Substituted dibenzo[b, f]azepines as proteasome activators

Patent metadata

Field	Value
Publication number	US-12060337-B2
Application number	US-202217671480-A
Country	US
Kind code	B2
Filing date	Feb 14, 2022
Priority date	Jun 5, 2017
Publication date	Aug 13, 2024
Grant date	Aug 13, 2024

Abstract

The disclosure is directed to substituted dibenzo[b,f]azepines of the formula (II):

wherein the variables n, X 3 , R 1 , R 2 , R 4 , and R 5 are defined herein, and uses of such compounds to treat conditions including neurodegenerative diseases and cancers.

First claim

What is claimed is:

1. A compound of formula (II):

or a pharmaceutically acceptable salt thereof,
wherein:
X 3 is —CH 2 CH 2 —;
R 1 is H, halo, alkyl, O(alkyl), aryl, or O(aryl);
R 2 is H, halo, alkyl, O(alkyl), aryl, or O(aryl);
R 4 is halo, alkyl, O(alkyl), or S(alkyl);
R 5 is C(O)NR 6 R 7 or C(O)OR 6 ;
R 6 is H, alkyl, or aryl;
R 7 is H, alkyl, or aryl; or
R 6 and R 7 , taken together with the nitrogen atom to which they are attached, form a heterocyclyl; and

n is 1.

2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is H.

3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 is H.

4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
R 1 id H; and
R 2 is H.

5. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R is halo, O(alkyl), or S(alkyl).

6. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4 is halo.

7. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
(i) R 6 is H or alkyl; and
R 7 is H or alkyl; or

(ii) R 6 and R 7 , taken together with the nitrogen atom to which they are attached, form a heterocyclyl.

8. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
R 6 is H or (C 1 -C 6 ) alkyl; and
R 6 is H or (C 1 -C 6 ) alkyl.

9. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 6 and R 7 , taken together with the nitrogen atom to which they are attached, form a 5- or 6-membered heterocyclyl, wherein the 5- or 6-membered heterocyclyl contains one or more additional heteroatoms or heteroatomic groups independently selected from the group consisting of N, NR 8 , O, and S.

10. The compound of claim 9 , or a pharmaceutically acceptable salt thereof, wherein:
R 6 and R 7 , taken together with the nitrogen atom to which they are attached, form a 6-membered heterocyclyl, wherein the 6-membered heterocyclyl contains one additional heteroatom selected from the group consisting of NR 8 and O; and
R 8 is H or alkyl.

11. The compound of claim 10 , or a pharmaceutically acceptable salt thereof, wherein R 6 and R 7 , taken together with the nitrogen atom to which they are attached, form:

12. The compound of claim 1 , wherein the compound is selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

13. A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of claim 1 , or a pharmaceutically acceptable salt thereof.

14. A method for reducing the accumulation of intrinsically disordered proteins (IDPs) in a subject, wherein the method comprises administering to the subject in need thereof a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof.

15. The method of claim 14 , wherein the intrinsically disordered protein (IDP) is selected from the group consisting of B-cell lymphoma 2 (BCL-2), c-Fos, c-Myc, an oxidatively damaged protein, polyglutamine, superoxide dismutase 1 (SOD1), alpha-synuclein, and tau.

16. The method of claim 14 , wherein the subject has a neurodegenerative disease.

17. The method of claim 16 , wherein the neurodegenerative disease is selected from the group consisting of Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS, Lou Gehrig's disease), Huntington's disease (HD), and Parkinson's disease (PD).

18. The method of claim 14 , wherein the subject has cancer.

19. The method of claim 18 , wherein the cancer is selected from the group consisting of breast cancer, cervical cancer, colon cancer, glioblastoma, melanoma, myeloid leukemia, osteosarcoma, and small-cell lung carcinoma.

Assignees

• Univ Michigan State

Inventors

• Tepe Jetze J
• Lansdell Theresa A
• Njomen Evert
• Jones Corey Lee

Classifications

• C07D417/06

  linked by a carbon chain containing only aliphatic carbon atoms · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• C07D279/14

  condensed with carbocyclic rings or ring systems · CPC title

• C07D223/22

  Dibenz [b, f] azepines; Hydrogenated dibenz [b, f] azepines · CPC title

• C07D279/22 Primary

  with carbon atoms directly attached to the ring nitrogen atom · CPC title