Sepiapterin reductase inhibitors
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.
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 compound of claim 1 .
26. The compound of claim 3 , wherein
27. The compound of claim 7 , wherein
R 7 and R 9 are each independently selected from the group consisting of halo, C 1-5 alkyl, C 3-5 cycloalkyl, heterocyclyl 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 6 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 1-5 alkylene-aryl, and —C 1-5 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.