IP Library › Granted Patent US 8,575,193

Granted Patent B2

US 8,575,193 · App. 12/921,821 · Granted Nov 5, 2013

N-substituted tetrahydroisoquinoline/isoindoline hydroxamic acid compounds

Inventors: Thomas Maier (Stockach, DE); Thomas Beckers (Freiburg, DE); Christian Hesslinger (Zoznegg, DE)

Assignee: 4SC AG

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Quick Facts

Patent No.: US 8,575,193
App. No.: 12/921,821
Granted: Nov 5, 2013
Kind: B2

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Abstract

Compounds of a certain formula (I) wherein R1, R2, R3, X, Y, r, s, t, u and v have the meanings as defined in the specification, and the salts, solvates and hydrates thereof are novel effective HDAC 6 inhibitors.

Claims (171)

1. A compound of formula I

wherein

R1 is

R2 is H;

R3 is hydrogen, —OR4, —NR5R6, or an optionally substituted alicyclic, heteroalicyclic, aromatic or heteroaromatic radical, wherein

the alicyclic radical is a 3- to 6-membered monocyclic group,

the heteroalicyclic radical is a 5- to 6-membered monocyclic group containing one or two heteroatoms, each of which is selected from the group consisting of nitrogen, oxygen and sulfur,

the aromatic radical is phenyl or naphthyl,

the heteroaromatic radical is a 5- to 6-membered monocyclic group or a 9- to 10-membered bicyclic group containing one or two heteroatoms, each of which is selected from the group consisting of nitrogen, oxygen and sulfur,

and

the substituents of the optionally substituted alicyclic, heteroalicyclic, aromatic or heteroaromatic radical are each selected from the group consisting of halogen, 1-4C alkyl, 1-4C alkoxy and phenyl;

R4 is hydrogen, 1-4C alkyl or a substituted or unsubstituted alicyclic, heteroalicyclic, aromatic or heteroaromatic group, wherein each of these groups is as defined as in R3;

R5 and R6 are each independently H or 1-4C alkyl;

X is a single bond, —CH═CH—, —C≡C—, —NH—, oxygen or sulfur;

Y is —NH—, oxygen or sulfur;

r is 1 or 2,

one of s and u is 0 and the other is 1,

t is 0, 1, 2, 3, 4or 5, and

v is 0, 1, 2, 3 or 4;

or a salt thereof.

2. A compound of formula I according to claim 1 , wherein

t is 0or 1, and

v is 0, 1 or 2,

or a salt thereof.

3. A compound of formula I according to claim 1 , wherein

s is 1,

t is 1,

u is 0, and

v is 0, 1 or 2,

or a salt thereof.

4. A compound of formula I according to claim 1 , wherein

s is 0,

t is 1,

u is 1, and

v is 0, 1 or 2,

or a salt thereof.

5. A compound of formula I according to claim 1 , wherein

R3 is hydrogen, —OR4, —NR5R6, or an optionally substituted alicyclic, heteroalicyclic, aromatic or heteroaromatic radical, wherein

the alicyclic radical is selected from the group consisting of cyclopropyl and cyclobutyl,

the heteroalicyclic radical is tetrahydrofuryl,

the aromatic radical is phenyl,

the heteroaromatic radical is selected from the group consisting of imidazolyl, pyridyl, indolyl and quinolinyl, and

the substituents of the optionally substituted alicyclic, heteroalicyclic, aromatic or heteroaromatic radical are each selected from the group consisting of —CH 3 , —OCH 3 and phenyl;

R4 is —CH 3 or phenyl;

R5 and R6 are each independently H or —CH 3 ;

Y is oxygen;

s is 0, and

u is 1,

or a salt thereof.

6. A compound of formula I according to claim 1 , wherein

R3 is hydrogen, —OR4, —NR5R6, or an optionally substituted alicyclic, heteroalicyclic, aromatic or heteroaromatic radical, wherein

the alicyclic radical is selected from the group consisting of cyclopropyl and cyclobutyl,

the heteroalicyclic radical is tetrahydrofuryl,

the aromatic radical is phenyl,

the heteroaromatic radical is selected from the group consisting of imidazolyl, pyridyl, indolyl and quinolinyl, and

the substituents of the optionally substituted alicyclic, heteroalicyclic, aromatic or heteroaromatic radical are each selected from the group consisting of —CH 3 ,

—OCH 3 and phenyl;

R4 is —CH 3 or phenyl;

R5 and R6 are each independently H or —CH 3 ;

X is a single bond, —C≡C—, —NH—, or oxygen;

s is 1, and

u is 0,

or a salt thereof.

7. A compound of formula I according to claim 1 , wherein

r is 1,

or a salt thereof.

8. A compound of formula I according to claim 1 , wherein

R1 is

R2 is H, and

r is 2,

or a salt thereof.

9. A compound, which is

9.1. N-Hydroxy-2-(indol-3-ylacetyl)-1,2,3,4-tetrahydroisoquinoline-6-carboxamide

9.2. N-Hydroxy-2-(pyridin-2-ylacetyl)-1,2,3,4-tetrahydroisoquinoline-6-carboxamide,

9.3. 2-(Cyclobutylcarbonyl)-N-hydroxy-1,2,3,4-tetrahydroisoquinoline-6-carboxamide,

9.4. N6-Hydroxy-N2-methyl-3,4-dihydroisoquinoline-2,6(1H)-dicarboxamide,

9.5. N6-Hydroxy-N2-(3-methoxypropyl)-3,4-dihydroisoquinoline-2,6(1H)-dicarboxamide,

9.6. 3-Methoxypropyl-6-(hydroxycarbamoyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate,

9.7. N-Hydroxy-2-(3-pyridin-3-ylpropanoyl)-1,2,3,4-tetrahydroisoquinoline-6-carboxamide,

9.8. N-Hydroxy-2-(pyridin-3-ylacetyl)-1,2,3,4-tetrahydroisoquinoline-6-carboxamide,

9.9. 2-[4-(Dimethylamino)butanoyl]-N-hydroxy-1,2,3,4-tetrahydroisoquinoline-6-carboxamide,

9.10. N-Hydroxy-2-[(2-methyl-1H-imidazol-1-yl)acetyl]-1,2,3,4-tetrahydroisoquinoline-6-carboxamide,

9.11. N-Hydroxy-2-[(2-methoxyethoxy)acetyl]-1,2,3,4-tetrahydroisoquinoline-6-carboxamide,

9.12. 2-Acetyl-N-hydroxy-1,2,3,4-tetrahydroisoquinoline-6-carboxamide,

9.13. N-Hydroxy-2-(tetrahydrofuran-3-ylcarbonyl)-1,2,3,4-tetrahydroisoquinoline-6-carboxamide,

9.14. N-Hydroxy-2-(pyridin-2-ylacetyl)-1,2,3,4-tetrahydroisoquinoline-6-carboxamide,

9.15. N-Hydroxy-2-[(5-methoxy-1H-indol-2-yl)carbonyl]-1,2,3,4-tetrahydroisoquinoline-6-carboxamide,

9.16. N-Hydroxy-2-(cyclopropylcarbonyl)-1,2,3,4-tetrahydroisoquinoline-6-carboxamide,

9.17. 2-But-2-ynoyl-N-hydroxy-1,2,3,4-tetrahydroisoquinoline-7-carboxamide,

9.18. N-Hydroxy-2-(1H-indol-3-ylacetyl)-1,2,3,4-tetrahydroisoquinoline-7-carboxamide,

9.19. N-Hydroxy-2-(pyridin-3-ylacetyl)-1,2,3,4-tetrahydroisoquinoline-7-carboxamide,

9.20. N-Hydroxy-2-(tetrahydrofuran-3-ylcarbonyl)-1,2,3,4-tetrahydroisoquinoline-7-carboxamide,

9.21. N-Hydroxy-2-(pyridin-2-ylacetyl)-1,2,3,4-tetrahydroisoquinoline-7-carboxamide,

9.22. N7-Hydroxy-N2-(2-phenylethyl)-3,4-dihydroisoquinoline-2,7(1H)-dicarboxamide,

9.23. N-Hydroxy-2-(4-methylbenzoyl)-1,2,3,4-tetrahydroisoquinoline-7-carboxamide,

9.24. N-Hydroxy-2-[(5-methoxy-1H-indol-2-yl)carbonyl]-1,2,3,4-tetrahydroisoquinoline-7-carboxamide,

9.25. 2-Acetyl-N-hydroxy-1,2,3,4-tetrahydroisoquinoline-7-carboxamide,

9.26. Pyridin-3-ylmethyl 5-(hydroxycarbamoyl)-1,3-dihydro-2H-isoindole-2-carboxylate,

9.27. N-Hydroxy-2-(quinolin-2-ylcarbonyl)isoindoline-5-carboxamide,

9.28. N-Hydroxy-2-(quinolin-6-ylcarbonyl)isoindoline-5-carboxamide,

9.29. N-Hydroxy-2-(isoquinolin-3-ylcarbonyl)isoindoline-5-carboxamide,

9.30. 2-(Biphenyl-4-ylcarbonyl)-N-hydroxyisoindoline-5-carboxamide,

9.31. N-Hydroxy-2-(3-pyridin-3-ylpropanoyl)-1,2,3,4-tetrahydroisoquinoline-7-carboxamide,

9.32. N7-Hydroxy-N2-(3-methoxypropyl)-3,4-dihydroisoquinoline-2,7(1H)-dicarboxamide,

9.34. 3-Methoxypropyl 7-(hydroxycarbamoyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate,

9.35. N7-Hydroxy-N2-methyl-3,4-dihydroisoquinoline-2,7(1H)-dicarboxamide,

9.36. 2-(Cyclobutylcarbonyl)-N-hydroxy-1,2,3,4-tetrahydroisoquinoline-7-carboxamide,

9.37. N-Hydroxy-2-(1H-indol-5-ylcarbonyl)-1,2,3,4-tetrahydroisoquinoline-7-carboxamide,

9.38. N-Hydroxy-2-[(2-methoxyethoxy)acetyl]-1,2,3,4-tetrahydroisoquinoline-7-carboxamide,

9.39. N-Hydroxy-2-[3-(2-methyl-1H-imidazol-1-yl)propanoyl]-1,2,3,4-tetrahydroisoquinoline-7-carboxamide,

9.40. Benzyl 6-(hydroxycarbamoyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate,

9.41. N-Hydroxy-2-(phenoxyacetyl)-1,2,3,4-tetrahydroisoquinoline-6-carboxamide,

9.42. N-Hydroxy-2-(4-methylbenzoyl)-1,2,3,4-tetrahydroisoquinoline-6-carboxamide,

9.43. N6-Hydroxy-N2-[2-(1H-indol-3-yl)ethyl]-3,4-dihydroisoquinoline-2,6(1H)-dicarboxamide,

9.44. N6-Hydroxy-N2-benzyl-3,4-dihydroisoquinoline-2,6(1H)-dicarboxamide,

9.45. N6-Hydroxy-N2-(2-phenoxyethyl)-3,4-dihydroisoquinoline-2,6(1H)-dicarboxamide, or

9.46. N-hydroxy-2-(1H-Indol-5-ylcarbonyl)-1,2,3,4-tetrahydroisoquinoline-6-carboxamide,

or a salt thereof.

10. A compound of formula I according to claim 9 , which is