Degraders and Degrons for targeted protein degradation

Patent metadata

Field	Value
Publication number	US-11524949-B2
Application number	US-202016874475-A
Country	US
Kind code	B2
Filing date	May 14, 2020
Priority date	Nov 16, 2017
Publication date	Dec 13, 2022
Grant date	Dec 13, 2022

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, aliphatic, heteroaliphatic, heterocyclic, aryl, heteroaryl, —C(O)H, —C(O)OH, —C(O)alkyl, —C(O)Oalkyl, —C(O)(aliphatic, aryl, heteroaliphatic or heteroaryl), —C(O)O(aliphatic, aryl, heteroaliphatic, or heteroaryl), alkene, and alkyne;
R 4 is selected from the group consisting of hydrogen, aliphatic, heterocyclic, and heteroaliphatic;
R 5 is selected at each instance from the group consisting of hydrogen, alkyl, alkene, alkyne, halogen, hydroxyl, alkylhydroxyl, alkoxy, azide, amino, alkylamino, cyano, —NH(aliphatic), —N(aliphatic) 2 , —NHSO 2 (aliphatic), —N(aliphatic)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, aliphatic, heteroaliphatic, 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, aliphatic, heteroaliphatic, carbocyclic, heterocyclic, aryl, heteroaryl, halo, azide, cyano, hydroxyl, alkoxy, amine, —NH(aliphatic), and —N(aliphatic) 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 0;
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 or more 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 a 3, 4, 5, 6, 7, 8, or 10 membered heterocyclo or heteroaryl moiety containing at least one nitrogen atom through which it is directly attached, wherein the heterocyclo or heteroaryl moiety is substituted with R 12 at any desired position, wherein the heterocyclo or heteroaryl moiety is optionally further substituted with one or more substituents selected from R 5 ; and the heterocyclo or heteroaryl moiety is optionally further substituted with one or more oxo groups at a position allowed by valence;
or R 17a is selected from the group consisting of:

R 17b is selected from the group consisting of:

or R 17b is

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 or more substituents selected from R 5 ; and wherein the aryl, heteroaryl, and carbocycle moieties are optionally further substituted with one or more oxo groups at a position allowed by valence;
R 17c is selected from the group consisting of:

or R 17c is

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 or more substituents selected from R 5 ; and wherein the aryl, heteroaryl, and carbocycle moieties are optionally further substituted with one or more oxo groups at a position allowed by valence;
R 40 is selected at each instance from the group consisting of: hydrogen, alkyl, alkene, alkyne, halogen, hydroxyl, alkoxy, azide, amino, cyano, —NH(aliphatic), —N(aliphatic) 2 , —NHSO 2 (aliphatic), —N(aliphatic)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, aliphatic, heteroaliphatic, 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, or 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 a bivalent chemical group; and
Targeting Ligand is a small molecule that binds to a Target Protein, wherein the Target Protein is a mediator of a disease in a host in need of such therapy, and wherein the Targeting Ligand has a structure described in FIG. 1 QQ , FIG. 1 RR , FIG. 1 SS , FIG. 1 TT , FIG. 1 UU , FIG. 3 IIIII, FIG. 4 T , FIG. 4 U , FIG. 4 V , FIG. 4 W , FIG. 4 X , FIG. 4 Y , FIG. 4 Z , FIG. 4 AA , FIG. 4 BB , FIG. 4 CC , FIG. 4 DD , FIG. 4 EE , FIG. 6 R , FIG. 6 S , FIG. 6 T , or FIG. 6 U .

2. The compound of claim 1 , wherein the Target Protein is selected from the group consisting of androgen receptor, ATF2,

Assignees

• C4 Therapeutics Inc

Inventors

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

Classifications

• C07D211/88 Primary

  attached in positions 2 and 6, e.g. glutarimide · CPC title

• C07D241/18

  Oxygen or sulfur atoms · CPC title

• 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

• C07D417/04

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