Bromodomain inhibitors

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

wherein,

R 2 is selected from CH 3 , CH 2 CH 3 , CH 2 CF 3 , CH 2 F, CHF 2 , CF 3 , CH 2 D, CHD 2 , or CD 3 ;

X5 is C—R 5 or N;

X6 is C—R 6 or N;

X7 is C—R 7 or N;

X8 is C—R 8 or N; wherein no more than two of X5, X6, X7, or X8 may be N;

R 5 is hydrogen, halogen, —CN, —NHR 61 , —N(R 61 ) 2 , alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, wherein each R 61 is independently selected from alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl;

R 6 is hydrogen, halogen, —CN, —NHR 61 , —N(R 61 ) 2 , alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, wherein each R 61 is independently selected from alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl;

R 7 is hydrogen, halogen, —CN, —NHR 61 , —N(R 61 ) 2 , alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, wherein each R 61 is independently selected from alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl;

R 8 is hydrogen, halogen, or alkyl;

X2 is N or C—R 12 , wherein R 12 is hydrogen, halogen, alkyl, or alkoxy;

R 13 is —Y—Z;

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

Z is selected from —SO 2 R 21 , —N(R 22 )SO 2 R 21 , —SO 2 N(R 22 ) 2 , —N(R 22 )SO 2 N(R 22 ) 2 , —CON(R 22 ) 2 , —N(R 22 )CO 2 R 21 , —N(R 22 )CON(R 22 ) 2 , —N(R 22 )COR 21 , —COR 21 , —OC(O)N(R 22 ) 2 , —OSO 2 N(R 22 ) 2 , or —N(R 22 )SO 3 R 21 ;

X3 is N or C—R 14 , wherein R 14 is hydrogen, halogen, —CN, alkyl, cycloalkyl, or alkoxy;

X4 is N or C—R 15 , wherein R 15 is hydrogen, halogen, alkyl, —CN, or alkoxy;

R 16 is hydrogen, halogen, —N(H)COX, or —W—X, wherein W is a bond, —O—, —S—, or —NH—, and X is selected from alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, alkynyl, cycloalkylalkynyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl;

each R 21 is independently selected from alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl; and

each R 22 is independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl.

2. The compound, or a pharmaceutically acceptable salt thereof, of claim 1 , having the structure of Formula (Ib),

wherein,

R 2 is selected from CH 3 ;

X5 is C—H;

X6 is C—R 6 ;

X7 is C—R 7 ;

X8 is C—H;

R 6 is hydrogen, or halogen;

R 7 is hydrogen, or halogen;

X2 is C—H;

R 13 is —Y—Z;

Y is selected from a bond, or —CH 2 —;

Z is selected from —SO 2 R 21 , —N(R 22 )SO 2 R 21 , —SO 2 N(R 22 ) 2 , —N(R 22 )SO 2 N(R 22 ) 2 , —CON(R 22 ) 2 , —N(R 22 )CO 2 R 21 , —N(R 22 )CON(R 22 ) 2 , —N(R 22 )COR 21 , —OC(O)N(R 22 ) 2 , —OSO 2 N(R 22 ) 2 , or —N(R 22 )SO 3 R 21 ;

X3 is C—R 14 , wherein R 14 is hydrogen, halogen, C 1 -C 3 alkyl, or C 1 -C 3 alkoxy;

X4 is C—R 15 , wherein R 15 is hydrogen, or halogen;

R 16 is —W—X, wherein W is a bond, —O—, —S—, or —NH—, and X is selected from alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl;

each R 21 is independently selected from alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl; and

each R 22 is independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl.

3. The compound, or a pharmaceutically acceptable salt thereof, of claim 2 , wherein R 6 is halogen, and R 7 is hydrogen.

4. The compound, or a pharmaceutically acceptable salt thereof, of claim 2 , wherein R 6 is hydrogen, and R 7 is halogen.

5. The compound, or a pharmaceutically acceptable salt thereof, of claim 2 , wherein R 6 is hydrogen, and R 7 is hydrogen.

6. The compound, or a pharmaceutically acceptable salt thereof, of claim 2 , wherein Y is a bond.

7. The compound, or a pharmaceutically acceptable salt thereof, of claim 6 , wherein Z is —N(R 22 )SO 2 R 21 , or —N(R 22 )SO 2 N(R 22 ) 2 .

8. The compound, or a pharmaceutically acceptable salt thereof, of claim 6 , wherein Z is —SO 2 R 21 .

9. The compound, or a pharmaceutically acceptable salt thereof, of claim 8 , wherein R 21 is heterocyclyl, or heterocyclylalkyl.

10. The compound, or a pharmaceutically acceptable salt thereof, of claim 7 , wherein R 22 is hydrogen or methyl.

11. The compound, or a pharmaceutically acceptable salt thereof, of claim 8 , wherein R 21 is alkyl, cycloalkyl, or cycloalkylalkyl.

12. The compound, or a pharmaceutically acceptable salt thereof, of claim 11 , wherein the alkyl is a C 1 -C 4 alkyl.

13. The compound, or a pharmaceutically acceptable salt thereof, of claim 2 , wherein W is a bond or —NH—.

14. The compound, or a pharmaceutically acceptable salt thereof, of claim 2 , wherein W is —O—.

15. The compound, or a pharmaceutically acceptable salt thereof, of claim 13 , wherein X is alkyl.

16. The compound, or a pharmaceutically acceptable salt thereof, of claim 14 , wherein X is alkyl.

17. The compound, or a pharmaceutically acceptable salt thereof, of claim 13 , wherein X is cycloalkylalkyl.

18. The compound, or a pharmaceutically acceptable salt thereof, of claim 14 , wherein X is cycloalkylalkyl.

19. The compound, or a pharmaceutically acceptable salt thereof, of claim 13 , wherein X is aryl.

20. The compound, or a pharmaceutically acceptable salt thereof, of claim 14 , wherein X is aryl.

21. The compound, or a pharmaceutically acceptable salt thereof, of claim 12 , wherein the C 1 -C 4 alkyl is a C 1 alkyl.

22. The compound, or a pharmaceutically acceptable salt thereof, of claim 2 , wherein Y is a bond, Z is —SO 2 R 21 , W is —O—, and X is aryl or cycloalkylalkyl.

23. A compound, or a pharmaceutically acceptable salt thereof, selected from:

N-[4-methyl-3-(2-methyl-1-oxoisoquinolin-4-yl)phenyl]methanesulfonamide;

4-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-2-methylisoquinolin-1-one;

4-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-6-fluoro-2-methylisoquinolin-1-one;

4-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-7-fluoro-2-methylisoquinolin-1-one;

4-[2-(2,4-difluorophenoxy)-5-methylsulfonylphenyl]-2-methylisoquinolin-1-one;

N-[4-(2,4-difluorophenoxy)-3-(2-methyl-1-oxoisoquinolin-4-yl)phenyl]ethanesulfonamide;

4-[2-(cyclopropylmethoxy)-5-ethylsulfonylphenyl]-2-methylisoquinolin-1-one;

4-[2-(cyclopropylmethoxy)-5-ethylsulfonylphenyl]-6-fluoro-2-methylisoquinolin-1-one;

2-methyl-4-[5-methylsulfonyl-2-(oxolan-3-yloxy)phenyl]isoquinolin-1-one;

2-methyl-4-[5-methylsulfonyl-2-(oxan-4-yloxy)phenyl]isoquinolin-1-one;

4-(2-ethoxy-5-methylsulfonylphenyl)-2-methylisoquinolin-1-one;

2-methyl-4-(5-methylsulfonyl-2-propoxyphenyl)isoquinolin-1-one;

2-methyl-4-[5-methylsulfonyl-2-(oxan-3-yloxy)phenyl]isoquinolin-1-one;

4-[2-(trans-4-hydroxycyclohexyl)oxy-5-methylsulfonylphenyl]-2-methylisoquinolin-1-one;

4-[5-ethylsulfonyl-2-(trans-4-hydroxycyclohexyl)oxyphenyl]-2-methylisoquinolin-1-one;

4-[2-(trans-4-aminocyclohexyl)oxy-5-methylsulfonylphenyl]-2-methylisoquinolin-1-one;

4-[2-(cis-4-aminocyclohexyl)oxy-5-methylsulfonylphenyl]-2-methylisoquinolin-1-one;

4-(2-but-2-ynoxy-5-methylsulfonylphenyl)-2-methylisoquinolin-1-one;

4-(2-but-2-ynoxy-5-ethylsulfonylphenyl)-2-methylisoquinolin-1-one;

6-fluoro-4-[2-(trans-4-hydroxycyclohexyl)oxy-5-methylsulfonylphenyl]-2-methylisoquinolin-1-one;

7-fluoro-4-[2-(trans-4-hydroxycyclohexyl)oxy-5-methylsulfonylphenyl]-2-methylisoquinolin-1-one;

4-[5-ethylsulfonyl-2-(trans-4-hydroxycyclohexyl)oxyphenyl]-6-fluoro-2-methylisoquinolin-1-one;

4-[5-ethylsulfonyl-2-(trans-4-hydroxycyclohexyl)oxyphenyl]-7-fluoro-2-methylisoquinolin-1-one;

2-methyl-4-[5-methylsulfonyl-2-(oxolan-3-ylamino)phenyl]isoquinolin-1-one;

2-methyl-4-[5-methylsulfonyl-2-(oxan-4-ylamino)phenyl]isoquinolin-1-one;

4-[2-[(trans-4-hydroxycyclohexyl)amino]-5-methylsulfonylphenyl]-2-methylisoquinolin-1-one;

4-[2-(cyclopropylmethylamino)-5-ethylsulfonylphenyl]-2-methylisoquinolin-1-one;

4-[2-(cyclopropylmethylamino)-5-methylsulfonylphenyl]-2-methylisoquinolin-1-one;

4-[2-(cyclopropylmethylamino)-5-ethylsulfonylphenyl]-7-fluoro-2-methylisoquinolin-1-one;

4-[2-(cyclopropylmethylamino)-5-methylsulfonylphenyl]-7-fluoro-2-methylisoquinolin-1-one;

4-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-2-methyl-6-(trifluoromethyl)isoquinolin-1-one;

4-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-6-methoxy-2-methylisoquinolin-1-one;

[4-(cyclopropylmethoxy)-3-(2-methyl-1-oxoisoquinolin-4-yl)phenyl]sulfamate;

N-[2-(2-methyl-1-oxoisoquinolin-4-yl)-4-methylsulfonylphenyl]-cyclopropanecarboxamide;

N-[2-(2-methyl-1-oxoisoquinolin-4-yl)-4-methylsulfonylphenyl]propanamide;

N-[2-(2-methyl-1-oxoisoquinolin-4-yl)-4-methylsulfonylphenyl]acetamide;

2-methyl-4-(5-methylsulfonyl-2-propylphenyl)isoquinolin-1-one;

4-(2-ethyl-5-methylsulfonylphenyl)-2-methylisoquinolin-1-one;

4-(2-butyl-5-methylsulfonylphenyl)-2-methylisoquinolin-1-one;

4-[2-(2-cyclopropylethyl)-5-methylsulfonylphenyl]-2-methylisoquinolin-1-one;

4-[2-(cyclopropylmethoxy)-5-propan-2-ylsulfonylphenyl]-2-methylisoquinolin-1-one;

4-[2-(cyclopropylmethoxy)-5-propan-2-ylsulfonylphenyl]-6-methoxy-2-methylisoquinolin-1-one;

4-[5-(ethylsulfonylmethyl)-2-(2,2,2-trifluoroethoxy)phenyl]-2-methylisoquinolin-1-one; and

2-methyl-4-[5-(methylsulfonylmethyl)-2-(2,2,2-trifluoroethoxy)phenyl]isoquinolin-1-one.

24. The compound, or a pharmaceutically acceptable salt thereof, of claim 1 having the structure 4-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-6-fluoro-2-methylisoquinolin-1-one.

25. The compound, or a pharmaceutically acceptable salt thereof, of claim 1 having the structure 4-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-7-fluoro-2-methylisoquinolin-1-one.

26. The compound, or a pharmaceutically acceptable salt thereof, of claim 1 having the structure 4-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-2-methylisoquinolin-1-one.

27. The compound, or a pharmaceutically acceptable salt thereof, of claim 1 having the structure 4-[2-(2,4-difluorophenoxy)-5-methylsulfonylphenyl]-2-methylisoquinolin-1-one.

28. The compound, or a pharmaceutically acceptable salt thereof, of claim 1 having the structure 4-[2-(cyclopropylmethoxy)-5-ethylsulfonylphenyl]-2-methylisoquinolin-1-one.

29. A pharmaceutical composition comprising a compound of Formula (I) as described in claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

30. A pharmaceutical composition comprising a compound of claim 28 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.