Bifunctional molecules for degradation of EGFR and methods of use
The present application provides bifunctional compounds of Formula (I): which act as protein degradation inducing moieties for EGFR and/or a mutant thereof. The present application also describes methods for the targeted degradation of EGFR and/or a mutant thereof through the use of the bifunctional compounds that link a ubiquitin ligase-binding moiety to a ligand that is capable of binding to EGFR and/or a mutant thereof which can be utilized in the treatment of disorders modulated by EGFR or a mutant thereof.
1. A compound of Formula:
or an enantiomer, diastereomer, stereoisomer, or pharmaceutically acceptable salt thereof, wherein:
the Linker is a group that covalently binds to
and the Degron;
the Degron is
each R 17 is independently C 1 -C 3 alkyl;
q′ is 0, 1, 2, 3 or 4; and
R 18 is H or C 1 -C 3 alkyl,
R 19 is C 1 -C 3 alkyl,
wherein the Degron is covalently bonded to the Linker via
A is phenyl or pyridinyl;
X is CH, C(C 1 -C 3 ) alkyl, or N;
R 1 is H or (C 1 -C 3 ) alkyl;
R 2 is (C 6 -C 10 ) aryl, or heteroaryl comprising one or two 5- to 7-membered rings and 1-4 heteroatoms selected from N, O, and S, wherein the aryl and heteroaryl are each optionally substituted with one or more R 4 ;
each R 4 is independently selected from (C 1 -C 4 ) alkyl, (C 1 -C 4 ) haloalkyl, (C 1 -C 4 ) alkoxy, (C 1 -C 4 ) haloalkoxy, halogen, NO 2 , OH, CN, C(O)R 6 , C(O)OR 6 , C(O)NR 6 R 7 , NR 6 R 7 , (C 3 -C 7 ) cycloalkyl, heterocyclyl comprising a 5- to 7-membered ring and 1-3 heteroatoms selected from N, O, and S, (C 6 -C 10 ) aryl, and heteroaryl comprising one or two 5- to 7-membered rings and 1-4 heteroatoms selected from N, O, and S, wherein the alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are each optionally substituted with one or more R 5 ;
each R 5 is independently selected from (C 1 -C 4 ) alkyl, (C 1 -C 4 ) haloalkyl, (C 1 -C 4 ) alkoxy, (C 1 -C 4 ) haloalkoxy, halogen, NO 2 , OH, and CN;
each R 6 is independently H or (C 1 -C 3 ) alkyl;
each R 7 is independently H or (C 1 -C 1 ) alkyl;
R 3 is (C 1 -C 3 ) alkyl or
X 2 is N or CR 8 ;
R 8 is H, (C 1 -C 4 ) alkyl, (C 1 -C 4 ) haloalkyl, (C 1 -C 4 ) alkoxy, (C 1 -C 4 ) haloalkoxy, halogen, NO 2 ,
NH 2 , OH, or CN;
each R 9 is independently selected from (C 1 -C 4 ) alkyl, (C 1 -C 4 ) haloalkyl, (C 1 -C 4 ) alkoxy, (C 1 -C 4 ) haloalkoxy, halogen, NO 2 , NH 2 , OH, and CN;
n is 0 or 1; and
p is 0, 1, 2, or 3.
2. The compound of claim 1 , wherein the Linker is
wherein
p1 is an integer selected from 0 to 12;
p2 is an integer selected from 0 to 12;
p3 is an integer selected from 0 to 6;
each W is independently absent, CH 2 , O, S, NH, or NR 10 ;
Z is absent, CH 2 , O, NH, NR 10 , C( 0 )(CH 2 ) 0-3 , or NHC(O)(CH 2 ) 0-3 ;
each R 10 is independently H or C 1 -C 3 alkyl;
Q is absent or CH 2 C(O)NH; and
wherein the Linker is covalently bonded to the Degron via the
next to Q.
3. The compound of claim 2 , wherein X is N.
4. The compound of claim 2 , wherein A is phenyl.
5. The compound of claim 2 , wherein n is 0.
6. The compound of claim 2 , wherein R 3 is
7. The compound of claim 2 , wherein R 1 is H.
8. The compound of claim 2 , wherein R 2 is
9. The compound of claim 2 , wherein
10. The compound of claim 2 , wherein the Linker is selected from:
wherein TL is the connecting point to
11. The compound of claim 2 , wherein the Linker is selected from:
wherein TL is the connecting point to
12. The compound of claim 1 , wherein the compound is selected from:
or a pharmaceutically acceptable salt thereof.
13. The compound of claim 1 , wherein the compound is selected from:
or a pharmaceutically acceptable salt thereof.
14. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 , or an enantiomer, diastereomer, stereoisomer, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
15. A method for the treatment of cancer mediated by epidermal growth factor receptor (EGFR), or a mutant thereof, comprising administering a therapeutically effective amount of a compound of claim 1 optionally in a pharmaceutically acceptable carrier to a human in need thereof;
wherein the cancer is lung cancer, colon cancer, or breast cancer.
16. The method of claim 15 , wherein the disease is lung cancer.
17. The method of claim 15 , wherein the disease is colon cancer.
18. The method of claim 15 , wherein the disease is breast cancer.
19. The compound of claim 1 , wherein the compound is
or a pharmaceutically acceptable salt thereof.