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, -alkylene-(O); -alkylene-N(R)C(O)—, -alkylene-(heterocyclyl)-C(O)—, -alkylene-C(O)N(R)—, -alkylene-C(O)—, -alkylene-N(R)—, -alkylene-N (R)C(O)N(R)—, -alkylene-N(R)SO 2 —, -alkylene-(aryl)-, -alkylene-(heterocyclyl)-, -alkylene-(heterocyclyl)-alkylene-, -aryl-alkylene-N(R)C(O)—; -aryl-C(O)N(R)—, -aryl-N(R)C(O)—, -(heterocyclyl)-alkylene-, -heterocyclyl-alkylene-N(R)C(O)—; -heterocyclyl-C(O)N(R)—, —O-heterocyclyl-; -alkylene-O—; -heterocyclyl-C(O)—; cycloalkylene; or clycloalkylene-O—;
C is
R is H, alkyl, or aryl;
R 1 is independently H, alkyl, halide, alkoxy, CF 3 , OH, alkylene-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, alkylene-aryl, or heterocycloalkyl;
are a 3-12 membered heterocycloalkylene unsubstituted or substituted by one or more instance of R 1 ;
X is C(R c ) or N;
both instances of R a are H, or taken together form a bond, or a (C 1 -C 4 )alkylene bridge;
R b is H, or (C 1 -C 6 )alkyl; and
R c is H, alkyl, aryl, OH, or halide;
or a pharmaceutically acceptable salt thereof;
provided that the compound of formula (I) is not
2 . The compound of claim 1 , wherein
is a 3-12 membered heterocycloalkylene substituted with one or more instances of R 1 .
3 . The compound of claim 1 , wherein
is an unsubstituted 3-12 membered heterocycloalkylene.
4 . The compound of claim 1 , wherein at least one instance of R 1 is alkyl, halide, OMe, OH, alkylene-OH, or NH 2 .
5 . (canceled)
6 . (canceled)
7 . The compound of claim 1 , wherein B is selected from the group consisting of:
R is Me, or Ph;
m is 0, 1, 2, or 3;
n is 0, or 1; and
p is 0, 1, or 2.
8 . The compound of claim 1 , wherein X is N.
9 . The compound of claim 8 , wherein C is selected from the group consisting of:
10 . The compound of claim 1 , wherein X is C(R c ).
11 . The compound of claim 10 , wherein C is
12 . The compound of claim 10 , wherein:
C represents
R 3 , R 6 , and R 7 are independently H, halide, CF 3 , alkyl, alkylene-alkoxy, aryl, hydroxyl, or alkoxy; and
n′ is independently 0, 1, or 2.
13 . (canceled)
14 . (canceled)
15 . (canceled)
16 . The compound of claim 12 , wherein one instance of n′ is 0, and one instance of n′ is 1.
17 . The compound of claim 12 , wherein R 3 is H, halide, Me, OMe, or Ph.
18 . The compound of claim 12 , wherein R 6 is H; and R 7 is H, or CH 2 OH.
19 . The compound of claim 12 , wherein C is selected from the group consisting of:
20 . The compound of claim 10 , wherein:
C represents
R 3 , R 6 , and R 7 are independently H, halide, CF 3 , alkyl, alkylene-alkoxy, aryl, hydroxyl, or alkoxy; and
n′ is independently 0, 1, or 2.
21 . The compound of claim 20 , wherein C is
22 . The compound of claim 1 , wherein R 2 is H, (C 1 -C 4 )alkyl, cyclopropyl, CH 2 OMe, phenyl, —CH 2 Ph, pyridinyl, or indolyl.
23 . (canceled)
24 . (canceled)
25 . The compound of claim 22 , wherein R 2 is unsubstituted phenyl.
26 . The compound of claim 22 , wherein R 2 is substituted phenyl.
27 . The compound of claim 26 , 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.
28 . (canceled)
29 . (canceled)
30 . The compound of claim 22 , wherein R 2 is unsubstituted pyridinyl.
31 . The compound of claim 22 , wherein R 2 is substituted pyridinyl.
32 . (canceled)
33 . The compound of claim 22 , wherein R 2 is
34 . The compound of claim 1 , wherein A is
35 . The compound of claim 1 , wherein the compound is selected from the group consisting of:
36 . The compound of claim 1 , wherein the compound is selected from the group consisting of:
37 . The compound of claim 1 , wherein the compound is selected from the group consisting of:
38 . The compound of claim 1 , wherein the compound is selected from the group consisting of:
39 . The compound of claim 1 , wherein the compound is selected from the group consisting of:
40 . The compound of claim 1 , wherein the compound is selected from the group consisting of:
41 . The compound of claim 1 , wherein the compound is selected from the group consisting of:
42 . The compound of claim 1 , wherein the compound is selected from the group consisting of:
43 . The compound of claim 1 , wherein the compound is selected from the group consisting of:
44 . A pharmaceutical composition, comprising a compound of claim 1 ; and a pharmaceutically acceptable excipient.
45 . A method of treating a disease or condition selected from the group consisting of idiopathic pulmonary fibrosis, diabetic nephropathy, focal segmental glomerulosclerosis, chronic kidney disease, nonalcoholic steatohepatitis, primary biliary cholangitis, primary sclerosing cholangitis, solid tumors, hematological tumors, organ transplant, Alport syndrome, interstitial lung disease, radiation-induced fibrosis, bleomycin-induced fibrosis, asbestos-induced fibrosis, flu-induced fibrosis, coagulation-induced fibrosis, vascular injury-induced fibrosis, aortic stenosis, and cardiac fibrosis, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of claim 1 .
46 - 52 . (canceled)