IP Library › Granted Patent US 11,629,136

Granted Patent B1

US 11,629,136 · App. 17/875,301 · Granted Apr 18, 2023

Substituted pyridine derivatives as SARM1 inhibitors

Inventors: Rao Kolluri (San Francisco, CA); Christopher Michael Tegley (San Carlos, CA); Liusheng Zhu (Foster City, CA); Sean Pomeroy Brown (Half Moon Bay, CA); Charles Howard Reynolds (Austin, TX); Andrew Stewart Tasker (Simi Valley, CA); Cheryl A. Grice (Redwood City, CA)

Assignee: NURA BIO, INC.

C07D401/06 C07D417/14

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Quick Facts

Patent No.: US 11,629,136
App. No.: 17/875,301
Granted: Apr 18, 2023
Kind: B1

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Abstract

This disclosure is drawn to pyridine derivatives, compositions thereof, and associated methods, useful for inhibition of SARM1 activity and/or for treating or preventing neurological disorders.

Claims (107)

1. A compound of Formula IIa:

or a pharmaceutically acceptable salt thereof, wherein:

Q is -Cy, —C 1-4 alkyl-Cy, —CF 3 , or C 1-4 alkyl-CF 3 ;

R 1 is H;

R 2 is H or C 1-4 alkyl;

R 4 and R 4a are each independently selected from H, halo, and C 1-4 alkyl;

each R 5 is independently selected from halo and C 1-4 alkyl, wherein R 5 is attached to a carbon atom;

R 6 and R 7 are each independently selected from H, —OR a , —NR c R d , C 1-4 alkyl, and C 1-4 haloalkyl;

Cy is selected from C 6-10 aryl, C 3-7 cycloalkyl, 5-6 membered heteroaryl, and 4-7 membered heterocycloalkyl, each optionally substituted by 1, 2, 3, 4, or 5 R Cy substituents independently selected from halo, C 1-4 alkyl, C 1-4 haloalkyl, CN, NO 2 , OR a , SR a , C(O)R b , C(O)NR c R d , C(O)OR a , OC(O)R b , OC(O)NR c R d , NR c R d , NR c C(O)R b , NR c C(O)OR a , NR c C(O)NR c R d , C(═NR e )R b , C(═NR e )NR c R d , NR c C(═NR e )NR c R d , NR c S(O)R b , NR c S(O) 2 R b , NR c S(O) 2 NR c R d , S(O)R b , S(O)NR c R d , S(O) 2 R b , and S(O) 2 NR c R d ;

or two adjacent R Cy substituents together with the atoms to which they are attached form a fused phenyl, C 3-7 cycloalkyl, 5-6 membered heteroaryl, or 4-7 membered heterocycloalkyl ring, each optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from halo, C 1-4 alkyl, C 1-4 haloalkyl, CN, NO 2 , OR a , SR a , C(O)R b , C(O)NR c R d , C(O)OR a , OC(O)R b , OC(O)NR c R d , NR c R d , NR c C(O)R b , NR c C(O)OR a , NR c C(O)NR c R d , C(═NR e )R b , C(═NR e )NR c R d , NR c C(═NR e )NR c R d , NR c S(O)R b , NR c S(O) 2 R b , NR c S(O) 2 NR c R d , S(O)R b , S(O)NR c R d , S(O) 2 R b , and S(O) 2 NR c R d ;

each R a , R b , R c , and R d is independently selected from H, C 1-4 alkyl, and C 1-4 haloalkyl, wherein said C 1-4 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, and C 1-4 haloalkoxy;

each R e is independently selected from H, C 1-4 alkyl, and CN;

n is 0, 1, or 2; and

m is 1 or 2.

2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 is H.

3. The compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein R 4 is H.

4. The compound of claim 3 , or a pharmaceutically acceptable salt thereof, wherein R 4a is H.

5. The compound of claim 4 , or a pharmaceutically acceptable salt thereof, wherein R 6 and R 7 are each independently selected from H and OH.

6. The compound of claim 5 , or a pharmaceutically acceptable salt thereof, wherein at least one of R 6 and R 7 is H.

7. The compound of claim 6 , or a pharmaceutically acceptable salt thereof, wherein both R 6 and R 7 are H.

8. The compound of claim 6 , or a pharmaceutically acceptable salt thereof, wherein R 6 is OH and R 7 is H.

9. The compound of claim 6 , or a pharmaceutically acceptable salt thereof, wherein Q is —CF 3 .

10. The compound of claim 6 , or a pharmaceutically acceptable salt thereof, wherein Q is -Cy.

11. The compound of claim 10 , or a pharmaceutically acceptable salt thereof, wherein Cy is selected from C 6-10 aryl and 5-6 membered heteroaryl, each optionally substituted by 1, 2, 3, 4, or 5 R Cy substituents independently selected from halo, C 1-4 alkyl, C 1-4 haloalkyl, CN, NO 2 , OR a , SR a , C(O)R b , C(O)NR c R d , C(O)OR a , OC(O)R b , OC(O)NR c R d , NR c R d , NR c C(O)R b , NR c C(O)OR a , NR c C(O)NR c R d , C(═NR e )R b , C(═NR e )NR c R d , NR c C(═NR e )NR c R d , NR c S(O)R b , NR c S(O) 2 R b , NR c S(O) 2 NR c R d , S(O)R b , S(O)NR c R d , S(O) 2 R b , and S(O) 2 NR c R d .

12. The compound of claim 11 , or a pharmaceutically acceptable salt thereof, wherein Cy is a 5-6 membered heteroaryl optionally substituted by 1, 2, 3, or 4 R Cy substituents independently selected from halo, C 1-4 alkyl, C 1-4 haloalkyl, CN, NO 2 , OR a , SR a , C(O)R b , C(O)NR c R d , C(O)OR a , OC(O)R b , OC(O)NR c R d , NR c R d , NR c C(O)R b , NR c C(O)OR a , NR c C(O)NR c R d , C(═NR e )R b , C(═NR e )NR c R d , NR c C(═NR e )NR c R d , NR c S(O)R b , NR c S(O) 2 R b , NR c S(O) 2 NR c R d , S(O)R b , S(O)NR c R d , S(O) 2 R b , and S(O) 2 NR c R d .

13. The compound of claim 12 , or a pharmaceutically acceptable salt thereof, wherein Cy is thiazoyl optionally substituted by 1 or 2 R Cy substituents independently selected from halo, C 1-4 alkyl, C 1-4 haloalkyl, CN, NO 2 , OR a , SR a , C(O)R b , C(O)NR c R d , C(O)OR a , OC(O)R b , OC(O)NR c R d , NR c R d , NR c C(O)R b , NR c C(O)OR a , NR c C(O)NR c R d , C(═NR e )R b , C(═NR e )NR c R d , NR c C(═NR e )NR c R d , NR c S(O)R b , NR c S(O) 2 R b , NR c S(O) 2 NR c R d , S(O)R b , S(O)NR c R d , S(O) 2 R b , and S(O) 2 NR c R d .

14. The compound of claim 13 , or a pharmaceutically acceptable salt thereof, wherein Cy is

15. The compound of claim 13 , or a pharmaceutically acceptable salt thereof, wherein each R Cy substituent is independently selected from halo, C 1-4 alkyl, C 1-4 haloalkyl, CN, OR a , C(O)R b , C(O)NR c R d , C(O)OR a , NR c R d , NR c C(O)R b , NR c S(O) 2 R b , S(O) 2 R b , and S(O) 2 NR c R d .

16. The compound of claim 9 , or a pharmaceutically acceptable salt thereof, wherein n is 0.

17. The compound of claim 16 , or a pharmaceutically acceptable salt thereof, wherein m is 1.

18. A compound selected from:

4-((2-(2,2,2-Trifluoroethyl)-1H-imidazol-4-yl)methyl)pyridine;

4-((2-(3,3,3-trifluoropropyl)-1H-imidazol-4-yl)methyl)pyridine;

2-(4-(Pyridin-4-ylmethyl)-1H-imidazol-2-yl)acetonitrile;

3-(4-(Pyridin-4-ylmethyl)-1H-imidazol-2-yl)propanenitrile;

rac-4-(1-(2-(2,2,2-Trifluoroethyl)-1H-imidazol-4-yl)ethyl)pyridine;

(R)-4-(1-(2-(2,2,2-Trifluoroethyl)-1H-imidazol-4-yl)ethyl)pyridine;

(S)-4-(1-(2-(2,2,2-Trifluoroethyl)-1H-imidazol-4-yl)ethyl)pyridine;

5-((4-(Pyridin-4-ylmethyl)-1H-imidazol-2-yl)methyl)thiazole;

4-((5-(2,2,2-Trifluoroethyl)-1H-1,2,4-triazol-3-yl)methyl)pyridine;

2-(Pyridin-4-ylmethyl)-4-(2,2,2-trifluoroethyl)thiazole;

4-(Pyridin-4-ylmethyl)-2-(2,2,2-trifluoroethyl)thiazole;

rac-4-(1-(5-(2,2,2-trifluoroethyl)-1H-pyrrol-2-yl)ethyl)pyridine;

(S)-2,2,2-Trifluoro-1-(5-(pyridin-4-ylmethyl)-1H-imidazol-2-yl)ethan-1-ol;

(R)-2,2,2-Trifluoro-1-(5-(pyridin-4-ylmethyl)-1H-imidazol-2-yl)ethan-1-ol;

2,2,2-Trifluoro-1-(5-(pyridin-4-ylmethyl)-1H-imidazol-2-yl)ethan-1-one;

(E/Z)-2,2,2-Trifluoro-1-(5-(pyridin-4-ylmethyl)-1H-imidazol-2-yl)ethan-1-one oxime;

4-((5-Methyl-2-(2,2,2-trifluoroethyl)-1H-imidazol-4-yl)methyl)pyridine;

(S)-2,2,2-trifluoro-1-(4-(pyridin-4-ylmethyl)-1H-imidazol-2-yl)ethan-1-amine;

(R)-2,2,2-trifluoro-1-(4-(pyridin-4-ylmethyl)-1H-imidazol-2-yl)ethan-1-amine;

(S)-2,2,2-Trifluoro-N-methyl-1-(5-(pyridin-4-ylmethyl)-1H-imidazol-2-yl)ethan-1-amine;

(R)-2,2,2-Trifluoro-N-methyl-1-(5-(pyridin-4-ylmethyl)-1H-imidazol-2-yl)ethan-1-amine;

(S)-2,2,2-Trifluoro-N,N-dimethyl-1-(5-(pyridin-4-ylmethyl)-1H-imidazol-2-yl)ethan-1-amine;

(R)-2,2,2-Trifluoro-N,N-dimethyl-1-(5-(pyridin-4-ylmethyl)-1H-imidazol-2-yl)ethan-1-amine;

(E/Z)-2, 2, 2-Trifluoro-1-(4-(pyridin-4-ylmethyl)thiazol-2-yl) ethan-1-one oxime;

(R)-2,2,2-Trifluoro-1-(5-(pyridin-4-ylmethyl)thiazol-2-yl)ethan-1-amine;

(S)-2,2,2-Trifluoro-1-(5-(pyridin-4-ylmethyl)thiazol-2-yl)ethan-1-amine;

(S)-(4-(Pyridin-4-ylmethyl)-1H-imidazol-2-yl)(thiazol-5-yl)methanol;

(R)-(4-(Pyridin-4-ylmethyl)-1H-imidazol-2-yl)(thiazol-5-yl)methanol;

(5-((3-Methylpyridin-4-yl)methyl)-1H-imidazol-2-yl)(thiazol-5-yl)methanol;

3,5-Dichloro-4-((2-(2,2,2-trifluoroethyl)-1H-imidazol-5-yl)methyl)pyridine;

1-(4-((3-Chloropyridin-4-yl)methyl)-1H-imidazol-2-yl)-2,2,2-trifluoroethan-1-ol;

(S)-2,2,2-trifluoro-1-(4-((S)-1-(pyridin-4-yl)ethyl)-1H-imidazol-2-yl)ethan-1-ol;

(R)-2,2,2-trifluoro-1-(4-((S)-1-(pyridin-4-yl)ethyl)-1H-imidazol-2-yl)ethan-1-ol;

(S)-2,2,2-trifluoro-1-(4-((R)-1-(pyridin-4-yl)ethyl)-1H-imidazol-2-yl)ethan-1-ol;

(R)-2,2,2-trifluoro-1-(4-((R)-1-(pyridin-4-yl)ethyl)-1H-imidazol-2-yl)ethan-1-ol;

3-Methyl-4-((2-(2,2,2-trifluoroethyl)-1H-imidazol-4-yl)methyl)pyridine;

(R)-2,2,2-Trifluoro-1-(4-(pyridin-4-ylmethyl)-1H-imidazol-2-yl)-1-(thiazol-5-yl)ethan-1-ol;

(S)-2,2,2-Trifluoro-1-(4-(pyridin-4-ylmethyl)-1H-imidazol-2-yl)-1-(thiazol-5-yl)ethan-1-ol;

3-Chloro-4-((2-(2,2,2-trifluoroethyl)-1H-imidazol-4-yl)methyl)pyridine;

2-Chloro-4-((2-(2,2,2-trifluoroethyl)-1H-imidazol-5-yl)methyl)pyridine;

2-Fluoro-4-((2-(2, 2, 2-trifluoroethyl)-3H-imidazol-4-yl)methyl)pyridine;

(S)-(5-((3-Methylpyridin-4-yl)methyl)-1H-imidazol-2-yl)(thiazol-5-yl)methanol;

(R)-(5-((3-Methylpyridin-4-yl)methyl)-1H-imidazol-2-yl)(thiazol-5-yl)methanol;

(R)-(5-(Pyridin-4-ylmethyl)-1H-imidazol-2-yl)(thiazol-2-yl)methanol;

(S)-(5-(Pyridin-4-ylmethyl)-1H-imidazol-2-yl)(thiazol-2-yl)methanol;

(R)-1,1,1-Trifluoro-2-(5-(pyridin-4-ylmethyl)-1H-imidazol-2-yl)propan-2-ol;

(S)-1,1,1-Trifluoro-2-(5-(pyridin-4-ylmethyl)-1H-imidazol-2-yl)propan-2-ol;

(S)-4-((2-(2,2,2-trifluoro-1-methoxyethyl)-1H-imidazol-5-yl)methyl)pyridine;

(R)-4-((2-(2,2,2-trifluoro-1-methoxyethyl)-1H-imidazol-5-yl)methyl)pyridine;

(R)-2,2,2-Trifluoro-1-(5-((2-fluoropyridin-4-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol;

(S)-2,2,2-Trifluoro-1-(5-((2-fluoropyridin-4-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol;

Pyridin-2-yl(5-(pyridin-4-ylmethyl)-1H-imidazol-2-yl)methanol;

3-Fluoro-4-((2-(2,2,2-trifluoroethyl)-1H-imidazol-4-yl)methyl)pyridine;

(S)-2,2,2-Trifluoro-1-(4-((3-methylpyridin-4-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol;

(R)-2,2,2-Trifluoro-1-(4-((3-methylpyridin-4-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol;

(S)-2,2,2-Trifluoro-1-(4-((3-fluoropyridin-4-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol;

(R)-2,2,2-Trifluoro-1-(4-((3-fluoropyridin-4-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol;

1,1,1,3,3,3-Hexafluoro-2-(4-(pyridin-4-ylmethyl)-1H-imidazol-2-yl)propan-2-ol; and

1,1,1-Trifluoro-2-(4-(pyridin-4-ylmethyl)-1H-imidazol-2-yl)propan-2-ol

or a pharmaceutically acceptable salt of any of the aforementioned.

19. A pharmaceutical composition comprising at least one pharmaceutically acceptable carrier and a compound of claim 1 , or a pharmaceutically acceptable salt thereof.

20. The compound of claim 1 that is