Bromodomain inhibitors

1. A compound of Formula I, or a pharmaceutically acceptable salt thereof,

wherein,

X 2 is C—R 12 , in which R 12 is hydrogen, halogen, alkyl, or alkoxy;

X 5 is C—R 15 , in which R 15 is hydrogen, halogen, —CN, alkyl or alkoxy;

X 6 is C—R 16 , in which R 16 is hydrogen, halogen, or —W-X, wherein W is a bond, —O—, —S—, or —NH—, and X is alkyl, alkynyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkynyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl;

Ring A is selected from the group consisting of:

wherein:

R 1 is hydrogen, alkyl, alkylsulfonyl, alkylsulfinyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl;

R 2 is alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl; and

each R 3 is independently hydrogen, halogen, alkyl, alkoxy, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl; and

G is:

2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein G is:

3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein G is:

4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein G is:

5. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein ring A is selected to provide one of:

6. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein ring A is selected to provide one of:

7. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:

R 16 is hydrogen or —W—X, wherein W is —O—, —S— or —NH— and X is alkyl, alkynyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkynyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl;

R 1 is hydrogen, alkyl, alkylsulfonyl, alkylsulfinyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl; and

R 2 is alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl.

8. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:

R 16 is —W—X, wherein W is —O— and X is alkyl aryl, cycloalkyl, or cycloalkylalkyl;

R 1 is hydrogen or alkyl; and

R 2 is alkyl.

9. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 16 is:

10. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 16 is:

11. A compound selected from one of the following:

N-[6-(1,5-dimethyl-6-oxopyridin-3-yl)-1-[(3-fluorophenyl)methyl]-2-methylbenzimidazol-4-yl]ethanesulfonamide;

N-[6-(1,5-dimethyl-6-oxopyridin-3-yl)-1-[(4-fluorophenyl)methyl]indazol-4-yl]ethanesulfonamide;

N-[2-cyclopropyl-7-(2-methyl-1-oxoisoquinolin-4-yl)-1,3-benzoxazol-5-yl]ethanesulfonamide;

4-[5-(cyclopropylmethoxy)-2-ethyl-1,1-dioxo-3H-1,2-benzothiazol-6-yl]-2-methylisoquinolin-1-one;

4-[5-(cyclopropylmethoxy)-1-methylsulfonyl-2,3-dihydroindol-6-yl]-2-methylisoquinolin-1-one;

4-[5-(cyclopropylmethoxy)-1-ethylsulfonyl-2,3-dihydroindol-6-yl]-2-methylisoquinolin-1-one;

N-[1-benzyl-6-(2-methyl-1-oxoisoquinolin-4-yl)indol-4-yl]methanesulfonamide;

N-[1-benzyl-6-(1,5-dimethyl-6-oxopyridin-3-yl)indol-4-yl]methanesulfonamide;

N-[1-benzyl-6-(1,5-dimethyl-6-oxopyridin-3-yl)-2,3-dihydroindol-4-yl]methanesulfonamide;

N-[1-benzyl-6-(2-methyl-1-oxoisoquinolin-4-yl)-2,3-dihydroindol-4-yl]methanesulfonamide;

N-[1-benzyl-6-(1,5-dimethyl-6-oxopyridin-3-yl)benzotriazol-4-yl]ethanesulfonamide N-[6-(1,5-dimethyl-6-oxopyridin-3-yl)-1-[(4-fluorophenyl)methyl]benzotriazol-4-yl]ethanesulfonamide;

4-[6-(cyclopropylmethoxy)-1-methyl-3-methyl sulfonylindazol-5-yl]-2-methylisoquinolin-1-one;

4-[6-(cyclopropylmethoxy)-3-ethyl sulfonyl-1 methylindazol-5-yl]-2-methylisoquinolin-1-one;

N-[1-benzyl-6-(1,5-dimethyl-6-oxopyridin-3-yl)benzimidazol-4-yl]methanesulfonamide

N-[6-(1,5-dimethyl-6-oxopyridin-3-yl)-1-[(3-fluorophenyl)methyl]benzimidazol-4-yl]methanesulfonamide;

N-[6-(1,5-dimethyl-6-oxopyridin-3-yl)-1-[(3-fluorophenyl)methyl]benzimidazol-4-yl]ethanesulfonamide;

N-[6-(1,5-dimethyl-6-oxopyridin-3-yl)-1-[(3-fluorophenyl)methyl]-2-methylbenzimidazol-4-yl]methanesulfonamide;

N-[6-(1,5-dimethyl-6-oxopyridin-3-yl)-1-[(4-fluorophenyl)methyl]-2-methylbenzimidazol-4-yl]methanesulfonamide;

N-[1-[(2,4-difluorophenyl)methyl]-6-(1,5-dimethyl-6-oxopyridin-3-yl)benzimidazol-4-yl]ethanesulfonamide;

N-[1-benzyl-6-(1,5-dimethyl-6-oxopyridin-3-yl)indazol-4-yl]ethanesulfonamide;

N-[6-(1,5-dimethyl-6-oxopyridin-3-yl)-2-methyl-1-(1-phenylethyl)benzimidazol-4-yl]methanesulfonamide;

4-[7-(cyclopropylmethoxy)-4-ethylsulfonyl-2,3-dihydro-1,4-benzoxazin-6-yl]-2-methylisoquinolin-1-one;

N-[1-(cyclopropylmethyl)-6-(1,5-dimethyl-6-oxopyridin-3-yl)-2-ethoxybenzimidazol-4-yl]methanesulfonamide;

N-[1-(cyclopropylmethyl)-6-(1,5-dimethyl-6-oxopyridin-3-yl)-2-methoxybenzimidazol-4-yl]methanesulfonamide;

N-[1-(cyclopropylmethyl)-6-(1,5-dimethyl-6-oxopyridin-3-yl)-2-(trifluoromethyl)benzimidazol-4-yl]methanesulfonamide;

or a pharmaceutical salt of any of these compounds.

12. A pharmaceutical composition comprising the compound of claim 1 or 11 .

13. An oral dosage form comprising the pharmaceutical composition of claim 12 .

14. A medicament comprising the pharmaceutical composition of claim 12 for use in the treatment of cancer or other neoplastic disease.

15. A method of modulating the epigenetic status of a cell comprising contacting the cell with the compound of claim 1 .

16. A method for inhibiting the activity of a bromodomain-containing protein in a biological sample comprising contacting the biological sample with the compound of claim 1 .

17. A method for treating cancer or neoplastic disease in a subject in need of such treatment comprising administering to the subject a therapeutically effective amount of a compound of claim 1 .

18. A compound of Formula II, or a pharmaceutically acceptable salt thereof,

wherein,

X 2 is C—R 12 , wherein R 12 is hydrogen, halogen, alkyl, or alkoxy;

X 3 is C—R 13 , wherein R 13 is —Y—Z, in which

Y is a bond, —CH 2 —, or —CH(C 1 -C 4 alkyl)-;

Z is —SO 2 R b , —N(R a )SO 2 R b , —SO 2 N(R a ) 2 , —N(R a )SO 2 N(R a ) 2 , —CON(R a ) 2 , —N(R a )CO 2 R a , —N(R a )CON(R a ) 2 , —N(R a )COR a , —OC(O)N(R a ) 2 , —OSO 2 N(R a ) 2 , or —N(R a )SO 3 R b ;

each R a is independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl; and

R b is selected from alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl;

X 6 is C—R 16 , wherein R 16 is hydrogen, halogen, or —W—X, wherein W is a bond, —O—, —S—, or —NH—, and X is alkyl, alkynyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkynyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl;

Ring B is selected to provide one of:

and wherein:

R 1 is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl; and

each R 3 is independently hydrogen, halogen, alkyl, alkylsulfonyl, alkylsulfinyl, alkoxy, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl; and

G is:

19. The compound of claim 18 , or a pharmaceutically acceptable salt thereof, wherein G is:

20. The compound of claim 18 , or a pharmaceutically acceptable salt thereof, wherein G is:

21. The compound of claim 18 , or a pharmaceutically acceptable salt thereof, wherein G is:

22. The compound of claim 18 , or a pharmaceutically acceptable salt thereof, wherein ring B is selected to provide one of the following:

23. The compound of claim 18 , or a pharmaceutically acceptable salt thereof, wherein ring B is selected to provide one of the following:

24. The compound of claim 18 , or a pharmaceutically acceptable salt thereof, wherein:

R 13 is —Y—Z, in which Y is a bond or —CH 2 —, Z is —SO 2 R b , —N(R a )SO 2 R b , or —SO 2 N(R a ) 2 , each R a is independently hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, and R b is alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl;

R 1 is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl; and

R 3 is hydrogen, halogen, alkyl, alkylsulfonyl, alkylsulfinyl, alkoxy, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl.

25. The compound of claim 18 , or a pharmaceutically acceptable salt thereof, wherein:

R 13 is —Y—Z, in which Y is a bond or —CH 2 —, Z is —SO 2 R b or —N(R a )SO 2 R b , each R a is independently hydrogen or alkyl, and R b is alkyl;

R 1 is alkyl, cycloalkylalkyl, or aralkyl; and

R 3 is hydrogen, halogen, alkyl, or alkoxy.

26. A pharmaceutical composition comprising the compound of claim 18 .

27. An oral dosage form comprising the pharmaceutical composition of claim 26 .

28. A medicament comprising the pharmaceutical composition of claim 26 for use in the treatment of cancer or other neoplastic disease.

29. A method of modulating the epigenetic status of a cell comprising contacting the cell with the compound of claim 18 .

30. A method for inhibiting the activity of a bromodomain-containing protein in a biological sample comprising contacting the biological sample with the compound of claim 18 .

31. A method for treating cancer or neoplastic disease in a subject in need of such treatment comprising administering to the subject a therapeutically effective amount of a compound of claim 18 .