3,4-Di-substituted cyclobutene-1,2-diones as CXC-chemokine receptor ligands
View Patent ↗There are disclosed compounds of the formula or a pharmaceutically acceptable salt or solvate thereof which are useful for the treatment of chemokine-mediated diseases such as acute and chronic inflammatory disorders and cancer.
1. A compound of the formula:
and the pharmaceutically acceptable salts and solvates thereof, wherein:
A is selected from the group consisting of:
wherein said A group is substituted with 1 to 6 substituents each independently selected from the group consisting of: unsubstituted alkyl;
wherein said A group is substituted with 1 to 6 substituents each independently selected from the group consisting of: unsubstituted alkyl;
wherein one or both rings of said A group is substituted with 1 to 6 substituents each independently selected from the group consisting of: unsubstituted alkyl;
wherein one or both rings of said A group is substituted with 1 to 6 substituents each independently selected from the group consisting of: unsubstituted alkyl;
B is:
wherein R 3 is selected from the group consisting of:
—C(O)NR 13 R 14 ,
n is 0;
R 2 is selected from the group consisting of: hydrogen, OH, —C(O)OH, —SH, —SO 2 NR 13 R 14 , —NHC(O)R 13 , —NHSO 2 NR 13 R 14 , —NHSO 2 R 13 , —NR 13 R 14 , —C(O)NR 13 R 14 , —C(O)NHOR 13 , —C(O)NR 13 OH, —S(O 2 )OH, —OC(O)R 13 ;
R 4 is independently selected from the group consisting of: hydrogen, cyano, halogen, alkyl, alkoxy, —OH, —CF 3 , —OCF 3 , —NO 2 , —C(O)R 13 , —C(O)OR 13 , —C(O)NHR 17 , —C(O)NR 13 R 14 , —SO (t) NR 13 R 14 , —SO (t) R 13 , —C(O)NR 13 OR 14 , and unsubstituted or substituted aryl,
wherein there are 1 to 6 substituents on said substituted aryl group and each substituent is independently selected from the group consisting of: R 9 groups;
each R 5 and R 6 are the same or different and are independently selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, —CF 3 , —OCF 3 , —NO 2 , —C(O)R 13 , —C(O)OR 13 , —C(O)NR 13 R 14 , —SO (t) NR 13 R 14 , —C(O)NR 13 OR 14 , cyano, and unsubstituted aryl;
each R 7 and R 8 is independently selected from the group consisting of: H, unsubstituted or substituted alkyl, unsubstituted or substituted cycloalkyl, alkynyl and alkenyl; and wherein there are one or more substituents on said substituted R 7 and R 8 groups, wherein each substituent is independently selected from the group consisting of:
a) halogen,
b) —CF 3 ,
c) —COR 13 ,
d) —OR 13 ,
e) —NR 13 R 14 ,
f) —NO 2 ,
g) —CN,
h) —SO 2 OR 13 ,
i) —CO 2 R 13 ,
j) —C(O)NR 13 R 14 ,
k) —NR 13 C(O)R 14 , and
l) —NR 13 CO 2 R 14 ;
each R 9 is independently selected from the group consisting of:
—R 13 ;
each R 13 and R 14 is independently selected from the group consisting of: H and unsubstituted alkyl;
each R 15 is independently selected from the group consisting of: H, alkyl, aryl, arylalkyl, cycloalkyl and heteroaryl;
R 17 is selected from the group consisting of: —SO 2 alkyl, —SO 2 aryl, —SO 2 cycloalkyl, and —SO 2 heteroaryl;
R 30 is selected from the group consisting of: alkyl, cycloalkyl, —CN, —NO 2 , or —SO 2 R 15 provided that R 15 is not H; and
t is 0, 1 or 2.
2. The compound of claim 1 wherein B is:
3. The compound of claim 1 wherein B is:
R 2 is —OH, and R 13 and R 14 are each the same or different alkyl group.
4. The compound of claim 1 wherein B is:
R 3 selected from the group consisting of:
5. The compound of claim 1 wherein B is:
and R 2 is —OH.
6. The compound of claim 1 wherein B is
R 13 and R 14 are each the same or different alkyl group.
7. The compound of claim 1 wherein B is
8. The compound of claim 7 wherein R 2 —OH.
9. The compound of claim 7 wherein R 13 and R 14 are the same or different alkyl group.
10. The compound of claim 9 wherein the R 2 substituent is —OH.
11. The compound of claim 9 wherein R 13 and R 14 methyl.
12. The compound of claim 11 wherein the R 2 substituent is —OH.
13. The compound of claim 1 wherein A is
wherein the furan ring is unsubstituted or substituted.
14. The compound of claim 1 wherein A is
wherein the furan ring is substituted.
15. The compound of claim 1 wherein A is
wherein the furan ring is substituted with at least one alkyl group.
16. The compound of claim 13 wherein R 7 and R 8 are independently selected from the group consisting of: H and alkyl.
17. The compound of claim 16 wherein R 7 is H, and R 8 is alkyl.
18. The compound of claim 15 wherein R 7 and R 8 are independently selected from the group consisting of: H and alkyl.
19. The compound of claim 18 wherein R 7 is H, and R 8 is alkyl.
20. The compound of claim 1 wherein A is selected from the group consisting of:
wherein the above rings are unsubstituted, or the above rings are substituted with 1 to 3 substituents independently selected from the group consisting of: alkyl, R 7 is selected from the group consisting of: H, —CF 3 , —CF 2 CH 3 , methyl, ethyl, isopropyl, cyclopropyl and t-butyl; and R 8 is H.
21. The compound of claim 2 wherein A is
wherein the furan ring is unsubstituted or substituted.
22. The compound of claim 2 wherein A is
wherein the furan ring is substituted with at least one alkyl group.
23. The compound of claim 22 wherein R 7 and R 8 are independently selected from the group consisting of: H and alkyl.
24. The compound of claim 23 wherein R 7 is H and R 8 is alkyl.
25. The compound of claim 3 wherein A is
wherein the furan ring is unsubstituted or substituted.
26. The compound of claim 25 wherein A is
wherein the furan ring is substituted with at least one alkyl group.
27. The compound of claim 26 wherein R 7 and R 8 are independently selected from the group consisting of: H and alkyl.
28. The compound of claim 27 wherein R 7 is H and R 8 is alkyl.
29. The compound of claim 7 wherein A is
wherein the furan ring is unsubstituted or substituted.
30. The compound of claim 7 wherein A is
wherein the furan ring is substituted with at least one alkyl group.
31. The compound of claim 30 wherein R 7 and R 8 are independently selected from the group consisting of: H and alkyl.
32. The compound of claim 31 wherein R 7 is H and R 8 is alkyl.
33. The compound of claim 8 wherein A is
wherein the furan ring is unsubstituted or substituted.
34. The compound of claim 8 wherein A is
wherein the furan ring is substituted with at least one alkyl group.
35. The compound of claim 34 wherein R 7 and R 8 are independently selected from the group consisting of: H and alkyl.
36. The compound of claim 35 wherein R 7 is H and R 8 is alkyl.
37. The compound of claim 10 wherein A is
wherein the furan ring is unsubstituted or substituted.
38. The compound of claim 10 wherein A is
wherein the furan ring is substituted with at least one alkyl group.
39. The compound of claim 38 wherein R 7 and R 8 are independently selected from the group consisting of: H and alkyl.
40. The compound of claim 39 wherein R 7 is H and R 8 is alkyl.
41. The compound of claim 1 wherein:
(1) A is selected from the group consisting of:
wherein the above rings are unsubstituted, or the above rings are substituted with 1 to 3 substituents independently selected from the group consisting of: alkyl, R 7 is selected from the group consisting of: H, —CF 3 , —CF 2 CH 3 , methyl, ethyl, isopropyl, cyclopropyl and t-butyl; and R 8 is H; and
(2) B is:
wherein:
R 2 is selected from the group consisting of: H, OH, —NHC(O)R 13 and —NHSO 2 R 13 ;
R 4 is selected from the group consisting of: H, —NO 2 , cyano, —CH 3 or —CF 3 ;
R 5 is selected from the group consisting of: H, —CF 3 , —NO 2 , halogen and cyano; and
R 6 is selected from the group consisting of: H, alkyl and —CF 3 ; and
each R 13 and R 14 is independently selected from the group consisting of: methyl and ethyl.
42. The compound of claim 1 wherein
(1) A is selected from the group consisting of:
wherein:
R 2 is —OH;
R 4 is selected form the group consisting of: H, —CH 3 and —CF 3 ;
R 5 is selected from the group consisting of: H and cyano;
R 6 is selected from the group consisting of: H, —CH 3 and —CF 3 ;
R 13 and R 14 are methyl.
43. The compound of claim 1 wherein said compound is a calcium salt.
44. The compound of claim 1 wherein said compound is a sodium salt.
45. The compound of claim 1 wherein said compound is:
or a pharmaceutically acceptable salt or solvate thereof.
46. The compound of claim 1 wherein said compound is:
or a pharmaceutically acceptable salt or solvate thereof.
47. The compound of claim 1 wherein said compound is:
or a pharmaceutically acceptable salt or solvate thereof.
48. The compound of claim 1 wherein said compound is:
or a pharmaceutically acceptable salt or solvate thereof.
49. The compound of claim 1 wherein said compound is:
or a pharmaceutically acceptable salt or solvate thereof.
50. The compound of claim 1 wherein said compound is:
or a pharmaceutically acceptable salt or solvate thereof.
51. The compound of claim 1 wherein said compound is:
or a pharmaceutically acceptable salt or solvate thereof.
52. The compound of claim 1 wherein said compound is:
or a pharmaceutically acceptable salt or solvate thereof.
53. The compound of claim 1 selected from the group consisting of
54. The compound of claim 53 wherein said compound is a calcium or sodium salt.
55. The compound of claim 47 wherein said compound is a calcium or sodium salt.
56. The compound of claim 48 wherein said compound is a calcium or sodium salt.
57. A pharmaceutical composition comprising an effective amount of a compound of claim 1 in combination with a pharmaceutically acceptable carrier.
58. The compound of claim 1 wherein said compound is selected from the group consisting of:
59. The compound of claim 1 selected from the group consisting of:
60. The compound of claim 1 selected from the group consisting of:
61. The compound of claim 1 selected from the group consisting of:
62. The compound of claim 1 wherein said compound is:
63. The compound of claim 1 wherein said compound is:
64. The compound of claim 1 wherein said compound is:
65. The compound of claim 1 wherein said compound is:
66. The compound of claim 1 wherein said compound is:
67. The compound of claim 1 wherein said compound is:
68. The compound of claim 1 wherein said compound is:
69. The compound of claim 1 wherein said compound is:
or a pharmaceutically acceptable salt thereof.
70. The compound of claim 1 wherein said compound is:
or a pharmaceutically acceptable salt thereof.
71. The compound of claim 1 wherein said compound is:
or a pharmaceutically acceptable salt thereof.
72. The compound of claim 1 wherein said compound is:
or a pharmaceutically acceptable salt thereof.
73. The compound of claim 1 wherein said compound is:
or a pharmaceutically acceptable salt thereof.
74. The compound of claim 1 wherein said compound is:
or a pharmaceutically acceptable salt thereof.
75. The compound of claim 1 wherein said compound is:
or a pharmaceutically acceptable salt thereof.
76. The compound of claim 1 selected from the group consisting of:
77. The compound of claim 61 wherein said compound is a calcium or sodium salt.
78. The compound of claim 76 wherein said compound is a calcium or sodium salt.
79. A compound of the formula:
or a pharmaceutically acceptable salt or solvate thereof.
80. The compound of claim 79 wherein said compound is a calcium or sodium salt.
81. A compound having the formula
82. A compound having the formula
or a pharmaceutically acceptable salt thereof.