Nucleotide analogs

• US 5,798,340 A
• Filed: 05/06/1996
• Issued: 08/25/1998
• Est. Priority Date: 09/17/1993
• Status: Expired due to Term

• Current Assignee: Gilead Sciences Inc.
• Original Assignee: Gilead Sciences Inc.
• Inventors: Jones, Robert J., Arimilli, Murty N., Lee, William A., Bischofberger, Norbert W., Prisbe, Ernest J., Louie, Michael S.
• Primary Examiner(s): Wilson, James O.
• Application Number:
  US08/617,849
• Time in Patent Office: 841 Days
• Field of Search: 536/27.14, 536/27.21, 536/27.6, 536/27.7, 536/27.8, 536/27.81, 536/28.2, 536/28.5, 536/28.51, 536/28.52, 536/28.53, 536/28.54, 536/28.55, 544/242, 544/243, 544/244, 544/264, 544/265, 544/267, 544/303, 544/304, 544/310, 514/45, 514/46, 514/47, 514/48, 514/49, 514/50, 514/51
• US Class Current: 514/45
• CPC Class Codes: C07F 9/6512 having the nitrogen atoms in positions 1 and 3
• CPC Class Codes: C07F 9/65616 containing the ring system having three or more than three double bonds between ring members or between ring members and non-ring members, e.g. purine or analogs
• CPC Class Codes: C07F 9/657181 the ring phosphorus atom and, at least, one ring oxygen atom being part of a (thio)phosphonic acid derivative
• CPC Class Codes: C07F 9/65742 non-condensed with carbocyclic rings or heterocyclic rings or ring systems
• CPC Class Codes: C07F 9/65744 condensed with carbocyclic or heterocyclic rings or ring systems
• CPC Class Codes: C07F 9/65785 the ring phosphorus atom and, at least, one ring sulfur atom being part of a thiophosphonic acid derivative
• 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

Nucleotide analogs characterized by the presence of an amidate lirked amino acid or an ester linked group which is bonded to the phosphorus atom of phosphonate nucleotide analogs are disclosed. The analogs comprise a phosphoamidate or ester bond that is hydrolysed in vivo to yield a corresponding phosphonate nucleotide analog. Methods and intermediates for the synthesis and use are described.

Claims

1. A compound of the formula Ib ##STR47## and stereoisomers and salts of such compounds wherein X¹ is S;

L¹ is an oxyester or a thio ester; and

the carbon atom designated # has linked substituents that are in the R, S or RS configuration.

2. The compound of claim 1 wherein L¹ is OR³⁵ wherein

R³⁵ is R or R³¹ ;

R is H,

C₃ -C₂₄ acyloxyalkyl

C₆ -C₂₄ acyloxyarylalkyl.

C₃ -C₂₄ acyloxyalkoxyalkyl.

C₃ -C₂₄ acyloxyhaloalkyl.

C₁ -C₂₀ alkyl which is unsubstituted or substituted by substituents independently selected from the group consisting of OH, O, N and halogen.

C₃ -C₂₀ aryl which is unsubstituted or substituted by substituents independently selected from the group consisting of C₁ -C₆ alkyl, C₁ -C₆ alkoxy. C₁ -C₆ haloalkyl (1 to 3 halogen atoms), cyano. nitro, OH, O, N and halogen, or

C₄ -C₂₀ aryl-alkyl which is unsubstituted or substituted in the aryl moiety by substituents independently selected from the group consisting of C₁ -C₆ alkyl, C₁ -C₆ alkoxy, C₁ -C₆ haloalkyl (1 to 3 halogen atoms), cyano, nitro, OH, O, N and halogen

R³¹ is 2,3-dihydro-6-hydroxyindene;

sesamol;

catechol monoester;

--CH₂ --C(O)--N(R⁷)₂ wherein R⁷ is H or C₁ -C₄ alkyl and each R⁷ is the same or different;

--CH₂ --S(O)(R⁷);

--CH₂ --S(O)₂ (R⁷);

--CH₂ --CH(OC(O)CH₂ R⁷)--CH₂ (OC(O)CH₂ R⁷);

cholesteryl;

a monosaccharide;

a disaccharide;

an oligosaccharide (3 to 9 monosaccharide residues), enolpyruvate;

glycerol;

an a-D-b-diglyceride;

trimethoxybenzyl;

triethoxybenzyl;

2-alkyl pyridinyl (C_1-4 alkyl);

##STR48## C₃ -C₆ aryl substituted by 3, 4 or 5 halogen atoms or 1 or 2 atoms or groups selected from the group consisting of halogen, C₁ -C₁₂ alkoxy, cyano, nitro, OH, C₁ -C₁₂ haloalkyl, C₁ -C₁₂ alkyl, C₂ -C₁₂ alkenyl and C₂ -C₁₂ alkynyl;

or

C₁ -C₄ alkylene--C₃ -C₆ aryl substituted in the aryl moiety by 3 to 5 halogen atoms or 1 to 2 atoms or groups selected from the group consisting of halogen, C₁ -C₁₂ alkoxy, cyano, nitro, OH, C₁ -C₁₂ haloalkyl, C₁ -C₁₂ alkyl, C₂ -C₁₂ alkenyl and C₂ -C₁₂ alkynyl.

3. The compound of claim 2, herein B is ##STR49## wherein R¹⁵ is H, OH, F, Cl, Br, I, OR¹⁶, SH, SR¹⁶, NH₂, or NHR¹⁷ ;

R¹⁶ is C₁ -C₆ alkyl

R¹⁷ is C₁ -C₆ alkyl;

R¹⁸ is N, CF, CCl, CBr, CI, CR¹⁹ or CSR¹⁹, COR¹⁹ ;

R¹⁹ is H, C₁ -C₉ alkyl, C₂ -C₉ alkenyl, C₂ -C₉ alkynyl or C₇ -C₉ aryl-alkyl unsubstituted or substituted by OH , N F, Cl, Br or I;

R²⁰ is N or CH;

R²¹ is N, CH, CCN, CCF₃, CC.tbd.CH or CC(O)NH₂ ;

R²² is H, OH, NH₂, SH, SCH₃, SCH₂ CH₃, SCH₂ CCH, SCH₂ CHCH₂, SC₃ H₇, NH(CH₃), N(CH₃)₂, NH(CH₂ CH₃), N(CH₂ CH₃)₂, NH(CH₂ CCH), NH(CH₂ CHCH₂), NH(C₃ H₇) or halogen;

R²³ is H, OH, F, Cl, Br, I, SCH₃, SCH₂ CH₃, SCH₂ CCH, SCH₂ CHCH₂, SC₃ H₇, OR¹⁶ NH₂, or NHR¹⁷ ; and

R²⁴ is O, S or Se.

4. The compound of claim 3 wherein B is cytosin-1-yl, 6-azacytosin-1-yl, 5-fluorocytosin-1-yl, adenin-9-yl, guanin-9-yl or 2, 6-diaminopurin-9-yl.

5. The compound of claim 3 wherein R³¹ is 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-ethoxy-5-hydroxyphenyl, 2-ethoxy-4-hydroxyphenyl 3,5-dimethoxyphenyl, 2,4-difluorophenyl, 2-(haloalkyl)-phenyl, 3-(haloalkyl)phenyl, 4-(haloalkyl)-phenyl, 2-cyanophenyl, 3-cyanophenyl, 4-cyanophenyl, 2-ethoxyphenyl, 3-ethoxyphenyl, 4-ethoxyphenyl, 2-carboethoxyphenyl, 3-carboethoxyphenyl, 4-carboethoxyphenyl, or 2-haloalkylbenzyl, 3-haloalkylbenzyl or 4-haloalkylbenzyl.

30. A method comprising orally administering to a subject an antivirally-effective dose of a compound of claim 2.

31. The method of claim 30 wherein the compound is enriched or resolved at the phosphate atom chiral center.

6. A compound of the formula (OR³¹)₂ P(O)--Z¹ --B or (OR) (OR³¹)P(O)--Z¹ --B, wherein;

B is a heterocyclic base;

Z¹ is selected from the group consisting of --CH₂ --O--CH₂ --CH₂ --, --CH₂ --O--C--H(CH₂ OH)--CH₂ --, --CH₂ --O--C--H(CH₃)--CH₂ --, --CH_2--O--C--H(CH₂ F)--CH₂ --, --CH₂ --O--C--H(CH═

CH₂)--CH₂ --and --CH₂ --O--C--H(CH₂ N₃)--CH₂ -;

R is H,

C₃ -C₂₄ 1-acyloxy-1-alkyl,

C₆ -C₂₄ 1-acyloxy-1-aryl-1-alkyl,

C₃ -C₂₄ 1-acyloxy-2-alkoxy-1-alkyl,

C₃ -C₂₄ 1-acyloxy-2-halo-1-alkyl,

C₁ -C₂₀ alkyl which is unsubstituted or substituted by substituents independently selected from the group consisting of OH, O, N and halogen,

C₃ -C₂₀ aryl which is unsubstituted or substituted by substituents independently selected from the group consisting of C₁ -C₆ alkyl, C₁ -C₆ alkoxy, C₁ -C₆ haloalkyl, cyano, nitro, OH, O, N and halogen, or

C₄ -C₂₀ aryl-alkyl which is unsubstituted or substituted in the aryl moiety by substituents independently selected from the group consisting of C₁ -C₆ alkyl, C₁ -C₆ alkoxy, C₁ -C₆ haloalkyl, cyano, nitro, OH, O, N and halogen;

R³¹ is 2,3-dihydro-6-hydroxyindene;

sesamol;

catechol monoester;

--CH₂ --S(O)(R⁷) wherein R² is hydrogen or C_1-4 alkyl --CH₂ --S(O)₂ (R⁷);

--CH₂ --CH(OC(O)CH₂ R⁷)--CH₂ (OC(O)CH₂ R⁷);

cholesteryl;

a monosaccharide;

a disaccharide;

an oligosaccharide (3 to 9 monosaccharide residues), enolpyruvate;

glycerol;

an a-D-b-diglyceride;

trimethoxybenzyl;

triethoxybenzyl;

2-alkyl pyridinyl (C_1-4 alkyl);

##STR50## C₃ -C₆ aryl substituted by 3, 4 or 5 halogen atoms or 1 or 2 atoms or groups selected from the group consisting of halogen, C₁ -C₁₂ alkoxy, cyano, nitro, OH, C₁ -C₁₂ haloalkyl, C₁ -Cl₂ alkyl, C₂ -C₁₂ alkenyl and C₂ -C₁₂ alkynyl;

or

C₁ -C₄ alkylene-C₃ -C₆ aryl substituted in the aryl moiety by 3 to 5 halogen atoms or 1 to 2 atoms or groups selected from the group consisting of halogen, C₁ -C₁₂ alkoxy, cyano, nitro, OH, C₁ --C₁₂ haloalkyl, C₁ -C₁₂ alkyl, C₂ -C₁₂ alkenyl and C₂ -C₁₂ alkynyl, provided that when Z¹ is --CH₂ --O--CH₂ --CH₂ --and B is adenin-9-yl, both R³¹ are not 4-nitrobenzyl or 4-trifluoromethyl-benzyl.

7. The compound of claim 6 wherein R³¹ is 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, -fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-ethoxy-5-hydroxyphenyl, 2-ethoxy-4-hydroxyphenyl 3,5-dimethoxyphenyl, 2,4-difluorophenyl, 2-(haloalkyl)-phenyl, 3-(haloalkyl)phenyl, 4-(haloalkyl)-phenyl, 2-cyanophenyl, 3-cyanophenyl, 4-cyanophenyl, 2-ethoxyphenyl, 2-carboethoxyphenyl, 3-carboethoxyphenyl, 4-carboethoxyphenyl, or 2-haloalkylbenzyl, 3-haloalkylbenzyl or 4-haloalkylbenzyl.

8. The compound of claim 7 wherein B is cytosin-1-yl, 6-azacytosin-1-yl, 5-fluorocytosin-1-yl, adenin-9-yl, guanin-9-yl or 2, 6-diaminopurin-9-yl.

38. The compound of claim 6 wherein R³¹ is 2,3-dihydro-6-hydroxyindene;

sesamol;

catechol monoester;

--CH₂ --S(O)(R⁷);

--CH₂ --S(O)₂ (R⁷);

--CH₂ --CH(OC(O)CH₂ R⁷)--CH₂ (OC(O)CH₂ R⁷);

cholesteryl;

a monosaccharide;

a disaccharide;

an oligosaccharide, enolpyruvate;

glycerol;

trimethoxybenzyl;

triethoxybenzyl;

2-alkyl pyridinyl (C_1-4 alkyl);

##STR68## C₃ -C₆ aryl substituted by 1 or 2 cyano, nitro, C₁ -C₁₂ haloalkyl, C₂ -C₁₂ alkenyl or C₂ -C₁₂ alkynyl groups;

or

C₁ -C₄ alkylene-C₃ -C₆ aryl substituted in the aryl moiety by 1 to 2 cyano, nitro, C₁ -C₁₂ haloalkyl, C₂ -C₁₂ alkenyl or C₂ -C₁₂ alkynyl groups.

9. A compound of the formula (L¹)₂ P(O)--Z--B¹ wherein

L¹ is an oxyester or a thioester;

B¹ is a protected heterocyclic base; and

Z--B¹ is ##STR51## wherein R²⁷ is H, OH, halogen, N₃, C₁ -C₄ alkyl, C₁ -C₄ alkoxy or when, R²⁶ is S, R²⁷ is absent;

R²⁸ is H, OH, halogen, N₃, C₁ -C₄ alkyl or C₁ -C₄ alkoxy;

R²⁹ is S, CHF or CF₂ ;

R³³ is H, OH, TBSO, halogen, cyano, CH₂ N₃, C₁ -C₄ alkyl, C₁ -C₄ alkoxy, CH₂ OH or azido; and

R³⁴ is H, CH₂ CN or CF₃.

10. The compound of claim 9 wherein B¹ is ##STR52## wherein R¹⁸ is N, CF, CCl, CBr, CI, CR¹⁹ or CSR¹⁹, COR¹⁹ ;

R²⁰ is N or CH;

R²¹ is N, CH, CCN, CCF₃, CC.tbd.CH or CC(O)NH₂ ;

R^22A is R³⁹ or R²² provided that R²² is not NH₂ ;

R²² is H, OH, NH₂,SH, SCH₃, SCH₂ CH₃, SCH₂ CCH, SCH₂ CHCH₂, SC₃ H₇, NH(CH₃), N(CH₃)₂, NH(CH₂ CH₃), N(CH₂ CH₃)₂, NH(CH₂ CCH), NH(CH₂ CHCH₂), NH(C₃ H₇) or halogen (F, Cl, Br or I);

R^23A is R³⁹ or R²³ provided that R²³ is not NH₂ ;

R²³ is H, OH, F, Cl, Br, I, SCH₃, SCH₂ CH₃, SCH₂ CCH, SCH₂ CHCH₂, SC₃ H₇, OR¹⁶, NH₂, or NHR¹⁷ ;

R²⁴ is O, S or Se; and

R³⁹ is NHR⁴⁰, NHC(O)R³⁶ or NCR⁴¹ N(R³⁸)₂ wherein,

R³⁶ is C₁ -C₁₉ alkyl, C₁ -C₁₉ alkenyl, C₃ -C₁₀ aryl, adamantoyl, alkylanyl, or C₃ -C₁₀ aryl substituted with 1 or 2 atoms or groups selected from halogen, methyl, ethyl, methoxy, ethoxy, hydroxy and cyano;

R³⁸ is C₁ -C₁₀ alkyl, or both R³⁸ together are 1-morpholino, 1-piperidine or 1-pyrrolidine;

R⁴⁰ is C_1-20 alkyl; and

R⁴¹ is hydrogen or CH₃.

11. The compound of claim 10 wherein L¹ is R or R³¹ wherein

R is

C₃ -C₂₄ 1-acyloxy-1-alkyl,

C₆ -C₂₄ 1-acyloxy-1-aryl-1-alkyl,

C₃ -C₂₄ 1-acyloxy-2-alkoxy-1-alkyl,

C₃ -C₂₄ 1-acyloxy-2-halo-1-alkyl,

C₁ -C₂₀ alkyl which is unsubstituted or substituted by substituents independently selected from the group consisting of OH, O, N and halogen,

C₃ -C₂₀ aryl which is unsubstituted or substituted by substituents independently selected from the group consisting of C₁ -C₆ alkyl, C₁ -C₆ alkoxy, C₁ -C₆ haloalkyl (1 to 3 halogen atoms), cyano, nitro, OH, O, N and halogen,

C₄ -C₂₀ aryl-alkyl which is unsubstituted or substituted in the aryl moiety by substituents independently selected from the group consisting of C₁ -C₆ alkyl, C₁ -C₆ alkoxy, C₁ -C₆ haloalkyl (1 to 3 halogen atoms), cyano, nitro, OH, O, N and halogen,

C₃ -C₆ aryl substituted by 3 to 5 halogen atoms or 1 to 2 atoms or groups independently selected from the group consisting of halogen, C₁ -C₁₂ alkoxy, cyano, nitro, hydroxy, C₁ -C₁₂ haloalkyl, C₁ -C₁₂ alkyl, C₂ -C₁₂ alkenyl and C₂ -C₁₂ alkynyl, or

C₁ -C₄ alkylene-C₃ -C₆ aryl substituted in the aryl moiety by 3 to 5 halogen atoms or 1 to 2 atoms or groups independently selected from the group consisting of halogen, C₁ -C₁₂ alkoxy, cyano, nitro, hydroxy, C₁ -C₁₂ haloalkyl, C₁ -C₁₂ alkyl, C₂ -C₁₂ alkenyl and C₂ -C₁₂ alkynyl;

and

R³¹ is 2,3-dihydro-6-hydroxyindene;

sesamol;

catechol monoester;

--CH₂ --C(O)--N(R⁷)₂ wherein each R⁷ is hydrogen or C_1-4 alky and is the same or different;

--CH₂ --S(O)(R⁷);

--CH₂ --S(O)₂ (R⁷);

--O--CH₂ --CH(OC(O)CH₂ R⁷) --CH₂ (OC(O)CH₂ R⁷);

cholesteryl;

a monosaccharide;

a disaccharide;

an oligosaccharide (3 to 9 monosaccharide residues), enolpyruvate;

glycerol;

an a-D-b-diglyceride;

trimethoxybenzyl;

triethoxybenzyl;

2-alkyl pyridinyl (C_1-4 alkyl);

##STR53##

39. The compound of claim 11 wherein

R is

C₃ -C₂₀ aryl which is substituted by substituents independently selected from the group consisting of C₁ -C₆ haloalkyl (1 to 3 halogen atoms), cyano and nitro,

C₄ -C₂₀ aryl-alkyl which is substituted in the aryl moiety by substituents independently selected from the group consisting of C₁ -C₆ haloalkyl (1 to 3 halogen atoms), cyano and nitro,

C₃ -C₆ aryl substituted by atoms or groups independently selected from the group consisting of cyano, nitro, C₁ -C₁₂ haloalkyl, C₂ -C₁₂ alkenyl and C₂ -C₁₂ alkynyl, or

C₁ -C₄ alkylene-C₃ -C₆ aryl substituted in the aryl moiety by 1 to 2 atoms or groups independently selected from the group consisting of cyano, nitro, C₁ -C₁₂ haloalkyl, C₂ -C₁₂ alkenyl and C₂ -C₁₂ alkynyl;

and

R³¹ is 2,3-dihydro-6-hydroxyindene;

sesamol;

catechol monoester;

--CH₂ --S(O)(R⁷);

--CH₂ --S(O)₂ (R⁷);

--O--CH₂ --CH(OC(O)CH₂ R⁷)--CH₂ (OC(O)CH₂ R⁷);

cholesteryl;

a monosaccharide;

a disaccharide;

an oligosaccharide (3 to 9 monosaccharide residues), enolpyruvate;

glycerol;

trimethoxybenzyl;

triethoxybenzyl;

2-alkyl pyridinyl (C_1-4 alkyl);

##STR69##

12. A compound of the formula (OR³⁵)(OR³⁵)P(O)--Z--B, wherein;

B is a heterocyclic base;

R³⁵ is independently R or R³¹, wherein R is independently

H,

C₃ -C₂₄ 1-acyloxy-1-alkyl,

C₆ -C₂₄ 1-acyloxy-1-aryl-1-alkyl,

C₃ -C₂₄ 1-acyloxy-2-alkoxy-1-alkyl,

C₃ -C₂₄ 1-acyloxy-2-halo-1-alkyl,

C₁ -C₂₀ alkyl which is unsubstituted or substituted by substituents independently selected from the group consisting of OH, O, N and halogen,

C₃ -C₂₀ aryl which is unsubstituted or substituted by substituents independently selected from the group consisting of C₁ -C₆ alkyl, C₁ -C₆ alkoxy, C₁ -C₆ haloalkyl (1 to 3 halogen atoms), cyano, nitro, OH, O, N and halogen,

C₄ -C₂₀ aryl-alkyl which is unsubstituted or substituted in the aryl moiety by substituents independently selected from the group consisting of C₁ -C₆ alkyl, C₁ -C₆ alkoxy, C₁ -C₆ haloalkyl (1 to 3 halogen atoms), cyano, nitro, OH, O, N and halogen,

C₃ -C₆ aryl substituted by 3 to 5 halogen atoms or 1 to 2 atoms or groups independently selected from the group consisting of halogen, C₁ -C₁₂ alkoxy, cyano, nitro, hydroxy, C₁ -C₁₂ haloalkyl, C₁ -C₁₂ alkyl, C₂ -C₁₂ alkenyl and C₂ -C₁₂ alkynyl, or

C₁ -C₄ alkylene-C₃ -C₆ aryl substituted in the aryl moiety by 3 to 5 halogen atoms or 1 to 2 atoms or groups independently selected from the group consisting of halogen, C₁ -C₁₂ alkoxy, cyano, nitro, hydroxy, C₁ -C₁₂ haloalkyl, C₁ -C₁₂ alkyl, C₂ -C₁₂ alkenyl and C₂ -C₁₂ alkynyl;

R³¹ is 2,3-dihydro-6-hydroxyindene;

sesamol;

catechol monoester;

--CH₂ --C(O)--N(R⁷)₂ wherein each R⁷ is the same or different;

--CH₂ --S(O)(R⁷);

--CH₂ --S(O)₂ (R⁷);

--CH₂ --CH(OC(O)CH₂ R⁷)--CH₂ (OC(O)CH₂ R⁷);

cholesteryl;

a monosaccharide;

a disaccharide;

an oligosaccharide (3 to 9 monosaccharide residues), enolpyruvate;

glycerol;

an a-D-b-diglyceride;

trimethoxybenzyl;

triethoxybenzyl;

2-alkyl pyridinyl (C_1-4 alkyl);

##STR54## Z--B is selected from the group consisting of ##STR55## wherein R²⁷ is H, OH, halogen, N₃, C₁ -C₄ alkyl, C₁ -C₄ alkoxy or when, R²⁶ is S, R²⁷ is absent;

R³³ is H, OH, TBSO, halogen, cyano, CH₂ N₃, C₁ -C₄ alkyl, C₁ -C₄ alkoxy, CH₂ OH or azido; and

R³⁴ is H, CH₂ CN or CF₃.

13. The compound of claim 12 wherein R³⁵ is independently hydrogen, phenyl, benzyl, adamantoyl oxymethyl, pivaloyloxymethyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-ethoxy-5-hydroxyphenyl, 2-ethoxy-4-hydroxyphenyl 3,5-dimethoxyphenyl, 2,4-difluorophenyl, 2-(haloalkyl)-phenyl, 3-(haloalkyl)phenyl, 4-(haloalkyl)-phenyl, 2-cyanophenyl, 3-cyanophenyl, 4-cyanophenyl, 2-ethoxyphenyl, 2-carboethoxyphenyl, 3-carboethoxyphenyl, 4-carboethoxyphenyl, or 2-haloalkylbenzyl, 3-haloalkylbenzyl or 4-haloalkylbenzyl.

14. The compound of claim 13 wherein B¹ is N⁴ -benzoylcytosin-1-yl, N⁴ -(6-aminohexyl)cytosin-1-yl, N⁴ -(10-aminodecyl) cytosin-1-yl, or N⁴ -(14-aminolauryl)cytosin-1-yl.

15. A compound of claim 12 wherein the compound is labeled with a detectable moiety selected from the group of an enzyme, radioisotope, stable free radical, fluorophor, and a chemiluminescent group.

40. The compound of claim 12, wherein;

R is independently

H,

C₃ -C₂₄ 1-acyloxy-1-alkyl,

C₆ -C₂₄ 1-acyloxy-1-aryl-1-alkyl,

C₃ -C₂₄ 1-acyloxy-2-alkoxy-1-alkyl,

C₃ -C₂₄ 1-acyloxy-2-halo-1-alkyl,

C₃ -C₂₀ aryl which is substituted by substituents independently selected from the group consisting of C₁ -C₆ haloalkyl (1 to 3 halogen atoms), cyano and nitro,

C₄ -C₂₀ aryl-alkyl which is substituted in the aryl moiety by substituents independently selected from the group consisting of C₁ -C₆ haloalkyl (1 to 3 halogen atoms), cyano and nitro,

C₃ -C₆ aryl substituted by 1 to 2 atoms or groups independently selected from the group consisting of cyano, nitro, C₁ -C₁₂ haloalkyl, C₂ -C₁₂ alkenyl and C₂ -C₁₂ alkynyl, or

C₁ -C₄ alkylene-C₃ -C₆ aryl substituted in the aryl moiety by 1 to 2 atoms or groups independently selected from the group consisting of cyano, nitro, C₁ -C₁₂ haloalkyl, C₂ -C₁₂ alkenyl and C₂ -C₁₂ alkynyl;

R³¹ is 2,3-dihydro-6-hydroxyindene;

sesamol;

catechol monoester;

--CH₂ --S(O)(R⁷);

--CH₂ --S(O)₂ (R⁷);

--CH₂ --CH(OC(O)CH₂ R⁷)--CH₂ (OC(O)CH₂ R⁷);

cholesteryl;

a monosaccharide;

a disaccharide;

an oligosaccharide (3 to 9 monosaccharide residues), enolpyruvate;

glycerol;

trimethoxybenzyl;

triethoxybenzyl;

2-alkyl pyridinyl (C_1-4 alkyl);

##STR70##

16. A compound of the formula (R³¹ O)₂ P(O)--CH₂ --OH or (R³¹ O)₂ P(OSi(CH₃)₃) wherein

R³¹ is trimethoxybenzyl;

triethoxybenzyl;

2-alkyl pyridinyl (C₁ -4 alkyl);

##STR56## wherein R⁷ is hydrogen or C_1-4 alkyl;

or C₃ -C₆ aryl substituted by 3, 4 or 5 halogen atoms or 1 or 2 atoms or groups selected from halogen, C₁ -C₁₂ alkoxy, cyano, nitro, C₁ -C₁₂ haloalkyl, C₁ -C₁₂ alkyl or C_2-12 alkynyl, provided that for compound (R³¹ O)₂ P(O)--CH₂ --OH, R³¹ is not phenyl.

17. A method to synthesize a compound of structure (R³ O)₂ P(O)--CH₂ OH comprising silylating a compound of structure (R³¹ O)₂ P(O)H with about 1 equivalent of bis(trimethylsilyl)trifluoroacetamide, drying the resulting compound and reacting the resulting compound with paraformaldehyde containing catalytic amounts of a lewis acid, wherein R³¹ is trimethoxybenzyl;

triethoxybenzyl;

2-alkyl pyridinyl (C_1-4 alkyl);

##STR57## wherein R⁷ is hydrogen or C₁₄ alkyl;

C₃ -C₆ aryl substituted by 3, 4 or 5 halogen atoms or 1 or 2 atoms or groups selected from halogen, C₁ -C₁₂ alkoxy, cyano, nitro, C₁ -C₁₂ haloalkyl, C₁ -C₁₂ alkyl or C_2-12 alkynyl.

18. A method to synthesize a compound of structure ##STR58## by reacting a compound of structure ##STR59## with iodine and (R³¹ O)₂ P(O)--CH₂ --OH at high temperature, wherein B² is a heterocyclic base or a protected heterocyclic base;

R³¹ is trimethoxybenzyl;

triethoxybenzyl;

2-alkyl pyridinyl (C_1-4 alkyl);

##STR60## wherein R⁷ is hydrogen or C₁ -4 alkyl;

C₃ -C₆ aryl substituted by 3, 4 or 5 halogen atoms or 1 or 2 atoms or groups selected from halogen, C₁ -C₁₂ alkoxy, cyano, nitro, C₁ -C₁₂ haloalkyl, C₁ -C₁₂ alkyl or C_2-12 alkynyl; and

R⁴⁴ is iodine or fluorine.

19. A compound having the formula ##STR61## and stereoisomers and salts of such compounds wherein B is a purine or pyrimidine base;

R³⁵ is R or R³¹ ;

R is 2-alkoxyphenyl, 3-alkoxyphenyl, 4-alkoxyphenyl (C₁ -C₁₂ alkyl), 2-halophenyl, 3-halophenyl, 4-halophenyl, 2,3-dihalophenyl, 2,4-dihalophenyl, 2,5-dihalophenyl, 2,6-dihalophenyl, 3,4-dihalophenyl, 3,5-dihalophenyl, 4-haloalkylphenyl (1-5 halogens, C₁ -C₁₂ alkyl), carboalkoxyphenyl (C₁ -C₄ alkyl), 2-haloalkylbenzyl, 3-haloalkylbenzyl, 4-haloalkylbenzyl (1 to 5 halogen atoms, C₁ -C₁₂ alkyl), alkylsalicylphenyl (C₁ -C₄ alkyl), alkoxy ethyl (C₁ -C₆ alkyl), aryloxy ethyl (C₆ -Cg aryl optionally substituted by OH, NH₂, halo, C₁ -C₄ alkyl or C₁ -C₄ alkyl substituted by OH or by 1 to 3 halo atoms), 2-pyrrolyl, 3-pyrrolyl, 2-thienyl, 3-thienyl, 2-imidazolyl, 4-imidazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl, 3-pyrazolyl, 4-pyrazolyl, 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-ethoxyphenyl, 3-ethoxyphenyl, 4-ethoxyphenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2,4-difluorophenyl, 2,4-dichlorophenyl, 2-trifluoromethylphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 2-trichloromethylphenyl, 3-trichloromethylphenyl, 4-trichloromethylphenyl, 2-cyanophenyl, 3-cyanophenyl, 4-cyanophenyl, 2-carboethoxyphenyl, 3-carboethoxyphenyl, 4-carboethoxyphenyl, 2,3-dicarboethoxyphenyl, 2,4-dicarboethoxyphenyl, 2,5-dicarboethoxyphenyl, 2,6-dicarboethoxyphenyl, 3,4-dicarboethoxyphenyl, 3,5-dicarboethoxyphenyl, 1-pyridinyl, 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, 2-nitrophenyl, 3-nitrophenyl, 4-nitrophenyl, 4-trifluoromethylbenzyl, 2-ethylsalicylphenyl, 3-ethylsalicylphenyl, 4-ethylsalicylphenyl, 2-acetylphenyl, 3-acetylphenyl, 4-acetylphenyl, 1,8-dihydroxy-naphthyl, 2,2'"'"'-dihydroxybiphenyl, methoxy ethyl, phenoxymethyl, phenoxy ethyl, --C₆ H₄ --CH₂ --N(CH₃)₂ or N-ethylmorpholino;

R³¹ is 2,3-dihydro-6-hydroxyindene, sesamol, catechol monoester, --CH₂ --S(O)(R⁷), wherein R⁷ is hydrogen or C_1-4 alkyl, --CH₂ --S(O)₂ (R⁷), --CH₂ --CH(OC(O)CH₂ R⁷)--CH₂ (OC(O)CH₂ R⁷), cholesteryl, enolpyruvate, glycerol, an a-D-b-diglyceride, trimethoxybenzyl, triethoxybenzyl or 2-alkyl pyridinyl (C_1-4 alkyl);

R⁷ is H or C₁ -C₄ alkyl; and

the carbon atom designated # has linked substituents that are in the R, S or RS configuration.

20. The compound of claim 19 wherein R³⁵ is R.

21. The compound of claim 19 wherein R is 2-alkoxyphenyl , 3-alkoxpenyl, 4-alkoxyphenyl (C₁ -C₁₂ alkyl), 2-halophenyl, 3-halophenyl, 4- halophenyl, 2,3-dihalophenyl, 2,4-dihalophenyl, 2,5-dihalophenyl, 2,6-dihalophenyl, 3,4-dihalophenyl, 3,5-dihalophenyl, 4-haloalkylphenyl (1-5 halogens, C₁ -C₁₂ alkyl), carboalkoxyphenyl (C₁ -C₄ alkyl), 2-haloalkylbenzyl, 3-haloalkylbenzyl, 4-haloalkylbenzyl (1 to 5 halogen atoms, C₁ -C₁₂ alkyl), alkylsalicylphenyl (C₁ -C₄ alkyl), alkoxy ethyl (C₁ -C₆ alkyl) or aryloxy ethyl (C₆ -C₉ aryl optionally substituted by OH, NH₂, halo, C₁ -C₄ alkyl or C₁ -C₄ alkyl substituted by OH or by 1 to 3 halo atoms).

22. The compound of claim 21 wherein B is cytosine, 5-fluoytosine, 5-methylcytosine, adenine, guanine, 2,6-diaminopurine, 2-aminopurine, hypoxanthine or thymine.

23. The compound of claim 21 wherein R is alkylsalicylphenyl.

24. The compound of claim 23 wherein B is cytosine.

25. The compound of claim 19 wherein R is 2-pyrrolyl, 3-pyrrolyl, 2-thienyl, 3-thienyl, 2-imidazolyl, 4-imidazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl, 3-pyrazolyl, 4-pyrazolyl, 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-ethoxyphenyl, 3-ethoxyphenyl, 4-ethoxyphenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2,4-difluorophenyl, 2,4-dichlorophenyl, 2-trifluoromethylphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 2-trichloromethylphenyl, 3-trichloromethylphenyl, 4-trichloromethylphenyl, 2-cyanophenyl, 3-cyanophenyl, 4-cyanophenyl, 2-carboethoxyphenyl, 3-carboethoxyphenyl, 4-carboethoxyphenyl, 2,3-dicarboethoxyphenyl, 2,4-dicarboethoxyphenyl, 2,5-dicarboethoxyphenyl, 2,6-dicarboethoxyphenyl, 3,4-dicarboethoxyphenyl, 3,5-dicarboethoxyphenyl, 1-pyridinyl, 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, 2-nitrophenyl, 3-nitrophenyl, 4-nitrophenyl, 4-trifluoromethylbenzyl, 2-ethylsalicylphenyl, 3-ethylsalicylphenyl, 4-ethylsalicylphenyl, 2-acetylphenyl, 3-acetylphenyl, 4-acetylphenyl, 1,8-dihydroxy-naphthyl, 2,2'"'"'-dihydroxybiphenyl, methoxy ethyl, phenoxymethyl, phenoxy ethyl, --C₆ H₄ --CH₂ --N(CH₃)₂ or N-ethylmorpholino.

26. The compound of claim 25 wherein B is cytosine, 5-fluorocytosine, 5-methylcytosine, adenine, guanine, 2,6-diaminopurine, 2-aminopurine, hypoxanthine or thymine.

27. The compound of claim 19 wherein B is cytosine, 5-fluorocytosine, 5-methylcytosine, adenine, guanine, 2,6-diaminopurine, 2-aminopurine, hypoxanthine or thymine.

32. A method comprising orally administering to a subject an antivirally-effective dose of a compound of claim 19 having the structure ##STR63##

33. The method of claim 32 wherein the compound is enriched or resolved at the phosphate atom chiral center.

28. A method comprising orally administering to a subject an antivirally-effective dose of a compound having the structure ##STR62## and salts of such compounds wherein the carbon atom designated # has linked substituents that are in the R, S or RS configuration, B is cytosine and R³⁵ is alkylsalicylphenyl (C₁ -C₄ alkyl).

29. The method of claim 28 wherein the compound is enriched or resolved at the phosphate atom chiral center.

34. A compound of the formula (OR³⁵)(OR³⁵)P(O)--Z--B, wherein;

B is a heterocyclic base;

R³⁵ is independently R or R³¹, wherein R is independently

H,

C₃ -C₂₄ 1-acyloxy-1-alkyl,

C₆ -C₂₄ 1-acyloxy-1-aryl-1-alkyl,

C₃ -C₂₄ 1-acyloxy-2-alkoxy-1-alkyl,

C₃ -C₂₄ 1-acyloxy-2-halo-1-alkyl,

C₁ -C₂₀ alkyl which is unsubstituted or substituted by substituents independently selected from the group consisting of OH, O, N and halogen,

C₃ -C₂₀ aryl which is unsubstituted or substituted by substituents independently selected from the group consisting of C₁ -C₆ alkyl, C₁ -C₆ alkoxy, C₁ -C₆ haloalkyl (1 to 3 halogen atoms), cyano, nitro, OH, O, N and halogen,

C₄ -C₂₀ aryl-alkyl which is unsubstituted or substituted in the aryl moiety by substituents independently selected from the group consisting of C₁ -C₆ alkyl, C₁ -C₆ alkoxy, C₁ -C₆ haloalkyl (1 to 3 halogen atoms), cyano, nitro, OH, O, N and halogen,

C₃ -C₆ aryl substituted by 3 to 5 halogen atoms or 1 to 2 atoms or groups independently selected from the group consisting of halogen, C₁ -Cl2 alkoxy, cyano, nitro, hydroxy, C₁ -C₁₂ haloalkyl, C₁ -C₁₂ alkyl, C₂ -C₁₂ alkenyl and C₂ -C₁₂ alkynyl, or

C₁ -C₄ alkylene-C₃ -C₆ aryl substituted in the aryl moiety by 3 to 5 halogen atoms or 1 to 2 atoms or groups independently selected from the group consisting of halogen, C₁ -C₁₂ alkoxy, cyano, nitro, hydroxy, C₁ -C₁₂ haloalkyl, C₁ -C₁₂ alkyl, C₂ -C₁₂ alkenyl and C₂ -C₁₂ alkynyl;

R³¹ is 2,3-dihydro-6-hydroxyindene;

sesamol;

catechol monoester;

--CH₂ --S(O)(R⁷) wherein R⁷ is hydrogen or C_1-4 alkyl;

--CH₂ --S(O)₂ (R⁷);

--O--CH₂ --CH (OC(O)CH₂ R⁷)--CH₂ (OC(O)CH₂ R⁷);

cholesteryl;

a monosaccharide;

a disaccharide;

an oligosaccharide (3 to 9 monosaccharide residues), enolpyruvate;

glycerol;

an a-D-b-diglyceride;

trimethoxybenzyl;

triethoxybenzyl;

2-alkyl pyridinyl (C_1-4 alkyl);

##STR64## C₃ -C₆ aryl substituted by 3, 4 or 5 halogen atoms or 1 or 2 atoms or groups selected from the group consisting of halogen, C₁ -C₁₂ alkoxy, cyano, nitro, OH, C₁ -C₁₂ haloalkyl, C₁ -C₁₂ alkyl, C₂ -C₁₂ alkenyl and C₂ -C₁₂ alkynyl;

or

C₁ -C₄ alkylene C₃ -C₆ aryl substituted in the aryl moiety by 3 to 5 halogen atoms or 1 to 2 atoms or groups selected from the group consisting of halogen, C₁ -C₁₂ alkoxy, cyano, nitro, OH, C₁ -C₁₂ haloalkyl, C₁ -C₁₂ alkyl, C₂ -C₁₂ alkenyl and C₂ -C₁₂ alkynyl;

Z--B is selected from the group consisting of ##STR65## wherein, R²⁵ is CH₂, CHF or O;

R²⁶ is CH or S, provided that when R²⁵ is CH, R²⁶ is not S;

R²⁷ is H, OH, halogen, N₃, C₁ -C₄ alkyl, C₁ -C₄ alkoxy or when, R²⁶ is S, R²⁷ is absent;

R²⁸ is H, OH, halogen, N₃, C₁ -C₄ alkyl or C₁ -C₄ alkoxy; and

R²⁹ is S, CHF or CF₂.

35. The compound of claim 34 wherein B is cytosin-1-yl, 6-azacytosin-1-yl, 5-fluorocytosin-1-yl, adenin-9-yl, guanin-9-yl or 2, 6-diaminopurin-9-yl.

37. The compound of claim 34 wherein B² is N⁴ -benzoylcytosin-1-yl, N⁴ -(6-aminohexyl)cytosin-1-yl, N⁴ -(10-aminodecyl)cytosin-1-yl, N⁴ -(14-aminolauryl) cytosin-1-yl, cytosin-1-yl, 6-azacytosin-1-yl, 5-fluorocytosin-1-yl, adenin-9-yl, guanin-9-yl or 2, 6-diaminopurin-9-yl.

36. A compound of the formula ##STR66## wherein substituents linked to the carbon atom designated # are in the R, S or RS configuration;

B² is a protected or unprotected heterocyclic base; and

R³¹ is 2,3-dihydro-6-hydroxyindene;

sesamol;

catechol monoester;

--CH₂ --S(O)(R⁷) wherein R⁷ is hydrogen or C_1-4 alkyl;

--CH₂ --S(O)₂ (R⁷);

--O--CH₂ --CH (OC(O)CH₂ R⁷)--CH₂ (OC(O)CH₂ R⁷);

cholesteryl;

a monosaccharide;

a disaccharide;

an oligosaccharide containing 3 to 9 monosaccharide residues, enolpyruvate;

glycerol;

an a-D-b-diglyceride;

trimethoxybenzyl;

triethoxybenzyl;

2-alkyl pyridinyl (C_1-4 alkyl);

##STR67## C₃ -C₆ aryl substituted by 3, 4 or 5 halogen atoms or 1 or 2 atoms or groups selected from the group consisting of halogen, C₁ -C₁₂ alkoxy, cyano, nitro, OH, C₁ -C₁₂ haloalkyl, C₁ -C₁₂ alkyl, C₂ -C₁₂ alkenyl and C₂ -C₁₂ alkynyl;

or

C₁ -C₄ alkylene-C₃ -C₆ aryl substituted in the aryl moiety by 3 to 5 halogen atoms or 1 to 2 atoms or groups selected from the group consisting of halogen, C₁ -C₁₂ alkoxy, cyano, nitro, OH, C₁ -C₁₂ haloalkyl, C₁ -C₁₂ alkyl, C₂ -C₁₂ alkenyl and C₂ -C₁₂ alkynyl.

41. A compound having the structure (OR³⁵)₂ P(O)--Z--B, wherein each R³⁵ is the same and the compound is designated by numbers assigned to (OR³⁵)₂, Z and B according to the convention, R³⁵.Z.B,

wherein the structures for R³⁵, Z and B are designated by numbers respectively and wherein

R35 structure 1 is --O--C₆ H₄ F, 2 is --O--C₆ H₃ F₂, 3 is --O--C₆ H₄ --OCH₃, 4 is --O--C₆ H₃ --(OCH₃)₂, 5 is --O--C₆ H₄ --OC₂ H₅, 6 is --O--C₆ H₃ --(OC₂ H₅)₂, 7 is --O--CH₂ --C₆ H₄ F, 8 is --O--C₆ H₄ --(C(O)--O--C₂ H₅)₂, 9 is --O--C₆ H₄ --C(O)--O--C₂ H₅, 10 is --O--C₆ H₃ --(O--C(O)--CH₃)₂, 11 is --O--C₆ H₃ --C(O)--O--C₃ H₇, 12 is --O--CH₂ --C₆ H₄ --O--CO--CH₃, 13 is --O--C₅ H₄ N, 14 is --O--C₆ H₃ --(OC₂ H₅)(OH), 15 is --O--C₆ H₅ and 16 is --O--CH₂ --O--C(O)--C(CH₃)₃, and

Z--B structure 1 is --P(O)--CH₂ --O--CH₂ --CH₂ --B, 2 is --P(O)--CH₂ --O--C--H(CH₂ --OR⁴)--CH₂ --B, 3 is --P(O)--CH₂ --O--C--H (CH₃)--CH₂ --B, 4 is --P(O)--CH₂ --O--C--H(CH₂ F)--CH₂ --B, 5 is --P(O)--CH₂ --O--C--H(CH═

CH₂)--CH₂ --B, 6 is --P(O)--CH₂ --O--C--H(CH₂ N₃)--CH₂ --B, 7 is ##STR71## and 8 is ##STR72## and B structure 1 is adenin-9-yl, 2 is guanin-9-yl, 3 is cytosin-1-yl, 4 is 2, 6-diaminopurin-9-yl, 5 is 2-aminopurin-9-yl, 6 is thymidin-1-yl and 7 is 5-fluorocytosin-1-yl, wherein the compound is named 1.1.1, 2.1.1, 3.1.1, 4.1.1, 5.1.1, 6.1.1, 7.1.1, 8.1.1, 9.1.1, 10.1.1, 11.1.1, 12.1.1, 13.1.1, 14.1.1, 1.2.1, 2.2.1, 3.2.1, 4.2.1, 5.2.1, 6.2.1, 7.2.1, 8.2.1, 9.2.1, 10.2.1, 11.2.1, 12.2.1, 13.2.1, 14.2.1, 1.3.1, 2.3.1, 3.3.1, 4.3.1, 5.3.1, 6.3.1, 7.3.1, 8.3.1, 9.3.1, 10.3.1, 11.3.1, 12.3.1, 13.3.1, 14.3.1, 1.4.1, 2.4.1, 3.4.1, 4.4.1, 5.4.1, 6.1, 7.4.1, 8.4.1, 9.4.1, 10.4.1, 11.4.1, 12.4.1, 13.4.1, 14.4.1, 1.5.1, 2.5.1, 3.5.1, 4.5.1, 5.5.1, 6.5.1, 7.5.1, 8.5.1, 9.5.1, 10.5.1, 11.5.1, 12.5.1, 13.5.1, 14.5.1, 1.6.1, 2.6.1, 3.6.1, 4.6.1, 5.6.1, 6.6.1, 7.6.1, 8.6.1, 9.6.1, 10.6.1, 11.6.1, 12.6.1, 13.6, 1, 14.6.1, 1.7.1, 2.7.1, 3.7.1, 4.7.1, 5.7.1, 6.7.1, 7.7.1, 8.7.1, 9.7.1, 10.7.1, 11.7.1, 12.7.1, 13.7.1, 14.7.1, 15.7.1, 16.7.1, 1.8.1, 2.8.1, 3.8.1, 4.8.1, 5.8, 1, 6.8.1, 7.8.1, 8.8.1, 9.8.1, 10.8.1, 11.8.1, 12.8.1, 13.8.1, 14.8.1, 15.8.1, 16.8.1, 1.1.2, 2.1.2, 3.1.2, 4.1.2, 5.1.2, 6.1.2, 7.1.2, 8.1.2, 9.1.2, 10.1.2, 11.1.2, 12.1.2, 13.1.2, 14.1.2, 1.2.2, 2.2.2, 3.2.2, 4.2.2, 5.2.2, 6.2.2, 7.2.2, 8.2.2, 9.2.2, 10.2.2, 11.2.2, 12.2.2, 13.2.2, 14.2.2, 1.3.2, 2.3.2, 3.3.2, 4.3.2, 5.3.2, 6.3.2, 7.3.2, 8.3.2, 9.3.2, 10.3.2, 11.2, 12.32, 13.3.2, 14.3.2, 1.4.2, 2.4.2, 3.4.2, 4.4.2, 5.4.2, 6.4.2, 7.4.2, 8.4.2, 9.4.2, 10.4.2, 11.4.2, 12.4.2, 13.4.2, 14.4.2, 1.5.2, 2.5.2, 3.5.2, 4.5.2, 5.5.2, 6.5.2, 7.5.2, 8.5.2, 9.5.2, 10.5.2, 11.5.2, 12.5.2, 13.5.2, 14.5.2, 1.6.2, 2.6.2, 3.6.2, 4.6.2, 5.6.2, 6.6.2, 7.6.2, 8.6.2, 9.6.2, 10.6.2, 11.6.2, 12.6.2, 13.6.2, 14.6.2, 1.7.2, 2.7.2, 3.7.2, 4.7.2, 5.7.2, 6.7.2, 7.7.2, 8.7.2, 9.7.2, 10.7.2, 11.7.2, 12.7.2, 13.7.2, 14.7.2, 15.7.2, 16.7.2, 1.8.2, 2.8.2, 3.8.2, 4.82, 5.8.2, 6.82, 7.82, 8.8.2, 9.8.2, 10.8.2, 11.8.2, 12.8.2, 13.8.2, 14.8.2, 15.8.2, 16.8.2, 1.1.3, 2.1.3, 3.1.3, 4.1.3, 5.1.3, 6.1.3, 7.1.3, 8.1.3, 9.1.3, 10.1.3, 11.1.3, 12.1.3, 13.1.3, 14.1.3, 1.2.3, 2.2.3, 3.2.3, 4.2.3, 5.2.3, 6.2.3, 7.2.3, 8.2.3, 9.2.3, 10.2.3, 11.2.3, 12.2.3, 13.2.3, 14.2.3, 1.3.3, 2.33, 3.3.3, 4.3.3, 5.3.3, 6.3.3, 7.3.3, 8.3.3, 9.3.3, 10.3.3, 11.3.3, 12.3.3, 13.3.3, 14.3.3, 1.4.3, 2.4.3, 3.4.3, 4.4.3, 5.4.3, 6.4.3, 7.4.3, 8.4.3, 9.43, 10.4.3, 11.4.3, 12.4.3, 13.4.3, 14.4.3, 15.3, 2.5.3, 3.5.3, 4.5.3, 5.5.3, 6.5.3, 7.5.3, 8.5.3, 9.5.3, 10.5.3, 11.5.3, 12.5.3, 13.5.3, 14.5.3, 1.6.3, 2.6.3, 3.6.3, 4.6.3, 5.6.3, 6.6.3, 7.6.3, 8.6.3, 9.6.3, 10.6.3, 11.6.3, 12.6.3, 13.6.3, 14.6.3, 1.7.3, 2.7.3, 3.7.3, 4.7.3, 5.73, 6.7.3, 7.7.3, 8.7.3, 9.7.3, 10.7.3, 11.7.3, 12.7.3, 13.7.3, 14.7.3, 15.7.3, 16.7.3, 1.8.3, 2.8.3, 3.8.3, 4.8.3, 5.8.3, 6.8.3, 7.8.3, 8.8.3, 9.8.3, 10.8.3, 11.8.3, 12.8.3, 13.8.3, 14.8.3, 15.8.3, 16.8.3, 1.1.4, 2.1.4, 3.1.4, 4.1.4, 5.14, 6.1.4, 7.1.4, 8.1.4, 9.1.4, 10.1.4, 11.1.4, 12.1.4, 13.1.4, 14.1.4, 1.2.4, 2.2.4, 3.2.4, 4.24, 5.2.4, 6.2.4, 7.24, 8.2.4, 9.2.4, 10.2.4, 11.2.4, 12.2.4, 13.2.4, 14.2.4, 1.3.4 , 2.3.4, 3.3.4, 4.3.4, 5.3.4, 6.3.4, 7.3.4, 8.3.4, 9.3.4, 10.3.4, 11.3.4, 12.3.4, 13.3.4, 14.3.4, 1.4.4, 2.4.4, 3.4.4, 4.4.4, 5.4.4, 6.4.4, 7.4.4, 8.4.4, 9.4.4, 10.4.4, 11.4.4, 12.4.4, 13.4.4, 14.4.4, 1.5.4, 2.5.4, 3.5.4, 4.5.4, 5.5.4, 6.5.4, 7.5.4, 8.5.4, 9.5.4, 10.5.4, 11.5.4, 12.5.4, 13.5.4, 14.5.4, 1.6.4, 2.6.4, 3.6.4, 4.6.4, 5.6.4, 6.6.4, 7.6.4, 8.6.4, 9.6.4, 10.6.4, 11.6.4, 12.6.4, 13.64, 14.6.4, 1.7.4, 2.7.4, 3.7.4, 4.4, 5.7.4, 6.7.4, 7.7.4, 8.7.4, 9.7.4, 10.7.4, 11.7.4, 12.7.4, 13.7.4, 14.7.4, 15.7.4, 16.7.4, 1.8.4, 2.8.4, 3.8.4, 4.8.4, 5.8.4, 6.8.4, 7.8.4, 8.8.4, 9.8.4, 10.8.4, 11.8.4, 12.8.4, 13.8.4, 14.8.4, 15.8.4, 16.8.4, 1.1.5 2.1.5, 3.1.5, 4.1.5, 5.1.5, 6.1.5, 7.1.5, 8.1.5, 9.1.5, 10.1.5, 11.1.5, 12.1.5, 13.1.5, 14.1.5, 1.2, 5, 2.2.5, 3.2.5, 4.2.5, 5.2.5, 6.2.5, 7.2.5, 8.2.5, 9.2.5, 10.2.5, 11.2.5, 12.2.5, 13.2.5, 14.2.5, 1.3.5, 2.3.5, 3.3.5, 4.3.5, 5.3.5, 6.3.5, 7.3.5, 8.3.5, 9.3.5, 10.3.5, 11.3.5, 12.3.5, 13.3.5, 14.3.5, 1.4.5, 2.4.5, 3.4.5, 4.4.5, 5.4.5, 6.4.5, 7.4.5, 8.4.5, 9.4.5, 10.4.5, 11.4.5, 12.4.5, 13.4.5, 14.4.5, 1.5.5, 2.5.5, 3.5.5, 4.5.5, 5.5.5, 6.5.5, 7.5.5, 8.5.5, 9.5.5, 10.5.5, 11.5.5, 12.5.5, 13.5.5, 14.5.5, 1.6.5, 2.6.5, 3.6.5, 4.6.5, 5.6.5, 6.6.5, 7.6.5, 8.6.5, 9.6.5, 10.6.5, 11.6.5, 12.6.5, 13.6.5, 14.6.5, 1.7.5, 2.7.5, 3.7.5, 4.7.5, 5.7.5, 6.7.5, 7.7.5, 8.7.5, 9.7.5, 10.7.5, 11.7.5, 12.7.5, 13.7.5, 14.7.5, 15.7.5, 16.7.5, 1.8.5, 2.8.5, 3.8.5, 4.8.5, 5.8.5, 6.8.5, 7.8.5, 8.8.5, 9.8.5, 10.8.5, 11.8.5, 12.8.5, 13.8.5, 14.8.5, 15.8.5, 16.8.5, 1.1.6, 2.1.6, 3.1.6, 4.1.6, 5.1.6, 6.1.6, 7.1.6, 8.1.6, 9.1.6, 10.1.6, 11.1.6, 12.1.6, 13.1.6, 14.1.6, 1.2.6, 2.2.6, 3.2.6, 4.2.6, 5.2.6, 6.2.6, 7.2.6, 8.2.6, 9.2.6, 10.2.6, 11.2.6, 12.2.6, 13.2.6, 14.2.6, 1.3.6, 2.3.6, 3.3.6, 4.3.6, 5.3.6, 6.3.6, 7.3.6, 8.3.6, 9.3.6, 10.3.6, 11.3.6, 12.3.6, 13.3.6, 14.3.6, 1.4.6, 2.4.6, 3.4.6, 4.4.6, 5.4.6, 6.4.6, 7.4.6, 8.4.6, 9.4.6, 10.4.6, 11.4.6, 12.4.6, 13.4.6, 14.4.6, 1.5.6, 2.5.6, 3.5.6, 4.5.6, 5.5.6, 6.5.6, 7.5.6, 8.5.6, 9.5.6, 10.5.6, 11.5.6, 12.5.6, 13.5.6, 14.5.6, 1.6.6, 2.6.6, 3.6.6, 4.6.6, 5.6.6, 6.6.6, 7.6.6, 8.6.6, 9.6.6, 10.6.6, 11.6.6, 12.6.6, 13.6.6, 14.6.6, 1.7.6, 2.7.6, 3.7.6, 4.7.6, 5.7.6, 6.7.6, 7.7.6, 8.7.6, 9.7.6, 10.7.6, 11.7.6, 12.7.6, 13.7.6, 14.7.6, 15.7.6, 16.7.6, 1.8.6, 2.8.6, 3.8.6, 4.8.6, 5.8.6, 6.8.6, 7.8.6, 8.8.6, 9.8.6, 10.8.6, 11.8.6, 12.8.6, 13.8.6, 14.8.6, 15.8.6, 16.8.6, 1.1.7, 2.1.7, 3.1.7, 4.1.7, 5.1.7, 6.1.7, 7.1.7, 8.1.7, 9.1.7, 10.1.7, 11 1.7, 12.1.7, 13.1.7, 14.1.7, 1.2.7, 2.2.7, 3.2.7, 4.2.7, 5.2.7, 6.2.7, 7.2.7, 8.2.7, 9.2.7, 10.2.7, 11.2.7, 12.2.7, 13.2.7, 14.2.7, 1.3.7, 2.3.7, 3.3.7, 4.3.7, 5.3.7, 6.3.7, 7.3.7, 8.3.7, 9.3.7, 10.3.7, 11.3.7, 12.3.7, 13.3.7, 14.3.7, 1.4.7, 2.4.7, 3.4.7, 4.4.7, 5.4.7, 6.4.7, 7.4.7, 8.4.7, 9.4.7, 10.4.7, 11.4.7, 12.4.7, 13.4.7, 14.4.7, 1.5.7, 2.5.7, 3.5.7, 4.5.7, 5.5.7, 6.5.7, 7.5.7, 8.5.7, 9.5.7, 10.5.7, 11, 5.7, 12.5.7, 13.5.7, 14.5.7, 1.6.7, 2.6.7, 3.6.7, 4.6.7, 5.6.7, 6.6.7, 7.6.7, 8.6.7, 9.6.7, 10.6.7, 11.6.7, 12.6.7, 13.6.7, 14.6.7, 1.7.7, 2.7.7, 3.7.7, 4.7.7, 5.7.7, 6.7.7, 7.7.7, 8.7.7, 9.7.7, 10.7.7, 11.7.7, 12.7.7, 13.7.7, 14.7.7, 15.7.7, 16.7.7, 1.8.7, 2.8.7, 3.8.7, 4.8.7, 5.8.7, 6.8.7, 7.8.7, 8.8.7, 9.8.7, 10.8.7, 11.8.7, 12.8.7, 13.8.7, 14.8.7, 15.8.7 or 16.8.7.