Acyclic nucleoside phosphonate diesters.

DIESTERS OF ACYCLIC NUCLEOSIDE PHOSPHONATE

Cross references to related requests

This application claims the usefulness of the Provisional Application in the United States No. 61 / 784,964, filed on Friday, March 15, 2013, which, hereby is incorporated herein in its entirety by means of references .

Declaration of conformity with the rights of inventions, made under the auspices of federal research and development

This invention was made with government support in accordance with grant numbers DA014361, DA011560 and GM103450 granted by the National Institutes of Health. The government has certain rights over the invention.

Reference to a sequence listing, a table or a list of the computer program presented as an ascii file

The sequence listing in file 88654900583_ST25.TXT, created on March 11, 2014, 1,866 bytes, IBM-PC machine format, MS-Windows operating system, incorporated herein by reference.

Background

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The present invention relates, among other things, to the compositions and methods for treating viral diseases and cancer. In one aspect it refers to lipophilic antivirals and nucleoside phosphonate diesters, their preparation and the methods of using the compounds to treat viral diseases and cancer.

Viruses and infectious particles that can replicate their DNA and RNA only in host cells. Viral infections can cause 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, chicken pox, BK virus, JC virus and pre-cancer lesions caused by infections with the human papillomavirus (cervical intraepithelial neoplasia, vaginal and anal intraepithelial neoplasia). Viral diseases can also cause cancer in humans and other species. Viruses known to cause cancer include but are not limited to human papillomavirus (VE), hepatitis B virus (HBV), hepatitis C virus (HCV) HIV and Epstein Barr virus (EBV). Vaccination has been successful in preventing diseases caused by various viruses. Antiviral agents are known to interfere with DNA synthesis and viral RNA and viral replication, because of this they are used to prevent or treat viral infections in mammals and humans. For example, drug combinations are used

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antivirals to treat AIDS, hepatitis B, hepatitis C, herpes simplex virus, cytomegalovirus and influenza. Despite these successes, viral diseases still represent a major public health problem, so improved anti-cancer agents and antiviral agents are required. For example, there is currently no approved antiviral treatment for human papillomavirus infections.

Many antiviral drugs correspond to nucleoside or nucleotide analogs. Examples of these include azidothymidine, acyclovir, ganciclovir, lamivudine and emtricitabine. Acyclic nucleoside phosphonates (ANP) correspond to a class of nucleotide analogs and result in effective antiviral agents. Adefovir, tenofovir and cidofovir (CDV) correspond to ANP that have been approved for clinical use against human infections of HBV, HIV and CMV, respectively.

ANPs are known in the art for not being readily absorbed by the digestive tract of mammals given their molecular weight and the presence of the double negative charge in the phosphonate. Because of their poor oral pharmacokinetic properties, ANPs are usually converted into prodrugs to produce clinically useful therapeutic agents. It has been shown that masking one or both negative charges by fractions, improves absorption and transport to small intestinal enterocytes where said fractions adhere, releasing the ANP to the circulation; Examples include tenofovir disoproxil fumarate and adefovir dipivoxil. Another proposal is to prepare alkoxyalkyl or alkyl monoesters of the ANP to increase the oral bioavailability of the drug. With the proposal of the ANP alkoxyalkyl monoester, side effects may appear when overexposed to tissues not selected as i ® 1 small intestine. For example, in enterocytes, division

». Carrier enzyme enzymes for a phospholipase C or a sphingomyelinase acid to ANP can result in local toxicity given anabolic phosphorylation after ANP diphosphate, which can inhibit the synthesis of enterocyte DNA. The lipophilic ANP diester compounds are anticipated to undergo minor division due to the intact prodrug of the ANP in the small intestine enterocytes after oral administration, reducing GI side effects and releasing more substance from the drug to the bloodstream, thus as producing higher levels of the drug substance in the blood.

ANP or its alkyl or alkoxyalkyl monoesters may have limited absorption in certain selected tissues, such as the central nervous system. An additional advantage 20 of the nucleoside phosphonate diesters corresponds to the masking of the remaining negative charge on the oxygen phosphonate with a second masking group that can increase the penetration of the drug substance into the central nervous system (CNS) for treatment. 25 viral infections of the CNS (for example, HIV or JC virus) or for the treatment of brain cancers such as glioblastoma. Cancer cells easily synthesize DNA and undergo uncontrolled cell division. The lipophilic acyclic nucleoside phosphonate (ANP) diester compositions described herein can be metabolized in their phosphates that inhibit or block DNA synthesis and cell division in selected cancer cells, generating cell death while reducing Substantial effect on non-malignant cells. Exposure of several types of cancer cells to diesters of nucleoside phosphonates may result in a higher cytotoxicity than is observed in normal non-malignant cells. For example, leukemias, lymphomas, brain neoplasms such as glioblastoma and cervical cancer cells may be more susceptible to cytotoxic effects when exposed to lipophilic ANP diesters compared to their corresponding non-malignant cell lines. The lipophilic acyclic nucleoside phosphonate diesters show greater selective toxicity, improved access to the central nervous system and effective topical absorption for the treatment of skin cancers, viral skin infections, cervical intraepithelial neoplasia (CIN), anal and vaginal intraepithelial dysplasia, Venereal warts and related infections caused by human papillomavirus when compared to acyclic nucleoside phosphonate monoester monoester compositions.

The compounds presented herein contain negative charges of ANP phosphonate masked with functional groups provided for more effective use as topical agents for the treatment of skin cancers and viral infections. In particular, the compounds set forth herein, provided for the effective treatment of cervical, vaginal, rectal and penile epithelial infections due to human papillomavirus, 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 venereal warts and cervical, rectal, penile and vaginal cancer.

Short description

In the first aspect, there is a compound provided with the structure of Formula (I),

Nuc

O \\ / O — L

O \\ or stereoisomer, salt, hydride, solvate or crystalline form thereof. With respect to Formula (I), L corresponds to a lipophilic carrier, substituted and unsubstituted alkyl, substituted and unsubstituted heteroalkyl or glyceryl substituted with O- with the formula -CH2CH (OR¹) -CH2 (OR²) (II), where R¹ and R² correspond to substituted or unsubstituted alkyl independently or substituted or unsubstituted aryl independently. R corresponds

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to a substituted or unsubstituted lower alkyl, a substituted or unsubstituted lower heteroalkyl, a substituted or unsubstituted lower cycloalkyl, a substituted or unsubstituted lower heterocycloalkyl, a substituted or unsubstituted lower heteroaryl. X corresponds to hydrogen, a substituted or unsubstituted lower alkyl, a substituted or unsubstituted lower heteroalkyl.

In another aspect, there is a method of treatment provided for a viral disease, including administration to a subject requiring it, in a therapeutically effective amount of a compound of Formula (I).

In another aspect, a method of treating cancer in a subject, including administration to a subject requiring it, is provided in a therapeutically effective amount of a compound of Formula (I).

In another aspect, a method of treatment is provided to kill or inhibit the growth of a transformed cell, including contact with a transformed cell with a therapeutically effective amount of a compound of Formula (I).

In another aspect, a method of treating a proliferative disorder in a subject, including administration to a subject requiring it, is provided in a therapeutically effective amount of a compound of Formula (I).

In another aspect, there is a pharmaceutical composition provided that includes a compound according to Formula (I) and a pharmaceutically acceptable excipient.

In another aspect, a method for the synthesis of a compound with the structure of Formula (I) according to Scheme 2 set forth herein is provided. The method includes contact with a protected nucleoside B_Nuc with structure of Formula (21) with an ester with structure of Formula (2-2) in the presence of a strong base under suitable conditions to generate a monoester with structure of Formula (2-3); and by reacting the monoester provided with L-OH in the presence of a coupling agent, a compound is thus synthesized with the structure of Formula (I).

In another aspect, a compound of the Formula (la) or a pharmaceutically acceptable salt, hydride, solvate or crystalline form thereof is provided:

^BNuc (a) O

I, 0 — L^to | O — R^to

X^to (the).

For Formula (la), Bn_UC(a) a naturally occurring purine, a naturally occurring pyrimidine, a naturally occurring purine or a naturally occurring pyrimidine may correspond; L^to it may correspond to an unsubstituted C12-24 alkyl, an unsubstituted C13-29 heteroalkyl or a substituted glyceryl portion, wherein the glyceryl portion may be substituted with one or more groups selected from an alkyl

C13-29 unsubstituted, an unsubstituted C13-29 heteroalkyl, a substituted or unsubstituted aryl (Ci-ε alkyl), a substituted or unsubstituted heteroaryl (Ci-e alkyl) and a substituted or unsubstituted heterocycloalkyl (Ci- alkyl β); R^to it can be selected from an unsubstituted C1-6 alkyl, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl (Ci-β alkyl), a substituted or unsubstituted heteroaryl substituted (Ci-β alkyl) and a substituted or unsubstituted heterocycloalkyl (Ci-ε alkyl); and X^to hydrogen, an unsubstituted Ci-g alkyl, a substituted C-halogen may result₆ alkyl, a C1-6 substituted hydroxy alkyl or an unsubstituted C1-6 alkoxy.

In another aspect, a pharmaceutical composition is provided which may include an effective amount of a compound provided herein (for example, a compound of the Formula (la)) or a pharmaceutically acceptable salt, hydride, solvate or crystalline form of the same, as well as a pharmaceutically acceptable excipient.

In another aspect, a compound is provided as set forth herein (for example, a compound of Formula (la)) or a pharmaceutically acceptable salt, hydride, solvate or crystalline form thereof, for use in the Treatment of a disease veers in a subject, where the viral disease can be selected from human papillomavirus, HIV, hepatitis B virus, hepatitis C virus, variola virus,

<img file="MX367403B_D0004.tif" />

vaccine virus, an adenovirus, a cytomegalovirus, herpes simplex virus 1, herpes simplex virus 2, Epstein Barr virus, BK virus, JC virus, feline leukemia virus and feline immunodeficiency virus.

In another aspect, a compound is provided as presented herein (for example, a compound of Formula (la)) or a pharmaceutically acceptable salt, hydride, solvate or crystalline form thereof, for use in the treatment against Cervical cancer in a subject.

In another aspect, a compound is provided as set forth herein or a pharmaceutically acceptable salt, hydride, solvate or crystalline form thereof, for use in inhibiting the growth of a cell transformed by a virus, wherein the virus can be selected from the human papillomavirus, HIV, hepatitis B virus, hepatitis C virus, variola virus, vaccine virus, an adenovirus, a cytomegalovirus, herpes simplex virus 1, herpes simplex virus 2, Epstein Barr virus, BK virus, JC virus, feline leukemia virus and feline immunodeficiency virus.

In another aspect a compound is provided as set forth herein (for example, a compound of the Formula (la)) or a pharmaceutically acceptable salt, hydride, solvate or crystalline form thereof, in the preparation of a medicament. to treat a viral disease in a subject, wherein the viral disease can be selected from human papillomavirus, HIV, hepatitis B virus, hepatitis C virus, variola virus, vaccine virus, an adenovirus, a cytomegalovirus, herpes simplex virus 1, herpes simplex virus 2, Epstein Barr virus, BK virus, JC virus, feline leukemia virus and feline immunodeficiency virus.

In another aspect, a use of a compound as set forth herein is provided (for example, a compound of the Formula (la)) or a pharmaceutically acceptable salt, hydride, solvate or crystalline form thereof, in the Preparation of a medicament for the treatment of cervical cancer in a subject.

In another aspect, the use of a compound as set forth herein (for example, a compound of the Formula (la)) or a pharmaceutically acceptable salt, hydride, solvate or crystalline form thereof, is provided in the preparation of a medicament for the inhibition of the growth of a cell transformed by a virus, wherein the virus can be selected from the human papillomavirus, HIV, hepatitis B virus, hepatitis C virus, variola virus, vaccine virus, an adenovirus, a cytomegalovirus, herpes simplex virus 1, herpes simplex virus 2, Epstein Barr virus, BK virus, JC virus, feline leukemia virus and feline immunodeficiency virus.

In another aspect, a method of synthesizing a compound with structure of Formula (la) is provided.

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Brief description of the drawings

Fig. 1 provides a crornatogram of a compound (rapid elution) and a compound Ib (slow elution), as described in Example 2. X axis: time (min); Y axis (milliabsorption units, mAu). Solvent: 50: 50: 0.1 Water: Acetonitrile: TFA.

Detailed description

I. Definitions

The abbreviations used herein have their conventional meaning in chemistry and biological arts. The chemical structures and formula set forth herein are constructed in accordance with the standard rules of chemical valences known in the chemical arts.

Where the substituent groups are specified by their conventional chemical formula, written from left to right, chemically identical substituents that may result from writing the structure from right to left, for example, -CH2O- is equivalent to -OCH2-.

As used in the present invention, the term "alkyl", by itself or as part of a substituent, means, unless otherwise indicated, and includes a branched or straight chain (ie, unbranched) or the combination of the same, which can be fully saturated mono or polyunsaturated and can include di or multivalent radicals, with the number of designated carbon atoms (i.e., C1-C10

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means one to ten carbons). The alkyl corresponds to an uncycled 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, homologs and isomers of, by example, npentyl, n-hexyl, n-heptyl, n-octyl and the like.

An unsaturated alkyl group corresponds to one that contains one or more double bonds (an alkenyl group) or triple bonds (an alkynyl group). Examples of an unsaturated alkyl group include, but are not limited to, the alkenyl vinyl, 2-propenyl, crotyl, 2-isopentenyl, 2- (butadienyl) groups,

2,4-pentadienyl, 3- (1,4-pentadienyl), and the alkynyl ethynyl, 1- and 3-propynyl, 3-butynyl groups and the higher homologs and isomers.

An alkoxy corresponds to an alkyl attached to the rest of the molecule by means of a linker oxygen (-O-).

The term "alkylene", by itself or as part of another substituent, means, unless otherwise indicated, a bivalent radical derived from an alkyl, as exemplified, but not limited by, -CH2CH2CH2CH2-. Often, an alkyl (or alkylene) group will contain from 1 to 24 carbon atoms or 10 or less carbon atoms. A lower alkyl or lower alkylene corresponds to a shorter chain of an alkyl or alkylene group, generally with eight or less carbon atoms.

The term "heteroalkyl," by itself or as part of another substituent, means, unless otherwise indicated, a stable branched or straight chain or combinations thereof, consisting of at least one carbon atom and at least one heteroatom selected. from the group consisting of O, N, P, Si and S, and where the sulfur and nitrogen atoms can be optionally oxidized and the nitrogen heteroatom can be optionally quaternized. The heteroatoms O, N, P, S and Si can be placed in any interior position of the heteroalkyl group or in the position in which the alkyl group is attached to the rest of the molecule. Heteroalkyl corresponds to an uncycled chain. Examples include, but are not limited to: -CH2-CH2-O-CH3, -CH₂-CH₂-NH-CH₃, -CH2-CH₂-N (CH₃) -CH₃, -CH₂-S-CH₂-CH₃, -CH2-CH2, -S (O) -CH₃, -CH2-CH2-S (O)₂-CH₃, -CH = CH-O-CH₃, -Yes (CH₃)₃, -CH₂-CH = N-OCH₃, -CH = CH-N (CH₃) -CH₃, -O-CH₃, -O-CH₂-CH₃ and -CN. Up to two heteroatoms can be found consecutively, such as -CH₂-NH-OCH₃.

Similarly, the term heteroalkylene, by itself or as part of another substituent, means, unless otherwise indicated, a bivalent radical derived from a heteroalkyl, as exemplified, but not limited by, -CH2-CH2 -S-CH2-CH2- and -CH2-S-CH2-CH2-NH-CH2-. For heteroalkylene groups, heteroatoms can also occupy both ends of the chain (for example, alkyleneoxy, alkylenedioxy, alkyloeneamine, alkynenediamine and the like). Furthermore, for alkylene and heteroalkylene linking groups, no implication is involved.

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no orientation of the address in which the formula of the linking group is written. For example, the formula -C (O) 2R '~ represents both -C (O)₂R'- as -R'C (O)₂-.

As described above, heteroalkyl groups, as used herein, include those groups that are attached to the rest of the molecule by means of a heteroatom, such as -NR'R '', -OR ', -SR ', I am₂R '. Where heteroalkyl is defined, followed by definitions of specific heteroalkyl groups, such as -NR'R '' or the like, it will be understood that the terms heteroalkyl and -NR'R '' are neither redundant nor mutually exclusive. Instead, heteroalkyl groups are listed to add clarity. Thus, the term heteroalkyl should not be construed herein as excluding specific heteroalkyl groups, such as -NR'R '' or the like.

The terms cycloalkyl and heterocycloalkyl, by themselves or in combination with other terms, mean, unless otherwise indicated, cyclic versions of alkyl and heteroalkyl respectively. Cycloalkyl and heteroalkyl do not correspond to aromatic compounds. In addition, for the heterocycloalkyl, a heteroatom can occupy the position at which the heterocycle binds to the rest of the molecule. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1cyclohexenyl, 3-cyclohexenyl, cycloheptyl and the like. Examples of heterocycloalkyl include, but are not limited to, 1- (1,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl, 3piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl , tetrahydrothien-2-yl, tetrahydrothien-3-yl, 1-piperazinyl, 2-piperazinyl and the like.

A cycloalkylene and a heterocycloalkylene, alone or as part of another substituent, represents a bivalent radical derived from a cycloalkyl and a heterocycloalkyl, respectively.

The terms halo or halogen, by themselves or as part of another substituent, represent, unless otherwise indicated, a fluorine, chlorine, bromine, or iodine atom. In addition, 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" represents, unless otherwise indicated, -C (O) R 'where R * corresponds to a substituted or unsubstituted alkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heteroalkyl, a substituted heterocycloalkyl or unsubstituted, a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl.

The term aryl represents, unless indicated

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on the contrary, a hydrocarbon substituent, aromatic, polyunsaturated, which may correspond to a single or multiple ring (preferably 1 to 3 rings) fused together (ie, a fused ring aryl) or covalently bonded. A fused ring aryl refers to multiple rings fused together where at least one of the fused rings corresponds to an aryl ring.

The term "heteroaryl" refers to aryl groups (or rings) containing between one and four heteroatoms selected from N, O and S, where nitrogen and sulfur atoms are optionally oxidized and nitrogen atoms are quaternized from optional way. Thus, the term heteroaryl includes fused ring heteroaryl groups (ie, several fused rings together where at least one of the fused rings corresponds to a heteroaromatic ring). A fused 5,6-heteroarylene ring refers to two rings fused together, where one ring contains 5 members and the other ring contains 6 members, and where at least one ring corresponds to a heteroaryl ring. In the same way, a fused heteroarylene ring refers to two rings fused together, where one ring contains 6 members and the other ring contains 6 members, and where at least one ring corresponds to a heteroaryl ring. Also, a fused 6,5-heteroarylene ring refers to two rings fused together, where one ring contains 6 members and the other ring

<img file="MX367403B_D0009.tif" />

It contains 5 members, and wherein at least one ring corresponds to a heteroaryl ring. A heteroaryl group can be attached to the rest of the molecule by means of a carbon or a heteroatom. Non-limiting examples of aryl and heteroaryl groups include phenyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, 4imidazolyl, pyrazinyl, 2-oxazolyl, 4 -oxazolyl, 2-phenyl-4oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2 -pyridyl, 3-pyridyl, 4-pyridyl,

2-pyrimidyl, 4-pyrimidyl, 5-benzothiazolyl, purinyl, 2-benzimidazolyl, 5-indolyl, 1-isoquinolyl, 5-isoquinolyl, 2quinoxalinyl, 5-quinoxalinyl, 3-quinolyl and 6-quinolyl. The substituents of each of the above heteroaryl and aryl ring systems indicated are selected from the group of acceptable substituents described below. An arylene and a heteroarylene, alone or as part of another substituent, represent a bivalent radical derived from an aryl and a heteroaryl, respectively.

In short, the term "aryl" when used in combination with other terms (e.g., aryloxy, arylthioxy, arylalkyl) includes both aryl and heteroaryl rings, as defined above. Thus, the term aryloalkyl [eg, aryl (Ci-e alkyl)] includes those radicals in which an aryl group is attached to a

<img file="MX367403B_D0010.tif" />

alkyl group (for example, benzyl (Bn), phenethyl, pyridylomethyl and the like) including those alkyl groups in which a carbon atom (for example, a methylene group) has been replaced by, for example, an oxygen atom (by example, phenoxymethyl, 2-pyridyloxymethyl, 3- (1-naphthyloxy) propyl and the like). Thus, the term "heteroaryloaiquyl" (eg, heteroaryl (Ci-6 alkyl)] refers to those radicals in which a heteroaryl group is attached to an alkyl group. The term "heterocycloalkylalkyl [eg, heterocycloalkyl (Ci-6 alkyl)] refers to those radicals in which a heterocycloalkyl is attached to an alkyl group.

The term oxo, as used herein, represents an oxygen that contains a double bond with a carbon atom.

The term "alkylsulfonyl," as used herein, represents a fraction with the formula -S (O2) -R ', where R' corresponds to an alkyl group as defined above. R 'may contain a specific number of carbons (for example, C1-C4 alkylsulfonyl).

Each of the above terms (for example, alkyl, heteroalkyl, aryl and heteroaryl) includes substituted and unsubstituted forms of the indicated radical. The preferable substituents for each type of radical are given below.

Substituents for alkyl and heteroalkyl radicals

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(including those groups often referred to as alkylene, alkenyl, heteroalkylene, heteroalkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl and heterocycloalkenyl) may correspond to one or more of a variety of groups selected from, but not limited to, -OR ', = 0, = NR ', = N-OR', -NR'R '', -SR ', -halogen, -SiR'R''R' '', -OC (O) R ', -C (O ) R ', -CO₂R ', -CONR'R, -OC (O) NR'R' ', -NRC (O) R', -NR'-C (0) NR R ', -NR' 'C (0) ₂R ', -NR-C (NR'RR') = NR '', -NR-C (NR 'R' ') = NR' '', 10 S (O) R ', -S (O)₂R ', -S (O) ₂NR'R '', -NRS0₂R ', -CN and -N0₂ in a number within the range from zero to (2m '+ l), where m' corresponds to the total number of carbons in said radical. R ', R, R' '' and R '' '' preferably each independently refers to hydrogen, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl substitute (for example, aryl substituted with 1-3 halogens), substituted or unsubstituted alkyl, alkoxy, or thioalkoxy groups, or arylalkyl groups. When a compound includes more than one group R, for example, each one of the groups R is independently selected from each group R ', R' ', R' '' and R '' '' when more than one of These groups are present. When R 'and R' 'are attached to the same nitrogen atom, they can be combined with the nitrogen atom to form a 4-, 5-, 6- or 7- ring member. For example, -NR'R '' includes, but is not limited to, 1-pyrrolidinyl and

<img file="MX367403B_D0012.tif" />

4-morpholinyl. From the analysis of substituents presented above, one skilled in the art will understand that the term "substituted alkyl" includes groups such as carbon atoms bonded to groups other than hydrogen, such as haloalkyl (eg, -CF₃ and -CH2CF3) and acyl (for example, -C (O) CH₃, -C (O) CF₃, -C (O) CH₂0CH₃ and the like).

Similar to the substituents described for the alkyl radical, the substituents for the aryl and heteroaryl groups are varied and selected from, for example: -OR ', -NR'R, -SR', -halogen, -SiR'R '' R '' ', -OC (O) R', -C (O) R ', -CO2R', -CONR'R, -OC (O) NR'R, -NRC (O) R ', -NR' -C (O) N RR ', -NRC (O)₂R ', -NR-C (NR'R R') = NR, -NR-C (NR'R) = NR -S (O) R ', -S (O)₂R ', -S (O) ₂NR'R '', -NRSO2R ', -CN, -NO₂, -R ', -N ₃, -CH (F)₂, fluoro (C1-C4) alkoxy and fluoro (C1-C4) alkyl, in a number found in the range between zero and the total number of open valences in the aromatic ring system; and where 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 aryl and substituted or unsubstituted heteroaryl. When a compound includes more than one R group, for example, each of the R groups is independently selected as R ', R, R' '' and R '' '' groups when more than one of these groups is found Present.

<img file="MX367403B_D0013.tif" />

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

Two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally form a ring of the formula -TC (O) - (CRR ') _that-U-, where T and U independently correspond to -NR-, -O-, -CRR'- or a single bond and q results between 0 and 3. Alternatively, two of the substituents on adjacent atoms of the aryl or heteroaryl ring can be optionally replaced with a substituent of the formula -A- (CH2) _r-B-, where A and B independently correspond to -CRR '~, -O-, -NR-, -S-, -S (O) -, -S (O)₂-, -S (O)₂NR'- or a single bond and r results in an integer between 1 and 4. One of the single bonds of the new ring formed can be replaced by a double bond. Alternatively, two of the substituents on the adjacent atoms of the aryl or heteroaryl ring can be optionally replaced with a substituent of the formula - (CRR ')_S-X'- (C^,'R^,,')_d-, where syd are independently, integers between 0 and 3 and X 'corresponds to -O-, -NR'-, -S-, —S (O) -, —S (O) ₂- bear)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, as well as substituted or unsubstituted heteroaryl.

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

A substituent group, as used herein, represents a group selected from the following fractions:

(A) -OH, -NH₂, -SH, -CN, -CF₃, -DO NOT₂, oxo, halogen, unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, unsubstituted heteroaryl; and (B) alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, substituted with at least one substituent selected from:

(i) oxo, -OH, -NH2, -SH, -CN, -CF3, -NO2, halogen, unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, unsubstituted heteroaryl; and (ii) alkyl, heteroalkyl, 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, heterocycloalkyl, aryl or heteroaryl, 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.

A limited size substituent or limited size substituent group as used herein represents a group selected from all the substituents described above for a substituent group, wherein each substituted or unsubstituted alkyl corresponds to a substituted C1-C29 alkyl or unsubstituted, each substituted or unsubstituted heteroalkyl corresponds to a substituted or unsubstituted 2 to 30-membered heteroalkyl, each substituted or unsubstituted cycloalkyl corresponds to a substituted or unsubstituted Cg-Cg cycloalkyl, each substituted or unsubstituted heterocycloalkyl corresponds to a substituted or unsubstituted 3 to 8-membered heterocycloalkyl, each substituted or unsubstituted aryl corresponds to a Cg-aryl Cio substituted or unsubstituted and each substituted or unsubstituted heteroaryl corresponds to a substituted or unsubstituted 5-10 membered heteroaryl.

A lower substituent or lower substituent group as used herein represents a group selected from all the substituents described above for a substituent group, wherein each substituted or unsubstituted alkyl corresponds to a substituted or unsubstituted Ci-Cg alkyl. substitute, each substituted or unsubstituted heteroalkyl corresponds to a substituted or unsubstituted 2- to 8-membered heteroalkyl, each substituted or unsubstituted cycloalkyl corresponds to a substituted or unsubstituted C3-C7 cycloalkyl, each substituted or unsubstituted heterocycloalkyl corresponds to a substituted or unsubstituted 3 to 7-membered heterocycloalkyl, each substituted or unsubstituted aryl corresponds to a substituted CgC10 aryl or unsubstituted and each substituted or unsubstituted heteroaryl corresponds to a substituted or unsubstituted 5- to 9-membered heteroaryl.

In some embodiments, each substituted group described in

<img file="MX367403B_D0014.tif" />

The compounds herein are substituted with at least one substituent group. More specifically, in some embodiments each substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene and / or substituted heteroarylene described in the compounds of the present are substituted with at least one substituent group. In some embodiments, at least one or even all members of these groups are substituted with at least one substituent group of limited size. In some embodiments, at least one or even all members of these groups are substituted with at least one lower substituent group.

In some embodiments of the compounds presented, each substituted or unsubstituted alkyl may correspond to a substituted or unsubstituted C1-C30 alkyl, each substituted or unsubstituted heteroalkyl corresponds to a substituted or unsubstituted 2 to 30-membered heteroalkyl, each substituted cycloalkyl or unsubstituted corresponds to a substituted or unsubstituted C3-C8 cycloalkyl, each substituted or unsubstituted heterocycloalkyl corresponds to a substituted or unsubstituted 3 to 8-membered heterocycloalkyl, each substituted or unsubstituted aryl corresponds to a substituted or unsubstituted Cg-Cio aryl and each substituted or unsubstituted heteroaryl corresponds to a heteroaryl of 5 to 10

<img file="MX367403B_D0015.tif" />

substituted or unsubstituted members. In some embodiments of the compounds presented, each substituted or unsubstituted alkylene corresponds to a substituted or unsubstituted C1-C30 alkylene, each substituted or unsubstituted heteroalkylene corresponds to a substituted or unsubstituted 2 to 30-membered heteroalkylene, each substituted or substituted cycloalkylene unsubstituted corresponds to a substituted or unsubstituted Cg-Cg cycloalkylene, each substituted or unsubstituted heterocycloalkylene corresponds to a substituted or unsubstituted 3 to 8-membered heterocycloalkylene, each substituted or unsubstituted arylene corresponds to a substituted or unsubstituted Ce-Cio arylene and / or each substituted or unsubstituted heteroarylene corresponds to a heteroarylene 5 to 10 members substituted or unsubstituted.

In some embodiments, each substituted or unsubstituted alkyl corresponds to a substituted or unsubstituted Ci-Cg alkyl, each substituted or unsubstituted heteroalkyl corresponds to a substituted or unsubstituted 2 to 8-membered heteroalkyl, each substituted or unsubstituted cycloalkyl corresponds to a substituted or unsubstituted C3-C7 cycloalkyl, each substituted or unsubstituted heterocycloalkyl corresponds to a substituted or unsubstituted 3 to 7-membered heterocycloalkyl, each substituted or unsubstituted aryl corresponds to a substituted or unsubstituted CgC10 aryl and / or each substituted or unsubstituted heteroaryl corresponds to a substituted or unsubstituted 5- to 9-membered heteroaryl. In some modalities of

<img file="MX367403B_D0016.tif" />

presented compounds, each substituted or unsubstituted alkylene corresponds to a substituted or unsubstituted Ci-Ce alkylene, each substituted or unsubstituted heteroalkylene corresponds to a substituted or unsubstituted 2 to 8-membered heteroalkylene, each substituted or unsubstituted cycloalkylene corresponds to a C3-C7 substituted or unsubstituted cycloalkylene, each substituted or unsubstituted heterocycloalkylene corresponds to a substituted or unsubstituted 3 to 7-membered heterocycloalkylene, each substituted or unsubstituted arylene corresponds to a substituted or unsubstituted Cg-Cio arylene and / or each substituted or unsubstituted heteroarylene corresponds to a heteroarylene 5 to 9 members substituted or unsubstituted.

The term "pharmaceutically acceptable salt" includes salts of the active compounds that are prepared with relatively non-toxic acids and bases, depending on the particular substituents found in the compounds described herein. When the compounds described herein contain relatively acidic functionalities, basic addition salts can be obtained by contacting the neutral form of said compound with a sufficient amount of the desired base, either pure or in a suitable inert solvent. Examples of pharmaceutically acceptable basic addition salts include sodium, potassium, calcium, ammonium, organic amino or magnesium salts, as well as a similar salt. When the compounds described herein contain relatively basic functionalities, acid addition salts can be obtained by contacting the neutral form of said compound 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, carbonic, carbonic monohydrogen, phosphoric, phosphoric monohydrogen, phosphoric dihydrogen, monohydrogen sulfide, iodhydric or phosphoric, as well. as its similar, in the same way as salts derived from relatively non-toxic organic acids such as acetic, propionic, isobutyric, maleic, malonic acid, benzoic, succinic, suberic, fumaric, lactic, mandelic, italic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, oxalic, methanesulfonic and the like. Also included are salts from amino acids such as arginate and the like, as well as salts of organic acids such as glucuronic or galacturonic acid and the like (see, for example, Berge et al., Pharmaceutical Salts, Journal of Pharmaceutical Science, 1977, 66: 1-19). Certain specific compounds described herein contain both basic and acidic functionalities that allow the compounds to become basic or acidic addition salts.

Thus, the compounds described herein [for example, a compound of Formula (I) and / or a compound of Formula (la)] may exist as salts, as with pharmaceutically acceptable acids. Examples of such salts include

<img file="MX367403B_D0017.tif" />

hydrochlorides, hydrobromides, sulfates, methanesulfonates, nitrates, maleates, acetates, citrates, smokers, tartrates (for example, (+) - 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.

The neutral forms of the compounds can be regenerated by contacting the salt with a base or an acid and isolating the original compound in the conventional manner. The original form of the compound differs in certain physical properties from the various salt forms, such as solubility in polar solvents.

In addition to the salt forms, the compounds described herein, [eg, a compound of Formula (I) and / or a compound of Formula (la)] can be found in the form of a prodrug. The prodrugs of the compounds described herein correspond to those compounds that undergo chemical changes with ease under physiological conditions to provide a compound described herein. In addition, prodrugs can convert the compounds described herein by chemical or biochemical methods in an ex vivo environment. For example, prodrugs can slowly become compounds described herein when placed in a stock in a transdermal patch with suitable enzymes or chemical reagents. The term fraction refers to the chemical entity reversibly bound to the drug that

<img file="MX367403B_D0018.tif" />

improves the performance aspect of masking a problematic functional group.

Certain compounds described herein [eg, a compound of Formula (I) and / or a compound of Formula (la)] may exist in non-soluble forms, as well as in soluble forms, including hydrated forms. In general, soluble forms are equivalent to insoluble forms and are therefore part of the method. Certain compounds described herein [eg, a compound of Formula (I) and / or a compound of Formula (la)] may exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the contemplated and intended uses. Certain compounds described herein [eg, a compound of Formula (I) and / or a compound of Formula (la)] may possess asymmetric atoms (optical centers) or double bonds; It covers racemic mixtures, diastomers, tautomers, geometric isomers and individual isomers. The compounds described herein [eg, a compound of Formula (I) and / or a compound of Formula (la)] do not include those known in the art as too unstable when synthesized and / or isolated.

The compounds described herein [for example, a compound of Formula (I) and / or a compound of Formula (la)] may also contain unnatural proportions of atomic isotopes of one or more of the atoms constituting said compounds . For example, the compounds can be labeled as

<img file="MX367403B_D0019.tif" />

radioactive isotopes, such as tritium (³H), iodine-125 (¹²⁵I), or carbon-14 (¹⁴C). All isotopic variations of the compounds, whether or not radioactive, are included.

The symbol «/ w indicates the point of union of a chemical fraction with the rest of a molecule or chemical formula.

II. Compounds

In a first aspect, a compound with the structure of Formula (I) is provided:

<img file="MX367403B_D0020.tif" />

or stereoisomer, salt, hydride, solvate or crystalline form thereof. For the compound with the structure of Formula (Y), B_Nuc corresponds to a naturally occurring purine or pyrimidine base, or an analogue thereof; L corresponds to a lipophilic carrier fraction, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, or O-substituted glyceryl with the formula -CH2CH (OR¹) -CH2 (OR²) (II), where R¹ and R²correspond independently to a substituted or unsubstituted alkyl, or substituted or unsubstituted aryl; R corresponds to a substituted or unsubstituted lower alkyl, a substituted or unsubstituted lower heteroalkyl, a substituted or unsubstituted lower cycloalkyl, a lower heterocycloalkyl

<img file="MX367403B_D0021.tif" />

substituted or unsubstituted, a substituted or unsubstituted aryl, or a substituted or unsubstituted lower heteroaryl; and X corresponds to a hydrogen, a substituted or unsubstituted lower alkyl or a substituted or unsubstituted lower heteroalkyl.

In some embodiments, the compound corresponds to a stereoisomer with the structure of Formula (I). In some embodiments, the compound corresponds to a salt of a compound with the structure of Formula (I). In some embodiments, the compound corresponds to a solvate of a compound of the Formula (I). In some embodiments, the compound corresponds to a crystalline form of a compound with the structure of Formula (I).

The terms purine or naturally occurring pyrimidine base and the like refer, in the common and usual manner as used in the art, to purine or pyrimidine bases, for example, guanine, cytosine adenine, thymine, uracil or 2,6-diaminopurine. The naturally occurring purine or pyrimidine base binding can be found at any available site, for example, guanin-9-yl, adenin-9-yl, cytosin-l-yl, timin-1-yl, uracil-l-yl, 2,6-diaminopurin-9-yl and the like. When bound to the rest of the compounds described herein, the naturally occurring pyrimidine or purine base corresponds to a monovalent form (the form of a chemical fraction or substituent as is known in the art).

The terms naturally occurring purine or pyrimidine base and the like are referred to, in common mode and

<img file="MX367403B_D0022.tif" />

usual as used in the art, to a chemical analog of a naturally occurring purine or pyrimidine base. When bound to the rest of the compounds described herein, the naturally occurring pyrimidine or purine base analog corresponds to a monovalent form (the form of a chemical fraction or substituent as is known in the art).

Consequently, in some modalities, B_Wildebeestc corresponds a naturally occurring purine or pyrimidine base. In some modalities, Bnuc corresponds to a naturally occurring purine base. In some embodiments, Bnuc corresponds to a naturally occurring pyrimidine base. In some embodiments, Bnuc corresponds to a naturally occurring purine or pyrimidine base analog. In some modalities, B_Nuc corresponds to an analogue of a naturally occurring base. In some modalities, B_Nuc corresponds to an analogue of a naturally occurring pyrimidine base.

The terms lipophilic carrier and the like, refer to a chemical fraction that transmits increased lipophilicity when incorporated into a compound with the structure of Formula (I). In some embodiments, the lipophilic carrier corresponds to a substituted or unsubstituted Cg-24 alkyl. In some embodiments, the lipophilic carrier corresponds to a substituted or unsubstituted Cg-24 heteroalkyl. In some embodiments, the lipophilic carrier corresponds to a substituted or unsubstituted Cg-24 alkoxyalkyl. Exemplary lipophilic carriers include

<img file="MX367403B_D0023.tif" />

glyceryl fractions with substituted or unsubstituted alkyl and / or substituted or unsubstituted aryl substituents. In some embodiments, the substitution in a glyceryl fraction is carried out by substitution of O- with a substituted or unsubstituted alkyl and / or via substitution of 0- with a substituted or unsubstituted aryl. Thus, the lipophilic fraction L transmits lipophilicity and therefore can include glyceryl ether linked to the compounds (for example, 10-octadecyl-2-O-benzyl) where the hydroxyls of glyceryl hydroxyls are replaced with substituted or unsubstituted alkyl groups, or substituted or unsubstituted aryl, which do not transmit hydrophilicity and the glyceryl carbon atoms are no longer substituted. In some embodiments, L corresponds to a glyceryl substituted with O- of the Formula -CH₂CH (OR¹) -CH₂ (OR²) (II), where R¹ and R² corresponds to a substituted or unsubstituted alkyl independently or to a substituted or unsubstituted aryl.

In some embodiments, L corresponds to a substituted or unsubstituted alkyl, a substituted or unsubstituted heteroalkyl, or an O- substituted glyceryl of the formula -CH₂CH (OR¹) -CH₂ (OR²) (II), where R¹ and R² they correspond independently to a substituted or unsubstituted alkyl, or to a substituted or unsubstituted aryl. In some embodiments, L corresponds to a glyceryl substituted with O-. In one embodiment L corresponds to 10-alkyl-2-O-benzyl-sn-glyceryl. In some embodiments, L corresponds to 10-octadecyl-2-O-benzyl-sn

<img file="MX367403B_D0024.tif" />

glyceryl In some embodiments, L corresponds to an unsubstituted alkyl. In some embodiments, L corresponds to an alkyl of limited unsubstituted size. In some embodiments, L corresponds to Cs-24 alkyl. In some embodiments, L corresponds to an unsubstituted heteroalkyl. In some embodiments, L corresponds to a heteroalkyl of limited unsubstituted size. In some embodiments, L corresponds to a Cs-24 heteroalkyl. In some embodiments, L corresponds to a non-alkoxyalkyl substitute. In some embodiments, L corresponds to an unsubstituted limited size alkoxyalkyl. In some embodiments, L corresponds to a Ce-24 alkoxyalkyl.

In some embodiments, R corresponds to a substituted or unsubstituted lower alkyl, a substituted or unsubstituted lower heteroalkyl, a substituted or unsubstituted lower cycloalkyl, a substituted or unsubstituted lower heterocycloalkyl, a substituted aryl or without replacing; or to a lower substituted or unsubstituted heteroaryl. In some embodiments, R corresponds to a substituted or unsubstituted lower alkyl. In some embodiments, R corresponds to a lower substituted or unsubstituted heteroalkyl. In some embodiments, R corresponds to a glyceryl substituted with O- of the formula -CH₂CH (OR³) -CH_Z (OR⁴) (III), where R³ and R⁴ they correspond independently to a substituted or unsubstituted alkyl, or to a substituted or unsubstituted aryl. In some R modalities, it corresponds to a substituted or unsubstituted lower cycloalkyl.

<img file="MX367403B_D0025.tif" />

In some embodiments, R corresponds to a substituted or unsubstituted lower heterocycloalkyl. In some embodiments, R corresponds to a substituted or unsubstituted hexopyranosyl. In some embodiments R corresponds to a substituted or unsubstituted aryl. In some embodiments, R corresponds to a lower substituted or unsubstituted heteroaryl. In some embodiments R corresponds to a lower unsubstituted alkyl. In some embodiments, R corresponds to a lower unsubstituted heteroaryl. In some embodiments, R corresponds to a lower unsubstituted cycloalkyl. In some embodiments, R corresponds to a lower unsubstituted heterocycloalkyl. In some embodiments, R corresponds to an unsubstituted aryl. In some embodiments, R corresponds to a lower unsubstituted heteroaryl. In some embodiments, R corresponds to smaller substituted or unsubstituted limited cycloalkyl. In some embodiments, R corresponds to smaller substituted or unsubstituted limited heterocycloalkyl. In some embodiments, R corresponds to a substituted or unsubstituted limited size aryl. In some embodiments, R corresponds to lower substituted or unsubstituted heteroaryl. In some embodiments, R corresponds even to substituted or unsubstituted Ci-s alkyl. In some embodiments, R corresponds to a substituted or unsubstituted Ci-β heteroalkyl. In some embodiments, R corresponds to a substituted or unsubstituted C4-8 cycloalkyl. In some embodiments, R corresponds to a substituted or unsubstituted C4-8 heterocycloalkyl. In some

<img file="MX367403B_D0026.tif" />

modalities, R corresponds to a substituted or unsubstituted Ce-io aryl. In some embodiments, R corresponds to a substituted or unsubstituted Cg-io heteroaryl. In some embodiments, R corresponds to an unsubstituted Ci-s alkyl. In some embodiments, R corresponds to an unsubstituted C2-8 heteroalkyl. In some embodiments, R corresponds to an unsubstituted C4-8 cycloalkyl. In some embodiments, R corresponds to an unsubstituted heterocycloalkyl Ch. In some embodiments, R corresponds to an unsubstituted Cg-io aryl. In some embodiments, R is unsubstituted Ce-ίο heteroaryl.

In some embodiments, R corresponds to a substituted or unsubstituted phenyl, a substituted or unsubstituted naphthyl, a substituted or unsubstituted benzyl, a substituted or unsubstituted glyceryl; or to a substituted or unsubstituted hexopyranosyl. In some embodiments, R corresponds to a substituted phenyl. In some embodiments, R corresponds to a substituted naphthyl. In some embodiments, R corresponds to a substituted benzyl. In some embodiments, R corresponds to a substituted glyceryl. In some embodiments, R corresponds to a substituted hexopyranosyl. In some embodiments, R corresponds to an unsubstituted phenyl. In some embodiments, R corresponds to an unsubstituted naphthyl. In some embodiments, R corresponds to an unsubstituted benzyl. In some embodiments, R corresponds to an unsubstituted glyceryl. In some embodiments, R corresponds to an unsubstituted hexopyranosyl.

<img file="MX367403B_D0027.tif" />

In some embodiments, X corresponds to hydrogen, a substituted or unsubstituted lower alkyl or a substituted or unsubstituted lower heteroalkyl. In some modalities, X corresponds to hydrogen. In some embodiments, X corresponds to a lower substituted or unsubstituted alkyl. In some embodiments, X corresponds to a lower substituted or unsubstituted heteroalkyl. In some embodiments, X corresponds to a lower unsubstituted alkyl. In some embodiments, X corresponds to a lower unsubstituted heteroalkyl. In some embodiments, X corresponds to a substituted or unsubstituted limited size alkyl. In some embodiments, X corresponds to a substituted or unsubstituted limited size heteroalkyl. In some embodiments, X corresponds to an alkyl of limited unsubstituted size. In some embodiments, X corresponds to a heteroalkyl of limited unsubstituted size. In some embodiments, X corresponds to methyl. In some embodiments, X corresponds to methoxymethyl. In some embodiments, X corresponds to hydroxymethyl. In some embodiments, X corresponds to fluoromethyl.

In some embodiments, the compound with structure of Formula (I) has the structure of Formula (1-1):

<img file="MX367403B_D0028.tif" />

O — R (ii)

<img file="MX367403B_D0029.tif" />

For the compound with the structure of Formula (1-1), Bnuc results as described for any embodiment of the compound of Formula (I) set forth herein.

In some embodiments, L results as described for any modality of the compound of Formula (I) described herein. In some embodiments, L corresponds to octadecyloxyethyl, hexadecyloxypropyl or 10-octadecyl-2-Obenzyl-sn-glyceryl. In some embodiments, L corresponds to octadecyloxyethyl. In some embodiments, L corresponds to hexadecyloxypropyl. In some modalities L corresponds to 1-0octadecyl-2-0-benzyl-sn-glyceryl.

In some embodiments, R results as described for any modality of the compound of Formula (I) described herein. In some embodiments, R corresponds to a substituted or unsubstituted phenyl, a substituted or unsubstituted naphthyl, a substituted or unsubstituted benzyl, a substituted or unsubstituted glyceryl or a substituted or unsubstituted hexopyranosyl. In some embodiments, R corresponds to a substituted naphthyl. In some embodiments, R corresponds to a substituted benzyl. In some embodiments, R corresponds to a substituted glyceryl. In some embodiments, R corresponds to a substituted hexopyranosyl. In some embodiments, R corresponds to an unsubstituted phenyl. In some embodiments, R corresponds to an unsubstituted naphthyl. In some embodiments, R corresponds to an unsubstituted benzyl. In some embodiments, R corresponds to an unsubstituted glyceryl. In some embodiments, R corresponds to an unsubstituted hexopyranosyl.

In some embodiments, the compound with structure of Formula (I) contains the structure of Formula (1-2):

®Nuc (1-2)

For the compound with the structure of Formula (1-2), in a B mode_Nuc It is as described for any embodiment of the compound of Formulas (I) - (Il) set forth herein.

In some embodiments, L results as described for any modality of the compound of Formulas (I) - (Il) set forth herein.

In some embodiments, R results as described for any modality of the compound of Formulas (I) - (Il) set forth herein.

In some embodiments, the compound with structure of Formula (I) contains the structure of Formula (1-3):

®Nuc d-3)

For the compound with the structure of Formula (1-3), in

<img file="MX367403B_D0030.tif" />

<img file="MX367403B_D0031.tif" />

a Bn mode_uc It results as described for any embodiment of the compound of Formulas (1) - (1-2) set forth herein.

In some embodiments, L results as described for any modality of the compound of Formulas (1) - (1-2) set forth herein.

In some embodiments, R results as described for any modality of the compound of Formulas (1) - (1-2) set forth herein.

In some embodiments, the compound with structure of Formula (I) contains the structure of Formula (1-4):

Bnuc O

Q ——L 'i ·' '—R hct (1-4)

For the compound with the structure of Formula (1-4), in a B mode_WILDEBEESTc results as described for any embodiment of the compound of Formulas (1) - (1-3) set forth herein.

In some embodiments, L results as described for any modality of the compound of Formulas (1) - (1-3) set forth herein.

In some embodiments, R results as described for any modality of the compound of Formulas (1) - (1-3) set forth herein.

In some embodiments, the compound with structure of the

Formula (I) contains the structure of Formula (1-5):

<img file="MX367403B_D0032.tif" />

For the compound with the structure of Formula (1-5), in a Bn mode_ORc results as described for any embodiment of the compound of Formulas (1) - (1-4) set forth herein.

In some embodiments, L results as described for any modality of the compound of Formulas (1) - (1-4) set forth herein.

In some embodiments, R results as described for any modality of the compound of Formulas (1) - (1-4) set forth herein.

In another aspect, a compound of Formula (la) or a pharmaceutically acceptable salt, hydride, solvate or crystalline form thereof is provided:

<img file="MX367403B_D0033.tif" />

For this aspect, B_NuC(a) it may correspond to a naturally occurring purine, a naturally occurring pyrimidine, a non-naturally occurring purine or a naturally occurring pyrimidine. L^to may corresponds to an alkyl

<img file="MX367403B_D0034.tif" />

C12-24 unsubstituted, an unsubstituted C13-29 heteroalkyl or a substituted glyceryl moiety. The glyceryl fraction may be substituted by one or more groups selected from an unsubstituted C13-29 alkyl, an unsubstituted C13-29 heteroalkyl, a substituted or unsubstituted aryl (Ci-g alkyl), a substituted or unsubstituted heteroaryl ( Ci-β alkyl) and a substituted or unsubstituted heterocycloalkyl (Ci-e alkyl). R^to it can be selected from an unsubstituted C1-6 alkyl, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl (Ci-β alkyl), a substituted or unsubstituted heteroaryl substitute (Ci-β alkyl) a substituted or unsubstituted heterocycloalkyl (Ci-g alkyl). X^to it may correspond to hydrogen, unsubstituted C1-6 alkyl, halogen substituted Ci-β alkyl, a hydroxy substituted C1-6 alkyl or an unsubstituted C1-6 alkoxy.

In some modalities, X^to it may correspond to hydrogen, unsubstituted C1-6 alkyl, halogen substituted C1-6 alkyl, a hydroxy substituted C1-6 alkyl or an unsubstituted C1-6 alkoxy. In some modalities, X^to It can correspond to hydrogen. In some modalities, X^to It may correspond to unsubstituted Ci-e alkyl. In some modalities, X^to It can correspond to methyl. In some modalities, X^to it may correspond to a hydroxy substituted C1-6 alkyl. In some modalities, X^to It can correspond to -CH2OH. In some embodiments, X may correspond to a C1-6 alkoxy. In some modalities, X^to It can correspond to methoxy. In some

<img file="MX367403B_D0035.tif" />

modalities, X^to it may correspond to a halogen substituted Ci-6 alkyl. · In some modalities, X^to it may correspond to a substituted Ci-6 alkyl fluoro. In some modalities, X^to may correspond to -CH₂F.

In addition to any modality presented above, in some modalities L^to it may correspond to an unsubstituted C13-29 heteroalkyl. In some modalities, L^to It may contain the structure - (CH2) 1-6-O- (CH2) 11-21-CH3. In some modalities, L^toIt may contain the structure - (CH2) 2-O- (CH2) 17-CH3. In some modalities, L^to It may contain the structure - (CH2) 3-0- (CH2) 15-CH3. In some modalities, L^to can contain the structure - (CH₂) i-e0- (CHz) 10-20- (CHCH3) -CH₃.

Beyond any modality presented above, in some modalities L^to may corresponds to a fraction of substituted glyceryl. In some modalities, L^to can contain the structure - (CH2) -CH (OR^{to the}) - (CH2) -O (CH₂) 11-21-CH3, where R^{to the} it may correspond to a substituted or unsubstituted aryl (Ci-g alkyl), a substituted or unsubstituted heteroaryl (Ci-β alkyl) or a substituted or unsubstituted heterocycloalkyl (Ci-β alkyl). In one mode, R^{to the} it may correspond to an aryl (Ci-β alkyl). In one mode, R^{to the} it may correspond to an unsubstituted aryl (Ci-e alkyl). In one mode, R^{to the} it may correspond to a substituted heteroaryl (Ci-e alkyl). In one mode, R^{to the} may correspond to an unsubstituted heteroaryl (Ci-e alkyl) · In an R mode^{to the} may correspond to a heterocycloalkyl

<img file="MX367403B_D0036.tif" />

substituted (Ci-é alkyl). In one mode, R^{to the} it may correspond to an unsubstituted heterocycloalkyl (Ci-e alkyl).

In some modalities, L^to can contain the structure ° \

<img file="MX367403B_D0037.tif" />

In addition to any modality of the compound of the Formula (la), in some modalities R^to it can correspond to a substituted or unsubstituted aryl. In some embodiments, the substituted aryl may correspond to a substituted phenyl. In some embodiments, the unsubstituted aryl may correspond to an unsubstituted phenyl. In some embodiments, the substituted aryl may correspond to a substituted naphthyl. In some embodiments, the unsubstituted aryl may correspond to an unsubstituted naphthyl.

In addition to any modality of the compound of the Formula (la), in some modalities R^to it may correspond to a substituted or unsubstituted aryl (Ci-e alkyl). In some embodiments, the substituted aryl (Ci-g alkyl) may correspond to a substituted benzyl. In some embodiments, the unsubstituted aryl (Ci-g alkyl) may correspond to an unsubstituted benzyl.

In addition to any modality of the compound of the Formula (la), in some modalities R^to it may correspond to a substituted or unsubstituted heterocycloalkyl (Ci-β alkyl). In some embodiments, the substituted or unsubstituted heterocycloalkyl (Ci-e alkyl) results in a substituted or unsubstituted galactosyl.

In addition to any modality of the compound of Formula (la), in some modalities B_NuC(a) may correspond to a purine that occurred naturally. In some embodiments, Bnucoi may correspond to a naturally occurring pyrimidine. In some embodiments, Bnuc (s) may correspond to an unnaturally occurring pyridine. In some modalities, B_NuC(a) may correspond to an unnaturally occurring pyrimidine. The term occurred unnaturally and the like, in the context of groups B_Wildebeestc (a) purine or pyrimidine nucleosides, refers to fractions with a purine or pyrimidine nucleus and additional chemical modifications not found in naturally occurring systems. Examples of purines include adenine, guanine, hypoxanthine, xanthine, theobromine, caffeine, uric acid, isoguanin, 2,6-diaminopurine. Examples of pyrimidines include cytosine, thymine and uracil.

In some modalities, BNuc (a) can be selected from:

<img file="MX367403B_D0038.tif" />

<img file="MX367403B_D0039.tif" />

In some embodiments a compound of Formula (la) may have the structure:

<img file="MX367403B_D0040.tif" />

In some embodiments a compound of Formula (la) may have the structure:

<img file="MX367403B_D0041.tif" />

In some embodiments, a compound of Formula (la) may have the structure:

<img file="MX367403B_D0042.tif" />

<img file="MX367403B_D0043.tif" />

X^to can can can

In some modalities have the structure:

a compound of the

<img file="MX367403B_D0044.tif" />

O — R

X^to

In some modalities have the structure:

Formula (la) a compound of the

<img file="MX367403B_D0045.tif" />

X^to

In some modalities have the structure:

Formula (la) a compound of the

<img file="MX367403B_D0046.tif" />

X^to

In some embodiments, the compound may

Formula (the) selected

<img file="MX367403B_D0047.tif" />

<img file="MX367403B_D0048.tif" />

OR

<img file="MX367403B_D0049.tif" />

or

<img file="MX367403B_D0050.tif" />

<img file="MX367403B_D0051.tif" />

<img file="MX367403B_D0052.tif" />

<img file="MX367403B_D0053.tif" />

<img file="MX367403B_D0054.tif" />

<img file="MX367403B_D0055.tif" />

<img file="MX367403B_D0056.tif" />

<img file="MX367403B_D0057.tif" />

, or a pharmaceutically acceptable salt, hydride, solvate or crystalline form of any of the foregoing.

As can be seen from Formulas (I) and (la), there are several modalities. For example, there are presented modalities directed to compounds of the Formula (I) and a compound of the Formula (la) based on the identity of the acyclic nucleoside phosphonate scaffolding. This is not intended to be an explicit or implicit admission that the modalities are independent or distinctive, nor should it be interpreted that way. On the contrary, it is intended to express information so that the full scope of Formulas (I) and (la) can be understood. Also, the following modalities and aspects thereof, were not conceived to limit the total scope of the structure of Formula (I) and / or the structure of Formula (la).

<img file="MX367403B_D0058.tif" />

Tables 1 to 10 presented below set out structures contemplated in this document. The structures of Tables 1 to 10 are not intended to limit the total scope of the contemplated compounds represented by the structure of Formulas (I), (I-1), (1-2), (1-3), (1-4), (1-5) and (la). On the other hand, it is contemplated that any of the acyclic nucleoside phosphonate scaffolds (ANP) (PME-, (R) -PMP, (S) -MPMP-, (S) -HPMP- and (S) -FPMP-) or its isomers can be used in combination with any of the contemplated combinations of pyrimidine or purine bases, occurring or modified naturally (Bnuc / Bnuco)), L / L^to and R / R^to. In addition, since the phosphorus atom of the ANP diester is a potential chiral center, it is understood that the stereochemical configurations Rp and Sp are possible (ie, Cahn-Ingold-Prelog nomenclature as is known in the art). Therefore, the structures shown below include possible stereochemical configurations for phosphorus.

<img file="MX367403B_D0059.tif" />

Table 1. Phosphonomethoxye diester compounds (PME)

<td colspan="5">Bhuc ^ Nu ^ ·) 0 B »iucAiue (·) 0 BnucAíucW O k ^ O ^ PO-LA. * 0_XOR_X^ Í »- O-UL · k ^ O ^ PO-LA. · Ó-R / R * ° OR / R * ° ¿-WR · RpoSp (depends on substituents) Rp_r Sp (racemic)</td>

<td>Coepoesfe No.</td><td>BsUBüm.)</td><td>LL *</td><td>RR '</td><td>Name</td>

<td></td><td>gnanin-9-Üo</td><td>octadecüoxietüo</td><td>beneflo</td><td>Phosphonomethoxy) GuaBina</td>

<td>the</td><td>gU. &lt;LEVEL-9-IT</td><td>octadecüoxietüo</td><td>bancil</td><td>benzyl octadecyloxiatus 9 &lt;2phosphonoinetox »ethyl) guanine</td>

<td>Ib (lauto)</td><td>guiiiin-9 * ilo</td><td>octadecyloxy</td><td>bancil</td><td>benzyl ocUdecoxyethyl 9- (2phosphonomethoxyethyl) £ ianine</td>

<td> 2</td><td>adenin-9-üo</td><td>octadecyloxye</td><td>benço</td><td>octo benzocoxyoxy 9- (2 phosphonomethoxyethylene) adenine</td>

<td> 3</td><td>un-1-uncle cites</td><td>octadecyloxyeflo</td><td>bancil</td><td>bencüo octadecüoxietüo l- (2fosfonoxnMoxi «linden) citosim</td>

<td> 4</td><td>timin-l-üo</td><td>octadacüoxiatüo</td><td>benço</td><td>bencüo octadacüoxiatüo l- (2-</td>

<td> 5</td><td>nracil-l-ilo</td><td>octadecüoxietüo</td><td>benço</td><td>bencüo octadecüoxietüo 9- (2fosfonom «toxiatüo&gt; u» cüo</td>

<td> 6</td><td>2,6diarninopurm -9-ilo</td><td>octadecyloxye</td><td>benço</td><td>bancilo octadecüoxMUo 9- (2- phosphononaethoxyethyl) -2,6-diaininopurin</td>

<td> 7</td><td>guanin-9-üo</td><td>hexadacüoxipropílo</td><td>benço</td><td>bencüo hexadecüoxtpropüo 9- (2fo j fonometoxietüo) zuanina</td>

<td> 8</td><td>adenin-9-üo</td><td>haxadecüoxipropüo</td><td>benço</td><td>benzuo hexadacüoxipropüo 9- (2fosfonometoxtetüo) adanim</td>

<td> 9</td><td>cttosin-l-üo</td><td>hexadecüoxipropflo</td><td>benço</td><td>benzüo hexadecüoxtpropüo l- (2fosfonomatoxi «tÜo) cttosina</td>

<td> 10</td><td>tfffiwt-1 -ilo</td><td>hexadacÜoxypropyl</td><td>benço</td><td>benzyl hexadecüoxqpropyl 1 - (2foifonoxnatoxiotüo) taiM</td>

<td> 11</td><td>uracü-l-üo</td><td>hexadecüoxipropüo</td><td>benço</td><td>benzüo hexadacüoxipropüo 9- (2fosfonomatoxiatüo) uraeüo</td>

<td> 12</td><td>2,6di &amp; B &amp; ÍXlOpUrál -941o</td><td>hexadecüoxtpropüo</td><td>benço</td><td>benzüo haxadeeüoxypropyl 9- (2phosphonomethoxyato) -2_!6-di * íienojRirin</td>

<td> 13</td><td>fuanin-9-ilo</td><td>1 -O-octadacil-2-Obencüo-ίΛ glyceryl</td><td>benço</td><td>b «cdo lO-octadacÜo-2-0-b« ncflosn glicarüo 9- (2foifonometoñetüo) pumina</td>

<td> 14</td><td>adanin-9-üo</td><td>l -O-octadecüo-2-Obencüo- «n ¿icarilo</td><td>beacüo</td><td>bencüo lO-octtóetílo-2-CLbencüo- 5n ^ fKcerüo9- (2- fo sfonometoxwtito) adenine</td>

<td> 15</td><td>cytosia-l-flo</td><td>1 -O-octadacüo-2-0bencüo-r »^ icarilo</td><td>benço</td><td>bencüo lO-octadecüo-2-O-bencüoínglicerüo l- (2- fo sfonometoxi «tüo) cito stna</td>

<td> 16</td><td>tixnin-l-do</td><td>1 -O-octadecue -2-0benzyl-su glycan</td><td>benço</td><td>bencüo lO-octadacüo-2-O-bencÜosn glicerüo l- (2-fbsfonoizMtOKÍ • tflo) tinMM</td>

<td> 17</td><td>nracü-l-üo</td><td>1 -O-octadecuo -2 -0benzyl-SM icaryl</td><td>benço</td><td>bencüo lO-octadecüo-2-O-becÍloím ffcarüo 9- (2-fosfononietootíetüojuracüo</td>

<td colspan="5">B «txAucfe) O ΒνιμΑιμ &lt;β) 0 0 k ^ o ^ é-o-ω. * Ι ^ ο ^ ρ-ο-ΐΛ. · k ^ o ^ ¿&gt; -o-ui · Ó-WR ° 0-WR ° ° OR / R * RpoSp (depends on substituents) Rp. Sp (racemic)</td>

<td>Ccmpvesto No.</td><td>1 ^ * · ίΐ ^^ * Γ · (ΐ ·)</td><td>LL '</td><td>RK '</td><td>Name</td>

<td> 18</td><td>2,6-port-9-flo</td><td>1 -O-octaotolo -2-0benctlo-rn glyceryl</td><td>benço</td><td>VencÜo ld-octadecilc-2-O-tHmcílo¿n glycyl 9- (2-phosphonom «itoxi-« linden) 2,6-diammopurin</td>

<td> 19</td><td>Guanta-9-Üo</td><td>Ecyloxyethyl ociad</td><td>phenyl</td><td>Octadecyloxyethyl phenyl I-C2fo s Pheomethoxyethyl) pMaina</td>

<td> 20</td><td>aden.in-9-ilo</td><td>Ecyloxyethyl ociad</td><td>phenyl</td><td>phenyl or ^ idecyloxieblo 9- (2- io s fonomethoxyethyl) phedenine</td>

<td> 21</td><td>I quote sin-1-ilo</td><td>octad ethyloxyethyl</td><td>phenyl</td><td>&amp; nilo octadttiioxtátilo l- (2fo s fonomethoxfetilojcito s toa</td>

<td> 22</td><td>both-1-do</td><td>Oetadecyloxietite</td><td>phenyl</td><td>phenyl octadecyloxyethyl l- (2phosphonomethoxyethyljttoitoa</td>

<td> 23</td><td>ttracil-1-yl</td><td>octadecyloxyethyl</td><td>phenylc</td><td>phenyl octedecyloxy dioyl 9- (2fo s fonomethoxy «tilo) nrscilo</td>

<td> 24</td><td>2,6dliianiaoptSjHB -9-ilo</td><td>octadecyloxyethyl</td><td>phenyl</td><td>octadacyloxyethyl phenyl 9- (2- phosphonomethox methyl) -2,6-diazontoport</td>

<td> 25</td><td>maTtiru ^. ¿l ©</td><td>hexadecyloxypropyl</td><td>phenyl</td><td>phenyl h «xadacyloxyq&gt; ropyl 9- (2 phosphonometonethyl) giMiito *</td>

<td> 25</td><td>adenin-9-yl</td><td>hexadecyloxy ipropyl</td><td>phenyl</td><td>phenyl hexadecyloxypropyl 9- (2fo sphonomethoxyethyl) adentoa</td>

<td> 27</td><td>cftosto-1-ilo</td><td>hexadecyloxypropyl</td><td>phenyl</td><td>phenyl haxadocyloxypropyl l- (2phosphonomethoxyethyljitostoa</td>

<td> 28</td><td>tanto-1-ilo</td><td>hexadectloxiproptlo</td><td>phenyl</td><td>¿Enilohexadeciloxtoropilo 1- (1fo s fonomtf oxyethyl) emtoa</td>

<td> 29</td><td>uracil-1-yl</td><td>hexadecyloxy ^ Mropyl</td><td>phenyl</td><td>hexadoctloxypropyl phenyl 9- (2fo s fononaetoxMtiIo) nracil</td>

<td> 30</td><td>2.6- -9-flo</td><td>hexadecyloxypropyl</td><td>phenyl</td><td>phecado hecadocyloxy ^ ropyl 9- (2fo s fonomethoxyethyl) -2,6-diamtoopurin</td>

<td> 31</td><td>Guanto-9-ilo</td><td>1 -O-octadecile-2-Obenzyl-ΐη glyceryl</td><td>phenyl</td><td>phenyl 10-octadecyl-2-O-benzyl-in iceryl 9- (2phosphononiMoxí «tito) gtMuaina</td>

<td> 32</td><td>adtuto-9-ilo</td><td>1 -O-octadecyl-2-Οbenzyl-íM gócenlo</td><td>phenyl</td><td>phenyl 10-octadecyl-2-Ob «actIo-0i ^ c «flo9- (2- fos fonometoxMtil) * d «atoa</td>

<td> 33</td><td>I quote sin- 1-ilo</td><td>I -O-octocyl--2 -0 »bencüo-rn glyceryl</td><td>phenyl</td><td>Ienyl L- (2-octedecyl-2-0-bmcilo-an $ ic «rilo l- (2- phosphonomethoxy «linden) cytostoa</td>

<td> 34</td><td>timin-i-ilo</td><td>1 -O-octadecyl-2-Obenciicoi glyceryl</td><td>phenyl</td><td>phenyl l-0-oct * decyl-2-¡9-b * nc¿lo &lt;n glycoryl l- (2- phosphonomethoxyethyl) ttoiin</td>

<td> 35</td><td>«Racil-1-yl</td><td>l-0-octad «Üo-2-0benzyl -sn glyceryl</td><td>phenyl</td><td>phenyl 10-octedocyl-2-O-benzyl-on glyceryl H2phosphonomrtoxMlo) tiracil</td>

<td colspan="5">BliudBNueí ·) 0 0 BwuAlwje) 0 k ^ O ^ PO-UL * k ^ O ^ -O-UL Ó-R / R * ° O-RfR * ° OR / R * RpoSp (depends on substituent coughs) Rp, Sp (racértco)</td>

<td>Compose No.</td><td>Bx ^ Bx ^ s »)</td><td>THE*</td><td>R / R</td><td>Name</td>

<td> 36</td><td>2,6diamiBopurin -9-ilo</td><td>1 -Oo otad estío -2 «- €&gt; bencdo-ín glycerito</td><td>background</td><td>ftnílo lO-octadecyl-2-O-benzyl-íM glycol «rilo 9- (2-fo» fonoizi «toxi« linden) -2j6 · JíamirtnpiiriTi</td>

<td> 37</td><td>fu * nin-9-ilo</td><td>octadeeyloxyethyl</td><td>ethyl</td><td>• octededoxium ethyl 9- (2fo s phono methoxyethyl) fuenin</td>

<td> 38</td><td>odenin-9-üo</td><td>octadecdoxietdo</td><td>ethyl</td><td>• Ethyl octadecyloxyotyl 9 &lt;2 phosphonomethoxyethyl) * d «nina</td>

<td> 39</td><td>cytosin-l-do</td><td>octadecydoethyl</td><td>ethyl</td><td>«Cilodecyloxyethyl 1 - (2tosphonomethoxyethyl) cytosine»</td>

<td> 40</td><td>timin-l-ilo</td><td>octadecdoxietdo</td><td>"linden</td><td>• tilo octidntiloxkthyl 1 &lt;2phosphonom «to» «linden) ttmiEUi</td>

<td> 41</td><td>uracil-l-ito</td><td>octadecyloxiotóo</td><td>ethyl</td><td>«Linden octadectloxyotyl 9- {2fo sfonoBMtoxi« linden) uracil</td>

<td> 42</td><td>2.6- -9-ito</td><td>octsdocüexiotdo</td><td>"linden</td><td>ethyl octadecyloxyethyl 9- (2phosphonoa «tO3ti« linden) -2,6-diaBiinopurin</td>

<td> 43</td><td>ju «nin-9-ilo</td><td>hoxadociloxtpropyl</td><td>ethyl</td><td>«Titus hoxadeeitoxypropyl 9- (2phosphonon» toxiethyl) gu anine</td>

<td> 44</td><td>• denin-9-do</td><td>hexadecdoxipropdo</td><td>ethyl</td><td>♦ linden haxadecyloxypropyl 9- (2phosphonomethoxyethylene) »deniDa</td>

<td> 45</td><td>I quote »ml-Uo</td><td>hoxedectloxqjtopílo</td><td>•linden</td><td>• titobaxadocitoxtpropito l- (2fosfonomMoxtotilo) cytosine</td>

<td> 46</td><td>tünin-l-do</td><td>hexattocyte ^ ptopito</td><td>ethyl</td><td>• linden baxadtcitoxipropito l- (2phosphonomethoxietite) tbnina</td>

<td> 47</td><td>ur «cil-l-ilo</td><td>hexadecyloxtpropyl</td><td>ethyl</td><td>• linden baxadacitoxipropdo 9- (2phosphononact »« tito) nracite</td>

<td> 48</td><td>2,6dUminopurin -9-do</td><td>hexadekoxypropyl</td><td>•linden</td><td>«Linden htxadecitoxtpropito 9- (2fosfoaom« toxi * tdo) -2,6-dtaminopunn</td>

<td> 49</td><td>gu «iin-9-ilo</td><td>1 -O-octedocil-2-Ob «ncdo-xn ffcerdo</td><td>•linden</td><td>• linden i-ó-octadecite-2-O-bencyte- »» Toerdo9- (2- fosfonom «toxi« tito) guaniBa</td>

<td> 50</td><td>• donin-9-ilo</td><td>1 -O-octad «cdo-2-0boncilo-íM jücerüo</td><td>•linden</td><td>«Linden lO-octadecyl-2-O-bMOIL-a tf «ñto9- (2- fosfonom «toxi« ttto) ad «aina</td>

<td> 51</td><td>cytosin-l-do</td><td>1 -O-octadecÜo-2-Obonctlo-OT gUcerdo</td><td>•linden</td><td>Mflo lO- «ctadKito-¿-Ob« DCtto-fM Laughing l- (2- foifononwtoxtotilojatosina</td>

<td> 52</td><td>timiB-1-ilo</td><td>l -O-octadecüo-2-Οbmcilo-5M gltcorílo</td><td>etdo</td><td>• tito l-0-ocmd «cito-2-0-b« Káto- »t giieerdo l- (2- phosphonomet »ethyl) timtna</td>

<td> 53</td><td>wtcil-l-ito</td><td>lO-ocbKÍecílo-2-Ob «ncdo-ín ¿ic« do</td><td>ethyl</td><td>«Tdo lO-octadacito-2-Ob« ncito-0t Gltoerite 9 &lt;2- phosphonom «toxiethyl) uracyte</td>

<img file="MX367403B_D0060.tif" />

<td colspan="5">®NucA ^ ·) 0 BüMcAiu ^ a) 0 BnucAn ^ *) 0 Ó-R / R * ° OR / R * ° OR / R * Rp or Sp (depends on substituents) Rp. Sp (racemic)</td>

<td>Compound No.</td><td></td><td>L / L *</td><td>R / R '</td><td>Name</td>

<td> 54</td><td>2, diaminopurin -9-ilo</td><td>l -O-octadecflo-2-Obíneilc-3! glyceryl</td><td>ethyl</td><td>ethyl lO-octadecyl-2-O-benzyl-sn glyceryl 9- {2-phosphonoaMto »« t0o} -2j6dtaminopurin</td>

<td> 55</td><td>gnanin-9-ilo</td><td>octadecyloxyethyl</td><td>galactosyl</td><td>galactosuo octadecyloxyethyl 9- &lt;2fo s fbnomethoxy »linden) gtianine</td>

<td> 65</td><td>ad «iin-9-ilo</td><td>octadecyloxyethyl</td><td>galactosyl</td><td>galactosyl octadecyloxyethyl 9 &lt;2 · phosphonomethoxy * tylo) adenine</td>

<td> 57</td><td>cytosin-l-yl</td><td>octadecyloxyethyl</td><td>galactosyl</td><td>galactosyl oetaacdoxiethyl l- (2fo s phonomethoxyethyljitosine</td>

<td> 58</td><td>timin-l-ilo</td><td>octadecyloxyethyl</td><td>galactosyl</td><td>galactosyl octadecyloxyethyl 1 - &lt;2 phosphonomethoxy ethyl) thiinine</td>

<td> 59</td><td>uracil-l-ilo</td><td>octadecyloxyethyl</td><td>galactosyl</td><td>galactosyl octadecyloxyethyl 9 &lt;2fos phonoinetoxyathyl) ur * cyl</td>

<td> 60</td><td>2,6 diaminopttrin -9-yl</td><td>octadecyloxyethyl</td><td>plactosyl</td><td>^ octadecÜoxMlo 9- (2 phosphonomethoxyethyl) -2,6-diaminoptinn</td>

<td> 51</td><td>guaoin-9-ilo</td><td>hexadectloxypropyl</td><td>galactosyl</td><td>gdactosyl hexadecyloxyqwopyl 9- (2fo sphonomethoxyethyl) guanine</td>

<td> 62</td><td>adento-9-yl</td><td>hexadecyloxypropyl</td><td>galactosyl</td><td>galactosyl hexadecyloxypropyl 9- (2fo s £ onomethoxyathyl) adenine</td>

<td> 63</td><td>cytosin-l-ilo</td><td>bexadectloxypropyl</td><td>galactosyl</td><td>j ^ data Uoliexadecyloxypropyl l- {2phosphonomethoxyethyl) cytosine</td>

<td> 64</td><td>timin-I-ilo</td><td>hexadecyloxypropyl</td><td>galactosyl</td><td>galactosyl hexadectloxypropyl l- (2fo s fonomethoxythiojtimine</td>

<td> 65</td><td>uracil-l-ilo</td><td>headeciloxipr opilo</td><td>galactosyl</td><td>galactosyl hexadecyloxypropyl 9- (2fo s fonomethoxyethyljuracil</td>

<td> 66</td><td>2,6-diaminopurin -9-yl</td><td>hexadecyloxypropyl</td><td>galactosyl</td><td>galactosyl hexadecylox ^ ropyl 9- (2 phosphonomethoxyethyl) -2_l6-diaminopurin</td>

<td> 67</td><td>guanin-9-ilo</td><td>1 -O-octadecüo-2-Obenctlo-í »glyceryl</td><td>galactosyl</td><td>galactosyl 10-octadecyl-2-obenzyl-sn glyceryl 9- {2-</td>

<td> 68</td><td>adenin-9-yl</td><td>10-Octodecyl-2-Obenzyl-M glyceryl</td><td>galactosyl</td><td>galactosyl l-0-octadacüo-2 - &lt;? benctto-sn gücerilo 9 - (2phosphonomethoxyethyl) ad «niaa</td>

<td> 69</td><td>cytosin-l-yl</td><td>1 -O-octadectlo-2-Obenzyl-sn glyceryl</td><td>galactosyl</td><td>galactosyl lO-octadectlo-2-0bmscilo-sn glyceryl l- (2phosphonomethoxyethyl) cytosim</td>

<td> 70</td><td>timin-l-ilo</td><td>1 -O-octadecyl-2- &lt;9-benzyl-íH glyceryl</td><td>galactosyl</td><td>galactosyl l- €&gt; -octodoctlo-2- (2benzyl-SM glyceryl l- (2phosphonomethoxycyloxytiniine</td>

<td> 71</td><td>uracil-l-ilo</td><td>1 -O-octadecyl -2-0 benzyl-sn do it</td><td>galactosyl</td><td>gabctosyl 10-octadecyl-2-obenzyl-sn glyceryl 9- (2 fo sfonomtfo3riethyl) uracil</td>

<img file="MX367403B_D0061.tif" />

^BNucAtac (a) O BnucAmucC ·} O BnucAíwH O k ^ O ^ PO-UL * k ^^ P-Ο-ΙΛ · kxOs ^^ - OÓ-fWR * ° 0-RR * ⁰ O-WR *

Rp or Sp (depends on substituent cough) Rp, $ p (racemic)

<td>CotapMSB No.</td><td>IfcwBxw.)</td><td>ΙΛ *</td><td>Laugh-</td><td>Name</td>

<td> 72</td><td>1,6- dtaminopurin -9-ilo</td><td>10-octadecyl-2-obenzyl-sn icoryl</td><td>galactosyl</td><td>galactosyl l-Ó-octadactlo-2-Ο- bancüo-sn glyceryl 9- {2- tosfonoxnetoxyethyl) -2,6-diaininopurin</td>

Table 2. ^ Hbsfonanetoxypropyl diester compounds [(RJ-PMP]

<td colspan="5">^BNuc®Nuc (a) 0 ^BHuc®Nuc (·) 0 Brik / BnucW O k ^ O ^ P-Ο-ΙΛ. · k / Ox ^ PO-LA? k ^ Os ^ PO-tA. · H₃ Ó-R / R · ° ÓHi ¿“RW ° ¿Hj ° - *** RpoSp (depends on supportive cough) Sp, Sp (racemic)</td>

<td>I competed k&gt; No.</td><td></td><td>ΙΛ, '</td><td>RK *</td><td>Name</td>

<td> 73</td><td></td><td>octadecyloxyethyl</td><td>good luck</td><td>benzyl octaáecdoxieülo 9- (R) - [(2fosfonometoxOpropiloJpumina</td>

<td> 74</td><td>®άβηίη-9-11ο</td><td>cctadecil xtetílo</td><td>benzyl</td><td>benzyl octedecyloxyethyl 9- (10 - ((2phosphonomethoxypropyljedinine</td>

<td> 75</td><td>cytoin-I-ile</td><td>Ociad ¿Ciloxtethyl</td><td>beneilo</td><td>benzyl octoethyloxyethyl 1- (8) - ((2-sicononictoxy) prcpyl] cytosine *</td>

<td> 76</td><td>tímin-l-ilo</td><td>octadecyloxyethyl</td><td>benzyl</td><td>benzyl octocyloxyethyl 1 - (^) 4 (2- phosphonomethoxypropyl] Smcn ·</td>

<td> 77</td><td>utecil-l-ilo</td><td>octadecyloxye</td><td>benzyl</td><td>benzyl octocüoxietílo 1- (10 - ((2fo e fonometoxOptopilo) uractlo</td>

<td> 78</td><td>1,6di &amp;&amp; ifiopufi &amp; - $ - ik</td><td>oetadecúoxyethyl</td><td>benzyl</td><td>kcib octMleciloxUtil 9- (8) - ((2fbsfonomethoxy) prcpilo] 2,6¿3 tarn taapifoto</td>

<td> 79</td><td>gQffi3Ín-9-Í10</td><td>Hxadectloxtptopil</td><td>benzyl</td><td>benzyl ¿exsdecyloxypropyl 9- (8) - ((2phosonon&gt; ethoxy) pr &lt;giyl] fuaniiia</td>

<td>SW</td><td>ad «in -9-flo</td><td>hexadociloxijMropilo</td><td>benzyl</td><td>benzyl hexadecyloxypropyl 9- (R&gt; [(2fo * phonomethoxy) prcp¿o] edMiiM</td>

<td>YES</td><td>cytosin-l-yl</td><td>hexadecyloxypropyl</td><td>benzyl</td><td>benzyl hexadecyloxypropyl 1- (8) - ((2fosfonoz &amp; ttoxi) prcpdo] cttosine</td>

<td> 82</td><td>tsmin- 1</td><td>bexadecüoxtptopilo</td><td>benzyl</td><td>benzyl bexadocyloxypropyl 1- (8) - ((2phosphonomethoxy) propyl] thymine</td>

<td> 83</td><td>uxacil-l-ilo</td><td>hoxadecyloxypropyl</td><td>benzyl</td><td>benzyl hexadocyloxy ^ ropyl 1- (8) - ((2phosphonomethoxy) propyl] trKIL</td>

<td> 84</td><td>2,6diu &amp; iciQpwtíxi -9-ilo</td><td>hoxadecyloxypropyl</td><td>benzyl</td><td>benzyl hexadecdoxipropyl 9- (8) - ((2phosphonoznethoxy) piOpyl] 2,6diaminopuin</td>

<td> 85</td><td></td><td>1 -Oo ctadecyl -2-Obenzyl-ín glioeryl</td><td>benzyl</td><td>Benzyl L-0-OCUdecyl-2-0-Benzyl- £ M Icyryl 9- (8) - ((2- phosphonomethoxy) propyl] guanin &amp;</td>

<td colspan="5">^ * uc®Huc (a) or ^bNuc®Huc (·) 0 &amp; Nuc / B | iuc (a) 0 LO .PO-IA. ” Ljx JO-UV L JO., Po-ul · ¿H, Ó-fWR * ¿Hj O-WR * ¿h₃^that- ^ RpoSp (depends on substituents) φ, Sp (eroder)</td>

<td>COBtpS «lto No.</td><td>Βχ ^ ΖΒ &amp; μμ</td><td>UL *</td><td>R / R</td><td>Name</td>

<td> 8«</td><td>adanin-9-ilo</td><td>1 -O-octadecyl-2-Ob «tctlo-jn ¿icerilo</td><td>benzyl</td><td>benzyl l- (9-oct »dectlo-2-0-bíncilo-sH ^ chorus 9-OMO- phosphonomethoxy) propyl] edtniu</td>

<td> 87</td><td>cytosin-l-yl</td><td>1 -O-octadecyl-2-Obenzyl-at glyceryl</td><td>benctlo</td><td>benzyl l-0-o &lt;± edoeilo-2-0-bencflo-sn glyceryl 1- (8) - ((2- fo s fonometoxQprcpilojcitos tna</td>

<td> 88</td><td>timin-l-ilo</td><td>I -O-octadecyl-2-Obenzyl-í&gt; t glyceryl</td><td>benzyl</td><td>benzyl 1 -O-octadacyl-2-O-benzyl-m glyceryl 1- (Λ) - [(2- fos fon ometoxi) propyl timins</td>

<td> 89</td><td>uractl-l-ilo</td><td>1 -O-octadacil-2-Obencilo-iji güesMÜo</td><td>benzyl</td><td>Benzyl lO-oetedecyl-2-O-bonctlo-XH glyceryl 1- (5) - ((2- phosphonomethoxy) propyl] urecil</td>

<td> 90</td><td>2,6dÍBXfitBOpiiríC -9-tlo</td><td>1 -O-oct »doctlc-2-Ob®tctlo-s» i glyceryl</td><td>benctlo</td><td>benzyl 1 -0-octade «üo-2-0-benzyl &lt;&gt; - í&gt; t glyceryl 9- (5) - ((2- phosphonomethoxy) pr &lt;ipyl] 2,6- OjpUfífi</td>

<td> 91</td><td>guaniii-9-ilo</td><td>octsdoctloxietílo</td><td>finile</td><td>ftmflo octedecyloxyethyl 9- (5) - ((2fosionomethoxy) prcpilo] guanma</td>

<td> 92</td><td>adenin-9-yl</td><td>oeudeetloxyethyl</td><td>phenyl</td><td>fsnilo ocWtoloxietío 9- (5) - ((2fo sfonometoxjjprcpilojadenina</td>

<td> 93</td><td>cytosin-l-yl</td><td>oetadecyloxyethyl</td><td>phenyl</td><td>phenyl octadecyloxyethyl 1- (5) - ((2fo s fonometo ») pr opilo Jeitos ¿na</td>

<td> 94</td><td>timin-l-ilo</td><td>octsdecitaiteethyl</td><td>phenyl</td><td>phenyl octadecyloxyethyl 1- (5) - ((2fo s fonomethoxy) propyl] timin ·</td>

<td> 95</td><td>uracil-l-ilo</td><td>octadecyloxyethyl</td><td>phenyl</td><td>Phenyl octadecyloxyethyl 1- (5) - ((2 phosphonomethoxOpropyl] uaKilo</td>

<td> 9«</td><td>2.6-. opufoi -9-ilo</td><td>octadecyloxyethyl</td><td>phenyl</td><td>phenyl oc &amp; of «loxietflo9- (fM (2- phosphonomMoxy) propyl] 2,6- diammopurin</td>

<td> 97</td><td>fnmin-9-ilo</td><td>hexadecyloxyproptlo</td><td>phenyl</td><td>phenyl hexadeeiloxypropyl 9- (1 ^ - ((2phosphonomet)) propyl] gu «nina</td>

<td> 98</td><td>adenin-9-yl</td><td>hexadecyloxyproptlo</td><td>phenyl</td><td>phenyl hexadecyloxypropyl 9- (5) - ((2fo s tonomethoxy) propyl] adenine</td>

<td> 99</td><td>citostn-l-do</td><td>hexadectloxiproptlo</td><td>phenyl</td><td>phenyo b «* deoxypropyl 1- (5) - ((2phosphonomethoxy) propyl} citmine</td>

<td> 188</td><td>timin-l-ilo</td><td>hexadectloxypropyl</td><td>phenyl</td><td>phenyl hexadectloxypropyl 1 - (^) - ((2phosphonomethoxy) prcpyl] timim</td>

<td> 101</td><td>uractl-l-ilo</td><td>hexad «áoxtpropilo</td><td>phenyl</td><td>fcoilo hcockdloxipíopile</td>

<td> 102</td><td>2,6ditzcüiopwriD -9-ilo</td><td>baxadecilox iproptlo</td><td>phenyl</td><td>(hexadecyloxyqpropyl 9- (5) - ((2 phosphonomethoxy) prcipyl] 2,6-</td>

<td> 103</td><td>pumin-9-tlo</td><td>1 -O-octadecÜo -2 -Obeneyl-sa glyceryl</td><td>phenyl</td><td>phenyl l-0-ocudecyl-2-0-benzyl-i « glyceryl 9- (5) - ((2- foephonometoajpropÜoleaMBM</td>

<img file="MX367403B_D0062.tif" />

<td colspan="5">Bnuc / Bnwcí ·) 0 Bnuc®Nuc (·) 0 Bttac / BwucW 0 l ^ O ^ PO-LO. · k ^ O ^ PO-lA · ζ ^ Ο ^ Ρ-Ο-UL · H₃ Ó-R / R * ° ¿H₃ OR / R * ° h₃ O-WR * Rp or Sp (depends on substituents) Rp. Sp (racemic)</td>

<td>Compound No.</td><td></td><td>LL '</td><td>RR '</td><td>Name</td>

<td> 104</td><td>adenin-9-yl</td><td>lO-octadecyl-2-Obencil-do you throw it away</td><td>phenyl</td><td>fenüo l-ü-PCtiMhcib-2-0-b «icilo- £ n Uceryl 9- (2ί) - [(2 · fosfonom &amp; o ») propik] * d * nina</td>

<td>IOS</td><td>citostn-l-ilo</td><td>l -O-octadecüo-2-Obencilo-iM throw it away</td><td>ftnilo</td><td>phenyl lG-edadecyl-lO-benzyl-cn glyceryl l- (R) - [(2phosphonomate ») proper] cytosine ·</td>

<td> 106</td><td></td><td>1 -O-octadecyl-2-Obenzyl-rn gfceril</td><td>edge</td><td>phenyl l * O-octaMeyl-2-Ob «n&gt; cilo-et ¿Ie «Üo 1-« M (2 · phosphonomethoxy) propyl] tiniini</td>

<td> 107</td><td>araeil-l-ilo</td><td>1 -O-octad «rilo -2-Obencilo-iM throw it away</td><td>phenyl</td><td>phenyl l- (9-octadecuo-2 - (? - benzyl-Unite Throw it 1- (RH (2fo sphonomethoxy) propyl] uracil</td>

<td>IOS</td><td>2.6- -9-do</td><td>l - O-octadecyl -2-Obencilo-ín throw it away</td><td>phenyl</td><td>phenyl ldo &lt;Aadecilo-2-0-b «ticOo-en ! Ücerflo9- &lt;R&gt; -K2- phosphonomet »jpropyl] 2,6- diaxninopurin</td>

<td> 109</td><td>imanin-Q -Uo</td><td>octadecyloxyethyl</td><td>ethyl</td><td>Ethyl octadecyloxyethyl 9- (10 - ((2 phosphonomethoxyJpropilojBMnina</td>

<td> 110</td><td>ademn-9-ilo</td><td>octadecyloxyethyl</td><td>ethyl</td><td>ethyl octadecyloxyethyl 9 - (^) - ((2phosphonomethoxy) propyl] adenine *</td>

<td> 111</td><td>cytosin-l-yl</td><td>octadecyl oxyettil</td><td>ethyl</td><td>ethyl octadecyloxyethyl l &lt;R) - [(2 phosphononiethoxy) propuo] ctto5ina</td>

<td> 112</td><td>ttoin-l-ilo</td><td>octadecyloxyethyl</td><td>ethyl</td><td>ethyl octadecyloxyethyl l- (R) - ((2phosphonomethoxy) prapyl] thymine</td>

<td> 113</td><td>nracil-l-ilo</td><td>ociad ectyloxtethyl</td><td>ethyl</td><td>ethyl octocyloxythiotyl l- (R) - [(2fo sfonomethoxy) prcpilo] mcflo</td>

<td> 114</td><td>2,6diAxninopunn -9-Üo</td><td>octadecyloxyethyl</td><td>ethyl</td><td>Ethyl octadecyloxiotyl9- (20 * [(? - phosphonomethoxy) prcpyl] 2,6- dtaminopurin</td>

<td> 115</td><td>gsjanm-9-ílo</td><td>hexadecyloxypropyl</td><td>ethyl</td><td>ethyl hexadecyloxypropyl 9- (10 - ((2phosphonomethoxy) propyl] guanine</td>

<td> 116</td><td>adanín-9-ilo</td><td>hexadecyloxypropyl</td><td>ethyl</td><td>ethyl hexadecyloxypropyl 9- (5) - ((2-</td>

<td> 117</td><td>cytosin-l-yl</td><td>hexadecyloxypropyl</td><td>ethyl</td><td>«Linden h« xsd «dleKipropUo 1- (5) - ((2fo $ £ oaomethoxy) propyl Jeitos ¿na</td>

<td> 118</td><td>timin-l-tlo</td><td>hexadecyloxypropyl</td><td>ethyl</td><td>ethyl hexadecyloxy ^ ropyl 1- (5) - ((2fo s fonomethoxy) pÑptlo jtimina</td>

<td> 119</td><td>uracil-l-ilo</td><td>hexadecyloxypropyl</td><td>ethyl</td><td>ethyl bexadecyloxypropyl 1- (5) - ((2fosfonometoti) propito] wtcíl</td>

<td> 120</td><td>2,6 diaminopurm -9-yl</td><td>hexadecyloxypropyl</td><td>ethyl</td><td>• linden hexadecyloxypropyl 9- (5) - ((2- Íosfonon&gt; «tox0prcpilo] 26 / Uimtnnpnrin</td>

<td> 121</td><td>gÜSfiÍQ-9-ilo</td><td>1 -O-octadecyl-2-Obencilo-sn fUcwflo</td><td>•linden</td><td>ethyl lO-oetadecyl-2-Ob «neilo-M glycerflo 9- (5) - ((2- phosphonomethoxOprcpilolguarina</td>

<td colspan="5">^BN «/^BNuc (·) 0 ^BNuc^{/ B}»Luc (·) 0 eMm ^ Nwci ·) 0 k ^ O ^ PO-UL * k ^ O ^, PO-UL · k ^ O ^ POL / L · ¿Hj Ó-R / R * ° ¿H_s Í-IVR »° ¿h₃ O-WR * RpoSp (depends on their Sustensors) Rp, Sp (racemic)</td>

<td>COB ^ RSfe No.</td><td></td><td>LV</td><td>RR *</td><td>Name</td>

<td> 122</td><td>adenin-9-yl</td><td>1 -O-octadecyl-2-0bsncdo-s »glyceryl</td><td>"linden</td><td>Silo l -O-octidecyl-lO-beacyl-m beryl 9- (R) - [(2fosfonomMoxi) prcptto] id »nina</td>

<td> 123</td><td>cytosin-l-yl</td><td>l-ü-octadecyl-2-0b® »cilo-s» glyceryl</td><td>•linden</td><td>ethyl lO-oct * decyl-2-Ob «ncilo-wi ¿Ucerilo 1- (jR) - [(2phosphonomethoxy) prop ilo Jeitos im.</td>

<td> 124</td><td>timin-l-ilo</td><td>l -O-octadecyl-2-Ob «cilo-jn glyceryl</td><td>ethyl</td><td>• linden l-Ó-octiKlecilo-2-O-benzyl-fn giicwilo 1 W «2- fosfonom «toxi) proptlo] túnim</td>

<td> 125</td><td>uracyl-l-yl</td><td>1 -O-octadecyl-2-Obencil-cn throw it away</td><td>ethyl</td><td>• linden l-0-octadecyl-2-0-b «acyl-« n Bfcerílo 1- (R&gt;. [(2- phosphonomethoxQprcpiloJwacilo</td>

<td> 12«</td><td>2,6dtaaunopurin -9-yl</td><td>1 -O-octadecyl-2-Obenzyl-m glyceryl</td><td>ethyl</td><td>Phenium lO-octactate ^ -2-O * b «ncilo-0t jliwrilo 9- (104 (2fosfonomSoxi) prgpilo] 2,6d¿ &amp; xn.tnopurin</td>

<td> 127</td><td>gtutnin-9-Ílo</td><td>octadecyloxyethyl</td><td>galactosyl</td><td>gelact silo octadecyloxyUtil 9- (10 - ((2fos fonomethoxy) propyl] pumina</td>

<td> 128</td><td>adenin-9-yl</td><td>octadecyloxyethyl</td><td>galactosyl</td><td>gakctosilo octMkcüoxtotilo 9 * (Λ) · [{2phosphonomet ») pfopilo] adentna</td>

<td> 129</td><td>cytosin-l-yl</td><td>octadecyloxyethyl</td><td>galactosyl</td><td>galsctos ilo octndecyloxyathyl 1- (10 - ((2phosphonomethoxy) propyl] cytosin »</td>

<td> 130</td><td>timin-l-ilo</td><td>octadecyloxyethyl</td><td>I boast silo</td><td>ffdactos Uodecyloxyethyl 1- (10 - ((2phosphononHtoxy) propyl) ttmim</td>

<td> 131</td><td>uractl-l-ilo</td><td>octadecyloxyethyl</td><td>(alactosyl</td><td>pdactosyl octadecyloxycyclic 1- (10 - ((2fo s fonomethoxQprcpiloJtanKilo</td>

<td> 132</td><td>2,6-diaminopurin -9-yl</td><td>octadecyloxyethyl</td><td>galactosyl</td><td>^ lactosSo octodecyloxyotyl 9- (10 - ((2fo s fonomethoxy) propyl] 2.6 diaminopurin</td>

<td> 133</td><td>gitawin.QUm</td><td>hexadecyloxypropyl</td><td>galactosyl</td><td>Sehctosyl hexadecyloxypropyl 9- (10 [(2-phosphonosnethoxy) proptlo] pi «ntne</td>

<td> 134</td><td>adenin-9-yl</td><td>hexadecyloxypropyl</td><td>galactosyl</td><td>galactosyl haxad «cyloxypropyl ((2-phosphonomethoxOprcpiloJ ^ enin ·</td>

<td> 135</td><td>cytosin-1-yl</td><td>hexadecyloxypropyl</td><td>PÚKtOSÜO</td><td>galactosyl hexadecyloxypropyl 1- (10 «2 -ios fonotn« toxi) propyl) cytosine</td>

<td> 136</td><td>timin-l-ilo</td><td>hexadecyloxypropyl</td><td>gilactosyl</td><td>galactosyl hexadecyloxypropyl [(2-phosphonoasetexy) pr &lt;&gt; pdo] thymine</td>

<td> 137</td><td>uoKil-l-ilo</td><td>hexadecyloxtpropyl</td><td>gehctosyl</td><td>galactosyl hncadecilox ^ ropflo 1- (10 ((l-fosfoncmetoxOprcipitoJirtcil</td>

<td> 138</td><td>2,6diomuropurine -9-ilo</td><td>hexadecyloxypropyl</td><td>galactosyl</td><td>gslactosOo hexadecyloxyproptlo 9- (jQ [(l-phosfeaonMoxiJpfcptloP ^ · díAznínopuxiii</td>

<td> 139</td><td>guanin-9-ilo</td><td>lO-octadecyl-2-Obenciloo! glicertlo</td><td>pdactosyl</td><td>galactosyl lO-octedecflo-2-Obencdo-SH gücerílo 9- (10- «2 phosphonoraSoxOpropylolineManúia</td>

<td colspan="5">^BNuc /^BNw &lt;«) O ^BHuc®Nuc (a) 0 βΝικ / ΒΝυφ) 0 k ^ O ^ PO-UL »k ^ O ^ IO-LA. · k ^ O ^ PO-UL · Ch₃ Ó-WR * ° ¿H₃ OR / R * ° ¿«3 O-WR · fip or 8¡p (depends on toe theirMuyenles) ffy,% (racemic)</td>

<td>Compete No.</td><td></td><td>LL *</td><td>R / R '</td><td>Name</td>

<td> 140</td><td>* danto-9-ilo</td><td>l -O-octadecyl-2-0benzyl-r «gücerilo</td><td>(winged silo</td><td>gahcto silo lO-octadecyl-2-Obenolo-íM icerflo 9- (5) - ((2fo s £ onomethoxy) pr opilo Jadenina</td>

<td> 141</td><td>I quote without-I-ilo</td><td>1 -O-octadeeyl-2-Ob «xcilo-» s enjoy it</td><td>gahctoiOo</td><td>galactosyl 10-octadecyl-2-Obmcflo-i »glyceryl 1- (5) - ((2phosphonomethoxy) propyl] cytosine</td>

<td> 142</td><td>tímin »! Uln</td><td>l -0-octadecyl-2-C&gt; bencilooi gfceríto</td><td>galactosOo</td><td>galactosyl 1-O-octadecdo-2-Οbenzüo-oi glyceryl 1- (5) - ((2fosfonomatoxQprcpilojtimim</td>

<td> 143</td><td>uracil-l-ilo</td><td>1 -O-octadecyl-2-Όbenzyl-m glyceryl</td><td>galactosyl</td><td>galactosyl lO-octadecyl-2-Obenzyl-ín glyceryl 1- (5) - ((2fotfonometox&gt;) proptlo] vacillus</td>

<td> 144</td><td>2.6- dtisníAopuxixi -9-Üo</td><td>1 -O-octadecyl-2 -0-benzyl-Pi glyceryl</td><td>gahctosyl</td><td>galactosyl 10-octadacyl-2-obenzyl-sH glyceryl 9- (5) - ((2fos foDomatoxOpropyl) 2.0dUm.tnopwiB</td>

Table 3. Diester compounds (S) -3-methoxy-2-fo5phonmethoxypropyl {(S) -A £ PMP]

<td colspan="5">^B»Tac /^BHuc (») O ^BNuc /^BNuc (a) O ^BNuc®Nuc (a) O k \ ck, POL / L · „Ι, Ο ^ .Ρ-0-L / L · _ L, O PO-UL * -WR- _HaC.₀J O-WR- π ^ -oJ O * »· φ or (depends on your coughs) φ, (racemic)</td>

<td>Compict</td><td></td><td>UL *</td><td>Rflt *</td><td>Name</td>

<td> 145</td><td>goanin-9-ilo</td><td>octadaxyoxyethyl</td><td>benço</td><td>Bacrylic octadacyloxyathyl 9- (5) - ((3nj «toxi-2- phosphonomethoxy) pr «pilo] guanizia</td>

<td> 146</td><td>adenin-9-yl</td><td>octadecyloxyethyl</td><td>benzyl</td><td>bathe it octodaetloxiatílo9- (S) - [(3znatoxi-2- fosfonom »toxi) propyl] adMin *</td>

<td> 147</td><td>cytosin-l-yl</td><td>octadecyloxyathyl</td><td>benzyl</td><td>bancOo octadecyloxyethyl 1- (5) - ((3methoxy-2- phosphonomethoxOprepilolcitosma</td>

<td> 148</td><td>ttain-l-ito</td><td>octadecyloxyethyl</td><td>good luck</td><td>benzyl octadecyloxyethyl 1- (5) - ((3m ^ oxy-2-phosphonon »toxi) propyl) timiBa</td>

<td> 149</td><td>uracil- 1-yl</td><td>octadecyloxyethyl</td><td>bancüo</td><td>benzyl octadecyloxyethyl 1- (5) - ((3methoxy-2- : phonomethoxy) pr opyl] hesitation</td>

<td> 150</td><td>2.6- -9-tlo</td><td>octadecyloxyiatyl</td><td>benzyl</td><td>benzyl octadeeOoxyethyl 9- (5) - ((3matoxt-2-fos £ onomatoxy) propyl P4 * dtaminopurir .__________________________</td>

<td colspan="5">®Nuc®Muc (a) 9 ®Nuc / ®Nuc (·) 0 ®Ι &amp; κ / ®Νϋβ (·) 0 k ^ O ^^ - O-UL ₀ 0 ^ 0. ^^ - 0-UL ₀ l ^ O ^ PO-UL HjC-O ^ ¿-WR · _HjC_₀J ¿-WR · HjC-O ^ ¿-WR * or Sp (depends on substituent cough) sp (raeémtoo)</td>

<td>Compotsto N ©.</td><td>Bs — ®W »J</td><td>LV</td><td>RR *</td><td>Name »</td>

<td> 151</td><td>gaaxiín-9 ~ ilo</td><td>hexadecyloxypropyl</td><td>banctlo</td><td>bracüo hexadecyloxy ^ ropyl 9- (3) - ((3 methoxy-2- fosfonomMo ») propuo] fttaxda ·</td>

<td> 152</td><td>• denin-9-ilo</td><td>hexadecyloxypropyl</td><td>kiss him</td><td>hexadeeyloxypropyl bracyl 9 - (^ - (0methoxy-2- phosphonomethoxQprt ^ iloJedraine</td>

<td> 153</td><td>I quote sin- 1-ilo</td><td>hexadecyloxypropyl</td><td>bwcílo</td><td>benzyloxypropyl 1- (3) - ((3-methoxy-2-) phbsphonomethoxy) propyl] cytosuia</td>

<td> 154</td><td>tunin-1-ilo</td><td>hexadectloxypropyl</td><td>kissed</td><td>hexedecyloxypropyl 1- (3) - ((3-methoxy-2-fosft®oiartoxy) propyl] thymine</td>

<td> 155</td><td>urectl-1-yl</td><td>hexadecyloxypropyl</td><td>benctlo</td><td>Benexyl Bexadecyloxypropyl 1- (3) - (0methoxy-2- fosfonom * toxi) propyl] urecil</td>

<td> 16«</td><td>2.6- diamiuopurin -9-ilo</td><td>hexadecyloxypropyl</td><td>btnctto</td><td>beneilo hexadectlox ^ roptlo 9 - (^ - (0mMoxi-2-phosphonon »toxi) propyl] 2,6diaminoptirin</td>

<td> 157</td><td></td><td>1 - 0- octadecyl-2-0 beacyl-m glyceryl</td><td>benctlo</td><td>beneilo lC ^ octadecílo-2-¿&gt; -beneík&gt; - »t gfceryl 9- (S) - [(3-methoxy-2-</td>

<td> 158</td><td>adram-9-ilo</td><td>lO-octadecyl-2-Obeacilo-rn j ^ kerilo</td><td>beneilo</td><td>^ icMilo 9- (3) - [(3-inatoxy-2phosphonomethoxy) pr opyl Jadrain *</td>

<td> 155</td><td>cttosin-I-ilo</td><td>1 -O-octadeeyl -2-0benzyl-m jjlyceryl</td><td>b «Üo</td><td>Bene-1-O-octadecyl-2-O-benzyl-at-lliethyl 1- (3) - ((3-methoxy-2-phosphonomethoxy) prcipyl] cytosine</td>

<td>i «e</td><td>Κυτητι-1-t1rt</td><td>1 -O-octadecyl-2-0beneyl-imgtaryl</td><td>beneilo</td><td>beneilo lO-octodtwilo-lO-braciloglyceryl 1 - (3) - [(3 -methoxy-2 phosphonomethoxyijpropilojüniiiia</td>

<td> 161</td><td>uracil-1-yl</td><td>1 - 0-octadecilo-2-0bencüo-ra eiicírüo</td><td>bexcílo</td><td>beneilo l-0-oct * decyl-2-0-benzyl- »i S ^ teerdo 1- (3) - ((3-methoxy-2 foifonomethoxyQpropylJuracil</td>

<td> 161</td><td>2.6- Itammapnrm -9-üo</td><td>1 -O-octadeetlo-2-Obeneyl-ΐΜ gkewilo</td><td>btmcilo</td><td>have OO-oetédecyl-2-O-beaeiio-w fKcertlo 9- (3) - ((3-methoxy-2phosphonomethoxy) propyl] 2,6-</td>

<td> 163</td><td>gBanin-9-ilo</td><td>octadecyloxyethyl</td><td>phenyl</td><td>octedecyloxyethyl fryl 9- (3) - ((3- methoxy-2- fosfonomMoxí) propilo] jnanina</td>

<td> 164</td><td>• dantn-9-ilo</td><td>octad «ciloxy« linden</td><td>phenyl</td><td>Eetayl oetadecyloxyethyl 9- (3) - ((3methoxy-2phosphonomethoxy) propylojedraiiia</td>

<td> 165</td><td>citosin-l-ílo</td><td>octtdocuoxyethyl</td><td>friar</td><td>phenoxy octyloxytetio 1- (3) - ((3methoxy-2- phosphonomet3d) propyl] cytosine</td>

<td colspan="5">Βμμ «®ΜιΜ ·) O ^BNw / Bnuc (·) O ΒΝοβ®Νϋφ) O k ^ Ox ^ POW. · ₆ kX ^ PO-UL » ₀ l ^ O ^ -O-LA. ·_HjC-oJ ¿-WR · h ^ -qJ O-WR · A ** Φ or Sp (depends on substituents) Rp, Sp (racemic)</td>

<td>Compete! * N ·.</td><td>BjwBsrti</td><td>LL</td><td>RR *</td><td>Name</td>

<td> 16«</td><td>®tais * l * ílo</td><td>octidocdoxiotyl</td><td>phenyl</td><td>octtdocyloxtotyl background 1- (8) - ((3methoxy-2-fbsphotioznotoxy) propyl] tiiiuni</td>

<td> 167</td><td>UMCd-I-ilo</td><td>octodocdoxietdo</td><td>phenyl</td><td>octocuroxycyclic bottom 1- (8) - ((3methoxy-2- phosphonomethoxy) propdo] uracdo</td>

<td> 168</td><td>2.6- -9-ilo</td><td>oetadecüoxietüo</td><td>phenyl</td><td>octododoxotic background 9- (S&gt; ((3motoxi-2-fosfonomotoxi) pn&gt; ptlo] 2j6gj ΰιτηίη ftpnrw</td>

<td> 169</td><td>gnym ^ -3 -í | q</td><td>hexadecdoxtpropyl</td><td>friar</td><td>Hoxadocdoxipropy fray 9- (8) - ((3motoxi-2- phosphonomethoxy) propdo] pi »r¿na</td>

<td> 170</td><td>adrain-9-ílo</td><td>hexadecyloxypropylene</td><td>friar</td><td>fine hoxodocdoxqpopilo 9- (8) - ((3motoxi-2- fosfonomotoxí) pr «pilo] odonine</td>

<td> 171</td><td>cytosin-l-do</td><td>hexodecyloxypropylene</td><td>friar</td><td>hoxodoedoxipfopílo friar l- (8&gt; [(3- nwtoxi-2- fo $ fonomotoxí) propdo) cytosin *</td>

<td> 172</td><td>timin-l-üo</td><td>hexedecyloxypropyl</td><td>phenyl</td><td>boudoeiloxypropyl 1 - (8) - ((3-methoxy-2-phosphonom »toxi) propdo] tiinin»</td>

<td> 173</td><td>uracil-l-üo</td><td>hexodecyloxypropyl</td><td>background</td><td>hexadeedoxipropus frado 1- (8) - ((3motoxi-2- phosphonomotoxy) propyl] ur «dlo</td>

<td> 174</td><td>2,6diraiinopufin -9-do</td><td>hoxsdecdoxipropyl</td><td>friar</td><td>Frado hoxadocyloxypropyl 9- (8) - ((3motoxt-2-fosfraoiMtox0propilo] 2j6diominopnrin</td>

<td> 175</td><td></td><td>1 -O-octodocüo-2-Obracdo-m glycerdo</td><td>phenyl</td><td>frado lO-octadocdo-2-O-boncdo-fn glycerdo 9- (S) - (C3-ei * toxí-2- fo s fonomoto »)]&gt; r« j&gt; do] pianina</td>

<td> 176</td><td>• drain-9-üo</td><td>1 - &lt;? - oetadecilo-2-Obencilo-sn glycerdo</td><td>friar</td><td>friar l-0-oct * deciio-2-0-ben «do-« n ^ wmío 9- (S&gt; ((3-motoxi-2fosfonometon) propilo] odraina</td>

<td> 177</td><td>cytosin-i-do</td><td>1 -O-octodecyl-2-Obracdo-í »glycerdo</td><td>friar</td><td>background lO-octocyl-2-O-boncÜo-et gUcerdo l- (S) - ((3-nMti&gt; xi-2fo tfonomotoxi) prcpdo] utoeina</td>

<td> 178</td><td></td><td>1 -O-ocUdecilo-2-Obracílo-in giicerilo</td><td>friar</td><td>irado id-octodocdo-2-0-boncdo- »t gUcardo 1- {8) - ((3-ηΗήοχΐ-2- fo »fonomMori) propílo] tim« m</td>

<td> 179</td><td>urocd-l-ilo</td><td>1 -0-ocadocílo-2-0 · bonedo-jH fícenlo</td><td>friar</td><td>frado t-0-octeaocdo-2-Ó-ben&gt; cilo- «n glycope 1- (8) - ((3-motoxi-2fosfonomotoxi) prcpdo] uracÜo</td>

<td> 180</td><td>2,6diti &amp; ínopQrüi -9-ib</td><td>1 -O-octadecyl -2-0 benzyl-sn glycerdo</td><td>friar</td><td>phenyl IO-octadotyl-2-O-bracdo-im glyceryl 9- (3) - ((3-niethoxy-2phosphononioto »í) pr« pdo] 2,6-</td>

<td> 181</td><td>gttarUn-Q - {], $</td><td>e &lt;ctad «cii» ieHlo</td><td>ethyl</td><td>octodocdoxiotyl ear 9- (S) - ((3-nMthoxy · 2-phosphonomotoxy) propdo1íurain *</td>

<td colspan="5">Bnw / Bhucí ·) 0 Bhik / BnucC ») 0 Bn» ic / Bnuc (·) O L. .po-ul · L.CL .Ρ-Ο-4Λ. ·_Λ L. 0. JO-UL * H, CO^J «- * H, C-0^J O- ™ · Η, Ο-Ο ^ ** Ep or Sp (depends on the substituents) Rp, (racemic)</td>

<td>coapmtto No.</td><td></td><td>IJL *</td><td>R® '</td><td>Name</td>

<td> 182</td><td>• deniB-9-ilo</td><td>octadeloxiefil</td><td>"linden</td><td>«Üo octadtciloxietío 9- (S) - [(3-inetoxi2-fosfoaozn« toxi) propilo] adaniiia</td>

<td> 183</td><td>cytoin-l-ilo</td><td>octadcyloxyethyl</td><td>ethyl</td><td>• linden oct »d« ciloxy «linden 1 - (5) - ((3-tnetoxi2-fosfonomitoxt) propflo] cttoMn *</td>

<td> 184</td><td>timia-l-ilo</td><td>octadecyloxyethyl</td><td>ethyl</td><td>• tilo octadecyloxyMthyl l- (S) - [(3-methoxy2-phosphonoi &amp; * toxi) propite] tistiBa</td>

<td> 18$</td><td>ur «cil-l-ilo</td><td>oct * d «only« linden</td><td>ethyl</td><td>• linden octadecyloxwthyl l - ($) - [(3-m «toxi · 2-phosphonota« toxí) ptopilo] uacflo</td>

<td> 186</td><td>2,6diammopurin -9-2o</td><td>octadecyloxye</td><td>ethyl</td><td>«Ethyl octadecyloxyethyl 9- (5) - [(3-m * toxi2-phosphonotnethoxy) propyl] 2,6dtasoíDoparin</td>

<td> 187</td><td></td><td>hexadecyloxtpropyl</td><td>ethyl</td><td>• linden haxadecyloxypropyl 9- (5) - [βjnetoxy-2- fosfoaom «tojti) pr« jpilo] guiaina</td>

<td> 188</td><td>«Danin-9-ilo</td><td>hexycyloxypropyl</td><td>ethyl</td><td>• linden baxadteflox ^ ropyl 9- (5) - (0m «toxi-2-</td>

<td> 189</td><td>cttoiin-1-yl</td><td>hexadecyloxypropyl</td><td>ethyl</td><td>• linden h «ixad» ctIoxipropiL 1- (5) - ((3m «toxi-2phosphonomethoxy) propyl] cytosine *</td>

<td> 190</td><td>Tuais-1 -ilo</td><td>haxadecyloxypropyl</td><td>ethyl</td><td>• linden hexadecyloxypropyl 1- (5) - (0m * toxi-2-phosphaaomMoxi) pr &lt;»jxlo] timim</td>

<td> 191</td><td>urecyl-l-yl</td><td>hexadeoloxypropyl</td><td>ethyl</td><td>ethyl hexamethyloxypripyl 1- (5) - (0methoxy-2- phosphonojnetoxy) propyl jumolo</td>

<td> 192</td><td>2.6ú &amp; zxK &amp; opuxw. -9-do</td><td>hexadtyloxypropyl</td><td>ethyl</td><td>• lime hexadacyloxyproptto 9- (5) - (0zaóoxi-2-fosfanoii »toxi) propólo] 2¿6Híflmitnnp '» rj_n</td>

<td> 193</td><td>guanin-9-ilo</td><td>l -O-octadecyl-2-Obencil-m ¿icerito</td><td>ethyl</td><td>• tüo l- (7-octedecilo-2-0-b «ieilo-s&gt; i ghcwilo 9- (S) - ((3-m «&lt;oxt-2- phosphonomethoxypiopilojgueiiin</td>

<td> 194</td><td>adenm-9-yl</td><td>1 -O-octtdecyl-2 ~ O ~ benolo-XH gli «rilo</td><td>•linden</td><td>ethyl lO-octadecyl-2-G-benolo-sn glyceryl 9- (5) - [(3-m «toxi-2fosíbnom« toxi) prcptlo] id «nina</td>

<td> 19$</td><td>cytosm-l-ilo</td><td>1-Oct-0 * decflo-2-0 benzio-; » glicertlo</td><td>ethyl</td><td>• linden lO-octadecOo-2-0-b «nolo-sn Uceolo l- (S) - [(3-tn «toxi-2- tosiononietcxi) propyl] cytosine</td>

<td> 196</td><td>timin-l-üo</td><td>1 -O-octadecyl-2-0b «ncilci-sM ^ ictrilo</td><td>"linden</td><td>• linden l-0-oct »d» ctlo-2-0-l&gt; ancilo-¿&gt; t glyceryl l- (S) - [(3-methoxy-2ios foBomethoxy) prcptlo] tiniite</td>

<td> 197</td><td>uraól-l-üo</td><td>1 -0-oct * decyl-2-0benzyl-ΐχ flioyryl</td><td>ethyl</td><td>• linden l-0-oct * decyl-2-0-benzyl-in glyceryl l- (5) - [(3-methoxy-2phosphoncnietoKÍ) prcpilo] ur * cilo</td>

<td colspan="5">^BHuc®Mue &lt;·) 0 ^BNu «®Huc (·) 0 ^BlW®Nuc (·) O koJ-0-yi. ₀ Lo ^ p-0-ul _or Co. .po-ml j ^ C-oJ Ó-WR _MjC_₀J O-WR »OR / R * RpoSp (depends on substituents) φ, Sp (racemic)</td>

<td>compute No.</td><td>Bnu / BnuM</td><td>THE*</td><td>R / R</td><td>Name</td>

<td> 198</td><td>2,6 diaminopurin -9-ito</td><td>l - O-octadecyl -2-Obenzyl-rw glyceryl</td><td>•linden</td><td>í «xüo í-d-octadecyl-2-O-benzyl-cn glyceryl 9- (S) - ((3-methoxy-2fo s phonomethoxy) pr opyl) 2,6diaminopurta</td>

<td> 199</td><td>gMom-9-do</td><td>ocUdeciloxíetüo</td><td>galactosyl</td><td>galactosyl octadecyloxyethyl 9- (S) - [(3 · methoxy-2phosphonomethoxy) propyl guanine</td>

<td> 200</td><td>adenin-9-yl</td><td>octadeciioxietuo</td><td>galactosyl</td><td>galactosyl octásacyl oxyethyl 9- (3) - ((3methoxy-2- fos fonomethoxOpropylJadanin</td>

<td> 201</td><td>I quote sin-l-ilo</td><td>octadecyloxyethyl</td><td>galactosyl</td><td>Octadacyloxyethyl galactosyl 1- (3) - ((3methoxy-2phosphonon&gt; ethoxy) p "ipyl] cytosine</td>

<td> 202</td><td>tünin-l-ilo</td><td>octadecyloxyethyl</td><td>galactosyl</td><td>galactosyl octadacyloxyethylene 1- (3) - ((3nxethoxy-2-phosphonoinMoxi) propuo] tinüna</td>

<td> 203</td><td>uracil-l-ilo</td><td>octadeedoxietflo</td><td>galactosyl</td><td>^ lactosyl octadecyloxyethyl 1- (3) - ((3znetoxy-2- fo sfonom «toxt) prciptlo] uraeilo</td>

<td> 204</td><td>2,6diax &amp; i &amp; opufin</td><td>octadecyloxyethyl</td><td>galactosyl</td><td>galactosyl octadecyloxyethyl 9- (3) - ((3methoxy-2-phosphonomethoxy) propyl] 2.6diaminopnrtn</td>

<td> 205</td><td>punin-9-do</td><td>hexadecyloxypropyl</td><td>gxlactosyl</td><td>galactosyl hexadecyloxypropyl 9- (3) [(3-methoxy-2- fosfonoinet: oñ) propyl] gttanina</td>

<td> 206</td><td>ad «un-9-ilo</td><td>hexadecyloxypropyl</td><td>galactosyl</td><td>galactosyl hexadecyloxypropyl 9- (3) ((3-methoxy-2phosphonomethoxOpropylojadaaine</td>

<td> 207</td><td>citosin-l-ílo</td><td>hexadoxy oxpropyl</td><td>galactosyl</td><td>galactosyl hexadecyloxypropyl 1- (3) ((3-methoxy-2- fo s phbnometo ») propylocytosine</td>

<td> 208</td><td>tünin-l-ilo</td><td>hexadecyloxypropyl</td><td>galactosyl</td><td>galactosyl hexadecyloxyproplo 1- (3) - ((3-nj «toxi-2- phosphonomethoxy) prtpüo} thymine</td>

<td> 209</td><td>uracil-l-ilo</td><td>hexadecyloxypropyl</td><td>galactosyl</td><td>galactosyl hexadecyloxypropyl 1- (3) ((3-methoxy-2- fos foDometox0pr «j&gt; Ílo] uracil</td>

<td> 210</td><td>2,5ditminopurin -9-yl</td><td>hexadecyloxypropyl</td><td>galactosyl</td><td>galactosyl haxadecyloxtproptlo 9- (3) [(3-methoxy * 2iphosphonomethoxy) pr «pilo] 2,6dtamtiiopwrw</td>

<td> 211</td><td>guanin-9-ilo</td><td>1 -O-octadecyl-2 -0beBcilo-m glyceryl</td><td>galactosyl</td><td>galactosyl 10-octadecyl-2-obenzyl-cn glyceryl 9- (5) - ((3-methoxy-2phosphonom ^ oxy) prcyl] guaniBa</td>

<td> 212</td><td>adenin-9-yl</td><td>1-O-octadecyl-2-Obencil-j »jICIMIIo</td><td>galactosyl</td><td>pdactosyl l-0-octadecUo-2- &lt;2 beocyl-fn gücertlo 9- (S) - ((3-motoxi-2phosphonomethoxyptopiloladmine</td>

<td colspan="5">^BNu &lt;/ ®Nuc (·) 0 Bnuc / Bnuc ^) or ^BH &lt;* c ^ Nuc (·) 0 Υ, Ο ^ -Ο-ΙΛ * ₀ Υ, Ο ^ Ρ-Ο-ΙΛ _or Υ, Ο ^ Ρ-Ό-ΙΛ. · ^ C-oJ Ó-R / R · OR / R · O-WR * f ^ oSp (depends on substituents) Rp, Sp (racemic)</td>

<td>CftBJHMS »N».</td><td></td><td>LV</td><td>RR '</td><td>No »tm</td>

<td> 213</td><td>cytosin-l-yl</td><td>1 - O-octadecyl -2-0 beacyl-an jiiceril</td><td>Aladosilo</td><td>gúadosílo lO-octadaetlo-2-OWcíIo-ím {Uceolo l- (5&gt; [(3-nMrtoxi-2fosfbnoinetoxi) propyl Jeitos ina</td>

<td> 214</td><td>timin-l-ilo</td><td>1 -O-odadocilo-2-0bencüo-áM</td><td>galactos lio</td><td>{aladosyl lO-octadecyl-2-Obenzyl-ssi {Uceolo l- (5) - [(3-methoxy-2fosfoaomMo »^» ropiloJtinMBi</td>

<td> 215</td><td>urecil-l-yl</td><td>lO-odadecilo-2-Obencilooi Uceolo</td><td>Aladosilo</td><td>¡Aladosilo lO-octadecdo-2-Obenciloot {Uceolo l- (S&gt; ((3-n »doxi-2fo s fonometoxijpropilo Juracilo</td>

<td> 215</td><td>2,6diaminopuóa -9-uncle</td><td>1 -O-octad «cilo-2-Obancilo-sn Uceolo</td><td>galadosilo</td><td>jalad osilo lO-octadecyl-2-Obenzyl-sn glyceryl 9- {S) - [(3-nietoxs-2phosphonomethoxy) propyl] 2,6diuoinopuríH</td>

Table 4. diester Computers of (^ S-hydroxy-l-fadbiteinetox ^ n ^ flD [&lt;S&gt; HPMP]

<td colspan="5">®ltac®Nuc (a) OO ^BNuc ^ Nuc (·) 0 &lt;^, O ^, PO-UL · LO.P-0-ΙΛ. · LO ^ .P-0-ΙΛ · · _H0J Rp © Sp (depends on substituent cough) Rp, Sp (cluster)</td>

<td>CeaftpiMsto Ne.</td><td></td><td>UL *</td><td>WR *</td><td>Name</td>

<td> 217</td><td>guanin-9&gt; ilo</td><td>octadecsloxietílo</td><td>benzyl</td><td>benzyl octadecyloxyethyl 9 - ($) - [(3- hydroxy-2- phosphonomethoxy) propyl] guanine</td>

<td> 218</td><td>adeuffl-9-tlo</td><td>octadecyloxyethyl</td><td>beacílo</td><td>benzyl octadecyloxyethyl 9- (S) - [(3-hydroxy-2- phosphonomethoxOpropylJadenine</td>

<td> 219</td><td>Otosin-1-yl</td><td>octadecyloxyethyl</td><td>bmctlo</td><td>Benzyl odadectloxyethyl 1- (5) - ((3-hydroxy-2- fo sfonometoxijpropilojcitosina</td>

<td> 220</td><td></td><td>odasiecylocytyl</td><td>benzyl</td><td>benzyl octadecyloxyethyl 1- (5) - ((3-hydroxy-2-phosphonomethoxy) propyl] thiinine</td>

<td> 221</td><td>uracil-l-flo</td><td>octadecyloxidflo</td><td>benzyl</td><td>benzyl odedectloxieUio 1- (5) - ((3-hydroxy-2 phosphonomotosd ^ repdojuracil</td>

<td> 222</td><td>2.6 -9-ilo</td><td>octadecyloxyethyl</td><td>benzyl</td><td>benzyl octadecyloxyethyl 9- (5) - ((3-hydroxy-2-phosphonometaxy) piopyl] 2,6disniinopuris</td>

<td> 223</td><td>guanüs-9-ίΙο</td><td>hexadecyloxyprop</td><td>benzyl</td><td>benzyl hexadecyloxyprip opyl 9- (5) - (0htdroxi-2- fo sfonoxnetoxi) pr opilo Jemaina</td>

<td colspan="5">®Huc®Muc (·) O ^ Nuc / ®Nuc (a) 0 &amp; m »c®N« c (a) 0 k ^ Ox ^ P-CM-Λ. · Ι_χχ0_χχΡ-0 “ΙΛ · l ^ O ^ PO-UL ' } Ó-WR * ° _or J OR / R * ° _HO&gt; OR / R * HO HO ^MORpoSp (depends on substituents)% 5¡p (racemic)</td>

<td>Cooipttsto No.</td><td></td><td>THE,*</td><td>R® *</td><td>Name</td>

<td> 224</td><td>adanta-9-ilo</td><td>haxadectloxypropyl</td><td>benzyl</td><td>haxadadoxipropyl side 9- (5) - (0hydroxy-2- fosfonomatoxQprcptlo Jadeóla *</td>

<td> 225</td><td>citoria-1-uncle</td><td>hwadedoxipropflo</td><td>side</td><td>benzyl bexadedoxipropyl 1- (5) - (0htdroxi-2- foifonou3etoxi) proptlo] citMtaa</td>

<td> 226</td><td>tata-1-lo</td><td>bexadecdoxipropdo</td><td>side</td><td>side bexadacílox ^ ropilo l ^ 5h [0bi ^ oxi-2-fosfowmateKi) p «mib&gt;] tiiaÍEik</td>

<td> 227</td><td>urad-i-ílo</td><td>bexadadoxipropyl</td><td>benzyl</td><td>BeacUo Haxadecyloxypropyl 1- (5) - (0bidroxi-2- phosphonoznetonj ownjuracil</td>

<td> 228</td><td>2,6dúunin opurüi -9-do</td><td>bexadecyloxypropyl</td><td>side</td><td>side haxadadoxtpropyl 9- (5) - (0- hydroxy-S-phosphonometexOptopiloJZ.Odiamtaopurta</td>

<td> 229</td><td>gtumin-9-ilo</td><td>1-O-octadedo-2-Obendo-sn do it</td><td>side</td><td>side í-0-octad * do-2 - &lt;^ band © -ar Icario 9 - ($) - [(3-hydroxy-2- fosfbnomatoxOpropiloJpuanin *</td>

<td> 230</td><td>adanta-9-i! o</td><td>1 -O-octadacil-2-Obendo-ín Do it</td><td>side</td><td>side iO-octadecüo-2-O-bendo-cn ¿icedo 9- (S) - ((3-hydroxy-2phosphonomet ») purpose] * d¡tnta *</td>

<td> 231</td><td>eitojin-l-ilo</td><td>1 -O-Oct * decdo-2-Obando-m ¿icario</td><td>benzyl</td><td>side l- &lt;2-octadacil-2-0-bancdo- £ n Scerflo l- (S) - ((3-hydroxy-2- £ osfonometo ») propdo] citosta *</td>

<td> 232</td><td>tírm-ft .. 1</td><td>1 -O-octedado-2-Ob «ado-ín ¿icetio</td><td>side</td><td>side l-CMctadacyte-2-O-benzyl-SH icaryl 1 - (5) - [(3-hydroxy-2phosphonoraatoxQpropiiumJtinitae</td>

<td> 233</td><td>uiacil-l-ilo</td><td>1 -O-octadecyl-2-Obancyl -sn ¿iceril</td><td>side</td><td>side lO-octadacüo-2-O-banedo-xn ¿Icerilo l- (S) - ((3-hydroxy-2- phosphonoznatoxOpropylJuíactlo</td>

<td> 234</td><td>2.6- düunúi opwric -9-do</td><td>1 -O-octadacdo-2 -Obando-sn ¿icarílo</td><td>drunk</td><td>lO-octadecyl-lG-bancilo-oi tearito 9- (S) - ((3-hydroxy-2-phosphonomethoxy) prcpyl] 2,6útflz &amp; ípupuit</td>

<td> 236</td><td>Guanta-9-ilo</td><td>octadacdoxietüo</td><td>phenyl</td><td>octadadoxiatflo phenyl 9- (5) - ((3-hydroxy-2- fojfononwtoxi) propyl) pi * nina</td>

<td> 236</td><td>adenta-9-yl</td><td>octodedoxiethyl</td><td>fief</td><td>octadadoxydlo phenyl 9- (5) - ((3bidroxy-2- fo sfonomatoxi) proplo] adtaun *</td>

<td> 237</td><td>I quote without-1-do</td><td>octadtcücxtethyl</td><td>fief</td><td>octadadoxietlo phenyl I - (5) - ((3btdroxi-2- fo s fonometo ») purpose] citosin *</td>

<td> 238</td><td>-do</td><td>octadecyloxyethyl</td><td>background</td><td>octadedoxiethyl phenyl 1 - (5) - ((3-hydroxy-l-photophonomethoxOpropdoJttaunt</td>

<td> 239</td><td>uracd-l-do</td><td>octadacyloxyethyl</td><td>fantastic</td><td>Phenyl octadecloxyethyl 1- (5) - ((3-hydroxy-2-phosphonomethoxy) propoule] urad</td>

<td colspan="5">.................................................. .................................................. ........... Η ................... Ή .................. ....................................... β .......... ..... 75 ............................................ ...............................................^bIW ** Nw (·) OR “Nuc'ONuít ·) 0 0 L ^ o ^ -po-ιλ * kjx, po ~ ue Ljx.p-0-ul ΧΧί&gt; Χ XX »\ Ζ ΧΧ | ϊ Ó-WR- ° J O-WR · ° hqJ θ '*** · ΗΟ ΗΟ Rp or Sp (depends on substitute cough) Rp. Sp (racérmco)</td>

<td>Full Ne.</td><td></td><td>LL *</td><td>RK '</td><td>Name</td>

<td> 240</td><td>2,5- TRIAnnjmHri -9-ilo</td><td>octadecyloxyethyl</td><td>fonflo</td><td>octodecyloxythiotyl fief 9- (3) - ((3-hydroxy-2-forphonomethoxy) ptopdo] 2,6diuxd &amp; opurai</td>

<td> 241</td><td>gUaQtD-9-ΐΙθ</td><td>hexadecdoxipropy</td><td>fssüo</td><td>Hexad type Mloxipropdo 9- (3) - ((3-hydroxy-2-phosphonomet ») propyl) gnanin</td>

<td> 242</td><td>adenin-9-do</td><td>hexadecdoxipropdo</td><td>background</td><td>hoxadociioxipropdo 9- (3) - ((3htdroxi-2- Osphonomethoxy) propdo] adenüia.</td>

<td> 243</td><td>cytosin-l-do</td><td>hexadecyloxypiopyl</td><td>background</td><td>Enilo kexndocüoxqxopdo 1- (3) - ((3-hydroxy-2- phosphononythoxy) propou] cstosine</td>

<td> 244</td><td>timin-l-ílo</td><td>haxadacdoxipropdo</td><td>background</td><td>kexodocilox ^ ropdo background 1- (3) - ((3htdroxi-2-fo sfonom «texi) propyl] tinbB</td>

<td> 245</td><td>nracd-l-do</td><td>hexadecdoxipropdo</td><td>background</td><td>Hoxadocdoxipropyl bottom 1- (3) - ((3-hydroxy-2- phosphonomethoxy) prcpyl] uracil</td>

<td> 245</td><td>2,6 diaminopudn -9-yl</td><td>hexadocdoxipropyl</td><td>background</td><td>fendo hoxndecdoxipropdo 9 &lt;S&gt; ((3-hydroxy-2-phosphoi »aotoxy) picyl] 2,6¿minminopurin</td>

<td> 247</td><td></td><td>I -O-octadecdo-2 - (? Bancdo-sn doadadlo</td><td>background</td><td>background lO-octadecdo-2-O-benzotot gfceryl 9- (5) - ((3-hydroxy-2phosphonomotoxOpropylolciutnin</td>

<td> 248</td><td>adenin-9-do</td><td>1 -O-octadacüo-2-ObaneÜo-fM do it all</td><td>background</td><td>fendo lO-octaaecdo-2- (7-bancilo-0t think about it 9- (S) - [(3-liydroxy-2- phosphonomethoxy) propdo) ad »nina</td>

<td> 249</td><td>citoein-l-do</td><td>1 -O-octadecyl-2 -0bancilo-jn do it all</td><td>background</td><td>fendo lO-ociedecdo-3-CMmcilo-sH glyceryl l- (S) - [(3-liydroxy-2phosphonomethoxy) pfopdo] cytosine</td>

<td> 250</td><td>thymus-1 -ilrt</td><td>lO-octadecüo-2-Obencilo-rn do it all</td><td>background</td><td>fendo 1 -O-ocadocdo-2-O-benzyl-íM read it 1- (5) - ((3-hydxoxy-2phosphonomethoxQpropüojtñnina</td>

<td> 251</td><td>ntacil-l-üo</td><td>lC-octadecyl-2-Οbenzyl-fM enjoy it</td><td>background</td><td>background lP-octedecdo-2-0-bancilo- &lt;sn Roedlo l- (S) - [(3-htdroxi-2- phosphonomethoxyijpropüojuraeil</td>

<td> 252</td><td>2,6-diaminopurin -9-yl</td><td>1 -O-ocUdociIo-2-Oboncilo-SM güeerflo</td><td>background</td><td>/ «Do í-Ó-ocmecdo-2-Ob« ícilo-sn Do you read it 9- (S) - [(3-hydtoxy-2 phosphonomethoxOpropylJ ^ edúninopmn</td>

<td> 253</td><td>Juanin-9-ilo</td><td>octtí * cdoxi »linden</td><td></td><td>etho octadedoxium 9- (5) - ((3-hydrató2-fojfonometoxOpropilo] &lt;MaÍM</td>

<td> 254</td><td>adenin-9-yl</td><td>ocUdeciioxtotilo</td><td>"linden</td><td>ethyl octsdeeyloxyethyl 9- (5) - [(3 -hydrated2 -foxphonomethoxy) propyl jadonine</td>

<td> 255</td><td>CÜOJHJ-l-ÜO</td><td>cOdecyloxtethyl</td><td>ethyl</td><td>ethyl oetadacdoxiethyl l- (S) - [(3-hydrazó- 2-phosphonomdoxy) ptopyl] cttotin *</td>

<td colspan="5">O trust O ¡Ot Ά nA^orNutf^andMvc (») 0« wWRíucte) 0 0 k ^ O ^ IO-tA »ζ ^, Ο ^, Ρ-Ο-ΙΛ · k ^ O ^ PO-UL ·_hoJ Ó-WR · ° OR / R · ° _M0J OR / R * Rp or Sp (depends on substituents)% Sp (racemic)</td>

<td>CompMSto N «.</td><td>BsURfc «</td><td>LL *</td><td>R / R *</td><td>Name</td>

<td>2se</td><td>tímin-l-ilo</td><td>octad «ciloxyethyl</td><td>ethyl</td><td>• lime octtiecüoxyethyl l- (S) - ((3-hydra · · 2-phosphonomatoxOpropyl] thymine</td>

<td> 257</td><td>nraeii-l-tlo</td><td>octadecyloxyethyl</td><td>ethyl</td><td>• ethyl octadecyloxyethyl HS) - [(3-hydro »- 2 -fos foaoBwtoxi) propílo] uflKilo</td>

<td> 258</td><td>2.6- -9-ilo</td><td>octudeciloxietíc</td><td>ethyl</td><td>Ethyl octadecyloxyethyl 9- (S) - [(3-hydroxy2-fos fonomethoxy) propyl] 2 fi dio Qtcopwrw.</td>

<td>2S9</td><td>guanin-9-ílo</td><td>hexadacyloxypropyl</td><td>ethyl</td><td>ethyl bexadecyloxypropyl 9- (5) - (0hydroxy-2- phosphonoroethoxy) propium] gB «nin *</td>

<td> 250</td><td>adentn-9-tlo</td><td>hexadecyloxypropyl</td><td>ethyl</td><td>Ethyl licxadecyloxypropyl 9- (5) - (0hydroxy-2- phosphonomethoxy) propflo] »deniM</td>

<td> 251</td><td>cytosin-l-yl</td><td>bexadecdoxtpropyl</td><td>ethyl</td><td>ethyl haxadecyloxypropyl 1- (5) - (0hydroxy-2- phosphonomethoxy) ptopyl] cytosta *</td>

<td> 252</td><td>timia-l-tlo</td><td>bexadecyloxypropyl</td><td>ethyl</td><td>• linden baxadacilox ^ ropdo 1- (5) - (0bidroxi-2 -fo sfo nomethoxy) propyl] tmsM</td>

<td> 253</td><td>uracil-l-üo</td><td>haxadecyloxypropyl</td><td>ethyl</td><td>• lime bexadecyloxypropyl 1- (6) - (0bidroxy-2- fo ifonomatoxy) prcpilo] ur * cilo</td>

<td> 254</td><td>2,6diaxnüiopurin -9-ilo</td><td>bexadecyloxypropyl</td><td>ethyl</td><td>• linden baxadacyloxtoptopyl 9- (5) - (0hydroxt-2-phosphonomethoxy) propyl] 2,6-</td>

<td> 255</td><td></td><td>1 -O-octadecflo-2 - Obáñalo-sn glyceril</td><td>ethyl</td><td>ethyl 1 -O-octadecyl-2-O-benzyl-ín do it 9- (S) - [(3-hydroxy-2-</td>

<td> 255</td><td>adenin-9-tlo</td><td>1-O-octadeate-2-Obeaeyl-fn glyceryl</td><td>ethyl</td><td>ícenlo 9- (S) - [(3-bidroxy-2phosphonomethoxy) propose it «denin *</td>

<td> 267</td><td>cytosia-1-yl</td><td>1 - O-octad * cilo -2-Obencílo-ΐη {fícenlo</td><td>ethyl</td><td>• tüo lO-omdacilo-2-Ob «ncilo-íM glyceryl 1 - (5) - ((3-hydroxy-2phosphonom * toxi) propyl] cytosüia</td>

<td> 258</td><td>.Πα</td><td>1 -O-octadecyl-2-Obeacyl-s »glycaryl</td><td>ethyl</td><td>• linden lO-octadecyl-2-Ob «ncilo-0i fícenlo 1 - (5) - ((3-hydroxy-2fo s foaom« toxQprepilo] tiiatnt</td>

<td> 269</td><td>UMCíH-ilo</td><td>1 -O-octadectlo-2-Obencilo-f »Fícenlo</td><td>•linden</td><td>ethyl lO-octadeeito-2-O-beactlo-í » glyceryl l- (S) - [(3-hydroxy-2- phosphonomethoxy) prcpyl] urethio</td>

<td> 270</td><td>2.6- dtAxniccpufxi -9-ilo</td><td>lO-octadecyl-2-Obeactlooi do it</td><td>ethyl</td><td>Fentlo lO-octade &lt;: ilo-2-Ob®icilo- »! glyceryl 9- (S) - [(3-hydroxy-2fos foaooiethoxy) propyl] X6 - Hinminapnrin</td>

<td> 271</td><td>$ 2 * &amp; i &amp; ~ 9 «ilo</td><td>ociad eciloxtetdo</td><td>plactosyl</td><td>JalactoMlo octadcyloxyethyl 9- (5) - ((3-hydroxy-2-</td>

<td colspan="5">®Nuc / 8h «c (·) 0 Bnuc®Nwc (·) 0 0 k ^ Oxx? ~ o-iA · U ^ o ^ po-ul · k ^ o ^ lo-tn. HO- 'Ht / ° HO' ^¿-MPRp or Sp (depends on substituents) Sp (racemic)</td>

<td>Ceapotito N®.</td><td>Bnm / B &amp; mC »)</td><td>UL '</td><td>RR *</td><td>Name</td>

<td> 272</td><td>adenm-9-do</td><td>octadecüoxieitílo</td><td>galactosdo</td><td>gabctosdo octedectloxyethyl 9- (5) - ((3hydroxy-2phosphonomMoxi) ptocyte] idbnin *</td>

<td> 273</td><td>cytosia-l-do</td><td>eighteenth century</td><td>galactosdo</td><td>^ octelecyloxyethyl reader 1- (5) - ((3hydrox-2- fosfonom «toxi) prepilo] cttmtBk</td>

<td> 274</td><td>timin-l-do</td><td>octedecyloxyethyl</td><td>galactosdo</td><td>crawling silo octededoxiethyl 1- (5) - ((3-hydroxy-2-phosphoi »nietaxy) pn&gt; pilo] timffla</td>

<td> 275</td><td>uracil-1-yl</td><td>octaciedox</td><td>galactcsil</td><td>galactosyl octadecyloxyele 1- (5) - ((3-hydroxy-2- phospho &amp; om «toxi) propyl] w« cilo</td>

<td> 276</td><td>2,6díu ^ üiopufúi -9-ÜO</td><td>octadeewoxietdo</td><td>galactosdo</td><td>galactosyl octadecyloxyethyl 9- (5) - ((3húkoxi-l-phosfoaoBetaxOpropiloP.edi &amp; xsbiop'urizi</td>

<td> 277</td><td></td><td>bexadekoxypropyl</td><td>galactosdo</td><td>9-(5) hexadcctloxypropyl crawler ((3-hydroxy-2- fo s fonoa «toxí) propilo] fu« niiMi</td>

<td> 278</td><td>adenin-9-do</td><td>hexadecdoxipropyl</td><td>galactosdo</td><td>9-(5) ((3-hydroxy-2-) hexylurethoxypropyl crawler fb s fonoo »toxi) prepdo] adhQin«</td>

<td> 279</td><td>cytosm-l-Üo</td><td>bexadecdoxipropyl</td><td>galactosdo</td><td>crawling silo Eexadecdoxiptopdo 1- (5) - {(3-hydroxy-2- íosfoBoaMtoxi) prcpdo] cit &lt;»ina</td>

<td> 280</td><td>timin-l-ilo</td><td>bexadecdoxipropdo</td><td>gdectosyl</td><td>hexadecdoxipropyl galactosdo 1 - (5) - ((3-hydroxy-2- fosfoBom «o3tí) prcpito] &amp; nüB</td>

<td> 281</td><td>uracd-l-do</td><td>hexadecyloxypropyl</td><td>gahetosyl</td><td>haxadecdoxipropdo galactosdo 1- (5) ((3-hydroxy-2- fos foBonMtoxi) prcpdoh »acdo</td>

<td> 282</td><td>2.6- düusin opurtQ -9-ilo</td><td>hexadecüoxipropdo</td><td>gxlectostio</td><td>galactosdo headeedoxipropdo 9- (5) - ((3-bidroxy-2- phosphonom «toxi) prepdo] 2,6- diaminopurin</td>

<td> 283</td><td>guantB-9-do</td><td>l -O-octadecyl * 2-Obencüo- £ n glyceryl</td><td>gxleetoryl</td><td>galactosdo lO-octadecito-2-Obencdo-m Ricardo 9- (5) - ((3-hydroxy-2fosfoBometos) pr «9ÜolntaQiaa</td>

<td> 284</td><td>adenbi-9-do</td><td>lO-octadecdo-2-Obancilo -m tceryl</td><td>ptactosium</td><td>galactosdo lO-octadecflo-2-Ob * Bcdo-SH glyceryl 9- (S) - ((3-hydroxy-2fo s fonomethoxy) propu] adenine</td>

<td> 285</td><td>I quote without-1-do</td><td>1 - O-octadecdo -2-0beacdo-ín glyceryl</td><td>plectosyl</td><td>galactosdo l-0-o «tadecflo-2-0beBcdo-sM glyceryl l- (5) - [(3-hydroxy-2 phosphonomethoxy) prc! pdo] citostiMt</td>

<td> 286</td><td>timin-l-ilo</td><td>10-octadecdo-2-Obencdo-in glyceryl</td><td>gahctosüo</td><td>galactosdo lO-octadecdo-2-Obencdo-a »glyceryl 1- (5) - ((3-htdroxi-2fosfoBoxn« toxÍ) propdo] thixniaa</td>

<td colspan="5">—B - TB -------------------- E - JB ----------------- B - JE ---------------^B»W ° Nec (a) f ° W^BNuc (a) 0 ^andMu¿ ° ltac (·) 0 kyO ^ P-Ο-ΙΛ · l ^ yO ^ PO-LA. · k ^^ O ^ PO-UL * J 'd ~ WR * ° J OR / R · ° wqU OR / R · HO HO ¹⁴⁰Rp or Sp (depends on substituent effects)% Sp (racemic)</td>

<td>Buy yourself No.</td><td></td><td>LV</td><td>R / R *</td><td>Name</td>

<td> 287</td><td>uracil-1-tlo</td><td>1 -0- oetadecyl -2 -0benzyl-ín ffcertlo</td><td>galactosdo</td><td>gelactostlo lO-octadecyl-2-Obenctlo-sn Bcarilo l- (S) - [(3-htdro »-2fo s Íonometox0proptlo] nractlo</td>

<td> 288</td><td>2,6 diaminopurin -9-uncle</td><td>lO-octadecflo-2-0beucilo-ín gfceril</td><td>plactostlo</td><td>phalactosüo lO-octadacyl-2-Obenctlo-nt jiiceril 9- (S) - ((3-h »droxi-2phosphonomethoxOpropyl P. Sdiaminopurin</td>

Table 5. diester compounds of (S) -3-fhioro-2-fo $ fonomethoxypropyl [(S) -FPNfP]

<td colspan="5">^BNuJ^BNuc (a) O ^BNik /^BNuc (8) 0 ^BNuJ^BNoc &lt;·) 0 L ^ O ^ PO-Wl · U ^ O ^ P-OHA · k ^^ PO-UL¹_FJ Ó-MP * _FJ OR / R ^W_FJ Rp or Sp (depends on substituents) Rp, sp (racemic)</td>

<td>Cospoeito No.</td><td></td><td>LV</td><td>R / R *</td><td>It does not open</td>

<td> 289</td><td>guaoin-9-tto</td><td>octtdfccyloxyethyl</td><td>benzyl</td><td>benzyl octadectloxyethyl 9- (5) - ((3fluoro-2- fo yes onomethoxy) propyl] piiniaa</td>

<td> 290</td><td>adeain-9-íto</td><td>octid «ciloxy« linden</td><td>benzyl</td><td>benzyl octadectloxyethyl 9- (S&gt; [(3fluoro-2- fo s phonoznctoxy) propyl] adMüna</td>

<td> 291</td><td>I quote without-1-item</td><td>octsdectloxyeiyl</td><td>benzyl</td><td>benzyl octadectloxyethyl l - (5) - ((3fluoro-2- fostonomatoxOpropilo Jeitos ina</td>

<td> 292</td><td>timiB-1-üo</td><td>octadecyloxytethyl</td><td>benzyl</td><td>benzyl octadecyloxytethyl l- (5) - [(3-fluoro -2-phosphoncmethoxy) prcito] tinüna</td>

<td> 293</td><td>uracil-l-ilo</td><td>octedecyloxyethyl</td><td>benzyl</td><td>benzyl octadectloxyethyl 1- (5) - ((3Ouoro-2-phosphonomethoxy) ptopyl} tmyllo</td>

<td> 294</td><td>2,6di &amp; zoiiioptiftc -9-ilo</td><td>octedeciloxiattlo</td><td>benzyl</td><td>benzyl octadeethyloxythio 9- (5) - ((3fluoro -2 -fo sphonomethoxy) pcopyl] 2,6diaxntnopurin</td>

<td> 295</td><td>guanin-9-ilo</td><td>headaeiloxipropUo</td><td>benzyl</td><td>benzyl bexadekoxypropyl 9- (5) - (0fluoro-2- foifonometo9d) prcpilo] pi «aína</td>

<td> 296</td><td>adenin-9-yl</td><td>hexadcyloxypropyl</td><td>benzyl</td><td>benzyl haxadecyloxypropyl 9- (5) - ((3fluoro-2- osfonom «toxi) propyl] adMiina</td>

<td> 297</td><td>cytosin-l-yl</td><td>hextdecücxiptOpilo</td><td>benzyl</td><td>benzyl hexadecyloxypropyl 1- (5) - ((3fiuoro-2- phosphonomethoxy) proptlo] cytosin *</td>

<td> 298</td><td>tiXBÚQ * 1 “Ílo</td><td>hcxadcciloxiprcptlo</td><td>benzyl</td><td>benzyl hexadactloxtproptlo 1- (5) - (0fhioro -2 -foSfonotnetcxiJptoptloltiiniu</td>

<td colspan="5">Búuc / Bllticfaj o ^BNw /^BN »c (a) O ^BNwc / BNue (·) O k ^ O ^ P-Ο-ΙΛ. · k ^ O ^ ¿»- * O ~ UL * k ^ O ^^ - O-UL · Ó-fW ^α_FJ ó-w ^W pU OR / R Rp O Sp (depends on substituents) φ, sp (racemic)</td>

<td>Ceapeesto N «.</td><td></td><td>ΙΛ</td><td>R / R *</td><td>Name</td>

<td> 299</td><td>nracil-l-ílo</td><td>bexadecyloxypropyl</td><td>benzyl</td><td>benzyl hexadecdoxipropyl 1- (6) - (0-uoro-2-phosphonoxnethoxy) propyl] ur®: ilo</td>

<td> 300</td><td>2,6 diisaiziopunzi -9-Uo</td><td>lexadecyloxyptoptlo</td><td>benzyl</td><td>benzyl hexadocyloxypropyl 9- (6) - (0fluoro-2-phosphonometcttOpei&gt; piloP, 6diaminopurin</td>

<td> 301</td><td></td><td>10-Ocudecyl-2-Obenzyl-sn glyceryl</td><td>benzyl</td><td>benzyl l-0-octadecyl-2-C&gt; -beneio-; n glyceryl 9- (S) - [(3-fluoro-2phosphonomethoxy) pr &lt;3pyl] guanine</td>

<td> 302</td><td>adenin-9-ílo</td><td>1 -O-octadecyl-2-Obenctlo- ^ i glyceryl</td><td>benzyl</td><td>benzyl l-0-octadecdo-2-0-benzyl-¿»gücerilo 9- (S) - [(3-flnoro-2fo s fonomethoxOpropyl] admina</td>

<td> 303</td><td>citosin-l-üo</td><td>1 -O-octadecyl-2-Obancilo-í »fix it</td><td>benzyl</td><td>Benzyl lO-ocüdetílo-2-O-benzyl-sn ¿icerilo 1 - (5) - ((3-ñuoro-2fosfonometoxOpropilojcitosina</td>

<td> 304</td><td>Tirain-1 -ilo</td><td>1-0- octadecyl-2-Obenzyl-rn glyceryl</td><td>benzyl</td><td>benzyl 10-octedecyl-2-O-benzyl-sn gfcerite l- (S) - ((3-fluorc-2phosphonomethoxy) propyl] tüním</td>

<td> 305</td><td>uracil-l-ilo</td><td>l -O-octadecyl-2-Obenzyl-j »glyceryl</td><td>benzyl</td><td>benzyl lO-octadecyl-2-O-benzyl-ai glyceryl I- (S) - [(3-fluoro-2phosphononaethoxOpr opyl Juracil</td>

<td> 306</td><td>2,6diezEüsopwrixi -9-ilo</td><td>I -O-octedecyl -2-Obenzyl - M glyceryl</td><td>benzyl</td><td>benzyl lOo ^ adecilo-2-O-benzyl ^ n gócenlo 9- (5) - ((3-fluoro-2fo s fon ometoxy) propyl] 2,6diixzüsopuns</td>

<td> 307</td><td>gujmiu * 9 * ilo</td><td>octadecyloxyethyl</td><td>phenyl</td><td>Phenyl octadecyloxyethyl 9- (5) - ((3fluoro-2- fo sfonomethoxyJpropiloJpMnína</td>

<td> 308</td><td>sdeuixi-9 ~ ilo</td><td>octedecyloxyethyl</td><td>phenyl</td><td>phenyl octedecyloxyene 9- (5) - ((3fluoro-2- phosphonomethoxy) propyl] adaniu</td>

<td> 309</td><td>cytosin-l-yl</td><td>octadecyloxyethylene</td><td>phenyl</td><td>phenyl octadecyloxyethyl 1- (5) - ((3fluoro-2- fo $ fonomethoxy) prcpilo] citMina</td>

<td> 310</td><td>timm-l-flo</td><td>octadecydoethyl</td><td>phenyl</td><td>phenyl octadecyloxyethyl 1- (5) - ((3fluoro-2-phosphoi »inethoxy) propyl] thymine</td>

<td> 311</td><td>urecil-l-yl</td><td>octadecyloxyethyl</td><td>phenyl</td><td>octedecyloxyethyl phenyl 1- (5) - ((3Qnoro-2-foifoi »metaxy) ptopyl] uMcilo</td>

<td> 312</td><td>2,6-diaminopurin -9-yl</td><td>octadecyloxyethyl</td><td>phenyl</td><td>Phenyl octadecyloxyethyl 9- (5) - ((3ftooro-2-phosphonomotxy) propyl] 2,6-</td>

<td> 313</td><td>guantn-9-ilo</td><td>bexadecyloxypropyl</td><td>phenyl</td><td>phenyl hexadectloxypropyl 9- (5) - ((3noro-2- phosphonomethoxy) propyl] guanine</td>

<td> 314</td><td>adenin-9-yl</td><td>bexadecyloxypropyl</td><td>phenyl</td><td>phenyl bexadectloxypropyl 9- (5) - ((3flaoro-2- fo s fonomethoxy) prapyl] to &lt;ienine</td>

<td colspan="5">^BNue / ®Nuc (·) 0 0 Β ^ κ /^ΒΝυ «(β) or k ^ O ^ PO-UL * k ^ O ^ P-0-ΙΛ. · k ^ O ^ Í'-O-UL · pj ¿-R / R · ^α pj 0-Rfl? pj O-WR * Φ or Sp (depends on substituents) φ, φ (racemic)</td>

<td>ΙΌΒψΒβΏ No.</td><td></td><td>UL *</td><td>R / R *</td><td>Name</td>

<td> 315</td><td>CYTOSÍB-1 -ilo</td><td>haxadecyloxypropyl</td><td>phenyl</td><td>phenyl h «adecyloxypropyl 1- (8) - ((3fluoro-2- phosphonomethoxOpropylocytosine</td>

<td> 316</td><td>timin-l-ilo</td><td>héxsd ^ iloxipropüo</td><td>phenyl</td><td>btxadeefloxypropyl phenyl 1- (8) - ((3fluoro-2-fotibnojnet &lt;w &amp; w&gt; pfl «] enrin *</td>

<td> 317</td><td>nracil-l-ílo</td><td>boateUoxtpropyl</td><td>phenyl</td><td>phenyl hexadecyloxypropuo 1- (8) - ((3fh&gt; gold-2-phosphonomethac) pmpyl} tttacilo</td>

<td> 318</td><td>2.6d £ Q3Í130pUfÍ &amp; -9 · ΐ1ο</td><td>bexadecylxtpropyl</td><td>phenyl</td><td>fontlo hexadecyloxypropyl 9- (8H (3fluoro- 2 -fo sphonomethoxy) propyl] 2,6diaminopurin</td>

<td> 319</td><td>gnanin-9-ílo</td><td>1 -O-octadecyl-2-Obenzyl-sM glyceryl</td><td>phenyl</td><td>phenyl 1 -0-o «tedecyl-2-0-benzyl-« n glyceryl 9- &lt;S} - ((3-fluoro-2fos fon ometoxy) propyl] guanine</td>

<td> 328</td><td>adantn-9-ilo</td><td>1 -O-oct * docilo-2-Obenctlo-sn glyceryl</td><td>phenyl</td><td>phenyl lC ^ ctadetyl-2-O-benzyl-iSM ^ iceryl 9- (8) - ((3-ñnoro-2fosfonomMoxi) propilo] adanin *</td>

<td> 321</td><td>cytosin-l-yl</td><td>1 -O-octadecyl-2 - &lt;? Benzyl -sn glyceryl</td><td>phenyl</td><td>femlo l-0-octadecyl-2-0-bancilo- £ n glyceryl 1- (8) - ((3-fluoro-2phosphonomethoxy) propyl] cytosine</td>

<td> 322</td><td>tunain-l-do</td><td>1 -O-octadecyl-2-Obencil-on</td><td>fenüo</td><td>phenyl iO-octadecyl-2-O-benzyl-on gUceryl l- (S) - ((3-fluoro-2phosphonomethoxy) propyl] thiintna</td>

<td> 323</td><td>uracil-l-ilo</td><td>l -0-octadecyl-2- &lt;2benzyl-rn glyceryl</td><td>background</td><td>phenyl lO-octadecyl-2-O-benzyl-cn glyceryl 1 - (8) - ((3-fluoro-2phosphonomethoxy) propyl] uracil</td>

<td> 324</td><td>2.6- -9-ilo</td><td>10-octadecyl-2-obenzyl-glyceryl</td><td>phenyl</td><td>phenyl 1-Ο-ο &lt;ίί6 · β0ο-2-6Μ&gt; · η «&amp;&gt; · ®ι ¿Icerilo 9- (S) - [(3-ftaoro-2fo s fonometo ») propyl] X6diaminopurin</td>

<td> 325</td><td>guanin-9-iio</td><td>octadecyloxyethyl</td><td>ethyl</td><td>ethyl octadecyloxyethyl $ - (8) - ((3-fiuoro2 -fo sfonomethoxy) propueo] guansna</td>

<td> 326</td><td>ad «nin-9 * ilo</td><td>octadecyloxyethyl</td><td>ethyl</td><td>ethyl octadecyloxyethyl 9- (S) - [(3-fiuoro2 -fo s fonometoxt) j&gt; ropilo] also</td>

<td> 327</td><td>cytosin-l-yl</td><td>octadecyloxyethyl</td><td>•linden</td><td>• linden octadecyloxy-1- (8) - ((3-flnoro2-phosphonomttoxy) propyl} cytorine</td>

<td> 328</td><td></td><td>octadecyloxyethyl</td><td>ethyl</td><td>• linyl octadacyloxylethyl l- (S) - [(3-fluoro2 -fo sfonoxMtoxi) pr opilo Jtimina</td>

<td> 329</td><td>uracil-l-ilo</td><td>octadecyloxyethyl</td><td>ethyl</td><td>• lime octadecyloxyethyl l- (S) - [(3-flnoro2-phosphonomethoxy) propyl] uactlo</td>

<td> 330</td><td>2,6-dithxfitphiopurtxi -9-yl</td><td>octadecyloxyethyl</td><td>ethyl</td><td>• tito octadecyloxyethyl 9- (8) - ((3-tivore 2-fo s fbnomethoxy) propyl] 2,6diaxninopurtn</td>

<td> 331</td><td>^ iaatn-9-ilo</td><td>hexadecyloxypropyl</td><td>•linden</td><td>ethyl hexadecyloxypropyl 9- (5) - ((3- fiuoro-2- fo $ foncjnetoxi) proptlo] guxnina</td>

<td colspan="5">Bhw / Bnucí ·) 0 ^BNuc /^BHuc (a) or Bnuc / BiM · »or k ^ jS ^ PO-UL * ζ ^ Ο ^ Ρ-0-Ul · k ^ O ^^ - 0-ΙΛ. · pj Ó-R / R * ^α_F&gt; OR / R * ” _FJ ¿-R / R * RpoSp (depends on assorting coughs) Rp, Sp (stereogenic)</td>

<td>Veapoess No.</td><td></td><td>ML *</td><td>R / R</td><td>Name</td>

<td> 332</td><td>adenin-9-yl</td><td>Imadeyloxypropyl</td><td>ethyl</td><td>• linden bexadecyloxtproptlo 9- (3) - (0fluoro-2- phosphonomethoxy) propyl] adanine</td>

<td> 333</td><td>cytosin-l-yl</td><td>bexadecyloxypropyl</td><td>ethyl</td><td>ethyl hexadacyloxypropyl 1- (3) - (0fluoro-2- fos £ onomethoxy) propyl Jeitos ina</td>

<td> 334</td><td>timin-l - {Jo</td><td>hexadekoxypropyl</td><td>• tslo</td><td>ethyl hexadecyloxypropyl 1- (3) - ((3fluoro-2-forf &lt;u »metcací ^ propdo] thymine</td>

<td> 335</td><td>uracil-l-ilo</td><td>hexadeeiloxypropyl</td><td>ethyl</td><td>• tilohexadecyloxypropyl 1- (3) - (0fhj gold -2 -ib sphonomethoxy) propyl) uracil</td>

<td> 336</td><td>2,6-diaminopurin -9-yl</td><td>hax &amp; deciloxypropyl</td><td>•linden</td><td>ethyl hexadecyloxtpropyl 9- (3) - (0fluoro-2-phosphor »methoxy) propyl] 2,6dtaxainopuíiii</td>

<td> 337</td><td>guuin-9-tlo</td><td>1 -O-octadecflo-2-0benzyl-ei glyceryl</td><td>ethyl</td><td>ethyl lO-octa ^ KÜo-2-O-benedo-m «• rilo 9-ÍS) - ((3-fluoro-2- fosfonom «toxí) prepilo] 9» niiia</td>

<td> 338</td><td>adenin-9-yl</td><td>1 -O-octadecyl-2-Obencil-sn ¿cotilo</td><td>ethyl</td><td>«1-O-octadecyl-2-O-beneyl-0i glyceryl 9- (S) - [(3-fluoro-2fo sphonomethoxy) propyl] adenine</td>

<td> 339</td><td>cytosin-l-ilo</td><td>1 -O-octadecyl-2-Obencil-SH do it</td><td>ethyl</td><td>• linden lO-octadacyl-2-O-benzyl-sn glyceryl l- (S) - [(3-flaoro-2phosphonomethoxy) propyl Jeitos ina</td>

<td> 34«</td><td>w &lt;1ft</td><td>10-octadecyl-2-Obenctlo-sn glyceryl</td><td>ethyl</td><td>ethyl lO-ocWecílo-2-0-b «Kilo-m ¿Icerflo l- (S). [(3-fluoro-2phosphonomethoxOproptkJtimim</td>

<td> 341</td><td>uracil-l-ilo</td><td>10-octadecyl-2-0benctlo-cn glyceryl</td><td>ethyl</td><td>ethyl lO-octadecyl-2-O-benzyl-sn IcMñlo l- (3) - ((3-fluoro-2 · phosphonomethoxy) prcpyl] uracil</td>

<td> 342</td><td>2.6- 4 ¡tarrtin Op Vftn -9-ilo</td><td>1 -O-octadecyl-2 -0sancilo-rn glyceryl</td><td>ethyl</td><td>phenyl l-0-octaaecilo-2-0-b «cfloisn Icerüo 9- (S) - ((3-fluoro-2phosphonomatoxy) propyl] 2,6diaminopurin</td>

<td> 343</td><td>guanin-9-ilo</td><td>octadecyloxyethyl</td><td>galactosyl</td><td>galactosyl octadecyloxyethyl 9- (3) - ((3- fluoro-2- phosphonomet ») propylojpianine</td>

<td> 344</td><td>ad «nin-9-ilo</td><td>octadecdoxiathyl</td><td>galactosyl</td><td>galactosyl octaaecyloxyethyl 9- (3) - ((3fluoro-2- PhosphbnomatoxQpropylJadaaine</td>

<td> 345</td><td>citosin-l-flo</td><td>octadecyloxyethyl</td><td>galactosyl</td><td>galactosyl octadecyloxyethyl 1- (3) - ((3fluoro-2- phosphonomethoxy) pr &lt;! pilo) cttosine</td>

<td> 346</td><td>timin-l-ilo</td><td>octadecyloxyethyl</td><td>galactosyl</td><td>galactosyl octadecyloxyethyl 1- (5) - ((3 £ hioro-2-phosphonoiBetaxi) piopyl] thymine</td>

<td> 347</td><td>uracil-l-ilo</td><td>octadecyloxyethyl</td><td>galactosyl</td><td>galactosyl octadecyloxyethyl 1- (3) - ((3fluoro-2-fo sphonomethoxyijpropylojuracil</td>

<td colspan="5">^BNuJBnoc (*&gt; 0 ^BN «/^BHue (a) 0 β ^ κ ^ Νικί ·) O i ti I II I II k ^ O ^ PO-UL * k ^ O ^ PO-LA * k ^ O ^ POL / l? - Á Rrt »· ** i A fMH ^W i ¿-R / R · p-— 'Q- * R / RF *** Ο * · Κ / Κ * F *** ^Wφ or φ (depends on substitute cough) Rp_t Sp (racémtoo)</td>

<td>UOBPMMD No.</td><td>ΒΚμ / Βνμ&gt;)</td><td>THE*</td><td>W</td><td>Name</td>

<td> 348</td><td>2,6diamtnopurin -9-ilo</td><td>octadecyloxyethyl</td><td>galactosyl</td><td>galactosyl octadecyloxyethyl 9- (5) - ((3fiaoro-2-fo sphonometaxy) propyl] 2,6-duaninopurin</td>

<td> 349</td><td></td><td>hexadecyloxtoropyl</td><td>ptactoid</td><td>galactosyl hexadecyloxypropyl 9- (3) ((3-phthaoro-2- phosphonomethoxy) prcpilo) guaEiiia</td>

<td> 35®</td><td>adenin-9-yl</td><td>hexadecyloxypropyl</td><td>galactosyl</td><td>galactosyl hexadecaloxypropyl 9- (3) [(3-flitoro-2- fo s fonomethoxy) propyl Jadenine</td>

<td> 351</td><td>cttosin-1-yl</td><td>hexadecyloxypropyl</td><td>galactosyl</td><td>galactosyl hexadecyloxypropyl 1- (5) - [(3-flttoro-2- fosfon.omMoxí ^ propilo] cytosine</td>

<td> 352</td><td>♦ tmm-1-uncle</td><td>hexadecyloxypropyl</td><td>galactosyl</td><td>galactosyl hexadoctloxyproptlo 1- (5) ((3-flaoro-2- fo s fonomethoxy) prcpilo] thymine</td>

<td> 353</td><td>uracil-l-Üo</td><td>hexadecyloxypropyl</td><td>galactosyl</td><td>galactosyl hexadacylxtoroptlo 1- (3) «3-fluoro-2- ios fbnometoxijpropilojuracil</td>

<td> 354</td><td>2,6diax &amp; üiopuris -Me</td><td>hexadecyloxypropyl</td><td>galactosyl</td><td>galactosyl hexadecyloxypropyl 9- (3) - [(3-fluoro-2- fo s fonomethoxy) propyl] 2,6- diaminopurin</td>

<td> 355 .</td><td>guanin-9-ilo</td><td>lO-octadecyl-2-Obencil-r »¿« rilo</td><td>galactosyl</td><td>galactosyl lO-oetadecyl-2-Obenzyl-s »glyceryl 9- {S) - [(3-fluoro-2phosphonomethox0ptapyl] giumina</td>

<td> 355</td><td>ad «in-9-üo</td><td>10-octadeeyl-2-Obenctlo-rn glyceryl</td><td>galactosyl</td><td>^ lactosyl l-0-oc¿decÍlo-2- &lt;7beBcdo-sH ¿icarilo 9- (S) - ((3-fluoro-2fosfoBometon) propilo] adKiiiia</td>

<td> 357</td><td>cytosin-l-yl</td><td>l -O-octadecyl-2-Obenzyl-jK glyceryl</td><td>galactosyl</td><td>galactosyl lO-octadecÜo-2-Ob «cío-cn ¿ícerilo l- (S) - ((3-Qaoro-2phosphonomethoxy) prcpilo] I quote $ iM</td>

<td> 358</td><td>timin-1-yl</td><td>1 -O-octocyl-2-Obenzyl-s »glyceryl</td><td>galactosyl</td><td>galactosyl lO-octadecyl-2-Obenctlo-sM glyceryl l- (S) - [(3-fluoro-2 · fo s foaomatoxí) propuo) thymine</td>

<td> 359</td><td>uraed-l-ilo</td><td>l -O-octedecyl -2 -0 · benzyl-i »glyceryl</td><td>galactosyl</td><td>galactosyl lv-octadacyl-2-0bonctlo-snglicoryl l- (S) - [(3-fluoro-2fos fonomethoxy) prcpyl] iaacyl</td>

<td> 36®</td><td>2,6 diaminoperia -9-do</td><td>lO-octadecyl-2-0benzyl -im do it</td><td>galactosyl</td><td>galactosyl lO-octadacyl-2-0benzene-SH ¿tcerilo9- (S) - ((3-fluoro-2phosphonomet ») propflo] 2,6dtaxninopuriu</td>

Table 6. Fodbnon ^ uxtetflo (MS) diester compounds

<td colspan="5">^BNuc /^BNuc (a) 0 ^BNu &lt;/^BNuc {a) 0 ^BMuc®Nuc (a) 0 k &gt;&gt; ^ - O-UL · k ^ O ^ -O-UL · k ^ O ^ -O-Ul / Ó-R / R¹ &lt;* OR / R * “¿-R / R * Rpor Sp (depends on substituents) Rp. Sp (racemic)</td>

<td>Compoesto No.</td><td>EbwoBxwX)</td><td>ΙΛ *</td><td>R / R *</td><td>Name</td>

<td> 361</td><td>gnanin-9-flo</td><td>octadecyloxye</td><td>naftüo</td><td>Naphthyl octadecyloxyethyl 9- &lt;2fos phonomatonatüo) pianine</td>

<td> 362</td><td>adenin-9 «tlo</td><td>octadecyloxyethyl</td><td>naphthyl</td><td>naphthio octocyloxyacyte 9- (2 phosphonomethoxyethyl) adenine</td>

<td> 363</td><td>I quote sin- 1-ilo</td><td>octaaecüoxtetüo</td><td>naftüo</td><td>naftüo octadecüoxietüo l- (2fo s phonomotoxyethyl) cytosine</td>

<td> 364</td><td>Hxaui-I «mess</td><td>octadecyloxye</td><td>nañüo</td><td>nañüo octadeciloxietüo l- (2fo s fononietoxietílo) tiinina</td>

<td> 365</td><td>uractl-l-ilo</td><td>octadecüoxietüo</td><td>nafhlo</td><td>naftüo octadecüoxietüo 9- (2fosfonomatoxMtüo) uracü</td>

<td> 366</td><td>2,6diammopurin -9-ilo</td><td>octadecüoxietüo</td><td>naphthyl</td><td>naftüo octadeciloxietüo 9¿2- fo sfonometoxietüo) -2,6-diaminopt&gt; rin</td>

<td> 367</td><td>guanín-9-üo</td><td>hexadecüoxipropüo</td><td>naftüo</td><td>nañflo hexadecÜoxipropyl 9- (2- phosphoaometo3deülo) giMnina</td>

<td> 368</td><td>adenin-9-üo</td><td>hexadecüoxipropüo</td><td>naftüo</td><td>nañüo hexadecüoxipropüo 9- (2- iosphonomethoxyethene) adenine</td>

<td> 369</td><td>citosin-l-üo</td><td>hexadecüoxipropüo</td><td>naphthyl</td><td>naftüo hexadecüoxipropüo l- (2fosfonometoxietüo) cytosine</td>

<td> 370</td><td></td><td>hexadecüoxipropüo</td><td>naftüo</td><td>naftüo hexadecüoxipropüo l- (2fo sfonometoxietüo) ümina</td>

<td> 371</td><td>uracü- 1-tlo</td><td>hexadecüoxipropüo</td><td>naphthyl</td><td>naftüo hexadecüoxipropüo 9- (2fosíbnoznetox¿ «tüo) uracüo</td>

<td> 372</td><td>2.6- d iamtff ft pitrén -9-ilo</td><td>heXiMtheiloxipropdo</td><td>naphthyl</td><td>nañüo haxadecilox ^ ropüo 9- (2fosfonomMoxj ^ o&gt; 2,6-diaininopttrin</td>

<td> 373</td><td>guanín-9-üo</td><td>1 -O-ocUdecflo-2-0benzyl-rn ^ ieeril</td><td>naftüo</td><td>nañüo l-0-octadacüo-2-Ob «nctlo- &lt;m glicarüo 9- (2-</td>

<td> 374</td><td>adsnin-9-üo</td><td>1 -O-octadecyl-2-Obencüo-sn glyceryl</td><td>naphthyl</td><td>nañüo l-0-octadaci ^^ O-bencflo-®r glyceryl 9- (2phosphonomethoxyethyljadenine</td>

<td> 376</td><td>cytosin-l-yl</td><td>1 - G-octadacüo-2-0bencüo-sw glyceryl</td><td>naphthyl</td><td>nañüo lO-octadecyl-2-O-benzue-ín glyceryl l- (2- fo $ fonomat03ó «tüo) citosine</td>

<td> 376</td><td>timtn-1 - {lo</td><td>l -O-octadecüo-2 -0bencüo -sn ^ icerilo</td><td>naftüo</td><td>naphthyl lO-octadecüo-2-O-bencüo-cn ^ tcerilo l- (2-fosfonomatoxiotilojtüxiixui</td>

<td> 377</td><td>uracü-l-üo</td><td>l -O-octadecüo-2-Obencüo-cn glyceryl</td><td>naphthyl</td><td>naphthyl l- £&gt; -octadecyl-2-0-benzene &lt;n glyceryl 9- (2-phosphonoxnethoxietflojuraeil</td>

<td> 378</td><td>2,6dtísaúiopuftíi -9-Üo</td><td>1 -O-octadecyl-2-Obencüo-m gUcerüo</td><td>naphthyl</td><td>Naphthyl lO-octadecüo-2-O-bencüo-m gaseadlo 9- (2-fosfonomotoxi-etüo) - 2,6 -diamin opurin</td>

Table 7. Diester compounds of (R) -phosphon &lt;n&gt; ethoxypiopoule [(IQ4PMPJ

<td colspan="5">®Nuc®Nuc (·) OR ^BHuc^ZBNuc (·) 0 ^BNuc®Nuc (·) 0 k ^ O ^ PO-UL * Ι ^, Ο ^ Ι-0-LA. · k ^ Ox ^ POW. ' H₃ Ó-fVR ° ° H₃ Í-WR * ° ¿H₃ θ * ”** Φ or Sp (depends on suspuents) Rp, Sp (racénuco)</td>

<td>ComjMMito Ko.</td><td>BswB&gt; wí)</td><td>W</td><td>R / R</td><td>Name</td>

<td> 379</td><td>guanín-9-tlo</td><td>octadecyloxyethyl</td><td>naityl</td><td>Naphthyl octadecyloxyethyl phosphonomdo) propyl] | uanine</td>

<td> 380</td><td>adenin-9-yl</td><td>octadecyloxyethyl</td><td>nafhlo</td><td>Naphthyl octadecyloxyethyl 9- (10 - ((2phosphonomethoxy) prci&gt; iloladmma</td>

<td> 381</td><td>cytosin-l-yl</td><td>octadecyloxyethyl</td><td>naftilc</td><td>Naphthyl OctocyloxyrtylT ^) - t (IphosphononwtoxOpropylJitosine</td>

<td> 382</td><td>tünin-l-flo</td><td>octadecyloxyethyl</td><td>naphthyl</td><td>Naphthyl octadecyloxyethyl l- (R) - [(2fo s fonomethoxy) propyl] thiinine</td>

<td> 383</td><td>uraeil-I-ilo</td><td>octadecyloxyethyl</td><td>naityl</td><td>Naphthyl octadecyloxyethyl l- (R) - [{2phosphonomethoxy) propyl] w »cyl</td>

<td> 384</td><td>2,6-diaminopurin -9-yl</td><td>octadecyloxyethyl</td><td>naphthyl</td><td>Naphthyl octadecyloxyethyl 9- (11) - ((2phosphonomethoxy) propyl] 2,6-diaminopuon</td>

<td>38S</td><td>®ι «ηίη-9-ΰο</td><td>hexadecyloxypropyl</td><td>naphthyl</td><td>naphthyl hexadecyloxyqMropdo 9- (10 - ((2 phosphonoMtoxi) p € cptlo] gaantna</td>

<td> 385</td><td>adenin-9-yl</td><td>hexadectloxqtropil</td><td>naphthyl</td><td>naphthyl hexadecuoxtpropyl 9- (104 (2 phosphonomethoxy) prcpyl] a (knina</td>

<td> 387</td><td>cytosin-l-yl</td><td>hexadecyloxypropyl</td><td>naphthyl</td><td>naphthyl hexadecyloxypropyl 1- (104 (2 £ osfononaetoa) prcpilojcitostaa</td>

<td> 388</td><td>♦ rmfo-l U'lrt</td><td>hexadecyloxypropyl</td><td>naphthyl</td><td>naphthyl hexadecyloxypropyl 1- (104 (2fos £ onoinethoxy) pr opyl jtimine</td>

<td> 389</td><td>uracil-l-ilo</td><td>hexadecyloxypropyl</td><td>naphthyl</td><td>naphthyl hexadecyloxypropyl 1- (104 (2fo $ fonometata) prepilo] wacito</td>

<td> 390</td><td>2,6dtaxntnopurin -9-ilo</td><td>hexadecyloxypropyl</td><td></td><td>naphthyl hexadecfloxypropyl 9- (1) 4 (2phosphonomethoxy) propyl] 2,6diflrrttFiftpnrm</td>

<td> 391</td><td>fuanin-9-ilo</td><td>i 47-octadecyl -2-0beneyl-m glyceryl</td><td>naphthyl</td><td>Naphthyl lO-octadecyl-2-O-benedo-m Uceolo 9- (1) - ((2- phosphonomethoxy) propyl] pianine</td>

<td> 392</td><td>adenin-9-ϋο</td><td>1 - O-octad acyl -2-0benzyl-sn ¡licertlo</td><td>naphthyl</td><td>Naphthyl lO-octadecyl-2-O-bancillus-0i Uceolo 9- (1) - ((2- phosphonomethoxy) propyl] adanine</td>

<td> 393</td><td>cytosin-l-yl</td><td>1 -O-octadecyl-2-Obeneyl-sn</td><td>naphthyl</td><td>naphthyl l - ^ - octadecyl-ZO-baaciio-oi Uceolo 1- (1) - ((2fosfonometoxQpr opilo jeitos ina</td>

<td> 394</td><td>timixi-1-ílo</td><td>1 -O- octadecyl-2-Ohenzyl-sn glyceryl</td><td>naphthyl</td><td>Naphthyl lO-octadecyl ^ -O-benzylO'Oi Uceolo 141) 4 (2 phosphonomets ^ prcpilojtimine</td>

<td>39S</td><td>uracil-l-ilo</td><td>1 - O-octadecyl-2 -Obenzyl-w</td><td>naphthyl</td><td>Naphthyl lO-octadecyl-2-O-benzyl-in Only 14104 (2- phosphonomethoxy) propyl] uraci!</td>

<img file="MX367403B_D0063.tif" />

O Snwc®Nuc (·) ........ O Ó

U ^ O ^ PO-UL · k ^ O ^ PO-LA. · K ^ O ^ PO-UL ¿h₃ ó-wr ⁰ H₃ ¿~ R / r * ° ¿h₃ θ '^ fi¡i&gt; o (depends on substitute coughs) φ, φ (racemic)

<td>Make No.</td><td>ΒΜμ / Ι &amp; £ μ (·)</td><td>THE*</td><td>EUR *</td><td>Name</td>

<td> 396</td><td>2,6di &amp; minopufín -9-ilo</td><td>1 -O-octadecyl-2-Οbenctlo-sn ¿icortlo</td><td></td><td>naphthyl l-0-octirf * c * lo-2- &lt;2-b «wflo-s» t Foerilo9- (5&gt; [(2- phosphonomatoxy) pr0pyl] 2,6- diaminopurin</td>

Tabh 8. Diester compounds of (S) -3-methoxy-2-phosphonomethoxy repeat [(S) -X £ PMP]

<td colspan="5">^BNuc®Nuc (a) O ®Nu &lt;/ ®Huc (·) O ^ Νικ ^ ΝιιβΙ ·) 0 L ΛΚ J »-O-LA * _n k O POL / l. · k .0. J »-O-UI * Η, ε-Ο ' ^OR- ^ h, co-^: or - ** h ^ -o-^{; OR}’^{, UR}· φ or S £ »(depends on your Suspects) Φ, Sip (cluster)</td>

<td>CdWpQtlto N®.</td><td></td><td>THE·</td><td>R / R *</td><td>Name</td>

<td> 397</td><td>^ mnín-9-tlo</td><td>octadecyloxyethyl</td><td>naphthyl</td><td>Naphthyl octadecyloxyethyl 9- (3) - ((3methoxy-2phosphonometomTpropilol ^ samna</td>

<td> 398</td><td>• deoin-9-ilo</td><td>octadecyloxyethyl</td><td>mftílo</td><td>methoxy-2phosphonomethox9propyl] adanma</td>

<td> 399</td><td>cytosin-l-yl</td><td>octadecyloxyethyl</td><td>nafttlo</td><td>Naphthyl octadecfloxiatyl 1- (5) - ((3- methoxy-2- phosphonomethoxy) pr «pilo] cytosine</td>

<td> 400</td><td>timin-l-uo</td><td>octadecyloxyethyl</td><td>naphthyl</td><td>Naphthyl octadecyloxyathyl 1- (5) - ((3methoxy-2-fos £ c "oinethoxy) propyio] thymine</td>

<td> 401</td><td>urecyl-l-yl</td><td>octadecyloxyethyl</td><td>naphthyl</td><td>Naphthyl octadecyloxyethyl 1- (5) - ((3methoxy-2- phosphonoznetoxijpropyl] wacilo</td>

<td> 402</td><td>2,6 dumainoputin -9-tlo</td><td>octadecyloxyethyl</td><td>naphthyl</td><td>Naphthyl octadecyloxyethyl 9- (5) - ((3m "oxy-2-phosph &lt;mon" toxi) propyl] 2,6diaminopurin</td>

<td> 403</td><td>guanin-9-Üo</td><td>hexadacúoxypropyl</td><td>naphthyl</td><td>naphthyl hexadecyloxypropyl 9- (5) - ((4methoxy-2- phosphonomatoxOpropylJpianine</td>

<td> 404</td><td>adenin-9-yl</td><td>hexadecyloxypropyl</td><td>naphthyl</td><td>naphthyl haxadecÜox ^ ropiio 4- {4&gt; ((4matoxi-2- fo s fo nomethoxy) prcipyl] «i» nina</td>

<td> 405</td><td>cttosin-l-ílo</td><td>hexadecyloxyprop do</td><td>naphthyl</td><td>naphthyl hexadecyloxypropyl 1- (5) - ((3mctoxy-2- fo sfonom «toxi) prcpilo] citosfti *</td>

<td> 406</td><td></td><td>hexadedlowropyl</td><td>naphthyl</td><td>naphthyl haxadeexoxypropyl 1- (5) - ((3matoxy-2 -fo sfonon »toxi) propyl] tiniine</td>

<td colspan="5">^BMuc®Muc («&gt; O ^BWuc®Nu «(·) 0 ^BMw &lt;Ai «(·) θ_or k ^ O ^ PO-UL ₀ l ^ O ^ POL / L · HjC-O-¹ HjC-O- 'Η, Ο-Ο ^ ^-WR· Rp or Sp (depends on susBuvenfe faith) Rp. S¡p (racemic)</td>

<td>Coapsito Me.</td><td></td><td>LL *</td><td>RZR '</td><td>Name</td>

<td> 407</td><td>oracil-l-ilo</td><td>hexadecyloxypropyl</td><td>naphthyl</td><td>naphthyl bexodecyloxtproptlo 1- (5) - ((3methoxy-2- fostonomethoxy) propyl] uracil</td>

<td> 408</td><td>2,4dtaxntnopurin -9-flo</td><td>hexadecyloxypropyl</td><td>naphthyl</td><td>naphthyl hexadetyloxypropyl 9- (5) - ((3methoxy-2-fos phonomatoxy) propyl] 2 ^ * ·</td>

<td> 409</td><td>guxnin-9-ilo</td><td>1 -O-octadecyl-2-Obenzyl-; n glyceryl</td><td>naphthyl</td><td>Naphthyl 1-O-octadectlo-l-ó-Venceo · ®¹»Glyceryl 9- (S) - ((3-inotoxy-2phosphonomethoxy) propyl] guanine</td>

<td> 410</td><td>• denin-9-ilo</td><td>1 -O-octadecyl-2-Obenzyl -s «glyceryl</td><td>naphthyl</td><td>Naphthyl lO-octadecyl-2-O-benzyl-n-glyceryl 9- (S) - [(3-methoxy-2-phosphonomethoxy) pr0ptlo] adenine</td>

<td> 411</td><td>cytosiB-1-flo</td><td>1 -O-octadecyl-2-Obenzyl-jn glyceryl</td><td>naphthyl</td><td>naphthyl l-0-octad «üo-2-0-benzyl &lt;n glyceryl 1 - (5) - ((3-njethoxy-2fbs phonomotoxy) propyl} cttostiia</td>

<td> 412</td><td>timin-l-ilo</td><td>1 -O-octadecyl-2-Obenciio-sn glyceryl</td><td>naphthyl</td><td>naphthyl ld-octadecdo-2-d-bonctio-íH glyceryl l- (5) - [(3-methoxy-2fo s phonomethoxy) pr opyl Jtiinin</td>

<td> 413</td><td>uracil-l-ilo</td><td>1 -O-octedecyl-2-Obenzyl-jn glyceryl</td><td>naphthyl</td><td>naphthyl l-0-octadecyl-2-0-b »ncilo &lt;» glyceryl l- (5) - [(3-nietoxi-2- fos £ onom ^ oxy) prc |&gt; iio] nt »cylo</td>

<td> 414</td><td>2.6 dayminopurm -9-Üo</td><td>1 -O-octadecyl-2 -Obenzyl-ΐ »glyceryl</td><td>naphthyl</td><td>imMo lO-octadecyl-í-O-benzyl-oi glyceryl 9 &lt;5) - [(3-nMrtoxi-2phosphonomet ") prcipyl] 2,6diaminopurin</td>

Table 9. diester compounds (S) -3-hydroii-2-fasfonoinetoiipropyl [(SHXPMP]

<td colspan="5">^BNuc®NucW O BnuJBnwcí ·) O Buag / B ^,} Q k ^ .O ^ P-0-ΙΛ. · l ^^ PO-UL · k ^ O ^ PO-UL · J δ-R / R * ° J O-Rfff ° O '»W HO HO ^MORp or φ (depends on your Susudents) SP (racemic)</td>

<td>CCB] MMS1D w.</td><td></td><td>UL *</td><td>R / R</td><td>Name</td>

<td>41S</td><td>guanin-9-ilo</td><td>octadecyloxyethyl</td><td>naphthyl</td><td>Naphthyl octadecyloxyethyl 9- (5) - ((3-hydroxy-2- phosphonomethoxy) prcptlo] guanine</td>

<td> 416</td><td>adenin-9-yl</td><td>octadecyloxyethyl</td><td>naphthyl</td><td>Naphthyl octadecyloxyethyl 9- (5) - ((3-hydroxy-2- fo * fononaethoxy) propyl] admina</td>

<td colspan="5">0 ° Nu¿^BNuc (») 0“ «« / “νμ ·) 0 k ^ O ^ -O-UL · k &gt;&gt; ^ P - &lt;&gt; ~ UL · k &gt;&gt; ^ PO-Ut · &gt; ¿-WR · ° J OR / R ° J OR / R * HO ^ HO^{X H0}ffyoSp (depends on your SuyeflIes) Rp, Sp (racemic)</td>

<td>Cemputo No.</td><td>Bb &amp; MZ &amp; eM $ ü</td><td>UL *</td><td>R / R *</td><td>It does not open</td>

<td> 417</td><td>cytosin-l-yl</td><td>octadeloxietflo</td><td>naphthyl</td><td>Naphthyl octadecyloxyethyl 1- (5) - ((3-hydroxy-2- phosphonomethoxQpropylJitosine</td>

<td>41S</td><td></td><td></td><td>naphthyl</td><td>Naphthyl octadecyloxyethyl 1- (5) - ((3-hydroxy-2-foifo Donketoxi) prnpdo] tiznion</td>

<td> 419</td><td>uracil-l-ilo</td><td>octadecyloxyethyl</td><td>naphthyl</td><td>Naphthyl octadecyloxyethyl 1- (5) - ((3hydroxt-2- fo s phonomethoxy) propyl] txacil</td>

<td> 420</td><td>2,6disnWQOptttÍQ -9-ilo</td><td>octadecyloxyethyl</td><td>naphthyl</td><td>Naphthyl octadecyloxyethyl 9- (5) - ((3-hydroxy-2-fo rphonometexy) propyl] 2,6-</td>

<td> 421</td><td>geanin-9-ilo</td><td>hexadtcyloxy ipropyl</td><td>naphthyl</td><td>naphthyl hexadecyloxypropyl 9- (5) - ((3- hydroxy-2- fosfonomatoxüprcpilolgnanina</td>

<td> 422</td><td>ad * nin-9-ilo</td><td>hexadecyloxypropyl</td><td>naphthyl</td><td>naftflo haxadecyloxypropyl 9- (5) - ((3- Wro »-2- phosphonoinethoxy) propyl] adanine</td>

<td> 423</td><td>cytosin-l-yl</td><td>hexadecyloxypropyl</td><td>naphthyl</td><td>naphthyl hexadecyloxypropyl 1- (5) - ((3- hydroxy-2- phosphonomMoxQpropylJitosine</td>

<td> 424</td><td>tiniixi-1-ilo</td><td>hexadecyloxypropyl</td><td>naphthyl</td><td>naphthyl hexadecyloxypropyl 1- (5) - ((3-hydroxy-2-phosphonomethox0pn&gt; pyl] timta</td>

<td> 425</td><td>uracil-1-fl.o</td><td>hexadecyloxypropyl</td><td>naphthyl</td><td>naphthyl hexadecyloxypropyl 1- (5) - ((3-hydroxy-2- phosphonomethoxy) propyl] uracil</td>

<td> 426</td><td>2.6- / 3 tam m rt pnr &lt;n -9-ilo</td><td>hexadectloxqiropílo</td><td>naphthyl</td><td>9-(5) - ((3-hydroxt-2-phosphonomethoxy) ptvpeo naphthyl naphthyl_t6disnitiiopwrtQ</td>

<td> 427</td><td>guanin-9-ilo</td><td>1 -O-octsdecyl-2-Obenzyl-m glyceryl</td><td>naphthyl</td><td>Naphthyl lO-octadecyl-2-O-be &amp; cyl-0t glyceryl 9- (5) - ((3-htdroxi-2fo s phonoinethoxy) propyl] guanine</td>

<td> 428</td><td>adenin-9-yl</td><td>1 -O-octadecyl-2-Obonctlo-¿n glyceryl</td><td>naphthyl</td><td>Naphthyl 1-O-octadecyl-2-O-benzylocn glyceryl 9- (S} - ((3-hydroxy-2MfbnonMtoxi) prcpilo Jadonina</td>

<td> 429</td><td>cytosin-l-yl</td><td>1 -O-octadecyl-2-Obenzyl-rn glyceryl</td><td>naphthyl</td><td>Naphthyl lO-octadecyl-2-O-benzylooi glyceryl 1- (5) - [(3-hydroxy-2phosonoxynethoxy) propyl] cytosine</td>

<td> 430</td><td>tunain-l-ilo</td><td>1 -O-octadecyl-2-Obenzyl-rn glyceryl</td><td>naphthyl</td><td>naphthyl lO-octadecyl-2-O-bendlo-ot gliearyl l- (5) - [(3-hydroxy-2fostoMynetoxy) propyl] thiinine</td>

<td> 431</td><td>uracii-l-ilo</td><td>1 -O-octadecyl-2-Obenzyl-m glyceryl</td><td>naphthyl</td><td>naphthyl l- &lt;9-octadecyl-2-0-benzyl-fK glyceryl l- (5) - ((3-hydroxy-2fo s phonomethoxy) propyl] uracil</td>

<td colspan="5">B | Ju &lt;/ Bhuc (·) 0 Bn »k / ®Huc (·) 0 ^BNu ^ ®Mu € (·) or ^ χΟχχΡ-Ο-ΙΛ. · l ^ O ^ PO-UL * l ^ O ^ PO-UL · J Ó-R / R * ° J O-WR * ° ¿Ο - »* HO HO ^H0Rp or Sp (depends on »substituents) Φ. Sp (racérmco)</td>

<td>COBJMMSto Ne.</td><td></td><td>LL *</td><td>R® *</td><td>Name</td>

<td> 432</td><td>2.6diaiaiiiopurtii -9-ilo</td><td>1 -O-octedeetlo-2-0benctlo-sn ¿icerilo</td><td>naphthyl</td><td>naftib lO-octadecyl-2-O-benzyl-sn, ie 9- (5) - ((3-hydroxy -2phosphonomic «toxi) prcpyl] 2,6diaminopurin</td>

Table 10. (S) -34taoro-2-phosphoiM diester compounds&gt; metox4&gt; clothes ((SJ-fPMPJ

<td colspan="5">^BNu &lt;/^BNuc (a) O ^BNu &lt;/^BNuc (a) 0 ^BNuc^{/ B}Nuc (·) 0 k ^ O ^ PO-ΙΛ · k ^ O ^ PO-UL · k ^ O ^ PO-LA._FJ Ó-R / R · ° _FJ AR / R * ° _FJ OR / R * Rp or Sp (depends on substituents) Rp, S¡p (taoéwmoo)</td>

<td>COBJMHBto</td><td></td><td>ΙΛ *</td><td>R® *</td><td>Name</td>

<td> 433</td><td>guanin-9-ilo</td><td>octadacyloxyethyl</td><td>naftüo</td><td>oaftfflo octadecüoxMlo 9- (5) - ((3fluoro-2- phosphonomethoxy) propyl] guano</td>

<td> 434</td><td>adanin-9-Üo</td><td>octadecyloxyethyl</td><td>nañilo</td><td>Naphthyl octadecyloxyethyl 9- (5) - ((3fiaoro-2- fosfoQomMoxí) pr &lt;g&gt; tlo] * dKmna</td>

<td> 435</td><td>cytosin-1-yl</td><td>octadecyloxyethyl</td><td>uaphthyl</td><td>Naphthyl octadKiloxMilo 1- (5) - ((3ll &lt;xo * 3 * fosio &amp; omitoxi) pf &lt;3püo) quotes! aa</td>

<td> 43«</td><td>timin-l-üo</td><td>octad «ciloxi« tüo</td><td>aaftil</td><td>Naphthyl octadecyloxyethyl l- (S) - [C3-fluor -2-phosphonemethoxy) propyl} timink</td>

<td> 437</td><td>ur * cil-l-tlo</td><td>octedectloxyethyl</td><td>naphthyl</td><td>Naphthyl octadecyloxytetuo l- (5) - ((3fluoro-2-fo ^ onomethoxOpinptb] utvflo</td>

<td> 438</td><td>2,6dtsmiaoptuin -9-flo</td><td>octadecyloxyethyl</td><td>naphthyl</td><td>Naphthyl octadscyloxyethyl 9- (5) - ((3fluoro-2-phosphonomethoxt) propyl] 2, «diaminopurin</td>

<td> 439</td><td>guantn-9-ilo</td><td>hexadecdoxtpropüo</td><td>naftlo</td><td>naphthyl hexadecyloxypropyl 9- (5) - ((4ñeoro-2- fosfonom «to») pr «pylo] giianina</td>

<td> 440</td><td>• dMtia-9-ilo</td><td>hextdecyloxypropyl</td><td>nattil</td><td>naphthyl liexadectlox ^ roptlo 9- (3) - ((3fluoro-2- phosphonomonoxy) prqpyl] * denine</td>

<td> 441</td><td>citosin-l-üo</td><td>hexadrhoxypropyl</td><td>naphthyl</td><td>naphthyl hexndecfloxypropylo 1- (5) - ((3ftnoro-2- fo sfonometo ») propyl] cytosine</td>

<td> 442</td><td>timin-l-ilo</td><td>h «x * deciloxypropyl</td><td>naphthyl</td><td>naphthyl hexadecyloxypropyl 1- (S&gt; [(3fluoro -2-fo sphonomethoxy) ptop tlo] timin *</td>

<td> 443</td><td>urecil-l-yl</td><td>lithoxypropyl</td><td>naphthyl</td><td>naphthyl hexachopropyl 1- (5) - ((3fliioro -2-phosphonoznetogu) wptlohmolo</td>

<td colspan="5">Bnw / Bnucí ·) O ^BNuc®Nuc (·) or ®Nuc®Nmc (») 0 k ^ O ^ PO-UL · l ^ O ^ PO-UL * k ^ O ^ PO-UL *_FJ Ó-R / R * ° ¿-WR · ° _FJ OR / R * Rp or (depends on the susfitoyenles) Rp, (racemic)</td>

<td>ccapwto Do not.</td><td>ΒΝμ / ΒΝικ (·}</td><td>LL '</td><td>R'R *</td><td>Name</td>

<td> 444</td><td>2,6-diaminopurtxi -9-yl</td><td>bexadecyloxypropyl</td><td>naphthyl</td><td>naM® hexadecyloxypropyl 9- (5) - ((3flaoro-2 -fo sphonomethoxy) pfopyl] 2,6-</td>

<td> 445</td><td>g »artín» Q -¿1 ©</td><td>1 -O-octadacyl-2 ~ O ~ benzyl-sn glyceryl</td><td>naphthyl</td><td>Naphthyl lO-octadecyl-lO-benzyl-ips Glyceryl 9- (5) - ((3-fluoro-2fo s fonomethoxy) prcpyl] gu * nixia</td>

<td> 446</td><td>adanin-9-tlo</td><td>10-octedecyl-2-obenciloot glyceryl</td><td>naphthyl</td><td>Naphthyl lO-octadacyl-Z-Ó-benzyl-et glyceryl 9- (5) - ((3-fiuoro-2fo s fonometoxijpr opilo jadtnina</td>

<td> 447</td><td>cytosin-l-yl</td><td>1 -O-octadecyl-2-Obenctlo- ^ t glyceryl</td><td>aañflo</td><td>Naphthyl L-0-octadecyl-2-0-benzyl-en glyceryl l- (5) - ((3-ñuoro-2fo s fonomethoxy) prcp ilo jeitos ina</td>

<td> 448</td><td>tonin-l-ilo</td><td>1 -O-octadecílo-2-Obencilo-0i idícerilo</td><td>naphthyl</td><td>Naphthyl lO-octadecyl-2-O-benzyl-in glyceryl l- (S) - ((3-fluoro-2phosphonomethoxQprcpÜojtimim</td>

<td> 449</td><td>uracil-l-üo</td><td>l -O-octadecüo-2-Obencilo -sn gjicerilo</td><td>naphthyl</td><td>naphthyl lO-octedm ^ o-2-Ü-benzyl-cM glyceryl 1- (5) - ((3-fluoro-2fos fonomtfo ») prcpilo] uracil</td>

<td> 450</td><td>2,6 diinxiaopuna -9-yl</td><td>1 -O-octadecflo-2-Obencüo-SM glyceryl</td><td>naphthyl</td><td>naphthyl lO-octadecyl-2-O-benzyl-cM fícenlo 9- (5) - ((3-fluoro-2fo s fonomethoxy) prcpyl} 2,6disxiiiiiopuíiii</td>

Specific compounds contemplated herein include;

O l ^ /^OR^ PO (CH₂hO (CH₂)₁₇CH3

OR

Λ »tsopropiiden glycerol octadecyloxyethyl

9 ¿2- (phosphonomethoxy) ethyl] guanine

<img file="MX367403B_D0064.tif" />

<img file="MX367403B_D0065.tif" />

OH glyceryl octadecyloxyethyl

9- [2- (phosphonomethoxy) ethyl] guanine

<img file="MX367403B_D0066.tif" />

<img file="MX367403B_D0067.tif" />

<img file="MX367403B_D0068.tif" />

<img file="MX367403B_D0069.tif" />

mannosyl octadecyloxyethyl

<img file="MX367403B_D0070.tif" />

benzyl odadecyloxyeto

9 ^ R&gt; [3-methoxy-2- (phosforKxnetoxt) propyl] guanma

<img file="MX367403B_D0071.tif" />

NH?

<img file="MX367403B_D0072.tif" />

Octadecyloxyethyl Phenyl

9- (RH3-methoxy-2- (phosphonomethoxy) propyl guanine phenyl hexadecyloxypropyl

9- (R) - [3-fluoro-2- (phosphonorhethoxy) propyl] adenine

III. Methods of Use

In another aspect, a method of treatment for viral diseases in a subject is provided. The method includes the administration, to a subject that requires it, of a therapeutically effective amount of a compound with the structure of any of the Formulas (I), (1-1), (1-2), (1- 3), (1-4), (I5) and / or (the). In some modalities, L / L^to of any of the Formulas (I), (1-1), (1-2), (1-3), (1-4), (1-5) and / or (la) are a lipophilic carrier.

Exemplary viral diseases include human papillomavirus, HIV, hepatitis B virus, hepatitis C virus, variola virus (smallpox), vaccine virus, an adenovirus, cytomegalovirus (CMV), herpes simplex virus, Epstein Barr virus, BK virus, JC virus, any of the double stranded DNA viruses, feline leukemia virus, feline immunodeficiency virus and the like. A therapeutically effective amount of a compound of the Formula (I) can be administered to a human or mammal that requires treatment against a viral disease.

In some embodiments, the compound is administered by a route (topical, intravitreal, oral, intravenous, etc.), which results in the delivery of an amount sufficient to inhibit virus replication. In some embodiments, the compound can be administered topically. For example, the compound can be administered topically in the form of a cream, a gel or an ointment.

In another aspect, a method of treatment is provided for a disease or disorder in a subject that requires it, the method includes administration to a subject that requires it in a therapeutically effective amount of a compound with the structure of any of the Formulas (I), (I-1), (1-2), (I3), (1-4), (1-5) and / or (la). Aspects for the treatment against cancer and other neoplastic disorders contemplated herein are based on the surprising discovery that the compounds of Formulas (I) and / or (la) are effective in the

<img file="MX367403B_D0073.tif" />

death or growth inhibition of cells transformed by human papillomavirus (HPV), for example cervical cancer cells and lesions caused by cervical intraepithelial neoplasia (CIN). Consequently, a therapeutically effective amount of a compound of Formula (I), (I-1), (1-2), (1-3), (1-4), (1-5) and / or (la) can be administered by the appropriate route (topical, oral, intravenous, etc.) to eliminate or inhibit the growth of infected or transformed cells. Cells are transformed by another type of virus, such as herpes simplex virus type 2 (HSV-2), can also be treated with a compound of Formula (I), (I1), (1-2), (1- 3), (1-4), (1-5) and / or (the).

In another aspect, a method of treatment is provided for a subject suffering from cancer. The method includes the administration to a subject that requires a therapeutically effective amount of a compound with the structure of any of the Formulas (I), (1-1), (1-2), (1-3) , (1-4), (1-5) and / or (la). In some modalities, L / L^to of any of Formulas (I), (1-1), (1-2), (1-3), (1-4), (1-5) and / or (la) corresponds to a lipophilic carrier.

In some modalities, cancer corresponds to leukemia, carcinoma and / or sarcoma, such as cancer of the brain, breast, cervical, colon, pancreas, head and neck, liver, kidney, lung, non-small cell carcinoma, prostate, melanoma , mesothelioma, ovary, sarcoma, stomach, uterus and / or medulloblastoma.

<img file="MX367403B_D0074.tif" />

Additional examples include Hodgkin's disease, non-Hodgkin's lymphoma, multiple myeloma, neuroblastoma, ovarian cancer, rhabdomyosarcoma, essential thrombocytosis, primary macroglobulinemia, primary brain tumors, malignant pancreatic insulanoma, malignant carcinoid, urinary bladder cancer, dermatological premalignant lesions, testicular cancer, lymphomas, thyroid cancer, neuroblastoma, esophageal cancer, urinary tract cancer, malignant hypercalcemia, endometrial cancer, adenocarcinoma cancer and endocrine and exocrine pancreas neoplasms. In some modalities, the cancer corresponds to liver cancer, colon cancer, breast cancer, melanoma, acute myeloid leukemia, chronic myeloid leukemia and / or non-small cell lung carcinoma.

In another aspect, a method for the treatment of a proliferative disorder in a subject is provided. The method includes the administration to a subject that requires a therapeutically effective amount of a compound with the structure of any of the Formulas (I), (I-1), (1-2), (I3), ( 1-4), (1-5) and / or (la). Proliferative disorder can be caused by the human papillomavirus. Exemplary proliferative disorders include, for example, cervical intraepithelial neoplasia (NIC), vulvar intraepithelial neoplasia (NIV), anal intraepithelial neoplasia (NIA) or penile and venereal warts. In some modalities, L / L^to of any of the Formulas (I), (1-1), (1-2), (1-3), (1-4), (1-5) and / or (la) corresponds to a lipophilic carrier.

In another aspect, a method is provided to kill or inhibit the growth of a transformed cell. The method includes contacting a transformed cell with a therapeutically effective amount of a compound of any of Formulas (I), (1-1), (1-2), (1-3), (1-4 ), (1-5) and / or (the).

In another aspect, a compound of the Formula (la) or an embodiment thereof or a pharmaceutically acceptable salt, hydride, solvate or crystalline form is provided for use in the treatment of a viral disease in a subject, in where viral disease can be selected from human papillomavirus (HPV), HIV, hepatitis B virus, hepatitis C virus, variola virus, vaccine virus, adenovirus, cytomegalovirus, herpes simplex virus type 1, herpes simplex virus type 2, Epstein Barr virus, BK virus, JC virus, feline leukemia virus and feline immunodeficiency virus.

In some modalities, the virus may correspond to the human papillomavirus. According to the CDC, HPV is the most common sexually transmitted infection (STD). HPV viruses can be classified into HPV of mucosa and skin. Within each of these groups, individual viruses are referred to as high risk or low risk. More than 40 types of HPV can infect the genital areas of men and women, and several types of HPV can infect the mouth and throat. In addition, HPV is the most common cause of cervical cancer. Other types of HPV include, but are not limited to, 2, 3, 4, 5, 6, 8, 11, 16, 18, 31,

<img file="MX367403B_D0075.tif" />

33, 35, 39, 45, 51, 52, 56, 58, 59, 63, 66, 68, 69 and 82. In some embodiments, the use results for the treatment of a plurality of human papillomavirus types, by example, the types described herein. In some 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 some embodiments, the human papillomavirus can be selected from human papillomavirus type 11, type 16 and type 18.

In another aspect, the use of a compound of the Formula (la) or a modality thereof or a pharmaceutically acceptable salt, hydride, solvate or crystalline form thereof is provided in the preparation of a medicament for the treatment they turn against a disease in a subject, where the viral disease can be selected from human papillomavirus, HIV, hepatitis B virus, hepatitis C virus, variola virus, vaccine virus, an adenovirus, a cytomegalovirus, herpes simplex virus type 1, herpes simplex virus type 2, Epstein Barr virus, BK virus, JC virus, feline leukemia virus and feline immunodeficiency virus.

In some modalities, the virus may correspond to the human papillomavirus. In some embodiments, the use corresponds to treatment against a plurality of human papillomavirus types, for example, the types described herein. In some modalities, the use corresponds to more than 2 types of HPV, more than 5 types of HPV or more than 10 types of HPV.

<img file="MX367403B_D0076.tif" />

HPV In some embodiments, the human papillomavirus can be selected from human papillomavirus type 11, type 16 and type 18.

In another aspect, a method of treatment is provided to a subject with a viral disease. The method includes the administration to a subject with a viral disease, which requires an effective amount of a compound of the Formula (la) or a modality thereof, or an acceptable salt, hydride, solvate or crystalline form of Pharmaceutical manner thereof, wherein the viral disease can be selected from human papillomavirus, HIV, hepatitis B virus, hepatitis C virus, variola virus, vaccine virus, an adenovirus, a cytomegalovirus, herpes simplex virus type 1, herpes simplex virus type 2, Epstein Barr virus, BK virus, JC virus, feline leukemia virus and feline immunodeficiency virus, thereby treating viral disease.

In another aspect, a compound of Formula (la) or modality thereof, or a pharmaceutically acceptable salt, hydride, solvate or crystalline form thereof is provided for use in the treatment of cervical cancer in a subject. In some embodiments, cervical cancer can be caused by an HPV infection, for example, a type 16 HPV infection.

In another aspect, the use of a compound of the Formula (the) or modality thereof, or a pharmaceutically acceptable salt, hydride, solvate or crystalline form thereof, is provided in the preparation of a medicament for the treatment against cervical cancer in a subject. In some embodiments, cervical cancer can be caused by an HPV infection, for example, a type 16 HPV infection.

In another aspect, a method of treating a subject with cervical cancer is provided. The method includes the administration of an effective amount of a compound of the Formula (la) or a modality thereof, or a pharmaceutically acceptable salt, hydride, solvate or crystalline form thereof, thereby treating the subject with cancer. cervical In some modalities cervical cancer can be caused by an HPV infection, for example, a type 16 HPV infection.

In another aspect, there is provided a compound of Formula (la) or modality thereof, or a pharmaceutically acceptable salt, hydride, solvate or crystalline form thereof, for use in inhibiting the growth of a cell transformed by a virus. , where the virus can be selected from human papillomavirus, HIV, hepatitis B virus, hepatitis C virus, variola virus, vaccine virus, adenovirus, cytomegalovirus, herpes simplex virus type 1, herpes simplex virus type 2, Epstein Barr virus, BK virus, JC virus, feline leukemia virus and feline immunodeficiency virus.

In another aspect, the use of a compound of the Formula (the) or modality thereof, or a pharmaceutically acceptable salt, hydride, solvate or crystalline form thereof, is provided in the preparation of a medicament for inhibiting growth. of a cell transformed by a virus, where the virus can be selected from human papillomavirus, HIV, hepatitis B virus, hepatitis C virus, variola virus, vaccine virus, an adenovirus, a cytomegalovirus, herpes simplex virus type 1, herpes simplex virus type 2, Epstein Barr virus, BK virus, JC virus, feline leukemia virus and feline immunodeficiency virus.

In another aspect, a method for inhibiting the growth of a cell transformed by a virus is provided. The method includes contacting a compound of Formula (la) or modality thereof, or a pharmaceutically acceptable salt, hydride, solvate or crystalline form thereof, with a cell transformed by a virus, wherein the virus can be selected. among human papillomavirus, HIV, hepatitis B virus, hepatitis C virus, variola virus, vaccine virus, an adenovirus, a cytomegalovirus, herpes simplex virus type 1, herpes simplex virus type 2, Epstein Barr virus, BK virus, JC virus, feline leukemia virus and feline immunodeficiency virus, thereby inhibiting the growth of the cell transformed by a virus.

IV. Synthesis methods

In another aspect, a method is provided for the synthesis of the compounds of Formula (I), as illustrated in Scheme 1 presented below. For Scheme 1, the substituents Bnuc, X, R and L are described herein for Formula (I).

In another aspect, a method is provided for the synthesis of the compounds of the Formula (la), as illustrated in the Scheme presented below. For Scheme 1, substituents B_Nuc (a), X^to, R^to and L^to are described herein for Formula (la).

The method includes the reaction of an ANP monoester suitably substituted with R-OH or R^to-OH in the presence of a coupling agent such as (benzotriazol-l-yloxy) -tripyrrolidinophosphonium hexafluorophosphate (PYBOP®) to generate a diester. Methods for the preparation of ANP monoesters are widely known. For example, see Beadle, J. R et al. Journal of Medicinal Chemistry, 2006, 49: 2010-2015 and Valiaeva, N. et al. Antiviral Research, 2006, 72: 10-19. The use of PYBOP® for the synthesis of phosphonate diesters was first described in Campagne, JM. et al. Tetrahedron Letters, 1993, 34: 6743-6744. Other coupling or condensing reagents, for example uronic, carbodiimide, imidazolium and hydrochloric acid reagents, can also be used (for a review of the coupling agents see, for example, El-Faham, A. &amp; Albericio, F. Chemical Reviews , 2011, 111: 6557-6602).

Scheme 1

<img file="MX367403B_D0077.tif" />

Scheme the

<img file="MX367403B_D0078.tif" />

In another aspect, a method for the synthesis of compounds of Formula (I) is provided. The method includes the steps presented below in Scheme 2:

<img file="MX367403B_D0079.tif" />

Scheme 2

<img file="MX367403B_D0080.tif" />

In the method of Scheme 2, Bnuc corresponds to a naturally occurring purine or pyrimidine base, or an analogue thereof; L results in a lipophilic carrier, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, or an O- substituted glyceryl of the formula -CH₂CH (OR¹) -CH₂ (OR²) (II), where R¹ and R² correspond independently to substituted or unsubstituted alkyl, or substituted or unsubstituted aryl; R corresponds to a substituted or unsubstituted lower alkyl, a substituted or unsubstituted lower heteroalkyl, a substituted or unsubstituted lower cycloalkyl, a substituted or unsubstituted lower heterocycloalkyl, a substituted or unsubstituted aryl or a lower heteroaryl substituted or unsubstituted; X corresponds to hydrogen, substituted or unsubstituted lower alkyl or substituted or unsubstituted lower heteroalkyl; as well, and corresponds to an outgoing group.

The method includes 1) the contact of a protected nucleoside Bnuc with structure of Formula (2-1) with an ester with structure

<img file="MX367403B_D0081.tif" />

of the Formula (2-2) in the presence of a strong base under the appropriate conditions to generate a monoester with a structure of the Formula (2-3) with L-OH in the presence of a coupling agent as is known in the art , thereby synthesizing a compound with structure of Formula (I).

In another aspect, a method is provided for the synthesis of compounds of the Formula (la). The method includes the following as provided in Scheme 2a. For Scheme 2^to, the substituents Bnucoiz X^to, R^to and L^to result as described for Formula (la) herein and Y^to It can correspond to an outgoing group.

Scheme 2a

<img file="MX367403B_D0082.tif" />

<img file="MX367403B_D0083.tif" />

LMDH --------- »» Coupling Agent

<img file="MX367403B_D0084.tif" />

The method includes:

1) the contact of a protected nucleoside

Bnuco) with structure of Formula (2-la) with an ester with structure of Formula (2-2a) in the presence of a strong base under suitable conditions to generate a monoester with the structure of Formula (2-3a) with L^to-OH in the presence of a coupling agent as is known in the art, thereby synthesizing a compound with structure of the Formula (la).

In some embodiments, the method includes the steps presented below in Scheme 2-1, specifically, the contact of a protected nucleoside (general structure 2-1 where Bnuc corresponds to a naturally occurring purine or pyrimidine base, with a ester of general structure 2-2 (where Ϊ corresponds to a leaving group such as p-toluenesulfonyl, methanesulfonyl, trifluoromethanesulfonyl, bromine, iodine or the like) in the presence of a strong base and a suitable solvent producing ANP 2-3 monoesters with L-OH (i.e., hydroxy form of L) in the presence of a coupling agent such as PYBOP® to generate a diester of Formula (I)

Scheme 2-1

<img file="MX367403B_D0085.tif" />

<img file="MX367403B_D0086.tif" />

In another aspect, a method is provided for the synthesis of a compound with structure of Formula (I) according to Scheme 2-1. B_Nuc, X, R and L are described for Formula (I) herein and may correspond to a leaving group; said method comprises: the contact of a compound of the Formula (2-1) containing a B_Nuc protected with a compound of the Formula (2-2) in the presence of a strong base to form a compound of Formula (2-3); and the reaction of the compound of Formula (2-3) with L-OH in the presence of a coupling agent to form the compound of Formula (I).

2-la scheme

<img file="MX367403B_D0087.tif" />

In another aspect, a method is provided for the synthesis of a compound with the structure of Formula (la) according to Scheme 2-la.

For this method, B_NuC(a) may correspond to

<img file="MX367403B_D0088.tif" />

a naturally occurring purine, a naturally occurring pyrimidine, an unnaturally occurring purine or an unnaturally occurring pyrimidine; L^to it may correspond to an unsubstituted C12-24 alkyl, an unsubstituted C13-29 heteroalkyl or a substituted glyceryl fraction, wherein the glyceryl fraction may be substituted with one or more groups selected from an unsubstituted C13-29 alkyl, a heteroalkyl C13-29 unsubstituted, a substituted or unsubstituted aryl (Ci-s alkyl), a substituted or unsubstituted heteroaryl (Ci-β alkyl) and a substituted or unsubstituted heterocycloalkyl (Ci-e alkyl); R^toit can be selected from Ci-β alkyl, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl (Ci-e alkyl), a substituted or unsubstituted heteroaryl (alkyl Ci-δ) and a substituted or unsubstituted heterocycloalkyl (Ci-β alkyl); X^to it may correspond to hydrogen, an unsubstituted C1-6 alkyl, a halogen substituted C1-6 alkyl, a hydroxy substituted C1-6 alkyl or an unsubstituted C1-6 alkoxy; as well as, and^to may correspond to an outgoing group; said method comprises: the contact of a compound of Formula (2la) containing a B_WILDEBEESTc (a) protected with a compound of the Formula (2-2a) in the presence of a strong base to form a compound of the Formula (2-3a); as well as, the reaction of the compound of Formula (2-3) with L^to-OH in the presence of a coupling agent to form the compound of the Formula (la).

100

<img file="MX367403B_D0089.tif" />

In another aspect, a method is provided for synthesizing a compound of Formula (I) as described in 3, shown below. For Scheme 3, substituents B_Nuc, X, R and L correspond to the description for Formula (I) of this document.

Scheme 3

Bnuc

<img file="MX367403B_D0090.tif" />

I

3-2

The method includes the contact of an appropriately protected nucleoside (general structure 3-1 where Bn_uc corresponds to a purified or naturally occurring Purine or pyrimidine base), with a diester of general structure 3-2 (where Y corresponds to a leaving group such as ptoluenesulfonyl, methanesulfonyl, trifluoromethanesulfonyl, bromine, iodine or the like) in the presence of a strong base and a suitable solvent to produce a compound of Formula (I).

In another aspect, a method for synthesizing a compound of Formula (la) is provided as described in Scheme 3a.

For Scheme 3a, the substituents BNuc (a), X^to, R^to and L^to they turn out

101 as described for Formula (la) of the present and Y^tocorresponds to an outgoing group.

Scheme 3rd strong base

HgC _IM. »P ..... Q ya O — R» 3-2a

The method includes contact of a suitably protected nucleoside (3-la), with a 3-2 diester (where Y^to corresponds to a leaving group such as p-toluenesulfonyl, methanesulfonyl, trifluoromethanesulfonyl, bromine, iodine or the like) in the presence of a strong base and a suitable solvent to produce a compound of Formula (la).

V. Pharmaceutical compositions

In another aspect, pharmaceutical compositions are provided, including a compound of Formula (I) and / or a compound of Formula (la) in combination with a pharmaceutically acceptable excipient (eg, the carrier).

The terms pharmaceutically acceptable carrier, pharmaceutically acceptable excipient and

102

<img file="MX367403B_D0091.tif" />

The like are used herein to refer to pharmaceutical excipients, for example, pharmaceutically or physiologically acceptable inorganic or organic carrier substances suitable for enteral or parenteral application that do not react harmfully with the active agent. Suitable pharmaceutically acceptable carriers include water, saline solutions (such as Ringer's solution), alcohols, oils, jellies and carbohydrates such as lactose, amylose or starch, fatty acid esters, hydroxymethylcellulose and polyvinyl pyrrolidine. Said preparations can be sterilized and, if desired, mixed with auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts to influence osmotic pressure, aggregates, dyes and / or aromatic substances, among others, which do not react harmfully. with the compounds described herein.

The compounds described herein can be administered alone or together to the subject. The joint administration is intended to include simultaneous or sequential administration of the compounds individually or in combination (more than one compound). The preparations can also be combined, when desired, with other active substances (for example, to reduce metabolic degradation).

A. Formulations

103

The compounds described herein can be prepared and administered in a wide variety of oral, parenteral and topical dosage forms. Accordingly, the compounds described herein can be administered via injection (for example, intravenously, intramuscularly, intracutaneously, subcutaneously, intraduodenally or intraperitoneally). Also, the compounds described herein can be administered by inhalation for example, intranasally. In addition, the compounds described herein can be administered transdermally. It is also conceived that multiple routes of administration (eg, intramuscular, oral, transdermal) can be used to administer the compounds described herein. Therefore, the pharmaceutical compositions comprise a pharmaceutically acceptable carrier or excipient and one or more compounds are contemplated.

To prepare the pharmaceutical compositions, pharmaceutically acceptable carriers can be in solid or liquid form. Solid form preparations include powders, tablets, pills, pills, suppositories and dispersed granules. A solid carrier may correspond to one or more substances that can also act as diluents, flavoring agents, binders, preservatives, tablet disintegrating agents or an encapsulating material.

In powders, the transporter corresponds to a divided solid

<img file="MX367403B_D0092.tif" />

104 finely in a mixture with the active component divided equally. In Tablets, the active component is mixed with the carrier that contains the necessary binding properties in suitable proportions and compacted in the desired shape and size.

The powders and tablets preferably contain between 5% and 70% active compound. Magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth gum, methylcellulose, sodium carboxymethylcellulose, a low melting wax , cocoa butter and the like. The term preparation is intended to include the Formulation of the active component with encapsulating material as a carrier, providing a capsule in which, the active component with or without other carriers, is surrounded by a carrier, which is in association with it. Similarly, pills and tablets are included. Tablets, powders, capsules, pills and tablets can be used as solid dose forms for oral administration.

To prepare suppositories, a low melting point wax, such as a mixture of glycerides of the fatty acids or cocoa butter, initially melts and the active component is dispersed homogeneously in the mixture, as for example, when stirred. The homogeneous molten mixture is poured into molds of convenient size, allowed to cool and solidify in this way.

<img file="MX367403B_D0093.tif" />

105

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

When parenteral application is required or desired, particularly suitable mixtures correspond to sterile injectable solutions, preferably aqueous or oily solutions, as well as suspensions, emulsions or implants, including suppositories. In particular, transporters for parenteral administration include aqueous solutions of dextrose, cyclodextrins, physiological serum, pure water, ethanol, glycerol, propylene glycol, peanut oil, sesame oil, polyoxyethylene block polymers and the like. Blisters result in convenient dose units. The compounds described herein can also be incorporated into liposomes or administered via patches or transdermal pumps. Pharmaceutical mixtures suitable for use include those described, for example, in Pharmaceutical Sciences (17th Ed., Mack Pub. Co., Easton, PA) and WO 96/05309, the teachings of both are incorporated herein by reference.

Aqueous solutions suitable for oral use can be prepared by dissolving the active component in water and adding suitable colorants, flavors, stabilizers and / or thickening agents, as desired. Suspensions

<img file="MX367403B_D0094.tif" />

106 Aqueous agents suitable for oral use can be made by dispersing the finely divided active component in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose and other well-known suspending agents.

Also included are solid form preparations that are intended to become, shortly after use, liquid form preparations for oral administration. Such liquid forms include solutions, suspensions and emulsions. These preparations may contain, in addition to the active components, colorants, flavors, aggregates, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents and the like.

The pharmaceutical preparation is preferably in the form of a dose unit. In such form, the preparation is subdivided into dose units containing the appropriate amounts of the active component. The dosage unit form may correspond to a packaged preparation, the package containing discrete amounts of preparation, such as tablets, capsules and packaged powder ampoules or ampoules. Also, the dosage unit form may correspond to a capsule, tablet, pill or tablet itself, or it may correspond to the appropriate number of these in package form. In some embodiments, the dosage unit form may be in the form of a pre-filled applicator with a composition.

<img file="MX367403B_D0095.tif" />

107 Pharmaceutical described herein (for example, a pharmaceutical composition containing an effective amount of a compound of the Formula (I) and / or a compound of the Formula (la)). In some embodiments, the pre-filled applicator can be filled with a pharmaceutical composition in the form of a cream, a gel or an ointment containing the compound described herein (for example, a compound of Formula (I) and / or a compound of Formula (la)).

The amount of active component in a dose unit preparation can be varied or adjusted from 0.1 mg to 10,000 mg, usually 1.0 mg to 1000 mg, more commonly 10 mg to 500 mg, according to the particular application and potency of the components. assets. The composition may, if desired, also contain other compatible therapeutic agents.

Some compounds may have limited solubility in water and therefore require a surfactant or other suitable solvent in the composition. Such solvents include: Polysorbate 20, 60 and 80; Pluronic F-68, F-84 and P-103; cyclodextrin; and polyoxyl 35 castor oil. Such solvents are generally used at a level between about 0.01% and about 2% by weight.

A viscosity higher than that of simple aqueous solutions may be desirable to decrease variability in the administration of the Formulations, to decrease the physical separation of the components of a suspension or emulsion from the Formulation and / or otherwise, improve the Formulation.

108

Such viscosity generating agents include, for example, polyvinyl alcohol, polyvinyl pyrrolidine, methylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, carboxymethylcellulose, hydroxypropylcellulose, chondroitin sulfate and salts thereof, hyaluronic acid and salts thereof; as well as combinations of the above. Such agents are generally employed at a level between about 0.01% and about 2% by weight.

The compositions may also include components to allow sustained release and / or comfort. Such components include high molecular weight, anionic mucomimetic polymers, gelling polysaccharides and finely divided drug carrier substrates. These components are discussed in greater detail in US patents. No. 4,911,920; 5,403,841; 5,212,162; and 4,861,760. The full contents of these patents are incorporated herein by reference in their entirety for all their purposes.

B. Effective doses

Pharmaceutical compositions include compositions wherein the active ingredient is contained in a pharmaceutically effective amount, that is, in an amount effective to achieve its intended purpose. The actual effective amount for a particular application will depend, among other things, on the condition in question. For example, when administered in

109 methods for the treatment against cancer, said compositions will contain an amount of active ingredient effective to achieve the desired result (for example, the decrease of cancer cells in a subject).

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

For any compound described herein, the amount of therapeutically effective can be determined initially by cell culture assays. Therapeutically effective amounts for use in humans can be estimated subsequently with animal models, using conventional techniques that are confirmed or perfected in real clinical trials.

The doses may vary depending on the requirements of the patient and the compound used. The dose administered to a patient should be sufficient to generate a beneficial therapeutic response in the patient as time goes by.

110

-ís ss lioli -7

The dose size will also be determined by the existence, nature and extent of any adverse side effects. Usually, treatment with small doses is initiated, which are lower than the optimal dose of the compound. Subsequently, the dose is gradually increased until the optimum effect is achieved under these circumstances. In one embodiment, the dose range corresponds from 0.001% to 10% P / v. In another embodiment, the dose range is from 0.1% to 5% P / v.

Dosage amounts and ranges can be adjusted individually to provide effective levels of compound administered for the particular clinical indication to be treated. This will provide a therapeutic regimen that is proportional to the severity of the individual's disease status.

Using the teachings provided herein, an effective prophylactic or therapeutic treatment regimen can be planned that does not cause substantial toxicity but remains fully effective in treating the clinical symptoms demonstrated by the particular patient. This planning should involve the careful selection of the active compound when considering factors such as the potency of the compound, the relative bioavailability, the patient's body weight, presence and severity of adverse side effects, preferable mode of administration and the toxicological profile of the chosen agent.

111

C. Toxicity

The relationship between toxicity and the therapeutic effect for a particular compound is known as its therapeutic index and can be expressed as the relationship between LD₅q (the amount of lethal compound for 50% of the population) and EDso (the amount of compound effective for 50% of the population). Compounds that exhibit high therapeutic indices are preferred. The therapeutic index information obtained from cell culture assays and / or animal studies can be used to formulate a range of doses for use in humans. The dose of said compounds preferably falls within a range of plasma concentrations that include ED₅₀ With little or no toxicity. The dose may vary in this range depending on the dose form used and the route of administration used. See, for example, Fingí et al., In: The Pharmacological Basis of Therapeutics, Cap.l, pl, 1975. The specific physician can choose the exact Formulation, the route of administration and the dose they can choose when observing the condition of the patient and the particular method in which the compound is used.

SAW. Examples

General chemical methods: All reagents were of commercial quality, and used for further purification unless otherwise indicated. Chromatographic purification was used with the flash method with silica gel 60 (EMD Chemicals,

112

Inc., 0.063-0.037 mm (230-400 mesh)). The specters^ΧΗ NMR were recorded on a Varian HG spectrophotometer operating at 400 MHz and reported in units of parts per million (ppm) relative to internal tetramethylsilane at 0.00 ppm. Routine electrospray ionization (ESI-MS) mass spectra were recorded on a Finnigan LCQDECA spectrometer and high resolution mass spectra (HRMS) were recorded on an Agilent 6230 exact mass mass spectrometer in negative mode. ESI. The purity of the compounds of interest is characterized by high efficiency liquid chromatography (HPLC) using a Beckman Coulter System Gold chromatography system. The analytical column corresponded to FENOMENEX® SYNERGI ™ Polar-RP (4.6 x 150 mm) equipped with a SECURITYGUARD ™ protection column. Mobile phase A corresponded to 95% water / 5% methanol and mobile phase B corresponded to 95% methanol / 5% water. Isocratic elution was used at a flow rate of 0.8 mL / min. Compounds were detected by absorption of ultraviolet (UV) light at 274 nm. The homogeneity of the compounds of interest was also confirmed by means of a thin layer chromatography (TLC) using Gtech Analtech silica gel plates (250 pm) and the solvent system: CHCla / MeOH / with NH4OH / H2O (70: 30: 3: 3 v / v). The results of the CCF were visible 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-ODE113

PMEG).

H₂N

<img file="MX367403B_D0096.tif" />

Do not

Q JO (CH2) 2O (CH2)₁₇CH3

X / I

OH

ODE-PMEG h₂n

<img file="MX367403B_D0097.tif" />

<img file="MX367403B_D0098.tif" />

benzyl alcohol

PyBOP, DIEA, NN-OMF 62% produced

OR

L ^_/OR_{x /}F'-O (CH₂)₂O (CH₂)_{1 ?}ch₃ or

Bn-ODE-PMEG

<img file="MX367403B_D0099.tif" />

To 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-l-yloxy) tripyrrolidinophosphonium hexafluorophosphate (PYBOP®, 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) my, 1.4 mmol). 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, then the silica gel absorbed the residue and purified with flash column chromatography. Elution with CHzC ^ / MeOH (0-5%) generated 0.15 g (62%) of Compound 1 as a white powder.¹H NMR (CDCls / methanold₄) δ 7.56 (s, 1 H); 7.35-7.40 (m, 5H); 5.08 (dd, J = 9Hz, Jl = 2Hz,

2H); 4.19 (t, J = 7Hz, 2H); 4.09-4.17 (m, 2H); 3.87 (t, J = 5Hz, 2H),

114

3.85 (dd, J = 8Hz, Jl = 2Hz, 2H); 3.57 (t, J = 5Hz, 2H); 3.44 (t, J = 7Hz, 2H); 1.50-1.60 (m, 2H); 1.20-1.38 (m, 30H); 0.89 (t, J = 7Hz, 3H). MS (El): 676.34 (M + H)⁺, 698.41 (M + Na)⁺.

Example 2

Resolution of benzyl octadecyloxyethyl 9- [2 (phosphonomethoxy) ethyl] guanine chiral entantiomers P.

<img file="MX367403B_D0100.tif" />

Preparative HPLC

Lux Cellulose-1, reverse phase

<img file="MX367403B_D0101.tif" />

<img file="MX367403B_D0102.tif" />

The Bn-ODE-PMEG of Example 1 was obtained as a mixture of enantiomers due to phosphorus chirality. The enantiomers were separated on a Lux ™ Cellulose-1 column (Fenomenex®, Torrance, CA, USA) using inverted phase conditions (mobile phase 50: 50: 0.1 20mM AmmAc: AcN: TEA). The absolute stereochemistry of the chiral P enantiomers was not determined. The preparative chromatographic resolution of the material obtained in Example 1 provided two enantiomers that are characterized as the (fast elution enantiomer) and Ib (elution enantiomer

115

<img file="MX367403B_D0103.tif" />

slow). A chromatogram is provided as an example in Fig. 1.

In the examples presented below, the preparation of a racemic mixture is described, however, the method of Example 2 or modifications thereof known in the art can be used to resolve each into optically active enantiomers or diastomers as required.

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

<img file="MX367403B_D0104.tif" />

benzyl alcohol

PyBOP, DEA. Ν, Ν-DMF 50% produced

<img file="MX367403B_D0105.tif" />

To a solution of octadecyloxyethyl 9- [2- (phosphonomethoxy) ethyl] adenine (ODE PMEA) [prepared according to: Valiaeva, N. et al. ñntiviral Research 2006, 72: 10-19] (0.2 g, 0.35 mmol), (benzotriazol-l-yloxy) -tripyrrolidinophosphonium hexafluorophosphate (PYBOP®, 0.27 g, 0.525 mmol), anhydrous benzyl alcohol (0.05 mi, 0.525 mmol) was added ) in dry N, N-DMF, diisopropylethylamine (DIEA, 0.24 ml, 1.4 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 washed with a saturated sodium bicarbonate solution (2 x 10 ml). The ethyl acetate layer was evaporated, then the residue was purified with silica gel column chromatography using

<img file="MX367403B_D0106.tif" />

116

CH2C12 / MeOH (0-5%) to generate 0.12 g (50%) of compound 2. ^XH NMR (CDCl₃/ methanol-d₄) δ 8.25 (s, 1 H); 7.99 (s, 1 H); 7.30-7.40 (m, 5H); 5.07 (dd, J = 9Hz, Jl = 2Hz, 2H); 4.38 (t, J = 7Hz, 2H); 4.08-4.18 (m, 2H); 3.88 (t, J = 5Hz, 2H), 3.83 (dd, J = 8Hz, Jl = 2Hz, 2H); 3.56 (t, J = 5Hz, 2H); 3.42 (t, J = 7Hz, 2H); 1.50-1.60 (m, 2H); 1.20-1.38 (m, 30H); 0.88 (t, J = 7Hz, 3H). MS (El): 660.55 (M + H)⁺.

EXAMPLE 4. Preparation of 9-(S) ~ [3-hydroxy-2- (phosphonomethoxy) propyl] adenine (Compound 218, BnODE- (S) -HPMPA) benede octadecyloxyethyl. Method 1:

N

HN-Tr

N

<img file="MX367403B_D0107.tif" />

or p'-O (CH₂ugly (CHUpCH₃ beneilo alcohol

HN-Tr

<img file="MX367403B_D0108.tif" />

Tr-O

PyBOP DIEA, Ν, Ν-DMF 50% produced or

P £ -O (CH₂)₂O (CH₂) ,, Clt,

NH-

<img file="MX367403B_D0109.tif" />

l T ^x&gt; 80% acetic acid $

HO '

To a solution of octadecyloxyethyl 9- (S) - [3-trityloxy-2 (phosphonomethoxy) propyl] -N⁶-trityloadenine (prepared as described in: Beadle, JR et al. Journal of Medicinal Chemistry

2006, 49: 2010-2015) (0.42 g, 0.38 mmol), was added (benzotriazole

117

1-yloxy) -tripyrrolidinophosphonium hexafluorophosphate (PYBOP®, 0.30 g, 0.58 mmol), benzyl alcohol (0.06 ml, 0.58 mmol) in dry N, ΝΟΜΕ (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), then washed with a saturated sodium bicarbonate solution (2x10 ml). The ethyl acetate was evaporated and the residue was purified with silica gel column chromatography using CHgClg / MeOH (0-5%) to generate 0.23 g (51%) of the product. NMR (CDClg / methanol-dJ δ 7.89 (s, 1H); 7.16-7.40 (m, 36H); 5.03 (dd, J = 9Hz, Jl = 2Hz, 2H); 4.27-4.44 (m, 2H); 4.06- 4.14 (m, 1H); 3.91-4.04 (m, 2H), 3.83 (dd, J = 8Hz, Jl = 2Hz, 2H); 3.40-

3.50 (m, 2H); 3.27-3.40 (m, 4H); 1.42-1.58 (m, 2H); 1.18-1.38 (m, 30H); 0.88 (t, J = 7Hz, 3H). MS (El): 1174.27 (M + H) +

The protected intermediate (0.13 g, 0.11 mmol) in 80% acetic acid (10 ml) was added and stirred at 30 ° C for 3 h. After cooling, the solvent was evaporated and the residue was purified with silica gel column chromatography to generate compound 218 (0.04 g, 52% yield).¹H NMR (CDCls / methanol-dA) δ 8.25 (s, 1H); 7.89 (s, 1 H); 7.26-7.38 (m, 5H); 5.09 (dd, J = 9Hz, Jl = 2Hz, 2H); 4.28-4.43 (m, 2H); 4.06-4.18 (m, 1 H); 3.95-4.05 (m, 2H), 3.80 (dd, J = 8Hz, Jl = 2Hz, 2H); 3.50-3.60 (m, 2H); 3.25-3.38 (m, 4H); 1.49-1.60 (m, 2H); 1.10-1.40 (m, 30H); 0.88 (t, J = 7Hz, 3H). MS (El): 690.49 (M + H)⁺, 712.47 (M + H)⁺.

Method 2:

<img file="MX367403B_D0110.tif" />

118

<img file="MX367403B_D0111.tif" />

sodium t-butoxy

NN-DMF

<img file="MX367403B_D0112.tif" />

octaoflcoosstarsoí

PyBOP DlgA, NM-DMF 50% produced

<img file="MX367403B_D0113.tif" />

A mixture of 9- (S) - [3-trityloxy-2-hydroxypropyl] - N⁶trityloadenine [prepared as in: Webb, RR, Nucleosides &amp; Nucleotides, 1989, 8: 619-24] (1.4g, 2.0 mmol) and sodium tertbutoxide (0.39 g, 4 mmol) in dry N, N-DMF (10 ml) it was stirred at room temperature for 30 min, then benzyl ptoluenesulfonyloxymethylphosphonate (0.94g, 2.5 mmol, see Example 6) was added. The mixture was stirred at 80 ° C over night. The solvent was evaporated and then the residue was purified with silica gel column chromatography to generate benzyl 9 (S) - [3-trityloxy-2- (phosphonomethoxy) propyl] -Añ-trityloadenine 0.75 g (42%). Ή NMR (CDCl₃/ methanol-d4) δ 8.09 (s, 1 H); 7.88 (s, 1 H); 7.08-7.60 (m, 30H); 4.84-4.88 (m, 2H); 4.20-4.30 (m, 2H); 3.78-4.90 (m, 1 H); 3.50-3.72 (m, 2H), 2.99-3.18 (m, 2H).

To a solution of this intermediate (0.2 g, 0.22 mmol), (benzotriazol-l-yloxy) -tripyrrolidinophosphonium was added

<img file="MX367403B_D0114.tif" />

119 hexafluorophosphate (PYBOP®, 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). 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 a saturated sodium bicarbonate solution (2 x 10 ml). The ethyl acetate layer was evaporated and then the residue was purified with silica gel column chromatography using CHgCls / MeOH (0-5%) to generate 0.15 g (58%) of the product. ¹H NMR (CDC13 / methanol-d4) δ: 7.93 (s, 1H); 7.87 (s, 1 H); 7.16-7.42 (m, 35H); 5.00 (dd, J = 9Hz, Ji = 2Hz, 2H); 4.27-4.44 (m, 2H); 4.06-4.14 (m, 1H); 3.91-4.04 (m, 2H), 3.83 (dd, J = 8Hz, Ji = 2Hz, 2H); 3.40-

3.50 (m, 2H); 3.27-3.40 (m, 4H); 1.42-1.58 (m, 2H); 1.18-1.38 (m, 30H); 0.88 (t, J = 7Hz, 3H). MS (El): 1174.29 (M + H)⁺; 1196.52 (M + Na)⁺.

The protected compound (0.15 g, 0.13 mmol) was treated with 80% aqueous acetic acid (10 mL) at 30 ° C for 3 h. The solvents were evaporated and then the residue was purified with silica gel column chromatography to generate compound 218 (0.06g, 68%).¹H NMR (CDC13 / methanol-d₄) δ: 8.24 (s, 1 H); 7.52 (s, 1 H); 7.34-

7.38 (m, 5H); 5.06 (dd, J = 9Hz, Ji = 2Hz, 2H); 4.28-4.46 (m, 2H); 4.06-4.16 (m, 2H); 3.95-4.16 (m, 1H), 3.76-3.87 (m, 2H); 3.52-3.66 (m, 4H); 3.39-3.48 (m, 2H); 1.49-1.60 (m, 2H); 1.20-1.40 (m, 30H); 0.89 (t, J = 7Hz, 3H). MS (El): 690.47 (M + H)⁺, 712.45 (M + Na)⁺.

Example 5

Preparation of isopropylidene glyceryl

<img file="MX367403B_D0115.tif" />

120 octadecyloxyethyl 9- (2-phosphonomethoxyethyl) guanine.

<img file="MX367403B_D0116.tif" />

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 h. The solvent was evaporated in vacuo together 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.

A saturated sodium bicarbonate solution (5 ml) was added and the mixture was stirred for 30 min. The toluene fraction was evaporated and purified with silica gel column chromatography to generate 0.05g of IPG-ODE-PMEG (23%). Ή NMR (CDCls / methanol-dJ Ó: 8.91 (s,

1 HOUR); 8.15 (s, 1 H); 4.44-4.52 (m, 2H); 4.18-4.34 (m, 2H); 4.13-4.18 (m, 1 H); 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 = 7Hz, 3H); 1.36 (t, J = 7Hz, 3H); 1.22-1.34 (m, 30H), 0.89 (t, J = 7Hz, 3H). MS (El):

700.37 (M + H)⁺, 722.43 (M + Na)⁺.

<img file="MX367403B_D0117.tif" />

121

Example 6. Preparation of benzyl ptoluenesulfonyloxymethyl phosphonate, sodium salt.

Diethyl p-toluenesulfonyloxymethyl phosphonate (3.2 g, 9.9 mmol) was dissolved in N, N-DMF (10 mL) and then bromotrimethylsilane (10 mL) was added. The mixture was stirred at room temperature overnight. The solvent was evaporated together with toluene (2 x 10 ml). A mixture of ethanol and water (10ml) was added and then the mixture was stirred for 30 min at room temperature. The solvents were evaporated together with the 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 h. The solvents were evaporated together with the toluene (2 x 10 ml). The residue was suspended in toluene (25 ml) and then the anhydrous benzyl alcohol (1.5 ml, 15.0 mmol) was added. The mixture was stirred at room temperature overnight. A solution of saturated sodium bicarbonate (15 ml) was added and then the mixture was stirred for 30 min. The toluene fraction was evaporated and the residue was purified with silica gel column chromatography to generate 2.94 g of benzyl p-toluenesulfonyloxymethyl phosphonate, sodium salt (81%). NMR (CDCÍ3 / methanol-d₄) δ: 7.7 2 (d, J = 8Hz, 2H); 7.30-7.33 (m, 7H); 4.88 (d, J = 7Hz, 2H); 4.02 (d, J = 9Hz, 2H); 2.44 (s, 3H).

Example 7. Preparation of benzyl 10-octadecyl-2-Obenzyl-sn-glyceryl

9- (S) - [(3-hydroxypropyl-2

<img file="MX367403B_D0118.tif" />

122 phosphonomethoxy) propyl] adenine (Compound 230, Bn-ODBG- (S) -HPMPA).

<img file="MX367403B_D0119.tif" />

<img file="MX367403B_D0120.tif" />

To a solution of benzyl 9- (S) - [3-trityloxy-2 (phosphonomethoxy) propyl] - N ^ -trityloadenine (prepared as in Example 4, Method 2) (0.4 g, 0.44 mmol), (benzotriazole) was added -l-yloxy) -tripyrrolidinophosphonium hexafluorophosphate (PYBOP®, 0.27 g, 0.51 mmol), 10-octadecyl-2-O-benzyl-snglycerol (0.22 g, 0.51 mmol) in dry N, N-DMF (1 mL), diisopropylethylamine (DIEA, 0.30ml, 1.7 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 a saturated sodium bicarbonate solution (2 x 10 ml). The ethyl acetate layer was evaporated and then the residue was purified with silica gel column chromatography using CH₂C12 / MeOH (0-5%) to generate 0.15 g (58%) of the product. ¹H NMR (CDCl₃/ methanol-d₄) δ: 7.88 (s, 1 H); 7.87 (s, 1 H); 7.19-7.42 (m,

<img file="MX367403B_D0121.tif" />

123

40Η); 4.95-5.03 (m, 2H); 4.57-4.60 (m, 2H); 4.29-4.39 (m, 2H);

4.16-4.28 (m, 2H), 4.00-4.12 (m, 1H); 3.90-3.98 (m, 1 H); 3.65-3.81 (m, 4H); 3.45-3.49 (m, 2H); 1.46-1.53 ​​(m, 2H); 1.22-1.32 (m, 30H); 0.88 (t, J = 7Hz, 3H). MS (El): 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 h. The solvents were evaporated and the residue was purified with silica gel column chromatography to generate compound 230 (0.13g, 65%).¹H NMR (CDClg / methanol-di) δ: 8.22 (s, 1H); 7.65 (s, 1 H); 7.27-7.35 (m, 10H); 4.99-5.04 (m, 2H); 4.58-4.66 (m, 2H); 4.33-4.43 (m, 1 H);

4.16-4.33 (m, 2H), 3.94-4.12 (m, 2H); 3.80-3.88 (m, 1 H); 3.68-3.78 (m, 2H); 3.38-3.62 (m, 4H); 1.50-1.58 (m, 2H); 1.22-1.38 (m, 30H); 0.89 (t, J = 7Hz, 3H). MS (El): 810.47 (M + H)⁺, 832.44 (M + Na)⁺.

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

<img file="MX367403B_D0122.tif" />

<img file="MX367403B_D0123.tif" />

t-biztcoctóo de sos ».

¿TídMF^-’^-*

<img file="MX367403B_D0124.tif" />

o-otadecfcoóetarvoi

PyBOP DIEA. N.N-DMF

<img file="MX367403B_D0125.tif" />

8% acetic acod

<img file="MX367403B_D0126.tif" />

<img file="MX367403B_D0127.tif" />

A mixture of 1- (S) - [3-trityloxy-2-hydroxypropyl] - N⁴-

<img file="MX367403B_D0128.tif" />

124 monomethoxytritylocytosine [prepared as described in: Beadle, JR, et al., PCT Int. Appl. WO 2005/087788 A2, published on 22Sep-2005] (1.84g, 2.63 mmol) and sodium tert-butoxide (1.24g, 3.29mmol) in dry DMF (20 ml) was stirred at room temperature for 30 min. Benzyl p-toluenesulfonyloxymethylphosphonate (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 with silica gel column chromatography to generate benzyl 1- (5) - [3-trityloxy-2- (phosphonomethoxy) propyl] -N⁴monomethoxytritylocytosine 1.25g (52%). ^XH NMR (CDClj / methanol-di) δ: 7.12-7.48 (m, 24H); 7.05 (d, J = 9Hz, 1H); 6.79 (d, J = 9Hz, 1H); 4.70 (dd, Ji = 30 Hz, J₂= 6Hz, 2H); 4.20-4.30 (m, 2H); 3.78-4.90 (m, 1 H); 3.77 (s, 3 H); 3.50-3.72 (m, 2H), 2.99-3.18 (m, 2H). (El): 883.99 (M + H)⁺, 906.22 (M + Na)⁺.

To a solution of this intermediate (0.6g, 0.66mmol), (benzotriazol-l-yloxy) -tripyrrolidinophosphonium hexafluorophosphate (PYBOP®, 0.52 g, 0.99 mmol), octadecyloxyethanol (0.31g, 0.52 mmol) was added in dry DMF DMF (5ml), diisopropylethylamine (DIEA, 0.46ml, 2.65 mmol). 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 a saturated solution of sodium bicarbonate (2 x 10 ml). The ethyl acetate was evaporated and the residue was purified with silica gel column chromatography using CHgCWMeOH (0-5%) to generate the product. ²Η NMR (CDCls / methanol-da) δ: 7.18-7.44 (m, 34H); 7.13

<img file="MX367403B_D0129.tif" />

125 (dd, Ji = 14Hz, J₂= 7Hz, 1H); 6.85 (dd, Ji = 14Hz, J₂= 7Hz, 1H); 5.00 (dd, Ji = 8Hz, J₂= 3Hz, 2H); 4.04-4.12 (m, 2H); 3.88-3.95 (m, 1H); 3.80 (s, 3H); 3.58-3.79 (m, 4H); 3.45-3.57 (m, 2H); 3.16-3.22 (m, 1 H); 3.02-3.08 (m, 1H); 1.43-1.52 (m, 2H); 1.08-1.38 (m, 30H); 0.88 (t, J = 7Hz, 3H). (El): 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 h. The solvents were evaporated and the residue was purified with column chromatography to generate compound 219 (0.16 g, 64%).^LH NMR (CDCla / methanol-dd δ: 7.40-7.42 (m, 5H); 7.38 (dd, Ji = 14Hz, J₂= 7Hz, 1H); 5.73 (dd, Ji = 14Hz, J₂= 7Hz, 1H); 5.12 (dd, Ji = 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, 2H), 1.20-1.40 (m, 30H), 0.89 (t, J = 7Hz, 3H). Mass spectrum (ESI): 666.54 (M + H)⁺, 688.52 (M + Na)⁺.

Example 9. Preparation of benzyl 10-octadecyl-2-Obenzyl-sn-glyceryl 1- (S) - [3-hydroxy-2 (phosphonomethoxy) propyl] cytosine (Compound 231, Bn-ODBG (S) HPMPC). To an intermediate solution of Example 8, benzyl 1 (S) - [3-trityloxy-2- (phosphonomethoxy) propyl] N⁴-monomethoxytrityl cytosine (0.57g, 0.63mmol), (benzotriazol-l-yloxy) tripyrrolidinophosphonium hexafluorophosphate (PYBOP®, 0.49 g, 0.95 mmol) and lO-octadecyl-2-O-benzyl-sn-glycerol (0.41g, was added 0.95 mmol) in dry DMF (5ml), diisopropylethylamine (DIEA, 0.44ml, 2.52

126 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 washed with saturated sodium bicarbonate solution (2x10 ml). The ethyl acetate was evaporated and the residue was purified with silica gel column chromatography using CH2C12 / MeOH (0-5%) to generate 0.30 g (36%) of the product.¹H NMR (CDCl₃/ methanol-d₄) δ: 7.19-7.45 (m, 39H); 7.15 (dd, Ji = 14Hz, J₂= 7Hz, 1H); 6.82 (dd, Ji = 14Hz, J₂= 7Hz, 1H); 5.00 (dd, Ji = 8Hz, J₂= 3Hz, 2H); 4.69-4.71 (m, 2H); 4.05 (s, 3H), 3.96-4.05 (m, 2H); 3.82-3.90 (m, 1 H); 3.50-3.80 (m, 4H); 3.40-3.53 (m, 2H); 3.24-3.40 (m, 4H); 3.02-3.08 (m, 1H); 1.43-1.50 (m, 2H); 1.20-1.40 (m, 30H); 0.88 (t, J = 7Hz, 3H). (El): 1301.06 (M + H)⁺, 1322.58 (M + Na)⁺.

The protected compound (0.30g, 0.23 mmol) was treated with 80% acetic acid (20 mL) at 30 ° C for 3 h. The solvents were evaporated and the residue was purified with column chromatography to generate compound 231 (0.10g, 55%).^XH NMR (CDCl₃/ methanol-d₄) δ: 7.31-7.40 (m, 10H); 7.28 (dd, Ji = 14Hz, J₂= 7Hz, 1H); 5.66 (dd, Ji = 14Hz, J₂= 7Hz, 1H); 5.07 (dd, Ji = 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, 2H), 1.20-1.40 (m, 30H), 0.89 (t, J = 7Hz, 3H). Mass spectrum (ESI): 786.43 (M + H)⁺, 808.41 (M + Na)⁺.

Example 10

Preparation of phenyl octadecyloxyethyl 9- [2 (phosphonomethoxy) ethyl] guanine (Compound 19, F-ODE-PMEG):

127 ° 9

ΗΝ | Γ% ^ΗΡί “| Γ% ti 2 i®¹*®¹PytiOP _Η 2 ² L ^ P_V^ - &lt;XCH₂), OR (CH₂)₁₇CH₃ * ² lJVj-íxch ^ ch,), ^,

ODE-PMEG] J Ph-OOE-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-l-yloxy) tripyrrolidinophosphonium hexafluorophosphate (PYBOP®, 0.34 g, 0.66 mmol) and phenol (0.06 g, 0.66 mmol) in anhydrous N, N-DMF, diisopropylethylamine (DIEA, 0.30 mi, 1.8 mmol). The mixture is stirred at room temperature for 30 min and then the solvent is evaporated in vacuo. The residue is dissolved in ethyl acetate (50 ml) and washed with saturated sodium bicarbonate solution (2 x 10 ml). The ethyl acetate layer is evaporated and the crude residue is purified with silica gel flash column chromatography using CHzClg / MeOH (0-5%) to yield 0.09 g (31%) of compound 19 as a white powder.¹H NMR (CDCls / methanol-dd δ: 7.66 (s, 1H); 7.36 (t, J = 8Hz, 2H); 7.20 (t, J = 7Hz, 1H); 7.13 (d, J = 8Hz, 2H); 4.23-4.30 (m, 4H); 4.03 (dd, J = 8Hz, Ji = 2Hz, 2H); 3.93 (t, J = 5Hz, 2H); 3.61 (t, J = 5Hz, 2H), 3.41-3.45 ( m, 2H); 1.50-1.60 (m, 2H); 1.20-1.38 (m, 30H); 0.89 (t, J = 7Hz, 3H). MS (El): 662.43 (M + H)⁺, 684.39 (M + Na)⁺.

Example 11. Preparation of benzyl octadecyloxyethyl 9-

<img file="MX367403B_D0130.tif" />

128 (S) -] 3-Methoxy-2- (phosphonomethoxy) propyl] adenine (Compound 146,

Bn-ODE- (S) -MPMPA).

OQ or ^N

HiC-O ODE ^ SPMMIPA

Tenido alcohol PyBOP

DIEAN.H-DMF

NH_?^N

Η-, Ο-Ο · - t_Z \ Bn-ODE- (8) -IIPMPA

To 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 &amp; Medicinal Chemistry, 2011, 19: 4616-4625]), (benzotriazol-1-yloxy) -tripyrrolidinophosphonium hexafluorophosphate (PYBOP®, 0.78 g, 0.66 mmol) and benzyl alcohol (0.16 mi, 1.50 mmol) in anhydrous N, N- 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 evaporated in vacuo. The residue was dissolved in ethyl acetate (50 ml) and then washed with saturated NaHCCh (2 x 10 ml). The ethyl acetate layer was evaporated and the residue was purified with silica gel flash column chromatography using CfbCWMeOH (0-5%) to generate 0.29 g (41%) of compound 146.¹H NMR (CDCla / methanol-dd δ 8.24 (d, J = 5.50 Hz, 1 H), 8.05 (d, J = 7.33 Hz, 1 H), 7.30 - 7.39 (m, 5 H), 5.00-5.15 (m , 2H); 4.40-4.45 (m, 1H); 4.28-4.36 (m, 1H); 400-4.18 (m, 3H); 3.80-3.98 (m, 2H); 3.40-3.60 (m, 6H); 3.35 (s, 3H); 1.45 - 1.60 (m, 2 H), 1.22 - 1.36 (m, 30 H), 0.89 (t, J = 7Hz, 3H). MS (El): 704.52 (M + H)⁺, 726.45 (M + Na)⁺.

129

<img file="MX367403B_D0131.tif" />

Example 12. Preparation of phenyl octadecyloxyethyl 9- (S) ~ [3-methoxy-2- (phosphonomethoxy) propyl] adenine (Compound 164, F-ODE (S) -ΜΡΜΡΆ).

N

<img file="MX367403B_D0132.tif" />

OR

HjC —O ** '

ODE- (S¡-MPMPA phenol. PyBOP

D1EA. N, N-DMF

<img file="MX367403B_D0133.tif" />

9- [3-Methoxy-2A solution of octadecyloxyethyl (phosphonomethoxy) propyl] adenine (ODE (S) -MPMPA, 0.62 g, 1.00 mmol) [prepared as described in: Valiaeva, N. et al. Bioorganic &amp; Medicinal Chemistry, 2011, 19: 4616-4625], is added (benzotriazol1-yloxy) -tripyrrolidinophosphonium hexafluorophosphate (PYBOP®, 0.78 g, 0.66 mmol) and phenol (0.14 g, 1.50 mmol) in dry N, N-DMF , diisopropylethylamine (DIEA, 0.70 ml, 4.0 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 then washed with saturated sodium bicarbonate (2 x 10 ml). The ethyl acetate layer was evaporated. The crude residue was purified with silica gel flash column chromatography using ΟΗςΟΙζ / ΜθΟΗ (0-5%) to generate 0.29 g (41%) of compound 164 as an off-white solid. NMR (CDCla / methanol-dá) δ 8.23 ​​(d, 7 = 5.50 Hz, 1 H), 8.05 (d, J = 7.33 Hz, 1 H), 7.29 - 7.37 (m, 2 H), 7.20 (d, J = 6.60 Hz, 1 H), 7.12 - 7.16 (m, 1 H), 7.08 (dt, J = 8.71, 1.15 Hz, 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),

<img file="MX367403B_D0134.tif" />

130

1.48 - 1.59 (m, 2 Η), 1.22 - 1.36 (m, 30 Η), 0.89 (t, J = 7Hz, 3H).

MS (El): 704.52 (M + H)⁺, 726.45 (M + Na)⁺.

Example 13. Preparation of Beneficial Hexadecyloxypropyl 9 [2- (phosphonomethoxy) ethyl] guanine (Compound 25, Bn-HDP-PMEG)

HjN or

<img file="MX367403B_D0135.tif" />

O 'diea.nn-dmf

H_?N

<img file="MX367403B_D0136.tif" />

HDP-PMEG

Bn-HDP-PMEG

To 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-l-yloxy) tripyrrolidinophosphonium hexafluorophosphate (PYBOP®, 0.39 g, 0.74 mmol) and beneyl alcohol (0.10 ml, 0.74 mmol) in dry N, N-DMF, diisopropylethylamine (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 with silica gel flash column chromatography using CH₂Cl₂/ MeOH (0-5%) to generate 0.03 g (10%) of compound 25 as a white powdered solid. ¹H NMR (CDCl₃/ methanol-d4) δ: 7.62 (s, 1 H), 7.30 - 7.44 (m, 5 H), 5.07 (dd, J = 8.98, 2.02 Hz, 2 H), 4.05 - 4.24 (m, 4H), 3.83 (m, 4H),

3.31 - 3.42 (m, 4 H), 1.87 (m, 2 H), 1.54 (m, 2 H), 1.17

1.38

131 (m, 26 Η), 0.86 - 0.91 (m, 3 Η). MS (El): 662.46 (M + H)⁺, 684.46 (M + Na)⁺.

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

<img file="MX367403B_D0137.tif" />

aloohal benzyl, PyaOF

DIEA. Ν, Ν-DMF

ODE¿R) -PMPA

<img file="MX367403B_D0138.tif" />

octadecyloxyethyl 9— [2—

To a solution of (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 (PYBOP®, 0.40 g, 0.77 mmol) and benzyl alcohol (0.08 ml, 0.77 mmol) in dry N, ΝΟΜΕ, was added diisopropylethylamine (DIEA, 0.35 ml, 2.0 mmol). The sample was stirred at room temperature for 30 min and then the solvent was evaporated under vacuum. The resulting residue was dissolved in ethyl acetate (50 ml) and washed with saturated NaHCCh (2 x 10 ml). The ethyl acetate layer was evaporated and the crude product was purified with silica gel flash column chromatography using CH₂Cl₂/ MeOH (0-5%) to generate 0.24 g (70%) of compound 74. ^XH NMR (400 MHz, CDCls + methanol-dJ δ ppm 8.24 (s, 1

H), 8.03 (d, J = 4.40 Hz, 1 H), 7.30

7.42 (m, 5 H), 4.99

5.14 (m, 2 Η), 4.35 (d, J = 14.66 Hz, 1 H), 4.07-4.20 (m, 3 H), 3.92 (ddd, J = 13.75, 8.98, 4.77 Hz, 2 H), 3.65 - 3.73 (m, 1 H), 3.50 -

3.61 (m, 2 H), 3.38 - 3.47 (m, 2 H), 1.49 - 1.61 (m, 2 H), 1.27 (m, 30 H), 1.21 (d, J = 6.23 Hz, 3 H), 0 . 09 (t, J = 8.00 Hz, 3 H). MS (El): 674.48 (M + H)⁺, 693.46 (M + Na)⁺.

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

<img file="MX367403B_D0139.tif" />

nh₂ nh | Γ \\? phenol. PyBOP

V OH ^DIEA' ^Ν·^Μ-°^ΜΙ^CH3 ODE- (R) -PMPA

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-liloxy) -tripyrrolidinophosphonium hexafluorophosphate (PYBOP®, 0.40 g, 0.77 mmol) and phenol (0.072 g, 0.77 mmol) in dry N, N-DMF, se added diisopropylethylamine (DIEA, 0.35 ml, 2.0 mmol). The mixture was stirred at room temperature for 30 min and then the solvent was evaporated under vacuum. 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 on silica gel column chromatography using CH2C12 / MeOH (0-5%) to generate 0.25 g (75%) of compound 94.¹H

133

NMR (400 MHz, CDCI3 + methanol-dj δ ppm 8.24 (d, J = 3.30 Hz, 1 H), 8.05 (d, J = 6.23 Hz, 1 H), 7.29 - 7.37 (m, 2 H), 7.17 - 7.24 (m, 1 H), 7.05 - 7.15 (m, 2 H), 4.37 (d, J = 1.47 Hz, 1 H), 4.04 - 4.31 (m, 4 H), 3.94 - 4.03 (m, 1 H) , 3.86 (dd, J = 9.53, 1.10 Hz, 1 H), 3.60 (d, J = 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, J = 8.00 Hz, 3 H) MS (El): 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)

A

O p'-O (CH₂)₂0 (CH₂),₇CH3 alcohol beftcüo, PyñOP

EMEA, NN-DMF

ODE-jRH'MPO

HN

Jkp JL / O

HjN M&gt; 0 ^ -OjCHjhOíCHjhrCHa * O ^CHav — ¿.) Bn-ODE- (R) -PMP &lt;3

To 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 (PYBOP®, 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) is added. The mixture was stirred at room temperature for 30 min and then the solvent was evaporated under vacuum. The residue was dissolved in ethyl acetate (50 ml) and washed with sodium bicarbonate solution

<img file="MX367403B_D0140.tif" />

134 saturated (2 x 10 mi). The ethyl acetate layer was evaporated and then the crude product was purified with silica gel column chromatography using CHzClz / MeOH (0-5%) to yield 60 mg (29%) of compound 73. NMR (400 MHz, CDC13 + methanol-d4) δ ppm 7.82 (d, J = 5.50 Hz, 1 Η), 7.75 (d, J = 7.33 Hz, 1 Η), 7.43 - 7.53 (m, 2 Η), 7.33 - 7.43 (m, 3 Η), 5.01 - 5.17 (m, 1 Η), 4.07-418 (m, 2 H), 3.82 - 4.03 (m, 2 Η), 3.69 - 3.81 (m, 1 Η), 3.51 - 3.64 (m, 1 Η), 3.44 (d, J = 7.70 Hz, 1 Η), 3.36 (dt, J = 3.30, 1.65 Hz, 3 Η), 1.54 (m, 2 Η), 1.21-1.35 (m , 30 Η), 1.18 (dd, J = 6.23, 2.57 Hz, 3 Η), 0.88 (t, J = 8.00 Hz, 3 H). MS (El): 690.49 (M + H)⁺, 712.48 (M + Na)⁺.

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

<img file="MX367403B_D0141.tif" />

OOe- (S) -FPMPe aaMaiapeitoPie &lt;y

DEA, HN-DMF

OR

Js / O ^F- '—í ¿Bn-ODE4S) .FPMPG

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. Common., 1993, 58: 1645-1667], 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. It was isolated

<img file="MX367403B_D0142.tif" />

135

Octadecyloxyethyl (S) -9- [3-fluoro-2 (phosphonomethoxy) propyl] guanine (ODE (S) -FPMPG) with column chromatography to generate 0.11 g (17%) of the product. NMR (CDCl₃/ methanol-d₄), δ 8.18 (s, 1 H); 4.50-4.75 (m, 2H); 4.43-4.49 5 (m, 1 H); 4.07-4.16 (m, 1 H); 3.98-4.17 (m, 2H); 3.84-3.72 (m, 1H);

3.56-3.60 (m, 2H); 3.42-3.48 (m, 2H); 3.35-3.37 (m, 1 H); 1.52-1.60 (m, 2H); 1.20-1.34 (m, 30H); 0.88 (t, J = 7Hz, 3H). MS (El): 600.30 (MH) '.

A stirred mixture of ODE- (S) -FPMPG (0.11 g, 0.18 mmol), benzyl alcohol (0.06 mL, 0.54 mmol) and (benzotriazol-l-yloxy) tripyrrolidinophosphonium hexafluorophosphate (PYBOP®, 0.28 g, 0.54 mmol) in dry DMF, it was treated with diisopropylethylamine (DIEA, 0.25 ml, 1.44 mmol) for 4 hours at room temperature. The solvent was evaporated under vacuum. The residue was dissolved in 15 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 with silica gel column chromatography using CHsCWMeOH (0-5%) to yield 90 mg (71%) of

<td></td><td>compound 289.</td><td>¹H NMR</td><td>(400 MHz, CDCls + methanol-di)</td><td>δ ppm 7.77</td><td>(s, 1</td>

<td> 20</td><td>H), 7.46-7.54</td><td>(ni, 2</td><td>H), 7.34-7.42 (m, 3 H),</td><td> 5.04 - 5.17</td><td>(m, 1</td>

<td></td><td>H), 4.42 - 4.52</td><td>(m, 2</td><td>H), 4.19-4.38 (m, 2 H),</td><td> 4.09 - 4.19</td><td>(m, 2</td>

<td></td><td>H), 3.88-4.06</td><td>(m, 2</td><td>H), 3.64-3.73 (m, 1 H),</td><td> 3.55 - 3.64</td><td>(m, 1</td>

<td></td><td>H), 3.41-3.50</td><td>(m, 1</td><td>H), 3.18 (d, &lt;J = 7.33 Hz, 1</td><td>H), 1.49-1.</td><td>60 (m,</td>

<td> 25</td><td>2 H), 1.21-1. (MH) ', 730.52</td><td>35 (m, (M + Na)⁺</td><td>30 H), 0.88 (t, J = 7Hz, 3H)</td><td>. MS (El):</td><td> 708.50</td>

<img file="MX367403B_D0143.tif" />

136

Example 18. Preparation of Naphthyl octadecyloxyethyl 9 (S) - [3-methoxy-2- (phosphonomethoxy) propyl] adenine (Compound 398, Npt-ODE- (S) -MPMPA)

<img file="MX367403B_D0144.tif" />

HjC-Ο ODE &lt;S) -MPMPA

1-niftd, PyBOP S'ea, n'n-dmf

NHb · x O

HgG-O- 'HpMJOB-fSRPMPA

To a solution of octadecyloxyethyl 9- [3-methoxy-2 (phosphonomethoxy) propyl] adenine (ODE MPMPA, 0.30 g, 0.49 mmol) [prepared as described in: Valiaeva, N. et al. Bioorganic &amp; Medicinal Chemistry, 2011, 19: 4616-4625], (benzotriazol-l-yloxy) tripyrrolidinophosphonium hexafluorophosphate (PYBOP®, 0.38 g, 0.73 mmol) and 1-naphthol (0.11 g, 0.73 mmol) in dry N, N- DMF, diisopropylethylamine (DIEA, 0.35 ml, 2.0 mmol) is added. The mixture was stirred at room temperature overnight and then the solvent was evaporated under vacuum. 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 then the crude product was purified with silica gel column chromatography using CHzClz / MeOH (0-5%) to yield 0.20 g (56%) of compound 398 as an off-white solid.¹H NMR (400 MHz, CDCI3 + methanol-di) δ ppm 8.18 (d, J = 8.07 Hz, 1 H), 8.02-8.11 (m, 1 H),

7.94 (s, 1 H), 7.86 - 7.90 (m, 1 H), 7.69-7.74 (m, 1 H), 7.48 -

7.57 (m, 2 H), 7.34 - 7.43 (m, 2 H), 4.38 - 4.46 (m, 1 H), 4.26 4.37 (m, 3 H), 4.09 - 4.24 (m, 2 H), 3.99 - 4.09 (m, 1 H), 3.59

<img file="MX367403B_D0145.tif" />

137 (t, &lt;7 = 4.58 Hz, 1 Η), 3.47 - 3.56 (m, 2 Η), 3.30 - 3.45 (m, 5 Η),

1.49 (d, &lt;7 = 6.60 Hz, 2 Η), 1.19 - 1.34 (m, 30 Η), 0.85 - 0.93 (t, J = 7Hz, 3H). MS (El): 740.54 (M + H)⁺, 762.52 (M + Na)⁺.

Example 19. Preparation of Naphthyl octadecyloxyethyl 9- [2 (phosphonomethoxy) ethyl] guanine (Compound 361, Npt-ODE-PMEG)

A

HíN 1Ί [pJí-OÍCHíhOtCHi), ^

OH

ODE-PMEG

1-naphtal, PyBOP

DIEA, N. NOMF

Q nn Arl

To Ay °

Ί | ] Npt-ODE-PMEG

To 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-l-yloxy) -tripyrrolidinophosphonium hexafluorophosphate (PYBOP®, 0.39 g, 0.75 mmol) and 1-naphthol (0.11 g, 0.75 mmol) in dry N, N-DMF, was added diisopropylethylamine (DIEA, 0.35 ml, 2.0 mmol). The mixture was stirred at room temperature overnight and then the solvent was evaporated under vacuum. 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 with silica gel flash column chromatography using CH₂Cl₂/ MeOH (0-5%) to generate 0.23 g (65%) of compound 361. ²H

NMR (CDCl₃/ methanol-d₄) δ: NMR (400 MHz, CDCl₃+ methanol-d₄) δ ppm

8.07 - 8.12 (m, 1 Η), 7.87 (dd, &lt;7 = 5.87, 3.30 Hz, 1 Η), 7.71 (d, J = 5.87 Hz, 1 H), 7.59 (d, &lt;7 = 4.40 Hz, 1 Η), 7.52 - 7.56 (m, 1 Η),

<img file="MX367403B_D0146.tif" />

138

7.39 - 7.43 (m, 1 Η), 4.30 (ddd, J = 8.62, 5.68, 3.30 Hz, 2 H), 4.16 - 4.21 (m, 2 H), 4.14 (d, J = 8.07 Hz, 2 H), 3.64 - 3.72 (m, 2 H), 3.56 - 3.61 (m, 1 H), 3.38 (d, J = 4.77 Hz, 1 H), 3.19 (q, J = 7.45 Hz, 2 H), 1.45 - 1.54 ( m, 2 H), 1.15 - 1.35 (m, 30 H), 0.88 (t, J = 7Hz, 3H). MS (El): 712.49 (M + H)⁺, 734.41 (M + Na)⁺.

Example 20. Preparation of Benetyl octadecyloxyethyl 9 (S) - [3-hydroxy-2- (phosphonomethoxy) propyl] uracil (Compound 221, Bn-ODE- (S) -HPMPU).

<img file="MX367403B_D0147.tif" />

.octadeciojdetanot, PyBOP, DIEA, N, N-DMF r 80% aqCH3COOH, 50C

<img file="MX367403B_D0148.tif" />

HC

Bn-ODE- (S) -HPMPU

To a solution of beneyl 9- [3-trityloxy-2 (phosphonomethoxy) propyl] -4-methoxy-uracil (0.1 g, 0.15 mmol), (benzotriazol-l-yloxy) -tripyrrolidinophosphonium hexafluorophosphate (PYBOP®, 0.11 g, 0.20 mmol) and octadecyloxyethanol (0.06 g, 0.20 mmol) in dry N, N-DMF was added diisopropylethylamine (DIEA, 0.03 mL, 0.20 mmol). The mixture was stirred at room temperature overnight. The solvent was evaporated under vacuum. The residue was dissolved in ethyl acetate (50 ml), washed with saturated sodium bicarbonate (2x10 ml) and then the ethyl acetate layer was concentrated under vacuum. The resulting crude product was purified with silica gel flash column chromatography using

139

CH2C12 / MeOH (0-5%) to generate 0.024 g (17%) of benzyl octadecyloxyethyl 9- [3-trityloxy-2- (phosphonomethoxy) propyl] -4methoxyuracil ¹H NMR (400 MHz, CDCls + methanol) δ ppm 7.56 (d, J = 5.50 Hz, 1 H), 7.16 - 7.51 (m, 15 H), 5.46 (d, J = 5.50 Hz, 1 H), 5.10 ( d, J = 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, 3 H), 3.12 (m, 1 H), 1.42-1.62 (m, 2 H), 1.-5-1.38 (m, 30 H), 0.88 (t, J = 6.97 Hz, 3 H). MS (El): 945.66 (M + Na)⁺The protected intermediate was stirred in 80% aqueous acetic acid overnight at 50 ° C. The solvent was then evaporated under vacuum and the residue was purified with flash column chromatography to generate O. Olg (59%) of compound 221. MS (El): 667.54 (M + H)⁺, 689.56 (M + Na)⁺.

Example 21. Preparation of ethyl octadecyloxyethyl 9- (S) ~ [3-methoxy-2- (phosphonomethoxy) propyl] adenine (Compound 182, EtODE- (S) -MPMPA).

NH, í ^OHH3C-0 OD € - (S) -MPMPA ethanol. PyBOP

DIEA. NN-DMF

NH, w «i °. HjC-O - et4®e- &lt;S) -MPMPA

To 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 &amp; Medicinal Chemistry, 2011, 19: 4616-4625], (benzotriazol-l-yloxy) -tripyrrolidinophosphonium hexafluorophosphate, (PYBOP®, 0.38 g, 0.73 mmol), in ethanol (25 ml), diisopropylethylamine (DIEA, 0.35) my, 2.0 mmol). The mixture was stirred at room temperature overnight. Then the solvent was evaporated under vacuum. The residue was dissolved in ethyl acetate (50 ml) and then washed with saturated sodium bicarbonate (2 x 10 ml). The ethyl acetate was evaporated and the residue was purified with silica gel flash column chromatography using CHjCla / MeOH (0-5%) to generate 0.26 g (84%) of compound 182 as a white solid.^XH NMR (400 MHz, CDCla + methanol-di) δ ppm 8.26 (s, 1 H), 8.08 (d, &lt;7 = 2.20 Hz, 1 H), 4.72-4.74 (m, 1 H), 4.62-64 ( m, 1 H), 4.44-4.50 (m, 1 H), 4.28-4.35 (m, 1 H), 4.10 - 4.18 (m, 2 H), 4.03-4.10 (m, 2 H), 3.81-3.89 ( m, 1 H), 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, &lt;7 = 7.20 Hz, 3 H). MS (El): 642.69 (M + H)⁺, 664.61 (M + Na)⁺.

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

HH, NH₂

HsC-O ODE-íSy-MPMPDAP

H₃C- ° j) Bn-ODE- (S¡-MPMPDAP

To a solution of octadecyloxyethyl 9- (S) - [3-methoxy-2

141 (phosphonomethoxy) propyl] -2,6-diaminopurine (ODE- (S) -MPMP DAP, 0.20 g, 0.32 mmol) [prepared as described in: Valiaeva, N. et al. Bioorganic &amp; Medicinal Chemistry, 2011, 19: 4616-4625], ((benzotriazol-l-yloxy) -tripyrrolidinophosphonium hexafluorophosphate (PYBOP®) (0.21 g, 0.40 mmol) and benzyl alcohol (0.04 ml, 0.40 mmol) in dry N, N-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 under vacuum. 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 with silica gel flash column chromatography using CH2C12 / MeOH (0-5%) to generate 0.12 g (54%) of compound 150.^XH NMR (400 MHz, CDCls + methanol-dzi) δ ppm 7.63 - 7.68 (m, 1 H), 7.31 - 7.43 (m, 5 H), 5.02 - 5.13 (m, 2 H), 4.59 (s, 1 H ), 4.50 (s, 1 H), 4.23 (d, &lt;7 = 3.67 Hz, 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, &lt;7 = 6.6 Hz, 3 H). MS (El): 719.62 (M + H)⁺, 741.56 (M + Na) ⁺ .

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

Method. Compounds were incubated in a certain range of concentrations with human fibroblasts or cell lines

142 Human cervical carcinogens in a monolayer culture and after 4 days, the viable cell number was determined by a neutral red reduction as described above (Valiaeva N, et al., Chemotherapy, 2010, 56 (1): 549). The cell lines of the American Type Culture Collection were obtained. The results were plotted and it was determined that the concentration reduced neutral red levels by 50% (CC50) in triplicate. Although viral replication ceases to occur in human cervical cancer cell lines, Caski cells were transformed by HPV-16 and Hela cells were transformed by HPV-18.

Results As tabulated in Table 11 presented below, these results demonstrate that the compounds described herein were 23.6 times (for example, Compound 219) up to 3,750 times (for example, Compound 1) more effective in reducing the number of viable cells in cervical cancer lines compared to normal non-transformed human fibroblasts.

143

<img file="MX367403B_D0149.tif" />

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

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

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

<td> 219</td><td> 52</td><td> 2.0</td><td> 2.2</td>

<td> 218</td><td> 5.2</td><td> 0.055</td><td> 0.029</td>

<td> 1</td><td> 15</td><td> 0.004</td><td> 0.009</td>

Example 24. Antiproliferative activity of the compounds in leukemia cells to human T cells (MT-2).

Method of cytotoxicity determination. MT-2 cells were incubated with the drug for 72 hrs and harvested. Flow counting microspheres (Beckman Coulter, Miami, FL) were added to the cell suspension followed by propidium iodide staining and analyzed using flow cytometer and the 50% cytotoxic concentration (CCso) of cell counts was calculated and the viability.

Results The compounds set forth herein are effective antiproliferative agents in leukemia cells to human T cells (MT-2) (Table 12).

<img file="MX367403B_D0150.tif" />

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

<td>Compound #</td><td>CCso, 50% Cytotoxic concentration μΜΜΤ2 T-cell leukemia cell</td>

<td> 1</td><td> 0.036 ± 0.04</td>

<td>the</td><td> &lt;0.01</td>

<td>Ib</td><td> &lt;0.01</td>

<td> 2</td><td> &lt;0.010</td>

Example 25. Anti-HIV activity.

HIV antiviral test method. MT-2 cells were maintained in RPMI 1640 supplemented with 10% FBS, 10 mM HEPES regulatory solution, 50 IU penicillin / ml and 50 pg streptomycin / ml. The viral activity of each compound is determined by vaccinating MT-2 cells with HIV-Ilai at a multiplicity of infection (MOI) of 0.001 TCIDso / cell, followed by incubation in the presence of serial dilutions of drug three times (three deposits per dilution ). Four days after infection, culture supernatants were collected, used with 0.5% Triton X100 and tested for the concentration of p24 antigens using a commercial ELISA test (Perkin Elmer Life Sciences, Boston, MA). The antiviral activity of each compound is expressed as the ECso, which represents the concentration required to inhibit the production of p24 antigen by 50%.

Method of cytotoxicity determination. They incubated

145 MT-2 cells with the drug for 72 hrs and were collected. Flow counting microspheres (Beckman Coulter, Miami, FL) were added to the cell suspension followed by propidium iodide staining and analyzed using flow cytometer and 50% cytotoxic concentration (CC50) of cell counts was calculated. and the viability.

Results Table 13 shows that the compounds expressed herein contain considerable antiviral activity against HIV-1 and demonstrate selectivity.

Table 13. Antiviral activity in HIV-1 infected human lymphoblastic leukemia cells

<td></td><td colspan="3">HIV ANTIVIRAL ACTIVITY IN MT-2 CELLS</td>

<td>Compound #</td><td>ECso, μΜ</td><td>CCso, μΜ</td><td>selectivity index</td>

<td> 1</td><td>&lt;1χ10-⁵</td><td> 0.036 ± 0.04</td><td> &gt;3600</td>

<td> 2</td><td>&lt;1x10-⁵</td><td>&lt;1x10 '²</td><td> -</td>

<td> 218</td><td> 0.13±0.14(3)</td><td> 2.3±1.6 (3)</td><td> 17.7</td>

<td> 219</td><td> 2.7±2.1 (3)</td><td> 18±3.6 (3)</td><td> 6.7</td>

<td> 230</td><td> 0.05±0.03 (3)</td><td> 19±2.6 (3)</td><td> 380</td>

<td> 231</td><td> 2.2±2.1 (3)</td><td> 22±3.0 (3)</td><td> 10</td>

<td colspan="4">ECso, 50% effective dose; CC50, 50% cytotoxic dose, CC50 / EC50 selectivity index. Test: dep24 reduction.</td>

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

Method. Foreskin fibroblast cells were infected

146 Human primary duct (HFF) in 96-well plates at an MOI of 0.01 PFU / cell with strain G of herpes simplex virus type 2 and incubated for 3 days. It was aspirated, then the medium and the cell monolayers were stained with crystal violet, rinsed with distilled water. The crystal violet associated with the cells was quantified in a spectrophotometer and the concentration of the compound that was sufficient to reduce virus replication to 50% (ECso) was calculated. Cytotoxicity was measured in parallel by similar methods to produce the concentration that reduces the number of cells to 50% (CC50).

Results The results were tabulated in Table 14 presented below.

Table 14. Antiviral effect of diesters in HFF cells infected with HSV-2

<td>Compound #</td><td>ECso, μΜ</td><td>CCso, μΜ</td><td>selectivity index</td>

<td> 219</td><td> 0.10</td><td> 13.1</td><td> 131</td>

<td> 218</td><td> 0.04</td><td> 6.91</td><td> 173</td>

<td> 231</td><td> 0.80</td><td> 34.8</td><td> 43.5</td>

<td> 230</td><td> 0.71</td><td> 37.1</td><td> 52.2</td>

<td> 221</td><td> 3.8</td><td> &gt;10</td><td> &gt;2.6</td>

Example 27. Effect of oral octadecyloxyethyl-benzyl- (ODE-bn-) acyclic nucleoside phosphate diesters

147 and ODE monoesters of acyclic nucleoside phosphonates in the body weight of Balb-c mice.

Method. Compounds were administered as indicated by daily oral probe doses for 5 days. Weights were measured before and on day 6 after 5 doses.

Results As tabulated in Table 15 presented below, these results demonstrate that the ODE monoesters of cidofovir (CDV) and PMEG lose 14.7% and 19.1% of body weight, respectively, which represented a statistically significant increase compared to the zero day (p = 0.0007 and p &lt;0.001). However, the oral benede ODE diesters of the CDV and the nucleoside phosphonates of the PMEG do not exhibit statistically significant effects (ns) on body weight compared to the unmodified compounds.

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

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

<td>ODE-CDV</td><td>20 mg / kg / day</td><td>19.88i0.55 (6)</td><td>16.96Ü.38 (6)</td><td> 0.0007</td>

<td>ODE-bn-CDV (Compound 219)</td><td>20 mg / kg / day</td><td> 19.03±1.16 (6)</td><td>19.27Ü.32 (6)</td><td>ns</td>

<td></td><td></td><td></td><td></td><td></td>

<td>ODE-PMEG</td><td>4 mg / kg / day</td><td>19.17i0.581 (3)</td><td>15.5i0.514 (3)</td><td> &lt;0.001</td>

<td>ODE-bn-PMEG (Compound 1)</td><td>4 mg / kg / day</td><td> 18.63±0.728 (3)</td><td> 18.42±1.00 (3)</td><td>ns</td>

<img file="MX367403B_D0151.tif" />

148

Example 28. Antiviral effect of ANP diesters in cells infected with human cytomegalovirus (AD169).

Method. Human primary foreskin fibroblast cells (HFF) were infected in 96-well plates at an MOI of 0.01 PFU / cell with the human cytomegalovirus strain AD169 and incubated for 14 days. The medium was then aspirated and the cell monolayers were stained with crystal violet and rinsed with distilled water. The crystal violet associated with the cells was quantified on a spectrophotometer and the concentration of the compound that was sufficient to reduce virus replication by 50% (EC50) was calculated · Cytotoxicity was measured in parallel by similar methods to produce the concentration that reduce the number of cells to 50% (CC50).

Results The results tabulated in Table 16 are as follows.

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

<td>Compound #</td><td>ECso, μΜ</td><td>CCso, μΜ</td><td>selectivity index</td>

<td> 219</td><td> &lt;0.03</td><td> 84.2</td><td> &gt;2807</td>

<td> 218</td><td> &lt;0.03</td><td> 7.49</td><td> &gt;250</td>

<td> 231</td><td> &lt;0.03</td><td> 19.0</td><td> &gt;633</td>

<td> 230</td><td> &lt;0.03</td><td> 3.72</td><td> &gt;124</td>

<td> 1</td><td> &lt;0.03</td><td> 51.5</td><td> &gt;1717</td>

<td> 2</td><td> 0.11</td><td> 18.3</td><td> 166</td>

<img file="MX367403B_D0152.tif" />

149

Example 29. Antiviral effect of ANP diesters in cells infected with vaccine virus (Copenhagen)

Method: Human primary foreskin fibroblast cells (HFF) were infected in 96-well plates at an MOI of 0.01 PFU / cell with the Copenhagen strain of vaccine virus and incubated for 7 days. The medium was then aspirated and the cell monolayers were stained with crystal violet and rinsed with distilled water. The crystal violet associated with the cells was quantified on a spectrophotometer and the concentration of the compound that was sufficient to reduce virus replication by 50% (EC) was calculated.₅o) - Cytotoxicity was measured in parallel by similar methods to produce the concentration that reduced the number of cells to 50% (CC50) Results. The results were tabulated in Table 17, below.

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

<td>Compound #</td><td>ECso, μΜ</td><td>CCso, μΜ</td><td>selectivity index</td>

<td> 219</td><td> 0.09</td><td> &gt;100</td><td> &gt;1110</td>

<td> 218</td><td> &lt;0.03</td><td> &gt;100</td><td> &gt;3330</td>

<td> 231</td><td> 0.23</td><td> &gt;100</td><td> &gt;435</td>

<td> 230</td><td> 0.06</td><td> 97.5</td><td> 1625</td>

<img file="MX367403B_D0153.tif" />

150

Example 30. Antiviral effect of ANP diesters in cells infected with the BK virus (Gardner strain)

Method: Human primary foreskin fibroblast cells (HFF) were infected in 96-well plates at an MOI of 0.01 PFU / cell and incubated for 14 days. The medium was then aspirated and the total DNA was isolated, the number of genomic copies was quantified by means of qPCR using the primers 5'- AGT GGA TGG GCA GCC TAT GTA-3 '(SEQ ID NO: 1), 5'- TCA ΤΆΤ CTG GGT CCC CTG GA-3 '(SEQ ID NO: 2) and probe 5'-6-FAM AGG TAG AAG AGG ΤΤΆ GGG TGT TTG ATG GCA CAG TAMRA-3' (SEQ ID NO: 3). In a parallel experiment in uninfected cells, cytotoxicity was determined with CELLTITER-GLO® finding that the concentration

<td>reduced the number of</td><td>cells in a</td><td> 50%</td><td>(DC₅₀) .</td><td></td><td></td>

<td>Results</td><td>The results</td><td>I know</td><td>tabulate in</td><td>the</td><td>Table 18, a</td>

<td>continuation.</td><td></td><td></td><td></td><td></td><td></td>

<td>Table 18. Effect</td><td>antiviral of</td><td>the</td><td>diesters</td><td>ANP</td><td>in cells</td>

infected with BK virus (Gardner strain)

<td>Compound #</td><td>ECso, μΜ</td><td>CCso, μΜ</td><td>selectivity index</td>

<td> 219</td><td> &lt;0.03</td><td> 6.54</td><td> &gt;218</td>

<td> 218</td><td> &lt;0.03</td><td> 2.80</td><td> &gt;93</td>

<td> 231</td><td> &lt;0.03</td><td> 13.29</td><td> &gt;443</td>

<td> 230</td><td> 0.06</td><td> 19.61</td><td> 327</td>

<td> 1</td><td> &lt;0.03</td><td> 3.06</td><td> &gt;102</td>

<td> 2</td><td> &lt;0.03</td><td> 7.14</td><td> &gt;238</td>

151

<img file="MX367403B_D0154.tif" />

Example 31. Antiviral effect of ANP diesters in HFF cells infected with HSV-1 (E-377).

Method. Human primary foreskin fibroblast cells (HFF) were infected in 96-well plates at an MOI of 0.01 PFU / cell with strain E377 of herpes simplex virus type 1 and incubated for 3 days. Then, the medium was aspirated and the cell monolayers were stained with crystal violet and rinsed with distilled water. The crystal violet associated with the cells was quantified on a spectrophotometer and the concentration of the compound that was sufficient to reduce virus replication by 50% (EC) was calculated.₅o). Cytotoxicity was measured in parallel by similar methods to produce the concentration that reduced cell numbers to 50% (CC₅o)

Results The results were tabulated in Table 19, below.

Table 19. Antiviral effect of ANP diesters in HFF cells infected with HSV-1 (E-377)

<td>Compound #</td><td>ECso, μΜ</td><td>CCso, μΜ</td><td>selectivity index</td>

<td> 219</td><td> 1.25</td><td> 19.3</td><td> 15.4</td>

<td> 218</td><td> 0.92</td><td> 14.5</td><td> 15.8</td>

<td> 231</td><td> 1.40</td><td> 88.3</td><td> 63</td>

<td> 230</td><td> 2.77</td><td> 82.2</td><td> 30</td>

<td> 1</td><td> 1.08</td><td> &gt;100</td><td> &gt;93</td>

<td> 2</td><td> &gt;4.0</td><td> 16.6</td><td> &lt;4.2</td>

<img file="MX367403B_D0155.tif" />

152

Example 32. Antiviral effect of ANP diesters in HEK293 cells infected with HPV-11.

Method. A plasmid of origin content was transfected with HPV-11 El and E2 protein expression vectors to HEK 293 cells. At 4 hrs of transfection, the cells were treated with dilution compounds and the cells were incubated for 48 hrs. . The origin of virus replication with Dpnl and exonuclease III was detected to remove bacterial plasmid DNA contributed by non-replication. The remaining replicated DNA was quantified by means of qPCR. Toxicity was determined by exclusion of trypan blue.

Results The results were tabulated in Table 20, below.

Table 20. Antiviral effect of ANP diesters in HEK 293 cells infected with HPV-11

<td>Compound #</td><td>ECso, μΜ</td><td>CCso, μΜ</td><td>selectivity index</td>

<td> 1</td><td> 0.49</td><td> &gt;100</td><td> &gt;204</td>

<td>the</td><td>[l.OÓ.ECw]</td><td> -</td><td> -</td>

<td>Ib</td><td>[1.16, ECw]</td><td> -</td><td> -</td>

<td> 218</td><td> 0.77</td><td> &gt;100</td><td> &gt;370</td>

<td> 2</td><td> 0.27</td><td> &gt;100</td><td> &gt;130</td>

<td> 219</td><td> 2.04</td><td> &gt;10</td><td> &gt;4.9</td>

<td> 230</td><td> 0.56</td><td> &gt;10</td><td> &gt;17.9</td>

<td> 231</td><td> 1.56</td><td> &gt;10</td><td> &gt;6.41</td>

153 ** EC90 represents the concentration required to reduce viral replication by 90%.

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

Method. A plasmid of origin content was transfected with HPV-16 E and E2 protein expression vectors to HEK 293 cells. At 4 hrs of transfection, the cells were treated with dilution compounds and the cells were incubated for 48 hrs. . The origin of virus replication with Dpnl and exonuclease III was detected to remove bacterial plasmid DNA contributed by non-replication. The remaining replicated DNA was quantified by means of qPCR. Toxicity was determined by exclusion of trypan blue.

Results The results were tabulated in Table 21, below.

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

<td>Compound #</td><td>EC50, μΜ</td><td>CCso, μΜ</td><td>selectivity index</td>

<td> 218</td><td> 0.24</td><td> &gt;10</td><td> &gt;41.7</td>

<td> 219</td><td> 2.23</td><td> &gt;10</td><td> &gt;4.48</td>

<td> 1</td><td> 0.20</td><td> &gt;10</td><td> &gt;50</td>

<td> 19</td><td> 5.27</td><td> &gt;10</td><td> &gt;1.9</td>

<td> 2</td><td> 0.99</td><td> &gt;10</td><td> &gt;10.1</td>

<img file="MX367403B_D0156.tif" />

154

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

Method. Primary human keratinocytes (FKs) were transfected with a VPH-18 genomic plasmid containing G418 resistance gene, which was generated by Cre-loxP-mediated cleavage recombination. After 4 days of selection with G418, the surviving cells were cultured for 2-3 days and were used to grow as cultures in large quantities where the FK cells were stratified and differentiated as squamous epithelium in 10 days or more. The HPV-18 viral DNA usually develops within 10-14 days after large-scale cultures are removed from the air medium interface. The efficacy and toxicity of the tested compounds added at three concentrations to the medium were determined from day 6 or 8 until day 14. The medium is changed every two days. Prior to collection, BrdU is added to the medium at 100 pg / ml to document the replication of the host cell's DNA. A set of cultures is collected in large quantities (with or without the test compounds) for the real-time quantitative PRC (qPRC) to determine the number of copies of HPV-18 DNA / cell. Another set of cultures in large quantities is fixed in formalin, embedded in paraffin and toxicity determined by histology. Additional sections are subjected to in situ hybridization to locate viral DNA amplification and

155 BrdU incorporation, which denotes the replication of the host and suprabasal stratum host DNA.

Results The results were tabulated in Table 22, below.

Table 22. Antiviral effect of ANP diesters in large quantities of primary human keratinocytes infected with HPV18

<td>Compound #</td><td>ECso, μΜ</td><td>CCso, μΜ</td><td>selectivity index</td>

<td> 218</td><td> 0.25</td><td> &gt;10</td><td> &gt;39</td>

<td> 219</td><td> 1.06</td><td> &gt;10</td><td> &gt;9.4</td>

<td> 1</td><td> 0.21</td><td> 10</td><td> 48</td>

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

Method. COS7 cells in 96-well plates were infected at an MOI of 0.01 PFU / cell with JC virus MAD-1 strain and incubated for 7 days. The medium was then aspirated and the total DNA was isolated, the number of genomic copies was quantified by means of qPCR using the 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 the 5'-6-FAM-CCC TTT GTT TGG CTG CT-TAMRA-3 (SEQ ID NO: 6) probe in conjunction with plasmid pMP508 to provide a standard curve for quantification. In a parallel experiment

<img file="MX367403B_D0157.tif" />

156 In non-infected cells, cytotoxicity was determined with CELLTITER-GLO®, finding that the concentration reduced the number of cells by 50% (CC₅₀) .

Results The results were tabulated in Table 23, below.

Table 23. Antiviral effect of ANP diesters in COS7 cells infected with JC virus (MAD-1)

<td>Compound #</td><td>ECso, μΜ</td><td>CCso, μΜ</td><td>selectivity index</td>

<td> 1</td><td> 0.07</td><td> 63.8</td><td> 911</td>

<td> 2</td><td> &gt;4</td><td> 10.6</td><td> &lt;2.7</td>

<td> 218</td><td> &gt;4</td><td> 10.2</td><td> &lt;2.6</td>

<td> 219</td><td> &gt;4</td><td> 12.8</td><td> &lt;3.2</td>

<td> 230</td><td> &gt;4</td><td> 18.4</td><td> &lt;4.6</td>

<td> 231</td><td> &gt;20</td><td> 62.6</td><td> &lt;3</td>

Example 36. Antiviral effect of ANP diesters in human peripheral blood mononuclear cells infected with HIVÍ92US727.

Method. HIV assays based on human peripheral blood mononuclear cells (PBMC) were performed as previously described (KM Watson, et al., 2008, Antimicrob Agents Chemother. 52: 2787). The PBMC stimulated with FA, cultured in the presence of IL-2 at 1x10 was suspended for a short time.⁶ cells / mL and were added to a base plate

<img file="MX367403B_D0158.tif" />

157 96 well round. Serially diluted test materials were added to the plate in triplicate, followed by the appropriate pre-titled HIV strain. The culture was incubated for 7 days at 37 ° C / 5% CO₂. After incubation, the supernatants were collected for virus replication analysis by the reverse transcriptase activity of the supernatants, likewise, the cells were analyzed for viability with XTT reduction of tetrazolium tincture (2,3-bis (2- methoxy-4-nitro-5-sulfophenyl) -5 [(phenylamine) carbonyl] -2H-tetrazolium hydroxide). All trials were carried out in triplicate. Microsoft Excel 2007 was used to analyze and graph the data. The percentage reduction in virus replication compared to untreated virus controls was calculated for each compound. The percentage cell control value was calculated for each compound by comparing the uninfected cells treated with the drug with the uninfected cells only under the medium.

Results The results were tabulated in Table 24, below.

158

Table 24. Antiviral effect of ANP diesters in human peripheral blood mononuclear cells infected with HIV192US727

<td>Compound #</td><td>ECso, μΜ</td><td>CCso, μΜ</td><td>Selectivity Index</td>

<td> 218</td><td> &lt;0.010</td><td> 0.23</td><td> &gt;23.0</td>

<td> 230</td><td> &lt;0.10</td><td> 0.55</td><td> &gt;5.5</td>

<td> 219</td><td> &lt;0.10</td><td> 2.87</td><td> &gt;28.7</td>

<td> 231</td><td> &lt;0.30</td><td> 19.0</td><td> &gt;63.3</td>

<td> 2</td><td> &lt;0.010</td><td> 11.0</td><td> &gt;1100</td>

<td> 1</td><td> &lt;0.010</td><td> 0.04</td><td> &gt;4.0</td>

<td> 19</td><td> &lt;0.003</td><td> 0.018</td><td> &gt;9.0</td>

<td> 25</td><td> &lt;0.002</td><td> 0.25</td><td> &gt;125</td>

<td> 164</td><td> &lt;0.40</td><td> 15.0</td><td> &gt;37.5</td>

<td> 146</td><td> &lt;0.04</td><td> 12.5</td><td> &gt;312</td>

<td> 74</td><td> &lt;0.005</td><td> 24.6</td><td> &gt;4920</td>

<td> 92</td><td> &lt;0.005</td><td> 24.1</td><td> &gt;4820</td>

<td> 73</td><td> &lt;0.005</td><td> 11.3</td><td> &gt;2260</td>

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

Method. Antiviral assays for HBV are conducted (Korba &amp; Gerin, Antivir. Res., 1992, 19:55 and lyer, et al., Antivir Agents Chem Chemother., 2004, 48: 2199) using confluent cell cultures 2.2.15 ( genotype ayw; parenteral cell HepG2) kept in flat-bottom tissue culture trays with 96 wells. Convergence is required in this system of

<img file="MX367403B_D0159.tif" />

159 cultures for active replication of high levels of HBV equivalent to that observed in chronically infected individuals (Sells, et al., J. Virol., 1988, 62: 2836; Korba &amp; Gerin, Antivir. Res., 1992, 19:55). Cultures are treated for 7 days. The levels of HBV DNA in the culture medium (representing the production of HBV virion) are evaluated with quantitative point hybridization for 24 hrs. Cytotoxicity was evaluated (A₅io) with the absorption of neutral red tincture for 24 hrs. After the last treatment. Lamivudine (LMV) is used as the standard test control. The EC50, EC90 and CC50 values ​​are calculated with linear regression analysis (MS EXCEL®, QUATTROPRO®) using a combination of data from all treated crops (Korba &amp; Gerin, 1992, Id .; Okuse, et al., Antivir. Res ., 2005, 65:23). Standard deviations for the EC50 and EC90 values ​​of the standard errors generated by the regression analysis are calculated. EC50 and EC90 correspond to drug concentrations at which a 2-fold or 10-fold decrease in HBV DNA is observed (relative to the average levels of untreated cultures), respectively. CC50 corresponds to the concentration of drug at which a twice lower level of absorption of the neutral red pigment is observed (in relation to the average levels of the untreated cultures).

Results The results were tabulated in Table 25, below.

<img file="MX367403B_D0160.tif" />

160

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

<td>Compound #</td><td>ECso, μΜ</td><td>CC50, μΜ</td><td>selectivity index</td>

<td> 2</td><td> 0.88</td><td> &gt;100</td><td> &gt;113</td>

<td> 218</td><td> 0.76</td><td> &gt;100</td><td> &gt;132</td>

<td> 219</td><td> 0.45</td><td> &gt;100</td><td> &gt;223</td>

<td> 19</td><td> 43.0</td><td> &gt;100</td><td> &gt;2.33</td>

<td> 1</td><td> 0.44</td><td> &gt;100</td><td> &gt;226</td>

<td> 146</td><td> 33.0</td><td> &gt;100</td><td> &gt;3.03</td>

<td> 164</td><td> 0.46</td><td> &gt;100</td><td> &gt;216</td>

<td> 74</td><td> 6.5</td><td> 64</td><td> 10</td>

<td> 92</td><td> 7.3</td><td> 68</td><td> 9.3</td>

<td> 73</td><td> 34</td><td> 63</td><td> 1.9</td>

<img file="MX367403B_D0161.tif" />

VII. Modalities

Next, a first set of modalities P1-P7.

Modality Pl. A compound with the structure of Formula (I):

Bnuc O _ __L

R (I) or stereoisomer, salt, hydride, solvate or crystalline form thereof, wherein B_Nuc a naturally occurring purine or pyrimidine base, or an analog thereof, results; L corresponds to a lipophilic carrier, an alkyl

161 substituted or unsubstituted, substituted or unsubstituted heteroalkyl, or O-substituted glyceryl of the Formula -CH2CH (OR¹) -CH2 (OR²) (II), where R¹ and R² correspond independently to substituted or unsubstituted alkyl, or substituted or unsubstituted aryl; R results in a 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 corresponds to hydrogen, substituted or unsubstituted lower alkyl, or substituted or unsubstituted lower heteroalkyl.

P2 mode. A method of treating a viral disease in a subject, comprising the administration to a subject that requires it, of a therapeutically effective amount of a P1 Modality compound.

P3 mode. A method of treating cancer in a subject, which comprises the administration to a subject that requires it in a therapeutically effective amount of a compound of the P1 Modality.

P4 mode. A method to eliminate or inhibit the growth of a transformed cell, which comprises contact with a transformed cell with a therapeutically effective amount of a compound of the P1 Modality.

P5 mode. A method for treating a

162 Proliferative disorder in a subject, which comprises the administration to a subject that requires a therapeutically effective amount of a compound of the P1 Modality.

P6 mode. A pharmaceutical composition comprising a compound in accordance with Modality P1 and a pharmaceutically acceptable excipient.

P7 mode. A method for the synthesis of a compound with the structure of Formula (I) according to Scheme 2:

Scheme 2

<img file="MX367403B_D0162.tif" />

<img file="MX367403B_D0163.tif" />

where Bn_uc corresponds to a naturally occurring purine or pyrimidine base, or analogous thereof; L represents a lipophilic carrier, O-substituted glyceryl of the Formula -CHzCH (OR¹) -CHj (OR²) (II), where R¹ and R² correspond independently to substituted or unsubstituted alkyl, or substituted or unsubstituted aryl; R results in a lower substituted or unsubstituted alkyl, lower substituted heteroalkyl or

163

<img file="MX367403B_D0164.tif" />

unsubstituted, substituted or unsubstituted lower cycloalkyl, substituted or unsubstituted lower heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted lower heteroaryl; and X corresponds to hydrogen, substituted or unsubstituted lower alkyl, or substituted or unsubstituted lower heteroalkyl; likewise Y represents a leaving group; The method includes: 1) the contact of a protected nucleoside B_Nuc with structure of Formula (2-1), with an ester with structure of Formula (2-2) in the presence of a strong base under suitable conditions to generate a monoester with structure of Formula (2-3); as well as 2) the reaction of said monoester with a structure of Formula (2-3) with L-OH in the presence of a coupling agent, thus synthesizing a compound with a structure of Formula (I).

Subsequent modalities including the following.

Hydride mode, solvate

one. A compound of the Formula (la), or a pharmaceutically acceptable salt, or crystalline form thereof:

®Nuc (a)

<img file="MX367403B_D0165.tif" />

—L^to

X^to

O — R^to (the) where: B_Wildebeestc (ai corresponds to a naturally occurring purine, a naturally occurring pyrimidine, an unnaturally occurring purine or a

<img file="MX367403B_D0166.tif" />

164 Unnaturally occurring pyrimidine; L^to it represents an unsubstituted C12-24 alkyl, an unsubstituted C13-29 heteroalkyl or a glyceryl fraction, wherein the glyceryl fraction is substituted with one or more groups selected from an unsubstituted C13-29 alkyl, a C13- heteroalkyl. 29 unsubstituted, a substituted or unsubstituted aryl (Ci-6 alkyl), a substituted or unsubstituted heteroaryl (Ci-6 alkyl) and a substituted or unsubstituted heterocycloalkyl (Ci-e alkyl); R^to from the group consisting of an unsubstituted Ci-6 alkyl, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl (Ci-6&gt; alkyl, a substituted or unsubstituted heteroaryl (Ci-e alkyl) and a substituted or unsubstituted heterocycloalkyl (Ci- alkyl₆); as well as X^to represents hydrogen, a Ci alkyl₆ unsubstituted, a halogen substituted with C1-6 alkyl, a hydroxy substituted with Ci-¡alkyl or an unsubstituted C1-6 alkoxy.

<td></td><td>Modality</td><td> 2.</td><td>The</td><td>compound</td><td>from</td><td>the</td><td>Modality</td><td> 1,</td><td>in</td><td>where</td><td>X^to</td>

<td>it is</td><td>hydrogen.</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td>Modality</td><td> 3.</td><td>The</td><td>compound</td><td>from</td><td>the</td><td>Modality</td><td> 1,</td><td>in</td><td>where</td><td>X^to</td>

<td>it is</td><td>methyl.</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td>Modality</td><td> 4 .</td><td>The</td><td>compound</td><td>from</td><td>the</td><td>Modality</td><td> 1,</td><td>in</td><td>where</td><td>X^to</td>

<td>it is</td><td>methoxy</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td>Modality</td><td> 5.</td><td>The</td><td>compound</td><td>from</td><td>the</td><td>Modality</td><td> 1,</td><td>in</td><td>where</td><td>X^to</td>

it is a fluoro substituted with C1-6 alkyl.

165

<img file="MX367403B_D0167.tif" />

Modality 6. The compound of Modality 5, where X^toIt is a CH2F.

Modality 7. The compound of Modality 1, where X^toit's a CH₂OH

Modality 8. The compound of any of Modalities 1-7, where L^to it is an unsubstituted C13-29 heteroalkyl.

Modality 9. The compound of Modality 8, where L^tocontains the structure - (CH2) 1-6-O- (CH₂) 11-21-CH3.

Modality 10. The compound of Modality 9, where L^tocontains the structure - (CH₂) ₂-0- (CH₂) 17-CH3.

Modality 11. The compound of Modality 9, where L^tocontains the structure - (CH₂) ₃-OR- (CH₂) 15-CH3.

Modality 12. The compound of Modality 8, where L^tocontains the structure - (CH₂) i-₆-OR- (CH₂) 10-20- (CHCH₃) -CH₃.

Modality 13. The compound of any of Modalities 1-7, where L^to It is a fraction of substituted glyceryl.

Modality 14. The compound of Modality 13, where L^tocontains the structure - (CH2) -CH (OR^{to the}) - (CH2) -O (CH₂) 11-21-CH3, where R^{to the} corresponds to a substituted or unsubstituted aryl (Cie alkyl), a substituted or unsubstituted heteroaryl (Ci- alkyl₆) and a substituted or unsubstituted heterocycloalkyl (Ci-alkyl₆).

Modality 15. The compound of Modality 14, where L^to It contains the structure.

<img file="MX367403B_D0168.tif" />

166

O (CH₂) i₇CH₃

<img file="MX367403B_D0169.tif" />

Modality 16. The compound of Modality 1, where R^toIt is a substituted or unsubstituted aryl.

Modality 17. The compound of Modality 16, wherein the substituted or unsubstituted aryl corresponds to a substituted or unsubstituted phenyl.

Modality 18. The compound of Modality 16, wherein the substituted or unsubstituted aryl corresponds to a substituted or unsubstituted naphthyl.

Modality 19. The compound of Modality 1, where R^tocorresponds to a substituted or unsubstituted aryl (Ci-e alkyl).

Modality 20. The compound of Modality 19, wherein the substituted or unsubstituted aryl (Ci-e alkyl) results in a substituted or unsubstituted benzyl.

Modality 21. The compound of Modality 1, where R^toa substituted or unsubstituted heterocycloalkyl results (Cl-6 alkyl).

Modality 22. The compound of Modality 21, wherein the substituted or unsubstituted heterocycloalkyl (Ci-β alkyl) is a substituted or unsubstituted galactosyl.

Modality 23. The compound of Modality 1, where

<img file="MX367403B_D0170.tif" />

167

BNuc (a) corresponds to a naturally occurring purine.

Modality 24. The compound of Modality 1, where

B_NuC(a) represents a naturally occurring pyrimidine.

Modality 25. The compound of Modality 1, where

Bnucoi is a purine that occurred unnaturally.

Modality 26. The compound of Modality 1, where

BNuc (a) is a non-naturally occurring pyrimidine.

Modality 27. The compound of Modality 1, where

Bwuc (a) is selected from the group consisting of:

<img file="MX367403B_D0171.tif" />

jwv '«/ vw kA / v \ p

<img file="MX367403B_D0172.tif" />

Mocféffídad 28. The Of &amp; npuestX d ^ fa Modality 1, where the compound contains the structure:

<img file="MX367403B_D0173.tif" />

X^to

Modality 29. The compound of Modality 1, wherein the compound contains the structure:

168 ^BNuc (a) O i λ n — L^to | b — R^to

X^to

Modality 30. The compound of Modality 1 where the compound contains the structure:

<img file="MX367403B_D0174.tif" />

<img file="MX367403B_D0175.tif" />

<img file="MX367403B_D0176.tif" />

Modality 31.

The compound of Modality 1, wherein the compound is selected from any of the compounds in the

Tables 1-10, or a hydride salt, solvate or crystalline form thereof pharmaceutically acceptable.

Modality 32. The compound of Modality 1, wherein the compound is selected from the group consisting of:

<img file="MX367403B_D0177.tif" />

<img file="MX367403B_D0178.tif" />

169

<img file="MX367403B_D0179.tif" />

<img file="MX367403B_D0180.tif" />

<img file="MX367403B_D0181.tif" />

<img file="MX367403B_D0182.tif" />

170

<img file="MX367403B_D0183.tif" />

<img file="MX367403B_D0184.tif" />

<img file="MX367403B_D0185.tif" />

<img file="MX367403B_D0186.tif" />

171

<img file="MX367403B_D0187.tif" />

172

NHh

<img file="MX367403B_D0188.tif" />

<img file="MX367403B_D0189.tif" />

NHp

<img file="MX367403B_D0190.tif" />

<img file="MX367403B_D0191.tif" />

173

<img file="MX367403B_D0192.tif" />

<img file="MX367403B_D0193.tif" />

174

<img file="MX367403B_D0194.tif" />

or a pharmaceutically acceptable salt, hydride, solvate or crystalline form thereof of any of the foregoing.

Modality 33. A pharmaceutical composition that includes an effective amount of a compound of any of modalities 1-32, or a pharmaceutically acceptable salt, hydride, solvate or crystalline form thereof and a pharmaceutically acceptable excipient.

Modality 34. The pharmaceutical composition of modality 33, wherein the pharmaceutical composition is in the form of a cream, a gel or an ointment.

Modality 35. The pharmaceutical composition of modality 33 or 34, wherein the pharmaceutical composition corresponds to a topical formulation.

Modality 36. The use of a compound of any of the modalities 1-32, or a salt, hydride, solvate or crystalline form thereof pharmaceutically acceptable, in the preparation of a medicament for the treatment of a viral disease in a subject , where the viral disease is selected from

175 group consisting of human papillomavirus, HIV, hepatitis B virus, hepatitis C virus, variola virus, vaccine virus, an adenovirus, a cytomegalovirus, herpes simplex virus type 1, herpes simplex virus type 2, Epstein virus Barr, BK virus, JC virus, feline leukemia virus and feline immunodeficiency virus.

Modality 37. The use of modality 36, wherein said virus corresponds to the human papillomavirus.

Modality 38. The use of modality 37, said compound, or a pharmaceutically acceptable salt, hydride, solvate or crystalline form thereof, for use in the treatment of a plurality of human papillomavirus types.

Modality 39. The use of modality 37, wherein the human papillomavirus is selected from the group consisting of human papillomavirus type 11, type 16 and type 18.

Modality 40. The use of a compound of any of the modalities 1-32, or a salt, hydride, solvate or crystalline form thereof pharmaceutically acceptable, in the preparation of a medicament for treating cervical cancer in a subject.

Modality 41. The use of a compound of any of the modalities 1-32, or a pharmaceutically acceptable salt, hydride, solvate or crystalline form thereof, in the preparation of a medicament for the inhibition of the growth of a cell transformed by a virus, where the virus is

<img file="MX367403B_D0195.tif" />

176 Select from the group consisting of human papillomavirus, HIV, hepatitis B virus, hepatitis C virus, variola virus, vaccine virus, an adenovirus, a cytomegalovirus, herpes simplex virus type 1, herpes simplex virus type 2, Epstein Barr virus, BK virus, JC virus, feline leukemia virus and feline immunodeficiency virus.

Modality 42. A compound of any of modalities 1-32, or a pharmaceutically acceptable salt, hydride, solvate or crystalline form thereof, for use in the treatment of a viral disease in a subject, wherein the viral disease is selected from group consisting of human papillomavirus, HIV, hepatitis B virus, hepatitis C virus, variola virus, vaccine virus, an adenovirus, a cytomegalovirus, herpes simplex virus type 1, herpes simplex virus type 2, Epstein Barr virus, BK virus, JC virus, feline leukemia virus and feline immunodeficiency virus.

Modality 43. The compound of modality 42, wherein said virus corresponds to the human papillomavirus.

Modality 44. The compound of modality 43, or a pharmaceutically acceptable salt, hydride, solvate or crystalline form thereof, for use in the treatment of a plurality of human papillomavirus types.

Modality 45. The compound of modality 43, wherein the human papillomavirus is selected from the group consisting of human papillomavirus type 11, type 16 and type 18.

<img file="MX367403B_D0196.tif" />

177

Modality 46. A compound of any of the modalities 1-32, or a salt, hydride, solvate or crystalline form thereof pharmaceutically acceptable, for use in the treatment of cervical cancer in a subject.

Modality 47. A compound of any of modalities 1-32, or a pharmaceutically acceptable salt, hydride, solvate or crystalline form thereof, for use in inhibiting the growth of a cell transformed by a virus, wherein the virus is selected from the group consisting of human papillomavirus, HIV, hepatitis B virus, hepatitis C virus, variola virus, vaccine virus, an adenovirus, a cytomegalovirus, herpes simplex virus type 1, herpes simplex virus type 2, Epstein Barr virus, BK virus, JC virus, feline leukemia virus and feline immunodeficiency virus.

Modality 48. A method for the synthesis of the compound of Formula (la) in accordance with Modality 1:

<img file="MX367403B_D0197.tif" />

where: BNuctai corresponds to a naturally occurring purine, a naturally occurring pyrimidine, a purine

<img file="MX367403B_D0198.tif" />

178 unnaturally occurring or an unnaturally occurring pyrimidine;

L^to it results in an unsubstituted C12-24 alkyl, an unsubstituted C13-29 heteroalkyl or a substituted glyceryl fraction, wherein the glyceryl fraction is substituted with one or more groups selected from an unsubstituted C13-29 alkyl, a C13- heteroalkyl 29 unsubstituted, a substituted or unsubstituted aryl (Ci-6I alkyl, a substituted or unsubstituted heteroaryl (Ci-s alkyl) and a substituted or unsubstituted heterocycloalkyl (Ci-β alkyl); R^to is selected from the group consisting of an unsubstituted Ci-e alkyl, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl (Ci-6 alkyl), a heteroaryl substituted or unsubstituted (Ci-e alkyl) and a substituted or unsubstituted heterocycloalkyl (Ci-e alkyl); X^to represents hydrogen, an unsubstituted C1-6 alkyl, a halogen substituted with C1-6 alkyl, a hydroxy substituted C1-6 alkyl or an unsubstituted C1-6 alkoxy; as well as, and^to It is a leaving group; The method includes: contacting a compound of the Formula (2-la) containing a BNu_C(a) protected with a compound of the Formula (2-2a) in the presence of a strong base to form a compound of the Formula (2-3a); and react to the compound of the Formula (2-3a) with L^to-OH in the presence of a coupling agent to form the compound of Formula (la).