Inhibitors of (alpha-v)(beta-6) integrin
Disclosed are small molecule inhibitors of αvβ6 integrin, and methods of using them to treat a number of diseases and conditions.
1. A compound of formula (I):
A-B-C (I)
wherein:
A is
B is alkylene-N(R)C(O)—, -alkylene-(heterocyclyl)-C(O)—, or -heterocyclyl-C(O)—;
Cis
wherein
each n′ is 0;
R 3 is H, halide, CF 3 , alkyl, alkylene-alkoxy, aryl, hydroxyl, or alkoxy;
R 6 is H, halide, CF 3 , alkyl, alkylene-alkoxy, aryl, hydroxyl, or alkoxy; and
R 7 is H, halide, CF 3 , alkyl, alkylene-alkoxy, aryl, hydroxyl, or alkoxy;
R is H, alkyl, or aryl;
each R 1 is independently H, alkyl, halide, alkoxy, CF 3 , OH, alkylene-OH, NO 2 , —N(H)R, or NH 2 ; and
R 2 is H, alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, cycloalkyl, -alkylene-alkoxy, alkylene-aryl, or heterocycloalkyl;
provided that all instances of R 1 and R 2 are not simultaneously H,
or a pharmaceutically acceptable salt thereof.
2. The compound of claim 1 , wherein at least one instance of R 1 is alkyl, halide, OMe, OH, alkylene-OH, or NH 2 .
3. The compound of claim 2 , wherein R 1 is alkyl, or halide.
4. The compound of claim 1 , wherein all instances of R 1 are H.
5. The compound of claim 1 , wherein B is selected from the group consisting of:
wherein
R is H or Me;
m is 0, 1, 2, or 3; and
n is 0 or 1.
6. The compound of claim 1 , wherein:
R 6 and R 7 are each H.
7. The compound of claim 6 , wherein R 3 is H, halide, Me, or OMe.
8. The compound of claim 5 , wherein C is
9. The compound of claim 1 , wherein R 2 is (C 1 -C 4 )alkyl, cyclopropyl, CH 2 OMe, phenyl, —CH 2 Ph, pyridinyl, or indolyl.
10. The compound of claim 9 , wherein R 2 is H.
11. The compound of claim 9 , wherein R 2 is Me.
12. The compound of claim 9 , wherein R 2 is unsubstituted phenyl.
13. The compound of claim 9 , wherein R 2 is substituted phenyl.
14. The compound of claim 13 , wherein the substituted phenyl is substituted with one or more independent instances of alkoxy, OH, halide, —N(H)C(O)alkyl, —C(O)NH 2 , or —C(O)alkyl.
15. The compound of claim 14 , wherein the substituted phenyl is substituted with at least one halide.
16. The compound of claim 15 , wherein the halide is Cl.
17. The compound of claim 9 , wherein R 2 is unsubstituted pyridinyl.
18. The compound of claim 9 , wherein R 2 is substituted pyridinyl.
19. The compound of claim 18 , wherein the substituted pyridinyl is substituted with NH 2 or OH.
20. The compound of claim 9 , wherein R 2 is
21. The compound of claim 8 , wherein A is
22. A pharmaceutical composition, comprising a compound of claim 1 ; and a pharmaceutically acceptable excipient.
23. The compound of claim 1 , wherein the compound is selected from the group consisting of:
24. The compound of claim 1 , wherein the compound is:
25. The compound of claim 1 , wherein the compound is:
26. The compound of claim 1 , wherein the compound is:
27. The compound of claim 1 , wherein the compound is:
28. The compound of claim 1 , wherein the compound is:
29. The compound of claim 1 , wherein the compound is selected from the group consisting of:
30. The compound of claim 1 , wherein:
a. A is
b. B is selected from the group consisting of:
wherein n is 0 or 1 and m is 2 or 3; and
c. C is
wherein R 3 is H or F, and R 2 is selected from the group consisting of: alkyl, unsubstituted phenyl, and phenyl substituted with one or more independent instances of alkyl, alkoxy, or halide.
31. The compound of claim 1 , wherein:
A is
B is -alkylene-N(R)C(O)—, -alkylene-(heterocyclyl)-C(O)—, or -heterocyclyl-C(O)—, and R is H or alkyl;
C is
wherein R 3 is H or halide; and
R 2 is alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, cycloalkyl, -alkylene-alkoxy, alkylene-aryl, or heterocycloalkyl;
or a pharmaceutically acceptable salt thereof.
32. The compound of claim 31 , wherein R 2 is selected from the group consisting of: alkyl, and substituted or unsubstituted aryl.
33. The compound of claim 31 , wherein R 3 is H or F.
34. The compound of claim 32 , wherein R 2 is selected from the group consisting of: alkyl, and substituted or unsubstituted phenyl.
35. The compound of claim 34 , wherein B is selected from the group consisting of:
wherein
R is H or Me;
m is 2, or 3; and
n is 0, or 1.
36. The compound of claim 35 , wherein R 2 is selected from the group consisting of: alkyl, unsubstituted phenyl, or phenyl substituted with one or more independent instances of alkyl, alkoxy, or halide.
37. The compound of claim 36 , wherein R is H or Me; and R 3 is H or F.
38. The compound of claim 37 , wherein R 3 is H.
39. The compound of claim 31 , wherein R 2 is phenyl substituted with one or more independent instances of alkyl, cycloalkyl, alkoxy, —CF 3 , Cl or F.
40. The compound of claim 37 , wherein R 2 is (C 1 -C 4 ) alkyl.
41. The compound of claim 37 , wherein R 2 is Me.
42. The compound of claim 37 , wherein R 2 is unsubstituted phenyl.
43. The compound of claim 35 , wherein B is
44. The compound of claim 43 , wherein R 2 is unsubstituted phenyl or phenyl substituted with one or more independent instances of alkoxy, Cl or F.
45. The compound of claim 43 , wherein R 2 is Me.
46. The compound of claim 35 , wherein B is
wherein R is H; and R 2 is H, (C 1 -C 4 )alkyl, unsubstituted phenyl, or phenyl substituted with one or more independent instances of alkoxy, and halide.
47. The compound of claim 46 , wherein R 2 is Me, unsubstituted phenyl, or phenyl substituted with one or more independent instances of alkoxy, and Cl.
48. The compound of claim 37 , wherein R is H; R 2 is Me, or unsubstituted phenyl; and R 3 is H.
49. A compound of claim 1 , wherein:
A is
B is
wherein n is 0 or 1; and
C is
wherein R 2 is Me, unsubstituted phenyl, or phenyl substituted with one or more independent instances of alkoxy, CF 3 , and halide;
or a pharmaceutically acceptable salt thereof.
50. The compound of compound 49 , wherein R 2 is unsubstituted phenyl, or phenyl substituted with one or more independent instances of alkoxy, Cl and F; and R 3 is H or F.
51. The compound of claim 50 , wherein R 3 is H.
52. The compound of claim 51 , wherein R 2 is unsubstituted phenyl or phenyl substituted with one or more independent instances of alkoxy, Cl and F.
53. The compound of claim 1 , wherein:
A is
B is selected from the group consisting of:
wherein m is 2 or 3, and
wherein n is 0 or 1; and
C is
wherein R 3 is H or F; and R 2 is methyl, unsubstituted phenyl, or phenyl substituted with one or more independent instances of alkoxy, CF 3 , Cl or F.
54. The compound of claim 1 , wherein B is alkylene-N(R)C(O)—; R 3 is H or halide; R 6 is H; R 7 is H; R is H; each R 1 is independently H, alkyl, halide, or alkoxy; and R 2 is H, alkyl, substituted phenyl or phenyl substituted with one or more independent instances of alkyl, alkoxy, or halide.
55. The compound of claim 54 , wherein A is
and R 2 is alkyl, substituted phenyl or phenyl substituted with one or more independent instances of alkyl, alkoxy, or halide.
56. The compound of claim 1 , wherein B is -alkylene-(heterocyclyl)-C(O)—; R 3 is H or halide; R 6 is H; R 7 is H; R is H; each R 1 is independently H, alkyl, halide, or alkoxy; and R 2 is H, alkyl, substituted phenyl or phenyl substituted with one or more independent instances of alkyl, alkoxy, or halide.
57. The compound of claim 56 , wherein A is
and R 2 is alkyl, substituted phenyl or phenyl substituted with one or more independent instances of alkyl, alkoxy, or halide.
58. The compound of claim 1 , wherein B is heterocyclyl-C(O); R 3 is H or halide; R 6 is H; R 7 is H; R is H; each R 1 is independently H, alkyl, halide, or alkoxy; and R 2 is H, alkyl, substituted phenyl or phenyl substituted with one or more independent instances of alkyl, alkoxy, or halide.
59. The compound of claim 58 , wherein A is
and R 2 is alkyl, substituted phenyl or phenyl substituted with one or more independent instances of alkyl, alkoxy, or halide.