Degraders and degrons for targeted protein degradation

Patent metadata

Field	Value
Publication number	US-12570626-B2
Application number	US-202218079815-A
Country	US
Kind code	B2
Filing date	Dec 12, 2022
Priority date	Nov 16, 2017
Publication date	Mar 10, 2026
Grant date	Mar 10, 2026

Abstract

Pharmaceutical Degraders and Degrons for use in therapeutic applications are described herein.

First claim

We claim:

1 . A compound of Formula:

or a pharmaceutically acceptable salt thereof;
wherein:
W 1 is C═O;
W 2 is C═O;
R 2 is selected at each instance from the group consisting of hydrogen, alkyl, heteroalkyl, heterocyclic, aryl, heteroaryl, —C(O)H, —C(O)OH, —C(O)alkyl, —C(O)Oalkyl, —C(O)(aryl or heteroaryl), —C(O)O(aryl or heteroaryl), alkene, and alkyne;
R 4 is selected from the group consisting of hydrogen, alkyl, and heterocyclic;
R 5 is selected at each instance from the group consisting of hydrogen, alkyl, alkene, alkyne, F, Cl, hydroxyl, alkylhydroxyl, alkoxy, azide, amino, alkylamino, cyano, —NH(alkyl), —N(alkyl) 2 , —NHSO 2 (alkyl), —N(alkyl)SO 2 alkyl, —NHSO 2 (aryl, heteroaryl, or heterocyclic), —N(alkyl)SO 2 (aryl, heteroaryl, or heterocyclic), —NHSO 2 alkenyl, —N(alkyl)SO 2 alkenyl, —NHSO 2 alkynyl, —N(alkyl)SO 2 alkynyl, haloalkyl, heteroalkyl, carbocyclic, C(O)R 40 , aryl, aryloxy, heterocyclo, heteroaryl, arylalkyl, O-arylalkyl, nitro, nitroso, sulfone, sulfoxide, thioalkyl, thiol, haloalkyl, and cycloalkyl;
R 10 and R 11 are independently selected from the group consisting of hydrogen, alkyl, carbocyclic, heterocyclic, aryl, heteroaryl, F, Cl, azide, cyano, hydroxyl, alkoxy, amine, —NH(alkyl), and —N(alkyl) 2 ;
or R 10 and R 11 together with the carbon to which they are bound form a 3-, 4-, 5-, or 6-membered spirocarbocycle, or a 4-, 5-, or 6-membered spiroheterocycle comprising 1 or 2 heteroatoms selected from N, O, and S;
R 13 and R 14 are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxy, amino, —NHalkyl, and —N(alkyl) 2 ;
or R 13 and R 14 together with the carbon atom to which they are attached form C(O), C(S), C═CH 2 , a 3-, 4-, 5-, or 6-membered spirocarbocycle, or a 4-, 5-, or 6-membered spiroheterocycle comprising 1 or 2 heteroatoms selected from N and O;
R 16 is selected from the group consisting of:

or R 16 is a 4, 5, 6, 7, 8, 9, or 10 membered carbocyclo or aryl moiety, wherein the carbocyclo or aryl moiety is substituted with R 12 at any desired position; wherein the carbocyclo or aryl moiety is optionally further substituted with one, two, or three substituents selected from R 5 ; and wherein the carbocyclo or aryl moiety is attached through a carbon atom;
or R 16 is

 R 17 is selected from the group consisting of R 17a , R 17b , and R 17c ,
R 17a is selected from the group consisting of:

or R 17a is selected from the group consisting of

or R 17a is selected from the group consisting of:

R 17b is selected from the group consisting of:

or R 17b is —NR 2 aryl, —NR 2 heteroaryl, or NR 2 carbocycle, wherein the aryl, heteroaryl, and carbocycle moieties are substituted with a R 12 at any desired position, wherein the aryl, heteroaryl, and carbocycle moieties are optionally further substituted with one, two, or three substituents selected from R 5 ; and wherein the aryl, heteroaryl, and carbocycle moieties are optionally further substituted with one oxo group at a position allowed by valence;
R 17c is selected from the group consisting of:

or R 17c is —O-aryl, —O-heteroaryl, or —O-carbocycle, wherein the aryl, heteroaryl, and carbocycle moieties are substituted with a R 12 at any desired position, wherein the aryl, heteroaryl, and carbocycle moieties are optionally further substituted with one, two, or three substituents selected from R 5 ; and wherein the aryl, heteroaryl, and carbocycle moieties are optionally further substituted with one oxo group at a position allowed by valence;
R 40 is selected at each instance from the group consisting of: hydrogen, alkyl, alkene, alkyne, F, Cl, hydroxyl, alkoxy, azide, amino, cyano, —NH(alkyl), —N(alkyl) 2 , —NHSO 2 (alkyl), —N(alkyl)SO 2 alkyl, —NHSO 2 (aryl, heteroaryl or heterocyclic), —N(alkyl)SO 2 (aryl, heteroaryl or heterocyclic), —NHSO 2 alkenyl, —N(alkyl)SO 2 alkenyl, —NHSO 2 alkynyl, —N(alkyl) SO 2 alkynyl, haloalkyl, aryl, heteroaryl, heteroalkyl, heterocyclic, and carbocyclic;
is selected from the group consisting of a single and a double bond;
Y is independently selected from the group consisting of N, CH, and CR 5 ;
Z 1 is selected from the group consisting of CH 2 , CHR 2 , C(R 2 ) 2 , NR 2 , O, and S;
Z 2 is selected from the group consisting of NH, O, S, NR 2 , C=O, S=O, and SO 2 ;
wherein when R 12 is bonded to a Y, then Y is CR 12 ; when R 12 is bonded to a Z 1 that is nitrogen, then Z 1 is NR 12 ; when R 12 is bonded to Z 1 that is carbon, then Z 1 is CR 2 R 12 ; when R 12 is bonded to a Z 2 , then Z 2 is NR 12 ;
R 12 is -(Linker) A - Targeting Ligand;
(Linker) A is

X 1 and X 2 are independently selected from the group consisting of bond, NH, NR 2 , CH 2 , CHR 2 , C(R 2 ) 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, —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 2 )-, —CH(—NH 2 )-, —C(—O-R 26 ) alkyl-, —C(—NHR 2 )alkyl-, —C(R 40 R 40 )-, —alkyl(R 27 )-alkyl(R 28 )-, —C(R 27 R 28 )-, —NHC(O)NH-, —N(R 2 )C(O)N(R 2 )-, —N(H)C(O)N(R 2 )-, alkene, haloalkyl, alkoxy, alkyneheteroarylalkyl, aryl, arylalkyl, heterocycle, heteroaryl, and carbocycle;
each of which R 20 , R 21 , R 22 , R 23 , and R 24 is optionally substituted with one, two, or three substituents selected from R 101 ;
R 101 is independently selected at each occurrence from the group consisting of hydrogen, alkyl, alkene, alkyne, haloalkyl, alkoxy, hydroxyl, aryl, heteroaryl, heterocycle, arylalkyl, heteroarylalkyl, heterocycloalkyl, aryloxy, heteroaryloxy, CN, —COOalkyl, COOH, NO 2 , F, Cl, CF 3 , NH 2 , NHalkyl, and N(alkyl) 2 ;
R 26 is selected from the group consisting of hydrogen, alkyl, silane, arylalkyl, heteroarylalkyl, alkene, alkyne, aryl, heteroaryl, and heterocyclic;
R 27 and R 28 are independently selected from the group consisting of hydrogen, alkyl, 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-,

Assignees

• C4 Therapeutics Inc

Inventors

• Phillips Andrew J
• Nasveschuk Christopher G
• Henderson James A
• He Minsheng
• Lazarski Kiel

Classifications

• C07D413/04

  directly linked by a ring-member-to-ring-member bond · CPC title

• C07D403/04

  directly linked by a ring-member-to-ring-member bond · CPC title

• C07D471/04

  Ortho-condensed systems · CPC title

• C07D417/04

  directly linked by a ring-member-to-ring-member bond · CPC title

• C07D241/18

  Oxygen or sulfur atoms · CPC title