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US 9,694,084 B2Granted
Methods to induce targeted protein degradation through bifunctional molecules
AssigneeDana-Farber Cancer Institute, Inc.
InventorsJames Bradner, Dennis Buckley, Georg Winter
Life of this patent
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Abstract
The present application provides bifunctional compounds which act as protein degradation inducing moieties. The present application also relates to methods for the targeted degradation of endogenous proteins through the use of the bifunctional compounds that link a cereblon-binding moiety to a ligand that is capable of binding to the targeted protein which can be utilized in the treatment of proliferative disorders. The present application also provides methods for making compounds of the application and intermediates thereof.
Claims84
A compound selected from:
- or an enantiomer, diastereomer, stereoisomer, or a pharmaceutically acceptable salt thereof, wherein:
- Y is a bond, (CH2)1-6, (CH2)0-6—O, (CH2)0-6—C(O)NR2′, (CH2)0-6—NR2′C(O), (CH2)0-6—NH, or (CH2)0-6—NR2;
- X is C(O) or C(R3)2;
- X1-X2 is C(R3)═N or C(R3)2—C(R3)2;
- each R1 is independently halogen, OH, C1—C6 alkyl, or C1—C6 alkoxy;
- R2 is C1—C6 alkyl, C(O)—C1—C6 alkyl, or C(O)—C3-C6 cycloalkyl;
- R2′ is H or C1-C6 alkyl;
- each R3 is independently H or C1—C3 alkyl;
- each R3 ′ is independently C1—C3 alkyl;
- each R4 is independently H or C1—C3 alkyl and at least one R4 is C1—C3 alkyl;
- or two R4, together with the carbon atom to which they are attached, form a C3—C6 carbocycle or a 4-, 5-, or 6-membered heterocycle comprising 1 or 2 heteroatoms selected from N and O;
- R5 is H, deuterium, C1—C3 alkyl, F, or Cl;
- m is 0, 1, 2 or 3;
- n is 0, 1 or 2;
- the Linker is
- each W is independently absent, CH2, O, S, NH or NR5;
- Z is absent, CH2, O, NH or NR5;
- Q is absent or —CH2C(O)NH—;
- p1 is selected from 0, 1, 2, 3, 4, 5, and 6;
- p2 is selected from 0, 1, 2, 3, 4, 5, and 6;
- p3 is selected from 1, 2, 3, 4, and 5;
- the Targeting Ligand binds to a targeted protein selected from SMARCA2, and Ras;
- wherein the Targeting Ligand is selected from:
- R is the attachment point to the Linker;
- o is 0, 1, 2, 3, 4, 5, 6, 7, or 8;
- and
- A is N or CH.
24 more elements
A compound selected from:
- or an enantiomer, diastereomer, stereoisomer, or a pharmaceutically acceptable salt thereof, wherein:
- Y is a bond, (CH2)1-6, (CH2)0-6—O, (CH2)0-6—C(O)NR2′, (CH2)0-6—NR2′C(O), (CH2)0-6—NH, or (CH2)0-6—NR2;
- X is C(O) or C(R3)2;
- X1-X2 is C(R3)═N or C(R3)2—C(R3)2;
- each R1 is independently halogen, OH, C1—C6 alkyl, or C1—C6 alkoxy;
- R2 is C1—C6 alkyl, C(O)—C1—C6 alkyl, or C(O)—C3—C6 cycloalkyl;
- R2′ is H or C1C6 alkyl;
- each R3 is independently H or C1—C3 alkyl;
- each R3′ is independently C1—C3 alkyl;
- each R4 is independently H or C1—C3 alkyl;
- or two R4 , together with the carbon atom to which they are attached, form a C(O), C3—C6 carbocycle, or a 4-, 5-, or 6-membered heterocycle comprising 1 or 2 heteroatoms selected from N and 0;
- R5 is H, deuterium, C1—C3 alkyl, F, or Cl;
- m is 0, 1, 2 or 3;
- n is 1 or 2;
- the Linker is
- each W is independently absent, CH2, O, S, NH or NR5;
- Z is absent, CH2, O, NH or NR5;
- Q is absent or —CH2C(O)NH—;
- p1 is selected from 0, 1, 2, 3, 4, 5, and 6;
- p2 is selected from 0, 1, 2, 3, 4, 5, and 6;
- p3 is selected from 1, 2, 3, 4, and 5;
- the Targeting Ligand binds to a targeted protein selected from SMARCA2, and Ras;
- wherein the Targeting Ligand is selected from:
- R is the attachment point to the Linker;
- o is 0, 1, 2, 3, 4, 5, 6, 7, or 8;
- and
- A is N or CH.
24 more elements
Dependencies are inferred from the claim text.