N/O-linked degrons and degronimers for protein degradation

Patent metadata

Field	Value
Publication number	US-12441740-B2
Application number	US-202418973867-A
Country	US
Kind code	B2
Filing date	Dec 9, 2024
Priority date	Jun 20, 2017
Publication date	Oct 14, 2025
Grant date	Oct 14, 2025

Abstract

This invention provides Degronimers that have E3 Ubiquitin Ligase targeting moieties (Degrons) that can be linked to a targeting ligand for a protein that has been selected for in vivo degradation, and methods of use and compositions thereof as well as methods for their preparation. The invention also provides Degrons that can be used to treat disorders mediated by cereblon or an Ikaros family protein, and methods of use and compositions thereof as well as methods for their preparation.

First claim

We claim:

1. A compound of Formula:

or a pharmaceutically acceptable salt thereof;
wherein:
n is 0, 1, or 2;
R 4 is selected at each instance from C 1-6 -alkyl, hydroxyl, C 1-6 -alkoxy, amino, —NHC 1-6 -alkyl, —N(C 1-6 -alkyl) 2 , and C 1-6 -haloalkyl;
R 5 is selected at each instance from C 1-6 -alkyl, halogen, hydroxyl, C 1-6 -alkoxy, amino, cyano, —NH(C 1-6 -alkyl), —N(C 1-6 -alkyl) 2 , —C(O)R 4 , and C 1-6 -haloalkyl;
R 12 is Linker-H;
Linker is selected from:

wherein:
Heteroaryl is a 5- or 6-membered heteroaryl containing 1 or 2 heteroatoms selected from nitrogen, oxygen, and sulfur;
Aryl is phenyl;
Heterocycle is a 4- to 6-membered heterocycle containing 1 to 4 nitrogen atoms, 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, or 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms;
X 1 and X 2 are independently selected from bond, NH, NR 25 , CH 2 , CHR 25 , C(R 25 ) 2 , O, and S;
R 20 , R 21 , R 23 , and R 24 are independently selected from bond, C 1-6 -alkyl, —C(O)—, —O—, —NH—, —N(C 1-6 -alkyl)-, C 2-6 -alkene, C 1-6 -haloalkyl, C 2-6 -alkyne, phenyl, 4- to 6-membered heterocycle containing 1 to 4 nitrogen atoms, 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, or 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, and 5- or 6-membered heteroaryl;
each of which R 20 , R 21 , R 23 , and R 24 is optionally substituted with one substituent independently selected from R 101 ;
R 101 is independently selected at each occurrence from hydrogen, C 1-6 -alkyl, C 1-6 -haloalkyl, C 1-6 -alkoxy, hydroxyl, phenyl, 5- or 6-membered heteroaryl, 4- to 6-membered heterocycle containing 1 to 4 nitrogen atoms, 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, or 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, CN, —C(O)OC 1-6 -alkyl, C(O)OH NO 2 , F, Cl, Br, NH 2 , NHC 1-6 -alkyl, and N(C 1-6 -alkyl) 2 ; and
R 25 is selected at each instance from C 1-6 -alkyl, —C(O)H, —C(O)OH, —C(O)C 1-6 -alkyl, and —C(O)OC 1-6 -alkyl.

2. The compound of claim 1 , wherein R 20 , R 21 , R 23 , and R 24 are independently selected from bond, C 1-6 -alkyl, —C(O)—, —O—, —NH—, —N(C 1-6 -alkyl)-, phenyl, and 4- to 6-membered heterocycle containing 1 or 2 nitrogen atoms.

3. The compound of claim 1 , wherein the Linker is

4. The compound of claim 1 , wherein the Linker is

5. The compound of claim 1 , wherein the Linker is

6. The compound of claim 1 , wherein R 20 , R 21 , R 23 , and R 24 are not substituted.

7. The compound of claim 1 , wherein n is 0.

8. The compound of claim 1 , wherein heterocycle is piperidinyl or piperazinyl.

9. The compound of claim 1 , wherein at least one R 5 is F.

10. The compound of claim 1 , wherein the compound is

or a pharmaceutically acceptable salt thereof.

11. The compound of claim 10 , wherein the Linker is

12. The compound of claim 10 , wherein the Linker is

13. The compound of claim 10 , wherein the Linker is

14. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.

15. The pharmaceutical composition of claim 14 , wherein the compound is

or a pharmaceutically acceptable salt thereof.

16. A method for the treatment of a hematopoietic malignancy disorder comprising administering an effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof to a patent in need thereof, wherein the hematopoietic malignancy disorder can be treated by modulating the function or activity of cereblon-containing E3 ubiquitin ligase protein complex.

17. The method of claim 16 , wherein the hematopoietic malignancy disorder is mediated by Ikaros or Aiolos.

18. The method of claim 16 , wherein the hematopoietic malignancy disorder is acute myelogenous leukemia or lymphoblastic leukemia.

19. The method of claim 16 , wherein the hematopoietic malignancy disorder is multiple myeloma.

Assignees

• C4 Therapeutics Inc

Inventors

• Phillips Andrew J
• Nasveschuk Christopher G
• Henderson James A
• Liang Yanke
• He Minsheng
• Duplessis Martin
• Chen Chi-Li

Classifications

• G07F17/3288

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• G07F17/3272

  Games involving multiple players · CPC title

• G07F17/3246

  involving coins and/or banknotes · CPC title

• G07F17/3244

  Payment aspects of a gaming system, e.g. payment schemes, setting payout ratio, bonus or consolation prizes · CPC title

• G07F17/3225

  Data transfer within a gaming system, e.g. data sent between gaming machines and users · CPC title