DIMERIC PEPTIDE INHIBITORS OF APOPTOSIS PROTEINS
The present technology is directed to compounds, compositions, and methods related to treatment of cancers and viral infections mediated by IAPs. In particular the present compounds and compositions may be used to treat IAP-mediated ovarian cancer and hepatitis B infection.
1 . A compound of Formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt of the compound or the stereoisomer of the compound:
wherein
X is a bond to the Linker or, when the Linker is attached to positions, 2, 3, or 4 on the pyrrolidine ring, X is selected from
wherein
Y is H or halogen;
R 1 and R 3 are independently selected from a substituted or unsubstituted C 1-6 alkyl or a C 3-6 cycloalkyl group;
R 2 is H or a substituted or unsubstituted C 1-6 alkyl group;
m is 1, 2, 3, 4, 5, or 6;
n is 0, 1 or 2; and
Linker is selected from the group consisting of
2 . The compound of claim 1 wherein Linker is
3 . The compound of claim 1 wherein n is 1.
4 . The compound of claim 1 , wherein X is a bond to Linker.
5 . The compound of claim 1 wherein Linker is
6 . The compound of claim 1 wherein m is 1, 2 or 3.
7 . The compound of claim 1 wherein Linker is
8 . The compound of claim 7 wherein X is a bond to Linker.
9 - 10 . (canceled)
11 . The compound of claim 1 wherein Linker is
12 . The compound of claim 11 wherein m is 1, 2 or 3.
13 . The compound of claim 1 wherein Linker is attached to the 3 position of the pyrrolidine of the compound of Formula I.
14 . The compound of claim 1 wherein X is
and n is 1.
15 . The compound of claim 1 wherein X is
and Y is F.
16 . The compound of claim 1 wherein R 1 is a methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, i-butyl, t-butyl, cyclopropyl, cyclobutyl, cyclohexyl, or cyclopentyl group.
17 . The compound of claim 1 wherein R 2 is a methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, or t-butyl group.
18 . The compound of claim 1 wherein R 3 is a methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, i-butyl, t-butyl, cyclopropyl, cyclobutyl, cyclohexyl, or cyclopentyl group.
19 . The compound of claim 1 wherein the compound is selected from
20 . A composition comprising the compound of claim 1 and a pharmaceutically acceptable carrier.
21 . A pharmaceutical composition comprising an effective amount of the compound of claim 1 for treating a cancer or a viral infection mediated by an IAP.
22 . The pharmaceutical composition of claim 21 wherein the cancer or viral infection mediated by an IAP is selected from the group consisting of ovarian cancer, fallopian tube cancer, peritoneal cancer, and hepatitis B infection.
23 . A method of treatment comprising administering an effective amount of a compound of claim 1 , or administering a pharmaceutical composition comprising an effective amount of a compound of claim 1 , to a subject suffering from a cancer or a viral infection mediated by an IAP.
24 . The method of claim 23 , wherein the cancer or viral infection is selected from the group consisting of ovarian cancer, fallopian tube cancer, peritoneal cancer, and hepatitis B infection.
25 . A compound of Formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt of the compound or the stereoisomer of the compound:
wherein
X is a bond to the Linker or, when the Linker is attached to positions, 2, 3, or 4 on the pyrrolidine ring, X is selected from
wherein
Y is H or halogen;
R 1 is a C 3-6 cycloalkyl group;
R 2 is H or a substituted or unsubstituted C 1-6 alkyl group;
R 3 is selected from a substituted or unsubstituted C 1-6 alkyl or a C 3-6 cycloalkyl group;
m is 1, 2, 3, 4, 5, or 6;
n is 0, 1 or 2; and
Linker is
26 . The compound of claim 25 wherein m is 2 or 3.
27 . The compound of claim 25 the compound is
28 . A pharmaceutical composition comprising an effective amount of the compound of claim 25 for treating a cancer or a viral infection mediated by an IAP.
29 . The pharmaceutical composition of claim 28 wherein the cancer or viral infection mediated by an IAP is selected from the group consisting of ovarian cancer, fallopian tube cancer, peritoneal cancer, and hepatitis B infection.
30 . A method of treatment comprising administering an effective amount of a compound of claim 25 , or administering a pharmaceutical composition comprising an effective amount of a compound of claim 25 , to a subject suffering from a cancer or a viral infection mediated by an IAP.
31 . The method of claim 30 , wherein the cancer or viral infection is selected from the group consisting of ovarian cancer, fallopian tube cancer, peritoneal cancer, and hepatitis B infection.