Fumarate analogs and uses thereof

Patent metadata

Field	Value
Publication number	US-9475781-B2
Application number	US-201514815589-A
Country	US
Kind code	B2
Filing date	Jul 31, 2015
Priority date	Aug 4, 2014
Publication date	Oct 25, 2016
Grant date	Oct 25, 2016

Abstract

Aspects of the present disclosure include compounds that find use for the treatment of a variety of autoimmune and inflammatory diseases and disorders. Embodiments of the present disclosure also relate to pharmaceutical compositions that include these compounds, methods of using these compounds in the treatment of various diseases and disorders, processes for preparing these compounds and intermediates useful in these processes.

First claim

What is claimed is:

1. A compound of formula (A):

wherein either:
Y 1 is X a and Y 2 is hydrogen, or Y 2 is X a and Y 1 is hydrogen;
wherein X a is selected from carboxylic acid, carboxyl ester, heterocyclyl, substituted heterocyclyl, heteroaryl and substituted heteroaryl; and

R 1 is selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl and —R 15 , wherein R 15 comprises a linking group and a compound of formula (A);
or a salt or stereoisomer thereof.

2. The compound of claim 1 , wherein the compound is of formula (Ia) or (Ib):

wherein R 15 comprises a linking group and a compound of formula (Ia) or (Ib).

3. The compound of claim 1 , wherein X a is a substituted heterocyclyl or a substituted heteroaryl, wherein the substituent on X a is X 1 , wherein X 1 is C 1-6 alkyl or a progroup.

4. The compound of claim 1 , wherein the compound is a compound of formula (IIa) or (IIb):

wherein
R 1 is selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl and —R 15 , wherein R 15 comprises a linking group and a compound of formula (IIa) or (IIb); and
X 1 is hydrogen, C 1-6 alkyl or a progroup;
or a salt or stereoisomer thereof.

5. The compound of claim 4 , wherein R 1 is aryl, substituted aryl, heteroaryl, or substituted heteroaryl.

6. The compound of claim 4 , wherein R 1 is hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl.

7. The compound of claim 6 , wherein R 1 is hydrogen, methyl, ethyl, isopropyl, cyclopentyl, 4-tetrahydropyranyl, —CH 2 CH 2 OCH 3 , —CH 2 OCH 3 , —CH 2 C(O)OCH 3 , or —CH 2 CH(CH 3 ) 2 OH.

8. The compound of claim 3 , wherein X 1 is C 1-6 alkyl.

9. The compound of claim 7 , wherein X 1 is methyl or tert-butyl.

10. The compound of claim 3 , wherein X 1 is a progroup of the formula:

wherein
L 1 is a linking group;
X 2 is optional and selected from O, N and S;
R 2 is selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, acyl, aminoacyl, carboxyl, carboxyl ester, cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl; and
R 3 and R 4 are each independently optional and selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, oxo, cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl; or
R 2 together with X 2 and either R 3 or R 4 form a heterocyclyl, substituted heterocyclyl, heteroaryl or substituted heteroaryl.

11. The compound of claim 10 , wherein X 1 is selected from:

wherein
L 1 is a C 1-6 alkyl or substituted C 1-6 alkyl;
R 5 and R 6 are each independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl; or
R 5 and R 6 together with the nitrogen to which they are attached form a heterocyclyl, substituted heterocyclyl, heteroaryl or substituted heteroaryl; and
R 7 is selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, and —OR 14 where R 14 is selected from alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl.

12. The compound of claim 11 , wherein X 1 is selected from:

wherein
R 8 , R 9 , R 10 , R 11 , R 12 and R 13 are each independently selected from hydrogen, alkyl and substituted alkyl.

13. The compound of claim 12 , wherein R 8 and R 9 are each independently selected from hydrogen and C 1-6 alkyl.

14. The compound of claim 13 , wherein R 8 and R 9 are each hydrogen.

15. The compound of claim 13 , wherein R 8 is hydrogen and R 9 is C 1-6 alkyl.

16. The compound of claim 12 , wherein R 10 , R 11 , R 12 and R 13 are each independently selected from hydrogen and C 1-6 alkyl.

17. The compound of claim 16 , wherein R 10 , R 11 , R 12 and R 13 are each hydrogen.

18. The compound of claim 16 , wherein one of R 10 , R 11 , R 12 and R 13 is methyl and the remaining are hydrogen.

19. The compound of claim 16 , wherein two of R 10 , R 11 , R 12 and R 13 are methyl and the remaining are hydrogen.

20. The compound of claim 1 , wherein the linking group is —(CH 2 ) n —Z y —(CH 2 ) m —,
wherein
n is an integer from 1 to 6;
m is 0 or an integer from 1 to 6;
y is 0 or 1; and
Z is O, NH, —O—P(O)(OH)—O—, S, S(O), SO 2 or —O—S(O) 2 —O—.

21. The compound of claim 20 , wherein the compound has one of the following formulae:

wherein
X 1a and X 1b are each independently selected from C 1-6 alkyl and a progroup; and
Z is O, NH, —O—P(O)(OH)—O—, S, S(O), SO 2 or —O—S(O) 2 —O—.

22. The compound of claim 1 , wherein R 1 is:

wherein X 1b is selected from C 1-6 alkyl and a progroup.

23. The compound of claim 22 , wherein the compound has one of the following formulae:

wherein X 1 and X 1b are each independently selected from C 1-6 alkyl and a progroup.

24. The compound of claim 23 , wherein X 1 and X 1b are each independently a C 1-6 alkyl.

25. The compound of claim 24 , wherein the compound has the structure:

26. The compound of claim 1 , wherein the compound is selected from:

Assignees

• Rigel Pharmaceuticals Inc

Inventors

• Duncton Matthew
• Bhamidipati Somasekhar
• Yu Jiaxin
• Darwish Ihab
• Singh Rajinder

Classifications

• A61P37/06

  Immunosuppressants, e.g. drugs for graft rejection · CPC title

• A61P37/02

  Immunomodulators · CPC title

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title

• A61P29/00

  Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] · CPC title

• A61P17/06

  Antipsoriatics · CPC title