Chemical compounds

• US 6,455,513 B1
• Filed: 08/24/1999
• Issued: 09/24/2002
• Est. Priority Date: 03/13/1995
• Status: Expired due to Fees

• Current Assignee: Cardiff University, Rega Foundation
• Original Assignee: Cardiff University, Rega Foundation
• Inventors: Balzarini, Jan, McGuigan, Christopher
• Primary Examiner(s): BERCH, MARK L
• Application Number:
  US09/382,084
• Time in Patent Office: 1,127 Days
• Field of Search: 514/81, 514/86, 544/243, 544/244, 544/105, 544/118
• US Class Current: 514/81
• CPC Class Codes: A61K 31/675 having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 31/18 for HIV
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/04 Immunostimulants
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07F 9/6512 having the nitrogen atoms in positions 1 and 3
• CPC Class Codes: C07H 19/10 with the saccharide radical esterified by phosphoric or polyphosphoric acids
• CPC Class Codes: C07H 19/20 with the saccharide radical esterified by phosphoric or polyphosphoric acids

Abstract

Aryl substituted phosphoryl derivatives of the formula

In which Ar is phenyl, naphthyl, or pyridyl, Y is O or S, X¹ is O, NR³, S, CR³R⁴, CR³W¹ or CW¹W², X² and X⁶ are a bond or X⁶ is CH₂ and X² is O, NR³, S, CR³R⁴, CR³W¹ or CW¹W², R³ and R⁴ are H, alkyl or phenyl, groups, W¹ and W² are heteroatoms, X³ is alkylene, X⁴ is oxygen or CH₂, X⁵ is a bond or CH₂, Z is O, NR⁵, S, alkyl or phenyl, R⁵ is H, alkyl or phenyl, J is H, alkyl, phenyl, or a heterocyclic or polycyclic group, Q is O, NR⁶, S, CR⁶R⁷, CR⁶W³ or CW³W⁴, R⁶ and R⁷ are H, alkyl, or phenyl, and W³ and W⁴ are hetero atoms, T¹ and T² are H or CH₂R⁸, R⁸ is H, OH or F, or T¹ and T² together are —CH═CH— or —C(R⁹)(R¹⁰)C(R¹¹)(R¹²)—, R⁹ is H, halogeno, CN, NH₂, CO-alkyl, or alkyl, R¹⁰, R¹¹, and R¹² are H, N₃, halogen, CN, NH₂, CO-alkyl, or alkyl, and B is a purine or pyrimidine base, have antiviral activity, as for example against HIV. Particularly preferred are thymine and adenine derivatives of amino acid phenoxyphosphoroamides. A typical embodiment is 2′,3′-dideoxy-2,′3′-didehydrothymidine 5′-(phenyl methoxy alaninyl) phosphoroamidate which can be prepared from phenyl methoxy alaninyl phosphorochloridate and 2′,3′-dideoxy-2′,3′-didehydrothymidine.

Claims

1. A compound of the formula:

wherein;

Ar is phenyl, naphthyl, or pyridyl, unsubstituted or substituted with from 1 to 3 substituents selected from the group consisting of halogeno, halomethyl, hydroxy, carboxy, carboxyalkyl, alkoxy, alkanoyl, alkanoyloxy, phenoxy, benzoyl, benzoyloxy, amino, alkylamino, dialkylamino, cyano, azido, nitro, mercapto, and alkylthio;

Y is ═

O or ═

S;

X² and X⁶ taken together are direct bond or X⁶ is —

CH₂— and

X² is

X³ is alkylene of 1 to 6 carbon atoms;

X¹ is;

Z is

 

alkylene, or phenylene in which R⁵ is hydrogen, alkyl, or phenyl, unsubstituted or substituted with from 1 to 3 substituents selected from the group consisting of halogeno, halomethyl, hydroxy, carboxy, carboxyalkyl, alkoxy, alkanoyl, alkanoyloxy, phenoxy, benzoyl, benzoyloxy, amino, alkylamino, dialkylamino, cyano, azido, nitro, mercapto, and alkylthio;

each of R³ and R⁴ independently is hydrogen, alkyl, or phenyl, unsubstituted or substituted with from 1 to 3 substituents selected from the group consisting of halogeno, halomethyl, hydroxy, carboxy, carboxyalkyl, alkoxy, alkanoyl, alkanoyloxy, phenoxy, benzoyl, benzoyloxy, amino, alkylamino, dialkylamino, cyano, azido, nitro, mercapto, and alkylthio;

X⁴ is ═

O or ═

CH₂;

X⁵ is a direct bond or —

CH₂—

;

J is hydrogen, alkyl of 1 to 16 carbon atoms, cycloalkyl of 3 to 12 carbon atoms, benzyl, phenyl, unsubstituted or substituted with from 1 to 3 substituents selected from the group consisting of halogeno, halomethyl, hydroxy, carboxy, carboxyalkyl, alkoxy, alkanoyl, alkanoyloxy, phenoxy, benzoyl, benzoyloxy, amino, alkylamino, dialkylamino, cyano, azido, nitro, mercapto, and alkylthio, or a heterocyclic group selected from the group consisting of pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, tetrahydrofuranyl, pyranyl, pyronyl, pyridyl, pyrazinyl, pyridazinyl, piperidyl, piperazinyl, morpholinyl, benzofuranyl, isobenzofuryl, indolyl, oxyindolyl, isoindolyl, indazolyl, indolinyl, 7-azaindolyl, isoindazolyl, benzopyranyl, coumarinyl, isocoumarinyl, quinolyl, isoquinolyl, napthridinyl, cinnolinyl, quinazolinyl, pyridopyridyl, benzoxazinyl, quinoxalinyl, chromenyl, chromanyl, isochromanyl, and carbolinyl;

Q is

each of R⁶ and R⁷ independently is hydrogen, alkyl, or phenyl, unsubstituted or substituted with from 1 to 3 substituents selected from the group consisting of halogeno, halomethyl, hydroxy, carboxy, carboxyalkyl, alkoxy, alkanoyl, alkanoyloxy, phenoxy, benzoyl, benzoyloxy, amino, alkylamino, dialkylamino, cyano, azido, nitro, mercapto, and alkylthio;

each of W¹, W², W³, and W⁴ independently is fluoro, chloro, bromo, or iodo;

T¹ and T² taken together are;

in which R⁹ is hydrogen, halogeno, cyano, amino, CO-alkyl, or alkyl and R¹⁰, R¹¹, and R¹² independently are hydrogen, azido, halogeno, cyano, amino, CO-alkyl, or alkyl; and

B is a monovalent radical of unsubstituted thymine, cytosine, adenine, or guanine, or a monovalent radical of substituted uracil, thymine, cytosine, adenine, or guanine in which the substituents are selected from halogeno, halomethyl, hydroxy, carboxy, carboxyalkyl, alkoxy, alkanoyl, alkanoyloxy, phenoxy, benzoyl, benzoyloxy, amino, alkylamino, dialkylamino, cyano, azido, nitro, mercapto, alkylthio, alkyl, and benzyl;

or a pharmaceutically acceptable salt or ester thereof.

2. A compound according to claim 1 in which each of X² and Q is oxygen, X⁶ is —

CH₂—

, X⁵ is a direct bond, and T¹ and T² together are —

CH═

CH—

.

3. A compound according to claim 1 in which each of X², X⁴, Q, Y, and Z is oxygen, X¹ is —

NH—

, X⁵ is a direct bond, X⁶ is —

CH₂—

, and T¹ and T² together are —

CH═

CH—

.

4. A compound according to claim 3 in which B is thymine.

5. A compound according to claim 1 in which each of X² and Q is oxygen, X⁶ is —

CH₂—

, X⁵ is a direct bond, and T¹ and T² taken together are;

in which R⁹, R¹⁰, R¹¹, and R¹² are as therein defined.

6. A compound according to claim 5 in which B is adenine or thymine.

7. A compound according to claim 6 in which each of Y, X⁴, and Z is oxygen, and X¹ is —

NH—

.

8. A pharmaceutical composition comprising a quantity of a compound according to claim 1 at least sufficient to produce an anti-viral effect in combination with a pharmaceutical carrier.

9. A compound of the formula

wherein:

Ar is phenyl, naphthyl, or pyridyl, unsubstituted or substituted with from 1 to 3 substituents selected from the group consisting of halogeno, halomethyl, hydroxy, carboxy, carboxyalkyl, alkoxy, alkanoyl, alkanoyloxy, phenoxy, benzoyl, benzoyloxy, amino, alkylamino, dialkylamino, cyano, azido, nitro, mercapto, and alkylthio;

Y is ═

O or ═

S;

X² and X⁶ taken together are direct bond or X⁶ is —

CH₂— and

x2 is

R¹ is hydrogen, methyl, prop-2-yl, n-butyl, but-2-yl, benzyl, 3-guanidinopropyl, carbamoylmethyl, carboxymethyl, mercaptomethyl, 2-amino-2-carboxyethyldithiomethyl, 2-carboxyethyl, 2-carbamoylethyl, 1 H-imidazolemethyl, 4-aminobutyl, 2-methylthioethyl, hydroxymethyl, 1-hydroxyethyl, 1 H-indol-3-yl-methyl, or 4-hydroxybenzyl;

each of R³ and R⁴ independently is hydrogen, alkyl, or phenyl, unsubstituted or substituted with from 1 to 3 substituents selected from the group consisting of halogeno, halomethyl, hydroxy, carboxy, carboxyalkyl, alkoxy, alkanoyl, alkanoyloxy, phenoxy, benzoyl, benzoyloxy, amino, alkylamino, dialkylamino, cyano, azido, nitro, mercapto, and alkylthio and each of W¹ and W² independently is fluoro, chloro, bromo, or iodo;

X⁵ is a direct bond or —

CH₂—

;

J is hydrogen, alkyl of 1 to 16 carbon atoms, cycloalkyl of 3 to 12 carbon atoms, benzyl phenyl, unsubstituted or substituted with from 1 to 3 substituents selected from the group consisting of halogeno, halomethyl, hydroxy, carboxy, carboxyalkyl, alkoxy, alkanoyl, alkanoyloxy, phenoxy, benzoyl, benzoyloxy, amino, alkylamino, dialkylamino, cyano, azido, nitro, mercapto, and alkylthio;

or a heterocyclic group selected from the group consisting of pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, tetrahydrofuranyl, pyranyl, pyronyl, pyridyl, pyrazinyl, pyridazinyl, piperidyl, piperazinyl, morpholinyl, benzofuranyl, isobenzofuryl, indolyl, oxyindolyl, isoindolyl, indazolyl, indolinyl, 7-azaindolyl, isoindazolyl, benzopyranyl, coumarinyl, isocoumarinyl, quinolyl, isoquinolyl, napthridinyl, cinnolinyl, quinazolinyl, pyridopyridyl, benzoxazinyl, quinoxalinyl, chromenyl, chromanyl, isochromanyl, and carbolinyl;

Q is

in which each of R⁶ and R⁷ independently is hydrogen, alkyl, or phenyl, unsubstituted or substituted with from 1 to 3 substituents selected from the group consisting of halogeno, halomethyl, hydroxy, carboxy, carboxyalkyl, alkoxy, alkanoyl, alkanoyloxy, phenoxy, benzoyl, benzoyloxy, amino, alkylamino, dialkylamino, cyano, azido, nitro, mercapto, and alkylthio;

each of W³ and W⁴ independently is fluoro, chloro, bromo, or iodo;

T¹ and T² taken together are;

in which R⁹ is hydrogen, halogeno, cyano, amino, CO-alkyl, or alkyl and R¹⁰, R¹¹, and R¹² independently are hydrogen, azido, halogeno, cyano, amino, CO-alkyl, or alkyl; and

B is a monovalent radical of unsubstituted thymine, cytosine, adenine, or guanine, or a monovalent radical of substituted uracil, thymine, cytosine, adenine, or guanine in which the substituents are selected from halogeno, halomethyl, hydroxy, carboxy, carboxyalkyl, alkoxy, alkanoyl, alkanoyloxy, benzyloxy, benzyloyl, benzoyloxy, amino, alkylamino, dialkylamino, cyano, azido, nitro, mercapto, alkylthio, alkyl, and benzyl;

or a pharmaceutically acceptable salt or ester thereof.

10. A compound according to claim 9 in which each of X² and Q is oxygen, X⁶ is —

CH₂—

, X⁵ is a direct bond, and T¹ and T2 together are —

CH═

CH—

.

11. A compound according to claim 10 in which each of X⁴ and Y is oxygen.

12. A compound according to claim 11 in which B is thymine.

13. A compound according to claim 9 in which each of X² and Q is oxygen, X⁶ is —

CH₂—

, X⁵ is a direct bond, and T¹ and T² taken together are;

in which R⁹, R¹⁰, R¹¹, and R¹² are as therein defined.

14. A compound according to claim 13 in which B is adenine or thymine.

15. A compound according to claim 14 in which each of Y and X⁴ is oxygen.

16. A compound according to claim 9 having the formula:

in which

Ar is phenyl, unsubstituted or substituted with chloro, bromo, fluoro, trifluoromethyl, methyl or ethyl,

R¹ is hydrogen, methyl, prop-2-yl, n-butyl, but-2-yl, benzyl, 3-guanidinopropyl, carbamoylmethyl, carboxymethyl, mercaptomethyl, 2-amino-2-carboxyethyidithiomethyl, 2-carboxyethyl, 2-carbamoylethyl, 1H-imidazolemethyl, 4-aminobutyl, 2-methylthioethyl, hydroxymethyl, 1-hydroxyethyl, 1H-indol-3-yl-methyl, or 4-hydroxybenzyl;

preferably 1 substituent. Substituents include halo, halomethyl (such as CF₃ and CCl₃), oxo, hydroxy, carboxy, carboxyalkyl, alkoxy, alkanoyl, alkanoyloxy, aryloxy, aryloyl, aryloyloxy, amino, alkylamino, dialkylamino, cyano, azide, nitro, thiol, alkylthiol, sulphonyl, sulphoxide, heterocyclic, alkyl, benzyl, and aryl (such as phenyl and substituted phenyl). B is a monovalent radical of unsubstituted thymine, cytosine, adenine, or guanine, or a monovalent radical of substituted uracil, thymine, cytosine, adenine, or guanine in which the substituents are as defined above;

e.g., halo, halo-methyl, oxo, hydroxy, carboxy, carboxyalkyl, alkoxy, alkanoyl, alkanoyloxy, aryloxy, aryloyl, aryloyloxy, amino, alkylamino, dialkylamino, cyano, azide, nitro, thiol, alkylthiol, sulphonyl, sulphoxide, heterocyclic, alkyl, benzyl, and aryl.

Preferably, B is adenine or thymine naturally occurring amino acid such as alanine (R¹ is methyl), arginine (R¹ is 3-guanidinopropyl), asparagine (R¹ is carbamoylmethyl), aspartic acid (R¹ is carboxymethyl), cysteine (R¹ is mercaptomethyl), cystine (R¹ is 2-amino-2-carboxyethyidithiomethyl), glycine (R¹ is hydrogen), glutamic acid (R¹ is 2-carboxyethyl), glutamine (R¹ is 2-carbamoylethyl), histidine (R¹ is 1 H-imidazolemethyl), isoleucine (R¹ is but-2-yl), leucine (R¹ is butyl), lysine (R¹ is 4-aminobutyl), methionine (R¹ is 2-methylthioethyl), phenylalanine (R¹ is benzyl), serine (R¹ is hydroxymethyl), threonine (R¹ is 1-hydroxyethyl), tryptophan (R¹ is 1H-indol-3-ylmethyl), tyrosine (R¹ is 4-hydroxybenzyl), and valine (R¹ is prop-2-yl).

Preferably R¹ is “

X³ is a C_1-6 alkylene group, X³ may be a C_1-6 substituted or unsubstituted, branched or unbranched, methylene chain,”

B is adenine or thymine, and

J, R⁹, R¹⁰, R¹¹, and R¹² are as therein defined.

17. A compound according to claim 16 in which J is hydrogen.

18. A compound according to claim 16 in which B is thymine.

22. A pharmaceutical composition comprising a quantity of a compound according to claim 9 least sufficient to produce an anti-viral effect in combination with a pharmaceutical carrier.

19. The compound having the formula:

in which Ar is 4-ethylphenyl, R¹ is methyl, and J is methyl;

in which Ar is phenyl, R¹ is methyl, and J is methyl;

in which Ar is 4-fluorophenyl, R¹ is methyl, and J is methyl;

in which Ar is 3-trifluoromethylphenyl, R¹ is methyl, and J is methyl;

in which Ar is 3,5-dichlorophenyl, R¹ is methyl, and J is methyl;

in which Ar is phenyl, R¹ is methyl, and J is benzyl;

in which Ar is 2,4-dibromophenyl, R¹ is methyl, and J is methyl;

in which Ar is pentafluorophenyl, R¹ is methyl, and J is methyl;

in which Ar is phenyl, R¹ is methyl, and J is hexyl;

in which Ar is phenyl, R¹ is benzyl, and J is methyl;

in which Ar is phenyl, R¹ is but-2-yl, and J is methyl;

in which Ar is phenyl, R¹ is prop-2-yl, and J is methyl;

in which Ar is phenyl, R¹ is hydrogen, and J is methyl;

in which Ar is phenyl, R¹ is 2-methylthioethyl, and J is methyl;

in which Ar is 2,4-dibromophenyl, R¹ is methyl, and J is benzyl;

in which Ar is phenyl, R¹ is benzyl, and J is benzyl;

in which Ar is phenyl, R¹ is benzyl, and J is tert.-butyl;

in which Ar is phenyl, R¹ is methyl, and J is cyclohexyl;

in which Ar is phenyl, R¹ is methyl, and J is tert.-butyl;

in which Ar is phenyl, R¹ is carboxymethyl, and J is methyl;

in which Ar is phenyl,

R¹ is 3-guanidinopropyl, and J is methyl;

in which Ar is phenyl, R¹ is methyl, and J is n-pentyl;

in which Ar is phenyl, R¹ is methyl, and J is 2,2-dimethylpropyl;

in which Ar is phenyl, R¹ is methyl, and J is 1-naphthyl;

or in which Ar is phenyl, R¹ is methyl, and J is 2-naphthyl.

20. A compound of the formula:

wherein;

Y is ═

O or ═

S;

X¹ is;

X² and X⁶ taken together are direct bond or X⁶ is —

CH₂—

; and

X² is

in which each of R³ and R⁴ independently is hydrogen, alkyl, or aryl and

each of R³ and R⁴ independently is hydrogen, alkyl, or phenyl, unsubstituted or substituted with from 1 to 3 substituents selected from the group consisting of halogeno, halomethyl, hydroxy, carboxy, carboxyalkyl, alkoxy, alkanoyl, alkanoyloxy, phenoxy, benzoyl, benzoyloxy, amino, alkylamino, dialkylamino, cyano, azido, nitro, mercapto, and alkylthio;

X³ is (i) alkylene of 1 to 6 carbon atoms, or (ii) CHR¹ in which R¹ is 3-guanidinopropyl, mercaptomethyl, 2-amino-2-carboxyethyldithiomethyl, carboxymethyl, 2-carboxyethyl, carbamoylmethyl, 2-carbamoylethyl, 1H-imidazolemethyl, 4-aminobutyl, 2-methylthioethyl, hydroxymethyl, 1-hydroxyethyl, 1H-indol-3-ylmethyl, benzyl, or 4-hydroxybenzyl;

X⁴ is ═

O or ═

CH₂;

X⁵ is a direct bond or —

CH₂—

;

Q is

each of R⁶ and R⁷ independently is hydrogen, alkyl, or phenyl, unsubstituted or substituted with from 1 to 3 substituents selected from the group consisting of halogeno, halomethyl, hydroxy, carboxy, carboxyalkyl, alkoxy, alkanoyl, alkanoyloxy, phenoxy, benzoyl, benzoyloxy, amino, alkylamino, dialkylamino, cyano, azido, nitro, mercapto, and alkylthio, and each of W¹, W², W³, and W⁴ independently is fluoro, chloro, bromo, or iodo;

T¹ and T² taken together are;

in which R⁹ is hydrogen, halo, cyano, amino, CO-alkyl, or alkyl and R¹⁰, R¹¹, and R¹² independently are hydrogen, azido, halo, amino, CO-alkyl, or alkyl; and

B is a monovalent radical of unsubstituted thymine, cytosine, adenine, or guanine, or a monovalent radical of substituted uracil, thymine, cytosine, adenine, or guanine in which the substituents are selected from halogeno, halomethyl, hydroxy, carboxy, carboxyalkyl, alkoxy, alkanoyl, alkanoyloxy, phenoxy, benzoyl, benzoyloxy, amino, alkylamino, dialkylamino, cyano, azido, nitro, mercapto, alkylthio, alkyl, and benzyl;

or a pharmaceutically acceptable salt or ester thereof.

21. A compound according to claim 20 in which each of Y and X⁴ is oxygen, X¹ is —

NH—

, and X³is —

CHR¹—

.

31. A compound according to claim 21 in which each of X² and Q is oxygen, X⁶ is —

CH₂—

, X⁵ is a direct bond, and T¹ and T² together are —

CH═

CH—

.

32. A compound according to claim 31 in which B is thymine.

33. A compound according to claim 31 in which R¹ is hydrogen, methyl, prop-2-yl, n-butyl, but-2-yl, hydroxymethyl, mercaptomethyl, 1-hydroxyethyl, 2-methylthioetyhyl, carboxymethyl, 2-carboxyethyl, carbamoylmethyl, 2-carbamoylethyl, 4-aminobutyl, benzyl, 4-hydroxbenzyl, 3-guanidinopropyl, 2-amino-2-carboxyethyldithiomethyl, 1-H-imidazolemethyl, or 1H-indol-3-ylmethyl.

23. compound of the formula:

wherein;

Ar is phenyl, naphthyl, or pyridyl, unsubstituted or substituted with from 1 to 3 substituents selected from the group consisting of halogeno, halomethyl, hydroxy, carboxy, carboxyalkyl, alkoxy, alkanoyl, alkanoyloxy, phenoxy, benzoyl, benzoyloxy, amino, alkylamino, dialkylamino, cyano, azido, nitro, mercapto, and alkylthio;

Y is ═

O or ═

S;

X² and X⁶ taken together are direct bond or X⁶ is —

CH₂— and

X²is

X³ is —

CR¹R²—

in which each of R¹ and R² is hydrogen, alkyl of 1 to 6 carbon atoms, or phenyl;

X¹ is;

Z is

 

alkylene, or phenylene in which R⁵ is hydrogen, alkyl, or phenyl, unsubstituted or substituted with from 1 to 3 substituents selected from the group consisting of halogeno, halomethyl, hydroxy, carboxy, carboxyalkyl, alkoxy, alkanoyl, alkanoyloxy, phenoxy, benzoyl, benzoyloxy, amino, alkylamino, dialkylamino, cyano, azido, nitro, mercapto, and alkylthio;

each of R³ and R⁴ independently is hydrogen, alkyl, or phenyl, unsubstituted or substituted with from 1 to 3 substituents selected from the group consisting of halogeno, halomethyl, hydroxy, carboxy, carboxyalkyl, alkoxy, alkanoyl, alkanoyloxy, phenoxy, benzoyl, benzoyloxy, amino, alkylamino, dialkylamino, cyano, azido, nitro, mercapto, and alkylthio;

X⁴ is ═

O or ═

CH₂;

X⁵ is a direct bond or —

CH₂—

;

J is hydrogen, alkyl of 1 to 16 carbon atoms, cycloalkyl of 3 to 12 carbon atoms, benzyl, phenyl, unsubstituted or substituted with from 1 to 3 substituents selected from the group consisting of halogeno, halomethyl, hydroxy, carboxy, carboxyalkyl, alkoxy, alkanoyl, alkanoyloxy, phenoxy, benzoyl, benzoyloxy, amino, alkylamino, dialkylamino, cyano, azido, nitro, mercapto, and alkylthio, or a heterocyclic group selected from the group consisting of pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, tetrahydrofuranyl, pyranyl, pyronyl, pyridyl, pyrazinyl, pyridazinyl, piperidyl, piperazinyl, morpholinyl, benzofuranyl, isobenzofuryl, indolyl, oxyindolyl, isoindolyl, indazolyl, indolinyl, 7-azaindolyl, isoindazolyl, benzopyranyl, coumarinyl, isocoumarinyl, quinolyl, isoquinolyl, napthridinyl, cinnolinyl, quinazolinyl, pyridopyridyl, benzoxazinyl, quinoxalinyl, chromenyl, chromanyl, isochromanyl, and carbolinyl;

Q is

each of R⁶ and R⁷ independently is hydrogen, alkyl, or phenyl, unsubstituted or substituted with from 1 to 3 substituents selected from the group consisting of halogeno, halomethyl, hydroxy, carboxy, carboxyalkyl, alkoxy, alkanoyl, alkanoyloxy, phenoxy, benzoyl, benzoyloxy, amino, alkylamino, dialkylamino, cyano, azido, nitro, mercapto, and alkylthio;

each of W¹, W², W³, and W⁴ independently is fluoro, chloro, bromo, or iodo;

T¹ and T² taken together are;

in which R⁹ is hydrogen, halogeno, cyano, amino, CO-alkyl, or alkyl and R¹⁰, R¹¹, and R¹² independently are hydrogen, azido, halogeno, cyano, amino, CO-alkyl, or alkyl; and

B is a monovalent radical of unsubstituted thymine, cytosine, adenine, or guanine, or a monovalent radical of substituted uracil, thymine, cytosine, adenine, or guanine in which the substituents are selected from halogeno, halomethyl, hydroxy, carboxy, carboxyalkyl, alkoxy, alkanoyl, alkanoyloxy, phenoxy, benzoyl, benzoyloxy, amino, alkylamino, dialkylamino, cyano, azido, nitro, mercapto, alkylthio, alkyl, and benzyl;

or a pharmaceutically acceptable salt or ester thereof.

24. A compound according to claim 23 in which R¹ is hydrogen, each of X² and Q is oxygen, X⁶ is —

CH₂—

, X⁵ is a direct bond, and T¹ and T² together are —

CH═

CH—

.

25. A compound according to claim 23 in which R¹ is hydrogen, each of X², X⁴, Q, Y, and Z is oxygen, X¹ is —

NH—

, X⁵ is a direct bond, X⁶ is —

CH₂—

, and T¹ and T2 together are —

CH═

CH—

.

26. A compound according to claim 25 in which B is thymine.

27. A compound according to claim 23 in which R¹ is hydrogen, each of X² and Q is oxygen, X⁶ is —

CH₂—

, X⁵ is a direct bond, and T¹ and T² taken together are;

in which R⁹, R¹⁰, R¹¹, and R¹² are as therein defined.

28. A compound according to claim 27 in which B is adenine or thymine.

29. A compound according to claim 28 in which each of Y, X⁴, and Z is oxygen, and X¹ is —

NH—

.

30. A pharmaceutical composition comprising a quantity of a compound according to claim 23 at least sufficient to produce an anti-viral effect in combination with a pharmaceutical carrier.