US2022185806A1PendingUtilityA1
Inhibiting ubiquitin specific peptidase 30
Est. expiryOct 6, 2037(~11.2 yrs left)· nominal 20-yr term from priority
Inventors:Justin Andrew CaravellaBingsong HanCuixian LiuStephanos IoannidisAlexandre Joseph BuckmelterDavid RichardMatthew W. MartinSteven MischkeScot Richard Mente
C07D 261/18A61K 31/426C07D 413/14C07D 277/82C07D 417/06C07D 295/185C07D 417/04C07D 417/12C07D 277/56C07C 261/04C07D 213/75C07D 231/40C07D 263/48C07D 295/135C07D 277/46C07D 413/10C07D 261/04A61K 31/167C07C 2602/08C07C 2601/04C07D 241/04A61K 31/427C07D 261/14C07D 265/30A61K 31/415
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Claims
Abstract
The present disclosure relates to chemical entities useful as inhibitors of Ubiquitin Specific Peptidase 30 (USP30), pharmaceutical compositions comprising the chemical entities, and methods of using the chemical entities. The chemical entities as disclosed herein can be useful in the treatment of a disease, disorder, or condition involving mitochondrial dysfunction, including neurodegenerative diseases, motor neuron diseases, metabolic disorders, and cancers, among other ailments.
Claims
exact text as granted — not AI-modified1 . A compound of Formula (I):
or a pharmaceutically acceptable salt thereof, wherein:
R is independently chosen from hydrogen, OH, CN, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, halogen, (C 3 -C 6 ) cycloalkyl, and (C 3 -C 6 ) heterocycloalkyl;
n is 0, 1, or 2;
wherein, if n is 2, the R groups can combine to form a fused ring system with R 1 ;
R 1 is a 3-6 membered carbocyclic or heterocyclic ring;
R 2 is chosen from amides, reverse amides, and ureas;
X is independently chosen from hydrogen, alkyl, and heteroalkyl, wherein the alkyl and heteroalkyl can optionally cyclize with R, R 1 , or R 3 or with another X group when multiple X groups are present;
R 3 is chosen from hydrogen, halogen, alkyl, heteroalkyl, haloalkyl, alkoxy, heteroalkoxy, haloalkoxy, carbonylalkyl, carbonylheteroalkyl, carbocyclic, heterocyclic, aryl, and heteroaryl, wherein any rings are optionally substituted with 1 or 2 R;
R 4 is independently chosen from alkyl, heteroalkyl, haloalkyl, alkoxy, cycloalkoxy, heteroalkoxy, haloalkoxy, carboxyalkyl, heterocarboxyalkyl, carbocyclic, heterocyclic, aryl and heteroaryl, wherein any rings are optionally substituted with 1 or 2 Y groups;
Y is independently chosen from hydrogen, OH, CN, N(X) 2 , (C 1 -C 6 ) alkyl, (C 1 -C 6 ) heteroalkyl, (C 1 -C 6 ) alkoxy, (C 1 -C 6 ) haloalkyl, (C 1 -C 6 ) haloalkoxy, halogen, (C 3 -C 6 ) cycloalkyl, (C 3 -C 6 ) heterocycloalkyl, (C 5 -C 8 ) aryl, and (C 4 -C 8 ) heteroaryl; and
m is 0, 1, or 2.
2 . The compound of claim 1 , wherein
R 1 is a 4-membered carbocyclic or heterocyclic ring.
3 . (canceled)
4 . The compound of claim 1 , wherein R 1 is chosen from cyclobutane and cyclopentane.
5 - 6 . (canceled)
7 . The compound of claim 1 , wherein R 2 is an amide.
8 . The compound of claim 1 , wherein R 3 is chosen from aryl and heteroaryl rings.
9 . The compound of claim 1 , wherein R 3 is chosen from thiazole, indenyl, pyrazole, and phenyl rings.
10 . The compound of claim 1 , wherein R 3 is chosen from carbocyclic and heterocyclic rings.
11 . The compound of claim 1 , wherein m is 0.
12 . The compound of claim 1 , wherein R 4 is chosen from carbocyclic and heterocyclic rings optionally substituted with 1 or 2 Y.
13 . The compound of claim 1 , wherein R 4 is chosen from alkyl, heteroalkyl, and haloalkyl.
14 . The compound of claim 1 , wherein R 4 is chosen from aryl and heteroaryl rings optionally substituted with 1 or 2 Y.
15 . The compound of claim 1 , wherein R is halogen.
16 . (canceled)
17 . A pharmaceutical composition comprising the compound of claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
18 . A compound selected from:
Compound 10-1
cis-4-(cyanoamino)-N-(5-cyclohexyl-1,3- thiazol-2-yl)cyclohexane-1-carboxamide;
Compound 10-2
trans-4-(cyanoamino)-N-(5-cyclohexyl- 1,3-thiazol-2-yl)cyclohexane-1- carboxamide;
Compound 10-3
(1R,2R)-2-(cyanoamino)-N-(5- cyclohexyl-1,3-thiazol-2- yl)cyclopentane-1-carboxamide;
Compound 10-4
(1R,3S)-3-(cyanoamino)-N-(5- cyclohexyl-1,3-thiazol-2-yl)cyclohexane- 1-carboxamide;
Compound 10-5
(1S,3S)-3-(cyanoamino)-N-(5- cyclohexyl-1,3-thiazol-2-yl)cyclohexane- 1-carboxamide;
Compound 10-6
(1S,3R)-3-(cyanoamino)-N-(5- cyclohexyl-1,3-thiazol-2-yl)cyclohexane- 1-carboxamide;
Compound 10-7
(1R,2S)-2-(cyanoamino)-N-(5- cyclohexyl-1,3-thiazol-2- yl)cyclopentane-1-carboxamide;
Compound 10-8
(1S,2R)-2-(cyanoamino)-N-(5- cyclohexyl-1,3-thiazol-2- yl)cyclopentane-1-carboxamide;
Compound 10-9
(1S,2S)-2-(cyanoamino)-N-(5- cyclohexy1-1,3-thiazol-2- yl)cyclopentane-1-carboxamide;
Compound 10-10
(1S,3S)-3-(cyanoamino)-N-[5-(oxan-4- yl)-1,3-thiazol-2-yl]cyclopentane-1- carboxamide;
Compound 10-11
(1R,3R)-3-(cyanoamino)-N-[5-(oxan-4- yl)-1,3-thiazol-2-yl]cyclopentane-1- carboxamide;
Compound 11-1
trans-2-(cyanoamino)-N-(5-cyclohexyl- 1,3-thiazol-2-yl)cyclopropane-1- carboxamide;
Compound 11-2
cis-2-(cyanoamino)-N-(5-cyclohexy1-1,3- thiazol-2-yl)cyclopropane-1- carboxamide;
Compound 2-2
(3S)-3-(cyanoamino)-N-(5-cyclohexyl- 1,3-thiazol-2-yl)pyrrolidine-1- carboxamide;
Compound 2-3
(3R)-3-(cyanoamino)-N-(5-cyclohexyl- 1,3-thiazol-2-yl)pyrrolidine-1- carboxamide;
Compound 12-1
(1R,3S)-3-(cyanoamino)-N-(5-phenyl- 1,3-thiazol-2-yl)cyclopentane-1- carboxamide;
Compound 12-2
(1S,3S)-3-(cyanoamino)-N-(1-phenyl- 1H-pyrazol-3-yl)cyclopentane-1- carboxamide;
Compound 12-3
(1S,3S)-3-(cyanoamino)-N-(5- cyclohexy1-1,3-thiazol-2- yl)cyclopentane-1-carboxamide;
Compound 12-4
(1S,3S)-3-(cyanoamino)-N-(5-phenyl- 1,3-thiazol-2-yl)cyclopentane-1- carboxamide;
Compound 12-5
(1S,3S)-3-(cyanoamino)-N-(2,3-dihydro- 1H-inden-5-yl)cyclopentane-1- carboxamide;
Compound 12-6
{[(1S,3S)-3-(4-phenylpiperazine-1- carbonyl)cyclopentyl]amino}carbonitrile;
Compound 12-7
(1S,3R)-N-(5-tert-buty1-1,3-thiazol-2-y1)- 3-(cyanoamino)cyclopentane-1- carboxamide;
Compound 12-8
{[(3S)-1-[2-(2,3-dichlorophenyl)-1,3- thiazole-4-carbonyl]pyrrolidin-3- yl]amino}carbonitrile; and
Compound 12-9
({1-[2-(2,4-dichlorophenyl)-1,3-thiazole- 4-carbonyl]piperidin-4- yl}amino)carbonitrile
or a pharmaceutically acceptable salt thereof.
19 . A pharmaceutical composition comprising the compound of claim 18 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
20 . The compound of claim 1 , wherein R 1 is chosen from cyclopropane, cyclobutane, cyclopentane, cyclohexane, and pyrrolidine.
21 . The compound of claim 20 , wherein R 3 is chosen from aryl and heteroaryl rings.
22 . The compound of claim 21 , wherein R 4 is chosen from carbocyclic and heterocyclic rings optionally substituted with 1 or 2 Y.
23 . The compound of claim 8 , wherein R 4 is chosen from carbocyclic and heterocyclic rings optionally substituted with 1 or 2 Y.Join the waitlist — get patent alerts
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