USP14 inhibitors for treating or preventing viral infections
AssigneesPresident and Fellows of Harvard College, Health Research, Inc.
InventorsDaniel J. Finley, Dilip Nag, Laura D. Kramer
Life of this patent
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Abstract
Disclosed herein are methods of treating or preventing a viral infection resulting from infection by a flavivirus, comprising administering to a subject a small molecule inhibitor of USP14, represented by Formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, prodrug, chemically-protected form, enantiomer or stereoisomer thereof, and pharmaceutical compositions comprising an effective amount of a compound of Formula (I) for use in the method.
Claims22
A method of treating or preventing a viral infection in a subject comprising administering to the subject an effective amount of a compound, or a pharmaceutically acceptable salt, solvate, hydrate, prodrug, chemically-protected form, enantiomer or stereoisomer thereof, wherein the compound is represented by Formula I
- wherein, independently for each occurrence,
- A is aryl, heteroaryl, carbocyclyl, heterocyclyl, or biaryl;
- R1 is hydrogen, alkyl, haloalkyl, fluoroalkyl, lower alkoxy, halo or trifluoromethyl;
- G is —N═ or —C(R2)═;
- Z is ═C(R8)—, ═C(R2)— or ═N—;
- R2 is hydrogen, alkyl, haloalkyl, fluoroalkyl, lower alkoxy, halo or trifluoromethyl;
- or, when G is —C(R2)═ and Z is ═C(R2)—, the two R2 taken together are
- X is
- or heteroaryl;
- Y is —CH2NR3R4, —CH2(N-heterocyclyl), —CH2NH(CH2)nNH(alkyl), —CH2NH(CH2)nN(alkyl)2, —CH2NH(CH2)n(N-heterocyclyl), —CH2N(alkyl)(CH2)nNH(alkyl), —CH2N(alkyl)(CH2)nN(alkyl)2, —CH2N(alkyl)(CH2)n(N-heterocyclyl), —CH2NH(CH2)nO(alkyl), —CH2N(alkyl)(CH2)nO(alkyl), —NR3R4, —NR5NR6R7, —NR5(N-heterocyclyl), or —N-heterocyclyl;
- n is 1, 2, 3 or 4;
- R3 is hydrogen, alkyl, substituted alkyl, alkoxyalkyl, haloalkyl, fluoroalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl;
- R4 is hydrogen, alkyl, substituted alkyl, alkoxyalkyl, haloalkyl, fluoroalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl;
- R5 is hydrogen, alkyl, substituted alkyl, alkoxyalkyl, haloalkyl, fluoroalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl;
- R6 is hydrogen, alkyl, substituted alkyl, alkoxyalkyl, haloalkyl, fluoroalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl;
- R7 is hydrogen, alkyl, substituted alkyl, alkoxyalkyl, haloalkyl, fluoroalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl;
- R8 is hydrogen, alkyl, substituted alkyl, alkoxyalkyl, haloalkyl, fluoroalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl;
- R9 is alkyl;
- or two R9 taken together with the nitrogen to which they are bound are an N-heterocyclyl group;
- and
- R10 is hydrogen, alkyl, haloalkyl, fluoroalkyl, alkoxy, alkoxyalkyl, halo, trifluoromethyl, sulfoxymethyl, sulfonamido, amino, amido, N-heterocyclyl, aminoalkyl, amidoalkyl, or N-heterocyclylalkyl.
A method of inhibiting replication of a virus in a host cell comprising contacting the host cell with an effective amount of a compound, or a pharmaceutically acceptable salt, solvate, hydrate, prodrug, chemically-protected form, enantiomer or stereoisomer thereof, wherein the compound is represented by Formula I
- wherein, independently for each occurrence,
- A is aryl, heteroaryl, carbocyclyl, heterocyclyl, or biaryl;
- R1 is hydrogen, alkyl, haloalkyl, fluoroalkyl, lower alkoxy, halo or trifluoromethyl;
- G is —N═ or —C(R2)═;
- Z is ═C(R8)—, ═C(R2)— or ═N—;
- R2 is hydrogen, alkyl, haloalkyl, fluoroalkyl, lower alkoxy, halo or trifluoromethyl;
- or, when G is —C(R2)═ and Z is ═C(R2)—, the two R2 taken together are
- X is
- or heteroaryl;
- Y is —CH2NR3R4, —CH2(N-heterocyclyl), —CH2NH(CH2)nNH(alkyl), —CH2NH(CH2)nN(alkyl)2, —CH2NH(CH2)n(N-heterocyclyl), —CH2N(alkyl)(CH2)nNH(alkyl), —CH2N(alkyl)(CH2)nN(alkyl)2, —CH2N(alkyl)(CH2)n(N-heterocyclyl), —CH2NH(CH2)nO(alkyl), —CH2N(alkyl)(CH2)nO(alkyl), —NR3R4, —NR5NR6R7, —NR5(N-heterocyclyl), or —N-heterocyclyl;
- n is 1, 2, 3 or 4;
- R3 is hydrogen, alkyl, substituted alkyl, alkoxyalkyl, haloalkyl, fluoroalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl;
- R4 is hydrogen, alkyl, substituted alkyl, alkoxyalkyl, haloalkyl, fluoroalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl;
- R5 is hydrogen, alkyl, substituted alkyl, alkoxyalkyl, haloalkyl, fluoroalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl;
- R6 is hydrogen, alkyl, substituted alkyl, alkoxyalkyl, haloalkyl, fluoroalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl;
- R7 is hydrogen, alkyl, substituted alkyl, alkoxyalkyl, haloalkyl, fluoroalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl;
- R8 is hydrogen, alkyl, substituted alkyl, alkoxyalkyl, haloalkyl, fluoroalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl;
- R9 is alkyl;
- or two R9 taken together with the nitrogen to which they are bound are an N-heterocyclyl group;
- and
- R10 is hydrogen, alkyl, haloalkyl, fluoroalkyl, alkoxy, alkoxyalkyl, halo, trifluoromethyl, sulfoxymethyl, sulfonamido, amino, amido, N-heterocyclyl, aminoalkyl, amidoalkyl, or N-heterocyclylalkyl.
Dependencies are inferred from the claim text.