Bifunctional molecules for degradation of egfr and methods of use
AssigneeDana-Farber Cancer Institute, Inc.
InventorsNATHANAEL S. GRAY, JAEBONG JANG, DRIES DE CLERCQ, MICHAEL ECK, PASI JANNE
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Abstract
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.
Claims26
A bifunctional compound of the Formula I:
- or an enantiomer, diastereomer, stereoisomer, or pharmaceutically acceptable salt thereof, wherein:
- the Linker is of Formula L0:
- wherein the Linker is covalently bonded to the Degron via the
- next to Q, and covalently bonded to
- via the
- next to Z;
- the Degron is Formula D1c:
- A is phenyl or pyridinyl;
- X is CH, C(C1-C3) alkyl, or N;
- R1 is H or (C1-C3) alkyl;
- R2 is (C6-C10) 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 R4;
- each R4 is independently selected from (C1-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) alkoxy, (C1-C4) haloalkoxy, halogen, NO2, OH, CN, C(O)R6, C(O)OR6, C(O)NR6R7, NR6R7, (C3-C7) cycloalkyl, heterocyclyl comprising a 5- to 7-membered ring and 1-3 heteroatoms selected from N, O, and S, (C6-C10) 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 R5;
- each R5 is independently selected from (C1-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) alkoxy, (C1-C4) haloalkoxy, halogen, NO2, OH, and CN;
- each R6 is independently H or (C1-C3) alkyl;
- each R7 is independently H or (C1-C3) alkyl;
- R3 is (C1-C3) alkyl or
- X2 is N or CR8;
- R8 is H, (C1-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) alkoxy, (C1-C4) haloalkoxy, halogen, NO2, NH2, OH, or CN;
- each R9 is independently selected from (C1-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) alkoxy, (C1-C4) haloalkoxy, halogen, NO2, NH2, OH, and CN;
- n is 0 or 1;
- p is 0, 1, 2, or 3;
- 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, CH2, or O;
- Z is absent, CH2, O, or C(O)(CH2)0-3;
- Q is absent or heterocycle;
- each R14 is independently C1-C3 alkyl;
- each R16 is independently halogen, OH, C1-C6 alkyl, or C1-C6 alkoxy;
- q is 0, 1, or 2;
- and
- v is 0, 1, 2, or 3.
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21-30. (canceled)
32-36. (canceled)
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41-42. (canceled)
Dependencies are inferred from the claim text.