Granted Patent B2

US 12,421,276 · App. 17/228,481 · Granted Sep 23, 2025

Inventors: Leen H. Kawas (Seattle, WA); Jasbir Singh (Seattle, WA); Lansing Joseph Stewart (Seattle, WA); William R. Baker (Seattle, WA)

Assignee: Athira Pharma, Inc.

C07K5/06078A61K9/0019C07K5/021

Abstract

Claims (158)

1. A method for treating a neurogenerative disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of formula (I):

or a tautomer or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of the tautomer, wherein:

n is 1, 2, 3, 4, 5, 6, 7, 8, or 9;

m is 0, 1, 2, 3, or 4;

R 1 is C 1 -C 12 alkyl or C 1 -C 12 substituted alkyl;

R 2 is selected from

each Y is independently —Z—(CH 2 ) q —W—R b ;

q is 0-4;

Z and W are independently selected from CH 2 , NR c , and R b ,

or Z and W are taken together to form a C 3 -C 8 heterocycloalkyl;

each R c is independently hydrogen or C 1 -C 4 alkyl;

each R b is independently selected from hydrogen, C 1 -C 12 alkyl, C 1 -C 12 substituted alkyl, C 3 -C 8 heterocycloalkyl, and C 3 -C 8 substituted heterocycloalkyl;

r is 0-5;

U is heterocycloalkyl;

R 3 and R 4 are independently hydrogen or C 1 -C 12 alkyl,

or R 3 and R 4 are taken together to form a spirocyclic ring system;

R 5 is hydrogen; and

each R 6 is independently selected from hydrogen, deuterium, CH 3 , F, 19 F, and 18 F;

wherein each heterocyclic ring contains up to four heteroatoms selected from O, N, and S;

with the proviso that when both Z and W are heteroatoms, the value of q cannot be 1.

2. The method of claim 1 , wherein:

n is 5;

m is 0;

R 1 is C 1 -C 12 alkyl;

R 2 is selected from

each Y is independently —Z—(CH 2 ) q —W—R b ;

q is 0, 1, or 2;

Z and W are independently selected from CH 2 , NR c , and R b ,

or Z and W are taken together to form a C 3 -C 8 heterocycloalkyl;

each R c is independently hydrogen or C 1 -C 4 alkyl;

each R b is independently selected from hydrogen, C 1 -C 12 alkyl, C 1 -C 12 substituted alkyl, C 3 -C 8 heterocycloalkyl, and C 3 -C 8 substituted heterocycloalkyl;

r is 1;

U is heterocycloalkyl;

R 3 and R 4 are each hydrogen,

or R 3 and R 4 are taken together to form a spirocyclic ring system; and

R 5 is hydrogen;

wherein each heterocyclic ring contains up to four heteroatoms selected from O and N; and

with the proviso that when both Z and W are heteroatoms, the value of q cannot be 1.

3. The method of claim 2 , wherein R 1 is C 5 alkyl.

4. The method of claim 2 , wherein R 2 is

5. The method of claim 4 , wherein the compound is a pharmaceutically acceptable salt.

6. The method of claim 2 , wherein R 2 is

7. The method of claim 2 , wherein R 2 is —C(═O)—Y.

8. The method of claim 2 , wherein R 2 is —C(═O)—(CH 2 ) r U.

9. The method of claim 2 , wherein R 3 and R 4 are each hydrogen.

10. The method of claim 2 , wherein R 3 and R 4 are taken together to form a spirocyclic ring system.

11. The method of claim 2 , wherein the compound is a pharmaceutically acceptable salt.

12. The method of claim 1 , wherein R 1 is C 1 -C 12 alkyl.

13. The method of claim 1 , wherein R 1 is C 1 -C 12 alkyl optionally substituted with 1-5 substituents independently selected from alkoxy, cyano, halo, and hydroxy.

14. The method of claim 1 , wherein:

R 1 is C 1 -C 12 alkyl optionally substituted with 1-5 substituents independently selected from alkoxy, cyano, halo, and hydroxy;

each R b is independently selected from hydrogen; C 1 -C 12 alkyl optionally substituted with 1-5 substituents independently selected from alkoxy, cyano, halo, and hydroxy; and C 3 -C 8 heterocycloalkyl optionally substituted with 1-5 substituents selected from C 1 -C 6 alkyl, alkoxy, cyano, halo, hydroxy, and oxo.

15. The method of claim 1 , wherein the neurodegenerative disease is Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, spinal cord injury, traumatic brain injury, sensorineural hearing, or vision loss.

16. The method of claim 15 , wherein the neurodegenerative disease is Alzheimer's disease.

17. The method of claim 15 , wherein the neurodegenerative disease is Parkinson's disease.

18. A method for treating a neurogenerative disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of formula (II):

or a tautomer or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of the tautomer, wherein:

n is 3, 4, 5, 6, 7, 8, or 9;

m is 0, 1, 2, 3, or 4;

R 1 is selected from C 1 -C 12 alkyl, C 1 -C 12 substituted alkyl, C 2 -C 12 alkenyl, C 2 -C 12 substituted alkenyl, C 2 -C 12 alkynyl, and C 2 -C 12 substituted alkynyl;

R 2 is selected from hydrogen,

each Y is independently —Z—(CH 2 ) q —W—R b ,

or —C(═O)—Y forms an amide bond through a nitrogen atom on Y, and Y is selected from glycine, sarcosine, N,N-dimethylglycine, alanine, valine, leucine, isoleucine, lysine, ornithine, arginine, serine, and threonine;

q is 0-4;

each Z and W is independently selected from CH 2 , O, S, NR c , and R b ,

or Z and W are taken together to form a C 3 -C 8 heterocycloalkyl or C 4 -C 10 heteroaryl or bicyclic ring system in which one of the rings is a C 4 -C 10 heteroaryl;

each R c is independently selected from hydrogen, C 1 -C 4 alkyl, and C 3 -C 6 cycloalkyl;

each R b is independently selected from hydrogen, C 1 -C 12 alkyl, C 1 -C 12 substituted alkyl, C 3 -C 8 cycloalkyl, C 3 -C 8 substituted cycloalkyl, C 3 -C 8 heterocycloalkyl, and C 3 -C 8 substituted heterocycloalkyl;

U is selected from pyridine, 1,4-dihydropyridine, N-alkyl-1,4-dihydropyridine, and C-imidazole, or U is aryl, heteroaryl or heterocycloalkyl;

R 3 and R 4 are independently selected from hydrogen, C 1 -C 12 alkyl, C 1 -C 12 substituted alkyl, C 2 -C 12 alkenyl, C 2 -C 12 substituted alkenyl, C 2 -C 12 alkynyl, and C 2 -C 12 substituted alkynyl,

or R 3 and R 4 are taken together to form a fused bicyclic ring system or a spirocyclic ring system; and

each R 6 is independently selected from hydrogen, deuterium, CH 3 , F, 19 F, and 18 F;

wherein each heterocyclic and heteroaryl ring contains up to four heteroatoms selected from O, N, and S;

with the proviso that when both Z and W are heteroatoms, the value of q cannot be 1;

and with the proviso that when R 2 is hydrogen, at least one of the R 3 or R 4 groups is not hydrogen.

19. The method of claim 18 , wherein:

R 1 is selected from C 1 -C 12 alkyl optionally substituted with 1-5 substituents independently selected from alkoxy, cyano, halo, and hydroxy; C 2 -C 12 alkenyl optionally substituted with 1-5 substituents independently selected from alkoxy, cyano, halo, and hydroxy; and C 2 -C 12 alkynyl optionally substituted with 1-5 substituents independently selected from alkoxy, cyano, halo, and hydroxy;

each R b is independently selected from hydrogen; C 1 -C 12 alkyl optionally substituted with 1-5 substituents independently selected from alkoxy, cyano, halo, and hydroxy; C 3 -C 8 cycloalkyl optionally substituted with 1-5 substituents selected from C 1 -C 6 alkyl, alkoxy, cyano, halo, hydroxy, and oxo; and C 3 -C 8 heterocycloalkyl optionally substituted with 1-5 substituents selected from C 1 -C 6 alkyl, alkoxy, cyano, halo, hydroxy, and oxo; and

R 3 and R 4 are independently selected from hydrogen; C 1 -C 12 alkyl optionally substituted with 1-5 substituents independently selected from alkoxy, cyano, halo, and hydroxy; C 2 -C 12 alkenyl optionally substituted with 1-5 substituents independently selected from alkoxy, cyano, halo, and hydroxy; and C 2 -C 12 alkynyl optionally substituted with 1-5 substituents independently selected from alkoxy, cyano, halo, and hydroxy.

20. The method of claim 18 , wherein the compound is of formula (III):

or a tautomer or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of the tautomer, wherein:

R 1 is a C 1 -C 12 alkyl or C 1 -C 12 substituted alkyl;

R 2 is selected from hydrogen,

each Y is independently —Z—(CH 2 ) q —W—R b ;

q is 0-4;

Z and W are independently selected from CH 2 , O, S, NR c , and R b ,

or Z and W are taken together to form a C 3 -C 8 heterocycloalkyl or C 4 -C 10 heteroaryl or bicyclic ring system in which one of the rings is a C 4 -C 10 heteroaryl;

each R c is independently selected from hydrogen, C 1 -C 4 alkyl, and C 3 -C 6 cycloalkyl;

each R b is independently selected from hydrogen, C 1 -C 12 alkyl, C 1 -C 12 substituted alkyl, C 3 -C 8 cycloalkyl, C 3 -C 8 substituted cycloalkyl, C 3 -C 8 heterocycloalkyl, and C 3 -C 8 substituted heterocycloalkyl; and

R 3 and R 4 are independently selected from hydrogen, C 1 -C 12 alkyl, C 1 -C 12 substituted alkyl, C 2 -C 12 alkenyl, C 2 -C 12 substituted alkenyl, C 2 -C 12 alkynyl, and C 2 -C 12 substituted alkynyl,

or R 3 and R 4 are taken together to form a fused bicyclic ring system or a spirocyclic ring system, wherein the fused ring is C 3 -C 8 heterocycloalkyl, C 6 -C 10 aryl, or C 4 -C 10 heteroaryl;

wherein each heterocyclic and heteroaryl ring contains up to four heteroatoms selected from O, N, and S;

with the proviso that when both Z and W are heteroatoms, the value of q cannot be 1;

and with the proviso that when R 2 is hydrogen, at least one of the R 3 or R 4 groups is not hydrogen.

21. The method of claim 20 , wherein:

R 1 is a C 1 -C 12 alkyl;

R 2 is —C(═O)—Y; and

R 3 and R 4 are each hydrogen.

22. The method of claim 20 , wherein:

R 1 is a C 1 -C 12 alkyl;

R 2 is —C(═O)—CH(NH 2 ) i Pr; and

R 3 and R 4 are each hydrogen.

23. The method of claim 20 , wherein:

R 1 is a C 1 -C 12 alkyl;

R 2 is —C(═O)—CH(NH 2 ) i Pr;

R 3 and R 4 are each hydrogen;

m is 1 or 2; and

R 6 is F.

24. The method of claim 20 , wherein:

R 1 is a C 1 -C 12 alkyl;

R 2 is

and

R 3 and R 4 are each hydrogen.

25. The method of claim 18 , wherein:

m is 0;

R 1 is a C 1 -C 12 alkyl; and

R 3 and R 4 are taken together to form a spirocyclic ring system.

26. The method of claim 18 , wherein:

m is 1 or 2;

R 1 is a C 1 -C 12 alkyl;

R 3 and R 4 are taken together to form a spirocyclic ring system; and

R 6 is selected from hydrogen, deuterium, F, 19 F, and 18 F.

27. The method of claim 18 , wherein the neurodegenerative disease is Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, spinal cord injury, traumatic brain injury, sensorineural hearing, or vision loss.

28. The method of claim 27 , wherein the neurodegenerative disease is Alzheimer's disease.

29. The method of claim 27 , wherein the neurodegenerative disease is Parkinson's disease.

30. A method for treating a neurogenerative disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound selected from:

or a tautomer or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of the tautomer.

31. The method of claim 30 , wherein the compound is:

or a pharmaceutically acceptable salt thereof.

32. The method of claim 31 , wherein the neurodegenerative disease is Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, spinal cord injury, traumatic brain injury, sensorineural hearing, or vision loss.

33. The method of claim 32 , wherein the neurodegenerative disease is Alzheimer's disease.

34. The method of claim 32 , wherein the neurodegenerative disease is Parkinson's disease.

35. The method of claim 30 , wherein the compound is:

or a pharmaceutically acceptable salt thereof.

36. The method of claim 35 , wherein the neurodegenerative disease is Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, spinal cord injury, traumatic brain injury, sensorineural hearing, or vision loss.

37. The method of claim 36 , wherein the neurodegenerative disease is Alzheimer's disease.

38. The method of claim 36 , wherein the neurodegenerative disease is Parkinson's disease.

39. The method of claim 30 , wherein the compound is:

or a pharmaceutically acceptable salt thereof.

40. The method of claim 39 , wherein the neurodegenerative disease is Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, spinal cord injury, traumatic brain injury, sensorineural hearing, or vision loss.

41. The method of claim 40 , wherein the neurodegenerative disease is Alzheimer's disease.

42. The method of claim 40 , wherein the neurodegenerative disease is Parkinson's disease.

43. The method of claim 30 , wherein the compound is:

or a pharmaceutically acceptable salt thereof.

44. The method of claim 43 , wherein the compound is:

45. The method of claim 44 , wherein the neurodegenerative disease is Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, spinal cord injury, traumatic brain injury, sensorineural hearing, or vision loss.

46. The method of claim 45 , wherein the neurodegenerative disease is Alzheimer's disease.

47. The method of claim 45 , wherein the neurodegenerative disease is Parkinson's disease.

48. The method of claim 43 , wherein the neurodegenerative disease is Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, spinal cord injury, traumatic brain injury, sensorineural hearing, or vision loss.

49. The method of claim 48 , wherein the neurodegenerative disease is Alzheimer's disease.

50. The method of claim 48 , wherein the neurodegenerative disease is Parkinson's disease.

51. The method of claim 43 , wherein the compound is:

52. The method of claim 51 , wherein the neurodegenerative disease is Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, spinal cord injury, traumatic brain injury, sensorineural hearing, or vision loss.

53. The method of claim 52 , wherein the neurodegenerative disease is Alzheimer's disease.

54. The method of claim 52 , wherein the neurodegenerative disease is Parkinson's disease.

55. The method of claim 30 , wherein the neurodegenerative disease is Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, spinal cord injury, traumatic brain injury, sensorineural hearing, or vision loss.

56. The method of claim 55 , wherein the neurodegenerative disease is Alzheimer's disease.

57. The method of claim 55 , wherein the neurodegenerative disease is Parkinson's disease.

Assignments (3)

Continuity (3)

References Cited (400)