INHIBITING (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
wherein all instances of R 1 are H;
B is selected from the group consisting of:
q is 0, 1, 2, or 3; and p is 0, 1, or 2;
C is
wherein n is 0; and
R 2 is
and n in R 2 is 0 or 1;
R 4 is independently selected from alkyl, —C(F 2 )CH 3 , cycloalkyl, heterocycloalkyl, -alkylene-cycloalkyl, —O-alkylene-cycloalkyl, —O-cycloalkyl, —O-alkyl, -alkylene-O-alkyl, -alkylene-O-cycloalkyl, and -alkylene-O-alkylene-cycloalkyl;
R 5 is F;
R a is H; and
the absolute configuration at any stereocenter is R, S, or a mixture thereof,
or a pharmaceutically acceptable salt thereof.
2 . The compound of claim 1 , wherein B is
3 . The compound of claim 2 , wherein q is 2.
4 . The compound of claim 3 , wherein A is
5 . The compound of claim 4 , wherein R 4 is cycloalkyl.
6 . The compound of claim 4 , wherein R 4 is heterocycloalkyl.
7 . The compound of claim 4 , wherein R 4 is —O-alkylene-cycloalkyl.
8 . The compound of claim 4 , wherein R 4 is selected from
9 . The compound of claim 4 , wherein R 4 is selected from
10 . The compound of claim 4 , wherein R 2 is
wherein n in R 2 is 1.
11 . The compound of claim 10 , wherein R 4 is
12 . The compound of claim 10 , wherein R 4 is
13 . The compound of claim 10 , wherein R 4 is
14 . The compound of claim 10 , wherein R 4 is
15 . The compound of claim 1 , having the formula:
or a pharmaceutically acceptable salt thereof.
16 . The compound of claim 1 , having the formula:
or a pharmaceutically acceptable salt thereof.
17 . The compound of claim 1 , having the formula:
or a pharmaceutically acceptable salt thereof.
18 . The compound of claim 1 , having the formula:
or a pharmaceutically acceptable salt thereof.
19 . The compound of claim 1 , having the formula:
or a pharmaceutically acceptable salt thereof.
20 . A pharmaceutical composition formulated for oral delivery of an αvβ6 integrin inhibitor, the composition comprising the αvβ6 integrin inhibitor compound of claim 1 or a pharmaceutically acceptable salt thereof as the active compound and a pharmaceutically acceptable carrier formulated for oral therapeutic administration of the αvβ6 integrin inhibitor compound.
21 . A compound of formula (I):
A-B-C (I)
wherein:
A is
wherein all instances of R 1 are H;
B is selected from the group consisting of:
q is 0, 1, 2, or 3; and p is 0, 1, or 2;
C is
wherein n is 0; and
R 2 is
and n in R 2 is 0;
R 4 is independently selected from alkyl, —C(F 2 )CH 3 , cycloalkyl, heterocycloalkyl, -alkylene-cycloalkyl, —O-alkylene-cycloalkyl, —O-cycloalkyl, —O-alkyl, -alkylene-O-alkyl, -alkylene-O-cycloalkyl, and -alkylene-O-alkylene-cycloalkyl;
R a is H; and
the absolute configuration at any stereocenter is R, S, or a mixture thereof,
or a pharmaceutically acceptable salt thereof.
22 . The compound of claim 21 , wherein:
A is
B is
q is 2;
C is
wherein n is 0; and
R 4 is heterocycloalkyl;
R a is H; and
the absolute configuration at any stereocenter is R, S, or a mixture thereof;
or a pharmaceutically acceptable salt thereof.
23 . The compound of claim 22 , having the formula:
or a pharmaceutically acceptable salt thereof.
24 . A pharmaceutical composition formulated for oral delivery of an αvβ6 integrin inhibitor, the composition comprising the αvβ6 integrin inhibitor compound of claim 21 as an active compound and a pharmaceutically acceptable carrier formulated for oral therapeutic administration of the αvβ6 integrin inhibitor compound.
25 . A compound of formula (I):
A-B-C (I)
wherein:
A is
wherein all instances of R 1 are H;
B is selected from the group consisting of:
q is 0, 1, 2, or 3; and p is 0, 1, or 2;
C is
wherein n is 0; and
R 2 is
and m in R 2 is 0 or 1;
R 4 is independently selected from alkyl, —C(F 2 )CH 3 , cycloalkyl, heterocycloalkyl, -alkylene-cycloalkyl, —O-alkylene-cycloalkyl, —O-cycloalkyl, —O-alkyl, -alkylene-O-alkyl, -alkylene-O-cycloalkyl, and -alkylene-O-alkylene-cycloalkyl;
R 5 is F;
R a is H; and
the absolute configuration at any stereocenter is R, S, or a mixture thereof,
or a pharmaceutically acceptable salt thereof.
26 . The compound of claim 25 , wherein:
B is
q is 2;
C is
wherein n is 0, and
R 4 is cycloalkyl;
R a is H; and
the absolute configuration at any stereocenter is R, S, or a mixture thereof;
or a pharmaceutically acceptable salt thereof.
27 . The compound of claim 25 , having the formula:
or a pharmaceutically acceptable salt thereof.
28 . The compound of claim 25 , having the formula:
or a pharmaceutically acceptable salt thereof.
29 . A pharmaceutical composition formulated for oral delivery of an αvβ6 integrin inhibitor, the composition comprising the αvβ6 integrin inhibitor compound of claim 25 as an active compound and a pharmaceutically acceptable carrier formulated for oral therapeutic administration of the αvβ6 integrin inhibitor compound.
30 . The compound of claim 1 , wherein the compound is selected from the group consisting of: