Substituted adefovir compounds, compositions thereof, and methods of treatment therewith

Abstract

Provided herein are Adefovir Compounds having the following structure: (I), wherein R1, R2, R3, and Ar are as defined herein, compositions comprising Adefovir Compounds, and methods for treating or preventing EBV-associated disease or condition.

Description

New International Patent Application January 7, 2026 Tahrget Therapeutics Ltd. 107653PCSUBSTITUTED ADEFOVIR COMPOUNDS, COMPOSITIONS THEREOF, AND METHODS OF TREATMENT THEREWITHFIELD

[0001] Provided herein are certain substituted adefovir compounds, compositions comprising of such compounds, methods for treating or preventing EBV-associated conditions comprising administering such substituted adefovir compounds to a subject in need thereof, and methods for preparing such compounds.BACKGROUND

[0002] Epstein-Barr virus (EBV), also known as human herpesvirus 4 (HHV-4), is a gammaherpesvirus and the first human tumor virus identified. It was initially discovered in Burkitt lymphoma (BL) in 1964 and later linked to various lymphomas, including Hodgkin lymphoma (HL), non-HL in post-transplant and HIV-infected patients, T-cell lymphoma, and natural killer (NK) / T-cell lymphoma (Gewurz et al., Fields Virology, 11, 324-88 (2021)). EBV is also associated with epithelial cancers such as nasopharyngeal carcinoma (NPC) and certain gastric cancers, as well as non-malignant diseases like infectious mononucleosis (IM), oral hairy leukoplakia, multiple sclerosis (MS) and systemic lupus erythematosus (SLE) (Damania et al., Cell, 185, 3652-670 (2022)).

[0003] EBV employs sophisticated mechanisms to evade innate and adaptive immune responses, suppress apoptosis and differentiation, and promote cell proliferation and angiogenesis. The virus can either replicate or establish latency, with cycles of latency and reactivation heightening the risk of oncogenesis. For instance, EBV infects germinal center B cells during class switching, contributing to BL, or rescues mutant B cells with non-functional B-cell receptors (BCRs), leading to HL. Highly replicative EBV variants facilitate infection of nasopharyngeal epithelial cells, promoting mutations that sustain viral latency. EBV also modulates host genome methylation, influencing oncogenic pathways in gastric cancer and NPC. The virus's non-coding RNAs further regulate cell proliferation. These diverse mechanisms result in a spectrum of outcomes, from acute IM to autoimmune conditions like MS and SLE (Damania et al., Cell, 185, 3652-670 (2022)).

[0004] Recent studies have highlighted EBV’s role in the etiology of MS, revealing that the virus initiates autoreactive immune responses through high-affinity molecular mimicry between EBV nuclear antigen 1 (EBNA1) and the central nervous system (CNS) protein GlialCAM. This triggers immune dysregulation and CNS demyelination (Lanz et al., Nature, 603, 321-27 (2022)). MS, a chronic inflammatory and demyelinating disease, has long had an uncertain cause. A longitudinal study of over 10 million U.S. military personnel demonstrated a dramatic 32-fold increased risk of MS following EBV infection, with no similar association for other viruses like cytomegalovirus. Neurodegeneration biomarkers, such as neurofilament light chain, begin to rise only after EBV seroconversion, establishing a strong temporal link between EBV infection and MS pathogenesis (Bjornevik et al., Science, 375, 296-301 (2022)). These discoveries pave the way for innovative strategies, such as vaccines or antivirals targeting EBV, to prevent or mitigate MS.

[0005] Recent studies also highlighted EBV’s role in the etiology of SLE. A high frequency of Epstein-Barr virus reactivation is a risk factor for SLE. Neoself-reactive CD4+T cells were significantly expanded in SLE patients and neoself-reactive lupus T cells were activated by Epstein-Barr-virus-reactivated cells through downregulation of the invariant chain (Mori et al., Cell, 187, 6071-608 (2024)).

[0006] Current EBV treatments primarily use nucleoside and nucleotide analogues, such as acyclovir and ganciclovir, which inhibit viral DNA replication. However, these agents are limited in clinical efficacy due to their low potency on the viral DNA polymerase and their inability to achieve effective concentrations in EBV-infected tissues. Furthermore, diseases such as IM, NPC, and post-transplant lymphoproliferative disorders (PTLD) involve immune-mediated mechanisms, reducing the effectiveness of these antivirals. Corticosteroids are sometimes employed for immunopathological symptoms, but their long-term efficacy is inconsistent and can impair immune function (Andrei et al., Molecules, 24, 997 (2019)).Emerging therapies, such as tabelecleucel (tab-cel®), an allogeneic EBV-specific T-cell therapy targeting latent EBV-infected cells, show promise in conditions like rituximab-refractory EBV + PTLD. However, challenges like high costs, side effects (e.g., tumor flare reactions, graft-versus-host disease), and limited applicability to broader EBV-associated diseases highlight the need for more universally effective treatments.

[0007] Recent research has identified tenofovir prodrugs, such as tenofovir alafenamide (TAF), as potent inhibitors of EBV lytic DNA replication. These drugs target viral DNApolymerase through the active metabolite tenofovir-diphosphate, which competes with dATP, specifically disrupting late-stage viral DNA replication and gene transcription. TAF demonstrates high specificity for lytic replication with minimal cytotoxicity, retaining inhibitory effects after removal (Drosu et al., Proc. Natl. Acad. Set. U.S.A., 117, 12368-12374 (2020)).

[0008] There remains a significant need for safe and effective methods of treating, preventing and managing EBV-associated diseases, particularly for MS and SLE that are refractory to standard treatments, such as corticosteroids, infusion therapy and certain other medications, while reducing or avoiding the toxicities and / or side effects associated with conventional therapies.

[0009] Citation or identification of any reference in this section of this application is not to be construed as an admission that the reference is prior art to the present application.SUMMARY OF THE INVENTION

[0010] The invention provides herein are compounds having the following formula (I):(I),or a pharmaceutically acceptable salt, hydrate, solvate, tautomer, isotopolog, or stereoisomer thereof, wherein:Ri and R2 are each independently H or C1-6 alkyl, or Ri and R2 together with the single carbon to which they are bound form a C3-7 cycloalkyl;R3 is independently hydrogen, an optionally substituted C1-8 alkyl, an optionally substituted C2-8 alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkyl(Ci-C4 alkyl)-, an optionally substituted cycloalkenyl, an optionally substituted cycloalkenyl(Ci-C4 alkyl)-, an optionally substituted aryl, an optionally substituted aryl(Ci-C4 alkyl)-, an optionally substituted heteroaryl, an optionally substituted heteroaryl (Ci-C4 alkyl)-, an optionally substituted heterocyclyl, or an optionally substituted heterocyclyl(Ci-C4 alkyl)-; andAr is independently an optionally substituted phenyl, an optionally substituted naphthyl, or an optionally substituted hydronaphthyl.

[0011] In some embodiments, Ar is substituted with one or more substituents independently selected from F, Cl, Br, CH3, CH2CH3, n-propyl, isopropyl, n-butyl, secbutyl, isobutyl, t-butyl, n-pentyl, isopentyl, CH2F, CHF2, CF3, CH2CH2F, CH2CHF2, CH2CF3, CH(CH3)CF3, CH2CH2CF3, OH, 0CH3, OCH2CH3, O-isopropyl, O-n-propyl, O-n-butyl, O-isobutyl, O-t-butyl, OCF3, O-cyclopropyl, O-cyclobutyl, OCH2-cyclopropyl, OCH2.cyclobutyl, CONH2, CONH(CH3), CON(CH3)2, SO2CH3, SO2CH2CH3, SO2-isopropyl, cyclopropyl, cyclobutyl, CH2-cyclopropyl, CH2-cyclobutyl.

[0012] In some embodiments, the compound is of formula (II):

[0013] In some embodiments, Ri and R2 are each independently H or methyl, or Ri and R2 together with the single carbon to which they are bound form a C3 cycloalkyl; R3 is independently methyl, ethyl, propyl, isopropyl or cyclopropyl; and Ar is independently phenyl, p-chlorophenyl, naphthyl, or 5,6,7,8-tetrahydro-naphthyl, wherein the phenyl is optionally substituted with one or more substituents independently selected from F, Cl, CH3, CN, or CONH2.

[0014] In some embodiments, the compound is of formula (III):(HI),wherein R3 is methyl, ethyl, propyl, isopropyl or cyclopropyl.

[0015] In some embodiments, the compound is of formula (IV):wherein R3 is methyl, ethyl, propyl, isopropyl or cyclopropyl.

[0016] In some embodiments, the compound is of formula (V):(V),wherein R3 is methyl, ethyl, propyl, isopropyl or cyclopropyl, and Ar is p- chlorophenyl, naphthyl, or 5,6,7,8-tetrahydro-naphthyl.

[0017] In some embodiments, the compound is of formula (VI):(VI),wherein R3 is methyl, ethyl, propyl, isopropyl or cyclopropyl, and Ar is p- chlorophenyl, naphthyl, or 5,6,7,8-tetrahydro-naphthyl.

[0018] In some embodiments, the compound is selected from the group consisting of

[0019] In some embodiments, the compound is selected from the group consisting of

[0020] In some embodiments, the compound is selected from the group consisting of

[0021] In some embodiments, the compound is selected from the group consisting of

[0022] The invention further provides a pharmaceutical composition comprising acompound of the invention or a pharmaceutically acceptable salt, hydrate, solvate, tautomer, isotopologue, or stereoisomer thereof, and a pharmaceutically acceptable carrier, excipient or vehicle.

[0023] The invention further provides a method for the treatment or prevention of Epstein-Barr- Virus (EBV)-associated disease or condition, comprising administering to a subject in need thereof a compound or a pharmaceutical composition of the invention.

[0024] In some embodiments, the EBV associated disease or condition is infectious mononucleosis, nasopharyngeal carcinoma, Burkitt’s lymphoma, Hodgkin’s lymphoma, gastric carcinoma, systemic lupus erythematosus (SLE), multiple sclerosis (MS), Post-Transplant Lymphoproliferative Disorders (PTLD) and the suppression of EBV reactivation in immunocompromised individuals such as transplant patients.

[0025] The invention further provides a compound or a pharmaceutical composition of the invention for use in a method for the treatment or prevention of Epstein-Barr- Virus (EBV)-associated disease or condition, wherein the method comprises administering to a subject in need thereof the compound or the pharmaceutical composition.

[0026] In some embodiments, the EBV-associated disease or condition is infectious mononucleosis, nasopharyngeal carcinoma, Burkitt’s lymphoma, Hodgkin’s lymphoma, gastric carcinoma, systemic lupus erythematosus (SLE), multiple sclerosis (MS) and Post-Transplant Lymphoproliferative Disorders (PTLD) and the suppression of EBV reactivation in immunocompromised individuals such as transplant patients.

[0027] The invention further provides a method for preparing a compound of formula (I):"(I),wherein the method comprises contacting 2-(6-aminopurin-9-yl)ethoxymethylphosphonic acid NH2R,7Sr°-R3(Adefovir) with Ar-OH and ° , in the presence of a base, in a solvent, under conditions suitable to provide a compound of formula (I), wherein:Ri and R2 are each independently H or methyl, or Ri and R2 together with the single carbon to which they are bound form a C3 cycloalkyl;R3 is independently methyl, ethyl, propyl, isopropyl or cyclopropyl; andAr is independently phenyl, p-chlorophenyl, naphthyl, or 5,6,7,8-tetrahydro-naphthyl, wherein the phenyl is optionally substituted with one or more substituents independently selected from F, Cl, CH3, CN, or CONH2.

[0028] The present embodiments can be understood more fully by reference to the detailed description and examples, which are intended to exemplify non-limiting embodiments.DETAILED DESCRIPTION OF THE INVENTION DEFINITIONS

[0029] As used herein, the terms “comprising” and “including” can be used interchangeably. The terms “comprising” and “including” are to be interpreted as specifying the presence of the stated features or components as referred to, but does not preclude the presence or addition of one or more features, or components, or groups thereof. Additionally, the terms “comprising” and “including” are intended to include examples encompassed by the term “consisting of’. Consequently, the term “consisting of’ can be used in place of the terms “comprising” and “including” to provide for more specific embodiments of the invention.

[0030] The term “consisting of’ means that a subject-matter has at least 90%, 95%, 97%, 98% or 99% of the stated features or components of which it consists. In one embodiment the term “consisting of’ excludes from the scope of any succeeding recitation any other features or components, excepting those that are not essential to the technical effect to be achieved.

[0031] As used herein, the term “or” is to be interpreted as an inclusive “or” meaning any one or any combination. Therefore, “A, B or C” means any of the following: “A; B; C; A and B; A and C; B and C; A, B and C”. An exception to this definition will occur only when a combination of elements, functions, steps or acts are in some way inherently mutually exclusive.

[0032] As used herein and unless otherwise specified, an “alkyl” group is a saturated, partially saturated, or unsaturated straight chain or branched non-cyclic hydrocarbon having from 1 to 10 carbon atoms, typically from 1 to 8 carbons or, in some embodiments, from 1 to 6, 1 to 4, or 2 to 6 or carbon atoms. Representative alkyl groups include -methyl, -ethyl, -n-propyl, -n-butyl, -n-pentyl and -n-hexyl; while saturated branched alkyls include -isopropyl, -sec-butyl,-isobutyl, -tert-butyl, -isopentyl, -neopentyl, tert-pentyl, 2-methylpentyl, 3 -methylpentyl, -4-methylpentyl, -2,3 -dimethylbutyl and the like. An “alkenyl” group is an alkyl group that contains one or more carbon-carbon double bonds. An “alkynyl” group is an alkyl group that contains one or more carbon-carbon triple bonds. Examples of unsaturated alkyl groups include, but are not limited to, vinyl, allyl, -CH=CH(CH3), -CH=C(CH3)2, -C(CH3)=CH2, -C(CH3)=CH(CH3), -C(CH2CH3)=CH2, -C=CH, -C=C(CH3), -C=C(CH2CH3), -CH2C=CH, -CH2C=C(CH3) and -CEhO CEhCHs), among others. An alkyl group can be substituted or unsubstituted. When the alkyl groups described herein are said to be “substituted,” they may be substituted with any substituent or substituents as those found in the exemplary compounds and embodiments disclosed herein, as well as halogen; hydroxy; alkoxy; cycloalkyloxy, aryloxy, heterocyclyloxy, heteroaryloxy, heterocycloalkyoxy, cycloalkylalkyloxy, aralkyloxy, heterocyclylalkyloxy, heteroarylalkyloxy, heterocycloalkyalkyloxy; oxo (=0); amino, alkylamino, cycloalkylamino, arylamino, heterocyclylamino, heteroarylamino, heterocycloalkylamino; imino; imido; amidino; guanidino; enamino; acylamino; sulfonylamino; urea, nitrourea; oxime; hydroxylamino; alkoxyamino; aralkoxyamino; hydrazino; hydrazido; hydrazono; azido; nitro; thio (-SH), alkylthio; =S; sulfinyl; sulfonyl; aminosulfonyl; phosphonate; phosphinyl; acyl; formyl; carboxy; ester; carbamate; amido; cyano; isocyanato; isothiocyanato; cyanato; thiocyanato; or -B(0H)2.

[0033] As used herein and unless otherwise specified, a “cycloalkyl” group is a saturated, or partially saturated cyclic alkyl group of from 3 to 10 carbon atoms having a single cyclic ring or multiple condensed or bridged rings which can be optionally substituted. In some embodiments, the cycloalkyl group has 3 to 8 ring members, whereas in other embodiments the number of ring carbon atoms ranges from 3 to 5, 3 to 6, or 3 to 7. Such cycloalkyl groups include, by way of example, single ring structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 1 -methylcyclopropyl, 2-methylcyclopentyl,2-methylcyclooctyl, and the like, or multiple or bridged ring structures such asl-bicyclo[l.l.l]pentyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, adamantyl and the like. Examples of unsaturared cycloalkyl groups include cyclohexenyl, cyclopentenyl, cyclohexadienyl, butadienyl, pentadienyl, hexadienyl, among others. A cycloalkyl group can be substituted or unsubstituted. Such substituted cycloalkyl groups include, by way of example, cyclohexanol and the like.

[0034] As used herein and unless otherwise specified, an “aryl” group is an aromaticcarbocyclic group of from 6 to 14 carbon atoms having a single ring e.g., phenyl) or multiple condensed rings (e.g., naphthyl or anthryl). In some embodiments, aryl groups contain 6-14 carbons, and in others from 6 to 12 or even 6 to 10 carbon atoms in the ring portions of the groups. Particular aryl groups include phenyl, biphenyl, naphthyl and the like. An aryl group can be substituted or unsubstituted. The phrase “aryl groups” also includes groups containing fused rings, such as fused aromatic-aliphatic ring systems (e.g., indanyl, tetrahydronaphthyl, and the like).

[0035] As used herein and unless otherwise specified, a “heteroaryl” group is an aromatic ring system having one to four heteroatoms as ring atoms in a heteroaromatic ring system, wherein the remainder of the atoms are carbon atoms. In some embodiments, heteroaryl groups contain 3 to 6 ring atoms, and in others from 6 to 9 or even 6 to 10 atoms in the ring portions of the groups. Suitable heteroatoms include oxygen, sulfur and nitrogen. In certain embodiments, the heteroaryl ring system is monocyclic or bicyclic. Non-limiting examples include but are not limited to, groups such as pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, benzisoxazolyl (e.g., benzo[d]isoxazolyl), thiazolyl, pyrolyl, pyridazinyl, pyrimidyl, pyrazinyl, thiophenyl, benzothiophenyl, furanyl, benzofuranyl, indolyl (e.g., indol-2-onyl), isoindolin-l-onyl, azaindolyl, pyrrol opyridyl (e.g., lH-pyrrolo[2,3-b]pyridyl), indazolyl, benzimidazolyl (e.g., lH-benzo[d]imidazolyl), azabenzimidazolyl, imidazopyridyl (e.g., lH-imidazo[4,5-b]pyridyl), pyrazol opyridyl, triazolopyridyl, benzotri azolyl (e.g.,lH-benzo[d][l,2,3]triazolyl), benzoxazolyl (e.g., benzo[d]oxazolyl), benzothiazolyl, benzothiadi azolyl, isoxazolopyridyl, thianaphthal enyl, purinyl, xanthinyl, adeninyl, guaninyl, quinolinyl, isoquinolinyl, 3,4-dihydroisoquinolin-l(2H)-onyl, tetrahydroquinolinyl, quinoxalinyl, and quinazolinyl groups. A heteroaryl group can be substituted or unsubstituted.

[0036] As used herein and unless otherwise specified, a “heterocyclyl” is an aromatic ring system (also referred to as heteroaryl) or non-aromatic cycloalkyl (also referred to as heterocycloalkyl) in which one to four of the ring carbon atoms are independently replaced with a heteroatom. Suitable heteroatoms include oxygen, sulfur and nitrogen. In some embodiments, heterocyclyl groups include 3 to 10 ring members, whereas other such groups have 3 to 5, 3 to 6, or 3 to 8 ring members. Heterocyclyls can also be bonded to other groups at any ring atom (i.e., at any carbon atom or heteroatom of the heterocyclic ring). A heterocyclyl group can be substituted or unsubstituted. Heterocyclyl groups encompass unsaturated, partially saturated and saturated ring systems, such as, for example, imidazolyl, imidazolinyl and imidazolidinyl (e.g.,imidazolidin-4-onyl or imidazolidin-2,4-dionyl) groups. The phrase heterocyclyl includes fused ring species, including those comprising fused aromatic and non-aromatic groups, such as, for example, 1- and 2-aminotetraline, benzotri azolyl (e.g., lH-benzo[d][l,2,3]triazolyl), benzimidazolyl (e.g., lH-benzo[d]imidazolyl), 2,3-dihydrobenzo[l,4]dioxinyl, and benzo[l,3]dioxolyl. The phrase also includes bridged polycyclic ring systems containing a heteroatom such as, but not limited to, quinuclidyl. Representative examples of a heterocyclyl group include, but are not limited to, aziridinyl, azetidinyl, azepanyl, oxetanyl, pyrrolidyl, imidazolidinyl (e.g., imidazolidin-4-onyl or imidazolidin-2,4-dionyl), pyrazolidinyl, thiazolidinyl, tetrahydrothiophenyl, tetrahydrofuranyl, dioxolyl, furanyl, thiophenyl, pyrrolyl, pyrrolinyl, imidazolyl, imidazolinyl, pyrazolyl, pyrazolinyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, benzisoxazolyl (e.g., benzo[d]isoxazolyl), thiazolyl, thiazolinyl, isothiazolyl, thiadiazolyl, oxadiazolyl, piperidyl, piperazinyl (e.g., piperazin-2-onyl), morpholinyl, thiomorpholinyl, tetrahydropyranyl (e.g., tetrahydro-2H-pyranyl), tetrahydrothiopyranyl, oxathianyl, dioxyl, dithianyl, pyranyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, triazinyl, dihydropyridyl, dihydrodithiinyl, dihydrodithionyl, l,4-dioxaspiro[4.5]decanyl, homopiperazinyl, quinuclidyl, indolyl (e.g., indol-2-onyl), isoindolin-l-onyl, indolinyl, isoindolyl, isoindolinyl, azaindolyl, pyrrol opyridyl (e.g, lH-pyrrolo[2,3-b]pyridyl), indazolyl, indolizinyl, benzotriazolyl (e.g. lH-benzo[d][l,2,3]triazolyl), benzimidazolyl(e.g., lH-benzo[d]imidazolyl or lH-benzo[d]imidazol-2(3H)-onyl), benzofuranyl, benzothiophenyl, benzothiazolyl, benzoxadi azolyl, benzoxazinyl, benzodithiinyl, benzoxathiinyl, benzothiazinyl, benzoxazolyl (e.g., benzo[d]oxazolyl), benzothiazolyl, benzothiadiazolyl, benzo [1,3] dioxolyl, pyrazolopyridyl (e.g., lH-pyrazolo[3,4-b]pyridyl, lH-pyrazolo[4,3-b]-pyridyl), azabenzimidazolyl, imidazopyridyl (e.g., lH-imidazo[4,5-b]pyridyl), tri azol opyridyl, isoxazolopyridyl, purinyl, xanthinyl, adeninyl, guaninyl, quinolinyl, isoquinolinyl,3,4-dihydroisoquinolin-l(2H)-onyl, quinolizinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, naphthyridinyl, pteridinyl, thianaphthal enyl, dihydrobenzothiazinyl, dihydrobenzofuranyl, dihydroindolyl, dihydrobenzodioxinyl, tetrahydroindolyl, tetrahydroindazolyl, tetrahydrobenzimidazolyl, tetrahydrobenzotriazolyl,tetrahydropyrrol opy ri dy 1 , tetrahy dropy razol opy ri dy 1 , tetrahy droimi dazopy ri dy 1 , tetrahydrotriazolopyridyl, tetrahydropyrimidin-2(lH)-one and tetrahydroquinolinyl groups. Representative non-aromatic heterocyclyl groups do not include fused ring species that comprise a fused aromatic group. Examples of non-aromatic heterocyclyl groups include aziridinyl,azetidinyl, azepanyl, pyrrolidyl, imidazolidinyl (e.g., imidazolidin-4-onyl or imidazolidin-2,4-dionyl), pyrazolidinyl, thiazolidinyl, tetrahydrothiophenyl, tetrahydrofuranyl, piperidyl, piperazinyl (e.g., piperazin-2-onyl), morpholinyl, thiomorpholinyl, tetrahydropyranyl (e.g., tetrahydro-2H-pyranyl), tetrahydrothiopyranyl, oxathianyl, dithianyl, l,4-dioxaspiro[4.5]decanyl, homopiperazinyl, quinuclidyl, or tetrahydropyrimidin-2(lH)-one. Representative substituted heterocyclyl groups may be mono-substituted or substituted more than once, such as, but not limited to, pyridyl or morpholinyl groups, which are 2-, 3-, 4-, 5-, or 6-substituted, or disubstituted with various substituents such as those listed below.

[0037] As used herein, the following heterocyclyl names refer to the structures in the table below. In some embodiments, the point of attachment is via the ring nitrogen atom.>>><

[0038] As used herein and unless otherwise specified, a “cycloalkylalkyl” group is a radical of the formula: -alkyl-cycloalkyl, wherein alkyl and cycloalkyl are defined above.Substituted cycloalkylalkyl groups may be substituted at the alkyl, the cycloalkyl, or both the alkyl and the cycloalkyl portions of the group. Representative cycloalkylalkyl groups include but are not limited to cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cyclopropylethyl, cyclobutylethyl, cyclopentylethyl, cyclohexylethyl, cyclopentylpropyl, cyclohexylpropyl and the like.

[0039] As used herein and unless otherwise specified, an “aralkyl” group is a radical of the formula: -alkyl-aryl, wherein alkyl and aryl are defined above. Substituted aralkyl groups may be substituted at the alkyl, the aryl, or both the alkyl and the aryl portions of the group. Representative aralkyl groups include but are not limited to benzyl and phenethyl groups and aralkyl groups wherein the aryl group is fused to a cycloalkyl group such as indan-4-yl ethyl.

[0040] As used herein and unless otherwise specified, a “heterocyclylalkyl” group is a radical of the formula: -alkyl-heterocyclyl, wherein alkyl and heterocyclyl are defined above. A “heteroarylalkyl” group is a radical of the formula: -alkyl-heteroaryl, wherein alkyl and heteroaryl are defined above. A “heterocycloalkylalkyl” group is a radical of the formula:-alkyl-heterocycloalkyl, wherein alkyl and heterocycloalkyl are defined above. Substituted heterocyclylalkyl groups may be substituted at the alkyl, the heterocyclyl, or both the alkyl and the heterocyclyl portions of the group. Representative heterocylylalkyl groups include but are not limited to morpholin-4-yl ethyl, morpholin-4-yl propyl, furan-2-yl methyl, furan-3-yl methyl, pyri din-3 -yl methyl, tetrahydrofuran -2 -yl ethyl, and indol-2-yl propyl.

[0041] As used herein and unless otherwise specified, a “halogen” is fluorine, chlorine, bromine or iodine.

[0042] As used herein and unless otherwise specified, a “hydroxyalkyl” group is an alkyl group as described above substituted with one or more hydroxy groups.

[0043] As used herein and unless otherwise specified, an “alkoxy” group is -O-(alkyl), wherein alkyl is defined above. An “alkylthio” group is -S-(alkyl), wherein alkyl is defined above.

[0044] As used herein and unless otherwise specified, an “alkoxyalkyl” group is -(alkyl)-O-(alkyl), wherein alkyl is defined above.

[0045] As used herein and unless otherwise specified, a “cycloalkyloxy” group is -O-(cycloalkyl), wherein cycloalkyl is defined above.

[0046] As used herein and unless otherwise specified, an “aryloxy” group is -O-(aryl), wherein aryl is defined above.

[0047] As used herein and unless otherwise specified, a “heterocyclyloxy” group is -O-(heterocyclyl), wherein heterocyclyl is defined above. A “heteroaryloxy” group is -O-(heteroaryl), wherein heteroaryl is defined above. A “heterocycloalkyloxy” group is -O-(heterocycloalkyl), wherein heterocycloalkyl is defined above.

[0048] As used herein and unless otherwise specified, an “amino” group is a radical of the formula: -NH2, -NH(R#), or -N(R#)2, wherein each R#is independently an alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl (e.g., heteroaryl or heterocycloalkyl), or heterocyclylalkyl (e.g., heteroarylalkyl or heterocycloalkylalkyl) group defined above, each of which is independently substituted or unsubstituted.

[0049] In one embodiment, an “amino” group is an “alkylamino” group, which is a radical of the formula: -NH-alkyl or -N(alkyl)2, wherein each alkyl is independently defined above. The term “cycloalkylamino”, “arylamino”, “heterocyclylamino”, “heteroarylamino”, “heterocycloalkylamino”, or the like, mirrors the above description for “alkylamino” where the term “alkyl” is replaced with “cycloalkyl”, “aryl”, “heterocyclyl”, “heteroaryl”, “heterocycloalkyl”, or the like, respectively.

[0050] As used herein and unless otherwise specified, a “carboxy” group is a radical of the formula: -C(O)OH.

[0051] As used herein and unless otherwise specified, an “acyl” group is a radical of the formula: -C(O)(R#) or -C(O)H, wherein R#is defined above. A “formyl” group is a radical of the formula: -C(O)H.

[0052] As used herein and unless otherwise specified, an “amido” group is a radical of the formula: -C(O)-NH2, -C(O)-NH(R#), -C(O)-N(R#)2, -NH-C(O)H, -NH-C(O)-(R#), -N(R#)-C(O)H, or -N(R#)-C(O)-(R#), wherein each R#is independently defined above.

[0053] In one embodiment, an “amido” group is an “aminocarbonyl” group, which is a radical of the formula: -C(O)-NH2, -C(O)-NH(R#), -C(O)-N(R#)2, wherein each R#is independently defined above.

[0054] In one embodiment, an “amido” group is an “acylamino” group, which is a radical of the formula: -NH-C(O)H, -NH-C(O)-(R#), -N(R#)-C(O)H, or -N(R#)-C(O)-(R#), wherein each R#is independently defined above.

[0055] As used herein and unless otherwise specified, a “sulfonylamino” group is a radical of the formula: -NHSO2(R#) or -N(R#)SO2(R#), wherein each R#is defined above.

[0056] As used herein and unless otherwise specified, an “ester” group is a radical of the formula: -C(O)-O-(R#) or -O-C(O)-(R#), wherein R#is defined above.

[0057] In one embodiment, an “ester” group is an “alkoxycarbonyl” group, which is a radical of the formula: -C(O)-O-(alkyl), wherein alkyl is defined above. The term “cycloalkyloxy carbonyl”, “aryloxy carbonyl”, “heterocyclyloxycarbonyl”, “heteroaryloxycarbonyl”, “heterocycloalkyloxycarbonyl”, or the like, mirrors the above description for “alkoxycarbonyl” where the term “alkoxy” is replaced with “cycloalkyloxy”, “aryloxy”, “heterocyclyloxy”, “heteroaryloxy”, “heterocycloalkyloxy”, or the like, respectively.

[0058] As used herein and unless otherwise specified, a “carbamate” group is a radical of the formula: -O-C(O)-NH2, -O-C(O)-NH(R#), -O-C(O)-N(R#)2, -NH-C(O)-O-(R#), or -N(R#)-C(O)-O-(R#), wherein each R#is independently defined above.

[0059] As used herein and unless otherwise specified, a “urea” group is a radical of the formula: -NH(CO)NH2, -NHC(O)NH(R#), -NHC(O)N(R#)2, -N(R#)C(O)NH2, -N(R#)C(O)NH(R#), or -N(R#)C(O)N(R#)2, wherein each R#is independently defined above.

[0060] As used herein and unless otherwise specified, a “sulfinyl” group is a radical of the formula: -S(O)R#, wherein R#is defined above.

[0061] As used herein and unless otherwise specified, a “sulfonyl” group is a radical of the formula: -S(O)2R#, wherein R#is defined above.

[0062] As used herein and unless otherwise specified, an “aminosulfonyl” group is a radical of the formula: -SO2NH2, -SO2NH(R#), or -SO2N(R#)2, wherein each R#is independently defined above.

[0063] When the groups described herein, with the exception of alkyl group, are said to be “substituted,” they may be substituted with any appropriate substituent or substituents.Illustrative examples of substituents are those found in the exemplary compounds andembodiments disclosed herein, as well as halogen; alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, heterocycloalky, cycloalkylalkyl, aralkyl, heterocyclylalkyl, heteroarylalkyl, heterocycloalkyalkyl, optionally further substituted; hydroxy; alkoxy; cycloalkyloxy, aryloxy, heterocyclyloxy, heteroaryloxy, heterocycloalkyoxy, cycloalkylalkyloxy, aralkyloxy, heterocyclylalkyloxy, heteroarylalkyloxy, heterocycloalkyalkyloxy; oxo (=0); oxide (e.g., a nitrogen atom substituted with an oxide is called N-oxide); amino, alkylamino, cycloalkylamino, arylamino, heterocyclylamino, heteroarylamino, heterocycloalkylamino; imino; imido; amidino; guanidino; enamino; acylamino; sulfonylamino; urea, nitrourea; oxime; hydroxylamino; alkoxyamino; aralkoxyamino; hydrazino; hydrazido; hydrazono; azido; nitro; thio (-SH), alkylthio; =S; sulfinyl; sulfonyl; aminosulfonyl; phosphonate; phosphinyl; acyl; formyl; carboxy; ester; carbamate; amido; cyano; isocyanato; isothiocyanato; cyanato; thiocyanato; or -B(0H)2.

[0064] As used herein, the term “Adefovir Compound” refers to compounds of formula (I) as well as to further embodiments provided herein. In one embodiment, an “Adefovir Compound” is a compound set forth in Table 1. The term “Adefovir Compound” includes pharmaceutically acceptable salts, hydrates, solvates, tautomers, isotopologues, and stereoisomers of the compounds provided herein.

[0065] As used herein, the term “pharmaceutically acceptable salt(s)” refers to a salt prepared from a pharmaceutically acceptable non-toxic acid or base including an inorganic acid and base and an organic acid and base. Suitable pharmaceutically acceptable base addition salts of the compounds of formula (I) include, but are not limited to metallic salts made from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc or organic salts made from lysine, N,N’ -dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methyl-glucamine) and procaine. Suitable non-toxic acids include, but are not limited to, inorganic and organic acids such as acetic, alginic, anthranilic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethenesulfonic, formic, fumaric, furoic, galacturonic, gluconic, glucuronic, glutamic, glycolic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phenylacetic, phosphoric, propionic, salicylic, stearic, succinic, sulfanilic, sulfuric, tartaric acid, and p-toluenesulfonic acid. Specific non-toxic acids include hydrochloric, hydrobromic, maleic, phosphoric, sulfuric, and methanesulfonic acids. Examples of specific salts thus include hydrochloride and mesylate salts. Others are well-known in the art, see for example,Remington ’s Pharmaceutical Sciences, 18theds., Mack Publishing, Easton PA (1990) or Remington: The Science and Practice of Pharmacy, 19theds., Mack Publishing, Easton PA (1995).

[0066] As used herein and unless otherwise indicated, the term “stereoisomer” or “stereomerically pure” means one stereoisomer of a substituted adefovir compound that is substantially free of other stereoisomers of that compound. For example, a stereomerically pure compound having one chiral center will be substantially free of the opposite enantiomer of the compound. A stereomerically pure compound having two chiral centers will be substantially free of other diastereomers of the compound. A typical stereomerically pure compound comprises greater than about 80% by weight of one stereoisomer of the compound and less than about 20% by weight of other stereoisomers of the compound, greater than about 90% by weight of one stereoisomer of the compound and less than about 10% by weight of the other stereoisomers of the compound, greater than about 95% by weight of one stereoisomer of the compound and less than about 5% by weight of the other stereoisomers of the compound, or greater than about 97% by weight of one stereoisomer of the compound and less than about 3% by weight of the other stereoisomers of the compound. The substituted adefovir compound can have chiral centers and can occur as racemates, individual enantiomers or diastereomers, and mixtures thereof. All such isomeric forms are included within the embodiments disclosed herein, including mixtures thereof.

[0067] The use of stereomerically pure forms of such substituted adefovir compound, as well as the use of mixtures of those forms, are encompassed by the embodiments disclosed herein. For example, mixtures comprising equal or unequal amounts of the enantiomers of a particular substituted adefovir compound may be used in methods and compositions disclosed herein. These isomers may be asymmetrically synthesized or resolved using standard techniques such as chiral columns or chiral resolving agents. See, e.g., Jacques, J., etal., Enantiomers, Racemates and Resolutions (Wiley-Interscience, New York, 1981); Wilen, S. H., et al. , Tetrahedron 332 25 (1977); Eliel, E. L., Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); Wilen, S. H., Tables of Resolving Agents and Optical Resolutions p. 268 (E.L. Eliel, Ed., Univ, of Notre Dame Press, Notre Dame, IN, 1972); Todd, M., Separation Of Enantiomers : Synthetic Methods (Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim, Germany, 2014);Toda, F., Enantiomer Separation: Fundamentals and Practical Methods (Springer Science & Business Media, 2007); Subramanian, G. Chiral Separation Techniques: A Practical Approach(John Wiley & Sons, 2008); Ahuja, S., Chiral Separation Methods for Pharmaceutical and Biotechnological Products (John Wiley & Sons, 2011).

[0068] It should also be noted the Adefovir Compounds can include E and Z isomers, or a mixture thereof, and cis and trans isomers or a mixture thereof. In certain embodiments, the substituted adefovir compounds are isolated as either the E or Z isomer. In other embodiments, the Adefovir Compounds are a mixture of the E and Z isomers.

[0069] “Tautomers” refers to isomeric forms of a compound that are in equilibrium with each other. The concentrations of the isomeric forms will depend on the environment the compound is found in and may be different depending upon, for example, whether the compound is a solid or is in an organic or aqueous solution. For example, in aqueous solution, pyrazoles may exhibit the following isomeric forms, which are referred to as tautomers of each other:

[0070] As readily understood by one skilled in the art, a wide variety of functional groups and other structures may exhibit tautomerism and all tautomers of compounds of formula (I) are within the scope of the present invention.

[0071] It should also be noted the Adefovir Compounds can contain unnatural proportions of atomic isotopes at one or more of the atoms. For example, the compounds may be radiolabeled with radioactive isotopes, such as for example tritium (3H), iodine-125 (125I), sulfur-35 (35S), or carbon-14 (14C), or may be isotopically enriched, such as with deuterium (2H), carbon-13 (13C), or nitrogen-15 (15N). As used herein, an “isotopologue” is an isotopically enriched compound. The term “isotopically enriched” refers to an atom having an isotopic composition other than the natural isotopic composition of that atom. “Isotopically enriched” may also refer to a compound containing at least one atom having an isotopic composition other than the natural isotopic composition of that atom. The term “isotopic composition” refers to the amount of each isotope present for a given atom. Radiolabeled and isotopically enriched compounds are useful as therapeutic agents, e.g., cancer therapeutic agents, research reagents, e.g., binding assay reagents, and diagnostic agents, e.g., in vivo imaging agents. All isotopic variations of the Adefovir Compounds as described herein, whether radioactive or not, are intended to be encompassed within the scope of the embodiments provided herein. In some embodiments, there are provided isotopologues of the Adefovir Compounds, for example, the isotopologues are deuterium, carbon-13, and / or nitrogen-15 enriched Adefovir Compounds. Asused herein, “deuterated”, means a compound wherein at least one hydrogen (H) has been replaced by deuterium (indicated by D or2H), that is, the compound is enriched in deuterium in at least one position.

[0072] It is understood that, independently of stereomerical or isotopic composition, each Adefovir Compound referred to herein can be provided in the form of any of the pharmaceutically acceptable salts discussed herein. Equally, it is understood that the isotopic composition may vary independently from the stereomerical composition of each Adefovir Compound referred to herein. Further, the isotopic composition, while being restricted to those elements present in the respective Adefovir Compound or salt thereof, may otherwise vary independently from the selection of the pharmaceutically acceptable salt of the respective Adefovir Compound.

[0073] It should be noted that if there is a discrepancy between a depicted structure and a name for that structure, the depicted structure is to be accorded more weight.

[0074] “Treating” as used herein, means an alleviation, in whole or in part, of a disorder, disease or condition, or one or more of the symptoms associated with a disorder, disease, or condition, or slowing or halting of further progression or worsening of those symptoms, or alleviating or eradicating the cause(s) of the disorder, disease, or condition itself. In one embodiment, the disorder is MS as described herein or a symptoms thereof.

[0075] “Preventing” as used herein, means a method of delaying and / or precluding the onset, recurrence or spread, in whole or in part, of a disorder, disease or condition; barring a subject from acquiring a disorder, disease, or condition; or reducing a subject’s risk of acquiring a disorder, disease, or condition. In one embodiment, the disorder is MS, as described herein, or symptoms thereof.

[0076] The term “effective amount” in connection with an Adefovir Compound means an amount capable of treating or preventing a disorder, disease or condition, or symptoms thereof, disclosed herein.

[0077] The term “subject” includes an animal, including, but not limited to, an animal such a cow, monkey, horse, sheep, pig, chicken, turkey, quail, cat, dog, mouse, rat, rabbit or guinea pig, in one embodiment a mammal, in another embodiment a human. In one embodiment, a subject is a human having or at risk for having MS, or a symptomthereof.

[0078] In general, the technical teaching of one embodiment can be combined with that described in other embodiments provided herein.ADEFOVIR COMPOUNDS

[0079] The invention provides herein compounds having the following formula (I):(I),or a pharmaceutically acceptable salt, hydrate, solvate, tautomer, isotopolog, or stereoisomer thereof, wherein:Ri and R2 are each independently H or C1-6 alkyl, or Ri and R2 together with the single carbon to which they are bound form a C3-7 cycloalkyl;R3 is independently hydrogen, an optionally substituted C1-8 alkyl, an optionally substituted C2-8 alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkyl(Ci-C4 alkyl)-, an optionally substituted cycloalkenyl, an optionally substituted cycloalkenyl(Ci-C4 alkyl)-, an optionally substituted aryl, an optionally substituted aryl(Ci-C4 alkyl)-, an optionally substituted heteroaryl, an optionally substituted heteroaryl (Ci-C4 alkyl)-, an optionally substituted heterocyclyl, or an optionally substituted heterocyclyl(Ci-C4 alkyl)-; andAr is independently an optionally substituted phenyl, an optionally substituted naphthyl, or an optionally substituted hydronaphthyl.

[0080] In some embodiments, Ar is substituted with one or more substituents independently selected from F, Cl, Br, CH3, CH2CH3, n-propyl, isopropyl, n-butyl, secbutyl, isobutyl, t-butyl, n-pentyl, isopentyl, CH2F, CHF2, CF3, CH2CH2F, CH2CHF2, CH2CF3, CH(CH3)CF3, CH2CH2CF3, OH, 0CH3, OCH2CH3, O-isopropyl, O-n-propyl,O-n-butyl, O-isobutyl, O-t-butyl, OCF3, O-cyclopropyl, O-cyclobutyl, OCH2-cyclopropyl, OCH2.cyclobutyl, CONH2, CONH(CH3), CON(CH3)2, SO2CH3, SO2CH2CH3, SO2-isopropyl, cyclopropyl, cyclobutyl, OU-cyclopropyl, CH2-cyclobutyl.

[0081] In some embodiments, the compound is of formula (II):

[0082] In some embodiments, Ri and R2 are each independently H or methyl, or Ri and R2 together with the single carbon to which they are bound form a C3 cycloalkyl; R3 is independently methyl, ethyl, propyl, isopropyl or cyclopropyl; and Ar is independently phenyl, p-chlorophenyl, naphthyl, or 5,6,7,8-tetrahydro-naphthyl, wherein the phenyl is optionally substituted with one or more substituents independently selected from F, Cl, CH3, CN, or CONH2.

[0083] In some embodiments, the compound is of formula (III):(HI),wherein R3 is methyl, ethyl, propyl, isopropyl or cyclopropyl.

[0084] In some embodiments, the compound is of formula (IV):wherein R3 is methyl, ethyl, propyl, isopropyl or cyclopropyl.

[0085] In some embodiments, the compound is of formula (V):(V),wherein R3 is methyl, ethyl, propyl, isopropyl or cyclopropyl, and Ar is p- chlorophenyl, naphthyl, or 5,6,7,8-tetrahydro-naphthyl.

[0086] In some embodiments, the compound is of formula (VI):(VI),wherein R3 is methyl, ethyl, propyl, isopropyl or cyclopropyl, and Ar is p- chlorophenyl, naphthyl, or 5,6,7,8-tetrahydro-naphthyl.

[0087] In some embodiments, the compound is selected from the group consisting of

[0088] In some embodiments, the compound is selected from the group consisting of

[0089] In some embodiments, the compound is selected from the group consisting of

[0090] In some embodiments, the compound is selected from the group consisting ofMETHODS FOR MAKING ADEFOVIR COMPOUNDS

[0091] The invention further provides a method for preparing a compound of formula (I):wherein the method comprises contacting 2-(6-aminopurin-9-yl)ethoxymethylphosphonic acidNH2R'i0'R3(Adefovir) with Ar-OH and ° , in the presence of a base, in a solvent, under conditions suitable to provide a compound of formula (I), wherein:Ri and R2 are each independently H or methyl, or Ri and R2 together with the single carbon to which they are bound form a C3 cycloalkyl;R3 is independently methyl, ethyl, propyl, isopropyl or cyclopropyl; andAr is independently phenyl, p-chlorophenyl, naphthyl, or 5,6,7,8-tetrahydro-naphthyl, wherein the phenyl is optionally substituted with one or more substituents independently selected from F, Cl, CH3, CN, or CONH2.

[0092] The Adefovir Compounds can be made using conventional organic syntheses and commercially available starting materials. By way of example and not limitation, Adefovir Compounds of formula (I) and (II) can be prepared as outlined in Scheme 1 shown below as well as in the examples set forth herein. It should be noted that one skilled in the art would know how to modify the procedures set forth in the illustrative schemes and examples to arrive at the desired products.Scheme 1

[0093] As shown in Scheme 1, compounds of formula (I) can be synthesized by contacting 2-(6-aminopurin-9-yl)ethoxymethylphosphonic acid (Adefovir) with Ar-OH and, in the presence of a base, in a solvent, under conditions suitable to provide a compound of formula (I).METHODS OF USE

[0094] The Adefovir Compounds have utility as pharmaceuticals to treat, prevent or improve medical conditions in animals or humans, including treatment and prevention of diseases set forth below. The methods provided herein comprise the administration of an effective amount of one or more Adefovir Compound(s) to a subject in need thereof.

[0095] The invention provides methods for the treatment or prevention of Epstein-Barr-Virus (EBV)-associated disease or condition, wherein the method comprises administering to a subject in need thereof an effective amount of a compound or a pharmaceutical composition of the invention.

[0096] The invention further provides a compound or a pharmaceutical composition of the invention for use in a method for the treatment or prevention of Epstein-Barr- Virus (EBV)-associated disease or condition, wherein the method comprises administering to a subject in need thereof an effective amount of the compound or the pharmaceutical composition.

[0097] In some embodiments, the EBV-associated disease or condition is infectious mononucleosis, nasopharyngeal carcinoma, Burkitt’s lymphoma, Hodgkin’s lymphoma, gastric carcinoma, systemic lupus erythematosus (SLE), multiple sclerosis (MS), Post-Transplant Lymphoproliferative Disorders (PTLD) and the suppression of EBV reactivation in immunocompromised individuals such as transplant patients.

[0098] In one specific aspect provided herein are methods for treating or preventing MS, comprising administering to a subject in need thereof an effective amount of an Adefovir Compound as described herein. In one aspect provided herein are methods for treating MS, comprising administering to a subject in need thereof an effective amount of an Adefovir Compound as described herein. In one aspect provided herein are methods for preventing MS, comprising administering to a subject in need thereof an effective amount of an Adefovir Compound as described herein. For example, the Adefovir Compound is a compound from Table 1.

[0099] Provided herein are also compounds for use in a method for the treatment or prevention of MS, comprising administering to a subject in need thereof an effective amount of an Adefovir Compound. In some embodiments, provided herein arecompounds for use in the treatment of MS, comprising administering to a subject in need thereof an effective amount of an Adefovir Compound as described herein. In someembodiments, provided herein are compounds for use in the prevention of MS, comprising administering to a subject in need thereof an effective amount of an Adefovir Compound as described herein. For example, the Adefovir. Compound is a compound from Table 1.

[0100] In another specific aspect provided herein are methods for treating or preventing SLE, comprising administering to a subject in need thereof an effective amount of an Adefovir Compound as described herein. In one aspect provided herein are methods for treating SLE, comprising administering to a subject in need thereof an effective amount of an Adefovir Compound as described herein. In one aspect provided herein are methods for preventing SLE, comprising administering to a subject in need thereof an effective amount of an Adefovir Compound as described herein. For example, the Adefovir Compound is a compound from Table 1.

[0101] Provided herein are also compounds for use in a method for the treatment or prevention of SLE, comprising administering to a subject in need thereof an effective amount of an Adefovir Compound. In some embodiments, provided herein are compounds for use in the treatment of SLE, comprising administering to a subject in need thereof an effective amount of an Adefovir Compound as described herein. In some embodiments, provided herein are compounds for use in the prevention of SLE, comprising administering to a subject in need thereof an effective amount of an Adefovir Compound as described herein. For example, the Adefovir Compound is a compound from Table 1.PHARMACEUTICAL COMPOSITIONS AND ROUTES OF ADMINISTRATION

[0102] The invention further provides a pharmaceutical composition comprising a compound of the invention or a pharmaceutically acceptable salt, hydrate, solvate, tautomer, isotopologue, or stereoisomer thereof, and a pharmaceutically acceptable carrier, excipient or vehicle.

[0103] The Adefovir Compounds can be administered to a subject orally, topically or parenterally in the conventional form of preparations, such as capsules, microcapsules, tablets, granules, powder, troches, pills, suppositories, injections, suspensions, syrups, patches, creams, lotions, ointments, gels, sprays, solutions and emulsions. Suitable formulations can be prepared by methods commonly employed using conventional,organic or inorganic additives, such as an excipient (e.g., sucrose, starch, mannitol, sorbitol, lactose, glucose, cellulose, talc, calcium phosphate or calcium carbonate), a binder (e.g., cellulose, methylcellulose, hydroxymethylcellulose, polypropylpyrrolidone, polyvinylpyrrolidone, gelatin, gum arabic, polyethyleneglycol, sucrose or starch), a disintegrator (e.g., starch, carboxymethylcellulose, hydroxypropyl starch, low substituted hydroxypropylcellulose, sodium bicarbonate, calcium phosphate or calcium citrate), a lubricant (e.g., magnesium stearate, light anhydrous silicic acid, talc or sodium lauryl sulfate), a flavoring agent (e.g., citric acid, menthol, glycine or orange powder), a preservative (e.g, sodium benzoate, sodium bisulfite, methylparaben or propylparaben), a stabilizer (e.g., citric acid, sodium citrate or acetic acid), a suspending agent (e.g., methylcellulose, polyvinyl pyrrolidone or aluminum stearate), a dispersing agent (e.g., hydroxypropylmethylcellulose), a diluent (e.g., water), and base wax (e.g., cocoa butter, white petrolatum or polyethylene glycol). The effective amount of the Adefovir Compounds in the pharmaceutical composition may be at a level that will exercise the desired effect; for example, about 0.005 mg / kg of a subject’s body weight to about 10 mg / kg of a subject’s body weight in unit dosage for both oral and parenteral administration.

[0104] The dose of an Adefovir Compound to be administered to a subject is rather widely variable and can be subject to the judgment of a health-care practitioner. In general, the Adefovir Compounds can be administered one to four times a day in a dose of about 0.001 mg / kg of a subject’s body weight to about 10 mg / kg of a subject’s body weight, but the above dosage may be properly varied depending on the age, body weight and medical condition of the subject and the type of administration. In one embodiment, the dose is about 0.001 mg / kg of a subject’s body weight to about 5 mg / kg of a subject’s body weight, about 0.01 mg / kg of a subject’s body weight to about 5 mg / kg of a subject’s body weight, about 0.05 mg / kg of a subject’s body weight to about 1 mg / kg of a subject’s body weight, about 0.1 mg / kg of a subject’s body weight to about 0.75 mg / kg of a subject’s body weight or about 0.25 mg / kg of a subject’s body weight to about 0.5 mg / kg of a subject’s body weight. In one embodiment, one dose is given per day. In any given case, the amount of the Adefovir Compound administered will depend on such factors as the solubility of the active component, the formulation used and the route ofadministration.

[0105] In another embodiment, provided herein are methods for the treatment or prevention of a disease or disorder comprising the administration of about 0.01 mg / day to about 750 mg / day, about 0.1 mg / day to about 375 mg / day, about 0.1 mg / day to about 150 mg / day, about 0.1 mg / day to about 75 mg / day, about 0.1 mg / day to about 50 mg / day, about 0.1 mg / day to about 25 mg / day, or about 0.1 mg / day to about 10 mg / day of an Adefovir Compound to a subject in need thereof.

[0106] In another embodiment, provided herein are unit dosage formulations that comprise between about 0.1 mg and 500 mg, about 1 mg and 250 mg, about 1 mg and about 100 mg, about 1 mg and about 50 mg, about 1 mg and about 25 mg, or between about 1 mg and about 10 mg of an Adefovir Compound.

[0107] In a particular embodiment, provided herein are unit dosage formulations comprising about 0.1 mg or 100 mg of an Adefovir Compound.

[0108] In another embodiment, provided herein are unit dosage formulations that comprise 0.5 mg, 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 30 mg, 35 mg, 50 mg, 70 mg, 100 mg, 125 mg, 140 mg, 175 mg, 200 mg, 250 mg, 280 mg, 350 mg, 500 mg, 560 mg, 700 mg, 750 mg, 1000 mg or 1400 mg of an Adefovir Compound.

[0109] An Adefovir Compound can be administered once, twice, three, four or more times daily. In a particular embodiment, doses of 100 mg or less are administered as a once daily dose and doses of more than 100 mg are administered twice daily in an amount equal to one half of the total daily dose.

[0110] An Adefovir Compound can be administered orally for reasons of convenience. In one embodiment, when administered orally, an Adefovir Compound is administered with a meal and water. In another embodiment, the Adefovir Compound is dispersed in a liquid, such as water or juice (e.g., apple juice or orange juice) and administered orally as a solution or a suspension.

[0111] The Adefovir Compound can also be administered intradermally, intramuscularly, intraperitoneally, percutaneously, intravenously, subcutaneously, intranasally, epidurally, sublingually, intracerebrally, intravaginally, transdermally, rectally, mucosally, by inhalation, or topically to the ears, nose, eyes, or skin. The mode of administration is left to the discretion of the health-care practitioner, and can depend in-part upon the site of the medical condition.

[0112] In one embodiment, provided herein are capsules containing an Adefovir Compound without an additional carrier, excipient or vehicle.

[0113] In another embodiment, provided herein are compositions comprising an effective amount of an Adefovir Compound and a pharmaceutically acceptable carrier or vehicle, wherein a pharmaceutically acceptable carrier or vehicle can comprise an excipient, diluent, or a mixture thereof. In one embodiment, the composition is a pharmaceutical composition.

[0114] The compositions can be in the form of tablets, chewable tablets, capsules, solutions, parenteral solutions, troches, suppositories and suspensions and the like.Compositions can be formulated to contain a daily dose, or a convenient fraction of a daily dose, in a dosage unit, which may be a single tablet or capsule or convenient volume of a liquid. In one embodiment, the solutions are prepared from water-soluble salts, such as the hydrochloride salt. In general, all of the compositions are prepared according to known methods in pharmaceutical chemistry. Capsules can be prepared by mixing an Adefovir Compound with a suitable carrier or diluent and filling the proper amount of the mixture in capsules. The usual carriers and diluents include, but are not limited to, inert powdered substances such as starch of many different kinds, powdered cellulose, especially crystalline and microcrystalline cellulose, sugars such as fructose, mannitol and sucrose, grain flours and similar edible powders.

[0115] Tablets can be prepared by direct compression, by wet granulation, or by dry granulation. Their formulations usually incorporate diluents, binders, lubricants and disintegrators as well as the compound. 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 are substances such as starch, gelatin and sugars such as lactose, fructose, glucose and the like. Natural and synthetic gums are also convenient, including acacia, alginates, methylcellulose, polyvinylpyrrolidine and the like.Polyethylene glycol, ethylcellulose and waxes can also serve as binders.

[0116] A lubricant might be necessary in a tablet formulation to prevent the tablet and punches from sticking in the dye. The lubricant can be chosen from such slippery solids as talc, magnesium and calcium stearate, stearic acid and hydrogenated vegetable oils. Tablet disintegrators are substances that swell when wetted to break up the tablet andrelease the compound. They include starches, clays, celluloses, algins and gums. More particularly, corn and potato starches, methylcellulose, agar, bentonite, wood cellulose, powdered natural sponge, cation-exchange resins, alginic acid, guar gum, citrus pulp and carboxymethyl cellulose, for example, can be used as well as sodium lauryl sulfate.Tablets can be coated with sugar as a flavor and sealant, or with film-forming protecting agents to modify the dissolution properties of the tablet. The compositions can also be formulated as chewable tablets, for example, by using substances such as mannitol in the formulation.

[0117] When it is desired to administer an Adefovir Compound as a suppository, typical bases can be used. Cocoa butter is a traditional suppository base, which can be modified by addition of waxes to raise its melting point slightly. Water-miscible suppository bases comprising, particularly, polyethylene glycols of various molecular weights are in wide use.

[0118] The effect of the Adefovir Compound can be delayed or prolonged by proper formulation. For example, a slowly soluble pellet of the Adefovir Compound can be prepared and incorporated in a tablet or capsule, or as a slow-release implantable device. The technique also includes making pellets of several different dissolution rates and filling capsules with a mixture of the pellets. Tablets or capsules can be coated with a film that resists dissolution for a predictable period of time. Even the parenteral preparations can be made long-acting, by dissolving or suspending the Adefovir Compound in oily or emulsified vehicles that allow it to disperse slowly in the serum.EXAMPLES

[0119] The following examples are presented by way of illustration, not limitation. Compounds are named using the automatic name generating tool provided in ChemBiodraw Ultra (Cambridgesoft), which generates systematic names for chemical structures, with support for the Cahn-Ingold-Prelog rules for stereochemistry. One skilled in the art can modify the procedures set forth in the illustrative examples to arrive at the desired products.

[0120] Abbreviations used:EXAMPLE 1: SYNTHESIS OF ADEFOVIR COMPOUNDS Example 1-1

[0121] isopropyl (((2-(6-amino-9H-purin-9-yl)ethoxy)methyl)(phenoxy)phosphoryl)-L-alaninate: A mixture of ((2-(6-amino-9H-purin-9-yl)ethoxy)methyl)phosphonic acid (1.0 g, 3.66 mmol), isopropyl L-alaninate (1.2 g, 7.32 mmol), triethylamine (2.2 g, 220 mmol) and phenol (1.7 g, 18.3 mmol) in pyridine (15.0 mL) was heated to 60 °C for 5 min. PPhs (6.72 g, 25.6 mmol) and 2-(pyridin-2-yldisulfanyl)pyridine (5.64 g, 25.6 mmol) was added to the above reaction mixture. The reaction was stirred for 2 h at 60 °C. The reaction mixture was cooled to room temperature and concentrated to dryness. The residue was partitioned between ethylacetate (60 mL) and saturated sodium bicarbonate (20 mL). The organic phase was separated and washed with brine (30 mL), dried with anhydrous sodium sulfate, filtered and the filtrate was concentrated to dryness reduced pressure. The residue was purified by silica gel chromatography (silica gel 100 - 200 mesh, methanol: di chloromethane, 0 - 5%) to afford the product of isopropyl (((2-(6-amino-9H-purin-9-yl)ethoxy)methyl)(phenoxy)phosphoryl)-L-alaninate (0.6 g, 35.45% yield) as a brown oil. LCMS: MS (ESI+): m / z = 463.3

[0122] isopropyl ((S)-((2-(6-amino-9H-purin-9-yl)ethoxy)methyl)(phenoxy)phosphoryl)-L-alaninate and isopropyl ((R)-(2-(6-amino-9H-purin-9-yl)ethoxy)(phenoxy)phosphoryl)-L-alaninate: (((2-(6-amino-9H-purin-9-yl)ethoxy)methyl)(phenoxy)phosphoryl)-L-alaninate (300 mg) was purified by prep-SFC (column: DAICELCHIRALPAK®IC, 250*25 mm 10 pm; mobile phase A: CO2, mobile phase B: MeOH; flow rate: 80 mL / min; gradient: isocratic 55% B; wave length: 254 nm;RT1: 4.450 min; RT2: 4.974 min) to afford isopropyl ((S)-((2-(6-amino-9H-purin-9-yl)ethoxy)methyl)(phenoxy)phosphoryl)-L-alaninate (46.5 mg, Yield 15.5%) and isopropyl ((R)-(2-(6-amino-9H-purin-9-yl)ethoxy)(phenoxy)phosphoryl)-L-alaninate (58.2 mg, Yield 20.01%) as a white solid.

[0123] QC data of isopropyl ((S)-((2-(6-amino-9H-purin-9-yl)ethoxy)methyl)(phenoxy)phosphoryl)-L-alaninate: LCMS: MS (ESI+): m / z = 463.3;JH NMR (400 MHz, CDCI3) 88.34 (s, 1H), 8.01 (s, 1H), 7.30 (d, J= 7.8 Hz, 2H), 7.15 (t, J= 7.4 Hz, 1H), 7.09 (d, J= 8.0 Hz, 2H), 5.96 (s, 2H), 4.97 (m, 1H), 4.5 - 4.4 (m, 2H), 4.10 -4.01 (m, 1H), 3.92 - 3.85 (m, , 2H), 3.93 - 3.85 (m, 2H), 3.58 (t, J= 10.3 Hz, 1H), 1.26 (d, J= 7.2 Hz, 3H), 1.23 - 1.19 (m, 6H).

[0124] QC data of isopropyl ((R)-(2-(6-amino-9H-purin-9-yl)ethoxy)(phenoxy)phosphoryl)-L-alaninate: LCMS: MS (ESI+): m / z = 463.3; 'HNMR (400 MHz, CDCI3) 68.36 (s, 1H), 7.98 (s, 1H), 7.24 (d, J= 8.0 Hz, 2H), 7.13 (s, 1H), 7.07 (d, J= 8.0 Hz, 2H), 5.84 (s, 2H), 5.01 (s, 1H), 4.43 - 4.34 (m, 2H), 4.11 - 3.97 (m, 1H), 3.92 (t, J= 4.9 Hz, 2H), 3.85 (d, J= 8.0 Hz, 2H), 3.67 (t, J= 10.3 Hz, 1H), 1.29 (d, J= 7.2 Hz, 3H), 1.23 (d, J= 8.0 Hz, 6H).Example 1-2

[0125] isopropyl (R)-2-((((2-(6-amino-9H-purin-9-yl)ethoxy)methyl)(phenoxy)phosphoryl)amino)-2-methylpropanoate and isopropyl (S)-2-((((2-(6-amino-9H-purin-9-yl)ethoxy)methyl)(phenoxy)phosphoryl)amino)-2-methylpropanoate are synthesized following the scheme below:

[0126] isopropyl 2-amino-2-methylpropanoate: To a mixture of compound 2-amino-2-methylpropanoic acid (5 g, 48.49 mmol) in IPA (40 mL) was added SOCI2 (8.65 g, 72.73mmol) dropwise in portions at rt under N2 atmosphere. The resulting mixture was stirred for 16 h at 85 °C under N2 atmosphere. The resulting mixture was concentrated under vacuum to afford compound 5 (6.5 g, 92.33% yield) as a white solid. 'H NMR (400 MHz, CDCI3): 58.91 (br s, 2H), 5.11 - 5.05 (m, 1H), 1.70 (s, 6H), 1.29 (d, J = 6.2 Hz, 6H).

[0127] bis(trimethylsilyl) ((2-(6-amino-9H-purin-9-yl)ethoxy)methyl)phosphonate :To a mixture of compound 1 (5 g, 18.30 mmol) in ACN (60 mL) was added bromo(trimethyl)silane (14.01 g, 91.5 mmol) dropwise in portions at 0 °C under N2 atmosphere. The resulting mixture was stirred for 16 h at rt under N2 atmosphere. The resulting mixture wasconcentrated under vacuum to afford crude compound 2 (7.5 g) which was used in the next step directly without further purification.

[0128] isopropyl-2-((((2-(6-amino-9H-purin-9-yl)ethoxy)methyl)(phenoxy)phosphoryl)amino)-2-methylpropanoate: To a mixture of compound 2 (7.5 g, 17.96 mmol) in pyridine (60 mL) / TEA (12 mL) was added 2-(pyridin-2-yldisulfanyl)pyridine (23.74 g, 107.76 mmol), Triphenylphosphine (28.26 g, 107.76 mmol), phenol (2.54 g, 26.94 mmol) and compound 5 (3.91 g, 26.94 mmol) at rt. The resulting mixture was stirred for 16 h at 50 °C under N2 atmosphere. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with [DCM / MeOH] (0~5%) to afford crude product. The product was further purified by prep-HPLC(GLISON GX-281) Column: sunfire Prep C18 OBD, 19*250 mm, 10 um; Mobile Phase A: 0.1% TFA / H2O B: ACN ; flow rate: 20 ml / min; gradient: 30-40% Retention Time: 8-9 min of 22 min) to afford compound 6 (800 mg, 9.35% yield) as a colorless oil. LCMS (ESI): m / z = 477.6 [M+H]+.

[0129] isopropyl (R)-2-((((2-(6-amino-9H-purin-9-yl)ethoxy)methyl)(phenoxy)phosphoryl)amino)-2-methylpropanoate and isopropyl (S)-2-((((2-(6-amino-9H-purin-9-yl)ethoxy)methyl)(phenoxy)phosphoryl)amino)-2-methylpropanoate: The racemic product 6 (180 mg, 0.38 mmol) was separated by pre-SFC (System:K-Prep LAB100G; Column name: DAICELCHIRALCEL®OD; Column size: 250*40 mm 10 pm; Mobile Phase A: Hexane; Mobile Phase B: EtOH; A:B: 80:20; Wavelength: 254 nm; Flow: 50ml / min; Column temp: RT; Injection: 0.5ml ) to afford isopropyl (R)-2-((((2-(6-amino-9H-purin-9-yl)ethoxy)methyl)(phenoxy)phosphoryl)amino)-2-methylpropanoate (55 mg, 30.68 % yield) as a white solid and isopropyl (R)-2-((((2-(6-amino-9H-purin-9-yl)ethoxy)methyl)(phenoxy)phosphoryl)amino)-2-methylpropanoate (53 mg, 29.44 % yield) as a white solid.

[0130] QC data of isopropyl (R)-2-((((2-(6-amino-9H-purin-9-yl)ethoxy)methyl)(phenoxy)phosphoryl)amino)-2-methylpropanoate: LCMS: MS (ESI+): m / z = 447.5 [M+H]+; 'HNMR (400 MHz, CDCI3) 88.32 (s, 1H), 8.03 (s, 1H), 7.30 - 728 (m, 2H), 7.16 - 7.08 (m, 3H), 6.35 (br, 2H), 5.05 - 4.99 (m, 1H), 4.44 - 4.42 (m, 2H), 3.97 - 3.92 (m, 3H), 3.89 - 3.81 (m, 2H), 1.52 (s, 3H), 1.44 (s, 3H), 1.24 (d, J = 6.4 Hz, 6H).

[0131] QC data of isopropyl (S)-2-((((2-(6-amino-9H-purin-9-yl)ethoxy)methyl)(phenoxy)phosphoryl)amino)-2-methylpropanoate: LCMS: MS (ESI+): m / z =477.5 [M+H]+; 'HNMR (400 MHz, CDC13) 68.31 (s, 1H), 8.07 (s, 1H), 7.32 - 7.27 (m, 2H), 7.17 - 7.09 (m, 3H), 6.76 (br, 2H), 5.05 - 4.99 (m, 1H), 4.45 - 4.42 (m, 2H), 3.98 - 3.91 (m, 3H), 3.86 (dd, J = 7.8, 1.4 Hz, 2H), 1.53 (s, 3H), 1.44 (s, 3H), 1.24 (t, J = 6.4 Hz, 6H).EXAMPLE 2: CELL-BASED ASSAYS

[0132] EBV-Specific qPCR Assay Using Chemically Induced P3HR1 Cells. The following is an example of a assay that can be used to determine the anti -proliferative activity of Adefovir Compounds in a P3HR1 cell line at 10 days post-treatment. Primers and probes used in the assay were ordered HPLC cleaned: 5' EBV-F primer: 5'-TGA CCT CTT GCA TGG CCT CT-3' (Eurogentec Deutschland GmbH, 20 mer, nt 109283-109302); 3' EBV-R primer: 5'-CCT CTT TTC CAA GTC AGA ATT TGA C-3' (Eurogentec Deutschland GmbH, 25 mer, nt 109358-109334); EBV-F AM probe: 5'-CCA TCT ACC CAT CCT ACA CTG CGC TTT ACA-3' (Applied Biosystems by Thermo Fisher Scientific, 30 mer, nt 109332-109303), labelled with 5'-FAM and 3'-TAMRA. The amplicon size was 76 base pairs.

[0133] P3HR1 cells were cultured in 250ml T75 cell culture flasks (Greiner, #658175), and TPA was added to induce lytic cycle activation to a final concentration of 80 ng / mL.Induced cells were then plated into flat-bottom 96-well plates at 50 pL per well and incubated at 37°C in a humidified incubator for 90 minutes.

[0134] Adefovir Compounds were prepared by diluting them in RPMI 1640 Medium (Gibco, #31870-025) to the desired working concentrations (80 nM to 50 pM). After cell induction, 50 pL of the prepared compound solution was added to each well, resulting in a total reaction volume of 100 pL. Plates were incubated for 10 to 11 days at 37°C.

[0135] Cell supernatants were collected by transferring cell suspensions to pointed-bottom 96-well plates, followed by centrifugation at 2000 rpm for 5 minutes. A 20 pL aliquot of the supernatant from each well was transferred to a qPCR plate. A Protease K digestion was performed on each supernatant sample to ensure complete release of viral DNA.

[0136] The qPCR reactions were set up in a total volume of 50 pL per well, containing 5' EBV-F (2 pL, 5 pM) and 3' EBV-R (2 pL, 5 pM) primers, the EBV-F AM-Sonde (1 pL, 10 pM) probe, biology-grade water (10 pL), ABI Universal Master Mix (25 pL, Thermo Fisher Scientific) and the Extracted Sample (10 pL). Thermal cycling conditions included an initial UNG step at 50°C for 2 minutes, pre-denaturation at 95°C for 10 minutes, and 40 cycles of 95°C for 15 seconds (denaturation) and 60°C for 60 seconds (annealing and extension). Fluorescence signals were recorded using the FAM channel with ROX as a passive reference.

[0137] Ct values were recorded and normalized to controls or standards to assess the efficacy of the tested compounds. Comparisons of Ct shifts between treated and untreated groups were used to evaluate antiviral activity. Additionally, fluorescence intensity readings from a PicoMD ImageXpressR Pico device (Molecular Devices LLC, San Jose, CA, USA) were utilized to validate the qPCR results. Cell viability IC50 values were calculated using a four parameter logistic model (sigmoidal dose-response model):y = (A+ ((B-A) / (l + ((C / x)AD))))wherein:A = YxiinB — Y\laxC = EC50D = Hill slopeIC50 = the concentration of the compound when Y = 50% of DMSO controlY = cell viability measured as luminescence unit, andx = concentration of compound.EXAMPLE 3: IN VIVO ASSAYS

[0138] Adefovir Compounds have been, or will be tested in EBV infection models and have shown, or will be shown, to be effective as treatments therein.EXAMPLE 4: ACTIVITY TABLES

[0139] Each of the Adefovir Compounds in Table 1, was tested against published Tenofovir Compounds in one or more EBV cellular assay, for example, the P3HR-1 cellular assay. It was found that all of the compounds are active and have an IC50 below 25 pM in the assay, with some compounds having an IC50 below 200 nM (activity level D), some an IC50 from 200 nM to 500 nM (activity level C), some an IC50 from 501 nM to 1 pM (activity level B), and others having an IC50 above 1 pM (activity level A).Table 1>"><< >>"><><&<< <><>>><"&">>"<"><""">><>>"" >&&<<""<"<<<"><> > < "<&<""<"<

[0140] Each of the Adefovir Compounds in Table 2, was tested against published Tenofovir Compounds in one or more EBV cellular assay, for example, the P3HR-1 cellular assay. It was found that all of the compounds are active and have an IC50 below 25 pM in the assay, with some compounds having an IC50 below 100 nM (activity level D), some an IC50 from 100 nM to 1 pM (activity level C), some an IC50 from 1 pM to 10 pM (activity level B), and others having an IC50 above 10 pM (activity level A).Table 2.">"<>><"

[0141] The results in Table 2 indicate that compounds 2-6 and 2-7 showed substantially improved potency compared with Adefovir and Adefovir Dipivoxil in the EBV cellular assay.

[0142] A number of references have been cited, the disclosures of which are incorporated herein by reference in their entirety.

[0143] The embodiments described above are intended to be merely exemplary, and those skilled in the art will recognize, or will be able to ascertain using no more than routine experimentation, numerous equivalents of specific compounds, materials, andprocedures. All such equivalents are considered to be within the scope of the inventionand are encompassed by the appended claims.

Claims

What is claimed is:

1. A compound of formula (I):<(I),or a pharmaceutically acceptable salt, hydrate, solvate, tautomer, isotopolog, or stereoisomer thereof,wherein:Ri and R2 are each independently H or C1-6 alkyl, or Ri and R2 together with the single carbon to which they are bound form a C3-7 cycloalkyl;R3 is independently hydrogen, an optionally substituted C1-8 alkyl, an optionally substituted C2-8 alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkyl(Ci-C4 alkyl)-, an optionally substituted cycloalkenyl, an optionally substituted cycloalkenyl(Ci-C4 alkyl)-, an optionally substituted aryl, an optionally substituted aryl(Ci-C4 alkyl)-, an optionally substituted heteroaryl, an optionally substituted heteroaryl(Ci-C4 alkyl)-, an optionally substituted heterocyclyl, or an optionally substituted heterocyclyl(Ci-C4 alkyl)-; andAris independently an optionally substituted phenyl, an optionally substituted naphthyl, or an optionally substituted hydronaphthyl.

2. The compound or a pharmaceutically acceptable salt, hydrate, solvate, tautomer, isotopolog, or stereoisomer thereof of claim 1, wherein Ar is substituted with one or more substituents independently selected from F, Cl, Br, CH3, CH2CH3, n-propyl, isopropyl, n- butyl, sec-butyl, isobutyl, t-butyl, n-pentyl, isopentyl, CH2F, CHF2, CF3, CH2CH2F, CH2CHF2, CH2CF3, CH(CH3)CF3, CH2CH2CF3, OH, 0CH3, OCH2CH3, O-isopropyl, O-n-propyl, O-n-butyl, O-isobutyl, O-t-butyl, OCF3, O-cyclopropyl, O-cyclobutyl, OCH2.cyclopropyl, OCH2.cyclobutyl, CONH2, CONH(CH3), CON(CH3)2, SO2CH3, SO2CH2CH3, SO2-isopropyl, cyclopropyl, cyclobutyl, CH2-cyclopropyl, CH2-cyclobutyl.

3. The compound or a pharmaceutically acceptable salt, hydrate, solvate, tautomer, isotopolog, or stereoisomer thereof of claim 1 or 2, wherein the compound is of formula (II):

4. The compound or a pharmaceutically acceptable salt, hydrate, solvate, tautomer, isotopolog, or stereoisomer thereof of any one of claims 1 to 3, wherein:Ri and R2 are each independently H or methyl, or Ri and R2 together with the single carbon to which they are bound form a C3 cycloalkyl;R3 is independently methyl, ethyl, propyl, isopropyl or cyclopropyl; andAr is independently phenyl, p-chlorophenyl, naphthyl, or 5,6,7,8-tetrahydro-naphthyl, wherein the phenyl is optionally substituted with one or more substituents independently selected from F, Cl, CH3, CN, or CONH2.

5. The compound or a pharmaceutically acceptable salt, hydrate, solvate, tautomer, isotopolog, or stereoisomer thereof of any one of claims 1 to 4, wherein the compound is of formula (III):wherein R3 is methyl, ethyl, propyl, isopropyl or cyclopropyl.

6. The compound or a pharmaceutically acceptable salt, hydrate, solvate, tautomer, isotopolog, or stereoisomer thereof of any one of claims 1 to 4, wherein the compound is of formula (III):(IV),wherein R3 is methyl, ethyl, propyl, isopropyl or cyclopropyl.

7. The compound or a pharmaceutically acceptable salt, hydrate, solvate, tautomer, isotopolog, or stereoisomer thereof of any one of claims 1 to 4, wherein the compound is of formula (V):(V),wherein R3 is methyl, ethyl, propyl, isopropyl or cyclopropyl, and Ar is p-chlorophenyl, naphthyl, or 5,6,7,8-tetrahydro-naphthyl.

8. The compound or a pharmaceutically acceptable salt, hydrate, solvate, tautomer, isotopolog, or stereoisomer thereof of any one of claims 1 to 4, wherein the compound is of formula (VI):(VI),wherein R3 is methyl, ethyl, propyl, isopropyl or cyclopropyl, and Ar is p-chlorophenyl, naphthyl, or 5,6,7,8-tetrahydro-naphthyl.

9. The compound or a pharmaceutically acceptable salt, hydrate, solvate, tautomer, isotopolog, or stereoisomer thereof of any one of claims 1 to 8, wherein the compound is selected from the group consisting of-10. The compound or a pharmaceutically acceptable salt, hydrate, solvate, tautomer, isotopolog, or stereoisomer thereof of any one of claims 1 to 9, wherein the compound is selected from the group consisting ofil. The compound or a pharmaceutically acceptable salt, hydrate, solvate, tautomer, isotopolog, or stereoisomer thereof of any one of claims 1 to 10, wherein the compound is selected from the group consisting of- so12. A pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt, hydrate, solvate, tautomer, isotopologue, or stereoisomer thereof of any one of claims 1 to 11, and a pharmaceutically acceptable carrier, excipient or vehicle.

13. A method for the treatment or prevention of Epstein-Barr- Virus (EBV)-associated disease or condition, comprising administering to a subject in need thereof a compound of any one of claims 1 to 11, or a pharmaceutical composition of claim 12.

14. The method of claim 13, wherein the EBV associated disease or condition is infectious mononucleosis, nasopharyngeal carcinoma, Burkitt’s lymphoma, Hodgkin’s lymphoma, gastric carcinoma, systemic lupus erythematosus (SLE), multiple sclerosis (MS), PostTransplant Lymphoproliferative Disorders (PTLD) and the suppression of EBV reactivation in immunocompromised individuals such as transplant patients.

15. A compound of any one of claims 1 to 11 or a pharmaceutical composition of claim 12 for use in a method for the treatment or prevention of Epstein-Barr- Virus (EBV)-associated disease or condition, wherein the method comprises administering to a subject in need thereof the compound or the pharmaceutical composition.

16. The compound or pharmaceutical composition for use of claim 15, wherein the EBV- associated disease or condition is infectious mononucleosis, nasopharyngeal carcinoma, Burkitt’s lymphoma, Hodgkin’s lymphoma, gastric carcinoma, systemic lupus erythematosus (SLE), multiple sclerosis (MS), Post-Transplant Lymphoproliferative Disorders (PTLD) and the suppression of EBV reactivation in immunocompromised individuals such as transplant patients.

7. A method for preparing a compound of formula (I):(I),wherein the method comprises contacting 2-(6-aminopurin-9-yl)ethoxymethylphosphonicacid (Adefovir) with Ar-OH and, in the presence of a base, in a solvent, under conditions suitable to provide a compound of formula (I), wherein:Ri and R2 are each independently H or methyl, or Ri and R2 together with the single carbon to which they are bound form a C3 cycloalkyl;R3 is independently methyl, ethyl, propyl, isopropyl or cyclopropyl; andAr is independently phenyl, p-chlorophenyl, naphthyl, or 5,6,7,8-tetrahydro-naphthyl, wherein the phenyl is optionally substituted with one or more substituents independently selected from F, Cl, CH3, CN, or CONH2.

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