Substituted pyridine derivatives as SARM1 inhibitors
This disclosure is drawn to substituted pyridine compounds and compositions, and associated methods, useful for inhibition of SARM1 activity and/or for treating or preventing a neurological diseases.
1. A compound of Formula Ic:
or a pharmaceutically acceptable salt thereof, wherein:
A is N or N + —O—;
Q 1 and Q 2 are each independently selected from CH and N;
W is O, S, or NR N ;
--- is a single bond;
X is CR 5 R 6 and Y is CR 8 R 9 ;
Ring Z is C 6-10 aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl, or 4-10 membered heterocycloalkyl;
R N is H, C 1-4 alkyl, or CN;
R 1 is halo, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, or C 1-4 haloalkoxy;
R 2C is selected from H, C 1-4 alkyl, C 1-4 hydroxyalkyl, C 1-4 cyanoalkyl, and C 3-7 cycloalkyl;
R 3 and R 5 , together with the atoms to which they are attached and together with any intervening atoms, form a 5-7 membered heterocycloalkyl ring optionally substituted by 1, 2, or 3 substituents independently selected from oxo, halo, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, and C 1-4 haloalkoxy;
each R 4 is independently halo, nitro, cyano, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 haloalkyl, C 1-4 alkoxy, or C 1-4 haloalkoxy;
R 6 , R 8 , and R 9 are each independently selected from H, halo, NH 2 , OH, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 cyanoalkyl, C 1-4 alkoxy, and C 1-4 haloalkoxy;
m is 0, 1, or 2; and
n is 0, 1, 2, 3, 4, or 5.
2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein A is N.
3. The compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein W is O or S.
4. The compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein W is O.
5. The compound of claim 4 , or a pharmaceutically acceptable salt thereof, wherein Ring Z is C 6-10 aryl or 5-10 membered heteroaryl.
6. The compound of claim 5 , or a pharmaceutically acceptable salt thereof, wherein Ring Z is 5-6 membered heteroaryl.
7. The compound of claim 6 , or a pharmaceutically acceptable salt thereof, wherein Ring Z is pyridyl, pyrimidinyl, thienyl, thiazolyl, isoxazolyl, or pyrazolyl.
8. The compound of claim 5 , or a pharmaceutically acceptable salt thereof, wherein Ring Z is selected from the following (a)-(i).
9. The compound of claim 5 , or a pharmaceutically acceptable salt thereof, wherein m is 0 or 1.
10. The compound of claim 5 , or a pharmaceutically acceptable salt thereof, wherein m is 0.
11. The compound of claim 5 , or a pharmaceutically acceptable salt thereof, wherein Ring Z is
12. The compound of claim 5 , or a pharmaceutically acceptable salt thereof, wherein n is 1.
13. The compound of claim 5 , or a pharmaceutically acceptable salt thereof, wherein each R 4 is independently F, Cl, Br, I, CN, NO 2 , methyl, ethyl, CF 3 , CHF 2 , OCF 3 , or OCHF 2 .
14. The compound of claim 13 , or a pharmaceutically acceptable salt thereof, wherein each R 4 is independently F or Cl.
15. The compound of claim 5 , or a pharmaceutically acceptable salt thereof, wherein each R 4 is F.
16. The compound of claim 5 , or a pharmaceutically acceptable salt thereof, wherein R 8 and R 9 are each independently selected from H and methyl.
17. The compound of claim 5 , or a pharmaceutically acceptable salt thereof, wherein R 3 and R 5 , together with the atoms to which they are attached and together with any intervening atoms, form an unsubstituted 5-7 membered heterocycloalkyl ring.
18. The compound of claim 16 , or a pharmaceutically acceptable salt thereof, wherein R 8 and R 9 are each H.