Peptidomimetic proteasome inhibitors

1. A compound of Formula (I):

wherein

R is H or C 1-6 alkyl;

R′ is H or C 1-6 alkyl;

R 1 is H or C 1-6 alkyl;

or R and R 1 are taken together with the carbon to which they are attached to form a C 3-8 cycloalkyl ring;

R 2 is independently selected at each occurrence thereof from

or —(CH 2 ) n C(O)NR 6 R 7 ;

R 3 is independently selected at each occurrence thereof from the group consisting of H, C 1-12 alkyl, —Boc, —C(O)(CH 2 ) n R 5 , —(CH 2 ) n C(O)R 5 , —C(O)OR 5 , —C(O)(CH 2 ) n NR 6 R 7 , —S(O) 2 R 5 , monocyclic and bicyclic heteroaryl, monocyclic and bicyclic heterocyclyl, and monocyclic and bicyclic non-aromatic heterocycle, wherein monocyclic and bicyclic heteroaryl, monocyclic and bicyclic heterocyclyl, and monocyclic and bicyclic non-aromatic heterocycle can be optionally substituted from 1 to 3 times with R 8 ;

R 4 is H, halogen, NH 2 , NHCOOC 1-12 alkyl, or C 1-12 alkyl;

R 5 is selected from the group consisting of C 1-12 alkyl, monocyclic or bicyclic C 3-10 cycloalkyl, C 3-12 cycloalkylalkyl, C 1-12 alkoxy, monocyclic and bicyclic aryl, monocyclic and bicyclic heteroaryl, monocyclic and bicyclic heterocyclyl, and monocyclic and bicyclic non-aromatic heterocycle, wherein C 1-12 alkyl, monocyclic or bicyclic C 3-10 cycloalkyl, C 3-12 cycloalkylalkyl, C 1-12 alkoxy, monocyclic and bicyclic aryl, monocyclic and bicyclic heteroaryl, monocyclic and bicyclic heterocyclyl, and monocyclic and bicyclic non-aromatic heterocycle can be optionally substituted from 1 to 3 times with R 8 ;

R 6 , R 7 are each independently selected from the group consisting of H, C 1-6 alkyl, and arylalkyl;

or R 6 and R 7 are taken together with the nitrogen to which they are attached to form a piperidine, pyrrolidine, azepane, or morpholine ring, wherein piperidine, pyrrolidine, azepane, or morpholine ring can be optionally substituted 1 to 3 times with R 9 ;

R 8 is selected independently at each occurrence thereof from the group consisting of halogen, C 1-6 alkyl, C 3-8 cycloalkyl, aryl, and arylalkyl, wherein C 1-6 alkyl, C 3-8 cycloalkyl, aryl, and arylalkyl can be optionally substituted 1 to 3 times with R 9 ;

R 9 is selected from the group consisting of H, halogen, C 1-6 alkyl, C 3-8 cycloalkyl, and aryl, wherein C 1-6 alkyl can be optionally substituted 1 to 3 times with halogen;

R 10 is H or arylalkyl;

W is CHR 2 , NR 2 , or

X is selected from the group consisting of —C(O)—NH—, monocyclic and bicyclic heteroaryl, monocyclic and bicyclic heterocyclyl, and monocyclic and bicyclic non-aromatic heterocycle;

Y is optional and, if present, is —(CH 2 ) m —;

Z is optional and, if present, is aryl or bicyclic heteroaryl;

is the point of attachment to NHR 3 moiety;

is the point of attachment to C(O) moiety;

k is 1 or 2;

m is 0, 1, or 2; and

n is 0, 1, 2, 3, or 4,

with the proviso that R 2 is not —CH 2 C(O)NH 2 , —CH 2 C(O)NHCH 2 C(CH 3 ) 3 , or —(CH 2 ) 2 C(O)NH 2 ,

or an oxide thereof, a pharmaceutically acceptable salt thereof, a solvate thereof, or a prodrug thereof.

2. The compound according to claim 1 which has the Formula (IA), Formula (TB), or Formula (IC):

3. The compound according to claim 1 , wherein R and R 1 are taken together with the carbon to which they are attached to form

group, and wherein

is the point of attachment to NH; and

is the point of attachment to X.

4. The compound according to claim 1 , wherein R 3 is

wherein

is the point of attachment to the corresponding carbon atom of the structure of Formula (I).

5. The compound according to claim 1 , wherein R 4 is NH 2 or NHBoc.

6. The compound according to claim 1 , wherein X is

wherein

is the point of attachment to C(R 1 )(R 2 ) moiety;

is the point of attachment to Y, Z, or R 4 .

7. The compound according to claim 1 , wherein Z is

and

wherein

is the point of attachment to Y or X;

is the point of attachment to R 4 .

8. The compound according to claim 1 , wherein the compound of Formula (I) is selected from the group consisting of:

9. The compound according to claim 1 which has the Formula

wherein

R is H or C 1-6 alkyl;

R 1 is H or C 1-6 alkyl;

or R and R 1 are taken together with the carbon to which they are attached to form a C 3-8 cycloalkyl ring;

R 2 is independently selected at each occurrence thereof from the group consisting of C 1-6 alkyl, and —(CH 2 ) n C(O)NR 6 R 7 , wherein C 1-6 alkyl can be optionally substituted from 1 to 3 times with a substituent selected independently at each occurrence thereof from OH or C(O)OR 10 ;

R 3 is independently selected at each occurrence thereof from the group consisting of H, —Boc, —C(O)(CH 2 ) n R 5 , —(CH 2 ) n C(O)R 5 , —C(O)OR 5 , —C(O)(CH 2 ) n NR 6 R 7 , —S(O) 2 R 5 , monocyclic and bicyclic heteroaryl, monocyclic and bicyclic heterocyclyl, and monocyclic and bicyclic non-aromatic heterocycle, wherein monocyclic and bicyclic heteroaryl, monocyclic and bicyclic heterocyclyl, and monocyclic and bicyclic non-aromatic heterocycle can be optionally substituted from 1 to 3 times with C 1-6 alkyl;

R 4 is H, C 1-12 alkyl, or halogen;

R 5 is selected from the group consisting of C 1-12 alkyl, monocyclic or bicyclic C 3-10 cycloalkyl, C 3-12 cycloalkylalkyl, C 1-12 alkoxy, monocyclic and bicyclic aryl, monocyclic and bicyclic heteroaryl, monocyclic and bicyclic heterocyclyl, and monocyclic and bicyclic non-aromatic heterocycle, wherein C 1-12 alkyl, monocyclic or bicyclic C 3-10 cycloalkyl, C 3-12 cycloalkylalkyl, C 1-12 alkoxy, monocyclic and bicyclic aryl, monocyclic and bicyclic heteroaryl, monocyclic and bicyclic heterocyclyl, and monocyclic and bicyclic non-aromatic heterocycle can be optionally substituted from 1 to 3 times with R 8 ;

R 6 , R 7 are each independently selected from the group consisting of H, C 1-6 alkyl, and arylalkyl;

or R 6 and R 7 are taken together with the nitrogen to which they are attached to form a piperidine, pyrrolidine, azepane, or morpholine ring, wherein piperidine, pyrrolidine, azepane, or morpholine ring can be optionally substituted 1 to 3 times with R 9 ;

R 8 is selected independently at each occurrence thereof from the group consisting of halogen, C 1-6 alkyl, C 3-8 cycloalkyl, aryl, and arylalkyl, wherein C 1-6 alkyl, C 3-8 cycloalkyl, aryl, and arylalkyl can be optionally substituted 1 to 3 times with R 9 ;

R 9 is selected from the group consisting of H, halogen, C 1-6 alkyl, C 3-8 cycloalkyl, and aryl, wherein C 1-6 alkyl can be optionally substituted 1 to 3 times with halogen;

R 10 is H or arylalkyl;

X is monocyclic and bicyclic heteroaryl, monocyclic and bicyclic heterocyclyl, or monocyclic and bicyclic non-aromatic heterocycle;

Y is optional and, if present, is —(CH 2 ) m —;

Z is optional and, if present, is aryl;

m is 0, 1, or 2; and

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

or an oxide thereof, a pharmaceutically acceptable salt thereof, a solvate thereof, or a prodrug thereof.

10. The compound according to claim 9 which has the Formula (I′A), Formula (PB), Formula (I′C), Formula (I'D), Formula (I′E), Formula (I′F), Formula (I′G), Formula (I′C′), Formula (I'D′), Formula (I′E′), Formula (I′F′), or Formula (I′G′):

or

wherein

A is NH, N, O, or S,

is a single or a double bond; and

B is NH, N, O, or S.

11. The compound according to claim 1 , wherein R 1 is H or Me.

12. The compound according to claim 1 , wherein R and R 1 are taken together with the carbon to which they are attached to form

group, and wherein

is the point of attachment to NH; and

is the point of attachment to X.

13. The compound according to claim 1 , wherein R 2 is selected from the group consisting of

wherein

is the point of attachment to the corresponding carbon atom of the structure of Formula (I).

14. The compound according to claim 1 , wherein R 3 is selected from the group consisting of H, Boc,

wherein

is the point of attachment to the corresponding carbon atom of the structure of Formula (I).

15. The compound according to claim 1 , wherein R 4 is H, Me, or F.

16. The compound according to claim 1 , wherein X is selected from the group consisting of

wherein

is the point of attachment to C(R 1 )(R 2 ) moiety;

is the point of attachment to Y, Z, or R 4 .

17. The compound according to claim 1 , wherein Y is —CH 2 —.

18. The compound according to claim 1 , wherein Z is

and

wherein

is the point of attachment to Y or X;

is the point of attachment to R 4 .

19. The compound according to claim 1 , wherein the compound of Formula (I′) is selected from the group consisting of:

20. A compound of Formula:

or an oxide thereof, a pharmaceutically acceptable salt thereof, a solvate thereof, or a prodrug thereof.

21. A compound of Formula (II):

wherein

R is H or C 1-6 alkyl;

R 1 is H or C 1-6 alkyl;

or R and R 1 are taken together with the carbon to which they are attached to form a C 3-8 cycloalkyl ring;

R 2 is independently selected at each occurrence thereof from the group consisting of C 1-6 alkyl, and —(CH 2 ) n C(O)NR 6 R 7 , wherein C 1-6 alkyl can be optionally substituted from 1 to 3 times with a substituent selected independently at each occurrence thereof from OH or C(O)OR 10 ;

R 3 is independently selected at each occurrence thereof from the group consisting of H, —Boc, —C(O)(CH 2 ) n R 5 , —(CH 2 )—C(O)R 5 , —C(O)OR 5 , —C(O)(CH 2 )—NR 6 R 7 , —S(O) 2 R 5 , monocyclic and bicyclic heteroaryl, monocyclic and bicyclic heterocyclyl, and monocyclic and bicyclic non-aromatic heterocycle, wherein monocyclic and bicyclic heteroaryl, monocyclic and bicyclic heterocyclyl, and monocyclic and bicyclic non-aromatic heterocycle can be optionally substituted from 1 to 3 times with C 1-6 alkyl;

R 4 is H, C 1-12 alkyl, or halogen;

R 5 is selected from the group consisting of C 1-12 alkyl, monocyclic or bicyclic C 3-10 cycloalkyl, C 3-12 cycloalkylalkyl, C 1-12 alkoxy, monocyclic and bicyclic aryl, monocyclic and bicyclic heteroaryl, monocyclic and bicyclic heterocyclyl, and monocyclic and bicyclic non-aromatic heterocycle, wherein C 1-12 alkyl, monocyclic or bicyclic C 3-10 cycloalkyl, C 3-12 cycloalkylalkyl, C 1-12 alkoxy, monocyclic and bicyclic aryl, monocyclic and bicyclic heteroaryl, monocyclic and bicyclic heterocyclyl, and monocyclic and bicyclic non-aromatic heterocycle can be optionally substituted from 1 to 3 times with R 8 ;

R 6 , R 7 are each independently selected from the group consisting of H, C 1-6 alkyl, and arylalkyl;

or R 6 and R 7 are taken together with the nitrogen to which they are attached to form a piperidine, pyrrolidine, azepane, or morpholine ring, wherein piperidine, pyrrolidine, azepane, or morpholine ring can be optionally substituted 1 to 3 times with R 9 ;

R 8 is selected independently at each occurrence thereof from the group consisting of halogen, C 1-6 alkyl, C 3-8 cycloalkyl, aryl, and arylalkyl, wherein C 1-6 alkyl, C 3-8 cycloalkyl, aryl, and arylalkyl can be optionally substituted 1 to 3 times with R 9 ;

R 9 is selected from the group consisting of H, halogen, C 1-6 alkyl, C 3-8 cycloalkyl, and aryl, wherein C 1-6 alkyl can be optionally substituted 1 to 3 times with halogen;

R 10 is H or arylalkyl;

X is monocyclic and bicyclic heteroaryl, monocyclic and bicyclic heterocyclyl, or monocyclic and bicyclic non-aromatic heterocycle;

Y is optional and, if present, is —(CH 2 ) m —;

Z is optional and, if present, is aryl;

W is N or CH;

m is 0, 1, or 2; and

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

or an oxide thereof, a pharmaceutically acceptable salt thereof, a solvate thereof, or a prodrug thereof.

22. A pharmaceutical composition comprising a therapeutically effective amount of the compound according to claim 1 and a pharmaceutically acceptable carrier.