Proteasome activity enhancing compounds

1. A compound having a structure of Formula (II), or a pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof:

wherein:

Q 1 is C(R a ) or nitrogen;

Q 2 is selected from the group consisting of C(R 3 ) and N;

Q 6 and Q 7 are each CH;

R 1 , R 2 , R 3b , R 3e , R 3g , and R g are each independently selected from the group consisting of hydrogen and optionally substituted C 1 -C 10 alkyl;

R 3 is independently selected from the group consisting of hydrogen, optionally substituted C 1 -C 10 alkyl, optionally substituted C 2 -C 10 alkenyl, optionally substituted C 2 -C 10 alkynyl, optionally substituted C 3 -C 12 cycloalkyl, optionally substituted C 3 -C 12 cycloalkenyl, optionally substituted aryl, halo, OR c , N 3 , NR d R d , C(O)OR c , NO 2 , CN, C(O)R c , C(O)C(O)R c , C(O)NR d R d , NR d C(O)R c , NR d S(O) n R c , N(R d )(COOR c ), NR d C(O)C(O)R c , NR d C(O)NR d R d , NR d S(O) n NR d R d , NR d S(O) n R c , S(O) n R c , S(O) n NR d R d , OC(O)OR c , (C═NR d )R c , OC(O)R c , optionally substituted heterocyclic and optionally substituted heteroaryl;

R 3c is selected from the group consisting of hydrogen, optionally substituted C 1 -C 10 alkyl, optionally substituted C 2 -C 10 alkenyl, optionally substituted C 2 -C 10 alkynyl, optionally substituted C 3 -C 12 cycloalkyl, optionally substituted C 3 -C 12 cycloalkenyl, optionally substituted aryl, halo, N 3 , OR c , NR d R d , C(O)OR c , NO 2 , CN, C(O)R c , C(O)C(O)R c , C(O)NR d R d , NR d C(O)R c , NR d S(O) n R c , N(R d )(COOR c ), NR d C(O)C(O)R c , NR d C(O)NR d R d , NR d S(O) n NR d R d , NR d S(O) n R c , S(O) n R c , S(O) n NR d R d , OC(O)OR c , (C═NR d )R c , OC(O)R c , optionally substituted heterocyclic, and optionally substituted heteroaryl;

R 3f is halo or CN;

Z is selected from the group consisting of NR b R b , optionally substituted aryl, optionally substituted heterocyclic, optionally substituted heteroaryl, optionally substituted C 3 -C 12 cycloalkyl, optionally substituted C 3 -C 12 cycloalkenyl, and OR c ;

each R a is independently selected from the group consisting of hydrogen, optionally substituted C 1 -C 10 alkyl, optionally substituted C 2 -C 10 alkenyl, optionally substituted C 2 -C 10 alkynyl, optionally substituted C 3 -C 12 cycloalkyl, optionally substituted C 3 -C 12 cycloalkenyl, optionally substituted aryl, halo, N 3 , OR c , NR d R d , C(O)OR C , NO 2 , CN, C(O)R c , C(O)C(O)R C , C(O)NR d R d , NR d C(O)R C , NR d S(O) n R c , N(R d )(COOR c ), NR d C(O)C(O)R c , NR d C(O)NR d R d , NR d S(O) n NR d R d , NR d S(O) n R c , S(O) n R c , S(O) n NR d R d , OC(O)OR c , (C═NR d )R c , OC(O)R c , optionally substituted heterocyclic, and optionally substituted heteroaryl;

each R b is independently selected from the group consisting of hydrogen, optionally substituted C 1 -C 10 alkyl, optionally substituted C 2 -C 10 alkenyl, optionally substituted C 2 -C 10 alkynyl, optionally substituted C 1 -C 10 alkoxy, optionally substituted C 3 -C 12 cycloalkyl, optionally substituted C 3 -C 12 cycloalkenyl, optionally substituted heterocyclic, optionally substituted aryl, and optionally substituted heteroaryl;

each R c is independently selected from the group consisting of hydrogen, optionally substituted C 1 -C 10 alkyl, optionally substituted C 2 -C 10 alkenyl, optionally substituted C 2 -C 10 alkynyl, optionally substituted C 3 -C 12 cycloalkyl, optionally substituted C 3 -C 12 cycloalkenyl, optionally substituted heterocyclic, optionally substituted aryl, and optionally substituted heteroaryl;

each R d is independently selected from the group consisting of hydrogen, optionally substituted C 1 -C 10 alkyl, optionally substituted C 2 -C 10 alkenyl, optionally substituted C 2 -C 10 alkynyl, optionally substituted C 1 -C 10 alkoxy, optionally substituted C 3 -C 12 cycloalkyl, optionally substituted C 3 -C 12 cycloalkenyl, optionally substituted heterocyclic, optionally substituted aryl, and optionally substituted heteroaryl; or two geminal R d groups are taken together with the nitrogen atom to which they are attached to form an optionally substituted heterocyclic or an optionally substituted heteroaryl;

each R e is independently selected from the group consisting of hydrogen, optionally substituted C 1 -C 10 alkyl, optionally substituted C 2 -C 10 alkenyl, optionally substituted C 2 -C 10 alkynyl, optionally substituted C 3 -C 12 cycloalkyl, optionally substituted C 3 -C 12 cycloalkenyl, optionally substituted heterocyclic, optionally substituted aryl and optionally substituted heteroaryl; and

each n is independently 0, 1 or 2.

2. The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein Q 1 is C(R a ) and R a is selected from the group consisting of hydrogen and optionally substituted C 1 -C 10 alkyl.

3. The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein Q 1 is C(R a ) and R a is selected from the group consisting of hydrogen and methyl.

4. The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein Q 2 is CH.

5. The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein Q 2 is N.

6. The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein R 1 , R 2 , R 3b , R 3e , R 3g , and R g are each hydrogen.

7. The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein R 3c is optionally substituted C 1 -C 10 alkyl.

8. The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein R 3c is methyl.

9. The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein R 3c is C 1 -C 10 alkyl substituted with C(O)OR c or OC(O)R c .

10. The compound of claim 9 , or a pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein R c is hydrogen or C 1 -C 10 alkyl.

11. The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein R 3c is C 1 -C 10 alkyl substituted with C(O)NR d R d .

12. The compound of claim 11 , or a pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein each R d is independently hydrogen or C 1 -C 10 alkyl.

13. The compound of claim 11 , or a pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein two geminal R d groups are taken together with the nitrogen atom to which they are attached to form an optionally substituted heterocyclic.

14. The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein R 3f is halo.

15. The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein R 3f is CN.

16. The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein Z is selected from the group consisting of heterocycloalkyl, heterocycloalkenyl, heterobicycloalkyl, heterobicycloalkenyl, heteropolycycloalkyl, and heteropolycycloalkenyl.

17. The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein Z is N-heterocyclic.

18. The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein Z is selected from the group consisting of optionally substituted pyrrolidin-1-yl, optionally substituted piperidin-1-yl, optionally substituted piperazin-1-yl, and optionally substituted morpholin-1-yl.

19. The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein Z is optionally substituted piperazin-1-yl.

20. The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein:

Z is

wherein:

G is absent, C(R n ), O, or S; and

each R m and R n are each independently selected from the group consisting of hydrogen, optionally substituted C 1 -C 10 alkyl, optionally substituted C 2 -C 10 alkenyl, optionally substituted C 2 -C 10 alkynyl, optionally substituted C 3 -C 12 cycloalkyl, optionally substituted C 3 -C 12 cycloalkenyl, optionally substituted aryl, halo, N 3 , OR c , NR d R d , C(O)OR c , NO 2 , CN, C(O)R c , C(O)C(O)R c , C(O)NR d R d , NR d C(O)R c , NR d S(O) n R c , N(R d )(COOR c ), NR d C(O)C(O)R c , NR d C(O)NR d R d , NR d S(O) n NR d R d , NR d S(O) n R c , S(O) n R c , S(O) n NR d R d , OC(O)OR c , (C═NR d )R c , OC(O)R c , optionally substituted heterocyclic, and optionally substituted heteroaryl.

21. The compound of claim 20 , or a pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein:

each R m is hydrogen;

G is C(R n );

R a is OR c ; and

R e is methyl.

22. The compound of claim 20 , or a pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein:

each R m is hydrogen; and

G is O.

23. The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein:

Q 1 is C—CH 3 ;

Q 2 is N or CH;

R 1 , R 2 , R 3b , R 3e , R 3g , and R g are each hydrogen;

R 3c is methyl, optionally substituted with C(O)NR d R d ;

R 3f is CN; and

Z is selected from the group consisting of optionally substituted piperidin-1-yl, optionally substituted piperazin-1-yl, and optionally substituted morpholin-1-yl.

24. The compound of claim 23 , or a pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein Q 2 is N.

25. The compound of claim 23 , or a pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein Q 2 is CH.

26. The compound of claim 23 , or a pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein R 3 , is methyl.

27. The compound of claim 23 , or a pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein R 3 , is methyl substituted with C(O)NR d R d and one R d is hydrogen and the other R d is methyl.

28. The compound of claim 23 , or a pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein R 3c is methyl substituted with C(O)NR d R d and two geminal R d groups are taken together with the nitrogen atom to which they are attached to form an optionally substituted heterocyclic.

29. The compound of claim 23 , or a pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein Z is

and further wherein:

each R m is hydrogen; and

G is O.

30. The compound of claim 23 , or a pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein Z is

and further wherein:

each R m is hydrogen;

G is C( Rn ) 2 ;

each R n is independently hydrogen or O Rc ; and

R, is selected from the group consisting of hydrogen and optionally substituted C 1 -C 10 alkyl.

31. A compound, or a pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein the compound is selected from the group consisting of:

32. A pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient and a compound of claim 1 , or a pharmaceutically acceptable salt, solvate, clathrate or prodrug thereof.

33. A pharmaceutical composition comprising:

a pharmaceutically acceptable carrier or excipient;

an agent selected from the group consisting of a proteostasis regulator and a pharmacologic chaperone; and

a compound of claim 1 , or a pharmaceutically acceptable salt, solvate, clathrate or prodrug thereof.

34. A method of treating a patient suffering from a condition associated with a dysfunction in proteostasis comprising administering to said patient an effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt, solvate, clathrate or prodrug thereof.

35. A method of alleviating the symptoms of cancer selected from the group consisting of breast cancer, colon cancer, pancreatic cancer, prostate cancer, lung cancer, ovarian cancer, cervical cancer, multiple myeloma, basal cell carcinoma, neuroblastoma, hematologic cancer, rhabdomyosarcoma, liver cancer, skin cancer, leukemia, basal cell carcinoma, bladder cancer, endometrial cancer, glioma, lymphoma, and gastrointestinal cancer in a subject in need thereof comprising administering to said subject an effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt, solvate, clathrate or prodrug thereof.