Compounds for enzyme inhibition
One aspect of the invention relates to inhibitors that preferentially inhibit immunoproteasome activity over constitutive proteasome activity. In certain embodiments, the invention relates to the treatment of immune related diseases, comprising administering a compound of the invention. In certain embodiments, the invention relates to the treatment of cancer, comprising administering a compound of the invention.
1. A compound having a structure of formula (I) or a pharmaceutically acceptable salt thereof,
wherein each Ar is independently an aromatic group optionally substituted with 1 to 4 substituents;
each A is independently selected from C═O, C═S, and SO 2 ; or
A is optionally a covalent bond when adjacent to an occurrence of Z;
B is absent or is N(R 9 )R 10 ;
L is absent;
M is absent or is C 1-12 alkyl;
Q is absent;
X is selected from O, S, NH, and N—C 1-6 alkyl;
Y is absent or is selected from C═O and SO 2 ;
each Z is independently selected from O, S, NH, and N—C 1-6 alkyl; or
Z is optionally a covalent bond when adjacent to an occurrence of A;
R 1 is selected from H, —C 1-6 alkyl-B, C 1-6 hydroxyalkyl, C 1-6 alkoxyalkyl aryl, and C 1-6 aralkyl;
R 2 and R 3 are each independently selected from aryl, C 1-6 aralkyl, heteroaryl, and C 1-6 heteroaralkyl;
R 4 is N(R 5 )L-Q-R 6 ;
R 5 is hydrogen;
R 6 is selected from hydrogen, C 1-6 alkyl, C 1-6 alkenyl, C 1-6 alkynyl, Ar—Y—, carbocyclyl, heterocyclyl, an N-terminal protecting group, aryl; C 1-6 aralkyl, R 11 ZAZ—C 1-8 alkyl-, R 14 Z—C 1-8 alkyl-, (R 11 O)(R 12 O)P(═O)O—C 1-8 alkyl-ZAZ—C 1-8 alkyl-, R 11 ZAZ—C 1-8 alkyl-ZAZ—C 1-8 alkyl-, heterocyclylMZAZ—C 1-8 alkyl-, (R 11 O)(R 12 O)P(═O)O—C 1-8 alkyl-, (R 13 ) 2 N—C 1-12 alkyl-, (R 13 ) 3 N + —C 1-12 alkyl-, heterocyclylM-, carbocyclylM-, R 14 SO 2 C 1-8 alkyl-, and R 14 SO 2 NH; or
R 5 and R 6 together are C 1-6 alkyl-Y—C 1-6 alkyl, C 1-6 alkyl-ZAZ—C 1-6 alkyl, ZAZ—C 1-6 alkyl-ZAZ—C 1-6 alkyl, ZAZ—C 1-6 alkyl-ZAZ, or C 1-6 alkyl-A, thereby forming a ring;
R 7 and R 8 are independently selected from hydrogen, C 1-6 alkyl, and C 1-6 aralkyl;
R 9 is selected from hydrogen, OH, and C 1-6 alkyl; and
R 10 is an N-terminal protecting group;
R 11 and R 12 are independently selected from hydrogen, metal cation, C 1-6 alkyl, C 1-6 alkenyl, C 1-6 alkynyl, aryl, and C 1-6 aralkyl;
each R 13 is independently selected from hydrogen and C 1-6 alkyl; and
R 14 is independently selected from hydrogen, C 1-6 alkyl, C 1-6 alkenyl, C 1-6 alkynyl, carbocyclyl heterocyclyl, aryl, and C 1-6 aralkyl; and
R 15 is selected from C 1-6 alkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, —C(O)OC 1-6 alkyl,—C(O)NH C 1-6 alkyl, and C 1-6 aralkyl; provided that in any occurrence of the sequence ZAZ, at least one member of the sequence must be other than a covalent bond.
2. A compound of claim 1 , wherein R 6 is an N-terminal protecting group.
3. A compound of claim 2 , wherein R 6 is selected from t-butoxycarbonyl, benzyloxycarbonyl, benzoyl, fluoren-9-ylmethoxycarbonyl, triphenylmethyl, and trichlorethoxycarbonyl.
4. A compound of claim 1 , wherein the carbon bearing R 1 has a D stereochemical configuration.
5. The compound of claim 1 , wherein A is C=O.
6. The compound of claim 1 , wherein M is C 1-8 alkyl.
7. The compound of claim 1 , wherein B is absent.
8. The compound of claim 1 , wherein X is O.
9. The compound of claim 1 , wherein Z is O.
10. The compound of claim 1 , wherein R 7 and R 8 are H.
11. The compound of claim 1 , wherein R 9 is C 1-6 alkyl.
12. The compound of claim 1 , wherein R 11 and R 12 are independently selected from hydrogen, metal cation, and C 1-6 alkyl.
13. The compound of claim 1 , wherein R 1 is selected from C 1-6 alkyl-B and C 1-6 aralkyl.
14. The compound of claim 13 , wherein R 1 is substituted with one or more substituents selected from hydroxyl, halogen, amide, amine, carboxylic acid or a salt thereof, ester, thiol, or thioether.
15. The compound of claim 14 , wherein R 1 is selected from methyl, ethyl, isopropyl, carboxymethyl, and benzyl.
16. The compound of claim 1 , wherein R 2 is selected from C 1-6 aralkyl and C 1-6 heteroaralkyl.
17. The compound of claim 16 , wherein R 2 is selected from C 1-6 alkylphenyl, C 1-6 alkylindolyl, C 1-6 alkylthienyl, C 1-6 alkylthiazolyl, and C 1-6 alkylisothiazolyl.
18. The compound of claim 17 , wherein R 2 is substituted with one or more substituents selected from hydroxy, halogen, amide, amine, carboxylic acid or a salt thereof, ester, thiol, or thioether.
19. The compound of claim 17 , wherein R 2 is substituted with one or more substituents selected from alkyl, trihaloalkyl, alkoxy, hydroxyl, and cyano.
20. The compound of claim 17 , wherein R 2 is selected from C 1-6 alkylphenyl and C 1-6 alkylindolyl.
21. The compound of claim 1 , wherein R 3 is selected from C 1-6 aralkyl and C 1-6 heteroaralkyl.
22. The compound of claim 21 , wherein R 3 is substituted with one or more substituents selected from hydroxy, halogen, amide, amine, carboxylic acid or a salt thereof, ester, thiol, or thioether.
23. The compound of claim 21 , wherein R 3 is substituted with one or more substituents selected from alkyl, trihaloalkyl, alkoxy, hydroxyl, and cyano.
24. The compound of claim 21 , wherein R 3 is selected from C 1-6 alkylphenyl and C 1-6 alkylindolyl.
25. The compound of claim 1 , wherein R 6 is selected from C 1-6 alkyl, C 1-6 alkenyl, C 1-6 alkynyl, C 1-6 aralkyl, and C 1-6 heteroaralkyl.
26. The compound of claim 1 , wherein R 5 is C 1-6 alkyl and R 6 is selected from butyl, allyl, propargyl, phenylmethyl, 2-pyridyl, 3-pyridyl, and 4-pyridyl.
27. The compound of claim 1 , wherein R 7 and R 8 are independently selected from hydrogen and C 1-6 alkyl.
28. The compound of claim 1 , wherein the carbon bearing R 2 has a D stereochemical configuration.
29. A compound of claim 1 , wherein the carbon bearing R 3 has a D stereochemical configuration.
30. A pharmaceutical composition comprising a compound according to claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.