Histone deacetylases (HDACs) inhibitors

1. A compound having the structure

or a pharmaceutically acceptable salt thereof,

(I) wherein:

R 1 is hydrogen, (C 1 -C 6 )alkyl, or (C 3 -C 6 )cycloalkyl;

R 2 is (C 6 -C 18 )aryl, (C 6 -C 18 )aryl(C 3 -C 18 )alkyl, (C 3 -C 18 )heteroaryl(C 1 -C 6 )alkyl, halo(C 6 -C 18 )aryl(C 1 -C 6 )alkyl, or (C 1 -C 6 )alkoxy(C 6 -C 18 )aryl(C 1 -C 6 )alkyl;

R 3 is N-hydroxyamino-oxo(C 2 -C 6 )alkenyl;

R 4 is hydrogen, halogen, N-hydroxyamino-oxo(C 2 -C 6 )alkenyl, or N-hydroxyaminocarbonyl(C 6 -C 18 )aryl(C 1 -C 6 )alkylene;

R 5 is hydrogen, halogen, N-hydroxy amino-oxo(C 2 -C 6 )alkenyl, N-hydroxyaminocarbonyl(C 6 -C 18 )aryl(C 1 -C 6 )alkylene, or amino(C 6 -C 18 )aryl-oxo(C 2 -C 6 )alkenyl; and

R 6 is hydrogen, N-hydroxyamino-oxo(C 2 -C 6 )alkenyl, N-hydroxyamino(C 6 -C 18 )aryl(C 1 -C 6 )alkylene, or N-hydroxyaminocarbonyl(C 6 -C 18 )aryl(C 1 -C 6 )alkylene;

(II) or wherein:

R 1 , R 2 , R 4 and R 6 are each as defined in (I) above;

R 3 is hydrogen or N-hydroxyamino-oxo(C 2 -C 6 )alkenyl; and

R 4 is N-hydroxyamino-oxo(C 2 -C 6 )alkenyl, or N-hydroxyaminocarbonyl(C 6 -C 18 )aryl(C 1 -C 6 )alkylene;

(III) or wherein:

R 1 , R 2 , R 4 and R 6 are each as defined in (I) above;

R 3 is as defined in (II) above; and

R 5 is N-hydroxyamino-oxo(C 2 -C 6 )alkenyl, N-hydroxyaminocarbonyl(C 6 -C 18 )aryl(C 1 -C 6 )alkylene, or amino(C 6 -C 18 )aryl-oxo(C 2 -C 6 )alkenyl;

(IV) or wherein:

R 1 , R 2 , R 4 , R 5 are each as defined in (I) above;

R 3 is as defined in (II) above; and

R 6 is N-hydroxyamino-oxo(C 2 -C 6 )alkenyl, N-hydroxyamino(C 6 -C 18 )aryl(C 1 -C 6 )alkylene, or N-hydroxyaminocarbonyl(C 6 -C 18 )aryl(C 1 -C 6 )alkylene.

2. The compound of claim 1 ,

(A) wherein:

R 1 is hydrogen, methyl, ethyl, cyclopropyl, or isopropyl:

R 2 is phenyl, benzyl, 2-phenylethyl, 3-phenylpropyl, 2-(1H-indol-3-yl)ethyl, 2-(4-fluorophenyl)ethyl, or 2-(4-methoxyphenyl)ethyl;

R 3 is (2E)-3-N-hydroxyamino-3-oxo-propenyl;

R 4 is hydrogen, fluoro, (2E)-3-N-hydroxyamino-3-oxo-propenyl, or 4-(N-hydroxyaminocarbonyl)benzyl;

R 5 is hydrogen, chloro, fluoro, (2E)-3-N-hydroxyamino-3-oxo-propenyl, 4-(N-hydroxyaminocarbonyl)benzyl, or (2E)-3-N-(2-aminophenyl)-3-oxo-propenyl; and

R 6 is hydrogen, (2E)-3-N-hydroxyamino-3-oxo-propenyl, 4-(N-hydroxyaminocarbonyl)phenyl, or 4-(N-hydroxyaminocarbonyl)benzyl, or a salt thereof;

(B) or wherein:

R 1 , R 2 , R 5 and R 6 are each as defined in (A) above;

R 3 is hydrogen or (2E)-3-N-hydroxyamino-3-oxo-propenyl; and

R 4 is (2E)-3-N-hydroxyamino-3-oxo-propenyl, or 4-(N-hydroxyaminocarbonyl)benzyl;

(C) or wherein:

R 1 , R 2 , R 4 and R 6 are each as defined in (A) above;

R 3 is as defined in (B) above; and

R 5 is (2E)-3-N-hydroxyamino-3-oxo-propenyl, 4-(N-hydroxyaminocarbonyl)benzyl, or (2E)-3-N-(2-aminophenyl)-3-oxo-propenyl;

(D) or wherein:

R 1 , R 2 , R 4 and R 5 are each as defined in (A) above;

R 3 is as defined in (B) above; and

R 6 is (2E)-3-N-hydroxyamino-3-oxo-propenyl, 4-(N-hydroxyaminocarbonyl)phenyl, or 4-(N-hydroxyaminocarbonyl)benzyl, or a salt thereof.

3. The compound of claim 2 ,

(i) wherein:

R 1 is hydrogen, methyl, ethyl, cyclopropyl, or isopropyl;

R 2 is phenyl, benzyl, 2-phenylethyl, 3-phenylpropyl, 2-(1H-indol-3-yl)ethyl, 2-(4-fluorophenyl)ethyl, or 2-(4-methoxyphenyl)ethyl;

R 3 is (2E)-3-N-hydroxyamino-3-oxo-propenyl;

R 4 is hydrogen, (2E)-3-N-hydroxyamino-3-oxo-propenyl, or 4-(N-hydroxyaminocarbonyl)benzyl;

R 5 is hydrogen, (2E)-3-N-hydroxyamino-3-oxo-propenyl, 4-(N-hydroxyaminocarbonyl)benzyl, or (2E)-3-N-(2-aminophenyl)-3-oxo-propenyl; and

R 6 is hydrogen, (2E)-3-N-hydroxyamino-3-oxo-propenyl, 4-(N-hydroxyaminocarbonyl)phenyl, or 4-(N-hydroxyaminocarbonyl)benzyl, or a salt thereof;

(ii) or wherein:

R 1 , R 2 , R 4 and R 5 are each as defined in (i) above;

R 3 is hydrogen or (2E)-3-N-hydroxyamino-3-oxo-propenyl; and

R 6 is (2E)-3-N-hydroxyamino-3-oxo-propenyl, or 4-(N-hydroxyaminocarbonyl)benzyl;

(iii) or wherein:

R 1 , R 2 , R 4 and R 6 are each as defined in (i) above;

R 3 is as defined in (ii) above; and

R 5 is (2E)-3-N-hydroxyamino-3-oxo-propenyl, 4-(N-hydroxyaminocarbonyl)benzyl, or (2E)-3-N-(2-aminophenyl)-3-oxo-propenyl;

(iv) or wherein:

R 1 , R 2 , R 4 and R 5 are each as defined in (i) above;

R 3 is as defined in (ii) above; and

R 6 is (2E)-3-N-hydroxyamino-3-oxo-propenyl, 4-(N-hydroxyaminocarbonyl)phenyl, or 4-(N-hydroxyaminocarbonyl)benzyl, or a salt thereof.

4. The compound of claim 2 , wherein

R 1 is ethyl;

R 2 is 2-phenylethyl;

R 3 is hydrogen;

R 4 is fluoro;

R 5 is (2E)-3-N-hydroxyamino-3-oxo-propenyl; and

R 6 is hydrogen, or a salt thereof.

5. The compound of claim 2 , wherein

R 1 is ethyl;

R 2 is 2-phenylethyl;

R 3 is hydrogen;

R 4 is (2E)-3-N-hydroxyamino-3-oxo-propenyl;

R 5 is chloro or fluoro; and

R 6 is hydrogen, or a salt thereof.

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

(2E)-3-(3,4-dihydro-2-methyl-4-oxo-3-phenylquinazolin-5-yl)-N-hydroxyacrylamide,

(2E)-3-(3,4-dihydro-2-methyl-4-oxo-3-phenylquinazolin-6-yl)-N-hydroxyacrylamide,

(2E)-3-(3,4-dihydro-2-methyl-4-oxo-3-phenylquinazolin-7-yl)-N-hydroxyacrylamide,

(2E)-3-(3,4-dihydro-2-methyl-4-oxo-3-phenylquinazolin-8-yl)-N-hydroxyacrylamide,

(2E)-3-(3-benzyl-3,4-dihydro-2-methyl-4-oxoquinazolin-7-yl)-N-hydroxyacrylamide,

(2E)-3-(3,4-dihydro-2-methyl-4-oxo-3-phenethylquinazolin-7-yl)-N-hydroxyacrylamide,

(2E)-3-(3-(2-(1H-indol-3-yl)ethyl)-3,4-dihydro-2-methyl-4-oxoquinazolin-7-yl)-N-hydroxyacrylamide,

(2E)-3-(3,4-dihydro-4-oxo-3-phenethylquinazolin-7-yl)-N-hydroxyacrylamide,

(2E)-3-(2-ethyl-3, 4-dihydro-4-oxo-3-phenethylquinazolin-7-yl)-N-hydroxyacrylamide,

(2E)-3-(2-ethyl-3,4-dihydro-4-oxo-3-(3-phenylpropyl)quinazolin-7-yl)-N-hydroxyacrylamide,

(2E)-3-(2-cyclopropyl-3,4-dihydro-4-oxo-3-phenethylquinazolin-7-yl)-N-hydroxyacrylamide,

(2E)-3-(3,4-dihydro-2-isopropyl-4-oxo-3-phenethylquinazolin-7-yl)-N-hydroxyacrylamide,

(2E)-3-(3-(4-methoxyphenethyl)-2-ethyl-3,4-dihydro-4-oxoquinazolin-7-yl)-N-hydroxyacrylamide,

(2E)-3-(3-(4-fluorophenethyl)-2-ethyl-3,4-dihydro-4-oxoquinazolin-7-yl)-N-hydroxyacrylamide,

4-((2-ethyl-3,4-dihydro-4-oxo-3-phenethylquinazolin-6-yl)methyl)-N-hydroxybenzamide,

4-((2-ethyl-3,4-dihydro-4-oxo-3-phenethylquinazolin-7-yl)methyl)-N-hydroxybenzamide,

4-((2-ethyl-3,4-dihydro-4-oxo-3-phenethylquinazolin-8-yl)methyl)-N-hydroxybenzamide,

4-(2-ethyl-3,4-dihydro-4-oxo-3-phenethylquinazolin-8-yl)-N-hydroxybenzamide, and

(2E)-N-(2-aminophenyl)-3-(3,4-dihydro-2-methyl-4-oxo-3-phenethylquinazolin-7-yl)acrylamide.

7. The compound of claim 2 , wherein the compound is (2E)-3-(2-ethyl-6-fluoro-3,4-dihydro-4-oxo-3-phenethylquinazolin-7-yl)-N-hydroxyacrylamide, or a salt thereof.

8. The compound of claim 2 , wherein the compound is (2E)-3-(2-ethyl-7-fluoro-3,4-dihydro-4-oxo-3-phenethylquinazolin-6-yl)-N-hydroxyacrylamide, (2E)-3-(7-chloro-2-ethyl-3,4-dihydro-4-oxo-3-phenethylquinazolin-6-yl)-N-hydroxyacrylamide, or a salt thereof.

9. A composition comprising a therapeutically effective amount of the compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or vehicle.

10. A composition comprising a therapeutically effective amount of the compound of claim 3 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or vehicle.

11. A composition comprising a therapeutically effective amount of the compound of claim 4 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or vehicle.

12. A composition comprising a therapeutically effective amount of the compound of claim 5 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or vehicle.

13. A composition comprising a therapeutically effective amount of the compound of claim 6 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or vehicle.

14. A method for improving learning ability in a subject with Alzheimer's disease, comprising:

administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of a compound selected from the group consisting of

(2E)-3-(3,4-dihydro-2-methyl-4-oxo-3-phenylquinazolin-5-yl)-N-hydroxyacrylamide;

(2E)-3-(3,4-dihydro-2-methyl-4-oxo-3-phenylquinazolin-6-yl)-N-hydroxyacrylamide;

(2E)-3-(3,4-dihydro-2-methyl-4-oxo-3-phenylquinazolin-7-yl)-N-hydroxyacrylamide;

(2E)-3-(3,4-dihydro-2-methyl-4-oxo-3-phenylquinazolin-8-yl)-N-hydroxyacrylamide;

(2E)-3-(3-benzyl-3,4-dihydro-2-methyl-4-oxoquinazolin-7-yl)-N-hydroxyacrylamide;

(2E)-3-(3,4-dihydro-2-methyl-4-oxo-3-phenethylquinazolin-7-yl)-N-hydroxyacrylamide;

(2E)-3-(3-(2-(1H-indol-3-yl)ethyl)-3,4-dihydro-2-methyl-4-oxoquinazolin-7-yl)-N-hydroxyacrylamide;

(2E)-3-(3,4-dihydro-4-oxo-3-phenethylquinazolin-7-yl)-N-hydroxyacrylamide;

(2E)-3-(2-ethyl-3,4-dihydro-4-oxo-3-phenethylquinazolin-7-yl)-N-hydroxyacrylamide;

(2E)-3-(2-ethyl-3,4-dihydro-4-oxo-3-(3-phenylpropyl)quinazolin-7-yl)-N-hydroxyacrylamide;

(2E)-3-(2-cyclopropyl-3,4-dihydro-4-oxo-3-phenethylquinazolin-7-yl)-N-hydroxyacrylamide;

(2E)-3-(3,4-dihydro-2-isopropyl-4-oxo-3-phenethylquinazolin-7-yl)-N-hydroxyacrylamide;

(2E)-3-(3-(3-(4-methoxyphenethyl)-2-ethyl-3,4-dihydro-4-oxoquinazolin-7-yl)-N-hydroxyacrylamide;

(2E)-3-(3-(4-fluorophenethyl)-2-ethyl-3,4-dihydro-4-oxoquinazolin-7-yl)-N-hydroxyacrylamide;

(2E)-3-(7-chloro-2-ethyl-3,4-dihydro-4-oxo-3-phenethylquinazolin-6-yl)-N-hydroxyacrylamide;

4-((2-ethyl-3,4-dihydro-4-oxo-3-phenethylquinazolin-6-yl)methyl)-N-hydroxybenzamide;

(2E)-N-(2-aminophenyl)-3-(3,4-dihydro-2-methyl-4-oxo-3-phenethylquinazolin-7-yl)acrylamide,

and a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or vehicle to treat the Alzheimer's disease.

15. The method of claim 14 , wherein the compound is selected from the group consisting of

(2E)-3-(3,4-dihydro-2-methyl-4-oxo-3-phenylquinazolin-7-yl)-N-hydroxyacrylamide, and

(2E)-3-(3,4-dihydro-2-methyl-4-oxo-3-phenethylquinazolin-7-yl)-N-hydroxyacrylamide.