Acyclic nucleoside phosphonate diesters for use in treating human papilloma virus, cervical intraepithelial neoplasia, anal intraepithelial neoplasia, or vulvar intraepithelial neoplasia

CROSS-REFERENCES TO RELATED APPLICATIONS [0001] This application claims the benefit of U.S. Provisional Application No. 61/793,993, filed March 15, 2013, the content of which is incorporated herein by reference in its entirety 10 and for all purposes.

STATEMENT AS TO RIGHTS TO INVENTIONS MADE UNDER FEDERALLY SPONSORED RESEARCH AND DEVELOPMENT [0002] This invention was made with government support under grant numbers AI-071803, AI-074057 and EY07366 awarded by the National Institutes of Health. The Government has 15 certain rights in the invention.

REFERENCE TO A SEQUENCE LISTING, A TABLE, OR A COMPUTER PROGRAM LISTING APPENDIX SUBMITTED AS AN ASCII FILE [0003] The Sequence Listing written in file 88654-900583 ST25.TXT, created March 11, 2014, 1,866 bytes, machine format IBM-PC, MS-Windows operating system, is hereby incorporated by reference.

BACKGROUND [0004] The present disclosure relates, inter alia, to compositions and methods for treating viral diseases and cancer, In one aspect it relates to lipophilic antiviral and anticancer acyclic nucleoside phosphonate diesters, preparation thereof, and methods of using the compounds to 25 treat viral diseases and cancer.

[0005] Viruses are infectious particles that can replicate their DNA and RNA only within host cells. Viral infections may lead to mild or severe illnesses in humans and mammals. Examples of viral infections include hepatitis B and C, smallpox, herpes simplex, cytomegalovirus, human immunodeficiency virus (HIV), influenza, adenovirus, chickenpox, 30 BK virus, JC virus and precancerous lesions caused by infections with the human papillomavirus (cervical intraepithelial neoplasia, vaginal and anal intraepithelial neoplasia). Viral infection may also lead to cancer in humans and other species. Viruses known to cause

WO 2014/143643

PCT/US2014/027005 cancer include but are not limited to human papilloma virus (HPV), hepatitis B virus (HBV), hepatitis C virus (HCV), HIV and Epstein Barr virus (EBV). Vaccination has been successful in preventing infection from many viruses. Antiviral agents are known that interfere with viral DNA or RNA synthesis and viral replication and are used to prevent or treat viral infections in mammals and humans. For example, combinations of antiviral drugs are used to treat AIDS, hepatitis B, hepatitis C, herpes simplex viruses, cytomegalovirus and influenza. Despite these successes, viral diseases remain an important public health problem and improved antiviral agents and anticancer agents are needed. For example, there is presently no approved antiviral treatment for human papillomavirus infections.

[0006] Many antiviral drugs are nucleoside or nucleotide analogs. Examples of antiviral nucleoside analogs include azidothymidine, acyclovir, ganciclovir, lamivudine and emtricitabine. Acyclic nucleoside phosphonates (ANPs) are a class of nucleotide analogs and are effective antiviral agents. Adefovir, tenofovir and cidofovir (CDV) are ANPs that have been approved for clinical use against human infections with HBV, HIV and CMV, respectively.

[0007] ANPs are known in the art not to be absorbed readily from the gastrointestinal tract of mammals because of their molecular weight and the presence of the double negative charge on the phosphonate. Because of their poor oral pharmacokinetic properties, ANPs are usually converted to prodrugs to produce clinically useful therapeutic agents. It has been demonstrated that masking one or both negative charges with promoieties improves the uptake and transport into the small intestinal enterocytes where the promoiety is cleaved, releasing the ANP into the circulation; examples include tenofovir disoproxil fumarate and adefovir dipivoxil. Another approach is to prepare alkoxyalkyl or alkyl monoesters of ANPs to increase oral bioavailability of the drug. With the alkoxyalkyl ANP monoester approach, side effects may occur when non-targeted tissues such as the small intestine are overexposed. For example, in enterocytes, enzymatic cleavage of the promoiety by a phospholipase C or an acid sphingomyelinase to the ANP may result in local toxicity because of further anabolic phosphorylation to the ANP diphosphate which may inhibit enterocyte DNA synthesis. Lipophilic ANP diester compounds are anticipated to undergo less cleavage from intact prodrug to ANP in the small intestine enterocytes following oral administration reducing GI side effects and releasing more drug substance into the circulation and producing higher levels of the drug substance in the blood.

WO 2014/143643

PCT/US2014/027005 [0008] ANPs or their alkyl or alkoxyalkyl monoesters may exhibit limited uptake in certain target tissues such as the central nervous system. An additional advantage of nucleoside phosphonate diesters is the masking of the remaining negative charge on the phosphonate oxygen with a second masking group which can increase penetration of the drug substance into the central nervous system (CNS) for treatment of CNS viral infections (for example, HIV or JC virus) or for treatment of brain cancers such as glioblastoma. Cancer cells rapidly synthesize DNA and undergo uncontrolled cell division. The lipophilic acyclic nucleoside phosphonate (ANP) diester compositions described herein can be metabolized to their diphosphates which inhibit or block DNA synthesis and cell division in target cancer cells, leading to cell death while having substantially lesser effects on non-malignant cells. Exposure of various types of cancer cells to acyclic nucleoside phosphonates diesters may result in much greater cytotoxicity than that observed in normal non-malignant cells. For example, leukemias, lymphomas, brain neoplasms such as glioblastoma and cervical cancer cells may be more susceptible to the cytotoxic effects when exposed to lipophilic ANP diesters than the corresponding non-malignant cell lines. Lipophilic acyclic nucleoside phosphonate diesters exhibit more selective toxicity, improved access to the central nervous system and effective topical uptake for treatment of skin cancers, viral skin infections, cervical intraepithelial neoplasia (CIN), vaginal and anal intraepithelial dysplasia, venereal warts and related infections caused by the human papillomavirus when compared to acyclic nucleoside phosphonate monoester compositions.

[0009] Compounds disclosed herein having both ANP phosphonate negative charges masked with functional groups provide for more effective use as topical agents for treatment of skin cancers and viral infections. In particular, compounds disclosed herein provide for efficacious treatment for infections of the cervical, vaginal, rectal and penile epithelium with the human papilloma virus including the 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 cervical, rectal, penile and vaginal cancer and venereal warts.

BRIEF SUMMARY [0010] In a first aspect, there is provided a compound with structure of Formula (I),

<img file="IL241554A_D0001.tif" />

X (I),

WO 2014/143643

PCT/US2014/027005 or stereoisomer, salt, hydrate, solvate, or crystalline form thereof. Regarding Formula (I), L is a lipophilic promoiety, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, or O-substituted glyceryl having the formula -C^CMOR'j-CI l₂(OR²) (II), wherein R¹ and R² are independently substituted or unsubstituted alkyl or substituted or unsubstituted aryl. R is substituted or unsubstituted lower alkyl, substituted or unsubstituted lower heteroalkyl, substituted or unsubstituted lower cycloalkyl, substituted or unsubstituted lower heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted lower heteroaryl. X is hydrogen, substituted or unsubstituted lower alkyl, or substituted or unsubstituted lower heteroalkyl.

[0011] In another aspect, there is provided a method of treating a viral disease in a subject, including administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (I).

[0012] In another aspect, there is provided a method for treating cancer in a subject, including administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (I).

[0013] In another aspect, there is provided a method for killing or inhibiting the growth of a transformed cell, including contacting a transformed cell with a therapeutically effective amount of a compound of Formula (I).

[0014] In another aspect, there is provided a method for treating a proliferative disorder in a subject, including administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (I).

[0015] In another aspect, there is provided a pharmaceutical composition which includes a compound according to Formula (I), and a pharmaceutically acceptable excipient.

[0016] In another aspect, there is provided a method for synthesis of a compound with structure of Formula (1) according to Scheme 2 disclosed herein. The method includes contacting a protected nucleoside Bn_Uc with structure of Formula (2-1) with an ester with structure of Formula (2-2) in the presence of a strong base under conditions suitable to afford a monoester with structure of Formula (2-3); and reacting the afforded monoester with L-OH in the presence of a coupling agent, thereby synthesizing a compound with structure of Formula (I).

WO 2014/143643

PCT/US2014/027005 [0017] In another aspect, there is provided a compound of Formula (la), or a pharmaceutically acceptable salt, hydrate, solvate or crystalline form thereof

<img file="IL241554A_D0002.tif" />

X^a (la),

10018] For Formula (la), B&gt;;_Uc(a) can be a naturally occurring purine, a naturally occurring pyrimidine, a non-naturally occurring purine or a non-naturally occurring pyrimidine; L^a can be an unsubstituted C12-24 alkyl, an unsubstituted C 13.29 heteroalkyl or a substituted glyceryl moiety, wherein the glyceryl moiety can be substituted with one or more groups selected from an unsubstituted C13.29 alkyl, an unsubstituted C53.29 heteroalkyl, a substituted or unsubstituted aryl(Ci_6 alkyl), a substituted or unsubstituted heteroaryl(Ci_6 alkyl) and a substituted or unsubstituted heterocycloalkyl(Cj.6 alkyl); R^a can be selected from 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(Cj.6 alkyl), a substituted or unsubstituted heteroaryl(Ci.g alkyl) and a substituted or unsubstituted heterocycloalkyl(Ci_6 alkyl); and X^a can be hydrogen, an unsubstituted C1.6 alkyl, a halogen substituted Cue alkyl, a hydroxy substituted Cu₆ alkyl or an unsubstituted Cu ₆ alkoxy.

[0019] In another aspect, there is provided a pharmaceutical composition that can include an effective amount of a compound as disclosed herein (for example, a compound of Formula (la)), or a pharmaceutically acceptable salt, hydrate, solvate or crystalline form thereof, and a pharmaceutically acceptable excipient.

[0020] In another aspect, there is provided a compound as disclosed herein (for example, a compound of Formula (la)), or a pharmaceutically acceptable salt, hydrate, solvate or crystalline form thereof, for use in treating a viral disease in a subject, wherein the viral disease can be selected from human papilloma virus, HIV, hepatitis B virus, hepatitis C virus, variola virus, vaccinia 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.

[0021] In another aspect, there is provided a compound as disclosed herein (for example, a compound of Formula (la)), or a pharmaceutically acceptable salt, hydrate, solvate or crystalline form thereof, for use in treating cancer of the cervix in a subject.

WO 2014/143643

PCT7US2014/027005 [0022] In another aspect, there is provided a compound as disclosed herein, or a pharmaceutically acceptable salt, hydrate, solvate or crystalline form thereof, for use in inhibiting growth of a cell transformed by a virus, wherein the virus can be selected from human papilloma virus, HIV, hepatitis B virus, hepatitis C virus, variola virus, vaccinia 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.

[0023] In another aspect, there is provided a compound as disclosed herein (for example, a compound of Formula (la)), or a pharmaceutically acceptable salt, hydrate, solvate or crystalline form thereof, in the preparation of a medicament for treating a viral disease in a subject, wherein the viral disease can be selected from human papilloma virus, HIV, hepatitis B virus, hepatitis C virus, variola virus, vaccinia 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.

[0024] In another aspect, there is provided use of a compound as disclosed herein (for example, a compound of Formula (la)), or a pharmaceutically acceptable salt, hydrate, solvate or crystalline form thereof, in the preparation of a medicament for treating cancer of the cervix in a subject.

[0025] In another aspect, there is provided use of a compound as disclosed herein (for example, a compound of Formula (la)), or a pharmaceutically acceptable salt, hydrate, solvate or crystalline form thereof, in the preparation of a medicament for inhibiting growth of a cell transformed by a virus, wherein the virus can be selected from human papilloma virus, HIV, hepatitis B virus, hepatitis C virus, variola virus, vaccinia 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.

[0026] In another aspect, there is provided a method of synthesis of a compound with structure of Formula (la).

BRIEF DESCRIPTION OF THE DRAWINGS [0027] Fig. 1 provides a chromatogram of compound la (fast-eluting) and compound lb (slow eluting), as described in Example 2. X-axis: time (min); Y-axis (milli-absorption units, mAu). Solvent: 50:50:0.1 Water:Acetonitrile:TFA.

WO 2014/143643

PCT/US2014/027005

DETAILED DESCRIPTION

I. Definitions [0028] The abbreviations used herein have their conventional meaning within the chemical and biological arts. The chemical structures and formulae set forth herein are constructed according to the standard rules of chemical valency known in the chemical arts.

[0029] Where substituent groups are specified by their conventional chemical formulae, written from left to right, they equally encompass the chemically identical substituents that would result from writing the structure from right to left, e.g,, -CHjO- is equivalent to -OCH·,-.

[0030] As used herein, the term “alkyl,” by itself or as part of another substituent, means, unless otherwise stated, and includes a straight (i.e., unbranched) or branched chain, or combination thereof, which may be fully saturated, mono- or polyunsaturated and can include di- and multivalent radicals, having the number of carbon atoms designated (i.e,, Ci-C|₀means one to ten carbons). Alkyl is an uncyclized chain. Examples of saturated hydrocarbon radicals include, but are not limited to, groups such as methyl, ethyl, n-propyl, isopropyl, nbutyl, t-butyl, isobutyl, sec-butyl, (cyclohexyl)methyl, homologs and isomers of, for example, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like.

[0031] An unsaturated alkyl group is one having one or more double bonds (an “alkenyl group”) or triple bonds (an “alkynyl group”). Examples of unsaturated alkyl groups include, but are not limited to, the alkenyl groups vinyl, 2-propenyl, crotyl, 2-isopentenyl, 2(butadienyl), 2,4-pentadienyI, 3-(1,4-pentadienyl),and the alkynyl groups ethynyl, 1- and 3propynyl, 3-butynyl, and the higher homologs and isomers.

[0032] An alkoxy is an alkyl attached to the remainder of the molecule via an oxygen linker (-O-).

[0033] The term “alkylene,” by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from an alkyl, as exemplified, but not limited by, -CH2CH2CH2CH2-. Typically, an alkyl (or alkylene) group will have from 1 to 24 carbon atoms, or 10 or fewer carbon atoms. A “lower alkyl” or “lower alkylene” is a shorter chain alkyl or alkylene group, generally having eight or fewer carbon atoms.

[0034] The term “heteroalkyl,” by itself or in combination with another term, means, unless otherwise stated, a stable straight or branched chain, or combinations thereof, consisting of at

WO 2014/143643

PCT7US2014/027005 least one carbon atom and at least one heteroatom selected from the group consisting of Ο, N, P, Si, and S, and wherein the nitrogen and sulfur atoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized. The heteroatom(s) Ο, N, P, S, and Si may be placed at any interior position of the heteroalkyl group or at the position at which the alkyl group is attached to the remainder of the molecule. Heteroalkyl is an uncyclized chain. Examples include, but are not limited to: “CH2-CFI2-O-CH3, -CH₂-CH₂-NH-CH₃, -CH₂-CH₂-N(CH₃)-CH₃, -CH₂-S-CI-I₂-CH₃, -CH₂-CH₂, -S(O)-CH₃, -CH₂-CH₂-S(O)₂-CH₃, -CH=CH-O-CH₃, -Si(CH₃)₃, -CH₂-CH=N-OCH₃, -CH=CH-N(CH₃)-CH₃, -0-CH3, “O-CH₂-CH₃, and -CN. Up to two heteroatoms may be consecutive, such as, for example, -CH₂-NH-OCH₃.

[0035] Similarly, the term “heteroalkylene,” by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from 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 either or both of the chain termini (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, and the like). Still further, for alkylene and heteroalkylene linking groups, no orientation of the linking group is implied by the direction in which the formula of the linking group is written. For example, the formula -C(O)2R'- represents both -C(O)₂R'- and -R'C(O)₂-.

[0036] As described above, heteroalkyl groups, as used herein, include those groups that are attached to the remainder of the molecule through a heteroatom, such as -NR'R, -OR', -SR', and/or -SO₂R'. Where “heteroalkyl” is recited, followed by recitations of specific heteroalkyl groups, such as -NR'R or the like, it will be understood that the terms heteroalkyl and -NR’R are not redundant or mutually exclusive. Rather, the specific heteroalkyl groups are recited to add clarity. Thus, the term “heteroalkyl” should not be interpreted herein as excluding specific heteroalkyl groups, such as -NR'R or the like.

[0037] The terms “cycloalkyl” and “heterocycloalkyl,” by themselves or in combination with other terms, mean, unless otherwise stated, cyclic versions of “alkyl” and “heteroalkyl,” respectively. Cycloalkyl and heteroalkyl are not aromatic. Additionally, for heterocycloalkyl, a heteroatom can occupy the position at which the heterocycle is attached to the remainder of the molecule. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like. Examples of heterocycloalkyl include, but are not limited to,

WO 2014/143643

PCT/US2014/027005 l-(l,2,5,6-tetrahydropyridyl), 1-piperidinyi, 2-piperidinyl, 3-piperidinyi, 4-morpholinyl, 3morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-y], tetrahydrothien-2-yl, tetrahydrothien-3-yl, 1-piperazinyl, 2-piperazinyl, and the like.

[0038] A “cycloalkylene” and a “heterocycloalkylene,” alone or as part of another substituent, means a divalent radical derived from a cycloalkyl and heterocycloalkyl, respectively.

[0039] The terms “halo” or “halogen,” by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom. Additionally, terms such as “haloalkyl” are meant to include monohaloalkyl and polyhaloalkyl. For example, the term “halo(Ci-ChalkyI” includes, but is not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like.

[0040] The term “acyl” means, unless otherwise stated, -C(O)R* where R* is a substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroaikyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0041] The term “aryl” means, unless otherwise stated, a polyunsaturated, aromatic, hydrocarbon substituent, which can be a singie ring or multiple rings (preferably from 1 to 3 rings) that are fused together (i.e., a fused ring aryl) or linked covalently, A fused ring aryl refers to multiple rings fused together wherein at least one of the fused rings is an aryl ring.

[0042] The term “heteroaryl” refers to aryl groups (or rings) that contain from one to four heteroatoms selected from N, O, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom(s) are optionally quaiernized, Thus, the term “heteroaryl” includes fused ring heteroaryl groups (i.e., multiple rings fused together wherein at least one of the fused rings is a heteroaromatic ring). A 5,6-fused ring heteroarylene refers to two rings fused together, wherein one ring has 5 members and the other ring has 6 members, and wherein at least one ring is a heteroaryl ring. Likewise, a 6,6-fused ring heteroarylene refers to two rings fused together, wherein one ring has 6 members and the other ring has 6 members, and wherein at least one ring is a heteroaryl ring. And a 6,5-fused ring heteroarylene refers to two rings fused together, wherein one ring has 6 members and the other ring has 5 members, and wherein at least one ring is a heteroaryl ring. A heteroaryl group can be attached to the remainder of the molecule through a carbon or heteroatom.

WO 2014/143643

PCT/US2014/027005

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, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4isoxazolyl, 5-isoxazolyl, 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, 2-quinoxalinyl, 5quinoxalinyl, 3-quinolyl, and 6-quinolyl. Substituents for each of the above noted aryl and heteroaryl ring systems are selected from the group of acceptable substituents described below. An “arylene” and a “heteroarylene,” alone or as part of another substituent, mean a divalent radical derived from an aryl and heteroaryl, respectively.

[0043] For brevity, 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 “arylalkyl” [e.g., aryl(Cj.₆ alkyl)] is meant to include those radicals in which an aryl group is attached to an alkyl group (e.g., benzyl (Bn), phenethyl, pyridylmethyl, and the like) including those alkyl groups in which a carbon atom (e.g., a methylene group) has been replaced by, for example, an oxygen atom (e.g., phenoxymethyl, 2-pyridyloxymethyl, 3(l-naphthyloxy)propyl, and the like). Thus, the term “heteroarylalkyl” [e.g., heteroaryl(Ci_6 alkyl)] refers to those radicals in which a heteroaryl group is attached to an alkyl group. The term “heterocycloalkylalkyl” [e.g., heterocycloalkyl(Ci-₆ alkyl)] refers to those radicals in which a heterocycloalkyl is attached to an alkyl group.

[0044] The term “oxo,” as used herein, means an oxygen that is double bonded to a carbon atom.

[0045] The term “alkylsulfonyl,” as used herein, means a moiety having the formula -S(O2)-R', where R' is an alkyl group as defined above. R¹ may have a specified number of carbons (e.g., “C1-C4 alkylsulfonyl”).

[0046] Each of the above terms (e.g,, “alkyl,” “heteroalkyl,” “aryl,” and “heteroaryl”) includes both substituted and unsubstituted forms of the indicated radical. Preferred substituents for each type of radical are provided below.

[0047] Substituents for the alkyl and heteroalkyl radicals (including those groups often referred to as alkylene, alkenyl, hetcroalkylene, heteroalkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, and heterocycloalkenyl) can be one or more of a variety of groups selected from, but not limited to, -OR', =O, =NR', —N-OR¹, -NR'R, -SR', -halogen,

WO 2014/143643

PCI7US2014/027005

-SiR^rRR'’', -OC(O)R', -C(O)R', -CO₂R^r, -CONR’R, -OC(O)NR’R, -NRC(O)R',

-NR'-C(O)NRR’, -NRC(O)₂R'_S -NR-C(NR'RR')=NR^i,,,_! -NR-C(NR'R’')=NR’, -S(O)R',

-S(O)₂R', -S(O)₂NR'R, -NRSO₂R', -CN, and -NO₂ in a number ranging from zero to (2m'+l), where m' is the total number of carbon atoms in such radical, R’, R, R’, and R each preferably independently refer to hydrogen, substituted or unsubstitutcd heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl (e.g., aryl substituted with 1-3 halogens), substituted or unsubstituted alkyl, alkoxy, or thioalkoxy groups, or arylalkyl groups. When a compound includes more than one R group, for example, each of the R groups is independently selected 10 as are each R¹, R, R¹, and R group when more than one of these groups is 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-membered ring. For example, -NR’R includes, but is not limited to, 1-pyrrolidinyl and 4-morpholinyl. From the above discussion of substituents, one of skill in the art will understand that the term “substituted alkyl” is meant to include groups including carbon atoms bound to groups other than hydrogen groups, such as haloalkyl (e.g., -CF3 and -CH_zCFa) and acyl (e.g., -C(O)CH3, -C(O)CF3, -C(O)CH₂OCH₃, and the like).

[0048] Similar to the substituents described for the alkyl radical, substituents for the aryl and heteroaryl groups are varied and are selected from, for example: -OR¹, -NR'R,

-SR', -halogen, -SiR'RR’, -OC(O)R’_S -C(O)R’, -CO₂R', -CONR'R¹', -OC(O)NR'R,

-NR'^!C(O)R’, ~NR'-C(O)NRR^,) -NRC(O)2R', -NR-C(NR^,RR^,)=NR''S -NR-C(NR'R)=NR’_; -S(O)R', -S(O)₂R', -S(O)₂NR'R, -NRSO₂R', -CN, -NO₂, -R'₍ -N₃, -CH(Ph)₂, fluoro(Ci-C₄)alkoxy, and fluoro(Ci-C4)alkyl, in a number ranging from zero to the total number of open valences on 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 are each R', R, R’, and R groups when more than one of these groups is present.

[0049] Two or more substituents may optionally be joined to form aryl, heteroaryl, cycloalkyl, or heterocycloalkyl groups. Such so-called ring-forming substituents are typically, though not necessarily, found attached to a cyclic base structure. In embodiments,

II

WO 2014/143643

PCT/US2014/027005 the 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 yet another embodiment, the ring-forming substituents arc attached to nonadjacent members of the base structure.

[0050] Two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally form a ring of the formula -T-C(O)-(CRR’)_q-U-, wherein T and U are independently -NR-, -0-, -CRR'-, or a single bond, and q is an integer of from 0 to 3. Alternatively, two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -A-(CH2)_r-B-, wherein A and B ate independently -CRR'-, -O-, -NR-, -S-, -S(O) -, -S(O)₂-, -S(O)₂NR'-, or a single bond, and r is an integer of from 1 to 4. One of the single bonds of the new ring so formed may optionally be replaced with a double bond. Alternatively, two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -(CRR')_S-X'- (C”R')d-, where s and d are independently integers of from 0 to 3, and X' is -O-, -NR'-, -S-, -S&lt;O)-₅ -S(O)₂-, or -S(O)₂NR’-. The substituents R, R', R, and R’ are preferably independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.

[0051] As used herein, the terms “heteroatom” or “ring heteroatom” are meant to include oxygen (O), nitrogen (N), sulfur (S), phosphorus (P), and silicon (Si).

[0052] A “substituent group,” as used herein, means a group selected from the following moieties:

(A) -OH, -NH₂, -SH, -CN, -CF₃, -NO₂, 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:

WO 2014/143643

PCI7US2014/027005 (i) oxo, -OH, -NH₂, -SH, -CN, -CF₃, -N0₂, halogen, unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloaikyl, unsubstiiuted aryl, unsubstituted heteroaryl, and (ii) alkyl, heteroalkyl, cycloalkyl, heterocycloaikyl, aryl, and heteroaryl, substituted with at least one substituent selected from:

(a) oxo, -OH, -NH₂, -SH, -CN, -CF₃, -N0₂, halogen, unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloaikyl, unsubstituted aryl, unsubstituted heteroaryl, and (b) alkyl, heteroalkyl, cycloalkyl, heterocycloaikyl, aryl, or heteroaryl, substituted with at least one substituent selected from:

oxo, -OH, -NH_2j -SH, -CN, -CF₃, -N0₂, halogen, unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloaikyl, unsubstituted aryl, and unsubstiiuted heteroaryl.

[0053] A “size-limited substituent” or “ size-limited substituent group,” as used herein, means a group selected from all of the substituents described above for a “substituent group,” wherein each substituted or unsubstituted alkyl is a substituted or unsubstituted Ci-C₂s alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 30 membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C₃-C₈ cycloalkyl, each substituted or unsubstituted heterocycloaikyl is a substituted or unsubstituted 3 to 8 membered heterocycloaikyl, each substituted or unsubstituted aryl is a substituted or unsubstituted C₆-Ci₀ aryl, and each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5 to 10 membered heteroaryl.

[0054] A “lower substituent” or “ lower substituent group,” as used herein, means a group selected from all of the substituents described above for a “substituent group,” wherein each substituted or unsubstituted alkyl is a substituted or unsubstituted Ci-C₈ alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 8 membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C₃C₇ cycloalkyl, each substituted or unsubstituted heterocycloaikyl is a substituted or unsubstituted 3 to 7 membered heterocycloaikyl, each substituted or unsubstituted aryl is a substituted or unsubstituted C₆-C_!0 aryl, and each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5 to 9 membered heteroaryl.

WO 2014/143643

PCT/US2014/027005 [0055] In embodiments, each substituted group described in the compounds herein is substituted with at least one substituent group. More specifically, in embodiments, each substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and/or substituted heteroarylene described in the compounds herein are substituted with at least one substituent group. In embodiments, at least one or all of these groups are substituted with at least one size-limited substituent group. In embodiments, at least one or all of these groups are substituted with at least one lower substituent group.

[0056] In embodiments of the compounds herein, each substituted or unsubstituted alkyl may be a substituted or unsubstituted C|-C -:,o alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 30 membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C₃-C₈ cycloalkyl, each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to 8 membered heterocycloalkyl, each substituted or unsubstituted aryl is a substituted or unsubstituted C₆Cio aryl, and/or each substituted or unsubstituted heteroaryi is a substituted or unsubstituted 5 to 10 membered heteroaryl. In embodiments of the compounds herein, each substituted or unsubstituted alkylene is a substituted or unsubstituted C1-C30 alkylene, each substituted or unsubstituted heteroalkylene is a substituted or unsubstituted 2 to 30 membered heteroalkylene, each substituted or unsubstituted cycloalkylcne is a substituted or unsubstituted C₃-C₈ cycloalkylene, each substituted or unsubstituted heterocycloalkylene is a substituted or unsubstituted 3 to 8 membered heterocycloalkylene, each substituted or unsubstituted arylene is a substituted or unsubstituted Cg-Cjo arylene, and/or each substituted or unsubstituted heteroarylene is a substituted or unsubstituted 5 to 10 membered heteroarylene.

[0057] In embodiments, each substituted or unsubstituted alkyl is a substituted or unsubstituted Ci-C« alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 8 membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C3-C7 cycloalkyl, each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to 7 membered heterocycloalkyl, each substituted or unsubstituted aryl is a substituted or unsubstituted Cs-Cio aryl, and/or each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5 to 9 membered heteroaryl. In some embodiments, each substituted or unsubstituted alkylene is a substituted

WO 2014/143643

PCI7US2014/027005 or unsubstituted Ci-C_s alkylene, each substituted or unsubstituted heteroalkylene is a substituted or unsubstituted 2 to 8 membered heteroalkylene, each substituted or unsubstituted cycloalkylene is a substituted or unsubstituted C3-C7 cycloalkylene, each substituted or unsubstituted heterocycloalkylene is a substituted or unsubstituted 3 to 7 5 membered heterocycloalkylene, each substituted or unsubstituted arylene is a substituted or unsubstituted C₆-C|₀ arylene, and/or each substituted or unsubstituted heteroarylene is a substituted or unsubstituted 5 to 9 membered heteroarylene.

[0058] The term “pharmaceutically acceptable salts” is meant to include salts of the active compounds that are prepared with relatively nontoxic acids or bases, depending on the 10 particular substituents found on the compounds described herein. When compounds described herein contain relatively acidic functionalities, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium 15 salt, or a similar salt. When compounds described herein contain relatively basic functionalities, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as the salts derived from relatively nontoxic organic acids like acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic, ptolylsulfonic, citric, tartaric, oxalic, methanesulfonic, and the like. Also included are salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galactunoric acids and the like (jee, 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 be converted into either base or acid addition salts.

[0059] Thus, the compounds described herein [for example, a compound of Formula (I) and/or a compound of Formula (la)] may exist as salts, such as with pharmaceutically acceptable acids. Examples of such salts include hydrochlorides, hydrobromides, sulfates, methanesulfonates, nitrates, maleates, acetates, citrates, fumarates, tartrates (e.g., (+)15

WO 2014/143643

PCI7US2014/027005 tartrates, (-)-tartrates, or mixtures thereof including racemic mixtures), succinates, benzoates, and salts with amino acids such as glutamic acid. These salts may be prepared by methods known to those skilled in the art.

[0060] The neutral forms of the compounds can be regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. The parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents.

[0061] In addition to salt forms, compounds described herein [for example, a compound of Formula (I) and/or a compound of Formula (la)] can be in a prodrug form, Prodrugs of the compounds described herein are those compounds that readily undergo chemical changes under physiological conditions to provide a compound described herein. Additionally, prodrugs can be converted to a compounds described herein by chemical or biochemical methods in an ex vivo environment. For example, prodrugs can be slowly converted to a compounds described herein when placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent. The term “promoiety” is meant to refer to a chemical entity reversibly attached to the drug that improves an aspect of drug performance by masking a problematic functional group.

[0062] Certain compounds described herein [for example, a compound of Formula (I) and/or a compound of Formula (la)] can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms are equivalent to unsolvated forms and are encompassed. Certain compounds described herein [for example, 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 uses contemplated and are intended.

[0063] Certain compounds described herein [for example, a compound of Formula (I) and/or a compound of Formula (la)] can possess asymmetric atoms (optical centers) or double bonds; the racemates, diastereomers, tautomers, geometric isomers, and individual isomers arc encompassed. The compounds described herein [for example, a compound of Formula (I) and/or a compound of Formula (la)] do not include those that are known in the art to be too unstable to synthesize and/or isolate.

[0064] 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 at one

WO 2014/143643

PCT7US2014/027005 or more of the atoms that constitute such compounds. For example, the compounds may be radiolabeled with radioactive isotopes, such as for example tritium ( H), iodine-125 ( I), or carbon-14 (¹⁴C). AU isotopic variations of the compounds, whether radioactive or not, are encompassed.

[0065] The symbol denotes the point of attachment of a chemical moiety to the remainder of a molecule or chemical formula,

II. Compounds [0066] In a first aspect, there is provided a compound with structure of Formula (I):

<img file="IL241554A_D0003.tif" />

X (I) or stereoisomer, salt, hydrate, solvate, or crystalline form thereof. For the compound with structure of Formula (I), B_Nuc is a naturally occurring purine or pyrimidine base, or analog thereof; L is a lipophilic promoiety, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, or O-substituted glyceryl having the formula -CH2CH(OR’)-CH2(OR²) (Π), wherein R¹ and R² are independently substituted or unsubstituted alkyl, or substituted or unsubstituted aryl; R is substituted or unsubstituted lower alkyl, substituted or unsubstituted lower heteroalkyl, substituted or unsubstituted lower cycloalkyl, substituted or unsubstituted lower heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted lower heteroaryl; and X is hydrogen, substituted or unsubstituted lower alkyl, or substituted or unsubstituted lower heteroalkyl, [0067] In embodiments, the compound is a stereoisomer with the structure of Formula (I). In embodiments, the compound is a salt of a compound with the structure of Formula (I). In embodiments, the compound is a solvate of a compound with the structure of Formula (I). In embodiments, the compound is a crystalline form of a compound with the structure of Formula (1).

[0068] The terms “naturally occurring purine or pyrimidine base” and the like refer, in the usual and customary sense as employed in the art, to purine or pyrimidine bases, e.g., guanine, adenine, cytosine, thymine, uracil, or 2,6-diaminopurine. Attachment of the naturally occurring purine or pyrimidine base can be at any available site, e,g., guanin-9-yl,

WO 2014/143643

PCI7US2014/027005 adenine-9-yl, cytosine-1 -yl, thymin-l-yl, uracil-l-yl, 2,6-diaminopurin-9-yl, and the like.

When attached to the remainder of the compounds described herein, the naturally occurring purine or pyrimidine base is in monovalent from (the form of a chemical moiety or substituent as known in the art).

[0069] The terms “analog of naturally occurring purine or pyrimidine base” and the like refer, in the usual and customary sense, to a chemical analog of a naturally occurring purine or pyrimidine base, as known in the art. When attached to the remainder of the compounds described herein, the analog of naturally occurring purine or pyrimidine base is in monovalent from (the form of a chemical moiety or substituent as known in the art).

[0070] Accordingly, in embodiments, B_Nuc is a naturally occurring purine or pyrimidine base. In embodiments, B_Nllc is a naturally occurring purine base. In embodiments, B_Nuc is a naturally occurring pyrimidine base. In embodiments, B_NlJC is an analog of a naturally occurring purine or pyrimidine base. In embodiments, B_Nucis an analog of a naturally occurring base. In embodiments, Bnuc is an analog of a naturally occurring pyrimidine base.

[0071] The terms “lipophilic promoiety” and the like refer to a chemical moiety which imparts increased lipophilicity when incorporated into a compound with structure of Formula (I). In embodiments, the lipophilic promoiety is a substituted or unsubstituted C_s_₂4 alkyl. In embodiments, the lipophilic promoiety is a substituted or unsubstituted heteroaikyl. In embodiments, the lipophilic promoiety is a substituted or unsubstituted C_B.₂,| alkoxyalkyl. Exemplary lipophilic promoieties include glyceryl moieties having substituted or unsubstituted alkyl, and/or substituted or unsubstituted aryl substituents. In embodiments, substitution at a glyceryl moiety is via O~substitution with a substituted or unsubstituted alkyl, and/or via O-substitution with a substituted or unsubstituted aryl. Thus, the lipophilic promoiety, L, imparts lipophilicity and therefore may include glyceryl ether linked compounds (e.g., l-O-octadecyl-2-O-benzyl) wherein the hydrogens of the glyceryl hydroxyls are replaced with substituted or unsubstituted alkyl or substituted or unsubstituted aryl groups that do not impart hydrophilicity, and the carbons atoms of the glyceryl are not further substituted. In some embodiments, L is an O-substituted glyceryl having the formula -CH₂CH(OR' )-CH₂(OR²) (II), wherein R^! and R² are independently a substituted or unsubstituted alkyl or a substituted or unsubstituted aryl, [0072] In some embodiments, L is a substituted or unsubstituted alkyl, substituted or unsubstituted heteroaikyl, or an O-substituted glyceryl having the formula

WO 2014/143643

PCT/US2014/02700S

-CHaCHiOR'j-CHjCOR²) (II), wherein R¹ and R² are independently a substituted or unsubstituted alkyl or a substituted or unsubstituted aryl. In embodiments, L is an Osubstituted glyceryl. In one embodiment L is l-O-alkyl-2-O-benzyl-sn-glyceryl. In embodiments, L is l-O-octadecyl-2-O-benzyl-sn-glyceryl. In embodiments, L is an unsubstituted alkyl. In embodiments, L is a size-limited unsubstituted alkyl. In embodiments, L is Cg-24 alkyl. In embodiments, L is an unsubstituted heteroalkyl. In embodiments, L is a size-limited unsubstituted heteroalkyl. In embodiments, L is C₈.₂4 heteroalkyl. In embodiments, L is an unsubstituted alkoxyoalkyl. In embodiments, L is a size-limited unsubstituted alkoxyalkyl. In embodiments, L is C₈-₂4 alkoxyalkyl.

[0073] In embodiments, R is 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 substituted or unsubstituted lower heteroaryl. In embodiments, R is a substituted or unsubstituted lower alkyl. In embodiments, R is a substituted or unsubstituted lower heteroalkyl. In embodiments, R is an O-substituted glyceryl having the formula -CH₂CH(OR³)-CH₂(OR⁴) (III), wherein R³ and R⁴ are independently a substituted or unsubstituted alkyl or a substituted or unsubstituted aryl. In embodiments, R is a substituted or unsubstituted lower cycloalkyl. In embodiments, R is a substituted or unsubstituted lower heterocycloalkyl. In embodiments, R is a substituted or unsubstituted hexopyranosyl. In embodiments, R is an unsubstituted hexopyranosyl. In embodiments, R is a substituted or unsubstituted aryl. In embodiments, R is a substituted or unsubstituted lower heteroaryl, In embodiments, R is an unsubstituted lower alkyl. In embodiments, R is an unsubstituted lower heteroalkyl. In embodiments, R is an unsubstituted lower cycloalkyl. In embodiments, R is an unsubstituted lower heterocycloalkyl. In embodiments, R is an unsubstituted aryl. In embodiments, R is an unsubstituted lower heteroaryl. In embodiments, R is a size-limited substituted or unsubstituted lower cycloalkyl. In embodiments, R is a size-limited substituted or unsubstituted lower heterocycloalkyl. In embodiments, R is a size-limited substituted or unsubstituted aryl. In embodiments, R is a size-limited substituted or unsubstituted lower heteroaryl. In embodiments, R is Ci-₈ substituted or unsubstituted alkyl. In embodiments, R is Ci_8 substituted or unsubstituted heteroalkyl. In embodiments, R is C₄.₈ substituted or unsubstituted cycloalkyl. In embodiments, R is C4.8 substituted or unsubstituted heterocycloalkyl. In embodiments, R is Ce-io substituted or unsubstituted aryl. In embodiments, R is C₆uo substituted or unsubstituted heteroaryl. In embodiments, R is Ci_₈

WO 2014/143643

PCT/US2014/027005 unsubstituted alkyl. In embodiments, R is C₂._s unsubstituted heteroaikyl. In embodiments, R is C4.8 unsubstituted cycloalkyl. In embodiments, R is C4.8 unsubstituted heterocycloalkyl.

In embodiments, R is C₆__i0 unsubstituted aryl. In embodiments, R is C₆.io unsubstituted heteroaryl.

[0074] In embodiments, R is 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 embodiments, R is a substituted phenyl. In embodiments, R is a substituted naphthyl. In embodiments, R is a substituted benzyl. In embodiments, R is a substituted glyceryl. In embodiments, R is a substituted hexopyranosyl. In embodiments, R is an unsubstituted phenyl. In embodiments, R is an unsubstituted naphthyl. In embodiments, R is an unsubstituted benzyl. In embodiments, R is an unsubstituted glyceryl. In embodiments, R is an unsubstituted hexopyranosyl.

[0075] In embodiments, X is hydrogen, a substituted or unsubstituted lower alkyl, or a substituted or unsubstituted lower heteroalkyl. In embodiments, X is hydrogen. In embodiments, X is a substituted or unsubstituted lower alkyl. In embodiments, X is a substituted or unsubstituted lower heteroalkyl. In embodiments, X is an unsubstituted lower alkyl. In embodiments, X is an unsubstituted lower heteroaikyl. In embodiments, X is a sizelimited substituted or unsubstituted alkyl. In embodiments, X is a size-limited substituted or unsubstituted heteroaikyl. In embodiments, X is a size-limited unsubstituted alkyl. In embodiments, X is a size-limited unsubstituted heteroaikyl. In embodiments, X is methyl. In embodiments, X is methoxymethyl. In embodiments, X is hydroxymethyl. In embodiments, X is fluoromethyl.

[0076] In embodiments, the compound with structure of Formula (I) has the structure of Formula (1-1):

®Nuc O

I W /°

0—R (1-1).

[0077] For the compound with structure of Formula ¢1-1), Bnuc is as described for any of the embodiments of the compound of Formula (I) disclosed herein, [0078] In embodiments, L is as described for any of the embodiments of the compound of Formula (1) described herein. In embodiments, L is octadecyloxyethyl, hexadecyloxypropyl,

WO 2014/143643

PCT/US2014/027005 or l-O-octadecyl-2-O-benzyI-sn-glyceryl. In embodiments, L is octadecyloxyethyl. In embodiments, L is hexadecyloxypropyl. In embodiments, L is l-O-octadecyl-2-O-benzyl-snglyceryl.

[0079] In embodiments, R is as described for any of the embodiments of the compound of Formula (I) described herein. In embodiments, R is 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 embodiments, R is a substituted phenyl. In embodiments, R is a substituted naphthyl. In embodiments, R is a substituted benzyl. In embodiments, R is a substituted glyceryl. In embodiments, R is a substituted hexopyranosyl. In embodiments, R is an unsubstituted phenyl. In embodiments, R is an unsubstituted naphthyl. In embodiments, R is an unsubstituted benzyl. In embodiments, R is an unsubstituted glyceryl. In embodiments, R is an unsubstituted hexopyranosyl.

[0080] In embodiments, the compound with structure of Formula (I) has the structure of Formula (1-2):

B_Nuc (1-2).

[0081] For the compound with structure of Formula (1-2), in one embodiment B_Nuc is as described for any ofthe embodiments of the compound ofFormulae (1)-(1-1) disclosed herein.

[0082] In embodiments, L is as described for any of the embodiments of the compound of Formulae (1)-(1-1) described herein, [0083] In embodiments, R is as described for any of the embodiments of the compound of Formulae (1)-(1-1) described herein.

WO 2014/143643

PCT/US2014/027005 [0084] In embodiments, the compound with structure of Formula (I) has the structure of

Formula (1-3):

<img file="IL241554A_D0004.tif" />

j O—R (1-3).

[0085] For the compound with structure of Formula (1-3), in one embodiment B_Nuc is as described for any of the embodiments of the compound of Formulae (1)-(1-2) disclosed herein.

[0086] In embodiments, L is as described for any of the embodiments of the compound of Formulae (1)-(1-2) described herein.

[0087] In embodiments, R is as described for any of the embodiments of the compound of Formulae (1)-(1-2) described herein.

[0088] In embodiments, the compound with structure of Formula (I) has the structure of Formula (1-4):

<img file="IL241554A_D0005.tif" />

a O—R (1-4).

[0089] For the compound with structure of Formula (1-4), in one embodiment Bnuc is as described for any of the embodiments of the compound of Formulae (1)-(1-3) disclosed herein.

[0090] In embodiments, L is as described for any of the embodiments of the compound of Formulae (1)-(1-3) described herein.

[0091] In. embodiments, R is as described for any of the embodiments of the compound of Formulae (1)-(1-3) described herein.

[0092] In embodiments, the compound with structure of Formula (I) has the structure of Formula (1-5):

WO 2014/143643

PCT/US2014/027005 ^Nuc O

I \\ X)—L

O--R (1-5).

[0093] For the compound with structure of Formula (1-5), in one embodiment B_N11C is as described for any of the embodiments of the compound of Formulae (1)-(1-4) disclosed herein.

[0094] In embodiments, L is as described for any of the embodiments of the compound of Formulae (1)-(1-4) described herein.

[0095] In embodiments, R is as described for any of the embodiments of the compound of Formulae (1)-(1-4) described herein.

X^a [0096] In another aspect, there is provided a compound of Formula (la), or a pharmaceutically acceptable salt, hydrate, solvate or crystalline form thereof:

_O__L.

I 0 -R^a (la).

[0097] For this aspect, Bnuc(b) can be a naturally occurring purine, a naturally occurring pyrimidine, a non-naturally occurring purine or a non-naturally occurring pyrimidine. L^a can be an unsubstituted C‘i224 alkyl, an unsubstituted Ci3.29 heteroalkyl or a substituted glyceryl moiety. The glyceryl moiety may be substituted with one or more groups selected from an unsubstituted C)3.29 alkyl, an unsubstituted Cb-29 heteroalkyl, a substituted or unsubstituted aryl(Ci.6 alkyl), a substituted or unsubstituted heteroaryl(Ci_6 alkyl) and a substituted or unsubstituted heterocycloalkyl(Cns alkyl). R^d can be selected from an unsubstituted Cj alkyl, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl(C]_6 alkyl), a substituted or unsubstituted heteroaryl(Ci^ alkyl) and a substituted or unsubstituted heterocycloalkyl(Ci_6 alkyl). X^a can be hydrogen, an unsubstituted alkyl, a halogen substituted Ci.₆ alkyl, a hydroxy substituted Ci.₆ alkyl or an unsubstituted Cj.₆ alkoxy.

[0098] In embodiments, X^a can be hydrogen, an unsubstituted Cialkyl, a halogen substituted C^₆ alkyl, a hydroxy substituted C_k6 alkyl or an unsubstituted alkoxy. In

WO 2014/143643

PCT/US2014/027005 embodiments, X^a can be hydrogen. In embodiments, X^a can be an unsubstituted Cb6 alkyl. In embodiments, X^a can be methyl. In embodiments, X^a can be a hydroxy substituted Ci_6 alkyl. In embodiments, X^a can be -CI-I2OH, In embodiments, X can be an unsubstituted Cj.g alkoxy. In embodiments, X^a can be methoxy. In embodiments, X^a can be a halogen substituted C|.g alkyl. In embodiments, X^a can be a fluoro substituted C,alkyl. In embodiments, X^a can be -CH2F, [0099] Further to any embodiment above, in embodiments L^a can be an unsubstituted Ci37y heteroalkyl. In embodiments, L^a can have the structure-(CH2)u6-O“(CH₂)n.₂|-CH₃. In embodiments, L^a can have the structure-(CH2)2-O-(CH2)17-CH3. In embodiments, L^a can have the structure -(CH2)₃-O-(CH2)j5-CH₃. In embodiments, L^a can have the structure (CH₂)^-O-(CH₂)₁₀.₂₀-(CHCH₃)-CH₃.

[0100] Further to any embodiment above, in embodiments L^a can be a substituted glyceryl moiety. In embodiments, L^a can have the structure -(CH2)-CH(OR^a')-(CH2)-O(CH₂)] j.₂jCH₃, wherein R^ai can be a substituted or unsubstituted aryl(Ci_6 alkyl), a substituted or unsubstituted heteroaryl(C|.e alkyl) or a substituted or unsubstituted heterocycloalkyl(Ci_6 alkyl). In embodiment, R^al can be a substituted aryl(Ci_6 alkyl). In embodiment, R^al can be an unsubstituted aryl(Ci.6 alkyl). In embodiment, R^al can be a substituted heteroary!(Ci a alkyl). In embodiment, R^al can be an unsubstituted heteroaryl(C i .g alkyl). ). In embodiment, R^al can be a substituted heterocycloalkyl(C₁.₆ alkyl). In embodiment, R^al can be an unsubstituted heterocycIoalkyi(C|.6 alkyl).

[0101] In embodiments, L^a can have the structure

<img file="IL241554A_D0006.tif" />

[0102] Further to any embodiment of the compound of Formula (la), in embodiments R^acan be a substituted or unsubstituted aryl. In embodiments, the substituted aryl can be a substituted phenyl. In embodiments, the unsubstituted aryl can be an unsubstituted phenyl. In embodiments, the substituted aryl can be a substituted naphthyl. In embodiments, the unsubstituted aryl can be an unsubstituted naphthyl.

WO 2014/143643

PCT/US2014/027005 [0103] Further to any embodiment of the compound of Formula (la), in embodiments R^a can be a substituted or unsubstituted aryl(Ci_₆ alkyl). In embodiments, the substituted aryl(Ci.₆ alkyl) can be a substituted benzyl. In embodiments, the unsubstituted aryl(Ci.₆ alkyl) can be an unsubstituted benzyl.

[0104] Further to any embodiment of the compound of Formula (la), in embodiments R^a can be a substituted or unsubstituted heterocycloalkyl(Ci_₆ alkyl). In embodiments, the substituted or unsubstituted heterocycloalkyl(Ci^ alkyl) is a substituted or unsubstituted galactosyl.

[0105 ] Further to any embodiment of the compound of Formula (la), in embodiments

B_Nllc(_a) can be a naturally occurring purine. In embodiments, ΒνοΦ) can be a naturally occurring pyrimidine. In embodiments, B^_Uc(a) can be a non-naturally occurring purine. In embodiments, B_Nuc(_a) can be a non-naturally occurring pyrimidine. The term “non-naturally occurring” and the like, in the context of purine or pyrimidine nucleoside B_Nllc(a) groups, refers to moieties having a purine or pyrimidine core and additional chemical modifications 15 not found in naturally occurring systems. Examples of purines include adenine, guanine, hypoxanthine, xanthine, theobromine, caffeine, uric acid, isoguanine, 2,6-diaminopurine. Examples of pyrimidines include cytosine, thymine, and uracil.

[0106] In embodiments, B_Nuc(a) can be selected from:

<img file="IL241554A_D0007.tif" />

<img file="IL241554A_D0008.tif" />

WO 2014/143643

PCT/US2014/027005

<td> [0107]</td><td> In embodiments, a compound of Formula (la) can have the structure: !“=&lt;&gt; o-L· 1 cl x^a</td>

<td> [0108]</td><td> In embodiments, a compound of Formula (la) can have the structure: ^Nuc(a) O I O—L^a ] b—n^a x^a</td>

<td> 5 [0109]</td><td> In embodiments, a compound of Formula (la) can have the structure: ^Nuc(a) O 1 O -L^a k ,0. 1 o—R^a X^a</td>

<td> [0110]</td><td> In embodiments, a compound of Formula (la) can have the structure: ^BNuc(a) O I ,O- L^a ξ Ό—R^a X^a</td>

<td> [0111]</td><td> In embodiments, a compound of Formula (la) can have the structure: ^Nuc(a) 0 1 O — L^a j V--R^a</td>

<td> 10</td><td> x^a</td>

<td> [0112]</td><td> In embodiments, a compound of Formula (la) can have the structure: ^Nuc(a) O I \\ ,0—1?</td>

I b—R^s x^a

WO 2014/143643

PCI7US2014/027005 [0113] In embodiments, the compound can be selected from:

<img file="IL241554A_D0009.tif" />

<img file="IL241554A_D0010.tif" />

<img file="IL241554A_D0011.tif" />

<img file="IL241554A_D0012.tif" />

<img file="IL241554A_D0013.tif" />

<img file="IL241554A_D0014.tif" />

WO 2014/143643

PCT/US2014/027005

<img file="IL241554A_D0015.tif" />

<img file="IL241554A_D0016.tif" />

<img file="IL241554A_D0017.tif" />

<img file="IL241554A_D0018.tif" />

<img file="IL241554A_D0019.tif" />

WO 2014/143643

PCT/US2014/027005 h₂n

<img file="IL241554A_D0020.tif" />

(CH₂}₂-O-(CH₂)₁₇-CH₃ , or a pharmaceutically acceptable salt, hydrate, solvate or crystalline form of any of the foregoing.

[0114] As can be seen from Formulae (I) and (la), there are many embodiments. For example, there are disclosed embodiments directed to a compound of Formula (I) and a compound of Formula (la) based on the identity ofthe acyclic nucleoside phosphonate scaffold. This is not intended to be an explicit or implicit admission that the embodiments are independent or distinct nor should it be interpreted as such. Rather, it is intended to convey information so that the full breadth of Formulae (I) and (la) can be understood. Furthermore, the following embodiments, and aspects thereof, are not meant to be limiting on the full breadth ofthe structure of Formula (I) and/or the structure of Formula (la).

[0115] Tables 1-10 following disclose structures contemplated herein. The structures of Tables 1-10 and are not intended to be limiting on the full breadth of the contemplated compounds represented by the structure of Formulae (I), (1-1), (1-2), (1-3), (1-4), (1-5) and (la). Moreover, it is contemplated that any one of the contemplated acyclic nucleoside phosphonate (ANP) scaffolds (PME-, (R)-PMP-, (S)-MPMP-, (S)-HPMP- and (5)-FPMP-) or their stereoisomers, can be used in combination with any ofthe contemplated combinations of naturally occurring or modified purine or pyrimidine base (BM_U0/B^_UC(_aj), L/L and RZR . Additionally, as the phosphorus atom of the ANP diester is a potential chiral center, it is understood that Rp and Sp (i.e., Cahn-Ingold-Prelog nomenclature as known in the art) stereochemical configurations are possible. Therefore, the structures below include stereochemical configurations possible for phosphorus.

WO 2014/143643

PCT/US2014/027005

Table 1. Phosphonomethoxyethyl (PME) diester compounds

<td colspan="5"> BNuc/^Nuc(a) O BNuc/BNuc(a) O B_Nuc/BNuc(a) O P-O-L/L^a P-O-L/L^a P-Q-L/L^a 0-R/R^{a 0Γ} O-R/R^a °^r O-R/R^a Rp or Sp (depends on substituents) Rp, Sp (racemic)</td>

<td> Cmpd No.</td><td> Bnuc/Bn«(»)</td><td> L/L^fl</td><td> R/R</td><td> Name</td>

<td> 1W y_p)</td><td> guanin-9-yl</td><td> octadecyloxy ethyl</td><td> benzyl</td><td> benzyl octadecyl oxy ethyl 9-(2phosphonomethoxyethyl)guanine</td>

<td> la (fast)</td><td> guanin-9-yl</td><td> octadecyloxyethyl</td><td> benzyl</td><td> benzyl octadecyloxyethyl 9-(2phosphonomethoxyethyl)guanine</td>

<td> lb (slow)</td><td> guanin-9-yl</td><td> octadecyloxyethyi</td><td> benzyl</td><td> benzyl octadecyloxyethyl 9-(2phosphonomethoxyethyl)guanine</td>

<td> 2</td><td> adenine-9-yl</td><td> octadecyloxyethyl</td><td> benzyl</td><td> benzyl octadecyloxyethyl 9-(2- phosphonomethoxyethypadenme</td>

<td> 3</td><td> cytosine-1-yl</td><td> octadecyloxyethyl</td><td> benzyl</td><td> benzyl octadecyloxyethyl 1-(2phosphonomethoxyethyl)cytosine</td>

<td> 4</td><td> thymin-l-yl</td><td> octadecyl oxy ethyl</td><td> benzyl</td><td> benzyl octadecyloxyethyi 1-(2phosphonomethoxycthyl)thyinine</td>

<td> 5</td><td> uracil-1-yl</td><td> octadecyloxyethyl</td><td> benzyl</td><td> benzyl octadecyloxyethyi 9-(2phosphonomethoxyethyl)uracil</td>

<td> 6</td><td> 2,6- diaminopunn -9-yl</td><td> octadecyloxyethyl</td><td> benzyl</td><td> benzyl octadecyloxyethyi 9-(2phosphonomethoxyethyl)-2,6diaminopurine </td>

<td> 7</td><td> guanin-9-yl</td><td> hexadecyloxypropy 1</td><td> benzyl</td><td> benzyl hexadecyloxypropyl 9-(2- phosphonomethoxyethyi)guanine</td>

<td> 8</td><td> adenine-9-yl</td><td> hexadecyloxypropyl</td><td> benzyl</td><td> benzyl hexadecyloxypropyl 9-(2- phosphonoinethoxycthy])adeninc</td>

<td> 9</td><td> cytosine-l-yl</td><td> hexadecyloxypropyl</td><td> benzyl</td><td> benzyl hexadecyloxypropyl 1-(2phosphonomethoxyethyl)cytosine</td>

<td> 10</td><td> thymin-l-yl</td><td> hexadecyl oxy p ropy 1</td><td> benzyl</td><td> benzyl hexadecyloxypropyl 1-(2- phosphonomethoxyethy])thymine</td>

<td> 11</td><td> uracil-l-yl</td><td> hexadecyloxypropyl</td><td> benzyl</td><td> benzyl hexadecyloxypropyl 9-(2phosphonomethoxyethyljuracil</td>

<td> 12</td><td> 2,6- diaminopurin -9-yl</td><td> hexadecyloxypropyl</td><td> benzyl</td><td> benzyl hexadecyloxypropyl 9-(2phosp honom ethoxyethy I )-2,6diaminopurine</td>

<td> 13</td><td> guanin-9-yl</td><td> 1 -O-octadecyl-2- Obenzyl-jn glyceryl</td><td> benzyl</td><td> benzyl l-O-octadecyl-2-O-benzyl-sn glyceryl 9-(2- ph osphonont ethoxyethyl) guanine</td>

<td> 14</td><td> adenine-9-yl</td><td> l-(9-octadecyl-2-&lt;9benzyl-OT glyceryl</td><td> benzyl</td><td> benzyl l-&lt;9-octadecyl-2-(9-benzyl-5n glyceryl 9-(2phosphonomethoxyethyl)adenine</td>

<td> 15</td><td> cytosine-l-yl</td><td> 1-O-octadccy 1-2-(9benzyl-^n glyceryl</td><td> benzyl</td><td> benzyl l-(9-octadecyl-2-(9-benzyl-.m glyceryl 1-(2phosphonomethoxyethyl)cytosine</td>

<td> 16</td><td> thymin-l-yl</td><td> 1 -O-octadecy 1-2-(9benzyl-ό'Μ glyceryl</td><td> benzyl</td><td> benzyl l-O-octadecyl-Z-C’-benzyl-i'fl glyceryl l-(2-phosphonomethoxyethyl)thymine</td>

<td> 17</td><td> uracil-l-yl</td><td> l-O-octadecyl-2-Obenzyl-JH glyceryl</td><td> benzyl</td><td> benzyl I - O-octadecyl-2-(9-benzy 1-jb glyceryl 9-(2~phosphonomethoxyethyl)uracil</td>

<td> L</td><td> 2,6- diaminopurin -9-yl</td><td> 1 -O- octadecy 1-2-(9benzyi-sn glyceryl</td><td> benzyl</td><td> benzyl 1 -O-octadecyl-2- (9-benzyl-sn glyceryl 9-(2-phosphonomethoxyethy 1)-2,6-diamino purine</td>

WO 2014/143643

PCT/US2014/027005 ^Nuc/^Nuc(a) O ^NucZ^Nuc(a) O ®Nuc/^Nuc(a) O ''-.,.^O_X^P-O-L/L^a k__xO^^P~O-L/L^a l^O^P-O~UL^a

ΟΓ 1 nr

O-R/R^a O-R/R^a O-R/R^a

Rp or Sp (depends on substituents) Rp, Sp (racemic)

<td> Cmpd No.</td><td> Βνιιι/ΒνκΦ)</td><td> L/L</td><td> R/R</td><td> Name</td>

<td> 19</td><td> guanin-9-yl</td><td> octadccyloxyethyl</td><td> phenyl</td><td> phenyl octadecyloxyethyl 9-(2phosphonomethoxyethyl)guanine</td>

<td> 20</td><td> adenine-9-yl</td><td> octadecyloxyethyl</td><td> phenyl</td><td> phenyl octadccyloxyethyl 9-(2phosphonomethoxyethyl)adenine</td>

<td> 21</td><td> cytosine-1-yl</td><td> octadecyloxyethyl</td><td> phenyl</td><td> phenyl octadecyloxyethyl 1-(2- phosphonomethoxyethyl)cytosine</td>

<td> 22</td><td> thymin-l-yl</td><td> octadecyloxyethyl</td><td> phenyl</td><td> phenyl octadccyloxyethyl 1-(2phosphonomethoxy ethyljthy m i ne</td>

<td> 23</td><td> uracil-l-yl</td><td> octadccyloxyethyl</td><td> phenyl</td><td> phenyl octadccyloxyethyl 9-(2phosphonomethoxyethyl)uracil</td>

<td> 24</td><td> 2,6- diaminopurln -9-yl</td><td> octadecyloxyethyl</td><td> phenyl</td><td> phenyl octadccyloxyethyl 9-(2phosphonomethoxycthyl)-2,6diaminopurine</td>

<td> 25</td><td> guanin-9-yl</td><td> hexadecyloxypropyl</td><td> phenyl</td><td> phenyl hexadecyloxypropyl 9-(2phosphonomethoxyethyl)guanine</td>

<td> 26</td><td> adcnine-9-yl</td><td> hexadecyloxypropyl</td><td> phenyl</td><td> phenyl hexadecyloxypropyl 9-(2phosphonom ethoxy ethy l)adeni ne</td>

<td> 27</td><td> cytosine-l-yl</td><td> hexadecyloxyp ropy 1</td><td> phenyl</td><td> phenyl hexadecyloxypropyl 1-(2phosphonomethoxyethyl)cytosine</td>

<td> 28</td><td> thymin-l-yl</td><td> hexadecyloxypropyl</td><td> phenyl</td><td> phenyl hexadecyloxypropyl 1-(2phosphonomethoxyethyl/thymine</td>

<td> 29</td><td> uracil-l-yl</td><td> hexadecyloxypropyl</td><td> phenyl</td><td> phenyl hexadecyloxypropyl 9-(2ph osphonom ethoxyethyl )uracil</td>

<td> 30</td><td> 2,6diaminopurin -9-yl</td><td> hexadecyloxypropyl</td><td> phenyl</td><td> phenyl hexadecyloxypropyl 9-(2phosphonomethoxyethy 1)-2,6diamitlopurine</td>

<td> 31</td><td> guanin-9-yl</td><td> 1 -O-octadecy 1-2-0benzyl-sn glyceryl</td><td> phenyl</td><td> phenyl I -O-octadecy 1-2-O-benzyl-jn glyceryl 9-(2phosphonomethoxyethyl)guanine</td>

<td> 32</td><td> adenine-9-yl</td><td> 1 -O-octadecy 1 -2-0benzyl-j’H glyceryl</td><td> phenyl</td><td> phenyl 1 - O-octadecyl-2-O-benzy 1 -.v« glyceryl 9-(2phosphonomethoxyethyl)adenine</td>

<td> 33</td><td> cytosine-l-yl</td><td> l-O-octadecyl-2-Obenzyl-jn glyceryl</td><td> phenyl</td><td> phenyl 1 - O-octadecy 1-2- O-benzyl-jn glyceryl 1-(2phosphonomethoxyethyl)cytosine</td>

<td> 34</td><td> thymin-I-yl</td><td> 1-O-octadecy 1-2-0benzyl-jn glyceryl</td><td> phenyl</td><td> pheny 1 1 - O-octadecyl-2-O-benzy 1 -sn glyceryl 1-(2phosphonomethoxyethyl)thyrnine</td>

<td> 35</td><td> uracil-l-yl</td><td> l-O-octadecyl-2-Obenzyl-m glyceryl</td><td> phenyl</td><td> phenyl l-O-octadecyl-2-O-benzyJ-.w glyceryl 9-(2phosphonomethoxyethyl)uracil</td>

<td> 36</td><td> 2,6diaminopurin -9-yl</td><td> I - O-octad ecy 1-2-0benzyl-.yn glyceryl</td><td> phenyl</td><td> phenyl 1 - O-octadecy 1-2-O-benzy 1 -sn glyceryl 9-(2phosphonomethoxyethy 1)-2,6diam inopurine</td>

<td> 37</td><td> guanin-9-yl</td><td> octadecyl oxy ethyl</td><td> ethyl</td><td> ethyl octadecyloxyethyl 9-(2phosphonomethoxyethyl)guanine</td>

<td> 38</td><td> adenine-9-yi</td><td> octadecyloxyethyl</td><td> ethyl</td><td> ethyl octadecyloxyethyl 9-(2phosphonomcthoxyethyl)adenine</td>

WO 2014/143643

PCT/US2014/027005

<td colspan="5"> BNuc/BNu_C(a) O BNuc/B_Nuc(a) O BNuc/BN_uc(_a) 0 l...'^O,.^P-0-L/L⁵ k^O^,P-O-UL^a k^..O,.^POL/L^a 0-R/R^a °^Γ O-R/R^a °^Γ O^R/R“ Rp or Sp (depends on substituents) Rp, Sp (racemic)</td>

<td> Cmpd 1 No.</td><td> Bnii&lt;/Bn_uc(_r)</td><td> L/L</td><td> R/R</td><td> Name</td>

<td> 39</td><td> cytosine-1-yl</td><td> octadecyloxyethyl</td><td> ethyl</td><td> ethyl octadecyloxyethyl 1-(2phosphonomethoxyethy l)cy to sine</td>

<td> 40</td><td> thymin-l-yl</td><td> octadecyloxyethyl</td><td> ethyl</td><td> ethyl octadecyloxyethyl 1-(2phosphonomethoxyethyl)thymine</td>

<td> 41</td><td> uracil-l-yl</td><td> octadccyl oxy ethyl</td><td> ethyl</td><td> ethyl octadecyloxyethyl 9-(2phosphonomethoxyethyljuraci!</td>

<td> 42</td><td> 2,6diaminopurin -9-yl</td><td> octadecyloxyethyl</td><td> ethyl</td><td> ethyl octadecyloxyethyl 9-(2phosphonomethoxyethyl)-2,6diaminopurine</td>

<td> 43</td><td> guanin-9-yl</td><td> hexadecy loxypro py1</td><td> ethyl</td><td> ethyl hexadecyloxypropyl 9-(2phosphonomethoxy ethy l)guan i ne</td>

<td> 44</td><td> adenine-9-yl</td><td> hexadecyl ox y propyl</td><td> ethyl</td><td> ethyl hexadecyloxypropyl 9-(2phosphonomethoxyethy 1 )adenine</td>

<td> 45</td><td> cytosine-l-yl</td><td> hexadccyloxypropyl</td><td> ethyl</td><td> ethyl hexadecyloxypropyl 1-(2- phos phonomethoxyethy l)cy to si ne_____</td>

<td> 46</td><td> thymin-l-yl</td><td> hexadecyloxy p ropyl</td><td> ethyl</td><td> ethyl hexadecyloxypropyl 1-(2phosphonomethoxyethyl)thymine</td>

<td> 47</td><td> uracil-l-yl</td><td> hcxadecyloxypropyl</td><td> ethyl</td><td> ethyl hexadecyloxypropyl 9-(2phosphonomethoxyethy 1) uracil</td>

<td> 48</td><td> 2,6- diaminopurin -9-yl</td><td> hexadecyloxypropyl</td><td> ethyl</td><td> ethyl hexadecyloxypropyl 9-(2phosphonomcthoxyetbyl)-2,6diaminopurine</td>

<td> 49</td><td> guanin-9-yl</td><td> 1 -O-octadecyl-2-Obenzyl-jr? glyceryl</td><td> ethyl</td><td> ethyl l-0-octadecyi-2-0-benzyl-5H glyceryl 9-(2phosphonoTnethoxyethyl)guanine</td>

<td> 50</td><td> adenine-9-yl</td><td> 1 -O-octadecy 1-2- Obenzyl-jn glyceryl</td><td> ethyl</td><td> ethyl l-O-octadecyl-2-O-benz.yl-sn glyceryl 9-(2- phosphonomethoxy ethy i)aden 1 nc</td>

<td> — 51</td><td> cytosine-l-yl</td><td> l-O-octadecyl-2-Obenzyl-.rn glyceryl</td><td> ethyl</td><td> ethy! 1 -O-octadccy Ι-2-O-bcnz.y l-.ivi glyceryl 1-(2phosphonomethoxyethy 1 )cy tosinc</td>

<td> 52</td><td> thymin-l-yl</td><td> l-O-octadecyl-2-Obenzyl-jn glyceryl</td><td> ethyl</td><td> ethyl l-O-octadecyl-2-O-benzyi-in glyceryl 1-(2phosphonomethoxyethyl)thymine</td>

<td> 53</td><td> uracil-l-yl</td><td> l-O-octadecyl-2-Obenzyl-sn glyceryl</td><td> ethyl</td><td> ethyl l-O-octadecyl-2-O-benzyl-.vn glyceryl 9-(2phosphonomethoxyethy Ijuraci 1</td>

<td> 54</td><td> 2,6diaminopurin -9-yl</td><td> l-O-octadecyl-2-Obenzyl-.rrr glyceryl</td><td> ethyl</td><td> ethy! l-O-octadecyl-2-O-benzyl-jM glyceryl 9-(2phosphonomethoxyethyl)-2,6di aminopuri ne__.</td>

<td> 55</td><td> guanin-9-yl</td><td> octadecyloxyethyl</td><td> galactosyl</td><td> galactosyl octadecyloxyethyl 9-(2phosphonomethoxyethyl)guanine</td>

<td> 56</td><td> adenine-9-yl</td><td> octadecyl oxy ethyl</td><td> galactosyl</td><td> galactosyl octadecyl oxy ethyl 9-(2phosphonometh oxycthyljadenine_____</td>

<td> 57</td><td> cytosine-l-yl</td><td> octadecyloxyethyl</td><td> galactosyl</td><td> galactosyl octadecyloxyethyl 1-(2Dhosphonomethoxyethyl)cytosine_____</td>

<td> 58</td><td> thymin-l-yl</td><td> octadecyloxyethyl</td><td> galactosyl</td><td> galactosyl octadecyl oxy ethyl 1-(2phosphonomethoxyethyl)thymine</td>

WO 2014/143643

PCT/DS2014/027005

Bnuc/Bnuc(3) ο Bnuc/Bnuc(s) O BjY_uc/B_Nuc(_a) q

'..A\^^p-O-UL^a \^Α_νΖΡ· O- L/L^a p-OL/L^a

- . or i or

CR/R O-R/R^a O~R/R^a

Rp or Sp (depends on substituents) Rp, Sp (racemic)

<td> Cmpd No.</td><td></td><td> L/L</td><td> R/R”</td><td> Name</td>

<td> 59</td><td> uracil- 1-yi</td><td> octadecyl oxy ethyl</td><td> galactosyl</td><td> galactosyl octadecyloxyethyl 9-(2ph osphonom ethoxyethy !)uraci 1</td>

<td> 60</td><td> 2,6diaminopurin -9-yl</td><td> octadecyloxyethyl</td><td> galactosyl</td><td> galactosyl octadecyl oxyethy! 9-(2phosphonomethoxyethy!)-2,6diaminopurine</td>

<td> 61</td><td> guanin-9-yl</td><td> hexadecyl oxypropy 1</td><td> galactosyl</td><td> galactosyl hexadecyloxypropyl 9-(2phosphonomethoxyethyl)guanine</td>

<td> 62</td><td> adenine-9-yl</td><td> hexadecyl oxy propyl</td><td> galactosyl</td><td> galactosyl hexadecyloxypropyl 9-(2phosphonomelhoxyethyl )adeni ne</td>

<td> 63</td><td> cytosinc-l-yl</td><td> hexadecy 1 oxy propy 1</td><td> galactosyl</td><td> galactosyl hexadecyloxypropyl 1-(2phosphonomcthoxyethyl)cytosine</td>

<td> 64</td><td> thymin-l-yl</td><td> hexadecyloxypropyl</td><td> galactosyl</td><td> galactosyl hexadecyloxypropyl 1-(2phosphonomethoxyethy l)thym i ne</td>

<td> 65</td><td> uracil-l-yl</td><td> hexadecyloxypropyl</td><td> galactosyl</td><td> galactosyl hexadecyloxypropyl 9-(2phosphonomethoxyethyl)uracil</td>

<td> 66</td><td> 2,6- diaminopurin -9-yl</td><td> hexadecyloxypropyl</td><td> galactosyl</td><td> galactosyl hexadecyloxypropyl 9-(2phosphonomethoxyethyl)-2,6diaminopurine</td>

<td> 67</td><td> guanin-9-y!</td><td> l-O-octadecyl-2-(9benzyl-in glyceryl</td><td> galactosyl</td><td> galactosyl 1 -O-octadecyl-2- O-benzy 1 sn glyceryl 9-(2phosphonomethoxyethy 1 )guan ine</td>

<td> 68</td><td> adenine-9~yl</td><td> 1 -O-octadecyI-2-Obenzyl-ίΗ glyceryl</td><td> galactosyl</td><td> galactosyl 1 -O-octadecy 1-2- O-benzylsn glyceryl 9-(2phosphonomethoxyethyl)adenine</td>

<td> 69</td><td> cytosinc-l-yl</td><td> 1 -O-octadecy 1-2- Obcnzyl-jn glyceryl</td><td> galactosyl</td><td> galactosyl 1 -6&gt;-octadecyl-2-O-benzylsn glyceryl 1-(2phosphonomethoxyethyl)cytosine</td>

<td> 70</td><td> thymin-l-yl</td><td> 1 -O-octadecyl -2- Obenzyl-sn glyceryl</td><td> galactosyl</td><td> galactosyl l-O-octadecyi-2-O-benzylsn glyceryl 1-(2- phosphonom cthoxyethyl)thymi ne</td>

<td> 71</td><td> uracil-l-yl</td><td> 1 -O-octadecy 1-2- 0benzyl-jw glyceryl</td><td> galactosyl</td><td> gal actosy 1 1 - O-octadecy 1-2-O-benzy lsn glyceryl 9-(2phosphonomethoxyethyl)uracsl</td>

<td> 72</td><td> 2,6- diaminopurin -9-yl</td><td> 1 -O-octadecyl-2-Obenzyl-sn glyceryl</td><td> galactosyl</td><td> galactosyl 1 -O-octadecy 1-2- O-benzyl sn glyceryl 9-(2phosphonomethoxyethy 1)-2,6di aminopurine</td>

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

BNuc/BN_uc(_a) Q BNuc/Bftluc(a) O B_Nuc/B_Nuc(_a) q

L^O^P-O-UL³ L..._x.O...,^P-O-L/L^a L. ^O-,..^.P· O UL^aCH3 O-R/R^a °^Γ 0H3 O-R/R^a °^Γ 6h3 O~R/R^a

Rp or Sp (depends on substituents) Rp, Sp (racemic)

<td> Cmpd No.</td><td> ^Nnc^Niic(Fi)</td><td> L/L</td><td> R/R</td><td> Name</td>

WO 2014/143643

PCI7US2014/027005

<td colspan="5">^BNuc^^BNuc(a) 0 ^BNut/^BNuc(a) 0 ^BNuc^^BNuc(a) 0 L3_0^P-0-L/L^a k^O^P-O-L/L^a k^,O^,P-O“L/L^a - Ξ or / i , or n-pip^a CH₃ OR/R^a CH₃ O-R/R CH₃ ° Rp or Sp (depends on substituents) Rp, Sp (racemic)_____</td>

<td> Cmpd No.</td><td> BNuc/BNucfn)</td><td> L/L</td><td> R/R</td><td> Name</td>

<td> 73</td><td> guanin-9-yl</td><td> octadecyloxyethyl</td><td> benzyl</td><td> benzyl octadecyloxyethyl 9-(/?)-[(2phosphottom ethoxy )propy 1] guanine</td>

<td> 74</td><td> adenine-9-yl</td><td> octadecyl oxy ethyl</td><td> benzyl</td><td> benzyl octadecyl oxy ethyl 9-(//)-((2phosphonomethoxylpropy 1 ] adenine</td>

<td> 75</td><td> cytosine-l-yl</td><td> octadecyloxyethyl</td><td> benzyl</td><td> benzyl octadecyloxyethyl 1-(Λ)-[(2phosphonomethoxy)propy l]cy tos i ne</td>

<td> 76</td><td> thymin-l-yl</td><td> octadecyloxyethyl</td><td> benzyl</td><td> benzyl octadecyloxy ethyl 1-(//)-((2phosphonomethoxy)propyl]thymine</td>

<td> 77</td><td> uracil-l-yl</td><td> octadecyloxy ethyl</td><td> benzyl</td><td> benzyl octadecyl oxyethyl l-(R)-[(2phosphonomethoxy)piOpyl]uracil</td>

<td> 78</td><td> 2,6diaminopurin -9-yl</td><td> octadecyloxyethyl</td><td> benzyl</td><td> benzyl octadecyloxyethyl 9-(//)-((2- phosphonomethoxy)propyl]2,6diaminopurine </td>

<td> 79</td><td> guanin-9-yl</td><td> hcxadecyloxypropyl</td><td> benzyl</td><td> benzyl hexadecyl oxy propyl 9-(7/)-((2phosphonomethoxyjpropy 1] guan i ne</td>

<td> 80</td><td> adenine-9-yl</td><td> hexadecyloxypropyl</td><td> benzyl</td><td> benzyl hexadecyloxypropyl 9-(7/)-((2phosphonomethoxy)propyl]adenine</td>

<td> 81</td><td> cytosine-l-yl</td><td> hexadecyloxypropyl</td><td> benzyl</td><td> benzyl hexadecyloxypropyl 1 -(7/)-((2phosphonomethoxy)propyl]cytosine</td>

<td> 82</td><td> thymin-l-yl</td><td> hexa decyloxy propyl</td><td> benzyl</td><td> benzyl hexadecyloxypropyl 1 -(7/)-[(2phosphonomethoxy)propyl]thymine</td>

<td> 83</td><td> uracil-l-yl</td><td> hexadecyloxypropyl</td><td> benzyl</td><td> benzyl hexadecyloxypropyl 1-(//)-((2phcsphonomethoxy)propyl]uraci 1</td>

<td> 84</td><td> 2,6diaminopurin -9-yl</td><td> hexadecyloxypropyl</td><td> benzyl</td><td> benzyl hexadecyloxypropyl 9-(7/)-[(2phosphonomethoxy)pi'opyl]2,6diaminopurine</td>

<td> 85</td><td> guanin-9-yl</td><td> l-O-octadecyl-2-Obenzyl-j^ glyceryl</td><td> benzyl</td><td> benzyl l-O-octadecyl-2-O-benzyl-.w glyceryl 9-(//)-((2phosphonomethoxy)propyl]guanine</td>

<td> 86</td><td> adenine-9-yl</td><td> 1 - O-octadecy 1-2-0benzyl-sn glyceryl</td><td> benzyl</td><td> benzyl l-O-octadecyl-2-O-benzyl-sn glyceryl 9-(//)-((2phospbonomethoxy)propy!]adenine</td>

<td> 87</td><td> cytosine-l-yl</td><td> 1-O-octadecy 1-2-0benzyl-stt glyceryl</td><td> benzyl</td><td> benzyl 1-0- octadccyl -2-O-benzy 1 -sn glyceryl 1-(//)-((2phosphonomethoxy)propyl]cytosinc</td>

<td> 88</td><td> thymin-l-yi</td><td> l-O-octadecyl-2-O- bcnzyl-.w glyceryl</td><td> benzyl</td><td> benzyl 1 -O-octadecy 1-2-O-benzy 1-jn glyceryl 1-(//)-((2phosphonomethoxy)propyl]thymi ne</td>

<td> 89</td><td> uracil-l-yl</td><td> 1 -O-octadecy 1-2-0benzyl-sn glyceryl</td><td> benzyl</td><td> benzyl l-O-octadecyl-2-O-benzyl-OT glyceryl 1-(7/)-((2phosphonomethoxy)pi'opyl]uracil______</td>

<td> 90</td><td> 2,6diaminopurin -9-yl</td><td> l-O-octadecyl-2-Obcnzy'l-.v/? glyceryl</td><td> benzyl</td><td> benzyl l-O-octadecyl-2-O-benzyl-xn glyceryl 9-(//)-((2phosphonomethoxy)propyl]2,6diaminopurine</td>

<td> 91</td><td> guanin-9-yl</td><td> octadecyloxyethyl</td><td> phenyl</td><td> phenyl octadecyl oxy ethyl 9-(/?)-[(2phosphonom ethoxy)propyl]guanine</td>

<td> 92</td><td> adenine-9-yl</td><td> octadecyloxycthyl</td><td> phenyl</td><td> phenyl octadecyloxycthyl 9-(R)-[(2phosphonomethoxy)propyl]adenine</td>

<td> 93</td><td> cytosine-l-yl</td><td> j octadecyloxyethyl</td><td> phenyl</td><td> phenyl octadecyloxyethyl l-(7?)-[(2pho sphonomcthoxyjpropy l]cy tos i ne</td>

WO 2014/143643

PCT/US2014/027005

<td colspan="5"> ^Nuc^Nuc(a) 0 ^Nuc^Nuc(a) 0 ^Nuc^Nuc(a) O k,,.,O._vP-O-L/L^a χ^Ο,^Ρ-Ο-ΙΛ’ k^O.^,.P-O-L/L^a £ - or £ i or ‘ A CH₃ O-R/R^a CH3 O-R/R^a CH3 ^O_R/R Rp or Sp (depends on substituents) Rp, Sp (racemic)</td>

<td> Cmpd No.</td><td> BNi.L-/BN_lic(n&gt;</td><td> L/L‘</td><td> R/R</td><td> Name</td>

<td> 94</td><td> thymin-l-yl</td><td> octadecyloxyethy!</td><td> phenyl</td><td> phenyl octadecyloxyethyl 1-(//)-((2phosphonomcthoxy)propyi]thymine</td>

<td> 95</td><td> uracil-l-yl</td><td> octadecyloxyethyl</td><td> phenyl</td><td> phenyl octadecyloxyethyl 1-(7/)-((2phosphonomcthoxy)propyl]uracil</td>

<td> 96</td><td> 2,6- di aminopurin -9-yl</td><td> octadecyloxyethyl</td><td> phenyl</td><td> phenyl octadecyloxyethyl 9-(//)-((2pliosphonomethoxy)propyl]2,6diaminopurine</td>

<td> 97</td><td> guanin-9-yl</td><td> hexadecyloxypropyl</td><td> phenyl</td><td> phenyl hexadecyloxypropyl 9-(7/)-((2phosphonomethoxy)propyl]guanine</td>

<td> 98</td><td> adenine-9-yl</td><td> hexadecyloxypropyl</td><td> phenyl</td><td> phenyl hexadecyloxypropyl 9-(7/)-((2phosphonomethoxy)propy 1 Jaden i ne</td>

<td> 99</td><td> cytosine-1-yl</td><td> hexadecyloxypropyl</td><td> phenyl</td><td> phenyl hexadecyloxypropyl 1-(7/)-((2phosph onomcthoxyjpropy 1 ]cy tosine</td>

<td> 100</td><td> thymin-l-yl</td><td> hexadecyloxypropyl</td><td> phenyl</td><td> phenyl hexadecyloxypropyl 1-(//)-((2phos phonomethoxy)propyl J thy mi n e</td>

<td> 101</td><td> uracil-l-yl</td><td> hexadecyloxypropyl</td><td> phenyl</td><td> phenyl hexadecyloxypropyl 1-(7/)-((2phosphonomethoxy)propyl]uracil</td>

<td> 102</td><td> 2,6diaminopurin -9-yl</td><td> hexadecyloxypropyl</td><td> phenyl</td><td> phenyl hexadecyloxypropyl 9-(7/)-((2phosphonomethoxy)propyl]2,6diaminopurine</td>

<td> 103</td><td> guanin-9-yl</td><td> l-O-octadecyl-2-Obenzyl-.m glyceryl</td><td> phenyl</td><td> phenyl l-O-octadecyl-2-O-benzyl-jn glyceryl 9-(7/)-((2phosphonomethoxy)propyl]guanine</td>

<td> 104</td><td> adenine-9-yl</td><td> 1 -O-octadecy 1-2-0benzyl-s/? glyceryl</td><td> phenyl</td><td> phenyl 1 -O-octadecy 1 - 2-O-benzy l-i« glyceryl 9-(7/)-((2- phosphon omethoxyjpropyl ] ad enine</td>

<td> 105</td><td> cytosine-1-yl</td><td> l-O-octadecyl-2-Obenzyl-sn glyceryl</td><td> phenyl</td><td> phenyl l-O-octadecyl-2-O-benzyl-sn glyceryl 1-(//)-((2phosphonomethoxy)piOpyl]cytosine</td>

<td> 106</td><td> thymin-l-yl</td><td> l-O-octadecyl-2-Obetizyl-OT glyceryl</td><td> phenyl</td><td> phenyl l-O-octadecyl-2-O-benzyi-5n glyceryl 1-(//)-((2phosphonomethoxy)propyl]thymine</td>

<td> 107</td><td> uracil-l-yl</td><td> l-O-octadecyl-2-Obenzyl-ότί glyceryl</td><td> phenyl</td><td> phenyl 1 - O-octadecyl-2- O-benzy l-sn glyceryl 1-(//)-((2phosphonomethoxy )propyl]u raci 1</td>

<td> 108</td><td> 2,6diaminopurin -9-yl</td><td> l-O-octadecyI-2-Obenz.yl-OT glyceryl</td><td> phenyl</td><td> phenyl 1 - O-octadecyl-2- O-benzyl-w glyceryl 9-(//)-((2phosphonomethoxy)piOpyl]2,6diaminopurine</td>

<td> 109</td><td> guanin-9-y!</td><td> octadecyloxyethyl</td><td> ethyl</td><td> ethyl octadecyloxyethyl 9-(//)-((2phosphonomethoxy)propyl]guanine</td>

<td> 110</td><td> adenine-9-yl</td><td> octadecyloxyethyl</td><td> ethyl</td><td> ethyl octadecyloxyethyl 9-(//)-((2phosphonomethoxy)propy]]adenine</td>

<td> 111</td><td> cytosioe-l-yl</td><td> octadecyloxyethyl</td><td> ethyl</td><td> ethyl octadecyloxyethyl 1-(7/)-((2phosphonomethoxy)propyl]cytosine</td>

<td> 112</td><td> thymin-l-yl</td><td> octadecyloxyethyl</td><td> ethyl</td><td> ethyl octadecyloxyethy] 1-(7/)-((2phosphonomethoxy)propyl]thymine</td>

<td> 113</td><td> uracil-l-yl</td><td> octad ecyloxyethy 1</td><td> ethyl</td><td> ethyl octadecyloxyethyl 1-(7/)-((2phosphonomethoxy)propyljuracil</td>

WO 2014/143643

PCT/US2014/027005

<td colspan="5"> ^Nuc^Nuc(a) 0 B_h;_uc/B_tj_uc(_a) Q O L,2.-0^P-0 L/L^a k^0^P-O-L/L^a_x^O...^.P-O L/L^a - £ or £ 1 - or r n—R/R^a CH₃ O-R7R^a CH3 O-R/R^a CH3 ° Rp or Sp (depends on substituents) Rp, Sp (racemic) ____</td>

<td> Cmpd No.</td><td> Bhfuc/Bbhicin)</td><td> L/L“</td><td> R/R’¹</td><td> Name</td>

<td> 114</td><td> 2,6- diaminopurin -9-yl</td><td> octa decyloxy ethyl</td><td> ethyl</td><td> ethyl octadecyl oxyethyl 9-(2/)-((2phosphonomethoxy)propyl]2,6diaminopurine</td>

<td> 115</td><td> guanin-9-yl</td><td> hexadecyloxypropyl</td><td> ethyl</td><td> ethyl hexadecyloxypropyl 9-(//)-[(2phosphonomethoxy)piOpyl]guanine</td>

<td> 116</td><td> adenine-9-yl</td><td> hexadecyloxypropyl</td><td> ethyl</td><td> ethyl hexadecyloxypropyl phosphonomethoxy)propyl]adenme</td>

<td> 117</td><td> cytosine-1-yl</td><td> hexadecyloxypropyl</td><td> ethyl</td><td> ethyl hexadecyloxypropyl l-(/?)-{(2phosphonomcthoxy)propyl]cytosine</td>

<td> 118</td><td> thymiii-l-yl</td><td> h exadecyloxypropy 1</td><td> ethyl</td><td> ethyl hexadecyloxypropyl 1-(2/)-((2t&gt;hosphonomethoxy)propyl]thymine</td>

<td> 119</td><td> uracil-1 -yl</td><td> hexadecyloxypropyl</td><td> ethyl</td><td> ethyl hexadecyloxypropyl 1-(7/)-((2phosphonomethoxy)propyl]uracil</td>

<td> 120</td><td> 2,6- diamlnopurin -9-yl</td><td> hexadecyloxypropyl</td><td> ethyl</td><td> ethyl hexadecyloxypropyl 9-(7/)-((2phosphonomethoxy)propyl]2,6diaminopurine</td>

<td> 121</td><td> guanin-9-yl</td><td> l-O-octadecyl-2-Obenzyl-sn glyceryl</td><td> ethyl</td><td> ethy 1 1 -O-octadecy 1-2- O-benzy i-sn glyceryl 9-(7/)-((2- DhosDhonomethoxy)propyl]guanine</td>

<td> 122</td><td> adenine-9-yl</td><td> 1 -O-octadecyl-2-ΰbenzyl-M glyceryl</td><td> ethyl</td><td> ethyl l-(9-octadecyl-2-O-bcnzyl-srt glyceryl 9-(//)-((2phosphonomethoxy)propyl]adenine</td>

<td> 123</td><td> cytosine-1-yl</td><td> l-O-octadecyl-2-Obenzyl-j/i glyceryl</td><td> ethyl</td><td> ethyl 1 - O-octadecy !-2-O-benzy 1 -sn glyceryl 1-(7/)-((2phosphonomethoxy)propyl]cytosine</td>

<td> 124</td><td> thymin-l-yl</td><td> l-O-octadecyl-2-Obenzyl-sn glyceryl</td><td> ethyl</td><td> ethyl l-O-octadecyl-2-O-benzyl-.sn glyceryl 1-(7/)-((2- phosphonom ethoxy)propy l]thy mine</td>

<td> 125</td><td> uracil-l-yl</td><td> l-O-octadecyl-2-O- benzyl-.w glyceryl</td><td> ethyl</td><td> ethyl 1- O-octadecyl-2-O-benzy l-sn glyceryl 1-(//)-((2phosphonomethoxy)prapyl]uracil</td>

<td> 126</td><td> 2,6diaminopurin -9-yl</td><td> 1 - O-octadecy 1 -2- 0benzyl-sn glyceryl</td><td> ethyl</td><td> phenyl 1 -O-octadecy 1-2- O-benzy 1-jw glyceryl 9-(//)-((2phosphonomcthoxy) propyl]2,6diaminopurine</td>

<td> 127</td><td> guanin-9-yi</td><td> octadecyloxyethyl</td><td> galactosyl</td><td> galactosyl octadecyloxyethyl 9-(//)-((2phosphonometiioxy)propyljguanlne</td>

<td> 128</td><td> adenine-9-yl</td><td> octadecyloxyethyl</td><td> galactosyl</td><td> galactosyl octadecyloxyethyl 9-(7/)-((2phosphonomethoxy)propyljadenine</td>

<td> 129</td><td> cytosine-1-yl</td><td> octadecyloxyethyl</td><td> galactosyl</td><td> galactosyl octadecyloxyethyl 1-(//)-((2phosphonomethoxy)propyl]cytosine</td>

<td> 130</td><td> thymin-l-yl</td><td> octadecyloxyethyl</td><td> galactosyl</td><td> galactosyl octadecyloxyethyl 1-(//)-((2phosphonomethoxy)propyl]thymine</td>

<td> 131</td><td> uracil-l-yl</td><td> octadecyloxyethyl</td><td> galactosyl</td><td> galactosyl octadecyloxy ethyl 1-(2/)-((2phosphonomethoxy)piOpyl]uracil</td>

<td> 132</td><td> 2,6diaminopurin -9-yl</td><td> octadecyloxyethyl</td><td> galactosyl</td><td> galactosyl octadecyloxyethyl 9-(7/)-((2phosphonomethoxy)propyl]2,6diaminopurine</td>

<td> 133</td><td> guanin-9-yl</td><td> hexadecyloxypropyl</td><td> galactosyl</td><td> galactosyl hexadecyloxypropyl 9-(7/)- [(2-phosphonomethoxy)propy 1] guanine</td>

WO 2014/143643

PCT/US2014/027005 ^Nuc^Nuc(a) O ^Nuc^Nuc(a) O ^Nuc^Nuc(a) O k^.O^,P-O-L/L^a L.,__xO.._...P-G-L/L^a P-O-L/L³

- or £ i or ^; A

CH₃ O-R/R^a CH3 O-R/R^a CH3 °-R/R^a

Rp or Sp (depends on substituents) Rp, Sp (racemic)

<td> Cmpd No.</td><td> Βνιι&lt;/Βνιι&lt;:(·)</td><td> L/L</td><td> R/R</td><td> Name</td>

<td> 134</td><td> adenine-9-yl</td><td> hexadecyloxypropyl</td><td> galactosyl</td><td> galactosyl hcxad ecyl oxy propyl 9-(5)- [(2-phosphonomethoxy)propyl]adenine</td>

<td> 135</td><td> cytosine-1-yl</td><td> hexadecyloxypropyl</td><td> galactosyl</td><td> galactosyl bcxadecyloxypropyl !-(/?)[(2phosphonomethoxy)piOpyl]cytosine</td>

<td> 136</td><td> thymin-l-yl</td><td> hexadecyloxypropyl</td><td> galactosyl</td><td> galactosyl hexadecyloxy propyl 1-(5)[(2phosphonomethoxy)propyl]thymine</td>

<td> 137</td><td> uracil- 1-y I</td><td> hexadecyloxypropyl</td><td> galactosyl</td><td> galactosyl hexadecyloxypropyl 1-(5)- [(2-phosphonomethoxy)propyl]uracil</td>

<td> 138</td><td> 2,6diaminopurin -9-yl</td><td> hexadecyloxypropyl</td><td> galactosyl</td><td> galactosyl hexadecyloxypropyl 9-(5)[(2-phosphonomcthoxy)propyl]2,6dlaminopurine</td>

<td> 139</td><td> guanin-9-yl</td><td> l-O-octadecyl-2-Obenzyl-sr) glyceryl</td><td> galactosyl</td><td> galactosyl 1 - O-octadecy 1 -2-O-benzy 1 sn glyceryl 9-(5)-((2phosphonomethoxy)propyi]guanitie</td>

<td> 140</td><td> adenine-9-yl</td><td> l-O-octadecyi-2-Obenzyl-in glyceryl</td><td> galactosyl</td><td> galactosyl l-O-octadecyl-2~O-berizylsn glyceryl 9-(5)-((2phosphonomethoxy)propy!]adenine</td>

<td> 141</td><td> cytosine-l-yl</td><td> 1 -O-0ctadecyl-2-Obenzyl-sn glyceryl</td><td> galactosyl</td><td> galactosyl 1-O-octadecy 1 -2-O-benzy 1 sn glyceryl 1-(5)-((2phosphonomethoxy)propyllcytosine</td>

<td> 142</td><td> thymin-I-yl</td><td> l-O-octadecyl-2-Obenzyl-i-n glyceryl</td><td> galactosyl</td><td> galactosyl 1-O-octadecy 1 - 2-O-benzy 1 sn glyceryl 1-(5)-((2phosphonomethoxy)propyl]thymine</td>

<td> 143</td><td> uracil-1-yl</td><td> l-O-octadecyl-2-Obenzy 1-477 glyceryl</td><td> galactosyl</td><td> galactosyl l-O-octadecyl-2-O-benzylsn glyceryl l-(J?)-[(2phosphonomethoxy)propyl]uracil</td>

<td> 144</td><td> 2,6- diaminopurin -9-yl</td><td> l-O-octadecyl-2-Obenzyl-sn glyceryl</td><td> galactosyl</td><td> galactosyl 1 -O-octadecy Ι-2-O-benzy 1sn glyceryl 9-(5)-((2phosphonomethoxy)piOpyl]2,6di aminopurine</td>

Table 3. (S)-3-mcthoxy-2-phosphonmethoxypropyl [(S)-MPMP] diester compounds

<td colspan="5"> ^Nuc^Nuc(a) O ^Nuc^Nuc(a) 0 ®Nuc^Nuc(a) O 0 UL^a or k^O^P-O-UL^a or L..^O...__x,PO-UL^a η₃ο-ο-^Ξ h3co--^: °-R/*^a h3c-0-^{j O_R/Ra} Rp or Sp (depends on substituents) Rp, Sp (racemic)</td>

<td> Cmpd No.</td><td> Βνικ/Βνι,Φι)</td><td> L/L</td><td> R/R“</td><td> Name</td>

<td> 145</td><td> guanin-9-yl</td><td> octadecy loxy ethyl</td><td> benzyl</td><td> benzyl octadecyloxyethyl 9-(5)-((3methoxy-2- phosphonomethoxy)piOpyl]guanine</td>

<td> 146</td><td> adenine-9-yl</td><td> octadecyl oxy ethyl</td><td> benzyl .</td><td> benzyl octadecy! oxy ethyl 9-(5)-((3noethoxy-2phosphonomethoxy)propyl]adenlne</td>

WO 2014/143643

PCT/US2014/027005

<td colspan="5">^BNuc/^BNuc(a) 0 ^BNuc^^BNuc(a) 0 ^BNuc/^BNuc(a) O ί'.3..Ο...^Ρ·-°-υυ _or L, _XO^P O L/Lⁿ_or L ^0..„^P- O-UL^a h₃c-o^J °^RyRa h₃c-0- h₃c-0^ ^OPJRa Rp or Sp (depends on substituents) Rp, Sp (racemic) ___</td>

<td> Cmpd No.</td><td> B_NlK./B_N1,_c(_n)</td><td> L/L</td><td> R/R</td><td> Name</td>

<td> 147</td><td> cytosine-l-yl</td><td> octadecyl oxy ethyl</td><td> benzyl</td><td> benzyl octadecyloxyethyl 1-(9)-((3methoxy-2phosphonomethoxy)propy1]cytosine</td>

<td> 148</td><td> thymin-l-yl</td><td> octadecyl oxy ethyl</td><td> benzyl</td><td> benzyl octadecyloxyethy! 1-(9)-((3methoxy-2- phosph onomethoxy) propy 1 ] thy m ine</td>

<td> 149</td><td> uracil-l-yl</td><td> octadecyloxyethyl</td><td> benzyl</td><td> benzyl octadecyloxyethyl 1-(9)-((3methoxy-2phosphonomcthoxy)propyljui'acil</td>

<td> 150</td><td> 2,6diaminopurin -9-yl</td><td> octadecyloxyethyl</td><td> benzyl</td><td> benzyl octadecyloxyethyl 9-(9)-((3methoxy-2phosphonomethoxy)propyl]2,6diaminopurine </td>

<td> 151</td><td> guanin-9-yl</td><td> hexadecyloxypropyl</td><td> benzyl</td><td> benzyl hexadecyloxypropyl 9-(9)-((3methoxy-2phosphonomethoxy)propyl]guanine</td>

<td> 152</td><td> adenine-9-yl</td><td> hexadecyloxypropy!</td><td> benzyl</td><td> benzyl hexadecyloxypropyl 9-(9)-((3methoxy-2phosphonomethoxy)propyl]adenine</td>

<td> 153</td><td> cytosine-1-yl</td><td> hexadecyl oxypropy 1</td><td> benzyl</td><td> benzyl hexadecyloxypropyl 1-(9)-((3- methoxy-2phosphonomethoxvlpi'opyljcytosinc</td>

<td> 154</td><td> thymin-l-yl</td><td> hexadecyloxypropyl</td><td> benzyl</td><td> benzyl hexadecyloxypropyl 1-(9)-((3methoxy-2- phosphonomethoxy) propy 1] thy m i ne</td>

<td> 155</td><td> uracil-l-yl</td><td> hexadecyloxypropyl</td><td> benzyl</td><td> benzyl hexadecyloxypropyl 1-(9)-((3methoxy-2phosphonomethoxy)propyl]uracil</td>

<td> 156</td><td> 2,6diaminopurin -9-yl</td><td> hexadecyl oxy propyl</td><td> benzyl</td><td> benzyl hexadecyloxypropyl 9-(9)-((3methoxy-2phosphonomethoxy)propy 1(2,6 diaminopurine</td>

<td> 157</td><td> guanin-9-yl</td><td> 1-O-octadecy 1-2-0benzyl-j» glyceryl</td><td> benzyl</td><td> benzyl 1 -O-octadecy 1-2-O-benzy 1-jt? glyceryl 9-(9)-((3-methoxy-2phosphonomethoxy)propyl]guanine</td>

<td> 158</td><td> adenine-9-yl</td><td> l-O-octadecyl-2-Obenzyl-sn glyceryl</td><td> benzyl</td><td> benzyl 1 -O-octadccyl -2- O-benzy l-jn glyceryl 9-(9)-[(3-methoxy-2phosphonomethoxy)propyl]adenine</td>

<td> 159</td><td> cytosine-1-yl</td><td> 1-O-octadecy 1-2-0benzyl-jn glyceryl</td><td> benzyl</td><td> benzyl l-O-octadecyi-2-O-bcnzyl-jn glyceryl l-(5)-[(3-methoxy-2phosphonomethoxy)propyl]cytosine </td>

<td> 160</td><td> thymin-l-yl</td><td> I - O-octadecy 1-2- 0benzyl-J?: glyceryl</td><td> benzyl</td><td> benzyl 1 -O-octadecyl-2-O-benzy 1-sw glyceryl l-(9)-[(3-methoxy-2phosphonomethoxy)propyl]thymine</td>

<td> 161</td><td> uracil-l-yl</td><td> l-O-octadecyl-2-Obenzyl-sw glyceryl</td><td> benzyl</td><td> benzy 1 1 -O-octadecy 1-2- O-benzy 1-jn glyceryl l-(S)-[(3-methoxy-2phosphonomethoxy)propyl]uracil</td>

WO 2014/143643

PCT/US2014/027005

<td colspan="2"> ®Nuc/BNuc(a) 0</td><td colspan="2"> ^Nuc^Nuc(a) 0</td><td rowspan="2"> ^Nuc^Nuc(a) 0 JL³_or L /0. .P O L/L^a H_SC&gt;</td>

<td></td><td> ,.^0.._v.P-O- O-R/F</td><td> L/L· _or L ^ia h₃c-o-^</td><td> J^P-O-L O-R/R^;</td>

<td></td><td colspan="3"> Rp or Sp (depends on substituents)</td><td> Rp, Sp (racemic)</td>

<td> Cmpd No.</td><td> Bnik/Bnuc(h}</td><td> L/L</td><td> R/R</td><td> Name</td>

<td> 162</td><td> 2,6diaminopurin -9-yl</td><td> l-O-octadecyl-2-O- bcnzyl-.vn glyceryl</td><td> benzyl</td><td> benzyl 1 -O-octadecy 1-2- O-bcnzy l-j« glyceryl 9-(5)-[(3-methoxy-2phosphonomethoxy)propy 1 ] 2,6diaminopurine</td>

<td> 163</td><td> guanin-9-yi</td><td> octadecyloxyethyl</td><td> phenyl</td><td> phenyl octadecyl oxyethyl 9-(5)-((3methoxy-2phosphonomethoxy) propyl] guan i n e</td>

<td> 164</td><td> adenine-9-yl</td><td> octadecyl oxycthyl</td><td> phenyl</td><td> phenyl octadecyloxyethyl 9-(5)-((3methoxy-2phosphonomethoxy)propyl]adcnine</td>

<td> 165</td><td> cytosine-l-yl</td><td> octadecyloxy ethyl</td><td> phenyl</td><td> phenyl octadecyl oxyethyl 1 -(5)-((3methoxy-2phosphonomethoxy)piOpyl]cytosine</td>

<td> 166</td><td> thymin-l-yl</td><td> octadecyloxyethyl</td><td> phenyl</td><td> phenyl octadecyloxyethyl 1-(5)-((3mcthoxy-2phosphonomethoxy)propyl]thyniine</td>

<td> 167</td><td> uracil-1-yl</td><td> octadecyloxyethyl</td><td> phenyl</td><td> phenyl octadecyloxyethyl 1-(5)-((3methoxy-2phosphonorncthoxy) propyl] uracil</td>

<td> 168</td><td> 2,6diaminopurin -9-yl</td><td> octadecyl oxyethyl</td><td> phenyl</td><td> phenyl octadecyloxyethyl 9-(5)-((3methoxy-2- phosphonomethoxy)propyl]2,6dlaminopurine</td>

<td> 169</td><td> guanin-9-yl</td><td> hexadccy loxy propyl</td><td> phenyl</td><td> phenyl hexadecyloxypropyl 9-(5)-((3mcthoxy-2phosphonomethoxy)propyl]guanine</td>

<td> 170</td><td> adenine-9-yl</td><td> h exadecyloxy propyl</td><td> phenyl</td><td> phenyl hexadecyl oxy propyl 9-(5)-((3methoxy-2phosphonomethoxy)propyl ]adeni ne</td>

<td> 171</td><td> cytosine-l-yl</td><td> hexadecyloxypropyl</td><td> phenyl</td><td> phenyl hexadecyloxypropyl 1-(5)-((3methoxy-2- phosph onomethoxy)propy 1 ] cytosine</td>

<td> 172</td><td> thymin-l-y!</td><td> hexadecyloxypropyl</td><td> phenyl</td><td> phenyl hexadecyloxypropyl 1-(5)-((3methoxy-2phosphonomethoxy)propyl]thymine</td>

<td> 173</td><td> uracil-1-yl</td><td> hexadecyloxypropyl</td><td> phenyl</td><td> phenyl hexadecyloxypropyl 1-(5)-((3methoxy-2phosphonomethoxy)propyl|uracil</td>

<td> 174</td><td> 2,6diaminopurin -9-yl</td><td> hexadecyloxypropyl</td><td> phenyl</td><td> phenyl hexadecyloxypropyl 9-(5)-((3methoxy-2- phosphonomethoxy)piOpyl]2,6diaminopurine</td>

<td> 175</td><td> guanin-9-yl</td><td> l-O-octadecyl-2-Obenzyl-.M glyceryl</td><td> phenyl</td><td> ph eny 1 1 -O-octadecy 1 -2-0-benzy 1-sn glyceryl 9-(5)-((3-methoxy-2phosphonomethoxy)propyl]guanine</td>

<td> 176</td><td> adenine-9-yl</td><td> l-O-octadecyl-2-Obenzyl-sii glyceryl</td><td> phenyl</td><td> phenyl 1 -O-octadecy 1-2- O-benzyl-sn glyceryl 9-(5)-[(3-methoxy-2phosphonomethoxy)propyl]adenine</td>

WO 2014/143643

PCT/US2014/027005

<td colspan="2"> BNuc^Nuc(a) 0</td><td colspan="3" rowspan="2"> BNuc/BNuc(a) O ^Nuc^Nuc(a) O /L^a or P-ο· L/L^a or χ^Ο,^Ρ Ό-ίίΙ?</td>

<td rowspan="2"> H₃C</td><td rowspan="2"> ^O^P-O-L OR/R^; Rp or Sp</td>

<td> h₃c-o-^ (depends on substituen</td><td> O-R/R^a ts)</td><td> = O-R/R^a H-jC-O' Rp, Sp (racemic)</td>

<td> Cmpd No,</td><td></td><td> L/L</td><td> R/R“</td><td> Name</td>

<td> 177</td><td> cytosine-l-yi</td><td> 1 -O-octadecyl-2-Obenzyl-w glyceryl</td><td> phenyl</td><td> phenyl 1 -O-octadecy 1-2-O-benzy 1 -sn glyceryl l-(5)-[(3-methoxy-2phosphonomethoxy)propyl]cytosine</td>

<td> 178</td><td> thymin-l-yl</td><td> l-O-octadecyl-2-Obcnzyl-s/i glyceryl</td><td> phenyl</td><td> phenyl I - O-octadecy 1 -2- O-benzy 1-sn glyceryl 1-(5)-[(3-methoxy-2phosphonomethoxy)propyl]thymine</td>

<td> 179</td><td> uracil-l-yl</td><td> l-O-octadecyl-2-Obenzyl-srt glyceryl</td><td> phenyl</td><td> phenyl l-O-octadecyl-2-O-benzyl-.w glyceryl 1 -(5)-[(3-methoxy-2- phosphonom ethoxy)propyl]uracil_______</td>

<td> 180</td><td> 2,6diaminopurin -9-yl</td><td> l-O-octadecyl-2-Obenzyl-srr glyceryl</td><td> phenyl</td><td> phenyl 1 - O-octadecy I -2- C*-benzy 1-sn glyceryl 9-(5)-((3-methoxy-2phosphonomethoxy)propyl]2,6diam inopurine</td>

<td> 181</td><td> guanin-9-yl</td><td> octadecyl oxy ethyl</td><td> ethyl</td><td> ethyl octadecyloxycthyl 9-(5)-((3methoxy-2phosphonomethoxy)propyl]guanlne</td>

<td> 182</td><td> adcnine-9-yl</td><td> octadccy 1 oxy ethyl</td><td> ethyl</td><td> ethyl octadecyloxycthyl 9-(5)-((3methoxy-2phosphonomethoxy)propyl]adenine</td>

<td> 183</td><td> cytosine-l-yl</td><td> octadecyloxyethyl</td><td> ethyl</td><td> ethyl octadecyloxyethyl 1-(5)-((3methoxy-2phosphonomethoxy)propyl]cytosinc</td>

<td> 184</td><td> thymin-l-yl</td><td> octadecyloxy ethyl</td><td> ethyl</td><td> ethyl octadecyloxy ethyl 1-(5)-((3methoxy-2phosphonomethoxy)pro py l]thym i ne</td>

<td> 185</td><td> uracil-l-yl</td><td> octadecyloxyethyl</td><td> ethyl</td><td> ethyl octadecyloxycthyl 1-(5)-((3methoxy-2phosphonomethoxy)propyl] uracil_______</td>

<td> 186</td><td> 2,6diaminopurin -9-yl</td><td> octadecyloxycthyl</td><td> ethyl</td><td> ethyl octadecyloxycthyl 9-(5)-((3methoxy-2phosphonomethoxy)propyl]2,6- 1 diaminopurine</td>

<td> 187</td><td> guanin-9-yl</td><td> hexadecyloxypropyl</td><td> ethyl</td><td> ethyl hexadecyloxypropyl 9-(5)-((3methoxy-2phosphonomethoxy)propyl]guanine</td>

<td> 188</td><td> adeninc-9-y]</td><td> hexadecyloxypropyl</td><td> ethyl</td><td> ethyl hexadecyloxypropyl 9-(5)-((3methoxy-2- nhosphonomethox v)propy 1] adeni ne</td>

<td> 189</td><td> cytosine-l-yl</td><td> hexadecyloxypropyl</td><td> ethyl</td><td> ethyl hexadecyloxypropyl 1-(5)-((3methoxy-2phosphonomcthoxy)propyl]cytosine</td>

<td> 190</td><td> thymin-l-yl</td><td> hexadecyloxypropyl</td><td> ethyl</td><td> ethyl hexadecyloxypropyl 1-(5)-((3melhoxy-2- ph osphonomethoxy)propy 1] thy mi ne</td>

<td> 191</td><td> uracil-l-yl</td><td> | hexadecyloxypropyl</td><td> ethyl</td><td> ethyl hexadecyloxypropyl 1-(l5()-[(3methoxy-2phosphonomethoxy)propyl(uracil_______</td>

WO 2014/143643

PCT/US2014/027005

Bf4uc/BNuc(a) O Bfq_uc/Bfj_ucf_a) q Bfj_uc/BN_UC(_a) q

k.^O...^O-|JL^a or O- L/L^a or k^O^P-O-L/L³ h₃c-o^J 0-r/r³ ^-ο' o-r/r³_H3C^_oJ O-R/R^a

Rp or Sp (depends on substituents) Rp, Sp (racemic)

<td> Cmpd No.</td><td></td><td> L/L</td><td> R/R</td><td> Name</td>

<td> 192</td><td> 2,6diaminopurln -9-yl</td><td> hexadecyloxypropyl</td><td> ethyl</td><td> ethyl hexadecyloxypropyl 9-(5)-((3methoxy-2- phosphonomethoxy) propyl] 2,6diaminopurine</td>

<td> 193</td><td> guamn-9-yl</td><td> l-O-octadecyl-2-Obenzyl-jf? glyceryl</td><td> ethyl</td><td> ethyl l-O-octadecyl-2-O-benzyl-sn glyceryl 9-(5)-[(3-methoxy-2phosphonom ethoxy) propyl ] gu anine</td>

<td> 194</td><td> adenine-9-yl</td><td> l-&lt;7-octadecyl-2-&lt;9benzyl-j/j glyceryl</td><td> ethyl</td><td> ethyl l-O-octadecyl-2-O-benzyl-jfl glyceryl 9-(5)-( (3-methoxy-2phosphonomethoxy)piOpyl]adenine</td>

<td> 195</td><td> cytosine-l-yl</td><td> I -O-octadecyl-2-0ben/yl-.vn glyceryl</td><td> ethyl</td><td> ethyl 1 -O-octadecy 1-2-O-benzy! -sn glyceryl l-(5)-[(3-methoxy-2phosphonomethoxy)propyl]cytosine</td>

<td> 196</td><td> thymin-l-yl</td><td> 1 -O-octadecy 1-2-0benzyl-js glyceryl</td><td> ethyl</td><td> ethyl 1 -O-octadecyl-2-O-benzyl-jn glyceryl 1-(5)-((3-methoxy-2phosphonomethoxy)piOpyl]thymine</td>

<td> 197</td><td> uracil-l-yl</td><td> l-O-octadecyl-2-Obenzyl-sn glyceryl</td><td> ethyl</td><td> ethyl 1 -O-octadecy 1-2-O-benzy 1 -sn glyceryl 1-(5)-((3-methoxy-2phosphonomethoxy)propyl]uracil</td>

<td> 198</td><td> 2,6diaminopurin -9-yl</td><td> l-O-octadecyl-2-O- benzyl-szi glyceryl</td><td> ethyl</td><td> phenyl 1 -O oc.tadccy 1-2-O-benzyl-sn glyceryl 9-(5)-[(3-methoxy-2phosphonomethoxy)propyl]2,6diaminopurine</td>

<td> 199</td><td> guanin-9-yl</td><td> octadecyloxyethyi</td><td> galactosyl</td><td> galactosyl octadecyloxyethyi 9-(5)-((3methoxy-2phosphonomethoxy)propyl]guanine</td>

<td> 200</td><td> adenine-9-y!</td><td> octadecyloxyethyi</td><td> galactosyl</td><td> galactosyl octadecyloxyethyi 9-(5)-((3methoxy-2phosphonomethoxy)piOpyl]adenine</td>

<td> 201</td><td> cytosine-l-yl</td><td> octadecyloxyethyi</td><td> galactosyl</td><td> galactosyl octadecyloxyethyi 1 -(5)-((3methoxy-2phosphonomethoxy)propyl]cytosine</td>

<td> 202</td><td> thymin-l-yl</td><td> octadecyloxyethyi</td><td> galactosyl</td><td> galactosyl octadecyloxyethyi 1-(6)-((3methoxy-2phosphonomethoxy)propyl]thymine</td>

<td> 203</td><td> uracil-l-yl</td><td> octadecyl oxyethyl</td><td> galactosyl</td><td> galactosyl octadecyloxyethyi 1-(5)-((3methoxy-2phosphonomethoxy)propyl]uracil</td>

<td> 204</td><td> 2,6diaminopurin -9-yl</td><td> octadecyloxyethyi</td><td> galactosyl</td><td> galactosyl octadecyloxyethyi 9-(5)-((3methoxy-2- phosphonomethoxy)pro py 1 ] 2.,6diamlnopurine</td>

<td> 205</td><td> guanin-9-yl</td><td> hexadecyloxypropyl</td><td> galactosyl</td><td> galactosyl hexadecyloxypropyl 9-(5)[(3-methoxy-2phosphonomethoxy)propyl]guaninc</td>

<td> 206</td><td> adcnine-9-yl</td><td> hexadecyloxypropyl</td><td> galactosyl</td><td> galactosyl hexadecyloxypropyl 9-(5)[(3-methoxy-2phosphonomethoxy)propyl]adeninc</td>

WO 2014/143643

PCT/US2014/027005

<td colspan="5">^BNu&lt;?^BNuc(a) O ^BNuc^^BNuc(a) O ^BNut/^BNuc(a) O L3o^P-O-UL^a or L^.O^P-0-UL^a or L ^O.^P O-LJL^S - A - O 0/03 “ 0“R/R^a h₃c-o-^ °~^r/r h3c_o- ^0_r/r h3c-O'- Rp or Sp (depends on substituents) Rp, Sp (racemic)________</td>

<td> Cmpd No.</td><td> ®Nuc^Niic(a)</td><td> L/L</td><td> R/R</td><td> Name</td>

<td> 207</td><td> cytosine-1-yl</td><td> hexadecyloxypropyl</td><td> galactosyl</td><td> galactosyl hexadecyloxypropyl 1-(5)[(3-methoxy-2phosphonomethoxy) propy l]cytosi ne</td>

<td> 208</td><td> thymin-I-yl</td><td> hexadecyloxypropyl</td><td> galactosyl</td><td> galactosyl hexadecyloxypropyl 1-(5)[(3-mcthoxy-2phosphonomethoxy)propyl]thymine</td>

<td> 209</td><td> uracil-l-yl</td><td> hexadecyloxypropyl</td><td> galactosyl</td><td> galactosyl hexadecyloxypropyl 1-(5))(3-methoxy-2phosphonomethoxy) propy l]uracil_______</td>

<td> 210</td><td> 2,6diaminopurin -9-yl</td><td> hexadecyloxypropyl</td><td> galactosyl</td><td> galactosyl hexadecyloxypropyl 9-(5))(3-methoxy-2phosphonomethoxy)propy 1 )2,6diaminopurine</td>

<td> 211</td><td> guanin-9-yl</td><td> 1 -O-octadccy 1-2-(9benzyl-JW glyceryl</td><td> galactosyl</td><td> galactosyl l-(9-octadecyl-2-(9-benzylsn glyceryl 9-(5)-[(3-methoxy-2phosphonomethoxy)propyl]guanine</td>

<td> 212</td><td> adenine-9-y!</td><td> I - (9-octadecy 1-2- Obenzyl-w glyceryl</td><td> galactosyl</td><td> galactosyl l-(9-octadecyl-2-(9-benzylsn glyceryl 9-(5)-[(3-methoxy-2phosphonomethoxy)propyl]adenine</td>

<td> 213</td><td> cytosine-l-yl</td><td> l-O-octadecyl-2-Obenzyl-.w glyceryl</td><td> galactosyl</td><td> galactosyl l-O-octadecyl-2- O-benzylsn glyceryl 1 -(5)-[(3-methoxy-2phosphonomethoxy)propy 1 )cy tosi n e</td>

<td> 214</td><td> thymin-l-yl</td><td> l-C&gt;-octadecyl-2-&lt;9- benzyl-JM glyceryl</td><td> galactosyl</td><td> gal actosy 1 1 -&lt;9-octadecy 1-2- O- benzy 1 sn glyceryl l-(S)-[(3-methoxy-2phosphonomethoxy)propyl]thymlne</td>

<td> 215</td><td> uracil-l-yl</td><td> l-O-oetadecyl-2-Obenzyl-jn glyceryl</td><td> galactosyl</td><td> galactosyl 1 -O-octadecy Ι-2-O-benzylsn glyceryl l-(5)-[(3-methoxy-2Dhosphonomethoxy)propyl]uracil</td>

<td> 216</td><td> 2,6- diaminopurin -9-yl</td><td> l-(9-octadecyl-2-(9benzyl-jrr glyceryl</td><td> galactosyl</td><td> galactosyl l-O-octadecyl-Z-O-benzyl- sn glyceryl 9-(5}-[(3-methoxy-2phosphonomcthoxy)propyl]2,6- | diaminopurine </td>

Table 4. (S)-3-hydroxy-2-phosphonomethoxypropyl [(S)-HPMP] diester compounds ^BNuc^^BNuc(a) O

L^,O^PO-UL^a^BNuc^^BNuc(a) O

L .0. ,P-O'L/Lⁿ

HO^

O-R/R^a or

HO

O-R/R^a or ^BNuc'^BNuc(a) O

L o P O L/L

- OR/R^a

HO

Rp or Sp (depends on substituents)

Rp, Sp (racemic)

<td> Cmpd No.</td><td></td><td> L/L</td><td> R/R</td><td> Name</td>

<td> 217</td><td> —-------- guanin-9-yl</td><td> octadccyloxyethyl</td><td> benzyl</td><td> benzyl octadecyloxyethyl 9-(5)-)(3hydroxy-2phosphonomethoxy)propy l]gu anine</td>

WO 2014/143643

PCI7US2014/027005

<td colspan="2"> Bhiuc/BNucia) O ί ’ ri</td><td rowspan="2"> Bn_uc/Bnu JL^a or / - HO (depends on substitue</td><td rowspan="2"> c(a) 0 ,0, ^.P-0 O-RJ nts)</td><td rowspan="2"> BNuc^BN_UC(_a) 0 -L/L^a k^O^P-O-L/L R^{a or}_H0J ο-*'*’ Rp, Sp (racemic)</td>

<td> HO^Z'</td><td> ^O...^P-O-L. O-R/R' Rp or Sjt</td>

<td> Cmpd No.</td><td> B_Nuc/B_N1]C(_n(</td><td> L/L</td><td> R/R</td><td> Name</td>

<td> 218</td><td> adenine-9-yl</td><td> octadecyl oxyethyl</td><td> benzyl</td><td> benzyl octadecyl oxy ethyl 9-(5)-((3hydroxy-2phosphonomethoxylpropyljadenine</td>

<td> 219</td><td> cytosinc-l-yl</td><td> octadecyloxyethyl</td><td> benzyl</td><td> benzyl octadecyl oxyethyl 1-(6)-((3hydroxy-2- phosphonometh oxy)propyl ]cy to s 1 ne</td>

<td> 220</td><td> thymin-l-yl</td><td> octadecyl oxyetliy 1</td><td> benzyl</td><td> benzyl octadecyloxyethyl 1-(6)-((3hydroxy-2- phosphonomethoxy )propy l]thy m i ne</td>

<td> 221</td><td> uracil-l-yl</td><td> octadecyloxycthyl</td><td> benzyl</td><td> benzyl octadecyloxyethyl 1-(5)-((3hydroxy-2phosphonomethoxy)piOpyl]uracil</td>

<td> 222</td><td> 2,6- di aminopurin -9-yl</td><td> octadecyl oxyethy 1</td><td> benzyl</td><td> benzyl octadecyloxyethyl 9-(5)-((3hydroxy-2phosphonomethoxy)propyl]2,6diaminopurine</td>

<td> 223</td><td> guanin-9-yl</td><td> hexadecyloxypropyl</td><td> benzyl</td><td> benzyl hexadecyloxypropyl 9-(5)-((3hydroxy-2phosphonomcthoxy)propyl]guanine</td>

<td> 224</td><td> adenine-9-yl</td><td> hexadecyloxypropyl</td><td> benzyl</td><td> benzyl hexadecyloxypropyl 9-(6)-((3bydroxy-2phosphonomethoxy)propyl]adenine</td>

<td> 225</td><td> cytosine-l-yl</td><td> hexadecyloxypropyl</td><td> benzyl</td><td> benzyl hexadecyloxypropyl 1-(5)-((3hydroxy-2phosphonomethoxy)propyl]cytosine</td>

<td> 226</td><td> thymin-l-yl</td><td> hexadecyloxypropyl</td><td> benzyl</td><td> benzyl hexadecyloxypropyl 1-(5)-((3hydroxy-2- phosphonomethoxy) propyl] thy m ine</td>

<td> 227</td><td> uracil-l-yl</td><td> hexadecyloxypropyl</td><td> benzyl</td><td> benzyl hexadecyloxypropyl 1-(5)-((3hydroxy-2phosphonomethoxy)propyl]uracil</td>

<td> 228</td><td> 2,6diaminopurin -9-yl</td><td> hexadecyloxypropyl</td><td> benzyl</td><td> benzyl hexadecyloxypropyl 9-(5)-((3hydroxy-2- phosphonom ethoxy)pro py I ] 2,6diaminopurine</td>

<td> 229</td><td> guanin-9-yl</td><td> l-O-octadecyl-2-Obenzyl-jr; glyceryl</td><td> benzyl</td><td> benzyl l-0-octadecyI-2-0-benzyl-j« glyceryl 9-(5)-[(3-hydroxy-2phosphonomethoxy)propyl]guanine</td>

<td> 230</td><td> adenine-9-yl</td><td> l-O-octadecyl-2-Obenzyl-jn glyceryl</td><td> benzyl</td><td> benzyl l-O-octadecyl-2-O-benzyl-srt glyceryl 9-(5)-[(3-hydroxy-2phosphono methoxy) propy l]aden ine</td>

<td> 231</td><td> cytosine-l-yl</td><td> I -O-octadecy 1-2- 0ben/y :-.:.77 glyceryl</td><td> benzyl</td><td> benzyl l-O-octadecyl-2-O-benzyl-.w glyceryl 1-(6)-((3 -hydroxy-2phosphonomethoxy)propyi]cytosine</td>

<td> 232</td><td> thymin-l-yl</td><td> 1 -O-octadecy 1-2-0bcnzyl-jn glyceryl</td><td> benzyl</td><td> benzyl l-C*-octadecyl-2-0-benzyl-sw glyceryl ]-(S)-[(3-hydroxy-2phosphonomethoxy)propyl]thymine</td>

WO 2014/143643

PCT/LS2014/027005

<td colspan="5">^BNuc^/BNuc(a) 0 ^BNut/^BNuc(a) O ^BNuc^/BNuc(a) O 1^,0 P-O—L/L^a O-L/L^a L..^..O...^P-0-L/L _H0&gt; 0-WR’ θ’ _H0&gt; i™· °^Γ HOJ Rp or Sp (depends on substituents) Rp, Sp (racemic)</td>

<td> Cmpd No.</td><td> Bnuc/Bnu^)</td><td> L/L</td><td> R/R</td><td> Name</td>

<td> 233</td><td> uracil-l-yl</td><td> l-O-octadecyl-2-Obenzykw glyceryl</td><td> benzyl</td><td> benzyl l-O-octadecyl-2-O-benzyl-j« glyceryl 1-(5)-((3-hydroxy-2phosphonom ethoxy) propyl) uracil</td>

<td> 234</td><td> 2,6- diaminopurin -9-yl</td><td> 1 -O-octadecyl-2-Obenzyl-jn glyceryl</td><td> benzyl</td><td> benzyl 1 -0- octadecy I -2-O-benzy 1-sw glyceryl 9-(S)-[(3-hydroxy -2phosphonomethoxy)propylj2,6diaminopurine </td>

<td> 235</td><td> guanin-9-yl</td><td> octadecyloxyethyl</td><td> phenyl</td><td> phenyl octadecyloxyethyl 9-(5)-((3hydroxy-2phosphonomethoxy)propyl]guanine</td>

<td> 236</td><td> adenine-9-yl</td><td> octadecyloxyethyl</td><td> phenyl</td><td> phenyl octadecy! oxyethyl 9-(6)-((3hydroxy-2phosphonotnethoxy)propyl]adeninc</td>

<td> 237</td><td> cytosinc-l-yl</td><td> octadecyloxyethyl</td><td> phenyl</td><td> phenyl octadecyloxyethyl 1-(5)-((3hydroxy-2phosphonomethoxy)propyl]cytosine</td>

<td> 238</td><td> thymin-l-yl</td><td> octadecyloxyethyl</td><td> phenyl</td><td> phenyl octadecy 1 oxy ethyl 1-(6)-((3hydroxy-2phosphonomethoxy)propyl]thymlne</td>

<td> 239</td><td> uracil-l-yl</td><td> octadecyloxyethyl</td><td> phenyl</td><td> phenyl octadecyl oxy ethyl 1-(5)-((3hydroxy-2phosphonometh oxy)propyl]uracil_______</td>

<td> 240</td><td> 2,6- diaminopurin -9-yl</td><td> octadecyloxyethyl</td><td> phenyl</td><td> phenyl octadecyloxyethyl 9-(5)-((3hydroxy-2phosphonomethoxy)propy 1 ] 2,6di aminopurine</td>

<td> 241</td><td> guanin-9-yl</td><td> hexadecyloxypropyl</td><td> phenyl</td><td> phenyl hexadecyloxypropyl 9-(6)-((3- hydroxy-2- phosphonomethoxy)propyl]guanine</td>

<td> 242</td><td> adenine-9-yl</td><td> hexadecyloxypropyl</td><td> phenyl</td><td> phenyl hexadecyloxypropyl 9-(5)-((3hydroxy-2phosphonomethoxy)propyl]adenine</td>

<td> 243</td><td> cytosine-1-yl</td><td> hexadecyloxypropyl</td><td> phenyl</td><td> phenyl hexadecyloxypropyl 1-(5)-((3hydroxy-2phosphonomethoxy)propyl]cytosine</td>

<td> 244</td><td> lhymin-1-yl</td><td> hexadecyloxypropyl</td><td> phenyl</td><td> phenyl hexadecyloxypropyl 1-(6)-((3hydroxy-2phosphonomethoxy)propyl]thymine</td>

<td> 245</td><td> uracil-l-yl</td><td> hexadecyl oxy propyl</td><td> phenyl</td><td> phenyl hexadecyloxypropyl 1-(5)-((3hydroxy-2phosphonomethoxy)propyl]uracil______</td>

<td> 246</td><td> 2,6diaminopurln -9-yl</td><td> hexadecyloxypropyl</td><td> phenyl</td><td> phenyl hexadecyloxypropyl 9-(5)-((3hydroxy-2phosphonomethoxy)propyl]2,6diaminopurine __________________</td>

<td> 247</td><td> guanin-9-yl</td><td> l-O-cctadecyl-2-Obenzyl-jn glyceryl</td><td> phenyl</td><td> phenyl l-O-octadecyl-2-O-benzyl-jn glyceryl 9-(6)-((3-hydroxy-2phosphonomethoxy)propyi]guanine</td>

WO 2014/143643

PCT/US2014/027005 ^Nuc^Nuc(a) O

L XL ,.P-O-L/L^a

BNuJBNuc(a) O k JX ,P-O~L/L^a ^Nuc^Nuc(a) O

L ,CL _xP-O-L/l

HO'

O-R/R^a or

HO'

O-R/R^a or

HO'

R/R^a

Rp or Sp (depends on substituents)

Rp, Sp (racemic)

<td> Cmpd No.</td><td></td><td> L/L</td><td> R/R“</td><td> Name</td>

<td> 248</td><td> adenine-9-yl</td><td> 1 -O-octadecyl-2-Obenzyl-jn glyceryl</td><td> phenyl</td><td> phenyl l-O-octadecyi-2-O-benzyl-jrt glyceryl 9-(5)-[(3-hydroxy-2phosphonomethoxy)propyl]adenine</td>

<td> 249</td><td> cytosine-l-yl</td><td> 1 -O-octadecy ί-2-Οbenzyl-s„ glyceryl</td><td> phenyl</td><td> phenyl l-0-octadecyl-2-0-benzyl-.rn glyceryl l-(5)-[(3-hydroxy-2phosphonomethoxy)propyl]cytosine</td>

<td> 250</td><td> thymin-l-yl</td><td> 1-O-octadecy 1-2-0benzyl-jn glyceryl</td><td> phenyl</td><td> phenyl l-O-octadecyl-2-O-benzyl-j« glyceryl 1-(5)-((3-hydroxy-2phosphonomethoxy)propyl]thymine</td>

<td> 251</td><td> uracil-l-yl</td><td> l-O-octadecyl-2-Obenzyl-j» glyceryl</td><td> phenyl</td><td> phenyl 1 - O-octadecy 1-2-O-benzy I-sn glyceryl l-(5)-((3-hydroxy-2phosphon omethoxy)propy 1] uracil</td>

<td> 252</td><td> 2,6- dlaminopurin -9-yl</td><td> 1-O-octadecy 1-2-0benzyl-jn glyceryl</td><td> phenyl</td><td> phenyl 1-O-octadecy Ι-2-O-benzyl-jn glyceryl 9-(5)-[(3-hydroxy-2phosphonomethoxy)propy 1] 2,6diaminopurine</td>

<td> 253</td><td> guanin-9-yi</td><td> octadecyloxyethyl</td><td> ethyl</td><td> ethyl octadecyloxyethyl 9-(5)-((3hydroxy-2phosphonomethoxy)propyl]guanine</td>

<td> 254</td><td> adenine-9-yl</td><td> octadecyloxyethyl</td><td> ethyl</td><td> ethyl octadecyloxyethyl 9-(5)-((3hydroxy-2phosphonomethoxy)propyl]adenlne</td>

<td> 255</td><td> cytosine-1-yl</td><td> octadecyloxyethyl</td><td> ethyl</td><td> ethyl octadecyloxy ethyl 1-(5)-((3hydroxy-2phosphonomethoxy)piOpyl]cytosine</td>

<td> 256</td><td> thymin-l-yl</td><td> octadecyloxyethyl</td><td> ethyl</td><td> ethyl octadecyloxyethyl 1-(5)-((3hydroxy-2phosphonomethoxy)propyl]thymine</td>

<td> 257</td><td> uracil-l-yl</td><td> octadecyloxyethyl</td><td> ethyl</td><td> ethyl octadecyloxyethyl 1-(5)-((3hydroxy-2phosphonomethoxy)propyl]uracil</td>

<td> 258</td><td> 2,6- diaminopurin -9-yl</td><td> octadecyloxyethyl</td><td> ethyl</td><td> ethyl octadecyloxyethyl 9-(5)-((3hydroxy-2phosphonomethoxy)piOpyl]2,6diam inopurlne</td>

<td> 259</td><td> guanin-9-yl</td><td> hexadecyloxypropyl</td><td> ethyl</td><td> ethyl hexadecyl oxy propyl 9-(5)-((3hydroxy-2phosphonomethoxy)propyl]guanlne</td>

<td> 260</td><td> adenine-9-y!</td><td> hexadecy loxypropy 1</td><td> ethyl</td><td> ethyl hexadecyloxypropyl 9-(5)-((3hydroxy-2phosphonomethoxy)piOpyl]adenine</td>

<td> 261</td><td> cytosine-1-yl</td><td> hexadecy loxypropy!</td><td> ethyl</td><td> ethyl hexadecyioxypropyl 1-(5)-((3hydroxy-2phosphonomethoxy)propyl]cytosine</td>

<td> 262</td><td> thymin-l-yl</td><td> hexadecyloxypropyl</td><td> ethyl</td><td> ethyl hexadecyioxypropyl 1-(5)-((3hydroxy-2- phosphonomethoxy)propyl]thymine</td>

WO 2014/143643

PCT/US2014/027005

<td colspan="5">^BNuc^/BNuc(a) 0 ^BNu&lt;7^BNuc(a) 0 ^BNuc^/BNuc(a) 0 l^,Q^P-O-L/L^a k^O..^.,P~O-UL^a k^Ck^P-O-L/L - ; or i l or - o-R/R^a HO- HO- «θ' Rp or Sp (depends on substituents) Rp, Sp (racemic)</td>

<td> Cmpd No.</td><td></td><td> L/L</td><td> R/R</td><td> Name</td>

<td> 263</td><td> uracil-l-yl</td><td> hexadecyl oxy propyl</td><td> ethyl</td><td> ethyl hexadecyloxypropyl 1-(5)-((3hydroxy-2phospbonomethoxy) propyl | uracil</td>

<td> 264</td><td> 2,6- diaminopurin -9-yl</td><td> hexadecyloxypropyl</td><td> ethyl</td><td> ethyl hexadecyloxypropyl 9-(5)-((3hydroxy-2phosphonomethoxy)propyl]2,6diaminopurine</td>

<td> 265</td><td> guanin-9-yl</td><td> 1 - O-octadecy 1-2-0benzyl-jn glyceryl</td><td> ethyl</td><td> ethyl l-O-octadecyl-2-O-benzyl-s-n glyceryl 9-(S)-[(3-hydi'oxy-2phosphonomethoxy)propyl]guanine</td>

<td> 266</td><td> adenine-9-yl</td><td> l-O-octadecyl-2-Obenzyl-jn glyceryl</td><td> ethyl</td><td> ethyl l-O-octadecyl-2-O-benzyl-sri glyceryl 9-(S)-[(3-hydraxy-2phosphonomethoxy)propyl]adenine</td>

<td> 267</td><td> cytosine-1-yl</td><td> l-O-octadecyl-2-Oberizyl-j;; glyceryl</td><td> ethyl</td><td> ethyl 1 - O-octadecy 1-2-O-benzy 1 -.w glyceryl 1-(5)-[(3-hydroxy-2phosphonomethoxv)propyl]cytosine</td>

<td> 268</td><td> thymin-l-yi</td><td> 1-O-octadecy 1-2-0benzyl-j/t glyceryl</td><td> ethyl</td><td> ethyl l-O-octadecyl-2-O-benzyl-in glyceryl l-(5)-[(3-hydroxy-2phosphonomethoxy) propy l]thy mine</td>

<td> 269</td><td> uracil-l-yl</td><td> l-O-octadecyl-2-Obenzyl-sn glyceryl</td><td> ethyl</td><td> ethyl l-O-octadecyl-2-O-benzyl-jn glyceryl 1-(5)-[(3-hydroxy-2phosphonomethoxy)propyl]wacil______</td>

<td> 270</td><td> 2,6diaminopurin -9-yl</td><td> l-O-octadecyl-2-Obenzyl-sn glyceryl</td><td> ethyl</td><td> phenyl l-O-octadecy!-2-O-bcnzyl-sn glyceryl 9-(5)-[(3-hydroxy-2phosphonomethoxy)propyl]2,6diaminopurine </td>

<td> 271</td><td> guanin-9-yl</td><td> octadecyloxyethyl</td><td> galactosyl</td><td> galactosyl octadecyloxyethyl 9-(5)-((3hydroxy-2- DhosphonomethoxY)propyl]guanine</td>

<td> 272</td><td> adenine-9-yl</td><td> octadecyloxyethyl</td><td> galactosyl</td><td> galactosyl octadecyloxyethyl 9-(5)-[(3hydroxy-2phosphonomethoxy)propyl]adenine </td>

<td> 273</td><td> cytosine-1-yl</td><td> octadecyloxyethyl</td><td> galactosyl</td><td> galactosyl octadecyloxyethyl 1-(5)-((3hydrox-2phosphonomethoxy)propyl]cytosinc</td>

<td> 274</td><td> thymin-l-y!</td><td> octadecyloxyethyl</td><td> galactosyl</td><td> galactosyl octadecyloxyethyl 1-(5)-((3hydroxy-2phosphonomethoxy)pi'opyl]thymine</td>

<td> 275</td><td> uracil-l-yl</td><td> octadecyloxyethyl</td><td> galactosyl</td><td> galactosyl octadecyloxyethyl 1-(5)-((3hydroxy-2phosphonomethoxy)propyl]uracil</td>

<td> 276</td><td> 2,6diaminopurin -9-yl</td><td> octadecyloxyethyl</td><td> galactosyl</td><td> galactosyl octadecyloxyethyl 9-(5)-((3hydroxy-2- phosphonomethoxy)propy!]2,6- di aminopurine</td>

<td> 277</td><td> guanin-9-yl</td><td> hexadecyloxypropyl</td><td> galactosyl</td><td> galactosyl hexadecyloxypropyl 9-(5)[(3-hydroxy-2- | phosphonomethoxy)propyl]guanine</td>

WO 2014/143643

PCT/US2014/027005

<td colspan="2">^BNuc^^BNuc(a) 0</td><td colspan="2">^BNuc^^BNuc(a) 0</td><td rowspan="2">^BNuc^^BNuc(a) O -L/L^a k^.O...^P-0-L/L pa °^r i 0-R/R^a^R HO Rp, Sp (racemic)</td>

<td> HO</td><td> ^,0 P O-L 0W Rp or Sp</td><td> /L^a k,_, or 1 HO (depends on substitue</td><td> Λ P-O- O-R7 its)</td>

<td> Cmpd No.</td><td></td><td> L/L</td><td> R/R</td><td> Name</td>

<td> 278</td><td> adenine-9-yl</td><td> hexadecyloxypropyl</td><td> galactosyl</td><td> galactosyl hexadecyloxypropyl 9-(9)|(3-hydroxy-2phosphonomethoxy)propyl]adenine</td>

<td> 279</td><td> cytosine-l-yl</td><td> hexadecyloxypropy1</td><td> galactosyl</td><td> galactosyl hexadecyloxypropyl 1-(5)[(3-hydroxy-2phosphonomethoxy)piOpyl]cytosine</td>

<td> 280</td><td> thymin-l-yl</td><td> hexadecyloxypropyl</td><td> galactosyl</td><td> galactosyl hexadecyloxypropyl 1-(5)[(3-hydroxy-2phosphonomethoxy)propyl] thy mine</td>

<td> 281</td><td> uracil-l-yl</td><td> hexadecyloxypropyl</td><td> galactosyl</td><td> galactosyl hexadecyloxypropyl 1-(5)[(3-hydroxy-2phosphonomethoxy)piOpyl]iiracil</td>

<td> 282</td><td> 2,6- diaminopurin -9-yi</td><td> hexadecyloxypropyl</td><td> galactosyl</td><td> galactosyl hexadecyloxypropyl 9-(5)[(3-hydroxy-2phosphonomethoxy)propyl]2,6diaminopurine</td>

<td> 283</td><td> guanin-9-yl</td><td> 1 - O-octadecy 1 -2-0bcnzyl-in glyceryl</td><td> galactosyl</td><td> galactosyl l-O-octadecyl-2-O-benzylsn glyceryl 9-(5)-[(3 -hydroxy-2phosphonomethoxy)propyl]guanine</td>

<td> 284</td><td> adenine-9-yl</td><td> l-O-octadecyl-2-Obenzyl-sn glyceryl</td><td> galactosyl</td><td> galactosyl 1 -O-octadecyl-2-O-benzylsn glyceryl 9-(9)-[(3-hydroxy-2phospbonomethoxy)propyl]adeuinc</td>

<td> 285</td><td> cytosine-l-yl</td><td> l-O-octadccyl-2-O- benzyl-sn glyceryl</td><td> galactosyl</td><td> ga 1 actosy 1 1 - O-octadecy 1-2- O-benzylsn glyceryl l-(S)-[(3-hydroxy-2phosphonomethoxy)propyl]cytosine</td>

<td> 286</td><td> thymin-l-yl</td><td> l-O-octadecyl-2-Obenzyl-sn glyceryl</td><td> galactosyl</td><td> galactosyl 1 -O-octadecyl-2-O-benzylsn glyceryl 1-(9)-((3-hydroxy-2phosphonomethoxy)propy 1] thymine</td>

<td> 287</td><td> uracil-l-yl</td><td> l-O-octadecyl-2-Obenzyl-jn glyceryl</td><td> galactosyl</td><td> gal actosy 1 1 - O-octadecy 1-2- O-benzy 1sn glyceryl l-(S)-[(3-hydroxy-2phosphonomethoxy)propyl]uracil</td>

<td> 288</td><td> 2,6- diaminopurin -9-y!</td><td> 1 -O-octadecyl-2-Obenzyl-sn glyceryl</td><td> galactosyl</td><td> galactosyl l-O-octadecyl-2-O-benzylsn glyceryl 9-(5)-((3-hydroxy-2phosphonomethoxy)propyl]2,6diaminopurinc</td>

Table 5. (S)-3-fluoro-2-phosphonomethoxypropyI [(S)-FPMP] diester compounds ^BNuc/^BNuc(a) O

L ,.0... ,P-O-UL^a

Cmpd No.

^BNu&lt;?^BNtic(a) O l^Ck^P-O-UL?

i O-R/R^a^BNu&lt;/^BNuc(a) O L &gt;Ch ,p-O~L/L^a

O-R/R^a or

Rp or Sp (depends on substituents)

O~R/R^a

L/L‘

R/R or

Name

F'

Rp, Sp (racemic)

WO 2014/143643

PCT7US2014/027005 ^Nuc^Nuc(a) O ^Nuc^Nuc(a) O ®Nuc^Nuc(a) O χζ^Ο_νΡ-Ο-υυ L^.O^.P-O-L/L^a L^O^P“O-L/L^a

-= °r £ 1 or - 1 _F—⁷ O R/R^a F^- O-R/R^a F&gt; O-R/R

Rp or Sp (depends on substituents)_____________________ Rp, Sp (racemic)

<td> Cmpd No,</td><td> Βνμ/Βρμ»)</td><td> L/L</td><td> R/R</td><td> Name</td>

<td> 289</td><td> guanin-9-yl</td><td> octadecyioxyethyl</td><td> benzyl</td><td> benzyl octadecyioxyethyl 9-(5)-((3fluoro-2- phosphonomethoxy)propyl]guanine</td>

<td> 290</td><td> adenine-9-yl</td><td> ocladecyloxyethyl</td><td> benzyl</td><td> benzyl octadecyioxyethyl 9-(5)-((3fluoro-2- phosphonomethoxy)propyl]adenine</td>

<td> 291</td><td> cytosine-l-yl</td><td> octadecyioxyethyl</td><td> benzyl</td><td> benzyl octadecyioxyethyl 1-(5)-((3fluoro-2phosphonornethoxy)propyl]cytosine</td>

<td> 292</td><td> thymin-l-yl</td><td> octadecyioxyethyl</td><td> benzyl</td><td> benzyl octadecyioxyethyl 1-(5)-((3fluor -2- phosphonomcthoxy)piOpy 1 ] thy m ine</td>

<td> 293</td><td> uracil-1-yl</td><td> octadecyioxyethyl</td><td> benzyl</td><td> benzyl octadecyioxyethyl 1-(5)-((3fluoro-2phosphonomethoxy)propy!]uracil</td>

<td> 294</td><td> 2,6- diami nopurin -9-yl</td><td> octadecyioxyethyl</td><td> benzyl</td><td> benzyl octadecyioxyethyl 9-(5)-((3fluoro-2- phosphonomethoxy)propy 1]2,6diaminopurlne</td>

<td> 295</td><td> guanin-9-yl</td><td> hexadecyloxypropyl</td><td> benzyl</td><td> benzyl hexadecyloxypropyl 9-(5)-((3fluoro-2phosphonomethoxy)piOpyl]guanine</td>

<td> 296</td><td> adenine-9-yl</td><td> hexadecyloxypropyl</td><td> benzyl</td><td> benzyl hexadecyloxypropyl 9-(5)-((3fluoro-2phosphonomethoxy)prapyl |adenine</td>

<td> 297</td><td> cytosine-l-yl</td><td> hexadecyloxypropyl</td><td> benzyl</td><td> benzyl hexadecyloxypropyl 1-(5)-((3fluoro-2phosphonomethoxy)pi’opy[]cytosine</td>

<td> 298</td><td> thymin-l-yl</td><td> hexadecyl oxypropy I</td><td> benzyl</td><td> benzyl hexadecyloxypropyl 1-(5)-((3fluoro-2- phosphonomethoxy) propy 1 ] thy m ine</td>

<td> 299</td><td> uracil-l-yl</td><td> hexadecyl oxy propyl</td><td> benzyl</td><td> benzyl hexadecyloxypropyl 1-(5)-((3fluoro-2phosphonomethoxy)propyHuracil</td>

<td> 300</td><td> 2,6diaminopurin -9-yl</td><td> hexadecyloxypropyl</td><td> benzyl</td><td> benzyl hexadecyloxypropyl 9-(5)-((3fluoro-2- phosphonomethoxy)propy 1] 2,6diarninopurine</td>

<td> 301</td><td> guanm-9-yl</td><td> l-O-octadecyl-2-Obenzyl-jn glyceryl</td><td> benzyl</td><td> benzyl I-O-octadecyl-2-O-benzyl-jn glyceryl 9-(5)-[(3-fluoro-2phosphonomethoxy)propyljguanlne</td>

<td> 302</td><td> adenine-9-yl</td><td> 1-O-octadecy 1-2-0benzyl-srt glyceryl</td><td> benzyl</td><td> benzyl 1 -O-octadecyl- 2-O-benzy 1-sn glyceryl 9-(5)-[(3-fluoro-2phosphonomethoxy)propyl]adenine</td>

<td> 303</td><td> cytosine-l-yl</td><td> l-O-octadecyl-2-Obenzyl-.rw glyceryl</td><td> benzyl</td><td> benzyl 1 -O-octadecyl-2-O-benzyl-.srt glyceryl l-(5)-[(3-fluora-2phosphonomethoxy)propyl]cytosine</td>

<td> 304</td><td> thymin-l-yl</td><td> l-O-octadecyl-2-Obenzyl-sn glyceryl</td><td> benzyl</td><td> benzyl 1 -O-octadecy 1-2-O-benzy l-sn glyceryl l~(5)-[(3-fluoro-2phosphonomethoxy)propyl]thymine</td>

WO 2014/143643

PCT/US2014/027005

<td colspan="2"> SNuc^Nuc(a) 0</td><td rowspan="2"> Sb|_uc/BNuc(a) /L^a or £ F-'^- pends on substituents)</td><td rowspan="2"> O .P-O-UL^a i OR/R^a</td><td rowspan="2"> BNuc^Nuc(a) O L ,-0-, ^P-O-UL^a^or £ O-R/R^a Rp, Sp (racemic)</td>

<td> F-’</td><td> P O-L O-R/R^a Rp or Sp (de</td>

<td> Cmpd No.</td><td> Bnuc/Bnuc(h)</td><td> L/L</td><td> R/R</td><td> Name</td>

<td> 305</td><td> uracil-l-yl</td><td> I-O-octadecyl-2-Obenzyl-rn glyceryl</td><td> benzyl</td><td> benzyl l-O-octadecyl-2-O-benzyl-sn glyceryl l-(5)-[(3-fluoro-2phosphonomethoxy)propyl]uracil</td>

<td> 306</td><td> 2,6- di aminopurin -9-yl</td><td> 1-O-octadecy I-2-Obenzyl-sw glyceryl</td><td> benzyl</td><td> benzyl 1 - O-octadecy 1 -2-O-benzy l-.vn glyceryl 9-(S)-[(3-fluoiO-2phosphonomethoxy)propyl]2,6diaminopurine</td>

<td> 307</td><td> guanin-9-yl</td><td> octadecyloxy ethyl</td><td> phenyl</td><td> phenyl octadecyloxyethyl 9-(5)-((3- fluoro-2- phosphonom ethoxy) propy l]gu anine</td>

<td> 308</td><td> adenine-9-yl</td><td> octadccyl oxy ethyl</td><td> phenyl</td><td> phenyl octadecyloxyethyl 9-(5)-((3fluoro-2phosphonornethoxy)propyl]adenlne</td>

<td> 309</td><td> cytosine-l-yl</td><td> octadecyloxyethyl</td><td> phenyl</td><td> phenyl octadecyloxyethyl 1 -(5)-((3fluoro-2- phosphonomethoxy)propyllcytosine</td>

<td> 310</td><td> thymin-l-yl</td><td> octadecyloxy ethyl</td><td> phenyl</td><td> phenyl octadccyloxyethyl 1-(5)-((3fluoro-2- phosphonomethoxy) propy 1 ]thy mi ne</td>

<td> 311</td><td> uracil-l-yl</td><td> octadccyloxyethyl</td><td> phenyl</td><td> phenyl octadccyloxyethyl 1 -(5)-((3fluoro-2phosphonomethoxy)propyl]uracil</td>

<td> 312</td><td> 2,6diaminopurin -9-yl</td><td> octadecyloxyethyl</td><td> phenyl</td><td> phenyl octadecyl oxy ethyl 9-(5)-((3fluoro-2- phosp honomethoxy) propy 1 ]2,6diaminopurine </td>

<td> 313</td><td> guanin-9-yl</td><td> hexadecyloxypropyl</td><td> phenyl</td><td> phenyl hexadecyloxypropyl 9-(5)-((3fluoro-2phosphonomethoxylpropyllguanine</td>

<td> 314</td><td> adenine-9-yl</td><td> hexadecyloxypropyl</td><td> phenyl</td><td> phenyl hexadecyloxypropyl 9-(5)-((3fluoro-2phosphonomethoxy)propyl]adenine</td>

<td> 315</td><td> cytosine-1-yl</td><td> hexadecyloxypropyl</td><td> phenyl</td><td> phenyl hexadecyloxypropyl 1-(5)-((3fluoro-2ohosphonomethoxv)pi'opyl]cytoslne</td>

<td> 316</td><td> thymin-l-yl</td><td> hexadecyloxypropyl</td><td> phenyl</td><td> phenyl hexadecyloxypropyl 1-(5)-((3fluoro-2phosOhonomethoxy)propyl]thymine</td>

<td> 317</td><td> uracil-1-yl</td><td> hexadecyloxypropyl</td><td> phenyl</td><td> phenyl hexadecyloxypropyl 1-(5)-((3fluoro-2- phosphonomethoxy) propy l]uraci 1</td>

<td> 318</td><td> 2,6diaminopurin -9-yl</td><td> hcxadecy 1 oxy propyl</td><td> phenyl</td><td> phenyl hexadecyloxypropyl 9-(5)-((3fluoro-2- phosphonomethoxy)propyl]2,6- di am inopurine</td>

<td> 319</td><td> guanin-9-yl</td><td> 1 -O-octadecy 1-2- Obenzyl-sn glyceryl</td><td> phenyl</td><td> phenyl l-O-octadecyl-2-O-bcnzyl-s/i glyceryl 9-(5)-[(3-fluoro-2phosphonomethoxy)propyl J guan i ne</td>

<td> 320</td><td> adenine-9-yl</td><td> I-O-octadecyl-2-Obenzyl-sn glyceryl</td><td> phenyl</td><td> phenyl I - O-octadecy 1 -2-O-benzy 1-™ glyceryl 9-(5)-[(3-fluoro-2- 1 phosphonomethoxy)propyl]acienine</td>

WO 2014/143643

PCT/US2014/027005

<td colspan="5"> ^Nuc^Nuc(a) 0 ^Nuc/®Nuc(a) 0 ^Nuc^Nuc(a) O l.,_^O,.,.P-O-L/L^a |JL^a k,^,O,.^,P-O-L/L^a ; Ξ or £ i or £ 1 c-a _F--· O-R/R^a F—-^- O-R/R^a F_-“ O-R/R Rp or Sp (depends on substituents) Rp, Sp (racemic)</td>

<td> Cmpd No,</td><td> ®h’iic^®Nuc(jQ</td><td> L/L”</td><td> R/R</td><td> Name</td>

<td> 321</td><td> cytosine-l-yl</td><td> l-O-octadecyl-2-ϋbenzyl-j?; glyceryl</td><td> phenyl</td><td> phenyl l-O-octadecyl-2-O-benzyl-jn glyceryl l-(5)-[(3-iluoro-2phosphonomethoxy)propy 1 ] cytosine</td>

<td> 322</td><td> thymin-l-yl</td><td> 1 -O-octadecy 1-2- Obenzyl-jn glyceryl</td><td> phenyl</td><td> phenyl 1-O-octadecy 1 -2-O-benzyl -sn glyceryl I-(5)-[(3-fluoro-2phosphonomethoxy)piOpyl]thymine</td>

<td> 323</td><td> uracil-l-yl</td><td> l-O-octa.decyl-2-Obenzyl-jn glyceryl</td><td> phenyl</td><td> phenyl 1 -0- octadecy 1 -2-O-benzy 1 -sn glyceryl l-(5)-[(3-fluoro-2phosphonomethoxy)propyl]uracil</td>

<td> 324</td><td> 2,6diaminopurin -9-yl</td><td> 1-O-octadecy 1-2-0benzyl-jw glyceryl</td><td> phenyl</td><td> phenyl 1 -O-octadecyl-2-O-benzy 1 -sn glyceryl 9-(S)-[(3-fluoro-2phosphonomethoxy)propyl]2,6diaminopurine</td>

<td> 325</td><td> guanin-9-yl</td><td> octadecyloxycthyl</td><td> ethyl</td><td> ethyl octadecyloxycthyl 9-(5)-((3fluoro-2phosphonomethoxy)propyl(guanine</td>

<td> 326</td><td> adcnine-9-yl</td><td> octad ecyl oxy ethyl</td><td> ethyl</td><td> ethyl octadecyloxycthyl 9-(5)-((3fluoro-2phosphonomethoxy)propyl]adenine</td>

<td> 327</td><td> cytosine-l-yl</td><td> octadecyloxycthyl</td><td> ethyl</td><td> ethyl octadecyloxyethyl 1-(5)-((3fluoro-2phosphonomethoxy)propyl(cytosine</td>

<td> 328</td><td> thymin- 1-yl</td><td> octadecyloxyethyl</td><td> ethyl</td><td> ethyl octadecyloxycthyl 1-(5)-((3iluoro-2phosphonomethoxy)propyl]thymine</td>

<td> 329</td><td> uracil-l-yl</td><td> octadecyloxycthyl</td><td> ethyl</td><td> ethyl octadecyloxycthyl 1-(5)-((3fluoro -2- phosphonomethoxy) propy 1 ] uraci 1</td>

<td> 330</td><td> 2,6diaminopurin -9-yl</td><td> octadecyloxyethyl</td><td> ethyl</td><td> ethyl octadecyloxy ethyl 9-(5)-((3fluoro -2phosphonomethoxy)propy 1)2,6diaminopurine</td>

<td> 331</td><td> guanin-9-yl</td><td> hexadecyloxypropyl</td><td> ethyl</td><td> ethyl hexadecyloxypropyl 9-(5)-((3fluoro-2phosphonomethoxy)propyl]guanine</td>

<td> 332</td><td> adenine-9-yl</td><td> hexadecyloxypropyl</td><td> ethyl</td><td> ethyl hexadecyloxypropyl 9-(5)-((3fluoro-2- phosphonom ethoxy)propy Ijadeni ne</td>

<td> 333</td><td> cytosine-l-yl</td><td> hexadecyloxypropyl</td><td> ethyl</td><td> ethyl hexadecyloxypropyl 1-(5)-((3fluoro-2- phosphonomethoxy)propyl]cytosine</td>

<td> 334</td><td> thymin-l-yl</td><td> hexadecyloxypropyl</td><td> ethyl</td><td> ethyl hexadecyloxypropyl 1-(5)-((3fluoro-2- phosphonomethoxy)propyl]thymine</td>

<td> 335</td><td> uracil-l-yl</td><td> hexadecyloxypropyl</td><td> ethyl</td><td> ethyl hexadecyloxypropyl 1-(5)-((3fluoro-2phosphonomethoxy)propyl]uracil</td>

<td> 336</td><td> 2,6diamlnopurin -9-yl</td><td> hcxadccy loxypro py 1</td><td> ethyl</td><td> ethyl hexadecyloxypropyl 9-(5)-((3fluoro-2- phosphonomethoxy)propyl]2,6diammopurine</td>

WO 2014/143643

PCI7US2014/027005

<td colspan="2">^BNuc^/BNuc(a) 0</td><td rowspan="2">^BNuc/^BNuc(a) /L^a or 1 F- spends on substituents)</td><td rowspan="2"> 0 .p-o-l/l⁸ i O-R/R^a</td><td rowspan="2">^BNuc/^BNuc(a) 0 L ,P-O-L/L^a nr ' * ^or H O-R/R^a F Rp, Sp (racemic)</td>

<td> F-’</td><td> ^CL_x.P-O-L O-R/R^a Rp or Sp (de</td>

<td> Cmpd No.</td><td></td><td> L/L</td><td> R/R^s</td><td> Name</td>

<td> 337</td><td> guanin-9-yl</td><td> 1 - O-octadecyl -2-(9benzyl-sn glyceryl</td><td> ethyl</td><td> ethyl 1 - O-octadecy 1 -2-O-benzy !-sn glyceryl 9-(5)-[(3fluoro-2phosphonomethoxy)propyl] guani ne</td>

<td> 338</td><td> adenine-9-yl</td><td> 1 -(?-octadecyl-2-(9benzyl-.w? glyceryl</td><td> ethyl</td><td> ethyl l-O-octadecyl-2-O-benzyl-Jf! glyceryl 9-(5)-[(3-fl uoro-2phosphonomethoxy)propy 1 [adenine</td>

<td> 339</td><td> cytosine-l-yl</td><td> 1 -O-octadecy 1-2- Obenzyl-.fn glyceryl</td><td> ethyl</td><td> ethyl 1 - O-octadecy 1 -2-O-benzy\-sn glyceryl l-(S)-[(3-fluoro-2phosphonomethoxy)piOpyl]cytosine</td>

<td> 340</td><td> thymin- 1-yl</td><td> l-O-octadecyl-2-Obenzyl-jn glyceryl</td><td> ethyl</td><td> ethyl l-O-octadecyl-2-O-benzyl-xw glyceryl 1-(5)-[(3-fluoro-2phosphonomethoxy)propyl]thymine</td>

<td> 341</td><td> uracil-l-yl</td><td> l-O-octadecyl-2-Obenzyl-yn glyceryl</td><td> ethyl</td><td> ethyl 1- O-octadecy 1 -2-0- benzyl-in glyceryl l-(S)-[(3-iluoro-2phosphonomethoxy)propyl]uracil</td>

<td> 342</td><td> 2,6- diami nopurin -9-yl</td><td> 1 -O-octadecyl-2-Obenzyl-irt glyceryl</td><td> ethyl</td><td> phenyl l-O-octadecyl-2-O-benzyl-jn glyceryl 9-(S)-[(3-fluoro-2phosphonomethoxy)propyl]2,6diaminopurine</td>

<td> 343</td><td> guanin-9-yl</td><td> oetadecyloxyethyl</td><td> galactosyl</td><td> galactosyl oetadecyloxyethyl 9-(5)-((3fluoro-2phosphonomethoxy)propyl] guanine</td>

<td> 344</td><td> adenine-9-yl</td><td> octadecyloxy ethyl</td><td> galactosyl</td><td> galactosyl oetadecyloxyethyl 9-(5)-((3fluoro-2- phosphonomethoxy)propyl]adenine____</td>

<td> 345</td><td> cytosine-l-yl</td><td> octadecyloxycthyl</td><td> galactosyl</td><td> galactosyl oetadecyloxyethyl l-(5)-[(3fluoro-2phosphonomethoxy)propyl]cytosine</td>

<td> 346</td><td> thymin-l-yl</td><td> oetadecyloxyethyl</td><td> galactosyl</td><td> galactosyl oetadecyloxyethyl l-(S)-[(3fluoro-2phosphonomethoxy)propyl]thyminc</td>

<td> 347</td><td> uracil-l-yl</td><td> octadecyloxycthyl</td><td> galactosyl</td><td> galactosyl oetadecyloxyethyl 1-(5)-((3fluoro-2phosphonomethoxy)propyl]uracil</td>

<td> 348</td><td> 2,6diaminopurin -9-yl</td><td> oetadecyloxyethyl</td><td> galactosyl</td><td> galactosyl oetadecyloxyethyl 9-(5)-((3fluoro-2phosphonomethoxy)propyl]2,6diaminopurine </td>

<td> 349</td><td> guanin-9-yl</td><td> hexadecyloxypropyl</td><td> galactosyl</td><td> galactosyl hexadecyloxypropyl 9-(5)[(3-fluoro-2phosphonomethoxy)propyl]guanine</td>

<td> 350</td><td> adenine~9-yl</td><td> hexadecyloxypropyl</td><td> galactosyl</td><td> galactosyl hexadecyloxypropyl 9-(5)[(3-fluoro-2phosphonomethoxy)propyl]adenine</td>

<td> 351</td><td> cytosine-l-yl</td><td> hexadecyloxypropyl</td><td> galactosyl</td><td> galactosyl hexadecyloxypropyl 1-(5)- [(3-fluoiO-2- phosphonomethoxy)propyl]cytosine</td>

<td> 352</td><td> thymin-l-yl</td><td> hexadecyloxypropyl</td><td> galactosyl</td><td> galactosyl hexadecyloxypropyl 1-(5)[(3-fluoro-2phosphonomethoxy)propyl]thymine</td>

WO 2014/143643

PCT/US2014/027005

<td colspan="5"> Bnuc/Bnuc(3) ο Bnuc^Bnuc(3) O B_Nuc/B_Nuc(a) ο P“O-L/L^a P-O-L/L^a L^O^P-O-Ul? - Ξ or z ^ or z n—p/R^a_F^-- O-R/R^a_F--’ O-R/R^a ° Rp or Sp (depends on substituents) Rp, Sp (racemic)</td>

<td> Cmpd No.</td><td> Bnuc/Bn^h)</td><td> L/L</td><td> R/R</td><td> Name</td>

<td> 353</td><td> uracil-l-yl</td><td> hexadecyloxypropyl</td><td> galactosyl</td><td> galactosyl hexadecyloxypropyl 1-(5)[(3-fluoro-2pbosphonomethoxy)propyl Juraci 1</td>

<td> 354</td><td> 2,6- diaminopurin -9-yl</td><td> hexadecyloxypropyl</td><td> galactosyl</td><td> galactosyl hexadecyloxypropyl 9-(5)[(3-fluoro-2phosphonomethoxy)propyl]2,6diaminopurine </td>

<td> 355</td><td> guamn-9-yl</td><td> l-O-octadecyl-2-O- benzyl-jw glyceryl</td><td> galactosyl</td><td> galactosyl l-O-octadecyl-2-O-benzylsn glyceryl 9-(5)-[(3-fluoro-2phosphonometboxy) propy 1 ]guanine</td>

<td> 356</td><td> adenine-9-yl</td><td> l-O-octadecyl-2-Obenzyl-jrt glyceryl</td><td> galactosyl</td><td> galactosyl 1 -O-octadccy 1-2- O-benzy 1 sn glyceryl 9-(S)-[(3-fluoro-2phosphonomethoxy)propyl]adenine</td>

<td> 357</td><td> cytosine-1-yl</td><td> l-O-octadecyl-2-Obenzyl-Jrt glyceryl</td><td> galactosyl</td><td> galactosyl l-O-octadecyl-2-O-benzylsn glyceryl 1-(5)-((3-fluoro-2phosphonomethoxy) propy 1 (cytosi ne</td>

<td> 358</td><td> thymin-l-yl</td><td> l-Ooctadecyl-2-O benzyl-sn glyceryl</td><td> galactosyl</td><td> galactosyl l-O-octadecyl-2-O-benzylsn glyceryl l-(S)-[(3-fluoro-2phosphonomethoxy)propyl]thymine</td>

<td> 359</td><td> uracil-l-yl</td><td> l-O-octadecyl-2-Obenzyl-jn glyceryl</td><td> galactosyl</td><td> galactosyl l-O-octadccyl-2-O-benzylsn glyceryl l-(5)-[(3-fluoro-2phosphonomethoxy) propy l]uraci 1</td>

<td> 360</td><td> 2,6- diaminopurin -9-yl</td><td> l-O-octadecyl-2-Obenzyl-jn glyceryl</td><td> galactosyl</td><td> galactosyl 1 -O-octadecyl-2- O-benzy 1sn glyceryl 9-(5)-[(3-fluoro-2phosphonomethoxy)propyl]2,6diaminopurine</td>

Table 6. Phosphonoinethoxyethyl (PME) diester compounds

BNuJBNuc(a) O B_Nu_C/B_Nuc(a) q B_Nuc/B_Nllc(_a&gt; 0

13-0·^ POUM l^-O^P-O-UL³ &lt;^O^P-O-L/L^a0-R/R^a °^Γ OR/R^a °^Γ O-R/R^a

Rp or Sp (depends on substituents) Rp, Sp (racemic)

<td> Cmpd No.</td><td> Βν«»/ΒνιιΦ)</td><td> L/Ij</td><td> R/R</td><td> Name</td>

<td> 361</td><td> guanin-9-yl</td><td> octadecyloxyethyi</td><td> naphthyl</td><td> naphthyl octadecyloxyethyi 9-(2phosphonomethoxyethyl)guanine</td>

<td> 362</td><td> adenine-9-yi</td><td> octadecyloxyethyi</td><td> naphthyl</td><td> naphthyl octadecyloxyethyi 9-(2phosphonomethoxyethyl)adenlne</td>

<td> 363</td><td> cytosine-l-yl</td><td> octadecyloxyethyi</td><td> naphthyl</td><td> naphthyl octadecyloxyethyi 1-(2phosphonomethoxyethyl)cytosinc</td>

<td> 364</td><td> thymin-l-yl</td><td> octadecyloxyethyi</td><td> naphthyl</td><td> naphthyl octadecyloxyethyi 1-(2phosphonomethoxyethy 1 )thym ine</td>

<td> 365</td><td> uracil-l-yl</td><td> octadecyloxyethyi</td><td> naphthyl</td><td> naphthyl octadecyloxyethyi 9-(2phosphoiiomethoxyethyl)uracil</td>

WO 2014/143643

PCT/US2014/027005

<td colspan="2">^BNuc/^BNuc(a) 0</td><td colspan="2" rowspan="2">^BNuc/^BNuc(a) O O—L/L^a l^O^P-0-L/L^a or i R/R^a O-R/R r Sp (depends on substituents)</td><td rowspan="2">^BNuc/^BNuc(a) 0 AAK,'P“°~L/L^{a or} O-R/R^a Rp, Sp (racemic)</td>

<td></td><td> k^CL^Pδ- Rp o</td>

<td> Cmpd No.</td><td> Bnuc/Bnuc(h)</td><td> L/L^a</td><td> R/R“</td><td> Name</td>

<td> 366</td><td> 2,6- diaminopurin -9-yl</td><td> octadecyloxyethyl</td><td> naphthyl</td><td> naphthyl octadecyloxyethyl 9-(2phosphonomethoxyethyl)-2,6diaminopurine</td>

<td> 367</td><td> guanin-9-yl</td><td> hexadecyloxypropyl</td><td> naphthyl</td><td> naphthyl hexadecyloxypropyl 9-(2phosphonomethoxyethyl)guanine</td>

<td> 368</td><td> adenine-9-yl</td><td> hexadecy loxypropy1</td><td> naphthyl</td><td> naphthyl hexadecyloxypropyl 9-(2phosphonomethoxyethy 1 )ad en inc</td>

<td> 369</td><td> cytosine-1-yl</td><td> hexadecyloxypropyl</td><td> naphthyl</td><td> naphthyl hexadecyloxypropyl 1-(2phosphonomethoxyethy!)cytosine</td>

<td> 370</td><td> thymin-l-yl</td><td> hexadecyloxypropyl</td><td> naphthyl</td><td> naphthyl hexadecyloxypropyl 1-(2phosphonomethoxyethyl)thyminc</td>

<td> 371</td><td> uracil-l-yl</td><td> h exadecyloxy propyl</td><td> naphthyl</td><td> naphthyl hexadecyloxypropyl 9-(2phosphonomethoxy ethy l)uraci I</td>

<td> 372</td><td> 2,6- diaminopurin -9-yl</td><td> hexadecyl oxy propyl</td><td> naphthyl</td><td> naphthyl hexadecyloxypropyl 9-(2phosphonomethoxyetbyl)-2,6diarn inopurine</td>

<td> 373</td><td> guanin-9-yl</td><td> l-O-octadecyl-2-Obenzyl-sn glyceryl</td><td> naphthyl</td><td> naphthy 1 1 - O-octadecy 1-2- O-benzy 1sn glyceryl 9-(2phosphonomethoxyethyl)guanine</td>

<td> 374</td><td> adenine-9-yl</td><td> 1 -O-octadecy 1-2- Obenzyl-tw glyceryl</td><td> naphthyl</td><td> naphthyl l-O-ocladecyl-2-O-benzylsn glyceryl 9-(2phosphonomcthoxy ethy l)aden ine</td>

<td> 375</td><td> cytosine-1-yl</td><td> 1 -O-octadecy 1-2-0benzyl-.w glyceryl</td><td> naphthyl</td><td> naphthyl l-O-octadecyl-2-O-benzylsn glyceryl 1-(2phosphonomethoxyethy!)cytosine</td>

<td> 376</td><td> thymin-l-yl</td><td> 1 -O-octadecy 1-2-Obenzyl-.tw glyceryl</td><td> naphthyl</td><td> naphthyl 1 - O-octadecy I-2-O-benzy 1sn glyceryl l-(2-phosphonomethoxyethyl)thymine</td>

<td> 377</td><td> uracil-l-yl</td><td> 1 -O-octadecyl-2-Obenzyl-τη glyceryl</td><td> naphthyl</td><td> naphthyl l-O-octadccyl-2-O-benzylsn glyceryl 9-(2-phosphonomethoxyethyl)uracil</td>

<td> 378</td><td> 2,6diaminopurin -9-yl</td><td> 1 -O-octadecy 1-2-0benzyl-i'n glyceryl</td><td> naphthyl</td><td> naphthyl 1 -O-octadecy 1-2- O-benzylsn glyceryl 9-(2-phosphonomethoxyethyl)-2,6-diammopurine</td>

Table 7. (R)-phosphoiiomethoxypropyl [(R)-PMP] diester compounds

<td colspan="5">^BNuc^^BNuc(a) 0 ^BNuc/^BNuc(a) 0 ^BNuc®Nuc(a) 0 L^-O^P-CHUl? 5,^.O_x/PO L/L^a &lt;...^O^PO-L/L^a 0H₃ O-R/R^a °^Γ CH3 OR/R^a °^Γ CH3 O^R7Ra Rp or Sp (depends on substituents) Rp, Sp (racemic)</td>

<td> Cmpd No.</td><td></td><td> L/L</td><td> R/R</td><td> Name</td>

<td> 379</td><td> guanin-9-yl</td><td> octadecyl oxyethyl</td><td> naphthyl</td><td> naphthyl octadecyloxyethyl 9-(Λ)-[(2phosphonomethoxy)propyl]guanine</td>

<td> 380</td><td> adenine-9-yl</td><td> octadecyloxyethyl</td><td> naphthyl</td><td> naphthyl octadecyloxyethyl 9-(R)-[(2phosphonomethoxy)propyl]adenine</td>

WO 2014/143643

PCT/US2014/027005 ^BNuc^^BNuc(a) O ^BNut/^BNuc(a) O ^BNuc^^BNuc(a) O

Ι^Ο^,Ρ-Ο-ίΑ³ L^o...^P-O-L/L^a ^.0^P-O-L/L^a

0H₃ O-R/R^a θ' CH3 O-R/R^a θ' CH3 0“^^

Rp or Sp (depends on substituents) Rp, Sp (racemic)

<td> Cmpd No.</td><td></td><td> L/L</td><td> R/R</td><td> Name</td>

<td> 381</td><td> cytosine-l-yl</td><td> octadccyloxyethyl</td><td> naphthyl</td><td> naphthyl octadecyloxyethyl 1-(5)-((2phosphonomethoxy)propyl]cytosine</td>

<td> 382</td><td> thymin-l-yl</td><td> octadccyloxyethyl</td><td> naphthyl</td><td> naphthyl octadecyloxy ethyl 1-(5)-((2phosphon omethoxy) propy I] thy mi ne</td>

<td> 383</td><td> uracil-l-yl</td><td> octadecyloxyethyl</td><td> naphthyl</td><td> naphthyl octadccyloxyethyl 1-(5)-((2phosphonomethoxy)propy 1] uraci I</td>

<td> 384</td><td> 2,6- diaminopurin -9-yl</td><td> octadecyloxyethyl</td><td> naphthyl</td><td> naphthyl octadecyloxyethyl 9-(5)-((2phosphonomethoxy)propyl]2,6diaminopurine</td>

<td> 385</td><td> guanin-9-yl</td><td> hexadecyloxypropyl</td><td> naphthyl</td><td> naphthyl hexadecyloxypropyl 9-(5)(¢2- phosphonomethoxy)propy l]guan ine</td>

<td> 386</td><td> adenine-9-yl</td><td> hexadecyloxypropyl</td><td> naphthyl</td><td> naphthyl hexadecyloxypropyl 9-(5)- [(2-phosphonomethoxy)propyl]adenine</td>

<td> 387</td><td> cytosine-l-yl</td><td> hexadecyloxypropyl</td><td> naphthyl</td><td> naphthyl hexadecyloxypropyl 1-(5)[(2phosphonomcthoxy)propyl]cytosine</td>

<td> 388</td><td> thymin-l-yl</td><td> hexadecyloxypropyl</td><td> naphthyl</td><td> naphthyl hexadecyloxypropyl 1-(5)[(2- phosphonomethoxy)propy! J thymine</td>

<td> 389</td><td> uracil-l-yl</td><td> hexadecyloxypropyl</td><td> naphthyl</td><td> naphthyl hexadecyloxypropyl 1-(5)- [(2-phosphonomethoxy)propy 1] uraci 1</td>

<td> 390</td><td> 2,6diaminopurin -9-yl</td><td> hexadecyloxypropyl</td><td> naphthyl</td><td> naphthyl hexadecyloxypropyl 9-(5)[(2-phosph onom ethoxy)propy 1(2,6diaminopurine</td>

<td> 391</td><td> guanin-9-yl</td><td> l-O-octadecyl-2-Obenzyl-sn glyceryl</td><td> naphthyl</td><td> naphthyl l-O-octadecyl-2-O-benzyl-in glyceryl 9-(5)-((2phosphonomethoxy)propyl]guanine</td>

<td> 392</td><td> adenine-9-yl</td><td> l-O-octadecyl-2-Obenzyl-wt glyceryl</td><td> naphthyl</td><td> naphthyl 1 -O-octadecyl-2-O-benzy 1-sn glyceryl 9-(5)-((2phosphonomethoxy)propyl]adenine</td>

<td> 393</td><td> cytosine-l-yl</td><td> l-O-octadecyl-2-Obenzyl-.rti glyceryl</td><td> naphthyl</td><td> naphthyl l-O-octadecyl-2-O-benzyl-sn glyceryl 1-(5)-((2phosphonomethoxy)propyl]cytosine</td>

<td> 394</td><td> thymin-l-yl</td><td> 1-O-octadecyl-2-Obenzyl-sn glyceryl</td><td> naphthyl</td><td> n aphthy 1 1 - O-octadecy 1 -2-O-benzy \-sn glyceryl 1-(5)-((2phosphonomethoxy)propyl]thyminc</td>

<td> 395</td><td> uracil-l-yl</td><td> 1 - O-octadecyl -2-0benzyl-s·» glyceryl</td><td> naphthyl</td><td> naphthyl 1 -O-octadecyl-2-O-benzyl-rn glyceryl 1-(5)-((2phosphonomethoxy)propyl]uracil</td>

<td> 396</td><td> 2,6diaminopurin -9-yl</td><td> l-O-octadecyI-2-O- benzyl-.w glyceryl</td><td> naphthyl</td><td> naphthy 1 1 -O-octadecyl-2-O-benzy i-.w glyceryl 9-(5)-((2phosphonomethoxy)propy 1 ] 2,6diaminopurine</td>

WO 2014/143643

PCT/US2014/027005

Table 8. (S)-3-methoxy-2-phosphonmethoxypropyI [(S)-MPMP] diester compounds

<td colspan="2">^BNuc^^BNuc(a) 0</td><td colspan="2">^BNuc^/BNuc(a) O</td><td rowspan="2">^BNuc^^BNuc(a) O L^a_or k/0._x/P O-L/L^a 2 O-R/R^a h₃c cr Rp, Sp (racemic)</td>

<td> u₃co'’</td><td> ^O...^P-0-L O-R/R^E Rp or Sp</td><td>_or H₃C-Cr {depends on substituen</td><td> P~OL/ O-R/R^a ts)</td>

<td> Cmpd No.</td><td> ®Nuc^®Nuc(ji)</td><td> L/L</td><td> R/R</td><td> Name</td>

<td> 397</td><td> guanin-9-yl</td><td> octadecyl oxy ethyl</td><td> naphthyl</td><td> naphthyl octadecyioxyethyl 9-(5)-((3methoxy-2- phosphonomethoxy)propyl]guanine</td>

<td> 398</td><td> adenine-9-yl</td><td> octadecyloxyethyl</td><td> naphthyl</td><td> naphthyl octadecyioxyethyl 9-(5)-((3methoxy-2phosphonomethoxy)propy 1 ] adenine</td>

<td> 399</td><td> cytosine-l-yl</td><td> octadccyloxyethyl</td><td> naphthyl</td><td> naphthyl octadccyloxyethyl 1-(5)-((3methoxy-2- phosphonometh oxy)propyl]cytosi ne</td>

<td> 400</td><td> thymin-l-yl</td><td> octadecyloxyethyl</td><td> naphthyl</td><td> naphthyl octadecyioxyethyl 1-(5)-((3methoxy-2phosphonomethoxy)propyl]thymine</td>

<td> 401</td><td> uracil-l-yl</td><td> octadccy 1 oxy ethy 1</td><td> naphthyl</td><td> naphthyl octadccyloxyethyl 1-(5)-((3methoxy-2phosphonomethoxy)propyl]uracil</td>

<td> 402</td><td> 2,6diaminopurin -9-yl</td><td> octadecyloxyethyl</td><td> naphthyl</td><td> naphthyl octadecyioxyethyl 9-(5)-((3methoxy-2- phosphonom cthoxy)propy 1] 2,6diaminopurinc</td>

<td> 403</td><td> guanin-9-yl</td><td> hexadecyloxypropyl</td><td> naphthyl</td><td> naphthyl hexadecyloxypropyl 9-(5)-((3methoxy-2phosphonomethoxy)propyi]guanine</td>

<td> 404</td><td> adenine-9-yl</td><td> hexadecyloxypropyl</td><td> naphthyl</td><td> naphthyl hexadecyloxypropyl 9-(5)-((3- methoxy-2- phosphonomethoxy)propyl]adcnine____</td>

<td> 405</td><td> cytosine-l-yi</td><td> hexadecyloxypropyl</td><td> naphthyl</td><td> naphthyl hexadecyloxypropyl 1-(6)-((3methoxy-2- phosphonomethoxy) propyl ]cy tosine</td>

<td> 406</td><td> thymin-l-yl</td><td> hexadecyl oxypropyl</td><td> naphthyl</td><td> naphthyl hexadecyloxypropyl 1-(5)-((3- 1 methoxy-2phosphonomethoxy)propyl]thyniine</td>

<td> 407</td><td> uracil-l-yl</td><td> hexadecyloxypropyl</td><td> naphthyl</td><td> naphthyl hexadecyloxypropyl 1-(5)-((3methoxy-2- phosphonom ethoxy) propy ljuraci 1</td>

<td> 408</td><td> 2,6diaminopurin -9-yl</td><td> hexadecyloxypropyl</td><td> naphthyl</td><td> naphthyl hexadecyloxypropyl 9-(5)-((3methoxy-2- phospho nomethoxy)propy 1]2,6diaminopurine</td>

<td> 409</td><td> guanin-9-yl</td><td> 1-O-octadecy 1-2-(7benzyl-jn glyceryl</td><td> naphthyl</td><td> naphthyl l-O-octadecyl-2-O-benzyl-.w glyceryl 9-(5)-[(3-methoxy-2phosphonomethoxy)propyl]guanine___</td>

<td> 410</td><td> adenine-9-yl</td><td> l-(7-octadecyl-2-&lt;7- benzyl-ΐΜ glyceryl</td><td> naphthyl</td><td> naphthyl 1 -ΰ-octadecy 1-2- O-benzy 1-str glyceryl 9-(5)-[(3-methoxy-2phosphonomethoxy) propyl] adenine</td>

<td> 411</td><td> cytosine-l-yl</td><td> l-O-octadecyl-2-(7benzyl-in glyceryl</td><td> naphthyl</td><td> naphthyl 1 -O-octadecy 1-2- O-benzyl-sn glyceryl l-(5)-[(3-methoxy-2phospho nomethoxy)propy Ijcytosi nc</td>

WO 2014/143643

PCT/US2014/027005

<td colspan="5"> ^Nuc^Nuc(a) O B^_uc/B^_uc(_aj o ^Nuc^N_uc(_a) Q ^O ^ F¹ 0 UL^a_or ' ,.Ο , Ρ 0 UL· _or t,O._,.P-O-UL= HzC-O-' °-™“ H_sC-O-^? °-^R,R· H_SC-O^{J 0R,R}· Rp or Sp (depends on substituents) Rp, Sp (racemic)</td>

<td> Cmpd No.</td><td> BNuc/BNuc(a)</td><td> L/L</td><td> R/R</td><td> Name</td>

<td> 412</td><td> thymin-l-yl</td><td> l-O-octadecyl-2-Obenzyl-j/r glyceryl</td><td> naphthyl</td><td> naphthyl 1 - O-octadecyl-2- O-benzyl-sn glyceryl l-(5)-((3-methoxy-2phosphonomethoxy) propy l]thy m I ne</td>

<td> 413</td><td> uracii-l -yl</td><td> l-O-octadecyl-2-Obenzyl-sn glyceryl</td><td> naphthyl</td><td> naphthyl 1 -O-octadecy 1-2- O-benzyl-.vn glyceryl 1-(5)-((3 -methoxy-2phosphonomethoxy)propyl]uracil</td>

<td> 414</td><td> 2,6diaminopurin -9-yl</td><td> 1 -O-octadecyl-2- 0benzyl-Wi glyceryl</td><td> naphthyl</td><td> naphthyl l-O-octadecyl-2-O-benzyl-.sn glyceryl 9-(5)-[(3-methoxy-2phosphonomethoxy)propyl]2,6diaminopurine</td>

Table 9, (S)-3-hydroxy-2-phosphonomethoxypropyl [(S)-HPMP] diester compounds ^Nuc^Nuc(a) O ^Nuc^Nucta) O ^Nuc^Nuc(a) O k/O^.P-O-UL^a -...^Ο^^Ρ-Ό-υΐ³ k^O^P-O-UL

J 0-R/R^a °^r J O-R/R^{a 0Γ}_HnJ °~R/R^aHO HO^ ^H(J

Rp or Sp (depends on substituents) Rp, Sp (racemic)

<td> Cmpd No.</td><td> Bnu&lt;/Bnhc(ii)</td><td> L/L</td><td> R/R“</td><td> Name</td>

<td> 41S</td><td> guanin-9-y I</td><td> octadecyloxyethyl</td><td> naphthyl</td><td> naphthyl octadecyloxyethyi 9-(5)-((3hydroxy-2phosphonomethoxy)propyl]guanine</td>

<td> 416</td><td> adenine-9-yl</td><td> octadecyloxyethyi</td><td> naphthyl</td><td> naphthyl octadecyloxyethyi 9-(5/)-((3hydroxy-2phosphonomcthoxy)piOpyl]adenine</td>

<td> 417</td><td> cytosine-1-yl</td><td> octadecyloxyethyl</td><td> naphthyl</td><td> naphthyl octadecyloxyethyi 1-(5)-((3hydroxy-2· phosphonomethoxy)propy 1 ] cy tosi ne</td>

<td> 418</td><td> thymin-l-yl</td><td> octadecyloxyethyi</td><td> naphthyl</td><td> naphthyl octadecyloxyethyi 1-(5)-((3hydroxy-2phosphonomethoxy)ptOpyl]thymine</td>

<td> 419</td><td> uracil-l-yl</td><td> octadecyloxyethyi</td><td> naphthyl</td><td> naphthyl octadecyloxyethyi 1-(5)-((3hydroxy-2phosphonomethoxy)propyl]uracil</td>

<td> 420</td><td> 2,6diaminopurin -9-yl</td><td> octadecyloxyethyi</td><td> naphthyl</td><td> naphthyl octadecyloxyethyi 9-(5)-((3hydroxy-2- phos phonomethoxy)propyl] 2,6diaminopurine</td>

<td> 421</td><td> guanin-9-yl</td><td> hexadecy 1 oxy propy 1</td><td> naphthyl</td><td> naphthyl hexadecyioxypropyl 9-(5)-((3hydroxy-2phosphonomethoxy)propyl]guanine</td>

<td> 422</td><td> adenine-9-yl</td><td> hexadecyioxypropyl</td><td> naphthyl</td><td> naphthyl hexadecyioxypropyl 9-(5)-((3hydroxy-2phosphonomethoxy)propyl]adcnine</td>

WO 2014/143643

PCT/US2014/027005

<td colspan="2">^BNuc^^BNuc(a) 0</td><td colspan="3" rowspan="2">^BNuc^/BNuc(a) 0 ^BNuc^/BNuc(a) 0 /L^a L_X/O,^P 0 L/L^a L.^O...^P-0-UI. ^or J o-R/R^{a or} „_nJ o-r/r³</td>

<td rowspan="2"> HC&lt;</td><td rowspan="2"> P’O~L OR/R^a Rp or Sp</td>

<td colspan="2"> HO (depends on substituents)</td><td> Rp, Sp (racemic)</td>

<td> Cmpd No.</td><td> Bn„_c/B_Nu1:(»)</td><td> UL”</td><td> R/R</td><td> Name</td>

<td> 423</td><td> cytosine-1-yl</td><td> hcxadecyloxypropy 1</td><td> naphthyl</td><td> naphthyl hexadecyloxypropyl 1-(5)-((3hydroxy-2- ph os phonomethoxY)pro py Ijcy tos i ne</td>

<td> 424</td><td> thymin-L-yl</td><td> hexadecyloxypropyl</td><td> naphthyl</td><td> naphthyl hexadecyloxypropyl 1-(5)-((3hydroxy-2phosphonomethoxy)propyl]Lhymine</td>

<td> 425</td><td> uracil-l-yl</td><td> hexadecyloxypropyl</td><td> naphthyl</td><td> naphthyl hexadecyloxypropyl 1-(5)-((3- 1 hydroxy-2phosphonomethoxy)propyl]uracil</td>

<td> 426</td><td> 2,6- diaminopurin -9-yl</td><td> hexadecyloxypropyl</td><td> naphthyl</td><td> naphthyl hexadecyloxypropyl 9-(5)-((3hydroxy-2phosphonomethoxy)propyl]2,6diaminopurine</td>

<td> 427</td><td> guanin-9-yi</td><td> l-O-octadecyl-2-Obenzyl-jn glyceryl</td><td> naphthyl</td><td> naphthyl l-O-octadecyl-2-O-benzyl-.w glyceryl 9-(5)-((3-hydroxy-2phosphonomethoxy) propyl] guanine</td>

<td> 428</td><td> adenine-9-yl</td><td> 1 - O-octadecy 1-2-Obenzy l-sw glyceryl</td><td> naphthyl</td><td> naphthyl 1 -O-octadecyl-2- O-benzy 1 -x/r glyceryl 9-(5)-[(3-hydroxy-2phosphonomethoxy)propyl]adenine</td>

<td> 429</td><td> cytosine-l-yl</td><td> 1-O-octadecy 1-2-0benzyl-sn glyceryl</td><td> naphthyl</td><td> naphthyl l-O-octadecyl-2-O-benzyl-JW glyceryl 1-(5)-[(3-hydroxy-2phosphonomethoxy) propyl] cytosine</td>

<td> 430</td><td> thymin-l-yl</td><td> l-O-octadecyl-2-Obenzyl-sn glyceryl</td><td> naphthyl</td><td> naphthyl l-O-octadecyl-2-O-benzyl-.rri glyceryl l-(5)-[(3-hydroxy-2phosphonometh oxy)propyl]thymine</td>

<td> 431</td><td> uracil-l-yi</td><td> 1 - O-octadecy 1-2-0bcnzyl-xn glyceryl</td><td> naphthyl</td><td> naphthyl 1-O-octadecy 1-2-O-benzy l-jn glyceryl 1-(5)-((3-hydroxy-2phosphonomethoxy)propyl]ui-acil______</td>

<td> 432</td><td> 2,6diaminopurin -9-yl</td><td> l-O-octadecy]-2-Obenzyl-svi glyceryl</td><td> naphthyl</td><td> naphthyl l-O-octadecyl-2-O-benzyl-.wi glyceryl 9-(5)-[(3-hydroxy -2phosphonomethoxy)propyl]2,6diam inopurine</td>

Table 10. (S)-3-fluoro-2-phosphonomethoxypropyl [(S)-FPMP] diester compounds ^BNuc^^BNuc(a) O

L ,0. . PO“L/L^a^BNuc^^BNuc(a) O

L XX ,P”O—L/L^a

O-R/R^a or

F

O-R/R^a or ^BNuc^^BNuc(a) O

L AM .P~O-L/L^a i O R/R^a or on substituents)

F-

Rp, Sp (racemic)

<td> Cmpd No.</td><td> Bx'uc/Br.w:.}</td><td> L/L^a</td><td> R/R”</td><td> Name</td>

<td> 433</td><td> guanin-9-yl</td><td> octadecyloxyethyl</td><td> naphthyl</td><td> naphthyl octadecyloxyethyl 9-(,5)-((3fluoro-2- phosphonomethoxy) propyl] gu anine</td>

WO 2014/143643

PCT/US2014/027005

<td colspan="2">^BNuc/^BNuc(a) O</td><td rowspan="2">^BNuc^^BNuc(a) /L^a or £ p- spends on substituents)</td><td rowspan="2"> O ,P-O-L/L^! O-R/R^a</td><td rowspan="2">^BNu&lt;/^BNuc(a) 0 k^O^P-O-L/L^{3 or} i O-R/R^a F Rp, Sp (racemic)</td>

<td> F</td><td> R-O-L O-R/R⁸ Rp or Sp (dt</td>

<td> Cmpd No.</td><td></td><td> L/L</td><td> R/R</td><td> Name</td>

<td> 434</td><td> adenine-9-yl</td><td> octadecyloxyethyl</td><td> naphthyl</td><td> naphthyl octadecyloxyethy! 9-(5)-((3fluoro-2phosphonomethoxy)propyl]adenine</td>

<td> 435</td><td> cytosine-l-yl</td><td> octadecyl oxy ethyl</td><td> naphthyl</td><td> naphthyl octadecyloxyethyl 1-(5)-((3fluoro-2- phospho nomethoxy) propy 1] cytosi ne</td>

<td> 436</td><td> thymin-l-yl</td><td> octadecyloxyethy!</td><td> naphthyl</td><td> naphthyl octadecyloxyethyl 1-(5)-((3fluor -2phosphonomethoxy)propyl]thymine</td>

<td> 437</td><td> uracil-l-yl</td><td> octadecyloxyethyl</td><td> naphthyl</td><td> naphthyl octadecyloxyethy] 1-(5)-((3fluoro-2phosphonomethoxy)propy 1] uracil</td>

<td> 438</td><td> 2,6diaminopurin -9-yl</td><td> octadecyl oxyethyi</td><td> naphthyl</td><td> naphthyl octadecyloxyethyi 9-(5)-((3fluoro-2- phosphonomethoxy) propy 1)2,6diaminopurine</td>

<td> 439</td><td> guanin-9-yl</td><td> hexadecyloxypropyl</td><td> naphthyl</td><td> naphthyl hexadecyloxypropyl 9-(5)-((3fluoro-2phosphonomethoxy)propyl]guaninc</td>

<td> 440</td><td> adenine-9-yl</td><td> hexadecy 1 oxy propy 1</td><td> naphthyl</td><td> naphthyl hexadecyloxypropyl 9-(5)-((3fluoro-2- phosphonomethoxy) propy l]adenine</td>

<td> 441</td><td> cytosine-l-yl</td><td> hexadecyloxypropyl</td><td> naphthyl</td><td> naphthyl hexadecyloxypropyl 1-(5)-((3fluoro-2phosphonomethoxy)propyi]cytosine</td>

<td> 442</td><td> thymin-l-yl</td><td> hexadecyloxypropyl</td><td> naphthyl</td><td> naphthyl hexadecyloxypropyl 1-(5)-((3fluoro-2- phosphonomethoxy) propy IJthy mine</td>

<td> 443</td><td> uracil-l-yl</td><td> hexadecyloxypropyl</td><td> naphthyl</td><td> naphthyl hexadecyloxypropyl 1-(5)-((3fluoro-2phosphonomethoxy)propyl']uracil</td>

<td> 444</td><td> 2,6diaminopurin -9-yl</td><td> hexadecyloxypropyl</td><td> naphthyl</td><td> naphthyl hexadecyloxypropyl 9-(5)-((3fluoro-2- phosphonomethoxy)propy 1] 2,6diaminopurine</td>

<td> 445</td><td> guanin-9-yl</td><td> l-O-octadecyl-2-O- benzyl-.sn glyceryl</td><td> naphthyl</td><td> naphthyl 1 - O-octadecyl-2-O-benzyl -sn glyceryl 9-(5)-[(3-fluoro-2phosphonomethoxy)propyl]guanine</td>

<td> 446</td><td> adenine-9-yl</td><td> 1 -O-octadecyl-2-Obenzyl-jrt glyceryl</td><td> naphthyl</td><td> naphthyl l-O-octadecyW-O-benzyl-wt glyceryl 9-(5)-((3-fluoro-2phospho no methoxy)propyl] adenine</td>

<td> 447</td><td> cytosine-l-yl</td><td> l-O-octadecyl-2-Obenzyi-oi glyceryl</td><td> naphthyl</td><td> naphthyl l-O-octadecyl-2-O-benzyl-.m glyceryl l-(5)-[(3-fluoro-2phosphonomethoxy)propyl]cytosine</td>

<td> 448</td><td> thymin-l-yl</td><td> l-O-octadecyl-2-Obenzyl-jn glyceryl</td><td> naphthyl</td><td> naphthyl l-O-octadecyl-2-O-benzyl-sn glyceryl 1-(5)-[(3-Πηογο-2- phosphono methoxy)propy l]thymine</td>

<td> 449</td><td> uracil-l-yl</td><td> 1 -O-octadecy 1-2-0bcnzyl-.vn glyceryl</td><td> naphthyl</td><td> naphthyl 1 -O-octadecy 1-2-O-benzyl -sn glyceryl l-(5)-[(3-fluoro-2phosphonom ethoxy) propyl ] uracil</td>

WO 2014/143643

PCT/US2014/027005

<td colspan="5"> ®Nuc/^Nuc(a) O ^NucZ^Nuc(a) O ^Nuc/®Nuc(a) 0 k,^O,,^.P-O-L/L^a ί., ^Ο... ^Ρ-Ο· L/L^a L P-Q-L/L.^a - - or - 1 nr - OR/R^a_F&gt; O-R/R^a ...I O-R/R^a Rp or Sp (depends on substituents) Rp, Sp (racemic)</td>

<td> Cmpd No.</td><td> BNuc/BNuc(a)</td><td> L/L</td><td> R/R</td><td> Name</td>

<td> 450</td><td> 2,6diaminopurin -9-yl</td><td> 1 - O-octadecy 1-2-0benzyl-jw glyceryl</td><td> naphthyl</td><td> naphthyl 1 -O-octadecyl-2- O-benzy l-sn glyceryl 9-(S)-[(3-iluoro-2phosphonomethoxy) propy 1 ] 2,6 diaminopurine</td>

[0116] Specific compounds contemplated herein include:

<img file="IL241554A_D0021.tif" />

<img file="IL241554A_D0022.tif" />

<img file="IL241554A_D0023.tif" />

isopropylideneglyceryl octadecyloxyethyl

9~[2-(phosphonomethoxy)ethy!]guanine

<img file="IL241554A_D0024.tif" />

glyceryl octadecyloxyethyl

9-[2-(phosphonomethoxy)ethyi]guanine

O

<img file="IL241554A_D0025.tif" />

benzyl octadecyloxyethyI

9-(R)-[3-methoxy-2-(phosphonomethoxy)propyl] guanine

WO 2014/143643

PCI7US2014/027005

<img file="IL241554A_D0026.tif" />

<img file="IL241554A_D0027.tif" />

Phenyl octadecyioxyethyl phenyl hexadecyloxypropyl

9-(R)-[3-methoxy-2-(phosphonomethoxy)propyl] 9-(/?)-[3-fluoro-2-(phosphonomethoxy)propyl] guanine _anj adenine

ΙΠ. Methods of Use [0117] In another aspect, there is provided a method for treating a viral disease in a subject. The method includes administering to a subject in need thereof a therapeutically effective amount of a compound with structure of any of Formulae (I), (I-l), (1-2), (1-3), (1-4), (1-5) and/or (Ta). In embodiments, L/L^a of any of Formulae (I), (I-l), (1-2), (1-3), (1-4), (1-5) and/or (la) is a lipophilic promoiety.

[0118] Exemplary viral diseases include human papilloma virus, HIV, hepatitis B virus, hepatitis C virus, variola virus (smallpox), vaccinia virus, adenovirus, cytomegalovirus (CMV), herpes simplex viruses, Epstein Barr virus, BK virus, JC virus, any double stranded DNA virus, feline leukemia virus, feline immunodeficiency virus, and the like. A therapeutically effective amount of a compound of Formula (I) can be administered to a human or mammal in need of treatment of a viral disease.

[0119] In embodiments, the compound is administered by a route (topical, intravitreal, oral, intravenous etc.) which results in delivery of an amount sufficient to inhibit replication of the virus. In 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 [0120] In another aspect, there is provided a method for treating a disease or disorder in a subject in need thereof, the method including administering to a subject in need thereof a therapeutically effective amount of a compound with structure of any of Formulae (I), (I-l), (1-2), (1-3), (1-4), (1-5) and/or (la). Aspects for the treatment of cancer and other neoplastic disorders contemplated herein are based on the surprising discovery that compounds of Formulae (I) and/or (la) are effective in killing or inhibiting growth of cells that are transformed by human papillomavirus (HPV), for example cervical cancer cells and cervical

WO 2014/143643

PCT/US2014/027005 intraepithelial neoplasia (CIN) lesions. Accordingly, a therapeutically effective amount of a compound of Formula (I), (1-1), (1-2), (1-3), (1-4), (1-5) and/or (la) can be administered by an appropriate route (topical, orally, intravenous etc,) to kill or inhibit growth of infected/transformed cells. Cells that are transformed by other types of viruses, such as 5 herpes simplex virus-2 (HSV-2), also may be treated with a compound of Formula (I), (1-1), (1-2), (1-3), (1-4), (1-5) and/or (la).

[0121] In another aspect, there is provided a method for treating cancer in a subject. The method includes administering to a subject in need thereof a therapeutically effective amount of a compound with the structure of any of Formulae (I), (1-1), (1-2), (1-3), (1-4), (1-5) and/or 10 (la). In embodiments, L/L^a of any of Formulae (I), (1-1), (1-2), (1-3), (1-4), (1-5) and/or (la) is a lipophilic promoiety.

[0122] In embodiments, the cancer is leukemia, carcinoma and/or sarcoma, such as cancer of the brain, breast, cervix, colon, pancreas, head and neck, liver, kidney, lung, non-small cell lung, prostate, melanoma, mesothelioma, ovary, sarcoma, stomach, uterus and/or medulloblastoma. Additional examples include, Hodgkin’s Disease, Non-Hodgkin’s

Lymphoma, multiple myeloma, neuroblastoma, ovarian cancer, rhabdomyosarcoma, primary thrombocytosis, primary macroglobulinemia, primary brain tumors, malignant pancreatic insulanoma, malignant carcinoid, urinary bladder cancer, premalignant skin lesions, testicular cancer, lymphomas, thyroid cancer, neuroblastoma, esophageal cancer, genitourinary tract 20 cancer, malignant hypercalcemia, endometrial cancer, adrenal cortical cancer, and neoplasms of the endocrine and exocrine pancreas. In embodiments, the cancer is liver cancer, colon cancer, breast cancer, melanoma, acute myelogenous leukemia, chronic myelogenous leukemia, and/or non-small-cell lung cancer, [0123] In another aspect, there is provided a method for treating a proliferative disorder in 25 a subject. The method includes administering to a subject in need thereof a therapeutically effective amount of a compound with the structure of any of Formulae (I), (1-1), (1-2), (1-3), (1-4), (1-5) and/or (la). The proliferative disorder may be caused by the human papilloma virus. Exemplary proliferative disorders include, e.g., cervical intraepithelial neoplasia (CIN), vulvar intraepithelial neoplasia (VIN), anal intraepithelial neoplasia (AIN), or penile 30 and venereal warts. In embodiments, L/L^a of any of Formulae (I), (1-1), (1-2), (1-3), (1-4), (15) and/or (la) is a lipophilic promoiety.

WO 2014/143643

PCI7US2014/027005 [0124] In another aspect, there is provided a method for killing or inhibiting the growth of a transformed cell. The method includes contacting a transformed cell with a therapeutically effective amount of a compound of any one of Formulae (I), (I-l), (1-2), (1-3), (1-4), (1-5) and/or (la).

[0125] In another aspect, there is provided a compound of Formula (la) or embodiment thereof, or a pharmaceutically acceptable salt, hydrate, solvate or crystalline form thereof, for use in treating a viral disease in a subject, wherein the viral disease can be selected from human papilloma virus (HPV), HIV, hepatitis B virus, hepatitis C virus, variola virus, vaccinia 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.

[0126] In embodiments, the virus can be human papilloma virus. According to the CDC, HPV is the most common sexually transmitted infection (STI). HPV viruses can be classified into mucosal and cutaneous HPVs. Within each of these groups, the individual viruses are designated high risk or low risk. More than 40 types of HPV’s can infect the genital areas of women and men, and several HPV types can infect the mouth and throat. Additionally, HPV is the most common cause of cervical cancer. Type 16 is one of the most prominent strains of HPV and can cause cervical cancer. Other types ofEIPVs include, but are not limited to,, 2, 3, 4, 5, 6, 8, 11, 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 63, 66, 68, 69 and 82. In embodiments, the use is for treating a plurality of types of human papilloma virus, for example, types described herein. In embodiments, the use is for more than 2 types of HPV, more than 5 types of HPV or more than 10 types of HPV. In embodiments, the human papilloma virus can be selected from human papilloma virus type 11, type 16 and type 18.

[0127] In another aspect, there is provided use of a compound of Formula (la) or embodiment thereof, or a pharmaceutically acceptable salt, hydrate, solvate or crystalline form thereof, in the preparation of a medicament for treating a viral disease in a subject, wherein the viral disease can be selected from human papilloma virus, HIV, hepatitis B virus, hepatitis C virus, variola virus, vaccinia 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.

[0128] In embodiments, the virus can be human papilloma virus. In embodiments, the use is for treating a plurality of types of human papillomavirus, for example, types described

WO 2014/143643

PCT/US2014/027005 herein. In embodiments, the use is for more than 2 types of HPV, more than 5 types of HPV or more than 10 types of HPV. In embodiments, the human papilloma virus can be selected from human papilloma virus type 11, type 16 and type 18.

[0129] In another aspect, there is provided a method of treating a subject having a viral disease. The method include administering to the subject having a viral disease in need thereof an effective amount of a compound of Formula (la) or embodiment thereof, or a pharmaceutically acceptable salt, hydrate, solvate or crystalline form thereof, wherein the viral disease can be selected from human papilloma virus, HIV, hepatitis B virus, hepatitis C virus, variola virus, vaccinia virus, an adenovirus, a cytomegalovirus, herpes simplex virus I, herpes simplex virus 2, Epstein Barr virus, BK virus, JC virus, feline leukemia virus and feline immunodeficiency virus, thereby treating the viral disease.

[0130] In another aspect, there is provided a compound of Formula (la) or embodiment thereof, or a pharmaceutically acceptable salt, hydrate, solvate or crystalline form thereof, for use in treating cancer of the cervix in a subject. In some embodiments, the cancer of the cervix can be caused by a HPV infection, for example, a HPV infection of type 16.

[0131] In another aspect, there is provided use of a compound of Formula (la) or embodiment thereof, or a pharmaceutically acceptable salt, hydrate, solvate or crystalline form thereof, in the preparation of a medicament for treating cancer of the cervix in a subject. In some embodiments, the cancer of the cervix can be caused by a HPV infection, for example, a HPV infection of type 16.

[0132] In another aspect, there is provided a method of treating a subject having cancer of the cervix. The method includes administering an effective amount of a compound of Formula (la) or embodiment thereof, or a pharmaceutically acceptable salt, hydrate, solvate or crystalline form thereof, to a subject having cancer of the cervix in need thereof, thereby treating the subject having cancer of the cervix. In some embodiments, the cancer of the cervix can be caused by a HPV infection, for example, a HPV infection of type 16.

[0133] In another aspect, there is provided a compound of Formula (la) or embodiment thereof, or a pharmaceutically acceptable salt, hydrate, solvate or crystalline form thereof, for use in inhibiting growth of a cell transformed by a virus, wherein the virus can be selected from human papilloma virus, HIV, hepatitis B virus, hepatitis C virus, variola virus, vaccinia virus, an adenovirus, a cytomegalovirus, herpes simplex virus 1, herpes simplex virus 2,

WO 2014/143643

PCT/US2014/027005

Epstein Barr virus, BK virus, JC virus, feline leukemia virus and feline immunodeficiency virus.

[0134] In another aspect, there is provided use of a compound of Formula (la) or embodiment thereof, or a pharmaceutically acceptable salt, hydrate, solvate or crystalline form thereof, in the preparation of a medicament for inhibiting growth of a cell transformed by a virus, wherein the virus can be selected from human papilloma virus, HIV, hepatitis B virus, hepatitis C virus, variola virus, vaccinia 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.

[0135] In another aspect, there is provided a method of inhibiting growth of a cell transformed by a virus. The method includes contacting a compound of Formula (la) or embodiment thereof, or a pharmaceutically acceptable salt, hydrate, solvate or crystalline form thereof, with a cell transformed by a virus, wherein the virus can be selected from human papilloma virus, HIV, hepatitis B virus, hepatitis C virus, variola virus, vaccinia 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, thereby inhibiting growth of the cell transformed by a virus.

IV. Methods of Synthesis [0136] In another aspect, there is provided a method for synthesis of compounds of Formula (I), as depicted in Scheme 1 following. For Scheme I, substituents Bnuc, X, R and L are as described for Formula (I) herein.

[0137] In another aspect, there is provided a method for synthesis of compounds of Formula (la), as depicted in Scheme la following. For Scheme la, substituents B^uc/a), X, R^aand L^a are as described for Formula (la) herein.

[0138] The method includes reacting a suitably substituted ANP monoester with R-OH or R^a-OH in the presence of a coupling agent such as (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PYBOP®) to give a diester, Methods for preparing the ANP monoesters are well known. For examples, 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 synthesis of phosphonate diesters was first described in Campagne, J-M. et al. Tetrahedron Letters, 1993, 34:6743-6744. Other

WO 2014/143643

PCT7US2014/027005 coupling/condensation reagents, for example uronium, carbodiimide, imidazolium and acid chloride reagents, may also be used (for a review of coupling agents see, e.g., El-Faham, A.

&amp; Albericio, F. Chemical Reviews, 2011, 111:6557-6602).

<img file="IL241554A_D0028.tif" />

Scheme la

<img file="IL241554A_D0029.tif" />

<img file="IL241554A_D0030.tif" />

[0139] In another aspect, there is provided a method for synthesis of compounds of Formula (I). The method includes the steps provided in Scheme 2 following:

<img file="IL241554A_D0031.tif" />

WO 2014/143643

PCT/US2014/027005 [0140] In the method of Scheme 2, B_N,,_L is a naturally occurring purine or pyrimidine base, or analog thereof; L is a lipophilic promoiety, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, or O-substituted glyceryl having the formula -CH₂CH(OR')-CH2(OR²) (II), wherein R¹ and R² are independently substituted or unsubstituted alkyl or substituted or unsubstituted aryl; R is substituted or unsubstituted lower alkyl, substituted or unsubstituted lower heteroalkyl, substituted or unsubstituted lower cycloalkyl, substituted or unsubstituted lower heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted lower heteroaryl; X is hydrogen, substituted or unsubstituted lower alkyl, or substituted or unsubstituted lower heteroalkyl; and Y is a leaving group.

[0141] The method includes: I) contacting a protected nucleoside Bn_uc with structure of Formula (24) with an ester with structure of Formula (2-2) in the presence of a strong base under conditions suitable to afford a monoester with structure of Formula (2-3); and 2) reacting the monoester so formed with structure of Formula (2-3) with L-OH in the presence of a coupling agent as known in the art, thereby synthesizing a compound with structure of Formula (I).

[0142] In another aspect, there is provided a method for synthesis of compounds of Formula (la). The method includes the following as provided in Scheme 2a. For Scheme 2a, substituents B_Nuc(_a), X^a, R^a and L^a are as described for Formula (la) herein, and Y^a can be a

<img file="IL241554A_D0032.tif" />

<img file="IL241554A_D0033.tif" />

<img file="IL241554A_D0034.tif" />

[0143] The method includes: 1) contacting a protected nucleoside BN_uc(a) with structure of Formula (2-la) with an ester with structure of Formula (2-2a) in the presence of a strong base

WO 2014/143643

PCT7US2014/027005 under conditions suitable to afford a monoester with structure of Formula (2-3a); and 2) reacting the monoester so formed with structure of Formula (2-3a) with L^il-OH in the presence of a coupling agent as known in the art, thereby synthesizing a compound with structure of Formula (la).

[0144] In embodiments, the method includes the steps provided in Scheme 2-1 following, specifically, contacting a suitably protected nucleoside (general structure 2-1 where Bn_uc is a naturally occurring or modified purine or pyrimidine base, with an ester of general structure 2-2 (where Y is a leaving group such as p-toluenesulfonyl, methanesulfonyl, trifluoromethanesulfonyl, bromo, iodo, or the like) in the presence of a strong base and suitable solvent to yield ANP monoesters of Formula 2-3, and secondly, reacting ANP monoester 2-3 with L-OH (i.e., hydroxy form of L) in the presence of a coupling agent such as PYBOP® to give a diester of Formula (I).

Scheme 2-1

<img file="IL241554A_D0035.tif" />

[0145] In another aspect, there is provided method for synthesis of a compound with structure of Formula (I) according to Scheme 2-1. Bn_UC! X, R and L are as described for Formula (1) herein, and Y can be a leaving group; said method comprising: contacting a compound of Formula (2-1) that has a protected Bn_uc with a compound of Formula (2-2) in the presence of a strong base to form a compound of Formula (2-3); and reacting the compound of Formula (2-3) with L-OH in the presence of a coupling agent to form the compound of Formula (I).

WO 2014/143643

PCT71JS2014/027005

Scheme 2-la

<img file="IL241554A_D0036.tif" />

[0146] In another aspect, there is provided method for synthesis of a compound with structure of Formula (la) according to Scheme 2-la. For this method, B&gt;q_UC(_a) can be a naturally occurring purine, a naturally occurring pyrimidine, a non-naturally occurring purine or a non-naturally occurring pyrimidine; L can be an unsubstituted Cn-24 alkyl, an unsubstituted C,₃.₂₉ heteroaikyl or a substituted glyceryl moiety, wherein the glyceryl moiety can be substituted with one or more groups selected from an unsubstituted C;t₂₉ alkyl, an unsubstituted C₁₃.₂₉ heteroaikyl, a substituted or unsubstituted aryl(Cj.6 alkyl), a substituted or unsubstituted heteroaryl(Ci_6 alkyl) and a substituted or unsubstituted heterocycloalkyl(Cp6 alkyl); R^a can be selected from 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 alkyl), a substituted or unsubstituted heteroaryl(Ci-6 alkyl) and a substituted or unsubstituted heterocycloalkyI(Ci_6 alkyl); X^a can be hydrogen, an unsubstituted Ci_6 alkyl, a halogen substituted Ci-₆ alkyl, a hydroxy substituted Cp₆ alkyl or an unsubstituted C_b6 alkoxy; and Y^a can be a leaving group; said method comprising: contacting a compound of Formula (2-la) that has a protected Buuc(a) with a compound of Formula (2-2a) in the presence of a strong base to form a compound of Formula (2-3a); and reacting the compound of Formula (2~3a) with L^a-OH in the presence of a coupling agent to form the compound of Formula (la).

WO 2014/143643

PCT/US2014/027005 [0147] In another aspect, there is provided a method for synthesizing a compound of

Formula (I) as described in Scheme 3 following. For Scheme 3, substituents B_Nlc, X, R and

L are as described for Formula (I) herein,

Scheme 3 ^BNuc

<img file="IL241554A_D0037.tif" />

Ηοθ'~*~Ρ*“ Ό·........L I

I \ „

Y Ο--R

3-2 [0148] The method includes contacting a suitably protected nucleoside (general structure 31 where Bn_uc is a naturally occurring or modified purine or pyrimidine base), with a diester of general structure 3-2 (where Y is a leaving group such as p-tolucnesulfonyl, methanesulfonyl, trifluoromethanesulfonyl, bromo, iodo, or the like.) in the presence of a strong base and suitable solvent to yield a compound of Formula (I).

[0149] In another aspect, there is provided a method for synthesizing a compound of Formula (la) as described in Scheme 3a. For Scheme 3a, substituents BNuc(a)&gt; X^a, R^a and L^aare as described for Formula (la) herein, and Y^a is a leaving group.

Scheme 3a

<img file="IL241554A_D0038.tif" />

Y^a O---R^a³-^2a [0150] The method includes contacting a suitably protected nucleoside (3-1 a), with a diester 3-2 (where Y^a is a leaving group such as p-toluenesulfonyl, methanesulfonyl,

WO 2014/143643

PCT/US2014/027005 trifluoromethanesulfonyl, bromo, iodo, or the like) in the presence of a strong base and suitable solvent to yield a compound of Formula (la).

V. Pharmaceutical Compositions [0151] In another aspect, there is provided a pharmaceutical compositions including a compound of Formula (I) and/or a compound of Formula (la) in combination with a pharmaceutically acceptable excipient (e.g., carrier).

[0152] The terms “pharmaceutically acceptable carrier,” “pharmaceutically acceptable excipient” and the like as used herein refer to pharmaceutical excipients, for example, pharmaceutically, physiologically, acceptable organic or inorganic carrier substances suitable for enteral or parenteral application that do not deleteriously react with the active agent. Suitable pharmaceutically acceptable carriers include water, salt solutions (such as Ringer's solution), alcohols, oils, gelatins, and carbohydrates such as lactose, amylose or starch, fatty acid esters, hydroxymethycellulose, and polyvinyl pyrrolidine. Such preparations can be sterilized and, if desired, mixed with auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring, and/or aromatic substances and the like that do not deleteriously react with the compounds described herein.

[0153] The compounds described herein can be administered alone or can be coadministered to the subject. Coadministration is meant 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 (e.g., to reduce metabolic degradation).

A. Formulations [0154] The compounds described herein can be prepared and administered in a wide variety of oral, parenteral, and topical dosage forms. Thus, the compounds described herein can be administered by injection (e.g. intravenously, intramuscularly, intracutaneously, subcutaneously, intraduodenally, or intraperitoneally). Also, the compounds described herein can be administered by inhalation, for example, intranasally. Additionally, the compounds described herein can be administered transdermally. It is also envisioned that multiple routes of administration (e.g., intramuscular, oral, transdermal) can be used to administer the compounds described herein. Accordingly, pharmaceutical compositions comprising a

WO 2014/143643

PCT/US2014/027005 pharmaceutically acceptabie carrier or excipient and one or more compounds are contemplated.

[0155] For preparing pharmaceutical compositions, pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. A solid carrier can be one or more substances that may also act as diluents, flavoring agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material.

[0156] In powders, the carrier is a finely divided solid in a mixture with the finely divided active component. In tablets, the active component is mixed with the carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired.

[0157] The powders and tablets preferably contain from 5% to 70% of the active compound. Suitable carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like, The term “preparation” is intended to include the formulation of the active compound 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 thus in association with it. Similarly, cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid dosage forms suitable for oral administration.

[0158] For preparing suppositories, a low melting wax, such as a mixture of fatty acid glycerides or cocoa butter, is first melted and the active component is dispersed homogeneously therein, as by stirring. The molten homogeneous mixture is then poured into convenient sized molds, allowed to cool, and thereby to solidify.

[0159] 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 solution in aqueous polyethylene glycol solution.

[0160] When parenteral application is needed or desired, particularly suitable admixtures are injectable, sterile solutions, preferably oily or aqueous solutions, as well as suspensions, emulsions, or implants, including suppositories. In particular, carriers for parenteral administration include aqueous solutions of dextrose, cyclodextrins, saline, pure water,

WO 2014/143643

PCT/US2014/027005 ethanol, glycerol, propylene glycol, peanut oil, sesame oil, polyoxyethylene-block polymers, and the like. Ampoules are convenient unit dosages. The compounds described herein can also be incorporated into liposomes or administered via transdermal pumps or patches.

Pharmaceutical admixtures 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 of which are hereby incorporated by reference, [0161] 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. Aqueous suspensions suitable for oral use can be made by dispersing the 10 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.

[0162] Also included are solid form preparations that are intended to be converted, shortly before use, to liquid form preparations for oral administration. Such liquid forms include 15 solutions, suspensions, and emulsions. These preparations may contain, in addition to the active component, colorants, flavors, stabilizers, buffers, artificial and natural sweeteneis, dispersants, thickeners, solubilizing agents, and the like, [0163] The pharmaceutical preparation is preferably in unit dosage form. In such form the preparation is subdivided into unit doses containing appropriate quantities of the active 20 component. The unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packeted tablets, capsules, and powders in vials or ampoules. Also, the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form, In embodiments, the unit dosage form can be in the form of an applicator pre-filled with a pharmaceutical composition 25 described herein (for example, a pharmaceutical composition that contains an effective amount of a compound of Formula (1) and/or a compound of Formula (la)). In embodiments, the pre-filled applicator can be filled with a pharmaceutical composition in the form of a cream, a gel or an ointment that contains a compound described herein (for example, a compound of Formula (I) and/or a compound of Formula (la)).

[0164] The quantity of active component in a unit dose preparation may be varied or adjusted from 0,1 mg to 10000 mg, more typically 1.0 mg to 1000 mg, most typically 10 mg

WO 2014/143643

PCT/US2014/027005 to 500 mg, according to the particular application and the potency of the active component.

The composition can, if desired, also contain other compatible therapeutic agents.

[0165] Some compounds may have limited solubility in water and therefore may require a surfactant or other appropriate co-solvent in the composition. Such co-solvents include: Polysorbate 20, 60, and 80; Pluronic F-68, F-84, and P-103; cyclodextrin; and polyoxyl 35 castor oil. Such co-solvents are typically employed at a level between about 0.01 % and about 2% by weight.

[0166] Viscosity greater than that of simple aqueous solutions may be desirable to decrease variability in dispensing the formulations, to decrease physical separation of components of a suspension or emulsion of formulation, and/or otherwise to improve the formulation. Such viscosity building agents include, for example, polyvinyl alcohol, polyvinyl pyrrolidone, methyl cellulose, hydroxy propyl methylcellulose, hydroxyethyl cellulose, carboxymethyl cellulose, hydroxy propyl cellulose, chondroitin sulfate and salts thereof, hyaluronic acid and salts thereof, and combinations of the foregoing. Such agents are typically employed at a level between about 0.01% and about 2% by weight.

[0167] The compositions may additionally include components to provide 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 U.S. Pat. Nos. 4,911,920; 5,403,841; 5,212,162; and 4,861,760. The entire contents of these patents are incorporated herein by reference in their entirety for all purposes.

B. Effective Dosages [0168] Pharmaceutical compositions include compositions wherein the active ingredient is contained in a therapeutically effective amount, i.e., in an amount effective to achieve its intended purpose. The actual amount effective for a particular application will depend, inter alia, on the condition being treated. For example, when administered in methods to treat cancer, such compositions will contain an amount of active ingredient effective to achieve the desired result (e.g., decreasing the number of cancer cells in a subject).

[0169] The dosage and frequency (single or multiple doses) of compound administered can vary depending upon a variety of factors, including route of administration; size, age, sex, health, body weight, body mass index, and diet of the recipient; nature and extent of

WO 2014/143643

PCT/US2014/027005 symptoms of the disease being treated; presence of other diseases or other health-related problems; kind of concurrent treatment; and complications from any disease or treatment regimen. Other therapeutic regimens or agents can be used in conjunction with the methods and compounds described herein.

[0170] For any compound described herein, the therapeutically effective amount can be initially determined from cell culture assays. Therapeutically effective amounts for use in humans may subsequently be estimated from animal models using conventional techniques that are confirmed or refined in actual clinical trials.

[0171] Dosages may be varied depending upon the requirements of the patient and the compound being employed. The dose administered to a patient should be sufficient to effect a beneficial therapeutic response in the patient over time. The size of the dose also will be determined by the existence, nature, and extent of any adverse side effects. Generally, treatment is initiated with smaller dosages, which are less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect under circumstances is reached. In one embodiment, the dosage range is 0.001% to 10% w/v. In another embodiment, the dosage range is 0.1% to 5% w/v.

[0172] Dosage amounts and intervals can be adjusted individually to provide Levels of the administered compound effective for the particular clinical indication being treated. This will provide a therapeutic regimen that is commensurate with the severity of the individual s disease state.

[0173] Utilizing the teachings provided herein, an effective prophylactic or therapeutic treatment regimen can be planned that does not cause substantial toxicity and yet is entiiely effective to treat the clinical symptoms demonstrated by the particular patient. This planning should involve the careful choice of active compound by considering factors such as compound potency, relative bioavailability, patient body weight, presence and severity of adverse side effects, preferred mode of administration, and the toxicity profile of the selected agent.

C. Toxicity [0174] The ratio between toxicity and therapeutic effect for a particular compound is its therapeutic index and can be expressed as the ratio between LD50 (the amount of compound lethal in 50% of the population) and ED₅₀ (the amount of compound effective in 50% of the

WO 2014/143643

PCI7US2014/027005 population). Compounds that exhibit high therapeutic indices are preferred. Therapeutic index data obtained from cell culture assays and/or animal studies can be used in formulating a range of dosages for use in humans. The dosage of such compounds preferably lies within a range of plasma concentrations that include the ED₅₀ with little or no toxicity. The dosage may vary within this range depending upon the dosage form employed and the route of administration utilized. See, e.g. Fingl et al., In: THE PHARMACOLOGICAL BASIS OF Therapeutics, Ch. 1, p.l, 1975. The exact formulation, route of administration, and dosage can be chosen by the individual physician in view of the patient's condition and the particular method in which the compound is used.

VI. Examples [0175] General Chemistry Methods: Ail reagents were of commercial quality and used without further purification unless indicated otherwise. Chromatographic purification was done using the flash method with silica gel 60 (EMD Chemicals, Inc., 230 400 mesh).

NMR spectra were recorded on a Varian HG spectrophotometer operating at 400 MHz and are reported in units of parts per million (ppm) relative to internal tetramethylsilane at 0.00 ppm. Routine electrospray ionization mass spectra (ESI-MS) were recorded on a Finnigan LCQDECA spectrometer, and high resolution mass spectra (HRMS) were recorded on an Agilent 6230 Accurate-Mass TOFMS mass spectrometer in ESI negative mode. Purity of the target compounds was characterized by high performance liquid chromatography (HPLC) using a Beckman Coulter System Gold chromatography system. The analytical column was PHENOMENEX® SYNERGI™ Polar-RP (4.6 x 150 mm) equipped with a SECURITYGUARD™ protection column. Mobile phase A was 95% water/5% methanol and mobile phase B was 95 % methanol/5% water. At a flow rate of 0,8 mL/min, isocratic elution was used. Compounds were detected by ultraviolet light (UV) absorption at 274 nm. Homogeneity of the target compounds was also confirmed by thin layer chromatography (TLC) using Analtech silica gel-GF (250 pm) plates and the solvent system: CHCh/MeOH/con NH₄OH/H₂O (70:30:3:3 v/v). TLC results were visualized with UV light, phospray (Supelco, Bellefonte, PA, USA) and charring at 400 °C.

WO 2014/143643

PCT/US2014/027005 [0176] Example L Preparation of benzyl octadecyloxyethyl 9-[2-(phosphonomethoxy) ethyl]guanine, l-(Rp,Sp) (Cmpd 1, Bn-ODE-PMEG).

O

<img file="IL241554A_D0039.tif" />

ODE-PMEG

O benzyl alcohol

PyBOP, DIEA, N₍N-DMF 62% yield

<img file="IL241554A_D0040.tif" />

[0177] To a solution of octadecyloxyethyl 9-[2-(phosphonomethoxy)ethyl]guanine (ODE5 PMEG) [prepared accordingto: 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 Ν,Ν-DMF, diisopropylethylamine (DIEA, 0.24 ml, 1,4 mmol) was added. The mixture was stirred at room temperature for 30 min. The solvents were evaporated in vacuo. The residue was dissolved in ethyl acetate (50 ml) and extracted with saturated sodium bicarbonate (2 x ml). The ethyl acetate layer was evaporated, and then the residue was adsorbed on silica gel and purified by flash column chromatography. Elution with ClhCbyMcOH (0-5%) gave 0.15 g (62%) of Cmpd 1 as a white powder. 'HNMR (CDClj/methanol-cU) δ 7.56 (s, IH); 7.35-7.40 (m, 511); 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), 3.85 (dd, J=8Hz, Jl=2Hz, 2H); 3.57 (t, J=5Hz, 2H); 3.44 (t, &gt;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)⁺.

WO 2014/143643

PCT/US2014/027005 [0178] Example 2. Resolution of benzyl octadecyloxyethyi 9-[2-(phosphonomethoxy) ethyl]guanine P-chiral enantiomers.

<img file="IL241554A_D0041.tif" />

preparative HPLC____

LuxCellulose-1, reverse phase

<img file="IL241554A_D0042.tif" />

<img file="IL241554A_D0043.tif" />

[0179] Bn-ODE-PMEG of Example 1 was obtained as a mixture of enantiomers because of 5 the chirality at phosphorus. The enantiomers were separated on a Lux™ Cellulose-1 column (Phenomenex®, Torrance, CA USA) using reverse phase conditions (mobile phase of 50:50:0.1 20mM AmmAc:AcN:TFA). The absolute stereochemistry of the P-chiral enantiomers was not determined. The preparative chromatographic resolution of the material obtained in Example 1 provided two enantiomers that are characterized as la (fast eluting 10 enantiomer) and lb (slow eluting enantiomer). An example chromatogram is provided in

Fig. 1[0180] In the following examples, preparation of the 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 diastereomers as needed.

[0181] Example 3. Preparation of benzyl octadecyloxyethyi 9-[2-(phosphonomethoxy) ethyl]adenine (Cmpd 2, Bn-ODE-PMEA).

<img file="IL241554A_D0044.tif" />

o ,^O(CH₂)₂0(CH_a)₁₇CH₃

OH

ODE-PMEA benzyl alcohol PyBOP, DIEA, Ν,Ν-DMF 50% yield

<img file="IL241554A_D0045.tif" />

[0182] To a solution of octadecyloxyethyi 9-[2-(phosphonomethoxy)ethyl]adenine (ODE PMEA) [prepared according to: Valiaeva, N. et al. Antiviral Research 2006, 72:10-19] (0.2 g,

WO 2014/143643

PCT/US2014/027005

0.35 mmol), (benzotriazol-l-yloxy)-tripyrrolidinophosphonium hexafluorophosphate (PYBOP®, 0.27 g, 0,525 mmol), anhydrous benzyl alcohol (0.05 ml, 0.525 mmol) in dry Ν,Ν-DMF, diisopropylethylamine (DIEA, 0.24 ml, 1.4 mmol) was added. The mixture was stirred at room temperature for 30 min. The solvents were evaporated. The residue was dissolved in ethyl acetate (50 ml) and washed with a saturated solution of sodium bicarbonate (2x10 ml). The ethyl acetate layer was evaporated, and then the residue was purified by column chromatography on silica gel using CI^Ch/MeOH (0-5%) to give 0.12 g (50%) of compound 2. ’H NMR (CDCl₃/methanol-d₄) δ 8.25 (s, 1H); 7.99 (s, 1H); 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, 211); 3.88 (t, .To Hz, 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, 3FI). MS (El): 660.55 (M+H)⁺.

[0183] Example 4. Preparation of benzyl octadecyloxyethyi 9-(S)-[3-hydroxy-2(phosphonomethoxy)propyl] adenine (Cmpd 218, Bn-ODE-(S)-HPMPA).

[0184] Method 1:

HN-Tr

HN-Tr ·% fl

I O R- O(CH₂)₂O(CH₂), jCH₃; OH

Ir-O' benzyl alcohol

PyBOP, DIEA. Ν,Ν-DMF 50% yield

I O P_v-0(CH₂)₂0(CH₂)₁₇CH₃i o

Tr-O^ L'rtC'A nh₂

80% acetic acid

-N P

I O - O(CH_z)₂O(CH₂) „ch₃ ; O

HO''· — [0185] To a solution of octadecyloxyethyi 9-(S)-[3-trityloxy-2-(phosphonomethoxy) propyl]-N⁶-trityladenine (prepared as described in: Beadle, J, R. et al. Journal of Medicinal Chemistry 2006, 49:2010-2015) (0.42 g, 0.38 mmol), (benzotriazol-l-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PYBOP®, 0.30 g, 0.58 mmol), benzyl alcohol (0.06 ml, 0.58 mmol) in dry Ν,Ν-DMF (2 ml), diisopropylethylamine (DIEA, 0.4 ml, 1.52 mmol) was added. The mixture was stirred at room temperature for 30 min. The solvents were evaporated. The residue was dissolved in ethyl acetate (50 ml), and then washed with saturated solution of sodium bicarbonate (2x10 ml). Ethyl acetate was evaporated, and the residue was purified by column chromatography on silica gel using CtfcCl^MeOH (0-5%) to give 0.23 g (51%) ofthe product. NMR (CDCh/methanol-d^ 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 (tn, 1H); 3.91-4.04

WO 2014/143643

PCT/US2014/027005 (m, 2H), 3.83 (dd, J-KHz, 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)+ [0186] The protected intermediate (0.13 g, 0.11 mmol) was added to 80% aq acetic acid (10 ml) and stirred at 30 °C for 3 h. After cooling, the solvent was evaporated and the residue was purified by column chromatography on silica gel to give compound 218 (0.04 g, 52% yield). ’HNMR (CDCl₃/methanol-d₄) δ 8.25 (s, 1H); 7.89 (s, 1H); 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, 1H); 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)⁺.

[0187] Method 2:

<img file="IL241554A_D0046.tif" />

<img file="IL241554A_D0047.tif" />

sodium t-buloxide

N.N-DMF

<img file="IL241554A_D0048.tif" />

ociadecyioxyethanol

PyBOP, D|EA, N.N-DMF 50% yield

<img file="IL241554A_D0049.tif" />

[0188] A mixture of 9-(5)-[3-trityloxy-2-hydroxypropyl]- A^-trityladenine [prepared as in: Webb, R. R., Nucleosides &amp; Nucleotides, 1989, 8:619-24] (1.4g, 2.0 mmol) and sodium tertbutoxide (0.39 g, 4 mmol) in dry Ν,Ν-DMF (10 ml) were stirred at room temperature for 30 min, then benzyl p-toluenesulfonyloxymethylphosphonate (0.94g, 2.5 mmol, see Example 6) was added. The mixture was stirred at 80 °C overnight. The solvent was evaporated, and then the residue was purified by column chromatography on silica gel to give benzyl 9-(S)-[3trityloxy-2-(phosphonomethoxy)propyl]- A^-trityladenine 0.75 g (42%). 'HNMR (CDCl₃/methanol-d₄) δ 8.09 (s, 1H); 7.88 (s, 1H); 7.08-7.60 (m, 30H); 4.84-4.88 (m, 2H); 4.20-4.30 (m, 2H); 3.78-4.90 (m, 1H); 3.50-3.72 (m, 2H), 2.99-3.18 (m, 2H).

WO 2014/143643

PCT/US2014/027005 [0189] To a solution of this intermediate (0.2 g, 0.22 mmol), (benzotriazol-l-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PYBOP®, 0.17 g, 0.33 mmol) and octadecyloxyethanol (0.10g, 0.33 mmol) in dry Ν,Ν-DMF (2 ml), diisopropylethylamine (DIEA, 0.15ml, 0.88 mmol) was added. The mixture was stirred at room temperature for 30 min and the solvent was evaporated. The residue was dissolved in ethyl acetate (50 ml) and washed with saturated solution of sodium bicarbonate (2x10 ml). The ethyl acetate layer was evaporated, and then the residue was purified by column chromatography on silica gel using CHsCh/MeOH (0-5%) to give 0.15 g (58%) of the product. 'H NMR (CDCl₃/methanol· d₄) S: 7.93 (s, 1H); 7.87 (s, IH); 7.16-7.42 (m, 35H); 5.00 (dd, J=9Hz, J,=2Hz, 2H); 4.274.44 (m, 2H); 4.06-4.14 (m, 1H); 3.91-4.04 (m, 2H), 3.83 (dd, J=8Hz, J,=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 (ET): 1174.29 (M+H)⁺; 1196.52 (M+Na)⁺.

[0190] The protected compound (0.15 g, 0.13 mmol) was treated with 80% aq acetic acid (10 ml) at 30 °C for 3 h. The solvents were evaporated, and then the residue was purified by column chromatography on silica gel to give compound 218 (0,06g, 68%). 'HNMR (CDCl₃/methanol-d₄) δ: 8.24 (s, 1H); 7.52 (s, 1H); 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)'¹', 712.45 (Ml Na)⁺.

[0191] Example 5. Preparation of isopropylidene glyceryl oetadecyloxyethyl 9-(2 phosphonomethoxyethyl)guanine.

<img file="IL241554A_D0050.tif" />

[0192] To a suspension of oetadecyloxyethyl 9-[2-(phosphonomethoxy)ethyl]guanine (ODE PMEG)) [prepared according to: Valiaeva, N. et al.; Antiviral Research, 2006, 72:1019] (0.18 g, 0.30 mmol), oxalyl chloride (0.56 ml, 0,48 mmol) in dry toluene (5 ml), DMF

WO 2014/143643

PCT/US2014/027005 (0.06 ml) was added. The mixture was stirred at room temperature for 1 h. The solvent was evaporated in vacuum and co-evaporated with toluene (2x10 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 solution of saturated sodium bicarbonate (5 ml) was added, and the mixture was stirred for 30 min. The toluene fraction was evaporated and purified by column chromatography on silica gel to give 0.05g of TPG-ODE-PMEG (23%).

*H NMR (CDCl₃/methanol-d₄) δ: 8.91 (s, IH); 8.15 (s, IH); 4.44-4.52 (m,2H); 4.18-4.34 (m, 2H); 4.13-4.18 (m, IH); 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, .T~7Ilz, 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)⁺.

[0193] Example 6. Preparation of benzyl p-toluenesulfonyloxymethyl phosphonate, sodium salt.

[0194] Diethyl p-toluenesulfonyloxymethyl phosphonate (3.2 g, 9.9 mmol) was dissolved in Ν,Ν-DMF (10ml) and then bromotrimethylsilane (10 ml) was added. The mixture was stirred at room temperature overnight. The solvent was evaporated, and co-evaporated with toluene (2 x 10ml). An ethanol/water mixture (10ml) was added, and then mixture was stirred for 30 min at room temperature. The solvents were evaporated and co-evaporated with toluene (2 x 10ml). The residue was suspended in toluene (50 ml), and then oxalyl chloride (1.3 ml, 15.0 mmol) was added followed by Ν,Ν-DMF (0.01 ml). The mixture was stirred at room temperature for 1 h. The solvents were evaporated and co-evaporated with toluene (2 x 10ml). The residue was suspended in toluene (25 ml), and then anhydrous benzyl alcohol (1.5 ml, 15.0 mmol) was added. The mixture was stirred at room temperature overnight. 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 by column chromatography on silica gel to give 2.94 g of benzyl p-toluenesulfonyloxymethyl phosphonate, sodium salt (81%). ^lH NMR (CDCE/methanol-d^ 3:7.72 (d, J—8Hz, 2H), 7.307.33 (m, 7H); 4.88 (d, J=7Hz, 2H); 4.02 (d, J=9Hz, 2H); 2.44 (s, 3H).

WO 2014/143643

PCT/US2014/027005 [0195] Example 7. Preparation of benzyl l-O-octadecyl-2-O-bertzyl-sn-glyceryl 9-(S)-[(3hydroxypropyl-2-phosphonomethoxy)propyl]ademne (Cmpd 230, Bn-ODBG-(S)-HPMPA).

<img file="IL241554A_D0051.tif" />

<img file="IL241554A_D0052.tif" />

[0196] To a solution of benzyl 9-(S)-[3-trityloxy-2-(phosphonomethoxy)propyl]- bf'trityladenine (prepared as in Example 4, method 2) (0.4 g, 0.44 mmol), (benzotriazol-1yloxy)-tripyrrolidinophosphonium hexafluorophosphate (PYBOP®, 0.27 g, 0.51 mmol), l-OoctadecyI-2-O-benzyl-iw-glycerol (0.22 g, 0.51 mmol) in dry Ν,Ν-DMF (1 ml), diisopropylethylamine (DIEA, 0.30ml, 1.7 mmol) was added. The mixture was stirred at room temperature for 30 min, The solvents were evaporated. The residue was dissolved in ethyl acetate (50 ml), and then washed with a solution of saturated sodium bicarbonate (2 x 10 ml). The ethyl acetate layer was evaporated and then the residue was purified by column chromatography on silica gel using CHzClj/MeOH (0-5%) to give 0.15 g (58%) of the product. kNMR (CDCh/methanol-d^ δ: 7.88 (s, 1H); 7.87 (s, 1H); 7.19-7.42 (m, 40H); 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, 1H); 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, &gt;7Hz, 3H). MS (El): 1294.27 (M+H)⁺; 1316.57 (M+Na)⁺.

[0197] The protected compound (0.33 g, 0.13 mmol) was treated with 80% aq acetic acid (20 ml) at 30 °C for 3 h. The solvents were then evaporated and the residue was purified by column chromatography on silica gel to give compound 230 (0.13g, 65%). ^!HNMR (CDCl₃/methanol-d₄) 6: 8.22 (s, 1H); 7.65 (s, 1H); 7.27-7.35 (m, 10H); 4.99-5.04 (m, 2H);

4.58-4.66 (m, 2H); 4.33-4.43 (m, 111); 4.16-4.33 (m, 2H), 3.94-4.12 (m, 2H); 3.80-3.88 (m,

WO 2014/143643

PCT/US2014/027005

IH); 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)⁺.

[0198] Examples. Preparation of benzyl octadecyloxyethyl 1-(3)-[(3-hydroxy-2phosphonomethoxy)propyl]cytosine (Cmpd 219, Bn-ODE-(S)-HPMPC).

<img file="IL241554A_D0053.tif" />

<img file="IL241554A_D0054.tif" />

sodium t-butoxide

Ν,Ν-DMF

<img file="IL241554A_D0055.tif" />

octadecyloxyethanol

PyBOP, D1EA, Ν,Ν-DMF

NHMMTr

<img file="IL241554A_D0056.tif" />

<img file="IL241554A_D0057.tif" />

[0199] A mixture of l-(S)-[3-trityloxy-2-hydroxypropyl]- //-monomethoxytritylcytosine [prepared as described in: Beadle, J. R., et al., PCT Int. Appl. WO 2005/087788 A2, published Sept. 22, 2005] (1.84g, 2.63 mmol) and sodium iert-butoxide (1.24g, 3.29mmol) in dry DMF (20 ml) were stirred at room temperature for 30 min. Benzyl ptoluenesulfonyloxymethylphosphonate (0.94g, 2.5 mmol, see Example 6) were added and the mixture was stirred at 80 °C overnight. The solvent was evaporated, and the residue was purified by column chromatography on silica gel to give benzyl 1 -(5)-[3-trityloxy-2(phosphonomethoxy)propyl]- Y-monomethoxytritylcytosine 1.25g (52%). 'HNMR (CDCl₃/methanol-d₄) δ: 7.12-7.48 (m, 24H); 7.05 (d, J=9Hz, IH); 6.79 (d, J=9Hz, IH); 4.70 (dd, Ji=30 Hz, J₂=6Hz, 2H); 4.20-4.30 (m, 2H); 3.78-4.90 (m, IH); 3.77 (s, 3H); 3.50-3.72 (m, 2H), 2.99-3.18 (m, 2H). (El): 883.99 (M+H)⁺, 906.22 (M+Na)⁺.

[0200] To a solution of this intermediate (0.6g, 0,66mmol), (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PYBOP®, 0,52 g, 0.99 mmol), octadecyloxyethanol (0.31 g, 0.52 mmol) in dry DMF (5ml), diisopropylethylamine (D1EA, 0.46ml, 2,65 mmol) was added. The mixture was stirred at room temperature for 30 min and then the solvents were evaporated. The residue was dissolved in ethyl acetate (50 ml), and washed with saturated solution of sodium bicarbonate (2 x 10 ml). Ethyl acetate was

WO 2014/143643

PCT/US2014/027005 evaporated, and the residue was purified by column chromatography on silica gel using CII₂Cl₂/MeOH (0-5%) to give the product, ^lH NMR (CDCL/methanol-d,) 8: 7.18-7.44 (m, 34H); 7.13 (dd, J,=14Hz, J₂=7Hz, 1H); 6.85 (dd, J,=14Hz, J₂=7Hz, 1H); 5.00 (dd, J,=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); 3.453.57 (m, 2H); 3.16-3.22 (m, 1H); 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)⁺.

[0201] 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 by column chromatography to give compound 219 (0.16 g, 64%). ^]H NMR (CDCE/methanol-d^ 8: 7.40-7.42 (m, 5H); 7.38 (dd, J,=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), 3.403.50 (m, 2H); 1.50-1.62 (m, 2H), 1.20-1,40 (m, 30H), 0.89 (t, J=7Hz, 3H). Mass spec (ESI): 666.54 (M+H)⁺, 688.52 (M+Na)⁺.

[0202] Example 9. Preparation of benzyl l-O-octadecyl-2-O-benzyl-sn-glyceryl 1-(5)-(3hydroxy-2-(phosphonomethoxy)propylJcytosine (Cmpd 231, Bn-ODBG (S)-HPMPC).

[0203] To a solution of the intermediate from 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 l-O-octadecyl-2-O-benzyl-.sn-glycerol (0.4Ig, 0.95 mmol) in dry DMF (5ml), di isopropyl ethylamine (DIEA, 0.44ml, 2.52 mmol) was added. The mixture was stirred at room temperature for 30 min. The solvents were evaporated. The residue was dissolved in ethyl acetate (50 ml) and washed with saturated solution of sodium bicarbonate (2x10 ml). Ethyl acetate was evaporated, and the residue was purified by column chromatography on silica gel using CH₂Cl₂/MeOH (0-5%) to give 0.30 g (36%) of the product. ‘l-INMR (CDCh/methanol-d^ 8: 7.19-7.45 (m, 39H); 7.15 (dd, J,=14Hz, J₂=7Hz, 1H); 6.82 (dd, J,=14Hz, J₂=7Hz, 1H); 5.00 (dd, J,=8Hz, J₂=3Hz, 2H); 4.69-4.71 (m, 2H); 4.05 (s, 3FI), 3.96-4.05 (m, 2H); 3.82-3.90 (m, 1H); 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)⁺.

[0204] The protected compound (0.30g, 0.23 mmol) was then treated with 80% acetic acid (20 ml) at 30 °C for 3 h. The solvents were evaporated, and the residue was purified by column chromatography to give compound 231 (0.10g, 55%). ^lH NMR (CDClj/methanol-dz,)

WO 2014/143643

PCT/US2014/027005 δ: 7.31-7.40 (m, 10H); 7.28 (dd, J^UHz, J₂=7Hz, 1H); 5.66 (dd, Jj=14Hz, J₂=7Hz, 1H);

5.07 (dd, Jj=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 spec (ESI): 786.43 (M+H)⁺, 808.41 (M+Na)⁺.

[0205] Example 10. Preparation of phenyl octadecyloxyethyi 9-[2-(phosphonomethoxy) ethyl] guanine (Cmpd 19, Ph-ODE-PMEG):

<img file="IL241554A_D0058.tif" />

ODE-PMEG phenol, PyBOP

DIEA, Ν,Ν-DMF

<img file="IL241554A_D0059.tif" />

[0206] To a solution of octadecyloxyethyi 9-[2-(phosphonomethoxy)ethyl]guanine (ODEPMEG, 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 Ν,Ν-DMF, was added diisopropylethylamine (DIEA, 0.30 ml, 1.8 mmol). The mixture was stirred at room temperature for 30 min, and then the solvent was evaporated in vacuo. The residue was dissolved in ethyl acetate (50 ml) and washed with saturated sodium bicarbonate (2 x 10 ml) solution. The ethyl acetate layer was evaporated, and the crude residue was purified by flash column chromatography on silica gel using CH₂Cl₂/MeOH (0-5%) to afford 0.09 g (31%) of compound 19 as a white powder. 'H NMR (CDClj/tnethanol-cU) δ: 7.66 (s, 1PI); 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, 211); 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)⁺.

[0207] Example 11. Preparation of benzyl octadecyloxyethyi 9-(S)-[3-methoxy-2(phosphonomeihoxy)propyl]adenine (Cmpd 146, Bn-ODE-(S)-MPMPA).

<img file="IL241554A_D0060.tif" />

HsOO' ODEJSJ-MPMPA benzyl alcohol, PyBOP DIEA, Ν,Ν-DMF

<img file="IL241554A_D0061.tif" />

[0208] To a solution of octadecyloxyethyi 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)85

WO 2014/143643

PCT/US2014/027005 tripyrrolidinophosphonium hexafluorophosphate (PYBOP®, 0.78 g, 0.66 mmol), and benzyl alcohol (0.16 ml, 1.50 mmol) in anhydrous Ν,Ν-DMF, was added diisopropylethylamine (DIEA, 0.70 ml, 4.0 mmol). The mixture was stirred at room temperature for 30 min, and then solvents was evaporated in vacuo. The residue was dissolved in ethyl acetate (50 ml) and then washed with saturated NaHCO₃ (2x10 ml). The ethyl acetate layer was evaporated, and the residue was purified by flash column chromatography on silica gel using CH₂Cl₂/MeOH (0-5%) to give 0.29 g (41%) of compound 146. ’ll NMR (CDCl₃/methanol-d₄) δ 8.24 (d, 7=5.50 Hz, 1 H), 8.05 (d, 7=7.33 Hz, 1 H), 7.30 - 7.39 (tn, 5 H), 5.00-5.15 (m, 2H); 4.40-4.45 (m, IH); 4.28-4.36 (m, IH); 4,00-4.18 (m, 3H); 3.80-3.98 (m, 211); 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)⁺.

[0209] Example 12. Preparation of phenyl octadecyloxyethyl 9-(S)-[3-melhoxy-2(phosphonomethoxy)propyl]adenine (Cmpd 164, Ph-ODE-(S)-MPMPA).

nh₂

L O 03 o

V4t^{Hz)2O(CH2)17CH3 N}

HjC-O-'’ ODE-(S)-MPMPA HjC-O- Ph-ODE-(S)-MPMPA [0210] To a solution of octadecyloxy ethyl 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, /9:4616-4625], (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PYBOP®, 0.78 g, 0,66 mmol), and phenol (0.14 g, 1.50 mmol) in dry Ν,Ν-DMF, was added 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 by flash column chromatography on silica gel using CH₂CI₂/MeOH (0-5%) to give 0.29 g (41%&gt;) of compound 164 as an off white solid. 'H NMR (CDCl₃/methanol-d₄) δ 8.23 (d, 7=5.50 Hz, 1 H), 8.05 (d, 7=7.33 Hz, 1 H), 7.29 - 7.37 (m, 2 H), 7.20 (d, 7=6.60 Hz, 1 H), 7.12-7.16 (m, 1 H), 7.08 (dt, 7=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), 1.48 1.59 (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)⁺.

WO 2014/143643

PCT7US2014/027005 [0211] Example 13. Preparation of benzyl hexadecyloxypropyl 9-[2(phosphonomethoxy)ethyl] guanine (Cmpd 25, Bn-HDP-PMEG)

<img file="IL241554A_D0062.tif" />

HDP-PMEG benzyl alcohol, PyBOP

DIEA, Ν,Ν-DMF h₂n

O

HN

<img file="IL241554A_D0063.tif" />

p. r-o(CH2)_so(ch₂)₁₅ch₃

<img file="IL241554A_D0064.tif" />

Bn-HDP-PMEG [0212] 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 benzyl alcohol (0.10 ml, 0.74 mmol) in dry Ν,Ν-DMF, was added diisopropylethylamine (DIEA, 0.35 ml, 2.0 mmol). The mixture was stirred at room temperature for 30 min. The mixture was concentrated under vacuum. The resulting residue was dissolved in ethyl acetate (50 ml) and then washed with saturated sodium bicarbonate (2x10 ml). The ethyl acetate layer was evaporated, and the crude product was purified by flash column chromatography on silica gel using CH₂Cl₂/MeOH (0-5%) to give 0.03 g (10%) of compound 25 as a powdery white solid. ‘H NMR (CDCh/methanol-d*) δ: 7.62 (s, 1 H), 7.30 - 7.44 (m, 5 H), 5.07 (dd, 7=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 (m, 26 H), 0.86 - 0.91 (m, 3 H). MS (El): 662,46 (M+H)⁺, 684.46 (Ml-Na)'.

[0213] Example 14. Preparation of benzyl octadecyloxyethyl 9-(R)-[2(phosphonomethoxy)propyl] adenine (Cmpd 74, Bn-ODE-(R)-PMPA) nh₂ p ΐ O kjA-N 9 benzyl alcohol. PyBOP 'N N q p__n(Pu \ «ΓΗ 1..ΓΗ.

DIEA, Ν,Ν-DMF &lt;5η₃^0H CH_a \—¢ )) Bn-ODE-(R)-PMPA

ODE-[R)-PMPA [0214] To a solution of octadecyloxyethyl 9-[2-(phosphonomethoxy)propyl]aden ine (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], (benzotriazo 1-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PYBOP®, 0.40 g, 0.77 mmol), and benzyl alcohol (0.08 ml, 0.77 mmol) in dry Ν,Ν-DMF, was added diisopropyiethylamine (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 resulting residue was dissolved in ethyl acetate (50 ml) and washed with saturated NaHCO₃ (2x10 ml). The ethyl acetate layer was

WO 2014/143643

PCT/US2014/027005 evaporated, and the crude product was purified by flash column chromatography on silica gel using CH₂Cl₂/MeOH (0-5%) to give 0.24 g (70%) of compound 74. ^rH NMR (400 MHz, CDCij+methanol-du}) δ ppm 8.24 (s, 1 H), 8.03 (d, 7=4.40 Hz, 1 H), 7.30 - 7.42 (rn, 5 H), 4.99 - 5.14 (m, 2 H), 4.35 (d, 7=14.66 Hz, 1 H), 4.07 - 4.20 (m, 3 H), 3.92 (ddd, 7=13.75, 8.98, 4.77 Hz, 2 H), 3.65 - 3,73 (m, 1 H), 3.50 - 3.61 (tn, 2 H), 3.38 - 3.47 (m, 2 H), 1.49-1.61 (m, 2 H), 1.27 (m, 30 H), 1.21 (d, 7=6.23 Hz, 3 H), 0. 09 (t, 7=8.00 Hz,3 H). MS (El): 674.48 (M+H)⁺, 693.46 (M+Na)⁺.

[0215] Example 15. Preparation of phenyl octadecyloxyethyl 9-(R)-f2(phosphonomethoxy)propyl]adenine (Cmpd 94, Ph-ODE-(R)-PMPA)

<img file="IL241554A_D0065.tif" />

NH,

N n °

I ° ,6 OiCH₂)₂C;CH₂).₇C-h ₄ OH ^CH3 ODE-(R)-PMPA phenol, PyBOP

CHEA, Ν,Ν-DMF

<img file="IL241554A_D0066.tif" />

Ph-ODE.(R)PMPA ch₃

<img file="IL241554A_D0067.tif" />

[0216] To a solution of octadecyloxyethyl 9-[2-(phosphonomcthoxy)propyl]adenine (ODE PMPA, 0.30 g, 0.51 mmol) [prepared as described in: Painter, G et al. Antimicrobial Agents and Chemotherapy, 2007, 57:3505-3509], (benzotriazol-l-yloxy)-tripyrrolidinophosphomum hexafluorophosphate (PYBOP®, 0.40 g, 0.77 mmol), and phenol (0.072 g, 0.77 mmol) in dry Ν,Ν-DMF, was added di isopropylethylamine (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 (2x10 ml). The ethyl acetate layer was evaporated, and then the crude product was purified by column chromatography on silica gel using CH₂Cl₂/MeOH (0-5%) to afford 0.25 g (75%) of compound 94. ‘HNMR (400 MHz, CDC1₃ + methanol-d&lt;) 5 ppm 8.24 (d, 7=3.30 Hz, 1 H), 8.05 (d, 7=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, 7=1.47 Hz, 1 H), 4.04 - 4.31 (m, 4 H), 3.94 - 4.03 (m, 1 H), 3.86 (dd, 7=9.53, 1.10 Hz, 1 H), 3,60 (d, 7=4.03 Hz, 2H), 3.38- 3.47 1.48 - 1.60 (m,2H),

1.21 - 1.35 (m, 33 H), 0.89 (t, 7=8.00 Hz, 3 H). MS (El): 660.47 (M+H)⁺, 682.41 (M+Na)⁺,

WO 2014/143643

PCT/US2014/027005 [0217] Example 16. Preparation of benzyl octadecyloxyelhyl 9-(R)-[2(phosphonomethoxy)propyl] guanine (Cmpd 73, Bn-ODE-(R)-PMPG) o

X*X&gt; s h₂n n N I ^_0(CHz)₂0(CH₂)₁₇CH₃

CHj \—Z \ BnOOE-(R)-PMPG

O hⁿ^Vⁿ^ ,-. θ banzyl alcohol, PyBOP ^H:'^{N n}_DIEAN&gt;DMF L OH ch₃

ODE-(R)-PMPG [0218] To a solution of octadccyloxyethyl 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-l-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PYBOP®, 312 mg, 0.6 mmol), and benzyl alcohol (97 mg, 0,9 mmol) in dry Ν,Ν-DMF (30 ml), was added diisopropylethylamine (DIEA, 77 mg, 0.6 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 by column chromatography on silica gel using CH₂Cl₂/MeOH (0-5%) to afford 60 mg (29%) of compound 73. ^!H NMR (400 MHz, CDC13+methanol-d₄) δ ppm 7.82 (d, 7=5.50 Hz, 1 H), 7.75 (d, 7=7.33 Hz, 1 H), 7.43 7.53 (m,2H), 7.33 -7.43 (m, 3 H), 5.01 - 5.17 (m, 1 H), 4.07- 4.18 (m, 2 H), 3.82 -4.03 (m, 2 H), 3,69 - 3.81 (m, 1 H), 3.51 -3.64 (m, 1 H), 3.44 (d, 7=7.70 Hz, 1 H), 3.36 (dt, 7=3.30, 1.65 Hz, 3 H), 1.54 (m, 2H), 1.21-1.35 (m, 30 H), 1.18 (dd, 7=6.23, 2.57 Hz, 3 H), 0.88 (t, 7=8.00 Hz, 3 H). MS (El): 690.49 (M+H)⁺, 712.48 (M+Na)⁺.

[0219] Example 17. Preparation of benzyl octadecyloxyethyl (S)-9-[3-fluoro-2(phosphonomethoxy)propyl]guanine (Cmpd 289, Bn ODE-(S)-FPMPG) o

ηΑλ ο

HjN^N N /^ov^^{O(CH2)2O(CHi)l7CHa}OH ^F ODE-(S)-FPMPG [0220] 9-(S)-[3-Fluoro-2-(phosphonomethoxy)propyl]guanine [(S)-FPMPG, 0.32 g, 1.05 mmol) [prepared as described in: Jindfich, J. etal., Colled. Czech. Chem. Commun., 1993, 58:1645-1667], was esterified with octadecyloxyethanol (0.33 g, 1.05 mmol) using N,Ndicyclohexylcarbodiimide (DCC, 0.43 g, 2.1 mmol) in dry Ν,Ν-DMF (25 ml) at 50 °C overnight. Octadecyloxy ethyl (S)-9-[3-fluoro-2-(phosphonomethoxy)propyl]guanine (ODE(S)-FPMPG) was isolated by column chromatography to give 0.11 g (17%) of the benzyl alcohol, PyBOP

DIEA, Ν,Ν-DMF

Ο ° P^O(CH_z)₂O(CH_z)₁₇CH₃_/=,

F~ \—Z i Bn.ODE-(S)-FPMPG

WO 2014/143643

PCT/US2014/027005 product, 'H NMR (CDCl₃/methanol-d₄), δ 8.18 (s, 1H); 4.50-4.75 (m, 2H); 4.43-4.49 (m,

1H); 4.07-4.16 (m, 1H); 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, 1H); 1.52-1.60 (m, 2H); 1.20-1.34 (m, 30H); 0.88 (t, J=7Hz, 3H). MS (El): 600.30 (M-H)'.

[0221] A stirred mixture of ODE-(S)-FPMPG (0.11 g, 0.18 mmol), benzyl alcohol (0.06 ml, 0.54 mmol) and (benzotriazol-1-yloxy)-tripyrrolidinophosphonium hexafluorophosphate (PYBOP®, 0.28 g, 0.54 mmol) in dry DMF 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 ethyl acetate (50 ml), and washed with saturated sodium bicarbonate solution (2 x 10 ml). The ethyl acetate layer was evaporated, and then the crude product was purified by column chromatography on silica gel using CH₂Cl₂/MeOH (05%) to afford 90 mg (71%) of compound 289. ’HNMR (400 MHz, CDCl₃+mcthanol-d₄) δ ppm 7.77 (s, 1 H), 7.46 - 7.54 (m, 2 H), 7.34 - 7.42 (m, 3 Η), 5.04 - 5.17 (m, 1 H), 4.42 - 4.52 (m, 2 H), 4.19 - 4.38 (m, 2 H), 4.09 - 4.19 (m, 2 H), 3.88 - 4.06 (m, 2 H), 3.64 - 3.73 (m, 1 H), 3.55 - 3.64 (m, 1 H), 3.41 - 3.50 (m, 1 H), 3.18 (d, 7=7.33 Hz, 1 H), 1.49-1.60 (m, 2 H), 1.21 - 1.35 (m, 30 H), 0.88 (t, J=7Hz, 3H). MS (El): 708.50 (M-H)', 730.52 (M+Na)⁺.

[0222] Example 18. Preparation of naphthyl octadecyloxyethyl 9-(S)-[3-methoxy-2(phosphonomethoxy)propyl]adenine (Cmpd 398, Npl-ODE-(S)-MPMPA)

NH, NH₂

Ϊ lT

1-naphthot, PyBOP

DiEA, N.N-DMF : OH

HjC-O'' ODE-(S)-MPMPA [0223] To a solution of octadecyloxyethyl 9-[3-methoxy-2-(phosphonomethoxy) propyl]adenine (ODE ΜΡΜΡΑ, 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 1naphthol (0.11 g, 0.73 mmol) in dry Ν,Ν-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 washed with saturated sodium bicarbonate (2x10 ml). The ethyl acetate layer was evaporated, and then the crude product was purified by column chromatography on silica gel using CH₂Cl₂/MeOH (0-5%) to yield 0.20 g (56%) of compound 398 as an off white solid. ^lH / 0 ^N 1/^O_vY0(CH_z)₂0(CH₂)₁₇CH₃

O

H₃C-O Npt-ODE-|S).MPMPA

WO 2014/143643

PCT/US2014/027005

NMR (400 MHz, CDCfi + methanol-d₄) 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 (t, ,7=4,58 Hz, 1 H), 3.47 - 3.56 (m, 2 H), 3.30 - 3.45 (m, 5 H), 1.49 (d, &gt;6.60 Hz, 2 H), 1.19

- 1.34 (m, 30 H), 0.85 - 0.93 (t, J=7Hz, 3H). MS (El): 740.54 (M+H)⁺, 762.52 (M+Na)⁺.

[0224] Example 19. Preparation of naphthyl oetadecyloxyethyl 9-[2-(phosphonomethoxy) ethyl]guanine (Cmpd 361, Npt-ODE~PMEG) q

' ^M I o P^O(CH₂)₂O(CH₂)₁₇CH₃OH

ODE-PMEG

1-naphthol, PyBOP

DIEA, Ν,Ν-DMF

O

A*J0 «

H₂N N ΰ-_Ο(0Η_;)2Ο(Ο_Η2)₁₇ΟΗ₃ °·» ][ ] Npt-ODE-PMEG [0225] To a solution of oetadecyloxyethyl 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 Ν,Ν-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 by flash column chromatography on silica gel using CH/ClVMeOH (0-5%) to give 0.23 g (65%) of compound 361. 'fl NMR (CDCI₃/methanol-d₄) δ: ’ll NMR (400 MHz, CDCl₃+methanol-d₄) δ ppm 8,07 - 8.12 (m, 1 H), 7.87 (dd, &gt;5.87, 3.30 Hz, 1 H), 7,71 (d, &gt;5.87 Hz, 1 H), 7.59 (d, &gt;4.40 Hz, 1 H), 7.52 - 7.56 (m, 1 H), 7.39 - 7.43 (m, 1 H), 4.30 (ddd, &gt;8.62, 5.68, 3.30 Hz, 2 H), 4.16-4.21 (m, 2H), 4.14 (d, &gt;8.07 Hz, 2 H), 3.64 - 3.72 (m, 2 H), 3.56 - 3.61 (m, 1 H), 3.38 (d, &gt;4.77 Hz, 1 H), 3.19 (q, &gt;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)⁺.

WO 2014/143643

PCT/US2014/027005 [0226] Example 20. Preparation of benzyl octadecyioxyethyl 9-(S)-[3-hydroxy-2(phosphonomethoxy)propyl]uracil (Cmpd 221, Bn-ODE-(S)-HPMPU).

<img file="IL241554A_D0068.tif" />

1. octadecytoxyethariDl. PyBOP.DIEA, Ν,Ν-DMF

2, 80% aq CH3COOH. 5D C

HN

HO

<img file="IL241554A_D0069.tif" />

Bn-ODE-(S)-HPMPU [0227] To a solution of benzyl 9-[3-trityloxy-2-(phosphonomethoxy)propyl]-4-methoxyuracil (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 Ν,Ν-DMF was added diisopropylethylamine (D1EA, 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 by flash column chromatography on silica gel using CH₂Cl₂/MeOH (0-5%) to give 0.024 g (17%) of benzyl octadecyioxyethyl 9-[3-trityloxy-2(phosphonomethoxy)propyl]-4-methoxyuracil 'H NMR (400 MHz, CDCb+meihanol) δ ppm

7.56 (d, 7=5.50 Hz, 1 H), 7.16 - 7.51 (m, 15 H), 5.46 (d, 7=5.50 Hz, 1 H), 5.10 (d, 7=8.80 Hz, 2 H), 4.03 - 4.21 (m, 2 H), 3.86 - 3.99 (m, 1 H), 3.65 - 3.85 (m, 2 H), 3.37 - 3.60 (m, 4 H), 3.25 (s, 3 H), 3.12 (m, 1 H), 1.42-1.62 (m, 2 II), 1.-5-1.38 (m, 30 H), 0.88 (t, 7=6.97 Hz, 3 H). MS (El): 945.66 (M+Na)⁺' [0228] The protected intermediate was then stirred in 80% aq acetic acid overnight at 50 °C. The solvent was then evaporated under vacuum, and the residue was purified by flash column chromatography to give O.Olg (59%) of compound 221. MS (El): 667.54 (M+H)⁺,

689.56 (M+Na)⁺.

[0229] Example 21. Preparation of ethyl octadecyioxyethyl 9-(S)-[3-methoxy-2(phosphonomethoxy)propyl] adenine (Cmpd 182, Et-ODE-(S)-MPMPA).

nh₂ mvAL-N t I &gt; o ^N L A/-°(CHj)_zO(CH2)₁₇CH3 ; ^V OH

HaC-O'' ODE-(S)-MPMPA elhanol, PyBOP

DIEA, Ν,Ν-DMF

<img file="IL241554A_D0070.tif" />

H₃C-0

Et-ODE-(S)-MPMPA

WO 2014/143643

PCT/US2014/027005 [0230] 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-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate, (PYBOP®, 0.38 g, 0.73 mmol), in ethanol (25 ml), was added diisopropylethylamine (DIEA, 0.35 ml, 2.0 mmol). The mixture was stirred at room temperature overnight. The solvent was then evaporated under vacuum. The residue was dissolved in ethyl acetate (50 ml), and then washed with saturated sodium bicarbonate (2x10 ml). Ethyl acetate was evaporated, and the residue was purified by flash column chromatography on silica gel using CHbCh/MeOH (0-5%) to give 0.26 g (84%) of compound 182 as a white solid. 'H NMR (400 MEIz, CDCl₃+methanol-d₄) δ ppm 8.26 (s, 1 H), 8.08 (d, /=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), 4.284.35 (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 El), 3.40 (s, 3 H), 1.56 (m, 2 H), 1.19 - 1.37 (m, 33 H), 0.89 (t, /=7.20 Hz, 3 H). MS (El): 642.69 (M+H)⁺, 664.61 (M+Na)⁺, [0231] Example 22. Preparation of benzyl octadccyloxyethyl 9-[3-methoxy-2(phosphonomethoxy)propyl]-2,6-diammopurim (Cmpd 150, Bn-ODE(S)-MPMPDAP).

NH?

<img file="IL241554A_D0071.tif" />

H₃C-O- ODE-(S)-MPMPDAP benzyl alcohol PyBOP

DiEA, N.N DMF

H₂N

<img file="IL241554A_D0072.tif" />

O

O F&gt;-O(CH₂)₂O(CH₂)₁₇CH₃

<img file="IL241554A_D0073.tif" />

Bn-ODE-(S)-WIPMPDAP [0232] To a solution of octadecyl oxyethyl 9-(S)-[3-methoxy-2-(phosphonomethoxy) propyl]-2,6-diaminopurine (ODE-(S)-MPMP DAP, 0.20 g, 0.32 mmol) [prepared as described in: Valiaeva, N. et al. Bioorganic &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 Ν,Ν-DMF, was added diisopropylethylamine (DIEA, 0.07 ml, 0.40 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 (2x10 ml). The ethyl acetate layer was evaporated, and then the residue was purified by flash column chromatography on silica gel using CHjCb/MeOH (0-5%) to give 0,12 g (54%) of compound 150. ^!H NMR (400 MHz, CDCl₃+methanol-d₄) 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, /=3,67 Hz, 1 H), 3.99

WO 2014/143643

PCT/US2014/027005

-4.15 (m, 3 H), 3.84 - 3.92 (m, 2 H), 3.39 - 3.56 (tn, 5 H), 3.36 (s, 3 H), 1.49 - 1.58 (tn, 2 H),

1.17-1.35 (tn, 30 H), 0.89 (t, J-6.6 Hz, 3 H). MS (El): 719.62 (M+H)⁺, 741.56 (M+Na)⁺.

[0233] Example 23. Antiproliferative activity of nucleoside phosphonates diesters in normal human fibroblasts and in human cervical cancer lines in vitro.

[0234] Method. Compounds at a range of concentrations were incubated with normal fibroblasts or human cervical cancer cell lines in monolayer culture and after 4 days, viable cell number was determined by neutral red reduction as previously described (Valiaeva N, et al., Chemotherapy, 2010, 56(1):54-9). Cell lines were obtained from American Type Culture Collection. The results were plotted and the concentration which reduced neutral red levels by 50% (CC50) was determined in triplicate. Although viral replication is no longer occurring in the human cervical cancer cell lines, Caski cells were transformed by HPV-16 and Hela cells were transformed by HPV-18.

[0235] Results. As tabulated in Table 11 following, these results demonstrate that compounds described herein were 23.6 fold (e.g., Cmpd 219) to 3,750 fold (e.g., Cmpd 1) more effective in reducing viable cell number in the cervical cancer lines than in normal, nontransformed human fibroblasts.

Table 11. Antiproliferative activity of nucleoside 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> Norma! human fibroblasts (HFF)</td><td> Caski (HPV-16)</td><td> HeJa (HPV-18)</td>

<td> 219</td><td> 52</td><td> 2.0 1</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>

[0236] Example 24. Antiproliferative activity of compounds on human T cell leukemia cells (MT-2).

[0237] Method of cytotoxicity determination. MT-2 cells were incubated with drug for 72 hrs and harvested. Flow count beads (Beckman Coulter, Miami, FL) were added to the cell suspension followed by propidium iodide staining and analysis using flow cytometer and the 25 50% cytotoxic concentration (CC50) was calculated from the cell counts and viability.

WO 2014/143643

PCT/US2014/027005 [0238] Results. Compounds disclosed herein are effective antiproliferative agents in human T cell leukemia (MT-2) cells (Table 12).

Table 12,Antiproliferative activity in human MT-2 leukemic cells in vitro

<td> Compound #</td><td> CC50, 50% Cytotoxic concentration μΜΜΤ2 cells T cell leukemia</td>

<td> 1</td><td> 0.036 ±0.04</td>

<td> la</td><td> &lt;0.01</td>

<td> lb</td><td> &lt;0.01</td>

<td> 2</td><td> &lt;0.010</td>

[0239] Example 25. Anti-HIVactivity.

[0240] Method HIV antiviral assays. MT-2 cells were maintained in RPMI 1640 supplemented with 10% FBS, 10 mM HEPES buffer, 50 IU of pcniciliin/ml, and 50 pg of streptomycin/mi. The antiviral activity of each compound was determined by inoculating MT-2 cells with HIV-Ilm at a multiplicity of infection (MOI) of 0.001 TCID₅₀/cell, followed by incubation in the presence of threefold serial drug dilutions (three wells per dilution), Four days after infection, culture supernatants were harvested, lysed with 0,5% Triton X-100, and assayed for p24 antigen concentration using a commercial ELISA assay (Perkin Elmer Life Sciences, Boston, MA). The antiviral activity of each compound is expressed as the EC₅₀, which is the concentration required to inhibit p24 antigen production by 50%.

[0241] Method cytotoxicity determination. MT-2 cells were incubated with drug for 72 hrs and harvested. Flow count beads (Beckman Coulter, Miami, FL) were added to the cell suspension followed by propidium iodide staining and analysis using flow cytometer and the 50% cytotoxic concentration (CC50) was calculated from the cell counts and viability.

[0242] Results. Table 13 shows that compounds disclosed herein have considerable antiviral activity against HIV-1 and exhibit 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> EC50, μΜ</td><td> CC50, μΜ</td><td> Selectivity Index</td>

<td> 1</td><td> &lt;lxl0’⁵</td><td> 0.036 ±0.04</td><td> &gt;3600</td>

<td> 2</td><td> &lt;1x1 O'⁵</td><td> &lt;lxl0‘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>

WO 2014/143643

PCT/US2014/027005

<td></td><td colspan="3"> HIV ANTIVIRAL ACTIVITY IN MT-2 CELLS</td>

<td> Compound #</td><td> ECso, μΜ</td><td> CC₅₀, μΜ</td><td> Selectivity Index</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"> EC_S0, effective dose 50%; CC_sn, cytotoxic dose 50%, selectivity index CC_so/EC_So· Assay: p24 reduction.</td>

[0243] Example 26. Antiviral Effect of ANP diesters in HFF cells infected with HSV-2.

[0244] Method. Primary low passage human foreskin fibroblast (HFF) cells in 96-well plates were infected at an MOI of 0.01 PFU/cell with the G strain of herpes simplex virus type 2 and incubated for 3 days. Media was then aspirated and cell monolayers were stained with crystal violet and rinsed with distilled water. Crystal violet associated with the cells was then quantified in a spectrophotometer and the concentration of the compound that was sufficient to reduce virus replication by 50% (ECso) was calculated. Cytotoxicity was measured in parallel by similar methods to yield the concentration that reduced cell number 10 by 50% (CC₅₀).

[0245] Results. Results are tabulated in Table 14 following.

Table 14. Antiviral Effect of ANP diesters in HFF cells infected with HSV-2

<td> Compound #</td><td> ECjo, μΜ</td><td> CC₅₀, 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>

[0246] Example 27. Effect of oral Octadecyloxyethyl-benzyl-(ODE~bn~) acyclic nucleoside 15 phosphonate diesters and ODE-monoesters of acyclic nucleoside phosphonates on body weight in Balb-c Mice.

[0247] Method. Compounds were administered at the indicated doses by oral gavage daily for 5 days. Weights measured before and on day 6 after 5 doses.

WO 2014/143643

PCT/US2014/027005 [0248] Results. As tabulated in Table 15 following, these results demonstrate that ODEmonoesters of Cidofovir (CDV) and PMEG lost 14.7% and 19.1% of body weight, respectively, which was highly statistically significant versus day zero (p - 0.0007 and pO.OOl). However, oral ODE-benzyl diesters of the CDV and PMEG nucleoside phosphonates exhibited no statistically significant effects (“ns”) on body weight compared with the unmodified compounds.

Table 15. Effect of oral Octadecyloxyethyl-benzyl-(ODE-bn-) acyclic phosphonatc diesters and Octadecyloxyethyl-monoesters of acyclic nucleoside phosphonates on body weight in 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> 19.88+0.55 (6)</td><td> 16.96il.38 (6)</td><td> 0.0007</td>

<td> ODE-bn-CDV (Cmpd 219)</td><td> 20 mg/kg/day</td><td> 19.03+1.16(6)</td><td> 19.27+1.32 (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> 19.17+0.581 (3)</td><td> 15.5+0.514 (3)</td><td> &lt;0.001</td>

<td> ODE-bn-PMEG (Cmpd 1)</td><td> 4 mg/kg/day</td><td> 18.63i0.728 (3)</td><td> 18.42+1.00 (3)</td><td> ns</td>

[0249] Example 28. Antiviral Effect of ANP diesters in cells infected with human cytomegalovirus (ADI 69).

[0250] Method. Primary low passage human foreskin fibroblast (HFF) cells in 96-well plates were infected at an MOI of 0.01 PFU/cell with the AD169 strain of human cytomegalovirus and incubated for 14 days. Media was then aspirated and cell monolayers were stained with crystal violet and rinsed with distilled water. Crystal violet associated with the cells was then quantified in 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 yield the concentration that reduced cell number by 50% (CC50).

[0251] Results. Results are tabulated in Table 16 following.

WO 2014/143643

PCT/US2014/027005

Table 16. Antiviral Effect of ANP diesters in cells infected with human cytomegalovirus (AD 169)

<td> Compound #</td><td> EC_Sq, 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>

[0252] Example 29. Antiviral Effect of ANP diesters in cells infected with vaccinia virus (Copenhagen) [0253] Method: Primary low passage human foreskin fibroblast (HFF) cells in 96-well plates were infected at an MOT of 0.01 PFU/cell with the Copenhagen strain of vaccinia virus and incubated for 7 days. Media was then aspirated and cell monolayers were stained with crystal violet and rinsed with distilled water. Crystal violet associated with the cells was then 10 quantified in 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 yield the concentration that reduced cell number by 50% (CC₅₀).

[0254] Results. Results are tabulated in Table 17 following.

Table 17. Antiviral Effect of ANP diesters in cells infected with vaccinia virus (Copenhagen)

<td> Compound #</td><td> EC_SO, μΜ</td><td> CC_SO, 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>

WO 2014/143643

PCT/US2014/027005 [0255] Example 30. Antiviral Effect of ANP diesters in cells infectedBK virus (Gardner strain) [0256] Method: Primary low passage human foreskin fibroblast (HFF) cells in 96-well plates were infected at an MOI of 0.01 PFU/cell and incubated for 14 days. Media was then aspirated and total DNA was isolated and genome copy number was quantified by qPCR using the primers 5^s- AGT GGA TGG GCA GCC TAT GTA-3’ (SEQ ID NO: I), 5’- TCA TAT CTG GGT CCC CTG GA-3’ (SEQ ID NO:2) and probe 5’-6-FAM AGG TAG AAG AGG TTA GGG TGT TTG ATG GCA CAG TAMRA-3’(SEQ ID NOD). In a parallel experiment in uninfected cells cytotoxicity was determined by CELLTITER-GLO® find the concentration that reduced cell number by 50% (CC50).

[0257] Results. Results are tabulated in Table 18 following.

Table 18. Antiviral Effect of ANP dicsters in cells infected BK virus (Gardner strain)

<td> Compound #</td><td> ECjo, μΜ</td><td> CC₅₀, 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>

[0258] Example 31. Antiviral Effect of ANP diesters in HFF cells infected with

HSV-1 (E-377).

[0259] Method. Primary low passage human foreskin fibroblast (HFF) cells in 96-well plates were infected at an MOI of 0.01 PFU/cell with the E377 strain of herpes simplex virus type 1 and incubated for 3 days. Media was then aspirated and cell monolayers were stained with crystal violet and rinsed with distilled water. Crystal violet associated with the cells was then quantified in 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 yield the concentration that reduced cell number by 50% (CC₅₀).

[0260] Results. Results are tabulated in Table 19 following.

WO 2014/143643

PCT/US2014/027005

Table 19. Antiviral Effect of ANP diesters in HFF cells infected with HSV-1 (E-377)

<td> Compound #</td><td> EC50, μΜ</td><td> CC_S0, 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>

[0261] Example 32. Antiviral effect of ANP diesters in HPV-11 infected HEK 293 cells.

[0262] Method. An origin-containing plasmid was co-transfected with HPV-11 El and E2 5 protein expression vectors into HEK 293 ceils. At 4 hr post-transfection, cells were treated with compound dilutions and the cells were incubated for 48 hr. Replication of the virus origin was detected with Dpnl and exonuclease III to remove unreplicated input bacterial plasmid DNA. Remaining replicated DNA was quantified by qPCR. Toxicity was determined by trypan blue exclusion, [0263] Results. Results are tabulated in Table 20 following.

Table 20. Antiviral effect of ANP diesters in HPV-11 infected HEK 293 cells

<td> Compound #</td><td> EC50, μΜ</td><td> CC_S0, μΜ</td><td> Selectivity Index</td>

<td> 1</td><td> 0.49</td><td> &gt;100</td><td> &gt;204</td>

<td> la</td><td> [1.06, EC₉oJ</td><td> -</td><td></td>

<td> lb</td><td> [1.16, EC₉₀]</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>

** EC₉o is the concentration required to reduce viral replication by 90%.

[0264] Example 33. Antiviral effect of ANP diesters in HPV-16 infectedHEK 293 cells. [0265] Method, An origin-containing plasmid was co-transfected with HPV-16 El and E2 protein expression vectors into HEK 293 cells. At 4 hr post-transfection, cells were treated with compound dilutions and the cells were incubated for 48 hr. Replication of the virus

100

WO 2014/143643

PCT/US2014/027005 origin was detected with Dpnl and exonuclease III to remove unreplicated input bacterial plasmid DNA. Remaining replicated DNA was quantified by qPCR. Toxicity was determined by trypan blue exclusion.

[0266] Results. Results are tabulated in Table 21 following.

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

<td> Compound #</td><td> EC₅o, μΜ</td><td> CC₅₀, 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>

[0267] Example 34. Antiviral effect ofANP diesters in HPV-18 infected primary human keratinocyte rafts.

[0268] Method. Primary human keratinocytes (PHKs) were transfected with an HPV-18 genomic plasmid containing G418 resistance gene which was generated by Cre-loxPmediated excision recombination. After a 4 day selection with G418, the surviving cells were cultured for 2-3 day and used to develop into raft cultures where the PHK cells stratify and differentiate into a squamous epithelium in 10 or more days. HPV-18 viral DNA usually amplifies between 10-14 days after the raft cultures are lifted to the air-medium interface. Efficacy and toxicity ofthe test compounds were determined at three concentrations added to the media from day 6 or 8 until day 14. Medium is changed every other day. Prior to harvest, BrdU is added to the medium at 100 pg/ml to document host cell DNA replication. One set of raft cultures (with or without test compounds) is harvested for quantitative real time PCR (qPCR) to determine the copy number of HPV-18 DNA /cell. Another set of the raft cultures are fixed in formalin, embedded in paraffin and toxicity is determined by histology. Additional sections are subjected to in situ hybridization to localize viral DNA amplification and BrdU incorporation which denotes host DNA replication in basal and suprabasal strata.

[0269] Results. Results are tabulated in Table 22 following.

101

WO 2014/143643

PCT/US2014/027005

Table 22. Antiviral effect of ANP diesters in HPV-18 infected primary human keratinocyte rafts

<td> Compound #</td><td> EC₅o, 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>

[0270] Example 35. Antiviral effect of ANP diesters in JC virus (MAD-1) infected COS7 cells.

[0271] Method. COS7 cells in 96-well plates were infected at an MOI of 0.01 PFU/cell with the MAD-1 strain of JC virus and incubated for 7 days. Media was then aspirated and total DNA was isolated and genome copy number was quantified by qPCR using primers 5’-CTG GTC ATG TGG ATG CTG TCA-3’ (SEQ ID NO:4) and 5’-GCC AGC AGG CTG

TTG ATA CTG-3’ (SEQ ID NO:5) and probe 5’-6-FAM-CCC TTT GTT TGG CTG CTTAMRA-3 (SEQ ID NO:6) together with the plasmid pMP508 to provide a standard curve for quantitation. In a parallel experiment in uninfected cells, cytotoxicity was determined by CELLTITER-GLO® to find the concentration that reduced cell number by 50% (CC₅₃).

[0272] Results. Results are tabulated in Table 23 following.

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

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

[0273] Example 36. Antiviral effect of ANP diesiers in HIV-1 WUS727 infected human peripheral blood monocytes.

[0274] Method. Human peripheral blood monocyte (PBMC) based anti-HIV assays were 20 performed as previously described (K.M. Watson, et al., 2008, Antimicrob Agents

102

WO 2014/143643

PCT/US2014/027005

Chemother. 52:2787), Briefly, PHA-stimulated PBMCs cultured in the presence of IL-2 were suspended at 1 x 10⁶ cells/mL and were added to a 96-wel! round-bottom plate. Serially diluted test materials were added to the plate in triplicate followed by the appropriate pretitered strain of HIV. The culture was incubated for 7 days at 37 °C/5% CO₂. Following the incubation, supernatants were collected for analysis of virus replication by supernatant reverse transcriptase activity and cells analyzed for viability by tetrazolium dye XTT reduction (2,3-bis(2-methoxy-4-nitro-5-sulfophenyl)-5-[(phenylamino)carbonyl]-2Htetrazolium hydroxide). All the assays were carried out in triplicate. Microsoft Excel 2007 was used to analyze and graph data, The percent reduction in virus replication compared to 10 the untreated virus controls was calculated for each compound. The percent cell control value was calculated for each compound comparing the drug treated uninfected cells to the uninfected cells in medium alone.

[0275] Results. Results are tabulated in Table 24 following.

Table 24. Antiviral effect of ANP diesters in HIV-I92US727 infected human peripheral blood monocytes

<td> Compound #</td><td> EC_5n, μΜ I</td><td> CC₅₀, 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> 113______</td><td> &gt;2260</td>

103

WO 2014/143643

PCT/US2U14/027005 [0276] Example 37. Antiviral effect of ANP diesters on hepatitis B virus replication in

2.2.15 cells in vitro.

[0277] Method. HBV antiviral assays (Korba &amp; Gerin, Antivir. Res., 1992, 19:55 and Iyer, et al., Aniivir Agents Chem Chemother., 2004, 48:2199) are conducted using confluent cultures of 2.2.15 cells (genotype ayw; parental cel! HepG2) maintained on 96-well flatbottomed tissue culture plates. Confluence in this culture system is required for active, high levels of HBV replication 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. HBV DNA levels in the culture medium (representing HBV virion production) are assessed by quantitative blot hybridization 24 hrs. after the last treatment. Cytotoxicity is assessed (A_5]0) by uptake of neutral red dye 24 hr. following the last treatment. Lamivudine (LMV) is used as the standard assay control. ECso, EC₉o and CC_i(:, values are calculated by linear regression analysis (MS EXCEL®, QUATTROPRO®) using data combined from all treated cultures (Korba &amp; Gerin, 1992, Id.; Okuse, et al., Antivir. Res., 2005, 65:23). Standard deviations for EC₅₀ and EC90 values are calculated from the standard errors generated by the regression analyses. EC₅o and EC₉₀ are drug concentrations at which a 2-fold, or a 10-fold depression of HBV DNA (relative to the average levels in untreated cultures), respectively, is observed. CC₅₀ is the drug concentration at which a 2fold lower level of neutral red dye uptake (relative to the average levels in untreated cultures) is observed.

[0278] Results. Results are tabulated in Table 25 following.

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

<td> Compound #</td><td> EC50, 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>

104

WO 2014/143643

PCT/BS2014/027005

<td> Compound #</td><td> EC₅o, μΜ</td><td> CC_S0, μΜ</td><td> Selectivity Index</td>

<td> 73</td><td> 34</td><td> 63</td><td> 1.9</td>

VII. Embodiments [0279] A first set of embodiments P1-P7 follows, [0280] Embodiment Pl, A compound with structure of Formula (I):

<img file="IL241554A_D0074.tif" />

X (I) or stereoisomer, salt, hydrate, solvate, or crystalline form thereof, wherein B_Nuc is a naturally occurring purine or pyrimidine base, or analog thereof; L is a lipophilic promoiety, substituted or unsubstituted alkyl, substituted or unsubstituted heteroaikyl, or O-substituted glyceryl having the formula -CH₂CH(OR^l)-CH₂(OR²) (II), wherein R¹ and R² are independently substituted or unsubstituted alkyl, or substituted or unsubstituted aryl; R is substituted or unsubstituted lower alkyl, substituted or unsubstituted lower heteroaikyl, substituted or unsubstituted lower cycloalkyl, substituted or unsubstituted lower heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted lower heteroaryl; and X is hydrogen, substituted or unsubstituted lower alkyl, or substituted or unsubstituted lower heteroaikyl.

[0281] Embodiment P2. A method of treating a viral disease in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of embodiment Pl, [0282] Embodiment P3. A method for treating cancer in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of embodiment Pl.

[0283] Embodiment P4. A method of killing or inhibiting the growth of a transformed cell, comprising contacting a transformed cell with a therapeutically effective amount of a compound of embodiment Pl.

105

WO 2014/143643

PCT/US2014/027005 [0284] Embodiment P5. A method for treating a proliferative disorder in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of embodiment Pl.

[0285] Embodiment P6. A pharmaceutical composition comprising a compound according to embodiment Pl, and pharmaceutically acceptable excipient, [0286] Embodiment P7. A method for synthesis of a compound with structure of

Formula (I) according to Scheme 2:

Scheme 2

<img file="IL241554A_D0075.tif" />

<img file="IL241554A_D0076.tif" />

wherein Bn_Uc is a naturally occurring purine or pyrimidine base, or analog thereof; L is a lipophilic promoiety, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, or O-substituted glyceryl having the formula -CH₂CH(OR¹)-CH2(OR²) (II), wherein R¹ and R² are independently substituted or unsubstituted alkyl, or substituted or unsubstituted aryl; R is substituted or unsubstituted lower alkyl, substituted or unsubstituted lower heteroalkyl, substituted or unsubstituted lower cycloalkyl, substituted or unsubstituted lower heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted lower heteroaryl; and X is hydrogen, substituted or unsubstituted lower alkyl, or substituted or unsubstituted lower heteroalkyl; and Y is a leaving group; the method including: 1) contacting a protected nucleoside BNuc with structure of Formula (2-1) with an ester with structure of Formula (2-2) in the presence of a strong base under conditions suitable to afford a monoester with structure of Formula (2-3); and 2) reacting said monoester with structure of Formula (2-3) with L-OH in the presence of a coupling agent, thereby synthesizing a compound with structure of Formula (I).

[0287] Further embodiments include the following.

106

WO 2014/143643

PCT/US2014/027005 [0288] Embodiment 1. A compound of Formula (la), or a pharmaceutically acceptable

<img file="IL241554A_D0077.tif" />

salt, hydrate, solvate or crystalline form thereof: X^a (la) wherein:

B_Nuc(a) is a naturally occurring purine, a naturally occurring pyrimidine, a non-naturally occurring purine or a non-naturally occurring pyrimidine; L^a is an unsubstituted C12-24 alkyl, an unsubstituted Ci3.29 heteroalkyl or a substituted glyceryl moiety, wherein the glyceryl moiety is substituted with one or more groups selected from an unsubstituted C13-29 alkyl, an unsubstituted C13-29 heteroalkyl, a substituted or unsubstituted aryl(Ci_6 alkyl), a substituted or unsubstituted heteroaryl(Ci_6 alkyl) and a substituted or unsubstituted heterocycloalkyl(Ci_ 6 alkyl); Rⁿ 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(Cl.₆ alkyl), a substituted or unsubstituted heteroaryl(Ci_₆ alkyl) and a substituted or unsubstituted heterocycloalkyl(C_w alkyl); and X^ais hydrogen, an unsubstituted Ci__s alkyl, a halogen substituted Ci_₆ alkyl, a hydroxy substituted Ci_e alkyl or an unsubstituted C|.6 alkoxy.

[0289] Embodiment 2.

[0290] Embodiments.

[0291] Embodiment 4.

[0292] Embodiments.

substituted Cp&amp; alkyl.

[0293] Embodiment 6.

[0294] Embodiment 7.

[0295] Embodiments,

The compound of embodiment 1 wherein X^a is hydrogen.

The compound of embodiment 1 wherein X^a is methyl.

The compound of embodiment 1, wherein X^d is methoxy.

The compound of embodiment 1, wherein X^a is a fluoro

The compound of embodiment 5, wherein X^a is a CH₂F.

The compound of embodiment 1, wherein X^a is a CH₂OH,

The compound of any one of embodiments 1-7, wherein L^a is an unsubstituted C 13.29 heteroalkyl.

[0296] Embodiment 9. (CH₂)i_6-O-(CH₂)i 1-21-CH3.

[0297] Embodiment 10, (CH₂)₂-O-(CH₂)i7-CH₃.

The compound of embodiment 8, wherein L^a has the structure The compound of embodiment 9, wherein L^a has the structure

107

WO 2014/143643

PCT/US2014/027005 [0298] Embodiment 11. The compound of embodiment 9, wherein L has the structure (CH₂)₃-O-(CH₂)₁₅-CH₃.

[0299] Embodiment 12. The compound of embodiment 8, wherein L^a has the structure (CH₂)_t._e-O-(CH₂), ₀.₂₀-(CHCH₃)-CH₃.

[0300] Embodiment 13. The compound of any one of embodiments 1-7, wherein L^a is a substituted glyceryl moiety, [0301] Embodiment 14. The compound of embodiment 13, wherein L^a has the structure _(CH2)-CH(0R^al)-(CH2)-O(CH₂)ii-2i-CH3, wherein R^al is a substituted or unsubstituted aryl(C_b6 alkyl), a substituted or unsubstituted heteroaryl(Ci_₆ alkyl) and a substituted or unsubstituted heterocycloalkyl(Ci_₆ alkyl).

Embodiment 15.

The compound of embodiment 14, wherein L^a has the structure [0302]

<img file="IL241554A_D0078.tif" />

O(CH₂)₁₇CH₃

Embodiment 16.

[0303] unsubstituted aryl.

The compound of embodiment 1, wherein R^a is a substituted or

The compound of embodiment 16, wherein the substituted or [0304] Embodiment 17. unsubstituted aryl is a substituted or unsubstituted phenyl.

[0305] Embodiment 18. The compound of embodiment 16, wherein the substituted or unsubstituted aryl is a substituted or unsubstituted naphthyl.

[0306] Embodiment 19. The compound of embodiment 1, wherein R^a is a substituted or unsubstituted aryl(C_b6 alkyl).

[0307] Embodiment 20. The compound of embodiment 19, wherein the substituted or unsubstituted aryl(C_b6 alkyl) is a substituted or unsubstituted benzyl.

[0308] Embodiment 21. The compound of embodiment 1, wherein R^a is a substituted or unsubstituted heterocycloalkyl(C_b6 alkyl).

108

WO 2014/143643

PCT/US2014/027005 [0309] Embodiment 22. The compound of embodiment 21, wherein the substituted or unsubstituted heterocycloalkyl(Ci_6 alkyl) is a substituted or unsubstituted galactosyl.

[0310] Embodiment 23. occurring purine.

[0311] Embodiment 24. occurring pyrimidine.

[0312] Embodiment 25. naturally occurring purine.

The compound of embodiment 1, wherein Bn_Uc(s) is a naturally

The compound of embodiment 1, wherein Β^υφ) is a naturally

The compound of embodiment 1, wherein B_NuC(_a) is a non[0313] Embodiment 26. naturally occurring pyrimidine.

The compound of embodiment 1, wherein Β^φ} is a non|0314] Embodiment 27. The compound of embodiment 1, wherein B_Nuc(a) is selected

<img file="IL241554A_D0079.tif" />

The compound of embodiment 1, wherein the compound has [0315] Embodiment 28.

<img file="IL241554A_D0080.tif" />

[0316] Embodiment 29. The compound of embodiment 1, wherein the compound has the structure: X^a

<img file="IL241554A_D0081.tif" />

109

WO 2014/143643

PCT/US2014/027005 [0317] Embodiment 30.

The compound of embodiment 1, wherein the compound has

<img file="IL241554A_D0082.tif" />

[0318] Embodiment 31. The compound of embodiment 1, wherein the compound is 5 selected from any one of the compounds in Tables 1-10, or a pharmaceutically acceptable salt, hydrate, solvate or crystalline form thereof.

[0319] Embodiment 32. The compound of embodiment 1, wherein the compound is selected from the group consisting of:

<img file="IL241554A_D0083.tif" />

O

<img file="IL241554A_D0084.tif" />

110

WO 2014/143643

PCT/US2014/027005

Ο

<img file="IL241554A_D0085.tif" />

Ο

<img file="IL241554A_D0086.tif" />

<img file="IL241554A_D0087.tif" />

111

WO 2014/143643

PCT/US2014/027005

<img file="IL241554A_D0088.tif" />

<img file="IL241554A_D0089.tif" />

<img file="IL241554A_D0090.tif" />

<img file="IL241554A_D0091.tif" />

Π2

WO 2014/143643

PCT/US2014/027005

<img file="IL241554A_D0092.tif" />

113

WO 2014/143643

PCT/US 2014/0 2 7005

<img file="IL241554A_D0093.tif" />

114

WO 2014/143643

PCT/US2014/027005

<img file="IL241554A_D0094.tif" />

and

Ο

<img file="IL241554A_D0095.tif" />

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

[0320] Embodiment 33. A pharmaceutical composition including an effective amount of a compound of any one of embodiments 1-32, or a pharmaceutically acceptable salt, hydrate, solvate or crystalline form thereof, and a pharmaceutically acceptable excipient.

[0321] Embodiment 34. The pharmaceutical composition of embodiment 33, wherein the pharmaceutical composition is in the form of a cream, a gel or an ointment.

[0322] Embodiment 35, The pharmaceutical composition of embodiment 33 or 34, wherein the pharmaceutical composition is a topical formulation.

[0323] Embodiment 36. Use of a compound of any one of embodiments 1-32, or a pharmaceutically acceptable salt, hydrate, solvate or crystalline form thereof, in the preparation of a medicament for treating a viral disease in a subject, wherein the viral disease 15 is selected from the group consisting of human papilloma virus, HIV, hepatitis B virus, hepatitis C virus, variola virus, vaccinia 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.

115

WO 2014/143643

PCT7US2014/027005 [0324] Embodiment 37. The use of embodiment 36, wherein said virus is human papilloma virus.

[0325] Embodiment 38. The use of embodiment 37, said compound, or a pharmaceutically acceptable salt, hydrate, solvate or crystalline form thereof, for use in treating a plurality of types of human papilloma virus.

[0326] Embodiment 39. The use of embodiment 37, wherein the human papilloma virus is selected from the group consisting human papilloma virus type 11, type 16 and type 18.

[0327] Embodiment 40. Use of a compound of any one of embodiments 1-32, or a pharmaceutically acceptable salt, hydrate, solvate or crystalline form thereof, in the preparation of a medicament for treating cancer of the cervix in a subject.

[0328] Embodiment 41. Use of a compound of any one of embodiments 1-32, or a pharmaceutically acceptable salt, hydrate, solvate or crystalline form thereof, in the preparation of a medicament for inhibiting growth of a cell transformed by a virus, wherein the virus is selected from the group consisting of human papilloma virus, HIV, hepatitis B virus, hepatitis C virus, variola virus, vaccinia 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.

[0329] Embodiment 42. A compound of any one of embodiments 1-32, or a pharmaceutically acceptable salt, hydrate, solvate or crystalline form thereof, for use in treating a viral disease in a subject, wherein the viral disease is selected from the group consisting of human papilloma virus, HIV, hepatitis B virus, hepatitis C virus, variola virus, vaccinia 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.

[0330] Embodiment 43. The compound of embodiment 42, wherein said virus is human papilloma virus.

[0331] Embodiment 44. The compound of embodiment 43, or a pharmaceutically acceptable salt, hydrate, solvate or crystalline form thereof, for use in treating a plurality of types of human papilloma virus.

116

WO 2014/143643

PCT/US2014/027005 [0332] Embodiment 45. The compound of embodiment 43, wherein the human papilloma virus is selected from the group consisting human papilloma virus type 11, type 16 and type 18.

[0333] Embodiment 46. A compound of any one of embodiments 1-32, or a pharmaceutically acceptable salt, hydrate, solvate or crystalline form thereof, for use in treating cancer of the cervix in a subject.

[0334] Embodiment 47. A compound of any one of embodiments 1-32, or a pharmaceutically acceptable salt, hydrate, solvate or crystalline form thereof, for use in inhibiting growth of a cell transformed by a virus, wherein the virus is selected from the group consisting of human papilloma virus, HIV, hepatitis B virus, hepatitis C virus, variola virus, vaccinia 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.

[0335] Embodiment 48. A method for synthesis of the compound of Formula (la) according to Embodiment 1:

<img file="IL241554A_D0096.tif" />

wherein: BNue(a) is a naturally occurring purine, a naturally occurring pyrimidine, a nonnaturally occurring purine or a non-naturally occurring pyrimidine;

L^a is an unsubstituted C_t2.₂₄ alkyl, an unsubstituted C₁₃.₂₉ heteroaikyl or a substituted glyceryl moiety, wherein the glyceryl moiety is substituted with one or more groups selected from an unsubstituted alkyl, an unsubstituted C13-M heteroaikyl, a substituted or unsubstituted aryl(C]_6 alkyl), a substituted or unsubstituted heteroaryl(Ci.s alkyl) and a substituted or unsubstituted heterocycloalky l(Ci._s alkyl); R^a is selected from the group consisting of an unsubstituted alkyl, a substituted or unsubstituted aryl, a substituted or unsubstituted

117

WO 2014/143643

PCT/US2014/027005 heteroaryl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl(Ci-6 alkyl), a substituted or unsubstituted heteroaryl(Ci_g alkyl) and a substituted or unsubstituted heterocycloalkyI(Cj.₆ alkyl); X^a is hydrogen, an unsubstituted Cm alkyl, a halogen substituted Cm alkyl, a hydroxy substituted Cm alkyl or an unsubstituted Cm alkoxy; and Y^a is a leaving group; the method including: contacting a compound of Formula (2-1 a) that has a protected BN_UC(_a) with a compound of Formula (2-2a) in the presence of a strong base to form a compound of Formula (2-3a); and reacting the compound of Formula (2-3a) with L^a-OH in the presence of a coupling agent to form the compound of Formula (la).