Proteasome inhibitors
Disclosed herein are compounds of Formula (I) that include a sulfonate ester, ester or ether group. Compounds of Formula (I) can be included in pharmaceutical compositions, and can be used to treating and/or ameliorating a disease or condition, such as cancer, a microbial disease and/or inflammation.
1. A compound of Formula (I), or pharmaceutically acceptable salt, ester or prodrug thereof:
wherein:
R 1 has a structure selected from the group consisting of:
wherein R 4 is selected from the group consisting of a mono-substituted, a poly-substituted or an unsubstituted variant of the following residues: aryl, aryl(C 1-6 alkyl), heteroaryl, heteroaryl(C 1-6 alkyl), heterocyclyl, and heterocyclyl(C 1-6 alkyl);
wherein when R 4 is a substituted residue, the residue is substituted with one or more groups selected from among alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, acyl, acylamino, acyloxy, amino, mono-substituted amine, di-substituted amine, alkyl amino, aminoacyl, aminoacyloxy, oxyacylamino, halogen, mono-haloalkyl, di-haloalkyl, tri-haloalkyl, mono-haloalkoxy, di-haloalkoxy, tri-haloalkoxy, hydroxy, carboxylalkyl, thioketo, thiol, thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, —SO-alkyl, —SO-substituted alkyl, —SO-aryl, —SO-heteroaryl, —SO 2 —H, —SO 2 —OH, —SO 2 -alkyl, —SO 2 -aryl, —SO 2 -heteroaryl, boronate alkyl, boronic acid, (OH) 2 B-alkyl, phosphate and phosphate esters, phosphonooxy, phosphonooxyalkyl, azido, azidoalkyl, ammonium, aminoalkyl, salt of an aminoalkyl, carboxyalkyl, a salt of a carboxyalkyl, alkylamino, a salt of an alkylamino, dialkylamino, a salt of a dialkylamino, alkylthio, arylthio, carboxy, cyano, alkoxysulfinyl, thiocyano, boronic acidalkyl, boronic esteralkyl, sulfoalkyl, a salt of a sulfoalkyl, alkoxysulfonylalkyl, sulfooxyalkyl, a salt of a sulfooxyalkyl, alkoxysulfonyloxyalkyl, phosphonooxyalkyl, a salt of a phosphonooxyalkyl, (alkylphosphooxy)alkyl, phosphorylalkyl, a salt of a phosphorylalkyl, (alkylphosphoryl)alkyl, pyridinylalkyl, a salt of a pyridinylalkyl, a salt of a heteroarylalkyl guanidino, a salt of a guanidino, guanidinoalkyl, and
wherein A is selected from the group consisting of a mono-substituted, a poly-substituted or an unsubstituted variant of the following residues: heterocyclyl, aryl and heteroaryl; and
Z 1 is selected from the group consisting of O, S, N═N, O(CH 2 ) 1-6 , S(O) 2 N(R 17 ), S(O) 2 N(R 17 )(CH 2 ) 1-6 , C(═O)N(R 17 ), N(R 17 )C(═O), N(R 17 )C(═O)(CH 2 ) 1-6 , N(R 17 )C(═O)O(CH 2 ) 1-6 , S(O) 2 , C(═O), (CH 2 ) 1-6 C(═O), O(CH 2 ) 1-6 C(═O), (CH 2 ) 1-6 N(R 17 )C(═O), CH═CH—C(═O)N(R 17 ), CH═CH—C(═O), O(CH 2 ) 1-6 O, O(CH 2 ) 1-6 and N(R 17a )C(═O)N(R 17b ), wherein R 17 , R 17a and R 17b are independently selected from the group consisting of H, C 1-4 alkyl, a substituted or unsubstituted benzyl, an allyl, and t-butoxycarbonyl (t-BOC);
R 2 is selected from the group consisting of a hydrogen, a halogen, cyano, a mono-substituted, a poly-substituted or an unsubstituted variant of the following residues: C 1 -C 12 alkyl, C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, C 3 -C 12 cycloalkyl, C 3 -C 12 cycloalkenyl, C 3 -C 12 cycloalkynyl, C 3 -C 12 heterocyclyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, (cycloalkyl)alkyl, (heterocyclyl)alkyl, acyl, acylalkyl, alkyloxycarbonyloxy, carbonylacyl, aminocarbonyl, azido, azidoalkyl, mono-haloalkyl, di-haloakyl, tri-haloalkyl, aminoalkyl, salt of an aminoalkyl, carboxyalkyl, a salt of a carboxyalkyl, alkylamino, a salt of an alkylamino, dialkylamino, a salt of a dialkylamino, alkylthio, arylthio, carboxy, alkoxysulfinyl, thiocyano, boronic acidalkyl, boronic esteralkyl, sulfoalkyl, a salt of a sulfoalkyl, alkoxysulfonylalkyl, sulfooxyalkyl, a salt of a sulfooxyalkyl, alkoxysulfonyloxyalkyl, phosphonooxyalkyl, a salt of a phosphonooxyalkyl, (alkylphosphooxy)alkyl, phosphorylalkyl, a salt of a phosphorylalkyl, (alkylphosphoryl)alkyl, pyridinylalkyl, a salt of a pyridinylalkyl, a salt of a heteroarylalkyl guanidino, a salt of a guanidino, and guanidinoalkyl;
R 3 is selected from the group consisting of hydrogen, halogen, a mono-substituted, a poly-substituted or an unsubstituted variant of the following residues: C 1-6 alkyl, C 3-6 cycloalkyl, C 2-6 alkenyl, C 3-6 cycloalkenyl, aryl, and arylalkyl;
n is 1, 2 or 3;
E 1 and E 3 are each a substituted or unsubstituted heteroatom independently selected from the group consisting of O and S;
E 4 is a substituted or unsubstituted heteroatom selected from the group consisting of O, S and N;
E 5 is NH 2 , OH or SH;
E 2 is a substituted or unsubstituted N or —CH 2 — group; and
provided that when R 1 is
R 4 has a molecular weight equal to or greater than 92 g/mol; and
provided that when R 1 is
R 4 has a molecular weight equal to or greater than 77 g/mol.
2. The compound of claim 1 , wherein when R 1 is
R 4 has a molecular weight equal to or greater than 107 g/mol or when R 1 is
R 4 has a molecular weight equal to or greater than 92 g/mol.
3. The compound of claim 1 , wherein when R 1 is
R 4 has a molecular weight equal to or greater than 122 g/mol or when R 1 is
R 4 has a molecular weight equal to or greater than 107 g/mol.
4. The compound of claim 1 , wherein R 1 has a structure selected from the group consisting of:
wherein:
R 5a , R 5b , R 5c , R 5d , R 5e , R 9a , R 9b , R 9c , R 9d , R 9e , R 13a , R 13b , R 13c , R 13d and R 13e are each independently selected from the group consisting of: hydrogen, halo, nitro, cyano, a mono-substituted, a poly-substituted or an unsubstituted variant of the following residues:
C 1-24 alkyl, C 2-24 alkenyl, C 2-24 alkynyl,mono-haloalkyl,di-haloalkyl, tri-haloalkyl, mono-haloalkoxy, di-haloalkoxy, tri-haloalkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heterocyclyl, amino, mono-substituted amine, di-substituted amine, alkoxy, acyl, aminoalkyl, salt of an aminoalkyl, carboxyalkyl, a salt of a carboxyalkyl, alkylamino, a salt of an alkylamino, dialkylamino, a salt of a dialkylamino, alkylthio, arylthio, carboxy, alkoxysulfinyl, thiocyano, boronic acidalkyl, boronic esteralkyl, sulfoalkyl, a salt of a sulfoalkyl, alkoxysulfonylalkyl, sulfooxyalkyl, a salt of a sulfooxyalkyl, alkoxysulfonyloxyalkyl, phosphonooxyalkyl, a salt of a phosphonooxyalkyl, (alkylphosphooxy)alkyl, phosphorylalkyl, a salt of a phosphorylalkyl, (alkylphosphoryl)alkyl, pyridinylalkyl, a salt of a pyridinylalkyl, a salt of a heteroarylalkyl guanidino, a salt of a guanidino, and guanidinoalkyl;
R 6a , R 6b , R 6c , R 10a , R 10b , R 10c , R 14a , R 14b and R 14c are each independently selected from the group consisting of: hydrogen, halo, nitro, cyano, a mono-substituted, a poly-substituted or an unsubstituted variant of the following residues: C 1-24 alkyl, C 2-24 alkenyl, C 2-24 alkynyl, mono-haloalkyl, tri-haloalkyl, mono-haloalkoxy, di-haloalkoxy, tri-haloalkoxy, amino, mono-substituted amine, di-substituted amine, alkoxy, acyl, aminoalkyl, salt of an aminoalkyl, carboxyalkyl, a salt of a carboxyalkyl, alkylamino, a salt of an alkylamino, dialkylamino, a salt of a dialkylamino, alkylthio, arylthio, carboxy, alkoxysulfinyl, thiocyano, boronic acidalkyl, boronic esteralkyl, sulfoalkyl, a salt of a sulfoalkyl, alkoxysulfonylalkyl, sulfooxyalkyl, a salt of a sulfooxyalkyl, alkoxysulfonyloxyalkyl, phosphonooxyalkyl, a salt of a phosphonooxyalkyl, (alkylphosphooxy)alkyl, phosphorylalkyl, a salt of a phosphorylalkyl, (alkylphosphoryl)alkyl, pyridinylalkyl, a salt of a pyridinylalkyl, a salt of a heteroarylalkyl guanidino, a salt of a guanidino, and guanidinoalkyl;
R 7a , R 7b , R 7c , R 11a , R 11b , R 11c , R 15a , R 15b and R 15c are each independently selected from the group consisting of: hydrogen, halo, nitro, cyano, a mono-substituted, a poly-substituted or an unsubstituted variant of the following residues: C 1-24 alkyl, C 2-24 alkenyl, C 2-24 alkynyl, mono-haloalkyl, di-haloalkyl, tri-haloalkyl, mono-haloalkoxy, di-haloalkoxy, tri-haloalkoxy, amino, mono-substituted amine, di-substituted amine, alkoxy, acyl, aminoalkyl, salt of an aminoalkyl, carboxyalkyl, a salt of a carboxyalkyl, alkylamino, a salt of an alkylamino, dialkylamino, a salt of a dialkylamino, alkylthio, arylthio, carboxy, alkoxysulfinyl, thiocyano, boronic acidalkyl, boronic esteralkyl, sulfoalkyl, a salt of a sulfoalkyl, alkoxysulfonylalkyl, sulfooxyalkyl, a salt of a sulfooxyalkyl, alkoxysulfonyloxyalkyl, phosphonooxyalkyl, a salt of a phosphonooxyalkyl, (alkylphosphooxy)alkyl, phosphorylalkyl, a salt of a phosphorylalkyl, (alkylphosphoryl)alkyl, pyridinylalkyl, a salt of a pyridinylalkyl, a salt of a heteroarylalkyl guanidino, a salt of a guanidino, and guanidinoalkyl;
R 8a , R 8b , R 8c , R 8d , R 12a , R 12b , R 12c , R 12d , R 16a , R 16b , R 16c and R 16d are each independently selected from the group consisting of: hydrogen, halo, nitro, cyano, a mono-substituted, a poly-substituted or an unsubstituted variant of the following residues: C 1-24 alkyl, C 2-24 alkenyl, C 2-24 alkynyl, mono-haloalkyl, di-haloalkyl, tri-haloalkyl, mono-haloalkoxy, di-haloalkoxy, tri-haloalkoxy, amino, mono-substituted amine, di-substituted amine, alkoxy, acyl, aminoalkyl, salt of an aminoalkyl, carboxyalkyl, a salt of a carboxyalkyl, alkylamino, a salt of an alkylamino, dialkylamino, a salt of a dialkylamino, alkylthio, arylthio, carboxy, alkoxysulfinyl, thiocyano, boronic acidalkyl, boronic esteralkyl, sulfoalkyl, a salt of a sulfoalkyl, alkoxysulfonylalkyl, sulfooxyalkyl, a salt of a sulfooxyalkyl, alkoxysulfonyloxyalkyl, phosphonooxyalkyl, a salt of a phosphonooxyalkyl, (alkylphosphooxy)alkyl, phosphorylalkyl, a salt of a phosphorylalkyl, (alkylphosphoryl)alkyl, pyridinylalkyl, a salt of a pyridinylalkyl, a salt of a heteroarylalkyl guanidino, a salt of a guanidino, and guanidinoalkyl and —S(═O) 2 O − ;
B, D and F are each independently selected from the group consisting of a mono-substituted, a poly-substituted or an unsubstituted variant of the following residues: heterocyclyl, aryl, heteroaryl, cycloalkyl and cycloalkenyl;
C, E and G are each independently selected from the group consisting of a mono-substituted, a poly-substituted or an unsubstituted variant of the following residues: heterocyclyl, aryl, heteroaryl, cycloalkyl and cycloalkenyl;
A is selected from the group consisting of a mono-substituted, a poly-substituted or an unsubstituted variant of the following residues: heterocyclyl, aryl, heteroaryl, cycloalkyl and cycloalkenyl; and
Z 1 is selected from the group consisting of O, S, N═N, O(CH 2 ) 1-6 , S(O) 2 N(R 17 ), S(O) 2 N(R 17 )(CH 2 ) 1-6 , C(═O)N(R 17 ), N(R 17 )C(═O), N(R 17 )C(═O)(CH 2 ) 1-6 , N(R 17 )C(═O)O(CH 2 ) 1-6 , S(O) 2 , C(═O), (CH 2 ) 1-6 C(═O), O(CH 2 ) 1-6 C(═O), (CH 2 ) 1-6 , N(R 17 )C(═O), CH═CH—C(═O)N(R 17 ), CH═CH—C(═O), O(CH 2 ) 1-6 O, O(CH 2 ) 1-6 and N(R 17a )C(═O)N(R 17b ), wherein R 17 , R 17a and R 17b are independently selected from the group consisting of H, C 1-4 alkyl, a substituted or unsubstituted benzyl, an allyl, and t-butoxycarbonyl (t-BOC).
5. The compound of claim 4 , wherein R 1 is
and R a , R 5b , R 5c , R 5d , and R 5e are each independently selected from the group consisting of: hydrogen, halo, nitro, a mono-substituted, a poly-substituted or an unsubstituted variant of the following residues: C 1 - 24 alkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, mono-haloalkyl, di-haloalkyl, tri-haloalkyl, mono-haloalkoxy, di-haloalkoxy, tri-haloalkoxy, amino, mono-substituted amine, di-substituted amine, alkoxy, and carboxy.
6. The compound of claim 4 , wherein R 1 is
and B is a mono-substituted, a poly-substituted or an unsubstituted aryl ring.
7. The compound of claim 4 , wherein R 1 is
and C is a mono-substituted, a poly-substituted or an unsubstituted heterocyclyl ring.
8. The compound of claim 4 , wherein R 1 is
and C is a mono-substituted, a poly-substituted or an unsubstituted aryl ring.
9. The compound of claim 4 , wherein R 1 is
and Z 1 is O or N═N.
10. The compound of claim 4 , wherein R 1 is
and A is a mono-substituted, a poly-substituted or an unsubstituted aryl ring.
11. The compound of claim 4 , wherein R 1 is
and A is a mono-substituted, a poly-substituted or an unsubstituted heteroaryl ring.
12. The compound of claim 4 , wherein R 1 is
and R 9a , R 9b , R 9c , R 9d , and R 9e are each independently selected from the group consisting of: hydrogen, halo, nitro, cyano, a mono-substituted, a poly-substituted or an unsubstituted variant of the following residues: C 1-24 alkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, mono-haloalkyl, di-haloalkyl, tri-haloalkyl, mono-haloalkoxy, di-haloalkoxy, tri-haloalkoxy, amino, mono-substituted amine, di-substituted amine, alkoxy, and hydroxy.
13. The compound of claim 4 , wherein R 1 is
and D is a mono-substituted, a poly-substituted or an unsubstituted aryl ring.
14. The compound of claim 4 , wherein R 1 is
and E is a mono-substituted, a poly-substituted or an unsubstituted aryl ring.
15. The compound of claim 4 , wherein R 1 is
and Z 1 is selected from the group consisting of O, O(CH 2 ) 1-6 and N═N.
16. The compound of claim 4 , wherein R 1 is
and A is a mono-substituted, a poly-substituted or an unsubstituted aryl ring.
17. The compound of claim 4 , wherein R 1 is
and R 13a , R 13b , R 13c , R 13d and R 13e are each independently selected from the group consisting of:
hydrogen, halo, nitro, cyano, a mono-substituted, a poly-substituted or an unsubstituted variant of the following residues: C 1-24 alkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, mono-haloalkyl, di-haloalkyl, tri-haloalkyl, mono-haloalkoxy, di-haloalkoxy, tri-haloalkoxy, amino, mono-substituted amine, di-substituted amine, alkoxy, carboxy and hydroxy.
18. The compound of claim 4 , wherein R 1 is
and F is a mono-substituted, a poly-substituted or an unsubstituted aryl ring.
19. The compound of claim 4 , wherein R 1 is
and G is a mono-substituted, a poly-substituted or an unsubstituted aryl ring.
20. The compound of claim 4 , wherein R 1 is
and Z 1 is O or N═N.
21. The compound of claim 4 , wherein R 1 is
and A is a mono-substituted, a poly-substituted or an unsubstituted aryl ring.
22. The compound of claim 4 , wherein: R 1 is selected from the group consisting of:
23. The compound of claim 4 , wherein: R 1 is selected from the group consisting of:
24. The compound of claim 4 , wherein R 1 is selected from the group consisting of:
25. The compound of claim 1 , wherein R 3 is selected from the group consisting of a mono-substituted, a poly-substituted or an unsubstituted variant of the following residues: C 1-6 alkyl, C 3-6 cycloalkyl, C 2-6 alkenyl, C 3-6 cycloalkenyl, aryl, and arylalkyl.
26. The compound of claim 25 , wherein R 2 is selected from the group consisting of a mono-substituted, a poly-substituted or an unsubstituted C 1 -C 12 alkyl, a mono-substituted, a poly-substituted or an unsubstituted C 3 -C 12 cycloalkanyl, a mono-substituted, a poly-substituted or an unsubstituted C 3 -C 12 cycloalkenyl and a mono-substituted, a poly-substituted or an unsubstituted aryl; and R 3 is a mono-substituted, a poly-substituted or an unsubstituted C 1-6 alkyl.
27. The compound of claim 26 , wherein n is 2.
28. A pharmaceutical composition comprising one or more compounds of claim 1 , or pharmaceutically acceptable salt, ester or prodrug thereof, and one or more selected from the group consisting of a diluent, an excipient and a carrier.