IP Library › Granted Patent US 12,734,170

Granted Patent B2

US 12,734,170 · App. 18/573,752 · Granted Sep 15, 2026

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

Inventors: Matthew D. Alexander (San Diego, CA); Matthew D. Correa (San Diego, CA); Deepak Dalvie (San Diego, CA); Virginia Heather Sharron Grant (San Diego, CA); Joshua Hansen (La Jolla, CA); Roy L. Harris, III (San Diego, CA); Evan J. Horn (San Diego, CA); Dehua Huang (San Diego, CA); Christopher Mayne (Boulder, CO); Stephen Norris (San Diego, CA); Veronique Plantevin-Krenitsky (San Francisco, CA); John J. Sapienza (Chula Vista, CA); Lida Tehrani (San Diego, CA); Brandon W. Whitefield (San Diego, CA)

Assignee: Celgene Corporation

A61K31/506 A61K31/4545 A61K31/496 A61P35/00 C07D401/14

View Patent ↗

Loading inventors, assignments & file history…

Monitor This Case

Get email alerts when status or documents change.

Order Certified Copies

Most orders are placed with the USPTO same day — all within 24 business hours.

Order via The Patent Place →

Pre-filled with this patent's details

Quick Facts

Patent No.: US 12,734,170
App. No.: 18/573,752
Granted: Sep 15, 2026
Kind: B2

External Links

USPTO Patent Center↗ Full Patent PDF↗

Abstract

Provided herein are piperidine dione compounds having the following structure: (I) wherein Y, R 1 , R 2 , R 3 , R 4 , R N , 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.

Claims (98)

1 . A compound of formula I

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 . 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 )—.

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

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

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

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

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

12 . The compound of claim 1 , having formula II

or a pharmaceutically acceptable salt thereof.

13 . 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.

14 . 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.

15 . 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.

16 . 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-(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-((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-(6-(2,6-dioxopiperidin-3-yl)pyridin-3-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-(6-(2,6-dioxopiperidin-3-yl)pyridin-3-yl)acetamide;

2-((2S,6R)-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-(6-(2,4-dioxotetrahydropyrimidin-1 (2H)-yl)pyridin-3-yl)acetamide;

2-((2S,4r,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-dimethylpiperidin-1-yl)-N-(6-(2,6-dioxopiperidin-3-yl)pyridin-3-yl)acetamide;

2-((2S,4r,6R)-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-dimethylpiperidin-1-yl)-N-(6-(2,6-dioxopiperidin-3-yl)pyridin-3-yl)acetamide;

2-((2S,4s,6R)-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-dimethylpiperidin-1-yl)-N-(6-(2,6-dioxopiperidin-3-yl)pyridin-3-yl)acetamide;

2-((2S,4r,6R)-4-(3-(trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)propoxy)-2,6-dimethylpiperidin-1-yl)-N-(6-(2,6-dioxopiperidin-3-yl)pyridin-3-yl)acetamide;

2-((R)-4-(3-(trans-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)propyl)-2-(trifluoromethyl)piperazin-1-yl)-N-(6-(2,6-dioxopiperidin-3-yl)pyridin-3-yl)acetamide;

2-((R)-4-(3-(trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)propyl)-2-(trifluoromethyl)piperazin-1-yl)-N-(6-(2,6-dioxopiperidin-3-yl)pyridin-3-yl)acetamide;

2-((R)-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-(trifluoromethyl)piperazin-1-yl)-N-(6-(2,6-dioxopiperidin-3-yl)pyridin-3-yl)acetamide;

2-((R)-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-(trifluoromethyl)piperazin-1-yl)-N-(6-(2,6-dioxopiperidin-3-yl)pyridin-3-yl)acetamide;

2-((R)-4-(3-((trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)propyl)-2-(trifluoromethyl)piperazin-1-yl)-N-(6-(2,6-dioxopiperidin-3-yl)pyridin-3-yl)acetamide;

2-((2S,4r,6R)-4-(3-(trans-4-(3-(6-cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)propoxy)-2,6-dimethylpiperidin-1-yl)-N-(6-(2,6-dioxopiperidin-3-yl)pyridin-3-yl)acetamide;

2-((2S,4r,6R)-4-(2-(trans-4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)ethoxy)-2,6-dimethylpiperidin-1-yl)-N-(6-(2,6-dioxopiperidin-3-yl)pyridin-3-yl)acetamide;

2-((2R,4r,6S)-4-(2-((trans)-4-(3-(6-Cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)ethoxy)-2,6-dimethylpiperidin-1-yl)-N-(6-(2,6-dioxopiperidin-3-yl)pyridin-3-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)ethoxy)-2,6-dimethylpiperidin-1-yl)-N-(6-(2,6-dioxopiperidin-3-yl)pyridin-3-yl)acetamide;

2-((2R,4r,6S)-4-(2-(((trans)-4-(3-(6-Cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethoxy)-2,6-dimethylpiperidin-1-yl)-N-(6-(2,6-dioxopiperidin-3-yl)pyridin-3-yl)acetamide;

2-(4-(2-(((trans)-4-(3-(4-Cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-3,3-difluoropiperidin-1-yl)-N-(6-(2,6-dioxopiperidin-3-yl)pyridin-3-yl)acetamide; and

2-(4-(2-(((trans)-4-(3-(6-Cyano-5-(trifluoromethyl)pyridin-3-yl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)cyclohexyl)oxy)ethyl)-3,3-difluoropiperidin-1-yl)-N-(6-(2,6-dioxopiperidin-3-yl)pyridin-3-yl)acetamide;

or a pharmaceutically acceptable salt thereof.

17 . A pharmaceutical composition comprising an effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, excipient or vehicle.

18 . A method for the treatment of an androgen receptor mediated disease, the method comprising administering to a subject in need thereof an effective amount of a compound of claim 1 , wherein the androgen mediated disease is prostate cancer.

19 . A method for the treatment of an androgen receptor mediated disease, the method comprising administering to a subject in need thereof an effective amount of the pharmaceutical composition of claim 17 , wherein the androgen mediated disease is prostate cancer.

20 . The method of claim 18 , wherein the prostate cancer is castration resistant prostate cancer (CRPC).

Assignments (1)

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jul 31, 2024

From: ALEXANDER, MATTHEW D.; CORREA, MATTHEW D.; DALVIE, DEEPAK; GRANT, VIRGINIA HEATHER SHARRON; HANSEN, JOSHUA; HARRIS, ROY L., III; HORN, EVAN J.; HUANG, DEHUA; MAYNE, CHRISTOPHER; NORRIS, STEPHEN; PLANTEVIN-KRENITSKY, VERONIQUE; SAPIENZA, JOHN J.; TEHRANI, LIDA; WHITEFIELD, BRANDON W.

To: CELGENE CORPORATION

Reel/Frame 068139/0586 →

Continuity (2)

Provisional Application 63215294 · Jun 25, 2021

Related Publication 20240374591A1 · Nov 14, 2024

References Cited (32)

US 11149007B2 · Ammirante et al. · 2021 [cited by applicant]

US 11325889B2 · Ammirante et al. · 2022 [cited by applicant]

US 11560371B2 · Alexander et al. · 2023 [cited by applicant]

US 11634407B2 · Alexander et al. · 2023 [cited by applicant]

US 11739075B2 · Alexander et al. · 2023 [cited by applicant]

US 11883389B2 · Hui et al. · 2024 [cited by applicant]

US 20160214972A1 · Jin · 2016 [cited by examiner]

US 20180215731A1 · Crew et al. · 2018 [cited by applicant]

US 20180224435A1 · Chamberlain et al. · 2018 [cited by applicant]

US 20190240304A1 · Xu · 2019 [cited by applicant]

US 20200199073A1 · Ammirante et al. · 2020 [cited by applicant]

US 20230242509A1 · Alexander et al. · 2023 [cited by applicant]

US 20230348431A1 · Alexander et al. · 2023 [cited by applicant]

US 20240368083A1 · Ammirante et al. · 2024 [cited by applicant]

WO WO2019140387A1 · 2019 [cited by applicant]

WO WO2020006264A1 · 2020 [cited by applicant]

WO WO2021113557 · 2021 [cited by applicant]

WO WO2022272053 · 2022 [cited by applicant]

WO WO2022272061 · 2022 [cited by applicant]

WO WO2022272074 · 2022 [cited by applicant]

Pubchem, Substance Record for SID 145140517, Modify Date: May 31, 2019 [retrieved on Aug. 17, 2022]. Retrieved from the Internet: <URL: https://pubchem.ncbi.nlm.nih.gov/substance/145140517>. [cited by applicant]

Pubchem, Substance Record for SID 435776705, Modify Date: 321 Nov. 2020 [retrieved on Oct. 3, 2022]. Retrieved from the Internet: <URL: https://pubchem.ncbi.nlm.nih.gov/substance/435776705>. [cited by applicant]

Chen et al., 2009, “Antiandrogens and androgen depleting therapies in prostate cancer: novel agents for an established target,” Lancet Oncol, 10:981-91. [cited by applicant]

Mills, 2014, “Maintaining and reprogramming genomic androgen receptor activity in prostate cancer,” Nat Rev Cancer, 14:187-98. [cited by applicant]

Taplin, 2007, “Drug Insight: role of the androgen receptor in the development and progression of prostate cancer,” Nat Clin Pract Oncol, 4:236-44. [cited by applicant]

Wirth et al., 2007, “Antiandrogens in the Treatment of Prostate Cancer,” Eur Urol, 51(2):306-13. [cited by applicant]

Brinkmann et al., 1999, “Mechanisms of androgen receptor activation and function,” J Steroid Biochem Mol Biol, 69:307-13. [cited by applicant]

Tran et al., 2009, “Development of a Second-Generation Antiandrogen for Treatment of Advanced Prostate Cancer,” Science, 324:787-90. [cited by applicant]

Murtha et al., 1993, “Androgen Induction of a Human Prostate-Specific Kallikrein, hKLK2: Characterization of an Androgen Response Element in the 5′ Promoter Region of the Gene,” Biochemistry (Mosc.), 32:6459-64. [cited by applicant]

Wilen, et al., 1977, “Strategies in Optical Resolutions,” Tetrahedron 33:2725. [cited by applicant]

International Search Report and Written Opinion, dated Aug. 23, 2022, for International Patent Application No. PCT/US2022/034902 (7 pages). [cited by applicant]

Supplementary European Search Report dated May 7, 2025, for European Patent Application No. EP 22 82 9384 (8 pages). [cited by applicant]