Gemcitabine prodrugs, pharmaceutical compositions and uses thereof

A compound of structural Formula (I):

• or a pharmaceutically acceptable salt, hydrate, solvate or N-oxide thereof, wherein:
• R1 is hydrogen, acyloxyalkylcarbonyl, substituted acyloxyalkylcarbonyl, oxycarbonyl, substituted oxycarbonyl or
• R2 is hydrogen, acyloxyalkylcarbonyl, substituted acyloxyalkylcarbonyl, oxycarbonyl, substituted oxycarbonyl or
• R3 is —N═C(R10)(R11) or —NHR12;
• n and o are independently integers from 1 to 3;
• R4 and R7 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, acyl, substituted acyl, acyloxyalkylcarbonyl, substituted acyloxyalkylcarbonyl, arylalkyl, substituted arylalkyl, oxycarbonyl and substituted oxycarbonyl;
• R5 and R8 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, acyl, substituted acyl, acyloxyalkylcarbonyl, substituted acyloxyalkylcarbonyl, arylalkyl, substituted arylalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl, substituted heteroalkyl, oxycarbonyl and substituted oxycarbonyl;
• R6 and R9 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, acyl, substituted acyl, alkoxycarbonyl, substituted alkoxycarbonyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, carbamoyl, substituted carbamoyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl and substituted heteroarylalkyl;
• or optionally, R5 and R6 together with the nitrogen atom to which they are bonded form a cycloheteroalkyl or substituted cycloheteroalkyl ring;
• or optionally, R8 and R9 together with the nitrogen atom to which they are bonded form a cycloheteroalkyl or substituted cycloheteroalkyl ring;
• R10 and R11 are independently selected from the group consisting of hydrogen, acyl, substituted acyl, alkyl, substituted alkyl, alkoxy, substituted alkoxy, alkylamino, substituted alkylamino, amido, substituted amido, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, dialkylamino, substituted dialkylamino, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl and substituted heteroarylalkyl with the proviso that either R10 or R11 is hydrogen;
• R12 is hydrogen, acyloxyalkylcarbonyl, substituted acyloxyalkylcarbonyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, oxycarbonyl, substituted oxycarbonyl or
• p is an integer from 1 to 3;
• R13 is hydrogen, alkyl, substituted alkyl, acyl, substituted acyl, acyloxyalkylcarbonyl, substituted acyloxyalkylcarbonyl, arylalkyl, substituted arylalkyl, oxycarbonyl or substituted oxycarbonyl;
• R14 is hydrogen, alkyl, substituted alkyl, acyl, substituted acyl, acyloxyalkylcarbonyl, substituted acyloxyalkylcarbonyl, arylalkyl, substituted arylalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl, substituted heteroalkyl, oxycarbonyl or substituted oxycarbonyl;
• R15 is hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, acyl, substituted acyl, alkoxycarbonyl, substituted alkoxycarbonyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, carbamoyl, substituted carbamoyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl;
• and
• or optionally, R14 and R15 together with the nitrogen atom to which they are bonded form a cycloheteroalkyl or substituted cycloheteroalkyl ring;
• with the provisos that:
• neither R1 nor R2 is benzoyl, C18-C20 acyl, tert-butoxycarbonyl or phenylaminocarbonyl;
• R1 is not 3-carboxy-propionyl, 3-alkoxycarbonyl-propionyl or 3-aminocarbonyl-propionyl when R2 is hydrogen, R3 is —NHR12 and R12 is hydrogen;
• at least one of R1 and R2 is not hydrogen when either R3 is —NHR12 and R12 is hydrogen, or when R3 is —N═C(R10)(R11) and R10 and R11 are hydrogen;
• R3 is not methylcarbonylamino, tert-butylcarbonylamino, C16-C20 alkylcarbonylamino, benzylcarbonylamino, ethoxycarbonylamino, tert-butoxycarbonylamino, benzyloxycarbonylamino, phenylcarbonylamino or 4-methoxyphenylcarbonylamino;
• and
• when R3 is —NHR12 and R1 and R2 are hydrogen, then R12 is not methyl, hydroxymethyl, 2-carboxymethylamino, 2-alkoxylcarbonylmethylamino, 1-methyl-2-alkoxycarbonylmethylamino or triarylmethyl.