Nucleoside prodrugs and related uses

Abstract

Acyclic nucleoside prodrugs with improved metabolic stability and oral bioavailability are disclosed. Generally, the prodrugs are derivatives of acyclic nucleoside phosphonates containing a lipid-like moiety that can improve oral absorption and subsequent stability in the liver and plasma. Preferably, the lipid-like moiety can resist enzyme-mediated ω-oxidation, such as ω-oxidation catalyzed by cytochrome P450 enzymes. Pharmaceutical formulations of the acyclic nucleoside prodrugs are also disclosed. The acyclic nucleoside prodrugs and their pharmaceutical formulations can be used to treat viral infections, such as HIV infections, and / or viral-associated cancers, such as HPV-associated cancers.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Patent Application No. 62 / 890,452, filed August 22, 2019, and U.S. Provisional Patent Application No. 62 / 890,684, filed August 23, 2019, each of which is hereby incorporated by reference in its entirety for all purposes.

[0002] Technical Field The present disclosure relates to prodrugs of nucleosides and acyclic nucleoside phosphonates and derivatives thereof, pharmaceutical formulations and uses thereof. [Background technology]

[0003] background Many synthetic nucleoside analogues have been approved by regulatory agencies such as the FDA for therapeutic utility against a variety of human diseases. These drugs have found widespread clinical application against human immunodeficiency virus / acquired immunodeficiency syndrome (HIV / AIDS) as inhibitors of HIV reverse transcriptase (HIV-RT), a viral protein responsible for the reverse transcription of viral RNA into DNA.

[0004] One example is tenofovir (TFV), an acyclic nucleoside phosphonate that exhibits broad-spectrum activity against several viruses, including HIV, hepatitis B virus (HBV), and herpes simplex virus type 2 (HSV-2). Mechanistically, TFV undergoes two kinase-mediated phosphorylation events to generate the active TFV diphosphate, which inhibits viral DNA polymerase activity and abrogates viral replication. A key property of nucleoside phosphonates such as TFV is the metabolically stable phosphonate bond (-P-CH2), which prevents undesired enzymatic and chemical hydrolysis. Furthermore, these nucleoside phosphonates mimic nucleoside monophosphates, thereby bypassing the relatively slow initial phosphorylation event required by most nucleoside analogs. Although avoiding this initial phosphorylation event allows for facile conversion to their active metabolites, the phosphonate moiety confers a pronounced divalent anionic character to TFV and other acyclic analogs at physiological pH, limiting their ability to diffuse across cell membranes and resulting in rapid renal clearance, reduced bioavailability, and reduced antiviral activity and nephrotoxicity as a result of renal tubular outflow-mediated accumulation of TFV in the kidney.

[0005] To improve these properties, TFV prodrugs, namely TFV disoproxil fumarate (TDF) and TFV alafenamide fumarate (TAF) (shown below), have been designed to shield the double negative charge. Clinically approved TDF contains two isopropyloxymethyl carbonate functional groups that rely on an esterase-activated cleavage mechanism to release TFV. Although these two isopropyl carbonates increase the oral bioavailability of TFV, the ubiquitous distribution of esterases, particularly in the liver and plasma, renders TDF subject to significant hydrolysis. This results in systemic exposure of TFV, which accumulates in the kidney and bone, leading to nephrotoxicity, bone mineral deficiency (BMD), and other adverse side effects after prolonged exposure. On the other hand, TAF contains a phosphoramidate bond that is selectively cleaved intracellularly by cathepsin A, a serine protease primarily localized in endosomes and lysosomes. This selective intracellular cleavage mechanism overcomes the poor plasma stability of TDF, which generates circulating TFV that causes nephrotoxicity and BMD. Unfortunately, both TFV prodrugs tend to concentrate in the hepatic system, thereby limiting their availability to HIV-infected cells in other tissues. In dogs, for example, 65% of a single oral dose of TDF is extracted by the liver and concentrated in hepatocytes as TFV diphosphate due to undesired cleavage by carboxylesterase 1, thereby promoting hepatotoxicity. Furthermore, 17% is converted to plasma TFV, which is on the verge of bone and kidney sequestration and related toxicity. Due to this undesired metabolism, only 18% gains access to plasma intact and is thereby available for HIV-infected cell entry, while 82% is relegated to toxic side effects that impair patient adherence to antiretroviral therapy.

[0006] More recent strategies have focused on disguising acyclic nucleoside phosphonates as lysophospholipids to improve oral absorption and subsequent liver and plasma stability. In principle, this should increase systemic exposure and thereby increase the proportion of orally administered prodrugs that reach plasma intact. One example of these lipid prodrugs is hexadecyloxypropyl-9-R-[2-(phosphonomethoxy)propyl]-adenine, CMX157 (also shown below), a prodrug of TFV containing a hexadecyloxypropyl lipid tail (Painter et al., Antimicrob. Agents Chemother. 51, 3505-3509, 2007). However, CMX157 undergoes unwanted ω-oxidation at the terminal methyl group on the lipid chain by cytochrome P450 (CYP) enzymes localized in the small intestine and liver. This catabolic event begins with the introduction of a hydroxyl group at the end of the lipid chain, which then undergoes sequential oxidation by alcohol and aldehyde dehydrogenases to yield the corresponding carboxylic acid, which can then undergo β-oxidation, degrading the lipid chain two carbons at a time and pre-systemically releasing TFV and several unwanted metabolites, thereby substantially limiting the proportion of orally administered prodrug available to HIV-infected cells. [ka]

[0007] As reported by a 2010 meta-analysis of 84 clinical trials, only 62% of HIV patients reported a mean adherence rate of ≥90%, resulting in optimal viral suppression. If patients miss scheduled doses, resistant and infectious viruses can emerge, often necessitating second- or third-line treatment options that require stricter compliance for sustained efficacy. In addition to toxic side effects, patient adherence to chronic antiretroviral therapy is significantly hindered by frequent dosing. Because the absence of a cure necessitates variable compliance to ensure long-term viral suppression throughout a patient's life, antiretroviral success depends on lifelong adherence. This is supported by the inverse correlations between patient adherence and HIV viral load, the emergence of drug resistance, and progression to AIDS. Therefore, the frequency of currently required antiretroviral dosing remains a significant barrier. Finally, of the 20.9 million HIV / AIDS patients for whom TDF- and TAF-containing antiretrovirals are available, many suffer from organ-specific toxicities and frequent dosing schedules that compromise adherence, and the 15.8 million patients for whom treatment is not reasonably affordable are unable to access it, in part due to cost, which is significantly driven by the amount of drug needed to treat the target patient population. Thus, improved treatments are needed. Summary of the Invention [Means for solving the problem]

[0008] overview Acyclic nucleoside prodrugs with improved metabolic stability and oral bioavailability are disclosed. Generally, the prodrugs are derivatives of acyclic nucleoside phosphonates containing a lipid-like moiety that can improve oral absorption and subsequent stability in the liver and plasma. Preferably, the lipid-like moiety can resist enzyme-mediated ω-oxidation, such as ω-oxidation catalyzed by cytochrome P450 enzymes.

[0009] In some embodiments, the disclosed compounds have the structure of Formula I or a pharmaceutically acceptable salt thereof: [ka] (In the formula, L is an acyclic nucleoside phosphonate; W is absent or a saturated C1-C9 alkyl chain (i.e., a bridged C1-C9 alkylene); X is absent or selected from substituted methylene or ethylene, —O—, —S—, —S(═O)—, and —S(O)—; Y is saturated C2~C 20 Alkyl chain (i.e., bridge C2-C 20 alkylene); Z is selected from hydrogen, optionally substituted methyl or ethyl, optionally substituted unsaturated C2-C3 alkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, Si-substituted silyl, S-substituted thiol, O-substituted hydroxyl, ester, and -SF5; where when X is -O-, Z is not hydrogen, methyl or ethyl, wherein when both W and X are absent, Z is not hydrogen, methyl or ethyl; If W does not exist, then X does not exist either.) It has.

[0010] In some embodiments, both W and X are present.

[0011] In some embodiments, L has formula V: [ka] (In the formula, U is a nucleobase; V is -OR Y or -SR Z and; R 1, R 2 , R 3 and R 4 are independently selected from hydrogen, deuterium, halogen, azido, cyano, isocyano, nitrate, nitrosoxy, nitroso, nitro, formyl, carboxyl, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, azo, acyl, optionally O-substituted hydroxyl, optionally S-substituted mercapto, sulfinyl, sulfonyl, sulfonate, optionally N-substituted amino, optionally N-substituted amido, optionally N-substituted sulfamoyl, optionally Si-substituted silyl, ester, carbonate ester, optionally substituted carbamate, optionally N-substituted aminooxy and optionally N- and / or O-substituted hydroxyamino; R Y and R Z are independently selected from hydrogen, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted carbocyclyl, optionally substituted heterocarbocyclyl, optionally substituted aryl, and optionally substituted heteroaryl. It has the following structure.

[0012] In some embodiments, L has formula V': [ka] (In the formula, U, R 3 and R 4 is the same as defined above).

[0013] In some embodiments, L is: [ka] is selected from.

[0014] In some embodiments, W is a C1-C9 alkylene. In some embodiments, W is a straight chain C1-C9 alkylene, such as ethylene (-CH2CH2-) or propylene (-CH2CH2CH2-).

[0015] In some embodiments, X is selected from substituted methylene or ethylene, -O-, -S-, -S(=O)-, and -S(O)-. In some embodiments, X is -CF-, -O-, or -S-.

[0016] In some embodiments, Y is a linear C-C 20 In some embodiments, Y is a linear C-C alkylene. 20 It is alkylene.

[0017] In some embodiments, Z is selected from substituted methyl or ethyl, optionally substituted unsaturated C-C alkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, Si-substituted silyl, S-substituted thiol, O-substituted hydroxyl, ester, and —SF.

[0018] In some embodiments, Z is: -CD 3、 -CF 3、 -CD2CD3, -CF2CF3, -S-Ph, -O-Ph, -C≡CH 、 -C≡CCD3, -CH2FC≡C, -CHF2C≡C, -C≡CSi(CH3)3, -C≡CC(CH3)3, -C≡CCF3, -C≡CSF5, -Si(CH3)3, -C(CH3)3, -C(O)OCH3, -SF5, [ka] [ka] (In the formula, * indicates the point of attachment to Y. In some embodiments, Z is —CF 3 or —C≡CSi(CH 3 ) 3 .

[0019] In some embodiments, the compound has the following properties: W is -CH2CH2- or -CH2CH2CH2-; X is -CF2-, -O-, or -S-; Y is a linear C8-C 20 is alkylene; Z is selected from the group consisting of substituted methyl or ethyl, optionally substituted unsaturated C2-C3 alkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, Si-substituted silyl, S-substituted thiol, O-substituted hydroxyl, ester, and -SF5.

[0020] Representative compounds are described in the detailed description below.

[0021] In some embodiments, the compounds have greater human liver microsome (HLM) stability (t 1 / 2 For example, the compounds have an HLM t of greater than 45 minutes, 60 minutes, 90 minutes, or 120 minutes. 1 / 2 may have:

[0022] Pharmaceutical formulations of the disclosed compounds are also disclosed. Typically, the pharmaceutical formulation also contains a pharmaceutically acceptable carrier. In some embodiments, the pharmaceutical formulation is in the form of a tablet, capsule, pill, gel, cream, granule, solution, suspension, emulsion, or nanoparticle formulation. In some embodiments, the pharmaceutical formulation is an oral formulation.

[0023] Also disclosed are methods for treating a viral infection or a viral-associated cancer in a subject in need thereof. Generally, the method comprises administering to the subject an effective amount of a compound disclosed herein or a pharmaceutical formulation thereof. In some embodiments, the compound or pharmaceutical formulation is administered orally.

[0024] In some embodiments, the disclosed compounds and pharmaceutical formulations thereof are used to treat viral infections, such as those caused by human immunodeficiency virus (HIV), hepatitis virus, herpes virus, flavivirus, poxvirus, paramyxovirus, influenza, coronavirus, smallpox virus, human papillomavirus (HPV), or filovirus.

[0025] In some embodiments, the present disclosure also relates to methods of preparing the compounds disclosed herein, comprising combining one or more starting materials with reagents under conditions such that a product is formed.

[0026] An object of the present disclosure is to provide therapeutic agents with improved drug properties.

[0027] Another object of the present disclosure is to provide pharmaceutically acceptable formulations of the therapeutic agents disclosed herein.

[0028] It is yet another object of the present disclosure to provide improved antiviral and / or anticancer treatments comprising the therapeutic agents disclosed herein and their pharmaceutically acceptable formulations thereof. [Brief explanation of the drawings]

[0029] BRIEF DESCRIPTION OF THE DRAWINGS [Figure 1A] FIG. 1A illustrates the synthetic procedure involved in Example 3. [Figure 1B] FIG. 1B illustrates the synthetic procedures involved in Examples 1-2. [Figure 2] FIG. 2 illustrates the synthetic procedure involved in Example 5. [Figure 3] FIG. 3 illustrates the synthetic procedure for making hydroxyl-substituted alkynes with different carbon chain lengths. [Figure 4A] FIG. 4A illustrates the synthetic procedures involved in Examples 25-26. [Figure 4B] FIG. 4B illustrates the synthetic procedures involved in Examples 27-28. [Figure 5] FIG. 5 illustrates the synthetic procedure involved in Example 29. [Figure 6] FIG. 6 illustrates the synthetic procedures involved in Examples 30 and 31. [Figure 7] FIG. 7 illustrates the synthetic procedures involved in Examples 32-34. [Figure 8] FIG. 8 illustrates the synthetic procedure involved in Example 35. [Figure 9] FIG. 9 illustrates the synthetic procedure involved in Example 36. [Figure 10] FIG. 10 illustrates the synthetic procedure involved in Example 37. [Figure 11] FIG. 11 illustrates the synthetic procedure involved in Example 39. [Figure 12] FIG. 12 illustrates the synthetic procedure involved in Example 40. DETAILED DESCRIPTION OF THE INVENTION

[0030] Detailed Description Before describing the present disclosure in more detail, it is to be understood that this disclosure is not limited to particular embodiments described, as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, since the scope of the present disclosure will be limited only by the appended claims.

[0031] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Although any methods and materials similar or equivalent to those described herein can also be used in the practice or testing of this disclosure, the preferred methods and materials are now described.

[0032] All publications and patents cited in this application are incorporated herein by reference to the same extent as if each individual publication or patent was specifically and individually indicated to be incorporated by reference, and are incorporated herein by reference to disclose and describe the methods and / or materials in connection with which the publications are cited. The citation of any publication is for its disclosure prior to the filing date and should not be construed as an admission that the present disclosure is not entitled to antedate such publication by virtue of prior disclosure. Further, the dates of publication provided may be different from the actual publication dates which may need to be independently confirmed.

[0033] As will be apparent to those skilled in the art upon reading this disclosure, each of the individual embodiments described and illustrated herein has distinct components and properties that may be readily separated from or combined with the properties of any of the other embodiments without departing from the scope or spirit of the present disclosure. Any recited method may be carried out in the order of events recited or in any other order that is logically possible.

[0034] Embodiments of the present disclosure employ, unless otherwise indicated, techniques of medicine, organic chemistry, biochemistry, molecular biology, pharmacology, and the like, which are within the skill of the art, and such techniques are explained fully in the literature.

[0035] To the extent that the chemical formulas reported herein contain one or more unidentified chiral centers, it is intended that the formulas encompass all stable stereoisomers, enantiomers, and diastereomers. It is also understood that the formulas encompass all tautomeric forms.

[0036] It will also be appreciated that representative compounds of the present disclosure include ammonium salts of tenofovir-based prodrugs and 9-[2-(phosphonomethoxy)ethyl]guanine (PMEG)-based prodrugs. Other salts, nucleosides, and acyclic nucleosides not exemplified are equally applicable and are within the scope of the present disclosure.

[0037] I. Definition It must be noted that as used herein, the singular forms "a," "an," and "the" include plural references unless the context clearly dictates otherwise.

[0038] "Subject" refers to any animal, preferably a human patient, livestock, or household pet.

[0039] As used herein, the terms "prevent" and "preventing" include prevention of recurrence, spread, or onset. The present disclosure is not intended to be limited to complete prevention. In some embodiments, onset is delayed or the severity of the disease is reduced.

[0040] As used herein, the terms "treat" and "treating" are not limited to cases in which a subject (e.g., a patient) is cured and the disease is eradicated. Rather, embodiments of the present disclosure also contemplate treatment that merely alleviates symptoms and / or slows disease progression.

[0041] As used herein, the term "in combination with," when used to describe administration in conjunction with a further treatment, means that the agent can be administered before, along with, or after the further treatment, or a combination thereof.

[0042] "Linking group" refers to any of a variety of molecular configurations that can be used to bridge two molecular moieties together. An exemplary formula is -R m -, where R may individually and independently at each occurrence be -CR m R m-, -CHR m -, -CH-, -C-, -CH2-, -C(OH)R m , -C(OH)(OH)-, -C(OH)H, -C(Hal)R m -, -C(Hal)(Hal)-, -C(Hal)H-, -C(N3)R m -, -C(CN)R m -, -C(CN)(CN)-, -C(CN)H-, -C(N3)(N3)-, -C(N3)H-, -O-, -S-, -N-, -NH-, -NR m R is selected from -, -(C=O)-, -(C=NH)-, -(C=S)-, -(C=CH)-, which may individually and independently contain single, double or triple bonds between the R groups. m When branched with R, it can be terminated with a group such as -CH, -H, -CH=CH, -CCH, -OH, -SH, -NH, -N, -CN, or -Hal, or two branched Rs can form a cyclic structure. In certain examples, it is contemplated that the total R or "m" can be less than 100, 50, 25, or 10. Examples of linking groups include bridging alkyl groups and alkoxyalkyl groups. It is contemplated that the linking group can be an acyclic linking group, such as a substituted or unsubstituted alkoxyphosphonate, including a substituted or unsubstituted (phosphonomethoxy)ethyl.

[0043] As used herein, "alkyl" means an acyclic, straight or branched chain, unsaturated or saturated hydrocarbon, such as one containing 1 to 25 carbon atoms. For example, "C8-C 18 " refers to an alkyl containing 8 to 18 carbon atoms. Similarly, "C6-C 22" refers to an alkyl containing 6 to 22 carbon atoms. Representative saturated straight-chain alkyls include methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-septyl, n-octyl, n-nonyl, and the like; while saturated branched alkyls include isopropyl, sec-butyl, isobutyl, tert-butyl, isopentyl, and the like. Unsaturated alkyls contain at least one double or triple bond between adjacent carbon atoms (referred to as "alkenyl" or "alkynyl," respectively). Representative straight chain and branched alkenyls include ethylenyl, propylenyl, 1-butenyl, 2-butenyl, isobutylenyl, 1-pentenyl, 2-pentenyl, 3-methyl-1-butenyl, 2-methyl-2-butenyl, 2,3-dimethyl-2-butenyl, and the like; while representative straight chain and branched alkynyls include acetylenyl, propynyl, 1-butynyl, 2-butynyl, 1-pentynyl, 2-pentynyl, 3-methyl-1-butynyl, and the like.

[0044] As used herein, "heteroalkyl" refers to an alkyl group in which one or more carbon atoms are replaced with a heteroatom such as O, N, or S. Like alkyl groups, heteroalkyl groups can be linear or branched, saturated or unsaturated. Optionally, the nitrogen and / or sulfur heteroatoms can be oxidized and the nitrogen heteroatom can be quaternized. Suitable heteroalkyl groups can contain 1 to 25 carbon atoms and 1 to 4 heteroatoms.

[0045] Non-aromatic, monocyclic, or polycyclic alkyls are referred to herein as "carbocycle" or "carbocyclyl" groups. Representative saturated carbocycles include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like; while representative unsaturated carbocycles include cyclopentenyl, cyclohexenyl, and the like. In polycyclic carbocyclyl groups, the rings may be linked together in a pendant fashion (i.e., two rings are linked by a single bond), a spiro fashion (i.e., two rings are linked through one crucial common atom), a fused fashion (i.e., two rings share two adjacent atoms; in other words, two rings share one covalent bond), a bridged fashion (i.e., two rings share three or more atoms, with a bridge containing at least one atom separating the two bridged atoms), or a combination thereof. The "member" number of a carbocyclyl group refers to the total number of carbon atoms in the rings of the carbocyclyl group.

[0046] A "heterocarbocycle" or "heterocarbocyclyl" group is a carbon ring containing 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, where the nitrogen and / or sulfur heteroatoms can be optionally oxidized and the nitrogen heteroatom can be optionally quaternized. Heterocarbocycles can be saturated or unsaturated (but not aromatic), monocyclic, or polycyclic. Representative heterocarbocycles include morpholinyl, pyrrolidinonyl, pyrrolidinyl, piperidinyl, hydantoinyl, valerolactamyl, oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyridinyl, tetrahydropyrimidinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, and the like. The "membership" number of a heterocarbocyclyl group refers to the total number of carbon atoms and heteroatoms in the ring of the heterocarbocyclyl group.

[0047] The term "aryl" refers to groups containing homoaromatic (i.e., hydrocarbon) monocyclic, bicyclic, or tricyclic rings, preferably those having 6 to 12 members, such as phenyl, naphthyl, and biphenyl. Optionally, the aryl group is phenyl. In polycyclic aryl groups, the rings can be linked together in a pendant fashion or can be fused. The "member" number of an alkyl group refers to the total number of carbon atoms in the ring(s) of the alkyl group.

[0048] As used herein, "heteroaryl" or "heteroaromatic" refers to an aromatic heterocarbocycle having from 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulfur and containing at least one carbon atom, including both monocyclic and polycyclic ring systems. Polycyclic ring systems may, but need not, contain one or more non-aromatic rings, so long as one of the rings is aromatic. Representative heteroaryls are furyl, benzofuranyl, thiophenyl, benzothiophenyl, pyrrolyl, indolyl, isoindolyl, azaindolyl, pyridyl, quinolinyl, isoquinolinyl, oxazolyl, isoxazolyl, benzoxazolyl, pyrazolyl, imidazolyl, benzimidazolyl, thiazolyl, benzothiazolyl, isothiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, cinnolinyl, phthalazinyl, and quinazolinyl. Use of the term "heteroaryl" is intended to include N-alkylated derivatives such as a 1-methylimidazol-5-yl substituent. The "membership" number of a heteroaryl group refers to the total number of carbon atoms and heteroatoms in the ring(s) of the heteroaryl group.

[0049] As used herein, "heterocycle" or "heterocyclyl" refers to monocyclic and polycyclic ring systems containing one to four heteroatoms selected from nitrogen, oxygen, and sulfur and at least one carbon atom. Monocyclic and polycyclic ring systems can be aromatic, non-aromatic, or a mixture of aromatic and non-aromatic rings. Heterocycles include heterocarbocycles, heteroaryls, and the like. In polycyclic heterocyclyl groups, rings can be linked together in a pendant fashion (i.e., two rings are linked by a single bond), a spiro fashion (i.e., two rings are linked through one crucial common atom), a fused fashion (i.e., two rings share two adjacent atoms; in other words, two rings share one covalent bond), a bridged fashion (i.e., two rings share three or more atoms, with a bridge containing at least one atom separating the two bridged atoms), or a combination thereof. The "membership" number of a heterocyclyl group refers to the total number of carbon atoms and heteroatoms in the rings of the heterocyclyl group.

[0050] "Alkoxy" or "alkyloxy" refers to an alkyl group as defined above with the designated number of carbon atoms attached through an oxygen bridge. Examples of alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, t-butoxy, n-pentoxy, and s-pentoxy. Preferred alkoxy groups are methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, and t-butoxy.

[0051] "Alkoxyalkyl" refers to an alkoxy group as defined above with the indicated number of carbon atoms attached through an alkyl bridge (ie, -CH2-O-CH2CH3).

[0052] "Alkylamino" refers to an alkyl group as defined above with the indicated number of carbon atoms connected through an amino bridge. An example of an alkylamino is methylamino (i.e., -NH-CH3).

[0053] "Alkylthio" refers to an alkyl group as defined above with the indicated number of carbon atoms attached through a sulfur bridge. An example of an alkylthio is methylthio (i.e., -S-CH).

[0054] "Alkanoyl" refers to an alkyl group as defined above with the indicated number of carbon atoms connected through a carbonyl bridge (ie, --(C.dbd.O)alkyl).

[0055] The terms "cycloalkyl" and "cycloalkenyl" refer to mono-, bi-, or tricyclic homocyclic ring groups of 3 to 15 carbon atoms that are fully saturated and partially unsaturated, respectively (but not aromatic).

[0056] The term "halogen" or "Hal" refers to fluorine, chlorine, bromine and iodine.

[0057] The term "substituted" refers to a molecule in which at least one hydrogen atom has been replaced with a substituent. The molecule may be multiply substituted. In the case of an oxo substituent ("=O"), two hydrogen atoms are replaced. Exemplary substituents in this context include halogen, hydroxy, alkyl, alkoxy, nitro, cyano, oxo, carbocyclyl, carbocycloalkyl, heterocarbocyclyl, heterocarbocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, -NR a R b , -NR a C(=O)R b , -NR a C(=O)NR a R b , -NR a C(=O)OR b , -NR a SO2R b , -C(=O)R a , -C(=O)OR a , -C(=O)NR a R b , -OC(=O)NR a R b , -OR a, -SR a , -SOR a , -S(=O)2R a , -OS(=O)2R a and -S(=O)2OR a In this context, R a and R b may be the same or different and independently be hydrogen, halogen hydroxyl, alkyl, alkoxy, alkyl, amino, alkylamino, dialkylamino, carbocyclyl, carbocycloalkyl, heterocarbocyclyl, heterocarbocycloalkyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl.

[0058] The term "optionally substituted," as used herein, means that substitution is optional, and thus the specified atom can be unsubstituted.

[0059] It is understood that any substitution is subject to the permissible valencies of the substituted atom and substituent and that the substitution results in a stable compound, i.e., a compound that does not undergo spontaneous transformation by rearrangement, cyclization, elimination, etc., at room temperature.

[0060] The term "nucleoside" refers to a substituted non-aromatic five-membered ring, such as tetrahydrofuran-2-yl, substituted at the 5-position with a nucleobase or heterocyclic derivative thereof. The five-membered ring and / or nucleobase may be further substituted or derivatized. Examples of nucleosides containing modified adenosines or guanosines include, but are not limited to, hypoxanthine, xanthine, and 7-methylguanine. Examples of nucleosides containing modified cytidines, thymidines, or uridines include 5,6-dihydrouracil, 5-methylcytosine, and 5-hydroxymethylcytosine.

[0061] The term "acyclic nucleoside phosphonate" refers to a nucleobase or heterocyclic derivative thereof substituted with an acyclic linking group, such as a substituted or unsubstituted alkoxyphosphonate, including a substituted or unsubstituted (phosphonomethoxy)ethyl. Examples include tenofovir, cidofovir, adefovir, (9-[2-(phosphonomethoxy)ethyl]guanine), 9-(3-hydroxy-2-phosphonylmethoxypropyl)adenine, and 9-(2-phosphonylmethoxyethyl)-2,6-diaminopurine.

[0062] "Nucleobase" refers to any variation of a nitrogen-containing monocyclic or bicyclic heterocycle. Nucleobases generally have at least one optionally substituted amino group or carbonyl / hydroxyl group in the ring, or an optionally substituted amide group in the ring, linked to the ring. They generally have 2 to 4 nitrogen atoms in the ring. Examples of nucleobases include adenine, guanine, cytosine, uracil, thymine, inosine, and heterocycles of the following structure: [ka] Examples include:

[0063] With respect to nucleobases, the term is intended to encompass isobases, including 2'-deoxy-5-methylisocytidine (iC) and 2'-deoxy-isoguanosine (iG).

[0064] As used herein, the term "derivative" refers to a structurally similar compound that retains the full functional properties of the specified analog. Derivatives may be structurally similar because they lack one or more atoms, are substituted, are salts of different hydration / oxidation states, or have one or more atoms switched within the molecule, such as, but not limited to, the addition of a hydroxyl group, the substitution of an oxygen atom with a sulfur atom, or the substitution of an amino group with a hydroxyl group, the oxidation of a hydroxyl group to a carbonyl group, the reduction of a carbonyl group to a hydroxyl group, and the reduction of a carbon-carbon double bond to an alkyl group or the oxidation of a carbon-carbon single bond to a double bond. Optional derivatives have one or more of the same or different substituents. The derivatives may be prepared by any of a variety of synthetic methods or suitable adaptations provided in synthetic or organic chemistry textbooks, such as those provided in March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, Wiley, 6th Edition (2007) Michael B. Smith or Domino Reactions in Organic Synthesis, Wiley (2006) Lutz F. Tietze, which are incorporated herein by reference.

[0065] II. Compounds A nucleoside prodrug having the structure of Formula I, or a pharmaceutically acceptable salt thereof: [ka] (In the formula, L is an acyclic nucleoside phosphonate; W is absent or a saturated C1-C9 alkyl chain (i.e., a bridged C1-C9 alkylene); X is selected from absent or substituted methylene or ethylene, —O—, —S—, —S(═O)—, and —S(O)—; Y is saturated C2~C 20 Alkyl chain (i.e., bridge C2-C 20 alkylene); Z is selected from hydrogen, optionally substituted methyl or ethyl, optionally substituted unsaturated C-C alkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, Si-substituted silyl, S-substituted thiol, O-substituted hydroxyl, ester, and —SF. is disclosed.

[0066] Preferably, when X is -O-, Z is not hydrogen, methyl or ethyl.

[0067] Preferably, when both W and X are absent, Z is not hydrogen, methyl or ethyl.

[0068] Preferably, when W is absent, X is also absent.

[0069] In some embodiments, both W and X are present, ie, LOWXYZ.

[0070] In some embodiments, both W and X are absent, ie, LOYZ.

[0071] In some embodiments, W is present and X is absent, ie, LOWYZ.

[0072] The substituted or optionally substituted groups according to Formula I may have one or more substituents independently selected from deuterium, halogen, azido, cyano, isocyano, nitrate, nitrosoxy, nitroso, nitro, formyl, carboxyl, alkyl, heteroalkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, azo, acyl, hydroxyl, mercapto, sulfinyl, sulfonyl, sulfonate, sulfamoyl, amino, acylamino, amido, silyl, ester, carbonate, carbamate, aminooxy, hydroxyamino, and —SF5, wherein each substituent may be selected from one or more R AIn some embodiments, two substituents on the same atom may be joined together with the atom to form a cyclic moiety, such as a carbocyclic or heterocyclic ring.

[0073] For example, the Si-substituted silyl in Formula I can have 1, 2, or 3 substituents independently selected from those listed above. When there are multiple substituents, two of the substituents can be linked together with the Si atom to form a cyclic moiety, such as a heterocycle. In some embodiments, the substituents can be independently selected from alkyl, heteroalkyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl, where each substituent can be selected from one or more R A In some embodiments, the Si-substituted silyl has three substituents independently selected from alkyl, heteroalkyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl, where each substituent is selected from one or more R A Representative Si-substituted silyl groups include: [ka] These include, but are not limited to: R A is selected from the group consisting of, at each occurrence, halogen, alkyl optionally substituted with one or more halogens, heteroalkyl optionally substituted with one or more halogens, carbocyclyl optionally substituted with one or more halogens, heterocyclyl optionally substituted with one or more halogens, aryl optionally substituted with one or more halogens, heteroaryl optionally substituted with one or more halogens, —OH, —SH, —NH, —N, —OCN, —NCO, —ONO, —CN, —NC, —ONO, —CONH, —NO, —NO, —ONH, —SCN, —SNCS, —SF, —CF, —CHCF, —CHCl, —CHCl, —CHNH, —NHCOH, —CHO, —COOH, —SOH, —CHSOCH, —POH, —OPOH, —P(═O)(OR G1 )(ORG2 )、 -OP(=O)(OR G1 )(OR G2 )、 -BR G1 (OR G2 )、 -B(OR G1 )(OR G2 )、 -Si(R G1 )(R G2 )(R G3 ) or -GR G1 (where -G is, -O-, -S-, -NR G2 -, -C(=O)-, -S(=O)-, -SO2-, -C(=O)O-, -C(=O)NR G2 -, -OC(=O)-, -NR G2 C(=O)-, -OC(=O)O-, -OC(=O)NR G2 -, -NR G2 C(=O)O-, -NR G2 C(=O)NR G3 -, -C(=S)-, -C(=S)S-, -SC(=S)-, -SC(=S)S-, -C(=NR G2 )-, -C(=NR G2 )O-, -C(=NR G2 )NR G3 -, -OC(=NR G2 )-, -NR G2 C(=NR G3 -, -NR G2 SO2-, -C(=NR G2 )NR G3 -, -OC(=NR G2 )-, -NR G2 C(=NR G3 -, -NR G2 SO2-, -NR G2 SO2NR G3 -, -NR G2 C(=S)-, -SC(=S)NR G2 -, -NR G2 C(=S)S-, -NR G2 C(=S)NR G3 -, -SC(=NR G2 )-, -C(=S)NR G2 -, -OC(=S)NR G2 -, -NR G2 C(=S)O-, -SC(=O)NR G2 -, -NRG2 C(=O)S-, -C(=O)S-, -SC(=O)-, -SC(=O)S-, -C(=S)O-, -OC(=S)-, -OC(=S)O-, -SO2NR G2 -, -BR G2 -or-PR G2 -), where R G1 , R G2 and R G3 Each occurrence of R is independently a hydrogen atom, a halogen atom, an alkyl group optionally substituted with one or more halogens, a heteroalkyl group optionally substituted with one or more halogens, a carbocyclyl group optionally substituted with one or more halogens, a heterocyclyl group optionally substituted with one or more halogens, an aryl group optionally substituted with one or more halogens, or a heteroaryl group optionally substituted with one or more halogens. A -Si(R G1 )(R G2 )(R G3 ), then R G1 , R G2 and R G3 Two groups from may be linked together with the Si atom to form a cyclic moiety such as a heterocycle.

[0074] In some embodiments, two R on the same atom A may be joined together with its atoms to form a cyclic moiety, such as a carbocyclic or heterocyclic ring.

[0075] In some embodiments, the substituted or optionally substituted groups according to Formula I are deuterium, halogen, nitro, cyano, hydroxyl, trifluoromethoxy, trifluoromethyl, alkylsilyl (such as trimethylsilyl, methyl(methyl)(ethyl)silyl, triethylsilyl, triisopropylsilyl, methyl(methyl)(tert-butyl)silyl, methyl(methyl)(isobutyl)silyl), formyl, carboxyl, mercapto, sulfamoyl, alkyl (such as methyl, ethyl, isopropyl, tert-butyl), alkyloxy (such as methoxy, ethoxy), acyl (such as acetyl), acyloxy (such as acetoxy), amino, alkylamino (such as methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino), acylamino(acetylamino), carbamoyl, N-alkylcarbamoyl and -SF5. The alkyl group may have one or more substituents independently selected from -SF5 (N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, etc.), alkylthio (methylthio, ethylthio, etc.), alkylsulfinyl (methylsulfinyl, ethylsulfinyl, etc.), alkylsulfonyl (mesyl, ethylsulfonyl, etc.), alkyloxycarbonyl (methoxycarbonyl, ethoxycarbonyl, etc.), N-alkylsulfamoyl (N-methylsulfamoyl, N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, N-methyl-N-ethylsulfamoyl, etc.), arylalkyl (benzyl, etc.), arylcarbonyl (benzoyl, etc.), heteroalkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, and -SF5.

[0076] In some embodiments, the substituted or optionally substituted groups according to formula I are selected from the group consisting of deuterium, halogen, nitro, cyano, hydroxyl, trifluoromethoxy, trifluoromethyl, trimethylsilyl, amino, formyl, carboxyl, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-diamino, N,N-diamino, N-methyl-N-ethyl ... It may have one or more substituents independently selected from methylcarbamoyl, N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulfonyl, methoxycarbonyl, ethoxycarbonyl, N-methylsulfamoyl, N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, N-methyl-N-ethylsulfamoyl, benzyl, benzoyl, alkyl, carbocyclyl, aryl, and heterocyclyl.

[0077] As used herein, "alkylene" refers to a divalent functional group derived from an alkane (ie, an acyclic saturated hydrocarbon) by the removal of two hydrogen atoms from two different carbon atoms.

[0078] As used herein, "silyl" refers to a monovalent radical derived from silane by removal of a hydrogen atom, i.e., --SiH.sub.3.

[0079] As used herein, "thiol" refers to the monovalent radical --SH.

[0080] As used herein, "acyl" refers to -C(=O)R B (In the formula, R B is an alkyl, heteroalkyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl group). As noted above, an acyl group is one or more R A It may be optionally substituted with groups.

[0081] As used herein, "sulfonate" refers to -SO3 - Refers to...

[0082] As used herein, an "amide" is -C(=O)NR C R D (In the formula, R C and R D R is independently selected from hydrogen, alkyl, heteroalkyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl. C and R D If both R are hydrogen, the amide group is carbamoyl. As noted above, an amide group can be formed by one or more R A It may be optionally substituted with groups.

[0083] As used herein, "sulfamoyl" refers to -S(=O)2NH2. As noted above, a sulfamoyl group can be formed by one or more R A It may be optionally substituted with groups.

[0084] As used herein, an "ester" refers to an ester of -C(=O)OR E or -OC(=O)R F (In the formula, R E and R F are independently selected from alkyl, heteroalkyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl. As noted above, an ester group can be formed by one or more R A It may be optionally substituted with groups.

[0085] As used herein, a "carbonate" is defined as -OC(=O)OR H (In the formula, R H is an alkyl group, a heteroalkyl group, a carbocyclyl group, a heterocyclyl group, an aryl group, or a heteroaryl group). As noted above, the carbonate group may be formed by one or more R A It may be optionally substituted with groups.

[0086] As used herein, a "carbamate" is defined as -OC(=O)NR I R J or -NR K [(C=O)OR L ](wherein, R I , R J , R K and R L are independently selected from hydrogen, alkyl, heteroalkyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl. As noted above, a carbamate group is formed by combining one or more R A It may be optionally substituted with groups.

[0087] As used herein, "aminooxy" refers to -O-NH. As noted above, an aminooxy group is formed by one or more R A It may be optionally substituted with groups.

[0088] As used herein, "hydroxyamino" refers to -NH(OH). As noted above, a hydroxyamino group can be formed by one or more R A It may be optionally substituted with groups.

[0089] As used herein, "sulfinyl" refers to -S(=O)R M (In the formula, R M is an alkyl, heteroalkyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl group). As noted above, a sulfinyl group is one or more R A It may be optionally substituted with groups.

[0090] As used herein, "sulfonyl" refers to -S(=O)R N (In the formula, R N is an alkyl group, a heteroalkyl group, a carbocyclyl group, a heterocyclyl group, an aryl group, or a heteroaryl group). As noted above, a sulfonyl group is a group formed by one or more R A It may be optionally substituted with groups.

[0091] As used herein, "acylamino" refers to -NR O [C(=O)R P ](wherein, R O is hydrogen, an alkyl group, a heteroalkyl group, a carbocyclyl group, a heterocyclyl group, an aryl group, or a heteroaryl group; R P is an alkyl group, a heteroalkyl group, a carbocyclyl group, a heterocyclyl group, an aryl group, or a heteroaryl group). As noted above, an acylamino group is one or more R A It may be optionally substituted with groups.

[0092] "Pharmaceutically acceptable salt" refers to the modification of a parent compound by forming its acid or base salt. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines, and alkali or organic salts of acidic residues such as carboxylic acids or phosphoric acids. For parent compounds containing a basic residue, a pharmaceutically acceptable salt can be prepared by treating the compound with an appropriate amount of a non-toxic inorganic or organic acid; alternatively, a pharmaceutically acceptable salt can be formed in situ during the preparation of the parent compound. Representative salts of basic residues include salts with acids selected from hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, and nitric acid; suitable organic acids include acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pamoic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, sulfanilic acid, 2-acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, naphthalenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, and isethionic acid. For parent compounds containing acidic residues, pharmaceutically acceptable salts can be prepared by treating the compound with an appropriate amount of a non-toxic base; alternatively, pharmaceutically acceptable salts can be formed in situ during the preparation of the parent compound. Representative salts of acidic residues include salts with bases selected from ammonium hydroxide, sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide, magnesium hydroxide, ferrous hydroxide, zinc hydroxide, copper hydroxide, aluminum hydroxide, ferric hydroxide, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, lysine, arginine, and histidine. Optionally, pharmaceutically acceptable salts can be prepared by reacting the free acid or base form of the parent compound with a stoichiometric or greater amount of the appropriate base or acid, respectively, in water, an organic solvent, or a mixture thereof.Lists of suitable pharmaceutically acceptable salts can be found in Remington's Pharmaceutical Sciences, 20th Ed., Lippincott Williams & Wilkins, Baltimore, MD, 2000, p. 704; and Handbook of Pharmaceutical Salts: Properties, Selection, and Use, Stahl and Wermuth, Eds., Wiley-VCH, Weinheim, 2002.

[0093] In some embodiments, the pharmaceutically acceptable salts of the compounds disclosed herein are salts with ammonium hydroxide, i.e., ammonium salts.

[0094] The disclosed compounds can exist as mixtures of stereoisomers. In some embodiments, the compounds in the mixtures of stereoisomers can be in greater than 60%, 70%, 80%, 90%, 95%, or 98% diastereomeric or enantiomeric excess. In some embodiments, the compounds in the mixtures of stereoisomers can be in greater than 90% diastereomeric or enantiomeric excess.

[0095] Methods for making representative compounds are disclosed. The methods are compatible with a wide variety of functional groups and compounds, and therefore a wide variety of derivatives can be obtained from the disclosed methods. For example, a general method for phosphonate monoesterification of tenofovir and PMEG is illustrated in the Examples. Depending on the nature of the lipid-like moiety (i.e., -WXYZ) to be incorporated into the compounds, the synthetic methods involve the use of DCC or EDC as coupling agents in the presence of triethylamine (TEA) and DMAP. The reaction can be carried out at elevated temperatures (e.g., 90-105°C) for 18-24 hours, and the product can be purified immediately after deactivation with water. Purification of the compounds can be carried out using sequential normal-phase (DCM:MeOH:NH4Cl) and reverse-phase (HO:MeOH) column chromatography approaches. In some embodiments, a deprotection step in either NH3 / MeOH or AcOH / MeOH can be performed to generate the unprotected product.

[0096] A. Structural characteristics 1. “L” part L is an acyclic nucleoside phosphonate.

[0097] In some embodiments, L is a nucleobase or heterocyclic derivative thereof substituted with an acyclic linking group, where the acyclic linking group is a substituted or unsubstituted alkoxyphosphonate. In some embodiments, the alkoxyphosphonate is a substituted or unsubstituted (phosphonomethoxy)ethyl group.

[0098] In some embodiments, L is a group of formula V: [ka] (In the formula, U is a nucleobase; V is -OR Y or -SR Z and; R 1 , R 2 , R 3 and R 4are independently selected from hydrogen, deuterium, halogen, azido, cyano, isocyano, nitrate, nitrosoxy, nitroso, nitro, formyl, carboxyl, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, azo, acyl, optionally O-substituted hydroxyl, optionally S-substituted mercapto, sulfinyl, sulfonyl, sulfonate, optionally N-substituted amino, optionally N-substituted amido, optionally N-substituted sulfamoyl, optionally Si-substituted silyl, ester, carbonate ester, optionally substituted carbamate, optionally N-substituted aminooxy and optionally N- and / or O-substituted hydroxylamino; R Y and R Z are independently selected from hydrogen, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted carbocyclyl, optionally substituted heterocarbocyclyl, optionally substituted aryl, and optionally substituted heteroaryl. It has the following structure.

[0099] The optionally substituted group according to formula V can have one or more substituents independently selected from deuterium, halogen, azido, cyano, isocyano, nitrate, nitrosoxy, nitroso, nitro, formyl, carboxyl, alkyl, heteroalkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, azo, acyl, hydroxyl, mercapto, sulfinyl, sulfonyl, sulfonate, sulfamoyl, amino, acylamino, amido, silyl, ester, carbonate, carbamate, aminooxy, hydroxyamino, and —SF5, wherein each substituent can have one or more R groups as described above in formula I. AIn some embodiments, two substituents on the same atom may be joined together with the atom to form a cyclic moiety, such as a carbocyclic or heterocyclic ring.

[0100] In some embodiments, U is selected from adenine, guanine, cytosine, uracil, thymine, inosine, and heterocycles of the following structure: [ka] is selected from.

[0101] In some embodiments, U is adenine. In some embodiments, U is guanine. In some embodiments, U is cytosine. In some embodiments, U is [ka] is.

[0102] In some embodiments, V is -OR Y In some embodiments, R Y is hydrogen. In some embodiments, R Y is optionally substituted alkyl, such as benzyl. In some embodiments, R Y is optionally substituted aryl, such as phenyl or naphthyl.

[0103] In some embodiments, V is -SR Z In some embodiments, R Z is hydrogen. In some embodiments, R Z is optionally substituted alkyl, such as benzyl. In some embodiments, R Z is optionally substituted aryl, such as phenyl or naphthyl.

[0104] In some embodiments, R 1 , R 2 , R 3 and R4 are independently selected from hydrogen, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl.

[0105] In some embodiments, R 1 is hydrogen.

[0106] In some embodiments, R 2 is hydrogen.

[0107] In some embodiments, R 3 is hydrogen. In some embodiments, R 3 is optionally substituted alkyl. In some embodiments, R 3 is methyl or hydroxymethyl.

[0108] In some embodiments, R 4 is hydrogen. In some embodiments, R 4 is optionally substituted alkyl. In some embodiments, R 4 is methyl or hydroxymethyl.

[0109] In some embodiments, R 1 , R 2 , R 3 and R 4 is hydrogen.

[0110] In some embodiments, R 1 and R 2 is hydrogen and R 3 and R 4 One of them is hydrogen, and R 3 and R 4 and the other is optionally substituted alkyl. In some embodiments, R 1 , R 2 and R 3 is hydrogen and R4 is methyl or hydroxylmethyl. In some embodiments, R 1 , R 2 and R 4 is hydrogen and R 3 is methyl or hydroxymethyl.

[0111] In some embodiments, L has the structure of formula V': [ka] (In the formula, U, R 3 and R 4 is the same as defined above. In some embodiments, R 3 is hydrogen. In some embodiments, R 3 is optionally substituted alkyl. In some embodiments, R 3 is methyl or hydroxylmethyl. In some embodiments, R 4 is hydrogen. In some embodiments, R 4 is optionally substituted alkyl. In some embodiments, R 4 is methyl or hydroxylmethyl. In some embodiments, R 3 and R 4 In some embodiments, both R 3 and R 4 One of the groups is hydrogen, and R 3 and R 4 and the other is optionally substituted alkyl. In some embodiments, R 3 is hydrogen and R 4 is methyl or hydroxylmethyl. In some embodiments, R 4 is hydrogen and R 3 is methyl or hydroxymethyl.

[0112] In some embodiments, L is: [ka] The hydroxybenzoates are selected from a tenofovir moiety, a cidofovir moiety, an adefovir moiety, a 9-[2-(phosphonomethoxy)ethyl]guanine moiety, a 9-(3-hydroxy-2-phosphonylmethoxypropyl)adenine moiety (preferably the (S)-HPMPA stereoisomer), and a 9-(2-phosphonylmethoxyethyl)-2,6-diaminopurine moiety, such as

[0113] In some embodiments, L is [ka] is.

[0114] In some embodiments, L is [ka] is.

[0115] In some embodiments, L is [ka] is.

[0116] Other representative acyclic nucleoside phosphonates can be found in Clercq, Biochemical Pharmacology, 2007, 73, 911-922.

[0117] 2. “W” part W is absent or a saturated C1-C9 alkyl chain (i.e., C1-C9 alkylene). In some embodiments, W is absent. In some embodiments, W is a saturated C1-C9 alkyl chain (i.e., C1-C9 alkylene). In some embodiments, W is a saturated, linear C1-C9 alkyl chain (i.e., linear C1-C9 alkylene), such as methylene (-CH2-), ethylene (-CH2CH2-), propylene (-CH2CH2CH2-), butylene (-CH2CH2CH2CH2-), pentylene (-CH2CH2CH2CH2CH2-), hexylene (-CH2CH2CH2CH2CH2CH2-), heptylene (-CH2CH2CH2CH2CH2CH2CH2-), octylene (-CH2CH2CH2CH2CH2CH2CH2CH2CH2-), and nonylene (-CH2CH2CH2CH2CH2CH2CH2CH2CH2-).

[0118] In some embodiments, W is ethylene (-CH2CH2-), propylene (-CH2CH2CH2-), or nonylene (-CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2-). In some embodiments, W is ethylene (-CH2CH2-) or propylene (-CH2CH2CH2-).

[0119] 3. “X” part X is selected from absent or substituted methylene or ethylene, -O-, -S-, -S(=O)-, and -S(O)2-.

[0120] In some embodiments, X is absent. In some embodiments, X is selected from substituted methylene or ethylene, -O-, -S-, -S(=O)-, and -S(O)-. In some embodiments, the substituted methylene or ethylene contains one or more halogen substituents. In some embodiments, the one or more halogen substituents is fluorine.

[0121] In some embodiments, X is a substituted methylene, such as -CF2-. In some embodiments, X is -O-. In some embodiments, X is -S-.

[0122] 4. “Y” part Y is saturated C2~C 20 Alkyl chain (i.e., C2-C 20 In some embodiments, Y is a saturated, linear C-C alkylene. 20 Alkyl chain (i.e., linear C2-C 20 Alkylene), such as ethylene (-CH2CH2-), propylene (-CH2CH2CH2-), butylene (-CH2CH2CH2CH2-), pentylene (-CH2CH2CH2CH2CH2-), hexylene (-CH2CH2CH2CH2CH2CH2-), heptylene (-CH2CH2CH2CH2CH2CH2CH2-), octylene (-CH2CH2CH2CH2CH2CH2CH2CH2-), nonylene [-(CH2)9-], decylene [-(CH2) 10 -], undecylene [-(CH2) 11 -], dodecylene [-(CH2) 12 -], tridecylene [-(CH2) 13 -], tetradecylene [-(CH2) 14 -], pentadecylene [-(CH2) 15 -], hexadecylene [-(CH2) 16 -], heptadecylene [-(CH2) 17 -], octadecylene [-(CH2) 18 -], nonadecylene [-(CH2) 19 -] and icosylene [-(CH2) 20 -] etc.

[0123] In some embodiments, Y is a saturated, linear C2-C7 alkyl chain (i.e., linear C2-C7 alkylene). In some embodiments, Y is a saturated, linear C8-C 20 Alkyl chain (i.e., linear C8-C 20 alkylene).

[0124] 5. “Z” part Z is selected from hydrogen, optionally substituted methyl or ethyl, optionally substituted unsaturated C2-C3 alkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, Si-substituted silyl, S-substituted thiol, O-substituted hydroxyl, ester, and -SF5.

[0125] Examples of Z include -CD3, -CF3, -CD2CD3, -CF2CF3, -S-Ph, -O-Ph, and -C≡CH 、 -C≡CCD3, -CH2FC≡C, -CHF2C≡C, -C≡CSi(CH3)3, -C≡CC(CH3)3, -C≡CCF3, -C≡CSF5, -Si(CH3)3, -C(CH3)3, -C(O)OCH3, -SF5 and the following: [ka] (In the formula, * indicates the point of attachment to Y).

[0126] In some embodiments, Z is hydrogen, methyl, or ethyl. In some embodiments, Z is hydrogen.

[0127] In some embodiments, Z is selected from substituted methyl or ethyl, optionally substituted unsaturated C-C alkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, Si-substituted silyl, S-substituted thiol, O-substituted hydroxyl, ester, and —SF.

[0128] In some embodiments, Z is a substituted methyl or ethyl having one or more substituents. In some embodiments, the one or more substituents are independently selected from deuterium, halogen, and alkyl. In some embodiments, Z is selected from -CD3, -CF3, -C(CH3)3, -CD2CD3, and -CF2CF3. In some embodiments, Z is -CF3.

[0129] In some embodiments, Z is an optionally substituted unsaturated C2-C3 alkyl, which may have one or more substituents. For example, Z can be an optionally substituted C2-C3 alkynyl, such as optionally substituted ethynyl and optionally substituted propynyl (including optionally substituted 1-propynyl and optionally substituted 2-propynyl). In some embodiments, the one or more substitutions are independently selected from deuterium, halogen (such as fluorine), alkyl, heteroalkyl, carbocyclyl (such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl), heterocyclyl, aryl (such as phenyl), heteroaryl (such as pyridinyl and thiophenyl), silyl, and —SF5, where each substituent is selected from one or more R as described in Formula I above. A In some embodiments, Z is selected from the group consisting of -C≡CH, -C≡CCD3, -C≡CCH2F, -C≡CCHF2, -C≡CCF3, -C≡CSi(CH3)3, -C≡CC(CH3)3, -C≡CSF5, and the following: [ka] (In the formula, * indicates the point of attachment to Y. In some embodiments, Z is —C≡CSi(CH 3 ) 3 .

[0130] In some embodiments, Z is optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl. In some embodiments, the substituents are independently selected from halogen, alkyl, heteroalkyl, silyl, and -SF5, where each substituent is selected from one or more R as described in formula I above. A It may be further substituted by a group. Representative substituents for Z include fluorine, trifluoromethyl, ethynyl, 2-pentafluorosulfanylethynyl, 2-trimethylsilylethynyl, 2-(tert-butyl)ethynyl, tert-butyl, trimethylsilyl, and -SF5. In some embodiments, Z is an optionally substituted carbocyclyl, such as optionally substituted cyclopropyl, optionally substituted cyclobutyl, optionally substituted cyclopentyl, and optionally substituted cyclohexyl. In some embodiments, Z is an optionally substituted heterocyclyl. In some embodiments, Z is an optionally substituted aryl, such as an optionally substituted phenyl (e.g., phenyl, 2-flurophenyl, 3-flurophenyl, 4-fluorophenyl, 2,4,6-triflurophenyl, 2,3,4,5,6-pentaflurophenyl, 4-(tert-butyl)phenyl, 4-(pentafluorosulfanyl)phenyl, 4-(trifluoromethyl)phenyl, 4-ethynylphenyl, 4-(2-pentafluorosulfanylethynyl)phenyl, 4-(2-trimethylsilylethynyl)phenyl, 4-(2-(tert-butyl)ethynyl)phenyl, etc. In some embodiments, Z is an optionally substituted heteroaryl, such as an optionally substituted pyridinyl and an optionally substituted thiophenyl. In some embodiments, Z is an optionally substituted heteroaryl, such as an optionally substituted pyridinyl and an optionally substituted thiophenyl. [ka] (In the formula, * indicates the point of attachment to Y).

[0131] In some embodiments, Z is Si-substituted silyl having one or more substituents. When there are multiple substituents, two of the substituents may be linked together with the Si atom to form a cyclic moiety, such as a heterocycle. In some embodiments, the one or more substituents are independently selected from alkyl (such as methyl, ethyl, propyl, isopropyl, tert-butyl, and isobutyl), heteroalkyl, carbocyclyl (such as cyclohexyl and bicyclo[2.2.1]heptyl), heterocyclyl, aryl (such as phenyl), and heteroaryl, where each substituent is selected from one or more R as described in Formula I above. A In some embodiments, the Si-substituted silyl has three substituents independently selected from alkyl, heteroalkyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl, where each substituent is selected from one or more R A In some embodiments, Z is selected from the group: [ka] (In the formula, * indicates the point of attachment to Y. In some embodiments, Z is trimethylsilyl.

[0132] In some embodiments, Z is an S-substituted thiol having one substituent. In some embodiments, the substituent is one or more R A In some embodiments, the substituents are selected from alkyl, heteroalkyl, carbocyclyl, heterocyclyl, aryl (such as phenyl), and heteroaryl, which may be further substituted by groups. In some embodiments, the substituents are selected from one or more R A In some embodiments, Z is -S-Ph.

[0133] In some embodiments, Z is O-substituted hydroxyl having one substituent. In some embodiments, the substituent is one or more R as described in formula I above. AIn some embodiments, the substituents are selected from alkyl, heteroalkyl, carbocyclyl, heterocyclyl, aryl (such as phenyl), and heteroaryl, which may be further substituted by groups. In some embodiments, the substituents are selected from one or more R A In some embodiments, Z is -O-Ph.

[0134] In some embodiments, Z is an ester. In some embodiments, Z is —C(O)OCH 3 .

[0135] In some embodiments, Z is —SF 5 .

[0136] B. Metabolic Stability and Pharmaceutical Properties In some embodiments, the compounds have better stability than CMX157. In some embodiments, the compounds may be resistant to enzyme-mediated ω-oxidation, such as ω-oxidation catalyzed by cytochrome P450 enzymes (e.g., isoforms 3A4 and 2D6). The compounds may be more resistant to ω-oxidation by cytochrome P450 enzymes compared to CMX157.

[0137] In some embodiments, the compound is CMX157(t 1 / 2 Higher human liver microsome (HLM) stability (t = 42 min) than 1 / 2 In some embodiments, the compounds have an HLMt of greater than 45 minutes, preferably greater than 60 minutes, more preferably greater than 90 minutes, and most preferably greater than 120 minutes. 1 / 2 HLMt 1 / 2 Values ​​can be determined using the methods described in Example 38.

[0138] Lipid-derived prodrugs described herein, such as lipid-derived prodrugs of TFV, can avoid first-pass degradation of active drugs (e.g., TFV) in the liver by targeting lymphatic uptake. Once they gain access to enterocytes, these prodrugs can be transported to the endoplasmic reticulum (ER) by lipid-binding proteins. Once accumulated in the ER membrane, they associate with triglyceride- and phospholipid-rich lipoproteins called chylomicrons. Drug-associated chylomicrons are then secreted into the interstitium via vesicular transport. Due to tight intercellular junctions, chylomicrons are size-excluded from portal capillaries, resulting in preferential uptake into lymphatic vessels with larger intercellular gaps. Drug-associated chylomicrons are then transported to the thoracic duct, which empties into the systemic circulation just upstream of the heart and lungs. Thus, by associating with chylomicrons in enterocytes of the intestinal tract, lipid-soluble prodrugs have the ability to hijack physiological lipid transport mechanisms to efficiently access the lymphatic vasculature. This mechanism provides the TFV lipid-derived prodrugs disclosed herein with distinct advantages over TDF and TAF. First, by bypassing first-pass hepatic metabolism, TFV levels in the liver and plasma are reduced, reducing bone mineral deficiency, nephrotoxicity, and hepatotoxicity, as well as prolonging the duration of action. Furthermore, because the gut-associated and intestinal lymphatic systems receive 50-70% of the body's lymphocytes, lymphatic-delivered TFV prodrugs directly target the HIV reservoir.

[0139] In some embodiments, the lipid-derived prodrugs disclosed herein may resist specific mechanisms of first-pass hepatic metabolism because they contain functional groups that can inactivate critical metabolic sites. For example, lipid-derived prodrugs of TFV disclosed herein that target lymphatic uptake and chemically resist hepatic metabolism may reduce TDF- and TAF-induced organ-specific toxicity and extend the duration of drug action, both of which are expected to improve patient adherence to chronic antiretroviral dosing schedules. By efficiently accessing HIV-infected cells and extending their duration of action, these TFV prodrugs have the potential to dramatically reduce the amount of drug needed to treat all HIV / AIDS patients worldwide, especially those in developing countries who lack affordable access to treatment.

[0140] In some embodiments, lipid-derived prodrugs may be resistant to CYP-mediated ω-oxidation. In some embodiments, the lipid-derived prodrugs contain terminal functional groups that can resist or slow this enzymatic process. For example, the lipid-derived prodrugs may contain metabolically less reactive terminal alkynes, as exemplified in the present disclosure. The lipid-derived prodrugs containing terminal alkynes may benefit from a greater C-H bond dissociation energy (acetylene C-H = 133.3 kcal / mol) that can result in slower enzymatic oxidation compared to their saturated counterparts (ethane C-H = 101.1 kcal / mol). Introduction of a trifluoromethyl or pentafluoroethyl group on the terminal acetylene may attenuate ω-oxidation. Bioisosteric replacement of hydrogen with fluorine may overcome issues related to poor pharmacokinetic performance as a result of oxidative metabolism. Penta-deuteroethyl and tri-deuteromethyl analogs may resist ω-oxidation via kinetic isotope effects. Terminally silylated lipid-derived prodrugs may be resistant to CYP-mediated ω-oxidation because the termini of these compounds may be sterically congested and electronically deactivated compared to their unsubstituted alkane counterparts. Terminally CF3-substituted lipid-derived prodrugs may be resistant to CYP-mediated ω-oxidation because the termini of these compounds may be electronically deactivated compared to their unsubstituted alkane counterparts. Terminally carbocyclyl-, heterocyclyl-, aryl-, or heteroaryl-substituted lipid-derived prodrugs may be resistant to CYP-mediated ω-oxidation because the termini of these compounds may be sterically congested and electronically deactivated compared to their unsubstituted alkane counterparts.

[0141] Generally, the "L" portion of the lipid-derived prodrug determines the therapeutic effect. In some embodiments, the L portion can separate from the remainder of the structure after administration to become the active drug. The "WXYZ" fraction of the lipid-derived prodrug can modulate the bioavailability (particularly oral bioavailability) and pharmacokinetics of the lipid-derived prodrug.

[0142] C. Typical structure 1.LOWXYZ In some embodiments, both W and X are present, ie, LOWXYZ.

[0143] In some embodiments, the compound has the following properties: L is [ka] and; W is -CH2CH2- or -CH2CH2CH2-; X is -CF2-, -O-, or -S-; Y is saturated, linear C8-C 20 Alkyl chain (i.e., linear C8-C 20 alkylene); Z is selected from substituted methyl or ethyl, optionally substituted unsaturated C2-C3 alkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, Si-substituted silyl, S-substituted thiol, O-substituted hydroxyl, ester, and -SF5.

[0144] In some embodiments, the compound has the following properties: L is [ka] and; W is -CH2CH2- or -CH2CH2CH2-; X is -CF2-, -O-, or -S-; Y is saturated, linear C8-C 20 Alkyl chain (i.e., linear C8-C 20 alkylene); Z is -CD3, -CF3, -CD2CD3, -CF2CF3, -S-Ph, -O-Ph, -C≡CH 、-C≡CCD3, -CH2FC≡C, -CHF2C≡C, -C≡CSi(CH3)3, -C≡CC(CH3)3, -C≡CCF3, -C≡CSF5, -Si(CH3)3, -C(CH3)3, -C(O)OCH3, -SF5 and the following: [ka] [ka] (In the formula, * indicates the point of attachment to Y).

[0145] Representative compounds include the following compounds and pharmaceutically acceptable salts thereof (e.g., ammonium salts): [ka] 4,4-Difluoroicos-19-yn-1-yl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 4,4-Difluoroicosyl-19,19,20,20,20-d5 hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 4,4-Difluoro-18-(trimethylsilyl)octadec-17-yn-1-yl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 4,4-Difluoro-18-(trimethylsilyl)octadecyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 4,4,20,20,20-Pentafluoroicos-18-yn-1-yl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 4,4,20,20,20-Pentafluoroicosyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 3-((11-(phenylthio)undecyl)thio)propyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 3-((11-phenoxyundecyl)thio)propyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] Methyl 16-((3-((((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)(hydroxy)phosphoryl)oxy)propyl)thio)hexadecanoate [ka] 3-(hexadec-15-yn-1-ylthio)propyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 3-(octadec-17-yn-1-ylthio)propyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 3-((hexadecyl-15,15,16,16,16-d5)thio)propyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 3-((14-(trimethylsilyl)tetradec-13-yn-1-yl)thio)propyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 3-((14-(trimethylsilyl)tetradecyl)thio)propyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 3-((15,15-dimethylhexadecyl)thio)propyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 3-((16,16,16-trifluorohexadec-14-yn-1-yl)thio)propyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 3-((16,16,16-trifluorohexadecyl)thio)propyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 3-((12-phenyldodecyl)thio)propyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 3-((12-(thiophen-2-yl)dodecyl)thio)propyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 3-((13-(thiophen-2-yl)tridecyl)thio)propyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 3-((12-phenyldodec-11-yn-1-yl)thio)propyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 3-((12-(thiophen-2-yl)dodec-11-yn-1-yl)thio)propyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 3-((13-(thiophen-2-yl)tridec-12-yn-1-yl)thio)propyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 3-((12-(perfluorophenyl)dodecyl)thio)propyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 3-((12-(pyridin-3-yl)dodecyl)thio)propyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 3-((12-(perfluorophenyl)dodec-11-yn-1-yl)thio)propyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 3-((12-(pyridin-3-yl)dodec-11-yn-1-yl)thio)propyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 3-((12-cyclohexyldodec-11-yn-1-yl)thio)propyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 3-((12-Cyclohexyldodecyl)thio)propyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 3-((12-(4-fluorophenyl)dodec-11-yn-1-yl)thio)propyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 3-((12-(4-fluorophenyl)dodecyl)thio)propyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 3-((12-(3-fluorophenyl)dodec-11-yn-1-yl)thio)propyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 3-((12-(3-fluorophenyl)dodecyl)thio)propyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 3-((12-(2-fluorophenyl)dodec-11-yn-1-yl)thio)propyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 3-((12-(2-fluorophenyl)dodecyl)thio)propyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 3-((12-(2,4,6-trifluorophenyl)dodec-11-yn-1-yl)thio)propyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 3-((12-(2,4,6-trifluorophenyl)dodecyl)thio)propyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 3-((13-cyclopentyltridec-12-yn-1-yl)thio)propyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 3-((13-Cyclopentyltridecyl)thio)propyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 3-((14-cyclopropyltetradecyl)thio)propyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 3-((14-cyclopropyltetradec-13-yn-1-yl)thio)propyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 3-((10-(4-(tert-butyl)phenyl)dec-9-yn-1-yl)thio)propyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 3-((10-(4-(tert-butyl)phenyl)decyl)thio)propyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 3-((15,15-dimethylhexadec-13-yn-1-yl)thio)propyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 3-((13-cyclobutyltridec-12-yn-1-yl)thio)propyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 3-((13-cyclobutyltridecyl)thio)propyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 3-((13-(1-methylsiletan-1-yl)tridec-12-yn-1-yl)thio)propyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 3-((13-(1-methylsiletan-1-yl)tridecyl)thio)propyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 3-((13-(ethyldimethylsilyl)tridec-12-yn-1-yl)thio)propyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 3-((13-(ethyldimethylsilyl)tridecyl)thio)propyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 3-((13-(triethylsilyl)tridec-12-yn-1-yl)thio)propyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 3-((13-(triethylsilyl)tridecyl)thio)propyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 3-((13-(triisopropylsilyl)tridec-12-yn-1-yl)thio)propyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 3-((13-(triisopropylsilyl)tridecyl)thio)propyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 3-((13-(tert-butyldimethylsilyl)tridec-12-yn-1-yl)thio)propyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 3-((13-(tert-butyldimethylsilyl)tridecyl)thio)propyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 3-((11-(dimethyl(phenyl)silyl)undec-10-yn-1-yl)thio)propyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 3-((11-(dimethyl(phenyl)silyl)undecyl)thio)propyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 3-((11-(dimethyl(perfluorophenyl)silyl)undec-10-yn-1-yl)thio)propyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 3-((11-(dimethyl(perfluorophenyl)silyl)undecyl)thio)propyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 3-((12-(dimethyl(3,3,3-trifluoropropyl)silyl)dodec-11-yn-1-yl)thio)propyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 3-((12-(dimethyl(3,3,3-trifluoropropyl)silyl)dodecyl)thio)propyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 3-((11-(cyclohexyldimethylsilyl)undec-10-yn-1-yl)thio)propyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 3-((11-(cyclohexyldimethylsilyl)undecyl)thio)propyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 3-((11-(bicyclo[2.2.1]heptan-2-yldimethylsilyl)undec-10-yn-1-yl)thio)propyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 3-((11-(bicyclo[2.2.1]heptan-2-yldimethylsilyl)undecyl)thio)propyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 3-((12-(isobutyldimethylsilyl)dodecyl)thio)propyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 3-((12-(isobutyldimethylsilyl)dodec-11-yn-1-yl)thio)propyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 3-((15,15,16,16,16-pentafluorohexadecyl)thio)propyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 3-((15-(pentafluoro-λ 6 -sulfanyl)pentadecyl)thio)propyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 3-((15-(pentafluoro-λ 6 -sulfanyl)pentadec-14-yn-1-yl)thio)propyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 3-((9-(4-((pentafluoro-λ 6 -sulfanyl)ethynyl)phenyl)nonyl)thio)propyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 3-((11-(4-(pentafluoro-λ 6 -sulfanyl)phenyl)undecyl)thio)propyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 3-((11-(4-(trifluoromethyl)phenyl)undecyl)thio)propyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 3-((11-(4-(pentafluoro-λ 6 -sulfanyl)phenyl)undec-10-yn-1-yl)thio)propyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 3-((11-(4-(trifluoromethyl)phenyl)undec-10-yn-1-yl)thio)propyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 3-((10-(4-(trimethylsilyl)phenyl)decyl)thio)propyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 3-((10-(4-(trimethylsilyl)phenyl)dec-9-yn-1-yl)thio)propyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 3-((10-(4-ethynylphenyl)decyl)thio)propyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 3-((8-(4-((trimethylsilyl)ethynyl)phenyl)octyl)thio)propyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 3-((8-(4-(3,3-dimethylbut-1-yn-1-yl)phenyl)octyl)thio)propyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 3-((11-(phenylthio)undecyl)oxy)propyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 3-((11-phenoxyundecyl)oxy)propyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] Methyl 16-(3-((((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)(hydroxy)phosphoryl)oxy)propoxy)hexadecanoate [ka] 3-(hexadec-15-yn-1-yloxy)propyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 3-((hexadecyl-15,15,16,16,16-d5)oxy)propyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 3-((15-(trimethylsilyl)pentadec-14-yn-1-yl)oxy)propyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 3-((14-(trimethylsilyl)tetradec-13-yn-1-yl)oxy)propyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 3-((14-(trimethylsilyl)tetradecyl)oxy)propyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 3-((15,15-dimethylhexadecyl)oxy)propyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 3-((16,16,16-trifluorohexadec-14-yn-1-yl)oxy)propyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 3-((16,16,16-trifluorohexadecyl)oxy)propyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 3-((12-phenyldodecyl)oxy)propyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 3-((12-(thiophen-2-yl)dodecyl)oxy)propyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 3-((13-(thiophen-2-yl)tridecyl)oxy)propyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 3-((12-phenyldodec-11-yn-1-yl)oxy)propyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 3-((12-(thiophen-2-yl)dodec-11-yn-1-yl)oxy)propyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 3-((13-(thiophen-2-yl)tridec-12-yn-1-yl)oxy)propyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 3-((12-(pyridin-3-yl)dodecyl)oxy)propyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 3-((12-(pyridin-3-yl)dodec-11-yn-1-yl)oxy)propyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 3-((12-(perfluorophenyl)dodec-11-yn-1-yl)oxy)propyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 3-((12-(perfluorophenyl)dodecyl)oxy)propyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 3-((12-(4-fluorophenyl)dodec-11-yn-1-yl)oxy)propyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 3-((12-(4-fluorophenyl)dodecyl)oxy)propyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 3-((12-(3-fluorophenyl)dodec-11-yn-1-yl)oxy)propyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 3-((12-(3-fluorophenyl)dodecyl)oxy)propyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 3-((12-(2-fluorophenyl)dodec-11-yn-1-yl)oxy)propyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 3-((12-(2-fluorophenyl)dodecyl)oxy)propyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 3-((12-(2,4,6-trifluorophenyl)dodec-11-yn-1-yl)oxy)propyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 3-((12-(2,4,6-trifluorophenyl)dodecyl)oxy)propyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 3-((10-(4-(tert-butyl)phenyl)dec-9-yn-1-yl)oxy)propyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 3-((10-(4-(tert-butyl)phenyl)decyl)oxy)propyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 3-((15,15-dimethylhexadec-13-yn-1-yl)oxy)propyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 3-((14-cyclopropyltetradec-13-yn-1-yl)oxy)propyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 3-((14-Cyclopropyltetradecyl)oxy)propyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 3-((12-Cyclohexyldodec-11-yn-1-yl)oxy)propyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 3-((12-Cyclohexyldodecyl)oxy)propyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 3-((13-cyclopentyltridec-12-yn-1-yl)oxy)propyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 3-((13-Cyclopentyltridecyl)oxy)propyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 3-((13-cyclobutyltridec-12-yn-1-yl)oxy)propyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 3-((13-cyclobutyltridecyl)oxy)propyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 3-((13-(1-methylsiletan-1-yl)tridec-12-yn-1-yl)oxy)propyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 3-((13-(1-methylsiletan-1-yl)tridecyl)oxy)propyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 3-((13-(ethyldimethylsilyl)tridec-12-yn-1-yl)oxy)propyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 3-((13-(ethyldimethylsilyl)tridecyl)oxy)propyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 3-((13-(triethylsilyl)tridec-12-yn-1-yl)oxy)propyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 3-((13-(triethylsilyl)tridecyl)oxy)propyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 3-((13-(triisopropylsilyl)tridec-12-yn-1-yl)oxy)propyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 3-((13-(triisopropylsilyl)tridecyl)oxy)propyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 3-((13-(tert-butyldimethylsilyl)tridec-12-yn-1-yl)oxy)propyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 3-((13-(tert-butyldimethylsilyl)tridecyl)oxy)propyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 3-((11-(dimethyl(phenyl)silyl)undec-10-yn-1-yl)oxy)propyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 3-((11-(dimethyl(phenyl)silyl)undecyl)oxy)propyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 3-((11-(dimethyl(perfluorophenyl)silyl)undec-10-yn-1-yl)oxy)propyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 3-((11-(dimethyl(perfluorophenyl)silyl)undecyl)oxy)propyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 3-((12-(dimethyl(3,3,3-trifluoropropyl)silyl)dodec-11-yn-1-yl)oxy)propyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 3-((12-(dimethyl(3,3,3-trifluoropropyl)silyl)dodecyl)oxy)propyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 3-((11-(cyclohexyldimethylsilyl)undec-10-yn-1-yl)oxy)propyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 3-((11-(cyclohexyldimethylsilyl)undecyl)oxy)propyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 3-((11-(bicyclo[2.2.1]heptan-2-yldimethylsilyl)undec-10-yn-1-yl)oxy)propyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 3-((11-(bicyclo[2.2.1]heptan-2-yldimethylsilyl)undecyl)oxy)propyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 3-((12-(isobutyldimethylsilyl)dodecyl)oxy)propyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 3-((12-(isobutyldimethylsilyl)dodec-11-yn-1-yl)oxy)propyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 3-((15,15,16,16,16-pentafluorohexadecyl)oxy)propyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 3-((15-(pentafluoro-λ 6 -sulfanyl)pentadecyl)oxy)propyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 3-((15-(pentafluoro-λ 6 -sulfanyl)pentadec-14-yn-1-yl)oxy)propyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 3-((9-(4-((pentafluoro-λ 6 -sulfanyl)ethynyl)phenyl)nonyl)oxy)propyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 3-((11-(4-(pentafluoro-λ 6 -sulfanyl)phenyl)undecyl)oxy)propyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 3-((11-(4-(trifluoromethyl)phenyl)undecyl)oxy)propyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 3-((11-(4-(pentafluoro-λ 6 -sulfanyl)phenyl)undec-10-yn-1-yl)oxy)propyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 3-((11-(4-(trifluoromethyl)phenyl)undec-10-yn-1-yl)oxy)propyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 3-((10-(4-(trimethylsilyl)phenyl)decyl)oxy)propyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 3-((10-(4-(trimethylsilyl)phenyl)dec-9-yn-1-yl)oxy)propyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 3-((10-(4-ethynylphenyl)decyl)oxy)propyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 3-((8-(4-((trimethylsilyl)ethynyl)phenyl)octyl)oxy)propyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 3-((8-(4-(3,3-dimethylbut-1-yn-1-yl)phenyl)octyl)oxy)propyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 2-(Heptadec-16-yn-1-ylthio)ethyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 2-((15-(trimethylsilyl)pentadec-14-yn-1-yl)thio)ethyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 2-((16-(trimethylsilyl)hexadec-15-yn-1-yl)thio)ethyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 2-((15-(trimethylsilyl)pentadecyl)thio)ethyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 2-((16,16-dimethylheptadecyl)thio)ethyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 2-((17,17,17-trifluoroheptadec-15-yn-1-yl)thio)ethyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 2-((17,17,17-trifluoroheptadecyl)thio)ethyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 2-((18,18,18-trifluorooctadecyl)thio)ethyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 2-((13-phenyltridecyl)thio)ethyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 2-((13-(thiophen-2-yl)tridecyl)thio)ethyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 2-((14-(thiophen-2-yl)tetradecyl)thio)ethyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 2-((13-phenyltridec-12-yn-1-yl)thio)ethyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 2-((13-(thiophen-2-yl)tridec-12-yn-1-yl)thio)ethyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 2-((14-(thiophen-2-yl)tetradec-13-yn-1-yl)thio)ethyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 2-((13-(perfluorophenyl)tridecyl)thio)ethyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 2-((13-(pyridin-3-yl)tridecyl)thio)ethyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 2-((13-(perfluorophenyl)tridec-12-yn-1-yl)thio)ethyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 2-((13-(pyridin-3-yl)tridec-12-yn-1-yl)thio)ethyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 2-((13-cyclohexyltridec-12-yn-1-yl)thio)ethyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 2-((13-Cyclohexyltridecyl)thio)ethyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 2-((13-(4-fluorophenyl)tridec-12-yn-1-yl)thio)ethyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 2-((13-(4-fluorophenyl)tridecyl)thio)ethyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 2-((13-(3-fluorophenyl)tridec-12-yn-1-yl)thio)ethyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 2-((13-(3-fluorophenyl)tridecyl)thio)ethyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 2-((13-(2-fluorophenyl)tridec-12-yn-1-yl)thio)ethyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 2-((13-(2-fluorophenyl)tridecyl)thio)ethyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 2-((13-(2,4,6-trifluorophenyl)tridec-12-yn-1-yl)thio)ethyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 2-((13-(2,4,6-trifluorophenyl)tridecyl)thio)ethyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 2-((14-Cyclopentyltetradec-13-yn-1-yl)thio)ethyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 2-((14-Cyclopentyltetradecyl)thio)ethyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 2-((15-Cyclopropylpentadecyl)thio)ethyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 2-((15-cyclopropylpentadec-14-yn-1-yl)thio)ethyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 2-((11-(4-(tert-butyl)phenyl)undec-10-yn-1-yl)thio)ethyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 2-((11-(4-(tert-butyl)phenyl)undecyl)thio)ethyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 2-((16,16-dimethylheptadec-14-yn-1-yl)thio)ethyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 2-((14-Cyclobutyltetradec-13-yn-1-yl)thio)ethyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 2-((14-Cyclobutyltetradecyl)thio)ethyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 2-((14-(1-methylsiletan-1-yl)tetradec-13-yn-1-yl)thio)ethyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 2-((14-(1-methylsiletan-1-yl)tetradecyl)thio)ethyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 2-((14-(ethyldimethylsilyl)tetradec-13-yn-1-yl)thio)ethyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 2-((14-(ethyldimethylsilyl)tetradecyl)thio)ethyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 2-((14-(triethylsilyl)tetradec-13-yn-1-yl)thio)ethyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 2-((14-(triethylsilyl)tetradecyl)thio)ethyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 2-((14-(triisopropylsilyl)tetradec-13-yn-1-yl)thio)ethyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 2-((14-(triisopropylsilyl)tetradecyl)thio)ethyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 2-((14-(tert-butyldimethylsilyl)tetradec-13-yn-1-yl)thio)ethyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 2-((14-(tert-butyldimethylsilyl)tetradecyl)thio)ethyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 2-((12-(dimethyl(phenyl)silyl)dodec-11-yn-1-yl)thio)ethyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 2-((12-(dimethyl(phenyl)silyl)dodecyl)thio)ethyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 2-((12-(dimethyl(perfluorophenyl)silyl)dodec-11-yn-1-yl)thio)ethyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 2-((12-(dimethyl(perfluorophenyl)silyl)dodecyl)thio)ethyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 2-((13-(dimethyl(3,3,3-trifluoropropyl)silyl)tridec-12-yn-1-yl)thio)ethyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 2-((13-(dimethyl(3,3,3-trifluoropropyl)silyl)tridecyl)thio)ethyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 2-((12-(cyclohexyldimethylsilyl)dodec-11-yn-1-yl)thio)ethyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 2-((12-(cyclohexyldimethylsilyl)dodecyl)thio)ethyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 2-((12-(bicyclo[2.2.1]heptan-2-yldimethylsilyl)dodec-11-yn-1-yl)thio)ethyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 2-((12-(bicyclo[2.2.1]heptan-2-yldimethylsilyl)dodecyl)thio)ethyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 2-((13-(isobutyldimethylsilyl)tridecyl)thio)ethyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 2-((13-(isobutyldimethylsilyl)tridec-12-yn-1-yl)thio)ethyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 2-((16,16,17,17,17-pentafluoroheptadecyl)thio)ethyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 2-((16-(pentafluoro-λ 6 -sulfanyl)hexadecyl)thio)ethyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 2-((16-(pentafluoro-λ 6 -sulfanyl)hexadec-15-yn-1-yl)thio)ethyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 2-((10-(4-((pentafluoro-λ 6 -sulfanyl)ethynyl)phenyl)decyl)thio)ethyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 2-((12-(4-(pentafluoro-λ 6 -sulfanyl)phenyl)dodecyl)thio)ethyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 2-((12-(4-(trifluoromethyl)phenyl)dodecyl)thio)ethyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 2-((12-(4-(pentafluoro-λ 6 -sulfanyl)phenyl)dodec-11-yn-1-yl)thio)ethyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 2-((12-(4-(trifluoromethyl)phenyl)dodec-11-yn-1-yl)thio)ethyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 2-((11-(4-(trimethylsilyl)phenyl)undecyl)thio)ethyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 2-((11-(4-(trimethylsilyl)phenyl)undec-10-yn-1-yl)thio)ethyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 2-((11-(4-ethynylphenyl)undecyl)thio)ethyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 2-((9-(4-((trimethylsilyl)ethynyl)phenyl)nonyl)thio)ethyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 2-((9-(4-(3,3-dimethylbut-1-yn-1-yl)phenyl)nonyl)thio)ethyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 2-(heptadec-16-yn-1-yloxy)ethyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 2-((15-(trimethylsilyl)pentadec-14-yn-1-yl)oxy)ethyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 2-((16-(trimethylsilyl)hexadec-15-yn-1-yl)oxy)ethyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 2-((15-(trimethylsilyl)pentadecyl)oxy)ethyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 2-((16,16-dimethylheptadecyl)oxy)ethyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 2-((17,17,17-trifluoroheptadec-15-yn-1-yl)oxy)ethyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 2-((17,17,17-trifluoroheptadecyl)oxy)ethyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 2-((18,18,18-trifluorooctadecyl)oxy)ethyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 2-((13-phenyltridecyl)oxy)ethyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 2-((13-(thiophen-2-yl)tridecyl)oxy)ethyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 2-((14-(thiophen-2-yl)tetradecyl)oxy)ethyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 2-((13-phenyltridec-12-yn-1-yl)oxy)ethyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 2-((13-(thiophen-2-yl)tridec-12-yn-1-yl)oxy)ethyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 2-((14-(thiophen-2-yl)tetradec-13-yn-1-yl)oxy)ethyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 2-((13-(perfluorophenyl)tridecyl)oxy)ethyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 2-((13-(pyridin-3-yl)tridecyl)oxy)ethyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 2-((13-(perfluorophenyl)tridec-12-yn-1-yl)oxy)ethyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 2-((13-(pyridin-3-yl)tridec-12-yn-1-yl)oxy)ethyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 2-((13-cyclohexyltridec-12-yn-1-yl)oxy)ethyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 2-((13-Cyclohexyltridecyl)oxy)ethyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 2-((13-(4-fluorophenyl)tridec-12-yn-1-yl)oxy)ethyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 2-((13-(4-Fluorophenyl)tridecyl)oxy)ethyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 2-((13-(3-fluorophenyl)tridec-12-yn-1-yl)oxy)ethyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 2-((13-(3-fluorophenyl)tridecyl)oxy)ethyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 2-((13-(2-fluorophenyl)tridec-12-yn-1-yl)oxy)ethyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 2-((13-(2-fluorophenyl)tridecyl)oxy)ethyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 2-((13-(2,4,6-trifluorophenyl)tridec-12-yn-1-yl)oxy)ethyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 2-((13-(2,4,6-trifluorophenyl)tridecyl)oxy)ethyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 2-((14-Cyclopentyltetradec-13-yn-1-yl)oxy)ethyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 2-((14-Cyclopentyltetradecyl)oxy)ethyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 2-((15-Cyclopropylpentadecyl)oxy)ethyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 2-((15-cyclopropylpentadec-14-yn-1-yl)oxy)ethyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 2-((11-(4-(tert-butyl)phenyl)undec-10-yn-1-yl)oxy)ethyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 2-((11-(4-(tert-butyl)phenyl)undecyl)oxy)ethyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 2-((16,16-dimethylheptadec-14-yn-1-yl)oxy)ethyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 2-((14-Cyclobutyltetradec-13-yn-1-yl)oxy)ethyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 2-((14-Cyclobutyltetradecyl)oxy)ethyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 2-((14-(1-methylsiletan-1-yl)tetradec-13-yn-1-yl)oxy)ethyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 2-((14-(1-methylsiletan-1-yl)tetradecyl)oxy)ethyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 2-((14-(ethyldimethylsilyl)tetradec-13-yn-1-yl)oxy)ethyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 2-((14-(ethyldimethylsilyl)tetradecyl)oxy)ethyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 2-((14-(triethylsilyl)tetradec-13-yn-1-yl)oxy)ethyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 2-((14-(triethylsilyl)tetradecyl)oxy)ethyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 2-((14-(triisopropylsilyl)tetradec-13-yn-1-yl)oxy)ethyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 2-((14-(triisopropylsilyl)tetradecyl)oxy)ethyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 2-((14-(tert-butyldimethylsilyl)tetradec-13-yn-1-yl)oxy)ethyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 2-((14-(tert-butyldimethylsilyl)tetradecyl)oxy)ethyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 2-((12-(dimethyl(phenyl)silyl)dodec-11-yn-1-yl)oxy)ethyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 2-((12-(dimethyl(phenyl)silyl)dodecyl)oxy)ethyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 2-((12-(dimethyl(perfluorophenyl)silyl)dodec-11-yn-1-yl)oxy)ethyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 2-((12-(dimethyl(perfluorophenyl)silyl)dodecyl)oxy)ethyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 2-((13-(dimethyl(3,3,3-trifluoropropyl)silyl)tridec-12-yn-1-yl)oxy)ethyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 2-((13-(dimethyl(3,3,3-trifluoropropyl)silyl)tridecyl)oxy)ethyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 2-((12-(cyclohexyldimethylsilyl)dodec-11-yn-1-yl)oxy)ethyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 2-((12-(cyclohexyldimethylsilyl)dodecyl)oxy)ethyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 2-((12-(bicyclo[2.2.1]heptan-2-yldimethylsilyl)dodec-11-yn-1-yl)oxy)ethyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 2-((12-(bicyclo[2.2.1]heptan-2-yldimethylsilyl)dodecyl)oxy)ethyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 2-((13-(isobutyldimethylsilyl)tridecyl)oxy)ethyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 2-((13-(isobutyldimethylsilyl)tridec-12-yn-1-yl)oxy)ethyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 2-((16,16,17,17,17-pentafluoroheptadecyl)oxy)ethyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 2-((16-(pentafluoro-λ 6 -sulfanyl)hexadecyl)oxy)ethyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 2-((16-(pentafluoro-λ 6 -sulfanyl)hexadec-15-yn-1-yl)oxy)ethyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 2-((10-(4-((pentafluoro-λ 6 -sulfanyl)ethynyl)phenyl)decyl)oxy)ethyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 2-((12-(4-(pentafluoro-λ 6 -sulfanyl)phenyl)dodecyl)oxy)ethyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 2-((12-(4-(trifluoromethyl)phenyl)dodecyl)oxy)ethyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 2-((12-(4-(pentafluoro-λ 6 -sulfanyl)phenyl)dodec-11-yn-1-yl)oxy)ethyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 2-((12-(4-(trifluoromethyl)phenyl)dodec-11-yn-1-yl)oxy)ethyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 2-((11-(4-(trimethylsilyl)phenyl)undecyl)oxy)ethyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 2-((11-(4-(trimethylsilyl)phenyl)undec-10-yn-1-yl)oxy)ethyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 2-((11-(4-ethynylphenyl)undecyl)oxy)ethyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 2-((9-(4-((trimethylsilyl)ethynyl)phenyl)nonyl)oxy)ethyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate [ka] 2-((9-(4-(3,3-dimethylbut-1-yn-1-yl)phenyl)nonyl)oxy)ethyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate These include, but are not limited to:

[0146] Other representative compounds include the following compounds and pharmaceutically acceptable salts thereof (such as ammonium salts): [ka] 2-((18,18,18-trifluorooctadecyl)oxy)ethyl hydrogen((2-(2-amino-6-oxo-1,6-dihydro-9H-purin-9-yl)ethoxy)methyl)phosphonate [ka] 2-((18,18,18-trifluorooctadecyl)thio)ethyl hydrogen ((2-(2-amino-6-oxo-1,6-dihydro-9H-purin-9-yl)ethoxy)methyl)phosphonate [ka] 2-((19,19,19-trifluorononadecyl)oxy)ethyl hydrogen((2-(2-amino-6-oxo-1,6-dihydro-9H-purin-9-yl)ethoxy)methyl)phosphonate [ka] 2-((19,19,19-trifluorononadecyl)thio)ethyl hydrogen ((2-(2-amino-6-oxo-1,6-dihydro-9H-purin-9-yl)ethoxy)methyl)phosphonate [ka] 2-((15-(trimethylsilyl)pentadec-14-yn-1-yl)oxy)ethyl hydrogen((2-(2-amino-6-oxo-1,6-dihydro-9H-purin-9-yl)ethoxy)methyl)phosphonate [ka] 2-((15-(trimethylsilyl)pentadec-14-yn-1-yl)thio)ethyl hydrogen ((2-(2-amino-6-oxo-1,6-dihydro-9H-purin-9-yl)ethoxy)methyl)phosphonate [ka] 2-((16-(trimethylsilyl)hexadec-15-yn-1-yl)oxy)ethyl hydrogen((2-(2-amino-6-oxo-1,6-dihydro-9H-purin-9-yl)ethoxy)methyl)phosphonate [ka] 2-((16-(trimethylsilyl)hexadec-15-yn-1-yl)thio)ethyl hydrogen ((2-(2-amino-6-oxo-1,6-dihydro-9H-purin-9-yl)ethoxy)methyl)phosphonate [ka] 3-((16,16,16-trifluorohexadecyl)oxy)propyl hydrogen((2-(2-amino-6-oxo-1,6-dihydro-9H-purin-9-yl)ethoxy)methyl)phosphonate [ka] 3-((16,16,16-trifluorohexadecyl)thio)propyl hydrogen ((2-(2-amino-6-oxo-1,6-dihydro-9H-purin-9-yl)ethoxy)methyl)phosphonate [ka] 3-((14-(trimethylsilyl)tetradec-13-yn-1-yl)thio)propyl hydrogen((2-(2-amino-6-oxo-1,6-dihydro-9H-purin-9-yl)ethoxy)methyl)phosphonate [ka] 3-((14-(trimethylsilyl)tetradec-13-yn-1-yl)oxy)propyl hydrogen((2-(2-amino-6-oxo-1,6-dihydro-9H-purin-9-yl)ethoxy)methyl)phosphonate These include, but are not limited to:

[0147] In some embodiments, the compound has the following properties: L is [ka] and; W is a saturated, linear C1-C9 alkyl chain (i.e., linear C1-C9 alkylene); X is -CF2-, -O-, or -S-; Y is saturated, linear C2-C 20 Alkyl chain (i.e., linear C2-C 20 alkylene); Z is hydrogen, methyl or ethyl.

[0148] In some embodiments, the compound has the following properties: L is [ka] and; W is a saturated, linear C1-C9 alkyl chain (i.e., linear C1-C9 alkylene); X is -CF2- or -S-; Y is saturated, linear C2-C 20 Alkyl chain (i.e., linear C2-C 20 alkylene); Z is hydrogen, methyl or ethyl.

[0149] Representative compounds include the following compounds and pharmaceutically acceptable salts thereof (such as ammonium salts): [ka] [ka] [ka] [ka] These include, but are not limited to:

[0150] 2.LOYZ In some embodiments, both W and X are absent, ie, LOYZ.

[0151] In some embodiments, the compound has the following properties: L is [ka] and; Y is saturated, linear C8-C 20 Alkyl chain (i.e., linear C8-C 20 alkylene); Z is selected from substituted methyl or ethyl, optionally substituted unsaturated C2-C3 alkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, Si-substituted silyl, S-substituted thiol, O-substituted hydroxyl, ester, and -SF5.

[0152] In some embodiments, the compound has the following properties: L is [ka] and; Y is saturated, linear C8-C 20 Alkyl chain (i.e., linear C8-C 20 alkylene); Z is -CD3, -CF3, -CD2CD3, -CF2CF3, -S-Ph, -O-Ph, -C≡CH 、 -C≡CCD3, -CH2FC≡C, -CHF2C≡C, -C≡CSi(CH3)3, -C≡CC(CH3)3, -C≡CCF3, -C≡CSF5, -Si(CH3)3, -C(CH3)3, -C(O)OCH3, -SF5 and the following: [ka] [ka] (In the formula, * indicates the point of attachment to Y).

[0153] Representative compounds include the following compounds and pharmaceutically acceptable salts thereof (such as ammonium salts): [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] These include, but are not limited to:

[0154] III. Further Compounds According to an embodiment of the present disclosure, there is provided a compound represented by the following formula or a salt thereof: [ka] (In the formula, L is an acyclic nucleoside phosphonate or a linking group coupled to a nucleoside or nucleobase; W is a saturated C1-C9 alkyl chain or a direct bond between adjacent atoms thereof; X is selected from a substituted methylene or ethylene group or a heteroatom, or is a direct bond between adjacent atoms; Y is saturated C9~C 20 is an alkyl chain; Z is selected from an optionally substituted methyl or ethyl group, an optionally substituted unsaturated C2-C3 alkyl, or an optionally substituted heteroatom, or is absent; Optional substituents include alkyl, deuterium, halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, trimethylsilyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethyl ... (which may be selected from the group consisting of N,N-dimethylsulfamoyl, N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulfonyl, methoxycarbonyl, ethoxycarbonyl, N-methylsulfamoyl, N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, N-methyl-N-ethylsulfamoyl, benzyl, benzoyl, carbocyclyl, aryl, and heterocyclyl) is provided.

[0155] Further properties include: L is an acyclic nucleoside phosphonate, such as tenofovir, cidofovir, adefovir, (9-[2-(phosphonomethoxy)ethyl]guanine), 9-(3-hydroxy-2-phosphonylmethoxypropyl)adenine, or 9-(2-phosphonylmethoxyethyl)-2,6-diaminopurine; W is a saturated C2, C3 or C9 alkyl chain; X is selected from the group including CF2, O, S; Y is C 13 ~C 19 being an alkyl chain; and Z, [ka] CD3, CF3, CD2CD3, SPh, C≡CH、 C≡CCD3, CF2HC≡C, Si(CH3)3, C≡CSi(CH3)3, C≡CCF3, C(O)OCH3, C≡CSF5 and SF5, where * indicates the point of attachment to Y) to provide.

[0156] According to another embodiment of the present disclosure, a compound of the following formula or a salt thereof: [ka] (In the formula, L is an acyclic nucleoside phosphonate or a linking group coupled to a nucleoside or nucleobase; W is a C1-C9 alkyl chain or a direct bond between adjacent atoms thereof; X is selected from a substituted methylene or ethylene group and a heteroatom or is a direct bond between adjacent atoms; Y is C9~C 20 is an alkyl chain; The optional substituents may be selected from deuterium, halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulfonyl, methoxycarbonyl, ethoxycarbonyl, N-methylsulfamoyl, N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, N-methyl-N-ethylsulfamoyl, benzyl, benzoyl, carbocyclyl, aryl, and heterocyclyl. is provided.

[0157] According to another embodiment of the present disclosure, a compound of the following formula or a salt thereof: [ka] (In the formula, L is an acyclic nucleoside phosphonate or a linking group coupled to a nucleoside or nucleobase; Y is C9~C 20 is an alkyl chain; Z is selected from a substituted methyl or ethyl group, an optionally substituted unsaturated C2-C3 alkyl, and an optionally substituted heteroatom, or is absent; The optional substituents may be selected from deuterium, halogen, nitro, cyano, trifluoromethoxy, trifluoromethyl, amino, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulfonyl, N-methylsulfamoyl, N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, N-methyl-N-ethylsulfamoyl, benzyl, benzoyl, carbocyclyl, aryl, and heterocyclyl. is provided.

[0158] In certain embodiments, the present disclosure contemplates derivatives of the compounds disclosed herein, for example, those containing one or more of the same or different substituents.

[0159] IV. Pharmaceutical Formulations Pharmaceutical formulations containing the compounds disclosed herein are provided.Generally, the pharmaceutical formulations also contain pharmaceutically acceptable carriers.The pharmaceutical formulations can be in the form of tablets, capsules, pills, gels, granules, aerosols, solutions (aqueous solutions, such as saline or phosphate buffered saline), suspensions, nanoparticle formulations, emulsions, etc.

[0160] In some embodiments, the pharmaceutical formulation is an oral formulation. In some embodiments, the pharmaceutical formulation is a topical formulation.

[0161] The pharmaceutical preparations disclosed herein can generally be in the form of pharmaceutically acceptable salts as described herein.When the compounds of the present disclosure contain both acidic and basic groups, the compounds of the present disclosure can also form internal salts, and such compounds are within the scope of the present disclosure.When the compounds contain hydrogen-donating heteroatoms (such as NH), salts are intended to include the isomers formed by transferring the hydrogen atom to basic groups or atoms within the molecule.

[0162] Pharmaceutically acceptable salts of the present compounds include the acid addition and base salts thereof. Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include acetate, adipate, aspartate, benzoate, besylate, bicarbonate / carbonate, bisulfate / sulfate, borate, camsylate, citrate, cyclamate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hybenzate, hydrochloride / chloride, hydrobromide / bromide, hydroiodide / iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulfate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate / hydrogenphosphate / dihydrogenphosphate, pyroglutamate, saccharate, stearate, succinate, tannate, tartrate, tosylate, trifluoroacetate, and xinafoate. Suitable base salts are formed from bases that form non-toxic salts. Examples include ammonium, aluminum, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine, and zinc salts. Hemi-salts of acids and bases can also be formed, such as hemisulfate and hemicalcium salts. For a general description of suitable salts, see Handbook of Pharmaceutical Salts: Properties, Selection, and Use by Stahl and Wermuth (Wiley-VCH, 2002), which is incorporated herein by reference. In some embodiments, the pharmaceutically acceptable salt of the present compound is an ammonium salt.

[0163] Generally, the pharmaceutical formulation for use in the present disclosure comprises an effective amount of the compound disclosed herein and a suitable pharmaceutically acceptable carrier.The preparation can be prepared in a manner known per se, which usually comprises mixing at least one compound according to the present disclosure with one or more pharmaceutically acceptable carriers, and optionally, if necessary, under aseptic conditions, with other pharmaceutically active agents.See also standard handbooks, such as the latest edition of Remington's Pharmaceutical Sciences.

[0164] Generally, for pharmaceutical use, the compounds can be formulated as pharmaceutical preparations containing at least one compound disclosed herein, at least one pharmaceutically acceptable carrier, diluent or adjuvant, and optionally one or more additional pharmaceutically active agents.

[0165] The pharmaceutical preparations of the present disclosure are preferably in unit dosage form and may be suitably packaged (and appropriately labeled) in, for example, boxes, blisters, vials, bottles, sachets, ampoules, or any other suitable single-dose or multi-dose holders or containers, optionally accompanied by one or more leaflets containing product information and / or instructions for use. Generally, such unit dosages contain 1 to 1000 mg, usually 5 to 500 mg, e.g., about 10, 25, 50, 100, 200, 300, or 400 mg per unit dosage, of at least one compound of the present disclosure.

[0166] Depending on the mode of administration, the compounds described herein can be formulated in various ways. Formulations containing one or more compounds can be prepared in various pharmaceutical forms, such as granules, tablets, capsules, suppositories, powders, controlled-release formulations, liquids (aqueous solutions, e.g., saline, buffered saline, etc.), suspensions, emulsions, creams, gels, ointments, salves, lotions, or aerosols. Preferably, these formulations are used in solid dosage forms suitable for simple, preferably oral, precise dosage administration. Solid dosage forms for oral administration include, but are not limited to, tablets, soft or hard gelatin or non-gelatin capsules and caplets. However, liquid dosage forms such as solutions, syrups, suspensions, and shakes can also be utilized. In another embodiment, the formulations are administered topically. Suitable topical formulations include, but are not limited to, lotions, ointments, creams, and gels. In a preferred embodiment, the topical formulation is a gel. In another embodiment, the formulation is administered intranasally.

[0167] In certain embodiments, the pharmaceutical formulation comprises a compound disclosed herein and a propellant, hi certain embodiments, the aerosolized propellant is compressed air, ethanol, nitrogen, carbon dioxide, nitrous oxide, hydrofluoroalkane (HFA), 1,1,1,2-tetrafluoroethane, 1,1,1,2,3,3,3-heptafluoropropane, or a combination thereof.

[0168] In certain embodiments, the present disclosure contemplates a pressurized or non-pressurized container comprising a compound herein, hi certain embodiments, the container is a manual pump spray, an inhaler, a metered dose inhaler, a dry powder inhaler, a nebulizer, a vibrating mesh nebulizer, a jet nebulizer, or an ultrasonic nebulizer.

[0169] Formulations containing one or more of the compounds described herein can be prepared using pharmaceutically acceptable carriers, which are composed of substances considered to be safe and effective, and can be administered to individuals without causing undesired biological side effects or unwanted interactions. Carriers are all components present in pharmaceutical formulations other than the active ingredient. Generally, as used herein, "carriers" include, but are not limited to, diluents, binders, lubricants, disintegrants, fillers, pH adjusters, preservatives, antioxidants, solubility enhancers, and coating compositions.

[0170] Carriers also include all components of coating compositions, which may include excipients, plasticizers, pigments, colorants, stabilizers, and glidants. Delayed-release, sustained-release, and / or pulsatile-release dosage forms can be prepared as described in standard references such as "Pharmaceutical Dosage Forms Tablets," eds. Liberman et al. (New York, Marcel Dekker, Inc., 1989), "Remington - The Science and Practice of Pharmacy," 20th ed., Lippincott Williams & Wilkins, Baltimore, MD, 2000, and "Pharmaceutical Dosage Forms and Drug Delivery Systems," 6th Edition, Ansel et al. (Media, PA: Williams and Wilkins, 1995). These references provide information on carriers, materials, equipment, and processes for preparing tablets and capsules, and delayed-release dosage forms of tablets, capsules, and granules.

[0171] Examples of suitable coating materials include, but are not limited to, cellulose polymers such as cellulose acetate phthalate, hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate, and hydroxypropyl methylcellulose acetate succinate; polyvinyl acetate phthalate, acrylic acid polymers and copolymers and methacrylic resins commercially available under the trade name EUDRAGIT® (Roth Pharma, Westerstadt, Germany), zein, shellac, and polysaccharides.

[0172] Additionally, the coating material may contain conventional carriers such as plasticizers, pigments, colorants, glidants, stabilizers, pore formers, and surfactants.

[0173] Optional pharmaceutically acceptable excipients present in drug-containing tablets, beads, granules, or particles include, but are not limited to, diluents, binders, lubricants, disintegrants, colorants, stabilizers, and surfactants. Diluents, also called "fillers," are generally required to increase the bulk of solid dosage forms so that they provide a practical size for tablet compression or bead and granule formation. Suitable diluents include, but are not limited to, dicalcium phosphate dihydrate, calcium sulfate, lactose, sucrose, mannitol, sorbitol, cellulose, microcrystalline cellulose, kaolin, sodium chloride, dry starch, hydrolyzed starch, pregelatinized starch, silicon dioxide, titanium oxide, magnesium aluminum silicate, and powdered sugar.

[0174] Binders are used to impart cohesiveness to solid dosage formulations, thus ensuring that tablets or beads or granules remain intact after formation of the dosage form. Suitable binder materials include, but are not limited to, starch, pregelatinized starch, gelatin, sugars (including sucrose, glucose, dextrose, lactose and sorbitol), polyethylene glycol, waxes, natural and synthetic gums such as acacia, tragacanth, sodium alginate, celluloses including hydroxypropyl methylcellulose, hydroxypropyl cellulose, ethylcellulose and veegum, and synthetic polymers such as acrylic and methacrylic acid copolymers, methacrylic acid copolymers, methyl methacrylic acid copolymers, aminoalkyl methacrylic acid copolymers, polyacrylic acid / polymethacrylic acid, and polyvinylpyrrolidone.

[0175] Lubricants are used to facilitate tablet manufacture. Examples of suitable lubricants include, but are not limited to, magnesium stearate, calcium stearate, stearic acid, glycerol behenate, polyethylene glycol, talc, and mineral oil.

[0176] Disintegrants are used to facilitate the breakup or "disintegration" of the dosage form after administration and generally include, but are not limited to, starch, sodium starch glycolate, sodium carboxymethyl starch, sodium carboxymethylcellulose, hydroxypropyl cellulose, pregelatinized starch, clay, cellulose, arginine, gums or cross-linked polymers such as cross-linked PVP (Polyplasdone XL from GAF Chemical Corp).

[0177] Stabilizers are used to inhibit or retard drug decomposition reactions that include, by way of example, oxidative reactions.

[0178] The surfactant may be anionic, cationic, amphoteric, or nonionic. Suitable anionic surfactants include, but are not limited to, those containing carboxylic acid, sulfonic acid, and sulfate ions. Examples of anionic surfactants include sodium, potassium, and ammonium long-chain alkyl sulfonates and alkylaryl sulfonates, such as sodium dodecylbenzenesulfonate; sodium dialkyl sulfosuccinates, such as sodium dodecylbenzenesulfonate; sodium dialkyl sulfosuccinates, such as sodium bis-(2-ethylthiol)-sulfosuccinate; and alkyl sulfates, such as sodium lauryl sulfate. Cationic surfactants include, but are not limited to, quaternary ammonium compounds, such as benzalkonium chloride, benzethonium chloride, cetrimonium bromide, stearyldimethylbenzylammonium chloride, polyoxyethylene, and coconut amine. Examples of nonionic surfactants include ethylene glycol monostearate, propylene glycol myristate, glycerin monostearate, glyceryl stearate, polyglyceryl-4-oleate, sorbitan acylate, sucrose acylate, PEG-150 laurate, PEG-400 monolaurate, polyoxyethylene monolaurate, polysorbate, polyoxyethylene octylphenyl ether, PEG-1000 cetyl ether, polyoxyethylene tridecyl ether, polypropylene glycol butyl ether, Poloxamer® 401, stearoyl monoisopropanolamide, and polyoxyethylene hydrogenated tallow amide. Examples of amphoteric surfactants include sodium N-dodecyl-β-alanine, sodium N-lauryl-β-iminodipropionate, myristoamphoacetate, lauryl betaine, and lauryl sulfobetaine.

[0179] If desired, the tablets, beads, granules, or particles may also contain minor amounts of nontoxic auxiliary substances such as wetting or emulsifying agents, dyes, pH buffering agents, or preservatives.

[0180] The concentration of the compound relative to the carrier and / or other materials can vary from about 0.5 to about 100 wt.% (weight percent). For oral use, the pharmaceutical formulations generally contain from about 5 to about 100 wt.% of the active material. For other uses, the pharmaceutical formulations generally have from about 0.5 to about 50 wt.% of the active material.

[0181] The compositions described herein may be formulated for modified or controlled release. Examples of controlled release dosage forms include sustained release dosage forms, delayed release dosage forms, pulsatile release dosage forms, and combinations thereof.

[0182] Sustained-release formulations are generally prepared as diffusion or osmotic systems, as described, for example, in "Remington - The Science and Practice of Pharmacy" (20th ed., Lippincott Williams & Wilkins, Baltimore, MD, 2000). Diffusion systems generally consist of two types of devices, reservoirs and matrices, and are well known and described in the art. Matrix devices are generally prepared by compressing the drug with a slowly dissolving polymer carrier into tablet form. The three main types of materials used in the preparation of matrix devices are insoluble plastics, hydrophilic polymers, and fatty compounds. Plastic matrices include, but are not limited to, methyl acrylate-methyl methacrylate, polyvinyl chloride, and polyethylene. Hydrophilic polymers include, but are not limited to, cellulosic polymers such as methyl and ethyl cellulose, hydroxyalkyl celluloses such as hydroxypropyl cellulose, hydroxypropylmethyl cellulose, sodium carboxymethyl cellulose, and Carbopol® 934, polyethylene oxide, and mixtures thereof. Fatty compounds include, but are not limited to, various waxes such as carnauba wax and wax-type substances including glyceryl tristearate and hydrogenated castor oil or hydrogenated vegetable oil, or mixtures thereof.

[0183] In certain preferred embodiments, the plastic material is a pharmaceutically acceptable acrylic polymer, including, but not limited to, acrylic acid and methacrylic acid copolymers, methyl methacrylate, methyl methacrylate copolymers, ethoxyethyl methacrylate, cyanoethyl methacrylate, aminoalkyl methacrylate copolymers, poly(acrylic acid), poly(methacrylic acid), alkylamine methacrylate copolymers poly(methyl methacrylate), poly(methacrylic acid)(anhydride), polymethacrylic acid, polyacrylamide, poly(methacrylic anhydride), and glycidyl methacrylate copolymer.

[0184] In certain preferred embodiments, the acrylic polymer is comprised of one or more ammonio methacrylate copolymers, which are well known in the art and are described in NF XVII as fully polymerized copolymers of acrylic and methacrylic acid esters with a low content of quaternary ammonium groups.

[0185] In a preferred embodiment, the acrylic polymer is an acrylic resin lacquer, such as that commercially available from Rohm Pharma under the trade name Eudragit®. In a further preferred embodiment, the acrylic polymer comprises a mixture of two acrylic resin lacquers commercially available from Rohm Pharma under the trade names Eudragit® RL30D and Eudragit® RS30D, respectively. Eudragit® RL30D and Eudragit® RS30D are copolymers of acrylic and methacrylic esters with a low content of quaternary ammonium groups, with the molar ratio of ammonium groups to residual neutral (meth)acrylic esters being 1:20 in Eudragit® RL30D and 1:40 in Eudragit® RS30D. The average molecular weight is approximately 150,000. Eudragit® S-100 and Eudragit® L-100 are also preferred. The code designations RL (high permeability) and RS (low permeability) refer to the permeability properties of these substances. Eudragit® RL / RS mixtures are insoluble in water and digestive fluids. However, multiparticulate systems formed to contain them are swellable and permeable in aqueous solutions and digestive fluids.

[0186] The above polymers, such as Eudragit® RL / RS, can be mixed together in any desired ratio to ultimately obtain a sustained-release formulation with a desired dissolution profile. A desired sustained-release multiparticulate system can be obtained, for example, from 100% Eudragit® RL, 50% Eudragit® RL and 50% Eudragit® RS, and 10% Eudragit® RL and 90% Eudragit® RS. Those skilled in the art will recognize that other acrylic polymers, such as Eudragit® L, can also be used.

[0187] Alternatively, sustained-release formulations can be prepared using osmotic systems or by applying semipermeable coatings to the dosage form. In the latter case, the desired drug release profile can be achieved by combining low-permeability and high-permeability coating materials in appropriate proportions.

[0188] The above devices with different drug release mechanisms can be combined in a final dosage form containing one or more units. Examples of multiple units include, but are not limited to, multi-layer tablets and capsules containing tablets, beads, or granules. An immediate-release portion can be added to a sustained-release system either by applying an immediate-release layer on top of a sustained-release core using a coating or compression process, or in a multiple-unit system such as a capsule containing sustained- and immediate-release beads.

[0189] Sustained-release tablets containing hydrophilic polymers are prepared by techniques commonly known to those skilled in the art, such as direct compression, wet granulation, or dry granulation. These formulations typically incorporate a polymer, diluents, binders, and lubricants, as well as an active pharmaceutical ingredient. Common diluents include inert powdered substances such as starch, powdered cellulose, especially crystalline and microcrystalline cellulose, sugars such as fructose, mannitol, and sucrose, cereal flour, and similar edible powders. Typical diluents include, for example, various types of starch, lactose, mannitol, kaolin, calcium phosphate or sulfate, inorganic salts such as sodium chloride, and powdered sugar. Powdered cellulose derivatives are also useful. Typical tablet binders include starch, gelatin, and sugars such as lactose, fructose, and glucose. Natural and synthetic gums, including acacia, alginates, methylcellulose, and polyvinylpyrrolidone, can also be used. Polyethylene glycol, hydrophilic polymers, ethylcellulose, and waxes can also serve as binders. Lubricants are necessary in tablet formulations to prevent the tablet and punches from sticking in the die. Lubricants are selected from such slippery solids as talc, magnesium and calcium stearate, stearic acid and hydrogenated vegetable oils.

[0190] Sustained-release tablets containing wax materials are generally prepared using methods known in the art, such as direct blending, congealing, and aqueous dispersion. In the congealing method, the wax material and drug are mixed, either spray-congealed or congealed, sieved, and processed.

[0191] Delayed-release formulations are made by coating a solid dosage form with a polymer film that is insoluble in the acidic environment of the stomach and soluble in the neutral environment of the small intestine.

[0192] Delayed-release dosage units can be prepared, for example, by coating a drug or drug-containing composition with a selected coating material. The drug-containing composition can be, for example, a tablet for incorporation into a capsule, a tablet for use as an inner core in a "coated core" dosage form, or a plurality of drug-containing beads, particles, or granules for incorporation into either a tablet or a capsule. Preferred coating materials include biodegradable, gradually hydrolyzable, gradually water-soluble, and / or enzymatically degradable polymers, and can be conventional "enteric" polymers. As recognized by those skilled in the art, enteric polymers become soluble in the lower gastrointestinal tract, which is an environment with a higher pH, or are slowly degraded as the dosage form passes through the gastrointestinal tract, while enzymatically degradable polymers are degraded by bacterial enzymes present in the lower gastrointestinal tract, particularly in the colon.Suitable coating materials for effecting delayed release include cellulosic polymers such as hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxymethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl methyl cellulose acetate succinate, hydroxypropyl methyl cellulose phthalate, methyl cellulose, ethyl cellulose, cellulose acetate, cellulose acetate phthalate, cellulose acetate trimellitate, and sodium carboxymethyl cellulose; acrylic acid polymers and copolymers, preferably acrylic acid, methacrylic acid, methyl acrylate, ethyl acrylate, methyl methacrylate, and / or ethyl methacrylate, and products sold under the trade name Eudragit® (Rohm), including Eudragit® L30D-55 and L100-55 (soluble at pH 5.5 or above), Eudragit® L-100 (soluble at pH 6.0 or above), Eudragit® S (soluble at pH 7.0 or above as a result of a higher degree of esterification), and Eudragits® NE, RL, and RS (water-insoluble polymers with different permeability and extensibility). Examples of suitable coating materials include, but are not limited to, those formed from other methacrylic resins commercially available from Pharma; Westerstadt, Germany; vinyl polymers and copolymers such as polyvinylpyrrolidone, vinyl acetate, vinyl acetate phthalate, vinyl acetate crotonic acid copolymer, and ethylene-vinyl acetate copolymer; enzymatically degradable polymers such as azopolymers, pectin, chitosan, amylose, and guar gum; zein, and shellac. Combinations of different coating materials may also be used. Multi-layer coatings using different polymers may also be applied.

[0193] The preferred coating weight for a particular coating material can be readily determined by one skilled in the art by evaluating the individual release profiles for tablets, beads, and granules prepared with different amounts of various coating materials. It is the combination of materials, methods, and modes of application that produces the desired release characteristics, which can only be determined from clinical trials.

[0194] The coating composition may contain conventional additives, such as plasticizers, pigments, colorants, stabilizers, and glidants. Plasticizers are typically present to reduce coating brittleness and generally represent about 10% to 50% by weight of the dry polymer. Typical examples of plasticizers include polyethylene glycol, propylene glycol, triacetin, dimethyl phthalate, diethyl phthalate, dibutyl phthalate, dibutyl sebacate, triethyl citrate, tributyl citrate, acetyl triethyl citrate, castor oil, and acetylated monoglycerides. Stabilizers are preferably used to stabilize the particles in the dispersion. Typical stabilizers are nonionic emulsifiers such as sorbitan esters, polysorbates, and polyvinylpyrrolidone. Glidants are recommended to reduce tackiness during film formation and drying and generally represent approximately 25% to 100% by weight of the polymer in the coating solution. One effective glidant is talc. Other glidants such as magnesium stearate and glycerol monostearate may also be used. Pigments such as titanium dioxide may also be used. Small amounts of anti-foaming agents, such as silicones (e.g., simethicone), may also be added to the coating composition.

[0195] The formulation may provide pulsatile delivery of one or more compounds. "Pulsatile" means that multiple drug doses are released at spaced-apart time intervals. Generally, upon ingestion of the dosage form, release of the first dose is substantially immediate, i.e., the first drug release "pulse" occurs within about one hour of ingestion. This first pulse is followed by a first time interval (lag time), during which little or no drug is released from the dosage form, followed by release of a second dose. Similarly, a second, approximately drug-free interval between the second and third drug release pulses may be designed. The duration of the approximately drug-free interval varies depending on the dosage form design, e.g., twice-daily dosing profile, three-times-daily dosing profile, etc. For dosage forms providing a twice-daily dosing profile, the approximately drug-free interval has a duration of approximately 3 to 14 hours between the first and second doses. For dosage forms providing a three-times-daily dosing profile, the approximately drug-free interval has a duration of approximately 2 to 8 hours between each of the three doses.

[0196] In one embodiment, a pulsatile release profile is achieved in a dosage form that is a closed, preferably sealed, capsule containing at least two drug-containing "dosage units," where each dosage unit within the capsule provides a different drug release profile. The adjustment of the delayed-release dosage units is accomplished by a controlled-release polymer coating on the dosage unit or by incorporating the active agent in a controlled-release polymer matrix. Each dosage unit may comprise a compressed or molded tablet, where each tablet within the capsule provides a different drug release profile. For dosage forms that mimic a twice-daily dosing profile, the first tablet releases drug substantially immediately after ingestion of the dosage form, while the second tablet releases drug approximately 3 to less than 14 hours after ingestion of the dosage form. For dosage forms that mimic a thrice-daily dosing profile, the first tablet releases drug substantially immediately after ingestion of the dosage form, the second tablet releases drug approximately 3 to less than 10 hours after ingestion of the dosage form, and the third tablet releases drug at least 5 to approximately 18 hours after ingestion of the dosage form. Dosage forms can include more than three tablets. While dosage forms generally will not include more than three tablets, dosage forms that accommodate more than three tablets are available.

[0197] Alternatively, each dosage unit in a capsule may contain multiple drug-containing beads, granules, or particles. As is known in the art, drug-containing "beads" refer to beads made of a drug and one or more excipients or polymers. Drug-containing beads can be made by applying the drug to an internal support, such as inert sugar beads coated with the drug, or by creating a "core" containing both the drug and one or more excipients. As is also known, drug-containing "granules" and "particles" comprise drug particles that may or may not contain one or more additional excipients or polymers. In contrast to drug-containing beads, granules and particles do not contain an inert support. Granules generally contain drug particles and require further processing. Particles are generally smaller than granules and are not further processed. While beads, granules, and particles can be formulated to provide immediate release, beads and granules are generally used to provide delayed release.

[0198] In one embodiment, the compound is formulated for topical administration. Suitable topical dosage forms include lotions, creams, ointments, and gels. A "gel" is a semi-solid system containing a dispersion of an active agent, i.e., a compound, in a liquid vehicle that is rendered semi-solid by the action of a thickening agent or polymeric material dissolved or suspended in the liquid vehicle. The liquid may contain a fat-soluble component, an aqueous component, or both. Some emulsions may be gels or otherwise contain gel components. However, some gels are not emulsions because they do not contain a homogenized blend of immiscible components. Methods for preparing lotions, creams, ointments, and gels are well known in the art.

[0199] The pharmaceutical formulation may also contain one or more additional pharmaceutically active agents as described herein.

[0200] V. How to use In certain embodiments, the present disclosure relates to a method for treating or preventing a viral infection or a virus-associated cancer, comprising administering to a subject in need thereof an effective amount of a compound disclosed herein or a pharmaceutical formulation thereof. In some embodiments, the subject is at risk for, exhibits symptoms of, is suffering from, or has been diagnosed with a viral infection or a virus-associated cancer. In some embodiments, the compound or a pharmaceutical formulation thereof is administered orally. For example, the compound or a pharmaceutical formulation thereof may be administered orally to treat HIV infection. In some embodiments, the compound or a pharmaceutical formulation thereof is administered topically. For example, the compound or a pharmaceutical formulation thereof may be administered topically to treat HPV infection or HPV-associated cancer.

[0201] In some embodiments, the disclosed compounds and pharmaceutical formulations thereof are used to treat viral infections, such as those caused by human immunodeficiency virus (HIV), hepatitis virus, herpes virus, flavivirus, poxvirus, paramyxovirus, influenza, coronavirus, smallpox virus, human papillomavirus (HPV), or filovirus. In some embodiments, the disclosed compounds and pharmaceutical formulations thereof are used to treat HIV infection. In some embodiments, the disclosed compounds and pharmaceutical formulations thereof are used to treat hepatitis virus (such as HBV) infection. In some embodiments, the disclosed compounds and pharmaceutical formulations thereof are used to treat HPV infection. In some embodiments, the disclosed compounds and pharmaceutical formulations thereof are used to treat smallpox virus infection.

[0202] In some embodiments, the subject is infected with influenza A virus, including subtype H1N1, influenza B virus, influenza C virus, rotavirus A, rotavirus B, rotavirus C, rotavirus D, rotavirus E, smallpox virus, SARS-CoV, SARS-CoV-2, respiratory syncytial virus (RSV), human adenovirus types (HAdV-1-55), HPV types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, parvovirus B19, molluscum contagiosum virus, JC virus (JCV), BK virus, Merkel cell polyomavirus, Coxsackie A virus, norovirus, rubella virus, lymphocytic choriomeningitis virus (LCMV), yellow fever virus, measles virus, mumps virus, respiratory syncytial virus, At risk for, experiencing symptoms of, or diagnosed with, rabies virus, rinderpest virus, California encephalitis virus, hantavirus, rabies virus, Ebola virus, Marburg virus, herpes simplex virus type 1 (HSV-1), herpes simplex virus type 2 (HSV-2), varicella-zoster virus (VZV), Epstein-Barr virus (EBV), cytomegalovirus (CMV), herpes lymphotropic virus, roseolovirus, Kaposi's sarcoma-associated herpesvirus (human herpesvirus type 8 or HHV-8), hepatitis A (HAV), hepatitis B (HBV), hepatitis C (HCV), hepatitis D (HDV), hepatitis E (HEV), HIV, human T-lymphotropic virus type 1 (HTLV-1), Friend spleen-limited focus-forming virus (SFFV), or xenotropic MuLV-related virus (XMRV).

[0203] In certain embodiments, the viral infection is an alphavirus, flavivirus, coronavirus, orthomyxoviridae, paramyxoviridae, powassan virus, or filoviridae, hi certain embodiments, the viral infection is selected from MERS coronavirus, eastern equine encephalitis virus, western equine encephalitis virus, Venezuelan equine encephalitis virus, Ross River virus, Powassan virus, and chikungunya virus.

[0204] In some embodiments, the disclosed compounds and pharmaceutical formulations thereof are used to treat virus-associated cancers, such as HPV-associated cancers, HIV-associated cancers, EBV-associated cancers, HBV-associated cancers, HHV-8-associated cancers, HCV-associated cancers, and HTLV-1-associated cancers. In some embodiments, the virus-associated cancer is an HPV-associated cancer, including HPV-associated cervical cancer, vulvar cancer, vaginal cancer, penile cancer, anal cancer, oral and pharyngeal cancer, and head and neck cancer. In some embodiments, the HPV-associated cancer is HPV-associated cervical cancer.

[0205] In some embodiments, the methods disclosed herein may be used in combination with other antiviral agents, such as abacavir, acyclovir, adefovir, amantadine, amprenavir, Ampligen, arbidol, atazanavir, atripla, boceprevir, cidofovir, combivir, COMPLERA® (a combination of emtricitabine, rilpivirine, and tenofovir disoproxil fumarate), darunavir, delavirdine, didanosine, thiazolinone ... , docosanol, dolutegravir, edoxudine, efavirenz, emtricitabine, enfuvirtide, entecavir, famciclovir, fomivirsen, fosamprenavir, foscarnet, fosfonet, ganciclovir, ibacitabine, Immunovir, idoxuridine, imiquimod, indinavir, inosine, interferon type III, interferon type II, interferon type I, lamivudine, lopinavir, lovirid, mamivudine Raviroc, moroxydine, methisazone, nelfinavir, nevirapine, nexavir, oseltamivir, peginterferon alfa-2a, penciclovir, peramivir, pleconaril, podophyllotoxin, raltegravir, ribavirin, rimantadine, ritonavir, pyramidine, saquinavir, stavudine, STRIBILD® (a combination of elvitegravir, cobicistat, emtricitabine, and tenofovir disoproxil), It is contemplated to administer in combination with tenofovir, tenofovir disoproxil, tenofovir alafenamide fumarate, tipranavir, trifluridine, trizivir, tromantadine, TRUVADA® (a combination of emtricitabine and tenofovir disoproxil fumarate), valacyclovir, valganciclovir, vicriviroc, vidarabine, viramidine, zalcitabine, zanamivir, or zidovudine, and combinations thereof.

[0206] In certain embodiments, the present disclosure contemplates the treatment or prevention of a viral infection using the compounds disclosed herein and pharmaceutical formulations thereof, wherein the viral infection is HIV, hepatitis B virus, HPV, or smallpox virus.

[0207] The compounds and their pharmaceutical formulations can be administered by a variety of routes, including oral, topical, ocular, rectal, transdermal, subcutaneous, intravenous, intramuscular, or intranasal, depending primarily on the specific preparation used. In certain embodiments, the compounds and their pharmaceutical formulations are administered by inhalation through the lungs. In some embodiments, the compounds and their pharmaceutical formulations are administered orally. In some embodiments, the compounds and their pharmaceutical formulations are administered topically.

[0208] The compounds are generally administered in an "effective amount," meaning any amount of compound that, upon proper administration, is sufficient to achieve the desired therapeutic or prophylactic effect in the subject to which the compound is administered. Typically, depending on the condition to be prevented or treated and the route of administration, such an effective amount will typically be 0.01 to 1000 mg / kilogram patient body weight / day, more often 0.1 to 500 mg, e.g., 1 to 250 mg, e.g., about 5, 10, 20, 50, 100, 150, 200, or 250 mg / kilogram patient body weight / day, which may be administered as a single daily dose or divided into one or more daily administrations. The amount to be administered, the route of administration, and any further treatment regimen can be determined by the treating clinician, depending on factors such as the age, sex, and general condition of the patient, and the nature and severity of the disease / symptom to be treated.

[0209] The compounds described herein can be administered in combination with other pharmaceutically active agents.These compounds include, but are not limited to, analgesics, anti-inflammatory drugs, antipyretics, antidepressants, antiepileptic drugs, antihistamines, antimigraine drugs, antimuscarinic drugs, anxiolytic drugs, sedatives, hypnotics, antipsychotic drugs, bronchodilators, antiasthmatic drugs, cardiovascular drugs, corticosteroids, dopaminergic drugs, electrolytes, gastrointestinal drugs, muscle relaxants, nutrients, vitamins, parasympathomimetics, stimulants, appetite suppressants, and antinarcoleptic drugs.As used herein, "adjunctive administration" means that the compounds can be administered with one or more other active agents in the same dosage form or in separate dosage forms.

[0210] Specific examples of pharmaceutically active agents that may be co-administered with the compounds include aceclofenac, acetaminophen, atomoxetine, almotriptan, alprazolam, amantadine, amcinonide, aminocyclopropane, amitriptyline, amlodipine, amoxapine, amphetamine, aripiprazole, aspirin, atomoxetine, azasetron, azatadine, beclomethasone, benactyzine, benoxaprofen, bermoprofen, betamethasone, benzophenone, benzocaine ... Methasone, bicifadine, bromocriptine, budesonide, buprenorphine, bupropion, buspirone, butorphanol, butriptyline, caffeine, carbamazepine, carbidopa, carisoprodol, celecoxib, chlordiazepoxide, chlorpromazine, choline salicylate, citalopram, clomipramine, clonazepam, clonidine, clonitazene, clorazepate, clotiazepam, cloxazolam, clozapine, codeine, Luticosterone, cortisone, cyclobenzaprine, cyproheptadine, demexiptyline, desipramine, desmorphine, dexamethasone, dexanabinol, dextroamphetamine sulfate, dextromoramide, dextropropoxyphene, Dezocine, diazepam, dibenzepin, diclofenac sodium, diflunisal, dihydrocodeine, dihydroergotamine, dihydromorphine, dimetacrine, divalproex, zizatri triptan, dolasetron, donepezil, dothiepin, doxepin, duloxetine, ergotamine, escitalopram, estazolam, ethosuximide, etodolac, femoxetine, fenamic acid, fenoprofen, fentanyl, fludiazepam, fluoxetine, fluphenazine, flurazepam, flurbiprofen, flutazolam, fluvoxamine, frovatriptan, gabapentin, galantamine, gepirone, ginkgo biloba bilboa), granisetron, haloperidol, huperzine A, hydrocodone, hydrocortisone, hydromorphone, hydroxyzine, ibuprofen, imipramine, indiplon, indomethacin, indoprofen, iprindole, ipsapirone, ketanserin, ketoprofen, ketorolac, resopitron, levodopa, lipase, lofepramine, lorazepam, loxapine, maprotiline, mazindol,Mefenamic acid, melatonin, melitracen, memantine, meperidine, meprobamate, mesalamine, metapramine, metaxalone, methadone, methamphetamine, methocarbamol, methyldopa, methylphenidate, methyl salicylate, methysergide, metoclopramide, mianserin, mifepristone, milnacipran, minaprine, mirtazapine, moclobemide, modafinil (anti-narcolepsy), molindone, morphine, morphine hydrochloride, nabumetone, nadolol, naproxen, narcotoxin Liptan, nefazodone, neurontin, nomifensine, nortriptyline, olanzapine, olsalazine, ondansetron, opipramol, orphenadrine, oxaflozane, oxaprozin, oxazepam, oxitriptan, oxycodone, oxymorphone, pancrelipase, parecoxib, paroxetine, pemoline, pentazocine, pepsin, perphenazine, phenacetin, phendimetrazine, phenmetrazine, phenylbutazone, phenytoin, phosphatidylserine, pimozide, pi Lurindole, piroxicam, pizotifen, pizotyline, pramipexole, prednisolone, prednisone, pregabalin, propranolol, propizepine, propoxyphene, protriptyline, quazepam, quinupramine, reboxetine, reserpine, risperidone, ritanserin, rivastigmine, rizatriptan, rofecoxib, ropinirole, rotigotine, salsalate, sertraline, sibutramine, sildenafil, sulfasalazine, sulindac, sumatriptan, tacrine, temazepam, These include, but are not limited to, tetrabenazine, thiazides, thioridazine, thiothixene, tiapride, taziprinone, tizanidine, tofenacin, tolmetin, toloxatone, topiramate, tramadol, trazodone, triazolam, trifluoperazine, trimethobenzamide, trimipramine, tropisetron, valdecoxib, valproic acid, venlafaxine, viloxazine, vitamin E, zimeldine, ziprasidone, zolmitriptan, zolpidem, zopiclone and isomers, salts, and combinations thereof.

[0211] Additional pharmaceutically active agents may be formulated either together with or separately from the compounds disclosed herein for immediate release, controlled release, or a combination thereof. [Example]

[0212] Example The present disclosure will now be described in more detail with reference to the following non-limiting examples. It should be noted that the particular assays used in the Examples section are designed to provide an indication of activity.

[0213] General Chemical Synthesis and Characterization Automated flash column chromatography was performed using a Teledyne ISCO CombiFlash Companion system with silica gel packed columns (SiliCycle Inc. or RediSep® Rf). Analytical thin-layer chromatography (TLC, commercially available from Sigma-Aldrich) was performed on aluminum-supported silica gel plates (thickness: 200 μm) or glass-supported (thickness: 240 μm) silica gel plates using a fluorescent indicator (F-254). Visualization of compounds on TLC plates was accomplished with UV light (254 nm) and / or with phosphomolybdic acid (PMA) or cerium ammonium molybdate. In some cases, retention factors (R ) were measured on glass-supported silica gel plates (thickness: 240 μm) using PMA staining. f ) was determined and calculated as the average of triplicate runs. NMR spectra ( 1 H, 13 C. 19 F and 31 P) was obtained as an internal reference. 1 H=7.26 ppm, 13C=77.16 ppm; CD3OD: 1 H=3.31 ppm, 13 NMR samples were prepared in deuterated chloroform (CDCl) or deuterated methanol (CD3OD) using C = 49.0 ppm. 19 Trifluoroacetic acid ( 19 F=-76.55 ppm), while 31 As an absolute reference for P NMR 1 The residual chloroform peak in the H NMR was used. 31 Phosphate ( 31 A NMR spectrum (P = 40.48 ppm) was used. All NMR spectra were processed using MestReNova software. NMR data are reported to include chemical shifts (δ) reported in ppm, multiplicities indicated as s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), br (broad), or app (apparent), coupling constants (J) reported in Hz, and integrals normalized to a single atom (H, C, F, or P). High-resolution mass spectrometry (HRMS) was performed by the Emory University Mass Spectrometry Center, directed by Dr. Fred Strobel. Liquid chromatography-mass spectrometry (LC-MS) was performed on an Agilent 1200 HPLC equipped with a 6120 Quadrupole mass spectrometer (ESI-API) through an analytical reverse-phase Agilent C18 XDB eclipse column (50 mm x 4.6 mm, 3.5 μM) eluted with a mixture of HPLC-grade MeOH and HO or MeCN and HO (all with 0.1% formic acid). LC-MS samples were prepared in 75:25 MeOH / HO (with 0.1% formic acid). 1 The purity of the final compounds was assessed using H NMR and LC-MS. Melting points of intermediates and final compounds were taken on a RD-MP digital melting point apparatus.

[0214] The synthetic procedures for selected examples are described in Figures 1-12.

[0215] Example 1. Synthesis of ammonium pentadec-14-yn-1-yl (R)-(((1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate A. Synthesis of (pentadec-2-yn-1-yloxy)tetrahydro-2H-pyran (EJM-8-003) [ka] Dodecan-1-ol (10.0 g, 53.7 mmol, 1.00 eq) was added to a 1 L flask equipped with a stir bar. After dilution with DCM (268 mL), the resulting solution was vigorously stirred at room temperature. After the sequential addition of imidazole (4.75 g, 69.8 mmol, 1.30 eq), triphenylphosphine (18.3 g, 69.8 mmol, 1.30 eq), and iodine (17.7 g, 69.8 mmol, 1.30 eq), the resulting reaction mixture was vigorously stirred at room temperature under argon (Ar). The reaction progress was monitored by TLC. After 1.5 h, TLC showed conversion of the starting material to one major spot. The reaction mixture was inactivated with 150 mL of saturated aqueous sodium thiosulfate. The resulting organic layer was diluted with 200 mL of hexane, the small amount of precipitate was filtered, and the mother liquor was evaporated under reduced pressure to give a white solid. After the addition of 400 mL of hexane, the resulting slurry was vigorously stirred overnight under Ar. The next morning, the slurry was filtered and the mother liquor was evaporated under reduced pressure to give a yellow oil. The crude material was purified through a silica plug, eluting with 100% hexane to give a clear oil with a small amount of yellow solid remaining. This crude material was taken up in 100% pentane, filtered, and the mother liquor was evaporated under reduced pressure to give a clear oil that corresponded to the product 1-iodododecane (15.7 g, 53.0 mmol, 99% yield).

[0216] An oven-dried, flame-dried 250 mL flask equipped with a stir bar was charged with 2-(2-propynyloxy)tetrahydro-2H-pyran (4.77 g, 34.0 mmol, 1.00 eq), diluted with 40 mL THF and hexamethylphosphoramide (20.7 mL, 119 mmol, 3.50 eq), cooled to −78° C., and vigorously stirred under Ar. After the dropwise addition of n-butyllithium (2.5 M in hexanes, 15.0 mL, 34.0 mmol, 1.00 eq) via syringe pump at a rate of 17 mL / hr, the resulting reaction mixture was vigorously stirred at −78° C. under Ar for 10 min, then warmed to −30° C. and stirred for an additional 45 min. After the dropwise addition of a solution of 1-iodododecane (10.1 g, 34.0 mmol, 1.00 eq) in 14 mL of THF via a syringe pump at a rate of 17 mL / hr, the resulting reaction mixture was slowly warmed to room temperature and vigorously stirred overnight under Ar. The next morning, TLC showed complete conversion of the alkyl iodide and alkyne starting materials to a single spot (PMA staining). The reaction was quenched by the dropwise addition of saturated ammonium chloride solution, and the resulting aqueous layer was extracted three times with EtOAc. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to give 22.6 g of a yellow oil, which was purified via column chromatography eluting with 1:12 EtOAc:hexane to give a slightly yellow oil (8.40 g, 27.2 mmol, 80% yield).

[0217] B. Synthesis of Pentadec-2-yn-1-ol (EJM-8-004) [ka] A solution of (pentadec-2-yn-1-yloxy)tetrahydro-2H-pyran (8.40 g, 27.2 mmol, 1.00 eq) in methanol (136 mL) was added to a 500 mL flask equipped with a stir bar. After the addition of p-toluenesulfonic acid monohydrate (0.520 g, 2.72 mmol, 0.10 eq), the resulting reaction mixture was vigorously stirred at room temperature under Ar. The reaction progress was monitored by TLC. After 6.5 h, TLC showed almost complete conversion of the starting material to one major spot (PMA staining). The solvent was evaporated under reduced pressure to give a brown oil, which was purified via column chromatography eluting with 1:6 EtOAc:hexane to give a white solid (3.96 g, 17.7 mmol, 65% yield).

[0218] C. Synthesis of Pentadec-14-yn-1-ol (EJM-8-005) [ka] Sodium hydride (60% in mineral oil, 0.620 g, 15.6 mmol, 7.00 eq) was added to an oven-dried, flame-dried 50 mL flask equipped with a stir bar and reflux condenser. The dispersion was washed twice with 10 mL of hexane, then diluted with 8 mL of 1,3-diaminopropane, warmed to 70 °C, and vigorously stirred under Ar. Over the course of 1 h, the solution turned brown and was then cooled to room temperature with vigorous stirring under Ar. After the dropwise addition of a solution of pentadec-2-yn-1-ol (0.500 g, 2.23 mmol, 1.00 eq) in 1.3 mL of 1,3-diaminopropane, the resulting mixture was vigorously stirred at room temperature for 10 min, then warmed to 55 °C and stirred overnight under Ar. The next morning, the reaction mixture was cooled to 0 °C and inerted by dropwise addition of cold water. The aqueous layer was slowly acidified with 1 M aqueous hydrochloric acid to pH = 2. The resulting aqueous layer was extracted three times with hexane, and the combined organic layers were dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to give 400 mg of a brown solid. The crude material was dissolved in 1:4 EtOAc:hexane and filtered to attempt to remove insoluble material; however, the particles were fine enough to pass through the filter paper. The mother liquor was evaporated under reduced pressure and purified via column chromatography, eluting with 1:4 EtOAc:hexane to give a white crystalline solid (0.320 g, 1.43 mmol, 64% yield).

[0219] D. Synthesis of Ammonium Pentadec-14-yn-1-yl (R)-(((1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate (EJM-8-006) [ka] Tenofovir (100 mg, 0.350 mmol, 1.00 eq) was added to a flame-dried 25 mL flask equipped with a stir bar, diluted with pyridine (2.90 mL), and vigorously stirred at room temperature under Ar. After the addition of pentadec-14-yn-1-ol (117 mg, 0.520 mmol, 1.50 eq) and 2,4,6-triisopropylbenzenesulfonyl chloride (316 mg, 1.04 mmol, 3.00 eq), the resulting yellow reaction mixture was vigorously stirred overnight at room temperature under Ar. After 2 days, TLC showed significant product formation. The reaction mixture was quenched with saturated aqueous ammonium chloride, and the resulting mixture was evaporated under reduced pressure. The resulting white solid was diluted with 50 mL of 4:1 DCM:MeOH, and the resulting slurry was vigorously stirred overnight at room temperature under Ar. The next morning, the contents were filtered and the resulting mother liquor was evaporated under reduced pressure to give a white solid which was purified via column chromatography eluting with 80:20:3 DCM / MeOH / NH4OH to give a waxy white solid (0.064 g, 0.130 mmol, 37% yield). 1 H NMR(600MHz,CD3OD)δ 8.33(s,1H),8.21(s,1H),4.38(dd,J=14.4Hz,J=3.0Hz,1H),4.23(dd,J=14.4Hz,J=6.6Hz,1H),3.90(Sextet,J=3.4Hz,1H),3.70-3.78(m,3H), 3.46(dd,J=12.6Hz,J=10.2Hz,1H),2.14-2.18(m,3H),1.45-1.52(m,4H),1.40(p,J=7.5Hz,2H),1.22-1.28(m,16H),1.16(d,J=6.6Hz,3H). 13 C NMR(150MHz,CD3OD)δ 155.1,150.8,150.1,144.3,123.1,119.0,85.0,76.3(d,J=12.2Hz),68.8,65.7(d,J=5.9Hz),64.9 d(J=159.9Hz),31.7(d,J=6.2Hz),30.3,30.3,30.3,30.3,30.2,30.1,29.8,29.4,29.2,26.5,18.8,16.7. 31 P NMR(122MHz,CD3OD)δ 15.6.HRMS(APCI)m / z C24 H 41 O4N5P[M+H] + Calculated for: 494.28907, found: 494.28924. LC-MS (ESI) 50-95% MeOH in H2O (0.1% HCO2H), 6 min, rt = 5.430, m / z = 494.0 [M+H] + , 491.9 [MH] - .

[0220] Example 2. Synthesis of ammonium pentadecyl-14,14,15,15,15-d5(R)-(((1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate A. Synthesis of 14,14,15,15,15-Pentadeuteriopentadecane-1-ol (EJM-8-033) [ka] Pentadec-14-yn-1-ol (465 mg, 2.07 mmol, 1.00 eq) was added to an oven-dried flask equipped with a stir bar, diluted with THF (20.7 mL), cooled to −78 °C, and vigorously stirred under Ar. n-Butyllithium (2.5 M in hexanes, 2.49 mL, 6.22 mmol, 3.00 eq) was added dropwise via syringe pump at a rate of 4 mL / hr, and the resulting mixture was vigorously stirred under Ar at −78 °C for 30 min. After this time, the cold water bath was removed for 10 min, and then the reaction was slowly quenched with trideuterio(deuteriooxy)methane (0.470 mL, 10.4 mmol, 5.00 eq). The resulting mixture was vigorously stirred under Ar while slowly warming to room temperature over 2 h. After this time, the reaction mixture was partitioned between DO and EtOAc. The resulting aqueous layer was extracted twice with EtOAc, and the combined organic layers were dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to give 450 mg of a white solid, which corresponded to the product 15-deuteriopentadec-14-yn-1-ol. The crude material was used in the subsequent step without further purification.

[0221] 15-Deuteriopentadec-14-yn-1-ol (295 mg, 1.31 mmol, 1.00 eq) was added to an oven-dried 100 mL flask equipped with a stir bar. After dilution with EtOAc (26.2 mL) and addition of 10% palladium on carbon (20.9 mg, 0.020 mmol, 0.15 eq), the resulting heterogeneous mixture was vigorously stirred at room temperature under Ar. The solvent was degassed under house vacuum for 5 min, followed by an Ar purge. These two steps were repeated two more times. Finally, the solvent was degassed for one final cycle, this time purged with a balloon of deuterium gas. The resulting reaction mixture was vigorously stirred at room temperature under deuterium gas overnight. In the morning, the deuterium gas was removed from the flask using house vacuum and replaced with Ar three times. The heterogeneous mixture was filtered through a plug of Celite, which was subsequently washed with EtOAc. The solvent was evaporated under reduced pressure to give a white solid. The crude material was purified via column chromatography (CombiFlash, 24 g column, 35 mL / min) to afford a white solid (365 mg, 1.56 mmol, 78% yield over two steps) eluting with the following gradient: 0-3 min, 0% EtOAc in hexanes; 3-20 min, 0-25% EtOAc in hexanes; 20-25 min, 25% EtOAc in hexanes; 25-30 min, 25-50% EtOAc in hexanes.

[0222] B. Synthesis of Ammonium Pentadecyl-14,14,15,15,15-d5(R)-(((1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate (EJM-8-030) [ka] Tenofovir (200 mg, 0.700 mmol, 1.00 eq) was added to a flame-dried 25 mL flask equipped with a stir bar, diluted with pyridine (5.80 mL), and vigorously stirred at room temperature under Ar. After the addition of 14,14,15,15,15-pentadeuteriopentadecane-1-ol (228 mg, 0.970 mmol, 1.40 eq) and 2,4,6-triisopropylbenzenesulfonyl chloride (633 mg, 2.09 mmol, 3.00 eq), the resulting yellow reaction mixture was vigorously stirred at room temperature under Ar overnight. After 2 days, TLC showed significant product formation. The reaction mixture was quenched with saturated aqueous ammonium chloride, and the resulting mixture was evaporated under reduced pressure. The resulting white solid was diluted with 50 mL of 4:1 DCM:MeOH, and the resulting slurry was vigorously stirred at room temperature under Ar overnight. The following morning, the contents were filtered and the resulting mother liquor was evaporated under reduced pressure to give a white solid which was further purified via column chromatography (CombiFlash, 24 g column, 35 mL / min) eluting with 80:20:3 DCM / MeOH / NH4OH to give 143 mg of a white powder. 1 H NMR and LC-MS analysis indicated 8% (iPr)PhSOH contamination. This material was purified via column chromatography (CombiFlash, 12 g column, 30 mL / min) to afford a white solid (121 mg, 0.241 mmol, 35% yield) eluting with the following gradient: 0–3 min, 25% 80:20:3 DCM / MeOH / NH4OH in DCM; 3–20 min, 25–100% 80:20:3 DCM / MeOH / NH4OH in DCM; 20–30 min, 100% 80:20:3 DCM / MeOH / NH4OH. 1 H NMR(600MHz,CD3OD)δ 8.32(s,1H),8.20(s,1H),4.37(dd,J=3.6Hz,J=14.4Hz,1H),4.22(dd,J=6.6Hz,J=14.4Hz,1H),3.87-3.91(m,1H),3 .69-3.79(m,3H),3.46(dd,J=10.2Hz,J=12.6Hz,1H),1.47-1.52(m,2H),1.24-1.27(m,22H),1.16(d,J=6.0Hz,3H). 13C NMR(150MHz,CD3OD)δ 155.0,150.9,150.0,144.0,118.8,76.2(d,J=12.5Hz),65.5(d,J=5.9Hz),64.7(d,J=159.2Hz),48.7,32.2-32.1(m, 2C),31.5(d,J=6.2Hz),30.2(3C),30.1,30.1,29.9,29.8-29.6(m),29.8,26.3,22.6-21.8(m),16.7,13.6-13.0(m). 31 P NMR(122MHz,CD3OD)δ 15.5.HRMS(APCI)m / z C 24 H 39 D5O4N5P[MH] - Calculated for: 501.33720, Found: 501.33753. LC-MS (ESI) 75-95% MeOH in H2O (0.1% HCO2H), 5 min, rt = 4.385, m / z = 503.4 [M+H] + , 525.3 [M+Na] + , 499.6[MH] - ;50-95%MeOH in H2O (0.1%HCO2H), 8 min, rt=4.723, m / z=503.3[M+H] + , 525.3 [M+Na] + , 499.6(MH) - .

[0223] Example 3. Synthesis of ammonium hexadecyl-16,16,16-d3(R)-(((1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate A. Synthesis of ((pentadec-14-yn-1-yloxy)methyl)benzene (NP-1-009) [ka] Sodium hydride (60% in mineral oil, 196 mg, 4.90 mmol, 2.20 eq) was added to pentadec-14-yn-1-ol (500 mg, 2.23 mmol, 1.00 eq) in 10 mL THF and 0.5 mL DMF at 0 °C. After 30 min, benzyl bromide (0.300 mL, 2.50 mmol, 1.12 eq) was added dropwise, and the reaction was heated to 65 °C overnight. The next morning, the reaction was cooled to room temperature and subsequently quenched with saturated aqueous ammonium chloride. The resulting aqueous phase was extracted three times with EtOAc, and the combined organic phases were dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The crude material was purified via column chromatography to give a white solid (384 mg, 1.21 mmol, 55% yield).

[0224] B. Synthesis of (((hexadec-14-yn-1-yl-16,16,16-d3)oxy)methyl)benzene (EJM-8-028) [ka] A solution of ((pentadec-14-yn-1-yloxy)methyl)benzene (192 mg, 0.610 mmol, 1.00 eq) in THF (6.10 mL) was placed in a flask with a stir bar. The resulting mixture was added to an oven-dried three-neck flask, cooled to −78°C, and vigorously stirred under Ar. After the dropwise addition of n-butyllithium (2.5 M in hexanes, 0.320 mL, 0.670 mmol, 1.10 eq) via syringe pump at a rate of 1 mL / hr, the resulting mixture was stirred at −78°C for 1 h. After this time, the cold water bath was removed for 10 min and then replaced for another 10 min. Next, trideuterio(iodo)methane (0.110 mL, 1.83 mmol, 3.00 eq) was added dropwise, and the resulting reaction mixture was vigorously stirred under Ar at −78°C for 30 min, then slowly warmed to room temperature. After 20 min at room temperature, the reaction was quenched with saturated aqueous ammonium chloride, and the resulting aqueous layer was extracted three times with diethyl ether. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to give a yellow oil, which was further purified via column chromatography (CombiFlash, 24 g, 35 mL / min) eluting with the following gradient to give a clear oil (174 mg, 0.525 mmol, 86% yield): 0–3 min, 0% EtOAc in hexanes; 3–13 min, 0–5% EtOAc in hexanes; 13–23 min, 5% EtOAc in hexanes; 23–30 min, 5–10% EtOAc in hexanes.

[0225] C. Synthesis of hexadecan-16,16,16-d3-1-ol (EJM-8-034) [ka] A solution of (((hexadec-14-yn-1-yl-16,16,16-d3)oxy)methyl)benzene (174 mg, 0.520 mmol, 1.00 eq) in EtOAc (10.5 mL) was added to an oven-dried flask containing a stir bar. After the addition of 10% palladium on carbon (55.9 mg, 0.050 mmol, 0.100 eq), the resulting heterogeneous mixture was vigorously stirred at room temperature under Ar. The solvent was degassed under house vacuum for 5 min and then purged with Ar. These two steps were repeated two more times. Finally, the solvent was degassed for one final cycle, this time purged with a balloon of hydrogen gas. The resulting reaction mixture was vigorously stirred at room temperature under hydrogen overnight. In the morning, the hydrogen gas was removed from the flask using house vacuum and replaced with Ar three times. The reaction mixture was then filtered over Celite, which was subsequently washed thoroughly with EtOAc. The solvent was evaporated under reduced pressure to give 173 mg of a clear oil. The crude 16,16,16-trideuteriohexadecoxymethylbenzene was used in the subsequent step without further purification.

[0226] 16,16,16-Trideuteriohexadecoxymethylbenzene (173 mg, 0.520 mmol) was added to a 100 mL flask equipped with a stir bar and diluted with EtOH (10.3 mL) and a small volume of EtOAc to ensure complete dissolution. The resulting solution was vigorously stirred at room temperature under Ar. After the addition of 20% palladium hydroxide on carbon (72.4 mg, 0.103 mmol, 0.200 eq), the resulting heterogeneous mixture was vigorously stirred at room temperature under Ar. The solvent was degassed under house vacuum for 5 min and then purged with Ar. These two steps were repeated two more times. Finally, the solvent was degassed for one final cycle, this time purged with a balloon of hydrogen gas. The resulting reaction mixture was vigorously stirred under hydrogen gas overnight at room temperature. The next morning, TLC showed complete conversion of the starting material to one major product. The reaction mixture was filtered over a plug of Celite, which was subsequently washed with EtOAc. The resulting solution was evaporated under reduced pressure to give 150 mg of a white solid. The crude material was purified via column chromatography (CombiFlash, 12 g column, 25 mL / min) eluting with the following gradient to give a white solid (122 mg, 0.497 mmol, 96% yield over two steps): 0-3 min, 0% EtOAc in hexanes; 3-20 min, 0-25% EtOAc in hexanes; 20-30 min, 25% EtOAc in hexanes.

[0227] D. Synthesis of Ammonium Hexadecyl-16,16,16-d3(R)-(((1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate (EJM-8-036) [ka] Tenofovir (100 mg, 0.350 mmol, 1.00 eq) was added to a flame-dried 25 mL flask equipped with a stir bar and diluted with pyridine (3.48 mL). The resulting slurry was vigorously stirred at room temperature under Ar. After the addition of hexadecan-16,16,16-d3-1-ol (120 mg, 0.490 mmol, 1.40 eq) and 2,4,6-triisopropylbenzenesulfonyl chloride (316 mg, 1.04 mmol, 3.00 eq), the resulting yellow reaction mixture was vigorously stirred at room temperature under Ar overnight. After 2 days, TLC showed significant product formation. The reaction mixture was quenched with saturated aqueous ammonium chloride, and the resulting mixture was evaporated under reduced pressure. The resulting white solid was diluted with 60 mL of 5:1 DCM:MeOH, and the resulting slurry was vigorously stirred at room temperature under Ar for 1 h. After this time, the contents were filtered, the filtrate was washed thoroughly with 5:1 DCM to MeOH, and the resulting mother liquor was evaporated under reduced pressure to give a white solid. The crude material was further purified via column chromatography (CombiFlash, 12 g column, 30 mL / min) eluting with the following gradient to give a white solid (98.0 mg, 0.190 mmol, 55% yield): 0–3 min, 25% 80:20:3 DCM / MeOH / NH4OH in DCM; 3–20 min, 25–100% 80:20:3 DCM / MeOH / NH4OH in DCM; 20–30 min, 100% 80:20:3 DCM / MeOH / NH4OH. 1 H NMR(600MHz,CD3OD)δ 8.32(s,1H),8.20(s,1H),4.38(dd,J=3.3Hz,J=14.7Hz,1H),4.22(dd,J=6.6Hz,J=14.4Hz,1H),3.87-3.90(m,1H),3 .70-3.78(m,3H),3.46(dd,J=10.2Hz,J=12.6Hz,1H),1.47-1.52(m,2H),1.23-1.27(m,26H),1.16(d,J=6.6Hz,3H). 13C NMR(150MHz,CD3OD)δ 155.0,150.9,150.0,144.0,129.2,76.2(d,J=12.5Hz),65.5(d,J=5.7Hz),64.7(d,J=159.2Hz),48.7,32.5-32.3(m, 3C),31.5(d,J=6.0Hz),30.2(3C),30.2,30.2,29.9,29.9-29.8(m),26.3,23.2-22.5(m),16.7,14.3,14.1-13.4(m). 31 P NMR(122MHz,CD3OD)δ 15.6.HRMS(APCI)m / z C 25 H 41 D3O4N5P[MH] - Calculated for: 513.34029, found: 513.33931. LC-MS (ESI) 50-95% MeOH in H2O (0.1% HC02H), 8 min, rt = 4.613, m / z = 515.3 [M+H] + , 537.3 [M+Na] + .

[0228] Example 4. Synthesis of ammonium 4,4-difluoroicosyl (R)-(((1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate Synthesis of N-Methoxy-4-((4-methoxybenzyl)oxy)-N-methylbutanamide (EJM-8-038) [ka] Weinreb's salt (2.49 g, 25.6 mmol, 1.10 eq) was added to an oven-dried 500 mL flask equipped with a stir bar, diluted with DCM (155 mL), cooled to 0 °C, and vigorously stirred under Ar. After the dropwise addition of chloro(dimethyl)almane (25.6 mL, 25.6 mmol, 1.10 eq) via syringe pump at a flow rate of 10 mL / hr, the resulting mixture was vigorously stirred at 0 °C for 1 h under Ar. After the dropwise addition of γ-butyrolactone (1.79 mL, 23.2 mmol, 1.00 eq) via syringe pump at a rate of 4 mL / hr, the resulting reaction mixture was slowly warmed to room temperature and vigorously stirred overnight under Ar. After 22 h, the reaction was quenched by the dropwise addition of water. The resulting aqueous layer was extracted three times with DCM, and the combined organic layers were washed once with brine, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to give 2.49 g of a yellow oil. A solution of the crude material (2.49 g, 17.3 mmol, 1.00 eq) in 35 mL of DCM was added to an oven-dried 100 mL flask equipped with a stir bar, cooled to 0 °C, and vigorously stirred under Ar. After the dropwise addition of a solution of (4-methoxyphenyl)methyl 2,2,2-trichloroethaneimidate (3.62 mL, 17.4 mmol, 1.10 eq) in 15 mL of DCM via a syringe pump at a rate of 19 mL / hr, the resulting mixture was vigorously stirred at 0 °C under Ar for 10 min. After the addition of (1R)-(-)-10-camphorsulfonic acid (200 mg, 0.860 mmol, 0.05 eq), the resulting reaction mixture was allowed to warm slowly to room temperature overnight under Ar with vigorous stirring. After 17 h, the reaction was quenched with saturated aqueous sodium bicarbonate. The resulting aqueous layer was extracted four times with DCM, and the combined organic layers were dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to give 7.10 g of a mixture of a yellow oil and a white solid. Purification was performed via column chromatography (CombiFlash, 120 g column, 85 mL / min) eluting with a gradient mobile phase (0–3 min, 33% EtOAc in hexanes; 3–20 min, 33–75% EtOAc in hexanes; 20–25 min, 75% EtOAc in hexanes; 25–30 min, 75–100% EtOAc in hexanes) to give a clear oil (2.10 g, 7.86 mmol, 46% yield).

[0229] B. Synthesis of 1-((4-methoxybenzyl)oxy)icos-5-yn-4-one (EJM-8-056) [ka] Hexadequin-1-yne (0.253 mL, 0.900 mmol, 1.20 eq) was added to an oven-dried 50 mL three-neck flask equipped with a stir bar, diluted with 5 mL THF, cooled to -78 °C, and vigorously stirred for 15 min under Ar. At this temperature, the solution was cloudy, but stirring was vigorous. After the dropwise addition of freshly titrated n-butyllithium (2.0 M in hexanes, 0.486 mL, 0.970 mmol, 1.30 eq), the resulting mixture was stirred at -78 °C for 15 min. After this time, the mixture was warmed to 0 °C and vigorously stirred for 15 min under Ar. N-Methoxy-4-((4-methoxybenzyl)oxy)-N-methylbutanamide (200 mg, 0.750 mmol, 1.00 eq) was added to a 50 mL oven-dried flask equipped with a stir bar. The mixture was diluted with 2.5 mL of THF, cooled to -78 °C, and vigorously stirred under Ar for 15 min. The solution of lithiated alkyne was then transferred via cannula, and the resulting mixture was vigorously stirred at -78 °C under Ar for 30 min. After this time, TLC showed only starting material. Therefore, the reaction mixture was warmed to room temperature and stirred for 30 min. After this time, TLC showed the formation of a new product. The reaction mixture was stirred for an additional 90 min, after which time TLC showed further conversion of the starting material to a new product, but the concentrations of two impurities increased over time. Therefore, the reaction mixture was quenched with saturated aqueous ammonium chloride. The resulting aqueous layer was extracted three times with diethyl ether, and the combined organic layers were dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to give 455 mg of a slightly yellow oil, which was further purified via column chromatography (CombiFlash, 25 g column, 25 mL / min) eluting with a gradient mobile phase (0–3 min, 0% EtOAc in hexanes; 3–10 min, 0–33% EtOAc in hexanes; 10–13 min, 33% EtOAc in hexanes; 13–20 min, 33–100% EtOAc in hexanes; 20–25 min, 100% EtOAc in hexanes) to give 49 mg of the starting amide and a clear oil (195 mg, 0.455 mmol, 61% yield).

[0230] C. Synthesis of 1-(((4,4-difluoroicos-5-yn-1-yl)oxy)methyl)-4-methoxy-benzene (EJM-8-057) [ka] 1-((4-Methoxybenzyl)oxy)icos-5-yn-4-one (970 mg, 2.26 mmol, 1.00 eq) was dissolved in DCE (2.26 mL) and added to a microwave vial with a stir bar. The resulting solution was vigorously stirred under Ar for 5 min. After the dropwise addition of diethylaminosulfur trifluoride (0.900 mL, 6.79 mmol, 3.00 eq), followed by one drop of EtOH, the resulting reaction tube was sealed, warmed to 60 °C, and vigorously stirred for 2.5 h. After this time, the reaction mixture was inactivated by the dropwise addition of saturated aqueous sodium bicarbonate. The resulting aqueous layer was extracted twice with DCM, and the combined organic layers were dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to give a brown oil. TLC indicated some conversion to product with much of the starting material remaining. Therefore, the crude mixture was resubmitted to the reaction conditions using only 1 mL DCE and stirring at 60 °C for 4 h. After this time, the reaction mixture was quenched by the dropwise addition of saturated aqueous sodium bicarbonate. The resulting aqueous layer was extracted twice with DCM, and the combined organic layers were dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to give a brown oil. TLC showed more conversion to the product and some remaining starting material. The product was purified via column chromatography (CombiFlash, 30 g column, 35 mL / min) eluting with a gradient mobile phase (0–2 min, 0% EtOAc in hexanes; 2–15 min, 0–10% EtOAc in hexanes; 15–20 min, 10% EtOAc in hexanes; 20–25 min, 10–100% EtOAc in hexanes; 25–30 min, 100% EtOAc) to give 148 mg of starting material and a yellow oil (340 mg, 0.755 mmol, 33% yield).

[0231] D. Synthesis of 4,4-difluoroicosan-1-ol (EJM-8-058) [ka] 1-(((4,4-Difluoroicos-5-yn-1-yl)oxy)methyl)-4-methoxy-benzene (390 mg, 0.870 mmol, 1.00 eq) was added to a 50 mL flask equipped with a stir bar. After dilution with ethyl acetate (4.5 mL) and ethanol (4.5 mL), the resulting solution was vigorously stirred at room temperature under Ar. After the addition of palladium hydroxide on carbon (20% wt., 60.8 mg, 0.090 mmol, 0.100 eq), the resulting mixture was vigorously stirred under Ar. The mixture was then degassed under house vacuum for 5 min, followed by an Ar flush. This vacuum flush cycle was repeated two more times, after which it was evacuated one last time for 5 min, followed by an H2 flush. The resulting reaction mixture was vigorously stirred under a H2 balloon overnight at room temperature. In the morning, the reaction mixture was filtered over a plug of Celite, which was then thoroughly washed with EtOAc. The solvent was evaporated under reduced pressure to give an off-white solid. TLC indicated only approximately 50% conversion of the starting material to a new, lower Rf spot. Therefore, the crude material was resubmitted to the reaction conditions with a higher loading of palladium hydroxide on carbon (20% wt., 121 mg, 0.180 mmol, 0.200 eq), and the resulting reaction mixture was vigorously stirred under hydrogen overnight. The next morning, the reaction mixture was filtered over a plug of Celite, which was subsequently washed thoroughly with EtOAc. The solvent was evaporated under reduced pressure to give a white solid. TLC indicated nearly complete conversion of the starting material to a single, lower Rf spot (stained with PMA). The crude material was purified using column chromatography (CombiFlash, 10 g column, 35 mL / min) eluting with a gradient mobile phase (0–10 min, 0% MeOH in DCM; 10–20 min, 0–20% MeOH in DCM) to give a white solid (203 mg, 0.607 mmol, 70% yield).

[0232] E. Objectives for the synthesis of ammonium 4,4-difluoroicosyl (R)-(((1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate (EJM-8-060) [ka] 4,4-Difluoroicosyl (R)-(((1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate can be synthesized by coupling tenofovir with 4,4-difluoroicosan-1-ol using the methods described in Examples 1-3. A representative synthetic workflow is described below. Tenofovir (125 mg, 0.440 mmol, 1.00 eq) is added to a flame-dried 25 mL flask containing a stir bar. After dilution with pyridine (4.35 mL), the resulting slurry is vigorously stirred at room temperature under Ar. After addition of 4,4-difluoroicosan-1-ol (204 mg, 0.610 mmol, 1.40 eq) and 2,4,6-triisopropylbenzenesulfonyl chloride (395 mg, 1.31 mmol, 3.00 eq), the resulting reaction mixture is vigorously stirred at room temperature under Ar overnight. If TLC indicates significant product formation, the reaction mixture is quenched with saturated aqueous ammonium chloride, and the resulting mixture is evaporated under reduced pressure. The resulting solid is diluted with 200 mL of 3:1 DCM:MeOH, and the resulting slurry is vigorously stirred overnight at room temperature under Ar. The next morning, the contents are filtered, the filtrate is thoroughly washed with 3:1 DCM:MeOH, and the resulting mother liquor is evaporated under reduced pressure to give the product as a solid.

[0233] Example 5. Synthesis of ammonium 3-(hexadec-15-yn-1-yloxy)propyl (R)-(((1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate A. Synthesis of 2-(hexadec-2-yn-1-yloxy)tetrahydro-2H-pyran (MD-5-67) [ka] To a mixture of 2-(2-propynyloxy)tetrahydro-2H-pyran (2.0 mL, 14.2 mmol, 1.0 eq) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (5.1 mL, 42.8 mmol, 3.0 eq) in a 250 mL three-neck round-bottom flask was added anhydrous THF (40 mL) and cooled to -78 °C. After 30 min, n-butyllithium (2.5 M in hexane, 7.4 mL, 18.5 mmol, 1.3 eq) was added dropwise via syringe pump at a rate of 20 mL / hr. The mixture was stirred for 1 h, and then 1-bromotridecane (4.7 mL, 18.5 mmol, 1.3 eq) was added dropwise over 10 min. The reaction was allowed to warm to room temperature and stirred overnight. After 21 h, TLC analysis showed complete conversion to the product. (R f =0.43, 7.5% EtOAc / hexane, PMA stain). The reaction mixture was quenched by the addition of saturated ammonium chloride solution and extracted three times with EtOAc. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a crude oil. Purification by silica gel chromatography, eluting with 0-5% EtOAc / hexane, gave the product (3.5 g, 10.8 mmol, 76%) as an oil.

[0234] B. Synthesis of Hexadec-2-yn-1-ol (MD-5-68) [ka] To a cloudy solution of 2-(hexadec-2-yn-1-yloxy)tetrahydro-2H-pyran (2.5 g, 7.7 mmol, 1.0 eq) in methanol (20 mL) was added p-toluenesulfonic acid (133.4 mg, 0.78 mmol, 0.1 eq). The resulting homogeneous solution was stirred at room temperature overnight. After 16 h, TLC (7.5% EtOAc / hexane, PMA stain) showed complete conversion to the product. The reaction mixture was concentrated under reduced pressure, redissolved in hexane, adsorbed onto silica gel, and purified by silica gel flash chromatography, eluting with 0–10% EtOAc / hexane, to give the product (1.6 g, 6.7 mmol, 86%) as a white solid.

[0235] C. Synthesis of Hexadec-15-yn-1-ol (MD-5-69) [ka] In a three-neck round-bottom flask, a solution of sodium hydride (60% dispersion in mineral oil, 2.1 g, 53.3 mmol, 8.0 eq) in 1,3-diaminopropane (27.8 mL, 333.4 mmol, 50 eq) was heated at 70 °C for 1 h. After the reaction mixture was cooled to room temperature, hexadec-2-yn-1-ol (1.5 g, 6.6 mmol, 1.0 eq) was added portionwise as a solid, and the suspension was heated at 55 °C overnight. After 17 h, the reaction mixture was cooled to room temperature, inactivated with water, and acidified with 3 N aqueous HCl to pH = 2. The mixture was then extracted with hexane (x3), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a brown oil. The residue was purified by silica gel chromatography, eluting with 0–5% EtOAc / hexane, to give the product (1.0 g, 4.38 mmol, 65% yield) as a white solid.

[0236] D. Synthesis of 16-bromohexadec-1-yne (MD-5-70) [ka] To a solution of hexadec-15-yn-1-ol (500.0 mg, 2.1 mmol) in anhydrous DCM (3 mL) was added carbon tetrabromide (1043.2 mg, 3.1 mmol, 1.5 eq) and triphenylphosphine (825.1 mg, 3.1 mmol, 1.5 eq). The resulting pale yellow solution was stirred at room temperature for 30 min, and TLC analysis (7.5% EtOAc / hexane, PMA stain) indicated complete conversion. The reaction mixture was concentrated under reduced pressure, followed by the addition of hexane, which resulted in the precipitation of a solid. The solid was removed by filtration and rinsed with hexane. The filtrate was concentrated under reduced pressure to give a semi-solid, which was dried under high vacuum to give a white solid.

[0237] E. Synthesis of 3-(hexadec-15-yn-1-yloxy)propan-1-ol (MD-5-71) [ka] To a solution of 1,3-dihydroxypropane (0.5 mL, 7.0 mmol, 4.5 eq) in anhydrous DMF (3 mL) at 0 °C, sodium hydride (60% dispersion in mineral oil, 0.09 g, 2.3 mmol, 1.5 eq) was added portionwise and stirred at room temperature for 30 min. To this was added 16-bromohexadec-1-yne (0.5 g, 1.5 mmol, 1.0 eq), followed by potassium iodide (0.2 g, 1.5 mmol, 1.0 eq) and heated at 95 °C for 3 h. The reaction mixture was then cooled to 0 °C, quenched by slow addition of ice-cold water (15 mL), and extracted with EtOAc (30 mL). The organic layer was collected and rewashed with brine (2 × 15 mL). The organic layer was dried over Na2SO4, filtered, concentrated, and purified by silica gel chromatography, eluting with 0-30% EtOAc / hexanes to give the product (0.16 g, 0.5 mmol, 35% yield) as a white solid.

[0238] F. Synthesis of Ammonium 3-(hexadec-15-yn-1-yloxy)propyl (R)-(((1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate (MD-5-72) [ka] Commercially available tenofovir was dried overnight at 55°C in a vacuum oven prior to use. 3-(hexadec-15-yn-1-yloxy)propan-1-ol (155.0 mg, 0.522 mmol, 1.0 eq) and tenofovir (150.15 mg, 0.522 mmol, 1.0 eq) were placed in a 100 mL three-neck flask equipped with a condenser and suspended in anhydrous DMF (2 mL). Triethylamine (0.15 mL, 1.045 mmol, 2.0 eq) was added dropwise. To the resulting homogeneous solution, N,N'-dicyclohexylcarbodiimide (215.73 mg, 1.045 mmol, 2.0 eq) and 4-dimethylaminopyridine (6.3 mg, 0.052 mmol, 0.1 eq) were added, stirred at room temperature for 10 minutes, and then heated at 95°C overnight. After 17 h, TLC analysis indicated the product (30% MeOH / CHCl with 10% NHOH). The mixture was cooled to room temperature and loaded directly onto a silica gel column for purification, eluting with 0–30% MeOH (with 10% NHOH) / DCM to give the product as a white solid. The solid was again subjected to a second purification run on reverse-phase C18 chromatography (CombiFlash) eluting with 5–100% MeOH / H2O to give the product in a 70–90% gradient. The product fractions were pooled, concentrated, co-concentrated with methanol with 10% NH4OH (x3), and dried in vacuo to give the product (73.0 mg, 0.125 mmol, 24% yield) as a white solid. Melting point (MP) 135–160.9 °C. 1 H NMR (399 MHz, CD3OD) δ 8.31(s,1H),8.20(s,1H),4.37(dd,J=14.4,3.1Hz,1H),4.22(dd,J=14.4,6.7Hz ,1H),3.92-3.81(m,3H),3.71(dd,J=12.7,9.4Hz,1H),3.50-3.45(m,1H),3.42(t ,J=6.4Hz,2H),3.33(t,J=6.6Hz,2H),2.16-2.10(m,3H),1.77(p,J=5.5Hz,2H), 1.51-1.44(m,4H),1.42-1.33(m,2H),1.33-1.24(m,18H),1.16(d,J=6.2Hz,3H). 13C NMR(151MHz,CD3OD)δ 156.2,152.3,150.5,144.1,119.2,85.0,76.6(d,J=12.9Hz),71.8,69.0,68.2,65.1(d,J=159.9Hz),62. 8(d,J=5.5Hz),48.9,32.1(d,J=6.1Hz),30.5,30.4,30.4,30.4,30.3,29.9,29.5,29.4,27.0,18.9,16.7. 31 P NMR(162MHz,CD3OD)δ 15.45.HRMS(APCI)m / z C 28 H 49 N5O5P[M+H] + Calculated for: 566.34658, Found: 566.34623. LC-MS (ESI) 85-95% MeOH / H2O (0.1% HC02H), 5 min, 1.00 mL / min, rt = 2.56 min, m / z = 566.4 [M+H] + ;LC-MS(ESI)80-95%MeOH / H2O(0.1%HCO2H), 5 min, r=3.38 min, m / z=566.4[M+H] + .

[0239] Example 6. Synthesis of ammonium octadecyl (R)-(((1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate (MD-1-105) [ka] To a stirred suspension of dry tenofovir (200 mg, 0.696 mmol, 1.00 eq), DCC (287 mg, 1.39 mmol, 2.00 eq), and 1-octadecanol (188 mg, 0.696 mmol, 1.00 eq) in anhydrous DMF (2.3 mL) under an inert atmosphere, triethylamine (194 μL, 1.39 mmol, 2.00 eq) and DMAP (8.51 mg, 0.0696 mmol, 10 mol%) were added. The reaction mixture was stirred at room temperature for 10 min and then heated to 105 °C overnight. After confirming product formation by LC-MS, the reaction mixture was inactivated with water, stirred at room temperature for 20 min, and immediately purified by normal-phase column chromatography (0-70% DCM:DCM / MeOH / NH4OH (80:20:3)). The product fractions were collected, concentrated under reduced pressure, and purified by reverse-phase column chromatography (0-85% HO:MeOH). The product fractions were collected again, concentrated under reduced pressure, stirred with 7N ammonia in methanol (10 mL) at room temperature for 10 min, and dried under vacuum to give MD-1-105 (132 mg, 35% yield) as a white solid. MP = 154-184 °C (starting at decomp. 171 °C). 1 H NMR(600MHz,CD3OD)δ 8.33(s,1H),8.21(s,1H),4.39(dd,J=14.4,3.1Hz,1H),4.24(dd,J=14.5,6.7Hz,1H),3.91(pd,J=6.3,2.9Hz,1H),3.81-3.6 8(m,3H),3.48(dd,J=12.8,10.0Hz,1H),1.56-1.44(m,2H),1.35-1.21(m,30H),1.16(d,J=6.3Hz,3H),0.90(t,J=7.0Hz,3H). 13 C NMR(126MHz,CD3OD)δ 157.2,153.5,150.9,144.2,119.6,76.9(d,J=12.8Hz),65.9(d,J=5.9Hz),65.6(d,J=1 60.3Hz),33.1,32.1(d,J=6.3Hz),30.8,30.7,30.7,30.7,30.5,26.9,23.7,16.8,14.4. 31 P NMR(243MHz,CD3OD)δ 15.4.HRMS(APCI)m / z C 27H 51 N5O4P + [M+H] + Calculated for: 540.36732, found: 540.36763. HPLC: 95% MeOH in HO, 10 min, m / z = 540.4 (M+H), t = 2.440 min; 75-95% MeOH in HO, 10 min, m / z = 540.4 (M+H), t = 8.845 min.

[0240] Example 7. Synthesis of ammonium pentadecyl (R)-(((1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate (MD-1-106) [ka] MD-1-106 was synthesized following the general procedure for MD-1-105 using 1-pentadecanol (159 mg, 0.696 mmol, 1.00 eq). Purification afforded MD-1-106 as a white powder (124 mg, 36% yield). MP = 162-190 °C (starting at decomp. 179 °C). 1 H NMR(600MHz,CD3OD)δ 8.33(s,1H),8.21(s,1H),4.39(dd,J=14.5,3.1Hz,1H),4.24(dd,J=14.4,6.7Hz,1H),3.90(pd,J=6.3,3.1Hz,1H),3.80-3.6 8(m,3H),3.47(dd,J=12.8,10.0Hz,1H),1.55-1.44(m,2H),1.35-1.21(m,24H),1.16(d,J=6.3Hz,3H),0.90(t,J=7.0Hz,3H). 13 C NMR(126MHz,CD3OD)δ 157.1,153.3,150.9,144.3,119.5,76.9(d,J=12.9Hz),65.9(d,J=5.8Hz),65.5(d,J=1 59.7Hz),33.1,32.1(d,J=6.3Hz),30.8,30.8,30.7,30.7,30.5,26.9,23.7,16.8,14.4. 31 P NMR(243MHz,CD3OD)δ 15.3.HRMS(APCI)m / z C 24 H 45N5O4P + [M+H] + Calculated for: 498.32037, found: 498.32072. HPLC: 95% MeOH in HO, 10 min, m / z = 498.2 (M+H), t = 1.714 min; 75-95% MeOH in HO, 10 min, m / z = 498.2 (M+H), t = 5.635 min.

[0241] Example 8. Synthesis of ammonium 3-(hexadecylthio)propyl (R)-(((1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate A. Synthesis of 3-(dexadecylthio)propan-1-ol (MD-1-121) [ka] To an Ar-degassed solution of 3-mercaptopropanol (1.13 mL, 13.1 mmol, 2.00 eq) in DMF (33 mL) was added 1,8-diazabicyclo(5.4.0)undec-7-ene (1.96 mL, 13.1 mmol, 2.00 eq) and the solution was stirred at room temperature for 20 min. 1-Bromohexadecane (2.00 mL, 6.55 mmol, 1.00 eq) was added dropwise, and the reaction mixture was heated to 60 °C for 1.5 h. After complete conversion was confirmed by TLC, the reaction mixture was diluted with EtOAc (10x DMF volume). The organic layer was washed with saturated aqueous NH4Cl (4x), dried over Na2SO4, and concentrated to give an off-white solid. The solid was purified by column chromatography (0–40% EtOAc in hexanes) to give MD-1-121 (1.85 g, 89% yield) as a fluffy white solid.

[0242] B. Synthesis of Ammonium 3-(Hexadecylthio)propyl(R)-(((1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate (MD-1-123) [ka] MD-1-123 was synthesized using 3-(hexadecylthio)propan-1-ol (220 mg, 0.696 mmol, 1.00 eq) following the general procedure for MD-1-105. Purification afforded MD-1-123 (136 mg, 33% yield) as a white solid. MP = 160-184 °C (starting at decomp. 177 °C). 1 H NMR (400 MHz, CD3OD) δ 8.33(s,1H),8.21(s,1H),4.39(dd,J=14.4,3.1Hz,1H),4.24(dd,J=14.4,6.7 Hz,1H),3.95-3.78(m,3H),3.72(dd,J=12.7,9.5Hz,1H),3.47(dd,J=12.7,10 .1Hz,1H),2.50(t,J=7.3Hz,2H),2.46-2.41(m,2H),1.82-1.69(m,2H),1.56- 1.47(m,2H),1.39-1.21(m,26H),1.17(d,J=6.2Hz,3H),0.90(t,J=6.9Hz,3H). 13 C NMR(126MHz,CD3OD)δ 157.1,153.3,150.9,144.3,119.6,76.9(d,J=12.9Hz),65.5(d,J=160.0Hz),64.6(d,J=5.8Hz),33 .1,32.8,32.2(d,J=6.4Hz),30.8,30.8,30.8,30.7,30.7,30.5,30.4,29.9,29.2,23.7,16.8,14.4. 31 P NMR(162MHz,CD3OD)δ 15.4. HRMS(NSI)m / z C 28 H 53 N5O4PS + [M+H] + Calculated for: 586.35504, found: 586.35506. HPLC: 95% MeOH in HO, 10 min, m / z = 586.2 (M+H), t = 2.315 min; 75-95% MeOH in HO, 10 min, m / z = 586.3 (M+H), t = 8.697 min.

[0243] Example 9. Synthesis of ammonium 9-(decylthio)nonyl (R)-(((1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate A. Synthesis of 9-(decylthio)nonan-1-ol (MD-1-120) [ka] To an Ar-degassed solution of 1-decanethiol (3.70 mL, 17.9 mmol, 2 eq) in DMF (34 mL) was added 1,8-diazabicyclo(5.4.0)undec-7-ene (2.68 mL, 17.9 mmol, 2 eq), and the solution was stirred at room temperature for 20 min. 9-Bromo-1-nonanol (2.00 g, 8.96 mmol, 1.00 eq) in DMF (10 mL) was then added dropwise, and the reaction mixture was heated to 60 °C for 1.5 h. After complete conversion was confirmed by TLC, the reaction mixture was diluted with EtOAc (10 × DMF volume). The organic layer was washed with saturated aqueous NH4Cl (4 ×), dried over Na2SO4, and concentrated to give an off-white solid. The crude material was washed with cold hexane (3 ×) to give MD-1-120 (2.15 g, 76% yield) as a shiny white solid.

[0244] B. Synthesis of Ammonium 9-(Decylthio)nonyl (R)-(((1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate (MD-1-122) [ka] MD-1-122 was synthesized using 9-(decylthio)nonan-1-ol (220 mg, 0.696 mmol, 1.00 eq) following the general procedure for MD-1-105. Purification afforded MD-1-122 (122 mg, 30% yield) as a white solid. MP = 160-190 °C (starting at decomp. 176 °C). 1H NMR(600MHz,CD3OD)δ 8.33(s,1H),8.21(s,1H),4.39(dd,J=14.5,3.1Hz,1H),4.24(dd,J=14.5 ,6.7Hz,1H),3.91(pd,J=6.2,3.0Hz,1H),3.80-3.68(m,3H),3.47(dd,J=1 2.8,10.0Hz,1H),2.48(t,J=7.3Hz,2H),2.48(t,J=7.3Hz,2H),1.60-1.46 (m,6H),1.42-1.22(m,24H),1.16(d,J=6.2Hz,3H),0.90(t,J=7.0Hz,3H). 13 C NMR(126MHz,CD3OD)δ 156.7,152.8,150.9,144.5,119.5,76.9(d,J=12.8Hz),65.9(d,J=5.9Hz),65.5(d,J=159.7Hz),33.1,32 .9,32.1(d,J=6.3Hz),30.8,30.8,30.7,30.6,30.4,30.4,30.3,30.3,29.9,29.9,26.9,23.7,16.8,14.4. 31 P NMR(243MHz,CD3OD)δ 15.3.HRMS(APCI)m / z C 28 H 51 N5O4PS - [MH] - Calculated for: 584.34049. Found: 584.34077. HPLC: 95% MeOH in HO, 10 min, m / z = 586.3 (M+H), t = 1.459 min; 75-95% MeOH in HO, 10 min, m / z = 586.3 (M+H), t = 7.541 min.

[0245] Example 10. Synthesis of ammonium 3-((16-methoxy-16-oxohexadecyl)thio)propyl (R)-(((1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate A. Synthesis of methyl 16-((3-hydroxypropyl)thio)hexadecanoate (MD-1-28) [ka] To an Ar-degassed solution of 3-mercaptopropanol (2.35 mL, 27.2 mmol, 2.00 eq) in DMF (68 mL) was added 1,8-diazabicyclo(5.4.0)undec-7-ene (4.07 mL, 27.2 mmol, 2.00 eq), and the solution was stirred at room temperature for 20 min. Next, 16-bromohexadecanoate (4.75 g, 13.6 mmol, 2.00 eq) in DMF (10 mL) was added dropwise, and the reaction mixture was heated to 60 °C for 1.5 h. After confirming complete conversion by TLC, the reaction mixture was diluted with EtOAc (5 × DMF volume). The organic layer was washed with water (4 ×) and brine, dried over MgSO4, and concentrated to give an off-white solid. The solid was purified by column chromatography (0–40% EtOAc in hexanes) to give MD-1-28 (4.29 g, 88% yield) as a white solid.

[0246] B. Synthesis of Ammonium 3-((16-Methoxy-16-oxohexadecyl)thio)propyl(R)-(((1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate (MD-1-124) [ka] MD-1-124 was synthesized by the following general procedure for MD-1-105 using methyl 16-((3-hydroxypropyl)thio)hexadecanoate (251 mg, 0.696 mmol, 1.00 eq). Purification afforded MD-1-124 (139 mg, 32% yield) as a white solid. MP = 146-169 °C (starting at decomp. 163 °C). 1H NMR(600MHz,CD3OD)δ 8.32(s,1H),8.20(s,1H),4.38(dd,J=14.4,3.2Hz,1H),4.24(dd,J=14.4,6.7Hz,1H),3. 93-3.80(m,3H),3.72(dd,J=12.8,9.5Hz,1H),3.65(s,3H),3.47(dd,J=12.8,10.0Hz,1H ),2.51(t,J=7.3Hz,2H),2.44(t,J=7.3Hz,2H),2.31(t,J=7.4Hz,2H),1.82-1.70(m,2H) ,1.60(p,J=7.2Hz,2H),1.52(p,J=7.3Hz,2H),1.37-1.25(m,22H),1.16(d,J=6.2Hz,3H). 13 C NMR(151MHz,CD3OD)δ 176.1,157.0,153.2,150.9,144.3,119.6,76.9(d,J=12.8Hz),65.5(d,J=159.9Hz),64.6(d,J=5.7Hz),52 .0,34.8,32.8,32.2(d,J=6.3Hz),30.8,30.7,30.7,30.7,30.7,30.6,30.4,30.2,29.9,29.2,26.0,16.8. 31 P NMR(243MHz,CD3OD)δ 15.3.HRMS(APCI)m / z C 29 H 51 N5O6PS - [MH] - Calculated for: 628.33031. Found: 628.33149. HPLC: 85-95% MeOH in HO, 10 min, m / z = 630.3 (M+H), t = 1.757 min; 75-95% MeOH in HO, 10 min, m / z = 630.3 (M+H), t = 4.839 min.

[0247] Example 11. Synthesis of ammonium 3-((11-(phenylthio)undecyl)thio)propyl (R)-(((1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate A. Synthesis of 11-(phenylthio)undecane-1-ol (MD-1-116) [ka] To an Ar-degassed solution of thiophenol (1.62 mL, 15.9 mmol, 2.00 eq) in DMF (30 mL) was added 1,8-diazabicyclo(5.4.0)undec-7-ene (2.38 mL, 15.9 mmol, 2.00 eq), and the solution was stirred at room temperature for 20 min. 11-Bromo-1-undecanol (2.00 g, 7.96 mmol, 1.00 eq) in DMF (10 mL) was added dropwise, and the reaction mixture was heated to 60 °C for 1.5 h. After complete conversion was confirmed by TLC, the reaction mixture was diluted with EtOAc (10 × DMF volume). The organic layer was washed with saturated aqueous NH4Cl (4 ×) and brine, dried over Na2SO4, and concentrated to give a pale yellow solid. The crude product was washed with cold hexane (3 ×) to give MD-1-116 (1.95 g, 87% yield) as a white solid.

[0248] B. Synthesis of 3-((11-(phenylthio)undecyl)thio)propan-1-ol (MD-1-118) [ka] To a solution of 11-(phenylthio)undecan-1-ol (1.00 g, 3.57 mmol, 1.00 eq) and triethylamine (745 μL, 5.35 mmol, 1.50 eq) in DCM (9 mL) at 0 °C under an inert atmosphere was added methanesulfonyl chloride (414 μL, 5.35 mmol, 1.50 eq) dropwise. The reaction mixture was stirred at 0 °C for 15 min and then warmed to room temperature for 30 min. Upon complete conversion as determined by TLC, the reaction mixture was diluted with DCM. The organic layer was washed with saturated aqueous NH4Cl (2x), saturated aqueous NaHCO3, and brine, dried over Na2SO4, and concentrated to give 11-(phenylthio)undecyl methanesulfonate (1.27 g, >95% yield) as a yellow oil, which was used immediately without further purification.

[0249] To an Ar-degassed solution of 3-mercaptopropanol (612 μL, 7.08 mmol, 2.00 eq) in DMF (12 mL) was added 1,8-diazabicyclo(5.4.0)undec-7-ene (1.06 mL, 7.08 mmol, 2.00 eq), and the solution was stirred at room temperature for 20 min. 11-(Phenylthio)undecyl methanesulfonate in DMF (5 mL) was added dropwise, and the reaction mixture was heated to 60° C. for 1.5 h. After complete conversion was confirmed by TLC, the reaction mixture was diluted with EtOAc (10× DMF volume), and the combined organics were washed with saturated aqueous NH4Cl (4×) and brine, dried over Na2SO4, and concentrated to give a pale yellow solid. The solid was purified by column chromatography (0-40% EtOAc in hexanes) and the product fractions were collected, concentrated and washed with cold hexanes (3x) to afford MD-1-118 (858 mg, 68% yield over two steps) as a white solid.

[0250] C. Synthesis of Ammonium 3-((11-(phenylthio)undecyl)thio)propyl(R)-(((1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate (MD-1-119) [ka] MD-1-119 was synthesized by the following general procedure for MD-1-105 using 3-((11-(phenylthio)undecyl)thio)propan-1-ol (247 mg, 0.696 mmol, 1.00 eq). Purification afforded MD-1-119 (111 mg, 25% yield) as a white solid. MP = 146-173 °C (starting at decomp. 167 °C). 1H NMR(400MHz,CD3OD)δ 8.33(s,1H),8.21(s,1H),7.33-7.23(m,4H),7.17-7.12(m,1H),4.38(dd,J=14.4,3.1Hz,1H ),4.23(dd,J=14.4,6.7Hz,1H),3.94-3.79(m,3H),3.72(dd,J=12.7,9.4Hz,1H),3.47(dd,J =12.8,10.1Hz,1H),2.95-2.88(m,2H),2.50(t,J=7.3Hz,2H),2.46-2.41(m,2H),1.82-1.69 (m,2H),1.65-1.56(m,2H),1.51(p,J=7.1Hz,2H),1.46-1.22(m,14H),1.16(d,J=6.2Hz,3H). 13 C NMR(126MHz,CD3OD)δ 156.7,152.8,150.9,144.4,138.3,130.1,129.9,126.7,119.6,76.9(d,J=12.9Hz),65.4(d,J=159.6Hz),64.6 (d,J=5.8Hz),34.3,32.8,32.2(d,J=6.2Hz),30.8,30.6,30.6,30.6,30.3,30.3,30.2,29.9,29.7,29.2,16.8. 31 P NMR(162MHz,CD3OD)δ 15.4.HRMS(APCI)m / z C 29 H 45 N5O4PS2 - [MH] - Calculated for: 622.26561. Found: 622.26573. HPLC: 85-95% MeOH in HO, 10 min, m / z = 624.2 (M+H), t = 1.866 min; 75-95% MeOH in HO, 10 min, m / z = 624.2 (M+H), t = 5.534 min.

[0251] Example 12. Synthesis of ammonium 3-(hexadec-15-yn-1-ylthio)propyl (R)-(((1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate A. Synthesis of trimethyl(16-((tetrahydro-2H-pyran-2-yl)oxy)hexadec-1-yn-1-yl)silane (MD-1-154) [ka] To a solution of trimethylsilylacetylene (6.88 mL, 49.7 mmol, 3.00 eq) in THF (28 mL) at −78°C under an inert atmosphere, n-BuLi (2.5 M in hexane, 19.9 mL, 49.7 mmol, 3.00 eq) was added dropwise. The reaction mixture was stirred at −78°C for 15 min and then warmed to −40°C for 1 h. HMPA (8.64 mL, 49.7 mmol, 3.00 eq) and 2-(14-bromododecoxy)tetrahydropyran (6.25 g, 16.6 mmol, 1.00 eq) in THF were added dropwise at −40°C. The reaction mixture was stirred at −40°C for 1 h and then warmed to 0°C for 5 h. After complete conversion was confirmed by TLC, the reaction mixture was inactivated with saturated aqueous NH4Cl, and the aqueous layer was extracted with EtOAc (3x). The collected organics were washed with saturated aqueous NH4Cl and brine, dried over Na2SO4, and concentrated to give a golden-brown oil. The residue was purified by column chromatography (0-1% EtOAc in hexanes) to give MD-1-154 (5.72 g, 88% yield) as a colorless oil.

[0252] B. Synthesis of 16-(trimethylsilyl)hexadec-15-yn-1-ol (MD-1-158) [ka] To a solution of MD-1-154 (5.72 g, 14.5 mmol) in MeOH (48 mL) under an inert atmosphere, p-toluenesulfonic acid monohydrate (276 mg, 1.45 mmol, 10 mol%) was added, and the reaction mixture was stirred at room temperature overnight. Upon complete conversion confirmed by TLC, the reaction mixture was concentrated under reduced pressure and purified by column chromatography (0-10% EtOAc in hexanes) to give MD-1-158 (3.09 g, 69% yield) as a white crystalline solid.

[0253] C. Synthesis of 3-((16-(trimethylsilyl)hexadec-15-yn-1-yl)thio)propan-1-ol (MD-1-162) [ka] To a solution of MD-1-158 (2.53 g, 8.14 mmol, 1.00 eq) and triethylamine (1.70 mL, 12.2 mmol, 1.50 eq) in anhydrous DCM (20 mL) at 0 °C under an inert atmosphere was added methanesulfonyl chloride (945 μL, 12.2 mmol, 1.50 eq) dropwise. The reaction mixture was stirred at 0 °C for 15 min and then warmed to room temperature for 30 min. After complete conversion was confirmed by TLC, the reaction mixture was diluted with DCM. The organic layer was washed with saturated aqueous NH4Cl (2x), saturated aqueous NaHCO3, and brine, dried over Na2SO4, and concentrated to give 16-(trimethylsilyl)hexadec-15-yn-1-yl methanesulfonate (3.07 g, >95% yield) as a yellow oil, which was used immediately without further purification.

[0254] To an Ar-degassed solution of 3-mercaptopropanol (1.36 mL, 15.8 mmol, 2.00 eq) in anhydrous DMF (30 mL) was added 1,8-diazabicyclo(5.4.0)undec-7-ene (2.36 mL, 15.8 mmol, 2.00 eq), and the solution was stirred at room temperature for 20 min. 16-(Trimethylsilyl)hexadec-15-yn-1-yl methanesulfonate (3.07 g, 7.89 mmol, 1.00 eq) in DMF (10 mL) was added dropwise, and the reaction mixture was heated to 60 °C for 2.5 h. After complete conversion was confirmed by TLC, the reaction mixture was diluted with EtOAc (10x DMF volume). The organic layer was washed with saturated aqueous NH4Cl (4x), dried over Na2SO4, and concentrated to give a yellow oil. The residue was purified by column chromatography (0-10% EtOAc in hexanes) to give MD-1-162 (2.67 g, 88% yield) as a colorless oil.

[0255] D. Synthesis of 3-(hexadec-15-yn-1-ylthio)propan-1-ol (MD-1-165) [ka] To a solution of MD-1-162 (2.21 g, 5.75 mmol, 1.00 eq) in anhydrous THF (38 mL) was added tetrabutylammonium fluoride (1 M in THF, 11.5 mL, 11.5 mmol, 2.00 eq), and the reaction mixture was stirred at room temperature for 45 min. After complete conversion was confirmed by TLC, the reaction mixture was diluted with EtOAc. The organic layer was washed with saturated aqueous NH4Cl (2x), dried over Na2SO4, and concentrated to give a colorless oil. The residue was purified by column chromatography (0–20% EtOAc in hexanes) to give MD-1-165 (1.56 g, 87% yield) as a white powder.

[0256] E. Synthesis of Ammonium 3-(hexadec-15-yn-1-ylthio)propyl (R)-(((1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate (MD-1-182) [ka] To a stirred suspension of dry tenofovir (200 mg, 0.696 mmol, 1.00 eq), DCC (287 mg, 1.39 mmol, 2.00 eq), and 3-(hexadec-15-yn-1-ylthio)propan-1-ol (218 mg, 0.696 mmol, 1.00 eq) in anhydrous NMP (2.3 mL) under an inert atmosphere, triethylamine (194 μL, 1.39 mmol, 2.00 eq) and DMAP (8.51 mg, 0.0696 mmol, 10 mol%) were added. The reaction mixture was stirred at room temperature for 10 min and then heated to 100 °C overnight. After confirming product formation by LC-MS, the reaction mixture was inactivated with water, stirred at room temperature for 20 min, and immediately purified by normal-phase column chromatography (0-80% DCM:DCM / MeOH / NH4OH (80:20:3)). The product fractions were collected and concentrated under reduced pressure to give a pale orange solid. This solid was taken up in a solution of NHOH in methanol (1:1) and purified by reverse-phase column chromatography (0-85% HO:MeOH). The product fractions were collected and concentrated under reduced pressure to give MD-1-182 (206 mg, 51% yield) as a white solid. 1 H NMR (600 MHz, CD3OD) δ 8.33(s,1H),8.22(s,1H),4.39(dd,J=14.4,3.2Hz,1H),4.24(dd,J=14.5,6. 7Hz,1H),3.95-3.81(m,3H),3.73(dd,J=12.8,9.4Hz,1H),3.49(dd,J=12.8,1 0.0Hz,1H),2.51(t,J=7.3Hz,2H),2.47-2.42(m,2H),2.18-2.13(m,3H),1.8 2-1.71(m,2H),1.55-1.46(m,4H),1.43-1.25(m,20H),1.17(d,J=6.3Hz,3H). 13C NMR(151MHz,CD3OD)δ 157.1,153.3,150.9,144.3,119.6,85.1,76.9(d,J=13.1Hz),69.3,65.5(d,J=160.0Hz),64.6(d,J=5.7H z),32.8,32.2(d,J=6.3Hz),30.8,30.7,30.7,30.7,30.7,30.4,30.2,29.9,29.8,29.7,29.2,19.0,16.8. 31 P NMR(243MHz,CD3OD)δ 15.4.HRMS(NSI)m / z C 28 H 49 N5O4PS + [M+H] + Calculated for: 582.3237, found: 582.3232. HPLC: 85-95% MeOH in HO, 10 min, m / z = 582.2 (M+H), t = 2.057 min; 45-95% MeOH in HO, 10 min, m / z = 582.3 (M+H), t = 6.502 min.

[0257] Example 13. Synthesis of ammonium 3-((12-phenyldodec-11-yn-1-yl)thio)propyl (R)-(((1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate A. Synthesis of 2-((12-phenyldodec-11-yn-1-yl)oxy)tetrahydro-2H-pyran (MD-1-168) [ka] To a solution of phenylacetylene (5.40 mL, 49.2 mmol, 3.00 eq) in THF (27 mL) at −78°C under an inert atmosphere, n-BuLi (2.5 M in hexane, 19.7 mL, 49.2 mmol, 3.00 eq) was added dropwise. The reaction mixture was stirred at −78°C for 15 min and then warmed to −40°C for 1 h. HMPA (8.56 mL, 49.2 mmol, 3.00 eq) and 2-(10-bromodecoxyl)tetrahydropyran (5.27 g, 16.4 mmol, 1.00 eq) in THF were added dropwise at −40°C. The reaction mixture was stirred at −40°C for 1 h and then warmed to 0°C for 5 h. After confirming conversion by TLC, the reaction mixture was inactivated with saturated aqueous NH4Cl, and the aqueous layer was extracted with EtOAc (3x). The collected organics were washed with saturated aqueous NH4Cl and brine, dried over Na2SO4, and concentrated to give a golden-brown oil. The residue was purified by column chromatography (0-1% EtOAc in hexanes) to give MD-1-168 (4.96 g, 88% yield) as a pale yellow oil.

[0258] B. Synthesis of 12-phenyldodec-11-yn-1-ol (MD-1-170) [ka] To a solution of MD-1-168 (4.96 g, 14.5 mmol, 1 eq) in MeOH (48 mL) under an inert atmosphere, p-toluenesulfonic acid monohydrate (276 mg, 1.45 mmol, 10 mol%) was added, and the reaction mixture was stirred at room temperature overnight. Upon complete conversion confirmed by TLC, the reaction mixture was concentrated under reduced pressure and purified by column chromatography (0–10% EtOAc in hexanes) to give MD-1-170 (3.03 g, 81% yield) as a colorless oil.

[0259] C. Synthesis of 3-((12-phenyldodec-11-yn-1-yl)thio)propan-1-ol (MD-1-174) [ka] To a solution of MD-1-170 (2.61 g, 10.1 mmol, 1.00 eq) and triethylamine (2.11 mL, 15.1 mmol, 1.50 eq) in anhydrous DCM (25 mL) at 0 °C under an inert atmosphere was added methanesulfonyl chloride (1.17 mL, 15.1 mmol, 1.50 eq) dropwise. The reaction mixture was stirred at 0 °C for 15 min and then warmed to room temperature for 30 min. After complete conversion was confirmed by TLC, the reaction mixture was diluted with DCM. The organic layer was washed with saturated aqueous NaHCO (2x) and brine, dried over NaSO, and concentrated to give 12-phenyldodec-11-yn-1-yl methanesulfonate (3.29 g, >95% yield) as a yellow oil, which was used immediately without further purification.

[0260] To an Ar-degassed solution of 3-mercaptopropanol (1.69 mL, 19.5 mmol, 2.00 eq) in anhydrous DMF (40 mL) was added 1,8-diazabicyclo(5.4.0)undec-7-ene (2.92 mL, 19.5 mmol, 2.00 eq), and the solution was stirred at room temperature for 20 min. 12-Phenyldodec-11-yn-1-yl methanesulfonate (3.29 g, 9.76 mmol, 1.00 eq) in DMF (10 mL) was added dropwise, and the reaction mixture was heated to 60 °C for 2 h. After complete conversion was confirmed by TLC, the reaction mixture was diluted with EtOAc (10 × DMF volume). The organic layer was washed with water (4 ×) and saturated aqueous NH4Cl, dried over Na2SO4, and concentrated to give a pale yellow oil. The residue was purified by column chromatography (0-10% EtOAc in hexanes) to give MD-1-174 (3.09 g, 95% yield) as a white crystalline solid.

[0261] D. Synthesis of Ammonium 3-((12-phenyldodec-11-yn-1-yl)thio)propyl(R)-(((1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate (MD-1-183) [ka] MD-1-183 was synthesized by following the general procedure for MD-1-182 using 3-((12-phenyldodec-11-yn-1-yl)thio)propan-1-ol (232 mg, 0.696 mmol, 1.00 eq). Purification afforded MD-1-183 (235 mg, 56% yield) as a waxy white solid. 1 H NMR(600MHz,CD3OD)δ 8.32(s,1H),8.21(s,1H),7.34-7.31(m,2H),7.29-7.23(m,3H),4.38(dd,J=14.4,3.2Hz,1H ),4.23(dd,J=14.5,6.7Hz,1H),3.93-3.80(m,3H),3.72(dd,J=12.8,9.4Hz,1H),3.48(dd,J =12.7,10.0Hz,1H),2.50(t,J=7.3Hz,2H),2.46-2.42(m,2H),2.39(t,J=7.0Hz,2H),1.82-1 .69(m,2H),1.62-1.55(m,2H),1.54-1.43(m,4H),1.38-1.25(m,10H),1.16(d,J=6.2Hz,3H). 13 C NMR(151MHz,CD3OD)δ 156.7,152.8,150.9,144.4,132.4,129.3,128.5,125.6,119.6,90.9,81.6,76.9(d,J=13.0Hz),65.4(d,J=159.9 Hz),64.6(d,J=5.7Hz),32.8,32.2(d,J=6.4Hz),30.8,30.6,30.6,30.3,30.2,29.9,29.9,29.9,29.2,20.0,16.8. 31 P NMR(243MHz,CD3OD)δ 15.4.HRMS(NSI)m / z C 30 H 45 N5O4PS + [M+H] + Calculated for: 602.2924, found: 602.2918. HPLC: 85-95% MeOH in HO, 10 min, m / z = 602.2 (M+H), t = 2.022 min; 60-95% MeOH in HO, 10 min, m / z = 602.2 (M+H), t = 8.347 min.

[0262] Example 14. Synthesis of ammonium 3-((12-phenyldodecyl)thio)propyl (R)-(((1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate A. Synthesis of 12-phenyldodecan-1-ol (MD-1-175) [ka] Palladium on carbon (10 wt%, 1.09 g, 10 mol%) was added to a solution of MD-1-170 (2.65 g, 10.2 mmol, 1.00 eq) in anhydrous MeOH (102 mL) under an inert atmosphere. After purging the system under house vacuum, the reaction mixture was subjected to a balloon of hydrogen gas and stirred for 20 h. Upon confirmation of complete conversion by TLC, the reaction mixture was filtered through a pad of Celite and concentrated to give a white solid. The solid was purified by column chromatography (0–10% EtOAc in hexanes) to give MD-1-175 (2.18 g, 81% yield) as a white powder.

[0263] B. Synthesis of 3-((12-phenyldodecyl)thio)propan-1-ol (MD-1-181) [ka] To a solution of MD-1-175 (2.09 g, 7.95 mmol, 1.00 eq) and triethylamine (1.66 mL, 11.9 mmol, 1.50 eq) in anhydrous DCM (20 mL) at 0 °C under an inert atmosphere was added methanesulfonyl chloride (924 μL, 11.9 mmol, 1.50 eq) dropwise. The reaction mixture was stirred at 0 °C for 15 min and then warmed to room temperature for 30 min. After complete conversion was confirmed by TLC, the reaction mixture was diluted with DCM. The organic layer was washed with saturated aqueous NaHCO (2x) and brine, dried over NaSO, and concentrated to give 12-phenyldodecyl methanesulfonate (2.69 g, >95% yield) as a yellow oil, which was used immediately without further purification.

[0264] To an Ar-degassed solution of 3-mercaptopropanol (1.36 mL, 15.8 mmol, 2.00 eq) in anhydrous DMF (30 mL) was added 1,8-diazabicyclo(5.4.0)undec-7-ene (2.36 mL, 15.8 mmol, 2.00 eq), and the solution was stirred at room temperature for 20 min. 12-Phenyldodecylmethanesulfonate (2.69 g, 7.89 mmol, 1.00 eq) in DMF (10 mL) was added dropwise, and the reaction mixture was heated to 60 °C for 2.5 h. After complete conversion was confirmed by TLC, the reaction mixture was diluted with EtOAc (10 × DMF volume). The organic layer was washed with water (4 ×) and saturated aqueous NH4Cl, dried over Na2SO4, and concentrated to give a pale yellow oil. The residue was purified by column chromatography (0-10% EtOAc in hexanes) to give MD-1-181 (2.37 g, 89% yield) as a white powder.

[0265] C. Synthesis of Ammonium 3-((12-phenyldodecyl)thio)propyl(R)-(((1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate (MD-1-184) [ka] MD-1-184 was synthesized by following the general procedure for MD-1-182 using 3-((12-phenyldodecyl)thio)propan-1-ol (234 mg, 0.696 mmol, 1.00 eq). Purification afforded MD-1-184 (263 mg, 62% yield) as a white solid. 1H NMR(600MHz,CD3OD)δ 8.32(s,1H),8.21(s,1H),7.25-7.21(m,2H),7.17-7.10(m,3H),4.38(dd,J=14.4,3.2Hz,1H ),4.23(dd,J=14.4,6.7Hz,1H),3.94-3.81(m,3H),3.72(dd,J=12.8,9.4Hz,1H),3.48(dd,J =12.8,10.0Hz,1H),2.61-2.56(m,2H),2.51(t,J=7.3Hz,2H),2.46-2.42(m,2H),1.83-1.70 (m,2H),1.64-1.56(m,2H),1.51(p,J=7.3Hz,2H),1.37-1.24(m,16H),1.16(d,J=6.2Hz,3H). 13 C NMR(151MHz,CD3OD)δ 155.3,151.3,149.5,143.1,142.6,128.0,127.8,125.2,118.2,75.5(d,J=12.8Hz),64.0(d,J=159.9Hz) ,63.2(d,J=5.6Hz),35.5,31.4,31.4,30.8(d,J=6.7Hz),29.4,29.3,29.2,29.0,28.9,28.5,27.8,15.4. 31 P NMR(243MHz,CD3OD)δ 15.4. HRMS(NSI)m / z C 30 H 49 N5O4PS + [M+H] + Calculated for: 606.3237, found: 606.3230. HPLC: 85-95% MeOH in HO, 10 min, m / z = 606.2 (M+H), t = 3.206 min; 75-95% MeOH in HO, 10 min, m / z = 606.2 (M+H), t = 6.863 min.

[0266] Example 15. Synthesis of ammonium 3-(octadecylthio)propyl (R)-(((1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate A. Synthesis of 3-(octadecylthio)propan-1-ol (MD-1-177) [ka] To an Ar-degassed solution of 3-mercaptopropanol (1.30 mL, 15.0 mmol, 2.00 eq) in anhydrous DMF (27 mL) was added 1,8-diazabicyclo(5.4.0)undec-7-ene (2.24 mL, 15.0 mmol, 2.00 eq), and the solution was stirred at room temperature for 20 min. 1-Bromooctadecane (2.5 g, 7.50 mmol, 1.00 eq) in DMF (15 mL) was added dropwise, and the reaction mixture was heated to 60 °C for 3 h. After complete conversion was confirmed by TLC, the reaction mixture was diluted with EtOAc (10x DMF volume). The organic layer was washed with water (4x) and saturated aqueous NH4Cl, dried over Na2SO4, and concentrated to give an off-white solid. The solid was purified by column chromatography (0–15% EtOAc in hexanes) to give MD-1-177 (2.34 g, 90% yield) as a white powder.

[0267] B. Synthesis of Ammonium 3-(Octadecylthio)propyl(R)-(((1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate (MD-1-185) [ka] MD-1-185 was synthesized by the following general procedure for MD-1-182 using 3-(octadecylthio)propan-1-ol (240 mg, 0.696 mmol, 1.00 eq). Purification afforded MD-1-185 (269 mg, 61% yield) as a white solid. 1H NMR (600 MHz, CD3OD) δ 8.33(s,1H),8.21(s,1H),4.39(dd,J=14.4,3.2Hz,1H),4.24(dd,J=14.4,6.7 Hz,1H),3.94-3.81(m,3H),3.72(dd,J=12.8,9.5Hz,1H),3.48(dd,J=12.8,10 .0Hz,1H),2.51(t,J=7.3Hz,2H),2.47-2.42(m,2H),1.82-1.71(m,2H),1.56- 1.48(m,2H),1.38-1.24(m,30H),1.16(d,J=6.3Hz,3H),0.89(t,J=7.3Hz,3H). 13 C NMR(151MHz,CD3OD)δ 157.2,153.5,150.9,144.2,119.6,76.9(d,J=13.0Hz),65.5(d,J=160.0Hz),64.6(d,J=5.6Hz),33 .1,32.8,32.3(d,J=6.3Hz),30.8,30.8,30.8,30.7,30.7,30.5,30.4,29.9,29.2,23.7,16.8,14.4. 31 P NMR(243MHz,CD3OD)δ 15.4. HRMS(NSI)m / z C 30 H 57 N5O4PS + [M+H] + Calculated for: 614.3863, found 614.3862. HPLC: 95% MeOH in HO, 10 min, m / z = 614.3 (M+H), t = 2.054 min; 85-95% MeOH in HO, 10 min, m / z = 614.3 (M+H), t = 6.976 min.

[0268] Example 16. Synthesis of ammonium 3-(icosylthio)propyl (R)-(((1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate A. Synthesis of 3-(icosylthio)propan-1-ol (MD-1-179) [ka] To an Ar-degassed solution of 3-mercaptopropanol (1.19 mL, 13.8 mmol, 2.00 eq) in anhydrous DMF (25 mL) was added 1,8-diazabicyclo(5.4.0)undec-7-ene (2.07 mL, 13.8 mmol, 2.00 eq), and the solution was stirred at room temperature for 20 min. 1-Bromoicosane (2.5 g, 7.89 mmol, 1.00 eq) in DMF (10 mL) was added dropwise, and the reaction mixture was heated to 65 °C for 4 h. After complete conversion was confirmed by TLC, the reaction mixture was diluted with EtOAc (10x DMF volume). The organic layer was washed with saturated aqueous NH4Cl (4x), dried over Na2SO4, and concentrated to give an off-white solid. The solid was purified by column chromatography (0–10% EtOAc in hexanes) to give MD-1-179 (2.12 g, 82% yield) as a white powder.

[0269] B. Synthesis of Ammonium 3-(icosylthio)propyl (R)-(((1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate (MD-1-186) [ka] MD-1-186 was synthesized by the following general procedure for MD-1-182 using 3-(icosylthio)propan-1-ol (260 mg, 0.696 mmol, 1.00 eq). Purification afforded MD-1-186 (274 mg, 60% yield) as a white solid. 1 H NMR (600 MHz, CD3OD) δ 8.32(s,1H),8.20(s,1H),4.38(dd,J=14.4,3.2Hz,1H),4.23(dd,J=14.5,6.7Hz ,1H),3.93-3.80(m,3H),3.71(dd,J=12.7,9.4Hz,1H),3.47(dd,J=12.7,10.0Hz ,1H),2.51(t,J=7.3Hz,2H),2.46-2.42(m,2H),1.82-1.70(m,2H),1.52(tt,J=7 .6,6.4Hz,2H),1.39-1.24(m,34H),1.16(d,J=6.3Hz,3H),0.90(t,J=7.0Hz,3H). 13C NMR(151MHz,CD3OD)δ 157.2,153.5,151.0,144.2,119.6,76.9(d,J=13.0Hz),65.5(d,J=159.9Hz),64.6(d,J=5.7Hz), 33.1,32.8,32.3(d,J=6.4Hz),30.8,30.8,30.7,30.7,30.5,30.4,29.9,29.2,23.7,16.8,14.4. 31 P NMR(243MHz,CD3OD)δ 15.3.HRMS(NSI)m / z C 32 H 61 N5O4PS + [M+H] + Calculated for: 642.4176, found: 642.4177. HPLC: 95% MeOH in HO, 10 min, m / z = 642.4 (M+H), t = 3.178 min; 85-95% MeOH in HO, 15 min, m / z = 642.4 (M+H), t = 11.720 min.

[0270] Example 17. Synthesis of ammonium 3-((14-(trimethylsilyl)tetradec-13-yn-1-yl)thio)propyl(R)-(((1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate A. Synthesis of trimethyl(14-((tetrahydro-2H-pyran-2-yl)oxy)tetradec-1-yn-1-yl)silane (MD-1-155) [ka] To a solution of trimethylsilylacetylene (7.08 mL, 51.1 mmol, 3.00 eq) in THF (28 mL) at −78°C under an inert atmosphere, n-BuLi (2.5 M in hexane, 20.5 mL, 51.1 mmol, 3.00 eq) was added dropwise. The reaction mixture was stirred at −78°C for 15 min and then warmed to −40°C for 1 h. HMPA (8.90 mL, 51.1 mmol, 3.00 eq) and 2-(12-bromododecoxy)tetrahydropyran (5.96 g, 17.0 mmol, 1.00 eq) in THF were added dropwise at −40°C. The reaction mixture was stirred at −40°C for 1 h and then warmed to 0°C for 5 h. After complete conversion was confirmed by TLC, the reaction mixture was inactivated with saturated aqueous NH4Cl, and the aqueous layer was extracted with EtOAc (3x). The collected organics were washed with saturated aqueous NH4Cl and brine, dried over Na2SO4, and concentrated to give a golden-brown oil. The residue was purified by column chromatography (0-1% EtOAc in hexanes) to give MD-1-155 (5.49 g, 88% yield) as a colorless oil.

[0271] B. Synthesis of 14-(trimethylsilyl)tetradec-13-yn-1-ol (MD-1-157) [ka] To a solution of MD-1-155 (5.49 g, 15.0 mmol, 1 eq) in MeOH (50 mL) under an inert atmosphere, p-toluenesulfonic acid monohydrate (285 mg, 1.50 mmol, 10 mol%) was added, and the reaction mixture was stirred at room temperature overnight. Upon complete conversion confirmed by TLC, the reaction mixture was concentrated under reduced pressure and purified by column chromatography (0–10% EtOAc in hexanes) to give MD-1-157 (3.03 g, 72% yield) as a colorless oil.

[0272] C. Synthesis of 3-((14-(trimethylsilyl)tetradec-13-yn-1-yl)thio)propan-1-ol (MD-1-160) [ka] To a solution of MD-1-157 (2.06 g, 7.29 mmol, 1.00 eq) and triethylamine (1.52 mL, 10.9 mmol, 1.50 eq) in anhydrous DCM (18 mL) at 0 °C under an inert atmosphere was added methanesulfonyl chloride (846 μL, 10.9 mmol, 1.50 eq) dropwise. The reaction mixture was stirred at 0 °C for 15 min and then warmed to room temperature for 30 min. After complete conversion was confirmed by TLC, the reaction mixture was diluted with DCM. The organic layer was washed with saturated aqueous NH4Cl (2x), saturated aqueous NaHCO3, and brine, dried over Na2SO4, and concentrated to give 14-(trimethylsilyl)tetradec-13-yn-1-yl methanesulfonate (2.60 g, >95% yield) as a yellow oil, which was used immediately without further purification.

[0273] To an Ar-degassed solution of 3-mercaptopropanol (1.24 mL, 14.4 mmol, 2.00 eq) in anhydrous DMF (26 mL) was added 1,8-diazabicyclo(5.4.0)undec-7-ene (2.15 mL, 14.4 mmol, 2.00 eq), and the solution was stirred at room temperature for 20 min. 14-(Trimethylsilyl)tetradec-13-yn-1-yl methanesulfonate (2.60 g, 7.20 mmol, 1.00 eq) in DMF (10 mL) was added dropwise, and the reaction mixture was heated to 60 °C for 2.5 h. After complete conversion was confirmed by TLC, the reaction mixture was diluted with EtOAc (10x DMF volume). The organic layer was washed with saturated aqueous NH4Cl (4x), dried over Na2SO4, and concentrated to give a yellow oil. The residue was purified by column chromatography (0-10% EtOAc in hexanes) to give MD-1-160 (2.22 g, 86% yield) as a colorless oil.

[0274] D. Synthesis of Ammonium 3-((14-(trimethylsilyl)tetradec-13-yn-1-yl)thio)propyl(R)-(((1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate (MD-1-187) [ka] To a stirred suspension of dry tenofovir (200 mg, 0.696 mmol, 1.00 eq), DCC (287 mg, 1.39 mmol, 2.00 eq), and 3-((14-(trimethylsilyl)tetradec-13-yn-1-yl)thio)propan-1-ol (248 mg, 0.696 mmol, 1.00 eq) in anhydrous NMP (2.3 mL) under an inert atmosphere, triethylamine (194 μL, 1.39 mmol, 2.00 eq) and DMAP (8.51 mg, 0.0696 mmol, 10 mol%) were added. The reaction mixture was stirred at room temperature for 10 min and then heated to 100 °C overnight. After confirming product formation by LC-MS, the reaction mixture was inactivated with water, stirred at room temperature for 20 min, and immediately purified by normal phase column chromatography (0-80% DCM:MeOH). The product fractions were collected and concentrated under reduced pressure to give a pale orange solid. The solid was taken up in an 80% MeOH solution in water, and diammonium phosphate (460 mg, 3.48 mmol, 5.00 eq) was added. The mixture was stirred for 20 min and immediately purified by reverse-phase column chromatography (0-85% HO:MeOH). The product fractions were collected and concentrated under reduced pressure to give MD-1-187 (226 mg, 52% yield) as a white solid. 1 H NMR(600MHz,CD3OD)δ 8.34(s,1H),8.22(s,1H),4.39(dd,J=14.4,3.1Hz,1H),4.24(dd,J=14.5,6.8Hz, 1H),3.94-3.80(m,3H),3.73(dd,J=12.8,9.4Hz,1H),3.48(dd,J=12.7,10.0Hz,1 H),2.50(t,J=7.3Hz,2H),2.46-2.42(m,2H),2.20(t,J=7.0Hz,2H),1.81-1.70(m ,2H),1.54-1.45(m,4H),1.42-1.24(m,16H),1.17(d,J=6.2Hz,3H),0.11(s,9H). 13C NMR(151MHz,CD3OD)δ 156.5,152.4,150.8,144.6,119.5,108.7,84.8,76.9(d,J=12.8Hz),65.4(d,J=160.3Hz),64.6(d,J=5.8Hz) ,32.8,32.2(d,J=6.4Hz),30.8,30.7,30.7,30.7,30.6,30.4,30.1,29.9,29.8,29.7,29.18,20.4,16.8,0.3. 31 P NMR(243MHz,CD3OD)δ 15.5. HRMS(APCI)m / z C 29 H 51 N5O4PSSi - [MH] - Calculated for: 624.3174, found: 624.3178. HPLC: 95% MeOH in HO, 10 min, m / z = 626.3 (M+H), t = 2.716 min; 75-95% MeOH in HO, 10 min, m / z = 626.3 (M+H), t = 7.843 min.

[0275] Example 18. Synthesis of ammonium 3-(dodecylthio)propyl (R)-(((1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate A. Synthesis of 3-(dodecylthio)propan-1-ol (MD-1-192) [ka] To an Ar-degassed solution of 3-mercaptopropanol (1.46 mL, 16.9 mmol, 2.00 eq) in anhydrous DMF (42 mL) was added 1,8-diazabicyclo(5.4.0)undec-7-ene (2.52 mL, 16.9 mmol, 2.00 eq), and the solution was stirred at room temperature for 20 min. 1-Iodododecane (2.08 mL, 8.44 mmol, 1.00 eq) was added dropwise, and the reaction mixture was heated to 65 °C for 3 h. After complete conversion was confirmed by TLC, the reaction mixture was diluted with EtOAc (10x DMF volume). The organic layer was washed with water (2x), saturated aqueous NH4Cl (2x), dried over Na2SO4, and concentrated to give an off-white solid. The solid was purified by column chromatography (0–15% EtOAc in hexanes) to give MD-1-192 (1.92 g, 87% yield) as a white powder.

[0276] B. Synthesis of Ammonium 3-(Dodecylthio)propyl(R)-(((1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate (MD-1-217) [ka] MD-1-217 was synthesized by the following general procedure for MD-1-182 using 3-(dodecylthio)propan-1-ol (181 mg, 0.696 mmol, 1.00 eq). Purification afforded MD-1-217 (232 mg, 61% yield) as a white solid. 1 H NMR (600 MHz, CD3OD) δ 8.33(s,1H),8.21(s,1H),4.39(dd,J=14.4,3.2Hz,1H),4.24(dd,J=14.4,6.8H z,1H),3.95-3.81(m,3H),3.72(dd,J=12.8,9.4Hz,1H),3.48(dd,J=12.8,10.0H z,1H),2.51(t,J=7.3Hz,2H),2.44(t,J=7.3Hz,2H),1.82-1.71(m,2H),1.52(p, J=7.2Hz,2H),1.38-1.23(m,18H),1.17(d,J=6.2Hz,3H),0.90(t,J=7.0Hz,3H). 13C NMR(151MHz,CD3OD)δ 156.6,152.5,150.8,144.5,119.6,76.9(d,J=12.9Hz),65.4(d,J=160.0Hz),64.6(d,J=5.6Hz), 33.1,32.8,32.2(d,J=6.2Hz),30.8,30.8,30.7,30.7,30.5,30.4,29.9,29.2,23.7,16.8,14.4. 31 P NMR(243MHz,CD3OD)δ 15.4.HRMS(NSI)m / z C 24 H 45 N5O4PS + [M+H] + Calculated value: 530.2924, measured value: 530.2916.

[0277] Example 19. Synthesis of ammonium 3-(tetradecylthio)propyl (R)-(((1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate A. Synthesis of 3-(tetradecylthio)propan-1-ol (MD-1-193) [ka] To an Ar-degassed solution of 3-mercaptopropanol (1.56 mL, 18.0 mmol, 2.00 eq) in anhydrous DMF (45 mL) was added 1,8-diazabicyclo(5.4.0)undec-7-ene (2.70 mL, 18.0 mmol, 2.00 eq), and the solution was stirred at room temperature for 20 min. 1-Bromotetradecane (2.68 mL, 9.02 mmol, 1.00 eq) was added dropwise, and the reaction mixture was heated to 65 °C for 3 h. After complete conversion was confirmed by TLC, the reaction mixture was diluted with EtOAc (10x DMF volume). The organic layer was washed with water (2x) and saturated aqueous NH4Cl (2x), dried over Na2SO4, and concentrated to give an off-white solid. The solid was purified by column chromatography (0–15% EtOAc in hexanes) to give MD-1-193 (2.57 g, >95% yield) as a white powder.

[0278] B. Synthesis of Ammonium 3-(tetradecylthio)propyl(R)-(((1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate (MD-1-218) [ka] MD-1-218 was synthesized by the following general procedure for MD-1-182 using 3-tetradecylsulfanylpropan-1-ol (201 mg, 0.696 mmol, 1.00 eq). Purification afforded MD-1-218 (216 mg, 54% yield) as a white solid. 1 H NMR (600 MHz, CD3OD) δ 8.33(s,1H),8.21(s,1H),4.39(dd,J=14.4,3.1Hz,1H),4.24(dd,J=14.4,6.8H z,1H),3.94-3.81(m,3H),3.73(dd,J=12.8,9.4Hz,1H),3.49(dd,J=12.8,10.0H z,1H),2.51(t,J=7.2Hz,2H),2.44(t,J=7.3Hz,2H),1.82-1.71(m,2H),1.52(p, J=7.2Hz,2H),1.39-1.23(m,22H),1.17(d,J=6.2Hz,3H),0.90(t,J=7.0Hz,3H). 13 C NMR(151MHz,CD3OD)δ 156.5,152.4,150.8,144.5,119.6,76.9(d,J=12.9Hz),65.4(d,J=160.1Hz),64.6(d,J=5.6Hz),33 .1,32.8,32.2(d,J=6.2Hz),30.8,30.8,30.8,30.7,30.7,30.5,30.4,29.9,29.2,23.7,16.8,14.4. 31 P NMR(243MHz,CD3OD)δ 15.5.HRMS(NSI)m / z C 26 H 49 N5O4PS + [M+H] + Calculated value: 558.3237, measured value: 558.3231.

[0279] Example 20. Synthesis of ammonium 6-(tridecylthio)hexyl (R)-(((1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate A. Synthesis of 6-(tridecylthio)hexan-1-ol (MD-1-194) [ka] To an Ar-degassed solution of 6-mercaptohexanol (2.08 mL, 15.2 mmol, 2.00 eq) in anhydrous DMF (45 mL) was added 1,8-diazabicyclo(5.4.0)undec-7-ene (2.27 mL, 15.2 mmol, 2.00 eq), and the solution was stirred at room temperature for 20 min. 1-Bromotridecane (1.94 mL, 7.60 mmol, 1.00 eq) was added dropwise, and the reaction mixture was heated to 65 °C for 3 h. After complete conversion was confirmed by TLC, the reaction mixture was diluted with EtOAc (10x DMF volume). The organic layer was washed with water (2x) and saturated aqueous NH4Cl (2x), dried over Na2SO4, and concentrated to give an off-white solid. The solid was purified by column chromatography (0–15% EtOAc in hexanes) to give MD-1-194 (2.19 g, 91% yield) as a white solid.

[0280] B. Synthesis of Ammonium 6-(Tridecylthio)hexyl (R)-(((1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate (MD-1-219) [ka] MD-1-219 was synthesized by the following general procedure for MD-1-182 using 6-(tridecylthio)hexan-1-ol (220 mg, 0.696 mmol, 1.00 eq). Purification afforded MD-1-219 (258 mg, 62% yield) as a white solid. 1H NMR(600MHz,CD3OD)δ 8.31(s,1H),8.20(s,1H),4.38(dd,J=14.4,3.1Hz,1H),4.23(dd,J=14.4,6.8Hz,1H),3.90(pd,J=6.3,3.1Hz,1H),3.79-3.68(m,3H), 3.46(dd,J=12.7,10.1Hz,1H),2.49-2.44(m,4H),1.58-1.46(m,6H),1.40-1.24(m,24H),1.17(d,J=6.2Hz,3H),0.90(t,J=7.0Hz,3H). 13 C NMR(151MHz,CD3OD)δ 157.1,153.3,150.9,144.3,119.6,76.9(d,J=12.8Hz),65.8(d,J=6.0Hz),65.5(d,J=159.8Hz),33.1,32 .9,32.8,32.0(d,J=6.2Hz),30.8,30.8,30.8,30.7,30.7,30.5,30.3,29.9,29.6,26.5,23.7,16.8,14.4. 31 P NMR(243MHz,CD3OD)δ 15.4.HRMS(APCI)m / z C 28 H 51 N5O4PS - [MH] - Calculated value: 584.3405, measured value: 584.3408.

[0281] Example 21. Synthesis of ammonium 12-(heptylthio)dodecyl (R)-(((1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate (MD-1-220) A. Synthesis of 12-(heptylthio)dodecan-1-ol (MD-1-195) [ka] To an Ar-degassed solution of 1-heptanethiol (2.66 mL, 17.0 mmol, 2.00 eq) in anhydrous DMF (32 mL) was added 1,8-diazabicyclo(5.4.0)undec-7-ene (2.54 mL, 17.0 mmol, 2.00 eq), and the solution was stirred at room temperature for 20 min. 12-Bromo-1-dodecanol (2.25 g, 8.48 mmol, 1.00 eq) in DMF (10 mL) was added dropwise, and the reaction mixture was heated to 65 °C for 3 h. After complete conversion was confirmed by TLC, the reaction mixture was diluted with EtOAc (10x DMF volume). The organic layer was washed with water (2x) and saturated aqueous NH4Cl (2x), dried over Na2SO4, and concentrated to give an off-white solid. The solid was purified by column chromatography (0-10% EtOAc in hexanes) to give MD-1-195 (2.36 g, 88% yield) as a white powder.

[0282] B. Synthesis of Ammonium 12-(heptylthio)dodecyl (R)-(((1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate (MD-1-220) [ka] To a stirred suspension of dry tenofovir (200 mg, 0.696 mmol, 1.00 eq), DCC (287 mg, 1.39 mmol, 2.00 eq), and 12-(heptylthio)dodecan-1-ol (220 mg, 0.696 mmol, 1.00 eq) in anhydrous NMP (2.3 mL) under an inert atmosphere, TEA (194 μL, 1.39 mmol, 2.00 eq) and DMAP (8.51 mg, 0.0696 mmol, 10 mol%) were added. The reaction mixture was stirred at room temperature for 10 min and then heated to 100 °C overnight. After confirming product formation by LC-MS, the reaction mixture was inactivated with water, stirred at room temperature for 20 min, and immediately purified by normal-phase column chromatography (0-80% DCM:DCM / MeOH / NH4OH (80:20:3)). The product fractions were collected and concentrated under reduced pressure to give a pale orange solid. The solid was taken up in a solution of DCM:7N NH in MeOH (1:1, 10 mL) and stirred at room temperature overnight. The mixture was concentrated under reduced pressure and purified by reverse-phase column chromatography (0-90% HO:MeOH). The product fractions were collected and concentrated under reduced pressure to give MD-1-220 (291 mg, 69% yield) as a white solid. 1 H NMR(600MHz,CD3OD)δ 8.31(s,1H),8.20(s,1H),4.37(dd,J=14.4,3.1Hz,1H),4.23(dd,J=14.4,6.7Hz, 1H),3.89(pd,J=6.3,3.1Hz,1H),3.79-3.67(m,3H),3.46(dd,J=12.7,10.0Hz,1H ),2.51-2.47(m,2H),2.52-2.46(m,2H),1.60-1.51(m,4H),1.53-1.44(m,2H),1. 42-1.35(m,4H),1.35-1.21(m,20H),1.16(d,J=6.2Hz,3H),0.90(t,J=7.0Hz,3H). 13C NMR(151MHz,CD3OD)δ 157.2,153.5,150.9,144.2,119.6,76.9(d,J=12.7Hz),65.9(d,J=5.8Hz),65.6(d,J=159.8Hz),33.0,32 .9,32.1(d,J=6.4Hz),30.8,30.8,30.7,30.7,30.7,30.5,30.3,30.0,29.9,29.9,26.9,23.7,16.8,14.4. 31 P NMR(243MHz,CD3OD)δ 15.2.HRMS(NSI)m / z C 28 H 53 N5O4PS + [M+H] + Calculated value: 586.3550, measured value: 586.3542.

[0283] Example 22. Synthesis of ammonium 15-(butylthio)pentadecyl (R)-(((1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate A. Synthesis of 15-(butylthio)pentadecan-1-ol (MD-1-198) [ka] To an Ar-degassed solution of 1-butanethiol (1.74 mL, 16.3 mmol, 2.00 eq) in anhydrous DMF (31 mL) was added 1,8-diazabicyclo(5.4.0)undec-7-ene (2.43 mL, 16.3 mmol, 2.00 eq), and the solution was stirred at room temperature for 20 min. 15-Bromo-1-pentadecanol (2.5 g, 8.14 mmol, 1.00 eq) in DMF (10 mL) was added dropwise, and the reaction mixture was heated to 65 °C for 3 h. After complete conversion was confirmed by TLC, the reaction mixture was diluted with EtOAc (10x DMF volume). The organic layer was washed with water (2x) and saturated aqueous NH4Cl (2x), dried over Na2SO4, and concentrated to give an off-white solid. The solid was purified by column chromatography (0-10% EtOAc in hexanes) to give MD-1-198 (2.31 g, 90% yield) as a white powder.

[0284] B. Synthesis of Ammonium 15-(butylthio)pentadecyl (R)-(((1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate (MD-1-221) [ka] MD-1-221 was synthesized by the following general procedure for MD-1-220 using 15-(butylthio)pentadecan-1-ol (220 mg, 0.696 mmol, 1.00 eq). Purification afforded MD-1-221 (211 mg, 50% yield) as a white solid. 1 H NMR(600MHz,CD3OD)δ 8.31(s,1H),8.20(s,1H),4.37(dd,J=14.4,3.1Hz,1H),4.23(dd,J=14.4,6.7Hz,1 H),3.89(pd,J=6.3,3.0Hz,1H),3.79-3.67(m,3H),3.46(dd,J=12.7,10.0Hz,1H),2 .50(t,J=7.2Hz,2H),2.49(t,J=7.3Hz,2H),1.59-1.52(m,4H),1.53-1.44(m,2H),1 .45-1.36(m,4H),1.33-1.21(m,20H),1.16(d,J=6.2Hz,3H),0.92(t,J=7.4Hz,3H). 13 C NMR(151MHz,CD3OD)δ 157.2,153.5,150.9,144.2,119.6,76.9(d,J=12.8Hz),65.9(d,J=5.8Hz),65.6(d,J=160.1Hz),33.0,32.9, 32.6,32.1(d,J=6.3Hz),30.8,30.8,30.8,30.7,30.7,30.7,30.7,30.5,30.3,29.9,26.9,23.0,16.8,14.0. 31 P NMR(243MHz,CD3OD)δ 15.2.HRMS(NSI)m / z C 28 H 53 N5O4PS + [M+H] + Calculated value: 586.3550, measured value: 586.3546.

[0285] Example 23. Synthesis of ammonium 2-(heptadecylthio)ethyl (R)-(((1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate A. Synthesis of (heptadecylthio)ethan-1-ol (MD-1-212) [ka] To an Ar-degassed solution of 1-bromoheptadecane (2.50 g, 7.82 mmol, 1.00 eq) in DMF (39 mL) was added cesium carbonate (5.10 g, 15.7 mmol, 2.00 eq). 2-Mercaptoethanol (1.10 mL, 15.7 mmol, 2.00 eq) was added dropwise to the suspension, and the reaction mixture was stirred at room temperature overnight. After complete conversion was confirmed by TLC, the reaction mixture was diluted with EtOAc (500 mL). The organic layer was washed with HO (2x) and saturated aqueous NH4Cl (2x), dried over Na2SO4, and concentrated to give an off-white solid. The solid was purified by column chromatography (0–10% EtOAc in hexanes) to give MD-1-212 (2.29 g, 92% yield) as a white powder.

[0286] B. Synthesis of Ammonium 2-(Heptadecylthio)ethyl (R)-(((1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate (MD-1-222) [ka] MD-1-222 was synthesized by following the general procedure for MD-1-220 using (heptadecylthio)ethan-1-ol (220 mg, 0.696 mmol, 1.00 eq) and purification afforded MD-1-222 (231 mg, 55% yield) as a white solid. 1H NMR(600MHz,CD3OD)δ 8.32(s,1H),8.20(s,1H),4.38(dd,J=14.5,3.2Hz,1H),4.23(dd,J=14.4,6 .7Hz,1H),3.94-3.84(m,3H),3.72(dd,J=12.8,9.4Hz,1H),3.49(dd,J=12.8 ,10.1Hz,1H),2.62(hept,J=7.0Hz,2H),2.48(t,J=7.3Hz,2H),1.50(p,J=7 .2Hz,2H),1.36-1.23(m,28H),1.16(d,J=6.2Hz,3H),0.90(t,J=7.0Hz,3H). 13 C NMR(151MHz,CD3OD)δ 157.2,153.5,151.0,144.2,119.6,77.0(d,J=12.9Hz),65.6(d,J=160.3Hz),65.5(d,J=5.9Hz),33 .5(d,J=6.3Hz),33.2,33.1,31.0,30.8,30.8,30.8,30.7,30.7,30.5,30.4,29.9,23.7,16.8,14.4. 31 P NMR(243MHz,CD3OD)δ 15.2.HRMS(NSI)m / z C 28 H 53 N5O4PS + [M+H] + Calculated value: 586.3550, measured value: 586.3541.

[0287] Example 24. Synthesis of ammonium 3-((11-phenoxyundecyl)thio)propyl (R)-(((1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate A. Synthesis of ((11-bromoundecyl)oxy)benzene (MD-1-211) [ka] To a solution of 11-bromo-1-undecanol (3.00 g, 11.9 mmol, 1.00 eq), phenol (1.12 g, 11.9 mmol, 1.00 eq), and triphenylphosphine (3.13 g, 11.9 mmol, 1.00 eq) in THF (24 mL) under an inert atmosphere at 0 °C, DIAD (2.59 mL, 13.1 mmol, 1.10 eq) was added dropwise. The reaction mixture was allowed to warm to room temperature and stirred overnight. After complete conversion was confirmed by TLC, the reaction mixture was concentrated and immediately purified by column chromatography (0–1% EtOAc in hexanes) to give MD-1-211 (2.75 g, 70% yield) as a colorless oil.

[0288] B. Synthesis of 3-((11-phenoxyundecyl)thio)propan-1-ol (MD-1-213) [ka] To an Ar-degassed solution of ((11-bromoundecyl)oxy)benzene (2.75 g, 8.40 mmol, 1.00 eq) in DMF (21 mL) was added cesium carbonate (5.47 g, 16.8 mmol, 2.00 eq). 3-Mercaptopropanol (1.45 mL, 16.8 mmol, 2.00 eq) was added dropwise to the suspension, and the reaction mixture was stirred at room temperature overnight. After complete conversion was confirmed by TLC, the reaction mixture was diluted with EtOAc (500 mL). The organic layer was washed with HO (2x) and saturated aqueous NH4Cl (2x), dried over Na2SO4, and concentrated to give an off-white solid. The solid was purified by column chromatography (0–15% EtOAc in hexanes) to give MD-1-213 (2.54 g, 89% yield) as a white powder.

[0289] C. Synthesis of Ammonium 3-((11-phenoxyundecyl)thio)propyl(R)-(((1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate (MD-1-223) [ka] MD-1-223 was synthesized by the following general procedure for MD-1-220 using 3-((11-phenoxyundecyl)thio)propan-1-ol (236 mg, 0.696 mmol, 1.00 eq). Purification afforded MD-1-223 (309 mg, 71% yield) as a white solid. 1 H NMR(600MHz,CD3OD)δ 8.31(s,1H),8.20(s,1H),7.26-7.21(m,2H),6.90-6.85(m,3H),4.37(dd,J=14.4,3.2Hz ,1H),4.23(dd,J=14.4,6.7Hz,1H),3.95(t,J=6.4Hz,2H),3.92-3.80(m,3H),3.71(dd,J =12.8,9.4Hz,1H),3.47(dd,J=12.7,10.0Hz,1H),2.50(t,J=7.3Hz,2H),2.44(t,J=7.3H z,2H),1.81-1.70(m,4H),1.54-1.44(m,4H),1.39-1.26(m,12H),1.16(d,J=6.2Hz,3H). 13 C NMR(151MHz,CD3OD)δ 160.6,157.2,153.4,150.9,144.2,130.4,121.5,119.6,115.5,76.9(d,J=13.0Hz),68.9,65.5(d,J=159.9Hz) ,64.6(d,J=5.7Hz),32.8,32.2(d,J=6.3Hz),30.8,30.7,30.7,30.6,30.5,30.4,30.4,29.9,29.2,27.2,16.8. 31 P NMR(243MHz,CD3OD)δ 15.3.HRMS(NSI)m / z C 29 H 47 N5O5PS + [M+H] + Calculated value: 608.3030, measured value: 608.3022.

[0290] Example 25. Synthesis of ammonium [(1R)-2-(6-aminopurin-9-yl)-1-methyl-ethoxy]methyl-(18-trimethylsilyloctadec-17-ynoxy)phosphinate A. Synthesis of 2-octadec-2-ynoxytetrahydropyran (NP-PD-023) [ka] To an oven-dried 250 mL flask equipped with a stir bar was added 2-(2-propynyloxy)tetrahydro-2H-pyran (5.02 mL, 35.7 mmol, 1.00 eq), hexamethylphosphoramide (21.7 mL, 125 mmol, 3.50 eq), and THF (100 mL). The reaction mixture was cooled to −78° C. and vigorously stirred under Ar. n-Butyllithium (2.00 M in THF, 23.2 mL, 46.4 mmol, 1.30 eq) was added dropwise via an oven-dried pressure-equalizing addition funnel over 15 min, and the reaction was vigorously stirred at −78° C. for approximately 1 h. 1-Bromopentadecane (13.4 mL, 46.4 mmol, 1.30 eq) was then slowly added dropwise via a pressure-equalizing addition funnel over 10 min, after which the resulting reaction mixture was allowed to warm to room temperature overnight with vigorously stirring under Ar. The next day, TLC showed that all of the starting alkyne had been consumed. The reaction mixture was quenched with a saturated solution of ammonium chloride and then extracted three times with EtOAc. The organic phases were then combined, washed with brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo. Subsequent purification of the resulting crude material by column chromatography (2% to 10% EtOAc / hexanes) afforded a clear oil (7.86 g, 22.4 mmol, 63% yield).

[0291] B. Synthesis of Octadec-2-yn-1-ol (NP-PD-026) [ka] A solution of 2-octadec-2-ynoxytetrahydropyran (7.86 g, 22.4 mmol, 1.00 eq) in methanol (100 mL) was added to a 100 mL flask equipped with a stir bar. To this solution was added p-toluenesulfonic acid monohydrate (427 mg, 2.24 mmol, 0.10 eq), and the reaction mixture was vigorously stirred at room temperature for 3 h. TLC confirmed complete consumption of the starting material. The reaction mixture was then concentrated in vacuo, and the resulting crude material was purified by column chromatography (2% to 10% EtOAc / hexanes) to give a white solid (3.18 g, 11.9 mmol, 53%).

[0292] C. Synthesis of cctadec-17-yn-1-ol (NP-PD-028) [ka] Sodium hydride (60% in mineral oil, 3.82 g, 95.5 mmol, 8.00 eq) was added to an oven-dried 250 mL flask equipped with a stir bar under an Ar atmosphere. After dilution with 1,3-diaminopropane (40.0 mL), the flask was placed in a preheated oil bath at 70 °C. After stirring at this temperature for 1 h, the reaction mixture was cooled to 55 °C. Octadec-2-yn-1-ol (3.18 g, 11.9 mmol, 1.00 eq) was then dissolved in 1,3-diaminopropane (10.0 mL) and slowly added dropwise to the reaction mixture at this temperature. The reaction mixture was then vigorously stirred overnight. The next morning, the reaction was cooled to 0 °C, quenched with water, and acidified to pH 2 with 1 N aqueous HCl. The resulting aqueous phase was then extracted three times with hexane. The combined organic phases were then dried over magnesium sulfate and concentrated in vacuo. The resulting crude material was then purified by column chromatography (5% to 20% EtOAc / hexanes) to give a white solid (1.91 g, 7.17 mmol, 60%).

[0293] D. Synthesis of 18-trimethylsilyloctadec-17-yn-1-ol (NP-PD-049) [ka] Octadec-17-yn-1-ol (200 mg, 0.751 mmol, 1.00 eq), hexamethylphosphoramide (0.392 mL, 2.25 mmol, 3.00 eq), and THF (3.00 mL) were added to an oven-dried 25 mL flask equipped with a stir bar under an Ar atmosphere. The flask was then cooled to 0 °C, after which n-BuLi (2.30 M in THF, 0.979 mL, 2.25 mmol, 3.00 eq) was added slowly dropwise. The reaction was then warmed to room temperature and continued to stir vigorously for 2 h, after which trimethylsilyl chloride (0.476 mL, 3.75 mmol, 5.00 eq) was added dropwise to the reaction mixture. After an additional 2 h at room temperature, the reaction was quenched with saturated ammonium chloride and extracted three times with EtOAc. The organic phases were combined, washed with brine, dried over magnesium sulfate, and concentrated in vacuo. The resulting crude product was purified by column chromatography (100% hexane to 10% EtOAc / hexane) to give a white solid (160 mg, 0.473 mmol, 63%).

[0294] E. Synthesis of Ammonium [(1R)-2-(6-aminopurin-9-yl)-1-methyl-ethoxy]methyl-(18-trimethylsilyloctadec-17-ynoxy)phosphinate (NP-PD-042) [ka] To an oven-dried 25 mL flask equipped with a stir bar under an Ar atmosphere was added tenofovir (100 mg, 0.348 mmol, 1.00 eq) and pyridine (2.00 mL). This was followed by the addition of 18-trimethylsilyloctadec-17-yn-1-ol (177 mg, 0.522 mmol, 1.50 eq) and 2,4,6-triisopropylbenzenesulfonyl chloride (316 mg, 1.05 mmol, 3.00 eq). The reaction was vigorously stirred at room temperature for 48 hours under Ar. The reaction was concentrated in vacuo, taken up in a saturated solution of ammonium chloride, and concentrated again in vacuo. The resulting salt was then vigorously stirred in a 4:1 solution of DCM and MeOH for approximately 1 hour. The reaction was filtered and the resulting filtrate was collected, concentrated in vacuo and purified by column chromatography (100% DCM to 100% 80:20:3 DCM:MeOH:NH4OH) to give a white solid (51.0 mg, 0.0816 mmol, 24%). 1 H NMR(500MHz,CD3OD)δ 8.31(s,1H),8.20(s,1H),4.38(dd,J=14.4,2.8Hz,1H),4.23(dd,J=14.4,6.8Hz,1H),3.93-3.86(m,1H),3.76-3.68(m,3H),3.46(dd,J= 12.5,10.3Hz,1H),2.20(t,J=6.9Hz,2H),1.52-1.44(m,4H),1.43-1.37(m,2H),1.34-1.20(m,22H),1.17(d,J=6.2Hz,3H),0.11(s,9H). 13 C NMR(126MHz,CD3OD)δ 157.0,153.2,150.9,144.2,119.5,108.7,84.8,76.9(d,J CP =13.1Hz), 65.9(d,J CP =6.2Hz), 65.5(d,J CP =160.2Hz), 32.1(d,J CP =6.4Hz),30.8(2C),30.7(2C),30.5,30.1,29.7(2C),26.9,20.4,16.8,0.3. 31 P NMR(121MHz,CD3OD)δ 15.27.HRMS(ESI)m / z C 30 H55 N5O4PSi[M+H] + Calculated for 608.37554 Found 608.37562. LCMS (ESI) 95% ISO MeOH in H2O (0.1% HCO2H), 9 min, rt = 3.838, m / z = 608.4 [M+H] + , 606.3[MH] - ;85-95%MeOH in H2O (0.1%HCO2H), 10 min, rt=6.163, m / z=608.4[M+H] + , 606.4[MH] - .

[0295] Example 26. Synthesis of ammonium [(1R)-2-(6-aminopurin-9-yl)-1-methyl-ethoxy]methyl-(18-trimethylsilyloctadecoxy)phosphinate A. Synthesis of 18-trimethylsilyloctadecan-1-ol (NP-PD-050) [ka] To an oven-dried 25 mL flask equipped with a stir bar was added 18-trimethylsilyloctadec-17-yn-1-ol (297 mg, 0.877 mmol, 1.00 eq) and EtOH (6.00 mL) and a sealed hydrogen balloon was attached. The solution was then degassed under house vacuum for approximately 10 minutes, and the reaction flask was then purged with Ar. This cycle was repeated two more times, after which a catalytic amount of palladium on carbon (10% wt, 93.3 mg, 0.0877 mmol, 0.10 eq) was added. The reaction flask was once again placed under vacuum, followed by a final purge with hydrogen from the attached hydrogen balloon. The reaction was then allowed to stir vigorously under a hydrogen atmosphere at room temperature for 18 hours. After this time, the heterogeneous reaction mixture was filtered over a bed of Celite, and the filtrate was collected and concentrated in vacuo. The resulting crude product was purified by column chromatography (5% to 20% EtOAc / hexanes) to give a white solid (276 mg, 0.805 mmol, 92%).

[0296] B. Synthesis of Ammonium [(1R)-2-(6-aminopurin-9-yl)-1-methyl-ethoxy]methyl-(18-trimethylsilyloctadecoxy)phosphinate (NP-PD-051) [ka] To an oven-dried 25 mL flask equipped with a stir bar under an Ar atmosphere was added tenofovir (150 mg, 0.522 mmol, 1.00 eq) and pyridine (2.00 mL). This was followed by the addition of 18-trimethylsilyloctadecan-1-ol (268 mg, 0.783 mmol, 1.50 eq) and 2,4,6-triisopropylbenzenesulfonyl chloride (475 mg, 1.57 mmol, 3.00 eq). The reaction was vigorously stirred under Ar at room temperature for 48 hours. The reaction was concentrated in vacuo, taken up in a saturated solution of ammonium chloride, and concentrated again in vacuo. The resulting salt was then vigorously stirred in a 4:1 solution of DCM and MeOH for approximately 1 hour. The reaction was filtered and the resulting filtrate was collected, concentrated in vacuo and purified by column chromatography (100% DCM to 100% 80:20:3 DCM:MeOH:NH4OH) to give a white solid (87.0 mg, 0.142 mmol, 27%). 1 H NMR(500MHz,CD3OD)δ 8.31(s,1H),8.21(s,1H),4.38(dd,J=14.4,2.8Hz,1H),4.23(dd,J=14.4,6.9Hz,1H),3.93-3.86(m,1H),3.77-3.69(m,3H),3 .47(dd,J=12.6,10.2Hz,1H),1.51-1.45(m,2H),1.31-1.23(m,30H),1.17(d,J=6.2Hz,3H),0.51-0.47(m,2H),-0.03(s,9H). 13 C NMR(126MHz,CD3OD)δ 156.7,152.8,150.8,144.3,119.5,77.0(d,J CP =13.2Hz), 65.9(d,J CP =6.3Hz), 65.5(d,J CP =159.6Hz), 34.7, 32.1(d,J CP=6.3Hz),30.8(2C),30.7,30.5(2C),26.9,25.1,17.6,16.9,-1.4. 31 P NMR(121MHz,CD3OD)δ 15.27.HRMS(APCI)m / z C 30 H 59 N5O4PSi[M+H] + Calculated for 612.40684 Found 612.40676. LCMS (ESI) 95% ISO MeOH in H2O (0.1% HCO2H), 7 min, rt = 5.087, m / z = 612.5 [M+H] + , 610.4[MH] - .

[0297] Example 27. Synthesis of ammonium [(1R)-2-(6-aminopurin-9-yl)-1-methyl-ethoxy]methyl-(20,20,20-trifluoroicos-18-ynoxy)phosphinate A. Synthesis of 2-nonadeca-2-ynoxytetrahydropyran (NP-PD-092) [ka] To an oven-dried 250 mL flask equipped with a stir bar was added 2-(2-propynyloxy)tetrahydro-2H-pyran (2.01 mL, 14.3 mmol, 1.00 eq), hexamethylphosphoramide (8.69 mL, 49.9 mmol, 3.50 eq), and THF (50.0 mL). The reaction mixture was cooled to −78° C. and vigorously stirred under Ar. n-Butyllithium (2.00 M in THF, 9.27 mL, 18.6 mmol, 1.30 eq) was added dropwise over 15 min via an oven-dried pressure-equalizing addition funnel, and the reaction was vigorously stirred for approximately 1 h at −78° C. Hexadecyl bromide (5.67 mL, 18.6 mmol, 1.30 eq) was then added dropwise slowly over 10 min via a pressure-equalizing addition funnel, after which the resulting reaction mixture was allowed to warm to room temperature overnight with vigorously stirring under Ar. The next day, TLC showed that all of the starting alkyne had been consumed. The reaction mixture was quenched with saturated ammonium chloride solution and then extracted three times with EtOAc. The organic phases were then combined, washed with brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo. Subsequent purification of the resulting crude material by column chromatography (2% to 10% EtOAc / hexanes) afforded a clear oil (3.89 g, 10.7 mmol, 75%).

[0298] B. Synthesis of Nonadeque-2-yn-1-ol (NP-PD-094) [ka] A solution of 2-nonadecan-2-ynoxytetrahydropyran (3.88 g, 10.6 mmol, 1.00 eq) in methanol (40.0 mL) was added to a 100 mL flask equipped with a stir bar. To this solution was added p-toluenesulfonic acid monohydrate (183 mg, 1.06 mmol, 0.10 eq), and the reaction mixture was vigorously stirred at room temperature for 3 h. TLC confirmed complete consumption of the starting material. The reaction mixture was then concentrated in vacuo, and the resulting crude material was purified by column chromatography (2% to 10% EtOAc / hexanes) to yield a white solid (2.24 g, 7.99 mmol, 75%).

[0299] C. Synthesis of Nonadeque-18-yn-1-ol (NP-PD-095) [ka] Sodium hydride (60% in mineral oil, 2.56 g, 63.9 mmol, 8.00 eq) was added to an oven-dried 250 mL flask equipped with a stir bar under an Ar atmosphere. After dilution with 1,3-diaminopropane (20.0 mL), the flask was placed in a preheated oil bath at 70 °C. After stirring at this temperature for 1 h, the reaction mixture was cooled to 55 °C. Nonadequin-2-yn-1-ol (2.24 g, 7.99 mmol, 1.00 eq) was then dissolved in 1,3-diaminopropane (13.0 mL) and slowly added dropwise to the reaction mixture at this temperature. The reaction mixture was then vigorously stirred overnight. The next morning, the reaction was cooled to 0 °C, quenched with water, and acidified to pH 2 with 1 N aqueous HCl. The resulting aqueous phase was then extracted three times with hexane. The combined organic phases were then dried over magnesium sulfate and concentrated in vacuo. The resulting crude material was then purified by column chromatography (5% to 20% EtOAc / hexanes) to give a white solid (1.24 g, 4.42 mmol, 55%).

[0300] D. Synthesis of 1-methoxy-4-(nonadeca-18-ynoxymethyl)benzene (NP-PD-096) [ka] Sodium hydride (60% in mineral oil, 481 mg, 12.0 mmol, 2.50 eq) was added to a solution of nonadecan-18-yn-1-ol (1.35 g, 4.81 mmol, 1.00 eq) in DMF (20.0 mL) in a 100 mL oven-dried flask equipped with a stir bar at 0 °C under an Ar atmosphere. The reaction mixture was warmed to room temperature, and after approximately 40 min, p-methoxybenzyl chloride (0.980 mL, 7.22 mmol, 1.50 eq) was added dropwise to the reaction mixture at room temperature. The reaction was heated to 50 °C and vigorously stirred overnight under Ar. The next day, the reaction mixture was cooled to room temperature, quenched with a saturated solution of ammonium chloride, and extracted three times with EtOAc. The organic phases were combined, washed with brine, dried over magnesium sulfate, and concentrated in vacuo. The resulting crude material was then purified by column chromatography (5% to 20% EtOAc / hexanes) to give a white solid (1.45 g, 3.62 mmol, 75%).

[0301] D. Synthesis of 1-methoxy-4-(20,20,20-trifluoroicos-18-ynoxymethyl)benzene (NP-PD-098) [ka] An oven-dried 50 mL flask equipped with a stir bar under an atmosphere of air (balloon) was charged with copper(I) iodide (610 mg, 3.20 mmol, 1.50 eq), KCO (885 mg, 6.40 mmol, 3.00 eq), and N,N,N',N'-tetramethylethylenediamine (0.483 mL, 3.20 mmol, 1.50 eq) in DMF (10.0 mL). The resulting blue mixture was stirred vigorously at room temperature for 15 min. (Trifluoromethyl)trimethylsilane (0.630 mL, 4.27 mmol, 2.00 eq) was added to the reaction mixture, and the reaction was stirred for an additional 5 min before being cooled to 0 °C. To the reaction mixture was added (in one portion) a solution of 1-methoxy-4-(nonadequa-18-ynoxymethyl)benzene (855 mg, 2.13 mmol, 1.00 eq) and (trifluoromethyl)trimethylsilane (0.630 mL, 4.27 mmol, 2.00 eq) in DMF (10.0 mL). The reaction was allowed to warm to room temperature and stirred vigorously for 48 h. For workup, the reaction was quenched with HO and extracted three times with DCM. The organic phases were combined, dried over MgSO, filtered, and concentrated in vacuo. The crude material was then purified by column chromatography (5% to 20% EtOAc / hexanes) to give a white solid (906 mg, 1.93 mmol, 91%).

[0302] E. Synthesis of 20,20,20-trifluoroicos-18-yn-1-ol (NP-PD-101) [ka] In a 25 mL flask equipped with a stir bar, 1-methoxy-4-(20,20,20-trifluoroicos-18-ynoxymethyl)benzene (900 mg, 1.92 mmol, 1.00 eq) was dissolved in a mixture of MeOH (9.00 mL) and HO (0.900 mL). The reaction was cooled to 0 °C, and cerium ammonium nitrate, CAN (3.16 g, 5.76 mmol, 3.00 eq) was added in portions. The reaction mixture was then warmed to room temperature and vigorously stirred for 3 h or until TLC confirmed the consumption of the starting material. It was then quenched with HO, followed by three extractions with DCM. The organic phase was dried over magnesium sulfate and concentrated in vacuo. The crude material was purified by column chromatography (100% hexanes to 20% EtOAc / hexanes) to give a white solid (574 mg, 1.65 mmol, 86%).

[0303] F. Synthesis of Ammonium [(1R)-2-(6-aminopurin-9-yl)-1-methyl-ethoxy]methyl-(20,20,20-trifluoroicos-18-ynoxy)phosphinate (NP-PD-102) [ka] To an oven-dried 25 mL flask equipped with a stir bar under an Ar atmosphere were added tenofovir (100 mg, 0.348 mmol, 1.00 eq) and pyridine (2.00 mL). This was followed by the addition of 20,20,20-trifluoroicos-18-yn-1-ol (182 mg, 0.522 mmol, 1.50 eq) and 2,4,6-triisopropylbenzenesulfonyl chloride (316 mg, 1.05 mmol, 3.00 eq). The reaction was vigorously stirred under Ar at room temperature for 48 h. The reaction was concentrated in vacuo, taken up in a saturated solution of ammonium chloride, and concentrated again in vacuo. The resulting salt was then vigorously stirred in a 4:1 solution of DCM and MeOH for approximately 1 h. The reaction was filtered, and the resulting filtrate was collected, concentrated in vacuo, and purified first by silica gel column chromatography (100% DCM to 100% 80:20:3 DCM:MeOH:NHOH) and then by RP C18 column chromatography (10% MeOH / HO to 100% MeOH) to give a white solid (69.0 mg, 0.109 mmol, 31%). 1 H NMR(500MHz,CD3OD)δ 8.32(s,1H),8.21(s,1H),4.38(dd,J=14.4,3.1Hz,1H),4.23(dd,J=14.4,6.9Hz,1H),3.90(pd,J=6.3,3.0Hz,1H),3.7 8-3.67(m,3H),3.47(dd,J=12.7,10.0Hz,1H),2.38(dt,J=7.3,3.6Hz,1H),1.62-1.20(m,31H),1.17(d,J=6.2Hz,3H). 13 C NMR(151MHz,CD3OD)δ 156.9,153.0,150.9,144.3,119.5,115.6(q,J CF =254.9Hz), 94.5, 91.5(q,J CF =6.2Hz), 77.0(d,J CP =12.8Hz), 68.7(q,J CF =51.9Hz), 65.9(d,J CP =5.8Hz), 65.5(d,J CP =159.9Hz), 32.1(d,J CP=6.3Hz),30.8,30.7(2C),30.6(2C),30.5(2C),30.1,30.0,29.8(2C),29.7,28.3,26.9,21.3,18.6,16.8. 19 F NMR(376MHz,CD3OD)δ -51.45(t,J=4.0Hz,3F). 31 P NMR(121MHz,CD3OD)δ 15.27.HRMS(APCI)m / z C 29 H 46 O4N5F3P[MH] - Calculated for 616.32450 Found 616.32505. LCMS (ESI) 95% ISO MeOH in H2O (0.1% HCO2H), 9 min, rt = 1.260, m / z = 618.4 [M+H] + , 616.2[MH] - ;85-95%MeOH in H2O (0.1%HCO2H), 10 min, rt=2.946, m / z=618.4[M+H] + , 616.3[MH] - .

[0304] Example 28. Synthesis of ammonium [(1R)-2-(6-aminopurin-9-yl)-1-methyl-ethoxy]methyl-(20,20,20-trifluoroicosoxy)phosphinate A. Synthesis of 20,20,20-trifluoroicosan-1-ol (NP-PD-106) [ka] To an oven-dried 25 mL flask equipped with a stir bar and a sealed hydrogen balloon was added 20,20,20-trifluoroicos-18-yn-1-ol (230 mg, 0.660 mmol, 1.00 eq) and EtOH (5.00 mL). The solution was then degassed under house vacuum for approximately 10 minutes, and the reaction flask was then purged with Ar. This cycle was repeated two more times, after which a catalytic amount of palladium hydroxide on carbon (20% wt, 46.3 mg, 0.0660 mmol, 0.100 eq) was added. The reaction flask was once again placed under vacuum, followed by a final purge with hydrogen from the attached hydrogen balloon. The reaction was then allowed to stir vigorously under a hydrogen atmosphere at room temperature for 18 hours. After this time, the heterogeneous reaction mixture was filtered over a bed of Celite, and the filtrate was collected and concentrated in vacuo. The resulting crude product was purified by column chromatography (5% to 20% EtOAc / hexanes) to give a white solid (170 mg, 0.482 mmol, 73%).

[0305] B. Synthesis of Ammonium [(1R)-2-(6-aminopurin-9-yl)-1-methyl-ethoxy]methyl-(20,20,20-trifluoroicosoxy)phosphinate (NP-PD-105) [ka] In an oven-dried 25 mL flask equipped with a stir bar, triethylamine (0.0992 mL, 557 mmol, 2.00 eq) was added to tenofovir (80.0 mg, 0.279 mmol, 1.00 eq), 20,20,20-trifluoroicosan-1-ol (147 mg, 0.418 mL, 1.50 eq), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (107 mg, 0.418 mmol, 2.00 eq), and 4-dimethylaminopyridine (3.40 mg, 0.0279 mmol, 0.100 eq) in MeCN (2.00 mL) at room temperature under an Ar atmosphere. The reaction mixture was then heated to 90° C. and vigorously stirred at this temperature overnight. The next day, the reaction was concentrated in vacuo, and the resulting crude material was taken up in a 1:1 mixture of DCM (4.00 mL) and 7 M NH solution in MeOH (4.00 mL) and stirred vigorously for approximately 2 h. It was then concentrated in vacuo, followed by purification by column chromatography (100% DCM to 80:30:3 DCM:MeOH:NHOH) and then a second purification by RPC18 column chromatography (10% MeOH / HO to 100% MeOH) to give a white solid (39.0 mg, 0.0611 mmol, 22%). 1 H NMR(500MHz,CD3OD)δ 8.33(s,1H),8.21(s,1H),4.39(dd,J=14.4,3.1Hz,1H),4.23(dd,J=14.4,6.8Hz,1H),3.95-3.87(m,1H),3.79-3.69(m ,3H),3.48(dd,J=12.8,10.0Hz,1H),2.19-2.04(m,2H),1.58-1.44(m,4H),1.42-1.21(m,30H),1.17(d,J=6.2Hz,3H). 13 C NMR(151MHz,CD3OD)δ 157.0,153.2,150.9,144.3,128.9(q,J CF =275.4Hz), 119.6, 76.9(d,J CP =12.9Hz), 65.9(d,J CP =5.9Hz), 65.5(d,J CP =159.8Hz), 34.4(q,J CF =28.2Hz), 32.1(d,J CP=6.3Hz),30.8(2C),30.7(2C),30.5(2C),30.3,29.8,26.9,23.0(q,J CF =3.0Hz), 16.8. 19 F NMR(376MHz,CD3OD)δ -68.71(t,J=11.2Hz,3F). 31 P NMR(121MHz,CD3OD)δ 15.28.HRMS(APCI)m / z C 29 H 50 O4N5F3P[MH] - Calculated for 620.35580 Found 620.35498. LCMS (ESI) 95% ISO MeOH in H2O (0.1% HCO2H), 9 min, rt = 1.367, m / z = 622.4 [M+H] + , 620.3[MH] - ;85-95%MeOH in H2O (0.1%HCO2H), 10 min, rt=4.007, m / z=622.4[M+H] + , 620.4[MH] - .

[0306] Example 29. Synthesis of ammonium 3-((14-trimethylsilyl)tetradec-13-yn-1-yl)propyl (R)-(((1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate A. Synthesis of 2-tetradec-2-ynoxytetrahydropyran (NP-PD-121) [ka] To an oven-dried 250 mL flask equipped with a stir bar was added 2-(2-propynyloxy)tetrahydro-2H-pyran (5.02 mL, 35.7 mmol, 1.00 eq), 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (12.9 mL, 107 mmol, 3.00 eq), and THF (100 mL). The reaction mixture was cooled to −78° C. and vigorously stirred under Ar. n-Butyllithium (2.30 M in THF, 20.2 mL, 46.4 mmol, 1.30 eq) was added dropwise over 15 min via an oven-dried pressure-equalizing addition funnel, and the reaction was vigorously stirred for approximately 1 h at −78° C. 1-Bromoundecane (10.4 mL, 46.4 mmol, 1.30 eq) was then added dropwise slowly over 10 min via a pressure-equalizing addition funnel, and the resulting reaction mixture was then allowed to warm to room temperature overnight with vigorous stirring under Ar. The next day, TLC indicated that all of the starting alkyne had been consumed. The reaction mixture was quenched with a saturated solution of ammonium chloride and then extracted three times with EtOAc. The organic phases were then combined, washed with brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The resulting crude material was then purified by column chromatography (2% to 10% EtOAc / hexanes) to give a clear oil (6.64 g, 22.5 mmol, 63%).

[0307] B. Synthesis of Tetradec-2-yn-1-ol (NP-PD-122) [ka] A solution of 2-tetradec-2-ynoxytetrahydropyran (6.64 g, 22.6 mmol, 1.00 eq) in methanol (100 mL) was added to a 100 mL flask equipped with a stir bar. To this solution was added p-toluenesulfonic acid monohydrate (428 mg, 2.26 mmol, 0.10 eq), and the reaction mixture was vigorously stirred at room temperature for 3 h. TLC confirmed complete consumption of the starting material. The reaction mixture was then concentrated in vacuo, and the resulting crude material was purified by column chromatography (2% to 10% EtOAc / hexanes) to yield a white solid (3.77 g, 17.9 mmol, 80%).

[0308] C. Synthesis of Tetradec-13-yn-1-ol (NP-PD-123) [ka] Sodium hydride (60% in mineral oil, 5.73 g, 143 mmol, 8.00 eq) was added to an oven-dried 250 mL flask equipped with a stir bar under an Ar atmosphere. After dilution with 1,3-diaminopropane (40.0 mL), the flask was placed in a preheated oil bath at 70 °C. After stirring at this temperature for 1 h, the reaction mixture was cooled to 55 °C. Tetradec-2-yn-1-ol (3.77 g, 17.9 mmol, 1.00 eq) was then dissolved in 1,3-diaminopropane (10.0 mL) and slowly added dropwise to the reaction mixture at this temperature. The reaction mixture was then vigorously stirred overnight. The next morning, the reaction was cooled to 0 °C, quenched with water, and acidified to pH 2 with 1 N aqueous HCl. The resulting aqueous phase was then extracted three times with hexane. The combined organic phases were then dried over magnesium sulfate and concentrated in vacuo. The resulting crude material was then purified by column chromatography (5% to 20% EtOAc / hexanes) to give a white solid (2.50 g, 11.9 mmol, 66%).

[0309] D. Synthesis of 2-(3-tetradec-13-ynoxypropoxy)tetrahydropyran (NP-PD-124) [ka] Tetradec-13-yn-1-ol (600 mg, 2.85 mmol, 1.00 eq) was added to a 25 mL flask equipped with a stir bar and a reflux condenser. Tetradec-13-yn-1-ol was then diluted with THF (3.00 mL) and saturated aqueous NaOH (3.00 mL). Tetrabutylammonium bromide (184 mg, 0.571 mmol, 0.200 eq) and 2-(3-bromopropoxy)tetrahydropyran (0.532 mL, 3.14 mmol, 1.10 eq) were added to the reaction mixture, which was then heated to reflux (75 °C) and stirred vigorously overnight. The next day, the reaction mixture was cooled to room temperature and then partitioned between DCM and water. The resulting aqueous layer was extracted three times with DCM, and the resulting organic phases were combined, washed with brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The crude material obtained was purified by column chromatography (100% hexanes to 10% EtOAc / hexanes) to give a clear oil (486 mg, 1.38 mmol, 48%).

[0310] E. Synthesis of trimethyl-[14-(3-tetrahydropyran-2-yloxypropoxy)tetradec-1-ynyl]silane (NP-PD-127) [ka] Under an Ar atmosphere, 2-(3-tetradec-13-ynoxypropoxy)tetrahydropyran (801 mg, 2.27 mmol, 1.00 eq), 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (0.824 mL, 6.82 mmol, 3.00 eq), and THF (10.0 mL) were added to an oven-dried 25 mL flask equipped with a stir bar. The flask was then cooled to −78° C., and n-BuLi (2.00 M in THF, 2.84 mL, 5.68 mmol, 2.50 eq) was then added dropwise slowly. After 2 h at −78° C., the reaction was warmed to 0° C. and allowed to stir vigorously for 1 h. The reaction was then recooled to −78° C., and trimethylsilyl chloride (0.307 mL, 5.68 mmol, 2.50 eq) was added dropwise to the reaction mixture. The reaction was then allowed to warm to room temperature overnight. The next morning, the reaction was quenched with saturated ammonium chloride solution and extracted three times with EtOAc. The organic phases were combined, washed with brine, dried over magnesium sulfate, and concentrated in vacuo. The resulting crude product was purified by column chromatography (100% hexanes to 10% EtOAc / hexanes) to give a clear oil (528 mg, 1.24 mmol, 55%).

[0311] F. Synthesis of 3-(14-trimethylsilyltetradec-13-ynoxy)propan-1-ol (NP-PD-128) [ka] A solution of trimethyl-[14-(3-tetrahydropyran-2-yloxypropoxy)tetradec-1-ynyl]silane (520 mg, 1.22 mmol, 1.00 eq) in methanol (5.00 mL) was added to a 100 mL flask equipped with a stir bar. To this solution was added p-toluenesulfonic acid monohydrate (23.3 mg, 0.122 mmol, 0.100 eq), and the reaction mixture was vigorously stirred at room temperature for 3 h. TLC confirmed complete consumption of the starting material. The reaction mixture was then concentrated in vacuo, and the resulting crude material was purified by column chromatography (2% to 10% EtOAc / hexanes) to yield a clear oil (310 mg, 0.910 mmol, 74%).

[0312] G. Synthesis of Ammonium 3-((14-trimethylsilyl)tetradec-13-yn-1-yl)propyl (R)-(((1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate (NP-PD-130) [ka] To an oven-dried 25 mL flask equipped with a stir bar under an Ar atmosphere was added tenofovir (170 mg, 0.592 mmol, 1.00 eq) and pyridine (2.00 mL). This was followed by the addition of 3-(14-trimethylsilyltetradec-13-ynoxy)propan-1-ol (302 mg, 0.888 mmol, 1.50 eq) and 2,4,6-triisopropylbenzenesulfonyl chloride (538 mg, 1.78 mmol, 3.00 eq). The reaction was vigorously stirred under Ar at room temperature for 48 h. The reaction was concentrated in vacuo, taken up in a saturated solution of ammonium chloride, and concentrated again in vacuo. The resulting salt was then vigorously stirred in a 4:1 solution of DCM and MeOH for approximately 1 h. The reaction was filtered and the resulting filtrate was collected, concentrated in vacuo, and purified first by silica gel column chromatography (100% DCM to 100% 80:20:3 DCM:MeOH:NHOH) and then by RP C18 column chromatography (10% MeOH / HO to 100% MeOH) to give a white solid (145 mg, 0.231 mmol, 39%). 1 H NMR (500 MHz, CD3OD) δ 8.31(s,1H),8.21(s,1H),4.38(dd,J=14.4,3.2Hz,1H),4.23(dd,J=14.4,6.8 Hz,1H),3.94-3.82(m,3H),3.72(dd,J=12.8,9.5Hz,1H),3.52-3.39(m,3H),3. 33(t,J=6.6Hz,2H),2.19(t,J=7.0Hz,2H),1.80-1.73(m,2H),1.54-1.44(m,4 H),1.43-1.34(m,2H),1.32-1.25(m,14H),1.17(d,J=6.2Hz,3H),0.10(s,9H).13 C NMR(126MHz,CD3OD)δ 156.8,152.9,150.9,144.3,119.5,108.7,84.8,76.9(d,J CP =12.7Hz), 72.0, 68.4, 65.4(d,J CP =160.4Hz), 63.1(d,J CP =5.6Hz), 49.1, 32.4(d,J CP =6.1Hz),30.8,30.72(2C),30.6(2C),30.1,29.7(2C),27.3,20.4,16.9. 31 P NMR(121MHz,CD3OD)δ 15.45 HRMS(APCI)m / z C 29 H 51 Calculated for O5N5PSi[MH] 608.34026 Found 608.34068. LCMS (ESI) 95% ISO MeOH in H2O (0.1% HCO2H), 7 min, rt = 2.025, m / z = 610.4 [M+H] + , 608.3MH] - ;85-95%MeOH in H2O (0.1%HCO2H), 10 min, rt=3.023, m / z=610.4[M+H] + , 608.2[MH] - .

[0313] Example 30. Synthesis of ammonium [(1R)-2-(6-aminopurin-9-yl)-1-methyl-ethoxy]methyl-[3-(16,16,16-trifluorohexadec-14-ynoxy)propoxy]phosphinate A. Synthesis of 3-[(4-methoxyphenyl)methoxy]propan-1-ol (NP-PD-143) [ka] A solution of 1,3-dihydroxypropane (4.58 mL, 63.9 mmol) in DMSO (50 mL) was cooled to 0 °C. At this temperature, potassium hydroxide (3.58 g, 63.9 mmol) was added in portions, and the mixture was stirred at room temperature until most of the KOH pellets were dissolved. It was then treated with 4-methoxybenzyl chloride (PMBCl) (4.33 mL, 31.9 mmol) at room temperature. The reaction was stirred for 18 h. When TLC indicated complete consumption of PMBCl, the mixture was cooled back to 0 °C, diluted with DCM, and carefully inactivated by the addition of 1 N HCl. It was then warmed back to room temperature, the phases were separated, and the aqueous layer was extracted three times with DCM. The combined organic extracts were dried over MgSO and then concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (10-50% EtOAc / hexanes) to give 3-[(4-methoxyphenyl)methoxy]propan-1-ol (4.26 g, 21.7 mmol, 68% yield) as a clear oil.

[0314] B. Synthesis of 1-(3-bromopropoxymethyl)-4-methoxy-benzene (NP-PD-144) [ka] Triphenylphosphine (8.54 g, 32.6 mmol) was added to a solution of 3-[(4-methoxyphenyl)methoxy]propan-1-ol (4.26 g, 21.7 mmol) and carbon tetrabromide (8.64 g, 26.1 mmol) in DCM (100 mL) at 0° C. The reaction mixture was stirred for 1 h, then the solvent was removed in vacuo and the residue was purified by column chromatography on silica gel (5–40% EtOAc / hexanes) to give 1-(3-bromopropoxymethyl)-4-methoxy-benzene (3.13 g, 12.1 mmol, 56% yield) as a clear oil.

[0315] C. Synthesis of 1-methoxy-4-(3-pentadec-14-ynoxypropoxymethyl)benzene (NP-PD-145) [ka] NP-PD-144 (3.25 g, 14.5 mmol, 1.20 eq) was added to a 250 mL flask equipped with a stir bar and a reflux condenser. Pentadec-14-yn-ol was then diluted with THF (20 mL) and saturated aqueous NaOH (20 mL). Tetrabutylammonium bromide (779 mg, 2.42 mmol, 0.200 eq) and 1-(3-bromopropoxymethyl)-4-methoxybenzene (3.13 g, 12.1 mmol, 1.00 eq) were added to the reaction mixture, which was then heated to reflux (75 °C) and stirred vigorously overnight. The next day, the reaction mixture was cooled to room temperature and then partitioned between DCM and water. The resulting aqueous layer was extracted three times with DCM, and the resulting organic phases were combined, washed with brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The resulting crude material was purified by column chromatography (100% hexanes to 10% EtOAc / hexanes) to give a clear oil (2.01 g, 4.99 mmol, 41%).

[0316] D. Synthesis of 1-methoxy-4-[3-(16,16,16-trifluorohexadec-14-ynoxy)propoxymethyl]benzene (NP-PD-146) [ka] Copper(I) iodide (1.35 g, 7.08 mmol, 1.50 eq), KCO (1.96 g, 14.2 mmol, 3.00 eq), and N,N,N',N'-tetramethylethylenediamine (1.06 mL, 7.08 mmol, 1.50 eq) in DMF (10 mL) were placed in an oven-dried 100 mL flask equipped with a stir bar under an air atmosphere (balloon). The resulting blue mixture was stirred vigorously at room temperature for 15 min. (Trifluoromethyl)trimethylsilane (1.40 mL, 9.44 mmol, 2.00 eq) was added to the reaction mixture, and the reaction was stirred for an additional 5 min before being cooled to 0 °C. To the reaction mixture was added (in one portion) a solution of NP-PD-145 (1.90 g, 4.72 mmol, 1.00 eq) and (trifluoromethyl)trimethylsilane (1.40 mL, 9.44 mmol, 2.00 eq) in DMF (10 mL). The reaction was allowed to warm to room temperature and stirred vigorously for 48 h. For workup, the reaction was quenched with HO and extracted three times with DCM. The organic phases were combined, dried over MgSO, filtered, and concentrated in vacuo. The crude material was then purified by column chromatography (5% to 20% EtOAc / hexanes) to give a clear oil (1.53 g, 3.25 mmol, 69%).

[0317] E. Synthesis of 3-(16,16,16-trifluorohexadec-14-ynoxy)propan-1-ol (NP-PD-147) [ka] In a 25 mL flask equipped with a stir bar, NP-PD-146 (1.53 g, 3.25 mmol) was dissolved in a mixture of methanol (10 mL) and water (1 mL). The reaction was cooled to 0 °C, and cerium ammonium nitrate (5.35 g, 9.75 mmol) was added portionwise. The reaction mixture was then warmed to room temperature and stirred vigorously for 3 h or until TLC confirmed the consumption of the starting material. It was then quenched with HO, followed by extraction three times with DCM. The organic phase was dried over magnesium sulfate and concentrated in vacuo. The resulting crude material was purified by column chromatography (100% hexanes to 20% EtOAc / hexanes) to give 3-(16,16,16-trifluorohexadec-14-ynoxy)propan-1-ol (1.08 g, 3.08 mmol, 95% yield) as a white solid.

[0318] F. Synthesis of Ammonium [(1R)-2-(6-aminopurin-9-yl)-1-methyl-ethoxy]methyl-[3-(16,16,16-trifluorohexadec-14-ynoxy)propoxy]phosphinate (NP-PD-149) [ka] To an oven-dried 25 mL flask equipped with a stir bar under an Ar atmosphere was added tenofovir (250 mg, 0.870 mmol, 1.00 eq) and pyridine (3.00 mL). This was followed by the addition of 3-(16,16,16-trifluorohexadec-14-ynoxy)propan-1-ol (458 mg, 1.31 mmol, 1.50 eq) and 2,4,6-triisopropylbenzenesulfonyl chloride (791 mg, 2.61 mmol, 3.00 eq). The reaction was vigorously stirred under Ar at room temperature for 48 hours. The reaction was concentrated in vacuo, taken up in a saturated solution of ammonium chloride, and concentrated again in vacuo. The resulting salt was then vigorously stirred in a 4:1 solution of DCM and MeOH for approximately 1 hour. The reaction was filtered, and the resulting filtrate was collected, concentrated in vacuo, and purified first by silica gel column chromatography (100% DCM to 100% 80:20:3 DCM:MeOH:NHOH) and then by RP C18 column chromatography (10% MeOH / HO to 100% MeOH). The product fractions were once again collected, concentrated under reduced pressure, stirred with 7N ammonia in methanol (10 mL) at room temperature for 10 minutes, and dried under vacuum to give a white solid (105 mg, 0.165 mmol, 19%). 1 H NMR(500MHz,CD3OD)δ 8.34(s,1H),8.22(s,1H),4.40(dd,J=14.4,3.2Hz,1H),4.24(dd,J=14.4,6.7Hz,1H),3 .95-3.84(m,3H),3.73(dd,J=12.8,9.4Hz,1H),3.50(dd,J=12.8,9.9Hz,1H),3.44(t,J= 6.4Hz,2H),3.35(t,J=6.6Hz,2H),2.43-2.36(m,2H),1.82-1.74(m,2H),1.58(p,J=7.1H) z,2H),1.54-1.46(m,2H),1.46-1.38(m,2H),1.33-1.25(m,16H),1.16(d,J=6.2Hz,3H). 13 C NMR(151MHz,CD3OD)δ 156.2,151.9,150.8,144.7,119.5,115.7(q,J CP =254.9Hz), 91.6(q,J CF=6.2Hz), 76.9(d,J CP =12.7Hz), 72.0, 68.4, 65.3(d,J CP =159.9Hz), 63.1(d,J CP =5.6Hz), 32.4(d,J CP =6.3Hz),30.8,30.7(3C),30.6,30.5,30.0,29.8,28.3,27.3,18.6,16.8. 19 F NMR(376MHz,CD3OD)δ -51.54(t,J=3.9Hz,3F). 31 P NMR(121MHz,CD3OD)δ 15.53.HRMS(APCI)m / z C 28 H 44 Calculated for O5N5F3P[MH] 618.30376 Found 618.30418. LCMS (ESI) 95% ISO MeOH in H2O (0.1% HCO2H), 5 min, rt = 0.704, m / z = 620.4 [M+H] + , 618.2[MH] - ;25-95%MeOH in H2O (0.1%HCO2H), 6 min, rt=4.417, m / z=620.2[M+H] + , 618.2[MH] - .

[0319] Example 31. Synthesis of ammonium [(1R)-2-(6-aminopurin-9-yl)-1-methyl-ethoxy]methyl-[3-(16,16,16-trifluorohexadecoxy)propoxy]phosphinate A. Synthesis of 3-(16,16,16-trifluorohexadecoxy)propan-1-ol (NP-PD-156) [ka] To an oven-dried 50 mL flask equipped with a stir bar and fitted with a sealed hydrogen balloon was added 3-(16,16,16-trifluorohexadec-14-ynoxy)propan-1-ol (580 mg, 1.66 mmol, 1.00 eq) and EtOAc (10 mL). The solution was then degassed under house vacuum for approximately 10 minutes, and then the reaction flask was purged with Ar. This cycle was repeated two more times, after which a catalytic amount of palladium hydroxide on carbon (20% wt, 116 mg, 0.166 mmol, 0.10 eq) was added. The reaction flask was once again placed under vacuum, followed by a final purge with hydrogen from an attached hydrogen balloon. The reaction was then allowed to stir vigorously under a hydrogen atmosphere at room temperature for 18 hours. After this time, the heterogeneous reaction mixture was filtered over a bed of Celite, and the filtrate was collected and concentrated in vacuo. The resulting crude product was purified by column chromatography (5% to 20% EtOAc / hexanes) to give a white solid (460 mg, 1.30 mmol, 78%).

[0320] B. Synthesis of Ammonium [(1R)-2-(6-aminopurin-9-yl)-1-methyl-ethoxy]methyl-[3-(16,16,16-trifluorohexadecoxy)propoxy]phosphinate (NP-PD-158) [ka] To an oven-dried 25 mL flask equipped with a stir bar under an Ar atmosphere was added tenofovir (200 mg, 0.696 mmol, 1.00 eq) and pyridine (3.00 mL). This was followed by the addition of 3-(16,16,16-trifluorohexadecoxy)propan-1-ol (370 mg, 1.05 mmol, 1.50 eq) and 2,4,6-triisopropylbenzenesulfonyl chloride (633 mg, 2.09 mmol, 3.00 eq). The reaction was vigorously stirred under Ar at room temperature for 48 h. The reaction was concentrated in vacuo, taken up in a saturated solution of ammonium chloride, and concentrated again in vacuo. The resulting salt was then vigorously stirred in a 4:1 solution of DCM and MeOH for approximately 1 h. The reaction was filtered, and the resulting filtrate was collected, concentrated in vacuo, and purified first by silica gel column chromatography (100% DCM to 100% 80:20:3 DCM:MeOH:NHOH) and then by RP C18 column chromatography (10% MeOH / HO to 100% MeOH). The product fractions were once again collected, concentrated under reduced pressure, stirred with 7N ammonia in methanol (10 mL) at room temperature for 10 minutes, and dried under vacuum to give a white solid (203 mg, 0.317 mmol, 46%). 1 H NMR(600MHz,CD3OD)δ 8.32(s,1H),8.20(s,1H),4.38(dd,J=14.4,3.2Hz,1H),4.24(dd,J=14.4,6.6Hz,1H),3 .93-3.84(m,3H),3.71(dd,J=12.8,9.5Hz,1H),3.47(dd,J=12.8,9.9Hz,1H),3.44(t,J =6.4Hz,2H),3.34(t,J=6.6Hz,2H),2.17-2.07(m,2H),1.82-1.73(m,2H),1.57-1.52(m ,2H),1.51-1.47(m,2H),1.41-1.35(m,2H),1.33-1.26(m,20H),1.16(d,J=6.2Hz,3H). 13 C NMR(151MHz,CD3OD)δ 157.0,153.2,150.9,144.3,128.9(q,J CF =275.5Hz), 119.6, 76.9(d,J CF=13.0Hz),72.0,68.5,66.0,64.9,63.1(d,J CP =5.7Hz), 34.4(q,J CF =28.1Hz), 32.4(d,J CP =6.4Hz),30.8(2C),30.7(2C),30.6,30.5,30.3,29.8,27.3,23.0(q,J CF =2.9Hz), 16.8. 19 F NMR(376MHz,CD3OD)δ -68.76(t,J=11.2Hz,3F). 31 P NMR(162MHz,CD3OD)δ 15.39.HRMS(APCI)m / z C 28 H 48 Calculated for O5F3N5P[MH]-, 622.33506. Found, 622.33497. LCMS (ESI) 95% ISO MeOH in H2O (0.1% HCO2H), 7 min, rt = 4.143, m / z = 624.3 [M+H] + , 622.3[MH] - ;85-95%MeOH in H2O (0.1%HCO2H), 10 min, rt=5.133, m / z=624.3[M+H] + , 622.2[MH] - .

[0321] Example 32. Synthesis of ammonium 4-pentadecoxybutoxy-[[rac-(1R)-2-(6-aminopurin-9-yl)-1-methyl-ethoxy]methyl]phosphinate A. Synthesis of 4-pentadecoxybutan-1-ol (NP-PD-148) [ka] Sodium hydride (60% suspension in mineral oil, 103 mg, 2.57 mmol) was added to butane-1,4-diol (0.23 mL, 2.6 mmol) in DMF (10 mL) at 0 °C in an oven-dried two-neck flask under an Ar atmosphere. After vigorously stirring at 0 °C for 1 h, 1-bromopentadecane (0.50 mL, 1.7 mmol) was added dropwise. The reaction mixture was then warmed to room temperature and vigorously stirred for 5 h before being slowly quenched with water. The reaction mixture was extracted three times into DCM. The organic phases were combined, dried over MgSO4, and concentrated in vacuo. The resulting crude product was then purified by column chromatography (5% to 30% EtOAc / hexanes) to afford 4-pentadecoxybutan-1-ol (405 mg, 1.35 mmol, 79% yield) as a white solid.

[0322] B. Synthesis of Ammonium 4-Pentadecoxybutoxy-[[rac-(1R)-2-(6-aminopurin-9-yl)-1-methyl-ethoxy]methyl]phosphinate (NP-PD-150) [ka] To an oven-dried 25 mL flask equipped with a stir bar under an Ar atmosphere was added tenofovir (250 mg, 0.870 mmol, 1.00 eq) and pyridine (3.00 mL). This was followed by the addition of 4-pentadecoxybutan-1-ol (392 mg, 1.31 mmol, 1.50 eq) and 2,4,6-triisopropylbenzenesulfonyl chloride (791 mg, 2.61 mmol, 3.00 eq). The reaction was allowed to stir vigorously under Ar at room temperature for 48 hours. The reaction was concentrated in vacuo, taken up in a saturated solution of ammonium chloride, and concentrated again in vacuo. The resulting salt was then stirred vigorously in a 4:1 solution of DCM and MeOH for approximately 1 hour. The reaction was filtered and the resulting filtrate was collected, concentrated in vacuo, and purified first by silica gel column chromatography (100% DCM to 100% 80:20:3 DCM:MeOH:NHOH) and then by RP C18 column chromatography (10% MeOH / HO to 100% MeOH) to give a white solid (278 mg, 0.474 mmol, 54%). 1 H NMR(600MHz,CD3OD)δ 8.31(s,1H),8.20(s,1H),4.37(dd,J=14.4,3.2Hz,1H),4.23(dd,J=14.4,6 .7Hz,1H),3.93-3.86(m,1H),3.83-3.74(m,2H),3.71(dd,J=12.7,9.5Hz,1 H),3.47(dd,J=12.7,10.0Hz,1H),3.39-3.35(m,4H),1.60-1.54(m,4H),1. 54-1.48(m,2H),1.28(s,24H),1.16(d,J=6.2Hz,3H),0.90(t,J=7.0Hz,3H). 13 C NMR(151MHz,CD3OD)δ 157.2,153.5,151.0,144.3,119.6,76.9(d,J CP =13.1Hz),71.9,71.5,66.1,65.7(d,J CP =5.7Hz),65.0,33.1,30.8(5C),30.7(2C),30.6,30.5,28.9(d,J CP =6.5Hz),27.3,27.1,23.7,16.8,14.4. 31P NMR(162MHz,CD3OD)δ 15.27.HRMS(APCI)m / z C 28 H 51 O5N5P[MH] - Calculated value: 568.36333 Measured value: 568.36270.

[0323] Example 33. Synthesis of ammonium [rac-(1R)-2-(6-aminopurin-9-yl)-1-methyl-ethoxy]methyl-(5-tetradecoxypentoxy)phosphinate A. Synthesis of 5-tetradecoxypentan-1-ol (NP-PD-152) [ka] In an oven-dried two-neck flask under an Ar atmosphere, sodium hydride (60% suspension in mineral oil, 108 mg, 2.71 mmol) was added to pentane-1,5-diol (0.28 mL, 2.7 mmol) in DMF (16 mL) at 0 °C. After vigorously stirring at 0 °C for 1 h, 1-bromotetradecane (500 g, 1.80 mmol) was added dropwise. The reaction mixture was then warmed to room temperature and vigorously stirred for 5 h before being slowly quenched with water. The reaction was then extracted three times into DCM. The organic phases were combined, dried over MgSO4, and concentrated in vacuo. The resulting crude product was then purified by column chromatography (5% to 30% EtOAc / hexanes) to give 5-tetradecoxypentan-1-ol (257 mg, 0.856 mmol, 47% yield) as a white solid.

[0324] B. Synthesis of Ammonium [rac-(1R)-2-(6-aminopurin-9-yl)-1-methyl-ethoxy]methyl-(5-tetradecoxypentoxy)phosphinate (NP-PD-154) [ka] To an oven-dried 25 mL flask equipped with a stir bar under an Ar atmosphere was added tenofovir (120 mg, 0.418 mmol, 1.00 eq) and pyridine (2.00 mL). This was followed by the addition of 5-tetradecoxypentan-1-ol (188 mg, 0.627 mmol, 1.50 eq) and 2,4,6-triisopropylbenzenesulfonyl chloride (380 mg, 1.25 mmol, 3.00 eq). The reaction was vigorously stirred under Ar at room temperature for 48 hours. The reaction was concentrated in vacuo, taken up in a saturated solution of ammonium chloride, and concentrated again in vacuo. The resulting salt was then vigorously stirred in a 4:1 solution of DCM and MeOH for approximately 1 hour. The reaction was filtered, and the resulting filtrate was collected, concentrated in vacuo, and purified first by silica gel column chromatography (100% DCM to 100% 80:20:3 DCM:MeOH:NHOH) and then by RP C18 column chromatography (10% MeOH / HO to 100% MeOH) to give a white solid (85 mg, 0.15 mmol, 35%). 1 H NMR(600MHz,CD3OD)δ 8.31(s,1H),8.20(s,1H),4.37(dd,J=14.4,3.2Hz,1H),4.23(dd,J=14.4,6.8Hz,1H),3.93-3.86(m,1H),3.79-3.68(m,3H),3.46(d d,J=12.7,10.1Hz,1H),3.37(q,J=6.4Hz,4H),1.56-1.49(m,6H),1.36-1.26(m,24H),1.16(d,J=6.2Hz,3H),0.90(t,J=7.0Hz,3H). 13 C NMR(151MHz,CD3OD)δ 157.2,153.5,151.0,144.2,119.6,76.9(d,J CP =12.8Hz), 71.9(d,J CP =15.1Hz), 66.1, 65.8(d,J CP =5.9Hz),65.0,33.1,31.9(2C),30.8(3C),30.7,30.6,30.5(2C),27.3,23.7,23.6,16.8,14.4. 31 P NMR(162MHz,CD3OD)δ 15.27.HRMS(APCI)m / z C28 H 51 O5N5P[MH] - Calculated value: 568.36333 Measured value: 568.36284.

[0325] Example 34. Synthesis of ammonium 2-heptadecoxyethoxy-[[rac-(1R)-2-(6-aminopurin-9-yl)-1-methyl-ethoxy]methyl]phosphinate A. Synthesis of 2-heptadecoxylethanol (NP-PD-151) [ka] In an oven-dried two-neck flask under an Ar atmosphere, sodium hydride (60% suspension in mineral oil, 188 mg, 4.70 mmol) was added to ethylene glycol (0.26 mL, 4.7 mmol) in DMF (16 mL) at 0 °C. After vigorously stirring at 0 °C for 1 h, 1-bromoheptadecane (1.0 g, 3.13 mmol) was added in portions. The reaction mixture was then allowed to warm to room temperature overnight. The next morning, the reaction was slowly quenched with water. The reaction was then extracted three times into DCM. The organic phases were combined, dried over MgSO4, and concentrated in vacuo. The resulting crude product was then purified by column chromatography (5% to 30% EtOAc / hexanes) to afford 2-heptadecoxylethanol (237 mg, 0.789 mmol, 25% yield) as a white solid.

[0326] B. Synthesis of Ammonium 2-Heptadecoxyethoxy-[[rac-(1R)-2-(6-aminopurin-9-yl)-1-methyl-ethoxy]methyl]phosphinate (NP-PD-157) [ka] To an oven-dried 25 mL flask equipped with a stir bar under an Ar atmosphere was added tenofovir (120 mg, 0.418 mmol, 1.00 eq) and pyridine (2.00 mL). This was followed by the addition of 2-heptadecoxylethanol (188 mg, 0.627 mmol, 1.50 eq) and 2,4,6-triisopropylbenzenesulfonyl chloride (380 mg, 1.25 mmol, 3.00 eq). The reaction was vigorously stirred under Ar at room temperature for 48 hours. The reaction was concentrated in vacuo, taken up in a saturated solution of ammonium chloride, and concentrated again in vacuo. The resulting salt was then vigorously stirred in a 4:1 solution of DCM and MeOH for approximately 1 hour. The reaction was filtered, and the resulting filtrate was collected, concentrated in vacuo, and purified first by silica gel column chromatography (100% DCM to 100% 80:20:3 DCM:MeOH:NHOH) and then by RP C18 column chromatography (10% MeOH / HO to 100% MeOH) to give a white solid (58 mg, 0.099 mmol, 24%). 1 H NMR(600MHz,CD3OD)δ 8.33(s,1H),8.20(s,1H),4.38(dd,J=14.4,3.2Hz,1H),4.23(dd,J=14.4,6.6Hz,1H),3.96-3.86(m,3H),3.73(dd,J=12.8,9.4Hz ,1H),3.53-3.44(m,3H),3.41-3.34(m,2H),1.51-1.44(m,2H),1.34-1.23(m,28H),1.15(d,J=6.3Hz,3H),0.90(t,J=7.0Hz,3H). 13 C NMR(151MHz,CD3OD)δ 157.2,153.5,151.0,144.3,119.6,76.9(d,J CP =12.7Hz), 72.3, 71.7(d,J CP =6.8Hz), 66.2, 65.1(d,J CP =5.6Hz),33.1,30.8(4C),30.7,30.6,30.5,27.2,23.7,16.8,14.4. 31 P NMR(162MHz,CD3OD)δ 15.52.HRMS(APCI)m / z C 28 H 51O5N5P[MH] - Calculated value: 568.36333 Measured value: 568.36321.

[0327] Example 35. Synthesis of ammonium octadec-17-yn-1-yl ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate A. Synthesis of Octadec-17-yn-1-ol (BI-1-019) [ka] To a stirred solution of 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (9.1 mL, 74.9 mmol, 12.2 eq) in THF (10 mL) in a flame-dried flask under an inert atmosphere, sodium acetylide (1.97 g, 14.8 mmol, 1.20 eq) was added at room temperature. Next, 2-(16-bromohexadecoxy)tetrahydropyran (2.50 g, 6.17 mmol, 1.00 eq) in concentrated THF solution was slowly added to the reaction mixture over 5 min. The reaction was then stirred overnight at room temperature. The next day, TLC (hexane / EtOAc 4:1, stained with PMA) showed mostly starting material. To drive the reaction forward, dry potassium iodide (0.250 g, 1.51 mmol, 0.245 eq) was added, and the reaction mixture was heated to 60 °C for 2 h. After this time, TLC indicated no further reaction progress. Therefore, the reaction mixture was heated to 80°C and stirred for an additional 2 hours. After this time, TLC indicated no further reaction progress. Therefore, the reaction was cooled to 0°C, additional sodium acetylide (0.296 g, 6.17 mmol, 1.00 eq) was added, and the resulting reaction mixture was allowed to warm slowly to room temperature. After 1.5 hours, TLC indicated some reaction progress. DMPU (0.37 mL, 3.09 mmol, 0.500 eq) and additional potassium iodide were added, and the resulting reaction mixture was stirred vigorously at room temperature overnight. The next day, a small aliquot of the reaction was quenched with saturated aqueous sodium bicarbonate. The resulting aqueous layer was extracted with EtOAc, and the combined organic layers were dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The crude material was1 H NMR revealed complete consumption of the starting material, formation of the desired alkyne and alkene by-product (via E2 elimination) in a 4:1 ratio. Therefore, the bulk reaction mixture was quenched with water, diluted with brine, and the resulting aqueous layer was extracted three times with EtOAc. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The crude material was purified via silica gel column chromatography (RediSep® Gold column, hexane / EtOAc, 0–9% EtOAc over 20 min) to give a mixture of the desired alkyne and alkene by-product. Next, the product mixture was dissolved in DCM (20 mL) and treated with m-CPBA (1.60 g, 9.26 mmol, 1.50 eq). The progress of the resulting reaction was monitored by TLC (hexane / EtOAc 4:1, stained with KMnO). After 5 h, TLC revealed selective consumption of the alkene. Therefore, the reaction mixture was washed with saturated sodium bicarbonate, which was back-extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The resulting residue was purified via silica gel co...

Claims

1. A compound having the structure of Formula I, or a pharma- ceutically acceptable salt thereof: 【Chemistry 1】 (In the formula, L is a structure of formula V: 【Chemistry 2】 (In the formula, U is a nucleobase; V is -OR Y or -SR Z ; R 1 , R 2 , R 3 and R 4 are independently selected from the group consisting of hydrogen, deuterium, halogen, azide, cyano, isocyano, nitrate, nitrosoxy, nitroso, nitro, formyl, carboxyl, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, azo, acyl, optionally O-substituted hydroxyl, optionally S-substituted mercapto, sulfinyl, sulfonyl, sulfonate, optionally N-substituted amino, optionally N-substituted amido, optionally N-substituted sulfamoyl, optionally Si-substituted silyl, ester, carbonate, optionally substituted carbamate, optionally N-substituted aminooxy and optionally N- and / or O-substituted hydroxylamino; R Y and R Z are independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted carbocyclyl, optionally substituted heterocarbocyclyl, optionally substituted aryl, and optionally substituted heteroaryl. having W is saturated C １ ~C ９ Alkyl chain (i.e. C １ ~C ９ alkylene); X is a substituted methylene or ethylene, -O-, -S-, -S(=O)-, or -S(O) ２ - selected from the group consisting of; Y is saturated C ２ ~C ２０ Alkyl chain (i.e. C ２ ~C ２０ alkylene); Z is -C≡CCD3, -C≡CCH2F, -C≡CCHF2, -C≡CCF3, -C≡CC(CH3)3, 【Chemistry 3】 (wherein * indicates the point of attachment to Y) Si-substituted silyl, and -SF ５ (selected from the group consisting of:

2. L is a structure of formula V': 【Chemistry 4】 (In the formula, U, R ３ and R ４ is the same as defined in claim 1) 2. The compound of claim 1 having the formula:

3. L, 【Chemistry 5】 3. The compound of claim 2 selected from the group consisting of:

4. L, 【Chemistry 6】 4. The compound of claim 3,

5. L, 【Chemistry 7】 4. The compound of claim 3,

6. W is linear C １ ~C ９ The compound according to any one of claims 1 to 5, which is an alkylene.

7. W is ethylene (-CH ２ CH ２ -) or propylene (-CH ２ CH ２ CH ２ The compound according to claim 6, wherein

8. X is -CF ２ The compound according to any one of claims 1 to 7, which is -, -O- or -S-.

9. Y is linear C ２ ~C ２０ The compound according to any one of claims 1 to 8, which is an alkylene.

10. Y is linear C ８ ~C ２０ The compound of claim 9 which is an alkylene.

11. Z, 【Chemistry 8】 (wherein * indicates the point of attachment to Y) The compound according to any one of claims 1 to 10, selected from the group consisting of:

12. Z, 【Chemistry 9】 (In the formula, ＊ indicates the point of attachment to Y) The compound according to any one of claims 1 to 10, selected from the group consisting of:

13. Z is -C≡CSi(CH ３ ) ３ The compound according to any one of claims 1 to 10,

14. L 【Chemistry 10】 and W is -CH ２ CH ２ -or-CH ２ CH ２ CH ２ - and X is -CF ２ -, -O- or -S-; Y is linear C ８ ~C ２０ The compound of claim 1 which is an alkylene.

15. 4,4-difluoro-18-(trimethylsilyl)octadec-17-yn-1-yl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 4,4,20,20,20-pentafluoroicos-18-yn-1-yl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 3-((14-(trimethylsilyl)tetradec-13-yn-1-yl)thio)propyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 3-((16,16,16-trifluorohexadec-14-yn-1-yl)thio)propyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 3-((12-phenyldodec-11-yn-1-yl)thio)propyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 3-((12-(thiophen-2-yl)dodec-11-yn-1-yl)thio)propyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 3-((13-(thiophen-2-yl)tridec-12-yn-1-yl)thio)propyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 3-((12-(perfluorophenyl)dodec-11-yn-1-yl)thio)propyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 3-((12-(pyridin-3-yl)dodec-11-yn-1-yl)thio)propyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 3-((12-cyclohexyldodec-11-yn-1-yl)thio)propyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 3-((12-(4-fluorophenyl)dodec-11-yn-1-yl)thio)propyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 3-((12-(3-fluorophenyl)dodec-11-yn-1-yl)thio)propyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 3-((12-(2-fluorophenyl)dodec-11-yn-1-yl)thio)propyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 3-((12-(2,4,6-trifluorophenyl)dodec-11-yn-1-yl)thio)propyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 3-((13-cyclopentyltridec-12-yn-1-yl)thio)propyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 3-((14-cyclopropyltetradec-13-yn-1-yl)thio)propyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 3-((10-(4-(tert-butyl)phenyl)dec-9-yn-1-yl)thio)propyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 3-((15,15-dimethylhexadec-13-yn-1-yl)thio)propyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 3-((13-cyclobutyltridec-12-yn-1-yl)thio)propyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 3-((13-(1-methylsiletan-1-yl)tridec-12-yn-1-yl)thio)propyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 3-((13-(ethyldimethylsilyl)tridec-12-yn-1-yl)thio)propyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 3-((13-(triethylsilyl)tridec-12-yn-1-yl)thio)propyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 3-((13-(triisopropylsilyl)tridec-12-yn-1-yl)thio)propyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 3-((13-(tert-butyldimethylsilyl)tridec-12-yn-1-yl)thio)propyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 3-((11-(dimethyl(phenyl)silyl)undec-10-yn-1-yl)thio)propyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 3-((11-(dimethyl(perfluorophenyl)silyl)undec-10-yn-1-yl)thio)propyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 3-((12-(dimethyl(3,3,3-trifluoropropyl)silyl)dodec-11-yn-1-yl)thio)propyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 3-((11-(cyclohexyldimethylsilyl)undec-10-yn-1-yl)thio)propyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 3-((11-(bicyclo[2.2.1]heptan-2-yldimethylsilyl)undec-10-yn-1-yl)thio)propyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 3-((12-(isobutyldimethylsilyl)dodec-11-yn-1-yl)thio)propyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 3-((15-(pentafluoro-lambda6-sulfanyl)pentadec-14-yn-1-yl)thio)propyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 3-((11-(4-(pentafluoro-lambda6-sulfanyl)phenyl)undec-10-yn-1-yl)thio)propyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 3-((11-(4-(trifluoromethyl)phenyl)undec-10-yn-1-yl)thio)propyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 3-((10-(4-(trimethylsilyl)phenyl)dec-9-yn-1-yl)thio)propyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 3-((15-(trimethylsilyl)pentadec-14-yn-1-yl)oxy)propyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 3-((14-(trimethylsilyl)tetradec-13-yn-1-yl)oxy)propyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 3-((16,16,16-trifluorohexadec-14-yn-1-yl)oxy)propyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 3-((12-phenyldodec-11-yn-1-yl)oxy)propyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 3-((12-(thiophen-2-yl)dodec-11-yn-1-yl)oxy)propyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 3-((13-(thiophen-2-yl)tridec-12-yn-1-yl)oxy)propyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 3-((12-(pyridin-3-yl)dodec-11-yn-1-yl)oxy)propyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 3-((12-(perfluorophenyl)dodec-11-yn-1-yl)oxy)propyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 3-((12-(4-fluorophenyl)dodec-11-yn-1-yl)oxy)propyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 3-((12-(3-fluorophenyl)dodec-11-yn-1-yl)oxy)propyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 3-((12-(2-fluorophenyl)dodec-11-yn-1-yl)oxy)propyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 3-((12-(2,4,6-trifluorophenyl)dodec-11-yn-1-yl)oxy)propyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 3-((10-(4-(tert-butyl)phenyl)dec-9-yn-1-yl)oxy)propyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 3-((15,15-dimethylhexadec-13-yn-1-yl)oxy)propyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 3-((14-cyclopropyltetradec-13-yn-1-yl)oxy)propyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 3-((12-cyclohexyldodec-11-yn-1-yl)oxy)propyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 3-((13-cyclopentyltridec-12-yn-1-yl)oxy)propyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 3-((13-cyclobutyltridec-12-yn-1-yl)oxy)propyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 3-((13-(1-methylsiletan-1-yl)tridec-12-yn-1-yl)oxy)propyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 3-((13-(ethyldimethylsilyl)tridec-12-yn-1-yl)oxy)propyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 3-((13-(triethylsilyl)tridec-12-yn-1-yl)oxy)propyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 3-((13-(triisopropylsilyl)tridec-12-yn-1-yl)oxy)propyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 3-((13-(tert-butyldimethylsilyl)tridec-12-yn-1-yl)oxy)propyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 3-((11-(dimethyl(phenyl)silyl)undec-10-yn-1-yl)oxy)propyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 3-((11-(dimethyl(perfluorophenyl)silyl)undec-10-yn-1-yl)oxy)propyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 3-((12-(dimethyl(3,3,3-trifluoropropyl)silyl)dodec-11-yn-1-yl)oxy)propyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 3-((11-(cyclohexyldimethylsilyl)undec-10-yn-1-yl)oxy)propyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 3-((11-(bicyclo[2.2.1]heptan-2-yldimethylsilyl)undec-10-yn-1-yl)oxy)propyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 3-((12-(isobutyldimethylsilyl)dodec-11-yn-1-yl)oxy)propyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 3-((15-(pentafluoro-lambda6-sulfanyl)pentadec-14-yn-1-yl)oxy)propyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 3-((11-(4-(pentafluoro-lambda6-sulfanyl)phenyl)undec-10-yn-1-yl)oxy)propyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 3-((11-(4-(trifluoromethyl)phenyl)undec-10-yn-1-yl)oxy)propyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 3-((10-(4-(trimethylsilyl)phenyl)dec-9-yn-1-yl)oxy)propyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 2-((15-(trimethylsilyl)pentadec-14-yn-1-yl)thio)ethyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 2-((16-(trimethylsilyl)hexadec-15-yn-1-yl)thio)ethyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 2-((17,17,17-trifluoroheptadec-15-yn-1-yl)thio)ethyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 2-((13-phenyltridec-12-yn-1-yl)thio)ethyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 2-((13-(thiophen-2-yl)tridec-12-yn-1-yl)thio)ethyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 2-((14-(thiophen-2-yl)tetradec-13-yn-1-yl)thio)ethyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 2-((13-(perfluorophenyl)tridec-12-yn-1-yl)thio)ethyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 2-((13-(pyridin-3-yl)tridec-12-yn-1-yl)thio)ethyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 2-((13-cyclohexyltridec-12-yn-1-yl)thio)ethyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 2-((13-(4-fluorophenyl)tridec-12-yn-1-yl)thio)ethyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 2-((13-(3-fluorophenyl)tridec-12-yn-1-yl)thio)ethyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 2-((13-(2-fluorophenyl)tridec-12-yn-1-yl)thio)ethyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 2-((13-(2,4,6-trifluorophenyl)tridec-12-yn-1-yl)thio)ethyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 2-((14-cyclopentyltetradec-13-yn-1-yl)thio)ethyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 2-((15-cyclopropylpentadec-14-yn-1-yl)thio)ethyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 2-((11-(4-(tert-butyl)phenyl)undec-10-yn-1-yl)thio)ethyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 2-((16,16-dimethylheptadec-14-yn-1-yl)thio)ethyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 2-((14-cyclobutyltetradec-13-yn-1-yl)thio)ethyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 2-((14-(1-methylsiletan-1-yl)tetradec-13-yn-1-yl)thio)ethyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 2-((14-(ethyldimethylsilyl)tetradec-13-yn-1-yl)thio)ethyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 2-((14-(triethylsilyl)tetradec-13-yn-1-yl)thio)ethyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 2-((14-(triisopropylsilyl)tetradec-13-yn-1-yl)thio)ethyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 2-((14-(tert-butyldimethylsilyl)tetradec-13-yn-1-yl)thio)ethyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 2-((12-(dimethyl(phenyl)silyl)dodec-11-yn-1-yl)thio)ethyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 2-((12-(dimethyl(perfluorophenyl)silyl)dodec-11-yn-1-yl)thio)ethyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 2-((13-(dimethyl(3,3,3-trifluoropropyl)silyl)tridec-12-yn-1-yl)thio)ethyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 2-((12-(cyclohexyldimethylsilyl)dodec-11-yn-1-yl)thio)ethyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 2-((12-(bicyclo[2.2.1]heptan-2-yldimethylsilyl)dodec-11-yn-1-yl)thio)ethyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 2-((13-(isobutyldimethylsilyl)tridec-12-yn-1-yl)thio)ethyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 2-((16-(pentafluoro-lambda6-sulfanyl)hexadec-15-yn-1-yl)thio)ethyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 2-((12-(4-(pentafluoro-lambda6-sulfanyl)phenyl)dodec-11-yn-1-yl)thio)ethyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 2-((12-(4-(trifluoromethyl)phenyl)dodec-11-yn-1-yl)thio)ethyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 2-((11-(4-(trimethylsilyl)phenyl)undec-10-yn-1-yl)thio)ethyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 2-((15-(trimethylsilyl)pentadec-14-yn-1-yl)oxy)ethyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 2-((16-(trimethylsilyl)hexadec-15-yn-1-yl)oxy)ethyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 2-((17,17,17-trifluoroheptadec-15-yn-1-yl)oxy)ethyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 2-((13-phenyltridec-12-yn-1-yl)oxy)ethyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 2-((13-(thiophen-2-yl)tridec-12-yn-1-yl)oxy)ethyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 2-((14-(thiophen-2-yl)tetradec-13-yn-1-yl)oxy)ethyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 2-((13-(perfluorophenyl)tridec-12-yn-1-yl)oxy)ethyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 2-((13-(pyridin-3-yl)tridec-12-yn-1-yl)oxy)ethyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 2-((13-cyclohexyltridec-12-yn-1-yl)oxy)ethyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 2-((13-(4-fluorophenyl)tridec-12-yn-1-yl)oxy)ethyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 2-((13-(3-fluorophenyl)tridec-12-yn-1-yl)oxy)ethyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 2-((13-(2-fluorophenyl)tridec-12-yn-1-yl)oxy)ethyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 2-((13-(2,4,6-trifluorophenyl)tridec-12-yn-1-yl)oxy)ethyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 2-((14-cyclopentyltetradec-13-yn-1-yl)oxy)ethyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 2-((15-cyclopropylpentadec-14-yn-1-yl)oxy)ethyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 2-((11-(4-(tert-butyl)phenyl)undec-10-yn-1-yl)oxy)ethyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 2-((16,16-dimethylheptadec-14-yn-1-yl)oxy)ethyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 2-((14-cyclobutyltetradec-13-yn-1-yl)oxy)ethyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 2-((14-(1-methylsiletan-1-yl)tetradec-13-yn-1-yl)oxy)ethyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 2-((14-(ethyldimethylsilyl)tetradec-13-yn-1-yl)oxy)ethyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 2-((14-(triethylsilyl)tetradec-13-yn-1-yl)oxy)ethyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 2-((14-(triisopropylsilyl)tetradec-13-yn-1-yl)oxy)ethyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 2-((14-(tert-butyldimethylsilyl)tetradec-13-yn-1-yl)oxy)ethyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 2-((12-(dimethyl(phenyl)silyl)dodec-11-yn-1-yl)oxy)ethyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 2-((12-(dimethyl(perfluorophenyl)silyl)dodec-11-yn-1-yl)oxy)ethyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 2-((13-(dimethyl(3,3,3-trifluoropropyl)silyl)tridec-12-yn-1-yl)oxy)ethyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 2-((12-(cyclohexyldimethylsilyl)dodec-11-yn-1-yl)oxy)ethyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 2-((12-(bicyclo[2.2.1]heptan-2-yldimethylsilyl)dodec-11-yn-1-yl)oxy)ethyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 2-((13-(isobutyldimethylsilyl)tridec-12-yn-1-yl)oxy)ethyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 2-((16-(pentafluoro-lambda6-sulfanyl)hexadec-15-yn-1-yl)oxy)ethyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 2-((12-(4-(pentafluoro-lambda6-sulfanyl)phenyl)dodec-11-yn-1-yl)oxy)ethyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 2-((12-(4-(trifluoromethyl)phenyl)dodec-11-yn-1-yl)oxy)ethyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 2-((11-(4-(trimethylsilyl)phenyl)undec-10-yn-1-yl)oxy)ethyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 2-((15-(trimethylsilyl)pentadec-14-yn-1-yl)oxy)ethyl hydrogen((2-(2-amino-6-oxo-1,6-dihydro-9H-purin-9-yl)ethoxy)methyl)phosphonate, 2-((15-(trimethylsilyl)pentadec-14-yn-1-yl)thio)ethyl hydrogen ((2-(2-amino-6-oxo-1,6-dihydro-9H-purin-9-yl)ethoxy)methyl)phosphonate, 2-((16-(trimethylsilyl)hexadec-15-yn-1-yl)oxy)ethyl hydrogen((2-(2-amino-6-oxo-1,6-dihydro-9H-purin-9-yl)ethoxy)methyl)phosphonate, 2-((16-(trimethylsilyl)hexadec-15-yn-1-yl)thio)ethyl hydrogen ((2-(2-amino-6-oxo-1,6-dihydro-9H-purin-9-yl)ethoxy)methyl)phosphonate, 3-((14-(trimethylsilyl)tetradec-13-yn-1-yl)thio)propyl hydrogen ((2-(2-amino-6-oxo-1,6-dihydro-9H-purin-9-yl)ethoxy)methyl)phosphonate, 3-((14-(trimethylsilyl)tetradec-13-yn-1-yl)oxy)propyl hydrogen((2-(2-amino-6-oxo-1,6-dihydro-9H-purin-9-yl)ethoxy)methyl)phosphonate, 4,4-difluoro-18-(trimethylsilyl)octadecyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 3-((14-(trimethylsilyl)tetradecyl)thio)propyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 3-((12-(perfluorophenyl)dodecyl)thio)propyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 3-((12-(4-fluorophenyl)dodecyl)thio)propyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 3-((12-(3-fluorophenyl)dodecyl)thio)propyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 3-((12-(2-fluorophenyl)dodecyl)thio)propyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 3-((12-(2,4,6-trifluorophenyl)dodecyl)thio)propyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 3-((10-(4-(tert-butyl)phenyl)decyl)thio)propyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 3-((13-(1-methylsiletan-1-yl)tridecyl)thio)propyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 3-((13-(ethyldimethylsilyl)tridecyl)thio)propyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 3-((13-(triethylsilyl)tridecyl)thio)propyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 3-((13-(triisopropylsilyl)tridecyl)thio)propyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 3-((13-(tert-butyldimethylsilyl)tridecyl)thio)propyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 3-((11-(dimethyl(phenyl)silyl)undecyl)thio)propyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 3-((11-(dimethyl(perfluorophenyl)silyl)undecyl)thio)propyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 3-((12-(dimethyl(3,3,3-trifluoropropyl)silyl)dodecyl)thio)propyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 3-((11-(cyclohexyldimethylsilyl)undecyl)thio)propyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 3-((11-(bicyclo[2.2.1]heptan-2-yldimethylsilyl)undecyl)thio)propyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 3-((12-(isobutyldimethylsilyl)dodecyl)thio)propyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 3-((15-(pentafluoro-lambda 6-sulfanyl)pentadecyl)thio)propyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 3-((9-(4-((pentafluoro-lambda6-sulfanyl)ethynyl)phenyl)nonyl)thio)propyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 3-((11-(4-(pentafluoro-lambda6-sulfanyl)phenyl)undecyl)thio)propyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 3-((11-(4-(trifluoromethyl)phenyl)undecyl)thio)propyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 3-((10-(4-(trimethylsilyl)phenyl)decyl)thio)propyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 3-((10-(4-ethynylphenyl)decyl)thio)propyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 3-((8-(4-((trimethylsilyl)ethynyl)phenyl)octyl)thio)propyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 3-((8-(4-(3,3-dimethylbut-1-yn-1-yl)phenyl)octyl)thio)propyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 3-((12-cyclohexyldodecyl)thio)propyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 3-((14-(trimethylsilyl)tetradecyl)oxy)propyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 3-((12-(perfluorophenyl)dodecyl)oxy)propyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 3-((12-(4-fluorophenyl)dodecyl)oxy)propyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 3-((12-(3-fluorophenyl)dodecyl)oxy)propyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 3-((12-(2-fluorophenyl)dodecyl)oxy)propyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 3-((12-(2,4,6-trifluorophenyl)dodecyl)oxy)propyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 3-((10-(4-(tert-butyl)phenyl)decyl)oxy)propyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 3-((13-(1-methylsiletan-1-yl)tridecyl)oxy)propyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 3-((13-(ethyldimethylsilyl)tridecyl)oxy)propyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 3-((13-(triethylsilyl)tridecyl)oxy)propyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 3-((13-(triisopropylsilyl)tridecyl)oxy)propyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 3-((13-(tert-butyldimethylsilyl)tridecyl)oxy)propyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 3-((11-(dimethyl(phenyl)silyl)undecyl)oxy)propyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 3-((11-(dimethyl(perfluorophenyl)silyl)undecyl)oxy)propyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 3-((12-(dimethyl(3,3,3-trifluoropropyl)silyl)dodecyl)oxy)propyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 3-((11-(cyclohexyldimethylsilyl)undecyl)oxy)propyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 3-((11-(bicyclo[2.2.1]heptan-2-yldimethylsilyl)undecyl)oxy)propyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 3-((12-(isobutyldimethylsilyl)dodecyl)oxy)propyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 3-((15-(pentafluoro-lambda6-sulfanyl)pentadecyl)oxy)propyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 3-((9-(4-((pentafluoro-lambda6-sulfanyl)ethynyl)phenyl)nonyl)oxy)propyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 3-((11-(4-(pentafluoro-lambda6-sulfanyl)phenyl)undecyl)oxy)propyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 3-((11-(4-(trifluoromethyl)phenyl)undecyl)oxy)propyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 3-((10-(4-(trimethylsilyl)phenyl)decyl)oxy)propyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 3-((10-(4-ethynylphenyl)decyl)oxy)propyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 3-((8-(4-((trimethylsilyl)ethynyl)phenyl)octyl)oxy)propyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 3-((8-(4-(3,3-dimethylbut-1-yn-1-yl)phenyl)octyl)oxy)propyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 3-((12-cyclohexyldodecyl)oxy)propyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 2-((15-(trimethylsilyl)pentadecyl)thio)ethyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 2-((13-(perfluorophenyl)tridecyl)thio)ethyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 2-((13-(4-fluorophenyl)tridecyl)thio)ethyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 2-((13-(3-fluorophenyl)tridecyl)thio)ethyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 2-((13-(2-fluorophenyl)tridecyl)thio)ethyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 2-((13-(2,4,6-trifluorophenyl)tridecyl)thio)ethyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 2-((11-(4-(tert-butyl)phenyl)undecyl)thio)ethyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 2-((14-(1-methylsiletan-1-yl)tetradecyl)thio)ethyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 2-((14-(ethyldimethylsilyl)tetradecyl)thio)ethyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 2-((14-(triethylsilyl)tetradecyl)thio)ethyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 2-((14-(triisopropylsilyl)tetradecyl)thio)ethyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 2-((14-(tert-butyldimethylsilyl)tetradecyl)thio)ethyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 2-((12-(dimethyl(phenyl)silyl)dodecyl)thio)ethyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 2-((12-(dimethyl(perfluorophenyl)silyl)dodecyl)thio)ethyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 2-((13-(dimethyl(3,3,3-trifluoropropyl)silyl)tridecyl)thio)ethyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 2-((12-(cyclohexyldimethylsilyl)dodecyl)thio)ethyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 2-((12-(bicyclo[2.2.1]heptan-2-yldimethylsilyl)dodecyl)thio)ethyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 2-((13-(isobutyldimethylsilyl)tridecyl)thio)ethyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 2-((16-(pentafluoro-lambda6-sulfanyl)hexadecyl)thio)ethyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 2-((10-(4-((pentafluoro-lambda6-sulfanyl)ethynyl)phenyl)decyl)thio)ethyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 2-((12-(4-(pentafluoro-lambda6-sulfanyl)phenyl)dodecyl)thio)ethyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 2-((12-(4-(trifluoromethyl)phenyl)dodecyl)thio)ethyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 2-((11-(4-(trimethylsilyl)phenyl)undecyl)thio)ethyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 2-((11-(4-ethynylphenyl)undecyl)thio)ethyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 2-((9-(4-((trimethylsilyl)ethynyl)phenyl)nonyl)thio)ethyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 2-((9-(4-(3,3-dimethylbut-1-yn-1-yl)phenyl)nonyl)thio)ethyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 2-((13-cyclohexyltridecyl)thio)ethyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 2-((15-(trimethylsilyl)pentadecyl)oxy)ethyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 2-((13-(perfluorophenyl)tridecyl)oxy)ethyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 2-((13-(4-fluorophenyl)tridecyl)oxy)ethyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 2-((13-(3-fluorophenyl)tridecyl)oxy)ethyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 2-((13-(2-fluorophenyl)tridecyl)oxy)ethyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 2-((13-(2,4,6-trifluorophenyl)tridecyl)oxy)ethyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 2-((11-(4-(tert-butyl)phenyl)undecyl)oxy)ethyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 2-((14-(1-methylsiletan-1-yl)tetradecyl)oxy)ethyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 2-((14-(ethyldimethylsilyl)tetradecyl)oxy)ethyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 2-((14-(triethylsilyl)tetradecyl)oxy)ethyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 2-((14-(triisopropylsilyl)tetradecyl)oxy)ethyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 2-((14-(tert-butyldimethylsilyl)tetradecyl)oxy)ethyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 2-((12-(dimethyl(phenyl)silyl)dodecyl)oxy)ethyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 2-((12-(dimethyl(perfluorophenyl)silyl)dodecyl)oxy)ethyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 2-((13-(dimethyl(3,3,3-trifluoropropyl)silyl)tridecyl)oxy)ethyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 2-((12-(cyclohexyldimethylsilyl)dodecyl)oxy)ethyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 2-((12-(bicyclo[2.2.1]heptan-2-yldimethylsilyl)dodecyl)oxy)ethyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 2-((13-(isobutyldimethylsilyl)tridecyl)oxy)ethyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 2-((16-(pentafluoro-lambda6-sulfanyl)hexadecyl)oxy)ethyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 2-((10-(4-((pentafluoro-lambda6-sulfanyl)ethynyl)phenyl)decyl)oxy)ethyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 2-((12-(4-(pentafluoro-lambda6-sulfanyl)phenyl)dodecyl)oxy)ethyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 2-((12-(4-(trifluoromethyl)phenyl)dodecyl)oxy)ethyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 2-((11-(4-(trimethylsilyl)phenyl)undecyl)oxy)ethyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 2-((11-(4-ethynylphenyl)undecyl)oxy)ethyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 2-((9-(4-((trimethylsilyl)ethynyl)phenyl)nonyl)oxy)ethyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 2-((9-(4-(3,3-dimethylbut-1-yn-1-yl)phenyl)nonyl)oxy)ethyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 2-((13-cyclohexyltridecyl)oxy)ethyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, and 2. The compound of claim 1 selected from the group consisting of pharma- ceutically acceptable salts thereof.

16. 3-((14-(trimethylsilyl)tetradec-13-yn-1-yl)thio)propyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 3-((14-(trimethylsilyl)tetradec-13-yn-1-yl)oxy)propyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 2-((15-(trimethylsilyl)pentadec-14-yn-1-yl)thio)ethyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 2-((16-(trimethylsilyl)hexadec-15-yn-1-yl)thio)ethyl hydrogen ((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 2-((15-(trimethylsilyl)pentadec-14-yn-1-yl)oxy)ethyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 2-((16-(trimethylsilyl)hexadec-15-yn-1-yl)oxy)ethyl hydrogen((((R)-1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphonate, 2-((15-(trimethylsilyl)pentadec-14-yn-1-yl)oxy)ethyl hydrogen((2-(2-amino-6-oxo-1,6-dihydro-9H-purin-9-yl)ethoxy)methyl)phosphonate, 2-((15-(trimethylsilyl)pentadec-14-yn-1-yl)thio)ethyl hydrogen ((2-(2-amino-6-oxo-1,6-dihydro-9H-purin-9-yl)ethoxy)methyl)phosphonate, 2-((16-(trimethylsilyl)hexadec-15-yn-1-yl)oxy)ethyl hydrogen((2-(2-amino-6-oxo-1,6-dihydro-9H-purin-9-yl)ethoxy)methyl)phosphonate, 2-((16-(trimethylsilyl)hexadec-15-yn-1-yl)thio)ethyl hydrogen ((2-(2-amino-6-oxo-1,6-dihydro-9H-purin-9-yl)ethoxy)methyl)phosphonate, 3-((14-(trimethylsilyl)tetradec-13-yn-1-yl)thio)propyl hydrogen ((2-(2-amino-6-oxo-1,6-dihydro-9H-purin-9-yl)ethoxy)methyl)phosphonate, 3-((14-(trimethylsilyl)tetradec-13-yn-1-yl)oxy)propyl hydrogen((2-(2-amino-6-oxo-1,6-dihydro-9H-purin-9-yl)ethoxy)methyl)phosphonate, and 16. The compound of claim 15 selected from the group consisting of pharma- ceutically acceptable salts thereof.

17. A pharmaceutical formulation comprising a compound according to any one of claims 1 to 16 and a pharma- ceutically acceptable carrier.

18. 18. The pharmaceutical formulation of claim 17 in the form of a tablet, capsule, pill, gel, cream, granule, solution, suspension, emulsion or nanoparticle formulation.

19. 19. The pharmaceutical formulation of claim 17 or 18, which is an oral formulation.

20. 20. The pharmaceutical formulation of any one of claims 17 to 19 for treating a viral infection or a virus-associated cancer in a subject in need thereof.

21. 21. The pharmaceutical formulation of claim 20, wherein the pharmaceutical formulation is administered orally.

22. 22. The pharmaceutical formulation of claim 20 or 21, wherein the viral infection is an infection caused by human immunodeficiency virus (HIV), hepatitis virus, herpes virus, flavivirus, poxvirus, paramyxovirus, influenza, coronavirus, smallpox virus, human papillomavirus (HPV) or filovirus.

23. 23. The pharmaceutical formulation of claim 22, wherein the viral infection is an HIV infection.

24. 22. The pharmaceutical formulation of claim 20 or 21, wherein the virus-associated cancer is an HPV-associated cancer.

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