Inhibitors of (α-v)(β-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 represented by formula (I):
A-B-C (I)
wherein:
A is
B is -alkylene-N(R)C(O)—, -alkylene-(heterocyclyl)-C(O)—, -aryl-alkylene-N(R)C(O)—, -aryl-N(R)C(O)—, -heterocyclyl-alkylene-N(R)C(O)—, or -heterocyclyl-C(O)—;
C is
R is independently H, alkyl, or aryl;
R 1 is independently H, alkyl, halide, alkoxy, CF 3 , OH, NO 2 , —N(H)R, or NH 2 ;
R 2 is H, alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, cycloalkyl, -alkylene-alkoxy, alkoxy, OH, -alkylene-aryl, heterocycloalkyl, —N(R)C(O)R 4 , —N(R)SO 2 R 4 -, —N(R)-aryl, or —N(R)-heteroaryl;
R 3 is independently alkyl, halide, alkoxy, CF 3 , OH, NO 2 , or NH 2 ;
R 4 is alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -alkylene-heterocyclyl, -alkylene-N(R)C(O)R 5 , or -alkylene-N(R)—SO 2 Me;
R 5 is alkyl, or cycloalkyl;
R 6 is H, or alkyl;
X is N;
R d is H, or (C 1 -C 6 )alkyl;
a is independently 0, or 1; and
b is 0, 1, 2, 3, or 4;
or a pharmaceutically acceptable salt thereof.
2. The compound of claim 1 , wherein R is H or Me.
3. The compound of claim 1 , wherein at least one instance of R 1 is alkyl, halide, alkoxy, CF 3 , OH, —N(H)R, or NH 2 .
4. The compound of claim 3 , wherein R 1 is alkyl, or halide.
5. The compound of claim 1 , wherein all instances of R 1 are H.
6. The compound of claim 1 , wherein B is —(C 1 -C 6 )alkylene-N(R)—C(O)—.
7. The compound of claim 6 , wherein B is
R is H, Me or Ph; and
n is 1, 2, or 3.
8. The compound of claim 1 , wherein at least one instance of a is 0.
9. The compound of claim 1 , wherein at least one instance of a is 1.
10. The compound of claim 1 , wherein b is 0.
11. The compound of claim 1 , wherein b is 1, or 2.
12. The compound of claim 1 , wherein R 3 is independently alkyl, halide, alkoxy, or NH 2 .
13. The compound of claim 1 , wherein R 6 is H.
14. The compound of claim 1 , wherein R 6 is Me.
15. The compound of claim 1 , wherein C is selected from the group consisting of:
16. The compound of claim 1 , wherein R 2 is H, alkyl, aryl, heteroaryl, hydroxyl, or alkoxy.
17. The compound of claim 16 , wherein R 2 is substituted or unsubstituted phenyl.
18. The compound of claim 1 , wherein R 2 is N(H)C(O)R 4 , —N(R)SO 2 R 4 -, —N(H)-aryl, or —N(H)-heteroaryl.
19. The compound of claim 18 , wherein R 2 is —N(H)-2-pyridinyl, or —N(H)-2,4-pyrimidinyl.
20. The compound of claim 18 , wherein R 2 is —N(H)C(O)Me.
21. The compound of claim 18 , wherein
R 4 is Me,
and
Y is H, F, or Cl.
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 selected from the group consisting of:
25. The compound of claim 1 , wherein the compound is selected from the group consisting of:
26. The compound of claim 1 , wherein the compound is selected from the group consisting of:
27. The compound of claim 1 , wherein the compound is selected from the group consisting of:
28. The compound of claim 1 , wherein the compound is selected from the group consisting of:
29. The compound of claim 1 , wherein the compound is:
30. The compound of claim 10 , wherein R d is H.
31. The compound of claim 30 , wherein R 6 is H.
32. The compound of claim 31 , wherein all instances of R 1 are H.
33. The compound of claim 32 , wherein R is H or Me.
34. The compound of claim 33 , wherein B is
and n is 1, 2 or 3.
35. The compound of claim 34 , wherein R is H.
36. The compound of claim 35 , wherein R 2 is H, alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, cycloalkyl, -alkylene-alkoxy, alkoxy, OH, -alkylene-aryl, heterocycloalkyl, —N(R)C(O)R 4 , —N(R)SO 2 R 4 -, —N(R)-aryl, or —N(R)— heteroaryl.
37. The compound of claim 36 , wherein R 2 is H.
38. The compound of claim 1 , wherein R is H; each R 1 is H; R 6 is H; R d is H; and b is 0.
39. The compound of claim 38 , wherein B is -alkylene-N(R)C(O)—.
40. The compound of claim 38 , wherein B is -alkylene-(heterocyclyl)-C(O)—.
41. The compound of claim 38 , wherein B is -heterocyclyl-alkylene-N(R)C(O)—.
42. The compound of claim 38 , wherein B is -heterocyclyl-C(O)—.