PROTEASOME ENHANCERS AND USES THEREOF

Abstract

Described herein are compounds astemizole derivatives, methods for making such compounds, and the use of such compounds in the treatment of cancer, an inflammatory disease or condition or neurodegenerative diseases, such as Parkinson’s disease, Alzheimer’s disease, Huntington’s disease, and ALS.

Description

Claims

1. A compound of the formula (I): or a pharmaceutically acceptable salt, polymorph, prodrug, solvate or clathrate thereof, wherein:R1 is aryl or heteroaryl;R2 is H, alkyl, aryl or heteroaryl;X1 is alkyl or alkenyl;X2 is N or CR3, wherein R3 is absent, hydrogen, alkyl, heterocyclyl, or aryl;R4 is hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl; andR5 is hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl.

2. (canceled)

3. (canceled)

4. (canceled)

5. (canceled)

6. (canceled)

7. (canceled)

8. (canceled)

9. (canceled)

10. The compound of claim 1, wherein the compound of formula (I) is; a compound of the formula (Ia): or a pharmaceutically acceptable salt, polymorph, prodrug, solvate or clathrate thereof; wherein:R6 is aryl or heteroaryl; or. a compound of the formula (Ib) or (Ic): or a pharmaceutically acceptable salt, polymorph, prodrug, solvate or clathrate thereof, wherein: n is 0, 1 or 2.

11. (canceled)

12. The compound of claim 1, wherein the compound of formula (I) is a compound of the formula: pharmaceutically acceptable salts, polymorphs, prodrugs, solvates or clathrates thereof.

13. A compound of the formula: or a pharmaceutically acceptable salt, polymorph, prodrug, solvate or clathrate thereof, wherein:R1 is aryl or heteroaryl;R2 is H, alkyl, aryl or heteroaryl;X1 is alkyl or alkenyl;X2 is N or CR3, wherein R3 is absent, hydrogen, alkyl, heterocyclyl, or aryl; andR6 is aryl or heteroaryl.

14. (canceled)

15. A compound of the formula (II) and (IIa)-(IId): or a pharmaceutically acceptable salt, polymorph, prodrug, solvate or clathrate thereof, wherein:q is 0, 1, 2 or 3;each X1 is independently alkyl or alkenyl;R8 and R9 are each independently alkyl, cycloalkyl aryl, heteroaryl, acyl, amide or carbamate; andW is N or C-R10; X is N or C-R10; Y is N or C-R10; and Z is N or C-R10; wherein each R10 is independently H, halo, alkyl, haloalkyl, alkoxy or heterocyclyl; ortwo R10 groups on adjacent carbon atoms, together with those carbon atoms, can form a cycloalkenyl, aryl or heterocyclyl; orR9 and an R10, together with the atoms to which they are attached, can form a heterocylyl group.

16. (canceled)

17. (canceled)

18. (canceled)

19. (canceled)

20. (canceled)

21. The compound of claim 15, wherein the compound is a compound of the formula: or a pharmaceutically acceptable salt, polymorph, prodrug, solvate or clathrate thereof.

22. A compound of the formula (III): or a pharmaceutically acceptable salt, polymorph, prodrug, solvate or clathrate thereof, wherein:q is 0, 1, 2 or 3;X1 is alkyl or alkenyl;W is N or C-R10; X is N or C-R10; Y is N or C-R10; and Z is N or C-R10; wherein each R10 is independently H, halo, alkyl, haloalkyl, alkoxy or heterocyclyl; ortwo R10 groups on adjacent carbon atoms, together with those carbon atoms, can form a cycloalkenyl, aryl or heterocyclyl; orR9 and an R10, together with the atoms to which they are attached, can form a heterocylyl group; andR12 and R13 are each independently alkyl, cycloalkyl aryl, heteroaryl, acyl, amide or carbamate.

23. The compound of claim 22, wherein X1 is -(CH2)n-, wherein n is 0, 1, or 2.

24. The compound of claim 22, wherein R10 is alkoxy of the formula -OR11, wherein R11 is alkyl, cycloalkyl or aryl, heteroaryl, acyl, amide or carbamate.

25. The compound of claim 22, wherein the compound is a compound of the formula: or a pharmaceutically acceptable salt, polymorph, prodrug, solvate or clathrate thereof.

26. The compound of claim 22, wherein the compound is a compound wherein R9 and R10 or R9 and R13 together with the atoms to which they are attached, form a heterocylyl group: or a pharmaceutically acceptable salt, polymorph, prodrug, solvate or clathrate thereof.

27. The compound of claim 22, wherein the compound is a compound of the formula: or a pharmaceutically acceptable salt, polymorph, prodrug, solvate or clathrate thereof.

28. A compound of the formula (IV): or a pharmaceutically acceptable salt, polymorph, prodrug, solvate or clathrate thereof, wherein:q is 0, 1, 2 or 3;X1 is alkyl or alkenyl;W is N or C-R10; X is N or C-R10; Y is N or C-R10; and Z is N or C-R10; wherein each R10 is independently H, halo, alkyl, haloalkyl, alkoxy or heterocyclyl; ortwo R10 groups on adjacent carbon atoms, together with those carbon atoms, can form a cycloalkenyl, aryl or heterocyclyl; orR9 and an R10, together with the atoms to which they are attached, can form a heterocylyl group; andR14 is aryl or heterocyclyl; orR9 and R14, together with the atoms to which they are attached, can form an aryl or a hetorcyclyl.

29. (canceled)

30. (canceled)

31. The compound of claim 28, wherein the compound is a compound of the formula: or a pharmaceutically acceptable salt, polymorph, prodrug, solvate or clathrate thereof.

32. The compound of claim 28, wherein the compound is a compound wherein R9 and R10 or R9 and R14, together with the atoms to which they are attached, form a heterocylyl group: or a pharmaceutically acceptable salt, polymorph, prodrug, solvate or clathrate thereof.

33. A compound of the formula (V): or a pharmaceutically acceptable salt, polymorph, prodrug, solvate or clathrate thereof, wherein:q is 0, 1, 2 or 3;X1 is alkyl or alkenyl;Z1 is absent, N or C-R10;each W is N or C-R10; each X is N or C-R10; each Y is N or C-R10; and each Z is N or C-R10;wherein each R10 is independently H, halo, alkyl, haloalkyl, alkoxy or heterocyclyl; andtwo R10 groups on adjacent carbon atoms, together with those carbon atoms, can form a cycloalkenyl, aryl or heterocyclyl; orR9 and an R10, together with the atoms to which they are attached, can form a heterocylyl group.

34. (canceled)

35. (canceled)

36. The compound of claim 33, wherein the compound is a compound of the formula or a pharmaceutically acceptable salt, polymorph, prodrug, solvate or clathrate thereof.

37. (canceled)

38. The compound of claim 33, wherein the compound is a compound of the formula: or a pharmaceutically acceptable salt, polymorph, prodrug, solvate or clathrate thereof.

39. (canceled)

40. A pharmaceutical composition comprising at least one of astemizole and one or more compounds of claim 1 and one or more pharmaceutically acceptable excipients.

41. A method for (i) treating a neurodegenerative disease; (ii) reducing, substantially eliminating or eliminating dysregulation of proteostasis; or reducing, or (iii) substantially eliminating or eliminating accumulation of intrinsically disordered proteins comprising administering a therapeutically effective amount of at least one of astemizole and at least one compound of claim 1 to a subject in need thereof.

42. (canceled)

43. (canceled)

44. (canceled)

45. (canceled)

46. (canceled)

47. (canceled)

48. (canceled)

49. (canceled)

50. (canceled)