Degradation of cyclin-dependent kinase 8 (CDK8) by conjugation of CDK8 inhibitors with E3 ligase ligand and methods of use

1. A bifunctional compound of Formula X:

wherein:

the Targeting Ligand is of Formula TL-I:

wherein:

A is

X is N or CH;

X 2 is N or CH;

X 3 is N or CH;

X 4 is N or CH;

each R 1 is independently (C 1 -C 4 ) alkyl or (C 1 -C 4 ) haloalkyl;

each R 2 is independently (C 1 -C 4 ) alkyl, (C 1 -C 4 ) haloalkyl, (C 1 -C 4 ) alkoxy, (C 1 -C 4 ) haloalkoxy, halogen, OH, or NH 2 ;

each R 3 is independently (C 1 -C 4 ) alkyl, (C 1 -C 4 ) haloalkyl, (C 1 -C 4 ) alkoxy, (C 1 -C 4 ) haloalkoxy, halogen, OH, or NH 2 ;

each R 4 is independently (C 1 -C 4 ) alkyl, (C 1 -C 4 ) haloalkyl, (C 1 -C 4 ) alkoxy, (C 1 -C 4 ) haloalkoxy, halogen, OH, or NH 2 ; and

t, n, o, and r are each independently 0, 1, 2, or 3;

wherein the Targeting Ligand is bonded to the Linker via the next to

the Linker is a bond or a carbon chain that serves to link the Targeting Ligand with the Degron,

wherein,

the carbon chain optionally comprises one, two, three, or more heteroatoms selected from N, O, and S,

and wherein,

one or more chain carbon atoms in the carbon chain are optionally substituted with one or more substitutents selected from oxo, (C 1 -C 6 ) alkyl, (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) alkynyl, (C 1 -C 3 ) alkoxy, OH, halogen, NH 2 , NH(C 1 -C 3 ) alkyl, N(C 1 -C 3 ) 2 , CN, (C 3 -C 8 ) cycloalkyl, heterocyclyl, and phenyl; and

the Degron is of Formula D1:

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,

wherein the Degron is covalently bonded to the Linker via the

or a stereoisomer or pharmaceutically acceptable salt thereof.

2. The bifunctional compound of claim 1 , wherein A is

3. The bifunctional compound of claim 1 , wherein X is N.

4. The bifunctional compound of claim 1 , wherein X 2 is N.

5. The bifunctional compound of claim 1 , wherein X 3 is N.

6. The bifunctional compound of claim 1 , wherein r is 1 and R 4 is (C 1 -C 4 ) haloalkyl.

7. The bifunctional compound of claim 1 , wherein the Targeting Ligand is of Formula TL-Ia, TL-Ib, TL-Ic, TL-Id, TL-Ie, or TL-If:

8. The bifunctional compound of claim 1 , wherein the Linker is of Formula L0:

or a 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, C(O), (CH 2 ) J C(O)NH, CH 2 , O, NH, or NR 19 ;

each R 19 is independently (C 1 -C 3 ) alkyl;

j is 1, 2, or 3; 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 .

9. A pharmaceutical composition comprising a therapeutically effective amount of the bifunctional compound of claim 1 , or a stereoisomer or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

10. A method of treating cancer, wherein the cancer is leukemia or lymphoma, comprising administering to a subject in need thereof an effective amount of bifunctional compound or pharmaceutically acceptable salt or stereoisomer of claim 1 .

11. The bifunctional compound of claim 1 , which is

or a stereoisomer or pharmaceutically acceptable salt thereof.

12. The bifunctional compound of claim 11 , which is

or a stereoisomer or pharmaceutically acceptable salt thereof.

13. The method of claim 10 , wherein the cancer is leukemia.

14. The method of claim 10 , wherein the cancer is lymphoma.