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US 2019/0169158 A1Published application
Small Molecule Activators of Parkin Enzyme Function
AssigneeMayo Foundation for Medical Education and Research
InventorsWolfdieter Springer, Fabienne C. Fiesel, Thomas R. Caulfield
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Abstract
The present disclosure relates to compounds for activating the enzymatic activity of an E3 ubiquitin ligase and methods for treating a disease or disorder in a subject with diminished E3 ubiquitin ligase enzymatic activity. In some embodiments, the present disclosure provides a compound of Formula (I) or a compound of Formula (II) or pharmaceutically acceptable salts thereof.
Claims114
A compound of Formula I:
- or a pharmaceutically acceptable salt thereof, wherein:
- A is CH or O;
- B is CH or N;
- D is C or N;
- E is CH or N;
- W is C or N;
- X is C or N;
- Y is C or N;
- Z is C or N;
- R1 is H, C1-4 alkyl, phenyl, or hetAr1;
- R2 is H;
- R3 is H;
- or R2 and R3, together with Y and X, form a 6-membered cycloalkyl ring;
- R7 is H;
- or, optionally, when n is 0, R1 and R7, together with the atoms to which they are attached, form a 6-membered cycloalkyl ring;
- R4 is H, C1-4 alkyl, halogen, CF3, or phenyl;
- R5 is H, C1-4 alkyl, C4-10 cycloalkyl, phenyl optionally substituted with halogen, (C1-3 alkyl)O(C4-6 cycloalkyl), O(C1-4 alkyl)(C4-6 cycloalkyl), S(C1-4 alkyl), S(C4-6 cycloalkyl), (C1-3 alkyl)(C4-9 hetCyc1), het Ar1, or O(phenyl) optionally substituted with CN;
- R6 is H or C1-4 alkyl;
- hetAr1 is a 6-membered heteroaryl ring having 1-3 ring nitrogen atoms optionally substituted with C1-4 alkyl;
- hetCyc1 is a 6-10-membered bicyclic ring having at least one ring heteroatom which is nitrogen and at least one of the rings is aromatic;
- m is 0 or 1;
- n is 0 or 1;
- p is 0 or 1;
- and
- the dashed lines can be single or double bonds.
22 more elements
A compound of Formula II:
- or a pharmaceutically acceptable salt thereof, wherein:
- A is CH, N, or S;
- B is CH, N, O, or S;
- D is C or N;
- E is CH or N;
- L is C1-3 alkylene or C(═O);
- W is CH, CH2, N, or NRa;
- X is CH, CH2, N, or NRb;
- Y is CH, CH2 or O;
- Z is N or CR2′;
- R1 is H or C1-3 alkyl;
- R2 is absent or C1-6 alkylene;
- R2′ is H or C1-6 alkyl;
- or, when Z is CR2′, R2 and R2′, together with C, can be taken together to form a C1-6 heterocyclic ring;
- R3 is H, halogen, C1-3 alkyl, C3-6 cycloalkyl, or C1-3 alkoxy;
- R4 is H or C1-3 alkyl;
- R4′ is H or C1-3 alkyl;
- Ra is H or C1-3 alkyl;
- Rb is C1-3 alkyl;
- m is 0, 1 or 2;
- n is 1 or 2;
- p is 0 or 1;
- and
- the dashed lines can be single or double bonds;
- with the proviso that when n is 2, R1 is methyl, D is C, R3 is H, and A, B, and E are all CH, then at least one of W, X, and Y is not CH2.
22 more elements
Dependencies are inferred from the claim text.