US2019022116A1PendingUtilityA1
N4-Hydroxycytidine and Derivatives and Anti-Viral Uses Related Thereto
Est. expiryDec 26, 2034(~8.4 yrs left)· nominal 20-yr term from priority
A61P 31/12A61P 31/16A61P 31/18A61P 31/14A61P 35/00C07H 19/10A61K 31/7068C07H 19/073C07H 19/11A61K 45/06C07H 19/067A61K 9/0073Y02A50/30
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Claims
Abstract
This disclosure relates to N4-hydroxycytidine derivatives, compositions, and methods related thereto. In certain embodiments, the disclosure relates to the treatment and prophylaxis of viral infections.
Claims
exact text as granted — not AI-modified1 . A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound having Formula I,
or salt thereof, wherein
Q is O, —O(C═O)—, —O(C═O)Lipid, —O(C═O)V—, NH, or NR 7 ;
V is O, NH, NR 7 , S, CH 2 , or CHR 7 ;
W is CH 2 , NH, S or O;
X is CH 2 , CHMe, CMe 2 , CHF, CF 2 , or CD 2 ;
Y is N or CR″;
Z is N or CR″;
each R″ is independently selected from is H, D, F, Cl, Br, I, CH 3 , CD 3 , CF 3 , alkyl, acyl, alkenyl, alkynyl, hydroxyl, formyl or SCH 3 ;
R 1 is hydrogen, monophosphate, diphosphate, triphosphate,
alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, carbanoyl, esteryl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkyl sulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, phosphoramidyl, or phosphate wherein R 1 is optionally substituted with one or more, the same or different, R 20 ;
Y 1 is O or S;
Y 2 is OH, OR 12 , OAlkyl, or BH 3 − M + ;
Y 3 is OH or BH 3 − M + ;
R 2 is hydrogen, alkyl, alkenyl, alkynyl, ethynyl, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, hydroxymethyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, azido, or heterocyclyl, wherein R 2 is optionally substituted with one or more, the same or different, R 20 ;
R 3 is hydrogen, hydroxy, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R 3 is optionally substituted with one or more, the same or different, R 20 ;
R 4 is hydrogen, hydroxy, alkyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R 4 is optionally substituted with one or more, the same or different, R 20 ;
R 5 is hydrogen, hydroxy, alkoxy, alkyl, alkenyl, alkynyl, ethynyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, allenyl, halogen, nitro, cyano, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R 5 is optionally substituted with one or more, the same or different, R 20 ;
R 6 is hydrogen, hydroxy, alkoxy, alkyl, ethynyl, allenyl, halogen, nitro, cyano, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R 6 is optionally substituted with one or more, the same or different, R 20 ;
each R 7 is independently selected from absent, hydrogen, —(C═O)Oalkyl, —(C═O)alkyl, —(C═O)NHalkyl, —(C═O)N-dialkyl, —(C═O)Salkyl, hydroxy, alkoxy, alkyl, higher alkyl, (C 6 -C 16 )alkyl, (C 6 -C 22 )alkyl, halogen, nitro, cyano, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein each R 7 is optionally substituted with one or more, the same or different, R 20 ;
R 8 is hydrogen, deuterium, alkyl, alkenyl, alkynyl, halogen, nitro, cyano, hydroxy, benzyloxy, amino, amido, mercapto, formyl, carboxy, carbamoyl, azido, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkyl sulfonyl, aryl sulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R 8 is optionally substituted with one or more, the same or different, R 20 ;
R 9 is hydrogen, methyl, ethyl, tert-butyl, alkyl, higher alkyl, (C 6 -C 16 )alkyl, (C 6 -C 22 )alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, cycloalkyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkyl sulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R 9 is optionally substituted with one or more, the same or different, R 20 ;
R 10 is hydrogen, alkyl, branched alkyl, cycloalkyl, lipid methyl, ethyl, isopropyl, cyclopentyl, cyclohexyl, butyl, pentyl, hexyl, neopentyl, benzyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkyl sulfonyl, aryl sulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R 10 is optionally substituted with one or more, the same or different, R 20 ;
R 11 is hydrogen, deuterium, alkyl, methyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R 11 is optionally substituted with one or more, the same or different, R 20 ;
R 12 is hydrogen, alkyl, aryl, phenyl, 1-naphthyl, 2-naphthyl, aromatic, heteroaromatic, 4-substituted phenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, naphthyl, or heterocyclyl, wherein R 12 is optionally substituted with one or more, the same or different, R 20 ;
R 13 is hydrogen, deuterium, alkyl, alkenyl, alkynyl, halogen, nitro, cyano, hydroxy, amino, amido, mercapto, formyl, carboxy, carbamoyl, lipid, azido, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkyl sulfonyl, aryl sulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R 13 is optionally substituted with one or more, the same or different, R 20 ;
R 14 is hydrogen, deuterium, alkyl, alkenyl, alkynyl, halogen, nitro, cyano, hydroxy, amino, amido, mercapto, formyl, carboxy, carbamoyl, lipid, azido, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkyl sulfonyl, aryl sulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R 14 is optionally substituted with one or more, the same or different, R 20 ;
R 20 is deuterium, alkyl, alkenyl, alkynyl, halogen, nitro, cyano, hydroxy, amino, amido, mercapto, formyl, carboxy, carbamoyl, azido, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkyl sulfonyl, aryl sulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R 13 is optionally substituted with one or more, the same or different, R 21 ; and
R 21 is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethyl sulfonyl, methoxycarbonyl, ethoxycarbonyl, N-methylsulfamoyl, N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, N-methyl-N-ethylsulfamoyl, carbocyclyl, aryl, or heterocyclyl;
Lipid is a C 6-22 alkyl, alkoxy, polyethylene glycol, or aryl substituted with an alkyl group.
2 . The pharmaceutical composition of claim 1 , wherein Q-R 7 is OH.
3 . The pharmaceutical composition of claim 1 , wherein R 1 is
R 8 is hydrogen, hydroxy, or benzyloxy, and
R 9 is (C 6 -C 22 )alkyl.
4 . The pharmaceutical composition of claim 1 , wherein a compound of formula I has formula IB,
or salts thereof, wherein
V is absent, O, NH, NR 15 , S, CH 2 , or CHR 15 ;
X is CH 2 , CHMe, CMe 2 , CHF, CF 2 , or CD 2 ;
Y is H, D, F, Cl, Br, I, CH 3 , CD 3 , CF 3 , alkyl, acyl, alkenyl, alkynyl, hydroxyl, formyl or SCH 3 ;
R 1 is hydrogen, monophosphate, diphosphate, triphosphate,
alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, carbanoyl, esteryl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkyl sulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, phosphoramidyl, or phosphate wherein R 1 is optionally substituted with one or more, the same or different, R 20 ;
Y 1 is O or S;
Y 2 is OH, OR 12 , OAlkyl, or BH 3 − M + ;
Y 3 is OH or BH 3 − M + ;
R 4 is hydrogen, hydroxy, alkyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R 4 is optionally substituted with one or more, the same or different, R 20 ;
R 5 is hydrogen, hydroxy, alkoxy, alkyl, alkenyl, alkynyl, ethynyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, allenyl, halogen, nitro, cyano, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R 5 is optionally substituted with one or more, the same or different, R 20 ;
R 8 is hydrogen, deuterium, alkyl, alkenyl, alkynyl, halogen, nitro, cyano, hydroxy, benzyloxy, amino, amido, mercapto, formyl, carboxy, carbamoyl, azido, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkyl sulfonyl, aryl sulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R 8 is optionally substituted with one or more, the same or different, R 20 ;
R 9 is hydrogen, methyl, ethyl, tert-butyl, alkyl, higher alkyl, (C 6 -C 16 )alkyl, (C 6 -C 22 )alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, cycloalkyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkyl sulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R 9 is optionally substituted with one or more, the same or different, R 20 ;
R 10 is hydrogen, alkyl, branched alkyl, cycloalkyl, lipid methyl, ethyl, isopropyl, cyclopentyl, cyclohexyl, butyl, pentyl, hexyl, neopentyl, benzyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkyl sulfonyl, aryl sulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R 10 is optionally substituted with one or more, the same or different, R 20 ;
R 11 is hydrogen, deuterium, alkyl, methyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R 11 is optionally substituted with one or more, the same or different, R 20 ;
R 12 is hydrogen, alkyl, aryl, phenyl, 1-naphthyl, 2-naphthyl, aromatic, heteroaromatic, 4-substituted phenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, naphthyl, or heterocyclyl, wherein R 12 is optionally substituted with one or more, the same or different, R 20 ;
R 13 is hydrogen, deuterium, alkyl, alkenyl, alkynyl, halogen, nitro, cyano, hydroxy, amino, amido, mercapto, formyl, carboxy, carbamoyl, lipid, azido, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkyl sulfonyl, aryl sulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R 13 is optionally substituted with one or more, the same or different, R 20 ;
R 14 is hydrogen, deuterium, alkyl, alkenyl, alkynyl, halogen, nitro, cyano, hydroxy, amino, amido, mercapto, formyl, carboxy, carbamoyl, lipid, azido, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkyl sulfonyl, aryl sulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R 14 is optionally substituted with one or more, the same or different, R 20 ;
R 15 is hydrogen, Lipid, —(C═O)Oalkyl, —(C═O)alkyl, —(C═O)NHalkyl, —(C═O)N-dialkyl, —(C═O)Salkyl, hydroxy, alkoxy, alkyl, higher alkyl, (C 6 -C 16 )alkyl, (C 6 -C 22 )alkyl, halogen, nitro, cyano, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkyl sulfonyl, aryl sulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R 15 is optionally substituted with one or more, the same or different, R 20 ;
R 20 is deuterium, alkyl, alkenyl, alkynyl, halogen, nitro, cyano, hydroxy, amino, amido, mercapto, formyl, carboxy, carbamoyl, azido, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkyl sulfonyl, aryl sulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R 13 is optionally substituted with one or more, the same or different, R 21 ; and
R 21 is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethyl sulfonyl, methoxycarbonyl, ethoxycarbonyl, N-methylsulfamoyl, N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, N-methyl-N-ethylsulfamoyl, carbocyclyl, aryl, or heterocyclyl;
Lipid is a C 6-22 alkyl, alkoxy, polyethylene glycol, or aryl substituted with an alkyl group.
5 . The composition of claim 1 , wherein the compound is selected from:
1-(3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-4-((nonanoyloxy)amino)pyrimidin-2-one, 1-(3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-4-((((heptyloxy)carbonyl)oxy)amino)pyrimidin-2-one, and isopropyl(((3,4-dihydroxy-5-(4-(hydroxyamino)-2-oxopyrimidin-1(2H)-yl)tetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)alaninate.
6 . The pharmaceutical composition of claim 1 wherein a compound of formula I has Formula IC,
or salts thereof, wherein
X is CH 2 , CHMe, CMe 2 , CHF, CF 2 , or CD 2 ;
Y is H, D, F, Cl, Br, I, CH 3 , CD 3 , CF 3 , alkyl, acyl, alkenyl, alkynyl, hydroxyl, formyl or SCH 3 ;
R 1 is hydrogen, monophosphate, diphosphate, triphosphate,
alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, carbanoyl, esteryl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkyl sulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, phosphoramidyl, or phosphate wherein R 1 is optionally substituted with one or more, the same or different, R 20 ;
Y 1 is O or S;
Y 2 is OH, OR 12 , OAlkyl, or BH 3 − M + ;
Y 3 is OH or BH 3 − M + ;
R 4 is hydrogen, hydroxy, alkyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R 4 is optionally substituted with one or more, the same or different, R 20 ;
R 5 is hydrogen, hydroxy, alkoxy, alkyl, alkenyl, alkynyl, ethynyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, allenyl, halogen, nitro, cyano, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R 5 is optionally substituted with one or more, the same or different, R 20 ;
R 8 is hydrogen, deuterium, alkyl, alkenyl, alkynyl, halogen, nitro, cyano, hydroxy, benzyloxy, amino, amido, mercapto, formyl, carboxy, carbamoyl, azido, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkyl sulfonyl, aryl sulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R 8 is optionally substituted with one or more, the same or different, R 20 ;
R 9 is hydrogen, methyl, ethyl, tert-butyl, alkyl, higher alkyl, (C 6 -C 16 )alkyl, (C 6 -C 22 )alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, cycloalkyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkyl sulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R 9 is optionally substituted with one or more, the same or different, R 20 ;
R 10 is hydrogen, alkyl, branched alkyl, cycloalkyl, lipid methyl, ethyl, isopropyl, cyclopentyl, cyclohexyl, butyl, pentyl, hexyl, neopentyl, benzyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkyl sulfonyl, aryl sulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R 10 is optionally substituted with one or more, the same or different, R 20 ;
R 11 is hydrogen, deuterium, alkyl, methyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R 11 is optionally substituted with one or more, the same or different, R 20 ;
R 12 is hydrogen, alkyl, aryl, phenyl, 1-naphthyl, 2-naphthyl, aromatic, heteroaromatic, 4-substituted phenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, naphthyl, or heterocyclyl, wherein R 12 is optionally substituted with one or more, the same or different, R 20 ;
R 13 is hydrogen, deuterium, alkyl, alkenyl, alkynyl, halogen, nitro, cyano, hydroxy, amino, amido, mercapto, formyl, carboxy, carbamoyl, lipid, azido, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkyl sulfonyl, aryl sulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R 13 is optionally substituted with one or more, the same or different, R 20 ;
R 14 is hydrogen, deuterium, alkyl, alkenyl, alkynyl, halogen, nitro, cyano, hydroxy, amino, amido, mercapto, formyl, carboxy, carbamoyl, lipid, azido, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkyl sulfonyl, aryl sulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R 14 is optionally substituted with one or more, the same or different, R 20 ;
R 15 is hydrogen, —(C═O)Oalkyl, —(C═O)alkyl, —(C═O)NHalkyl, —(C═O)N-dialkyl, —(C═O)Salkyl, hydroxy, alkoxy, alkyl, higher alkyl, (C 6 -C 16 )alkyl, (C 6 -C 22 )alkyl, halogen, nitro, cyano, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkyl sulfonyl, aryl sulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R 15 is optionally substituted with one or more, the same or different, R 20 ;
R 20 is deuterium, alkyl, alkenyl, alkynyl, halogen, nitro, cyano, hydroxy, amino, amido, mercapto, formyl, carboxy, carbamoyl, azido, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkyl sulfonyl, aryl sulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R 13 is optionally substituted with one or more, the same or different, R 21 ; and
R 21 is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethyl sulfonyl, methoxycarbonyl, ethoxycarbonyl, N-methylsulfamoyl, N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, N-methyl-N-ethylsulfamoyl, carbocyclyl, aryl, or heterocyclyl;
Lipid as described herein.
7 . The pharmaceutical composition of claim 1 , wherein a compound of formula I has Formula ID,
or salt thereof, wherein
W is CH 2 , NH, S or O;
X is CH 2 , CHMe, CMe 2 , CHF, CF 2 , or CD 2 ;
Y is N or CR″;
Z is N or CR″;
each R″ is independently selected from is H, D, F, Cl, Br, I, CH 3 , CD 3 , CF 3 , alkyl, acyl, alkenyl, alkynyl, hydroxyl, formyl or SCH 3 ;
R 1 is hydrogen, monophosphate, diphosphate, triphosphate,
alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, carbanoyl, esteryl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkyl sulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, phosphoramidyl, or phosphate wherein R 1 is optionally substituted with one or more, the same or different, R 20 ;
Y 1 is O or S;
Y 2 is OH, OR 12 , OAlkyl, or BH 3 − M + ;
Y 3 is OH or BH 3 − M + ;
R 2 is hydrogen, alkyl, alkenyl, alkynyl, ethynyl, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, hydroxymethyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, azido, or heterocyclyl, wherein R 2 is optionally substituted with one or more, the same or different, R 20 ;
R 3 is hydrogen, hydroxy, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R 3 is optionally substituted with one or more, the same or different, R 20 ;
R 4 is hydrogen, hydroxy, alkyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R 4 is optionally substituted with one or more, the same or different, R 20 ;
R 5 is hydrogen, hydroxy, alkoxy, alkyl, alkenyl, alkynyl, ethynyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, allenyl, halogen, nitro, cyano, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R 5 is optionally substituted with one or more, the same or different, R 20 ;
R 6 is hydrogen, hydroxy, alkoxy, alkyl, ethynyl, allenyl, halogen, nitro, cyano, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R 6 is optionally substituted with one or more, the same or different, R 20 ;
R 8 is hydrogen, deuterium, alkyl, alkenyl, alkynyl, halogen, nitro, cyano, hydroxy, benzyloxy, amino, amido, mercapto, formyl, carboxy, carbamoyl, azido, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkyl sulfonyl, aryl sulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R 8 is optionally substituted with one or more, the same or different, R 20 ;
R 9 is hydrogen, methyl, ethyl, tert-butyl, alkyl, higher alkyl, (C 6 -C 16 )alkyl, (C 6 -C 22 )alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, cycloalkyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkyl sulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R 9 is optionally substituted with one or more, the same or different, R 20 ;
R 10 is hydrogen, alkyl, branched alkyl, cycloalkyl, lipid methyl, ethyl, isopropyl, cyclopentyl, cyclohexyl, butyl, pentyl, hexyl, neopentyl, benzyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkyl sulfonyl, aryl sulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R 10 is optionally substituted with one or more, the same or different, R 20 ;
R 11 is hydrogen, deuterium, alkyl, methyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R 11 is optionally substituted with one or more, the same or different, R 20 ;
R 12 is hydrogen, alkyl, aryl, phenyl, 1-naphthyl, 2-naphthyl, aromatic, heteroaromatic, 4-substituted phenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, naphthyl, or heterocyclyl, wherein R 12 is optionally substituted with one or more, the same or different, R 20 ;
R 13 is hydrogen, deuterium, alkyl, alkenyl, alkynyl, halogen, nitro, cyano, hydroxy, amino, amido, mercapto, formyl, carboxy, carbamoyl, lipid, azido, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkyl sulfonyl, aryl sulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R 13 is optionally substituted with one or more, the same or different, R 20 ;
R 14 is hydrogen, deuterium, alkyl, alkenyl, alkynyl, halogen, nitro, cyano, hydroxy, amino, amido, mercapto, formyl, carboxy, carbamoyl, lipid, azido, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkyl sulfonyl, aryl sulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R 14 is optionally substituted with one or more, the same or different, R 20 ;
R 15 is hydrogen, —(C═O)Oalkyl, —(C═O)alkyl, —(C═O)NHalkyl, —(C═O)N-dialkyl, —(C═O)Salkyl, hydroxy, alkoxy, alkyl, higher alkyl, (C 6 -C 16 )alkyl, (C 6 -C 22 )alkyl, halogen, nitro, cyano, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkyl sulfonyl, aryl sulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R 15 is optionally substituted with one or more, the same or different, R 20 ;
R 15′ is hydrogen, —(C═O)Oalkyl, —(C═O)alkyl, —(C═O)NHalkyl, —(C═O)N-dialkyl, —(C═O)Salkyl, hydroxy, alkoxy, alkyl, higher alkyl, (C 6 -C 16 )alkyl, (C 6 -C 22 )alkyl, halogen, nitro, cyano, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkyl sulfonyl, aryl sulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein each R 7 is optionally substituted with one or more, the same or different, R 20 ;
R 15 and R 15′ can form a ring that is optionally substituted with one or more, the same or different, R 20 ;
R 20 is deuterium, alkyl, alkenyl, alkynyl, halogen, nitro, cyano, hydroxy, amino, amido, mercapto, formyl, carboxy, carbamoyl, azido, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkyl sulfonyl, aryl sulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R 13 is optionally substituted with one or more, the same or different, R 21 ; and
R 21 is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethyl sulfonyl, methoxycarbonyl, ethoxycarbonyl, N-methylsulfamoyl, N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, N-methyl-N-ethylsulfamoyl, carbocyclyl, aryl, or heterocyclyl;
Lipid is a C 6-22 alkyl, alkoxy, polyethylene glycol, or aryl substituted with an alkyl group.
8 . The pharmaceutical composition of claim 1 wherein a compound of formula I has Formula IE,
or salt thereof, wherein
Q is O, —O(C═O)—, —O(C═O)Lipid, —O(C═O)V—, NH, or NR 7 ;
V is O, NH, NR 7 , S, CH 2 , or CHR 7 ;
W is CH 2 , NH, S or O;
X is CH 2 , CHMe, CMe 2 , CHF, CF 2 , or CD 2 ;
Y is N or CR″;
Z is N or CR″;
each R″ is independently selected from is H, D, F, Cl, Br, I, CH 3 , CD 3 , CF 3 , alkyl, acyl, alkenyl, alkynyl, hydroxyl, formyl or SCH 3 ;
R 2 is hydrogen, alkyl, alkenyl, alkynyl, ethynyl, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, hydroxymethyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, azido, or heterocyclyl, wherein R 2 is optionally substituted with one or more, the same or different, R 20 ;
R 3 is hydrogen, hydroxy, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R 3 is optionally substituted with one or more, the same or different, R 20 ;
R 4 is hydrogen, hydroxy, alkyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R 4 is optionally substituted with one or more, the same or different, R 20 ;
R 5 is hydrogen, hydroxy, alkoxy, alkyl, alkenyl, alkynyl, ethynyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, allenyl, halogen, nitro, cyano, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R 5 is optionally substituted with one or more, the same or different, R 20 ;
R 6 is hydrogen, hydroxy, alkoxy, alkyl, ethynyl, allenyl, halogen, nitro, cyano, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R 6 is optionally substituted with one or more, the same or different, R 20 ;
each R 7 is independently selected from absent, hydrogen, —(C═O)Oalkyl, —(C═O)alkyl, —(C═O)NHalkyl, —(C═O)N-dialkyl, —(C═O)Salkyl, hydroxy, alkoxy, alkyl, higher alkyl, (C 6 -C 16 )alkyl, (C 6 -C 22 )alkyl, halogen, nitro, cyano, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein each R 7 is optionally substituted with one or more, the same or different, R 20 ;
R 15 is hydrogen, —(C═O)Oalkyl, —(C═O)alkyl, —(C═O)NHalkyl, —(C═O)N-dialkyl, —(C═O)Salkyl, hydroxy, alkoxy, alkyl, higher alkyl, (C 6 -C 16 )alkyl, (C 6 -C 22 )alkyl, halogen, nitro, cyano, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkyl sulfonyl, aryl sulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R 15 is optionally substituted with one or more, the same or different, R 20 ;
R 15′ is hydrogen, —(C═O)Oalkyl, —(C═O)alkyl, —(C═O)NHalkyl, —(C═O)N-dialkyl, —(C═O)Salkyl, hydroxy, alkoxy, alkyl, higher alkyl, (C 6 -C 16 )alkyl, (C 6 -C 22 )alkyl, halogen, nitro, cyano, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkyl sulfonyl, aryl sulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein each R 7 is optionally substituted with one or more, the same or different, R 20 ;
R 15 and R 15′ can form a ring that is optionally substituted with one or more, the same or different, R 20 ;
If Q=-O(C═O)V— and V=NR 7 then the R 7 s can together form a ring that is optionally substituted with one or more, the same or different, R 20 ;
R 20 is deuterium, alkyl, alkenyl, alkynyl, halogen, nitro, cyano, hydroxy, amino, amido, mercapto, formyl, carboxy, carbamoyl, azido, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkyl sulfonyl, aryl sulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R 13 is optionally substituted with one or more, the same or different, R 21 ; and
R 21 is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethyl sulfonyl, methoxycarbonyl, ethoxycarbonyl, N-methylsulfamoyl, N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, N-methyl-N-ethylsulfamoyl, carbocyclyl, aryl, or heterocyclyl;
Lipid is a C 6-22 alkyl, alkoxy, polyethylene glycol, or aryl substituted with an alkyl group.
9 . The pharmaceutical composition of claim 1 , wherein a compound of formula I has Formula II,
or salt thereof, wherein
Q is O, —O(C═O)—, —O(C═O)Lipid, —O(C═O)V—, NH, or NR 7 ;
V is O, NH, NR 7 , S, CH 2 , or CHR 7 ;
W is CH 2 , NH, S or O;
X is CH 2 or O;
Y is N or CR″;
Z is N or CR″;
each R″ is independently selected from is H, D, F, Cl, Br, I, CH 3 , CD 3 , CF 3 , alkyl, acyl, alkenyl, alkynyl, hydroxyl, formyl or SCH 3 ;
R 1 is monophosphate, diphosphate, triphosphate,
Y 1 is O or S;
Y 2 is OH, OR 12 , OAlkyl, or BH 3 − M + ;
Y 3 is OH or BH 3 − M + ;
R 2 is hydrogen, alkyl, alkenyl, alkynyl, ethynyl, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, hydroxymethyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, azido, or heterocyclyl, wherein R 2 is optionally substituted with one or more, the same or different, R 20 ;
R 3 is hydrogen, hydroxy, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R 3 is optionally substituted with one or more, the same or different, R 20 ;
R 4 is hydrogen, hydroxy, alkyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R 4 is optionally substituted with one or more, the same or different, R 20 ;
R 5 is hydrogen, hydroxy, alkoxy, alkyl, alkenyl, alkynyl, ethynyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, allenyl, halogen, nitro, cyano, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R 5 is optionally substituted with one or more, the same or different, R 20 ;
R 6 is hydrogen, hydroxy, alkoxy, alkyl, ethynyl, allenyl, halogen, nitro, cyano, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R 6 is optionally substituted with one or more, the same or different, R 20 ;
each R 7 is independently selected from absent, hydrogen, —(C═O)Oalkyl, —(C═O)alkyl, —(C═O)NHalkyl, —(C═O)N-dialkyl, —(C═O)Salkyl, hydroxy, alkoxy, alkyl, higher alkyl, (C 6 -C 16 )alkyl, (C 6 -C 22 )alkyl, halogen, nitro, cyano, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein each R 7 is optionally substituted with one or more, the same or different, R 20 ;
R 8 is hydrogen, deuterium, alkyl, alkenyl, alkynyl, halogen, nitro, cyano, hydroxy, benzyloxy, amino, amido, mercapto, formyl, carboxy, carbamoyl, azido, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkyl sulfonyl, aryl sulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R 8 is optionally substituted with one or more, the same or different, R 20 ;
R 9 is hydrogen, methyl, ethyl, tert-butyl, alkyl, higher alkyl, (C 6 -C 16 )alkyl, (C 6 -C 22 )alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, cycloalkyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkyl sulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R 9 is optionally substituted with one or more, the same or different, R 20 ;
R 10 is hydrogen, alkyl, branched alkyl, cycloalkyl, lipid methyl, ethyl, isopropyl, cyclopentyl, cyclohexyl, butyl, pentyl, hexyl, neopentyl, benzyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkyl sulfonyl, aryl sulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R 10 is optionally substituted with one or more, the same or different, R 20 ;
R 11 is hydrogen, deuterium, alkyl, methyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R 11 is optionally substituted with one or more, the same or different, R 20 ;
R 12 is hydrogen, alkyl, aryl, phenyl, 1-naphthyl, 2-naphthyl, aromatic, heteroaromatic, 4-substituted phenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, naphthyl, or heterocyclyl, wherein R 2 is optionally substituted with one or more, the same or different, R 20 ;
R 13 is hydrogen, deuterium, alkyl, alkenyl, alkynyl, halogen, nitro, cyano, hydroxy, amino, amido, mercapto, formyl, carboxy, carbamoyl, lipid, azido, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkyl sulfonyl, aryl sulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein IC is optionally substituted with one or more, the same or different, R 20 ;
R 14 is hydrogen, deuterium, alkyl, alkenyl, alkynyl, halogen, nitro, cyano, hydroxy, amino, amido, mercapto, formyl, carboxy, carbamoyl, lipid, azido, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkyl sulfonyl, aryl sulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R 4 is optionally substituted with one or more, the same or different, R 20 ;
If Q=-O(C═O)V— and V=NR 7 then the R 7 s can together form a ring that is optionally substituted with one or more, the same or different, R 20 ;
R 20 is deuterium, alkyl, alkenyl, alkynyl, halogen, nitro, cyano, hydroxy, amino, amido, mercapto, formyl, carboxy, carbamoyl, azido, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkyl sulfonyl, aryl sulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R 13 is optionally substituted with one or more, the same or different, R 21 ; and
R 21 is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethyl sulfonyl, methoxycarbonyl, ethoxycarbonyl, N-methylsulfamoyl, N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, N-methyl-N-ethylsulfamoyl, carbocyclyl, aryl, or heterocyclyl;
Lipid as described herein.
10 . The pharmaceutical composition of claim 1 , further comprising a propellant.
11 . The pharmaceutical composition of claim 10 , wherein the propellant is compressed air, ethanol, nitrogen, carbon dioxide, nitrous oxide, hydrofluoroalkanes (HFA), 1,1,1,2,-tetrafluoroethane, 1,1,1,2,3,3,3-heptafluoropropane or combinations thereof.
12 . A pressurized container comprising a pharmaceutical composition of claim 1 .
13 . The container of claim 12 which is a manual pump spray, inhaler, meter-dosed inhaler, dry powder inhaler, nebulizer, vibrating mesh nebulizer, jet nebulizer, or ultrasonic wave nebulizer.
14 . A method of treating or preventing a viral infection comprising administering in effective amount of a compound of claim 1 or 9 to a subject in need thereof.
15 . The method of claim 14 wherein the viral infection is an alphavirus or MERS coronaviruses.
16 . The method of claim 14 wherein the virus is selected from MERS coronavirus, Eastern equine encephalitis virus, Western equine encephalitis virus, Venezuelan equine encephalitis virus, Chikungunya virus, and Ross River virus.
17 . The method of claim 14 wherein the compound is administered through the lungs.
18 . A method of treating or preventing Eastern equine encephalitis virus, Western equine encephalitis virus, Venezuelan equine encephalitis virus, Chikungunya virus, and Ross River virus infection, orthomyxoviridae virus or paramyxoviridae virus or RSV virus, or influenza virus, or filoviridae virus or ebola virus infection comprising administering in effective amount of a compound to a patient in need thereof with the structure:
19 . A method of treating or preventing a human coronavirus, SARS coronavirus, MERS coronavirus, Eastern equine encephalitis virus, Western equine encephalitis virus, Venezuelan equine encephalitis virus, Chikungunya virus, and Ross River infection infection, orthomyxoviridae virus or paramyxoviridae virus or RSV virus, or influenza virus, or filoviridae virus or ebola virus infection in a patient comprising administering in effective amount of a compound with the formula:
or salts thereof, wherein
V is absent, O, NH, NR 15 , S, CH 2 , or CHR 15 ;
X is CH 2 , CHMe, CMe 2 , CHF, CF 2 , or CD 2 ;
Y is H, D, F, Cl, Br, I, CH 3 , CD 3 , CF 3 , alkyl, acyl, alkenyl, alkynyl, hydroxyl, formyl or SCH 3 ;
R 1 is hydrogen, monophosphate, diphosphate, triphosphate,
alkyl,
halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, carbanoyl, esteryl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkyl sulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, phosphoramidyl, or phosphate wherein R 1 is optionally substituted with one or more, the same or different, R 20 ;
Y 1 is O or S;
Y 2 is OH, OR 12 , OAlkyl, or BH 3 − M + ;
Y 3 is OH or BH 3 − M + ;
R 4 is hydrogen, hydroxy, alkyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R 4 is optionally substituted with one or more, the same or different, R 20 ;
R 5 is hydrogen, hydroxy, alkoxy, alkyl, alkenyl, alkynyl, ethynyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, allenyl, halogen, nitro, cyano, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R 5 is optionally substituted with one or more, the same or different, R 20 ;
R 8 is hydrogen, deuterium, alkyl, alkenyl, alkynyl, halogen, nitro, cyano, hydroxy, benzyloxy, amino, amido, mercapto, formyl, carboxy, carbamoyl, azido, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkyl sulfonyl, aryl sulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R 8 is optionally substituted with one or more, the same or different, R 20 ;
R 9 is hydrogen, methyl, ethyl, tert-butyl, alkyl, higher alkyl, (C 6 -C 16 )alkyl, (C 6 -C 22 )alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, cycloalkyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkyl sulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R 9 is optionally substituted with one or more, the same or different, R 20 ;
R 10 is hydrogen, alkyl, branched alkyl, cycloalkyl, lipid methyl, ethyl, isopropyl, cyclopentyl, cyclohexyl, butyl, pentyl, hexyl, neopentyl, benzyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkyl sulfonyl, aryl sulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R 10 is optionally substituted with one or more, the same or different, R 20 ;
R 11 is hydrogen, deuterium, alkyl, methyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R 11 is optionally substituted with one or more, the same or different, R 20 ;
R 12 is hydrogen, alkyl, aryl, phenyl, 1-naphthyl, 2-naphthyl, aromatic, heteroaromatic, 4-substituted phenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, naphthyl, or heterocyclyl, wherein R 12 is optionally substituted with one or more, the same or different, R 20 ;
R 13 is hydrogen, deuterium, alkyl, alkenyl, alkynyl, halogen, nitro, cyano, hydroxy, amino, amido, mercapto, formyl, carboxy, carbamoyl, lipid, azido, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkyl sulfonyl, aryl sulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R 13 is optionally substituted with one or more, the same or different, R 20 ;
R 14 is hydrogen, deuterium, alkyl, alkenyl, alkynyl, halogen, nitro, cyano, hydroxy, amino, amido, mercapto, formyl, carboxy, carbamoyl, lipid, azido, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkyl sulfonyl, aryl sulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R 14 is optionally substituted with one or more, the same or different, R 20 ;
R 15 is hydrogen, Lipid, —(C═O)Oalkyl, —(C═O)alkyl, —(C═O)NHalkyl, —(C═O)N-dialkyl, —(C═O)Salkyl, hydroxy, alkoxy, alkyl, higher alkyl, (C 6 -C 16 )alkyl, (C 6 -C 22 )alkyl, halogen, nitro, cyano, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkyl sulfonyl, aryl sulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R 15 is optionally substituted with one or more, the same or different, R 20 ;
R 20 is deuterium, alkyl, alkenyl, alkynyl, halogen, nitro, cyano, hydroxy, amino, amido, mercapto, formyl, carboxy, carbamoyl, azido, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkyl sulfonyl, aryl sulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R 13 is optionally substituted with one or more, the same or different, R 21 ; and
R 21 is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethyl sulfonyl, methoxycarbonyl, ethoxycarbonyl, N-methylsulfamoyl, N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, N-methyl-N-ethylsulfamoyl, carbocyclyl, aryl, or heterocyclyl;
Lipid as described herein.
20 . A method of treating or preventing MERS coronavirus, Eastern equine encephalitis virus, Western equine encephalitis virus, Venezuelan equine encephalitis virus, Chikungunya virus, and Ross River virus infection, orthomyxoviridae virus or paramyxoviridae virus or RSV virus, or influenza virus, or filoviridae virus or ebola virus infection in a patient comprising administering in effective amount of a compound with the formula:
or salts thereof.
21 . A method of treating or preventing MERS coronavirus, Eastern equine encephalitis virus, Western equine encephalitis virus, Venezuelan equine encephalitis virus, Chikungunya virus, and Ross River virus infection, orthomyxoviridae virus or paramyxoviridae virus or RSV virus, or influenza virus, or filoviridae virus or ebola virus infection infection in a patient comprising administering in effective amount of a compound with the formula:
or salts thereof.
22 . A method of treating or preventing MERS coronavirus, Eastern equine encephalitis virus, Western equine encephalitis virus, Venezuelan equine encephalitis virus, Chikungunya virus, and Ross River virus infection, orthomyxoviridae virus or paramyxoviridae virus or RSV virus, or influenza virus, or filoviridae virus or ebola virus infection in a patient comprising administering in effective amount of a compound with the formula:
or salt thereof.Join the waitlist — get patent alerts
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