US2013045992A1PendingUtilityA1
Compositions and Methods for Enhancing Proteasome Activity
Est. expiryJan 28, 2030(~3.5 yrs left)· nominal 20-yr term from priority
A61P 7/00A61P 35/00A61P 3/10A61P 43/00A61P 25/14A61P 27/12A61P 25/28A61P 27/02A61P 25/02C07D 471/04C07D 487/04C07D 207/333C07D 401/12C07D 403/06C07D 209/08G01N 2500/04C07D 233/64C07D 207/335A61K 31/4439C07B 2200/07C07D 209/44A61P 21/00C07D 401/06C07D 401/10G01N 33/573C07D 401/04A61P 19/08G01N 2333/948C07D 403/04C07D 401/14A61P 17/00
44
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Claims
Abstract
Proteinopathies result from the proteasome not acting efficiently enough to eliminate harmful proteins and prevent the formation of the pathogenic aggregates. As described herein, inhibition of proteasome-associated deubiquitinase Usp 14 results in increased proteasome efficiency. The present invention therefore provides novel compositions and methods for inhibition of Usp14, enhancement of proteasome activity and treatment of proteinopathies.
Claims
exact text as granted — not AI-modified1 . A compound represented by formula II:
or a pharmaceutically acceptable salt, solvate, hydrate, prodrug, chemically-protected form, enantiomer or stereoisomer thereof; wherein, independently for each occurrence,
A is aryl, heteroaryl, carbocyclyl, heterocyclyl, or biaryl;
R 1 is hydrogen, alkyl, haloalkyl, fluoroalkyl, lower alkyoxy, halo or trifluoromethyl;
Z is ═C(R 8 )—, ═C(R 2 )— or ═N—;
R 2 is hydrogen, alkyl, haloalkyl, fluoroalkyl, lower alkyoxy, halo or trifluoromethyl; or,
when Z is ═C(R 2 )—, the two R 2 taken together are
X is
or heteroaryl;
Y is —CH 2 NR 3 R 4 , —CH 2 (N-heterocyclyl), —CH 2 NH(CH 2 ) n NH(alkyl), —CH 2 NH(CH 2 ) n N(alkyl) 2 , —CH 2 NH(CH 2 ) n (N-heterocyclyl), —CH 2 N(alkyl)(CH 2 ) n NH(alkyl), —CH 2 N(alkyl)(CH 2 ) n N(alkyl) 2 , —CH 2 N(alkyl)(CH 2 ) n (N-heterocyclyl), —CH 2 NH(CH 2 ) n O(alkyl), —CH 2 N(alkyl)(CH 2 ) n O(alkyl), —NR 3 R 4 , —NR 5 NR 6 R 7 or —NR 5 (N-heterocyclyl);
n is 1, 2, 3 or 4;
R 3 is hydrogen, alkyl, substituted alkyl, alkoxyalkyl, haloalkyl, fluoroalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl;
R 4 is hydrogen, alkyl, substituted alkyl, alkoxyalkyl, haloalkyl, fluoroalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl;
R 5 is hydrogen, alkyl, substituted alkyl, alkoxyalkyl, haloalkyl, fluoroalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl;
R 6 is hydrogen, alkyl, substituted alkyl, alkoxyalkyl, haloalkyl, fluoroalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl;
R 7 is hydrogen, alkyl, substituted alkyl, alkoxyalkyl, haloalkyl, fluoroalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl;
R 8 is hydrogen, alkyl, substituted alkyl, alkoxyalkyl, haloalkyl, fluoroalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl;
R 9 is alkyl; or two R 9 taken together with the nitrogen to which they are bound are an N-heterocyclyl group; and
R 10 is hydrogen, alkyl, haloalkyl, fluoroalkyl, alkyoxy, alkoxyalkyl, halo, trifluoromethyl, amino, amido, N-heterocyclyl, aminoalkyl, amidoalkyl, or N-hetrocyclylalkyl; provided that when A is 4-fluorophenyl, R 1 is methyl, R 2 is methyl, X is
and Y is —CH 2 (piperidin-1-yl), Z is not ═C(H)—; and that when A is 4-methylphenyl, R 1 is methyl, R 2 is methyl, X is
and Y is —CH 2 (4-methylpiperidin-1-yl), Z is not ═C(H)—.
2 . The compound of claim 1 , wherein A is aryl or heteroaryl.
3 . The compound of claim 1 , wherein A is phenyl, pyridin-2-yl, pyridin-3-yl or pyrimidin-2-yl, optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, halo, haloalkyl, fluoroalkyl, hydroxy, alkoxy, alkyenyloxy, alkynyloxy, carbocyclyloxy, heterocyclyloxy, haloalkoxy, fluoroalkyloxy, formyl, alkylcarbonyl, haloalkylcarbonyl, fluoroalkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, carboxy, alkoxycarbonyl, haloalkoxycarbonyl, fluoroalkoxycarbonyl, alkenyloxycarbonyl, alkynyloxycarbonyl, alkylcarbonyloxy, haloalkylcarbonyloxy, fluoroalkylcarbonyloxy, alkenylcarbonyloxy, alkynylcarbonyloxy, amino, amido, azido, aminosulfonyl, aminosulfinyl, cyano, nitro, phosphinyl, phosphoryl, silyl, silyloxy, and any of said substituents bound to the heterocyclyl group through a methylene or ethylene moiety.
4 . The compound of claim 1 , wherein A is phenyl, optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from the group consisting of alkyl, halo, haloalkyl, fluoroalkyl, hydroxy, alkoxy, haloalkoxy, fluoroalkyloxy, amino, azido, cyano, and nitro.
5 - 9 . (canceled)
10 . The compound of claim 1 , wherein A is phenyl substituted in the four position optionally further substituted in the two position with a substituent independently selected from the group consisting of alkyl, halo, haloalkyl, fluoroalkyl, hydroxy, alkoxy, haloalkoxy, fluoroalkyloxy, amino, azido, cyano, and nitro.
11 . The compound of claim 1 , wherein A is
12 - 13 . (canceled)
14 . The compound of claim 1 , wherein A is pyridin-2-yl, optionally substituted in the four position with a substituent selected from the group consisting of alkyl, halo, haloalkyl, fluoroalkyl, hydroxy, alkoxy, haloalkoxy, fluoroalkyloxy, amino, azido, cyano, and nitro.
15 . The compound of claim 1 , wherein A is
16 - 20 . (canceled)
21 . The compound of claim 1 , wherein R 1 and R 2 are independently selected from the group consisting of hydrogen, alkyl, and haloalkyl.
22 - 30 . (canceled)
31 . The compound of claim 1 , wherein R 1 is methyl; and R 2 is methyl.
32 . (canceled)
33 . The compound of claim 1 , wherein Z is ═C(R 8 )—; and R 8 is hydrogen or alkyl.
34 . (canceled)
35 . The compound of claim 1 , wherein Z is ═N—.
36 . The compound of claim 1 , wherein Z is ═C(R 2 )—; and the two R 2 taken together are
37 . The compound of claim 1 , wherein X is
38 - 44 . (canceled)
45 . The compound of claim 1 , wherein Y is —CH 2 NR 3 R 4 ; R 3 is hydrogen or alkyl; and R 4 is hydrogen or alkyl.
46 . (canceled)
47 . The compound of claim 1 , wherein Y is
48 . The compound of claim 1 , wherein Y is —CH 2 (N-heterocyclyl), which is optionally substituted with one, two, three, four or five substituents independently selected from the group consisting of alkyl, haloalkyl, fluoroalkyl, halo, hydroxyl, alkoxy, haloalkoxy, fluoroalkoxy, amino and nitro.
49 . The compound of claim 1 , wherein Y is —CH 2 (piperidin-1-yl), —CH 2 (piperazin-1-yl), —CH 2 (hexahydropyrimidin-1-yl), —CH 2 (morpholin-1-yl) or —CH 2 (1,3-oxazinan-3-yl), which is optionally substituted with one, two, three, four or five substituents independently selected from the group consisting of alkyl, haloalkyl, fluoroalkyl, halo, hydroxyl, alkoxy, haloalkoxy, fluoroalkoxy, amino and nitro.
50 . (canceled)
51 . The compound of claim 1 , wherein Y is
52 . The compound of claim 1 , wherein Y is —CH 2 NH(CH 2 ) n NH(alkyl), —CH 2 NH(CH 2 ) n N(alkyl) 2 , —CH 2 NH(CH 2 ) n N(alkylene), —CH 2 N(alkyl)(CH 2 ) n NH(alkyl), —CH 2 N(alkyl)(CH 2 ) n N(alkyl) 2 or —CH 2 N(alkyl)(CH 2 ) n N(alkylene).
53 . The compound of claim 1 , wherein Y is —CH 2 NH(CH 2 ) n O(alkyl) or —CH 2 N(alkyl)(CH 2 ) n O(alkyl); and n is 2, 3, or 4.
54 - 57 . (canceled)
58 . The compound of claim 1 , wherein Y is
59 - 72 . (canceled)
73 . A compound, or a pharmaceutically acceptable salt, solvate, hydrate, prodrug, chemically-protected form, enantiomer or stereoisomer thereof, selected from the group consisting of
wherein W is methyl, fluoro, chloro, nitro, methoxy, ethoxy, —SO 2 NH 2 or —C(═O)NH 2 .
74 . A pharmaceutical composition comprising a pharmaceutically acceptable excipient; and a compound selected from the group consisting of:
(a) IU1, or a pharmaceutically acceptable salt, solvate, hydrate, prodrug, chemically-protected form, enantiomer or stereoisomer thereof; (b) a compound of formula II, or a pharmaceutically acceptable salt, solvate, hydrate, prodrug, chemically-protected form, enantiomer or stereoisomer thereof; and (c) a compound, or a pharmaceutically acceptable salt, solvate, hydrate, prodrug, chemically-protected form, enantiomer or stereoisomer thereof, selected from the group consisting of:
wherein W is methyl, fluoro, chloro, nitro, methoxy, ethoxy, —SO 2 NH 2 or —C(═O)NH 2 ,
wherein the compound of formula II is represented by:
or a pharmaceutically acceptable salt, solvate, hydrate, prodrug, chemically-protected form, enantiomer or stereoisomer thereof; wherein, independently for each occurrence,
A is aryl, heteroaryl, carbocyclyl, heterocyclyl, or biaryl;
R 1 is hydrogen, alkyl, haloalkyl, fluoroalkyl, lower alkyoxy, halo or trifluoromethyl;
Z is ═C(R 8 )—, ═C(R 2 )— or ═N—;
R 2 is hydrogen, alkyl, haloalkyl, fluoroalkyl, lower alkyoxy, halo or trifluoromethyl; or,
when Z is ═C(R 2 )—, the two R 2 taken together are
X is
or heteroaryl;
Y is —CH 2 NR 3 R 4 , —CH 2 (N-heterocyclyl), —CH 2 NH(CH 2 NH(alkyl), —CH 2 NH(CH 2 ) n N(alkyl) 2 , —CH 2 NH(CH 2 )(N-heterocyclyl), —CH 2 N(alkyl)(CH 2 ) n NH(alkyl), —CH 2 N(alkyl)(CH 2 ) n N(alkyl) 2 , —CH 2 N(alkyl)(CH 2 ) n (N-heterocyclyl), —CH 2 NH(CH 2 ) n O(alkyl), —CH 2 N(alkyl)(CH 2 ) n O(alkyl), —NR 3 R 4 , —NR 5 NR 6 R 7 or —NR 5 (N-heterocyclyl);
n is 1, 2, 3 or 4;
R 3 is hydrogen, alkyl, substituted alkyl, alkoxyalkyl, haloalkyl, fluoroalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl;
R 4 is hydrogen, alkyl, substituted alkyl, alkoxyalkyl, haloalkyl, fluoroalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl;
R 5 is hydrogen, alkyl, substituted alkyl, alkoxyalkyl, haloalkyl, fluoroalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl;
R 6 is hydrogen, alkyl, substituted alkyl, alkoxyalkyl, haloalkyl, fluoroalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl;
R 7 is hydrogen, alkyl, substituted alkyl, alkoxyalkyl, haloalkyl, fluoroalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl;
R 8 is hydrogen, alkyl, substituted alkyl, alkoxyalkyl, haloalkyl, fluoroalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl;
R 9 is alkyl; or two R 9 taken together with the nitrogen to which they are bound are an N-heterocyclyl group; and
R 10 is hydrogen, alkyl, haloalkyl, fluoroalkyl, alkyoxy, alkoxyalkyl, halo, trifluoromethyl, amino, amido, N-heterocyclyl, aminoalkyl, amidoalkyl, or N-hetrocyclylalkyl; provided that when A is 4-fluorophenyl, R 1 is methyl, R 2 is methyl, X is
and Y is —CH 2 (piperidin-1-yl), Z is not ═C(H)—; and that when A is 4-methylphenyl, R 1 is methyl, R 2 is methyl, X is
and Y is —CH 2 (4-methylpiperidin-1-yl), Z is not ═C(H)—.
75 . A method of inhibiting the deubiquitination activity of a Usp14 protein comprising contacting the Usp14 protein with a compound selected from the group consisting of:
(a) IU1, or a pharmaceutically acceptable salt, solvate, hydrate, prodrug, chemically-protected form, enantiomer or stereoisomer thereof; (b) a compound of formula II, or a pharmaceutically acceptable salt, solvate, hydrate, prodrug, chemically-protected form, enantiomer or stereoisomer thereof; and (c) a compound, or a pharmaceutically acceptable salt, solvate, hydrate, prodrug, chemically-protected form, enantiomer or stereoisomer thereof, selected from the group consisting of:
wherein W is methyl, fluoro, chloro, nitro, methoxy, ethoxy, —SO 2 NH 2 or —C(═O)NH 2 ,
wherein the compound of formula II is represented by:
or a pharmaceutically acceptable salt, solvate, hydrate, prodrug, chemically-protected form, enantiomer or stereoisomer thereof; wherein, independently for each occurrence,
A is aryl, heteroaryl, carbocyclyl, heterocyclyl, or biaryl;
R 1 is hydrogen, alkyl, haloalkyl, fluoroalkyl, lower alkyoxy, halo or trifluoromethyl;
Z is ═C(R 8 )—, ═C(R 2 )— or ═N—;
R 2 is hydrogen, alkyl, haloalkyl, fluoroalkyl, lower alkyoxy, halo or trifluoromethyl; or,
when Z is ═C(R 2 )—, the two R 2 taken together are
X is
or heteroaryl;
Y is —CH 2 NR 3 R 4 , —CH 2 (N-heterocyclyl), —CH 2 NH(CH 2 ) n NH(alkyl), —CH 2 NH(CH 2 ) n N(alkyl) 2 , —CH 2 NH(CH 2 )(N-heterocyclyl), —CH 2 N(alkyl)(CH 2 ) n NH(alkyl), —CH 2 N(alkyl)(CH 2 ) n N(alkyl) 2 , —CH 2 N(alkyl)(CH 2 ) n (N-heterocyclyl), —CH 2 NH(CH 2 ) n O(alkyl), —CH 2 N(alkyl)(CH 2 ) n O(alkyl), —NR 3 R 4 , —NR 5 NR 6 R 7 or —NR 5 (N-heterocyclyl);
n is 1, 2, 3 or 4;
R 3 is hydrogen, alkyl, substituted alkyl, alkoxyalkyl, haloalkyl, fluoroalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl;
R 4 is hydrogen, alkyl, substituted alkyl, alkoxyalkyl, haloalkyl, fluoroalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl;
R 5 is hydrogen, alkyl, substituted alkyl, alkoxyalkyl, haloalkyl, fluoroalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl;
R 6 is hydrogen, alkyl, substituted alkyl, alkoxyalkyl, haloalkyl, fluoroalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl;
R 7 is hydrogen, alkyl, substituted alkyl, alkoxyalkyl, haloalkyl, fluoroalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl;
R 8 is hydrogen, alkyl, substituted alkyl, alkoxyalkyl, haloalkyl, fluoroalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl;
R 9 is alkyl; or two R 9 taken together with the nitrogen to which they are bound are an N-heterocyclyl group; and
R 10 is hydrogen, alkyl, haloalkyl, fluoroalkyl, alkyoxy, alkoxyalkyl, halo, trifluoromethyl, amino, amido, N-heterocyclyl, aminoalkyl, amidoalkyl, or N-hetrocyclylalkyl; provided that when A is 4-fluorophenyl, R 1 is methyl, R 2 is methyl, X is
and Y is —CH 2 (piperidin-1-yl), Z is not ═C(H)—; and that when A is 4-methylphenyl, R 1 is methyl, R 2 is methyl, X is
and Y is —CH 2 (4-methylpiperidin-1-yl), Z is not ═C(H)—.
76 . A method of enhancing protein degradation by a proteasome in a cell comprising contacting the cell with a compound selected from the group consisting of:
(a) IU1, or a pharmaceutically acceptable salt, solvate, hydrate, prodrug, chemically-protected form, enantiomer or stereoisomer thereof; (b) a compound of formula II, or a pharmaceutically acceptable salt, solvate, hydrate, prodrug, chemically-protected form, enantiomer or stereoisomer thereof; and (c) a compound, or a pharmaceutically acceptable salt, solvate, hydrate, prodrug, chemically-protected form, enantiomer or stereoisomer thereof, selected from the group consisting of:
wherein W is methyl, fluoro, chloro, nitro, methoxy, ethoxy, —SO 2 NH 2 or —C(═O)NH 2 ,
wherein the compound of formula II is represented by:
or a pharmaceutically acceptable salt, solvate, hydrate, prodrug, chemically-protected form, enantiomer or stereoisomer thereof; wherein, independently for each occurrence,
A is aryl, heteroaryl, carbocyclyl, heterocyclyl, or biaryl;
R 1 is hydrogen, alkyl, haloalkyl, fluoroalkyl, lower alkyoxy, halo or trifluoromethyl;
Z is ═C(R 8 )—, ═C(R 2 )— or ═N—;
R 2 is hydrogen, alkyl, haloalkyl, fluoroalkyl, lower alkyoxy, halo or trifluoromethyl; or, when Z is ═C(R 2 )—, the two R 2 taken together are
X is
or heteroaryl;
Y is —CH 2 NR 3 R 4 , —CH 2 (N-heterocyclyl), —CH 2 NH(CH 2 ) n NH(alkyl), —CH 2 NH(CH 2 ) n N(alkyl) 2 , —CH 2 NH(CH 2 )(N-heterocyclyl), —CH 2 N(alkyl)(CH 2 N(alkyl), —CH 2 N(alkyl)(CH 2 ) 2 N(alkyl) 2 , —CH 2 N(alkyl)(CH 2 ) n (N-heterocyclyl), —CH 2 NH(CH 2 ) n O(alkyl), —CH 2 N(alkyl)(CH 2 ) n O(alkyl), —NR 3 R 4 , —NR 5 NR 6 R 7 or —NR 5 (N-heterocyclyl);
n is 1, 2, 3 or 4;
R 3 is hydrogen, alkyl, substituted alkyl, alkoxyalkyl, haloalkyl, fluoroalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl;
R 4 is hydrogen, alkyl, substituted alkyl, alkoxyalkyl, haloalkyl, fluoroalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl;
R 5 is hydrogen, alkyl, substituted alkyl, alkoxyalkyl, haloalkyl, fluoroalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl;
R 6 is hydrogen, alkyl, substituted alkyl, alkoxyalkyl, haloalkyl, fluoroalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl;
R 7 is hydrogen, alkyl, substituted alkyl, alkoxyalkyl, haloalkyl, fluoroalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl;
R 8 is hydrogen, alkyl, substituted alkyl, alkoxyalkyl, haloalkyl, fluoroalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl;
R 9 is alkyl; or two R 9 taken together with the nitrogen to which they are bound are an N-heterocyclyl group; and
R 10 is hydrogen, alkyl, haloalkyl, fluoroalkyl, alkyoxy, alkoxyalkyl, halo, trifluoromethyl, amino, amido, N-heterocyclyl, aminoalkyl, amidoalkyl, or N-hetrocyclylalkyl; provided that when A is 4-fluorophenyl, R 1 is methyl, R 2 is methyl, X is
and Y is —CH 2 (piperidin-1-yl), Z is not ═C(H)—; and that when A is 4-methylphenyl, R 1 is methyl, R 2 is methyl, X is
and Y is —CH 2 (4-methylpiperidin-1-yl), Z is not ═C(H)—.
77 . A method of treating or preventing a proteinopathy in a subject comprising administering to the subject a compound selected from the group consisting of:
(a) IU1, or a pharmaceutically acceptable salt, solvate, hydrate, prodrug, chemically-protected form, enantiomer or stereoisomer thereof; (b) a compound of formula II, or a pharmaceutically acceptable salt, solvate, hydrate, prodrug, chemically-protected form, enantiomer or stereoisomer thereof; and (c) a compound, or a pharmaceutically acceptable salt, solvate, hydrate, prodrug, chemically-protected form, enantiomer or stereoisomer thereof, selected from the group consisting of:
wherein W is methyl, fluoro, chloro, nitro, methoxy, ethoxy, —SO 2 NH 2 or —C(═O)NH 2 ,
wherein the compound of formula II is represented by:
or a pharmaceutically acceptable salt, solvate, hydrate, prodrug, chemically-protected form, enantiomer or stereoisomer thereof; wherein, independently for each occurrence,
A is aryl, heteroaryl, carbocyclyl, heterocyclyl, or biaryl;
R 1 is hydrogen, alkyl, haloalkyl, fluoroalkyl, lower alkyoxy, halo or trifluoromethyl;
Z is ═C(R 8 )—, ═C(R 2 )— or ═N—;
R 2 is hydrogen, alkyl, haloalkyl, fluoroalkyl, lower alkyoxy, halo or trifluoromethyl; or,
when Z is ═C(R 2 )—, the two R 2 taken together are
X is
or heteroaryl;
Y is —CH 2 NR 3 R 4 , —CH 2 (N-heterocyclyl), —CH 2 NH(CH 2 NH(alkyl), —CH 2 NH(CH 2 ) n N(alkyl) 2 , —CH 2 NH(CH 2 ) n (N-heterocyclyl), —CH 2 N(alkyl)(CH 2 ) n NH(alkyl), —CH 2 N(alkyl)(CH 2 ) 2 N(alkyl) 2 , —CH 2 N(alkyl)(CH 2 )N-heterocyclyl), —CH 2 NH(CH 2 ) n O(alkyl), —CH 2 N(alkyl)(CH 2 ) n O(alkyl), —NR 3 R 4 , —NR 5 NR 6 R 7 or —NR 5 (N-heterocyclyl);
n is 1, 2, 3 or 4;
R 3 is hydrogen, alkyl, substituted alkyl, alkoxyalkyl, haloalkyl, fluoroalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl;
R 4 is hydrogen, alkyl, substituted alkyl, alkoxyalkyl, haloalkyl, fluoroalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl;
R 5 is hydrogen, alkyl, substituted alkyl, alkoxyalkyl, haloalkyl, fluoroalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl;
R 6 is hydrogen, alkyl, substituted alkyl, alkoxyalkyl, haloalkyl, fluoroalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl;
R 7 is hydrogen, alkyl, substituted alkyl, alkoxyalkyl, haloalkyl, fluoroalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl;
R 8 is hydrogen, alkyl, substituted alkyl, alkoxyalkyl, haloalkyl, fluoroalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl;
R 9 is alkyl; or two R 9 taken together with the nitrogen to which they are bound are an N-heterocyclyl group; and
R 10 is hydrogen, alkyl, haloalkyl, fluoroalkyl, alkyoxy, alkoxyalkyl, halo, trifluoromethyl, amino, amido, N-heterocyclyl, aminoalkyl, amidoalkyl, or N-hetrocyclylalkyl; provided that when A is 4-fluorophenyl, R 1 is methyl, R 2 is methyl, X is
and Y is —CH 2 (piperidin-1-yl), Z is not ═C(H)—; and that when A is 4-methylphenyl, R 1 is methyl, R 2 is methyl, X is
and Y is —CH 2 (4-methylpiperidin-1-yl), Z is not ═C(H)—.
78 - 79 . (canceled)
80 . A method of treating or preventing a disease, for which enhanced protein breakdown may be therapeutic, in a subject comprising administering to the subject a compound selected from the group consisting of:
(a) IU1, or a pharmaceutically acceptable salt, solvate, hydrate, prodrug, chemically-protected form, enantiomer or stereoisomer thereof; (b) a compound of formula II, or a pharmaceutically acceptable salt, solvate, hydrate, prodrug, chemically-protected form, enantiomer or stereoisomer thereof; and (c) a compound, or a pharmaceutically acceptable salt, solvate, hydrate, prodrug, chemically-protected form, enantiomer or stereoisomer thereof, selected from the group consisting of:
wherein W is methyl, fluoro, chloro, nitro, methoxy, ethoxy, —SO 2 NH 2 or —C(═O)NH 2 ,
wherein the compound of formula II is represented by:
or a pharmaceutically acceptable salt, solvate, hydrate, prodrug, chemically-protected form, enantiomer or stereoisomer thereof; wherein, independently for each occurrence,
A is aryl, heteroaryl, carbocyclyl, heterocyclyl, or biaryl;
R 1 is hydrogen, alkyl, haloalkyl, fluoroalkyl, lower alkyoxy, halo or trifluoromethyl;
Z is ═C(R 8 )—, ═C(R 2 )— or ═N—;
R 2 is hydrogen, alkyl, haloalkyl, fluoroalkyl, lower alkyoxy, halo or trifluoromethyl; or,
when Z is ═C(R 2 )—, the two R 2 taken together are
X is
or heteroaryl;
Y is —CH 2 NR 3 R 4 , —CH 2 (N-heterocyclyl), —CH 2 NH(CH 2 ) n NH(alkyl), —CH 2 NH(CH 2 ) n N(alkyl) 2 , —CH 2 NH(CH 2 )(N-heterocyclyl), —CH 2 N(alkyl)(CH 2 ) n NH(alkyl), —CH 2 N(alkyl)(CH 2 ) n N(alkyl) 2 , —CH 2 N(alkyl)(CH 2 ) n (N-heterocyclyl), —CH 2 NH(CH 2 ) n O(alkyl), —CH 2 N(alkyl)(CH 2 ) n O(alkyl), —NR 3 R 4 , —NR 5 NR 6 R 7 or —NR 5 (N-heterocyclyl);
n is 1, 2, 3 or 4;
R 3 is hydrogen, alkyl, substituted alkyl, alkoxyalkyl, haloalkyl, fluoroalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl;
R 4 is hydrogen, alkyl, substituted alkyl, alkoxyalkyl, haloalkyl, fluoroalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl;
R 5 is hydrogen, alkyl, substituted alkyl, alkoxyalkyl, haloalkyl, fluoroalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl;
R 6 is hydrogen, alkyl, substituted alkyl, alkoxyalkyl, haloalkyl, fluoroalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl;
R 7 is hydrogen, alkyl, substituted alkyl, alkoxyalkyl, haloalkyl, fluoroalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl;
R 8 is hydrogen, alkyl, substituted alkyl, alkoxyalkyl, haloalkyl, fluoroalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl;
R 9 is alkyl; or two R 9 taken together with the nitrogen to which they are bound are an N-heterocyclyl group; and
R 10 is hydrogen, alkyl, haloalkyl, fluoroalkyl, alkyoxy, alkoxyalkyl, halo, trifluoromethyl, amino, amido, N-heterocyclyl, aminoalkyl, amidoalkyl, or N-hetrocyclylalkyl; provided that when A is 4-fluorophenyl, R 1 is methyl, R 2 is methyl, X is
and Y is —CH 2 (piperidin-1-yl), Z is not ═C(H)—; and that when A is 4-methylphenyl, R 1 is methyl, R 2 is methyl, X is
and Y is —CH 2 (4-methylpiperidin-1-yl), Z is not ═C(H)—.
81 . (canceled)
82 . A method of enhancing proteasome function in a subject comprising administering to the subject a compound selected from the group consisting of
(a) IU1, or a pharmaceutically acceptable salt, solvate, hydrate, prodrug, chemically-protected form, enantiomer or stereoisomer thereof; (b) a compound of formula II, or a pharmaceutically acceptable salt, solvate, hydrate, prodrug, chemically-protected form, enantiomer or stereoisomer thereof; and (c) a compound, or a pharmaceutically acceptable salt, solvate, hydrate, prodrug, chemically-protected form, enantiomer or stereoisomer thereof, selected from the group consisting of:
wherein W is methyl, fluoro, chloro, nitro, methoxy, ethoxy, —SO 2 NH 2 or —C(═O)NH 2 ,
wherein the compound of formula II is represented by:
or a pharmaceutically acceptable salt, solvate, hydrate, prodrug, chemically-protected form, enantiomer or stereoisomer thereof; wherein, independently for each occurrence,
A is aryl, heteroaryl, carbocyclyl, heterocyclyl, or biaryl;
R 1 is hydrogen, alkyl, haloalkyl, fluoroalkyl, lower alkyoxy, halo or trifluoromethyl;
Z is ═C(R 8 )—, ═C(R 2 )— or ═N—;
R 2 is hydrogen, alkyl, haloalkyl, fluoroalkyl, lower alkyoxy, halo or trifluoromethyl; or,
when Z is ═C(R 2 )—, the two R 2 taken together are
X is
or heteroaryl;
Y is —CH 2 NR 3 R 4 , —CH 2 (N-heterocyclyl), —CH 2 NH(CH 2 ) n NH(alkyl), —CH 2 NH(CH 2 ) n N(alkyl) 2 , —CH 7 NH(CH 2 )(N-heterocyclyl), —CH 2 N(alkyl)(CH 2 ) n NH(alkyl), —CH 2 N(alkyl)(CH 2 ) n N(alkyl) 2 , —CH 2 N(alkyl)(CH 2 ) n (N-heterocyclyl), —CH 2 NH(CH 2 ) n O(alkyl), —CH 2 N(alkyl)(CH 2 ) n O(alkyl), —NR 3 R 4 , —NR 5 NR 6 R 7 or —NR 5 (N-heterocyclyl);
n is 1, 2, 3 or 4;
R 3 is hydrogen, alkyl, substituted alkyl, alkoxyalkyl, haloalkyl, fluoroalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl;
R 4 is hydrogen, alkyl, substituted alkyl, alkoxyalkyl, haloalkyl, fluoroalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl;
R 5 is hydrogen, alkyl, substituted alkyl, alkoxyalkyl, haloalkyl, fluoroalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl;
R 6 is hydrogen, alkyl, substituted alkyl, alkoxyalkyl, haloalkyl, fluoroalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl;
R 7 is hydrogen, alkyl, substituted alkyl, alkoxyalkyl, haloalkyl, fluoroalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl;
R 8 is hydrogen, alkyl, substituted alkyl, alkoxyalkyl, haloalkyl, fluoroalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl;
R 9 is alkyl; or two R 9 taken together with the nitrogen to which they are bound are an N-heterocyclyl group; and
R 10 is hydrogen, alkyl, haloalkyl, fluoroalkyl, alkyoxy, alkoxyalkyl, halo, trifluoromethyl, amino, amido, N-heterocyclyl, aminoalkyl, amidoalkyl, or N-hetrocyclylalkyl;
provided that when A is 4-fluorophenyl, R 1 is methyl, R 2 is methyl, X is
and Y is —CH 2 (piperidin-1-yl), Z is not ═C(H)—; and that when A is 4-methylphenyl, R 1 is methyl, R 2 is methyl, X is
and Y is —CH 2 (4-methylpiperidin-1-yl), Z is not ═C(H)—.
83 - 84 . (canceled)
85 . An isolated proteasome comprising enzymatically inactive Uch37 and further comprising enzymatically active Usp14.
86 . The proteasome of claim 85 , wherein said proteasome comprises vinylsulfone-Uch37 adducts.
87 . The proteasome of claim 85 , wherein said Usp14 is a recombinant protein.
88 . The proteasome of claim 85 , wherein said proteasome is a human proteasome or a murine proteasome.
89 . An isolated proteasome comprising enzymatically active Usp14 and lacking enzymatically active Uch37.
90 . The proteasome of claim 89 , wherein said Usp14 is a recombinant protein.
91 . The proteasome of claim 89 , wherein said proteasome is a human proteasome or a murine proteasome.
92 - 96 . (canceled)
97 . A method of screening for an inhibitor of Usp14 comprising:
(a) providing a proteasome comprising enzymatically inactive Uch37 and further comprising enzymatically active Usp14; (b) contacting said proteasome with a test compound and a Usp14 substrate; and (c) determining whether said test compound inhibits the deubiquitination of said substrate.
98 - 108 . (canceled)Join the waitlist — get patent alerts
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