-methoxy-4-[(E)-[(5-methoxy-1,1-dioxo-1,2-benzothiazol-3-yl)-(2-morpholinoethyl) hydrazono]methyl]phenol

2-methoxy-4-[(E)-[(5-methoxy-1,1-dioxo-1,2-benzothiazol-3-yl)-(3-morpholino propyl)hydrazono]methyl]phenol hydrochloride

4-[(E)-[3-hydroxypropyl-(5-methoxy-1,1-dioxo-1,2-benzothiazol-3-yl)hydrazono]methyl]-2-methoxy-phenol

2-methoxy-4-[(E)-[(5-methoxy-1,1-dioxo-1,2-benzothiazol-3-yl)-(2-methoxyethyl) hydrazono]methyl]phenol

2-methoxy-4-[(E)-[methyl-(5-methyl-1,1-dioxo-1,2-benzothiazol-3-yl)hydrazono]methyl]phenol

2-methoxy-4-[(E)-[(5-methyl-1,1-dioxo-1,2-benzothiazol-3-yl)-(2-morpholinoethyl) hydrazono]methyl]phenol hydrochloride

4-[(E)-[2-hydroxyethyl-(5-methyl-1,1-dioxo-1,2-benzothiazol-3-yl)hydrazono]methyl]-2-methoxy-phenol

2-methoxy-4-[(E)-[2-methoxyethyl-(5-methyl-1,1-dioxo-1,2-benzothiazol-3-yl) hydrazono]methyl]phenol

2-methoxy-4-[(E)-[(5-methoxy-1,1-dioxo-1,2-benzothiazol-3-yl)-methyl-hydrazono]methyl]phenol

4-[(E)-[(5-fluoro-1,1-dioxo-1,2-benzothiazol-3-yl)-methyl-hydrazono]methyl]-2-methoxy-phenol

and pharmaceutically acceptable salts thereof.

7. The compound of claim 3 , which is selected from the group consisting of:

4-[(E)-[(5,7-dimethoxy-1,1-dioxo-1,2-benzothiazol-3-yl)-methyl-hydrazono]methyl]-2-methoxy-phenol

4-[(E)-[(5,7-dimethoxy-1,1-dioxo-1,2-benzothiazol-3-yl)-(2-hydroxyethyl)hydrazono]methyl]-2-methoxy-phenol

4-[(E)-[(5,7-dimethoxy-1,1-dioxo-1,2-benzothiazol-3-yl)-(2-morpholinoethyl) hydrazono]methyl]-2-methoxy-phenol hydrochloride

4-[(E)-[(5,7-dimethoxy-1,1-dioxo-1,2-benzothiazol-3-yl)-(2-methoxyethyl)hydrazono]methyl]-2-methoxy-phenol

4-[(E)-[(5-fluoro-7-methyl-1,1-dioxo-1,2-benzothiazol-3-yl)-methyl-hydrazono]methyl]-2-methoxy-phenol

2-methoxy-4-[(E)-[(7-methoxy-1,1-dioxo-1,2-benzothiazol-3-yl)-methyl-hydrazono]methyl]phenol

4-[(E)-[2-hydroxyethyl-(7-methoxy-1,1-dioxo-1,2-benzothiazol-3-yl)hydrazono]methyl]-2-methoxy-phenol

2-methoxy-4-[(E)-[(7-methoxy-1,1-dioxo-1,2-benzothiazol-3-yl)-(2-morpholinoethyl) hydrazono]methyl]phenol hydrochloride

2-methoxy-4-[(E)-[(7-methoxy-1,1-dioxo-1,2-benzothiazol-3-yl)-(2-methoxyethyl) hydrazono]methyl]phenol

4-[(E)-[2-hydroxyethyl-(7-methoxy-5-methyl-1,1-dioxo-1,2-benzothiazol-3-yl) hydrazono]methyl]-2-methoxy-phenol

2-methoxy-4-[(E)-[2-methoxyethyl-(7-methoxy-5-methyl-1,1-dioxo-1,2-benzothiazol-3-yl)hydrazono]methyl]phenol

2-methoxy-4-[(E)-[(7-methoxy-5-methyl-1,1-dioxo-1,2-benzothiazol-3-yl)-methyl-hydrazono]methyl]phenol

2-methoxy-4-[(E)-[(7-methoxy-5-methyl-1,1-dioxo-1,2-benzothiazol-3-yl)-(2-morpholinoethyl)hydrazono]methyl]phenol hydrochloride

and pharmaceutically acceptable salts thereof.

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

2-methoxy-4-[(E)-[methyl-(6-methyl-1,1-dioxo-1,2-benzothiazol-3-yl)hydrazono]methyl]phenol

3-[[(E)-(4-hydroxy-3-methoxy-phenyl)methyleneamino]-methyl-amino]-1,1-dioxo-1,2-benzothiazole-6-carboxylic acid

2-methoxy-4-[(E)-[(6-methoxy-1,1-dioxo-1,2-benzothiazol-3-yl)-methyl hydrazono]methyl]phenol

4-[(E)-[(6-fluoro-1,1-dioxo-1,2-benzothiazol-3-yl)-methyl-hydrazono]methyl]-2-methoxy-phenol

and pharmaceutically acceptable salts thereof.

9. A pharmaceutical composition comprising a compound of claim 1 or one of its pharmaceutically acceptable salts and at least one pharmaceutically acceptable vehicle.

10. A method of treatment of malignant mesothelioma, which comprises administering a compound of claim 1 or a pharmaceutically acceptable salt thereof to a patient in need thereof.

11. A method of treatment of tumor cells where YAP is localized in the nucleus of said cells, which comprises administering a compound of claim 1 or a pharmaceutically acceptable salt thereof to a patient in need thereof.

12. The method of claim 11 , wherein the tumor is lung, thyroid, ovarian, colorectal, prostate, pancreas, esophagus, liver, breast or skin tumor.

13. A pharmaceutical composition comprising a compound of claim 2 or one of its pharmaceutically acceptable salts and at least one pharmaceutically acceptable vehicle.

14. A pharmaceutical composition comprising a compound of claim 3 or one of its pharmaceutically acceptable salts and at least one pharmaceutically acceptable vehicle.

15. A pharmaceutical composition comprising a compound of claim 4 or one of its pharmaceutically acceptable salts and at least one pharmaceutically acceptable vehicle.

16. A method of treatment of malignant mesothelioma, which comprises administering a compound of claim 2 or a pharmaceutically acceptable salt thereof to a patient in need thereof.

17. A method of treatment of malignant mesothelioma, which comprises administering a compound of claim 3 or a pharmaceutically acceptable salt thereof to a patient in need thereof.

18. A method of treatment of malignant mesothelioma, which comprises administering a compound of claim 4 or a pharmaceutically acceptable salt thereof to a patient in need thereof.