USRE49816EActiveUtility
Dipeptides as inhibitors of human immunoproteasomes
Est. expiryJan 10, 2034(~7.5 yrs left)· nominal 20-yr term from priority
C07K 5/06104C07K 5/0606C07K 5/06026C07K 5/06069C07K 5/06086C07K 5/06113C07K 5/06139C07K 5/06191C07K 5/0806C07K 5/0821A61K 38/00A61P 29/00A61P 35/00A61P 37/06
44
PatentIndex Score
0
Cited by
201
References
76
Claims
Abstract
The compounds of the present invention are represented by the following compounds having Formula (I) where the substituents R 1 -R 10 , X, Y, k, m, n, q, and s are as defined herein. These compounds are used in the treatment of cancer, immunologic disorders, autoimmune disorders, neurodegenerative disorders, or inflammatory disorders or for providing immunosuppression for transplanted organs or tissues.
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1. A compound of Formula (Ia):
wherein
R 1a is selected from the group consisting of bicyclic aryl, monocyclic and bicyclic heteroaryl, and monocyclic and bicyclic non-aromatic heterocycle, wherein bicyclic aryl, monocyclic and bicyclic heteroaryl, and monocyclic and bicyclic non-aromatic heterocycle can be optionally substituted from 1 to 3 times with a substituent selected independently at each occurrence thereof from the group consisting of halogen, cyano, C 1-6 alkyl, and C 1-6 alkoxy;
R 2a is selected from the group consisting of C 1-6 alkyl, —CH 2 OC 1-6 alkyl, CH 2 Ar, and heteroaryl, wherein aryl (Ar) can be optionally substituted from 1 to 3 times with a substituent selected independently at each occurrence thereof from the group consisting of halogen, cyano, C 1-6 alkyl, and C 1-6 alkoxy;
R 3a is selected from the group consisting of —CH 2 OC 1-6 alkyl, —(CH 2 ) m C(O)NHR 5a , and —CH 2 C(O)R 5a ;
R 4a is selected from the group consisting of —C(O)(CH 2 ) n Ph, —C(O)CH 2 NR 6a R 7a , —SO 2 Ar, —SO 2 C 1-6 alkyl, —C(O)(CH 2 ) n Het, —C(O)C 1-6 alkyl, —C(O)CF 3 , heteroaryl, and —(CH 2 ) n NR 6a R 7a , wherein aryl (Ar) and heteroaryl (Het) can be optionally substituted from 1 to 3 times with a substituent selected independently at each occurrence thereof from the group consisting of halogen, cyano, C 1-6 alkyl, and C 1-6 alkoxy;
R 5a is selected from the group consisting of C 1-6 alkyl, C 1-6 alkoxy, non-aromatic heterocycle, —NR 6a R 7a , and —CR 8a R 9a ;
R 6a , R 7a , R 8a , and R 9a are each independently selected from the group consisting of H, C 1-6 alkyl, and —(CH 2 ) k OH;
or R 6a and R 7a are taken together with the nitrogen to which they are attached to form a piperidine, pyrrolidine, azepane, azetidine, or morpholine ring;
or R 8a and R 9a are taken together with the carbon to which they are attached to form an oxetane ring;
m is 1 or 2;
n is 0, 1, 2, or 3; and
k is 1, 2, or 3.
2. A pharmaceutical composition comprising a therapeutically effective amount of the compound according to claim 1 and a pharmaceutically acceptable carrier.
3. The compound according to claim 1 , wherein m is 1.
4. The compound according to claim 1 , wherein m is 2.
5. The compound according to claim 1 , wherein R 5a is selected from the group consisting of C 1-6 alkyl, C 1-6 alkoxy, non-aromatic heterocycle, and —CR 8a R 9a .
6. The compound according to claim 3 , wherein R 1a is selected from the group consisting of
7. The compound according to claim 3 , wherein R 2a is selected from the group consisting of Me, —CH 2 OMe, and
8. The compound according to claim 3 , wherein R 3a is selected from the group consisting of —CH 2 OMe,
9. The compound according to claim 3 , wherein R 4a is selected from the group consisting of trifluoroacetyl,
p is 0, 1, 2, or 3;
r is 0, 1, 2, 3, 4, or 5;
t is 0, 1, 2, 3, or 4; and
R is selected from the group consisting of H, halogen, cyano, C 1-6 alkyl, and C 1-6 alkoxy.
10. The compound according to claim 3 , wherein the compound has a structure selected from the group consisting of:
11. A method of treating cancer, immunologic disorders, autoimmune disorders, neurodegenerative disorders, or inflammatory disorders in a subject or for providing immunosuppression for transplanted organs or tissues in a subject, said method comprising:
administering to the subject in need thereof a compound of the Formula (Ia):
wherein
R 1a is selected from the group consisting of bicyclic aryl, monocyclic and bicyclic heteroaryl, and monocyclic and bicyclic non-aromatic heterocycle, wherein bicyclic aryl, monocyclic and bicyclic heteroaryl, and monocyclic and bicyclic non-aromatic heterocycle can be optionally substituted from 1 to 3 times with a substituent selected independently at each occurrence thereof from the group consisting of halogen, cyano, C 1-6 alkyl, and C 1-6 alkoxy;
R 2a is selected from the group consisting of C 1-6 alkyl, —CH 2 OC 1-6 alkyl, —CH 2 Ar, and heteroaryl, wherein aryl (Ar) can be optionally substituted from 1 to 3 times with a substituent selected independently at each occurrence thereof from the group consisting of halogen, cyano, C 1-6 alkyl, and C 1-6 alkoxy;
R 3a is selected from the group consisting of —CH 2 OC 1-6 alkyl, —CH m C(O)NHR 5a , and —CH 2 C(O)R 5a ;
R 4a is selected from the group consisting of —C(O)(CH 2 ) n Ph, —C(O)CH 2 NR 6a R 7a , —SO 2 Ar, —SO 2 C 1-6 alkyl, —C(O)(CH 2 ) n Het, —C(O)C 1-6 alkyl, —C(O)CF 3 , heteroaryl, and —(CH 2 ) n NR 6a R 7a , wherein aryl (Ar) and heteroaryl (Het) can be optionally substituted from 1 to 3 times with a substituent selected independently at each occurrence thereof from the group consisting of halogen, cyano, C 1-6 alkyl, and C 1-6 alkoxy;
R 5a is selected from the group consisting of C 1-6 alkyl, C 1-6 alkoxy, non-aromatic heterocycle, —NR 6a R 7a , and —CR 8a R 9a ;
R 6a , R 7a , R 8a , and R 9a are each independently selected from the group consisting of H, C 1-6 alkyl, and —(CH 2 ) k OH;
or R 6a and R 7a are taken together with the nitrogen to which they are attached to form a piperidine, pyrrolidine, azepane, azetidine, or morpholine ring;
or R 8a and R 9a are taken together with the carbon to which they are attached to form an oxetane ring;
m is 1 or 2;
n is 0, 1, 2, or 3; and
k is 1, 2, or 3.
12. The method of claim 11 , wherein m is 1.
13. The method of claim 11 , wherein m is 2.
14. The method of claim 11 , wherein R 5a is selected from the group consisting of C 1-6 alkyl, C 1-6 alkoxy, non-aromatic heterocycle, and —CR 8a R 9a .
15. The method of claim 12 , wherein R 1a is selected from the group consisting of
16. The method of claim 12 , wherein R 2a is selected from the group consisting of Me, —CH 2 OMe, and
17. The method of claim 12 , wherein R 3a is selected from the group consisting of —CH 2 OMe,
18. The method of claim 12 , wherein R 4a is selected from the group consisting of trifluoroacetyl,
p is 0, 1, 2, or 3;
r is 0, 1, 2, 3, 4, or 5;
t is 0, 1, 2, 3, or 4; and
R is selected from the group consisting of H, halogen, cyano, C 1-6 alkyl, and C 1-6 alkoxy.
19. The method of claim 12 , wherein the compound of Formula (I) is selected from the group consisting of:
20. The method of claim 12 , wherein an autoimmune disorder is treated, said autoimmune disorder being selected from the group consisting of arthritis, colitis, and lupus.
21. The method of claim 12 , wherein immunosuppression is provided for transplanted organs or tissues, said immunosuppression being used to prevent transplant rejection.
22. The method of claim 12 , wherein an inflammatory disorder is treated, said inflammatory disorder being Crohn's disease.
23. The method of claim 12 , wherein cancer is treated, said cancer being selected from the group consisting of neoplastic disorders, hematologic malignancies, and lymphocytic malignancies.
24. A compound of Formula (I):
wherein
R 1 is bicyclic aryl optionally substituted 1 time with a substituent selected independently at each occurrence thereof from the group consisting of halogen and C 1-6 alkyl;
R 2 is selected from the group consisting of C 1-6 alkyl, —CH 2 OC 1-6 alkyl, and —CH 2 Ar, wherein aryl (Ar) can be optionally substituted 1 time with halogen;
R 3 is independently selected at each occurrence thereof from the group consisting of —CH 2 OC 1-6 alkyl and —(CH 2 ) m C(O)NHR 5 ;
R 4 is selected from the group consisting of —C(O)(CH 2 ) n Ph, —SO 2 Ar, —SO 2 C 1-6 alkyl, —C(O)(CH 2 ) n Het, and —C(O)C(O)Het, wherein aryl (Ar) and heteroaryl (Het) can be optionally substituted 1 time with C 1-6 alkyl;
R 5 is selected from the group consisting of C 1-4 alkyl and —CR 8 R 9 ;
R 8 and R 9 are taken together with the carbon to which the are attached to form an oxetane ring;
X is —(CH 2 ) q —,
Y is O;
m is 1 or 2,
n is 0 or 2;
q is 1; and
s is 1.
25. The compound according to claim 24, wherein R 1 is
optionally substituted 1 time with a substituent selected independently at each occurrence thereof from the group consisting of halogen and C 1-6 alkyl.
26. The compound according to claim 24, wherein R 2 is selected from the group consisting of Me, —CH 2 OMe, and
27. The compound according to claim 24, wherein R 3 is selected from the group consisting of
and —CH 2 OMe.
28. The compound according to claim 24, wherein R 4 is selected from the group consisting of
p is 2;
r is 0; and
R is C 1-6 alkyl.
29. The compound according to claim 24, wherein the compound has a structure selected from the group consisting of:
30. The compound according to claim 24, wherein the compound has a structure of:
31. The compound according to claim 24, wherein the compound has a structure of:
32. The compound according to claim 24, wherein the compound has a structure of:
33. The compound according to claim 24, wherein the compound has a structure of:
34. The compound according to claim 24, wherein the compound has a structure of:
35. The compound according to claim 24, wherein the compound has a structure of:
36. The compound according to claim 24, wherein the compound has a structure of:
37. The compound according to claim 24, wherein the compound has a structure of:
38. The compound according to claim 24, wherein R 1 is a bicyclic aryl substituted 1 time with fluoride, R 2 is —CH 2 OMe, R 3 is
R 4 is
and R is Me.
39. The compound according to claim 24, wherein R 1 is a bicyclic aryl substituted 1 time with fluoride, R 2 is —CH 2 OMe, R 3 is
R 4 is
and R is Me.
40. The compound according to claim 24, wherein R 1 is a bicyclic aryl substituted 1 time with fluoride, R 2 is —CH 2 OMe, R 3 is
and R 4 is
41. The compound according to claim 24, wherein R 1 is a bicyclic aryl substituted 1 time with fluoride, R 2 is Me, R 3 is
and R 4 is
42. The compound according to claim 24, wherein R 1 is a bicyclic aryl substituted 1 time with fluoride, R 2 is —CH 2 OMe, R 3 is
and R 4 is
43. The compound according to claim 24, wherein R 1 is a bicyclic aryl substituted 1 time with fluoride, R 2 is Me, R 3 is
and R 4 is
and p is 2.
44. A method of treating cancer, immunologic disorders, autoimmune disorders, neurodegenerative disorders, or inflammatory disorders in a subject or for providing immunosuppression for transplanted organs or tissues in a subject, said method comprising
administering to the subject in need thereof a compound of the Formula (I):
wherein
R 1 is bicyclic aryl optionally substituted 1 time with a substituent selected independently at each occurrence thereof from the group consisting of halogen and C 1-6 alkyl;
R 2 is selected from the group consisting of C 1-6 alkyl, —CH 2 OC 1-6 alkyl, and —CH 2 Ar, wherein aryl (Ar) can be optionally substituted 1 time with halogen;
R 3 is independently selected at each occurrence thereof from the group consisting of —CH 2 OC 1-6 alkyl and —(CH 2 ) m C(O)NHR 5 ;
R 4 is selected from the group consisting of —C(O)(CH 2 ) n Ph, —SO 2 Ar, —SO 2 C 1-6 alkyl, —C(O)(CH 2 ) n Het, and —C(O)C(O)Het, wherein aryl (Ar) and heteroaryl (Het) can be optionally substituted 1 time with C 1-6 alkyl;
R 5 is selected from the group consisting of C 1-4 alkyl and —CR 8 R 9 ;
R 8 and R 9 are taken together with the carbon to which they are attached to form an oxetane ring;
X is —(CH 2 ) q —;
Y is O;
m is 1 or 2;
n is 0 or 2;
q is 1; and
s is 1.
45. The method of claim 44, wherein R 1 is
optionally substituted 1 time with a substituent selected independently at each occurrence thereof from the group consisting of halogen and C 1-6 alkyl.
46. The method of claim 44, wherein R 2 is selected from the group consisting of Me, —CH 2 OMe, and
47. The method of claim 44, wherein R 3 is selected from the group consisting of
and —CH 2 OMe.
48. The method of claim 44, wherein R 4 is selected from the group consisting of
p is 2;
r is 0; and
R is C 1-6 alkyl.
49. The method of claim 44, wherein the compound has a structure selected from the group consisting of:
50. The method of claim 44, wherein the compound has a structure of:
51. The method of claim 44, wherein the compound has a structure of:
52. The method of claim 44, wherein the compound has a structure of:
53. The method of claim 44, wherein the compound has a structure of:
54. The method of claim 44, wherein the compound has a structure of:
55. The method of claim 44, wherein the compound has a structure of:
56. The method of claim 44, wherein the compound has a structure of:
57. The method of claim 44, wherein the compound has a structure of:
58. The method of claim 44, wherein R 1 is a bicyclic aryl substituted 1 time with fluoride, R 2 is —CH 2 OMe, R 3 is
R 4 is
and R is Me.
59. The method of claim 44, wherein R 1 is a bicyclic aryl substituted 1 time with fluoride, R 2 is —CH 2 OMe, R 3 is
R 4 is
and R is Me.
60. The method of claim 44, wherein R 1 is a bicyclic aryl substituted 1 time with fluoride, R 2 is —CH 2 OMe, R 3 is
and R 4 is
61. The method of claim 44, wherein R 1 is a bicyclic aryl substituted 1 time with fluoride, R 2 is Me, R 3 is
and R 4 is
62. The method of claim 44, wherein R 1 is a bicyclic aryl substituted 1 time with fluoride, R 2 is —CH 2 Ome, R 3 is
and R 4 is
63. The method of claim 44, wherein R 1 is a bicyclic aryl substituted 1 time with fluoride, R 2 is Me, R 3 is
and R 4 is
and p is 2.
64. The method of claim 44, wherein an autoimmune disorder is treated, said autoimmune disorder being selected from the group consisting of arthritis, colitis, and lupus.
65. The method of claim 44, wherein immunosuppression is provided for transplanted organs or tissues, said immunosuppression being used to prevent transplant rejection.
66. The method of claim 44, wherein an inflammatory disorder is treated, said inflammatory disorder being Crohn's disease.
67. The method of claim 44, wherein cancer is treated, said cancer being selected from the group consisting of neoplastic disorders, hematologic malignancies, and lymphocytic malignancies.
68. A pharmaceutical composition comprising a therapeutically effective amount of the compound according to claim 24 and a pharmaceutically acceptable carrier.
69. The compound according to claim 24, wherein R 1 is a bicyclic aryl substituted 1 time with fluoride, R 2 is Me, R 3 is
R 4 is
and p is 2.
70. The compound according to claim 24, wherein R 1 is a bicyclic aryl substituted 1 time with fluoride, R 2 is Me, R 3 is
R 4 is
and R is methyl.
71. The compound according to claim 24, wherein R 1 is
R 2 is
R 3 is
and R 4 is
and p is 2.
72. The compound according to claim 1, wherein R 1a is
R 2a is —CH 2 OMe, R 3a is
R 4a is
and p is 3.
73. The method of claim 44, wherein R 1 is a bicyclic aryl substituted 1 time with fluoride, R 2 is Me, R 3 is
R 4 is
and p is 2.
74. The method of claim 44, wherein R 1 is a bicyclic aryl substituted 1 time with fluoride, R 2 is Me, R 3 is
R 4 is
and R is methyl.
75. The method of claim 44, wherein R 1 is
R 2 is
R 3 is
and R 4 is
and p is 2.
76. The method of claim 11, wherein R 1a is
R 2a is —CH 2 Ome, R 3a is
R 4a is
and p is 3.Cited by (0)
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