Cyclic amines as bromodomain inhibitors

1. A compound of Formula I:

or a stereoisomer, tautomer, pharmaceutical acceptable salt, or hydrate thereof, wherein:

W 1 is selected from N and CR 1 ;

W 2 is selected from N and CR 2 ;

W 3 is selected from N and CR 3 ;

W 4 is selected from N and CR 4 ;

each W may be the same or different from each other;

A is selected from N and CH;

R 1 , and R 4 are each independently selected from hydrogen, alkyl, alkenyl, alkynyl, alkoxy, thioalkyl, aryloxy, aryl, amino, hydroxyl, and halogen;

R 2 and R 3 are each independently selected from hydrogen, alkyl, alkenyl, alkynyl, alkoxy, thioalkyl, aryloxy, aryl, hydroxyl, and halogen;

two adjacent substituents selected from R 1 , R 2 , R 3 , and R 4 may be connected in a 5- or 6- membered ring to form a bicyclic carbocycle or bicyclic heterocycle;

AR1 is a group selected from the following:

B is a group selected from the following:

each ring system may be substituted with one or more substituents independently selected from R 10 and R 11 ;

R 5 is selected from hydrogen, alkoxy, alkyl, thioalkyl, aryloxy, aryl, hydroxyl, and halogen;

R 6 is selected from hydrogen, alkoxy, alkyl, thioalkyl, aryloxy, aryl, and halogen;

R 7 is selected from hydrogen, alkyl, —SO 2 R 12 , —C(O)NR 12 R 13 , and —C(O)R 12 ;

R 8 and R 9 are independently selected from hydrogen, aryl, alkenyl, alkyl, —SO 2 R 12 , —C(O)NR 12 R 13 , and —C(O)R 12 ;

R 10 and R 11 are independently selected from hydrogen, halogen, alkyl, alkoxy, aryl, and hydroxyl;

R 12 and R 13 are independently selected from hydrogen, aryl, and alkyl;

Y is selected from NH, O, and S;

and

two adjacent substituents selected from R 5 , R 6 , R 6 , R 9 , R 10 , and R 11 may be connected in a 5- or 6-membered ring to form a carbocycle or heterocycle.

2. The compound according to claim 1

wherein R 1 , and R 4 are independently selected from hydrogen, alkyl, alkoxy, halogen, and amino and R 2 and R 3 are independently from hydrogen, alkyl, alkoxy, and halogen;

wherein at least one of R 1 -R 4 is not hydrogen;

wherein R 5 is selected from hydrogen, alkyl, alkoxy, and halogen;

wherein R 6 is selected from hydrogen and alkoxy optionally substituted with a hydroxyl or amino;

and/or

wherein Y is N.

3. The compound according to claim 2 ,

wherein AR1 is selected from

wherein B is selected from

wherein R 7 is selected from hydrogen and alkyl;

wherein R 8 and R 9 are independently selected from hydrogen and alkyl;

wherein R 10 and R 11 are independently selected from hydrogen and halogen;

wherein R 12 and R 13 are independently selected from hydrogen and alkyl.

4. A compound according to claim 1 selected from:

2-(3-(4-Isopropylpiperazin-1-yl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one;

2-(3-(4-Isopropylpiperazin-1-yl)-5-methoxyphenyl)-5,7-dimethoxyquinazolin-4(3H)-one;

5,7-Dimethoxy-2-(6-(4-(2-methoxyethyl)piperazin-1-yl)pyridin-2-yl)quinazolin-4(3H)-one;

2-(6-(4-(2-Hydroxyethyl)piperazin-1-yl)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one;

2-(6-(4-Isobutylpiperazin-1-yl)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one;

5,7-Dimethoxy-2-(6-(4-(2-(methylsulfonyl)ethyl)piperazin-1-yl)pyridin-2-yl)quinazolin-4(3H)-one;

Methyl 2-(4-(6-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)pyridin-2-yl)piperazin-1-yl)acetate;

2-(6-(4-(1-Hydroxypropan-2-yl)piperazin-1-yl)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one;

2-(4-(6-(5,7-Dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)pyridin-2-yl)piperazin-1-yl)propanamide;

2-(4-(6-(5,7-Dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)pyridin-2-yl)piperazin-1-yl)acetic acid;

3-(4-(6-(5,7-Dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)pyridin-2-yl)piperazin-1-yl)propanoic acid;

2-(5-(2-(Isopropylamino)ethoxy)-6-(4-isopropylpiperazin-1-yl)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one bis(trifluoroacetate);

2-(5-(2-Hydroxyethoxy)-6-(4-isopropylpiperazin-1-yl)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one acetate;

2-(6-(4-Isopropylpiperazin-1-yl)-5-methoxypyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one;

5,7-Dimethoxy-2-(6-(4-methylpiperazin-1-yl)pyridin-2-yl)quinazolin-4(3H)-one Hydrochloride;

5,7-Dimethoxy-2-(6-morpholinopyridin-2-yl)quinazolin-4(3H)-one Hydrochloride;

2-(6-(4-Isopropylpiperazin-1-yl)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one Hydrochloride;

5,7-Dimethoxy-2-(6-(4-(methylsulfonyl)piperazin-1-yl)pyridin-2-yl)quinazolin-4(3H)-one Hydrochloride;

5,7-Dimethoxy-2-(6-(4-propionylpiperazin-1-yl)pyridin-2-yl)quinazolin-4(3H)-one dihydrochloride;

2-(3-(4-Isopropylpiperazin-1-yl)-5-(trifluoromethoxy)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one;

7-Fluoro-2-(6-(4-isopropylpiperazin-1-yl)pyridin-2-yl)-5-methoxyquinazolin-4(3H)-one Hydrochloride;

7-(Benzyloxy)-2-(6-(4-isopropylpiperazin-1-yl)pyridin-2-yl)-5-methoxyquinazolin-4(3-H)-one Hydrochloride;

2-(6-(4-Isopropylpiperazin-1-yl)pyridin-2-yl)-5-methoxy-7-phenylquinazolin-4(3H)-one;

8-(Benzyloxy)-2-(3-(4-isopropylpiperazin-1-yl)phenyl)-5-methoxyquinazolin-4(3H)-one;

4-(6-(5,7-Dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)pyridin-2-yl)-N-isopropylpiperazine-1-carboxamide Hydrochloride;

2-(6-(4-Isopropyl-2-oxopiperazin-1-yl)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one Hydrochloride;

2-(6-(4-(Dimethylamino)piperidin-1-yl)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one;

5,7-Dimethoxy-2-(6-(4-methyl-3-oxopiperazin-1-yl)pyridin-2-yl)quinazolin-4(3H)-one;

2-(3-Chloro-5-(piperazin-1-yl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one, and

2-(3-Chloro-5-(4-isopropylpiperazin-1-yl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one.

5. A compound according to claim 1 , wherein R 6 is selected from the group represented by Formula II:

wherein:

D is selected from O and S;

E is selected from O, N, and S;

R 14 and R 15 are independently selected from hydrogen, alkyl, and cycloalkyl, wherein if E is O or S, only one of R 14 and R 15 is present; and

n is selected from 1, 2, and 3.

6. The compound according to claim 5

wherein D is oxygen

wherein n=1;

wherein R 14 and R 15 are independently selected from hydrogen, and alkyl;

and/or

wherein R 6 is selected from hydrogen, methoxy,

7. A pharmaceutical composition comprising a compound according to any one of claims 1 - 6 and a pharmaceutically acceptable carrier.

8. The compound of claim 2 , wherein R 1 is independently selected from alkoxy, halogen, and amino, and R 3 is independently selected from alkoxy, and halogen.

9. The compound of claim 8 , wherein R 1 is independently selected from methoxy, fluoride, and a substituted piperazine, and R 3 is independently selected from methoxy and fluoride.

10. The compound of claim 9 , wherein R 1 and R 3 are independently selected from alkoxy.

11. The compound of claim 2 , wherein R 1 and R 3 are methoxy and R 2 and R 4 are hydrogen.

12. The compound of claim 2 , wherein R 5 is selected from hydrogen, methyl, ethyl, propyl, and isopropyl, methoxy, ethoxy, propoxy, isopropoxy, —OCF 3 , fluoride, and chloride.

13. The compound of claim 12 , wherein R 5 is selected from hydrogen, methoxy, ethoxy, —OCF 3 , fluoride, chloride, methyl, and ethyl.

14. The compound of claim 2 , wherein R 6 is selected from hydrogen, methoxy, and ethoxy.

15. The compound of claim 2 , wherein R 6 is selected from hydrogen, methoxy;

16. The compound of claim 3 , wherein B is selected from

17. The compound of claim 3 , wherein R 8 and R 9 are independently selected from hydrogen, methyl, and ethyl.

18. The compound of claim 3 , wherein R 12 and R 13 are independently selected from hydrogen, methyl, ethyl, propyl, and isopropyl.

19. The compound of claim 6 , wherein R 14 and R 15 are independently selected from hydrogen and C1-C5 alkyl.