Cereblon binders for the degradation of ikaros

Patent metadata

Field	Value
Publication number	US-11753397-B2
Application number	US-202017031550-A
Country	US
Kind code	B2
Filing date	Sep 24, 2020
Priority date	Mar 26, 2018
Publication date	Sep 12, 2023
Grant date	Sep 12, 2023

Abstract

The invention provides cereblon binders of Formulas:or pharmaceutically acceptable salts thereof, for the degradation of Ikaros or Aiolos by the ubiquitin proteasome pathway along with their use in therapeutic applications to treat medical disorders including, but not limited to cancer.

First claim

We claim:

1. A compound selected from the following Formulas:

or a pharmaceutically acceptable salt thereof;
wherein:
R 1 is selected from:
a. haloalkyl and alkyl; either of which is optionally substituted with 1, 2, or 3 substituents independently selected from aryl, cycloalkyl, heteroaryl, —SO 2 R 5 , —NR 2 —C(O)—R 3 , —C(O)OR 4 , and —C(O)—R 3 ; wherein when the haloalkyl or alkyl group has two or more carbons it can additionally be optionally substituted with 1, 2, 3, or 4 substituents independently selected from —OC(O)—R 3 , —NR 4 R 4 , and —OR 4 , wherein these additional substituents are not on the carbon alpha to the pyrazole;
b. cycloalkyl and aryl; either of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from alkyl, alkenyl, alkynyl, halogen, cyano, heteroaryl, aryl, cycloalkyl, heterocycle, —NR 2 R 2 , —OR 2 , —NR 2 —C(O)—R 3 , —O—C(O)—R 3 , and —C(O)—R 3 ;
c. heteroaryl optionally substituted with 1, 2, 3, or 4 substituents independently selected from alkyl, alkenyl, halogen, cyano, heteroaryl, aryl, cycloalkyl, —NR 4 R 4 , —OR 4 , —NR 2 —C(O)—R 3 , —O—C(O)—R 3 , and —C(O)—R 3 ; wherein the heteroaryl group is only substituted such that no N—O or N—N bonds are formed;
d. heterocycle substituted with 1, 2, 3, or 4 substituents independently selected from alkyl, alkenyl, alkynyl, halogen, cyano, heteroaryl, aryl, cycloalkyl, heterocycle, —NR 2 R 2 , —OR 2 , —NR 2 —C(O)—R 3 , —O—C(O)—R 3 , —C(O)—R 3 , —SO 2 R 5 , —C(O)—R 5 , and R 5 ; wherein the heterocycle group is only substituted such that no N—O or N—N bonds are formed;
e. (CR 4 R 2 )—(CR 2 R 2 ) o -heterocycle optionally substituted with 1, 2, 3, or 4 substituents independently selected from alkyl, alkenyl, alkynyl, halogen, cyano, heteroaryl, aryl, cycloalkyl, heterocycle, —NR 2 R 2 , —OR 2 , —NR 2 —C(O)—R 3 , —O—C(O)—R 3 , —C(O)—R 3 , —SO 2 R 5 , —C(O)—R 5 , and R 5 ; wherein the heterocycle group is only substituted such that no N—O or N—N bonds are formed; and
f. bicyclic heterocycle or multicyclic heterocycle optionally substituted with 1, 2, 3, or 4 substituents independently selected from alkyl, alkenyl, alkynyl, halogen, cyano, heteroaryl, aryl, cycloalkyl, heterocycle, —NR 2 R 2 , —OR 2 , —NR 2 —C(O)—R 3 , —O—C(O)—R 3 , —C(O)—R 3 , —SO 2 R 5 , —C(O)—R 5 , and R 5 ; wherein the bicyclic heterocycle group is only substituted such that no N—O or N—N bonds are formed;

R 2 at each instance is independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heterocycle, heteroaryl, and cycloalkyl;
R 3 is selected from hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, aryl, heterocycle, heteroaryl, —NR 2 R 2 , and —OR 4 ;
R 4 at each instance is independently selected from hydrogen, alkyl, alkenyl, cycloalkyl, haloalkyl, aryl, heterocycle, heteroaryl, and alkynyl;
R 5 is selected from hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heteroaryl, heterocycle, aryl, —O-cycloalkyl, —O-aryl, —O-heteroaryl, —O-heterocycle, —O-alkyl, —NR 2 — cycloalkyl, —NR 2 -aryl, —NR 2 -heteroaryl, —NR 2 -heterocycle, —NR 2 -alkyl, —CH 2 -cycloalkyl, —CH 2 -aryl, —CH 2 -heteroaryl, —CH 2 -heterocycle, —OR 2 , and —NR 2 R 2 ; each of which except for hydrogen is optionally substituted with 1, 2, 3, or 4 substituents independently selected from alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocycle, aryl, heteroaryl, cyano, halogen, —OR 2 , and —NR 2 R 2 ;
m and o are independently selected from 0, 1, 2, 3, 4, and 5;
x is 0, 1, 2, 3, or 4;
n is 0, 1, 2, 3, or 4;
y is 1, 2, 3, 4, 5, or 6;
R 11 is selected from
a. haloalkyl and alkyl; each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from —NR 2 —C(O)—R 3 , —O—C(O)—R 3 , and —C(O)—R 3 ; wherein when the haloalkyl or alkyl group has two or more carbons it can additionally be optionally substituted with 1, 2, 3, or 4 substituents independently selected from —OC(O)—R 3 , —NR 4 R 4 , and —OR 4 , wherein these additional substituents are not on the carbon alpha to the pyrazole;
b. cycloalkyl, heteroaryl, and aryl; each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from alkyl, alkenyl, F, Cl, Br, I, cyano, heteroaryl, aryl, cycloalkyl, —NR 4 R 4 , —OR 4 , —NR 2 —C(O)—R 3 , —O—C(O)—R 3 , and —C(O)—R 3 ;
c. (CR 2 R 2 ) n -heterocycle substituted with 1, 2, 3, or 4 substituents independently selected from alky, alkenyl, halogen, cyano, heteroaryl, aryl, cycloalkyl, —NR 4 R 4 , —OR 4 , —NR 2 —C(O)—R 3 , —O—C(O)—R 3 , —C(O)—R 3 , and —SO 2 R 5 ; wherein the heterocycle group is only substituted such that no N—O or N—N bonds are formed; and
d. bicyclic heterocycle optionally substituted with 1, 2, 3, or 4 substituents independently selected from alkyl, alkenyl, alkynyl, halogen, cyano, heteroaryl, aryl, cycloalkyl, heterocycle, —NR 2 R 2 , —OR 2 , —NR 2 —C(O)—R 3 , —O—C(O)—R 3 , —C(O)—R 3 , —SO 2 R 5 , —C(O)—R 5 , and R 5 ; wherein the bicyclic heterocycle group is only substituted such that no N—O or N—N bonds are formed;

R 12 is selected from alkyl, haloalkyl, alkenyl, alkynyl, heteroaryl, aryl, cycloalkyl, heterocycle, —C(O)—R 3 , —SO 2 R 5 , and —C(O)—R 5 ;
R 13 at each instance is independently selected from alkyl, alkenyl, alkynyl, halogen, cyano, heteroaryl, aryl, cycloalkyl, heterocycle, —NR 2 R 2 , —OR 2 , —NR 2 —C(O)—R 3 , —O—C(O)—R 3 , —C(O)—R 3 , —SO 2 R 5 , —C(O)—R 5 , and R 5 ; or two R 13 s may together with the carbon(s) to which they are attached be replaced with a spiro or fused, heterocycle or carbocycle ring, or two R 13 s may together with the carbon to which they are attached be replaced with an aryl ring;
R 20 is heterocycle substituted with 1, 2, 3, or 4 substituents independently selected from alkyl, alkenyl, alkynyl, halogen, cyano, heteroaryl, aryl, cycloalkyl, heterocycle, —NR 2 R 2 , —OR 2 , —NR 2 —C(O)—R 24 , —O—C(O)—R 24 , —C(O)—R 24 , —SO 2 R 24 , and R 24 ; wherein the heterocycle group is only substituted such that no N—O or N—N bonds are formed;
R 21 and R 22 are independently selected from hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, —(C 2 -C 6 alkenylene)-cycloalkyl, —(C 2 -C 6 alkynylene)-cycloalkyl, halogen, and cyano;
R 23a and R 23b are independently selected from hydrogen, alkyl, cycloalkyl, and —(C 1 -C 6 alkylene)-NR 2 R 2 ;
or R 21 and R 23a are joined together with the carbons to which they are attached to form a 5- to 6-membered carbocyclic ring;
or R 22 and R 23a are joined together with the carbons to which they are attached to form a 5- to 6-membered carbocyclic ring;
R 24 is selected at each occurrence from alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heteroaryl, heterocycle, aryl, —O-cycloalkyl, —O-aryl, —O-heteroaryl, —O-heterocycle, —O-alkyl, —NR 2 -cycloalkyl, —NR 2 -aryl, —NR 2 -heteroaryl, —NR 2 -heterocycle, —NR 2 -alkyl, —CH 2 -cycloalkyl, —CH 2 -aryl, —CH 2 -heteroaryl, —CH 2 -heterocycle, —OR 2 , and —NR 2 R 2 ; wherein each R 24 is optionally substituted with 1, 2, 3, or 4 groups independently selected from R 25 ; and
R 25 is selected at each occurrence from: alkyl; alkenyl; alkynyl; haloalkyl; cycloalkyl; heterocycle; aryl optionally substituted with 1, 2, or 4 groups independently selected from alkyl, alkoxy, or halogen; heteroaryl optionally substituted with 1, 2, or 3 groups independently selected from alkyl, alkoxy, or halogen; —CH 2 -cycloalkyl; —CH 2 -aryl optionally substituted with 1, 2, or 3 groups independently selected from alkyl, alkoxy, or halogen; —CH 2 -heteroaryl optionally substituted with 1, 2, or 3 groups independently selected from alkyl, alkoxy, or halogen; —CH 2 -heterocycle; —CH 2 —NH—C(O)CH 3 ; —C(O)-cycloalkyl; —C(O)-aryl optionally substituted with 1, 2, or 3 groups independently selected from alkyl, alkoxy, or halogen; —C(O)-h

Assignees

• C4 Therapeutics Inc

Inventors

• Henderson James A
• Veits Gesine Kerstin
• He Minsheng
• Nasveschuk Christopher G
• Phillips Andrew J
• Good Andrew Charles

Classifications

• C07D401/14 Primary

  containing three or more hetero rings · CPC title

• C07D451/00

  Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof · CPC title

• C07D413/14

  containing three or more hetero rings · CPC title

• C07D405/14

  containing three or more hetero rings · CPC title

• A61P29/00

  Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] · CPC title