Inhibitors of SARM1
The present disclosure provides compounds and methods useful for inhibiting SARM1 and/or treating and/or preventing axonal degeneration.
1. A compound of the formula:
or a pharmaceutically acceptable salt thereof, wherein:
R 1 is a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms selected from oxygen, nitrogen and sulfur;
G is CH, CR x or N;
R x is C 1 -C 3 alkyl, halogen or cyano;
X is CH 2 , NH, N(C 1 -C 3 alkyl) or O;
Y is C(R P ) 2 or NH;
Z is bond, CH 2 or —CH 2 CH 2 —;
R 2a is —(C 1 -C 3 alkyl)R 3 ;
R 2b is hydrogen, halogen, C 1 -C 3 alkyl or —(C 1 -C 3 alkyl)R 3 ;
R P is independently hydrogen, halogen or NH 2 ;
R 3 is a phenyl ring or a 5- to 6-membered heteroaryl ring having 1-3 heteroatoms selected from oxygen, nitrogen and sulfur, wherein the phenyl ring or 5- to 6-membered heteroaryl ring are optionally substituted with 1 to 2 R q ;
R q is halogen, cyano or —CF 3 .
2. The compound according to claim 1 , wherein R 2b is hydrogen, or a pharmaceutically acceptable salt thereof.
3. The compound according to claim 2 , wherein R 1 is selected from
or a pharmaceutically acceptable salt thereof.
4. The compound according to claim 3 , wherein G is N, or a pharmaceutically acceptable salt thereof.
5. The compound according to claim 4 , wherein X is CH 2 , Y is CH 2 , and Z is CH 2 , or a pharmaceutically acceptable salt thereof.
6. The compound according to claim 5 , wherein R 2a is —CH 2 —R 3 , or a pharmaceutically acceptable salt thereof.
7. The compound according to claim 6 , wherein R 3 is selected from
or a pharmaceutically acceptable salt thereof.
8. The compound according to claim 7 , wherein R 3 is selected from
or a pharmaceutically acceptable salt thereof.
9. The compound according to claim 1 , which is:
or a pharmaceutically acceptable salt thereof.
10. The compound according to claim 9 , which is:
or a pharmaceutically acceptable salt thereof.
11. The compound according to claim 1 , which is:
or a pharmaceutically acceptable salt thereof.
12. The compound according to claim 11 , which is:
or a pharmaceutically acceptable salt thereof.
13. A pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt thereof according to claim 1 with one or more pharmaceutically acceptable carriers, diluents, or excipients.
14. A method comprising a step of:
administering a compound according to claim 1 , or a pharmaceutically acceptable salt thereof, to a patient who (i) has a condition characterized by axonal degeneration or (ii) is at risk of developing a condition characterized by axonal degeneration.
15. A method of treating or preventing axonal degeneration comprising administering to a patient in need thereof a compound according to claim 1 , or a pharmaceutically acceptable salt thereof.
16. A method of inhibiting SARM1 comprising contacting a biological sample with a compound according to claim 1 , or a pharmaceutically acceptable salt thereof.
17. A method of treating amyotrophic lateral sclerosis in a patient, comprising administering to a patient in need of such treatment and effective amount of a compound according to claim 1 , or a pharmaceutically acceptable salt thereof.
18. A method of treating multiple sclerosis in a patient, comprising administering to a patient in need of such treatment and effective amount of a compound according to claim 1 , or a pharmaceutically acceptable salt thereof.
19. A method of treating progressive supranuclear palsy in a patient, comprising administering to a patient in need of such treatment and effective amount of a compound according to claim 1 , or a pharmaceutically acceptable salt thereof.