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 method for the treatment of an immune-related disease in a patient wherein the immune-related disease is selected from the group consisting of Sjogren's syndrome, rheumatoid arthritis, transplant rejection, and graft versus host disease, the method comprising administering to the patient a compound having a structure of formula (I) or a pharmaceutically acceptable salt thereof,
wherein
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 or is selected from C═O, C═S, and SO 2 ;
M is C 1-2 alkyl;
Q is absent or is selected from O, NH, and N—C 1-6 alkyl;
X is selected from O, S, NH, and N—C 1-6 alkyl;
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 selected from hydrogen, OH, aryl C 1-6 alkyl, and C 1-6 alkyl;
R 6 is selected from an N-terminal protecting group, heterocyclylMZAZC 1-6 alkyl-, heterocyclylM-, and carbocyclylM;
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; and
R 15 is selected from C 1-6 alkyl and C 1-6 hydroxyalkyl;
provided that in any occurrence of the sequence ZAZ, at least one member of the sequence must be other than a covalent bond.
2. The method of claim 1 , wherein L is C═O, Q is absent, M is C 1-8 alkyl and R 6 is heterocyclylM- and the heterocyclyl moiety is morpholino.
3. A method for the treatment of an immune-related disease in a patient wherein the immune-related disease is selected from the group consisting of Sjogren's syndrome, rheumatoid arthritis, transplant rejection, and graft versus host disease, the method comprising administering to the patient a compound having the structure:
or a pharmaceutically acceptable salt thereof.
4. The method of claim 1 , wherein R 7 and R 8 are independently selected from hydrogen and C 1-6 aralkyl.
5. The method of claim 4 , wherein R 7 and R 8 are both hydrogen.
6. The method of claim 1 , wherein R 15 is selected from methyl, ethyl, hydroxymethyl, and 2-hydroxyethyl.
7. The method of claim 1 , wherein R 5 is hydrogen.
8. The method of claim 1 , wherein L and Q are absent.
9. The method of claim 1 , wherein R 6 is an N-terminal protecting group.
10. The method of claim 9 , wherein R 6 is selected from t-butoxycarbonyl and benzyloxycarbonyl.
11. The method of claim 1 , wherein the carbon bearing R 1 has a D stereochemical configuration.
12. The method of claim 11 , wherein R 1 is selected from methyl, ethyl, isopropyl, carboxymethyl, and benzyl.
13. The method of claim 1 , wherein R 2 is selected from C 1-6 alkyl-phenyl, C 1-6 alkyl-indolyl, C 1-6 alkyl-thienyl, C 1-6 alkyl-thiazolyl, and C 1-6 alkyl-isothiazolyl.
14. The method of claim 13 , wherein R 2 is selected from
wherein D is selected from hydrogen, methoxy, t-butoxy, hydroxy, cyano, trifluoromethyl, and C 1-4 alkyl, wherein C 1-4 alkyl may be substituted or not with substituents selected from the group consisting of a halogen, a hydroxyl, a carbonyl, a thiocarbonyl, an alkoxyl, a phosphoryl, a phosphate, a phosphonate, a phosphinate, an amino, an amido, an amidine, an imine, a cyano, a nitro, an azido, a sulfhydryl, an alkylthio, a sulfate, a sulfonate, a sulfamoyl, a sulfonamido, a sulfonyl, a heterocyclyl, an aralkyl, or an aromatic or heteroaromatic moiety; and
R is hydrogen or a suitable protecting group.
15. The method of claim 1 , wherein R 3 is selected from C 1-6 alkyl-phenyl and C 1-6 alkyl-indolyl.
16. The method of claim 15 , wherein R 3 is selected from
wherein D is selected from hydrogen, methoxy, t-butoxy, hydroxy, cyano, trifluoromethyl, and C 1-4 alkyl, wherein C 1-4 alkyl may be substituted or not with substituents selected from the group consisting of a halogen, a hydroxyl, a carbonyl, a thiocarbonyl, an alkoxyl, a phosphoryl, a phosphate, a phosphonate, a phosphinate, an amino, an amido, an amidine, an imine, a cyano, a nitro, an azido, a sulfhydryl, an alkylthio, a sulfate, a sulfonate, a sulfamoyl, a sulfonamido, a sulfonyl, a heterocyclyl, an aralkyl, or an aromatic or heteroaromatic moiety; and
R is hydrogen or a suitable protecting group.
17. The method of claim 1 , wherein R 6 is selected from heterocyclylMZAZ-C 1-8 alkyl-, heterocyclylM-, and carbocyclylM-.
18. The method of claim 17 , wherein R 6 is heterocyclylMZAZ-C 1-8 alkyl-, and heterocyclylM-.
19. The method of claim 1 , wherein L is C═O, Q is absent, M is C 1-8 alkyl and R 6 is heterocyclylM- and the heterocyclyl moiety is selected from morpholino, piperidino, piperazino, and pyrrolidino.
20. A method for the treatment or prevention of graft versus host disease in a patient, comprising administering to the patient a compound having a structure of formula (I) or a pharmaceutically acceptable salt thereof,
wherein
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 or is selected from C═O, C═S, and SO 2 ;
M is C 1-2 alkyl;
Q is absent or is selected from O, NH, and N—C 1-6 alkyl;
X is selected from O, S, NH, and N—C 1-6 alkyl;
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 selected from hydrogen, OH, aryl C 1-6 alkyl, and C 1-6 alkyl;
R 6 is selected from an N-terminal protecting group, heterocyclylMZAZC 1-6 alkyl-, heterocyclylM-, and carbocyclylM;
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; and
R 15 is selected from C 1-6 alkyl and C 1-6 hydroxyalkyl;
provided that in any occurrence of the sequence ZAZ, at least one member of the sequence must be other than a covalent bond.
21. The method of claim 20 , wherein R 7 and R 8 are independently selected from hydrogen and C 1-6 aralkyl.
22. The method of claim 21 , wherein R 7 and R 8 are both hydrogen.
23. The method of claim 20 , wherein R 15 is selected from methyl, ethyl, hydroxymethyl, and 2-hydroxyethyl.
24. The method of claim 20 , wherein R 5 is hydrogen.
25. The method of claim 20 , wherein L and Q are absent.
26. The method of claim 20 , wherein R 6 is an N-terminal protecting group.
27. The method of claim 26 , wherein R 6 is selected from t-butoxycarbonyl and benzyloxycarbonyl.
28. The method of claim 20 , wherein the carbon bearing R 1 has a D stereochemical configuration.
29. The method of claim 28 , wherein R 1 is selected from methyl, ethyl, isopropyl, carboxymethyl, and benzyl.
30. The method of claim 20 , wherein R 2 is selected from C 1-6 alkyl-phenyl, C 1-6 alkyl-indolyl, C 1-6 alkyl-thienyl, C 1-6 alkyl-thiazolyl, and C 1-6 alkyl-isothiazolyl.
31. The method of claim 30 , wherein R 2 is selected from
wherein D is selected from hydrogen, methoxy, t-butoxy, hydroxy, cyano, trifluoromethyl, and C 1-4 -alkyl, wherein C 1-4 -alkyl may be substituted or not with substituents selected from the group consisting of a halogen, a hydroxyl, a carbonyl, a thiocarbonyl, an alkoxyl, a phosphoryl, a phosphate, a phosphonate, a phosphinate, an amino, an amido, an amidine, an imine, a cyano, a nitro, an azido, a sulfhydryl, an alkylthio, a sulfate, a sulfonate, a sulfamoyl, a sulfonamido, a sulfonyl, a heterocyclyl, an aralkyl, or an aromatic or heteroaromatic moiety; and
R is hydrogen or a suitable protecting group.
32. The method of claim 20 , wherein R 3 is selected from C 1-6 alkyl-phenyl and C 1-6 alkyl-indolyl.
33. The method of claim 32 , wherein R 3 is selected from
wherein D is selected from hydrogen, methoxy, t-butoxy, hydroxy, cyano, trifluoromethyl, and C 1-4 -alkyl, wherein C 1-4 -alkyl may be substituted or not with substituents selected from the group consisting of a halogen, a hydroxyl, a carbonyl, a thiocarbonyl, an alkoxyl, a phosphoryl, a phosphate, a phosphonate, a phosphinate, an amino, an amido, an amidine, an imine, a cyano, a nitro, an azido, a sulfhydryl, an alkylthio, a sulfate, a sulfonate, a sulfamoyl, a sulfonamido, a sulfonyl, a heterocyclyl, an aralkyl, or an aromatic or heteroaromatic moiety; and
R is hydrogen or a suitable protecting group.
34. The method of claim 20 , wherein R 6 is selected from heterocyclylMZAZ-C 1-8 alkyl-, heterocyclylM-, and carbocyclylM-.
35. The method of claim 34 , wherein R 6 is heterocyclylMZAZ-C 1-8 alkyl-, and heterocyclylM-.
36. The method of claim 20 , wherein L is C═O, Q is absent, M is C 1-8 alkyl and R 6 is heterocyclylM- and the heterocyclyl moiety is selected from morpholino, piperidino, piperazino, and pyrrolidino.
37. The method of claim 36 , wherein L is C═O, Q is absent, M is C 1-8 alkyl and R 6 is heterocyclylM- and the heterocyclyl moiety is morpholino.
38. The method of claim 20 , wherein the compound is administered prior to transplantation, during transplantation, after transplantation, or any combination thereof.
39. A method for the treatment or prevention of graft versus host disease in a patient, comprising administering to the patient a compound having the structure:
or a pharmaceutically acceptable salt thereof.
40. The method of claim 39 , wherein the compound is administered prior to transplantation, during transplantation, after transplantation, or any combination thereof.
41. A method for the treatment or prevention of transplant rejection in a patient, comprising administering to the patient a compound having a structure of formula (I) or a pharmaceutically acceptable salt thereof,
wherein
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 or is selected from C═O, C═S, and SO 2 ;
M is C 1-2 alkyl;
Q is absent or is selected from O, NH, and N—C 1-6 alkyl;
X is selected from O, S, NH, and N—C 1-6 alkyl;
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 selected from hydrogen, OH, aryl C 1-6 alkyl, and C 1-6 alkyl;
R 6 is selected from an N-terminal protecting group, heterocyclylMZAZC 1-6 alkyl-, heterocyclylM-, and carbocyclylM;
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; and
R 15 is selected from C 1-6 alkyl and C 1-6 hydroxyalkyl;
provided that in any occurrence of the sequence ZAZ, at least one member of the sequence must be other than a covalent bond.
42. The method of claim 41 , wherein R 7 and R 8 are independently selected from hydrogen and C 1-6 aralkyl.
43. The method of claim 42 , wherein R 7 and R 8 are both hydrogen.
44. The method of claim 41 , wherein R 15 is selected from methyl, ethyl, hydroxymethyl, and 2-hydroxyethyl.
45. The method of claim 41 , wherein R 5 is hydrogen.
46. The method of claim 41 , wherein L and Q are absent.
47. The method of claim 41 , wherein R 6 is an N-terminal protecting group.
48. The method of claim 47 , wherein R 6 is selected from t-butoxycarbonyl and benzyloxycarbonyl.
49. The method of claim 41 , wherein the carbon bearing R 1 has a D stereochemical configuration.
50. The method of claim 49 , wherein R 1 is selected from methyl, ethyl, isopropyl, carboxymethyl, and benzyl.
51. The method of claim 41 , wherein R 2 is selected from C 1-6 alkyl-phenyl, C 1-6 alkyl-indolyl, C 1-6 alkyl-thienyl, C 1-6 alkyl-thiazolyl, and C 1-6 alkyl-isothiazolyl.
52. The method of claim 51 , wherein R 2 is selected from
wherein D is selected from hydrogen, methoxy, t-butoxy, hydroxy, cyano, trifluoromethyl, and C 1-4 alkyl, wherein C 1-4 alkyl may be substituted or not with substituents selected from the group consisting of a halogen, a hydroxyl, a carbonyl, a thiocarbonyl, an alkoxyl, a phosphoryl, a phosphate, a phosphonate, a phosphinate, an amino, an amido, an amidine, an imine, a cyano, a nitro, an azido, a sulfhydryl, an alkylthio, a sulfate, a sulfonate, a sulfamoyl, a sulfonamido, a sulfonyl, a heterocyclyl, an aralkyl, or an aromatic or heteroaromatic moiety; and
R is hydrogen or a suitable protecting group.
53. The method of claim 41 , wherein R 3 is selected from C 1-6 alkyl-phenyl and C 1-6 alkyl-indolyl.
54. The method of claim 53 , wherein R 3 is selected from
wherein D is selected from hydrogen, methoxy, t-butoxy, hydroxy, cyano, trifluoromethyl, and C 1-4 -alkyl, wherein C 1-4 -alkyl may be substituted or not with substituents selected from the group consisting of a halogen, a hydroxyl, a carbonyl, a thiocarbonyl, an alkoxyl, a phosphoryl, a phosphate, a phosphonate, a phosphinate, an amino, an amido, an amidine, an imine, a cyano, a nitro, an azido, a sulfhydryl, an alkylthio, a sulfate, a sulfonate, a sulfamoyl, a sulfonamido, a sulfonyl, a heterocyclyl, an aralkyl, or an aromatic or heteroaromatic moiety; and
R is hydrogen or a suitable protecting group.
55. The method of claim 41 , wherein R 6 is selected from heterocyclylMZAZ-C 1-8 alkyl-, heterocyclylM-, and carbocyclylM-.
56. The method of claim 55 , wherein R 6 is heterocyclylMZAZ-C 1-8 alkyl-, and heterocyclylM-.
57. The method of claim 41 , wherein L is C═O, Q is absent, M is C 1-8 alkyl and R 6 is heterocyclylM- and the heterocyclyl moiety is selected from morpholino, piperidino, piperazino, and pyrrolidino.
58. The method of claim 57 , wherein L is C═O, Q is absent, M is C 1-8 alkyl and R 6 is heterocyclylM- and the heterocyclyl moiety is morpholino.
59. The method of claim 41 , wherein the transplant rejection occurs following the transplantation of cells into the patient.
60. The method of claim 41 , wherein the compound is administered prior to transplantation, during transplantation, after transplantation, or any combination thereof.
61. A method for the treatment or prevention of transplant rejection in a patient, comprising administering to the patient a compound having the structure:
or a pharmaceutically acceptable salt thereof.
62. The method of claim 61 , wherein the compound is administered prior to transplantation, during transplantation, after transplantation, or any combination thereof.
63. A method for the treatment of rheumatoid arthritis in a patient, comprising administering to the patient a compound having a structure of formula (I) or a pharmaceutically acceptable salt thereof,
wherein
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 or is selected from C═O, C═S, and SO 2 ;
M is C 1-12 alkyl;
Q is absent or is selected from O, NH, and N—C 1-6 alkyl;
X is selected from O, S, NH, and N—C 1-6 alkyl;
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 selected from hydrogen, OH, aryl C 1-6 alkyl, and C 1-6 alkyl;
R 6 is selected from an N-terminal protecting group, heterocyclylMZAZC 1-6 alkyl-, heterocyclylM-, and carbocyclylM;
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; and
R 15 is selected from C 1-6 alkyl and C 1-6 hydroxyalkyl;
provided that in any occurrence of the sequence ZAZ, at least one member of the sequence must be other than a covalent bond.
64. The method of claim 63 , wherein R 7 and R 8 are independently selected from hydrogen and C 1-6 aralkyl.
65. The method of claim 63 , wherein R 7 and R 8 are both hydrogen.
66. The method of claim 63 , wherein R 15 is selected from methyl, ethyl, hydroxymethyl, and 2-hydroxyethyl.
67. The method of claim 63 , wherein R 5 is hydrogen.
68. The method of claim 63 , wherein L and Q are absent.
69. The method of claim 63 , wherein R 6 is an N-terminal protecting group.
70. The method of claim 69 , wherein R 6 is selected from t-butoxycarbonyl and benzyloxycarbonyl.
71. The method of claim 63 , wherein the carbon bearing R 1 has a D stereochemical configuration.
72. The method of claim 71 , wherein R 1 is selected from methyl, ethyl, isopropyl, carboxymethyl, and benzyl.
73. The method of claim 63 , wherein R 2 is selected from C 1-6 alkyl-phenyl, C 1-6 alkyl-indolyl, C 1-6 alkyl-thienyl, C 1-6 alkyl-thiazolyl, and C 1-6 alkyl-isothiazolyl.
74. The method of claim 73 , wherein R 2 is selected from
wherein D is selected from hydrogen, methoxy, t-butoxy, hydroxy, cyano, trifluoromethyl, and C 1-4 -alkyl, wherein C 1-4 -alkyl may be substituted or not with substituents selected from the group consisting of a halogen, a hydroxyl, a carbonyl, a thiocarbonyl, an alkoxyl, a phosphoryl, a phosphate, a phosphonate, a phosphinate, an amino, an amido, an amidine, an imine, a cyano, a nitro, an azido, a sulfhydryl, an alkylthio, a sulfate, a sulfonate, a sulfamoyl, a sulfonamido, a sulfonyl, a heterocyclyl, an aralkyl, or an aromatic or heteroaromatic moiety; and
R is hydrogen or a suitable protecting group.
75. The method of claim 63 , wherein R 3 is selected from C 1-6 alkyl-phenyl and C 1-6 alkyl-indolyl.
76. The method of claim 75 , wherein R 3 is selected from
wherein D is selected from hydrogen, methoxy, t-butoxy, hydroxy, cyano, trifluoromethyl, and C 1-4 -alkyl, wherein C 1-4 -alkyl may be substituted or not with substituents selected from the group consisting of a halogen, a hydroxyl, a carbonyl, a thiocarbonyl, an alkoxyl, a phosphoryl, a phosphate, a phosphonate, a phosphinate, an amino, an amido, an amidine, an imine, a cyano, a nitro, an azido, a sulfhydryl, an alkylthio, a sulfate, a sulfonate, a sulfamoyl, a sulfonamido, a sulfonyl, a heterocyclyl, an aralkyl, or an aromatic or heteroaromatic moiety; and
R is hydrogen or a suitable protecting group.
77. The method of claim 63 , wherein R 6 is selected from heterocyclylMZAZ-C 1-8 alkyl-, heterocyclylM-, and carbocyclylM-.
78. The method of claim 77 , wherein R 6 is heterocyclylMZAZ-C 1-8 alkyl-, and heterocyclylM-.
79. The method of claim 63 , wherein L is C═O, Q is absent, M is C 1-8 alkyl and R 6 is heterocyclylM- and the heterocyclyl moiety is selected from morpholino, piperidino, piperazino, and pyrrolidino.
80. The method of claim 79 , wherein L is C═O, Q is absent, M is C 1-8 alkyl and R 6 is heterocyclylM- and the heterocyclyl moiety is morpholino.
81. A method for the treatment of rheumatoid arthritis in a patient, comprising administering to the patient a compound having the structure:
or a pharmaceutically acceptable salt thereof.
82. A method for the treatment of Sjogren's syndrome in a patient, comprising administering to the patient a compound having a structure of formula (I) or a pharmaceutically acceptable salt thereof,
wherein
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 or is selected from C═O, C═S, and SO 2 ;
M is C 1-2 alkyl;
Q is absent or is selected from O, NH, and N—C 1-6 alkyl;
X is selected from O, S, NH, and N—C 1-6 alkyl;
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 selected from hydrogen, OH, aryl C 1-6 alkyl, and C 1-6 alkyl;
R 6 is selected from an N-terminal protecting group, heterocyclylMZAZC 1-6 alkyl-, heterocyclylM-, and carbocyclylM;
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; and
R 15 is selected from C 1-6 alkyl and C 1-6 hydroxyalkyl;
provided that in any occurrence of the sequence ZAZ, at least one member of the sequence must be other than a covalent bond.
83. The method of claim 82 , wherein R 7 and R 8 are independently selected from hydrogen and C 1-6 aralkyl.
84. The method of claim 82 , wherein R 7 and R 8 are both hydrogen.
85. The method of claim 82 , wherein R 15 is selected from methyl, ethyl, hydroxymethyl, and 2-hydroxyethyl.
86. The method of claim 82 , wherein R 5 is hydrogen.
87. The method of claim 82 , wherein L and Q are absent.
88. The method of claim 82 , wherein R 6 is an N-terminal protecting group.
89. The method of claim 88 , wherein R 6 is selected from t-butoxycarbonyl and benzyloxycarbonyl.
90. The method of claim 82 , wherein the carbon bearing R 1 has a D stereochemical configuration.
91. The method of claim 90 , wherein R 1 is selected from methyl, ethyl, isopropyl, carboxymethyl, and benzyl.
92. The method of claim 82 , wherein R 2 is selected from C 1-6 alkyl-phenyl, C 1-6 alkyl-indolyl, C 1-6 alkyl-thienyl, C 1-6 alkyl-thiazolyl, and C 1-6 alkyl-isothiazolyl.
93. The method of claim 92 , wherein R 2 is selected from
wherein D is selected from hydrogen, methoxy, t-butoxy, hydroxy, cyano, trifluoromethyl, and C 1-4 -alkyl, wherein C 1-4 -alkyl may be substituted or not with substituents selected from the group consisting of a halogen, a hydroxyl, a carbonyl, a thiocarbonyl, an alkoxyl, a phosphoryl, a phosphate, a phosphonate, a phosphinate, an amino, an amido, an amidine, an imine, a cyano, a nitro, an azido, a sulfhydryl, an alkylthio, a sulfate, a sulfonate, a sulfamoyl, a sulfonamido, a sulfonyl, a heterocyclyl, an aralkyl, or an aromatic or heteroaromatic moiety; and
R is hydrogen or a suitable protecting group.
94. The method of claim 82 , wherein R 3 is selected from C 1-6 alkyl-phenyl and C 1-6 alkyl-indolyl.
95. The method of claim 94 , wherein R 3 is selected from
wherein D is selected from hydrogen, methoxy, t-butoxy, hydroxy, cyano, trifluoromethyl, and C 1-4 -alkyl, wherein C 1-4 -alkyl may be substituted or not with substituents selected from the group consisting of a halogen, a hydroxyl, a carbonyl, a thiocarbonyl, an alkoxyl, a phosphoryl, a phosphate, a phosphonate, a phosphinate, an amino, an amido, an amidine, an imine, a cyano, a nitro, an azido, a sulfhydryl, an alkylthio, a sulfate, a sulfonate, a sulfamoyl, a sulfonamido, a sulfonyl, a heterocyclyl, an aralkyl, or an aromatic or heteroaromatic moiety; and
R is hydrogen or a suitable protecting group.
96. The method of claim 82 , wherein R 6 is selected from heterocyclylMZAZ-C 1-8 alkyl-, heterocyclylM-, and carbocyclylM-.
97. The method of claim 87 , wherein R 6 is heterocyclylMZAZ-C 1-8 alkyl-, and heterocyclylM-.
98. The method of claim 82 , wherein L is C═O, Q is absent, M is C 1-8 alkyl and R 6 is heterocyclylM- and the heterocyclyl moiety is selected from morpholino, piperidino, piperazino, and pyrrolidino.
99. The method of claim 98 , wherein L is C═O, Q is absent, M is C 1-8 alkyl and R 6 is heterocyclylM- and the heterocyclyl moiety is morpholino.
100. A method for the treatment of Sjogren's syndrome in a patient, comprising administering to the patient a compound having the structure:
or a pharmaceutically acceptable salt thereof.