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US 2026/0232812 A1Published application
Bifunctional molecules for targeted protein degradation
OwnerAndrea TESTA, Callum MACGREGOR +2inventors
InventorsAndrea TESTA, Callum MACGREGOR, David MCGARRY, Gregor MEIER
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Abstract
The present disclosure relates to a novel class of bifunctional molecules that are useful in a targeted or selective degradation of a protein.
Claims30
A bifunctional molecule comprising the general formula:
- wherein TBL is a target protein binding ligand;
- L is a linker;
- and
- Z comprises a structure according to formula (ZI):
- wherein:
- ring A2 is an optionally substituted 4- to 7-membered monocyclic N-heterocycloalkyl or an optionally substituted 7- to 12-membered bicyclic N-heterocycloalkyl, each optionally containing one or two additional ring heteroatoms selected from N, O and S;
- R2 is absent or is selected from the group consisting of aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, substituted heterocycloalkyl, NRy, —CH(aryl)-, CH(substituted aryl)-, —CH(heteroaryl)- and —CH(substituted heteroaryl)-;
- Ry is optionally substituted C1-6alkyl or H;
- R3 is selected from the group consisting of C1-6 alkyl, cycloalkyl, substituted cycloalkyl, alkylcycloalkyl, substituted alkylcycloalkyl, alkyl heterocycloalkyl, substituted alkylcycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl, wherein the C1-6 alkyl is optionally substituted with one or more halo, N, O and S;
- and
- L shows the point of attachment of the linker;
- and further wherein Z is not:
- or a pharmaceutically acceptable salt thereof.
10 more elements
2-5. (canceled)
(canceled)
9-23. (canceled)
(canceled)
(canceled)
31-33. (canceled)
37-39. (canceled)
44-45. (canceled)
A compound according to formula (VI):
- wherein;
- ring A2 is an optionally substituted 4- to 7-membered monocyclic N-heterocycloalkyl or an optionally substituted 7- to 12-membered bicyclic N-heterocycloalkyl, each optionally containing one or two additional ring heteroatoms selected from N, O and S;
- R2 is absent or is selected from the group consisting of aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, substituted heterocycloalkyl, NRy, —CH(aryl)-, —CH(substituted aryl)-, —CH(heteroaryl)- and —CH(substituted heteroaryl)-;
- Ry is optionally substituted C1-6alkyl or H;
- R3 is selected from the group consisting of C1-6 alkyl, cycloalkyl, substituted cycloalkyl, alkylcycloalkyl, substituted alkylcycloalkyl, alkyl heterocycloalkyl, substituted alkylcycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl, wherein the C1-6 alkyl is optionally substituted with one or more halo;
- and
- G is configured to enable attachment of the Z moiety to another chemical structure via formation of a new covalent bond.
4 more elements
A compound comprising the structure having Formula (ZI):
- wherein:
- ring A2 is an optionally substituted 4- to 7-membered monocyclic N-heterocycloalkyl or an optionally substituted 7- to 12-membered bicyclic N-heterocycloalkyl, each optionally containing one or two additional ring heteroatoms selected from N, O and S;
- R2 is absent or is selected from the group consisting of aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, substituted heterocycloalkyl, NRy, —CH(aryl)-, —CH(substituted aryl)-, —CH(heteroaryl)- and —CH(substituted heteroaryl)-;
- Ry is optionally substituted C1-6alkyl or H;
- R3 is selected from the group consisting of C1-6 alkyl, cycloalkyl, substituted cycloalkyl, alkylcycloalkyl, substituted alkylcycloalkyl, alkyl heterocycloalkyl, substituted alkylcycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl, wherein the C1-6 alkyl is optionally substituted with one or more halo;
- and
- L is a linker.
4 more elements
(canceled)
51-52. (canceled)
Dependencies are inferred from the claim text.