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

Patent metadata

Field	Value
Publication number	US-11560371-B2
Application number	US-202117356283-A
Country	US
Kind code	B2
Filing date	Jun 23, 2021
Priority date	Jun 24, 2020
Publication date	Jan 24, 2023
Grant date	Jan 24, 2023

Abstract

Provided herein are piperidine dione compounds having the following structure:

wherein R 1 , R 2 , R 3 , R 4 , L, V, X, A, A′, a and m 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

What is claimed is:

1. A compound of formula I

or a pharmaceutically acceptable salt, tautomer, isotopolog, or stereoisomer thereof, wherein
R 1 is C 1-3 alkyl;
A is CH 2 or C═O;
A′ is NH or O;
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;
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)-;
X is N or CR X ;
R X is hydrogen, halogen, —O(C 1-6 alkyl) 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 R 1 is methyl.

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 m is 0, 1, 2, 3 or 4.

6. The compound of claim 1 , wherein L is substituted or unsubstituted —O(CH 2 ) p —, O(CH 2 ) p O— or —(CH 2 ) p —, and p is 1-4.

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

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

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

10. The compound of claim 1 , having formula II

or a pharmaceutically acceptable salt, tautomer, isotopolog, or stereoisomer thereof.

11. The compound of claim 1 , wherein the compound is selected from the group consisting of
2-((2S,6R)-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-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1 -methyl-1H-indazol-7-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-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-7-yl)acetamide,
2-((2R,6S)-4-(2-((trans-4-(3-(3-chloro-4-cyanophenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperazin-1-yl)-N-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-7-yl)acetamide,
2-((2R,6S)-4-(2-((trans-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperazin-1-yl)-N-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-7-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-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-7-yl)propenamide,
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-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-7-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-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-7-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-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-7-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-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-7-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-(3 -(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1 -methyl-1H-indazol-7-yl)acetamide,
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-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-7-yl)acetamide,
2-((2R,6S)-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-(3 -(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1 -methyl-1H-indazol-7-yl)acetamide,
2-((2R,4s,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-dimethylpiperidin-1-yl)-N-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-7-yl)acetamide,
2-((2R,4r,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-dimethylpiperidin-1-yl)-N-(3 -(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-7-yl)acetamide,
4-(3-(trans-4-(2-((3R, 5S)-4-(2-((3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-7-yl)oxy)ethyl)-3,5-dimethylpiperazin-1-yl)ethoxy)cyclohexyl)-4,4-dimethyl-5 -oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile,
4-(3-(trans-4-(2-((3S,5R)-4-(3-((3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-7-yl)oxy)propyl)-3,5-dimethylpiperazin-1-yl)ethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazoli din-1-yl)-2-(trifluoromethyl)benzonitrile,
2-((2R,6S)-4-(4-(trans-4-(3 -(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)butyl)-2,6-dimethylpiperazin-1-yl)-N-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-7-yl)acetamide,
4-(3-(trans-4-(2-((3R, 5S)-4-(2-((3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-7-yl)amino)ethyl)-3,5-dimethylpiperazin-1-yl)ethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazoli din-1-yl)-2-(trifluoromethyl)benzonitrile,
4-(3-(trans-4-(2-((3R, 5S)-4-(2-((3 -(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-7-yl)amino)ethyl)-3,5-dimethylpiperazin-1-yl)ethoxy)cyclohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazoli din-1-yl)-2-(trifluoromethyl)benzonitrile,
2-((S)-4-(2-((trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-2-(trifluoromethyl)piperazin-1-yl)-N-(3 -(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-7-yl)acetamide,
2-((2S, 6R)-4-(2-((trans-4-(3-(4-cyano-3-(pentafluoro-k 6 -sulfaneyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-l-yl)cyclohexyl)oxy)ethyl)-2,6-dimethylpiperazin-1-yl)-N-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-7-yl)acetamide,
2-((R)-4-(3-(trans-4-(3-(6-cyano-5-(trifluoromet

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

• C07D401/14 Primary

  containing three or more hetero rings · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• C07D403/14 Primary

  containing three or more hetero rings · CPC title

• A61K31/513

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