US2023128765A1PendingUtilityA1
Small Molecule Activators of Parkin Enzyme Function
Assignee: MAYO FOUND MEDICAL EDUCATION & RESPriority: Jul 28, 2016Filed: Jun 16, 2022Published: Apr 27, 2023
Est. expiryJul 28, 2036(~10 yrs left)· nominal 20-yr term from priority
A61P 25/16C07D 403/14C07D 233/64C07D 413/12A61P 25/00C07D 487/04C12Y 603/02019C07D 498/04A61P 25/28A61P 35/00A61K 31/195C07D 413/14C07D 257/04A61K 31/437C07D 401/04C07D 471/04C07D 401/12A61K 31/4178A61K 31/4184G01J 5/00C12N 9/93C07D 403/12C07D 471/10C07D 471/06A61K 31/4439C07D 213/56C07D 417/14A61K 31/506C07D 235/16C07D 235/04C07D 403/04C07D 409/14A61K 31/501A61K 31/551C07D 401/10
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Claims
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 Ior a compound of Formula II.or pharmaceutically acceptable salts thereof.
Claims
exact text as granted — not AI-modified1 - 39 . (canceled)
40 . 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 C 1-3 alkylene or C(═O);
W is CH, CH 2 , N, or NR a ;
X is CH, CH 2 , N, or NR b ;
Y is CH, CH 2 or O;
Z is N or CR 2' ;
R 1 is H or C 1 - 3 alkyl;
R 2 is absent or C 1-6 alkylene;
R 2' is H or C 1-6 alkyl;
or, when Z is CR 2' , R 2 and R 2' , together with C, can be taken together to form a C 1-6 heterocyclic ring;
R 3 is H, halogen, C 1-3 alkyl, C 3-6 cycloalkyl, or C 1-3 alkoxy;
R 4 is H or C 1-3 alkyl;
R 4' is H or C 1-3 alkyl;
R a is H or C 1-3 alkyl;
R b is C 1-3 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, R 1 is methyl, D is C, R 3 is H, and A, B, and E are all CH, then at least one of W, X, and Y is not CH 2 .
41 - 45 . (canceled)
46 . The compound of claim 40 , wherein D is C.
47 - 49 . (canceled)
50 . The compound of claim 40 , wherein L is methylene.
51 . The compound of claim 40 , wherein W is CH 2 .
52 . The compound of claim 40 , wherein W is N.
53 - 58 . (canceled)
59 . The compound of claim 40 , wherein Z is N.
60 . The compound of claim 40 , wherein R 2 is absent.
61 - 62 . (canceled)
63 . The compound of claim 40 , wherein R 1 is H.
64 . The compound of claim 40 , wherein R 1 is methyl.
65 - 66 . (canceled)
67 . The compound of claim 40 , wherein R 3 is H, halogen, or C 3 - 6 cycloalkyl.
68 - 69 . (canceled)
70 . The compound of claim 40 , wherein R 4 and R 4' are each H.
71 . (canceled)
72 . The compound of claim 40 , wherein n is 1.
73 . The compound of claim 40 , wherein n is 2.
74 . The compound of claim 40 , wherein m is 1 or 2.
75 . The compound of claim 40 , wherein p is 0.
76 . The compound of claim 40 , wherein p is 1.
77 . The compound of claim 40 , wherein the compound of Formula II is selected from the group consisting of:
and
or a pharmaceutically acceptable salt thereof.
78 . The compound of claim 40 , wherein the compound of Formula II is a compound of Formula IIa:
or a pharmaceutically acceptable salt thereof, wherein:
A is CH or N;
B is N, O, or S;
D is C or N;
E is CH or N;
W is CH 2 or NR a ;
X is CH, CH 2 , N, or NR b ;
Y is CH, CH 2 or O;
L is C 1-3 alkylene or C(═O);
R 1 is H or C 1-3 alkyl;
R 3 is C 1-3 alkyl or C 1-3 alkoxy;
R 4 is H or C 1-3 alkyl;
R 4’ is H or C 1-3 alkyl;
R a is H or C 1-3 alkyl;
R b is C 1-3 alkyl;
n is 1 or 2;
m is 0, 1 or 2;
p is 0 or 1; and
the dashed lines can be single or double bonds.
79 . The compound of claim 40 , wherein the compound of Formula II is a compound of Formula IIb:
or a pharmaceutically acceptable salt thereof, wherein:
R 1 is C 1–3 alkyl; and
R 5 is (C 1-3 alkyl)phenyl.
80 . A pharmaceutical composition comprising a compound of claim 40 , or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.
81 . A method of activating the enzymatic activity of an E3 ubiquitin ligase in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound of claim 40 , or a pharmaceutically acceptable salt thereof.
82 - 91 . (canceled)
92 . A method of treating a disease or disorder associated with diminished E3 ubiquitin ligase enzymatic activity in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound of claim 40 , or a pharmaceutically acceptable salt thereof.
93 . The method of claim 92 , wherein the E3 ubiquitin ligase is selected from the group consisting of Parkin, ARIH1 (HHARI), ARIH2 (TRIAD1), RNF31 (HOIP), RBCK1 (HOIL-1L), MUL1 (MAPL, MULAN), MARCH5 (MITOL), E3A, mdm2, anaphase-promoting complex (APC), UBR5 (EDD1), SOCS, LNXp80, CBX4, CBLL1, HACE1, HECTD1, HECTD2, HECTD3, HECW1, HECW2, HERC1, HERC2, HERC3, HERC4, HUWE1, ITCH, NEDD4, NEDD4L, PPIL2, PRPF19, PIAS1, PIAS2, PIAS3, PIAS4, RANBP2, RNF4, RBX1, SMURF1, SMURF2, STUB1, TOPORS, TRIP12, UBE3A, UBE3B, UBE3C, UBE4A, UBE4B, UBOX5, UBR5, WWP1, and WWP2.
94 . (canceled)
95 . The method of claim 92 , wherein the disease or disorder is Parkinson’s disease.
96 - 114 . (canceled)Join the waitlist — get patent alerts
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