Degradation of protein kinases by conjugation of protein kinase inhibitors with E3 ligase ligand and methods of use

1. A bifunctional compound of Formula X:

wherein:

the Targeting Ligand (TL) is of Formula TL-I:

wherein:

X 1 is NR 5 or O;

each R 1 and each R 4 are 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 ;

R 2 and R 3 are each independently H, (C 1 -C 4 ) alkyl, or (C 1 -C 4 ) haloalkyl;

R 5 is H, (C 1 -C 4 ) alkyl, (C 1 -C 4 ) haloalkyl, or C(O)(C 1 -C 4 ) alkyl;

n1 is 0, 1, 2 or 3; and

n2 is 0, 1, or 2,

wherein the Targeting Ligand is bonded to the Linker via the

next to

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

wherein

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

and wherein

the carbon chain optionally comprises two or more unsaturated chain carbon atoms,

and wherein,

one or more chain carbon atoms in the carbon chain are optionally substituted with one or more substituents 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 alkyl) 2 , CN, C 3 -C 8 cycloalkyl, heterocyclyl, phenyl, and heteroaryl; 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 35 , (CH 2 ) 0-6 —NR 35 C(O), (CH 2 ) 0-6 —NH, or (CH 2 ) 0-6 —NR 36 ,

Z 3 is C(O) or C(R 37 ) 2 ,

R 35 is H or C 1 -C 6 alkyl;

R 36 is C 1 -C 6 alkyl or C(O)—C 1 -C 6 alkyl;

each R 37 is independently H or C 1 -C 3 alkyl;

each R 38 is independently C 1 -C 3 alkyl;

R 39 is H, deuterium, C 1 -C 3 alkyl, F, or Cl;

each R 40 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 a stereoisomer or pharmaceutically acceptable salt thereof.

2. The bifunctional compound of claim 1 , wherein the Targeting Ligand is of Formula TL-Ia:

3. The bifunctional compound of claim 1 , wherein the Linker is of Formula L1:

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, or NR 34 ;

Z 1 is absent, C(O), CH 2 , O, (CH 2 ) j NR 34 , O(CH 2 ) j C(O)NR 34 , C(O)NR 34 , (CH 2 ) j C(O)NR 34 , NR 34 C(O), (CH 2 ) j NR 34 C(O), C(O)NR 34 (CH 2 ) j C(O)NR 34 , C(O)(CH 2 ) j C(O)NR 34 , (CH 2 ) k NR 34 (CH 2 ) j C(O)NR 34 , or NR 34 (CH 2 ) j C(O)NR 34 ;

each R 34 is independently H or C 1 -C 3 alkyl;

j is 1, 2, or 3;

k is 1, 2, or 3; and

Q 1 is absent, C(O), NHC(O)(CH 2 ) 0-1 , OCH 2 C(O), O(CH 2 ) 1-2 , or

wherein the Linker is covalently bonded to a Degron via the

next to Q 1 , and covalently bonded to a Targeting Ligand (TL) via the

next to Z 1 .

4. The bifunctional compound of claim 3 , wherein the Linker is selected from:

5. The bifunctional compound of claim 1 , wherein the Degron is of Formula D1a, D1b, D1c, D1d, D1e, D1f, D1g, D1h, D1i, D1j, D1k, or D1l:

6. 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.

7. A method of treating a hematologic cancer, comprising administering to a subject in need thereof an effective amount of a compound of claim 1 .

8. The bifunctional compound of claim 1 , wherein X 1 is NR 5 .

9. The bifunctional compound of claim 8 , wherein R 5 is H.

10. The bifunctional compound of claim 1 , wherein R 2 is H.

11. The bifunctional compound of claim 1 , wherein R 3 is H.

12. The bifunctional compound of claim 1 , wherein n1 is 1.

13. The bifunctional compound of claim 1 , wherein n2 is 2.

14. The bifunctional compound of claim 1 , wherein each R 1 is independently halogen.

15. The bifunctional compound of claim 1 , wherein each R 4 is independently (C 1 -C 4 ) alkyl.

16. The bifunctional compound of claim 1 , which is:

or stereoisomer or pharmaceutically acceptable salt thereof.

17. The bifunctional compound of claim 16 , which is

or stereoisomer or pharmaceutically acceptable salt thereof.

18. The method of claim 7 , wherein the hematologic cancer is leukemia.

19. The method of claim 7 , wherein the hematologic cancer is lymphoma.