Cereblon binding compounds, compositions thereof, and methods of treatment therewith

Patent metadata

Field	Value
Publication number	US-2024374591-A1
Application number	US-202218573752-A
Country	US
Kind code	A1
Filing date	Jun 24, 2022
Priority date	Jun 25, 2021
Publication date	Nov 14, 2024
Grant date	—

Abstract

Provided herein are piperidine dione compounds having the following structure: (I) wherein Y, R1, R2, R3, R4, RN, L, V, X, a, m, and n are as defined herein, compositions comprising an effective amount of a piperidine dione compound, and methods for treating or preventing an androgen receptor mediated disease.

First claim

1 . A compound of formula I

or
a pharmaceutically acceptable salt thereof, wherein
n is 0-3;
each R 1 is independently selected from halogen, CN, and C 1-3 alkyl;
a is 1 or 2;
R 2 and R 3 are each independently selected from H, and C 1-3 alkyl, or R 2 and R 3 and the carbon to which they are attached form a substituted or unsubstituted C 3-6 cycloalkyl;
m is 0-8;
each R 4 is independently substituted or unsubstituted C 1-3 alkyl, or two R 4 groups, together with the same carbon atom or adjacent carbon atoms to which they are attached, form a substituted or unsubstituted C 3-6 cycloalkyl, or two R 4 groups together with the non-adjacent carbon atoms to which they are attached form a substituted or unsubstituted 4-7-membered heterocyclyl;
Y is CH or N;
X is N or CR X ;
R X is hydrogen, halogen, —O(C 1-6 alkyl) or —(C 1-9 alkyl);
L is substituted or unsubstituted —O(C 1-6 alkyl)-, —(C 1-6 alkyl)O—, —O(C 1-6 alkyl)O—, or —(C 1-9 alkyl)-;
V is

wherein
B is N, CH, or CR B ;
each R B is independently selected from halogen, and substituted or unsubstituted C 1-6 alkyl;
R C is halogen, CF 3 or SF 5 ;
R 5 and R 6 are C 1-3 alkyl, or R 5 and R 6 , together with the carbon atom to which they are attached, form a substituted or unsubstituted C 3-6 cycloalkyl or a 3-6 membered heterocyclyl; and
b is 0-2.

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

3 . The compound of claim 1 , wherein a is 1, and R 2 and R 3 are both H.

4 . The compound of claim 1 , wherein each R 4 is substituted or unsubstituted methyl.

5 . The compound of claim 1 , wherein each R 4 is independently selected from methyl and CF 3 .

6 . (canceled)

7 . (canceled)

8 . (canceled)

9 . (canceled)

10 . (canceled)

11 . (canceled)

12 . (canceled)

13 . (canceled)

14 . (canceled)

15 . The compound of claim 1 , wherein L is —O(CH 2 )(CH 2 )—, —O(CH 2 )(CH 2 )(CH 2 )—, —O(CH 2 )(CH 2 )O—, —O(CH 2 )(CH 2 )(CH 2 )O—, —(CH 2 )(CH 2 )—, —(CH 2 )(CH 2 )(CH 2 )—, or —(CH 2 )(CH 2 )(CH 2 )(CH 2 )—.

16 . (canceled)

17 . The compound of claim 1 , wherein B is CH.

18 . The compound of claim 1 , wherein B is N.

19 . The compound of claim 1 , wherein b is 0.

20 . The compound of claim 1 , wherein R C is CF 3 , Cl or SF 5 .

21 . (canceled)

22 . The compound of claim 1 , wherein R 5 and R 6 are methyl.

23 . The compound of claim 1 , having formula II

or a pharmaceutically acceptable salt, thereof.

24 . The compound of claim 1 , having formula III

or a pharmaceutically acceptable salt thereof, wherein
each R 4m is independently hydrogen or substituted or unsubstituted methyl, wherein the substituents, when present are selected from 1 to 5 halo;
Y is CH or N;
L is substituted or unsubstituted —O(C 1-3 alkyl)-, —O(C 1-3 alkyl)O— or —(C 1-4 alkyl)-;
n is 0;
V is

B is N or CH;
R C is halogen, CF 3 or SF 5 ; and
R 5 and R 6 are C 1-3 alkyl.

25 . The compound of claim 1 , having formula IV

or a pharmaceutically acceptable salt thereof, wherein
Y is CH or N;
L is substituted or unsubstituted —O(C 1-3 alkyl)-, —O(C 1-3 alkyl)O— or —(C 1-4 alkyl)-;
n is 0;
V is

B is N or CH;
R C is halogen, CF 3 or SF 5 ; and
R 5 and R 6 are C 1-3 alkyl.

26 . The compound of claim 1 , having formula V

or a pharmaceutically acceptable salt thereof, wherein
Y is CH or N;
L is substituted or unsubstituted —O(C 1-3 alkyl)-, —O(C 1-3 alkyl)O— or —(C 1-4 alkyl)-;
n is 0;
V is

B is N or CH;
R C is halogen, CF 3 or SF 5 ; and
R 5 and R 6 are C 1-3 alkyl.

27 . The compound of claim 1 , wherein the compound is selected from the group consisting of
2-((2R,6S)-4-(2-((trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperazin-1-yl)-N-(6-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)pyridin-3-yl)acetamide; 2-((2R,6S)-4-(2-((trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperazin-1-yl)-N-(6-(2,6-dioxopiperidin-3-yl)pyridin-3-yl)acetamide; 2-((2R,6S)-4-(3-(trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)propyl)-2,6-dimethylpiperazin-1-yl)-N-(6-(2,6-dioxopiperidin-3-yl)pyridin-3-yl)acetamide; 2-((2R,6S)-4-(3-((trans-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)propyl)-2,6-dimethylpiperazin-1-yl)-N-(6-(2,6-dioxopiperidin-3-yl)pyridin-3-yl)acetamide; 2-((2R,6S)-4-(3-((trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)propyl)-2,6-dimethylpiperazin-1-yl)-N-(6-(2,6-dioxopiperidin-3-yl)pyridin-3-yl)acetamide; 2-((2R,6S)-4-(2-((trans-4-(3-(5-chloro-6-cyanopyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperazin-1-yl)-N-(6-(2,6-dioxopiperidin-3-yl)pyridin-3-yl)acetamide; 2-((2R,6S)-4-(3-((trans-4-(3-(3-chloro-4-cyanophenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)propyl)-2,6-dimethylpiperazin-1-yl)-N-(6-(2,6-dioxopiperidin-3-yl)pyridin-3-yl)acetamide; 2-((2R,6S)-4-(3-(trans-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)propyl)-2,6-dimethylpiperazin-1-yl)-N-(6-(2,6-dioxopiperidin-3-yl)pyridin-3-yl)acetamide; 3-((2R,6S)-4-(2-((trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperazin-1-yl)-N-(6-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)pyridin-3-yl)propenamide; 2-((2S,6R)-4-(3-(trans-4-(3-(3-chloro-4-cyanophenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)propyl)-2,6-dimethylpiperazin-1-yl)-N-(6-(2,6-dioxopiperidin-3-yl)pyridin-3-yl)acetamide; 2-((2S,6R)-4-(3-(trans-4-(3-(5-chloro-6-cyanopyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)propyl)-2,6-dimethylpiperazin-1-yl)-N-(6-(2,6-dioxopiperidin-3-yl)pyridin-3-yl)acetamide; 2-((2R,6S)-4-(2-((trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperazin-1-yl)-N-(6-

Assignees

• Celgene Corp

Inventors

• Alexander Matthew D
• Correa Matthew D
• Dalvie Deepak
• Grant Virginia Heather Sharron
• Hansen Joshua
• Harris Iii Roy L
• Horn Evan J
• Huang Dehua
• Mayne Christopher
• Norris Stephen
• Plantevin-Krenitsky Veronique
• Sapienza John J
• Tehrani Lida
• Whitefield Brandon W

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• C07D401/14 Primary

  containing three or more hetero rings · CPC title

• A61K31/496

  Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin · CPC title

• A61K31/4545

  containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine · CPC title

• A61K31/513

  having oxo groups directly attached to the heterocyclic ring, e.g. cytosine · CPC title