Sepiapterin reductase inhibitors

Patent metadata

Field	Value
Publication number	US-9963462-B2
Application number	US-201615282000-A
Country	US
Kind code	B2
Filing date	Sep 30, 2016
Priority date	Sep 30, 2015
Publication date	May 8, 2018
Grant date	May 8, 2018

Abstract

Inhibitors of sepiapterin reductase and uses of sepiapterin reductase inhibitors in analgesia, treatment of acute and chronic pain, anti-inflammation, and immune cell regulation are disclosed.

First claim

What is claimed is:

1. A compound of formula V or V′, or a pharmaceutically acceptable salt thereof:

wherein:
is a single bond;
Y 1 is N;

is a pyrrolyl ring optionally substituted with F, Cl, or C 1-3 alkyl;
n is 0 or 1;
each R 6 is selected from the group consisting of C 1-5 alkyl, C 3-5 cycloalkyl, C 1-5 haloalkyl, halo, and benzyl;
Q is CH, CR 6 , or N;
R 3 and R 4 , taken together with the nitrogen atom to which they are attached form a 3-, 4-, 5-, 6-, or 7-membered monocyclic ring having 1 or 2 heteroatom ring atoms, or 6-, 7-, 8-, 9-, 10-, 11-, 12-, 13-, or 14-membered spiro, fused, and/or bridged polycyclic ring having 1 or 2 heteroatom ring atoms, and the heteroatom ring atoms are selected from nitrogen, oxygen, and sulfur.

2. The compound of claim 1 , wherein

is selected from the group consisting of:

3. The compound of claim 1 , wherein

and is optionally substituted with one to four substituents selected from the group consisting of F, Cl, and C 1-3 alkyl.

4. The compound of claim 1 , wherein

5. The compound of claim 3 , wherein

6. The compound of claim 1 , wherein

is selected from the group consisting of

7. The compound of claim 6 , wherein

8. The compound of claim 1 , wherein R 3 and R 4 , taken together with nitrogen atom to which they are attached form a 3-, 4-, 5-, 6-, or 7-membered ring having 1 or 2 heteroatom ring atoms selected from nitrogen, oxygen, and sulfur.

9. The compound of claim 8 , wherein the 3-, 4-, 5-, 6-, or 7-membered ring is piperidinyl, pyrrolidinyl, azetidinyl, piperazinyl, morpholinyl, thiomorpholinyl, aziridinyl, oxaziridinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, azepanyl, diazepanyl, or diazabicycloheptane.

10. The compound of claim 1 , wherein

m is 0, 1, 2, or 3;
R 7 and R 9 are each independently selected from the group consisting of halo, C 1-5 alkyl, C 3-5 cycloalkyl, heterocycloalkyl, C 1-5 haloalkyl, C 1-5 haloalkylene-OH, C 1-5 alkylene-CN, C 1-5 alkoxy, C 1-5 haloalkoxy, aryloxy, heteroaryloxy, CN, OH, —NHR 8 , —NR 8 CO 2 R 8a , —SO 2 R 8 , —CO 2 R 8 , —CONHR 8 , aryl, and heteroaryl, or
two R 7 groups, together with the carbon atom(s) to which they are attached, form a 3-, 4-, 5-, 6-, 7-, or 8-membered cycloalkyl, a 3-, 4-, 5-, 6-, 7-, or 8-membered heterocyclic ring, aryl, or a 5- or 6-membered heteroaryl ring; and
R 8 and R 8a are each independently selected from the group consisting of H, C 1-5 alkyl, —C 0-5 alkylene-aryl, and —C 0-5 alkylene-heteroaryl; or
one R 7 group and R 9 , together with the atoms to which they are attached, form a 5- or 6-membered heterocyclic ring or 5- or 6-membered heteroaryl ring, and wherein the heterocyclic ring and heteroaryl ring have 1 or 2 heteroatom ring atoms selected from nitrogen, oxygen, and sulfur.

11. The compound of claim 1 , wherein

R 7 and R 9 are each independently selected from the group consisting of halo, C 1-5 alkyl, C 3-5 cycloalkyl, heterocyclic ring, C 1-5 haloalkyl, C 1-5 haloalkylene-OH, C 1-5 alkylene-CN, C 1-5 alkoxy, C 1-5 haloalkoxy, aryloxy, heteroaryloxy, CN, OH, —NHR 8 , —NR 8 CO 2 R 8a , —SO 2 R 8 , —CO 2 R 8 , —CONHR 8 , aryl, and heteroaryl; and
R 8 and R 8a are each independently selected from the group consisting of H, C 1-5 alkyl, —C 0-5 alkylene-aryl, and —C 0-5 alkylene-heteroaryl, and wherein the heterocyclic ring or heteroaryl is a 5- or 6-membered ring having 1 or 2 heteroatom ring atoms selected from nitrogen, oxygen, and sulfur.

12. The compound of claim 11 , wherein R 7 or R 9 is selected from the group consisting of C 3-5 cycloalkyl, heterocycloalkyl, aryloxy, heteroaryloxy, aryl, and heteroaryl.

13. The compound of claim 12 , wherein R 7 is oxazolyl or pyridinyl, each of which is optionally substituted with CN or F.

14. The compound of claim 13 , wherein R 7 is selected from the group consisting of

15. The compound of claim 12 , wherein R 9 is C 3-5 cycloalkyl.

16. The compound of claim 15 , wherein R 9 is cyclopropyl or cyclobutyl, each of which is optionally substituted with 1, 2, 3, or 4 F atoms.

17. The compound of claim 16 , wherein R 9 is selected from the group consisting of

18. The compound of claim 1 , wherein the compound is

or a pharmaceutically acceptable salt thereof.

19. The compound of claim 1 , wherein the compound is

or a pharmaceutically acceptable salt thereof.

20. The compound of claim 1 , wherein the compound is

or a pharmaceutically acceptable salt thereof.

21. The compound of claim 1 , wherein the compound is

or a pharmaceutically acceptable salt thereof.

22. The compound of claim 1 , wherein the compound is

or a pharmaceutically acceptable salt thereof.

23. The compound of claim 1 , wherein the compound is

or a pharmaceutically acceptable salt thereof.

24. The compound of claim 1 , wherein the compound is

or a pharmaceutically acceptable salt thereof.

25. A method of treating a subject suffering from pain, comprising administering to the subject a therapeutically effective amount of the co

Assignees

• Quartet Medicine Inc
• Ecole Polytechnique Fed Lausanne Epfl
• Max Planck Gesellschaft

Inventors

• Tebbe Mark Joseph
• Atton Holly Victoria
• Avery Craig
• Bromidge Steven Mark
• Kerry Mark
• Kotey Adrian Kotei
• Monck Nathaniel J
• Meniconi Mirco
• Ridgill Mark Peter
• Tye Heather
• Saiah Eddine
• Johnsson Kai Peter
• Gorska Katarzyna Irena
• Peng Hairuo
• Mccall John Michael

Classifications

• A61P37/02

  Immunomodulators · CPC title

• C07D495/04 Primary

  Ortho-condensed systems · CPC title

• A61P29/00

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

• A61P25/04

  Centrally acting analgesics, e.g. opioids · CPC title

• C07D491/107

  with only one oxygen atom as ring hetero atom in the oxygen-containing ring · CPC title