Proteasome activity enhancing compounds

1. A compound having the Formula (Ib):

or a pharmaceutically acceptable salt, solvate, or clathrate thereof; wherein:

each of R 1 and R 2 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;

each of R 3b and R 3c 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;

R 4 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)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 5 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)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;

wherein substituents of optionally substituted Z, R 1 , R 2 , R 3b , R 3c , R 4 , and R 5 are each independently selected from the group consisting of C 1 -C 10 alkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, C 3 -C 12 cycloalkyl, C 3 -C 12 cycloalkenyl, 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)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 , heterocyclic, and heteroaryl;

Z is:

wherein R t 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 y is selected from the group consisting of hydrogen and optionally substituted C 1 -C 10 alkyl;

each n is independently 0, 1 or 2;

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; and

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.

2. The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, or clathrate thereof, wherein substituents of optionally substituted Z, R 1 , R 2 , R 3b , R 3c , R 4 and R 5 are each independently selected from the group consisting of C 1 -C 4 alkyl, halo, OR c , CN, S(O) n R c , heterocyclyl, and heteroaryl.

3. The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, or clathrate thereof, wherein each of R 1 and R 2 is hydrogen.

4. The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, or clathrate thereof, wherein R 4 is halo.

5. The compound of claim 4 , or a pharmaceutically acceptable salt, solvate, or clathrate thereof, wherein R 4 is Cl.

6. The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, or clathrate thereof, wherein R 5 is hydrogen or C 1 -C 10 alkyl.

7. The compound of claim 6 , or a pharmaceutically acceptable salt, solvate, or clathrate thereof, wherein R 5 is methyl.

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

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

each of R 1 and R 2 is hydrogen;

R 4 is Cl;

R 5 is methyl; and

R 3b is hydrogen.

10. The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, or clathrate thereof, wherein R 3c is independently selected from the group consisting of 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, wherein

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; and

each n is independently 0, 1 or 2.

11. The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, or clathrate thereof, wherein R 3c is independently selected from the group consisting of C 1 -C 10 alkyl substituted with CN; S(O) n R c , wherein R c is C 1 -C 10 alkyl or C 3 -C 12 cycloalkyl, and n is 2; optionally substituted heterocyclic; or and optionally substituted heteroaryl.

12. The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, or clathrate thereof, wherein R t is selected from the group consisting of hydrogen, C 1 -C 10 alkyl, and OR c , wherein R c is hydrogen or C 1 -C 10 alkyl; and R v is hydrogen or C 1 -C 4 alkyl.

13. The compound of claim 1 , said compound selected from the group consisting of:

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

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

each of R 1 , R 2 , and R 3b is hydrogen;

R 3 is optionally substituted C 1 -C 3 alkyl;

R 4 is halo or CN;

R 5 is methyl;

Z is

R v is hydrogen;

R t is hydrogen or OR c ; and

R c is hydrogen or optionally substituted C 1 -C 10 alkyl.

16. The compound of claim 15 , or a pharmaceutically acceptable salt, solvate, or clathrate thereof, wherein R 3c is substituted methyl.

17. The compound of claim 15 , or a pharmaceutically acceptable salt, solvate, or clathrate thereof, wherein R 3c is C 1 -C 3 alkyl substituted with CN.

18. The compound of claim 15 , or a pharmaceutically acceptable salt, solvate, or clathrate thereof, wherein R 3c is methyl substituted with CN.

19. The compound of claim 15 , or a pharmaceutically acceptable salt, solvate, or clathrate thereof, wherein R 3c is C 1 -C 3 alkyl substituted with S(O) n R c , wherein n is 2 and R c is selected from the group consisting of C 1 -C 10 alkyl, C 3 -C 12 cycloalkyl, and oxetanyl.

20. The compound of claim 15 , or a pharmaceutically acceptable salt, solvate, or clathrate thereof, wherein R 3c is C 1 -C 3 alkyl substituted with optionally substituted imidazolyl.

21. The compound of claim 15 , or a pharmaceutically acceptable salt, solvate, or clathrate thereof, wherein:

R t is OR c ; and

R c is hydrogen or methyl.