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

Patent metadata

Field	Value
Publication number	US-10899768-B2
Application number	US-201716343977-A
Country	US
Kind code	B2
Filing date	Nov 22, 2017
Priority date	Nov 22, 2016
Publication date	Jan 26, 2021
Grant date	Jan 26, 2021

Abstract

The present application provides bifunctional compounds of Formula (X):

or an enantiomer, diastereomer, or stereoisomer thereof, or pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof, which act as protein degradation inducing moieties for protein kinases. The present application also relates to methods for the targeted degradation of one or more protein kinases through the use of the bifunctional compounds that link a ubiquitin ligase-binding moiety to a ligand that is capable of binding to one or more protein kinases which can be utilized in the treatment of disorders modulated by protein kinases.

First claim

The invention claimed is:

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.

Assignees

• Dana Farber Cancer Inst Inc

Inventors

• Bradner James
• Buckley Dennis
• Rosenbaum Mette Ishoey
• Winter Georg

Classifications

• C07D209/34 Primary

  in position 2 · CPC title

• C07D495/04

  Ortho-condensed systems · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title

• C07D417/14

  containing three or more hetero rings · CPC title

• A61K47/555

  pre-targeting systems involving an organic compound, other than a peptide, protein or antibody, for targeting specific cells · CPC title