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US 2016/0243247 A1Published application
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.
Claims122
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 a group that covalently binds to the Targeting Ligand and Y;
- and
- the Targeting Ligand binds to a targeted protein selected from FKBP, CREBBP, TRIM24/BRPF1, glucocorticoid receptors, estrogen/androgen receptors, DOT1L, BRAF, HER3, Bcl-2/Bcl-XL, HDAC, and PPAR-gamma.
14 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 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;
- 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 O;
- 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 a group that covalently binds to the Targeting Ligand and Y;
- and
- the Targeting Ligand binds to a targeted protein selected from FKBP, CREBBP, TRIM24/BRPF1, glucocorticoid receptor, estrogen/androgen receptor, DOT1L, BRAF, HER3, Bcl-2/Bcl-XL, HDAC, and PPAR-gamma.
14 more elements
A compound selected from:
- or an enantiomer, diastereomer, or stereoisomer thereof.
A compound selected from:
- or an enantiomer, diastereomer, or stereoisomer thereof, wherein:
- X is H, deuterium, C1-C3 alkyl, or halogen;
- R is a Linker;
- the Linker is a group that covalently binds to a Targeting Ligand;
- and
- the Targeting Ligand is capable of binding to or binds to a targeted protein that mediates a disease.
3 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 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 a group that covalently binds to the Targeting Ligand and Y;
- and
- the Targeting Ligand binds to a targeted protein selected from BRD1, BRD2, BRD3, BRD4, BRD5, BRD6, BRD7, BRD8, BRD9, BRD10, and BRDT.
14 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 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 a group that covalently binds to the Targeting Ligand and Y;
- and
- the Targeting Ligand binds to a BET bromodomain-containing protein.
14 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 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;
- 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 O;
- 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 a group that covalently binds to the Targeting Ligand and Y;
- and
- the Targeting Ligand binds to a targeted protein selected from BRD1, BRD2, BRD3, BRD4, BRD5, BRD6, BRD7, BRD8, BRD9, BRD10, and BRDT.
14 more elements
The compound of claim 120 wherein the targeted protein is BRD4.
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;
- 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 O;
- 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 a group that covalently binds to the Targeting Ligand and Y;
- and
- the Targeting Ligand binds to a BET bromodomain-containing protein.
14 more elements
Dependencies are inferred from the claim text.