Dipeptides as inhibitors of human immunoproteasomes

Patent metadata

Field	Value
Publication number	US-RE49816-E
Application number	US-201516893086-A
Country	US
Kind code	E1
Filing date	Jan 12, 2015
Priority date	Jan 10, 2014
Publication date	Jan 30, 2024
Grant date	Jan 30, 2024

Abstract

The compounds of the present invention are represented by the following compounds having Formula (I) where the substituents R 1 -R 10 , X, Y, k, m, n, q, and s are as defined herein. These compounds are used in the treatment of cancer, immunologic disorders, autoimmune disorders, neurodegenerative disorders, or inflammatory disorders or for providing immunosuppression for transplanted organs or tissues.

First claim

What is claimed is:

1. A compound of Formula (Ia):

wherein
R 1a is selected from the group consisting of bicyclic aryl, monocyclic and bicyclic heteroaryl, and monocyclic and bicyclic non-aromatic heterocycle, wherein bicyclic aryl, monocyclic and bicyclic heteroaryl, and monocyclic and bicyclic non-aromatic heterocycle can be optionally substituted from 1 to 3 times with a substituent selected independently at each occurrence thereof from the group consisting of halogen, cyano, C 1-6 alkyl, and C 1-6 alkoxy;
R 2a is selected from the group consisting of C 1-6 alkyl, —CH 2 OC 1-6 alkyl, CH 2 Ar, and heteroaryl, wherein aryl (Ar) can be optionally substituted from 1 to 3 times with a substituent selected independently at each occurrence thereof from the group consisting of halogen, cyano, C 1-6 alkyl, and C 1-6 alkoxy;
R 3a is selected from the group consisting of —CH 2 OC 1-6 alkyl, —(CH 2 ) m C(O)NHR 5a , and —CH 2 C(O)R 5a ;
R 4a is selected from the group consisting of —C(O)(CH 2 ) n Ph, —C(O)CH 2 NR 6a R 7a , —SO 2 Ar, —SO 2 C 1-6 alkyl, —C(O)(CH 2 ) n Het, —C(O)C 1-6 alkyl, —C(O)CF 3 , heteroaryl, and —(CH 2 ) n NR 6a R 7a , wherein aryl (Ar) and heteroaryl (Het) can be optionally substituted from 1 to 3 times with a substituent selected independently at each occurrence thereof from the group consisting of halogen, cyano, C 1-6 alkyl, and C 1-6 alkoxy;
R 5a is selected from the group consisting of C 1-6 alkyl, C 1-6 alkoxy, non-aromatic heterocycle, —NR 6a R 7a , and —CR 8a R 9a ;
R 6a , R 7a , R 8a , and R 9a are each independently selected from the group consisting of H, C 1-6 alkyl, and —(CH 2 ) k OH;
or R 6a and R 7a are taken together with the nitrogen to which they are attached to form a piperidine, pyrrolidine, azepane, azetidine, or morpholine ring;
or R 8a and R 9a are taken together with the carbon to which they are attached to form an oxetane ring;
m is 1 or 2;
n is 0, 1, 2, or 3; and
k is 1, 2, or 3.

2. A pharmaceutical composition comprising a therapeutically effective amount of the compound according to claim 1 and a pharmaceutically acceptable carrier.

3. The compound according to claim 1 , wherein m is 1.

4. The compound according to claim 1 , wherein m is 2.

5. The compound according to claim 1 , wherein R 5a is selected from the group consisting of C 1-6 alkyl, C 1-6 alkoxy, non-aromatic heterocycle, and —CR 8a R 9a .

6. The compound according to claim 3 , wherein R 1a is selected from the group consisting of

7. The compound according to claim 3 , wherein R 2a is selected from the group consisting of Me, —CH 2 OMe, and

8. The compound according to claim 3 , wherein R 3a is selected from the group consisting of —CH 2 OMe,

9. The compound according to claim 3 , wherein R 4a is selected from the group consisting of trifluoroacetyl,

p is 0, 1, 2, or 3;
r is 0, 1, 2, 3, 4, or 5;
t is 0, 1, 2, 3, or 4; and
R is selected from the group consisting of H, halogen, cyano, C 1-6 alkyl, and C 1-6 alkoxy.

10. The compound according to claim 3 , wherein the compound has a structure selected from the group consisting of:

11. A method of treating cancer, immunologic disorders, autoimmune disorders, neurodegenerative disorders, or inflammatory disorders in a subject or for providing immunosuppression for transplanted organs or tissues in a subject, said method comprising:
administering to the subject in need thereof a compound of the Formula (Ia):

wherein
R 1a is selected from the group consisting of bicyclic aryl, monocyclic and bicyclic heteroaryl, and monocyclic and bicyclic non-aromatic heterocycle, wherein bicyclic aryl, monocyclic and bicyclic heteroaryl, and monocyclic and bicyclic non-aromatic heterocycle can be optionally substituted from 1 to 3 times with a substituent selected independently at each occurrence thereof from the group consisting of halogen, cyano, C 1-6 alkyl, and C 1-6 alkoxy;
R 2a is selected from the group consisting of C 1-6 alkyl, —CH 2 OC 1-6 alkyl, —CH 2 Ar, and heteroaryl, wherein aryl (Ar) can be optionally substituted from 1 to 3 times with a substituent selected independently at each occurrence thereof from the group consisting of halogen, cyano, C 1-6 alkyl, and C 1-6 alkoxy;
R 3a is selected from the group consisting of —CH 2 OC 1-6 alkyl, —CH m C(O)NHR 5a , and —CH 2 C(O)R 5a ;
R 4a is selected from the group consisting of —C(O)(CH 2 ) n Ph, —C(O)CH 2 NR 6a R 7a , —SO 2 Ar, —SO 2 C 1-6 alkyl, —C(O)(CH 2 ) n Het, —C(O)C 1-6 alkyl, —C(O)CF 3 , heteroaryl, and —(CH 2 ) n NR 6a R 7a , wherein aryl (Ar) and heteroaryl (Het) can be optionally substituted from 1 to 3 times with a substituent selected independently at each occurrence thereof from the group consisting of halogen, cyano, C 1-6 alkyl, and C 1-6 alkoxy;
R 5a is selected from the group consisting of C 1-6 alkyl, C 1-6 alkoxy, non-aromatic heterocycle, —NR 6a R 7a , and —CR 8a R 9a ;
R 6a , R 7a , R 8a , and R 9a are each independently selected from the group consisting of H, C 1-6 alkyl, and —(CH 2 ) k OH;
or R 6a and R 7a are taken together with the nitrogen to which they are attached to form a piperidine, pyrrolidine, azepane, azetidine, or morpholine ring;
or R 8a and R 9a are taken together with the carbon to which they are attached to form an oxetane ring;
m is 1 or 2;
n is 0, 1, 2, or 3; and
k is 1, 2, or 3.

12. The method of claim 11 , wherein m is 1.

13. The method of claim 11 , wherein m is 2.

14. The method of claim 11 , wherein R 5a is selected from the group consisting of C 1-6 alkyl, C 1-6 alkoxy, non-aromatic heterocycle, and —CR 8a R 9a .

15. The method of claim 12 , wherein R 1a is selected from the group consisting of

16. The method of claim 12 , wherein R 2a is selected from the group consisting of Me, —CH 2 OMe, and

17. The method of claim 12 , wherein R 3a is selected from the group consisting of —CH 2 OMe,

18. The method of claim 12 , wherein R 4a is selected from the group consisting of trifluoroacetyl,

p is 0, 1, 2, or 3;
r is 0, 1, 2, 3, 4, or 5;
t is 0, 1, 2, 3, or 4; and
R is selected

Assignees

• Univ Cornell

Inventors

• Lin Gang
• Nathan Carl
• Ding Aihao
• Ma Xiaojing

Classifications

• C07K5/06104 Primary

  with the first amino acid being acidic · CPC title

• C07K5/0606

  the side chain containing heteroatoms not provided for by C07K5/06086 - C07K5/06139, e.g. Ser, Met, Cys, Thr · CPC title

• C07K5/06026

  the side chain containing 0 or 1 carbon atom, i.e. Gly or Ala · CPC title

• C07K5/06069

  Ser-amino acid · CPC title

• C07K5/06086

  with the first amino acid being basic · CPC title