Substituted 1,6-dihydropyridinones and 1,2-dihydroisoquinolinones as bet inhibitors

1. A compound of Formula (I):

or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing,

wherein:

R a is hydrogen, halogen, or C 1 -C 4 alkyl;

R b is hydrogen, halogen, cyano, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C(O)NR 10 R 11 , NR 10 R 11 , NR 10 C(O)R 11 , NR 10 S(O) 2 R 11 , OR 10 , S(O) 2 R 10 , S(O) 2 NR 10 R 11 , C 3 -C 6 cycloalkyl, or 3- to 6-membered heterocyclyl;

R e is hydrogen, halogen, cyano, C 1 -C 4 alkyl, or 3- to 6-membered heterocyclyl;

R 1 is hydrogen or C 1 -C 4 alkyl, wherein the C 1 -C 4 alkyl is optionally substituted by 1 or more OH substituents;

R 2 is hydrogen, halogen, cyano, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C(O)NR 10 R 11 , NR 10 R 11 , NR 10 C(O)R 11 , NR 10 S(O) 2 R 11 , OC 1 -C 4 alkyl, OC 1 -C 4 haloalkyl, S(O) 2 R 10 , S(O) 2 NR 10 R 11 , C 3 -C 6 cycloalkyl, or 3- to 6-membered heterocyclyl;

R 3 is hydrogen, halogen, cyano, C 1 -C 4 alkyl, (CH 2 ) m W 3 R g , (CH 2 ) m N(R f )C(O)OR h , (CH 2 ) m N(R f )W 3 R g , C(O)NR 13 R 14 , NR 13 R 14 , NR 13 C(O)R 14 , NR 13 C(O)NR 13 R 14 , NR 13 S(O) 2 R 14 , NR 13 S(O) 2 NR 13 R 14 , OR 13 , S(O) 2 R 1 , or S(O) 2 NR 13 R 14 , wherein the C 1 -C 4 alkyl is optionally substituted by 1 or more substituents independently selected from the group consisting of oxo, halogen, cyano, and OH;

R 4 is hydrogen, (CH 2 ) m W 3 R g , or (CH 2 ) m N(R f )W 3 R g ;

each W 3 is independently —C(O)— or —S(O) 2 —;

each R f is independently hydrogen, C 1 -C 4 alkyl, or C 3 -C 6 cycloalkyl;

each R g is independently CR g1 =CHR g2 or C≡CR g2 ;

each R g1 is independently hydrogen, cyano, or C 1 -C 4 alkyl, wherein each C 1 -C 4 alkyl is optionally and independently substituted by 1 or more substituents independently selected from the group consisting of NH 2 , NHCH 3 , N(CH 3 ) 2 , OH, and OCH 3 ;

each R g2 is independently hydrogen, cyano, or C 1 -C 4 alkyl, wherein each C 1 -C 4 alkyl is optionally and independently substituted by 1 or more substituents independently selected from the group consisting of NH 2 , NHCH 3 , N(CH 3 ) 2 , OH, and OCH 3 ;

each R h is independently C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl;

each R 5 is independently hydrogen, halogen, cyano, C 1 -C 4 alkyl, C(O)NR 10 R 11 , C(O)OR 10 , NR 10 R 11 , NR 10 C(O)R 11 , NR 10 S(O) 2 R 11 , OR 10 , S(O) 2 R 10 , S(O) 2 NR 10 R 11 , C 3 -C 6 cycloalkyl, 3- to 6-membered heterocyclyl, C 6 -C 14 aryl, or 5- to 10-membered heteroaryl, wherein each C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C(O)NR 10 R 11 , C(O)OR 10 , NR 10 R 11 , NR 10 C(O)R 11 , NR 10 S(O) 2 R 11 , OR 10 , S(O) 2 R 10 , S(O) 2 NR 10 R 11 , C 3 -C 6 cycloalkyl, 3- to 6-membered heterocyclyl, C 6 -C 14 aryl, and 5- to 10-membered heteroaryl is optionally and independently substituted by 1 or more independently selected R 12 substituents;

W 1 is a bond, —NR w1 —, or —O—;

R w1 is hydrogen, C 1 -C 4 alkyl, or C 3 -C 6 cycloalkyl, wherein the C 1 -C 4 alkyl is optionally substituted by 1 or more substituents independently selected from the group consisting of halogen, oxo, and OH;

R c is hydrogen, halogen, cyano, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 3 -C 6 cycloalkyl, 3- to 6-membered heterocyclyl, C 6 -C 14 aryl, or 5- or 6-membered heteroaryl, wherein the C 3 -C 6 cycloalkyl, 3- to 6-membered heterocyclyl, C 6 -C 14 aryl, or 5- or 6-membered heteroaryl is optionally substituted by 1 or more independently selected R c1 substituents;

each R c1 is independently oxo, halogen, cyano, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C(O)NR 10 R 11 , NR 10 R 11 , NR 10 C(O)R 11 , NR 10 S(O) 2 R 11 , OR 10 , S(O) 2 R 10 , S(O) 2 NR 10 R 11 , C 3 -C 6 cycloalkyl, or 3- to 6-membered heterocyclyl;

W 2 is a bond;

R d is hydrogen, C 1 -C 4 alkyl, or 3- to 6-membered heterocyclyl;

each R 10 is independently hydrogen, C 1 -C 4 alkyl, C 1 -C 3 alkylene-C 3 -C 6 cycloalkyl, C 1 -C 3 alkylene-3- to 6-membered heterocyclyl, C 2 -C 4 alkenyl, C(O)R 12 , C 3 -C 6 cycloalkyl, or 3- to 6-membered heterocyclyl, wherein each C 1 -C 4 alkyl is optionally and independently substituted by 1 or more substituents independently selected from the group consisting of oxo, halogen, cyano, C(O)NR 13 R 14 , NR 13 R 14 , and OH;

each R 11 is independently hydrogen, C 1 -C 4 alkyl, C 1 -C 3 alkylene-C 3 -C 6 cycloalkyl, C 1 -C 3 alkylene-3- to 6-membered heterocyclyl, C 2 -C 4 alkenyl, C(O)R 12 , C 3 -C 6 cycloalkyl, or 3- to 6-membered heterocyclyl, wherein each C 1 -C 4 alkyl is optionally and independently substituted by 1 or more substituents independently selected from the group consisting of oxo, halogen, cyano, C(O)NR 13 R 14 , NR 13 R 14 , and OH; or

each R 10 and R 11 , taken together with the atoms to which they are attached, form a 3- to 6-membered heterocyclyl, wherein each 3- to 6-membered heterocyclyl is optionally and independently substituted by 1 or more substituents independently selected from the group consisting of oxo, halogen, cyano, C 1 -C 4 alkyl, and OH, and further wherein each C 1 -C 4 alkyl substituent is optionally and independently substituted by 1 or more substituents independently selected from the group consisting of oxo, halogen, cyano, and OH;

each R 12 is independently halogen, C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, or 3- to 6-membered heterocyclyl, wherein each C 1 -C 4 alkyl is optionally and independently substituted by 1 or more substituents independently selected from the group consisting of oxo, halogen, cyano, NR 13 R 14 , NR 13 C(O)R 14 , and OH;

each R 13 is independently hydrogen, C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, or 3- to 6-membered heterocyclyl, wherein each C 1 -C 4 alkyl is optionally and independently substituted by 1 or more substituents independently selected from the group consisting of oxo, halogen, cyano, and OH;

each R 14 is independently hydrogen, C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, or 3- to 6-membered heterocyclyl, wherein each C 1 -C 4 alkyl is optionally and independently substituted by 1 or more substituents independently selected from the group consisting of oxo, halogen, cyano, and OH; or

each R 13 and R 14 , taken together with the atoms to which they are attached, form a 3- to 6-membered heterocyclyl, wherein each 3- to 6-membered heterocyclyl is optionally and independently substituted by 1 or more substituents independently selected from the group consisting of oxo, halogen, cyano, C 1 -C 4 alkyl, and OH, and further wherein each C 1 -C 4 alkyl substituent is optionally and independently substituted by 1 or more substituents independently selected from the group consisting of oxo, halogen, cyano, and OH; and

each m is independently 0, 1, 2, 3, or 4;

with the proviso that at least one of R 3 and R 4 is (CH 2 ) m W 3 R 9 or (CH 2 ) m N(R f )W 3 R g .

2. The compound of claim 1 , wherein the compound is of Formula (II):

or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

3. The compound of claim 1 , wherein the compound is of Formula (V):

or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

4. The compound of claim 3 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein each R 5 is independently hydrogen.

5. The compound of claim 1 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R a is hydrogen.

6. The compound of claim 1 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R b is hydrogen, C(O)NR 10 R 11 , NR 10 R 11 , or NR 10 VC(O)R 11 .

7. The compound of claim 1 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R b is NR 10 R 11 .

8. The compound of claim 1 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R e is hydrogen.

9. The compound of claim 1 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 1 is hydrogen or C 1 -C 4 alkyl.

10. The compound of claim 1 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 1 is C 1 -C 4 alkyl.

11. The compound of claim 1 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 2 is hydrogen, halogen, cyano, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, OC 1 -C 4 alkyl, or OC 1 -C 4 haloalkyl.

12. The compound of claim 1 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 3 is hydrogen, (CH 2 ) m W 3 R 9 , or (CH 2 ) m N(R f )W 3 R g .

13. The compound of claim 1 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 3 is hydrogen.

14. The compound of claim 1 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 4 is (CH 2 ) m W 3 R g or (CH 2 ) m N(R f )W 3 R g .

15. The compound of claim 1 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 4 is (CH 2 ) m N(R f )W 3 R g .

16. The compound of claim 1 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein W 1 is —O—.

17. The compound of claim 16 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R c is phenyl, wherein the phenyl is optionally substituted by 1 or more independently selected R c1 substituents.

18. The compound of claim 1 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R d is hydrogen.

19. The compound of claim 1 , wherein the compound is selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

20. The compound of claim 1 , wherein the compound is selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

21. The compound of claim 1 , wherein the compound is:

or a pharmaceutically acceptable salt thereof.

22. The compound of claim 1 , wherein the compound is:

or a pharmaceutically acceptable salt thereof.

23. The compound of claim 1 , wherein the compound is:

or a pharmaceutically acceptable salt thereof.

24. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and the compound of claim 1 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.

25. A kit comprising the compound of claim 1 , or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.