RS57796B1

Acyclic nucleoside phosphonate diesters

Abstract

This record has no abstract on file.

RS57796B1, drawing sheet 1 — Sheet 1 of 202

Term

7.5 yearsto projected expiry

Projected expiry 14 March 2034, counted from filing; an application has no term until it is granted.

26 claims: 6 independent, 20 dependent

1
Patentni zahtevi 1. Jedinjenje Formule (Ia), ili njegova farmaceutski prihvatljva so:naznačeno time da: BNuc(a) je: L a je nesupstituisani C13-29 heteroalkil;R a je izabran od grupe koja se sastoji od nesupstituisani Ci-6 alkil, supstituisani ili nesupstituisani aril, supstituisani ili nesupstituisani heteroaril, supstituisani ili nesupstituisani heterocikloalkil, supstituisani ili nesupstituisani aril(Ci-6 alkil), supstituisani ili nesupstituisani heteroaril(Ci-6 alkil) i supstituisani ili nesupstituisani heterocikloalkil(Ci-6 alkil);X a je vodonik, nesupstituisani Ci-6 alkil, halogen supstituisani Ci-6 alkil, hidroksi supstituisani Ci-6 alkil ili nesupstituisani Ci-6 alkoksi;naznačeno time da alkil može biti potpuno zasićen, mono- ili polinezasićen;i naznačeno time da supstituent je izabran od sledećih delova: -ΟΗ, -NH2, -SH, -CN, -CF3, NO2, okso, halogen, nesupstituisani alkil, nesupstituisani heteroalkil, nesupstituisani cikloalkil, nesupstituisani heterocikloalkil, nesupstituisani aril, i nesupstituisani heteroaril. 111 57796 Β1
2
Jedinjenje prema patentnom zahtevu 1, naznačeno time da X a je vodonik, metil, metoksi, CH 2 OH ili CH 2 F.
3
Jedinjenje prema patentnom zahtevu 1 ili patentnom zahtevu 2, naznačeno time da L a ima strukturu -(СН 2 )2-О-(СН 2 )17-СНз, -(СН 2 )з-О-(СН 2 )15-СНз ili -(СН 2 )1-б-0-(СН 2 )1о- 2 о-(СНСНз)-СНз.
4
Jedinjenje prema patentnom zahtevu 1, naznačeno time da R a je (a) supstituisani ili nesupstituisani fenil ili supstituisani ili nesupstituisani naftil;(b) supstituisani ili nesupstituisani benzil;ili (c) supstituisani ili nesupstituisani galaktozil.
5
Jedinjenje prema patentnom zahtevu 1, naznačeno time da Bnuc(h) je:
6
Jedinjenje prema patentnom zahtevu 1, naznačeno time da jedinjenje ima strukturu:X a naznačeno time da X a je izabrano od metil, metoksi, CH 2 OH i CH 2 F. 112 57796 Β1
7
Jedinjenje prema patentnom zahtevu 1, naznačeno time da jedinjenje je izabrano od grupe koja se sastoji:o 113 57796 Β1 Ο 114 57796 Β1 ΝΗ-2 115 57796 Β1 νη 2 νη 2 νη 2 116 57796 Β1 н 3 ссг 117 57796 Β1 ili farmaceutski prihvatljve soli bilo kog od prethodnog.
8
Farmaceutska kompozicija koja sadrži efikasnu količinu jedinjenja prema bilo kom od patentnih zahteva 1-7, ili njena farmaceutski prihvatljiva so, i farmaceutski prihvatljv ekscipijent.
9
Farmaceutska kompozicija prema patentnom zahtevu 8, naznačeno time da je farmaceutska kompozicija topikalna formulacija.
10
Jedinjenje prema bilo kom od patentnih zahteva 1-7, ili njegova farmaceutski prihvatljva so, za upotrebu u tretiranju virusne bolesti kod subjekta, naznačeno time da je virusna bolest izabrana iz grupe koja se sastoji od humanog papiloma virusa, HIV, hepatitis B virusa, hepatitis C virusa, variola virusa, vakcinia virusa, adenovirusa, citomegalovirusa, herpes simpleks virusa 1, herpes simpleks virusa 2, Epstein Barr virusa, BK virusa, JC virusa, cervikalne intraepitelne neoplazije, analne intraepitelne neoplazije, i vulvalne intraepitelne neoplazije, virusa mačje leukemije i virusa mačje imunodeficijencije. 118 57796 Β1
11
Jedinjenje za upotrebu prema patentnom zahtevu 10, naznačeno time da virus je humani papiloma virus, izbomo dodatno naznačeno time da:(a) jedinjenje, ili njegova farmaceutski prihvatljva so, je za upotrebu u tretiranju više tipova humanog papiloma virusa;ili (b) humani papiloma virus je izabran iz grupe koja se sastoji od humanog papiloma virusa tip 11. tip 16 i tip 18.
12
Jedinjenje prema bilo kom od patentnih zahteva 1-7, ili njegova farmaceutski prihvatljva, za upotrebu u tretiranju kancera cerviksa kod subjekta.
13
Jedinjenje prema bilo kom od patentnih zahteva 1-7, ili njegova farmaceutski prihvatljva so, za upotrebu u inhibiranju rasta ćelije transformisane virusom, naznačeno time da virus je izabran iz grupe koja se sastoji od humanog papiloma virusa, HIV, hepatitis B virusa, hepatitis C virusa, variola virusa, vakcinia virusa, adenovirusa, citomegalovirusa, herpes simpleks virusa 1, herpes simpleks virusa 2, Epstein Barr virusa, BK virusa, JC virusa, cervikalne intraepitelne neoplazije, analne intraepitelne neoplazije, i vulvalne intraepitelne neoplazije, virusa mačje leukemije i virusa mačje imunodeficijencije.
14
Jedinjenje prema patentnom zahtevu 1 koje ima hemijsku strukturu:
15
Farmaceutska kompozicija koja sadrži jedinjenje kao što je definisano prema patentnom zahtevu 14 formule 119 57796 Β1 i farmaceutski prihvatljv ekscipijent.
16
Farmaceutska kompozicija prema patentnom zahtevu 15 za upotrebu u tretiranju virusnih bolesti kod subjekta, naznačeno time da je virusna bolest izabrana iz grupe koja se sastoji od humanog papiloma virusa, HIV, hepatitis B virusa, hepatitis C virusa, variola virusa, vakcinia virusa, adenovirusa, citomegalovirusa, herpes simpleks virusa 1, herpes simpleks virusa 2, Epstein Barr virusa, BK virusa, JC virusa, cervikalne intraepitelne neoplazije, analne intraepitelne neoplazije, i vulvalne intraepitelne neoplazije.
17
Farmaceutska kompozicija prema patentnom zahtevu 8 ili patentnom zahtevu 15, pogodna za transdermalnu isporuku.
18
Farmaceutska kompozicija prema patentnom zahtevu 8 ili patentnom zahtevu 15, pogodna za topikalni dozni oblik.
19
Farmaceutska kompozicija prema patentnom zahtevu 8 ili patentnom zahtevu 15, pogodna za primenu injekcijom.
20
Farmaceutska kompozicija prema patentnom zahtevu 8 ili patentnom zahtevu 15, pogodna za oralni dozni oblik.
21
Farmaceutska kompozicija za upotrebu prema patentnom zahtevu 16, naznačeno time da je virusna bolest humani papiloma virus.
22
Farmaceutska kompozicija za upotrebu prema patentnom zahtevu 16, naznačeno time da humani papiloma virus sadrži humani papiloma virus tip 11. 120 57796 Β1
23
Farmaceutska kompozicija za upotrebu prema patentnom zahtevu 16, naznačeno time da humani papiloma virus sadrži humani papiloma virus tip 16.
24
Farmaceutska kompozicija za upotrebu prema patentnom zahtevu 16, naznačeno time da humani papiloma virus sadrži humani papiloma virus tip 18.
25
Jedinjenje prema patentnom zahtevu 4, naznačeno time da R a je benzil.
26
Jedinjenje prema patentnom zahtevu 3, naznačeno time da L a je -(СН2)2-О-(СНг)17-СНз.

Independent claims26

2,472 paragraphs in 27 sections, as filed

DECLARATION ON THE RIGHTS OF THE INVENTION CREATED UNDER FEDERALLY SPONSORED RESEARCH AND DEVELOPMENT [0001] The present invention was created with the support of government projects under project numbers AI-071803, AI-074057 and ΕΥ07366 assigned by Nacional. The government has certain rights in relation to the invention.

BACKGROUND The present disclosure relates, inter alia, to compositions for use in the treatment of viral diseases and cancers. In one aspect it relates to lipophilic antiviral and anticancer diesters of acyclic nucleoside phosphonates, their preparation, and said compounds for use in the treatment of viral diseases and cancers.

Viruses are infectious particles that can replicate their DNA and RNA only within host cells. Viral infections can lead to mild or severe diseases in humans and mammals. Examples of viral infections include hepatitis B and C, smallpox, herpes simplex, cytomegalovirus, human immunodeficiency virus (HIV), influenza, adenovirus, smallpox, BK virus, JC virus and precancerous lesions caused by human papillomavirus infections (cervical intraepithelial neoplasia, vaginal and anal intraepithelial neoplasia). Viral infections can also lead to cancer in humans and other species. Viruses known to cause cancer include, but are not limited to, human papilloma virus (HPV), hepatitis B virus (HBV), hepatitis C virus (HCV), HIV, and Epstein Barr virus (EBV). Vaccination has been successful in preventing infections with many viruses. Antiviral agents are known to affect viral DNA or RNA synthesis and virus replication and have been used to prevent or treat viral infections in mammals and humans. For example, combinations of antiviral drugs have been used to treat AIDS, hepatitis B, hepatitis C, herpes simplex virus, cytomegalovirus, and influenza. Despite these successes, viral diseases remain a significant public health problem and improved antiviral and anticancer agents are needed. For example, there is currently no approved antiviral treatment for human papillomavirus infections.

57796 Β1 Many antiviral drugs are nucleoside or nucleotide analogs. Examples of antiviral nucleoside analogs include azidothymidine, acyclovir, ganciclovir, lamivudine, and emtricitabine. Acyclic nucleoside phosphonates (ANPs) are a class of nucleotide analogs and are effective antiviral agents. Adefovir, tenofovir and cidofovir (CDV) are ANPs approved for clinical use against human infections with HBV, HIV and CMV, respectively. As an additional example, WO 2007/130783 discloses acyclic nucleoside phosphonates which are alkoxyalkyl monoesters of nucleoside phosphonates.

It is known in the art that ANPs are not easily absorbed from the mammalian gastrointestinal tract due to their molecular weight and the presence of a double negative charge on the phosphonate. Due to their poor oral pharmacokinetic properties, ANPs are usually converted to prodrugs to provide clinically useful therapeutic agents. Masking of one or both negative charges with groups has been shown to improve uptake and transport into small intestinal enterocytes where the group is excised, releasing ANP into the circulation; examples include tenofovir disoproxil fumarate and adefovir dipivoxil. Another approach is to prepare alkoxyalkyl or alkyl monoester ANPs to increase the oral bioavailability of the drug. With the alkoxyalkyl ANP monoester approach, side effects can occur when non-targeted tissues such as the small intestine are overexposed. For example, in enterocytes, enzymatic cleavage of the phospholipase C or acid sphingomyelinase group to ANP may result in local toxicity due to additional anabolic phosphorylation to ANP diphosphate which may inhibit enterocyte DNA synthesis. It is predicted that lipophilic ANP diester compounds undergo minor excision from intact prodrug to ANP in small intestine enterocytes after oral administration reducing GI side effects and releasing more drug substances into the circulation and producing higher drug substance levels in the blood.

ANPs or their alkyl or alkoxyalkyl monoesters may show limited uptake in certain target tissues such as the central nervous system. An additional advantage of the nucleoside phosphonate diester is the masking of the residual negative charge on the phosphonate oxygen with another masking group that may increase the penetration of the drug into the central nervous system (CNS) for the treatment of viral CNS infections (e.g., HIV or JC virus) or for brain treatment. which is glioblastoma. Cancer cells rapidly synthesize DNA and undergo uncontrolled cell division. The acyclic nucleoside phosphonate (ANP) lipophilic diester compositions described herein can be metabolized to their diphosphates that inhibit or block DNA synthesis and cell division in cancer target cells, resulting in cell death with significantly less effects on non-malignant cells. Exposure to different types of cancer cells by acyclic nucleoside phosphonate diesters can result in much less cytotoxicity than that observed in normal non-malignant cells. For example,

57796 Leί leukemias, lymphomas, brain neoplasms such as glioblastoma, and cancer cells may be more sensitive to cytotoxic effects when exposed to lipophilic ANP diesters than corresponding non-malignant cell lines. Lipophilic diesters of acyclic nucleoside phosphonate show more selective toxicity, improved access to the central nervous system and effective topical adoption for the treatment of skin cancer, viral skin infections, cervical intraepithelial neoplasia (CIN), vaginal and anal intraepithelial dysplasia, venereal warts and venereal warts. compared to acyclic nucleoside phosphonate monoester compositions.

The compounds disclosed herein with both negatively charged ANP phosphonate masks with functional groups provide a more effective use of topical agents for the treatment of skin cancer and viral infections. In particular, the compounds disclosed herein provide effective treatment of infections of the cervical, vaginal, rectal and penile epithelium with human papilloma virus including high risk subtypes such as 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68, 73, and 82 which are associated with cancers of the cervix, rectum, penis, and vagina, and venereal warts.

SUMMARY Compounds with the structure of Formula (I) are disclosed herein,

(I), or a stereoisomer, salt, hydrate, solvate, or crystalline form thereof. In relation to Formula (I), L is a lipophilic group, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, or O-substituted glyceryl of formula -CFkCHCORO-CFkCOR2) (P), wherein R1 and R2 independently substituted or unsubstituted alkyl or substituted or unsubstituted aryl. R is substituted or unsubstituted lower alkyl, substituted or unsubstituted lower heteroalkyl, substituted or unsubstituted lower cycloalkyl, substituted or unsubstituted lower heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted lower heteroaryl. X is hydrogen, substituted or unsubstituted lower alkyl, or substituted or unsubstituted lower heteroalkyl.

57796 000ί In another aspect of the disclosure, treatment of a viral disease in a subject is provided, including administration to a subject in need of a therapeutically effective amount of a compound

Formulas (I).

In another aspect of the invention, the treatment of cancer in a subject is provided, including administration to a subject in need of a therapeutically effective amount of a compound of Formula (I).

In another aspect of the invention, there is provided the killing or inhibition of the growth of a transformed cell, including contacting the transformed cell with a therapeutically effective amount of a compound of Formula (I).

In another aspect of the invention, there is provided the treatment of a proliferative disorder in a subject, including administration to a subject in need thereof of a therapeutically effective amount of a compound of Formula (I).

Also disclosed herein is a pharmaceutical composition comprising a compound of Formula (I), and a pharmaceutically acceptable excipient.

Also disclosed herein is a process for the synthesis of compounds of the structure of Formula (I) according to Scheme 2 disclosed herein. The method comprises contacting the protected Bnuc nucleoside with the structure of Formula (2-1) with an ester with the structure of Formula (2-2) in the presence of a strong base under conditions suitable to obtain a monoester with the structure of Formula (2-3); and reacting the resulting monoester with L-OH in the presence of a coupling agent, thereby synthesizing a compound with the structure of Formula (I).

In one aspect, the invention provides a compound of Formula (Ia), or a pharmaceutically acceptable salt form thereof:

57796 Yes

La may be unsubstituted C13-29 heteroalkyl; Ra may be selected from unsubstituted C 1-6 alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl (C 1-6 alkyl), substituted or unsubstituted 6-substituted heteroaryl or C 1-6 substituted heteroaryl or heterocycloalkyl (C1-6 alkyl); and Xa may be hydrogen, unsubstituted C 1-6 alkyl, halogen substituted C 1-6 alkyl, hydroxy substituted C 1-6 alkyl or unsubstituted C 1-6 alkoxy. In another aspect of the invention, there is provided a pharmaceutical composition which may include an effective amount of a compound as disclosed herein (e.g., a compound of Formula (Ia)), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

In another aspect of the invention, there is provided a compound as disclosed herein (e.g., a compound of Formula (Ia)), or a pharmaceutically acceptable salt thereof, for use in treating a viral disease in a subject, wherein the viral disease is selected from the group consisting of consisting of human papilloma virus, HIV, hepatitis B virus, hepatitis C virus, smallpox virus, vaccine virus, adenovirus, cytomegalovirus, herpes simplex virus 1, herpes simplex virus 2, Epstein Barr virus, BK virus, JC virus, cervical intraepithelial neoplasia, anal intraepithelial neoplasia, and vulval intraepithelial neoplasia, feline leukemia virus, and feline immunodeficiency virus.

In another aspect of the invention, there is provided a compound as disclosed herein, or a pharmaceutically acceptable salt thereof, for use in inhibiting the growth of virus-transformed cells, wherein the virus may be selected from human papilloma virus, HIV, hepatitis B virus , hepatitis C virus, smallpox virus, vaccinia virus, adenovirus, cytomegalovirus, herpes simplex virus 1, herpes simplex virus 2, Epstein Barr virus, BK virus, JC virus, cervical intraepithelial neoplasia, anal intraepithelial neoplasia, and vulval intraepithelial neoplasia, feline leukemia virus, and feline immunodeficiency virus. In another aspect of the invention, there is provided a compound as disclosed herein (e.g., a compound of Formula (Ia)), or a pharmaceutically acceptable salt, hydrate, solvate or

57796 A crystalline form, for the preparation of a medicament for treating a viral disease in a subject, wherein the viral disease may be selected from human papillomavirus, HIV, hepatitis B virus, hepatitis C virus, smallpox virus, vaccinia virus, adenovirus, cytomegalovirus, herpes simplex virus 1, herpes simplex virus 2, Epstein Barr virus, BK virus, JC virus, cervical intraepithelial neoplasia, anal intraepithelial neoplasia, and vulval intraepithelial neoplasia, feline leukemia virus and feline immunodeficiency virus.

In another aspect of the invention, there is provided the use of a compound as disclosed herein (e.g., a compound of Formula (Ia)), or a pharmaceutically acceptable salt, hydrate, solvate or crystalline form thereof, for the preparation of a medicament for inhibiting cell growth transformed with virus, wherein the virus may be selected from human papilloma virus, HIV, hepatitis B virus, hepatitis C virus, smallpox virus, vaccinia virus, adenovirus, cytomegalovirus, herpes simplex virus 1, herpes simplex virus 2, Epstein Barr virus, BK virus, JC virus, cervical intraepithelial neoplasia, anal intraepithelial neoplasia, and vulval intraepithelial neoplasia, feline leukemia virus and feline immunodeficiency virus e.

A process for the synthesis of compounds with the structure of Formula (Ia) is also disclosed herein.

BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 provides a chromatogram of compound Ia (fast-eluting) and compound 1b (slow-eluting), as described in Example 2. X-axis: time (min); Y-axis (milli-absorption units, mAu). Solvent: 50: 50: 0.1 water: acetonitrile: TFA.

DETAILED DESCRIPTION

I. Definitions The abbreviations used herein have their conventional meaning within the chemical and biological techniques. The chemical structures and formulas given here are constructed in accordance with the standard rules of chemical valence known in chemical engineering.

57796 Grupe1 Where groups of substituents specified by their conventional chemical formulas, written from left to right, equally encompass chemically identical substituents that would result if the structure were written from right to left, e.g., -CH2O- is equivalent to

-OCH2-.

As used herein, the term alkyl, alone or as part of another substituent, means, unless otherwise indicated, and includes a straight (i.e., unbranched) or branched chain, or a combination thereof, which may be fully saturated, mono or polyunsaturated and may include di- and multivalent radicals, with the indicated number of carbon atoms (i.e., C1-C10 denotes one to ten carbon atoms). Alkyl is an uncyclized chain. Examples of saturated hydrocarbon radicals include, but are not limited to, groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, (cyclohexyl) methyl, homologues and isomers, for example , n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like.

An unsaturated alkyl group is one that has one or more double bonds (alkenyl groups) or triple bonds (alkynyl groups). Examples of unsaturated alkyl groups include, but are not limited to, alkenyl groups, vinyl, 2-propenyl, crotyl, 2-isopentenyl, 2- (butadienyl), 2,4-pentadienyl, 3- (1,4-pentadienyl), and alkynyl groups of ethynyl , 1- and 3-propynyl, 3-butynyl, and more homologues and isomers.

Alkoxy is alkyl attached to the remainder of the molecule via an oxygen linker (-O-).

The term alkylene, alone or as part of another substituent, means, unless otherwise indicated, a divalent radical derived from alkyl, as exemplified, but not limited to, -CH2CH2CH2CH2-. Typically, an alkyl (or alkylene) group will have from 1 to 24 carbon atoms, or 10 or fewer carbon atoms. Lower alkyl or lower alkylene is a shorter chain alkyl or alkylene grape, generally having eight or fewer carbon atoms.

The term heteroalkyl, alone or in combination with another term, means, unless otherwise indicated, a stable straight or branched chain, or a combination thereof, consisting of at least one carbon atom and at least one heteroatom selected from the group consisting of Ο, Ν, P, Si, and S, and wherein the nitrogen and sulfur atoms can be optionally oxidized, and the nitrogen heteroatom can optionally be quatezed. The heteroatom (i) Ο, N, P, S, and Si can be placed at any internal position of the heteroalkyl group or at the position where the alkyl group is attached to the rest of the molecule. Heteroalkyl is an uncyclized chain. Examples include, but are not limited to: -CH2-CH2-OCH3, -CH2-CH2-NH-CH3, -CH2-CH2-N (CH3) SN 2, -CH 2 -S-CH 2 -CH 3, -CH 2 -CH 2, -S (O) -CH3, -CH2-CH2-S (O) 2-CH3, -SN = SN-O-CH2, Si (CH3) 3, -CH2-CH = N-OCH3, -CH = CH-N (CH3) -CH3, -O-CH3, -O-CH2-CH3, and -CN. Up to two heteroatoms can be sequential, such as, for example, -CH2-NH-OCH3.

57796 Similarly, the term heteroalkylene, alone or as part of another substituent, means, unless otherwise indicated, a divalent radical derived from heteroalkyl, as exemplified, but not limited to, -CH2-CH2-S-CH2-CH2 - and -CH2-SCH2-CH2-NH-CH2-. For heteroalkylene groups, heteroatoms may also occupy any or both chain terminals (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylendiamino, and the like). Additionally, for alkylene and heteroalkylene linking groups, no orientation of the linking group is implied by the direction in which the formula of the linking group is written. For example, the formula -C (O) 2R'represents both -C (O) 2R'- and -R'C (O)2-.

As previously described, heteroalkyl groups, as used herein, include those groups that are attached to the remainder of the molecule via a heteroatom, such as -NR'R, -OR ', SR', and / or -SO2R '. Where said heteroalkyl, followed by reference to specific heteroalkyl groups, such as -NR'R or the like, it is understood that the terms heteroalkyl and -NR'R are not redundant or mutually exclusive. Rather, specific heteroalkyl groups are listed to provide clarity. Therefore, the term heteroalkyl is not to be construed herein as excluding specific heteroalkyl groups, such as -NR'R or the like.

The terms cycloalkyl and heterocycloalkyl, alone or in combination with other terms, mean, unless otherwise indicated, cyclic versions of alkyl and heteroalkyl, respectively. Cycloalkyl and heteroalkyl are non-aromatic. Additionally, for heterocycloalkyl, the heteroatom may occupy a position where the heterocycle is attached to the rest of the molecule. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like. Examples of heterocycloalkyl include, but are not limited to, 1- (1,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3 -yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl, 1-piperazinyl, 2-piperazinyl, and the like.

Cycloalkylene and heterocycloalkylene, alone or as part of another substituent, means a divalent radical derived from cycloalkyl and heterocycloalkyl, respectively.

The terms halo or halogen, alone or as part of another substituent, mean, unless otherwise indicated, a fluorine, chlorine, bromine, or iodine atom. Additionally, it is intended that terms such as haloalkyl include monohaloalkyl and polyhaloalkyl. For example, the term halo (C1-C4) alkyl includes, but is not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like.

The term acyl means, unless otherwise indicated, -C (O) R * wherein R * is substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted or unsubstituted heteroaryl.

57796 Β1 The term aryl means, unless otherwise indicated, a polyunsaturated, aromatic, hydrocarbon substituent, which may be a single ring or more rings (preferably up to 1 to 3 rings) fused together (i.e., a fused aryl ring) or linked covalently.

An aryl fused ring refers to multiple rings fused together wherein at least one of the fused rings is an aryl ring.

The term heteroaryl refers to aryl groups (or rings) containing from one to four heteroatoms selected from N, O, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom (s) is optionally quatezed. . Thus, the term heteroaryl includes heteroaryl groups of a fused ring (i.e., multiple rings fused together wherein at least one of the fused is a heteroaromatic ring). The 5,6-fused heteroarylene ring refers to two rings fused to each other, wherein one ring has 5 members and the other ring has 6 members, and wherein at least one ring is a heteroaryl ring. Similarly, a 6,6-fused heteroarylene ring refers to two mutually fused rings, wherein one ring has 6 members and the other ring has 6 members, and wherein at least one ring is a heteroaryl ring. And the 6,5-fused heteroarylene ring refers to two mutually fused rings, wherein one ring has 6 members and the other ring has 5 members, and wherein at least one ring is a heteroaryl ring. The heteroaryl group may be attached to the rest of the molecule via a carbon or heteroatom. Non-limiting examples of aryl and heteroaryl groups include phenyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl , 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl , 2-pyridyl, 3-pyridyl, 4-pyridyl, 2pyrimidinyl, 4-pyrimidinyl, 5-benzothiazolyl, purinyl, 2-benzimidazolyl, 5-indolyl, 1-isoquinolyl, 5-isoquinolyl, 2-quinoxalinyl, 5-quinoxalinyl, 3-quinolyl, and 6-quinolyl. Substituents for each of the aforementioned aryl and heteroaryl ring systems are selected from the group of acceptable substituents described below. Arylene and heteroarylene, alone or as part of another substituent, denote a divalent radical derived from aryl and heteroaryl, respectively.

For the sake of brevity, the term aryl when used in combination with other terms (e.g., aryloxy, arylthioxy, arylalkyl) includes both aryl and heteroaryl rings as previously defined. Thus, ternyl arylalkyl [e.g., aryl (C1-6 alkyl)] includes those radicals in which the aryl grape is attached to the alkyl grape (e.g., benzyl (Bn), phenethyl, pyridylmethyl, and the like) including those alkyl groups in which a carbon atom (e.g., a methylene group) is replaced by, for example, an oxygen atom (e.g., phenoxymethyl, 2-pyridyloxymethyl, 3- (1-naphthyloxy) propyl, and the like). Thus, the term heteroarylalkyl [e.g., heteroaryl (C 1-6 alkyl)] refers to those radicals in which the heteroaryl group is attached to an alkyl group. The term heterocycloalkylalkyl [e.g.

57796 Βί heterocycloalkyl (C 1-6 alkyl)] refers to those radicals in which heterocycloalkyl is attached to an alkyl group.

The term oxo, as used herein, means oxygen that is bonded by a double bond to a carbon atom.

The term alkylsulfonyl, as used herein, means a group having the formula S (O2) -R ', wherein R' is an alkyl group as previously defined. R 1 may have the indicated number of carbons (e.g., C 1 -C 4 alkylsulfonyl).

Each of the preceding terms (e.g., alkyl, heteroalkyl, aryl, and heteroaryl) includes both substituted and unsubstituted forms of said radical. Preferred substituents for each type of radical are provided below.

Substituents for alkyl and heteroalkyl radicals (including those groups often referred to as alkylene, alkenyl, heteroalkylene, heteroalkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, and heterocycloalkenyl) may be one or more groups selected from, but not limited to na, -OR ', = 0, = NR', = N-0R ', -NR'R, -SR', -halogen, -SiR'RR "', -OC (O) R', -C ) R ', -CO2R', -CONR'R, -OC (O) NR'R, -NRC (O) R ', -NR'-C (O) NRR "', -NRC (O) 2R ', -NRC (NR'RR "') = NR" ", -NR-C (NR'R) = NR"', -S (O) R ', -S (O) 2R ', S (O) 2NR'R, -NRSO2R', -CN, and -NO2 in a number ranging from zero to (2m '+ 1), where m' is the total number of carbon atoms in such radical. R 1, R 2, R 3, and R 1 "each preferably independently refer to hydrogen, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl (e.g., aryl substituted with 1-3 halogen), substituted or unsubstituted alkyl, alkoxy, or thioalkoxy groups, or arylalkyl groups. When the compound includes more than one R group, for example, each of the R groups is independently selected such that each R ', R, R', and R "" group when more than one of these groups is present. When R 1 and R are attached to the same nitrogen atom, they can combine with the nitrogen atom to form a 4-, 5-, 6-, or 7-membered ring. For example, NR'R includes, but is not limited to, 1-pyrrolidinyl and 4-morpholinyl. From the foregoing consideration of substituents, one skilled in the art will appreciate that the term substituted alkyl includes groups that include carbon atoms attached to groups other than hydrogen groups, such as haloalkyl (e.g., -CF3 and -CH2CF3) and acyl (e.g., -C (O) CH3, -C (O) CF.3, -C (O) CH2OCH3, and the like).

Similar to the substituents described for the alkyl radical, the substituents for the aryl and heteroaryl groups are different and are selected from, for example: -OR ', -NR'R, -SR', -halogen, -SiR'RR "', - OC (O) R ', C (O) R', -CO2R ', -CONR'R, -OC (O) NR'R, -NRC (O) R', -NR'-C (O) NRR ” ', NRC (O) 2R', -NR-C (NR'RR "') = NR" ", -NR-C (NR'R) = NR"', -S (O) R ', -S ( O) 2R ', S (O)2NR'R, -NRSO2R ', -CN, -NO2, -R', -N3, -CH (Ph) 2, fluoro (C1-C4) alkoxy, and fluoro (CiC4) alkyl, in a number ranging from zero to the total number of open valences on the aromatic

57796 Β1 ring system; and wherein R ', R, R' ", and R" "are preferably independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted a unsubstituted heteroaryl. When the compound includes more than one R group, for example, each of the R groups is independently selected such that each is R ', R, R', and R "" groups when more than one of these groups is present.

Two or more substituents may optionally be combined to form aryl, heteroaryl, cycloalkyl, or heterocycloalkyl grapes. Such so-called ring-forming substituents are typically, though not necessarily, linked to the structure of the cyclic base. In embodiments, the ring-forming substituents are attached to adjacent members of the base structure. For example, two ring-forming substituents attached to adjacent members of the cyclic base structure form a fused ring structure. In another embodiment, the ring-forming substituents are attached to one member of the base structure. For example, two ring-forming substituents attached to a single member of the cyclic base structure form a spirocyclic structure. In another embodiment, the ring-forming substituents are attached to non-adjacent members of the base structure.

Two of the substituents on adjacent aryl or heteroaryl ring atoms may optionally form a ring of formula -TC (O) - (CRR ') qU-, wherein T and U are independently -NR-, -O-, -CRR'-, or a simple bond, iq is an integer from 0 to 3. Alternatively, two of the substituents on adjacent aryl or heteroaryl ring atoms may be optionally substituted with a substituent of formula -A- (SNg) g-V, wherein A and B are independently -CRR '-, -O-, -NR-, -S-, -S (O) -, -S (O) 2-, -S (O) 2NR'-, or a simple bond, ir is an integer from 1 to 4. One of the simple connections of the new ring made in this way can be optionally replaced with a double connection. Alternatively, two of the substituents on adjacent aryl or heteroaryl ring atoms may be optionally substituted with a substituent of formula (CRR ') s-X' - (CR "') d-, wherein sid is independently an integer from 0 to 3, and X' is -O-, -NR'-, -S-, S (O) -, -S (O)2-, or -S (O) 2NR'-. The substituents R, R ', R, and R' "are preferably independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.

As used herein, the terms ring heteroatom or heteroatom include oxygen (O), nitrogen (N), sulfur (S), phosphorus (P), and silicon (Si).

A substituent group, as used herein, means a group selected from the following moieties:

57796 Β1 (Α) -ΟΗ, -ΝΗ2, -SH, -CN, -SBz, -ΝΟ2, oxo, halogen, unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, unsubstituted heteroaryl, and (B) alkyl, heteroalkyl, cycloalkyl heteroaryl, substituted with at least one substituent selected from:

(i) oxo, -ΟΗ, -NH2, -SH, -CN, -CF3, -NO2, halogen, unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, unsubstituted heteroaryl, and, (ii) alkyl , cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, substituted with at least one substituent selected from:

(a) oxo, -OH, -NH2, -SH, -CN, -CF3, -NO2, halogen, unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, unsubstituted heteroaryl, and (b) alkyl, heteroalkyl, cycloalkyl, heterocyclo substituted with at least one substituent selected from:

oxo-OH, -NH2, -SH, -CN, -CF3, -NO2, halogen, unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, and unsubstituted heteroaryl.

Restricted size substituent or limited size substituent group, as used herein, means a group selected from all substituents described previously for the substituent group, wherein each substituted or unsubstituted alkyl is substituted or unsubstituted C1-C29 alkyl, each substituted or unsubstituted heteroalkyl is substituted or unsubstituted 2 to 30 membered heteroalkyl, each substituted or unsubstituted cycloalkyl is substituted or unsubstituted S 2 -C 8 cycloalkyl, each substituted or unsubstituted heterocycloalkyl is substituted or unsubstituted 3 to 8 membered heterocycloalkyl, each substituted or unsubstituted aryl is substituted or unsubstituted S and unsubstituted substituted or unsubstituted 5 to 10 membered heteroaryl.

Lower substituent or lower substituent group, as used herein, means a group selected from all the substituents described above for a substituent group, wherein each substituted or unsubstituted alkyl is substituted or unsubstituted C 1 -C 6 alkyl, each substituted or unsubstituted heteroalkyl is substituted or unsubstituted 2 to 8 membered heteroalkyl, each substituted or unsubstituted cycloalkyl is substituted or unsubstituted C3-C7 cycloalkyl, each substituted or unsubstituted heterocycloalkyl is substituted or unsubstituted 3 to 7 membered heterocycloalkyl, each substituted or unsubstituted aryl is

57796 Β1 substituted or unsubstituted Sb-C10 aryl, and each substituted or unsubstituted heteroaryl is substituted or unsubstituted 5 to 9 membered heteroaryl.

In embodiments, each substituted group described in the compounds herein is substituted with at least one substituent group. More specifically, in embodiments, each substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heteroaryl, substituted heterocycloalkyl, and substituted heterocycloalkyl substituted with at least one substituent group. In embodiments, at least one or all of these groups are substituted with at least one limited size substituent group. In embodiments, at least one or all of these groups are substituted with at least one lower substituent group.

In embodiments of the compounds herein, each substituted or unsubstituted alkyl may be substituted or unsubstituted C 1 -C 10 alkyl, each substituted or unsubstituted heteroalkyl is substituted or unsubstituted 2 to 30 membered heteroalkyl, each substituted or unsubstituted substituted cycloalkyl C5 cycloalkyl, substituted or unsubstituted heterocycloalkyl is substituted or unsubstituted 3 to 8 membered heterocycloalkyl, each substituted or unsubstituted aryl is substituted or unsubstituted Sb-C10 aryl, and / or each substituted or unsubstituted heteroaryl is substituted or unsubstituted 5 to 10 membered heteroaryl. In embodiments of the compounds herein, each substituted or unsubstituted alkylene is substituted or unsubstituted C 1 -C 50 alkylene, each substituted or unsubstituted heteroalkylene is substituted or unsubstituted 2 to 30 membered heteroalkylene, each substituted or unsubstituted cycloalkylalkylene is substituted C 1-3 alkylene is substituted substituted or unsubstituted heterocycloalkylene is substituted or unsubstituted 3 to 8 membered heterocycloalkylene, each substituted or unsubstituted arylene is substituted or unsubstituted Sb-C10 arylene, and / or each substituted or unsubstituted heteroarylene is substituted or unsubstituted 5 to 10 membered heteroarylene.

In embodiments, each substituted or unsubstituted alkyl is substituted or unsubstituted C1-C8 alkyl, each substituted or unsubstituted heteroalkyl is substituted or unsubstituted 2 to 8 membered heteroalkyl, substituted or unsubstituted cycloalkyl, each substituted cycloalkyl is substituted substituted or unsubstituted heterocycloalkyl is substituted or unsubstituted 3 to 7 membered heterocycloalkyl, each substituted or unsubstituted aryl is substituted or unsubstituted Sb-C10 aryl, and / or substituted or unsubstituted heteroaryl is substituted or unsubstituted 5 to 9 membered heteroaryl. In some embodiments, each substituted or unsubstituted alkylene is

57796 ΒΙ substituted or unsubstituted C 1 -C 6 alkylene, each substituted or unsubstituted heteroalkylene is substituted or unsubstituted 2 to 8 membered heteroalkylene, each substituted or unsubstituted cycloalkylene is substituted or unsubstituted C 3 -C 7 cycloalkylene or unsubstituted unsubstituted or substituted members of heterocycloalkylene, each substituted or unsubstituted arylene is substituted or unsubstituted Sb-C10 arylene, and / or each substituted or unsubstituted heteroarylene is substituted or unsubstituted 5 to 9 membered heteroarylene.

The term pharmaceutically acceptable salts includes salts of active compounds which are prepared from relatively non-toxic acids or bases, depending on the particular substituents present on the compounds described herein. When the compounds described herein contain relatively acidic functional groups, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either pure or in a suitable inert solvent. Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salts, or the like. When the compounds described herein contain relatively basic functional groups, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either pure or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids such as hydrochloric, hydrobromic, nitric, carbon, carbon monohydrocarbon, phosphoma, phosphoma monohydrogen, phosphoma dihydrogen, sulfoma, sulfoma monohydrogen, acid and hydrogen iodide salts. derived from relatively non-toxic organic acids such as acetic, propionic, isobutema, maleic, malonic, benzoic, amber, suberic, fumaceous, lactic, almond, phthalic, benzenesulfonic, ptolylsulfonic, lemon, wine, oxalic, methanesulfonic, and the like. Also included are amino acid salts such as arginate and the like, and organic acid salts such as glucuronic or galacturonic acid and the like (see, e.g., Berge et al., Pharmaceutical Sauce, Joumal of Pharmaceutical Science, 1977, 66: 1- 19). Certain specific compounds described herein contain both basic and acidic functional groups that allow the compounds to be converted to either basic or acid addition salts.

Thus, the compounds described herein [e.g., a compound of Formula (I) and / or a compound of Formula (Ia)] may exist as salts, such as with pharmaceutically acceptable acids. Examples of such salts include hydrochlorides, hydrobromides, sulfates, methanesulfonates, nitrates, maleates, acetates, citrates, fumarates, tartrates (e.g., (+) - tartrates, (-) - tartrates, or mixtures thereof including racemic mixtures), succinates, benzoates , and salts with amino acids such as glutamic acid. These salts can be prepared by methods known to those skilled in the art.

57796 Β1 Neutral forms of the compounds can be regenerated by contacting the salt with a base or acid and isolating the parent compound in a conventional manner. The initial form of the compound differs from the different salt forms in certain physical properties, such as solubility in polar solvents.

In addition to the salt forms, the compounds described herein [e.g., a compound of Formula (I) and / or a compound of Formula (Ia)] may be in the form of a prodrug. Prodrugs of the compounds described herein are those compounds that readily undergo chemical changes under physiological conditions to provide the compound described herein. Additionally, prodrugs can be converted to the compounds described herein by chemical and biological methods in an ex vivo environment. For example, prodrugs can be slowly converted to the compounds described herein when placed in a reservoir of a transdermal patch with a suitable enzyme or chemical reagent. The term pro-moiety means a chemical entity reversibly linked to a drug that improves the aspect of drug performance by masking the problematic functional group.

Certain compounds described herein [e.g., a compound of Formula (I) and / or a compound of Formula (Ia)] may exist in unsolvated forms as well as in solvated forms, including hydrated forms. In general, solvate forms are equivalent to unsolvated forms and are included. Certain compounds described herein [e.g., a compound of Formula (I) and / or a compound of Formula (Ia)] may exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent to the intended uses and are intended to be included.

Certain compounds described herein [e.g., a compound of Formula (I) and / or a compound of Formula (Ia)] may possess asymmetric atoms (optical centers) or double bonds; included racemates, diastereomers, tautomers, geometric isomers, and individual isomers. The compounds described herein [e.g., a compound of Formula (I) and / or a compound of Formula (Ia)] do not include those known in the art to be too unstable to be synthesized and / or isolated.

The compounds described herein [e.g., a compound of Formula (I) and / or a compound of Formula (Ia)] may also contain unnatural proportions of atomic isotopes on one or more atoms that make up such compounds. For example, compounds may be radiolabeled with radioactive isotopes, such as tritium (3H), iodine-125125I), or carbon-1414C). All isotopic variations of the compounds, whether radioactive or not, are included.

The symbol APJHR denotes the point of attachment of a chemical moiety to the remainder of a molecule or chemical formula.

II. Compounds

57796 Βί A compound with the structure of Formula (I) is described herein:

or a stereoisomer, salt, hydrate, solvate, or crystalline form thereof. For a compound with the structure of Formula (I), BN is a naturally occurring purine or pyrimidine base, or an analog thereof; L-lipophilic pro-moiety, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, or O-substituted glyceryl of formula -CthCHCOR ^ -CthCOR2) (I), where R1 and R2 are independently substituted or unsubstituted alkyl, or substituted or unsubstituted aryl; R is substituted or unsubstituted lower alkyl, substituted or unsubstituted lower heteroalkyl, substituted or unsubstituted lower cycloalkyl, substituted or unsubstituted lower heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted lower heteroaryl; and X is hydrogen, substituted or unsubstituted lower alkyl, or substituted or unsubstituted lower heteroalkyl.

The compound may be a stereoisomer having the structure of Formula (I). The compound may be a salt of a compound of formula (I). The compound may be a solvate of a compound of the structure of Formula (I). The compound may be a crystalline form of a compound of formula (I).

The terms naturally occurring purine or pyrimidine bases and the like refer, in a conventional manner as used in the art, to purine or pyrimidine bases, e.g., guanine, adenine, cytosine, thymine, uracil, or 2, 6-diaminopurine. The binding of naturally occurring purine or pyrimidine bases may be at any available site, e.g., guanin-9-yl, adenin-9-yl, cytosin-1-yl, thymin-1-yl, uracil-1-yl , 2,6-diaminopurin-9-yl, and the like. When attached to the remainder of the compounds as described herein, the purine or pyrimidine base as it occurs in nature is in a monovalent form (a chemical moiety or substituent as is known in the art).

The terms naturally occurring purine or pyrimidine base analog and the like refer, in a conventional manner, to a naturally occurring chemical purine or pyrimidine base analog, as is known in the art. When bound to the remainder of the compounds described herein, the naturally occurring purine or pyrimidine base analog is in monovalent form (a chemical moiety or substituent as known in the art).

57796 ΒΙ Accordingly, Bnuc can be a purine or pyrimidine base that occurs in nature. Bnuc can be a purine base that occurs in nature. Bnuc may be a naturally occurring pyrimidine base. Bnuc can be an analogue of a purine or pyrimidine base that occurs in nature. Bnuc may be an analogue of a purine base that occurs in nature. Bnuc may be a naturally occurring pyrimidine base analogue.

The terms lipophilic pro-moiety and the like refer to a chemical moiety that imparts increased lipophilicity when incorporated into a compound of the structure of Formula (I). The lipophilic pro-moiety may be substituted or unsubstituted C 1-4 alkyl. The lipophilic pro-moiety may be substituted or unsubstituted C8-24 heteroalkyl. The lipophilic pro-moiety may be substituted or unsubstituted C5-24 alkoxyalkyl. Examples of lipophilic pro-moieties include a glycerol moiety with substituted or unsubstituted alkyl, and / or substituted or unsubstituted aryl substituents. Substitution on the glyceryl moiety may be via O-substitution with substituted or unsubstituted alkyl, and / or via O-substitution with substituted or unsubstituted aryl. Thus, the lipophilic pro-moiety, L, confers lipophilicity and may therefore include glyceryl ether-bound compounds (e.g., 10-octadecyl-2-obenzyl) wherein the glyceryl hydroxyl hydrogens are replaced by substituted or unsubstituted alkyl or substituted or unsubstituted aryl groups. give hydrophilicity, and the carbon atoms of the glyceryl are not further substituted. L may be O-substituted glyceryl having the formula -CH2CH (OR1) -CH22) (P), where R1 and R2 are independently substituted or unsubstituted alkyl or substituted or unsubstituted aryl.

L may be substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, or O-substituted glyceryl of the formula -CFhCHCOR ^ -CFhCOR2) (P), where R1 and R2 are independently substituted or unsubstituted alkyl or substituted or unsubstituted aryl. L may be O-substituted glyceryl. L may be 10-alkyl-2-O-benzyl-sn-glyceryl. L may be 1-Octadecyl-2-O-benzyl-sn-glyceryl. L may be unsubstituted alkyl. L may be unsubstituted alkyl of limited size. L may be C2-24 alkyl. L may be unsubstituted heteroalkyl. L may be unsubstituted heteroalkyl of limited size. L may be C8-24 heteroalkyl. L may be unsubstituted alkoxyalkyl. L may be unsubstituted alkoxyalkyl of limited size. L may be C5-24 alkoxyalkyl.

R may be substituted or unsubstituted lower alkyl, substituted or unsubstituted lower heteroalkyl, substituted or unsubstituted lower cycloalkyl, substituted or unsubstituted lower heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted. R may be substituted or unsubstituted lower alkyl. R may be substituted or unsubstituted lower heteroalkyl. R may be O-substituted glyceryl of formula -CH2CH (OR3) CFhCOR4) (ΠΙ), where R3 and R4 are independently substituted or unsubstituted alkyl or substituted or unsubstituted aryl. R may be substituted or unsubstituted lower cycloalkyl. R can be

57796 Β1 substituted or unsubstituted lower heterocycloalkyl. R may be substituted or unsubstituted hexopyranosyl. R may be unsubstituted hexopyranosyl. R may be substituted or unsubstituted aryl. R may be substituted or unsubstituted lower heteroaryl. R may be unsubstituted lower alkyl. R may be unsubstituted lower heteroalkyl. R may be unsubstituted lower cycloalkyl. R may be unsubstituted lower heterocycloalkyl. R may be unsubstituted aryl. R may be unsubstituted lower heteroaryl. R may be substituted or unsubstituted lower cycloalkyl of limited size. R may be substituted or unsubstituted lower heterocycloalkyl of limited size. R may be substituted or unsubstituted aryl of limited size. R may be substituted or unsubstituted lower heteroaryl of limited size. R may be C1-8 substituted or unsubstituted alkyl. R may be C1-8 substituted or unsubstituted heteroalkyl. R may be C4-8 substituted or unsubstituted cycloalkyl. R may be C4-8 substituted or unsubstituted heterocycloalkyl. R may be Sb-10 substituted or unsubstituted aryl. R may be Sb-10 substituted or unsubstituted heteroaryl. R may be C1-8 unsubstituted alkyl. R may be C2-8 unsubstituted heteroalkyl. R may be C4-8 unsubstituted cycloalkyl. R may be C4-8 unsubstituted heterocycloalkyl. R may be Sb-10 unsubstituted aryl. R may be Sb-10 unsubstituted heteroaryl.

R may be substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted benzyl, substituted or unsubstituted glyceryl, or substituted or unsubstituted hexopyranosyl. R may be substituted phenyl. R may be substituted naphthyl. R may be substituted benzyl. R may be substituted glyceryl. R may be substituted hexopyranosyl. R may be unsubstituted phenyl. R may be unsubstituted naphthyl. R may be unsubstituted benzyl. R may be unsubstituted glyceryl. R may be unsubstituted hexopyranosyl.

X may be hydrogen, substituted or unsubstituted lower alkyl, or substituted or unsubstituted lower heteroalkyl. X may be hydrogen. X may be substituted or unsubstituted lower alkyl. X may be substituted or unsubstituted lower heteroalkyl. X may be unsubstituted lower alkyl. X may be unsubstituted lower heteroalkyl. X may be substituted or unsubstituted alkyl of limited size. X may be substituted or unsubstituted heteroalkyl of limited size. X may be unsubstituted alkyl of limited size. X may be unsubstituted heteroalkyl of limited size. X may be methyl. X may be methoxymethyl. X may be hydroxymethyl. X may be fluoromethyl.

A compound with the structure of Formula (I) may have the structure of Formula (I-1):

57796 Β1

For a compound of the structure of Formula (1-1), Bnuc is as described for any of the compounds of Formula (I) disclosed herein.

L is as described for any of the compounds of Formula (I) described herein. L may be octadecyloxyethyl, hexadecyloxypropyl, or 10-octadecyl-2-O-benzyl-sn-glyceryl. L may be octadecyloxyethyl. L may be hexadecyloxypropyl. L may be 10-octadecyl-2-O-benzyl-glyceryl.

R is as described for any of the compounds of Formula (I) described herein. R may be substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted benzyl, substituted or unsubstituted glyceryl, or substituted or unsubstituted hexopyranosyl. R may be substituted phenyl. R may be substituted naphthyl. R may be substituted benzyl. R may be substituted glyceryl. R may be substituted hexopyranosyl. R may be unsubstituted phenyl. R may be unsubstituted naphthyl. R may be unsubstituted benzyl. R may be unsubstituted glyceryl. R may be unsubstituted hexopyranosyl.

The compound of the structure of Formula (I) may have the structure of Formula (1-2):

For a compound with the structure of Formula (1-2), Bnuc is as described for any of the compounds of Formula (I) - (II) disclosed herein.

It is as described for any of the compounds of Formula (I) - (II) described herein.

R is as described for any of the compounds of Formula (I) - (II) described herein.

A compound with the structure of Formula (I) may have the structure of Formula (1-3):

57796 Β1

For a compound with the structure of Formula (1-3), Bnuc is as described for any of the compounds of Formula (1) - (1-2) disclosed herein.

E is as described for any of the compounds of Formula (1) - (1-2) described herein.

R is as described for any of the compounds of Formula (1) - (1-2) described herein.

The compound of the structure of Formula (I) may have the structure of Formula (1-4):

O — R

For compounds with the structure of Formula (1-4), Bnuc is as described for any of the compounds of Formula (1) - (1-3) disclosed herein.

E is as described for any of the compounds of Formula (1) - (1-3) described herein.

R is as described for any of the compounds of Formula (1) - (1-3) described herein.

Compounds with the structure of Formula (1) may have the structure of Formula (1-5):

For a compound with the structure of Formula (1-5), Bnuc is as described for any of the compounds of Formula (1) - (1-4) disclosed herein.

E is as described for any of the compounds of Formula (1) - (1-4) described herein.

R is as described for any of the compounds of Formula (1) - (1-4) described herein.

In one aspect of the present invention, there is provided a compound of Formula (Ia), or a pharmaceutically acceptable salt thereof:

57796 Β1 ®Nu <Xa)

Ο.

O — Ra

XS (la).

For this aspect, B.Nuc (a) is

La is unsubstituted C13-29 heteroalkyl. Ra is selected from the group consisting of unsubstituted C1-6 alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl (C1-6 alkyl), substituted or unsubstituted alkyl heteroaryl. and substituted or unsubstituted heterocycloalkyl (C1-6 alkyl). Xa is hydrogen, unsubstituted

C1-6 alkyl, halogen substituted C1-6 alkyl, hydroxy substituted C1-6 alkyl or unsubstituted

C1-6 alkoxy. In this aspect, the alkyl may be fully saturated, mono- or poly-unsaturated. In this aspect, the substituent is selected from the following moieties: -ΟΗ, -NH2, -SH, -CN, -CF3, -NO2, oxo, halogen, unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl and .

In embodiments, Xa is hydrogen, unsubstituted C 1-6 alkyl, halogen substituted

C1-6 alkyl, hydroxy substituted C1-6 alkyl or unsubstituted C1-6 alkoxy. In embodiments, Xa may be hydrogen. In embodiments, Xa may be unsubstituted C1-6 alkyl. In embodiments, Xa may be methyl. In embodiments, Xa may be hydroxy substituted C1-6 alkyl. In embodiments, Xa may be -CH2OH. In embodiments, X may be unsubstituted C 1-6 alkoxy. In embodiments, Ha may be methoxy. In embodiments, Xa may be halogen substituted C 1-6 alkyl. In examples

57796 Β1 performances, Xa may be fluoro substituted C1-6 alkyl. In embodiments, Xa may be CH2F.

In addition to any preceding embodiment, in embodiments La is unsubstituted C13-29 heteroalkyl. In embodiments, La may have the structure - (CH2) i-6O- (SNg) 11-21-SNz. In embodiments, La may have the structure - (CH2) g-O- (CH2) 17-CH2. In embodiments, La may have the structure - (SN2) z-O- (SN2) 15-SNz. In embodiments, La may have a structure - (SN2) 1-b-O- (SN2) 10-20- (SNSNz) -SNz.

In addition to any embodiment of the compound of Formula (Ia), in embodiments Ra may be substituted or unsubstituted aryl. In embodiments, the substituted aryl may be substituted phenyl. In embodiments, the unsubstituted aryl may be unsubstituted phenyl. In embodiments, the substituted aryl may be substituted naphthyl. In embodiments, the unsubstituted aryl may be unsubstituted naphthyl.

In addition to any embodiment of the compound of Formula (Ia), in embodiments Ra may be substituted or unsubstituted aryl (C 1-6 alkyl). In embodiments, the substituted aryl (C 1-6 alkyl) may be substituted benzyl. In embodiments, the unsubstituted aryl (C 1-6 alkyl) may be unsubstituted benzyl.

In addition to any embodiment of the compounds of Formula (Ia), in embodiments Ra may be substituted or unsubstituted heterocycloalkyl (C1-6 alkyl). In embodiments, substituted or unsubstituted heterocycloalkyl (C 1-6 alkyl) is substituted or unsubstituted galactosyl.

In embodiments a, BNuc (a) may be selected from:

In embodiments, the compound of Formula (Ia) may have the structure:

57796 Yes

In embodiments, the compound of Formula (Ia) may have the structure:

Xand In embodiments, the compound of Formula (Ia) may have the structure:

In embodiments, the compound of Formula (Ia) may have the structure:

Vmis (a)

Q

La In embodiments, the compound of Formula (Ia) may have the structure:

In embodiments, the compound of Formula (Ia) may have the structure:

57796 Β1

In embodiments, the compound may be selected from:

57796 ΒΙ

no2

ΝΗ;

57796 Β1

or pharmaceutically acceptable salts of any of the foregoing.

As can be seen from Formula (Ia), there are many embodiments. For example, disclosed embodiments are directed to a compound of Formula (Ia) based on the identity of the support structure of an acyclic nucleoside phosphonate. It is not intended that this be an explicit or implicit acknowledgment that the examples of performance are independent or distinct nor should it be construed as such. Rather, the intention is to convey information so that the full breadth of Formula (Ia) can be understood. In addition, the following embodiments, and aspects thereof, are not intended to be limiting to the full breadth of the structure of Formula (Ia).

Tables 1-10 follow the disclosed structures provided herein. It is not intended that the structures in Tables 1-10 be limiting to the full breadth of the predicted compounds represented by the structure of Formula (Ia). Additionally, it is contemplated that any of the predicted support structures of acyclic nucleoside phosphonate (ANP) (PME-, (/?) - PMP-, (S) -MPMP-, (S) -HPMP- and (S) -FPMP-) or stereoisomers thereof, may be used in combination with any of the provided combinations of natural or modified purine or pyrimidine base (Bnuc / Bnuc (h)), L / La and R / Ra. Additionally, since the phosphorus atom of the ANP diester is a potential chiral center, it is understood that Rp and Sp (i.e., Cahn-Ingold-Prelog nomenclature as known in the art) of stereochemical configuration are possible. Therefore, the structures below include stereochemical configurations possible for phosphorus. * indicates a reference example.

57796 V1

Table 1. Phosphonomethoxyethyl (PME) diester compound

<td></td><td>44 OO c</td><td>okl nor</td><td>okl nor</td><td>you cΟ ο C</td><td>§ 44 0 c</td><td>5 ° π e 0 S</td><td>S ° η</td><td rowspan="2">iloxy 2.6-</td><td rowspan="2">“G4 § (U β -β <2</td><td rowspan="2">“Η § ω ε 42 £</td>

57796 ΒΙ

<td></td><td>ipropyl 1- (2yl) cytosine</td><td>ipropyl 1- (2- til) thymine</td><td>ipropyl 9- (2- til) uracil</td><td>ipropyl 9- (2i-diaminopurine</td><td>nzil-sn glyceryl 9- (2- il) guanine</td><td>nzyl-sn glyceryl 9- (2yl) adenine</td><td>nzyl-sn glyceryl 1- (2- or) cytosine</td><td>nzyl-sn glyceryl 1- (2- til) thymine</td><td>nzil-sn glyceryl 9- (2- til) uracil</td><td>nzyl-sn glyceryl 9- (2i-diaminopurine</td><td>ethyl 9- (2yl) guanine</td><td>ethyl 9- (2yl) adenine</td><td>ethyl 1- (2yl) cytosine</td><td>phonomethoxyethyl) thymine</td><td>phonomethoxyethyl) uracil</td><td>ifonomethoxyethyl) -2,6- rin</td><td>propyl 9- (2-</td>

<td rowspan="2">► Ν Λ</td><td>> ο Ο 'i oz</td><td>'ο 5 44 - ο</td><td>34 r5 sl -2 34</td><td>ilok D-2,</td><td>'' sl o</td><td>£ OJ, About 44</td><td>'' fig</td><td>0-b □ xi</td><td>-? £ Ο ο</td><td>Sž</td><td> -4 ω O 'i 03 44</td><td>44 52 O 'fig OZ</td><td>> ο ο '«03 J4</td><td>'ν MS</td><td> £</td><td>12 & sch?</td><td> 44 £</td>

57796 Β1

<td>Name</td><td>Q 'sl 24 O m— »o</td><td>Rch -ο ο cd * -ι Ο. & S sl Ο 'i ο 2 Ο (□</td><td>SH, «ο υ * -ι Ο. & 2 sl Ο 'i 2 44 υ 2 ο ο</td><td>& -D i-4 - “2 02 'ΰ' S 2 44 « 0 8 £</td><td>l £ ο 2 (Η .---- Ο. χ 2 sl Ο 44 05 ο 8 g</td><td>Dpil 9- (2-phos: iaminopurine</td><td>2-O-benzyl-ethoxyethyl) gu</td><td>sl Ό Д. цđ 'С £ 17 C 'L QQ 'sl o 1 °1 + -4 SČ SJ</td><td>2-O-benzyl-stoxyethyl) cyl</td><td>2-O-benzyl-ethoxyethyl) thi</td><td>2-0-benzyl-ethoxyethyl) ed</td><td>2-0-benzyl-s ethyl) -2,6-dia</td><td>E 0 c 2 fig 2 1 pc.</td><td>Ε ο β 2 SL 2 1 SC,</td><td>Ε ο β 2 SL 2</td><td>C ο C 2 SL 2 1 SC I</td><td>C ο C 2 SL 2 1 SC,</td><td>• - (2-phosphonor minopurine</td><td>Έ. the 1- 'sl 44 ^ O 'υ</td>

<td></td><td>d fo</td><td>44 5 ω, ο</td><td>44 £ ο, ο</td><td>44 0 About 22</td><td>24 ο Ο tg</td><td>44 O</td><td>in β Ό, O</td><td>ο Ο Ό Ο</td><td>cn</td><td> -0 2</td><td> 0 2</td><td>Q £ Q</td><td>4-4 Q</td><td>4-4 Q</td><td>4-4 ο</td><td>0J</td><td>_ό</td><td></td><td> 2</td>

<td></td><td></td><td>, Ο ¢ 4- (</td><td> ¢4-(</td><td>, O ¢ 4-4</td><td>, ¢ ¢ 4-4</td><td rowspan="2">Ό cd fig 44 O 'S</td><td> 0 1</td><td> 0 1</td><td> 0 1</td><td>Oh 1</td><td>Oh 1</td><td>1-0phospho</td><td>75 Q Ό cd</td><td>75 Q Ό cđ</td><td>75 ο Ό εϋ</td><td>υ Q Ό cd</td><td>Ο Q Ό ctf</td><td>0 Q Ό cd</td><td>ο</td>

<td></td><td></td><td></td><td></td><td></td><td></td><td>phenyl</td><td> '2 ¢4-4</td><td>phenyl</td><td>phenyl</td><td>phenyl</td><td>phenyl</td><td> 4-4 44 0</td><td> 4-4 44 0</td><td>4-4 44 Ο</td><td> 44 0</td><td> 2 0</td><td> 44 0</td><td></td>

<td rowspan="2">the river</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td>υ ο Ό cd</td><td>'5 Ο Ό cd</td><td>75 0 Ό ctf</td><td>'5 Ο Ό cd</td><td>'5 0 Ό rt</td><td rowspan="2">_2 υ 8 vd Ό ctf</td><td rowspan="2">-4 υ 8 ad Ό ctf</td><td rowspan="2">tadecil- glyc</td><td rowspan="2">-4 <□ 8 ad Ό cd</td><td rowspan="2">-4 υ 8 m Ό ctf</td><td rowspan="2">^ + no 8 ad Ό cd</td><td>73 Q Ό cd</td><td>75 Q Ό ctf</td><td>75 ο Ό ctf</td><td>75 Q Ό cd</td><td>75 Q Ό cd</td><td>75 Q Ό cd</td><td>'δ ο from</td>

57796 Β1

<td></td><td>_ρ</td><td></td><td>Ψ S</td><td>- (2n</td><td>I CS</td><td>I 'Ρ Q SL 44 Ο 4— » Q Ε ο</td><td>liceril 9- (2in</td><td>ι ΰ 04 ΐ Q D £</td><td>I MS, Q d S</td><td>liceril l- (2- n</td><td>liceril 9- (2- il</td><td>liceril 9- (2- nopurine</td><td>9- (2- .η</td><td>9- (2- .η</td><td>1- (2- in</td><td>l- (2- n</td>

<td></td><td>Ρ P JC)</td><td>o</td><td>ο & s</td><td>1— (g 'cl'D ο 32</td><td>__. Κ Κ S Ο 37</td><td>* 2 α SL. D 'O £</td><td>PS T δ)</td><td>S 'S ι ίϋ</td><td>1-sn) cyto</td><td>1-sn l) tiir</td><td>1-sn l) ura</td><td>1-sn diarr</td><td>S Ο Ρ 1-Η 0 £ fig</td><td>j3 ο Ο Ό with L</td><td>ρ ο ο 'sl 2.</td><td>'-R P .8 sl £ 24</td>

<td> ►</td><td>Q</td><td>Q- <'—- » with</td><td>Η Ο- <'-R ».a</td><td>'S</td><td>. & ω sl 'sg</td><td>9-4 D ά ο</td><td>and 1</td><td>enzyme ethyl</td><td>enzyme ethyl</td><td>'n * 3 d O</td><td>N Ό C ω</td><td>'s <> S CN</td><td>· Ρ Ο ΰ gr 2</td><td>'ο 3 ^ P S2</td><td>-r ο -R gr 2</td><td>go</td>

<td rowspan="2">N Ζ</td><td>fig 44</td><td>fig About 44</td><td>fig Ο 44</td><td></td><td>44 Ο Ο 7?</td><td>Ch §</td><td>-? jž</td><td> -? £</td><td>Υ</td><td> £ 44</td><td></td><td></td><td>Ο sl *</td><td>Ο fig 2 44</td><td>About sl *</td><td>1 o</td>

<td></td><td>υ ο Ό Ρ SL 44</td><td>'5 Q Ό Ρ SL 4-i</td><td>'5 ο Ό Ρ SL 4th</td><td>'5 Q Ό Ρ SL 4</td><td>'5 o Ό P fig 4-J</td><td>-4 υ 8 vd Ό cd 4- »4-ί</td><td>-4 υ 8 ad Ό cd £</td><td>ktadecyl- glyc</td><td>-4 o 8 ad Ό cd £</td><td>-4 o 8 m Ό cd £</td><td>^ 4 4 8 ad Ό α £</td><td>octadeci</td><td>octadeci</td><td>octadeci</td><td>octadeci</td>

57796 Β1

<td></td><td>9- (2cil</td><td>9- (2nopurine</td><td>Π 9- (2- .η</td><td>1 Qz 1 ο \ ~, Ε</td><td>il 1- (2- in</td><td>1 1 α α</td><td>1 CJz 1 O \ Γ73</td><td>SC § X g</td><td>σ \ ο υ Tb d .S</td><td>η glyceryl 9- (2in</td><td>; n glyceryl l- (2in</td><td>; n glyceryl l- (2n</td><td>η glyceryl 9- (2il</td><td>η glyceryl 9- (2- nopurine</td>

<td> ►</td><td>ω X 'sl GD ο.a • -N SL' o</td><td>zyloxyet 2,6-diai</td><td rowspan="2">* - <3 . & ad sl 22444 Ο ο 'G5 8 ο ° Ctf ο</td><td>r> Ό. & Fig. 22444 Ο Q</td><td rowspan="2">* - ± d. & 'O Fig. 224 4 * O o Ή 8 o ° Cđ Q</td><td>5- .D Ο sl ΓΖ3 44 Ό o ω gD</td><td>. & D sl —- <'-β Q _Q G7č 'fig</td><td>iloxipr 2,6-diai</td><td rowspan="2">'ν β d Μ Ο ίΞ? Ξθ · ΰ ό - Φ ο -4— »ι- <Ο</td><td>O-benzyl, ethyl) ad</td><td rowspan="2">yl-2-O-benzyloxyethyl) cit</td><td>0-benzi : sietil) tii</td><td>0-benzyethyl) ur</td><td>0-benzi 2,6-diai</td>

<td></td><td>H-h</td><td>* - »E</td><td>X SL</td><td>X SL</td><td>From fig</td><td>Sl Q</td><td>χ Ε</td><td>Ο fig</td><td>about 7l</td><td>About fig</td><td>° Q</td><td>ο Ε</td>

<td></td><td rowspan="2">galak fos</td><td>eđ, O 00 'tl</td><td>ο, ο F</td><td>ο, ο</td><td>o, o tj cd</td><td>o £</td><td>ο £ 4- »</td><td>ο ο 3 £</td><td>ό £</td><td>ό <2 1</td><td>ό £ 1</td><td>ό 1</td><td>1 ο 1</td><td>1-0fonoi</td>

<td>octadeci</td><td>octadeci</td><td>hexadecyl</td><td>hexadecyl</td><td>hexadecyl</td><td>hexadecyl</td><td>hexadecyl</td><td>hexadecyl</td><td>Di 0 8 μ Ό цđ —ј Ο</td><td>-octadecyl- glyc</td><td>-octadecyl- glyc</td><td>-octadecyl- glyc</td><td>-octadecyl- glyc</td><td>-octadecyl- glyc</td>

57796 V1

Table 2. (R) -phosphonomethoxypropyl [(R) -PMP] diester compound

<td></td><td>(R) - [(2 guanine</td><td>(R) - [(2adenine</td><td>(R) - [(2cytosine</td><td>(R) - [2] thymine</td><td>(R) - [(2-) 1 uracil</td><td>(R) - [(2-) [iaminopurine</td><td>ί 9- (R) - [(2-) Iguana</td><td>L9- (R) - [(2-) adenine</td><td>ί l- (R) - [(2cytosine</td><td>1 £ '| 1— ('ΰ</td>

<td>Name</td><td>adecyloxyethyl9nethoxy) propyl]</td><td>adecyloxyethyl9nethoxy) propyl]</td><td>adecyloxyethylethoxy) propyl]</td><td>adecyloxyethylmethoxy) propyl</td><td>adecyloxyethyl (methoxy) propyl]</td><td>adecyloxyethyl9- si) propyl] 2,6-d</td><td>.decyloxypropyl] non-oxy) propyl</td><td>.decyloxypropyl] letoxy) propyl]</td><td>.decyloxypropyl letoxy) propyl]</td><td>.decyloxypropyl] methoxy) propyl]</td>

57796 Β1

<td></td><td> 1</td><td>d1 '3 *</td><td>ril 9- (R) - η</td><td>ril 9- (R) - n</td><td>ril 1- (R) - n</td><td>ril 1- (R) -</td><td>ril 1- (R) - [</td><td>ril 9- (R) apurine</td><td>'fig Ο -4- »Ο g</td><td>'sl 44 Ο 4- »Q 3</td><td>'sl 44 Ο 4- »Q 3</td><td>'sl 44 O 4- »Q 3</td><td>'sl 44 Ο 4- »Q 3</td><td>'sl 44 Ο 4- »Q 3</td><td>I CN</td>

<td></td><td>1- (R) - [uracil</td><td>A ° § 04 sZ</td><td>η glyce] guani</td><td>n glyce] adeni</td><td>o 'JS .U o · - <-4—> ad'3 C 1 ---- 1</td><td>n glice ljtimin</td><td>n glice ljuraci]</td><td>η glyce diamines</td><td>ο α <2 SL ο</td><td>ο C £ SL ο</td><td>ο C £ SL ο</td><td>oc £ sl o</td><td>ο C £ SL ο</td><td>ο c (S d ο ΐ</td><td rowspan="2">> il 9- (R) - [(liguanin</td>

<td>Name</td><td>, β = β, fig =) 4 'SJ J2 '3 2</td><td>sl G73 44 £ 2 3 ^ ·</td><td>-2-O-ben: ethoxy) ex</td><td>-2-O-ben: ethoxy) ex</td><td>-2-O-ben: ethoxy) ex</td><td>-2-0-ben: netoxy) p</td><td>2-0-ben: thietoxy) p</td><td>S ZZ1 Q GTh X ο. -Λ ο 9 Κ MS</td><td>Α § Ο οι σχ gd -Η Ο.</td><td>11 9- (R) - [• pil] aden</td><td>11 1- (R) - [ipyl] cytosis</td><td>il l- (R) - [opiljtimii</td><td>11 l- (R) - [sawdust</td><td>11 9- (R) - [ , 6-diamir</td><td>ο ο Γ-! -ι &1 & 'sl = -> 44 ϊλ Ρ3 Ο</td>

57796 Β1

<td></td><td>9- (R) - [(2-adenine</td><td>1- (R) - [(2cytosine</td><td>1- (R) - [(2-) Jtimin</td><td>1- (R) - [(2-) Juracil</td><td>9- (R) - [(2iaminopurine</td><td>n glyceryl 9- (R) - ljguanin</td><td>n glyceryl 9- (R) - ljadenin</td><td>n glyceryl 1- (R) - 1] cytosine</td><td>n glyceryl 1- (R) yltimine</td><td>n glyceryl 1- (R) - iljuracil</td><td>n glyceryl 9- (R) diaminopurine</td><td>R) - [(2 guanine</td><td>R) - [(2adenine</td><td>R) - [(2cytosine</td><td>R) - [(2thymin</td>

<td>> 'S</td><td>0 0 £ + O2 o. &1SL / —s</td><td>: 0 0 C4 & OO (- <Si. & & 'sl / -></td><td>Zl 2 2 sl -rt</td><td>P- g 2 SL -1-I</td><td>sipropyl pil] 2,6-d</td><td>benzyl-s csi) propi</td><td rowspan="2">-2-O-benzyl-s ricoxy) propyl</td><td>SL »- ( ,. o. G73 O S il C C- Q</td><td>sl p. Λ O GD ίΗ N P. C Q sl -φ</td><td>benzyl-s xy) prop</td><td>benzyl-opyl] 2,6-</td><td>σχ: 0 11 SL</td><td>σχ: 0 & 0 £ 2 & sl 'U</td><td>_ '2 0 ο 2 2 SL</td><td>sethyl 1- ( i) propyl]</td>

<td>ζ</td><td> 5 94 2 2</td><td>94 fig 5 94 2 1</td><td>44 S 2 • 1- * -4— » υ cj</td><td>44 J2 0 2 υ о</td><td>44 o rg & Q</td><td>-2-0netol</td><td>-2-0nctok</td><td>§ 9 <N g</td><td>-2-0meto</td><td>A * O <Ν Έ</td><td>44 fig q 44: 0 o υ «</td><td>fig About 94</td><td>94 fig .2</td><td>44 S 2 • i- (-4- » υ о</td>

<td></td><td>Ό £ ctf § sl U C Q & G- <(4-1</td><td>ο § »2 44 6 2 2 D— fig</td><td>Ό 0 cđ 2 sl C 44 t2 Q 4 = o</td><td>-rt C ao sl D 44, Ο Q 1 + -1 4 = $</td><td>sl U -4— »9 ^ o Q t—14 = E</td><td>QC 2 o Ό 4h ctf sl 44 2</td><td>Ć-> D 2 +2 Ό <+ č ctf sl 4- »Ο</td><td>υ g QC 2 £ sl 2 2</td><td>'υ £ 2 £ 3 2 44 Ύ</td><td>'ogo fo 'rt <* “* z sl 2 2 44' V</td><td>8 3 w ε 2 years</td><td>Ό g Λ ο 4 “» Φ Ε Ο r ° (4- ( SL</td><td>ό Ez 5 ο 2 0 ο 2 —Η SL</td><td>2 Š 3 2 5 Ο rO (4- (· - <SL</td><td>Ό E sz o tž c 94 o O ¢ 9 ___, fig</td>

<td></td><td></td><td>- <, O</td><td></td><td> 2</td><td>- Fr.</td><td>Oh 1</td><td></td><td>Ο ι</td><td>About CN</td><td>About SC</td><td>O o</td><td>'0 .Ο</td><td> 0 0</td><td>0 .ο</td><td></td>

<td>s Z</td><td>O \ 1</td><td> 1</td><td></td><td>Α</td><td>About _</td><td>o \ 1</td><td>o \ 1</td><td> 1</td><td></td><td> 2</td><td>Ο</td><td>αχ</td><td>ο \ 1</td><td> 1</td><td></td>

57796 ΒΙ

<td></td><td>1 SC ΓΞ X Ο</td><td>α c ο & Ć g</td><td>) - [(2- ηϊη</td><td>1 sch X d Α '2</td><td>and s α 5</td><td>1 MS V β</td><td>1 pc Α υ</td><td>) - [(2inopurine</td><td>O \ ΐ b S υ ο</td><td>ceryl 9- (R) - lenin</td><td>ceryl 1- (R) - tozin</td><td>ceryl 1- (R) - min</td><td>ceryl 1- (R) - racil</td><td>iceryl 9- (R) ninouxine</td><td>R) - [(2-) nin</td>

<td></td><td>ethyl 1- (R) - [) propyl] ura</td><td>ethyl 9- (R) - | 1] 2,6-diam</td><td>propyl 9- (R propylgua</td><td>propyl 9- [R propyl] ade</td><td>propyl 1- [R propyl] citc</td><td>cd § Ό βί & sh. 2 2 & Ο-</td><td>propyl 1- (R) propyl</td><td>οί E V .3 o \ Ο <Ν »-I ΞΞ1 SH ΓΟ</td><td>S S. L ο N Ο β .Ο</td><td>enzil-sn gli si) propyl] ad</td><td>enzil-sn gli ii) propyl] ci</td><td rowspan="2">, -O-benzyl-sn or nontoxy) propyl] ti</td><td>enzil-sn gli; si) propyl] ui</td><td>'oc 0 c tz T cho 8 g-</td><td>oxyethyl 9- (l propylgua</td>

<td>N Ζ</td><td>sl -w 44 š. = O</td><td>SL 'D 5Z Q. OS</td><td></td><td>SL 'Zh' 44 "</td><td>sl sl °%</td><td>SL SL 5 2</td><td>FIG 0 o</td><td>loksi prop</td><td>Ο -2 ί ω</td><td> 4? 44 0 2 \ 2</td><td>1 'i About 2 1 o</td><td>1 0 0 ΰ L d</td><td>9 D</td><td>υ U 44 Ό O</td>

<td></td><td>Ό 2 cd O</td><td>—J fig</td><td>o d o S</td><td>About C2 3 ₽</td><td>E</td><td>ω Ο Ό Ο</td><td>2 2 o</td><td>Ο fig Ό 44</td><td>ο 'υ g</td><td>р — ј О 'o 2</td><td>OQC</td><td>γξ e ο η</td><td>Ί7 c</td><td rowspan="2">75 2 _O Q</td><td>EO r></td>

<td></td><td>Oh O <+ h</td><td>5Ζ m- » ° ε</td><td>Fig. C 44, Ο Q ι + h</td><td>SL CO Q ĆZ</td><td>sl č o Q sD</td><td>sl D Q fig</td><td>sl D <4-4</td><td>SL 2 Ο £</td><td>'rt .ο</td><td>-rt 53, 0</td><td>* rt <4—</td><td>β SS «2</td><td>Ό ctf fQ</td><td rowspan="2">g E 2 years ? 1 Ο τϊ IO</td><td>G7h D N, Ο</td>

57796 Β1

<td></td><td>'^ Oč Q Q_</td><td>3 3 ω ο.</td><td>'£ Ο- .22 ο</td><td>.3 ο</td><td>'-L Q \ O</td><td>about 3 k & &1 o</td><td>About rp &1 Ο</td>

<td></td><td>ο ¢ 5 - ^ - »&</td><td>ο ¢ 5 4- »fig</td><td>ο SL 'Η Ο</td><td>Ο SL</td><td>About 6 r></td><td>Ν <£</td><td>Ν “</td>

<td>- (R) - [zin</td><td>and c</td><td>I S? 2</td><td>- (R) - [inopu</td><td>sn gli (guanii</td><td>00 β β -ΰ T D</td><td>sn gli (cytosis</td><td>sn gli (] thymine</td>

<td>pil 1 Jcito</td><td>'· ^ Λ ”</td><td>cd JH G73 3 Ο.</td><td>pil 9 iiam</td><td>N O. β O</td><td>S & I k</td><td>Ν C n</td><td>SS</td>

<td>About GD</td><td>ο 'o.</td><td></td><td>o t</td><td>Q 1n</td><td></td><td>Q g</td><td>Q 5_</td>

<td>'Ć «ć</td><td>sl Π</td><td>SL ο.</td><td></td><td>0 'g</td><td rowspan="2">2 2 r ^ O</td><td>About fig</td><td>o £</td>

<td>xadeci imctox</td><td>ύ ο q ctf r ^ sl G 44 Ο</td><td>'ύ ·% ο ο ”2 ω sg Ο</td><td>'3 £ Q Octf SL 44 44</td><td>(U υ β Q 5 S β E 4- », O 44 Vi</td><td>o E Ό O β β 5 3 About fig</td><td>G7č Q 8 2 Ό Ο cđ β S £</td><td>ss (U o Ό β β 3 cn</td>

57796 Β1

57796 V1

Table 3. (S) -3-Methoxy-2-phosphonomethoxypropyl [(S) -MPMP] compound diester

<td>Name</td><td>benzyl octadecyloxyethyl 9- (S) - [(3-methoxy-2-phosphonomethoxy) propyl] guanine</td><td>benzyl octadecyloxyethyl 9- (S) - [(3- methoxy-2- phosphonomethoxy) propyl] adenine</td><td>benzyl octadecyloxyethyl 1- (S) - [(3-methoxy-2-phosphonomethoxy) propyl] cytosine</td><td>benzyl octadecyloxyethyl 1- (S) - [(3-methoxy-2-phosphonomethoxy) propyl] thymine</td><td>benzyl octadecyloxyethyl 1- (S) - [(3- methoxy-2- fo s phonomethoxy) propyl] uracil</td><td>benzyl octadecyloxyethyl 9- (S) - [(3methoxy-2-phosphonomethoxy) propyl] 2,6diaminopurine</td><td>benzyl hexadecyloxypropyl 9- (S) - [(3- methoxy-2-</td>

<td>CQ sž</td><td>benzyl</td><td>benzyl</td><td>benzyl</td><td>benzyl</td><td>benzyl</td><td>benzyl</td><td>benzyl</td>

<td>l</td><td>octadecyloxyethyl</td><td>octadecyloxyethyl</td><td>octadecyloxyethyl</td><td>octadecyloxyethyl</td><td>octadecyloxyethyl</td><td>octadecyloxyethyl</td><td>hexadecyloxypropyl</td>

<td>s '«. sz with Z 03</td><td>guanine-9-yl</td><td>adenin-9-yl</td><td>cytosine-1-yl</td><td>thymine-l-yl</td><td>uracil-l-yl</td><td>2,6-diamino-purine 9-il</td><td>guanine-9-yl</td>

57796 Β1

<td>Name</td><td>phosphonomethoxy) propyl] guanine</td><td>benzyl hexadecyloxypropyl 9- (S) - [(3-methoxy-2-phosphonomethoxy) propyl] adenine</td><td>benzyl hexadecyloxypropyl 1- (S) - [(3-methoxy-2-phosphonomethoxy) propyl] cytosine</td><td>benzyl hexadecyloxypropyl 1- (S) - [(3-methoxy-2-phosphonomethoxy) propyl] thymine</td><td>benzyl hexadecyloxypropyl 1- (S) - [(3-methoxy-2-phosphonomethoxy) propyl] uracil</td><td>benzyl hexadecyloxypropyl 9- (S) - [(3-methoxy-2-phosphonomethoxy) propyl] 2,6-diaminopurine</td><td>benzyl 10-octadecyl-2-O-benzyl-sn glyceryl 9- (S) - [(3-methoxy-2-phosphonomethoxy) propyl] guanine</td><td>benzyl 10-octadecyl-2-O-benzyl-sn glyceryl 9- (S) - [(3-methoxy-2-phosphonomethoxy) propyl] adenine</td><td>benzyl 10-octadecyl-2-O-benzyl-sn glyceryl 1- (S) - [(3-methoxy-2H-phonomethoxy) propyl] cytosine</td><td>benzyl 10-octadecyl-2-O-benzyl-sn glyceryl 1- (S) -L (3-methoxy-2H-phonomethoxy) propyl] thymine</td><td>benzyl 10-octadecyl-2-O-benzyl-sn glyceryl 1- (S) - [(3-methoxy-2-</td>

<td>CQ Ρύ c2</td><td></td><td>benzyl</td><td>benzyl</td><td>benzyl</td><td>benzyl</td><td>benzyl</td><td>benzyl</td><td>benzyl</td><td>benzyl</td><td>benzyl</td><td>benzyl</td>

<td>Λ nJ</td><td></td><td>hexadecyloxypropyl</td><td>hexadecyloxypropyl</td><td>hexadecyloxypropyl</td><td>hexadecyloxypropyl</td><td>hexadecyloxypropyl</td><td>10-octadecyl-2-O-benzyl glyceryl</td><td>10-octadecyl-2-O-benzyl glyceryl</td><td>10-octadecyl-2-O-benzyl glyceryl</td><td>10-octadecyl-2-O-benzyl glyceryl</td><td>10-octadecyl-2-O-benzyl glyceryl</td>

<td>s Z s Z 03</td><td></td><td>adenin-9-yl</td><td>cytosine-1-yl</td><td>thymine-l-yl</td><td>uracil-l-yl</td><td>2,6-diamino-purine 9-il</td><td>guanine-9-yl</td><td>adenin-9-yl</td><td>cytosine-1-yl</td><td>thymine-l-yl</td><td>uracil-l-yl</td>

57796 Β1

<td>Name</td><td>fo s phonomethoxy) propyl] uracil</td><td>benzyl 10-octadecyl-2-O-benzyl-sn glyceryl 9- (S) - [(3-methoxy-2-phosphonomethoxy) propyl] 2,6-diaminopurine</td><td>phenyl octadecyloxyethyl 9- (S) - [(3-methoxy-2-phosphonomethoxy) propyl] guanine</td><td>phenyl octadecyloxyethyl 9- (S) - [(3- methoxy-2- phosphonomethoxy) propyl] adenine</td><td>phenyl octadecyloxyethyl 1- (S) - [(3- methoxy-2- fo s phonomethoxy) propyl] cytosine</td><td>phenyl octadecyloxyethyl 1- (S) - [(3- methoxy-2- fo s phonomethoxy) propyl] thymine</td><td>phenyl octadecyloxyethyl 1- (S) - [(3- methoxy-2- fo s phonomethoxy) propyl] uracil</td><td>phenyl octadecyloxyethyl 9- (S) - [(3-methoxy-2-phosphonomethoxy) propyl] 2,6-diaminopurine</td><td>phenyl hexadecyloxypropyl 9- (S) - [(3- methoxy-2- phosphonomethoxy) propyl] guanine</td><td>phenyl hexadecyloxypropyl 9- (S) - [(3- methoxy-2- phosphonomethoxy) propylladenine</td>

<td>CQ Ρύ c2</td><td></td><td>benzyl</td><td>phenyl</td><td>phenyl</td><td>phenyl</td><td>phenyl</td><td>phenyl</td><td>phenyl</td><td>phenyl</td><td>phenyl</td>

<td>Λ +</td><td></td><td>10-octadecyl-2-O-benzyl glyceryl</td><td>octadecyloxyethyl</td><td>octadecyloxyethyl</td><td>octadecyloxyethyl</td><td>octadecyloxyethyl</td><td>octadecyloxyethyl</td><td>octadecyloxyethyl</td><td>hexadecyloxypropyl</td><td>hexadecyloxypropyl</td>

<td>'«H sz s Z m</td><td></td><td>2,6-diamino-purine 9-il</td><td>guanine-9-yl</td><td>adenin-9-yl</td><td>cytosine-1-yl</td><td>thymine-l-yl</td><td>uracil-l-yl</td><td>2,6-diamino-purine 9-il</td><td>guanine-9-yl</td><td>adenin-9-yl</td>

57796 Β1

C fig

Γ4*

57796 Β1

<td>Name</td><td>ethyl octadecyloxyethyl 9- (S) - [(3- methoxy-2- phosphonomethoxy) propyl] guanine</td><td>ethyl octadecyloxyethyl 9- (S) - [(3- methoxy-2- phosphonomethoxy) propyl] adenine</td><td>ethyl octadecyloxyethyl 1- (S) - [(3-methoxy-2-phosphonomethoxy) propyl] cytosine</td><td>ethyl octadecyloxyethyl 1- (S) - [(3- methoxy-2- fo s phonomethoxy) propyl] thymine</td><td>ethyl octadecyloxyethyl 1- (S) - [(3- methoxy-2- fo s phonomethoxy) propyl] uracil</td><td>ethyl octadecyloxyethyl 9- (S) - [(3-methoxy-2-phosphonomethoxy) propyl] 2,6-diaminopurine</td><td>ethyl hexadecyloxypropyl 9- (S) - [(3-methoxy-2-phosphonomethoxy) propyl] guanine</td><td>ethyl hexadecyloxypropyl 9- (S) - [(3-methoxy-2-phosphonomethoxy) propyl] adenine</td><td>ethyl hexadecyloxypropyl 1- (S) - [(3- methoxy-2- fo s phonomethoxy) propyl] cytosine</td><td>ethyl hexadecyloxypropyl 1- (S) - [(3-methoxy-2-phosphonomethoxy) propyl] thymine</td>

<td>Λ</td><td>octadecyloxyethyl</td><td>octadecyloxyethyl</td><td>octadcycloxyctyl</td><td>octadecyloxyethyl</td><td>fig O '5 Ό cd č— » Oh</td><td>fig O '5 Ό h— » o</td><td>hexadecyloxypropyl</td><td>hexadecyloxypropyl</td><td>hexadecyloxypropyl</td><td>hexadecyloxypropyl</td>

<td>s Z s Z m</td><td>guanine-9-yl</td><td>adenin-9-yl</td><td>cytosine-1-yl</td><td>thymine-l-yl</td><td>1 1 υ cd d</td><td>2,6-diamino-purine 9-il</td><td>guanine-9-yl</td><td>adenin-9-yl</td><td>cytosine-1-yl</td><td>thymine-l-yl</td>

57796 ΒΙ

57796 ΒΙ

<td>Name</td><td>galactosyl octadecyloxyethyl 1- (S) - [(3-methoxy-2-phosphonomethoxy) propyl] cytosine</td><td>galactosyl octadecyloxyethyl 1- (S) - [(3-methoxy-2-phosphonomethoxy) propyl] thymine</td><td>galactosyl octadecyloxyethyl 1- (S) - [(3-methoxy-2-phosphonomethoxy) propyl] uracil</td><td>galactosyl octadecyloxyethyl 9- (S) - [(3-methoxy-2-phosphonomethoxy) propyl] 2,6-diaminopurine</td><td>galactosyl hexadecyloxypropyl 9- (S) - [(3-methoxy-2- phosphonomethoxy) propyl] guanine</td><td>galactosyl hexadecyloxypropyl 9- (S) [(3-methoxy-2-phosphonomethoxy) propyl] adenine</td><td>galactosyl hexadecyloxypropyl 1- (S) [(3-methoxy-2-phosphonomethoxy) propyl] cytosine</td><td>galactosyl hexadecyloxypropyl 1- (S) - [(3-methoxy-2- fo s phonomethoxy) propyl] thymine</td><td>galactosyl hexadecyloxypropyl 1- (S) [(3-methoxy-2-phosphonomethoxy) propyl] uracil</td><td>galactosyl hexadecyloxypropyl 9- (S) - [(3-methoxy-2phosphonomethoxy) propyl] 2,6-diaminopurine</td>

<td>CQ Ρύ c2</td><td>galactosyl</td><td>galactosyl</td><td>galactosyl</td><td>galactosyl</td><td>Ή o 4- »tZ 73 ed</td><td>'no -4- » 7Š 73 oc</td><td>galactosyl</td><td>galactosyl</td><td>galactosyl</td><td>galactosyl</td>

<td>Λ</td><td>octadecyloxyethyl</td><td>octadecyloxyethyl</td><td>octadcycloxyctyl</td><td>octadecyloxyethyl</td><td>2 Fig. 34 Ο '5 Q Ό ctf Fig. 34 Q 33</td><td>'C4 2 Fig. 34 Ο 73 ο Ό SL 34 Ο 33</td><td>hexadecyloxypropyl</td><td>hexadecyloxypropyl</td><td>hexadecyloxypropyl</td><td>hexadecyloxypropyl</td>

<td>s Z s Z m</td><td>cytosine-1-yl</td><td>thymine-l-yl</td><td>uracil-l-yl</td><td>2,6-diamino-purine 9-il</td><td>I 1 .С с ad</td><td>I Ο \ 1 .S D ο Ό</td><td>cytosine-1-yl</td><td>thymine-l-yl</td><td>uracil-l-yl</td><td>2,6-diamino-purine 9-il</td>

57796 Β1

<td>Name</td><td>galactosyl 10-octadecyl-2-O-benzyl-sn glyceryl 9- (S) - [(3-methoxy-2phosphonomethoxy) propyl] guanine</td><td>galactosyl 10-octadecyl-2-O-benzyl-sn glyceryl 9- (S) - [(3-methoxy-2phosphonomethoxy) propyl] adenine</td><td>galactosyl 10-octadecyl-2-O-benzyl-sn glyceryl 1- (S) - [(3-methoxy-2phosphonomethoxy) propyl] cytosine</td><td>galactosyl 10-octadecyl-2-O-benzyl-sn glyceryl 1- (S) - [(3-methoxy-2-phosphonomethoxy) propyl] thymine</td><td>galactosyl 10-octadecyl-2-O-benzyl-sn glyceryl 1- (S) - [(3-methoxy-2fo with phonomethoxy) propyl] uracil</td><td>galactosyl 10-octadecyl-2-O-benzyl-sn glyceryl 9- (S) - [(3-methoxy-2phosphonomethoxy) propyl] 2,6-diaminopurine</td>

<td>CQ Ρύ c2</td><td>galactosyl</td><td>galactosyl</td><td>galactosyl</td><td>galactosyl</td><td>Ή o + - »</td><td>galactosyl</td>

<td>Λ +</td><td>10-octadecyl-2-O-benzyl glyceryl</td><td>10-octadecyl-2-O-benzyl glyceryl</td><td>10-octadecyl-2-O-benzyl glyceryl</td><td>10-octadecyl-2-O-benzyl glyceryl</td><td>10-octadecyl-2-O-benzyl glyceryl</td><td>10-octadecyl-2-O-benzyl glyceryl</td>

<td>'«H sz s Z m</td><td>guanine-9-yl</td><td>adenin-9-yl</td><td>cytosine-1-yl</td><td>thymine-l-yl</td><td>1 1 υ cd μD</td><td>1 cc 04 1 o S Ύ g σ \ -v 1 sch</td>

57796 V1

Table 4. (S) -3-Hydroxy-2-phosphonomethoxypropyl [(S) -HPMP] diester compound

<td></td><td> 04 73 2</td><td>U -S</td><td rowspan="2">04 »-4 Ό .5 d Ν ι Ο ΠΊ 03</td><td>0-1 rg d</td><td rowspan="2">9 oz 2 years σ-> z</td><td>2 S</td><td>) - [ι gu</td><td>) - [! ad</td><td>Α υ</td>

<td></td><td>Ό e υ 2 Q Ο</td><td>tadecil isfonor</td><td>-— ο υ 2 ο Ο</td><td>X ο υ s Ό Λ Ч- »Ο</td><td>o g ω o d « cš sl</td><td>03 Ο ο Ό U Λ Ε</td><td>Ό <+ h Λ SL sl Ο 24 <7</td><td>¢ ¢ 3 ί ί sl Ο 24 Τ '</td><td>Ό <+ h Λ SL sl Ο 24 'V</td>

57796 Β1

57796 Β1 ►

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57796 Β1

<td rowspan="2"></td><td rowspan="2">-benzyl-sn glyceryl oxy-2- ropiljuracil</td><td rowspan="2">-benzyl-sn glyceryl raxy-2- 2,6-diaminopurine</td><td rowspan="2">S) - [(3-hydroxy-2- opiljguanin</td><td rowspan="2">S) - [(3-hydroxy-2- Opiljadenin</td><td rowspan="2">S) - [(3-hydroxy-2- Opiljcitosin</td><td rowspan="2">S) - [(3-hydroxy-2-propyl] thymine</td><td rowspan="2">S) - [(3-hydroxy-2-propyluracil</td><td rowspan="2">S) - [(3-hydroxy-2- 2,6-diaminopurine</td><td rowspan="2">opyl 9- (S) - ((3xy) propyl] guanine</td><td rowspan="2">opyl 9- (S) - ((3xy) propyl] adenine</td><td rowspan="2">opyl 1- (S) - ((3xy) propyl] cytosine</td><td rowspan="2">opyl 1- (S) - [(3-oxy) propyl] thymine</td><td rowspan="2">opil 1- (S) - [(3- ixi) propyl] uracil</td><td colspan="3"> , £ (2,</td>

<td>N Ζ</td><td>£ 3 1 '44 gd <t> ο j A c</td><td>O \ 't? —SL Ζ3 44 Ε 2 sl Ο</td><td>o> - <fig 3 ο sl Ο</td><td>sythyl 1 ethoxy)</td><td>'fig 7 o Q -7 Q sl <- <</td><td>sl G7 44 £ 2 'S g</td><td>04 -C: β ο ί- »X ο σχ fig</td><td>Q £ soo go co, o</td><td>£ 3 β ο, ο</td><td>Q ssoo go co, o</td><td>SL 7 1 υ £</td><td>fig 44 'u</td><td>Ε ο α £</td><td>ο 7 cd</td>

<td></td><td>ΐΐ 1-0 fos</td><td>the 1-0 background</td><td>Ό sl £ £ 44 Ο</td><td>-ο £ cd Ο 4—> CL 44 Ο</td><td>o £ £ 44 O</td><td>o O 44 O</td><td>Ό “ 2 £ 44 Oh</td><td>Ό Ε ctf Ο £ ο ο £</td><td>Ο ί -7 £ OQC</td><td>Ι ι g7 sl ΰ ο Ο 5-1</td><td>Ο ι -7 £ OQC</td><td>Q .Λ 3 * Q</td><td>ο .L 3 3 3 S</td><td>Q 'ΰ Q</td><td>SL 44 Ο ΙΌ</td><td></td>

<td></td><td rowspan="2">8 ad Ό ctf</td><td rowspan="2">8 Ό 7</td><td>73 Ό Ό ctf</td><td>73 Ό Ό ctf</td><td>73 Q Ό 7</td><td>73 Q Ό 7</td><td>tadeci</td><td>73 Q Ό ctf</td><td>'u ο Ό Λ</td><td>'3 Q Ό Λ</td><td>'3 Q Ό sZ</td><td>'3 Q Ό Λ</td><td>'3 ο Ό Λ</td><td></td><td>'3 ο Ό 7</td><td></td>

57796 Β1

<td></td><td>ΐ Q</td><td>ΐ ο</td><td>ΐ Q</td><td>ΐ Q</td><td>ΐ ο</td><td>crril urine</td><td>S1 '2 sZ</td><td>S <9> §</td><td>. .2 CO S</td><td>.2 CO '2</td><td>1 υ</td><td>1 ΓΌ</td><td colspan="2"> 1 40</td>

<td></td><td>C cd τ I = 3 Λ CN or S -9 7? ο 44 ο.</td><td>I ° ι 1 χ MS D 'S 03 § AŽ &</td><td>5— SL -4- » В сч '3 S -Λ 2Z1 C sl XO 44 С.</td><td>β Ε sl Η £ <Ν '-, Ν .n β ο 44 ο</td><td>£ £ £, Ν -Λ 03 S »ο. ο 44 θ</td><td>sl N l 1 S £ eč £ S .Λ Ό jM 4</td><td>V & 04 2 X P. 4- »Z —- 4 X fig</td><td>- k £ D</td><td>ρ. ', ο 5X & X .X4 Q fig</td><td rowspan="2">iloxyethyl l- (non-oxy) prop</td><td>V Ο \ XQ</td><td>0 Yes Fig. 44</td><td>Ρ X</td>

<td rowspan="2">► Ν Λ</td><td>X) g ο1 Η + h 0 ^ 5 LX</td><td rowspan="3">yl-2-O (3-hydroxy) oxy</td><td>χξ 2 °1 N + h Ο 9 Β L 44 -> n</td><td>χ> 2 2 Ο £ 77 I η SL</td><td>χ> 2 Ο £ .77 ', DZ fig</td><td>Α ε <Ν Ο oz £ f £ £ Ο-</td><td>s 44 ο 44 q</td><td>0 £ S</td><td>FIG £ £ Q</td><td>sl η * Ο U Ε</td><td>SL 4ί , Ο</td><td>o -4- »O 2</td><td>β ο. ο</td>

<td></td><td>υ χ χ</td><td rowspan="2">ktadec ? - (S) - [) nomet</td><td>υ χ -9</td><td>υ 1—1 ο</td><td>υ χ ω</td><td> £</td><td>ctf S</td><td>β β</td><td>C3 3</td><td>ctf 0</td><td>ctf</td><td>X</td>

<td></td><td>ktade 9- (S) - name</td><td>ktade 1- (S) - name</td><td>ktade 1- (S) onom</td><td>u Α c β ° £ £ §</td><td>Ίύ sl J2 £ X 2</td><td>4— ». '- “ί SL ° tS ^ n 4h ι— <1</td><td>χ ° £ • iH 1</td><td>££ Ο sl 3 £</td><td rowspan="2">• 4_j <- (- 44 π Ο u X £ ς1</td><td rowspan="2">44 sl o 0</td><td>• 4— » 44 Ο</td><td>fig £ sch</td><td>X</td>

<td></td><td>ο χ</td><td>About sD</td><td>OX</td><td>0 χ</td><td>Q Čn</td><td></td><td>Ν (Ν</td><td>С СЧ</td><td>Ν 7,</td><td>s</td><td></td><td></td>

<td></td><td>I ^ t-h</td><td rowspan="2">In FIG θ £ I ^ 4-n</td><td>1 <-m</td><td>1 £</td><td>and fig</td><td rowspan="2">1-0 οηοπ</td><td>D) 1</td><td>About i(</td><td>of CN</td><td>Ο · Λ</td><td>o h</td><td> 0</td><td></td><td></td>

<td></td><td>the village 1 X</td><td>os</td><td> 0 <3 1</td><td>ο £</td><td>• 4_j ιΗ \> SL</td><td>X fig</td><td> 4-» §</td><td>¢ 2 CZ 1 Ο</td><td>3 O</td><td> •4—»</td><td>44 Ο 1-</td><td></td>

57796 Β1

αο □η □ 4 η ο

η η

* + t η

-X00 η *

η * ΓΟΟ η *

57796 V1

Table 5. (S) -3-Fluoro-2-phosphonomethoxypropyl [(S) -FPMP] diester compound

<td>N</td><td></td><td></td><td></td><td></td><td> ι +</td><td>Ο .77</td><td>About 77</td>

<td>z</td><td>Q SL 'S 44 o u</td><td>ethoxy oxide</td><td>Q SL 'S 44 ^ -> O 02</td><td>.2 44 <l o 44 * iq ο</td><td>2 sl Q C> + j o 2</td><td>.2 ο sl Ϊ + 44 Ο <ο .77</td><td>g 'sl Ο' ο “</td><td>fig . & L4 z / i Q</td>

57796 Β1

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<td></td><td>1 ε</td><td>«2 £ 6 ρ ο</td><td>44 ο £ β The G5</td><td>44 o O fig</td><td>'. o gr <44 Q sl Q, O</td><td>-4, Ο gr 9- < Ο sl Ο, ο</td><td>o gr <44 CJ sl o, O</td><td>About Mr. Q 2</td><td>l <2 'G1 ™ Q 2</td><td>ecil-fosl dia</td><td>£ Q b</td><td>£ £ b</td><td>£ ο</td><td>£ a £ δ ΓΡ ο</td><td>£ ω £ 6</td>

<td></td><td>Q Nč 44 'n Ρ</td><td>Q 44 'δ Ρ</td><td>Ο 44 'ν Ρ</td><td>Q c 43 £ fig</td><td>zil 1-0 [(3-fluc</td><td>zil 1-0 [(3-fluc</td><td>zil 1-0 [(3-fluc</td><td>zil 1-0 [(3-flu <</td><td>zil 1-0 [(3-flu</td><td>ο α 1 'n</td><td>fcnil o f</td><td>phenyl o f</td><td>phenyl ο f</td><td>phenyl ο</td><td>phenyl ο</td>

57796 ΒΙ

<td></td><td></td><td>1 pc 2</td><td>1 pc 2</td><td>1 pc 2</td><td>1 CN 2</td><td>1 MS 2</td><td>1 MS 2 -c</td><td>1 SC 1</td><td rowspan="2">? .s 04 C -Η ϋ 11</td><td>1- (S) ozine</td><td>1- (S) nin</td><td>1- (S) - acyl</td><td>1 1 04 4D</td><td>I MS</td><td>CN</td>

<td></td><td>) - [(3.) -diar</td><td>A 3)</td><td></td><td>(S) - [iljcit</td><td>1 SG 77</td><td>Σ δ s / u 53</td><td>(S) - [ -diar</td><td>_Γ Ο s k sl &</td><td>α ο SL ^ * 0</td><td>7 ο c k sl &</td><td>l-sn; si) pr</td><td>1-sn; si) pr <</td><td>1-sn; ; si) pi 1</td><td>1 3 C2 S 7</td><td>Λ Μ</td>

<td rowspan="2">> 'S</td><td>CZJ 40</td><td>04 o 0 k d</td><td>'O04 Q ---- Ol Ή, / 5;</td><td>·, Α ο 0 '04 D</td><td>D ο ο ο: & 04 .77</td><td>1 & Ο __, Ο 03 & 04</td><td>-3 Ξ 09 'C4 03</td><td>benz ethox</td><td>Ν Ο Ο ω 2</td><td>benz ethox</td><td>benzi netok</td><td>benzi aetoki</td><td>benzi Tictok jpurir</td><td>Ο 04 D</td><td>ο ι 0 Ο></td>

<td>£ 3 & About Mr. . i— <0</td><td>b,</td><td>£ S4</td><td>δ,</td><td>Ο « 04 Ο</td><td>Ο fig 0 34 C3 ο</td><td>Ο 04 Ο Ο 04 ο</td><td>ό S 0 o</td><td>D 2 Ο ο</td><td>0 9 0 ο</td><td> 9 §</td><td> ' 0 9 §</td><td>ό г §</td><td> 1</td><td>7i 7λ “Ή</td>

57796 Β1

<td></td><td>fluoro-2- ozin</td><td>fluoro-2- nin</td><td>1 pc I so o2 D υ rr ^ ctf</td><td>С г§1 сд Е</td><td>3-fluoro-2- anin</td><td>3-fluoro-2- enin</td><td>3-fluoro-2- ozin</td><td>Z-Piogo-2- you</td><td>sch έ ο ο ¢ 2 021 U <τ> sa</td><td>Z-Piogo-2ninopurine</td><td>liceril 9- (S) pil] guanine</td><td>liceril 9- (S) ipiljadcnin</td><td>lyceryl 1- (S) pyl] cytosine</td><td>lyceryl 1- (S) □ piljtimin</td><td>liceryl 1- (S) jpiljuracil</td>

<td></td><td>1- (S) - [(3-propylcite</td><td>i- (S) - [(3-) ) propyl] tii</td><td>1- (S) - [(3-i ) propyl] ur</td><td rowspan="2">cA, g Ό 1 1 \ o iSn 1 F — 1 O GR Q.</td><td>ϋ β A & o2 V β 04 g 02 »</td><td>il 9- (S) - [ipropyl</td><td>X— '-4— »D 02 V 22 O 02 22</td><td>L · —1 IO μ ^ - * d</td><td>μ ^ V D1 ο (Η ο.</td><td rowspan="2">ViV v 04 f \ f 22 Q.</td><td>enzil-sn g Jtoxy) pro</td><td>enzyl-sn g ethoxy) prc</td><td rowspan="2">benzyl-sn g ethoxy) pro</td><td>enzyl-sn g ethoxy) pr</td><td>ad s β Λ SL .rH 1 sl gd N O S ** S 0</td>

<td>Λ Ζ</td><td>Ο</td><td>Ο O</td><td>QO</td><td>2 .a k</td><td>About fig c 22 Ο</td><td>About fig</td><td>About fig & * 22 O</td><td>O l 2</td><td>2 & λ £</td><td>2 o & &</td><td>l c ° 2 1 h</td><td>9 g</td><td>A « ° S</td><td>the §</td><td>Α о 9 β</td>

<td></td><td>11 octadecik phosphonors</td><td>il octadecyk phosphonoi</td><td>the octadecyl phosphonoi</td><td>the octadecyl sfonometok</td><td>hexadecyl phosphonors</td><td>hexadecyl phosphonor</td><td>hexadecyl phosphonors</td><td>hexadecyl phosphonoi</td><td>Ο Τ> s ο 2 Ό sl ctf fOh SL ¢ -1- (44 ο 42</td><td>hexadecyl sfonometok</td><td>-O-octades fluoro-2-foi</td><td>-O-octades -fluoro-2-fo</td><td>-O-octades fluoro-2-phos</td><td>-O-octades 1-fluoro-2-fc</td><td>-O-octades -fluoro-2-fc</td>

57796 Β1

<td rowspan="3">Name</td><td>with 1 g</td><td>o X ^ 4 4- »Q_ Q D></td><td>. about XX O. q 4 =></td><td>ο X »-4 4-» Ο. Ο ζΧ</td><td>-Η »Η</td><td>-n Jn 'X .ω .X4</td><td>gH 4- »ΖΖ1 of X</td>

<td></td><td>1 About g =:</td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>α ά s</td><td>ά β</td><td>α ό β</td><td>(= 1 CO X</td><td>α I CO,</td><td>α ο1 Β SP ο</td><td>.2 Si</td><td>glyc thousand</td>

<td>cyloxip netoxy)</td><td>ο. Ο 1-4 SL 1 Ο ο X γΧ ° 3 E</td><td>Β .'Τ? 'and Ώ ο ο 2 rp ω υ β</td><td>g- <'SL sl 44' ο ° -S ω 3 Ε</td><td>β · £ SL 04 04 Ο 2 ω '3 Ε</td><td>.2v sl Ο 44 ο Ο. '3</td><td rowspan="2">tadecyl-2- phosphone</td><td rowspan="2">tadecyl-2phosphonone</td>

<td>1 sl, Ο</td><td> * §</td><td>13 years sl, Ο</td><td>-χ X χ ο</td><td>Ό CX ο sl CZ</td><td>= σ ο β ο SL</td><td>ο Α</td><td></td>

57796 ΒΙ

<td></td><td>Q ϋ</td><td>QE</td><td>about Mrs.</td>

<td></td><td>zil-sn gl) propyl]</td><td>zil-sn gl i) propiT</td><td>zil-sn gl i) propyl</td><td>zil-sn gl si) propil</td>

<td></td><td>Ο ω</td><td>About 2</td><td>About 2</td><td>0 S ο</td>

<td></td><td>lOo uoro-2</td><td rowspan="2">the 10 -fluoro-</td><td rowspan="2">the 10 -fluoro-</td><td>l-O-fluoro</td>

57796 V1

Table 6. Phosphonomethoxyethyl (PME) diester compound

<td>Name</td><td>naphthyl octadecyloxyethyl 9- (2-phosphonomethoxyethyl) guanine</td><td>naphthyl octadecyloxyethyl 9- (2-phosphonomethoxyethyl) adenine</td><td>naphthyl octadecyloxyethyl 1- (2-phosphonomethoxyethyl) cytosine</td><td>naphthyl octadecyloxyethyl 1- (2-phosphonomethoxyethyl) thymine</td><td>naphthyl octadecyloxyethyl 9- (2-phosphonomethoxyethyl) uracil</td><td>naphthyl octadecyloxyethyl 9- (2-phosphonomethoxyethyl) -2,6diaminopurine</td><td>naphthyl hexadecyloxypropyl 9- (2phosphonomethoxyethyl) guanine</td><td>naphthyl hexadecyloxypropyl 9- (2-phosphonomethoxyethyl) adenine</td><td>naphthyl hexadecyloxypropyl 1- (2phosphonomethoxyethyl) cytosine</td><td>naphthyl hexadecyloxypropyl 1- (2-phosphonomethoxyethyl) thymine</td><td>naphthyl hexadecyloxypropyl 9- (2-phosphonomethoxyethyl) uracil</td><td>naphthyl hexadecyloxypropyl 9- (2-phosphonomethoxyethyl) -2,6diaminopurine</td><td>naphthyl 10-octadecyl-2-O-benzyl-sn glyceryl 9- (2- phosphonomethoxyethyl) guanine</td>

<td>l PŽ</td><td>naphthyl</td><td>naphthyl</td><td>naphthyl</td><td>naphthyl</td><td>naphthyl</td><td>naphthyl</td><td>naphthyl</td><td>naphthyl</td><td>naphthyl</td><td>naphthyl</td><td>naphthyl</td><td>naphthyl</td><td>naphthyl</td>

<td>CQ</td><td>octadecyloxyethyl</td><td>octadecyloxyethyl</td><td>octadecyloxyethyl</td><td>octadecyloxyethyl</td><td>octadecyloxyethyl</td><td>octadecyloxyethyl</td><td>hex adecyloxypropyl</td><td>hex adecyloxypropyl</td><td>hex adecyloxypropyl</td><td>hex adecyloxypropyl</td><td>hex adecyloxypropyl</td><td>hex adecyloxypropyl</td><td>10-octadecyl-2-obenzyl-sn glyceryl</td>

<td>'«S с З s Z 03</td><td>guanine-9-yl</td><td>adenin-9-yl</td><td>cytosine-1-yl</td><td>thymine-l-yl</td><td>uracil-l-yl</td><td>2,6-diamino-purin-9-yl</td><td>guanine-9-yl</td><td>1 O \ 1 .s α <td>cytosine-1-yl</td><td>thymine-l-yl</td><td>uracil-l-yl</td><td>1 σ ' 1 cc 02 1 Oh S -S 1 40 pcs</td><td>guanine-9-yl</td>

57796 Β1

<td>> N Λ Ζ</td><td>ί-2-Ob intoxication</td><td>[-2-0-b Letoxy</td><td>k2-Ob tetoxy</td><td>[-2-0-b non-oxy</td><td>U2-Ob > ethyl) -2</td>

<td></td><td>q (D</td><td>About 9 p.m.</td><td> 0</td><td>Oh</td><td> 9 0</td>

<td></td><td>ό</td><td>ό</td><td>ό</td><td>ό</td><td>About 2</td>

57796 V1

Table 7. (R) -phosphonomethoxypropyl [(R) -PMP] diester compound

57796 Β1

<td></td><td></td><td rowspan="2">propyl 9- ] 2,6-diar</td><td>C η.</td><td>C Ο-</td><td>C C4</td><td>c 4 =:</td><td>c D</td><td rowspan="2">2-0-ben si) propyl]</td>

<td>Naz:</td><td>* - + σ 'θ2' θ2 ο Ο JH 02 02</td><td>2-0-be letoxy)</td><td>2-0-be leloxy)</td><td>2-0-be letoxy)</td><td>2-0-be netoxy</td><td>2-0-be netoxy</td>

57796 V1

Table 8. (S) -3-Methoxy-2-phosphonomethoxypropyl [(S) -MPMP] compound diester

<td></td><td>9- (S) propi</td><td>9- (S) ProP</td><td>1- (S) propi</td><td>z — s sh, CZ3 ο ^ z t +t )</td><td>1- (S) iprop</td><td>ć / a ' V <Ν 034 77</td><td>il9- (propi</td><td>v <34 Ο $ + 72 &</td><td>ill- (propi</td>

<td>ra Z</td><td>Η SL ο 44 ι + Ω</td><td>and 1</td><td>rt sl Ο 44 1-4 Ω</td><td>'2 74 02 O</td><td>1-4 FIG . 3 o</td><td>72 00 Ή ° 02 (_ <</td><td>Ο SL Λ 0</td><td>About fig 44 Λ Ω</td><td>About fig 44 SH Ω</td>

<td></td><td>44 ω ο α</td><td>44 U Q β</td><td>44 02 ο α</td><td></td><td>44 ω About Mr.</td><td>44 7 ^ Ο ™</td><td>SL »4 3</td><td> % 3</td><td>SL l χ 3</td>

<td></td><td>octadecyl phosphonoi</td><td>octadecyl phosphonoi</td><td>octadecyl phosphonoi</td><td>octadecyl phosphonc</td><td>octadecyl phosphono:</td><td>oktadecil 'onomctol ·</td><td>72 Ο υ C2 02, Ο * S Q</td><td>72 o u 6 02, O Ό 44o <<2 44 02</td><td>70 C υ C2 02, ο * S Q</td>

57796 Β1

<td></td><td>24 Ο 4— » Ο d _n</td><td>24 Ο 4— »<D</td><td>24 2 o z o & d O</td><td>lyceryl propyl</td><td>liceril piljadi</td><td>liceril piljcit</td><td>ΐ 2 ο 2 2</td><td>liceril ipiljur</td><td>04 Ο cί c> ρ.</td>

<td>Name</td><td> *—1 04 2 'and Mr. & S I 24 E</td><td>04 2 2 § <· β ο, ο 04 4-> sl Ο 44 Ε</td><td>ksipropil S si) propyl] 2</td><td>ecil-2-0-b i-2-phosphon guanine</td><td>ecil-2-0-b -phosphonomes</td><td>ecil-2-0-b -phosphonome</td><td>ecil-2-0-b 1-phosphonorr</td><td>ecil-2-0-b -phosphon</td><td rowspan="2">ktadecyl-2-O-bei xy-2-phosphonome diaminopam:</td>

<td></td><td>2 § rt c O ou 2 TZ fig</td><td>2 ο rt S7 ο cQ Ό SL</td><td>2 2 o υ UU 2 years</td><td> 2 2 2 9 1</td><td>2 SZ ι 4— »· ι-4 24 " o</td><td>2 CU ι 4— »· ι-4 24 ™ About 24</td><td>g-l 2 9 ο</td><td>Ό ctf X ? ο</td>

<td></td><td>l, ο sl 0- <</td><td>α ο SL <4- (</td><td>O OJ 04</td><td>o</td><td>About 2</td><td>ό 3</td><td>Ο U</td><td>-L 4- »ο a</td><td> 9 2</td>

<td></td><td>44 Q</td><td>44 Q</td><td>24 fa u, P</td><td>I ΓΩ</td><td>2 years</td><td> 6</td><td>2 S 1</td><td>Λ 6</td><td> 9 9</td>

<td>s Ζ</td><td>ι</td><td> 2</td><td>About _</td><td>O \ 1</td><td>Ο \ I</td><td>I</td><td> 1</td><td></td><td>Ο</td>

57796 V1

Table 9. (S) -3-Hydroxy-2-phosphonomethoxypropyl [(S) -HPMP] diester compound

<td></td><td>- (S) - [(3ropiljgi.</td><td>- (S) - [(3- • robbery</td><td>S'M s & 1 »n</td><td>- (S) - [(3propyl</td><td>ό 3 ί / 2 & X »N</td><td>in V? V <N</td><td>vd οί V sh σ \ Ρ ΪΗ Λ</td><td>η 9- (S) propyl</td><td>Ο V SH Ο 1- GZ S4</td>

<td>l Ζ</td><td>sl * - »</td><td>network tox</td><td>network tox</td><td>ΰ 44 O Q »-» · 4_ » SL 01</td><td>.2 ο sl tg?</td><td>'ΰ ο ο ϊ-Η SL</td><td>8 44 S4 ο “Ο</td><td>8 44 Ct, Ο cn Q</td><td>ρ,</td>

<td></td><td>'o § -sl</td><td>children fund</td><td>children phono</td><td>8, ο Ό</td><td> ο ο D Ό <+ - <</td><td>ο 2 Q ω β 0</td><td>ω 1 Ό</td><td>ω, Q 'rt D fig</td><td>ο 1 Ό</td>

<td></td><td>o</td><td>Oh</td><td>o</td><td>ο</td><td>Ο</td><td>ο Ο</td><td>8 <Ν</td><td>About CN</td><td> 8</td>

57796 ΒΙ

<td></td><td>(S) - [[whistle</td><td>(S) - [(piljur</td><td rowspan="2">'- (S) - [( , 6-dian</td><td>7 fig 'n</td><td>44 Ο 4— »Q</td><td>7 ο SL —L ι 7 Ν</td><td>with fig 'n</td><td>44 Ο 4— »Q</td><td>zil-sn -2- lištirn</td><td>C ctf SL 0 £ ' 3 'ν 03</td><td>zil-sn osphc aminc</td>

<td>Ν Λ Ζ</td><td>ο £ 0 η sz 2 'С ŽЖ ε</td><td>'2 2 χ. & 2 sl Ο g</td><td>l α £ ο 7 0. & Τ- sl Ό 3 ^ 'SL</td><td>o 1 rq '5</td><td>S <2 S 0 0X1 1</td><td>Ο 1 ς ς1144 * 7 CO Ο '-Ι ν> 4— »ο X ο</td><td>o 1 CN 1 '5</td><td><2 .1 MS υ 1</td><td>cil-2-0 [(3-hydroxy)</td><td>cil-2-Ο [(3-hydroxy)</td><td>cil-2-Ο droxyropyl] 2,</td>

<td></td><td>Ό fig S <2</td><td>Q <+3 Ό fig Ctf fOh sl 0n 3 ^ / 1</td><td>Ο JU Ό £ β 5 SL χ 44 Ο</td><td>44 Oh 1 o 1</td><td>0 2 33 1 CO</td><td>£ Ο ¢ ¢ 3 1 FIG 9 2</td><td>44 Ο 1 ο 1</td><td>0 Ε Ε I CO</td><td>% A £ Q 0n 1</td><td>£ Ο 1 1</td><td>-0-ok (S) - [(imctok</td>

57796 V1

Table 10. (S) -3-Fluoro-2-phosphonomethoxypropyl [(S) -FPMP] compound diester

i \

O = CLi> O

fiQ

<td>'S</td><td>ethyl 9- (C xy) propyl</td><td>ethyl 9- (C xy) propyl</td><td>V o 2 D 2 3</td><td>«2 Rč v 2 2 * 'ΰ sl 2</td><td>ethyl 1- (S) xy) prop</td><td>ethyl 9- (S ropil] 2.6 ·</td><td>σχ 9 0> 1 l 2+ about -77 fig C9 94</td><td>σχ §χ ο 77 fig Rč 94</td><td>2 'λ 0 ε & l ο 77 SL Λ 94</td>

<td></td><td>& 1 S</td><td>sl o 94 10 E</td><td> £ 2 2 8</td><td>and 2 0 Q 0 6</td><td>S 0 α ω 0 6</td><td rowspan="2">octadecylox nomethoxy) pi</td><td>sl Q 44 2 2 years</td><td>and 2 44 2 2 6</td><td>2 £ 2 ο 2 E</td>

<td></td><td>υ oo d 2 o 44 § O 0</td><td>§ 1 Ε 2 44 o O 0</td><td>octadecy phosphonoi</td><td>8 8 0, O fig 44 0 o</td><td>8 8 Ό, Ο SL</td><td>sq (U c 2 2 S g</td><td> 'G § Q g 0 £ S g <2</td><td>2 Ο Ο C 0 £ Μ <-t— <S% 44 £</td>

57796 Β1

<td></td><td>-fluoro 1</td><td>-fluoro ίΐ</td><td>-fluoro lopurin</td><td>d \ c Is S) Ο ---</td><td>σχ 'ο Ό ° β Έ υ </td><td>N ΐ · Ε Ο ° Ο --1</td><td>1 C ΐ 1 ο D9 <-> Γ73</td><td>ceril 1ljuraci</td><td>ceryl 9il] 2.6-</td>

<td>Name</td><td> P- < o __ α Och l ο O fig . & £</td><td>ι & Ο 02 ο. C2 ο 2 »C2 '3 2</td><td>σχ & ο2 Ο ο. β η. & £</td><td>2-0-benzyl nomethoxy</td><td>2-0-benzy inomethox</td><td>2-0-benzyl nomethoxy</td><td>2-0-benzy onomethoxy</td><td>2-0-benzyl Dnomethox</td><td>2-0-benzyl 'onometok minopurir</td>

57796 Β1 Specific compounds provided herein include:

isopropylidenegl iceryl oldadecyloxyethyl

9- [2- (phosphonomethoxy) e ti i] gmiii n glyceryl octadecyloxyethyl

9- [2 - (phosphonomethoxy) ef ilgoanin

PO (CH2)2<3 (CH2)1;7CH3 o

benzyl octadeyloxyethyl mannosyl octadecyloxyethyl 9- (R) - [3-methoxy-2- (f0, sphonomeroxy) ppyl] hydrochloride

9- [2- (phosphoumethoxy) ethyl] gxiaum

NH3MA ^ N Q 9

1 ^ Ч ^ Р “О (SNg) JO (SNg),#SN? fenii cikiadeciloksžetil feiiil heksadeciloksipiopil

9- (R> [. 3-methoxy-2- (forphonomethoxy) propyl] guaam 9- (R) - [3-fluoro-2- (phosphiomethoxy) propyl]; adenine

III. Methods for Use A compound with the structure of any of Formulas (I), (1-1), (1-2), (1-3), (1-4), (1-5) and / or (Ia) for use in treating a viral disease in a subject. The compound is administered to a subject in need thereof in a therapeutically effective amount. L / La Formula (I), (1-1), (1-2), (1-3), (1-4), (1-5) and / or (Ia) may be a lipophilic pro-moiety.

57796 Examples of viral diseases include human papilloma virus, HIV, hepatitis B virus, hepatitis C virus, smallpox virus, vaccinia virus, adenovirus, cytomegalovirus (CMV), herpes simplex viruses, Epstein Barr virus, BK virus, JC virus, any double-stranded DNA virus, feline leukemia virus, feline immunodeficiency virus, and the like. A therapeutically effective amount of a compound of Formula (I) may be administered to a human or mammal in need of treatment for a viral disease.

The compound can be administered via (topical, intravitreal, oral, intravenous, etc.) resulting in delivery of an amount sufficient to inhibit virus replication. The compound may be administered topically. For example, the compound may be administered topically in the form of a cream, gel or ointment.

A compound with the structure of any of Formulas (I), (I-1), (1-2), (1-3), (1-4), (1-5) and / or () is disclosed herein. Ia) for use in treating a disease or disorder in a subject in need thereof, wherein the compound is administered to a subject in need thereof in a therapeutically effective amount. Aspects for the treatment of cancer and other neoplastic disorders provided herein are based on the surprising discovery that compounds of Formula (I) and / or (Ia) are effective in killing or inhibiting the growth of cells transformed with human papilloma virus (HPV), for example cervical cancer cells. and cervical intraepithelial neoplastic lesions (CIN). Accordingly, a therapeutically effective amount of a compound of Formula (I), (1-1), (1-2), (1-3), (1-4), (1-5) and / or (Ia) may be administered appropriately (topically, orally, intravenously, etc.) to kill or inhibit the growth of infected / transformed cells. Cells that have been transformed with other types of virus, such as herpes simplex virus-2 (HSV-2), can also be treated with a compound of Formula (I), (1-1), (1-2), (1-3 ), (1-4), (1-5) and / or (Ia).

Also disclosed herein is a compound with the structure of any of Formulas (I), (1-1), (1-2), (1-3), (1-4), (1-5) and / or ( Ia) for use in treating cancer in a subject. The compound is administered to a subject in need thereof in a therapeutically effective amount. L / Fa from any of Formulas (I), (1-1), (1-2), (1-3), (1-4), (1-5) and / or (Ia) may be a lipophilic pro-moiety .

The cancer may be leukemia, cancer and / or sarcoma, such as cancer of the brain, breast, cervix, colon, pancreas, head and neck, liver, kidney, lung, non-small cell lung, prostate, melanoma, mesothelioma, egg sarcoma, stomach, uterus and / or medulloblastoma. Additional examples include, Hodgkin's disease, Non-Hodgkin's lymphoma, multiple myeloma, neuroblastoma, ovarian cancer, rhabdomyosarcoma, primary thrombocytosis, primary macroglobulinemia, primary brain tumors, malignant pancreatic insulanoma, malignant leukemic carcinoid , testicular cancer, lymphoma, thyroid cancer, neuroblastoma, esophageal cancer, urogenital tract cancer, malignant hypercalcemia, endometrial cancer, adrenal cortex cancer, and endocrine and exocrine neoplasms

57796 Β1 pancreas. The cancer may be liver cancer, colon cancer, breast cancer, melanoma, acute myelogenous leukemia, chronic myelogenous leukemia, and / or non-small cell lung cancer.

Also disclosed herein is a compound with the structure of any of Formulas (I), (1-1), (12), (1-3), (1-4), (1-5) and / or / Ia ) for use in the treatment of a proliferative disorder in a subject. The compound is administered to a subject in need thereof in a therapeutically effective amount. The proliferative disorder can be caused by the human papilloma virus. Examples of proliferative diseases include, for example, cervical intraepithelial neoplasia (CIN), vulval intraepithelial neoplasia (VIN), anal vulvar intraepithelial neoplasia (AIN), or penile and venereal warts. L / La from any of Formulas (I), (1-1), (1-2), (1-3), (1-4), (1-5) and / or (Ia) may be a lipophilic pro-moiety .

Also disclosed herein is a compound according to any one of Formulas (I), (1-1), (1-2), (1-3), (1-4), (1-5) and / or / Ia for use in killing or inhibiting the growth of a transformed cell, wherein the transformed cell is contacted with a therapeutically effective amount of a compound of any of Formula (I), (1-1), (1-2), (1-3), 1-4), (1-5) and / or (Ia).

In one aspect of the present invention, there is provided a compound of Formula (Ia) or an embodiment thereof, or a pharmaceutically acceptable salt thereof, for use in treating a viral disease in a subject, wherein the viral disease may be selected from human papilloma virus (HPV), HIV, hepatitis B virus, hepatitis C virus, smallpox virus, vaccinia virus, adenovirus, cytomegalovirus, herpes simplex virus 1, herpes simplex virus 2, Epstein Barr virus, BK virus, JC virus, feline leukemia virus and feline immunodeficiency virus.

In embodiments, the virus may be a human papilloma virus. According to the CDC, HPV is the most common sexually transmitted infection (STI). HPV viruses can be classified into mucosal and cutaneous HPVs. Within each of these groups, individual viruses were labeled as high-risk or low-risk. More than 40 types of HPV's can infect the genital areas of women and men, and several types of HPV can infect the mouth and throat. Additionally, HPV is the most common cause of cervical cancer. Type 16 is one of the most prominent strains of HPV and can cause cervical cancer. Other types of HPVs include, but are not limited to,, 2, 3, 4, 5, 6, 8, 11, 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 63 , 66, 68, 69 and 82. In embodiments, it is used to treat several types of human papilloma virus, for example, the types described herein. In embodiments, the use is for more than 2 types of HPV, more than 5 types of HPV, or more than 10 types of HPV. In embodiments, the human papilloma virus may be selected from human papilloma virus type 11, type 16 and type 18.

In another aspect, there is provided a compound of Formula (Ia) or an embodiment thereof, or a pharmaceutically acceptable salt thereof, for use in the treatment of cervical cancer.

57796 Β1 subject code. In some embodiments, the cervical cancer may be caused by an HPV infection, for example, a type 16 HPV infection.

In another aspect, there is provided a compound of Formula (Ia) or an embodiment thereof, or a pharmaceutically acceptable salt thereof, for use in inhibiting the growth of a virus-transformed cell, wherein the virus may be selected from human papilloma virus, HIV, hepatitis B virus, hepatitis C virus, smallpox virus, vaccinia virus, adenovirus, cytomegalovirus, herpes simplex virus 1, herpes simplex virus 2, Epstein Barr virus, BK virus, JC virus, feline leukemia virus and feline immunodeficiency virus.

IV. Synthesis Methods A process for the synthesis of compounds of Formula (I), as shown in the following Scheme 1, is also disclosed herein. For Scheme 1, the substituents Bnuc, X, R and L are as described for Formula (I) herein.

In another aspect, a process for the synthesis of a compound of Formula (Ia) is provided, as shown in the following Scheme Ia. For Scheme la, BNuc (a) substituents, Xa, Ra and La are as described for Formula (Ia) herein.

The process comprises reacting a suitably substituted ANP monoester with R-OH or RaOH in the presence of a coupling agent such as (benzotriazol-1-yloxy) -tripyrrolidinophosphonium hexafluorophosphate (ΡΥΒΟΡ®) to give the diester. Methods for preparing ANP monoesters are well known. For examples, see Beadle, J. R et al. Joumal of Medicinal Chemistry, 2006, 49: 2010-2015, and Valiaeva, N. et al. Antiviral Research, 2006, 72: 10-19. The use of ΡΥΒΟΡ® for the synthesis of phosphonate diesters was first described in Campagne, JM. et al. Tetrahedron Letters, 1993, 34: 6743-6744. Other coupling / condensing reagents may also be used, for example uronium, carbodiimide, imidazolium and acid chloride reagents, (for an overview of coupling agents see, e.g., El-Faham, A. & Albericio, F. Chemical Reviews, 2011, 111: 6557-6602).

Scheme 1

57796 Β1

Scheme la ό

A process for the synthesis of compounds of Formula (I) is also disclosed herein. The procedure includes the steps provided in the following Scheme 2:

Scheme 2

X 2-3 X In the process of Scheme 2, Bnuc is a natural purine or pyrimidine base, or an analog thereof; L is a lipophilic pro-moiety, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, or O-substituted glyceryl of the formula -CH2CH (OR1) -CH2 (OR2) (II), wherein R1 and R2 independently substituted or unsubstituted alkyl or substituted or unsubstituted aryl; R is substituted or unsubstituted lower alkyl, substituted or

57796 Β1 unsubstituted lower heteroalkyl, substituted or unsubstituted lower cycloalkyl, substituted or unsubstituted lower heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted lower heteroaryl; X is hydrogen, substituted or unsubstituted lower alkyl, or substituted or unsubstituted lower heteroalkyl; and Y is a leaving group.

The method comprises: 1) contacting a protected nucleoside Bnuc with a structure of Formula (2-1) with an ester having the structure of Formula (2-2) in the presence of a strong base under conditions suitable to obtain a monoester with the structure of Formula (2-3); and 2) reacting the monoester salt formed with the structure of Formula (2-3) with L-OH in the presence of a coupling agent as known in the art, thereby synthesizing a compound with the structure of Formula (I).

In another aspect, a process for the synthesis of a compound of Formula (Ia) is provided. The procedure includes the following if provided in Scheme 2a. For Scheme 2a, the substituents Bnuc (h), Xa, Ra and La are as described for Formula (Ia) herein, and Ya may be an outgoing group.

Scheme 2a

The method comprises: 1) contacting a protected nucleoside Bnuc (h) with a structure of Formula (2-Ia) with an ester of the structure of Formula (2-2a) in the presence of a strong base under conditions suitable to obtain a monoester with a structure of Formula (2) -For); and 2) reacting the monoester thus formed with the structure of Formula (2-Za) with La-OH in the presence of a coupling agent as known in the art, thereby synthesizing a compound with the structure of Formula (Ia).

The method may include the steps provided in the following Scheme 2-1, specifically, contacting a suitably protected nucleoside (general structure 2-1) wherein Bnuc is a natural or modified purine or pyrimidine base, with an ester of general structure 2-2 (where Y is a leaving group such as p-toluenesulfonyl, methanesulfonyl, anesulfonyl, bromo, iodo, or the like) in the presence of a strong base and a suitable solvent to give ANP monoesters of Formula 2-3, and second, the reaction of ANP monoester 2-3 with L-OH (i.e., hydroxy form L) in the presence of a coupling agent such as ΡΥΒΟΡ® to give a diester of Formula (I).

57796 Β1

Scheme 2-1

Also disclosed herein is a process for the synthesis of compounds of the structure of Formula (I) according to Scheme 2-1. Bnuc, X, R and L are as described for Formula (I) herein, and Y may be a leaving group; said method comprising: contacting a compound of Formula (2-1) having a protected Bnuc with a compound of Formula (2-2) in the presence of a strong base to form a compound of Formula (2-3); and reacting a compound of Formula (2-3) with L-OH in the presence of a coupling agent to form a compound of Formula (I).

Scheme 2-la

In another aspect, a process is provided for the synthesis of a compound with the structure of Formula (Ia) according to Semi 2-la. For this procedure, Bnuc (h) is as described for Formula (Ia)

57796 Β1 here; La is unsubstituted C13-29 heteroalkyl; Ra may be selected from unsubstituted C 1-6 alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl (C 1-6 alkyl), substituted or unsubstituted heteroalkyl (C 1-6). C1-6 alkyl); Xa may be hydrogen, unsubstituted C 1-6 alkyl, halogen substituted C 1-6 alkyl, hydroxy substituted C 1-6 alkyl or unsubstituted C 1-6 alkoxy; and Ya may be an outgoing group; said method comprising: contacting a compound of Formula (2-Ia) having a protected Bnuc (h) with a compound of Formula (2-2a) in the presence of a strong base to form a compound of Formula (2-Za); and reacting a compound of Formula (2-Za) with La-OH in the presence of a coupling agent to form a compound of Formula (Ia).

Also disclosed herein is a process for the synthesis of compounds of Formula (I) as described in the following Scheme 3. For Scheme 3, substituents BNuc, X, R and L are as described for Formula (I) herein.

Scheme 3

The method comprises contacting a suitably protected nucleoside (of general structure 3-1 wherein Bnuc is a natural or modified purine or pyrimidine base), with a diester of general structure 3-2 (wherein Y is a leaving group such as p-toluenesulfonyl, methanesulfonyl, trifluoromethanesulfonyl, bromo, iodo, or the like.) in the presence of a strong base and a suitable solvent to give a compound of Formula (I).

In another aspect, a method is provided for the synthesis of a compound of Formula (Ia) as described in Scheme 3a. For Scheme Za, substituents V. \ is (a), Xa, Ra and La are as described for Formula (Ia) herein, and Ya is an outgoing group.

Scheme For

57796 Β1

The method comprises contacting a suitably protected nucleoside (3-Ia) with diester 3-2 (wherein Ya is a leaving group such as p-toluenesulfonyl, methanesulfonyl, trifluoromethanesulfonyl, bromo, iodo, or the like) in the presence of a strong base and a suitable solvent to give a compound of Formula (Ia).

V. Pharmaceutical Compositions A pharmaceutical composition comprising a compound of Formula (I) and / or a compound of Formula (Ia) in combination with a pharmaceutically acceptable excipient (e.g., a carrier) is also disclosed herein.

The terms pharmaceutically acceptable carrier, pharmaceutically acceptable excipient and the like as used herein in relation to pharmaceutical excipients, for example, pharmaceutically, physiologically acceptable organic or inorganic carrier substances suitable for enteral or parenteral administration that do not react adversely with the active agent . Suitable pharmaceutically acceptable carriers include water, salt solutions (such as Ringer's solution), alcohols, oils, gelatins, and carbohydrates such as lactose, amylose or starch, fatty acid esters, hydroxymethylcellulose, and polyvinyl pyrrolidine. Such preparations may be sterilized and, if desired, mixed with excipients such as lubricants, preservatives, stabilizers, humectants, emulsifiers, salts affecting the basal pressure, buffers, coloring agents, and / or flavoring agents and the like. which do not react adversely with the compounds described herein.

The compounds described herein may be administered separately or may be co-administered to a subject. The intent is that the co-administration involves the simultaneous or sequential administration of a compound alone or in combination (more than one compound). The compositions may also be combined, if desired, with other active substances (e.g., to reduce metabolic degradation).

57796 Β1

Α. Formulations The compounds described herein may be prepared and administered in a variety of oral, parenteral, and topical dosage forms. Thus, the compounds described herein may be administered by injection (e.g., intravenously, intramuscularly, intracutaneously, subcutaneously, intraduodenally, or intraperitoneally). Also, the compounds described herein may be administered by inhalation, for example, intranasally. Additionally, the compounds described herein may be administered transdermally. It is also contemplated that multiple routes of administration (e.g., intramuscular, oral, transdermal) may be used to administer the compounds described herein. Accordingly, pharmaceutical compositions comprising a pharmaceutically acceptable carrier or excipient and one or more compounds are contemplated.

For the preparation of pharmaceutical compositions, pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, pills, capsules, sachets, suppositories, and dispersible granules. The solid carrier may be one or more substances which may also act as diluents, flavorings, binders, preservatives, tablet disintegrants, or encapsulating material.

In powders, the carrier is a finely divided solid in admixture with a finely divided active ingredient. In tablets, the active component is mixed with a carrier which has the necessary binding properties in suitable proportions and is compact in relation to the shape and size desired.

Powders and tablets preferably contain from 5% to 70% of active compound. Suitable carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, low melting wax, coconut butter, and the like. The intention is that the term preparation includes the formulation of an active compound with an encapsulating material as a carrier by providing a capsule in which the active component with or without other carriers is surrounded by a carrier, which is thus attached to it. Similarly, bags and lozenges are included. Tablets, powders, capsules, pills, sachets, and lozenges can be used as solid dosage forms suitable for oral administration.

For the preparation of suppositories, a low melting point wax, such as a mixture of fatty acid glycerides or coconut butter, is first melted and the active ingredient is homogeneously dispersed therein, such as by mixing. The molten homogeneous mixture is then poured into molds of suitable size, allowed to cool, and thus to solidify.

Liquid form preparations include solutions, suspensions, and emulsions, for example, water or water / propylene glycol solutions. For parenteral injection, liquid preparations may be formulated in solution in aqueous polyethylene glycol.

57796 When parenteral preparation is required or desired, particularly suitable compositions are injectable, sterile solutions, preferably oily or aqueous solutions, as well as suspensions, emulsions, or implants, including suppositories. In particular, carriers for parenteral administration include aqueous solutions of dextrose, cyclodextrins, saline, pure water, ethanol, glycerol, propylene glycol, peanut oil, sesame oil, polyoxyethylene-block polymers, and the like. Ampoules are suitable unit doses. The compounds described herein may also be incorporated into liposomes or administered via transdermal pumps or patches. Pharmaceutical compositions suitable for use include those described, for example, in PHARMACEUTICAL SCIENCES (17th Ed., Mack Pub. Co., Easton, PA) and WO 96/05309.

Aqueous solutions suitable for oral use can be prepared by dissolving the active component in water and adding suitable dyes, flavors, stabilizers, and / or thickeners. Aqueous suspensions suitable for oral use can be made by dispersing the finely divided active component in water with a viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, and other well-known suspending agents.

Also included are solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for oral administration. Such liquid forms include solutions, suspensions, and emulsions. These preparations may contain, in addition to the active component, dyes, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizers, and the like. The pharmaceutical composition is preferably in unit dosage form. In this form, the preparation is divided into unit doses containing appropriate amounts of the active component. The unit dosage form can be a packaged preparation, a package containing separate amounts of the preparation, such as packaged tablets, capsules, and powders in vials or ampoules. Also, the unit dosage form may be a capsule, tablet, sachet, or lozenge alone, or it may be an appropriate number of any of these in the form of a pack. In embodiments, the unit dosage form may be in the form of an applicator pre-filled with the pharmaceutical composition described herein (e.g., a pharmaceutical composition comprising an effective amount of a compound of Formula (Ia)). In embodiments, the pre-filled applicator may be filled with a pharmaceutical composition in the form of a cream, gel or ointment containing a compound described herein (e.g., a compound of Formula (Ia)).

The amount of active ingredient in a unit dose formulation may vary or be adjusted from 0.1 mg to 10000 mg, more typically 1.0 mg to 1000 mg, most typically 10 mg to 500 mg, according to the particular application and potency of the active ingredient. The composition may, if desired, also contain other compatible therapeutic agents.

57796 Β1 Some compounds may have limited solubility in water and may therefore require a surfactant or other suitable co-solvent in the composition. Such co-solvents include: Polysorbate 20, 60, and 80; Pluronic F-68, F-84, and P-103; cyclodextrin; and polyoxyl 35 castor oil. Such co-solvents are typically used at the level between the eyes

0.01% and about 2% by weight.

A viscosity higher than that of ordinary aqueous solutions may be desirable to reduce variability in the release of formulations, to reduce the physical separation of the components of the suspension or emulsion of the formulation, and / or to otherwise improve the formulation. Such viscosity agents include, for example, polyvinyl alcohol, polyvinyl pyrrolidone, methyl cellulose, hydroxy propyl methylcellulose, hydroxyethyl cellulose, carboxymethyl cellulose, hydroxy propyl cellulose, chondroitin sulfate and its salts, hyaluronic acid and its salts, and a combination thereof. Such agents are typically used at a level between about 0.01% and about 2% by weight.

The compositions may further include components to provide sustained release and / or comfort. Such components include high molecular weight anionic mucomimetic polymers, gelatinizing polysaccharides, and finely divided drug-carrying substances. These components are discussed in more detail in U.S. Pat. Br. 4,911,920; 5,403,841; 5,212,162; and 4,861,760.

В. Effective Dosages Pharmaceutical compositions comprising compositions comprising the active ingredient in a therapeutically effective amount, i.e., in an amount effective to achieve its intended purpose. The actual amount effective for a particular application will depend, among other things, on the condition being treated. For example, when used in methods of treating cancer, such compositions will contain an amount of active ingredient effective to achieve the desired result (e.g., reducing the number of cancer cells in a subject).

The dose and frequency (single or multiple doses) of the administered compound may vary depending on various factors, including the route of administration; size, age, sex, health status, body weight, body mass index, and diet of the recipient; the nature and extent of the symptoms of the disease being treated; the presence of other diseases or other health-related problems; type of concomitant treatment; and a complication of any disease or treatment regimen. Other therapeutic regimens or agents may be used in conjunction with the methods and compounds described herein.

57796 Β1 For any of the compounds described herein, a therapeutically effective amount may be initially determined from cell culture assays. Therapeutically effective amounts for use in humans can be subsequently estimated from animal models using conventional techniques that have been validated or adapted in actual clinical studies.

Doses may vary due to the requirements of the patient and the compound being used. The dose administered to the patient should be sufficient to elicit a useful therapeutic response in the patient over time. The dose will also be determined by the existence, nature, and extent of any adverse side effects. Generally, treatment is initiated with lower doses, which are less than the optimal dose of the compound. Therefore, the dose is increased in small increments until the optimal effect is achieved under the given circumstances. In one embodiment, the dose range is 0.001% to 10% w / v. In another embodiment, the dose range is 0.1% to 5% w / v.

The dose amount and intervals can be adjusted individually to ensure that the levels of compound administered are effective for the particular clinical indication being treated. This will provide a therapeutic regimen that is commensurate with the severity of the individual's condition.

Using the indications provided herein, an effective prophylactic or therapeutic regimen can be planned that does not cause significant toxicity and is still fully effective for the treatment of clinical symptoms shown by a particular patient. This planning should include careful selection of the active compound taking into account factors such as compound potency, relative bioavailability, patient body weight, presence and severity of adverse side effects, preferred route of administration, and toxicity profile of the selected agent.

C. Toxicity The relationship between toxicity and therapeutic effect for a particular compound is its therapeutic index and can be expressed if the relationship between LD50 (amount of compound lethal for 50% of the population) and ED50 (amount of compound effective for 50% of the population). Compounds showing high therapeutic indices are preferred. Therapeutic index data obtained from cell culture assays and / or animal studies can be used to formulate a dose range for use in humans. Doses of such compounds preferably lie within the range of plasma concentrations that include ED50 with little or no toxicity. The dose may vary within this range depending on the dosage form administered and the route of administration used. See, e.g. Fingl et al., In: THE PHARMACOEOGICAL BASIS OF THERAPEUTICS, Ch.l, pl, 1975. The exact formulation, route of administration, and dosage may be chosen by the individual physician in relation to the patient's condition and the particular procedure in which the compound is used.

57796 Β1

VI. Examples General Chemical Procedures: All reagents were of commercial quality and used without further purification unless otherwise indicated. Chromatographic purification was performed using a flash procedure with silica gel 60 (EMD Chemicals, Inc., 230-400 mesh). 1 N NMR spectra were recorded on a Varian HG spectrophotometer operating at 400 MHz and reported in parts per million (ppm) relative to the inta tetramethylsilane at 0.00 ppm. Routine electrospray ionization mass spectra (ESI-MS) were recorded on a Finni-gan LCQDECA spectrometer, and high resolution mass spectra (HRMS) were recorded on an Agilent 6230 Accurate-Mass TOFMS mass spectrometer in ESI negative mode. Purity of the target compounds was characterized by high performance liquid chromatography (HPLC) using a Beckman Coulter System Gold chromatographic system. The analytical column was ΡΗΕΝΟΜΕΝΕΧ® SYNERGI ™ Polar-RP (4.6 x 150 mm) equipped with a SECURI-TYGUARD (protection column. Mobile phase A was 95% water / 5% methanol and mobile phase B was 95% methanol / 5% water. At a flow rate of 0.8 mL / min, isocratic elution was used. The compounds were detected by absorbing ultraviolet light (UV) at 274 nm. The homogeneity of the target compound was also confirmed by thin layer chromatography (TLC) using Analtech silica gel-GF (250 mm) plates and solvent systems: SNS1z / MeON / sop NH4OH / H2O (70: 30: 3: 3 v / v). TLC results were visualized with UV light, phospray (Supelco, Bellefonte, PA, USA) and carbonization at 400 ° C.

Example 1. Preparation of benzyl octadecyloxyethyl 9- [2- (phosphonomethoxy) ethyl] guanine, 1- (Rp, Sp) (Compound 1, Bn-ODE-PMEG).

[0164]

ODE-PMEG

beshil alcohol

----------------------......>.

Py8QP; DIEA. N.NOMF 62% prhios

N '> ϋ

N9

57796 Β1 In a solution of octadecyloxyethyl 9- [2- (phosphonomethoxy) ethyl] guanine (ODE-PMEG) [prepared according to: Valiaeva, N. et al .; Antiviral Research, 2006, 72: 10-19] (0.21 g, 0.35 mmol), (benzotriazol-1-yloxy) -tripyrrolidinophosphonium hexafluorophosphate (ΡΥΒΟΡ®, 0.27 g, 0.525 mmol) and anhydrous benzyl alcohol (0.05 ml, 0.525 mmol) in dry N, N-DMF, diisopropylethylamine (DIEA, 0.24 mL, 1.4 mmol) was added. The mixture was stirred at room temperature for 30 min. The solvents were evaporated in vacuo. The residue was dissolved in ethyl acetate (50 ml) and extracted with saturated sodium bicarbonate (2 x 10 ml). The ethyl acetate layer was evaporated, and then the residue was adsorbed onto silica gel and purified by flash column chromatography. Elution with CthCh / MeOH (0-5%) gave 0.15 g (62%) of Compound 1 as a white powder. 1 H NMR (CDCl 3 / methanol-ck) b 7.56 (s, 1H); 7.35-7. 40 (m, 5H); 5.08 (dd, J = 9 Hz, J1 = 2 Hz, 2 H); 4.19 (t, J = 7 Hz, 2 H); 4.09-4. 17 (m, 2H); 3.87 (t, J = 5 Hz, 2 H), 3.85 (dd, J = 8 Hz, J = 2 Hz, 2 H); 3.57 (t, J = 5 Hz, 2 H); 3.44 (t, J = 7 Hz, 2 H); 1.50-1. 60 (m, 2 H); 1.20-1. 38 (m, 30H); 0.89 (t, J = 7 Hz, ZN). MS (EI): 676.34 (M + H)+, 698.41 (M + Na)+.

Example 2. Decomposition of β-chiral enantiomers of benzyl octadecyloxyethyl 9- [2 (phosphonomethoxy) ethyl] guanine.

[0166]

rgfagaptaa HPI.C

.................................................. ...... fn

Lux cellulose-l, reveizna iaza

Bn-OOE-PMEG

The Bn-ODE-PMEG of Example 1 was obtained as a mixture of enantiomers due to chirality on phosphorus. Enantiomers were separated on a Lux ™ cellulose-1 column (Phenomenex®, Torrance, CA USA) using reverse phase conditions (mobile phase 50: 50: 0.1 20 mM AmmAc: AcN: TFA). The absolute stereochemistry of β-chiral enantiomers has not been determined. Preparative chromatographic decomposition of the material obtained in Example 1 gave two enantiomers which were characterized as la (fast eluting enantiomer) and 1b (slow eluting enantiomer). An example of a chromatogram is given in FIG. 1.

57796 Β1 In the following examples, the preparation of a racemic mixture is described, however, the process of

Example 2, or modifications thereof known from the prior art, can be used to decompose each into optically active enantiomers or diastereomers as needed.

Example 3. Preparation of benzyl octadecyloxyethyl 9- [2- (phosphonomethoxy) ethyl] adenine (Compound 2,

Bn-ODE-PMEA).

[0169]

ΝΗ »on

OOE-PMEA '50ft> yield

Yes

Sn-ODE-PMEA

In a solution of octadecyloxyethyl 9- [2- (phosphonomethoxy) ethyl] adenma (ODE PMEA) [prepared according to: Valiaeva, N. et al. Antiviral Research 2006, 72: 10-19] (0.2 g, 0.35 mmol), (benzotriazol-1-yloxy) -tripyrrolidinophosphonium hexafluorophosphate (ΡΥΒΟΡ®, 0.27 g, 0.525 mmol), anhydrous benzyl alcohol (0.05 mL, 0.525 mmol) in dry Ν, Ν-DMF, diisopropylethylamine (DIEA, 0.24 mL, 1.4 mmol) was added. The mixture was stirred at room temperature for 30 min. The solvents were evaporated. The residue was dissolved in ethyl acetate (50 ml) and washed with saturated sodium bicarbonate solution (2x10 ml). The ethyl acetate layer was evaporated, and then the residue was purified by silica gel column chromatography using SNgSE / MsON (0-5%) to give 0.12 g (50%) of compound 2. 1 H NMR CDCl 3 / methanol-cU) b 8.25 (s, 1H); 7.99 (s, 1 H); 7.30-7. 40 (m, 5H); 5.07 (dd, J = 9Hz, J1 = 2Hz, 2H); 4.38 (t, J = 7 Hz, 2 H); 4.08-4. 18 (m, 2H); 3.88 (t, J = 5 Hz, 2 H), 3.83 (dd, J = 8 Hz, J = 2 Hz, 2 H); 3.56 (t, J = 5 Hz, 2 H); 3.42 (t, J = 7 Hz, 2 H); 1.50-1. 60 (m, 2 H); 1.20-1. 38 (m, 30H); 0.88 (t, J = 7 Hz, ZN). MS (EI): 660.55 (M + H)+.

Example 4. Preparation of benzyl octadecyloxyethyl 9- (S) - [3-hydroxy-2- (phosphonomethoxy) propyl] adenine (Compound 218, Bn-ODE- (S) -HPMPA).

Procedure 1:

[0171]

57796 ΒΙ

80¾ sirćetda .. kiselsns benzsl aljkohol

RuEKŽ DIEA, $ 0% pnnos

In a solution of octadecyloxyethyl 9- (S) - [3-trityloxy-2- (phosphonomethoxy) propyl] -N6trityladenine (prepared as described in: Beadle, JR et al., Joumal of Medicinal Chemistry 2006, 49: 2010- 2015) (0.42 g, 0.38 mmol), (benzotriazol-1-yloxy) tripyrrolidinophosphonium hexafluorophosphate (ΡΥΒΟΡ®, 0.30 g, 0.58 mmol), benzyl alcohol (0.06 mL, 0.58 mmol) in dry N, N-DMF (2 mL) , diisopropylethylamine (DIEA, 0.4 ml,

1.52 mmol). The mixture was stirred at room temperature for 30 min. The solvents were evaporated. The residue was dissolved in ethyl acetate (50 ml), and then washed with saturated sodium bicarbonate solution (2x10 ml). Ethyl acetate was evaporated, and the residue was purified by silica gel column chromatography using CFhCh / MeOH (0-5%) to give 0.23 g (51%) of product.

1 H NMR (CDCl 3 / methanol-cU) δ 7.89 (s, 1H); 7.16-7.40 (m, 36 H); 5.03 (dd, J = 9 Hz, J1 = 2 Hz, 2 H); 4.27-4. 44 (m, 2H); 4.06-4.14 (m, 1H); 3.91-4.04 (m, 2 H), 3.83 (dd, J = 8 Hz, J1 = 2 Hz, 2 H); 3.40-3. 50 (m, 2 H); 3.27-3. 40 (m, 4H); 1.42-1. 58 (m, 2H); 1.18-1. 38 (m, 30H); 0.88 (t, J = 7 Hz, ZN). MS (EI): 1174.27 (M + H)+ The protected intermediate (0.13 g, 0.11 mmol) was added to 80% aqueous acetic acid solution (10 mL) and stirred at 30 ° C for 3 hours. After cooling, the solvent was evaporated and the residue was purified by silica gel column chromatography to give compound 218 (0.04 g, 52% yield). 1 H NMR (CDCl 3 / methanol-ck) δ 8.25 (s, 1H); 7.89 (s, 1 H); 7.26-7. 38 (m, 5H); 5.09 (dd, J = 9 Hz, J1 = 2 Hz, 2 H); 4.28-4. 43 (m, 2H); 4.06-4. 18 (m, 1H); 3.95-4.05 (m, 2 H), 3.80 (dd, J = 8 Hz, J 1 = 2 Hz, 2 H); 3.50-3. 60 (m, 2 H); 3.25-3. 38 (m, 4H); 1.49-1. 60 (m, 2 H); 1.101.40 (m, 30 H); 0.88 (t, J = 7 Hz, ZN). MS (EI): 690.49 (M + H)+, 712.47 (M + H)+.

Procedure 2:

[0174]

57796 Β1

ΜΝ-Tg

natfijmn t-lšutoksjd.

M-DMF

octadecyl ciethanol

RubOR. Di £ ANM-DMP

S0% pmics

H ^ -Tr

L <GNo.'

YES H1Č 'j

O lJ ^ HSM * feCKGHili ίΟΗ, Ο u

H // 2

S €?% Sftgefaia .C ^ ejša | A ^ -OiCHA'Ol ^ VCHj

- -> 4, vy

L no <

Mixture of 9- (S) - [3-trityloxy-2-hydroxypropyl] -N6-trityladenine [prepared as in: Webb, RR, Nucleosides & Nucleotides, 1989, 8: 619-24] (1.4g, 2.0 mmol ) and sodium tert-butoxide (0.39 g, 4 mmol) in dry N, N-DMF (10 mL) was stirred at room temperature for 30 min, then benzyl p-toluenesulfonyloxymethylphosphonate was added (0.94 g, 2.5 mmol, see Example 6). The mixture was stirred at 80 ° C overnight. The solvent was evaporated, and then the residue was purified by silica gel column chromatography to give benzyl 9- (S) - [3-trityloxy-2 (phosphonomethoxy) propyl] -N6-trityladenine 0.75 g (42%). 1 H NMR (CDCl 3 / methanol-cU) δ 8.09 (s, 1H); 7.88 (s, 1 H); 7.08-7.60 (m, 30 H); 4.84-4. 88 (m, 2H); 4.20-4. 30 (m, 2 H); 3.78 - 4.90 (m, 1 H); 3.50-3.72 (m, 2 H), 2.99-3.18 (m, 2 H).

To a solution of this intermediate (0.2 g, 0.22 mmol), (benzotriazol-1-yloxy) tripyrrolidinophosphonium hexafluorophosphate (ΡΥΒΟΡ®, 0.17 g, 0.33 mmol) and octadecyloxyethanol (0.10g, 0.33 mmol) in dry N, N-DMF (2 mL), diisopropylethylamine (DIEA, 0.15ml, 0.88 mmol) was added. The mixture was stirred at room temperature for 30 min and the solvent was evaporated. The residue was dissolved in ethyl acetate (50 ml) and washed with saturated sodium bicarbonate solution (2 x 10 ml). The ethyl acetate layer was evaporated and then the residue was quenched by silica gel column chromatography using CFhCl / MeOH (0-5%) to give 0.15 g (58%) of product. 1 N NMR (CDCl 3 / methanol-ck) b: 7.93 (s, 1H); 7.87 (s, 1 H); 7.16-7. 42 (m, 35H); 5.00 (dd, J = 9Hz, J1 = 2Hz, 2H); 4.27-4. 44 (m, 2H); 4.06-4. 14 (m, 1 H); 3.91-4.04 (m, 2 H), 3.83 (dd, J = 8 Hz, J1 = 2 Hz, 2 H); 3.40-3. 50 (m, 2 H); 3.27-3. 40 (m, 4H); 1.42-1. 58 (m, 2H); 1.18-1. 38 (m, 30H); 0.88 (t, J = 7 Hz, ZN). MS (EI): 1174.29 (M + H)+;

1196.52 (M + Na)+.

57796 Β1 The protected compound (0.15 g, 0.13 mmol) was treated with 80% aqueous acetic acid solution (10 mL) at 30 ° C for 3 hours. The solvents were evaporated, and then the residue was purified by silica gel column chromatography to give compound 218 (0.06g, 68%). 1 N NMR (CDCl 3 / methanol-cU) b: 8.24 (s, 1H); 7.52 (s. 1H); 7.34-7. 38 (m, 5H); 5.06 (dd, J = 9 Hz, J1 = 2 Hz, 2 H); 4.28-4. 46 (m, 2H); 4.06-4. 16 (m, 2H); 3.95 - 4.16 (m, 1 H), 3.76 - 3.87 (m, 2 H); 3.52-3. 66 (m, 4H); 3.39-3. 48 (m, 2H); 1.49-1. 60 (m, 2 H); 1.20-1. 40 (m, 30H); 0.89 (t, J = 7 Hz, ZN). MS (EI): 690.47 (M + H)+, 712.45 (M + Na)+.

Example 5. Preparation of isopropylidene glyceryl octadecyloxyethyl 9- (2-phosphonomethoxyethyl) guanine.

[0178]

To a suspension of octadecyloxyethyl 9- [2- (phosphonomethoxy) ethyl] guanine (ODE PMEG)) [prepared according to: Valiaeva, N. et al .; Antiviral Research, 2006, 72: 10-19] (0.18 g, 0.30 mmol), oxalyl chloride (0.56 mL, 0.48 mmol) in dry toluene (5 mL), DMF (0.06 mL) was added. The mixture was stirred at room temperature for 1 hour. The solvent was evaporated in vacuo and co-evaporated with toluene (2 x 10 mL). The residue was dissolved in toluene (5 mL) and isopropylidene glycerol (0.09 g, 0.6 mmol) was added. The mixture was stirred at room temperature overnight.

Saturated sodium bicarbonate solution (5 ml) was added and the mixture was stirred for 30 min. The toluene fraction was evaporated and purified by column chromatography on silica gel to give 0.05g of IPG-ODE-PMEG (23%). 1 H NMR (CDCl 3 / methanol-dt) δ: 8.91 (s, 1H); 8.15 (s. 1H); 4.44-

4.52 (m, 2 H); 4.18-4. 34 (m, 2H); 4.13-4. 18 (m, 1H); 4.02-4. 13 (m, 2H); 3.95-4. 18 (m, 2H); 3.68-3. 84 (m, 2H); 3.60-3. 67 (m, 2H); 3.44-3. 52 (m, 2H); 1.42 (t, J = 7 Hz, ZN); 1.36 (t, J = 7 Hz, ZN); 1.22-1. 34 (m, 30H), 0.89 (t, J = 7Hz, ZN). MS (EI): 700.37 (M + H)+, 722.43 (M + Na)+.

Example 6. Preparation of benzyl p-toluenesulfonyloxymethylphosphonate, sodium salt.

57796 Β1 Diethyl p-toluenesulfonyloxymethyl phosphonate (3.2 g, 9.9 mmol) was dissolved in N, N-DMF (10ml) and then bromotrimethylsilane (10ml) was added. The mixture was stirred at room temperature overnight. The solvent was evaporated and co-evaporated with toluene (2 x 10 mL). An ethanol / water mixture (10ml) was added and then the mixture was stirred for 30 min at room temperature. The solvents were evaporated and co-evaporated with toluene (2 x 10 mL). The residue was suspended in toluene (50 mL), and then oxalyl chloride (1.3 mL, 15.0 mmol) was added, followed by N, N-DMF (0.01 mL). The mixture was stirred at room temperature for 1 hour. The solvents were evaporated and co-evaporated with toluene (2 x 10 mL). The residue was suspended in toluene (25 mL), and then anhydrous benzyl alcohol (1.5 mL, 15.0 mmol) was added. The mixture was stirred at room temperature overnight. Saturated sodium bicarbonate solution (15 ml) was added and then the mixture was stirred for 30 min. The toluene fraction was evaporated and the residue was purified by column chromatography on gel images to give 2.94 g of benzyl p-toluenesulfonyloxymethyl phosphonate, sodium salt (81%). 31 H NMR (CDCl 3 / methanolCl) δ: 7.72 (d, J ~ 8Hz, 2H); 7.30-7. 33 (m, 7H); 4.88 (d, J = 7 Hz, 2 H); 4.02 (d, J = 9 Hz, 2 H); 2.44 (s, ZN).

Reference Example 7. Preparation of Benzyl 10-octadecyl-2-O-benzyl-sn-glyceryl 9- (S) - [(3-hydroxypropyl-2-phosphonomethoxy) propyl] adenine (Compound 230, Bn-ODBG- (S) -HPMPA) .

[0181]

To a solution of benzyl 9- (S) - [3-trityloxy-2- (phosphonomethoxy) propyl] -N6-trityladenine (prepared as in Example 4, method 2) (0.4 g, 0.44 mmol), (benzotriazole-1) -yloxy)

57796 Β1 tripyrrolidinophosphonium hexafluorophosphate (ΡΥΒΟΡ®, 0.27 g, 0.51 mmol), 10-octadecyl-2O-benzyl-sn-glycerol (0.22 g, 0.51 mmol) in dry Ν, Ν-DMF (1 ml), diisopropylethylamine was added, 0.30ml, 1.7mmol). The mixture was stirred at room temperature for 30 min. The solvents were evaporated. The residue was dissolved in ethyl acetate (50 mL), and then washed with saturated sodium bicarbonate solution (2 x 10 mL). The ethyl acetate layer was evaporated and then the residue was purified by silica gel column chromatography using SNgOg / MsON (0-5%) to give 0.15 g (58%) of product. 1 H NMR (CDCl 3 / methanol-cU) b: 7.88 (s, 1H); 7.87 (s, 1 H); 7.19-7. 42 (m, 40H); 4.95-5. 03 (m, 2H); 4.57-4. 60 (m, 2 H); 4.29-4. 39 (m, 2H); 4.16-4.28 (m, 2 H), 4.00-4.12 (m, 1 H); 3.90 - 3.98 (m, 1 H); 3.65-3. 81 (m, 4H); 3.45-3. 49 (m, 2H); 1.46-

1.53 (m, 2 H); 1.22-1. 32 (m, 30H); 0.88 (t, J = 7 Hz, ZN). MS (EI): 1294.27 (M + H)+; 1316.57 (M + Na)+.

The protected compound (0.33 g, 0.13 mmol) was treated with 80% aqueous acetic acid (20 mL) at 30 ° C for 3 hours. The solvents were then evaporated and the residue was purified by silica gel column chromatography to give compound 230 (0.13g, 65%). 1 H NMR (CDCl 3 / methanol-cU) b: 8.22 (s, 1H); 7.65 (s, 1 H); 7.27-7. 35 (m, 10H); 4.995.04 (m, 2 H); 4.58-4. 66 (m, 2H); 4.33-4. 43 (m, 1H); 4.16-4.33 (m, 2 H), 3.94-4.12 (m, 2 H); 3.80-3. 88 (m, 1H); 3.68-3. 78 (m, 2H); 3.38 - 3.62 (m, 4 H); 1.50-1. 58 (m, 2H); 1.22-1. 38 (m, 30H); 0.89 (t, J = 7 Hz, ZN). MS (EI): 810.47 (M + H)+, 832.44 (M + Na)+.

Example 8. Preparation of benzyl octadecyloxyethyl 1 - [(S) - [(3-hydroxy-2phosphonomethoxy) propyl] cytosine (Compound 219, Bn-ODE- (S) -HPMPC).

[0184]

57796 Β1 oktsttecjlcksseSaaol

RuKZR. DfEA, N.JMJMF

NHMMTt

NHMMTr

f'i o

LA i ό

n Ο

O ns <L

Mixture of 1- (S) - [3-trityloxy-2-hydroxypropyl] -N-trifluoroxytritylcytosine [prepared as described in: Beadle, JR, et al., PCT International Application WO 2005/087788 A2, published 22.9.2005] (1.84g, 2.63 mmol) and sodium yt-butoxide (1.24g, 3.29mmol) in dry DMF (20 ml) was stirred at room temperature for 30 min. Benzyl ptoluensulfonyloxymethylphosphonate (0.94g, 2.5 mmol, see Example 6) was added and the mixture was stirred at 80 ° C overnight. The solvent was evaporated, and the residue was purified by silica gel column chromatography to give benzyl 1- (S) - [3-trityloxy-2- (phosphonomethoxy) propyl] -N-monomethoxytritylcytosine 1.25g (52%). 1 N NMR (CDCl 3 / methanol-ck) δ: 7.12-7.48 (m, 24H); 7.05 (d, J = 9 Hz, 1 H); 6.79 (d, J = 9 Hz, 1 H); 4.70 (dd, L = 30 Hz, J 2 = 6 Hz, 2H); 4.20-4. 30 (m, 2 H); 3.78 - 4.90 (m, 1 H); 3.77 (s, ZN); 3.50-3.72 (m, 2 H), 2.99-3.18 (m, 2 H). (EI): 883.99 (M + H)+, 906.22 (M + Na)+.

To a solution of this intermediate (0.6g, 0.66mmol), (benzotriazol-1-yloxy) tripyrrolidinophosphonium hexafluorophosphate (ΡΥΒΟΡ®, 0.52 g, 0.99 mmol), octadecyloxyethanol (0.3 lg, 0.52 mmol) in dry DMF (5ml) diisopropylethylamine (DIEA, 0.46ml, 2.65 mmol) was added. The mixture was stirred at room temperature for 30 min and then the solvents were evaporated. The residue was dissolved in ethyl acetate (50 ml), and washed with saturated sodium bicarbonate solution (2 x 10 ml). Ethyl acetate was evaporated, and the residue was purified by silica gel column chromatography using SNgSE / MsON (0-5%) to give the product. 1 N NMR (CDCl 3 / methanol-cU) δ: 7.18-7.44 (m, 34H); 7.13 (dd, J1 = 14Hz, J2 = 7Hz, 1H); 6.85 (dd, J1 = 14Hz, J2 = 7Hz, 1H); 5.00 (dd, J1 = 8Hz, J2 = 3Hz, 2H); 4.04-4.12 (m, 2 H); 3.88-3. 95 (m, 1 H); 3.80 (s, ZN); 3.58-3. 79 (m, 4H); 3.45-3. 57 (m, 2H); 3.16-3. 22 (m, 1H);

57796 Β1

3.02-3.08 (m, 1 H); 1.43-1. 52 (m, 2H); 1.08-1. 38 (m, 30H); 0.88 (t, J = 7 Hz, ZN). (EI): 1180.10 (M + H)+, 1202.57 (M + Na)+.

The protected compound (0.44g, 0.37 mmol) was treated with 80% acetic acid (20 mL) at 30 ° C for 3 hours. The solvents were evaporated, and the residue was purified by column chromatography to give compound 219 (0.16 g, 64%). 1 H NMR (CDCl 3 / methanol-cU) δ: 7.40-7.42 (m, 5H); 7.38 (dd, J1 = 14Hz, J2 = 7Hz, 1H); 5.73 (dd, J1 = 14Hz, J2 = 7Hz, 1H); 5.12 (dd, J1 = 8Hz, J2 = 3Hz, 2H); 4.10-4.20 (m, 2H), 3.99-4.10 (m, 2H), 3.50-3.80 (m, 7H), 3.40-3.50 (m, 2H); 1.50-1.62 (m, 2 H), 1.20-1.40 (m, 30 H), 0.89 (t, J = 7 Hz, ZN). Mass spec (ESI): 666.54 (M + H)+, 688.52 (M + Na)+.

Reference Example 9. Preparation of Benzyl 10-octadecyl-2-O-benzyl-sn-glyceryl 1- (S) - [3-hydroxy-2- (phosphonomethoxy) propyl] cytosine (Compound 231, Bn-ODBG (S) -HPMPC).

To a solution of the intermediate of Example 8, benzyl 1- (S) - [3-trityloxy-2 (phosphonomethoxy) propyl] N4-monomethoxytrityl cytosine (0.57g, 0.63mmol), (benzotriazol-1yloxy) -tripyrrolidinophosphonium hexafluorophosphate (ΡΥΒΟΡ®, 0.49 g, 0.95 mmol) and 1-Octadecyl-2-O-benzyl-5n-glycerol (0.4lg, 0.95 mm) in dry DMF (5ml), diisopropylethylamine (DIEA, 0.44ml, 2.52 mmol) was added. The mixture was stirred at room temperature for 30 min. The solvents were evaporated. The residue was dissolved in ethyl acetate (50 ml) and washed with saturated sodium bicarbonate solution (2x10 ml). Ethyl acetate was evaporated, and the residue was purified by silica gel column chromatography using CthCh / MeOH (0-5%) to give 0.30 g (36%) of product. 1 H NMR (CDCl 3 / methanol-1H) δ: 7.19-7.45 (m, 39H); 7.15 (dd, J1 = 14Hz, J2 = 7Hz, 1H); 6.82 (dd, J1 = 14Hz, J2 = 7Hz, 1H); 5.00 (dd, J1 = 8Hz, J2 = 3Hz, 2H); 4.69-4. 71 (m, 2H); 4.05 (s, ZN), 3.96-4.05 (m, 2H); 3.82 - 3.90 (m, 1 H); 3.50-3. 80 (m, 4 H); 3.40-3. 53 (m, 2H); 3.24-3. 40 (m, 4 H); 3.02-3.08 (m, 1 H); 1.43-1. 50 (m, 2 H); 1.20-1. 40 (m, 30H); 0.88 (t, J = 7 Hz, ZN). (EI): 1301.06 (M + H)+, 1322.58 (M + Na)+.

The protected compound (0.30g, 0.23 mmol) was then treated with 80% acetic acid (20 mL) at 30 ° C for 3 hours. The solvents were evaporated, and the residue was purified by column chromatography to give compound 231 (0.10g, 55%). 1 NMR (CDCl 3 / methanol-cU) δ: 7.31-7.40 (m, 10H); 7.28 (dd, J1 = 14Hz, J2 = 7Hz, 1H); 5.66 (dd, J1 = 14Hz, J2 = 7Hz, 1H); 5.07 (dd, J1 = 8Hz, J2 = 3Hz, 2H); 4.63-4. 66 (m, 2H), 4.18-4.27 (m, 2H), 4.02-4.14 (m, 2H), 3.90-3.98 (m, 2H), 3.40-3.84 (m, 8H); 1.50-1.62 (m, 2 H), 1.20-1.40 (m, 30 H), 0.89 (t, J = 7 Hz, ZN). Mass spec (ESI): 786.43 (M + H)+, 808.41 (M + Na)+.

57796 Β1

Example 10. Preparation of phenyl octadecyloxyethyl 9- [2- (phosphonomethoxy) ethyl] guanine (Compound 19,

Ph-ODEPMEG):

[0190]

ODE-PMEG

LMSA, N> OMF o

PtvOOE-PMEG To a solution of octadecyloxyethyl 9- [2- (phosphonomethoxy) ethyl] guanine (ODE-PMEG, 0.26 g, 0.44 mmol) [prepared according to: Valiaeva, N. et al. Antiviral Research 2006, 72: 10-19], (benzotriazol-1-yloxy) -tripyrrolidinophosphonium hexafluorophosphate (ΡΥΒΟΡ®, 0.34 g, 0.66 mmol) and phenol (0.06 g, 0.66 mmol) in anhydrous Ν, Ν-DMF, was added diisopropylethylamine (DIEA, 0.30 mL, 1.8 mmol). The mixture was stirred at room temperature for 30 min, and then the solvent was evaporated in vacuo. The residue was dissolved in ethyl acetate (50 ml) and washed with saturated sodium bicarbonate solution (2 x 10 ml). The ethyl acetate layer was evaporated, and the crude residue was triturated by flash chromatography on silica gel using CthCh / MeOH (0-5%) to give 0.09 g (31%) of compound 19 as a white powder. 1 NMR (CDCl 3 / methanol-cU) δ: 7.66 (s, 1H); 7.36 (t, J = 8 Hz, 2 H); 7.20 (t, J = 7 Hz, 1 H); 7.13 (d, J = 8 Hz, 2 H); 4.23-4. 30 (m, 4H); 4.03 (dd, J = 8Hz, J1 = 2Hz, 2H); 3.93 (t, J = 5 Hz, 2 H); 3.61 (t, J = 5 Hz, 2 H), 3.41-3.45 (m, 2 H), 1.50-1.60 (m, 2 H); 1.20-1. 38 (m, 30H); 0.89 (t, J = 7 Hz, ZN). MS (EI): 662.43 (M + H) +, 684.39 (M + Na)+.

Example 11. Preparation of benzyl octadecyloxyethyl 9- (S) - [3-methoxy-2 (phosphonomethoxy) propyl] adenine (Compound 146, Bn-ODE- (S) -MPMPA).

[0192] o § 't OH. ..... X

HiC'O 'ODE- (S) -MPSifPA beaail alkoisijL

an-OOE + SFMPMPA In a solution of octadecyloxyethyl 9- [3-methoxy-2- (phosphonomethoxy) propyl] adenine (ODE-S) MPMPA, 0.62 g, 1.00 mmol) [prepared as described in: Valiaeva, N et al. Bioorganic & Medicinal Chemistry, 2011, 19: 4616-4625]), (benzotriazol-1-yloxy) tripyrrolidinophosphonium hexafluorophosphate (ΡΥΒΟΡ®, 0.78 g, 0.66 mmol) and benzyl alcohol (0.16 ml, 1.50 mmol) in anhydrous Ν, Ν- DMF, diisopropylethylamine (DIEA, 0.70 mL, 4.0 mmol) was added. The mixture was stirred at room temperature for 30 min, and then the solvents were washed

57796 ΒΙ under vacuum. The residue was dissolved in ethyl acetate (50 mL) and then washed with saturated NaHCO 3 (2 x 10 mL). The ethyl acetate layer was evaporated and the residue was purified by flash column chromatography on silica gel using CFhCl / MeOH (0-5%) to give 0.29 g (41%) of compound 146. 1 H NMR (CDCl 3 / methanol-cU) δ 8.24 (d, .7 = 5.50 Ηζ, 1 H), 8.05 (d, 7 = 7.33 Hz, 1 H), 7.30 - 7.39 (m, 5 H), 5.00- 5.15 (m, 2 H); 4.40-4. 45 (m, 1H); 4.28 - 4.36 (m, 1 H); 4,004.18 (m, ZN); 3.80-3. 98 (m, 2H); 3.40-3. 60 (m, 6H); 3.35 (s, 3 H), 1.45 - 1.60 (m, 2 H), 1.22 1.36 (m, 30 H), 0.89 (t, J = 7 Hz, ZN). MS (EI): 704.52 (M + H)+, 726.45 (M + Na)+.

Example 12. Preparation of phenyl octadecyloxyethyl 9- (S) - [3-methoxy-2 (phosphonomethoxy) propyl] ddenine (Compound 164, Ph-ODE- (S) -MPMPA).

[0194]

NH-

ODE- {S) -iW₽IWPA

31EA,

Pft4JDE- (S} -MFIWPA [0195] In a solution of octadecyloxyethyl 9- [3-methoxy-2- (phosphonomethoxy) propyl] adenine (ODE (S) MPMPA, 0.62 g, 1.00 mmol) [prepared as described in: Valiaeva , N. et al., Bioorganic & Medicinal Chemistry, 2011, 19: 4616-4625], (benzotriazol-1-yloxy) -tripyrrolidinophosphonium hexafluorophosphate (ΡΥΒΟΡ®, 0.78 g, 0.66 mmol) and phenol (0.14 g, 1.50 mmol) in dry N, NDMF, diisopropylethylamine (DIEA, 0.70 mL, 4.0 mmol) was added. The mixture was stirred at room temperature for 30 min, and then the solvent was evaporated in vacuo. The residue was dissolved in ethyl acetate (50 ml), and then washed with saturated sodium bicarbonate (2 x 10 ml). The ethyl acetate layer was evaporated. The crude residue was purified by flash column chromatography on silica gel using CthCh / MeOH (0-5%) to give 0.29 g (41%) of compound 164 as an off-white solid.ΧΗ NMR (CDCl 3 / methanol-cU) δ 8.23 (d, 7 = 5.50 Ηζ, 1 H), 8.05 (d, 7 = 7.33 Ηζ, 1 H), 7.29 - 7.37 (m, 2 H), 7.20 (d, 7 = 6.60 Ηζ, 1 H), 7.12 - 7.16 (m, 1 H), 7.08 (dt, 7 = 8.71, 1.15 Ηζ, 1 H), 4.30 - 4.45 (m, 2 H), 4.11 - 4.28 (m, 3 H), 3.98 - 4.07 (m, 2 H), 3.42 - 3.63 (m, 6 H), 3.34 (s, 3 H), 1.48 - 1.59 (m, 2 H), 1.22 - 1.36 (m, 30 H) ), 0.89 (t, J = 7 Hz, ZN). MS (EI): 704.52 (M + H)+, 726.45 (M + Na)+.

Example 13. Preparation of benzyl hexadecyloxypropyl 9- [2- (phosphonomethoxy) ethyl] guanine (Compound 25, Bn-HDPPMEG)

57796 ΒΙ

NOR-RRLEb. .Ό4- * hj χ HxS **

Bn-HCP-PMEG

In a solution of hexadecyloxypropyl 9- [2- (phosphonomethoxy) propyl] guanine (HDP PMEG, 0.28 g, 0.49 mmol) [prepared according to: Valiaeva, N. et al., Antiviral Research, 2006, 72: 10-19] , ((Benzotriazol-1-yloxy) -tripyrrolidinophosphonium hexafluorophosphate (ΡΥΒΟΡ®, 0.39 g, 0.74 mmol) and benzyl alcohol (0.10 mL, 0.74 mmol) in dry Ν, Ν-DMF, diisopropylethylamine was added (DIEA, 0.35 mL, 2.0 mmol) ). The mixture was stirred at room temperature for 30 min. the mixture was concentrated in vacuo. The resulting residue was dissolved in ethyl acetate (50 mL) and then washed with saturated sodium bicarbonate (2 x 10 mL). The ethyl acetate layer was evaporated and the crude product was purified by flash column chromatography on silica gel using SSCN / MeOH (0-5%) to give 0.03 g (10%) of compound 25 as a white powder. 1 H NMR (CDCl 3 / methanol-ck) δ: 7.62 (s, 1H), 7.30 - 7.44 (m, 5H), 5.07 (dd, 7 = 8.98, 2.02 Hz, 2H), 4.05 - 4.24 (m , 4H), 3.83 (m, 4H), 3.31 - 3.42 (m, 4H), 1.87 (m, 2H), 1.54 (m,

H), 1.17 - 1.38 (m, 26 H), 0.86 - 0.91 (m, 3 H). MS (EI): 662.46 (M + H)+, 684.46 (M + Na)+.

Example 14. Preparation of benzyl octadecyloxyethyl 9- (R) - [2- (phyphonomethoxy) propyl] adenine (Compound 74, Bn-ODE- (R) -PMPA)

ΝΙ · ζ: Md

ž. V

Bn-ODE-iR) -PMPA

To a solution of octadecyloxyethyl 9- [2- (phosphonomethoxy) propyl] adenine (ODE- (R) -PMPA, 0.30 g, 0.51 mmol) [prepared as described in: Painter, G et al. Antimicrobial Agents and Chemotherapy, 2007, 51: 3505-3509], (benzotriazol-1-yloxy) -tripyrrolidinophosphonium hexafluorophosphate (ΡΥΒΟΡ®, 0.40 g, 0.77 mmol), and benzyl alcohol (0.08 ml, 0.77 mmol) in dry Ν, Ν -DMF, diisopropylethylamine (DIEA, 0.35 mL, 2.0 mmol) was added. The mixture was stirred at room temperature for 30 min, and then the solvent was evaporated in vacuo. The resulting residue was dissolved in ethyl acetate (50 mL) and washed with saturated NaHCO 3 (2 x 10 mL). The ethyl acetate layer was evaporated, and the crude product was purified by flash column chromatography on silica gel using CFhCh / MeOH (0-5%) to give 0.24 g (70%) of compound 74. Ή NMR (400 MHz, CDCl 3 + methanol-cU) b ppm 8.24 (s, 1H), 8.03 (d, 7 = 4.40 Ηζ, 1H), 7.30 - 7.42 (m,

57796 Β1

Η), 4.99 - 5.14 (m, 2 (), 4.35 (d, 1 = 14.66 Ηζ, 1 Η), 4.07 - 4.20 (m, 3 Η), 3.92 (ddd, /=13.75, 8.98, 4.77 Ηζ, 2 Η), 3.65 - 3.73 (m, 1 (), 3.50 - 3.61 (m, 2 (), 3.38 - 3.47 (m, 2 (),

1.49 - 1.61 (m, 2 Η), 1.27 (m, 30 Η), 1.21 (d, /=6.23 Ηζ, 3 Η), 0. 09 (t, /=8.00 Ηζ, 3 Η). MS (ΕΙ): 674.48 (Μ + Η)+, 693.46 (M + Na)+.

Example 15. Preparation of phenyl octadecyloxyethyl 9- (R) - [2- (phosphonomethoxy) propyl] adenine (Compound 94, Ph-ODE- (R) -PMPA)

3,9

Of> ^ R) -PMPA

RuVOR

£) IKA. NN-OM?

^ H2 ]: \\ о

GK

Ph-O- (R) -PMPA [0201] To a solution of octadecyloxyethyl 9- [2- (phosphonomethoxy) propyl] adenine (ODE PMPA, 0.30 g, 0.51 mmol) [prepared as described in: Painter, G et al. Antimicrobial Agents and Chemotherapy, 2007, 51: 3505-3509], (benzotriazol-1-yloxy) -tripyrrolidinophosphonium hexafluorophosphate (ΡΥΒΟΡ®, 0.40 g, 0.77 mmol), and phenol (0.072 g, 0.77 mmol) in dry Ν, Ν- DMF, d was added isoisopropylethylamine (DIEA, 0.35 mL, 2.0 mmol) was added. The mixture was stirred at room temperature for 30 min, and then the solvent was evaporated in vacuo. The residue was dissolved in ethyl acetate (50 ml), and washed with saturated sodium bicarbonate solution (2 x 10 ml). The ethyl acetate layer was evaporated, and then the crude product was purified by silica gel column chromatography using SNgSk / MeON (0-5%) to give 0.25 g (75%) of compound 94. 1 H NMR (400 MHz, CDCl 3)3 + methanol-ik) b ppm 8.24 (d, /=3.30 Ηζ, 1 H), 8.05 (d, /=6.23 Ηζ, 1 H), 7.29 - 7.37 (m, 2 H), 7.17 - 7.24 (m, 1 H), 7.05 - 7.15 (m, 2H), 4.37 (d, /=1.47 Ηζ, 1H), 4.04 - 4.31 (m, 4H), 3.94 - 4.03 (m, 1H), 3.86 (dd, /=9.53, 1.10 Ηζ, 1 H), 3.60 (d, /=4.03 Hz, 2 H), 3.38 - 3.47 (m, 2 H), 1.48 - 1.60 (m, 2 H), 1.21 - 1.35 (m, 33 H), 0.89 (t, / = 8.00 Hz, 3 H). MS (EI): 660.47 (M + H)+, 682.41 (M + Na)+.

Example 16 Preparation of benzyl octadecyloxyethyl 9- (R) - [2- (phosphonomethoxy) propyl] guanine (Compound 73, Bn-ODE- (R) -PMPG) [0202]

57796 Β1

OOE ^ RH »MPG

In a solution of octadecyloxyethyl 9- (R) - [2- (phosphonomethoxy) propyl] guanine (Bn-ODE- (R) PMPG, 180 mg, 0.3 mmol) [prepared as described in: Painter, G et al . Antimicrobial Agents and Chemotherapy, 2007, 51: 3505-3509], (benzotriazol-1-yloxy) tripyrrolidinophosphonium hexafluorophosphate (ΡΥΒΟΡ®, 312 mg, 0.6 mmol) and benzyl alcohol (97 mg, 0.9 mmol) in dry N, N-DMF (30 mL), diisopropylethylamine (DIEA, 77 mg, 0.6 mmol) was added. The mixture was stirred at room temperature for 30 min, and then the solvent was evaporated in vacuo. The residue was dissolved in ethyl acetate (50 ml), and washed with saturated sodium bicarbonate solution (2 x 10 ml). The ethyl acetate layer was evaporated, and then the crude product was purified by silica gel column chromatography using CFECh / Me-OH (0-5%) to give 60 mg (29%) of compound 73. NMR (400 MHz, CDCl 3 + methanol-cU) b ppm 7.82 (d, 7 = 5.50 Ηζ, 1 H), 7.75 (d, / = 7.33 Ηζ, 1 H), 7.43 - 7.53 (m, 2 H), 7.33 - 7.43 (m, 3H), 5.01 - 5.17 (m, 1H), 4.07- 4.18 (m, 2H), 3.82 - 4.03 (m, 2H), 3.69 - 3.81 (m, 1H), 3.51 3.64 (m, 1H), 3.44 (d, /=7.70 Ηζ, 1H), 3.36 (dt, /=3.30, 1.65 Hz, 3 H), 1.54 (m, 2 H), 1.211.35 (m, 30 H), 1.18 (dd, /=6.23, 2.57 Hz, 3 H), 0.88 (t, /=8.00 Hz, 3 H). MS (EI): 690.49 (M + H)+, 712.48 (M + Na)+.

Example 17. Preparation of hensyl octadecyloxyethyl (S) -9- [3-fluoro-2- (phosphonomethoxy) propyl] guanine (Compound 289, Bn ODE- (S) -FPMPG) [0204]

BnODE ^ SJ-FPMPG [920) 9- (S) - [3-Fluoro-2- (phosphonomethoxy) propyl] guanine [(S) -FPMPG, 0.32 g, 1.05 mmol) [prepared as described in: Jindrich, J. et al., Collect. Czech. Chem. Commun., 1993, 58: 1645-1667], was esterified with octadecyloxyethanol (0.33 g, 1.05 mmol) using N, N-dicyclohexylcarbodiimide (DCC, 0.43 g, 2.1 mmol) in dry N, N-DMF (25 mL) at 50 ° C overnight. Octadecyloxyethyl (S) -9- [3-fluoro-2- (phosphonomethoxy) propyl] guanine (ODE (S) FPMPG) was isolated by column chromatography to give 0.11 g (17%) of product. 1 NMR (CDCl 3 / methanol-cU), δ 8.18 (s, 1H); 4.50-4. 75 (m, 2H); 4.43-4. 49 (m, 1H); 4.07-4.16

57796 Β1 (m, 1H); 3.98-4. 17 (m, 2H); 3.84-3. 72 (m, 1H); 3.56-3. 60 (m, 2 H); 3.42-3. 48 (m, 2H); 3.353.37 (m, 1 H); 1.52-1.60 (m, 2 H); 1.20-1. 34 (m, 30H); 0.88 (t, J = 7 Hz, ZN). MS (EI): 600.30 (MH & lt; + & gt;).

A mixed mixture of ODE- (S) -FPMPG (0.11 g, 0.18 mmol), benzyl alcohol (0.06 ml, 0.54 mmol) and (benzotriazol-1-yloxy) -tripyrrolidinophosphonium hexafluorophosphate (ΡΥΒΟΡ®, 0.28 g, 0.54 mmol) in dry DMF was treated with diisopropylethylamine (DIEA, 0.25 mL, 1.44 mmol) for 4 h at room temperature. The solvent was evaporated in vacuo. The residue was dissolved in ethyl acetate (50 ml), and washed with saturated sodium bicarbonate solution (2 x 10 ml). The ethyl acetate layer was evaporated, and then the crude product was purified by silica gel column chromatography using CFhCh / MeOH (0-5%) to give 90 mg (71%) of compound 289. 1 H NMR (400 MHz, CDCl 3 + methanol-cU) b ppm 7.77 (s, 1H), 7.46 - 7.54 (m, 2 H), 7.34 - 7.42 (m, 3 H), 5.04 - 5.17 (m, 1 H), 4.42 - 4.52 (m, 2H), 4.19 - 4.38 (m, 2H), 4.09 - 4.19 (m, 2H), 3.88 - 4.06 (m, 2H), 3.64 - 3.73 (m, 1 H), 3.55 - 3.64 (m, 1H), 3.41 - 3.50 (m, 1H), 3.18 (d, J = 7.33 Hz, 1H), 1.49-1.60 (m, 2H), 1.21 - 1.35 m, 30 H), 0.88 (t, J = 7 Hz, ZN). MS (EI): 708.50 (MH & lt; + & gt;), 730.52 (M + Na) & lt; + & gt ;.

Example 18. Preparation of naphthyl octadecyloxyethyl (phosphonomethoxy) propyl] adenine (Jed398, Npt-ODE- (S) -MPMPA) [0207]

9- (S) - [3-methoxy-2 [0208] Octadecyloxyethyl 9- [3-methoxy-2- (phosphonomethoxy) propyliadine (ODE MPMPA, 0.30 g, 0.49 mmol) solution [prepared as described in: Valiaeva, N. et al. Bioorganic & Medicinal Chemistry, 2011, 19: 4616-4625], (benzotriazol-1-yloxy) -tripyrrolidinophosphonium hexafluorophosphate (ΡΥΒΟΡ®, 0.38 g, 0.73 mmol), and 1-naphthol (0.11 g, 0.73 mmol) in dry Ν, Ν-DMF, diisopropylethylamine (DIEA, 0.35 mL, 2.0 mmol) was added. The mixture was stirred at room temperature overnight, and then the solvent was evaporated in vacuo. The residue was dissolved in ethyl acetate (50 ml) and washed with saturated sodium bicarbonate (2 x 10 ml). The ethyl acetate layer was evaporated, and the crude product was purified by silica gel column chromatography using CFhCl2 / MeOH (0-5%) to give 0.20 g (56%) of compound 398 as an off-white solid. 1 NMR (400 MHz, CDCl 3 + methanol-cU) b ppm 8.18 (d, 7 = 8.07 Hz, 1

57796 Β1

Η), 8.02-8.11 (m, 1 Η), 7.94 (s, 1 Η), 7.86 - 7.90 (m, 1 Η), 7.69-7.74 (m, 1 Η), 7.48 - 7.57 (m,

Η), 7.34 - 7.43 (m, 2 Η), 4.38 - 4.46 (m, 1 (), 4.26 - 4.37 (m, 3 Η), 4.09 - 4.24 (m, 2 Η),

3.99 - 4.09 (m, 1), 3.59 (t, 7 = 4.58, 1), 3.47 - 3.56 (m, 2), 3.30 - 3.45 (, 5), 1.49 (d, 7 = 6.60) Ηζ, 2 Η), 1.19 - 1.34 (m, 30 Η), 0.85 - 0.93 (t, J = 7Hz, ZN). MS (EI):

740.54 (M + H) & lt; + & gt ;, 762.52 (M + Na) & lt; + & gt ;.

Example 19. Preparation of naphthyl octadecyloxyethyl 9- [2- (phosphonomethoxy) ethylguanine (Jed 361, NptODEPMEG) [0209]

v * on

O & Ž

A solution of octadecyloxyethyl 9- [2- (phosphonomethoxy) ethyl] guanine (ODE PMEG, 0.29 g, 0.50 mmol) [prepared according to: Valiaeva, N. et al. Antiviral Research 2006, 72: 10-19], (benzotriazol-1-yloxy) -tripyrrolidinophosphonium hexafluorophosphate (ΡΥΒΟΡ®, 0.39 g, 0.75 mmol), and 1-naphthol (0.11 g, 0.75 mmol) in dry Ν, Ν-DMF , diisopropylethylamine (DIEA, 0.35 mL, 2.0 mmol) was added. The mixture was stirred at room temperature overnight and then the solvent was evaporated in vacuo. The residue was dissolved in ethyl acetate (50 ml) and then washed with saturated sodium bicarbonate (2 x 10 ml). The ethyl acetate layer was evaporated. The crude product was purified by flash column chromatography on silica gel using SNgSE / MsON (0-5%) to give 0.23 g (65%) of compound 361..1 H NMR (CDCl 3 / methanol-ck) b: .1 H NMR (400 MHz, CDCl 3 + methanol-cU) b ppm 8.07 - 8.12 (m, 1 H), 7.87 (dd, 7 = 5.87, 3.30 Ηζ, 1 H), 7.71 (d, 7 = 5.87 Ηζ, 1 H) ), 7.59 (d, 7 = 4.40 Ηζ, 1 H), 7.52 - 7.56 (m, 1 H), 7.39 - 7.43 (m, 1 H), 4.30 (ddd, 7 = 8.62, 5.68, 3.30 Hz, 2 H ), 4.16 - 4.21 (m, 2 H), 4.14 (d, 7 = 8.07 Hz, 2 H), 3.64 - 3.72 (m, 2 H), 3.56 - 3.61 (m, 1 H), 3.38 (d, 7). = 4.77 Ηζ, 1 H), 3.19 (q, 7 = 7.45 Hz, 2 H), 1.45 - 1.54 (m, 2 H), 1.15 - 1.35 (m, 30 H), 0.88 (t, J = 7Hz, ZN) ). MS (EI): 712.49 (M + H) & lt; + & gt ;, 734.41 (M + Na) & lt; + & gt ;.

Example 20. Preparation of benzyl octadecyloxyethyl 9- (S) - [3-hydroxy-2 (phosphonomethoxy) propyl] uracil (Jed221, Bn-ODE- (S) -HPMPU).

[0211]

57796 Β1

Tg-SN ο

«Α.

>, J +

PvŠ0₽, WA. C.M> MR “<Y

J S. /;Benzyl 9- [3-trityloxy-2- (phosphonomethoxy) propyl] -4-methoxy-uracilA (0.1 g, 0.15 mmol), (benzotriazol-1-yloxy) - tripyrrolidinophosphonium hexafluorophosphate (ΡΥΒΟΡ®, 0.11 g, 0.20 mmol), and octadecyloxyethanol (0.06 g, 0.20 mmol) in dry Ν, Ν-DMF was added diisopropylethylamine (DIEA, 0.03 mL, 0.20 mmol). The mixture was stirred at room temperature overnight. The solvent was evaporated in vacuo. The residue was dissolved in ethyl acetate (50 ml), washed with saturated sodium bicarbonate (2x10 ml), and then the ethyl acetate layer was concentrated in vacuo. The resulting crude product was purified by flash column chromatography on silica gel using CtkCh / MeOH (0-5%) to give 0.024 g (17%) of benzyl octadecyloxyethyl 9- [3-trityloxy-2- (phosphonomethoxy) propyl]. -4methoxyuracil Ή NMR (400 MHz, CDCl 3 + methanol) b ppm 7.56 (d, 7 = 5.50 Ηζ, 1 H), 7.16 7.51 (m, 15 H), 5.46 (d, 7 = 5.50 Ηζ, 1 H), 5.10 (d, 7 = 8.80 Hz, 2 H), 4.03 - 4.21 (m, 2 H), 3.86 - 3.99 (m, 1 H), 3.65 - 3.85 (m, 2 H), 3.37 - 3.60 (m, 4 H) ), 3.25 (s, 3H), 3.12 (m, 1H), 1.421.62 (m, 2 H), 1.-5-1.38 (m, 30H), 0.88 (t, 7 = 6.97 Hz, 3H). MS (EI): 945.66 (M + Na) & lt; + & gt ;.

The protected intermediate was then stirred in 80% aq. acetic acid solution overnight at 50 ° C. The solvent was then evaporated in vacuo, and the residue was purified by flash column chromatography to give O.Olg (59%) of compound 221. MS (EI): 667.54 (M + H) +, 689.56 (M + Na) ) +.

Example 21. Preparation of ethyl octadecyloxyethyl 9- (S) - [3-methoxy-2 (phosphonomethoxy) propyliadenine (Jed 182, Et-ODE- (S) -MPMPA).

[0214]

A solution of octadecyloxyethyl 9- (S) - [3-methoxy-2- (phosphonomethoxy) propyl] -adenine (ODE- (S) -MPMPA, 0.30 g, 0.49 mmol) [prepared as described in: Valiaeva, N. et al. Bioorganic & Medicinal Chemistry, 2011, 19: 4616-4625], (benzotriazol-1-yloxy) tripyrrolidinophosphonium hexafluorophosphate, (ΡΥΒΟΡ®, 0.38 g, 0.73 mmol), in ethanol (25 mL), diisopropylethylamine was added (DIEA, 0.35 mL) , 2.0 mmol). The mixture was stirred at room temperature

57796 Β1 temperature overnight. The solvent was then evaporated in vacuo. The residue was dissolved in ethyl acetate (50 ml), and then washed with saturated sodium bicarbonate (2 x 10 ml). Ethyl acetate was evaporated, and the residue was purified by flash column chromatography on silica gel using SSC / MeOH (0-5%) to give 0.26 g (84%) of compound 182 as a white solid. 1 H NMR (400 MHz, CDCl 3)3+ methanol-d4) b ppm 8.26 (s, 1H), 8.08 (d, /=2.20 Ηζ, 1H), 4.724.74 (m, 1H), 4.62-64 (m, 1H), 4.44- 4.50 (m, 1H), 4.28-4.35 (m, 1H), 4.10 - 4.18 (m, 2H), 4.03-4.10 (m, 2H), 3.81-3.89 (m, 1H), 3.53 - 3.64 (m, 3 H), 3.42 - 3.52 (m, 3 H), 3.40 (s, 3 H), 1.56 (m, 2 H), 1.19 - 1.37 (m, 33 H), 0.89 (t, / = 7.20 Hz, 3H). MS (EI): 642.69 (M + H) & lt; + & gt ;, 664.61 (M + Na) & lt; + & gt ;.

Example 22. Preparation of benzyl octadecyloxyethyl 9- [3-methoxy-2- (phosphonomethoxy) propyl] -2,6 diaminopurine (Jed 150, Bn-ODE (S) -MPMPDAP).

[0216]

HH. ·

H? Bi

A solution of octadecyloxyethyl 9- (S) - [3-methoxy-2- (phosphonomethoxy) propyl] -2,6-diaminopurine (ODE- (S) -MPMP DAP, 0.20 g, 0.32 mmol) [prepared as described in : Valiaeva, N. et al. Bioorganic & Medicinal Chemistry, 2011, 19: 4616-4625], ((benzotriazol-1-yloxy) -tripyrrolidinophosphonium hexafluorophosphate (ΡΥΒΟΡ®), (0.21 g, 0.40 mmol), and benzyl alcohol (0.04 ml, 0.40 mmol) in dry Ν , Ν-DMF, diisopropylethylamine (DIEA, 0.07 mL, 0.40 mmol) was added. The mixture was stirred at room temperature overnight, and then the solvent was evaporated in vacuo. The residue was dissolved in ethyl acetate (50 ml), and then washed with saturated sodium bicarbonate (2x10 ml). The ethyl acetate layer was evaporated, and then the residue was purified by flash column chromatography on silica gel using CH 2 Cl 2 / MeOH (0-5%) to give 0.12 g (54%) of compound 150 * N NMR (400 MHz, CDCl3+ methanol-d4) b ppm 7.63 - 7.68 (m, 1H), 7.31 - 7.43 (m, 5H), 5.02 - 5.13 (m, 2H), 4.59 (s, 1H), 4.50 (s, 1 H), 4.23 (d, /=3.67 Ηζ, 1 H), 3.99 - 4.15 (m, 3 H), 3.84 - 3.92 (m, 2 H), 3.39 - 3.56 (m, 5 H), 3.36 (s, 3 H), 1.49 - 1.58 (m, 2 H), 1.17 - 1.35 (m, 30 H), 0.89 (t, /=6.6 Hz, 3 H). MS (EI): 719.62 (M + H) & lt; + & gt ;, 741.56 (M + Na) & lt; + & gt ;.

Example 23. Antiproliferative activity of nucleoside phosphonate diesters in normal human fibroblasts and in human lines of cervical cancer in vitro.

100

57796 ΒΙ [0218] Procedure. Compounds in the concentration range were incubated with normal fibroblasts or human cervical cancer cell lines in monolayer culture and after 4 days, the number of viable cells with neutral red reduction was determined as previously described (Valiaeva N, et al., Chemotherapy, 2010, 56 (1): 54-9). Cell lines were obtained from the American Ture Culture Collection. The results were plotted and the concentration that reduced the neutral red levels by 50% (CC50) was determined in triplicate. Although viral replication no longer occurred in human cervical cancer cell lines, Caski cells were transformed with HPV-16 and Hela cells were transformed with HPV-18.

Results. As given in the following Table 11, these results show that the compounds described here were 23.6-fold (e.g., Jed 219) to 3,750 times (e.g., Jed 1) more effective in reducing the number of viable cells in cervical cancer cell lines than in normal, untransformed human fibroblasts.

Table 11. Antiproliferative activity of nucleoside phosphonate diesters in normal human fibroblasts and in human lines of cervical cancer in vitro

<td></td><td colspan="3">Cytotoxic concentration 50% (CC50) μΜ</td>

<td>Compound #</td><td>Normal human fibroblasts (HFF)</td><td>Caski (HPV-16)</td><td>Hela (HPV-18)</td>

Example 24. Antiproliferative activity of a compound on human T cell leukemia cells (MT-2). A method for determining cytotoxicity. MT-2 cells were incubated with the drug for 72 hours and collected. Flow count beads (Beckman Coulter, Miami, FL) were added to the cell suspension followed by propidium iodide staining and analysis using a flow cytometer and 50% cytotoxic concentration (CC50) was calculated from cell number and viability. Results. The compounds disclosed herein are effective antiproliferative agents in human T cell leukemia (MT-2) cells (Table 12).

Table 12. Antiproliferative activity in human MT-2 leukemia cells in vitro

<td>Compound #</td><td>CC50, 50% cytotoxic concentration μΜ MT2 of T cell leukemia</td>

101

57796 Β1

Example 25. Anti-HIV activity.

NGU antivirus test procedure. MT-2 cells were maintained in RPMI 1640 with the addition of 10% FBS, 10 mM HEPES buffer, 50 IU penicillin / ml, and 50 pg streptomycin / ml. The antiviral activity of each compound was determined by inoculation of MT-2 cells with HIV-ILAI at a multiplicity of infection (MOI) of 0.001 TCID50 / cell, followed by incubation in the presence of triple serial drug dilutions (three wells per dilution). Four days after infection, culture supernatants were collected, lysed with 0.5% Triton H-100, and tested for p24 antigen concentration using a commercial ELISA assay (Perkin Elmer Life Sciences, Boston, MA). The antiviral activity of each compound is expressed as EC50, which is the concentration necessary to inhibit p24 antigen production by 50%.

Method for determining cytotoxicity. MT-2 cells were incubated with the drug for 72 hours and collected. Flow count beads (Beckman Coulter, Miami, FL) were added to the cell suspension followed by propidium iodide staining and analysis using a flow cytometer and 50% cytotoxic concentration (CC50) was calculated from cell number and viability.

Results. Table 13 shows that the compounds described herein have significant antiviral activity against HIV-1 and show selectivity.

Table 13. Antiviral activity in HIV-1 infected human lymphoblastic leukemia cells (* = reference compound)

<td></td><td colspan="2">HIV ANTI - VIRUS ACTIVITY</td><td>MT-2 CELLS</td>

<td>Compound #</td><td>EC 50, μΜ</td><td>CCso, μΜ</td><td>Selectivity index</td>

<td colspan="4">EC50, effective dose 50%; CC50, cytotoxic dose 50%, selectivity index CC50, EC50 · Test: p24 reduction.</td>

Example 26. Antiviral effect of ANP diesters in HFF cells infected with HSV-2.

Procedure. Primarily low-passage human foreskin fibroblast (HFF) cells in 96-well plates were infected with an MOI of 0.01 PFU / cell with G strain of herpes simplex virus type 2 and incubated for 3 days. The medium was then aspirated and the monolayers of cells were stained with violet crystal and washed with distilled water. The cell-bound violet crystal was then quantified in a spectrophotometer and the concentration of compound was sufficient to

102

57796 Β1 reduce virus replication by 50% (EC50) was calculated. Cytotoxicity was measured in parallel by similar procedures to obtain a concentration that reduced the number of cells by 50% (CC50).

Results. The results are shown in the following Table 14.

Table 14. Antiviral effect of ANP diesters in HFF cells infected with HSV-2 (* = reference compound)

<td>Compound #</td><td>EC 50, μΜ</td><td>CCso, μΜ</td><td>Selectivity index</td>

Example 27. Effect of oral octadecyloxyethyl-hensyl- (ODE-hn-) diesters of acyclic nucleoside phosphonate and ODEmonoester of acyclic nucleoside phosphonate on body weight in Balb-c mice.

Procedure. The compounds were administered in the prescribed doses by oral gavage daily for 5 days. Weights were measured before and on day 6 after 5 doses.

Results. As shown in the following Table 15, these results show that ODEmonoesters Cidofovir (CDV) and PMEG led to weight loss of 14.7% and 19.1%, respectively, which was statistically very significant versus zero day (p = 0.0007 ip <0.001) . However, oral ODE-benzyl diesters CDV and PMEG nucleoside phosphonates did not show statistically significant effects (ns) on body weight compared to unmodified compounds.

Table 15. Effect of oral octadecyloxyethyl-benzyl- (ODE-bn-) diesters of acyclic nucleoside phosphonate and ODEmonoester of acyclic nucleoside phosphonate on body weight in Balb-c mice

<td>Uniting</td><td>Dose</td><td>Day 0</td><td>Day 6</td><td>p value, 0 vs 6</td>

103

57796 Β1

Example 28. Antiviral effect of ANP diesters in cells infected with human cytomegalovirus (AD1 69).

Procedure. Primarily low-passage human foreskin fibroblast (HFF) cells in 96-well plates were infected with an MOI of 0.01 PFU / cell with the AD169 strain of human cytomegalovirus and incubated for 14 days. The medium was then aspirated and the monolayers of cells were stained with violet crystal and washed with distilled water. The cell-bound violet crystal was then quantified in a spectrophotometer and the concentration of compound sufficient to reduce virus replication by 50% (EC50) was calculated. Cytotoxicity was measured in parallel by similar procedures to obtain a concentration that reduced the number of cells by 50% (CC50).

Results. The results are shown in the following Table 16.

Table 16. Antiviral effect of ANP diesters in cells infected with human cytomegalovirus (AD169) (* = reference compound)

<td>Compound #</td><td>EC 50, μΜ</td><td>CCso, μΜ</td><td>Selectivity index</td>

Example 29. Antiviral effect of ANP diesters in cells infected with vaccine virus (Copenhagen) Method '. Primarily low-passage human foreskin fibroblast (HFF) cells in 96-well plates were infected with a MOI of 0.01 PFU / cell with Copenhagen strain of vaccine virus vaccine and incubated for 7 days. The medium was then aspirated and the cell monolayers were stained with crystal violet and washed with distilled water. The cell-bound violet crystal was then quantified in a spectrophotometer and the concentration of compound sufficient to reduce virus replication by 50% (EC50) was calculated. Cytotoxicity was measured in parallel by similar procedures to obtain a concentration that reduced the number of cells by 50% (CC50).

Results. The results are shown in the following Table 17.

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57796 Β1

Table 17. Antiviral effect of ANP diesters in cells infected with vaccine virus (Copenhagen) (* = reference compound)

<td>Compound #</td><td>EC 50, μΜ</td><td>CCso, μΜ</td><td>Selectivity index</td>

Example 30. Antiviral effect of ANP diesters in cells infected with BK virus (Gardner strain) Procedure: We receive low-pass human prepuce phlebroblast (HFF) cells in 96-well plates infected with a MOI of 0.01 PFU / cell and incubated . The medium was then aspirated and the total DNA was isolated and the genome copy number was quantified with qPCR using a primer 5'-AGT GGA TGG GCA GCC TAT GTA-3 '(SEQ W N0: 1), 5'-TCA TAT CTG GGT CCC CTG GA -3 '(SEQ ID NO: 2) and test 5'-6-FAM AGG TAG AAG AGG TTA GGG TGT TTG ATG GCA CAG TAMRA-3' (SEQ ID NO: 3). In a parallel experiment on uninfected cells, cytotoxicity was determined with CELLTITER-GLO® to find a concentration that reduced the number of cells by 50% (CC50).

Results. The results are shown in the following Table 18.

Table 18. Antiviral effect of ANP diesters in cells infected with BK virus (Gardner strain) (* = reference compound)

<td>Compound #</td><td>EC 50, μΜ</td><td>CCso, μΜ</td><td>Selectivity index</td>

Example 31. Antiviral effect of ANP diesters in HFF cells infected with HSV-1 (E-377). Procedure. Primarily low-passage human foreskin fibroblast (HFF) cells in 96-well plates were infected with an MOI of 0.01 PFU / cell with E377 strain of herpes simplex virus type 1 and incubated for 3 days. The medium was then aspirated and the monolayers of cells were stained with violet crystal and washed with distilled water. The violet crystal that bound with

105

57796 The cells were then quantified in a spectrophotometer and the concentration of compound sufficient to reduce virus replication by 50% (EC50) was calculated. Cytotoxicity was measured in parallel by similar procedures to obtain a concentration that reduced the number of cells by 50% (CC50).

Results. The results are shown in the following Table 19.

Table 19. Antiviral effect of ANP diesters in HFF cells infected with HSV-1 (E377) (* = reference compound)

<td>Compound #</td><td>EC 50, μΜ</td><td>CCso, μΜ</td><td>Selectivity index</td>

Example 32. Antiviral effect of ANP diesters in HPV-11 infected HEK 293 cells.

Procedure. The plasmid containing origin was co-transfected with HPV-11 E1 and E2 protein expression vectors into HEK 293 cells. At 4 h after transfection, cells were treated with compound dilutions and cells were incubated for 48 h. Origen replication of the virus was detected with Dpn1 and exonuclease III to remove unreported replicate bacterial plasmid DNA. The remaining replicated DNA was quantified with qPCR. Toxicity was determined by excluding trypan blue.

Results. The results are shown in the following Table 20.

Table 20. Antiviral effect of ANP diesters in HPV-11 infected HEK 293 cells (* = reference compound)

<td>Compound #</td><td>EC 50, μΜ</td><td>CCso, μΜ</td><td>Selectivity index</td>

106

57796 Β1 ** ECgo is the concentration necessary to reduce viral replication by 90%.

Example 33. Antiviral effect of ANP diesters in HPV-16 infected HEK 293 cells.

Procedure. The plasmid containing origin was co-transfected with HPV-16 E1 and E2 protein expression vectors into HEK 293 cells. At 4 h after transfection, cells were treated with compound dilutions and cells were incubated for 48 h. Origen replication of the virus was detected with Dpn1 and exonuclease III to remove unreported replicate bacterial plasmid DNA. The remaining replicated DNA was quantified with qPCR. Toxicity was determined by excluding trypan blue.

Results. The results are shown in the following Table 21.

Table 21. Antiviral effect of ANP diesters in HPV-16 infected HEK 293 cells.

<td>Compound #</td><td>EC50, μΜ</td><td>CC50, μΜ</td><td>Selectivity index</td>

Example 34. Antiviral effect of ANP diesters in HPV-18 infected shelves of primary human keratinocytes.

Procedure. Primary human keratinocytes (PHKs) were transfected with the HPV-18 genomic plasmid containing the G418 resistance gene generated by Cre-loxP-mediated excision recombination. After 4 days of selection with G418, the surviving cells were cultured for 2-3 days and used for development in raft culture where PHK cells stratified and differentiated into squamous epithelium for 10 or more days. HPV-18 viral DNA usually replicates between 10-14 days after the raft cultures are lifted into the air-medium interface. The efficacy and toxicity of the test compound were determined at three concentrations added to the medium from day 6 or 8 to day 14. The medium was changed every other day. Prior to collection, BrdU was added to the medium at 100 pg / ml to document replication of the host cell DNA. One set of raft cultures (with or without test compounds) was collected for real-time quantitative PCR (qPCR) to determine the number of copies of HPV-18 DNA / cell. The next set of raft cultures was fixed in formalin, molded into paraffin, and toxicity was determined histologically. Additional cross-sections were subjected to in situ hybridization to localize viral DNA amplification and BrdU incorporation denoting host DNA replication in the basal and suprabasal layers.

Results. The results are shown in the following Table 22.

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Table 22. Antiviral effect of ANP diesters in HPV-18-infected shelves of primary human keratinocytes

<td>Compound #</td><td>EC50, μΜ</td><td>CC50, μΜ</td><td>Selectivity index</td>

Example 35. Antiviral effect of ANP diesters in JC virus (MAD-1) infected COS7 cells.

Procedure. COS7 cells in 96-well plates were infected at a MOI of 0.01 PFU / cell with MAD-1 strain JC virus and incubated for 7 days. The medium was then aspirated and the total DNA was isolated and the genome copy number was quantified with qPCR using primers 5'-CTG GTC ATG TGG ATG CTG TCA-3 '(SEQ ID NO: 4) and 5'-GCC AGC AGG CTG TTG ATA CTG -3 '(SEQ ID NO: 5) and probes 5'-6-FAM-CCC TTT GTT TGG CTG CTTAMRA-3 (SEQ ID NO: 6) together with plasmid pMP5O8 to provide a standard quantification curve. In a parallel experiment in uninfected cells, cytotoxicity was determined with CEEETITER-GEO® to find the concentration that reduced the number of cells by 50% (CC50).

Results. The results are shown in the following Table 23.

Table 23. Antiviral effect of ANP diesters in JC virus (MAD-1) infected COS7 cells (* = reference compound)

<td>Jedin.jenje #</td><td>EC 50, μΜ</td><td>CCso, μΜ</td><td>Selectivity index</td>

Example 36. Antiviral effect of ANP diesters in HIV-192US727 infected human peripheral blood monocytes.

Procedure. Anti-HIV tests based on human blood cells (PBMC) were performed as previously described (KM Watson, et al., 2008, Antimicrob Agents Chemother. 52: 2787). Briefly, PHA-stimulated PBMCs cultured in the presence of IL-2 were suspended in 1 X 106 cells / mE and added to a 96-well round bottom plate. Serially diluted test materials were added to the plate in triplicate followed

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57796 ΒΙ Appropriate pre-titrated strain of HIV. The culture was incubated for 7 days at 37 ° C / 5% CO2. After incubation, supematants were collected from viral replication analysis via supematant reverse transcriptase activity and cells were analyzed for viability with HTT reduction of tetrazolium dye (2,3-bis (2-methoxy-4-nitro-5-sulfophenyl) -5 [ (phenylamino) carbonyl] -2H-tetrazolium hydroxide). All tests were performed in triplicate. Microsoft Excel 2007 was used for data analysis and charts. The percentage reduction in viral replication compared to controls with untreated virus were calculated for each compound. The percentage of cell control values was calculated for each compound compared to drug-treated uninfected cells and uninfected cells in medium alone.

Results. The results are shown in the following Table 24.

Table 24. Antiviral effect of ANP diesters in HIV-192US727 infected human peripheral blood monocytes. (* = reference compound)

<td>Compound #</td><td>EC 50, μΜ</td><td>CCso, μΜ</td><td>Selectivity index</td>

Example 37. Antiviral effect of ANP diesters on hepatitis B virus replication in 2.2.15 cells in vitro.

Procedure. HBV antiviral assays assays (Korba & Gerin, Antivir. Res., 1992, 19:55 and Iyer, et al., Antivir Agents Chem Chemother., 2004, 48: 2199) were performed using confluent cultures of 2.2.15 cells (genotype ayw HepG2 stem cell) maintained on 96-well flat-bottomed tissue culture plates. Confluence in this culture system is necessary for active, high levels of HBV replication equivalent to that observed in chronically-infected individuals (Sells, et al., J. Virol., 1988, 62: 2836; Korba & Gerin, Antivir. Res., 1992, 19:55). Cultures were treated for 7 days. HBV DNA levels in culture medium

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57796 Β1 (representing HBV virion production) were assessed by quantitative blot hybridization 24 h after the last treatment. Cytotoxicity was assessed (Α510) by taking a neutral red color 24 h after the last treatment. Lamivudine (LMV) was used as a standard control test. EC50, EC90 and CC50 values were calculated by linear regression (MS EXCEL®, QUATTROPRO®) using data combined from all treated cultures (Korba & Gerin, 1992, Id. ', Okuse, et al., Antivir. Res., 2005, 65:23). Standard deviations for EC50 and EC90 values were calculated from standard errors generated by regression analyzes. EC50 and EC90 are drug concentrations at which 2-fold, or 10-fold, HBV DNA depression (relative to average levels in untreated cultures) was observed, respectively. CC50 is the drug concentration at which a 2-fold lower level of neutral red uptake was observed (compared to average levels in untreated cultures).

Results. The results are shown in the following Table 25.

Table 25. Antiviral effect of ANP diesters on hepatitis B virus replication in 2.2.15 cells in vitro.

<td>Compound #</td><td>EC 50, μΜ</td><td>CC50, μΜ</td><td>Selectivity index</td>

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Acyclic nucleoside phosphonate diesters

Abstract

Term

DETAILED DESCRIPTION

O — R

Q

57796 V1

57796 V1

57796 V1

57796 V1

S

I

C

Q

C

Q

57796 V1

57796 V1

57796 V1

57796 V1

57796 V1

57796 V1

ODE-PMEG

N9

M-DMF

H // 2

ODE-PMEG

NH-

31EA,

GK

Priority claims9

Members66

Numbers

Titles2

Classification