# US 7,608,602 B2 · Gemcitabine prodrugs, pharmaceutical compositions and uses thereof

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- Number: US 7,608,602 B2
- Document ID: US7608602B2
- Status: Granted
- Kind: B2
- Application number: 11/844,922
- Filed: 2007-08-24
- Published: 2008-01-24
- Granted: 2009-10-27
- Earliest claimed: 2002-11-04
- Assignees: XenoPort, Inc.
- Inventors: Mark A. Gallop; Ge Peng; Thomas F. Woiwode; Kenneth C. Cundy
- Web page: https://patentgrep.com/patent/US7608602B2

## CPC

- C07H 19/06: Pyrimidine radicals
- A61P 35/00: Antineoplastic agents
- C07H: SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS (derivatives of aldonic or saccharic acids C07C, C07D; aldonic acids, saccharic acids C07C59/105, C07C59/285; cyanohydrins C07C255/16; glycals C07D; compounds of unknown constitution C07G; polysaccharides, derivatives thereof C08B; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification C12N15/00; sugar industry C13)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The present invention provides gemcitabine prodrugs, methods of making gemcitabine prodrugs, pharmaceutical compositions of gemcitabine prodrugs and methods of using gemcitabine prodrugs and pharmaceutical compositions of using gemcitabine prodrugs to treat or prevent diseases or disorders such as cancer or viral infections.

## Claims

### Claim 1

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.

### Claim 2 (depends on 1)

The compound of claim 1, wherein:
R1, R2 and R12 are independently hydrogen, acyloxyalkylcarbonyl, substituted acyloxyalkylcarbonyl, oxycarbonyl or substituted oxycarbonyl;
n, o and p are 1;
R4, R7 and R13 are independently selected from the group consisting of hydrogen, acyl, substituted acyl, acyloxyalkylcarbonyl, substituted acyloxyalkylcarbonyl, oxycarbonyl and substituted oxycarbonyl;
R10 and R11 are independently selected from the group consisting of hydrogen, alkoxy, substituted alkoxy, alkylamino, substituted alkylamino, amido, substituted amido, dialkylamino and substituted dialkylamino; and
R6, R9 and R15 are independently selected from the group consisting of hydrogen, alkanyl, substituted alkanyl, aryl, substituted aryl, arylalkanyl, substituted arylalkanyl, cycloalkanyl, heteroarylalkyl and substituted heteroarylalkanyl.

### Claim 3 (depends on 1)

The compound of claim 1, wherein:
R1 is hydrogen or
R2 and R12 are independently hydrogen, acyloxycarbonyl, substituted acyloxycarbonyl, oxycarbonyl or substituted oxycarbonyl.

### Claim 4 (depends on 1)

The compound of claim 1, wherein:
R1 is hydrogen or
R2 is hydrogen or
R12 is hydrogen, acyloxycarbonyl, substituted acyloxycarbonyl, oxycarbonyl or substituted oxycarbonyl.

### Claim 5 (depends on 1)

The compound of claim 1, wherein:
R1 is hydrogen or
R2 is hydrogen, acyloxycarbonyl, substituted acyloxycarbonyl, oxycarbonyl or substituted oxycarbonyl; and
R12 is hydrogen or

### Claim 6 (depends on 1)

The compound of claim 1, wherein:
R1 is hydrogen or
R2 is hydrogen or
R12 is hydrogen or

### Claim 7 (depends on 1)

The compound of claim 1, wherein:
R1 is hydrogen or
R2 is hydrogen, acyloxycarbonyl, substituted acyloxycarbonyl, oxycarbonyl or substituted oxycarbonyl; and
R10 and R11 are independently selected from the group consisting of hydrogen, alkoxy, substituted alkoxy, alkylamino, substituted alkylamino, amido, substituted amido, dialkylamino and substituted dialkylamino.

### Claim 8 (depends on 1)

The compound of claim 1, wherein:
R1 is hydrogen or
R2 is hydrogen or
R10 and R11 are independently selected from the group consisting of hydrogen, alkoxy, substituted alkoxy, alkylamino, substituted alkylamino, amido, substituted amido, dialkylamino and substituted dialkylamino.

### Claim 9 (depends on 1)

The compound of claim 1, wherein:
R1 is
R2 is hydrogen;
R3 is —NHR12 and R12 is hydrogen, acyl, substituted acyl, acyloxyalkylcarbonyl, substituted acyloxyalkylcarbonyl, oxycarbonyl or substituted oxycarbonyl;
n is 1;
R4 and R5 are hydrogen;
R6 is hydrogen, methyl, isopropyl, isobutyl, sec-butyl, tert-butyl, cyclopentyl, cyclohexyl, —CH2OH, —CH(OH)CH3, —CH2CO2H, —CH2CH2CO2H, —CH2CONH2, —CH2CH2CONH2, —CH2CH2SCH3, —CH2SH, —CH2(CH2)3NH2, —CH2CH2CH2NHC(NH)NH2, phenyl, benzyl, 4-hydroxybenzyl, 4-imidazolylmethyl or 3-indolylmethyl;
or optionally, R5 and R6 together with the nitrogen atom to which they are bonded form an azetidine, pyrrolidine or piperidine ring; and
R12 is hydrogen, oxycarbonyl or substituted oxycarbonyl.

### Claim 10 (depends on 1)

The compound of claim 1, wherein:
R1 is oxycarbonyl or substituted oxycarbonyl;
R2 is hydrogen; and
R3 is —NHR12 and R12 is hydrogen, acyloxyalkylcarbonyl, substituted acyloxyalkylcarbonyl, oxycarbonyl or substituted oxycarbonyl.

### Claim 11 (depends on 1)

The compound of claim 1, wherein:
R1 is hydrogen or
R2 is hydrogen;
R3 is —N═C(R10)(R11) and R10 and R11 are independently selected from the group consisting of hydrogen, alkoxy, substituted alkoxy, alkylamino, substituted alkylamino, amido, substituted amido, arylalkyl, substituted arylalkyl, dialkylamino, substituted dialkylamino, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl and substituted heteroarylalkyl;
n is 1;
R4 and R5 are hydrogen;
R6 is hydrogen, methyl, isopropyl, isobutyl, sec-butyl, tert-butyl, cyclopentyl, cyclohexyl, —CH2OH, —CH(OH)CH3, —CH2CO2H, —CH2CH2CO2H, —CH2CONH2, —CH2CH2CONH2, —CH2CH2SCH3, —CH2SH, —CH2(CH2)3NH2, —CH2CH2CH2NHC(NH)NH2, phenyl, benzyl, 4-hydroxybenzyl, 4-imidazolylmethyl or 3-indolylmethyl;
or optionally, R5 and R6 together with the nitrogen atom to which they are bonded form an azetidine, pyrrolidine or piperidine ring; and
R10 and R11 are independently selected from the group consisting of hydrogen, alkoxy, substituted alkoxy, alkylamino, substituted alkylamino, dialkylamino and substituted dialkylamino.

### Claim 12 (depends on 1)

The compound of claim 1, wherein:
R1 is oxycarbonyl or substituted oxycarbonyl;
R2 is hydrogen; and
R3 is —N═C(R10)(R11) and R10 and R11 are independently selected from the group consisting of hydrogen, alkoxy, substituted alkoxy, alkylamino, substituted alkylamino, amido, substituted amido, arylalkyl, substituted arylalkyl, dialkylamino, substituted dialkylamino, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl and substituted heteroarylalkyl.

### Claim 13 (depends on 1)

The compound of claim 1, wherein:
R1 is hydrogen;
R2 is
R3 is —NHR12 and R12 is hydrogen, acyloxyalkylcarbonyl, substituted acyloxyalkylcarbonyl, oxycarbonyl or substituted oxycarbonyl;
o is 1;
R7 and R8 are hydrogen;
R9 is hydrogen, methyl, isopropyl, isobutyl, sec-butyl, tert-butyl, cyclopentyl, cyclohexyl, —CH2OH, —CH(OH)CH3, —CH2CO2H, —CH2CH2CO2H, —CH2CONH2, —CH2CH2CONH2, —CH2CH2SCH3, —CH2SH, —CH2(CH2)3NH2, —CH2CH2CH2NHC(NH)NH2, phenyl, benzyl, 4-hydroxybenzyl, 4-imidazolylmethyl or 3-indolylmethyl;
or optionally, R8 and R9 together with the nitrogen atom to which they are bonded form an azetidine, pyrrolidine or piperidine ring; and
R12 is hydrogen, oxycarbonyl or substituted oxycarbonyl.

### Claim 14 (depends on 1)

The compound of claim 1, wherein:
R1 is hydrogen;
R2 is
R3 is —N═C(R10)(R11);
o is 1;
R7 and R8 are hydrogen;
R9 is hydrogen, methyl, isopropyl, isobutyl, sec-butyl, tert-butyl, cyclopentyl, cyclohexyl, —CH2OH, —CH(OH)CH3, —CH2CO2H, —CH2CH2CO2H, —CH2CONH2, —CH2CH2CONH2, —CH2CH2SCH3, —CH2SH, —CH2(CH2)3NH2, —CH2CH2CH2NHC(NH)NH2, phenyl, benzyl, 4-hydroxybenzyl, 4-imidazolylmethyl or 3-indolylmethyl;
or optionally, R8 and R9 together with the nitrogen atom to which they are bonded form an azetidine, pyrrolidine or piperidine ring; and
R10 and R11 are independently selected from the group consisting of hydrogen, alkoxy, substituted alkoxy, alkylamino, substituted alkylamino, dialkylamino and substituted dialkylamino.

### Claim 15 (depends on 1)

The compound of claim 1, wherein:
R1 is hydrogen;
R2 is oxycarbonyl or substituted oxycarbonyl;
R3 is —N═C(R10)(R11); and
R10 and R11 are independently selected from the group consisting of hydrogen, alkoxy, substituted alkoxy, alkylamino, substituted alkylamino, amido, substituted amido, arylalkyl, substituted arylalkyl, dialkylamino, substituted dialkylamino, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl and substituted heteroarylalkyl.

### Claim 16 (depends on 1)

The compound of claim 1, wherein: R3 is
R1 and R2 are independently selected from the group consisting of hydrogen, acyl and oxycarbonyl;
p is 1;
R13 and R14 are hydrogen; and
R15 is hydrogen, methyl, isopropyl, isobutyl, sec-butyl, tert-butyl, cyclopentyl, cyclohexyl, —CH2OH, —CH(OH)CH3, —CH2CO2H, —CH2CH2CO2H, —CH2CONH2, —CH2CH2CONH2, —CH2CH2SCH3, —CH2SH, —CH2(CH2)3NH2, —CH2CH2CH2NHC(NH)NH2, phenyl, benzyl, 4-hydroxybenzyl, 4-imidazolylmethyl or 3-indolylmethyl;
or optionally, R14 and R15 together with the nitrogen atom to which they are bonded form an azetidine, pyrrolidine or piperidine ring.

### Claim 17 (depends on 1)

The compound of claim 1, wherein:
R1 and R2 are independently selected from the group consisting of hydrogen, oxycarbonyl or substituted oxycarbonyl;
R3 is —NHR12 ; and
R12 is acyloxyalkylcarbonyl, substituted acyloxyalkylcarbonyl, oxycarbonyl or substituted oxycarbonyl.

### Claim 18 (depends on 1)

The compound of claim 1, wherein:
R1 and R2 are independently selected from the group consisting of hydrogen or —C(O)OR9;
R is —NHR12 and R12 is —C(O)OR36;
R19 is C1-6 alkyl;
R36 is selected from the group consisting of C3-6 alkyl, C3-7 cycloalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl or CH2R57; and
R57 is trifluoromethyl, cyano, C1-4 alkanesulfonyl, benzenesulfonyl or substituted benzenesulfonyl;
provided that R36 is not tert-butyl or benzyl.

### Claim 19 (depends on 1)

The compound of claim 1, wherein:
R1 and R2 are independently selected from the group consisting of hydrogen or —C(O)OR19;
R3 is —NHR12 and R12 is
R19 is C1-6 alkyl;
R31 and R32 are independently selected from the group consisting of hydrogen, C1-4 alkyl, substituted C1-4 alkyl, C1-4 alkoxycarbonyl, C3-6 cycloatkyl, C3-6 cycloalkoxycarbonyl, phenyl, substituted phenyl, C7-9 phenylalkyl and pyridyl,
or optionally, R2 and R3 together with the carbon atom to which they are attached form a C3-6 cycloalkyl ring; and
R33 is selected from the group consisting of C1-6 alkyl, substituted C1-6 alkyl, C3-6 cycloalkyl, phenyl, substituted phenyl, C7-9 phenylalkyl, pyridyl and substituted pyridyl.

### Claim 20 (depends on 1)

The compound of claim 1, wherein:
R1 and R2 are independently hydrogen or oxycarbonyl;
R3 is —NHR12 where R12 is
wherein:
X is O or CH2;
q is 1 or2;
R52 is H or CO2H;
W is O or NR54;
R54 is hydrogen or C1-4 alkyl;
R53 is selected from the group consisting of C1-4 alkyl, —C(O)R30, —C(O)OR36,
wherein:
R30 is selected from the group consisting of C1-6 alkyl, substituted C1-6 alkyl, C3-6 cycloalkyl, phenyl, substituted phenyl, C7-9 phenylalkyl, pyridyl or substituted pyridyl
R31 is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, cyclopentyl, cyclohexyl, phenyl, benzyl, phenethyl or 3-pyridyl;
R32 is hydrogen;
R33 is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pent-1-yl, pent-2-yl, pent-3-yl, 2-methylbut-1-yl, 3-methylbut-1-yl, 1,1-dimethoxyethyl, 1,1-diethoxyethyl, phenyl, 2-methylphenyl, 2,6-dimethylphenyl, 2-methoxyphenyl, 4-methoxyphenyl, 2,6-dimethoxyphenyl, benzyl, phenethyl, styryl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or 3-pyridyl;
R36 is selected from the group consisting of C1-6 alkanyl, C3-6 alk-1-en-2-yl, 2-C3-7 cycloalkyl-eth-1-en-2-yl, 2-phenyleth-1-en-2-yl, substituted 2-phenyleth-1-en-2-yl, C3-7 cycloalkanyl, C5-7 cycloalk-1-en-1-yl, phenyl, naphthyl, halophenyl, methoxyphenyl, cyanophenyl, carboxyphenyl, C1-4 alkoxycarbonylphenyl, aminophenyl, halobenzyl, methoxybenzyl, cyanobenzyl, carboxybenzyl, C1-4 alkoxycarbonylbenzyl, aminobenzyl, furyl, thienyl, pyrrolyl, imidazoyl, oxazolyl, pyridyl, pyrimidyl, pyrazinyl or triazinyl;
R55 is selected from the group consisting of hydrogen, methyl, isopropyl, isobutyl, sec-butyl, tert-butyl, cyclopentyl, cyclohexyl, —CH2OH, —CH(OH)CH3, —CH2CO2H, —CH2CH2CO2H, —CH2CONH2, —CH2CH2CONH2, —CH2CH2SCH3, —CH2SH, —CH2(CH2)3NH2, —CH2CH2CH2NHC(NH)NH2, phenyl, benzyl, 4-hydroxybenzyl, 4-imidazolylmethyl or 3-indolylmethyl; and
R56 is hydrogen, C1-4 alkyl;
or optionally, R55 and R56 together with the carbon to which they are attached form a cycloalkyl or cycloheteroalkyl ring;
provided that when X is O, q is 1, R52 is CO2H, W is NR54, R54 is hydrogen, and R53 is
then R1 and R2 are not both hydrogen.

### Claim 21 (depends on 20)

The compound of claim 20, wherein:
X is O;
q is 1;
R52 is hydrogen;
W is NR54 and R54 is hydrogen;
R53 is
R55 is hydrogen, methyl, isopropyl, isobutyl, sec-butyl, tert-butyl, cyclopentyl, cyclohexyl, —CH2OH, —CH(OH)CH3, —CH2CO2H, —CH2CH2CO2H, —CH2CONH2, —CH2CH2CONH2, —CH2CH2SCH3, —CH2SH, —CH2(CH2)3NH2, —CH2CH2CH2NHC(NH)NH2, phenyl, benzyl, 4-hydroxybenzyl, 4-imidazolylmethyl or 3-indolylmethyl;
R56 is hydrogen; and
R1 and R2 are each hydrogen.

### Claim 22 (depends on 20)

The compound of claim 20, wherein:
X is O;
q is 1;
R52 is CO2H;
W is NR54 and R54 is hydrogen;
R53 is
R55 is hydrogen, methyl, isopropyl, isobutyl, sec-butyl, tert-butyl, cyclopentyl, cyclohexyl, —CH2OH, —CH(OH)CH3, —CH2CO2H, —CH2CH2CO2H, —CH2CONH2, —CH2CH2CONH2, —CH2CH2SCH3, —CH2SH, —CH2(CH2)3NH2, —CH2CH2CH2NHC(NH)NH2, phenyl, benzyl, 4-hydroxybenzyl, 4-imidazolylmethyl or 3-indolylmethyl;
R1 is —C(O)R19 and R19 is C1-6 alkyl; and
R2 and R56 are each hydrogen.

### Claim 23 (depends on 20)

The compound of claim 20, wherein:
X is O;
q is 1;
R52 is hydrogen;
W is NR54 and R54 is methyl;
R53 is methyl; and
R1 and R2 are each hydrogen.

### Claim 24 (depends on 20)

The compound of claim 20, wherein:
X is O;
q is 1;
R52 is hydrogen;
W is O;
R53 is —C(O)R30;
R30 is C1-6 alkyl, substituted C1-6 alkyl, C3-6 cycloalkyl, phenyl, substituted phenyl, C7-9 phenylalkyl, pyridyl or substituted pyridyl; and
R1 and R2 are each hydrogen.

### Claim 25 (depends on 20)

The compound of claim 20, wherein:
X is O;
q is 1;
R52 is hydrogen;
W is O or NR54 and R54 is hydrogen;
R53 is —C(O)OR36;
R36 is C1-6 alkanyl, C3-6 alk-1-en-2-yl, 2-C3-7 cycloalkyl-eth-1-en-2-yl, 2-phenyleth-1-en-2-yl, substituted 2-phenyleth-1-en-2-yl, C3-7 cycloalkanyl, C5-7, cycloalk-1-en-1-yl, phenyl, naphthyl, halophenyl, methoxyphenyl, cyanophenyl, carboxyphenyl, C1-4 alkoxycarbonylphenyl, aminophenyl, halobenzyl, methoxybenzyl, cyanobenzyl, carboxybenzyl, C1-4 alkoxycarbonylbenzyl, aminobenzyl, furyl, thienyl, pyrrolyl, imidazoyl, oxazolyl, pyridyl, pyrimidyl, pyrazinyl or triazinyl; and
R1 and R2 are each hydrogen.

### Claim 26 (depends on 20)

The compound of claim 20, wherein:
X is CH2;
q is 1;
R52 is hydrogen;
W is O;
R53is —C(O)R30;
R30 is C1-6 alkyl, substituted C1-6 alkyl, C3-6 cycloalkyl, phenyl, substituted phenyl, C7-9 phenylalkyl, pyridyl or substituted pyridyl; and R1 and R2 are each hydrogen.

### Claim 27 (depends on 20)

The compound of claim 20, wherein:
X is CH2;
q is 1;
R52 is hydrogen;
W is O or NR54 and R54 is hydrogen;
R53 is —C(O)OR36;
R36 is C1-6 alkanyl, C3-6 alk-1-en-2-yl, 2-C3-7 cycloalkyl-eth-1-en-2-yl, 2-phenyleth-1-en-2-yl, substituted 2-phenyleth-1-en-2-yl, C3-7 cycloalkanyl, C5-7 cycloalk-1-en-1-yl, phenyl, naphthyl, halophenyl, methoxyphenyl, cyanophenyl, carboxyphenyl, C1-4 alkoxycarbonylphenyl, aminophenyl, halobenzyl, methoxybenzyl, cyanobenzyl, carboxybenzyl, C1-4 alkoxycarbonylbenzyl, aminobenzyl, furyl, thienyl, pyrrolyl, imidazoyl, oxazolyl, pyridyl, pyrimidyl, pyrazinyl or triazinyl; and
R1 and R2 are each hydrogen.

### Claim 28 (depends on 20)

The compound of claim 20, wherein:
X is O;
q is 1;
R52 is hydrogen;
W is NR54 and R54 is hydrogen or methyl; and
R53 is
wherein:
R31 is hydrogen, methyl, ethyl, propyl, isopropyl, tert-butyl, cyclopentyl, cyclohexyl or phenyl and R32 is hydrogen; and
R33 is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pent-1-yl, pent-2-yl, pent-3-yl, 2-methylbut-1-yl, 3-methylbut-1-yl, 1,1-dimethoxyethyl, 1,1-diethoxyethyl, phenyl, 2-methyiphenyl, 2,6-dimethylphenyl, 2-methoxyphenyl, 4-methoxyphenyl, 2,6-dimethoxyphenyl, benzyl, phenethyl, styryl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or 3-pyridyl; and R1 and R2 are each hydrogen.

### Claim 29 (depends on 1)

The compound of claim 1, wherein the compound is chosen from:
β-1-(4-Allyloxycarbonylamino-2-oxo-1H-pyrimidin-1-yl)-2-deoxy-2,2-difluororibose;
β-1-(4-Benzyloxycarbonylamino-2-oxo-1H-pyrimidin-1-yl)-2-deoxy-2,2-difluororibose;
β-1-(4-Amino-2-oxo-1H-pyrimidin-1-yl)-3-O-(L-valinyl)-2-deoxy-2,2-difluororibose;
β-1-(4-Amino-2-oxo-1H-pyrimidin-1-yl)-5-O-(L-valinyl)-2-deoxy-2,2-difluororibose;
β-1-(4-Amino-2-oxo-1H-pyrimidin-1-yl)-3-O-(L-tert-butylglycinyl)-2-deoxy-2,2-difluororibose;
β-1-(4-Amino-2-oxo-1H-pyrimidin-1-yl)-5-O-(L-tert-butylglycinyl)-2-deoxy-2,2-difluororibose;
β-1-(4-Amino-2-oxo-1H-pyrimidin-1-yl)-3-O-(L-phenylalaninyl)-2-deoxy-2,2-difluororibose;
β-1-(4-Amino-2-oxo-1H-pyrimidin-1-yl)-5-O-(L-phenylalaninyl)-2-deoxy-2,2-difluororibose;
β-1-(4-Amino-2-oxo-1H-pyrimidin-1-yl)-3-O-(L-isoleucinyl)-2-deoxy-2,2-difluororibose;
β-1-(4-Amino-2-oxo-1H-pyrimidin-1-yl)-5-O-(L-isoleucinyl)-2-deoxy-2,2-difluororibose;
β-1-(4-Ethoxycarbonylamino-2-oxo-1H-pyrimidin-1-yl)-2-deoxy-2,2-difluororibose;
β-1-(4-Ethoxycarbonylamino-2-oxo-1H-pyrimidin-1-yl)-5-O-(tert-butyldimethylsilyl)-2-deoxy-2,2-difluororibose;
β-1-(4-Ethoxycarbonylamino-2-oxo-1H-pyrimidin-1-yl)-3-O-(N-tert-butyloxycarbonyl-L-valinyl)-5-O-(tert-butyldimethylsilyl)-2-deoxy-2,2-difluororibose;
β-1-(4-Ethoxycarbonylamino-2-oxo-1H-pyrimidin-1-yl)-3-O-(L-valinyl)-2-deoxy-2,2-difluororibose;
β-1-(4-Ethoxycarbonylamino-2-oxo-1H-pyrimidin-1-yl)-3-O-(tetrahydropyranyl)-5-O-(tert-butyldimethylsilyl)-2-deoxy-2,2-difluororibose;
β-1-(4-Ethoxycarbonylamino-2-oxo-1H-pyrimidin-1-yl)-3-O-(tetrahydropyranyl)-2-deoxy-2,2-difluororibose;
β-1-(4-Ethoxycarbonylamino-2-oxo-1H-pyrimidin-1-yl)-3-O-(tetrahydropyranyl)-5-O-(N-tert-butoxycarbonyl-L-valinyl)-2-deoxy-2,2-difluororibose;
β-1-(4-Ethoxycarbonylamino-2-oxo-1H-pyrimidin-1-yl)-5-O-(L-valinyl)-2-deoxy-2,2-difluororibose;
β-1-(4-Allyloxycarbonylamino-2-oxo-1H-pyrimidin-1-yl)-5-O-(tert-butyldimethylsilyl)-2-deoxy-2,2-difluororibose;
β-1-(4-Allyloxycarbonylamino-2-oxo-1H-pyrimidin-1-yl)-3-O-(4-carboxybutyro-1-yl)-2-deoxy-2,2-difluororibose;
β-1-(4-Amino-2-oxo-1H-pyrimidin-1-yl)-3-O-(4-carboxybutyro-1-yl)-2-deoxy-2,2-difluororibose;
β-1-(4-Allyloxycarbonylamino-2-oxo-1H-pyrimidin-1-yl)-3-O-(tetrahydropyranyl)-5-O-(tert-butyldimethylsilyl)-2-deoxy-2,2-difluororibose;
β-1-(4-Allyloxycarbonylamino-2-oxo-1H-pyrimidin-1-yl)-3-O-(tetrahydropyranyl)-2-deoxy-2,2-difluororibose;
β-1-(4-Allyloxycarbonylamino-2-oxo-1H-pyrimidin-1-yl)-5-O-(4-carboxybutyro-1-yl)-2-deoxy-2,2-difluororibose;
β-1-(4-Amino-2-oxo-1H-pyrimidin-1-yl)-5-O-(4-carboxybutyro-1-yl)-2-deoxy-2,2-difluororibose;
β-1-(4-Pentyloxycarbonylamino-2-oxo-1H-pyrimidin-1-yl)-2-deoxy-2,2-difluororibose;
β-1-(4-Amino-2-oxo-1H-pyrimidin-1-yl)-5-O-(pentyloxycarbonyl)-2-deoxy-2,2-difluororibose;
β-1-(4-Amino-2-oxo-1H-pyrimidin-1-yl)-3-O-(pentyloxycarbonyl)-2-deoxy-2,2-difluororibose;
β-1-(4-Amino-2-oxo-1H-pyrimidin-1-yl)-3-O-(pentyloxycarbonyl)-2-deoxy-2,2-difluororibose;
β-1-(4-Pentyloxycarbonylamino-2-oxo-1H-pyrimidin-1-yl)-5-O-(pentyloxycarbonyl)-2-deoxy-2,2-difluororibose;
β-1-(4-Amino-2-oxo-1H-pyrimidin-1-yl)-3-O-(pentyloxycarbonyl)-5-O-(pentyloxycarbonyl)-2-deoxy-2,2-difluororibose;
β-1-(4-Pentyloxycarbonylamino-2-oxo-1H-pyrimidin-1-yl)-3-O-(pentyloxycarbonyl)-5-O-(pentyloxycarbonyl)-2-deoxy-2,2-difluororibose;
β-1-(4-amino-2-oxo-1H-pyrimidin-1-yl)-3,5-O-di-(tert-butyldimethylsilyl)-2-deoxy-2,2-difluororibose;
β-1-(4-Phenyloxycarbonylamino-2-oxo-1H-pyrimidin-1-yl)-2-deoxy-2,2-difluororibose;
β-1-(4-(4-Methoxyphenyl)oxycarbonylamino-2-oxo-1H-pyrimidin-1-yl)-2-deoxy-2,2-difluororibose;
β-1-(4-(1,1,1-Trifluoroethyl)oxycarbonylamino-2-oxo-1H-pyrimidin-1-yl)-2-deoxy-2,2-difluororibose;
β-1-(4-(4-Methoxybenzyl)oxycarbonylamino-2-oxo-1H-pyrimidin-1-yl)-2-deoxy-2,2-difluororibose;
β-1-(4-(Propen-2-yl)oxycarbonylamino-2-oxo-1H-pyrimidin-1-yl)-2-deoxy-2,2-difluororibose;
β-1-(4-Pentyloxycarbonylamino-2-oxo-1H-pyrimidin-1-yl)-2-deoxy-2,2-difluororibose;
β-1-(4-(2-Carboxy-2-methyl)ethoxycarbonylamino-2-oxo-1H-pyrimidin-1-yl)-2-deoxy-2,2-difluororibose;
β-1-(4-Pentyloxycarbonylamino-2-oxo-1H-pyrimidin-1-yl)-5-O-acetyl-2-deoxy-2,2-difluororibose;
β-1-(4-Pentyloxycarbonylamino-2-oxo-1H-pyrimidin-1-yl)-3-O-acetyl-2-deoxy-2,2-difluororibose;
β-1-(4-Acetoxymethoxycarbonylamino-2-oxo-1H-pyrimidin-1-yl)-2-deoxy-2,2-difluororibose;
β-1-(4-(1-Isobutanoyloxyethoxy)carbonylamino-2-oxo-1H-pyrimidin-1-yl)-2-deoxy-2,2-difluororibose;
β-1-(4-(2,6-Dimethylbenzoyl)oxymethoxycarbonylamino-2-oxo-1H-pyrimidin-1-yl)-2-deoxy-2,2-difluororibose;
β-1-(4-(2-Methylbenzoyl)oxymethoxycarbonylamino-2-oxo-1H-pyrimidin-1-yl)-2-deoxy-2,2-difluororibose;
β-1(4-Acetoxymethoxycarbonylamino-2-oxo-1H-pyrimidin-1-yl)-5-O-(L-valinyl)-2-deoxy-2,2-difluororibose;
β-1-{[4-((2S)-((2S)-Aminopropionylamino)-2-carboxy)ethoxycarbonylamino]-2-oxo-1H-pyrimidin-1-yl }-2-deoxy-2,2-difluororibose;
β-1-{[4-((2S)-((2S)-Amino-3,3-dimethylbutyroylamino)-2-carboxy)ethoxycarbonylamino]-2-oxo-1H-pyrimidin-1-yl}-2-deoxy-2,2-difluororibose;
β-1-{[4-((2S)-(Aminoacetylamino)-2-carboxy)ethoxycarbonylamino]-2-oxo-1H-pyrimidin-1-yl}-2-deoxy-2,2-difluororibose;
β-1-{[4-((2S)-((2S)-Aminophenacetylamino)-2-carboxy)ethoxycarbonylamino]-2-oxo-1H-pyrimidin-1-yl}-2-deoxy-2,2-difluororibose;
β-1-{[4-((2S)-(2-Amino-2-methylpropionylamino)-2-carboxy)ethoxycarbonylamino]-2-oxo-1H-pyrimidin-1-yl}-2-deoxy-2,2-difluororibose;
β-1-{[4-((2S)-(1-Amino-cyclohexanecarbonylamino)-2-carboxy)ethoxycarbonylamino]-2-oxo-1H-pyrimidin-1-yl}-2-deoxy-2,2-difluororibose;
β-1-(4-(2-Acetoxyethoxy)carbonylamino-2-oxo-1H-pyrimidin-1-yl)-2-deoxy-2,2-difluororibose;
β-1-(4-(2-Pivaloyloxyethoxy)carbonylamino-2-oxo-1H-pyrimidin-1-yl)-2-deoxy-2,2-difluororibose;
β-1-(4-(2-Cyclohexanecarboxyethoxy)carbonylamino-2-oxo-1H-pyrimidin-1-yl)-2-deoxy-2,2-difluororibose;
β-1-{[4-(2-((2S)-Amino-3-methylbutyroylamino)-ethoxycarbonylamino]-2-oxo-1H-pyrimidin-1-yl}-2-deoxy-2,2-difluororibose;
β-1-{[4-(2-((2S)-Amino-3-phenylpropionylamino)-ethoxycarbonylamino]-2-oxo- 1H-pyrimidin-1-yl}-2-deoxy-2,2-difluororibose;
β-1-{[4-(2-(Phenyloxycarbonylamino)-ethoxycarbonylamino]-2-oxo-1H-pyrimidin-1-yl}-2-deoxy-2,2-difluororibose;
β-1-{[4-(3-(Benzyloxycarbonylamino)-propoxycarbonylamino]-2-oxo-1H-pyrimidin-1-yl}-2-deoxy-2,2-difluororibose;
β-1-[4-(2-Dimethylamino-ethoxycarbonylamino)-2-oxo-1H-pyrimidin-1-yl]-2-deoxy-2,2-difluororibose;
β-1-[4-(4-Acetoxybutyroylamino)-2-oxo-1H-pyrimidin-1-yl]-2-deoxy-2,2-difluororibose;
β-1-[4-(4-Pivaloyloxybutyroylamino)-2-oxo-1H-pyrimidin-1-yl]-2-deoxy-2,2-difluororibose;
β-1-{[4-(2-((1-Pivaloyloxy-2,2-dimethylpropyl)oxycarbonylamino)-ethoxycarbonylamino]-2-oxo-1H-pyrimidin-1-yl}-2-deoxy-2,2-difluororibose;
β-1-{[4-(2-((1-Pivaloyloxy-2,2-dimethylpropyl)oxycarbonylmethylamino)-ethoxycarbonylamino]-2-oxo-1H-pyrimidin-1-yl}-2-deoxy-2,2-difluororibose;
β-1-{[4-(2-((1-Acyloxyalkyl)oxycarbonylamino)-ethoxycarbonylamino]-2-oxo-1H-pyrimidin-1-yl}-2-deoxy-2,2-difluororibose;
β-1-{[4-(2-((Isobutanoyloxymethyl)oxycarbonylamino)-ethoxycarbonylamino]-2-oxo-1 11-pyrimidin-1-yl}-2-deoxy-2,2-difluororibose;
β-1-{[4-(2-((Acetoxymethyl)oxycarbonylamino)-ethoxycarbonylamino]-2-oxo-1H-pyrimidin-1-yl}-2-deoxy-2,2-difluororibose;
β-1-{[4-(2-((1-Isobutanoyloxyethyl)oxycarbonylamino)-ethoxycarbonylamino]-2-oxo-1H-pyrimidin-1-yl}-2-deoxy-2,2-difluororibose;
β-1-{[4-(2-((1-Acetoxy-2-methylpropyl)oxycarbonylamino)-ethoxycarbonylamino]-2-oxo-1H-pyrimidin-1-yl}-2-deoxy-2,2-difluororibose;
β-1-{[4-(2-((1-Isobutanoyloxy-2-methylpropyl)oxycarbonylamino)-ethoxycarbonylamino]-2-oxo-1H-pyrimidin-1-yl}-2-deoxy-2,2-difluororibose;
β-1-{[4-(2-((1-Pivaloyloxy-2-methylpropyl)oxycarbonylamino)-ethoxycarbonylamino]-2-oxo-1H-pyrimidin-1-yl}-2-deoxy-2,2-difluororibose;
β-1-{[4-(2-((1-Pivaloyloxyethyl)oxycarbonylamino)-ethoxycarbonylamino]-2-oxo-1H-pyrimidin-1-yl}-2-deoxy-2,2-difluororibose;
β-1-{[4-(2-((1-Acetoxyethyl)oxycarbonylamino)-ethoxycarbonylamino]-2-oxo-1H-pyrimidin-1-yl}-2-deoxy-2,2-difluororibose;
β-1-{[4-(2-((1-Acyloxyalkyl)oxycarbonylmethylamino)-ethoxycarbonylamino]-2-oxo-1H-pyrimidin-1-yl}-2-deoxy-2,2-difluororibose;
β-1-{[4-(2-((Acetoxymethyl)oxycarbonylmethylamino)-ethoxycarbonylamino]-2-oxo-1H-pyrimidin-1-yl}-2-deoxy-2,2-difluororibose;
β-1-{[4-(2-((1-Isobutanoyloxyethyl)oxycarbonylmethylamino)-ethoxycarbonylamino]-2-oxo-1H-pyrimidin-1-yl}-2-deoxy-2,2-difluororibose;
β-1-{[4-(2-((1-Acetoxy-2-methylpropyl)oxycarbonylmethylamino)-ethoxycarbonylamino]-2-oxo-1H-pyrimidin-1-yl}-2-deoxy-2,2-difluororibose;
β-1-{[4-(2-((1-Isobutanoyloxy-2-methylpropyl)oxycarbonylmethylamino)-ethoxycarbonylamino]-2-oxo-1H-pyrimidin-1-yl}-2-deoxy-2,2-difluororibose;
β-1-{[4-(2-((1-Pivaloyloxy-2-methylpropyl)oxycarbonylmethylamino)-ethoxycarbonylamino]-2-oxo-1H-pyrimidin- 1-yl}-2-deoxy-2,2-difluororibose;
β-1-{[4-(2-((1-Pivaloyloxyethyl)oxycarbonylmethylamino)-ethoxycarbonylamino]-2-oxo-1H-pyrimidin-1-yl}-2-deoxy-2,2-difluororibose;
β-1-{[4-(2-((1-Acetoxyethyl)oxycarbonylmethylamino)-ethoxycarbonylamino]-2-oxo-1H-pyrimidin-1-yl}-2-deoxy-2,2-difluororibose;
β-1-{[4-(2-((1-(2,6-Dimethylbenzoyl)oxymethyl)oxycarbonymethylamino)-ethoxycarbonylamino]-2-oxo-1H-pyrimidin-1-yl}-2-deoxy-2,2-difluororibose;
β-1-{[4-(2-((1 (2,6Dimethylbenzoyl)oxy-2-methylpropyl)oxycarbonylmethylamino)-ethoxycarbonylamino]-2-oxo-1H-pyrimidin-1-yl}-2-deoxy-2,2-difluororibose;
β-1-{[4-(2-((1-(2-Methylbenzoyl)oxy-2-methylpropyl)oxycarbonylmethylamino)-ethoxycarbonylamino]-2-oxo-1H-pyrimidin-1-yl}-2-deoxy-2,2-difluororibose; and
a pharmaceutically acceptable salt of any of the foregoing, a pharmaceutically acceptable solvate of any of the foregoing, a pharmaceutically acceptable hydrate of any of the foregoing, or a pharmaceutically acceptable N-oxide of any of the foregoing.

### Claim 30 (depends on 1)

A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable vehicle.

### Claim 31 (depends on 29)

A pharmaceutical composition comprising the compound of claim 29 and a pharmaceutically acceptable vehicle.