Heterocyclic compounds as BET inhibitors
Novel bromodomain and extraterminal domain (BET) inhibitors and to therapeutic methods of treating conditions and diseases using these novel BET inhibitors are provided.
1. A compound of Formula (J):
or a tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein:
each is independently a single bond or double bond;
X is O or S;
R 1 is hydrogen, C 1 -C 3 alkyl, —(C 1 -C 3 alkylene)OH, C 1 -C 3 haloalkyl, or C 3 -C 4 cycloalkyl;
G 1 is CR a , wherein:
R a is hydrogen, halogen, or C 1 -C 4 alkyl;
Z 1 is C—W 1 —R c ; wherein:
each W 1 is independently —O— or —NR w1 —, wherein:
R w1 is hydrogen, C 3 -C 6 cycloalkyl, or C 1 -C 4 alkyl optionally substituted by oxo, —OH, or halogen, and
R c is independently C 3 -C 6 cycloalkyl, 4- to 6-membered heterocyclyl, C 6 -C 14 aryl, or 5- or 6-membered heteroaryl, each of which is independently optionally substituted by R c1 , wherein each R c1 is independently halogen, C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, 3- to 6-membered heterocyclyl, cyano, oxo, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, C 1 -C 4 haloalkyl, —OR 10 , —NR 10 R 11 , —C(O)NR 10 R 11 ,
—NR 10 C(O)R 11 , —S(O) 2 R 10 , —NR 10 S(O) 2 R 11 , or —S(O) 2 NR 10 R 11 ;
Z 2 is C—W 2 —R d , wherein:
W 2 is —O—, —NR w2 —, or a bond, wherein:
R w2 is hydrogen, C 3 -C 6 cycloalkyl, or C 1 -C 4 alkyl optionally substituted by oxo, —OH, or halogen, and
R d is independently hydrogen, halogen, cyano, 3- to 6-membered heterocyclyl, or C 1 -C 4 alkyl;
Z 3 is C—R e , wherein:
R e is independently hydrogen, halogen, cyano, 3- to 6-membered heterocyclyl, or C 1 -C 4 alkyl;
M 1 is S or CR 1a ;
M 2 is S or CR 2a , provided that
(1) when M 1 is S, then the adjacent to M 1 is a single bond and the adjacent to M2 is a double bond,
(2) when M 2 is S, then the adjacent to M 2 is a single bond and the adjacent to M 1 is a double bond, and
(3) either M 1 or M 2 is S;
R 1a and R 2a are each independently hydrogen, halogen, C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, 3- to 6-membered heterocyclyl, 5- to 10-membered heteroaryl, cyano, oxo, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, —OR 10 , —NR 10 R 11 , —C(O)OR 10 , —C(O)NR 10 R 11 , —NR 10 C(O)R 11 , —S(O) 2 R 10 ,
—NR 10 S(O) 2 R 11 or —S(O) 2 NR 10 R 11 , each of which is independently optionally substituted by R 12 ;
R 2 is hydrogen, halogen, C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, 3- to 6-membered heterocyclyl, —(C 1 -C 3 alkylene)3- to 6-membered heterocyclyl, 5- to 10-membered heteroaryl, cyano, oxo, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, —OR 10 , —NR 10 R 11 , —C(O)OR 10 , —C(O)NR 10 R 11 ,
—NR 10 C(O)R 11 , —S(O) 2 R 10 , —NR 10 S(O) 2 R 11 , or —S(O) 2 NR 10 R 11 , each of which is independently optionally substituted by R 12 ;
R 3 is —(CH 2 ) m NR 13 S(O) 2 R 14 wherein m is 0, 1, 2 or 3; C 3 -C 6 cycloalkyl optionally substituted by halogen, oxo, —CN, or —OH; C 1 -C 4 alkyl substituted by halogen, oxo, —CN, or —OH; or C 2 -C 6 alkenyl;
R 10 and R 11 are each independently hydrogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 alkenyl, C 3 -C 6 cycloalkyl, C 6 -C 14 aryl, 3- to 6-membered heterocyclyl, —(C 1 -C 3 alkylene)C 3 -C 6 cycloalkyl, —(C 1 -C 3 alkylene) 3- to 6-membered heterocyclyl, —(C 1 -C 3 alkylene) C 6 -C 14 aryl, —NR 15 R 16 , or —C(O)R 12 , wherein each of R 10 and R 11 is independently optionally substituted by halogen, oxo, —CN, —CF 3 ,
—OH, —NR 13 R 14 , —C(O)NR 13 R 14 , or C 1 -C 4 alkyl optionally substituted by halogen, oxo, —CN, —CF 3 , or —OH,
or R 10 and R 11 are taken together with the atom or atoms to which they are attached to form a 3- to 6-membered heterocyclyl ring optionally substituted by halogen, oxo, —CN, —CF 3 , —OH, or C 1 -C 4 alkyl optionally substituted by halogen, oxo, —CN, or —OH;
each R 12 is independently halogen, cyano, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, —OR 15 , —NR 15 R 16 , —C(O)NR 15 R 16 , —NR 15 C(O)R 16 , —S(O) 2 R 15 , —NR 15 S(O) 2 R 16 , —S(O) 2 NR 15 R 16 , C 3 -C 6 cycloalkyl, 3- to 6-membered heterocyclyl, or C 1 -C 4 alkyl, each of which is independently optionally substituted by halogen, oxo, —CF 3 , —CN, —OH, —NR 13 R 14 , or —NR 13 C(O)R 14 ;
R 13 and R 14 are independently hydrogen, C 1 -C 4 alkyl C 3 -C 6 cycloalkyl, or 3- to 6-membered heterocyclyl, each of which is independently optionally substituted by halogen, oxo, —CN, or —OH,
or R 13 and R 14 are taken together with the atom or atoms to which they are attached to form a 3- to 6-membered heterocyclyl ring optionally substituted by halogen, oxo, —CN, —OH, or C 1 -C 4 alkyl optionally substituted by halogen, oxo, —CN, or —OH; and
each R 15 and R 16 are independently hydrogen, C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, or 3- to 6-membered heterocyclyl, each of which is independently optionally substituted by halogen, oxo, —CN, or —OH,
or R 15 and R 16 are taken together with the atoms to which they are attached to form a 3- to 6-membered heterocyclyl ring optionally substituted by halogen, oxo, —CN, —OH, or C 1 -C 4 alkyl optionally substituted by halogen, oxo, —CN, or —OH.
2. The compound of claim 1 , wherein the compound is a compound of Formula (I):
or a tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein:
each is independently a single bond or double bond;
X is O or S;
R 1 is hydrogen, C 1 -C 3 alkyl, —(C 1 -C 3 alkylene)OH, C 1 -C 3 haloalkyl, or C 3 -C 4 cycloalkyl;
G 1 is CR a , wherein:
R a is hydrogen, halogen, or C 1 -C 4 alkyl;
Z 1 is C—W 1 —R c ; wherein:
each W 1 is independently —O— or —NR w1 —, wherein:
R w1 is hydrogen, C 3 -C 6 cycloalkyl, or C 1 -C 4 alkyl optionally substituted by oxo, —OH, or halogen, and
R c is independently 4- to 6-membered heterocyclyl, C 6 -C 14 aryl, or 5- or 6-membered heteroaryl, each of which is independently optionally substituted by R c1 , wherein each R c1 is independently halogen, C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, 3- to 6-membered heterocyclyl, cyano, oxo, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, C 1 -C 4 haloalkyl, —OR 10 , —NR 10 R 11 , —C(O)NR 10 R 11 , —NR 10 C(O)R 11 , —S(O) 2 R 10 , —NR 10 S(O) 2 R 11 , or —S(O) 2 NR 10 R 11 ;
Z 2 is C—W 2 —R d , wherein:
W 2 is —O—, —NR w2 —, or a bond, wherein:
R w2 is hydrogen, C 3 -C 6 cycloalkyl, or C 1 -C 4 alkyl optionally substituted by oxo, —OH, or halogen, and
R d is independently hydrogen, halogen, cyano, 3- to 6-membered heterocyclyl, or C 1 -C 4 alkyl;
Z 3 is C—R e , wherein:
R e is independently hydrogen, halogen, cyano, 3- to 6-membered heterocyclyl, or C 1 -C 4 alkyl;
M 1 is S or CR 1a ;
M 2 is S or CR 2a , provided that
(1) when M 1 is S, then the adjacent to M 1 is a single bond and the adjacent to M 2 is a double bond,
(2) when M 2 is S, then the adjacent to M 2 is a single bond and the adjacent to M 1 is a double bond, and
(3) at least one of M 1 and M 2 is not S;
R 1a and R 2a are each independently hydrogen, halogen, C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, 3- to 6-membered heterocyclyl, 5- to 10-membered heteroaryl, cyano, oxo, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, —OR 10 , —NR 10 R 11 , —C(O)OR 10 , —C(O)NR 10 R 11 , —NR 10 C(O)R 11 , —S(O) 2 R 10 ,
—NR 10 S(O) 2 R 11 or —S(O) 2 NR 10 R 11 , each of which is independently optionally substituted by R 12 ;
R 2 is halogen, C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, 3- to 6-membered heterocyclyl, —(C 1 -C 3 alkylene)3- to 6-membered heterocyclyl, 5- to 10-membered heteroaryl, cyano, oxo, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, —OR 10 , —NR 10 R 11 , —C(O)OR 10 , —C(O)NR 10 R 11 , —NR 10 C(O)R 11 , —S(O) 2 R 10 , —NR 10 S(O) 2 R 11 , or —S(O) 2 NR 10 R 11 , each of which is independently optionally substituted by R 12 ;
R 3 is —(CH 2 ) m NR 13 S(O) 2 R 14 , C 3 -C 6 cycloalkyl, or C 1 -C 4 alkyl substituted by halogen, oxo, —CN, or —OH, wherein m is 0, 1, 2 or 3;
R 10 and R 11 are each independently hydrogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 alkenyl, C 3 -C 6 cycloalkyl, 3- to 6-membered heterocyclyl, —(C 1 -C 3 alkylene)C 3 -C 6 cycloalkyl, —(C 1 -C 3 alkylene) 3- to 6-membered heterocyclyl, —NR 15 R 16 , or —C(O)R 12 , wherein each of R 10 and R 11 is independently optionally substituted by halogen, oxo, —CN, —CF 3 , —OH, —NR 13 R 14 , —C(O)NR 13 R 14 , or C 1 -C 4 alkyl optionally substituted by halogen, oxo, —CN, —CF 3 , or —OH,
or R 10 and R 11 are taken together with the atom or atoms to which they are attached to form a 3- to 6-membered heterocyclyl ring optionally substituted by halogen, oxo, —CN, —CF 3 , —OH, or C 1 -C 4 alkyl optionally substituted by halogen, oxo, —CN, or —OH;
each R 12 is independently halogen, cyano, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, —OR 15 , —NR 15 R 16 , —C(O)NR 15 R 16 , —NR 15 C(O)R 16 , —S(O) 2 R 15 , —NR 15 S(O) 2 R 16 , —S(O) 2 NR 15 R 16 , C 3 -C 6 cycloalkyl, 3- to 6-membered heterocyclyl, or C 1 -C 4 alkyl, each of which is independently optionally substituted by halogen, oxo, —CF 3 , —CN, —OH, —NR 13 R 14 , or —NR 13 C(O)R 14 ;
R 13 and R 14 are independently hydrogen, C 1 -C 4 alkyl C 3 -C 6 cycloalkyl, or 3- to 6-membered heterocyclyl, each of which is independently optionally substituted by halogen, oxo, —CN, or —OH,
or R 13 and R 14 are taken together with the atom or atoms to which they are attached to form a 3- to 6-membered heterocyclyl ring optionally substituted by halogen, oxo, —CN, —OH, or C 1 -C 4 alkyl optionally substituted by halogen, oxo, —CN, or —OH; and
each R 15 and R 16 are independently hydrogen, C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, or 3- to 6-membered heterocyclyl, each of which is independently optionally substituted by halogen, oxo, —CN, or —OH,
or R 15 and R 16 are taken together with the atoms to which they are attached to form a 3- to 6-membered heterocyclyl ring optionally substituted by halogen, oxo, —CN, —OH, or C 1 -C 4 alkyl optionally substituted by halogen, oxo, —CN, or —OH.
3. The compound of claim 1 , or a tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein the compound is of Formula (II),
4. The compound of claim 1 , or a tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein the compound is of Formula (III),
5. The compound of claim 1 , or a tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein X is O.
6. The compound of claim 1 , or a tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein G 1 is CH.
7. The compound of claim 1 , or a tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein Z 1 is C—W 1 —R c and R c is C 6 -C 14 aryl optionally substituted by R c1 .
8. The compound of claim 7 , or a tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R′ is phenyl optionally substituted by halogen or C 1 -C 4 alkyl.
9. The compound of claim 1 , or a tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein Z 2 is CH.
10. The compound of claim 1 , or a tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein Z 3 is CH.
11. The compound of claim 1 , or a tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 1 is C 1 -C 3 alkyl.
12. The compound of claim 1 , or a tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 2 is —C(O)NR 10 R 11 , 5- to 10-membered heteroaryl, —(C 1 -C 3 alkylene)3- to 6-membered heterocyclyl, or C 1 -C 4 alkyl, each of which is independently optionally substituted by R 12 .
13. The compound of claim 12 , or a tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 2 is —C(O)NR 10 R 11 which is optionally substituted by R 12 , wherein R 10 and R 11 are each independently hydrogen, C 1 -C 4 alkyl, or C 3 -C 6 cycloalkyl, or R 10 and R 11 are taken together with the atom or atoms to which they are attached to form a 3- to 6-membered heterocyclyl ring optionally substituted by halogen.
14. The compound of claim 12 , or a tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 2 is 5- to 10-membered heteroaryl optionally substituted by R 12 .
15. The compound of claim 1 , or a tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 3 is —(CH 2 ) m NR 13 S(O) 2 R 14 or C 1 -C 4 alkyl substituted by halogen, oxo, —CN, or —OH.
16. The compound of claim 1 , or a tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 3 is —(CH 2 ) m NR 13 S(O) 2 R 14 .
17. The compound of claim 1 , or a tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 3 is
18. The compound of claim 1 , or a tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 3 is C 1 -C 4 alkyl substituted by —OH.
19. The compound of claim 18 , or a tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 3 is
20. The compound of claim 1 , or a tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 1a is hydrogen.
21. The compound of claim 1 , or a tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 2a is hydrogen.
22. The compound of claim 1 , wherein the compound is selected from the group consisting of:
or a pharmaceutically acceptable salt of any of the foregoing.
23. A pharmaceutical composition comprising the compound of claim 1 , or a tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, and a pharmaceutically acceptable carrier.
24. A kit comprising the compound of claim 1 , or a tautomer or stereoisomer thereof, or a pharmaceutically acceptable salt of any of the foregoing.
25. The compound of claim 22 , or a pharmaceutically acceptable salt thereof, wherein the compound is
26. The compound of claim 22 , or a pharmaceutically acceptable salt thereof, wherein the compound is
27. The compound of claim 22 , or a pharmaceutically acceptable salt thereof, wherein the compound is
28. The compound of claim 22 , or a pharmaceutically acceptable salt thereof, wherein the compound is
29. The compound of claim 22 , or a pharmaceutically acceptable salt thereof, wherein the compound is
30. The compound of claim 22 , or a pharmaceutically acceptable salt thereof, wherein the compound is
31. The compound of claim 22 , or a pharmaceutically acceptable salt thereof, wherein the compound is