Substituted [1,2,4]triazolo[4,3-c]pyrimidines that induce degradation of embryonic ectoderm development (EED) protein
Disclosed are compounds that bind to embryonic ectoderm development (EED) protein and proteolysis-targeting chimeric (PROTAC) derivatives thereof that induce degradation of EED. The disclosed compounds may be characterized as substituted [1,2,4]triazolo[4,3-c]pyrimidin-5-amine compounds having the Formula I: where R 1 is as disclosed herein. The disclosed PROTAC derivatives thereof typically include a first targeting moiety that binds to BED (M EED ) which may be derived from the disclosed [1,2,4]triazolo[4,3-c]pyrimidin-5-amine compounds having the Formula I that bind to EED. The first targeting moiety typically is linked via a bond or a linker (L) to a second targeting moiety that binds to an E3 ubiquitin ligase (M E3 ). As such, the disclosed PROTACS may be described as having a formula M EED -L-M E3 or M E3 -L-M EED .
1 . A compound of Formula I:
or a pharmaceutically acceptable salt thereof,
wherein:
R 1 is:
R 2 is alkyl, C(O)H, C(O)CH 2 CH(CH 2 CH 2 CH 3 ) 2 , C(O)—(CH 2 ) m CH 3 , C(O)CH 2 OCH 3 , C(O)—(CH 2 CH 2 O)˜H, C(O)—(CH 2 CH 2 O) m CH 3 , O(alkyl), S(O) 2 H, or S(O) 2 CH 3 ;
m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15,16, 17, 18, 19, or 20;
n is 1; and
x is 1;
with the proviso that if R 2 is C(O)—(CH 2 CH 2 O) m CH 3 , then m is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15,16, 17, 18, 19, or 20.
2 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is:
3 . The compound of claim 1 , wherein the compound is selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
4 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier, excipient, or diluent and a compound of claim 1 , or a pharmaceutically acceptable salt thereof.
5 . A method for treating cancer in a subject, wherein the method comprises administering to the subject tin need thereof a therapeutically effective amount of the pharmaceutical composition of claim 4 .
6 . The method of claim 5 , wherein the cancer is selected from the group consisting of breast cancer, cancer of the central nervous system, colon cancer, leukemia, melanoma, multiple myeloma, non-small cell lung cancer, ovarian cancer, prostate cancer, and renal cancer.