Degradation of cyclin-dependent kinase 9 (CDK9) by conjugation of CDK9 inhibitors with E3 ligase ligand and methods of use
The present application provides bifunctional compounds of Formula (I): or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, which act as protein degradation inducing moieties for cyclin-dependent kinase 9 (CDK9), the present application also relates to methods for the targeted degradation of CDK9 through the use of the bifunctional compounds that link a ubiquitin ligase-binding moiety to a ligand that is capable of binding to CDK9 which can be utilized in the treatment of disorders modulated by CDK9.
1. A bifunctional compound of Formula X:
wherein:
the Targeting Ligand is of Formula TL-I:
or an enantiomer, diastereomer, stereoisomer, or pharmaceutically acceptable salt thereof, wherein:
A is O, NR 5 , or NR 5 C(O);
B is S(O) t , O, or NR 6 ;
X is N or CH;
R 1 is H, (C 1 -C 4 ) alkyl, or (C 1 -C 4 ) haloalkyl;
R 2 is H, (C 1 -C 4 ) alkyl, or (C 1 -C 4 ) haloalkyl;
R 3 is H, (C 1 -C 4 ) alkyl, (C 1 -C 4 ) haloalkyl, (C 1 -C 4 ) alkoxy, or (C 1 -C 4 ) haloalkoxy;
R 4 is (C 1 -C 4 ) alkyl, (C 1 -C 4 ) haloalkyl, (C 1 -C 4 ) alkoxy, or (C 1 -C 4 ) haloalkoxy;
R 5 is H or (C 1 -C 3 ) alkyl;
R 6 is H or (C 1 -C 3 ) alkyl; and
t is 0, 1, or 2,
wherein the Targeting Ligand is bonded to the Linker via the
next to
the Linker is a group that covalently binds to the Targeting Ligand and the Degron; and
the Degron is of Formula D1 or D2:
or an enantiomer, diastereomer, or stereoisomer thereof, wherein:
Y is a bond, (CH 2 ) 1-6 , (CH 2 ) 0-6 —O, (CH 2 ) 0-6 —C(O)NR 11 , (CH 2 ) 0-6 —NR 11 C(O), (CH 2 ) 0-6 —NH, or (CH 2 ) 0-6 —NR 12 ;
Z is C(O) or C(R 13 ) 2 ;
R 11 is H or C 1 -C 6 alkyl;
R 12 is C 1 -C 6 alkyl or C(O)—C 1 -C 6 alkyl;
each R 13 is independently H or C 1 -C 3 alkyl;
each R 14 is independently C 1 -C 3 alkyl;
R 15 is H, deuterium, C 1 -C 3 alkyl, F, or Cl;
each R 16 is independently halogen, OH, C 1 -C 6 alkyl, or C 1 -C 6 alkoxy;
q is 0, 1, or 2; and
v is 0, 1, 2, or 3, or
or an enantiomer, diastereomer, or stereoisomer thereof, wherein:
each R 17 is independently C 1 -C 3 alkyl;
q′ is 0, 1, 2, 3 or 4; and
R 18 is H or C 1 -C 3 alkyl,
wherein the Degron is bonded to the Linker via
2. The bifunctional compound of claim 1 , wherein A is NH or NHC(O).
3. The bifunctional compound of claim 1 , wherein B is S.
4. The bifunctional compound of claim 1 , wherein R 1 is H.
5. The bifunctional compound of claim 1 , wherein R 2 is H.
6. The bifunctional compound of claim 1 , wherein R 3 is H.
7. The bifunctional compound of claim 1 , wherein R 4 is (C 1 -C 4 ) alkyl.
8. The bifunctional compound of claim 1 , wherein X is N.
9. The bifunctional compound of claim 1 , wherein X is CH.
10. The bifunctional compound of claim 1 , wherein the Targeting Ligand is of Formula TL-Ia or TL-Ib:
11. The bifunctional compound of claim 1 , wherein the Targeting Ligand is of Formula TL-Ic or TL-Id:
12. The bifunctional compound of claim 1 , wherein the Targeting Ligand is of Formula TL-Ie or TL-If:
13. The bifunctional compound of claim 1 , wherein the Linker is of Formula L0:
or an enantiomer, diastereomer, or stereoisomer thereof, wherein:
p1 is an integer selected from 0 to 12;
p2 is an integer selected from 0 to 12;
p3 is an integer selected from 1 to 6;
each W is independently absent, CH 2 , O, S, NH, or NR 19 ;
Z 1 is absent, CH 2 C(O)NH, CH 2 , O, NH, NR 19 ,
each R 19 is independently C 1 -C 3 alkyl;
R 20 is absent, CH═CH, CH═CH(CH 2 ) 1-3 , or (CH 2 ) 1-3 CH═CH, wherein R 20 is bonded to the remainder of the Linker; and
Q is absent or NHC(O)CH 2 ,
wherein the Linker is covalently bonded to a Degron via the
next to Q, and covalently bonded to a Targeting Ligand via the
next to Z 1 .
14. The bifunctional compound of claim 13 , wherein the Linker is selected from:
15. The bifunctional compound of claim 1 , wherein the Degron is of Formula D1.
16. The bifunctional compound of claim 15 , wherein the Degron is of Formula D1a or D1b:
17. The bifunctional compound of claim 1 , wherein the Degron is of Formula D2.
18. A pharmaceutical composition comprising a therapeutically effective amount of the bifunctional compound of claim 1 , or an enantiomer, diastereomer, stereoisomer, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
19. A method of inhibiting a kinase or modulating the amount of a kinase, inhibiting or modulating the amount of cyclin-dependent kinase 9 (CDK9), or treating a disease in which CDK9 plays a role, comprising administering to a subject in need thereof an effective amount of a bifunctional compound of claim 1 .
20. The bifunctional compound of claim 2 , wherein A is NH.
21. The bifunctional compound of claim 2 , wherein A is NHC(O).
22. The bifunctional compound of claim 1 , selected from:
23. The bifunctional compound of claim 22 , which is