IP Library › Granted Patent US 11,945,796

Granted Patent B2

US 11,945,796 · App. 17/475,896 · Granted Apr 2, 2024

Substituted pyridine derivatives as SARM1 inhibitors

Inventors: Sean Pomeroy Brown (Half Moon Bay, CA); Keira Garland (San Francisco, CA); Shilpa Sambashivan (Los Altos, CA); Christopher Michael Tegley (Daly City, CA); Liusheng Zhu (Foster City, CA)

Assignee: NURA BIO, INC.

C07D401/14 A61K45/06 C07D401/06 C07D405/14 C07D409/14 C07D417/14 C07B2200/05

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Quick Facts

Patent No.: US 11,945,796
App. No.: 17/475,896
Granted: Apr 2, 2024
Kind: B2

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Abstract

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 neurological diseases.

Claims (143)

1. A compound of Formula Ib:

or a pharmaceutically acceptable salt thereof, wherein:

X 2 is —(CR 6 R 7 ) m or —(CR 6 R 7 ) p —C(═O)—(CR 6 R 7 ) q —;

A is halo, CN, Cy, or C 1-3 haloalkyl;

R 1 , R 2 , R 3 , R 4 , and R 5 are each independently selected from H, D, halo, CH 3 , CH 2 CH 3 , CD 3 , CH 2 CD 3 , and CD 2 CD 3 ;

R 6 and R 7 are each independently selected from H, D, halo, methyl, ethyl, and C 1-3 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 , NRCS(O)R b , NRCS(O) 2 R b , NRCS(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 , NRcS(O)R b , NRcS(O) 2 R b , NRCS(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;

m is 1, 2, or 3;

n is 0, 1, or 2;

p is 0, 1, or 2; and

q is 0, 1, or 2.

2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein X 2 is —(CR 6 R 7 ) m —.

3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein X 2 is CH 2 .

4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein A is halo, CN, or C 1-3 haloalkyl.

5. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein A is F, CN, CHF 2 , or CF 3 .

6. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein one of R 1 and R 2 is H and the other of R 1 and R 2 is H, D, halo, CH 3 , CH 2 CH 3 , or CD 3 .

7. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein one of R 1 and R 2 is H and the other of R 1 and R 2 is H, CH 3 , CH 2 CH 3 , or CD 3 .

8. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3 and R 4 are each independently selected from H, halo, and CH 3 .

9. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3 and R 4 are each independently selected from H and halo.

10. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3 and R 4 are each independently selected from H and F.

11. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3 and R 4 are both H.

12. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein each R 5 is independently selected from H, halo, and CH 3 .

13. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein each R 5 is independently selected from H and CH 3 .

14. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 6 and R 7 are each independently selected from H, halo, and methyl.

15. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 6 and R 7 are each independently selected from H and methyl.

16. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 6 and R 7 are both H.

17. The compound of claim 1 , or pharmaceutically acceptable salt thereof, wherein Cy is C 3-7 cycloalkyl.

18. The compound of claim 1 , or pharmaceutically acceptable salt thereof, wherein Cy is 4-7 membered heterocycloalkyl substituted by 2 R C y substituents that together with the atoms to which they are attached form a fused phenyl.

19. The compound of claim 1 , 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, NO2, 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 , NRCS(O)R b , NRCS(O) 2 R b , NRCS(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 , NRCS(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 .

20. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Cy is selected from phenyl and 5-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 , NRCC(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 , NRCS(O)R b , NRCS(O) 2 R b , NRCS(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 .

21. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein n is 0 or 1.

22. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein n is 0.

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

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

25. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein p is 0 or 1 and q is 0 or 1.

26. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein one of p and q is 1 and the other is 0.

27. A compound of claim 1 , which is selected from:

2-(3-(Pyridin-4-ylmethyl)-1H-pyrazol-1-yl)acetonitrile;

4-((1-(2,2-Difluoroethyl)-1H-pyrazol-3-yl)methyl)pyridine;

(rac)-2-(3-(1-(Pyridin-4-yl)ethyl)-1H-pyrazol-1-yl)acetonitrile;

(R)-2-(3-(1-(Pyridin-4-yl)ethyl)-1H-pyrazol-1-yl)acetonitrile;

(S)-2-(3-(1-(Pyridin-4-yl)ethyl)-1H-pyrazol-1-yl)acetonitrile;

(S)-4-(1-(1-(2,2,2-Trifluoroethyl)-1H-pyrazol-3-yl)ethyl)pyridine;

(R)-4-(1-(1-(2,2,2-Trifluoroethyl)-1H-pyrazol-3-yl)ethyl)pyridine;

(rac)-4-(1-(1-(2,2-Difluoroethyl)-1H-pyrazol-3-yl)ethyl)pyridine;

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

(rac)-4-(1-(1-(2,2,2-Trifluoroethyl)-1H-pyrazol-3-yl)ethyl-2,2,2-d 3 )pyridine;

(rac)-4-(1-(4-Fluoro-1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl)ethyl)pyridine;

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

(rac)-4-(1-(1-(2,2,2-Trifluoroethyl)-1H-pyrazol-3-yl)ethyl)pyridine;

(rac)-4-(1-(1-(2,2-Difluoroethyl)-1H-pyrazol-3-yl)ethyl-2,2,2-d 3 )pyridine;

(rac)-4-(1-(1-(2,2,2-Trifluoroethyl)-1H-pyrazol-3-yl)propyl)pyridine;

(R)-3-Fluoro-4-(1-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl)ethyl)pyridine;

(S)-3-Fluoro-4-(1-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl)ethyl)pyridine;

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

(rac)-4-(1-(1-(2,2,2-Trifluoroethyl)-1H-pyrazol-3-yl)ethyl-1,2,2,2-d 4 )pyridine;

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

(rac)-4-(1-(1-(2,2,2-Trifluoroethyl)-1H-pyrazol-3-yl)ethyl-1-d)pyridine;

4-((5-Methyl-1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl)methyl)pyridine;

(rac)-4-(1-(1-Benzyl-1H-pyrazol-3-yl)ethyl)pyridine;

(R)-4-(1-(1-(2,2-Difluoroethyl)-1H-pyrazol-3-yl)ethyl)pyridine;

(S)-4-(1-(1-(2,2-Difluoroethyl)-1H-pyrazol-3-yl)ethyl)pyridine;

(rac)-3-Chloro-4-(1-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl)ethyl)pyridine;

(R)-3-Chloro-4-(1-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl)ethyl)pyridine;

(S)-3-Chloro-4-(1-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl)ethyl)pyridine;

(R)-4-(1-(1-(2,2-Difluoroethyl)-1H-pyrazol-3-yl)ethyl-2,2,2-d 3 )pyridine; and

(S)-4-(1-(1-(2,2-Difluoroethyl)-1H-pyrazol-3-yl)ethyl-2,2,2-d 3 )pyridine, or a pharmaceutically acceptable salt of any of the aforementioned.

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

29. A method of inhibiting SARM1 comprising contacting the SARM1 with a compound of claim 1 , or a pharmaceutically acceptable salt thereof.

30. The method of claim 29 wherein the contacting is carried out in vitro.

31. The method of claim 29 wherein the contacting is carried out in vivo.

32. A method of inhibiting axonal degeneration in a patient in need thereof comprising administering to the patient an inhibiting amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof.

33. The method of claim 32 wherein the axonal degeneration is caused by abnormal reduction or depletion of NAD+ in the axons.

34. A method of treating a disease associated with abnormal expression or activity of SARM1 in a patient in need thereof comprising administering to the patient a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof.

35. The compound of claim 1 that is