WO2025240608A1 - Cyclo-oxymethylene phosphonamidates and related compounds and their use in treating medical conditions - Google Patents

Abstract

Substituted cyclo-oxymethylene phosphonamidates and related compounds, pharmaceutical compositions, their use for inhibiting LINE1 reverse transcriptase and/or HERV-K reverse transcriptase activity, and their use in the treatment of medical disorders, such as cancer, are disclosed herein.

Description

CYCLO-OXYMETHYLENE PHOSPHONAMIDATES AND RELATED COMPOUNDS AND THEIR USE IN TREATING MEDICAL CONDITIONS CROSS REFERENCE TO RELATED APPLICATIONS _{[0001] This application claims the benefit of and priority to United States Provisional Patent} Application serial number 63/647,509, filed May 14, 2024, the contents of which are hereby incorporated by reference. REFERENCE TO AN ELECTRONIC SEQUENCE LISTING _{[0002] This application contains a Sequence Listing which has been submitted electronically} via Patent Center in XML format and is hereby incorporated by reference in its entirety. Said XML copy, created on May 13, 2025, is named 217871_seqlist.xml and is 2,719 bytes in size. FIELD OF THE DISCLOSURE _{[0003] Substituted cyclo-oxymethylene phosphonamidates and related compounds,} pharmaceutical compositions, their use for inhibiting LINE1 reverse transcriptase and/or HERV- K reverse transcriptase activity, and their use in the treatment of medical disorders, such as cancer, are disclosed herein. BACKGROUND _{[0004] Cancer continues to be a significant health problem despite the substantial research} efforts and scientific advances reported in the literature for treating this disease. Solid tumors, including prostate cancer, breast cancer, and lung cancer remain highly prevalent among the world population. Leukemias and lymphomas also account for a significant proportion of new cancer diagnoses. Current treatment options for these cancers are not effective for all patients and/or can have substantial adverse side effects. New therapies are needed to address this unmet need in cancer therapy. _{[0005] Accordingly, the need exists for new therapeutic methods that provide improved} efficacy and/or reduced side effects for treating medical disorders, such as cancer, inflammatory or immune disorders, or neurodegenerative disorders. The present disclosure addresses the foregoing needs and provides other related advantages. SUMMARY _{[0006] Substituted cyclo-oxymethylene phosphonamidates and related compounds,} pharmaceutical compositions, their use for inhibiting LINE1 reverse transcriptase and/or HERV- K reverse transcriptase activity, and their use in the treatment of medical disorders, such as cancer, are disclosed herein. In particular, one aspect of the disclosure provides a collection of substituted cyclo-oxymethylene phosphonamidates and related compounds, such as a compound represented by Formula I: or a pharmaceutically acceptable salt thereof, where the variables are as defined in the detailed description. Further description of additional collections of substituted cyclo-oxymethylene phosphonamidates and related compounds are described in the detailed description. The compounds may be part of a pharmaceutical composition comprising a pharmaceutically acceptable carrier. _{[0007] Another aspect of the disclosure provides a method of treating a disorder selected} from the group consisting of cancer, an inflammatory disorder, a neurodegenerative disorder, and an immune disorder. The method comprises administering a therapeutically effective amount of a compound described herein, such as a compound of Formula I, to a subject in need thereof to treat the disorder, as further described in the detailed description. _{[0008] Another aspect of the disclosure provides a method of inhibiting LINE1 reverse} transcriptase activity. The method comprises contacting a LINE1 reverse transcriptase with an effective amount of a compound described herein, such as a compound of Formula I in order to inhibit the activity of said LINE1 reverse transcriptase, as further described in the detailed description. _{[0009] Another aspect of the disclosure provides a method of inhibiting HERV-K reverse} transcriptase activity. The method comprises contacting a HERV-K reverse transcriptase with an effective amount of a compound described herein, such as a compound of Formula I in order to inhibit the activity of said HERV-K reverse transcriptase, as further described in the detailed description. DETAILED DESCRIPTION _{[0010] Substituted cyclo-oxymethylene phosphonamidates and related compounds,} pharmaceutical compositions, their use for inhibiting LINE1 reverse transcriptase and/or HERV- K reverse transcriptase activity, and their use in the treatment of medical disorders, such as cancer, are disclosed herein. The practice of the present disclosure employs, unless otherwise indicated, conventional techniques of organic chemistry, pharmacology, molecular biology (including recombinant techniques), cell biology, biochemistry, and immunology. Such techniques are explained in the literature, such as in “Comprehensive Organic Synthesis” (B.M. Trost & I. Fleming, eds., 1991-1992); “Comprehensive Organic Synthesis” (P. Knochel & G.A. Molander, eds., 2014), “Handbook of experimental immunology” (D.M. Weir & C.C. Blackwell, eds.); “Current protocols in molecular biology” (F.M. Ausubel et al., eds., 1987, and periodic updates); and “Current protocols in immunology” (J.E. Coligan et al., eds., 1991), each of which is herein incorporated by reference in its entirety. _{[0011] Various aspects of the disclosure are set forth below in sections; however, aspects of} the disclosure described in one particular section are not to be limited to any particular section. Further, when a variable is not accompanied by a definition, the previous definition of the variable controls. Definitions _{[0012] Compounds of the present disclosure include those described generally herein, and are} further illustrated by the classes, subclasses, and species disclosed herein. As used herein, the following definitions shall apply unless otherwise indicated. These definitions apply regardless of whether a term is used by itself or in combination with other terms, unless otherwise indicated. Hence, the definition of “alkyl” applies to “alkyl” as well as the “alkyl” portions of “-O-alkyl” etc. For purposes of this disclosure, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75^th Ed. Additionally, general principles of organic chemistry are described in “Organic Chemistry”, Thomas Sorrell, University Science Books, Sausalito: 1999, and “March’s Advanced Organic Chemistry”, 5^th Ed., Ed.: Smith, M.B. and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are hereby incorporated by reference. _{[0013] The term “aliphatic” or “aliphatic group”, as used herein, means a straight-chain (i.e.,} unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation, or a monocyclic hydrocarbon or bicyclic hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic (also referred to herein as “cycloaliphatic”), that has a single point of attachment to the rest of the molecule. Unless otherwise specified, aliphatic groups contain 1-6 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-5 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1-4 aliphatic carbon atoms. In still other embodiments, aliphatic groups contain 1-3 aliphatic carbon atoms, and in yet other embodiments, aliphatic groups contain 1-2 aliphatic carbon atoms. In some embodiments, “cycloaliphatic” refers to a monocyclic C3-C6 hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic, that has a single point of attachment to the rest of the molecule. Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl groups and hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl. _{[0014] As used herein, the term “bicyclic ring” or “bicyclic ring system” refers to any bicyclic} ring system, i.e. carbocyclic or heterocyclic, saturated or having one or more units of unsaturation, having one or more atoms in common between the two rings of the ring system. Thus, the term includes any permissible ring fusion, such as ortho-fused or spirocyclic. As used herein, the term “heterobicyclic” is a subset of “bicyclic” that requires that one or more heteroatoms are present in one or both rings of the bicycle. Such heteroatoms may be present at ring junctions and are optionally substituted, and may be selected from nitrogen (including N-oxides), oxygen, sulfur (including oxidized forms such as sulfones and sulfonates), phosphorus (including oxidized forms such as phosphates), boron, etc. In some embodiments, a bicyclic group has 7-12 ring members and 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. As used herein, the term “bridged bicyclic” refers to any bicyclic ring system, i.e. carbocyclic or heterocyclic, saturated or partially unsaturated, having at least one bridge. As defined by IUPAC, a “bridge” is an unbranched chain of atoms or an atom or a valence bond connecting two bridgeheads, where a “bridgehead” is any skeletal atom of the ring system which is bonded to three or more skeletal atoms (excluding hydrogen). In some embodiments, a bridged bicyclic group has 7-12 ring members and 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Such bridged bicyclic groups are well known in the art and include those groups set forth below where each group is attached to the rest of the molecule at any substitutable carbon or nitrogen atom. Unless otherwise specified, a bridged bicyclic group is optionally substituted with one or more substituents as set forth for aliphatic groups. Additionally, or alternatively, any substitutable nitrogen of a bridged bicyclic group is optionally substituted. Exemplary bicyclic rings include: _{[0015] Exemplary bridged bicyclics include: [0016] The term “lower alkyl” refers to a C1-4 straight or branched alkyl group. Exemplary} lower alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl. _{[0017] The term “lower haloalkyl” refers to a C1-4 straight or branched alkyl group that is} substituted with one or more halogen atoms. _{[0018] The term “heteroatom” means one or more of oxygen, sulfur, nitrogen, phosphorus, or} silicon (including, any oxidized form of nitrogen, sulfur, phosphorus, or silicon; the quaternized form of any basic nitrogen or; a substitutable nitrogen of a heterocyclic ring, for example N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR⁺ (as in N-substituted pyrrolidinyl)). _{[0019] The term “unsaturated,” as used herein, means that a moiety has one or more units of} unsaturation. _{[0020] As used herein, the term “bivalent C1-8 (or C1-6) saturated or unsaturated, straight or} branched, hydrocarbon chain”, refers to bivalent alkylene, alkenylene, and alkynylene chains that are straight or branched as defined herein. _{[0021] The term “alkylene” refers to a bivalent alkyl group. An “alkylene chain” is a} polymethylene group, i.e., –(CH2)n–, wherein n is a positive integer, preferably from 1 to 6, from 1 to 4, from 1 to 3, from 1 to 2, or from 2 to 3. A substituted alkylene chain is a polymethylene group in which one or more methylene hydrogen atoms are replaced with a substituent. Suitable substituents include those described below for a substituted aliphatic group. _{[0022] The term “-(C0 alkylene)-“ refers to a bond. Accordingly, the term “-(C0-3 alkylene)-”} encompasses a bond (i.e., C₀) and a -(C_1-3 alkylene)- group. _{[0023] The term “alkenylene” refers to a bivalent alkenyl group. A substituted alkenylene} chain is a polymethylene group containing at least one double bond in which one or more hydrogen atoms are replaced with a substituent. Suitable substituents include those described below for a substituted aliphatic group. _{[0024] The term “halogen” means F, Cl, Br, or I. [0025] The term “aryl” used alone or as part of a larger moiety as in “aralkyl,” “aralkoxy,” or} “aryloxyalkyl,” refers to monocyclic or bicyclic ring systems having a total of five to fourteen ring members, wherein at least one ring in the system is aromatic and wherein each ring in the system contains 3 to 7 ring members. The term “aryl” may be used interchangeably with the term “aryl ring.” In certain embodiments of the present disclosure, “aryl” refers to an aromatic ring system which includes, but not limited to, phenyl, biphenyl, naphthyl, anthracyl and the like, which may bear one or more substituents. Also included within the scope of the term “aryl,” as it is used herein, is a group in which an aromatic ring is fused to one or more non–aromatic rings, such as indanyl, phthalimidyl, naphthimidyl, phenanthridinyl, or tetrahydronaphthyl, and the like. The term “phenylene” refers to a multivalent phenyl group having the appropriate number of open valences to account for groups attached to it. For example, “phenylene” is a bivalent phenyl group when it has two groups attached to it (e.g., “phenylene” is a trivalent phenyl group when it has three groups attached to it (e.g., The term “arylene” refers to a bivalent aryl group. _{[0026] The terms “heteroaryl” and “heteroar–,” used alone or as part of a larger moiety, e.g.,} “heteroaralkyl,” or “heteroaralkoxy,” refer to groups having 5 to 10 ring atoms, preferably 5, 6, or 9 ring atoms; having 6, 10, or 14 ^ electrons shared in a cyclic array; and having, in addition to carbon atoms, from one to five heteroatoms. The term “heteroatom” refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quaternized form of a basic nitrogen. Heteroaryl groups include, without limitation, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl. The terms “heteroaryl” and “heteroar–”, as used herein, also include groups in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocyclyl rings, where unless otherwise specified, the radical or point of attachment is on the heteroaromatic ring or on one of the rings to which the heteroaromatic ring is fused. Nonlimiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H–quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, and tetrahydroisoquinolinyl. A heteroaryl group may be mono– or bicyclic. The term “heteroaryl” may be used interchangeably with the terms “heteroaryl ring,” “heteroaryl group,” or “heteroaromatic,” any of which terms include rings that are optionally substituted. The term “heteroaralkyl” refers to an alkyl group substituted by a heteroaryl, wherein the alkyl and heteroaryl portions independently are optionally substituted. _{[0027] The term “heteroarylene” refers to a multivalent heteroaryl group having the appropriate} number of open valences to account for groups attached to it. For example, “heteroarylene” is a bivalent heteroaryl group when it has two groups attached to it; “heteroarylene” is a trivalent heteroaryl group when it has three groups attached to it. The term “pyridinylene” refers to a multivalent pyridine radical having the appropriate number of open valences to account for groups attached to it. For example, “pyridinylene” is a bivalent pyridine radical when it has two groups attached to it (e.g., “pyridinylene” is a trivalent pyridine radical when it has three groups attached to it (e.g. _{[0028] As used herein, the terms “heterocycle,” “heterocyclyl,” “heterocyclic radical,” and} “heterocyclic ring” are used interchangeably and refer to a stable 5– to 7–membered monocyclic or 7–10–membered bicyclic heterocyclic moiety that is either saturated or partially unsaturated, and having, in addition to carbon atoms, one or more, preferably one to four, heteroatoms, as defined above. When used in reference to a ring atom of a heterocycle, the term "nitrogen" includes a substituted nitrogen. As an example, in a saturated or partially unsaturated ring having 0–3 heteroatoms selected from oxygen, sulfur or nitrogen, the nitrogen may be N (as in 3,4–dihydro– 2H–pyrrolyl), NH (as in pyrrolidinyl), or ⁺NR (as in N–substituted pyrrolidinyl). _{[0029] A heterocyclic ring can be attached to its pendant group at any heteroatom or carbon} atom that results in a stable structure and any of the ring atoms can be optionally substituted. Examples of such saturated or partially unsaturated heterocyclic radicals include, without limitation, tetrahydrofuranyl, tetrahydrothiophenyl pyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, 2-oxa-6- azaspiro[3.3]heptane, and quinuclidinyl. The terms “heterocycle,” “heterocyclyl,” “heterocyclyl ring,” “heterocyclic group,” “heterocyclic moiety,” and “heterocyclic radical,” are used interchangeably herein, and also include groups in which a heterocyclyl ring is fused to one or more aryl, heteroaryl, or cycloaliphatic rings, such as indolinyl, 3H–indolyl, chromanyl, phenanthridinyl, or tetrahydroquinolinyl. A heterocyclyl group may be mono– or bicyclic. The term “heterocyclylalkyl” refers to an alkyl group substituted by a heterocyclyl, wherein the alkyl _{and heterocyclyl portions independently are optionally substituted. The term “oxo-heterocyclyl”} refers to a heterocyclyl substituted by an oxo group. The term “heterocyclylene” refers to a multivalent heterocyclyl group having the appropriate number of open valences to account for groups attached to it. For example, “heterocyclylene” is a bivalent heterocyclyl group when it has two groups attached to it; “heterocyclylene” is a trivalent heterocyclyl group when it has three groups attached to it. _{[0030] As used herein, the term “partially unsaturated” refers to a ring moiety that includes at} least one double or triple bond. The term “partially unsaturated” is intended to encompass rings having multiple sites of unsaturation, but is not intended to include aryl or heteroaryl moieties, as herein defined. _{[0031] As described herein, compounds of the disclosure may contain “optionally substituted”} moieties. In general, the term “substituted,” whether preceded by the term “optionally” or not, means that one or more hydrogens of the designated moiety are replaced with a suitable substituent. Unless otherwise indicated, an “optionally substituted” group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position. Combinations of substituents envisioned by this disclosure are preferably those that result in the formation of stable or chemically feasible _{compounds. The term “stable,” as used herein, refers to compounds that are not substantially} altered when subjected to conditions to allow for their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein. _{[0032] Each optional substituent on a substitutable carbon is a monovalent substituent} independently selected from halogen; –(CH2)0–4R°; –(CH2)0–4OR°; -O(CH2)0-4R^o, –O–(CH2)0– 4C(O)OR°; –(CH2)0–4CH(OR°)2; –(CH2)0–4SR°; –(CH2)0–4Ph, which may be substituted with R°; –(CH₂)_0–4O(CH₂)_0–1Ph which may be substituted with R°; –CH=CHPh, which may be substituted with R°; –(CH2)0–4O(CH2)0–1-pyridyl which may be substituted with R°; –NO2; –CN; – N3; -(CH2)0–4N(R°)2; –(CH2)0–4N(R°)C(O)R°; –N(R°)C(S)R°; –(CH2)0–4N(R°)C(O)NR°2; -N(R°)C(S)NR°₂; –(CH₂)_0–4N(R°)C(O)OR°; –N(R°)N(R°)C(O)R°; -N(R°)N(R°)C(O)NR°₂; -N(R°)N(R°)C(O)OR°; –(CH₂)_0–4C(O)R°; –C(S)R°; –(CH₂)_0–4C(O)OR°; –(CH₂)_0–4C(O)SR°; -(CH2)0–4C(O)OSiR°3; –(CH2)0–4OC(O)R°; –OC(O)(CH2)0–4SR–, SC(S)SR°; –(CH2)0–4SC(O)R°; –(CH2)0–4C(O)NR°2; –C(S)NR°2; –C(S)SR°; –SC(S)SR°, -(CH2)0–4OC(O)NR°2; _{-C(O)N(OR°)R°; –C(O)C(O)R°; –C(O)CH2C(O)R°; –C(NOR°)R°; -(CH2)0–4SSR°; –(CH2)0–} 4S(O)2R°; –(CH2)0–4S(O)2OR°; –(CH2)0–4OS(O)2R°; –S(O)2NR°2; –S(O)(NR°)R°; – S(O)2N=C(NR°2)2; -(CH2)0–4S(O)R°; -N(R°)S(O)2NR°2; –N(R°)S(O)2R°; –N(OR°)R°; – C(NH)NR°₂; –P(O)₂R°; -P(O)R°₂; -OP(O)R°₂; –OP(O)(OR°)₂; SiR°₃; –(C_1–4 straight or branched alkylene)O–N(R°)2; or –(C1–4 straight or branched alkylene)C(O)O–N(R°)2. _{[0033] Each R° is independently hydrogen, C1–6 aliphatic, –CH2Ph, –O(CH2)0–1Ph, -CH2-(5-6} membered heteroaryl ring), or a 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R°, taken together with their intervening atom(s), form a 3–12–membered saturated, partially unsaturated, or aryl mono– or bicyclic ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which may be substituted by a divalent substituent on a saturated carbon atom of R° selected from =O and =S; or each R° is optionally substituted with a monovalent substituent independently selected from halogen, –(CH₂)_0–2R^l, –(haloR^l), –(CH₂)_0–2OH, –(CH₂)_0–2OR^l, – (CH2)0–2CH(OR^l)2; -O(haloR^l), –CN, –N3, –(CH2)0–2C(O)R^l, –(CH2)0–2C(O)OH, –(CH2)0– 2C(O)OR^l, –(CH2)0–2SR^l, –(CH2)0–2SH, –(CH2)0–2NH2, –(CH2)0–2NHR^l, –(CH2)0–2NR^l2, –NO2, – SiR^l ₃, –OSiR^l ₃, -C(O)SR^l _, –(C_1–4 straight or branched alkylene)C(O)OR^l, or –SSR^l. _{[0034] Each Rl is independently selected from C1–4 aliphatic, –CH2Ph, –O(CH2)0–1Ph, or a 5–} 6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and wherein each R^l is unsubstituted or where preceded by halo is substituted only with one or more halogens; or wherein an optional substituent on a saturated carbon is a divalent substituent independently selected from =O, =S, =NNR^*2, =NNHC(O)R^*, =NNHC(O)OR^*, =NNHS(O)2R^*, =NR^*, =NOR^*, –O(C(R^*2))2–3O–, or – S(C(R^* ₂))_2–3S–, or a divalent substituent bound to vicinal substitutable carbons of an “optionally _{substituted” group is –O(CR* 2)2–3O–, wherein each independent occurrence of R* is selected} from hydrogen, C1–6 aliphatic or an unsubstituted 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. _{[0035] When R* is C1–6 aliphatic, R* is optionally substituted with halogen, –} R^l, -(haloR^l), -OH, –OR^l, –O(haloR^l), –CN, –C(O)OH, –C(O)OR^l, –NH2, –NHR^l, –NR^l2, or – NO2, wherein each R^l is independently selected from C1–4 aliphatic, –CH2Ph, –O(CH2)0–1Ph, or a 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and wherein each R^l is unsubstituted or where preceded by halo is substituted only with one or more halogens. _{[0036] An optional substituent on a substitutable nitrogen is independently –R†, –NR† 2, –} C(O)R^†, –C(O)OR^†, –C(O)C(O)R^†, –C(O)CH2C(O)R^†, -S(O)2R^†, -S(O)2NR^†2, –C(S)NR^†2, – C(NH)NR^†2, or –N(R^†)S(O)2R^†; wherein each R^† is independently hydrogen, C1–6 aliphatic, unsubstituted –OPh, or an unsubstituted 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, two independent occurrences of R^†, taken together with their intervening atom(s) form an unsubstituted 3–12–membered saturated, partially unsaturated, or aryl mono– or bicyclic ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; wherein when R^† is C1–6 aliphatic, R^† is optionally substituted with halogen, –R^l, -(haloR^l), -OH, –OR^l, – O(haloR^l), –CN, –C(O)OH, –C(O)OR^l, –NH2, –NHR^l, –NR^l2, or –NO2, wherein each R^l is independently selected from C_1–4 aliphatic, –CH₂Ph, –O(CH₂)_0–1Ph, or a 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and wherein each R^l is unsubstituted or where preceded by halo is substituted only with one or more halogens. _{[0037] As used herein, the term "pharmaceutically acceptable salt" refers to those salts which} are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1–19, incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of this disclosure include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2–hydroxy–ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2–naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3–phenylpropionate, phosphate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p–toluenesulfonate, undecanoate, valerate salts, and the like. _{[0038] Further, acids which are generally considered suitable for the formation of} pharmaceutically useful salts from basic pharmaceutical compounds are discussed, for example, by P. Stahl et al., Camille G. (eds.) Handbook of Pharmaceutical Salts. Properties, Selection and Use. (2002) Zurich: Wiley-VCH; S. Berge et al., Journal of Pharmaceutical Sciences (1977) 66(1) 1-19; P. Gould, International J. of Pharmaceutics (1986) 33201-217; Anderson et al., The Practice of Medicinal Chemistry (1996), Academic Press, New York; and in The Orange Book (Food & Drug Administration, Washington, D.C. on their website). These disclosures are incorporated herein by reference. _{[0039] Salts derived from appropriate bases include alkali metal, alkaline earth metal,} ammonium and N⁺(C_1–4alkyl)₄ salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and aryl sulfonate. _{[0040] Unless otherwise stated, structures depicted herein are also meant to include all isomeric} (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, the R and S configurations for each asymmetric center, Z and E double bond isomers, and Z and E conformational isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of the disclosure. Unless otherwise stated, all tautomeric forms of the compounds of the disclosure are within the scope of the disclosure. Additionally, unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures including the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by a ¹³C- or ¹⁴C-enriched carbon are within the scope of this disclosure. Such compounds are useful, for example, as analytical tools, as probes in biological assays, or as therapeutic agents in accordance with the present disclosure. _{[0041] Diastereomeric mixtures can be separated into their individual diastereomers on the} basis of their physical chemical differences by methods known to those skilled in the art, such as, for example, by chromatography and/or fractional crystallization. Enantiomers can be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., chiral auxiliary such as a chiral alcohol or Mosher’s acid chloride), separating the diastereomers and converting (e.g., hydrolyzing) the individual diastereomers to the corresponding pure enantiomers. Alternatively, a particular enantiomer of a compound of the present disclosure may be prepared by asymmetric synthesis. Still further, where the molecule contains a basic functional group (such as amino) or an acidic functional group (such as carboxylic acid) diastereomeric salts are formed with an appropriate optically- active acid or base, followed by resolution of the diastereomers thus formed by fractional crystallization or chromatographic means known in the art, and subsequent recovery of the pure enantiomers. _{[0042] Individual stereoisomers of the compounds of the disclosure may, for example, be} substantially free of other isomers, or may be admixed, for example, as racemates or with all other, or other selected, stereoisomers. Chiral center(s) in a compound of the present disclosure can have the S or R configuration as defined by the IUPAC 1974 Recommendations. Further, to the extent a compound described herein may exist as a atropisomer (e.g., substituted biaryls), all forms of such atropisomer are considered part of this disclosure. _{[0043] Chemical names, common names, and chemical structures may be used} interchangeably to describe the same structure. If a chemical compound is referred to using both a chemical structure and a chemical name, and an ambiguity exists between the structure and the name, the structure predominates. It should also be noted that any carbon as well as heteroatom with unsatisfied valences in the text, schemes, examples and tables herein is assumed to have the sufficient number of hydrogen atom(s) to satisfy the valences. _{[0044] The terms “a” and “an” as used herein mean “one or more” and include the plural} unless the context is inappropriate. _{[0045] The term “alkyl” refers to a saturated straight or branched hydrocarbon, such as a} straight or branched group of 1-12, 1-10, or 1-6 carbon atoms, referred to herein as C1-C12 alkyl, C₁-C₁₀ alkyl, and C₁-C₆ alkyl, respectively. Exemplary alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3- methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1- butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, etc. _{[0046] The term “cycloalkyl” refers to a monovalent saturated cyclic, bicyclic, or bridged} cyclic (e.g., adamantyl) hydrocarbon group of 3-12, 3-8, 4-8, or 4-6 carbons, referred to herein, e.g., as “C3-C6 cycloalkyl,” derived from a cycloalkane. Exemplary cycloalkyl groups include cyclohexyl, cyclopentyl, cyclobutyl, and cyclopropyl. The term “cycloalkylene” refers to a bivalent cycloalkyl group. _{[0047] The term “haloalkyl” refers to an alkyl group that is substituted with at least one} halogen. Exemplary haloalkyl groups include -CH2F, -CHF2, -CF3, -CH2CF3, -CF2CF3, and the like. The term “haloalkylene” refers to a bivalent haloalkyl group. The term “halomethyl” refers to a haloalkyl group containing a single carbon atom. _{[0048] The term “hydroxyalkyl” refers to an alkyl group that is substituted with at least one} hydroxyl. Exemplary hydroxyalkyl groups include -CH₂CH₂OH, -C(H)(OH)CH₃, -CH2C(H)(OH)CH2CH2OH, and the like. _{[0049] The terms “alkenyl” and “alkynyl” are art-recognized and refer to unsaturated} aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double or triple bond respectively. _{[0050] The term “carbocyclylene” refers to a multivalent carbocyclyl group having the} appropriate number of open valences to account for groups attached to it. For example, “carbocyclylene” is a bivalent carbocyclyl group when it has two groups attached to it; “carbocyclylene” is a trivalent carbocyclyl group when it has three groups attached to it. _{[0051] The terms “alkoxyl” or “alkoxy” are art-recognized and refer to an alkyl group, as} defined above, having an oxygen radical attached thereto. Representative alkoxyl groups include methoxy, ethoxy, propyloxy, tert-butoxy and the like. The term “haloalkoxyl” refers to an alkoxyl group that is substituted with at least one halogen. Exemplary haloalkoxyl groups include -OCH₂F, -OCHF₂, -OCF₃, -OCH₂CF₃, -OCF₂CF₃, and the like. _{[0052] The term “oxo” is art-recognized and refers to a “=O” substituent. For example, a} cyclopentane substituted with an oxo group is cyclopentanone. _{[0053] The symbol “ ” indicates a point of attachment. [0054] When a chemical structure containing a ring is depicted with a substituent having a} bond that crosses a ring bond, the substituent may be attached at any available position on the ring. For example, the chemical structure encompasses and . In the context of a polycyclic fused ring, when a chemical structure containing a polycyclic fused ring is depicted with one or more substituent(s) having a bond that crosses multiple rings, the one or more substituent(s) may be independently attached to any of the rings crossed by the bond. To illustrate, the chemical structure encompasses, for example, _{[0055] When any substituent or variable occurs more than one time in any constituent or the} compound of the disclosure, its definition on each occurrence is independent of its definition at every other occurrence, unless otherwise indicated. _{[0056] One or more compounds of the disclosure may exist in unsolvated as well as solvated} forms with pharmaceutically acceptable solvents such as water, ethanol, and the like, and it is intended that the disclosure embrace both solvated and unsolvated forms. “Solvate” means a physical association of a compound of this disclosure with one or more solvent molecules. This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In certain instances the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid. “Solvate” encompasses both solution-phase and isolatable solvates. Non-limiting examples of suitable solvates include ethanolates, methanolates, and the like. “Hydrate” is a solvate wherein the solvent molecule is H₂O. _{[0057] As used herein, the terms “subject” and “patient” are used interchangeably and refer to} organisms to be treated by the methods of the present disclosure. Such organisms preferably include, but are not limited to, mammals (e.g., murines, simians, equines, bovines, porcines, canines, felines, and the like), and most preferably includes humans. _{[0058] The term “IC50” is art-recognized and refers to the concentration of a compound that is} required to achieve 50% inhibition of the target. _{[0059] As used herein, the term “effective amount” refers to the amount of a compound} sufficient to effect beneficial or desired results (e.g., a therapeutic, ameliorative, inhibitory or preventative result). An effective amount can be administered in one or more administrations, applications or dosages and is not intended to be limited to a particular formulation or administration route. As used herein, the term “treating” includes any effect, e.g., lessening, reducing, modulating, ameliorating or eliminating, that results in the improvement of the condition, disease, disorder, and the like, or ameliorating a symptom thereof. _{[0060] As used herein, the term “pharmaceutical composition” refers to the combination of an} active agent with a carrier, inert or active, making the composition especially suitable for diagnostic or therapeutic use in vivo or ex vivo. _{[0061] As used herein, the term “pharmaceutically acceptable carrier” refers to any of the} standard pharmaceutical carriers, such as a phosphate buffered saline solution, water, emulsions (e.g., such as an oil/water or water/oil emulsions), and various types of wetting agents. The compositions also can include stabilizers and preservatives. For examples of carriers, stabilizers and adjuvants, see e.g., Martin, Remington’s Pharmaceutical Sciences, 15th Ed., Mack Publ. Co., Easton, PA [1975]. _{[0062] For therapeutic use, salts of the compounds of the present disclosure are contemplated} as being pharmaceutically acceptable. However, salts of acids and bases that are non- pharmaceutically acceptable may also find use, for example, in the preparation or purification of a pharmaceutically acceptable compound. _{[0063] In addition, when a compound of the disclosure contains both a basic moiety (such as,} but not limited to, a pyridine or imidazole) and an acidic moiety (such as, but not limited to, a carboxylic acid) zwitterions (“inner salts”) may be formed. Such acidic and basic salts used within the scope of the disclosure are pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salts. Such salts of the compounds of the disclosure may be formed, for example, by reacting a compound of the disclosure with an amount of acid or base, such as an equivalent amount, in a medium such as one in which the salt precipitates or in an aqueous medium followed by lyophilization. _{[0064] Throughout the description, where compositions are described as having, including, or} comprising specific components, or where processes and methods are described as having, including, or comprising specific steps, it is contemplated that, additionally, there are compositions of the present disclosure that consist essentially of, or consist of, the recited components, and that there are processes and methods according to the present disclosure that consist essentially of, or consist of, the recited processing steps. _{[0065] As a general matter, compositions specifying a percentage are by weight unless} otherwise specified. I. Substituted Cyclo-oxymethylene Phosphonamidates and Related Compounds _{[0066] Substituted cyclo-oxymethylene phosphonamidates and related compounds, are} disclosed herein. The compounds may be used in the pharmaceutical compositions and therapeutic methods described herein. Exemplary compounds are described in the following sections, along with exemplary procedures for making the compounds. _{[0067] One aspect of the disclosure provides a compound represented by Formula I:} or a pharmaceutically acceptable salt thereof; wherein: R¹ is -OH, -O-(phenyl substituted with m instances of R⁵), -O-(C1-4 alkylene)-OC(O)O- (C_1-10 alkyl), or -N(R⁶)(R⁷); R² is -OR¹⁰, -N(R⁶)(R⁷), or -(C_1-4 alkylene)-C(O)O-(C_1-10 alkyl); R³ is halo, C1-6 alkyl, C2-4 alkynyl, cyano, C1-6 haloalkyl, or -CD3; R⁴ is hydrogen, halo, or deuterium; R⁵ represents independently for each occurrence halo, C_1-6 alkyl, C_1-4 alkoxyl, or -(C_0-4 alkylene)-C(R⁸)3; R⁶ represents independently for each occurrence hydrogen or C1-6 alkyl; R⁷ represents independently for each occurrence -C(R⁸)₂-C(O)O-R⁹; or when R⁶ and R⁷ are attached to the same nitrogen atom, R⁶ and R⁷ together with the nitrogen atom to which they are attached, form a 5- or 6- membered saturated heterocyclic ring, substituted with n instances of R¹¹; R⁸ represents independently for each occurrence hydrogen, C_1-6 alkyl, -(C_0-4 alkylene)- C(O)O-R⁹, -N(R⁶)-C(O)O-R⁹, or -(C0-4 alkylene)-phenyl; R⁹ represents independently for each occurrence C1-10 alkyl, -(C0-3 alkylene)-phenyl, or - (C_0-3 alkylene)-(3-6 membered saturated monocyclic carbocyclic ring); R¹⁰ is hydrogen or -(C1-4 alkylene)-OC(O)O-(C1-10 alkyl); R¹¹ is -(C0-4 alkylene)-C(O)O-(C1-10 alkyl); m is 0, 1, 2, or 3; and n is 0, 1, or 2. _{[0068] In certain embodiments, the compound is a compound of Formula I. In certain} embodiments, the compound is a pharmaceutically acceptable salt of a compound of Formula I. In certain embodiments, the pharmaceutically acceptable salt is an ammonium salt. _{[0069] As defined generally above, R1 is -OH, -O-(phenyl substituted with m instances of} R⁵), -O-(C1-4 alkylene)-OC(O)O-(C1-10 alkyl), or -N(R⁶)(R⁷). In certain embodiments, R¹ is -OH. _{In certain embodiments, R1 is -O-(phenyl substituted with m instances of R5). In certain} embodiments, R¹ is -O-(C1-4 alkylene)-OC(O)O-(C1-10 alkyl). In certain embodiments, R¹ is - N(R⁶)(R⁷). _{[0070] In certain embodiments, R1 is -O-(phenyl substituted with m instances of R5) or -O(C1- 4} alkylene)-OC(O)O-(C_1-10 alkyl). In certain embodiments, R¹ is -O-(C_1-2 alkylene)-OC(O)O-(C_1- 3 alkyl). In certain embodiments, R¹ is -O-(C1-2 alkylene)-OC(O)O-(C4-10 alkyl). In certain embodiments, R¹ is selected from those disclosed in Table 1, below. _{[0071] As defined generally above, R2 is -OR10, -N(R6)(R7), or -(C1-4 alkylene)-C(O)O-(C1-10} alkyl). In certain embodiments, R² is -OR¹⁰. In certain embodiments, R² is -OH. In certain embodiments, R² is -N(R⁶)(R⁷). In certain embodiments, R² is -NH(R⁷). In certain embodiments, R² is -(C1-4 alkylene)-C(O)O-(C1-10 alkyl). [_{0072] In certain embodiments, R2 is -OH,} , , , , , , _{In certain embodiments,} R² is selected from those disclosed in Table 1, below. [_{0073] As defined generally above, R3 is halo, C1-6 alkyl, C2-4 alkynyl, cyano, C1-6 haloalkyl,} or -CD₃. In certain embodiments, R³ is halo. In certain embodiments, R³ is C_1-6 alkyl. In certain embodiments, R³ is C2-4 alkynyl. In certain embodiments, R³ is cyano. In certain embodiments, R³ is C1-6 haloalkyl. In certain embodiments, R³ is -CD3. [_{0074] In certain embodiments, R3 is halo, C1-6 alkyl, C2-4 alkynyl, cyano, C1-6 haloalkyl, or -} CD3. In certain embodiments, R³ is C1-6 alkyl, C2-4 alkynyl, cyano, C1-6 haloalkyl, or -CD3. In certain embodiments, R³ is methyl or ethynyl. In certain embodiments, R³ is methyl. In certain embodiments, R³ is ethynyl. In certain embodiments, R³ is cyano, -CF₃, or -CD₃. In certain embodiments, R³ is F, Cl, Br, or I. In certain embodiments, R³ is F or Cl. In certain embodiments, R³ is selected from those disclosed in Table 1, below. [_{0075] As defined generally above, R4 is hydrogen, halo, or deuterium. In certain} embodiments, R⁴ is hydrogen. In certain embodiments, R⁴ is halo. In certain embodiments, R⁴ is F, Cl, Br, or I. In certain embodiments, R⁴ is F or Cl. In certain embodiments, R⁴ is F. In certain embodiments, R⁴ is deuterium. In certain embodiments, R⁴ is selected from those disclosed in Table 1, below. _{[0076] As defined generally above, R5 represents independently for each occurrence halo, C1- 6} alkyl or C_1-4 alkoxyl, or -(C_0-4 alkylene)-C(R⁸)₃. In certain embodiments, R⁵ represents independently for each occurrence -(C0-4 alkylene)-C(R⁸)3. In certain embodiments, R⁵ represents independently for each occurrence halo. In certain embodiments, R⁵ represents independently for each occurrence C_1-6 alkyl. In certain embodiments, R⁵ represents independently for each occurrence C1-4 alkoxyl. _{[0077] In certain embodiments, R5 is halo, C1-6 alkyl or C1-4 alkoxyl, or -(C0-4 alkylene)-} C(R⁸)₃. In certain embodiments, R⁵ is -(C_0-4 alkylene)-C(R⁸)₃. In certain embodiments, R⁵ is halo. In certain embodiments, R⁵ is C_1-6 alkyl. In certain embodiments, R⁵ is C_1-4 alkoxyl. In certain embodiments, R⁵ is F, Cl, Br, or I. In certain embodiments, R⁵ is bromo. In certain embodiments, R⁵ is methyl. In certain embodiments, R⁵ is methoxy. In certain embodiments, R⁵ is R⁵ is -(C_0-2 alkylene)-CH(R⁸)₂. In certain embodiments, R⁵ is selected from those disclosed in Table 1, below. _{[0078] As defined generally above, R6 represents independently for each occurrence} hydrogen or C_1-6 alkyl. In certain embodiments, R⁶ represents independently for each occurrence C1-6 alkyl. In certain embodiments, R⁶ is hydrogen. In certain embodiments, R⁶ is C1-6 alkyl. In certain embodiments, R⁶ is methyl. In certain embodiments, R⁶ is ethyl. In certain embodiments, R⁶ is represents independently for each occurrence hydrogen or methyl. In certain embodiments, R⁶ is selected from those disclosed in Table 1, below. _{[0079] As defined generally above, R7 represents independently for each occurrence -C(R8)2-} C(O)O-R⁹. In certain embodiments, R⁷ represents independently for each occurrence -CH2- C(O)O-R⁹. In certain embodiments, R⁷ represents independently for each occurrence -CHR⁸- C(O)O-R⁹. In certain embodiments, R⁷ represents independently for each occurrence -CHR⁸- C(O)O-(C1-10 alkyl). In certain embodiments, R⁷ represents independently for each occurrence - CH(CH₃)-C(O)O-(C_1-10 alkyl). In certain embodiments, R⁷ is -CH₂-C(O)O-R⁹. In certain embodiments, R⁷ is -CHR⁸-C(O)O-R⁹. In certain embodiments, R⁷ is -CHR⁸-C(O)O-(C1-10 alkyl). In certain embodiments, R⁷ is -CH(CH₃)-C(O)O-(C_1-10 alkyl). In certain embodiments, R⁷ is selected from those disclosed in Table 1, below. _{[0080] As defined generally above, when R6 and R7 are attached to the same nitrogen atom,} R⁶ and R⁷ together with the nitrogen atom to which they are attached, form a 5- or 6- membered _{saturated heterocyclic ring, substituted with n instances of R11. In certain embodiments, when R6} and R⁷ are attached to the same nitrogen atom, R⁶ and R⁷, together with the nitrogen atom to which they are bonded, form a 5-membered saturated heterocyclic ring, substituted with n instances of R¹¹. In certain embodiments, when R⁶ and R⁷ are attached to the same nitrogen atom, R⁶ and R⁷, together with the nitrogen atom to which they are bonded, form a 6-membered saturated heterocyclic ring, substituted with n instances of R¹¹ _. In certain embodiments, R⁶ and R⁷ are selected from those disclosed in Table 1, below. _{[0081] As defined generally above, R8 represents independently for each occurrence} hydrogen, C1-6 alkyl, -(C0-4 alkylene)-C(O)O-R⁹, -N(R⁶)-C(O)O-R⁹, or -(C0-4 alkylene)-phenyl. In certain embodiments, R⁸ represents independently for each occurrence C_1-6 alkyl. In certain embodiments, R⁸ represents independently for each occurrence -(C0-4 alkylene)-C(O)O-R⁹. In certain embodiments, R⁸ represents independently for each occurrence N(R⁶)-C(O)O-R⁹. In certain embodiments, R⁸ represents independently for each occurrence -(C_0-4 alkylene)-phenyl. In certain embodiments, R⁸ is hydrogen. _{[0082] In certain embodiments, R8 represents independently for each occurrence hydrogen,} C_1-6 alkyl, -(C_0-4 alkylene)-C(O)O-(C_1-10 alkyl), or -N(H)-C(O)O-(C_1-10 alkyl). In certain embodiments, R⁸ represents independently for each occurrence hydrogen or C_1-6 alkyl. In certain embodiments, R⁸ represents independently for each occurrence -(C0-4 alkylene)-C(O)O-R⁹ or - N(R⁶)-C(O)O-R⁹. In certain embodiments, R⁸ is C1-6 alkyl. In certain embodiments, R⁸ is -(C0-4 alkylene)-C(O)O-R⁹. In certain embodiments, R⁸ is -(C_0-4 alkylene)-phenyl. In certain embodiments, R⁸ is -N(R⁶)-C(O)O-R⁹. In certain embodiments, R⁸ is selected from those disclosed in Table 1, below. _{[0083] As defined generally above, R9 represents independently for each occurrence C1-10} alkyl, -(C0-3 alkylene)-phenyl, or -(C0-3 alkylene)-(3-6 membered saturated monocyclic carbocyclic ring). In certain embodiments, R⁹ represents independently for each occurrence C1-10 alkyl. In certain embodiments, R⁹ represents independently for each occurrence -(C_0-3 alkylene)- phenyl. In certain embodiments, R⁹ represents independently for each occurrence -(C_0-3 alkylene)-(3-6 membered saturated monocyclic carbocyclic ring). In certain embodiments, R⁹ represents independently for each occurrence -(C0-3 alkylene)-phenyl or -(C0-3 alkylene)-(3-6 membered saturated monocyclic carbocyclic ring). In certain embodiments, R⁹ represents independently for each occurrence C1-3 alkyl. In certain embodiments, R⁹ represents independently for each occurrence C4-10 alkyl. In certain embodiments, R⁹ represents independently for each occurrence C_1-3 alkyl, -(C_0-3 alkylene)-phenyl, or -(C_0-3 alkylene)-(3-6 membered saturated monocyclic carbocyclic ring). In certain embodiments, R⁹ represents independently for each occurrence C4-10 alkyl, -(C0-3 alkylene)-phenyl, or -(C0-3 alkylene)-(3-6 membered saturated monocyclic carbocyclic ring). _{[0084] In certain embodiments, R9 is C1-10 alkyl. In certain embodiments, R9 is -(C0-3} alkylene)-phenyl. In certain embodiments, R⁹ is -(C0-3 alkylene)-(3-6 membered saturated monocyclic carbocyclic ring). In certain embodiments, R⁹ is -(C0-3 alkylene)-phenyl or -(C0-3 alkylene)-(3-6 membered saturated monocyclic carbocyclic ring). In certain embodiments, R⁹ is C1-3 alkyl. In certain embodiments, R⁹ is C4-10 alkyl. In certain embodiments, R⁹ is C1-3 alkyl, - (C0-3 alkylene)-phenyl, or -(C0-3 alkylene)-(3-6 membered saturated monocyclic carbocyclic ring). In certain embodiments, R⁹ is C_4-10 alkyl, -(C_0-3 alkylene)-phenyl, or -(C_0-3 alkylene)-(3-6 membered saturated monocyclic carbocyclic ring). In certain embodiments, R⁹ represents independently for each occurrence a -(C0-3 alkylene)-(3 membered saturated monocyclic carbocyclic ring). In certain embodiments, R⁹ represents independently for each occurrence a - (C_0-3 alkylene)-(4 membered saturated monocyclic carbocyclic ring). In certain embodiments, R⁹ is selected from those disclosed in Table 1, below. _{[0085] As defined generally above, R10 is hydrogen or -(C1-4 alkylene)-OC(O)O-(C1-10 alkyl).} In certain embodiments, R¹⁰ is hydrogen. In certain embodiments, R¹⁰ is -(C_1-4 alkylene)- OC(O)O-(C1-10 alkyl). In certain embodiments, R¹⁰ is hydrogen or -(C1-4 alkylene)-OC(O)O-(C1-3 alkyl). In certain embodiments, R¹⁰ is hydrogen or -(C1-4 alkylene)-OC(O)O-(C4-10 alkyl). In certain embodiments, R¹⁰ is -(C_1-4 alkylene)-OC(O)O-(C_1-3 alkyl). In certain embodiments, R¹⁰ is -(C_1-4 alkylene)-OC(O)O-(C_4-10 alkyl). In certain embodiments, R¹⁰ is selected from those disclosed in Table 1, below. _{[0086] As defined generally above, R11 is -(C0-4 alkylene)-C(O)O-(C1-10 alkyl). In certain} embodiments, R¹¹ is -C(O)O-(C_1-10 alkyl). In certain embodiments, R¹¹ is -C(O)O-(C_1-3 alkyl). In certain embodiments, R¹¹ is selected from those disclosed in Table 1, below. _{[0087] As defined generally above, m is 0, 1, 2, or 3. In certain embodiments, m is 0. In} certain embodiments, m is 1. In certain embodiments, m is 2. In certain embodiments, m is 3. In certain embodiments, m is selected from the values represented in the compounds in Table 1, below. _{[0088] As defined generally above, n is 0, 1, or 2. In certain embodiments, n is 0. In certain} embodiments, n is 1. In certain embodiments, n is 2. In certain embodiments, n is selected from the values represented in the compounds in Table 1, below. _{[0089] In certain embodiments, the compound of Formula I is represented by Formula I-a or} I-b, or a pharmaceutically acceptable salt thereof: wherein all variables therein are as defined for Formula I, above. _{[0090] In certain embodiments, the compound of Formula I is represented by Formula I-c, or} a pharmaceutically acceptable salt thereof: I-c wherein all variables therein are as defined for Formula I, above. In some embodiments, a compound is of Formula I-c, wherein R² is -N(R⁶)(R⁷). In some embodiments, a compound is of Formula I-c, wherein R³ is alkynyl. In some embodiments, a compound is of Formula I-c, wherein R⁴ is hydrogen. In some embodiments, a compound is of Formula I-c, wherein R² is - N(R⁶)(R⁷), R³ is C2 alkynyl, and R⁴ is hydrogen. _{[0091] In certain embodiments, the compound of Formula I is represented by Formula I-d, or} a pharmaceutically acceptable salt thereof: wherein all variables therein are as defined for Formula I, above. _{[0092] In certain embodiments, the compound is a pharmaceutically acceptable salt of a} compound of Formula I, represented by Formula I-e: wherein X is a pharmaceutically acceptable acid, and wherein all other variables therein are as defined for Formula I, above. In certain embodiments, the ratio of acid to free base is between 0.5 and 3. In certain embodiments, the ratio of acid to free base is between 1 and 2. In certain embodiments, the ratio of acid to free base is about 1. In certain embodiments, the ratio of acid to free base is about 2. _{[0093] The description above describes multiple embodiments relating to compounds of} Formula I. The patent application specifically contemplates all combinations of the embodiments. _{[0094] Another aspect of the disclosure provides a compound in Table 1, below, or a} pharmaceutically acceptable salt thereof. In certain embodiments, the compound is a compound in Table 1, below. TABLE 1. _{[0095] Methods for preparing compounds described herein are illustrated in the Examples} below, and the following literature references. Strategies and procedures for preparing cyclo- oxymethylene phosphonic acids and esters and related compounds described herein (such as compounds in Table 1) are described in, for example, R. L. Mackman, et al. Bioorg. Med. Chem. Lett.2007, Vol.17, No.24, p.6785-6789, Boojamra, C. G. et al. Bioorg. Med. Chem.2009, Vol. 17, p.1739-1746, and Coe, D. M. J. Chem. Soc. Perkin 1: Org Bio-Organic Chem.1992, Vol. 20, p.2695-2704, and references in each of the foregoing. Strategies and procedures for preparing phosphonamidate, and other phosphorous-containing, compounds described herein (such as compounds in Tables 1, 2, 3, and 4) are described in, for example, WO 2004/096286, WO 2006/110157, WO 2006/015261, U.S.7,871,991, WO 2010/005986, WO 2012/159047, and Slusarczyk, M. et al. “Phosphoramidates and phosphonamidates (ProTides) with antiviral activity,” Antiviral Chemistry and Chemotherapy (2018), Vol.26, p.1-31, and references in each of the foregoing. Each of the foregoing is hereby incorporated by reference in its entirety. _{[0096] It is understood by one skilled in the art of organic synthesis that the functionality} present on various portions of the molecule should be compatible with the reagents and reactions proposed. Substituents not compatible with the reaction conditions will be apparent to one skilled in the art, and alternate methods are therefore indicated (for example, use of protecting groups or alternative reactions). Protecting group chemistry and strategy is well known in the art, for example, as described in detail in “Protecting Groups in Organic Synthesis”, T. W. Greene and P. G. M. Wuts, 3^rd edition, John Wiley & Sons, 1999, the entire contents of which are hereby incorporated by reference. For example, the exocyclic nitrogen atom of cytosine, and 5- substituted cytosine, nucleobases may be protected using, for example, a substituted trityl protecting group. [_{0097] The modular synthetic routes described herein and in the foregoing references can also} be readily modified by one of skill in the art of organic synthesis to provide additional substituted cyclo-oxymethylene phosphonamidates and related compounds using strategies and reactions well known in the art, as described in, for example, “Comprehensive Organic Synthesis” (B.M. Trost & I. Fleming, eds., 1991-1992). Generic Scheme 1 [_{0098] The starting nucleoside 1 is oxidized to the 5’ carboxylic acid under Jone’s oxidation} conditions. The hydroxy carboxylic acid 2 then undergoes decarboxylative elimination under Mitsunobu conditions to give the glycal shown in scheme 1. The glycal 3 is then treated with iodine monobromide generating and iodonium intermediate which is opened stereoselectively with the phosphono alcohol shown in scheme 1. The diethyl phosphonate 4 is cleaved with trimethylsilyl bromideTMS-Br to give yield the iodo phosphonic acid. The subsequent iodide 5 is treated with oxone and undergoes oxidative elimination. The phosphonic acid 6 is then alkylated with an alkyl chloride under basic conditions to provide the final compound 7. Generic Scheme 2 [_{0099] The glycal 8 made by methods shown is scheme 1, is treated with iodine} monobromide generating and iodonium intermediate which is opened stereoselectively with the phosphonamidate alcohol shown in scheme 2. The iodo phosphonamidate 9 is treated with Oxone and undergoes oxidative elimination to provide the final compound 10. Generic Scheme 3 [_{0100] Glycal 8 made by methods shown in scheme 1, is treated with iodine monobromide} generating and iodonium intermediate which is opened stereoselectively with the diphenoxyphosphonate alcohol shown in scheme 3. The iodo diphenoxyphosphonate 11 is treated with Oxone and undergoes oxidative elimination. The diphenoxyphosphate is treated with NH₃ to give rise to the mono deprotected phosphonic acid 13. The phosphonic acid is activated with BOP-Cl and treated with an amine to yield the final phosphonamidate 14. Generic Scheme 4 [_{0101] The phosphonic acid 15 (produced by methods shown in scheme) 1 is activated by use} of PPh3 and Adrithiol. The activated species is then treated with excess amine to provide the final bisphosphonamidate 16. Generic Scheme 5 [_{0102] The phosphonic acid 15 (produced by methods shown in scheme) 1 is activated by use} of triphenylphosphine and Aldrithiol. The activated species is then treated with excess an amine to provide the final bisphosphonamidate 17. Generic Scheme 6

[_{0103] The 5-iodo pyrimidine analog 18 (made under conditions shown in scheme 1) is} coupled to trimethyl silyl acetylene under Sonogashira conditions. The diethyl phosphonate 19 is hydrolyzed to the phosphonic acid using TMS-Br . Alkyne 20 is then deprotected using ammonium fluoride in methanol giving rise to phosphonic acid 21 which is activated by the addition of PPh3 and Aldrithiol. The activated species is then treated with a phenol species and an amine to provide the final phosphonamidate 22. II. Methods of Treating Medical Disorders [_{0104] Another aspect of the disclosure provides methods for treating medical disorders.} This is described in more detail below. [_{0105] Transposable elements (or transposons) are genomic DNA sequences that have the} ability to move within the genome which leads to altering its organization, increase its size and creates duplications and redundancy. (Ukadike and Mustelin, J. Clin. Med., 10:856 (2021)). These genomic sequences are believed to have been introduced into the human genome by either an infection by exogenous retroviruses that infected human ancestors millions of years ago or ancient descendants of retroviruses which retained the ability to embed and replicate in human germline genome. (Ukadike and Mustelin, 2021). _{[0106] Long Interspersed Nuclear Element 1 (LINE-1) are class I transposable elements in} the DNA of some organisms and comprise about 17% of the human genome. LINE-1 harbors two open reading frames, ORF1 and ORF2, which in turn respectively encode ORF1p which has nucleic acid chaperone activity and ORF2p with reverse transcriptase (RT) and endonuclease activities. (Reviewed in Babushok and Kazazian, Hum. Mut.28:527-539, (2007)). LINE-1 retrotransposition activity is mediated by ORF2p. The majority of LINE-1 elements in the human genome contain inactivating mutations but a small percentage of LINE-1 elements are intact and have retained the ability to retrotranspose. This ability varies both among individuals and among cell types within an individual. Active LINE-1 elements are thought to disrupt the genome through insertions, deletions, rearrangements and recombinations. (Garcia-Perez et al, Development, 143:4101-4114 (2016)). LINE-1 activity is normally tightly regulated in the germline by DNA methylation, histone modifications, and piRNA. _{[0107] Retrotransposons are transposable elements which are associated with the} pathogenesis of many diseases such as cancer, autoimmune disease and neurological disorders, among others. (Zhang, et al, Frontiers in Cell and Dev. Bio., 8:657 (Aug.2020); Kuriyama et al, Nature: Scientific Reports, 11:23146 (2021)). LINE-1 RNA and protein overexpression can promote apoptosis, DNA damage and repair, and cellular plasticity, which can promote tumor progression. Furthermore, DNA damage caused by repetitive sequences (genome-wide or interspersed) hypomethylation can induce an inflammatory microenvironment. (Zhang, 2020). _{[0108] High LINE-1 activity has been found in many tumor tissues. LINE-1 mediated gene} rearrangement can trigger oncogene amplification. Additionally, LINE-1 can mediate the deletion of tumor suppressor genes (Zhange, 2020). Inhibition of LINE-1 RT in cancer cells, either via RNA interface-dependent silencing of active LINE-1 elements or using RT inhibitory compounds can reduce cancer cell proliferation, promote cancer cell differentiation and can retard tumor progression in certain animal models. (Sciamann et al, Frontiers in Chemistry, 4:6 (Feb.2016)). _{[0109] LINE-1 RT uses a procedure termed target-site-primed reverse transcription (TPRT)} which involves nicking of the genomic DNA followed by reverse transcription and insertion of LINE-1 into the genome. The products of LINE-1 reverse transcription are potential triggers of DNA sensing receptors such as cGAS, which is a DNA sensor that activates the STING pathway leading to type I interferon production. (Zhao, J. Autoimmunity, 90:105-115 (2018)). Hypomethylated and highly expressed LINE-1 has been found in many patients with autoimmune diseases such as systemic lupus erythematosus (SLE), Sjögren’s syndrome (SS) and psoriasis. (Zhang et al). LINE-1 has also been found to be significantly upregulated in patients with dermatomyositis (DM), which patients also showed significantly elevated levels of interferon α and interferon β. (Kuriyama et al, J. Am. Acad, Dermatol., 84(4):1103-1105 (2020)). _{[0110] Interferon overproduction is a characteristic feature of type I interferonopathies.} These include rare genetic diseases with occurrence rates from 1:10,000 to 1:1,000,000. Pathological overexpression of type I interferon causes immune system hyperactivation that leads to systemic inflammation which can affect the nervous system, lung and blood vessels, among other organ systems. (Nesterova et al. "Congenital and Acquired Interferonopathies: Differentiated Approaches to Interferon Therapy". Innate Immunity in Health and Disease, Ed. Saxena and Prakash, IntechOpen, 2020). LINE-1 expression has been shown to induce type I interferons, which lead to type I interferonopathies. (Ukadike and Mustelin, 2021). These diseases have very limited effective treatment options so there is a high unmet medical need in this area. _{[0111] LINE-1 expression is high in brain tissue as compared to other organs. LINE-1 is} active in neural progenitor cells and overexpression of LINE-1 increases somatic mosaicism. LINE-1 has also been implicated in neurological disorders such as ataxia telangiectasia (AT) and Rett syndrome. LINE-1 is also implicated in the aging process and frontotemporal lobe degeneration. (Zhang, 2020). _{[0112] Human endogenous retroviruses (HERVs) comprise nearly 8% of the human genome} and are believed to be derived from ancient integrations of retroviruses into the germline. The biology of HERVs is poorly defined, but there is accumulating evidence supporting pathological roles in diverse diseases such as cancer, autoimmune and neurodegenerative diseases. Functional proteins are produced by HERV-encoded genes including reverse transcriptases (RTs), which could be a contributor to the pathology attributed to aberrant HERV-K expression. _{[0113] HERVs play a role in early development by rewiring the gene regulatory network of} the preimplantation embryo (Fu et al, Biomolecules, 11(6):829 (2021)). HERV expression appears to be a hallmark of the undifferentiated state, the acquisition of phenotypic plasticity and stem cell character (Balestrieri et al, Frontiers in Microbiology, 9:1448 (2018)); traits associated with aggressive cancer and poor patient outcomes. HERV expression is normally tightly controlled in normal adult tissues but is reported to be aberrantly expressed in cancer (Downey et al, Int. J. Cancer, 137(6):1249-1257 (2015)), inflammatory diseases (Greenig, PeerJ 7:e6711 (2019)), neurological diseases (Kury et al, Trends Mol. Med., 24(4):379-394 (2018)), aging (Gorbunova et al, Nature, 596(7870):43-53 (2021)), and viral disease (Romer, Frontiers in Neuroscience, 15:648629-648629 (2021)). There are numerous reports of upregulation of HERV-K [HML-2 (human endogenous MMTV-like) subtype] derived mRNA and protein in a variety of solid and liquid tumor types (Dervan et al, Front. Onc., 11:658489 (2021); Hohn et al, Front. Onc., 3:246 (2013)). The disease association with endogenous retroviruses and the expression of HERV encoded proteins during disease states suggests that anti-retroviral therapy could be explored in the management of these conditions. A. First Therapeutic Method _{[0114] Another aspect of the disclosure provides a method of treating a disorder selected} from the group consisting of cancer, an inflammatory disorder, a neurodegenerative disorder, and an immune disorder. The method comprises administering a therapeutically effective amount of a compound described in Section I above, such as a compound of Formula I, to a subject in need thereof to treat the disorder. In certain embodiments, the particular compound of Formula I is a compound defined by embodiments described in Section I, above, either singly or in combination. _{[0115] In certain embodiments, the disorder is an immune disorder that is a viral infection. [0116] Additional exemplary features that may characterize the First Therapeutic Method} described herein are provided below and include, for example, disorders and patients to be treated. B. Second Therapeutic Method _{[0117] Another aspect of the disclosure provides a method of treating a disorder selected} from the group consisting of cancer, an inflammatory disorder, a neurodegenerative disorder, and an immune disorder other than a viral infection. The method comprises administering to a subject in need thereof a therapeutically effective amount of a compound described in Section I above, such as compound of Formula I, to treat the disorder. In certain embodiments, the particular compound of Formula I is a compound defined by embodiments described in Section I, above, either singly or in combination. _{[0118] In certain embodiments, the compound is a compound in Table 1, above, or a} pharmaceutically acceptable salt thereof. In certain embodiments, the compound is a compound in Table 1, above. _{[0119] Additional exemplary features that may characterize the Second Therapeutic Method} described herein are provided below and include, for example, disorders and patients to be treated. C. Additional Exemplary Features of the First and Second Therapeutic Methods _{[0120] Additional exemplary features that may characterize the First and Second Therapeutic} Methods described herein are provided below and include, for example, disorders and patients to be treated. A more thorough description of such features is provided below. The disclosure embraces all permutations and combinations of these features. Pharmaceutical Compositions and Additional Therapeutic Agents _{[0121] In certain embodiments, the compound of Formula I, or other compound defined by} the embodiments above, is administered in a pharmaceutical composition comprising the compound and a pharmaceutically acceptable carrier, as further described in Section V, below. _{[0122] In certain embodiments, the method further comprises administering an effective} amount of an additional therapeutic agent, as further described in Section IV, below. Viral Infection _{[0123] In certain embodiments, the viral infection is an infection by human} immunodeficiency viruses 1 or 2 (HIV-1 or HIV-2), human T-cell leukemia viruses 1 or 2 (HTLV-1 or HTLV-2), respiratory syncytial virus (RSV), human papilloma virus (HPV), adenovirus, hepatitis B virus (HBV), hepatitis C virus (HCV), Epstein-Barr virus (EBV), varicella zoster virus (VZV), cytomegalovirus (CMV), herpes simplex viruses 1 or 2 (HSV-1 or HSV-2), human herpes virus 8 (HHV-8, also known as Kaposi's sarcoma-associated virus), or a flavivirus selected from Yellow Fever virus, Dengue virus, Japanese Encephalitis, and West Nile virus. _{[0124] In certain embodiments, the viral infection is an infection by human} immunodeficiency viruses 1 or 2 (HIV-1 or HIV-2). In certain embodiments, the viral infection is an infection by human immunodeficiency virus 1 (HIV-1). In certain embodiments, the viral infection is an infection by human immunodeficiency virus 2 (HIV-2). In certain embodiments, the viral infection is an infection by human T-cell leukemia viruses 1 or 2 (HTLV-1 or HTLV-2). In certain embodiments, the viral infection is an infection by respiratory syncytial virus (RSV). In certain embodiments, the viral infection is an infection by human papilloma virus (HPV). In certain embodiments, the viral infection is an infection by adenovirus. In certain embodiments, the viral infection is an infection by hepatitis B virus (HBV). In certain embodiments, the viral infection is an infection by hepatitis C virus (HCV). In certain embodiments, the viral infection is an infection by Epstein-Barr virus (EBV). In certain embodiments, the viral infection is an infection by varicella zoster virus (VZV). In certain embodiments, the viral infection is an infection by cytomegalovirus (CMV). In certain embodiments, the viral infection is an infection by herpes simplex viruses 1 or 2 (HSV-1 or HSV-2). In certain embodiments, the viral infection is an infection by human herpes virus 8 (HHV-8, also known as Kaposi's sarcoma-associated virus). In certain embodiments, the viral infection is an infection by a flavivirus selected from Yellow Fever virus, Dengue virus, Japanese Encephalitis, and West Nile virus. _{[0125] In certain embodiments, the viral infection is an infection by an adenovirus. In certain} embodiments, the viral infection is an infection by a herpesvirus. In certain embodiments, the viral infection is an infection by a poxvirus. In certain embodiments, the viral infection is an infection by a parvovirus. In certain embodiments, the viral infection is an infection by a reovirus. In certain embodiments, the viral infection is an infection by a picornavirus. In certain embodiments, the viral infection is an infection by a rhinovirus or enterovirus. In certain embodiments, the viral infection is an infection by a togavirus. In certain embodiments, the viral infection is an infection by an orthomyxovirus. In certain embodiments, the viral infection is an infection by a rhabdovirus. In certain embodiments, the viral infection is an infection by a retrovirus. In certain embodiments, the viral infection is an infection by a hepadnavirus. _{[0126] In certain embodiments, the viral infection is an infection by a coronavirus. In some} embodiments, the coronavirus is an alpha, beta, gamma, or delta coronavirus. In certain embodiments, the viral infection is an infection by a coronavirus selected from 229E (alpha coronavirus), NL63 (alpha coronavirus), OC43 (beta coronavirus), HKU1 (beta coronavirus), MERS-CoV (beta coronavirus), SARS-CoV (beta coronavirus), and SARS-CoV-2 (coronavirus disease 2019, or COVID-19). _{[0127] In certain embodiments, the viral infection is an infection by an influenza virus. In} certain embodiments, the viral infection is an infection by a type A or type B influenza virus. In certain embodiments, the viral infection is an infection by an influenza virus selected from H5N1, H1N1, and H3N2. _{[0128] In certain embodiments, the viral infection is an infection by a poliovirus. In certain} embodiments, the viral infection is an infection by a type 1 poliovirus. In certain embodiments, the viral infection is an infection by a type 2 poliovirus. In certain embodiments, the viral infection is an infection by a type 3 poliovirus. Cancer _{[0129] In certain embodiments, the disorder is cancer. In certain embodiments, the cancer is} a solid tumor or leukemia. In certain embodiments, the cancer is a solid tumor. In certain embodiments, the cancer is a carcinoma or melanoma. In certain embodiments, the cancer is a carcinoma. In certain embodiments, the cancer is a sarcoma. In certain embodiments, the cancer is a melanoma. In certain embodiments, the cancer is a lymphoma. In certain embodiments, the cancer is a leukemia. _{[0130] In certain embodiments, the cancer is breast cancer, ovarian cancer, uterine cancer,} cervical cancer, prostate cancer, testicular cancer, lung cancer, leukemia, head and neck cancer, oral cancer, esophageal cancer, stomach cancer, bile duct and gallbladder cancers, bladder cancer, urinary tract cancer, colon cancer, rectal cancer, thyroid cancer, pancreatic cancer, kidney cancer, liver cancer, brain cancer, skin cancer, or eye cancer. _{[0131] In certain embodiments, the cancer has (i) expression of LINE1 RNA, LINE1 ORF1} polypeptide, and/or LINE1 ORF2 polypeptide; (ii) activity of LINE1 reverse transcriptase; (iii) expression of HERV-K RNA, and/or (iv) activity of HERV-K reverse transcriptase. _{[0132] In certain embodiments, the cancer has (i) expression of LINE1 RNA, LINE1 ORF1} polypeptide, and/or LINE1 ORF2 polypeptide; and/or (ii) activity of LINE1 reverse transcriptase. In certain embodiments, the cancer has expression of LINE1 RNA, LINE1 ORF1 polypeptide, and/or LINE1 ORF2 polypeptide. In certain embodiments, the cancer has expression of LINE1 RNA. In certain embodiments, the cancer has expression of LINE1 ORF1 polypeptide. In certain embodiments, the cancer has expression of LINE1 ORF2 polypeptide. In certain embodiments, the cancer has activity of LINE1 reverse transcriptase. _{[0133] In certain embodiments, the cancer has (i) expression of HERV-K RNA, and/or (ii)} activity of HERV-K reverse transcriptase. In certain embodiments, the cancer has expression of HERV-K RNA. In certain embodiments, the cancer has activity of HERV-K reverse transcriptase. _{[0134] In certain embodiments, the cancer has elevated (i) levels of LINE1 RNA, LINE1} ORF1 polypeptide, and/or LINE1 ORF2 polypeptide; (ii) activity of LINE1 reverse transcriptase; (iii) levels of HERV-K RNA, and/or (iv) activity of HERV-K reverse transcriptase. _{[0135] In certain embodiments, the cancer has elevated (i) levels of LINE1 RNA, LINE1} ORF1 polypeptide, and/or LINE1 ORF2 polypeptide; and/or (ii) activity of LINE1 reverse transcriptase. In certain embodiments, the cancer has elevated levels of LINE1 RNA, LINE1 ORF1 polypeptide, and/or LINE1 ORF2 polypeptide. In certain embodiments, the cancer has elevated levels of LINE1 RNA. In certain embodiments, the cancer has elevated levels of LINE1 ORF1 polypeptide. In certain embodiments, the cancer has elevated levels of LINE1 ORF2 polypeptide. In certain embodiments, the cancer has elevated activity of LINE1 reverse transcriptase. _{[0136] In certain embodiments, the cancer has elevated (i) levels of HERV-K RNA, and/or} (ii) activity of HERV-K reverse transcriptase. In certain embodiments, the cancer has elevated levels of HERV-K RNA. In certain embodiments, the cancer has elevated activity of HERV-K reverse transcriptase. _{[0137] In certain embodiments, the cancer is pancreatic cancer, colorectal cancer, breast} cancer, prostate cancer, esophageal cancer, head and neck cancer, renal cancer, ovarian cancer, or lung cancer. In certain embodiments, the cancer is pancreatic cancer, colorectal cancer, breast cancer, prostate cancer, renal cancer, ovarian cancer, or lung cancer. In certain embodiments, the cancer is pancreatic cancer. In certain embodiments, the cancer is pancreatic adenocarcinoma. In certain embodiments, the cancer is colorectal cancer. In certain embodiments, the cancer comprises microsatellite instable (MSI) colorectal cancer or microsatellite stable (MSS) colorectal cancer. In certain embodiments, the cancer is breast cancer. In certain embodiments, the cancer is prostate cancer. In certain embodiments, the cancer is esophageal cancer. In certain embodiments, the cancer is head and neck cancer. In certain embodiments, the cancer is renal cancer. In certain embodiments, the cancer is ovarian cancer. In certain embodiments, the cancer is lung cancer. In certain embodiments, the cancer is non-small cell lung carcinoma or small cell lung carcinoma. In certain embodiments, the cancer is non-small cell lung carcinoma . In certain embodiments, the cancer is small cell lung carcinoma. _{[0138] In certain embodiments, the cancer is an epithelial cancer. In certain embodiments,} the epithelial cancer is pancreatic cancer, colorectal cancer, breast cancer, prostate cancer, esophageal cancer, head and neck cancer, renal cancer, ovarian cancer, or lung cancer. In certain embodiments, the epithelial cancer is pancreatic cancer, colorectal cancer, breast cancer, prostate cancer, renal cancer, ovarian cancer, or lung cancer. In certain embodiments, the colorectal cancer comprises microsatellite instable (MSI) colorectal cancer or microsatellite stable (MSS) colorectal cancer. _{[0139] In certain embodiments, the cancer is a preneoplastic or early cancer lesion. In certain} embodiments, the cancer is intraductal papillary mucinous neoplasm (IPMN), pancreatic intraepithelial neoplasia (PanIN), ductal carcinoma in situ (DCIS), or Barrett’s Esophagus. In certain embodiments, the cancer intraductal papillary mucinous neoplasm (IPMN). In certain embodiments, the cancer is pancreatic intraepithelial neoplasia (PanIN). In certain embodiments, the cancer is ductal carcinoma in situ (DCIS). In certain embodiments, the cancer is Barrett’s Esophagus. _{[0140] In certain embodiments, the cancer has elevated levels of pericentrometric human} satellite II (HSATII) RNA. In some embodiments, the cancer is a microsatellite instable (MSI) cancer. In some embodiments, the cancer is a microsatellite stable (MSS) cancer. _{[0141] In certain embodiments, the cancer is selected from B cell lymphomas (e.g., B cell} chronic lymphocytic leukemia, B cell non-Hodgkin lymphoma, cutaneous B cell lymphoma, diffuse large B cell lymphoma), basal cell carcinoma, bladder cancer, blastoma, brain metastasis, breast cancer, Burkitt lymphoma, carcinoma (e.g., adenocarcinoma (e.g., of the gastroesophageal junction)), cervical cancer, colon cancer, colorectal cancer (colon cancer and rectal cancer), endometrial carcinoma, esophageal cancer, Ewing sarcoma, follicular lymphoma, gastric cancer, gastroesophageal junction carcinoma, gastrointestinal cancer, glioblastoma (e.g., glioblastoma multiforme, e.g., newly diagnosed or recurrent), glioma, head and neck cancer (e.g., head and neck squamous cell carcinoma), hepatic metastasis, Hodgkin' s and non-Hodgkin' s lymphoma, kidney cancer (e.g., renal cell carcinoma and Wilms' tumors), laryngeal cancer, leukemia (e.g., chronic myelocytic leukemia, hairy cell leukemia), liver cancer (e.g., hepatic carcinoma and hepatoma), lung cancer (e.g., non-small cell lung cancer and small-cell lung cancer), lymphoblastic lymphoma, lymphoma, mantle cell lymphoma, metastatic brain tumor, metastatic cancer, myeloma (e.g., multiple myeloma), neuroblastoma, ocular melanoma, oropharyngeal cancer, osteosarcoma, ovarian cancer, pancreatic cancer (e.g., pancreatic ductal adenocarcinoma), prostate cancer (e.g., hormone refractory (e.g., castration resistant), metastatic, metastatic hormone refractory (e.g., castration resistant, androgen independent)), renal cell carcinoma (e.g., metastatic), salivary gland carcinoma, sarcoma (e.g., rhabdomyosarcoma), skin cancer (e.g., melanoma (e.g., metastatic melanoma)), soft tissue sarcoma, solid tumor, squamous cell carcinoma, synovia sarcoma, testicular cancer, thyroid cancer, transitional cell cancer (urothelial cell cancer), uveal melanoma (e.g., metastatic), verrucous carcinoma, vulval cancer, and Waldenstrom macroglobulinemia. _{[0142] In some embodiments, the cancer is a virus-associated cancer. As used herein, the} term “virus-associated cancer” means any cancer in which a virus is known to play a role. For example, Epstein-Barr virus (EBV) has been reported to be associated with the endemic variant of Burkitt lymphoma and certain other lymphomas. Infection by human papilloma virus (HPV) is believed to be responsible for certain types of cervical and/or genital cancer. Human T-cell leukemia virus 1 (HTLV-1) has been reported to be linked adult T-cell leukemia/lymphoma (ATLL). Human T-cell leukemia virus 2 (HTLV-2) has been reported to be linked to cutaneous T-cell lymphoma. Human herpes virus 8 (HHV-8) is believed to cause Kaposi’s sarcoma in patients with AIDS. In certain embodiments, the cancer is a cancer associated with EBV, HPV, HTLV-1, HTLV-2, or HHV-8. In certain embodiments, the cancer is Burkitt lymphoma, cervical cancer, genital cancer, adult T-cell leukemia/lymphoma, cutaneous T-cell lymphoma, or Kaposi’s sarcoma. _{[0143] In some embodiments, the cancer is a cancer other than a virus-associated cancer. In} certain embodiments, the cancer is a cancer other than a cancer associated with EBV, HPV, HTLV-1, HTLV-2, or HHV-8. In certain embodiments, the cancer is a cancer other than Burkitt lymphoma, cervical cancer, genital cancer, adult T-cell leukemia/lymphoma, cutaneous T-cell lymphoma, or Kaposi’s sarcoma. In some embodiments, the cancer is a tumor associated with Li-Fraumeni syndrome. _{[0144] In some embodiments, the cancer is mesothelioma, hepatobiliary (hepatic and biliary} duct), bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular melanoma, ovarian cancer, colon cancer, rectal cancer, cancer of the anal region, stomach cancer, gastrointestinal (gastric, colorectal, and duodenal), uterine cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, Hodgkin’s Disease, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, prostate cancer, testicular cancer, chronic or acute leukemia, chronic myeloid leukemia, lymphocytic lymphomas, cancer of the bladder, cancer of the kidney or ureter, renal cell carcinoma, carcinoma of the renal pelvis, non-Hodgkin’s lymphoma, spinal axis tumors, brain stem glioma, pituitary adenoma, adrenocortical cancer, gall bladder cancer, multiple myeloma, cholangiocarcinoma, fibrosarcoma, neuroblastoma, retinoblastoma, or a combination of one or more of the foregoing cancers. _{[0145] In some embodiments, the cancer is hepatocellular carcinoma, ovarian cancer, ovarian} epithelial cancer, fallopian tube cancer, papillary serous cystadenocarcinoma, uterine papillary serous carcinoma (UPSC), prostate cancer, testicular cancer, gallbladder cancer, hepatocholangiocarcinoma, soft tissue and bone synovial sarcoma, rhabdomyosarcoma, osteosarcoma, chondrosarcoma, Ewing sarcoma, anaplastic thyroid cancer, adrenocortical adenoma, pancreatic cancer, pancreatic ductal carcinoma, pancreatic adenocarcinoma, gastrointestinal/stomach (GIST) cancer, lymphoma, squamous cell carcinoma of the head and neck (SCCHN), salivary gland cancer, glioma, or brain cancer, neurofibromatosis-1 associated malignant peripheral nerve sheath tumors (MPNST), Waldenstrom’s macroglobulinemia, or medulloblastoma. _{[0146] In some embodiments, the cancer is hepatocellular carcinoma (HCC),} hepatoblastoma, colon cancer, rectal cancer, ovarian cancer, ovarian epithelial cancer, fallopian tube cancer, papillary serous cystadenocarcinoma, uterine papillary serous carcinoma (UPSC), hepatocholangiocarcinoma, soft tissue and bone synovial sarcoma, rhabdomyosarcoma, osteosarcoma, anaplastic thyroid cancer, adrenocortical adenoma, pancreatic cancer, pancreatic ductal carcinoma, pancreatic adenocarcinoma, glioma, neurofibromatosis-1 associated malignant peripheral nerve sheath tumors (MPNST), Waldenstrom’s macroglobulinemia, or medulloblastoma. _{[0147] In some embodiments, the cancer is selected from renal cell carcinoma, or kidney} cancer; hepatocellular carcinoma (HCC) or hepatoblastoma, or liver cancer; melanoma; breast cancer; colorectal carcinoma, or colorectal cancer; colon cancer; rectal cancer; anal cancer; lung cancer, such as non-small cell lung cancer (NSCLC) or small cell lung cancer (SCLC); ovarian cancer, ovarian epithelial cancer, ovarian carcinoma, or fallopian tube cancer; papillary serous cystadenocarcinoma or uterine papillary serous carcinoma (UPSC); prostate cancer; testicular cancer; gallbladder cancer; hepatocholangiocarcinoma; soft tissue and bone synovial sarcoma; rhabdomyosarcoma; osteosarcoma; chondrosarcoma; Ewing sarcoma; anaplastic thyroid cancer; adrenocortical carcinoma; pancreatic cancer; pancreatic ductal carcinoma or pancreatic adenocarcinoma; gastrointestinal/stomach (GIST) cancer; lymphoma; squamous cell carcinoma of the head and neck (SCCHN); salivary gland cancer; glioma, or brain cancer; neurofibromatosis-1 associated malignant peripheral nerve sheath tumors (MPNST); Waldenstrom’s macroglobulinemia; and medulloblastoma. _{[0148] In some embodiments, the cancer is renal cell carcinoma, hepatocellular carcinoma} (HCC), hepatoblastoma, colorectal carcinoma, colorectal cancer, colon cancer, rectal cancer, anal cancer, ovarian cancer, ovarian epithelial cancer, ovarian carcinoma, fallopian tube cancer, papillary serous cystadenocarcinoma, uterine papillary serous carcinoma (UPSC), hepatocholangiocarcinoma, soft tissue and bone synovial sarcoma, rhabdomyosarcoma, osteosarcoma, chondrosarcoma, anaplastic thyroid cancer, adrenocortical carcinoma, pancreatic cancer, pancreatic ductal carcinoma, pancreatic adenocarcinoma, glioma, brain cancer, neurofibromatosis-1 associated malignant peripheral nerve sheath tumors (MPNST), Waldenstrom’s macroglobulinemia, or medulloblastoma. _{[0149] In some embodiments, the cancer is hepatocellular carcinoma (HCC), hepatoblastoma,} colon cancer, rectal cancer, ovarian cancer, ovarian epithelial cancer, ovarian carcinoma, fallopian tube cancer, papillary serous cystadenocarcinoma, uterine papillary serous carcinoma (UPSC), hepatocholangiocarcinoma, soft tissue and bone synovial sarcoma, rhabdomyosarcoma, osteosarcoma, anaplastic thyroid cancer, adrenocortical carcinoma, pancreatic cancer, pancreatic ductal carcinoma, pancreatic adenocarcinoma, glioma, neurofibromatosis-1 associated malignant peripheral nerve sheath tumors (MPNST), Waldenstrom’s macroglobulinemia, or medulloblastoma. _{[0150] In some embodiments, the cancer is hepatocellular carcinoma (HCC). In some} embodiments, the cancer is hepatoblastoma. In some embodiments, the cancer is colon cancer. In some embodiments, the cancer is rectal cancer. In some embodiments, the cancer is ovarian cancer, or ovarian carcinoma. In some embodiments, the cancer is ovarian epithelial cancer. In some embodiments, the cancer is fallopian tube cancer. In some embodiments, the cancer is papillary serous cystadenocarcinoma. In some embodiments, the cancer is uterine papillary serous carcinoma (UPSC). In some embodiments, the cancer is hepatocholangiocarcinoma. In some embodiments, the cancer is soft tissue and bone synovial sarcoma. In some embodiments, the cancer is rhabdomyosarcoma. In some embodiments, the cancer is osteosarcoma. In some embodiments, the cancer is anaplastic thyroid cancer. In some embodiments, the cancer is adrenocortical carcinoma. In some embodiments, the cancer is pancreatic cancer, or pancreatic ductal carcinoma. In some embodiments, the cancer is pancreatic adenocarcinoma. In some embodiments, the cancer is glioma. In some embodiments, the cancer is malignant peripheral nerve sheath tumors (MPNST). In some embodiments, the cancer is neurofibromatosis-1 associated MPNST. In some embodiments, the cancer is Waldenstrom’s macroglobulinemia. In some embodiments, the cancer is medulloblastoma. _{[0151] In certain embodiments, the cancer is a leukemia (e.g., acute leukemia, acute} lymphocytic leukemia, acute myelocytic leukemia, acute myeloblastic leukemia, acute promyelocytic leukemia, acute myelomonocytic leukemia, acute monocytic leukemia, acute erythroleukemia, chronic leukemia, chronic myelocytic leukemia, chronic lymphocytic leukemia), polycythemia vera, lymphoma (e.g., Hodgkin’s disease or non-Hodgkin’s disease), Waldenstrom's macroglobulinemia, multiple myeloma, or heavy chain disease. In certain embodiments, the cancer is a solid tumor such as a sarcoma or carcinoma (e.g., fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing’s tumor, leiomyosarcoma, rhabdomyosarcoma, colon carcinoma, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinomas, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatoma, bile duct carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilm's tumor, cervical cancer, uterine cancer, testicular cancer, lung carcinoma, small cell lung carcinoma, bladder carcinoma, epithelial carcinoma, glioma, astrocytoma, glioblastoma multiforme (GBM, also known as glioblastoma), medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, schwannoma, neurofibrosarcoma, meningioma, melanoma, neuroblastoma, and retinoblastoma). _{[0152] In some embodiments, the cancer is glioma, astrocytoma, glioblastoma multiforme} (GBM, also known as glioblastoma), medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, schwannoma, neurofibrosarcoma, meningioma, melanoma, neuroblastoma, or retinoblastoma. _{[0153] In some embodiments, the cancer is acoustic neuroma, astrocytoma (e.g. Grade I –} Pilocytic Astrocytoma, Grade II – Low-grade Astrocytoma, Grade III – Anaplastic Astrocytoma, or Grade IV – Glioblastoma (GBM)), chordoma, CNS lymphoma, craniopharyngioma, brain stem glioma, ependymoma, mixed glioma, optic nerve glioma, subependymoma, medulloblastoma, meningioma, metastatic brain tumor, oligodendroglioma, pituitary tumors, primitive neuroectodermal (PNET) tumor, or schwannoma. In some embodiments, the cancer is a type found more commonly in children than adults, such as brain stem glioma, craniopharyngioma, ependymoma, juvenile pilocytic astrocytoma (JPA), medulloblastoma, optic nerve glioma, pineal tumor, primitive neuroectodermal tumors (PNET), or rhabdoid tumor. _{[0154] In certain embodiments, the cancer is associated with LINE1 reverse transcriptase. In} certain embodiments, the cancer is associated with high levels of LINE1 RT activity and/or expression. In certain embodiments, the cancer is associated with HERV-K reverse transcriptase. In certain embodiments, the cancer is associated with high levels of HERV-K RT activity and/or expression. Inflammatory Disorders _{[0155] In certain embodiments, the disorder is an inflammatory disorder. In certain} embodiments, the inflammatory disorder is rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, inflammatory bowel disease, Crohn’s disease, ulcerative colitis, nonalcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), cholestatic liver disease, or sclerosing cholangitis, psoriasis, dermatitis, vasculitis, scleroderma, asthma, bronchitis, chronic obstructive pulmonary disease (COPD), pulmonary fibrosis, pulmonary hypertension, sarcoidosis, myocarditis, pericarditis, gout, myositis, Sjogren’s syndrome, or systemic lupus erythematosus. _{[0156] In certain embodiments, the inflammatory disorder is rheumatoid arthritis,} osteoarthritis, or ankylosing spondylitis. In certain embodiments, the inflammatory disorder is inflammatory bowel disease, Crohn’s disease, or ulcerative colitis. In certain embodiments, the inflammatory disorder is nonalcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), cholestatic liver disease, or sclerosing cholangitis. In certain embodiments, the inflammatory disorder is psoriasis, dermatitis, vasculitis, or scleroderma. In certain embodiments, the inflammatory disorder is asthma, bronchitis, chronic obstructive pulmonary disease (COPD), pulmonary fibrosis, pulmonary hypertension, sarcoidosis, myocarditis, or pericarditis. In certain embodiments, the inflammatory disorder is gout, myositis, Sjogren’s syndrome, or systemic lupus erythematosus. _{[0157] In certain embodiments, the inflammatory disorder is associated with LINE1 reverse} transcriptase. In certain embodiments, the inflammatory disorder is associated with high levels of LINE1 RT activity and/or expression. In certain embodiments, the inflammatory disorder is associated with HERV-K reverse transcriptase. In certain embodiments, the inflammatory disorder is associated with high levels of HERV-K RT activity and/or expression. Immune Disorders _{[0158] In certain embodiments, the disorder is an immune disorder other than a viral} infection. _{[0159] In certain embodiments, the immune disorder is a type I interferonopathy. In certain} embodiments, the type I interferonopathy is a congenital disorder associated with type I interferon overexpression. In certain embodiments, the immune disorder is selected from Aicardi-Goutieres syndrome (AGS), Singleton-Merten syndrome, proteasome-associated autoinflammatory syndromes, chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE), STING-associated vasculopathy with onset in infancy (SAVI), Japanese autoinflammatory syndrome with lipodystrophy (JASL), spondyloenchondrodysplasia (SPENCD), ISG15 deficiency, Ubiquitin-Specific Peptidase 18 deficiency (pseudo-TORCH syndrome), chronic atypical neurophilic dermatitis with lipodystrophy, DNA II deficiency, trichoheptoenteric syndrome 2, retinal vasculopathy with cerebral leukodystrophy, familial chilblain lupus, and X-linked reticulate pigmentary disorder (XLPDR). In another embodiment, the type I interferonopathy is an acquired disorder in the interferon (IFN) system. _{[0160] In certain embodiments, the immune disorder results in an overproduction of} interferon. In certain embodiments, the immune disorder results in an overproduction of type I interferon. _{[0161] In certain embodiments, the immune disorder is selected from the group consisting of} achalasia, Addison’s disease, adult Still’s disease, agammaglobulinemia, alopecia areata, amyloidosis, ankylosing spondylitis, anti-GBM/anti-TBM nephritis, antiphospholipid syndrome, autoimmune angioedema, autoimmune dysautonomia, autoimmune encephalitis, autoimmune hepatitis, autoimmune inner ear disease (AIED), autoimmune myocarditis, autoimmune oophoritis, autoimmune orchitis, autoimmune pancreatitis, autoimmune retinopathy, autoimmune urticaria, axonal & neuronal neuropathy (AMAN), Balo disease, Behcet’s disease, benign mucosal pemphigoid, bullous pemphigoid, Castleman disease (CD), celiac disease, Chagas disease, chronic inflammatory demyelinating polyneuropathy (CIDP), chronic recurrent multifactorial osteomyelitis (CRMO), Churg-Strauss syndrome or eosinophilic granulomatosis, cicatricial pemphigoid, Cogan’s syndrome, cold agglutinin disease, complex regional pain syndrome (previously called reflex sympathetic dystrophy), congenital heart block, coxsackle myocarditis, CREST syndrome, Crohn’s disease, cutaneous lupus erythematosus (CLE), dermatitis herpetiformis, dermatomyositis, Devic’s disease (neuromyelitis optica), discoid lupus, Dressler’s syndrome, endometriosis, eosinophilic esophagitis (EoE), eosinophilic fasciitis, erytherna nodosum, essential mixed cryoglobulinemia, Evans syndrome, fibromyalgia, fibrosing alveolitis, giant cell arteritis (temporal arteritis), giant cell myocarditis, glomerulonephritis, Goodpasture’s syndrome, granulomatosis with polyangiitis, graft versus host disease, Graves’ disease, Guillain-Barre syndrome, Hashimoto’s thyroiditis, hemolytic anemia, Henoch-Schonlein purpura (HSP), herpes gestationis or pemphigoid gestationis (PG), hidradenitis suppurativa (acne inversa), inflammatory bowel disease, IgA nephropathy, IgG4-related sclerosing disease, immune thrombocytopenic pupura (ITP), inclusion body myositis (IBM), interstitial cystitis (IC), juvenile arthritis, juvenile diabetes (type I diabetes), juvenile myositis (JM), Kawasaki disease, Lambert-Eaton syndrome, lichen planus, lichen sclerosus, ligneous conjunctivitis, linear IgA disease (LAD), lupus nephritis, lyme disease (chronic), Meniere’s disease, microscopic polyangiitis (MPA), mixed connective tissue disease (MCTD), multifocal motor neuropathy, multiple sclerosis, myasthenia gravis, myelin oligodendrocyte glycoprotein antibody disorder, myositis, narcolepsy, neonatal lupus, neutropenia, ocular cicatricial pemphigoid, optic neuritis, palindromic rheumatism, pediatric autoimmune neuropsychiatric disorders associated with streptococcus infections (PANDAS), paraneoplastic cerebellar degeneration (PCD), paroxysmal nocturnal hemoglobinuria (PNH), pars planitis (peripheral uveitis), Parsonage-Turner syndrome, pemphigus, peripheral neuropathy, perivenous encephalomyelitis, pernicious anemia (PA), POEMS syndrome, polyarteritis rheumatica, polymyositis, postmyocardial infarction syndrome, postpericardiotomy syndrome, primary biliary cholangitis, primary sclerosing cholangitis, progesterone dermatitis, progressive hemifacial atrophy (Parry Romberg syndrome), psoriasis, psoriatic arthritis, pure red cell aplasia, pyoderma gangrenosum, Raynoud’s phenomena, reactive arthritis, relapsing polychondritis, restless leg syndrome (RLS), retroperitoneal fibrosis, rheumatic fever, rheumatoid arthritis (RA), sarcoidosis, Schmidt syndrome (autoimmune polyendocrine syndrome type II), scleritis, scleroderma, Sjogren’s disease, stiff person syndrome, Susac’s syndrome, sympathetic ophthalmia, systemic lupus erythematosus (SLE), Takayasu’s arteritis, thrombotic thrombocytopenic pupura, thyroid eye disease, Tolosa-Hunt syndrome, transverse myelitis, ulcerative colitis, undifferentiated connective tissue disease, uveitis, vasculitis, vitiligo, Vogt-Koyanagi-Harada disease, and warm autoimmune hemolytic anemia. _{[0162] In certain embodiments, the immune disorder is arthritis, psoriasis, systemic lupus} erythematosus (SLE), graft versus host disease, scleroderma, polymyositis, inflammatory bowel disease, dermatomyositis, ulcerative colitis, Crohn’s disease, vasculitis, psoriatic arthritis, Reiter's syndrome, exfoliative psoriatic dermatitis, pemphigus vulgaris, Sjogren’s syndrome, autoimmune uveitis, glomerulonephritis, post myocardial infarction cardiotomy syndrome, pulmonary hemosiderosis, amyloidosis, sarcoidosis, aphthous stomatitis, thyroiditis, gastritis, adrenalitis (Addison's disease), ovaritis, primary biliary cirrhosis, myasthenia gravis, gonadal failure, hypoparathyroidism, alopecia, psoriasis, malabsorption syndrome, pernicious anemia, hepatitis, hypopituitarism, diabetes insipidus, or sicca syndrome. _{[0163] In certain embodiments, the immune disorder is a type 1 interferonopathy, type 1} diabetes, Aicardi-Goutieres syndrome (AGS), arthritis, psoriasis, systemic lupus erythematosus (SLE), lupus nephritis, cutaneous lupus erythematosus (CLE), familial chilblain lupus, systemic sclerosis, STING-associated vasculopathy with onset in infancy (SAVI), graft versus host disease, scleroderma, polymyositis, inflammatory bowel disease, dermatomyositis, ulcerative colitis, Crohn’s disease, vasculitis, psoriatic arthritis, Reiter’s syndrome, exfoliative psoriatic dermatitis, pemphigus vulgaris, Sjogren’s syndrome, autoimmune uveitis, glomerulonephritis, post myocardial infarction cardiotomy syndrome, pulmonary hemosiderosis, amyloidosis, sarcoidosis, aphthous stomatitis, thyroiditis, gastritis, adrenalitis (Addison's disease), ovaritis, primary biliary cirrhosis, myasthenia gravis, gonadal failure, hypoparathyroidism, alopecia, malabsorption syndrome, pernicious anemia, hepatitis, hypopituitarism, diabetes insipidus, or sicca syndrome. _{[0164] In certain embodiments, the immune disorder is a type 1 interferonopathy, type 1} diabetes, Aicardi-Goutieres syndrome (AGS), arthritis, psoriasis, systemic lupus erythematosus (SLE), lupus nephritis, cutaneous lupus erythematosus (CLE), familial chilblain lupus, systemic sclerosis, STING-associated vasculopathy with onset in infancy (SAVI), graft versus host disease, scleroderma, polymyositis, inflammatory bowel disease, dermatomyositis, ulcerative colitis, Crohn’s disease, vasculitis, psoriatic arthritis, Reiter’s syndrome, exfoliative psoriatic dermatitis, pemphigus vulgaris, Sjogren’s syndrome, autoimmune uveitis, glomerulonephritis, post myocardial infarction cardiotomy syndrome, pulmonary hemosiderosis, amyloidosis, sarcoidosis, aphthous stomatitis, thyroiditis, gastritis, adrenalitis (Addison's disease), ovaritis, primary biliary cirrhosis, myasthenia gravis, gonadal failure, hypoparathyroidism, alopecia, malabsorption syndrome, pernicious anemia, hypopituitarism, diabetes insipidus, or sicca syndrome. _{[0165] In certain embodiments, the immune disorder is a type 1 interferonopathy, type 1} diabetes, Aicardi-Goutieres syndrome (AGS), systemic lupus erythematosus (SLE), lupus nephritis, cutaneous lupus erythematosus (CLE), familial chilblain lupus, systemic sclerosis, STING-associated vasculopathy with onset in infancy (SAVI), Sjogren’s syndrome, dermatomyositis, inflammatory bowel disease, Crohn’s disease, or ulcerative colitis. _{[0166] In certain embodiments, the immune disorder is a type 1 interferonopathy, type 1} diabetes, Aicardi-Goutieres syndrome (AGS), systemic lupus erythematosus (SLE), lupus nephritis, cutaneous lupus erythematosus (CLE), dermatomyositis, or Sjogren’s syndrome. _{[0167] In certain embodiments, the immune disorder is a type 1 interferonopathy. In certain} embodiments, the immune disorder is type 1 diabetes, Aicardi-Goutieres syndrome (AGS), systemic lupus erythematosus (SLE), lupus nephritis, cutaneous lupus erythematosus (CLE), familial chilblain lupus, systemic sclerosis, STING-associated vasculopathy with onset in infancy (SAVI), Sjogren’s syndrome, or dermatomyositis. In certain embodiments, the immune disorder is systemic lupus erythematosus (SLE), lupus nephritis, cutaneous lupus erythematosus (CLE), or familial chilblain lupus. In certain embodiments, the immune disorder is systemic lupus erythematosus (SLE), lupus nephritis, or cutaneous lupus erythematosus (CLE). In certain embodiments, the immune disorder is type 1 diabetes, Aicardi-Goutieres syndrome (AGS), systemic sclerosis, STING-associated vasculopathy with onset in infancy (SAVI), Sjogren’s syndrome, or dermatomyositis. In certain embodiments, the immune disorder is Aicardi- Goutieres syndrome (AGS), familial chilblain lupus, or STING-associated vasculopathy with onset in infancy (SAVI). _{[0168] In certain embodiments, the immune disorder is type 1 diabetes. In certain} embodiments, the immune disorder is Aicardi-Goutieres syndrome (AGS). In certain embodiments, the immune disorder is systemic lupus erythematosus (SLE). In certain embodiments, the immune disorder is lupus nephritis. In certain embodiments, the immune disorder is cutaneous lupus erythematosus (CLE). In certain embodiments, the immune disorder is familial chilblain lupus. In certain embodiments, the immune disorder is systemic sclerosis. In certain embodiments, the immune disorder is STING-associated vasculopathy with onset in infancy (SAVI). In certain embodiments, the immune disorder is Sjogren’s syndrome. In certain embodiments, the immune disorder is dermatomyositis. _{[0169] In certain embodiments, the immune disorder is inflammatory bowel disease, Crohn’s} disease, or ulcerative colitis. In certain embodiments, the immune disorder is inflammatory bowel disease. In certain embodiments, the immune disorder is Crohn’s disease. In certain embodiments, the immune disorder is ulcerative colitis. In certain embodiments, the autoimmune disorder is drug-induced colitis. In certain embodiments, the autoimmune disorder is colitis associated with the administration of checkpoint inhibitors. _{[0170] In certain embodiments, the immune disorder is associated with LINE1 reverse} transcriptase. In certain embodiments, the immune disorder is associated with high levels of LINE1 RT activity and/or expression. In certain embodiments, the immune disorder is associated with HERV-K reverse transcriptase. In certain embodiments, the immune disorder is associated with high levels of HERV-K RT activity and/or expression. Neurodegenerative Disorders _{[0171] In certain embodiments, the disorder is a neurodegenerative disorder. In certain} embodiments, the neurodegenerative disorder is Alzheimer’s disease, amyotrophic lateral sclerosis (ALS), multiple sclerosis, Parkinson’s disease, Huntington’s disease, peripheral neuropathy, age-related macular degeneration, Creutzfeldt-Jacob disease, stroke, prion disease, frontotemporal dementia, Pick’s disease, progressive supranuclear palsy, spinocerebellar ataxias, Lewy body disease, dementia, multiple system atrophy, epilepsy, bipolar disorder, schizophrenia, an anxiety disorder, or major depression. In certain embodiments, the neurodegenerative disorder is Alzheimer’s disease, amyotrophic lateral sclerosis (ALS), multiple sclerosis, Parkinson’s disease, Huntington’s disease, or dementia. In certain embodiments, the neurodegenerative disease is amyotrophic lateral sclerosis (ALS) or progressive supranuclear palsy. _{[0172] In certain embodiments, the neurological disorder is peripheral neuropathy, age-} related macular degeneration, Creutzfeldt-Jacob disease, stroke, prion disease, frontotemporal dementia, Pick’s disease, progressive supranuclear palsy, spinocerebellar ataxias, Lewy body disease, dementia, multiple system atrophy, epilepsy, bipolar disorder, schizophrenia, an anxiety disorder, or major depression. _{[0173] In certain embodiments, the neurodegenerative disorder is Alzheimer’s disease. In} certain embodiments, the neurodegenerative disorder is amyotrophic lateral sclerosis (ALS). In certain embodiments, the neurodegenerative disorder is multiple sclerosis. In certain embodiments, the neurodegenerative disorder is Parkinson’s disease. In certain embodiments, the neurodegenerative disorder is Huntington’s disease. In certain embodiments, the neurodegenerative disorder is dementia. In certain embodiments, the neurodegenerative disorder is age-related macular degeneration. In certain embodiments, the neurodegenerative disorder is progressive supranuclear palsy. _{[0174] In certain embodiments, the neurodegenerative disorder is associated with LINE1} reverse transcriptase. In certain embodiments, the neurodegenerative disorder is associated with high levels of LINE1 RT activity and/or expression. In certain embodiments, the neurodegenerative disorder is associated with HERV-K reverse transcriptase. In certain embodiments, the neurodegenerative disorder is associated with high levels of HERV-K RT activity and/or expression. Subjects _{[0175] In certain embodiments, the subject has (i) expression of LINE1 RNA, LINE1 ORF1} polypeptide, and/or LINE1 ORF2 polypeptide; (ii) activity of LINE1 reverse transcriptase; (iii) expression of HERV-K RNA, and/or (iv) activity of HERV-K reverse transcriptase. _{[0176] In certain embodiments, the subject has (i) expression of LINE1 RNA, LINE1 ORF1} polypeptide, and/or LINE1 ORF2 polypeptide; and/or (ii) activity of LINE1 reverse transcriptase. In certain embodiments, the subject has (i) elevated expression of LINE1 RNA, LINE1 ORF1 polypeptide, and/or LINE1 ORF2 polypeptide; and/or (ii) elevated activity of LINE1 reverse transcriptase. In certain embodiments, the subject has expression of LINE1 RNA, LINE1 ORF1 polypeptide, and/or LINE1 ORF2 polypeptide. In certain embodiments, the subject has expression of LINE1 RNA. In certain embodiments, the subject has expression of LINE1 ORF1 polypeptide. In certain embodiments, the subject has expression of LINE1 ORF2 polypeptide. In certain embodiments, the subject has activity of LINE1 reverse transcriptase. _{[0177] In certain embodiments, the subject has (i) expression of HERV-K RNA, and/or (ii)} activity of HERV-K reverse transcriptase. In certain embodiments, the subject has expression of HERV-K RNA. In certain embodiments, the subject has activity of HERV-K reverse transcriptase. _{[0178] In certain embodiments, the subject has elevated (i) levels of LINE1 RNA, LINE1} ORF1 polypeptide, and/or LINE1 ORF2 polypeptide; (ii) activity of LINE1 reverse transcriptase; (iii) levels of HERV-K RNA, and/or (iv) activity of HERV-K reverse transcriptase. _{[0179] In certain embodiments, the subject has elevated (i) levels of LINE1 RNA, LINE1} ORF1 polypeptide, and/or LINE1 ORF2 polypeptide; and/or (ii) activity of LINE1 reverse transcriptase. In certain embodiments, the subject has elevated levels of LINE1 RNA, LINE1 ORF1 polypeptide, and/or LINE1 ORF2 polypeptide. In certain embodiments, the subject has elevated levels of LINE1 RNA. In certain embodiments, the subject has elevated levels of LINE1 ORF1 polypeptide. In certain embodiments, the subject has elevated levels of LINE1 ORF2 polypeptide. In certain embodiments, the subject has elevated activity of LINE1 reverse transcriptase. _{[0180] In certain embodiments, the subject has elevated (i) levels of HERV-K RNA, and/or} (ii) activity of HERV-K reverse transcriptase. In certain embodiments, the subject has elevated levels of HERV-K RNA. In certain embodiments, the subject has elevated activity of HERV-K reverse transcriptase. _{[0181] In certain embodiments, the subject is a human. In certain embodiments, the subject is} an adult human. In certain embodiments, the subject is a pediatric human. In certain embodiments, the subject is a companion animal. In certain embodiments, the subject is a canine, feline, or equine. Uses of Compounds _{[0182] Another aspect of the disclosure provides for the use of a compound described herein} (such as a compound of Formula I, or other compounds described above) for treating a medical disorder, such as a medical disorder described herein (for example, cancer). _{[0183] Another aspect of the disclosure provides for the use of a compound described herein} (such as a compound of Formula I, or other compounds described above) in the manufacture of a medicament. In certain embodiments, the medicament is for treating a disorder described herein, such as cancer. III. Methods of Inhibiting LINE1 and/or HERV-K Reverse Transcriptase Activity _{[0184] Another aspect of the disclosure provides methods for inhibiting reverse transcriptase} activity. This is described in more detail below. _{[0185] Another aspect of the disclosure provides a method of inhibiting LINE1 reverse} transcriptase activity. The method comprises contacting a LINE1 reverse transcriptase with an effective amount of a compound described in Section I above, such as a compound of Formula I, in order to inhibit the activity of said LINE1 reverse transcriptase. In certain embodiments, the particular compound of Formula I is a compound defined by embodiments described in Section I, above, either singly or in combination. In certain embodiments, the method further comprises inhibiting HERV-K reverse transcriptase activity in the subject. _{[0186] Another aspect of the disclosure provides a method of inhibiting LINE1 reverse} transcriptase activity in a subject suffering from a disorder selected from the group consisting of cancer, an inflammatory disorder, a neurodegenerative disorder, and an immune disorder other than a viral infection. The method comprises contacting a LINE1 reverse transcriptase with an effective amount of a compound described in Section I above, such as a compound of Formula I, in order to inhibit the activity of said LINE1 reverse transcriptase. In certain embodiments, the particular compound of Formula I, is a compound defined by embodiments described above, either singly or in combination. In certain embodiments, the method further comprises inhibiting HERV-K reverse transcriptase activity in the subject. In certain embodiments, the disorder is a disorder defined by one of the embodiments described in Section II, above, such as cancer. _{[0187] Another aspect of the disclosure provides a method of inhibiting HERV-K reverse} transcriptase activity. The method comprises contacting a HERV-K reverse transcriptase with an effective amount of a compound described in Section I above, such as a compound of Formula I, in order to inhibit the activity of said HERV-K reverse transcriptase. In certain embodiments, the particular compound of Formula I is a compound defined by embodiments described in Section I, above, either singly or in combination. In certain embodiments, the method further comprises inhibiting LINE1 reverse transcriptase activity in the subject. _{[0188] Another aspect of the disclosure provides a method of inhibiting HERV-K reverse} transcriptase activity in a subject suffering from a disorder selected from the group consisting of cancer, an inflammatory disorder, a neurodegenerative disorder, and an immune disorder other than a viral infection. The method comprises contacting a HERV-K reverse transcriptase with an effective amount of a compound described in Section I above, such as a compound of Formula I, in order to inhibit the activity of said HERV-K reverse transcriptase. In certain embodiments, the particular compound of Formula I, is a compound defined by embodiments described above, either singly or in combination. In certain embodiments, the method further comprises inhibiting LINE1 reverse transcriptase activity in the subject. In certain embodiments, the disorder is a disorder defined by one of the embodiments described in Section II, above, such as cancer. _{[0189] Compounds may be tested for ability to inhibit activity of LINE1 reverse transcriptase} or HERV-K reverse transcriptase, for example, as described in the Examples. IV. Combination Therapy _{[0190] Another aspect of the disclosure provides for combination therapy. Substituted cyclo-} oxymethylene phosphonamidates or related compounds described herein (e.g., a compound of Formula I, or other compounds described above) or their pharmaceutically acceptable salts may be used in combination with additional therapeutic agents to treat medical disorders (e.g., according to the methods described in Section II, with disorders such as a cancer). Accordingly, in some embodiments, a method of the disclosure further comprises administering an effective amount of an additional therapeutic agent. _{[0191] Each of the methods described herein for treating disease using combination therapy} may be further characterized according to the additional therapeutic agent used in the method. For example, in certain embodiments, the additional therapeutic agent is tenofovir, a prodrug thereof, or a pharmaceutically acceptable salt of either of the foregoing. In certain embodiments, the additional therapeutic agent is tenofovir, tenofovir alafenamide, tenofovir amibufenamide, tenofovir disoproxil, or tenofovir exalidex; or a pharmaceutically acceptable salt thereof. In certain embodiments, the additional therapeutic agent is tenofovir, tenofovir alafenamide, tenofovir amibufenamide, tenofovir disoproxil, or tenofovir exalidex. _{[0192] In certain embodiments, the additional therapeutic agent is tenofovir, or a} pharmaceutically acceptable salt thereof. In certain embodiments, the additional therapeutic agent is tenofovir. In certain embodiments, the additional therapeutic agent is tenofovir alafenamide, or a pharmaceutically acceptable salt thereof. In certain embodiments, the additional therapeutic agent is tenofovir alafenamide. In certain embodiments, the additional therapeutic agent is tenofovir amibufenamide, or a pharmaceutically acceptable salt thereof. In certain embodiments, the additional therapeutic agent is tenofovir amibufenamide. In certain embodiments, the additional therapeutic agent is tenofovir disoproxil, or a pharmaceutically acceptable salt thereof. In certain embodiments, the additional therapeutic agent is tenofovir disoproxil, or a fumarate, succinate, maleate, orotate, aspartate, or phosphate salt thereof. In certain embodiments, the additional therapeutic agent is tenofovir disoproxil, or a fumarate, succinate, or maleate salt thereof. In certain embodiments, the additional therapeutic agent is tenofovir disoproxil. In certain embodiments, the additional therapeutic agent is tenofovir exalidex, or a pharmaceutically acceptable salt thereof. In certain embodiments, the additional therapeutic agent is tenofovir exalidex, or a potassium salt thereof. In certain embodiments, the additional therapeutic agent is tenofovir exalidex. _{[0193] In some embodiments, the present disclosure provides a method of treating a disclosed} disease or condition comprising administering to a patient in need thereof an effective amount of a compound disclosed herein or a pharmaceutically acceptable salt thereof and co-administering simultaneously or sequentially an effective amount of one or more additional therapeutic agents, such as those described herein. In some embodiments, the method includes co-administering one additional therapeutic agent. In some embodiments, the method includes co-administering two additional therapeutic agents. In some embodiments, the combination of the disclosed compound and the additional therapeutic agent or agents acts synergistically. _{[0194] One or more other therapeutic agents may be administered separately from a} compound or composition of the disclosure, as part of a multiple dosage regimen. Alternatively, one or more other therapeutic agents may be part of a single dosage form, mixed together with a compound of this disclosure in a single composition. If administered as a multiple dosage regime, one or more other therapeutic agent and a compound or composition of the disclosure may be administered simultaneously, sequentially or within a period of time from one another, for example within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 hours from one another. In some embodiments, one or more other therapeutic agent and a compound or composition of the disclosure are administered as a multiple dosage regimen more than 24 hours apart. _{[0195] The doses and dosage regimen of the active ingredients used in the combination} therapy may be determined by an attending clinician. In certain embodiments, the substituted cyclo-oxymethylene phosphonamidate or related compound described herein (e.g., a compound of Formula I, or other compounds described above) and the additional therapeutic agent(s) (e.g. the second, third, or fourth, or fifth anti-cancer agent, described below) are administered in doses commonly employed when such agents are used as monotherapy for treating the disorder. In other embodiments, the substituted cyclo-oxymethylene phosphonamidate or related compound described herein (e.g., a compound of Formula I, or other compounds described above) and the additional therapeutic agent(s) (e.g. the second, third, or fourth, or fifth anti-cancer agent, described below) are administered in doses lower than the doses commonly employed when such agents are used as monotherapy for treating the disorder. In certain embodiments, the substituted cyclo-oxymethylene phosphonamidate or related compound described herein (e.g., a compound of Formula I, or other compounds described above) and the additional therapeutic agent(s) (e.g. the second, third, or fourth, or fifth anti-cancer agent, described below) are present in the same composition, which is suitable for oral administration. _{[0196] In certain embodiments, the substituted cyclo-oxymethylene phosphonamidate or} related compound described herein (e.g., a compound of Formula I, or other compounds described above) and the additional therapeutic agent(s) (e.g. the second, third, or fourth, or fifth anti-cancer agent, described below) may act additively or synergistically. A synergistic combination may allow the use of lower dosages of one or more agents and/or less frequent administration of one or more agents of a combination therapy. A lower dosage or less frequent administration of one or more agents may lower toxicity of the therapy without reducing the efficacy of the therapy. _{[0197] Another aspect of this disclosure is a kit comprising a therapeutically effective amount} of the substituted cyclo-oxymethylene phosphonamidate or related compound described herein (e.g., a compound of Formula I, or other compounds described above), a pharmaceutically acceptable carrier, vehicle or diluent, and optionally at least one additional therapeutic agent listed above. Cancer _{[0198] Accordingly, another aspect of the disclosure provides a method of treating cancer in a} patient. The method comprises administering to a subject in need thereof (i) a therapeutically effective amount of a substituted cyclopentene-oxymethylene phosphonamidate or related compound described herein and (ii) a second anti-cancer agent, in order to treat the cancer. _{[0199] In certain embodiments, the second anti-cancer agent is radiation therapy. [0200] In certain embodiments, the second anti-cancer agent is a therapeutic antibody. In} certain embodiments, the therapeutic antibody targets one of the following: CD20, CD30, CD33, CD52, EpCAM, CEA, gpA33, a mucin, TAG-72, CAIX, PSMA, a folate-binding protein, a ganglioside, Le, VEGF, VEGFR, VEGFR2, VEGFR3, integrin αVβ3, integrin α5β1, EGFR, ERBB2, ERBB3, MET, IGF1R, EPHA3, TRAILR1, TRAILR2, TRAILR3, RANKL, FAP, tenascin, CD19, KIR, NKG2A, CD47, CEACAM1, c-MET, VISTA, CD73, CD38, BAFF, interleukin-1 beta, B4GALNT1, interleukin-6, and interleukin-6 receptor. _{[0201] In certain embodiments, the second anti-cancer agent is a therapeutic antibody} selected from the group consisting of rituximab, ibritumomab tiuxetan, tositumomab, obinutuzumab, ofatumumab, brentuximab vedotin, gemtuzumab ozogamicin, alemtuzumab, IGN101, adecatumumab, labetuzumab, huA33, pemtumomab, oregovomab, minetumomab, cG250, J591, Mov18, farletuzumab, 3F8, ch14.18, KW-2871, hu3S193, lgN311, bevacizumab, IM-2C6, CDP791, ramucirumab, etaracizumab, volociximab, cetuximab, panitumumab, nimotuzumab, 806, trastuzumab, pertuzumab, MM-121, AMG 102, METMAB, SCH 900105, AVE1642, IMC-A12, MK-0646, R1507, CP 751871, KB004, IIIA-4, mapatumumab, HGS- ETR2, CS-1008, denosumab, sibrotuzumab, F19, 81C6, MEDI551, lirilumab, MEDI9447, daratumumab, belimumab, canakinumab, dinutuximab, siltuximab, and tocilizumab. _{[0202] In certain embodiments, the second anti-cancer agent is a cytokine. In certain} embodiments, the cytokine is IL-12, IL-15, GM-CSF, or G-CSF. _{[0203] In certain embodiments, the second anti-cancer agent is sipuleucel-T, aldesleukin (a} human recombinant interleukin-2 product having the chemical name des-alanyl-1, serine-125 human interleukin-2), dabrafenib (a kinase inhibitor having the chemical name N-{3-[5-(2- aminopyrimidin-4-yl)-2-tert-butyl-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6- difluorobenzenesulfonamide), vemurafenib (a kinase inhibitor having the chemical name propane-1-sulfonic acid {3-[5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4- difluoro-phenyl}-amide), or 2-chloro-deoxyadenosine. In certain embodiments, the second anti- cancer agent is pazopanib, sorafenib, axitinib, lenvatinib, afatinib, erlotinib, gefitinib, osimertinib, or vandetanib. _{[0204] In certain embodiments, the second anti-cancer agent is a placental growth factor, an} antibody-drug conjugate, an oncolytic virus, or an anti-cancer vaccine. In certain embodiments, the second anti-cancer agent is a placental growth factor. In certain embodiments, the second anti-cancer agent is a placental growth factor comprising ziv-aflibercept. In certain embodiments, the second anti-cancer agent is an antibody-drug conjugate. In certain embodiments, the second anti-cancer agent is an antibody-drug conjugate selected from the group consisting of brentoxumab vedotin and trastuzumab emtransine. _{[0205] In certain embodiments, the second anti-cancer agent is an oncolytic virus. In certain} embodiments, the second anti-cancer agent is the oncolytic virus talimogene laherparepvec. In certain embodiments, the second anti-cancer agent is an anti-cancer vaccine. In certain embodiments, the second anti-cancer agent is an anti-cancer vaccine selected from the group consisting of a GM-CSF tumor vaccine, a STING/GM-CSF tumor vaccine, and NY-ESO-1. In certain embodiments, the second anti-cancer agent is a cytokine selected from IL-12, IL-15, GM- CSF, and G-CSF. _{[0206] In certain embodiments, the second anti-cancer agent is an immune checkpoint} inhibitor (also referred to as immune checkpoint blockers). Immune checkpoint inhibitors are a class of therapeutic agents that have the effect of blocking immune checkpoints. See, for example, Pardoll in Nature Reviews Cancer (2012) vol.12, pages 252-264. In certain embodiments, the immune checkpoint inhibitor is an agent that inhibits one or more of (i) cytotoxic T‑lymphocyte-associated antigen 4 (CTLA4), (ii) programmed cell death protein 1 (PD1), (iii) PDL1, (iv) LAB3, (v) B7-H3, (vi) B7-H4, and (vii) TIM3. In certain embodiments, the immune checkpoint inhibitor is ipilumumab. In certain embodiments, the immune checkpoint inhibitor is pembrolizumab. In certain embodiments, the immune checkpoint inhibitor is atezolizumab, cemiplimab, cemiplimab-rwlc, dostarlimab, durvalumab, or nivolumab. _{[0207] In certain embodiments, the second anti-cancer agent is a monoclonal antibody that} targets a non-checkpoint target (e.g., Herceptin). In certain embodiments, the second anti-cancer agent is a non-cytoxic agent (e.g., a tyrosine-kinase inhibitor). _{[0208] In certain embodiments, the second anti-cancer agent is selected from mitomycin,} ribomustin, vincristine, tretinoin, etoposide, cladribine, gemcitabine, mitobronitol, methotrexate, doxorubicin, carboquone, pentostatin, nitracrine, zinostatin, cetrorelix, letrozole, raltitrexed, daunorubicin, fadrozole, fotemustine, thymalfasin, sobuzoxane, nedaplatin, aminoglutethimide, amsacrine, proglumide, elliptinium acetate, ketanserin, doxifluridine, etretinate, isotretinoin, streptozocin, nimustine, vindesine, cytarabine, bicalutamide, vinorelbine, vesnarinone, flutamide, drogenil, butocin, carmofur, razoxane, sizofilan, carboplatin, mitolactol, tegafur, ifosfamide, prednimustine, picibanil, levamisole, teniposide, improsulfan, enocitabine, lisuride, oxymetholone, tamoxifen, progesterone, mepitiostane, epitiostanol, formestane, colony stimulating factor-1, colony stimulating factor-2, denileukin diftitox, interleukin-2, leutinizing hormone releasing factor, interferon-alpha, interferon-2 alpha, interferon-beta, and interferon- gamma. _{[0209] In certain embodiments, the second anti-cancer agent is paclitaxel, docetaxel,} cisplatin, epirubicin, 5-fluorouracil, or capecitabine. In certain embodiments, the second anti- cancer agent is ixabepilone or eribulin. In certain embodiments, the second anti-cancer agent is ART558. In certain embodiments, the second anti-cancer agent is lapatinib, neratinib, or tucatinib. In certain embodiments, the second anti-cancer agent is fulvestrant. In certain embodiments, the second anti-cancer agent is anastrozole or exemestane. In certain embodiments, the second anti-cancer agent is MK2206. In certain embodiments, the second anti-cancer agent is dacomitinib, mobocertinib, necitumumab, or amivantamab. In certain embodiments, the second anti-cancer agent is pemetrexed. In certain embodiments, the second anti-cancer agent is brigatinib. In certain embodiments, the second anti-cancer agent is capmatinib or tepotinib. In certain embodiments, the second anti-cancer agent is entrectinib. In certain embodiments, the second anti-cancer agent is pralsetinib or selpercatinib. In certain embodiments, the second anti-cancer agent is ipilimumab. In certain embodiments, the second anti-cancer agent is sotorasib. In certain embodiments, the second anti-cancer agent is topotecan or irinotecan. In certain embodiments, the second anti-cancer agent is lurbinectedin, melphalan, or thiotepa. In certain embodiments, the second anti-cancer agent is trifluridine or tipiracil. In certain embodiments, the second anti-cancer agent is megestrol. In certain embodiments, the second anti-cancer agent is sunitinib. In certain embodiments, the second anti-cancer agent is lanreotide or lutetium. In certain embodiments, the second anti-cancer agent is belzutifan. _{[0210] In certain embodiments, the second anti-cancer agent is an ALK Inhibitor, an ATR} Inhibitor, an A2A Antagonist, a Base Excision Repair Inhibitor, a Bcr-Abl Tyrosine Kinase Inhibitor, a Bruton's Tyrosine Kinase Inhibitor, a CDC7 Inhibitor, a CHK1 Inhibitor, a Cyclin- Dependent Kinase Inhibitor, a DNA-PK Inhibitor, an Inhibitor of both DNA-PK and mTOR, a DNMT1 Inhibitor, a DNMT1 Inhibitor plus 2-chloro-deoxyadenosine, an HDAC Inhibitor, a Hedgehog Signaling Pathway Inhibitor, an IDO Inhibitor, a JAK Inhibitor, a mTOR Inhibitor, a MEK Inhibitor, a MELK Inhibitor, a MTH1 Inhibitor, a PARP Inhibitor, a Phosphoinositide 3- Kinase Inhibitor, an Inhibitor of both PARP1 and DHODH, a Proteasome Inhibitor, a Topoisomerase-II Inhibitor, a Tyrosine Kinase Inhibitor, a VEGFR Inhibitor, or a WEE1 Inhibitor. _{[0211] In certain embodiments, the second anti-cancer agent is an ALK Inhibitor. In certain} embodiments, the second anti-cancer agent is an ALK Inhibitor comprising ceritinib, lorlatinib, or crizotinib. In certain embodiments, the second anti-cancer agent is an ATR Inhibitor. In certain embodiments, the second anti-cancer agent is an ATR Inhibitor comprising AZD6738, BAY1895344, M4344, or VX-970. In certain embodiments, the second anti-cancer agent is an A2A Antagonist. In certain embodiments, the second anti-cancer agent is a Base Excision Repair Inhibitor comprising methoxyamine. In certain embodiments, the second anti-cancer agent is a Base Excision Repair Inhibitor, such as methoxyamine. In certain embodiments, the second anti-cancer agent is a Bcr-Abl Tyrosine Kinase Inhibitor. In certain embodiments, the second anti-cancer agent is a Bcr-Abl Tyrosine Kinase Inhibitor comprising dasatinib or nilotinib. In certain embodiments, the second anti-cancer agent is a Bruton's Tyrosine Kinase Inhibitor. In certain embodiments, the second anti-cancer agent is a Bruton's Tyrosine Kinase Inhibitor comprising ibrutinib. In certain embodiments, the second anti-cancer agent is a CDC7 Inhibitor. In certain embodiments, the second anti-cancer agent is a CDC7 Inhibitor comprising RXDX-103 or AS-141. _{[0212] In certain embodiments, the second anti-cancer agent is a CHK1 Inhibitor. In certain} embodiments, the second anti-cancer agent is a CHK1 Inhibitor comprising MK-8776, ARRY- 575, AZD7762, or SAR-020106. In certain embodiments, the second anti-cancer agent is a Cyclin-Dependent Kinase Inhibitor. In certain embodiments, the second anti-cancer agent is a Cyclin-Dependent Kinase Inhibitor comprising abemaciclib, palbociclib, or ribociclib. In certain embodiments, the second anti-cancer agent is a DNA-PK Inhibitor. In certain embodiments, the second anti-cancer agent is a DNA-PK Inhibitor comprising MSC2490484A. In certain embodiments, the second anti-cancer agent is Inhibitor of both DNA-PK and mTOR. In certain embodiments, the second anti-cancer agent comprises CC-115. _{[0213] In certain embodiments, the second anti-cancer agent is a DNMT1 Inhibitor. In} certain embodiments, the second anti-cancer agent is a DNMT1 Inhibitor comprising decitabine, RX-3117, guadecitabine, NUC-8000, or azacytidine. In certain embodiments, the second anti- cancer agent comprises a DNMT1 Inhibitor and 2-chloro-deoxyadenosine. In certain embodiments, the second anti-cancer agent comprises ASTX-727. _{[0214] In certain embodiments, the second anti-cancer agent is a HDAC Inhibitor. In certain} embodiments, the second anti-cancer agent is a HDAC Inhibitor comprising OBP-801, CHR- 3996, etinostate, resminostate, pracinostat, CG-200745, panobinostat, romidepsin, mocetinostat, belinostat, AR-42, ricolinostat, KA-3000, or ACY-241. _{[0215] In certain embodiments, the second anti-cancer agent is a Hedgehog Signaling} Pathway Inhibitor. In certain embodiments, the second anti-cancer agent is a Hedgehog Signaling Pathway Inhibitor comprising sonidegib or vismodegib. In certain embodiments, the second anti-cancer agent is an IDO Inhibitor. In certain embodiments, the second anti-cancer agent is an IDO Inhibitor comprising INCB024360. In certain embodiments, the second anti- cancer agent is a JAK Inhibitor. In certain embodiments, the second anti-cancer agent is a JAK Inhibitor comprising ruxolitinib or tofacitinib. In certain embodiments, the second anti-cancer agent is a mTOR Inhibitor. In certain embodiments, the second anti-cancer agent is a mTOR Inhibitor comprising everolimus or temsirolimus. In certain embodiments, the second anti- cancer agent is a MEK Inhibitor. In certain embodiments, the second anti-cancer agent is a MEK Inhibitor comprising cobimetinib or trametinib. In certain embodiments, the second anti-cancer agent is a MELK Inhibitor. In certain embodiments, the second anti-cancer agent is a MELK Inhibitor comprising ARN-7016, APTO-500, or OTS-167. In certain embodiments, the second anti-cancer agent is a MTH1 Inhibitor. In certain embodiments, the second anti-cancer agent is a MTH1 Inhibitor comprising (S)-crizotinib, TH287, or TH588. _{[0216] In certain embodiments, the second anti-cancer agent is a PARP Inhibitor. In certain} embodiments, the second anti-cancer agent is a PARP Inhibitor comprising MP-124, olaparib, BGB-290, talazoparib, veliparib, niraparib, E7449, rucaparib, or ABT-767. In certain embodiments, the second anti-cancer agent is a Phosphoinositide 3-Kinase Inhibitor. In certain embodiments, the second anti-cancer agent is a Phosphoinositide 3-Kinase Inhibitor comprising alpelisib or idelalisib. In certain embodiments, the second anti-cancer agent is an inhibitor of both PARP1 and DHODH (i.e., an agent that inhibits both poly ADP ribose polymerase 1 and dihydroorotate dehydrogenase). _{[0217] In certain embodiments, the second anti-cancer agent is a Proteasome Inhibitor. In} certain embodiments, the second anti-cancer agent is a Proteasome Inhibitor comprising bortezomib or carfilzomib. In certain embodiments, the second anti-cancer agent is a Topoisomerase-II Inhibitor. In certain embodiments, the second anti-cancer agent is a Topoisomerase-II Inhibitor comprising vosaroxin. _{[0218] In certain embodiments, the second anti-cancer agent is a Tyrosine Kinase Inhibitor.} In certain embodiments, the second anti-cancer agent is a Tyrosine Kinase Inhibitor comprising bosutinib, cabozantinib, imatinib or ponatinib. In certain embodiments, the second anti-cancer agent is a VEGFR Inhibitor. In certain embodiments, the second anti-cancer agent is a VEGFR Inhibitor comprising regorafenib. In certain embodiments, the second anti-cancer agent is a WEE1 Inhibitor. In certain embodiments, the second anti-cancer agent is a WEE1 Inhibitor comprising AZD1775. _{[0219] In certain embodiments, the second anti-cancer agent is an agonist of OX40, CD137,} CD40, GITR, CD27, HVEM, TNFRSF25, or ICOS. In certain embodiments, the second anti- cancer agent is an agonist of OX40, CD137, CD40, or GITR. In certain embodiments, the second anti-cancer agent is an agonist of CD27, HVEM, TNFRSF25, or ICOS. _{[0220] In certain embodiments, the second anti-cancer agent is tenofovir, a prodrug thereof,} or a pharmaceutically acceptable salt of either of the foregoing. In certain embodiments, the second anti-cancer agent is tenofovir, tenofovir alafenamide, tenofovir amibufenamide, tenofovir disoproxil, or tenofovir exalidex; or a pharmaceutically acceptable salt thereof. In certain embodiments, the second anti-cancer agent is tenofovir, tenofovir alafenamide, tenofovir amibufenamide, tenofovir disoproxil, or tenofovir exalidex. _{[0221] In certain embodiments, the second anti-cancer agent is tenofovir, or a} pharmaceutically acceptable salt thereof. In certain embodiments, the second anti-cancer agent is tenofovir. In certain embodiments, the second anti-cancer agent is tenofovir alafenamide, or a pharmaceutically acceptable salt thereof. In certain embodiments, the second anti-cancer agent is tenofovir alafenamide. In certain embodiments, the second anti-cancer agent is tenofovir amibufenamide, or a pharmaceutically acceptable salt thereof. In certain embodiments, the second anti-cancer agent is tenofovir amibufenamide. In certain embodiments, the second anti- cancer agent is tenofovir disoproxil, or a pharmaceutically acceptable salt thereof. In certain embodiments, the second anti-cancer agent is tenofovir disoproxil, or a fumarate, succinate, maleate, orotate, aspartate, or phosphate salt thereof. In certain embodiments, the second anti- cancer agent is tenofovir disoproxil, or a fumarate, succinate, or maleate salt thereof. In certain embodiments, the second anti-cancer agent is tenofovir disoproxil. In certain embodiments, the second anti-cancer agent is tenofovir exalidex, or a pharmaceutically acceptable salt thereof. In certain embodiments, the second anti-cancer agent is tenofovir exalidex, or a potassium salt thereof. In certain embodiments, the second anti-cancer agent is tenofovir exalidex. _{[0222] In certain embodiments, the method further comprises administering to the subject a} third anti-cancer agent. In certain embodiments, the method further comprises administering to the subject a fourth anti-cancer agent. In certain embodiments, the method further comprises administering to the subject a fifth anti-cancer agent. _{[0223] In certain embodiments, the third anti-cancer agent is one of the second anti-cancer} agents described above. In certain embodiments, the fourth anti-cancer agent is one of the second anti-cancer agents described above. In certain embodiments, the fifth anti-cancer agent is one of the second anti-cancer agents described above. Inflammatory Disorders _{[0224] Another aspect of the disclosure provides a method of treating an inflammatory} disorder in a patient. The method comprises administering to a subject in need thereof (i) a therapeutically effective amount of a substituted cyclo-oxymethylene phosphonamidate or related compound described herein and (ii) a second therapeutic agent, in order to treat the inflammatory disorder. _{[0225] In certain embodiments, the second therapeutic agent is a small molecule or a} recombinant biologic agent. In certain embodiments, the second therapeutic agent is selected from acetaminophen, non-steroidal anti-inflammatory drugs (NSAIDS) such as aspirin, ibuprofen, naproxen, etodolac (Lodine®) and celecoxib, colchicine (Colcrys®), corticosteroids such as prednisone, prednisolone, methylprednisolone, hydrocortisone, and the like, probenecid, allopurinol, febuxostat (Uloric®), sulfasalazine (Azulfidine®), antimalarials such as hydroxychloroquine (Plaquenil®) and chloroquine (Aralen®), methotrexate (Rheumatrex®), gold salts such as gold thioglucose (Solganal®), gold thiomalate (Myochrysine®) and auranofin (Ridaura®), D-penicillamine (Depen® or Cuprimine®), azathioprine (Imuran®), cyclophosphamide (Cytoxan®), chlorambucil (Leukeran®), cyclosporine (Sandimmune®, Neoral®), tacrolimus, sirolimus, mycophenolate, leflunomide (Arava®) and “anti-TNF” agents such as etanercept (Enbrel®), infliximab (Remicade®), golimumab (Simponi®), certolizumab pegol (Cimzia®) and adalimumab (Humira®), “anti-IL-1” agents such as anakinra (Kineret®) and rilonacept (Arcalyst®), anti-T cell antibodies such as Thymoglobulin, IV Immunoglobulins (IVIg), canakinumab (Ilaris®), anti-Jak inhibitors such as tofacitinib, antibodies such as rituximab (Rituxan®), “anti-T-cell” agents such as abatacept (Orencia®), “anti-IL-6” agents such as tocilizumab (Actemra®), diclofenac, cortisone, hyaluronic acid (Synvisc® or Hyalgan®), monoclonal antibodies such as tanezumab, anticoagulants such as heparin (Calcinparine® or Liquaemin®) and warfarin (Coumadin®), antidiarrheals such as diphenoxylate (Lomotil®) and loperamide (Imodium®), bile acid binding agents such as cholestyramine, alosetron (Lotronex®), lubiprostone (Amitiza®), laxatives such as Milk of Magnesia, polyethylene glycol (MiraLax®), Dulcolax®, Correctol® and Senokot®, anticholinergics or antispasmodics such as dicyclomine (Bentyl®), Singulair®, beta-2 agonists such as albuterol (Ventolin® HFA, Proventil® HFA), levalbuterol (Xopenex®), metaproterenol (Alupent®), pirbuterol acetate (Maxair®), terbutaline sulfate (Brethaire®), salmeterol xinafoate (Serevent®) and formoterol (Foradil®), anticholinergic agents such as ipratropium bromide (Atrovent®) and tiotropium (Spiriva®), inhaled corticosteroids such as beclomethasone dipropionate (Beclovent®, Qvar®, and Vanceril®), triamcinolone acetonide (Azmacort®), mometasone (Asthmanex®), budesonide (Pulmocort®), and flunisolide (Aerobid®), Afviar®, Symbicort®, Dulera®, cromolyn sodium (Intal®), methylxanthines such as theophylline (Theo- Dur®, Theolair®, Slo-bid®, Uniphyl®, Theo-24®) and aminophylline, IgE antibodies such as omalizumab (Xolair®), nucleoside reverse transcriptase inhibitors such as zidovudine (Retrovir®), abacavir (Ziagen®), abacavir/lamivudine (Epzicom®), abacavir/lamivudine/zidovudine (Trizivir®), didanosine (Videx®), emtricitabine (Emtriva®), lamivudine (Epivir®), lamivudine/zidovudine (Combivir®), stavudine (Zerit®), and zalcitabine (Hivid®), non-nucleoside reverse transcriptase inhibitors such as delavirdine (Rescriptor®), efavirenz (Sustiva®), nevirapine (Viramune®) and etravirine (Intelence®), nucleotide reverse transcriptase inhibitors such as tenofovir (Viread®), protease inhibitors such as amprenavir (Agenerase®), atazanavir (Reyataz®), darunavir (Prezista®), fosamprenavir (Lexiva®), indinavir (Crixivan®), lopinavir and ritonavir (Kaletra®), nelfinavir (Viracept®), ritonavir (Norvir®), saquinavir (Fortovase® or Invirase®), and tipranavir (Aptivus®), entry inhibitors such as enfuvirtide (Fuzeon®) and maraviroc (Selzentry®), integrase inhibitors such as raltegravir (Isentress®), doxorubicin (Hydrodaunorubicin®), vincristine (Oncovin®), bortezomib (Velcade®), and dexamethasone (Decadron®) in combination with lenalidomide (Revlimid®), anti-IL36 agents such as BI655130, Dihydroorotate dehydrogenase inhibitors such as IMU-838, anti-OX40 agents such as KHK-4083, microbiome agents such as RBX2660, SER- 287, Narrow spectrum kinase inhibitors such as TOP-1288, anti-CD40 agents such as BI-655064 and FFP-104, guanylate cyclase agonists such as dolcanatide, sphingosine kinase inhibitors such as opaganib, anti-IL-12/IL-23 agents such as AK-101, Ubiquitin protein ligase complex inhibitors such as BBT- 401, sphingosine receptors modulators such as BMS-986166, P38MAPK/PDE4 inhibitors such as CBS-3595, CCR9 antagonists such as CCX-507, FimH antagonists such as EB-8018, HIF-PH inhibitors such as FG-6874, HIF-1α stabilizer such as GB- 004, MAP3K8 protein inhibitors such as GS-4875, LAG-3 antibodies such as GSK-2831781, RIP2 kinase inhibitors such as GSK-2983559, Farnesoid X receptor agonist such as MET-409, CCK2 antagonists such as PNB-001, IL-23 Receptor antagonists such as PTG-200, Purinergic P2X7 receptor antagonists such as SGM-1019, PDE4 inhibitors such as Apremilast, ICAM-1 inhibitors such as alicaforsen sodium, Anti- IL23 agents such as guselkumab, brazikumab and mirkizumab, ant-IL-15 agents such as AMG-714, TYK-2 inhibitors such as BMS-986165, NK Cells activators such as CNDO-201, RIP-1 kinase inhibitors such as GSK-2982772, anti- NKGD2 agents such as JNJ-4500, CXCL-10 antibodies such as JT-02, IL-22 receptor agonists such as RG-7880, GATA-3 antagonists such as SB-012, and Colony-stimulating factor-1 receptor inhibitors such as edicotinib. _{[0226] In certain embodiments, the second therapeutic agent is tenofovir, a prodrug thereof,} or a pharmaceutically acceptable salt of either of the foregoing. In certain embodiments, the second therapeutic agent is tenofovir, tenofovir alafenamide, tenofovir amibufenamide, tenofovir disoproxil, or tenofovir exalidex; or a pharmaceutically acceptable salt thereof. In certain embodiments, the second therapeutic agent is tenofovir, tenofovir alafenamide, tenofovir amibufenamide, tenofovir disoproxil, or tenofovir exalidex. _{[0227] In certain embodiments, the second therapeutic agent is tenofovir, or a} pharmaceutically acceptable salt thereof. In certain embodiments, the second therapeutic agent is tenofovir. In certain embodiments, the second therapeutic agent is tenofovir alafenamide, or a pharmaceutically acceptable salt thereof. In certain embodiments, the second therapeutic agent is tenofovir alafenamide. In certain embodiments, the second therapeutic agent is tenofovir amibufenamide, or a pharmaceutically acceptable salt thereof. In certain embodiments, the second therapeutic agent is tenofovir amibufenamide. In certain embodiments, the second therapeutic agent is tenofovir disoproxil, or a pharmaceutically acceptable salt thereof. In certain embodiments, the second therapeutic agent is tenofovir disoproxil, or a fumarate, succinate, maleate, orotate, aspartate, or phosphate salt thereof. In certain embodiments, the second therapeutic agent is tenofovir disoproxil, or a fumarate, succinate, or maleate salt thereof. In certain embodiments, the second therapeutic agent is tenofovir disoproxil. In certain embodiments, the second therapeutic agent is tenofovir exalidex, or a pharmaceutically acceptable salt thereof. In certain embodiments, the second therapeutic agent is tenofovir exalidex, or a potassium salt thereof. In certain embodiments, the second therapeutic agent is tenofovir exalidex. _{[0228] In certain embodiments, the method further comprises administering to the subject a} third therapeutic agent. In certain embodiments, the method further comprises administering to the subject a fourth therapeutic agent. In certain embodiments, the method further comprises administering to the subject a fifth therapeutic agent. _{[0229] In certain embodiments, the third therapeutic agent is one of the second therapeutic} agents described above. In certain embodiments, the fourth therapeutic agent is one of the second therapeutic agents described above. In certain embodiments, the fifth therapeutic agent is one of the second therapeutic agents described above. Immune Disorders Other Than a Viral Infection _{[0230] Another aspect of the disclosure provides a method of treating an immune disorder} other than a viral infection in a patient. The method comprises administering to a subject in need thereof (i) a therapeutically effective amount of a substituted cyclo-oxymethylene phosphonamidate or related compound described herein and (ii) a second therapeutic agent, in order to treat the immune disorder other than a viral infection. _{[0231] In certain embodiments, the second therapeutic agent is pentoxifylline,} propentofylline, torbafylline, cyclosporine, methotrexate, tamoxifen, forskolin and analogs thereof, tar derivatives, steroids, vitamin A and its derivatives, vitamin D and its derivatives, a cytokine, a chemokine, a stem cell growth factor, a lymphotoxin, an hematopoietic factor, a colony stimulating factor (CSF), erythropoietin, thrombopoietin, tumor necrosis factor-α (TNF), TNF-⊖, granulocyte-colony stimulating factor (G-CSF), granulocyte macrophage-colony stimulating factor (GM-CSF), interferon-α, interferon-β, interferon-γ, interferon-λ, stem cell growth factor designated “S1 factor”, human growth hormone, N-methionyl human growth hormone, bovine growth hormone, parathyroid hormone, thyroxine, insulin, proinsulin, relaxin, prorelaxin, follicle stimulating hormone (FSH), thyroid stimulating hormone (TSH), luteinizing hormone (LH), hepatic growth factor, prostaglandin, fibroblast growth factor, prolactin, placental lactogen, OB protein, mullerian-inhibiting substance, mouse gonadotropin-associated peptide, inhibin, activin, vascular endothelial growth factor, integrin, NGF-β, platelet-growth factor, TGF-α, TGF-β, insulin-like growth factor-I, insulin-like growth factor-II, macrophage-CSF (M- CSF), IL-1, IL-la, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-11, IL-12, IL-13, IL- 14, IL-15, IL-16, IL-17, IL-18, IL-21, IL-25, LIF, FLT-3, angiostatin, thrombospondin, endostatin, or lymphotoxin. _{[0232] In certain embodiments, the second therapeutic agent is tenofovir, a prodrug thereof,} or a pharmaceutically acceptable salt of either of the foregoing. In certain embodiments, the second therapeutic agent is tenofovir, tenofovir alafenamide, tenofovir amibufenamide, tenofovir disoproxil, or tenofovir exalidex; or a pharmaceutically acceptable salt thereof. In certain embodiments, the second therapeutic agent is tenofovir, tenofovir alafenamide, tenofovir amibufenamide, tenofovir disoproxil, or tenofovir exalidex. _{[0233] In certain embodiments, the second therapeutic agent is tenofovir, or a} pharmaceutically acceptable salt thereof. In certain embodiments, the second therapeutic agent is tenofovir. In certain embodiments, the second therapeutic agent is tenofovir alafenamide, or a pharmaceutically acceptable salt thereof. In certain embodiments, the second therapeutic agent is tenofovir alafenamide. In certain embodiments, the second therapeutic agent is tenofovir amibufenamide, or a pharmaceutically acceptable salt thereof. In certain embodiments, the second therapeutic agent is tenofovir amibufenamide. In certain embodiments, the second therapeutic agent is tenofovir disoproxil, or a pharmaceutically acceptable salt thereof. In certain embodiments, the second therapeutic agent is tenofovir disoproxil, or a fumarate, succinate, maleate, orotate, aspartate, or phosphate salt thereof. In certain embodiments, the second therapeutic agent is tenofovir disoproxil, or a fumarate, succinate, or maleate salt thereof. In certain embodiments, the second therapeutic agent is tenofovir disoproxil. In certain embodiments, the second therapeutic agent is tenofovir exalidex, or a pharmaceutically acceptable salt thereof. In certain embodiments, the second therapeutic agent is tenofovir exalidex, or a potassium salt thereof. In certain embodiments, the second therapeutic agent is tenofovir exalidex. _{[0234] In certain embodiments, the method further comprises administering to the subject a} third therapeutic agent. In certain embodiments, the method further comprises administering to the subject a fourth therapeutic agent. In certain embodiments, the method further comprises administering to the subject a fifth therapeutic agent. _{[0235] In certain embodiments, the third therapeutic agent is one of the second therapeutic} agents described above. In certain embodiments, the fourth therapeutic agent is one of the second therapeutic agents described above. In certain embodiments, the fifth therapeutic agent is one of the second therapeutic agents described above. Viral Infection _{[0236] Another aspect of the disclosure provides a method of treating an immune disorder} that is a viral infection in a patient. The method comprises administering to a subject in need thereof (i) a therapeutically effective amount of a substituted cyclo-oxymethylene phosphonamidate or related compound described herein and (ii) a second therapeutic agent, in order to treat the immune disorder that is a viral infection. In certain embodiments, the immune disorder is a viral infection other than an influenza viral infection. _{[0237] In certain embodiments, the second therapeutic agent is an anti-HIV agent. In certain} embodiments, the second therapeutic agent is a nucleoside reverse transcriptase inhibitor (NRTI), non-nucleoside reverse transcriptase inhibitor, protease inhibitor, or fusion inhibitor. In certain embodiments, the second therapeutic agent is 3TC (Lamivudine), AZT (Zidovudine), (−)- FTC, ddI (Didanosine), ddC (zalcitabine), abacavir (ABC), tenofovir (PMPA), D-D4FC (Reverset), D4T (Stavudine), Racivir, L-FddC, L-FD4C, NVP (Nevirapine), DLV (Delavirdine), EFV (Efavirenz), SQVM (Saquinavir mesylate), RTV (Ritonavir), IDV (Indinavir), SQV (Saquinavir), NFV (Nelfinavir), APV (Amprenavir), LPV (Lopinavir), or the fusion inhibitor T20. _{[0238] In certain embodiments, the second therapeutic agent is ddC, abacavir, ddI, ddA, 3TC,} AZT, D4T, FTC, FddC, Fd4C, Atazanavir, Adefovir dipivoxyl, Tenofovir disoproxil, Etecavir, Indinavir, KHI-227.2-[3-[3-(S)-[[(Tetrahydrofuranyloxy)carbonyl]amino]-4-phenyl-2(R)- hydroxybutyl]]-N-(1,1-dimethylethyl)decahydro-3-isoquinolinecarboxamide, VB-11,328, KNI- 174, Val-Val-Sta, CPG53820, HOEt-N2 aza-peptide isostere, 2,5-Diamino-N,N′-bis(N- benzyloxycarbonyluelyl)-1,6-diphenyl-3(S),4(S)-hexanediol BzOCValPhe[diCHOH(SS] PheValBzOC, 2,5,-Diamino-N,N′-bis(N-benzyloxycarbonyluelyl)-1,6-diphenyl-3(R),4(R)- hexanediol BzOCValPhe[diCHOH(RR]PheValBzOC, [bis(SATE)ddAMP], BILA 2186 BS, Agenerase, A-98881, A-83962, A-80987, (2-Naphthalcarbonyl)Asn[decarbonylPhe- hydroxyethyl]ProOtertButyl, A-81525, XM323, Tipranavir, SDZ PRI 053, SD146, Telinavir, (R)2QuinCOAsnPhe[CHOHCH2]PipCONHtBu, Saquinavir, R-87366, DMP 460, L685,434, L685,434-OEtNMe2, L689,502, Lasinavir, Aluviran P9941, Palinavir, or Penicillin. In certain embodiments, the second therapeutic agent is ddC, abacavir, ddI, ddA, 3TC, AZT, D4T, FTC, FddC, or Fd4C. _{[0239] In certain embodiments, the second therapeutic agent is tenofovir, a prodrug thereof,} or a pharmaceutically acceptable salt of either of the foregoing. In certain embodiments, the second therapeutic agent is tenofovir, tenofovir alafenamide, tenofovir amibufenamide, tenofovir disoproxil, or tenofovir exalidex; or a pharmaceutically acceptable salt thereof. In certain embodiments, the second therapeutic agent is tenofovir, tenofovir alafenamide, tenofovir amibufenamide, tenofovir disoproxil, or tenofovir exalidex. _{[0240] In certain embodiments, the second therapeutic agent is tenofovir, or a} pharmaceutically acceptable salt thereof. In certain embodiments, the second therapeutic agent is tenofovir. In certain embodiments, the second therapeutic agent is tenofovir alafenamide, or a pharmaceutically acceptable salt thereof. In certain embodiments, the second therapeutic agent is tenofovir alafenamide. In certain embodiments, the second therapeutic agent is tenofovir amibufenamide, or a pharmaceutically acceptable salt thereof. In certain embodiments, the second therapeutic agent is tenofovir amibufenamide. In certain embodiments, the second therapeutic agent is tenofovir disoproxil, or a pharmaceutically acceptable salt thereof. In certain embodiments, the second therapeutic agent is tenofovir disoproxil, or a fumarate, succinate, maleate, orotate, aspartate, or phosphate salt thereof. In certain embodiments, the second therapeutic agent is tenofovir disoproxil, or a fumarate, succinate, or maleate salt thereof. In certain embodiments, the second therapeutic agent is tenofovir disoproxil. In certain embodiments, the second therapeutic agent is tenofovir exalidex, or a pharmaceutically acceptable salt thereof. In certain embodiments, the second therapeutic agent is tenofovir exalidex, or a potassium salt thereof. In certain embodiments, the second therapeutic agent is tenofovir exalidex. _{[0241] In certain embodiments, the method further comprises administering to the subject a} third therapeutic agent. In certain embodiments, the method further comprises administering to the subject a fourth therapeutic agent. In certain embodiments, the method further comprises administering to the subject a fifth therapeutic agent. _{[0242] In certain embodiments, the third therapeutic agent is one of the second therapeutic} agents described above. In certain embodiments, the fourth therapeutic agent is one of the second therapeutic agents described above. In certain embodiments, the fifth therapeutic agent is one of the second therapeutic agents described above. Neurodegenerative Disorders _{[0243] Another aspect of the disclosure provides a method of treating a neurodegenerative} disorder in a patient. The method comprises administering to a subject in need thereof (i) a therapeutically effective amount of a substituted cyclo-oxymethylene phosphonamidate or related compound described herein and (ii) a second therapeutic agent, in order to treat the neurodegenerative disorder. _{[0244] In certain embodiments, the second therapeutic agent is a dopaminergic treatment, a} cholinesterase inhibitor, an antipsychotic drug, deep brain stimulation (for example, to stop tremor and refractory movement disorders), riluzole, a caffein A2A receptor antagonist, pramipexole, or rasagilin. _{[0245] In certain embodiments, the second therapeutic agent is tenofovir, a prodrug thereof,} or a pharmaceutically acceptable salt of either of the foregoing. In certain embodiments, the second therapeutic agent is tenofovir, tenofovir alafenamide, tenofovir amibufenamide, tenofovir disoproxil, or tenofovir exalidex; or a pharmaceutically acceptable salt thereof. In certain embodiments, the second therapeutic agent is tenofovir, tenofovir alafenamide, tenofovir amibufenamide, tenofovir disoproxil, or tenofovir exalidex. _{[0246] In certain embodiments, the second therapeutic agent is tenofovir, or a} pharmaceutically acceptable salt thereof. In certain embodiments, the second therapeutic agent is tenofovir. In certain embodiments, the second therapeutic agent is tenofovir alafenamide, or a pharmaceutically acceptable salt thereof. In certain embodiments, the second therapeutic agent is tenofovir alafenamide. In certain embodiments, the second therapeutic agent is tenofovir amibufenamide, or a pharmaceutically acceptable salt thereof. In certain embodiments, the second therapeutic agent is tenofovir amibufenamide. In certain embodiments, the second therapeutic agent is tenofovir disoproxil, or a pharmaceutically acceptable salt thereof. In certain embodiments, the second therapeutic agent is tenofovir disoproxil, or a fumarate, succinate, maleate, orotate, aspartate, or phosphate salt thereof. In certain embodiments, the second therapeutic agent is tenofovir disoproxil, or a fumarate, succinate, or maleate salt thereof. In certain embodiments, the second therapeutic agent is tenofovir disoproxil. In certain embodiments, the second therapeutic agent is tenofovir exalidex, or a pharmaceutically acceptable salt thereof. In certain embodiments, the second therapeutic agent is tenofovir exalidex, or a potassium salt thereof. In certain embodiments, the second therapeutic agent is tenofovir exalidex. _{[0247] In certain embodiments, the method further comprises administering to the subject a} third therapeutic agent. In certain embodiments, the method further comprises administering to the subject a fourth therapeutic agent. In certain embodiments, the method further comprises administering to the subject a fifth therapeutic agent. _{[0248] In certain embodiments, the third therapeutic agent is one of the second therapeutic} agents described above. In certain embodiments, the fourth therapeutic agent is one of the second therapeutic agents described above. In certain embodiments, the fifth therapeutic agent is one of the second therapeutic agents described above. V. Pharmaceutical Compositions and Dosing Considerations _{[0249] As indicated above, the disclosure provides pharmaceutical compositions, which} comprise a therapeutically-effective amount of one or more of the compounds described above, formulated together with one or more pharmaceutically acceptable carriers (additives) and/or diluents. The pharmaceutical compositions may be specially formulated for administration in solid or liquid form, including those adapted for the following: (1) oral administration, for example, drenches (aqueous or non-aqueous solutions or suspensions), tablets, e.g., those targeted for buccal, sublingual, and systemic absorption, boluses, powders, granules, pastes for application to the tongue; (2) parenteral administration, for example, by subcutaneous, intramuscular, intravenous or epidural injection as, for example, a sterile solution or suspension, or sustained-release formulation; (3) topical application, for example, as a cream, ointment, or a controlled-release patch or spray applied to the skin; (4) intravaginally or intrarectally, for example, as a pessary, cream or foam; (5) sublingually; (6) ocularly; (7) transdermally; or (8) nasally. _{[0250] In certain embodiments, the disclosure provides a pharmaceutical composition} comprising a compound described herein (e.g., a compound of Formula I) and a pharmaceutically acceptable carrier. In certain embodiments, the disclosure provides a pharmaceutical composition comprising a compound described herein (e.g., a compound of Formula I), an additional therapeutic agent (e.g., a compound described in Section IV), and a pharmaceutically acceptable carrier. _{[0251] The phrase “therapeutically effective amount” as used herein means that amount of a} compound, material, or composition comprising a compound of the present disclosure which is effective for producing some desired therapeutic effect in at least a sub-population of cells in an animal at a reasonable benefit/risk ratio applicable to any medical treatment. _{[0252] The phrase “pharmaceutically acceptable” is employed herein to refer to those} compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio. _{[0253] Wetting agents, emulsifiers and lubricants, such as sodium lauryl sulfate and} magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the compositions. _{[0254] Examples of pharmaceutically-acceptable antioxidants include: (1) water soluble} antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol, and the like; and (3) metal chelating agents, such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like. _{[0255] Formulations of the present disclosure include those suitable for oral, nasal, topical} (including buccal and sublingual), rectal, vaginal and/or parenteral administration. The formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy. The amount of active ingredient which can be combined with a carrier material to produce a single dosage form will vary depending upon the host being treated, the particular mode of administration. The amount of active ingredient which can be combined with a carrier material to produce a single dosage form will generally be that amount of the compound which produces a therapeutic effect. Generally, out of one hundred percent, this amount will range from about 0.1 percent to about ninety-nine percent of active ingredient, preferably from about 5 percent to about 70 percent, most preferably from about 10 percent to about 30 percent. _{[0256] In certain embodiments, a formulation of the present disclosure comprises an excipient} selected from the group consisting of cyclodextrins, celluloses, liposomes, micelle forming agents, e.g., bile acids, and polymeric carriers, e.g., polyesters and polyanhydrides; and a compound of the present disclosure. In certain embodiments, an aforementioned formulation renders orally bioavailable a compound of the present disclosure. _{[0257] Methods of preparing these formulations or compositions include the step of bringing} into association a compound of the present disclosure with the carrier and, optionally, one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association a compound of the present disclosure with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product. _{[0258] Formulations of the disclosure suitable for oral administration may be in the form of} capsules, cachets, pills, tablets, lozenges (using a flavored basis, usually sucrose and acacia or tragacanth), powders, granules, or as a solution or a suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as pastilles (using an inert base, such as gelatin and glycerin, or sucrose and acacia) and/or as mouth washes and the like, each containing a predetermined amount of a compound of the present disclosure as an active ingredient. A compound of the present disclosure may also be administered as a bolus, electuary or paste. _{[0259] In solid dosage forms of the disclosure for oral administration (capsules, tablets, pills,} dragees, powders, granules, troches and the like), the active ingredient is mixed with one or more pharmaceutically-acceptable carriers, such as sodium citrate or dicalcium phosphate, and/or any of the following: (1) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and/or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds and surfactants, such as poloxamer and sodium lauryl sulfate; (7) wetting agents, such as, for example, cetyl alcohol, glycerol monostearate, and non-ionic surfactants; (8) absorbents, such as kaolin and bentonite clay; (9) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, zinc stearate, sodium stearate, stearic acid, and mixtures thereof; (10) coloring agents; and (11) controlled release agents such as crospovidone or ethyl cellulose. In the case of capsules, tablets and pills, the pharmaceutical compositions may also comprise buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard-shelled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like. _{[0260] A tablet may be made by compression or molding, optionally with one or more} accessory ingredients. Compressed tablets may be prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface-active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. _{[0261] The tablets, and other solid dosage forms of the pharmaceutical compositions of the} present disclosure, such as dragees, capsules, pills and granules, may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical-formulating art. They may also be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile, other polymer matrices, liposomes and/or microspheres. They may be formulated for rapid release, e.g., freeze-dried. They may be sterilized by, for example, filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved in sterile water, or some other sterile injectable medium immediately before use. These compositions may also optionally contain opacifying agents and may be of a composition that they release the active ingredient(s) only, or preferentially, in a certain portion of the gastrointestinal tract, optionally, in a delayed manner. Examples of embedding compositions which can be used include polymeric substances and waxes. The active ingredient can also be in micro-encapsulated form, if appropriate, with one or more of the above-described excipients. _{[0262] Liquid dosage forms for oral administration of the compounds of the disclosure} include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. Suspensions, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof. _{[0263] Dosage forms for the topical or transdermal administration of a compound of this} disclosure include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. The active compound may be mixed under sterile conditions with a pharmaceutically-acceptable carrier, and with any preservatives, buffers, or propellants which may be required. The ointments, pastes, creams and gels may contain, in addition to an active compound of this disclosure, excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof. Ophthalmic formulations, eye ointments, powders, solutions and the like, may be used for compounds described herein. _{[0264] Besides inert diluents, the oral compositions can also include adjuvants such as} wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents. _{[0265] Transdermal patches have the added advantage of providing controlled delivery of a} compound of the present disclosure to the body. Such dosage forms can be made by dissolving or dispersing the compound in the proper medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate of such flux can be controlled by either providing a rate controlling membrane or dispersing the compound in a polymer matrix or gel. _{[0266] Pharmaceutical compositions of this disclosure suitable for parenteral administration} comprise one or more compounds of the disclosure in combination with one or more pharmaceutically-acceptable sterile isotonic aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use. _{[0267] Examples of suitable aqueous and nonaqueous carriers which may be employed in the} pharmaceutical compositions of the disclosure include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants. _{[0268] These compositions may also contain adjuvants such as preservatives, wetting agents,} emulsifying agents and dispersing agents. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like into the compositions. In addition, prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents which delay absorption such as aluminum monostearate and gelatin. _{[0269] When the compounds of the present disclosure are administered as pharmaceuticals, to} humans and animals, they can be given per se or as a pharmaceutical composition containing, for example, 0.1 to 99% (more preferably, 10 to 30%) of active ingredient in combination with a pharmaceutically acceptable carrier. _{[0270] The preparations of the present disclosure may be given orally, parenterally, topically,} or rectally. They are of course given in forms suitable for each administration route. For example, they are administered in tablets or capsule form, by injection, inhalation, eye lotion, ointment, suppository, etc. administration by injection, infusion or inhalation; topical by lotion or ointment; and rectal by suppositories. Oral administrations are preferred. _{[0271] The phrases “parenteral administration” and “administered parenterally” as used} herein means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal and intrasternal injection and infusion. _{[0272] The phrases “systemic administration,” “administered systemically,” “peripheral} administration” and “administered peripherally” as used herein mean the administration of a compound, drug or other material other than directly into the central nervous system, such that it enters the patient’s system and, thus, is subject to metabolism and other like processes, for example, subcutaneous administration. _{[0273] These compounds may be administered to humans and other animals for therapy by} any suitable route of administration, including orally, nasally, as by, for example, a spray, rectally, intravaginally, parenterally, intracisternally and topically, as by powders, ointments or drops, including buccally and sublingually. _{[0274] Regardless of the route of administration selected, the compounds of the present} disclosure, which may be used in a suitable hydrated form, and/or the pharmaceutical compositions of the present disclosure, are formulated into pharmaceutically-acceptable dosage forms by conventional methods known to those of skill in the art. _{[0275] Actual dosage levels of the active ingredients in the pharmaceutical compositions of} this disclosure may be varied so as to obtain an amount of the active ingredient which is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient. _{[0276] The selected dosage level will depend upon a variety of factors including the activity} of the particular compound of the present disclosure employed, or the ester, salt or amide thereof, the route of administration, the time of administration, the rate of excretion or metabolism of the particular compound being employed, the rate and extent of absorption, the duration of the treatment, other drugs, compounds and/or materials used in combination with the particular compound employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts. _{[0277] A physician or veterinarian having ordinary skill in the art can readily determine and} prescribe the effective amount of the pharmaceutical composition required. For example, the physician or veterinarian could start doses of the compounds of the disclosure employed in the pharmaceutical composition at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved. _{[0278] In general, a suitable daily dose of a compound of the disclosure will be that amount} of the compound which is the lowest dose effective to produce a therapeutic effect. Such an effective dose will generally depend upon the factors described above. Preferably, the compounds are administered at about 0.01 mg/kg to about 200 mg/kg, more preferably at about 0.1 mg/kg to about 100 mg/kg, even more preferably at about 0.5 mg/kg to about 50 mg/kg. When the compounds described herein are co-administered with another agent (e.g., as sensitizing agents), the effective amount may be less than when the agent is used alone. _{[0279] If desired, the effective daily dose of the active compound may be administered as} two, three, four, five, six or more sub-doses administered separately at appropriate intervals throughout the day, optionally, in unit dosage forms. Preferred dosing is one administration per day. [_{0280] The disclosure further provides a unit dosage form (such as a tablet or capsule)} comprising a substituted cyclo-oxymethylene phosphonamidate or related compound described herein in a therapeutically effective amount for the treatment of a medical disorder described herein. EXAMPLES [_{0281] The disclosure now being generally described, will be more readily understood by} reference to the following examples, which are included merely for purposes of illustration of certain aspects and embodiments of the present disclosure, and are not intended to limit the disclosure. Starting materials described herein can be obtained from commercial sources or may be readily prepared from commercially available materials using transformations known to those of skill in the art. EXAMPLE 1 – Synthesis of ammonium ((((2R,5R)-5-(5-methyl-2,4-dioxo-3,4- dihydropyrimidin-1(2H)-yl)-2,5-dihydrofuran-2-yl) oxy) methyl) phosphonate, Compound I-1

_{[0282] Step 1: To a stirred solution of 1-((2R,4S,5R)-4-hydroxy-5-(hydroxymethyl)} tetrahydrofuran-2-yl)-5-methylpyrimidine-2,4(1H,3H)-dione (5 g, 20.6 mmol) and Celite545 (10 g) in acetone (100 mL) was added Jones’ reagent (12.3 g, 61.9 mmol, 2 M in H2SO4) dropwise at 0 °C under N₂ atmosphere. The mixture was stirred for 2 h at room temperature. The reaction was quenched with isopropanol at 0 °C. The solids were filtered out and the filter cake was washed with the THF. The filtrate was concentrated under reduced pressure. The resulting mixture was extracted with THF/EA (6 x 150 mL, 1:1). The combined organic layers were washed with brine and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure to afford (2S,3S,5R)-3-hydroxy-5-(5-methyl-2,4-dioxo-3,4- dihydropyrimidin-1(2H)-yl) tetrahydrofuran-2-carboxylic acid (3.2 g, crude) which was used in the next step directly without further purification. LC/MS (ES, m/z): 257 [M+H]⁺. _{[0283] Step 2: To a stirred solution of (2S,3S,5R)-3-hydroxy-5-(5-methyl-2,4-dioxo-3,4-} dihydropyrimidin-1(2H)-yl) tetrahydrofuran-2-carboxylic acid (3.2 g, crude) and PPh3 (4.91 g, 18.7 mmol) in DCM (50 mL) was added DIAD (2.45 g, 18.7 mmol) dropwise at room temperature under N₂ atmosphere, then stirred for 1 hour at 0 °C. The resulting mixture was used in the next step directly without further purification. LC/MS (ES, m/z): 193 [M-H]-. _{[0284] Step 3: To the above solution was added diethyl (hydroxymethyl)phosphonate (4.16} g, 24.7 mmol) in DCM (40 mL) and IBr (5.37 g, 25.9 mmol) in DCM (40 mL) dropwise at -40 °C under N2 atmosphere, then stirred for 2 h at room temperature. The reaction was quenched with a saturated solution of NaHCO3 and 10% Na2S2O3 at 0°C. The mixture was extracted with DCM (3 x 50 mL), and the combined extracts were washed with brine and dried over anhydrous Na2SO4. The solids were filtered out and the filtrations were combined and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with (DCM/MeOH=12:1) to afford diethyl ((((2R,3S,5R)-3-iodo-5-(5-methyl-2,4-dioxo-3,4- dihydropyrimidin-1(2H)-yl) tetrahydrofuran-2-yl) oxy) methyl) phosphonate (1.5 g, 25%) as a solid. LC/MS (ES, m/z): 487 [M-H]-. _{[0285] Step 4: To a stirred solution of diethyl ((((2R,3S,5R)-3-iodo-5-(5-methyl-2,4-dioxo-} 3,4-dihydropyrimidin-1(2H)-yl) tetrahydrofuran-2-yl) oxy) methyl) phosphonate (1.5 g, 3.07 mmol) and 2,6-lutidine (13.2 g, 123 mmol) in ACN (100 mL) was added TMSBr (4.71 g, 30.5 mmol) dropwise at room temperature under N2 atmosphere, then stirred for 1 h at 50 °C, cooled to room temperature and concentrated under reduced pressure. To the residue was added concentrated NH3^.H2O and the mixture was stirred for 30 min at room temperature under N2 atmosphere, then concentrated under reduced pressure. The residue was purified by reverse- phase flash chromatography under the following conditions (column, C18 silica gel; mobile phase, ACN in H₂O (0.1% FA), 10% to 50% gradient in 20 min; detector, UV 254 nm) to afford ((((2R,3S,5R)-3-iodo-5-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl) tetrahydrofuran-2- yl) oxy) methyl) phosphonic acid (700 mg, 53%) as a white solid. LC/MS (ES, m/z): 431 [M-H]-. _{[0286] Step 5: A solution of ((((2R,3S,5R)-3-iodo-5-(5-methyl-2,4-dioxo-3,4-} dihydropyrimidin-1(2H)-yl) tetrahydrofuran-2-yl) oxy) methyl) phosphonic acid (200 mg, 463 μmol) and DBU (211 mg, 1.39 mmol) in DMF (5 mL) was stirred for 2 h at 50 °C under N2 atmosphere, allowed to cool to room temperature and concentrated under reduced pressure. The residue was purified by prep HPLC under the following conditions (Column: xBridge Prep Phenyl 5 μm OBD 19*250 mm; Mobile Phase A: H2O (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: isocratic 35% B - 65% B in 20 min; wavelength: 220/254 nm; RT1(min): 14). The product-containing fraction was collected and concentrated under reduced pressure, the residue was re-dissolved in ACN and H2O, and then was lyophilized to afford ammonium ((((2R,5R)-5-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2,5- dihydrofuran-2-yl) oxy) methyl) phosphonate (51.2 mg, 33%) as a white solid. _{[0287] LC/MS (ES, m/z): 609 [2M+H]+. HPLC conditions: (Column: Atlantis T33 μm} 4.6*100 mm; Mobile Phase A: H2O+0.05% TFA; B: CAN+0.05% TFA; Flow rate: 1.20 mL/min; Gradient: 0% B to 95% B in 8.00 min, 95% B to 95% B in 2 min, 95% B to 10% B in 0.50 min; wavelength: 254 nm; RT1(min): 2.139). _{[0288] 1H NMR (400 MHz, DMSO-d6) δ 7.29 (s, 1H), 6.72 (d, J = 1.7 Hz, 1H), 6.39 (d, J =} 5.8 Hz, 1H), 6.18 (d, J = 5.9 Hz, 1H), 5.87 (s, 1H), 3.57 (t, J = 11.2 Hz, 2H), 1.76 (s, 3H). EXAMPLE 2 – Synthesis of ((((2R,5R)-5-(5-chloro-2,4-dioxo-3,4-dihydropyrimidin-1(2H)- yl)-2,5-dihydrofuran-2-yl) oxy) methyl) phosphonate, diammonium salt, Compound I-2 [_{0289] Step 1: To a stirred solution of 1-((2R,4S,5R)-4-hydroxy-5-(hydroxymethyl)} tetrahydrofuran-2-yl)pyrimidine-2,4(1H,3H)-dione (5 g, 21.9 mmol) in pyridine (50 mL) was added Ac2O (4.71 g, 46 mmol) at room temperature under an inert atmosphere, then stirred for 16 h.. The reaction mixture was concentrated under reduced pressure, diluted with water and extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with saturated citric acid solution and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography, eluting with DCM/MeOH (9:1) to afford ((2R,3S,5R)-3-acetoxy-5-(2,4-dioxo-3,4-dihydropyrimidin- 1(2H)-yl) tetrahydrofuran-2-yl) methyl acetate (7.5 g, 95%) as an off-white solid. LC/MS (ES, m/z): 313 [M+H]⁺. _{[0290] Step 2: To a stirred solution of ((2R,3S,5R)-3-acetoxy-5-(2,4-dioxo-3,4-} dihydropyrimidin-1(2H)-yl) tetrahydrofuran-2-yl) methyl acetate (7.5 g, 24 mmol) in AcOH (50 mL) and CH3CN (50 mL) was added CAN (26.4 g, 48 mmol) and LiCl (1.1 g, 26 mmol) in portionwise at rt under an inert atmosphere, then stirred for 5 h at 80 °C, cooled to room temperature, quenched with ice water at 0^oC, and extracted with EtOAc (3 x 250 mL). The combined organic layers were washed with brine anddried over anhydrous Na2SO4. Upon filtration, the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography, eluting with DCM/MeOH (20:1) to afford ((2R,3S,5R)-3-acetoxy-5-(5-chloro- 2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl) tetrahydrofuran-2-yl) methyl acetate (8 g, 96%,) as a light yellow solid. LC/MS (ES, m/z): 347/349 [M+H]⁺. _{[0291] Step 3: A solution of NH3 (g) in MeOH (90 mL, 7M) was added ((2R,3S,5R)-3-} acetoxy-5-(5-chloro-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl) tetrahydrofuran-2-yl) methyl acetate (8 g, 23.1 mmol) and the mixture was stirred for 15 hours at rt. The mixture was concentrated and purified by silica gel column chromatography, eluting with DCM/MeOH (9:1) to afford 5-chloro-1-((2R,4S,5R)-4-hydroxy-5-(hydroxymethyl) tetrahydrofuran-2-yl) pyrimidine-2,4(1H,3H)-dione (6 g, 94%) as a light yellow solid. LC/MS (ES, m/z): 263/265 [M+H]⁺. _{[0292] Step 4: To a stirred solution of 5-chloro-1-((2R,4S,5R)-4-hydroxy-5-(hydroxymethyl)} tetrahydrofuran-2-yl) pyrimidine-2,4 (1H,3H)-dione (6 g, 22.8 mmol) and Celite 545 (6 g) in acetone (60 mL) was added Jones' reagent (5.44 mL, 10.88 mmol, 2M in H2SO4) at 0°C under an inert atmosphere. The mixture was stirred for 1h at rt, quenched with IPA (60 mL) at 0°C and stirred for 0.5 h. The mixture was filtered through Celite, washed with THF and concentrated. The residue was extracted with EtOAc/THF (3 x 100 mL, 1:1), washed with brine, and dried over Na2SO4. Upon filtration, the filtrate was concentrated under reduced pressure to afford (2S,3S,5R)-5-(5-chloro-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-3-hydroxytetrahydrofuran-2- carboxylic acid (900 mg, crude) which was used in the next step directly without further purification. LC/MS (ES, m/z): 277/279 [M+H]⁺. _{[0293] Step 5: To a stirred solution of (2S,3S,5R)-5-(5-chloro-2,4-dioxo-3,4-} dihydropyrimidin-1(2H)-yl)-3-hydroxytetrahydrofuran-2-carboxylic acid (800 mg) in DCM (10 mL) were added PPh3 (1.21 g, 4.62 mmol) and DIAD (932 mg, 4.61 mmol) at room temperature under an inert atmosphere, then stirred for 1 h.. LC/MS (ES, m/z): 215/217 [M+H]⁺. _{[0294] Step 6: A solution of dimethyl hydroxymethylphosphonate (1.11 g, 7.92 mmol) in} DCM (10 mL) was added to the reaction mixture above at -40 °C under an inert atmosphere, followed by addition of IBr (1.72 g, 8.32 mmol) in DCM (10 mL), and stirred for 12 h.. The resulting mixture was concentrated under reduced pressure, diluted with water and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine and dried over anhydrous Na₂SO₄. Upon filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE/EtOAc (1:1) to afford dimethyl ((((2R,3S,5R)-5-(5-chloro-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-3- iodotetrahydrofuran-2-yl) oxy) methyl) phosphonate (400 mg, 20%) as a yellow solid. LC/MS (ES, m/z): 481/483 [M+H]⁺. _{[0295] Step 7: To a stirred solution of dimethyl ((((2R,3S,5R)-5-(5-chloro-2,4-dioxo-3,4-} dihydropyrimidin-1(2H)-yl)-3-iodotetrahydrofuran-2-yl) oxy) methyl) phosphonate (400 mg, 830 μmol) and 2,6-lutidine (3.57 g, 33.3 mmol) in CH₃CN (10 mL) was added TMS-Br (1.27 g, 8.32 mmol) at 0°C under an inert atmosphere. The solution wasstirred for 1 h at 50 °C followed by cooling to room temperature, dilution with 33% NH3*H2O and extraction with EtOAc (3 x 50 mL). The combined organic layers were washed with brine and dried over anhydrous Na₂SO₄. Upon filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep TLC (DCM/MeOH 10:1) to afford ((((2R,3S,5R)-5-(5-chloro-2,4-dioxo-3,4- dihydropyrimidin-1(2H)-yl)-3-iodotetrahydrofuran-2-yl) oxy) methyl) phosphonic acid (200 mg, 53%) as a yellow solid. LC/MS (ES, m/z): 453/455 [M+H]⁺. _{[0296] Step 8: To a stirred solution of ((((2R,3S,5R)-5-(5-chloro-2,4-dioxo-3,4-} dihydropyrimidin-1(2H)-yl)-3-iodotetrahydrofuran-2-yl) oxy) methyl) phosphonic acid (200 mg, 440 μmol) in DMF (5 mL) was added DBU (201 mg, 1.33 mmol) at rt under an inert atmosphere, followed by stirring for 2 h at 50 °Cthen cooling to room temperature and concentration under reduced pressure. The residue was purified by prep HPLC under the following conditions (Column: xBridge Prep Phenyl 5 μm OBD 19*250 mm; Mobile Phase A: water (10 mmol/L NH₄HCO₃), Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: isocratic 35% B - 65% B in 20 min; wavelength: 220/254 nm; RT1 (min): 14). The product-containing fraction was collected and concentrated under reduced pressure, the residue was re-dissolved in CH₃CN and H₂O, and then was lyophilized to afford ((((2R,5R)-5-(5-chloro-2,4-dioxo-3,4- d_{ihydropyrimidin-1(2H)-yl)-2,5-dihydrofuran-2-yl) oxy) methyl) phosphonate, diammonium salt} (32.7 mg, 20%) as a white solid. [_{0297] LC/MS (ES, m/z): 323/325 [M-H]-; HPLC conditions: (Column: Atlantis T33 μm} 4.6*100 mm; Mobile Phase A: H2O+0.05% TFA; B: ACN+0.05% TFA; Flow rate: 1.20 mL/min; Gradient: 0% B to 95% B in 8.00 min, 95% B to 95% B in 2.00 min, 90% B to 10% B in 0.50 min; wavelength: 254 nm; RT1 (min): 2.14). [_{0298] 1H NMR (400 MHz, DMSO-d6) δ 7.56 (s, 1H), 6.68 (t, J = 1.7 Hz, 1H), 6.43 – 6.35} (m, 1H), 6.22 – 6.17 (m, 1H), 5.93 (s, 1H), 3.65 – 3.52 (m, 2H). EXAMPLE 3 – Synthesis of diisopropyl (((((((2R,5R)-5-(5-methyl-2,4-dioxo-3,4- dihydropyrimidin-1(2H)-yl)-2,5-dihydrofuran-2-yl) oxy) methyl) phosphoryl) bis(oxy)) bis(methylene)) bis(carbonate), Compound I-3 [_{0299] A solution of ammonium ((((2R,5R)-5-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-} 1(2H)-yl)-2,5-dihydrofuran-2-yl) oxy) methyl) phosphonate (50 mg, 116 μmol) was suspended in pyridine (5 mL). The mixture was evaporated to a residue by rotary evaporation for 20 minutes, then re-suspended in NMP (4 mL) and cyclohexane (4 mL), followed by evaporation to a residue via rotary evaporation. TEA (187 mg, 1.86 mmol) and TBAB (82.1 mg, 255 μmol) were added at 45 °C, followed by chloromethyl isopropyl carbonate (176 mg, 1.16 mmol) at 50 °C, and stirring for an additional 15 h at 50 °C under an inert atmosphere. The mixture was allowed to cool down to rt and concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography under the following conditions (column, C18 silica gel; mobile phase, ACN in H2O (0.1% FA), 0% to 100% gradient in 20 min; detector, UV 254 nm) to afford the crude product, which was purified by prep HPLC under the following conditions (Column: SunFire Prep OBD C18 Column, 19*250 mm, 5 μm; Mobile Phase A: H2O (0.1% FA), Mobile Phase B: ACN; Flow rate: 25 mL/min; Gradient: 37% B to 50% B in 12 min; wavelength: 254 nm/220 nm; RT1 (min): 8.21). The product-containing fraction was collected and concentrated under reduced pressure, the residue was re-dissolved in ACN and H2O, and then was lyophilized to afford diisopropyl (((((((2R,5R)-5-(5-methyl-2,4-dioxo-3,4- dihydropyrimidin-1(2H)-yl)-2,5-dihydrofuran-2-yl)oxy)methyl)phosphoryl) bis(oxy))bis(methylene)) bis(carbonate) (4.4 mg, 7%) as a white solid. [_{0300] LC/MS (ES, m/z): 554 [M+NH4]+; LC/MS conditions: (Column: Shim‐pack Scepter} C18, 3 μm 3.0*33 mm; Mobile Phase A: H2O/5 mM NH4HCO3; B: ACN; Flow rate: 1.50 mL/min; Gradient: 0% B to 60% B in 1.70 min, 60% B to 95% B in 0.60 min, 95% B to 95% B in 0.50 min; wavelength: 254 nm; RT1 (min): 1.428). [_{0301] 1H NMR (400 MHz, DMSO-d6) δ 11.41 (s, 1H), 7.08 (s, 1H), 6.79 (s, 1H), 6.39 – 6.33} (m, 2H), 5.81 (s, 1H), 5.60 (t, J = 13.1 Hz, 4H), 4.91 – 4.77 (m, 2H), 4.13 (d, J = 9.3 Hz, 2H), 1.76 (s, 3H), 1.25 (dd, J = 6.2, 3.0 Hz, 12H). EXAMPLE 4 – Synthesis of ethyl (((((2S,5S)-5-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin- 1(2H)-yl)-2,5-dihydrofuran-2-yl) oxy) methyl) (phenoxy)phosphoryl)-L-Alaninate, Compound I-4

[_{0302] Step 1: To a stirred solution of 1-((2S,5S)-4-hydroxy-5-(hydroxymethyl)} tetrahydrofuran-2-yl)-5-methylpyrimidine-2,4(1H,3H)-dione (5 g, 20.6 mmol) and Celite 545 (5 g) in acetone (100 mL) was added Jones’ reagent (12.3 g, 61.9 mmol, 2 M in H2SO4) dropwise at 0 °C under an inert atmosphere, then stirred for 2 h at room temperature. The reaction was quenched with IPA at 0 °C, and the mixture was stirred for additional 1 h at rt, followed by filtration and washing the filter cake with THF. The filtrate was concentrated under reduced pressure. The resulting mixture was extracted with THF/EtOAc (6 x 150 mL, 1:1). The combined organic layers were washed with brine and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure to afford (2R,5S)-3-hydroxy-5-(5- methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl) tetrahydrofuran-2-carboxylic acid (2 g) which was used in the next step directly without further purification. LC/MS (ES, m/z): 257 [M+H]⁺. [_{0303] Step 2: To a stirred solution of (2R,5S)-3-hydroxy-5-(5-methyl-2,4-dioxo-3,4-} dihydropyrimidin-1(2H)-yl) tetrahydrofuran-2-carboxylic acid (700 mg) and PPh3 (1.07 g, 4.1 mmol) in DCM (15 mL) was added DIAD (830 mg, 4.1 mmol) dropwise at 0 °C under an inert atmosphere. The resulting mixture was stirred for 1 h at rt under an inert atmosphere, and was used in the next step directly without further purification. LC/MS (ES, m/z): 193 [M-H]-. _{[0304] Step 3: To the above mixture was added ethyl ((hydroxymethyl)(phenoxy)} phosphoryl)-L-alaninate (1.57 g, 5.46 mmol) in DCM (10 mL) and IBr (1.19 g, 5.73 mmol) in DCM (10 mL) dropwise over 10 min at -40 °C under an inert atmosphere, followed by stirring for an additional 12 hat rt. The reaction was quenched with a mixture of 10% Na₂S₂O₃,saturated NaHCO3 at 0 °C, and the mixture was extracted with EtOAc (3 x 150 mL). The combined organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography, eluting with (PE/EtOAc=1:1) to afford ethyl (((((2S,3S,5S)-3-iodo-5- (5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl) tetrahydrofuran-2-yl) oxy) methyl) (phenoxy)phosphoryl)-L-alaninate (420 mg, 24%) as a yellow solid. LC/MS (ES, m/z): 606 [M- H]-. _{[0305] Step 4: To a stirred solution of ethyl (((((2S,3S,5S)-3-iodo-5-(5-methyl-2,4-dioxo-3,4-} dihydropyrimidin-1(2H)-yl) tetrahydrofuran-2-yl) oxy) methyl) (phenoxy)phosphoryl)-L- alaninate (100 mg, 165 μmol) in 2-butanone (2 mL) and phosphate buffer (1.3 mL, 0.2 M, pH=7) was added Oxone (554 mg, 3.3 mmol) in H2O (2 mL), and NaOH (2 mL, 2 M in H2O) over 30 minutes which maintained the pH at 6-8. The reaction was stirred at rt for 2 hours under an inert atmosphere. The reaction was then quenched with 10% Na₂S₂O₃ ,saturated NaHCO₃ and extracted with EtOAc (2 x 20 mL). The extracts were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by Prep TLC (DCM/MeOH=15:1) to afford the crude product. The crude product was purified by prep HPLC under the following conditions (Column: X-Select Prep OBD C18 Column, 30*150 mm, 5 μm; Mobile Phase A: water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 30% B to 50% B in 7 min; wavelength: 254 nm/220 nm; RT1(min): 6.56). The product-containing fraction was collected and concentrated under reduced pressure. The residue was re-dissolved in ACN and H2O, and then was lyophilized to afford ethyl (((((2S,5S)-5-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2,5-dihydrofuran-2-yl) oxy) methyl) (phenoxy)phosphoryl)-L-alaninate (17.9 mg, 23%) as a white solid. _{[0306] LC/MS (ES, m/z): 478 [M-H]-; LC/MS conditions: (Column: Shim‐pack Scepter C18,} 3 μm, 3.0*33 mm; Mobile Phase A: water/5 mM NH4HCO3; B: ACN; Flow rate: 1.50 mL/min; Gradient: 0% B to 60% B in 1.70 min, 60% B to 95% B in 0.60 min, 95% B to 95% B in 0.50 min; wavelength: 254 nm; RT1 (min): 1.204). _{[0307] 1H NMR (400 MHz, DMSO-d6) δ 11.41 (s, 1H), 7.39 – 7.30 (m, 2H), 7.20 – 7.15 (m,} 4H), 6.79 (d, J = 1.8 Hz, 1H), 6.48 – 6.39 (m, 1H), 6.33 (dt, J = 5.8, 1.3 Hz, 1H), 5.91 – 5.83 (m, 1H), 5.82 – 5.73 (m, 1H), 4.13 – 3.83 (m, 5H), 1.67 (dd, J = 18.4, 1.2 Hz, 3H), 1.22 –1.13 (m, 6H). EXAMPLE 5 – Synthesis of ethyl ((S or R)-((((2S,5S)-5-(5-methyl-2,4-dioxo-3,4- dihydropyrimidin-1(2H)-yl)-2,5-dihydrofuran-2-yl) oxy) methyl) (phenoxy)phosphoryl)-L- alaninate, Compound I-5, and ethyl ((R or S)-((((2S,5S)-5-(5-methyl-2,4-dioxo-3,4- dihydropyrimidin-1(2H)-yl)-2,5-dihydrofuran-2-yl) oxy) methyl) (phenoxy)phosphoryl)-L- alaninate, Compound I-6 [_{0308] The ethyl (((((2S,5S)-5-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2,5-} dihydrofuran-2-yl) oxy) methyl) (phenoxy)phosphoryl)-L-alaninate (50 mg, 103 μmol) was purified by prep chiral HPLC under the following conditions: (Column: JW-CHIRAL ART Cellulose-SA 20*250 mm, 5 μm; Mobile Phase A: EtOH--HPLC, Mobile Phase B: MTBE (0.5% 2 M NH3-MeOH)-HPLC; Flow rate: 20 mL/min; Gradient: 65% B to 65% B in 18 min; wavelength: 220/254 nm; RT1 (min): 10.42, RT2 (min): 15.58). The first eluting isomer fraction was collected and concentrated under vacuum, the residue was re-dissolved in ACN and H₂O, and then was lyophilized to afford Compound I-5, ethyl ((S or R)-((((2S,5S)-5-(5-methyl-2,4- dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2,5-dihydrofuran-2- yl)oxy)methyl)(phenoxy)phosphoryl)-L-alaninate (6.9 mg, 14%) as a white solid; The second eluting isomer fraction was collected and concentrated under reduced pressure, the residue was re-dissolved in ACN and H2O, and then was lyophilized to afford Compound I-6, ethyl ((R or S)-((((2S,5S)-5-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2,5-dihydrofuran-2-yl) oxy) methyl) (phenoxy)phosphoryl)-L-alaninate (14.7 mg, 29%) as a white solid. _{[0309] Compound I-5 LC/MS (ES, m/z): 478 [M-H]-; LC/MS conditions: (Column: Shim‐} pack Scepter C18, 3 μm, 3.0*33 mm; Mobile Phase A: water/5 mM NH₄HCO₃; B: ACN; Flow rate: 1.50 mL/min; Gradient: 0% B to 60% B in 1.70 min, 60% B to 95% B in 0.60 min, 95% B to 95% B in 0.50 min; wavelength: 254 nm; RT1 (min): 1.200). _{[0310] Chiral HPLC conditions: (Column: CHIRALPAK IA‐3, 3 μm 4.6*50 mm; Mobile} Phase: MTBE (0.1% DEA): EtOH=65:35; Flow rate: 1.00 mL/min, 6 min; wavelength: 254 nm; RT1(min): 2.234). _{[0311] 1H NMR (400 MHz, DMSO-d6) δ 11.41 (s, 1H), 7.39 – 7.30 (m, 2H), 7.21 – 7.12 (m,} 4H), 6.79 (d, J = 1.8 Hz, 1H), 6.47 – 6.29 (m, 2H), 5.85 – 5.78 (m, 2H), 4.11 – 3.83 (m, 5H), 1.65 (d, J = 1.2 Hz, 3H), 1.19 – 1.14 (m, 6H). _{[0312] Compound I-6 LC/MS (ES, m/z): 478 [M-H]-; LC/MS conditions: (Column: Shim‐} pack Scepter C18, 3 μm 3.0*33 mm; Mobile Phase A: water/5mM NH₄HCO₃; B: ACN; Flow rate: 1.50 mL/min; Gradient: 0% B to 60% B in 1.70 min, 60% B to 95% B in 0.60 min, 95% B to 95% B in 0.50 min; wavelength: 254 nm; RT1 (min): 1.193). _{[0313] Chiral HPLC conditions: (Column: CHIRALPAK IA‐3, 3 μm 4.6*50 mm; Mobile} Phase: MTBE (0.1% DEA): EtOH=65:35; Flow rate: 1.00 mL/min, 6 min; wavelength: 254 nm; RT1(min): 3.637). _{[0314] 1H NMR (400 MHz, DMSO-d6) δ 11.41 (s, 1H), 7.35 (t, J = 7.8 Hz, 2H), 7.21 – 7.12} (m, 4H), 6.79 (s, 1H), 6.43 – 6.33 (m, 2H), 5.89 (s, 1H), 5.76 (dd, J = 12.6, 9.9 Hz, 1H), 4.13 – 3.85 (m, 5H), 1.70 (s, 3H), 1.21 – 1.11 (m, 6H). EXAMPLE 6 – Synthesis of ammonium ((((2R,5R)-4-fluoro-5-(5-methyl-2,4-dioxo-3,4- dihydropyrimidin-1(2H)-yl)-2,5-dihydrofuran-2-yl) oxy) methyl) phosphonate, Compound I-7

[_{0315] Step 1: To a stirred solution of (2S,3R,4S,5R)-4-fluoro-3-hydroxy-5-(5-methyl-2,4-} dioxo-3,4-dihydropyrimidin-1(2H)-yl) tetrahydrofuran-2-carboxylic acid (4.2 g, crude) and PPh3 (6.1 g, 22.9 mmol) in DCM (60 mL) was added DIAD (4.6 g, 22.9 mmol) dropwise at 0 ^oC under an inert atmosphere, then stirred for one additional hour. The resulting mixture was used in the next step directly without further purification. LC/MS (ES, m/z): 213 [M+H]⁺. [_{0316] Step 2: To the above mixture was added diethyl hydroxymethylphosphonate (5.2 g,} 30.1 mmol) in DCM (20 mL) and IBr (6.5 g, 31.7 mmol) in DCM (20 mL) dropwise at -40 °C under an inert atmosphere, then stirred for 2 h.. The reaction was quenched with a mixture of 10% Na2S2O3 and saturated NaHCO3, then the mixture was extracted with EtOAc (3 x 50 mL). The extracts were dried over anhydrous Na₂SO₄. Upon filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography, eluting with (DCM/MeOH=10:1) to afford diethyl ((((2R,3R,4R,5R)-4-fluoro-3-iodo-5-(5- methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl) tetrahydrofuran-2-yl) oxy) methyl) phosphonate (2.6 g, 34%) as a white solid. LC/MS (ES, m/z): 507 [M+H]⁺. _{[0317] Step 3: To a stirred solution of diethyl ((((2R,3R,4R,5R)-4-fluoro-3-iodo-5-(5-methyl-} 2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl) tetrahydrofuran-2-yl) oxy) methyl) phosphonate (2.6 g, 5.13 mmol) in 2-butanone (75 mL) and phosphate buffer (50 mL, 0.2 M, pH=7) were added oxone (63.2 g, 102 mmol) in H2O (75 mL) and NaOH (2 M in H2O) over 10 minutes maintaining the pH=6-8. The reaction was stirred at rt for 15h, then the reaction was quenched with 10% Na2S2O3, saturated NaHCO3, then extracted with EtOAc (2 x 200 mL). The extract was washed with brine, and dried over anhydrous Na2SO4. Upon filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography, eluting with (DCM/MeOH=10:1) to afford diethyl ((((2R,5R)-4-fluoro-5-(5-methyl-2,4-dioxo- 3,4-dihydropyrimidin-1(2H)-yl)-2,5-dihydrofuran-2-yl) oxy) methyl) phosphonate (1.08 g, 53%) as a white solid. LC/MS (ES, m/z): 379 [M+H]⁺. _{[0318] Step 4: To a stirred solution of diethyl ((((2R,5R)-4-fluoro-5-(5-methyl-2,4-dioxo-3,4-} dihydropyrimidin-1(2H)-yl)-2,5-dihydrofuran-2-yl) oxy) methyl) phosphonate (600 mg, 1.62 mmol) in ACN (8 mL) was added 2,6-lutidine (6.8 g, 63.4 mmol) and TMS-Br (4.8 g, 31.7 mmol) dropwise at rt under an inert atmosphere. The reaction was then stirred for 1 h at 50 °C under an inert atmosphere, cooled to room temperature and concentrated under reduced pressure. The residue was quenched with concentrated NH3*H2O and stirred for 15 min, then concentrated under reduced pressure. The residue was purified by prep HPLC under the following conditions (Column: Xbridge BEH Prep OBD Amide, 19*250 mm, 5 μm; Mobile Phase A: water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 82% B to 72% B in 12 min; wavelength: 254 nm / 220 nm nm; RT1(min): 7.32). The product-containing fraction were collected and concentrated under reduced pressure. The residue was re-dissolved in ACN and H2O, and then was lyophilized to afford ammonium ((((2R,5R)-4-fluoro-5-(5-methyl-2,4- dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2,5-dihydrofuran-2-yl) oxy) methyl) phosphonate (43.3 mg, 7%) as an off-white solid. _{[0319] LC/MS (ES, m/z): 321 [M-H]-; HPLC conditions: (Column: Atlantis T34.6*100 nm,} 3 μm; Mobile Phase A: H2O+0.05% TFA, Mobile Phase B: ACN+0.05% TFA; Flow rate: 1.50 mL/min; Gradient: 0% B to 30% B in 6.00 min, 30% B to 95% B in 2.00 min, 95% B to 95% B in 2.00 min; wavelength: 254 nm; RT1 (min): 2.91). [_{0320] 1H NMR (400 MHz, Methanol-d4) δ 7.59 (d, J = 1.5 Hz, 1H), 6.80 (dd, J = 3.5, 1.3} Hz, 1H), 5.92 – 5.83 (m, 2H), 3.92 (dd, J = 12.7, 9.5 Hz, 1H), 3.70 (dd, J = 12.7, 9.3 Hz, 1H), 1.93 (d, J = 1.3 Hz, 3H). EXAMPLE 7 – Synthesis of ((((((2R,5R)-4-fluoro-5-(5-methyl-2,4-dioxo-3,4- dihydropyrimidin-1(2H)-yl)-2,5-dihydrofuran-2-yl) oxy) methyl) phosphoryl) bis(oxy)) bis(methylene) diisopropyl bis(carbonate), Compound I-8 [_{0321] In 5 mL of pyridine was suspended ammonium ((((2R,5R)-4-fluoro-5-(5-methyl-2,4-} dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2,5-dihydrofuran-2-yl) oxy) methyl) phosphonate (50 mg, 140 μmol). The mixture was evaporated to a residue by rotary evaporation for 20 minutes, then the residue was resuspended in NMP (4 mL) and cyclohexane (4 mL). The mixture was evaporated to a residue by rotary evaporation for 20 minutes, then TEA (56 mg, 560 μmol) and TBAB (50 mg, 150 μmol) were added at 45 °C, followed by chloromethyl isopropyl carbonate (107 mg, 700 μmol) at 50 °C. The solution was heated to 50 °C for 15 h at under an inert atmosphere. After cooling to rt, the residue was purified by reverse-phase flash chromatography under the following conditions (column, C18 silica gel; mobile phase, ACN in water (0.1% FA), 0% to 100% gradient in 20 min; detector, UV 254 nm) to afford the crude product, which was purified by prep HPLC under the following conditions (Column: XSelect Prep OBD C18 Column, 30*150 mm, 5 μm; Mobile Phase A: water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 30% B to 60% B in 8 min; wavelength: 254/220 nm, RT1(min): 6.6). The product-containing fraction was collected and concentrated under reduced pressure. The residue was re-dissolved in ACN and H₂O, and then was lyophilized to afford ((((((2R,5R)-4- fluoro-5-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2,5-dihydrofuran-2-yl) oxy) methyl) phosphoryl) bis(oxy)) bis(methylene) diisopropyl bis(carbonate) (13.3 mg, 17%) as an off-white solid. [_{0322] LC/MS (ES, m/z): 553 [M-H]-;. LC/MS conditions: (Column: Luna Omega PS C18} 2.1*30 mm, 3 μm; Mobile Phase A: water/0.1% FA, Mobile Phase B: ACN/0.07% FA; Flow rate: 1.20 mL/min; Gradient: 5% B to 60% B in 1.69 min, 60% B to 100% B in 0.60 min, 100% B to 100% B in 0.50 min; wavelength: 254 nm; RT1 (min): 1.193). [_{0323] 1H NMR (400 MHz, DMSO-d6) δ 11.56 (s, 1H), 7.27 (d, J = 1.5 Hz, 1H), 6.75 (d, J =} 3.2 Hz, 1H), 6.11 (s, 1H), 5.83 (d, J = 4.3 Hz, 1H), 5.66 – 5.55 (m, 4H), 4.92 – 4.75 (m, 2H), 4.17 (d, J = 9.6 Hz, 2H), 1.80 (d, J = 1.2 Hz, 3H), 1.25 (dd, J = 6.3, 3.5 Hz, 12H). EXAMPLE 8 – Synthesis of ethyl (((((2R,5R)-5-(5-chloro-2,4-dioxo-3,4-dihydropyrimidin- 1(2H)-yl)-2,5-dihydrofuran-2-yl) oxy) methyl) (phenoxy)phosphoryl)-L-alaninate, Compound I-9

[_{0324] Step 1: To a stirred solution of 5-chloro-1-((2R,4S,5R)-4-hydroxy-5-(hydroxymethyl)} tetrahydrofuran-2-yl) pyrimidine-2,4 (1H,3H)-dione (950 mg, 3.62 mmol) and Celite 545 (1.8 g) in acetone (30 mL) was added Jones' reagent (5.4 mL, 10.8 mmol, 2 M in H₂SO₄) dropwise at 0 °C, then stirred for 1 h at rt, quenched with IPA at 0 °C and stirred for 0.5 h at rt. The mixture was filtered through Celite, flushed with THF and concentrated. The residue was extracted with EtOAc/THF (3 x 50 mL, 1:1), and washed with brine, dried over anhydrous Na2SO4, and concentrated to afford (2S,3S,5R)-5-(5-chloro-2,4-dioxo-3H-pyrimidin-1-yl)-3-hydroxyoxolane- 2-carboxylic acid (400 mg) which was used in the next step directly without further purification. LC/MS (ES, m/z): 277/279 [M+H]⁺. [_{0325] Step 2: To a stirred solution of (2S,3S,5R)-5-(5-chloro-2,4-dioxo-3H-pyrimidin-1-yl)-} 3-hydroxyoxolane-2-carboxylic acid (380 mg) and PPh3 (540 mg, 2.06 mmol) in DCM (20 mL) was added DIAD (417, 2.06 mmol) at rt under an inert atmosphere, then stirred for 1 h.. The reaction mixture was used directly in the next step without purification. LC/MS (ES, m/z): 215/217 [M+H]⁺. [_{0326] Step 3: To the above mixture was added ethyl} ((hydroxymethyl)(phenoxy)phosphoryl)-L-alaninate (790 mg, 2.75 mmol) in DCM (3 mL) and IBr (598 mg, 2.89 mmol) in DCM (5 mL) dropwise at -40 °C under an inert atmosphere, then stirred for 2 h at rt under an inert atmosphere. After quenching with a mixture of saturated NaHCO3 and 10% Na2S2O3, the residue was extracted with EtOAc (3 x 20 mL). The organic layer was washed with brine and dried over anhydrous Na₂SO₄. Upon filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep TLC (DCM/MeOH=17:1) to afford ethyl (((((2R,3S,5R)-5-(5-chloro-2,4-dioxo-3,4-dihydropyrimidin- 1(2H)-yl)-3-iodotetrahydrofuran-2-yl) oxy) methyl) (phenoxy)phosphoryl)-L-alaninate (120 mg, 15%) as a yellow solid. LC/MS (ES, m/z): 628/630 [M+H]⁺. _{[0327] Step 4: To a stirred solution of ethyl (((((2R,3S,5R)-5-(5-chloro-2,4-dioxo-3,4-} dihydropyrimidin-1(2H)-yl)-3-iodotetrahydrofuran-2-yl) oxy) methyl) (phenoxy)phosphoryl)-L- alaninate (120 mg, 191 μmol) in 2-butanone (8 mL) and phosphate buffer (0.5 M, 5.2 mL, pH=7) was added a solution of Oxone (643 mg, 3.82 mmol) in H2O (8 mL) and NaOH (2 M in H2O), maintaining pH 6~8. The mixture was stirred for 1h at rt, then the reaction was quenched with 10% Na2S2O3 and saturated NaHCO3, and extracted with EtOAc (2 x 20 mL). The extracts were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by Prep TLC (DCM/MeOH=15:1) to afford the crude product, which was purified by prep HPLC under the following conditions (Column: SunFire Prep OBD C18 Column, 19*250 mm, 5 μm; Mobile Phase A: water (0.1% FA), Mobile Phase B: ACN; Flow rate: 25 mL/min; Gradient: 30% B to 40% B in 12 min; wavelength: 254 nm/220 nm; RT1 (min): 8.21). The product-containing fraction was collected and concentrated under reduced pressure. The residue was re-dissolved in ACN and H2O, and then was lyophilized to afford ethyl (((((2R,5R)-5-(5-chloro-2,4-dioxo-3,4- dihydropyrimidin-1(2H)-yl)-2,5-dihydrofuran-2-yl) oxy) methyl) (phenoxy)phosphoryl)-L- alaninate (4 mg, 4%) as an off-white solid. _{[0328] LC/MS (ES, m/z): 500/502 [M+H]+;. LC/MS conditions: (Column: Shim-pack} Scepter C18, 33*3.0 mm, 3.0 μm; Mobile Phase A: H2O+5 mM NH4HCO3; Mobile Phase B: ACN; Flow rate: 1.50 mL/min; Gradient: 0% B to 95% B in 1.2 min, 95% B to 95% B in 0.6 min, 95% B to 10% B in 0.02 min; wavelength: 254 nm; RT1 (min): 0.737). _{[0329] 1H NMR (400 MHz, DMSO-d6) δ 11.82 (s, 1H), 7.49 (d, J = 2.5 Hz, 1H), 7.38 – 7.31} (m, 2H), 7.17 (dd, J = 7.8, 6.1 Hz, 3H), 6.80 – 6.75 (m, 1H), 6.49 – 6.32 (m, 2H), 5.93 – 5.65 (m, 2H), 4.14 – 3.97 (m, 4H), 3.97 – 3.85 (m, 1H), 1.22 – 1.11 (m, 6H). EXAMPLE 9 – Synthesis of ((((((2R,5R)-5-(5-chloro-2,4-dioxo-3,4-dihydropyrimidin- 1(2H)-yl)-2,5-dihydrofuran-2-yl) oxy) methyl) phosphoryl) bis(oxy)) bis(methylene) diisopropyl bis(carbonate), Compound I-10

[_{0330] Step 1: To a stirred solution of (2S,3S,5R)-5-(5-chloro-2,4-dioxo-3H-pyrimidin-1-yl)-} 3-hydroxyoxolane-2-carboxylic acid (3 g, 10.8 mmol) and PPh₃ (4.2 g, 16.2 mmol) in DCM (30 mL) was added DIAD (3.2 g, 16.2 mmol) dropwise at 0 °C under an inert atmosphere, then stirred for 1 h at 0 °C.. The resulting mixture was used in the next step directly without further purification. LC/MS (ES, m/z): 215/217 [M+H]⁺. [_{0331] Step 2: To the above mixture were added diethyl (hydroxymethyl)phosphonate (4.7 g,} 27.9 mmol) in DCM (12 mL) and IBr (6.3 g, 30.7 mmol) in DCM (12 mL) dropwise at -40 °C under an inert atmosphere. The reaction was then stirred for 2 additional hours before being. quenched with a mixture of 10% Na₂S₂O₃ and saturated NaHCO₃ at 0 °C. The aqueous layer wasextracted with EtOAc (3 x 150 mL). The combined organic layers were washed with brine and dried over anhydrous Na2SO4. Upon filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography, eluting with (PE/EtOAc=1:2) to afford diethyl ((((2R,3S,5R)-5-(5-chloro-2,4-dioxo-3,4-dihydropyrimidin- 1(2H)-yl)-3-iodotetrahydrofuran-2-yl) oxy) methyl) phosphonate (3 g, 42%) as a white solid. LC/MS (ES, m/z): 509/511 [M+H]⁺. _{[0332] Step 3: A solution of diethyl ((((2R,3S,5R)-5-(5-chloro-2,4-dioxo-3,4-} dihydropyrimidin-1(2H)-yl)-3-iodotetrahydrofuran-2-yl) oxy) methyl) phosphonate (800 mg, 1.5 mmol) and DBU (718 mg, 4.7 mmol) in THF (8 mL) was stirred for 1 h at 60 °C under an inert atmosphere, cooled to room temperature and concentrated under reduced pressure. The residue was purified by Prep TLC (DCM/MeOH=10:1) to afford diethyl ((((2R,5R)-5-(5-chloro-2,4- dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2,5-dihydrofuran-2-yl) oxy) methyl) phosphonate (380 mg, 63%) as a white solid. LC/MS (ES, m/z): 381/383 [M+H]⁺. _{[0333] Step 4: A solution of diethyl ((((2R,5R)-5-(5-chloro-2,4-dioxo-3,4-dihydropyrimidin-} 1(2H)-yl)-2,5-dihydrofuran-2-yl) oxy) methyl) phosphonate (360 mg, 946 μmol) and TMS-Br (1.4 g, 9.4 mmol) in DMF (10 mL) was stirred for 1 h at 50 °C under an inert atmosphere, cooled to room temperature and concentrated under reduced pressure. The reaction was quenched with concentrated NH₃*H₂O at 0 °C. The reaction was concentrated under reduced pressure and the residue was purified by reverse-phase flash chromatography under the following conditions (column, C18 silica gel; mobile phase, ACN in H2O (10 mmol/L NH4HCO3), 10% to 20% gradient in 10 min; detector, UV 254 nm) to afford ((((2R,5R)-5-(5-chloro-2,4-dioxo-3,4- dihydropyrimidin-1(2H)-yl)-2,5-dihydrofuran-2-yl) oxy) methyl) phosphonic acid (200 mg, 65%) as a white solid. LC/MS (ES, m/z): 325/327 [M+H]⁺. _{[0334] Step 5: A solution of ((((2R,5R)-5-(5-chloro-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-} yl)-2,5-dihydrofuran-2-yl) oxy) methyl) phosphonic acid (150 mg, 462 μmol) was suspended in pyridine (5 mL), then evaporated to a residue by rotary evaporation for 20 minutes. The residue was resuspended in NMP (4 mL) and cyclohexane (4 mL), then evaporated to a residue by rotary evaporation for 20 minutes. To the above mixture was added TEA (187 mg, 1.8 mmol) and TBAB (164 mg, 508 μmol) at 45 °C, followed by chloromethyl isopropyl carbonate (352 mg, 2.3 mmol) at 50 °C. The resulting mixture was stirred for an additional 15 h at 50 °C under an inert atmosphere, allowed to cool down to room temperature and concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography under the following conditions (column, C18 silica gel; mobile phase, ACN in water (0.1% FA), 0% to 100% gradient in 20 min; detector, UV 254 nm) to afford the crude product, which was purified by prep HPLC under the following conditions (Column: X-Select Prep OBD C18 Column, 30*150 mm, 5 μm; Mobile Phase A: water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 30% B to 50% B in 7 min; wavelength: 254 nm/220 nm; RT1 (min): 6.56). The product-containing fraction was collected and concentrated under reduced pressure, then the residue was re- dissolved in ACN and H2O, and was lyophilized to afford ((((((2R,5R)-5-(5-chloro-2,4-dioxo- 3,4-dihydropyrimidin-1(2H)-yl)-2,5-dihydrofuran-2-yl) oxy) methyl) phosphoryl) bis(oxy)) bis(methylene) diisopropyl bis(carbonate) (21.4 mg, 8%) as a white solid. [_{0335] LC/MS (ES, m/z): 555/557 [M-H]-; LC/MS conditions: (Column: Shim‐pack Scepter} C18, 33*3.0 mm, 3 μm; Mobile Phase A: water/5 mM NH4HCO3, Mobile Phase B: ACN; Flow rate: 1.50 mL/min; Gradient: 10% B to 95% B in 1.20 min, 95% B to 95% B in 1.80 min, 95% B to 10% B in 1.82 min; wavelength: 254/220 nm; RT1 (min): 0.852). [_{0336] 1H NMR (400 MHz, DMSO-d6) δ 11.99 (s, 1H), 7.42 (s, 1H), 6.78 (t, J = 1.7 Hz, 1H),} 6.49 – 6.28 (m, 2H), 5.83 (d, J = 1.4 Hz, 1H), 5.72 – 5.48 (m, 4H), 4.92 – 4.73 (m, 2H), 4.23 – 4.09 (m, 2H), 1.26 (dd, J = 6.3, 3.2 Hz, 12H). EXAMPLE 10 – Synthesis of isopropyl (((((2R,5R)-5-(5-bromo-2,4-dioxo-3,4- dihydropyrimidin-1(2H)-yl)-2,5-dihydrofuran-2-yl) oxy) methyl) (phenoxy)phosphoryl)-L- alaninate, Compound I-12

[_{0337] Step 1: To a stirred mixture of diphenyl phosphonate (3 g, 12.8 mmol) was added (Z)-} 2,2,2-trifluoro-N-(trimethylsilyl) acetimidic acid (2.44 g, 13.1 mmol) at 0 °C under an inert atmosphere, then stirred at 38 °C for 1.5 h. BnOCH₂Cl (2.05 g, 13 mmol) was added dropwise over 15 min at rt, then heated for an additional 2 h at 75 °C. The reaction was cooled to room temperature, and diluted with DCM (3 x 150 mL), washed with brine, and the combined organic layers were dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EtOAc (3:1) to afford diphenyl ((benzyloxy)methyl) phosphonate (3.6 g, 74%) as a colorless oil. LC/MS (ES, m/z): 355 [M+H]⁺. [_{0338] Step 2: To a stirred solution of diphenyl ((benzyloxy)methyl) phosphonate (3.6 g, 10} mmol) in THF (50 mL) was added KOH (0.68 g, 12 mmol) which was dissolved in H2O (1 mL) dropwise at 0 °C under an inert atmosphere, then stirred for one additional hour. The residue was acidified to pH 1 with 12 M HCl (aq.) and the resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine and dried over anhydrous Na2SO4. Upon filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography, eluting with DCM/MeOH (12:1) to afford phenyl hydrogen ((benzyloxy)methyl) phosphonate (1.5 g, 51%) as a yellow oil. LC/MS (ES, m/z): 279 [M+H]⁺. _{[0339] Step 3: A solution of phenyl hydrogen ((benzyloxy)methyl) phosphonate (1.5 g, 5.3} mmol), isopropyl L-alaninate hydrochloride (820 mg, 7 mmol) and NMI (6.64 g, 80 mmol) in ACN (50 mL) was stirred at 0 °C under an inert atmosphere followed by the addition of BOP-Cl (5.49 g, 21 mmol) in portionwise at 0 °C. The resulting mixture was stirred for 12 h at room temperature under an inert atmosphere, then extracted with EtOAc (3 x 200 mL). The resulting mixture was washed with brine and the organic layers were dried over anhydrous Na₂SO₄. Upon filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE/EtOAc (1:2) to afford isopropyl (((benzyloxy)methyl) (phenoxy)phosphoryl)-L-alaninate (500 mg, 23%) as a yellow oil. LC/MS (ES, m/z): 392 [M+H]⁺. _{[0340] Step 3: To a stirred solution of isopropyl (((benzyloxy)methyl)} (phenoxy)phosphoryl)-L-alaninate (500 mg, 1.2 mmol) in MeOH (10 mL) was added wet Pd/C (100 mg, 10%) under an inert atmosphere. The flask was evacuated and purged three times with N2, followed by flushing with H2. The mixture was stirred for 12 h at room temperature under an atmosphere of H₂, then filtered; the filter cake was washed with MeOH (3 x 10 mL). The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography, eluting with PE/EtOAc (1:9) to afford isopropyl ((hydroxymethyl)(phenoxy)phosphoryl)-L-alaninate (190 mg, 47%) as a yellow oil. LC/MS (ES, m/z): 302 [M+H]⁺. _{[0341] Step 4: To a stirred solution of 5-bromo-1-((2R,4S,5R)-4-hydroxy-5-(hydroxymethyl)} tetrahydrofuran-2-yl) pyrimidine-2,4(1H,3H)-dione (200 mg, 600 μmol) and Celite 545 (587 mg, 9.7 mmol) in acetone (5 mL) was added Jones' reagent (387 mg, 1.9 mmol) dropwise at 0 °C under an inert atmosphere. The reaction was then stirred for 1 h at rt, quenched with IPA (3 mL) at 0°C, and stirred for 0.5 h at rt. The mixture was filtered through Celite, washed with THF (2 x 50 mL), and concentrated. The residue was extracted with EtOAc/THF (50 mL, 1:1), washed with brine, dried over Na₂SO₄ and concentrated to afford (2S,3S,5R)-5-(5-bromo-2,4-dioxo-3,4- dihydropyrimidin-1(2H)-yl)-3-hydroxytetrahydrofuran-2-carboxylic acid (100 mg, 48%) as an off-white solid. LC/MS (ES, m/z): 321/323 [M+H]⁺. _{[0342] Step 6: To a stirred solution of (2S,3S,5R)-5-(5-bromo-2,4-dioxo-3,4-} dihydropyrimidin-1(2H)-yl)-3-hydroxytetrahydrofuran-2-carboxylic acid (100 mg, 300 μmol) and PPh3 (122 mg, 400 μmol) in DCM (3 mL) were added DIAD (94 mg, 400 μmol) at room temperature under an inert atmosphere. The reaction was then stirred for 1 h at room temperature.. The reaction mixture was used directly in the next step without purification. LC/MS (ES, m/z): 259/261 [M+H]⁺. _{[0343] Step 7: The reaction mixture of (R)-5-bromo-1-(2,3-dihydrofuran-2-yl) pyrimidine-} 2,4(1H,3H)-dione (90 mg, 300 μmol) in DCM (2 mL) was cooled to -40 °C and isopropyl ((hydroxymethyl)(phenoxy)phosphoryl)-L-alaninate (209 mg, 700 μmol) in DCM (0.5 mL) was added dropwise under an inert atmosphere. A solution of IBr (150 mg, 700 μmol) in DCM (0.5 mL) was added dropwise at -40 °C, and the mixture was warmed to rt and stirred for one additional hour. The reaction was quenched with a mixture of NaHCO3 (500 mg), Na2S2O3 (100 mg) and H2O (2 mL). The organic layer was washed with brine (10 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with DCM/MeOH (17:1) to afford isopropyl (((((2R,3S,5R)-5-(5-bromo-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-3- iodotetrahydrofuran-2-yl) oxy) methyl) (phenoxy)phosphoryl)-L-alaninate (80 mg, 34%) as an off-white solid. LC/MS (ES, m/z): 686/688 [M+H]⁺. _{[0344] Step 9: To a stirred solution of isopropyl (((((2R,3S,5R)-5-(5-bromo-2,4-dioxo-3,4-} dihydropyrimidin-1(2H)-yl)-3-iodotetrahydrofuran-2-yl) oxy) methyl) (phenoxy)phosphoryl)-L- alaninate (80 mg, 100 μmol) and buffer (3.4 mL, 0.2 M, pH=7) in MEK (5.3 mL) was added Oxone (392 mg, 2.3 mmol) and H2O (3 mL) at room temperature. The solution was neutralized to pH 7 with NaOH (2 M, aq.), and stirred for 2 h at room temperature. The reaction was quenched with Na₂S₂O₃(aq.) and NaHCO₃(aq.) at room temperature. The aqueous layer was extracted with EtOAc (3 x 50 mL). The resulting mixture was concentrated under reduced pressure. The residue was purified by Prep TLC (DCM/MeOH = 18:1) to afford crude product, which was purified by prep HPLC under the following conditions (Column: X-Select Prep OBD C18 Column, 30*150 mm, 5 μm; Mobile Phase A: water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 30% B to 50% B in 7 min; wavelength: 254 nm/220 nm; RT1(min): 6.56). The product-containing fraction was collected and concentrated under reduced pressure, the residue was re-dissolved in ACN and H₂O, and then was lyophilized to afford isopropyl (((((2R,5R)-5-(5-bromo-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2,5-dihydrofuran- 2-yl) oxy) methyl) (phenoxy)phosphoryl)-L-alaninate (24.3 mg, , 37%) as an off-white solid. [_{0345] LC/MS (ES, m/z): 558/560 [M+H]+,. LC/MS conditions: (Column: Luna Omega PS} C18, 30 * 2.1 mm, 3.0 μm; Mobile Phase A: water/0.1% FA, Mobile Phase B: ACN/0.07% FA; Flow rate: 1.50 mL/min; Gradient: 5% B to 100% B in 1.20 min, 100% B to 100% B in 0.60 min, 100% B to 5% B in 0.02 min; wavelength: 254 nm; RT1(min): 0.691). [_{0346] 1H NMR (400 MHz, DMSO-d6) δ 11.98 (s, 1H), 7.55 (d, J = 4.2 Hz, 1H), 7.40 – 7.29} (m, 2H), 7.21 – 7.12 (m, 3H), 6.76 (dt, J = 6.5, 1.8 Hz, 1H), 6.48 – 6.33 (m, 2H), 5.90 (d, J = 20.9 Hz, 1H), 5.77 -5.58 (m, 1H), 4.96 – 4.78 (m, 1H), 4.14 – 3.99 (m, 2H), 3.94 – 3.82 (m, 1H), 1.27 – 1.12 (m, 9H). EXAMPLE 11 – Synthesis of isopropyl (2S)-2-[(([(2R,5R)-5-[2,4-dioxo-5-(trifluoromethyl)- 3H-pyrimidin-1-yl]-2,5-dihydrofuran-2-yl]oxymethyl(phenoxy)phosphoryl) amino]propanoate, Compound I-13 [_{0347] To a solution of isopropyl (2S)-2-[(([(2R,3S,5R)-5-[2,4-dioxo-5-(trifluoromethyl)-3H-} pyrimidin-1-yl]-3-iodooxolan-2-yl] oxymethyl(phenoxy)phosphoryl) amino] propanoate (80.0 mg, 0.12 mmol) in MEK (1 mL) was added phosphate buffer (0.2M, pH=7, 1 mL) and Oxone (398 mg, 2.37 mmol) at 0°C under an inert atmosphere. The mixture was neutralized to pH 7 with NaOH aqueous (2 M), then stirred for 2h at room temperature and extracted with EtOAc. The combined organic layers were washed with brine and dried over anhydrous Na2SO4. Upon filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by prep HPLC under the following conditions: Column: SunFire Prep OBD C18 Column, 19*250 mm, 5μm; Mobile Phase A: water (0.1% FA), Mobile Phase B: ACN; Flow rate: 25 mL/min; Gradient: 45% B to 60% B in 12min; wavelength: 254nm/220 nm; RT1 (min): 8.24. The product-containing fractions were combined and evaporated partially to remove the solvents, then lyophilized overnight to afford isopropyl (2S)-2-[(([(2R,5R)-5-[2,4-dioxo-5- (trifluoromethyl)-3H-pyrimidin-1-yl]-2,5-dihydrofuran-2- yl]oxymethyl(phenoxy)phosphoryl)amino]propanoate (2.7 mg, 4.2%) as a white solid. [_{0348] LC/MS (ES, m/z): 548 (M+H+); 99.4% purity. HPLC conditions: (Column: Shim‐} pack Scepter C18, 33*3.0 mm, 3.0 μm; Mobile Phase A: water/5mM NH4HCO3, Mobile Phase B: ACN; Flow rate: 1.50 mL/min; Gradient: 10% B to 90% B in 1.19 min, 90% B to 90% B in 0.6 min, 90% B to 10% B in 0.02 min. wavelength: 254 nm; RT 1 (min): 0.900). [_{0349] 1H NMR (400 MHz, DMSO-d6) δ 11.95 (brs, 1H), 7.76 - 7.74 (m, 1H), 7.37 - 7.32 (m,} 2H), 7.18 - 7.13 (m, 3H), 6.80 (d, J = 6.4 Hz, 1H), 6.50 - 6.44 (m, 1H), 6.37 (d, J = 6.0 Hz, 1H), 5.98 - 5.93 (m, 1H), 5.75 - 5.59 (m, 1H), 4.88 - 4.82 (m, 1H), 4.08 - 4.04 (m, 2H), 3.87 - 3.82 (m, 1H), 1.18 – 1.16 (m, 9H). EXAMPLE 12 – Synthesis of isopropyl (2S)-2-[({[(2R,5R)-5-(5-chloro-2,4-dioxo-3H- pyrimidin-1-yl)-2,5-dihydrofuran-2-yl]oxy}methyl(phenoxy)phosphoryl)amino]propanoate, Compound I-14 [_{0350] To a solution of (2S)-2-[({[(2R,3S,5R)-5-(5-chloro-2,4-dioxo-3H-pyrimidin-1-yl)-3-} iodooxolan-2-yl]oxy}methyl(phenoxy)phosphoryl)amino]propanoate in MEK (1 mL) was added phosphate buffer (0.2M, pH=7, 1 mL) and Oxone (398 mg, 2.4 mmol) at 0°C under an inert atmosphere. The mixture was neutralized to pH 7 with NaOH (2M), then stirred for 2h at rt, followed by extraction with EtOAc. The combined organic layers were washed with brine and dried over anhydrous Na₂SO₄. Upon filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by prep HPLC under the following conditions (Column: SunFire Prep OBD C18 Column, 19*250 mm, 5μm; Mobile Phase A: water (0.1% FA), Mobile Phase B: ACN; Flow rate: 25 mL/min; Gradient: 45% B to 60% B in 12 min; wavelength: 254nm/220nm; RT1 (min): 8.24). The product-containing fractions were combined and evaporated partially to remove the solvents, then lyophilized overnight to afford isopropyl (2S)-2-[({[(2R,5R)-5-(5-chloro-2,4-dioxo-3H-pyrimidin-1-yl)-2,5-dihydrofuran-2-yl] oxy} methyl(phenoxy)phosphoryl) amino] propanoate (2.6 mg, 3.25%) as a white solid. [_{0351] LC/MS (ES, m/z): 514;516 (M+H+). 98.8% purity. HPLC conditions: (Column:} HALO‐PCS‐C18, 30*2.1 mm, 2.7 μm; Mobile Phase A: water/0.1%FA, Mobile Phase B: ACN/0.07%FA; Flow rate: 1.5mL/min; Gradient: 5% B to 50% B in 1.69 min,50% B to 100% B in 0.6 min, 100% B to 100% B in 0.5 min，100% B to 5% B in 0.03 min. wavelength: 254 nm; RT1 (min): 1.277). [_{0352] 1H NMR (400 MHz, DMSO-d6) δ 11.95 (br s, 1H), 7.49 (s, 1H), 7.37 - 7.32 (m, 2H),} 7.18 - 7.15 (m, 3H), 6.78 - 6.76 (m, 1H), 6.48 - 6.41 (m, 1H), 6.35 - 6.33 (m, 1H), 5.92 - 5.88 (m, 1H), 5.74 - 5.65 (m, 1H), 4.87 - 4.83 (m, 1H), 4.10 - 4.03 (m, 2H), 3.88 - 3.86 (m, 1H), 1.19 – 1.13 (m, 9H). EXAMPLE 13 - Synthesis of Dipentyl (((((2R,5R)-5-(5-chloro-2,4-dioxo-3,4- dihydropyrimidin-1(2H)-yl)-2,5-dihydrofuran-2-yl) oxy) methyl) (phenoxy)phosphoryl)-L- aspartate, Compound I-15 [_{0353] To a stirred solution of ((((2R,5R)-5-(5-chloro-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-} yl)-2,5-dihydrofuran-2-yl) oxy) methyl) phosphonate (500 mg, 1.54 mmol) and phenol (870 mg, 9.24 mmol) in pyridine (8 mL) were added dipentyl L-aspartate (506 mg, 1.85 mmol) and TEA (1.7 g, 16.94 mmol) at rt under an inert atmosphere. The resulting mixture was stirred at 60°C for 30 min. To another solution of 2-PySSPy-2 (2.4 g, 11.09 mmol) in pyridine (8 mL) were added PPh3 (2.9 g, 11.09 mmol) at room temperature under an inert atmosphere. The resulting mixture was stirred for 30 min at room temperature. After which point the latter reaction mixture was added to the initial solution via syringe and stirred for 12 h at 60 °C under an inert atmosphere. The reaction was cooled to room temperature and concentrated under reduced pressure. The residue was purified by Prep-HPLC with the following conditions: Column: X-Select Prep OBD C18 Column, 30*150 mm, 5 μm; Mobile Phase A: Water (0.1%FA), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 30% B to 50% B in 7 min; wavelength: 254 nm/ 220 nm; RT1 (min): 6.56. The fraction was collected and concentrated under reduced pressure, the residue was re-dissolved in ACN and H2O, and then was lyophilized to afford dipentyl (((((2R,5R)-5-(5- chloro-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2,5-dihydrofuran-2-yl) oxy) methyl) (phenoxy)phosphoryl)-L-aspartate (314.9 mg, 32%) as a white solid. LC-MS (ES, m/z): 655/657 [M+H]+; [_{0354] Conditions for the LC/MS: (Column: Luna Omega PS C18, 30*2.1 mm; Mobile Phase} A: water/0.1%FA, Mobile Phase B: ACN/0.07%FA; Flow rate: 1.50 mL/min; Gradient: 3% B to 60% B in 1.70 min, 60% B to 100% B in 0.60 min, 100% B to 100% B in 0.50 min, 100% B to 5% B in 0.03 min; Wave Length: 254/220 nm; RT1 (min): 1.423) EXAMPLE 14 - Synthesis of diammonium ((((2S,5S)-5-(5-chloro-2,4-dioxo-3,4- dihydropyrimidin-1(2H)-yl)-2,5-dihydrofuran-2-yl) oxy) methyl) phosphonate phosphonate, Compound I-21

[_{0355] Step 1: To a stirred solution of (2S,3S,5S)-5-(5-chloro-2,4-dioxo-3H-pyrimidin-1-yl)-} 3-hydroxyoxolane-2-carboxylic acid (1 g, 3.62 mmol) in THF (15 mL) were added PPh3 (1.9 g, 7.23 mmol) and DIAD (1.46 g, 7.23 mmol) at 0 °C under an inert atmosphere. The resulting mixture was stirred for 1 h at room temperature. After which point, the resulting mixture was used in the next step directly without further purification. LC/MS (ES, m/z): 215/217 [M+H]+. [_{0356] Step 2: To the above mixture were added diethyl hydroxymethylphosphonate (1.22 g,} 7.23 mmol) in DCM (5 mL) and IBr (1.65 g, 7.96 mmol) in DCM (45 mL) dropwise at -40 °C under an inert atmosphere. The resulting mixture was stirred for additional 2 h at 0 °C. The reaction was quenched with a mixture of 10% aqueous Na₂S₂O₃ and sat. NaHCO₃. The resulting mixture was extracted with EtOAc (3 x 200 mL), dried over anhydrous Na2SO4. Upon filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with (PE/EtOAc=1:3) to afford diethyl ((((2S,3R,5S)-5-(5-chloro-2,4- dioxo-3,4-dihydropyrimidin-1(2H)-yl)-3-iodotetrahydrofuran-2-yl) oxy) methyl) phosphonate (700 mg, 19%) as a white solid. LC/MS (ES, m/z): 509/511 [M+H]+. [_{0357] Step 3: To a stirred mixture of diethyl ((((2S,3R,5S)-5-(5-chloro-2,4-dioxo-3,4-} dihydropyrimidin-1(2H)-yl)-3-iodotetrahydrofuran-2-yl) oxy) methyl) phosphonate (100 mg, 197 μmol) in 2-butanone (100 mL) and phosphate buffer (4 mL, 0.5 M, pH=7) were added a solution of Oxone (2.64 g, 3.94 mmol) in H2O (10 mL) and NaOH (3 mL, 2 M in H2O) over 10 min which was maintained pH 6-8. The resulting mixture was stirred for 16 h at room temperature under N2 atmosphere. The reaction was quenched with a mixture of 10% aqueous Na₂S₂O₃ and sat. NaHCO3, extracted with EtOAc (3 x 50 mL), washed with brine, dried over anhydrous Na2SO4. Upon filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with (DCM/EtOAc=1:10) to afford diethyl ((((2S,5S)- 5-(5-chloro-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2,5-dihydrofuran-2-yl) oxy) methyl) phosphonate (40 mg, 53%) as a white solid. LC/MS- (ES, m/z): 381/383 [M+H]+. _{[0358] Step 4: To a stirred solution of ((((2S,5S)-5-(5-chloro-2,4-dioxo-3,4-dihydropyrimidin-} 1(2H)-yl)-2,5-dihydrofuran-2-yl) oxy) methyl) phosphonate (40 mg, 105 μmol) in DMF (2 mL) was added TMS-Br (402 mg, 2.63 mmol) at 0 °C under an inert atmosphere. The resulting mixture was stirred for three additional hours at rt. The resulting mixture was quenched with conc. NH3*H2O at 0 °C. The mixture was concentrated under reduced pressure. The residue was purified by Prep-HPLC (Column: Atlantis Prep T3 OBD Column 19*250 mm, 5 μm; Mobile Phase A: Water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 3% B to 30% B in 7 min; wavelength: 254 nm/220 nm; RT1 (min): 6.4). The fraction was collected and concentrated under reduced pressure, the residue was re-dissolved in ACN and H2O, and then was lyophilized to afford diammonium ((((2S,5S)-5-(5-chloro-2,4-dioxo-3,4-dihydropyrimidin-1(2H)- yl)-2,5-dihydrofuran-2-yl) oxy) methyl) phosphonate (18.8 mg 47%) as a white solid. _{[0359] LC/MS (ES, m/z): 323/325 [M-H]-; [0360] Conditions for the HPLC: (Column: HALO C18 100*4.6 mm, 2.7 μm; Mobile Phase} A: Water/0.05% TFA, Mobile Phase B: ACN/0.05% TFA; Flow rate: 1.20 mL/min; Gradient: 0% B to 95% B in 8 min, 95% B to 95% B in 2 min, 95% B to 10% B in 0.5 min; wavelength: 254 nm; RT1 (min): 2.56). _{[0361] 1H NMR (400 MHz, DMSO- d6) δ 7.56 (s, 1H), 6.70 (s, 1H), 6.43 (s, 1H), 6.21 (s, 1H),} 6.06 (s, 1H), 3.61 (s, 2H). EXAMPLE 15 - Synthesis of isopropyl (((((2S,5S)-5-(5-chloro-2,4-dioxo-3,4- dihydropyrimidin-1(2H)-yl)-2,5-dihydrofuran-2-yl) oxy) methyl) (phenoxy)phosphoryl)-L- alaninate, Compound I-22

[_{0362] Step 1: To a stirred solution of 5-chloropyrimidine-2,4(1H,3H)-dione (362 mg, 2.47} mmol) in HMDS (5.5 ml) was added TMS-Cl (330 mg, 3.04 mmol) at rt. The resulting mixture was heated for 2 h at 120 °C under an inert atmosphere. The resulting mixture was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in CHCl₃ (10 mL), then were added p-nitrophenol (93 mg, 666 μmol), pyridine (45 mg, 571 μmol) and (2R,3S,5R)-5-chloro-2-(((4-methylbenzoyl) oxy) methyl) tetrahydrofuran-3-yl 4-methylbenzoate (740 mg, 1.91 mmol). The resulting mixture was stirred overnight at 30 °C and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with (PE/EtOAc = 2:3) to afford the crude product. The crude product was purified by Prep- Achiral-SFC with the following conditions (Column: CHIRALPAK IH 5*25 cm, 5 μm; Mobile Phase A: CO2, Mobile Phase B: MeOH (1%-2 M-NH3-MeOH); Flow rate: 140 mL/min; Gradient: isocratic 42 % B; Column Temperature (°C): 35; Back Pressure (bar): 100; wavelength: 220 nm; RT1 (min): 5.95; RT2(min): 7.17; Sample Solvent: MeOH+DCM; Injection Volume: 6 mL). The first fraction was collected and concentrated under reduced pressure, the residue was re-dissolved in ACN and H2O, and then was lyophilized to afford (2R,3S,5S)-5-(5- chloro-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-(((4-methylbenzoyl) oxy) methyl) tetrahydrofuran-3-yl 4-methylbenzoate (420 mg, 44%) as an off-white solid. LC/MS (ES, m/z): 499/501 [M+H]⁺. _{[0363] Step 2. To a solution of NH3 (g) in MeOH (10 mL, 7 M), (2R,3S,5S)-5-(5-chloro-2,4-} dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-(((4-methylbenzoyl) oxy) methyl) tetrahydrofuran-3-yl 4-methylbenzoate (420 mg, 842 μmol) was added. The mixture was stirred for 15 h at room temperature under an inert atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with (DCM/MeOH = 10:1) to afford 5-chloro-1-((2S,4S,5R)-4-hydroxy-5-(hydroxymethyl) tetrahydrofuran-2-yl) pyrimidine-2,4(1H,3H)-dione (200 mg, 90%) as an off-white solid. LC/MS (ES, m/z): 261/263 [M-H]-. _{[0364] Step 3. To a stirred solution of 5-chloro-1-((2S,4S,5R)-4-hydroxy-5-(hydroxymethyl)} tetrahydrofuran-2-yl) pyrimidine-2,4(1H,3H)-dione (200 mg, 761 μmol) in acetone (5 mL) was added Celite 545 (200 mg) and Jones’ reagent (1.2 mL, 2.28 mmol, 2 M in H2SO4) at 0 °C under an inert atmosphere. The resulting mixture was stirred for 2 h after which point, the reaction was quenched with IPA at 0 °C. The resulting mixture was filtered and the filter cake was washed with THF. The resulting filtrate was diluted with water and extracted with EtOAc/THF (3 x 100 mL, 1:1). The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄. Upon filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with (PE/EtOAc=1:1) to afford (2S,3S,5S)-5-(5-chloro- 2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-3-hydroxytetrahydrofuran-2-carboxylic acid (150 mg, 71%) as a light yellow solid. LC/MS (ES, m/z): 277/279 [M+H]⁺. _{[0365] Step 4: To a stirred solution of (2S,3S,5S)-5-(5-chloro-2,4-dioxo-3,4-} dihydropyrimidin-1(2H)-yl)-3-hydroxytetrahydrofuran-2-carboxylic acid (150 mg, 542 μmol) in DCM (10 mL) were added PPh3 (284 mg, 1.08 mmol) and DIAD (219 mg, 1.08 mmol) at 0 °C under an inert atmosphere. The resulting mixture was stirred for 1 h at rt and used in the next step directly without further purification. LC/MS (ES, m/z): 215/217 [M+H]⁺. _{[0366] Step 5. To the mixture described in step 4 were added diphenyl} hydroxymethylphosphonate (285 mg, 1.08 mmol) in DCM (5 mL) and IBr (245 mg, 1.19 mmol) in DCM (5 mL) dropwise at -40 °C under an inert atmosphere. The resulting mixture was stirred for an additional 2 h at 0 °C. The reaction was quenched with a mixture of 10% aqueous Na2S2O3 and sat. NaHCO3. The resulting mixture was extracted with EtOAc (3 x 50 mL), and dried over anhydrous Na₂SO₄. Upon filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with (PE/EA=1:1) to afford diphenyl ((((2S,3R,5S)-5-(5-chloro-2,4-dioxo-3,4-dihydropyrimidin- 1(2H)-yl)-3-iodotetrahydrofuran-2-yl) oxy) methyl) phosphonate (365 mg) which was used in the next step directly without further purification. LC/MS (ES, m/z): 603/605 [M-H]-. _{[0367] Step 6: To a stirred solution of ethyl ((((2S,3R,5S)-5-(5-chloro-2,4-dioxo-3,4-} dihydropyrimidin-1(2H)-yl)-3-iodotetrahydrofuran-2-yl) oxy) methyl) phosphonate (365 mg) in 2-butanone (9 mL) and phosphate buffer (14 mL, 0.5 M, pH=7) were added a solution of Oxone (7.4 g, 12.1 mmol) in H2O (29.6 mL) and NaOH (6 mL, 2 M in H2O) over 10 min which was maintained at pH 6-8. The reaction was stirred at room temperature for 18 hbefore being . quenched with a mixture of 10% aqueous Na₂S₂O₃ and sat. NaHCO₃. The aqueous layer wasextracted with EtOAc (3 x 50 mL), washed with brine, and dried over anhydrous Na2SO4. Upon filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with (PE/EtOAc=1:2) to afford diphenyl ((((2S,5S)-5- (5-chloro-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2,5-dihydrofuran-2-yl) oxy) methyl) phosphonate (210 mg) which was used in the next step directly without further purification. LC/MS (ES, m/z): 477/479 [M+H]⁺. _{[0368] Step 7: A mixture of diphenyl ((((2S,5S)-5-(5-chloro-2,4-dioxo-3,4-dihydropyrimidin-} 1(2H)-yl)-2,5-dihydrofuran-2-yl) oxy) methyl) phosphonate (210 mg) in conc. NH3*H2O (3 mL) was heated for 1 h at 60 °C. The resulting mixture was cooled to rt and concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography with the following conditions (column, C18 silica gel; mobile phase, ACN in Water (10 mmol/L NH4HCO3), 0% to 100% gradient in 20 min; detector, UV 254 nm) to afford phenyl hydrogen ((((2S,5S)-5-(5-chloro-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2,5-dihydrofuran-2-yl) oxy) methyl) phosphonate (70 mg, 40%) as a solid. LC/MS (ES, m/z): 399/401 [M-H]-. _{[0369] Step 8. To a stirred solution of phenyl hydrogen ((((2S,5S)-5-(5-chloro-2,4-dioxo-3,4-} dihydropyrimidin-1(2H)-yl)-2,5-dihydrofuran-2-yl) oxy) methyl) phosphonate (70 mg, 175 μmol) and isopropyl L-alaninate (29 mg, 227 μmol) in ACN (3 mL) were added NMI (215 mg, 2.62 mmol) and BOP-Cl (133 mg, 525 μmol) at 0 °C under an inert atmosphere. The resulting mixture was stirred for 1.5 h at rt before being. quenched with water at 0 °C, extracted with EtOAc (3 x 20 mL), and dried over anhydrous Na₂SO₄. Upon filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC with the following conditions (Column: X-Select Prep OBD C18 Column, 30*150 mm, 5 μm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 30% B to 50% B in 7 min; wavelength: 254 nm/220 nm; RT1(min): 6.56). The fraction was collected and concentrated under reduced pressure, the residue was re-dissolved in ACN and H2O, and then was lyophilized to afford isopropyl (((((2S,5S)-5-(5-chloro-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2,5- dihydrofuran-2-yl) oxy) methyl) (phenoxy)phosphoryl)-L-alaninate (22.5 mg, 24%) as an off- white solid. LC/MS (ES, m/z): 514/516 [M+H]⁺; _{[0370] Conditions for the LC/MS: (Column: Shim-pack Scepter C18, 33*3.0 mm, 3.0 μm;} Mobile Phase A: Water/5 mM NH₄HCO₃, Mobile Phase B: Acetonitrile; Flow rate: 1.50 mL/min; Gradient: 10% B to 50% B in 1.70 min, 50% B to 90% B in 0.60 min, 90% B to 90% B in 0.60 min, 90% B to 10% B in 0.03 min; wavelength: 254/220 nm; RT1 (min): 1.499). _{[0371] 1H NMR (400 MHz, DMSO-d6) δ 11.84 (s, 1H), 7.49 (d, J = 6.3 Hz, 1H), 7.35 (dd, J =} 8.7, 7.1 Hz, 2H), 7.22 – 7.12 (m, 3H), 6.77 (q, J = 1.8 Hz, 1H), 6.47 – 6.44 (m, 1H), 6.36 – 6.31 (m, 1H), 5.92 (d, J = 10.2 Hz, 1H), 5.77 – 5.65 (m, 1H), 4.88 – 4.79 (m, 1H), 4.15 – 3.96 (m, 2H), 3.94 – 3.81 (m, 1H). EXAMPLE 16 - Synthesis of isopropyl (((((2R,5R)-5-(5-chloro-2,4-dioxo-3,4- dihydropyrimidin-1(2H)-yl)-2,5-dihydrofuran-2-yl) oxy) methyl) (4-methoxyphenoxy) phosphoryl)-L-alaninate, Compound I-29 [_{0372] To a stirred solution of ((((2R,5R)-5-(5-chloro-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-} yl)-2,5-dihydrofuran-2-yl) oxy) methyl) phosphonate (40 mg, 112 μmol) and 4-methoxyphenol (83 mg, 672 μmol) in pyridine (1 mL) were added isopropyl L-alaninate (22 mg, 134 μmol) and TEA (124 mg, 1.2 mmol) at room temperature under an inert atmosphere. The resulting mixture was stirred at 60°C for 30 min. To another solution of 2-PySSPy-2 (177 mg, 806 μmol) in pyridine (1 mL) were added PPh₃ (210 mg, 806 μmol) and the resulting mixture was stirred for 30 min. The latter reaction mixture was added to the initial solution via syringe and stirred for 12 h at 60 °C under an inert atmosphere. The reaction was cooled to rt and concentrated to dryness. The residue was purified by Prep-HPLC with the following conditions: Column: X-Select Prep OBD C18 Column, 30*150 mm, 5 μm; Mobile Phase A: Water (0.1%FA), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 30% B to 50% B in 7 min; wavelength: 254 nm/220 nm; RT1(min): 6.56. The fraction was collected and concentrated under reduced pressure, the residue was re-dissolved in ACN and H2O, and then was lyophilized to afford isopropyl (((((2R,5R)-5- (5-chloro-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2,5-dihydrofuran-2-yl) oxy) methyl) (4- methoxyphenoxy) phosphoryl)-L-alaninate (14.8 mg, 24.%) as a white solid. LC/MS- (ES, m/z): 544/546 [M+H]⁺; [_{0373] Conditions for the LC/MS: (Column: Luna Omega PS C18, 30*2.1 mm, 3.0 μm;} Mobile Phase A: water/0.1% FA, Mobile Phase B: ACN/0.07% FA; Flow rate: 1.50 mL/min; Gradient: 5% B to 50% B in 1.70 min, 50% B to 100% B in 0.60 min, 100% B to 100% B in 0.50 min, 100% B to 5% B in 0.03 min; Wave Length: 254/220 nm; RT1(min): 1.346). [_{0374] 1H NMR (400 MHz, DMSO-d6) δ 11.87 (s, 1H), 7.49 (d, J = 6.0 Hz, 1H), 7.11 – 7.04} (m, 2H), 6.93 – 6.83 (m, 2H), 6.80 – 6.73 (m, 1H), 6.50 – 6.40 (m, 1H), 6.37 – 6.31 (m, 1H), 5.89 (d, J = 18.5 Hz, 1H), 5.70 – 5.53 (m, 1H), 4.90 – 4.80 (m, 1H), 4.11 – 3.96 (m, 2H), 3.91 – 3.79 (m, 1H), 3.72 (d, J = 1.7 Hz, 3H), 1.26 – 1.11 (m, 9H). EXAMPLE 17 - Isopropyl ((4-bromophenoxy) ((((2R,5R)-5-(5-chloro-2,4-dioxo-3,4- dihydropyrimidin-1(2H)-yl)-2,5-dihydrofuran-2-yl) oxy) methyl) phosphoryl)-L-alaninate, Compound I-33 [_{0375] To a stirred solution of ammonium ((((2R,5R)-5-(5-chloro-2,4-dioxo-3,4-} dihydropyrimidin-1(2H)-yl)-2,5-dihydrofuran-2-yl) oxy) methyl) phosphonate (70 mg, 195 μmol), 4-bromophenol (202 mg, 1.22 mmol) and isopropyl L-alaninate hydrochloride (39 mg, 234 μmol) in pyridine (4 mL) was added Et3N (217 mg, 2.13 mmol) at room temperature under an inert atmosphere. The resulting mixture was stirred at 60 °C for 30 min. After which point,a stirred solution of 2-PySSPy-2 (310 mg, 1.41 mmol) in pyridine (4 mL) was added PPh₃ (369 mg, 1.42 mmol) at rt. the resulting solution was added to the previous solution via syringe. The resulting mixture was heated to 60 °C for 15 h. The resulting mixture was cooled to rt and concentrated under reduced pressure. The residue was purified by Prep-TLC (DCM/MeOH = 10:1) to afford crude product. The crude product was purified by Prep-HPLC with the following conditions: Column: X-Select Prep OBD C18 Column, 30*150 mm, 5 μm; Mobile Phase A: Water(0.1%FA), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 30% B to 50% B in 7 min; wavelength: 254 nm/220 nm; RT1 (min): 6.56. The fraction was collected and concentrated under reduced pressure, the residue was re-dissolved in ACN and H2O, and then lyophilized to afford isopropyl ((4-bromophenoxy) ((((2R,5R)-5-(5-chloro-2,4-dioxo-3,4-dihydropyrimidin- 1(2H)-yl)-2,5-dihydrofuran-2-yl) oxy) methyl) phosphoryl)-L-alaninate (21.6 mg, 19%) as an off-white solid. LC/MS (ES, m/z): 592/594 [M+H]⁺; _{[0376] Conditions for the LC/MS: (Column: Luna Omega PS C18, 30*2.1 mm, 3 μm; Mobile} Phase A: water/0.1% FA, Mobile Phase B: ACN/0.07% FA; Flow rate: 1.20 mL/min; Gradient: 5% B to 100% B in 1.20 min, 100% B to 100% B in 0.60 min, 100% B to 5% B in 0.02 min; wavlength: 254 nm; RT1 (min): 0.778). _{[0377] 1H NMR (400 MHz, DMSO-d6) δ 11.98 (s, 1H), 7.59 – 7.51 (m, 2H), 7.48 (d, J = 5.2} Hz, 1H), 7.18 – 7.10 (m, 2H), 6.78 (dd, J = 7.3, 1.8 Hz, 1H), 6.50 – 6.42 (m, 1H), 6.37 – 6.33 (m, 1H), 5.91 (d, J = 19.5 Hz, 1H), 5.70 – 5.85 (m, 1H), 4.70 – 4.90 (m, 1H), 4.18 – 3.98 (m, 2H), 3.95 – 3.80 (m, 1H), 1.29 – 1.08 (m, 9H). EXAMPLE 18 - Synthesis of isopropyl ((R or S)-((((2R,5R)-5-(5-ethynyl-2,4-dioxo-3,4-dihy dropyrimidin-1(2H)-yl)-2,5-dihydrofuran-2-yl)oxy)methyl)(phenoxy)phosphoryl)-L-alanin at, Compound I-27 and isopropyl ((R or S)-((((2R,5R)-5-(5-ethynyl-2,4-dioxo-3,4-dihydropy rimidin-1(2H)-yl)-2,5-dihydrofuran-2-yl)oxy)methyl)(phenoxy)phosphoryl)-L-alaninate, Co mpound I-28

[_{0378] Step 1: To a solution of idoxuridine (20 g, 56.48 mmol) and Celite 545 (60 g) in} acetone (400 mL) was added Jones’ reagent (100 mL, 2M) dropwise at 0 °C. The resulting mixture was stirred for 2 h at room temperature. The resulting mixture was filtered. The filtrate was diluted with brine at room temperature. The mixture was extracted with EtOAc:THF (1:1). The combined organic layers were washed with brine, dried over anhydrous Na2SO4. Upon filtration, the filtrate was concentrated under reduced pressure. This resulted in (2S,3S,5R)-3- hydroxy-5-(5-iodo-2,4-dioxo-3H-pyrimidin-1-yl) oxolane-2-carboxylic acid (15 g, crude) as a light yellow solid was used in the next step directly without further purification.. LC-MS (ES, m/z): 369 (M+H⁺). [_{0379] Step 2: To a solution of (2S,3S,5R)-3-hydroxy-5-(5-iodo-2,4-dioxo-3H-pyrimidin-1-} yl) oxolane-2-carboxylic acid (15 g, crude) and PPh3 (15.9 g, 61.05 mmol) in DCM (150 mL) was added DIAD (12.35 g, 61.05 mmol) dropwise at 0°C under an inert atmosphere. The resulting mixture was stirred for 2h at room temperature under an inert atmosphere. The resulting mixture was quenched by the addition of water. The mixture was extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. This resulted in 1-[(2R)-2,3-dihydrofuran- 2-yl]-5-iodo-3H-pyrimidine-2,4-dione (12 g) as a yellow solid was used in the next step without further purification. LC/MS (ES, m/z): 307(M+H⁺). [_{0380] Step 3: To a solution of 1-[(2R)-2,3-dihydrofuran-2-yl]-5-iodo-3H-pyrimidine-2,4-} dione (12 g, 39.2 mmol) and diphenyl hydroxymethylphosphonate (15.6 g, 58.8 mmol) in DCM (100 mL) was added iodobromane (16.2 g, 78.2 mmol) in portions at -40°C under an inert atmosphere. The resulting mixture was stirred for 2 h at rt under an inert atmosphere. The reaction was quenched by the addition of a solution of sodium thiosulfate. and mixture was extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4. Upon filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with petroleum ether/EtOAc (1:1) to afford diphenyl {[(2R,3S,5R)-3-iodo-5-(5-iodo-2,4-dioxo-3H-pyrimidin-1-yl)oxolan-2- yl]oxy} methylphosphonate (3 g, 8% yield in three steps) as a white solid. LC/MS (ES, m/z): 697 (M+H⁺). _{[0381] Step 4: To a solution of diphenyl {[(2R,3S,5R)-3-iodo-5-(5-iodo-2,4-dioxo-3H-} pyrimidin-1-yl)oxolan-2-yl]oxy}methylphosphonate (3 g, 4.2 mmol) in THF (10 mL) was added DBU (1.31 g, 8.61 mmol) dropwise at rt. The resulting mixture was stirred for 30 min at 60 °C under an inert atmosphere. The reaction was cooled to room temperature and quenched by the addition of H2O. The mixture was extracted with EtOAc. The combined organic layers were washed with brine, and dried over anhydrous Na₂SO₄. Upon filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by reverse phase flash with the following conditions: Column: C18; Mobile Phase A: Water (0.1%FA), Mobile Phase B: ACN; Flow rate: 100 mL/min; Gradient: 10% B to 50% in 15 min, detector: wavelength 254nm to afford diphenyl {[(2R,5R)-5-(5-iodo-2,4-dioxo-3H-pyrimidin-1-yl)-2,5-dihydrofuran-2-yl] oxy} methylphosphonate (1.5 g, 54%) as a white solid. LC/MS (ES, m/z): 569(M+H⁺). _{[0382] Step 5: To a solution of diphenyl {[(2R,5R)-5-(5-iodo-2,4-dioxo-3H-pyrimidin-1-yl)-} 2,5-dihydrofuran-2-yl]oxy}methylphosphonate (1.5 g, 2.64 mmol), ethynyltrimethylsilane (0.29 g, 2.90 mmol) and TEA (0.80 g, 7.92mmol) in 1,4-dioxane (15 mL) was added CuI (0.10 g, 0.52mmol) and Pd(PPh3)4 (0.31 g, 0.26mmol) at room temperature under an inert atmosphere. The resulting mixture was heated to 60°C for 4h under an inert atmosphere. The reaction was cooled to room temperature and quenched by the addition of water at room temperature. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with NH4Cl, and dried over anhydrous Na2SO4. Upon filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by reverse phase flash with the following conditions: Column: C18; Mobile Phase A: water(0.1%FA), Mobile Phase B: ACN; Flow rate: 100 mL/min; Gradient: 10% B to 50% in 15min, detector: wavelength 254 nm. This resulted in diphenyl {[(2R,5R)-5-{2,4-dioxo-5-[2-(trimethylsilyl) ethynyl]-3H-pyrimidin-1-yl}-2,5- dihydrofuran-2-yl] oxy} methylphosphonate (1.0 g, 70%) as a yellow solid. LC/MS (ES, m/z): 539(M+H⁺). _{[0383] Step 6: To a stirred solution of diphenyl {[(2R,5R)-5-{2,4-dioxo-5-[2-} (trimethylsilyl)ethynyl]-3H-pyrimidin-1-yl}-2,5-dihydrofuran-2-yl]oxy}methylphosphonate (1.0 g, 1.85 mmol) in THF:H₂O (1:1,15 mL) was added NaOH (0.15 g, 3.70 mmol) in portions at room temperature. The resulting solution was stirred for 2h at room temperature and then concentrated under reduced pressure. The crude product was used in the next step without further purification.nLC/MS (ES, m/z): 463(M+H⁺). _{[0384] Step 7: To a solution of {[(2R,5R)-5-{2,4-dioxo-5-[2-(trimethylsilyl)ethynyl]-3H-} pyrimidin-1-yl}-2,5-dihydrofuran-2-yl]oxy}methyl(phenoxy)phosphinic acid (1.0 g, 2.16 mmol) in THF (15 mL) was added NH₄F (1.2 g, 32.43 mmol) at room temperature. The resulting solution was stirred at room temperature for 1 h. The resolution mixture was concentrated under reduced pressure. The crude product was purified by reverse phase flash with the following conditions: Column: C18; Mobile Phase A: water(0.1%FA), Mobile Phase B: ACN; Flow rate: 100 mL/min; Gradient: 10% B to 50% in 15min, detector: wavelength 254nm. This resulted in {[(2R,5R)-5-(5-ethynyl-2,4-dioxo-3H-pyrimidin-1-yl)-2,5-dihydrofuran-2-yl] oxy} methyl(phenoxy)phosphinic acid (600 mg, 83% yield over two steps) as a white solid. LC/MS (ES, m/z): 391(M+H⁺). _{[0385] Step 8: To a solution of {[(2R,5R)-5-(5-ethynyl-2,4-dioxo-3H-pyrimidin-1-yl)-2,5-} dihydrofuran-2-yl] oxy} methylphosphonic acid (400 mg, 1.02 mmol) in ACN (10 mL) were added NMI (2.52 g, 30.75 mmol) and L-Alanine benzyl ester hydrochloride (446 mg, 2.66 mmol) at 0°C for 5 min under an inert atmosphere. Bis(2-oxo-1,3-oxazolidin-3-yl) phosphinoyl chloride (2.08 g, 8.2 mmol) was added portionwise at 0°C. The resulting mixture was stirred at room temperature for 2 h under an inert atmosphere. The reaction was quenched by the addition of Water at room temperature. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with brine, and dried over anhydrous Na2SO4. The resulting mixture was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions: Column: X-Select Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: water (0.1%FA), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 30% B to 50% B in 7 min; wavelength: 254 nm/220 nm; RT1(min): 6.56). The product-containing fractions were combined and evaporated partially to remove the solvents, then lyophilized overnight to afford isopropyl (2S)-2-[({[(2R,5R)-5-(5-ethynyl-2,4-dioxo-3H-pyrimidin-1-yl)-2,5- dihydrofuran-2-yl] oxy} methyl(phenoxy)phosphoryl) amino] propionate (180 mg). The racemate was separated by Prep-chiral-HPLC with the following conditions (Column: JW- CHIRAL ART Cellulose-SC, 20*250mm, 5 µm; Mobile Phase A: EtOH: DCM=1: 1--HPLC, Mobile Phase B: Hex (0.5% 2M NH₃-MeOH) -HPLC; Flow rate: 20 mL/min; Gradient: 50% B to 50% B in 10.5min; wavelength: 220/254 nm; RT1 (min): 7.21; RT2 (min): 8.56; Sample Solvent: EtOH-HPLC; Injection Volume: 0.3 mL; Number of Runs: 12). The product-containing fractions were combined and evaporated partially to remove the solvents, then lyophilized overnight to afford (second peak, 50.2 mg, 9%) as a white solid and (front peak, 41.5 mg, 8%) as a white solid. LC/MS(ES, m/z): 503(M+H⁺). [_{0386] Conditions for the HPLC: (Column: Shim‐pack Scepter C183.0um 3.0*33mm;} Mobile Phase A: 5mM NH4HCO3 in H2O/Acetonitrile (95:5, v/v), Mobile Phase B: Acetonitrile; Flow rate: 1.5000 mL/min; Gradient: 5% B to 90% B in 1.19 min,90% B to 90% B in 0.60 min, 100% B to 5% B in 0.02 min. wavelength: 254 nm; RT (min): 0.813. [_{0387] 1H NMR (400 MHz, DMSO-d6) δ 11.78 (br s, 1H), 7.49 (s, 1H), 7.36 – 7.32 (m, 2H),} 7.18 – 7.14 (m, 3H), 6.75 (s,1H), 6.42 – 6.34 (m, 2H), 5.88 (s, 1H), 5.76 – 5.70 (m, 1H), 4.88 – 4.81 (m, 1H), 4.09 (s, 1H), 4.06 – 4.02 (m, 2H), 3.91 – 3.84 (m, 1H), 1.19 – 1.14 (m, 9H). EXAMPLE 19 - Synthesis of butyl (2S)-2-[({[(2R,5R)-5-(5-ethynyl-2,4-dioxo-3H-pyrimidin- 1-yl)-2,5-dihydrofuran-2-yl] oxy} methyl(phenoxy)phosphoryl) amino] propanoate, Compo und I-30 [_{0388] To a stirred mixture of {[(2R,5R)-5-(5-ethynyl-2,4-dioxo-3H-pyrimidin-1-yl)-2,5-} dihydrofuran-2-yl]oxy}methylphosphonic acid (100 mg, 0.32 mmol), butyl (2S)-2- aminopropanoate (46.21 mg, 0.32 mmol) and phenol (131.80 mg, 1.40 mmol) in pyridine (1 mL) was added Et3N (483.11 mg, 4.77 mmol) at 60℃. The resulting mixture was stirred for 20 min at 60 °C, followed by the addition of a solution of 2-(pyridin-2-yldisulfanyl)pyridine (490.84 mg, 2.23 mmol) and PPh₃ (584.37 mg, 2.23 mmol) in pyridine (1 mL) at room temperature. The resulting mixture was stirred overnight at 60℃. The reaction was cooled to room temperature and quenched by the addition of water. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with brine, and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by prep-HPLC with the following conditions: Column: X-Select Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: water (0.1%FA), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 30% B to 50% B in 7 min; wavelength: 254nm/220nm nm; RT 1 (min): 6.56. The product-containing fractions were combined and evaporated partially to remove the solvents, then lyophilized overnight to afford butyl (2S)-2-[({[(2R,5R)-5-(5-ethynyl-2,4-dioxo-3H- pyrimidin-1-yl)-2,5-dihydrofuran-2-yl] oxy} methyl(phenoxy)phosphoryl) amino] propanoate (10.9 mg, 7%) as a white solid. LC/MS (ES, m/z): 518(M+H⁺). [_{0389] Conditions for the HPLC: (Column: Shim‐pack Scepter C183.0um 3.0*33mm;} Mobile Phase A: 5mM NH4HCO3 in H2O/Acetonitrile(95:5, V/V), Mobile Phase B: Acetonitrile; Flow rate: 1.5000 mL/min; Gradient: 5% B to 90% B in 1.19 min,90% B to 90% B in 0.60 min, 90% B to 5% B in 0.02 min. wavelength: 254 nm; RT(min): 0.898. EXAMPLE 20 -Synthesis of benzyl (2S)-2-[({[(2R,5R)-5-(5-ethynyl-2,4-dioxo-3H-pyrimidin -1-yl)-2,5-dihydrofuran-2-yl] oxy} methyl(phenoxy)phosphoryl) amino] propanoate, Compo und I-36 [_{0390] To a solution of {[(2R,5R)-5-(5-ethynyl-2,4-dioxo-3H-pyrimidin-1-yl)-2,5-} dihydrofuran-2-yl] oxy} methyl(phenoxy)phosphinic acid (150 mg, 0.38 mmol) and L-alanine benzyl ester hydrochloride (215 mg, 0.99 mmol) in ACN (5 mL) was added NMI (946 mg, 11.52 mmol) at 0°C. The resulting solution was stirred for 5 min under an inert atmosphere. To the solution was added bis(2-oxo-1,3-oxazolidin-3-yl) phosphinoyl chloride (782 mg, 3.07 mmol) portionwise at 0°C. The resulting mixture was stirred at room temperature for 2 h under an inert atmosphere. The reaction was quenched by the addition of water at room temperature. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with brine, and dried over anhydrous Na2SO4, and filtered. The resulting solution was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions (Column: XSelect CSH Prep C18 OBD Column, 19*250 mm, 5μm; Mobile Phase A: water (0.05%FA), Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 3% B to 30% B in 8 min; wavelength: 254 nm/220nm; RT1(min): 7.5. The product-containing fractions were combined and evaporated partially to remove the solvents, then lyophilized overnight to afford benzyl (2S)-2-[({[(2R,5R)-5-(5-ethynyl-2,4-dioxo-3H-pyrimidin-1-yl)-2,5-dihydrofuran-2-yl] oxy} methyl(phenoxy)phosphoryl) amino] propionate (10 mg 5%) as a white solid. LC/MS (ES, m/z): 552(M+H⁺). [_{0391] Conditions for the HPLC: (Column: HALO C182.7 µm 100*4.6mm; Mobile Phase} A: water/0.05%TFA, Mobile Phase B: ACN/0.05%TFA; Flow rate: 1.5000 mL/min; Gradient: 30% B to 60% B in 8.00min,60% B to 95% B in 2.00 min, 95% B to 95% B in 2.00 min. wavelength: 254 nm; RT 1 (min):4.29min, RT 2 (min):4.43min. [_{0392] 1H NMR (400 MHz, DMSO-d6) δ 11.79 (br s, 1H), 7.49 (s,1H), 7.41 – 7.30 (m, 7H),} 7.16 – 7.14 (m, 3H), 6.76 – 6.73 (m,1H), 6.43 – 6.27 (m, 2H), 5.90 – 5.73 (m, 2H), 5.15 – 5.06 (m, 2H), 4.08 – 3.96 (m, 4H), 1.29 – 1.13 (m, 3H). EXAMPLE 21 – Preparation of Diisobutyl 2,2'-((((((2R,5R)-5-(5-chloro-2,4-dioxo-3,4- dihydropyrimidin-1(2H)-yl)-2,5-dihydrofuran-2-yl) oxy) methyl) phosphoryl) bis(azanediyl)) (2S,2'S)-bis(3-phenylpropanoate), Compound I-59 _{[0393] Step 1: To a stirred solution of (tert-butoxycarbonyl)-L-phenylalanine (3 g, 11.3} mmol) in DCM (150 mL) were added EDCI (7 g, 37.3 mmol), DMAP (2 g, 16.9 mmol), TEA (2.5 g, 24.9 mmol) and 2-methylpropan-1-ol (92 mg, 12.4 mmol) at room temperature under N2 atmosphere. The resulting mixture was stirred for 12 h at room temperature. The reaction was quenched with 10% aqueous citric acid at 0 °C, extracted with DCM (3 x 150 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with (PE/EA=5:1) to afford isobutyl (tert-butoxycarbonyl)-L- phenylalaninate (2.7 g, 74%) as a light yellow oil. LC-MS (ES, m/z): 322 [M+H]⁺ _{[0394] Step 2: To a solution of HCl (g) in 1,4-dioxane (10 ml, 4 M) was added isobutyl (tert-} butoxycarbonyl)-L-phenylalaninate (1 g, 3.11 mmol) and stirred for 2 h at room temperature under N2 atmosphere. The resulting mixture was added PE and the solid was collected by filtration, then washed with PE and dried to afford isobutyl L-phenylalaninate hydrochloride (730 mg, 91%) as a white solid. LC-MS (ES, m/z): 222 [M+H]⁺. _{[0395] Step 3: To a stirred solution of ((((2R,5R)-5-(5-chloro-2,4-dioxo-3,4-} dihydropyrimidin-1(2H)-yl)-2,5-dihydrofuran-2-yl) oxy) methyl) phosphonic acid (60 mg, 185 μmol), NMI (91 mg, 1.11 mmol) and isobutyl L-phenylalaninate hydrochloride (61 mg, 277 μmol) in ACN (3 mL) was added BOP-Cl (71 mg, 277 μmol) at -10 °C under N2 atmosphere. The resulting mixture was stirred for 2 h at -10 °C under N2 atmosphere. The reaction was quenched by the addition of water at 0 °C. The resulting mixture was extracted with EA (3 x 20 mL). The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep- TLC (DCM/MeOH=15:1) to afford the crude product. The crude product was further purified by Prep-HPLC. The fractions with the desired product were collected and concentrated under vacuum, the residue was re-dissolved in ACN and H2O, and then was lyophilized to afford diisobutyl 2,2'-((((((2R,5R)-5-(5-chloro-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2,5- dihydrofuran-2-yl) oxy) methyl) phosphoryl) bis(azanediyl)) (2S,2'S)-bis(3-phenylpropanoate) (8.4 mg, 6% yield) as a white solid. EXAMPLE 22 -Synthesis of ethyl (((((2R,5R)-5-(5-ethyl-2,4-dioxo-3,4-dihydropyrimidin-1( 2H)-yl)-2,5-dih drofuran-2-yl)oxy)methyl)(phenoxy)phosphoryl)-L-alaninate (I-61)

[_{0396] Step 1: To a stirred solution of 5-ethyl-1-((2R,4S,5R)-4-hydroxy-5-} (hydroxymethyl)tetrahydrofuran-2-yl)pyrimidine-2,4(1H,3H)-dione (1.78 g, 6.95 mmol) and NaHCO₃ (2.33 g, 27.78 mmol) in H₂O (10 mL) and ACN (10 mL) were added phenyl-λ³- iodanediyl diacetate (8.95 g, 27.78 mmol) and 2,2,6,6-tetramethylpiperidin-1-olate (1.03 g, 6.6 mmol) portion wise at 0 °C. The resulting mixture was stirred for 1 h at room temperature. The aqueous layer was washed with EtOAc (5 x 10 mL), then acidified to pH = 1 with conc. HCl. The resulting mixture was stirred for additional 1 h at room temperature. The precipitated solids were collected by filtration and washed with water. This resulted in (2S,3S,5R)-5-(5-ethyl- 2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-3-hydroxytetrahydrofuran-2-carboxylic acid (800 mg, 42.6% yield) as a white solid. LC-MS:(ES, m/z): 271[M+H]⁺. [_{0397] Step 2: To a stirred mixture of (2S,3S,5R)-5-(5-ethyl-2,4-dioxo-3,4-dihydropyrimidin-} 1(2H)-yl)-3-hydroxytetrahydrofuran-2-carboxylic acid (800 mg, 2.96 mmol) and PPh3 (1165 mg, 4.44 mmol) in DCM (8 mL) was added DIAD (898 mg, 4.44 mmol) dropwise at 0 °C under an inert atmosphere. The resulting mixture was stirred for 3 h at room temperature and then concentrated under reduced pressure. The residue was purified by Prep-TLC (petroleum ether/EtOAc = 1:1) to afford (R)-1-(2,3-dihydrofuran-2-yl)-5-ethylpyrimidine-2,4(1H,3H)-dione (400 mg, 1.92 mmol, 64.9% yield) as a yellow solid. LC-MS:(ES, m/z): 209 [M+H]⁺. [_{0398] Step 3: To a solution of (R)-1-(2,3-dihydrofuran-2-yl)-5-ethylpyrimidine-2,4(1H,3H)-} dione (400 mg, 1.92 mmol) in DCM (4 mL) were added diphenyl hydroxymethylphosphonate (761 mg, 2.88 mmol) and iodobromane (795 mg, 3.84 mmol) portion wise at -40 °C under an inert atmosphere. The resulting mixture was stirred for 1 h at -40 °C and additional 1 h at room temperature. The reaction was quenched by the addition of sat. sodium hyposulfite (aq.) (5 mL), then extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄ and filtrated to remove the solid. The resulting filtrate was concentrated under reduced pressure. This resulted in diphenyl ((((2R,3S,5R)-5-(5-ethyl-2,4-dioxo-3,4- dihydropyrimidin-1(2H)-yl)-3-iodotetrahydrofuran-2-yl)oxy)methyl)phosphonate (400 mg, 34.7% yield) as a yellow solid. LC-MS:(ES, m/z): 599 [M+H]⁺. _{[0399] Step 4: To a solution of diphenyl ((((2R,3S,5R)-5-(5-ethyl-2,4-dioxo-3,4-} dihydropyrimidin-1(2H)-yl)-3-iodotetrahydrofuran-2-yl)oxy)methyl)phosphonate (400 mg, 0.67 mmol) in THF (4 mL), was added DBU (204 mg, 1.34 mmol) under an inert atmosphere. The resulting mixture was stirred for 2 h at 50 °C and then cooled to room temperature. The resulting mixture was diluted with EtOAc (10 mL). The mixture was acidified to pH 6 with H₃PO₄ in water (30% wt.) at 0 °C. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and filtrated to remove the solid. The resulting filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with petroleum ether/EtOAc (5:2) to afford diphenyl ((((2R,5R)-5-(5-ethyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2,5-dihydrofuran-2- yl)oxy)methyl)phosphonate (300 mg, 95.5% yield) as a yellow solid. LC-MS:(ES, m/z): 471 [M+H]⁺. _{[0400] Step 5: To a stirred mixture of diphenyl ((((2R,5R)-5-(5-ethyl-2,4-dioxo-3,4-} dihydropyrimidin-1(2H)-yl)-2,5-dihydrofuran-2-yl)oxy)methyl)phosphonate (300 mg, 0.64 mmol) in H₂O (3 mL) and THF (3 mL) was added NaOH (102 mg, 2.55 mmol) under an inert atmosphere. The resulting mixture was stirred for 3 h at room temperature and quenched by the addition of water. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and filtrated to remove the solid. The resulting filtrate was concentrated under reduced pressure. The residue was purified by reversed- phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, ACN in Water (0.1% FA), 0% to 100% gradient in 20 min; detector, UV 254 nm. This resulted in phenyl hydrogen ((((2R,5R)-5-(5-ethyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2,5- dihydrofuran-2-yl)oxy)methyl)phosphonate (200 mg, 79.6% yield) as a yellow solid. LCMS:(ES, m/z): 395 [M+H]⁺ _{[0401] Step 6: To a stirred mixture of phenyl hydrogen ((((2R,5R)-5-(5-ethyl-2,4-dioxo-3,4-} dihydropyrimidin-1(2H)-yl)-2,5-dihydrofuran-2-yl)oxy)methyl)phosphonate (100 mg, 0.25 mmol), 1-methyl-1H-imidazole (208 mg, 2.54 mmol) and ethyl (2S)-2-aminopropanoate (30 mg, 0.25 mmol) in ACN (2 mL) was added bis(2-oxo-1,3-oxazolidin-3-yl)phosphinoyl chloride (516 mg, 2.03 mmol) at 0 °C under an inert atmosphere. The resulting mixture was stirred for 16 h at room temperature and then concentrated under reduced pressure. The residue was purified by Prep-TLC (DCM/MeOH = 10:1) to afford crude product, which was further purified by Prep- HPLC with the following conditions: Column: XSelect CSH Prep C18 OBD Column, 19*250 mm, 5 μm; Mobile Phase A: Water(0.1%FA), Mobile Phase B: MeOH; Flow rate: 20 mL/min; Gradient (B%): 40% B to 60% B in 18 min; Wavelength: 254nm/220nm; RT1(min): 17.5. This resulted in ethyl (((((2R,5R)-5-(5-ethyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2,5- dihydrofuran-2-yl)oxy)methyl)(phenoxy)phosphoryl)-L-alaninate (2.1 mg, 1.68% yield) as an off-white solid. _{[0402] LC-MS:(ES, m/z): 494 [M+H] +. [0403] 1H NMR (400 MHz, DMSO-d6) δ 11.41 (s, 1H), 7.40 – 7.31 (m, 2H), 7.22 – 7.06 (m,} 4H), 6.84 – 6.78 (m, 1H), 6.42 – 6.31 (m, 2H), 5.87 – 5.66 (m, 2H), 4.13 – 3.83 (m, 5H), 2.20 – 2.04 (m, 2H), 1.22 – 1.12 (m, 6H), 0.99 – 0.84 (m, 3H). EXAMPLES 23 and 24 -Synthesis of isobutyl ((R or S)-((((2R,5R)-5-(5-ethynyl-2,4-dioxo- 3,4-dihydropyrimidin-1(2H)-yl)-2,5-dihydrofuran-2-yl) oxy) methyl) (phenoxy)phosphoryl)-L-alaninate (I-62), isobutyl ((R or S)-((((2R,5R)-5-(5-ethynyl-2,4- dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2,5-dihydrofuran-2-yl) oxy) methyl) (phenoxy)phosphoryl)-L-alaninate (I-63)

[_{0404] Step 1: To a stirred solution of phenyl hydrogen ((((2R,5R)-5-(5-ethynyl-2,4-dioxo-} 3,4-dihydropyrimidin-1(2H)-yl)-2,5-dihydrofuran-2-yl)oxy)methyl)phosphonate (200 mg, 0.51 mmol) and NMI (420 mg, 5.12 mmol) in ACN (20 mL) was added isobutyl L-alaninate hydrochloride (391 mg, 1.54 mmol) in portions at 0°C under nitrogen atmosphere. The mixture was stirred for 4 hs at rt. The mixture was diluted with EtOAc, washed with brine, dried over anhydrous Na2SO4. The solids were filtered out and the filtration was combined and concentrated under reduced pressure. The resulting residue was purified by Prep-TLC (DCM/MeOH = 20/1) to afford isobutyl (((((2R,5R)-5-(5-ethynyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2,5- dihydrofuran-2-yl)oxy)methyl)(phenoxy)phosphoryl)-L-alaninate (160 mg, 60.34% yield) as an off-white solid. LC-MS(ES, m/z): 518 [M+H]⁺. [_{0405] Step 2 : The isobutyl (((((2R,5R)-5-(5-ethynyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-} yl)-2,5-dihydrofuran-2-yl)oxy)methyl)(phenoxy)phosphoryl)-L-alaninate (160 mg, 309 mmol) was purified by Prep-HPLC with the following condition: Column: Sunfire Prep C18 OBD Column, 19 * 250 mm, 5 μm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient (B%): 24% B to 56% B in 8 min; Wavelength: 254 nm/220 nm; RT1(min): 6.89, RT2(min): 7.00. The first eluting isomer fraction was collected and concentrated under vacuum, the residue was re-dissolved in ACN and H₂O, and then was lyophilized to afford isobutyl ((S)-((((2R,5R)-5-(5-ethynyl-2,4-dioxo-3,4-dihydropyrimidin- 1(2H)-yl)-2,5-dihydrofuran-2-yl) oxy) methyl) (phenoxy)phosphoryl)-L-alaninate (I-62)(35.8 mg, 22.3% yield) as a white solid; The second eluting isomer fraction was collected and concentrated under vacuum, the residue was re-dissolved in ACN and H₂O, and then was lyophilized to give isobutyl ((R)-((((2R,5R)-5-(5-ethynyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)- yl)-2,5-dihydrofuran-2-yl) oxy) methyl) (phenoxy)phosphoryl)-L-alaninate (I-63)(51.3 mg, 32.1% yield) as a white solid. _{[0406] LC-MS (ES, m/z): 518 [M+H]+; 1H NMR (400 MHz, DMSO) δ 11.79 (s, 1H), 7.51 (s,} 1H), 7.40 – 7.26 (m, 2H), 7.22 – 7.08 (m, 3H), 6.75 (dt, J = 2.0, 1.0 Hz, 1H), 6.37 (ddt, J = 22.3, 5.8, 1.4 Hz, 2H), 5.92 – 5.68 (m, 2H), 4.10 (s, 1H), 4.07 – 3.91 (m, 3H), 3.86 (dd, J = 10.6, 6.7 Hz, 1H), 3.76 (dd, J = 10.5, 6.5 Hz, 1H), 1.84 (m, 1H), 1.21 (d, J = 7.1 Hz, 3H), 0.95 – 0.80 (m, 6H). LC-MS (ES, m/z): 518 [M+H]⁺ _{[0407] 1H NMR (400 MHz, DMSO) δ 11.79 (s, 1H), 7.50 (s, 1H), 7.36 (dd, J = 8.4, 7.3 Hz,} 2H), 7.17 (ddt, J = 7.0, 2.7, 1.6 Hz, 3H), 6.77 (t, J = 1.8 Hz, 1H), 6.40 (ddt, J = 46.9, 5.9, 1.4 Hz, 2H), 5.92 (q, J = 1.0 Hz, 1H), 5.67 (dd, J = 12.8, 9.9 Hz, 1H), 4.14 – 3.91 (m, 4H), 3.87 – 3.73 (m, 2H), 1.93 – 1.75 (m, J = 6.7 Hz, 1H), 1.19 (d, J = 7.1 Hz, 3H), 0.87 (d, J = 6.7 Hz, 6H) EXAMPLES 25 and 26 - Synthesis of dipentyl ((R or S)-((((2R,5R)-5-(5-ethynyl-2,4-dioxo- 3,4-dihydropyrimidin-1(2H)-yl)-2,5-dihydrofuran-2-yl)oxy)methyl)(phenoxy)phosphoryl)- _{L-aspartate, peak 1 (I-64) and dipentyl ((R or S)-((((2R,5R)-5-(5-ethynyl-2,4-dioxo-3,4-} dihydropyrimidin-1(2H)-yl)-2,5-dihydrofuran-2-yl)oxy)methyl)(phenoxy)phosphoryl)-L- aspartate, peak 2 (I-65).

[_{0408] Step 1: To a solution of {[(2R,5R)-5-(5-ethynyl-2,4-dioxo-3H-pyrimidin-1-yl)-2,5-} dihydrofuran-2-yl] oxy} methyl(phenoxy)phosphinic acid (1.0 g, 2.6 mmol) in ACN (10 mL) were added NMI (2.1 g, 25.6 mmol) and dipentyl L-aspartate (710.3 mg, 2.6 mmol) at 0 °C. This was followed by the addition of bis(2-oxo-1,3-oxazolidin-3-yl) phosphoryl chloride (2.0 g, 7.7 mmol) portion wise at 0 °C. The resulting mixture was stirred for 2 h at room temperature and then quenched by the addition of water. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄ and filtrated to remove the solid. The resulting filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: Column: xBridge Prep Phenyl 5μm OBD 19*250mm; Mobile Phase A: Water (10mmol/L NH₄HCO₃), Mobile Phase B: MEOH; Flow rate: 20 mL/min mL/min; Gradient (B%): isocratic 22-52B in 10 min; Wavelength: 220/254 nm; RT1(min): 8.01. This resulted in dipentyl (((((2R,5R)-5-(5- ethynyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2,5-dihydrofuran-2- yl)oxy)methyl)(phenoxy)phosphoryl)-L-aspartate (800 mg, 48.4% yield) as a white solid. LC- MS (ES, m/z): 646 [M+H] ⁺. [_{0409] Step 2: Dipentyl (((((2R,5R)-5-(5-ethynyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-} 2,5-dihydrofuran-2-yl)oxy)methyl)(phenoxy)phosphoryl)-L-aspartate (500 mg, 0.7 mmol) was separated by Prep-Chiral-HPLC with the following conditions: Column: CHIRALPAK IE-3; Mobile Phase A: Hex (0.1% DEA): (EtOH: DCM=1: 1)=50: 50; Flow rate: 1 mL/min mL/min; Gradient (B%): isocratic. This resulted in dipentyl ((R*)-((((2R,5R)-5-(5-ethynyl-2,4-dioxo-3,4- dihydropyrimidin-1(2H)-yl)-2,5-dihydrofuran-2-yl)oxy)methyl)(phenoxy)phosphoryl)-L- aspartate (peak 1, I-64, 168.6 mg, 33.7 %yield) as a white semi-solid and dipentyl ((R*)- ((((2R,5R)-5-(5-ethynyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2,5-dihydrofuran-2- yl)oxy)methyl)(phenoxy)phosphoryl)-L-aspartate (peak 2, I-65, 166.5 mg, 33.6 %yield) as a white semi-solid. [_{0410] LC-MS (ES, m/z): 646 [M+H]+. [0411] 1H NMR (400 MHz, DMSO) δ 11.79 (s, 1H), 7.50 (s, 1H), 7.34 (t, J = 7.7 Hz, 2H),} 7.16 (dd, J = 11.5, 7.6 Hz, 3H), 6.77 (s, 1H), 6.45 (d, J = 5.8 Hz, 1H), 6.34 (d, J = 5.9 Hz, 1H), 5.95 (s, 1H), 5.75 (dd, J = 12.8, 10.5 Hz, 1H), 4.23 (m, 1H), 4.10 (m, 2H), 4.05 – 3.96 (m, 3H), 3.92 (m, 2H), 2.57 (d, J = 6.4 Hz, 2H), 1.51 (m, 4H), 1.26 (m, 8H), 0.85 (m, 6H). [_{0412] LCMS:(ES, m/z): 646 [M+H]+. [0413] 1H NMR (400 MHz, DMSO) δ 11.80 (s, 1H), 7.49 (s, 1H), 7.39 – 7.30 (m, 2H), 7.22 –} 7.13 (m, 3H), 6.75 (d, J = 1.8 Hz, 1H), 6.39 (dd, J = 5.9, 1.5 Hz, 1H), 6.34 (dd, J = 5.8, 1.3 Hz, 1H), 5.92 – 5.81 (m, 2H), 4.24 (m, 1H), 4.09 – 3.88 (m, 7H), 2.73 (dd, J = 16.2, 7.2 Hz, 1H), 2.60 (dd, J = 16.3, 6.3 Hz, 1H), 1.60 – 1.44 (m, 4H), 1.26 (m, 8H), 0.85 (m, 6H). EXAMPLE 27 - Synthesis of cyclobutyl (((((2R,5R)-5-(5-ethynyl-2,4-dioxo-3,4- dihydropyrimidin-1(2H)-yl)-2,5-dihydrofuran-2-yl)oxy)methyl)(phenoxy)phosphoryl)-L- alaninate (I-66) [_{0414] Step 1 - To a stirred mixture of phenyl hydrogen ((((2R,5R)-5-(5-ethynyl-2,4-dioxo-} 3,4-dihydropyrimidin-1(2H)-yl)-2,5-dihydrofuran-2-yl)oxy)methyl)phosphonate (2.5 g, 6.40 mmol) and cyclobutyl L-alaninate (825 mg, 5.76 mmol) in ACN (25 mL) was added NMI (5.26 g, 64.1 mmol) and bis(2-oxo-1,3-oxazolidin-3-yl)phosphinoyl chloride (13.0 g, 51.2 mmol) at 0°C. The resulting mixture was stirred for an additional 1.5 h at room temperature and then quenched by the addition of water. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and filtrated to remove the solid. The resulting filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (CH2Cl2 / MeOH 9:1) to afford the crude product, which was further purified by Prep-HPLC with the following conditions Column: XSelect CSH Fluoro Phenyl 30*150 mm, 5μm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL/min mL/min; Gradient (B%): 20% B to 40% B in 10 min; Wavelength: 254nm/220nm; RT1(min): 7.36. This resulted in cyclobutyl (((((2R,5R)-5-(5-ethynyl-2,4-dioxo-3,4- dihydropyrimidin-1(2H)-yl)-2,5-dihydrofuran-2-yl)oxy)methyl)(phenoxy)phosphoryl)-L- alaninate (249.9 mg, 7.57% yield) as a white solid. [_{0415] LC-MS(ES,m/z): 516 [M+H]+. [0416] 1H NMR (400 MHz, DMSO-d6) δ 11.65 (s, 1H), 7.51 (s, 1H), 7.38 – 7.30 (m, 2H),} 7.18 – 7.15 (m, 3H), 6.76 (d, J = 8.1 Hz, 1H), 6.48 – 6.40 (m, 1H), 6.39 – 6.33 (m, 1H), 5.92 – 5.86 (m, 1H), 5.81 – 5.64 (m, 1H), 4.92 – 4.83(m, 1H), 4.12 – 4.00 (m, 3H), 3.89 – 3.86(m, 1H), 2.89 – 2.20(m, 2H), 1.97 – 1.91 (m, 2H), 1.73 – 1.70 (m, 1H), 1.73 – 1.70 (m, 1H), 1.64 – 1.52 (m, 1H), 1.18 (dd, J = 7.2, 5.3 Hz, 3H). EXAMPLE 28 - Synthesis of cyclopropylmethyl (((((2R,5R)-5-(5-ethynyl-2,4-dioxo-3,4- dihydropyrimidin-1(2H)-yl)-2,5-dihydrofuran-2-yl)oxy)methyl)(phenoxy)phosphoryl)-L- alaninate (I-67) [_{0417] Step 1 - To a stirred mixture of phenyl hydrogen ((((2R,5R)-5-(5-ethynyl-2,4-dioxo-} 3,4-dihydropyrimidin-1(2H)-yl)-2,5-dihydrofuran-2-yl)oxy)methyl)phosphonate (1.7 g, 4.35 mmol), NMI (3.58 g, 43.5 mmol) and cyclopropylmethyl L-alaninate (561 mg, 3.92 mol) in ACN (20 mL) was added bis(2-oxo-1,3-oxazolidin-3-yl)phosphinoyl chloride (8.87 g, 34.8 mmol) dropwise at 0 °C. The resulting mixture was stirred for 1.5 h at room temperature and then quenched by the addition of water (100 mL). The resulting mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄ and filtered to remove solid. The resulting filtrate was concentrated under reduced pressure giving rise to a residue which was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, ACN in Water (0.1% FA), 10% to 50% gradient in 10 min; detector, UV 254 nm. The resulting crude product was further purified by Prep-HPLC. This resulted in cyclopropylmethyl (((((2R,5R)-5-(5-ethynyl-2,4-dioxo-3,4- dihydropyrimidin-1(2H)-yl)-2,5-dihydrofuran-2-yl)oxy)methyl)(phenoxy)phosphoryl) -L- alaninate (345.5 mg, 15.4% yield) as a white solid. [_{0418] LC-MS (ES, m/z): 516 [M+H]+. [0419] 1H NMR (400 MHz, DMSO-d6) δ11.78 (s, 1H), 7.51 (d, J = 2.8 Hz, 1H), 7.40 – 7.28} (m, 2H), 7.25 – 7.13 (m, 3H), 6.79 – 6.72 (m, 1H), 6.49 – 6.37 (m, 1H), 6.37 – 6.30 (m, 1H), 5.93 – 5.83 (m, 1H), 5.82 – 5.61 (m, 1H), 4.18 – 3.78 (m, 6H), 1.20 (t, J = 7.2 Hz, 3H), 1.11 – 0.97 (m, 1H), 0.54 – 0.44 (m, 2H), 0.30 – 0.21 (m, 2H). EXAMPLE 29 - Synthesis of 1,4-dipentyl (2S)-2-{[4-bromophenoxy({[(2R,5R)-5-(5-ethynyl- 2,4-dioxo-3H-pyrimidin-1-yl)-2,5-dihydrofuran-2-yl]oxy}methyl)phosphoryl]amino} butanedioate (I-68) [_{0420] Step 1 - To a stirred mixture of diammonium {[(2R,5R)-5-(5-ethynyl-2,4-dioxo-3H-} pyrimidin-1-yl)-2,5-dihydrofuran-2-yl]oxy}methylphosphonate (100 mg, 0.29 mmol) and 1,4- dipentyl (2S)-2-aminobutanedioate (79 mg, 0.29mmol) in Pyridine (1 mL) were added Et3N (319 mg, 3.16 mmol) and 4-bromophenol (219 mg, 1.26 mmol). The resulting mixture was stirred for 20 min at 60 °C, and the solution was assigned as solution A. To a solution of 2-(pyridin-2- yldisulfanyl) pyridine (443 mg, 2.01 mmol) in Pyridine (1 mL), was added PPh3 (527 mg, 2.01 mmol). The resulting mixture was stirred for 20 min at room temperature, and it was assigned as solution B. To solution A was added solution B and the resulting mixture was stirred for 3 h at 60 °C. The mixture was coolled to room temperature and concentrated under reduced pressure. The residue was purified by Prep-TLC (CH2Cl2 / MeOH 10:1) to afford crude product, which was further purified by Prep-HPLC with the following conditions: Column: X-Select Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 30% B to 70% B in 9 min; Wavelength: 254nm/220nm; RT1(min): 6.56. The fraction was collected and concentrated under reduced pressure, the residue was re-dissolved in MeOH and H₂O, and then lyophilized to afford 1,4-dipentyl (2S)-2-{[4- bromophenoxy({[(2R,5R)-5-(5-ethynyl-2,4-dioxo-3H-pyrimidin-1-yl)-2,5-dihydrofuran-2- yl]oxy}methyl)phosphoryl]amino}butanedioate (3.2 mg, 1.54%) as a yellow oil. _{[0421] LC-MS:(ES, m/z): 724/726 [M+H]+. [0422] 1H NMR (400 MHz, DMSO-d6) δ 11.80 (s, 1H), 7.56 – 7.51 (m, 2H), 7.49 (d, J = 2.1} Hz, 1H), 7.19 – 7.08 (m, 2H), 6.81 – 6.74 (m, 1H), 6.50 – 6.37 (m, 1H), 6.34 (d, J = 5.9 Hz, 1H), 5.97 – 5.76 (m, 2H), 4.27 – 3.83 (m, 8H), 2.79 – 2.61 (m, 1H), 2.59 (d, J = 6.2 Hz, 1H), 1.62 – 1.42 (m, 4H), 1.30 – 1.21 (m, 8H), 0.91 – 0.81 (m, 6H). EXAMPLE 30 – Synthesis of Additional Compounds _{[0423] The compounds listed in Table 2 below were prepared using experimental procedures} and strategies described in Examples 1-29, the Detailed Description, and related strategies and procedures known to those skilled in the art of organic synthesis. Table 2 also lists each compound’s ¹H NMR characterization data and mass-to-charge ratio observed by LC/MS. Chemical structures are presented in Table 1 above. TABLE 2. _{EXAMPLE 31 – Stable Cellular Assay for Inhibiting LINE1 Reverse Transcriptase [0424] Exemplary compounds were tested for ability to inhibit LINE1 reverse transcriptase} using a stable artificial-intron Cis LINE1 reporter assay. Assay procedures and results are described below. Part I – Procedure for Stable Artificial-Intron Cis LINE1 Reporter Assay _{[0425] A stable firefly Tet-On 3G (Takara, cat no 631183) cell line expressing a bi-} directional inducible LINE1 construct was generated as described in Xie, Y. et al. “Cell division promotes efficient retrotransposition in a stable L1 reporter cell line,” Mobile DNA (2013) 4:10. Single cell clones were screened for high Luciferase expression and the highest expression Firefly expressing clone was chosen for compound testing. _{[0426] Test compounds were serially diluted in DMSO and spotted in 96-well plates.} Subsequently the HeLa L1 artificial-intron reporter cells were plated into the compound- containing wells (8,000 cells/well), and the cells were induced for reporter expression with doxycycline (Sigma cat no D9891) at a final concentration of 500 ng/mL. Luminescence was measured 72 h after plating using the Dual-Glo Luciferase Assay System (Promega cat no E2940) following the manufacturer’s instructions. The Firefly Luciferase activity (normalized against its activity in a control well without test compound) was used to report LINE1 activity. Part II – Results _{[0427] Experimental results are provided in Table 3, below. The symbol “***” indicates an} IC₅₀ less than or equal to 0.05 µM. The symbol “**” indicates an IC₅₀ in the range of greater than 0.05 µM to less than or equal to 0.5 µM. The symbol “*” indicates an IC50 greater than 0.5 µM. TABLE 3. _{EXAMPLE 32 – Biochemical Assay for Inhibiting LINE1 Reverse Transcriptase [0428] Exemplary compounds may be tested for ability to inhibit LINE1 reverse transcriptase} using a homogeneous time-resolved fluorescence (HTRF) assay. Assay procedures are described below. Part I – Procedure for Homogeneous Time-Resolved Fluorescence LINE1 RT Assay _{[0429] The LINE1 reverse transcriptase homogeneous time-resolved fluorescence (HTRF)} assay is performed with recombinant MBP-tagged LINE1 protein (238-1061) (generated and purified according to procedures in Dai L. et al. BMC Biochemistry 2011; 12:18) in a 384-well format. Test compound is serially diluted in DMSO and further diluted in the assay buffer (50 mM Tris-HCl, 50 mM KCl, 10 mM MgCl2, 10 mM DTT, pH 8.1) to achieve a final DMSO concentration of 1%. The serially diluted compound is mixed with 64 ng/well of LINE1 enzyme, 5 nM of pre-annealed template/biotin-primer pair (synthesized at Generay Biotechnology), 10 nM of Fluorescein-12-dCTP fluorescent probe (Perkin Elmer), and 1 µM dGTP/dCTP/dTTP (Thermo Fisher Scientific) in the assay buffer. The template/biotin-primer sequences are as follows: (SEQ ID NO:1) (SEQ ID NO:2) . _{[0430] After incubating at 25°C for 60 minutes, the detection reagent (20 mM EDTA with} streptavidin-terbium cryptate, Cisbio Bioassay) in the PPI buffer (Cisbio Bioassay) is added, and the mixture is incubated at 25°C for 30 minutes. At the end of the incubation, fluorescence is read at ex/em=337/485 nm and ex/em=337/520 nm on an Envision 2104 plate reader (Perkin Elmer). The fluorescence ratio at 520/485 nm is used for the calculation. Percent inhibition is calculated with the DMSO sample as 0% inhibition and no enzyme as 100% inhibition. The IC50 is calculated by fitting the compound dose inhibition curve with a 4-parameter non-linear regression equation. _{EXAMPLE 33 – Biochemical Assay for Inhibiting HERV-K Reverse Transcriptase [0431] Exemplary compounds may be tested for ability to inhibit HERV-K reverse} transcriptase using a homogeneous time-resolved fluorescence (HTRF) assay. Assay procedures are described below. Part I – Procedure for Homogeneous Time-Resolved Fluorescence HERV-K RT Assay _{[0432] The HERV-K reverse transcriptase homogeneous time-resolved fluorescence (HTRF)} assay is performed in a 384-well format with HERV-K reverse transcriptase (2-596)- _{8His protein. Baculoviruses are created using Bac-to-Bac technology (Invitrogen). pFastBac} donor plasmids containing HERV-K reverse transcriptase sequence (NCBI GenBank number AAC63291.1, J. Virology (1999) Vol.73, No.3, pp.2365-2375) are transformed into DH10 Bac cells following the manufacturer’s instructions. Recombinant bacmids are then isolated clonally and transfected into SF9 cells with lipofectin. HERV-K reverse transcriptase is expressed in the SF9 insect cells and then purified using immobilized metal affinity chromatography (IMAC) followed by size-exclusion chromatography (SEC). _{[0433] Test compound is serially diluted in DMSO and further diluted in the assay buffer (50} mM Tris-HCl, 50 mM KCl, 10 mM MgCl₂, 10 mM DTT, pH 8.1) to achieve a final DMSO concentration of 1%. The serially diluted compound is mixed with 16 ng/well of HERV-K enzyme, 5 nM of pre-annealed template/biotin-primer pair (synthesized at Geneway Biotechnology), and 10 nM of Fluorescein-12-dCTP fluorescent probe (Perkin Elmer). The template/biotin-primer sequences are: (SEQ ID NO:1) (SEQ ID NO:2) . _{[0434] After incubating at 25°C for 30 minutes, the detection reagent 20 mM EDTA with} streptavidin-terbium cryptate (Cisbio Bioassay) in the PPI buffer (Cisbio Bioassay) is added, and the mixture is incubated at 25°C for 60 minutes. At the end of the incubation, fluorescence is read at ex/em=337/485 nm and ex/em=337/520 nm on an Envision 2104 plate reader (Perkin Elmer). The fluorescence ratio at 520/485 nm is used for the calculation. Percent inhibition is calculated with the DMSO sample as 0% inhibition and no enzyme as 100% inhibition. The IC50 are calculated by fitting the compound dose inhibition curve with a 4-parameter non-linear regression equation. EXAMPLE 34 – Cellular Assay for Altering IFN Production in THP1 TREX1 KO Cells _{[0435] THP1-Dual™ KO-TREX1 cells were purchased from Invivogen (cat# thpd-kotrex).} The THP1-Dual™ KO-TREX1 cells were cultured in RPMI 1640, 10% heat-inactivated fetal bovine serum, 25 mM HEPES, 10 µg/mL Blasticidin, and 100 µg/mL Zeocin. THP1-Dual™ KO-TREX1 cells were treated with a dose titration of test compound in the presence of 1 µM 5- aza-2ʹ-deoxycytidine (Sigma, cat# 189825). Type 1 Interferon and cell viability were assessed after five days of treatment. _{[0436] Stock solution of test compound was prepared in DMSO followed by a three-fold} dilution in DMSO. Additional 50x dilution was prepared in cell culture media for each dilution. 10 µL of diluted test compound was then added to a 384-well plate. _{[0437] THP1-Dual™ KO-TREX1 cells were treated with 1 µM 5-aza-2ʹ-deoxycytidine.} THP1-Dual™ KO-TREX1 cells (50 µL) were added to each well of the 384-well plate containing test compound titration at 10,000 cells/well. Cells were incubated at 37ºC, 5% CO₂ in a humidified incubator for five days. On day five, 20 µL of cell supernatant was transferred to a 384-well, white-walled plate, followed by addition to each well of 50 µL of QUANTI-LUC solution containing stabilizer. Luminescence was detected on a plate reader according to manufacturer’s instructions. _{[0438] For certain compounds, the assay was run in a 96-well format, with the following} modifications: _{● 190 mL, instead of 50 mL, of cells were added to each well, to provide 50,000 cells/well,} instead of 10,000 cells/well, ● _{Cells were incubated for 6 days, instead of 5 days, ● 25 mL, instead of 20 mL, of cell supernatant was added to the white-walled plate for} QUANTI-LUC treatment; and ● _{25 mL, instead of 30 mL, of CellTiter-Glo was added to assess cell viability. [0439] Percent inhibition of interferon was calculated using the following analysis: (Average} DMSO-Sample)/(Average DMSO-Average 30 µM control reagent)*100. The control reagent for inhibition of interferon was a specific nucleoside reverse-transcriptase inhibitor with molecular weight < 600 a.m.u. Percent induction of interferon was calculated using the following analysis: (Sample-Average DMSO)/(10 µM control reagent-Average DMSO)*100. The control reagent for induction of interferon was a specific nucleoside reverse-transcriptase inhibitor with molecular weight < 600 a.m.u. _{[0440] The remaining cells were assessed for cell viability by adding 30 µl of CellTiter-Glo} (Promega, G9683) solution to each well, and placed on a shaker for 10 minutes at room temperature. Luminescence was detected on a plate reader, according to manufacturer’s instructions. Percent inhibition of cell viability using CellTiter-Glo was calculated using the following analysis: (Average DMSO-Sample)/(Average DMSO-Average 20 µM control reagent)*100. The control reagent was Z-Leu-Leu-leucinal (see, for example, https://pubchem.ncbi.nlm.nih.gov/compound/462382). _{EXAMPLE 35 – Cancer Cell Viability Assay with 3D Cell Colonies [0441] Exemplary compounds may be tested for ability to reduce cancer cell viability using a} CellTiter-Glo assay with cancer cells cultured in 3D colonies. Assay procedures are described below. Part I – Procedure for Cancer Cell Viability Assay with 3D Cell Colonies _{[0442] Cancer cell lines are cultured in the following media: ● Ovarian cancer OVCAR-8 cells – RPMI media containing 10% FBS ● Ovarian cancer SK-OV-3 cells – McCoy’s 5a media containing 10% FBS ● Ovarian cancer SW756 cells – L-15 (100% air) + 10% FBS ● Esophageal cancer TE-1 cells – RPMVIII-1640 + 10% FBS ● Esophageal cancer KYSE-410 cells – RPMVIII-1640 + 5~10% FBS ● Esophageal cancer KYSE-70 cells – RPMVIII-1640 + 10% h.i.FBS. ● Pharyngeal cancer FaDu cells – MEM + 0.01mM NEAA + 10% FBS [0443] Cell colony formation is tested using a 3D methylcellulose-based CellTiter-Glo (CTG)} viability assay (Cat. No: G7573, Promega). Briefly, cells are inoculated into 96-well plates (at 1,500 cells per well) into a solution of 0.65% methylcellulose in growth media and incubated overnight at 37 °C in 5% CO₂. The next day, serially diluted test compound or positive control (cisplatin, Cat. No.6J015A89, Qilu Pharma) are added at the indicated concentrations, and the cells are incubated for 7 days. On day seven, 100 mL of CTG reagent is added, and the plates are incubated at room temperature for 20 min. Luminescence is read on an Envision Multi Label Reader according to manufacturer’s instructions. IC₅₀ values are determined using the following calculation: EXAMPLE 36 – In Vivo Decitabine Challenge Model _{[0444] Twenty 9-11 week old C57BL/6 mice are acclimated to the lab for at least 5 days.} Test compound is prepared for p.o. administration. Decitabine (Sigma) is dissolved in sterile PBS (pH 7.4) and dosed within 30 minutes of preparation of the solution. Doses of both test compound and decitabine are administered once a day, every day from Day 0 to Day 4. _{[0445] On Day 0, mice are split into four groups of five mice and given their first dose of} decitabine (i.p., 5 mg/kg) and test compound. Dosing groups were: _{[0446] Decitabine and test compound are administered daily from Day 0 to Day 4. All mice} are euthanized 1 hour after the last dose administration on Day 4. Spleens, liver, and terminal colon are collected, along with plasma from each animal. The fold changes in interferon- stimulated gene (ISG) expression are calculated by first normalizing to GAPDH gene using the Delta CT method. The CT (gene of interest) – CT (reference gene) is calculated to generate a delta CT for all samples. The fold change is then calculated by taking the Log2(Delta CT(control) – Delta CT (experimental). The control in this example is the PBS control animal group. The Taqman duplex assay (Thermo Fisher 4331182 and 4448489) is used according to the manufacturer’s instructions to determine levels of GAPDH v. IFIT2. EXAMPLE 37 – Decitabine-Stimulated Human PBMC Assay _{[0447] EasySep buffer (32 mL, Stem Cell, cat. #20144) is used to dilute 8 mL of LRSC buffy} coat (from fresh Leukopak) with gentle mixing. The diluted buffy coat (20 mL) is transferred into each of two SepMate 50 tubes, and the tubes are filled with 15 mL of Lyphoprep (Stem Cell, ct. #07851) density gradient. The SepMate tubes are then centrifuged at 1200G for 10 minutes at room temperature with the brake on. The top layer of supernatant is collected in SepMate tubes by quickly pouring it into a new 50 mL conical tube. The PBMCs are washed with EasySep buffer x2 by centrifuging at 300G for 5 minutes. The cells are resuspended in 30 mL of EasySep and centrifuged at 100G for 5 minutes with the brake off, and the platelets are removed. The cells are then resuspended in 6 mL of 1x RBC lysis buffer (InvitroGen) and incubated at 37 ºC for 5 minutes. Then, 25 mL of EasySep buffer is mixed into the tube and it is centrifuged at 300G for 5 minutes. The cells are resuspended in 10 mL of EasySep buffer and the cells are then counted with Cellometer (AO/PI). The PBMCs are resuspended in RPMI1640 (ThermoFisher) + 10% FBS (HyClone) + p/s at 3x10⁶/mL. The PBMCs (100 µL, 300k PBMCs) are then seeded in a 96-well flat bottom microplate (Corning) that is precoated with 100µL of anti-CD3 antibody (10µg/mL in PBS, Biolegend) or PBS at 4 ºC, one day before the assay is commenced. _{[0448] To each well, the following solutions are added: 1) 100 µL of cells (final cell number} per well is 3x10⁵ cell/well); 2) 25 µL of anti-CD28 antibody at 6x (5 µg/mL final concentration, Biolegend); 3) 25 µL of decitabine at 6x (10 µM final concentration); and 4) the Compound in DMSO is dispensed directly into each well with a d300e digital dispense (Tecan). The final concentration of DMSO for each well is normalized to 0.3% . The plate is incubated at 37 ºC without any agitation for 5 days. Samples are collected 120 hours after incubation to determine IFN-β and IL-2 levels using a U-PLEX Human IFNb Assay Sector (5PL) (MSD, cat. #K151VIK-2). _{[0449] After 5 days, the plate is spun down at 100xG for 5 minutes. Supernatants (100µL)} are collected for interferon β (IFN-β) analysis using the MSD assay noted above, and any residual supernatant is stored at -80ºC. Cell viability is checked to determine if cell death has an impact on the IFN-β levels detected. _{EXAMPLE 38 – Producing THP1 TREX1 KO Xenografts with Decitabine-Induced IFN [0450] The ability to produce THP1-DualTM KO-TREX1 xenografts in mice that displayed} decitabine-dependent IFN induction was tested. Assay procedures and results are described below. Part I – Procedure for Producing THP1 TREX1 KO Xenografts with Decitabine-Induced IFN _{[0451] CB-17 SCID female mice were inoculated subcutaneously with 10 million THP1-} Dual^TM KO-TREX1 cells in 200 μl PBS with Matrigel (1:1). Mice were randomized when tumor volume reached 350-400 mm³ and grouped at N=3 per treatment. Mice bearing THP1-Dual^TM KO-TREX1 xenograft tumors were then administered vehicle or decitabine (DAC) at 5mg/kg IP, once daily, starting on day 1, for 4 days. Decitabine was formulated in sterile PBS, pH 7.4. Tumors were harvested daily for 5 days starting on day 2, lysed with RIPA lysis buffer containing protease and phosphatase inhibitors, and grinded at 50 Hz for 5 min. Tumors were then centrifuged, and Pierce^TM BCA Protein Assay Kit was used to measure protein concentration. Equal amounts of proteins were added to 96-well black plates, and luciferase signal was measured using the QUANTI-Luc^TM detection medium according to manufacturer’s instructions. Luminescence was measured using the EnVision® 2105 Multimode Plate Reader. Part II – Results _{[0452] Data was normalized relative to vehicle. “DAC” is an abbreviation for decitabine;} “D2, 4h” depicts interferon data from day 2, with tumor harvested 4 hours after decitabine dosing; “D3, 4h” depicts interferon data from day 3, with tumor harvested 4 hours after decitabine dosing; “D4, 4h” depicts interferon data from day 4, with tumor harvested 4 hours after decitabine dosing; and “D4, 24h” depicts interferon data from day 5, with tumor harvested 24 hours after the final decitabine dosing on day 4. _{EXAMPLE 39 – Assay for Altering IFN Production in THP1 TREX1 KO Xenografts [0453] Exemplary compounds may be tested for their ability to alter IFN levels in THP1-} Dual^TM KO-TREX1 xenografts in mice (produced according to the procedure described in the preceding Example). Assay procedures are described below. Part I – Procedure for Altering IFN Production in THP1 TREX1 KO Xenografts _{[0454] CB-17 SCID female mice are inoculated subcutaneously with 10 million THP1-} Dual^TM KO-TREX1 cells in 200 μl PBS with Matrigel (1:1) and grouped when tumor volume reaches 350-400 mm³. Mice bearing THP1-Dual^TM KO-TREX1 xenograft tumors are then separated into 5 groups. Three groups are administered: (1) decitabine (DAC) at 5mg/kg IP, once daily, for 4 days, and (2) test compound at one of three doses, once daily, for 4 days. One group is administered decitabine (DAC) at 5mg/kg IP, once daily, for 4 days, and the test compound vehicle control. The final group is administered the vehicle control from both the test compound and the vehicle control from decitabine. Decitabine is formulated in sterile PBS, pH 7.4. _{[0455] Tumors are harvested daily for 5 days starting on day 2, lysed with RIPA lysis buffer} containing protease and phosphatase inhibitors, and grinded at 50 Hz for 5 min. Tumors are then centrifuged, and Pierce^TM BCA Protein Assay Kit is used to measure protein concentration. Equal amounts of proteins are added to 96-well black plates, and luciferase signal is measured using the QUANTI-Luc^TM detection medium according to manufacturer’s instructions. Luminescence is measured using the EnVision® 2105 Multimode Plate Reader. INCORPORATION BY REFERENCE _{[0456] The entire disclosure of each of the patent documents and scientific articles referred to} herein is incorporated by reference for all purposes. EQUIVALENTS _{[0457] The invention may be embodied in other specific forms without departing from the} spirit or essential characteristics thereof. The foregoing embodiments are therefore to be considered in all respects illustrative rather than limiting the invention described herein. Scope of the invention is thus indicated by the appended claims rather than by the foregoing description, and all changes that come within the meaning and range of equivalency of the claims are intended to be embraced therein.

Claims

Claims: 1_{. A compound represented by Formula I:} or a pharmaceutically acceptable salt thereof; wherein: R¹ is -OH, -O-(phenyl substituted with m instances of R⁵), -O-(C_1-4 alkylene)-OC(O)O- (C1-10 alkyl), or -N(R⁶)(R⁷); R² is -OR¹⁰, -N(R⁶)(R⁷), or -(C_1-4 alkylene)-C(O)O-(C_1-10 alkyl); R³ is halo, C_1-6 alkyl, C_2-4 alkynyl, cyano, C_1-6 haloalkyl, or -CD₃; R⁴ is hydrogen, halo, or deuterium; R⁵ represents independently for each occurrence halo, C1-6 alkyl, C1-4 alkoxyl, -(C0-4 alkylene)-C(R⁸)₃, or -(C_1-4 alkylene)-(C(R⁸)₂)-C(O)O-R⁹; R⁶ represents independently for each occurrence hydrogen or C_1-6 alkyl; R⁷ represents independently for each occurrence -C(R⁸)2-C(O)O-R⁹; or when R⁶ and R⁷ are attached to the same nitrogen atom, R⁶ and R⁷ together with the nitrogen atom to which they are attached, form a 5- or 6- membered saturated heterocyclic ring, substituted with n instances of R¹¹; R⁸ represents independently for each occurrence hydrogen, C_1-6 alkyl, -(C_0-4 alkylene)- C(O)O-R⁹, -N(R⁶)-C(O)O-R⁹, or -(C_0-4 alkylene)-phenyl; R⁹ represents independently for each occurrence C1-10 alkyl, -(C0-3 alkylene)-phenyl, or - (C0-3 alkylene)-(3-6 membered saturated monocyclic carbocyclic ring); R¹⁰ is hydrogen or -(C_1-4 alkylene)-OC(O)O-(C_1-10 alkyl); R¹¹ is -(C0-4 alkylene)-C(O)O-(C1-10 alkyl); m is 0, 1, 2, or 3; and n is 0, 1, or 2. _{2. The compound of claim 1, wherein the compound is a compound of Formula I. 3. The compound of claim 1, wherein the compound is a pharmaceutically acceptable salt of} a compound of Formula I. _{4. The compound of any one of claims 1-3, wherein the compound is represented by} Formula I-a or I-b, or a pharmaceutically acceptable salt thereof: _{5. The compound of any one of claims 1-4, wherein R1 is -OH. 6. The compound of any one of claims 1-4, wherein R1 is -O-(phenyl substituted with m} instances of R⁵) or -O-(C1-4 alkylene)-OC(O)O-(C1-10 alkyl). _{7. The compound of any one of claims 1-4, wherein R1 is -O-(C1-4 alkylene)-OC(O)O-(C1-10} alkyl). _{8. The compound of any one of claims 1-4, wherein R1 is -O-(C1-2 alkylene)-OC(O)O-(C1-3} alkyl). _{9. The compound of any one of claims 1-4, wherein R1 is -O-(C1-2 alkylene)-OC(O)O-(C4-10} alkyl). _{10. The compound of any one of claims 1-4, wherein R1 is -O-(phenyl substituted with m} instances of R⁵). _{11. The compound of any one of claims 1-4, wherein R1 is -N(R6)(R7). 12. The compound of any one of claims 1 or 2, wherein the compound is represented by} Formula I-c, or a pharmaceutically acceptable salt thereof:

_{13. The compound of any one of claims 1-12, wherein R2 is -OR10. 14. The compound of any one of claims 1-13, wherein R10 is hydrogen. 15. The compound of any one of claims 1-13, wherein R10 is -(C1-4 alkylene)-OC(O)O-(C1-10} alkyl). _{16. The compound of any one of claims 1-13, wherein R10 is -(C1-2 alkylene)-OC(O)O-(C1-3} alkyl). _{17. The compound of any one of claims 1-13, wherein R10 is -(C1-2 alkylene)-OC(O)O-(C4-10} alkyl). _{18. The compound of any one of claims 1-12, wherein R2 is -N(R6)(R7). 19. The compound of any one of claims 1-12, wherein R2 is -(C1-4 alkylene)-C(O)O-(C1-10} alkyl). _{20. The compound of any one of claims 1-12, wherein R2 is -OH,}

2_{1. The compound of claim 1 or 2, wherein the compound is represented by Formula I-d, or a} pharmaceutically acceptable salt thereof: 2_{2. The compound of any one of claims 1-21, wherein R4 is hydrogen. 23. The compound of any one of claims 1-21, wherein R4 is halo. 24. The compound of any one of claims 1-21, wherein R4 is F. 25. The compound of any one of claims 1-24, wherein R3 is halo, C1-6 alkyl, C2-4 alkynyl,} cyano, C1-6 haloalkyl, or -CD3. 2_{6. The compound of any one of claims 1-24, wherein R3 is C1-6 alkyl, C2-4 alkynyl, cyano,} C_1-6 haloalkyl, or -CD₃. 2_{7. The compound of any one of claims 1-24, wherein R3 is methyl. 28. The compound of any one of claims 1-24, wherein R3 is ethynyl.}

_{29. The compound of any one of claims 1-24, wherein R3 is cyano, -CF3, or -CD3. 30. A compound in Table 1 herein, or a pharmaceutically acceptable salt thereof. 31. A pharmaceutical composition comprising a compound of any one of claims 1-30 and a} pharmaceutically acceptable carrier. _{32. A method of treating a disorder selected from the group consisting of cancer, an} inflammatory disorder, a neurodegenerative disorder, and an immune disorder, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any one of claims 1-30 to treat the disorder. _{33. A method of treating a disorder selected from the group consisting of cancer, an} inflammatory disorder, a neurodegenerative disorder, and an immune disorder other than a viral infection, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any one of claims 1-30 to treat the disorder. _{34. The method of claim 32, wherein the disorder is an immune disorder that is a viral} infection. _{35. The method of claim 34, wherein the viral infection is an infection by human} immunodeficiency viruses 1 or 2 (HIV-1 or HIV-2), human T-cell leukemia viruses 1 or 2 (HTLV-1 or HTLV-2), respiratory syncytial virus (RSV), human papilloma virus (HPV), adenovirus, hepatitis B virus (HBV), hepatitis C virus (HCV), Epstein-Barr virus (EBV), varicella zoster virus (VZV), cytomegalovirus (CMV), herpes simplex viruses 1 or 2 (HSV-1 or HSV-2), human herpes virus 8 (HHV-8, also known as Kaposi's sarcoma- associated virus), or a flavivirus selected from Yellow Fever virus, Dengue virus, Japanese Encephalitis, and West Nile virus. _{36. The method of claim 32 or 33, wherein the disorder is cancer. 37. The method of claim 36, wherein the cancer is breast cancer, ovarian cancer, uterine} cancer, cervical cancer, prostate cancer, testicular cancer, lung cancer, leukemia, head and neck cancer, oral cancer, esophageal cancer, stomach cancer, bile duct and gallbladder cancers, bladder cancer, urinary tract cancer, colon cancer, rectal cancer, thyroid cancer, pancreatic cancer, kidney cancer, liver cancer, brain cancer, skin cancer, or eye cancer.

_{38. The method of claim 32 or 33, wherein the disorder is an inflammatory disorder. 39. The method of claim 38, wherein the inflammatory disorder is rheumatoid arthritis,} osteoarthritis, ankylosing spondylitis, inflammatory bowel disease, Crohn’s disease, ulcerative colitis, nonalcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), cholestatic liver disease, sclerosing cholangitis, psoriasis, dermatitis, vasculitis, scleroderma, asthma, bronchitis, chronic obstructive pulmonary disease (COPD), pulmonary fibrosis, pulmonary hypertension, sarcoidosis, myocarditis, pericarditis, gout, myositis, Sjogren's syndrome, or systemic lupus erythematosus. _{40. The method of claim 32 or 33, wherein the disorder is an immune disorder other than a} viral infection. _{41. The method of claim 40, wherein the immune disorder is a type 1 interferonopathy, type} 1 diabetes, Aicardi-Goutieres syndrome (AGS), arthritis, psoriasis, systemic lupus erythematosus (SLE), lupus nephritis, cutaneous lupus erythematosus (CLE), familial chilblain lupus, systemic sclerosis, STING-associated vasculopathy with onset in infancy (SAVI), graft versus host disease, scleroderma, polymyositis, inflammatory bowel disease, dermatomyositis, ulcerative colitis, Crohn’s disease, vasculitis, psoriatic arthritis, Reiter's syndrome, exfoliative psoriatic dermatitis, pemphigus vulgaris, Sjogren’s syndrome, autoimmune uveitis, glomerulonephritis, post myocardial infarction cardiotomy syndrome, pulmonary hemosiderosis, amyloidosis, sarcoidosis, aphthous stomatitis, thyroiditis, gastritis, adrenalitis (Addison's disease), ovaritis, primary biliary cirrhosis, myasthenia gravis, gonadal failure, hypoparathyroidism, alopecia, malabsorption syndrome, pernicious anemia, hepatitis, hypopituitarism, diabetes insipidus, or sicca syndrome. _{42. The method of claim 40, wherein the immune disorder is a type 1 interferonopathy, type} 1 diabetes, Aicardi-Goutieres syndrome (AGS), systemic lupus erythematosus (SLE), lupus nephritis, cutaneous lupus erythematosus (CLE), dermatomyositis, or Sjogren’s syndrome. _{43. The method of claim 32 or 33, wherein the disorder is a neurodegenerative disorder.}

_{44. The method of claim 43, wherein the neurodegenerative disorder is Alzheimer’s disease,} amyotrophic lateral sclerosis (ALS), multiple sclerosis, Parkinson’s disease, Huntington’s disease, peripheral neuropathy, age-related macular degeneration, Creutzfeldt-Jacob disease, stroke, prion disease, frontotemporal dementia, Pick’s disease, progressive supranuclear palsy, spinocerebellar ataxias, Lewy body disease, dementia, multiple system atrophy, epilepsy, bipolar disorder, schizophrenia, an anxiety disorder, or major depression. _{45. The method of any one of claims 32-44, wherein the method further comprises} administering an effective amount of an additional therapeutic agent. _{46. The method of any one of claims 32-45, wherein the subject has (i) expression of LINE1} RNA, LINE1 ORF1 polypeptide, and/or LINE1 ORF2 polypeptide; and/or (ii) activity of LINE1 reverse transcriptase. _{47. The method of any one of claims 32-46, wherein the subject has (i) expression of HERV-} K RNA and/or (ii) activity of HERV-K reverse transcriptase. _{48. The method of any one of claims 32-45, wherein the subject is a human. 49. A method of inhibiting LINE1 reverse transcriptase activity, comprising contacting a} LINE1 reverse transcriptase with an effective amount of a compound of any one of claims 1-30, in order to inhibit the activity of said LINE1 reverse transcriptase. _{50. A method of inhibiting HERV-K reverse transcriptase activity, comprising contacting a} HERV-K reverse transcriptase with an effective amount of a compound of any one of claims 1-30, in order to inhibit the activity of said HERV-K reverse transcriptase.