KRAS proteolysis targeting chimeras
Provided herein are KRAS proteolysis targeting chimeras (PROTACs), compositions comprising the KRAS PROTACs, and methods of making and using the KRAS PROTACs, e.g., to promote degradation of KRAS and/or treat KRAS-associated cancers. In an embodiment, the KRAS PROTAC has the following structural formula: or a pharmaceutically acceptable salt thereof, wherein values for the variables are as described herein.
1 . A compound of the following formula:
or a pharmaceutically acceptable salt thereof, wherein:
R 1 is
X 1 is N or C(R 10 );
R 10 is hydrogen, halogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )haloalkoxy, (C2-C6)alkenyl, (C2-C6)alkynyl, —CN, (C 1 -C 6 )alkoxy, —S—(C 1 -C 6 )alkyl or —S—(C 1 -C 6 )haloalkyl;
R 3 is
R 4 is hydrogen or fluoro;
L′ is
wherein * indicates point of attachment of L′ to Degron;
and
Degron is
wherein one or more of the hydrogen atoms on the benzene ring of the Degron is optionally replaced with a fluorine atom,
provided the compound is not
or a salt thereof.
2 . The compound of claim 1 , wherein X 1 is N.
3 . The compound of claim 1 , wherein X 1 is C(R 10 ), and R 10 is hydrogen, fluoro, chloro, methyl, —CF 3 , —OCF 3 , —CN, —OCH 3 , —SCH 3 , or —SCF 3 .
4 . The compound of claim 1 , wherein R 4 is fluoro.
5 . The compound of claim 1 , wherein Degron is
wherein one or more of the hydrogen atoms on the benzene ring of the Degron is optionally replaced with a fluorine atom.
6 . A compound of the following structure:
or a pharmaceutically acceptable salt thereof.
7 . A compound selected from:
or a pharmaceutically acceptable salt thereof.
8 . A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
9 . A pharmaceutical composition comprising a compound of claim 6 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
10 . A pharmaceutical composition comprising a compound of claim 7 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
11 . The compound of claim 1 , of the following formula:
or a pharmaceutically acceptable salt thereof.
12 . The compound of claim 1 , wherein R 3 is
13 . The compound of claim 1 , wherein R 3 is
14 . The compound of claim 5 , wherein Degron is
wherein one or more of the hydrogen atoms on the benzene ring of the Degron is optionally replaced with a fluorine atom.
15 . The compound of claim 5 , wherein Degron is
wherein one or more of the hydrogen atoms on the benzene ring of the Degron is optionally replaced with a fluorine atom.
16 . The compound of claim 7 , of the following structure:
or a pharmaceutically acceptable salt thereof.
17 . The compound of claim 7 , of the following structure:
or a pharmaceutically acceptable salt thereof.
18 . The compound of claim 7 , of the following structure:
or a pharmaceutically acceptable salt thereof.
19 . The compound of claim 7 , of the following structure:
or a pharmaceutically acceptable salt thereof.
20 . The compound of claim 7 , of the following structure:
or a pharmaceutically acceptable salt thereof.
21 . The compound of claim 7 , of the following structure:
or a pharmaceutically acceptable salt thereof.
22 . The compound of claim 7 , of the following structure:
or a pharmaceutically acceptable salt thereof.
23 . The compound of claim 7 , of the following structure:
or a pharmaceutically acceptable salt thereof.
24 . The compound of claim 7 , of the following structure:
or a pharmaceutically acceptable salt thereof.
25 . The compound of claim 7 , of the following structure:
or a pharmaceutically acceptable salt thereof.