N/O-linked Degrons and Degronimers for protein degradation

Patent metadata

Field	Value
Publication number	US-11459335-B2
Application number	US-201916721650-A
Country	US
Kind code	B2
Filing date	Dec 19, 2019
Priority date	Jun 20, 2017
Publication date	Oct 4, 2022
Grant date	Oct 4, 2022

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 5 is selected at each instance from the group consisting of hydrogen, alkyl, alkenyl, halogen, hydroxyl, alkoxy, amino, cyano, —NH(aliphatic), —N(aliphatic) 2 , —NHSO 2 (aliphatic), —N(aliphatic)SO 2 alkyl, —NHSO 2 (aryl, heteroaryl or heterocycle), C(O)R 4 , —N(alkyl)SO 2 (aryl, heteroaryl or heterocycle) —NHSO 2 alkenyl, —N(alkyl)SO 2 alkenyl, —NHSO 2 alkynyl, —N(alkyl)SO 2 alkynyl, haloalkyl, aliphatic, aryl, heteroaryl, and carbocyclic;
each of which R 5 can be optionally substituted with one or more substituents selected from the group consisting of alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkoxy, amino, —NHalkyl, —N(alkyl) 2 , aryl, heterocycle, heteroaryl, haloalkyl, and cycloalkyl;
R 4 is selected at each instance from the group consisting of alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkoxy, amino, —NHalkyl, —N(alkyl) 2 , —NHSO 2 alkyl, —N(alkyl)SO 2 alkyl, —NHSO 2 aryl, —N(alkyl)SO 2 aryl, —NHSO 2 alkenyl, —N(alkyl)SO 2 alkenyl, —NHSO 2 alkynyl, —N(alkyl)SO 2 alkynyl, and haloalkyl;
R 12 is Linker-Targeting Ligand;
Linker is:

X 1 and X 2 are independently selected from the group consisting of bond, NH, NR 25 , CH 2 , CHR 25 , C(R 25 ) 2 , O, and S;
R 20 , R 21 , R 22 , R 23 , and R 24 are independently selected from the group consisting of bond, alkyl, —C(O)— —C(O)O—, —OC(O)—, —C(O)alkyl, —C(O)Oalkyl, —C(S)—, —SO 2 —, —S(O)—, —C(S)—, —C(O)NH—, —NHC(O)—, —N(alkyl)C(O)—, —C(O)N(alkyl)-, —O—, —S—, —NH—, —N(alkyl)-, —CH(—O—R 26 )—, —CH(—NHR 25 )—, —CH(—NH 2 )—, —CH(—NR 25 2 )—, —C(—O—R 26 )alkyl-, —C(—NHR 25 )alkyl-, —C(—NH 2 )alkyl-, —C(—NR 25 2 )alkyl-, —C(R 4 R 4 )—, -alkyl(R 27 )-alkyl(R 28 )—, —C(R 27 R 28 )—, —P(O)(OR 26 )O—, —P(O)(OR 26 )—, —NHC(O)NH—, —N(R 25 )C(O)N(R 25 )—, —N(H)C(O)N(R 25 )—, polyethylene glycol, poly(lactic-co-glycolic acid), alkenyl, haloalkyl, alkoxy, alkyne, aryl, heterocycle, aliphatic, heteroaryl, polypropylene glycol, lactic acid, glycolic acid, and carbocycle;
each of which R 20 , R 21 , R 22 , R 23 , and R 24 is optionally substituted with one or more substituents selected from R 101 ;
R 101 is independently selected at each occurrence from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, hydroxyl, aryl, heteroaryl, heterocycle, arylalkyl, heteroarylalkyl, heterocycloalkyl, aryloxy, heteroaryloxy, CN, —COOalkyl, COOH, NO 2 , F, Cl, Br, I, CF 3 , NH 2 , NHalkyl, N(alkyl) 2 , and aliphatic;
R 25 is selected at each instance from the group consisting of alkyl, —C(O)H, —C(O)OH, —C(O)alkyl, —C(O)Oalkyl, alkenyl, and alkynyl;
R 26 is hydrogen, alkyl, silane, arylalkyl, heteroarylalkyl, alkenyl, or alkynyl;
R 27 and R 28 are independently selected from the group consisting of hydrogen, alkyl, and amine, or together with the carbon atom to which they are attached, form C(O), C(S), C═CH 2 , a C 3 -C 6 spirocarbocycle, or a 4-, 5-, or 6-membered spiroheterocycle comprising 1 or 2 heteroatoms selected from N and O, or form a 1 or 2 carbon bridged ring;
Targeting Ligand binds to a Targeted Protein, wherein the Targeted Protein is an androgen receptor;
the Targeting Ligand is selected from

heteroaryl is independently selected at each instance from a stable aryl ring system containing one or more heteroatoms selected from N, O, and S;
heterocycle is independently selected at each instance from a stable monocyclic 3-8 membered rings and a stable bicyclic 5-16 membered rings containing one or more heteroatoms selected from N, O, and S;
aliphatic is independently selected at each instance from alkyl, alkenyl, and alkynyl;
wherein the variables are selected such that the resulting compound is stable.

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

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

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

5. The compound of claim 4 , wherein the Linker is:

6. The compound of claim 5 , wherein X 2 is bond.

7. The compound of claim 6 , wherein R 21 is heterocycle.

8. The compound of claim 4 , wherein: R 20 , R 21 , R 22 , R 23 , and R 24 are independently selected from the group consisting of bond, alkyl, —C(O)— —(O)O—, —OC(O)—, —C(O)alkyl, —C(O)Oalkyl, —C(O)NH—, —NHC(O)—, —N(alkyl)C(O)—, —C(O)N(alkyl)-, —O—, —NH—, —N(alkyl)-, —CH(—O—R 26 )—, —CH(—NHR 25 )—, —CH(—NH 2 )—, —CH(—NR 25 2 )—, —C(—O—R 26 )alkyl-, aryl, heterocycle, and aliphatic.

9. The compound of claim 4 , wherein R 20 , R 21 , R 22 , R 23 , and R 24 are not substituted.

10. The compound of claim 1 , wherein the Linker is selected from:

11. The compound of claim 1 , wherein the Linker is selected from:

12. The compound of claim 1 , wherein R 5 is selected at each instance from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkoxy, and haloalkyl.

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

14. The compound of claim 1 , wherein the Targeting Ligand is:

15. The compound of claim 1 , wherein the Targeting Ligand is:

16. The compound of claim 1 , wherein the Targeting Ligand is:

17. The compound of claim 1 , wherein each heteroaryl group is independently selected from the group consisting of pyrrolyl, imidazolyl, pyrazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl, furyl, thienyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, and thiadiazolyl.

18. The compound of claim 1 , wherein each heterocycle group is independently selected from the group consisting of pyrrolidinyl, piperidinyl, pyrrolinyl, piperazinyl, and morpholinyl.

19. The compound of claim 1 , wherein n is 1.

20. The compound of claim 1 , wherein n is 2.

21. The compound of claim 16 , wherein n is 0.

22. The compound of claim 16 , wherein n is 1.

23. The compound of claim 16 , wherein n is 2.

Assignees

• C4 Therapeutics Inc

Inventors

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

Classifications

• C07D401/14

  containing three or more hetero rings · CPC title

• C07D401/12

  linked by a chain containing hetero atoms as chain links · CPC title

• C07D405/12

  linked by a chain containing hetero atoms as chain links · CPC title

• C07D207/456

  with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to other ring carbon atoms · CPC title

• C07D487/04

  Ortho-condensed systems · CPC title